WO2008003958A2 - Fused pyrimido compounds - Google Patents

Fused pyrimido compounds Download PDF

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Publication number
WO2008003958A2
WO2008003958A2 PCT/GB2007/002490 GB2007002490W WO2008003958A2 WO 2008003958 A2 WO2008003958 A2 WO 2008003958A2 GB 2007002490 W GB2007002490 W GB 2007002490W WO 2008003958 A2 WO2008003958 A2 WO 2008003958A2
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WO
WIPO (PCT)
Prior art keywords
optionally substituted
group
alkyl
optionally
methyl
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PCT/GB2007/002490
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French (fr)
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WO2008003958A3 (en
Inventor
Christopher Thomas Halsall
David Alan Rudge
Iain Simpson
Richard Andrew Ward
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication date
Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Priority to BRPI0714045-2A priority Critical patent/BRPI0714045A2/en
Priority to AU2007270931A priority patent/AU2007270931A1/en
Priority to MX2009000220A priority patent/MX2009000220A/en
Priority to EP07733455A priority patent/EP2046793A2/en
Priority to JP2009517423A priority patent/JP2009542613A/en
Priority to CA002656936A priority patent/CA2656936A1/en
Publication of WO2008003958A2 publication Critical patent/WO2008003958A2/en
Publication of WO2008003958A3 publication Critical patent/WO2008003958A3/en
Priority to IL196207A priority patent/IL196207A0/en
Priority to NO20090052A priority patent/NO20090052L/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to pyrirnidine derivatives, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy and the treating of conditions mediated by polo-like kinases.
  • Cyclin dependent kinase family have long been considered the master regulators of the cell cycle but an increasing number of diverse protein kinases are emerging as critical components of cell cycle progression. Among these are the polo-like kinase family (Plks), serine/threonine kinases that play multiple roles in regulating progress through cell cycle. In man, four distinct family members have been identified. These are Plkl, Plk2 (Snk), Plk3 (Fnk, Prk) and Plk4 (Sak).
  • Plkl The best characterized family member is Plkl which is conserved from yeast to man and has been implicated in numerous mitotic processes including activation of Cdc25C and Cdkl/Cyclin B at the G2-M transition, centrosome maturation, spindle formation and assembly (Glover et al. 1998, Genes Dev. 12:3777-87; Barr et al 2004, Nat. Rev. MoI. Cell Biol 5:429-441). In the later stages of mitosis Plkl is involved in separation of sister chromatids, activation of components of the anaphase-promoting complex and septin regulation during cytokinesis (van Vugt & Medema 2005, Oncogene 24:2844-2859).
  • Plkl is overexpressed in a broad spectrum of cancer types including breast, colorectal, endometrial, oesophageal, ovarian, prostate, pancreatic, non small cell lung cancers and melanomas (Wolf et al. 1997, Oncogene 14:543-549; Knecht et al. 1999, Cancer Res. 59:2794-2797; Wolf et al. 2000, Pathol. Res. Pract 196:753-759; Takahashi et al. 2003, Cancer Sci. 94:148-152). The expression of Plkl often correlates with poor patient prognosis.
  • Plkl inhibition specifically targets cancer cells with checkpoint defects while cells with intact checkpoint pathways are less affected.
  • Plk3 also appears to play roles in mitosis, like Plkl it has been reported to phosphorylate Cdc25C, regulate microtubule dynamics and is involved in centrosome function. Overexpression of Plk3 has been observed in both breast and ovarian carcinomas, with little or no expression in adjacent normal tissue. Increased protein level was associated with enhanced mitosis and was significantly linked to reduced median survival time of patients (Weichert et al. 2005, Virchows Arch 446: 442-450; Weichert et al. 2004 Br. J.Cancer 90:815-821).
  • PIk family members should be of therapeutic value for treatment of proliferative disease including solid tumours such as carcinomas and sarcomas and the leukaemias and lymphoid malignancies.
  • PIk inhibitors should be useful in the treatment of other disorders associated with uncontrolled cellular proliferation.
  • Pteridinone derivatives are known from the prior art as active substances with an antiproliferative activity.
  • WO 01/019825 and WO 03/020722 describe the use of pteridinone derivatives for the treatment of tumoural diseases.
  • tumours The resistance of many types of tumours calls for the development of new pharmaceutical compositions for combating tumours.
  • the aim of the present invention is to provide new compounds having an antiproliferative activity. According to a first aspect of the present invention there is provided a compound of formula (I):
  • R 3 represents hydrogen, an optionally substituted C 1 . 12 alk.yl group, an optionally substituted C 2 -i 2 alkenyl group, an optionally substituted C 2- i 2 alkynyl group, an optionally substituted C 6- i 4 aryl group, an optionally substituted C 3-12 cycloalkyl group, an optionally substituted C 3- i 2 cycloalkenyl group, an optionally substituted C 7-12 polycycloalkyl group, an optionally substituted C 7 _i 2 polycycloalkenyl group, an optionally substituted C 5 _i 2 spirocycloalkyl group, an optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, an optionally substituted 4- to 12-membered heterocycloalkenyl group comprising 1 or 2 heteroatoms, or an optionally substituted heteroaryl ring comprising 1, 2 or 3 heteroatoms each independently selected from nitrogen, oxygen or sulphur; R 4
  • R a represents H or an optionally substituted C ⁇ alkyl group
  • R b represents -L n -R 5 m , or R a and R b together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
  • R a2 represents H or an optionally substituted C 1-6 alkyl group
  • R b2 represents -L n -R 5 Hi, or R a2 and R b2 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms
  • R a3 represents H or an optionally substituted C 1-6 alkyl group
  • R b3 represents
  • R a4 represents H or an optionally substituted C 1-6 alkyl group
  • R b4 represents -L n -R 5 m 5 or R a4 and R b together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms
  • R a4 represents H or an optionally substituted C 1-6 alkyl group
  • R b4 represents -L n -R 5 m 5 or R a4 and R b together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms
  • R a4 represents H or an optionally substituted C 1-6 alkyl group
  • R b4 represents -L n -R 5 m 5 or R a4 and R b together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsatur
  • R a5 represents H or an optionally substituted C 1-6 alkyl group, and R 5 represents -L n -R 5 m , or R a5 and R b5 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
  • R a6 represents -L n -R 5 m ;
  • R >a7 . represents -L n -R m ;
  • R a8 represents -L n -R 5 m ;
  • L represents a linker selected from optionally substituted C 2-10 alkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 6 . 14 aryl, optionally substituted -C 2-4 alkyl-C 6-14 aryl, optionally substituted -C ⁇ H aryl-C ⁇ alkyl, optionally substituted C 3 .
  • R 5 represents a group selected from among hydrogen, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted piperazinylcarbonyl, optionally substituted pyrrolidinyl, optionally substituted tropenyl, optionally substituted diketomethylpiperazinyl, optionally substituted sulphoxomorpholinyl, optionally substituted sulphonylmorpholinyl, optionally substituted thiomorpholinyl, optionally substituted azacycloheptyl, optionally substituted granatane, optionally substituted oxogranat
  • R 8 , R 9 each independently represents hydrogen, optionally substituted Ci -6 alkyl, optionally substituted -C 1-4 alkyl-C 3-10 cycloalkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 6-14 aryl, optionally substituted
  • -C 1-4 alkyl-C 6-14 aryl optionally substituted pyranyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted C 1-4 alkyloxycarbonyl, optionally substituted optionally substituted C 6-14 arylcarbonyl, optionally substituted C 1-4 alkylcarbonyl, optionally substituted C 6-14 arylmethyloxycarbonyl, optionally substituted C 6-14 arylsulphonyl, optionally substituted C 1-4 alkylsulphonyl, optionally substituted C 6-14 aryl-C 1-4 alkylsulphonyl, or R and R together with the nitrogen atom to which they are attached form a 3- to 7-membered bridged or unbridged, saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
  • X 1 is O or S;
  • X 2 is O, S or H 2 ;
  • Ar represents a 5- or 6-membered aromatic or heteroaromatic ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R 1 , R 2 each independently represents hydrogen, an optionally substituted C ⁇ alkyl group or an optionally substituted C 3-6 cycloalkyl group, or R 1 and R 2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
  • R c , R d each independently represents hydrogen, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-6 cycloalkyl group, or R c and R d together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
  • R ⁇ , R g2 each independently represents hydrogen, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-6 cycloalkyl group, or R G and R g2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms; or optionally one of R 1 and R 3 , or R 2 and R 3 together represent a saturated or unsaturated
  • R c3 , R d3 each independently represents hydrogen, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-6 cycloalkyl group, or R c3 and R d3 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
  • R e3 represents hydrogen, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-6 cycloalkyl group;
  • R ⁇ , R g3 each independently represents hydrogen, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-6 cycloalkyl group, or R ⁇ and R g3 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms; or optionally one of R c3 and R ⁇ , or R d3 and R g3 , or R e3 and R ⁇ together represent a saturated or unsaturated C 1-4 alkyl bridge optionally comprising 1 heteroatom or when Z 1 is CR f R g , Z 2 is CR c R d or NR e and Z 3 is CR 1 R 2 ;
  • R 1 , R 2 each independently represents hydrogen, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-6 cycloalkyl group, or R 1 and R 2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
  • R c , R d each independently represents hydrogen, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-6 cycloalkyl group, or R° and R d together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
  • R e represents hydrogen, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-6 cycloalkyl group;
  • R f , R 8 each independently represents hydrogen, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-6 cycloalkyl group, or R f and R g together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms; or optionally one of R 1 and R 3 , or R 2 and R 3 , or R 1 and R c , or R 2 and R d , or R 1 and R e3 together represent a saturated or unsaturated C 1-4 alkyl bridge optionally comprising 1 heteroatom, or pharmacologically acceptable salts thereof.
  • alkyl group including alkyl groups which are a part of other groups, unless otherwise stated, includes branched and unbranched alkyl groups with 1 to 12 carbon atoms.
  • Examples of C 1-12 alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and dodecyl groups.
  • propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and dodecyl include all the possible isomeric forms.
  • propyl includes the two isomeric groups n-propyl and iso-propyl
  • butyl includes n-butyl, iso-butyl, sec-butyl and tert-butyl
  • pentyl includes iso- pentyl, neopentyl, etc.
  • one or more hydrogen atoms may optionally be replaced by other substituent groups.
  • ' -O" denotes an oxygen atom linked via a double bond.
  • All the hydrogen atoms of the alkyl group may optionally be replaced by substituent groups, for example a trifluoromethyl group is a methyl group wherein all the hydrogen atoms have been replaced with fluorine atoms.
  • alkyl bridge includes branched and unbranched alkyl bridging groups with 1 to 5 carbon atoms, for example methylene, ethylene, propylene, butylene and pentylene bridges. Unless otherwise stated, the terms propylene, butylene and pentylene include all the possible isomeric forms. In the aforementioned alkyl bridges, 1 or 2 C-atoms may optionally be replaced by one or more heteroatoms selected from among oxygen, nitrogen or sulphur.
  • alkenyl groups includes branched and unbranched alkylene groups with 2 to 10 carbon atoms comprising at least one carbon-carbon double bond.
  • Examples of C 2- i O alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl nonenyl and decenyl groups.
  • propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl and decenyl also include all the possible isomeric forms.
  • butenyl includes 1 -butenyl, 2-butenyl, 3 -butenyl, 1 -methyl- 1 -propenyl, 1-methy 1-2 -propenyl, 2-methyl-l -propenyl, 2-methyl-2-propenyl and 1 -ethyl- 1 -ethenyl.
  • alkynyl groups includes branched and unbranched alkynyl groups with 2 to 10 carbon atoms comprising at least one triple bond.
  • Examples of C 2-10 alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl groups.
  • propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl also include all the possible isomeric forms.
  • butynyl includes 1 -butynyl, 2-butynyl, 3 -butynyl and l-methyl-2-propynyl.
  • the hydrogen atoms of the alkynyl group may optionally also be replaced.
  • aryl includes aromatic ring systems with 6 to 14 carbon atoms, said aromatic ring systems comprising one or more rings having from 6 to 14 ring atoms wherein at least one ring is aromatic.
  • C 6-14 aryl groups include phenyl (C 6 ), indenyl (Cg), naphthyl (C 1O ), fluorenyl (C 13 ), anthracyl (C 14 ), and phenanthryl (C 14 ).
  • one or more hydrogen atoms may optionally be replaced by other substitutent groups.
  • aryl groups may be substituted by the following substituents groups: OH; NO 2 ; CN; NH 2 ; halogen, for example fluorine or chlorine; optionally substituted C 1-10 alkyl, for example methyl, ethyl, propyl or CF 3 ; optionally substituted -OC 1-3 alkyl, for example -OMe, -OEt, OCHF 2 , or OCF 3 ; -COOH, -COO-C 1-4 alkyl, for example -COOMe or -COOEt, or -CONH 2 .
  • substituents groups OH; NO 2 ; CN; NH 2 ; halogen, for example fluorine or chlorine; optionally substituted C 1-10 alkyl, for example methyl, ethyl, propyl or CF 3 ; optionally substituted -OC 1-3 alkyl, for example -OMe, -OEt, OCHF 2 , or OCF 3 ; -CO
  • heteroaryl comprising 1 or 2 nitrogen atoms includes heteroaromatic ring systems with 5 to 14 ring atoms, said heteroaromatic ring systems comprising one or more rings having from 5 to 14 ring atoms wherein at least one ring is aromatic and wherein one or two of the ring atoms are replaced by nitrogen atoms the remaining ring atoms being carbon atoms.
  • heteroaryl groups wherein up to two carbon atoms are replaced by one or two nitrogen atoms comprising one ring include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl and pyrimidinyl groups.
  • heteroaryl rings may optionally also be anellated by a further ring, for example a benzene ring.
  • heteroaryl groups wherein up to two carbon atoms are replaced by one or two nitrogen atoms comprising two rings include indolyl, benzimidazolyl, quinolinyl, isoquinolinyl and quinazolinyl.
  • one or more hydrogen atoms may optionally be replaced by other substituent groups.
  • heteroaryl groups may be substituted by the following substituents groups: F; Cl; Br; OH; OMe; Me; Et; CN; NH 2 ; CONH 2 ; optionally substituted phenyl; and optionally substituted heteroaryl, for example optionally substituted pyridyl.
  • optionally substituted heteroaryl ring comprising 1, 2 or 3 heteroatoms each independently selected from nitrogen, oxygen or sulphur
  • heteroaromatic ring systems with 5 to 14 ring atoms, said heteroaromatic ring systems comprising one or more rings having from 5 to 14 ring atoms wherein at least one ring is aromatic and wherein one, two or three of the ring atoms are replaced by nitrogen, oxygen or sulphur atoms the remaining ring atoms being carbon atoms.
  • Each of the aforementioned examples of heteroaryl rings may optionally also be anellated by a further ring, for example a benzene ring.
  • one or more hydrogen atoms may optionally be replaced by other substituent groups.
  • heteroaryl groups may be substituted by the following substituents groups: F; Cl; Br; OH; OMe; Me; Et; CN; NH 2 ; CONH 2 ; optionally substituted phenyl; and optionally substituted heteroaryl, for example optionally substituted pyridyl.
  • cycloalkyl groups includes cycloalkyl groups comprising 1 ring with 3-12 carbon atoms.
  • C 3-12 cycoalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl groups.
  • one or more hydrogen atoms may optionally be replaced by other substituent groups.
  • cycloalkenyl includes cycloalkenyl groups with 3- 12 carbon atoms comprising one ring, said ring comprising at least one carbon-carbon double bond.
  • C 3-12 cycloakenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, cycloundecenyl and cyclododecenyl groups.
  • heterocycloalkyl and heterocycloakenyl include 3- to 12-membered, for example 5-, 6- or 7-membered, heterocycles which may contain 1 to 4 heteroatoms selected from nitrogen, oxygen or sulphur.
  • Heterocycloalkyl denotes a saturated heterocycle
  • heterocycloakenyl denotes an unsaturated heterocycle.
  • heterocycloalkyl or heterocycloakenyl groups examples include tetrahydrofuran, tetrahydrofuranone, g ⁇ r ⁇ /r ⁇ -butyrolactone, alpha-pyvan, g ⁇ mm ⁇ -pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, thiolan, dithiolan, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrazole, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepan, oxazine, tetrahydro-oxazinyl, isothiazole, and pyrazolidine.
  • heterocycloalkyl or heterocycloakenyl groups may optionally be replaced by other substituent groups.
  • polycycloalkyl includes cycloalkyl groups comprising 3 to 12 carbon atoms and comprising 2 or more rings. Examples of polycycloalkyl groups include optionally substituted, bi-, tri-, tetra- or pentacyclic cycloalkyl groups, for example pinane, 2,2,2-octane, 2,2,1 -heptane or adamantane.
  • polycycloalkenyl unless otherwise stated, includes cycloalkenyl groups comprising 7 to 12 carbon atoms and comprising 2 or more rings wherein at least one ring comprises a carbon-carbon double bond.
  • polycycloalkenyl groups are optionally bridged and/or substituted bi-, tri-, tetra- or pentacyclic cycloalkenyl groups, for example bicycloalkenyl or tricycloalkenyl groups having at least one double bond, such as norbornene.
  • spirocycloalkyl unless otherwise stated, includes spirocycloalkyl groups comprising 5 to 12 carbon atoms and comprising 2 or more rings wherein two rings are joined at a spiro carbon centre. Examples of spirocycloalkyl groups include spiro[4.4]nonyl and spiro[3.4]octyl.
  • 5- or 6-membered aromatic or heteroaromatic ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur is a fully unsaturated, aromatic monocyclic ring containing 5 or 6 atoms of which one or more ring atoms is optionally a heteroatom selected from nitrogen, oxygen or sulphur, with the remaining ring atoms being carbon.
  • Examples of a 5- or 6-membered aromatic or heteroaromatic ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur include furyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl thiazolyl, thienyl and triazolyl rings.
  • 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms includes optionally substituted C 3-6 cylcoalkyl and optionally substituted C 3-6 cylcoalkenyl groups, and optionally substituted 3- to 6-membered heterocylcoalkyl and optionally substituted 3- to 6-membered heterocylcoalkenyl groups each with 1 or 2 heteroatoms.
  • halogen includes fluorine, chlorine, bromine or iodine.
  • alkyloxy (-OR wherein R is an alkyl), alkenyloxy (-OR wherein R is an alkenyl), alkynyloxy (-OR wherein R is an alkynyl), cycloalkyloxy (-OR wherein R is a cycloalkyl) and heterocycloalkoxy (-OR wherein R is a heterocycloalkyl) denote an -OR group wherein the respective alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl group is as hereinbefore described above.
  • -alkyl-aryl refers to an alkyl group with an aryl substituent.
  • -alkyl-cycloalkyl refers to an alkyl group with a cycloakyl substituent.
  • -aryl-alkyl refers to an aryl group with an alkyl substituent.
  • R 5 represents a substituted morpholinyl, piperidinyl, homopiperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, diketomethylpiperazinyl, sulphoxomorpholinyl, sulphonylrnorpholinyl, thiomorpholinyl, granatanyl, oxogranatanyl or azacycloheptyl, one or more substituents may be present and are as defined above for R 8 .
  • R 1 to R 9 may optionally be branched and/or substituted.
  • R 1 , R 2 each independently represents hydrogen, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-6 cycloalkyl group, or R 1 and R 2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
  • R c , R d each independently represents hydrogen, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-6 cycloalkyl group, or R° and R d together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
  • R 3 represents hydrogen, an optionally substituted C 1-12 alkyl group, an optionally substituted C 2-12 alkenyl group, an optionally substituted C 2-12 alkynyl group, an optionally substituted C 6-H aryl group, an optionally substituted C 3-12 cycloalkyl group, an optionally
  • 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 4- to 12-membered heterocycloalkenyl group comprising 1 or 2 heteroatoms, or optionally one of R 1 and R 3 , or R 2 and R 3 , or R 1 and R c , or R 2 and R d together represent a saturated or unsaturated C 1-4 alkyl bridge optionally comprising 1 heteroatom;
  • R 4 each independently represent -CN, hydroxy, -NR 6 R 7 , -NR 6 SO 2 R 7 , halogen, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-7 cycloalkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 1-5 alkyloxy group, an optionally substituted
  • R a and R b together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
  • R 82 represents H or an optionally substituted C ⁇ alkyl group, and R 2 represents -L n -R 5 m , or R a2 and R b2 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
  • R a3 represents H or an optionally substituted C 1-6 alkyl group
  • R b3 represents
  • R a4 represents H or an optionally substituted C 1-6 alkyl group
  • R b4 represents
  • R a4 and R b4 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
  • R a5 represents H or an optionally substituted C 1-6 alkyl group
  • R b5 represents
  • R a5 and R b5 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
  • R a6 represents -L n -R 5 m ;
  • R a7 represents -L n -R 5 m ;
  • R a8 represents -L n -R 5 m ;
  • R a9 represents -L n -R 5 m ;
  • R al ° represents -L n -R 5 m ;
  • L represents a linker selected from optionally substituted C 2 -i 0 alkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 6 . 14 aryl, optionally substituted -C 2-4 alkyl-C 6-14 aryl, optionally substituted -C 6-14 aryl-C 1-4 alkyl, optionally substituted C 3-12 cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen atoms; n is 0 or 1 m is 1 or 2
  • R 5 represents a group selected from among hydrogen, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted piperazinylcarbonyl, optionally substituted pyrrolidinyl, optionally substituted tropenyl, optionally substituted diketomethylpiperazinyl, optionally substituted sulphoxomorpholinyl, optionally substituted sulphonylmorpholinyl, optionally substituted thiomorpholinyl, optionally substituted azacycloheptyl, optionally substituted granatanyl, optionally substituted oxogranatanyl and -NR 8 R 9 ; R 6 , R 7 each independently represents hydrogen or an optionally substituted C ⁇ alkyl group;
  • R 8 , R 9 each independently represents hydrogen, optionally substituted C ⁇ alkyl, optionally substituted -C 1-4 alkyl-C 3-1 ocycloalkyl, optionally substituted Ca-iocycloalkyl, optionally substituted C 6-14 aryl, optionally substituted -C 1-4 alkyl-C 6-14 aryl, optionally substituted pyranyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted C 1-4 alkyloxycarbonyl, optionally substituted optionally substituted C 6-14 arylcarbonyl, optionally substituted C 1-4 alkylcarbonyl, optionally substituted Co-narylmethyloxycarbonyl, optionally substituted C 6 - 14 arylsulphonyl, optionally substituted C 1-4 alkylsulphonyl, optionally substituted C 6-14 aryl-C 1-4 alkylsulphonyl, or R 8 and R 9 together with the nitrogen atom to which
  • R 1 , R 2 each independently represents hydrogen, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-6 cycloalkyl group, or R 1 and R 2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
  • R c , R d each independently represents hydrogen, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-6 cycloalkyl group, or R e and R d together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
  • R 3 represents hydrogen, an optionally substituted C 1-12 alkyl group, an optionally substituted C 2-12 alkenyl group, an optionally substituted C 2-12 alkynyl group, an optionally substituted C 6- i 4 aryl group, an optionally substituted C 3- i 2 cycloalkyl group, an optionally substituted C 3- i 2 cycloalkenyl group, an optionally substituted C 7-12 polycycloalkyl group, an optionally substituted C ⁇ npolycycloalkenyl group, an optionally substituted Cs-nspirocycloalkyl group, an optionally substituted 3- to
  • 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 4- to 12-membered heterocycloalkenyl group comprising 1 or 2 heteroatoms, or optionally one of R 1 and R 3 , or R 2 and R 3 , or R 1 and R c , or R 2 and R d together represent a saturated or unsaturated Ci. 4 alk.yl bridge optionally comprising 1 heteroatom;
  • R 4 each independently represent -CN, hydroxy, -NR 6 R 7 , -NR 6 SO 2 R 7 , halogen, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-7 cycloalkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 1-5 alkyloxy group, an optionally substituted C 3-6 cycloalkyloxy group, an optionally substituted C 2-5 alkenyloxy group, an optionally substituted C 2-5 alkynyloxy group, an optionally substituted C 1-6 alkythio group, an optionally substituted C 1-6 alkylsulphoxo group or an optionally substituted C 1-6 alkylsulphonyl group, an optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 3- to 12-membered heterocycloalkoxy group comprising 1 or
  • n is 0 or 1 m is 1 or 2
  • R 5 represents a group selected from among hydrogen, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted piperazinylcarbonyl, optionally substituted pyrrolidinyl, optionally substituted tropenyl, optionally substituted diketomethylpiperazinyl, optionally substituted sulphoxomorpholinyl, optionally substituted sulphonylmorpholinyl, optionally substituted thiomorpholinyl, optionally substituted azacycloheptyl, optionally substituted granatanyl, optionally substituted oxogranatanyl and -NR 8 R 9 ;
  • R 6 , R 7 each independently represents hydrogen or an optionally substituted C 1-4 alkyl group
  • R 8 , R 9 each independently represents hydrogen, optionally substituted C 1-6 alkyl, optionally substituted -C 1-4 alkyl-C 3-1 ocycloalkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 6-14 aryl, optionally substituted -C 1-4 alkyl-C 6-14 aryl, optionally substituted pyranyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted C 1-4 alkyloxycarbonyl, optionally substituted optionally substituted C 6-14 arylcarbonyl, optionally substituted
  • R 1 , R 2 each independently represents hydrogen or an optionally substituted C 1-6 alkyl group, or R 1 and R 2 together with the carbon atom to which they are attached form a
  • R c , R d each independently represents hydrogen, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-6 cycloalkyl group, or R c and R d together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
  • R 3 represents hydrogen, an optionally substituted C 1-12 alkyl group, an optionally substituted C 2-12 alkenyl group, an optionally substituted C 2-12 alkynyl group, an optionally substituted C 6 - H aIyI group, an optionally substituted C 3-12 cycloalkyl group, an optionally substituted C 3 . 12 cycloalkenyl group, an optionally substituted
  • C 7-12 polycycloalkyl group an optionally substituted C 7-12 polycycloalkenyl group, an optionally substituted C5-i 2 spirocycloalkyl group, an optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 4- to 12-membered heterocycloalkenyl group comprising 1 or 2 heteroatoms, or optionally one of R 1 and R 3 , or R 2 and R 3 , or R 1 and R c , or R 2 and R d together represent a saturated or unsaturated Ci -4 alkyl bridge optionally comprising 1 heteroatom;
  • R 4 each independently represent -CN, hydroxy, -NR 6 R 7 , -NR 6 SO 2 R 7 , halogen, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-7 cycloalkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 1-5 alkyloxy group, an optionally substituted C 3-6 cycloalkyloxy group, an optionally substituted C 2-5 alkenyloxy group, an optionally substituted C 2-5 alkynyloxy group, an optionally substituted C 1-6 alkythio group, an optionally substituted C ⁇ alkylsulphoxo group or an optionally substituted
  • C 1-6 alkylsulphonyl group an optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 3- to 12-membered heterocycloalkoxy group comprising 1 or 2 heteroatoms;
  • p is 0, 1 or 2;
  • R 5 represents a group selected from among hydrogen, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted piperazinylcarbonyl, optionally substituted pyrrolidinyl, optionally substituted tropenyl, optionally substituted diketomethylpiperazinyl, optionally substituted sulphoxomorpholinyl, optionally substituted sulphonylmorpholinyl, optionally substituted thiomorpholinyl, optionally substituted azacycloheptyl, optionally substituted granatanyl, optionally substituted oxogranatanyl and -NR 8 R 9 ; R 6 , R 7 each independently represents hydrogen or an optionally substituted C ⁇ alkyl group; and R 8 , R 9 each independently represents hydrogen, optionally substituted C 1-6 alkyl, optionally substituted -C 1-4 alkyl-C 3- i cycloalkyl, optionally substituted C 3-10
  • R 1 , R 2 each independently represents hydrogen or an optionally substituted C 1-6 alkyl group, or R 1 and R 2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
  • R c , R d each independently represents hydrogen, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-6 cycloalkyl group, or R° and R d together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
  • R 3 represents hydrogen, an optionally substituted C 1-12 alkyl group, an optionally substituted C 2-12 alkenyl group, an optionally substituted C 2-12 alkynyl group, an optionally substituted C 6-14 aryl group, an optionally substituted C 3-12 cycloalkyl group, an optionally substituted C 3-12 cycloalkenyl group, an optional
  • 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 4- to 12-membered heterocycloalkenyl group comprising 1 or 2 heteroatoms, or optionally one of R 1 and R 3 , or R 2 and R 3 , or R 1 and R c , or R 2 and R d together represent a saturated or unsaturated C 1- 4alkyl bridge optionally comprising 1 heteroatom;
  • R 4a , R 4b , R 4c each independently represent -CN, hydroxy, -NR 6 R 7 , -NR 6 SO 2 R 7 , halogen, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-7 cycloalkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 1-5 alkyloxy group, an optionally substituted C 3-6 cycloalkyloxy group, an optionally substituted C 2-5 alkenyloxy group, an optionally substituted C 2-5 alkynyloxy group, an optionally substituted C ⁇ ⁇ alkythio group, an optionally substituted C 1-6 alkylsulphoxo group or an optionally substituted C 1-6 alkylsulphonyl group, an optionally substituted 3- to 12- membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 3- to 12-membere
  • R 5 represents a group selected from among hydrogen, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted piperazinylcarbonyl, optionally substituted pyrrolidinyl, optionally substituted tropenyl, optionally substituted diketomethylpiperazinyl, optionally substituted sulphoxomorpholinyl, optionally substituted sulphonylmorpholinyl, optionally substituted thiomorpholinyl, optionally substituted azacycloheptyl, optionally substituted granatanyl, optionally substituted oxogranatanyl and -NR 8
  • R 6 , R 7 each independently represents hydrogen or an optionally substituted C 1-4 alkyl group
  • R 8 , R 9 each independently represents hydrogen, optionally substituted C 1-6 alkyl, optionally substituted -C 1-4 alkyl-C 3-10 cycloalkyl, optionally substituted C 3-1 ocycloalkyl, optionally substituted C 6-14 aryl, optionally substituted -C 1-4 alkyl-C 6-14 aryl, optionally substituted pyranyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted C 1-4 alkyloxycarbonyl, optionally substituted optionally substituted C 6-14 arylcarbonyl, optionally substituted
  • the groups R 1 and R 2 may be identical or different and represent hydrogen or a CrC ⁇ alkyl group optionally substituted by one or more substituents selected from C 1-3 alkyloxy, Ci -3 alkylthio, C 1-3 alkyl-S(O) 2 , C 1-3 alkylamino and di-(C 1-3 alkyl)amino.
  • the groups R 1 and R 2 may be identical or different and represent hydrogen or a methyl or ethyl group.
  • the groups R 1 and R 2 are different wherein one of R 1 or R 2 represents hydrogen and the other represents a methyl or ethyl group.
  • R 1 and R 2 together represent a 2- to 5-membered alkyl bridge optionally comprising 1 to 2 heteroatoms selected from oxygen or nitrogen and optionally substituted by one or more substituents selected from C 1-3 alkyloxy, C 1-3 alkylthio, C 1-3 alkyl-S(O) 2 , C 1-3 alkylamino and di-(C 1-3 alkyl)amino.
  • R 1 and R 2 together represent an ethylene or propylene bridge.
  • the groups R e and R d may be identical or different and represent hydrogen or a Q-C ⁇ alkyl group optionally substituted by one or more substituents selected from C 1-3 alkyloxy, C 1-3 alkylthio, C 1-3 alkyl-S(O) 2 , C 1-3 alkylamino and di-(C 1-3 alkyl)amino.
  • the groups R c and R may be identical or different and represent hydrogen or a methyl or ethyl group.
  • the groups R c and R d are different wherein one of R c or R d represents hydrogen and the other represents a methyl or ethyl group.
  • R c and R d together represent a 2- to 5-membered alkyl bridge optionally comprising 1 to 2 heteroatoms selected from oxygen or nitrogen and optionally substituted by one or more substituents selected from C 1-3 alkyloxy, C 1-3 alkylthio, C 1-3 alkyl-S(O) 2 , C 1-3 alkylamino and di-(C 1-3 alkyl)amino.
  • R c and R d together represent an ethylene, propylene or butylene bridge.
  • at least one of R 1 , R 2 , R c , or R d is hydrogen.
  • R 1 , R 2 , R c , or R d are hydrogen.
  • R 1 and R 2 are hydrogen.
  • R 1 and R 2 are hydrogen, and one of R c or R d is hydrogen.
  • R 1 and R 2 are hydrogen, and one of R c or R d is hydrogen and the other is methyl.
  • R 1 and R 2 are hydrogen, and R c and R are methyl.
  • R 1 and R 2 are hydrogen, and R c and R d together represent an ethylene bridge.
  • R 3 represents hydrogen; a d-C 12 alkyl, for example ethyl, propyl, butyl, pentyl or hexyl, optionally substituted by one or more substituents selected from C 1-3 alkyloxy, C 1-3 alkylthio, C 1-3 alkyl-S(O) 2 , C 1-3 alkylamino and di-(C 1-3 alkyl)amino; a C 2 -C 12 alkenyl, for example C 5 -C 7 alkenyl, optionally substituted by one or more substituents selected from C 1-3 alkyloxy, C 1-3 alkylthio, C 1-3 alkyl-S(O) 2 , C 1-3 alkylamino and di-(C 1-3 alkyl)amino; a C 2 -C 12 alkenyl, for example C 5 -C 7 alkenyl,
  • C 5 -C 12 spirocycloalkyl optionally substituted by one or more substituents selected from C 1-3 alkyloxy, C 1-3 alkylthio, C 1-3 alkyl-S(O) 2 , C 1-3 alkylamino and di-(C 1-3 alkyl)amino;
  • s C 3 -C 12 heterocycloalkyl which contains 1 to 2 heteroatoms selected from oxygen, nitrogen or sulphur, for example pyranyl or piperinyl, pyrrolidinyl, pyrazinyl or morpholinyl, optionally substituted by one or more substituents selected from C 1-3 alkyloxy, C 1-3 alkylthio, C 1-3 alkyl- S(O) 2 , C 1-3 alkylamino and di-(C 1-3 alkyl)amino; and C 3 -C 12 heterocycloalkenyl which contains 1 to 2 heteroatoms selected from oxygen, nitrogen or s
  • R 3 represents isopropyl, isobutyl, isopentyl, cyclopentyl, phenyl or cyclohexyl.
  • R 3 represents cyclopentyl,or cyclohexyl.
  • R 1 and R 3 or R 2 and R 3 together represent a saturated or unsaturated C 3 -C 4 alkyl bridge optionally comprising 1 heteroatom selected from oxygen or nitrogen.
  • R 4 represents a group selected from among -CN; hydroxyl; -NR 6 R 7 ; halogen, for example chlorine or fluorine; d-C ⁇ alkyl, for example methyl, ethyl or propyl, optionally substituted by one or more substituents selected from C 1-3 alkyloxy, C 1-3 alkylthio, C 1-3 alkyl-S(O) 2 , C 1-3 alkylamino and di-(C 1-3 alkyl)amino; C 2 -C 6 alkenyl, for example ethenyl or propenyl, optionally substituted by one or more substituents selected from C 1-3 alkyloxy,
  • each R 4 may be the same or different and selected from methoxy, methyl, ethoxy, ethyl, propargyloxy, chlorine or fluorine.
  • p 2 and when each R is adjacent, both R 4 together with the aromatic ring atoms to which they are attached form a 4- to 7-member unsaturated ring optionally comprising 1 to 2 heteroatoms.
  • R 4b and R 4c are hydrogen and R 4a represents methoxy, methyl, ethoxy, chlorine or fluorine.
  • R is hydrogen and R 4a and R 4c may be the same or different and selected from methoxy, methyl, ethoxy, chlorine or fluorine.
  • R 4c is hydrogen and R 4a and R 4b together form a OCH 2 O bridge.
  • L represents a linker selected from among C 2 -C 10 alkyl, for example ethyl, propyl, butyl or pentyl, optionally substituted by one or more substituents selected from C 1-3 alkyloxy, C 1-3 alkylthio, C 1-3 alkyl-S(O) 2 , C 1-3 alkylamino and di-(Ci -3 alkyl)amino; C2-C 10 alkenyl, optionally substituted by one or more substituents selected from Ci -3 alkyloxy, C 1-3 alkylthio, C ⁇ 3 alkyl-S(O) 2 , C 1-3 alkylamino and dKC ⁇ alkytyamino; C 6 -C 14 aryl, for example phenyl, optionally substituted by one or more substituents selected from C 1-3 alkyloxy, C 1-3 alkylthio, C 1-3 alkyl-
  • L represents an optionally substituted a C 2-10 alkyl or an optionally substituted C 3-12 cycloalkyl linker.
  • L represents cyclohexyl, -C(CH 3 ) 2 -CH 2 - or -CH 2 -C(CH 3 ) 2 -CH 2 -.
  • n 0.
  • R 5 represents a group selected from among hydrogen, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted piperazinylcarbonyl, optionally substituted pyrrolidinyl, optionally substituted tropenyl, optionally substituted diketomethylpiperazinyl, optionally substituted sulphoxomorpholinyl, sulphonylmorpholmyl, optionally substituted thiomorpholinyl, optionally substituted granatanyl, optionally substituted oxogranatanyl -NR 8 R 9 and optionally substituted azacycloheptyl wherein each morpholinyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl,
  • R 5 represents hydrogen, -NR 8 R 9 or a piperidinyl, morpholinyl, pyrrolidinyl, sulphoxomorpholiny, piperazinyl, thiomorpholinyl, tropenyl, granatanyl, oxogranatanyl or azacycloheptyl each optionally substituted by one or more groups as defined for R 8 .
  • R 5 represents piperidinyl optionally substituted by one or more groups as defined for R 8 .
  • R 5 represents pyrrolidinyl optionally substituted by one or more groups as defined for R 8 .
  • R 5 represents granatanyl optionally substituted by one or more groups as defined for R 8 .
  • the groups R 6 and R 7 may be identical or different and represent hydrogen or Q-Qalkyl, for example methyl or ethyl.
  • the groups R and R may be identical or different and represent hydrogen; a d-C ⁇ alkyl, for example methyl, ethyl or propyl, optionally substituted by one or more substituents selected from C 1-3 alkyloxy, C 1-3 alkylthio, C 1-3 alkyl-S(O) 2 , C 1-3 alky lamino and di- (C 1-3 alkyl)amino; -C 1 -C 4 alkyl-C 3 -C 10 cycloalkyl, for example -CH 2 -cyclopropyl, optionally substituted by one or more substituents selected from C 1-3 alkyloxy, Ci -3 alkylthio, C 1-3 alkyl- S(O) 2 , C 1-3 alkylamino and di-(C 1-3 alkyl)amino; CrQocycloalkyl optionally substituted by one or more substituents selected from C 1-3 alkyloxy, Ci -3 alkylthio, C 1-3
  • Ci 3 alkyloxy, Ci -3 alkylthio, C 1-3 alkyl-S(O) 2 , C ⁇ alkylamino and di-(C 1-3 alkyl)amino; pyridinyl optionally substituted by one or more substituents selected from C 1-3 alky loxy, C 1-3 alkylthio, C 1-3 alkyl-S(O) 2 , C 1-3 alkylamino and di- (C 1-3 alkyl)amino; pyrimidinyl optionally substituted by one or more substituents selected from Ci.
  • C 1 -C 4 alkyloxycarbonyl optionally substituted by one or more substituents selected from C 1-3 alkyloxy, C 1-3 alkylthio, C 1-3 alkyl-S(O) 2 , C 1-3 alkylamino and di-(C 1-3 alkyl)amino;
  • C 6 -C 14 arylcarbonyl optionally substituted by one or more substituents selected from C 1-3 alkyloxy, C 1-3 alkylthio, C 1-3 alkyl-S(O) 2 , C 1-3 alkylamino and di-(C 1-3 alkyl)amino;
  • CrC 4 alkylcarbonyl optionally substituted by one or more substituents selected from C 1-3 alkyloxy, C 1-3 alkylthio, C 1-3 alkyl-S(O) 2 , C 1-3 alkylamino and di-(C 1-3 alkyl)amino;
  • R 9 represents methyl, ethyl or propyl.
  • R N represents C 1-3 alkyl. In another embodiment, for the compound of formula (I), R N represents methyl or ethyl.
  • n 1 and L is an optionally substituted C 2-10 alkyl linker.
  • n is 1 and L is an optionally substituted C 2-10 alkyl linker.
  • R 1 to R 4 , R 4a , R 4b , R 4c , R c , R d , R 6 and R 7 are as hereinbefore defined; and L represents a linker selected from among optionally substituted C 2-10 alkyl, optionally substituted C 2-1 oalkenyl, optionally substituted C 6-14 aryl, optionally substituted -C 2-4 alkyl-C 6-14 aryl, optionally substituted -C 6-14 aryl-C 1-4 alkyl, optionally substituted C 3-12 cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen ring atoms; n denotes 1; m denotes 1 or 2; R 5 denotes hydrogen or a group which is bound to L via a nitrogen atom, selected from optionally substituted morpholinyl, optionally substituted piperidinyl, optional
  • L represents a linker selected from optionally substituted C 2-1 oalkyl, optionally substituted C 2- i 0 alkenyl, optionally substituted C 6-14 aryl, optionally substituted -C 2- 4alkyl-C 6 .i 4 aryl, optionally substituted -C ⁇ H aryl-C ⁇ alkyl, optionally substituted C 3-12 cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen ring atoms; n denotes 0 or 1; m denotes 1 or 2; R 5 denotes hydrogen or a group which is bound to L via a carbon atom, selected from among piperidinyl, piperazinyl,
  • R 1 , R 2 , R c , R d , m, n and R 5 to R 8 are as hereinbefore defined; and R 3 represents an optionally substituted Ci -10 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-6 heterocycloalkyl or optionally substituted C 6-14 aryl group or R 1 and R 3 or R 2 and R 3 together represent a saturated or unsaturated C 3-4 alkyl bridge optionally comprising 1 or 2 heteroatoms; p is 0 or 1; R 4 represents OMe, OH, Me, Et, Pr, OEt, NHMe, NH 2 , F, CL, Br, 0-propargyl, O-butynyl, CN, SMe, NMe 2 , CONH 2 , ethynyl, propynyl, butyn
  • R 3 represents an optionally substituted C 1-1O aIlCyI, optionally substituted C 3 _ 7 cycloalkyl, optionally substituted C 3-6 heterocycloalkyl or optionally substituted C 6-14 aryl group;
  • p is 0 or 1;
  • R 4 represents OMe, OH, Me, Et, Pr, OEt, NHMe, NH 2 , F, CL, Br, 0-propargyl, O-butynyl, CN, SMe, NMe 2 , CONH 2 , ethynyl, propynyl, butynyl or allyl;
  • L represents a linker selected from optionally substituted C 2-1 oalkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 6-14 aryl, optionally substituted -C 2-4 alkyl-C 6-14 aryl, optionally substituted -
  • R 3 represents an optionally substituted C 1-10 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-6 heterocycloalkyl; p is 0, 1 or 2; R 4 each independently represents fluoro or OMe; L represents a linker selected from optionally substituted C2-i O alkyl; n denotes 0 or 1; m denotes 1 or 2; R 5 denotes a group selected from among -NR 8 R 9 and piperidinyl each optionally substituted by one or more groups as defined for R 8 ; R 8 , R 9 each independently represent Ci -6 alkyl; R 1 , R 2 are hydrogen; R c , R d are each independently selected from hydrogen, Me, or Et, or R c and R d together represent an ethylene bridge, or pharmacologically acceptable salts thereof.
  • R 3 represents an optionally substituted C 1-lo alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-6 heterocycloalkyl; p is 0, 1 or 2; R 4 each independently represents fluoro or OMe; L represents a linker selected from optionally substituted C 2-10 alkyl; n denotes 0 or 1; m denotes 1 or 2; R 5 denotes a group selected from among -NR 8 R 9 and pyrrolidinyl each optionally substituted by one or more groups as defined for R 8 ; R 8 , R 9 each independently represent C ⁇ alkyl; R 1 , R 2 are hydrogen; R c , R d are each independently selected from hydrogen, Me, or Et, or R c and R d together represent an ethylene bridge, or pharmacologically acceptable salts thereof.
  • R 3 represents an optionally substituted C 1-lo alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C ⁇ heterocycloalkyl; p is 0, 1 or 2; R 4 each independently represents fluoro or OMe; L represents a linker selected from optionally substituted C 2-10 alkyl; n denotes 0 or 1; m denotes 1 or 2; R 5 denotes a group selected from among -NR 8 R 9 and granatanyl each optionally substituted by one or more groups as defined for R 8 ; R 8 , R 9 each independently represent C 1-6 alkyl; R 1 , R 2 are hydrogen; R c , R d are each independently selected from hydrogen, Me, or Et, or R c and R d together represent an ethylene bridge, or pharmacologically acceptable salts thereof.
  • R 3 represents an optionally substituted C 1-10 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-6 heterocycloalkyl
  • L represents a linker selected from optionally substituted C 2-10 alkyl
  • n denotes 0 or 1
  • m denotes 1 or 2
  • R 5 denotes a group selected from among -NR 8 R 9 and piperidinyl each optionally substituted by one or more groups as defined for R 8
  • R 8 , R 9 each independently represent C 1-6 alkyl
  • R 1 , R 2 are hydrogen
  • R c , R d are each independently selected from hydrogen, Me, or Et, or R c and R d together represent an ethylene bridge
  • p is 0, 1 or 2
  • R 4b and R 4c are hydrogen and R 4a represents methoxy, methyl, ethoxy, chlorine or fluorine; and when
  • R 3 represents an optionally substituted C 1-10 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted Cs- ⁇ heterocycloalkyl
  • L represents a linker selected from optionally substituted C 2-10 alkyl
  • n denotes 0 or 1
  • m denotes 1 or 2
  • R 5 denotes a group selected from among -NR 8 R 9 and pyrrolidinyl each optionally substituted by one or more groups as defined for R
  • R , R each independently represent C 1-6 alkyl
  • R , R are hydrogen
  • R c , R d are each independently selected from hydrogen, Me, or Et, or R c and R together represent an ethylene bridge
  • p is 0, 1 or 2
  • R 4b and R 4c are hydrogen s and R 4a represents methoxy, methyl, ethoxy, chlorine or fluorine; and when
  • R 3 represents an optionally substituted C ⁇ oalkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-6 heterocycloalkyl
  • L represents a linker selected from optionally substituted C 2- i O alkyl
  • n denotes 0 or 1
  • m denotes 1 or 2
  • R 5 denotes a group selected from among -NR 8 R 9 and granatanyl each optionally substituted by one or more groups as defined for R 8
  • R 8 , R 9 each independently represent C 1-6 alkyl
  • R 1 , R 2 s are hydrogen
  • R c , R d are each independently selected from hydrogen, Me, or Et, or R c and R d together represent an ethylene bridge
  • p is 0, 1 or 2
  • R 4b and R 4c are hydrogen and R 4a represents methoxy, methyl, ethoxy, chlorine or flu
  • a compound selected from any io one of Examples 1, 2, 3, 6, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 25, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 41, 43, 44, 45, 46, 48, 49, 50, 52, 54, 55, 57, 58, 59, 60, 61, 62, 63, 64, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 82, 83, 84, 85, 86, 88, 90, 91, 92, 93, 94, 95, 96, 98, 109, 181, 185, 188, 189, 193, 194, 199, 200, 201, 203, 205, 206, 207, 208, 209, 210, 212, 213, 217, 235, 236, 237, 240, 241,
  • the compounds according to the first, second, third, fourth and fifth aspects of the invention may be present in the form of the individual optical isomers, mixtures of the
  • the compounds of formula (I) 5 (II), (Ha), (III) or (Ilia) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate, or an alkali metal salt such as a sodium or potassium salt.
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate, or an alkali metal salt such as a sodium or potassium salt.
  • the invention also relates to a process for preparing a compound of general formula (HI),
  • R 10 is a substituent selected from among OH, NH 2 -LR 5 , -O-methyl and -O-ethyl.
  • the term leaving group includes leaving groups such as for example —O-methyl,
  • the leaving group A is chlorine.
  • compounds of formula (IV) may be obtained by reaction of another compound of general formula (IV), wherein R3 is hydrogen, with an alkyl halide, in a polar solvent, such as, for example, N,N-dimethylacetamide, in the presence of a strong base, such as, for example, sodium hydride.
  • a polar solvent such as, for example, N,N-dimethylacetamide
  • Still furthermore compounds of formula (IV), where R°, R d , R 1 & R 2 are hydrogen, may be obtained by reaction of a compound of formula (XI)
  • a base such as triethylamine
  • a lewis acid such as titanium (IV) tetraethoxide
  • XVII wherein X is a leaving group, typically a halogen, such as chloro, in the presence of a base, such as triethylamine, in an organic solvent, such as dichloromethane.
  • a compound of formula (XVI) may also be obtained by the sequential reaction of 5- bromouracil,
  • a polar solvent such as ethanol and ii) a chlorinating agent, such as phosphorous oxychloride as for instance exemplified in Journal of Medicinal Chemistry (1966), 9(1), 121-6.
  • the invention also relates to a process for preparing a compound of general formula (XVIII),
  • the invention further relates to compounds of formula (I), (II), (Ha), (III) or (Ilia) fors use as pharmaceutical compositions.
  • compounds of formula (I), (II), (Ha), (III) or (Ilia) are of use as pharmaceutical compositions with an antiproliferative activity.
  • the invention also relates to the use of a compound of formula (I), (II), (Ha), (III) or (Ilia) for preparing a pharmaceutical composition for the treatment and/or prevention ofo cancer, infections, inflammatory and autoimmune diseases.
  • PIk inhibitors should be of therapeutic value for treatment of proliferative disease including solid tumours such as carcinomas and sarcomas and the leukaemias and lymphoid malignancies.
  • PIk inhibitors should be useful in the treatment of other disorders associated with uncontrolled cellular proliferation.
  • One aspect of the current invention therefore relates to the use of one or more of the compounds of formula (I), (II), (Ha), (III) or (Ilia) in the treatment of disorders characterised by excessive or anomalous cell proliferation.
  • Such diseases include for example: viral infections such as HIV and Kaposi's sarcoma; inflammatory and autoimmune diseases such as colitis, rheumatoid arthritis, Alzheimer's disease, glomerulonephritis and wound healing; bacterial, fungal and parasitic infections such as malaria and emphysema; dermatological diseases such as psoriasis; bone diseases; cardiovascular diseases such as restenosis and cardiomyopathy.
  • viral infections such as HIV and Kaposi's sarcoma
  • inflammatory and autoimmune diseases such as colitis, rheumatoid arthritis, Alzheimer's disease, glomerulonephritis and wound healing
  • bacterial, fungal and parasitic infections such as malaria and emphysema
  • dermatological diseases such as psoriasis
  • bone diseases such as restenosis and cardiomyopathy.
  • cardiovascular diseases such as restenosis and cardiomyopathy.
  • the invention also relates to a method of treating and/or preventing cancer, infections, inflammatory and autoimmune diseases, characterised in that a patient is given an effective amount of a compound of formula (I), (II), (Ha), (III) or (Ilia).
  • the invention also relates to pharmaceutical preparations, containing as active substance one or more compounds of general formula (I), (II), (Ha), (III) or (Ilia), or the physiologically acceptable salts thereof, optionally combined with conventional excipients and/or carriers.
  • the compounds of formula (I), (II) and (III) have activity as pharmaceuticals, in particular as modulators or inhibitors of PIk activity, and may be used in the treatment of proliferative and hyperproliferative diseases/conditions, examples of which include the following cancers: (1) carcinoma, including that of the bladder, brain, breast, colon, kidney, liver, lung, ovary, pancreas, prostate, stomach, cervix, colon, thyroid and skin;
  • lymphoid lineage including acute lymphocytic leukaemia, B cell lymphoma and Burketts lymphoma;
  • tumours of myeloid lineage including acute and chronic myelogenous leukaemias and promyelocytic leukaemia; (4) tumours of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; and
  • tumours including melanoma, seminoma, tetratocarcinoma, neuroblastoma and glioma.
  • the compounds of formula (I), (II) and (III) are useful in the treatment of tumours of the lung, breast and prostate.
  • the present invention provides a compound of formula (I), (II), (Ha), (III) or
  • the invention also provides a method of treating cancer which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (Ha), (III) or (Ilia), or a pharmaceutically acceptable salt thereof, as hereinbefore defined.
  • the invention still further provides a method of modulating polo-like kinase (PIk) activity which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (Ha), (III) or (Ilia), or a pharmaceutically acceptable salt thereof, as hereinbefore defined.
  • PIk polo-like kinase
  • the invention still further provides the use of a compound of formula (I), (II), (Ha), (III) or (Ilia), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
  • the invention still further provides the use of a compound of formula (I), (II), (Ha),
  • the compounds of formula (I), (II) and (III), and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I), (II), (Ha), (III) or (Ilia) compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99%w (per cent by weight), more preferably from 0.05 to 80%w, still more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50%w, of active ingredient, all percentages by weight being based on total composition.
  • the present invention also provides a pharmaceutical composition comprising a compound of formula (I), (II), (Ha), (III) or (Ilia), or a pharmaceutically acceptable salt thereof, as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), (II), (Ha), (III) or (Ilia), or a pharmaceutically acceptable salt thereof, as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally.
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate and anti oxidants such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate
  • granulating and disintegrating agents such as corn starch or algenic acid
  • binding agents such as starch
  • lubricating agents such as
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p- hydroxybenzoate, anti oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • preservatives such as ethyl or propyl p- hydroxybenzoate, anti oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil in water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally occurring gums such as gum acacia or gum tragacanth, naturally occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavouring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
  • compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non toxic parenterally acceptable diluent or solvent, for example a solution in 1,3 butanediol.
  • Suppository formulations may be prepared by mixing the active ingredient with a suitable non irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable excipients include, for example, cocoa butter and polyethylene glycols.
  • Topical formulations such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedure well known in the art.
  • Compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30 ⁇ or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose.
  • the powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50mg of active ingredient for use with a turbo inhaler device, such as is used for insufflation of the known agent sodium cromoglycate.
  • Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
  • a compound of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • a compound of the invention will be administered so that a daily dose in the range, for example, from 0.5 mg to 75 mg active ingredient per kg body weight is received, given if required in divided doses.
  • lower doses will be administered when a parenteral route is employed.
  • a dose in the range for example, from 0.5 mg to 30 mg active ingredient per kg body weight will generally be used.
  • a dose in the range for example, from 0.5 mg to 25 mg active ingredient per kg body weight will generally be used.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active ingredient.
  • the anti cancer treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti-tumour agents :- (i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5 fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin
  • cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5* -reductase such as finasteride;
  • antioestrogens for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene
  • antiandrogens for example
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6- chloro-2,3 -methylenedioxyanilino)-7- [2-(4-methylpiperazin- 1 -yl)ethoxy] -5-tetrahydropyran- 4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2- chloro-6-methylphenyl)-2- ⁇ 6-[4-(2-hydroxyethyl)piperazin-l-yl]-2-methylpyrimidin-4- ylamino ⁇ thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658- 6661), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase);
  • metalloproteinase inhibitors like marimastat
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti erbBl antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol.
  • inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3 -chloro-4-fluorophenyl)-7-methoxy-6-(3 -morpholinopropoxy)quinazolin-4-amme
  • tyrosine kinase inhibitors for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3 -chloro-4-fluorophenyl)-7-methoxy-6-(3 -morpholinopropoxy)quinazolin-4-amme
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti vascular endothelial cell growth factor antibody bevacizumab (AvastinTM) and VEGF receptor tyrosine kinase inhibitors such as 4- (4-bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene directed enzyme pro drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi drug resistance gene therapy;
  • immunotherapy approaches including for example ex vivo and in vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor, approaches to decrease T cell anergy, approaches using transfected immune cells such as cytokine transfected dendritic cells, approaches using cytokine transfected tumour cell lines and approaches using anti idiotypic antibodies; and
  • temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C;
  • chromatography means flash chromatography on silica gel;
  • SCX-2 cartridges are Ion Exchange SPE columns where the stationary phase is polymeric propylsulfonic acid. These are used to isolate amines.
  • chromatography in general, the course of reactions was followed by TLC or LCMS and reaction times are given for illustration only;
  • MS Mass spectra
  • HPLC component comprised generally either a Agilent 1100 or Waters Alliance HT (2790 & 2795) equipment and was run on a Phemonenex Gemini Cl 8 5mm, 50 x 2 mm column (or similar) eluting with either acidic eluent (for example, using a gradient between 0 - 95% water / acetonitrile with 5% of a 1% formic acid in 50:50 water :acetonitrile (v/v) mixture; or using an equivalent solvent system with methanol instead of acetonitrile), or basic eluent (for example, using a gradient between 0 - 95% water / acetonitrile with 5% of a 0.1% 880 Ammonia in acetonitrile mixture); and the MS component comprised generally a Waters ZQ mass spectrometer scanning over an appropriate mass range.
  • Example 1 4-[(2-Cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-10- yl)amino]-3-methoxy-iV-(l-methyl-4-piperidyl)benzainide
  • the reaction mixture was cooled to ambient temperature and loaded onto an SCX-2 column and then washed with MeOH (40 mL).
  • the crude compound was eluted from the SCX-2 column with NH 3 (40 mL, 7M in MeOH) and the volatiles removed under reduced pressure.
  • the crude material was then purified by column chromatography (SiO 2 , eluent gradient: 0-10% NH 3 [7M in MeOH] in DCM) then by preparative HPLC (Sunfire prep RPl 8, 19 x 100 mm column, eluting with a gradient composing of a 0.1% solution of TFA in H 2 O and a 0.1% solution of TFA in MeCN).
  • Example 5 The following examples were prepared by an analogous process to that used in the preparation of Example 5 utilising the appropriate pyrimidine derivative (Intermediates 10 - 13) as the electrophile and 4-amino-3-methoxy-iV-(l-methyl-4-piperidyl)benzamide (WO06/018220) as the aniline:
  • Example 12 is 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino] -3-methoxy-N- [2-(l-piperidyl)ethyl] benzamide
  • Example 12 The following examples were prepared by an analogous process to that used in the preparation of Example 12 utilising the acid described in Example 111 and the appropriate amines.
  • Example 26 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(3-imidazol-l-ylpropyl)-3-methoxy-benzamide
  • Example 31 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yI)amino]-N-(4-imidazol-l-ylbutyl)-3-methoxy-benzamide
  • Example 32 4-[(6-cycIopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)ethyl]benzamide
  • Example 12 The following examples were prepared by an analogous process to that used in the preparation of Example 12 utilising the acid described in Example 111 and the appropriate BOC- protected amines.
  • the reaction mixture Prior to SCX purification the reaction mixture was treated with 4N HCl in dioxane (1 mL) and stirred at room temperature for 24 hr. The reaction mixtures were absorbed onto SCX columns, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by preparative HPLC to give the title compounds
  • Example 42 N-(3-aminopropyl)-4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9-yl)amino]-3-methoxy-benzamide
  • Example 45 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-pyrrolidin-3-yl-benzamide
  • Example 48 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-2-fluoro-5-methoxy-N-(l-methyl-4-piperidyl)benzamide
  • the cooled reaction mixture was diluted with methanol and water (approx 50 mL) and loaded onto a 50 g SCX-2 cartridge washing with methanol (100 mL) and eluting with 7 N methanolic ammonia (100 mL).
  • the concentrated solution was purified by reversed phase HPLC. The title compound was obtained as a beige solid (178 mg, 45%).
  • Example 51 was prepared by an analogous process to that used in theo preparation of Example 51 utilising the acid described in Example 111 and the appropriate amines.
  • Example 52 s tert-butyl (3R)-3-[[4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10- tetrazabicycloJS ⁇ .Olundeca-SjlOjll-trien- ⁇ y ⁇ aminoj-S-methoxy- benzoyl]amino]pyrrolidine ⁇ l-carboxylate
  • reaction mixture was added to a 10 g SCX-2 column pre wet with MeOH (2 column volumes), flushed with MeOH (2 column volumes) then the crude product eluted with 2M ammonia in MeOH and solvents evaporated.
  • the residue was taken up in DCM and purified on silica eluting with a gradient of 0 - 10% 2M ammonia in MeOH / DCM then 10% 2M ammonia in MeOH / DCM.
  • Fractions containing product were combined and evaporated to a gum, ether was added and re-evaporated to give the title compound as a solid. (300 mg, 74%)
  • Example 56 was prepared by an analogous process to that used in the preparation of Example 56 utilising the BOC-protected material described in Example 54.
  • Example 57 N-[(lS,5R)-3-azabicyclo[3.1.0]hex-6-yl]-4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9-yl)amino]-3-methoxy-benzamide
  • Example 60 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(4-dimethylaminocyclohexyl)-3-methoxy-benzamide
  • Example 62 was prepared by an analogous process to that used in the preparation of Example 62 utilising the pyrrolidine analogue from Example 56
  • Example 63 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[(3S)-l-methylpyrrolidin-3-yl]benzamide
  • reaction mixture was stirred at room temperature for 30 mins and sodium triacetoxyborohydride (100 mg, 0.47 mmol) added and the reaction mixture stirred for a further 2 hrs.
  • the solvent was evaporated and the residue neutralised with sat. aq. sodium bicarbonate and extracted with DCM (15 mL), filtered through a PTFE cup and evaporated.
  • the resultant material was purified by reverse phase HPLC.
  • Example 65 Methyl (lS,3R)-3 ⁇ [4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9-yl)amino]-3-methoxy- benzoyl] amino] cy clopentane-1-carboxylate
  • Example 66 The following examples were prepared by an analogous process to that used in the preparation of Example 66, utilising the appropriate amines. NMR data was obtained on a selection of compounds as indicated.
  • Example 68 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3 ⁇ methoxy-N-(3-pyrrolidin-l-ylpropyl)benzamide
  • Example 72 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicycIo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-(l,2,2,6,6-pentamethyl-4-piperidyl)benzamide
  • Example 74 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-pyridin-3-yl-benzamide
  • Example 79 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[2-(l-methylpyrrolidin-2-yl)ethyl]benzamide
  • reaction mixture was loaded on to an SCX-3 column pre- wet with methanol.
  • the column was washed with methanol and then with 2% 7N ammonia/methanol to elute the crude product.
  • the product containing fractions were evaporated and the resultant material purified by reverse phase HPLC to give the title compound as a white solid (137mg, 40.8%).
  • Example 91 was prepared by an analogous process to that used in the preparation of Example 91 utilising Ammonium Chloride and 3 additional equivalents of DIPEA and5 collecting the product as a solid precipitated from the work-up procedure with DCM and saturated aqueous Sodium Bicarbonate solution.
  • H NMR 400.132 MHz, DMSOd 6 ) ⁇ l.73 (m, 6H), 2.00 (m, 2H), 2.64 (m, 2H), 3.23 (s, 3H), 3.68 (m, 2H), 3.99 (s, 3H), 4.86 (m, IH), 7.22 (s, IH), 7.57 (m, 2H), 7.78 (s, IH), 7.92 (s, IH), 8.13 (s, IH), 8.44 (d, IH); MS m/z 411 [M+H]+.
  • Example 66 The following examples were prepared by an analogous process to that used in the preparation of Example 66, utilising the appropriate amines. NMR data was obtained on compounds when indicated.
  • Example 93 io 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3 ⁇ methoxy-N-propyl-benzamide
  • 4-amino-N-cyclohexyl-benzamide (TimTec, 108 mg, 0.5 mmol), 10-Chloro-2-cyclopentyl-6- methyl-2,6,9,l l-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 1, lOOmg, 0.36 mmol), the 4-aminobenzamide (Aldrich, 59 mg, 0.43 mmol) and p-toluenesulphonic acid (137 mg, 0.72 mmol) were heated together in 4-methyl-2-pentanol (4ml) at 120 0 C for 22 hours.
  • Example 66 was prepared by an analogous process to that used in the preparation of Example 66 utilising the appropriate amine.
  • Example 100 4-[(6-cycIopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-propan-2-yl-benzamide 10-Chloro-2-cyclopentyl-6-methyl-2 5 6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1, 134mg, 0.48mmol), 4-amino-N-propan-2-yl-benzamide (Butt Park, 86 mg, 0.48 mmol) and p-toluenesulphonic acid monohydrate (227 mg, 1.19 mmol) in 4-methyl-2- pentanol (4 niL) were heated at 14O 0 C for 2h.
  • Example 103 6-cyclopentyl-9-[[2-methoxy-4-(2-pyrrolidin-l-ylethylamino)phenyl]amino]-2-methyl- 2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
  • reaction mixture was absorbed onto an SCX column, washed with methanol and eluted with ammonia in methanol.
  • Product containing fractions were concentrated and the material produced was purified by normal phase chromatography usingo 0-10% amrnoma/methanol to yield the title compound as a solid (100 mg, 42 %).
  • Example 104 The following examples were prepared by an analogous process to that used in the preparation of Example 103, utilising the appropriate aniline. NMR data is recorded where obtained. o Example 104:
  • Example 105 5 6-cyclopentyl-9-[[2-methoxy-4-[4-(2-methoxyethyl)piperazin-l-yl]phenyl]amino]-2- methyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
  • Example 113 were prepared by an analogous process to that used in the preparation of Example 113 utilising the appropriate aniline indicated.
  • Example 115 0 6-cyclopentyl-9-[[2-methoxy-4-(2-morpholin-4-ylethoxy)phenyl]amino]-2-methyl- 2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
  • Tris(dibenzylideneacetone) palladium (II) 28 mg, 0.03 mmol was added and the apparatus was evacuated and backfilled with nitrogen (x3) and then heated at 100°C for 8 h. The mixture was cooled, filtered and the
  • Example 118 The following example was prepared by an analogous process to that used in the preparation of Example 117 utilising the appropriate aniline available from Aldrich.
  • Example 118 Example 118:
  • Example 119 were prepared by an analogous process to that used in the 5 preparation of Example 119 utilising the appropriate substituted anilines. NMR analysis was undertaken where indicated.
  • Example 120 0 6-cyclopentyl-9-[(4-methoxyphenyl)amino]-2-methyl-2,6,8,10- tetrazabicyclo [5.4.0] undeca-8,10,12-trien-3-one 1 H NMR (400.132 MHz, DMSO-d ⁇ ) ⁇ 1.62 (m, 6H), 1.92 (m, 2H), 2.55 (m, 2H), 3.16 (s, 3H), 3.59 (m, 2H), 3.60 (s, 2H), 3.72 (s, 3H), 4.76 (m, IH), 6.83 (d, 2H), 7.59 (d, 2H), 8.00 (s, IH), 8.93 (s, IH)
  • Example 127 6-cyclopentyl-2-methyl-9-[(4-methylsulfonylphenyl)amino] -2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
  • Example 129 was prepared by an analogous process to that used in the preparation of Example 129 utilising the appropriate substituted anilines available as indicated.
  • N-[(4-aminophenyl)methyl]pyridine-2-carboxamide (Intermediate 49: 114mg, 0.5mmol), 10- Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1, 141 mg, 0.5 mmol) and p-toluenesulphonic acid monohydrate (239 mg, 1.25 mmol) were heated in 4-methyl-2-pentanol (3 mL) at 140°C for 2hours.
  • Example 134 The following examples were prepared by an analogous process to that used in the preparation of Example 133 utilising the appropriate substituted anilines available from ABCR Example 134:
  • Example 136 tert-butyl N-[[3-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-
  • Tris(dibenzylideneacetone) palladium (II) 28 mg, 0.03 mmol was added and the apparatus was evacuated and backfilled with nitrogen (x3) and then heated at 100 0 C for 8h. The mixture was cooled, filtered and the filtrate absorbed onto an SCX-3 column, washed with methanol and the product eluted with ammonia in methanol. Product containing fractionso were concentrated and purified by normal phase chromatography (1% methanol/DCM) to give the title compound as a white solid (57 mg, 24 %).
  • Example 136 was prepared by an analogous process to that used in the preparation of Example 136 utilising the appropriate substituted aniline available from Flurochem.
  • N-[2-(3-ammo-4-methoxy-phenyl)ethyi]acetamide (Compound 4- Organic Process Research 20 & Development 2004, 8, 628-642, 108 mg, 0.5 mmol), lO-Chloro ⁇ -cyclopentyl- ⁇ -methyl- 2,6,9,1 l-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 1, 140 mg, 0.5 mmol) and p-toluenesulphonic acid monohydrate (238 mg, 1.25 mmol) were heated at 140°C in 4- methyl-2-pentanol (3 niL) for 3 hours. The mixture was allowed to cool causing a solid to form.
  • Example 139 The following examples were prepared by an analogous process to that used in the preparation of Example 139, utilising the appropriate substituted anilines available as indicated.
  • Example 144 9-[(2-benzoylphenyl)amino]-6-cyclopentyl-2-methyl-2,6,8,10 ⁇ tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
  • Example 149 6-cyclopentyl-2-methyl-9-[(2-methylsulfonylphenyl)amino]-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
  • Example 154 2-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10 ? 12-trien-9- yl)amino]-N-ethyl-benzenesulfonamide
  • Example 158 6-cyclopentyl-2-methyl-9-[(2-pyrrol-l-ylphenyl)amino]-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
  • Example 159 6-cyclopentyl-2-methyl-9-[[2-(4-methylphenoxy)phenyl]amino]-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
  • Example 162 Q 6-cyclopentyl-9-[(3-ethoxyphenyl)amino]-2-methyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-3-one
  • Example 163 6-cyclopentyl-2-methyl-9-[(3-methyIsulfanylphenyl)amino]-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
  • Example 173 6-cyclopentyl-9-[[3-(hydroxymethyl)phenyl]amino]-2-methyl-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
  • Example 176 N-[3-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien- 9-yl)amino]-4-methoxy-phenyl]acetamide
  • Example 181 3-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-4-methoxy-N-(l-methyl-4-piperidyl)benzamide
  • Example 184 was prepared by an analogous process to that used in the preparation of Example 184 utilising 4-amino-3-chloro-N-(l-methyl-4-piperidyl)benzamide Intermediate is 55.
  • Example 187 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-2,6-difluoro-N-(l-methyl-4-piperidyl)benzamide
  • Example 188 was prepared by an analogous process to that used in the preparation of Example 188 utilising 4-amino-2-fluoro-N-(l-methyl-4-piperidyl)benzamide Intermediate 61.
  • Example 190 methyl 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12- trien-9-yl)amino]-3-hydroxy-benzoate
  • Example 191 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(2-morpholin-4-ylethyl)benzamide
  • Example 193 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methyI-N-(l-methyl-4-piperidyl)benzamide
  • Example 195 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-(2-methoxyethoxy)-N-(l-methyl-4-piperidyl)benzamide
  • Example 195 was prepared by an analogous process to that used in the preparation of Example 195 utilising a 2.0M methylamine solution in THF
  • Example 196 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-(2-methoxyethoxy)-N-methyl-benzamide
  • the resultant solution was treated with a few drops of 2M HCl (aq.) so as 5 to adjust pH to 2-3.
  • the aqueous solution was evaporated to dryness to give the carboxylic acid as a pale yellow gum, which was dissolved in DMF (1 mL) and treated with DIPEA (25 ⁇ L, 0.14 mmol) and HATU (40 mg. 0.11 mmol). Cyclohexylamine (11 ⁇ L, 0.10 mmol) was added and reaction mixture left to stir, at ambient temperature, overnight.
  • Example 200 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-ethoxy-N-(l-methyl-4-piperidyl)benzamide
  • Example 200 was prepared by an analogous process to that used in the preparation of Example 200 utilising the appropriate amines available from Aldrich
  • Example 204 3-methoxy-4-[(2-methyl-3-oxo-6-propan-2-yl-2,6,8,10-tetrazabicyclo[5.4.0]undeca- 7,9,ll-trien-9-yl)amino]benzoic acid
  • reaction mixture was loaded onto a SCX-3 column pre-wet with Methanol and the column washed with Methanol.
  • the column was eluted with Ammonia in Methanol and produict containing fractions evaporated.
  • the resultant material was dissolved in dichloromethane and chromatographed with 2-5-10-20% methanol/dichloromethane followed by 7N ammonia/methanol. Evaporation of product containing fractions gave a0 yellow foam foam which was purified by reverse phase HPLC to yield the title compound as an off white gum (75 mg, 46 %)
  • Example 205 The following examples were prepared by an analogous process to that used in the preparation of Example 205 utilising the appropriate amines available from Aldrich or Matrix
  • Example 206 0 N-(l-azabicyclo[2.2.2]oct-8-yl)-3-methoxy-4-[(2-methyl-3-oxo-6-propan-2-yl-2,6,8,10- tetrazabicyclo [5.4.0]undeca-7,9,l l-trien-9-yl)amino] benzamide
  • Example 207 0 N-(l-azabicyclo[2.2.2]oct-8-yl)-3-methoxy-4-[(2-methyl-3-oxo-6-propan-2-yl-2,6,8,10- tetrazabicyclo [5.4.0]undeca-7,9,l l-trien-9-yl)amino] benzamide
  • Example 207 0 N-(l-azabicyclo[2.2.2]oct-8-yl)-3-methoxy-4-[(2-methyl-3-oxo-6-propan-2-yl-2,6,8,10- tetrazabicyclo
  • reaction mixture was allowed to cool to room temperature and loaded onto a 10 g SCX-2 cartridge, washing with methanol (10 mL), water (10 mL) and methanol (10 mL) before the product was eluted off with 7 N methanolic ammonia which on evaporation of product containing fractions provided a brown oil which was purified by flash silica chromatography (Companion, 40 g, 0-10% methanolic ammonia/DCM) to give a pale yellow glass which was further purified by reverse phase HPLC to yield the title compound as a white solid (192 mg, 49 %).
  • flash silica chromatography Companion, 40 g, 0-10% methanolic ammonia/DCM
  • reaction mixture was diluted with methanol (5 mL) and water (2 mL) and resultant solution poured onto an SCX-3 cartridge (2 g).
  • the cartridge was washed with methanol ( ⁇ 30 mL) before eluting products with 2M ammonia methanol ( ⁇ 20 mL).
  • the Ammoniacal fraction was evaporated to give an amber gum which was purified by reverse phase HPLC to yield the title compound as a colourless glass (scratches down to a white solid) (80 mg, 75 %).
  • Example 212A 4-[(6-butan-2-yl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-9- yl)amino]-3-methoxy-N-(l-methyl-4-piperidyl)benzamide Chloropyrimidine used - 2-butan-2-yl-10-chloro-6-methyl-2,6,9,l 1- tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one Intermediate 87
  • Chloropyrimidine used 10-chloro-2-cyclobutyl-6-methyl-2,6,9,ll- tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one Intermediate 90
  • Chloropyrimidine used 10-chloro-2-(cyclopropylmethyl)-6-methyl-2,6,9,l 1- tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one Intermediate 93
  • reaction mixture was dissolved in methanol (5 mL) and water ( ⁇ 5 mL) and poured directly onto an SCX-3 cartridge (2 g). The cartridge was washed through with methanol ( ⁇ 30 mL), before elution of products with 2M ammonia in methanol ( ⁇ 30 mL).
  • Example 215 s 4-[(6-benzyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-(l-methyl-4-piperidyl)benzamide
  • Chloropyrimidine used 10-chloro-2-(cyclobutylmethyl)-6-methyl-2,6,9,ll-s tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5-one (Intermediate 102)
  • Example 218 4-[(2-methyl-3-oxo-6-propan-2-yl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-9- yl)amino]-N-(2-morpholin-4-ylethyl)benzamide

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Abstract

There is provided a compound of formula (I):processes for the manufacure thereof, pharmaceutical compoitions thereof and uses in therapy.

Description

NOVEL COMPOUNDS
The present invention relates to pyrirnidine derivatives, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy and the treating of conditions mediated by polo-like kinases.
Many of the current treatment regimes for cell proliferation diseases such as cancer and psoriasis utilise compounds that inhibit DNA synthesis. Compounds that inhibit DNA synthesis may often prove to be toxic to many types of cells. However, the marked toxic effect on rapidly dividing cells such as tumour cells is often seen to offer a benefit in light of the general toxic nature of such compounds. Therefore, alternative antiproliferative agents that act by mechanisms other than the inhibition of DNA synthesis may offer the potential for selective targeting of the proliferating cells.
The Cyclin dependent kinase family (Cdks) have long been considered the master regulators of the cell cycle but an increasing number of diverse protein kinases are emerging as critical components of cell cycle progression. Among these are the polo-like kinase family (Plks), serine/threonine kinases that play multiple roles in regulating progress through cell cycle. In man, four distinct family members have been identified. These are Plkl, Plk2 (Snk), Plk3 (Fnk, Prk) and Plk4 (Sak). The best characterized family member is Plkl which is conserved from yeast to man and has been implicated in numerous mitotic processes including activation of Cdc25C and Cdkl/Cyclin B at the G2-M transition, centrosome maturation, spindle formation and assembly (Glover et al. 1998, Genes Dev. 12:3777-87; Barr et al 2004, Nat. Rev. MoI. Cell Biol 5:429-441). In the later stages of mitosis Plkl is involved in separation of sister chromatids, activation of components of the anaphase-promoting complex and septin regulation during cytokinesis (van Vugt & Medema 2005, Oncogene 24:2844-2859).
Plkl is overexpressed in a broad spectrum of cancer types including breast, colorectal, endometrial, oesophageal, ovarian, prostate, pancreatic, non small cell lung cancers and melanomas (Wolf et al. 1997, Oncogene 14:543-549; Knecht et al. 1999, Cancer Res. 59:2794-2797; Wolf et al. 2000, Pathol. Res. Pract 196:753-759; Takahashi et al. 2003, Cancer Sci. 94:148-152). The expression of Plkl often correlates with poor patient prognosis. The conclusion that PIk 1 elevation is a cause and not a consequence of oncogenesis resulted from a study demonstrating that overexpression or constitutive expression of Plkl induces malignant transformation of mammalian cells, causing tumour formation in nude mice (Smith et al 1997, Biochem. Biophys. Res. Commun 234:397-405) Therapeutic potential for Plkl inhibition has been demonstrated in studies employing both antisense oligonucleotides (ASO) and small molecule RNA (siRNA). Reduction in the level of Plkl results in the inhibition of proliferation of tumour cells and loss of cell viability both in vivo and in vitro but does not inhibit proliferation of primary cells (Spankuch-Schmitt et al 2002, Oncogene 21: 3162-3171; Elez et al 2003, Oncogene 22:69-80). Microinjection of anti-Plkl antibodies induced mitotic catastrophe in HeLa tumour cells. These cells displayed abnormal distribution of chromatin and monoastral microtubules while normal fibroblast cells arrested transiently in G2 phase of cell cycle as single mononucleated cells (Lane & Nigg 1996 J.Cell Biol. 135:1701-1713). These results suggest that Plkl inhibition specifically targets cancer cells with checkpoint defects while cells with intact checkpoint pathways are less affected.
Although the exact functions of the other family members remains largely unknown, silencing of Plk2 in the presence of taxol or nocodazole significantly increases apoptosis suggesting Plk2 may prevent mitotic catastrophe following spindle damage (Burns et al. 2003, MoI Cell Biol 23: 5556-5571). Likewise silencing of Plk4 in mammalian cells induces apoptosis (Li et al. 2005, Neoplasia 7: 312-323) and plk4 null mouse embryos arrest with an increase in mitotic and apoptotic cells (Hudson et al. 2001, Curr Biol 11 : 441-446).
Plk3 also appears to play roles in mitosis, like Plkl it has been reported to phosphorylate Cdc25C, regulate microtubule dynamics and is involved in centrosome function. Overexpression of Plk3 has been observed in both breast and ovarian carcinomas, with little or no expression in adjacent normal tissue. Increased protein level was associated with enhanced mitosis and was significantly linked to reduced median survival time of patients (Weichert et al. 2005, Virchows Arch 446: 442-450; Weichert et al. 2004 Br. J.Cancer 90:815-821).
These findings suggest that pharmacological inhibitors of PIk family members should be of therapeutic value for treatment of proliferative disease including solid tumours such as carcinomas and sarcomas and the leukaemias and lymphoid malignancies. In addition PIk inhibitors should be useful in the treatment of other disorders associated with uncontrolled cellular proliferation.
Pteridinone derivatives are known from the prior art as active substances with an antiproliferative activity. WO 01/019825 and WO 03/020722 describe the use of pteridinone derivatives for the treatment of tumoural diseases.
The resistance of many types of tumours calls for the development of new pharmaceutical compositions for combating tumours.
The aim of the present invention is to provide new compounds having an antiproliferative activity. According to a first aspect of the present invention there is provided a compound of formula (I):
Figure imgf000004_0001
wherein
R3 represents hydrogen, an optionally substituted C1.12alk.yl group, an optionally substituted C2-i2alkenyl group, an optionally substituted C2-i2alkynyl group, an optionally substituted C6-i4aryl group, an optionally substituted C3-12cycloalkyl group, an optionally substituted C3-i2cycloalkenyl group, an optionally substituted C7-12polycycloalkyl group, an optionally substituted C7_i2polycycloalkenyl group, an optionally substituted C5_i2spirocycloalkyl group, an optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, an optionally substituted 4- to 12-membered heterocycloalkenyl group comprising 1 or 2 heteroatoms, or an optionally substituted heteroaryl ring comprising 1, 2 or 3 heteroatoms each independently selected from nitrogen, oxygen or sulphur; R4 each independently represent -CN, hydroxy, -NR6R7, -NR6SO2R7, halogen, an optionally substituted C1-6alkyl group, an optionally substituted C3-7Cy cloalkyl group, an optionally substituted C2-6alkenyl group, an optionally substituted C2-6alkynyl group, an optionally substituted C1-5alkyloxy group, an optionally substituted C3-6cycloalkyloxy group, an optionally substituted C2-5alkenyloxy group, an optionally substituted C2-5alkynyloxy group, an optionally substituted C1-6alkythio group, an optionally substituted C1-6alkylsulphoxo group or an optionally substituted C1-6alkylsulphonyl group, an optionally substituted 3- to 12-membered heterocy cloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 3- to 12-membered heterocycloalkoxy group comprising 1 or 2 heteroatoms; RN represents hydrogen, -NH2, -OH, -CN, -C=CH, -C(=O)NH2, C^alkyl, C-1-3alkylamino, C^alkylthio, C1-3alkyloxy, C1-3alkylcarbonyl, -CHO, or -SO2Me p is 0, 1 or 2;
Q is -C(=X1)-NRaRb, -S(O)2-NRa2Rb2, -(optionally substituted C1-3alkyl)g-NRa3Rb3, -S(O)k-Ra8, -C(=X2)-ORa9, -ORal° or -(5- or 6-membered aromatic or heteroaromatic ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur)-Ln-R5 m; g is 0 or 1 ; k is 0, 1 or 2;
Ra represents H or an optionally substituted C^alkyl group, and Rb represents -Ln-R5 m, or Ra and Rb together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
Ra2 represents H or an optionally substituted C1-6alkyl group, and Rb2 represents -Ln-R5Hi, or Ra2 and Rb2 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms; Ra3 represents H or an optionally substituted C1-6alkyl group, and Rb3 represents
-Ln-R5 m, -SO2NRa4Rb4, -C(=O)NRa5Rb5, -SO2Ra6, -C(=O)ORa7, or Ra3 and Rb3 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms; Ra4 represents H or an optionally substituted C1-6alkyl group, and Rb4 represents -Ln-R5 m5 or Ra4 and Rb together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
Ra5 represents H or an optionally substituted C1-6alkyl group, and R 5 represents -Ln-R5 m, or Ra5 and Rb5 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
Ra6 represents -Ln-R5 m;
R >a7 . represents -Ln-R m; Ra8 represents -Ln-R5 m;
R > ϋa9 „ re„„p„re_ „se „„n+t„s - TLn- τR> 5 . Ral° represents -Ln-R5 5
L represents a linker selected from optionally substituted C2-10alkyl, optionally substituted C2-10alkenyl, optionally substituted C6.14aryl, optionally substituted -C2-4alkyl-C6-14aryl, optionally substituted -C^Haryl-C^alkyl, optionally substituted C3.12cycloalkyl, optionally substituted C7-12polycycloalkyl group, optionally substituted C7-12ρolycycloalkenyl group, optionally substituted Cs.nspirocycloalkyl group and optionally substituted heteroaryl comprising 1 or 2 nitrogen atoms; n is 0 or 1 m is 1 or 2 R5 represents a group selected from among hydrogen, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted piperazinylcarbonyl, optionally substituted pyrrolidinyl, optionally substituted tropenyl, optionally substituted diketomethylpiperazinyl, optionally substituted sulphoxomorpholinyl, optionally substituted sulphonylmorpholinyl, optionally substituted thiomorpholinyl, optionally substituted azacycloheptyl, optionally substituted granatane, optionally substituted oxogranatane and -NR8R9; R6, R7 each independently represents hydrogen or an optionally substituted C1-4alkyl group;
R8, R9 each independently represents hydrogen, optionally substituted Ci-6alkyl, optionally substituted -C1-4alkyl-C3-10cycloalkyl, optionally substituted C3-10cycloalkyl, optionally substituted C6-14aryl, optionally substituted
-C1-4alkyl-C6-14aryl, optionally substituted pyranyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted C1-4alkyloxycarbonyl, optionally substituted optionally substituted C6-14arylcarbonyl, optionally substituted C1-4alkylcarbonyl, optionally substituted C6-14arylmethyloxycarbonyl, optionally substituted C6-14arylsulphonyl, optionally substituted C1-4alkylsulphonyl, optionally substituted C6-14aryl-C1-4alkylsulphonyl, or R and R together with the nitrogen atom to which they are attached form a 3- to 7-membered bridged or unbridged, saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms; X1 is O or S; X2 is O, S or H2;
Ar represents a 5- or 6-membered aromatic or heteroaromatic ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur; and
A1, A2 each independently represents N or CH; and wherein when Z1 is C=O, Z2 is CRcRd or NRe and Z3 is CR1R2;
R1, R2 each independently represents hydrogen, an optionally substituted C^alkyl group or an optionally substituted C3-6cycloalkyl group, or R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
Rc, Rd each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or Rc and Rd together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms; Re represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cy cloalkyl group; or optionally one of R1 and R3, or R2 and R3, or R1 and Rc, or R2 and Rd, or R1 and Re together represent a saturated or unsaturated C1-4alkyl bridge optionally comprising 1 heteroatom; or when Z2 is C=O, Z1 is CRβRg2 and Z3 is CR1R2; R1, R2 each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
Rβ, Rg2 each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or RG and Rg2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms; or optionally one of R1 and R3, or R2 and R3 together represent a saturated or unsaturated
C1-4alkyl bridge optionally comprising 1 heteroatom; or when Z3 is C=O, Z2 is CRc3Rd3 or NRe3 and Z1 is CR°Rg3;
Rc3, Rd3 each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or Rc3 and Rd3 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms; Re3 represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group;
Rβ, Rg3 each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or RΩ and Rg3 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms; or optionally one of Rc3 and Rβ, or Rd3 and Rg3, or Re3 and RΩ together represent a saturated or unsaturated C1-4alkyl bridge optionally comprising 1 heteroatom or when Z1 is CRfRg, Z2 is CRcRd or NRe and Z3 is CR1R2;
R1, R2 each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
Rc, Rd each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or R° and Rd together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
Re represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group;
Rf, R8 each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or Rf and Rg together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms; or optionally one of R1 and R3, or R2 and R3, or R1 and Rc, or R2 and Rd, or R1 and Re3 together represent a saturated or unsaturated C1-4alkyl bridge optionally comprising 1 heteroatom, or pharmacologically acceptable salts thereof.
The term alkyl group, including alkyl groups which are a part of other groups, unless otherwise stated, includes branched and unbranched alkyl groups with 1 to 12 carbon atoms. Examples of C1-12alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and dodecyl groups. Unless otherwise stated, the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and dodecyl include all the possible isomeric forms. For example, the term propyl includes the two isomeric groups n-propyl and iso-propyl, the term butyl includes n-butyl, iso-butyl, sec-butyl and tert-butyl, the term pentyl includes iso- pentyl, neopentyl, etc. In the above mentioned alkyl groups, one or more hydrogen atoms may optionally be replaced by other substituent groups. For example, alkyl groups may be substituted by the following substituents groups: =0; OH; NO2; CN; -NH2; halogen, for example fluorine or chlorine; optionally substituted d-ioalkyl, for example methyl, ethyl, propyl, trifluoromethyl; optionally substituted -OC1-3alkyl, for example OMe, OEt, -OCHF2, -OCF3; -COOH; -COO-C1-4alkyl, for example -COOMe or -COOEt; or -CONH2. ' -O" denotes an oxygen atom linked via a double bond. All the hydrogen atoms of the alkyl group may optionally be replaced by substituent groups, for example a trifluoromethyl group is a methyl group wherein all the hydrogen atoms have been replaced with fluorine atoms.
The term alkyl bridge, unless otherwise stated, includes branched and unbranched alkyl bridging groups with 1 to 5 carbon atoms, for example methylene, ethylene, propylene, butylene and pentylene bridges. Unless otherwise stated, the terms propylene, butylene and pentylene include all the possible isomeric forms. In the aforementioned alkyl bridges, 1 or 2 C-atoms may optionally be replaced by one or more heteroatoms selected from among oxygen, nitrogen or sulphur.
The term alkenyl groups (including those which are a part of other groups), unless otherwise stated, includes branched and unbranched alkylene groups with 2 to 10 carbon atoms comprising at least one carbon-carbon double bond. Examples of C2-iOalkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl nonenyl and decenyl groups. Unless otherwise stated, the abovementioned terms propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl and decenyl also include all the possible isomeric forms. For example, the term butenyl includes 1 -butenyl, 2-butenyl, 3 -butenyl, 1 -methyl- 1 -propenyl, 1-methy 1-2 -propenyl, 2-methyl-l -propenyl, 2-methyl-2-propenyl and 1 -ethyl- 1 -ethenyl.
In the above mentioned alkenyl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced by other substituent groups. For example, alkenyl groups may be substituted by the following substituents groups: =0; OH; NO2; CN; -NH2; halogen, for example fluorine or chlorine; optionally substituted C1-10alkyl, for example methyl, ethyl, propyl, trifluoromethyl; optionally substituted -OC1-3alkyl, for example OMe, OEt, -OCHF2, -OCF3; -COOH; -COO-C 1-4alkyl, for example -COOMe or -COOEt; or -CONH2. "=0" denotes an oxygen atom linked via a double bond. All the hydrogen atoms of the alkenyl group may optionally be replaced, for example a trifluoroethylene group is an ethylene group wherein all the hydrogen atoms have been replaced with fluorine atoms.
The term alkynyl groups (including those which are a part of other groups), unless otherwise stated, includes branched and unbranched alkynyl groups with 2 to 10 carbon atoms comprising at least one triple bond. Examples of C2-10alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl groups. Unless otherwise stated, the terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl also include all the possible isomeric forms. For example, the term butynyl includes 1 -butynyl, 2-butynyl, 3 -butynyl and l-methyl-2-propynyl.
In the above mentioned alkynyl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced by other substituent groups. For example, alkynyl groups may be substituted by the following substituents groups: =0; OH; NO2; CN; -NH2; halogen, for example fluorine or chlorine; optionally substituted C1-10alkyl, for example methyl, ethyl, propyl, trifluoromethyl; optionally substituted -OC1-3alkyl, for example OMe, OEt, -OCHF2, -OCF3; -COOH; -COO-C 1-4alkyl, for example -COOMe or -COOEt; or -CONH2. "=O" denotes an oxygen atom linked via a double bond. AU the hydrogen atoms of the alkynyl group may optionally also be replaced.
The term aryl includes aromatic ring systems with 6 to 14 carbon atoms, said aromatic ring systems comprising one or more rings having from 6 to 14 ring atoms wherein at least one ring is aromatic. Examples of C6-14aryl groups include phenyl (C6), indenyl (Cg), naphthyl (C1O), fluorenyl (C13), anthracyl (C14), and phenanthryl (C14). In the above mentioned aryl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced by other substitutent groups. For example, aryl groups may be substituted by the following substituents groups: OH; NO2; CN; NH2; halogen, for example fluorine or chlorine; optionally substituted C1-10alkyl, for example methyl, ethyl, propyl or CF3; optionally substituted -OC1-3alkyl, for example -OMe, -OEt, OCHF2, or OCF3; -COOH, -COO-C1-4alkyl, for example -COOMe or -COOEt, or -CONH2.
The term heteroaryl comprising 1 or 2 nitrogen atoms includes heteroaromatic ring systems with 5 to 14 ring atoms, said heteroaromatic ring systems comprising one or more rings having from 5 to 14 ring atoms wherein at least one ring is aromatic and wherein one or two of the ring atoms are replaced by nitrogen atoms the remaining ring atoms being carbon atoms. Examples of heteroaryl groups wherein up to two carbon atoms are replaced by one or two nitrogen atoms comprising one ring include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl and pyrimidinyl groups. Each of the aforementioned examples of heteroaryl rings may optionally also be anellated by a further ring, for example a benzene ring. Examples of heteroaryl groups wherein up to two carbon atoms are replaced by one or two nitrogen atoms comprising two rings include indolyl, benzimidazolyl, quinolinyl, isoquinolinyl and quinazolinyl. In the above mentioned heteroaryl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced by other substituent groups. For example, heteroaryl groups may be substituted by the following substituents groups: F; Cl; Br; OH; OMe; Me; Et; CN; NH2; CONH2; optionally substituted phenyl; and optionally substituted heteroaryl, for example optionally substituted pyridyl. The term optionally substituted heteroaryl ring comprising 1, 2 or 3 heteroatoms each independently selected from nitrogen, oxygen or sulphur includes heteroaromatic ring systems with 5 to 14 ring atoms, said heteroaromatic ring systems comprising one or more rings having from 5 to 14 ring atoms wherein at least one ring is aromatic and wherein one, two or three of the ring atoms are replaced by nitrogen, oxygen or sulphur atoms the remaining ring atoms being carbon atoms. Examples of heteroaryl rings wherein up to three carbon atoms are replaced by nitrogen, oxygen or sulphur comprising one ring include furyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl and triazolyl groups. Each of the aforementioned examples of heteroaryl rings may optionally also be anellated by a further ring, for example a benzene ring. Examples of heteroaryl rings wherein up to three carbon atoms are replaced by nitrogen, oxygen or sulphur atoms comprising two rings include indolyl, benzimidazolyl, benzoxazoyl, benzioxazoyl, quinolinyl, isoquinolinyl and quinazolinyl. In the above mentioned heteroaryl rings, unless otherwise stated, one or more hydrogen atoms may optionally be replaced by other substituent groups. For example, heteroaryl groups may be substituted by the following substituents groups: F; Cl; Br; OH; OMe; Me; Et; CN; NH2; CONH2; optionally substituted phenyl; and optionally substituted heteroaryl, for example optionally substituted pyridyl.
The term cycloalkyl groups, unless otherwise stated, includes cycloalkyl groups comprising 1 ring with 3-12 carbon atoms. Examples of C3-12cycoalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl groups. In the abovementioned cycloalkyl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced by other substituent groups. For example, cycloalkyl groups may be substituted by the following substituents groups: =0; OH; NO2; CN; -NH2; halogen, for example fluorine or chlorine; optionally substituted C1-10alkyl, for example methyl, ethyl, propyl, trifluoromethyl; optionally substituted -OC1-3alkyl, for example OMe, OEt, -OCHF2, -OCF3; -COOH; -COO-C1-4alkyl, for example -COOMe or -COOEt; or -CONH2. "=O" denotes an oxygen atom linked via a double bond.
The term cycloalkenyl, unless otherwise stated, includes cycloalkenyl groups with 3- 12 carbon atoms comprising one ring, said ring comprising at least one carbon-carbon double bond. Examples of C3-12cycloakenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, cycloundecenyl and cyclododecenyl groups. In the abovementioned cycloalkenyl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced by other substituent groups. For example, cycloalkenyl groups may be substituted by the following substituent groups: =0; OH; NO2; CN; -NH2; halogen, for example fluorine or chlorine; optionally substituted C1-10alkyl, for example methyl, ethyl, propyl, trifluoromethyl; optionally substituted -OC1-3alkyl, for example OMe, OEt, -OCHF2, -OCF3; -COOH; -COO-C1-4alkyl, for example -COOMe or -COOEt; or -CONH2. "=0" denotes an oxygen atom linked via a double bond. The terms heterocycloalkyl and heterocycloakenyl, unless otherwise described in the definitions, includes 3- to 12-membered, for example 5-, 6- or 7-membered, heterocycles which may contain 1 to 4 heteroatoms selected from nitrogen, oxygen or sulphur. Heterocycloalkyl denotes a saturated heterocycle, and heterocycloakenyl denotes an unsaturated heterocycle. Examples of heterocycloalkyl or heterocycloakenyl groups include tetrahydrofuran, tetrahydrofuranone, gαrø/røα-butyrolactone, alpha-pyvan, gαmmα-pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, thiolan, dithiolan, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrazole, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepan, oxazine, tetrahydro-oxazinyl, isothiazole, and pyrazolidine. In the abovementioned heterocycloalkyl or heterocycloakenyl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced by other substituent groups. For example, heterocycloalkyl or heterocycloakenyl groups may be substituted by the following substituents groups: =0; OH; CN; -NH2; halogen, for example fluorine or chlorine; optionally substituted C1-4alkyl, for example methyl, ethyl, propyl, trifluoromethyl; optionally substituted -OC1-3alkyl, for example OMe, OEt, -OCHF2, -OCF3; -COOH; -COO-C1-4alkyl, for example -COOMe or -COOEt; or -CONH2. "=0" denotes an oxygen atom linked via a double bond. The term polycycloalkyl, unless otherwise stated, includes cycloalkyl groups comprising 3 to 12 carbon atoms and comprising 2 or more rings. Examples of polycycloalkyl groups include optionally substituted, bi-, tri-, tetra- or pentacyclic cycloalkyl groups, for example pinane, 2,2,2-octane, 2,2,1 -heptane or adamantane. The term polycycloalkenyl, unless otherwise stated, includes cycloalkenyl groups comprising 7 to 12 carbon atoms and comprising 2 or more rings wherein at least one ring comprises a carbon-carbon double bond. Examples of polycycloalkenyl groups are optionally bridged and/or substituted bi-, tri-, tetra- or pentacyclic cycloalkenyl groups, for example bicycloalkenyl or tricycloalkenyl groups having at least one double bond, such as norbornene. The term spirocycloalkyl unless otherwise stated, includes spirocycloalkyl groups comprising 5 to 12 carbon atoms and comprising 2 or more rings wherein two rings are joined at a spiro carbon centre. Examples of spirocycloalkyl groups include spiro[4.4]nonyl and spiro[3.4]octyl.
The term 5- or 6-membered aromatic or heteroaromatic ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur is a fully unsaturated, aromatic monocyclic ring containing 5 or 6 atoms of which one or more ring atoms is optionally a heteroatom selected from nitrogen, oxygen or sulphur, with the remaining ring atoms being carbon. Examples of a 5- or 6-membered aromatic or heteroaromatic ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur include furyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl thiazolyl, thienyl and triazolyl rings.
The term 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms includes optionally substituted C3-6cylcoalkyl and optionally substituted C3-6cylcoalkenyl groups, and optionally substituted 3- to 6-membered heterocylcoalkyl and optionally substituted 3- to 6-membered heterocylcoalkenyl groups each with 1 or 2 heteroatoms.
The term halogen includes fluorine, chlorine, bromine or iodine. The terms alkyloxy (-OR wherein R is an alkyl), alkenyloxy (-OR wherein R is an alkenyl), alkynyloxy (-OR wherein R is an alkynyl), cycloalkyloxy (-OR wherein R is a cycloalkyl) and heterocycloalkoxy (-OR wherein R is a heterocycloalkyl) denote an -OR group wherein the respective alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl group is as hereinbefore described above.
The terms alkylthio, alkylsulphoxo and alkylsulphono denotes an -S(O)xR group wherein x=0, 1 or 2 respectively and R is an alkyl group as hereinbefore described above. The term -alkyl-aryl refers to an alkyl group with an aryl substituent. The term
-alkyl-cycloalkyl refers to an alkyl group with a cycloakyl substituent. The term -aryl-alkyl refers to an aryl group with an alkyl substituent. The terms alkoxycarbonyl (-(C=O)OR), alkylcarbonyl (-COR) and arylcarbonyl (-C0R) refer to a carbonyl group with an alkoxy, alkyl or aryl substituent. When R5 represents a substituted morpholinyl, piperidinyl, homopiperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, diketomethylpiperazinyl, sulphoxomorpholinyl, sulphonylrnorpholinyl, thiomorpholinyl, granatanyl, oxogranatanyl or azacycloheptyl, one or more substituents may be present and are as defined above for R8.
All the groups mentioned in the definition of R1 to R9 may optionally be branched and/or substituted.
According to a second aspect of the present invention there is provided a compound of formula (II):
Figure imgf000015_0001
(II) wherein
R1, R2 each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms; Rc, Rd each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or R° and Rd together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms; R3 represents hydrogen, an optionally substituted C1-12alkyl group, an optionally substituted C2-12alkenyl group, an optionally substituted C2-12alkynyl group, an optionally substituted C6-Haryl group, an optionally substituted C3-12cycloalkyl group, an optionally substituted C3-12cycloalkenyl group, an optionally substituted C7-i2polycycloalkyl group, an optionally substituted C7-12polycycloalkenyl group, an optionally substituted C5-12spirocycloalkyl group, an optionally substituted 3- to
12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 4- to 12-membered heterocycloalkenyl group comprising 1 or 2 heteroatoms, or optionally one of R1 and R3, or R2 and R3, or R1 and Rc, or R2 and Rd together represent a saturated or unsaturated C1-4alkyl bridge optionally comprising 1 heteroatom;
R4 each independently represent -CN, hydroxy, -NR6R7, -NR6SO2R7, halogen, an optionally substituted C1-6alkyl group, an optionally substituted C3-7cycloalkyl group, an optionally substituted C2-6alkenyl group, an optionally substituted C2-6alkynyl group, an optionally substituted C1-5alkyloxy group, an optionally substituted
C3-6cycloalkyloxy group, an optionally substituted C2-5alkenyloxy group, an optionally substituted C2_5alkynyloxy group, an optionally substituted d-βalkythio group, an optionally substituted C1-6alkylsulphoxo group or an optionally substituted Cμealkylsulphonyl group, an optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 3- to 12-membered heterocycloalkoxy group comprising 1 or 2 heteroatoms; RN represents hydrogen, -NH2, -OH, -CN, -C=CH, -C(=0)NH2, C1-3alkyl, C-1-3alkylamino, C1-3alkylthio, Ci-3alkyloxy, C1-3alkylcarbonyl, -CHO, or -SO2Me; p is 0, 1 or 2; Q is -C(=X1)-:NRaRb, -S(O)2-NR32R132, -(optionally substituted C1-3alkyl)g-NRa3Rb3,
-S(O)k-Ra8, -C(=X2)-ORa9, -ORal° or -(5- or 6-membered aromatic or heteroaromatic ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur)-Ln-R5 m; g is 0 or 1 ; k is 0, 1 or 2; Ra represents H or an optionally substituted C1-6alkyl group, and Rb represents
-Ln-R5 m, or Ra and Rb together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
R82 represents H or an optionally substituted C^alkyl group, and R 2 represents -Ln-R5 m, or Ra2 and Rb2 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
Ra3 represents H or an optionally substituted C1-6alkyl group, and Rb3 represents
-Ln-R5 m, -SO2NRa4Rb4, -C(=O)NRa5Rb5, -SO2Ra6, -C(=O)ORa7, or Ra3 and Rb3 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
Ra4 represents H or an optionally substituted C1-6alkyl group, and Rb4 represents
-Ln-R5 m, or Ra4 and Rb4 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
Ra5 represents H or an optionally substituted C1-6alkyl group, and Rb5 represents
-Ln-R5 In, or Ra5 and Rb5 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms; Ra6 represents -Ln-R5 m;
Ra7 represents -Ln-R5 m;
Ra8 represents -Ln-R5 m;
Ra9 represents -Ln-R5 m;
Ral° represents -Ln-R5 m; L represents a linker selected from optionally substituted C2-i0alkyl, optionally substituted C2-10alkenyl, optionally substituted C6.14aryl, optionally substituted -C2-4alkyl-C6-14aryl, optionally substituted -C6-14aryl-C1-4alkyl, optionally substituted C3-12cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen atoms; n is 0 or 1 m is 1 or 2
R5 represents a group selected from among hydrogen, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted piperazinylcarbonyl, optionally substituted pyrrolidinyl, optionally substituted tropenyl, optionally substituted diketomethylpiperazinyl, optionally substituted sulphoxomorpholinyl, optionally substituted sulphonylmorpholinyl, optionally substituted thiomorpholinyl, optionally substituted azacycloheptyl, optionally substituted granatanyl, optionally substituted oxogranatanyl and -NR8R9; R6, R7 each independently represents hydrogen or an optionally substituted C^alkyl group;
R8, R9 each independently represents hydrogen, optionally substituted C^alkyl, optionally substituted -C1-4alkyl-C3-1ocycloalkyl, optionally substituted Ca-iocycloalkyl, optionally substituted C6-14aryl, optionally substituted -C1-4alkyl-C6-14aryl, optionally substituted pyranyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted C1-4alkyloxycarbonyl, optionally substituted optionally substituted C6-14arylcarbonyl, optionally substituted C1-4alkylcarbonyl, optionally substituted Co-narylmethyloxycarbonyl, optionally substituted C6-14arylsulphonyl, optionally substituted C1-4alkylsulphonyl, optionally substituted C6-14aryl-C1-4alkylsulphonyl, or R8 and R9 together with the nitrogen atom to which they are attached form a 3- to 7-membered bridged or unbridged, saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms; and Z1 is C=O or CRfR8 wherein Rf, Rg each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or Rf and Rg together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms, or pharmacologically acceptable salts thereof. According to a third aspect of the present invention there is provided a compound of formula (Ha):
Figure imgf000019_0001
(Ha) wherein
R1, R2 each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
Rc, Rd each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or Re and Rd together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms; R3 represents hydrogen, an optionally substituted C1-12alkyl group, an optionally substituted C2-12alkenyl group, an optionally substituted C2-12alkynyl group, an optionally substituted C6-i4aryl group, an optionally substituted C3-i2cycloalkyl group, an optionally substituted C3-i2cycloalkenyl group, an optionally substituted C7-12polycycloalkyl group, an optionally substituted C^npolycycloalkenyl group, an optionally substituted Cs-nspirocycloalkyl group, an optionally substituted 3- to
12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 4- to 12-membered heterocycloalkenyl group comprising 1 or 2 heteroatoms, or optionally one of R1 and R3, or R2 and R3, or R1 and Rc, or R2 and Rd together represent a saturated or unsaturated Ci.4alk.yl bridge optionally comprising 1 heteroatom;
R4 each independently represent -CN, hydroxy, -NR6R7, -NR6SO2R7, halogen, an optionally substituted C1-6alkyl group, an optionally substituted C3-7cycloalkyl group, an optionally substituted C2-6alkenyl group, an optionally substituted C2-6alkynyl group, an optionally substituted C1-5alkyloxy group, an optionally substituted C3-6cycloalkyloxy group, an optionally substituted C2-5alkenyloxy group, an optionally substituted C2-5alkynyloxy group, an optionally substituted C1-6alkythio group, an optionally substituted C1-6alkylsulphoxo group or an optionally substituted C1-6alkylsulphonyl group, an optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 3- to 12-membered heterocycloalkoxy group comprising 1 or 2 heteroatoms;
RN represents hydrogen, -NH2, -OH, -CN, -C=CH, -C(=0)NH2, C1-3alkyl, C-1-3alkylamino, C1-3alkylthio, C1-3alkyloxy, C1-3alkylcarbonyl, -CHO, or -SO2Me; p is 0, 1 or 2; L represents a linker selected from optionally substituted C2-1oalkyl, optionally substituted C2-loalkenyl, optionally substituted C6-14aryl, optionally substituted
-C2-4alkyl-C6-14aryl, optionally substituted -C6-14aryl-Ci.4alkyl, optionally substituted C3-12cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen atoms; n is 0 or 1 m is 1 or 2
R5 represents a group selected from among hydrogen, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted piperazinylcarbonyl, optionally substituted pyrrolidinyl, optionally substituted tropenyl, optionally substituted diketomethylpiperazinyl, optionally substituted sulphoxomorpholinyl, optionally substituted sulphonylmorpholinyl, optionally substituted thiomorpholinyl, optionally substituted azacycloheptyl, optionally substituted granatanyl, optionally substituted oxogranatanyl and -NR8R9;
R6, R7 each independently represents hydrogen or an optionally substituted C1-4alkyl group; R8, R9 each independently represents hydrogen, optionally substituted C1-6alkyl, optionally substituted -C1-4alkyl-C3-1ocycloalkyl, optionally substituted C3-10cycloalkyl, optionally substituted C6-14aryl, optionally substituted -C1-4alkyl-C6-14aryl, optionally substituted pyranyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted C1-4alkyloxycarbonyl, optionally substituted optionally substituted C6-14arylcarbonyl, optionally substituted
C1-4alkylcarbonyl, optionally substituted C6-14arylmethyloxycarbonyl, optionally substituted C6-i4arylsulphonyl, optionally substituted C^alkylsulphonyl, optionally substituted C6-14aryl-C1.4alkylsulphonyl, or R8 and R9 together with the nitrogen atom to which they are attached form a 3- to 7-membered bridged or unbridged, saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms; and
Z1 is C=O or CRfRg wherein Rf, Rg each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or Rf and Rg together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms, or pharmacologically acceptable salts thereof.
In one embodiment of the second aspect of the invention, Z1 is C=O or CH2. According to a fourth aspect of the present invention there is provided a compound of formula (III):
Figure imgf000022_0001
(III) wherein
R1, R2 each independently represents hydrogen or an optionally substituted C1-6alkyl group, or R1 and R2 together with the carbon atom to which they are attached form a
3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
Rc, Rd each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or Rc and Rd together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
R3 represents hydrogen, an optionally substituted C1-12alkyl group, an optionally substituted C2-12alkenyl group, an optionally substituted C2-12alkynyl group, an optionally substituted C6-HaIyI group, an optionally substituted C3-12cycloalkyl group, an optionally substituted C3.12cycloalkenyl group, an optionally substituted
C7-12polycycloalkyl group, an optionally substituted C7-12polycycloalkenyl group, an optionally substituted C5-i2spirocycloalkyl group, an optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 4- to 12-membered heterocycloalkenyl group comprising 1 or 2 heteroatoms, or optionally one of R1 and R3, or R2 and R3, or R1 and Rc, or R2 and Rd together represent a saturated or unsaturated Ci-4alkyl bridge optionally comprising 1 heteroatom;
R4 each independently represent -CN, hydroxy, -NR6R7, -NR6SO2R7, halogen, an optionally substituted C1-6alkyl group, an optionally substituted C3-7cycloalkyl group, an optionally substituted C2-6alkenyl group, an optionally substituted C2-6alkynyl group, an optionally substituted C1-5alkyloxy group, an optionally substituted C3-6cycloalkyloxy group, an optionally substituted C2-5alkenyloxy group, an optionally substituted C2-5alkynyloxy group, an optionally substituted C1-6alkythio group, an optionally substituted C^alkylsulphoxo group or an optionally substituted
C1-6alkylsulphonyl group, an optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 3- to 12-membered heterocycloalkoxy group comprising 1 or 2 heteroatoms; p is 0, 1 or 2; L represents a linker selected from optionally substituted C2-1oalkyl, optionally substituted C2-10alkenyl, optionally substituted C6-14aryl, optionally substituted -C2-4alkyl-C6-i4aryl, optionally substituted -C6_14aryl-C1-4alkyl, optionally substituted C3-12cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen atoms; n is 0 or 1 ; m is 1 or 2;
R5 represents a group selected from among hydrogen, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted piperazinylcarbonyl, optionally substituted pyrrolidinyl, optionally substituted tropenyl, optionally substituted diketomethylpiperazinyl, optionally substituted sulphoxomorpholinyl, optionally substituted sulphonylmorpholinyl, optionally substituted thiomorpholinyl, optionally substituted azacycloheptyl, optionally substituted granatanyl, optionally substituted oxogranatanyl and -NR8R9; R6, R7 each independently represents hydrogen or an optionally substituted C^alkyl group; and R8, R9 each independently represents hydrogen, optionally substituted C1-6alkyl, optionally substituted -C1-4alkyl-C3-i0cycloalkyl, optionally substituted C3-10cycloalkyl, optionally substituted C6-i4aryl, optionally substituted -C1-4alkyl-C6-i4aryl, optionally substituted pyranyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted C1-4alkyloxycarbonyl, optionally substituted optionally substituted C6-14arylcarbonyl, optionally substituted C1-4alkylcarbonyl, optionally substituted C^narylmethyloxycarbonyl, optionally substituted Ce-^arylsulphonyl, optionally substituted C1-4alkylsulphonyl, optionally substituted C6-14aryl-C1-4alkylsulphonyl, or R8 and R9 together with the nitrogen atom to which they are attached form a 3- to 7-membered bridged or unbridged, saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms, or pharmacologically acceptable salt thereof.
According to a fifth aspect of the present invention there is provided a compound of formula (Ilia):
Figure imgf000024_0001
(Ilia) wherein
R1, R2 each independently represents hydrogen or an optionally substituted C1-6alkyl group, or R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms; Rc, Rd each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or R° and Rd together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms; R3 represents hydrogen, an optionally substituted C1-12alkyl group, an optionally substituted C2-12alkenyl group, an optionally substituted C2-12alkynyl group, an optionally substituted C6-14aryl group, an optionally substituted C3-12cycloalkyl group, an optionally substituted C3-12cycloalkenyl group, an optionally substituted C7-12polycycloalkyl group, an optionally substituted C7-12polycycloalkenyl group, an optionally substituted C5-12spirocycloalkyl group, an optionally substituted 3- to
12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 4- to 12-membered heterocycloalkenyl group comprising 1 or 2 heteroatoms, or optionally one of R1 and R3, or R2 and R3, or R1 and Rc, or R2 and Rd together represent a saturated or unsaturated C1-4alkyl bridge optionally comprising 1 heteroatom;
R4a , R4b, R4c each independently represent -CN, hydroxy, -NR6R7, -NR6SO2R7, halogen, an optionally substituted C1-6alkyl group, an optionally substituted C3-7cycloalkyl group, an optionally substituted C2-6alkenyl group, an optionally substituted C2-6alkynyl group, an optionally substituted C1-5alkyloxy group, an optionally substituted C3-6cycloalkyloxy group, an optionally substituted C2-5alkenyloxy group, an optionally substituted C2-5alkynyloxy group, an optionally substituted Cμδalkythio group, an optionally substituted C1-6alkylsulphoxo group or an optionally substituted C1-6alkylsulphonyl group, an optionally substituted 3- to 12- membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 3- to 12-membered heterocycloalkoxy group comprising 1 or 2 heteroatoms; p is the number of R4a> 4b> 4o groups that are not hydrogen and is selected from 0, 1 or 2; L represents a linker selected from optionally substituted C2-10alkyl, optionally substituted C2-10alkenyl, optionally substituted C6-14aryl, optionally substituted
-C2-4alkyl-C6-14aryl, optionally substituted -C6-14aryl-C1-4alkyl, optionally substituted C3-12cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen atoms; n is 0 or 1 ; m is 1 or 2; R5 represents a group selected from among hydrogen, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted piperazinylcarbonyl, optionally substituted pyrrolidinyl, optionally substituted tropenyl, optionally substituted diketomethylpiperazinyl, optionally substituted sulphoxomorpholinyl, optionally substituted sulphonylmorpholinyl, optionally substituted thiomorpholinyl, optionally substituted azacycloheptyl, optionally substituted granatanyl, optionally substituted oxogranatanyl and -NR8R9;
R6, R7 each independently represents hydrogen or an optionally substituted C1-4alkyl group; and R8, R9 each independently represents hydrogen, optionally substituted C1-6alkyl, optionally substituted -C1-4alkyl-C3-10cycloalkyl, optionally substituted C3-1ocycloalkyl, optionally substituted C6-14aryl, optionally substituted -C1-4alkyl-C6-14aryl, optionally substituted pyranyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted C1-4alkyloxycarbonyl, optionally substituted optionally substituted C6-14arylcarbonyl, optionally substituted
C1-4alkylcarbonyl, optionally substituted C6-14arylmethyloxycarbonyl, optionally substituted C6-14arylsulphonyl, optionally substituted C1-4alkylsulphonyl, optionally substituted C6-14aryl-C1-4alkylsulphonyl, or R8 and R9 together with the nitrogen atom to which they are attached form a 3- to 7-membered bridged or unbridged, saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms, or pharmacologically acceptable salt thereof.
In one embodiment, for compounds of the first, second, third, fourth and fifth aspects, the groups R1 and R2 may be identical or different and represent hydrogen or a CrCόalkyl group optionally substituted by one or more substituents selected from C1-3alkyloxy, Ci-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino. In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, the groups R1 and R2 may be identical or different and represent hydrogen or a methyl or ethyl group.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, the groups R1 and R2 are different wherein one of R1 or R2 represents hydrogen and the other represents a methyl or ethyl group.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R1 and R2 together represent a 2- to 5-membered alkyl bridge optionally comprising 1 to 2 heteroatoms selected from oxygen or nitrogen and optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R1 and R2 together represent an ethylene or propylene bridge.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, the groups Re and Rd may be identical or different and represent hydrogen or a Q-Cόalkyl group optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, the groups Rc and R may be identical or different and represent hydrogen or a methyl or ethyl group.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, the groups Rc and Rd are different wherein one of Rc or Rd represents hydrogen and the other represents a methyl or ethyl group.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, Rc and Rd together represent a 2- to 5-membered alkyl bridge optionally comprising 1 to 2 heteroatoms selected from oxygen or nitrogen and optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, Rc and Rd together represent an ethylene, propylene or butylene bridge. In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, at least one of R1, R2, Rc, or Rd is hydrogen.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, at least two of R1, R2, Rc, or Rd are hydrogen. In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R1 and R2 are hydrogen.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R1 and R2 are hydrogen, and one of Rc or Rd is hydrogen.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R1 and R2 are hydrogen, and one of Rc or Rd is hydrogen and the other is methyl.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R1 and R2 are hydrogen, and Rc and R are methyl.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R1 and R2 are hydrogen, and Rc and Rd together represent an ethylene bridge. In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R3 represents hydrogen; a d-C12alkyl, for example ethyl, propyl, butyl, pentyl or hexyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; a C2-C12alkenyl, for example C5-C7alkenyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; C2-C12alkynyl, for example Cs-C7alkynyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di- (C1-3alkyl)amino; a C6-C14aryl, for example phenyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, d-3alkylamino and di- (C1-3alkyl)amino; a C3-C12cycloalkyl, for example cyclopentyl or cyclohexyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, Ci-3alkyl- S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; a C3-Ci2cycloalkenyl, for example C5-C7cycloalkenyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, d-3alkylthio, C1-3alkyl-S(O)2, C^alkylamino and di-(C1-3alkyl)amino; C7-C12PoIyCyClOaIlCyI optionally substituted by one or more substituents selected from Ci-3alkyloxy, d-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; C7-C12polycycloalkenyl optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1.3alkyl)amino; C5-C12spirocycloalkyl optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; s C3-C12heterocycloalkyl which contains 1 to 2 heteroatoms selected from oxygen, nitrogen or sulphur, for example pyranyl or piperinyl, pyrrolidinyl, pyrazinyl or morpholinyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl- S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; and C3-C12heterocycloalkenyl which contains 1 to 2 heteroatoms selected from oxygen, nitrogen or sulphur, optionally substituted by one or io more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R3 represents isopropyl, isobutyl, isopentyl, cyclopentyl, phenyl or cyclohexyl.
In another embodiment, for compounds of the first, second, third, fourth and fifth
I5 aspects, R3 represents cyclopentyl,or cyclohexyl.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R1 and R3 or R2 and R3 together represent a saturated or unsaturated C3-C4alkyl bridge optionally comprising 1 heteroatom selected from oxygen or nitrogen.
In another embodiment, for compounds of the first, second, third, fourth and fifth
20 aspects, when p is 1 or 2, R4 represents a group selected from among -CN; hydroxyl; -NR6R7; halogen, for example chlorine or fluorine; d-Cβalkyl, for example methyl, ethyl or propyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; C2-C6alkenyl, for example ethenyl or propenyl, optionally substituted by one or more substituents selected from C1-3alkyloxy,
25 C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; C2-C6alkynyl, for example ethynyl, propynyl or butynyl, optionally substituted by one or more substituents selected from Ci-3alkyloxy, C^alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di- (C1-3alkyl)amino; d-C5alkyloxy, for example methoxy, ethoxy or propargyloxy, optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-
30 S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; C2-C5alkenyloxy optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; C2-C5alkynyloxy optionally substituted by one or more substituents selected from C^alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; Ci-Cόalkylthio optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, Ci-3alkyl-S(O)2, C1-3 alky lamino and di-(C1-3alkyl)amino; CrC6alkylsulphoxo optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3 alky lamino and di-(C1-3alkyl)amino and Q-Qalkylsulphonyl optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C i -3alky l)amino . In another embodiment, for compounds of the first, second, third and fourth aspects, when p is I5 R represents methoxy, methyl, ethoxy, chlorine or fluorine.
In another embodiment, for compounds of the first, second, third, and fourth aspects, when p is 2, each R4 may be the same or different and selected from methoxy, methyl, ethoxy, ethyl, propargyloxy, chlorine or fluorine. In another embodiment, for compounds of the first, second, third, and fourth aspects, when p is 2 and when each R is adjacent, both R4 together with the aromatic ring atoms to which they are attached form a 4- to 7-member unsaturated ring optionally comprising 1 to 2 heteroatoms.
In another embodiment, for compounds of the fifth aspect, when p is 1, R4b and R4c are hydrogen and R4a represents methoxy, methyl, ethoxy, chlorine or fluorine.
In another embodiment, for compounds of the fifth aspect, when p is 2, R is hydrogen and R4a and R4c may be the same or different and selected from methoxy, methyl, ethoxy, chlorine or fluorine.
In another embodiment, for compounds of the fifth aspect, when p is 2, R4c is hydrogen and R4a and R4b together form a OCH2O bridge.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, L represents a linker selected from among C2-C10alkyl, for example ethyl, propyl, butyl or pentyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(Ci-3alkyl)amino; C2-C10alkenyl, optionally substituted by one or more substituents selected from Ci-3alkyloxy, C1-3alkylthio, Cμ3alkyl-S(O)2, C1-3alkylamino and dKC^alkytyamino; C6-C14aryl, for example phenyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, Ci-3alkylamino and di-(C1-3alkyl)amino; -C2-C4alkyl-C6-C14aryl optionally substituted by one or more substituents selected from C^alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyi)amino; -C6-C14aryl-C1-C4alkyl optionally substituted by one or more substituents selected from Ci-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; C3-C12cycloalkyl, for example cyclohexyl, optionally substituted by one or more substituents selected from Ci-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; and heteroaryl which contains 1 or 2 nitrogen atoms optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, when n is 1, L represents an optionally substituted a C2-10alkyl or an optionally substituted C3-12cycloalkyl linker.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, when n is 1, L represents cyclohexyl, -C(CH3)2-CH2- or -CH2-C(CH3)2-CH2-.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, n is 0.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, m is 1. In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R5 represents a group selected from among hydrogen, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted piperazinylcarbonyl, optionally substituted pyrrolidinyl, optionally substituted tropenyl, optionally substituted diketomethylpiperazinyl, optionally substituted sulphoxomorpholinyl, sulphonylmorpholmyl, optionally substituted thiomorpholinyl, optionally substituted granatanyl, optionally substituted oxogranatanyl -NR8R9 and optionally substituted azacycloheptyl wherein each morpholinyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, diketomethylpiperazinyl, sulphoxomorpholinyl, sulphonylmorpholinyl, thiomorpholinyl, -NR8R9 and azacycloheptyl is optionally substituted by one or more groups as defined for R8. In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R5 represents hydrogen, -NR8R9 or a piperidinyl, morpholinyl, pyrrolidinyl, sulphoxomorpholiny, piperazinyl, thiomorpholinyl, tropenyl, granatanyl, oxogranatanyl or azacycloheptyl each optionally substituted by one or more groups as defined for R8. In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R5 represents piperidinyl optionally substituted by one or more groups as defined for R8.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R5 represents pyrrolidinyl optionally substituted by one or more groups as defined for R8.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R5 represents granatanyl optionally substituted by one or more groups as defined for R8.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, the groups R6 and R7 may be identical or different and represent hydrogen or Q-Qalkyl, for example methyl or ethyl.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, the groups R and R may be identical or different and represent hydrogen; a d-Cβalkyl, for example methyl, ethyl or propyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3 alky lamino and di- (C1-3alkyl)amino; -C1-C4alkyl-C3-C10cycloalkyl, for example -CH2-cyclopropyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, Ci-3alkylthio, C1-3alkyl- S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; CrQocycloalkyl optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and d-(C1-3alkyl)amino; C6-Ci4aryl, for example phenyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino;
Figure imgf000032_0001
for example benzyl optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, Ci-3alkylamino and di-(C1-3alkyl)amino; pyranyl optionally substituted by one or more substituents selected from C1.3alkyloxy, Ci-3alkylthio, C1-3alkyl-S(O)2, C^alkylamino and di-(C1-3alkyl)amino; pyridinyl optionally substituted by one or more substituents selected from C1-3 alky loxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di- (C1-3alkyl)amino; pyrimidinyl optionally substituted by one or more substituents selected from Ci.3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2,
Figure imgf000033_0001
and di-(Ci-3alkyl)ammo; pyranyl optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)arnino;
C1-C4alkyloxycarbonyl optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; C6-C14arylcarbonyl optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; CrC4alkylcarbonyl optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; C6-C14 arylmethyloxycarbonyl optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; C6-C14arylsulphonyl optionally substituted by one or more substituents selected from Ci-3alkyloxy, C1-3alkyltliio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; C1-C4alkylsulphonyl optionally substituted by one or more substituents selected from C^alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino and C6-C14aryl-C1-C4alkylsulphonyl optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3 alky lthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino. In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R8 represents methyl, ethyl or propyl.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R9 represents methyl, ethyl or propyl.
In another embodiment, for the compound of formula (I), RN represents C1-3alkyl. In another embodiment, for the compound of formula (I), RN represents methyl or ethyl.
In another embodiment, for the compound of formula (I), Z1 represents C=O or CRfRg. In another embodiment, for the compound of formula (I), Z1 represents C=O or CRfRg, and Z2 represents CR°Rd. In another embodiment, for the compound of formula (I), Z1 represents C=O or CH2. In another embodiment, for the compound of formula (I), Q represents -CH2-NRa3Rb3 or -C0=X1)-NRaRb, wherein X1 is O.
In another embodiment, for the compounds of formula (I), (II), (Ha), (III) or (Ilia), n is 1 and L is an optionally substituted C2-10alkyl linker. In another embodiment, for the compounds of formula (I), (II), (Ha), (III) or (Ilia), n is
0.
In a further embodiment of the invention there is provided a subset of compounds of formula (III) or (Ilia) wherein R1 to R4, R4a, R4b, R4c, Rc, Rd, R6 and R7 are as hereinbefore defined; and L represents a linker selected from among optionally substituted C2-10alkyl, optionally substituted C2-1oalkenyl, optionally substituted C6-14aryl, optionally substituted -C2-4alkyl-C6-14aryl, optionally substituted -C6-14aryl-C1-4alkyl, optionally substituted C3-12cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen ring atoms; n denotes 1; m denotes 1 or 2; R5 denotes hydrogen or a group which is bound to L via a nitrogen atom, selected from optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted pyrrolidinyl, optionally substituted tropenyl, optionally substituted diketomethylpiperazinyl, optionally substituted sulphoxomorpholinyl, optionally substituted sulphonylmorpholinyl, optionally substituted thiomorpholinyl, -NR8R9 and optionally substituted azacycloheptyl; R8, R9 independently represent hydrogen, C1-6alkyl, -C1-4alkyl-C3-10cycloalkyl, C3-1ocycloalkyl, C6-14aryl, -C1-4alkyl-C6-14aryl, pyranyl, pyridinyl, pyrimidinyl, C1-4alkyloxycarbonyl, C6-14arylcarbonyl, C1-4alkylcarbonyl, C6-14arylmethyloxycarbonyl, C6-14arylsulphonyl,
Figure imgf000034_0001
or C6-14aryl-C1-4alkylsulphonyl, or pharmacologically acceptable salts thereof.
In a still further embodiment of the invention there is provided another subset of compounds of formula (III) or (Ilia) wherein p, R1 to R4 R4a, R4b, R4c, Rc, Rd, R6 and R7 are as hereinbefore defined; L represents a linker selected from optionally substituted C2-1oalkyl, optionally substituted C2-i0alkenyl, optionally substituted C6-14aryl, optionally substituted -C2-4alkyl-C6.i4aryl, optionally substituted -C^Haryl-C^alkyl, optionally substituted C3-12cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen ring atoms; n denotes 0 or 1; m denotes 1 or 2; R5 denotes hydrogen or a group which is bound to L via a carbon atom, selected from among piperidinyl, piperazinyl, pyrrolidinyl, piperazinylcarbonyl, tropenyl, morpholinyl, granatanyl, oxogranatanyl and azacycloheptyl each optionally substituted by one or more groups as defined for R8; and R8 independently represent hydrogen, C1-6alkyl, -C1-4alkyl-C3-i0cycloalkyl, C3-10cycloalkyl, C6-14aryl, -C1-4alkyl-C6-14aryl, pyranyl, pyridinyl, pyriniidinyl, C^alkyloxycarbonyl, C6-14arylcarbonyl, C1-4alkylcarbonyl, C6-14arylmethyloxycarbonyl, C6-14arylsulphonyl, C1_4alkylsulphonyl or Ce-uaryl-d^alkylsulphonyl, or pharmacologically acceptable salts thereof.
In an additional embodiment of the invention there is provided an additional subset of compounds of formula (III) or (Ilia) wherein L, m, n, p, R3 to R9, RQ and Rd are as hereinbefore defined; and R1, R2 each independently represents hydrogen, Me, Et, Pr, or R1 and R2 together with the carbon atom to which they are attached form a 3- to 5- membered cycloalkyl ring, or pharmacologically acceptable salts thereof.
In an additional embodiment of the invention there is provided an additional subset of compounds of formula (III) or (Ilia) wherein L, m, n, p and R1 to R9 are as hereinbefore defined; and Rc, Rd each independently represents hydrogen, Me, Et, Pr, or Rc and Rd together with the carbon atom to which they are attached form a 3- to 5- membered cycloalkyl ring, or pharmacologically acceptable salts thereof.
In an additional embodiment of the invention there is provided an additional subset of compounds of formula (III) or (Ilia) wherein L, m, n, p and R3 to R9 are as hereinbefore defined; and at least two of R1, R2, Rc or Rd are hydrogen.
In an additional embodiment of the invention there is provided an additional subset of compounds of formula (III) or (Ilia) wherein L, m, n, p and R3 to R9 are as hereinbefore defined; R1 and R2 are hydrogen, and one of Rc or Rd is hydrogen.
In a further additional embodiment of the invention there is provided an additional subset of compounds of formula (III) or (Ilia) wherein R1, R2, Rc, Rd, m, n and R5 to R8 are as hereinbefore defined; and R3 represents an optionally substituted Ci-10alkyl, optionally substituted C3-7cycloalkyl, optionally substituted C3-6heterocycloalkyl or optionally substituted C6-14aryl group or R1 and R3 or R2 and R3 together represent a saturated or unsaturated C3-4alkyl bridge optionally comprising 1 or 2 heteroatoms; p is 0 or 1; R4 represents OMe, OH, Me, Et, Pr, OEt, NHMe, NH2, F, CL, Br, 0-propargyl, O-butynyl, CN, SMe, NMe2, CONH2, ethynyl, propynyl, butynyl or allyl; and L denotes a linker selected from among optionally substituted phenyl, phenylmethyl, cyclohexyl and branched C1-6alkyl, or pharmacologically acceptable salts thereof. In an additional embodiment of the invention there is provided an additional subset of compounds of formula (III) wherein R3 represents an optionally substituted C1-1OaIlCyI, optionally substituted C3_7cycloalkyl, optionally substituted C3-6heterocycloalkyl or optionally substituted C6-14aryl group; p is 0 or 1; R4 represents OMe, OH, Me, Et, Pr, OEt, NHMe, NH2, F, CL, Br, 0-propargyl, O-butynyl, CN, SMe, NMe2, CONH2, ethynyl, propynyl, butynyl or allyl; L represents a linker selected from optionally substituted C2-1oalkyl, optionally substituted C2-10alkenyl, optionally substituted C6-14aryl, optionally substituted -C2-4alkyl-C6-14aryl, optionally substituted -Cό^aryl-C^alkyl, optionally substituted C3-12cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen ring atoms; n denotes 0 or 1; m denotes 1 or 2; R5 denotes hydrogen or a group, which is bound to L via a carbon atom, selected from among -NR8R9, piperidinyl, piperazinyl, pyrrolidinyl, piperazinylcarbonyl, tropenyl, morpholinyl, granatanyl, oxogranatanyl and azacycloheptyl each optionally substituted by one or more groups as defined for R8; R8, R9 each independently represent hydrogen, C1-6alkyl, -C1-4alkyl-C3-1ocycloalkyl, C3-10cycloalkyl, C6-i4aryl, -C1-4alkyl-C6-14aryl, pyranyl, pyridinyl, pyrimidinyl, C1-4alkyloxycarbonyl, C6-14arylcarbonyl, C1-4alkylcarbonyl, Cό-Harylmethyloxycarbonyl, C6-14arylsulphonyl, C1-4alkylsulphonyl or C6-14aryl-C1-4alkylsulphonyl; R1, R2 are hydrogen; Rc, Rd are each independently selected from hydrogen, Me, or Et, or Rc and Rd together represent an ethylene bridge, or pharmacologically acceptable salts thereof. In an additional embodiment of the invention there is provided an additional subset of compounds of formula (III) wherein R3 represents an optionally substituted C1-10alkyl, optionally substituted C3-7cycloalkyl, optionally substituted C3-6heterocycloalkyl; p is 0, 1 or 2; R4 each independently represents fluoro or OMe; L represents a linker selected from optionally substituted C2-iOalkyl; n denotes 0 or 1; m denotes 1 or 2; R5 denotes a group selected from among -NR8R9 and piperidinyl each optionally substituted by one or more groups as defined for R8; R8, R9 each independently represent Ci-6alkyl; R1, R2 are hydrogen; Rc, Rd are each independently selected from hydrogen, Me, or Et, or Rc and Rd together represent an ethylene bridge, or pharmacologically acceptable salts thereof.
In an additional embodiment of the invention there is provided an additional subset of compounds of formula (III) wherein R3 represents an optionally substituted C1-loalkyl, optionally substituted C3-7cycloalkyl, optionally substituted C3-6heterocycloalkyl; p is 0, 1 or 2; R4 each independently represents fluoro or OMe; L represents a linker selected from optionally substituted C2-10alkyl; n denotes 0 or 1; m denotes 1 or 2; R5 denotes a group selected from among -NR8R9 and pyrrolidinyl each optionally substituted by one or more groups as defined for R8; R8, R9 each independently represent C^alkyl; R1, R2 are hydrogen; Rc, Rd are each independently selected from hydrogen, Me, or Et, or Rc and Rd together represent an ethylene bridge, or pharmacologically acceptable salts thereof.
In an additional embodiment of the invention there is provided an additional subset of compounds of formula (III) wherein R3 represents an optionally substituted C1-loalkyl, optionally substituted C3-7cycloalkyl, optionally substituted C^heterocycloalkyl; p is 0, 1 or 2; R4 each independently represents fluoro or OMe; L represents a linker selected from optionally substituted C2-10alkyl; n denotes 0 or 1; m denotes 1 or 2; R5 denotes a group selected from among -NR8R9 and granatanyl each optionally substituted by one or more groups as defined for R8; R8, R9 each independently represent C1-6alkyl; R1, R2 are hydrogen; Rc, Rd are each independently selected from hydrogen, Me, or Et, or Rc and Rd together represent an ethylene bridge, or pharmacologically acceptable salts thereof.
In an additional embodiment of the invention there is provided an additional subset of compounds of formula (Ilia) wherein R3 represents an optionally substituted C1-10alkyl, optionally substituted C3-7cycloalkyl, optionally substituted C3-6heterocycloalkyl; L represents a linker selected from optionally substituted C2-10alkyl; n denotes 0 or 1; m denotes 1 or 2; R5 denotes a group selected from among -NR8R9 and piperidinyl each optionally substituted by one or more groups as defined for R8; R8, R9 each independently represent C1-6alkyl; R1, R2 are hydrogen; Rc, Rd are each independently selected from hydrogen, Me, or Et, or Rc and Rd together represent an ethylene bridge; p is 0, 1 or 2; and when p is 1, R4b and R4c are hydrogen and R4a represents methoxy, methyl, ethoxy, chlorine or fluorine; and when p is 2, either R4b is hydrogen and R4a and R4° may be the same or different and selected from methoxy, methyl, ethoxy, chlorine or fluorine, or R4c is hydrogen and R4a and R4b together form a OCH2O bridge, or pharmacologically acceptable salts thereof.
In an additional embodiment of the invention there is provided an additional subset of compounds of formula (Ilia) wherein R3 represents an optionally substituted C1-10alkyl, optionally substituted C3-7cycloalkyl, optionally substituted Cs-βheterocycloalkyl; L represents a linker selected from optionally substituted C2-10alkyl; n denotes 0 or 1; m denotes 1 or 2; R5 denotes a group selected from among -NR8R9 and pyrrolidinyl each optionally substituted by one or more groups as defined for R ; R , R each independently represent C1-6alkyl; R , R are hydrogen; Rc, Rd are each independently selected from hydrogen, Me, or Et, or Rc and R together represent an ethylene bridge; p is 0, 1 or 2; and when p is 1, R4b and R4c are hydrogen s and R4a represents methoxy, methyl, ethoxy, chlorine or fluorine; and when p is 2, either R4b is hydrogen and R4a and R c may be the same or different and selected from methoxy, methyl, ethoxy, chlorine or fluorine, or R4c is hydrogen and R4a and R4b together form a OCH2O bridge, or pharmacologically acceptable salts thereof.
In an additional embodiment of the invention there is provided an additional subset ofo compounds of formula (Ilia) wherein R3 represents an optionally substituted C^oalkyl, optionally substituted C3-7cycloalkyl, optionally substituted C3-6heterocycloalkyl; L represents a linker selected from optionally substituted C2-iOalkyl; n denotes 0 or 1; m denotes 1 or 2; R5 denotes a group selected from among -NR8R9 and granatanyl each optionally substituted by one or more groups as defined for R8; R8, R9 each independently represent C1-6alkyl; R1, R2s are hydrogen; Rc, Rd are each independently selected from hydrogen, Me, or Et, or Rc and Rd together represent an ethylene bridge; p is 0, 1 or 2; and when p is 1, R4b and R4c are hydrogen and R4a represents methoxy, methyl, ethoxy, chlorine or fluorine; and when p is 2, either R4b is hydrogen and R4a and R4c may be the same or different and selected from methoxy, methyl, ethoxy, chlorine or fluorine, or R4c is hydrogen and R4a and R4b together form a OCH2O0 bridge, or pharmacologically acceptable salts thereof.
In a further aspect of the invention, there is provided a compound selected from any one of the Examples or pharmacologically acceptable salts thereof.
In a further aspect of the invention, there is provided a compound selected from any one of Examples 4, 7, 26, 27, 47, 51, 53, 56, 77, 97, 99, 101, 104, 106, 108, 110, 113, 114,s 135, 176, 182, 184, 191, 197, 202, 219, 234, 238, 239, 242, 269, 278, 279, 281, 282, 285, 289, 290, 293, 294, 295, 301, 302, 309, 310, 311, 330, 331, 390, 405, 411, 413, 416, 419, 429, 451, 1, 2, 3, 6, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 25, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 41, 43, 44, 45, 46, 48, 49, 50, 52, 54, 55, 57, 58, 59, 60, 61, 62, 63, 64, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 82, 83, 84, 85, 86, 88, 90, 91, 92, 93, 94, 95,o 96, 98, 109, 181, 185, 188, 189, 193, 194, 199, 200, 201, 203, 205, 206, 207, 208, 209, 210, 212, 213, 217, 235, 236, 237, 240, 241, 243, 244, 245, 246, 280, 283, 288, 291, 292, 298, 299, 300, 303, 304, 305, 306, 307, 308, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 325, 326, 327, 328, 329, 333, 334, 335, 336, 337, 338, 340, 341, 342, 343, 344, 345, 346, 347, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 382, 383, 384, 385, 386, s 387, 388, 389, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 406, 407, 408, 409, 412, 414, 415, 417, 418, 420, 421, 422, 423, 424, 425, 426, 427, 428, 430, 431, 432, 433, 434, 435, 436, 437, 438, 440, 441, 442, 443, 444, 445, 446 and 453 or pharmacologically acceptable salts thereof.
In a further aspect of the invention, there is provided a compound selected from any io one of Examples 1, 2, 3, 6, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 25, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 41, 43, 44, 45, 46, 48, 49, 50, 52, 54, 55, 57, 58, 59, 60, 61, 62, 63, 64, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 82, 83, 84, 85, 86, 88, 90, 91, 92, 93, 94, 95, 96, 98, 109, 181, 185, 188, 189, 193, 194, 199, 200, 201, 203, 205, 206, 207, 208, 209, 210, 212, 213, 217, 235, 236, 237, 240, 241, 243, 244, 245, 246, 280, 283, 288, is 291, 292, 298, 299, 300, 303, 304, 305, 306, 307, 308, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 325, 326, 327, 328, 329, 333, 334, 335, 336, 337, 338, 340, 341, 342, 343, 344, 345, 346, 347, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 382, 383, 384, 385, 386, 387, 388, 389, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402,
20 403, 404, 406, 407, 408, 409, 412, 414, 415, 417, 418, 420, 421, 422, 423, 424, 425, 426, 427, 428, 430, 431, 432, 433, 434, 435, 436, 437, 438, 440, 441, 442, 443, 444, 445, 446 and 453, or pharmacologically acceptable salts thereof.
The compounds according to the first, second, third, fourth and fifth aspects of the invention may be present in the form of the individual optical isomers, mixtures of the
25 individual enantiomers, diastereomers or racemates, in the form of the tautomers and also as solvates and/or in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids, such as for example acid addition salts with hydrohalic acids, for example hydrochloric or hydrobromic acid, or organic acids, such as for example oxalic, fumaric, diglycolic or methanesulphonic acid or metal salts such as a magnesium,
30 calcium, sodium or potassium salt The compounds of formula (I)5 (II), (Ha), (III) or (Ilia) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate, or an alkali metal salt such as a sodium or potassium salt.
Certain compounds of formula (I), (II), (Ha), (III) or (Ilia) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses the use of all geometric and optical isomers (including atropisomers) of the compounds of formula (I), (II),
(Ha), (III) or (Ilia) and mixtures thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention.
The invention also relates to a process for preparing a compound of general formula (HI),
Figure imgf000040_0001
(III) wherein R1 -R5, Rc, Rd m, n and L are as hereinbefore defined, comprising either a) reacting a compound of general formula (IV)
Figure imgf000041_0001
(IV) wherein R^R3 are as hereinbefore defined and A is a leaving group, with an optionally substituted compound of general formula (V):
Figure imgf000041_0002
(V) wherein R4 is as hereinbefore defined; and R10 denotes OH, NH-Lm-R5 n, OMe, OEt, and when R10 denotes OH, OMe or OEt optionally after previous hydrolysis of the ester group -COR10, reacting with an amine of general formula (VI): NH2 -Lm-R5 n
(VI) wherein R5 is as hereinbefore defined, to give a compound of formula (III); or
b) reacting a compound of general formula (VII)
Figure imgf000041_0003
(VII) wherein Rl-R3 are as hereinbefore defined with an optionally substituted compound of general formula (VIII):
Figure imgf000042_0001
(VIII) wherein Y is a leaving group, p and R4 are as hereinbefore defined; and R10 denotes
OH, NH-Lm-R5 n, OMe, OEt, and when R10 denotes OH, OMe or OEt optionally after previous hydrolysis of the ester group -COR10, reacting with an amine of general formula (VI):
NH2 -Lm-R5 n (VI) wherein R5 is as hereinbefore defined, to give a compound of formula (III).
In one embodiment R10 is a substituent selected from among OH, NH2-LR5, -O-methyl and -O-ethyl. The term leaving group includes leaving groups such as for example —O-methyl,
-SCN, chlorine, bromine, iodine, methanesulphonyl, trifluoromethanesulphonyl or p-toluenesulphonyl. In one embodiment the leaving group A is chlorine.
Methods for the preparation of compounds of Formula (V) are described in WO04/076454 and WO03/020722 and are incorporated herein by reference. Compounds of Formula (IV) where A is chlorine may also be obtained by the reductive cyclisation of a compound of formula (IX)
Figure imgf000042_0002
(IX) for example by palladium coupling.
Compounds of Formula (IV) may also be obtained by the cyclisation of a compound of formula (X)
Figure imgf000043_0001
(X) for example by under catalysis by a suitable palladium couplingcompound and in the presence of a suitable ligand and a suitable base.
Furthermore, compounds of formula (IV) may be obtained by reaction of another compound of general formula (IV), wherein R3 is hydrogen, with an alkyl halide, in a polar solvent, such as, for example, N,N-dimethylacetamide, in the presence of a strong base, such as, for example, sodium hydride.
Still furthermore compounds of formula (IV), where R°, Rd, R1 & R2 are hydrogen, may be obtained by reaction of a compound of formula (XI)
Figure imgf000043_0002
(XI)
with an amine, in the presence of a base, such as triethylamine, and a lewis acid, such as titanium (IV) tetraethoxide.
Compounds of formula (VII) may also be obtained by the reaction of a compound of formula (IV), wherein A is as hereinbefore defined, but typically chloro,
Figure imgf000044_0001
(IV) with ammonia or a suitably protected equivalent.
Compounds of Formula (IX), wherein A is chlorine, may also be obtained by reaction of 5-nitro-2,4-dichloropyrimidinee
Figure imgf000044_0002
with an amine of Formula (XII)
Figure imgf000044_0003
(XII) for example by heating in the presence of a base, such as potassium carbonate, in a polar organic solvent such as acetone.
Compounds of Formula (IX), wherein A is chlorine, may also be obtained by reaction of 5-bromo-2,4dichloropyrimide
Figure imgf000044_0004
with an amine of Formula (XIII)
Figure imgf000044_0005
(XIII) for example by heating in the presence of a base, such as triethylamine, in a polar organic solvent such as acetonitrile.
Compounds of Formula (XII), may also be obtained by reaction of esters of an appropriately substituted 3 -amino-propanoic acid (XIV)
Figure imgf000045_0001
(XIV) with a ketone or aldehyde, in the presence of a suitable reducing agent, such as, for example, sodium triacetoxyborohydride.. Compounds of Formula (XIII), may also be obtained by reaction of amides of propenoic acid (XV)
Figure imgf000045_0002
(XV) with an amine. Compounds of formula (XI) may also be obtained by the reaction of a compound of formula (XVI),
Figure imgf000045_0003
(XVI)
with a compound of formula (XVII),
Figure imgf000046_0001
(XVII) wherein X is a leaving group, typically a halogen, such as chloro, in the presence of a base, such as triethylamine, in an organic solvent, such as dichloromethane. A compound of formula (XVI) may also be obtained by the sequential reaction of 5- bromouracil,
Figure imgf000046_0002
with i) methylamine, in a polar solvent, such as ethanol and; ii) a chlorinating agent, such as phosphorous oxychloride as for instance exemplified in Journal of Medicinal Chemistry (1966), 9(1), 121-6.
The invention also relates to a process for preparing a compound of general formula (XVIII),
Figure imgf000046_0003
(XVIII) wherein R^R5, Rc, Rd m, n and L are as hereinbefore defined, comprising reacting a compound of general formula (XIX)
Figure imgf000047_0001
(XIX) with an amine of general formula (VI):
NH2 -Lm-R5 n (VI) wherein L and R5 are as hereinbefore defined.
Compounds of formula (XIX) may be obtained by hydrolysis of the corresponding esters.
Esters of general formula (XX)
Figure imgf000047_0002
(XX) may be obtained by the reduction of a compound of formula (XXI)
Figure imgf000048_0001
(XXI) which may be prepared as described above. It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I), (II), (Ha), (III) or (Ilia) may involve, at various stages, the addition and removal of one or more protecting groups. o The protection and deprotection of functional groups is described in in 'Protective
Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 3rd edition, T.W. Greene and P.G.M. Wuts, Wiley Interscience (19911999) and 'Protecting Groups', 3rd edition, P. J. Kocienski, Thieme (2005). The invention further relates to compounds of formula (I), (II), (Ha), (III) or (Ilia) fors use as pharmaceutical compositions.
In one embodiment of the invention, compounds of formula (I), (II), (Ha), (III) or (Ilia) are of use as pharmaceutical compositions with an antiproliferative activity.
The invention also relates to the use of a compound of formula (I), (II), (Ha), (III) or (Ilia) for preparing a pharmaceutical composition for the treatment and/or prevention ofo cancer, infections, inflammatory and autoimmune diseases.
These findings suggest that pharmacological inhibitors of PIk should be of therapeutic value for treatment of proliferative disease including solid tumours such as carcinomas and sarcomas and the leukaemias and lymphoid malignancies. In addition PIk inhibitors should be useful in the treatment of other disorders associated with uncontrolled cellular proliferation.
One aspect of the current invention therefore relates to the use of one or more of the compounds of formula (I), (II), (Ha), (III) or (Ilia) in the treatment of disorders characterised by excessive or anomalous cell proliferation.
Such diseases include for example: viral infections such as HIV and Kaposi's sarcoma; inflammatory and autoimmune diseases such as colitis, rheumatoid arthritis, Alzheimer's disease, glomerulonephritis and wound healing; bacterial, fungal and parasitic infections such as malaria and emphysema; dermatological diseases such as psoriasis; bone diseases; cardiovascular diseases such as restenosis and cardiomyopathy. The compounds in the present invention may be used for the prevention, short- or long-term treatment of the above- mentioned diseases, also in combination with other active substances used for the same indications.
The invention also relates to a method of treating and/or preventing cancer, infections, inflammatory and autoimmune diseases, characterised in that a patient is given an effective amount of a compound of formula (I), (II), (Ha), (III) or (Ilia).
The invention also relates to pharmaceutical preparations, containing as active substance one or more compounds of general formula (I), (II), (Ha), (III) or (Ilia), or the physiologically acceptable salts thereof, optionally combined with conventional excipients and/or carriers.
The compounds of formula (I), (II) and (III) have activity as pharmaceuticals, in particular as modulators or inhibitors of PIk activity, and may be used in the treatment of proliferative and hyperproliferative diseases/conditions, examples of which include the following cancers: (1) carcinoma, including that of the bladder, brain, breast, colon, kidney, liver, lung, ovary, pancreas, prostate, stomach, cervix, colon, thyroid and skin;
(2) hematopoietic tumours of lymphoid lineage, including acute lymphocytic leukaemia, B cell lymphoma and Burketts lymphoma;
(3) hematopoietic tumours of myeloid lineage, including acute and chronic myelogenous leukaemias and promyelocytic leukaemia; (4) tumours of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; and
(5) other tumours, including melanoma, seminoma, tetratocarcinoma, neuroblastoma and glioma. In one embodiment, the compounds of formula (I), (II) and (III) are useful in the treatment of tumours of the lung, breast and prostate.
Thus, the present invention provides a compound of formula (I), (II), (Ha), (III) or
(Ilia), or a pharmaceutically acceptable salt thereof, as hereinbefore defined for use in therapy, In a further aspect, the present invention provides the use of a compound of formula
(I), (II), (Ha), (III) or (Ilia), or a pharmaceutically acceptable salt thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
In the context of the present specification, the term "therapy" also includes
"prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.
The invention also provides a method of treating cancer which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (Ha), (III) or (Ilia), or a pharmaceutically acceptable salt thereof, as hereinbefore defined. The invention still further provides a method of modulating polo-like kinase (PIk) activity which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (Ha), (III) or (Ilia), or a pharmaceutically acceptable salt thereof, as hereinbefore defined.
The invention still further provides the use of a compound of formula (I), (II), (Ha), (III) or (Ilia), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
The invention still further provides the use of a compound of formula (I), (II), (Ha),
(III) or (Ilia), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating polo-like kinase (PIk) activity. The compounds of formula (I), (II) and (III), and pharmaceutically acceptable salts thereof, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I), (II), (Ha), (III) or (Ilia) compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99%w (per cent by weight), more preferably from 0.05 to 80%w, still more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50%w, of active ingredient, all percentages by weight being based on total composition. The present invention also provides a pharmaceutical composition comprising a compound of formula (I), (II), (Ha), (III) or (Ilia), or a pharmaceutically acceptable salt thereof, as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), (II), (Ha), (III) or (Ilia), or a pharmaceutically acceptable salt thereof, as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or carrier.
The pharmaceutical compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally.
The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate and anti oxidants such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil. Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p- hydroxybenzoate, anti oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil in water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally occurring gums such as gum acacia or gum tragacanth, naturally occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring and preservative agents. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non toxic parenterally acceptable diluent or solvent, for example a solution in 1,3 butanediol.
Suppository formulations may be prepared by mixing the active ingredient with a suitable non irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.
Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedure well known in the art. Compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30μ or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose. The powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50mg of active ingredient for use with a turbo inhaler device, such as is used for insufflation of the known agent sodium cromoglycate.
Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
The size of the dose for therapeutic purposes of a compound of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. In general, a compound of the invention will be administered so that a daily dose in the range, for example, from 0.5 mg to 75 mg active ingredient per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, from 0.5 mg to 30 mg active ingredient per kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, from 0.5 mg to 25 mg active ingredient per kg body weight will generally be used. Also, for example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active ingredient.
For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. The anti cancer treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents :- (i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5 fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);
(ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5* -reductase such as finasteride;
(iii) anti-invasion agents (for example c-Src kinase family inhibitors like 4-(6- chloro-2,3 -methylenedioxyanilino)-7- [2-(4-methylpiperazin- 1 -yl)ethoxy] -5-tetrahydropyran- 4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2- chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-l-yl]-2-methylpyrimidin-4- ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658- 6661), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase);
(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti erbBl antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol. 54, ppll-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3 -chloro-4-fluorophenyl)-7-methoxy-6-(3 -morpholinopropoxy)quinazolin-4-amme
(gefitinib, ZDl 839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI 774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3- morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family, inhibitors of the platelet-derived growth factor family such as imatinib, inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006)), inhibitors of cell signalling through MEK and/or AKT kinases, inhibitors of the hepatocyte growth factor family, c-kit inhibitors, abl kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZDl 152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;
(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and VEGF receptor tyrosine kinase inhibitors such as 4- (4-bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline
(ZD6474; Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy- 7-(3-pyrrolidin-l-ylproρoxy)quinazolme (AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SUl 1248 (sunitinib; WO 01/60814), compounds such as those disclosed in International Patent Applications WO97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin avb3 function and angiostatin);
(vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; (vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense; (viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene directed enzyme pro drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi drug resistance gene therapy;
(ix) immunotherapy approaches, including for example ex vivo and in vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor, approaches to decrease T cell anergy, approaches using transfected immune cells such as cytokine transfected dendritic cells, approaches using cytokine transfected tumour cell lines and approaches using anti idiotypic antibodies; and
(x) other inhibitors of cell cycle such as Eg5, Chkl or PARP inhibitors.
Examples The invention will now be further described with reference to the following illustrative examples in which, unless stated otherwise:
(i) temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C;
(ii) organic solutions were dried over anhydrous magnesium sulphate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30mmHg) with a bath temperature of up to 6O0C;
(iii) chromatography means flash chromatography on silica gel; (iv) SCX-2 cartridges are Ion Exchange SPE columns where the stationary phase is polymeric propylsulfonic acid. These are used to isolate amines. (v) in general, the course of reactions was followed by TLC or LCMS and reaction times are given for illustration only;
(vi) final products had satisfactory proton nuclear magnetic resonance (NMR) spectra and/or mass spectral data;
(vii) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required; (viii) when given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 400 MHz or 500MHz, in CDC13> DMSOd6 or DMSO-d6 + d4-AcOH unless otherwise indicated; (ix) chemical symbols have their usual meanings; SI units and symbols are used;
(x) solvent ratios are given in volume: volume (v/v) terms; and
(xi) Mass spectra (MS) data was generated on an LCMS system where the HPLC component comprised generally either a Agilent 1100 or Waters Alliance HT (2790 & 2795) equipment and was run on a Phemonenex Gemini Cl 8 5mm, 50 x 2 mm column (or similar) eluting with either acidic eluent (for example, using a gradient between 0 - 95% water / acetonitrile with 5% of a 1% formic acid in 50:50 water :acetonitrile (v/v) mixture; or using an equivalent solvent system with methanol instead of acetonitrile), or basic eluent (for example, using a gradient between 0 - 95% water / acetonitrile with 5% of a 0.1% 880 Ammonia in acetonitrile mixture); and the MS component comprised generally a Waters ZQ mass spectrometer scanning over an appropriate mass range. Chromatograms for Electrospray (ESI) positive and negative Base Peak Intensity, and UV Total Absorption Chromatogram from 220-3 OOnm, are generated and values for m/z are given; generally, only ions which indicate the parent mass are reported and unless otherwise stated the value quoted is the (M+H)+ for positive ion mode and (M-H)- for negative ion mode; (xii) Micorwave irradiation of reaction mixtures was performed using Emrys
Optimiser instrument;
(xiii) the following abbreviations have been used: AcOH acetic acid
CDCl3 deuterochloroform DCM dichloromethane
DIPEA iV,iV-diisopropylethylamine
DMA ΛζiV-dimethylacetamide
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide DMSO-d6 hexadeuterodimethylsulfoxide
EtOH ethanol EtOAc ethyl acetate
HATU 2-( 1H-7- Azabenzotriazol- 1 -y I)- 1 , 1 ,3 ,3-tetramethyl uronium hexafluorophosphate Methanaminium
HBTU O-Benzotriazole-N,N,N' ,N' -tetramethyl-uronium- hexafluoro-phosphate.
HPLC high performance liquid chromatography
MeCN acetonitrile
MeOH methanol
MeI methyl iodide
MS mass spectroscopy m/z mass to charge ratio
NMR nuclear magnetic resonance
SCX-2 ion exchange SPE column (polymeric propylsulfonic acid stationery phase)
THF terahydrofuran
TFA Trifluoroacetic acid
XANTPHOS 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene
Example 1: 4-[(2-Cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-10- yl)amino]-3-methoxy-iV-(l-methyl-4-piperidyl)benzainide
10-Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1; 99 mg, 0.34 mmol), 4-amino-3-methoxy-N-(l-methyl-4-piperidyl)benzamide (WO06/018220; 93 mg, 0.35 mmol) andp-toluenesulfonic acid (167 mg, 0.88 mmol) were dissolved in (i?/S)-4-methyl-2-pentanol (8 mL) and heated at reflux under a blanket of nitrogen for 24 h. The reaction mixture was cooled and loaded onto an SCX-2 column then washed with MeOH (15 mL). The crude compound was eluted from the SCX-2 column with NH3 (4OmL, 7M in MeOH) and the volatiles were removed under reduced pressure. Purification by column chromatography (SiO2, eluent gradient: 0-10% NH3 [7M in MeOH] in DCM), afforded the title compound (159 mg, 89%) as a solid. 1H NMR (400 MHz, CDCl3): δH 1.26 (t, 5H), 1.56 - 1.83 (m, 9H), 2.04 (s, 3H), 2.20 - 2.29 (m, 3H), 2.64 - 2.71 (m, 2H), 2.85 - 2.95 (m, 2H), 3.29 (s, 3H), 3.68 - 3.71 (m, 2H), 4.12 (q, IH), 4.90 (quintet, IH), 5.95 (d, IH), 7.24 (dd, IH), 7.42 (s, IH), 7.67 (s, IH), 7.94 (s, IH), 8.51 (d, IH); MS m/z 508 [M+H]+. s
Example 2;
4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-10- yl)amino]-iV-(l-methyl-4-piperidyl)benzamide
10-Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-oneo (Intermediate 1; 86 mg, 0.31 mmol), 4-amino-iV-(l-methyl-4-piperidyi)benzamide
(Intermediate 4; 72 mg, 0.31 mmol) andj?-toluene sulfonic acid (146 mg, 0.76 mmol) were dissolved in 4-methyl~2-pentanol (5 mL) and refluxed under an atmosphere of nitrogen for 18 hrs. The reaction mixture was loaded onto an SCX-2 column then washed with MeOH (15 mL). The crude compound was eluted from the SCX-2 column with NH3 (40 mL, 7M ins MeOH) and the volatiles were removed under reduced pressure. Purification by column chromatography (SiO2, eluent gradient: 0-10% NH3 [7M in MeOH] in DCM) then by preparative HPLC (Sunfire prep RP18, 19 x lOO mm column, eluting with a gradient of 0.1% solution of TFA in H2O and a 0.1% solution of TFA in MeCN). The product fractions were then loaded onto an SCX-2 column then washed with MeOH (10 mL). The product was0 eluted from the SCX-2 column with NH3 (30 mL, 7M in MeOH) and the volatiles removed under reduced pressure to give the title compound (38.5 mg, 26%) as a solid. 1H NMR (399.9 MHz, DMSO-d6) δH 1.58 - 1.78 (1OH, m), 1.92 - 2.04 (4H, m), 2.21 (3H, s), 2.58 - 2.60 (2H, m), 2.79 - 2.83 (2H, m), 3.18 (3H, s), 3.60 - 3.65 (2H, m), 3.71 - 3.79 (IH, m), 4.81 - 4.89 (IH, m), 7.76 (2H, d), 7.82 (2H, d), 7.99 (IH, d), 8.09 (IH, s), 9.44 (IH, s);5 MS m/z 478 [M+H]+.
Example 3;
4-[(4R/S)-(2-Cyclopentyl-4,6-dimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-
8,10,12-trien-10-yl)amino]-3-methoxy-iV-(l-methyl-4-piperidyl)benzamide 0 (4i?/S)-l 0-Chloro-2-cyclopentyl-4,6-dimethyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8,l 0, 12- trien-5-one (Intermediate 5; 106 mg, 0.36 mmol), 4-amino-iV-(l-methyl-4- piperidyl)benzamide (WO06018220; 95 mg, 0.36 mmol) andp-toluene sulphonic acid (170 mg, 0.89 mmol) were dissolved in (i?/iS)-4-methyl-2-pentanol (6 mL) and refluxed under a blanket of nitrogen for 24 hrs. The reaction mixture was cooled to ambient temperature and loaded onto an SCX-2 column and then washed with MeOH (40 mL). The crude compound was eluted from the SCX-2 column with NH3 (40 mL, 7M in MeOH) and the volatiles removed under reduced pressure. The crude material was then purified by column chromatography (SiO2, eluent gradient: 0-10% NH3 [7M in MeOH] in DCM) then by preparative HPLC (Sunfire prep RPl 8, 19 x 100 mm column, eluting with a gradient composing of a 0.1% solution of TFA in H2O and a 0.1% solution of TFA in MeCN). The product fractions were loaded onto an SCX-2 column then washed with MeOH (10 mL). The product was eluted from the SCX-2 column with NH3 (30 mL, 7M in MeOH) and the volatiles removed under reduced pressure to give the title compound (43.9 mg, 23%) as a solid.
1H NMR (400 MHz, DMSO-d6) δH 1.04 (d, 3H), 1.51 - 1.84 (m, 12H), 1.99 - 2.13 (m, 3H), 2.81 - 2.91 (m, 6H)5 3.20 (s, 3H), 3.45 (q, 2H), 3.78 (m, IH), 3.96 (s, 3H), 4.08 (s, IH), 4.75 (quintet, IH), 7.49 (d, IH), 7.75 (s, IH), 8.09 (d, IH), 8.40 (d, IH); MS m/z 522 [M+H]+.
Example 4:
4-[(2-Cyclopentyl-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-10- yl)amino]-3-methoxy-N-(l-methyl-4-piperidyl)benzamide
To a solution of 4-[(9-cyclopentyl-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5- b][l,4]diazepin-2-yl)amino]-3-methoxybenzoic acid (Intermediate 6; 240 mg, 0.60 mmol) and N-[(dimethylamino)(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N- methylmethanaminium hexafluorophosphate (275 mg, 0.72 mmol) in DMA (10 mL) was added l-methylpiperidin-4-amme (82 mg, 0.72 mmol) and DIPEA (210 uL, 1.20 mmol), and the reaction stirred at ambient temperature for 2 hr. The reaction mixture was loaded onto an SCX-2 column and washed with MeOH (20 mL). The crude product was then eluted from the SCX-2 column with NH3 (40 mL, 7M in MeOH) and the volatiles removed under reduced pressure. Purification by column chromatography (SiO2, eluent gradient: 5-10% MeOH in DCM) afforded the title compound (160 mg, 54%) as a solid. 1H NMR (400 MHz, DMSO-d6) δH 1.65 (m, 10H), 1.94 (m, 6H)5 2.21 (s, 3H), 2.71 (s, 3H), 2.82 (d, 2H), 3.00 (t, 2H), 3.48 (m, 2H), 3.94 (s, 3H), 4.86 (m, IH), 7.36 (s, IH), 7.46 (m, 2H), 7.53 (s, IH), 8.02 (d, IH), 8.46 (d, IH); MS m/z 494 [M+H]+.
Example 5:
4-[(2,6-Dimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10-yl)amino]-3- methoxy-iV-(l-methyl~4-piperidyl)benzamide
10-Chloro-2,6-dimethyl-2,6,9, 11 -tetrazabicyclo[5 A0]undeca-7,9, 11 -trien-5-one (Intermediate 9; 185 mg, 0.82 mmol), 4-amino-3-methoxy-JV-(l-methyl-4- piperidyl)benzamide (215 mg, 0.82 mmol) and/J-toluenesulphonic acid (389 mg, 2.05 mmol) in (i?/S)-4~methyl-2-pentanol (6 mL) were heated at 115 0C for 5 h. The reaction mixture was cooled to ambient temperature then passed through a SCX-2 cartridge and washed with MeOH (40 mL). The crude product was eluted off the SCX-2 cartridge with NH3 (40 mL, 7M in MeOH). Purification by preparative HPLC (Gemini RP C18 30xl00mm, gradient mobile phase: 10-80% MeCN/water + 0.5% NH3) afforded the title compound (180 mg, 48%) as a foam.
1H NMR (400 MHz, DMSO-d6) δH 1.60 (m, 2H), 1.78 (m, 2H), 1.90 (tr, 2H), 2.19 (s, 3H), 2.62 (tr, 2H), 2.79 (d, 2H), 3.09 (s, 3H), 3.20 (s, 3H), 3.73 (m, 3H), 3.95 (s, 3H), 7.51 (m, 2H), 7.75 (m, IH), 8.05 (d, IH), 8.11 (s, IH), 8.48 (d, IH); MS m/z 454 [M+H]+.
The following examples were prepared by an analogous process to that used in the preparation of Example 5 utilising the appropriate pyrimidine derivative (Intermediates 10 - 13) as the electrophile and 4-amino-3-methoxy-iV-(l-methyl-4-piperidyl)benzamide (WO06/018220) as the aniline:
Example 6;
3-Methoxy-4- [(6-methyl-5-oxo-2-propan-2-yl~2,6,9,l 1-tetrazabicyclo [5.4.0] undeca-
7,9,ll-trien-10-yl)amino]-iV-(l-methyl-4-piperidyl)benzamide
Example 7: 3-Methoxy-4-[[6-methyl-2-(3-methylbutyl)-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca- 7,9,1 l-trien-10-yl] amino] -JV-(l-methyl-4-piperidyl)benzamide
Example 8; 4-[(2-Cyclohexyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- yl)amino]-3-methoxy-N -(l-methyl-4-piperidyl)benzamide
Example 9:
3-Methoxy-4-[[6-methyl-2-(oxan-4-yl)-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0] undeca-7,9,11- trien-10-yl]amino]-N-(l-methyl-4-piperidyl)benzamide
Figure imgf000063_0001
Figure imgf000063_0002
Figure imgf000064_0001
Example 10:
4-[(2-Cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-10- yl)amino]-iV-(3-dimethylamino-2,2-dimethyl-propyl)-3-methoxy-benzamide hydrochloride
10-Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1; 238 mg, 0.85 mmol), 4-amino-N-(3-dimethylamino-2,2-dimethyl-propyl)-3- methoxy-benzamide (Intermediate 22; 250 mg, 0.85 mmol) and/?-toluenesulfonic acid (405 mg, 2.13 mmol) were dissolved in (i?/S)-4-methyl-2-pentanol (4 mL) and heated at reflux for 24 h. The reaction mixture was then cooled and loaded onto an SCX-2 column, which was then washed with MeOH (40 mL). The crude product was washed off the SCX-2 column with NH3 (50 mL, 7M in MeOH). Purification by column chromatography (SiO2, eluent gradient: 0-10% NH3 [7M in methanol] in DCM) give a pale yellow oil. HCl (0.43 uL, 2N in Et2O, 0.85 mmol) was added to a DCM (5 mL) solution of the yellow oil. Concentration under reduced pressure gave the title compound (188 mg, 40%) as a solid.
1H NMR (400 MHz, CDCl3): δH 1.00 (s, 6H), 1.60 - 1.84 (m, 6H), 2.02 - 2.34 (m, 2H), 2.37 (s, 2H), 2.39 (s, 6H), 2.65 - 2.69 (m, 2H), 3.29 (s, 3H), 3.38 (d, 2H), 3.68 - 3.72 (m, 2H), 3.98 (s, 3H), 4.87 - 4.96 (m, IH), 7.29 (dd, IH), 7.51 (d, IH), 7.67 (s, IH), 7.95 (s, IH), 8.51 (d, IH), 9.14 (t, IH); MS m/z 524 [M+H]+.
Example 11:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(l-cyclopropyl-4-piperidyl)-3-methoxy-benzamide 4- [(2-cycloρentyl-6-methy l-5-oxo-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien- 10- yl)amino]-3-methoxy-benzoic acid (Example 111; 150 mg, 0.36mmol), 1- cyclopropylpiperidin-4-amine (Intermediate 24, 77 mg, 0.55mmol) and HATU (208 mg, 0.55mmol) were stirred in DMF (92ml). DIPEA (191 mL, 1.09mmol) was added and the
5 mixture stirred at room temperature for 3 h. The mixture was absorbed onto an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by preparative HPLC to give the title compound as a pale brown solid (127mg, 66%). 1H NMR (399.9 MHz, DMSO-d6) δθ.29 (2H, s), 0.43 (2H, d), 1.48 - 1.81 (1 IH, m), 1.94 (2H,
I0 m), 2.24 (2H, t), 2.60 (2H, t), 2.96 (2H, d), 3.18 (3H, s), 3.63 (2H, t), 3.78 (IH, m), 3.95 (3H, s), 4.78 - 4.86 (IH, m), 7.46 - 7.51 (2H, m), 7.73 (IH, s), 8.04 (IH, d), 8.09 (IH, s), 8.39 (IH, d); MS m/z 534 [M+H]+.
Example 12; is 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino] -3-methoxy-N- [2-(l-piperidyl)ethyl] benzamide
A solution of HATU (147 mg, 0.385 mmol) in DMA (1 mL) was added to a mixture of 4-[(2- cyclopentyl-6-methyl-5-oxo-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien-10-yl)amino]- 3-methoxy-benzoic acid (Example 111; 144mg, 0.35 mmol), DIPEA (183uL, 1.05 mmol) and 20 2-(l-piperidyl)ethanamine (Aldrich, 56 mg 0.44 mmol) in DMA (1 mL). The resulting mixture was stirred at room temperature overnight. The mixture was absorbed onto an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by preparative reverse phase HPLC to give the title compound (86mg, 47% )
25
The following examples were prepared by an analogous process to that used in the preparation of Example 12 utilising the acid described in Example 111 and the appropriate amines.
30 Example 13: 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12- trien-9-yl)amino]-3-methoxy-N-(2-morpholin-4-ylethyl)benzamide
Example 14:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12- trien-9-yl)amino]-N-(2-dimethylaminoethyl)-3-methoxy-benzamide
Example 15:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-[(l-ethylpyrrolidin-2-yl)methyl]-3-methoxy-benzamide
Example 16:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12- trien-9-yl)amino]-3-methoxy-N-(2-pyrrolidin-l-ylethyl)benzamide
Example 17:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(5-diethylaminopentan-2-yl)-3-methoxy-benzamide
Example 18:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(2-diethylaminoethyl)-3-methoxy-benzamide
Example 19:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(3-dimethylaminopropyl)-3-methoxy-benzamide Example 20:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicycIo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[3-(4-methylpiperazin-l-yl)propyl]benzamide
Example 21:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(4-dimethylaminobutyl)-3-methoxy-benzamide
Example 22:
N-(l-azabicyclo[2.2.2]oct-8-yl)-4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10- tetrazabicyclo [5.4.0] undeca-8,10,12-trien-9-yl)amino]-3-methoxy-benzamide
Example 23:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8?10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[2-(2-oxoimidazolidin-l-yl)ethyl]benzamide
Example 24:
N-(2-acetamidoethyl)-4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10- tetrazabicyclo [5.4.0] undeca-8,10,12-trien-9-yl)amino]-3-methoxy-benzamide
Example 25:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-(3-morpholin-4-ylpropyl)benzamide
Example 26: 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(3-imidazol-l-ylpropyl)-3-methoxy-benzamide
Example 27:
4-[(6-cyclopentyI-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(2-imidazol-l-ylethyl)-3-methoxy-benzamide
Example 28;
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(l-dimethylaminopropan-2-yl)-3-methoxy-benzamide
Example 29:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[l-(2-methoxyethyl)-4-piperidyl]benzamide
Example 30:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8»10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(4-diethylaminobutyl)-3-methoxy-benzamide
Example 31: 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yI)amino]-N-(4-imidazol-l-ylbutyl)-3-methoxy-benzamide
Example 32: 4-[(6-cycIopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)ethyl]benzamide
Example 33:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-(4-pyrrolidin-l-ylbutyl)benzamide
Example 34:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[2-(4-methylpiperazin-l-yl)ethyl]benzamide
Example 35:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-[2-(3,3-difluoropyrrolidin-l-yl)ethyl]-3-methoxy-benzamide
Example 36:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8»10-tetrazabicyclo[5.4.0]undeca-8,10?12-trien-9- yl)amino]-N-[2-[(3R)-3-fluoropyrrolidin-l-yl]ethyl]-3-methoxy-benzamide
Example 37:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-[2-(4,4-difluoro-l-piperidyl)ethyl]-3-methoxy-benzamide
Example 38:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino] -3-methoxy-N- [3-(py ridin-2-ylamino)propyl] benzamide Example 39;
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-(l-methyl-3-piperidyl)benzamide
Figure imgf000070_0001
Figure imgf000070_0002
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
The following examples were prepared by an analogous process to that used in the preparation of Example 12 utilising the acid described in Example 111 and the appropriate BOC- protected amines. Prior to SCX purification the reaction mixture was treated with 4N HCl in dioxane (1 mL) and stirred at room temperature for 24 hr. The reaction mixtures were absorbed onto SCX columns, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by preparative HPLC to give the title compounds
Example 40:
N-(4-aminobutyl)-4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-9-yl)amino]-3-methoxy-benzamide
Example 41:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-(4-piperidyl)benzamide
Example 42: N-(3-aminopropyl)-4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9-yl)amino]-3-methoxy-benzamide
Example 43:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-(2-methylaminoethyl)benzamide
Example 44:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-(3-methylaminopropyl)benzamide
Example 45: 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-pyrrolidin-3-yl-benzamide
Example 46:
N-(3-amino-2,2-dimethyl-propyl)-4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9-yl)amino]-3-methoxy-benzamide
Example 47:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[[(3R)-pyrrolidin~3-yl]methyl]benzamide
Figure imgf000076_0001
Figure imgf000076_0002
Figure imgf000077_0001
Example 48: 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-2-fluoro-5-methoxy-N-(l-methyl-4-piperidyl)benzamide
10-chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10,12-trien-5-one (Intermediate I5 211 mg, 0.75 mmol) and 4-amino-2-fluoro-5-methoxy-N-(l-methyl-4- piperidyl)benzamide (Intermediate 27, 211 mg, 0.75 mmol) were combined with p-TSA (357 mg, 1.88 mmol) in 4-methyl-2-pentanol (1 mL) and heated to 150 °C for 18 hr. The cooled reaction mixture was diluted with methanol and water (approx 50 mL) and loaded onto a 50 g SCX-2 cartridge washing with methanol (100 mL) and eluting with 7 N methanolic ammonia (100 mL). The concentrated solution was purified by reversed phase HPLC. The title compound was obtained as a beige solid (178 mg, 45%).
1H NMR (399.902 MHz, DMSOd6) δ 1.50 - 1.81 (m, 10H), 1.90 - 2.00 (m, 4H), 2.16 (s, 3H), 2.58 - 2.61 (m, 2H), 2.72 (br d, 2H), 3.17 (s, 3H), 3.63 - 3.65 (m, 2H), 3.68 - 3.75 (m, IH), 3.92 (s, 3H), 4.83 (quintet, IH), 7.19 (d, IH), 7.79 - 7.82 (m, 2H), 8.11 (s, IH), 8.33 (d, IH); MS m/z 526 [M+H]+.
Example 49:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-(l-propan-2-yl-4-piperidyl)benzamide 4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien- 10- yl)amino]-3-methoxy -benzoic acid (Example 111; lOOmg, 0.24 mmol), N-Isopropyl-4- aminopiperidine (ABCR, 42 mg, 0.29 mmol), HATU (111 mg, 0.29mmol) and DIPEA (127 uL, 0.73 mmol) and DMF (3 mL) were combined and stirred at room temperature for 3 hours. The solvent was evaporated and the residue partitioned between DCM (10 mL) and water (10 mL). The organic phase was added to a 5g SCX-2 column pre-wet with MeOH (2 column volumes), flushed with MeOH (2 column volumes) and the crude product eluted with 2M ammonia in MeOH and solvents evaporated. The residue was taken up in DCM and purified on silica, eluting with a gradient of 0 - 5% MeOH / DCM followed by 5% then 10% and finally 15% MeOH / DCM. Fractions containing product were combined and evaporated to give the tile compound as a white solid (45 mg, 35%). i H NMR (400.132 MHz, CDCl3) δθ.99 (d, 6H), 1.55 - 1.73 (m, 8H), 2.00 (m, 4H), 2.27 (m,
2H), 2.60 (m, 2H), 2.69 (m, IH)5 2.81 (m, 2H)5 3.22 (s, 3H), 3.62 (m, 2H), 3.92 (m, 4H)5 4.83 (m, IH), 5.82 (d, IH), 7.14 (m, IH), 7.35 (d, IH), 7.59 (s, IH), 7.87 (s, IH), 8.43 (d, IH); MS m/z 536 [M+H]+.
Example 50; tert-butyl 4-[[4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-9-yl)amino]-3-methoxy-benzoyI]amino]piperidine-l-carboxylate
4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9, 1 l-tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien- 10- yl)amino]-3-methoxy-benzoic acid (Example 111; 113 mg, 0.27 mmol), tert-butyl 4- aminopiperidine-1-carboxylate (ABCR, 50mg, 0.25 mmol ), HATU (114 mg, 0.3 mmol) and DIPEA (130 uL, 0.75 mmol) and DMF (3 mL) were combined and stirred at room temperature for 3 hours. Solvent was evaporated and the residue partitioned between DCM (25 mL) and sat. aq. Bicarb. (25 mL) and gravity filtered through a PTFE cup. The organic phase was added to a silica column and eluted with a shallow gradient of 0 - 10% MeOH / DCM. Fractions containing product were combined and evaporated to a yellow gum to which ether was added and re-evaporated to give the title compound as an orange solid. (89mg,
70).
HNMR (400.132 MHz, CDCl3) δl.37 (m, HH), 1.53 - 1.71 (m, 6H), 1.97 (m, 4H), 2.60 (m, 2H), 2.86 (m, 2H), 3.22 (s, 3H), 3.62 (m, 2H), 3.91 (s, 3H), 4.05 (m, 3H), 4.83 (m, IH), 5.83 (d, IH), 7.15 (m, IH), 7.35 (m, IH), 7.60 (s, IH), 7.87 (s, IH), 8.44 (d, IH); MS m/z 594 [M+H]+.
Example 51:
Benzyl (lS,5R)-6-[[4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9-yl)amino]-3-methoxy-benzoyl]amino]-3- azabicy clo [3.1.0] hexane-3-carboxy late
4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-10- yl)amino]-3-methoxy-benzoic acid (Example 111; 113 mg, 0.27 mmol), benzyl (lS,5R)-6- amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 30; 50 mg, 0.25 mmol ), HATU (114 mg, 0.3 mmol) and DIPEA (130 uL, 0.75 mmol) and DMF (3 mL) were combined and stirred at room temperature for 3 hours. Solvent was evaporated and the residue partitioned between DCM (2 mL) and sat. aq. Bicarb. (2 mL), gravity filtered through a PTFE cup and solvents evaporated. The residue was taken up in DCM and purified on silica eluting with a gradient of 0 - 5% MeOH / DCM. Fractions containing product were combined and evaporated. The resultant material was purified by reversed phase HPLC.
HNMR (400.132 MHz, CDC13) δl.64 (m, 8H), 1.97 (m, 2H), 2.58 (m, 3H), 3.22 (s, 3H), s 3.46 (m, 2H), 3.62 (m, 2H), 3.78 (m, 2H), 3.90 (s, 3H), 4.82 (m, IH), 5.05 (s, 2H), 6.08 (s, IH), 7.12 (m, IH), 7.26 (m, 5H), 7.34 (d, IH), 7.61 (s, IH), 7.87 (s, IH), 8.43 (d, IH); MS m/z 626 [M+H]+.
The following examples were prepared by an analogous process to that used in theo preparation of Example 51 utilising the acid described in Example 111 and the appropriate amines.
Example 52; s tert-butyl (3R)-3-[[4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10- tetrazabicycloJS^.Olundeca-SjlOjll-trien-^y^aminoj-S-methoxy- benzoyl]amino]pyrrolidine~l-carboxylate
Amine available from Chempacific 0 H NMR (400.132 MHz, CDC13) δl.41 (s, 9H), 1.63 (m, 3H), 1.94 (m, 2H), 2.19 (m, IH), 2.60 (m, 2H), 3.26 (m, 4H), 3.43 (m, 2H), 3.65 (m, 3H), 3.91 (s, 3H), 4.59 (m, IH), 4.84 (m, IH), 6.01 (d, IH), 7.15 (m, 5H), 7.35 (d, IH), 7.62 (s, IH), 7.88 (s, IH), 8.45 (d, IH); MS m/z 580 [M+H]+. 5 Example 53: tert-butyl (3S)-3-[[4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9-yl)amino]-3-methoxy- benzoyl]amino]pyrrolidine-l-carboxylate
Amine available from Chempacific o HNMR (400.132 MHz, CDCl3) δl.41 (s, 9H), 1.64 (m, 6H), 1.93 (m, 3H), 2.19 (m, IH), 2.60 (m, 2H), 3.26 (m, 4H), 3.43 (m, 2H), 3.65 (m, 3H), 3.91 (s, 3H), 4.59 (m, IH), 4.84 (m, IH), 6.02 (d, IH), 7.15 (m, IH), 7.35 (d, IH), 7.62 (s, IH), 7.88 (s, IH), 8.45 (d, IH); MS m/z 580 [M+H]+.
Example 54; Benzyl 4-[[4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-9-yl)amino]-3-methoxy-benzoyl]amino]piperidine-l-carboxylate
4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien- 10- yl)amino]-3-methoxy-benzoic acid (Example 111 , 350 mg, 0.85 mmol), Benzyl 4- aminopiperidine-1-carboxylate (ABCR, 219 mg, 0.94 mmol ), HATU (388 mg, 1.02 mmol) and DIPEA (445 uL, 2.55 mmol) and DMF (5 mL) were combined and stirred at room temperature for 3 hours. Solvent was evaporated and the residues partitioned between DCM (2 mL) and sat. aq. Bicarb. (2 mL), gravity filtered through a PTFE cup and solvents evaporated. The residue was taken up in DCM and purified on silica eluting with a gradient of 0 - 5% MeOH / DCM. Fractions containing product were combined and evaporated. To give the title compound as an orange solid.
H NMR (400.132 MHz, CDCl3) δl.38 (m, 2H), 1.62 (m, 6H), 1.97 (m, 4H), 2.60 (m, 2H), 2.94 (m, 2H), 3.22 (s, 3H), 3.62 (m, 2H), 3.91 (s, 3H), 4.11 (m, 3H), 4.83 (m, IH), 5.07 (s, 2H), 5.82 (d, IH), 7.14 (m, IH), 7.27 (m, 5H), 7.34 (d, IH), 7.61 (s, IH), 7.87 (s, IH), 8.44 (d, IH); MS m/z 628 [M+H]+.
Example 55:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[(3R)-pyrrolidin-3-yl]benzamide tert-butyl (3R)-3-[[4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-9-yl)amino]-3-methoxy-benzoyl]amino]pyrrolidine-l-carboxylate (630 mg, 1 mmol) was dissolved in DCN (10 mL), TFA (10 mL) added and stirred at room temperature for 2 hr. The reaction mixture was added to a 10 g SCX-2 column pre wet with MeOH (2 column volumes), flushed with MeOH (2 column volumes) then the crude product eluted with 2M ammonia in MeOH and solvents evaporated. The residue was taken up in DCM and purified on silica eluting with a gradient of 0 - 10% 2M ammonia in MeOH / DCM then 10% 2M ammonia in MeOH / DCM. Fractions containing product were combined and evaporated to a gum, ether was added and re-evaporated to give the title compound as a solid. (300 mg, 74%)
HNMR (400.132 MHz, CDCl3) 61.62 (m, 8H), 1.98 (m, 2H), 2.19 (m, IH), 2.60 (m, 2H), 2.89 (m, 2H), 3.06 (m, IH), 3.17 (m, IH), 3.22 (s, 3H), 3.62 (m, 2H), 3.90 (s, 3H), 4.53 (m, IH)5 4.83 (m, IH), 6.24 (d, IH), 7.19 (m, IH), 7.37 (d, IH), 7.60 (s, IH), 7.87 (s, IH), 8.43 (d, IH); MS m/z 480 [M+H]+.
The following example was prepared by an analogous process to that used in the preparation of Example 56 utilising the BOC-protected material described in Example 54.
Example 56;
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[(3S)-pyrrolidin-3-yl]benzamide
HNMR (400.132 MHz, CDC13) δl.62 (m, 8H), 1.98 (m, 2H), 2.19 (m, IH), 2.60 (m, 2H), 2.85 (m, IH), 2.91 (m, IH), 3.06 (m, IH), 3.17 (m, IH), 3.22 (s, 3H), 3.62 (m, 2H), 3.90 (s, 3H), 4.53 (m, IH), 4.83 (m, IH), 6.24 (d, IH), 7.19 (m, IH), 7.37 (d, IH), 7.60 (s, IH), 7.87 (s, IH), 8.43 (d, IH); MS m/z 480 [M+H]+.
Example 57: N-[(lS,5R)-3-azabicyclo[3.1.0]hex-6-yl]-4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9-yl)amino]-3-methoxy-benzamide
Benzyl (1 S,5R)-6-[[4-[(6-cycloρentyl-2-methyl-3-oxo-2,6,8, 10-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-9-yl)amino]-3-methoxy-benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3- carboxylate (Example 51, 357mg, 0.57 mmol) was dissolved in MeOH (30 mL) and passed through the H-cube at 50 0C on full hydrogen mode at 1 mL per minute. The solution added to a 10 g SCX-2 column pre-wet with MeOH (2 column volumes), flushed with MeOH (2 column volumes) and crude product eluted with 2M ammonia in MeOH. The basic fractions were evaporated and the residue dissolved in DCM and purified on silica eluting with a gradient of 0 - 10% 2M ammonia in MeOH / DCM then 10% 2M ammonia in MeOH / DCM. Fractions containing product were combined and evaporated to a gum to which ether was added and re-evaporated to give the title compound as a cream solid. (172 mg, 42%). HNMR (400.132 MHz5 CDC13) δl.64 (m, 8H), 1.97 (m, 2H), 2.60 (m, 3H), 2.91 (m, 2H), 3.17 (m, 2H), 3.22 (s, 3H), 3.62 (m, 2H), 3.90 (s, 3H), 4.82 (m, IH), 6.02 (s, IH), 7.13 (m, IH), 7.35 (d, IH), 7.60 (s, IH), 7.87 (s, IH), 8.43 (d, IH); MS m/z 492 [M+H]+.
Example 58;
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(4-diethylaminocyclohexyl)-3-methoxy-benzamide
4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien- 10- yl)amino]-3-methoxy -benzoic acid (Example 111_, 100 mg, 0.24 mmol), N,N- diethylcyclohexane-l,4-diamine (ABChem, 46 mg, 0.28 mmol), HATU (111 mg, 0.29mmol) and DIPEA (127 uL, 0.73 mmol) and DMF (3 mL) were combined and stirred at room temperature for overnight. Solvent was evaporated and the residues partitioned between DCM (2 mL) and sat. aq. Bicarb. (2 mL), gravity filtered through a PTFE cup, solvent evaporated and the residue purified by reverse phase HPLC to give the title compound as a cream solid (114mg, 83%) MS m/z 564 [M+H]+. Retention Time 2.20 minutes
The following examples were prepared by an analogous process to that used in the preparation of Example 58 utilising the appropriate amines
Example 59:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-7-yl]benzamide Amine available from Chontech
HNMR (399.902 MHz, CDC13) δl.03 (m, 2H), 1.30 (m, 2H), 1.54 (m, 2H), 1.60 - 1.80 (m, 6H), 1.98 (m, 2H), 2.05 (m, 2H), 2.53 (m, 5H), 2.67 (m, 2H), 3.09 (m, 2H), 3.29 (s, 3H), 3.69 (m, 2H), 3.97 (s, 3H), 4.51 (m, IH), 4.90 (m, IH), 5.78 (d, IH), 7.23 (m, IH), 7.44 (m, IH), 7.66 (s, IH), 7.94 (s, IH), 8.49 (d, IH); MS m/z 548 [M+H]+.
Example 60: 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(4-dimethylaminocyclohexyl)-3-methoxy-benzamide
Amine available from ABChem
MS m/z 536 [M+H]+. Retention Time 1.92 minutes
Example 61:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(l-ethyl-4-piperidyl)-3-methoxy-benzamide 4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,l l-tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-10- yl)amino]-3-methoxy-N-(4-piperidyl)benzamide (Example 41; 80 mg, 0.16 mmol), Ethyl Bromide (ABCR, 13 uL, 0.18 mmol), Triethylamine (0.45 uL, 0.32 mmol) and DMF ( 3 mL) were combined and heated by microwave irradiation at 75 °C for 1 hr and thenat 80 °C for 30 minutes. The reaction mixture was purified by reverse phase HPLC to give the title compound as a white solide (56 mg, 66%)
H NMR (399.902 MHz, CDC13) δl.10 (t, 3H), 1.53 - 1.80 (m, 8H), 2.09 (m, 6H), 2.44 (m, 2H), 2.67 (m, 2H), 2.92 (m, 2H), 3.29 (s, 3H), 3.69 (m, 2H), 4.00 (m, 4H), 4.90 (m, IH), 5.90 (d, IH), 7.22 (m, IH), 7.42 (m, IH), 7.66 (s, IH), 7.94 (s, IH), 8.50 (d, IH); MS m/z 522 [M+H]+.
Example 62:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[(3R)-l-methylpyrrolidin-3-yl]benzamide
To 4~[(6-cycloρentyl-2-methyl-3-oxo-2,6,8, 10-tetrazabicyclo[5.4.0]undeca-8, 10,12-trien-9- yl)amino]-3-methoxy-N-[(3R)-pyrrolidin-3-yl]benzamide (Example 55, 140 mg, 0.29 mmol) dissolved in THF (2 mL) was added acetic acid (17uL, 0.29 mmol) followed by aqueous formaldehyde (1 mL). The reaction mixture was stirred at room temperature for 30 mins and sodium triacetoxyborohydride (100 mg, 0.47 mmol) added and the reaction mixture stirred for a further 2 hrs. The solvent was evaporated and the residue neutralised with sat. aq. sodium bicarbarbonate and extracted with DCM (2 x 5ml), gravity filtered through a PTFE cup and solvent evaporated. The resultant material was purified by reverse phase HPLC to give the title compound as a white solid ( 97mg, 67%) H NMR (399.902 MHz, CDC13) δl.60 - 1.80 (m, 7H), 2.05 (m, 2H)5 2.22 (m, IH), 2.38 (s, 3H), 2.44 (m, IH), 2.55 (m, IH), 2.67 (m, 2H), 2.77 (m, IH), 2.96 (m, IH), 3.29 (s, 3H), 3.69 (m, 2H), 3.97 (s, 3H), 4.69 (m, IH), 4.91 (m, IH), 6.45 (d, IH), 7.27 (m, IH), 7.43 (m, IH), 7.67 (s, IH), 7.94 (s, IH), 8.50 (d, IH); MS m/z 494 [M+H]+.
The following example was prepared by an analogous process to that used in the preparation of Example 62 utilising the pyrrolidine analogue from Example 56
Example 63: 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[(3S)-l-methylpyrrolidin-3-yl]benzamide
HNMR (399.902 MHz, CDCl3) δl.60 - 1.80 (m, 7H), 2.05 (m, 2H), 2.22 (m, IH), 2.38 (s, 3H), 2.44 (m, IH), 2.55 (m, IH), 2.67 (m, 2H), 2.77 (m, IH), 2.96 (m, IH), 3.29 (s, 3H), 3.69 (m, 2H), 3.97 (s, 3H), 4.68 (m, IH), 4.91 (m, IH), 6.45 (d, IH), 7.27 (m, IH), 7.43 (m, IH), 7.67 (s, IH), 7.94 (s, IH), 8.50 (d, IH); MS m/z 494 [M+H]+.
Example 64:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[(lS,5R)-3-methyl-3-azabicyclo[3.1.0]hex-6-yl]benzamide To N-[(lS,5R)-3-azabicyclo[3.1.0]hex-6-yl]-4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9-yl)amino]-3-methoxy-benzamide (Example 57, 114 mg, 0.23 mmol) dissolved in THF (2 mL) was added acetic acid (13 uL, 0.23 mmol) (material came out of solution), followed by aqueous formaldehyde (0.5 mL, material all dissolved again). The reaction mixture was stirred at room temperature for 30 mins and sodium triacetoxyborohydride (100 mg, 0.47 mmol) added and the reaction mixture stirred for a further 2 hrs. The solvent was evaporated and the residue neutralised with sat. aq. sodium bicarbonate and extracted with DCM (15 mL), filtered through a PTFE cup and evaporated. The resultant material was purified by reverse phase HPLC.
H NMR (399.902 MHz, CDCl3) δl.56 - 1.80 (m, 8H), 2.04 (m, 2H), 2.30 (s, 3H), 2.39 (m, 2H), 2.66 (m, 2H), 3.12 (m, IH), 3.17 (m, 2H), 3.29 (s, 3H), 3.69 (m, 2H), 3.96 (s, 3H), 4.89 (m, IH), 6.06 (s, IH), 7.18 (m, IH), 7.43 (m, IH), 7.66 (s, IH), 7.94 (s, IH), 8.48 (d, IH); MS m/z 506 [M+H]+.
Example 65: Methyl (lS,3R)-3^[4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9-yl)amino]-3-methoxy- benzoyl] amino] cy clopentane-1-carboxylate
4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien- 10- yl)amino]-3-methoxy-benzoic acid (Example 111_, 1.1 g, 2.7 mmol), methyl (lS,3R)-3- aminocyclopentane-l-carboxylate (Intermediate 31; 528 mg, 2.94 mmol ), HATU (1.22 g, 3.22 mmol) and DIPEA (1.86 mL, 10.68 mmol) and DMF (10 mL) were combined and stirred at room temperature overnight. Solvent was evaporated and the residue partitioned between saturated sodium carbonate and DCM then gravity filtered through a PTFE cup. The organic phase was passed through a silica pad eluting with EtOAc. Fractions containing product were combined and evaporated to give a brown gum which was dissolved in MeOH and added to a 50g SCX-2 column pre-wet with MeOH (2 column volumes). Flushed with MeOH (2 column volumes) and product eluted with 2M ammonia in MeOH. Solvent was evaporated to a yellow gum, ether was added then re-evaporated to give the title compound as a yellow foam (1.21 g, 84%) H NMR (399.902 MHz, CDCl3) δl.62 (m, 2H), 1.75 (m, 4H), 1.95 (m, 4H), 2.02 - 2.22 (m, 4H), 2.67 (m, 2H), 3.02 (m, IH), 3.29 (s, 3H), 3.69 (m, 2H), 3.72 (s, 3H), 3.99 (s, 3H), 4.60 (m, IH), 4.91 (m, IH), 7.25 (m, IH), 7.38 (m, IH), 7.49 (m, IH), 7.67 (s, IH), 7.94 (s, IH), 8.53 (d, IH); MS m/z 537 [M+H]+.
Example 66:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)ammo]-N-[2-(dipropan~2-ylamino)ethyl]-3-methoxy-benzamide
A solution of 4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,l l-tetrazabicyclo[5.4.0]undeca-7,9,l 1- trien-10-yl)ammo]-3-methoxy-benzoic acid (Example 111_, 100 mg, 0.24 mmol), DIPEA ( 0.127 mL, 0.73 mmol) and HATU (120 mg, 0.32 mmol) in DMF (2 mL) was stirred at ambient temperature for 10 mins. The pale brown solution was add to N,N-dipropan-2- ylethane-l,2-diamine (ABCR, 43 mg, 0.3 mmol) and the resulting solution stirred at ambient temperature for 18 hours. The reaction solution was purified by reverse phase HPLC to give the title compound as a white solid (43 mg, 33%); MS m/z 538 [M+H]+. Retention Time 2.49 mins.
The following examples were prepared by an analogous process to that used in the preparation of Example 66, utilising the appropriate amines. NMR data was obtained on a selection of compounds as indicated.
Example 67:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-pyridin-4-yl-benzamide
Example 68: 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3~methoxy-N-(3-pyrrolidin-l-ylpropyl)benzamide
Example 69:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[3-(l-piperidyl)propyl]benzamide
Example 70:
N-[3-(azepan-l-yl)propyl]-4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9-yl)amino]-3-methoxy-benzamide
Example 71:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,840-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[(lS,5R)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]benzamide
Example 72: 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicycIo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-(l,2,2,6,6-pentamethyl-4-piperidyl)benzamide
Example 73;
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[l-(l-piperidyl)propan-2-yl]benzamide
Example 74: 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-pyridin-3-yl-benzamide
Example 75:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[2-methyl-2-(l-piperidyl)propyl]benzamide
Example 76:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-(pyridin-3-ylmethyl)benzamide
Example 77:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-(4-methoxyphenyl)benzamide
Example 78:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(3-diethylaminopropyl)-3-methoxy-benzamide
IH NMR (400.132 MHz5 DMSOd6) δ 0.95 (t, 6H)5 1.66 (m, 8H), 1.94 (m, 2H), 2.45 (m, 6H)5 2.59 (m, 2H), 3.17 (s, 3H), 3.63 (m, 2H)5 3.94 (s, 3H), 4.81 (m, IH), 7.45 (d, 2H)5 7.48 (s, IH)5 7.73 (S5 IH)5 8.08 (s, IH), 8.38 (s, IH), 8.38 (d, 2H)
Example 79: 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[2-(l-methylpyrrolidin-2-yl)ethyl]benzamide
Example 80:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-(pyridin-4-ylmethyl)benzamide
Example 81:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-(2-methyl-l-pyrrolidin-l-yl-propan-2-yl)benzamide
1H NMR (400.132 MHz, DMSO-d6) δ 1.37 (s, 6H), 1.67 (m, 10H), 1.94 (m, 2H), 2.60 (m, 6H), 2.78 (s, 2H), 3.17 (s, 3H), 3.63 (m, 2H), 3.94 (s, 3H), 4.80 (m, IH), 7.37 (d, IH), 7.42 (s, IH), 7.48 (s, IH)5 7.72 (s, IH), 8.08 (s, IH), 8.36 (d, IH)
Example 82:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-[[(2S)-l-(cyclopropylmethyl)pyrrolidin-2-yl]methyl]-3-methoxy-benzamide 1HNMR (400.132 MHz, DMSOd6) δ 0.01 (m, 2H), 0.34 (m, 2H), 0.80 (m, IH), 1.59 (m, 10H), 1.84 (m, 2H), 1.96 (m, IH), 2.12 (m, IH), 2.50 (m, 3H), 2.64 (m, IH), 3.01 (m, 2H), 3.08 (s, 3H), 3.32 (m, IH), 3.53 (m, 2H), 3.84 (s, 3H), 4.71 (m, IH), 7.36 (d, IH), 7.39 (s, IH), 7.63 (s, IH), 7.98 (s, IH), 8.12 (t, IH), 8.28 (d, IH)
Example 83:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[[l-(pyrrolidin-l-ylmethyl)cyclopropyl]methyl]benzamide
1E NMR (400.132 MHz, DMSO-d6) δ 0.29 (s, 2H), 0.51 (s, 2H), 1.66 (m, 10H), 1.94 (m, 2H), 2.43 (s, 2H), 2.51 (m, 4H), 2.59 (m, 2H), 3.18 (s, 3H), 3.37 (d, 2H), 3.63 (m, 2H), 3.95 (s, 3H), 4.82 (m, IH), 7.38 (d, IH), 7.47 (s, IH), 7.74 (s, IH), 8.09 (s, IH), 8.38 (d, IH), 8.49 (t, IH). Example 84;
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[(l-methyl-3-piperidyl)methyl]benzamide
1H NMR (400.132 MHz, DMSOd6) δ 0.92 (m, IH), 1.44 (m, IH), 1.73 (m, 10H), 1.94 (m, 2H), 2.13 (s, 3H), 2.64 (m, 5H), 3.15 (m, 2H), 3.18 (s, 3H), 3.63 (m, 2H), 3.95 (s, 3H)5 4.81 (m, IH), 7.49 (m, 2H), 7.73 (s, IH), 8.08 (s, IH), 8.32 (t, IH), 8.38 (d, IH)
Example 85:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-[2-(l-methyl-2-piperidyl)ethyl]benzamide
1H NMR (400.132 MHz, DMSOd6) δ 1.45 (m, 14H), 1.95 (m, 4H), 2.21 (s, 3H), 2.59 (m, 2H), 2.76 (m, IH), 3.17 (s, 3H), 3.31 (m, 2H), 3.63 (m, 2H), 3.94 (s, 3H), 4.81 (m, IH), 7.46
(m, 2H), 7.72 (s, IH), 8.08 (s, IH), 8.35 (t, IH), 8.38 (d, IH)
Figure imgf000090_0001
Figure imgf000090_0002
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Example 86:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino] -3-methoxy-N-(l-tert-butyl-4-piperidyl)benzamide
A solution of N-[(lS,5R)-3-azabicyclo[3.1.0]hex-6-yl]-4-[(6-cyclopentyl-2-methyl-3-oxo- 2,6,8, 10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9-yl)amino]-3-methoxy-benzamide (Example 57, 250mg, O.όlmmol), l-tert-butylpiperidin-4-amine (Activate, 96mg, O.όlmmol), HATU (349mg, 0.92mmol) and DIPEA (32IuL, 1.83mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was loaded on to an SCX-3 column pre- wet with methanol. The column was washed with methanol and then with 2% 7N ammonia/methanol to elute the crude product. The product containing fractions were evaporated and the resultant material purified by reverse phase HPLC to give the title compound as a white solid (137mg, 40.8%). 1H NMR (399.9 MHz, DMSO-d6) δl.04 (9H, s), 1.55 (2H, s), 1.62 - 1.63 (3H, m), 1.73 (3H, d), 1.80 (2H, d), 1.95 (2H, t), 2.10 (2H, t), 2.60 (2H, t), 3.01 (2H, d), 3.18 (3H, s), 3.62 -3.64 (2H, t), 3.72 (IH, m), 3.95 (3H, s), 4.79 - 4.84 (IH, m), 7.46 (IH, d), 7.50 (IH, d), 7.73 (IH, s), 8.02 (IH, d), 8.09 (IH, s), 8.39 (IH, d); MS m/z 549[M+H]+.
Example 87:
(lS,3R)-3-[[4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-9-yl)amino]-3-methoxy-benzoyl]amino]cyclopentane-l-carboxylic acid To a solution of Methyl (lS,3R)-3-[[4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9-yl)amino]-3-methoxy- benzoyl]amino]cyclopentane-l-carboxylate (Example 65, 1.21 g, 2.25 mmol) in 4:1 THF / water (20 mL) was added lithium hydroxide (472 mg, 11.25 mmol) and the reaction mixture stirred at room temperature overnight. The solvent was evaporated and the residue diluted with water. IM citric acid was added until precipitation ceased (pH 3 — 4) and the resultant suspension stirred for 20 minutes. The resulting cream precipitate was filtered off, washed with water followed by isohexane and dried under vacuum to yield the title compound (1.08 g, 92%)
HNMR (399.902 MHz, DMSOd6) δl.62 - 1.95 (m, 12H), 2.07 (m, IH), 2.59 (m, 3H), 2.72 (m, 2H), 3.18 (s, 3H), 3.63 (m, 2H), 3.95 (s, 3H), 4.28 (m, IH), 4.81 (m, IH), 7.51 (m, 2H), 7.74 (s, IH), 8.09 (s, IH), 8.38 (d, IH), 8.85 (s, IH); MS m/z 523 [M+H]+.
Example 88:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-[(lR,3S)-3-(dimethylcarbamoyl)cyclopentyl]-3-methoxy-benzamide
A solution of (1 S,3R)-3-[[4-[(6-cycloρentyl-2-methyl-3-oxo-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-9-yl)ammo]-3-methoxy- benzoyl]amino]cyclopentane-l-carboxylic acid (Example 87, 100 mg, 0.19 mmol), HATU
(80 mg, 0.21 mmol) and DIPEA (100 uL, 0.73 mmol) in DMF (3 mL) was stirred at room temperature for 10 minutes. Dimethylamine solution in THF (1 mL) was added and the reaction mixture stirred at room temperature overnight. Solvent was evaporated and the resultant marterial purified by reverse phase HPLC to yield the title compound as a yellow solid (80 mg, 86%)
H NMR (400.132 MHz, CDCl3) 51.62 (m, 2H), 1.75 (m, 4H), 1.84 (m, 2H), 2.06 (m, 6H), 2.67 (m, 2H), 2.99 (s, 3H), 3.11 (s, 3H), 3.31 (m, 4H), 3.69 (m, 2H), 3.99 (s, 3H)5 4.58 (m, s IH), 4.91 (m, IH), 7.53 (m, 2H), 7.67 (s, IH), 7.93 (s, IH), 8.44 (d, IH), 8.51 (d, IH); MS m/z 550 [M+H]+.
Example 89:
N-cyclohexyl-4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-o 8,10,12-trien-9~yl)amino] benzamide
A solutiom of 4-amino-N-cyclohexyl-benzamide (TimTec, 108 mg, 0.5 mmol), 10-Chloro-2- cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1, 140mg, 0.5mmol) and p-toluenesulphonic acid monohydrate(238mg, 1.25mmol) in 4- methyl-2-pentanol (3ml) was heated at 14O0C for 3h. The mixture was allowed to cools causing a solid to form. Methanol and DCM were added to give a solution that was absorbed onto an SCX-3 column and washed with methanol. The product with eluted with arnmonia/niethanol and the product containing fractions were concentrated. Purification by preparative, reverse phase chromatography (Note 1) gave the title compound as a white solid (35mg, 15%). 0 1H NMR (399.9 MHz, DMSO-(I6) δl.l 1 - 1.19 (IH, m), 1.26 - 1.37 (4H5 m), 1.60 - 1.85 (HH, m), 1.97 - 2.01 (2H, m), 2.59 (2H, m), 3.18 (3H, s), 3.62 - 3.65 (2H, m), 3.72 - 1.76 (IH, m), 4.85 (IH, m), 7.75 - 7.81 (4H, m), 7.93 (IH, d), 8.09 (IH, s), 9.44 (IH, s); MS m/z 463 [M+H]+. 5 Example 90:
N-cyclohexyl-4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-9-yl)amino]-3-methoxy-benzamide
A solution of HATU (147 mg, 0.385 mmol) in DMA (1 niL) was added to a mixture of 4-[(2- cyclopentyl-6-methyl-5-oxo-2,6,9,l l-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10-yl)amino]-0 3-methoxy-benzoic acid (Example 111, 144mg, 0.35 mmol), DIPEA (183 uL, 0.385 mmol) and Cyclohexylamine (Aldrich, 44 mg, 0.44 mmol) in DMA (1 mL). The resulting mixture was stirred at room temperature overnight. The mixture was absorbed onto an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated in vacuo. The resultant material was purified by preparative reverse phase HPLC to yield the title compound as a white solid (7 mg, 4%). m/z 493 [M+H]+. Retention Time 2.57 minutes
Example 91;
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino] -3-me thoxy-N-methyl-benzamide 4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,l l-tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-10- yl)amino]-3-methoxy-benzoic acid (Example 111_, lOOmg, 0.24 mmol), 2M Methylamine in THF (365 uL, 0.73 mmol), HATU (111 mg, 0.29mmol) and DIPEA (127 uL, 0.73 mmol) and DMF (3 mL) were combined and stirred at ambient temperature overnight. Solvent was evaporated and the residue partitioned between DCM (2 mL) and sat. aq. Bicarb. (2 mL), ands gravity filtered through a PTFE cup. The organic phase was added to a silica column, eluting with a gradient of 0 - 10% MeOH / DCM and solvent evaporated from product containing fractions. The resultant material was purified by reverse phase HPLC to yield the title compound as a white solid. (45 mg, 44 %) i H NMR (400.132 MHz, CDCl3) δl.62 (m, 6H), 1.98 (m, 2H), 2.60 (m, 2H), 2.95 (d, 3H),0 3.22 (s, 3H), 3.62 (m, 2H), 3.90 (s, 3H), 4.83 (m, IH), 6.00 (d, IH), 7.17 (m, IH), 7.37 (d, IH), 7.59 (s, IH), 7.87 (s, IH), 8.44 (d, IH); MS m/z 454 [M+H]+.
The following example was prepared by an analogous process to that used in the preparation of Example 91 utilising Ammonium Chloride and 3 additional equivalents of DIPEA and5 collecting the product as a solid precipitated from the work-up procedure with DCM and saturated aqueous Sodium Bicarbonate solution.
Example 92; o 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- y l)amino] -3-methoxy-benzamide H NMR (400.132 MHz, DMSOd6) δl.73 (m, 6H), 2.00 (m, 2H), 2.64 (m, 2H), 3.23 (s, 3H), 3.68 (m, 2H), 3.99 (s, 3H), 4.86 (m, IH), 7.22 (s, IH), 7.57 (m, 2H), 7.78 (s, IH), 7.92 (s, IH), 8.13 (s, IH), 8.44 (d, IH); MS m/z 411 [M+H]+.
s The following examples were prepared by an analogous process to that used in the preparation of Example 66, utilising the appropriate amines. NMR data was obtained on compounds when indicated.
Example 93: io 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3~methoxy-N-propyl-benzamide
Example 94:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- I5 yl)amino]-N-(cyclopropylmethyl)-3-methoxy-benzamide
Example 95:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-propan-2-yl-benzamide
20 1H NMR (400.132 MHz, DMSOd6) δ 1.19 (d, 6H), 1.67 (m, 6H), 1.95 (m, 2H), 2.59 (m, 2H), 3.18 (s, 3H), 3.63 (m, 2H), 3.95 (s, 3H), 4.12 (m, IH), 4.82 (m, IH), 7.49 (m, 2H), 7.72 (s, IH), 8.04 (d, IH)5 8.08 (s, IH), 8.38 (d, IH)
Example 96:
25 N-benzyl-4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo [5.4.0] undeca-8,10,12- trien-9-yl)amino]-3-methoxy-benzamide
Figure imgf000097_0001
Figure imgf000098_0001
Example 97; 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]benzamide
4-amino-N-cyclohexyl-benzamide (TimTec, 108 mg, 0.5 mmol), 10-Chloro-2-cyclopentyl-6- methyl-2,6,9,l l-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 1, lOOmg, 0.36 mmol), the 4-aminobenzamide (Aldrich, 59 mg, 0.43 mmol) and p-toluenesulphonic acid (137 mg, 0.72 mmol) were heated together in 4-methyl-2-pentanol (4ml) at 1200C for 22 hours. The reaction was cooled to ambient temperature and passed down a 5g SCX-2 column pre-wet with methanol. The product was eluted with 2M NH3/MeOH and solvent evaporated. The resultant material was purified by reverse phase HPLC to yield the title compound as a white solid (37 mg, 27%) 1H NMR (400.132 MHz, DMSOd6) δ 1.67 (m, 6H), 1.97 (m, 2H), 2.59 (m, 2H), 3.18 (s, 3H), 3.63 (m, 2H), 4.84 (m, IH), 7.08 (s, IH), 7.77 (s, IH), 7.79 (s, 4H), 8.08 (s, IH), 9.46 (s, lH); MS m/z 381 [M+H]+.
The following example was prepared by an analogous process to that used in the preparation of Example 66 utilising the appropriate amine.
Example 98; N-cyclobutyl-4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8510-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-9-yl)amino]-3-methoxy-benzamide
1H NMR (400.132 MHz, DMSOd6) δ 1.67 (m, 8H), 1.95 (m, 2H), 2.09 (m, 2H), 2.23 (m, 2H), 2.59 (m, 2H), 3.18 (s, 3H), 3.63 (m, 2H), 3.95 (s, 3H), 4.43 (m, IH), 4.82 (m, IH), 7.48 (m, 2H), 7.72 (s, IH), 8.09 (s, IH), 8.41 (m, 2H); MS m/z 465 [M+H]+.
Example 99:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10jl2-trien-9- yl)amino]-3-methoxy-N-phenyl-benzamide
10-Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1, 100 mg, 0.36 mmol), 4-amino-3-methoxy-N-phenyl-benzamide (Apin, 104 mg, 0.43 mmol) and p-toluenesulphonic acid monohydrate (137 mg, 0.72 mmol) were vortexed and heated together in 4-methyl-2-pentanol (4 mL) at 1000C for 24 hours.. The crude reaction mixture was loaded onto an SCX-2 (5g) column pre-wet with MeOH. The column was washed with MeOH and the product eluted with 2M NH3/MeOH. Solvent was evaporated and the resultant material was purified by reverse phase HPLC to yield the title compound as a white solid ( 64 mg, 36 %). MS m/z 487 [M+H]+. Retention Time 3.81 minutes
Example 100: 4-[(6-cycIopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-propan-2-yl-benzamide 10-Chloro-2-cyclopentyl-6-methyl-256,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1, 134mg, 0.48mmol), 4-amino-N-propan-2-yl-benzamide (Butt Park, 86 mg, 0.48 mmol) and p-toluenesulphonic acid monohydrate (227 mg, 1.19 mmol) in 4-methyl-2- pentanol (4 niL) were heated at 14O0C for 2h. The reaction mixture was loaded onto an SCX-3 s column pre-wet with methanol. The column was washed with methanol to remove p- toluenesulphonic acid monohydate and then eluted with 2% 7N ammonia/methanol.. Product containing fractions were evaporated and the resultant material purified by reverse phase HPLC to yield the title compound as a white solid (121 mg, 60%). 1H NMR (399.9 MHz, DMSOd6) δl.17 (6H, d), 1.63 (4H, m), 1.74 (2H, m), 1.97 - 1.99 (2H,
I0 d), 2.58 - 2.61 (2H, t), 3.18 (3H, s), 3.62 - 3.65 (2H, t), 4.07 - 4.13 (IH, m), 4.85 (IH, m), 7.71 - 7.82 (4H, m), 7.95 - 7.97 (IH, d), 8.09 (IH, s), 9.44 (IH, s); MS m/z 423 [M+H]+.
The following examples were prepared by an analogous process to that used in the preparation of Example 100 utilising the appropriate aniline. is
Example 101:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino] -N-phenyl-benzamide
Amine available from Aldrich 20 1H NMR (399.9 MHz, DMSO-d6) δl.64 - 1.67 (4H, m), 1.72 - 1.75 (2H, m), 1.99 (2H, m),
2.60 (2H5 1), 3.19 (3H, s), 3.63 (2H, t), 4.87 (IH, m), 7.09 (IH, t), 7.35 (2H, m), 7.76 - 7.79 (2H, d), 7.90 (4H, s), 8.11 (IH, s), 9.55 (IH, s), 10.00 (IH, s); MS m/z 423 [M+H]+.
Example 102:
25 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-methyl-benzamide
Amine available from TimTec
1H NMR (399.9 MHz, DMSO-d6) δl.63 (4H, m), 1.70 - 1.74 (2H, m), 1.97 (2H, m), 2.58 -
2.61 (2H, t), 2.78 (3H, d), 3.18 (3H, s), 3.62 - 3.65 (2H, t), 4.84 (IH, m), 7.75 (2H, d), 7.81 so (2H, d), 8.09 (IH, s), 8.20 (IH5 d)5 9.46 (IH, s); MS m/z 395 [M+H]+.
Example 103: 6-cyclopentyl-9-[[2-methoxy-4-(2-pyrrolidin-l-ylethylamino)phenyl]amino]-2-methyl- 2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
10-Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1, 140 mg, 0.5 mmol) 2-methoxy-N'-(2-pyrrolidm-l-ylethyl)benzene-l,4- s diamine (Intermediate 35, 141 mg, 0.6 mmol), and p-toluenesulphonic acid monohydrate (227 mg, 1.19 mmol) in 4-methyl-2-pentanol (4 mL) were heated by microwave irradiation at 160 0C for 1 hour. The reaction mixture was absorbed onto an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and the material produced was purified by normal phase chromatography usingo 0-10% amrnoma/methanol to yield the title compound as a solid (100 mg, 42 %).
1H NMR (500.13 MHz, DMSO-d6) a 1.55 - 1.62 (4H, m), 1.68 - 1.75 (6H, m), 1.85 - 1.92 (2H, m), 2.54 - 2.56 (6H, m), 2.67 (2H, t), 3.15 - 3.19 (5H, m), 3.58 - 3.60 (2H, m), 3.80 (3H, S)5 4.64 - 4.71 (IH, m), 4.87 (IH, t), 6.19 (IH, dd), 6.36 (IH, d), 7.12 (IH, s), 7.67 (IH, d), 7.93 (IH, s); MS nVz 480 [MH-H]+. 5
The following examples were prepared by an analogous process to that used in the preparation of Example 103, utilising the appropriate aniline. NMR data is recorded where obtained. o Example 104:
6-cyclopentyl-9-[[2-methoxy-4-[methyl-(l-methyl-4-piperidyl)amino]phenyl]amino]-2- methyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Example 105: 5 6-cyclopentyl-9-[[2-methoxy-4-[4-(2-methoxyethyl)piperazin-l-yl]phenyl]amino]-2- methyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Example 106:
6-cyclopentyl-9-[[2-methoxy-4-[4-(l-piperidyl)-l-piperidyl]phenyl]amino]-2-methyl-0 2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one Example 107:
6-cycIopentyl-9-[[4-(2-dimethylaminoethylamino)-2-methoxy-phenyl]amino]-2-methyl-
2,6,840-tetrazabicyclo[5A0]undeca-8,1042-trien-3-one
1H NMR (400.13 MHz, CDCl3) δ 1.55 - 1.76 (7H, m), 1.99 - 2.02 (2H, m), 2.31 (6H, s), 2.60 - 2.66 (4H, m), 3.19 (2H, t), 3.27 (3H, s), 3.64 - 3.68 (2H, m), 3.85 (3H, s), 4.80 - 4.88 (IH, m), 6.23 - 6.26 (IH, m), 6.29 (IH, d), 7.09 (IH, s), 7.88 (IH, s), 8.03 (IH, d).
Example 108:
9-[[4-(4-cyclohexylpiperazin-l-yl)-2-methoxy-phenyl]amino]-6-cyclopentyl-2-methyl- 2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
IHNMR (400.13 MHz, CDCl3) δ 1.10 - 1.37 (4H, m), 1.55 - 1.78 (8H, m), 1.81 - 1.89 (2H, m), 1.95 - 2.05 (4H, m), 2.44 (IH, s), 2.65 - 2.67 (2H, m), 2.85 (4H, s), 3.24 (4H, s), 3.28 (3H, s), 3.66 - 3.69 (2H, m), 3.89 (3H, s), 4.82 - 4.91 (IH, m), 6.54 - 6.57 (2H, m), 7.24 (IH, s), 7.90 (IH, s), 8.19 (IH, d)
Example 109:
6-cyclopentyl-9-[[2-methoxy-4-(4-methyl-l,4-diazepan-l-yl)phenyl]amino]-2-methyl-
2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one IH NMR (400.13 MHz, CDCl3) δ 1.53 - 1.78 (6H, m), 1.97 - 2.08 (4H, m), 2.42 (3H, s), 2.62 - 2.68 (4H, m), 2.75 - 2.78 (2H, m), 3.27 (3H, s), 3.50 (2H, t), 3.58 - 3.62 (2H, m), 3.64 - 3.67 (2H, m), 3.87 (3H, s), 4.81 - 4.88 (IH, m), 6.27 (IH, d), 6.28 (IH, s), 7.06 (IH, s), 7.88 (IH, m), 8.02 (IH, d)
Example 110:
6-cyclopentyl-9-[[2-methoxy-4-(4-pyrrolidin-l-yH-piperidyl)phenyl]amino]-2-methyl- 2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Figure imgf000103_0001
Figure imgf000103_0002
Figure imgf000104_0001
Example 111:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-benzoic acid
To a solution of 10-Chloro-2-cyclopentyl-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-5-one (Intermediate 1, 10.62 g, 36 mmol) and 4-amino-3-methoxybenzoic acid (Aldrich, 6.795 g, 40.7 mmol) in ethanol (150 mL) was added water (450 mL) and cone hydrochloric acid 96 mL, 72 mmol). The mixture was heated under reflux for 36 hours. The reaction was cooled and a brown solid precipitate formed which was filtered, triturated with cold acetonitrile and dried in vacuo to give the title compound (10.1 g, 68 %). 1H NMR (399.9 MHz, DMSOd6) δl.55 - 1.75 (6H, m), 1.87 - 1.95 (2H, m), 2.71 - 2.75 (2H, m), 3.18 (3H, s), 3.71 - 3.76 (2H5 m), 3.95 (3H, s), 4.79 - 4.93 (IH, m), 7.58 - 7.62 (2H, m), 8.19 (IH, d), 8.19 (IH, s), 9.37 (IH, s); MS rn/z 412 [M+H]+. Example 112:
6-cyclopentyl-2-methyl-9-[(2,4,6-trimethoxyphenyl)amino]-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
2,4,6-trimethoxyaniline (Maybridge, 104 mg, 0.56 mmol), lO-Chloro-2-cyclopentyl-o- methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 1, 150 mg, 0.56 mmol) and p-toluenesulphonic acid monohydrate (268 mg, 1.41 mmol) in 4-methyl-2- pentanol (4 niL) were heated at 14O0C for 2h. The reaction solution was loaded on to an SCX- 3 column pre-wet with methanol. The column was washed with methanol to remove p- toluenesulphonic acid monohydate and then washed with 2% 7N ammonia/methanol to elute the crude product. Product containing fractions were evaporated and the resultant material purified by reverse phase HPLC to yield the title compound as a white solid (140mg, 58%) 1HNMR (399.9 MHz, DMSOd6) δl.32 - 1.68 (8H, m), 2.46 - 2.48 (2H, t), 3.13 (3H, s), 3.50 (2H, t), 3.70 (6H, s), 3.79 (3H, s), 4.32 (IH, m), 6.25 (2H, s), 7.37 (IH, s), 7.85 (IH, s); MS m/z 429 [M+H]+.
Example 113;
6-cyclopentyl-9-[[2-methoxy-4-[(l-methyl-4-piperidyl)oxy]phenyl]amino]-2-methyl- 2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
10-Chloro-2-cycloρentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1, 150 mg, 0.53 mmol), 2-methoxy-4-[(l-methyl-4-piperidyl)oxy]aniline (Intermediate 43 (124 mg, 0.53 mmol) and p-toluenesulphonic acid monohydrate (255 mg, 1.34 mmol) heated in 4-methyl-2-pentanol (4 mL) at 14O0C for 2h. The reaction solution was loaded on to an SCX-2 column pre-wet with methanol. The column was washed with methanol to remove p-toluenesulphonic acid monohydrate and then washed with 2% 7N ammonia/methanol to elute the crude product. Product containing fractions were evaporated and the resultant material purified by reverse phase HPLC to yield the title compound as a red gum (189 mg, 82 %).
1HNMR (399.9 MHz, DMSOd6) δl.53 - 1.56 (4H, m), 1.60 (2H, d), 1.63 - 1.68 (4H, m), 1.84 (2H, d), 1.92 (2H, d), 2.20 (3H, s), 2.18 - 2.22 (2H, m), 2.63 (2H, t), 3.15 (3H, s), 3.56 - 3.59 (2H, t), 3.81 (3H, s), 4.33 (IH, m), 4.64 (IH, m), 6.49 - 6.52 (IH, m), 6.62 (IH, d), 7.51 (IH, s), 7.82 (IH, d), 7.98 (IH, s); MS m/z 481 [M+H]+.
The following examples were prepared by an analogous process to that used in the preparation of Example 113 utilising the appropriate aniline indicated.
Example 114:
6-cycIopentyl-9-[[2-methoxy-4-(l-methylpyrrolidin-3-yl)oxy-phenyl]amino]-2-methyl-
2^840-tetrazabicyclo[5A0]undeca-8,10,12-trien-3-one Starting aniline - 2-methoxy-4-(l-methylpyrrolidin-3~yl)oxy-aniline Intermediate 45
1H NMR (399.9 MHz, DMSO-d6) δl.54 (3 H, d), 1.58 (IH, s), 1.66 (2H, s), 1.79 - 1.83 (2H, m), 1.85 (IH, s), 2.25 - 2.29 (IH, m), 2.30 (3H, s), 2.43 (IH, m), 2.53 - 2.56 (2H, t), 2.61 - 2.65 (IH, m), 2.66 - 2.68 (IH, m), 2.69 - 2.70 (IH, m), 2.81 - 2.85 (IH5 m), 3.15 (3H, s),s 3.56 - 3.59 (2H, m), 3.81 (3H, s), 4.65 (lH,m), 4.86 - 4.89 (IH, m), 6.41 - 6.44 (IH, m), 6.56 (IH, d), 7.51 (IH, s), 7.82 (IH, d), 7.98 (IH, s); MS m/z 467 [M+H]+.
Example 115: 0 6-cyclopentyl-9-[[2-methoxy-4-(2-morpholin-4-ylethoxy)phenyl]amino]-2-methyl- 2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Starting aniline - 2-methoxy-4-(2-morpholin-4-ylethoxy)aniline Intermediate 47 1H NMR (399.9 MHz, DMSOd6) δl.55 (3H, d), 1.59 (IH, s), 1.67 (2H, s), 1.85 (2H, s), 2.48 (4H, d), 2.53 - 2.56 (2H, t), 2.69 (2H, t), 3.15 (3H, s), 3.59 (2H, d), 3.59 (4H, d), 3.83 (3H, s),s 4.08 (2H, t), 4.67 (IH, s), 6.48 - 6.51 (IH, m), 6.63 (IH, d), 7.50 (IH, s), 7.86 (IH, d), 7.98 (IH, s); MS m/z 497 [M+H]+.
Example 116:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9-0 yl)amino]-2-(trifluoromethyl)benzonitrile
10-Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1, 157 mg, 0.56 mmol), 4-amino-2-methyl-benzonitrile (Aldrich, 95 mg, 0.51 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (27 mg, 0.05 mmol) were dissolved in 1,4-dioxane (7.5 niL). Caesium carbonate (330 mg, 1.01 mmol) was added and the mixture purged with a stream of nitrogen for 5 minutes. Tris(dibenzylideneacetone) palladium (II) (28 mg, 0.03 mmol) was added and the apparatus was evacuated and backfilled with nitrogen (x3) and then heated at 100°C for 8 h. The mixture was cooled, filtered and the
5 filtrate absorbed onto an SCX-3 column, washed with methanol and the product eluted with ammonia in methanol. Product containing fractions were concentrated and purified by preparative reverse phase chromatography to give the title compound as a white solid. (21mg, 10%) 1HNMR (399.9 MHz, DMSOd6) δl.57 - 1.72 (6H, m), 1.92 - 2.00 (2H, m), 2.61 (2H, m),
I0 3.19 (3H, s), 3.64 - 3.66 (2H, m), 4.82 - 4.90 (IH, m), 7.99 - 8.07 (2H, m), 8.16 (IH, s), 8.50 (IH, d), 10.15 (IH, s); MS m/z 431 [M+H]+.
Example 117:
4-[(6-cyclopentyI-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- I5 yl)amino]-N-(2-hydroxyethyl)benzenesulfonamide
4-amino-N-(2-hydroxyethyl)benzenesulfonamide (Maybridge; 108 mg, 0.5 mmol), 10- Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1, 140 mg, 0.5 mmol) and p-toluenesulphonic acid monohydrate (238 mg, 1.25 mmol) were heated at 14O0C in 4-methyl-2-pentanol (3 mL) for 3 hours. The mixture was
20 allowed to cool causing a solid to form. Methanol and DCM were added to give a solution that was absorbed onto and SCX-3 column and washed with methanol. The product with eluted with ammonia/methanol and the product containing fractions were concentrated. Purification by preparative, reverse phase chromatography gave the title compound as a white solid (122mg, 53%)..
25 1H NMR (399.9 MHz, DMSOd6) δl.59 - 1.74 (6H, d), 1.96 - 2.01 (2H, m), 2.57 - 2.61 (2H, m), 2.78 (2H, q), 3.19 (3H, s), 3.35 - 3.40 (2H, m), 3.62 - 3.65 (2H, m), 4.63 (IH, t), 4.80 - 4.88 (IH, m), 7.33 (IH, t), 7.64 - 7.68 (2H, m), 7.90 - 7.94 (2H, m), 8.11 (IH, s), 9.65 (IH, s); MS m/z 461 [M+H]+.
3o The following example was prepared by an analogous process to that used in the preparation of Example 117 utilising the appropriate aniline available from Aldrich. Example 118:
6-cyclopentyl-9-[[4-(2-dimethylaminoethoxy)phenyl]amino]-2-methyl-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one s 1HNMR (399.9 MHz, DMSO-d6) δl.55 - 1.71 (6H, m), 1.89 - 1.95 (2H, m), 2.22 (6H, s), 2.55 - 2.57 (2H, m), 2.61 (2H, t), 3.16 (3H, s), 3.58 - 3.61 (2H, m), 4.00 (2H, t), 4.72 - 4.81 (IH, m), 6.82 - 6.86 (2H, m), 7.56 - 7.60 (2H, m), 8.01 (IH, s), 8.95 (IH, s); MS m/z 425 [M+H]+. o Example 119:
N-[4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien- 9-yl)amino] phenyl] acetamide
10-Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo [5.4.0]undeca-8, 10, 12-trien-5 -one (Intermediate 1, 100 mg, 0.36 mmol), N-(4-aminoρhenyl)acetamide (Aldrich, 64 mg, 0.43s mmol) and p-toluenesulphonic acid (137 mg, 0.72 mmol) were heated together in 4-methyl-2- pentanol (4 mL) at 1200C for 22 hours. The reactions were cooled to ambient temperature and then passed down a 5g SCX-2 column pre-wet with methanol. The products were eluted with 2M NH3/MeOH and the solvent evaporated. The resukltatn material was purified by reverse phase HPLC to yield the title compound as a white solids (22 mg, 16%). 0 1H NMR (400.132 MHz, DMSO-d6) δ 1.64 (m, 6H), 1.94 (m, 2H), 2.01 (s, 3H), 2.56 (m, 2H), 3.16 (s, 3H), 3.60 (m, 2H), 4.78 (m, IH), 7.43 (d, 2H), 7.61 (d, 2H), 8.02 (s, IH), 9.06 (s, IH), 9.74 (s, IH); MS m/z 495 [M+H]+.
The following examples were prepared by an analogous process to that used in the 5 preparation of Example 119 utilising the appropriate substituted anilines. NMR analysis was undertaken where indicated.
Example 120: 0 6-cyclopentyl-9-[(4-methoxyphenyl)amino]-2-methyl-2,6,8,10- tetrazabicyclo [5.4.0] undeca-8,10,12-trien-3-one 1H NMR (400.132 MHz, DMSO-dό) δ 1.62 (m, 6H), 1.92 (m, 2H), 2.55 (m, 2H), 3.16 (s, 3H), 3.59 (m, 2H), 3.60 (s, 2H), 3.72 (s, 3H), 4.76 (m, IH), 6.83 (d, 2H), 7.59 (d, 2H), 8.00 (s, IH), 8.93 (s, IH)
Example 121:
6-cycIopentyl-2-methyl-9-[(4-morpholin-4-ylphenyl)amino]-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
1HNMR (400.132 MHz, DMSO-d6) δ 1.63 (m, 6H), 1.92 (m, 2H), 2.55 (m, 2H), 3.02 (m, 4H), 3.15 (s, 3H), 3.59 (m, 2H), 3.74 (m, 4H), 4.76 (m, IH), 6.85 (d, 2H), 7.56 (d, 2H), 7.99 (s, IH), 8.89 (s, IH); MS m/z 423 [M+H]+.
Example 122:
6-cyclopentyl-9-[(4-dimethylaminophenyl)amino]-2-methyl-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Example 123:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]benzenesulfonamide
Example 124:
9-[(l-acetyl-2,3-dihydroindol-5-yl)amino]-6-cyclopentyl-2-methyl-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Example 125:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(2-methoxyethyl)benzenesulfonamide 1H NMR (400.132 MHz, DMSO-d6) δ 1.66 (m, 6H), 1.96 (m, 2H), 2.59 (m, 2H), 2.88 (m, 2H), 3.17 (s, 3H), 3.18 (s, 3H), 3.30 (m, 2H), 3.63 (m, 2H), 4.83 (m, IH), 7.44 (t, IH), 7.66 (d, 2H)5 7.91 (d, 2H), 8.10 (s, IH), 9.64 (s, IH)
Example 126;
9-[(3-chloro-4-morpholin-4-yl-phenyl)amino]-6-cyclopentyl-2-methyl-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Example 127: 6-cyclopentyl-2-methyl-9-[(4-methylsulfonylphenyl)amino] -2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
1HNMR (400.132 MHz, DMSO-d6) δ 1.67 (m, 6H), 1.98 (m, 2H), 2.60 (m, 2H), 3.15 (s, 3H), 3.18 (s, 3H), 3.64 (m, 2H), 4.85 (m, IH), 7.77 (d, 2H), 7.98 (d, 2H), 8.11 (s, IH), 9.74 (s, IH)
Example 128;
9-[[4-(4-acetylpiperazin~l-yl)phenyl]amino]-6-cyclopentyl-2-methyl-2,6,8,10- tetrazabicyclo [5.4.0] undeca-8,10,12-trien-3-one
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Example 129;
6-cyclopentyl-2-methyl-9-[(3,4,5-trimethoxyphenyl)amino]-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
3,4,5-trimethoxyaniline (Aldrich, 104 mg, 0.56 mmol), 10-Chloro-2-cyclopentyl-6-methyl- 2,6,9,1 l-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 1, 150 mg, 0.56 mmol) and p-toluenesulphonic acid monohydrate (268 mg, 1.41 mmol) were heated at 14O0C in 4-methyl-2-pentanol (4 mL) for 2 hours. The reaction solution was loaded onto an SCX-3 column pre-wet methanol. The column was washed with methanol to remove p- toluenesulphonic acid monohydate and then washed with 2% 7N ammonia/methanol to elute the crude product. The product containing fractions were evaporated and the resultant material purified by reverse phase HPLC to yield the title compound as a purple solid (130mg, 54%). 1H NMR (399.9 MHz, DMSO-d6) δl.50 - 1.52 (2H, m), 1.57 - 1.61 (2H, m), 1.70 (2H, m), 1.95 (2H, m), 2.55 - 2.58 (2H, t), 3.17 (3H, s), 3.59 (2H, t), 3.63 (3H, s), 3.76 (6H, s), 4.86 (IH, d), 7.09 (2H5 s), 8.04 (IH, s), 8.97 (IH, s); MS m/z 429 [M+H]+.
The following example was prepared by an analogous process to that used in the preparation of Example 129 utilising the appropriate substituted anilines available as indicated.
Example 130:
6-cyclopentyl-2-methyl-9-[(2,3,4-trimethoxyphenyl)amino]-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Substituted aniline available from Apin
1H NMR (399.9 MHz, DMSOd6) δl.53 - 1.56 (2H, m), 1.58 (2H, d), 1.67 - 1.68 (2H, m), 1.88 (2H, t), 2.55 - 2.57 (2H, m), 3.16 (3H, s), 3.58 - 3.60 (2H, t), 3.79 (3H, s), 3.78 - 3.82 (6H, s), 4.69 (IH, m), 6.74 (IH, d), 7.70 (2H, t), 8.00 (IH, s); MS m/z 429 [M+H]+.
Example 131:
9-[[4-chloro-3-(hydroxymethyl)phenyl]amino]-6-cyclopentyl-2-methyl-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one Substituted aniline available from Aldrich
1HNMR (399.9 MHz, DMSOd6) 51.60 (3H, d), 1.62 - 1.62 (IH, m), 1.67 (2H5 d), 1.96 (2H5 s), 2.53 - 2.59 (2H5 1), 3.17 (3H, s), 3.60 - 3.63 (2H5 1), 4.53 (2H5 d), 4.88 (IH5 m), 5.27 (IH, t), 7.24 (IH5 d), 7.62 - 7.65 (IH5 m), 7.96 (IH5 d), 8.05 (IH5 s), 9.31 (IH5 s); MS m/z 402 [M+H]+.
Example 132:
6-cyclopentyl-2-methyl-9-[(2-pyridin-3-yl-lH-benzoimidazol-5-yl)amino]-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
10-Chloro-2-cyclopentyl-6-methyl-256,9511 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1, 134 mg, 0.50 mmol), 2-pyridin-3-yl-lH-benzoimidazol-5-amine (Flurocheni, 117 mg, 0.55 mmol) and cesium carbonate (328 mg, 1.00 mmol) were added to dioxane (4 mL) and the suspension bubbled with nitrogen for 10 minutes. Bis(dibenzylideneacetone)palladium (28 mg, 0.03 mmol) and 9,9-Dimethyl-4,5- bis(diphenylphosphino)xanthene (27 mg, 0.05 mmol) were added and the mixture heated to 110 °C overnight. The mixture was filtered and the filtrate purified by column chromatography with a 5% 7N ammonia in methanol/DCM solvent system. Product containing fractions were combined and evaporated to give the title compound as a solid (73 mg, 32 %)
1H NMR (499.8 MHz, DMSOd6 @ 373K) δl.64 (4H, m), 1.73 (2H, m), 2.00 (2H, m), 2.53 - 2.56 (2H, t), 3.21 (3H, s), 3.62 - 3.65 (2H, t), 4.82 - 4.85 (IH, m), 7.53 - 7.55 (3H, m), 8.04 (2H, s), 8.45 (IH, d), 8.64 - 8.65 (IH, m), 8.71 (IH, s), 9.32 (IH, d), 12.51 (IH, s); MS m/z 455 [M+H]+.
Example 133;
N-[[4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien- 9-y 1) amino] phenyl] methyl] py ridine-2-carboxamide
N-[(4-aminophenyl)methyl]pyridine-2-carboxamide (Intermediate 49: 114mg, 0.5mmol), 10- Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1, 141 mg, 0.5 mmol) and p-toluenesulphonic acid monohydrate (239 mg, 1.25 mmol) were heated in 4-methyl-2-pentanol (3 mL) at 140°C for 2hours. The mixture was cooled and diluted with methanol / DCM and absorbed on to an SCX-3 column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and puriried by preparative reverse phase chromatography to give the title compound as a white solid (63mg, 27%). 1HNMR (399.9 MHz, DMSOd6) δl.54 - 1.71 (6H, m), 1.89 - 1.96 (2H, m), 2.56 - 2.58 (2H, m), 3.16 (3H, s), 3.59 - 3.61 (2H, m), 4.44 (2H, d), 4.79 (IH, m), 7.23 (2H, d), 7.60 - 7.63 (IH, m), 7.65 - 7.67 (2H, m), 7.99 - 8.08 (3H, m), 8.64 - 8.66 (IH, m), 9.13 (IH, s), 9.18 (lH, t); MS m/z 472 [M+H]+.
The following examples were prepared by an analogous process to that used in the preparation of Example 133 utilising the appropriate substituted anilines available from ABCR Example 134:
6-cyclopentyl-2-methyl-9-[[4-(l-piperidylsulfonyl)phenyl]amino]-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
1H NMR (399.9 MHz5 DMSOd6) δl.34 - 1.39 (2H, m), 1.52 - 1.75 (1OH, m), 1.94 - 2.00 (2H, m), 2.57 - 2.61 (2H, m), 2.87 (4H, t), 3.19 (3H, s), 3.62 - 3.65 (2H, m), 4.84 (IH, m), 7.59 (2H, d), 7.94 - 7.96 (2H, m), 8.11 (IH, s), 9.71 (IH, s); MS m/z 485 [M+H]+.
Example 135:
6-cyclopentyl-2-methyl-9-[[4-(2-morpholin-4-ylethoxy)phenyl]amino]-2,6,8,10- tetrazabicyclo[5.4.0]undeca~8,10>12-trien-3-one
1H NMR (399.9 MHz, DMSOd6) δl.54 - 1.72 (6H, m), 1.89 - 1.95 (2H, m), 2.48 (4H, m),
2.66 - 2.70 (2H, m), 2.68 - 2.69 (2H, m), 3.16 (3H, s), 3.59 (6H, m), 4.05 (2H, t), 4.76 (IH, m), 6.84 - 6.87 (2H, m), 7.57 - 7.60 (2H, m), 8.01 (IH, s), 8.95 (IH, s); MS m/z 467 [M+H]+.
Example 136: tert-butyl N-[[3-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-
8,10,12-trien-9-yl)amino]phenyl]methyl]carbamate
10-Chloro-2-cyclopentyl-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8510,12-trien-5-one (Intermediate 1, 155 mg, 0.55 mmol), tert-butyl N-[(3-aminophenyl)methyl]carbamate (Chembasics, 111 mg, 0.50 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (27 mg, 0.05 mmol) were dissolved in 1,4-dioxane (7.5 mL) Caesium carbonate (326 mg, 1.05 mmol) was added and the mixture purged with a stream of nitrogen for 5 minutes.
Tris(dibenzylideneacetone) palladium (II) (28 mg, 0.03 mmol) was added and the apparatus was evacuated and backfilled with nitrogen (x3) and then heated at 1000C for 8h. The mixture was cooled, filtered and the filtrate absorbed onto an SCX-3 column, washed with methanol and the product eluted with ammonia in methanol. Product containing fractionso were concentrated and purified by normal phase chromatography (1% methanol/DCM) to give the title compound as a white solid (57 mg, 24 %). 1H NMR (399.9 MHz, DMSOd6) δl.41 (9H, s), 1.59 - 1.71 (6H, m), 1.96 (2H, m), 2.58 (2H, m), 3.17 (3H, s), 3.61 (2H, m), 4.09 (2H5 d), 4.85 (IH, m), 6.80 (IH, d), 7.18 (IH, t), 7.30 (IH, t), 7.57 (IH, d), 7.62 (IH, s), 8.04 (IH, s), 9.16 (IH, s); MS m/z 467 [M+H]+.
5
The following example was prepared by an analogous process to that used in the preparation of Example 136 utilising the appropriate substituted aniline available from Flurochem.
Example 137; io 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-2-methyl-isoindole-l,3-dione
1H NMR (399.9 MHz, DMSO-d6) δl.61 - 1.77 (6H, m), 1.95 - 1.98 (2H, m), 2.61 - 2.63 (2H, m), 3.04 (3H, s), 3.20 (3H, s), 3.65 - 3.68 (2H, m), 4.78 (IH5 m), 7.39 (IH, d), 7.74 (IH, t), 8.16 (IH, s), 8.81 (IH, d), 9.14 (IH, s); MS m/z 421 [M+H]+.
I5
Example 138:
N-[2-[3-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12- trien-9-yl)amino] -4-methoxy-phenyl] ethyl] acetamide
N-[2-(3-ammo-4-methoxy-phenyl)ethyi]acetamide (Compound 4- Organic Process Research 20 & Development 2004, 8, 628-642, 108 mg, 0.5 mmol), lO-Chloro^-cyclopentyl-ό-methyl- 2,6,9,1 l-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 1, 140 mg, 0.5 mmol) and p-toluenesulphonic acid monohydrate (238 mg, 1.25 mmol) were heated at 140°C in 4- methyl-2-pentanol (3 niL) for 3 hours. The mixture was allowed to cool causing a solid to form. Methanol and DCM were added to give a solution that was absorbed onto an SCX-3 25 column and washed with methanol. The product with eluted with ammonia/methanol and the product containing fractions were concentrated. Purification by preparative, reverse phase chromatography gave the title compound as a white solid (45 mg, 20 %). 1H NMR (399.9 MHz, DMSOd6) δl.55 - 1.70 (6H, m), 1.79 (3H, s), 1.93 - 1.96 (2H, m), 2.56 - 2.59 (2H, m), 2.64 (2H, t), 3.17 (3H, s), 3.20 - 3.26 (2H, m), 3.61 - 3.63 (2H, m), 3.86 so (3H, s), 4.85 (IH, m), 6.78 - 6.81 (IH, m), 6.95 (IH, d), 7.55 (IH, s), 7.86 (IH, t), 8.05 (IH, s), 8.12 (IH, d); MS m/z 453 [M+H]+. Example 139:
6-cyclopentyl-9-[(2-methoxyphenyl)amino]-2-methyl-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one 2-methoxyaniline (Aldrich, 22 mg, 0.18 mmol), 10-Chloro-2-cyclopentyl-6-methyl-2,6,9,l 1- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 1, 50 mg, 0.18 mmol) and p- toluenesulphonic acid monohydrate (84 mg, 0.44 mmol) were heated in 4-methyl-2-pentanol (1 mL) at 135°C for 24 hours. The mixture was cooled and diluted with methanol / DCM and absorbed on to an SCX-3 column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and puriried by preparative reverse phase chromatography to give the title compound as a white solid (42 mg, 64 %). MS m/z 368 [M+H]+, Retention Time 2.61 mins.
The following examples were prepared by an analogous process to that used in the preparation of Example 139, utilising the appropriate substituted anilines available as indicated.
Example 140:
6-cyclopentyl-9-[(2-ethoxyphenyl)amino]-2-methyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-3-one
Example 141:
6-cyclopentyl-2-methyl-9-[(2-methylsulfanylphenyl)amino]-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Example 142:
6-cyclopentyl-9-[(2-hydroxyphenyl)amino]-2-methyl-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Example 143: 6-cyclopentyl-9-[(2-ethylphenyl)amino]-2-methyl-2,6,8,10-tetrazabicyclo [5.4.0] undeca- 8,10,12-trien-3-one
Example 144: 9-[(2-benzoylphenyl)amino]-6-cyclopentyl-2-methyl-2,6,8,10~ tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Example 145:
2-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]benzenesulfonamide
Example 146:
6-cyclopentyl-2-methyl-9-[(2-phenoxyphenyl)amino]-2,6,8,10- tetrazabicyclo [5.4.0]undeca-8,10,12-trien-3-one
Example 147:
9-[(2-bromophenyl)amino]-6-cyclopentyl-2-methyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-
8,10,12-trien-3-one
Example 148:
6-cyclopentyl-2-methyl-9-[(2-phenylphenyl)amino]-2,6,8,10-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-3-one
Example 149: 6-cyclopentyl-2-methyl-9-[(2-methylsulfonylphenyl)amino]-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Example 150:
6-cyclopentyl-2-methyl-9-[(2-propan-2-ylphenyl)amino]-2,6,8,10- tetrazabicyclo [5.4.0] ιmdeca-8,10>12-trien-3-one Example 151:
9- [(2-butylphenyl)amino] -6-cyclopentyl-2-methyl-2,6,8,10-tetrazabicyclo [5.4.0] undeca- 8,10,12-trien-3-one Example 152:
6-cyclopentyl-2-methyl-9-[[2-(l-piperidyl)phenyl]amino]-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Example 153:
6-cyclopentyl-2-methyl-9-[[2-(4-tert-butylphenoxy)phenyl]amino]-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Example 154: 2-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10?12-trien-9- yl)amino]-N-ethyl-benzenesulfonamide
Example 155:
2-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino] -N-methyl-benzenesulfonamide
Example 156:
6-cyclopentyl-2-methyl-9-[[2-(2-morpholin-4-ylethylamino)phenyl]amino]-2,6,8,10- tetrazabicy clo [5.4.0] undeca-8,10,12-trien-3-one
Example 157:
9-[(2-benzylphenyl)amino]-6-cyclopentyl-2-methyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-
8,10,12-trien-3-one
Example 158: 6-cyclopentyl-2-methyl-9-[(2-pyrrol-l-ylphenyl)amino]-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Example 159: 6-cyclopentyl-2-methyl-9-[[2-(4-methylphenoxy)phenyl]amino]-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Example 160:
6-cyclopentyl-2-methyl-9-[[2-(morpholin-4-ylmethyl)phenyl]amino]-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10>12-trien-3-one
Figure imgf000120_0001
Figure imgf000120_0002
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Example 161:
6-cyclopentyl-9-[(3-methoxyphenyl)amino]-2-methyl-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
3-methoxyaniline (Aldrich, 22 mg, 0.18 mmol), lO-Chloro^-cyclopentyl-ό-methy 1-2,6,9,11- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 1, (50 mg, 0.18 mmol), and p- toluene sulphonic acid (84 mg, 0.44 mmol) were combined in 4-methyl-2-pentanol (1 mL). The solution was heated at reflux under a blanket of nitrogen for 12 hours. The reactiono mixture was cooled and passed through an SCX-2 column washed with methanol. The crude product were washed off with 7N ammonia in methanol and then concentrated in vacuo. The resultant material was purified by reverse phase HPLC to yield the title compound as a white solid. (39 mg, 59%); MS m/z 368 [M+H]+, Retention Time 2.46 mins. s The following examples were prepared by an analogous process to that used in the preparation of Example 161 utilising the appropriate substituted anilines available as indicated.
Example 162: Q 6-cyclopentyl-9-[(3-ethoxyphenyl)amino]-2-methyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-3-one
Example 163: 6-cyclopentyl-2-methyl-9-[(3-methyIsulfanylphenyl)amino]-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Example 164: 3-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]benzonitrile
Example 165:
9-[(3-acetylphenyl)amino]-6-cyclopentyl-2-methyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-3-one
Example 166:
6-cyclopentyl-9-[(3-ethylphenyl)amino]-2-methyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-3-one
Example 167:
3-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino] benzamide
Example 168:
6-cyclopentyl-9-[(3-ethynylphenyl)amino]-2-methyl-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Example 169: 9-[(3-benzoylphenyl)amino]-6-cyclopentyl-2-methyl-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Example 170:
3-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]benzenesulfonamide Example 171:
6-cyclopentyl-2-methyl-9-[(3-phenylphenyl)amino]-2,6,8,10-tetrazabicyclo[5.4.0]undeca-
8,10,12-trien-3-one
Example 172:
6-cyclopentyl-2-methyl-9-[(3-methylsulfonylphenyl)amino]-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Example 173: 6-cyclopentyl-9-[[3-(hydroxymethyl)phenyl]amino]-2-methyl-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Example 174:
6-cyclopentyl-2-methyl-9-[(3-propan-2-ylphenyl)amino]-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Example 175:
N-[2-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-
9-yl)amino]phenyl]benzenesulfonamide
Figure imgf000126_0001
Figure imgf000126_0002
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Example 176: N-[3-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien- 9-yl)amino]-4-methoxy-phenyl]acetamide
10-Chloro-2-cycloρentyl-6-methyl-2,6,9,l l-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 1, 100 mg, 0.36 mmol), N-(3-amino-4-methoxy~phenyl)acetamide (Aldrich, 77 mg, 0.43 mmol) and p-toluenesulphonic acid (137 mg, 0.72 mmol) heated together in A- methyl-2-pentanol (4ml) at 1200C for 22 hours. The reactions were cooled to ambient temperature and then passed down a 5g SCX-2 column pre-wet with methanol. The column was eluted with 2M NH3/MeOH and the solvent evaporated . The resultant material was purified by reverse phase HPLC to give the title compound as a white solid (46 mg, 30%)
1HNMR (400.132 MHz, DMSO-d6) δ 1.58 (m, 6H), 1.88 (m, 2H), 1.99 (s, 3H), 2.56 (m, 2H), 3.17 (s, 3H), 3.59 (m, 2H), 3.83 (s, 3H), 4.85 (m, IH), 6.93 (d, IH), 7.05 (d, IH), 7.56 (s, IH), 8.02 (s, IH), 8.37 (s, IH), 9.68 (s, IH); MS m/z 425 [M+H]+. The following examples were prepared by an analogous process to that used in the preparation of Example 176 utilising the appropriate substituted anilines available from Aldrich
s Example 177:
N-[3-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien- 9-yl)amino] phenyl] acetamide
MS m/z 395 [M+H]+. Retention Time 2.65 mins o Example 178:
6-cyclopentyl-9-[[5-(hydroxymethyl)-2-methyl-phenyl]amino]-2-methyl-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
MS m/z 382 [M+H]+. Retention Time 2.76 mins s Example 179:
6-cyclopentyl-9-[[3-(2-hydroxyethyl)phenyl]amino]-2-methyl-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
10-Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5 A0]undeca-8, 10, 12-trien-5-one (Intermediate 1, 134 mg, 0.48 mmol), 2-(3-aminophenyl)ethanol (ABChem Inc, 92 mg, 0.480 mmol) and p-toluenesulphonic acid monohydrate (227 mg, 1.19 mmol) were heated at 14O0C in 4-methyl-2-pentanol (4 mL) for 2 hours. The reaction solution was loaded onto an SCX-3 column pre-wet with Methanol. The column was washed with methanol to remove p- toluenesulphonic acid monohydate and then washed with 2% 7N ammonia/methanol to elute the crude product. Fraction containing products were evaporated and the resultant material5 purified by reverse phase HPLC to give the title compound as a white solid (92 mg, 50 %). 1HNMR (399.9 MHz, DMSOd6) δl.59 - 1.60 (4H, m), 1.69 - 1.71 (2H5 m), 1.96 - 1.98 (2H, m), 2.53 - 2.59 (2H, t), 2.69 (2H, t), 3.18 (3H, s), 3.60 (2H, t), 3.62 (2H, t), 4.62 (IH, s), 4.87 (IH5 ms), 6.77 (IH, d), 7.14 (IH, t), 7.46 - 7.49 (IH, m), 7.66 (IH, t), 8.04 (IH, s), 9.10 (IH, s); MS m/z 382 [M+H]+. 0 The following example was prepared by an analogous process to that used in the preparation of Example 183 utilising the appropriate substituted aniline available from sources as indicated
Example 180:
6-cyclopentyl-2-methyl-9-[[3-(2-morpholin-4-ylethoxy)phenyl]amino]-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
Substituted aniline available from ABCR
1HNMR (399.9 MHz, DMSOd6) δl.61 (4H, d), 1.71 (2H, s), 1.97 (2H5 s), 2.48 (4H, m), 2.59 (2H, t), 2.68 (2H, t), 3.17 (3H, s), 3.59 (4H, m), 3.62 (2H, m), 4.05 (2H, t), 4.80 - 4.90 (IH, m), 6.49 - 6.52 (IH, d), 7.13 (IH, t), 7.20 (IH, d), 7.51 (IH, t), 8.05 (IH, s), 9.13 (IH, s); MS m/z 467 [M+H]+.
Example 181: 3-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-4-methoxy-N-(l-methyl-4-piperidyl)benzamide
Synthetic route for substituted aniline available from WO06/018220
1H NMR (399.9 MHz, DMSOd6) δl.48 - 1.62 (8H, m), 1.71 - 1.77 (2H, d), 1.80 - 2.00 (4H, m), 2.17 (3H, s), 2.56 (2H, t), 2.77 (2H, d), 3.17 (3H, s), 3.59 (2H, t), 3.71 (IH, m), 3.91 (3H,0 s), 4.74 -4.79 (IH, m), 7.05 (IH, d), 7.48 - 7.51 (IH, m), 7.69 (IH, s), 7.99 (IH, d), 8.04 (IH, s), 8.57 (IH, d); MS m/z 509 [M+H]+.
Example 182:
6-cyclopentyl-9-[[5-(3-dimethylaminopyrrolidin-l-yl)-2-methoxy-phenyl]amino]-2-5 methyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
10-Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1, 150 mg, 0.53 mmol), l-(3-amino-4-methoxy-phenyl)-N,N-dimethyl- pyrrolidin-3 -amine (Intermediate 50; 141 mg, 0.53 mmol) and p-toluenesulphonic acid monohydrate (255 mg, 1.34 mmol) were combined and heated in 4-methyl-2-pentanol (4 mL)o at 14O0C for 2 hours. The reaction mixture was loaded onto a 2Og SCX-2 column was pre-wet with methanol. The column was washed with methanol twice to remove p-Toluene Sulphonic acid and then washed twice with 2% 7N ammonia/methanol to elute the crude product.. Product containing fractions were evaporated and the resultant material purified by reverse phase HPLC to yield the title compound as a white solid (140mg, 51.6%). 1HNMR (399.9 MHz, DMSOd6) 51.48 - 1.62 (8H5 m), 1.71 - 1.77 (2H, d), 1.80 - 2.00 (4H, s m), 2.17 (3H, s), 2.56 (2H, t), 2.77 (2H, d), 3.17 (3H, s), 3.59 (2H, t), 3.71 (IH, m), 3.91 (3H, s), 4.74 - 4.79 (IH, m), 7.05 (IH, d), 7.48 - 7.51 (IH, m), 7.69 (IH, s), 7.99 (IH, d), 8.04 (IH, s), 8.57 (IH, d); MS m/z 508 [M+H]+.
Example 183: o 6-cyclopentyl-2-methy 1-9- [(3-morpholin-4-ylsulfonylphenyl)amino] -2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
10-Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1,150 mg, 0.53 mmol), 3-(morpholinosulphonyl)aniline (Fluorochem; 130 mg, 0.53 mmol) and p-toluenesulphonic acid monohydrate (255 mg, 1.34 mmol) were combineds and heated at 1400C in 4-methyl-2-pentanol (4 mL) for 2 hours. The mixture was cooled and methanol and dichloromethane added to dissolve the solid that formed. The mixture was absorbed on to an SCX —3 column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated to give a white crystalline solid. This was suspended in methanol and filtered off and dried at 140°C under vacuum in a0 desiccator to give the title compound as a white crystalline solid (200mg, 77%)
1HNMR (399.9 MHz, DMSOd6) 51.57 - 1.70 (6H, m), 1.94 - 2.00 (2H, m), 2.57 - 2.60 (2H, m), 2.88 (4H, m), 3.18 (3H, s), 3.61 - 3.66 (6H, m), 4.91 (IH, m), 7.22 - 7.25 (IH, m), 7.53 (IH, t), 7.99 - 8.02 (IH, m), 8.09 (IH, s), 8.23 (IH, t), 9.57 (IH, s) MS m/z 487 [M+H]+. 5
Example 184:
3-chloro-4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicycIo[5.4.0]undeca-8,10,12- trien-9-yl)amino]-N-(2-morpholin-4-ylethyl)benzamide
4-amino-3-chloro-N-(2-morpholin-4-ylethyl)benzamide (Intermediate 52, 100 mg, 0.350 mmol), 10-Chloro-2-cyclopentyl-6-methy 1-2,6,9,1 l-tetrazabicyclo[5.4.0]undeca-8,10,12- trien-5-one (Intermediate 1, 124 mg, 0.44 mmol) and p-toluenesulphonic acid monohydrate (168 mg, 0.88 mmol) were heated at 14O0C in 4-methyl-2-pentanol (2.5 mL) for 3 hours. The mixture was allowed to cool causing a solid to form. Methanol and DCM were added to give a solution that was absorbed onto and SCX-3 column and washed with methanol. Elution of the product with ammonia / methanol, concentration and column chromatography (2% 7N s ammonia in methanol/DCM) gave material that was further purified by reverse phase HPLC to give the title compound as a white foam (87 mg, 47 %).
1HNMR (399.9 MHz, DMSOd6) δl.54 - 1.69 (6H, m), 1.86 - 1.89 (2H, m), 2.44 (6H, m), 2.59 (2H, m), 3.18 (3H, s), 3.37 - 3.42 (2H, m), 3.57 - 3.63 (6H, m), 4.69 - 4.77 (IH, m), 7.78 I0 - 7.81 (IH, m), 7.97 (IH, d), 8.09 (IH, s), 8.20 (IH, s), 8.27 (IH, d), 8.40 (IH, t); MS m/z 528
The following example was prepared by an analogous process to that used in the preparation of Example 184 utilising 4-amino-3-chloro-N-(l-methyl-4-piperidyl)benzamide Intermediate is 55.
Example 185:
3-chloro-4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12- 20 trien-9-yl)amino]-N-(l-methyl-4-piperidyl)benzamide
1HNMR (399.9 MHz, DMSOd6) δl.55 - 1.68 (8H, m), 1.77 (2H, s), 1.86 - 1.98 (4H, m), 2.18 (3H, s), 2.59 (2H, m), 2.78 (2H, d), 3.18 (3H, s), 3.62 (2H, m), 3.69 - 3.77 (IH, m), 4.73 (IH, m), 7.79 - 7.82 (IH, m), 8.00 (IH, d), 8.09 (IH, s), 8.19 (2H, d), 8.26 (IH, d); MS m/z 512 [M+H]+.
25
Example 186:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8>10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-hydroxy-N-(l-methyl-4-piperidyl)benzamide
To pyridine (1 mL) was cautiously added cone HCl (1 mL) . The mixture was heated at 2000C 30 until no more water was evolved. The mixture was cooled and 4-[(2-Cyclopentyl-6-methyl-5- oxo-2,6,9, 11 -tetrazabicyclo [5.4.0]undeca-8, 10,12-trien- 10-yl)amino]-3 -methoxy-N-( 1 - methyl-4-piperidyl)benzamide (Example 1, 100 mg, 0.2 mmol) was added and the solution reheated and stirred at 2000C for 30 minutes. The solution was cooled and water added followed by pH adjustment to neutral neutral pH by addition of NaHCCβ.
The aqueous solution was adsorbed on an SCX-3 column pre-wet with MeOH. The column was washed with MeOH and water and MeOH. Product was removed from the column by addition of NH3/MeOH (2N). Combined fractions were evaporated and the resultant material purified by reverse phase HPLC to give the title compound as a gum which on trituration with
DCM / hexane gave an amorphous solid (17 mg, 17 % )
1H NMR (399.9 MHz, DMSO-d6) δ 1.50-1.85 (m, 10H), 1.85-2.10 (m, 4H), 2.20 (s, 3H), 2.55-2.68 (m, 2H), 2.70-2.85 (m, 2H), 3.20 (s, 3H), 3.55-3.70 (m, 2H), 3.60-3.80 (m, IH),
4.75-4.90 (m, IH), 7.28-7.35 (d, IH), 7.38 (s, IH), 7.83 (s, IH), 7.95-8.05 (d, IH), 8.08 (s,
IH), 8.13-8.23 (d, IH), 10.2-10.5 (bs, IH); MS m/z 494 [M+H]+.
Example 187: 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-2,6-difluoro-N-(l-methyl-4-piperidyl)benzamide
10-amino-2-cyclopentyl-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5-one (Intermediate 57, 75 mg, 0.29 mmol), 4-bromo-2,6-difluoro-N-(l-methyl-4- piperidyl)benzamide (Intermediate 58, 105 mg, 0.31 mmol) and caesium carbonate (187 mg, 0.57 mmol) were added to dioxane (3 mL) and the suspension bubbled with nitrogen for 10 minutes. Bis(dibenzylideneacetone)palladium (16 mg, 0.028 mmol) and 9,9-Dimethyl-4,5- bis(diphenylphosphino)xanthene (15 mg, 0.026 mmol) were added and the mixture heated to 100 °C overnight. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with DCM and the filtrate added to a 5g SCX-2 column pre-wet with MeOH (2 column volumes), flushed with MeOH (2 column volumes) and the crude product eluted with 2M ammonia in MeOH and evaporated to a brown gum. The resultant material was purified by reverse phase HPLC to yield the title compound as a cream solid (107 mg, 73%).
H NMR (399.902 MHz, CDCl3) 81.59 (m, 4H), 1.72 (m, 4H), 2.04 (m, 4H), 2.16 (m, 2H), 2.29 (s, 3H)5 2.68 (m, 2H), 2.79 (m, 2H), 3.29 (s, 3H), 3.70 (m, 2H), 4.01 (m, IH), 4.86 (m, IH), 5.83 (d, IH), 7.10 (s, IH), 7.28 (s, IH), 7.31 (s, IH), 7.93 (s, IH); MS m/z 514 [M+H]+. Example 188:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-2,5-difluoro-N-(l-methyl-4-piperidyl)benzamide 10-Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10,12-trien-5-one (Intermediate 1, 100 mg, 0.36 mmol), 4-amino-2,5-difluoro-N-(l-methyl-4- piperidyl)benzamide (Intermediate 59, 87 mg, 0.32 mmol) and caesium carbonate (211 mg, 0.65 mmol) were added to dioxane (3 mL) and the suspension bubbled with nitrogen for 10 minutes. Bis(dibenzylideneacetone)palladium (11 mg, 0.019 mmol) and 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (17 mg, 0.029 mmol) were added and the mixture heated to 100 0C overnight. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with DCM and the filtrate added to a 5g SCX-2 column pre-wet with MeOH (2 column volumes), washed with MeOH (2 column volumes) and the crude product eluted with 2M ammonia in MeOH and evaporated to a brown gum. The resultant material was purified by reverse phase HPLC to yield the title compound as a white solid (34 mg,
%).
HNMR (399.902 MHz, CDCl3) 51.60 (m, 4H), 1.75 (m, 4H), 2.05 (m, 4H), 2.17 (m, 2H), 2.30 (s, 3H), 2.68 (m, 2H), 2.79 (m, 2H), 3.30 (s, 3H), 3.71 (m, 2H), 4.01 (m, IH), 4.88 (m, IH), 6.59 (m, IH), 7.29 (m, IH), 7.82 (m, IH), 7.96 (s, IH), 8.46 (m, IH); MS m/z 515 [M+H]+.
The following example was prepared by an analogous process to that used in the preparation of Example 188 utilising 4-amino-2-fluoro-N-(l-methyl-4-piperidyl)benzamide Intermediate 61.
Example 189; 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]~2-fluoro-N -(l-methyl-4-piperidyl)benzamide
HNMR (399.902 MHz, CDCl3) δl.59 (m, 4H), 1.73 (m, 4H), 2.05 (m, 4H), 2.18 (m, 2H), 2.30 (s, 3H), 2.68 (m, 2H), 2.79 (m, 2H), 3.29 (s, 3H), 3.70 (m, 2H), 4.03 (m, IH), 4.88 (m, IH), 6.56 (m, IH), 7.12 (m, 2H), 7.87 (m, IH), 7.94 (s, IH), 8.01 (m, IH); MS m/z 496 [M+H]+.
Example 190: methyl 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12- trien-9-yl)amino]-3-hydroxy-benzoate
10-Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10,12-trien-5-one (Intermediate 1; 180 mg, 0.64 mmol) and methyl 3-hydroxy-4-aminobenzoate (ABCR, 123 mg, 0.73 mmol) was taken up in ethanol (4 mL) and water (12 mL). To this was added concentrated hydrochloric acid (36%; 130 μl). The reaction was heated to 8O0C and stirred overnight.. The reaction was allowed to stand and cool overnight, before evaporating ethanol. The aqueous residue was diluted to ~30 mL with water and the solution basified to pH 9 by addition of a few drops of aq. Ammonia. The resultant mixture was extracted with DCM (2 x 50 mL). A solid persisted at the phase boundary. This solid was collected by suction filtration and dried to give the title compound as a purple/grey solid (64 mg). Combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and evaporated to a pink/brown solid which was taken up in small amount (~5 mL) of DCM and sonicated for 5 minutes. The solid was then collected by suction filtration and dried to give the title compound as a dusky pink solid (79 mg)
1H NMR (400.132 MHz, DMSOd6) δ 1.56 - 1.75 (m, 6H), 1.94 (m, 2H), 2.59 (m, 2H), 3.18 (s, 3H), 3.63 (m, 2H), 3.80 (s, 3H), 4.82 (m, IH), 7.44 (m, 2H), 7.84 (s, IH), 8.09 (s, IH), 8.35 (d, IH), 10.53 (s, IH); MS m/z 412 [M+H]+.
Example 191: 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(2-morpholin-4-ylethyl)benzamide
A solution of 4-amino-N-(2-morpholin-4-ylethyl)benzamide (Buttpark; 108mg, 0.43mmol) in EtOH (2 niL) was added to 10-Chloro-2-cyclopentyl-6-methyl-2,6,9,ll-
5 tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 1, 100 mg, 0.36 mmol). Water (6 mL) was added followed by concentrated hydrochloric acid (36%, 70 ul) and the solution heated at 800C for 28 hours and then left to cool over the weekend. The reaction mixture was loaded onto an SCX-2 (5g) column pre-wet with methanol. Product was eluted with 2M NH3/MeOH. Solvent evaporation gave crude product as a gum which was purified by reverse io phase HPLC to yield the title compound as a white solid (71 mg, 40 %)
1H NMR (400.132 MHz, DMSO-d6) δ 1.68 (m, 6H), 1.97 (m, 2H), 2.44 (m, 6H), 2.59 (m, 2H), 3.18 (s, 3H), 3.37 (m, 2H), 3.58 (m, 4H), 3.63 (m, 2H), 4.84 (m, IH), 7.77 (m, 4H), 8.08 (s, IH), 8.16 (t, IH), 9.45 (s, IH); MS m/z 494 [M+H]+.
is
Example 192:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(2-diethylaminoethyl)benzamide
20 10-Chloro-2-cycloρentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1, 100 mg, 0.36 mmol), 4-amino-N-(2-diethylaminoethyl)benzamide (Timtec, 101 mg, 0.43 mmol) and p-toluenesulphonic acid (137 mg, 0.72 mmol) were heated together in 4-methyl-2-pentanol (4 mL) at 1000C for 24 hours. The crude reaction mixture was loaded onto an SCX-2 (5g) column pre-wet with MeOH. The column was washed with MeOH and
25 the product eluted with 2M NH3/MeOH. Solvent evaporation gave material that was purified by reverse phase HPLC to yield the title compound as a white solid (123 mg, 71 %)
1HNMR (400.132 MHz, DMSO-d6) δ 0.98 (t, 6H), 1.66 (m, 6H), 1.96 (m, 2H), 2.52 (m, 6H), 2.59 (m, 2H), 3.18 (s, 3H), 3.30 (s, 2H), 3.63 (m, 2H), 4.84 (m, IH), 7.73 (d, 2H), 7.80 (d, 2H), 8.08 (s, IH), 8.12 (t, IH), 9.45 (s, IH); MS m/z 480 [M+H]+.
30
Example 193: 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methyI-N-(l-methyl-4-piperidyl)benzamide
A solution of 4-amino-3-methyl-N-(l-methyl-4-piperidyl)benzamide (Intermediate 63, 53 mg, 0.214 mmol), 10-Chloro-2-cyclopentyl-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]u ndeca- 8,10,12-trien-5-one (Intermediate 1, 60 mg, 0.214 mmol) and p-toluenesulphonic acid monohydrate (102 mg, 0.535 mmol) in 4-methyl-2-pentanol (4 mL) was heated at 100 0C. overnight. The reaction was cooled to room temperature (solid formed) dissolved in MeOH and added to a 2g SCX-2 column pre-wet with MeOH (2 column volumes). The column was washed with MeOH (2 column volumes) and then product eluted with 2M ammonia in MeOH and solvents evaporated. The resultant material was taken up in DCM and purified on silica eluting with a gradient of 0 - 10% MeOH / DCM then 10% MeOH / DCM. Fractions containing product were combined and evaporated to a clear gum to which ether was added and re-evaporated to a white solid which was further purified by b reverse phase HPLC.
H NMR (399.902 MHz, CDCl3) δl.54 - 1.70 (m, 6H), 1.75 (m, 2H), 2.02 (m, 4H), 2.17 (m, 2H), 2.31 (s, 3H), 2.37 (s, 3H), 2.67 (m, 2H), 2.82 (m, 2H), 3.29 (s, 3H), 3.68 (m, 2H), 3.99 (m, IH), 4.85 (m, IH), 5.86 (d, IH), 6.79 (s, IH), 7.59 (m, 2H), 7.92 (s, IH), 8.32 (d, IH); MS m/z 492 [M+H]+.
The following example was prepared by an analogous process to that used in the preparation of Example 193 utilising 4-amino-3-fluoro-N-(l-methyl-4-piperidyl)benzamide Intermediate 65
Example 194:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8?10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-fluoro-N-(l-methyl-4-piperidyl)benzamide
H NMR (399.902 MHz, CDCl3) δl.53 - 1.80 (m, 8H), 2.03 (m, 4H), 2.16 (m, 2H), 2.30 (s, 3H), 2.67 (m, 2H), 2.82 (m, 2H), 3.30 (s, 3H), 3.69 (m, 2H), 3.97 (m, IH), 4.87 (m, IH), 5.85 (d, IH), 7.22 (m, IH), 7.52 (m, 2H), 7.95 (s, IH), 8.57 (m, IH); MS m/z 496 [M+H]+.
Example 195: 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-(2-methoxyethoxy)-N-(l-methyl-4-piperidyl)benzamide
To a suspension of 4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-10-yl)amino]-3-(2-methoxyethoxy)benzoic acid (Intermediate 66, 55 mg, 0.12 mmol) in DMF (2 mL) was added DIPEA (42 ul, 0.16 mmol) and the mixture stirred for 5 minutes. HATU (60 mg, 0.16 mmol) was added to the resultant straw coloured solution. The solution was stirred for a further 10 minutes before addition of 4-amino-l-methylpiperidine (18 mg, 0.16 mmol) in DMF (0.5 mL). The reactions was stirred at ambient temperature for 6 hours and the crude reaction mixture waspurified by reverse phase HPLC to afford the title compound as a white solid (50 mg, 76 %)
1HNMR (400.132 MHz, DMSOd6) 5 1.55 - 1.83 (m, 10H), 1.89 - 2.10 (m, 4H), 2.23 (s, 3H), 2.59 (m, 2H), 2.84 (m, 2H), 3.18 (s, 3H), 3.38 (s, 3H), 3.64 (m, 2H), 3.73 - 3.81 (m, 3H), 4.26 (m, 2H), 4.79 (m, IH), 7.51 (d, IH), 7.54 (m, IH), 7.81 (s, IH), 8.06 (d, IH), 8.09 (s, IH), 8.42 (d, IH); MS m/z 552 [M+H]+.
The following example was prepared by an analogous process to that used in the preparation of Example 195 utilising a 2.0M methylamine solution in THF
Example 196; 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-(2-methoxyethoxy)-N-methyl-benzamide
1H NMR (400.132 MHz, CDCl3) δ 1.55 - 1.81 (m, 6H), 2.03 (m, 2H), 2.67 (m, 2H), 3.01 (d, 3H), 3.29 (s, 3H), 3.47 (s, 3H)5 3.69 (m, 2H), 3.80 (m, 2H), 4.28 (m, 2H), 4.88 (m, IH), 6.07 (m, IH), 7.28 (m, IH), 7.46 (m, IH), 7.80 (s, IH), 7.95 (s, IH), 8.52 (d, IH) ; MS m/z 469
Example 197:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(l-methyl-4-piperidyl)-3-propan-2-yloxy-benzamide To a solution of 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-9-yl)amino]-3-propan-2-yloxy-benzoic acid (Intermediate 69; 49 mg, 0.11 mmol) in DMF (2 niL) was added DIPEA (42 uL, 0.24 mmol) and HATU (61 mg, 0.16 mmol). The solutions were stirred for 5 minutes before addition of 4-amino-l- s methylpiperidine (ABCR, 16 mg, 0.14 mmol). The reaction mixture was stirred, at ambient temperature, overnight.
The crude reaction mixture was purified by reverse phase HPLC to afford the title compound as a white solid (29 mg, 49%)
1H NMR (400.132 MHz, DMSOd6) δ 1.36 (d, 6H), 1.54 - 1.80 (m, 10H)5 1.94 (m, 4H),o 2.17 (s, 3H), 2.59 (m, 2H), 2.78 (m, 2H), 3.18 (s, 3H), 3.64 (m, 2H), 3.74 (m, IH), 4.78 (m, 2H), 7.48 (m, IH), 7.52 (m, IH), 7.67 (s, IH), 8.04 (d, IH), 8.08 (s, IH), 8.41 (d, IH); MS m/z 536 [M+H]+.
5
Example 198:
N-cyclohexyl-4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-
8,10,12-trien-9-yl)amino]-3-(2-dimethylaminoethoxy)benzamide
To a stirred solution of Methyl 4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-0 tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien- 10-yl)amino]-3-(2-dimethylaminoethoxy)benzoate (Intermediate 72; 41 mg, 0.08 mmol) in Ethanol (2 niL) was added a solution of lithium hydroxide (8 mg, 0.33 mmol) in water (1 mL). The reaction was heated at 1000C by microwave irradiation with stirring, for 30 minutes, cooled, evaporated and the residue diluted with water (5 mL). The resultant solution was treated with a few drops of 2M HCl (aq.) so as5 to adjust pH to 2-3. The aqueous solution was evaporated to dryness to give the carboxylic acid as a pale yellow gum, which was dissolved in DMF (1 mL) and treated with DIPEA (25 μL, 0.14 mmol) and HATU (40 mg. 0.11 mmol). Cyclohexylamine (11 μL, 0.10 mmol) was added and reaction mixture left to stir, at ambient temperature, overnight. The crude reaction mixture was purified by reverse phase HPLC to afford the title compound0 as an offwhite solid (14 mg, 32 % ) 1HNMR (400.132 MHz, DMSO-d6) δ 1.10 - 1.37 (m, 6H), 1.55 - 1.99 (m, 12H), 2.28 (s, 6H), 2.59 (m, 2H), 2.65 (t, 2H), 3.18 (s, 3H), 3.63 (m, 2H), 3.77 (m, IH), 4.21 (t, 2H), 4.80 (m, IH), 7.50 (m, IH), 7.55 (m, IH), 7.98 (d, IH), 8.09 (s, IH), 8.39 (m, IH), 8.41 (s, IH); MS m/z 551 [M+H]+.
5
Example 199:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(l-methyl-4-piperidyl)-3-(trifluoromethoxy)benzamide
To a solution of 4-amino-N-(l-methyl-4-piperidyl)-3-(trifluoromethoxy)benzamide IQ (Intermediate 74, 104 mg, 0.33 mmol) 10-Chloro-2-cycloρentyl-6-methyl-2,6,9,l l- tetrazabicyclo[5.4.0]u ndeca-8,10,12-trien-5-one (Intermediate 1, 91 mg, 0.32 mmol) in anhydrous 1,4-dioxane (4 mL) was added caesium carbonate (222 mg ,0.68 mmol). Nitrogen was bubbled through the reaction mixture for 10 minutes, prior to addition of Tris(dibenzylideneacetone) palladium (II) (21 mg, 0.07 mmol) and 9,9-Dimethyl-4,5- I5 bis(diphenylphosphino)xanthene (21 mg, 0.11 mmol). The reaction was heated by microwave irradiation at 15O0C for 60 minutes.Further portions of 9,9-Dimethy 1-4,5- bis(diphenylphosphino)xanthene (19 mg) & Tris(dibenzylideneacetone) palladium (II (25 mg) added and mixture heated on hot plate at 1000C overnight. The reaction mixture was cooled and diluted to 10 mL with DCM. Insoluble material was filtered and the filter cake washed 20 with DCM. Evaporation to dryness of filtrate afforded a brown gum, which was taken up in methanol and poured onto an SCX-2 cartridge (5g, Silicycle). The Cartridge was washed with methanol (~75 mL) before eluting products with 2M ammonia in methanol (~50 mL). The ammoniacal fraction was evaporated to afford a brown gum which was purified by reverse phase HPLC to yield the title compound as a white solid (25 mg, 4 %)
2s 1HNMR (400.132 MHz, DMSOd6) δ 1.51 - 1.97 (m, 14H), 2.17 (s, 3H), 2.59 (m, 2H), 2.78 (m, 2H), 3.18 (s, 3H), 3.62 (m, 2H), 3.74 (m, IH), 4.74 (m, IH), 7.86 (m, 2H), 8.08 (s, IH), 8.25 (d, IH), 8.30 (d, IH), 8.57 (s, IH) MS m/z 562 [M+H]+.
30 Example 200: 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-ethoxy-N-(l-methyl-4-piperidyl)benzamide
A solution of HATU (63 mg, 0.165 mmol) in DMA (1 mL) was added to a mixture 4-[(2- cyclopentyl-6-methyl-5-oxo-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien-10-yl)amino]-
5 3-ethoxy-benzoic acid (Intermediate 75, 64 mg, 0.15 mmol), DIPEA (79 uL, 0.45 mmol) and the amine in DMA (1 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was added to an SCX-3 column pre-wet with Methanol, washed with methanol and product eluted with Ammonia in Methanol. Product containing fractions were evaporated and the resultant material purified by column chromatography, eluting with 0-10% io 7vVmethanolic ammonia in DCM, to give the title compound as clear glass (64 mg, 82 %) 1H NMR (399.9 MHz, CDCl3) δl.51 (3H, t), 1.61 - 1.82 (8H, m), 2.03 - 2.09 (2H, m), 2.21 - 2.29 (4H, m), 2.38 (3H, s), 2.67 - 2.70 (2H, m), 2.90 - 2.93 (2H, m), 3.31 (3H, s), 3.70 - 3.73 (2H, m), 4.00 - 4.08 (IH, m), 4.22 (2H, q), 4.92 (IH, quin), 6.07 (IH, d), 7.27 (IH, dd), 7.42 (IH, d), 7.72 (IH, s), 7.96 (IH, s), 8.52 (IH, d); MS m/z 522 [M+H]+.
I5
The following example was prepared by an analogous process to that used in the preparation of Example 200 utilising the appropriate amines available from Aldrich
Example 201:
20 N-(l-azabicyclo[2.2.2]oct-8-yl)-4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9-yl)amino]-3-ethoxy-benzamide
1HNMR (399.9 MHz, CDCl3) δl.51 (3H, t), 1.55 - 1.89 (1OH, m), 2.06 - 2.03 (6H, m), 2.67 - 2.70 (2H, m), 2.84 - 2.97 (4H, m), 3.07 - 3.13 (IH, m), 3.31 (3H, s), 3.44 - 3.50 (IH, m), 3.70 - 3.73 (2H, m), 4.20 - 4.26 (IH, m), 4.22 (2H, q), 4.91 (IH, quin), 6.55 (IH, d), 7.34 (IH, dd), 2s 7.47 (IH, d), 7.72 (IH, s), 7.96 (IH, s), 8.52 (IH, d); MS m/z 533 [M+H]+.
Example 202:
3o 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(2-dimethylaminoethyl)-3-ethoxy-benzamide 1H NMR (399.9 MHz, CDCl3) δl.52 (3H5 1), 1.62 - 1.82 (6H, m), 2.04 - 2.09 (2H5 m)5 2.39 (6H, s), 2.64 - 2.71 (4H5 m), 3.31 (3H5 s), 3.58 - 3.62 (2H5 m). 3.70 - 3.73 (2H5 m), 4.24 (2H5 q), 4.92 (IH5 quin)5 7.01 (IH5 s), 7.38 (IH5 dd), 7.49 (IH5 d), 7.71 (IH5 s), 7.96 (IH5 s), 8.52 (IH5 d); MS m/z 494 [M+H]+.
Example 203:
S-chloro-^^-methyl-S-oxo-ό-propan^-yl-ljό^^O-tetrazabicyclo [5.4.0] undeca-7,9,11- trien-9-yl)amino]-N-(l-methyl-4-piperidyl)benzamide 10-chloro-6-methyl-2-propan-2-yl-2,659,l l-tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one (Intermediate 76, lOOmg, 0.39mmol) and 4-amino-3-chloro-N-(l-methyl-4- piperidyl)benzamide (Intermediate 79; 127 mg, 0.47 mmol) were suspended in 4-methyl-2- pentanol (3 mL) and p-toluenesulphonic acid monohydrate (74 mg, 0.97 mmol) added. The mixture was heated at 140°C for 4 hours The mixture was cooled causing a white solid to formed. The whole mixture was diluted with MeOH to give a solution which was absorbed on to an SCX-3 column, washed with methanol and eluted with ammonia/methanol. Concentration and column chromatography (1-2-3-5% NH3 in MeOH/DCM) of the product containing fractions gave the title compound as a white solid (58mg, 31%). 1H NMR (399.9 MHz5 DMSOd6) δl.23 (6H, d), 1.54 - 1.64 (2H, m). 1.75 - 1.78 (2H5 m), 1.91 - 1.97 (2H5 m), 2.18 (3H, s), 2.60 (2H, m), 2.78 (2H, d), 3.18 (3H, s), 3.61 (2H, m), 3.69 - 3.75 (IH, m), 4.72 - 4.78 (IH, m), 7.81 - 7.84 (IH5 m), 7.99 (IH5 d), 8.09 (2H5 d), 8.21 (IH, d), 8.32 (IH5 d); MS m/z 486 [M+H]+.
Example 204: 3-methoxy-4-[(2-methyl-3-oxo-6-propan-2-yl-2,6,8,10-tetrazabicyclo[5.4.0]undeca- 7,9,ll-trien-9-yl)amino]benzoic acid
10-chloro-6-methyl-2-propan-2-yl-2,659, 11 -tetrazabicyclo[5 ,4.0]undeca-7,9, 11 -trien-5-one (Intermediate 76; 739 mg, 2.9 mmol) , 4-amino-3-rnethoxy-benzoic acid (Aldrich, 534 mg5 3.2 mmol), 4:1 Water / Etanol (6 mL) and concentrated aqueous hydrochloric acid (0.485 mL, 5.8 mmol)were combined and heated at reflux overnight under nitrogen. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with water followed by diethylether to give the title compound as an off white solid as the Hydrochloride salt (673 mg, 55 % )
1H NMR (399.9 MHz, DMSOd6) : δH : 1.25 (d, 6H)5 2.73(m, 2H), 3.19 (s, 3H), 3.72 (m, 2H), 3.95 (s, 3H), 4.89 (m, IH), 7.59 (s, IH), 7.67 (d, IH), 8.20 (m, 2H), 9.55 (s, IH); MS s m/z 386 [M+H]+.
Example 205:
3-methoxy-4-[(2-methyl-3-oxo-6-propan-2-yl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-
7,9,ll-trien-9-yl)amino]-N-[2-(l-piperidyl)ethyl]benzamide o To a solution of the hydrochloride salt of 3-methoxy-4-[(2-methyl-3-oxo-6~propan-2-yl- 2,6,8,10-tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-9-yl)amino]benzoic acid (Example 204; 127 mg, 0.33 mmol) and l-(2-arninoethyl)ρiperidine (Aldrich, 54uL, 0.38 mmol) and DIPEA (157 uL , 0.9 mmol) in anhydrous DMA (10 mL) at room temperature under nitrogen was added HATU (126 mg, 0.33 mmol) as a solid and the resulting solution stirred at rooms temperature overnight. The reaction mixture was loaded onto a SCX-3 column pre-wet with Methanol and the column washed with Methanol. The column was eluted with Ammonia in Methanol and produict containing fractions evaporated. The resultant material was dissolved in dichloromethane and chromatographed with 2-5-10-20% methanol/dichloromethane followed by 7N ammonia/methanol. Evaporation of product containing fractions gave a0 yellow foam foam which was purified by reverse phase HPLC to yield the title compound as an off white gum (75 mg, 46 %)
1H NMR (399.9 MHz, DMSOd6) : δH : 1.25 (d, 6H), 1.39 (m, 2H), 1.50 (m, 6H), 2.40 (m, 6H), 2.60 (m, 2H), 3.19 (s, 3H), 3.37 (m, 2H), 3.61 (m, 2H), 3.95 (s, 3H), 4.81 (m, IH), 7.49 (m, 2H), 7.69 (s, IH), 8.07 (s, IH), 8.22 (tr, IH), 8.41 (m, IH); MS m/z 496 [M+H]+. 5
The following examples were prepared by an analogous process to that used in the preparation of Example 205 utilising the appropriate amines available from Aldrich or Matrix
Example 206: 0 N-(l-azabicyclo[2.2.2]oct-8-yl)-3-methoxy-4-[(2-methyl-3-oxo-6-propan-2-yl-2,6,8,10- tetrazabicyclo [5.4.0]undeca-7,9,l l-trien-9-yl)amino] benzamide Example 207:
N-(2-dimethylaminoethyl)-3-methoxy-4-[(2-methyl-3-oxo-6-propan-2-yl-2,6,8,10- tetrazabicy clo [5.4.0] undeca-7 ,9,1 l-trien-9-yl)amino] benzamide
Example 208:
N-(3-dimethylamino-2,2-dimethyl-propyl)-3-methoxy-4-[(2-methyl-3-oxo-6-propan-2-yl-
2,6,8,10-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-9-yl)amino]benzamide
Example 209:
3-methoxy-4-[(2-methyl-3-oxo-6-propan-2-yl-2,6,8,10-tetrazabicyclo[5.4.0]undeca- 7,9,ll-trien-9-yl)amino]-N-(4-pyrrolidin-l-ylbutyl)benzamide
Figure imgf000145_0001
Figure imgf000145_0002
Figure imgf000146_0001
Example 210:
4- [(6-ethyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo [5.4.0] undeca-7,9,1 l-trien-9-yl)amino] - 3-methoxy-N-(l-methyl-4-piperidyl)benzamide
10-chloro-2-ethyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10512-trien-5-one Intermediate 81; 180 mg, 0.75 mmol), 4-amino-3-methoxy-N-(l-methyl-4- piρeridyl)benzamide (WO06/018220, 198 mg, 0.75 mmol) and p-toluenesulphonic acid (357 mg, 1.88 mmol) were heated in 4-methyl-2-pentanol (3 mL) to 140 °C for 18 hours. The reaction mixture was allowed to cool to room temperature and loaded onto a 10 g SCX-2 cartridge, washing with methanol (10 mL), water (10 mL) and methanol (10 mL) before the product was eluted off with 7 N methanolic ammonia which on evaporation of product containing fractions provided a brown oil which was purified by flash silica chromatography (Companion, 40 g, 0-10% methanolic ammonia/DCM) to give a pale yellow glass which was further purified by reverse phase HPLC to yield the title compound as a white solid (192 mg, 49 %).
1HNMR (399.902 MHz, DMSOd6) δ 1.24 (t, 3H), 1.60 (qd, 2H), 1.73 - 1.81 (m, 2H), 1.95 (td, 2H), 2.18 (s, 3H), 2.62 - 2.64 (m, 2H), 2.79 (br d, 2H), 3.18 (s, 3H), 3.62 (q, 2H), 3.70 - 3.79 (m, 3H), 3.96 (s, 3H), 7.49 - 7.53 (m, 2H), 7.70 (s, IH), 8.05 - 8.08 (m, 2H), 8.41 (d, IH); MS m/z 468 [M+H]+.
Example 211:
3-methoxy-4-[[2-methyl-6-(2-methylpropyl)-3-oxo-2,6,8?10-tetrazabicyclo[5.4.0]undeca- 7,9,ll-trien-9-yl]amino]-N-(l-methyl-4-piperidyl)benzamide
10-chloro-6-methyl-2-(2-methylpropyl)-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien-5- one (Intermediate 84; 65 mg, 0.24 mmol), 4-amino-3-methoxy-N-(l-methyl-4- piperidyl)benzamide (WO06/018220, 57 mg, 0.24 mmol) and p-toluene sulphonic acid (110 mg, 0.58 mmol) were taken up in 4-methyl-2-pentanol (1 mL) and heated to 16O0C by microwave irradiation for 1 hour. The reaction mixture was diluted with methanol (5 mL) and water (2 mL) and resultant solution poured onto an SCX-3 cartridge (2 g). The cartridge was washed with methanol (~30 mL) before eluting products with 2M ammonia methanol (~20 mL). The Ammoniacal fraction was evaporated to give an amber gum which was purified by reverse phase HPLC to yield the title compound as a colourless glass (scratches down to a white solid) (80 mg, 75 %).
1HNMR (400.132 MHz, DMSO-d6) δ 0.90 (d, 6H), 1.60 (m, 2H), 1.77 (m, 2H), 1.94 (m, 2H), 2.11 (m, IH), 2.17 (s, 3H), 2.64 (m, 2H), 2.78 (m, 2H), 3.19 (s, 3H), 3.50 (d, 2H), 3.68 - 3.79 (m, 3H), 3.95 (s, 3H), 7.49 (m, 2H), 7.70 (s, IH), 8.07 (d, IH), 8.08 (s, IH), 8.34 (m, IH); MS m/z 496 [M+H]+.
The following examples were prepared by an analogous process to that used in the preparation of Example 211 utilising the appropriate Chloropyrimidines indicated
Example 212A: 4-[(6-butan-2-yl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-9- yl)amino]-3-methoxy-N-(l-methyl-4-piperidyl)benzamide Chloropyrimidine used - 2-butan-2-yl-10-chloro-6-methyl-2,6,9,l 1- tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one Intermediate 87
1HNMR (400.132 MHz, DMSOd6) δ 0.87 (t, 3H), 1.23 (d, 3H), 1.49 - 1.70 (m, 4H), 1.77 (m, 2H)5 1.95 (t, 2H), 2.18 (s, 3H), 2.55 - 2.68 (m, 2H), 2.79 (m, 2H), 3.18 (s, 3H), 3.50 (m, s IH), 3.62 (m, IH), 3.74 (m, IH), 3.95 (s, 3H), 4.63 (m, IH), 7.48 - 7.52 (m, 2H), 7.68 (s, IH), 8.05 - 8.08 (m, 2H), 8.38 (m, IH); MS m/z 496 [M+H]+.
Example 212B;
4-[(6-cyclobutyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- I0 yl)amino]-3-methoxy-N-(l-methyl-4-piperidyl)benzamide
Chloropyrimidine used - 10-chloro-2-cyclobutyl-6-methyl-2,6,9,ll- tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one Intermediate 90
1HNMR (400.132 MHz, DMSO-d6) δ 1.55 - 1.80 (m, 6H), 1.95 (m, 2H), 2.10 (m, 2H), 2.18 (s, 3H), 2.25 (m, 2H), 2.58 (m, 2H), 2.79 (m, 2H), 3.18 (s, 3H), 3.66 (m, 2H), 3.74 (m, IH), is 3.95 (s, 3H), 4.52 (m, IH), 7.49 (m, IH), 7.53 (m, IH), 7.74 (s, IH), 8.06 (d, IH), 8.14 (s, IH), 8.45 (d, IH); MS m/z 494 [M+H]+.
Example 213;
4-[[6-(cyclopropylmethyl)-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12- 20 trien-9-yl]amino]-3-methoxy-N-(l-methyl-4-piperidyl)benzamide
Chloropyrimidine used 10-chloro-2-(cyclopropylmethyl)-6-methyl-2,6,9,l 1- tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one Intermediate 93
1HNMR (400.132 MHz, DMSOd6) δ 0.30 (m, 2H), 0.52 (m, 2H), 1.17 (m, IH), 1.60 (m, 2H), 1.77 (m, 2H), 1.95 (m, 2H), 2.17 (s, 3H), 2.65 (m, 2H), 2.79 (m, 2H), 3.19 (s, 3H), 3.51 25 (d, 2H), 3.69 - 3.81 (m, 3H), 3.95 (s, 3H), 7.49 (m, 2H), 7.71 (s, IH), 8.06 (d, IH), 8.09 (s, IH), 8.39 (m, IH); MS m/z 494 [M+H]+.
Example 214:
S-methoxy^-p-methyl-S-oxo^.ό^jlO-tetrazabicycloJS^.Olundeca-SjlOjπ-trien^- 30 yl)amino]-N-(l-methyl-4-piperidyl)benzamide 10-chloro-2-[(2,4-dimethoxyphenyl)methyl]-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca- 7,9,1 l-trien-5-one (Intermediate 96; 80 mg, 0.23 mmol), 4-amino-3-methoxy-N-(l-methyl-4- piperidyl)benzamide (WO06/018220; 52 mg, 0.20 mmol) and p-toluene sulphonic acid (110 mg, 0.58 mmol) were taken up in 4-methyl-2-pentanol (1.5 mL) and heated at 16O0C by microwave irradiation for 1 hour. The reaction mixture was dissolved in methanol (5 mL) and water (~5 mL) and poured directly onto an SCX-3 cartridge (2 g). The cartridge was washed through with methanol (~ 30 mL), before elution of products with 2M ammonia in methanol (~30 mL). Evaporation of ammoniacal fraction gave a brown gum which was purified by reverse phase HPLC to yield the title compound as a white solid (9 mg, 10 %) 1HNMR (400.132 MHz, DMSOd6) δ 1.60 (m, 2H), 1.77 (m, 2H), 1.94 (m, 2H), 2.17 (s, 3H), 2.61 (m, 2H), 2.78 (m, 2H), 3.21 (s, 3H), 3.54 (m, 2H), 3.73 (m, IH), 3.95 (s, 3H), 7.47 (m, 2H), 7.58 (m, 2H), 8.05 (d, IH), 8.10 (s, IH), 8.52 (m, IH); MS m/z 440 [M+H]+.
Example 215: s 4-[(6-benzyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-(l-methyl-4-piperidyl)benzamide
2-benzyl- 10-chloro-6-methyl-2,6,9, 11 -tetrazabicyclo[5 A0]undeca~7,9, 11 -trien-5-one (Intermediate 99; 42 mg, 0.14 mmol), 4-amino-3-rnethoxy-N-(l-methyl-4- piperidyl)benzamide (WO06/018220; 33 mg, 0.13 mmol) and p-toluene sulphonic acidQ monohydrate (54 mg, 0.28 mmol) were taken up in 4-methyl-2-pentanol (1.5 mL) and heated at 16O0C by microwave irradiation for 1 hour. The reaction mixture was dissolved in methanol (5 mL) and water (~5 mL) and poured directly onto an SCX-3 cartridge (2 g). The cartridge was washed through with methanol (~ 30 mL), before elution of products with 2M ammonia in methanol (-30 mL). Evaporation of the ammoniacal fraction gave an amber film5 which was purified by reverse phase HPLC to yield the title compound as an off-white solid (33 mg, 48 %)
1H NMR (400.132 MHz, DMSO-d6) δ 1.57 (m, 2H), 1.75 (m, 2H), 1.93 (m, 2H), 2.17 (s, 3H), 2.68 (m, 2H), 2.77 (m, 2H), 3.22 (s, 3H), 3.59 - 3.77 (m, 3H), 3.91 (s, 3H), 4.87 (s, 2H), 7.24 - 7.38 (m, 6H), 7.43 (m, IH), 7.71 (s, IH), 8.01 (d, IH), 8.14 (d, IH), 8.15 (s, IH); MSQ m/z 531 [M+H]+. Example 216:
3-methoxy-4-[[2-methyl-6-[(2-methyll,3-thiazol-4-yl)methyl]-3-oxo-2,6,8,10- tetrazabicyclo [5.4.0] undeca-7,9,1 l-trien-9-yl] amino] -N-(l-methyl-4-piperidyl)benzamide
10-chloro-6-methyl-2-[(2-methyl-l,3-thiazol-4-yl)methyl]-2,6,9,ll- tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one (Intermediate 101; 58 mg, 0.18 mmol), 4- amino-3-methoxy-N-(l-methyl-4-ρiρeridyl)benzamide (WO06/018220; 49 mg, 0.19 mmol) and p-toluene sulphonic acid (70 mg, 0.37 mmol) were taken up in 4-methyl-2-pentanol (2 mL) and heated to 16O0C in microwave by microwave irradiation for 1 hour. The reaction mixture was dissolved in methanol (5 mL) and water (~5 mL) and poured directly onto an SCX-3 cartridge (2 g). The cartridge was washed through with methanol (~ 30 mL), before elution of products with 2M ammonia in methanol (~30 mL). Evaporation of the ammoniacal fraction gave an amber film which was purified by reverse phase HPLC to yield the title compound as an off white solid (43 mg, 26 %)
1H NMR (400.132 MHz, DMSO-d6) δ 1.58 (m, 2H), 1.76 (m, 2H), 1.94 (m, 2H), 2.17 (s,s 3H), 2.67 (s, 3H), 2.72 (m, 2H), 2.77 (m, 2H)5 3.21 (s, 3H), 3.68 - 3.77 (m, 3H), 3.92 (s, 3H), 4.85 (s, 2H), 7.23 (m, IH), 7.29 (m, IH), 7.44 (d, IH), 7.71 (s, IH), 8.04 (d, IH), 8.08 (d, IH), 8.13 (s, IH); MS m/z 551 [M+H]+.
The following examples were prepared by an analogous process to that used in the preparation of Example 216 utilising the appropriate Chloropyrimidines indicated 0
Example 217:
4-[[6-(cyclobutylmethyl)-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12- trien-9-yl] amino] -3-methoxy-N-(l-methyl-4-piperidyl)benzamide
Chloropyrimidine used - 10-chloro-2-(cyclobutylmethyl)-6-methyl-2,6,9,ll-s tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5-one (Intermediate 102)
1HNMR (400.132 MHz, DMSOd6) δ 1.60 (m, 2H), 1.73 - 2.07 (m, 10H), 2.17 (s, 3H), 2.61 (m, 2H), 2.69 - 2.81 (m, 3H), 3.17 (s, 3H), 3.66 - 3.80 (m, 5H), 3.95 (s, 3H), 7.47 - 7.51 (m, 2H), 7.71 (s, IH), 8.07 (m, 2H), 8.35 (d, IH); MS m/z 509 [M+H]+. 0
Example 218: 4-[(2-methyl-3-oxo-6-propan-2-yl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-9- yl)amino]-N-(2-morpholin-4-ylethyl)benzamide
4-aniino-N-(2-morpholin-4-ylethyl)benzamide (Buttpark; 188mg, 0.75mmol) and 10-chloro- 6-methyl-2-propan-2-yl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien-5-one (Intermediate 76; 160mg, 0.63mmol) were heated together in 1:3 EtOH:water (8 ml) in the prescence of concentrated hydrochloric acid (126ul) for 24 hours. .The reaction was cooled to ambient temperature and then loaded onto an SCX-2 (5g) column pre-wet with methanol. The product was eluted with 2M NH3/MeOH and the solvent evaporated to give product as a brown gum. This was purified by reverse phase HPLC to give the title compound a white solid. (125 mg, 42 %)
1H NMR (400.132 MHz, DMSOd6) δ 1.25 (d, 6H), 2.44 (m, 6H), 2.59 (m, 2H), 3.18 (s, 3H), 3.37 (m, 2H), 3.59 (m, 6H), 4.85 (m, IH), 7.78 (m, 4H), 8.06 (s, IH), 8.15 (t, IH), 9.42 (s, lH); MS m/z 468 [M+H]+.
The following examples were prepared by an analogous process to that used in the preparation of Example 218 utilising the appropriate substituted anilines and Chloropyrimidines as indicated.
Example 219: 3-methoxy-4-[(2-methyl-3-oxo-6-propan-2-yl-2,6,8,10-tetrazabicyclo[5.4.0]undeca- 7,9,ll-trien-9-yl)amino]-N-(2-morpholin-4-ylethyl)benzamide
Prepared from Intermediate 76 and Intermediate 47.
1HNMR (400.132 MHz, DMSOd6) δ 1.29 (d, 6H), 2.49 (m, 6H), 2.52 (s, 3H), 2.65 (m, 2H), 3.44 (m, 2H), 3.65 (m, 6H), 4.00 (s, 3H), 4.87 (m, IH), 7.54 (m, 2H), 7.74 (s, IH), 8.12 (s, IH), 8.32 (t,lH), 8.47 (d, IH).
Example 220:
3-methoxy-4-[(2-methyl-3-oxo-6-phenyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12- trien-9-yl)amino]-N-(2-morpholin-4-ylethyl)benzamide 490
151
Prepared from Intermediate 103 and Intermediate 47.
1H NMR (400.132 MHz, DMSO-d6) δ 2.44 (m, 5H), 2.83 (m, 2H), 3.28 (s, 3H), 3.36 (m, 2H), 3.59 (m, 4H), 3.88 (s, 3H), 4.06 (m, 2H), 6.93 (d, IH), 7.35 (m, 4H), 7.47 (m, 3H), 7.64 (s, IH), 8.16 (t, IH), 8.29 (s, IH).
Example 221:
3-methoxy-4-[(2-methyl-3-oxo-6-phenyl-2,6,8?10-teti"azabicyclo[5.4.0]undeca-8,10,12- trien-9-yl)amino]-N-(l-methyl-4-piperidyl)benzamide
Prepared from Intermediate 103 and an intermediate decribed in WO06/018220. io 1H NMR (400.132 MHz, DMSOd6) δ 1.58 (m, 2H), 1.75 (m, 2H), 1.93 (m, 2H), 2.17 (s, 3H), 2.51 (s, 3H), 2.80 (m, 4H), 3.70 (m, IH), 3.89 (s, 3H), 4.06 (m, 2H), 6.96 (d, IH), 7.34 (m, 4H), 7.48 (m, 3H), 7.64 (s, IH), 7.97 (d, IH), 8.29 (s, IH).
I5
Example 222:
N-(3-dimethylamino-2,2-dimethyl-propyl)-4-[(2-methyl-3-oxo-6-propan-2-yl-2,6,8,10- tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-9-yl)amino]benzamide
Prepared from Intermediate 76 and Intermediate 22.
20 1HNMR (400.132 MHz, DMSOd6) δ 0.88 (s, 6H), 1.25 (d, 6H), 2.18 (s, 2H), 2.27 (s, 6H), 2.59 (m, 2H), 3.18 (s, 2H), 3.29 (s, 3H), 3.61 (m, 2H), 4.85 (m, IH), 7.73 (d, 2H), 7.81 (d, 2H), 8.06 (s, IH), 8.27 (t, IH), 9.42 (s, IH);
Example 223:
25 N-(3-dimethylamino-2,2-dimethyl-propyl)-4-[(2-methyl-3-oxo-6-phenyl-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9-yl)amino]benzamide
Prepared from Intermediate 103 and Intermediate 22.
1HNMR (400.132 MHz, DMSO-d6) δ 0.87 (s, 6H), 2.18 (s, 2H), 2.28 (s, 6H), 2.81 (m, 2H), 3.14 (d, 2H), 3.28 (s, 3H), 4.06 (m, 2H), 7.33 (m, 7H), 7.47 (m, 2H), 8.21 (t, IH), 8.31 (s, so IH), 9.52 (s, IH). Example 224:
4-[(2-methyl-3-oxo-6-phenyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yϊ)amino]-N-(l-methyl-4-piperidyl)benzamide Prepared form Intermediate 103 and Intermediate 4.
1HNMR (400.132 MHz, DMSOd6) δ 1.56 (m, 2H), 1.72 (m, 2H), 1.93 (m, 2H)5 2.16 (s, 3H), 2.78 (m, 4H), 3.28 (s, 3H), 3.68 (m, IH), 4.05 (m, 2H), 7.29 (m, 5H), 7.45 (m, 4H), 7.87 (d, IH), 8.31 (s, IH), 9.49 (s, IH)
Figure imgf000153_0001
Figure imgf000153_0002
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Figure imgf000154_0001
Example 225:
3-chloro-N-(3-dimethylamino-2,2-dimethyl-propyl)-4-[(2-methyl-3-oxo-6-phenyl- 2,6,8,10-tetrazabicycIo[5.4.0]undeca-8,10,12-trien-9-yl)amino]benzamide
4-amino-3-chloro-N-(3-dimethylamino-2,2-dimethyl-propyl)benzaniide (Intermediate 107; 99mg, 0.35mmol), 10-chloro-6-methyl-2-phenyl-2,6,93l l-tetrazabicyclo[5.4.0]undeca-7,9,l 1- trien-5-one (Intermediate 103; 99 mg, 0.35 mmol) and p-toluenesulphonic acid monohydrate (165 mg, 0.87 mmol) were heated at 14O0C in 4-methyl-2-ρentanol (2.5 mL) for 2 hours. The mixture was allowed to cool forming a dark orange clear solution which was loaded onto an SCX-3 column pre-wet with methanol. The column was washed with methanol to remove p- TsOH. and then eluted with 2% 7N ammonia/methanol to give the crude product which was purified by reverse phase HPLC to yield the title compound as a white solid (15 mg, 8 %). 1H NMR (399.9 MHz, DMSOd6) δθ.88 (6H, s), 2.17 (2H, s), 2.28 (6H, s), 2.82 - 2.85 (2H, m), 3.16 (2H, d), 4.04 - 4.08 (2H, m), 7.21 - 7.24 (IH, m), 7.28 - 7.30 (IH, m), 7.32 - 7.35 (2H, m), 7.46 (IH, s), 7.48 - 7.50 (IH, m), 7.56 (IH, d), 7.82 (IH, d), 8.02 (IH, s), 8.32 (IH, s), 8.37 (IH, t); MS m/z 537 [M+H]+. The following example was prepared by an analogous process to that used in the preparation of Example 225 utilising the appropriate substituted aniline (Intermediate 52)
Example 226:
5 3-chloro-4-[(2-methyl-3-oxo-6-phenyl-2,6,8?10-teti*azabicyclo[5.4.0]undeca-8,10,12-trien- 9-yl)amino]-N-(2-morpholin-4-ylethyl)benzamide
1H NMR (399.9 MHz, DMSOd6) 52.41 - 2.47 (6H, m), 2.84 (2H, t), 3.33 - 3.41 (2H, m), 3.59 (4H, t)5 4.05 - 4.08 (2H, m), 7.24 - 7.27 (IH, m), 7.31 - 7.35 (3H, m), 7.49 (2H, t), 7.55 (IH, q), 7.85 (IH, d), 8.00 (IH, s), 8.31 (2H, s); MS m/z 537 [M+H]+.
I0
Example 227:
4-[(2-methyl-3-oxo-6-phenyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(2-morpholin-4-ylethyl)benzamide
10-chloro-6-methyl-2-phenyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien-5-one is (Intermediate 103; 150 mg, 0.52 mmol), 4-amino-N-(2-morpholin-4-ylethyl)benzamide (Buttpark; 130 mg, 0.52 mmol) and p-toluenesulphonic acid monohydrate (248 mg, 1.30mmol) were heated in 4-methyl-2-pentanol (3 rnL) at 14O0C for 2 hours. The reaction mixture was cooled and loaded onto an SCX-3 column pre-wet methanol. The column was washed with methanol to remove p-toluenesulphonic acid monohydate and then washed with 20 2% 7N ammonia/methanol to elute the crude product. The product containing fractions were evaporated and the resultant material purified by reverse phase HPLC to give the title compound as a white solid (81 mg, 32.2 %).
1H NMR (399.9 MHz, DMSO-d6) δ 2.41 - 2.44 (6H, m), 2.82 (2H, t), 3.35 (3H, s), 3.38 - 3.39 (2H, t), 3.59 (4H5 1), 4.06 - 4.08 (2H, t), 7.26 (IH, s), 7.29 (IH, s), 7.31 - 7.35 (2H, m), 7.34 - 2s 7.34 (IH, m), 7.40 - 7.42 (2H, m), 7.49 (2H, t), 8.05 (IH, t), 8.31 (IH, s), 9.53 (IH, s); MS m/z 503 [M+H]+.
Example 228:
3-chloro-4-[(2-methyl-3-oxo-6-propan-2-yl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-7,9,ll- 30 trien-9-yl)amino]-N-(2-morpholin-4-ylethyl)benzamide 490
155
10-chloro-6-methyl-2-propan-2-yl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9,l 1 -trien-5-one (Intermediate 76 ; 150 mg, 0.59 mmol), 4-ammo-3-chloro-N-(2-morpholm-4- ylethyl)benzamide (Intermediate 52; 168 mg, 0.59 mmol), and p-toluenesulphonic acid monohydrate (281 mg, 1.47 mmol) were heated in 4-methyl-2-pentanol (4 niL) at 14O0C for 2 hours. The reaction mixture was cooled and loaded onto an SCX-3 column pre-wet with Methanol. The column was washed with methanol to remove p-toluenesulphonic acid monohydate and then washed with 2% 7N ammonia/methanol to elute the crude product. Product containing fractions were evaporated and the resultant material purified by reverse phase HPLC to yield the title compound as an orange gum (46 mg, 15.6 %). 1R NMR (399.9 MHz, DMSOd6) δ 1.20 (6H, d), 2.42 - 2.43 (3H, m), 2.44 - 2.49 (2H, m), 2.60 (2H, t), 3.18 (4H, t), 3.39 (2H, q), 3.60 - 3.62 (6H, m), 4.75 (IH, m), 7.80 - 7.82 (IH, m), 7.96 (IH, d), 8.07 (IH, s), 8.12 (IH, s), 8.32 (IH, d), 8.40 (IH, t); MS m/z 503 [M+H]+.
Example 229; 3-methoxy-4-[[6-(2-methoxyethyl)-2-methyl-3-oxo-2,6,8>10-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-9-yl]amino]-N-(l-methyl-4-piperidyl)benzamide
10-chloro-2-(2-methoxyethyl)-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien-5- one (Intermediate 109; 70 mg, 0.26 mmol), 4-amino-3-methoxy-N-(l-methyl-4- piperidyl)benzamide (WO06/018220; 63 mg, 0.26 mmol), and p-toluenesulphonic acid monohydrate (123 mg, 0.65 mmol) were combined in 4-Methy-2-pentanol (2 mL) and heated at 100 °C overnight. The reaction was cooled to room temperature and taken up in MeOH and added to a 2g SCX-2 column pre-wet with MeOH (2 column volumes). The column was washed with MeOH (2 column volumes) and the product eluted with 2M ammonia in MeOH and solvents evaporated. The resultant material was dissolved in DCM and purified on silica eluting with a gradient of 0 - 10% MeOH / DCM then 10% MeOH / DCM. Fractions containing product combined and evaporated to a clear gum to which ether was added and re-evaporated and the resultant material purified by reverse phase HPLC to give the title compound as a white solid. (40 mg, 31 %).
HNMR (399.902 MHz, CDCl3) 6 1.58 (m, 2H), 2.06 (m, 2H), 2.17 (m, 2H), 2.31 (s, 3H), 2.72 (m, 2H), 2.83 (m, 2H), 3.29 (s, 3H), 3.36 (s, 3H), 3.72 (m, 2H), 3.87 (m, 4H), 4.00 (m, 4H), 5.90 (d, IH), 7.23 (m, IH), 7.44 (d, IH), 7.65 (s, IH), 7.95 (s, IH), 8.42 (d, IH); MS m/z
Figure imgf000157_0001
Example 230: s 3-methoxy-4-[[6-(l-methoxypropan-2-yl)-2-methyl-3-oxo-2,6,8,10- tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-9-yl]amino]-N-(l-methyl-4-piperidyl)benzamide
10-chloro-2-( 1 -methoxypiOpan-2-yl)-6-methy 1-2,6,9, 11 -tetrazabicyclo [5.4.0]undeca-7,9, 11 - trien-5-one (Intermediate 112 60 mg, 0.21 mmol), 4-amino~3-methoxy-N-(l-methyl-4- piperidyl)benzamide (WO06/018220; 56 mg, 0.21 mmol), and p-toluenesulphonic acido monohydrate (100 mg, 0.53 mmol) were combined in 4-Methy-2-pentanol (2 rnL) and heated at 100 °C for 16 hrs. The reacrtion mixture was cooled to room temperature and dissolved in Methanol. The resultant solution was added to a 5g SCX-3 column pre wet with MeOH (2 column volumes). Flushed with MeOH (2 column volumes) and crude product eluted with 2M ammonia in MeOH and solvents evaporated. The resultant residue was dissolved ins DCM and purified on silica eluting with a gradient of 5 - 15% MeOH / DCM. Product containing fractions were combined and evaporated to a yellow gum which was purified by base modified reverse phase HPLC to give the title compound as a beige solid. (35 mg, 32%)
H NMR (399.902 MHz, CDCl3) δ 1.32 (d, 3H), 1.58 (m, 2H), 2.05 (m, 2H), 2.17 (m, 2H), 2.31 (s, 3H), 2.68 (m, 2H), 2.83 (m, 2H), 3.29 (s, 3H), 3.36 (s, 3H), 3.51 (m, IH), 3.62 (m,0 IH), 3.73 (m, 2H), 4.00 (m, 4H), 5.00 (m, IH), 5.90 (d, IH), 7.23 (m, IH), 7.43 (m, IH), 7.65 (s, IH), 7.94 (s, IH)5 8.47 (d, IH); MS m/z 503 [M+H]+.
Example 231:
4-[[6-(3-furylmethyl)-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5 9-yl]amino]-3-methoxy-N-(l-methyl-4-piperidyl)benzamide
10-chloro-2-(3-furylmethyl)-6-methyl-2,6,9, 11 -tetrazabicyclo [5.4.0]undeca-7,9, 11 -trien-5- one one (Intermediate 116; 67 mg, 0.23 mmol), 4-amino-3-methoxy-N-(l-methyl-4- piperidyl)benzamide (WO06/018220; 60 mg, 0.23 mmol), and p-toluenesulphonic acid monohydrate (109 mg, 0.57 mmol) were combined in 4-Methy-2-pentanol (2 niL) and heated0 at 100 0C for 16 hrs.. The reacrtion mixture was cooled to room temperature and dissolved in Methanol. The resultant solution was added to a 5g SCX-3 column pre wet with MeOH (2 B2007/002490
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column volumes). Flushed with MeOH (2 column volumes) and crude product eluted with 2M ammonia in MeOH and solvents evaporated. The resultant residue was dissolved in DCM and purified on silica eluting with a gradient of O - 15% MeOH / DCM. Product containing fractions were combined and evaporated to a yellow gum which was purified by base modified reverse phase HPLC to give the title compound as a yellow solid. (50 mg, 42%)
H NMR (400.132 MHz, CDCl3) δ 1.57 (m, 2H)5 2.04 (m, 2H), 2.17 (m, 2H), 2.31 (s, 3H), 2.64 (m, 2H), 2.82 (m, 2H), 3.31 (s, 3H), 3.71 (m, 2H), 3.98 (m, 4H), 4.67 (s, 2H), 5.88 (d, IH), 6.43 (s, IH), 7.14 (m, IH), 7.40 (m, IH), 7.43 (m, 2H), 7.71 (s, IH), 7.99 (s, IH), 8.45 (d, IH); MS m/z 520 [M+H]+.
Example 232:
4-[(6-cyclopropyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-(l-methyl-4-piperidyl)benzamide lO-chloiO^-cyclopropyl-ό-methyKZjδ^,! l-tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one (Intermediate 117 42mg, 0.16 mmol), 4-amino-3-methoxy-N-(l-methyl-4- piperidyl)benzamide (WO06/018220; 44 mg, 0.216 mmol), and p-toluenesulphonic acid monohydrate (79 mg, 0.41 mmol) were combined in 4-Methy-2-pentanol (2 rnL) and heated at 100 0C for 16 hrs. The reacrtion mixture was cooled to room temperature and dissolved in methanol. The resultant solution was added to a 5g SCX-3 column pre wet with MeOH (2 column volumes). Flushed with MeOH (2 column volumes) and crude product eluted with 2M ammonia in MeOH and solvents evaporated. The resultant residue was dissolved in DCM and purified on silica eluting with a gradient of 0 - 15% MeOH / DCM. Product containing fractions were combined and evaporated to a yellow gum which was purified by base modified reverse phase HPLC to give the title compound as a white solid. (34 mg, 43%) i H NMR (400.132 MHz, CDCl3) δ 0.64 (m, 2H), 0.92 (m, 2H), 1.59 (m, 2H), 2.05 (m, 2H),
2.17 (m, 2H), 2.31 (s, 3H), 2.67 (m, 2H), 2.86 (m, 3H), 3.26 (s, 3H), 3.82 (m, 2H), 4.00 (m, 4H), 5.90 (d, IH), 7.22 (m, IH), 7.44 (d, IH), 7.82 (s, IH), 7.99 (s, IH), 8.76 (d, IH); MS m/z 503 [M+H]+.
Example 233; 02490
158
N-cyclohexyl-3-methoxy-4-[[2-methyl-6-(l-methyl-4-piperidyl)-3-oxo-2,6,8,10- tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-9-yl]amino]benzamide
10-chloro-6-methyl-2-(l -methyl-4-piperidyl)-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 - trien-5-one (Intermediate 118; 39mg, 0.13 mmol), 4-amino-N-cyclohexyl-3-methoxy-
5 benzamide (Intermediate 119; 3 lmg, 0.13 mmol) and p-toluenesulphonic acid monohydrate (60 mg, 0.31 mmol) were combined in 4-Methy-2- pentanol (2 mL) and heated at 100 °C for 16 hrs. The reacrtion mixture was cooled to room temperature and dissolved in Methanol and added to a 5g SCX-3 column pre wet with MeOH (2 column volumes). Flushed with MeOH (2 column volumes) then crude product eluted io with 2M ammonia in MeOH and solvents evaporated. The resultant material was dissolved in DCM and purified on silica eluting with a shallow (25 column volumes) gradient of 0 - 10% MeOH / DCM. Product containing fractions were combined and evaporated to a yellow gum which was purified by base modified reverse phase HPLC to give the title compound as a white solid. (15 mg, 23%). is H NMR (400.132 MHz, CDCl3) δ 1.26 (m, 4H), 1.45 (m, 2H), 1.77 (m, 2H), 1.91 (m, 4H), 2.05 (m, 2H), 2.17 (m, 2H), 2.35 (s, 3H), 2.67 (m, 2H), 3.02 (m, 2H), 3.28 (s, 3H), 3.71 (m, 2H), 3.98 (m, 4H), 4.51 (m, IH), 5.88 (d, IH), 7.26 (m, IH), 7.38 (d, IH), 7.66 (s, IH), 7.94 (s, IH), 8.45 (d, IH); MS m/z 522 [M+H]+.
20
Example 234:
4-[(6-cyclopentyl-2,5-dimethyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-
9-yl)amino]-3-methoxy-N-(l-methyl-4-piperidyl)benzamide
25 10-chloro-2-cyclopentyl-3,6-dimethyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5- one (Intermediate 120; 25 mg, 0.42 mmol) and ), 4-amino-3-methoxy-N-(l-methyl-4- piperidyl)benzamide (WO06/018220; 112 mg, 0.42 mmol) were combined with p- toluenesulphonic acid monohydrate (202 mg, 1.06 mmol) in 4-methyl-2-pentanol (1 mL) and heated to 150 °C for 2 hr. The cooled reaction mixture was diluted with methanol (approx 50
30 mL) and loaded onto a 50 g SCX-2 cartridge washing with methanol (100 mL) and eluting with 7 N methanolic ammonia (100 mL). The concentrated solution was purified by base modified reverse phase HPLC to give the title compound as a white solid (65 mg, 30%)
1H NMR (399.902 MHz, CDC13) δ 1.29 (d, 3H), 1.54 - 1.89 (m, 9H), 1.95 - 2.23 (m, 6H), 2.32 (s, 3H), 2.56 (dd, IH), 2.72 (dd, IH), 2.84 (br d, 2H), 3.31 (s, 3H), 3.98 (s, 3H), 4.00 - 4.07 (m, IH), 4.63 - 4.71 (m, IH), 5.91 (d, IH), 7.23 (dd, IH), 7.42 (d, IH), 7.67 (s, IH), 7.97 (s, IH), 8.47 (d, IH); MS m/z 522 [M+H]+.
Example 235: 4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien- 10-yl)amino]-3-methoxy-N-(l-methyl-4-piperidyl)benzamide
A solution of HATU (221 mg, 0.55 mmol) in DMA (10 mL) was added to a mixture of the 4- [(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien- 10- yl)amino]-3-methoxy-benzoic acid (Example 242; 220 mg, 0.5 mmol), DIPEA(261 uL, 1.5 mmol) and 4-amino-3-methoxy-N-(l-methyl-4-piperidyl)benzamide (WO06/018220; 72 mg, 0.62 mmol) in DMA (10 mL). The resulting mixture was stirred at room temperature for 2 hours, then partially purified by SCX. The compound was retrieved from the SCX column using 7N ammonia in methanol, then concentrated in vacuo, and further purified by column chromatography, eluting with 0-10% ammonia (7N in methanol) in DCM. The pure material was recovered as an orange oil, which foamed and solidified under high vacuum. Trituration under ether gave the title compound as a pale yellow amorphous solid. (154 mg, 58%) 1HNMR (399.9 MHz, CDCl3) δl.22 (6H, s), 1.56 - 1.63 (2H, m), 1.72 - 1.93 (6H, m), 1.99 - 2.03 (2H, m), 2.14 (2H, d), 2.41 - 2.45 (2H, m), 2.48 (3H, s), 3.06 - 3.09 (2H, m), 3.32 (3H, s), 3.40 (2H, s), 4.00 (3H, s), 4.10 - 4.14 (IH, m), 5.29 - 5.38 (IH, m), 6.12 (IH, d), 7.28 (IH, dd), 7.44 (IH, d), 7.65 (IH, s), 7.88 (IH, s), 8.52 (IH, d); MS m/z 536 [M+H]+.
Example 236: Example 237:
4-[[(4S)-2-cyclopentyl-4-ethyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca- 8,lθ5l2-trien-10-yl]amino]-3-methoxy-N-(l-methyl-4-piperidyl)benzamide and 4-[[(4R)-2-cyclopentyl-4-ethyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-10-yl]amino]-3-methoxy-N-(l-methyl-4-piperidyl)benzamide 10-chloro-2-cycloρentyl-4-ethyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10512-trien- 5- one (Intermediate 123; 186 mg, 0.6 mmol), 4~amino-3-methoxy-N-(l-methyl-4- piperidyl)benzamide (WO06/018220; 159 mg, 0.6 mmol) were combined with p- toluenesulphonic acid monohydrate (286 mg, 1.5 mmol) in 4-methyl-2-pentanol (01 mL) and s at 1150C overnight. The cooled reaction mixture was dissolved in methanol, passed through an SCX-2 column and washed with methanol. The product was eluted off with 7N ammonia/methanol. Product containing fractions were evaporated and the resultant material was purified using base modified reverse phase HPLC to give a mixture of the title compounds as a brown foam (110 mg) 0
The individual enantiomers were separated by chiral column chromatography to as white foams
Enatiomer 1 (26 mg )
1HNMR (399.9 MHz, DMSO-d6) : δH : 0.89 (tr, 3H), 1.31 (m, 2H), 1.50-1.90 (m, 12H), 2.11s (m, 2H), 2.36 (m, 5H), 2.61 (m, IH), 3.00 (m, 2H), 3.21 (s, 3H), 3.42 (m, 2H), 3.84 (m, IH),
3.97 (s, 3H), 4.79 (tr, IH), 7.50 (m, 2H), 7.77 (m, IH), 8.12 (m, 2H), 8.39 (d, IH); MS m/z
536 [M+H]+.
Enantiomer 2 (26 mg)
1H NMR (399.9 MHz, DMSO-d6) : δH : 0.89 (tr, 3H), 1.31 (m, 2H), 1.50-1.90 (m, 12H), 2.110 (m, 2H), 2.36 (m, 5H), 2.61 (m, IH), 3.00 (m, 2H), 3.21 (s, 3H), 3.42 (m, 2H), 3.84 (m, IH),
3.97 (s, 3H), 4.79 (tr, IH), 7.50 (m, 2H), 7.77 (m, IH), 8.12 (m, 2H), 8.39 (d, IH).; MS m/z
536 [M+H]+.
Example 238: Example 239; 5 4-[[(4S)-2-cyclopentyl-6-methyl-5-oxo-4-propyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-10-yl]amino]-3-methoxy-N-(l-methyl-4-piperidyl)benzamide and
4- [[(4R)-2-cy clopentyl-6-methyl-5-oxo-4-propyl-2,6,9,l 1-tetrazabicyclo [5.4.0] undeca- 8,10,12-trien-10-yl]amino]-3-methoxy-N-(l-methyl-4-piperidyl)benzamide 0
10-chloro-2-cyclopentyl-6-methyl-4-propyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10,12- trien-5-one (Intermediate 124; 194 mg, 0.6 mmol), 4-amino-3-methoxy-N-(l-methyl-4- piperidyl)benzamide (WO06/018220; 159 mg, 0.6 mmol) were combined with p- toluenesulphonic acid monohydrate (286 mg, 1.5 mmol) in 4-methyl-2-pentanol (01 mL) and at 1150C overnight. The cooled reaction mixture was dissolved in methanol, passed through an SCX-2 column and washed with methanol. The product was eluted with 7N ammonia/methanol. Product containing fractions were evaporated and the resultant material purified using basic prep HPLC to give a mixture of the title compounds as a light brown foam (65 mg)
The individual enantiomers were separated by chiral column chromatography to as white foams Enantiomer 1 (15 mg )
1E NMR (399.9 MHz, DMSO-d6) : δ 0.84 (tr, 3H), 1.29 (m, 3H), 1.50-1.90 (m, 13H), 2.11 (m, 2H), 2.41 (m, 5H), 2.69 (m, IH), 3.02 (m, 2H), 3.20 (s, 3H), 3.40 (m, 2H), 3.85 (m, IH), 3.95 (s, 3H), 4.79 (tr, IH), 7.50 (m, 2H), 7.76 (m, IH), 8.12 (s, IH), 8.14 (d, IH), 8.40 (d, IH); MS m/z 550 [M+H]+. Enantiomer 2 (22 mg)
1H NMR (399.9 MHz, DMSO-d6) : δ 0.84 (tr, 3H), 1.29 (m, 3H), 1.50-1.90 (m, 13H), 2.11 (m, 2H), 2.41 (m, 5H), 2.69 (m, IH), 3.02 (m, 2H), 3.20 (s, 3H), 3.40 (m, 2H), 3.85 (m, IH), 3.95 (s, 3H), 4.79 (tr, IH), 7.50 (m, 2H), 7.76 (m, IH), 8.12 (s, IH), 8.14 (d, IH), 8.40 (d, IH); MS m/z 550 [M+H]+.
Example 240: Example 241: 4-[[(4S)-2-cyclopentyl-4,6-dimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12- trien-10-yl]amino]-3-methoxy-N-(l-methyl-4-piperidyl)benzamide and
4-[[(4R)-2-cyclopentyl-4,6-dimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12- trien-10-yl]amino]-3-methoxy-N-(l-methyl-4-piperidyl)benzamide 10-chloro-2-cyclopentyl-4,6-dimethyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5- one (Intermediate 125; 674 mg, 2.29 mmol), 4-amino-3-methoxy-N-(l-methyl-4- piperidyl)benzamide (WO06/018220; 602 mg, 2.29 mmol) andp-toluene sulphonic acid (1.09 g, 0.89 mmol) were dissolved in 4-methyl-2-pentanol (15 mL) and refluxed under a blanket of nitrogen for 24 hours. The reaction mixture was cooled and passed through an SCX-2 column washed with methanol. The crude product was eluted with 7N ammonia in methanol. Product containing fractions were evaporated and the resultant material purified by column chromatography, eluting with 0-10% ammonia methanol (7N) in DCM. The resultant material was purified by base modified reverse phase HPLC to give a mixture of the title compounds as a white solid (480 mg, 40%).
The individual enantiomers were separated by chiral column chromatography to as white gums which were dissolved separately in DCM then passed through SCX-2 columns and washed with methanol. The products were eluted off the columns using 7N ammonia in methanol and concentrated under reduced pressure to yield the enantiomers as white solids. Enatiomer 1 (118 mg)
1HNMR (399.902 MHz, DMSO-d6) δ 1.04 (d, 3H), 1.51 - 1.84 (m, 12H), 1.99 - 2.13 (m, 3H), 2.81 - 2.91 (m, 6H), 3.20 (s, 3H), 3.45 (q, 2H), 3.78 (m, IH), 3.96 (s, 3H), 4.08 (s, IH), 4.75 (quintet, IH), 7.49 (d, IH), 7.75 (s, IH), 8.09 (d, IH), 8.40 (d, IH); MS m/z 523 [M+H]+.
Enatiomer 2 (59 mg)
1H NMR (399.902 MHz, DMSO-d6) δ 1.04 (d, 3H), 1.51 - 1.84 (m, 12H), 1.99 - 2.13 (m, 3H), 2.81 - 2.91 (m, 6H), 3.20 (s, 3H), 3.45 (q, 2H), 3.78 (m, IH), 3.96 (s, 3H), 4.08 (s, IH), 4.75 (quintet, IH), 7.49 (d, IH), 7.75 (s, IH), 8.09 (d, IH), 8.40 (d, IH); MS m/z 523 [M+H]+.
Example 242:
4- [(2-cyclopentyl-4,4,6-trimethy l-5-oxo-2,6,9,l 1-tetrazabicy do [5.4.0] undeca-7,9,11-trien- 10-yl)amino]-3-methoxy-benzoic acid
To a solution of 10-chloro-2-cyclopentyl-4,4,6-trimethyl-2,6,9,l 1- tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one (Intermediate 126; 616 mg, 2. O mniol) and 4-amino-3~methoxybenzoic acid (378 mg, 2.2 mmol) in ethanol (5 niL) was added water (15 mL) and cone hydrochloric acid (0.335 mL). The mixture was heated under reflux for 36 hours. The reaction was cooled and a brown solid precipitated. This was filtered, dried and triturated under cold acetonitrile and then dried in vacuo to give the product as a pale brown solid (420 mg), 48%)
1 H NMR (400.13 MHz, DMSOd6) δl.15 (6H5 s), 1.55 - 1.90 (8H, m), 3.19 (3H, s), 3.53 (2H, s), 3.95 (3H, s), 5.07 - 5.16 (IH, m), 7.59 - 7.61 (2H, m), 8.11 (IH, s), 8.13 (IH, d), 9.53 s (IH, s); MS m/z 440 [M+H]+.
Example 243:
4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-
10-yl)amino]-3-methoxy-N-(l-methyl-3-piperidyl)benzamide o A solution of HATU (126 mg, 0.33 mmol) in DMA (5 mL) was added to a mixture of the 4- [(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien- 10- yl)amino]-3-methoxy-benzoic acid acid (Example 242 132 mg, 0.3 mmol), DIPEA (261 uL, 1.5 mmol) and 3-amino N-methylpiperidine dihydrochloride (71 mg, 0.375 mmol) in DMA (5 mL). The resulting mixture was stirred at room temperature for 2 hours, then partially purifieds by SCX. The compound was eluted from the SCX column using 7N ammonia in methanol, then concentrated in vacuo, and further purified by column chromatography, eluting with 0- 10% ammonia (7N in methanol) in DCM. The pure material was recovered as an orange oil, which foamed and solidified under high vacuum. Trituration under ether gave the title compound as a pale yellow amorphous solid (65 mg, 41%) 0 1H NMR (400.13 MHz, CDCl3) δl.03 (6H, s), 1.34 - 1.87 (12H, m), 2.17 (5H, s), 2.41 (2H, s), 3.13 (3H, s), 3.20 (2H, s), 3.82 (3H, s), 4.19 (IH, s), 5.10 - 5.20 (IH, m), 7.09 (IH, s), 7.20 (IH, s), 7.34 (IH, s), 7.43 (IH, s), 7.68 (IH, s), 8.31 (IH, d); MS m/z 536 [M+H]+.
5 Example 244:
4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien- 10-yl)amino]-3-methoxy-N-[l-(2-methoxyethyl)-4-piperidyl]benzamide
A solution of HATU (126 mg, 0.33 mmol) in DMA (5 mL) was added to a mixture of 4-[(2- cyclopentyl-4,4,6-trimethyl-5 -oxo-2,6,9, 11 -tetrazabicyclo [5.4.0]undeca-7,9, 11 -trien- 10-o yl)amino]-3-methoxy-benzoic acid acid (Example 242 132 mg, 0.3 mmol), DIPEA (261 uL, 1.5 mmol) and 4-amino N-(2-methoxyethyi)piperidine (60 mg, 0.375) in DMA (5 mL). The resulting mixture was stirred at room temperature for 2 hours, then partially purified by SCX. The compound was retrieved from the SCX column using 7N ammonia in methanol, then concentrated in vacuo, and further purified by column chromatography, eluting with 0-10% ammonia (7N in methanol) in DCM. The pure material was recovered as an orange oil, which foamed and solidified under high vacuum. Trituration under ether gave a pale yellow
5 amorphous solid. (55 mg, 32%)
1H NMR (400.13 MHz, CDCl3) δl.13 (6H, s), 1.43 - 1.56 (2H, m), 1.58 - 1.74 (4H, m), 1.87 - 1.97 (4H, m), 2.04 (2H, d), 2.44 (2H, t), 2.76 (2H, t), 3.10 - 3.12 (2H, m), 3.23 (3H, s), 3.29 - 3.30 (2H5 m), 3.30 (3H, s), 3.59 - 3.62 (2H, m), 3.90 (2H, s), 4.03 - 4.07 (IH, m), 5.20 - 5.28 (IH, m), 6.04 (IH, d), 7.17 - 7.20 (2H, m), 7.34 (IH, d), 7.55 (IH, s), 7.79 (IH, s), 8.42 (IH, io d). MS m/z 580 [M+H]+.
Example 245:
4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien- 15 10-y l)amino] -N-(I -methy 1-4-piperidy l)benzamide
A solution of HATU (126 mg, 0.33 mmol) in DMA (5 mL) was added to a mixture of 4-[(2- cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien- 10- yl)amino]benzoic acid , (Intermediate 129; 123 mg, 0.3 mmol) DIPEA (261 uL, 1.5 mmol) and 4-amino N-methylpiperidine (43 mg, 0.375) in DMA (5 mL). The resulting mixture was 20 stirred at room temperature for 2 hours, then partially purified by SCX. The compound was eluted from the SCX column using 7N ammonia in methanol, then concentrated in vacuo, and further purified by column chromatography, eluting with 0-10% ammonia (7N in methanol) in DCM. The pure material was recovered as an orange oil, which foamed and solidified under high vacuum. Trituration under ether gave a pale yellow amorphous solid. (100 mg,
25 66%)
1HNMR (400.13 MHz, CDCl3) δl.13 (6H, s), 1.43 - 1.53 (2H, m), 1.60 - 1.73 (4H, m), 1.83 - 1.95 (4H, m), 2.01 - 2.09 (2H, m), 2.37 - 2.42 (2H, m), 2.44 (3H, s), 3.06 (2H, d), 3.22 (3H, s), 3.30 (2H, s), 4.01 - 4.07 (IH5 m), 5.16 - 5.25 (IH, m), 6.07 (IH, d), 6.99 (IH, s), 7.58 (2H, d), 7.65 (2H, d), 7.77 (IH, s); MS m/z 506 [M+H]+.
30
Example 246; 4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9t-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-N-(l-methylpiperidin-4-yl)-3- methoxybenzamide
2'-chloro-9'-cyclopentyl-5'-methyl-8',9'-dihydrospiro[cyclopropane-l,7'-pyrimido[554- b][l,4]diazepin]-6'(5Η)-one (Intermediate 130; 153 mg, 0.5 mmol) 4-amino-3-methoxy-N- (l-methyl-4-piperidyl)benzamide (WO06/018220; 158 mg, 0.6 mmol) were combined with p- toluenesulphonic acid monohydrate (190 mg, 1.0 mmol) in 4-methyl-2-pentanol (4 mL) mixed and heated by microwave irradiation at 160°C for 1 hour, cleaned up partially by SCX, then purified by column chromatography, eluting with 0-6% methanolic ammonia in DCM, to give the product as a clear oil, which solidified on trituration with ether to give the title compound as a white solid (160 mg, 60%)
1H NMR (400.13 MHz, CDCl3) δ 0.61 - 0.64 (2H, m), 1.09 - 1.12 (2H, m), 1.42 - 1.52 (2H, m), 1.61 - 1.76 (6H, m), 1.98 - 2.11 (4H, m), 2.23 (2H, t), 2.35 (3H, s), 2.89 (2H, d), 3.30 (3H, s), 3.47 (2H5 s), 3.99 (3H, s), 3.99 - 4.10 (IH, m), 4.93 - 4.99 (IH3 m), 5.99 (IH, d), 7.26 (IH, dd), 7.43 (IH, d), 7.65 (IH, s), 7.87 (IH, s), 8.53 (IH, d)MS m/z 534 [M+H]+.
Example 247: 3-chloro-N-(2-morpholin-4-ylethyl)-4-[(3-oxo-6-phenyl-2,6,8,10- tetrazabicy clo [5.4.0] undeca-7,9,1 l-trien-9-yl)amino]benzamide
4-amino-3-chloro-N-(2-morpholin-4-ylethyl)benzamide (Intermediate 104; 104mg, 0.36mmol), 10-chloro-2-phenyl-2,6,9,l l-tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one (Intermediate 52; 100 mg, 0.36 mmol) and p-toluenesulphonic acid monohydrate (174 mg, 0.91mmol) were heated at 140°C in 4-methyl-2-pentanol (2.5ml) for 4.5 hrs. The reaction mixture was cooled and absorbed onto an SCX column, washed with methanol and eluted with ammonia in methanol. After concentration of the product containing fractions methanol was added to the residue and the suspension filtered to give the title compound as an off-white coloured solid (42 mg, 22%) 1H NMR (399.9 MHz, DMSOd6) δ 2.41 - 2.47 (6H, m), 2.89 (2H, m), 3.36 (2H, t), 3.59 (4H, m), 4.01 - 4.03 (2H, m), 7.19 - 7.22 (IH, m), 7.36 - 7.43 (3H, m), 7.51 - 7.55 (3H, m), 7.69 (IH, s), 7.83 (IH, d), 7.97 (IH, s), 8.27 (IH, t), 9.66 (IH, s); MS m/z 522 [M+H]+. The following example was prepared by an analogous process to that used in the preparation of Example 255 utilising 4-amino-3-chloro-N-(l-methyl-4-piperidyl)benzamide Intermediate 55 to give the title compound as a white solid (31 mg, 17%)
5 Example 248;
3-chloro-N-(l-methyl-4-piperidyl)-4-[(3-oxo-6-phenyl-2,6,8,10- tetrazabicyclo [5.4.0] undeca-8,10,12-trien-9-yI)amino]benzamide
1HNMR (399.9 MHz, DMSOd6) δl.54 - 1.58 (2H, m), 1.74 (2H, d), 1.91 - 1.97 (2H, m), 2.17 (3H, s), 2.74 - 2.79 (2H, m), 2.89 (2H, m), 3.64 - 3.74 (IH, m), 4.00 - 4.03 (2H, m), 7.20 I0 - 7.23 (IH, m), 7.35 - 7.41 (3H, m), 7.53 (3H, d), 7.68 (IH, s), 7.87 (IH, d), 7.96 (IH, s), 8.10 (IH, d), 9.65 (IH, s); MS m/z 506 [M+H]+.
I5
Example 249:
N-(2-morpholin-4-ylethyl)-4-[(3-oxo-6-phenyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-
7,9,ll-trien-9-yl)amino]benzamide
4-amino-N-(2-morpholin-4-ylethyl)benzamide (Buttpark; 188mg, 0.75mmol) and 10-chloro- 20 2-phenyl-2,6,9, 11 ~tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien-5-one (Intermediate 104; 160mg, 0.63mmol) were heated together in EtOH:water (8ml, 1:3) in the prescence of concentrated hydrochloric acid (126ul) for 24 hours. The mixture was cooled to ambient temperature and then loaded onto an SCX-2 (5g) column pre-wet with methanol. The product was eluted with 2M NH3/MeOH and the solvent evaporated to give product as a brown gum, which was 25 purified by base, modified reverse phase HPLC to yield the title compound as a white solid. (35 mg , 13%)
1HNMR (400.132 MHz, DMSO-d6) δ 2.43 (m, 4H), 2.88 (m, 3H), 3.34 (m, 2H), 3.59 (m, 4H), 3.99 (m, 3H), 7.18 (d, 2H), 7.38 (m, 5H), 7.53 (t, 2H), 7.93 (s, IH), 8.00 (m, IH), 9.28 (s, IH), 9.57 (s, IH); MS m/z 488 [M+H]+.
30
Example 250:
4-[(6-cyclopentyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9-yl)amino]-3- methoxy-N-(2-morpholin-4-yIethyl)benzamide 4-amino-3-niethoxy-N-(2-morpholin-4-ylethyl)benzamide (Intermediate 135 176 mg, 0.75 mmol) and 10-chloro-2-phenyl-2,6,9,l l-tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one (Intermediate 2 168 mg, 0.63mmol) were heated together in EtOH:water (8ml, 1 :3) in the prescence of concentrated hydrochloric acid (126ul) for 24 hours. The mixture was cooled to ambient temperature and then loaded onto an SCX-2 (5g) column pre-wet with methanol. The product was eluted with 2M NH3/MeOH and the solvent evaporated to give product as a brown gum, which was purified by base, modified reverse phase HPLC to yield the title compound as a white solid. (154 mg, 54%)
1HNMR (400.132 MHz, DMSO-d6) δ 1.73 (m, 8H), 2.45 (m, 6H), 2.62 (m, 2H), 3.39 (m, 4H), 3.58 (m, 6H), 3.94 (s, 3H), 5.09 (m, IH), 7.46 (m, 2H), 7.60 (s, IH), 7.80 (s, IH), 8.25 (t, IH), 8.38 (d, IH), 9.41 (s, IH); MS m/z 510 [M+H]+.
Example 251: 3-methoxy-N-(l-methyl-4-piperidyl)-4-[(3-oxo-6-phenyl-2,6,8,10- tetrazab icy clo [5.4.0] undeca-8,10,12-trien-9-yl)amino]benzamide
4-amino-3-methoxy-N-(l-methyl-4-piperidyl)benzamide (WO06/018220; 173 mg, 0.66 mmol) and lO-chloro-2-pheny 1-2,6,9,1 l-tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one (Intermediate 104; 150mg, 0.55mmol) were heated together in EtOHtwater (8 mL, 1 :3) in the presence of concentrated hydrochloric acid (110 ul) for 24 hours, p-toluenesulphonic acid monohydrate (105 mg, 0.55 mmol) was added and the mixture heated at 150 deg for 3h by microwave irradiation. The mixture was cooled to ambient temperature and loaded onto an SCX-2 (5 g) column pre-wet with methanol. The product was eluted with 2M NH3/MeOH and solvent evaporated to give a brown gum which was purified by base modified reverse phase HPLC to yield the title compound as a white solid (73 mg, 27%)
1HNMR (400.132 MHz, DMSOd6) δ 1.57 (m, 2H), 1.75 (m, 2H), 1.93 (m, 2H), 2.17 (s, 3H), 2.84 (m, 4H), 3.70 (m, IH), 3.87 (s, 3H), 4.01 (m, 2H), 6.91 (d, IH), 7.39 (m, 6H), 7.53 (m, 2H), 7.93 (s, IH), 7.95 (s, IH), 9.60 (s, IH); MS m/z 502 [M+H]+.
Example 252: N-(3-dimethylamino-2,2-dimethyl-propyl)-3-methoxy-4-[(3-oxo-6-phenyl-2,6,8,10- tetrazabicyclotS^.Ojundeca-SjlOjl^-trien^-y^aminoJbenzainide
4-amino-N-(3-dimethylamino-2,2-dimethyl-propyl)-3-methoxy-benzamide (Intermediate 22; 183mg, 0.66mmol) and 10-chloro-2-phenyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien- 5-one ( Intermediate 104; 150 mg, 0.55 mmol) were heated together in EtOH:water (8 mL, 1 :3) in the presence of concentrated hydrochloric acid (1 lOul) for 24 hours. IP A/DMA was added to aid solution followed by p-toluenesulphonic acid monohydrate (52mg, 0.27mmol) and the mixture heated by microwave irradiation for 1 hour at 1500C. The mixture was cooled to ambient temperature and loaded onto an SCX-2 (5g) column pre-wet with methanol. The product was eluted with 2M NH3/MeOH and the solvent evaporated to give product as a brown gum which was purified by base modified reverse phase HPLC to yield the title compound as a gum (13 mg, 5%) ES+518 (M+H), ES- 516 (M-H) Retention Time 2.18 minutes
Example 253:
4-[(6-cyclopentyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9-yl)amino]-
N-(3-dimethylamino-2,2-dimethyl-propyl)benzamide
4-amino-N-(3-dimethylamino-252-dimethyl-proρyl)benzamide (Intermediate 136; 113mg, 0.45mmol) andlO-chloro-2-cyclopentyl-2,6,9,l l-tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5- one (Intermediate 2; 120mg, 0.45mmoi) were heated together in EtOH: water (8ml, 1 :3) in the presence of 4-toluenesulphonic acid (214mg, 1.13mmol) for 23 hours. The reaction mixture was heated by microwave irradiation at 1500C for 20 minutes cooled to ambient temperature and loaded onto an SCX-2 (5g) column pre-wet with methanol. The product was eluted with 2M NH3/MeOH and the solvent evaporated to give product as a gum, which was purified by base modified reverse phase HPLC to yield the title compound as a white solid. (77 mg, 36%)
1H NMR (400.132 MHz, DMSO-d6) δ 0.88 (s, 6H), 1.61 (m, 4H), 1.74 (m, 2H), 1.90 (m, 2H), 2.19 (s, 2H), 2.27 (s, 6H), 2.61 (m, 2H), 3.18 (d, 2H), 3.57 (m, 2H), 5.14 (m, IH), 7.69 (d, 2H), 7.78 (d, 2H), 7.79 (s, IH), 8.30 (t, IH), 9.31 (s, IH), 9.38 (s, IH); MS m/z 480 [MH-H]+.
Example 254: 4- [(6-cy clopentyl-3-oxo-2,6,8,10-tetrazabicyclo [5.4.0] undeca-8,10,12-trien-9-yl)amino] - N-(l-methyl-4-piperidyl)benzamide
4-amino-N-(l-methyl-4-pipeπdyl)benzamide (Intermediate 4; 131mg, 0.56mmol) and 10- chloro-2-cyclopentyl-2,6,9,l l-tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one (Intermediate 2;
5 150mg, 0.56mmol) were heated together in 4-methyl-2-pentanol (4ml) in the presence of p- toluenesulphonic acid (266mg, 1.40mmol) for 24 hours. The mixture was cooled to ambient temperature and then loaded onto an SCX-2 (5g) column pre-wet with methanol. The product was eluted with 2M NH3/MeOH and the solvent evaporated to give crude product, which was purified by base modified reverse phase HPLC to yield the title compound as a white solid. io (56 mg, 22%)
1H NMR (400.132 MHz, DMSO-d6) δ 1.58 (m, 6H), 1.75 (m, 4H), 1.92 (m, 4H), 2.17 (s, 3H), 2.61 (m, 2H), 2.77 (m, 2H), 3.57 (m, 2H), 3.72 (m, IH), 5.14 (m, IH), 7.75 (m, 4H), 7.79 (s, IH), 7.95 (d, IH), 9.29 (s, IH), 9.38 (s, IH); MS m/z 464 [M+H]+.
15
Example 255:
3-chloro-4-[(6-cyclopentyl-3-oxo-2,6,8!110-tetrazabicyclo[5.4.0]uiideca-8,10,12-trien-9- yl)amino]-N-(3-dimethylamino-2,2-dimethyl-propyl)benzamide
4-amino-3-chloro-N-(3-dimethylamino-2,2-dimethyl-propyl)benzamide (Intermediate 107;
20 118mg, 0.37mmol), 10-chloro-2-cycloρentyl-2,6,9,l l-tetrazabicyclo[5.4.0]undeca-7,9,l 1- trien-5-one (Intermediate 2; lOOmg, 0.37mmol) and p-toluenesulphonic acid monohydrate (179mg, 0.94mmol) were heated at 14O0C in 4-methyl-2-pentanol for 2h. LC-MS indicated the reaction had not gone to completion with ~50% of product in the mixture. An SCX-3 column was washed with methanol then the solution was loaded onto it. The column was
25 washed with methanol and eluted with 7N ammonia/methanol to give the crude product. The mixture was concentrated the resultant material purified by base modified reverse phase HPLC to yield the title compound as an odd- white solid (24mg, 12.6%). 1H NMR (399.9 MHz, DMSOd6) δθ.89 (6H, s), 1.56 (4H, m), 1.71 (2H, s), 1.83 - 1.85 (2H, m), 2.18 (2H, s), 2.27 (6H, s), 2.62 (2H, t), 3.18 - 3.20 (2H, s), 3.57 (2H, t), 5.03 (IH, m), 7.73 so - 7.76 (IH, m), 7.80 (IH, s), 7.94 (IH, d), 8.03 (IH, s), 8.28 (IH, d), 8.46 (IH, s), 9.44 (IH, s); MS m/z 514 [M+H]+. Example 256:
4-[(6-cyclopentyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9-yl)amino]-
N-(2-morpholin-4-ylethyl)benzamide lO-chloro-2-cyclopenty 1-2,6,9,1 l-tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one (Intermediate 2; 150mg, 0.56mmol), 4-amino-N-(2-morpholin-4-ylethyl)benzamide (Buttpark ; 141mg, 0.56mmol) and p-toluenesulphonic acid monohydrate (268mg, 1.41mmol) were heated in 4-methyl-2-pentanol (4 mL) for 2 hours at 140°C.The reaction mixture was loaded onto an SCX-3 column pre-wet with methanol. The column was washed with methanol and 7N ammonia/methanol to elute the crude product. Product containing fractions were evaporated, dissolved in DMF and purified by base modified reverse phase HPLC to yield the title compound as a white solid (77 mg, 28.5%)
1HNMR (399.9 MHz, DMSOd6) δl.62 (2H, m), 1.67 (2H, m), 1.76 (2H, m), 1.91 (2H, m), 2.43 - 2.46 (6H, m), 2.62 (2H, t), 3.38 (2H, q), 3.58 (6H, t), 5.12 - 5.16 (IH, m), 7.74 - 7.77 (3H, m), 7.77 (2H, d), 8.15 (IH, t), 9.33 (IH, s), 9.40 (IH, s); MS m/z 481 [M+H]+.
The following example was prepared by an analogous process to that used in the preparation of Example 256 utilising 4-amino-3-chloro-N-(2-morpholin-4-ylethyl)benzamide Intermediate 50 to give the title compound as a yellow solid (44 mg, 15%)
Example 257:
3-chloro-4-[(6-cyclopentyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(2-morpholin-4-ylethyl)benzamide
1HNMR (399.9 MHz, DMSOd6) 51.57 (4H, d), 1.68 - 1.72 (2H, m), 1.85 (2H, s), 2.43 (6H, m), 2.62 (2H, t), 3.39 (2H, q), 3.58 (6H, t), 5.03 (IH, m), 7.78 (2H, t), 7.95 (IH, d), 8.00 (IH, s), 8.30 (IH, d), 8.39 (IH, t), 9.44 (IH5 s); MS m/z 515 [M+H]+.
Example 258:
S-methoxy^-lJό^l-methoxypropan^-y^-S-oxo^jόjSjlO-tetrazabicycloJS^.OJundeca- 7,9,ll-trien-9-yl]amino]-N-(l-methyl-4-piperidyl)benzamide 10-chloro-2-(l -methoxypropan-2-yl)-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien-5-one (Intermediate 137; 35 mg, 0.13 mmol) ), 4-amino-3-methoxy-N-(l-methyl-4- piperidyl)benzamide (WO06/018220; 34 mg, 0.13 mmol) and^-toluenesulphonic acid monohydrate (61 mg, 0.32 mmol) were dissolved in 4-methyl-2-pentanol (2 mL) and heated at 100 °C for 18 hrs. The reaction mixture was cooled to room temperature dissolved in MeOH and added to a 2g SCX-2 column pre wet with MeOH (2 column volumes). Flushed with MeOH (2 column volumes) and the product eluted with 2M ammonia in MeOH. Product containing fractions were evaporated and the resultant material purified by base modified reverse phase HPLC to yield the title compound as a cream coloured solid (13 mg, 20%) H NMR (399.902 MHz5 CDCl3) δl.29 (d, 3H), 1.61 (m, 2H), 2.06 (m, 2H), 2.18 (m, 2H), 2.31 (s, 3H), 2.77 (m, 2H), 2.84 (m, 2H), 3.36 (s, 3H), 3.54 (m, 2H), 3.68 (m, 2H), 3.97 (s, 3H), 4.00 (m, IH), 5.27 (m, IH), 5.90 (d, IH), 6.94 (s, IH), 7.23 (m, IH), 7.42 (d, IH), 7.60 (s, IH), 7.70 (s, IH), 8.43 (d, IH); MS m/z 498 [M+H]+.
Example 259;
4-[(6-cyclopentyl-2-ethyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-3-methoxy-N-(l-methyl-4-piperidyl)benzamide
10-chloro-2-cyclopentyl-6-ethyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 139; 221 mg, 0.75 mmol), 4-amino-3-methoxy-N-(l-methyl-4- piperidyl)benzamide (WO06/018220; 198 mg, 0.75 mmol) and p-toluenesulphonic acid (357 mg, 1.88 mmol) were heated in 4-methyl-2-pentanol (3 mL) at 140 °C for 18 hours. The reaction mixture was allowed to cool to room temperature and loaded onto a 10 g SCX-2 cartridge, washing with methanol (10 mL), water (10 mL) and methanol (10 mL) before the product was eluted off with 7 N methanolic ammonia to provide a brown oil upon evaporation of product containing fractions. The resultant material was purified by flash silica chromatography, 0-10% methanolic ammonia/DCM to give a pale yellow glass which was purified by base modified reverse phase HPLC to yield the title compound as a white solid (192 mg, 0.36 mmol, 49%).
1H NMR (399.902 MHz, DMSO-d6) δ 1.00 (t, 3H), 1.55 - 1.82 (m, 12H), 1.91 - 1.98 (m, 4H), 2.18 (s, 3H), 2.79 (d, 2H), 3.60 - 3.63 (m, 2H), 3.69 - 3.79 (m, 3H), 3.96 (s, 3H), 4.74 (quintet, IH), 7.48 - 7.51 (m, 2H), 7.77 (s, IH), 8.08 (d, IH), 8.13 (s, IH), 8.39 (d, IH); MS m/z 523 [M+H]+.
The following example was prepared by an analogous process to that used in the preparation of Example 259 utilising lO-chloro^-cyclopentyl-β-propan^-yl^ό^,! 1- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 142 to give the title compound as a white solid (77 mg, 14%)
Example 260:
4-[(6-cyclopentyl-3-oxo-2-propan-2-yl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-
9-yl)amino]-3-methoxy~N-(l-methyl-4-piperidyl)benzamide
1H NMR (399.902 MHz, DMSOd6) δ 1.14 (d, 6H), 1.54 - 1.81 (m, 12H), 1.92 - 1.98 (m, 4H), 2.18 (s, 3H), 2.79 (br d, 2H), 3.56 - 3.59 (m, 2H), 3.70 - 3.80 (m, IH), 3.96 (s, 3H), 4.40 (septet, IH), 4.63 (quintet, IH), 7.48 - 7.51 (m, 2H), 7.80 (s, IH), 8.03 (s, IH), 8.08 (d, IH), 8.40 (d, IH); MS m/z 536 [M+H]+.
Example 261: 2-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8jl0-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(l-methyl-4-piperidyl)l,3-thiazole-4-carboxamide
10-Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8,l 0, 12-trien-5-one (Intermediate 1; 150 mg, 0.53 mmol), 2-amino-N-(l-methyl-4-piperidyl)-l,3-thiazole-4- carboxamide (Intermediate 145; 123 mg, 0.48 mmol) and 9,9-Dimethyl-4,5- bis(diphenylphosphino)xanthene (26 mg, 0.04 mmol) were dissolved in 1,4-dioxane (4.5 mL) Caesium carbonate (315 mg, 0.97 mmol) was added and the mixture purged with a stream of nitrogen for 5 minutes. Tris(dibenzylideneacetone) palladium (II) (27mg, 0.03 mmol) was added and the apparatus was evacuated and backfilled three times with nitrogen and then heated at 100°C overnight. The mixture was cooled, filtered and the filtrate absorbed onto an SCX column, washed with methanol and the product eluted with ammonia in methanol. Product containing fractions were concentrated and purified by reverse phase preparative chromatography to give the title compound as a pale brown solid (80 mg, 34%) 1H NMR (399.9 MHz, DMSOd6) δl.49 - 1.83 (1OH, m), 1.99 - 2.05 (4H, m), 2.18 (3H, s), 2.61 (2H, t), 2.67 - 2.75 (2H, m), 3.19 (3H, s), 3.64 - 3.72 (3H, m), 5.00 (IH, m), 7.48 (IH, d), 7.66 (IH, s), 8.14 (IH, s), 11.28 (IH, s); MS m/z 485 [M+H]+.
The following example was prepared by an analogous process to that used in the preparation of Example 261 utilising 2-ammo-4-methyl-N-(l-methyl-4-piperidyl)-l,3-thiazole-5- carboxamide Intermediate 146. A solid that precipitated from the basic fractions of the SCX column was filtered off. The filtrate was concentrated and methanol added to the residue giving further precipitated material, which was filtered and combined with the original precipitate to give the title compound as a white solid (95mg, 40%)
Example 262:
2-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-4-methyl-N-(l-methyl-4-piperidyl)l,3-thiazole-5-carboxamide
1H NMR (399.9 MHz, DMSOd6) δl.50 - 1.76 (1OH, m), 1.90 - 2.03 (4H, m), 2.16 (3H, s), 2.43 (3H, s), 2.61 (2H, m), 2.74 (2H, d), 3.19 (3H, s), 3.60 - 3.67 (3H, m), 5.07 (IH, m), 7.60 (IH, d), 8.13 (lH, s), 11.33 (IH, s);
IHNMR (399.9 MHz, DMSO-dό) +d4 AcOH δl.63 - 1.90 (1OH, m), 1.86 - 1.92 (2H, m), 2.01 (2H, s), 2.44 (3H, s), 2.46 (3H, s), 2.61 (2H, t), 3.08 (2H, m), 3.18 (3H, s), 3.65 (2H, m), 3.78 - 3.85 (IH, m), 5.05 (IH, d), 8.12 (IH, s); MS m/z 499 [M+H]+.
Example 263:
2-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(l-methyl-4-piperidyl)l,3-thiazole-5-carboxamide
10-Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1; 148 mg, 0.53 mmol), 2-amino-N-(l-methyl-4-piperidyl)-l,3-thiazole-5- carboxamide (Intermediate 147; 115 mg, 0.48 mmol) and 9,9-Dimethyl-4,5- bis(diphenylphosphino)xanthene (25 mg, 0.04 mmol) were dissolved in 1,4-dioxane (5 mL) Caesium carbonate (312 mg, 0.96 mmol) was added and the mixture purged with a stream of nitrogen for 5 minutes. Tris(dibenzylideneacetone) palladium (II) (27mg, 0.03 mmol) was added and the apparatus was evacuated and backfilled three times with nitrogen and then heated at 100°C overnight. The mixture was cooled, filtered and the filtrate absorbed onto an SCX column, washed with methanol and the product eluted with ammonia in methanol. Product containing fractions were concentrated and purified by normal phase chromatography (5% ammonia in methanol/DCM) to give a yellow solid which was suspended in DCM, filtered and dried on the filter to give the title compound as a white solid (48mg, 21%). 1H NMR (399.9 MHz, DMSOd6) δl.50 - 1.79 (1OH, m), 1.90 - 2.04 (4H, m), 2.17 (3H, s), 2.62 (2H, t), 2.77 (2H, d), 3.19 (3H, s), 3.65 - 3.71 (3H, m), 5.09 (IH, m), 8.03 (IH, s), 8.07 (IH, d), 8.15 (IH, s), 11.45 (IH, s) ; MS m/z 485 [M+H]+.
The following example was prepared by an analogous process to that used in the preparation of Example 263 utilising 2-amino-N-(l-methyl-4-piperidyl)-l,3-oxazole-5-carboxamide Intermediate 148 the final product being purified by base modified reverse phase HPLC to give the title compound as a pale brown solid (25 mg, 41%)
Example 264:
2-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(l-methyl-4-piperidyl)l,3-oxazole-5-carboxamide
1H NMR (399.9 MHz, DMSO-d6) δl.48 - 1.76 (1OH, m), 1.85 - 1.97 (4H, m), 2.17 (3H, s), 2.56 - 2.61 (2H, m), 2.76 (2H, d), 3.18 (3H, s), 3.59 - 3.68 (3H, m), 4.79 (IH, m), 7.63 (IH, s), 8.03 (IH, d), 8.07 (IH, s), 10.64 (IH, s); MS m/z 469 [M+H]+.
Example 265:
2-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(l-methyl-4-piperidyl)l,3-oxazole-4-carboxamide
2-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien- 10- yl)amino]-l,3-oxazole-4-carboxylic acid (Intermediate 150; 85 mg, 0.23 mmol), HATU (131 mg, 0.34 mmol) and 4-amino-l-methylpiperidine (40 mg, 0.34 mmol) were stirred in DMF (5 mL) and DIPEA (120 μL, 0.68 mmol) added. The mixture was stirred overnight, absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by normal phase chromatography (5% ammonia in methanol/DCM) to give the title compound as a white solid (66 mg, 61%) 1H NMR (399.9 MHz, DMSOd6) δl.50 - 1.74 (1OH, m), 1.88 - 1.98 (4H, m), 2.16 (3H, s), 2.58 (2H, t), 2.82 (2H, d), 3.18 (3H, s), 3.60 - 3.63 (2H, m), 3.66 - 3.75 (IH, m), 4.71 - 4.80 (IH, m), 7.54 (IH, d), 8.06 (IH, s), 8.26 (IH, s), 10.46 (IH, s); MS m/z 469 [M+H]+.
Example 266:
9-[(6-chloropyridin-3-yl)amino]-6-cyclopentyl-2-methyl-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one 10-Chloro-2-cyclopentyl-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 1; 157 mg, 0.56 mmol), 5-amino-2-chloropyridine (65 mg, 0.51mmol) and 9,9- Dimethyl-4,5-bis(diphenylphosphino)xanthene (27 mg, 0.05 mmol) were dissolved in 1,4- dioxane (7.5 mL). Caesium carbonate (330 mg, 1.01 mmol) was added and the mixture purged with a stream of nitrogen for 5 minutes. Tris(dibenzylideneacetone) palladium (II) (28 mg, 0.03 mmol) was added and the apparatus was evacuated and backfilled three times with nitrogen and then heated at 100°C for 8h. The mixture was cooled, filtered and the filtrate absorbed onto an SCX column, washed with methanol and the product eluted with ammonia in methanol. Product containing fractions were concentrated and purified by preparative reverse phase chromatography to give the title compound as a white solid (14mg,0 7%)
1H NMR (399.9 MHz, DMSOd6) δl.56 - 1.74 (6H, m), 1.93 - 1.98 (2H, m), 2.57 - 2.60 (2H, m), 3.18 (3H, s), 3.61 - 3.64 (2H, m), 4.79 (IH, m), 7.40 (IH, d), 8.09 (IH, s), 8.18 - 8.20 (IH, m), 8.75 (IH, d), 9.51 (IH, s); MS m/z 373 [M+H]+. 5 Utilising the appropriate commercially available anilines, the following examples were prepared by an analogous process to that used in the preparation of Example 266.
Example 267; o 6-cyclopentyl-9-[(6-methoxypyridin-3-yl)amino]-2-methyl-2,6,8,10- tetrazabicyclo [5.4.0] undeca-8,10,12-trien-3-one 1HNMR (399.9 MHz, DMSO-d6) δl.52 - 1.73 (6H, m), 1.89 - 2.08 (2H, m), 2.53 - 2.58 (2H, m), 3.16 (3H, s), 3.58 - 3.61 (2H, m), 3.81 (3H, s), 4.69 - 4.77 (IH, m), 6.75 (IH, d), 7.98 - 8.04 (2H, m), 8.39 - 8.40 (IH, m), 9.04 (IH, s); MS m/z 369 [M+H]+.
Example 268;
6-cyclopentyl-2-methyI-9-(pyridin-4-ylamino)-2,6,8,10-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-3-one
1H NMR (399.9 MHz, DMSO-d6) 51.61 - 1.78 (6H, m), 1.97 - 2.08 (2H, m), 2.59 - 2.62 (2H, m), 3.19 (3H, s), 3.63 - 3.66 (2H, m), 4.81 - 4.89 (IH, m), 7.76 - 7.78 (2H, m), 8.13 (IH, s), 8.34 (2H, d), 9.81 (IH, s) MS m/z 339 [M+H]+.
Example 269;
6-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(l-methyl-4-piperidyl)pyridine-3-carboxamide 10-Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1; 100 mg, 0.36 mmol), 6-ammo-N-(l-methyl-4-piperidyi)pyridine~3- carboxamide ( Intermediate 152; 76 mg, 0.32 mmol) and caesium carbonate (211 mg, 0.65 mmol) were added to dioxane (3 mL) and the suspension bubbled with nitrogen for 10 minutes. Tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.02 mmol) and 9,9-dimethyl- 4,5-bis(diphenylphosphino)xanthene(17 mg , 0.03mmol) were added and the mixture heated at 100 0C overnight. The reaction mixture was cooled to room temperature filtered and the filter cake washed with DCM. The filtrate added to a 5g SCX-2 column pre wet with MeOH (2 column volumes). Flushed with MeOH (2 column volumes) and the crude product eluted with 2M ammonia in MeOH. Product containing fractions were evaporated to give a brown gum which was purified by base modified reverse phase HPLC to give the title compound as a white solid (117 mg, 75%)
HNMR (399.902 MHz, CDCl3) δl.54 - 1.80 (m, 8H), 2.03 (m, 4H), 2.17 (m, 2H), 2.31 (s, 3H), 2.68 (m, 2H), 2.82 (m, 2H), 3.30 (s, 3H), 3.70 (m, 2H), 4.00 (m, IH), 4.84 (m, IH), 5.85 (d, IH), 7.94 (s, IH), 7.99 (s, IH), 8.05 (m, IH), 8.40 (d, IH), 8.63 (m, IH); MS m/z 479 [M+Hf. The following example was prepared by an analogous process to that used in the preparation of Example 269 utilising 5-amino-N-(l-methyl-4-piperidyl)pyridine-2-carboxamide (Intermediate 153), to give the title compound as a yellow solid (104 mg, 61%)
Example 270;
5-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino]-N-(l-methyl-4-piperidyl)pyridine-2-carboxamide
HNMR (399.902 MHz, CDC13) δl.68 (m, 8H), 2.02 (m, 4H), 2.18 (m, 2H), 2.31 (s, 3H), 2.67 (m, 2H), 2.82 (m, 2H), 3.30 (s, 3H), 3.69 (m, 2H), 3.98 (m, IH), 4.85 (m, IH), 7.11 (s, IH), 7.78 (d, IH), 7.94 (s, IH), 8.13 (d, IH), 8.31 (m, IH), 8.59 (d, IH); MS m/z 479 [M+H]+.
Example 271:
3-methoxy-4-[(6-methyl-5-oxo-2-prop-2-ynyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca- 7,9,ll-trien-10-yl)amino]-N-(l-methyl-4-piperidyl)benzamide
9-chloro-2-methyl-6-prop-2-ynyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-3-one ( Intermediate 154; 53 mg, 0.21 mmol), 4-amino-3-methoxy-N-(l-methyl-4- piperidyl)benzamide (WO06/018220; 66 mg, 0.25 mmol) p-toluenesulphonic acid monohydrate acid (80 mg, 0.42 mmol) and isopropanol (4 mL) were combined in a 10 mL microwave reactor tube and heated in by microwave irradiation at 1500C for 80 minutes. The sample was transferred to an SCX (10 g) cartridge pre-wet with methanol, washed with methanol and eluted with methanolic ammonia. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as an off white gum (4 mg, 3%). MS m/z 478 [M+H]+. Retention Time 1.03 minutes Monitor Acid
Example 272:
3-methoxy-4-[[6-methyl-2-[(4-methylpentan-2-yloxycarbonimidoyl)methyl]-5-oxo- 2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10-yl]amino]-N-(l-methyl-4- piperidyl)benzamide
2-(l 0-chloro-6-methyl-5-oxo-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien-2- yl)acetonitrile (Intermediate 155; 97 mg, 0.39 mmol), 4-amino-3-methoxy-N-(l-methyl-4- piperidyl)benzamide (WO06/018220; 124mg,0.47mmol) and p-toluenesulphonic acid monohydrate (148 mg, 0.78 mmol) were heated together in 4-methyl-2-pentanol (4 mL) at 100 0C for 24 hours. The reaction mixture was diluted with water and methanol and the solution loaded onto an SCX-2 (5 g) column pre-wet with methanol. The column was washed with methanol (x2) and eluted with 2M NH3/MeOH. Fractions containing product identified as the addition product of the solvent and nitrile group were combined and evaporated. To the residue was added 4-amino-3-methoxy-N-(l-methyl-4-piperidyl)benzamide (WO06/018220 62 mg, 0.24 mmol) and p-toluenesulphonic acid monohydrate (74 mg, 0.39 mmol) and the mixture heated by microwave irradiation in isopropanol (4 mL) for 20 minutes at 150 0C. The cooled mixture was loaded onto an SCX-2 (5 g) column pre-wet with MeOH. The column was washed with MeOH and eluted with 2M NH3/MeOH. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a light brown solid (21 mg, 9%).
1U NMR (400.132 MHz, DMSO-d6) δ 0.75 (m, 2H), 0.81 (d, 3H), 1.13 (d, 3H), 1.24 (m, IH), 1.52 (m, 5H), 1.76 (m, 2H), 1.94 (m, 2H), 2.17 (s, 3H), 2.46 (m, 2H), 2.75 (m, 4H), 3.22 (s, 3H), 3.75 (m, 3H), 3.95 (s, 3H), 4.22 (s, IH), 4.91 (m, IH), 7.48 (m, 2H), 7.59 (s, IH), 7.80 (s, IH), 8.04 (d, IH), 8.43 (d, IH); MS m/z 582 [M+H]+.
Example 273:
4-[[2-[(3,5-dimethyl-l,2-oxazol-4-yl)methyl]-6-methyl-5-oxo-2,6,9,ll- tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10-yl]amino]-3-methoxy-N-(l-methyl-4- piperidyl)benzamide
9-chloro-6-[(3,5-dimethyl-l,2-oxazol-4-yl)methyl]-2-methyl-2,6,8,10- tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-3-one (Intermediate 156; 81 mg, 0.25 mmol), 4- ammo-3-methoxy-N-(l-methyl-4-piperidyl)benzamide (WO06/018220; 80 mg, 0.30 mmol) p- toluenesulphonic acid monohydrate acid (96 mg, 0.5 mmol) and isopropanol (4 mL) were combined in a 10 mL microwave reactor tube and heated in by microwave irradiation at 150 0C for 80 minutes. The sample was transferred to an SCX (20 g) cartridge pre-wet with methanol, washed with methanol and eluted with methanolic ammonia. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as an off white gum (61 mg, s 45%).
1H NMR (400.132 MHz, DMSOd6) δ 1.58 (2H, m), 1.76 (2H, m), 1.94 (2H, m), 2.08 (3H, s), 2.17 (3H, s), 2.36 (3H, s), 2.61 (2H, m), 2.78 (2H, m), 3.17 (3H, s), 3.53 (2H, m), 3.73 (IH, m), 3.95 (3H, s), 4.61 (2H, s), 7.49 (2H, m), 7.83 (IH5 s), 8.05 (IH, d), 8.19 (IH, s), 8.35 (IH, d). 0
Example 274;
4-[[2-(2-fluoroethyl)-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-
10-yl]amino]-3-methoxy-N-(l-methyl-4-piperidyl)benzamide
10-chloro-2-(2-fluoroethyl)-6-methyl-2,6,9,l l-tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one is (Intermediate 157; 86 mg, 0.33 mmol), 4-amino-3-methoxy-N-(l-methyl-4- piperidyl)benzamide (WO06/018220; 104 mg,0.40 mmol) and p-toluenesulphonic acid monohydrate (126 mg, 0.66 mmol) were heated together in 4-methyl-2-pentanol (4 mL) at 100 0C for 24 hours. The reaction mixture was diluted with water and methanol and the solution loaded onto an SCX-2 (5 g) column pre-wet with methanol. The column was washed 0 with methanol (x2) and the product eluted with 2M NH3/MeOH. Product containing fractions were combined and evaporated. The resultant material was purified by base modified reverse phase preparative HPLC to yield the title compound as a yellow solid (60 mg, 37%). 1HNMR (400.132 MHz, DMSO-d6) δ 1.59 (m, 2H), 1.75 (m, 2H), 1.94 (m, 2H), 2.17 (s, 3H)5 2.73 (m, 4H), 3.13 (s, 3H), 3.57 (m, 2H), 3.72 (s, 3H), 3.72 (m, IH)5 3.83 (t, 2H), 4.05 (t, 25 2H)5 6.91 (d, IH), 7.32 (m, 2H), 7.89 (s, IH)5 7.91 (d, IH); MS m/z 466 [M+H]+-HF.
Example 275:
N-cyclohexyl-4-[[2-(2-dimethylaminoethyl)-6-methyl-5-oxo-2,6,9,ll- tetrazabicyclo [5.4.0] ιmdeca-7,9,1 l-trien-10-yl] amino] -3-methoxy-benzamide
30 10-chloro-2-(2-dimethylaminoethyl)-6-methyl-2,6,9,l l-tetrazabicyclo[5.4.0]undeca-7,9,l 1- trien-5-one (Intermediate 158; 84 mg, 0.30 mmol), 4-amino-3-methoxy-N-(l-methyl-4- piperidyl)benzamide (WO06/018220; 90 mg, 0.36 mmol) and p-toluenesulphonic acid monohydrate (113 mg, 0.60 mmol) were heated together in IPA (4 mL) by microwave irradiation at 150 0C for 20 minutes. The reaction mixture was loaded onto an SCX-2 (5g) column pre-wet with methanol; the column was washed with methanol and the product eluted with 2M NH3/MeOH. Product containing fractions were combined and evaporated. The resultant material was purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (59 mg, 40%).
1H NMR (400.132 MHz, DMSO-d6) 5 1.24 (m, 5H), 1.72 (m, 6H), 2.19 (s, 6H), 2.54 (t, 2H), 2.62 (m, 2H), 3.17 (s, 3H), 3.70 (t, 3H), 3.75 (m, 2H), 3.95 (s, 3H), 7.48 (m, 2H), 7.70 (s, IH), 8.01 (d, IH), 8.07 (s, IH), 8.35 (d, IH); MS m/z 496 [M+H]+.
Example 276:
N-cyclohexyl-3-methoxy-4-[[6-methyl-5-oxo-2-[2-(l-piperidyl)ethyl]-2,6,9,ll- tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10-yl]amino]benzamide 10-chloro-6-methyl-2-[2-(l-piperidyl)ethyl]-2,6,9,l l-tetrazabicyclo[5.4.0]undeca-7,9,l 1- trien-5-one (Intermediate 159; 90 mg, 0.28 mmol), 4-amino-3-methoxy-N-(l-methyl-4- piperidyl)benzamide (WO06/018220; 83 mg, 0.34 mmol) and p-toluenesulphonic acid monohydrate (107 mg, 0.56 mmol) were heated together in IPA (4 mL) by microwave irradiation at 150 0C for 20 minutes. The reaction mixture was loaded onto an SCX-2 (5g) column pre-wet with methanol; the column was washed with methanol and the product eluted with 2M NH3/MeOH. Product containing fractions were combined and evaporated. The resultant material was purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (40 mg, 27%). 1H NMR (400.132 MHz, DMSO-d6) δ 1.15 (m, IH), 1.34 (m, 6H), 1.47 (m, 4H), 1.72 (m, 6H), 2.35 (m, 4H), 2.54 (t, 2H), 2.62 (m, 2H), 3.17 (s, 3H), 3.69 (t, 2H), 3.74 (m, 2H), 3.94 (s, 3H), 7.49 (m, 2H), 7.69 (s, IH), 8.01 (d, IH), 8.06 (s, IH), 8.33 (d, IH); MS m/z 536 [M+H]+.
Example 277:
N-cyclohexyl-3-methoxy-4-[[6-methyl-2-(2-morpholin-4-ylethyl)-5-oxo-2,6,9,ll- tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10-yl]amino]benzamide 10-chloro-6-methyl-2-(2-morpholin-4-ylethyl)-2,6,95ll-tetrazabicyclo[5.4.0]undeca-7,9,ll- trien-5-one (Intermediate 160; 95 mg, 0.29 mmol), -amino-3-methoxy-N-(l-methyl-4- piperidyl)benzamide (WO06/018220; 86 mg, 0.35 mmol) and p-toluenesulphonic acid monohydrate (110 mg, 0.58 mmol) were heated together in IPA (4 mL) by microwave irradiation at 150 0C for 20 minutes. The reaction mixture was loaded onto an SCX-2 (5g) column pre-wet with methanol; the column was washed with methanol and the product eluted with 2M NH3/MeOH. Product containing fractions were combined and evaporated. The resultant material was purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (56 mg, 36%). 1H NMR (400.132 MHz, DMSO-d6) δ 1.15 (m, IH), 1.32 (m, 4H), 1.72 (m, 6H), 2.39 (m, 4H), 2.60 (m, 4H), 3.17 (s, 3H), 3.55 (t, 4H), 3.73 (m, 4H), 3.94 (s, 3H), 7.48 (m, 2H), 7.72 (s, IH)5 8.01 (d, IH), 8.06 (s, IH), 8.30 (d, H); MS m/z 538 [M+H]+.
Example 278: 4-[(2-cyclopentyl-4,4-dimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien- 10-yl)amino]-3-methoxy-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-7-yl]benzamide
10-chloro-2-cyclopentyl-4,4-dimethyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5- one (Intermediate 127; 62 mg, 0.21 mmol) and 4-amino-3-methoxy-N-[(lS,5R)-9-methyl-9- azabicyclo[3.3.1]non-7-yl]benzamide (Intermediate 161; 63 mg, 0.21 mmol) were taken up in 4-methyl-2-pentanol (2 mL) and p-toluenesulphonic acid monohydrate (81 mg, 0.42 mmol) added. The reaction mixture was heated at 1600C by microwave irradiation for 60 minutes. The cooled reaction mixture was treated with a mixture of methanol & water (5:2 v/v, 7 mL) . The resultant solution was loaded onto an SCX-3 cartridge (5 g) pre-wet with methanol. The cartridge was washed through with Methanol (-40 mL). Products were then eluted with 2M ammonia in methanol (~30 mL). The ammoniacal solution was evaporated and the resultant material was purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (64 mg, 54%).
IH NMR (400.132 MHz, DMSO-d6) δ 0.90 - 0.95 (2H, m), 1.14 (6H, s), 1.41 - 1.50 (3H, m), 1.54 - 1.68 (4H, m), 1.71 - 1.78 (2H, m), 1.83 - 1.96 (4H, m), 2.01 - 2.10 (IH, m), 2.15 - 2.23 (2H, m), 2.42 (3H, s), 2.95 - 3.01 (2H, m), 3.27 - 3.28 (2H, m), 3.95 (3H, s), 4.28 - 4.39 (IH, m), 5.23 (IH, quintet), 7.45 - 7.49 (2H, m), 7.59 (IH, s), 7.88 - 7.90 (2H, m), 8.35 (IH, d), 9.45 (IH, s); MS m/z 562 [M+H]+.
Example 279:
5 4-(9'-cyclopentyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-3-fluoro-N-((lR,3r,5S)-9-methyl-9- azabicy clo [3.3.1] nonan-3-yl)benzamide
2'-chloro-9'-cyclopentyl-8',9'-dihydrospiro[cyclopropane-l,7'-pyrimido[4,5-b][l,4]diazepin]- 6'(5'H)-one (Intermediate 131; 256 mg, 0.875 mmol) and 4-amino-3-fluoro-N-[(lS,5R)-9-
I0 methyl-9-azabicyclo[3.3.1]non-7-yl]benzamide (Intermediate 162; 255 mg, 0.875 mmol) and the p-toluenesulphonic acid monohydrate (416 mg, 2.19 mmol) and 4-Methyl-2-pentanol (5 mL) were heated by microwave irradiation for 30 minutes at 160 0C. The cooled reaction mixture was dissolved up in methanol (50 mL) and loaded onto a SCX-2 cartridge (20 g) pre- wet with methanol. The cartridge was washed through with methanol (3 x 35 mL) and the is product eluted with 7 Nmethanolic ammonia (~100 mL). The ammoniacal solution was evaporated and the resultant material purified on a silica column loaded as a solution in DCM (20 mL) and eluted with a linear gradient of 0 to 10% 7N NH3/MeOH in DCM. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid
20 after trituration under diethyl ether (104 mg, 22%)
1H NMR (400.13 MHz, CDCl3) δ 0.77 - 0.80 (2H, m), 0.93 - 1.00 (2H, m), 1.17 - 1.30 (4H, m), 1.34 - 1.37 (2H, m), 1.47 (IH, s), 1.62 - 1.68 (4H, m), 1.88 - 1.93 (5H, m), 2.43 (3H, s), 2.40 - 2.49 (2H, m), 3.02 (2H, d), 3.27 (2H, s), 4.37 - 4.49 (IH, m), 4.98 - 5.07 (IH, m), 5.67 (IH, d), 7.11 (IH, d), 7.20 (IH, s), 7.41 - 7.44 (IH, m), 7.45 - 7.48 (IH, m), 7.63 (IH, s), 8.46
2s (IH, t); MS m/z 548 [M+H]+.
Example 280:
4-(9'-cyclopentyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-3-methoxy-N-((lR,3r,5S)-9-methyl-9- 3o azabicyclo[3.3.1]nonan-3-yl)benzamide 2'-chloro-9'-cyclopentyl-8',9'-dihydrospiro[cyclopropane-l,7'-pyriniido[4,5-b][l,4]diazepin]- 6'(5Η)-one (Intermediate 131; 293 mg, 1.0 mmol) and 4-amino-3-methoxy-N-[(lS,5R)-9- methyl-9-azabicyclo[3.3.1]non-7-yl]benzamide (Intermediate 161; 303 mg, 1.0 mmol) and the p-toluenesulphonic acid monohydrate (476 mg, 2.5 mmol) and 4-Methyl-2-pentanol (10 mL) were combined and heated with stirring at 120 0C overnight. The cooled reaction mixture was dissolved up in methanol (60 mL) and loaded onto a SCX-2 cartridge (20 g) pre-wet with methanol. The cartridge was washed through with methanol (3 x 35 mL) and the product eluted with 7 N methanolic ammonia (-100 mL). The ammoniacal solution was evaporated and the resultant material purified on a silica column loaded as a solution in DCM (17 mL) and eluted with a linear gradient of 0 to 10% 2N NH3MeOH in DCM. Product containing fractions were combined and evaporated and the resultant material triturated under diethyl ether. The resultant filtered solid was treated with warm DMF (3 mL) and acetonitrile (8 mL) upon cooling in an ice/water bath a solid precipitate formed which was filtered and dried to yield the title compound as a white solid (251 mg, 45%) 1HNMR (400.13 MHz, CDCl3) δ 0.77 - 0.79 (2H, m), 0.96 (2H, d), 1.19 - 1.33 (4H, m), 1.35 - 1.37 (2H, m), 1.44 - 1.48 (IH, m), 1.60 - 1.68 (4H, m), 1.85 - 1.98 (5H, m), 2.41 - 2.50 (2H, m), 2.43 (3H, s), 3.02 (2H, d), 3.25 (2H, s), 3.90 (3H, s), 4.41 - 4.46 (IH, m), 5.00 - 5.09 (IH, m), 5.75 (IH, d), 7.16 (IH, dd), 7.36 (IH, d), 7.55 (IH, s), 7.67 (IH, s), 7.75 (IH, s), 8.39 (IH, d); MS m/z 560 [M+H]+.
Example 281:
3-ethoxy-4-[(6-methyl-5-oxo-2-propan-2-yl-2,6,9,ll-tetrazabicyclo [5.4.0] undeca-7,9,11- trien-10-yl)amino]-N-(l-methyl-4-piperidyl)benzamide
To a stirred solution of 3-ethoxy-4-[(6-methyl-5-oxo-2-propan-2-yl-2,6,9,ll- tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-10-yl)amino]benzoic acid (Intermediate 163; 80 mg, 0.20 mmol), HATU (115 mg, 0.30 mmol) and 4-amino-l-methylpiperidine (Fluorochem; 35 mg, 0.30 mmol) in DMF (5 mL) was added diisopropylethylamine (105 μl, 0.60 mmol). The mixture was stirred for 2 hours at room temperature and then absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (5% ammonia in methanol/DCM) to yield the title compound as a white foam (87 mg, 88%). 1H NMR (399.9 MHz, DMSO-d6) δl.26 (6H5 d), 1.44 (3H, t), 1.55 - 1.65 (2H5 m), 1.77 (2H5 d), 1.92 - 1.98 (2H5 m), 2.18 (3H5 s), 2.60 (2H5 m). 2.79 (2H5 d), 3.18 (3H5 s), 3.62 (2H5 m), 3.70 - 3.78 (IH5 m), 4.21 (2H5 q), 4.78 - 4.85 (IH5 m), 7.49 - 7.53 (2H, m), 7.67 (IH5 s), 8.05 (2H5 m), 8.41 (IH5 d); MS m/z 496 [M+H]+.
Example 282:
3-ethoxy-N-(l-ethyl-4-piperidyl)-4-[(6-methyl-5-oxo-2-propan-2-yl-2,6,9,ll- tetrazabicyclofSAOlundeca^^ll^rien-lO-ytyaminojbenzamide
The title compound was prepared by an analogous method to the preparation of Example 281, on a 0.2 mmol scale, utilising 4-ammo-l-ethylpiperidine (Fluorochem; 39 mg5 0.3 mmol), as a white foam (67 mg, 66%).
1H NMR (399.9 MHz, DMSO-d6) δl.01 (3H5 1), 1.26 (6H, d), 1.44 (3H5 1), 1.52 - 1.62 (2H5 m), 1.77 - 1.80 (2H5 m), 1.94 (2H5 m), 2.34 (2H5 q), 2.60 (2H5 m), 2.89 (2H5 d), 3.18 (3H5 s), 3.62 (2H5 m). 3.72 - 3.80 (IH, m), 4.21 (2H5 q)5 4.78 - 4.85 (IH5 m), 7.48 - 7.52 (2H5 m), 7.67s (IH5 s)5 8.05 (2H5 m), 8.41 (IH5 d); MS m/z 510 [M+H]+.
Example 283:
3-ethoxy-N- [(I S,5R)-9-methyl-9-azabicy clo [3.3.1] non-7-yl]-4- [(6-methyl-5-oxo-2-propan-
2-yl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-10-yl)amino]benzamide 0 The title compound was prepared by an analogous method to the preparation of Example 281 , on a 0.2 mmol scale, utilising Endo-9-niethyl-9-azabicyclo[353,l]nonane-3-one (Chempacific; 47 mg, 0.3 mmol), as a white foam (71 mg, 66%).
1HNMR (399.9 MHz5 DMSO-d6) δθ.94 (2H5 d), 1.27 (6H5 d), 1.41 - 1.49 (6H5 m), 1.89 - 1.96 (2H5 m), 2.06 (IH5 m), 2.15 - 2.23 (2H, m), 2.42 (3H5 s), 2.61 (2H5 m), 2.99 (2H5 d), 3.185 (3H, s), 3.63 (2H, m), 4.22 (2H5 q), 4.30 - 4.38 (IH5 m), 4.78 - 4.85 (IH5 m). 7.49 - 7.53 (2H5 m), 7.67 (IH5 s), 7.90 (IH5 d), 8.07 (IH5 s), 8.42 (IH5 d); MS m/z 536 [M+H]+.
Example 284:
3-ethoxy-4-[(6-methyl-5-oxo-2-propan-2-yl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-o trien-10-yl)amino]-N-[(3R)-l-methylpyrrolidin-3-yl]benzamide 10-Chloro-6-methyl-2-propan-2-yl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9,l 1 -trien-5-one (Intermediate 10; 100 mg, 0.39mmol), 4-amino-3-ethoxy-N-[(3R)-l-methylpyrrolidin-3- yl]benzamide (Intermediate 166; 104 mg, 0.39 mmol) and 4-toluenesulphonic acid monohydrate (187 mg, 0.98 mmol) were heated in 4-methyl-2-pentanol (3 mL) at 140 °C for 3 hours. The cooled reaction mixture was absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. = Product containing fractions were concentrated and purified by base modified preparative reverse phase HPLC to yield the title compound as a white solid (114 mg, 61%). 1HNMR (399.9 MHz, DMSO-d6) δ 1.26 (6H, d), 1.44 (3H, t), 1.73 - 1.81 (IH, m), 2.12 - 2.20 (IH, m), 2.27 (3H, s), 2.37 - 2.46 (2H, m), 2.57 - 2.70 (4H, m), 3.18 (3H, s), 3.62 (2H, m), 4.21 (2H, q), 4.38 - 4.44 (IH, m), 4.78 - 4.85 (IH, m), 7.51 - 7.55 (2H, m), 7.67 (IH, s), 8.07 (IH, s), 8.28 (IH, d), 8.41 (IH, d); MS m/z 482 [M+H]+.
Example 285: N-(4-dimethylaminocyclohexyl)-3-ethoxy-4-[(6-methyl-5-oxo-2-propan-2-yl-2,6,9,ll- tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10-yl)amino]benzamide
The title compound was prepared by an analogous method to the preparation of Example 284, on a 0.26 mmol scale, utilising 4-amino-N-((ls,4s)-4-(dimemylamino)cyclohexyl)-3- ethoxybenzamide (Intermediate 167; 66 mg, 0.36 mmol), as a white solid (39 mg, 29%). 1H NMR (399.9 MHz, DMSO-d6) δ 1.26 (6H, d), 1.42 - 1.54 (7H, m), 1.72 - 1.80 (2H, m), 1.86 - 1.90 (2H, m), 2.99 - 2.03 (IH, m), 2.19 (6H, s), 2.60 (2H, m), 3.18 (3H, s), 3.62 (2H, m), 3.89 - 3.93 (IH, m), 4.21 (2H, q), 4.78 - 4.85 (IH, m), 7.51 - 7.56 (2H, m), 7.66 (IH, s), 8.00 (IH, d), 8.07 (IH, s), 8.41 (IH, d); MS m/z 525 [M+H]+.
Example 286:
N-(4-dimethylaminocyclohexyl)-3-ethoxy-4-[(6-methyl-5-oxo-2-propan-2-yl-2,6,9,ll- tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10-yl)amino]benzamide
The title compound was prepared by an analogous method to the preparation of Example 284, on a 0.26 mmol scale, utilising 4-amino-N-((lr,4r)-4-(dimethylamino)cyclohexyi)-3- ethoxybenzamide (Intermediate 168; 66 mg, 0.26 mmol), as a white solid (80 mg, 59%). 1H NMR (399.9 MHz, DMSO-d6) δ 1.23 - 1.39 (1OH, m). 1.44 (3H, t), 1.83 - 1.91 (4H, m), 2.11 - 2.19 (7H, m), 2.60 (2H, m), 3.18 (3H, s), 3.62 (2H, m), 3.71 - 3.75 (IH, m), 4.21 (2H, q), 4.78 - 4.85 (IH5 m), 7.48 - 7.52 (2H, m), 7.67 (IH, s), 8.01 (IH, d), 8.07 (IH, s), 8.41 (IH, d); MS m/z 525 [M+H]+.
Example 287:
5-ethoxy-2-fluoro-4-[(6-methyl-5-oxo-2-propan-2-yl-2,6,9,ll- tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10-yl)amino]-N-(l-methyl-4- piperidyl)benzamide The title compound was prepared by an analogous method to the preparation of Example 284, on a 0.39 mmol scale, utilising 4-amino-5-ethoxy-2-fTuoro-N-(l-methyl-4- piperidyl)benzamide (Intermediate 169; 116mg, 0.39 mmol), heating at 140 0C for 2 hours, as a white solid (73 mg, 37%). 1H NMR (399.9 MHz, DMSO-d6) δ 1.27 (6H, d), 1.42 (3H, t), 1.52 - 1.62 (2H, m), 1.78 (2H, d), 1.99 (2H, t), 2.17 (3H, s), 2.62 (2H, m), 2.74 (2H, d), 3.19 (3H5 s), 3.64 (2H, m), 3.69 - 3.79 (IH, m), 4.18 (2H5 q), 4.77 - 4.84 (IH5 m), 7.20 (IH5 d), 7.74 (IH5 d), 7.79 - 7.82 (IH, m), 8.10 (IH5 s), 8.35 (IH5 d); MS m/z 515 [M+H]+.
Example 288: 5-ethoxy-2-fluoro-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-7-yl]-4-[(6-methyl-5-oxo- 2-propan-2-yl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,H-trien-10-yl)amino]benzamide
The title compound was prepared by an analogous method to the preparation of Example 284, on a 0.39 mmol scale, utilising 4-amino-5-ethoxy-2-fluoro-N-[(lS,5R)-9-methyl-9- azabicyclo[3.3.1]non-7-yl]benzamide (Intermediate 170; 132mg, 0.39 mmol), heating at 140 °C for 2 hours, as a white solid (92 mg, 43%).
1H NMR (399.9 MHz, DMSO-d6) δ 0.92 (2H5 d), 1.28 (6H5 d), 1.39 - 1.46 (6H5 m), 1.87 - 1.94 (2H, m), 1.99 - 2.10 (IH5 m), 2.17 - 2.25 (2H5 m)5 2.42 (3H5 s), 2.62 (2H, m), 2.98 (2H5 d), 3.19 (3H5 s), 3.64 (2H, m), 4.18 (2H, q), 4.26 - 4.34 (IH, m), 4.78 - 4.85 (IH, m), 7.22 (IH, d), 7.65 - 7.68 (IH5 m), 7.75 (IH5 d), 8.11 (IH5 s)5 8.36 (IH5 d); MS m/z 555 [M+H]+. 490
187
Example 289:
5-chloro-2-fluoro-N-(l-methyl-4-piperidyl)-4-[(4,4,6-trimethyl-5-oxo-2-propan-2-yl-
2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10-yl)amino]benzamide
4-amino-5-chloro-2-fluoro-N-(l-niethyl-4-piperidyl)benzamide (Intermediate 173; 91 mg, s 0.32 mmol), 10-chloro-4,4,6-trimethyl-2-piOpan-2-yl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-5-one (Intermediate 178; 100 mg, 0.35 mmol) and XANTPHOS (17 mg, 0.03 mmol) were dissolved in 1,4-dioxane (7.5 mL). Caesium carbonate (225 mg, 0.64 mmol) was added and the system purged with a stream of nitrogen for 15 minutes before tris(dibenzylideneacetone) palladium (II) (18 mg, 0.02 mmol) was added. The apparatus waso evacuated and backfilled with nitrogen (x3) and then heated at 100 0C for 3 hours. The mixture was cooled, filtered and the filtrate absorbed on to an SCX column, which was washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (2.5% 3.5N ammonia in methanol/DCM) to yield the title compound as a white solid (96mg, 56%). s 1HNMR (399.9 MHz, DMSO-d6) δ 1.12 (6H, s), 1.21 (6H, d), 1.50 - 1.60 (2H, m), 1.77 - 1.80 (2H, m), 1.93 - 2.00 (2H, m), 2.17 (3H, s), 2.74 (2H, d), 3.21 (3H, s), 3.38 (2H, s), 3.67 - 3.72 (IH, m), 5.07 - 5.14 (IH, m), 7.67 (IH, d), 8.03 - 8.08 (3H, m), 8.31 - 8.36 (IH, m); MS m/z 532 [M+H]+. 0 Example 290:
5-chloro-N-(l-ethyl-4-piperidyl)-2-fluoro-4-[(4,4,6-trimethyl-5-oxo-2-propan-2-yl- Zjό^jll-tetrazabicycloJS^.Olundeca^^jll-trien-lO-y^aminolbenzamide
The title compound was prepared by an analogous method to the preparation of Example 289, on a 0.39 mmol scale, utilising 4-amino-5-chloro-N-(l-ethyl-4-piperidyl)-2-fluoro-benzamide5 (Intermediate 174; 96 mg, 0.32 mmol), as a white solid (67 mg, 38%).
1HNMR (399.9 MHz, DMSO-dό) δ 1.00 (3H, t), 1.12 (6H, s), 1.21 (6H, d), 1.48 - 1.58 (2H, m), 1.80 (2H5 d), 1.96 (2H, t), 2.32 (2H, q), 2.84 (2H, d), 3.21 (3H, s), 3.38 (2H, s), 3.68 - 3.76 (IH, m), 5.07 - 5.14 (IH, m), 7.67 (IH, d), 8.03 - 8.07 (3H, m), 8.32 - 8.36 (IH, m); MS m/z 546 [M+H]+. 0 2007/002490
188
Example 291:
5-chloro-N-(4-dimethylaminocyclohexyl)-2-fluoro-4-[(4,4,6-trimethyl-5-oxo-2-propan-2- yl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-tπen-10-yl)amino]benzamide
The title compound was prepared by an analogous method to the preparation of Example 289, on a 0.39 mmol scale, utilising 4-ammo-5-chloro-N-(4-dimethylaminocyclohexyl)-2-fluoro- benzamide (Intermediate 175; 100 mg, 0.32 mmol), as a white solid (109 mg, 61%). 1H NMR (399.9 MHz, DMSO-dβ) δ 1.12 (6H, s), 1.17 - 1.37 (8H, m), 1.46 - 1.58 (2H, m), 1.68 - 1.94 (4H, m), 2.13 - 2.18 (7H, m), 3.20 (3H, s), 3.38 (2H, s), 3.64 - 3.71 and 3.91 - 4.95 (each 0.5H, m), 5.08 - 5.15 (IH, m), 7.62 - 7.67 (IH, m), 7.98 - 8.04 (3H, m), 8.29 - 8.34 (IH, m); MS m/z 560 [M+H]+.
Example 292:
2-fluoro-5-methoxy-N-[(3R)-l-methylpyrrolidin-3-yl]-4-[(4,4,6-trimethyl-5-oxo-2- propan-2-yl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10-yl)amino]benzamides 10-chloro-4,4,6-trimethyl-2-ρropan-2-yl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien- 5-one (Intermediate 178; 100 mg, 0.35mmol), 4-amino-2-fluoro-5-methoxy-N-[(3R)-l- methylpyrrolidin-3-yl]benzamide (Intermediate 182; 95 mg, 0.35 mmol) and p- toluenesulphonic acid monohydrate (169 mg, 0.88 mmol) were heated in 4-methyl-2-pentanol (3 mL) at 140 0C for 3 hours. The mixture was cooled and absorbed on to an SCX column,0 which was washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by base modified preparative reverse phase HPLC to yield the title compound as a white solid (60 mg, 33%).
1HNMR (399.9 MHz, DMSO-d6) δ 1.12 (6H, s), 1.23 (6H, d), 1.68 - 1.76 (IH, m), 2.13 - 2.22 (IH, m), 2.27 (3H, s), 2.36 - 2.45 (2H, m), 2.59 - 2.64 (IH, m), 2.67 - 2.71 (IH, m), 3.20s (3H, s), 3.39 (2H, s), 3.93 (3H, s), 4.35 - 4.43 (IH, m), 5.09 - 5.16 (IH, m), 7.22 (IH, d), 7.75 (IH, d), 7.96 - 7.99 (IH, m), 8.03 (IH, s), 8.34 (IH, d); MS m/z 516 [M+H]+.
0
Example 293: 3-ethoxy-N-[(3R)-l-methylpyrrolidin-3-yl]-4-[(4,4,6-trimethyl-5-oxo-2-propan-2-yl- ijό^jll-tetrazabicyclolS^.Olundeca-T^jll-trien-lO-y^aminojbenzamide
The title compound was prepared by an analogous method to the preparation of Example 292, on a 0.35 mmol scale, utilising 4-amino-3-ethoxy-N-[(3R)-l-methylpyrrolidin~3- yl]benzamide (Intermediate 166; 94 mg, 0.35 mmol), as a white solid (106 mg, 59%). 1HNMR (399.9 MHz, DMSO-d6) δ 1.11 (6H, s), 1.23 (6H5 d), 1.44 (3H, t), 1.74 - 1.80 (IH, m), 2.15 - 2.19 (IH, m), 2.27 (3H, s), 2.38 - 2.47 (2H, m), 2.61 - 2.71 (2H, m), 3.20 (3H5 s), 3.38 (2H, s), 4.21 (2H, q), 4.39 - 4.43 (IH, m), 5.09 - 5.16 (IH5 m), 7.51 - 7.54 (2H5 m), 7.63 (IH, s), 7.98 (IH, s), 8.28 (IH, d), 8.38 (IH5 d); MS m/z 511 [M+H]+.
Example 294:
N-(4-dimethylaminocyclohexyl)-3-ethoxy-4-[(4,4,6-trimethyl-5-oxo-2-propan-2-yl-
2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10-yl)amino]benzamide The title compound was prepared by an analogous method to the preparation of Example 292, on a 0.26 mmol scale, utilising 4-amino-N-((ls54s)-4-(dimethylamino)cyclohexyl)-3- ethoxybenzamide (Intermediate 167; 80 mg, 0.26 mmol), as a white solid (91 mg, 59%). 1H NMR (399.9 MHz, DMSO-d6) δ 1.11 (6H, s), 1.23 (6H, d), 1.40 - 1.55 (7H5 m), 1.72 - 1.81 (2H5 m), 1.86 - 1.90 (2H, m), 2.01 - 2.05 (IH5 m), 2.19 (6H5 s), 3.20 (3H, s), 3.38 (2H, s), 3.88 - 3.95 (IH, m), 4.21 (2H, q), 5.09 - 5.16 (IH, m), 7.51 - 7.55 (2H, m), 7.62 (IH5 s), 7.97 - 8.01 (2H, m), 8.37 (IH, d); MS m/z 553 [M+H]+.
Example 295: N-(4-dimethylaminocyclohexyl)-3-ethoxy-4-[(4,4,6-trimethyl-5-oxo-2-propan-2-yl- 2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10-yl)amino]benzamide
The title compound was prepared by an analogous method to the preparation of Example 292, on a 0.26 mmol scale, utilising 4-amino-N-((lr,4r)-4-(dimethylamino)cyclohexyl)-3- ethoxybenzamide (Intermediate 168; 80 mg, 0.26 mmol), as a white solid (77 mg, 54%). 1H NMR (399.9 MHz, DMSO-d6) δ 1.11 (6H5 s), 1.23 (6H, d), 1.27 - 1.39 (4H, m), 1.44 (3H, t), 1.83 - 1.92 (4H5 m), 2.15 - 2.21 (7H5 m), 3.20 (3H, s), 3.38 (2H, s), 3.71 - 3.75 (IH, m), 02490
190
4.21 (2H, q), 5.09 - 5.15 (IH, m), 7.48 - 7.51 (2H, m), 7.63 (IH, s), 7.98 - 8.02 (2H, m), 8.37 (IH, d); MS m/z 553 [M+H]+.
Example 296:
5 5-ethoxy-2-fluoro-N-(l-methyl-4-piperidyl)-4-[(4,4,6-trimethyl-5-oxo-2-propan-2-yl- 2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10-yl)amino]benzamide
The title compound was prepared by an analogous method to the preparation of Example 292, on a 0.39 mmol scale, utilising 4-ammo-5-ethoxy-2-fluoro-N-(l-methyl-4- piperidyl)benzamide (Intermediate 169; 116 mg, 0.39 mmol), as a white solid (92 mg, 48%).o 1H NMR (399.9 MHz, DMSO-d6) δ 1.12 (6H, s), 1.21 - 1.24 (6H, d), 1.42 (3H, t), 1.52 - 1.62 (2H, m), 1.77 - 1.80 (2H, m), 1.94 - 2.00 (2H, m), 2.17 (3H, s), 2.69 - 2.75 (2H, m), 3.20 (3H, s), 3.39 (2H, s), 3.69 - 3.76 (IH, m), 4.18 (2H, q), 5.07 - 5.14 (IH, m), 7.20 (IH, d), 7.71 (IH5 d), 7.77 - 7.80 (IH, m), 8.02 (IH, s), 8.31 (IH, d); MS m/z 543 [M+H]+.
is Example 297:
5-ethoxy-2-fluoro-N-[(3R)-l-methylpyrrolidin-3-yl]-4-[(4,4,6-trimethyl-5-oxo-2-propan- 2-yl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10-yl)amino]benzamide
The title compound was prepared by an analogous method to the preparation of Example 292, on a 0.32 mmol scale, utilising 4-amino-5-ethoxy-2-fluoro-N-[(3R)-l-methylpyrrolidin-3- 0 yl]benzamide (Intermediate 186; 90 mg, 0.32 mmol), as a white foam (61 mg, 36%).
1HNMR (399.9 MHz, DMSO-d6) δ 1.12 (6H, s), 1.24 (6H, d), 1.42 (3H, t), 1.67 - 1.75 (IH, m), 2.13 - 2.22 (IH, m), 2.26 (3H, s), 2.34 - 2.47 (2H, m), 2.58 - 2.63 (IH, m), 2.66 - 2.70 (IH5 m), 3.20 (3H, s), 3.39 (2H, s), 4.18 (2H, q), 4.34 - 4.43 (IH, m), 5.07 - 5.14 (IH, m), 7.21 (IH, d), 7.71 (IH, s), 7.95 - 7.98 (IH, m), 8.02 (IH, s), 8.31 (IH, d); MS m/z 529
2s [M+H]+.
Example 298:
3-fluoro-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-4-[(4,4,6-trimethyl-5-oxo-2- propan-2-yl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-10-yl)amino]benzamide
30 10-chloro-4,4,6-trimethyl-2-propan-2-yl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien- 5-one (Intermediate 178; 43 mg, 0.15 mmol) and 4-amino-3-fluoro-N-(9-methyl-9- azabicyclo[3.3.1]non-7-yl)benzamide (Intermediate 162; 44 mg, 0.15 mmol) were combined with p-toluenesulphonic acid monohydrate (72 mg, 0.38 mmol) in 4-methyl-2-pentanol (1 mL) and heated by microwave irradiation for 50 minutes at 160 0C The cooled reaction mixture was diluted with methanol (5 mL) and loaded onto an SCX-3 cartridge (2 g) pre-wet with Methanol. The cartridge was washed with methanol (2 x 3 mL) and product eluted with 7 Nmethanolic ammonia (10 mL). The basic fraction was evaporated to give a yellow gum which was purified by base modified reverse phase HPLC to give the title compound as a white solid (46 mg, 57 %). 1H NMR (400 MHz, DMSO-d6) δ 0.9 (2H, d), 1.1 (6H, s), 1.15 (6H, d), 1.45 (4H, t), 1.9 (2H, m), 2.05 (IH, m), 2.2 (3H, m), 2.4 (3H, s), 2.95 (2H, d), 3.20 (3H, s), 3.3 (2H, s), 4.3 (IH, m), 5.1 (IH, m), 7.65 (2H, m), 7.95 (2H, m), 8.15 (2H5 m), 8.15 (IH, t), 8.55 (IH, s); MS m/z
Figure imgf000192_0001
Example 299: 3-methoxy-N-[(3R)-l-methylpyrrolidin-3-yl]-4-[(4,4,6-trimethyl-5-oxo-2-propaii-2-yl- 2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10-yl)amino]benzamide
10-chloro-4,4,6-trimethyl-2-propan-2-yl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien-5 - one (Intermediate 178; 75 mg, 0.27 mmol), 4-amino-3-methoxy-N-(l-methylpyrrolidin-3- yl)benzamide (Intermediate 187; 67 mg, 0.27 mmol) and p-toluenesulphonic acid 0 monohydrate (127 mg, 0.66 mmol) were heated at 140 0C in 4-methyl-2-pentanol (4 mL) for 2 hours. The reaction mixture was loaded onto an SCX-3 column pre-wet with methanol. The column was washed with methanol and eluted with 2% 7N ammonia/methanol to. Product containing fractions were evaporated and the residue dissolved in DMF and purified by base modified reverse phase HPLC to give the title compound as a white solid (23 mg, 17.5%).s 1HNMR (399.9 MHz, DMSOd6) 61.08 (6H5 s), 1.22 (6H, d), 1.78 (IH5 m), 2.18 (IH5 m), 2.23 (3H, s), 2.38 (IH5 m), 2.41 (IH5 m), 2.61 (IH, m), 2.64 (IH5 m), 3.18 (3H5 s), 3.37 (2H5 s), 3.95 (3H5 s), 4.41 (IH, m), 5.16 (IH5 m), 7.52 (IH5 s), 7.53 (IH, dd), 7.65 (IH5 s), 7.99 (IH, s), 8.29 (IH5 d), 8.40 (IH5 d); MS m/z 496 [M+H]+. 0 Example 300: N-(l-ethyl-4-piperidyl)-3-methoxy-4-[(4,4,6-trimethyl-5-oxo-2-propan-2-yl-2,6,9,ll- tetrazabicycloJSAOlundeca^^ll-trien-lO-ytyaminojbenzamide
The title compound was prepared by an analogous method to the preparation of Example 299, on a 0.27 mmol scale, utilising 4-amino-N-(l-ethyl-4-piperidyl)-3-methoxy-benzamide (Intermediate 190; 74 mg, 0.27 mmol), as a white solid (31 mg, 22%).
1HNMR (399.9 MHz, DMSO-d6) δl.00 (3H, t), 1.10 (6H. s), 1.22 (6H. d), 1.55 (2H, q), 1.78 (2H, d), 1.95 (2H, t), 2.31 (2H, q), 2.89 (2H, d), 3.17 (3H, s), 3.37 (2H, s), 3.75 (IH, m), 3.95 (3H, s), 5.16 (IH, m), 7.52 (IH, s), 7.53 (IH, dd), 7.65 (IH, s), 7.99 (IH, s), 8.29 (IH, d), 8.40 (IH, d); MS m/z 524 [M+H]+.
Example 301;
3-methoxy-N-(2-pyrrolidin-l-ylethyl)-4-[(4,4,6-trimethyl-5-oxo-2-propan-2-yl-2,6,9,ll- tetrazabicy clo [5.4.0] undeca-7,9,1 l-trien-10-yl)amino] benzamide
The title compound was prepared by an analogous method to the preparation of Example 299, on a 0.27 mmol scale, utilising 4-amino-N-(l-ethyl-4-piperidyl)-3-methoxy-benzamide (Intermediate 192; 70 mg, 0.27 mmol), as a white solid (52 mg, 38%). 1HNMR (399.9 MHz, DMSOd6) δl.10 (6H, s), 1.22 (6H, d), 1.68 (4H, m), 2.49 (4H, m), 2.60 (2H, t), 3.18 (3H, s), 3.38 (2H, s), 3.40 (2H, m), 3.95 (3H, s), 5.16 (IH, m), 7.52 (IH, s), 7.53 (IH, dd), 7.65 (IH, s), 7.99 (IH, s), 8.29 (IH, d), 8.40 (IH, d); MS m/z 510 [M+H]+.
Example 302;
N-(2-dimethylaminoethyl)-3-methoxy-4-[(4,4,6-trimethyl-5-oxo-2-propan-2-yl-2,6,9,ll- tetrazabicyclofS^.Olundeca^^^l-trien-lO-y^aminolbenzamide
The title compound was prepared by an analogous method to the preparation of Example 299, on a 0.27 mmol scale, utilising 4-amino-N-(2-dimethylaminoethyl)-3-methoxy-benzamide (Intermediate 194; 63 mg, 0.27 mmol), as a white solid (38 mg, 30%). 1HNMR (399.9 MHz, DMSOd6) δl.10 (6H, s), 1.22 (6H, d), 2.18 (6H, s), 2.39 (2H, t), 3.18 (3H, s), 3.35 (2H, t), 3.37 (2H, s), 3.95 (3H, s), 5.16 (IH, m), 7.52 (IH, s), 7.53 (IH, dd), 7.65 (IH, s), 7.99 (IH, s), 8.29 (IH, d), 8.40 (IH, d); MS m/z 510 [M+H]+.
Example 303: N-(3-dimethylaminopropyl)-3-methoxy-4-[(4,4,6-trimethyl-5-oxo-2-propan-2-yl-2,6,9,ll- tetrazabicyclo [5.4.0] undeca-7,9,1 l-trien-10-yl)amino] benzamide
The title compound was prepared by an analogous method to the preparation of Example 299, on a 0.27 mmol scale, utilising 4-amino-N-(2-dimethylaminoethyl)-3-methoxy-benzamide 5 (Intermediate 196; 67 mg, 0.27 mmol), as a white solid (8 mg, 6%).
1HNMR (399.9 MHz, DMSOd6) δl.10 (6H, s), 1.22 (6H, d), 1.68 (2H, m), 2.18 (3H, s), 2.28 (2H, t), 3.17 (3H, s), 3.29 (2H, t), 3.37 (2H, s), 3.95 (3H, s), 5.16 (IH, m), 7.52 (IH, s), 7.53 (IH, dd), 7.65 (IH, s), 7.99 (IH, s), 8.29 (IH, d), 8.40 (IH, d); MS m/z 498 [M+H]+.
I0 Example 304;
4-[(4,4-diethyl-6-methyl-5-oxo-2-propan-2-yl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca- 7,9,ll-trien-10-yl)amino]-3-methoxy-N-(l-methyl-4-piperidyl)benzamide
10-chloro-4,4-diethyl-6-methyl-2-propan-2-yl-2,6,9, 11 -tetrazabicyclo [5 A0]undeca~7,9, 11 - trien-5-one (Intermediate 198; 100 mg, 0.322 mmol), p-toluene sulphonic acid monohydrate is (153 mg, 0.81 mmol) and 4-amino-3-methoxy-N-(l-methyl-4-piperidyl)benzamide (WO06/018220; 84 mg, 0.322 mmol) were added to 4-methyl-2-pentanol (7 mL). The reaction was heated at 120 0C over the weekend. The reaction mixture was loaded on to an SCX column (10 g), pre-wet with methanol, washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and the resultant
20 material purified by base modified reverse phase preparative HPLC to yield the title compound, after drying under vacuum at 70 0C, as a white solid (97 mg, 56%) 1HNMR (400.132 MHz, CDCl3) δ 0.84 (t, 6H), 1.25 (d, 6H), 1.63 - 1.49 (m, 4H), 1.70 (sextet, 2H), 2.07 - 2.04 (m, 2H), 2.19 - 2.13 (m, 2H), 2.30 (s, 3H), 2.84 - 2.81 (m, 2H), 3.28 (s, 3H), 3.40 (s, 2H), 4.04 - 3.92 (m, 4H), 5.32 (sextet, IH), 5.93 (d, IH), 7.24 (dd, IH), 7.43
2s (d, IH), 7.59 (s, IH), 7.83 (s, IH), 8.48 (d, IH); MS m/z 538 [M+H]+.
Example 305;
4-[(4,4-diethyl-6-methyl-5-oxo-2-propan-2-yl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-
7,9,ll-trien-10-yl)amino]-N-(l-ethyl-4-piperidyl)-3-methoxy-benzamide The title compound was prepared by an analogous method to the preparation of Example 304, on a 0.322 mmol scale, utilising 4-amino-N-(l-emyl-4-piperidyl)-3-methoxy-benzamide (Intermediate 190; 89 mg, 0.322 mmol), as a white solid (89 mg, 30%). 1H NMR (400.132 MHz, CDCl3) δ 0.84 (t, 6H), 1.10 (t, 3H), 1.25 (d, 6H), 1.63 - 1.49 (m, 4H), 1.75 - 1.66 (m, 2H), 2.17 - 2.06 (m, 4H), 2.44 (q, 2H), 2.93 - 2.90 (m, 2H), 3.28 (s, 3H), 3.40 (s, 2H), 4.05 - 3.97 (m, 4H), 5.32 (septet, IH), 5.91 (d, IH), 7.23 (dd, IH), 7.43 (d, IH), 7.59 (s, IH), 7.83 (s, IH), 8.47 (d, IH); MS m/z 552 [M+H]+.
Example 306:
^^^-diethyl-δ-methyl-S-oxo-l-propan^-yl-ljό^jll-tetrazabicycIotS^.Ojundeca-
SjlO.ll-trien-lO-yOaminol-S-methoxy-N-IClS^^^-methyl-P-azabicyclopj.llnon^- yl]benzamide
The title compound was prepared by an analogous method to the preparation of Example 304, on a 0.322 mmol scale, utilising 4-amino-3-methoxy-N-[(lS,5R)-9-methyl-9- azabicyclo[3.3.1]non-3-yl]benzamide (Intermediate 202; 97 mg, 0.322 mmol), as a white solid (83 mg, 45%).
1H NMR (400.132 MHz, DMSO-d6) δ 0.78 (t, 6H), 1.22 (d, 6H), 1.60 - 1.40 (m, 6H), 1.89 -
1.77 (m, 2H), 2.16 - 2.03 (m, 2H), 2.42 - 2.33 (m, 2H), 3.18 (s, 3H), 3.29 (s, 4H), 3.41 (s, 2H), 3.69 - 3.57 (m, 2H), 3.97 (s, 3H), 4.70 - 4.52 (m, IH), 5.24 - 5.18 (m, IH), 7.53 - 7.51 (m,
2H), 7.67 (s, IH), 7.98 (s, IH), 8.31 - 8.22 (m, IH), 8.41 (d, IH), 9.27 - 9.18 (m, IH); MS m/z
578 [M+H]+.
Example 307:
4-[(4,4-diethyl-6-methyl-5-oxo-2-propan-2-yl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-10-yl)amino]-2-nuoro-5-methoxy-N-[(lS,5R)-9-methyl-9- azabicy clo [3.3.1] non-7-y 1] benzamide The title compound was prepared by an analogous method to the preparation of Example 304, on a 0.322 mmol scale, utilising 4-amino-3-methoxy-N-[(lS,5R)-9-methyl-9- azabicyclo[3.3.1]non-3-yl]benzamide (Intermediate 204; 103 mg, 0.322 mmol), as a white solid (100 mg, 52%).
1HNMR (400.132 MHz, CDCl3) δ 0.85 (t, 6H)5 1.05 - 1.03 (m, 2H)5 1.34 - 1.26 (m, 8H), 1.59 - 1.49 (m, 3H)5 1.70 (sextet, 2H)5 2.02 - 1.91 (m, 3H), 2.57 - 2.50 (m, 5H)5 3.10 - 3.07 (m, s 2H)5 3.29 (s, 3H)5 3.42 (s, 2H)5 3.95 (s, 3H)5 4.57 - 4.46 (m, IH), 5.30 (septet, IH)5 6.55 (dd, IH)5 7.57 (d5 IH)5 7.64 (s, IH), 7.85 (s, IH)5 8.38 (d, IH); MS m/z 596 [M+H]+.
Example 308:
4-[(4,4-diethyl-6-methyl-5-oxo-2-propan-2-yl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-o 7,9,ll-trien-10-yl)amino]-N-(l-ethyl-4-piperidyl)-2-fluoro-5-methoxy-benzamide
The title compound was prepared by an analogous method to the preparation of Example 304, on a 0.322 mmol scale, utilising 4-amino-N-(l-ethyl-4-piperidyl)-2-fluoro-5-methoxy- benzamide (Intermediate 205; 95 mg, 0.322 mmol), as a white solid (87 mg, 48%). 1HNMR (400.132 MHz, CDCl3) δ 0.85 (t, 6H)5 1.10 (t, 3H), 1.27 (d, 6H)5 1.75 - 1.49 (m,s 6H)5 2.08 - 2.06 (m, 2H)5 2.20 - 2.14 (m, 2H), 2.44 (q, 2H), 2.88 - 2.85 (m, 2H), 3.29 (s, 3H), 3.42 (s, 2H)5 3.95 (s, 3H)5 4.10 - 4.00 (m, IH), 5.33 - 5.26 (m, IH), 6.68 (dd, IH), 7.55 (d, IH)3 7.65 (s, IH)5 7.85 (s, IH)5 8.38 (d5 IH); MS m/z 570 [M+H]+.
Example 309: 0 4-[(4,4-diethyl-6-methyl-5-oxo-2-propan-2-yl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca- 7,9,ll-trien-10-yl)amino]-N-(2,2-dimethyl-3-pyrrolidin-l-yl-propyl)-3-methoxy- benzamide
The title compound was prepared by an analogous method to the preparation of Example 304, on a 0.33 mmol scale, utilising 4-amino-N-(2,2-dimethyl-3-pyrrolidin-l-yl-propyl)-3-5 methoxy-benzamide (Intermediate 206; 100 mg, 0.33 mmol), as a white solid (76 mg, 40%). 1HNMR (400.132 MHz, CDCl3) δ 0.84 (t, 6H), 1.01 (s, 6H), 1.24 (d, 6H), 1.53 (sextet, 2H), 1.71 (sextet, 2H), 1.86 - 1.81 (m, 4H), 2.57 (s, 2H), 2.72 - 2.68 (m, 4H)5 3.28 (s, 3H)5 3.40 - 3.39 (m, 4H), 3.97 (s, 3H)5 5.34 (septet, IH), 7.20 (dd, IH), 7.58 (d, IH), 7.62 (s, IH), 7.84 (s, IH), 8.44 (d, IH), 9.28 (s, IH); MS m/z 5780 [M+H]+. 0
Example 310: (R)-5-chloro-2-fluoro-4-(9'-isopropyl-5'-methyl-6'-oxo-5',6',8',9'- tetrahydrospiroJcyclopropane-l^'-pyrimidoJS^-blll^jdiazepinel-I'-ylainino)^-^- methylpyrrolidin-3-yl)benzamide
2'-chloro-9'-isopropyl-5'-methyl-8',9l-diliydrospiro[cyclopropane-l,7l-pyπmido[5,4- b][l,4]diazepin]-6'(5'H)-one (Intermediate 208; 88 nig, 0.32nimol), 4-amino-5-chloro-2- fluoro-N-[(3R)-l-methylpyrrolidin-3-yl]benzamide (Intermediate 207; 101 mg, 0.36 mmol) and XANTPHOS (17 mg, 0.03 mmol) were dissolved in 1,4-dioxane (7.5 mL). Caesium carbonate (229 mg, 0.65 mmol) was added and the system purged with a stream of nitrogen for 15 minutes before tris(dibenzylideneacetone) palladium (II) (18 mg, 0.02 mmol) was added. The apparatus was evacuated and backfilled with nitrogen (x3) and then heated at 100 0C for 3 hours. The mixture was cooled, filtered and the filtrate absorbed on to an SCX column, which was washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (2.5% 7N ammonia in MeOH/DCM) to yield the title compound as a pale yellow foam (148 mg, 90%). 1H NMR (399.9 MHz, DMSO-d6) δθ.70 - 0.73 (2H, m), 0.94 - 0.96 (2H, m), 1.15 (6H, d), 1.67 - 1.75 (IH, m), 2.12 - 2.21 (IH, m), 2.26 (3H, s), 2.33 - 2.43 (2H, m), 2.56 - 2.62 (IH, m), 2.67 - 2.71 (IH, m), 3.19 (3H, s), 3.49 (2H, s), 4.31 - 4.40 (IH, m), 4.79 - 4.86 (IH, m), 7.69 (IH, d), 8.04 (2H, m), 8.23 - 8.25 (IH, m), 8.36 - 8.41 (IH, m); MS m/z 516 [M+H]+.
Example 311:
5-chloro-N-(l-ethylpiperidin-4-yl)-2-fluoro-4-(9'-isopropyl-5'-methyl-6'-oxo-5',6',8',9t- tetrahydrospiro[cycIopropane-l,7'-pyrimido[5,4-b][l,4]diazepine]-2'- ylamino)benzamide
The title compound was prepared by an analogous method to the preparation of Example 310, on a 0.29 mmol scale, utilising 4-amino-5-chloro-N-(l-ethyl-4-piperidyl)-2-fluoro-benzamide
(Intermediate 174; 87 mg, 0.29 mmol), after purification by base modified reverse phase preparative HPLC, as a white solid (98 mg, 62%).
1HNMR (399.9 MHz, DMSOd6) δ 0.72 (2H, m), 0.94 (2H, m), 1.00 (3H, t), 1.17 (6H, d),
1.51 - 1.57 (2H, m), 1.80 (2H, d), 1.96 (2H, t), 2.32 (2H, q), 2.84 (2H, d), 3.18 (3H, s), 3.49 (2H, s), 3.67 - 3.78 (IH, m), 4.79 - 4.86 (IH, m), 7.67 (IH, d), 8.02 - 8.07 (3H, m), 8.38 (IH, d); MS m/z 544 [M+H]+. Example 312:
4-(9'-isopropyl-5'-methyl-6'-oxo-5t,6l,8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-3-methoxy-N-(2-(pyrrolidin-l- 5 yl)ethyl)benzamide
The title compound was prepared by an analogous method to the preparation of Example 284, on a 0.36 mmol scale, utilising 4-amino-3-methoxy-N-(2-pyrrolidin-l-ylethyl)benzamide (Intermediate 192; 94 mg, 0.36 mmol), heating at 140 °C for 2 hours, as a white solid (65 mg, 36%). io 1H NMR (399.9 MHz, DMSO-d6) δθ.69 (2H, t). 0.93 (2H, t), 1.19 (6H, d), 1.69 - 1.72 (4H, s), 2.71 (4H, s), 2.80 (2H, s), 3.17 (3H, s), 3.39 - 3.41 (2H, t), 3.48 (2H, s), 3.95 (3H, s), 4.82 - 4.86 (IH, m), 7.49 (IH, d), 7.50 (IH, s), 7.63 (IH, s), 7.99 (IH, s), 8.32 (IH, t), 8.43 (IH, d); MS m/z 509 [M+H]+.
15 Example 313:
N-(3-(dimethylamino)-2,2-dimethylpropyl)-4-(9'-isopropyl-5'-methyl-6'-oxo-5',6',8',9'- tetrahydrospiro[cycIopropane-l,7'-pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-3- methoxybenzamide
The title compound was prepared by an analogous method to the preparation of Example 20 284, on a 0.36 mmol scale, utilising 4-amino-N-(2,2-dimethyl-3-pyrrolidin-l-yl-propyi)-3- methoxy-benzamide (Intermediate 206; 100 mg, 0.36 mmol), heating at 140 0C for 2 hours, as a white solid (78 mg, 42%).
1H NMR (399.9 MHz, DMSO-dό) δθ.69 (2H, t), 0.89 (6H, s), 0.93 (2H, t), 1.18 (6H, d), 2.21
(2H, s), 2.25 (6H, s), 3.17 (3H, s), 3.21 (2H, d), 3.48 (2H, s), 3.95 (3H, s), 4.82 - 4.86 (IH, 25 m), 7.49 (IH, d), 7.50 (IH, s), 7.63 (IH, s), 7.99 (IH, s), 8.32 (IH, t), 8.43 (IH, d); MS m/z
525 [M+H]+.
Example 314:
4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- 30 yl)amino]-3-methoxy-N-(l-propyl-4-piperidyl)benzamide 4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien- 10- yl)amino]-3-methoxy-benzoic acid (Example 111; 231 mg, 0.56 mmol), DIPEA ( 0.3 mL, 1.68 mmol) and HATU (283 mg, 0.75 mmol) were stirred together in DMA (4 mL) at ambient temperature for 10 minutes. 4-amino-l-propylpiperidine (Fluorochem; 100 mg, 0.70
5 mmol) was added and the mixture stirred at room temperature for 4 hours. The reaction mixture was loaded onto an SCX-2 (1Og) column pre-wet with MeOH. The column was washed with MeOH (x2) and the product eluted with 2M NH3/MeOH. Product containing fractions were combined and evaporated and the residue purified by base modified reverse phase preparative HPLC. Product containing fractions were combined and evaporated to yield io the title compound as a gum (194 mg, 65%).
1H NMR (400.132 MHz, DMSO-d6) δ 0.86 (t, 3H), 1.44 (m, 2H), 1.66 (m, 10H), 1.94 (m, 4H), 2.24 (t, 2H), 2.59 (m, 2H), 2.87 (m, 2H), 3.18 (s, 3H), 3.63 (m, 2H), 3.76 (m, IH), 3.95 (s, 3H), 4.82 (m, IH), 7.48 (m, 2H), 7.72 (s, IH), 8.05 (d, IH), 8.08 (s, IH), 8.38 (d, IH); MS m/z 536 [M+H]+.
I5
Example 315:
3-chloro-4-[(2-cyclopentyl-6-methyI-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll- trien-10-yl)amino]-N-(2-dimethylaminoethyl)benzamide
10-Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one
20 (Intermediate 1; 80 mg, 0.285 mmol) and 4-amino-3-chloro-N-(2- dimethylaminoethyl)benzamide (Intermediate 213; 69 mg, 0.285 mmol), p-toluenesulphonic acid monohydrate ( 136 mg, 0.713 mmol) were combined in 4-Methyl-2-pentanol ( 2 mL) and heated at 100 0C overnight. Methanol was added to the cooled reaction mixture and the solution loaded onto an SCX-3 column (5 g) pre-wet with MeOH (2 column volumes). The
25 column was flushed with MeOH (2 column volumes) and eluted with 2M ammonia in MeOH. Product containing fractions were evaporated and the residue dissolved in DCM with a little MeOH. The resultant solution was purified on a silica column, eluting with a gradient of 0 - 5% 2M ammonia in MeOH / DCM then 10% 2M ammonia in MeOH / DCM. Product containing fractions were combined and evaporated and the residue purified by base modified
30 reverse phase preparative HPLC to yield the title compound as a white solid (21 mg, 15%). 1H NMR (399.902 MHz, CDC13) 51.56 - 1.79 (m, 6H), 2.02 (m, 2H), 2.29 (s, 6H), 2.53 (m, 2H), 2.68 (m, 2H), 3.30 (s, 3H), 3.51 (m, 2H), 3.70 (m, 2H), 4.87 (m, IH), 6.71 (s, IH), 7.53 . (s, IH), 7.68 (m, IH), 7.83 (m, IH), 7.95 (s, IH), 8.63 (d, IH); MS m/z 486 [M+H]+.
Example 316;
3-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll- trien-10-yl)amino]-N-(l-ethyl-4-piperidyl)benzamide
10-Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1; 80 mg, 0.285 mmol) and 4-amino-3-chloro-N-(l-ethyl-4- piperidyl)benzamide (Intermediate 212; 76 mg, 0.285 mmol), p-toluenesulphonic acid monohydrate ( 136 mg, 0.713 mmol) were combined in 4-Methyl-2-pentanol ( 2 mL) and heated at 100 0C overnight. Methanol was added to the cooled reaction mixture and the solution loaded onto an SCX-3 column (5 g) pre-wet with MeOH (2 column volumes). The column was flushed with MeOH (2 column volumes) and eluted with 2M ammonia in MeOH. Product containing fractions were evaporated and the residue dissolved in DCM with a little MeOH. The resultant solution was purified on a silica column, eluting with a gradient of 0 — 5% 2M ammonia in MeOH / DCM then 10% 2M ammonia in MeOH / DCM. Product containing fractions were combined and evaporated and the residue purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (22 mg, 15%). 1HNMR (399.902 MHz, CDCl3) δl.ll (t, 3H), 1.54 - 1.79 (m, 8H), 2.08 (m, 6H), 2.44 (q, 2H), 2.68 (m, 2H), 2.92 (m, 2H), 3.30 (s, 3H), 3.70 (m, 2H), 3.99 (m, IH), 4.87 (m, IH), 5.84 (d, IH), 7.54 (s, IH)5 7.62 (m, IH), 7.80 (m, IH), 7.96 (s, IH), 8.64 (d, IH); MS m/z 526 [MH-H]+.
Example 317;
3-chloro-4- [(2-cyclopentyl-6-methyl-5-oxo-2,6,9,l 1-tetrazabicyclo [5.4.0] undeca-7,9,11- trien-10-yl)amino]-N-(3-dimethylaminopropyl)benzamide The title compound was prepared by an analogous method to the preparation of Example 316, on a 0.356 mmol scale, utilising 4-amino-3-chloro-N-(3-dimethylaminopropyl)benzamide (Intermediate 214; 91 mg, 0.356 mmol), as a white solid (31 mg, 17%). 1H NMR (399.902 MHz, CDCl3) δl.55 - 1.80 (m, 8H), 2.03 (m, 2H), 2.33 (s, 6H), 2.53 (m, s 2H), 2.68 (m, 2H), 3.30 (s, 3H), 3.56 (m, 2H), 3.70 (m, 2H), 4.88 (m, IH), 7.54 (s, IH), 7.65 (d, IH), 7.84 (s, IH), 7.96 (s, IH), 8.57 (s, IH), 8.63 (d, IH); MS m/z 500 [M+H]+.
Example 318:
3-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,l 1-tetrazabicy clo [5.4.0] undeca-7,9,11-o trien-10-yl)amino]-N-(2-pyrroIidin-l-ylethyl)benzamide
The title compound was prepared by an analogous method to the preparation of Example 316, on a 0.356 mmol scale, utilising 4-amino-3-chloro-N-(2-pyrrolidin-l-ylethyl)benzamide (Intermediate 215; 95 mg, 0.356 mmol), as a white solid (39 mg, 21%). 1H NMR (399.902 MHz, CDCl3) δl.56 - 1.82 (m, 10H), 2.02 (m, 2H), 2.58 (m, 4H), 2.70 (m,s 4H), 3.30 (s, 3H), 3.55 (m, 2H), 3.70 (m, 2H), 4.87 (m, IH), 6.74 (s, IH), 7.53 (s, IH), 7.67 (m, IH), 7.84 (m, IH), 7.95 (s, IH), 8.63 (d, IH); MS m/z 512 [M+H]+.
Example 319; 4-[(2-cycIopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10-0 yl)amino]-N-[l-(cyclopropylmethyl)-4-piperidyl]-3-methoxy-benzamide
The title compound was prepared by an analogous method to the preparation of Example 314, on a 0.24 mmol scale, utilising l-(cyclopropylmethyl)-4-piperidinamine di hydrochloride (Aldrich; 95 mg, 0.356 mmol) and DIPEA (210 μL, 1.3 mmol) and stirring at ambient temperature for 24 hours, as a white solid (85 mg, 64%). 5 1H NMR (400.132 MHz, DMSO-d6) δ 0.00 (m, 2H), 0.38 (m, 2H), 0.75 (m, IH), 1.60 (m, 10H), 1.90 (m, 4H), 2.11 (d, 2H), 2.51 (m, 2H), 2.91 (m, 2H), 3.10 (s, 3H), 3.55 (m, 2H), 3.68 (m, IH), 3.87 (s, 3H), 4.74 (m, IH), 7.40 (m, 2H), 7.64 (s, IH), 7.98 (d, IH), 8.00 (s, IH), 8.30 (d, IH); MS m/z 548 [M+H]+. 0 Example 320; 2-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll- trien-10-yl)ammo]-5-methoxy-N-(l-methyl-4-piperidyl)benzamide
The title compound was prepared by an analogous method to the preparation of Example 316, on a 0.285 mmol scale, utilising 4-amino-2-chloro-5-methoxy-N-(l-methyl-4- 5 piperidyl)benzamide (Intermediate 216; 85 mg, 0.285 mmol), as a white solid (108 mg,
1HNMR (399.902 MHz, CDCl3) δl.61 (m, 4H), 1.76 (m, 4H), 2.09 (m, 4H), 2.20 (m, 2H), 2.31 (s, 3H), 2.68 (m, 2H), 2.78 (m, 2H), 3.29 (s, 3H), 3.71 (m, 2H), 3.94 (s, 3H), 4.03 (m, IH), 4.97 (m, IH), 6.56 (d, IH), 7.40 (s, IH), 7.63 (s, IH), 7.94 (s, IH), 8.62 (s, IH); MS m/z I0 542 [M+H]+.
Example 321;
5-chloro-4- [(2-cy clopentyl-6-methyl-5-oxo-2,6,9,l 1-tetrazabicy clo [5.4.0] undeca-7,9,11- trien-10-yl)amino]-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide is tert-butyl (3R)-3-[[5-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,l 1- tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-10-yl)amino]-2-fluoro-benzoyl]amino]pyrrolidine-l- carboxylate (Example 324; 175 mg, 0.29 mmol) was dissolved in 1,4-dioxane (5 mL) and 4M HCl(aq) in 1,4-dioxane (10 mL) added. The mixture was stirred at room temperature for 2 hours. TFA (2 mL) was added an the reaction stirred for a further 1 hour. The reaction was
20 concentrated, dissolved in DCM (10 mL) and TFA (3 mL) added. The reaction was stirred at room temperature for 1 hour, concentrated and the residue dissolved in methanol, absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and the residue purified by column chromatography (7.5% ammonia in methanol/DCM) to yield the title compound as a white
25 foam (112 mg, 77%).
1HNMR (399.9 MHz, DMSO-d6) δl.58 - 1.77 (8H, m), 1.92 - 2.02 (3H, m), 2.60 - 2.77 (5H, m), 2.87 - 3.01 (2H, m), 3.19 (3H, s), 3.65 (2H, m), 4.23 - 4.31 (IH, m), 4.76 - 4.84 (IH, m), 7.70 (IH, d), 8.07 - 8.17 (3H, m), 8.33 (IH, d); MS m/z 502 [M+H]+.
30 Example 322: 5-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll- trien-10-yl)amino]-2-fluoro-N-(l-methyl-4-piperidyl)benzamide
5-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien- 10-yl)amino]-2-fluoro-benzoic acid (Intermediate 219; 100 mg, 0.23 mmol), 4-amino-l- niethylpiperidine (Fluorochem; 40 mg, 0.35 mmol) and HATU (132 mg, 0.35 mmol) were stirred in DMF (3 mL). ΛζiV-diisopropylethylamine (121 μl, 0.69 mmol) was added and the mixture heated at 50 0C for 2 hours. The mixture was cooled and absorbed on to an SCX column, which was subsequently washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and the residue purified by base modified reverse phase preparative chromatography to yield the title compound as a white solid (58 mg, 48%)
1HNMR (399.9 MHz, DMSO-d6) δl.50 - 1.80 (1OH, m), 1.92 - 1.99 (4H, m), 2.17 (3H, s), 2.61 (2H, m), 2.74 (2H, d), 3.19 (3H, s), 3.63 - 3.74 (3H, m), 4.76 - 4.84 (IH, m), 7.67 (IH, d), 8.07 (IH, d) 8.14 (IH, m), 8.31 - 8.36 (IH, m); MS m/z 530 M+H]+.
Example 323:
5-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll- trien-10-yl)amino]-N-(l-ethyl-4-piperidyl)~2-fluoro-benzamide
The title compound was prepared by an analogous method to the preparation of Example 322, on a 0.23 mmol scale, utilising 4-amino-l-ethylpiperidine (Fluorochem; 45 mg, 0.35 mmol), as a white solid (60 mg, 48%).
1H NMR (399.9 MHz, DMSO-d6) δl.00 (3H, t), 1.59 (8H, d), 1.80 (2H, d), 1.93 - 1.98 (4H, m), 2.32 (2H, q), 2.61 (2H, m), 2.84 (2H, d), 3.19 (3H, s), 3.63 - 3.76 (3H, m), 4.76 - 4.84 (IH, m), 7.67 (IH, d), 8.08 (IH, d), 8.14 (2H, d), 8.31 - 8.36 (IH, m); MS m/z 544 [M+H]+.
Example 324: tert-butyl (3R)-3-[[5-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll- tetrazabicycloIS^.OJundeca^^jll-tnen-lO-y^aminol^-fluoro- benzoyl]amino]pyrrolidine-l-carboxylate The title compound was prepared by an analogous method to the preparation of Example 322, on a 0.46 mmol scale, utilising boc-R-(3R)-aminopyrrolidine (Aldrich; 130 mg, 0.75 mmol) and purification by normal phase chromatography (5% MeOH/DCM), as a white foam (179 mg, 65%).
1H NMR (399.9 MHz5 DMSO-d6) δl.42 (9H, s), 1.56 - 1.74 (7H, m), 1.87 - 1.97 (3H, m), 2.09 - 2.13 (IH, m), 2.60 - 2.64 (2H, m), 3.19 (4H, m), 3.37 - 3.44 (IH, m), 3.49 - 3.57 (IH5 s m), 3.63 - 3.67 (2H5 m), 4.38 (IH, m). 4.80 (IH5 m), 7.70 (IH5 d), 8.09 - 8.25 (2H5 m), 8.32 - 8.37 (IH5 m), 8.44 (IH5 d); MS m/z 602 [M+H]+.
Example 325:
5-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-o trien-10-yl)amino]-2-fluoro-N-[(3R)-l-methylpyrrolidin-3-yl]benzamide
5-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-256,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien- 10-yl)amino]-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide (Example 321; 95 mg, 0.19 mmol) was dissolved in 37% aqueous formaldehyde solution (1.1 mL) and acetic acid (120 μl5 1.89 mmol). Sodium acetate (156 mg, 1.89 mmol) was added and the mixture cooled in ans ice/water bath. Sodium cyanoborohydride (12 mg, 0.19 mmol) was added and the mixture allowed to warm to room temperature. After stirring for 1 hour, the mixture was absorbed on to an SCX column, and subsequently washed with methanol and eluted with ammonia in methanol. The product containing fractions were concentrated and purified by column chromatography (2% 7N ammonia in methanol/DCM) to yield the title compound as a white0 foam (69mg, 70%).
1H NMR (399.9 MHz, DMSO-d6) δl.58 - 1.73 (7H, m), 1.90 - 1.96 (2H, m), 2.12 - 2.21 (IH, m), 2.26 (3H5 s), 2.38 - 2.43 (3H5 m), 2.56 - 2.64 (3H5 m), 2.67 - 2.71 (IH, m), 3.19 (3H, s), 3.63 - 3.67 (2H, m), 4.34 - 4.36 (IH, m), 4.80 (IH, m), 7.69 (IH, d), 8.14 (2H, m), 8.27 (IH5 d), 8.33 (IH5 d); MS m/z 516 [M+H]+. 5
Example 326:
4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- yl)amino]-N-[(3R)-l-ethylpyrrolidin-3-yl]-3-methoxy-benzamide
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8510-tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-9-0 yl)amino]~3-methoxy-N-[(3R)-pyrrolidin-3-yl]benzamide (Example 55; 100 mg, 0.21 mmol) in DMF (3 mL) was added triethylamine (59 ul, 0.42 mmol) and ethyl bromide (Acros; 24 ul, 0.31 mmol). The reaction mixture was heated to 90 0C by microwave irradiation for 1 hour. The cooled reaction mixture was poured onto an SCX-3 cartridge (5 g) and the cartridge washed through with methanol (40 mL) and then eluted with 2M ammonia in methanol. Ammoniacal fractions were combined and evaporated. The residue was purified by base modified reverse phase preparative HPLC and product containing fractions combined and evaporated to yield the title compound as a white solid (27 mg, 25%) 1HNMR (400.132 MHz, DMSO-d6) δ 0.97 (t, 3H), 1.51 - 1.75 (m, 7H), 1.87 (m, 2H), 2.08 (m, IH), 2.32 - 2.68 (m, 8H), 3.10 (s, 3H), 3.56 (m, 2H), 3.88 (s, 3H), 4.32 (m, IH), 4.75 (m, IH), 7.44 (m, 2H), 7.65 (s, IH), 8.01 (s, IH), 8.22 (d, IH), 8.31 (d, IH); MS m/z 508 [M+H]+.
Example 327:
4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- yl)amino]-3-methoxy-N-[(3R)-l-propylpyrrolidin-3-yl]benzamide
The title compound was prepared by an analogous method to the preparation of Example 326, on a 0.21 mmol scale, utilising n-propyl bromide (Aldrich; 29 μL, 0.31 mmol) and heating for 45 minutes at 90 0C , as an off-white gum (63 mg, 58%).
1H NMR (400.132 MHz, DMSO-d6) 5 0.88 (t, 3H), 1.45 (m, 2H), 1.56 - 1.82 (m, 7H)5 1.95 (m, 2H), 2.14 (m, IH), 2.35 (m, 2H), 2.44 (m, 2H), 2.61 (m, 3H), 2.74 (m, IH), 3.17 (s, 3H), 3.63 (m, 2H), 3.95 (s, 3H), 4.39 (m, IH), 4.82 (m, IH), 7.50 (m, 2H), 7.72 (s, IH), 8.08 (s, IH), 8.27 (d, IH), 8.38 (d, IH); MS m/z 522 [M+H]+.
Example 328:
4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- yl)amino]-3-methoxy-N-[(3R)-l-(2-methoxyethyl)pyrrolidin-3-yl]benzamide The title compound was prepared by an analogous method to the preparation of Example 326, on a 0.21 mmol scale, utilising 2-bromoethyl methylether (Aldrich; 30 μL, 0.31 mmol) and heating for 45 minutes at 90 0C , as an off-white gum (57 mg, 50%).
1HNMR (400.132 MHz, DMSO-d6) δ 1.57 - 1.82 (m, 7H), 1.95 (m, 2H), 2.13 (m, IH), 2.52 (d, 2H)[obscured by DMSO], 2.59 (m, 4H), 2.69 (m, IH)5 2.79 (m, IH), 3.17 (s, 3H)5 3.24 (s, 3H)5 3.43 (t, 2H)5 3.63 (m, 2H), 3.95 (s, 3H)5 4.39 (m, IH), 4.82 (m, IH), 7.51 (m, 2H), 7.72 (s, IH), 8.08 (s, IH), 8.29 (d, IH)5 8.38 (d, IH); MS m/z 538 [M+H]+. Example 329:
4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicycIo[5.4.0]undeca-8,10,12-trien-10- yl)amino]-3-fluoro-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]benzamide 4-amino-3-fluoro-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-7-yl]benzamide (Intermediate 162; 1.0 g, 3.43 mmol), 10-Chloro~2-cyclopentyl-6-methyl-2,6,9,l l- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 1; 0.96 g, 3.43 mmol) and p- toluenesulphonic acid monohydrate (1.63 g, 8.56 mmol) were stirred and heated together at 110 0C in 4-methyl-2-pentanol (30 mL) for 18 hours. The cooled reaction mixture was diluted with water and methanol and the solution loaded onto an SCX-2 (2Og) column pre-wet with MeOH. The column was washed with MeOH ( 2 column volumes) and the product eluted with 2M NH3/MeOH (2 column volumes). Product containing fractions were combined and evaporated and the residue purified by chromatography on a silica column eluting with a 0- 100% gradient of 10% 2MNH3-MeOH in DCM. Product containing fractions were combined and evaporated to give a foam which on trituration with ethyl acetate yielded, on filtration, the title compound as a white solid (473 mg, 26%) 536 (M+H), ES- 534 (M-H) 1H NMR (400.132 MHz, DMSO-d6) 6 0.94 (m, 2H), 1.55 (m, 9H), 1.90 (m, 4H), 2.03 (m, IH), 2.19 (m, 3H), 2.42 (s, 3H), 2.58 (m, 2H), 2.98 (m, 2H), 3.17 (s, 3H), 3.60 (m, 2H), 4.32 (m, IH), 4.74 (m, IH), 7.69 (m, 2H), 8.00 (d, IH), 8.06 (s, IH), 8.12 (m, IH), 8.72 (s, IH); MS m/z 536 [M+H]+.
Example 330:
3,5-dichloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-
7,9,ll-trien-10-yl)amino]-2-fluoro-N-(l-methyl-4-piperidyl)benzamide 3,5-dichloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,l l-tetrazabicyclo[5.4.0]undeca-7,9,l 1- trien-10-yl)amino]-2-fluoro-benzoic acid (Intermediate 221; 85 mg, 0.18 mmol), HATU (104 mg, 0.27 mmol) and 4-ammo-l-methylpiperidine (32 mg, 0.27m mol) were stirred in DMF (3 mL) and diisopropylethylamine (95 μl, 0.54 mmol) added. The mixture was stirred for 2 hours and absorbed on to an SCX column, which was subsequently washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and the residue purified by column chromatography (4% ammonia in methanol/DCM) to yield the title compound as a white solid (67 mg, 66%). 1HNMR (399.9 MHz, DMSOd6) δl.26 - 1.65 (1OH, m), 1.79 (2H, d), 1.98 (2H, t), 2.17 (3H, s), 2.55 (2H + DMSO, m), 2.73 (2H, d), 3.15 (3H, s), 3.53 - 3.55 (2H, m), 3.67 - 3.74 (IH, m), 4.37 (IH, t), 7.65 (IH, d), 7.96 (IH, s), 8.43 (IH, d), 9.01 (IH, s); MS m/z 564 [M+H]+.
5 Example 331:
3,5-dichloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca- 7,9,ll-trien-10-yl)amino]-N-(4-dimethylaminocyclohexyl)-2-fluoro-benzamide
The title compound was prepared by an analogous method to the preparation of Example 330, on a 0.21 mmol scale, utilising utilising l-amino-4-dimethylaminocyclohexane (ABChemo Inc.; 30 μL, 0.31 mmol) and separation of the cis-isomer by column chromatography, as a white solid (21 mg, 19%).
1H NMR (500.13 MHz, DMSOd6) δl.38 - 1.92 (16H, m), 2.04 - 2.08 (IH, m), 2.18 (6H, s), 2.55 (2H + DMSO, m), 3.15 (3H, s), 3.53 - 3.55 (2H, m), 3.9 1 -3.95 (IH, m), 4.39 (IH, m), 7.63 (IH, d), 7.95 (IH, s), 8.39 (IH, d), 9.00 (IH, s); MS m/z 592 [M+H]+. 5
Example 332;
3,5-dichIoro-4-[(2-cyclopentyl-6-methyI-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-
7,9,ll-trien-10-yl)amino]-N-(4-dimethylaminocyclohexyl)-2-fluoro-benzamide
The title compound was prepared by an analogous method to the preparation of Example 330,o on a 0.21 mmol scale, utilising utilising l-amino-4-dimethylaminocyclohexane (ABChem
Inc.; 30 μL, 0.31 mmol) and separation of the trans-isomer by column chromatography, as a white solid (42 mg, 39%).
1HNMR (399.9 MHz, DMSO-d6) δl.22 - 1.68 (12H, m), 1.80 - 1.85 (2H, m), 1.90 - 1.95
(2H, m), 2.10 - 2.14 (IH, m), 2.18 (6H, s), 2.55 (2H + DMSO, m), 3.15 (3H, s), 3.53 - 3.565 (2H, m), 3.63 - 3.71 (IH, m), 4.33 - 4.42 (IH, m), 7.64 (IH, d), 7.95 (IH, s), 8.39 (IH, d),
9.01 (IH, s); MS m/z 592 [M+H]+.
Example 333;
4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10-0 yl)amino]-2-fluoro-5-methoxy-N-(2-pyrrolidin-l-yIethyl)benzamide 10-Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1; 80 mg, 0.285 mmol), 4-amino-2-fmoro-5-methoxy-N-(2-pyrrolidin-l- ylethyl)benzamide (Intermediate 228; 80 mg, 0.285 mmol), p-toluenesulphonic acid monohydrate (136 mg, 0.732 mmol) and 4-Methyl-2-pentanol (3 mL) were combined and heated at 100 0C overnight. The cooled reaction mixture was added to an SCX-2 column (5 g), pre-wet with MeOH (2 column volumes). The column was flushed with MeOH (2 column volumes) and eluted with 2M ammonia in MeOH. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC and product containing fractions combined and evaporated to yield the title compound as a cream solid (94 mg, 36%)
1H NMR (399.902 MHz, CDCl3) δl.63 (m, 2H), 1.77 (m, 8H), 2.06 (m, 2H), 2.58 (m, 4H), 2.68 (m, 2H), 2.72 (m, 2H), 3.30 (s, 3H), 3.60 (m, 2H), 3.71 (m, 2H), 3.95 (s, 3H), 4.91 (m, IH), 7.31 (m, IH), 7.57 (d, IH), 7.72 (s, IH), 7.95 (s, IH), 8.40 (d, IH); MS m/z 526 [M+H]+.
Example 334:
4-[(2-cycIopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,H-trien-10- yl)amino]-2,5-difluoro-N-[(3R)-l-methylpyrrolidin-3-yl]benzamide 10-Chloro-2-cyclopentyl-6-methyl-2,6,9,l l-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 1; 100 mg, 0.356 mmol), 4-amino-2,5-difluoro-N-[(3R)-l-methylpyrrolidin-3- yl]benzamide (Intermediate 229; 83 mg, 0.324 mmol) and caesium carbonate (211 mg, 0.648 mmol) was added to dioxane (3 mL) and the suspension bubbled with nitrogen for 10 minutes. Tris(dibenzylideneacetone) palladium (II) (11 mg, 0.019 mmol) and XANTPHOS (17 mg, 0.029 mmol) were added and the mixture heated to 100 0C overnight. The cooled reaction mixture was filtered and the filter cake washed with DCM and the filtrate evaporated. The residue was dissolved in DCM and purified on a silica column eluting with a gradient of 0 - 5% 2M ammonia in MeOH / DCM over 30 column volumes. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a yellow solid (91 mg, 56%) 1H NMR (399.902 MHz, CDCl3) 61.64 (m, 2H), 1.75 (m, 5H), 2.05 (m, 2H), 2.30 (m, IH), 2.41 (m, 4H), 2.67 (m, 4H), 2.89 (m, IH), 3.30 (s, 3H), 3.71 (m, 2H), 4.65 (m, IH), 4.88 (m, IH), 6.95 (m, IH), 7.30 (m, IH), 7.81 (m, IH), 7.96 (s, IH), 8.45 (m, IH); MS m/z 500 [M+H]+.
Example 335: 4-[(2-cycIopentyI-6-methyl-5-oxo-2,6,9,ll-tetrazabicycIo[5.4.0]undeca-7,9,ll-t*'ien-10- yl)amino]-2,5-difluoro-N-(2-pyrroIidin-l-ylethyl)benzamide
The title compound was prepared by an analogous method to the preparation of Example 334, on a 0.324 mmol scale, utilising 4-amino-2,5-difluoro-N-(2-pyrrolidin-l-ylethyl)benzamide (Intermediate 230; 87 mg, 0.324 mmol), as a white solid (117 mg, 70%). 1H NMR (399.902 MHz, CDCl3) 61.63 (m, 2H), 1.77 (m, 8H), 2.05 (m, 2H), 2.57 (m, 4H), 2.70 (m, 4H), 3.30 (s, 3H), 3.58 (m, 2H), 3.71 (m, 2H), 4.88 (m, IH), 7.28 (m, 2H), 7.82 (m, IH), 7.96 (s, IH), 8.46 (m, IH); MS m/z 514 [M+H]+.
Example 336: 2-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll- trien-10-yl)amino]-5-methoxy-N-[(3R)-l-metb.ylpyrrolidin-3-yl]benzamide
2-chloro-4-[(2-cyclopentyl-6-methy l-5-oxo-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien- 10-yl)amino]-5-methoxy-benzoic acid (Intermediate 231; lOOmg, 0.224 mmol), (3R)-I- methylpyrrolidin-3 -amine di Hydrochloride (Intermediate 184; 40 mg, 0.235 mmol), HATU (94 mg, 0.246 mmol) and DIPEA (195 μL, 1.12 mmol) were combined in DMF (3 mL) and stirred at room temperature overnight. The reaction mixture was added to an SCX-2 column (5 g) pre-wet with MeOH (2 column volumes), flushed with MeOH (2 column volumes) and eluted with 2M ammonia in MeOH. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (76 mg, 64%).
1H NMR (399.902 MHz, CDCl3) 81.62 (m, 2H), 1.78 (m, 5H), 2.11 (m, 2H), 2.31 (m, IH), 2.42 (m, 4H), 2.69 (m, 4H), 2.90 (m, IH), 3.29 (s, 3H), 3.71 (m, 2H), 3.94 (s, 3H), 4.68 (m, IH), 4.97 (m, IH), 6.97 (m, IH), 7.38 (s, IH), 7.63 (s, IH), 7.93 (s, IH), 8.61 (s, IH); MS m/z 528 [M+H]+.
Example 337: 2-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll- trien-10-yl)amino]-N-(l-ethyl-4-piperidyl)-5-methoxy-benzamide
The title compound was prepared by an analogous method to the preparation of Example 336, on a 0.224 mmol scale, utilising 4-amino-l -ethyl piperidine (Fluorochem; 32 mg, 0.246 mmol), as a white solid (97 mg, 79%).
1H NMR (399.902 MHz, CDCl3) δl.l 1 (t, 3H), 1.60 (m, 4H), 1.75 (m, 4H), 2.09 (m, 4H), 2.19 (m, 2H), 2.44 (m, 2H), 2.68 (m, 2H), 2.88 (m, 2H), 3.29 (s, 3H), 3.71 (m, 2H), 3.94 (s, 3H), 4.06 (m, IH), 4.97 (m, IH), 6.58 (d, IH), 7.40 (s, IH), 7.63 (s, IH), 7.94 (s, IH), 8.61 (s, IH); MS m/z 556 [M+H]+.
Example 338:
2-chloro-4- [(2-cyclopentyl-6-methyl-5-oxo-2,6,9,l l-tetrazabicyclo [5.4.0] undeca-7,9,11- trien-10-yl)amino]-N-(4-dimethylaminocyclohexyl)-5-methoxy-benzamide
The title compound was prepared by an analogous method to the preparation of Example 336, on a 0.224 mmol scale, utilising l-amino-4-dimethylaminocyclohexane (ABChem Inc.; 35 mg, 0.246 mmol), as a white solid (84 mg, 66%).
1H NMR (399.902 MHz, CDCl3) δl.26 - 1.76 (m, HH), 1.94 (m, 2H), 2.10 (m, 2H), 2.21 (m, 2H), 2.30 (m, 6H), 2.68 (m, 2H), 3.29 (m, 3H), 3.71 (m, 2H), 3.94 (m, 3.5H), 4.25 (m, 0.5H), 4.97 (m, IH), 6.46 (d, 0.5H), 6.85 (d, 0.5H), 7.39 (s, 0.5H), 7.45 (s, 0.5H), 7.63 (m, IH), 7.94 (m, IH), 8.62 (m, IH); MS m/z 570 [M+H]+.
Example 339:
2-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12- trien-lO-y^aminol-S-methoxy-N-tClSjS^^-methyl^-azabicyclop.S.llnon^- yl]benzamide
The title compound was prepared by an analogous method to the preparation of Example 336, on a 0.224 mmol scale, utilising Endo-9-methyl-9-azabicyclo[3,3,l]-nonan-3-amine (Chempacific; 38 mg, 0.246 mmol), as a white solid (84 mg, 64%). 1H NMR (399.902 MHz, CDCl3) δl .05 (m, 2H), 1.30 (m, 2H), 1.52 - 1.66 (m, 4H), 1.76 (m, 4H), 1.97 (m, 2H), 2.11 (m, 2H), 2.55 (m, 5H), 2.68 (m, 2H), 3.10 (m, 2H), 3.29 (s, 3H), 3.71 (m, 2H), 3.94 (s, 3H), 4.52 (m, IH), 4.98 (m, IH), 6.42 (d, IH), 7.41 (s, IH), 7.63 (s, IH), 7.94 (s, IH), 8.61 (s, IH); MS m/z 582 [M+H]+.
Example 340;
5 4- [(2-cy clopentyI-6-methyl-5-oxo-2,6,9, 11-tetrazabicyclo [5.4.0] undeca-7,9,11-trien-l 0- yl)amino]-3-methoxy-N-[l-(2-methylpropyl)-4-piperidyl]benzamide
The title compound was prepared by an analogous method to the preparation of Example 316, on a 0.49 mmol scale, utilising l-isobutylpiperidin-4-amine hydrochloride (Ambinter; 96 mg, 0.61 mmol) and DIPEA (340 μL, 1.6 mmol) and stirring at ambient temperature for 24 hours, io as a white solid (159 mg, 59%).
1H NMR (400.132 MHz, DMSO-d6) δ 0.87 (d, 6H), 1.68 (m, HH), 1.94 (m, 4H), 2.04 (d, 2H), 2.59 (m, 2H), 2.84 (m, 2H), 3.17 (s, 3H), 3.63 (m, 2H), 3.77 (m, IH), 3.95 (s, 3H), 4.81 (m, IH), 7.47 (s, IH), 7.50 (s, IH), 7.72 (s, IH), 8.04 (d, 2H), 8.08 (s, IH), 8.38 (d, IH); MS m/z 550 [M+H]+. is
Example 341;
7-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- yl)amino]-N-(l-methyl-4-piperidyl)benzo[l,3]dioxole-4-carboxamide
7-amino-N-( 1 -methy 1-4-piperidy l)benzo [1,3] dioxole-4-carboxamide (Intermediate 223 ;
20 60mg, 0.21mmol), 10-Chloro-2-cyclopentyl-6-methy 1-2,6,9, 11-tetrazabicyclo [5.4.0]undeca- 8,10,12-trien-5-one (Intermediate 1; 60 mg, 0.21 mmol) and p-toluenesulphonic acid monohydrate (102 mg, 0.53 mmol) were heated in 4-methyl-2-pentanol (3 mL) at 140 0C for 2 hours. The cooled reaction mixture was absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were
25 evaporated and the residue purified by normal phase chromatography (2.5% 7N NH3 in methanol/DCM) and then base modified reverse phase preparative HPLC to yield the title compound as a white solid (35 mg, 32%).
1H NMR (399.9 MHz, DMSOd6) δ 1.48 - 1.60 (6H, m), 1.63 - 1.69 (2H, m), 1.79 - 1.83 (4H, m), 2.00 - 2.05 (2H, m), 2.17 (3H, s), 2.55 - 2.58 (2H, m), 2.67 - 2.70 (2H, m), 3.17 (3H, so s), 3.59 (2H, m), 3.74 - 3.78 (IH, m), 4.69 - 1.77 (IH, m), 6.14 (2H, s), 7.23 (IH, d), 7.27 (IH, d), 7.48 - 7.51 (IH, m), 8.04 (IH, s), 8.60 (IH, s); MS m/z 522 [M+H]+. Example 342:
4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- yl)amino]-3-methoxy-N-(l-methyl-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-4- yl)benzamide The title compound was prepared by an analogous method to the preparation of Example 314, on a 0.49 mmol scale, utilising l-methyl-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-4-amine (CBI Building Blocks; 103 mg, 0.61 mmol) and DIPEA (260 μL, 1.47 mmol) and stirring at ambient temperature for 2 hours, as a single isomer of unspecified stereochemistry, as a white solid (52 mg, 19%). 1H NMR (400.132 MHz, DMSOd6) δ 1.09 (6H, m), 1.66 (1 IH, m), 1.94 (2H, m), 2.07 (2H, m), 2.16 (3H, s), 2.59 (2H, m), 2.81 (IH, m), 3.18 (3H, s), 3.63 (3H, m), 3.95 (3H, s), 4.81 (IH, m), 7.49 (2H, m), 7.73 (IH, s), 7.97 (IH, d), 8.08 (IH, s), 8.37 (IH, d); MS m/z 562 [M+H]+.
Example 343:
4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicycIo[5.4.0]undeca-7,9,ll-trien-10- yl)amino]-3-methoxy-N-(l-methyl-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-4- yl)benzamide
The title compound was prepared by an analogous method to the preparation of Example 314, on a 0.49 mmol scale, utilising l-methyl-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-4-amine
(CBI Building Blocks; 103 mg, 0.61 mmol) and DIPEA (260 μL, 1.47 mmol) and stirring at ambient temperature for 2 hours, as a single isomer of unspecified stereochemistry, as a white solid (102 mg, 37%).
1H NMR (400.132 MHz, DMSO-d6) δ 0.94 (IH, m), 1.21 (3H, m), 1.44 (2H, m), 1.66 (1OH, m), 1.88 (3H, m), 2.10 (2H, m), 2.19 (3H, s), 2.59 (2H, m), 3.18 (3H, s), 3.63 (2H, m), 3.96
(3H, s), 4.17 (IH, m), 4.81 (IH, m), 7.40 (IH, s), 7.45 (2H, d), 7.56 (IH, d), 7.75 (IH, s), 8.08
(IH, s), 8.37 (IH, d); MS m/z 562 [M+H]+.
Example 344: 4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-10- yl)amino]-2-fluoro-5-methoxy-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-7- yl]benzamide
4-amino-2-fluoro-5-methoxy-N-(9-methyl-9-azabicyclo[3.3.1]non-7-yl)benzamide (Intermediate 204; 50 mg, 0.16 mmol), lO-chloro^-cyclopentyl-ό-methyl^ό^l l- tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5-one (Intermediate 1; 45 mg, 0.16 mmol) and p- toluenesulphonic acid monohydrate (76 mg, 0.40 mmol) were stirred and heated together in A- methyl-2-pentanol (3 mL) at 110 0C for 18 hours.
A further portion of 10-chloro-2-cyclopentyl-6-methyl-2,6,9,l l-tetrazabicyclo[5.4.0]undeca- 7,9,1 l-trien-5-one (Intermediate 1; 20 mg, 0.07 mmol) was added and the mixture heated by microwave irradiation at 150 0C for lhour and 30 minutes.
The cooled reaction mixture was loaded onto an SCX-3 (5 g) column pre-wet with MeOH.
The column was washed with MeOH ( 2 column volumes) and eluted with 2M NH3/MeOH.
Product containing fractions were evaporated and the residue purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (48 mg, 53%).
1HNMR (400.132 MHz, DMSO-d6) 6 0.90 (m, 2H), 1.42 (m, 3H), 1.69 (m, 6H), 1.96 (m,
5H), 2.21 (m, 2H), 2.41 (s, 3H), 2.61 (m, 2H), 2.97 (m, 2H), 3.18 (s, 3H), 3.65 (m, 2H), 3.93
(s, 3H), 4.30 (m, IH), 4.84 (m, IH), 7.22 (d, IH), 7.67 (m, IH), 7.81 (s, IH), 8.12 (s, IH),
8.34 (d, IH); MS m/z 566 [M+H]+.
Example 345:
4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-10- yl)amino]-N-(l-ethyl-4-piperidyl)-3-fluoro-benzamide
10-chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien-5-one (Intermediate 1; 212 mg, 0.75 mmol), 4-amino-N-(l-ethylpiperidin-4-yl)-3-fluorobenzamide (Intermediate 225; 200 mg, 0.75 mmol) and p-toluenesulphonic acid monohydrate (0.335 mL, 1.88 mmol) were suspended in 4-Methyl-2-pentanol (5 mL) and sealed in a microwave tube. The reaction was heated to 160 °C for 30 minutes in the microwave reactor and allowed to cool to room temperature. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford the crude product as an orange oil which was purified by base modified reverse phase preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford the title compound as a white solid (35 mg, 9%). 1H NMR DMS0-d6 δ 0.65 (t, 2H), 0.9 (t, 2H), 1.0 (t. 3H), 1.5 (m, 7H), 1.6 (m, 2H), 1.9 (t, 2H), 2.3 (q, 2H), 2.9 (d, 2H), 3.2 (s, 3H), 3.4 (s, 2H), 3.6 (m, IH), 4.75 (m, IH), 7.65 (m, IH), 7.7 (m, IH), 7.95 (s, IH), 8.15 (m, IH), 8.6 (s, IH); MS m/z 510 [M+H]+.
Example 346:
N-[4-(azetidin-l-yl)cyclohexyl]-4-[(2-cyclopentyI-6-methyl-5-oxo-2,6,9,ll- tetrazabicycIo[5.4.0]undeca-7,9,ll-trien-10-yl)amino]-3-methoxy-benzamide
To a solution of 10-chloro-2-cyclopentyl-6-methyl-2,6,9,l l-tetrazabicyclo[5.4.0]undeca- 7,9,1 l-trien-5-one (Intermediate 1; 70 mg, 0.17 mmol) in DMF (3 mL) was added a solution of 4-(azetidin-l-yl)cyclohexan-l -amine (Intermediate 226; 39 mg, 0.25 mmol) in DMF (1 mL). DIPEA (90 uL, 0.51 mmol) was added, followed by HATU (98 mg, 0.26 mmol). The resultant mixture was stirred at ambient temperature for 4 hours.
The reaction mixture was evaporated and the residue partitioned between DCM (5 mL) and saturated aqueous sodium bicarbonate solution (5 mL). The organic phase was separated by gravity elution through a PTFE filter cup and evaporated to an amber gum which was purified by base modified reverse phase preparative HPLC to yield the title compound as an white solid (29 mg, 31% ) assigned as the trans isomer.
The cis isomer (Example 347) was isolated as a tan coloured solid (32 mg, 34%) 1H NMR (400.132 MHz, DMSOd6) δ 0.92 - 1.00 (2H, m), 1.29 - 1.38 (2H, m), 1.57 - 1.99 (15H, m), 2.58 - 2.60 (2H, m), 3.07 (4H, t), 3.17 (3H, s), 3.61 - 3.65 (2H, m), 3.66 - 3.76 (IH, m), 3.95 (3H, s), 4.82 (IH, quintet), 7.45 - 7.48 (2H, m), 7.72 (IH, s), 8.01 (IH, d), 8.08 (IH, s), 8.37 (IH, d); MS m/z 548 [M+H]+.
Example 347:
N-[4-(azetidin-l-yI)cyclohexyl]-4-[(2-cyclopentyI-6-methyl-5-oxo-2,6,9,H- tetrazabicycloIS^.OJundeca-T^jll-trien-lO-y^aminol-S-methoxy-benzamide The title compound was isolated from the reaction above to produce Example 346 as a tan coloured solid (32 mg, 34%).
1H NMR (400.132 MHz, DMSO-dό) δ 1.30 - 1.40 (2H5 m), 1.43 - 1.50 (2H5 m), 1.56 - 1.77 (1OH, m), 1.86 - 1.98 (4H, m), 2.18 - 2.23 (IH, m), 2.58 - 2.60 (2H, m), 3.07 (4H, t), 3.18 (3H, s), 3.62 - 3.65 (2H, m), 3.77 - 3.87 (IH, m), 3.95 (3H, s), 4.82 (IH, quintet), 7.50 - 7.54 (2H, m), 7.71 (IH, s), 8.04 (IH, d), 8.08 (IH, s), 8.37 (IH, d); MS m/z 548 [M+H]+.
Example 348: tert-butyl 3-[[4-[(2-cydopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca- 7,9,ll-trien-10-yl)amino]-3-methoxy-benzoyl]amino]azepane-l-carboxylate
The title compound was prepared by an analogous method to the preparation of Example 314, on a 0.30 mmol scale, utilising tert-butyl 3-aminoazepane-l-carboxylate (Anichem; 78 mg, 0.36 mmol) and DIPEA (151 μL, 0.91 mmol) and stirring at ambient temperature for 19 hours, as an amber gum (153 mg, 83%). 1H NMR (400.132 MHz, DMSO-d6) δ 1.24 - 1.46 (HH, m), 1.50 - 2.00 (14H, m), 2.57 - 2.61 (2H, m), 3.06 - 3.19 & 3.30 - 3.37 (IH, m), 3.18 (3H, s), 3.54 - 3.70 (3H, m), 3.95 (3H, s), 4.08 - 4.22 (IH, m), 4.75 - 4.87 (IH, m), 7.36 - 7.49 (2H, m), 7.74 (IH, s), 8.01 & 8.16 (2 x d, IH), 8.09 (IH, s), 8.39 (IH, d); MS m/z 608 (M+H)+
Example 349;
4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien- 10-yl)amino]-3-methoxy-N-(4-piperidyl)benzamide
10-chloro-2-cyclopentyl-4,4-dimethyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5- one (Intermediate 127; 50 mg, 0.16 mmol) and tert-butyl 4-[(4-amino-3-methoxy- benzoyl)amino]piperidine-l-carboxylate (Intermediate 234; 85 mg, 0.24 mmol) were dissolved in 4-methyl-2-pentanol (1 niL) and p-toluenesulphonic acid monohydrate (44 mg,
0.32 mmol) added. The reaction mixture was heated at 9O0C by microwave irradiation for 20 minutes and then at 15O0C for a further 45 minutes.
The reaction mixture was diluted with water (3 mL) and methanol (3 mL) and the solution poured directly onto an SCX-3 (2 g) cartridge. The cartridge was washed with methanol (30 mL) and then eluted with 2M ammonia in methanol. Evaporation to dryness of the ammoniacal fractions afforded an amber gum, which was purified by base modified reverse phase, preparative HPLC to yield the title compound as a white solid (32 mg, 38%). 1H NMR (400.132 MHz, DMSO-d6) δ 1.10 (s, 6H), 1.43 (m, 2H), 1.55 - 1.79 (m, 10H), 1.89 (m, 2H), 2.96 (m, 2H), 3.19 (s, 3H), 3.38 (s, 2H), 3.83 (m, IH), 3.95 (s, 3H), 5.19 (m, IH), 7.48 (m, 2H), 7.67 (s, IH), 7.99 (s, IH), 8.05 (d, IH), 8.36 (d, IH); MS m/z 522 [M+H]+.
Example 350:
4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-
10-yl)amino]-N-(l-ethyl-4-piperidyl)-3-methoxy-benzamide 10-chloro-2-cyclopentyl-4,4-dimethyl-2,6,9,l l-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5- one (Intermediate 127; 115 mg, 0.37 mmol) and 4-amino-N-(l-ethyl-4-piperidyi)-3-methoxy- benzamide (Intermediate 190; 104 mg, 0.37 mmol) were dissolved 4-methyl-2-pentanol (3 mL). p-Toluenesulphonic acid monohydrate (142 mg, 0.74 mmol) was added and mixture heated by microwave irradiation at 160 0C for 1 hour. After cooling, the reaction mixture was diluted with MeOH (5 mL) and poured directly onto an SCX-3 (5 g) cartridge. The cartridge was washed with methanol (40 mL) and eluted with 2M ammonia in methanol (40 mL). Evaporation to dryness of the ammoniacal fractions afforded a yellow gum which was purified by base modified reverse phase, preparative HPLC to yield the title compound as a white solid (125 mg, 61%). 1H NMR (400.132 MHz, DMSO-d6) δ 1.01 (t, 3H), 1.11 (s, 6H), 1.53 - 1.97 (m, 14H), 2.34 (q, 2H), 2.90 (m, 2H), 3.20 (s, 3H), 3.39 (s, 2H), 3.78 (m, IH), 3.96 (s, 3H), 5.20 (m, IH), 7.48 (m, 2H), 7.68 (s, IH), 8.00 (s, IH), 8.07 (d, IH), 8.37 (d, IH); MS m/z 550 [M+H]+.
Example 351:
4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien- 10-yl)amino]-N-(3-dimethylamino-2,2-dimethyl-propyl)-3-methoxy-benzamide
The title compound was prepared by an analogous method to the preparation of Example 350, on a 0.24 mmol scale, utilising 4-amino-N-(3-dimethylamino-2,2-dimethyl-propyl)-3- methoxy-benzamide (Intermediate 22; 68 mg, 0.24 mmol), as a white foam (47 mg, 53%). 1H NMR (400.132 MHz, DMSO-d6) δ 0.90 (s, 6H), 1.11 (s, 6H), 1.62 (m, 4H), 1.75 (m, 2H), 1.90 (m, 2H), 2.21 (s, 2H), 2.29 (s, 6H), 3.21 (m, 5H), 3.40 (s, 2H), 3.96 (s, 3H), 5.20 (m, IH), 7.42 (m, IH), 7.47 (d, IH), 7.70 (s, IH), 8.00 (s, IH), 8.39 (d, IH), 8.44 (t, IH); MS m/z 552 [MH-H]+.
Example 352;
4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12- trien-10-yI)amino]-2-fluoro-5-methoxy-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-7- yl]benzamide The title compound was prepared by an analogous method to the preparation of Example 350, on a 0.31 mmol scale, utilising 4-amino-2-fluoro-5-methoxy-N-[(lS,5R)-9-methyl-9- azabicyclo[3.3.1]non-7-yl]benzamide (Intermediate 204; 96 mg, 0.31 mmol) heating by microwave irradiation at 150 0C for 1 hour, as a white foam (47 mg, 53%). 1H NMR (400.132 MHz, CDCl3) δ 1.16 - 1.23 (8H, m), 1.52 - 1.65 (4H, m), 1.73 - 1.83 (5H, m), 1.97 - 2.11 (5H, m), 2.54 - 2.65 (5H, m), 3.17 - 3.26 (2H, m), 3.31 (3H, s), 3.40 (2H, s), 3.96(3H, s), 4.51 - 4.62 (IH, m), 5.29 (IH, quintet), 6.60 - 6.74 (IH, m), 7.57 (IH, d), 7.70 (IH, s), 7.88 (IH, s), 8.39 (IH, d); MS m/z 594 [M+H]+.
Example 353: 4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12- trien-10-yl)amino]-3-fluoro-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-7-yI]benzamide
The title compound was prepared by an analogous method to the preparation of Example 350, on a 0.34 mmol scale, utilising 4-amino-3-fluoro-N-[(lS,5R)-9-methyl-9- azabicyclo[3.3.1]non-7-yl]benzamide (Intermediate 162; 100 mg, 0.34 mmol) heating by microwave irradiation at 150 0C for 40 minutes, as a white foam (52 mg, 27%).
1H NMR (399.902 MHz, DMSO-d6) δ 0.9 (2H, d), 1.1 (6H, s), 1.45 (3H, m), 1.55 (4H, m), 1.7 (2H, m), 1.8 (2H, m), 1.9 (2H, m), 2.05 (IH, m) 2.2 (2H, m), 2.40 (2H, s), 3.0 (2H, d), 3.2 (3H, s), 3.35 (2H, s) 4.3 (IH, m), 5.2 (IH, m), 7.65 (IH, d), 7.70 (IH, d), 8.0 (2H, m), 8.15 (IH, t), 8.65 (IH, s); MS m/z 564 [M+H]+.
Example 354: 4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12- trien-10-yl)amino]-3-methoxy-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-7- yl]benzamide
The title compound was prepared by an analogous method to the preparation of Example 350, 5 on a 0.32 mmol scale, utilising 4-amino-3-methoxy-N-[(l S,5R)~9-methyl-9- azabicyclo[3.3.1]non-3-yl]benzamide (Intermediate 202; 99 mg, 0.32 mmol) heating thermally at 140 0C for 2 hours, as a white solid (104 mg, 56%).
1H NMR (399.9 MHz, DMSOd6) δθ.94 (2H, d), 1.10 (6H, s), 1.42 - 1.49 (3H, m), 1.63 (4H, s), 1.75 (2H, s), 1.89 - 1.96 (3H, m), 1.92 - 1.95 (2H, m), 2.16 - 2.21 (2H, m), 2.42 (3H, s), I0 2.99 (2H, d), 3.20 (3H, s), 3.39 (2H, s), 3.96 (3H, s), 4.32 - 4.38 (IH, m), 5.21 (IH, m), 7.47
(lH,d), 7.50 (IH, s), 7.68 (IH, s), 7.92 (IH, d), 8.00 (IH, s), 8.38 (IH, d); MS m/z 576
[M+H]+.
Example 355: is 4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien- 10-yl)amino]-N-(l-ethyl-4-piperidyl)-2,5-difluoro-benzamide
10-chloro-2-cyclopentyl-4,4-dimethyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5- one (Intermediate 127; lOOmg, 0.32mmol), 4-amino-N-(l-ethyl-4-piperidyl)-2,5-difluoro- benzamide (Intermediate 235; 101 mg, 0.36 mmol) and caesium carbonate (22 mg, 0.65
20 mmol) added to dioxane (5 mL) and the suspension bubbled with nitrogen for 10 minutes, tris(dibenzylideneacetone) palladium (II) (18 mg, 0.02 mmol) and XANTPHOS (17 mg, 0.03 mmol) were added and the mixture heated at 110 °C overnight. The mixture was filtered and the filtrate loaded onto an SCX (10 g) cartridge pre-wet with methanol, washed with methanol and eluted with methanolic ammonia. Product containing fractions were combined and
25 evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a white crystalline solid (97mg, 54%). 1HNMR (399.9 MHz, DMSO-d6) δl.00 (3H, t), 1.11 (6H, s), 1.48 - 1.55 (2H, m), 1.60 (4H, d), 1.73 (2H, s), 1.77 - 1.82 (2H, m), 1.88 (2H, d), 1.93 - 1.99 (2H, m), 2.32 (2H, q), 2.83 (2H, d), 3.20 (3H, s), 3.39 (2H, s), 3.70 - 3.74 (IH, m), 5.21 (IH, m), 7.40 - 7.45 (IH, m), 7.95 -
30 7.98 (IH, m), 8.02 (IH, s), 8.20 - 8.25 (IH, m), 8.88 (IH, s); MS m/z 556 [M+H]+. Example 356:
4- [(2-cy clopentyI-4,4,6-trimethyl-5-oxo-2,6,9,l 1-tetrazabicyclo [5.4.0] undeca-7,9,11-trien-
10-yl)amino]-2,5-difluoro-N-(l-methyl-4-piperidyl)benzamide
The title compound was prepared by an analogous method to the preparation of Example 355, on a 0.32 mmol scale, utilising 4-amino-2,5-difluoro-N-(l-methyl-4-piperidyl)benzamide (Intermediate 59; 96 mg, 0.32 mmol), as a white solid (38 mg, 22%). 1H NMR (399.9 MHz, DMSO-d6) δl.l l (6H, s), 1.54 - 1.58 (2H, m), 1.59 (3H, s), 1.74 (3H, d), 1.79 (2H, s), 1.87 (2H, s), 1.95 (IH, d), 1.99 (IH, s), 2.17 (3H, s), 2.75 (2H, d), 3.20 (3H, s), 3.37 (2H, s), 3.70 (IH, m), 5.22 (IH, m), 7.40 - 7.45 (IH, m), 7.95 - 7.98 (IH, m), 8.02 (IH, s), 8.20 - 8.25 (IH, m), 8.88 (IH, s); MS m/z 540 [M+H]+.
Example 357:
4- [(2-cy clopentyl-4,4,6-trimethyl-5-oxo-2,6,9,l 1-tetrazabicyclo [5.4.0] undeca-7,9,11-trien-
10-yl)amino]-N-(3-dimethylaminopropyl)-3-methoxy-benzamide The title compound was prepared by an analogous method to the preparation of Example 350, on a 0.32 mmol scale, utilising 4-amino-N-(3-dimethylaminopropyl)-3-methoxy-benzamide (Intermediate 196; 82 mg, 0.32 mmol) heating thermally at 140 0C for 2 hours, as a white solid (84 mg, 50%). 1H NMR (399.9 MHz, DMSO-d6) δ 1.11 (6H, s), 1.63 (2H, m), 1.65 - 1.71 (4H, m), 1.75 (2H, s), 1.86 - 1.89 (2H, t), 2.16 (6H, s), 2.28 - 2.34 (2H, t), 3.15 - 3.20 (3H, s), 3.28 - 3.31 (2H, m), 3.36 - 3.39 (2H, s), 3.95 (3H, s), 5.18 - 5.22 (IH, m), 7.47 - 7.50 (IH, m), 7.51 (IH, s), 7.68 (IH, s), 8.02 (IH, s). 8.37 (IH, s), 8.39 (IH, t); MS m/z 524 [M+H]+.
Example 358: 4- [(2-cyclopentyl-4,4,6-trimethyI-5-oxo-2,6,9,l 1-tetrazabicyclo [5.4.0] undeca-7,9,11-trien- 10-yl)amino]-3-methoxy-N-(2~pyrrolidin-l-ylethyl)benzamide The title compound was prepared by an analogous method to the preparation of Example 350, on a 0.32 mmol scale, utilising 4-amino-3-methoxy-N-(2-pyrrolidin-l-ylethyl)benzamide (Intermediate 192; 86 mg, 0.32 mmol) heating thermally at 140 0C for 2 hours, as a white solid (56 mg, 32%). 1H NMR (399.9 MHz, DMSO-d6) δ 1.11 (6H, s), 1.63 (3H, m), 1.68 - 1.71 (3H, m), 1.74 (3H, d), 1.86 - 1.89 (3H, m), 2.48 (4H, m), 2.58 (2H, t), 3.18 (3H, s), 3.39 (4H, t), 3.92 - 3.98 (3H, s), 5.18 (IH, m), 7.47 - 7.50 (IH, m), 7.51 (IH, s), 7.68 (IH, s), 8.02 (IH5 s). 8.29 (IH, 4), 8.39 (IH, d); MS m/z 536 [M+H]+.
Example 359:
4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,ll-tetrazabicycIo[5.4.0]undeca-7,9,ll-ti*ieii- 10-yl)amino]-N-(2-dimethylaminoethyl)-3-methoxy-benzamide
The title compound was prepared by an analogous method to the preparation of Example 350, on a 0.32 mmol scale, utilising 4-amino-N-(2-dimethylaminoethyl)-3-methoxy-benzamide (Intermediate 194; 77 mg, 0.32 mmol) heating thermally at 140 0C for 2 hours, as a white solid (37 mg, 22%).
1H NMR (399.9 MHz, DMSO-d6) δ 1.11 (6H, s), 1.63 - 1.68 (4H, m), 1.75 (2H, m), 1.92 (2H, m), 2.15 (6H, s), 2.40 (2H, t), 3.19 (3H, s), 3.33 - 3.37 (4H, m), 3.95 (3H, s), 5.18 (IH, m), 7.47 - 7.50 (IH, m), 7.51 (IH, s), 7.68 (IH, s), 8.02 (IH, s). 8.29 (IH, 4), 8.39 (IH, d); MS m/z 510 [M+H]+.
Example 360:
4- [(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,l 1-tetrazabicyclo [5.4.0] undeca-7,9,11-trien-
10-yl)amino]-3-methoxy-N-(4-pyrrolidin-l-ylcyclohexyl)benzamide To a solution of 4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,l 1- tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-10-yl)amino]-3-methoxy-benzoic acid (Intermediate 236; 83 mg, 0.19 mmol) in DMF (3 mL) was added a solution of 4-pyrrolidin-l- ylcyclohexan-1 -amine (Intermediate 237; 78 mg, 0.46 mmol). DIPEA (100 uL, 0.57 mmol) was added, followed by HATU (107 mg, 0.28 mmol). The resultant mixture was stirred at ambient temperature for 2 hours. The reaction mixture was evaporated to a gum, which was partitioned between DCM (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The organic phase was separated by gravity elution through a PTFE filter cup and evaporated to an amber gum which was purified by base modified reverse phase preparative HPLC to yield the title compound as an off white solid (34 mg, 30%). 1H NMR (400.132 MHz, CDCl3) 5 1.20 (s, 6H), 1.29 (m, 2H), 1.41 - 1.83 (m, 12H), 1.95 - 2.20 (m, 7H), 2.60 (m, 4H), 3.30 (s, 3H), 3.37 (s, 2H), 3.94 (m, IH), 3.97 (s, 3H), 5.31 (m, IH), 5.83 (d, IH), 7.20 (m, IH), 7.42 (d, IH), 7.60 (s, IH), 7.85 (s, IH), 8.47 (d, IH); MS m/z 590 [M+H]+.
Example 361: o 4-[(2-cyclopentyI-4,4,6-trimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien- 10-yI)amino]-2-fluoro-5-methoxy-N-(l-methyl-4-piperidyl)benzamide
The title compound was prepared by an analogous method to the preparation of Example 350, on a 0.49 mmol scale, utilising 4-amino-2-fluoro-5-methoxy-N-(l-methyl-4- piperidyl)benzamide (Intermediate 27; 144 mg, 0.51 mmol), as a white foam (66 mg, 24%).s 1H NMR (400.132 MHz, DMSO-d6) δ 1.11 (s, 6H), 1.52 - 1.68 (m, 6H), 1.76 (m, 4H), 1.95 (m, 4H), 2.16 (s, 3H), 2.73 (m, 2H), 3.20 (s, 3H), 3.40 (s, 2H), 3.73 (m, IH), 3.92 (s, 3H), 5.19 (m, IH), 7.19 (d, IH), 7.79 (m, 2H), 8.02 (s, IH), 8.31 (d, IH); MS m/z 554 [MH-H]+.
Example 362: 0 3-chloro-4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca- 7,9,ll-trien-10-yl)amino]-N-(3-dimethylaminopropyl)benzamide
The title compound was prepared by an analogous method to the preparation of Example 355, on a 0.34 mmol scale, utilising 4-amino-3-chloro-N-(3-dimethylaminopropyl)benzamide (Intermediate 214; 98 mg, 0.38 mmol), as an off-white solid (27 mg, 15%). S 1H NMR (400.132 MHz, DMSO-d6) d 1.10 (s, 6H), 1.50 - 1.74 (m, 8H), 1.83 (m, 2H), 2.15 (s, 6H), 2.27 (t, 2H), 3.19 (s, 3H), 3.28 (m, 2H), 3.37 (s, 2H), 5.11 (m, IH), 7.77 (m, IH), 7.96 (d, IH), 7.99 (s, IH), 8.11 (s, IH), 8.27 (d, IH), 8.48 (t, IH); MS m/z 528 [M+H]+.
Example 363: 0 4- [(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,l 1-tetrazabicyclo [5.4.0] ιmdeca-7,9,11-trien- 10-yl)amino]-N-(4-dimethylaminocyclohexyl)-3-methoxy-benzamide The title compound was prepared by an analogous method to the preparation of Example 350, on a 0.49 mmol scale, utilising 4-amino-N-(4-dimethylaminocyclohexyl)-3-methoxy- benzamide (Intermediate 239; 144 mg, 0.51 mmol), as a white foam (39 mg, 14%). 1H NMR (400.132 MHz, DMSO-d6) d 1.10 (s, 6H), 1.21 - 2.04 (m, 16H), 2.10 - 2.21 (m, s 7H), 3.19 (s, 3H), 3.38 (s, 2H), 3.72 & 3.92 (m, IH), 3.95 (s, 3H), 5.19 (m, IH), 7.49 (m, 2H), 7.66 (d, IH), 7.99 (s, IH), 8.01 (d, IH), 8.36 (d, IH); MS m/z 564 [M+H]+.
Example 364:
4- [(2-cy clopentyl-4,4,6-trimethyl-5-oxo-2,6,9,l 1-tetrazabicyclo [5.4.0] undeca-7,9,11-trien-o 10-yl)amino]-2-fluoro-5-methoxy-N-[(3R)-l-methylpyrrolidin-3-yl]benzamide
The title compound was prepared by an analogous method to the preparation of Example 350, on a 0.32 mmol scale, utilising 4-amino-2-fluoro-5-methoxy-N-[(3R)-l-methylpyrrolidin-3- yl]benzamide (Intermediate 182; 77 mg, 0.32 mmol) heating thermally at 140 0C for 3 hours, as a white solid (84 mg, 49%). s 1H NMR (399.9 MHz, DMSO-d6) δ 1.11 (6H, s), 1.64 - 1.76 (7H, m), 1.87 - 1.94 (2H, m), 2.13 - 2.22 (IH, m), 2.26 (3H, s), 2.34 - 2.45 (2H, m), 2.58 - 2.64 (IH, m), 2.66 - 2.71 (IH, m), 3.20 (3H, s), 3.41 (2H, s), 3.93 (3H, s), 4.36 - 4.41 (IH, m), 5.15 - 5.24 (IH, m), 7.22 (IH, d), 7.78 (IH, d), 7.97 - 8.00 (IH, m), 8.03 (IH, s), 8.32 (IH, d); MS m/z 540 [M+H]+. 0 Example 365:
4- [(2-cy clopentyl-4,4,6-trimethyl-5-oxo~2,6,9,l 1-tetrazabicyclo [5.4.0] ιmdeca-8,10,12- trien-10-yl)amino]-2-fluoro-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-7-yl]benzamide
The title compound was prepared by an analogous method to the preparation of Example 355, on a 0.32 mmol scale, utilising 4-amino-2-fluoro-N-[(lS,5R)-9-methyl-9-5 azabicyclo[3.3.1]non-7-yl]benzamide (Intermediate 241; 93 mg, 0.34 mmol), as an off-white solid (113 mg, 62%).
1H NMR (399.9 MHz, DMSO-d6) δθ.91 (2H, d), 1.11 (6H, s), 1.38 (IH, m), 1.42 (2H, m), 1.61 (2H, s), 1.64 (2H, t), 1.75 (IH, s), 1.84 (2H, m), 1.89 (2H, m), 2.03 (IH, m), 2.20 (2H, m), 2.39 (3H, s), 2.98 (2H, d), 3.17 (3H, s), 3.40 (2H, s), 4.28 (IH, m), 5.23 (IH, m), 7.380 (IH, d), 7.52 (IH, t), 7.64 (IH, m), 7.89 (IH, d), 8.01 (IH, s), 9.62 (Ih, s); MS m/z 565 [M+Hf. Example 366:
5-chloro-4- [(2-cy clopentyl-4,4,6-trimethyl-5-oxo-2,6,9,l 1-tetrazabicyclo [5.4.0] undeca-
7,9,ll-trien-10-yl)amino]-N-(4-dimethyIaminocyclohexyI)-2-fluoro-benzamide The title compound was prepared by an analogous method to the preparation of Example 355, on a 0.29 mmol scale, utilising 4-amino-5-chloro-N-(4-dimethylaminocyclohexyl)-2-fluoro- benzamide (Intermediate 175; 92 mg, 0.29 mmol) heating at 110 0C for 3 hours, as an off- white solid (55 mg, 32%). 1H NMR (399.9 MHz5 DMSOd6) δ 1.11 (6H, s), 1.25 - 1.37 (3H, m), 1.47 - 2.01 (13.5H, m), 2.13 (6.5H, d), 3.20 (3H, s), 3.40 (2H, s), 3.62 - 3.71 and 3.88 - 3.95 (each 0.5H5 m), 5.12 - 5.20 (IH, m), 7.65 - 7.68 (IH5 m), 7.99 - 8.04 (2H, m), 8.10 (IH5 d), 8.30 - 8.35 (IH5 m); MS m/z 587 [M+H]+.
Example 367: 3-chloro-4- [(2-cy cIopentyl-4,4,6-trimethyl-5-oxo-2,6,9,l 1-tetrazabicy do [5.4.0] undeca- 7,9,ll-trien-10-yl)amino]-N-(2,2-dimethyl-3-pyrrolidin-l-yl-propyI)benzamide
The title compound was prepared by an analogous method to the preparation of Example 355, on a 0.34 mmol scale, utilising 4-amino-3-chloro-N-(2,2-dimethyl-3-pyrrolidin-l-yl- propyl)benzamide (Intermediate 244; 123 mg, 0.39 mmol) heating at 1100C for 3 hours, as an off-white solid (35 mg, 18%).
1H NMR (400.132 MHz, DMSOd6) δ 0.90 (s, 6H), 1.10 (s, 6H), 1.49 - 1.85 (m, 12H), 2.42 (s, 2H), 2.60 (m, 4H), 3.19 (s, 3H), 3.21 (d, 2H), 3.36 (s, 2H), 5.09 (m, IH), 7.73 (m, IH), 7.88 (d, IH)5 7.98 (s, IH), 8.15 (s, IH), 8.25 (d, IH), 8.69 (t, IH); MS m/z 582 [M+H]+.
Example 368:
4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-
10-yl)amino]-N-(2,2-dimethyl-3-pyrrolidin-l-yI-propyI)-3-methoxy-benzamide The title compound was prepared by an analogous method to the preparation of Example 350, on a 0.33 mmol scale, utilising 4-amino-N-(2,2-dimethyl-3-pyrrolidin-l-yl-propyl)-3- methoxy-benzamide (Intermediate 206; 100 mg, 0.33 mmol) heating thermally at 120 0C for 3 days, as a white solid (55 mg, 29%).
1HNMR (400.132 MHz, CDCl3) δ 1.01 (s, 3H), 1.20 (s, 3H), 1.54 - 160 (m, 8H), 1.80 - 1.63 (m, 8H), 2.03 - 1.95 (m, 2H), 2.56 (s, 2H), 2.72 - 2.65 (m, 4H), 3.29 (s, 3H), 3.37 (s, 2H), 3.39 (d, 2H), 3.98 (s, 3H), 5.34 (quintet, IH), 7.20 (d, IH), 7.55 (s, IH), 7.61 (s, IH), 7.86 (s, IH), 8.43 (d, IH), 9.16 - 9.10 (m, IH); MS m/z 578 [M+H]+.
Example 369:
4-[(2-cyclopentyl-4,4,6-trimethyI-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien- 10-yl)amino]-N-[(3R)-l-ethylpyrrolidin-3-yl]-3-methoxy-benzamide
The title compound was prepared by an analogous method to the preparation of Example 350, on a 0.22 mmol scale, utilising 4-amino-N-[(3R)-l-ethylpyrrolidin-3-yl]-3-methoxy- benzamide (Intermediate 245; 70 mg, 0.26 mmol) heating by microwave irradiation at 160 0C for 1 hour, as a white solid (50 mg, 42%). 1H NMR (400.132 MHz, DMSOd6) δ 1.04 (t, 3H), 1.10 (s, 6H), 1.55 - 1.93 (m, 9H), 2.15 (m, IH), 2.43 (m, 4H), 2.65 (m, IH), 2.73 (m, IH), 3.19 (s, 3H), 3.38 (s, 2H), 3.95 (s, 3H), 4.40 (m, IH), 5.19 (m, IH), 7.51 (m, 2H), 7.67 (s, IH), 7.99 (s, IH), 8.28 (d, IH), 8.37 (d, IH); MS m/z 536 [M+H]+.
Example 370:
4- [(2-cyclopentyl-4,4,6-trimethyI-5-oxo-2,6,9,l 1-tetrazabicy clo [5.4.0] undeca-8,10,12- trien-10-yl)amino]-N-(l-ethyl-4-piperidyI)-2-fluoro-5-methoxy-benzamide
10-chloro-2-cyclopentyl-4,4,6-trimethyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien-5- one (Intermediate 127; 52 mg, 0.17 mmol), 4-amino-N-(l-ethyl-4-piperidyl)-2-fluoro-5- methoxy-benzamide (Intermediate 205; 50 mg, 0.17mmol) and p-toluenesulphonic acid monohydrate (81 mg, 0.43 mmol) were stirred and heated together in 4-methyl-2-pentanol (2 mL) by microwave irradiation at 150 0C for 1 hour. A further portion of 10-chloro-2- cyclopentyl-4,4,6-trimethyl-2,6,9,l l-tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one (lOmg) was added and reaction continued for a further 1 hour. The cooled solution was loaded onto an SCX-3 (5g) column pre-wet with MeOH. The column was washed with MeOH ( 2 column volumes) and eluted with 2M NH3/MeOH. Product containing fractions were combined and evaporated and the residue purified by base modified reverse phase preparative HPL to yield the title compound as a white solid (49 mg, 51%)
1H NMR (400.132 MHz, DMSOd6) δ 1.00 (t, 3H), 1.11 (s, 6H), 1.74 (m, 12H), 2.32 (q, 2H), 2.83 (m, 2H), 3.17 (s, 3H), 3.40 (s, 2H), 3.73 (m, IH), 3.92 (s, 3H), 5.19 (m, IH), 7.19 (d, 5 IH), 7.77 (s, IH), 7.80 (m, IH), 8.02 (s, IH), 8.31 (d, IH); MS m/z 568 [M+H]+.
Example 371:
4-[(2-cycIopentyI-4,4,6-trimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12- trien-10-yl)amino]-3-fluoro-N-(l-methyl-4-piperidyl)benzamide io The title compound was prepared by an analogous method to the preparation of Example 350, on a 0.45 mmol scale, utilising 4-amino-3-fluoro-N-(l-methyl-4-piperidyl)benzamide (Intermediate 65; 114 mg, 0.45 mmol) heating by microwave irradiation at 160 0C for 30 minutes, as a white solid (96 mg, 41%). 1H NMR (400.132 MHz, DMSOd6) δ 1.1 (s, 6H), 1.55 (m, 6H), 1.7 - 1.85 (m, 6H), 1.95 (t, is 2H)5 2.8 (d, 2H), 3.2 (s, 3H), 3.35 (s, 2H), 3.75 (m, IH), 5.15 (m, IH), 7.65 (m, IH), 7.7 (m, IH), 7.95 (s, IH), 8.15 (m, IH), 8.85 (s, IH); MS m/z 525 [M+H]+.
Example 372: 4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-
20 10-yl)amino]-N-(4-dimethylaminocyclohexyl)-2-fluoro-5-methoxy-benzamide
The title compound was prepared by an analogous method to the preparation of Example 350, on a 0.16 mmol scale, utilising 4-amino-N-(4-dimethylaminocyclohexyl)-2-fluoro-5- methoxy-benzamide (single undefined isomer) (Intermediate 248; 50 mg, 0.16 mmol) heating by microwave irradiation at 150 C for 1 hour, as a white solid (30 mg, 32%).
25 1H NMR (400.132 MHz, DMSOd6) δ 1.11 (6H, s), 1.63 (14H, m), 1.90 (2H, m), 2.07 (IH, m), 2.17 (6H, s), 3.20 (3H, s), 3.40 (2H, s), 3.92 (3H, s), 3.94 (IH, m), 5.19 (IH, m), 7.19 (IH, d), 7.71 (IH, m), 7.77 (IH, s), 8.02 (IH, s), 8.31 (IH, d); MS m/z 582 [M+H]+.
Example 373:
30 4- [(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,l 1-tetrazabicy clo [5.4.0] undeca-7,9,11-trien- 10-yl)amino]-N-(4-dimethylaminocyclohexyl)-2-fluoro-5-methoxy-benzamide The title compound was prepared by an analogous method to the preparation of Example 350, on a 0.16 mmol scale, utilising 4-ammo-N-(4-dimethylaminocyclohexyl)-2-fluoro-5- methoxy-benzamide (single undefined isomer) (Intermediate 249; 50 mg, 0.16 mmol) heating by microwave irradiation at 150 0C for 1 hour, as a white solid (50 mg, 54%). s 1HNMR (400.132 MHz, DMSOd6) δ 1.11 (6H, s), 1.30 (4H, m), 1.75 (12H,m), 2.12 (IH, m), 2.18 (6H, s), 3.20 (3H, s), 3.40 (2H, s), 3.69 (IH, m), 3.92 (3H, s), 5.18 (IH, m), 7.19 (IH, d), 7.73 (IH, m), 7.76 (IH, s), 8.02 (IH, s), 8.30 (IH, d); MS m/z 582 [M+H]+.
Example 374; o N-[4-(azetidin-l-yl)cyclohexyl]-4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,ll- tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10-yl)amino]-3-methoxy-benzainide
The title compound was prepared by an analogous method to the preparation of Example 346, utilising 10-chloro-2-cyclopentyl-4,4-dimethyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12- trien-5-one (Intermediate 127; 75 mg, 0.17 mmol) and 4-(azetidin-l-yl)cyclohexan-l -amines (Intermediate 226; 39 mg, 0.25 mmol) as an off white solid (35 mg, 36%) assigned as the trans isomer.
1HNMR (400.132 MHz, DMSOd6) δ 0.92 - 1.00 (2H, m), 1.10 (6H, s), 1.29 - 1.39 (2H, m), 1.58 - 1.94 (15H, m), 3.07 (4H, t), 3.19 (3H, s), 3.38 (2H, s), 3.67 - 3.76 (IH, m), 3.94 (3H, s), 5.19 (IH, quintet), 7.45 - 7.48 (2H, m), 7.67 (IH, s), 7.99 (IH, s), 8.00 (IH5 d), 8.36 (IH, d);0 MS m/z 576 [M+H]+.
5 Example 375;
N-[4-(azetidin-l-yl)cyclohexyl]-4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,ll- tetrazabicyclo[5.4.0]undeca-7,9,H-trien-10-yl)amino]-3-methoxy-benzamide
The title compound was isolated from the reaction above to produce Example 374, as an off white solid (35 mg, 36%) assigned as the cis isomer. o 1H NMR (400.132 MHz, DMSOd6) δ 1.03 (6H, s), 1.24 - 1.31 (2H, m), 1.37 - 1.42 (2H, m), 1.50 - 1.70 (1OH, m), 1.78 - 1.86 (4H, m), 2.12 - 2.16 (IH, m), 2.96 - 3.04 (4H, m), 3.12 (3H, s), 3.31 (2H, s), 3.69 - 3.79 (IH, m), 3.87 (3H, s), 5.12 (IH, quintet), 7.42 - 7.46 (2H5 m), 7.58 (IH, s), 7.91 (IH, s), 7.96 (IH, d), 8.28 (IH, d); MS m/z 576 [M+H]+.
Example 376;
5 4-[(2-cyclopentyl-4,4-diethyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicycIo[5.4.0]undeca-7,9,ll- trien-10-yl)amino]-N-(2,2-dimethyl-3-pyrroIidin-l-yl-propyl)-3-methoxy-benzamide
10-chloro-2-cyclopentyl-4,4-diethyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 - trien-5-one (Intermediate 250; 111 mg, 0.33 mmol), p-toluenesulphonic acid monohydrate (155 mg, 0.81 mmol) and 4-amino-N-(2,2-dimethyl-3-pyrrolidin-l-yl-propyl)-3-methoxy-
I0 benzamide (Intermediate 206; 100 mg, 0.33 mmol) were added to 4-methyl-2-pentanol (7 niL). The reaction was heated at 120 0C over the weekend. The sample was transferred to an SCX cartridge (10 g) pre-wet with methanol, then washed with methanol and eluted with methanolic ammonia. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title is compound as a white solid (55 mg, 27%).
1HNMR (400.132 MHz, CDCl3) δ 0.84 (t, 6H), 1.01 (s, 6H), 1.80 - 1.48 (m, 14H), 2.02 - 1.94 (m, 2H), 2.56 (s, 2H), 2.69 (s, 4H), 3.28 (s, 3H), 3.39 (d, 2H), 3.42 (s, 2H), 3.98 (s, 3H), 5.42 (quintet, IH), 7.20 (d, IH), 7.55 (s5 IH), 7.61 (s, IH), 7.84 (s, IH), 8.43 (d, IH), 9.14 (s, IH); MS m/z 606 [M+H]+.
20
25 Example 377:
4-[(2-cyclopentyl-4,4-diethyI-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-10-yI)amino]-3-methoxy-N-[(lS,5R)-9-methyI-9-azabicyclo[3.3.1]non-7- yl] benzamide
10-chloro-2-cyclopentyl-4,4-diethyl-6-methyl-2,6,9, 11 -tetrazabicyclo [5.4.0]undeca-7,9, 11- 30 trien-5-one (Intermediate 250; 100 mg, 0.30 mmol), p-toluenesulphonic acid monohydrate (142 mg, 0.75 mmol) and 4-amino-3-methoxy-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non- 3-yl]benzamide (Intermediate 202; 91 mg, 0.30 mmol) were added to 4-methyl-2-pentanol (7 mL). The reaction was heated at 120 0C over the weekend. The sample was transferred to an SCX cartridge (10 g) pre-wet with methanol, then washed with methanol and eluted with methanolic ammonia. Product containing fractions were combined and evaporated and the
5 resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (80 mg, 44%)
1H NMR (400.132 MHz, CDCl3) 6 0.84 (t, 6H), 1.09 - 1.07 (m, 2H), 1.44 - 1.38 (m, 2H), 1.63 - 1.48 (m, 6H), 1.80 - 1.66 (m, 6H), 2.03 - 1.94 (m, 3H), 2.56 - 2.49 (m, 4H), 3.14 - 3.11 (m, 2H), 3.28 (s, 3H), 3.42 (s, 2H), 3.97 (s, 3H), 4.58 - 4.47 (m, IH), 5.42 - 5.32 (m, IH), 5.94 (d, io IH), 7.25 (dd, IH), 7.25 (d, IH), 7.25 (d, IH), 7.44 (d, IH), 7.60 (s, IH), 7.83 (s, IH), 8.47 (d, IH); MS m/z 604 [M+H]+.
Example 378:
4- [(2-cy clopentyl-4,4-diethyI-6-methyl-5-oxo-2,6,9,l l-tetrazabicyclo [5.4.0] undeca- is 8,10,12-trien-10-yl)amino]-2-fluoro-5-methoxy-N-[(lS,5R)-9-methyl-9- azabicyclo[3.3.1]non-7-yl]benzamide
The title compound was prepared by an analogous method to the preparation of Example 377, utilising 4-amino-2-fluoro-5-methoxy-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3. l]non-7- yljbenzamide (Intermediate 204; 96 mg, 0.30 mmol), as a white solid (25 mg, 13%). 20 1H NMR (400.132 MHz, CDC13) δ 0.84 (t, 6H), 1.07 - 1.04 (m, 2H), 1.36 - 1.30 (m, 2H), 1.63 - 1.49 (m, 6H), 1.82 - 1.66 (m, 7H), 2.04 - 1.91 (m, 4H), 2.57 - 2.51 (m, 4H), 3.11 - 3.08 (m, 2H), 3.29 (s, 3H), 3.44 (s, 2H), 3.95 (s, 3H), 4.58 - 4.46 (m, IH), 5.36 (quintet, IH), 6.55 (dd, IH), 7.57 (d, IH), 7.67 (s, IH), 7.85 (s, IH), 8.37 (d, IH); MS m/z 622 [M+H]+.
25 Example 379:
4-[(2-cyclopentyl-4,4-diethyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll- trien-10-yl)amino]-N-(l-ethyl-4-piperidyl)-2-fluoro-5-methoxy-benzamide
The title compound was prepared by an analogous method to the preparation of Example 377, utilising 4-amino-N-(l-ethyl-4-piperidyl)-2-fluoro-5-methoxy-benzamide (Intermediate 205; 30 89 mg, 0.30 mmol), as a white solid (35 mg, 20%). 1H NMR (400.132 MHz, CDCl3) δ 0.84 (t, 6H), 1.10 (t, 3H), 1.62 - 1.49 (m, 6H), 1.81 - 1.65 (m, 6H), 2.08 - 1.98 (m, 4H), 2.19 - 2.13 (m, 2H), 2.43 (q, 2H), 2.89 - 2.86 (m, 2H), 3.29 (s, 3H), 3.44 (s, 2H), 3.95 (s, 3H), 4.09 - 3.99 (m, IH), 5.34 (quintet, IH), 6.68 (dd, IH), 7.55 (d, IH), 7.67 (s, IH), 7.84 (s, IH), 8.37 (d, IH); MS m/z 596 [M+H]+.
Example 380:
4-[(2-cyclopentyl-4,4-diethyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll- trien-10-yl)amino]-3-methoxy-N-(l-methyl-4-piperidyl)benzamide
The title compound was prepared by an analogous method to the preparation of Example 377, utilising 4-amino-3-methoxy-N-(l-methyl-4-piperidyl)benzamide (WO06/018220; 79 mg, 0.30 mmol), as a white solid (30 mg, 18%).
1H NMR (400.132 MHz, CDCl3) δ 0.84 (t, 6H), 1.64 - 1.48 (m, 6H), 1.80 - 1.66 (m, 6H), 2.00 - 1.92 (m, 2H), 2.07 - 2.05 (m, 2H), 2.20 - 2.14 (m, 2H), 2.31 (s, 3H), 2.84 - 2.81 (m, 2H), 3.28 (s, 3H), 3.42 (s, 2H), 4.03 - 3.92 (m, 4H), 5.38 (quintet, IH), 5.89 (d, IH), 7.22 (dd, IH), 7.41 (d, IH), 7.59 (s, IH), 7.84 (s, IH), 8.48 (d, IH); MS m/z 564 [M+H]+.
Example 381:
4-[(2-cycIopentyl-4,4-diethyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll- trien-10-yl)amino]-N-(l-ethyl-4-piperidyl)-3-methoxy-benzamide The title compound was prepared by an analogous method to the preparation of Example 377, utilising 4-amino-N-(l-ethyl-4-piperidyl)-3-methoxy-benzamide (Intermediate 190; 83 mg, 0.30 mmol), as a white solid (90 mg, 52%).
1HNMR (400.132 MHz, CDCl3) δ 0.77 (t, 6H), 1.03 (t, 3H), 1.56 - 1.41 (m, 6H), 1.73 - 1.59 (m, 6H), 1.95 - 1.87 (m, 2H), 2.10 - 1.98 (m, 4H), 2.37 (q, 2H), 2.86 - 2.83 (m, 2H), 3.22 (s, 3H), 3.35 (s, 2H), 3.98 - 3.91 (m, 4H), 5.31 (quintet, IH), 5.82 (d, IH), 7.15 (dd, IH), 7.34 (d, IH), 7.52 (s, IH), 7.77 (s, IH), 8.41 (d, IH); MS m/z 578 [M+H]+.
Example 382:
3-chloro-4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6l,8',9'-tetrahydrospiro[cyclopropane- l,7'-pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-N-(l-ethylpiperidin-4-yl)benzamide 2'-chloro-9'-cyclopentyl-5'-methyl-8',9'-diliydrospiro[cyclopropane-l,7l-pyrimido[5,4- b][l,4]diazepin]-6'(5Η)-one (Intermediate 130; 108 mg, 0.35 mmol) 4-amino-3-chloro-N-(l- ethyl-4-piperidyl)benzamide (Intermediate 212; 118 mg, 0.42 mmol), and p-toluenesulphonic acid monohydrate (133 mg, 0.7 mmol) were combined in 4-methyl-2-pentanol (4 mL) and heated by microwave irradiation at 160 °C for 1 hour. The reaction mixture was loaded onto to an SCX cartridge (10 g) pre-wet with methanol, then washed with methanol and eluted with methanolic ammonia. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (38 mg, 20%). 1HNMR (400.13 MHz, DMSOd6) δ 0.66 - 0.69 (2H, m), 0.90 - 0.93 (2H, m), 1.00 (3H, t), 1.41 - 1.70 (8H, m), 1.77 - 1.85 (4H, m), 1.90 - 1.96 (2H, m), 2.32 (2H, q), 2.88 (2H, d), 3.18 (3H, s), 3.47 (2H, s), 3.72 - 3.76 (IH, m), 4.74 - 4.82 (IH, m), 7.79 (IH, dd), 7.98 - 8.00 (2H, m), 8.08 (IH, s), 8.20 (IH, d), 8.30 - 8.34 (IH, m) MS m/z 552 [M+H]+.
Example 383;
4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-N-(l-ethyl-4-piperidyl)-3-methoxy- benzamide 2'-chloro-9'-cyclopentyl-5l-methyl-8',9'-dihydrospiro[cyclopropane-l,7'-pyrimido[5,4- b][l,4]diazeρin]-6'(5Η)-one (Intermediate 130; 100 mg, 0.33 mmol), 4-amino-N-(l-ethyl-4- piperidyl)-3-methoxy-benzamide (Intermediate 190; 91 mg, 0.33 mmol) and p- toluenesulphonic acid monohydrate (156 mg, 0.81 mmol) were heated at 140 0C in 4-methyl- 2-pentanol (4 mL) for 2 hours. The reaction mixture was loaded onto to an SCX-3 cartridge (10 g) pre-wet with methanol, then washed with methanol and eluted with 2% 7N ammonia/methanol. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (89 mg, 50%). 1H NMR (399.9 MHz, DMSOd6) δθ.67 - 0.69 (2H, t), 0.90 - 0.93 (2H, t), 1.01 (3H, t), 1.51 - 1.51 (IH, m), 1.52 (IH, d), 1.56 - 1.62 (4H, m), 1.68 (IH, s), 1.70 (IH, d), 1.78 (IH, d), 1.81 (IH, s), 1.93 (4H, d), 2.33 (2H, q), 2.90 (2H, d), 3.19 (3H, s), 3.49 (2H, s), 3.61 - 3.65 (IH, m), 3.96 (3H, s), 4.86 (IH, m), 7.47 (IH, t), 7.50 (IH, d), 7.68 (IH, s), 8.00 (IH, s), 8.07 (IH, d), 8.40 (IH, d); MS m/z 549 [M+H]+.
Example 384; 4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-3-methoxy-N-(2-pyrrolidin-l- ylethyl)benzamide
The title compound was prepared by an analogous method to the preparation of Example 383, utilising 4-amino-3-methoxy-N-(2-pyrrolidin-l-ylethyl)benzamide (Intermediate 192; 86 mg, 0.30 mmol), as a white solid (20 mg, 11%).
1H NMR (399.9 MHz, DMSO-d6) δθ.67 - 0.69 (2H, t), 0.90 - 0.93 (2H, t), 1.52 (2H, d), 1.61 (2H, t), 1.65 - 1.71 (7H, m), 1.89 - 1.92 (3H, m), 2.58 (2H, t), 3.18 (3H, s), 3.20 (2H, t) - found under water, 3.39 (2H, q), 3.49 (2H, s), 3.95 (3H, s), 4.86 (IH, s), 7.46 (IH, d), 7.48 - 7.51 (IH, m), 7.69 (IH, s), 7.99 (IH, s), 8.31 (IH, t), 8.40 - 8.42 (IH, m); MS m/z 535 [M+H]+.
Example 385:
4-(9 ' -cy clopentyl-5 ' -methy 1-6 ' -oxo-5 ' ,6 ' ,8 ' ,9 ' -tetrahy drospiro [cyclopropane- 1 ,7' - pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-3-methoxy-N-[(lS,5R)-9-methyl-9- azabicy clo [3.3.1] non-7-yl] benzamide
The title compound was prepared by an analogous method to the preparation of Example 383, utilising 4-amino-3 -methoxy-N- [( 1 S,5R)-9-methyl-9-azabicyclo [3.3.1 ]non-3 -yl]benzamide (Intermediate 202; 99 mg, 0.30 mmol), as a white solid (114 mg, 61%). 1H NMR (399.9 MHz, DMSO-d6) δθ.67 - 0.70 (2H, t), 0.90 - 0.93 (2H, t), 0.95 (2H, s), 1.42 - 1.48 (2H, m), 1.43 - 1.49 (2H, m), 1.54 (2H, t), 1.60 - 1.63 (IH, m), 1.68 (IH, s), 1.70 (IH, d), 1.89 - 1.97 (4H, m), 2.08 (IH, d), 2.16 - 2.24 (2H, m), 2.42 (3H, s), 2.98 - 3.01 (2H, d), 3.18 (3H, s), 3.49 (2H, s), 3.97 (3H, s), 4.34 (IH, m), 4.87 (IH, m), 7.47 (IH, d), 7.50 (IH, t), 7.68 (IH, s), 7.92 (IH, d), 8.00 (IH, s), 8.40 (IH, d); MS m/z 575 [M+H]+.
Example 386: 4-(9'-cyclopentyl-5'-methyI-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-N-(3-dimethylamino-2,2-dimethyl-propyl)-3- methoxy-benzamide
The title compound was prepared by an analogous method to the preparation of Example 383, utilising 4-amino-N-(3-dimethylamino-2,2-dimethyl-propyl)-3-methoxy-benzamide (Intermediate 22; 92 mg, 0.30 mmol), as a white solid (89 mg, 50%).
1HNMR (399.9 MHz, DMSO-d6) δθ.67 - 0.69 (2H, m), 0.89 (6H, s), 0.90 - 0.93 (2H, t), 1.51 (IH, d), 1.54 (IH, s), 1.58 (IH, d), 1.61 - 1.62 (IH, m), 1.69 (2H, d), 1.90 (2H, d), 2.21 (2H, s), 2.29 (6H, s), 3.19 (3H, s), 3.21 (2H, d), 3.48 (2H, s), 3.96 (3H, s), 4.86 (IH, m), 7.41 - 7.43 (IH, m), 7.47 (IH, d), 7.70 (IH, s), 7.99 (IH, s), 8.41 (IH, d), 8.44 (IH, t); MS m/z 551 [M+H]+.
Example 387:
4-(9 ' -cy clopenty 1-5 ' -methy 1-6 ' -oxo-5 ' ,6 ' ,8 ' ,9 ' -tetrahy drospiro [cyclopropane- 1 ,7' - pyrimido [5,4-b] [1,4] diazepine]-2'-ylamino)-N-(2-dimethylaminoethyl)-3-methoxy- benzamide
The title compound was prepared by an analogous method to the preparation of Example 383, utilising 4-amino-N-(2-dimethylaminoethyl)-3-methoxy-benzamide (Intermediate 194; 78 mg, 0.30 mmol), as a white solid (82 mg, 50%). 1HNMR (399.9 MHz, DMSO-d6) δθ.67 - 0.70 (2H, t), 0.92 (2H, t), 1.51 (IH, d), 1.55 (IH, d), 1.60 - 1.63 (2H, m), 1.70 (2H, t), 1.90 (2H, s), 2.19 (6H, s), 2.41 (2H, t), 3.18 (3H, s), 3.37 (2H, q), 3.49 (2H, s), 3.95 (3H, s), 4.86 (IH, m), 7.46 (IH, d), 7.48 - 7.51 (IH, d), 7.69 (IH, s), 7.99 (IH, d), 8.27 (IH, t), 8.39 - 8.42 (IH, m); MS m/z 509 [M+H]+.
Example 388:
4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7' pyrimido[5,4-b][l,4]diazepine]-2'-yIamino)-3-fluoro-N-[(lS,5R)-9-methyl-9- azabicyclo[3.3.1]non-7-yl]benzamide 2'-chloro-9'-cyclopentyl-5'-methyl-8',9l-dihydrospiro[cyclopropane-l,7l-pyrimido[5,4- b][l,4]diazepin]-6'(5'H)-one (Intermediate 130; 108 mg, 0.35 mmol) and 4-amino-3-fluoro-N- (9-methyl-9-azabicyclo[3.3.1]non-7-yl)benzamide (Intermediate 162; 102 mg, 0.35 mmol) were combined with p-toluenesulphonic acid monohydrate (167 mg, 0.88 mmol) in 4-methyl- 2-pentanol (2 mL) and heated by microwave irradiation for 25 minutes at 160 0C The cooled reaction mixture was diluted with methanol (10 mL) and loaded onto an SCX-3 cartridge (5 g) pre-wet with methanol. The cartridge was washed with methanol (2 x 5 mL) and eluted with 7 N methanolic ammonia (10 mL). Product containing fractions were evaporated and the resultant material purified by base modified reverse phase preparative HPLC to give the title compound as a white solid (54 mg, 28 %).
1H NMR (400 MHz, DMSOd6) δ 0.65 (t, 2H), 0.9 (m, 4H), 1.5 (m. 7H), 1.65 (m, 2H), 1.85 (m, 4H), 2.05 (m, IH), 2.2 (m, 2H), 2.4 (s, 3H), 3.0 (d, 2H), 3.2 (s, 3H), 3.45 (s, 2H), 4.3 (m, IH), 4.8 ( m, IH) 7.65 (m, IH), 7.75 (m, IH), 7.95 (m, 2H), 8.15 (t, IH), 8.65 (s, IH); MS m/z 562 [M+H]+.
Example 389;
5-chloro-4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane- l,7'-pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-2-fluoro-N-(l-methyl-4- piperidyl)benzamide 2'-chloro-9'-cyclopentyl-5'-methyl-8',9'-dihydrospiro[cyclopropane-l,7'-pyrimido[5,4- b][l,4]diazepin]-6'(5Η)-one (Intermediate 130; 85 mg, 0.30 mmol), 4-amino-5-chloro-2- fluoro-N-(l-methyl-4-piperidyl)benzamide (Intermediate 173; 101 mg, 0.33 mmol) and XANTPHOS (16 mg, 0.03 mmol) were dissolved in 1,4-dioxane (7.5 mL). Caesium carbonate (210 mg, 0.59 mmol) was added and the system purged with a stream of nitrogen for 15 minutes before tris(dibenzylideneacetone) palladium (II) (17 mg, 0.02 mmol) was added. The apparatus was evacuated and backfilled with nitrogen (x3) and then heated at 100 °C for 3 hours. The mixture was cooled, filtered and the filtrate absorbed on to an SCX column, which was subsequently washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (100 mg, 60%). 1HNMR (399.9 MHz, DMSOd6) δθ.69 - 0.71 (2H, m), 0.92 - 0.95 (2H, m), 1.51 - 1.64 (6H, m), 1.66 - 1.71 (2H, m), 1.77 - 1.80 (2H, m), 1.85 - 1.99 (4H, m), 2.17 (3H, s), 2.74 (2H, d), 3.19 (3H, s), 3.50 (2H, s), 3.66 - 3.73 (IH5 m), 4.80 - 4.88 (IH, m), 7.68 (IH, d), 8.04 - 8.09 (3H, m), 8.35 - 8.39 (IH, m); MS m/z 556 [M+H]+.
Example 390:
3-chloro-4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane- l,7'-pyrimido [5,4-b] [1,4] diazepine]-2'-ylamino)-N-(2-dimethylaminoethyl)benzamide
2'-chloro-9l-cyclopentyl-5'-methyl-8',9l-dihydrospiro[cyclopropane-l,7l-pyrimido[5,4- b][l,4]diazepin]-6'(5Η)-one (Intermediate 130; 100 mg, 0.33 mmol) and 4-amino-3-chloro- N-(2-dimethylaminoethyl)benzamide (Intermediate 213; 89 mg, 0.37 mmol) were dissolved in 1,4 dioxane (4 mL) and caesium carbonate (234 mg, 0.72 mmol) was added. The reaction mixture was sparged with nitrogen for 15 minutes prior to addition of tris- dibenzylideneacetonedipalladium (II) (19 mg, 0.02 mmol) followed by XANTPHOS (19 mg,s 0.03 mmol). The reaction mixture was heated at 100 0C overnight, cooled to room temperature and diluted with DCM (20 mL). The resultant mixture was filtered and the filtrate loaded onto an SCX-3 (5 g) cartridge. The cartridge was washed through with methanol (50 mL) and then eluted with 2M ammonia in methanol (50 mL). Evaporation of the ammoniacal fraction afforded an amber gum which was purified by acid modified reverse0 phase preparative HPLC. The resultant material was dissolved in MeOH/Water and poured onto an SCX-3 cartridge (2 g) and cartridge which was then washed with methanol and eluted with 2M ammonia in methanol, and the ammoniacal solution evaporated to yield the title compound as a solid (7 mg, 3%). 1H NMR (400.132 MHz, DMSO-d6) δ 0.67 (m, 2H), 0.91 (m, 2H), 1.41 - 1.69 (m, 6H), 1.83S (m, 2H), 2.19 (s, 6H), 2.41 (t, 2H), 3.18 (s, 3H), 3.35 (m, 2H), 3.47 (s, 2H), 4.78 (m, IH), 7.78 (m, IH), 7.97 (d, IH), 7.99 (s, IH), 8.10 (s, IH), 8.32 (d, IH), 8.37 (t, IH); MS m/z 512 [M+H]+.
Example 391: 0 3-chloro-4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane- l,7'-pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-N-(2-pyrrolidin-l-ylethyl)benzamide The title compound was prepared by an analogous method to the preparation of Example 390, utilising 4-amino-3-chloro-N-(2-pyrrolidin-l-ylethyl)benzamide (Intermediate 215; 97 mg, 0.36 mmol), as a white solid (7 mg, 3%). 1H NMR (400.132 MHz, DMSOd6) δ 0.67 (m, 2H), 0.91 (m, 2H), 1.50 (m, 4H), 1.67 (m, 6H), 1.83 (m, 2H), 2.58 (t, 2H), 3.18 (s, 3H), 3.38 (m, 2H), 3.47 (s, 2H), 4.78 (m, IH), 7.79 (m, IH), 7.97 (d, IH), 7.99 (s, IH), 8.10 (s, IH), 8.32 (d, IH), 8.42 (t, IH); MS m/z 538 [M+H]+.
Example 392:
3-chloro-4-(9 ' -cy clopenty 1-5' -methy 1-6 ' -oxo-5' ,6 ' ,8 ' ,9 ' -tetrahy drospiro [cy clopropane- l,7'-pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-N-(3-dimethylamino-2,2-dimethyl- propyl)benzamide
The title compound was prepared by an analogous method to the preparation of Example 390, utilising 4-amino-3-chloro-N-(3-dimethylamino-2,2-dimethyl-propyl)benzamide (Intermediate 107; 103 mg, 0.36 mmol), as a white solid (4 mg, 2%). 1HNMR (400.132 MHz, DMSOd6) δ 0.67 (m, 2H), 0.88 (s, 6H), 0.91 (m, 2H), 1.41 - 1.70 (m, 6H), 1.83 (m, 2H), 2.18 (s, 2H)5 2.27 (s, 6H), 3.19 (m, 5H), 3.46 (s, 2H), 4.77 (m, IH), 7.75 (m, IH), 7.94 (d, IH), 7.99 (s, IH), 8.13 (s, IH), 8.29 (d, IH), 8.46 (t, IH); MS m/z 554 [M+H]+.
Example 393:
5-chloro-4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane- l,7'-pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-N-(l-ethyl-4-piperidyl)-2-fluoro- benzamide
The title compound was prepared by an analogous method to the preparation of Example 389, utilising 4-amino-5-chloro-N-(l-ethyl-4-piperidyl)-2-fluoro-benzamide (Intermediate 174; 90 mg, 0.30 mmol), as a white solid (102mg, 60%). 1H NMR (399.9 MHz, DMSOd6) δ 0.69 - 0.71 (2H, m), 0.92 - 0.95 (2H, m), 1.00 (3H, t), 1.49 - 2.01 (14H, m), 2.32 (2H, q), 2.84 (2H, d), 3.19 (3H, s), 3.50 (2H, s), 3.68 - 3.74 (IH, m), 4.82 - 4.88 (IH5 m), 7.68 (IH, d), 8.04 - 8.08 (3H, m), 8.35 - 8.39 (IH, m); MS m/z 570 [M+H]+.
Example 394: 5-chloro-4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane- l,7'-pyrimido[5,4-b][l,4]diazepine]-2'-yIamino)-N-(4-dimethylaminocyclohexyl)-2- fluoro-benzamide
The title compound was prepared by an analogous method to the preparation of Example 389, utilising 4-amino-5-chloro-N-(4-dimethylaminocyclohexyl)-2-fluoro-benzamide (Intermediate 175; 94 mg, 0.30 mmol), as a white solid (65 mg, 37%).
1H NMR (399.9 MHz, DMSO-d6) δ 0.69 - 0.71 (2H, m), 0.92 - 0.95 (2H, m), 1.340 - 1.35(2H, m), 1.49 - 1.94 (14H, m), 2.25 - 2.30 (7H, m), 3.19 (3H, s), 3.50 (2H5 s), 3.67 - 3.71 and 3.91 - 3.97 (each 0.5H. m), 4.80 - 4.88 (IH, m), 7.65 - 7.68 (IH5 m), 8.01 - 8.04 (2H5 m), 8.08 (IH5 d), 8.34 - 8.38 (IH, m); MS m/z 584 [M+H]+.
Example 395:
4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-N-(l-ethyl-4-piperidyl)-2,5-difluoro- benzamide 2l-chloro-9'-cyclopentyl-5'-methyl-8',9'-dihydrospiro[cycloprόpane-l57'-pyrimido[554- b][l,4]diazepin]-6'(5Η)-one (Intermediate 130; 100 mg, 0.33 mmol), 4-amino-N-(l-ethyl-4- piperidyl)-255-difluoro-benzamide (Intermediate 235; 102 mg, 0.36 mmol) and caesium carbonate (213 mg5 0.65 mmol) added to dioxane (5 mL) and the suspension bubbled with nitrogen for 10 minutes, tris-dibenzylideneacetonedipalladium (II) (18 mg, 0.02 mmol) and XANTPHOS (17 mg5 0.03 mmol)were added and the mixture heated at 110 °C overnight. The mixture was filtered, and the filtrate loaded onto to an SCX-3 cartridge (10 g) pre-wet with methanol, then washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a light orange gum (99 mg, 55%). 1H NMR (399.9 MHz, DMSOd6) δθ.69 (2H, t), 0.93 (2H, t), 1.05 (3H, t), 1.52 - 1.58 (4H, m), 1.61 (2H5 m), 1.65 - 1.67 (2h, m), 1.80 (2H, d), 1.85 (2H, d), 2.10 - 2.12 (2H, t), 2.41 (2h, q), 2.91 (2H, d), 3.17 (3H, s), 3.45 (2H, s), 3.75 (IH, m), 4.80 - 4.85 (IH, m), 7.40 (Ih, dd), 7.95 (Ih, d), 8.19 (IH, s), 8.25 (IH, dd), 8.84 (Ih, s); MS m/z 554 [M+H]+.
Example 396:
4-(9 ' -cy clopenty 1-5 '-methy 1-6 ' -oxo-5 ' ,6 ' ,8 ' ,9 ' -tetrahy drospiro [cyclopropane- 1,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-2,5-difluoro-N-(l-methyl-4- piperidyl)benzamide The title compound was prepared by an analogous method to the preparation of Example 395, utilising 4-amino-2,5-difluoro-N-(l-methyl-4-piperidyl)benzamide (Intermediate 59; 97 mg, 0.36 mmol), as an off-white solid (122 mg, 69%)
1H NMR (399.9 MHz, DMSOd6) δθ.69 (2H, t), 0.93 (2H, t), 1.05 (3H, t), 1.52 - 1.58 (4H, m), 1.61 (2H, m), 1.65 - 1.67 (2h, m), 1.80 (2H, d), 1.85 (2H, d), 2.10 - 2.12 (2H, t), 2.22 (3H, s), 2.91 (2H, d), 3.17 (3H, s), 3.45 (2H, s), 3.75 (IH, m), 4.80 - 4.85 (IH, m), 7.40 (Ih, dd), 7.95 (Ih, d), 8.19 (IH, s), 8.25 (IH, dd), 8.84 (Ih, s); MS m/z 540 [M+H]+.
Example 397:
4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-yIamino)-2,5-difluoro-N-(2-pyrrolidin-l- ylethyl)benzamide
The title compound was prepared by an analogous method to the preparation of Example 395, utilising 4-amino-2,5-difluoro-N-(2-pyrrolidin-l-ylethyl)benzamide (Intermediate 230; 97 mg, 0.36 mmol), as a pale yellow gum (121 mg, 69%). 1H NMR (399.9 MHz, DMSO-d6) δθ.69 (2H, t), 0.93 (2H, t), 1.48 - 1.55 (4H, m), 1.58 - 1.64 (6H, m), 1.85 - 1.92 (2H, m), 2.57 (4H, m), 2.68 (2H, t), 3.17 (3H, s), 3.40 (2H, m), 3.45 (2H, s), 4.80 - 4.85 (IH, m), 7.40 (Ih, dd), 7.95 (Ih, d), 8.19 (IH, s), 8.25 (IH, dd), 8.84 (Ih, s); MS m/z 540 [M+H]+.
Example 398: 4-(9'-cycIopentyI-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-2-fluoro-5-methoxy-N-(2-pyrrolidin-l- ylethyl)benzamide
2'-chloro-9'-cyclopentyl-5'-metliyl-8',9'-diliydrospiro[cyclopropane-l,7'-pyrimido[5,4- b][l,4]diazepin]-6'(5'H)-one (Intermediate 130; 80 mg, 0.26 mmol), 4-amino-3-methoxy-N- (2-pyrrolidin-l-ylethyl)benzamide (Intermediate 192; 73 mg, 0.26 mmol) and p- toluenesulphonic acid monohydrate (124 mg, 0.65 mmol) were combined in 4-methyl-2- pentanol (3 mL) and heated at 100 °C for 18 hours. The cooled reaction mixture was loaded on to an SCX-2 column (5 g) pre-wet with MeOH (2 column volumes), flushed with MeOH (2 column volumes) then eluted with 2M ammonia in MeOH. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (85 mg, 59%) 1H NMR (399.902 MHz, CDCl3) δθ.62 (m, 2H), 1.11 (m, 2H), 1.46 (m, 2H), 1.72 (m, 4H), 1.79 (m, 4H), 2.03 (m, 2H), 2.58 (m, 4H), 2.72 (m, 2H), 3.29 (s, 3H)5 3.47 (s, 2H), 3.60 (m, 2H), 3.95 (s, 3H), 4.96 (m, IH), 7.31 (m, IH), 7.56 (d, IH), 7.70 (s, IH), 7.87 (s, IH), 8.41 (d, IH); MS m/z 552 [M+H]+.
Example 399:
4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-2-fluoro-5-methoxy-N-[(3R)-l- methylpyrrolidin-3-yl] benzamide
2'-chloro-9'-cyclopentyl-5'-methyl-8',9'-dihydrospiro[cyclopropane-l,7l-pyrimido[5,4- b][l,4]diazeρin]-6'(5Η)-one (Intermediate 130; 100 mg, 0.32 mmol), 4-amino-2-fluoro-5- methoxy-N-[(3R)-l-methylpyrrolidin-3-yl]benzamide (Intermediate 182; 87 mg, 0.32 mmol) and 4-toluenesulphonic acid monohydrate (154 mg, 0.81 mmol) were heated in 4-methyl-2- pentanol (3 mL) at 140 0C for 3 hours. The mixture was cooled and absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (80 mg, 46%). 1H NMR (399.9 MHz5 DMSO-d6) δ 0.67 - 0.72 (2H, m), 0.91 - 0.96 (2H, m), 1.53 - 1.75 (7H, m), 1.87 - 1.96 (2H, m), 2.13 - 2.22 (IH5 m), 2.26 (3H5 s), 2.34 - 2.45 (2H5 m), 2.57 - 2.64 (IH, m), 2.66 - 2.70 (IH, m), 3.18 (3H, s), 3.50 (2H, s), 3.93 (3H, s), 4.35 - 4.43 (IH, m), 4.83 - 4.92 (IH, m), 7.22 (IH, d), 7.77 (IH, s), 7.98 - 8.00 (IH, m), 8.03 (IH5 s), 8.35 (IH, d); MS m/z 539 [M+H]+.
Example 400;
4-(9'-cycIopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-2,5-difluoro-N-[(3R)-l-methylpyrrolidin-3- yljbenzamide
2'-chloro-9'-cyclopentyl-5'-methyl-8',9'-dihydrospiro[cyclopropane-l,7'-pyrimido[5,4- b][l,4]diazepin]-6'(5Η)-one (Intermediate 130; 109 mg, 0.36 mmol), aniline (Intermediate 229; 83 mg, 0.324 mmol), and caesium carbonate (211 mg, 0.648 mmol) added to dioxane (3 mL) and the suspension bubbled with nitrogen for 10 minutes. Tris- dibenzylideneacetonedipalladium (II) (11 mg, 0.02 mmol) and XANTPHOS (17 mg, 0.03 mmol) were added and the mixture heated to 100 °C for 16 hours. The reaction mixture was cooled to room temperature filtered, and the filter cake washed with DCM and the filtrate evaporated. The residue was dissolved in DCM and purified on a silica column eluting with a gradient of 0 - 5% 2M ammonia in MeOH / DCM over 30 column volumes. Product containing fractions were combined and evaporated and the residue purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (95 mg, 56%). 1H NMR (399.902 MHz, CDCl3) δθ.64 (m, 2H), 1.12 (m, 2H), 1.46 (m, 2H), 1.74 (m, 5H), 2.02 (m, 2H), 2.29 (m, IH), 2.42 (m, 4H), 2.67 (m, 2H), 2.90 (m, IH), 3.29 (s, 3H), 3.48 (s, 2H), 4.65 (m, IH), 4.93 (m, IH), 6.96 (m, IH), 7.28 (m, IH), 7.80 (m, IH), 7.88 (s, IH), 8.46 (m, IH); MS m/z 526 [M+H]+.
Example 401;
4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-N-(2,2-dimethyI-3-pyrrolidin-l-yl-propyl)-3- methoxy-benzamide
2'-chloro-9'-cyclopentyl-5'-methyl-8',9'-dihydrospiro[cyclopropane-l,7'-pyrimido[5,4- b][l,4]diazepin]-6'(5'H)-one (Intermediate 130; 101 mg, 0.33 mmol), p-toluenesulphonic acid monohydrate (155 mg, 0.81 mmol) and 4-amino-N-(2,2-dimethyl-3-pyrrolidin-l-yl-propyl)- 3-niethoxy-benzamide (Intermediate 206; 100 mg, 0.33 mmol) were added to 4-methyl-2- pentanol (7 inL). The reaction was heated at 120 0C over the weekend. The sample was transferred to an SCX cartridge (10 g) pre-wet with methanol, then washed with methanol and eluted with methanolic ammonia. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (34 mg, 18%). 1H NMR (400.132 MHz, CDCl3) δ 0.63 - 0.60 (m, 2H), 1.01 (s, 6H), 1.10 - 1.07 (m, 2H), 1.51
- 1.43 (m, 2H), 1.74 - 1.61 (m, 4H), 1.83 - 1.76 (m, 4H), 2.05 - 1.98 (m, 2H), 2.56 (s, 2H), 2.72 - 2.65 (m, 4H), 3.28 (s, 3H), 3.39 (d, 2H), 3.46 (s, 2H), 3.98 (s, 3H), 4.98 (quintet, IH), 7.20 (dd, IH), 7.55 (d, IH), 7.65 (s, IH), 7.87 (s, IH), 8.46 (d, IH), 9.15 (s, IH); MS m/z 576 [M+H]+.
Example 402:
3-chloro-4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cycIopropane- l,7'-pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-N-[(lS,5R)-9-methyl-9- azabicyclo[3.3.1]non-7-yl]benzamide
4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- yl)amino]-3-chloro-benzoic acid (Intermediate 253; 52 mg, 0.12 mmol) was suspended in
DMF (4 mL). DIPEA (62 ul, 0.35 mmol) was added to give a straw coloured solution. Endo- 9-methyl-9-azabicyclo[3,3,l]-nonan-3-amine (Chempacific; 26 mg, 0.16 mmol) was added, followed by HATU (67 mg, 0.17 mmol) and the resultant mixture was stirred at ambient temperature overnight.
The reaction mixture was evaporated to an amber gum, which was partitioned between DCM
(5 mL) and saturated aqueous sodium bicarbonate solution (5 mL). The organic phase was separated by gravity elution through a PTFE filter cup and the filtrate evaporated to dryness to afford an amber oil which was purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (46 mg, 56%)
1H NMR (400.132 MHz, DMSO-d6) δ 0.68 (m, 2H), 0.92 (m, 4H), 1.39 - 1.70 (m, 9H), 1.80
- 2.08 (m, 5H), 2.19 (m, 2H), 2.41 (s, 3H), 2.98 (m, 2H), 3.18 (s, 3H), 3.47 (s, 2H), 4.31 (m, IH), 4.78 (m, IH), 7.80 (m, IH), 7.99 (s, IH), 8.00 (d, IH), 8.05 (d, IH), 8.08 (s, IH), 8.32
(d, IH); MS m/z 578 [M+H]+. Example 403:
4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-N-[(3R)-l-ethylpyrrolidin-3-yl]-3-methoxy- benzamide
The title compound was prepared by an analogous method to the preparation of Example 350, utilising, 2'-chloro-9'-cyclopentyl-5'-methyl-8',9'-dihydrospiro[cyclopropane-l, T- pyrimido[5,4-b][l,4]diazepin]-6'(5'H)-one (Intermediate 130; 75 mg, 0.24 mmol), and 4- amino-N-[(3R)-l-ethylpyrrolidin-3-yl]-3-methoxy-benzamide (Intermediate 245; 70 mg, 0.26 mmol) heating by microwave irradiation at 160 0C for 1 hour, as an off-white foam (50 mg, 39%).
1HNMR (400.132 MHz, DMSO-d6) δ 1.04 (t, 3H), 1.10 (s, 6H), 1.55 - 1.93 (m, 9H), 2.15 (m, IH), 2.43 (m, 4H), 2.65 (m, IH), 2.73 (m, IH), 3.19 (s, 3H), 3.38 (s, 2H), 3.95 (s, 3H), 4.40 (m, IH), 5.19 (m, IH), 7.51 (m, 2H), 7.67 (s, IH), 7.99 (s, IH), 8.28 (d, IH), 8.37 (d, IH); MS m/z 536 [MH-H]+.
Example 404:
4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-2-fluoro-5-methoxy-N-[(lS,5R)-9-methyl-9- azabicyclo[3.3.1]non-3-yl]benzamide
2'-chloro-9t-cyclopentyl-5'-methyl-8',9'-dihydrospiro[cyclopropane-l,7'-pyrimido[5,4- b][l,4]diazepin]-6'(5Η)-one (Intermediate 130; 55 mg, 0.17 mmol), 4-amino-2-fluoro-5- methoxy-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-7-yl]benzamide (Intermediate 204; 53 mg, 0.17 mmol) and p-toluenesulphonic acid monohydrate (82 mg, 0.43 mmol) were heated in 4-methyl-2-pentanol (3 niL) at 140 0C for 2 hours. The reaction mixture was cooled and absorbed on to an SCX column, which was then washed with methanol and eluted with ammonia in methanol. Product containing fractions were evaporated and the residue purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (35mg, 35%). 1H NMR (399.9 MHz, DMSO-d6) δ 0.68 - 0.71 (2H5 m), 0.91 - 0.94 (4H, m), 1.40 - 1.46 (3H, m), 1.51 - 1.73 (6H, m), 1.86 - 1.94 (4H, m), 1.99 - 2.09 (IH, m), 2.18 - 2.25 (2H, m), 2.42 (3H, s), 2.98 (2H5 d), 3.19 (3H, s), 3.51 (2H, s), 3.94 (3H, s), 4.27 - 4.35 (IH, m), 4.84 - 4.92 (IH, m), 7.22 (IH, d), 7.66 - 7.69 (IH, m), 7.77 (IH, s), 8.03 (IH, s), 8.35 (IH, d); MS m/z 592 [M+H]+.
Example 405:
4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-2-fluoro-5-methoxy-N-[[l-(pyrrolidin-l- ylmethyl)cyclopropyl] methyl] benzamide
2'-chloro-9'-cyclopentyl-5'-methyl-8',9'-diliydrospiro[cyclopropane-l,7'-pyrimido[5,4- b][l,4]diazepin]-6'(5Η)-one (Intermediate 130; 70 mg, 0.23 mmol), 4-amino-2-fluoro-5- methoxy-N-[[l-(pyrrolidin-l-ylmethyl)cyclopropyl]methyl]benzamide (Intermediate 254; 70 mg, 0.22 mmol), and p-toluenesulphonic acid monohydrate (136 mg, 0.71 mmol) were stirred and heated together in 4-methyl-2-pentanol (3 mL) at 110 0C for 18 hours.
The cooled reaction solution was loaded onto an SCX-3 (5g) column pre-wet with MeOH. The column was washed with MeOH (2 column volumes) and the product eluted with 2M
NH3/MeOH. Product containing fractions were combined and evaporated and the residue purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (38 mg, 29%).
1H NMR (400.132 MHz5 DMSO-d6) δ 0.34 (2H, m), 0.50 (2H, m), 0.69 (2H5 m), 0.92 (2H5 m), 1.61 (12H, m), 1.92 (2H, m), 2.44 (2H, s), 2.50 (2H5 s), 3.18 (3H5 s), 3.36 (2H5 d), 3.51
(2H, s), 3.93 (3H, s), 4.89 (IH5 m), 7.37 (IH, d), 7.80 (IH5 s), 8.03 (IH5 s), 8.37 (2H5 d), 8.41
(IH5 m); MS m/z 592 [M+H]+.
Example 406: 4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-N-(l-ethyl-4-piperidyl)-3-fluoro-benzamide
2'-chloro-9'-cyclopentyl-5'-methyl-8',9'-dihydrospiro[cyclopropane-l,7'-pyrimido[5,4- b][l,4]diazeρin]-6'(5Η)-one (Intermediate 130; 231 mg, 0.75 mmol), 4-amino-N-(l- ethylpiperidin-4-yl)-3-fluorobenzamide (200 mg, 0.75 mmol) and p-toluenesulfonic acid monohydrate (335 mg, 1.88 mmol) were suspended in 4-Methyl-2-pentanol (5 mL) and sealed into a microwave tube. The reaction was heated to 160 °C for 30 minutes in the microwave reactor and allowed to cool to room temperature.
The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford an orange / brown oil which was purified by preparative
5 HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to yield the title compound as a white solid (48 mg, 12%).
1H NMR (400 MHz, DMSO-d6) δ 0.65 (t, 2H), 0.9 (t, 2H), 1.0 (t. 3H), 1.5 (m, 7H), 1.6 (m, 2H), 1.9 (t, 2H), 2.3 (q, 2H), 2.9 (d, 2H), 3.2 (s,3H), 3.4 (s, 2H), 3.6 ( m, IH), 4.75 9m, IH), io 7.65 (m, IH), 7.7 (m, IH), 7.95 (s, IH), 8.15 (m, IH), 8.6 (s, IH); MS m/z 537 [M+H]+.
Example 407:
4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-N-(l-ethyl-4-piperidyl)-2-fluoro-5-methoxy- ι5 benzamide
2'-chloro-9'-cyclopentyl-5'-methyl-8',9'-dihydrospiro[cyclopropane-l,7'-pyrimido[5,4- b][l,4]diazepin]-6'(5Η)-one (Intermediate 130; 121 mg, 0.39 mmol) and 4-amino-N-(l- ethyl-4-piperidyl)-2-fluoro-5-methoxy-benzamide (Intermediate 205; 116 mg, 0.39 mmol) were taken up in 4-methyl-2-pentanol (4 niL) and p-toluenesulphonic acid monohydrate (150
20 mg, 0.79 mmol) added. The reaction mixture was heated at 160 0C by microwave irradiation for 1 hour. The cooled reaction mixture was poured into a mixture of methanol & water (5:2 v/v, 7 niL) and the resultant solution loaded onto an SCX-3 cartridge (5 g), which had been pre-wet with methanol. The cartridge was washed through with methanol (40 mL) and eluted with 2M ammonia in methanol (30 mL). The ammoniacal solution was evaporated to give an
25 amber gum afforded which was purified by base modified reverse phase preparative HPLC which was re-purified by flash chromatography on a silica column eluting with 2.5-10% ammonia/methanol in DCM. Product containing fractions were combined and evaporated and the residue triturated with diethyl ether and resultant solid dried under vacuum, at 60 0C, for 3 hours to yield the title compound as a flocculent white solid (86 mg, 39%) so 1H NMR (400.132 MHz, DMSO-d6) δ 0.67 - 0.70 (2H, m), 0.91 - 0.94 (2H, m), 1.00 (3H, t), 1.48 - 1.99 (14H, m), 2.32 (2H, q), 2.82 - 2.85 (2H, m), 3.18 (3H, s), 3.50 (2H, s); 3.69 - 3.79 (IH, m), 3.93 (3H, s), 4.82 - 4.91 (IH, m), 7.20 (IH, d), 7.76 (IH, s), 7.79 - 7.82 (IH, m), 8.02 (IH, s), 8.34 (IH, d); MS m/z 566 [M+H]+.
Example 408:
5 7-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-N-(l-methyl-4-piperidyl)benzo[l,3]dioxole- 4-carboxamide
To 2'-chloro-9'-cyclopentyl-5'-metliyl-8',9'-dihydrospiro[cyclopropane-l,7'-pyriniido[4,5- b][l,4]diazepin]-6'(5'H)-one (Intermediate 130; 108 mg, 0.35 mmol) and 7-amino-N-(l-
I0 methylpiperidin-4-yl)benzo[d][l,3]dioxole-4-carboxamide (Intermediate 223; 98 mg, 0.35 mmol) in 4-methyl-2-pentanol (3 mL) was added p-toluenesulphonic acid monohydrate (139 mg, 0.73 mmol) and the reaction mixture heated at 160 0C by microwave irradiation for 1 hour. After cooling the reaction mixture was diluted with MeOH (5 mL) and water (2 mL). The is mixture was then submitted to ion exchange chromatography, using an SCX-2 column (10 g). After eluting through with methanol (100 mL) the crude product was eluted from the column using 2M ammonia in methanol (50 mL) and evaporated to afford a brown residue, which was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to
20 dryness to yield the title compound as a grey solid (43 mg, 22 %).
1HNMR (400.132 MHz, DMSO-d6) δ 0.57 - 0.59 (2H, m), 0.81 - 0.83 (2H, m), 1.31 - 1.60 (8H, m), 1.69 - 1.78 (4H, m), 1.92 - 1.97 (2H, m), 2.09 (3H, s), 2.58 - 2.65 (2H, m), 3.09 (3H, s), 3.36 (2H, s), 3.63 - 3.73 (IH, m), 4.71 (IH, quintet), 6.07 (2H, s), 7.14 (IH, d), 7.22 (IH, d), 7.45 (IH, d), 7.87 (IH, s), 8.51 (IH, s); MS m/z 548 [M+H]+.
25
Example 409:
4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrab.ydrospiro[cyclopentane-l,7'- 30 pyrimido[5,4-b][l,4]diazepine]-2'-yIamino)-3-methoxy-N-(l-methylpiperidin-4- yl)benzamide 2'-chloro-9'-cyclopentyl-5'-methyl-8',9'-diliydrospiro[cyclohexane-l,7'-pyrimido[5,4- b][l,4]diazepin]-6'(5'H)-one (Intermediate 255; 80 mg, 0.24 mmol), 4-amino-3-methoxy-N- (l-metliyl-4-piperidyl)benzamide (WO06/018220; 63mg, 0.24mmol) and p-toluenesulphonic acid monohydrate (114 mg, 0.60 mmol) were heated in 4-methyl-2-pentanol (3 mL) at 140 °C for 3 hours. The mixture was cooled and absorbed on to an SCX column, which was then washed with methanol and eluted with ammonia in methanol. Product containing fractions were evaporated and the residue purified on a silica column (2% 7N ammonia in methanol/DCM) to give the title compound as a white solid. (70 mg, 52%) 1H NMR (399.9 MHz, DMSO-d6) δl .31 - 1.37 (2H, m), 1.50 - 1.80 (14H, m), 1.89 - 2.06 (6H, m), 2.18 (3H, s), 2.79 (2H, d), 3.21 (3H, s), 3.43 (2H, s), 3.71 - 3.79 (IH, m), 3.96 (3H, s), 4.98 - 5.06 (IH, m), 7.47 - 7.51 (2H, m), 7.70 (IH, s), 8.02 (IH, s), 8.07 (IH, d), 8.38 (IH, d); MS m/z 562 [M+H]+.
Example 410: 3-methoxy-4-[[6-methyl-5-oxo-2-(2-oxocyclopentyl)-2,6,9,ll-tetrazabicyclo[5.4.0]undeca- 7,9,ll-trien-10-yl]amino]-N-(l-methyl-4-piperidyI)benzamide
10-chloro-6-methyl-2-(2-oxocyclopentyl)-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien- 5-one (Intermediate 261; 58 mg, 0.19 mmol), 4-amino-3-methoxy-N-(l-methyl-4- piperidyl)benzamide (WO06/018220; 53 mg, 0.20 mmol) and p-toluene sulphonic acid monohydrate (80 mg, 0.42 mmol) were dissolved in 4-methyl-2-pentanol (2 mL) and heated by microwave irradiation at 150 0C for 30 minutes. After cooling, the reaction mixture was dissolved in methanol (5 mL) and water (5 mL) and poured directly onto an SCX-3 cartridge (5 g). The cartridge was washed with methanol (50 mL), before elution of products with 2M ammonia in methanol (50 mL). The ammoniacal fraction was evaporated and the residue was purified by base modified reverse phase preparative HPLC to yield the title compound as a yellow solid (11 mg, 7%).
1H NMR (400.132 MHz, DMSO-d6) δ 1.60 (m, 2H), 1.73 - 2.09 (m, 8H), 2.17 (s, 3H), 2.25 (m, 2H), 2.62 (m, 2H), 2.78 (m, 2H), 3.19 (s, 3H), 3.60 (m, 2H), 3.74 (m, IH), 3.93 (s, 3H), 4.67 (m, IH), 7.48 (m, 2H), 7.74 (s, IH), 8.06 (d, IH), 8.13 (s, IH), 8.18 (d, IH); MS m/z 522 [M+H]+. Example 411:
2-chloro-4- [(2-cy clohexyl-6-methyl-5-oxo-2,6,9,l 1-tetrazabicyclo [5.4.0] undeca-7,9,11- trien-10-yl)amino] -5-fluoro-N-(l-methyI-4-piperidyl)benzamide
2-amino-9-cyclohexyl-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][l,4]diazepin-6(7H)-one (Intermediate 263; 100 mg, 0.36 mmol), 4-bromo-2-chloro-5-fluoro-N-(l-methylpiperidin-4- yl)benzamide (Intermediate 262; 133 mg, 0.38 mmol), xantphos (12.61 mg, 0.02 mmol), palladium(II) acetate (163 mg, 0.73 mmol) and caesium carbonate (14.20 mg, 0.04 mmol) were added to dioxane (10 mL) and heated at 103 0C overnight. The resulting solution was filtered and passed through a 5g SCX-3 column. The obtained yellow foam was triturated with hot ethyl acetate to afford a yellow solid.
1H NMR (400.132 MHz, DMSO-d6) 5 1.16 - 1.08 (m, IH), 1.43 - 1.35 (m, 2H), 1.63 - 1.48 (m, 5H), 1.80 - 1.71 (m, 6H), 2.08 - 1.99 (m, 2H), 2.19 (s, 3H), 2.59 - 2.56 (m, 2H), 2.78 - 2.75 (m, 2H), 3.17 (s, 3H), 3.71 - 3.60 (m, 3H), 4.41 - 4.36 (m, IH), 7.30 (d, IH), 8.06 (s, IH), 8.16 (d, IH), 8.26 (d, IH), 8.78 (s, IH); MS m/z 544 [M+H]+.
Example 412:
4-[(2-cyclohexyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- yl)amino]-2,5-difluoro-N-(l-methyl-4-piperidyl)benzamide
10-chloro-2-cyclohexyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien-5-one (Intermediate 266; 33 mg, 0.113 mmol), 4-amino-2,5-difluoro-N-(l-methyl-4- piperidyl)benzamide (Intermediate 59; 29 mg, 0.108 mmol) and caesium carbonate were added to dioxane (3 mL) and the suspension bubbled with nitrogen for 10 minutes, tris(dibenzylideneacetone) palladium (II) (4 mg, 0.006 mmol) and XANTPHOS (6 mg, 0.1 mmol) were added and the mixture heated at 100 °C for 16 hours. The reaction mixture was cooled to room temperature and filtered. The filter-cake was washed with DCM and the filtrate evaporated. The residue was dissolved in DCM and purified on a silica column eluting with a gradient of 0 - 5% 2M ammonia in MeOH / DCM over 30 column volumes. Fractions containing product were combined and evaporated to a solid, which was triturated with isohexane then filtered and dried to yield the title compound as a pale yellow solid (46 mg, 81%). 1H NMR (399.902 MHz, CDCl3) δl.18 (m, IH), 1.57 (m, 6H), 1.78 (m, IH), 1.91 (m, 4H), 2.06 (m, 2H), 2.17 (m, 2H), 2.30 (s, 3H), 2.68 (m, 2H), 2.80 (m, 2H), 3.29 (s, 3H), 3.71 (m, 2H), 4.01 (m, IH), 4.48 (m, IH), 6.58 (m, IH), 7.29 (m, IH), 7.82 (m, IH), 7.94 (s, IH), 8.38 (m, IH); MS m/z 528 [M+H]+.
Example 413;
4-[(2-cyclohexyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- yl)amino]-2,5-difluoro-N-[[l-(pyrroIidin-l-ylmethyl)cyclopropyl]methyl]benzamide
The title compound was prepared by an analogous method to the preparation of Example 411, utilising 4-amino-2,5-difluoro-N-[[l -(pyrrolidin- 1 -ylmethyl)cyclopropyl]methyl]benzamide
(Intermediate 269; 50 mg, 0.161 mmol) triturating the final product with diethyl ether prior to filtration and drying, as a white solid (42 mg, 46%).
1R NMR (399.902 MHz, CDCl3) δθ.39 (m, 2H), 0.57 (m, 2H), 1.17 (m, IH), 1.54 (m, 4H),
1.75 (m, 5H), 1.92 (m, 4H), 2.49 (s, 2H), 2.54 (m, 4H), 2.68 (m, 2H), 3.29 (s, 3H), 3.46 (m,s 2H), 3.72 (m, 2H), 4.50 (m, IH), 7.29 (m, IH), 7.83 (m, IH), 7.94 (s, IH), 8.32 (m, IH), 8.64
(m, IH); MS m/z 569 [M+H]+.
Example 414: 4-[(2-cyclohexyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10-0 yl)amino]-2,5-difluoro-N-[(3R)-l-methylpyrrolidin-3-yl]benzamide
The title compound was prepared by an analogous method to the preparation of Example 411, utilising 4-amino-2,5-difluoro-N-[(3R)-l-methylpyrrolidin-3-yl]benzamide (Intermediate 229; 41 mg, 0.161 mmol) triturating the final product with diethyl ether prior to filtration and drying, as a white solid (49 mg, 59%). s 1H NMR (399.902 MHz, CDCl3) δl.18 (m, IH), 1.54 (m, 4H), 1.76 (m, 2H), 1.91 (m, 4H), 2.29 (m, IH), 2.42 (m, 4H), 2.68 (m, 4H), 2.90 (m, IH), 3.29 (s, 3H), 3.72 (m, 2H), 4.48 (m, IH), 4.66 (m, IH), 6.94 (m, IH), 7.29 (m, IH), 7.81 (m, IH), 7.94 (s, IH), 8.37 (m, IH); MS m/z 514 [M+H]+. 0 Example 415: 4-[(2-cyclohexyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- yl)amino]-N-(l-ethyl-4-piperidyl)-2,5-difluoro-benzamide
The title compound was prepared by an analogous method to the preparation of Example 411, utilising 4-amino-N-(l-ethyl-4-piperidyl)-2,5-difluoro-benzamide (Intermediate 235; 46 mg, 0.161 mmol) triturating the final product with diethyl ether prior to filtration and drying, as a white solid (60 mg, 69%).
1H NMR (399.902 MHz, CDCl3) δl.10 (t, 3H), 1.18 (m, IH), 1.55 (m, 6H), 1.78 (m, IH), 1.91 (m, 4H), 2.11 (m, 4H), 2.43 (q, 2H), 2.68 (m, 2H), 2.89 (m, 2H), 3.29 (s, 3H), 3.71 (m, 2H), 4.04 (m, IH), 4.48 (m, IH), 6.59 (m, IH), 7.28 (m, IH), 7.82 (m, IH), 7.94 (s, IH), 8.38 (m, IH); MS m/z 542 [M+H]+.
Example 416:
4- [(2-cyclohexyl-6-methyl-5-oxo-2,6,9,l 1-tetrazabicyclo [5.4.0] undeca-7,9,1 l-trien-10- yl)amino]-2,5-difluoro-N-(2-pyrrolidin-l-ylethyl)benzamide The title compound was prepared by an analogous method to the preparation of Example 411, utilising 4-amino-2,5-difluoro-N-(2-pyrrolidin-l-ylethyl)benzamide (Intermediate 230; 43 mg, 0.161 mmol) triturating the final product with diethyl ether prior to filtration and drying, as a white solid (64 mg, 76%). 1H NMR (399.902 MHz, CDCl3) δl.18 (m, IH), 1.54 (m, 4H), 1.77 (m, 5H), 1.90 (m, 4H), 2.57 (m, 4H), 2.70 (m, 4H), 3.29 (s, 3H), 3.58 (m, 2H), 3.71 (m, 2H), 4.49 (m, IH), 7.29 (m, 2H), 7.82 (m, IH), 7.94 (s, IH), 8.39 (m, IH); MS m/z 526 [M+H]+. Example 417:
4-[(2-cyclohexyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- yl)amino]-3-fluoro-N-[(lS,5R)-9-methyI-9-azabicyclo[3.3.1]non-7-yl]benzamide The title compound was prepared by an analogous method to the preparation of Example 411, utilising 4-amino-3-fluoro-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-7-yl]benzamide (Intermediate 162; 150 mg, 0.515 mmol), the final product being taken up in methanol (1 mL) diluted with water and freeze dried, as a cream coloured solid (201 mg, 71%). 1H NMR (399.902 MHz, CDCl3) dl.06 (m, 2H), 1.18 (m, IH), 1.33 (m, 2H), 1.52 (m, 4H), 1.77 (m, IH), 1.95 (m, 8H), 2.52 (m, 5H), 2.67 (m, 2H), 3.11 (m, 2H), 3.29 (s, 3H), 3.70 (m, 2H), 4.49 (m, 2H)9 5.75 (d, IH), 7.24 (m, IH), 7.52 (m, 2H), 7.92 (s, IH), 8.56 (m, IH); MS
Figure imgf000249_0001
Example 418;
5 4-[(2-cyclohexyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- yl)amino] -3-methoxy-N- [(lR,5S)-9-methyl-9-azabicydo [3.3.1] non-7-yl] benzamide
The title compound was prepared by an analogous method to the preparation of Example 411, utilising 4-amino-3 -methoxy-N- [( 1 S,5R)-9-methyl-9-azabicyclo [3.3.1 ]non-3 -yl]benzamide (Intermediate 202; 154 mg, 0.509 mmol), the final product being purified by base modified
I0 reverse phase preparative HPLC, as a white solid (137 mg, 48%).
1H NMR (399.902 MHz, CDCl3) dl.04 (m, 2H), 1.19 (m, IH), 1.31 (m, 2H), 1.53 (m, 6H), 1.79 (m, IH), 1.96 (m, 6H), 2.54 (m, 5H), 2.67 (m, 2H), 3.10 (m, 2H), 3.28 (s, 3H), 3.70 (m, 2H), 3.97 (s, 3H), 4.50 (m, 2H), 5.77 (d, IH), 7.25 (m, IH), 7.40 (d, IH), 7.69 (s, IH), 7.91 (s, IH), 8.49 (d, IH); MS m/z 562 [M+H]+. is
Example 419:
4-[(2-cyclohexyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- yl)amino]-2-fluoro-5-methoxy-N-[[l-(pyrrolidin-l- ylmethyl)cyclopropyl]methyl]benzamide
20 The title compound was prepared by an analogous method to the preparation of Example 411, utilising 4-amino-2-fluoro-5-methoxy-N-[[l-(pyrrolidin-l- ylmethyl)cyclopropyl]methyl]benzamide (Intermediate 254; 65 mg, 0.204 mmol), the final product being purified by base modified reverse phase preparative HPLC, as a white solid (4 mg, 3%).
25 MS m/z 580 [M+H]+. Retention time 3.69 minutes
Example 420:
4-[(2-cyclohexyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- 30 yl)amino]-2-fluoro-5-methoxy-N-[(3R)-l-methylpyrrolidin-3-yl]benzamide The title compound was prepared by an analogous method to the preparation of Example 411, utilising 4-amino-2-fluoro-5 -methoxy-N- [(3R)- 1 -methylpyrrolidin-3 -yl]benzamide (Intermediate 182; 55 mg, 0.204 mmol), the final product being purified by base modified reverse phase preparative HPLC, as a white solid (20 mg, 19%). 1H NMR (399.902 MHz, CDCl3) 61.20 (m, IH), 1.56 (m, 4H), 1.78 (m, 2H)5 1.92 (m, 4H), 2.32 (m, IH), 2.43 (m, 4H), 2.68 (m, 4H)5 2.89 (m, IH), 3.28 (s, 3H), 3.72 (m, 2H), 3.95 (s, 3H), 4.52 (m, IH), 4.67 (m, IH), 7.00 (m, IH), 7.56 (m, IH), 7.76 (s, IH), 7.92 (s, IH), 8.31 (d, IH); MS m/z 526 [M+H]+.
Example 421:
4-[(2-cyclohexyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- yl)amino]-3-methoxy-N-[(3R)-l-methylpyrrolidin-3-yl]benzamide
The title compound was prepared by an analogous method to the preparation of Example 411, utilising 4-amino-3-methoxy-N-(l -methylpyrrolidin-3 -yl)benzamide (Intermediate 187; 51 mg, 0.204 mmol), the final product being purified by base modified reverse phase preparative HPLC, as a white solid (37 mg, 36%).
1H NMR (399.902 MHz, CDCl3) δl.22 (m, IH), 1.52 (m, 4H), 1.77 (m, 2H), 1.94 (m, 4H), 2.23 (m, IH), 2.44 (m, 4H), 2.56 (m, IH), 2.67 (m, 2H), 2.81 (m, IH), 2.98 (m, IH), 3.28 (s, 3H), 3.70 (m, 2H), 3.97 (s, 3H), 4.51 (m, IH), 4.70 (m, IH), 6.48 (d, IH), 7.31 (m, IH), 7.41 (m, IH), 7.70 (s, IH), 7.91 (s, IH), 8.49 (d, IH); MS m/z 508 [M+H]+.
Example 422:
4-[(2-cyclohexyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- yl)amino]-N-(l-ethyl-4-piperidyl)-2-fluoro-5-methoxy-benzamide The title compound was prepared by an analogous method to the preparation of Example 411, utilising 4-amino-N-(l-ethyl-4-piperidyl)-2-fluoro-5-methoxy-benzamide (Intermediate 205;
60 mg, 0.204 mmol), the final product being purified by base modified reverse phase preparative HPLC, as a white solid (27 mg, 24%).
1H NMR (399.902 MHz, CDCl3) δl.10 (t, 3H), 1.21 (m, IH), 1.55 (m, 6H), 1.78 (m, IH), 1.92 (m, 4H), 2.12 (m, 4H), 2.43 (q, 2H), 2.68 (m, 2H), 2.89 (m, 2H), 3.28 (s, 3H), 3.71 (m, 2H), 3.95 (s, 3H), 4.05 (m, IH), 4.52 (m, IH)5 6.67 (m, IH), 7.56 (d, IH), 7.74 (s, IH), 7.92 (s, IH), 8.32 (d, IH); MS m/z 554 [M+H]+.
Example 423: 4-[(2-cyclohexyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- yl)amino]-N-(l-ethyl-4-piperidyl)-3-methoxy-benzamide
The title compound was prepared by an analogous method to the preparation of Example 411, utilising 4-amino-N-(l-ethyl-4-piperidyl)-3-methoxy-benzamide (Intermediate 190; 57 mg, 0.204 mmol), the final product being purified by base modified reverse phase preparative HPLC, as a white solid (61 mg, 56%).
1HNMR (399.902 MHz, CDCl3) δl.ll (t, 3H), 1.21 (m, IH), 1.54 (m, 6H), 1.78 (m, IH), 1.94 (m, 4H), 2.12 (m, 4H), 2.44 (q, 2H), 2.67 (m, 2H), 2.92 (m, 2H), 3.28 (s, 3H)5 3.70 (m, 2H), 3.97 (s, 3H), 4.03 (m, IH), 4.50 (m, IH), 5.88 (d, IH), 7.23 (m, IH), 7.39 (m, IH), 7.68 (s, IH), 7.91 (s, IH), 8.50 (d, IH); MS m/z 536 [M+H]+.
Example 424:
4-[(2-cyclohexyI-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- yl)amino]-N-(3-dimethylaminopropyl)-3-methoxy-benzamide
The title compound was prepared by an analogous method to the preparation of Example 411, utilising 4-amino-N-(3-dimethylaminopropyl)-3-methoxy-benzamide (Intermediate 196; 51 mg, 0.204 mmol), the final product being purified by base modified reverse phase preparative
HPLC, as a white solid (50 mg, 48%).
1HNMR (399.902 MHz, CDCl3) δl.22 (m, IH), 1.54 (m, 4H), 1.76 (m, 3H), 1.95 (m, 4H),
2.30 (s, 6H), 2.51 (m, 2H), 2.67 (m, 2H), 3.28 (s, 3H), 3.58 (m, 2H), 3.70 (m, 2H), 3.97 (s, 3H), 4.53 (m, IH), 7.27 (m, IH)5 7.48 (m, IH), 7.72 (s, IH), 7.91 (s, IH), 8.38 (m, IH), 8.50
(d, lH); MS m/z 510 [M+H]+.
Example 425: 4-[(2-cy clohexyl-6-methyl-5-oxo-2,6,9,l 1-tetrazabicyclo [5.4.0] undeca-7,9,1 l-trien-10- yl)amino]-2-fluoro-5-methoxy-N-(2-pyrrolidin-l-ylethyl)benzamide
The title compound was prepared by an analogous method to the preparation of Example 411, utilising 4-amino-2-fluoro-5-methoxy-N-(2-pyrrolidin- 1 -ylethyl)benzamide (Intermediate 5 228; 57 mg, 0.204 mmol), the final product being purified by base modified reverse phase preparative HPLC, as a white solid (19 mg, 17%).
1H NMR (399.902 MHz, CDC13) δl.20 (m, IH), 1.56 (m, 4H), 1.77 (m, 5H), 1.91 (m, 4H), 2.58 (m, 4H), 2.70 (m, 4H)3 3.28 (s, 3H), 3.60 (m, 2H), 3.71 (m, 2H), 3.95 (s, 3H), 4.53 (m, IH), 7.32 (m, IH), 7.57 (d, IH), 7.73 (s, IH), 7.92 (s, IH), 8.33 (d, IH); MS m/z 540 [M+H]+.0
Example 426:
4-[(2-cyclohexyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- yl)amino]-N-(2-dimethylaminoethyl)-3-methoxy-benzamide
The title compound was prepared by an analogous method to the preparation of Example 411,s utilising 4-amino-N-(2-dimethylaminoethyl)-3-methoxy-benzamide (Intermediate 194; 48 mg, 0.204 mmol), the final product being purified by base modified reverse phase preparative
HPLC, as a white solid (31 mg, 31%).
1H NMR (399.902 MHz, CDCl3) δl.22 (m, IH), 1.54 (m, 4H), 1.76 (m, IH), 1.94 (m, 4H),
2.29 (s, 6H), 2.54 (m, 2H), 2.67 (m, 2H), 3.28 (s, 3H), 3.53 (m, 2H), 3.70 (m, 2H)5 3.97 (s,0 3H), 4.51 (m, IH), 6.74 (m, IH), 7.32 (m, IH), 7.43 (m, IH), 7.67 (s, IH), 7.91 (s, IH), 8.50
(d, IH); MS m/z 496 [M+H]+.
Example 427:
4-[(2-cyclohexyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10-5 yl)amino] -2-fluoro-5-methoxy-N-[(lR,5S)-9-methyl-9-azabicyclo [3.3.1] non-7- yl]benzamide
The title compound was prepared by an analogous method to the preparation of Example 411, utilising 4-amino-2-fluoro-5-methoxy-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3. l]non-7- yljbenzamide (Intermediate 204; 65 mg, 0.204 mmol), the final product being purified by0 base modified reverse phase preparative HPLC, as a white solid (52 mg, 44%). 1HNMR (399.902 MHz, CDCl3) 61.04 (m, 2H), 1.21 (m, IH)5 1.32 (m, 2H), 1.56 (m, 6H), 1.79 (m, IH), 1.95 (m, 6H), 2.54 (m, 5H), 2.68 (m, 2H), 3.09 (m, 2H), 3.28 (s, 3H), 3.72 (m, 2H), 3.95 (s, 3H), 4.53 (m, 2H), 6.53 (m, IH), 7.59 (d, IH), 7.75 (s, IH), 7.93 (s, IH), 8.31 (d, IH); MS m/z 580 [M+H]+.
Example 428:
4-[(2-cyclohexyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-10- yl)amino]-2-fluoro-N-(l-methyl-4-piperidyl)benzamide
10-chloro-2-cyclohexyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10,12-trien-5-one (Intermediate 267; 89 mg, 0.3 mmol) and 4-amino-3-fluoro-N-(l-methyl-4- piperidyl)benzamide (Intermediate 61; 76 mg, 0.3 mmol) were combined with p- toluenesulphonic acid monohydrate (143 mg, 0.75 mmol) in 4-methyl-2-pentanol (2 mL) and heated by microwave irradiation for 30 minutes at 160 0C. The cooled reaction mixture was diluted with methanol (10 mL) and filtered and the filtrate loaded onto an SCX-3 cartridge (5 g) pre-wet with methanol. The cartridge was washed with methanol (2 x 10 mL) and eluted with 7 iVmethanolic ammonia (20 mL). The basic fraction was evaporated to give a yellow solid, which was purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (55 mg, 37%). 1H NMR (400 MHz, DMSO-d6) δl.15 (m, 2H), 1.45 (m, 3H), 1.6 (m, 4H), 1.7 (m, IH), 1.8 (m, 6H), 1.95 (t, 2H), 2.15 (s, 3H), 2.6 (m, 2H), 2.7 (m, 2H), 3.15 (s, 3H), 3.65 (m, 2H), 3.7 (m, IH), 4.4 (t, IH), 7.5 (m, 2H), 7.7 (m, 2H), 8.1 (s, IH), 9.6 (s, IH); MS m/z 511 [M+H]+.
Example 429: 4-[(2-cyclohexyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-10- yl)amino]-3-fluoro-N-(l-methyl-4-piperidyl)benzamide
10-chloro-2-cyclohexyl-6-methyl-2,6,9,l l-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 267; 89 mg, 0.3 mmol) and 4-amino-3-fluoro-N-(l-methyl-4- piperidyl)benzamide (Intermediate 65; 76 mg, 0.3 mmol) were combined with p- toluenesulphonic acid monohydrate (143 mg, 0.75 mmol) in 4-methyl-2-pentanol (2 mL) and heated by microwave irradiation for 30 minutes at 160 0C The cooled reaction mixture was diluted with methanol (10 mL) and filtered and the filtrate loaded onto an SCX-3 cartridge (5 g) pre-wet with methanol. The cartridge was washed with methanol (2 x 10 mL) and eluted with 7 iV methanolic ammonia (20 mL). The basic fraction was evaporated to give a yellow gum, which was purified by base modified reverse phase preparative HPLC to give the title compound as a white solid (56 mg, 37 %).
1H NMR (400 MHz, DMSO-d6) δl.l (m, IH), 1.3 (q, 2H), 1.55 (m, 5H), 1.75 (m, 6H), 1.95 (t, 2H), 2.2 (s, 3H), 2.6 (m, 2H), 2.75 (d, 2H), 3.2 (s, 3H), 2.6 (m, 2H), 2.75 (d, 2H), 3.2 (s, 3H), 3.6 (m, 2H), 3.7 (m, IH), 4.3 (m, IH), 7.65 (m, IH), 7.7 (m, IH), 8.0 (s, IH), 8.1 (m, 2H), 8.7 (s, IH); MS m/z 511 [M+H]+.
Example 430;
4-(9'-cyclohexyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-3-methoxy-N-(l-methyl-4- piperidyl)benzamide s 2'-chloro-9'-cyclohexyl-5'-methyl-8',9'-dihydrospiro[cyclopropane- 1 ,7'-pyrimido[5,4- b][l,4]diazepin]-6'(5'H)-one (Intermediate 270; 100 mg, 0.31 mmol), 4-amino-3-methoxy-N- (l-methyl-4-piperidyl)benzamide (WO06/018220; 83 mg, 0.31 mmol) and p- toluenesulphonic acid monohydrate (149 mg, 0.78 mmol) were heated at 140 0C in 4-methyl- 2-pentanol (4 mL) for 2 hours. The reaction mixture was loaded onto an SCX-3 column was0 pre-wet with methanol and the column washed with methanol and eluted with 2% 7N ammonia/methanol. The ammoniacal fraction was evaporated and the residue purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (97 mg,
% O).
1H NMR (399.9 MHz, DMSO-d6) δθ.68 - 0.71 (2H, t), 0.92 - 0.95 (2H, t), 1.40 - 1.50 (4H,s m), 1.59 - 1.63 (2H, m), 1.65 - 1.68 (IH, m), 1.77 (2H, s), 1.79 (4H, t), 1.86 (IH, s), 1.93 - 1.98 (2H, m), 2.18 (3H, s), 2.80 (2H, d), 3.17 (3H, s), 3.51 (2H, s), 3.70 - 3.76 (IH, m), 3.96 (3H, s), 4.45 (IH, m), 7.46 (IH, m), 7.48 - 7.51 (IH, d), 7.67 (IH, s), 7.96 (IH, s), 8.09 (IH, d), 8.39 (IH, d); MS m/z 547 [M+H]+. 0 Example 431:
4-(9'-cyclohexyl-5'-methyI-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-N-(3-dimethylaminopropyl)-3-methoxy- benzamide
5 The title compound was prepared by an analogous method to the preparation of Example 430, utilising 4-amino-N-(3-dimethylaminopropyl)-3-methoxy-benzamide (Intermediate 196; 79 mg, 0.31 mmol), , as a white solid (96 mg, 58%).
1H NMR (399.9 MHz, DMSO-d6) δθ.68 - 0.71 (2H, t), 0.92 - 0.95 (2H, t), 1.47 - 1.51 (2H, m), 1.68 (4H, q), 1.76 - 1.78 (4H, m), 1.85 (2H, d), 2.15 (6H, s), 2.28 (2H, t), 3.17 (3H, s), io 3.25 (2H, t), 3.51 (2H, s), 3.96 (3H, s), 4.45 (IH, m), 7.45 - 7.47 (IH, m), 7.51 (IH, d), 7.67 (IH, s), 7.96 (IH, s), 8.40 (IH, d), 8.41 (IH, d); MS m/z 537 [M+H]+.
Example 432:
4-(9'-cyclohexyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- I5 pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-3-methoxy-N-[(lS,5R)-9-methyl-9- azabicyclo[3.3.1]non-7-yl]benzamide
The title compound was prepared by an analogous method to the preparation of Example 430, utilising 4-amino-3-methoxy-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]benzamide (Intermediate 202; 95 mg, 0.31 mmol), , as a white solid (111 mg, 61%). 20 1H NMR (399.9 MHz, DMSO-d6) δθ.68 - 0.71 (2H, m), 0.93 (2H, d), 0.93 (2H, d), 1.42 (2H, d), 1.45 - 1.47 (3H5 m), 1.49 (2H, d), 1.77 (4H, d), 1.85 (4H, d), 1.93 (2H, t), 2.21 (IH, d), 2.42 (3H, s), 2.99 (2H, d), 3.17 (3H, s), 3.51 (2H, s), 3.98 (3H, s), 4.29 - 4.34 (IH, m), 4.45 (IH, m), 7.47 (IH, d), 7.48 - 7.52 (IH, s), 7.67 (IH, s), 7.92 (IH, d), 7.97 (IH, s), 8.39 - 8.41 (IH, d); MS m/z 589 [M+H]+.
25
Example 433:
4-(9'-cyclohexyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-N-(l-ethyl-4-piperidyl)-3-methoxy- benzamide The title compound was prepared by an analogous method to the preparation of Example 430, utilising 4-amino-N-(l-ethyl-4-piperidyl)-3-methoxy-benzamide (Intermediate 190; 87 mg, 0.31 mmol), , as a white solid (122 mg, 70%).
1HNMR (399.9 MHz, DMSO-d6) δθ.68 - 0.71 (2H, t), 0.92 - 0.95 (2H, t), 1.01 (3H, t), 1.45 5 (3H, t), 1.57 - 1.61 (2H, m), 1.77 (4H, d), 1.82 - 1.86 (3H, m), 1.88 (2H, t), 1.93 (2H, d), 2.33 (2H, q), 2.90 (2H, d), 3.17 (3H, s), 3.51 (2H, s), 3.74 - 3.78 (IH, m), 3.96 (3H, s), 4.41 - 4.45 (IH, m), 7.46 (IH, d), 7.48 - 7.51 (IH, m), 7.67 (IH, s), 7.96 (IH, s), 8.09 (IH, d), 8.39 - 8.41 (IH, m); MS m/z 563 [M+H]+.
io Example 434:
4-(9'-cyclohexyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-N-(l-ethyl-4-piperidyl)-2,5-difluoro- benzamide
2l-chloro-9l-cyclohexyl-5'-methyl-8',9'-dihydrospiro[cyclopropane-l,7'-pyrimido[5,4- I5 b][l,4]diazepin]-6'(5'H)-one (Intermediate 270; 100 mg, 0.31 mmol), 4-amino-N-(l-ethyl~4- piperidyl)-2,5-difluoro-benzamide (Intermediate 235; 98 mg, 0.34 mmol) and caesium carbonate (204 mg, 0.62 mmol) added to dioxane (5 mL) and the suspension bubbled with nitrogen for 10 minutes. Tris(dibenzylideneacetone) palladium (II) (18 mg, 0.02 mmol) and XANTPHOS (17 mg, 0.03 mmol) added and the mixture heated at 110 °C overnight. The 20 mixture was filtered and the filtrate loaded onto an SCX-3 column was pre-wet with methanol and the column washed with methanol and eluted with 2% 7N ammonia/methanol. The ammoniacal fraction was evaporated and the residue purified by base modified reverse phase preparative HPLC to yield the title compound as a white crystalline solid (19 mg, 11%). 1HNMR (399.9 MHz, DMSO-d6) δθ.69 - 0.72 (2H, t), 0.93 - 0.96 (2H, t), 1.00 (3H, t), 1.42 2s (2H, t), 1.48 (2H, d), 1.49 - 1.54 (2H, m), 1.63 (2H, d), 1.70 (2H, d), 1.78 (4H, s), 1.95 (2H, d), 2.30 - 2.35 (2H, m), 2.84 (2H, d), 3.17 (3H, s), 3.50 (2H, s), 3.75 (IH, m), 4.46 (IH, m), 7.41 - 7.45 (IH, m), 7.98 (IH, d), 7.99 (IH, s), 8.13 - 8.18 (IH, m), 8.79 (IH, s); MS m/z 589 [M+H]+.
30 Example 435:
4-(9'-cyclohexyI-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-yIamino)-3-fluoro-N-[(lS,5R)-9-methyl-9- azabicy clo [3.3.1] non-7-yl] benzamide 2'-chloro-9'-cyclohexyl-5'-methyl-8',9'-diliydrospiro[cyclopropane-l,7l-pyrimido[5,4- b][l,4]diazepin]-6'(5'H)-one (Intermediate 270; 97 mg, 0.3 mmol) and 4-amino-3-fluoro-N- (9-methyl-9-azabicyclo[3.3.1]non-7-yl)benzamide (Intermediate 162; 88 mg, 0.3 mmol) were combined with p-toluenesulphonic acid monohydrate (143 mg, 0.75 mmol) in 4-methyl-2- pentanol (2 mL) and heated by microwave irradiation for 30 minutes at 160 0C. The cooled reaction mixture was diluted with methanol (5 mL) and loaded onto an SCX-3 (5 g) cartridge pre-wet with methanol. The cartridge was washed with methanol (2 x 10 mL) and product eluted with 7 iVmethanolic ammonia (20 mL). Product containing fractions were evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (82 mg, 48%). 1HNMR (400 MHz, DMSO-d6) δθ.7 (m, 2H), 0.95 (m, 4H), 1.15 (m, IH), 1.35 (m, 2H), 1.45 (m, 4H), 1.7 (m, 4H), 1.8 (d, 2H), 1.95 (m, 2H), 2.05 (m, IH), 2.15 (m, 2H), 2.9 (s, 3H), 2.95 (d, 2H), 3.15 (s, 3H), 3.45 (s, 2H), 4.35 (m, 2H), 7.65 (m, IH), 7.7 (m, IH), 7.9 (s, IH), 7.95 (m, IH), 8.2 (t, IH), 8.55 (s, IH); MS m/z 576 [M+H]+.
Example 436:
4-(9'-cyclohexyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-2,5-difluoro-N-(l-methyl-4- piperidyl)benzamide
The title compound was prepared by an analogous method to the preparation of Example 434, utilising 4-amino-2,5-difluoro-N-(l-methyl-4-piperidyl)benzamide (Intermediate 59; 93 mg, 0.34 mmol), as a white solid (76 mg, 44%).
1H NMR (399.9 MHz, DMSO-d6) δθ.69 - 0.72 (2H, t), 0.93 - 0.96 (2H, t), 1.44 (4H, m), 1.54 - 1.61 (2H, m), 1.71 (2H, d), 1.78 (4H, d), 1.94 - 1.99 (2H, m), 2.17 (3H, s), 2.73 (2H, d), 3.17 (3H, s), 3.29 (2H, d), 3.50 (2H, s), 3.65 - 3.72 (lH,m), 4.46 (IH, m), 7.41 - 7.45 (IH, m), 7.96 (IH, d), 7.98 (IH, s), 8.13 - 8.18 (IH, m), 8.78 (IH, s); MS m/z 554 [M+H]+. Example 437:
5-chloro-4-(9 ' -cy clohexy 1-5 ' -methy 1-6 ' -oxo-5 ' ,6 ' ,8 ' ,9 ' -tetrahy drospiro [cy clopropane-
1 ,7 ' -py rimido [5,4-b] [1 ,4] diazepine] -2 ' ~ylamino)-N-(4-dimethylaminocy clohexy l)-2~ fluoro-benzamide 2'-chloro-9'-cycloliexyl-5'-methyl-8',9'-dihydrospiro[cyclopropane- 1 ,7'-pyrimido[5,4- b][l,4]diazepin]-6'(5'H)-one (Intermediate 270; 103 mg, 0.32 mmol), 4-amino-5-chloro-N-(4- dimethylaininocyclohexyl)-2-fluoro-benzamide (Intermediate 175; 92 mg, 0.29 mmol), and XANTPHOS (16 mg, 0.03 mmol) were dissolved in 1,4-dioxane (7.5 mL). Caesium carbonate (210 mg, 0.59 mmol) was added and the system purged with a stream of nitrogen for 15 minutes before tris(dibenzylideneacetone) palladium (II) (17 mg, 0.02 mmol) was added. The apparatus was evacuated and backfilled with nitrogen (x3) and then heated at 100 °C for 3 hours. The mixture was cooled, filtered and the filtrate absorbed on to an SCX column, and the column then washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and the residue purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (49 mg, 28%).
1H NMR (399.9 MHz, DMSO-d6) δ 0.71 (2H, m), 0.94 (2H, m), 1.10 (2H, m), 1.25 - 1.84 (16H, m), 2.09 - 2.19 (7H, m), 3.18 (3H, s), 3.52 (2H, s), 3.63 - 3.70 and 3.88 - 3.94 (each 0.5H, m), 4.43 (IH, m), 7.67 (IH, d), 8.00 - 8.04 (3H, m), 8.27 (IH, d); MS m/z 598 [M+H]+.
Example 438: 4-(9 ' -cy clohexyl-5 ' -methy 1-6 '-oxo-5',6',8' ,9 '-tetrahy drospiro [cyclopropane- 1 ,7' - pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-2-fluoro-5-methoxy-N-[(3R)-l- methylpy rrolidin-3-yl] benzamide
2'-chloro-9'-cyclohexyl-5'-methyl-8l,9l-dihydrospiro[cyclopropane-l,7l-pyrimido[5,4- b][l,4]diazepin]-6'(5Η)-one (Intermediate 270; 103 mg, 0.32 mmol), 4-amino-2-fluoro-5- methoxy-N-[(3R)-l-methylρyrrolidin-3-yl]benzamide (Intermediate 182; 87 mg, 0.32 mmol) and p-toluenesulphonic acid monohydrate (154 mg, 0.81 mmol) were heated in 4-methyl-2- pentanol (3 mL) at 140 0C for 3 hours. The mixture was cooled and absorbed on to an SCX column, which was then washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (70 mg, 40%). 1H NMR (399.9 MHz, DMSO-d6) δ 0.70 - 0.73 (2H, m), 0.93 - 0.96 (2H, m), 1.10 1.20 (IH, 5 m), 1.40 - 1.54 (4H, m), 1.64 - 1.84 (6H, m), 2.13 - 2.22 (IH, m), 2.26 (3H, s), 2.33 - 2.47 (2H, m), 2.56 - 2.64 (IH, m), 2.66 - 2.71 (IH, m), 3.17 (3H, s), 3.53 (2H, s), 3.94 (3H, s), 4.34 - 4.41 (IH, m), 4.45 - 4.50 (IH, m), 7.22 (IH, d), 7.74 (IH, s), 7.99 (IH, s), 8.01 - 8.03 (IH, m), 8.26 (IH, d); MS m/z 554 [M+H]+.
io Example 439:
4-(9'-cyclohexyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-N-(3-dimethylamino-2,2-dimethyl-propyl)-3- methoxy-benzamide
2'-chloro-9'-cyclohexyl-5'-methyl-8',9'-dihydrospiro[cyclopropane-l,7'-pyrimido[5,4- I5 b][l,4]diazepin]-6'(5Η)-one (Intermediate 270; 86 mg, 0.27 mmol) and 4-amino-N-(3- dimethylamino-2,2-dimethyl-propyl)-3-methoxy-benzamide (Intermediate 22; 75 mg, 0.27 mmol) were taken up in 4-methyl-2-pentanol (3 niL) and p-toluenesulphonic acid monohydrate (102 mg, 0.54 mmol) added. The reaction mixture was heated at 160 0C for 1 hour by microwave irradiation. After cooling, the reaction mixture was diluted with methanol 20 (5 mL) and water (5 mL) and the resultant solution loaded onto an SCX-3 (5 g) cartridge. The cartridge was wahsed with methanol (40 mL) and then eluted with 2M ammonia in methanol (25 mL). Evaporation of the ammoniacal solution gave an opaque cream coloured film which was purified by base modified reverse phase preparative HPLC to yield the title compound as a white foam (83 mg, 55%)
25 1H NMR (400.132 MHz, DMSO-d6) δ 0.69 (m, 2H), 0.90 (s, 6H), 0.93 (m, 2H), 1.16 (m, IH), 1.44 (m, 4H), 1.62 - 1.88 (m, 5H), 2.22 (s, 2H), 2.28 (s, 6H), 3.17 (s, 3H), 3.21 (d, 2H), 3.50 (s, 2H), 3.96 (s, 3H), 4.45 (m, IH), 7.40 (m, IH), 7.47 (d, IH), 7.68 (s, IH), 7.96 (s, IH), 8.40 (d, IH), 8.50 (t, IH); MS m/z 564 [M+H]+.
30 Example 440:
4-(9'-cyclohexyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-N-(2,2-dimethyl-3-pyrrolidin-l-yl-propyl)-3- methoxy-benzamide The title compound was prepared by an analogous method to the preparation of Example 439, on a 0.33 mmol scale, utilising 4-amino-N-(2,2-dimethyl-3-pyrrolidin-l-yl-propyl)-3- methoxy-benzamide (Intermediate 206; 100 mg, 0.33 mmol) heating thermally at 120 0C over the weekend, as a white solid (46 mg, 24%). 1HNMR (400.132 MHz, CDCl3) δ 0.57 - 0.54 (m, 2H), 0.93 (s, 6H), 1.12 - 1.02 (m, 4H), 1.46 - 1.25 (m, 4H), 1.74 - 1.64 (m, 4H), 1.82 (d, 4H), 2.48 (s, 2H), 2.64 - 2.58 (m, 4H), 3.20 (s, 3H), 3.33 (d, 2H), 3.39 (s, 2H), 3.90 (s, 3H), 4.53 - 4.47 (m, IH), 7.19 - 7.17 (m, IH), 7.43 (s, IH), 7.58 (s, IH), 7.77 (s, IH), 8.38 (d, IH), 8.92 - 8.88 (m, IH); MS m/z 590 [M+H]+.
Example 441: 4-(9'-cyclohexyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-N-[(3R)-l-ethylpyrrolidin-3-yl]-3-methoxy- benzamide
The title compound was prepared by an analogous method to the preparation of Example 439, on a 0.24 mmol scale, utilising 4-amino-N-[(3R)-l-ethylpyrrolidin-3-yl]-3-methoxy-0 benzamide (Intermediate 245; 70 mg, 0.26 mmol), as a white solid (57 mg, 38%).
1H NMR (400.132 MHz, DMSO-d6) δ 0.69 (m, 2H), 0.93 (m, 2H), 1.04 (t, 3H), 1.15 (m, IH), 1.45 (m, 4H), 1.76 (m, 6H), 2.15 (m, IH), 2.43 (m, 4H), 2.66 (m, IH), 2.72 (m, IH), 3.16 (s, 3H), 3.50 (s, 2H), 3.96 (s, 3H), 4.42 (m, 2H), 7.50 (m, IH), 7.54 (d, IH), 7.66 (s, IH), 7.96 (s, IH), 8.31 (d, IH), 8.40 (d, IH); MS m/z 548 [M+H]+. 5
Example 442:
4-(9'-cyclohexyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-2-fluoro-5-methoxy-N-[(lS,5R)-9-methyl-9- azabicyclo[3.3.1]non-3-yl]benzamide o The title compound was prepared by an analogous method to the preparation of Example 439, on a 0.17 mmol scale, utilising 4-amino-3-methoxy-N-[(lS,5R)-9-methyl-9- azabicyclo[3.3.1]non-3-yl]benzamide (Intermediate 204; 55 mg, 0.17 minol), heating thermally at 140 0C for 2 hours, as a white solid (24 mg, 23%).
1HNMR (399.9 MHz, DMSO-d6) δ 0.70 - 0.73 (2H, m), 0.90 - 0.96 (4H, m), 1.13 - 1.20 (IH, m), 1.40 - 1.55 (7H, m), 1.67 (IH, d), 1.75 - 1.95 (6H, m), 2.01 - 2.11 (IH, m), 2.18 - s 2.26 (2H, m), 2.42 (3H, s), 2.98 (2H, d), 3.17 (3H, s), 3.53 (2H, s), 3.94 (3H, s), 4.27 - 4.34 (IH, m), 4.45 - 1.52 (IH, m), 7.22 (IH, d), 7.68 - 7.72 (IH, m), 7.74 (IH, s), 8.00 (IH, s), 8.26 (IH, d); MS m/z 606 [M+H]+.
Example 443; I0 4-(9 ' -cy clohexy 1-5 ' -methy 1-6 ' -oxo-5 ' ,6 ' ,8 ' ,9 ' -tetrahy drospiro [cyclopropane- 1,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-N-(l-ethyl-4-piperidyl)-2-fluoro-5-methoxy- benzamide
2'-chloro-9'-cyclohexyl-5'-methyl-8',9'-dihydrospiro[cyclopropane-l,7'-pyrimido[5,4- b][l,4]diazepin]-6'(5'H)-one (Intermediate 270; 54 mg, 0.17 mmol), 4-amino-N-(l-ethyl-4-
I5 piperidyl)-2-fluoro-5-methoxy-benzamide (Intermediate 205; 50 mg, 0.17 mmol), and p- toluenesulphonic acid monohydrate (81 mg, 0.43 mmol) were stirred together in 4-methyl-2- pentanol (3 mL) and heated at 110 0C for 18 hours. The cooled reaction mixture was loaded onto an SCX-3 (5 g) column pre-wet with MeOH. The column was washed with MeOH ( 2 column volumes) and eluted with 2M NH3/MeOH. Solvent evaporation of the combined
20 ammoniacal fractions gave a brown gum which was purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (48 mg, 49%) 1HNMR (400.132 MHz, DMSO-d6) δ 0.70 (m, 2H)5 0.94 (m, 2H), 1.00 (t, 3H), 1.14 (m, 2H), 1.61 (m, 12H), 1.96 (m, 2H), 2.32 (q, 3H), 2.83 (d, 2H), 3.17 (s, 3H), 3.52 (s, 2H), 3.72 (m, IH), 3.93 (s, 3H), 4.47 (m, IH), 7.19 (d, IH), 7.73 (s, IH), 7.82 (m, IH), 7.99 (s, IH),
2S 8.26 (d , IH); MS m/z 580 [M+H]+.
Example 444:
4-(9'-cyclohexyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-2-fluoro-5-methoxy-N-(2-pyrrolidin-l- 30 ylethyl)benzamide The title compound was prepared by an analogous method to the preparation of Example 443, on a 0.18 mmol scale, utilising 4-amino-2-fluoro-5-methoxy-N-(2-pyrrolidin-l- ylethyl)benzamide (Intermediate 228; 50 mg, 0.18 mmol), as a white solid (58 mg, 57%). 1HNMR (400.132 MHz, DMSO-d6) δ 0.71 (m, 2H), 0.94 (m, 2H), 1.15 (m, 2H), 1.61 (m, 12H), 2.50 (m, 4H), 2.58 (t, 3H), 3.16 (s, 3H), 3.39 (m, 2H), 3.52 (s, 2H), 3.93 (s, 3H), 4.48 (m, IH), 7.30 (d, IH), 7.76 (bs, IH), 7.91 (m, IH), 7.99 (s, IH), 8.27 (d, IH); MS m/z 566 [M+H]+.
Example 445: 4-(9'-cyclohexyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-2-fluoro-5-methoxy-N-[[l-(pyrrolidin-l- ylmethyl)cyclopropyl]methyl]benzamide
The title compound was prepared by an analogous method to the preparation of Example 443, on a 0.16 mmol scale, utilising 4-amino-2-fluoro-5-methoxy-N-[[l-(pyrrolidin-l- ylmethyl)cyclopropyl]methyl]benzamide (Intermediate 254; 52 mg, 0.16 mmol), as a white solid (53 mg, 55%).
1HNMR (400.132 MHz, DMSOd6) δ 0.34 (2H, m), 0.51 (2H, m), 0.71 (2H, m), 0.94 (2H, m), 1.16 (IH, m), 1.47 (5H, m), 1.72 (1OH, m), 2.44 (2H, s), 2.49 (2H, s), 3.17 (3H, s), 3.37 (2H, d), 3.53 (2H, s), 3.93 (3H, s), 4.48 (IH, m), 7.39 (IH, d), 7.78 (IH, s), 7.99 (IH, s), 8.26 (IH, d), 8.37 (IH, m); MS m/z 606 [M+H]+.
Example 446:
4-(9'-cyclohexyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cycIopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-3-fluoro-N-(l-methyl-4-piperidyl)benzamide 2'-chloro-9'-cyclohexyl-5l-methyl-8',9'-dihydrospiro[cyclopropane- 1 ,7'-pyrimido[5,4- b][l,4]diazepin]-6'(5Η)-one (Intermediate 270; 200 mg, 0.62 mmol), 4-amino-3-fluoro-N-(l- methylpiperidin-4-yl)benzamide (Intermediate 65; 157 mg, 0.62 mmol) and p- toluenesulfonic acid monohydrate (296 mg, 1.56 mmol) were suspended in 4-Methyl-2- pentanol (5 mL) and sealed into a microwave tube. The reaction was heated at 160 0C for 30 minutes in the microwave reactor and then allowed to cool to room temperature. The reaction mixture was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford a cream coloured solid which was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and
5 MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to yield the title compound as a white solid (125 mg, 37%).
1H NMR (400.132 MHz, DMSO-d6) δθ.65 (t, 2H), 0.95 (t, 2H), 1.1 (m, IH), 1.35 (q, 2H), 1.45 (q, 2H), 1.5-1.7 (m, 5H), 1.8 (m, 4H), 1.95 (t, 2H), 2.15 (t, 2H), 2.2 (s, 3H), 2.8 (d, 2H), 3.2 (s, 3H), 3.45 (s, 2H), 3.7 (m, IH), 4.4 (m, IH), 7.65 (m, IH), 7.7 (m, IH), 7.95 (s IH), io 8.15 (m, 2H), 8.6 (s, IH); MS m/z 536 [M+H]+.
Example 447:
4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll- trien-lO-y^aminol-l^-difluoro-N-lClSjS^^-methyl^-azabicycloIS.S.llnon^- I5 yl]benzamide p-Toluenesulphonic acid monohydrate (338 mg, 1.78 mmol) was added to 4-amino-2,5- difluoro-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-7-yl]benzamide (Intermediate 274; 220 mg, 0.71 mmol), and 2-chloro-9-cyclopentyl-5-methyl-8,9-dihydro-5H-pyrimido[5,4- b][l,4]diazepin-6(7H)-one (Intermediate 1; 200 mg, 0.71 mmol) in 4-methyl-2-pentanol (4
20 mL) at 25 0C. The resulting mixture was heated by microwave irradiation at 150 °C for 1 hour. The crude product was purified by ion exchange chromatography, using an SCX-3 (5g) column. The desired product was eluted from the column using 2M NH3/MeOH and product- containing fractions were evaporated to dryness. The residue was further purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (91 mg,
25 23.%).
1H NMR (400.132 MHz, DMSOd6) δ 0.90 - 0.93 (2H, m), 1.37 - 1.44 (4H, m), 1.57 - 1.71 (6H, m), 1.86 - 2.04 (4H, m), 2.17 - 2.24 (2H, m), 2.41 (3H, s), 2.58 - 2.61 (2H, m), 2.96 - 2.99 (2H, m), 3.18 (3H, s), 3.62 - 3.64 (2H, m), 4.21 - 4.33 (IH, m), 4.78 - 4.86 (IH, m), 7.42 - 7.46 (IH, m), 7.81 (IH, d), 8.11 (IH, s), 8.20 - 8.25 (IH, m), 8.91 (IH, s); MS m/z 555 so [M+H]+. Example 448;
4-(9'-cyclopentyl-5l-methyl-6'-oxo-5t,6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-2,5-difluoro-N-((lR,3r,5S)-9-methyl-9- azabicyclo[3.3.1]nonan-3-yI)benzamide
The title compound was prepared by an analogous method to the preparation of Example 446, on a 0.65 mmol scale, utilising 2'-chloro-9'-cyclopentyl-5'-methyl-8',9'- dihydrospiro[cyclopropane-l,7'-pyrimido[5,4-b][l,4]diazepin]-6'(5Η)-one (Intermediate 130; 200mg, 0.65 mmol), as a white solid (50 mg, 13%).
1H NMR (400.132 MHz, DMSO-d6) δ 0.67 - 0.70 (2H, m), 0.90 - 0.93 (4H5 m), 1.36 - 1.60 (7H, m), 1.64 - 1.71 (2H, m), 1.85 - 1.93 (4H, m), 1.97 - 2.04 (IH, m), 2.17 - 2.24 (2H, m), 2.40 (3H, s), 2.96 - 2.98 (2H, m), 3.18 (3H, s), 3.48 (2H, s), 4.21 - 4.32 (IH, m), 4.82 - 4.91 (IH, m), 7.42 - 7.46 (IH, m), 7.79 - 7.82 (IH, m), 8.02 (IH, s), 8.23 - 8.28 (IH, m), 8.85 (IH, s); MS m/z 581 [M+H]+.
Example 449;
4-(9'-cyclohexyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepine]-2'-ylamino)-2,5-difluoro-N-((lR,3r,5S)-9-methyl-9- azabicyclo[3.3.1]nonan-3~yl)benzamide
The title compound was prepared by an analogous method to the preparation of Example 446, on a 0.62 mmol scale, utilising 2'-chloro-9'-cyclohexyl-5'-methyl-8',9'- dihydrospiro[cyclopropane- 1 ,7'-pyrimido[5,4-b] [1 ,4]diazepin]-6'(5Η)-one (Intermediate 270; 200mg, 0.62 mmol), as a white solid (37 mg, 10%). 1H NMR (400.132 MHz, DMSOd6) δ 0.69 - 0.72 (2H, m), 0.90 - 0.95 (4H, m), 1.09 - 1.16 (IH, m), 1.33 - 1.50 (8H, m), 1.61 - 1.80 (4H, m), 1.86 - 1.92 (2H, m), 1.97 - 2.04 (IH, m), 2.16 - 2.24 (2H, m), 2.41 (3H, s), 2.96 - 2.98 (2H, m), 3.17 (3H, s), 3.50 (2H, s), 4.21 - 4.32 (IH, m), 4.43 - 4.49 (IH, m), 7.42 - 7.47 (IH, m), 7.81 - 7.84 (IH, m), 7.99 (IH, s), 8.13 - 8.18 (IH, m), 8.76 (IH, s); MS m/z 595 [M+H]+. Example 450;
4-(9'-cycIohexyl-6'-oxo-5',6',8',9l-tetrahydrospiro[cyclopropane-l,7'-pyrimido[5,4- b][l,4]diazepine]-2'-ylamino)-3-fluoro-N-((lR,3rj5S)-9-methyl-9-azabicyclo[3.3.1]nonan- 3-yl)benzamide
2'-chloro-9l-cyclohexyl-8l,9'-dihydrospiro[cyclopropane-l,7'-pyrimido[5,4-b][l,4]diazepin]- 6'(5Η)-one (100 mg, 0.33 mmol), 4-amino-3-fluoro-N-((lR,3r,5S)-9-methyl-9- azabicyclo[3.3.1]nonan-3-yl)benzamide (95 mg, 0.33 mmol) and p-Toluenesulfonic acid . H2O (155 mg, 0.81 mmol) were suspended in 4-Methyl-2-pentanol (2 mL) and sealed into a microwave tube. The reaction was heated to 160 °C for 25 minutes by microwave irradiation and then cooled to room temperature. The reaction mixture was filtered through a PTFE Filter cup to give an off white solid which was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to yield the title compound as a white solid (27 mg, 15 %).
1H NMR (400.132 MHz, DMSOd6) δ 0.8 (t, 2H), 0.9 (d, 2H), 1.1 (t, 2H), 1.2-1.5 (m, 8H), 1.6 ( b, 3H), 1.75 (d, 2H), 1.9 (m,2H), 2.0 (m, IH), 2.2 (m, 2H), 2.4 (s,3H), 2.95 (d, 2H), 3.4 (s, 2H), 4.3 (m, IH), 4.5 (m, IH), 7.55 (d, IH), 7.6 (d, IH), 7.85 (s, IH), 7.95 (d, IH), 8.15 (t, IH), 8.5 (s, IH), 9.5 (s, IH); MS m/z 563 [M+H]+.
Example 451;
4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-10- yl)amino] -3-methoxy-N- [(lR,5S)-9-methyl-3-oxa-9-azabicycIo [3.3.1] non-7-yl] benzamide p-Toluenesulphonic acid monohydrate (143 mg, 0.83 mmol) was added to 10-Chloro-2- cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1; 93 mg, 0.33 mmol) and 4-amino-3-methoxy-N-[(lR,5S)-9-methyl-3-oxa-9- azabicyclo[3.3.1]non-7-yl]benzamide (Intermediate 275; 100 mg, 0.33 mmol) in 4-methyl-2- pentanol (3 mL) at 250C. The resulting suspension was stirred at 110 °C for 18 hours. The reaction mixture was cooled to ambient temperature and purified by ion exchange chromatography, using an SCX-2 (5g) column. The desired product was eluted from the column using 2M NH3/MeOH and fractions were evaporated to dryness to afford the crude product as a gum which was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluent. Fractions containing the desired compound were combined and evaporated to dryness to afford the title compound as a white s solid (15 mg, 8 %).
1H NMR (400.132 MHz, DMSOd6) δ 1.36 - 1.40 (2H, m), 1.57 - 1.72 (6H, m), 1.89 - 1.95 (2H, m), 2.33 - 2.41 (2H, m), 2.45 (3H, s), 2.57 - 2.63 (4H, m), 3.17 (3H, s), 3.61 - 3.64 (2H, m), 3.71 - 3.74 (2H, m), 3.89 - 3.91 (2H, m), 3.93 (3H, s), 4.39 - 4.45 (IH, m), 4.74 - 4.82 (IH, m), 7.29 (IH, d), 7.38 (IH, s), 7.75 (IH, s), 8.07 (IH, s), 8.37 (IH, d), 8.83 (IH, d); MSo m/z 551 [M+H]+.
Example 452:
N-(azepan-3-yl)-4- [(2-cyclopentyI-6-methyl-5-oxo-2,6,9,l 1-tetrazabicyclo [5.4.0] undeca-
7,9,ll-trien-10-yl)amino]-3~methoxy-benzamide s A solution of tert-butyl 3-[[4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,l 1- tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien- 10-yl)amino]-3-methoxy-benzoyl]amino]azepane- 1 - carboxylate (Example 348; 149 mg, 0.25 mmol) in DCM (2 niL) was treated with TFA (1 mL) The resulting solution was stirred at ambient temperature for 5 hours. The reaction mixture was diluted with DCM (10 mL) and submitted to ion exchange 0 chromatography, using an SCX-3 column. The column was eluted with DCM (50 mL) and methanol (50 mL) before the desired product was eluted from the column using 2M NH3/MeOH. The ammoniacal solution was evaporated to dryness to afford the title compound as an amber gum (95 mg, 76 %). 1H NMR (400.132 MHz, DMSOd6) δ 1.41 - 1.92 (16H, m), 2.51 - 2.53 (2H, m), 2.60 - 2.67s (IH, m), 2.73 (IH, t), 2.92 (IH, dd), 3.10 (3H, s), 3.54 - 3.58 (2H, m), 3.88 (3H, s), 3.90 - 3.99 (IH, m), 4.70 - 4.79 (IH, m), 7.38 - 7.43 (2H, m), 7.66 (IH, s), 7.93 (IH, d), 8.01 (IH, s), 8.31 (IH, d); MS m/z 508 (M+H)+
Example 453: 0 4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- yl)amino]-3-methoxy-N-(l-methylazepan-3-yl)benzamide To a solution of N-(azepan-3-yl)-4-[(2-cyclopentyl-6-methyl-5-oxo~2,6,9,ll- tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-10-yl)amino]-3-methoxy-benzamide (Example 453; 88 mg, 0.17 mmol) in formaldehyde (1 mL, 13.35 mmol) and acetic acid (100 μL, 1.75 mmol), was added sodium acetate (142 mg, 1.73 mmol). The reaction mixture was cooled to s 0 °C with stirring. Sodium cyanoborohydride (12 mg, 0.19 mmol) was added and the reaction mixture stirred at 0 0C for 5 minutes before removing the cooling bath. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours and then submitted to ion exchange chromatography, using an SCX-3 column. The column was washed with methanol, before the crude products were eluted from the column using 2M NH3/MeOH. Evaporationo of the amnioniacal solution afforded the crude product as an amber gum which was purified by flash silica chromatography, elution gradient 5 to 10% 2M ammonia/MeOH in DCM. Pure fractions were combined and evaporated to dryness to give 4-(9-cyclopentyl-5-methyl-6-oxo- 6,7,8,9-tetraliydro-5H-pyrimido[5,4-b][l,4]diazepin-2-ylamino)-3-methoxy-N-(l- methylazepan-3-yl)benzamide as an amber glass (44 mg, 49 %) s 1HNMR (400.132 MHz, CDCl3) δ 1.53 - 1.86 (12H, m), 1.91 - 1.96 (IH, m), 2.03 - 2.10 (2H, m), 2.45 (3H, s), 2.65 - 2.70 (3H, m), 2.79 - 2.86 (2H, m), 3.30 (3H, s), 3.68 - 3.72 (2H, m), 3.99 (3H, s), 4.25 - 4.33 (IH, m), 4.91 (IH, quintet), 7.18 - 7.25 (IH, m), 7.31 (IH, d), 7.48 (IH, d), 7.65 (IH, s), 7.95 (IH, s), 8.51 (IH, d); MS m/z 522 (M+H)+ 0 Preparation of Intermediates: Intermediate 1:
10-Chloro-2-cyclopentyl-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5- one
To a cold (0 0C) solution of 9-chloro-6-cyclopentyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-5 8,10,12-trien-3-one (Intermediate 2; 241 mg, 0.90 mmol) in DMA (20 mL) was added MeI (62 uL, 0.99 mmol) followed by NaH (39 mg, 0.96 mmol) and the reaction mixture stirred at 00C for 30 mins then at ambient temperature for 1 hr. The solution was diluted with Ethyl Acetate (20 mL), washed with water (2 x 30 mL), brine (30 mL), dried (MgSO4) and the volatiles were removed under reduced pressure. Purification by column chromatography0 (SiO2, eluent gradient: 2% MeOH in DCM) afforded the title compound (187 mg, 74%) as a solid. 1H NMR (400 MHz5 DMSO-D6) δH 1.52 - 1.66 (m, 4H), 1.66 - 1.75 (m, 2H), 1.85 - 1.96 (m, 2H), 2.63 - 2.67 (m, 2H), 3.18 (s, 3H), 3.64 - 3.68 (m, 2H), 4.71 - 4.79 (m, IH), 8.15 (s, IH); MS 281, 283 [M+H]+.
Intermediate 2:
9-Chloro-6-cyclopentyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-3-one
To a solution of methyl 3-[(2-chloro-5-oxidoazonoyl-pyrimidin-4-yl)-cyclopentyl- aniino]propanoate (Intermediate 3; 1.00 g, 3.04 mmol) in AcOH (50 mL) was added powdered Fe (1.00 g, 3.04 mmol) and the reaction stirred at 70 0C for 30 mins. The reaction mixture was filtered hot through a pad of celite, washed with AcOH (25 mL) and the volatiles removed under reduced pressure. Purification by column chromatography (SiO2, eluent gradient: 0-100% Ethyl Acetate in hexane) gave the title compound (480 mg, 43%) as a solid. 1H NMR (400 MHz, CDCl3) δH 1.46 - 1.56 (m, 2H), 1.62 - 1.80 (m, 3H), 1.94 - 2.04 (m, 3H), 2.77 - 2.79 (m, 2H), 3.60 - 3.63 (m, 2H), 5.17 - 5.26 (m, IH), 7.79 (s, IH), 7.99 (s, IH); MS m/z 267, 269 [M+H]+.
Intermediate 3;
Methyl 3-[(2-chloro-5-oxidoazonoyl-pyrimidin-4-yl)-cyclopentyl-amino]propanoate
To a solution of methyl 3-(cyclopentylainino)propanoate (2.46 g, 14.37 mmol) in acetone (40 mL) was added K2CO3 (2.03 g, 14.65 mmol) and 2,4-dichloro-5-nitropyrimidine (3.07 g, 15.80 mmol) and the reaction mixture stirred at ambient temperature under an atmosphere of nitrogen for 18 hrs. The volatiles were removed under reduced pressure and the crude material was dissolved in Ethyl Acetate (50 mL), washed with water (2 x 50 mL), brine (50 mL), dried (MgSO4) and the volatiles removed under reduced pressure. Purification by column chromatography (SiO2, eluent gradient: 0-10% Ethyl Acetate in hexane) afforded the title compound (2.23 g, 53%) as a solid.
1H NMR (400 MHz, DMSO-d6): δH 1.44 - 1.54 (m, 2H), 1.62 - 1.78 (m, 4H), 1.86 - 1.96 (m, 2H), 2.69 (t, 2H), 3.61 (s, 3H), 3.66 (t, 2H), 3.71 - 3.80 (m, IH), 8.84 (s5 IH); MS m/z 329, 331 [M+H]+. Intermediate 4: 4-Amino-iV-(l-methyl-4-piperidyl)benzamide
^-Aminobenozoic acid (137 mg, 1 mmol), 4-amino-iV-methylpiperidine (114 mg, 1 mmol) and DIPEA (522 uL, 3 mmol) were dissolved in DMA (5 niL). HATU (570 mg, 1.5 mmol) in s DMA (5 mL) was added and the reaction stirred at ambient temperature for 2 h. The volatiles were removed under reduced pressure and NaHCO3 (50 mL, sat. aq.) was added. The resulting precipitate was removed by filtration and the aqueous phase neutralised with HCL (2N). The reaction mixture was then loaded onto an SCX-2 cartridge washing with copious quantities of water. The crude product was the eluted from the SCX-2 cartridge with NH3 (60o mL, 7M in MeOH). Purification by column chromatography (SiO2, eluent: 10% NH3 [7M in MeOH] in DCM) afforded the title compound (167 mg, 72%) as a solid. 1H NMR (400 MHz, DMSO-d6) δH 1.50 - 1.60 (2H, m), 1.69 - 1.73 (IH, m), 1.72 (IH, t), 1.89 - 1.96 (2H, m), 2.16 (3H, s), 2.75 (2H, d), 3.65 - 3.71 (IH, m), 5.52 - 5.54 (IH5 m), 6.52 - 6.55 (2H, m), 7.56 - 7.59 (2H, m), 7.69 (IH, d); MS m/z 234 [M+H]+. s
Intermediate 5:
10-chloro-2-cyclopentyl-4,6-dimethyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-
5-one 0 To a cold (-78 0C) solution of 10-chloro-2-cyclopentyl-6-methyl-2,6,9,l 1- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (90 mg, 0.32 mmol) in dry THF (4 mL) was added LiHMDS (640 μL, IM in THF, 0.64 mmol) dropwise over 10 mins. MeI (40 μL, 0.64 mmol) in THF (1 mL) was added and the reaction mixture was stirred at -78 0C for 20 mins and then at 0 °C for 1 hr. The reaction mixture was diluted with DCM (20 mL) and washed5 with water (2 x 20 mL), brine (40 mL), dried (MgSO4), filtered and the volatiles removed under reduced pressure to yield the title compound (106 mg, 100%) as a solid. MS m/z 295, 297 [MH-H]+.
Intermediate 6: 0 4- [(9-Cyclopentyl-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido [4,5-b] [1 ,4] diazepin-2- yl)amino]-3-methoxybenzoic acid Methyl 4-[(9-cyclopentyl-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b] [1 ,4]diazepin-2- yl)amino]-3-methoxybenzoate (Intermediate 7; 250 mg, 0.61 mmol) and HCl (2 mL, concentrated aqueous) were suspended in water (4 mL) and heated at reflux for 24 h. The reaction mixture was then cooled to ambient temperature and the volatiles were removed
5 under reduced pressure. The solid obtained was dissolved in MeOH:DCM (1 :10, 40 mL) and washed with NaHCO3 (saturated aqueous, 40 mL). The organic layer was then dried (MgSO4), Filtered and the volatiles removed under reduced pressure to afford the title compound (240 mg, 99%) as a solid. 1H NMR (400MHz, DMSO-d6) δH 1.57 (m, 4H), 1.73 (m, 2H), 1.88 (m, 4H), 2.70 (s, 3H), io 2.95 (t, 2H), 3.47 (m, 2H), 3.87 (s, 3H), 4.86 (quintet, IH), 7.20 (s, IH)9 7.42 (d, IH), 7.50 (s, IH), 7.52 (s, IH), 7.96 (s, IH), 8.28 (d, IH); MS m/z 398 [M+H]+.
Intermediate 7;
Methyl 4-[(9-cyclopentyl-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b] [l,4]diazepin-
I5 2-yl)amino]-3-methoxybenzoate
BH3-SMe2 (1.36 mL, 5.0 M in Et2O, 6.8 mmol) was added to solution of methyl 4-[(9- cyclopentyl-S-methyl-ό-oxo-δ^^^-tetrahydro-SH-pyrimido^jS-blfl^Jdiazepin-l- yl)amino]-3-methoxybenzoate (Intermediate 8; 290 mg, 0.68 mmol) in THF (4 mL) and stirred for 5 h at ambient temperature under an atmosphere of nitrogen. HCl (10 mL,
20 concentrated aqueous) was added and the resulting solution was stirred at ambient temperature for 16 h. The HCl solution was then diluted with water (50 mL), and loaded onto an SCX-2 column. The SCX-2 column was then washed with water (50 mL) and MeOH (50 mL). The product was then eluted from the SCX-2 column with NH3 (50 mL, 7M in MeOH). The volatiles were then removed under reduced pressure to afford the title compound (250
25 mg, 89%) as a solid.
1H NMR (400 MHz, DMSO-d6) δH 1.67 (m, 6H), 1.96 (m, 4H), 2.77 (s, 3H), 3.06 (t, 2H), 3.58 (m, 2H), 3.88 (s, 3H), 4.00 (s, 3H), 4.91 (quintet, IH), 7.57 (m, 3H), 7.71 (s, IH), 8.59 (d, lH); MS m/z 412 [M+H]+.
30 Intermediate 8: Methyl 4- [(9-cy clopentyl-5-methyl-6-oxo-6,7,8,9-tetrahy dro-5H-py rimido [4,5- b][l,4]diazepin-2-yl)amino]-3-methoxybenzoate
2-Chloro-9-cyclopentyl-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][l,4]diazepin-6-one (Intermediate 1; 500 mg, 1.78 mmol), methyl 4-amino-3-methoxybenzoate (324 mg, 1.78 mmol) and p-toluenesulfonic acid (847 mg, 4.45 mmol) were suspended in (2R/S)-4-methyl- 2-pentanol (10 mL) and heated at reflux for 5 h. The reaction mixture was cooled and loaded onto an SCX-2 column and washed with MeOH (20 mL). The crude product was then eluted from the SCX-2 column with NH3 (40 mL, 7M in MeOH) and the volatiles removed under reduced pressure. Purification by column chromatography (SiO2, eluent gradient 0-10% MeOH in DCM) afforded the title compound (290 mg, 38%) as a solid.
1H NMR (400.132 MHz, DMSO-d6) δH 1.71 (m, 6H), 2.00 (m, 2H), 2.65 (m, 2H), 3.23 (s, 3H), 3.69 (m, 2H), 3.89 (s, 3H), 4.01 (s, 3H), 4.87 (m, IH), 7.56 (d, IH), 7.64 (d, IH)5 7.90 (s, IH), 8.16 (s, IH), 8.55 (d, IH); MS m/z 426 [M+H]+.
Intermediate 9:
10-Chloro-2,6-dimethyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5-one
3 - [(5 -Bromo-2-chloro-py rimidin-4-y l)-methyl-amino] -N-methyl-propanamide (Intermediate 15; 2.09 g, 6.20 mmol), tris(dibenzylideneacetone)dipalladium(0) (171 mg, 0.19 mmol), (5- diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (288 mg, 0.50 mmol) and Cs2CO3 (2930 mg, 8.99 mmol) in 1,4-dioxane (50 mL) were heated at reflux for 16 h under an atmosphere of nitrogen. The reaction mixture was evaporated then suspended in DCM (20 mL) and filtered through a layer of celite washing with DCM (40 mL). Purification by column chromatography (SiO2, eluent gradient: 2-10% MeOH in DCM) afforded the title compound (190 mg, 19%) as a foam. 1H NMR (400 MHz5 DMSO-d6) δH 2.67 (tr, 2H), 3.08 (s, 3H), 3.20 (s, 3H), 3.72 (tr, 2H), 8.19 (s, IH); MS m/z 227 [M+H]+.
Intermediate 10 10-ChIoro-6-methyl-2-propan-2-yI-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5- one Intermediate 11:
10-Chloro-6-methyl-2-(3-methylbutyl)-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien- 5-one
Intermediate 12: 10-Chloro-2-cyclohexyl-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5-one Intermediate 13:
10-Chloro-6-methyl-2-(oxan-4-yl)-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5- one
Figure imgf000272_0001
Intermediates 10-13 were prepared, using the appropriate secondary amide (Intermediates 14, 16-18), by an analogous process to that used in the preparation of Intermediate 9.
Figure imgf000272_0002
Intermediate 14: 3-[(5-Bromo-2-chloro-pyrimidin-4-yl)-propan-2-yl-amino]-N-methyl-propanamide 5-Bromo-2,4-dichloropyrimidine (1.83 g, 8.00 mmol), N-methyl-3-(propan-2- ylamino)propanamide (Intermediate 14, 1.16 g, 8.00 mmol) and Et3N (1.2 mL, 8.16 mmol) were combined in MeCN (50 mL) and shaken at ambient temperature for 3 days before the solvent was removed under reduced pressure. Purification by column chromatography (SiO2, eluent gradient 2-10% MeOH to DCM) to afford the title compound (2.08 g, 78%) as a gum. 1H NMR (400 MHz, DMSO-d6) δH 1.16 - 1.20 (6H, m), 2.31 (2H, t), 2.55 - 2.58 (3H, d), 3.65 (2H, t), 4.55 - 4.62 (IH, septet), 7.71 - 7.72 (IH, br s), 8.39 (IH5 s); MS m/z 337 [M+H]+.
Intermediate 15:
3-[(5-Bromo-2-chloro-pyrimidin-4-yl)-methyl-amino]-N-methyl-propanamide
Intermediate 16
3-[(5-Bromo-2-chloro-pyrimidin-4-yl)-(3-methylbutyl)amino]-N-methyI-propanamide
Intermediate 17: 0 3- [(5-Bromo-2-chIoro-pyrimidin-4-yl)-cy clohexyl-amino] -N-methyl-propanamide
Intermediate 18: 3-[(5-Bromo-2-chloro-pyrimidin-4-yl)-(oxan-4-yl)amino]-N-methyl-propanamide
Figure imgf000273_0001
S Intermediates 15-18 were prepared in an analogous manner to intermediate 14 using 5-bromo-2,4- dichloropyrimidine as the electrophile and the appropriate known or described (Intermediates 19 - 21) β-aminoamides:
Figure imgf000274_0001
Intermediate 19:
N-Methyl-3~(propan-2-ylamino)propanamide
N-Methylacrylamide (851 mg, 10.00 mmol) and isopropylamine (1.71 niL, 1.18 g, 20.00 mmol) in MeOH (10 mL) were irradiated to 140 0C for 30 mins in a microwave reaction vessel. The reaction mixture was cooled and loaded onto a SCX-2 column and washed with MeOH (100 mL). The crude product was then eluted from the SCX-2 column with NH3 (100 mL, 7M in MeOH) and the volatiles removed under reduced pressure to afford the title compound (1.56 g, Quant.) as an oil, which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δH 0.96 (d, 6H), 2.18 (t, 2H), 2.57 (d, 3H), 2.65 - 2.71 (m, 3H), 7.81 (br s, IH).
Intermediate 20: N-Methyl-3-(3-methylbutylamino)propanamide
Intermediate 21: N-Methyl-3-(oxan-4-ylamino)propanamide
Figure imgf000275_0001
Intermediates 20 and 21 were prepared in an analogous manner to Intermediate 19 using the N-methylacrylamide as the α,β-unsaturated amide and the appropriate commercially available primary amine:
Figure imgf000275_0003
Intermediate 22:
4-amino~N-(3-dimethylamino-2,2-dimethyl-propyl)-3-methoxy-benzamide
Figure imgf000275_0002
A suspension of N-(3-dimethylamino-2,2-dimethyl-ρropyl)-3-methoxy-4-nitro-benzamide (Intermediate 23; 5.7 g, 18.40 mmol), 5% Pd on charcoal (569 mg) in EtOH (300 mL) was stirred at 40 0C under a hydrogen atmosphere for 16 h. The reaction mixture was then filtered through celite, washed with copious MeOH and the volatiles removed under reduced pressure to afford the title compound (5.36 g, Quant.) as a foam.
1U NMR (400 MHz, DMSOd6): δH 0.88 (m, 6H)5 2.18 (s, 2H), 2.28 (s, 6H), 3.18 (m, 2H), 3.82 (s, 3H), 5.21 (m, 2H), 6.63 (d, IH), 7.25 m, 2H), 8.11 (m, IH); MS m/z 280 [M+H]+.
Intermediate 23; N-(3-Dimethylamino-2,2-dimethyl-propyl)-3-methoxy-4-nitro-benzamide
To a suspension of 4-nitro-3-methoxybenzoic acid (Aldrich; 5.0 g, 25.3 mmol), N,N-2- tetramethyl-l,3-propanediamine (Aldrich; 4.64 mL, 27.83 mmol) and DIPEA (8.8 mL, 50.60 mmol) in anhydrous DMA (100 mL) under nitrogen at ambient temperature was added HATU (10.6 g, 27.83 mmol) and the resulting reaction mixture was stirred at 50 0C for 3 h and ambient temperature for a further 12 h. Evaporation removed any volatiles and the residue was dissolved in DCM (100 mL) and washed with NaHCO3 (100 mL), brine (100 mL), dried (MgSO4) and the volatiles removed under reduced pressure. Purification by column chromatography (SiO2, eluent gradient: 2-10% MeOH in DCM) afforded the title compound (5.7 g, 73%) as a solid.
1H NMR (400 MHz, DMSO-d6): δH 1.06 (s, 6H), 2.42 (s, 2H), 2.82 (s, 6H), 3.30 (s, 2H), 3.98 (s, 3H), 7.57 (dd, IH), 7.71 (s, IH), 8.93 (d, IH); MS m/z 310 [M+H]+.
Intermediate 24: l-cyclopropyIpiperidin-4-amine
N-benzyl-l-cyclopropyl-piperidin-4-amine (Intermediate 25; 2.3 g 10 mmol), 10% Palladium on Carbon (230 mg) and Methanol (230 mL) were combined and heated with stirring at 30}C under Hydrogen at 5 bar pressure for 16 hours.
The mixture was filtered and concentrated, taken up in DCM, dried (MgSO4) and concentrated to give the title compound (1.29g, 64%) as a yellow liquid 1HNMR (399.9 MHz, CDCl3) δθ.36 - 0.46 (4H, m), 1.26 - 1.36 (4H, m), 1.52 - 1.58 (IH, m), 1.76 - 1.82 (2H, m), 2.18 - 2.25 (2H, m), 2.63 - 2.70 (IH, m), 2.94 - 2.99 (2H, m); MS m/z 161.90 [M+H]+. Intermediate 25; N-benzyl-l-cyclopropyl-piperidin-4-amine l-cyclopropylpiperidin-4-one Intermediate 26 (3g, 21.55mmol), benzylamine (4.7ml,
43.10mmol) and acetic acid (1.25ml) were stirred together and sodium triacetoxyborohydride (6.86g, 32.33mmol) added portion-wise. DCM (20ml) was added and the mixture stirred at room temperature overnight. The mixture was concentrated and partitioned between ethyl acetate and 2M potassium carbonate solution. The aqueous layer was re-extracted with ethyl acetate and the combined organics washed with brine, dried (MgSO4) and concentrated. Column chromatography (2% 7N ammonia in methanol / DCM) gave a brown liquid which contained Benzylamine and thus was taken up in DCM and stirred with PS-benzaldehyde (NovaBiochem, =3.2mmol/g ; «1.5 equivalents compared to benzylamine) for 3h. The mixture was filtered and the combined filtrates concentrated to give the title compound (2.33 g, 47%) as a brown oil.
1H NMR (399.9 MHz, CDCl3) δθ.38 - 0.43 (4H, m), 1.33 - 1.40 (2H, m), 1.46 (IH, s), 1.52 - 1.57 (IH, m), 1.86 - 1.90 (2H, m), 2.18 - 2.24 (2H, m), 2.51 - 2.56 (IH, m), 2.96 - 3.01 (2H, m), 3.82 (2H, s), 7.22 - 7.25 (IH, m), 7.29 - 7.33 (4H, m)
Intermediate 26:
1 -cy clopropy lpiperidin-4-one
1 -Ethyl- l-methyl-4-oxopiperidinium iodide (Journal of the Chemical Society (1949), 708-15; 15 g, 55.74 mmol) was added to cyclopropylamine (Aldrich; 19.3 mL, 278.69 mmol) in toluene (150 mL). Sodium hydrogen carbonate (469 mg, 5.57 mmol) in water (21 mL) was added and the mixture heated at 78°C over night. The mixture was cooled and the layers separated. The aqueous layer was extracted (x2) with ethyl acetate and the combined organics washed with brine , dried (MgSO4) and concentrated. Column chromatography of the residue (2% MeOH/DCM) gave the title compound (4.1g, 53%) as a pale brown liquid. 1H NMR (399.9 MHz, CDCl3) δθ.47 - 0.53 (4H, m), 1.74 (IH, d), 2.40 - 2.44 (4H, m), 2.92 (4H, t) Intermediate 27; 4-amino-2-fluoro-5-methoxy-N-(l-methyl-4-piperidyl)benzamide
2-fluoro-5-methoxy-N-(l-methyl-4-piperidyl)-4-nitro-benzamide Intermediate 28; 1.3 g, 4.2 mmol) 10% Palladium on Carbon (100 mg) and Methanol (50 mL) were combined and stirred at 250C under Hydrogen at 1 bar pressure for 18 hours. The reaction mixture was filtered through a plug of celite, washing with ethanol and concentrated under reduced pressure to give the title compound (1.16 g, 100%.) as a yellow solid. 1H NMR (399.902 MHz, DMSO-D6) 5 1.54 (qd, 2H), 1.72 - 1.80 (m, 2H), 1.97 (td, 2H),
2.16 (s, 3H), 2.70 (br d, 2H), 3.67 - 3.74 (m, IH), 3.78 (s, 3H), 5.55 (s, 2H), 6.39 (d, IH), 7.05 (d, IH), 7.34 (t, IH); MS m/z 282.27 [M+H]+.
Intermediate 28: 2-fluoro-5-methoxy-N-(l-methyl-4-piperidyI)-4-nitro-benzamide
To a stirred solution of 2-fluoro-5-methoxy-4-nitro-benzoic acid (Intermediate 29; 861 mg, 4.00 mmol) in DMA (20 mL) was added 4-amino-l-methylpiperidine (Fluorochem; 503 mg, 4.40 mmol) followed by DIPEA (1.4 mL, 8.00 mmol) and HATU (1.68 g, 4.40 mmol) and the resulting yellow solution stirred at room temperature for 1 hr.. The solvent was removed under reduced pressure and the residue taken up in methanol (approx 10 mL) and loaded onto a 20 g SCX-2 cartridge washing with methanol (50 mL) and eluting with 7 N methanolic ammonia (50 mL) to give a yellow solid, 1.47 g. This was purified by flash silica chromatography (Companion, 40 g, 0-5% ammonia in methanol /.DCM) to give the desired product as a pale yellow solid (1.25g, 4.00 mmol, 100%.) 1HNMR (399.902 MHz, DMSO-D6) δ 1.54 (qd, 2H), 1.77 - 1.85 (m, 2H), 1.98 (td, 2H),
2.17 (s, 3H), 2.74 (br d, 2H), 3.72 (m, IH), 3.96 (s, 3H), 7.43 (d, IH), 7.98 (d, IH), 8.46 (d, IH); ); MS m/z 161.90 [M+H]+.
Intermediate 29: 2-fluoro-5-methoxy-4-nitro-benzoic acid
2,5-Difluoro-4-nitrobenzoic acid (Fluorochem; 100 mg, 0.43 mmol) and caesium carbonate (708 mg, 2.17 mmol) were taken up in diy DMF (2 mL) and dry methanol (120 uL, 2.88 mmol) was added and the reaction stirred at room temperature for 2 hrs. The reaction mixture was diluted with Ethyl Acetate (50 mL) and water (50 mL) and acidified to pHl with 2N HCl solution. The organics were removed and the aqueous further extracted with Ethyl Acetate (2 x 50 mL). The combined organics were washed with water (50 mL), brine (50 mL), dried over MgSO4 and concentrated under reduced pressure to give the title compound as a yellow solid (91 mg, 0.42 mmol, 98%). 1H NMR (399.902 MHz, CDC13) d 4.00 (s, 3H), 7.63 (d, IH), 7.70 (d, IH), 10.78 (br s, IH);
Figure imgf000279_0001
Intermediate 30: Benzyl (lR,5S)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate
Benzyl (lR,5S)-6-[(2-methylpropan-2-yl)oxycarbonylamino]-3-azabicyclo[3.1.0]hexane-3- carboxylate (Bioorganic & Medicinal Chemistry Letters (2004), 14(11), 2773-2776, Compound 9; 6.74g, 20.3mmol) was stirred and dissolved in DCM (90 mL) at ambient temperature and TFA (10ml) was added. The solution was stirred at room temperature for 2 hours. Sat. bicarbonate (100ml) was added followed by potassium carbonate solid until neutral. The DCM layer was separated and washed once more with water. The DCM solution was dried (MgSO4), filtered and evaporated to a gum. Yield = 4.05g (86%)
1HNMR (400.132 MHz, CDC13) δ 1.48 (s, 2H), 2.00 (s, IH), 3.43 (m, 4H), 5.02 (s, 2H), 7.25 (m, 7H).
Intermediate 31:
Methyl (lS,3R)-3-aminocyclopentane-l-carboxylate Hydrochloride Salt
(lS,3R)-3-aminocyclopentane-l-carboxylic acid (Acros; 952 mg, 7.37 mmol) was suspended in MeOH (15 ml) and cooled in an acetone / ice bath. Thionyl chloride (1.1 mL, 14.74 mmol) was added dropwise and the resulting pale yellow solution stirred in the acetone / ice bath for 30 minutes and then allowed to warm to room temperature, stirred at room temperature for 1 hr then heated at reflux for 1 hr. Solvents were evaporated to give the title compound as a cream solid after drying under high vacuum. (1.32g 100%)
H NMR (399.902 MHz, DMSO-D6) 51.65 (m, IH), 1.76 (m, IH), 1.93 (m, 3H), 2.27 (m, s IH), 2.87 (m, IH), 3.49 (m, IH), 3.64 (s, 3H), 8.09 (s, 3H)
Intermediate 32: [(2R)-l-(cyclopropylmethyl)pyrrolidin-2-yl]methanamine
Preparation contained in WO98/39295 0
Intermediate 33: [l-(pyrrolidin-l-ylmethyl)cyclopropyl]methanamine
To a solution of 1 -(pyrrolidine- l-carbonyl)cyclopropane-l-carboxamide (Intermediate 34;s 5.0 g, 27.5 mmol) in anhydrous THF (150 niL) was slowly added a 1 M anhydrous THF solution of Lithium Aluminium Hydride ( 138 mL, 138 mmol) controlling the reaction temperature at 400C with an ice / water bath.
The resultant clear solution was stirred overnight at room temperature under an inert gas flow to give a cloudy suspension. 0 Water (5.24 mL) was carefully added to the reaction mixture maintaining the reaction temperature at < 300C with an ice / water bath to give thick white slurry. 15% w/v aqueous
Soium Hydroxide solution (5.24 mL) was carefully added followed by water (15.71 mL). The reaction was filtered and the filtrate evaporated to dryness to give the title compound (3.26 g,
77%) 5
Intermediate 34: l-(pyrrolidine-l-carbonyl)cyclopropane-l-carboxamide
To l-(aminocarbonyl)-l -cyclopropane carboxylic acid (Aldrich; 25 g, 193.6 mmol) in DCM (625 mL) was added HATU (73.61 g, 193.6 mmol) and the suspension stirred for 30 minutes.0 Pyrrolidine (Aldrich; 24.25 mL) and Hunig's base (67 mL) was added and the reaction stirred at room temperature over the weekend. The reaction was evaporated to dryness, DCM added and extracted with water (3x 150 mL). The aqueous extracts were evaporated to dryness and the resultant material triturated with Ethyl acetate to give the title compound as a white solid 11.14 g, 32%)
Intermediate 35: 2-methoxy-N'-(2-pyrroIidin-l-ylethyl)benzene-l,4-diamine
To a stirred solution of 4-fluoro-2-methoxy-l-nitro-benzene (Fluorochem; 2.57 g; 15 mmol) in DMA was 2-pyrrolidin-l-ylethanamine (Aldrich; 1.88 g, 16.5 mmol) followed by DIPEA (2.97 mL, 18 mmol). The mixture was heated at 8O0C for 20 hours, then cooled to room temp. The mixture was concentrated in vacuo, dissolved in DCM and purified by SCX (50 g SCX 2 column). The product was eluted from the column with IN ammonia in methanol, concentrated in vacuo to give the title compound (53 mg) which was dissolved in Methanol as a 0.05 mmol solution and reduced using an H-cube hydrogenator. 10% Pd/C catalyst, 1 bar hydrogen (full hydrogen setting), 3 mL / min flow- rate at 5O0C. The resultant solution was concentrated in vacuo, and the resultant material purified by column chromatography, eluting with 0-10% ammonia/rnethanol in DCM, to give the title compound as a solid. MS m/z 236 [M+H]+, Retention Time 1.50 minutes.
In a similar manner intermediates 36-42 were prepared from the specified amines
Intermediate 36:
2-methoxy-N'-methyl-N'-(l-methyl-4-piperidyl)benzene-l,4-diamine
Intermediate 37:
2-methoxy-4- [4-(2-methoxyethyl)piperazin-l-yl] aniline
Intermediate 38: 2-methoxy-4-[4-(l-piperidyl)-l-piperidyl] aniline
Intermediate 39: N'-(2-dimethylaminoethyl)-2-methoxy-benzene-l,4-diamine
Intermediate 40:
4-(4-cyclohexylpiperazin-l-yl)-2-methoxy-aniline s
Intermediate 41: 2-methoxy-4-(4-methyl-l,4-diazepan-l-yl)aniline
Intermediate 42: o 2~methoxy-4-(4-pyrrolidin-l-yl-l-piperidyl)aniline
Figure imgf000282_0001
Figure imgf000283_0001
Intermediate 43: 2-methoxy-4-[(l-methyl-4-piperidyl)oxy]aniline
To a stirred solution of 4-(3-methoxy-4-nitro-phenoxy)-l-methyl-piperidine (Intermediate 44; 12.86 g, 48.34 mmol) in ethanol (250 mL) under nitrogen was added in one portion the Pd/C catalyst (10%, 1.29 g). The resulting mixture was evacuated and backfilled with nitrogen 4 x before hydrogen gas was introduced via a balloon. The reaction mixture was stirred at room temperature for 18 hrs. The catalyst was removed by filtration through celite and the filtrate concentrated under reduced pressure to give a light red oil (11.1 g, 47.0 mmol, 97%). 1H NMR (399.902 MHz, DMSO-D6) δ 1.52 - 1.63 (m, 2H), 1.82 - 1.90 (m, 2H), 2.06 - 2.15 (m, 2H), 2.17 (s, 3H), 2.56 - 2.65 (m, 2H), 3.73 (s, 3H), 4.10 (septet, IH), 4.28 (s, 2H), 6.32 (dd, IH), 6.45 (d, IH), 6.53 (d, IH); MS m/z 237.21 [M+H]+.
Intermediate 44:
4-(3-methoxy-4-nitro-phenoxy)-l-methyl-piperidine
To a solution of 4-Fluoro-2-methoxy-l -nitrobenzene (Apollo Scientific; 10.3 g, 60 mmol) in toluene (50 mL) and 25% KOH aq. (50 mL) , were added at room temperature, 4-hydroxy-l- methylpiperidine (13.8 g, 120 mmol) and tetra-n-butylammonium bromide (3.87 g, 12 mmol). The mixture was heated at 60 °C for 18 hrs. The reaction mixture was cooled to room temperature, poured onto ice-water (300 mL) and extracted with Ethyl Acetate (3 x 150 mL). The organic layer was extracted with dil HCl (2 M HCl, 300 mL)
The acidic aqueous layer was taken to pH 4/5 with 2 M NaOH solution and split between 2 x 50 g SCX-2 cartridges, washing with water and eluting with 7 N methanolic ammonia to give the title compound as a yellow oil, which slowly solidified over time (12.86 g, 80%)
1HNMR (399.902 MHz, DMSO-D6) 5 1.64 - 1.72 (m, 2H), 1.93 - 2.00 (m, 2H), 2.17 - 2.24 (m, 5H), 2.59 - 2.64 (m, 2H), 3.92 (s, 3H)9 4.60 (septet, IH), 6.71 (dd, IH), 6.78 (d, IH), 7.94 (d, IH); MS m/z 267.24 [M+H]+.
Intermediate 45:
2-methoxy-4-(l-methylpyrrolidin-3-yl)oxy-aniline
To a stirred solution of 3-(3-methoxy-4-nitro-phenoxy)-l-methyl-pyrrolidine (Intermediate 46; 5.50 g, 20.68 mmol) in ethanol (125 mL) under nitrogen was added in one portion the Pd/C catalyst (10%, 500 mg). The resulting mixture was evacuated and backfilled with nitrogen (x 4) before hydrogen gas was introduced via a balloon. The reaction mixture was stirred at room temperature for 18 hrs. The catalyst was removed by filtration through celite and the filtrate concentrated under reduced pressure to give a the title compound as a light red oil (4.74 g, 100%) 1H NMR (399.902 MHz, CDC13) δ 1.94 - 2.02 (m, IH), 2.22 - 2.30 (m, IH), 2.36 - 2.45 (m, IH), 2.38 (s, 3H), 2.73 - 2.83 (m, 3H), 3.50 (s, 2H), 3.81 (s, 3H), 4.74 (octet, IH), 6.26 (dd, IH), 6.45 (d, IH)5 6.61 (d, IH); MS m/z 223.22 [M+H]+.
Intermediate 46:
3-(3-methoxy-4-nitro-phenoxy)-l-methyl-pyrrolidine
To a solution of 4-Fluoro-2-methoxy-l -nitrobenzene (Apollo Scientific; 4.28 g, 25 mmol) in toluene (20 mL) and 25% KOH aq. (20 niL), were added at room temperature, l-methyl-3- pyrrolidiniol (5.0 g, 50 mmol) and tetra-n-butylammonium bromide (1.66 g, 5 mmol). The mixture was heated at 60 °C for 18 hrs. The reaction mixture was cooled to room temperature, poured onto ice-water (200 mL) and extracted with Ethyl Acetate (3 x 100 mL). The organic layer was washed with 2 M HCl (250 ml) and then loaded onto a 50 g SCX-2 cartridge, washing with water and eluting with 7 N methanolic ammonia to give the title compound as a yellow oil, which solidified on standing (5.50 g, 87%). 1H NMR (399.902 MHz, DMSO-D6) δ 1.73 - 1.84 (m, IH), 2.27 (s, 3H), 2.31 - 2.37 (m, 2H), 2.65 (dd, IH), 2.68 - 2.73 (m, IH), 2.77 (dd, IH), 3.92 (s, 3H), 5.02 - 5.07 (m, IH), 6.62 (dd, IH), 6.73 (d, IH), 7.95 (d, IH); MS m/z 253.23 [M+H]+.
Intermediate 47: 2-methoxy-4-(2-morpholin-4-ylethoxy)aniline
To 4-[2~(3-methoxy-4-nitro-phenoxy)ethyl]morpholine (Intermediate 48; 16.97 g, 60 mmol, leq) in ethanol (120 mL) was added 10% palladium on charcoal (850mg, 5%wt). The reaction was stirred at room temperature for 19hours. After filtering off the palladium residues the solvent was evaporated under reduced pressure. The product was dissolved in ethyl acetate (100ml) and extracted twice with 2M HCl. The aqueous layers were combined, washed with ethyl acetate then basified by the addition of 2N NaOH. The basic layer was re-acidified and captured onto mp-TsOH resin. After washing several times with methanol the product was released using 10% ammonia in methanol. After evaporation in vacuo the title compound was obtained as a dark brown oil. (14.5 g, 89%) 1HNMR (300.132 MHz, DMSO-D6) 52.49 - 2.51 (4H, m)52.69 (2H, t),3.60 (4H, t),3.74 (3H, s),3.98 (2H, t),4.62 (2H, s),6.30 (IH, dd),6.46 (IH, d),6.54 (IH, d); MS m/z 253 [M+H]+.
Intermediate 48: 4-[2-(3-methoxy-4-nitro-phenoxy)ethyl]morpholine
To a solution of 4-fluoro-2-methoxy-l-nitro-benzene (Apollo Scientific; 10.27 g, 60 mmol) in toluene (50 niL) and 25% KOH (aq) (50 niL), was added 4-(2-hydroxyethyl)morpholine (Aldrich; 15.75 g, 120 mmol) and tetra-n-butylammonium bromide (3.87 g, 12 mmol) at room temperature. The mixture was heated at 600C for 22 hours. The reaction mixture was cooled to room temperature, poured into water and extracted three times with ethyl acetate. The organic layers were combined and washed twice with 2M sodium hydroxide then brine. Dried with magnesium sulphate, filtered and evaporated under reduced pressure to yield the title compound as a yellow oil (16.97 g, 100%)
1HNMR (300.132 MHz, DMSO-D6) 62.48 (4H, t),2.72 (2H, t),3.58 (4H, t),3.93 (3H, s),4.23 (2H, t),6.68 (IH, dd),6.81 (IH, d),7.94 (IH, d); MS m/z 283 [M+H]+.
Intermediate 49:
N- [(4-aminophenyl)methyl] py ridine-2-carboxamide
Pyridine-2-carboxylate (Aldrich; 0.35 g, 2.84 mmol), 4-aminobenzylamine (Aldrich; 0.51 g, 4.26 mmol) and HATU (1.65g, 4.26mmol) were dissolved in DMF (7.5ml). N,N- Diisopropylethylamine (1.5ml, 8.53mmol) was added and the mixture stirred at room temperature for 2h. The mixture was absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and the residue purified by normal phase chromatography (2% MeOH/DCM) to give a yellow solid (440mg). which was suspended in DCM/Et2O and filtered to give the title compound as a pale yellow solid (235mg, 36%).
1H NMR (399.9 MHz, DMSOd6) δ4.33 (2H, d), 4.94 (2H5 s), 6.50 - 6.53 (2H, m), 7.00 - 7.03 (2H, m), 7.58 - 7.62 (IH, m), 7.98 - 8.07 (2H, m), 8.62 - 8.64 (IH, m), 8.98 (IH, t); MS m/z 228.03 [MH-H]+. Intermediate 50: l-(3-amino-4-methoxy-phenyl)-N,N-dimethyl-pyrrolidin-3-amine
4-methoxy-N-(l-methyl-4-piperidyl)-3-nitro-benzaniide (Intermediate 51; 400 nig, 1.4 mmol) 10% Palladium on Carbon (40 mg) and Methanol (50 mL) were combined and stirred s at 250C under Hydrogen at 5 bar pressure for 2 hours.
The reaction mixture was filtered and evaporated to dryness. The residue was purified by column chromatography using 5% 7N ammonia in MeOH/DCM as the solvent system.
Product containing fractions were combined and evaporated to give the title compound as a white solid (305mg, 85%). I0 1H NMR (399.9 MHz, DMSOd6) δl.55 - 1.61 (2H, m), 1.70 - 1.74 (2H, d), 1.89 - 1.96 (2H, t), 2.16 (3H, s), 2.74 - 2.77 (2H, d), 3.68 (IH, m), 3.81 (3H, s), 4.79 (2H, s), 6.81 (IH, d), 7.06
- 7.09 (IH, m), 7.14 (IH, d), 7.86 (IH, d); MS m/z 264.28 [M+H]+.
Intermediate 51; is 4-methoxy-N-(l-methyI-4-piperidyl)-3-nitro-benzamide
3-Nitro-4-methoxybenzoic acid (Aldrich; 300mg, 1.52mmol), l-methyl-4-aminopiperidine (Fluorochem; 174mg, 1.52mmol), HATU (868mg, 2.28mmol) and DIPEA (796uL, 4.56mmol) were stirred in DMF (6mL) at room temperature for 2 hours. The reaction mixture was loaded onto an SCX-3 column pre-washed with methanol . The column was washed with 20 methanol and then eluted with 2% 7N ammonia/methanol. Product containing fractions were combined and evaporated to give the title compound as an orange solid (341mg, 76.4%). 1H NMR (399.9 MHz, DMSOd6) δl.55 - 1.59 (2H, m), 1.75 (2H, d), 1.91 - 1.95 (2H, m), 2.17 (3H, s), 2.70 - 2.79 (2H, d), 3.68 - 3.78 (IH, m), 3.99 (3H, s), 7.46 (IH, d), 8.16 - 8.19 (IH, m), 8.41 (2H, d); MS m/z 294.31 [M+H]+.
25
Intermediate 52: 4-amino-3-chloro-N-(2-morphoIin-4-yIethyl)benzamide
3-chloro-N-(2-morpholin-4-ylethyl)-4-nitro-benzamide (Intermediate 53; 1.2 g, 3.82 mmol), iron powder (1.29 g, 22.95 mmol) and ammonium chloride (144 mg, 2.68 mmol) were heated 30 in ethanol (27 mL) and water (9 mlL at reflux for Ih. A few drops of acetic acid were added and heating continued for a further Ih. The reaction mixture was cooled, filtered and the filtrate concentrated. The residue was partitioned between DCM and sat NaHCO3. The organic layer was washed with brine, dried (MgSO4) and concentrated. Column chromatography of the residue gave the title compound as a white crystalline solid. (650mg, 60%) 1H NMR (399.9 MHz, DMSO-d6 + D2O) 52.38 - 2.46 (6H, m), 3.30 - 3.36 (2H, m), 3.55 - 3.59 (4H, m), 5.83 (IH, partially exchanged NH2), 6.79 (IH, d), 7.53 - 7.55 (IH, m), 7.73 (IH, d), 8.10 (IH, s); MS m/z 284.08 [M+H]+.
Intermediate 53: 3-chloro-N-(2-morpholin-4-ylethyl)-4-nitro-benzamide
3-chloro-4-nitro-benzoyl chloride (Intermediate 54; 1.1 g, 5.00 mmol) was dissolved in DCM (10 mL) and N,N-diisopropylethylamine (1.05 mL, 6.00 mmol) added. The mixture was cooled in an ice/water bath and 4-(2-aminoethyl)morpholine (Aldrich; 0.66 mL, 5.00 mmol) in DCM (5 mL) added dropwise. The mixture was allowed to warm to room temperature and stirred for 0.5 hr. The reaction mixture was washed with brine, 2N NaOH, dried (MgSO4) and concentrated. Column chromatography of the residue (2% MeoH/DCM) gave the title compound as a yellow solid. (1.2 g, 76%) 1H NMR (399.9 MHz, DMSO-d6) 52.43 (4H, t), 2.48 (2H, t), 3.39 - 3.44 (2H, m), 3.58 (4H, m), 7.98 - 8.01 (IH, m), 8.16 (IH, m), 8.19 (IH, d), 8.78 (IH, t); MS m/z 314.16 [M+H]+.
Intermediate 54: 3-chloro-4-nitro-benzoyl chloride
3-Chloro-4-nitrobenzoic acid (Apin; Ig, 4.96 mmol) was suspended in toluene (10 mL) and thionyl chloride (1.1 mL, 14.88 mmol) added. The mixture was heated to 85°C for 45min
Further thionyl chloride (1.1 mL) was added and the mixture heated at reflux. 0.5 hr. The reaction mixture was allowed to cool and stand overnight. The mixture was concentrated to give the title compound as a yellow liquid (1.15g, 100%).
1HNMR (399.9 MHz, CDCl3) 57.87 (IH, s), 8.07 - 8.10 (IH, m), 8.23 (IH, d); MS m/z 198.92 [M+H]+. Intermediate 55: 4-amino-3-chIoro-N-(l-methyl-4-piperidyl)benzamide
3-chloro-N-(l-methyl-4-piperidyl)-4-nitro-benzamide (Intermediate 56; 1.8 g, 6 mmol) hydrogenated over 2 hours with agitation at 298K and pressure of 5 bar using a 5% Pt/C catalyst and EtOH (50 niL) solvent. The catalyst was filtered and the filtrate concentrated to give a yellow crystalline solid which was dissolved in DCM and purified by column chromatography (5% MeOH/DCM) to give the title compound as a pale yellow crystalline solid (1.62 g, 100%) * H NMR (399.9 MHz, DMSOd6) 51.53 - 1.60 (2H, m), 1.71 - 1.74 (2H, m), 1.90 - 1.95 (2H, m), 2.16 (3H, s), 2.33 - 2.35 (IH, m), 2.67 - 2.69 (IH, m), 2.76 (2H, d), 3.66 - 3.70 (IH, m), 5.82 (2H, d), 6.78 (IH, d), 7.56 - 7.58 (IH, m), 7.76 (IH, d), 7.89 (IH, d); MS m/z 268.14 [M+H]+.
Intermediate 56:
3-chloro-N-(l-methyl-4-piperidyl)-4-nitro-benzamide
3-chloro-4-nitro-benzoyl chloride (Intermediate 54; 2.2 g, 10.00 mmol) was dissolved in DCM (20 mL) and N,N-diisopropylethylamine (2.095 niL, 12.00 mmol) added. The mixture was cooled in an ice/water bath and 4-amino-l-methylpiperidine (Fluorochem; 1.14 g, 10.00 mmol) in DCM (10 mL) added dropwise. The mixture was allowed to warm to room temperature and stirred for 0.5 hr. A white precipitate resulted. The reaction mixture was washed with 2N NaOH, filtered and the filter cake washed with water and dried on a sinter over the weekend to give the title compound as a white solid (1.80g, 60%) as a white solid. 1H NMR (399.9 MHz, DMSO-d6) δl.53 - 1.63 (2H, m), 1.79 (2H, t), 1.92 - 1.99 (2H, m), 2.17 (3H, s), 2.78 (2H, d), 3.70 - 3.77 (IH, m), 7.99 - 8.02 (IH, m), 8.18 (2H, t), 8.60 (IH, d); MS m/z 298.2 [M+H]+.
Intermediate 57:
10-amino-2-cyclopentyl-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5-one 10-Chloro-2-cyclopentyl-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 1; 250 mg; 0.89 mmol), Diphenylmethanimine (Fluka; 178 mg, 0.979 mmol) and caesium carbonate (580 mg, 1.78 mmol) were added to dioxane (3 mlL and the suspension bubbled with nitrogen for 10 minutes. Tris(Dibenzylideneacetone)Dipalladium(0) (49 mg; 0.053 mmol) and XANTPHOS (46 mg, 0.080 mmol) were added and the mixture heated to 100 °C for 16 hrs. The reaction mixture was cooled to room temperature filtered and the filter cake washed with DCM. The filtrate was evaporated and the resultant material taken up in DCM and purified on silica (the column was made neutral prior to purification, by wetting with iso-hexane, running a solution of 5% triethylamine in iso-hexane through followed by iso-hexane, material was then added) eluting with a gradient of 40 - 60% Ethyl Acetate / iso-hexane then 60% Ethyl Acetate / iso-hexane. Fractions containing the imine intermediate were combined and evaporated to a yellow solid (162 mg, 43%), which was dissolved in THF (10 ml). 2M aq HCl (3 mL) was added and the solution stirred at room temperature for 20 minutes. The reaction mixture was added to a 5g SCX-2 column pre-wet with MeOH (2 column volumes), flushed with MeOH (2 column volumes) and the a product eluted with 2M ammonia in MeOH. Solvents were evaporated to give the title compound as a white solid (80 mg, 80% from imine)
H NMR (399.902 MHz, DMSO-D6) ?1.46 (m, 4H), 1.59 (m, 2H), 1.83 (m, 2H), 3.03 (s, 3H), 3.46 (m, 2H), 4.60 (m, IH), 5.99 (s, 2H), 7.75 (s, IH); ); MS m/z 262 [M+H]+.
Intermediate 58: 4-bromo-2,6-difluoro-N-(l-methyl-4-piperidyl)benzamide
4-bromo-difluorobenzoic acid (Fluorochem; 3.0 g, 12.66 mol) and HBTU (5.3 g, 13.92 mol) were added to DMF (80 mL), to this was added the required 4-amino-l-methylpiperidine (Fluorochem; 1.59 g, 13.93 mol) and DIPEA (5.0 mL, 27.85 mol), the reaction was stirred for 48 hours, after which the solvent was removed in vacuo to yield a brown gum. The gum was treated with 2.0 M NaOH (50 mL) and extracted with DCM (3 x 200 ml). Combined extracts were dried and solvent removed in vacuo to yield a dark orange gum which was recrystallised from hot acetonitrile to give the title compound as a white solid (1.9 g, 45%) 1HNMR (400.132 MHz, DMSO-D6) δ 8.64 (d, IH), 7.55 (d, 2H), 3.74 - 3.64 (m, IH), 2.74 - 2.65 (m, 2H), 2.15 (s, 3H), 1.98 (t, 2H), 1.82 - 1.74 (m, 2H), 1.52 - 1.42 (m, 2H); MS m/z 334 [M+H]+.
5 Intermediate 59;
4-amino-2,5-difluoro-N-(l-methyl-4-piperidyl)benzamide
2,5-difluoro-N-(l-methyl-4-piperidyl)-4-nitro-benzamide (Intermediate 60; 633 mg 2.1 mmol), 10% Palladium on Carbon (70 mg) and Methanol (50 mL) were combined and stirred at 25}C under Hydrogen at 3 bar pressure for 16 hours.. io The catalyst was filtered off and the filtrate evaporated to give the title compound as a yellow solid. (554 mg, 97%)
HNMR (400.132 MHz, CDC13) δl.58 (m, 2H), 2.03 (m, 2H), 2.18 (m, 2H), 2.30 (s, 3H), 2.78 (m, 2H), 3.99 (m, IH), 4.14 (s, 2H), 6.47 (m, 2H), 7.71 (m, IH); MS m/z 334 [M+H]+.
is Intermediate 60:
2,5-difluoro-N-(l-methyl-4-piperidyl)-4-nitro-benzamide l,5-Difluoro-4-nitrobenzoic acid (Fluorochem; 1 g, 4.92 mmol), 4- Amino- 1- methylpiperidine (Fluorochem; 620 mg, 5.41 mmol), HAT (2.05 g, 5.41 mmol), DIPEA (2.57 mL, 14.76 mmol) and DMF (10 mL) were combined and stirred at room temperature for
20 18 hrs. Solvents were evaporated and the resultant material partitioned between DCM and water. Both phases were acidified with 2M aq HCl and added to a 50g SCX-2 column pre-wet with MeOH (2 column volumes). The column was flushed with MeOH (2 column volumes) and the crude product eluted with 2M ammonia in MeOH. Product containing fractions were evaporated in vacuo and the resultant material taken up in DCM and purified on silica eluting
25 with a gradient of 0 - 5% 2M ammonia in MeOH / DCM then 5% 2M ammonia in MeOH / DCM. Fractions containing product were combined and evaporated to give the title compound as a yellow solid. (635 mg, 43%)
H NMR (400.132 MHz, DMSO-D6) δ 1.53 (m, 2H), 1.80 (m, 2H), 1.98 (m, 2H), 2.16 (s, 3H), 2.73 (m, 2H), 3.70 (m, IH), 7.79 (m, IH), 8.21 (m, IH), 8.59 (d, IH); MS m/z 300 so [M+H]+. Intermediate 61;
4-amino-2-fluoro-N-( 1 -methyl-4-piperidyl)benzaniide
2-fluoro-N-(l-methyl-4-piperidyl)-4-nitro-benzamide (Intermediate 62; 1.62 g, 5.8 mmol), 10% Palladium on Carbon (160 mg) and Methanol (50 mL) were combined and stirred at 25^C under Hydrogen at 5 bar pressure for 16 hours..
The catalyst was filtered off and the filtrate evaporated to give a brown solid which was triturated with 5% MeOH / DCM . The precipitate was collected by filtration and dried under vacuum to yield the title compound as a beige solid (560 mg, 39%). H NMR (400.132 MHz, DMSO-D6) δl.74 (m, 2H), 1.99 (m, 2H), 2.76 (s, 3H), 3.09 (m, 2H), 3.42 (m, 2H), 3.97 (m, IH), 5.89 (s, 2H), 6.30 (m, IH), 6.39 (m, IH), 7.37 (m, IH), 7.67 (s, IH), 9.11 (s, IH); ); MS m/z 252 [M+H]+.
Intermediate 62; 2-fluoro-N-(l-methyl-4-piperidyl)-4-nitro-benzamide
2-Fluoro-4-nitrobenzoic acid (Aldrich; 3 g, 16.21 mmol), 4-Amino-l-methylpiperidine (Fluorochem; 2.03 g, 17.83 mmol), HATU (6.77 g, 17.83 mmol), DIPEA (8.5 mL, 48.63 mmol) and DMF (3 0 mL) were combined and stirred at ambient temperature for 18 hrs. Solvents evaporated and partitioned between DCM (200 ml) and water (100 ml). The aqueous phase was re-extracted with DCM (100 ml). The combined organic phases were dried
(MgSO4) and evaporated. The resultant material was taken up in DCM and purified on silica eluting with a gradient of 0 - 5% 2M ammonia in MeOH / DCM then 5% 2M ammonia in MeOH / DCM. Fractions containing product were combined and evaporated to give the title compound as a yellow solid (2.67 g, 59%) H NMR (400.132 MHz, DMSO-D6) δl.53 (m, 2H), 1.80 (m, 2H), 2.26 (m, 5H), 2.85 (m, 2H), 3.74 (m, IH), 7.72 (m, IH), 8.06 (m, IH), 8.12 (m, IH), 8.54 (d, IH); MS m/z 282 [M+H]+.
Intermediate 63: 4-amino-3-methyl-N-(l-methyl-4- piperidyl)benzamide
3-metliyl-N-(l-methyl-4-piperidyl)-4-nitro-benzamide (Intermediate 64: 3.34 g) 10% Palladium on Carbon (350 mg) and Methanol (50 niL) were combined and stirred at 25}C under Hydrogen at 5 bar pressure for 16 hours..
The catalyst was filtered off and washed with EtOH. The filtrate was evaporated to yield a cream solid., which was triturated with DCM filtered and dried under vacuum to give the title compound as a white solid (1.2 g)
HNMR (400.132 MHz, DMSO-D6) δl.75 (m, 2H), 1.96 (m, 2H), 2.08 (s, 3H), 2.74 (s, 3H), 3.04 (m, 2H), 3.38 (m, 2H), 3.96 (m, IH), 5.36 (s, 2H), 6.58 (d, IH), 7.47 (m, 2H), 7.86 (d, IH), 9.13 (s, IH); MS m/z 248 [M+H]+.
The following intermediate was prepared in a manner analogous to Intermediate 62 utilising 3-Methyl-4-nitrobenzoic acid, available form Aldrich, as the starting Nitro acid.
Intermediate 64:
3-methyl-N-(l-methyl-4-piperidyI)-4-nitro-benzamide
3-methyl-N-(l-methyl-4-piperidyl)-4-nitro-benzamide was prepared in a manner analogous to Intermediate 62 utilising 3-Methyl-4-nitrobenzoic acid, available form Aldrich, as the starting Nitro acid.
HNMR (400.132 MHz, DMSO-D6) δl.71 (m, 2H), 1.92 (m, 2H), 3.16 (m, 2H), 3.91 (m, IH), 7.86 (m, IH), 7.92 (s, IH), 8.06 (d, IH), 8.56 (d, IH); MS m/z 278 [M+H]+.
Intermediate 65: 4-amino-3-fluoro-N-(l-methyl-4-piperidyl)benzamide
4-Amino-3-Fluorobenzoic acid (Fluorochem; 1 g, 6.44 mmol), 4-Amino-l-methylpiperidine (Fluorochem; 811 mg, 7.09 mmol), HATU (2.70 g, 7.09 mmol), DIPEA (3.4 mL, 19.32 mmol) and DMF (15 mL) were combined and stirred for 18 hrs at room temperature. The solvent was evaporated and the resultant material dissolved in DCM (with a little MeOH to aid solubility) and chromatographed on silica eluting with a gradient of 0 - 10% 2M ammonia in MeOH / DCM. Fractions containing product were combined and evaporated to give an orange solid which was dissolved in MeOH and added to a 5Og SCX-2 column pre-wet with MeOH (2 column volumes). The column was flushed with MeOH (2 column volumes) and the product eluted with 2M ammonia in MeOH. Product containing fractions were evaporated to yield the title compound as a beige solid. (1.72 g, 100%) s H NMR (399.902 MHz, CDC13) ?1.55 (m, 2H), 2.03 (m, 2H), 2.14 (m, 2H), 2.29 (s, 3H), 2.81 (m, 2H), 3.95 (m, IH), 4.01 (s, 2H), 5.77 (d, IH), 6.75 (m, IH), 7.34 (m, IH), 7.45 (m, IH); MS m/z 252 [M+H]+.
Intermediate 66: o 4-[(2-cycIopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-10- yl)amino]-3-(2-methoxyethoxy)benzoic acid
To a stirred solution of Methyl 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8, 10,12-trien-9-yl)amino]-3-(2-methoxyethoxy)benzoate (Intermediate 67; 164 mg, 0.35 mmol) in ethanol (3 niL) was added a solution of lithiums hydroxide (22 mg, 0.92 mmol) in water (1 ml). The reaction was stirred at ambient temperature overnight. A further addition of lithium hydroxide (20 mg) as a solution in water (1 ml) was added and stirring continued for 2.5 hrs and then heated to 5O0C for 4 hrs. The reaction mixture was evaporated and the residue diluted with water (5 mL). The resultant opaque solution was treated with a few drops of 2M HCl (aq.) to adjust the pH to 2-3. A0 precipitate formed which was collected by suction filtration, washing through with more water and dried under vacuum, at 550C, for 3 hours to afford the title compound as an off white solid (113 mg, 71%)
1H NMR (400.132 MHz, DMSO-D6) δ 1.65 (m, 6H), 1.91 (m, 2H), 2.67 (m, 2H), 3.18 (s, 3H), 3.70 (m, 2H), 3.75 (m, 2H), 4.27 (m, 2H), 4.84 (m, IH), 7.57 - 7.63 (m, 2H), 8.13 (s,s IH), 8.27 (d, IH), 8.72 (m, IH); MS m/z 456.4 [M+H]+.
Intermediate 67: 0 Methyl 4- [(6-cy clopentyl^-methyl-S-oxo^.ό&lO-tetrazabicyclo [5.4.0] undeca-8,10,12- trien-9-yl)amino]-3-(2-methoxyethoxy)benzoate
To 10-ChloiO-2-cycloρentyl-6-methyl-2,6,9,l l-tetrazabicyclo[5.4.0]u ndeca-8,10,12-trien-5- one (Intermediate 1, 222 mg, 0.79 mmol) was added a solution of Methyl 4~amino-3-(2- methoxyethoxy)benzoate (Intermediate 68; 203 mg, 0.90 mmol) in ethanol (4 mL). Water (12 mL) was added followed by concentrated hydrochloric acid (36%; 160 μl). The reaction was heated to 8O0C and stirred overnight. The reaction was allowed to stand and cool overnight, before evaporating ethanol. The aqueous residue was diluted to ~50 mL with water and the solution basified to pH 9 by addition of a few drops of aq. Ammonia. The resultant emulsion was treated with a little brine and extracted with DCM (2 x 50 mL). Combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and evaporated to give an amber gum which was purified by flash chromatography on silica (4Og Si cartridge; ISCO companion), eluting first with a rising gradient of 25-75% ethyl acetate in iso-hexane and then a rising gradient of 0-10% methanol in DCM. Product containing fractions were combined and evaporated to give a yellow oil which crystallised on standing overnight. This solid was triturated with diethyl ether, solid collected by suction filtration and dried to afford the title compound as a cream solid (173 mg, 47 %)
1HNMR (400.132 MHz, CDCl3) ? 1.59 - 1.81 (m, 6H), 2.04 (m, 2H), 2.67 (m, 2H), 3.29 (s, 3H), 3.48 (s, 3H), 3.70 (m, 2H), 3.81 (m, 2H), 3.90 (s, 3H), 4.27 (m, 2H), 4.89 (m, IH), 7.58 (m, IH), 7.69 (m, IH), 7.87 (s, IH), 7.95 (s, IH), 8.56 (d, IH); ); MS m/z 470 [M+H]+.
Intermediate 68;
Methyl 4-amino-3-(2-methoxyethoxy)benzoate
To a solution of Methyl 3-hydroxy-4-aminobenzoate (ABCR: 97 mg, 0.58 mmol) in acetone (3 mL), in a microwave tube, was added Methoxyethyl bromide (Aldrich; 85 μl, 0.90 mmol) and powdered potassium carbonate (120 mg, 0.87 mmol). The reaction was heated in a microwave (150W, CEM explorer) to 1000C and held for 30 minutes.
A further addition of Methoxyethyl bromide (40 μl, 0.43 mmol) was made and the reaction heated to 12O0C for a further 30 minutes. The reaction was repeated in two batches as follows. To a solution of Methyl 3-hydroxy-4- aminobenzoate (135 mg, 0.81 mmol) in acetone (4 ml), in a microwave tube. Was added Potassium Carbonate (185 mg, 1.34 mmol) and Methoxyethyl bromide (115 μl, 1.22 mmol) The reaction was heated to 12O0C in a microwave and held for 1 hour. The reactions was cooled, treated with a further aliquot of methoxyethyl bromide (58 μl, 0.62 mmol) and reheated to 12O0C holding for a further hour. All three batches were combined and evaporated to dryness. The residue was partitioned between DCM (25 mL) and water (25 mL). The organic phase was separated and the aqueous phase re-extracted with DCM (20 mL). Combined organic phases were washed with brine, dried over magnesium sulphate and evaporated to give a brown oil which was purified by flash chromatography on silica (4Og Cartridge) eluting with a rising gradient of 25-50% ethyl acetate in iso-hexane. Product containing fractions were combined and evaporated to give the title compound as a dark orange oil (256 mg, 56%).
1HNMR (400.132 MHz, DMSO-D6) δ 3.38 (s, 3H), 3.74 (m, 2H), 3.80 (s, 3H), 4.16 (m, 2H), 5.61 (s, 2H), 6.72 (d, IH), 7.37 (m, IH), 7.45 (m, IH); MS m/z 226 [M+H]+.
Intermediate 69:
4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9- yl)amino] -3-propan-2-yloxy~benzoic acid
To a stirred solution of Methyl 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-9-yl)amino]-3-propan-2-yloxy-benzoate (Intermediate 70; 128 mg, 0.28 mmol) in Ethanol (3 mL) was added a solution of lithium hydroxide (26 mg, 0.92 mmol) in water (1.5 mL). The reaction was allowed to stir at 7O0C for 4 hours, cooled, evaporated and the residue diluted with water (10 mL). The resultant solution was treated with a few drops of 2M HCl (aq.) until a precipitate persisted, pH~ 3-4. The precipitate was collected by suction filtration, washing through with more water. Solid was dried under suction overnight to afford the title compound as a white solid (108 mg, 88 %)
1H NMR (400.132 MHz, DMSO-D6) δ 1.36 (d, 6H), 1.57 - 1.77 (m, 6H), 1.95 (m, 2H)3 2.61 (m, 2H), 3.18 (s, 3H), 3.65 (m, 2H), 4.69 - 4.85 (m, 2H), 7.52 - 7.56 (m, 2H), 7.83 (s, IH), 8.10 (s, IH), 8.46 (d, IH), 12.62 (s, IH); MS m/z 440 [M+H]+. Intermediate 70:
Methyl 4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-8,10,12- trien-9-yl)amino]-3-propan-2-yloxy-benzoate
To 10-Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]u ndeca-8, 10, 12-trien-5- one (Intermediate 1, 190 mg, 0.68 mmol) was added a solution of Methyl 4-amino-3-propan- 2-yloxy-benzoate (Intermediate 71, 145 mg, 0.69 mmol) in ethanol (4 mL), followed by water (12 mL). Concentrated hydrochloric acid (36%; 140 μl) was added and the reaction heated to 8O0C, with stirring, overnight. The reaction was allowed to stand and cool overnight, before evaporating ethanol. The aqueous residue was diluted to ~40 mL with water and the solution basified to pH 9 by addition of a few drops of aq. ammonia, The resultant emulsion was treated with a little brine and extracted with DCM (2 x 30 mL). The biphasic mixture was poured into a PTFE cup and the organic phase allowed to drip through under gravity. Evaporation of the organic phase afforded an amber gum, which was purified by flash chromatography on silica (4Og Si cartridge; ISCO companion), eluting with a rising gradient of 25-100% ethyl acetate in iso-hexane. Product containing fractions were combined and evaporated to give a colourless gum which was triturated with a small amount of diethyl ether and the resultant solid collected by suction filtration and dried to afford the title compound as a white solid (132 mg, 43 %)
1HNMR (400.132 MHz, DMSO-D6) δ 1.36 (d, 6H), 1.58 - 1.77 (m, 6H), 1.95 (m, 2H), 2.60 (m, 2H), 3.18 (s, 3H), 3.64 (m, 2H), 3.83 (s, 3H), 4.77 (m, 2H), 7.53 (m, IH), 7.57 (m, IH), 7.78 (s, IH), 8.10 (s, IH), 8.51 (d, IH); MS m/z 452 [M+H]+.
Intermediate 71:
Methyl 4-amino-3-propan-2~yloxy-benzoate Methyl 3-hydroxy-4-aminobenzoate (ABCR: 100 mg, 0.60 mmol) & caesium carbonate (396 mg, 1.22 mmol) were taken up in acetone (4 mL) and 2-iodopropane (90 μl, 0.90 mmol) added and reaction heated in microwave (CEM discover; 150 W) to 12O0C and held for 30 mins A further aliquot of 2-iodopropane (90 μl, 0.90 mmol) was added and reaction heated again to 12O0C in microwave, holding for a further 30 mins The reaction was repeated twice on a 0.89 mmol scale Reaction mixtures were combined and evaporated to dryness and the residue partitioned between, ethyl acetate (40 ml) and water (50 ml). The organic phase was separated and the aqueous re-extracted with ethyl acetate (40 ml). Combined organic extracts were washed with brine, dried over magnesium sulphate and evaporated to give a brown oil which was 5 purified by column chromatography, on silica (40 g cartridge; ISCO companion) eluting with a rising gradient of 5-50% ethyl acetate in iso-hexane. Product containing fractions were combined and evaporated to dryness to afford the product as a yellow oil (301 mg, 60%)
1H NMR (400.132 MHz, DMSO-D6) δ 1.28 (d, 6H), 3.75 (s, 3H), 4.53 (m, IH), 5.51 (s, 2H), 6.66 (d, IH), 7.31 (m, IH), 7.37 (m, IH); MS m/z 209.4 [M+H]+.
10
Intermediate 72:
4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-10- yl)amino]-3-(2-dimethylaminoethoxy)benzoic acid
Methyl 4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien- I5 10-yl)amino]-3-hydroxy-benzoate (Intermediate 73; 63 mg, 0.15 mmol) was dissolved in DMA (2 mL) and treated sequentially with potassium carbonate powder (fine mesh; 106 mg, 0.79 mmol) and dimetylaminoethyl bromide hydrobromide (ASDI; 61 mg, 0.26 mmol). The reaction mixture was heated to 1000C, with stirring for 1 hour and allowed to cool overnight, before pouring into water (40 ml). The mixture was extracted with DCM (2 x 30 ml) and the 20 organic extracts washed with brine, dried over magnesium sulphate, filtered and evaporated to give a brown liquid which was taken up in methanol and poured onto an SCX-3 cartridge (2 g). The cartridge was washed with methanol (~30 ml) before eluting products with 2M ammonia/methanol (~20 ml). The ammoniacal wash was evaporated to give the title compound as a brown gum (41 mg, 57% ) 25 MS m/z 483.4 [M+H]+, Retention Time 2.41 minutes.
Intermediate 73:
Methyl 4-[(2-cycIopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12- 30 trien-10-yl)amino]-3-hydroxy~benzoate 10-Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1; 180 mg, 0.64 mmol) and Methyl 3-hydroxy-4-aniinobenzoate (ABCR; 123 mg, 0.73 mmol) were taken up in ethanol (4 mL) and water (12 mL). Concentrated hydrochloric acid (36%; 130 μl) was added and the reaction heated to 8O0C and stirred overnight. The reaction was allowed to stand and cool overnight, before evaporating ethanol. The aqueous residue was diluted to ~30 ml with water and the solution basified to pH 9 by addition of a few drops of aqueous Ammonia. The resultant mixture was extracted with DCM (2 x 50 ml). A solid persisted at the phase boundary. This solid was collected by suction filtration and dried to give the title compound as a purple/grey solid (64 mg, 24%)
The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and evaporated to a pink/brown solid (153 mg) which was triturated with DCM (5 mL). The solid was then collected by suction filtration and dried to give the title compound as a dusky pink solid ( 79 mg, 30 %) 1 H NMR (400.132 MHz1 DMSO-D6) δ 1.57 - 1.75 (m, 6H), 1.95 (m, 2H), 2.59 (m, 2H), 3.18 (s, 3H), 3.63 (m, 2H), 3.80 (s, 3H), 4.82 (m, 1 H), 7.44 (m, 2H), 7.84 (s, 1H), 8.09 (s, 1 H), 8.36 (d, 1H); MS m/z 412.3 [M+H]+.
Intermediate 74; 4-amino-N-(l-methyl-4-piperidyl)-3-(trifluoromethoxy)benzamide
To a solution of 4-amino-3-(trifluoromethoxy)benzoic acid (Maybridge ; 1.05 g, 4.75 mmol) in DMF (20 ml) was added 4-amino-l-methylpiperidine (Fluorochem; 604 mg, 5.29 mmol) followed by DIPEA (1.6 ml, 9.19 mmol) and HATU (2.06 g, 5.42 mmol). The reaction mixture was stirred at ambient temperature O/N. The reaction mixture was evaporated to dryness and the residue partitioned between DCM (75 mL) and saturated aqueous sodium bicarbonate solution (75 mL). The aqueous phase was re-extraced with DCM (50 ml) and the combined organic phases washed with brine, dried over magnesium sulphate, filtered and evaporated to give the title compound as an amber gum (1.17 g, 78%)
1H NMR (400.132 MHz, DMSO-D6) δ 1.75 (m, 2H), 1.93 (m, 2H), 2.64 (s, 3H), 2.87 (m, 2H), 3.93 (m, IH), 5.93 (s, 2H), 6.80 (d, IH), 7.64 (m, 2H), 8.08 (d, IH); MS m/z 316.4 [M+H]+. Intermediate 75:
4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- yl)amino]-3-ethoxy-benzoic acid
To a solution of 10-Chloro-2-cyclopentyl-6-methyl-2,6,9,l l-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-5-one (Intermediate 1; 280 mg, 1 mmol) and 4-amino-3-ethoxybenzoic acid (WO 2001077101; 205 mg, 1.13 mmol) in ethanol (5 mL) was added water (15 mL) and cone hydrochloric acid (0.17 mL, 2 mmol) . The mixture was heated under reflux for 36 hours. The reaction was cooled and a brown solid precipitated. This was filtered and dried, triturated under cold acetonitrile and then dried in vacuo. To yield the title compound as a brown solid (190 mg; 45%) MS m/z 426 [M+H]+. Retention Time 1.58 minutes s Intermediate 76:
10-chloro-6-methyl-2-propan-2-yl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien-5-one 3-[(5-bromo-2-chloro-pyrimidin-4-yl)-propan-2-yl-amino]-N-methyl-propanamide (Intermediate 77; 2.67 g, 7.9 6mmol) was dissolved in dioxane (80 mL) and tris(dibenzylideneacetone) palladium (II) (146mg, 0.16 mmol), XANTPHOS (277 mg, 0.480 mmol) and Caesium carbonate (3.76 g, 11.54 mmol) added. The apparatus was evacuated and backfilled with nitrogen (x3) and then heated at 100°C for 24 hours. The mixture was filtered and concentrated and the residue purified by column chromatography (1% MeOH/DCM) to give the title compound as a viscous yellow oil (1.25g, 62%). 1H NMR (399.9 MHz, CDCl3) δl.18 (6H, d), 2.59 - 2.61 (2H, m), 3.22 (3H, s), 3.59 - 3.62s (2H, m), 4.82 - 4.88 (IH, m), 7.87 (IH, s); MS m/z 255.16 [M+H]+.
Intermediate 77: 3-[(5-bromo-2-chloro-pyrimidin-4-yl)-propan-2-yl-amino]-N-methyl-propanamide
N-methyl-3-(propan-2-ylamino)propanamide (Intermediate 78; 2 g, 13.87 mmol), 5-bromo-0 2,4-dichloropyrimidine (Aldrich; 3.8 g, 16.64 mmol) and triethylamine (2.3 mL, 16.64 mmol) were heated in acetonitrile (85 mL) at 100°C for 3h. The mixture was cooled and concentrated. The residue was dissolved in DCM, washed with water, dried (MgSO4) and concentrated. Column chromatography (0.5 - 1 - 2% 7N ammonia in methanol/DCM) gave: The the title compound as a pale yellow oil that crystallised on standing (2.67 g, 20%) 1HNMR (399.9 MHz, DMSO-d6) δl.20 (6H, d), 2.31 (2H, t), 2.55 (3H5 d), 3.65 (2H, t), 4.55 - s 4.62 (IH, m), 7.72 (IH, s), 8.39 (IH, s); MS m/z 337.05 [M+H]+.
Intermediate 78: N-methyl-3-(propan-2-ylamino)propanamide
Isopropylamine (Aldrich; 1.5ml, 17.62mmol) and methyl acrylamide (ABCR; 1.Og,o 11.75mmol) were combined in methanol (10ml). The mixture was heated in a microwave at
14O0C for 30min. The reaction was repeated and the combined reaction mixtures were concentrated to remove excess amine. The residue was re-dissolved in methanol and absorbed onto an SCX column (50g), washed with methanol and eluted with ammonia/methanol.
Concentration of the product containing fractions gave the title compound as a colourless oils (3.2g, 94%) .
1HNMR (399.9 MHz, CDCl3) δl.00 (6H5 d), 2.27 (2H5 1), 2.70 - 2.74 (4H, m), 2.76 - 2.80
(2H, m), 7.50 (IH, s)
Intermediate 79: 0 4-amino-3-chloro-N-(l-methyl-4-piperidyl)benzamide
3-chloro-N-(l-methyl-4-piperidyl)-4-nitro-benzamide (Intermediate 80; 270 mg, 1 mmol),
10% Palladium on Carbon (30 mg) and Methanol (50 mL) were combined and stirred at 25}C under Hydrogen at 5 bar pressure for 16 hours..
The catalyst was filtered off and solvents evaporated to give the title compound as a cream5 solid. (280 mg, 98%)
H NMR (400.132 MHz5 CDC13) δl.49 (m, 2H), 1.95 (m, 2H)5 2.09 (m, 2H), 2.24 (s, 3H)5 2.75 (m, 2H)5 3.89 (m, IH), 4.27 (s, 2H), 5.69 (d, IH)5 6.68 (m, IH), 7.41 (m, IH)5 7.62 (m, IH); MS m/z 268 [M+H]+. 0 Intermediate 80:
3-chloro-N-(l-methyl-4-piperidyl)-4-nitro-benzamide Reagents combined and stirred at room temperature overnight. LCMS after 18 hrs shows complete reaction. Solvents evaporated and residues partitioned between DCM (25 ml) and water (25 ml) then gravity filtered through a PTFE cup. Taken up in DCM and purified on silica eluting with a gradient of 0 - 5% 2M ammonia in MeOH / DCM then 5% 2M ammonia in MeOH / DCM. The peak corresponding to the product (which was only 1 spot by tic) was clearly split into 2 on the chromatography trace. The first peak (fractions 6 — 10 ) was labelled PHl 7082/048/1 and evaporated to a brown gum. The second peak (fractions 11 - 14) was labelled as PH17082/048/2 and evaporated to a white solid. Both products had identical LCMS traces and showed the mass ion for the desired product. NMR showed a difference in the aliphatic region and an additional small broad peak in the aromatic region of PHl 7082/048/1. It was concluded that PH17082/048/1 was a salt (possibly PF6 from HATU).
PHl 7082/048/1 was dissolved in MeOH and added to a 2g SCX-2 column pre-wet with MeOH (2 column volumes). The column was then flushed with MeOH (2 column volumes) and the product eluted with 2M ammonia in MeOH. This was then combined with the solid of PHl 7082/048/2 and evaporated to an off-white solid, 315mg.
H NMR (500.133 MHz, DMSO-D6) δl.66 (m, 2H), 1.85 (m, 2H), 2.14 (m, 2H), 2.25 (s, 3H), 2.83 (m, 2H), 3.78 (m, IH), 7.97 (m, IH), 8.09 (m, IH), 8.12 (m, IH), 8.26 (d, IH); MS m/z 298 [M+H]+.
Intermediate 81: 10-chloro-2-ethyl-6-methyI-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one
Tris(dibeπzylideneacetone)dipalladium(0) (52 mg, 0.06 mmol), XANTPHOS (98 mg, 0.17 mmol) and caesium carbonate (1.32 g, 4.06 mmol) were added to a stirred solution of 3-[(5- bromo-2-chloro-pyrimidin-4-yl)-ethyl-amino]-N-methyl-propanamide (Intermediate 82; 900 mg, 2.80 mmol) in 1,4-dioxane (28 mL). The apparatus was evacuated and backfilled with nitrogen twice and then heated to 100 °C for 18 hrs. The reaction mixture was filtered through a celite pad and dry loaded onto silica for purification by flash silica chromatography (companion, 40 g, 0-10% MeOH/DCM) to give the title compound as a yellow solid (638 mg, 2.65 mmol, 95%). 1H NMR (399.902 MHz, DMSO-D6) δ 1.17 (t, 3H), 2.66 - 2.69 (m, 2H), 3.19 (s, 3H), 3.57 (q, 2H), 3.72 - 3.74 (m, 2H), 8.13 (s, IH); MS m/z 241.14 [M+H]+.
Intermediate 82: 3-[(5-bromo-2-chloro-pyrimidin-4-yl)-ethyI-amino]-N-methyl-propanamide
5-Bromo-2,4-dichloropyrimidine (Aldrich; 1.14 g, 5.00 mmol), 3-ethylamino-N-methyl- propanamide (Intermediate 83; 0.642 g, 5.00 mmol) and triethylamine (0.71 mL, 5.10 mmol) were combined in acetonitrile (25 mL) and heated to 100 °C for 4 hrs. The solvent was removed under reduced pressure and the residue taken up in Ethyl Acetate, washed with water and purified by flash silica chromatography (companion, 40 g, 0-10% Methanol/DCM) to givethe title compound as a white solid (1.06 g, 3.3 mmol, 66%).
1H NMR (399.902 MHz, DMSO-D6) δ 1.18 (t, 3H), 2.46 (t, 2H), 2.58 (d, 3H), 3.67 (q, 2H), 3.81 (t, 2H), 7.85 (m, IH), 8.31 (s, IH); MS m/z 320.95 [M+H]+.
Intermediate 83:
3-ethylamino-N-methyl-propanamide
N-methylacrylamide (ABCR: 851 mg, 10.00 mmol) and ethylamine (2 M in methanol, 10 mL, 20.00 mmol) were combined in a microwave reaction vessel, which was sealed and irradiated at 140 0C for 30 mins. The reaction mixture was allowed to cool and then loaded directly onto a 50 g SCX-2 cartridge, washing with methanol (100 mL) and eluting the desired product with 7 N methanolic ammonia (100 mL). Concentration under reduced pressure of product containing fractions gave the title compound as a clear oil (1.285 g; 99%) 1H NMR (399.9 MHz, DMSOd6) δθ.93 - 0.99 (3H, m), 2.19 (2H, t), 2.52 - 2.52 (2H, m), 2.54 - 2.59 (3H, d), 2.68 (2H, t), 7.80 (IH, br s)
Intermediate 84:
10-chloro-6-methyl-2-(2-methyIpropyl)-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll- trien-5-one
3-[(5-bromo-2-chloro-pyrimidin-4-yl)-(2-methylpropyl)amino]-N-methyl-propanamide (Intermediate 85; 3.26 g, 9.32 mmol)) was suspended in dioxane (70 mL), Caesium Carbonate (6 g, 18,64 mmol) was added and the mixture bubbled with nitrogen for 10 minutes. Tris(dibenzylideneacetone)dipalladium(0) (512 mg, 0.56 mmol) and XANTPHOS (485 mg, 0.839 mmol) were added and the mixture heated at 100 0C for 24 hrs. The reaction mixture was cooled to room temperature, solvent evaporated and the residues partitioned between DCM (250 niL) and water (250 mL). The aqueous phase was re-extracted with DCM (200 mL) and the combined organic phases dried over MgSO4 and evaporated to a dark brown gum which was taken up in DCM and purified on silica, eluting with a gradient of 30 - 50% Ethyl Acetate / iso-hexane then 50% Ethyl Acetate / iso-hexane. Fractions containing product were combined and evaporated to a yellow solid, which was heated at reflux in iso-hexane (50 mL) for 15 minutes and allowed to cool to room temperature overnight. The resulting solid was filtered and dried to give the title compound as a pale yellow solid (1.02 g, 41%)
H NMR (400.132 MHz, CDC13) δθ.85 (d, 6H), 2.03 (m, IH), 2.65 (m, 2H), 3.23 (s, 3H), 3.45 (d, 2H), 3.69 (m, 2H), 7.89 (s, IH); MS m/z 269 [M+H]+. Intermediate 85: 3-[(5-bromo-2-chloro-pyrimidin-4-yl)-(2-methylpropyl)amino]-N-methyl-propanamide 5-Bromo-2,4-dichloropyrimidine (Aldrich; 2.82 g, 12.37 mmol), N-methyl-3-(2- methylpropylamino)propanamide (Intermediate 86; 1.78 g; 11.25 mmol) , Triethylamine (1.65 mL, 11.81 mmol) and DCM ( 40 mL) were combined and stirred over the weekend at room temperature. The reaction mixture was washed saturated aqueous sodium bicarbonate solution and gravity filtered through a PTFE cup and solvent evaporated. The residue was dissolved in DCM and passed through a silica column eluting with a gradient of 30 - 50% Ethyl Acetate / iso-hexane over 10 column volumes then 50% Ethyl Acetate / iso-hexane. Fractions containing product combined and evaporated to give the title compound as a white solid. (3.26 g, 83%) H NMR (400.132 MHz, CDCl3) δθ.84 (d, 6H), 1.98 (m, IH), 2.44 (m, 2H), 2.75 (d, 3H), 3.58 (m, 2H), 3.91 (m, 2H), 5.57 (s, IH), 8.11 (s, IH); MS m/z 351 [M+H]+.
Intermediate 86; N-methyl-3-(2-methylpropylamino)propanamide N-methylacrylamide (ABCR; 1 g, 11.75 mmol) was dissolved in EtOH (5 mL).
Isobutylamine (Aldrich; 2.33 mL, 23.5 mmol) was added and stirred at ambient temperature in a stoppered flask over the weekend. The reaction was then transferred to a microwave reactor vessel and heated in a microwave for 10 minutes at 140 0C. Solvents were evaporated in vacuo to give the title compound as a colourless liquid. (1.78 g, 96%)
H NMR (400.132 MHz, CDC13) δθ.93 (d, 6H), 1.74 (m, IH), 2.35 (m, 2H), 2.43 (d, 2H), 2.78 (d, 3H), 2.85 (m, 2H), 7.88 (s, IH)
Intermediate 87: 2-butan-2-yl-10-chIoro-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5-one
To a solution of 3-[(5-bromo-2-chloro-pyrimidin-4-yl)-butan-2-yl-amino]-N-methyl- propanamide (Intermediate 88; 559 mg, 1.60 mmol) in anhydrous 1,4-dioxane (15 mL) wass added Caesium Carbonate (1.04 g, 3.19 mmol). Nitrogen was bubbled through the reaction mixture for 10 minutes, prior to addition of Tris(dibenzylideneacetone)dipalladium(0) (87 mg, 0.095 mmol) and XANTPHOS (88 mg, 0.152 mmol). The reaction was heated to 1000C and stiired under nitrogen mfor 18 hrs. The reaction mixture was cooled and diluted to ~40 ml with DCM. The reaction mixture was filtered to remove insoluble material, washing filter0 cake through with DCM. The filtrate was evaporated to give a brown gum which was purified by flash chromatography on silica (4Og cartridge; ISCO companion) eluting with a 25-75% gradient of ethyl acetate in iso-hexane. Product containing fractions were combined and evaporated to give a waxy off white solid which was trituration with hot iso-hexane afforded, on cooling, and collection by suction filtration the title compound as a pale yellow solid (121s mg, 28%)
H NMR (400.132 MHz, DMSO-D6) δ 0.83 (t, 3H), 1.16 (d, 3H), 1.57 (m, 2H), 2.65 (m, 2H), 3.18 (s, 3H), 3.49 - 3.66 (m, 2H), 4.57 (m, IH), 8.12 (s, IH); MS m/z 269 [M+H]+.
Intermediate 88: 0 3-[(5-bromo-2-chloro-pyrimidin-4-yl)-butan-2-yl-amino]-N-methyl-propanamide To a solution of 3-(butan-2-ylamino)-N-methyl-propanamide (Intermediate 89; 563 mg, 3.56 mmol) in DCM (7 mL) was added triethylamine (550 μl, 3.94 mmol) and, as a solid, 5- bromo-2,4-dichloropyrimidine (Aldrich; 890 mg, 3.90 mmol). The reaction was stirred at ambient temperature overnight. Saturated aqueous Sodium Bicarbonate solution (10 mL) was added and the mixture shaken. The organic phase was collected by gravity elution through a PTFE filter cup. The DCM solution was injected directly onto 4Og Si cartridge and eluted with a 25-75% gradient of ethyl acetate in hexane. Product containing fractions were combined and evaporated to afford the title compound as a colourless crystalline solid (565 mg; 45%) 1HNMR (400.132 MHz, CDC13) 5 0.83 (t, 3H), 1.28 (d, 3H), 1.58 (m, IH), 1.72 (m, IH), 2.44 (m, 2H), 2.83 (d, 3H), 3.64 (m, IH), 3.85 (m, IH), 4.58 (m, IH)5 5.78 (m, IH), 8.23 (s, lH); MS m/z 351 [M+H]+.
Intermediate 89: 3-(butan-2-ylamino)-N-methyl-propanamide
A mixture of N-methylacrylamide (ABCR; 500 mg, 5.87 mmol), sec-butylamine (Aldrich; 530 mL, 5.22 mmol) and ethanol (4 mL) was heated in a microwave to 14O0C for 45 minutes and then at 15O0C for 30 minutes. The reaction mixture was cooled and poured onto an SCX- 2 cartridge (5g) and cartridge washed through with methanol (~50 mL). Products were then eluted with 2M ammonia in methanol (~50 mL) and evaporated to afford the title compound as a straw coloured oil (563 mg; 61%)
1HNMR (400.132 MHz, CDC13) δ 0.92 (t, 3H), 1.06 (d, 3H), 1.31 - 1.53 (m, 2H), 2.34 (m, 2H), 2.57 (m, IH), 2.78 - 2.94 (m, 5H), 7.77 (s, IH)
Intermediate 90:
10-chloro-2-cycIobutyl-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5-one
To a solution of 3-[(5-bromo-2-chloro-pyrimidin-4-yl)-cyclobutyl-amino]-N-methyl- propanamide (Intermediate 91; 600 mg, 1.73 mmol) in anhydrous 1,4-dioxane (15 mL) was added Caesium Carbonate (1.1 g, 3.38 mmol). Nitrogen was bubbled through the reaction mixture for 10 minutes, prior to addition of Tris(dibeπzylideneacetone)dipalladium(0) (99 mg, 0.11 mmol) and XANTPHOS (95 mg, 0.16 mmol). The reaction was heated to 1000C and stirred under nitrogen overnight
The reaction mixture was cooled and diluted to ~40 ml with DCM, filtered to remove insoluble material, washing filter cake through with DCM and evaporated to give a brown/green solid which was purified by flash chromatography on silica (12Og cartridge; ISCO companion) eluting with a 25-100% gradient of ethyl acetate in iso-hexane. Product containing fractions were combined and evaporated to give a waxy off white solid which was trituration with warm iso-hexane which afforded, on cooling and collection by suction filtration the title compound as a pale yellow solid (216 mg, 47%) 1H NMR (400.132 MHz, DMSO-D6) δ 1.68 (m, 2H), 2.09 (m, 2H), 2.21 (m, 2H), 2.63 (m, 2H), 3.19 (s, 3H), 3.69 (m, 2H), 4.43 (m, IH), 8.19 (s, IH); MS m/z 267.4 [M+H]+.
Intermediate 91; 3-[(5-bromo-2-chloro-pyrimidin-4-yl)-cyclobutyl-amino]-N-methyl-propanamide Using 3-(cyclobutylamino)-N-methyl-propanamide - Intermediate 92 and analogous conditions to Intermediate 88 the title compound was obtained as a white solid (609 mg)
1H NMR (400.132 MHz, CDC13) 6 1.62 - 1.79 (m, 2H), 2.16 - 2.34 (m, 4H), 2.45 (m, 2H), 2.81 (d, 3H), 3.95 (m, 2H), 4.72 (m, IH), 5.72 (m, IH), 8.24 (s, IH)
Intermediate 92:
3-(cyclobutylamino)-N-methyl-propanamide
Using cyclobutanamine - Aldrich and analogous conditions to Intermediate 89 the title compound was obtained as a pale yellow oil (541 mg)
1H NMR (400.132 MHz, CDC13) δ 1.64 - 1.75 (m, 4H), 2.23 (m, 2H), 2.33 (m, 2H), 2.77 - 2.81 (m, 5H), 3.26 (m, IH), 7.32 (m, IH)
Intermediate 93;
10-chloro-2-(cyclopropylmethyl)-6-methyI-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll- trien-5-one To a partial solution of 3-[(5-bromo-2-chloro-pyrimidin-4-yl)-(cyclopropylmethyl)ammo]-N- methyl-propanamide ( Intermediate 94; 426 mg, 1.18 mmol) in anhydrous 1,4-dioxane (15 mL) was added Caesium Carbonate (790 mg, 2.42 mmol). Nitrogen was bubbled through the reaction mixture for 10 minutes, prior to addition of s Tris(dibenzylideneacetone)dipalladium(0) (69 mg, 0.075 mmol) and XANTPHOS (62 mg, 0.107 mmol). The reaction was heated to 1000C and stirred under nitrogenfor 18 hrs. The reaction mixture was cooled and diluted to ~40 ml with DCM, filtered to remove insoluble material, washing the filter cake through with DCM, and evaporated to give a brown gum which was purified by flash chromatography on silica (4Og cartridge; ISCOo companion) eluting with a 25-75% gradient of ethyl acetate in iso-hexane. Product containing fractions were combined and evaporated to give a crystalline yellow translucent solid. Trituration with hot iso-hexane afforded, on cooling, and collection by suction filtration the title compound as a pale yellow solid (165 mg, 50%)
1H NMR (400.132 MHz, DMSO-D6) δ 0.00 (m, 2H), 0.33 (m, 2H), 0.59 (m, IH), 1.44 (q,s 2H), 2.60 (m, 2H), 3.11 (s, 3H)5 3.55 (m, 2H), 3.68 (m, 2H), 8.05 (s, IH) MS m/z 281.4 [M+H]+.
Intermediate 94:
3-[(5-bromo-2-chloro-pyrimidin-4-yl)-(cyclopropylmethyl)amino]-N-methyl-0 propanamide
Using 3-(cyclopropylmethylamino)-N-methyl-propanamide- Intermediate 95 and analogous conditions to Intermediate 88 the title compound was obtained as a white solid (431 mg)
1H NMR (400.132 MHz, CDC13) δ 0.35 (m, 2H), 0.60 (m, 2H), 1.14 (m, IH), 2.57 (m, 2H), 2.84 (d, 3H), 3.66 (d, 2H), 4.03 (m, 2H), 5.79 (m, IH), 8.21 (s, IH); MS m/z 349.0 [M+H]+.5
Intermediate 95: 3-(cyclopropylmethylamino)-N-methyl-propanamide
Using 2-Cyclopropylethanamine- Aldrich and analogous conditions to Intermediate 89 the title compound was obtained as a pale yellow oil (590 mg) 1H NMR (400.132 MHz, CDC13) δ 0.13 (m, 3H), 0.51 (m, 2H), 0.94 (m, IH), 2.36 (m, 2H), 2.49 (d, 2H), 2.81 (d, 3H), 2.90 (m, 2H), 7.59 (s, IH).
Intermediate 96; 10-chloro-2-[(2,4-dimethoxyphenyl)methyl]-6-methyl-2,6,9,ll- tetrazabicy clo [5.4.0] undeca-7,9,1 l-trien-5-one
To a solution of 3-[(5-bromo-2-chloro-pyrimidin-4-yl)~[(3,5- dimethoxyphenyl)methyl] amino] -N-methyl-propanamide (Intermediate 97; 2.1 g, 4.73 mmol) in 1,4-dioxane (50 mL) was added Caesium Carbonate (3.4 g, 10.44 mmol) and the reaction mixture sparged with argon for 20 minutes.
Tris(dibenzylideneacetone)dipalladium(0) (260 mg, 0.28 mmol) and XANTPHOS (248 mg,
0.43 mmol) were added and reaction mixture heated to 1000C and left to stir under nitrogen overnight.
The reaction mixture was cooled and diluted to ~100 ml with DCM., filtered to remove insoluble material, washing filter cake through with DCM and evaporated to give a dark yellow oil with some solid which was taken up in DCM (~20 ml) and insoluble material removed by filtration. The filtrate was purified by flash chromatography on silica (12Og cartridge) eluting with a rising gradient of 25-100% ethyl acetate in hexane. Product containing fractions were combined and evaporated to give the title compound as a pale0 yellow solid (690 mg)
1H NMR (400.132 MHz, DMSO-D6) δ 2.71 (m, 2H), 3.20 (s, 3H), 3.63 (m, 2H), 3.75 (s, 3H), 3.78 (s, 3H), 4.68 (s, 2H), 6.48 (m, IH), 6.59 (d, IH), 7.06 (d, IH), 8.17 (s, IH); MS m/z 363.3 [M+H]+. 5 Intermediate 97;
3-[(5-bromo-2-chIoro-pyrimidin-4-yl)-[(3,5-dimethoxyphenyl)methyl]amino]-N-methyl- propanamide
3-[(3,5-dimethoxyphenyl)methylamino]-N-methyl-propanamide (Intermediate 98; 1 g, 3.96 mmol) was dissolved in DCM (10 mL) and triethylamine (0.68 mL, 4.36 mmol). 5-bromo-o 2,4-dichloropyrimidine (Aldrich; 993 mg, 4.36 mmol) was added and the mixture stirred at room temperature for 18 hours. The mixture was diluted with DCM and washed with water, brine, dried (MgSO4), filtered and evaporated to give a yellow gum which was purified on a 4Og ISCO companion eluting with 50-70% ethyl acetate in iso-hexane to give the title compound as a white solid (461mg, 26%).
IHNMR (400.13MHz; DMSO-d6) δ 2.5 (m, 2H) under DMSO, 2.55 (d, 3H), 3.72 (s, 6H), 3.8 (t, 2H), 4.85 (s, 2H), 6.41 (s, 3H), 7.84 (bm, IH), 8.38 (s, IH); MS m/z 443/445 [M+H]+.
Intermediate 98; 3-[(3,5-dimethoxyphenyl)methylamino]-N-methyl-propanamide N-methylacrylamide (ABCR; 500mg, 5.87 mmol) and 3.5-dimethoxybenzylamine (Aldrich; 0.98 mL, 6.46 mmol) were dissolved in ethanol (4 mL) and heated in a microwave at 14O0C for 45 minutes. The mixture was poured onto a 2Og SCX-2 column, washed with methanol and eluted with 3.5N NH3 in methanol. The product fractions were evaporated to the title compound as a yellow oil (1.3 g, 88%). IH NMR (CDC13) 2.36 (t, 2H), 2.78 (d, 3H), 2.88 (t, 2H), 3.72 (s, 2H), 3.79 (s, 6H), 6.36 (m, IH), 6.45 (m, 2H), 7.31 (bs, IH); MS m/z 253 [M+H]+.
Intermediate 99: 2-benzyl-10-chloro-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5-one To a cooled (ice/water bath) suspension of sodium hydride (60% dispersion in mineral oil; 6.5 mg, 0.16 mmol) in DMA (0.5 mL) was added a solution of 10-chloro-6-methyl-2,6,9,l 1- tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5-one (Intermediate 100; 32 mg, 0.15 mmol) in DMA (1.0 mL). The reaction mixture was allowed to stir, under nitrogen, in an ice bath for 15 minutes prior to addition of Benzyl bromide (Aldrich; 20 μl, 0.17 mmol). The reaction mixture was stirred on an ice bath for 15 minutes and then at ambient temperature for 3 hrs A further addition of Sodium hydride (2 mg) was made and stirring continued for 6 hrs. Saturated ammonium chloride (0.5 ml) was added and the reaction mixture poured directly onto an SCX-3 cartridge (2g). The cartridge was washed with methanol (~30 mL) before eluting products with 2M ammonia in methanol (~30 mL). Product containing fractions were evaporated to dryness to give a colourless gum, which was combined with the cartridge methanol pre-wash and this solution evaporated to dryness. The resultant material was partitioned between DCM (10 mL) and water (10 niL). The organic phase was collected by gravity elution through a PTFE filter cup and evaporated to give the title compound as a pale yellow opaque gum (46 mg, 89%)
1HNMR (400.132 MHz, DMSO-D6) δ 2.71 (m, 2H), 3.22 (s, 3H), 3.66 (m, 2H), 4.82 (s, 5 2H), 7.27 - 7.38 (m, 5H), 8.21 (s, IH); MS m/z 303.3 [M+H]+.
Intermediate 100: 10-chIoro-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5-one
3-[(5-bromo-2-chloro-pyrimidin-4-yl)-[(3,5-dimethoxyphenyl)methyl]amino]-N-methyl- io propanamide (Intermediate 97; 83 mg, 0.23 mmol) was taken up in DCM (1 mL) and TFA (1 mL) and stirred for 30 minutes. A further addition of TFA (1 mL) was made and stirring continued overnight. The reaction mixture was diluted with DCM (25 m L) and poured directly onto a SCX-3 cartridge (2 g). The cartridge was washed through with methanol (~50 mL). Products were eluted with 2M ammonia in methanol and ammoniacal eluant evaporated is to dryness to afford the title compound as an off white solid (34 mg, 70%)
1HNMR (400.132 MHz, DMSO-D6) δ 2.66 (m, 2H), 3.21 (s, 3H), 3.52 (m, 2H), 8.14 (m, IH), 8.28 (m, IH); MS m/z 213.4 [M+H]+.
Intermediate 101:
20 10-chloro-6-methyl-2-[(2-methyl-l,3-thiazol-4-yl)methyl]-2,6,9,ll- tetrazabicy clo [5.4.0] undeca-7,9,1 l-trien-5-one
To a cooled (ice/water bath) suspension of sodium hydride (60% dispersion in mineral oil; 13 mg, 0.38 mmol) in DMA (0.5 mL) was added a solution of 10-chloro-6-methyl-2,6,9,l 1- tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one (Intermediate 100; 63 mg, 0.30 mmol) in 25 DMA (1 mL). The reaction mixture was allowed to stir, under nitrogen, in ice bath for 10 minutes prior to addition of 4-chlorometyl-2-methylthiazole (ASDI; 75 mg, 0.51 mmol). The reaction mixture was stirred in an ice bath for 20 minutes and then warmed to ambient temperature over 1 hour.
30 The reaction mixture was quenched by careful addition of saturated aqueous ammonium chloride (0.5 ml) and the reaction mixture was partitioned between DCM(IO mL) and water (10 mL). The organic phase was separated by gravity filtration through a PTFE filter cup and evaporation to dryness to give the title compound as a straw coloured gum (61 mg; 63%)
1HNMR (400.132 MHz, DMSO-D6) δ 2.64 (s, 3H), 2.74 (m, 2H), 3.21 (s, 3H), 3.78 (m, 2H), 4.82 (m, 2H), 7.31 (m, IH), 8.20 (s, IH); MS m/z 324.3 [M+H]+. Intermediate 102;
10-chloro-2-(cyclobutylmethyl)-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll- trien-5-one
To a cooled (ice/water bath) suspension of sodium hydride (60% dispersion in mineral oil; 13 mg, 0.38 mmol) in DMA (0.5 ml) was added a solution of (Intermediate 100; 63 mg, 0.30 mmol) in DMA (1 mL). The reaction mixture was allowed to stir, under nitrogen, on an ice bath for 10 minutes prior to addition of Bromomethyl cyclobutane (Aldrich; 40 μl, 0.36 mmol). The reaction mixture was stirred on an ice bath for 20 minutes and then warmed to ambient temperature over 1 hour. A further addition of Sodium hydride (2 mg) and Bromomethyl cyclobutane (20 μl, 0.18 mmol was made and the reaction stirred for a further hour
The reaction mixture was quenched by careful addition of saturated aqueous ammonium chloride (0.5 ml) and the reaction mixture partitioned between DCM(IO mL) and water (10 mL). The organic phase was separated by gravity filtration through a PTFE filter cup and evaporation to dryness gave the title compound as a pale yellow gum (71 mg, 84%) 1H NMR (400.132 MHz, DMSO-D6) δ 1.71 - 1.86 (m, 4H), 2.01 (m, 2H), 2.66 (m, 3H), 3.17 (s, 3H), 3.63 (d, 2H), 3.70 (m, 2H), 8.12 (s, IH); MS m/z 281.3 [M+H]+.
Intermediate 103:
10-chloro-6-methyl-2-phenyl-2,6,9,l 1-tetrazabicyclo [5.4.0] undeca-7,9,1 l-trien-5-one To a solution of 10-chloro-2-phenyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien-5-one (Intermediate 104; 1.185 g, 4.31 mmol) in DMA (100 mL) at O0C, was added methyl iodide (282 μL, 4.53 mmol) followed by sodium hydride (60% oil dispersion, 182 mg, 4.53 mmol) in one portion. The mixture was stirred at O0C for 4hrs and ice was then added, resulting in a brown sticky precipitate, which was filtered and washed with water. A white solid precipitated from the filtrate, which was filtered off and triturated with diethylether to give the title compound (494mg). The sticky brown precipitate was dissolved in DCM and suction columned in 2- 5% methanol/dichloromethane to give a yellow oil.
The aqueous filtrate was extracted with DCM and methanol, washed with saturated aqueous brine and evaporated to give a yellow oil which was purified by suction columned as above to give a yellow oil.
Both yellow oils were combined and triturated with diethylether to give the title compound as a white solid (401mg)
1H NMR (399.9 MHz, DMSO-D6) : δH : 2.89 (m, 2H), 3.29 (s, 3H), 4.06 (m, 2H), 7.30 (m, 3H), 7.42 (m, 2H), 8.38 (s, IH); MS m/z 289 [M+H]+.
Intermediate 104: 10-chloro-2-phenyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5-one
Methyl 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-phenyl-amino]propanoate (Intermediate 105; 21.855 g, 64.9 mmol), iron powder (5.44 g, 97.35 mmol) and acetic acid (200 mL) were heated at 8O0C for 2hrs and then stirred at room temperature overnight..
The reaction mixture was filtered through celite and the filter cake washed with dichloromethane. The solvent was evaporated and the resultant material was pre-absorbed onto silica with methanol/dichloromethane and then purified by vacuum filtration chromatography eluting with dichloromethane,. diethylether, . ethylacetate and finally. 20% methanol/dichloromethane. Product containing fractions were combined and evaporated To give a brown solid which was trituated with diethylether and then methanol and small % of dichloromethane to give the title compound as an off white solid (2.29 g) The silica from the filtration column was suspended in 20% methanol/dichloromethane and filtered and washed with a further portion of 20% methanol/dichloromethane. Evaporation afforded a yellow solid which was triturated with methanol and small % of dichloromethane to give the title compound as an off white solid (1.35g )
1H NMR (399.9 MHz, DMSO-D6) : δH : 2.89 (m, 2H), 3.98 (m, 2H)5 7.32 (m, 3H), 7.42 (m, 2H), 8.01 (s, IH), 9.90 (s, IH); MS m/z 275 [M+H]+.
Intermediate 105: Methyl 3- [(2-chloro-5-nitro-pyrimidin-4-yl)-phenyl-amino]propanoate
To a solution of; 3,4-dichloro-5-nitropyrimidine (Aldrich; 12.59 g, 64.9 mmol) in anhydrous THF (300 niL) at room temperature under a nitrogen atmosphere was added dropwise over 6hrs a solution of Methyl 3-anilinopropanoate (Intermediate 106; 12.795 g, 71.39 mmol) and Hunigs base (13.54 mL, 77.88 mmol) in anhydrous THF (300 niL) The reaction mixture was stirred over night at room temperature.
The solvent was evaporated at 4O0C and the residue dissolved in DCM and washed with water and saturated brine. The resulting organic phase was dried over anhydrous sodium sulphate then pre-absorbed onto silica and purified by vacuum filtration chromatography eluting with dichloromethane. Evaporation of product containing fractions afforded the title compound as a dark red oil (24.25g, >100%) MS m/z 275 [M+H]+. Retention time 2.32mins
Intermediate 106; Methyl 3-anilinopropanoate
Aniline (Acros; 59.89 mL, 657 mmol) , Methylacrylate (Acros; 62.54 mL, 690 mmol) and Glacial acetic acid (15 mL) an d were combined and heated at 790C overnight The reaction mixture was cooled to room temperature and added to ice water, a solid precipitated and was filtered off and dissolved in dichloromethane aliquot taken and pre- absorbed onto silica and purified by vacuum filtration chromatography eluting with DCM. Product containing fractions were combined and evaporated to give the title compound as a pale yellow sticky solid (14.33 g, 12%)
1HNMR (399.9 MHz, DMSO-D6) : δH : 2.57 (tr, 2H), 3.29 (tr, 2H), 3.61 (s, 3H), 5.57 (tr, IH), 6.55 (m, 3H), 7.08 (m, IH); MS m/z 180 [M+H]+.
Intermediate 107; 4-amino-3-chloro-N-(3-dimethylamino-2,2-dimethyl-propyl)benzamide
3-chloro-N-(3-dimethylamino-2,2-dimethyl-propyl)-4-nitro-benzamide (2.29 g, 7.67 mmol), iron powder (2.45 g, 43.79 mmol) and ammonium chloride (781 mg, 14.60 mmol) were heated in ethanol (50 mL) and water (18 mL) at reflux for one hour. A few drops of acetic acid were added and heating continued for a further hour. The reaction mixture was cooled, filtered and the filtrate concentrated. This residue was partitioned between saturated NaHCO3 (aq.) and DCM. The organic phase was washed with brine, dried with MgSO4 and concentrated. Column chromatography gave the title compound as an orange crystalline solid. (850mg, 39%) 1H NMR (399.9 MHz, DMSO-d6) δθ.86 (6H, s), 2.16 (2H, s), 2.26 (6H, s), 3.14 (2H, d), 5.83 (2H, s), 6.80 (IH, d), 7.52 - 7.54 (IH, m), 7.72 (IH, d), 8.15 (IH, t); MS m/z 286.16 [M+H]+.
Intermediate 108: 3-chIoro-N-(3-dimethylamino-2,2-dimethyl-propyl)-4-nitro-benzamide 3-chloro-4-nitro-benzoyl chloride (Intermediate 54; 2.2 g, 10.00 mmol) was dissolved in DCM (20 mL) and N,N-diisopropylethylamine (2.095 mL, 12.00 mmol) added. The mixture was cooled in an ice/water bath andN,N,2,2-tetramethyl-l,3-propanediamine (3.652 mL, 10.00 mmol) in DCM (10 mL) added dropwise. The mixture was allowed to warm to room temperaturet and stirred for 0.5h. The mixture was washed with brine, 2N NaOH (aq.), dried (MgSO4) and concentrated. Column chromatography of the residue (2% MeOH/DCM) gave the title compound as a yellow oil 17171/2/1 (2.29g, 77%).
1HNMR (399.9 MHz, DMSO-d6) δθ.89 (6H, s), 2.17 (2H, s), 2.26 (6H, s), 3.21 (2H, d), 7.96 - 7.98 (IH, m), 8.13 (IH, d), 8.18 (IH, d), 8.73 (IH, t); MS m/z 314.21 [M+H]+.
Intermediate 109:
10-chloro-2-(2-methoxyethyl)-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll- trien-5-one
3-[(5-bromo-2-chloro-pyrimidin-4-yl)-(2-methoxyethyl)amino]-N-methyl-propanamide (Intermediate 110; 1.12 g, 3.185 mmol) was suspended in dioxane (70 mL), Caesium Carbonate (2.08 g, 6.37 mmol) added and the mixture bubbled with nitrogen for 10 minutes. Tris(dibenzylideneacetone)dipalladium(0) (175 mg, 0.151 mmol) and XANTPHOS (166 mg, 0.287 mmol) were dded and the mixture heated to 100 °C for 20 hrs. A further 0.06 equivalent of Tris(dibenzylideneacetone)dipalladium(0) and 0.09 equvalent of XANTPHOS were added and heating continued for a further 2 hrs. The reaction mixture was cooled to room temperature filtered and the filter cake washed with DCM. The filtrate was evaporated and dissolved in DCM and purified on silica eluting with a gradient of 40 - 55% Ethyl Acetate / iso-hexane then 55% Ethyl Acetate / iso-hexane and finally 70% Ethyl Acetate / iso-hexane. Fractions containing product were combined and evaporated to a yellow solid. Which was purified by base modified reverse phase HPLC to yield the title compound as a white solid (157 mg, 18%) s H NMR (399.902 MHz5 CDC13) δ2.73 (m, 2H), 3.29 (s, 3H), 3.35 (s, 3H), 3.68 (m, 2H), 3.84 (m, 2H)5 3.90 (m, 2H)5 7.95 (s, IH); MS m/z 271 [M+H]+.
Intermediate 110: 3-[(5-bromo-2-chloro-pyrimidin-4-yl)-(2-methoxyethyl)amino]-N-methyl-propanamideo 3-(2-methoxyethylamino)-N-methyl-propanamide (Intermediate 111; 608 mg, 3.79 mmol) 5- Bromo-2,4-dichloropyrimidine (Aldrich; 950 mg, 4.17 mmol), Triethylamine (555 μL, 3.98 mmol), and DCM (5 mL) were combined and stirred over the weekend at room temperature. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution then gravity filtered through a PTFE cup and organic solvents evaporated. The residue was5 dissolved in DCM and passed through a silica column, eluting with 50% Ethyl Acetate / iso- hexane then 60% Ethyl Acetate / iso-hexane and finally 70% Ethyl Acetate / iso-hexane. Fractions containing product combined and evaporated to a colourless liquid which crystallised under high vacuum to give the title compound as a white solid (1.12 g, 84%) i HNMR (399.902 MHz, CDCl3) 62.57 (m, 2H), 2.82 (d, 3H), 3.35 (s, 3H), 3.63 (m, 2H)5 3.950 (m, 2H)5 4.01 (m, 2H), 5.80 (s, IH), 8.20 (s, IH); MS m/z 353 [M+H]+.
Intermediate 111: 3-(2-methoxyethylamino)-N-methyl-propanamide
N-Methylacrylamide (ABCR; 500 mg, 5.87 mmol), 2-Methoxyethylamine (Aldrich; 441 mg,5 5.87 mmol), and EtOH (2 mL) were combined and heated in a microwave at 140 0C for 40 minutes. The reaction mixture was cooled and added to a 5g SCX-2 column pre-wet with MeOH (2 column volumes), flushed with MeOH (2 column volumes) then the product eluted with 2M ammonia in MeOH. Product containing fractions were evaporated in vacuo to give the the title compound as a clear oil (608 mg, 65%) HNMR (399.902 MHz5 CDC13) 62.35 (m, 2H)5 2.79 (m, 5H), 2.88 (m, 2H), 3.37 (s, 3H), 3.49 (m, 2H)5 7.55 (s, IH)
Intermediate 112: s 10-chloro-2-(l-methoxypropan-2-yl)-6-methyI-2,6,9,ll-tetrazabicyclo[5.4.0]undeca- 7,9,1 l-trien-5-one
N-(254-dichloropyriniidin-5-yl)-N-methyl-prop-2-enamide (Intermediate 113; 318 mg, 1.37 mmol), 2-Amino-l-methoxypropane (152 μl, 1.44 mmol), Triethylamine (382 μl, 2.74 mmol), Titanium Tetra-ethoxide (29 μl, 0.137 mmol) and DCM (5 mL) were combined and stirred ato room temperature for lhr, heated to 40 °C for 3hrs, cooled to room temperature, washed with water and gravity filtered through a PTFE . The organic solution was purified by chromatographic separation on silica eluting with a shallow gradient (25 column volumes) of 10 - 50% Ethyl Acetate / iso-hexane. Product containing fractions were combined and evaporated to give the title compound as a clear gum (54 mg, 18%). s H NMR (399.902 MHz, CDC13) δl.25 (m, 3H), 2.69 (m, 2H), 3.29 (s, 3H), 3.34 (s, 3H)5 3.53 (m, 2H), 3.75 (m, 2H), 4.99 (m, IH), 7.94 (s, IH); MS m/z 285 [M+H]+.
Intermediate 113: N-(2,4-dichloropyrimidin-5-yI)-N-methyl-prop-2-enamide 0 5-Methylamino-2,4-Dichloropyrimidine (800 mg, 4.5 mmol) was dissolved in THF (18 mL) and triethylamine (1.88 mL, 13.5 mmol) was added. A solution of 3-chloropropionyl chloride (644 μl, 6.55 mmol) in DCM (2 mL) was added dropwise giving an instantaneous precipitate The reaction was stirred at room temperature for 30 minutes. The precipitate was filtered off and the filtrate evaporated and the resultant material dissolved in DCM, washed with water,5 saturated aqueous sodium bicarbonate solution and then gravity filtered through a PTFE cup. The organic solvent was evaporated to give the crude product as a yellow gum which was dissolved in THF (18 mL). Triethylamine (1.8 mL) was added and a further portion of 3- chloropropionyl chloride (215 μl, 2.25 mmol). The reaction was stirred at room temp for 1 hr then worked up as previously to give the title compound as a brown gum (624 mg, 60%)o MS m/z 232 [M+H]+. Retention Time 1.39mins Intermediate 114: 5-Methylamino-2,4-Dichloropyrimidine
To the methylamino- 5 -uracil (Intermediate 115; 6.81 g, 48.25 mmol) was added triethylamine (13.45 mL, 96.51 mmol) followed by phosphorus oxychloride (67.5 mL, 723 mmol) very slowly . The reaction was heated to reflux for 3 hrs cooled to room temperature and POC13 evaporated and the residues azeotroped with toluene. The residue was diluted with toluene (100 mL) . Ice (200 mL) was added and the mixture stirred for 5 minutes. The mixture was then neutralised to pH8 with saturated aqueous sodium bicarbonate solution and extracted with toluene (300 mL). The aqueous phase was re-extracted with DCM (5 x 300 mL). The toluene solution was washed with water (100 mL), dried (MgSO4) and evaporated. The combined DCM solutions were also washed with water (300 mL), dried (MgSO4), combined with the toluene solution and evaporated to a brown gum which was dissolved in DCM with a little MeOH and chromatographed on silica eluting with a gradient of 0 - 10% Ethyl Acetate / iso-hexane followed by 10% Ethyl Acetate / iso-hexane then 15% Ethyl Acetate / iso-hexane. Fractions containing impure product were re-chromatographed eluting with 10% Ethyl Acetate / iso-hexane until the impurity had come off then 15% Ethyl Acetate / iso-hexane. Product containing fractions were evaporated to give the title compound as a cream solid (2.58 g, 30%) 0 H NMR (399.902 MHz, CDC13) 52.98 (d, 3H), 4.35 (s, IH), 7.90 (s, IH); MS m/z 175 [M- H]+.
5
Intermediate 115: MethyIamino-5-uracil
5 Bromo Uracil (Aldrich; 49.66 g, 260 mmol) and 25% Methylamine in Ethanol (Aldrich; 200 mL ) were combined and heated in an autoclave at 160 0C for 6 hours. o The solution was cooled and evaporated and the residue washed with water, acetone and diethylether to give the title compound as a white solid (28 g, 70%) Intermediate 116:
10-chloro-2-(3-furyImethyl)-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien- 5-one one
3-Furylmethylamine (Maybridge; 175 mg, 1.8 mmol), N-(2,4-dichloropyrimidin-5-y I)-N- methyl-prop-2-enamide (Intermediate 113; 347 mg, 1.5 mmol), Triethylamine (420 μL, 3 mmol), Titanium Tetra-ethoxide (157 μL, 0.75 mmol) and DCM (5 mL) were combined and stirred at room temp for lhr, heated at 40 0C overnight then cooled to room temperature. The reaction mixture was washed with water then gravity filtered through a PTFE cup, the aqueous layer containing the titanium emulsion was washed with further DCM (3 x 10 mL) and the combined organic solutiuons gravity filtered through a PTFE cup and solvents evaporated. The residue was dissolved in DCM and purified by chromatographic separation on silica eluting with a shallow gradient (25 column volumes) of 10 - 50% Ethyl Acetate / iso-hexane. Product containing fractions were combined and evaporated to give the title compound as a yellow gum (67 mg, 15%)
H NMR (399.902 MHz, CDC13) 52.63 (m, 2H)5 3.31 (s, 3H)5 3.75 (m, 2H), 4.60 (s, 2H)5 6.49 (m, IH), 7.41 (m, IH), 7.50 (m, IH), 8.00 (s, IH); MS m/z 293 [M+H]+.
Intermediate 117:
10-chloro-2-cyclopropyI-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5- one
Cyclopropylamine (Aldrich; 150 μL, 2.18 mmol), N-(2,4-dichloropyrimidin-5-yl)-N-methyl- prop-2-enamide ( Intermediate 113; 337 mg, 1.45 mmol) Triethylamine (404 μL, 2.9 mmol), Titanium Tetra-ethoxide (152 μL, 0.725 mmol) and DCM (5 mL) were combined and stirred at room temp for lhr, heated at 40 °C for 4 hrs then cooled to room temperature. The reaction mixture was washed with water then gravity filtered through a PTFE cup, the aqueous layer containing the titanium emulsion was washed with further DCM (3 x 10 mL) and the combined organic solutiuons gravity filtered through a PTFE cup and solvents evaporated. The residue was dissolved in DCM and purified by chromatographic separation on silica eluting with a shallow gradient (25 column volumes) of 10 - 50% Ethyl Acetate / iso-hexane. Product containing fractions were combined and evaporated to give the title compound as a cream solid (42 mg, 11%)
H NMR (399.902 MHz, CDC13) δθ.58 (m, 2H), 0.91 (m, 2H), 2.68 (m, 2H), 2.85 (m, IH), 3.28 (s, 3H), 3.84 (m, 2H), 8.02 (s, IH); MS m/z 253 [M+H]+.
Intermediate 118;
10-chloro-6-methyl-2-(l-methyl-4-piperidyl)-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll- trien-5-one
4-Amino-l-methylpiperidine (Fluorochem; 200 mg, 1.74 mmol), N-(2,4-dichloropyrimidin- 5-yl)-N-methyl-prop-2-enamide ( Intermediate 113; 337 mg, 1.45 mmol) Triethylamine (404 μL, 2.9 mmol), Titanium Tetra-ethoxide (152 μL, 0.725 mmol) and DCM (5 mL) were combined and stirred at room temp for lhr, heated at 40 °C for 3 hrs then cooled to room temperature. The reaction mixture was washed with water then gravity filtered through a PTFE cup, the aqueous layer containing the titanium emulsion was washed with further DCM (3 x 10 mL) and the combined organic solutions gravity filtered through a PTFE cup and solvents evaporated. The residue was dissolved in DCM and purified by chromatographic separation on silica eluting with a shallow gradient (25 column volumes) of 0 - 5% 2M ammonia in MeOH / DCM. Product containing fractions were combined and evaporated to give the title compound as a yellow solid (39 mg)
Intermediate 119: 4-amino-N-cyclohexyl-3-methoxy-benzamide
EDAC(7.46 g, 3.90 mmol) was added to a stirred solution of 4-aniino-3-methoxy acid (Aldrich; 5 g, 2.9 mmol), cyclohexylamine (Aldrich; 5.13mL, 4.49 mmol) and DMAP (11 g, 9 mmol) in DCM (200 mL) and the reaction mixture was stirred for a 18hrs.under an atmosphere of nitrogen. The mixture was washed with IM citric acid solution (x3), saturated sodium bicarbonate solution and dried. The solvent was evaporated off and the residue triturated with diethylether to give the title compound as a pink solid (5.3 g, 71%) MS m/z 293 [M+H]+.
Intermediate 120: 10-chloro-2-cyclopentyl-3,6-dimethyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien- 5-one.
3-[(5-bromo-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-N-methyl-butanamide (Intermediate 121; 196 mg, 0.52 mmol) was dissolved in 1,4-dioxane (5 mL) and Tris(dibenzylideneacetone)dipalladium(0) 10 mg, 0.02 mmol), XANTPHOS (20 mg, 0.02 mmol) and Caesium Carbonate (247 m, 0.76 mmol) were added to a microwave reaction vessel which was sealed and irradiated at 150 0C for 30 min. A further addition of Tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.02 mmol) and XANTPHOS (20 mg, 0.02 mmol) was made and the reaction mixture irradiated at 150 °C for 2 hrs.. The cooled reaction mixture was filtered through a pad of celite and the filtrate concentrated down onto silica and purified by flash silica chromatography (companion, 12 g, 0-5% methanol/DCM). Product containing fractions were combined and evaporated to give the title compound as a yellow solid (126 mg, 82%).
1HNMR (399.902 MHz, CDCl3) δ 1.34 (d, 3H), 1.44 - 1.95 (m, 8H), 2.63 (dd, IH), 2.77 (dd, IH), 3.32 (s, 3H), 3.98 (ddq, IH), 4.56 (quintet, IH), 7.94 (s, IH); MS m/z 295.2 [M+H]+.
Intermediate 121: 3-[(5-bromo-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-N-methyl-butanamide
A stirred solution of 3-(cyclopentylamino)-N-methyl-butanamide (Intermediate 122; 887 mg, 4.80 mmol), 5-bromo-2,4-dichloropyrimidine (1.15 g, 5.04 mmol) and potassium carbonate (1.34 g, 9.60 mmol) in acetone (20 mL) were heated under reflux conditions to 65 °C for 3 days and then at 75 0C for a further 16 hrs.. The solvent was evaporated and the residue taken up in Ethyl Acetate (200 mL) and water (200 mL). The aqueous phase was separated and the organic phase further washed with water (200 mL) and brine (200 mL). The organic phase was evaporated and the residue purified by flash silica chromatography (companion, 40 g, 0- 10% MeOH/DCM) followed by base modified preparative HPLC (30-50% gradient) to give the title compound as a yellow solid (117 mg, 6%).
1H NMR (399.902 MHz, DMSO-d6) δ 1.29 (d, 3H), 1.36 - 1.51 (m, 2H), 1.65 - 1.93 (m, 6H), 4.03 (quintet, IH), 4.48 (sextet, IH), 7.69 (q, IH), 8.26 (s, IH), 5 protons obscured in DMSO signal. MS m/z 375.17 [M+H]+. Intermediate 122: 3-(cyclopentylamino)-N-methyl-butanamide
But-2-Enoic Acid Methylamide (Journal of Organic Chemistry (1981), 46(1), 27-34;
1 g, 10.0 mmol) and cyclopentlyamine (Aldrich; 1.49 mL, 15.0 mmol) were combined in methanol (6 mL) in a 10 mL microwave reaction vessel and the resultant solution heated to 140 0C for 60 minutes. The reaction mixture was concentrated under reduced pressure re- dissolved in methanol (6 mL) and reintroduced to a microwave reaction vessel with cyclopentylamine (1.49 mL, 15.0 mmol) and the sealed reaction vessel heated to 140 °C for a further 60 mins. The process was repeated with cyclopentylamine (3.0 mL, 30 mmol) added and the sealed reaction vessel irradiated to 140 0C for 2 hrs. The solvent was removed under reduced pressure and the residue dissolved in methanol (approx 10 mL) and loaded directly onto a 50 g SCX-2 cartridge, washing with methanol (100 mL) and eluting the desired product with 7 N methanolic ammonia (100 mL). Product containing fractions were combined and evaporated to give the title compound as a brown oil (1.65 g, 90%)
1H NMR (399.902 MHz, DMSOd6) δ 0.96 (d, 3H), 1.17 - 1.81 (m, 8H), 1.99 (dd, IH), 2.16 (dd, IH), 2.56 (d, 3H), 2.93 (m, IH), 3.09 (quintet, IH), 3.31 (br s, IH), 7.87 (br s, IH)
Intermediate 123:
10-chloro-2-cyclopentyl-4-ethyl-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10jl2- trien-5- one
To a solution of 10-Chloro-2-cyclopentyl-6-methyl-2,6,9,l l-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-5-one (Intermediate 1; 1 g, 3.56 mmol) in anhydrous THF (50 mL) at O0C was added dropwise a 2N solution of sodium bis (trimethylsilyl)amide in THF (1.96 mL, 3.92 mmol). The resulting solution was stirred at O0C for 10 minutes. Ethyl iodide (314 μL, 3.92 mmol) was added dropwise via a syringe and the reaction stirred at O0C for 2hrs and then at room temperature overnight. The reaction mixture was evaporated, taken up in water and extracted with DCM. The organic phase was washed with saturated brine and dried over magnesium sulphate. Evaporation afforded a gum, which was dissolved in DCM and purified by vacuum filtration chromatography, eluting with DCM and then 2. 2-5% Methanol / DCM. Product containing fractions were evaporated to give the title compound as a white foam (483 mg, 44%) 1H NMR (399.9 MHz, DMSO-D6) : δH : 0.81 (tr, 3H), 1.21-2.01 (m, 10H), 2.60 (m, IH), 3.15 (s, 3H), 3.39 (m, 2H), 4.68 (m, IH), 8.11 (s, IH); MS m/z 309 [M+H]+.
Intermediate 124:
10-chloro-2-cyclopentyl-6-methyl-4-propyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12- trien-5-one
To a solution of 10-Chloro-2-cyclopentyl-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca- 8,10,12-trien-5-one (Intermediate 1; 1 g, 3.56 mmol) in anhydrous THF (50 mL) at O0C was added dropwise a 2N solution of sodium bis (trimethylsilyl)amide in THF (1.96 mL, 3.92 mmol). The resulting solution was stirred at O0C for 10 minutes. 1-Iodopropane (Aldrich; 382 μL, 3.92 mmol) was added dropwise via a syringe and the reaction stirred at O0C for 2hrs and then at room temperature overnight.
The reaction mixture was evaporated, taken up in water and extracted with DCM. The organic phase was washed with saturated brine and dried over magnesium sulphate Evaporation afforded a gum, which was dissolved in DCM and purified by vacuum filtration chromatography, eluting with DCM and then 2. 2-5% Methanol / DCM.
Product containing fractions were evaporated to give the title compound as a yellow foam (467 mg, 41%)
1H NMR (399.9 MHz, DMSO-d6) : δH : 0.81 (tr, 3H), 1.21-2.1 (m, 12H)5 2.70 (m, IH), 3.20 (s, 3H)5 3.40 (m5 2H), 4.71 (m, IH), 8.13 (s, IH).; MS m/z 323 [M+H]+.
Intermediate 125:
10-chloro-2-cyclopentyI-4,6-dimethyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-
5-one
To a cold (-780C) magnetically stirred solution of 10-Chloro-2-cyclopentyl-6-methyl- 2,6,9,1 l-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 1 ; 801 mg, 2.85 mmol) in dry THF (15 mL) was added dropwise LHMDS (1 M in THF, 5.71 mL, 5.70 mmol). After 10 minutes at this temperature a solution of methyl iodide (356 uL, 5.70 mmol) in THF (3 mL) was added. The reaction mixture was stirred at —78 0C for 20 minutes and then at 0 °C one hour. The reaction mixture was diluted with DCM and washed with water, followed by brine. The separated organic phase was dried over MgSO4 , filtered and concentrated in vacuo. The crude material was dry-loaded onto silica and purified via column chromatography (0-50% Ethyl Acetate in hexane) to provide the title compound as a white solid. (613 mg, 73%) MS m/z 323 [M+H]+.
Intermediate 126:
10-chloro-2-cycIopentyl-4,4,6-trimethyI-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll- trien-5-one
Figure imgf000324_0001
To a stirred solution of 10-chloro-2-cyclopentyl-4,4-dimethyl-2,6,9, 11- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 127; 9.67 g, 32.8 mmol) in DMA (710 mL) under nitrogen was added methyl iodide (2.25 mL, 36.08 mmol). The mixture was cooled in ice/water to 2.50C. Sodium hydride (60% dispersion in mineral oil, 1.45 g, 36.08 mmol) was added in one portion. A small exotherm to 40C was observed. The reaction mixture was stirred on an ice/water bath for 1 hour, and then stirred at room temperature overnight. Solvent was removed in vacuo and the light-brown liquid residue was treated with water. This afforded a solid, which was filtered off and washed with water. The solid material was dissolved in DCM (200 mL) and the solution dried using MgSO4, filtered and evaporated to give an off white solid which was purified on a 330g Si column (Companion), loading as a solution in DCM (60 mL) The column having been equilibrated with 30% Ethyl Acetate in isohexane, and eluted with 30% Ethyl Acetate in isohexane for the first 5 minutes and then with a linear gradient slowly rising to 100% Ethyl Acetate. Product containing fractions were combined and evaporated to dryness to give the title compound as a white solid (9.29 g, 92%) IHNMR (400.13 MHz, CDCl3) δ 1.20 (6H, s), 1.47 - 1.56 (2H, m), 1.64 - 1.80 (4H, m), 1.94 - 2.02 (2H, m), 3.29 (3H, s), 3.40 (2H, s), 5.25 - 5.34 (IH, m), 7.86 (IH, s); MS m/z 309
Figure imgf000325_0001
Intermediate 127:
10-chloro-2-cyclopentyl-4,4-dimethyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-
5-one
I0 Ethyl 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2,2-dimethyl-propanoate (Intermediate 127; 23.73 g, 64 mmol) was dissolved in acetic acid (512 niL) by heating to 70-75°C under nitrogen in an oil bath. Iron powder (9.6 g) was added in portions over 10 minutes and the reaction stirred at 70°C for 3 hours. The reaction mixture was filtered whilst still hot through a bed of celite and the bed washed with DCM. The combined filtrate and is washings was evaporated to dryness and the resulting residue azeotroped three times with toluene. The residue was taken up in DCM and celite added before filtering through a small bed of celite The volume of DCM was reduced and the solution purified in two batches by loading directly onto Biotage Flash 75 and a 400g Si cartridge pre-conditioned with 50% Ethyl Acetate in isohexane. The cartridge was eluted with -500 ml of 50% Ethyl Acetate in
20 isohexane followed by Ethyl Acetate. Product containg fractions were combined and evaporated and the resulting yellow solid triturated under isohexane. The solid material was collected by filtration, washed with isohexane and dried by desiccation under high vacuum at room temperature to constant weight to give the title compound as an off white solid (9.67 g , 51%)
25 IH NMR (400.13 MHz, DMSO-d6) δ 1.14 (6H, s), 1.51 - 1.62 (4H, m), 1.69 - 1.74 (2H5 m), 1.75 - 1.85 (2H, m), 3.32 (2H, s), 5.02 - 5.11 (IH, m), 7.93 (IH, s), 9.72 (IH, s); MS m/z 295.3 [M+H]+.
30 Intermediate 128: Ethyl 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2,2-dimethyl-propanoate
To a stirred clear colourless solution of Ethyl 3-(cyclopentylamino)-2,2-dimethyl-propanoate (US 2004/0176380 Al; 29.8 g, 139.7 mmol) in the acetone (700 niL) at room temperature was added potassium carbonate (21.3 g, 153.7 mmol) followed by 2,4-dichloro-5- s nitropyrimidine (Aldrich; 29.8 Ig, 153.7 mmol). The reaction mixture was stirred vigorously at room temperature overnight. Potassium carbonate (7.75 g, 56 mmol) was added stirring continued for a further 4 hours. The reaction mixture was concentrated in vacuo to low volume and partitioned between Ethyl Acetate (600 mL) and water (400 mL). Phases were separated and the aqueous phase re-extracted with Ethyl Acetate (1x200 ml, 1x100 ml). Theo combined organic extracts were dried using MgSO4 and evaporated to dryness The residue was dissolved in DCM (150 mL) and purified in two batches using a Biotage Flash 75 system with 40Og Si column, conditioned with 10% Ethyl Acetate in isohexane and eluted with 10% Ethyl Acetate in isohexane. Product containing fractions were combined and evaporated giving the title compound as a yellow oil which solidified on standing in a freezer (27.90 gs 54%)
IHNMR (399.9 MHz, CDCl3) δ 1.22 (6H, s), 1.24 (3H, t), 1.50 - 1.62 (4H, m), 1.70 - 1.75 (2H, m), 1.89 - 1.95 (2H, m), 3.50 - 3.55 (IH, m), 3.82 (2H, s), 4.13 (2H, q), 8.74 (IH, s); ); MS m/z 371 [M+H]+. 0 Intermediate 129;
4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien- 10-yl)amino]benzoic acid
To a solution of 10-chloro-2-cyclopentyl-4,4,6-trimethyl-2,6,9,l 1- tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5-one (Intermediate 126; 308 mg, 1 mmol) and 4-5 amino-3-methoxybenzoic acid (Aldrich; 155 mg, 1.13 mmol) in ethanol (5 mL) was added water (15 mL) and concentrated hydrochloric acid (0.17 mL, 2 mmol). The mixture was heated under reflux for 36 hours. The reaction was cooled and a precipitate formed. This was filtered, dried and triturated under cold acetonitrile refiltered and dried in vacuo. To give the title compound as a brown solid (394 mg, 96%) o MS m/z 410 [M+H]+. Intermediate 130:
2'-chloro-9'-cyclopentyl-5'-methyl-8',9'-dihydrospiro[cyclopropane-l,7'-pyrimido[5,4- b][l,4]diazepin]-6'(5Η)-one
To a stirred solution of 2'-chloro-9'-cyclopentyl-8',9'-dihydrospiro [cyclopropane- 1,7'- s pyrimido[4,5-b][l,4]diazepin]-6'(5Η)-one (Intermediate 131; 15 g, 51.24 mmol ) in DMA (1 L) under nitrogen was added methyl iodide 3.51 mL, 56.36 mL). The mixture was cooled in ice/water to 40C. Sodium hydride (60% mineral oil dispersion; 2.26 g, 56.36 mmol) was added in one portion. A small exotherm to 60C was observed. The reaction mixture was stirred on an ice/water bath for 1 hour, the cooling bath was removed and the reaction stirredo at room temperature overnight. Solvent was evaporated in vacuo and the residue treated with water. This afforded a solid, which was filtered off and washed with water to give an off white solid, which was crystallised from IPA (100 mL) with hot filtration through fluted paper to remove a small amount insoluble matter. The crystallised material was filtered, washed with chilled IPA, and dried by dessication under high vacuum at room temperatures over the weekend to give the title compound as a white crystalline solid (12.78_g, 81%) 1H NMR (400.13 MHz, CDCl3) δ 0.56 - 0.59 (2H, m), 1.04 - 1.07 (2H, m), 1.28 - 1.37 (2H, m), 1.57 - 1.63 (4H, m), 1.88 - 1.96 (2H, m), 3.20 (3H, s), 3.40 (2H, s), 4.82 - 4.91 (IH, m), 7.79 (IH, s); MS m/z 307.09 [M+H]+. 0 Intermediate 131:
2'-chloro-9'-cyclopentyl-8',9'-dihydrospiro[cyclopropane-l,7'-pyrimido[4,5- b][l,4]diazepin]-6'(5'H)-one
Ethyl l-[[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]methyl]cyclopropane-l- carboxylate (Intermediate 132; 35.92 g, 97.4 mmol) was dissolved in the acetic acid (750 mL)5 and the solution stirred and heated to 70 0C under nitrogen. Iron powder (14.61 g) was added in portions over 10 minutes. Over the next 10-15 minutes the resulting exotherm took the reaction mixture temperature up to a maximum of 92 0C. The temperature then slowly dropped back to 75 0C. The dark reaction mixture was then stirred at 75 °C for 3 hours. The reaction mixture was filtered whilst still hot through a bed of celite and the bed washed0 through with DCM. The acetic acid/DCM filtrate was evaporated to dryness and the resulting residue azeotroped three times with toluene.. The residue was left under high vacuum at room temperature overnight, taken up in DCM and filtered through a small bed of celite. The celite was washed with DCM and the filtrate concentrated down to 250 mL and loaded onto a dry silica column pre-conditioned with DCM. The column was eluted with a 5-10% gradient of 7N NH3MeOH in DCM and product containing fractions were combined and evaporated. The resultant material was recrystallised from isopropanol. The solid precipitate was collected by filtration, washed with chilled isopropanol and dried by desiccation under high vacuum at room temperature to constant weight to yield the title compound as a grey solid (17.1 g.. 1H NMR (399.9 MHz, CDCl3) δ 0.79 - 0.84 (2H, m), 1.19 - 1.29 (2H, m), 1.36 - 1.41 (2H, m), 1.56 - 1.67 (4H, m), 1.85 - 1.95 (2H, m), 3.25 (2H, s), 4.95 - 5.04 (IH, m), 7.75 (IH, s), 8.56 (IH, s); MS m/z 292.97 [M+H]+.
Intermediate 132;
Ethyl l-[[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl- amino]methyl]cyclopropane-l-carboxylate To a stirred solution of Ethyl 1 - [(cyclopentylamino)methy 1] cyclopropane- 1 -carboxy late in acetone (700 mL) at room temperature was added potassium carbonate (29.0 g, 209.6 mmol) followed by the 2,4-dichloro-5-nitropyrimidine (Frontier Scientific; 29.81 g, 153.7 mmol). The reaction mixture was stirred vigorously at room temperature overnight, concentrated in vacuo to low volume and the brown residue partitioned between Ethyl Acetate (600 mL) and0 water (400 mL). Phases were separated and the aqueous re-extracted with Ethyl Acetate (1 x 200 mL, 1x100 mL). The combined organic extracts were dried using MgSO4 and evaporated to dryness giving a clear brown oil which solidified on standing. The resultant material was recrystallised from IPA. The solid was collected by filtration, washed with chilled IPA, sucked as dry as possible then dried to constant weight by desiccation under high vacuum at5 room temperature to yield the title compound as a light-brown solid (35.92 g, 70%)
1H NMR (400.13 MHz, CDCl3) δ 0.88 - 0.91 (2H, m), 1.07 (3H, t), 1.26 - 1.29 (2H, m), 1.44 - 1.53 (2H, m), 1.71 - 1.88 (6H, m), 3.65 (2H, s), 3.65 - 3.71 (IH, m), 4.01 (2H, q), 8.65 (IH, s); MS m/z 369.03 [M+H]+. o Intermediate 133: Ethyl l-[(cyclopentylamino)methyl]cyclopropane-l-carboxylate
To a stirred clear solution of Ethyl l-(aminomethyl)cyclopropane-l-carboxylate (Intermediate 134; 74.15 g, 191.6 mmol) in DCM (900 niL) under nitrogen at room temperature was added cyclopentanone (Aldrich; 17.5 mL, 195.4 mmol). The reaction was stirred at room temperature for 1.25 hours. Sodium acetate (Aldrich; 16.03 g, 195.4 mmol) was added, followed by sodium triacetoxyborohydride (Aldrich; 60.93 g, 287.4 mmol). The resulting suspension was stirred at room temperature overnight.
The reaction mixture was treated with saturated aqueous sodium bicarbonate solution (1 L) followed by slow addition of 2M NaOH (aq.) to pH 8-9. The aqueous phase was separatedo re-extracted with DCM (3 x 250 mL). The combined organic solutions were combined, dried with MgSO4 and evaporated, to give the title compound as a clear pale-yellow thin oil (39.39 g, 97%).
1H NMR (400.13 MHz, CDCl3) δ 0.79 - 0.81 (2H, m), 1.23 (3H, t), 1.24 - 1.28 (2H, m), 1.30 - 1.33 (2H, m), 1.46 - 1.57 (2H, m), 1.63 - 1.73 (2H, m), 1.77 - 1.86 (2H, m), 1.91 (IH, s), 2.69s (2H, s), 3.03 - 3.10 (IH, m), 4.11 (2H, q)
Intermediate 134:
Ethyl l-(aminomethyl)cyclopropane-l-carboxylate
Ethyl 1-cyanocyclopropane-l-carboxylate (Aldrich; 76.45 g, 550 mmol), Platinum Oxide (7.5O g ) and Acetic acid (1 L) were combined then stirred at room temperature under hydrogen at
4 bar pressure for 8 hours. The reaction mixture was filtered and the filtrate concentrated in vacuo to give the title compound as a colourless oil containing 4.5 equivalents of acetic acid.
(115 g, 51%)
1H NMR (400.13 MHz, CDCl3) δ 0.81 - 0.84 (2H, m), 1.01 (3H, t), 1.12 - 1.15 (2H, m), 1.775 (13.5H, s - AcOH), 2.89 (2H, s), 3.92 (2H, q), 10.12 (6.5H, br s - AcOH + NH2).
Intermediate 135: 4-amino-3-methoxy-N-(2-morpholin-4-ylethyl)benzamide 0 4-amino-3-methoxybenzoic acid (Aldrich; 5 g, 29.9 mmol) was stirred and dissolved in DMF (100 mL) at ambient temperature. 4-(2-aminoethyl)morpholine (Aldrich; 4.7 mL, 35.8 mmol) was added followed by DIPEA ( 15.6 mL, 89.7 mmol) and HATU (13.7 g, 36.0 mmol) causing a slight exotherm. The brown solution was stirred for 24h and the solvent evaporated to a brown gum.
A sample (1.2g) was dissolved in methanol and purified by loading on an SCX-2 (20 g) column pre-wet with methanol and eluted with 2M NH3/MeOH. Product containing fractions were combined and evaporated to give the title compound as a gum (726 mg)
The remaining product was purified in the same manner on SCX-2 columns (5 g per 50 g column). To give the title compound as an orange solid (9.55 g)
1H NMR (400.132 MHz, DMSO-D6) δ 2.43 (4H, m), 3.18 (2H, m), 3.34 (2H, m), 3.57 (4H, m), 3.80 (3H, s), 5.20 (2H, s), 6.61 (IH, d), 7.27 (2H, m), 7.96 (IH, t); MS m/z 280 [M+H]+.
Intermediate 136; 4-amino-N-(3-dimethylamino-2,2-dimethyl-propyl)benzamide
To a solution of 4-aminobenzoic acid (Aldrich; 4.0 g, 29.17 mmol) in DMF (100 mL) was added ΛζN^^-tetramethyl-i.i-diaminopropane (Aldrich; 5 mL, 31.38 mmol). An immediate solid precipitate formed. DIPEA (15 ml, 86.11 mmol) was added and the resultant suspension stirred HATU (13 g, 34.18 mmol) was added portionwise at such a rate and time interval as to maintain internal reaction temp <30°C} . The resultant yellow solution was stirred at ambient temperature, overnight. The solvent was removed in vacuo, and the residue partitioned between saturated aqueous sodium bicarbonate solution (250 mL) and DCM (250 mL). The organic phase was separated and the aqueous phase re-extracted with DCM (250 mL). Combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and evaporated to a viscous orange syrup which was purified by flash chromatography on silica eluting with 0-10% 0.2M methanolic ammonia in DCM. Product containing fractions were combined and evaporated to give the title compound as a pale straw coloured gum (1.134 g, 15% )
1H NMR (400.132 MHz, DMSOd6) δ 0.90 (m, 6H), 2.07 - 2.40 (m, 6H), 2.67 - 2.95 (m, 2H), 3.15 - 3.20 (m, 2H), 5.57 (s, 2H)5 6.56 (m, 2H), 7.55 (m, 2H), 7.97 - 8.17 (m, IH); MS m/z 250.5 [M+H]+.
Intermediate 137: 10-chloro-2-(l-methoxypropan-2-yl)-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5- one
To a solution of N-(2,4-dichloropyrimidin-5-yl)prop-2-enamide (Intermediate 138; 104 mg, 0.477 mmol ) n THF (2 niL) was added triethylamine (73 μL, 0.525 mmol) followed by 2- amino- 1-methoxypropane ( Aldrich; 50 μL, 0.477 mmol) and the reaction stirred at room temperature for 90 minutes.
The reaction mixture was heated in a microwave at 150 °C for 30 minutes. And then at 160 0C for a further 90 minutes. The solvents were evaporated and the residue chromatographed on silica eluting with a gradient of 30 - 100% Ethyl Acetate / iso-hexane. Product containing fractions were combined and evaporated to give the title compound as an off white solid (35 mg, 29%) MS m/z 250.5 [M+H]+.
Intermediate 138; N-(2,4-dichloropyrimidin-5-yl)prop-2-enamide
To a solution of 5-Amino-2,4-dichloropyrimidine (Chempacific; 100 mg, 0.610 mmol) in THF (2 mL) was added triethylamine (170 μL, 1.22 mmol) followed by 3-Chloropropionyl Chloride (Aldrich; 64 mL, 0.671 mmol) The reaction was stirred at room temperature for 18 hrs . The reaction was filtered and the solvent evaporated. The residue was dissolved in DCM and washed with water then gravity filtered through a PTFE cup and the organic filtrate evaporated to give the title compound as a yellow gum (104 mg). MS m/z 218 [M+H]+.
Intermediate 139: 10-chloro-2-cyclopentyl-6-ethyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one
Tris(dibenzyUdeneacetone)dipalladium(0) (81 mg, 0.09 mmol), XANTPHOS (153 mg, 0.26 mmol) and Caesium Carbonate (2.08 g, 6.37 mmol) were added to a stirred solution of 3-[(5- bromo-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-N-ethyl-propanamide (Intermediate 140; 1.65 g, 4.39 mmol) in 1,4-dioxane (44 niL). The apparatus was evacuated and backfilled with nitrogen twice and then heated to 100 0C for 18 hrs. The reaction mixture was filtered through a celite pad and dry loaded onto silica for purification by flash silica chromatography (companion, 40 g, 0-10% MeOH/DCM) to give the title compound as a yellow gum (1.26 g, 5 4.27 mmol, 97%).
1H NMR (399.902 MHz, DMSO-d6) δ 1.02 (t, 3H), 1.50 - 1.76 (m, 6H), 1.85 - 1.95 (m, 2H), 2.58 - 2.61 (m, 2H), 3.64 - 3.66 (m, 2H), 3.74 (q, 2H), 4.69 (quintet, IH), 8.21 (s, IH); MS m/z 295.15 [M+H]+.
io Intermediate 140:
3-[(5-bromo-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-N-ethyl-propanamide
5-Bromo-2,4-dichloropyrimidine (Aldrich; 1.825 g, 8.00 mmol), 3-(cyclopentylamino)-N- ethyl-propanamide (Intermediate 141; 1.48 g, 8.00 mmol) and triethylamine (1.2 mL, 8.16 mmol) were combined in acetonitrile (50 mL) and heated at 100 0C for 4 hours. The solvent is was removed under reduced pressure and the residue taken up in Ethyl Acetate, washed with water and purified by flash silica chromatography (companion, 40 g, 0-10% Methanol/DCM) to give the title compound as a brown oil, (2.14 g, 71%).
1H NMR (399.902 MHz, DMSO-d6) δ 0.99 (t, 3H), 1.45 - 1.58 (m, 2H), 1.60 - 1.77 (m, 4H), 1.78 - 1.90 (m, 2H), 2.33 (t, 2H), 3.03 (qd, 2H), 3.66 (t, 2H), 4.57 (quintet, IH), 7.79 (t, IH), 20 8.39 (s, IH); MS m/z 376.78 [M+H]+.
Intermediate 141: 3-(cyclopentylamino)-N-ethyl-propanamide
N-ethylacrylamide (ABCR: 1.045 g, 10.50 mmol) and cyclopentylamine (Aldrich; 987 uL, 25 10.00 mmol) in methanol (10 mL) were combined in a microwave reaction vessel, which was sealed and irradiated to 140 °C for 30 minutes. The reaction mixture was allowed to cool and loaded directly onto a 50 g SCX-2 cartridge, washing with methanol (100 mL) and eluting the desired product with 7 N methanolic ammonia (100 mL). Concentration under reduced pressure of combined product containing fractions afforded the title compound as a brown oil 30 (1.48 g, 80%) 1H NMR (399.9 MHz, DMSOd6) δl.01 (3H, t), 1.27 - 1.32 (2H, m), 1.41 - 1.53 (2H, m), 1.55 - 1.64 (2H, m), 1.65 - 1.69 (2H, m), 2.18 (2H, t), 2.67 (2H, t), 2.94 - 3.01 (IH, m), 3.03 - 3.09 (2H, m), 7.89 (IH, br s)
Intermediate 142:
10-chloro-2-cyclopentyl-6-propan-2-yl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12- trien-5-one
Tris(dibenzylideneacetone)dipalladium(0) (47 mg, 0.05 mmol), XANTPHOS (90 mg, 0.15 mmol) and Caesium carbonate (2.425 g, 7.44 mmol) were added to a stirred solution of PH17075-018 (purified reaction mixture, 2.00 g, 5.13 mmol) in 1,4-dioxane (50 mL). The apparatus was evacuated and backfilled with nitrogen twice and then heated to 100 °C for 1.5 hrs Tris(dibenzylideneacetone)dipalladium(0) (47 mg, 0.05 mmol) and XANTPHOS (90 mg,
0.15 mmol) were added and heating continued for a further 18 h.
Tris(dibenzylideneacetone)dipalladium(0) (47 mg, 0.05 mmol) was added and the temperature increased to 120 °C for 18 hr. The reaction mixture was transferred to a microwave vessel and irradiated at 150 °C for 30 minutes.
The reaction mixture was filtered through a pad of celite, concentrated down onto silica and purified by flash silica chromatography (Companion, 40 g, 0-5% MeOH/DCM). Product containing fractiosn were combined and evaporated to give the title compound as a yellow oil (532 mg,, 33%)
1HNMR (399.902 MHz, CDCl3) δ 1.24 (d, 6H), 1.50 - 1.80 (m, 6H), 1.97 - 2.07 (m, 2H), 2.57 - 2.60 (m, 2H), 3.66 - 3.69 (m, 2H), 4.52 (septet, IH), 4.73 (quintet, IH), 8.03 (s, IH); MS m/z 309 [M+H]+.
Intermediate 143: 3-[(5-bromo-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-N-propan-2-yl-propanamide To a stirred solution of 3-(cyclopentylamino)-N-propan-2-yl-propanamide (Intermediate 144; 1.90 g, 9.58 mmol) and triethylamine (1.36 mL, 9.77 mmol) in acetonitrile (100 mL) was added 5-bromo-234-dichloropryimidine (Aldrich; 2.30 g, 10.06 mmol) and the resulting solution heated at 100 °C for 18 hrs. The solvent was removed under reduced pressure and the residue was taken up in Ethyl Acetate (200 mL) and water (200 mL). The aqueous phase was removed and the organic phase washed with water (200 mL). The organic solution was loaded onto a 50 g SCX-2 cartridge, washing with methanol (50 mL), and Ethyl Acetate (50 mL), before eluting with 7 N methanolic ammonia. Product containing fractions were combined and evaporated and the residue purified by flash silica chromatography (companion, 120 g, 0-10% MeOH/DCM) to give clean the title compound a s a white solid (1.17 g, 31% ) 1H NMR (399.902 MHz, DMSOd6) δ 1.06 (d, 6H), 1.53 - 1.62 (m, 2H), 1.66 - 1.80 (m, 4H), 1.84 - 1.94 (m, 2H), 2.35 (t, 2H)5 3.69 (t, 2H), 3.84 (sextet, IH), 4.60 (quintet, IH), 7.71 (d, IH), 8.44 (s, IH); MS m/z 391 [M+H]+.
Intermediate 144: 3-(cyclopentylamino)-N-propan-2-yl-propanamide
N-Isopropylacrylamide (Aldrich; 1.19 g, 10.50 mmol) and cyclopentlyamine (Aldrich; 0.98 mL, 10.0 mmol) were combined in methanol (6 mL) in a 10 mL microwave reaction vessel and the resultant solution heated to 140 0C for 30 mins. The reaction mixture was loaded directly onto a 50 g SCX-2 cartridge, washing with methanol (100 mL) and eluting the desired product with 7 N methanolic ammonia (100 mL). The eluted product was concentrated under reduced pressure to give the title compound as a light brown oil (1.90 g,,
96%)
1H NMR (399.902 MHz, DMSOd6) δ 1.04 (d, 6H), 1.22 - 1.32 (m, 2H), 1.41 - 1.53 (m, 2H),
1.54 - 1.74 (m, 4H), 2.16 (t, 2H), 2.65 (t, 2H), 2.97 (quintet, IH), 3.76 - 3.88 (m, IH), 7.83 (br d, IH); MS m/z 199 [M+H]+.
Intermediate 145: 2-amino-N-(l-methyl-4-piperidyl)-l,3-thiazole-4-carboxamide 2-Aminothiazole-4-carboxylate hydrobromide salt (Chempacific; 1.13 g, 5.02 mmol), HATU (2.87 g, 7.53 mmol) and 4-amino-l-methylpiperidine (0.86 g, 7.53 mmol) were stirred in DMF (5 mL) and DIPEA (5.2 mL, 30.12 mmol) added. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue taken up in
5 methanol, absorbed onto an SCX column , washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined, evaporated and the residue and further purified by column chromatography (5% 7N NH3 in MeOH/DCM) Product containing fractions were combined and evaporated to give the title compound as a yellow solid (635mg, 53%). io 1HNMR (399.9 MHz, DMSO-d6) δl.49 - 1.59 (2H, m), 1.72 - 1.76 (2H, m), 1.98 (2H, t), 2.16 (3H, s), 2.67 - 2.70 (2H, m), 3.60 - 3.69 (IH, m), 7.09 (2H, s), 7.17 (IH, s), 7.38 - 7.40 (IH, m); MS m/z 241.44 [M+H]+.
Intermediate 146; is 2-amino-4-methyl-N-(l-methyl-4-piperidyl)-l,3-thiazole-5-carboxamide
Utilising 2-amino-4-methyl-l,3-thiazole-5-carboxylic acid — Buttpark and an analogous method to Intermediate 145 the title compound was obtained
1H NMR (399.9 MHz, DMSOd6) 51.49 - 1.59 (2H, m), 1.67 - 1.70 (2H, m), 1.88 - 1.94 (2H, m), 2.15 (3H, s), 2.31 (3H, s), 2.72 (2H, m), 3.56 - 3.62 (IH, m), 7.22 - 7.26 (3H, m); MS m/z 20 255.45 [M+H]+.
Intermediate 147: 2-amino-N~(l-methyl-4-piperidyl)-l,3-thiazole-5-carboxamide
Utilising 2-amino-l,3-thiazole-5-carboxylic acid Journal of Medicinal Chemistry (1972), 25 15(12), 1310-12. Compound 1 and an analogous method to Intermediate 145 the title compound was obtained
1HNMR (399.9 MHz, DMSOd6) δl.47 - 1.57 (2H, m), 1.71 (2H, d), 1.94 (2H, t), 2.17 (3H, s), 2.75 (2H, d), 3.59 - 3.65 (IH, m), 7.08 (2H, s), 7.36 (IH, s), 7.68 (IH, d). MS m/z 241.06
30
Intermediate 148: 2-amino-N-(l-methyl-4-piperidyl)-l,3-oxazole-5-carboxamide
Utilising 2-amino-l,3-oxazole-5-carboxylic acid — Intermediate 149 and an analogous method to Intermediate 145 the title compound was obtained
1U NMR (399.9 MHz, DMSOd6) δl.46 - 1.56 (2H, m), 1.70 - 1.74 (2H, m), 1.89 - 1.96 (2H, s m), 2.16 (3H, s), 2.76 (2H, d), 3.59 - 3.63 (IH, m), 7.38 (2H, s), 7.63 (IH, s), 7.82 (IH, d)); MS m/z 225.14 [M+H]+.
Intermediate 149: 2-amino-l,3-oxazole-5-carboxy lie acid o Ethyl 2-aminooxazole-4-carboxylate (Apollo Scientific; 1.175 g, 7.50 mmol) was dissolved in THF (15 mL) and water (8 mL). Lithium hydroxide monohydrate (1.58 g, 37.52 mmol) was added and the mixture stirred overnight at room temperature. The mixture was neutralised with 2N HCl(aqu) and concentrated. The residue was suspended in water and filtered and the solid collected dissolved in 2N NaOH(aqu), filtered and then acidified with acetic acid tos approximately pH4. The mixture was allowed to stand in an ice bath for 10 minutes and then filtered. The solid was dried on the filter and then in a dessicator overnight to give the title compound a s a yellow solid (194mg, 20%) 1HNMR (399.9 MHz, DMSO-d6) 57.37 (2H, s), 7.45 (IH, s), 12.60 (IH, brS). 0 Intermediate 150:
2-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10- yl)amino]-l,3-oxazole-4-carboxylic acid
Ethyl 2-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,l l-tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-10- yl)amino]-l,3-oxazole-4-carboxylate (Intermediate 151; 160 mg, 0.40 mmol) was dissolved in5 THF (1 mL) and water (0.5 mL). Lithium hydroxide monohydrate (84 mg, 2.0 mmol) was added and a few drops of methanol and the mixture stirred at room temperature overnight. The mixture was neutralised with 2N HCl(aqu) and concentrated. The residue was taken up in MeOH/Water and absorbed onto an SCX column, washed with methanol/water and eluted with ammonia in methanol. Product containing fractions were concentrated, the residue0 taken-up in DCM, dried (MgSO4) and concentrated to give the title compound as a white solid (90mg, 60%). 1H NMR (399.9 MHz, DMSOd6) δl.54 - 1.66 (6H, m), 1.92 (2H, s), 2.57 - 2.60 (2H, m), 3.17 (3H, s), 3.61 (2H, t), 4.77 (IH, t), 7.96 (IH, s), 8.06 (IH, s); MS m/z 373.20 [M+H]+.
Intermediate 151:
5 Ethyl 2-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien- 10-y l)amino] - 1 ,3-oxazole-4-carboxy late
10-Chloro-2-cyclopentyl-6-methyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10,12-trien-5-one (Intermediate 1; 248 mg, 0.88 mmol), ethyl 2-aminooxazole-4-carboxylate (Fluorochem; 125 mg, 0.80 mmol) and XANTPHOS (42 mg, 0.07 mmol) were dissolved in 1,4-dioxane (7.5 io mlL). Caesium carbonate (522 mg, 1.60 mmol) was added and the mixture purged with a stream of nitrogen for 5 minutes. Tris(dibenzylideneacetone) palladium (II) (44 mg, 0.05 mmol) was added and the apparatus was evacuated and backfilled with nitrogen (x3) and the reaction heated at 100°C overnight. The mixture was cooled, filtered and the filtrate absorbed onto an SCX column, washed with methanol and the product eluted with ammonia in is methanol. Product containing fractions were concentrated and purified by normal phase chromatography (5% methanol/DCM) to givethe title compound as a white solid (165mg, 51%)
1H NMR (399.9 MHz, DMSOd6) 51.29 (3H, t), 1.59 (6H, m), 1.95 (2H, m), 2.54 - 2.60 (2H, m), 3.18 (3H, s), 3.60 - 3.63 (2H, m), 4.27 (2H, q), 4.83 (IH, t), 8.08 (IH, s), 8.50 (IH, s),
20 10.65 (IH, s); MS m/z 401.24 [M+H]+.
Intermediate 152: 6-amino-N-(l-methyl-4-piperidyl)pyridine-3-carboxamide
6-Aminonicotinic acid (Aldrich; 2 g, 14.48 mmol)and 4-amino-l-methylpiperdine 25 (Fluorochem; 1.82 g, 15.92 g) were suspended in DMF (20 niL), DIPEA (7.5 mL, 43.44 mmol) and HATU (6.05 g, 15.92 mmol) were added and the reaction stirred at ambient temperature for 18 hrs. The solvent was evaporated and the residues stirred with water (50 mL for 1 hr filtered, acidified with 2M aq HCl and added to a 5Og SCX-2 column pre-wet with MeOH (2 column volumes). Flushed with MeOH (2 column volumes) then the crude 30 product eluted with 2M ammonia in MeOH and evaporated. The residue was dissolved in DCM with a little MeOH to help solubility and purified on silica eluting with a gradient of 10 - 20% 2M ammonia in MeOH / DCM. Fractions containing product combined and evaporated to give the title compound as a cream solid (1.75 g, 52%)
1H NMR (400.132 MHz, DMSOd6) 81.47 (m, 2H), 1.65 (m, 2H), 1.85 (m, 2H), 2.09 (s, 3H), 2.68 (m, 2H), 3.61 (m, IH), 6.33 (m, 3H), 7.73 (m, IH), 7.78 (d, IH), 8.36 (m, IH); MS m/z 5 235 [M+H]+.
Intermediate 153: 5-amino-N-(l-methyl-4-piperidyl)pyridine-2-carboxamide
Utilising 5-aminopyridine-2-carboxylic acid - Chempacific and an analogous method too intermediate 152 the title compound was obtained as cream solid (1.29 g, 31%)
1HNMR (400.132 MHz, DMSOd6) 61.60 (m, 2H), 1.72 (m, 2H), 1.97 (m, 2H), 2.16 (s, 3H), 2.71 (m, 2H), 3.69 (m, IH), 5.89 (s, 2H), 6.97 (m, IH), 7.69 (d, IH), 7.91 (m, IH), 7.97 (d, lH); MS m/z 235 [M+H]+. s Intermediate 154:
9-chloro-2-methyl-6-prop-2-ynyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-3-one
To a cooled (ice/water bath) suspension of sodium hydride (60% dispersion in mineral oil; 15 mg, 0.38 mmol) in DMA (1 niL) was carefully added a solution of 10-chloro-6-methyl- 2,6,9,1 l-tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one (Intermediate 100; 65 mg, 0.310 mmol) in DMA (1.5 mL). The reaction mixture was allowed to stir, under nitrogen, on an ice bath for 1 hour prior to addition of propargyl chloride (34 mg, 0.47 mmol). The reaction mixture was left to stir at ambient temperature overnight and then quenched by addition of sataurated aqueous ammonium chloride solution (0.5 mL) and stirred for 15 minutes. The resultant mixture was partitioned between DCM (10 mL) and water (10 mL). The organic5 phase was separated by filtration through PTFE filter cup. The aqueous phase was re- extracted with DCM (5 mL) and the combined organic solutions evaporated to dryness to yield the title compound as a beige coloured solid (52 mg, 67%)
1H NMR (400.132 MHz, DMSO) δ 2.70 (m, 2H), 3.20 (s, 3H)5 3.26 (t, IH), 3.80 (m, 2H), 4.33 (d, 2H), 8.25 (s, IH); MS m/z 251 [M+H]+. 0
Intermediate 155: 2-(10-chloro-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-2- yl)acetonitrile
The title compound was prepared by an analogous method to the preparation of Intermediate 154, on a 0.31 mmol scale, utilising bromoacetonitrile (Aldrich; 33 μL, 0.47 mmol), as an amber gum containing 0.6 equivalents of DMF (97 mg, 100%).
1R NMR (400.132 MHz, DMSO) δ 2.74 (m, 2H), 3.21 (s, 3H), 3.81 (m, 2H), 4.53 (s, 2H), 8.36 (s, IH); MS m/z 252 [M+H]+.
Intermediate 156; 9-chloro-6-[(3,5-dimethyl-l,2-oxazol-4-yI)methyl]-2-methyl-2,6,8,10- tetrazabicy clo [5.4.0] undeca-7,9,1 l-trien-3-one
To a stirred solution of 10-chloro-6-methyl-2,6,9,l l-tetrazabicyclo[5.4.0]undeca-7,9,l 1-trien- 5-one (Intermediate 100; 64 mg, 0.3 mmol ) in DMF (2 mL) was added sodium hydride (60% mineral oil dispersion; 18 mg, 0.36 mmol) and the solution stirred at room temperature until effervescence had ceased. 3 choromethyl-2,4-dimethylisoxazole (Aldrich; 52 mg, 0.36 mmol) was added and the reaction heated at 50 0C with stirring overnight. The solvent was evaporated and residue dissolved in methanol, transferred to an SCX cartridge pre-wet with methanol, washed with methanol and eluted with methanolic ammonia. Product containing fractions were combined and evaporated to yield the title compound as an off white solid (82 mg, 85%)
Intermediate 157:
10-chloro-2-(2-fluoroethyl)-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5- one The title compound was prepared by an analogous method to the preparation of Intermediate 154, on a 0.31 mmol scale, utilising l-bromo-2-fluoroethane (Apollo Scientific; 235 mg, 1.44 mmol), as a white crystalline solid containing 0.6 equivalents of DMF (86 mg, 100%). IH NMR (400.132 MHz, DMSO) d 2.71 (m, 2H), 3.19 (s, 3H), 3.81 (m, 2H), 3.88 - 3.97 (m, 2H), 4.62 - 4.77 (m, 2H), 8.18 (s, IH); MS m/z 259 [M+H]+.
Intermediate 158; 10-chloro-2-(2-dimethylaminoethyl)-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca- 7,9,1 l-trien-5-one
The title compound was prepared by an analogous method to the preparation of Intermediate 156, on a 0.3 mmol scale, utilising 2 chloroethyldimethylamine hydrochloride (Aldrich; 52 5 mg, 0.36 mmol) and Sodium Hydride (60% mineral oil dispersion; 36 mg, 0.75 mmol), as a solid (84 mg, 98%).
Intermediate 159:
10-chloro-6-methyl-2-[2-(l-piperidyl)ethyl]-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll- io trien-5-one
The title compound was prepared by an analogous method to the preparation of Intermediate
156, on a 0.3 mmol scale, utilising 2-chloroethylpiperidine hydrochloride (Aldrich; 55 mg,
0.36 mmol) and Sodium Hydride (60% mineral oil dispersion; 36 mg, 0.75 mmol), as a solid
(90 mg, 93%). is
Intermediate 160:
10-chloro-6-methyl-2-(2-morpholin-4-ylethyl)-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-
7,9,ll-trien-5-one
The title compound was prepared by an analogous method to the preparation of Intermediate 20 156, on a 0.3 mmol scale, utilising N-(2-chloroethyl)morpholine hydrochloride (Aldrich; 67 mg, 0.36 mmol) and Sodium Hydride (60% mineral oil dispersion; 36 mg, 0.75 mmol), as a solid (95 mg, 97%).
Intermediate 161:
2S 4-amino-3-methoxy-N-[(lS,5R)-9-methyl-9-azabicycIo[3.3.1]non-7-yl]benzamide A mixture of 4-Amino-3-Methoxybenzoic Acid (Aldrich; 5.015 g, 30 mmol) and Endo-9- methyl-9-azabicyclo[3,3,l]nonane-3-one (Chempacific; 5.095 g, 33 mol) were dissolved in DMF (150 niL), and to the solution was added DIPEA (10.4 mL, 60 mmol). The reaction was cooled on an ice-bath, and to the reaction was added, portionwise, HATU (12.55 g, 33 mmol).
30 The reaction mixture was stirred at ambient temperature for 18 hours. The solvent was removed by evaporation, and the residue was partitioned between Ethyl Acetate (200 mL), and saturated aqueous sodium carbonate solution (3 x 50 mL)., washed with brine (3 x 50 mL), dried over anhydrous magnesium sulphate, filtered, and the solvent removed by evaporation to give the crude product as an an oil (14g), which was purified on SCX-2 columns (4 x 50 g), developing and eluting with : 1) water; 2) MeOH ; and 3) 3.5MNH3- MeOH. The solvent was removed by evaporation to give the product as a semi-solid, which was triturated with diethylether and filtered to yield the title compound as a tan coloured solid (4.84 g, 53%).
1H NMR (400.1MHz ; DMSO-d6) δ 0.88-0.96 (IH, d), 1.38-1.50 (3H, m), 1.86-1.96 (2H, m), 2.00-2.10 (IH, m), 2.10-2.20 (2H, m), 2.42 (3H, s), 2.92-3.00 (2H, d), 3.82 (3H, s), 4.22-4.38 (IH, m), 5.17 (2H, s), 6.58-6.62 (IH, d), 7.28 (IH, s), 7.30 (IH, s), 7.60-7.64 (IH, d). MS m/z 292 [M+H]+.
Intermediate 162: ^amino-S-fluoro-N-^lSjS^^-methyl^-azabicycloJS.S.llnon-T-yllbenzamide 4-amino-3-fluorobenzoic acid (Fluorochem; 5.0 g, 32.2 mmol), HATU (13.5 g, 35.4 mmol) and DIPEA (18.5 mL, 106 mmol) were stirred together in anhydrous DMA (100 mL) for 25 minutes. Endo-9-methyl-9-azabicyclo[3,3,l]nonane-3-one (Chempacific; 5.5 g, 35.4 mmol) was added and the solution stirred at ambient temperature overnight. The solvent was evaporated and the residue dissolved in MeOH and loaded onto an SCX-20 column (5Og x 4) pre-wet with MeOH. The column was washed with MeOH (2 column volumes) and the product eluted with 2MNH3/MeOH (2 column volumes). The ammoniacal solution was evaporated and the resultant material purified on a silica column eluted with 0- 10% 2NH3/MeOH/DCM. Product containing fractions were evaporated to yield the title compound as a white solid after trituration with ethyl acetate (5.7 g, 61%) s 1H NMR (400.132 MHz5 DMSO-d6) δ 0.91 (m, 2H), 1.42 (m, 3H), 1.90 (m, 4H), 2.03 (m, IH), 2.14 (m, 3H), 2.40 (s, 3H), 2.96 (m, 2H), 4.27 (m, IH), 5.60 (bs, 2H), 6.74 (m, IH), 7.46 (m, IH), 7.53 (m, IH), 7.70 (d, IH); MS m/z 292 [M+H]+.
0
Intermediate 163: 3-ethoxy-4-[(6-methyl-5-oxo-2-propan-2-yl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll- trien-10-yl)amino] benzoic acid
10-Chloro-6-methyl-2-propan-2-yl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien-5-one (Intermediate 10; 625 mg, 2.45 mmol), 4-amino-3-ethoxybenzoic acid (Intermediate 164;
5 509 mg, 2.82 mmol) and 4-toluenesulphonic acid mono hydrate (1.17 g, 6.13 mmol) were heated at 140 0C in 4-methyl-2-pentanol (15 mL) for 1.5 hours. The mixture was cooled and filtered to yield the title compound as a white solid (135 mg, 14 %). The filtrate was absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (1%o - 3% MeOH/DCM) to yield the title compound as a white solid (115 mg, 12%)
1H NMR (399.9 MHz, DMSO-d6) δl.26 (6H, d), 1.44 (3H, t), 2.74 (2H, m), 3.18 (3H, s), 3.73 (2H, m), 4.22 (2H, q), 4.85 - 4.92 (IH, m), 7.57 (IH, d), 7.63 - 7.66 (IH, m), 8.20 (2H, m), 9.41 (IH, brs), 12.90 (IH, brs); MS m/z 400 [M+H]+. s Intermediate 164;
4-amino-3-ethoxybenzoic acid
A solution of 3-ethoxy-4-nitrobenzoic acid (Intermediate 165; 1.0 g, 4.74 mmol) ethanol:DMF (50 mL : 5 mL) over 5% Pd/C catalyst (100 mg) was hydrogenated with stirring at ambient temperature for 4 hours. The mixture was filtered and the catalyst washed with0 ethanol and the solvent evaporated and the residue that on trituration with diethyl ether yielded the title compound as an off white solid (688 mg, 81%)
1H NMR (400.132 MHz, DMSO-d6) 5 1.36 (t, 3H), 4.04 (q, 2H), 5.45 (bs, 2H), 6.63 (d, IH), 7.28 (s, IH), 7.35 (d, IH), 12.03 (bs, IH). 5 Intermediate 165:
3-ethoxy-4-nitrobenzoic acid
3-fluoro-4-nitrobenzoic acid (Apollo Scientific; 15 g, 81 mmol) and potassium hydroxide (10.5 g, 186.3 mmol) were stirred together in ethanol (150 mL) at ambient temperature. The reaction mixture was slowly heating to reflux over 10 minutes. The reaction refluxed 0 vigorously and a solid precipitate formed. The reaction was cooled, diluted with water (100 niL) and acidified with 2N HCl to give a precipitate which was filtered, washed with water and air dried to yield the title compound as a pale brown solid (16.88 g, 99%) 1H NMR (400.132 MHz, DMSO-d6) δ 1.35 (t, 3H), 4.29 (q, 2H), 7.63 (d, IH), 7.75 (s, IH), 7.95 (d, IH), 13.58 (s, IH); MS m/z 210 [M+H]+.
Intermediate 166:
4-amino-3-ethoxy-N-[(3R)-l-methylpyrrolidin-3-yl]benzamide
4-amino-3-ethoxybenzoic acid (Intermediate 164; 400 mg, 2.21 mmol), HATU (1.26 g, 3.31 mmol) and (3R)-l-methylpyrrolidin-3-amine di Hydrochloride (Intermediate 184; 453 mg, 3.31 mmol) were stirred in DMF (5 mL) and diisopropylethylamine (1.7 ml, 9.95 mmol) added. The mixture was stirred for 2 hours and then absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (2.5% ammonia in methanol/DCM) to yield the title compound as a yellow foam (396 mg, 68%). 1H NMR (399.9 MHz, DMSO-d6) δl.37 (3H, t), 1.70 - 1.78 (IH, m), 2.09 - 2.17 (IH, m), 2.25 (3H, s), 2.35 - 2.42 (2H, m), 2.56 - 2.62 (IH, m), 2.65 - 2.69 (IH, m), 4.05 (2H, q), 4.33 - 4.41 (IH, m), 5.16 (2H, s), 6.61 (IH, d), 7.30 - 7.54 (2H, m), 7.98 (IH, d); MS m/z 264 [M+H]+.
Intermediate 167:
4-amino-N-((ls,4s)-4-(dimethylamino)cyclohexyl)-3-ethoxybenzamide
The title compound was prepared by an analogous method to the preparation of Intermediate 166, on a 2.21 mmol scale, utilising l-amino-4-dimethylaminocyclohexane (ABChem Inc.; 472 mg, 3.31 mmol) and diisopropylethylamine 1.15 mL, 6.62 mmol), after separation of the cis isomer by column chromatography, as a yellow foam (162 mg, 24%).
1H NMR (399.9 MHz, DMSO-d6) δl.35 - 1.50 (7H, m), 1.68 - 1.78 (2H, m), 1.83 - 1.86 (2H, m), 2.00 (IH, m), 2.18 (6H, s), 3.87 (IH, m), 4.05 (2H, q), 5.13 (2H, s), 6.60 (IH, d), 7.31 (2H, m), 7.70 (IH, d); MS m/z 306 [M+H]+. Intermediate 168: 4-amino-N-((lr,4r)-4-(dimethylamino)cyclohexyl)-3-ethoxybenzamide
The title compound was prepared by an analogous method to the preparation of Intermediate 166, on a 2.21 mmol scale, utilising l-amino-4-dimethylaminocyclohexane (ABChem Inc.; 5 472 mg, 3.31 mmol) and diisopropylethylamine 1.15 mL, 6.62 mmol), after separation of the trans isomer by column chromatography, as a white solid (164 mg, 24%). 1HNMR (399.9 MHz, DMSO-d6) δl.20 - 1.39 (7H, m), 1.81 - 1.88 (4H, m), 2.12 (IH, t), 2.18 (6H, m), 3.64 - 3.70 (IH, m), 4.04 (2H, q), 5.14 (2H, s), 6.60 - 6.62 (IH, d), 7.28 (2H, m), 7.71 (IH, d) ; MS m/z 306 [M+H]+.
10
Intermediate 169: 4-amino-5-ethoxy-2-fluoro-N-(l-methyl-4-piperidyl)benzamide
17328/52/1
4-amino-5-ethoxy-2-fluorobenzoic acid (Intermediate 171; 190 mg, 0.95 mmol), HATU (545
I5 mg, 1.43 mmol) and 4-amino-l-methylpiperidine (Fluorochem; 164 mg, 1.43 mmol) were stirred in DMF (3 mL) and diisopropylethylamine (0.58 ml, 2.86 mmol) added. The mixture was stirred over night and then absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (3% ammonia in methanol/DCM) to yield the title
20 compound as a white crystalline solid (245mg, 86%).
1HNMR (399.9 MHz, DMSO-d6) δ 1.35 (3H, t), 1.50 - 1.55 (2H, m), 1.71 - 1.79 (2H, m), 1.94 - 1.99 (2H, m), 2.16 (3H, s), 2.68 - 2.71 (2H, m), 3.65 - 3.73 (IH, m), 4.00 (2H, q), 5.50 (2H, s), 6.40 (IH, d), 7.04 (IH, d), 7.33 (IH, t); MS m/z 296 [M+H]+.
25 Intermediate 170:
4-amino-5-ethoxy-2-fluoro-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-7-yl]benzamide
The title compound was prepared by an analogous method to the preparation of Intermediate 169, on a 0.5 mmol scale, utilising Endo-9-methyl-9-azabicyclo[3,3,l]nonane-3-one (Chempacific; 111 mg, 0.75 mmol), as a white solid (171 mg, 100%). 30 1H NMR (399.9 MHz, DMSOd6) δ 0.91 (2H, d), 1.32 - 1.44 (6H, m), 1.86 - 1.92 (2H, m), 1.99 - 2.10 (IH, m), 2.14 - 2.22 (2H, m), 2.40 (3H, s), 2.96 (2H, d), 4.01 (2H, q), 4.21 - 4.30 (IH, m), 5.48 (2H, s), 6.40 (IH, d), 7.05 (IH, d), 7.24 (IH, t); MS m/z 336 [M+H]+. Intermediate 171; 4-amino-5-ethoxy-2-fluorobenzoic acid
5-ethoxy-2-fluoro-4-nitrobenzoic acid (Intermediate 172; 1.24 g, 5.40 mmol) was stirred and dissolved in ethanol:DMF (50 niL : 5 mL) over 5% Pd/C (125mg) and hydrogenated at ambient temperature for 4 hours. The catalyst was filtered and washed with ethanol and the solvent evaporated. The resultant material was purified on a silica column, eluting with 0 — 5% MeOH/DCM. Product containing fractions were combined and evaporated to yield the title compound as a pale brown solid (433 mg, 40%) 1HNMR (400.132 MHz, DMSOd6) δ 1.33 (3H, t), 4.25 (2H, q), 7.66 (IH, d), 7.99 (IH, m), 13.99 (IH, s).
Intermediate 172: 5-ethoxy-2-fluoro-4-nitrobenzoic acid
2,5-difluoro-4-nitrobenzoic acid (Fluorochem; Ig, 4.92 mmol) was stirred and dissolved in DMF (10 mL) and caesium carbonate (4.8 g, 14.7 mmol) was added followed by ethanol (2.3 g, 49.9 mmol). The resulting white mixture was stirred at ambient temperature for 3 hours, diluted with water, acidified to pHl with 2N HCl (aq), extracted with EtOAc (x3). Combined extracts were washed with water, dried (MgSO4), filtered and evaporated to yield the title compound as a yellow solid (1.24 g, 100%).
1HNMR (400.132 MHz, DMSO-d6) δ 1.34 (3H, t), 4.00 (2H, q), 5.79 (2H, s), 6.38 (IH, d), 7.14 (IH, d), 12.32 (IH, s).
Intermediate 173:
4-amino-5-chloro-2-fluoro-N-(l-methyI-4-piperidyl)benzamide
4-amino-5-chloro-2-fluorobenzoic acid (Intermediate 176; 500 mg, 2.64 mmol), 4-amino-l- methylpiperidine (452 mg, 3.96 mmol) and diisopropylethylamine (1.38 ml, 7.91 mmol) were stirred in DMF (5 mL) and HATU (1.50 g, 3.96 mmol) added. The reaction mixture was stirred for 3 hours at room temperature. The mixture was absorbed on to an SCX column, which was washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated to give a crystalline solid that was suspended in diethyl ether and filtered to yield the title compound as a pale brown solid (572 mg, 76%). 1H NMR (399.9 MHz, DMSO-d6) δl.47 - 1.58 (2H, m), 1.71 - 1.76 (2H, m), 1.95 (2H, t), 2.15 (3H, s), 2.69 - 2.72 (2H, m), 3.67 (IH, m), 6.09 (2H, s), 6.55 (IH, d), 7.49 (IH, d), 7.61 s (IH, d); MS m/z 286 [M+H]+.
Intermediate 174: 4-amino-5-chloro-N-(l-ethyl-4-piperidyl)-2-fluoro-benzamide
The title compound was prepared by an analogous method to the preparation of Intermediate io 173, on a 2.64mol scale, utilising 4-amino-l-methylpiperidine (Fluorochem; 508 mg, 3.96 mmol) after purification on a silica column (gradient (3-4% ammonia in methanol/DCM), as a pale brown foam (647 mg, 82%).
1H NMR (399.9 MHz, DMSO-d6) δθ.99 (3H, t), 1.46 - 1.55 (2H, m), 1.75 - 1.78 (2H, m),
1.92 - 1.97 (2H, m), 2.31 (2H, q), 2.81 (2H, d), 3.67 - 3.71 (IH, m), 6.09 (2H, s), 6.53 - 6.57 is (IH, m), 7.48 (IH, d), 7.59 - 7.62 (IH, m); MS m/z 300 [M+H]+.
Intermediate 175: 4-amino-5-chloro-N-(4-dimethyIaminocyclohexyl)-2-fluoro-benzamide
The title compound was prepared by an analogous method to the preparation of Intermediate 20 173, on a 2.64mol scale, utilising l-amino-4-dimethylaminocyclohexane (ABChem Inc.;
472 mg, 3.31 mmol) after purification on a silica column (gradient (3-4% ammonia in methanol/DCM), as a pale brown foam (716 mg, 86%).
1H NMR (399.9 MHz, DMSOd6) δl.19 - 1.35 (2H, m), 1.47 - 1.54 (2H, m), 1.62 - 1.91 (4H, m), 2.03 - 2.13 (IH, m), 2.17 (6H, s), 3.59 - 3.68 and 3.85 - 3.90 (both 0.5H, m), 6.08 (2H, s), 25 6.53 - 6.57 (IH, m), 7.47 - 7.49 (IH, m), 7.52 - 7.56 (IH5 m); MS m/z 314 [M+H]+.
Intermediate 176: 4-amino-5-chloro~2-fluorobenzoic acid
4-Ammo-5-chloro-2-fluorobenzoic acid tert-butyl ester (Intermediate 177; 3.0 g, 12.21 30 mmol) was dissolved in DCM (75 niL) and trifluoroacetic acid (25 mL) added. The mixture was stirred for 1 hour at room temperature and then concentrated to yield the title compound as a pale yellow solid (2.45 g, 100%).
1H NMR (399.9 MHz, DMSOd6) 56.40 (2H, s), 6.53 - 6.56 (IH, m), 7.67 (IH, d), 12.56 (IH, s).
Intermediate 177:
4-Amino-5-chloro-2-fluorobenzoic acid tert-bxήyl ester
4-Amino-2-fluorobenzoic acid tert-butyl ester (ABChem Inc.; 1 g, 4.73 mmol) in DMF (15 niL) was added dropwise to N-chlorosuccinimide (633 mg, 4.73 mmol) in DMF (20 mL). The mixture was stirred at room temperature for 72 hours. The reaction mixture was poured into water (130 mL) and extracted with ethyl acetate (2 x 50 mL). The combined extracts were washed with water, brine, dried (MgSO4) and concentrated. Column chromatography
(5% ethyl acetate/isohexane) yielded the title compound as a pale yellow, crystalline solid
(321 mg, 27.5%). 1H NMR (399.9 MHz, DMSOd6) δl.50 (9H, s), 6.41 (2H, s), 6.54 (IH, d), 7.61 (IH, d)
Intermediate 178:
10-chloro-4,4,6-trimethyl-2-propan-2-yl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12- trien-5-one To a stirred solution of 10-Chloro-4,4-dimethyl-2-propan-2-y 1-2,6,9, 11- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 179; 2.96 g, 11.01 mmol) in DMA (240 mL), under nitrogen, was added methyl iodide (0.754 mL, 12.12 mmol). The mixture was cooled in an ice/water bath to 3 0C. Sodium hydride (60% mineral oil dispersion; 485 mg, 12.12 mmol) was added in one portion. The reaction mixture was stirred on an ice/water bath for 1 hour and then at room temperature overnight. The solvent was removed in vacuo and water was added to the resultant residue to afford a white solid, which was filtered off and washed well with water and dissolved in DCM (125 mL). The solution was dried using MgSO4, filtered and evaporated and the resultant solid, dissolved in DCM (25 mL), purified on a Silica column, equilibrated with 30% EtOAc in isohexane, and eluted with 30% -100% EtOAc in isohexane gradient. Product containing fractions were combined and evaporated to yield the title compound as a white solid (2.7 g, 87%) 1HNMR (400.13 MHz, CDCl3) δ 1.12 (6H, s), 1.13 (6H, d), 3.21 (3H, s), 3.29 (2H, s), 5.15 - 5.22 (IH, m), 7.78 (IH, s); MS m/z 283 [M+H]+.
Intermediate 179: 10-Chloro-4,4-dimethyl-2-propan-2-yl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12- trien-5-one
4-amino-5-cliloro-N-(4-dimethylaminocyclohexyl)-2-fluoro-benzamide (Intermediate 180; 6.7 g, 19.43 mmol) was stirred and dissolved in the acetic acid (155 mL) by heating to 70 °C under nitrogen. Iron powder (2.92 g) was added in one portion and the reaction mixture stirred at 70°C for 2.5 hours. The reaction mixture was filtered whilst hot through a bed of celite and the bed washed with DCM. The filtrate was evaporated to dryness and the resulting residue azeotroped three times with toluene. The resultant residue was purified on a Silica column pre-conditioned the column with 50% EtOAc in isohexane, loading as a solution in DCM to which had been added celite and the resultant mixture filtered through a small bed of celite. The column was eluted with a 50% - 100% EtOAc in isohexane, gradient. Product containing fractions were combined and evaporated to yield the title compound as a white solid (2.96 g, 57%)
1H NMR (400.13 MHz, CDCl3) δ 1.13 (6H, d), 1.19 (6H, s), 3.21 (2H, s), 5.23 - 5.30 (IH, m), 7.75 (IH, s), 8.39 (IH, s); MS m/z 269 [M+H]+.
Intermediate 180: 4-amino-5-chloro-N-(4-dimethylaminocyclohexyl)-2-fluoro-benzamide
To a stirred solution of the Name (Intermediate 181; 10 g; 53.4 mmol) ) in acetone (250 mL) at room temperature was added potassium carbonate (11.07 g, 80.1 mmol) followed by the 2,4-dichloro-5-nitropyrimidine (Apollo Scientific; 10.35 g, 53.4 mmol). The resulting yellow suspension was stirred vigorously at room temperature over the weekend. The reaction mixture was evaporated to dryness and the residue partitioned between EtOAc (250 mL) and water (150 mL). The phases were separated after filtration through a pad of celite, and the aqueous phase was re-extracted with EtOAc (2 x 100 mL, 1 x 75 mL). The combined organic extracts were dried using MgSO4 and evaporated to dryness. The resultant brown oil was purified on a silica column pre-conditioned with 10% EtOAc in isohexane and eluted with 10% EtOAc in isohexane. Product containing fractions were combined and evaporated to yield the title compound as a yellow crystalline solid (6.71 g, 36%)
MS m/z 350 [M+H]+. Retention time 2.72 minutes
5
Intermediate 181: ethyl 2,2-dimethyl-3-(propan-2-ylamino)propanoate
To a stirred solution of ethyl, 3~amino-2,2-dimethyrpropanoate (Macromolecules (1976),
9(2), 227-30; 30.85 g, 150.3 mmol) in DCM (500 mL) under nitrogen at room temperature io was added acetone (13.25 mL, 180.36 mmol). After stirring at room temperature for 1 hour sodium acetate (12.57 g, 153.31 mmol) was added, followed by sodium triacetoxyborohydride (47.8 g, 225.45 mmol). The resulting suspension was stirred at room temperature overnight.
Acetone (7 mL, 90 mmol), sodium acetate (7 g, 75 mmol) and sodium triacetoxyborohydride is (24 g, 112 mmol) were added and the reaction stirred again at room temperature overnight.
This procedure of adding additional reagents was repeated.
A saturated aqueous sodium hydrogen carbonate (1.1 L) was cautiously added to the stirred reaction mixture followed by 2N sodium hydroxide to pH = 8. The phases were separated and the aqueous phased re-extracted with DCM (2x500,1x400 ml). The combined organic extracts 20 were dried using MgSO4 and then evaporated at no less than 350 mharl This afforded the title compound as a clear almost-colourless liquid (27.50 g, 98%)
1H NMR (400.13 MHz, CDCl3) δ 1.02 (6H, d), 1.18 (6H, s), 1.24 (3H, t), 2.65 (2H, s), 4.08 -
4.16 (2H. m).
25 Intermediate 182:
4-amino-2-fluoro-5-methoxy-N-[(3R)-l-methylpyrrolidin-3-yl]benzamide 4-amino-2~fluoro-5-methoxybenzoic acid (Intermediate 183; 500 mg, 2.70 mmol), HATU (1.55 g, 4.05 mmol) and (3R)-l-methylpyrrolidin-3-amine di Hydrochloride (Intermediate 184; 631 mg, 3.31 mmol) were stirred in DMF (7.5 mL) and diisopropylethylamine (2.36 ml, 30 13.50 mmol) added. The reaction mixture was stirred for 2 hours and then absorbed on to an SCX column, which was then washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (2.5% ammonia in methanol/DCM) to yield the title compound as a viscous brown oil. (662 mg, 92%).
1HNMR (399.9 MHz5 DMSOd6) δl.62 - 1.70 (IH, m), 2.11 - 2.20 (IH, m), 2.25 (3H, s), 2.32 - 2.46 (2H, m), 2.54 - 2.67 (2H, m), 3.78 (3H, s), 4.34 - 4.39 (IH, m), 5.57 (2H, s), 6.39 s (IH, d), 7.07 (IH, d), 7.51 (IH, t); MS m/z 268 [MfH]+.
Intermediate 183: 4-amino-2-fluoro-5-methoxy-benzoic acid
2-fluoro-5-methoxy-4-nitrobenzoic acid (Intermediate 12; 7.76g, 36.1mmol) was stirred ando dissolved in ethanol (200 niL) over 5% Pd/C (770mg) and hydrogenated at ambient temperature for 4 hours. During this time product precipitated in the reaction. DMF (20 niL) was added to give a solution. The catalyst was filtered off and washed with EtOH and the solvent evaporated. The residue was triturated with diethyl ether to yield the title compound as a dark brown solid (3.06 g, 46%) s 1U NMR (400.132 MHz, DMSO-d6) δ 3.78 (s, 3H), 5.84 (bs, 2H), 6.37 (d, IH), 7.14 (d, IH), 12.25 (bs, IH).
Intermediate 184: (3R)-l-methylpyrrolidin-3-amine di Hydrochloride 0 tert-butyl N-[(3R)-l-methylpyrrolidin-3-yl]carbamate (Intermediate 185; 1.18 g, 5.67 mmol) was dissolved in 1,4-dioxane (10 mL) and 4M HCl in dioxane (10 mL) added. The mixture was stirred at room temperature for 1 hour and then concentrated to yield the title compound as a white hygroscopic solid (810 mg, 100%). 1H NMR (399.9 MHz, D2O) 2.19 - 2.29 (IH, m), 2.60 - 2.71 (IH, m), 3.10 (3H, M), 3.48 -s 3.67 (3H, m), 3.85 - 3.93 (IH, m), 4.18 - 4.26 (IH, m).
Intermediate 185 tert-butyl N- [(3R)-l-methylpyrrolidin-3-yl] carbamate
(3R)-3-(Bocamino)pyrrolidine (Fluorochem; 2.5 g, 13.42 mmol) was dissolved in 37%0 aqueous formaldehyde (78 mL) and acetic acid (8.5 mL, 134.23 mmol). Sodium acetate (11.0 g, 134.23 mmol) was added and the mixture cooled in an ice/water bath. Sodium cyanoboroliydride (844 mg, 13.42 mmol) was added and the mixture allowed to stir for 3 hours. Saturated aqueous sodium hydrogen carbonate was added until the mixture was basic. The mixture was extracted with DCM (x2) and the combined extracts dried (MgSO4) and concentrated. Column chromatography (2.5 - 5% 7N ammonia in methanol) yielded the title compound as a colourless liquid that crystallised on standing (1.20 g, 45%).
1H NMR (399.9 MHz, DMSOd6) δl.38 (9H, s), 1.51 - 1.59 (IH, m), 1.97 - 2.06 (IH, m), 2.20 (4H, m), 2.34 - 2.47 (2H, m), 2.61 - 2.65 (IH, m), 3.89 (IH, m), 6.90 (IH, d).
Intermediate 186;
4-amino-5-ethoxy-2-fluoro-N-[(3R)-l-methylpyrrolidin-3-yl]benzamide
The title compound was prepared by an analogous method to the preparation of Intermediate 169, on a 0.5 mmol scale, utilising (3R)- l-methylpyrrolidin-3 -amine di hydrochloride (Intermediate 184; 129 mg, 0.75 mmol), as a white solid (95 mg, 68%). 1H NMR (399.9 MHz, DMSOd6) δ 1.35 (3H, t), 1.62 - 1.70 (IH, m), 2.13 - 2.18 (IH, m), 2.25 (3H, s), 2.32 - 2.46 (2H, m), 2.59 - 2.68 (2H, m), 4.00 (2H, q), 4.30 - 4.38 (IH, m), 5.53 (2H, s), 6.40 (IH, d), 7.06 (IH, d), 7.50 (IH, t); MS m/z 282 [M+H]+.
Intermediate 187; 4-amino-3-methoxy-N-(l-methylpyrrolidin-3-yl)benzamide
A solution of 3-methoxy-N-[(3R)-l-methylpyrrolidin-3-yl]-4-nitro-benzamide (Intermediate
188; 227 mg, 0.81 mmol) in methanol (25 mL) was hydrogenated using 10% Pd/C catalyst.
Catalyst was filtered off and solvent evaporated to yield the title compound as a yellow gum
(200 mg, 100%). 1H NMR (399.9 MHz, DMSOd6) δl.76 (IH, m), 2.12 (IH, m), 2.28 (3H, s), 2.41 (2H, m),
2.61 (IH, m), 2.69 (IH, m), 3.80 (3H, s), 4.36 (IH, m), 5.18 (2H, s), 6.60 (IH, d), 7.29 (IH, s), 7.31 (IH, s), 7.99 (IH, d); MS m/z 250 [M+H]+.
Intermediate 188; 3-methoxy-N-[(3R)-l-methylpyrroIidin-3-yl]-4-nitro-benzamide 3-methoxy-4-nitro-benzoyl chloride (Intermediate 189; 374 mg, 1.73 mmol) was dissolved in DCM (20 mL) and N,N-diisopropylethylamine (0.96 mL, 5.54 mmol) added. The mixture was cooled in an ice/water bath and (3R)-l-methylpyrrolidin-3-amine di hydrochloride (Intermediate 184; 300 mg, 1.73 mmol) in DCM (10 mL) added dropwise. The mixture was allowed to warm to room temperature and stirred for 0.5 hour. The mixture was washed with brine, 2N NaOH (aq), dried with MgSO4 and evaporated to yield the title compound as a brown solid (227 mg, 46.9%).
1H NMR (399.9 MHz, DMSO-d6) δl.78 (IH, m), 2.19 (2H3 s), 2.26 (3H, s), 2.38 (IH, m), 2.65 (IH, m), 4.05 (3H, s), 4.41 (IH, m), 7.57 (IH, d), 7.72 (IH, s), 7.93 (IH, d), 8.70 (IH, d); MS m/z 280 [M+H]+.
Intermediate 189: 3-methoxy-4-nitro-benzoyl chloride 3-methoxy-4-nitrobenzoic acid (Aldrich; 9 g, 45.65 mmol) was suspended in toluene (90 mL) and thionyl chloride (9.99 mL, 136.95 mmol) added and the mixture heated to reflux for 1 hour. The reaction was evaporated to yield the title compound as a brown solid (9.84 g, 100%). 1H NMR (399.9 MHz, DMSO-d6) 54.00 (3H, s), 7.64 - 7.67 (IH, m), 7.78 (IH, d), 7.97 (IH, m).
Intermediate 190: 4-amino-N-(l-ethyl-4-piperidyl)-3-methoxy-benzamide
The title compound was prepared in quantitative yield by an analogous method to the preparation of Intermediate 187, on a 2 g scale utilising N-(l-ethyl-4-piperidyl)-3-methoxy-4- nitro-benzamide (Intermediate 191).
1H NMR (399.9 MHz, DMSO-d6) 50.99 - 1.02 (3H, t), 1.49 - 1.59 (2H, m), 1.75 (2H, d), 1.92 (2H, t), 2.32 (2H, q), 2.87 (2H, d), 3.68 - 3.76 (IH, m), 3.81 (3H, s), 5.19 (2H, s), 6.59 - 6.62 (IH, m), 7.28 - 7.30 (2H, m), 7.77 (IH, d); MS m/z 280 [M+H]+.
Intermediate 191; N-(l-ethyl-4-piperidyl)-3-methoxy-4-nitro-benzamide
The title compound was prepared by an analogous method to the preparation of Intermediate 188, on a 9.28 mmol scale utilising l-ethylpiperidin-4-amine (Fluorochem; 1.19 g, 9.28 mmol), as a brown solid (3.3 g, 100%) 1H NMR (399.9 MHz3 DMSO-d6) δl.01 (3H, t), 1.56 - 1.63 (2H, m), 1.82 (2H, m), 1.92 - 1.98 (2H, m), 2.34 (2H, q), 2.89 (2H, d), 3.75 - 3.79 (IH, m), 4.00 (3H, s), 7.54 - 7.57 (IH, m), 7.70 (IH, d), 7.96 (IH, d), 8.49 (IH, d); MS m/z 308 [M+H]+.
Intermediate 192:
4-amino-3-methoxy-N-(2-pyrroIidin-l-ylethyl)benzamide
The title compound was prepared in quantitative yield by an analogous method to the preparation of Intermediate 187, on a 2 g scale utilising 3-methoxy-4-nitro-N-(2-pyrrolidin-l- ylethyl)benzamide (Intermediate 193). s 1H NMR (399.9 MHz, DMSO-d6) δl.68 (4H, t), 2.49 (4H, s), 2.55 (2H, t), 3.36 (2H, d), 3.81 (3H, s), 5.20 (2H, s), 6.59 - 6.62 (IH, m), 7.26 - 7.29 (IH, m), 7.31 (IH, s), 8.00 (IH, s); MS m/z 280 [M+H]+.
Intermediate 193: 0 3-methoxy-4-nitro-N-(2-pyrrolidin-l-ylethyl)benzamide
The title compound was prepared by an analogous method to the preparation of Intermediate
188, on a 9.28 mmol scale utilising 2-pyrrolidin-l-ylethanamine (Aldrich; 1.06 g, 9.28 mmol), as a brown solid (2.3 g, 85%)
1H NMR (399.9 MHz, DMSO-d6) 51.67 - 1.72 (4H, m), 2.47 - 2.54 (4H, m), 2.60 (2H, t), 3.39s - 3.44 (2H, m), 3.99 (3H, s), 7.54 - 7.56 (IH, m), 7.72 (IH5 d), 7.96 (IH, d), 8.71 (IH, t); MS m/z 294 [M+H]+.
0 Intermediate 194:
4-amino-N-(2-dimethylaminoethyl)-3-methoxy-benzamide The title compound was prepared in quantitative yield by an analogous method to the preparation of Intermediate 187, on a 2 g scale utilising N-(2-dimethylaminoethyl)-3- methoxy-4-nitro-benzamide (Intermediate 195).
1H NMR (399.9 MHz, DMSO-d6) 52.19 (6H, s), 2.38 (2H, t), 3.38 (2H, m), 3.81 (3H, s), 5.20 5 (2H, s), 6.61 (IH, d), 7.25 - 7.28 (IH, m), 7.30 (IH, s), 7.96 (IH, t); MS m/z 238 [M+H]+.
Intermediate 195: N-(2-dimethylaminoethyl)-3-methoxy-4-nitro-benzamide
The title compound was prepared by an analogous method to the preparation of Intermediate io 188, on a 9.28 mmol scale utilising N,N-dimethylethane-l,2-diamine (Aldrich; 818 mg, 9.28 mmol), as a brown solid (2.5 g, 100%)
1HNMR (399.9 MHz, DMSO-d6) δ 2.24 (6H, s), 2.47 - 2.49 (2H, m), 3.37 - 3.41 (2H, m), 4.00 (3H, s), 7.55 - 7.57 (IH, m), 7.74 (IH, d), 7.96 (IH, d), 8.73 (IH, t); MS m/z 268 [MH-H]+.
I5
Intermediate 196: 4-amino-N-(3-dimethylaminopropyl)-3-methoxy-benzamide
The title compound was prepared in quantitative yield by an analogous method to the preparation of Intermediate 187, on a 2 g scale utilising N-(2-dimethylaminoethyl)-3- 20 methoxy-4-nitro-benzamide (Intermediate 197).
1H NMR (399.9 MHz, DMSOd6) δl.60 - 1.67 (2H, m), 2.14 (6H, s), 2.25 (2H, t), 3.21 - 3.26 (2H, m), 3.81 (3H, s), 5.19 (2H, s), 6.61 (IH, d), 7.25 - 7.30 (2H, m), 8.09 (IH, t); MS m/z 252 [M+H]+.
25 Intermediate 197:
N-(3 -dimethylaminopropyl)-3 -methoxy-4-nitro-benzamide
The title compound was prepared by an analogous method to the preparation of Intermediate 188, on a 9.28 mmol scale utilising N,N-dimethylpropane-l,3-diamine (Aldrich; 948 mg, 9.28 mmol), as a brown solid (2.33 g, 90%) 1H NMR (399.9 MHz, DMSO-d6) δl.65 - 1.72 (2H, m), 2.16 (6H, s), 2.29 (2H, t), 3.34 (2H, m), 4.00 (3H, s), 7.53 - 7.56 (IH, m), 7.72 (IH, d), 7.96 (IH, d), 8.77 (IH, t); MS m/z 282 [M+H]+.
Intermediate 198:
10-chloro-4,4-diethyl-6-methyl-2-propan-2-yl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca- 7,9,1 l-trien-5-one
To a stirred solution of 10-chloro-4,4-diethyl-2-propan-2-yl-2,6,9,l 1- tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one (Intermediate 197; 2.7 g, 9.1 mmol) in DMA (50 mL) under nitrogen was added methyl iodide (0.627 mL, 10.0 mmol). The mixture was cooled on an ice/water bath to 30C, and sodium hydride (60% mineral oil dispersion; 0.567 g, 11.8 mmol) added in one portion. The reaction was stirred overnight. The reaction was evaporated to dryness to afford a yellow solid, this was quenched with saturated NH4Cl (aq) (50 mL), extracted with DCM (3 X 100 mL), dried (MgSO4) and evaporated to yield a yellow solid. This was dissolved in a minimum amount of DCM, diethyl ether was added and the system was sonicated to afford an off white solid. (2.24 g, 80%)
1HNMR (400.132 MHz, CDC13) δ 0.84 (t, 6H), 1.20 (d, 6H), 1.68 - 1.50 (m, 4H), 3.27 (s, 3H), 3.41 (s, 2H), 5.31 (septet, IH), 7.83 (s, IH); MS m/z 311 [M+H]+.
Intermediate 199:
10-chloro-4,4-diethyI-2-propan-2-yl-2,6,9,ll-tetrazabicyclo [5.4.0] undeca-7,9,ll-trien-5- one
To a solution of 2,4-dichloro-5-nitropyrimidine (Aldrich; 5.1 g, 26.4 mmol) and K2CO3 (4.4 g, 31.6 mmol) in acetone (150 mL) was slowly added methyl 2-ethyl-2-[(propan-2- ylamino)methyl]butanoate (Intermediate 200; 5.3 g, 26.4 mmol) in acetone (30 mL). The mixture was stirred at room temperature for 18 hours. The reaction was filtered and the solvent evaporated. The residue and iron (4.4 g, 79.2 mmol) were added to acetic acid (175 mL) and heated at 80 0C overnight. The resulting solution was filtered and the solvent evaporated and the residue quenched with 2.0 N NaOH(aq) (75 mL), to the resultant emulsion, was added 10%MeOH/DCM (100 ml) and the suspension filtered through a pad of celite. The obtained filtrate was extracted with 10%MeOH/DCM (3 X 150 mlL, dried and the solvent removed. The resultant material was dissolved in DCM and filtered. Acetonitrile was added to the DCM and the DCM was slowly removed in vacuo to give a precipitate, which was filtered and dried to yield the title compound as a white solid. (3.1 g, 33%) 1H NMR (400.132 MHz, CDC13) δ 0.90 (t, 6H), 1.21 (d, 6H), 1.68 - 1.60 (m, 4H), 3.35 (s, 2H), 5.36 (septet, IH), 7.83 (s, IH), 8.65 (brs, IH); MS m/z 297 [M+H]+.
Intermediate 200: methyl 2-ethyl-2-[(propan-2-ylamino)methyl]butanoate
Methyl 2-(aminomethyl)-2-ethyl-butanoate (Intermediate 201; 8 g, 50 mmol) and acetone (4.35 g, 75 mmol) were added to methanol (230 niL) and stirred for 10 minutes before the rapid addition of sodium triacetoxyborohydride (15.9 g, 75 mmol). The reaction was stirred overnight before being evaporated to dryness. The residue was quenched with saturated K2CO3(aq) (100 niL), extracted with DCM (3 x 150 mL), dried and solvent evaporated to yield a dark liquids. Purification was achieved via distillation (65oC @ 0.18 mbar) to yield the title compound as clear oil (5.3 g, 53%)
1R NMR (400.132 MHz, CDCl3) δ 0.79 (t, 6H), 1.02 - 0.98 (m, 7H), 1.62 (q, 4H), 2.74 - 2.67 (m, 3H), 3.67 (s, 3H)
Intermediate 201: methyl 2-(aminomethyl)-2-ethyl-butanoate
Methylcyanoacetate (Aldrich; 20 g, 0.201 mol) was dissolved in THF (250 mL), to this was added DBU (75 mL, 0.505 mol) and ethyl bromide (40 mL, 0.606 mol). The reaction was stirred at 50 0C for 2 hours before being cooled and quenched with sat NH4Cl(aq). The organic layer was separated and the remaining aqueous was extracted with diethyl ether (2 x 100 mL), dried and solvent removed in vacuo to yield yellow oil. Purification was achieved via distillation at 70 0C at 0.5 mbar to afford methyl 2-cyano-2-ethyl-butanoate as a clear oil (20 g, 0.129 mol) which was reduced with hydrogen under pressure using Raney nickel catalyst (2 g). The reaction mixture was filtered and solvent evaporated to the title compound as a slightly dark oil. (16 g, 50%). Intermediate 202: 4-amino-3-methoxy-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]benzamide
The title compound was prepared in quantitative yield by an analogous method to the preparation of Intermediate 187, on a 2 g scale utilising (Intermediate 203). s 1U NMR (399.9 MHz, DMSOd6) δθ.92 (2H, d), 1.39 - 1.46 (3H, m), 1.88 - 1.95 (IH, m), 1.92 (IH, d), 2.06 (IH5 s), 2.12 - 2.20 (2H, m), 2.41 (3H, s), 2.97 (2H, d), 3.82 (3H, s), 4.30 (IH, d), 5.18 (2H, s), 6.61 (IH, d), 7.29 - 7.31 (2H, m), 7.63 (IH, d); MS m/z 304 [M+H]+.
Intermediate 203: o 3-methoxy-N-[(lS,5R)-9-methyI-9-azabicyclo[3.3.1]non-3-yl]-4-nitro-benzamide
The title compound was prepared by an analogous method to the preparation of Intermediate 188, on a 9.28 mmol scale utilising Endo-9-methyl-9-azabicyclo[3,3,l]-nonan-3-aniine (Chempacific; 1.435 g, 9.28 mmol), as a brown solid (1.6 g, 52%)
1H NMR (399.9 MHz, DMSOd6) δθ.93 (2H, d), 1.45 (3H, m), 1.89 - 1.95 (IH, m), 1.94 (IH,s d), 2.03 (IH, t), 2.18 - 2.23 (2H, m), 2.42 (3H, s), 3.00 (2H, d), 4.00 (3H, d), 4.31 - 4.35 (IH, m), 7.56 - 7.59 (IH, m), 7.72 (IH, d), 7.96 (IH, d), 8.37 (IH, d); MS m/z 332 [M-H]+.
Intermediate 204:
4-amino-2-fluoro-5-methoxy-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-7-0 yl]benzamide
4-amino-2-fluoro-5-methoxybenzoic acid (Intermediate 183; 0.75 g, 4.07 mmol), HATU (1.70 g, 4.48 mmol) and DIPEA (2.1 mL, 12.21 mmol) were stirred together in DMF (10 rnL) for 10 minutes. Endo-9-methyl-9-azabicyclo[3,3,l]-nonan-3-amine (Chempacific; 0.69 g, 4.48 mmol) in DMF (1 mL) was added and the brown solution stirred at ambient temperature5 for 2 hours. The solvent was evaporated and the residue dissolved in MeOH and loaded onto an SCX-2 (20 g) column pre-wet with MeOH. The column was washed with MeOH (2 column volumes) and the product eluted with 2M NH3/MeOH (2 column volumes). Product containing fractions were combined and evaporated and the resultant material purified on a silica column eluting with 0-10% 2MNH3/MeOH/DCM). Product containing fractions were0 combined and evaporated to yield the title compound as a dark brown gum (897 mg, 69%). 1HNMR (400.132 MHz, DMSO-d6) δ 0.91 (m, 2H)5 1.39 (m, 3H), 2.04 (m, 5H), 2.40 (s, 3H), 2.96 (m, 2H), 3.78 (s, 3H), 4.27 (m, IH), 5.53 (s, 2H), 6.39 (d, IH), 7.06 (d, IH), 7.24 (m, IH); MS m/z 322 [M+H]+.
Intermediate 205:
4-amino-N-(l-ethyI-4-piperidyl)-2-fluoro-5-methoxy~benzamide
The title compound was prepared by an analogous method to the preparation of Intermediate 188, on a 5.43 mmol scale utilising l-ethylpiperidin-4-amine (Fluorochem; 0.77 g, 5.97 mmol), as a gum (1.21 g, 76%). 1H NMR (400.132 MHz, DMSO-d6) δ 0.99 (t, 3H), 1.52 (m, 2H), 1.78 (m, 2H), 1.97 (m, 2H), 2.31 (q, 2H), 2.80 (m, 2H), 3.72 (m, IH), 3.77 (s, 3H), 5.54 (bs, 2H), 6.39 (d, IH), 7.05 (d, IH), 7.33 (m, IH); MS m/z 296 [M+H]+.
Intermediate 206:
4-amino-N-(2,2-dimethyl-3-pyrrolidin-l-yl-propyl)-3-methoxy-benzamide
A mixture of the 4-amino-3-methoxy-benzoic acid (Aldrich; 2 g, 12 mmol) and 2,2-dimethyl- 3-pyrrolidin-l-yl-propan-l-amine (WO 2004033419; 2.1 g, 13.2 mmol) were dissolved in DMF (50 mL), and to the solution was added DIPEA (3.1 g, 4.2 mL ). The reaction was0 cooled with an ice-bath, and to it was added, portionwise, HATU (5.02 g, 13.2 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The solvent was evaporated, and the residue was partitioned between Ethyl Acetate (100 mL), and saturated aqueous sodium carbonate solution (3 x 40 mL), washed with brine (3 x 40 mL), dried over anhydrous Magnesium sulphate, filtered, and the solvent evaporated. The residue was purified by5 chromatography on a silica column pre-conditioned with Ethyl acetate and eluted with 10% MeOH-DCM +1% NH3. Those fractions containing the desired product were combined and the solvent was evaporated to yield the title compound as a pale brown gum, which crystallised on standing. (500mgs ; 14%). 1H NMR (400.132 MHz, CDC13) : δ 1.00 (6H,s), 1.75-1.85 (4H,m), 2.55 (2H,s), 2.63-2.75o (4H,m), 3.35-3.39 (2H,d), 3.90 (3H,s), 6.61-6.65 (lH,d), 7.06-7.11 (lH,d), 7.47 (lH,s), 9.05 (lH,bs). MS m/z 306 [M+H]+. Intermediate 207: 4-amino-5-chloro-2-fluoro-N-[(3R)-l-methylpyrrolidin-3-yl]benzamide
4-amino-5-chloro-2-fluorobenzoic acid (Intermediate 176; 300 mg, 1.58 mmol), HATU (903 mg, 2.37 mmol) and (3R)-l-methylpyrrolidin-3-amine di Hydrochloride (Intermediate 184; 5 325 mg, 2.37 mmol) were stirred in DMF (5 mL) and diisopropylethylamine (1.2 mL, 7.12 mmol) added. The mixture was stirred for 2 hours at room temperature and then absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (5% ammonia in methanol/DCM) to yield the title compound as a pale orange solid (333 mg,0
1H NMR (399.9 MHz, DMSO-d6) δl.63 - 1.71 (IH, m), 2.09 - 2.18 (IH, m), 2.25 (3H, s), 2.33 - 2.41 (2H, m), 2.55 - 2.61 (IH, m), 2.64 - 2.69 (IH, m), 4.30 - 4.35 (IH, m), 6.10 (2H, s), 6.55 (IH, d), 7.50 (IH, d), 7.76 - 7.79 (IH, m) s Intermediate 208:
2'-chloro-9'-isopropyl-5'-methyl-8',9'-dihydrospiro[cyclopropane-l,7'-pyrimido[5,4- b] [l,4]diazepin]-6'(5'H)-one
To a solution of 2'-chloro-9?-isopropyl-8',9'-dihydrospiro[cyclopropane-l,7l-pyrimido[5,4- b][l,4]diazepin]-6'(5'H)-one (Intermediate 209; 5.055 g, 19 mmol) in DMA (300 mL) was0 added methyl iodide (1.305 mL, 20.9 mmol), followed by sodium hydride (60% mineral oil dispersion; 814 mg, 20.33 mmol). The mixture was stirred at room temperature for 30 minutes. The DMA was removed in vacuo, then water (50 mL) was added. The product precipitated as a sticky gum, which turned into a solid on sonication. The solid was collected by filtration to give a brown powder. This material was dissolved in DCM and dried over5 sodium sulfate, then purified by column chromatography, eluting with 25% ethyl acetate in hexane, to yield the title compound as a white solid (3.73 g, 70%)
1H NMR (400.13 MHz, CDCl3) δ 0.63 - 0.66 (2H, m), 1.11 - 1.16 (8H, m), 3.26 (3H, s), 3.44 (2H, s), 4.91 - 4.98 (IH, m), 7.84 (IH, s) ; MS m/z 281 [M+H]+. 0 Intermediate 209: I'-chloro^'-isopropyl-S'^'-dihydrospiroJcyclopropane-ljV-pyrimidotS^- b] [l,4]diazepin]-6'(5'H)-one
Ethyl l-[[(2-chloro-5-nitro-ρyrimidin-4-yl)-propan-2-yl-amino]metliyl]cyclopropane-l- carboxylate (Intermediate 208; 10.26 g, 30 mmol) was dissolved in acetic acid (500 mL) and heated to 70 0C. Iron powder (6 g) was added in portions over 10 minutes. The mixture was stirred at 70 °C for 3 hours. The reaction mixture was filtered hot through celite, and the pad washed with DCM. The filtrate was evaporated to dryness then sonicated in saturated aqueous sodium hydrogen carbonate solution to give a brown suspension. This was filtered, and the resulting solid washed with water. The solid was then sucked dry on a filter, and suspended in a small amount of methanol with sonication. The methanol suspension was then diluted with DCM (10 x excess), and filtered to give a yellow solution, which was dried over sodium sulphate, then concentrated in vacuo to give a yellow / green solid. The solid was triturated under cold methanol to yield the title compound as a white powder. (5 g, 63%) MS m/z 267 [M-H]+. Retention time 1.81 minutes.
Intermediate 210: ethyl l-[[(2-chloro-5-nitro-pyrimidin-4-yl)-propan-2-yl-amino]methyl]cyclopropane-l- carboxylate
To a solution of ethyl l-[(propan-2-ylamino)methyl]cyclopropane-l-carboxylate (Intermediate 211; 9.55 g, 50 mmol) in acetone (300 mL) was added potassium carbonate (7.05 g, 51 mmol) followed by 2,4-dichloro-5-nitropyrimidine (Aldrich; 10.675 g, 55 mmol). The mixture was stirred overnight at room temperature, concentrated in vacuo and partitioned between EtOAc and water. The EtOAc layer was separated, dried over sodium sulfate, then purified by column chromatography (EtOAc / isohexane 10:90), to yield the title compound as a yellow oil. (11 g, 64%)
1H NMR (400.13 MHz, CDC13) δ 0.75 - 0.78 (2H, m), 0.96 (3H5 1), 1.10 - 1.14 (8H, m), 3.42 - 3.48 (IH, m), 3.59 (2H, s), 3.87 - 3.93 (2H, m), 8.48 (IH, s); MS m/z 343 [M+H]+.
Intermediate 211; ethyl l-[(propan-2-ylamino)methyl]cyclopropane-l-carboxylate To a solution of ethyl l-(aminomethyl)cyclopropane-l-carboxylate (Intermediate 114; 20.65 g, 250 mmol) in DCM (200 mL) was added acetone (3.74 mlL, 51 mmol). After stirring at room temperature for 15 minutes, sodium acetate (4.185 g, 51 mmol) was added, followed by sodium triacetoxyborohydride (15.905 g, 75 mmol). The suspension was stirred at room 5 temperature for 2 days then partitioned between DCM and an aqueous solution of saturated sodium hydrogen carbonate. The organic layer was separated, then dried over sodium sulphate evaporated to yield the title compound as a clear oil (9.2 g, 100%). 1H NMR (400.13 MHz, CDC13) δ 0.60 - 0.63 (2H, m), 0.86 (6H, d), 1.02 - 1.09 (5H, m), 1.69 (IH, br s), 2.50 (2H, s), 2.58 - 2.64 (IH, m), 3.93 (2H, q). 0
Intermediate 212: 4-amino-3-chloro-N-(l-ethyl-4-piperidyl)benzamide
To a mixture of 4-amino-3-chloro-benzoic acid (Fluorochem; 2.575 g, 15 mmol) and 1- ethylpiperidin-4-amine (Fluorochem; 2.12 g, 16.5 mmol) in DMF (50 mL), was added
15 DIPEA (5.2 mL, 30 mmol).The mixture was cooled with an ice-bath. HATU (6.27g), added and the reaction mixture stirred at ambient temperature for 18 hours. The solvent was evaporated and the residue partitioned between saturated aqueous sodium bicarbonate solution (100 mL), and Ethyl Acetate (4 x 50 mL). The organic extracts were washed with brine (2 x 75 ml), dried over anhydrous Magnesium sulphate, filtered, and the solvent
20 evaporated to give the crude product as a gum, which was triturated with ether to yield the title compound as a tan solid (3.54 g, 84%).
1HNMR ;400.1MHz (DMSO-d6) δ 1.20-1.26 (3H,t), 1.65-1.85 (2H,bm), 1.92-2.10 (2H,bm), 2.90-3.20 (4H,m), 3.30 (3H,s), 3.40-3.60 (2H,bm), 3.90-4.05 (lH,m), 5.98 (2H,s), 6.77-6.81 (lH,d), 7.554-7.60(lH,dd), 7.88 (lH,s), 8.10 (lH,bs); MS m/z 282 [M+H]+.
25
Intermediate 213: 4-amino-3-chloro-N-(2-dimethyIaminoethyl)benzamide
The title compound was prepared by an analogous method to the preparation of Intermediate 30 212, on a 15 mmol scale utilising 2,2-Dimethyammoethylamine (Aldrich; 1.455 g, 16.5 mmol), as a white solid (1.45 g, 40%). 1H NMR ;400.1MHz (DMSO-d6) 5 2.83 (6H,s), 3.18-3.24 (2H,t), 3.50-3.58 (2H,quartet), 5.95 (2H,s), 6.80-6.83 (lH,d), 7.55-7.60 (lH,d), 7.76 (lH,s), 8.30-8.38 (lH,t); MS m/z 242 [M+H]+.
s Intermediate 214;
4-amino-3-chloro-N-(3-dimethylaminopropyl)benzamide
The title compound was prepared by an analogous method to the preparation of Intermediate 212, on a 15 mmol scale utilising 3 -Dimethylamino-1 -propylamine (Aldrich; 1.685 g, 16.5 mmol), as a tan coloured solid (3.25 g, 85%). o 1HNMR 400.1MHz,(DMSO-d6) δ 1.80-1.90 (2H,m), 2.77 (6H,s), 3.00-3.08 (2H,m), 3.25- 3.50 (2H,m), 5.88 (2H,s), 6.78-6.82 (lH,d), 7.53-7.59 (lH,dd), 7.75 (lH,s), 8.24-8.30 (lH,t); MS m/z 256 [M+H]+.
Intermediate 215: s 4-amino-3-chloro-N-(2-pyrrolidin-l-ylethyl)benzamide
The title compound was prepared by an analogous method to the preparation of Intermediate 212, on a 15 mmol scale utilising 2-pyrrolidin-l-ylethanamine (Aldrich; 1.885 g, 16.5 mmol), as a tan coloured solid (2.67 g, 66%).
1H NMR ^OO-IMHZ, (DMSO-d6) δ 1.80-2.05 (4H,m), 3.20-3.45 (6H,m), 3.48-3.58 (2H,q),0 5.92 (2H,s), 6.78-6.82 (lH,d), 7.55-7.60 (lH,dd), 7.77 (lH,s), 8.30-8.40 (lH,t); ); MS m/z 268 [M+H]+.
Intermediate 216: 4-amino-2-chIoro-5-methoxy-N-(l-methyl-4-piperidyl)benzamide 5 The title compound was prepared by an analogous method to the preparation of Intermediate 212, on a 3.06 mmol scale utilising 4-amino-2-chloro-5-methoxy-benzoic acid (Intermediate 217; 617 mg, 3.06 mmol) and l-methylpiperidin-4-amine (Fluorochem; 385 mg, 3.37 mmol), as an off-white solid (845 mg, 93%). 1H NMR (399.902 MHz, CDC13) 61.61 (m, 2H), 2.05 (m, 2H), 2.20 (m, 2H), 2.30 (s, 3H),o 2.76 (m, 2H), 3.88 (s, 3H), 4.03 (m, 3H), 6.57 (d, IH), 6.63 (s, IH), 7.34 (s, IH); MS m/z 298 [M+H]+. Intermediate 217: 4-amino-2-chloro-5-methoxy-benzoic acid
2-chloro-5-methoxy-4-nitro-benzoic acid (Intermediate 218; 762 nig, 3.8 nimol) was dissolved in EtOH (20 niL) and a catalytic amount of 5% Pt on carbon added under an inert atmosphere. The solution was de-gassed and stirred under an atmosphere of hydrogen at room temperature overnight. The catalyst was filtered off and washed with EtOH and solvent evaporated and the resultant material dried under vacuum to yield the title compound as an off-white solid. (617 mg, 98%) 1HNMR (399.902 MHz, DMSO-d6) 63.72 (s, 3H), 5.65 (br s, 2H), 6.59 (s, IH), 7.21 (s, IH), 12.30 (br s, IH); MS m/z 201 [M+H]+.
Intermediate 218: 2-chloro-5-methoxy-4-nitro-benzoic acid s l-chloro-4-methoxy-2-methyl-5-nitro-benzene (APIN; 1 g, 4.96 mmol) was suspended in water (100 niL), potassium permanganate (3.14 g, 19.84 mmol) was added and the mixture diluted further with water (140 niL). The mixture was very slowed heated up to reflux over a 2 hour period and then stirred at reflux for 4 hours then allowed to cool to room temperature overnight with stirring. After 18 hours the mixture was reheated to 80 °C and filtered hot, the0 manganese filter cake was washed with boiling water (100 niL), then the aqueous filtrate was treated with a couple of drops of sodium metabisulfite solution and the permanganate colour was removed to give a yellow solution. The solution was acidified to pH 2 with concentrated hydrochloric acid and partially evaporated down to a volume of (200 mL) and extracted with EtOAc (2 x 100 mL). Combined organic extracts were washed with brine, dried (MgSO4)5 and evaporated to yield the title compound as a yellow solid. (752 mg, 65%).
1HNMR (399.902 MHz, DMSO-d6) 53.98 (s, 3H), 7.67 (s, IH), 8.14 (s, IH), 14.03 (br s, IH); MS m/z 229 [M-H]+.
Intermediate 219: o 5-chloro-4- [(2-cyclopentyl-6-methyl-5-oxo-2,6,9,l 1-tetrazabicyclo [5.4.0] undeca-7,9,11- trien-10-yI)amino]-2-fluoro-benzoic acid tert-butyl 5-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca- 7,9,1 l-trien-10-yl)amino]-2-fluoro-benzoate (Intermediate 220; 220 mg, 0.45 mmol) was dissolved in DCM (7.5 niL) and trifluoroacetic acid (2.5 niL) added. The mixture was stirred at room temperature for 2 hours. The reraction mixture was evaporated, the residue dissolved in methanol/DCM and absorbed on to an SCX column, which was subsequently washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated to yield the title compound as a white solid (195 mg, 100%). 1R NMR (399.9 MHz, DMSO-d6) δl .54 - 1.73 (6H, m), 1.88 - 1.95 (2H, m), 2.58 - 2.63 (2H, m), 3.18 (3H, s), 3.61 - 3.65 (2H, m), 4.74 - 4.79 (IH, m), 7.70 (2H, brs), 7.70 (IH, d), 8.06 - 8.11 (2H, m); MS m/z 434 [M+H]+.
Intermediate 220: tert-butyl 5-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll- tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-10-yl)amiho]-2-fluoro-benzoate s 4-Amino-5-chloro-2-fluorobenzoic acid tert-butyl ester (Intermediate 177; 123 mg, 0.5 mmol) was dissolved in dioxane (7.5 niL). 10-Chloro-2-cyclopentyl-6-methyl-2,6,9,l l- tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 1; 155 mg, 0.55 mmol), XANTPHOS (27 mg, 0.05 mmol) and caesium carbonate (327 mg, 1.0 mmol) were added. The system was purged with a stream of nitrogen for 15 minutes and then 0 tris(dibenzylideneacetone) palladium (II) (28 mg, 0.03 mmol) added. The apparatus was evacuated and backfilled with nitrogen (x3) and then heated at 100 °C for 3 hours. The mixture was cooled, filtered and the filtrate absorbed on to an SCX column, which was subsequently washed with methanol and eluted with ammonia in methanol. Product containing fractions were evaporated and the residue purified by column chromatography (2%5 MeOH/DCM) to yield the title compound as a pale yellow foam (225mg, 92%).
1H NMR (399.9 MHz, DMSOd6) δl.53 - 1.74 (15H, m), 1.92 - 1.95 (2H, m), 2.62 (2H, t), 3.19 (3H, s), 3.65 (2H, t), 4.73 - 4.84 (IH, m), 7.85 (IH, d), 8.15 (IH, s), 8.24 (IH, s), 8.41 (IH, d); MS m/z 490 [M+H]+. o Intermediate 221: 3,5-dichloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca- 7,9,ll-trien-10-yl)amino]-2-fluoro-benzoic acid
The title compound was prepared by an analogous method to the preparation of Intermediate 219, utilising tert-butyl 3,5-dichloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,l l- 5 tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien- 10-yl)amino]-2-fluoro-benzoate (Intermediate 222; 236 mg, 0.45mmol), as an off-white solid (180 mg, 87%).
1HNMR (399.9 MHz, DMSO-d6 + d4 AcOH) δl.30 - 1.63 (8H, m), 2.55 (2H + DMSO, m), 3.15 (3H, s), 3.51 - 3.54 (2H, m), 4.31 (IH, m), 7.75 (IH, d), 7.97 (IH, s); MS m/z 468 [M+H]+.
10
Intermediate 222; tert-butyl 3,5-dichIoro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll- tetrazabicycloJS^.OJundeca-T^jll-trien-lO-y^aminoJ^-fluoro-benzoate
The title compound was prepared by an analogous method to the preparation of Intermediate is 220, utilising tert-butyl 4-amino-3,5-dichloro-2-fluoro-benzoate (Isolated as a by-product during the preparation of Intermediate 177; 236 mg, 0.45mmoi), as an off-white solid (180 mg, 87%).
1H NMR (399.9 MHz, DMSO-d6) δl.30 - 1.63 (17H, m), 2.55 (2H + DMSO-d6, m), 3.16
(3H, s), 3.52 - 3.54 (2H, m), 4.25 (IH, m), 7.89 (IH, d), 8.00 (IH, s), 9.18 (IH, s); MS m/z 20 524 [M+H]+.
Intermediate 223; 7-amino-N-(l-methyl-4-piperidyl)benzo[l,3]dioxole-4-carboxamide
N-(l-methyl-4-piperidyl)-7-nitro-benzo[l,3]dioxole-4-carboxamide (Intermediate 224; 290 is mg, 0.94 mmol) was suspended in methanol (50 mL) and the system purged with nitrogen.
10% Pd/C (30 mg) was added and the mixture stirred under a hydrogen atmosphere for 2 hours. The catalyst was filtered off and the filtrate evaporated to give the title compound as a white solid (249mg, 96%).
1H NMR (399.9 MHz, DMSO-d6) δ 1.43 - 1.53 (2H, m), 1.78 - 1.82 (2H5 m), 1.98 - 2.05 (2H, 30 m), 2.12 (3H, s), 2.67 (2H, d), 3.69 - 3.73 (IH, m), 5.48 (2H, d), 6.06 (2H, s), 6.32 (IH, d),
6.95 (IH, d), 7.11 (IH, d); MS m/z 278 [M+H]+. Intermediate 224;
N-(l-methyl-4-piperidyl)-7-nitro-benzo[l,3]dioxole-4-carboxamide
4-Amino-l-methylpiperidine (Fluorochem; 325 mg, 2.84 mmol), HATU (1.09 g, 2.84 mmol) and 7-nitrobenzo[l,3]dioxole-4-carboxylic acid (WO 2003082827; 400 mg, 1.89m mol) were stirred in DMF (5 mL) and diisopropylethylamine (0.99 ml, 5.68 mmol) added. The mixture was stirred for 2 hours at room temperature. The reaction mixture was loaded on to an SCX column, which was subsequently washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and the solid suspended in methanol and filtered off to yield the title compound as a yellow solid (295mg, 51%). 1HNMR (399.9 MHz, DMSOd6) δ 1.50 - 1.60 (2H, m), 1.78 - 1.82 (2H, m), 1.96 - 2.03 (2H, m), 2.17 (3H, s), 2.72 (2H, d), 3.72 - 3.76 (IH, m), 6.42 (2H, s), 7.28 (IH, d), 7.62 (IH, d), 7.94 (IH, d); MS m/z 308 [M+H]+.
Intermediate 225; 4-amino-N-(l-ethyl-4-piperidyl)-3-fluoro-benzamide
4-amino-3-fluorobenzoic acid (2.115 g, 13.6 mmol), 4-Amino-l -Ethyl Piperidine (Fluorochem; 1.923 g, 15 mmol), HATU ( 5.7 g, 15 mmol) and DIPEA (7.1 mL, 40.8 mmol) were combined in DMA (60 mL) and the resulting yellow solution stirred at room temperature for 20 minutes. The reaction was left over the weekend at room temperature, solvent evaporated and the residue dissolved in methanol (10 mL) and loaded onto an SCX-2 column (50 g) which pre-wet with MeOH (40 mL), flushed with MeOH (4 x 30 ml) and eluted with 7N ammonia in MeOH (4 x 30 mL). Product containing, ammoniacal fractions were combined to yield the title compound as a brown solid (0.819 g, 22%) MS m/z 266 [M+H]+. Retention time 1.5 minutes
Intermediate 226: 4-(azetidin-l-yl)cyclohexan-l-amine tert-butyl N-[4-(azetidin-l-yl)cyclohexyl]carbamate (Intermediate 227; 260 mg, 1.01 mmol) was taken up in DCM (3 mL) and TFA (2 mL) and stirred at ambient temperature for 3 hours. The reaction mixture was poured directly onto an SCX-3 cartridge (5 g). The cartridge was washed through with DCM (30 mL), followed by methanol (30 mL) and then eluted with 2M ammonia in methanol (25 mL). Ammoniacal fractions were combined and evaporated to yield the title compound as a colourless oil (124 mg, 80%)
1H NMR (400.132 MHz, CDC13) 5 1.04 (m, 2H), 1.36 - 1.56 (m, 4H), 1.80 (m, 2H), 1.87 - 2.10 (m, 3H), 2.63 & 2.79 (2 x m, IH), 3.16 (m, 4H).
Intermediate 227; tert-butyl N- [4-(azetidin-l~yl)cyclohexyl] carbamate
To a stirred solution of N-4-boc-aminocyclohexanone (500 mg, 2.34 mmol) in DCM (7 mL) was added azetidine (220 ul, 3.26 mmol) and the mixture stirred for 15 minutes. Sodium acetate (193 mg, 2.34 mmol) was added, followed by careful addition of sodium triacetoxyborohydride (746 mg, 3.52 mmol) The reaction mixture was stirred, at ambient temperature, under nitrogen for 3 hours, diluted with DCM to 25 mL total volume and filtered. The filtrate was poured onto and SCX-2 (10 g) cartridge and the cartridge washed with methanol (75 mL) then eluted with 2M ammonia in methanol (75 mL). The ammoniacal solution was evaporated, to give a waxy off white solid (200 mg). The SCX cartridge wash was resubmitted to a second SCX-2 cartridge (10 g) and the cartridge again washed with methanol (75 mL) and eluted with 2M ammonia/methanol (75 mL). The ammoniacal solution was evaporated to a colourless gum. Solid products were combined and triturated with isohexane. The resultant crystalline solid was collected by suction filtration and dried to yield the title compound as a white solid (104 mg). A second crop crystallised from the filtrate. This was again collected and dried to give the title compound as fine white needles (260 mg). Total yield (364 mg, 61%)
1H NMR (400.132 MHz, DMSO-d6) δ 0.80 - 0.90 (IH, m), 1.05 - 1.16 (IH, m), 1.21 - 1.30 (IH, m), 1.37 (9H, s), 1.41 - 2.09 (8H, m), 3.01 (4H, q), 3.06 - 3.26 (IH, m), 6.57 - 6.66 (IH, m). Intermediate 228: 4-amino-2-fluoro-5-methoxy-N-(2-pyrrolidin-l-ylethyl)benzamide
4-amino-2-fluoro-5-methoxybenzoic acid (Intermediate 183; 0.75 g, 4.07 mmol), HATU (1.70 g, 4.48 mmol) and DIPEA (2.1 mL, 12.21 mmol) were stirred together in DMF (10 mL) for 25mins. N-(2-aminoethyl)pyrrolidine (Aldrich; 0.51 g, 4.48 mmol) in DMF (2 mL) was added and the solution stirred at ambient temp for 2 hours. The solvent was evaporated and the residue dissolved in MeOH and loaded onto an SCX-2 (20 g) column pre-wet with MeOH. The column was washed with MeOH (2 column volumes) and eluted with 2MNH3/MeOH. Product containing fractions were combined and evaporated to a brown gum, which was purified on a silica column eluting with 0-10% 2MNH3/MeOH/DCM. Product containing fractions were combined and evaporated to yield the title compound as a pale brown solid (948 mg, 83%)
1H NMR (400.132 MHz, DMSO-d6) δ 1.69 (m, 4H), 2.48 (m, 4H), 2.56 (t, 2H), 3.36 (m, 4H)5 3.77 (s, 3H), 5.59 (s, 2H), 6.40 (d, IH), 7.13 (d, IH), 7.51 (m, IH); MS m/z 282 [M+H]+.
Intermediate 229: 4-amino-2,5-difluoro-N-[(3R)-l-methylpyrrolidin-3-yl]benzamide
4-amino-2,5-difluoro-benzoic acid (Rare Chemicals GmbH; 450 mg, 2.6 mmol), (3R)-I- methylpyrrolidin-3 -amine di Hydrochloride (Intermediate 184; 473 mg, 2.73 mmol), HATU (1.08 g2.86 mmol) and DIPEA (2.25 mL, 13 mmol) were combined in DMF (10 mL) and stirred at room temperature for 4 hours. The solvent was evaporated and the residue dissolved in MeOH and added to an SCX-2 column (20 g), pre-wet with MeOH (2 column volumes). The column was flushed with MeOH (2 column volumes) and eluted with 2M ammonia in MeOH. Product containing fractions were combined and evaporated and the resultant material dissolved in DCM and purified on a silica column eluting with 5% 2M ammonia in MeOH / DCM. Fractions containing product were combined and evaporated to a yellow gum. Diethylether was added and re-evaporated and dried under high vacuum to yield the title compound as a yellow gum, which slowly crystallised to a cream solid (550 mg, 83%) 1HNMR (399.902 MHz, CDC13) δl.71 (m, IH), 2.26 - 2.42 (m, 5H), 2.64 (m, 2H), 2.86 (m, IH), 4.13 (s, 2H), 4.62 (m, IH), 6.43 (m, IH)5 6.87 (m, IH), 7.70 (m, IH); MS m/z 256 [M+H]+.
5 Intermediate 230:
4-amino-2,5-difluoro-N-(2-pyrrolidin-l-ylethyl)benzamide
The title compound was prepared by an analogous method to the preparation of Intermediate 229, on a 5.77 mmol scale utilising 2-pyrrolidin-l-ylethanamine (Aldrich; 725 mg, 6.35 mmol), as a beige solid (648 mg, 42%) io 1H NMR (399.902 MHz, CDC13) δl.78 (m, 4H), 2.56 (m, 4H), 2.69 (m, 2H), 3.55 (m, 2H), 4.12 (s, 2H), 6.43 (m, IH)5 7.16 (m, IH)5 7.72 (m, 1 H); MS m/z 270 [M+H]+.
Intermediate 231:
2-chIoro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll- I5 trien-10-yl)amino]-5-methoxy-benzoic acid
10-Chloro-2-cyclopentyl-6-methyl-256,9, 11 -tetrazabicyclo[5.4.0]undeca-8, 10, 12-trien-5-one (Intermediate 1; 1 g, 3.56 mmol) and 2-Chloro-3-Methoxy-4- Amino-benzoic acid (Intermediate 223; ) were suspended in a water / EtOH (3:1) mixture (40 mL). Concentrated hydrochloric acid (712 μL5 7.12 mmol) was added and the reaction heated at 80 °C overnight. 20 The reaction mixture was cooled to room temperature and the resulting solid filtered and dried to give the title compound as a beige solid (951 mg, 60%)
1H NMR (399.902 MHz5 DMSO-d6) δl.61 (m, 6H), 1.91 (m, 2H)5 2.63 (m, 2H), 3.10 (s, 3H)5 3.66 (m, 2H), 3.88 (s, 3H)5 4.86 (m, IH), 7.42 (s, IH)5 8.12 (s5 IH)5 8.35 (s, IH), 8.91 (br s, IH)5 13.10 (br s, IH); MS m/z 446 [M+H]+.
25
Intermediate 232: 2-Chloro-3-Methoxy~4-Amino-benzoic acid
2-chloro-5-methoxy-4-nitro-benzoic acid (Intermediate 233; 5.87 g, 26.3 mmol) was dissolved in EtOH (100 mL) and a catalytic amount of 5% Pt on carbon added under an inert 30 atmosphere. The solution was de-gassed and then stirred under an atmosphere of hydrogen at room temperature for 6 hours. The catalyst was filtered off and washed with EtOH and the filtrate evaporated and the residue triturated with diethylether and the solid filtered and dried to yield the title compound as a yellow solid (4.53 g, 89%)
HNMR (399.902 MHz, DMSO-d6) 53.80 (s, 3H), 5.73 (s, 2H)5 6.67 (s, IH), 7.29 (s, IH), 12.42 (s, IH); MS m/z 201 [M+H]+.
Intermediate 233: 2-chloro-5-methoxy-4-nitro-benzoic acid l-chloro-4-methoxy-2-methyl-5-nitro-benzene (APIN Chemicals; 12.58 g, 62.4 mmol) was suspended in water (600 mL) and heated to 90 °C under nitrogen. Potassium permanganate (2 eq, 19.74 g, 125 mmol) in water (500 mL) was added over a period of 25 minutes and then the mixture was heated at reflux for 2 hours. A further addition of potassium permanganate (19.74 g, 125 mmol) in water (500 mL) was made over 15 minutes with the reaction temperature reduced to 91 °C and then heating continued at reflux for 3 hours and then cooled to room temperature and allowed to stand overnight. The reaction was re-heated to reflux and further addition of potassium permanganate (9.86 g 62.5 mmol) in water (200 mL) made over 5 minutes and the reaction heated at reflux for 2 hours for a further 2 hours.
The reaction mixture was cooled to 80 °C and filtered hot through a pad of celite. The reactor vessel was washed with water (500 mL) and the Manganese filter cake was washed with boiling water (1200 mL). The combined aqueous washings were cooled to room temperature and any excess permanganate colour was removed by the addition of aqueous sodium metabisulfite solution. The resulting yellow solution was acidified to pH 1 with concentrated aqueous hydrochloric acid and the volume reduced from approximately 4000 mL to 3000 mL in vacuo. The aqueous layer was extracted with EtOAc (2 x 1000 mL) and the combined organic extracts washed with brine (500 mL), dried over MgSO4 and evaporated to yield the title compound as a yellow solid. (8.45 g, 58%)
1H NMR (399.902 MHz, DMSO-d6) δ 3.98 (s, 3H), 7.67 (s, IH), 8.14 (s, IH), 14.02 (br s, IH); MS m/z 229 [M-H]+.
Intermediate 234: tert-butyl 4-[(4-amino-3-methoxy-benzoyl)amino]piperidine-l-carboxylate To a solution of 4-amino-3-niethoxybenzoic acid (Aldrich; 2.4 g, 14.36 mmol) in DMF (100 mL) was added 4-amino-l-bocpiperidine (Aldrich; 3.15 g, 15.72 mmol) and DIPEA (7.5 niL, 43.06 mmol). The resultant solution was carefully treated portionwise (2-3 portions) with HATU (6.88 g, 18.09 mmol) and the resultant mixture was stirred, under nitrogen, at ambient
5 temperature overnight.
The solvent was removed in vacuo and the residue partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL). The organic phase was separated and washed with water (150 mL) and brine (150 mL), dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on a io silica cartridge eluting with a rising gradient of 0- 10% Methanol in DCM. Product containing fractions were combined and evaporated to yield the title compound as a peach coloured foam (2.88 g, 57%)
IH NMR (400.132 MHz, DMSO) δ 1.35 - 1.47 (HH, m), 1.72 - 1.80 (2H, m), 2.76 - 2.90 (2H, m), 3.81 (3H, s), 3.91 - 4.00 (3H, m), 5.20 (2H, s), 6.61 (IH, d), 7.28 - 7.30 (2H, m), is 7.80 (IH, d); MS m/z 348 [M-H]+.
Intermediate 235: 4-amino-N-(l-ethyl-4-piperidyl)-2,5-difluoro-benzamide
The title compound was prepared by an analogous method to the preparation of Intermediate 20 229, on a 5.77 mmol scale utilising 4-amino-l-ethylpiperidine (Fluorochem; 815 mg, 6.35 mmol), as an orange solid (1.23 g, 75%)
1H NMR (399.902 MHz, CDC13) δl.09 (t, 3H), 1.57 (m, 2H), 2.04 (m, 2H), 2.14 (m, 2H), 2.42 (q, 2H), 2.86 (m, 2H), 4.02 (m, IH), 4.13 (s, 2H), 6.43 (m, IH), 6.51 (m, IH), 7.72 (m, IH); MS m/z 284 [M+H]+.
25
Intermediate 236:
4- [(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,l 1-tetrazabicy clo [5.4.0] undeca-7,9,11-trien-
10-yl)amino]-3-methoxy-benzoic acid
10-chloro-2-cyclopentyl-4,4-dimethyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5- 30 one (Intermediate 127; 200 mg, 0.65 mmol) and 4-arnino-3methoxybenzoic acid (Aldrich; 130 mg, 0.78 mmol) were taken up in water/ethanol (3:1 v/v; 4 mL). Concentrated hydrochloric acid (130 ul, 1.30 mmol) was added and reaction heated by microwave irradiation at 12O0C for 30 minutes.
The reaction mixture was drowned into water (20 mL) and a precipitated solid collected by suction filtration and dried in vacuum oven, at 550C for 90 minutes, to give a dark pink 5 crystalline solid (180 mg).
The filtrate was evaporated to dryness to give further solid, which was combined with the first batch and triturated with an MeCN/Water mix gave a pink solid which was again collected by suction filtration (160 mg).
The filtrate was evaporated and combined with the solid purified by flash chromatography on io a silica cartridge eluting with 0-5% MeOH in DCM. to give the title compound as an off white solid (85 mg, 30%).
1H NMR (400.132 MHz, DMSO-d6) 5 1.16 (s, 6H)5 1.56 - 1.93 (m, 8H), 3.20 (s, 3H), 3.52 (s,
2H), 3.96 (s, 3H), 5.14 (m, IH), 7.60 (m, 2H), 8.08 (s, IH), 8.19 (d, IH), 9.18 (br s, IH) OH just visible at 12.84 (br s, IH); MS m/z 440 [M+H]+.
I5
Intermediate 237; 4-pyrrolidin-l-ylcyclohexan-l-amine tert-butyl N-(4-pyrrolidin-l-ylcyclohexyl)carbamate (Intermediate 238; 222 mg, 0.83 mmol) was taken up in DCM (1.5 mL) and TFA (1 mL). The reaction mixture was stirred at ambient
20 temperature for 3 hours, poured directly onto an SCX-3 cartridge (2 g), pre-wet with DCM. The cartridge was washed through with DCM (10 mL), followed by methanol (30 mL) and then eluted with 2M ammonia in Methanol (25 mL). Evaporation to dryness of the ammoniacal solution yielded the title compound as an amber coloured oil (103 mg, 74%) 1H NMR (400.132 MHz, DMSO-d6) δ 0.94 - 1.20 (m, 4H), 1.63 (m, 4H), 1.73 (m, 2H), 1.87
2S (m, 3H), 2.45 (m, 4H), 3.29 (br m, IH)
Intermediate 238; tert-butyl N-(4-pyrrolidin-l-ylcyclohexyl)carbamate
The title compound was prepared by an analogous method to the preparation of Intermediate 30 227, on a 2.34 mmol scale utilising pyrrolidine (Aldrich; 250 μL, 3.04 mmol), as a white solid (175 mg, 44%). 1HNMR (400.132 MHz, DMSO-d6) δ 1.15 (m, 4H), 1.38 (s, 9H), 1.64 (m, 4H), 1.75 (m, 2H), 1.88 (m, 3H), 2.45 (m, 4H), 3.15 (m, IH), 6.64 (m, IH).
Intermediate 239: 4-amino-N-(4-dimethylaminocyclohexyl)-3-methoxy-benzamide
4-amino-N-(4-dimethylaminocyclohexyl)-3-methoxy-benzaniide (Intermediate 240; 500 mg, 1.56 nimol) was reduced with 10% Pd/C (60 mg) and hydrogen to yield the title compound (454 mg, 100%).
1H NMR (399.9 MHz, DMSO-d6) δl.25 - 1.30 (2H, m), 1.40 - 1.44 (2H, m), 1.71 - 1.74 (IH, m), 1.80 (2H, m), 1.82 (2H, m), 2.19 (6H, d due to racemic mixture), 3.82 (3H, s), 3.65 and 3.85 (0.5H each due to racemic mixture), 5.16 (2H, s), 7.26 (IH, dd), 7.30 (IH, d), 7.71 (IH, t); MS m/z 292 [M+H]+.
Intermediate 240: 4-amino-N-(4-dimethylaminocyclohexyl)-3-methoxy-benzamide
3-methoxy-4-nitro-benzoyl chloride (Intermediate 189; 1.0 g, 4.64 mmol) was dissolved in DCM (20 mL) and cooled on an ice bath. DIPEA (970 uL) was added dropwise. l-amino-4- dimethylaminocyclohexane (ABChem Inc.; 660 mg, 4.64 mmol) was dissolved in DCM (10 mL) and added to the reaction solution. The reaction mixture was brought back to room temperature and stirred for 2 hours. The reaction mixture was washed with brine and NaOH (aq). The organic layer was extracted by filtering through a PTFE cup and evaporated to yield the title compound as an orange solid (1.54 g, 100%).
1H NMR (399.9 MHz, DMSOd6) δl.29 - 1.35 (2H, m), 1.45 - 1.48 (IH, m), 1.52 - 1.56 (IH, m), 1.75 (IH, m), 1.85 - 1.87 (2H, d), 1.95 (2H, d), 2.20 (6H, d due to N-dimethyl should be singlet but is doublet due to stereoisomers), 3.71 and 3.91 (two x 0.5H due to stereoisomers), 3.99 (3H, s), 7.51 (IH, t), 7.60 (IH, d), 7.92 (IH, t), 844 (IH, t); MS m/z 332 [M+H]+.
Intermediate 241:
4-amino-2-fluoro-N- [(I $,5R)-9-methyl-9-azabicycIo [3.3.1] non-7-yl] benzamide 2-fluoro-N-[(l S,5R)-9-methyl-9-azabicyclo[3.3.1 ]non-7-yl]-4-nitro-benzamide
(Intermediate 242; 500 mg, 1.56 mmol) was reduced using 10% PdVC (50mg) and hydrogen stirring at room temperature for 3 hours. The catalyst was removed by filtration and the filtrate evaporated to yield the title compound (454 mg, 100%).
1H NMR (399.9 MHz, DMSOd6) δ 0.90 (2H3 d), 1.38 - 1.40 (3H, m), 1.85 - 1.95 (2H, m), 1.99 - 2.05 (IH, m), 2.14 - 2.22 (2H, m), 2.40 (3H, s), 2.96 (2H, d), 4.20 - 4.28 (IH5 m), 5.81 s - 5.85 (2H, s), 6.28 - 6.32 (IH5 d), 6.38 - 6.43 (IH, m), 7.20 - 7.24 (IH5 1), 7.38 - 7.41 (IH5 t); MS m/z 292 [M+H]+.
Intermediate 242: 2-fluoro-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-7-yl]-4-nitro-benzamide io 2-fluoro-4-nitro-benzoyl chloride (Intermediate 243; 2.40 g, 11.79 mmol) was dissolved in DCM (20 niL) and cooled on an ice bath. DIPEA (2.46 mL5 14.15 mmol) was added dropwise followed by Endo-9-methyl-9-azabicyclo[3,3,l]-nonan-3-amine (Chempacific; 1.82 g, 11.79 mmol) dissolved in DCM (10 niL). The reaction mixture was allowed to return to room temperature and stirred for 2 hours and then washed with brine and NaOH (aq). The i5 organic layer was evaporated to yield the title compound as an orange solid (3 g, 79%)
IH NMR (399.9 MHz5 DMSOd6) δ 0.93 (2H, d), 1.34 - 1.41 (2H, m), 1.46 (IH5 1), 1.90 (IH5 t), 1.94 (2H, d), 2.21 - 2.29 (2H5 m), 2.41 (3H5 s), 2.98 - 3.00 (2H5 m), 4.23 - 4.34 (IH, m), 7.79 - 7.83 (IH, m), 8.08 - 8.16 (IH5 m), 8.18 - 8.24 (IH, m), 8.41 (IH5 d); MS m/z 292 [M+H]+.
20
Intermediate 243: 2-fluoro-4-nitro-benzoyl chloride
2-fluoro-4-nitrobenzoic acid (Fluorochem; 2.5 g, 13.51 mmol) was suspended in toluene (25 mL) and thionyl chloride (2.96 mL, 40.52 mmol) added. The reaction mixture was heated at 25 reflux for 1.5 hours, allowed to cool and evaporated to give the title compound as a yellow liquid which gradually solidified on standing (2.74 g, 100%) 1H NMR (399.9 MHz, DMSOd6) δ7.90 - 8.10 (3H5 m).
Intermediate 244: 30 4-amino-3-chloro-N-(2,2-dimethyl-3-pyrrolidin-l-yl-propyl)benzamide A mixture of the 4-amino-3-chloro-benzoic acid (Fluorochem; 2.49 g, 14.5 mmol) and 2,2- dimethyl-3-pyrrolidin-l-yl-propan-l -amine (Chemstep; 2.49 g, 15.95 mmol) were dissolved in DMF (50 mL), and to the solution was added DIPEA (5.1 mL, 29.0 mmol).The reaction mixture was cooled with an ice-bath, and HATU (6.06 g, 15.95 mmol) added, portionwise. The reaction mixture was stirred at ambient temperature for 18 hours. The solvent was evaporated and the residue partitioned between Ethyl Acetate (100 mL), and saturated aqueous sodium carbonate solution (3 x 40 mL), washed with brine (3 x 40 mL), dried over anhydrous Magnesium sulphate, filtered, and the solvent evaporated to give the crude product as an oily semi-solid, which was triturated with diethyl ether and filtered to yield the title compound as a pale yellow crystalline solid (850 mg, 19%) The mother-liquors from the trituration were purified on a silica column, pre-equilibrated ethyl acetate and eluting with 10% MeOH-DCM + 1%NH3. Product containing fractions were combined and evaporated to give the title compound as a viscous, yellow oil (1.72 g, 38%) 1H NMR (400.1MHz , CDCl3) δ 1.00 (6H,s), 1.82-1.88 (4H,m), 2.56 (2H,s), 2.65-2.72 (4H,bs), 3.33-3.36 (2H,d), 4.30 (2H,s), 6.73-6.77 (lH,d), 7.55-7.60 (lH,dd), 7.65 (lH,s), 9.38 (IH5S). MS m/z 310 [M+H]+.
Intermediate 245: 4-amino-N-[(3R)-l-ethylpyrrolidin-3-yl]-3-methoxy-benzamide
To a solution of 4-amino-3-methoxybenzoic acid (Aldrich; 424 mg , 2.54 mmol) and (3R)-I- ethylpyrrolidin-3 -amine (Intermediate 246; 312 mg, 2.73 mmol) in DMF (10 mL) was added DIPEA (1.4 ml, 8.04 mmol). The resultant solution was treated with HATU (1.21 g, 3.18 mmol) and stirred, under nitrogen, at ambient temperature overnight. The reaction mixture was evaporated to a brown, viscous oil, which was partitioned between DCM (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The organic phase was separated and aqueous phase re-extracted with DCM (20 mL). Combined organic solutions were evaporated to dryness and the residue purified on a silica column, eluting with a gradient of 0-10% methanol in DCM. Product containing fractions were combined and evaporated. The resultant material was dissolved in methanol and loaded onto an SCX-2 (10 g) cartridge. The cartridge was washed with methanol (75 mL) and then eluted with 2M ammonia/methanol. The animoniacal solution was evaporated to yield the title compound as an orange gum (210 mg, 31%).
Intermediate 246: (3R)-l-ethylpyrrolidin-3-amine tert-butyl N-[(3R)-l-ethylpyrrolidin-3-yl]carbamate (Intermediate 247; 945 mg, 4.41 mmol) was taken up in DCM (8 mL) and TFA (4 mL) and stirred at ambient temperature for 3 hours.
The reaction mixture was loaded onto an SCX-3 cartridge (5 g), pre-wet with DCM. The cartridge was washed with DCM (30 mL), followed by methanol (30 mL), then eluted with
2M ammonia in methanol (30 mL). The ammoniacal solution was evaporated to dryness to yield the title compound as an amber oil (152 mg)
The SCX-cartridge pre-wash, which was highly coloured, was poured onto an SCX-3 (20 g) cartridge and the cartridge flushed with methanol (150 mL) and then eluted with 2M ammonia in methanol (100 mL). Evaporation of the ammoniacal fraction afforded a further batch of the title compound as an amber oil (165 mg)
Combined yield (317 mg, 63%)
1H NMR (400.132 MHz, DMSO-d6) δ 0.99 (3H, t), 1.28 - 1.36 (IH, m), 1.93 - 2.02 (IH, m),
2.08 (IH, dd), 2.32 - 2.42 (3H, m), 2.46 - 2.49 (IH, m), 2.60 - 2.65 (IH, m), 3.26 - 3.33 (IH, m).
Intermediate 247: tert-butyl N- [(3R)-l-ethylpyrrolidin-3-yl] carbamate
To a solution of (3R)-(+)-3-(t-butyoxycarbonylamino)pyrrolidine (Fluka; 1.54 g, 8.27 mmol) in DMF (25 mL) was added triethylamine (2.3 mL, 16.50 mmol) and ethyl bromide (Aldrich;
1 mL, 13.40 mmol). The reaction mixture was heated by microwave irradiation at 100 0C in for 1 hour.
The reaction mixture was poured into water (400 mL) and the mixture extracted with diethyl ether (2 x 300 mL). The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and evaporated to dryness to yield the title compound as an amber coloured oil (825 mg, 47%). 1H NMR (400.132 MHz3 DMSO-d6) δ 0.99 (t, 3H), 1.38 (s, 9H), 1.53 (m, IH), 1.99 (m, IH), 2.20 (m, IH)5 2.32 - 2.48 (m, 4H), 2.67 (m, IH), 3.88 (m, IH)5 6.87 (m, IH).
Intermediate 248;
4-amino-N-(4-dimethylaminocyclohexyl)-2-fluoro-5-methoxy-benzamide
4-amino-2-fluoro-5-methoxy-benzoic acid (Intermediate 183; 0.75 g, 4.07 mmol), HATU (1.70 g, 4.48 mmol) and DIPEA (2.1 ml, 12.21 mmol) were stirred together in DMF (10 mL) for 10 minutes at ambient temperature, l-amino-4-dimethylaminocyclohexane (ABChem Inc.; 0.637 g, 4.48 mmol) in DMF (2 mL) was added and the reaction mixture stirred at ambient temperature overnight.
The solvent was evaporated and the residue dissolved in MeOH and loaded onto an SCX-2 (20 g) column pre-wet with MeOH. The column was washed with MeOH (2 column volumes) and the eluted with 2MNH3/MeOH. Product containing fractions were combined and evaporated to give a brown gum which was purified on a silica column eluting with 0-10% 2MNH3/MeOH/DCM to give a single unassigned isoform of the title compound as a pale brown gum (250 mg, 20%)
1H NMR (400.132 MHz, DMSO-d6) δ 1.63 (m, 8H)5 2.08 (m5 IH), 2.18 (s, 6H)5 3.77 (s, 3H)5 3.91 (m, IH)5 5.54 (bs, 2H)5 6.40 (d, IH), 7.06 (d, IH), 7.24 (m, IH); MS m/z 310 [M+H]+. A second unassigned isoform was also isolated and designated Intermediate 249 (394 mg, 31%)
Intermediate 249: 4-amino-N-(4-dimethylaminocyclohexyI)-2-fluoro-5-methoxy-benzamide The title compound was obtained as a single unassigned isoform described above in the preparation of Intermediate 248 as a white solid (394 mg, 31%).
1HNMR (400.132 MHz5 DMSO-d6) δ 1.28 (m5 4H)5 1.85 (m, 4H), 2.11 (m, IH), 2.18 (s5 6H), 3.66 (m, IH), 3.77 (s, 3H), 5.53 (bs, 2H), 6.38 (d, IH), 7.04 (d, IH), 7.26 (m, IH); MS m/z 310 [M+H]+.
Intermediate 250: lO-chloro-2-cy clopentyl-4,4-diethyl-6-methyl-2,6,9,l 1-tetrazabicyclo [5.4.0] undeca- 7,9,1 l-trien-5-one
To a stirred solution of 10-chloro-2-cyclopentyl-454-diethyl-2,6,9,l l- tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one (Intermediate 251; 2.5 g, 7.76 mmol) in DMA (50 niL) under nitrogen was added methyl iodide (0.627 mL, 10.0 mmol). The mixture was cooled on an ice/water bath to 30C, and sodium hydride (60% mineral oil dispersion; 0.567 g, 11.8 mmol) added in one portion. The reaction mixture was stirred on the ice/water bath for 1 hour before warming to room temperature and the reaction stirred for 4 hours. The reaction mixture was evaporated to dryness to afford a black solid, which was quenched with saturated aqueous NH4Cl solution (50 mL), extracted with DCM (3 X 100 mL), dried and solvent removed in vacuo to yield a black solid which was purified on a silica column eluting with DCM. The obtained solid was added to a diethyl ether and sonicated and the resultant material filtered and dried to yield the title compound as an off white solid (2.1 g, 80%). 1HNMR (400.132 MHz, CDC13) δ 0.83 (t, 6H), 1.77 - 1.48 (m, 10H), 1.99 - 1.91 (m, 2H), 3.27 (s, 3H), 3.43 (s, 2H), 5.34 (quintet, IH), 7.82 (s, IH); MS m/z 337 [M+H]+.
Intermediate 251:
10-chloro-2-cyclopentyl-4,4-diethyI-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5- one To a solution of methyl 2-[(cyclopentylamino)methyl]-2-ethyl-butanoate (Intermediate 252; 7.1 g, 31.3 mmol) in acetone (150 mL) was added potassium carbonate (5.3 g, 38.0 mmol) followed by 2,4-dichloro-5-nitropyrimidine (Aldrich; 6.1 g, 31.3 mmol). The black mixture was stirred at room temperature for 18 hours. The reaction was filtered and the solvent removed in vacuo to yield a black gum, which was dissolved in acetic acid (175 mL) and iron (7.0 g, 125 mmol) added and the reaction heated at 80 0C overnight. The resulting solution was filtered and the solvent removed in vacuo, the black solid/gum was quenched with water (75 mL) and to this was added sodium carbonate until basic, the resultant black emulsion was filtered through a pad of celite. The obtained mixture was extracted with DCM (3 X 150 mL), dried and the solvent removed in vacuo to yield a black solid. This was passed through a bond elute column (50 g) eluting with 0-1% MeOH in DCM to afford a brown solid, which was triturated with diethyl ether to yield the title compound as a white solid (3.05 g, 30%) 1HNMR (400.132 MHz, CDC13) δ 0.90 (t, 6H), 1.57 - 1.48 (m, 2H), 1.81 - 1.61 (m, 6H), 1.98 - 1.91 (ni5 2H), 3.36 (s, 2H), 5.31 (quintet, IH), 7.80 (s, IH), 8.40 (s, IH); MS m/z 323 [MH-H]+.
Intermediate 252; methyl 2-[(cyclopentylamino)methyl]-2-ethyl-butanoate
The title compound was prepared by an analogous method to the preparation of Intermediate 200, on a 50 mniol scale utilising Cyclopetanone (Aldrich; 6.33 g, 75 mmol), and distillation at 50 0C and 0.53 mbar pressure, as a clear oil (7.5 g, 65%) 1H NMR (400.132 MHz, CDC13) δ 0.79 (t, 6H), 1.32 - 1.24 (m, 2H), 1.53 - 1.46 (m, 2H), 1.68 - 1.57 (m, 6H), 1.83 - 1.72 (m, 2H), 2.67 (s, 2H), 2.99 (quintet, IH), 3.66 (s, 3H).
s Intermediate 253:
4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien- 10-yl)amino]-3-chloro-benzoic acid
2'-chloro-9'-cyclopentyl-5'-methyl-8',9'-dihydrospiro[cyclopropane-l,7'-pyrimido[5,4- b][l,4]diazepin]-6'(5Η)-one (Intermediate 130; 496 mg, 1.62 mmol) and 4-amino-3-0 chlorobenzoic acid (Fluorochem; 278 mg, 1.62 mmol) were taken up in water/ethanol (3:1 v/v; 12 mL). Concentrated hydrochloric acid (330 uL, 3.30 mmol) was added and the reaction heated at reflux overnight.
The reaction mixture was cooled and then poured into IM NaOH(aq) (75 mL), and DCM (50 mL) added. The aqueous phase was separated and washed with DCM (50 mL) then acidifieds until a precipitate formed (~pH 2-3) which was collected by suction filtration and dried, under vacuum, at 7O0C, for 2 hours to afford a pale pink solid. The material was taken up in 10% MeOH in DCM (10 mL) and a fine suspension resulted. The mixture was filtered and the collected solid dried to yield the title compound as a pink solid, (58 mg, 8%) MS m/z 442 [M+H]+. Retention time 1.26 minutes 0
Intermediate 254: 4-amino-2-fluoro-5-methoxy-N-[[l-(pyrrolidin-l- ylmethyl)cyclopropyl]methyl]benzamide
4-amino-2-fluoro-5-methoxy-benzoic acid (Intermediate 183; 500 mg, 2.70 mmol), [1- (pyrrolidin-l-ylmethyl)cyclopropyl]methanamine (Intermediate 33; 417 mg, 2.70 mmol),
5 HATU (1.545 g, 4.05 mmol) and DIPEA (1.415 mL, 8.10 mmol) were dissolved in DMF (8 mL) and left to stir for 3 hours at room temperature. The reaction mixture was loaded onto an SCX-3 column pre-washed with methanol. The column was washed with methanol eluted with 2% 7N ammonia/methanol. Product containing fractions were combined and evaporated and the residue purified on a silica column (5-12% MeOH ammonia/DCM gradient elution) to io yield the title compound as an orange-brown solid (200 mg, 23%).
1H NMR (399.9 MHz, DMSO-d6) 60.29 (2H, broad s), 0.50 (2H, broad s), 1.70 (4H, broad s), 2.45 (4H, s), 2.50 (2H, s), 3.30 (2H, d), 3.75 (3H, s), 5.60 (2H, s), 6.40 (IH5 d), 7.15 (IH, d), 8.05 (IH, t); MS m/z 322 [M+H]+.
I5 Intermediate 255:
2'-chloro-9'-cyclopentyl-5'-methyl-8',9'-dihydrospiro[cyclohexane-l,7'-pyriinido[5,4- b] [l,4]diazepin]-6f (5Η)-one
2l-chloro-9'-cyclopentyl-8',9'-dihydrospiro[cyclohexane-l,7'-pyrimido[5,4-b][l,4]diazepm]- 6'(5Η)-one (Intermediate 256; 300 mg, 0.94 mmol) was dissolved in N,N-dimethylacetamide
20 (10 mL) and methyl iodide (65 mL, 1.03 mmol) added followed by sodium hydride (41 mg of a 60% dispersion in mineral oil, 1.00 mmol). The reaction mixture was stirred for 30 minutes. A drop of water added was added and then the reaction mixture was diluted with water and extracted with ethyl acetate (x2). The combined organic extracts were dried (MgSO4) and concentrated and the residue purified by column chromatography (1% MeOH/DCM) to give a
25 sticky white solid (Note 4) that was suspended in diethyl ether and filtered off to yield the title compound as a white crystalline solid (242 mg, 77%).
1H NMR (399.9 MHz, DMSO-d6) δl.30 - 1.37 (2H, m), 1.51 - 1.62 (8H, m), 1.68 - 1.74 (2H, m), 1.84 - 1.91 (2H, m), 1.96 - 2.04 (2H, m), 3.21 (3H, s), 3.47 (2H, s), 4.88 - 4.96 (IH5 m), 8.09 (IH, s); MS m/z 335 [M+H]+.
30
Intermediate 256: 2'-chloro-9'-cyclopentyl-8',9'-dihydrospiro[cyclohexane-l,7'-pyrimido[5,4- b] [l,4]diazepin]-6'(5'H)-one
Methyl l-(aminomethyl)cyclopentane-l-carboxylate (Intermediate 257; 940 mg, 2.46 mmol) was dissolved in acetic acid (40 mL) and the mixture heated to 70 0C. Iron powder (412 mg, 7.37 mmol) was added and the mixture heated for 4 hours, filtered whilst still warm and concentrated. The residue was suspended between DCM and saturated aqueous sodium hydrogen carbonate solution and the mixture was filtered. The layers were then separated and the organic layer dried (MgSO4) and concentrated to give a green, viscous oil. On addition of methanol a white solid formed which was filtered off to yield the title compound (300mg, 38%).
1HNMR (399.9 MHz, DMSO-d6) δl.45 - 1.63 (1OH, m), 1.68 - 1.75 (2H, m), 1.79 - 1.86 (2H, m), 1.96 - 2.01 (2H, m), 3.42 (2H5 s), 5.06 - 5.15 (IH, m), 7.87 (IH, s), 9.70 (IH, s); MS m/z 321 [M+H]+.
Intermediate 257; methyl l-(aminomethyl)cyclopentane-l-carboxylate
Methyl l-[(cyclopentylamino)methyl]cyclopentane-l-carboxylate (Intermediate 258; 1.60 g, 7.10 mmol), 2,4-dichloro-5-nitropyrimidine (Aldrich; 1.66 g, 8.52 mmol) and triethylamine (1.2 mL, 8.52 mmol) were stirred in acetonitrile (50 mL) for 4 hours. The reaction mixture was evaporated and the residue dissolved in DCM, washed with water, dried (MgSO4) and evaporated. The residue was purified on a silica column eluting with 1% methanol/DCM to yield the title compound as a yellow oil that crystallised on standing (945 mg, 35%). 1HNMR (399.9 MHz, DMSO-d6) 51.43 - 1.70 (12H, m), 1.80 - 1.87 (2H, m), 1.97 - 2.01 (2H, m), 3.46 - 3.55 (IH, m), 3.58 (3H, s), 3.77 (2H, s), 8.90 (IH, s); MS m/z 383 [M+H]+.
Intermediate 258: methyl l-[(cyclopentylamino)methyl]cyclopentane-l-carboxylate
Methyl l-(aminomethyl)cyclopentane-l-carboxylate (Intermediate 259; 1.5 g, 9.54 mmol) and cyclopentanone (1.0 mL, 11.45 mmol) were stirred in DCM (40 mL). Sodium acetate (940 mg, 11.45 mmol) and sodium triacetoxyborohydride (3.04 g, 14.31 mmol) were added. The mixture was stirred at room temperature for 48 hours. The reaction mixture was filtered and the filtrate concentrated. The residue was dissolved in methanol and absorbed on to an SCX column, which was then washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated to yield the title compound as a colourless oil (1.64g, 81%). 1H NMR (399.9 MHz, DMSO-d6) δl.21 - 1.34 (2H, m), 1.39 - 1.70 (13H, m), 1.88 - 1.94 (2H, m), 2.63 (2H, s), 2.90 - 2.96 (IH, m), 3.59 (3H, s).
Intermediate 259: methyl l-(aminomethyl)cyclopentane-l-carboxylate 17328/13 Reaction carried out in RSL (P Walker - No.009/07, 09/01/2007)
Methyl 1-cyanocyclopentane-l-carboxylate (Intermediate 260; 6 g, 39.2 mmol) in acetic acid (70 mL) was hydrogenated using Pt O2 (600 mg) as a catalyst at room temperature under 4 Bar pressure for 4 hours. The reaction mixture was filtered and concentrated. The residue was taken up in methanol and absorbed on to an SCX column (3x 50g), which was then washed with methanol and eluted with ammonia in methanol. Concentration of product containing fractions yielded the title compound as a pale yellow liquid (6.18g, 100%). 1H NMR (399.9 MHz, DMSO-d6) 51.38 (2H, s), 1.52 - 1.58 (6H, m), 1.87 - 1.93 (2H, m), 2.67 (2H, s), 3.61 (3H5 s).
Intermediate 260: methyl 1-cyanocyclopentane-l-carboxylate
Methyl cyanoacetate (Fluka ; 25 g, 252.3 mmol) and potassium carbonate (83.7 g, 605.5 mmol) were stirred in DMF (250 mL). 1,4-Dibromobutane (Aldrich; 30.1 mL, 252.3 mmol) was slowly added. This caused and exotherm that continued after the addition was completed and a water bath was used to prevent the temperature exceeding 90 °C. The mixture slowly cooled to ambient temperature and was stirred overnight and then heated at 750C for 3 hours. The reaction mixture was cooled and filtered and the filtrate concentrated to about half volume. The mixture was diluted with water (250 mL) and extracted with diethyl ether (2 x 65 mL). The combined organic extracts were washed with IN hydrochloric acid, brine, dried (MgSO4) and evaporated to yield the title compound as a pale yellow liquid (31.73 g, 82%).
1H NMR (399.9 MHz, CDC13) δl.86 - 1.91 (4H, m), 2.25 - 2.29 (4H, m), 3.83 (3H, s). Intermediate 261; 10-chloro-6-methyI-2-(2-oxocyclopentyl)-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll- trien-5-one lO-chloro-6-methy 1-2,6,9,1 l-tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one (Intermediate 100; 256 mg, 1.20 mmol) was taken up in DMA (10 niL) and cooled on an ice-bath, with stirring, under nitrogen. Sodium hydride (60% in mineral oil; 232 mg, 5.8 mmol) was carefully added portionwise and the reaction mixture left to stir for 5 minutes, before removing cooling bath and stirring for a further 30 minutes. A solution of 2- chlorocyclopentanone (Aldrich; 600 uL, 6.00 mmol) in DMA (5 mL) was then added. The reaction mixture was heated to 100 0C and stirred for 3.5 hours and then allowed to cool, before addition of saturated aqueous ammonium chloride solution (1 mL). The mixture was partitioned between DCM (40 mL) and water (40 mL). Phases were separated and the aqueous phase re-extracted with DCM (40 mL). Combined extracts were washed with brine, dried over magnesium sulphate, filtered and evaporated. The residue was purified on a silica column eluting with ethyl acetate. Product containing fractions were combined and evaporated to yield the title compound as a sticky brown gum (211 mg, 60%) MS m/z 295 [M+H]+.
Intermediate 262; 4-bromo-2-chloro-5-fluoro-N-(l-methyl-4-piperidyl)benzamide
4-bromo-2-chloro-5-fluoro-benzoic acid (Apollo Scientific; 5.0 g, 19.8 mmol) was added to DMF (250 mL), to this was added HBTU (9.8 g, 25.7 mmol), N-methyl-4-aminopiρeridne (Fluorochem; 2.5 g, 21.8 mmol) and DIPEA (7.0 mL, 39.5 mmol). The reaction was stirred overnight, evaporated to dryness, quenched with 2.0 N NaOH (100 mL), extracted with DCM (3 x 100 mL), dried and solvent removed in vacuo. The residue was dissolved in hot acetonitrile, allowed to cool filtered, and the filtrate passed through a SCX column and the residue, after evaporation of product containing fractions, recrystallised from hot acetonitrile to yield the title compound as a white solid (5.0 g, 82%). 1HNMR (400.132 MHz, CDCl3) δ 1.64 - 1.55 (m, 2H), 2.07 - 2.03 (m, 2H), 2.19 - 2.14 (m, 2H), 2.29 (s, 3H), 2.79 - 2.76 (m, 2H), 4.04 - 3.95 (m, IH), 6.13 (brd, IH), 7.48 (d, IH), 7.62 (d, IH); MS m/z 350 [M+H]+.
Intermediate 263: 10-amino-2-cyclohexyl-6-methyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5-one lO-amino-2-cyclohexy 1-2,6,9,1 l-tetrazabicyclo[5.4.0]undeca-7,9,l l-trien-5-one (Intermediate 264; 1.0 g, 3.83 mmol) was dissolved in DMF (65 ml), to this was added sodium hydride (60% mineral oil dispersion; 0.37 g, 7.66 mmol) in one portion. The reaction was stirred under nitrogen for 30 minutes before being cooling 0 0C. Methyl Iodide (0.238 niL, 3.83 mmol) in DMF (10 mL) was slowly added to the reaction and the reaction stirred at 0 0C for 2 hours. The reaction was quenched with MeOH and solvent removed invacuo. The resultant slurry was quenched with saturated aqueous NH4Cl solution (50 mL), extracted with DCM (3 x 50 mL), dried and solvent evaporated to yield a yellow gum which was purified on a silica column eluting with 0-5% MeOH in DCM. On evaporation of product containing fractions the residue was dissolved in a small amount of DCM, to this was added diethyl ether (50 mL), and the solution slowly evaporated until a precipitate formed. The solution was then sonicated and the precipitate filtered and dried to yield the title compound as a white solid. (0.55g, 52%)
1HNMR (400.132 MHz, CDC13) δ 1.18 - 1.07 (m, IH), 1.52 - 1.34 (m, 4H), 1.74 - 1.68 (m, IH), 1.85 - 1.80 (m, 4H), 2.63 - 2.61 (m, 2H), 3.24 (s, 3H), 3.64 - 3.61 (m, 2H), 4.41 - 4.35 (m, IH), 4.66 (brs, 2H), 7.77 (s, IH); MS m/z 276 [M+H]+.
Intermediate 264:
10-amino-2-cyclohexyl-2,6,9,H-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5-one
2,4-dichloro-5-nitropyrimidine (Aldrich; 10 g, 0.052 mol) was dissolved in THF (250 mL). To this was added DIPEA (11 mL, 0.062 mol) and the reaction cooled to 0 0C. Methyl 3- (cyclohexylamino)propanoate (9.5 g, 0.052 mol) in THF (30 mL) was slowly added. The cooling bath was removed and the reaction was stirred at room temperature for 1 hour. To the reaction mixture was added saturated NH4OH(aq) (100 mL), and the reaction heated at 55 0C for 4 hours using a dry ice condenser. The reaction mixture was extracted with DCM (3 x 100 ml), and combined organic extracts dried and evaporated. The residue was dissolved in methanol (200 niL). Ammonium formate (33 g, 0.52 mol) and 10% palladium (1.5 g) were added. The reaction was heated at reflux for 5 hours, filtered and the methanol evaporated to
5 yield a dark orange solid, which was quenched with 2.0 N NaOH(aq) (100 niL), extracted with DCM (3 x 150 mL), and combined extracts dried and evaporated to yield an orange solid. Hot acetonitrile was added, this was stirred and then sonicated to give a precipitate that was filtered and dried to yield the title compound as a yellow solid (7.5 g, 55%). 1H NMR (400.132 MHz, CDCl3) δ 1.18 - 1.05 (m, IH), 1.48 - 1.37 (m, 4H), 1.84 - 1.68 (m, io 5H), 2.68 - 2.66 (m, 2H), 3.62 - 3.59 (m, 2H), 4.74 - 4.65 (m, IH), 5.34 (brs, 2H), 7.59 (s, IH), 9.57 (s, IH); MS m/z 262 [M+H]+.
Intermediate 265: methyl 3-(cyclohexylamino)propanoate is Cyclohexylamine (Aldrich; 17 g, 0.174 mol) was dissolved in THF (300 mL). To this was added methyl acrylate (Aldrich; 15 g, 0.174 mol) in one portion. The reaction mixture was stirred over the weekend. The solvent was evaporated with care due to the volatility of the product and the residue distilled at 72 0C at 0.30 mbar to yield the title compound as a clear oil (23.7 g, 74%).
20 1H NMR (400.132 MHz, CDC13) δ 1.31 - 1.01 (m, 6H), 1.63 - 1.57 (m, IH)5 1.75 - 1.70 (m, 2H), 1.89 - 1.85 (m, 2H), 2.46 - 2.39 (m, IH), 2.50 (t, 2H), 2.90 (t, 2H), 3.68 (s, 3H).
Intermediate 266: lO-chloro-2-cy clohexyl-6-methyl-2,6,9,l 1-tetrazabicy clo [5.4.0] undeca-7,9,1 l-trien-5-one
25 10-chloro-2-cyclohexyl-2,6,9, 11 -tetrazabicyclo[5.4.0]undeca-7,9, 11 -trien-5-one (Intermediate 267; 5.87 g, 20.91 mmol) was suspended in DMA (450 mL) under nitrogen. Methyl iodide (3.26 g, 23 mmol) was added and the suspension cooled to 5 °C on an ice-water bath. Sodium hydride (60% mineral oil dispersion; 920 mg, 23 mmol) was added in a single portion and the resulting mixture stirred on the ice- water bath for 30 minutes allowed to warm to room
30 temperature and stirred for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL) and the solvent evaporated. The residue was partitioned between DCM (200 mL) and water (300 mL) and the aqueous phase re-extracted with DCM (100 mL). The combined organic phases were dried (MgSO4) and the evaporated. The residue was taken up in DCM and purified on a silica column eluting with a gradient of 10 - 50% EtOAc / isohexane over 10 column volumes. Fractions containing product were combined and evaporated to yield the title compound as a cream solid (5.02 g, 81%) 1E NMR (399.902 MHz, CDCl3) δl.13 (m, IH), 1.47 (m, 4H), 1.72 (m, IH), 1.85 (m, 4H), 2.66 (m, 2H), 3.28 (s, 3H), 3.69 (m, 2H), 4.47 (m, IH), 7.93 (s, IH); MS m/z 295 [M+H]+.
Intermediate 267: 10-chloro-2-cyclohexyl-2,6,9,ll-tetrazabicyclo[5.4.0]undeca-7,9,ll-trien-5-one
Methyl 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclohexyl-amino]propanoate (Intermediate 238; 19.03 g, 55.52 mmol) was dissolved in acetic acid (440 mL) and heated to 70 °C under a nitrogen atmosphere. Iron powder (8.37 g, 150 mmol) was added cautiously, giving a slow exotherm to 82 0C, and the mixture stirred at 70 0C for 2 hours. The reaction mixture was cooled to approximately 60 °C and filtered through a pad of celite. The celite was washed through with DCM (500 mL) and the filtrate evaporated and the residue azeotroped with toluene. The resultant material was dissolved in DCM and diluted with EtOAc to give a precipitate which was filtered off. The filtrate was added to a very short pad of silica and eluted with EtOAc and the eluent evaporated to give an orange solid, which was dissolved in0 DCM (500 mL) and washed with saturated aqueous sodium bicarbonate solution (300 mL). The organic phase contained some insoluble material which was filtered off to give a cream solid. The filtrate was evaporated to dryness and the resulting dark brown gum triturated with DCM (20 mL) and filtered to give a cream solid. The two solids were combined and washed with a small amount of DCM then dried under high vacuum to yield the title compound as aS cream solid (5.87 g, 38%)
1H NMR (399.902 MHz, DMSO-d6) δl.13 (m, IH), 1.34 (m, 2H), 1.52 (m, 2H), 1.66 (m, 3H), 1.80 (m, 2H), 2.66 (m, 2H), 3.60 (m, 2H), 4.53 (m, IH), 7.84 (s, IH), 9.68 (s, IH); MS m/z 281 [M+H]+. 0 Intermediate 268: methyl 3- [(2-chloro-5-nitro-pyrimidin-4-yl)-cyclohexyl-amino] propanoate To methyl 3-(cyclohexylamino)propanoate (Intermediate 265; 15 g, 80.96 mmol) in acetone (300 mL) at room temperature was added powdered potassium carbonate (16.8 g, 121 mmol). 2,4-Dichloro-5-nitropyrimidine (Frontier Scientific; 17.27 g, 89.06 mmol) in acetone (100 mL) was added over 10 minutes and the resulting yellow mixture stirred at room temperature for 16 hours. The solvent was evaporated and the residue partitioned between EtOAc (500 mL) and water (500 mL). The aqueous phase was re-extracted with EtOAc (2 x 200 mL). The combined organic solutions were evaporated to approx half the volume, washed with brine (200 mL) and evaporated. The residue was taken up in DCM and purified on a silica column, eluting with 10% EtOAc / isohexane. Product containing fractions were combined and evaporated to yield the title compound as a yellow solid (19.03 g, 62%)
1H NMR (399.902 MHz, CDCl3) δl.27 (m, 2H), 1.49 - 1.68 (m, 4H), 1.85 (m, 4H), 2.70 (m, 2H), 3.20 (m, IH), 3.71 (s, 3H), 3.82 (m, 2H), 8.63 (s, IH); MS m/z 343 [M+H]+.
Intermediate 269: 4-amino-2,5-difluoro-N-[[l-(pyrrolidin-l-ylmethyl)cycIopropyl]methyl]benzamide 4-amino-2,5-difluoro-benzoic acid (Rare Chemicals GmbH; 700 mg, 4.04 mmol), [1- (pyrrolidin-l-ylmethyl)cyclopropyl]methanamine (Intermediate 33; 655 mg, 4.25 mmol), HATU (1.69 g, 4.44 mmol) and DIPEA (2.1 mL, 12.12 mmol) were combined in DMF (10 mL) and stirred at room temperature for 2 hours. The reaction mixture divided into two portions and each loaded on to an SCX-2 column (20 g) pre-wet with MeOH (2 column volumes), flushed with MeOH (2 column volumes) and eluted with 2M ammonia in MeOH. Product containing fractions were evaporated and the residue taken up in DCM and purified on a silica column eluting with a 0 - 5% gradient of 2M ammonia in MeOH / DCM then 5% 2M ammonia in MeOH / DCM. Fractions containing product were combined and evaporated to yield the title compound as an orange gum which solidified on standing to an orange solid (472 mg, 38%)
1H NMR (399.902 MHz, CDCl3) 60.37 (m, 2H), 0.55 (m, 2H), 1.75 (m, 4H), 2.50 (m, 6H), 3.42 (m, 2H), 4.08 (s, 2H), 6.43 (m, IH), 7.70 (m, IH), 8.53 (m, IH); MS m/z 310 [M+H]+.
Intermediate 270: 2'-chloro-9'-cyclohexyl-5'-methyl-8',9T-dihydrospiro[cyclopropane-l,7'-pyrimido[5,4- b] [l,4]diazepm]-6'(5'H)-one
To a stirred solution of 2'-chloro-9'-cyclohexyl-8^9'~dihydrospiro[cyclopropane-l,7'- pyrimido[5,4-b][l,4]diazepin]-6'(5'H)-one (Intermediate 271; 849 mg, 2.767 mmol) in DMA (60 mL) under nitrogen was added methyl iodide (190 μL, 3.044 mmol). The mixture was cooled on an ice/water bath and sodium hydride (60% mineral oil dispersion; 122 mg, 3.044 mmol) added in one portion. The reaction mixture was stirred on the ice/water bath for 1 hour, the cooling bath removed and allowed it to warm to room temperature. After 1.5 hours the solvent was evaporated and the residue treated with an excess of water. This afforded a solid, which was filtered off and washed well with water and then dried by dessication under high vacuum over P2O5 overnight. To yield the title compound as an off-white solid (887 mg, 100%)
1H NMR (400.13 MHz, CDCl3) δ 0.57 - 0.60 (2H, m), 0.97 - 1.04 (IH, m), 1.05 - 1.08 (2H, m), 1.18 - 1.28 (2H, m), 1.34 - 1.44 (2H, m), 1.60 - 1.67 (IH, m), 1.71 - 1.78 (4H, m), 3.19 (3H, s), 3.40 (2H, s), 4.42 - 4.50 (IH, m), 7.77 (IH, s); MS m/z 321 [M+H]+.
Intermediate 271:
2'-chloro-9'-cyclohexyl-8',9l-dihydrospiro[cyclopropane-l,7'-pyrimido[5,4- b][l,4]diazepin]-6'(5'H)-one Ethyl l-[[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclohexyl-amino]methyl]cyclopropane-l- carboxylate (Intermediate 272; 3.89 g, 10.16 mmol) was dissolved in the acetic acid (75 mL) and the solution heated with stirring to 72 0C under nitrogen on an oil bath. Iron powder (1.5 g) was added in one portion giving a small exotherm to 75 0C over the subsequent 15 minutes. The reaction temperature dropped back to 72 0C and the reaction was maintained at this temperature for 3 hours and then allowed to cool to room temperature overnight. The reaction mixture was reheated and filtered hot through celite, and the pad washed with more acetic acid. The filtrate was concentrated in vacuo, then sonicated in saturated aqueous sodium hydrogen carbonate solution to give a brown suspension. This was filtered, and the resulting solid washed with water. The solid was sucked dry, and suspended in methanol with sonication. The suspension was then diluted with DCM, and sodium sulphate added. This mixture was filtered to give a yellow solution, which was concentrated in vacuo to give a yellow solid, which was triturated under cold methanol to give the product as a white powder. The mother liquors were purified on a silica column, to give more clean product, which was combined with the first batch to yield the title compound as a white solid (850 mg, 27%). s 1H NMR ^OO-D MHz, DMSOd6) δ 0.88 - 0.91 (2H, m), 1.05 - 1.15 (IH, m), 1.15 - 1.18 (2H, m), 1.31 - 1.42 (4H, m), 1.61 - 1.63 (3H, m), 1.74 - 1.81 (2H, m), 3.44 (2H, s), 4.44 (IH, s), 7.93 (IH, s), 9.77 (IH, s); MS m/z 307 [M+H]+.
Intermediate 272: o ethyl l-[[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclohexyl-amino]methyl]cyclopropane-l- carboxylate
To a solution of ethyl l-[(cyclohexylamino)methyl] cyclopropane- 1-carboxylate (Intermediate 273; 7.175 g, 34 mmol) in acetone (200 mL) was added potassium carbonate 7.05 g, 51 mmol) followed by 2,4-dichloro-5-nitropyrimidine (Aldrich; 9.235 g, 47.6 mmol). Thes reaction mixture was stirred at room temperature for 5 hours. A further addition of 2,4- dichloro-5-nitropyrimidine (4.62 g, 23.8 mmol) and potassium carbonate ( 3.5 g, 25.5 mmol) was made and the reaction stirred overnight at room temperature. The reaction mixture was then concentrated in vacuo and partitioned between EtOAc and water. The EtOAc layer was separated, dried over sodium sulphate and purified on a silica column eluting with EtOAc /0 isohexane 10:90, to yield the title compound as a yellow oil (12 g, 92%).
1H NMR (400.13 MHz, CDCl3) δ 0.76 - 0.83 (2H, m), 0.90 - 0.97 (IH5 m), 1.00 (4H, s), 1.04 - 1.10 (2H, m), 1.13 - 1.15 (2H, m), 1.56 (6H, m), 2.93 - 2.99 (IH, m), 3.69 (2H, s), 3.94 (2H, q), 8.49 (IH, s); MS m/z 383 [M+H]+. 5 Intermediate 273: ethyl l-[(cyclohexylamino)methyl] cyclopropane-1-carboxylate
To a solution of ethyl l-(aminomethyl)cyclopropane- 1-carboxylate (Intermediate 114; 20.65 g, 50 mmol) in DCM (200 mL) was added cyclohexanone (Aldrich; 5.28 mL, 51 mmol). After stirring at room temperature for 15 minutes, sodium acetate (4.185 g, 75 mmol) was0 added, followed by sodium triacetoxyborohydride (15.905 g, 75 mmol). The suspension was stirred at room temperature for 2 days then partitioned between DCM and saturated aqueous sodium hydrogen carbonate solution. The organic solution was dried over sodium sulphate and evaporated to yield the title compound as a colourless oil (7.2 g, 64%). 1H NMR (400.13 MHz, CDCl3) δ 0.55 - 0.58 (2H, m), 0.81 - 0.97 (4H5 m), 0.99 - 1.08 (7H, m), 1.34 - 1.39 (IH, m), 1.47 - 1.51 (2H, m), 1.57 - 1.65 (2H, m), 2.14 - 2.21 (IH, m), 2.49 s (2H, s), 3.88 (2H, q).
Intermediate 274:
4~amino-2,5-difluoro-N-[(l S,5R)-9-methyl-9-azabicyclo [3.3.1] non-7-yl] benzamide
A mixture of the 4-Amino-2,5-Difluorobenzoic Acid (Rarechem; 2.4 g, 13.87 mmol) and io Endo-9-methyl-9-azabicyclo[3,3,l]-nonan-3-amine (Chempacific; 2.355 g, 15.26 mmol) was dissolved in DMF (150 niL), and to the solution was added DIPEA (5.3 mL, 27.74 mmol). The reaction was cooled on an ice-bath, and HATU( 5.805 g, 15.26 mmol) was added, portionwise. The reaction mixture was then stirred at ambient temperature for 18 hours, solvent evaporated, and the residue partitioned between ethyl acetate (200 mL), and saturated I5 aqueous sodium carbonate solution (3 x 50 mL), washed with brine (3 x 50 mL), dried over anhydrous magnesium sulphate, filtered, and the solvent evaporated. The residue was purified on an SCX-2 column (50 g), developing and eluting with 1) water ; 2) MeOH ; and 3) 3.5M NH3-MeOH.The solvent was evaporated to yield the title compound as a tan crystalline solid ( 2.58 g, 60%).
20 1H NMR (400.1MHz; CDCl3) δ 1.00-1.10 (2H,d), 1.23-1.33 (2h,dt), 1.48-1.58 (lH.m), 1.85- 2.03 (4H,d+m), 2.50 (3H,s), 2.44-2.56 (2H,m), 3.04-3.12 (2H,d), 4.20 (2H,s), 4.42-4.56 (lH,m), 6.33-6.50 (lH,m), 6.42-6.50 (lH,dd),7.70-7.77 (lH,dd). MS m/z 310 [M+H]+.
Intermediate 275: 25 4-amino-3-methoxy-N-[(lR,5S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]non-7-yl]benzamide
N-Ethyldiisopropylamine (0.119 mL, 0.68 mmol) was added to 4-amino-3-methoxybenzoic acid (Aldrich; 114 mg, 0.68 mmol), (lR,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7- amine (Bioorganic & Medicinal Chemistry Letters (1992), 2(6), 519-22, 107 mg, 0.68 mmol) and HATU (260 mg, 0.68 mmol) in DMF (5 mL) at 250C. The resulting solution was 30 stirred at ambient temperature for 6 hours. The DMF was evaporated to give a brown gum as residue, which was purified by ion exchange chromatography, using an SCX-2 (5g) column pre-wet with methanol. The desired product was eluted from the column using 2M NH3/MeOH and purified fractions were evaporated to dryness to afford a brown gum which was purified by flash silica chromatography, elution gradient 0 to 100% 5% MeOH/DCM in DCM. Pure fractions were combined and evaporated to dryness to afford the title compound as a beige coloured gum (205 mg, 98 %).
1HNMR (400.132 MHz, CDCl3) δ 1.38 (2H, d), 2.39 - 2.45 (2H, m), 2.53 (3H, s), 2.58 - 2.68 (4H, m), 3.64 (2H, d), 3.83 (3H, s), 4.58 - 4.64 (IH, m), 5.60 (2H, s), 6.59 (IH, d), 7.09 (IH, d), 7.33 (IH, d), 8.80 (IH, d); MS m/z 306 [M+H]+.
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Biological Assays for inhibition of PLK
The following assay was used to measure the effects of the compounds of the present invention as PIk kinase inhibitors.
In Vitro Plkl Enzyme Assay The assay uses Scintillation Proximity Assay (SPA) technology (Antonsson et al.,
Analytical Biochemistry, 1999, 267: 294-299) to determine the ability of test compounds to inhibit phosphorylation by recombinant Plkl. The full-length Plkl protein is expressed in insect cells as an N-terminal 6His tag fusion and purified by standard Nickel chelate purification techniques using the His tag. The amino terminal fragment of Cdc25C (encoding residues 1-165) is expressed in
E.coli as a GST fusion and purified using the GST tag by standard purification techniques. Test compounds were prepared as 1OmM stock solutions in dimethyl sulphoxide (DMSO) and diluted into water as required to give a range of final assay concentrations. Aliquots (5μl) of each compound dilution were dispensed into a well of a 384-well flat bottom white polystyrene plate (Matrix, Catalogue No. 4316). A 35μl mixture of recombinant purified Plkl enzyme (12ng/well), purified GST-Cdc25C (150ng/well), adenosine triphosphate (ATP; 64nM), 33P-labelled adenosine triphosphate (33P-ATP; 60 nCi/well) in a buffer solution [comprising 5OmM HEPES pH7.5 buffer, 1OmM manganese chloride (MnCl2), ImM dithiothreitol (DTT), lmg/ml bovine serum albumin (BSA), lOOμM sodium vanadate (Na3VO4), lOOμM sodium fluoride (NaF) and 1OmM sodium glycerophosphate] was added and the reactions incubated at ambient temperature for 90 minutes.
Reactions were stopped by addition of EDTA (HOmM) and the Cdc25C substrate captured via its GST tag to anti-GST antibody (Molecular Probes, Cat No A-5800) coated Protein A PVT SPA beads (Amersham Biosciences, Catalogue No. RPQ0019; 250μg/well) in 5OmM HEPES pH7.5 buffer containing 0.05% (w/v) sodium azide and incubated for up to 2 hours, followed by the addition of 20μl of 4M caesium chloride (final assay concentration of IM). Plates were then left in the dark overnight before counting on a Packard TopCount NXT.
Radiolabelled phosphorylated substrate is formed in situ as a result of Plkl mediated phosphorylation. The SPA beads contain a scintillant that can be stimulated to emit light.
This stimulation only occurs when a radiolabelled phosphorylated substrate is bound to the surface of the coated SPA bead causing the emission of blue light that can be measured on a scintillation counter. Accordingly, the extent of Plkl mediated Cdc25C phosphorylation was assessed. The raw assay data were then analysed by non-linear regression analysis and Plkl enzyme inhibition for a given test compound is expressed as an IC50 value.
The following examples were tested in this assay and were measured to have IC50 values less than 100 uM
4, 50, 51, 53, 54, 74, 77, 88, 94, 96, 99, 116,
117, 118, 120, 121, 122, 123, 125, 133, 134, 135, 136, 137, 114400,, 114411,, 114444,, 114455,, 114466,, 147, 148, 149, 151, 153, 154, 155,
156, 157, 158, 159, 160, 163, 164, 166, 168, 169, 172, 174, 175, 177, 180, 183, 187, 199, 205, 239, 247, 248, 249, 251, 253, 254, 255, 256, 257, 258, 260, 261, 263, 264, 265, 266, 268, 273, 275, 276, 277, 433, with the following examples having IC50 values less than IuM
7, 8, 12, 24, 31, 32, 35, 36, 37, 38, 52, 65,
67, 70, 76, 80, 81, 89, 90, 93, 95, 98, 105, 107,
109, 112, 113, 115, 124, 128, 129, 130, 131, 132, 138, 139,
143, 150, 161, 162, 165, 173, 178, 179, 182, 184, 191, 195,
196, 197, 200, 212, 215, 216, 220, 223, 225, 226, 227, 228,
230, 233, 238, 243, 244, 250, 259, 262, 267, 272, 282, 323,
383, 410, with the following having IC50 values less than 0.3 uM
1, 2, 5, 6, 9, 10, 11, 13, 14, 15, 16, 17,
18, 19, 20, 21, 22, 23, 25, 26, 27, 28, 29, 30, 33, 34, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,
49, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 69,
71, 72, 73, 75, 78, 82, 83, 84, 85, 86, 87, 91,
92, 110000,, 110022,, 110044,, H 11 l1,, 111144,, 119, 142, 170, 176, 181, 185,
186, 188, 189, 193, 194, 201, 202, 203, 206, 207, 208, 209, 210, 211, 212, 213, 217, 218, 219, 221, 222, 224, 229, 231,
232, 234, 235, 236, 237, 240, 241, 245, 246, 269, 270, 281,
283, 314, 315, 316, 317, 318, 319, 320, 321, 322, 325, 326,
327, 328, 382, 385, 386, 387, 430, 431, 432.
For example, Examplel4 was measured to have an IC50 of HOnM, Cell IC50 92 nM.
Cellular Assay
Chromosome condensation in mitosis is accompanied by phosphorylation of histone H3 on serine 10. Dephosphorylation begins in anaphase and ends at early telophase, thus histone H3 serine 10 phosphorylation acts as an excellent mitotic marker and is used to determine the ability of compounds of the present invention to block cells in mitosis. Cells of the human colon tumour cell line HT29 were seeded into 96 well black plates (Costar, Catalogue No 3904) in phenol red free Dulbecco's Modified Eagles Medium (DMEM) supplemented with 10% (v/v) FCS and 1% (v/v) L-Glutamine and incubated overnight at 370C. Test compounds were solubilised in DMSO, diluted to give a range of
5 final assay concentrations, added to cells and incubated for 24h at 370C. After 24 hours, cells were fixed in 3.7% (v/v) formaldehyde then permeabilised and blocked for 10 minutes in lOOμl 0.5% (v/v) Triton X-IOO, 1% (w/v) bovine serum albumin (BSA) in phosphate buffered saline (PBS). After washing with PBS, 50μl primary antibody (1:500 dilution of rabbit anti- phosphohistone H3 (Upstate Catalogue No 06-570) in 1% BSA, 0.05% Tween 20) was added io to the cells that were left for 1 hour at room temperature. Cells were again washed with PBS and incubated with 50μl secondary antibody (1:1000 Alexa Fluor 488 goat anti-rabbit (Molecular Probes Cat No A-11008) and Hoechst (1:10000) diluted in PBS 0.05% (v/v) Tween 20 and left for 1 hour at room temperature in the dark. Cells were washed with PBS then covered with fresh PBS and stored at 40C until analysis. Images are acquired and is analysed in an automated manner using the Cellomics ArrayScan II or VTi. In this assay both hoechst and phosphohistone H3 staining are measured. Hoechst staining generates a valid cell count while phosphohistone H3 staining determines the number of mitotic cells. Inhibition of PIk leads to an increase in the population of histone H3 SerlO positive cells, indicating inhibition of proliferation is brought about primarily by arrest of cells in the mitotic
20 phase of the cell cycle. The raw assay data were analysed by non-linear regression analysis and used to determine an IC50 value for each compound.
The following example compounds when tested in this assay and had an IC50 value of less than 3OuM 5, 23, 24, 40, 42, 89, 103, 105, 107, 112, 115, 122, 123, 124, 125, 126, 127, 128, 129, 131, 132, 133, 138, 143, 159, 165, 167, 170, 171, 173, 177, 178, 179, 180, 186, 187,
25 192, 195, 212, 215, 218, 220, 221, 223, 224, 228, 229, 230, 231, 232, 233, 248, 253, 256, 257, 263, 264, 265, 270, 271, 272, 275, 277, 284, 286, 287, 296, 297, 332, 410 with the following examples having an IC50 less than IuM 4, 7, 26, 27, 47, 51, 53, 56, 77, 97, 99, 101, 104, 106, 108, 110, 113, 114, 135, 176, 182, 184, 191, 197, 202, 219, 234, 238, 239, 242, 269, 278, 279, 281, 282, 285, 289, 290, 293, 294, 295, 301, 302, 309, 310, 311, 330, 331, 390, 405, 411,
30 413, 416, 419, 429, 451 with the following example have an IC50 of less than 0.3 uM 1, 2, 3, 6, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 25, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 41, 43, 44, 45, 46, 48, 49, 50, 52, 54, 55, 57, 58, 59, 60, 61, 62, 63, 64, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 82, 83, 84, 85, 86, 88, 90, 91, 92, 93, 94, 95, 96, 98, 109, 181, 185, 188, 189, 193, 194, 199, 200, 201, 203, 205, 206, 207, 208, 209, 210, 212, 213, 217, 235, 236, 237, 240, 241, 243, 244, 245, 246, 280, 283, 288, 291, 292, 298, 299, 300, 303, 304, 305, 306, 307, 308, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 325, 326, 327, 328, 329, 333, 334, 335, 336, 337, 338, 340, 341, 342, 343, 344, 345, 346, 347, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 382, 383, 384, 385, 386, 387, 388, 389, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 406, 407, 408, 409, 412, 414, 415, 417, 418, 420, 421, 422, 423, 424, 425, 426, 427, 428, 430, 431, 432, 433, 434, 435, 436, 437, 438, 440, 441, 442, 443, 444, 445, 446 and 453. For example, Example 14 was measured to have an IC50 92 nM.
Figure imgf000400_0001
Figure imgf000400_0002
Figure imgf000401_0001
Figure imgf000402_0001
Figure imgf000403_0001
Figure imgf000404_0001
Figure imgf000405_0001
Figure imgf000406_0001
Figure imgf000407_0001
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Figure imgf000409_0001
Figure imgf000410_0001
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Figure imgf000414_0001
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Figure imgf000425_0001
Figure imgf000427_0001
Figure imgf000428_0001
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Figure imgf000430_0001
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Figure imgf000438_0001
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Figure imgf000440_0001
Figure imgf000440_0002
Figure imgf000441_0001
Figure imgf000442_0001
Figure imgf000443_0001
Figure imgf000444_0001
Figure imgf000445_0001
Figure imgf000446_0001
Figure imgf000447_0001
Figure imgf000448_0001
Figure imgf000449_0002
Figure imgf000449_0001
Figure imgf000449_0003
Figure imgf000450_0001
Figure imgf000451_0001
Figure imgf000452_0001
Figure imgf000452_0002
Figure imgf000453_0001
Figure imgf000454_0001
Figure imgf000455_0001
Figure imgf000456_0001
Figure imgf000457_0001
Figure imgf000458_0001
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Figure imgf000460_0001
Figure imgf000461_0001
Figure imgf000462_0002
Figure imgf000462_0001
Figure imgf000462_0003
Figure imgf000463_0001
Figure imgf000463_0002

Claims

1. A compound of formula (I):
Figure imgf000464_0001
(I)
wherein
R3 represents hydrogen, an optionally substituted C1-12alkyl group, an optionally substituted C2-12alkenyl group, an optionally substituted C2-12alkynyl group, an optionally substituted C6-14aryl group, an optionally substituted C3-12cycloalkyl group, an optionally substituted C3-12cycloalkenyl group, an optionally substituted C7-12polycycloalkyl group, an optionally substituted C7-12polycycloalkenyl group, an optionally substituted C5-12spirocycloalkyl group, an optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, an optionally substituted 4- to 12-membered heterocycloalkenyl group comprising 1 or 2 heteroatoms, or an optionally substituted heteroaryl ring comprising 1, 2 or 3 heteroatoms each independently selected from nitrogen, oxygen or sulphur; R4 each independently represent -CN, hydroxy, -NR6R7, -NR6SO2R7, halogen, an optionally substituted Ci-6alkyl group, an optionally substituted C3-7cycloalkyl group, an optionally substituted C2-6alkenyl group, an optionally substituted C2-6alkynyl group, an optionally substituted
Figure imgf000464_0002
group, an optionally substituted C3_6cycloalkyloxy group, an optionally substituted C2-5alkenyloxy group, an optionally substituted C2-5alkynyloxy group, an optionally substituted C1-6alkythio group, an optionally substituted Cuδalkylsulphoxo group or an optionally substituted C1-6alkylsulphonyl group, an optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 3- to 12-memberedheterocycloalkoxy group comprising 1 or 2 heteroatoms;
RN represents hydrogen, -NH2, -OH, -CN, -C=CH, -CO=O)NH2, C1-3alkyl,
C-1-3alkylamino, d-salkylthio, C1-3alkyloxy, C1-3alkylcarbonyl, -CHO, or -SO2Me p is 0, 1 or 2;
Q is
Figure imgf000465_0001
-S(O)2-NRa2Rb2, -(optionally substituted C1-3alkyl)g-NRa3Rb3,
-S(O)k-Ra8, -C(=X2)-ORa9, -ORal° or -(5- or 6-membered aromatic or heteroaromatic ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur)-Ln-R5 m; g is 0 or 1 ; k is 0, 1 or 2;
Ra represents H or an optionally substituted C1-6alkyl group, and R represents
-Ln-R5 m» or Ra and Rb together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
Rώ represents H or an optionally substituted C1-6alkyl group, and Rb2 represents
-Ln-R5 m> or R12 and Rb2 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
Ra3 represents H or an optionally substituted C1-6alkyl group, and Rb3 represents
-Ln-R5 m, -SO2NRa4RM, -C(=O)NRa5Rb5, -SO2Ra6, -C(=O)ORa7, or Ra3 and Rb3 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
Ra4 represents H or an optionally substituted C1-6alkyl group, and Rb4 represents
-Ln-R5 Oi, or Ra4 and Rb4 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
Ra5 represents H or an optionally substituted Ci-6alkyl group, and Rb5 represents
-Ln-R5 m, or Ra5 and Rb5 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms; 490
465
Ra6 represents -Ln-R5 m;
Ra7 represents -Ln-R5 m;
Ra8 represents -Ln-R5 m;
Ra9 represents -Ln-R5 m;
Ral° represents -Ln-R5 m;
L represents a linker selected from optionally substituted C2-loalkyl, optionally substituted C2-10alkenyl, optionally substituted C6-14aryl, optionally substituted
-C2-4alkyl-C6.14aryl, optionally substituted -C6-14aryl-C1-4alkyl, optionally substituted
C3-12cycloalkyl, optionally substituted C7-12polycycloalkyl group, optionally substituted C7-12polycycloalkenyl group, optionally substituted C5-12spirocycloalkyl group and optionally substituted heteroaryl comprising 1 or 2 nitrogen atoms; n is 0 or 1 m is 1 or 2
R5 represents a group selected from among hydrogen, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted piperazinylcarbonyl, optionally substituted pyrrolidinyl, optionally substituted tropenyl, optionally substituted diketomethylpiperazinyl, optionally substituted sulphoxomorpholinyl, optionally substituted sulphonylmorpholinyl, optionally substituted thiomorpholinyl, optionally substituted azacycloheptyl, optionally substituted granatane, optionally substituted oxogranatane and -NR8R9;
R6, R7 each independently represents hydrogen or an optionally substituted C1-4alkyl group;
R8, R9 each independently represents hydrogen, optionally substituted C1-6alkyl, optionally substituted -C1-4alkyl-C3-10cycloalkyl, optionally substituted
C3-10cycloalkyl, optionally substituted C6-14aryl, optionally substituted
-C1-4alkyl-C6-14aryl, optionally substituted pyranyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted C1-4alkyloxycarbonyl, optionally substituted optionally substituted C6-14arylcarbonyl, optionally substituted
C1-4alkylcarbonyl, optionally substituted C6-14arylmethyloxycarbonyl, optionally substituted C6-i4arylsulphonyl, optionally substituted C1-4alkylsulphonyl, optionally substituted C6-14aryl-C1-4alkylsulphonyl, or R8 and R9 together with the nitrogen atom to which they are attached form a 3- to 7-membered bridged or unbridged, saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
X1 is O or S;
X2 is O, S or H2;
Ar represents a 5- or 6-membered aromatic or heteroaromatic ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur; and
A1, A2 each independently represents N or CH; and wherein when Z1 is C=O, Z2 is CRcRd or NRe and Z3 is CR1R2;
R1, R2 each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
Rc, Rd each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or Rc and Rd together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
Re represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group; or optionally one of R1 and R3, or R2 and R3, or R1 and Rc, or R2 and Rd, or R1 and Re together represent a saturated or unsaturated C^alkyl bridge optionally comprising 1 heteroatom; or when Z2 is C=O, Z1 is CRβRg2 and Z3 is CR1R2;
R1, R2 each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
Rβ, Rg2 each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or RG and Rg2 together with 490
467
the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms; or optionally one of R1 and R3, or R2 and R3 together represent a saturated or unsaturated C1-4alkyl bridge optionally comprising 1 heteroatom; or when Z3 is C=O5 Z2 is CRc3Rd3 or NRe3 and Z1 is CRβRg3;
Rc3, Rd3 each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or Rc3 and Rd3 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
Re3 represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group;
Rβ, Rg3 each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or Rβ and Rg3 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms; or optionally one of Rc3 and Rβ, or Rd3 and Rg3, or Re3 and Rβ together represent a saturated or unsaturated C1-4alkyl bridge optionally comprising 1 heteroatom or when Z1 is CRfRg, Z2 is CRcRd or NRe and Z3 is CR1R2;
R1, R2 each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
Rc, Rd each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or Rc and Rd together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
Re represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group;
Rf, Rs each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or Rf and Rg together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms; or optionally one of R1 and R3, or R2 and R3, or R1 and Rc, or R2 and Rd, or R1 and Re3 together represent a saturated or unsaturated C1-4alkyl bridge optionally comprising 1 heteroatom, or pharmacologically acceptable salts thereof.
2. A compound of formula (II):
Figure imgf000469_0001
(H) wherein
R1, R2 each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
Rc, Rd each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or RQ and Rd together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
R3 represents hydrogen, an optionally substituted
Figure imgf000469_0002
group, an optionally substituted C2-i2alkenyl group, an optionally substituted C2-12alkynyl group, an optionally substituted C6.14aryl group, an optionally substituted C3-i2cycloalkyl group, an optionally substituted C3-12cycloalkenyl group, an optionally substituted C7-12polycycloalkyl group, an optionally substituted C7-12polycycloalkenyl group, an optionally substituted Cs- spirocycloalkyl group, an optionally substituted 3- to
12-menibered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 4- to 12-membered heterocycloalkenyl group comprising 1 or 2 heteroatoms, or optionally one of R1 and R3, or R2 and R3, or R1 and Rc, or R2 and Rd together represent a saturated or unsaturated C1-4alkyl bridge optionally comprising 1 heteroatom;
R4 each independently represent -CN, hydroxy, -NR6R7, -NR6SO2R7, halogen, an optionally substituted C1-6alkyl group, an optionally substituted C3-7cycloalkyl group, an optionally substituted C2-6alkenyl group, an optionally substituted C2-6alkynyl group, an optionally substituted C1-5alkyloxy group, an optionally substituted
C3-6cycloalkyloxy group, an optionally substituted C2-5alkenyloxy group, an optionally substituted C2-5alkynyloxy group, an optionally substituted C1-6alkythio group, an optionally substituted C1-6alkylsulphoxo group or an optionally substituted
C1-6alkylsulphonyl group, an optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 3- to 12-membered heterocycloalkoxy group comprising 1 or 2 heteroatoms;
RN represents hydrogen, -NH2, -OH, -CN, -C=CH, -C(K))NH2, C1-3alkyl,
C-μsalkylamino, C1-3alkylthio, C1-3alkyloxy, C1-3alkylcarbonyl, -CHO, or -SO2Me; p is 0, 1 or 2;
Q is -C(=X1)-NRaRb ) -S(O)2-NRa2Rb2, -(optionally substituted C1-3alkyl)g-NRa3Rb3,
-S(O)k-Ra8, -C(=X2)-ORa9, -ORal° or -(5- or 6-membered aromatic or heteroaromatic ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur)-Ln-R5 m; g is O or 1; k is 0, 1 or 2;
Ra represents H or an optionally substituted Ci-6alkyl group, and Rb represents
-Ln-R5 Hi, or Ra and Rb together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring'optionally comprising 1 to 2 additional heteroatoms; Ra2 represents H or an optionally substituted C1-6alkyl group, and Rb2 represents
-Ln-R5 m, or Ra2 and Rb2 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
Ra3 represents H or an optionally substituted C1-6alkyl group, and Rb3 represents
-Ln-R5 m, -SO2NRa4RM, -C(=O)NRa5Rb5, -SO2Ra6, -C(=O)ORa7, or Ra3 and Rb3 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
Ra4 represents H or an optionally substituted C1-6alkyl group, and Rb4 represents
-Ln-R5 m, or Ra4 and Rb4 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
Ra5 represents H or an optionally substituted C1-6alkyl group, and Rb5 represents
-Ln-R5Bi, or Ra5 and Rb5 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms;
Ra6 represents -Ln-R5 m;
Ra7 represents -Ln-R5 m;
Ra8 represents -Ln-R5 m;
Ra9 represents -Ln-R5 m;
Ral° represents -Ln-R5 m;
L represents a linker selected from optionally substituted C2-10alkyl, optionally substituted C2-10alkenyl, optionally substituted C6-14aryl, optionally substituted
-C2-4alkyl-C6-14aryl, optionally substituted -C^aryl-C^alkyl, optionally substituted
C3-12cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen atoms; n is 0 or 1 m is 1 or 2
R5 represents a group selected from among hydrogen, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted piperazinylcarbonyl, optionally substituted pyrrolidinyl, optionally substituted tropenyl, optionally substituted diketomethylpiperazinyl, 490
471
optionally substituted sulphoxomorpholinyl, optionally substituted sulphonylmorpholinyl, optionally substituted thiomorpholinyl, optionally substituted azacycloheptyl, optionally substituted granatanyl, optionally substituted oxogranatanyl and -NR8R9;
R6, R7 each independently represents hydrogen or an optionally substituted C1-4alkyl group;
R8, R9 each independently represents hydrogen, optionally substituted Ci-6alkyl, optionally substituted -C1-4alkyl-C3-10cycloalkyl, optionally substituted C3-1ocycloalkyl, optionally substituted C6-14aryl, optionally substituted -C1-4alkyl~C6-14aryl, optionally substituted pyranyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted C^alkyloxycarbonyl, optionally substituted optionally substituted C6-14arylcarbonyl, optionally substituted C1-4alkylcarbonyl, optionally substituted Ce-uarylmethyloxycarbonyl, optionally substituted C6-14arylsulphonyl, optionally substituted C1-4alkylsulphonyl, optionally substituted C6-14aryl-C1-4alkylsulphonyl, or R8 and R9 together with the nitrogen atom to which they are attached form a 3- to 7-membered bridged or unbridged, saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms; and Z1 is C=O or CRfRg wherein Rf, Rs each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or Rf and Rg together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms, or pharmacologically acceptable salts thereof.
3. A compound according to Claim 1 or 2 wherein RN represents C1-3alkyl.
4. A compound according to any one of Claims 1 to 3 wherein RN represents methyl or ethyl.
5. A compound according to any one of Claims 1 to 4 wherein Q represents -CC=X1VNR5R15, wherein X1 is O, or -CH2-NRa3Rb3. 02490
472
6. A compound of formula (Ha) :
Figure imgf000473_0001
(Ha) wherein
R1, R2 each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
Rc, Rd each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or Re and Rd together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
R3 represents hydrogen, an optionally substituted C^ alkyl group, an optionally substituted C2-12alkenyl group, an optionally substituted C2-12alkynyl group, an optionally substituted Cβ-uaryl group, an optionally substituted C3-12cycloalkyl group, an optionally substituted . C3.12cycloalkenyl group, an optionally substituted C7-12polycycloalkyl group, an optionally substituted C7-12polycycloalkenyl group, an optionally substituted C5-12spirocycloalkyl group, an optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally 490
473
substituted 4- to 12-membered heterocycloalkenyl group comprising 1 or 2 heteroatoms, or optionally one of R1 and R3, or R2 and R3, or R1 and RQ, or R2 and Rd together represent a saturated or unsaturated C^alkyl bridge optionally comprising 1 heteroatom;
R4 each independently represent -CN, hydroxy, -NR6R7, -NR6SO2R7, halogen, an optionally substituted C1-6alkyl group, an optionally substituted C3-7cycloalkyl group, an optionally substituted C2-6alkenyl group, an optionally substituted C2-6alkynyl group, an optionally substituted C1-5alkyloxy group, an optionally substituted
C3-6cycloalkyloxy group, an optionally substituted C2-5alkenyloxy group, an optionally substituted C2-5alkynyloxy group, an optionally substituted C1-6alkythio group, an optionally substituted C1-6alkylsulphoxo group or an optionally substituted
C1-6alkylsulphonyl group, an optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 3- to 12-membered heterocycloalkoxy group comprising 1 or 2 heteroatoms;
RN represents hydrogen, -NH2, -OH, -CN, -C=CH, -CC=O)NH2, C1-3alkyl,
C-1-3alkylamino, C1-3alkylthio, C1-3alkyloxy, C1-3alkylcarbonyl, -CHO, or -SO2Me; p is 0, 1 or 2;
L represents a linker selected from optionally substituted C2-1oalkyl, optionally substituted C2-10alkenyl, optionally substituted C6-14aryl, optionally substituted
-C2-4alkyl-C6-14aryl, optionally substituted -C6-14aryl-C1-4alkyl, optionally substituted
C3-i2cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen atoms; n is 0 or 1 m is 1 or 2
R5 represents a group selected from among hydrogen, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted piperazinylcarbonyl, optionally substituted pyrrolidinyl, optionally substituted tropenyl, optionally substituted diketomethylpiperazinyl, optionally substituted sulphoxomorpholinyl, optionally substituted sulphonylmorpholinyl, optionally substituted thiomorpholinyl, optionally substituted 490
474
azacycloheptyl, optionally substituted granatanyl, optionally substituted oxogranatanyl and -NR8R9;
R6, R7 each independently represents hydrogen or an optionally substituted C1-4alkyl group;
R8, R9 each independently represents hydrogen, optionally substituted C1-6alkyl, optionally substituted -C1-4alkyl-C3.1ocycloalkyl, optionally substituted C3-1ocycloalkyl, optionally substituted C6-i4aryl, optionally substituted -C1-4alkyl-C6-14aryl, optionally substituted pyranyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted C1-4alkyloxycarbonyl, optionally substituted optionally substituted C6-14arylcarbonyl, optionally substituted C1-4alkylcarbonyl, optionally substituted Ce-uarylmethyloxycarbonyl, optionally substituted C6-14arylsulphonyl, optionally substituted C1-4alkylsulphonyl, optionally substituted C6-14aryl-C1-4alkylsulphonyl, or R and R together with the nitrogen atom to which they are attached form a 3- to 7-membered bridged or unbridged, saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms; and Z1 is C=O or CRfRg wherein Rf, R8 each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or Rf and Rg together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms, or pharmacologically acceptable salts thereof.
7. A compound according to Claim 6 wherein Z1 is C=O or CH2.
8. A compound of formula (III) :
Figure imgf000476_0001
(III) wherein
R1, R2 each independently represents hydrogen or an optionally substituted C1-6alkyl group, or R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
Rc, Rd each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or Rc and Rd together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
R3 represents hydrogen, an optionally substituted C1-12alkyl group, an optionally substituted C2-12alkenyl group, an optionally substituted C2-12alkynyl group, an optionally substituted C6-14aryl group, an optionally substituted C3.12cycloalkyl group, an optionally substituted C3-i2cycloalkenyl group, an optionally substituted C7-12polycycloalkyl group, an optionally substituted C7-12polycycloalkenyl group, an optionally substituted C5-i2spirocycloalkyl group, an optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 4- to 12-membered heterocycloalkenyl group comprising 1 or 2 heteroatoms, or optionally one of R1 and R3, or R2 and R3, or R1 and Rc, or R2 and Rd together represent a saturated or unsaturated C1-4alkyl bridge optionally comprising 1 heteroatom;
R4 each independently represent -CN, hydroxy, -NR6R7, -NR6SO2R7, halogen, an optionally substituted C1-6alkyl group, an optionally substituted C3-7cycloalkyl group, an optionally substituted C2-6alkenyl group, an optionally substituted C2-6alkynyl group, an optionally substituted C1-5alkyloxy group, an optionally substituted C3-6cycloalkyloxy group, an optionally substituted C2-5alkenyloxy group, an optionally substituted C2-salkynyloxy group, an optionally substituted C1-6alkythio group, an optionally substituted C1-6alkylsulphoxo group or an optionally substituted C1-6alkylsulphonyl group, an optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 3- to 12-membered heterocycloalkoxy group comprising 1 or 2 heteroatoms; p is 0, 1 or 2;
L represents a linker selected from optionally substituted C2-1oalkyl, optionally substituted C2-10alkenyl, optionally substituted C6-14aryl, optionally substituted -C2-4alkyl-C6-14aryl, optionally substituted
Figure imgf000477_0001
optionally substituted C3-12cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen atoms; n is O or 1; m is 1 or 2;
R5 represents a group selected from among hydrogen, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted piperazinylcarbonyl, optionally substituted pyrrolidinyl, optionally substituted tropenyl, optionally substituted diketomethylpiperazinyl, optionally substituted sulphoxomorpholinyl, optionally substituted sulphonylmorpholinyl, optionally substituted thiomorpholinyl, optionally substituted azacycloheptyl, optionally substituted granatanyl, optionally substituted oxogranatanyl and -NR8R9;
R6, R7 each independently represents hydrogen or an optionally substituted d_4alkyl group; and R8, R9 each independently represents hydrogen, optionally substituted Ci-6alkyl, optionally substituted -C1-4alkyl-C3-10cycloalkyl, optionally substituted C3-10cycloalkyl, optionally substituted C6-Haryl, optionally substituted -Ci-4alkyl-C6-14aryl, optionally substituted pyranyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted C1-4alkyloxycarbonyl, optionally substituted optionally substituted C6-14arylcarbonyl, optionally substituted C1-4alkylcarbonyl, optionally substituted Cό-uarylmethyloxycarbonyl, optionally substituted C6-14arylsulphonyl, optionally substituted C^alkylsulphonyl, optionally substituted C6-14aryl-C1-4alkylsulphonyl, or R8 and R9 together with the nitrogen atom to which they are attached form a 3- to 7-membered bridged or unbridged, saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms, or pharmacologically acceptable salt thereof.
9. A compound according to any one of Claims 6 to 8 wherein R1 and R2 are hydrogen.
10. A compound according to Claim 9 wherein one of Rc or Rd is hydrogen.
11. A compound according to Claim 10 wherein one of Rc or R is hydrogen and the other is methyl.
12. A compound according to Claim 9 wherein Rc and Rd are methyl.
13. A compound according to Claim 9 wherein Rc and Rd together represent an ethylene bridge.
14. A compound according to Claim 9 wherein Rc and Rd may be identical or different and represent hydrogen or a C!-C6alkyl group optionally substituted by one or more substituents selected from C^alkyloxy, C1-3alkylthio, C1-SaUCyI-S(O)2, C1-3alkylamino and di- (C1-3alkyl)amino. 490
478
15. A compound according to any one of Claims 1 to 14 wherein R3 represents cyclopentyl or cyclohexyl.
16. A compound according to any one of Claims 1 to 15 wherein when p is 1, R4 represents methoxy, methyl, ethoxy, chlorine or fluorine.
17. A compound according to any one of Claims 1 to 15 wherein when p is 2, each R4 may be the same or different and selected from methoxy, methyl, ethoxy, ethyl, propargyloxy, chlorine or fluorine.
18. A compound according to any one of Claims 1 to 15 wherein when p is 2 and when each R4 is adjacent, both R4 together with the aromatic ring atoms to which they are attached form a 4- to 7-member unsaturated ring optionally comprising 1 to 2 heteroatoms.
19. A compound according to any one of Claims 1 to 18 wherein when n is 1, L represents an optionally substituted a C2-1oalkyl or an optionally substituted C3-12cycloalkyl linker.
20. A compound according to Claim 19 wherein when n is 1, L represents cyclohexyl, - C(CH3)2-CH2- or -CH2-C(CH3)2-CH2-.
21. A compound according to any one of Claims 1 to 20 wherein n is 0.
22. A compound according to any one of Claims 1 to 21 wherein m is 1 and R5 represents hydrogen, -NR8R9 or a piperidinyl, morpholinyl, pyrrolidinyl, sulphoxomorpholiny, piperazinyl, thiomorpholinyl, tropenyl, granatanyl, oxogranatanyl or azacycloheptyl each optionally substituted by one or more groups as defined for R8.
23. A compound according to Claim 22 wherein R5 represents a piperidinyl, pyrrolidinyl, or granatanyl each optionally substituted by one or more groups as defined for R8. B2007/002490
479
24. A compound according to Claims 22 or 23 wherein R represents methyl, ethyl or propyl, and/or R9 represents methyl, ethyl or propyl.
25. A compound according to Claim 8 wherein R3 represents an optionally substituted Ci-ioalkyl, optionally substituted C3-7Cy cloalkyl, optionally substituted C3-6heterocycloalkyl or optionally substituted C6-14aryl group; p is 0 or 1; R4 represents OMe, OH, Me, Et, Pr, OEt, NHMe, NH2, F, CL, Br, O-propargyl, O-butynyl, CN, SMe, NMe2, CONH2, ethynyl, propynyl, butynyl or allyl; L represents a linker selected from optionally substituted C2-i0alkyl, optionally substituted C2-10alkenyl, optionally substituted C6-14aryl, optionally substituted -C2-4alkyl-C6-14aryl, optionally substituted -C6-14aryl-C1-4alkyl, optionally substituted C3-12cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen ring atoms; n denotes O or 1; m denotes 1 or 2; R5 denotes hydrogen or a group, which is bound to L via a carbon atom, selected from among -NR8R9, piperidinyl, piperazinyl, pyrrolidinyl, piperazinylcarbonyl, tropenyl, morpholinyl, granatanyl, oxogranatanyl and azacycloheptyl each optionally substituted by one or more groups as defined for R ; R , R each independently represent hydrogen, C1-6alkyl, -C1-4alkyl-C3-1ocycloalkyl, C3-10Cy cloalkyl, C6-14aryl,
Figure imgf000480_0001
C6-14arylcarbonyl, C1-4alkylcarbonyl, Q-Harylmethyloxycarbonyl, C6-14arylsulphonyl,
Figure imgf000480_0002
or C6-14aryl-C1-4alkylsulphonyl; R1, R2 are hydrogen; Rc, Rd are each independently selected from hydrogen, Me, or Et, or Rc and Rd together represent an ethylene bridge, or pharmacologically acceptable salts thereof.
26. A compound according to Claim 25 wherein R3 represents an optionally substituted C1-10alkyl, optionally substituted C3-7cycloalkyl, optionally substituted C^όheterocycloalkyl; p is O, 1 or 2; R4 each independently represents fluoro or OMe; L represents a linker selected from optionally substituted C2-i0alkyl; n denotes O or 1; m denotes 1 or 2; R5 denotes a group selected from among -NR8R9 and piperidinyl each optionally substituted by one or more groups as defined for R8; R8, R9 each independently represent C1-6alkyl; R1, R2 are hydrogen; Rc, Rd are each independently selected from hydrogen, Me, or Et, or Rc and Rd together represent an ethylene bridge, or pharmacologically acceptable salts thereof.
27. A compound according to Claim 25 wherein wherein R3 represents an optionally substituted CMoalkyl, optionally substituted C3-7cycloalkyl, optionally substituted C3-6heterocycloalkyl; p is 0, 1 or 2; R4 each independently represents fluoro or OMe; L represents a linker selected from optionally substituted C2-10alkyl; n denotes 0 or 1; m denotes 1 or 2; R5 denotes a group selected from among -NR8R9 and pyrrolidinyl each optionally substituted by one or more groups as defined for R8; R8, R9 each independently represent C1-6alkyl; R1, R2 are hydrogen; Rc, Rd are each independently selected from hydrogen, Me, or Et, or Rc and Rd together represent an ethylene bridge, or pharmacologically acceptable salts thereof.
28. A compound according to Claim 25 wherein wherein R3 represents an optionally substituted C1-10alkyl, optionally substituted C3-7cycloalkyl, optionally substituted C3-6heterocycloalkyl; p is 0, 1 or 2; R4 each independently represents fluoro or OMe; L represents a linker selected from optionally substituted C2-10alkyl; n denotes 0 or 1 ; m denotes 1 or 2; R5 denotes a group selected from among -NR8R9 and granatanyl each optionally substituted by one or more groups as defined for R8; R8, R9 each independently represent C^alkyl; R1, R2 are hydrogen; Re, Rd are each independently selected from hydrogen, Me, or Et, or Rc and Rd together represent an ethylene bridge, or pharmacologically acceptable salts thereof.
29. A compound of formula (Ilia):
Figure imgf000481_0001
(HIa) wherein
R1, R2 each independently represents hydrogen or an optionally substituted C1-6alkyl group, or R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
Rc, Rd each independently represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group, or Rc and Rd together with the carbon atom to which they are attached form a 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms;
R3 represents hydrogen, an optionally substituted C1-12alkyl group, an optionally substituted C2-12alkenyl group, an optionally substituted C2-12alkynyl group, an optionally substituted C6-14aryl group, an optionally substituted C3-12cycloalkyl group, an optionally substituted C3-12cycloalkenyl group, an optionally substituted C7-12polycycloalkyl group, an optionally substituted C7-i2polycycloalkenyl group, an optionally substituted C5-12spirocycloalkyl group, an optionally substituted 3- to 12-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally substituted 4- to 12-membered heterocycloalkenyl group comprising 1 or 2 heteroatoms, or optionally one of R1 and R3, or R2 and R3, or R1 and Rc, or R2 and Rd together represent a saturated or unsaturated C1-4alkyl bridge optionally comprising 1 heteroatom;
R 4a R 4b ? R 4c each independentiy represent -CN, hydroxy, -NR6R7, -NR6SO2R7, halogen, an optionally substituted C1-6alkyl group, an optionally substituted C3-7cycloalkyl group, an optionally substituted C2-6alkenyl group, an optionally substituted C2-6alkynyl group, an optionally substituted Ci-5alkyloxy group, an optionally substituted C3-6cycloalkyloxy group, an optionally substituted C2-5alkenyloxy group, an optionally substituted C2-5alkynyloxy group, an optionally substituted Ci-6alkythio group, an optionally substituted C1-6alkylsulphoxo group or an optionally substituted d-βalkylsulphonyl group, an optionally substituted 3- to 12- membered heterocycloalkyl group comprising 1 or 2 heteroatoms, or an optionally 490
482
substituted 3- to 12-membered heterocycloalkoxy group comprising 1 or 2 heteroatoms; p is the number of R4a'4b'4c groups that are not hydrogen and is selected from 0, 1 or 2; L represents a linker selected from optionally substituted C2-10alkyl, optionally substituted C2-1oalkenyl, optionally substituted C6-14aryl, optionally substituted -C2-4alkyl-C6-14aryl, optionally substituted
Figure imgf000483_0001
optionally substituted C3-12cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen atoms; n is 0 or 1 ; m is 1 or 2;
R5 represents a group selected from among hydrogen, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted piperazinylcarbonyl, optionally substituted pyrrolidinyl, optionally substituted tropenyl, optionally substituted diketomethylpiperazinyl, optionally substituted sulphoxomorpholinyl, optionally substituted sulphonylmorpholinyl, optionally substituted thiomorpholinyl, optionally substituted azacycloheptyl, optionally substituted granatanyl, optionally substituted oxogranatanyl and -NR8R9;
R6, R7 each independently represents hydrogen or an optionally substituted C1-4alkyl group; and
R8, R9 each independently represents hydrogen, optionally substituted C1-6alkyl, optionally substituted -C1-4alkyl-C3-10cycloalkyl, optionally substituted C3-10cycloalkyl, optionally substituted C6-Haryl, optionally substituted -C1-4alkyl-C6-14aryl, optionally substituted pyranyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted C1-4alkyloxycarbonyl, optionally substituted optionally substituted C6_14arylcarbonyl, optionally substituted
Figure imgf000483_0002
optionally substituted Cό-Harylmethyloxycarbonyl, optionally substituted C6.14arylsulphonyl, optionally substituted C1-4alkylsulphonyl, optionally substituted C6-14aryl-C1-4alkylsulphonyl, or R8 and R9 together with the nitrogen atom to which they are attached form a 3- to 7-membered bridged or unbridged, saturated or unsaturated heterocyclic ring optionally comprising 1 to 2 additional heteroatoms,macologically acceptable salt thereof.
30. A compound according to Claim 29 wherein R3 represents an optionally substituted C1-loalkyl, optionally substituted C3-7cy cloalkyl, optionally substituted C^heterocycloalkyl; L represents a linker selected from optionally substituted C2-1oalkyl; n denotes 0 or 1 ; m denotes 1 or 2; R5 denotes a group selected from among -NR8R9 and piperidinyl each optionally substituted by one or more groups as defined for R8; R8, R9 each independently represent C1-6alkyl; R1, R2 are hydrogen; Rc, Rd are each independently selected from hydrogen, Me5 or Et, or Rc and Rd together represent an ethylene bridge; p is 0, 1 or 2; and when p is I5 R4b and R4c are hydrogen and R4a represents methoxy, methyl, ethoxy, chlorine or fluorine; and when p is 2, either R4b is hydrogen and R4a and R4° may be the same or different and selected from methoxy, methyl, ethoxy, chlorine or fluorine, or R4c is hydrogen and R4a and R4b together form a OCH2O bridge, or pharmacologically acceptable salts thereof.
31. A compound according to Claim 29 wherein R3 represents an optionally substituted C1-loalkyl, optionally substituted C3-7cycloalkyl, optionally substituted C3-6heterocycloalkyl; L represents a linker selected from optionally substituted C2-1oalkyl; n denotes 0 or 1; m denotes 1 or 2; R5 denotes a group selected from among -NR8R9 and pyrrolidinyl each optionally substituted by one or more groups as defined for R8; R8, R9 each independently represent C1-6alkyl; R1, R2 are hydrogen; Rc, Rd are each independently selected from hydrogen, Me, or Et, or Rc and Rd together represent an ethylene bridge; p is 0, 1 or 2; and when p is 1, R4b and R4c are hydrogen and R4a represents methoxy, methyl, ethoxy, chlorine or fluorine; and when p is 2, either R4b is hydrogen and R4a and R4c may be the same or different and selected from methoxy, methyl, ethoxy, chlorine or fluorine, or R4c is hydrogen and R4a and R4b together form a OCH2O bridge, or pharmacologically acceptable salts thereof.
32. A compound according to Claim 29 wherein R3 represents an optionally substituted C1-10alkyl, optionally substituted C3-7cycloalkyl, optionally substituted C3-6heterocycloalkyl; L represents a linker selected from optionally substituted C2-10alkyl; n denotes 0 or 1; m denotes 1 or 2; R5 denotes a group selected from among -NR8R9 and granatanyl each optionally substituted by one or more groups as defined for R8; R8, R9 each independently represent C1-6alkyl; R1, R2 are hydrogen; Rc, Rd are each independently selected from hydrogen, Me, or Et, or R° and Rd together represent an ethylene bridge; p is 0, 1 or 2; and when p is 1, R4b and R4c are hydrogen and R4a represents methoxy, methyl, ethoxy, chlorine or fluorine; and when p is 2, either R4b is hydrogen and R4a and R4c may be the same or different and selected from methoxy, methyl, ethoxy, chlorine or fluorine, or R4c is hydrogen and R4a and R4b together form a OCH2O bridge, or pharmacologically acceptable salts thereof.
33. A compound according to any one of Claims 25, 26, 27, 28, 30, 31 or 32 wherein R3 represents cyclopentyl or cyclohexyl.
34. A compound according to Claims 33 wherein R8 represents methyl, ethyl or propyl, and/or R9 represents methyl, ethyl or propyl.
35. A compound selected from any one of the Examples or pharmacologically acceptable salts thereof.
36. A compound selected from any one of Examples 4, 7, 26, 27, 47, 51, 53, 56, 77, 97, 99, 101, 104, 106, 108, 110, 113, 114, 135, 176, 182, 184, 191, 197, 202, 219, 234, 238, 239, 242, 269, 278, 279, 281, 282, 285, 289, 290, 293, 294, 295, 301, 302, 309, 310, 311, 330, 331, 390, 405, 411, 413, 416, 419, 429, 451, 1, 2, 3, 6, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 25, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 41, 43, 44, 45, 46, 48, 49, 50, 52, 54, 55, 57, 58, 59, 60, 61, 62, 63, 64, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 82, 83, 84, 85, 86, 88, 90, 91, 92, 93, 94, 95, 96, 98, 109, 181, 185, 188, 189, 193, 194, 199, 200, 201, 203, 205, 206, 207, 208, 209, 210, 212, 213, 217, 235, 236, 237, 240, 241, 243, 244, 245, 246, 280, 283, 288, 291, 292, 298, 299, 300, 303, 304, 305, 306, 307, 308, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 325, 326, 327, 328, 329, 333, 334, 335, 336, 337, 338, 340, 341, 342, 343, 344, 345, 346, 347, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 382, 383, 384, 385, 386, 387, 388, 389, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 406, 407, 408, 409, 412, 414, 415, 417, 418, 420, 421, 422, 423, 424, 425, 426, 427, 428, 430, 431, 432, 433, 434, 435, 436, 437, 438, 440, 441, 442, 443, 444, 445, 446 and 453, or pharmacologically acceptable salts thereof.
37. A compound selected from any one of Examples 1, 2, 3, 6, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 25, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 41, 43, 44, 45, 46, 48, 49, 50, 52, 54, 55, 57, 58, 59, 60, 61, 62, 63, 64, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 82, 83, 84, 85, 86, 88, 90, 91, 92, 93, 94, 95, 96, 98, 109, 181, 185, 188, 189, 193, 194, 199, 200, 201, 203, 205, 206, 207, 208, 209, 210, 212, 213, 217, 235, 236, 237, 240, 241, 243, 244, 245, 246, 280, 283, 288, 291, 292, 298, 299, 300, 303, 304, 305, 306, 307, 308, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 325, 326, 327, 328, 329, 333, 334, 335, 336, 337, 338, 340, 341, 342, 343, 344, 345, 346, 347, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 382, 383, 384, 385, 386, 387, 388, 389, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 406, 407, 408, 409, 412, 414, 415, 417, 418, 420, 421, 422, 423, 424, 425, 426, 427, 428, 430, 431, 432, 433, 434, 435, 436, 437, 438, 440, 441, 442, 443, 444, 445, 446 and 453, or pharmacologically acceptable salts thereof.
38. A process for preparing a compound of general formula (III),
Figure imgf000486_0001
wherein R^R5, Rc, Rd m, n, p and L are as hereinbefore defined, comprising reacting a compound of general formula (IV)
Figure imgf000487_0001
(IV) wherein R^-R3 are as hereinbefore defined and A is a leaving group, with an optionally substituted compound of general formula (V):
Figure imgf000487_0002
(V) wherein p and R4 are as hereinbefore defined; and R10 denotes OH, NH-Lm-R5 n, OMe, OEt, and when R10 denotes OH, OMe or OEt optionally after previous hydrolysis of the ester group -COR10, reacting with an amine of general formula (VI):
NH2 -Lm-R5 n
(VI) wherein R5 is as hereinbefore defined, to give a compound of formula (III).
39. A process for preparing a compound of general formula (XI),
Figure imgf000488_0001
wherein R^R5, Rc, Rd m, n, p and L are as hereinbefore defined, comprising reacting a compound of general formula (XII)
Figure imgf000488_0002
with an amine of general formula (VI):
NH2 -Lm-R5 n
(VI) wherein L and R are as hereinbefore defined.
40. A pharmaceutical composition comprising a compound of formula (I), (II), (Ha)5 (III) or (Ilia), or a pharmaceutically acceptable salt thereof, as claimed in any one claims 1 to 37 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
41. A process for the preparation of a pharmaceutical composition as claimed in claim 40 which comprises mixing a compound of formula (I), (II), (Ha), (III) or (Ilia), or a pharmaceutically acceptable salt thereof, as defined in any one of claim 1 to 37 with a pharmaceutically acceptable adjuvant, diluent or carrier.
42. A compound of formula (I), (II), (Ha), (III) or (Ilia), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 37 for use in therapy.
43. Use of a compound of formula (I), (II), (Ha), (III) or (Ilia), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 37 in the manufacture of a medicament for the treatment of cancer.
44. Use of a compound of formula (I), (II), (Ha), (III) or (Ilia), or a pharmaceutically acceptable salt thereof, as claimed in any one claims 1 to 37 in the manufacture of a medicament for modulating polo-like kinas (PIk) activity.
45. A method of treating cancer which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), (II), (Ha), (III) or (Ilia), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 37.
46. A method of modulating polo-like kinase (PIk) activity which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (Ha), (III) or (Ilia), or a pharmaceutically acceptable salt thereof, as claimed in any one claims 1 to 37.
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US7709471B2 (en) 2010-05-04
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US20080009482A1 (en) 2008-01-10
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