WO2003053958A1 - Quinazolinedione derivatives - Google Patents

Quinazolinedione derivatives Download PDF

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WO2003053958A1
WO2003053958A1 PCT/GB2002/005770 GB0205770W WO03053958A1 WO 2003053958 A1 WO2003053958 A1 WO 2003053958A1 GB 0205770 W GB0205770 W GB 0205770W WO 03053958 A1 WO03053958 A1 WO 03053958A1
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Prior art keywords
group
optionally substituted
alk
methoxy
oxazol
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PCT/GB2002/005770
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French (fr)
Inventor
Hazel Joan Dyke
Marianna Dilani Richard
Alan Findlay Haughan
Andrew Sharpe
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Celltech R & D Limited
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Priority claimed from GB0130585A external-priority patent/GB0130585D0/en
Priority claimed from GB0204137A external-priority patent/GB0204137D0/en
Application filed by Celltech R & D Limited filed Critical Celltech R & D Limited
Priority to AU2002352444A priority Critical patent/AU2002352444A1/en
Publication of WO2003053958A1 publication Critical patent/WO2003053958A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This invention relates to a series of quinazolinediones and their derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
  • IMPDH lnosine-5'-monophosphate dehydrogenase
  • NAD ⁇ -nicotinamide adenine dinucleotide
  • XMP xanthosine-5'-monophosphate
  • Guanine nucleotides are essential to the cell for RNA and DNA synthesis, intermediates in signalling pathways and as energy sources for metabolic pathways.
  • IMPDH is ubiquitous in eukaryotes, bacteria and protozoa (Y. Natsumeda & S.F. Carr, Ann. N.Y. Acad.. 696, pp. 88-93, (1993)).
  • IMPDH type I and type II form active tetramers in solution, with subunit molecular weights of 56 kDa (Y. Yamada et. al., Biochemistry, 27, pp. 2737-2745, (1988)). It is thought that type I is the predominant isoform expressed in normal cells, whilst type II is upregulated in neoplastic and replicating cells. Studies have postulated that selective inhibition of type II IMPDH could provide a therapeutic advantage by reducing potential toxicity effects caused by inhibiting the type I isoform (Pankiewicz K.W, Expert Opin. Ther. Patents 11 (7) pp 1161 -1170, (2001)).
  • IMPDH is an attractive target for selectively inhibiting the immune system without also inhibiting the proliferation of other cells.
  • MPA Mycophenolic acid
  • Kj 33 nM
  • MPA has been demonstrated to block the response of B and T-cells to mitogen or antigen (A.C. Allison et. al., Ann. N. Y. Acad. Sci.. 696, 63, (1993) ).
  • Immunosuppressants such as MPA are useful drugs in the treatment of transplant rejection and autoimmune diseases.
  • MPA is characterized by undesirable pharmacological properties, such as gastrointestinal toxicity.
  • Mycophenolate mofetil a prodrug which quickly liberates free MPA in vivo, was recently approved to prevent acute allograft rejection following kidney transplantation (i.e. renal allograft failure) and heart transplantation.
  • kidney transplantation i.e. renal allograft failure
  • heart transplantation i.e. renal allograft failure
  • Mycophenolate mofetil has also been used for the treatment of rheumatoid arthritis.
  • mycophenolate mofetil has also been described (R. Bentley, Chem. Rev.. 100, pp. 3801-3825, (2000)).
  • Mycophenolate mofetil has also been postulated to be of use for the treatment of atopic dermatitis (Grundmann-Kollman M et al, Archives of Dermatology. 137 (7), pp.
  • Nucleoside analogues such as tiazofurin, bavirin and mizoribine also inhibit IMPDH (L. Hedstrom, et. al., Biochemistry. 29, pp. 849-854, (1990) ). These nucleoside analogues are competitive inhibitors of IMPDH, but also inhibit other NAD dependant enzymes. This lack of specificity limits the therapeutic application of these compounds. New agents with improved selectivity for IMPDH would represent a significant improvement over these nucleoside analogues.
  • Mizorbine (Bredinin®) has been approved in Japan for multiple indications in transplantation and autoimmune diseases including prevention of rejection after renal transplantation, idiopathic glomerulonephritis, lupus nephritis and rheumatoid arthritis.
  • Vertex has recently disclosed a series of novel IMPDH inhibitors (WO 97/40028), of which VX-497 has been evaluated for the treatment of psoriasis.
  • IMPDH plays a role in other metabolic events. Increased IMPDH activity has been observed in rapidly proliferating human leukemic cell lines and other tumour cell lines, indicating IMPDH as a target for anti-cancer as well as immunosuppressive chemotherapy (M. Nagai et. al., Cancer Res.. 51 , pp. 3886-3890, (1991), Pankiewicz K.W., Exp. Opin. Ther. Patents. 11 , pp. 1161-1170, (2001) ). IMPDH has also been shown to play a role in the proliferation of smooth muscle cells, indicating that inhibitors of IMPDH may be useful in preventing restenosis or other hyperproliferative vascular diseases (CR. Gregory et. al., Transplantation. 59, pp. 655-61 , (1995); PCT publication WO 94/12184; and PCT publication WO 94/ 01105).
  • IMPDH has been shown to play a role in viral replication in some virus-infected cell lines. (S.F. Carr, J. Biol. Chem.. 268, pp. 27286-27290, (1993) ). VX-497 is currently being evaluated for the treatment of hepatitis C in humans. Thus, there remains a need for potent IMPDH inhibitors with improved pharmacological properties. Such inhibitors would have therapeutic potential as immunosuppressants, anti-cancer agents, anti-inflammatory agents, antipsoriatic and anti-viral agents.
  • WO98/56770 generally discloses the synthesis of a class of substituted quinazolinediones. However, these are not disclosed for use as IMPDH inhibitors.
  • the present inventors disclose new potent IMPDH inhibitors based on substituted quinazolinedione derivatives.
  • X and Y which may be the same or different, is each an O or S atom;
  • R 1 is an aliphatic, cycloaliphatic or cycloalkyl-alkyl- group;
  • R 2 is an optionally substituted heteroaromatic group;
  • R 3 is the group -Alk 1 -L 1 -Alk 2 -R 4 in which Alk 1 is a covalent bond or an optionally substituted aliphatic or heteroaliphatic chain, L 1 is a covalent bond or a linker atom or group, Alk 2 is a covalent bond or an optionally substituted aliphatic or heteroaliphatic chain and
  • R 4 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group; and the salts, solvates, hydrates, tautomers, isomers or N-oxides thereof.
  • certain compounds of formula (1 ) may exist as geometric isomers (E or Z isomers).
  • the compounds may also have one or more chiral centres, and exist as enantiomers or diastereomers.
  • the invention is to be understood to extend to all such geometric isomers, enantiomers, diastereomers and mixtures thereof, including racemates.
  • Formula (1) and the formulae hereinafter are intended to represent all individual isomers and mixtures thereof, unless stated or shown otherwise.
  • Quinazolinediones may also exist as tautomers, one possible example is illustrated below:
  • the compounds of the invention may be administered in a pharmaceutically acceptable pro-drug form, for example, as a protected carboxylic acid derivative, e.g. as an acceptable ester.
  • the pro-drugs may be converted in vivo to the active compounds of formula (1), and the invention is intended to extend to such pro-drugs.
  • Such prodrugs are well known in the literature, see for example International Patent Application No. WO 00/23419, Bodor N. (Alfred Benson Symposium, 1982, 17, 156-177), Singh G. et al (J. Sci. Ind. Res., 1996, 55, 497-510) and Bundgaard H. (Design of Prodrugs, 1985, Elsevier, Amsterdam).
  • aliphatic group is intended to include optionally substituted straight or branched C M oalkyl, e.g. C 1 - 6 alkyl, C 2 - ⁇ oalkenyl e.g. C ⁇ -ealkenyl or C- 2 - 10 alkynyi e.g. C 2 - 6 alkynyl groups.
  • Optional substituents when present on these groups include those optional substituents mentioned hereinafter.
  • alkyl whether present as a group or part of a group includes straight or branched d-ioalkyl groups, for example Ci- ⁇ alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl or neopentyl groups.
  • Optional substituents when present on those groups include those optional substituents mentioned hereinafter.
  • alkenyl or “alkynyi” are intended to mean straight or branched C 2 - 10 alkenyl or C- 2 - ⁇ oalkynyl groups such as or C 2 - 6 alkynyl groups such as -CHCH 2 , -CHCHCH 3 , -CH 2 CHCHCH 3 , -CCH, -CH 2 CCH and -CH 2 CCCH 3 groups. Such groups may be substituted by those optional substituents mentioned hereinafter.
  • aliphatic groups include optionally substituted C ⁇ -6 alkyl groups such as -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 )CH 2 CH 3 , -CH 2 CH(CH 3 ) 2> - CH 2 C(CH 3 ) 3 , -C(CH 3 ) 3 , -(CH 2 ) 4 CH 3 , -(CH 2 ) 5 CH 3 , or or C 2 - 6 alkynyl groups such as -CHCH 2 , -CHCHCH 3 , -CH 2 CHCH 2 , -CHCHCH 2 CH 3 , -CH 2 CHCHCH 3 , -(CH 2 ) 2 CHCH 2 , -CCH, -CCCH 3 , -CH 2 CCH, -CCCH 2 CH 3 , -CH 2 CCCH 3
  • aliphatic chain is intended to include those alkyl, alkenyl or alkynyi groups as just described where a terminal hydrogen atom is replaced by a covalent bond to give a divalent chain.
  • aliphatic chains include optionally substituted Ci- 6 alkylene chains such as -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -,-(CH 2 ) 2 CH 2 -, -(CH 2 ) 3 CH 2 -,
  • More particular examples include optionally substituted d- 3 alkylene chains selected from -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -C(CH 3 ) 2 - and -CH 2 CH(CH 3 )- chains.
  • Heteroaliphatic chains represented by Alk 1 or Alk 2 in the compounds of formula (1) include the aliphatic chains just described but with each additionally containing one, two, three or four heteroatoms or heteroatom-containing groups.
  • Particular heteroatoms or groups include atoms or groups L 3 where L 3 is a linker atom or group.
  • L 3 is a linker atom or group.
  • Each L 3 atom or group may interrupt the aliphatic group, or may be positioned at its terminal carbon atom to connect the group to an adjoining atom or group.
  • Particular examples include optionally substituted -L 3 CH 2 -, -CH 2 L 3 -, -L 3 CH(CH 3 )-, -CH(CH 3 )L 3 -, -CH 2 L 3 CH 2 -, -L 3 CH 2 CH 2 -, -L 3 CH 2 CH(CH 3 )-, -CH(CH 3 )CH 2 L 3 -, -CH 2 CH 2 L 3 -, -CH 2 L 3 CH 2 CH 2 -, -CH 2 L 3 CH 2 CH 2 L 3 -, -(CH 2 ) 2 L 3 CH 2 -, -(CH 2 ) 3 L 3 CH 2 -, -L 3 (CH 2 ) 2 CH 2 -, -L 3 CH 2 CHCH-, -CHCHCHCH 2 L 3 -, -(CH 2 ) 2 L 3 CH 2 -, -(CH 2 ) 3 L 3 CH 2 -, -L 3 (CH 2 ) 2 CH 2 -, -
  • L 3 When L 3 is present in heteroaliphatic chains as a linker atom or group it may be any divalent linking atom or group. Particular examples include -O- or -S- atoms or -C(O)-, -C(S)-, -S(O)-, -S(0) 2 -, -C(O)0-, -OC(O)-, -N(R 5 )- [where R 5 is a hydrogen atom or a straight or branched C h alky!
  • cycloaliphatic group includes optionally substituted non-aromatic cyclic or multicyclic, saturated or partially saturated C 3- ⁇ o ring systems, such as, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, adamantyl, norbomyl, norbomenyl, bicyclo[2.2.1]heptanyl or bicyclo[2.2.1]heptenyl.
  • Particular examples include optionally substituted C 3-6 cycloalkyl ring systems such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
  • Optional substituents present on those groups include those substituents mentioned hereinafter.
  • cycloalkyl-alkyl- group refers to a C ⁇ -6 alkyl group (as described herein) where a terminal hydrogen atom is replaced by a C3-6 cycloalkyl ring (as described herein). Examples include -(CH 2 ) ⁇ -6 -cyclopropyl, -(CH 2 ) 1-6 - cyclobutyl, -(CH 2 ) ⁇ -6 -cyclopentyl or -(CH 2 ) ⁇ - 6 -cyclohexyl.
  • heterocycloaliphatic group refers to an optionally substituted 3 to 10 membered saturated or partially saturated monocyclic or saturated or partially saturated multicyclic hydrocarbon ring system containing one, two, three or four L 2 linker atoms or groups.
  • L 2 atoms or groups include -O- or -S- atoms or -C(O)-, -C(0)O-, -OC(O)-, -C(S)-,
  • Optional substituents present on the heterocycloaliphatic groups include those substituents mentioned hereinafter.
  • heterocycloaliphatic groups include optionally substituted cyclobutanonyl, cyclopentanonyl, cyclohexanonyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolinyl, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, oxazolidinyl, oxazolidinonyl, dioxolanyl, e.g. 1 ,3- dioxolanyl, imidazolinyl, e.g.
  • 2-imidazolinyl imidazolidinyl, pyrazolinyl, e.g. 2- pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, e.g.
  • Cycloaliphatic groups may be linked to the remainder of the compound of formula (1) by any available ring carbon atom.
  • Heterocycloaliphatic groups may be linked to the remainder of the compound of formula (1) by any available ring carbon or, where available, ring nitrogen atom.
  • R 4 in compounds of formula (1) is an optionally substituted heterocycloaliphatic or cycloaliphatic ring, these may optionally be fused to an optionally substituted monocyclic C 6-12 aromatic group, such as phenyl or an optionally substituted monocyclic C 1-9 heteroaromatic group, such as a 5 or 6 membered heteroaromatic group, containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • the optional substituents which may be present on the aliphatic, alkyl, alkenyl, alkynyi, cycloaliphatic or heterocycloaliphatic groups, described above and generally herein include one, two, three or more substituents, which each may be the same or different, selected from halogen atoms, or alkoxy, haloalkyl, haloalkoxy, hydroxy (-OH), thiol (-SH), alkylthio, amino(-NH 2 ), substituted amino, optionally substituted C 6-12 arylamino, -CN, -C0 2 H, -CO 2 R 6 (where R 6 is an optionally substituted C- ⁇ -6 alkyl group), -SO 3 H, -SOR 7 (where R 7 is a C 1 - 6 alkyl group) -SO 2 R 7 , -S0 3 R 7 , -OC0 2 R 7 , -C(0)H, -C(O)R 7 , -OC
  • the optional substituents which may be present on aliphatic or heteroaliphatic chains represented by Alk 1 or Alk 2 include one, two, three or more substituents where each substituent may be the same or different and is selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or -OH, -CN,
  • C 1-6 alkyl group e.g -CO 2 CH 3 or -CO 2 C(CH 3 ) 3 ; -CONHR 11 , e.g. -CONHCH 3 ; -CON(R 11 ) 2 , e.g. -CON(CH 3 ) 2 ; -COR 11 , e.g. -COCH 3 ; C ⁇ -6 alkoxy, e.g. methoxy or ethoxy; haloCi- ⁇ alkoxy, e.g. trifluoromethoxy or difluoromethoxy; thiol (-SH); -S(0)R 11 , e.g.
  • -S(O)CH 3 ; -S(O) 2 R 11 e.g. -S(0) 2 CH 3 ; C ⁇ -6 alkylthio e.g. methylthio or ethylthio; amino; -NHR 11 , e.g. -NHCH 3 or -N(R 11 ) 2 , e.g.
  • L 1 is present in compounds of formula (1) as a linker atom or group it may be any such atom or group as hereinbefore described in relation to L 3 linker atoms and groups.
  • Alk 1 in compounds of formula (1) is a covalent bond then L 1 , when present, is a -C(O)-, -C(S)-, -S(0) 2 -, -CON(R 5 )-, -CSN(R 5 )- or -S(0) 2 N(R 5 )- group, where R 5 is as herein defined.
  • R 5 , R 5a , R 7 , R 8 , R 9 or R 10 is present as a C ⁇ -6 alkyl group it may be a straight or branched C ⁇ - 6 alkyl group e.g. a C ⁇ - 3 alkyl group such as methyl, ethyl or /-propyl.
  • Optional substituents which may be present on R 11 include for example one, two or three substituents which may be the same or different selected from fluorine, chlorine, bromine or iodine atoms or hydroxy or C ⁇ - 6 alkoxy e.g. methoxy or ethoxy groups.
  • halogen atom is intended to include fluorine, chlorine, bromine or iodine atoms.
  • haloalkyl is intended to include the alkyl groups just mentioned substituted by one, two or three of the halogen atoms just described. Particular examples of such groups include -CF 3) -CCI 3 , -CHF 2 , -CHCI 2 , -CH 2 F, and -CH 2 CI groups.
  • alkoxy as used herein is intended to include straight or branched C M0 alkoxy for example C 1-6 alkoxy such as methoxy, ethoxy, ⁇ -propoxy, /-propoxy and f-butoxy.
  • "Haloalkoxy” as used herein includes any of those alkoxy groups substituted by one, two or three halogen atoms as described above. Particular examples include -OCF 3 , -OCCI 3 , -OCHF 2 , -OCHCI 2 , -OCH 2 F and -OCH 2 CI groups.
  • alkylthio is intended to include straight or branched C 1-10 alkylthio, e.g. C 1-6 alkylthio such as methylthio or ethylthio groups.
  • aromatic group and "aryl group” are intended to include for example optionally substituted monocyclic ring C 6-12 aromatic groups, such as phenyl, or bicyclic fused ring C 6-12 aromatic groups, such as, 1- or 2-naphthyl groups.
  • heteroaromatic group and “heteroaryl group” are intended to include for example optionally substituted C- ⁇ -9 heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulfur or nitrogen atoms (or oxidised versions thereof).
  • the heteroaromatic groups may be for example monocyclic or bicyclic fused ring heteroaromatic groups.
  • Monocyclic heteroaromatic groups include for example five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulfur or nitrogen atoms.
  • Bicyclic heteroaromatic groups include for example eight- to thirteen- membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • Each of these aromatic or heteroaromatic groups may be optionally substituted by one, two, three or more R 12 atoms or groups as defined below.
  • monocyclic ring heteroaromatic groups of this type include pyrrolyl, furyl, thienyl, imidazolyl, N-C 1-6 alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, triazinyl, pyridyl-N-oxide, dihydropyrazolonyl or imidazolonyl.
  • bicyclic ring heteroaromatic groups of this type include benzofuryl, benzothienyl, benzotriazolyl, indolyl, indazolinyl, benzimidazolyl, imidazo[1 ,2-a]pyridyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzopyranyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]-pyridyl, quinolinyl, isoquinolinyl or phthalazinyl.
  • R 2 or R 4 heteroaromatic groups may be attached to the remainder of the compound of formula (1) by any carbon or hetero e.g. nitrogen atom as appropriate.
  • Optional substituents which may be present on the aromatic or heteroaromatic groups include one, two, three or more substituents, each selected from an atom or group R 12 in which R 12 is -R 12a or -Alk 3 (R 12a ) f , where R 12a is a halogen atom, or an amino (-NH 2 ), substituted amino, nitro, cyano, hydroxyl (-OH), substituted hydroxyl, amidino, formyl, carboxyl (-CO 2 H), esterified carboxyl, thiol (-SH), substituted thiol, -COR 13 [where R 13 is an -Alk 3 (R 1 a ) f , heterocycloaliphatic, cycloaliphatic, aryl or heteroaryl group], -CSR 13 , -S0 3 H, -SOR 13 , -S0 2 R 13 , -S0 3 R 13 , -SO 2 NH 2 , -S
  • Alk 3 is a straight or branched C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene chain, optionally interrupted by one, two or three -O- or -S- atoms or -S(O) g - [where g is an integer 1 or 2] or -N(R 14 )- groups; and f is zero or an integer 1 , 2 or 3. It will be appreciated that when two R 13 or R 14 groups are present in one of the above substituents, the R13 or R groups may be the same or different.
  • t f is an integer 1 , 2 or 3, it is to be understood that the substituent or substituents R 12a may be present on any suitable carbon atom in -Alk 3 . Where more than one R 12a substituent is present these may be the same or different and may be present on the same or different atom in -Alk 3 . Clearly, when f is zero and no substituent R 12a is present the chain represented by Alk 3 becomes a corresponding group.
  • R 1 a is a substituted amino group it may be for example a group -NHR 13 [where R 13 is as defined above] or a group -N(R 13 ) 2 wherein each R 13 group is the same or different.
  • R 1 a is a substituted hydroxyl or substituted thiol group it may be for example a group -OR 13 or a -SR 13 group respectively.
  • Esterified carboxyl groups represented by the group R 12a include groups of formula -CO 2 Alk 4 wherein Alk 4 is an optionally substituted C 1 - 6 alkyl group.
  • Alk 3 is present in or as a substituent it may be for example a methylene, ethylene, n-propylene, /-propylene, n-butylene, /-butylene, s-butylene, t- butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three -O- or -S-, atoms or -S(O)-, -S(0) 2 - or -N(R 15 )- groups.
  • f is the integer 1
  • 2 or 3 more particular examples include C ⁇ -3 alkylene chains, especially -CH 2
  • each may be for example an optionally substituted 2- or 3-pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperazinyl, imidazolinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, oxazolidinyl or thiazolidinyl group.
  • Het 2 may represent for example, an optionally substituted cyclopentyl or cyclohexyl group.
  • Optional substituents which may be present on -NHet 1 or -Het 2 include those substituents described above in relation to aromatic groups.
  • Particularly useful atoms or groups represented by R 12 include fluorine, chlorine, bromine or iodine atoms, or C -6 alkyl, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl, optionally substituted phenyl, pyridyl, pyrimidinyl, pyrrolyl, furyl, thiazolyl, thienyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl or piperidinyl, C ⁇ ehydroxyalkyl, e.g.
  • carboxyC 1-6 alkyl e.g. carboxyethyl, C -6 alkylthio e.g. methylthio or ethylthio, carboxyC 1-6 alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3- carboxypropylthio, C 1-6 alkoxy, e.g. methoxy or ethoxy, hydroxyC ⁇ alkoxy, e.g.
  • 2-hydroxyethoxy optionally substituted phenoxy, pyridyloxy, thiazolyoxy, phenylthio or pyridylthio, C 5-7 cycloalkoxy, e.g. cyclopentyloxy, haloC ⁇ alkyl, e.g. trifluoromethyl, haloC 1-6 alkoxy, e.g. thfluoromethoxy, C 1-6 alkylamino, e.g. methylamino or ethylamino, amino (-NH2), aminoC 1-6 alkyl, e.g. aminomethyl or aminoethyl, C 1-6 dialkylamino, e.g.
  • aminoC 1-6 alkylamino e.g. aminoethylamino, Het 1 NC ⁇ - 6 alkylamino e.g. morpholinopropylamino, C 1-6 alkylaminoC 1-6 alkyl, e.g. ethylaminoethyl, C 1-6 dialkylaminoC 1-6 alkyl, e.g. diethylaminoethyl, aminoC 1-6 alkoxy, e.g. aminoethoxy, C 1-6 alkylaminoC 1-6 alkoxy, e.g.
  • methylaminoethoxy C 1-6 dialkylaminoCi- ⁇ alkoxy, e.g. dimethylaminoethoxy, diethylaminoethoxy, diisopropylaminoethoxy, or dimethylaminopropoxy, hydroxyC 1-6 alkylamino e.g. hydroxyethylamino, imido, such as phthalimido or naphthalimido, e.g. 1 ,8- naphthalimido, nitro, cyano, amidino, formyl [HC(O)-], carboxyl (-C0 2 H), -C ⁇ 2 Alk 4 [where Alk 4 is as defined above], C-
  • C 1-6 alkylaminosulphonyl e.g. methylamino-sulphonyl or ethylaminosulphonyl
  • C 1-6 dialkylaminosulphonyl e.g. dimethyl-aminosulphonyl or diethylaminosulphonyl, optionally substituted phenylamino-sulphonyl, carboxamido (-CONH 2 )
  • C 1-6 alkylaminocarbonyl e.g. methylamino-carbonyl or ethylaminocarbonyl
  • C -6 dialkylaminocarbonyl e.g.
  • dimethylaminocarbonylamino or diethyl- aminocarbonylamino C 1-6 alkylaminocabonylC 1-6 alkylamino, e.g. methylamino- carbonylmethylamino, aminothiocarbonylamino, C 1-6 alkylaminothiocarbonyl- amino, e.g. methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C ⁇ . 6 dialkylaminothiocarbonylamino, e.g.
  • Ci- ⁇ alkyl- sulphonylamino e.g. methylsulphonylamino or ethylsulphonylamino
  • C 1-6 dialkyl sulphonylamino e.g.
  • dimethylsulphonylamino or diethylsulphonyl-amino optionally substituted phenylsulphonylamino, aminosulphonylamino (-NHSO 2 NH 2 ), C ⁇ alkylaminosulphonylamino, e.g. methylamino sulphonylamino or ethylaminosulphonylamino, C 1-6 dialkylamino sulphonylamino, e.g. dimethylaminosulphonylamino or diethylamino sulphonylamino, optionally substituted morpholinesulphonylamino or morpholinesulphonylC ⁇ .
  • two adjacent R 12 substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C ⁇ alkylenedioxy group such as methylenedioxy or ethylenedioxy or a C 3 - 6 cycloalkyl or 3-10 membered monocylic heterocycloaliphatic group as defined herein.
  • a cyclic group such as a cyclic ether, e.g. a C ⁇ alkylenedioxy group such as methylenedioxy or ethylenedioxy or a C 3 - 6 cycloalkyl or 3-10 membered monocylic heterocycloaliphatic group as defined herein.
  • R 12 substituents are present, these need not necessarily be the same atoms and/or groups. In general, the substituent(s) may be present at any available ring position in the aromatic or heteroaromatic group.
  • Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.
  • Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isothionates, arylsulphonates, e.g. p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
  • Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
  • Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
  • optionally substituted alkyl groups present in ester groups of formulae -C0 2 R 6 and -C0 2 Alk 4 include C ⁇ -6 alkyl groups as herein described, in particular C ⁇ -3 alkyl groups.
  • Optional substituents, which may be present on these alkyl groups include optionally substituted cycloaliphatic, aromatic or heteroaromatic groups as herein defined.
  • Particular examples include optionally substituted C 3 - 6 cycloalkyl wherein the optional substituents include for example one, two or three substituents which may be the same or different selected from fluorine, chlorine, bromine or iodine atoms or hydroxy or Ci-e alkoxy e.g.
  • substituents include for example one, two or three substituents which may be the same or different selected from fluorine, chlorine, bromine, straight or branched Ci- ⁇ alkyl, methoxy, OCF 3 , OCF 2 H, CF 3 , CN, NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CO 2 CH 3) C0 2 CH 2 CH 3 , -CO 2 C(CH3) 3) or -COCH 3 , -NHCOCH3, -N(CH 3 )COCH 3 or CO 2 H.
  • One useful group of compounds of the invention has the formula (1) wherein both X and Y is each a S atom.
  • a particularly preferred group of compounds has the formula (1) wherein X is an O atom and Y is a S atom.
  • Another preferred group of compounds has the formula (1) wherein both X and Y is each an O atom.
  • Examples of aliphatic groups, which may represent R 1 include C ⁇ -6 alkyl groups as herein described. More particular examples include C ⁇ -3 alkyl groups, such as -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 or -CH(CH 3 )CH 3 .
  • Examples of cycloaliphatic groups which may represent R 1 include C 3-6 cycloalkyl groups, such as those described previously.
  • cycloalkyl-alkyl- groups which may represent R 1 include C ⁇ -3 alkyl groups (as described herein) where a terminal hydrogen atom is replaced by a C 3-6 cycloalkyl ring (as described herein), for example, cyclopropylCH 2 -.
  • R 1 is in particular a Ci-e alkyl group. Especially preferred is when R 1 is a C ⁇ -3 alkyl group. Most especially preferred is when R 1 is a methyl group.
  • R 1 is in particular a haloalkyl group. Especially preferred is when R 1 is a CHF 2 or CH 2 F group.
  • a particularly preferred group of compounds of the invention has the formula (1) wherein R 2 is an optionally substituted monocyclic heteroaromatic group, especially a five-membered heteroaromatic group containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • Particular preferred heteroaromatic groups which may represent R 2 include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, N-C 1-6 alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl or pyrazolyl.
  • R 2 is an oxazolyl group.
  • R 3 is preferably represented by the groups -Alk 1 - L 1 -Alk 2 -R 4 , -Alk 1 -L 1 -R 4 , -Alk 1 -R 4 , -L 1 -Alk 2 -R 4 , -L 1 -R 4 or -R 4 wherein Alk 1 , L 1 , Alk 2 and R 4 are as herein defined.
  • a particularly preferred group of compounds of the invention has the formula (1) wherein R 3 is the group -Alk 1 -L 1 -R 4 .
  • Another group of compounds of the invention has the formula (1) wherein R 3 is the group -Alk 1 -L 1 -Alk 2 -R 4 .
  • Alk 1 is a covalent bond or an optionally substituted aliphatic chain, in particular a C ⁇ -6 alkylene chain, especially an optionally substituted -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 - or -CH 2 CH(CH 3 )- chain, most especially a C ⁇ -3 alkylene chain such as -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
  • Alk 2 when present in compounds of formula (1), is preferably a C ⁇ -3 alkyl chain as defined herein.
  • One particular group of compounds of the invention has the formula (1 ) wherein Alk 2 is a covalent bond.
  • L 1 when present in compounds of formula (1), include -O- or -S- atoms or -C(0>, -C(S)-, -S(O)-, -S(O) 2 -, -C(0)0-, -OC(O)-, -N(R 5 )- [where R 5 is as defined hereinbefore], -CON(R 5 )-, -CSN(R 5 )-, -N(R 5 )CO-, -N(R 5 )CS-, -S(0) 2 N(R 5 )- or -N(R 5 )S(O) 2 - groups.
  • R 5 is especially a hydrogen atom or a C ⁇ -3 alkyl group, particularly a methyl group.
  • R 4 in one particular group of compounds of formula (1 ), is a hydrogen atom or an optionally substituted C 3-6 cycloalkyl, 3 to 10 membered saturated monocyclic heterocycloaliphatic, especially 3 to 6 membered, phenyl or 5 to 6 membered heteroaromatic group.
  • More particular examples include a hydrogen atom or an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, ⁇ /-C ⁇ - 6 alkylpiperazinyl, especially N- methylpiperazinyl, ⁇ /-C ⁇ -6 alkylpyrrolidinyl, especially ⁇ /-methylpyrrolidinyl, N- Ci- 6 alkylpiperidinyl, especially ⁇ /-methylpiperidinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrrolyl, furyl, thienyl, imi
  • R 3 is the group -Alk 1 -L 1 -R 4 in which Alk 1 is an optionally substituted aliphatic chain, L 1 is a covalent bond and R 4 is a hydrogen atom.
  • Alk 1 in compounds of this type preferably forms an optionally substituted straight or branched C ⁇ -6 alkyl chain such as those as herein defined, especially optionally substituted -CH 2 -, -CH 2 CH 2 -, -(CH 2 ) 2 CH 2 -, -(CH 2 ) 3 CH 2 - or -CH 2 C(CH 3 ) 2 -.
  • Optional substituents which may be present on these groups include those as herein defined for Alk 1 substituents, especially -CN, -C0 2 H, -CO 2 R 11 [where R 11 is as herein defined] -CONHR 11 , -CON(R 11 ) 2 , -COR 11 , C ⁇ -6 alkoxy, particularly methoxy or ethoxy; haloC ⁇ -6 alkoxy, particularly trifluoromethoxy or difluoromethoxy; -S(O)R 11 , -S(O) 2 R 11 , amino, -NHR 11 or -N(R 11 ) 2 , groups.
  • R 11 is in particular a C ⁇ -3 alkyl group.
  • Alk 1 is an optionally substituted -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 - chain and the optional substituent is a -NH(CH 3 ) or -N(CH 3 ) 2 group, especially a -N(CH 3 ) 2 group.
  • Further preferred substituents include -CN, -CO 2 H, -C0 2 CH 3 , -CO 2 CH 2 CH 3 , -C0 2 C(CH 3 ) 3 , -CONH 2 , -CONHCH 3 or -CON(CH 3 ) 2 .
  • R 3 in another particular group of compounds of this type is a -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 or - CH 2 C(CH 3 ) 3 group, especially a -CH 3 group.
  • R 3 is the group -Alk 1 -L 1 -R 4 in which Alk 1 is an optionally substituted aliphatic chain, L 1 is a covalent bond and R 4 is an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group especially an optionally substituted heterocycloaliphatic, aromatic or heteroaromatic group.
  • Alk 1 in compounds of this type is in particular a C ⁇ -3 alkyl chain, especially -CH 2 -, CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
  • R 4 in compounds of this type is especially an optionally substituted 3-10 membered saturated monocyclic heterocycloaliphatic, phenyl or monocyclic heteroaromatic group.
  • Particular R 4 examples include optionally substituted azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, ⁇ /-C 1-6 alkylpiperazinyl, especially ⁇ /-methylpiperazinyl, ⁇ /-C ⁇ - 6 alkylpyrrolidinyl, especially ⁇ /-methylpyrrolidinyl, ⁇ /-C1-6 alkylpiperidinyl, especially N- methylpiperidinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrrolyl
  • R 4 is a morpholinyl, pyrrolidinonyl, ⁇ /-methylpiperazinyl, tetrahydropyranyl, imidazolyl, pyridyl, pyrrolidinyl, pyrazolyl, piperidinyl or N- methylpyrrolidinyl group.
  • R 3 in another group of compounds of formula (1) is the group -Alk 1 -L 1 -R 4 in which Alk 1 is a covalent bond or an optionally substituted aliphatic chain, L 1 is a linker group and R 4 is an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group.
  • L 1 in compounds of this type is especially a -C(O)-, -C(S)- or -S(0) 2 group or a -CON(R 5 )- or - N(R 5 )CO- group.
  • R 4 is an optionally substituted phenyl or monocyclic heteroaromatic group, especially a 5 to 6 membered heteroaromatic group.
  • R 4 is in particular an optionally substituted phenyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl group.
  • R 3 is the group -Alk 1 -L 1 -Alk 2 -R 4 in which Alk 1 is an optionally substituted aliphatic chain, L 1 is a linker atom or group, Alk 2 is a covalent bond or an optionally substituted aliphatic or heteroaliphatic chain and R 4 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group.
  • Alk 1 in compounds of this type preferably forms an optionally substituted straight or branched C ⁇ -6 alkylene chain such as those as herein defined, especially optionally substituted -CH 2 -, -CH 2 CH 2 -, -(CH 2 ) 2 CH 2 -, -(CH 2 ) 3 CH 2 - or -CH 2 C(CH 3 ) 2 -;
  • L 1 is preferably -O-, -C(O)-, -C(S)-, -S(O) 0 - 2 -, -N(R 5 )- [where R 5 is a hydrogen atom or a straight or branched C 1 - 6 alkyl group, especially methyl], -CON(R 5 )-, -CSN(R 5 )-, -N(R 5 )CO-, -N(R 5 )CS-, -S(0) 2 N(R 5 )- or -N(R 5 )S(O) 2 -;
  • Alk 1 is most preferably a C ⁇ -3 alkylene chain, especially -CH 2 -, CH 2 CH 2 - or -CH 2 CH 2 CH 2 -; L 1 is most preferably -O-, - N(R 5 )-, -CON(R 5 )- or -N(R 5 )CO- [where R 5 is especially a hydrogen atom or a methyl group] and Alk 2 is most preferably a covalent bond or an optionally substituted C ⁇ - 3 alkylene chain, especially -CH 2 -, CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
  • Optional substituents which may in particular be present on Alk 2 include -CN, -C0 2 H, -C0 2 R 11 [where R 11 is as herein defined] -CONHR 11 , -CON(R 11 ) 2 , -COR 11 , d- ⁇ alkoxy, particularly methoxy or ethoxy; haloC ⁇ . 6 alkoxy, particularly trifluoromethoxy or difluoromethoxy; -S(O)R 11 , -S(O) 2 R 11 , amino, -NHR 11 or -N(R 11 ) 2 , groups.
  • R 11 is in particular a C 1-3 alkyl group.
  • One group of optional substituents which may be present on cycloaliphatic or heterocycloaliphatic groups in compounds of formula (1) and in particular on the group R 4 are one, two, three or more groups selected from Ci- 3 alkoxy, OCF 3 , OCF 2 H, CF 3 , Ci -3 alkylthio, -CN, NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , C0 2 CH 3 , CO 2 CH 2 CH 3 , -CO 2 C(CH 3 ) 3 , or -COCH 3 , -NHCOCH 3 , -N(CH 3 )COCH 3> CO 2 H or optionally substituted straight or branched C 1-3 alkyl, wherein the optional alkyl substituent is in particular a CN, C ⁇ -3 alkoxy, NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCH 3 , CON(CH 3 )
  • One group of optional substituents which may be present on aromatic or heteroaromatic groups in compounds of formula (1) and in particular in R 4 aromatic or heteroaromatic groups, are one, two, three or more atoms or groups selected from fluorine, chlorine, bromine, straight or branched C ⁇ -6 alkyl, methoxy, OCF 3 , OCF 2 H, CF 3 , CN, NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2> C0 2 CH 3 , C0 2 CH 2 CH 3 , -CO 2 C(CH 3 ) 3 , or -COCH 3 , - NHCOCH 3 , -N(CH 3 )COCH 3 , -SCH 3 , -SO 2 CH 3 , C0 2 H or optionally substituted morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, wherein the optional substituent is
  • Particular compounds of the invention include:
  • Compounds of formula (1) are potent inhibitors of IMPDH.
  • the ability of the compounds to act in this way may be simply determined by employing tests such as those described in the Examples hereinafter.
  • the compounds of the invention may be used in the treatment of IMPDH- associated disorders.
  • the invention extends to such a use and in general to the use of the compounds of formula (1) for the manufacture of a medicament for treating such diseases and disorders.
  • IMPDH-associated disorders refers to any disorder or disease state in which inhibition of the enzyme IMPDH (inosine monphosphate dehydrogenase, EC1.1.1.205, of which there are presently two known isozymes referred to as IMPDH type 1 and IMPDH type 2) would modulate the activity of cells (such as lymphocytes or other cells) and thereby ameliorate or reduce the symptoms or modify the underlying cause(s) of that disorder or disease. There may or may not be present in the disorder or disease an abnormality associated directly with the IMPDH enzyme.
  • IMPDH inosine monphosphate dehydrogenase
  • IMPDH-associated disorders include transplant rejection and autoimmune disorders, such as rheumatoid arthritis, lupus, multiple sclerosis, juvenile diabetes, asthma, and inflammatory bowel disease, as well as inflammatory disorders, cancer and tumors, T-cell mediated hypersensitivity diseases, ischemic or reperfusion injury, viral replication diseases, proliferative disorders and vascular diseases.
  • Use of the compounds of the present invention is exemplified by, but is not limited to, treating a range of disorders such as: treatment of transplant rejection (e.g. kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts (such as employed in burn treatment), heart valve xenografts, serum sickness, and graft vs.
  • transplant rejection e.g. kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts (such as employed in burn treatment), heart valve xenografts, serum sickness, and graft vs.
  • autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, juvenile diabetes, asthma, inflammatory bowel disease (such as Crohn's disease and ulcerative colitus), pyoderma gangrenum, lupus (systemic lupus erythematosis), myasthenia gravis, psoriasis, eczema, dermatitis, dermatomyosis, atopic dermatitis; multiple sclerosis, seborrhoea, pulmonary inflammation, eye uveitis, hepatitis, Grave's disease, Hashimoto's thyroiditis, autoimmune thyroiditis, Behcet's or Sjorgen's syndrome (dry eyes/mouth), pernicious or immunohaemolytic anaemia, Addison's disease (autoimmune disease of the adrenal glands), idiopathic adrenal insufficiency, autoimmune polyglandular disease (also known as
  • IMPDH is also known to be present in bacteria and thus may regulate bacterial growth.
  • the IMPDH-inhibitor compounds of the present invention may be useful in treatment or prevention of bacterial infection, alone or in combination with other antibiotic agents.
  • the compounds of the present invention are useful for the treatment of the afore mentioned exemplary disorders irrespective of their etiology, for example, for the treatment of lupus, psoriasis, inflammatory bowl disease, multiple sclerosis, atopic dermatitis, transplant rejection or rheumatoid arthritis.
  • the compounds of the present invention are of particular use for the treatment of DNA or RNA viral replication diseases, such as hepatitis (including hepatitis B and hepatitis C) cytomegalovirus, human immundeficiency virus (HIV) and influenza.
  • the compounds of the present invention are of particular use for the treatment of cancer and tumour disorders, such as solid tumors, lymphoma, leukemia and other forms of cancer.
  • the compounds of formula (1) can be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, anti-inflammatory agents, antibiotics, anticancer agents and immunosuppressants.
  • therapeutic or prophylactic agents such as anti-virals, anti-inflammatory agents, antibiotics, anticancer agents and immunosuppressants.
  • the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • compositions of this invention comprise a compound formula (1) or a salt thereof; an additional agent selected from an immunosuppressant, an anti-cancer agent, an anti-viral agent, anti-inflammatory agent, anti-fungal agent, anti-vascular hyperproliferation agent or an antibiotic agent; and any pharmaceutically acceptable carrier, adjuvant or vehicle.
  • additional immunosuppression agents include, but are not limited to, cyclosporin A, FK506, rapamycin, leflunomide, deoxyspergualin, prednisone, azathioprine, OKT3, ATAG, interferon and mizoribine.
  • Additional anti-cancer agents include, but are not limited to, cis-platin, actinomycin D, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, tenipaside, taxol, colchicine, cyclosporin A, phenothiazines, interferon and thioxantheres.
  • Additional anti-viral agents include, but are not limited to, Cytovene, Ganiclovir, trisodium phosphonoformate, Ribavirin, d4T, ddl, AZT and acyclovir.
  • Additional anti-vascular hyperproliferative agents include, but are not limited to, HMG Co-A reductase inhibitors such as lovastatin, thromboxane A2 synthetase inhibitors, eicosapentanoic acid, ciprostene, trapidil, ACE inhibitors, low molecular weight heparin, and rapamycin.
  • compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, vaginal or rectal administration, or a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives.
  • the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
  • compositions for oral administration may be suitably formulated to give controlled release of the active compound
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for formula (1) may be formulated for parenteral administration by injection e.g. by bolus injection or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials.
  • the compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen- free water, before use.
  • the compounds of formula (1) may be coated on particles such as microscopic gold particles.
  • the compounds of formula (1) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichloro- fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • suitable propellant e.g. dichlorodifluoromethane, trichloro- fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • the compounds of formula (1) may be formulated as a suppository.
  • These formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is a solid at room temperature but liquid at the body temperature.
  • suitable non-irritating excipient include for example cocoa butter and polyethylene glycols.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack or dispensing device may be accompanied by instructions for administration.
  • daily dosages may range from around 100ng/kg to 100mg/kg e.g. around 0.01 mg/kg to 40mg/kg body weight for oral or buccal administration, from around 10ng/kg to 50mg/kg body weight for parenteral administration and around 0.05mg to around 1000mg e.g. around 0.5mg to around 1000mg for nasal administration or administration by inhalation or insufflation.
  • the compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. Many of the reactions described are well-known standard synthetic methods which may be applied to a variety of compounds and as such can be used not only to generate compounds of the invention, but also where necessary the intermediates thereto.
  • R 1 -R 3 when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (1) unless otherwise indicated.
  • reactive functional groups for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.
  • Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W. in “Protective Groups in Organic Synthesis", John Wiley and Sons, (1999) and the examples herein].
  • deprotection may be the final step in the synthesis of a compound of formula (1) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups.
  • Compounds of formula (1 ) in which X is O and Y is S may be prepared according to one of several general methods, including the methods shown in Scheme B and Scheme C. The starting materials for these routes are the amines of formula (ii).
  • Amines of general formula (ii) may be prepared in a variety of ways.
  • the amine of formula (ii) where R 1 is a methyl group and R 2 is an oxazole group may be prepared using methods known in the literature, (CAS 198821-79-3).
  • a compound of formula (iii), where Z is a halogen atom e.g. CI or Br or a suitable leaving group e.g. trifluoromethylsulfonyloxy (OTf) and - NRR' is a nitro group or an amine group (which may be suitably protected), may be reacted with a derivative of the desired heteroaromatic group (R 2 -W, where W is as described below) utilising a palladium catalysed cross coupling reaction.
  • R 2 -W where W is as described below
  • the resulting coupled product may require further manipulation, depending on the nature of the -NRR' group, in order to obtain an amine of formula (ii).
  • an amine of formula (ii) For example, when -NRR' is a nitro group this may be reduced to an amine using standard techniques, or when -NRR' is a protected amine the protecting group may be removed using standard methodology.
  • the various R 2 -W derivatives are either commercially available or may be prepared using methods known to those skilled in the art.
  • the compounds of formula (iii) are either commercially available or may be prepared using methods known to those skilled in the art.
  • the compound of formula (iii) may be prepared by alkylation of the phenol precursor of (iii) using standard techniques.
  • bromides of formula (iv) may be treated with zinc cyanide in the presence of a suitable catalyst, e.g. a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0), in an appropriate solvent, such as DMF ( ⁇ /, ⁇ /-dimethylformamide). It may be appropriate to carry out such a reaction at elevated temperature, such as 100°C.
  • a suitable catalyst e.g. a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0)
  • an appropriate solvent such as DMF ( ⁇ /, ⁇ /-dimethylformamide).
  • DMF ⁇ /, ⁇ /-dimethylformamide
  • Nitriles of formula (v) may be converted into amides of formula (vi) by hydrolysis, for example using sodium perborate tetrahydrate in aqueous methanol at elevated temperature, for example 50°C.
  • Thioureas of formula (vii) may be obtained from amides of formula (vi) by treatment with an isothiocyanate of formula (viii) in a suitable solvent, such as acetone, at an appropriate temperature, such as reflux temperature.
  • Thioureas of formula (vii) may be converted into compounds of formula (1) by cyclisation. Cyclisation may be achieved using an adaptation of the method described by Chan and Shish (Heterocycles, 1987, 26, 3193). Thus, heating a thiourea of formula (vii) with sodium hydroxide in aqueous ethanol provides a compound of formula (1).
  • R a in a thiourea of formula (vii) is an acyl group, such as p-tolylmethanoyl, it is lost during the reaction and a compound of formula (1) in which R 3 is H will be produced.
  • Amides of formula (vi) may be prepared using a variety of alternative procedures known to those skilled in the art, including the methods described in a recent patent application, WO0181340. Standard functional group interconversions known to those skilled in the art may be employed.
  • esters of formula (ix) may be treated with thiophosgene in the presence of a suitable base, such as triethylamine, in an appropriate solvent such as dichloromethane to provide an isothiocyanate of formula (x). Heating an isothiocyanate of formula (x) with an amine of formula (xi) in an appropriate solvent, such as THF, at a suitable temperature, such as reflux temperature, provides a compound of formula (1).
  • Esters of formula (ix) may be prepared by any suitable method known to those skilled in the art, including the methods described in a recent patent application, WO0181340. Amines of formula (xi) may be commercially available, previously described compounds, or prepared using any standard method known to those skilled in the art.
  • amines of formula (ix) may be treated with triphosgene in the presence of a suitable base such as triethylamine in an appropriate solvent such as dichloromethane to afford intermediate isocyanate (xii). This may be reacted, without isolating, with an amine of formula (xi) to yield ureas of formula (xiii). The urea thus formed may then be heated to reflux in a mixture of ethanol and water in the presence of sodium hydroxide to afford the desired quinazolinedione of general formula (1).
  • a suitable base such as triethylamine in an appropriate solvent such as dichloromethane
  • ureas of formula (xiii) may then be heated to reflux in a mixture of ethanol and water in the presence of sodium hydroxide to afford the desired quinazolinedione of general formula (1).
  • the ureas of formula (xiii) may be heated to reflux in a solvent such as ethylene glycol dimethyl ether with a non-nucleophilic, non-hydrolysing base such as 1 ,5- diazabicyclo[4.3.0]non-5-ene to yield the diones of formula (1 ).
  • a solvent such as ethylene glycol dimethyl ether
  • a non-nucleophilic, non-hydrolysing base such as 1 ,5- diazabicyclo[4.3.0]non-5-ene
  • amines of formula (xiv) may be treated with a commercially available chloroformate of formula (xv) using a suitable base such as di/sopropylethylamine in an appropriate solvent such as dichloromethane to give a carbamate of formula (xvi).
  • a suitable base such as di/sopropylethylamine in an appropriate solvent such as dichloromethane
  • the free acid in compounds of formula (xvi) may then be coupled with amines of formula (xi) using standard conditions known to those skilled in the art to give an amide of formula (xvii).
  • Appropriate coupling conditions may involve the use of a coupling reagent such as pyBOP ® (benzotriazol-1-yloxytris (pyrrolidino)phosphonium hexafluorophosphate) in the presence of suitable base such as diisopropylethylamine in a suitable solvent such as dichloromethane.
  • suitable base such as diisopropylethylamine
  • suitable solvent such as dichloromethane.
  • the amides of formula (xv) may then be heated in an appropriate solvent such as DMF to afford the desired quinazolinediones of general formula (1).
  • amines of formula (xiv) may be reacted with an acylating reagent attached to an inert support (represented by the black circle in Scheme F), such as a polystyrene resin, employing for example hydroxymethyl polystyrene p-nitrophenylcarbonate (xviii) and N- methylmorpholine (NMM) in DCM, to give an intermediate resin-bound carbamate (xix).
  • an acylating reagent attached to an inert support (represented by the black circle in Scheme F)
  • an inert support represented by the black circle in Scheme F
  • an inert support represented by the black circle in Scheme F
  • the free acids (xix) may then coupled with amines of formula (xi) using standard conditions such as PyBOP in the presence of a suitable base such as di-/so-propylethylamine in a suitable solvent such as dichloromethane or ⁇ /-methylpyrrolidinone to give resin-bound amides of formula (xx). Heating compounds of formula (xx) in an appropriate solvent such as DMF cleaves the desired quinazolinediones of formula (1) from the resin.
  • a suitable base such as di-/so-propylethylamine
  • a suitable solvent such as dichloromethane or ⁇ /-methylpyrrolidinone
  • substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, thioacylation, halogenation, sulphonylation, nitration, formylation and coupling procedures. It will be appreciated that these methods may also be used to obtain or modify other compounds of any of formula (1) or any preceding intermediates where appropriate functional groups exist in these compounds.
  • ester groups such as -C0 2 R 6 , -C0 2 R 11 or -C0 2 Alk 4 in the compounds may be converted to the corresponding acid [-CO 2 H] by acid- or base-catalysed hydrolysis depending on the nature of the groups R 6 , R 1 or Alk 4 .
  • Acid- or base- catalysed hydrolysis may be achieved for example by treatment with an organic or inorganic acid, e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxan or an alkali metal hydroxide, e.g. lithium hydroxide in an aqueous alcohol, e.g. aqueous methanol.
  • an acid [-CO 2 H] may be prepared by hydrolysis of the corresponding nitrile [-CN], using for example a base such as sodium hydroxide in a refluxing alcoholic solvent, such as ethanol.
  • -OH groups may be generated from the corresponding ester [e.g. CO 2 Alk 4 or C0 2 R 11 ] or aldehyde [-CHO] by reduction, using for example a complex metal hydride such as lithium aluminium hydride or sodium borohydride in a solvent such as methanol.
  • a complex metal hydride such as lithium aluminium hydride or sodium borohydride in a solvent such as methanol.
  • an alcohol may be prepared by reduction of the corresponding acid [-C0 2 H], using for example lithium aluminium hydride in a solvent such as tetrahydrofuran.
  • Alcohol groups may be converted into leaving groups, such as halogen atoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g.
  • trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g. p-toluenesulfonyloxy group using conditions known to those skilled in the art.
  • an alcohol may be reacted with thionyl chloride in a halogenated hydrocarbon e.g., dichloromethane to yield the corresponding chloride.
  • a base e.g., triethylamine may also be used in the reaction.
  • alcohol or phenol groups may be converted to ether groups groups by coupling a phenol with an alcohol in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate.
  • a phosphine e.g. triphenylphosphine
  • an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate.
  • ether groups may be prepared by deprotonation of an alcohol, using a suitable base e.g. sodium hydride followed by subsequent addition of an alkylating agent, such as an alkylhalide.
  • Aldehyde [-CHO] groups may be obtained by oxidation of a corresponding alcohol using well known conditions.
  • an oxidising agent such as a periodinane e.g. Dess Martin
  • a solvent such as a halogenated hydrocarbon, e.g. dichloromethane.
  • An alternative oxidation may be suitably activating dimethyl sulfoxide using for example, oxalyl chloride, followed by addition of an alcohol, and subsequent quenching of the reaction by the addition of an amine base, such as triethylamine.
  • Suitable conditions for this reaction may be using an appropriate solvent, for example, a halogenated hydrocarbon, e.g. dichloromethane at -78°C followed by subsequent warming to room temperature.
  • primary amine (-NH 2 ) or secondary amine (-NH-) groups may be alkylated using a reductive alkylation process employing an aldehyde and a borohydride, for example sodium triacetoxyborohyride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, a ketone such as acetone, or an alcohol, e.g. ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.
  • amine [-NH 2 ] groups may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e.g. ethanol at ambient temperature.
  • a nitro [-N0 2 ] group may be reduced to an amine [-NH 2 ], for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol e.g. methanol, or by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid.
  • a metal catalyst for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol e.g. methanol
  • an acid such as hydrochloric acid
  • amine (-CH 2 NH 2 ) groups may be obtained by reduction of nitriles (-CN), for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon, or Raney nickel, in a solvent such as an ether e.g. a cyclic an ether, e.g. a cyclic ether such as tetrahydrofuran, at a temperature from -78°C to the reflux temperature.
  • a metal catalyst for example palladium on a support such as carbon, or Raney nickel
  • Aromatic halogen substituents in the compounds may be subjected to halogen- metal exchange by treatment with a base, for example a lithium base such as n-butyl or t- butyl lithium, optionally at a low temperature, e.g. around -78°C, in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent.
  • a base for example, a lithium base such as n-butyl or t- butyl lithium, optionally at a low temperature, e.g. around -78°C, in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent.
  • a formyl group may be introduced by using dimethylformamide as the electrophile
  • a thiomethyl group may be introduced by using dimethyldisulphide as the electrophile.
  • Aromatic halogen substituents may also be subjected to palladium
  • sulphur atoms in the compounds may be oxidised to the corresponding sulphoxide or sulphone using an oxidising agent such as a peroxy acid, e.g. 3- chloroperoxybenzoic acid, in an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane, at around ambient temperature.
  • an oxidising agent such as a peroxy acid, e.g. 3- chloroperoxybenzoic acid
  • an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane
  • N-oxides of compounds of formula (1) may be prepared for example by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70°C to 80°C, or alternatively by reaction with a peracid such as peracetic acid in a solvent, e.g. dichloromethane, at ambient temperature.
  • an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid
  • an elevated temperature for example around 70°C to 80°C
  • a peracid such as peracetic acid in a solvent, e.g. dichloromethane
  • Salts of compounds of formula (1) may be prepared by reaction of a compound of formula (1) with an appropriate base or acid in a suitable solvent or mixture of solvents e.g. an organic solvent such as an ether e.g. diethylether, or an alcohol, e.g. ethanol or an aqueous solvent using conventional procedures. Salts of compounds of formula (1) may be exchanged for other salts by use of conventional ion-exchange chromatography procedures.
  • a suitable solvent or mixture of solvents e.g. an organic solvent such as an ether e.g. diethylether, or an alcohol, e.g. ethanol or an aqueous solvent using conventional procedures.
  • Salts of compounds of formula (1) may be exchanged for other salts by use of conventional ion-exchange chromatography procedures.
  • diastereomeric derivatives e.g. salts
  • a mixture of enantiomers of formula (1) e.g. a racemate
  • an appropriate chiral compound e.g. a chiral base
  • the diastereomers may then be separated by any convenient means, for example by crystallisation and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
  • a racemate of formula (1) may be separated using chiral High Performance Liquid Chromatography.
  • a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
  • Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.
  • 2-lsothiocvanato-4-methoxy-5-oxazol-5-yl-benzoic acid methyl ester To a solution of 2-amino-4-methoxy-5-oxazol-5-yl-benzoic acid methyl ester (CAS 371251-37-5) (1.0g) in dry DCM (60ml) under nitrogen cooled to -78°C was added TEA (1.2ml) followed by thiophosgene (0.34ml) dropwise. The reaction mixture was allowed to warm to 0°C and stirred for 30 mins.
  • Example 15 3-(7-Methoxy- ⁇ -oxazol-5-yl-4-oxo-2-thioxo-1.4- dihvdro-,2/-/-quinazolin-3-vD-propionic acid ethyl ester From Intermediate 5 (300mg), ⁇ -alanine ethyl ester hydrochloride (158mg) and TEA (0.29ml). Triturating with water afforded the title compound as an off- white solid (361 mg, 93%).
  • Example 23 r2-(7-Methoxy-6-oxazol-5-yl-4-oxo-2-thioxo-1.4- dihvdro-2H-quinazolin-3-yl)-ethylamino1-acetic acid ethyl ester From Intermediate 5 (40mg), ⁇ /- ⁇ -aminoethylglycine ethyl ester.2HCI (30mg) and TEA (0.1 ml). Triturating with water and then purification by preparative HPLC afforded the title compound as an off-white solid (2mg).
  • Example 13 (87mg), lithium hydroxide hydrate (21 mg), water (1 ml), THF (2ml) and MeOH (2ml) were combined and stirred at room temperature for 16 hrs. Then heated to reflux for 6 hrs. The solvents were then removed in vacuo and the residue triturated with aqueous 1 N HCI to give the title compound as an off-white solid (82mg, 98%).
  • Example 27.4-(7-Methoxy-6-oxazol-5-yl-4-oxo-2-thioxo-1.4-dihvdro-2H- quinazolin-3-yl)-butyric acid From Example 14 (348mg), and lithium hydroxide (76mg). Triturating with aqueous 1 N HCI gave the title compound as an off-white solid (323mg, 96%).
  • Example 25 (20mg), 4-aminopyridine (6mg), TEA (10 drops), EDC (12mg), DMAP (1mg) and DMF (3ml) were combined and stirred at room temperature for 2 days. The reaction was then evaporated to dryness and purified by preparative HPLC to give the title compound as an off-white solid (2mg).
  • 1 H NMR 300MHz (d 6 -DMSO) 8.25 (3H, m), 8.15 (3H, m), 7.5 (2H, d), 7.4 (1 H, s), 6.75 (1 H, s), 5.25 (2H, s), 3.95 (3H, s).
  • Example 29 3-(3-Amino-propyh-7-methoxy-6-oxazol-5-yl-2-thioxo-
  • Example 24 To a suspension/solution of Example 24 (100mg) in DCM (20ml) was added trifluoroacetic acid (5ml) and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue triturated in DCM/Et 2 O to afford the title compound as an off-white solid (97mg, 95%).
  • Example 29 To a suspension of Example 29 (50mg) in dry DCM (10ml) was added TEA (0.02ml) followed by nicotinic acid (14mg), EDC (26mg) and HOBT (18mg). DMF (5ml) was added and the mixture stirred at room temperature overnight. Trituration in water followed by trituration in DCM afforded the title compound as an off-white solid (28mg, 57%).
  • Example 37 7-Methoxy-6-oxazol-5-yl-3-(tetrahvdro-pyran-2- ylmethyl)-7H-quinazoline-2.4-dione
  • EtOH/water 15ml/2ml
  • NaOH NaOH
  • water 2ml
  • the resulting clear solution was heated at reflux for 3 hours.
  • the EtOH was removed in vacuo and the aqueous residue acidified to pH7 with aqueous 2M HCI.
  • the resulting precipitate was filtered off and dried in vacuo to yield by the title compound as a yellow solid (72mg, 75%).
  • Example 40 (7-Methoxy-6-oxazol-5-yl-2,4-dioxo-1,4-dihvdro-2H- quinazolin-3-yl)-acetonitrile From Intermediate 14 (98mg) and DBN (0.044ml). The resulting precipitate was filtered off, washed with DME and washed with Et 2 0 to yield the title compound as a white solid (56mg, 63%). TLC R f 0.40 (5% MeOH/DCM).
  • Example 42 ⁇ H7-Methoxy-6-oxazol-5-yl-2.4-dioxo-1.4-dihvdro-2H- quinazolin-3-yl)-ethyll-acetamide From Intermediate 16 (220mg) and DBN (0.086ml). The resulting precipitate was filtered off and triturated in hot MeOH to afford the title compound as a solid (175mg, 87%). TLC R f 0.29 (EtOAc).
  • Example 46 7-Methoxy-3-r3-(5-methyl-7H-pyrazol-4-yl)-propy ⁇ -6- oxazol-5-yl-7H-quinazoline-3.4-dione
  • 2-amino-4-methoxy-5-oxazol-5-yl-benzoic acid methyl ester (CAS 371251-37-5) (200mg) in dry THF (20ml) under nitrogen cooled to -78°C was added triphosgene (84mg) followed by TEA (0.23ml) dropwise.
  • the reaction mixture was allowed to warm to 0°C and stirred for 30 mins.
  • Hydroxymethylpolystyrene resin (10.2g, 100-2— mesh, 0.98gmol "1 ) was suspended in anhydrous DCM (120ml), treated with ⁇ /-Methylmorpholine (2.20ml) and cooled in an ice-bath. 4-Nitrophenylchloroformate (4.03g) was added in one portion and the mixture stirred in the ice bath for 5 minutes, then at room temperature for 18 hours. The resin was filtered under a nitrogen atmosphere, washed with DCM (4 x 40ml), and dried overnight in a vacuum desiccator. The resultant pale pink resin (12.3g) was placed in a round-bottomed flask.
  • DIPEA (10.5ml), HOBT (4.05g) and 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid (CAS 371251-38-6) (11.71g) were dissolved in a 1 :1 mixture of anhydrous DCM/DMF (200ml) and transferred onto the resin via cannular. After stirring at room temperature for 18 hours, the mixture was filtered, and the resin was washed with DMF (4 x 30ml) followed by DCM (4 x 30ml), then dried in a vacuum desiccator to constant weight, as a beige solid (11.56 g).
  • the resin thus produced was placed in a glass tube with DMF (1 ml), and heated to 125°C under an atmosphere of nitrogen for 16 hours.
  • the reaction mixture was then filtered into a tared flask, and the resin washed with DMF (2 x 2ml), then 1 :1 MeOH/DCM (3 x 2ml). Evaporation of the filtrate yielded the title compound as beige solid (4.6mg, 11%).
  • Example 55 3-Cvclopropylmethyl-7-methoxy-6-oxazol-5-yl-1 H- quinazoline-2.4-dione From the 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid loaded resin (116mg), and aminomethylcyclopropane (71 mg). The title compound was obtained as an off-white solid (5.8mg, 19%). LCMS 314 [M+1] + , RT 2.86 mins.
  • Example 57 7-Methoxy-3-r2-(6-methoxy-1 H-indol-3-yl ⁇ ethvn-6- oxazol-5-yl-1 H-quinazoline-2.4-dione From the 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid loaded resin (116mg), and 6-methoxytryptamine (190mg). The title compound was obtained as an off-white solid (7.4mg, 17%). LCMS 433 [M+1] + , RT 3.08 mins.
  • Example 58 7-Methoxy-3-(2-methoxyethylj-6-oxazol-5-yl-1 H- quinazoline-2.4-dione
  • Example 40 To a solution of Example 40 (20mg) in dry DMF (3ml) was added sodium azide (5mg) and ammonium chloride (4mg). The mixture was heated at 120°C overnight. The solvent was removed in vacuo and the residue taken up in aqueous Na 2 CO 3 (20ml) and washed with EtOAc (20ml). The aqueous layer was acidified with aqueous 1N HCI and extracted with EtOAc (2 x 30ml). The combined organic layers were died over MgS04, filtered and the solvent removed in vacuo to afford the title compound as a solid (10mg, 44%).
  • Example 44 A solution of Example 44 (315mg) in formic acid (8ml) was stirred at room temperature for 4 hours. The mixture was taken up in water (20ml) and washed with Et 2 0 (20ml). The aqueous layer was basified with solid Na 2 C0 3 and washed with EtOAc (20ml). The aqueous layer was acidified to pH7 with aqueous 1 N HCI and the resulting solid filtered off and dried in vacuo to yield the title compound as a solid (150mg, 62%). TLC R f 0.03 (10% MeOH/DCM).
  • Example 64 2H-quinazolin-3-yl)-butv ⁇ -methanesulphonamide
  • methyl sulphonyl chloride 0.2ml
  • TEA 0.2ml
  • the mixture was heated at 60°C for 5 hours.
  • the mixture was concentrated in vacuo and the residue dissolved in EtOAc (50ml), washed with aqueous 1 N HCI, the organic layer was separated, dried over MgS0 4 , filtered and the solvent removed in vacuo. Purification by preparative HPLC afforded the title compound as a solid (1 mg, 1%).
  • Example 64 To a solution of Example 64 (56mg) in dry DCM / DMF (15ml / 3ml) under nitrogen was added TEA (0.04ml). The mixture was cooled to 0°C and carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester (3S)-tetrahydro-furan-3-yl ester (CAS 138499-08-8) (43mg) was added in a single portion. The reaction mixture was allowed to warm to room temperature and stirred over the weekend. The solvents were removed in vacuo. Trituration in Et 2 0, trituration in MeOH, followed by purification by preparative HPLC afforded the title compound as a white solid (6.8mg, 9%).
  • the ability of the compounds of the invention to inhibit the IMPDH enzymes may be determined using the following assays:
  • IMPDH catalyses the NAD dependent oxidation of IMP to XMP with concomitant reduction of the cofactor.
  • IMPDH activity was determined by monitoring the production of the fluorescent product, NADH. Assays were performed in a final volume of 200/yl containing IMPDH (2/yg), NAD (100 /M), IMP (100/yM), 1% DMSO, 30mM KCl and 100mM Tris/HCI, pH7.5. Fluorescence (excitation 340nm / emission 465nm) was read continuously at 25°C for 30 minutes. From this data, initial rates (i.e. change in fluorescence intensity per minute) were calculated.
  • test compounds were prepared at an initial concentration of 1.0mM in 100% DMSO, then diluted in assay buffer to 0.2mM. Further dilutions were made in assay buffer containing 20% DMSO, prior to diluting 20-fold into the assay, to allow testing across the range 0.3nM to 10 M.
  • Peripheral blood mononuclear cells were isolated from freshly taken human blood using standard procedures. Cells were plated out in RPMI medium containing 5% human serum in the presence and absence of inhibitor. PHA (25 ⁇ l of 30 ⁇ g/ml solution to each well) was added and the plates were incubated at 37°C in an atmosphere of 95% air/5% C0 for 48 hours. O. ⁇ Ci of tritiated thymidine was added to each well and the plates were incubated for a further 18 hours. The contents of the plate were transferred to a filter plate and the cells washed with saline. The plates were dried, microscintillation fluid was added to each well and the plate was counted on a scintillation counter. IC 50 values were calculated by plotting inhibitor concentration versus %inhibition.
  • the assay described above can be carried out using anti-CD3 (40 ⁇ l of 3750ng/ml concentration to each well) stimulation instead of PHA.

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Abstract

A compound of formula (1): wherein: X and Y, which may be the same or different, is each an O or S atom; R1 is an aliphatic, cylcoaliphatic or cycloalkyl-akyl-group; R2 is an optionally substituted heteroaromatic group; R3 is the group Alk?1-L1-Alk2-R4¿ in which Alk1 is a covalent bond or an optionally substituted aliphatic or heteroaliphatic chain, L1 is a covalent bond or a linker atom or group, Alk2 is a covalent bond or an optionally substituted aliphatic or thereoaliphatic chain and R4 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group; and the salts, solvates, hydrates, tautomers, isomers or N-oxides thereof. The compounds of the present invention are potent inhibitors of IMPDH.

Description

QUINAZOLINEDIONE DERIVATIVES
This invention relates to a series of quinazolinediones and their derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
lnosine-5'-monophosphate dehydrogenase (IMPDH; EC 1.1.1.205) is an enzyme involved in the de novo synthesis of guanine nucleotides. IMPDH catalyses the β-nicotinamide adenine dinucleotide (NAD)-dependant oxidation of inosine-5'-monophosphate (IMP) to xanthosine-5'-monophosphate (XMP) (Jackson R.C. et al., Nature. 256, pp. 331-333, (1975)). Guanine nucleotides are essential to the cell for RNA and DNA synthesis, intermediates in signalling pathways and as energy sources for metabolic pathways.
IMPDH is ubiquitous in eukaryotes, bacteria and protozoa (Y. Natsumeda & S.F. Carr, Ann. N.Y. Acad.. 696, pp. 88-93, (1993)). Two isoforms of human IMPDH, designated type I and type II, have been identified and sequenced (F.R. Collart and E. Huberman, J. Biol. Chem.. 263, pp. 15769-15772, (1988); Y. Natsumeda et al J. Biol. Chem.. 265, pp 5292-5295, (1990)). Each is 514 amino acids and they share 84% sequence identity. Both IMPDH type I and type II form active tetramers in solution, with subunit molecular weights of 56 kDa (Y. Yamada et. al., Biochemistry, 27, pp. 2737-2745, (1988)). It is thought that type I is the predominant isoform expressed in normal cells, whilst type II is upregulated in neoplastic and replicating cells. Studies have postulated that selective inhibition of type II IMPDH could provide a therapeutic advantage by reducing potential toxicity effects caused by inhibiting the type I isoform (Pankiewicz K.W, Expert Opin. Ther. Patents 11 (7) pp 1161 -1170, (2001)).
The de novo synthesis of guanine nucleotides, and thus the activity of IMPDH, is particularly important in B and T-lymphocytes. These cells depend on the de novo, rather than the salvage pathway to generate sufficient levels of nucleotides necessary to initiate a proliferative response to mitogen or antigen (A.C. Allison et. al., Lancet II. 1179, (1975) and A.C. Allison et. al., Ciba Found. Svmp., 48, 207, (1977) ). Thus, IMPDH is an attractive target for selectively inhibiting the immune system without also inhibiting the proliferation of other cells.
Mycophenolic acid (MPA) and some of its derivatives have been described in United States patents 5,380,879 and 5,444,072 and PCT publications WO 94/01105 and WO 94/12184 as potent, uncompetitive, reversible inhibitors of human IMPDH type I (Kj = 33 nM) and type II (Kj = 9 nM). MPA has been demonstrated to block the response of B and T-cells to mitogen or antigen (A.C. Allison et. al., Ann. N. Y. Acad. Sci.. 696, 63, (1993) ).
Immunosuppressants, such as MPA, are useful drugs in the treatment of transplant rejection and autoimmune diseases. (R.E. Morris, Kidney Intl.. 49, Suppl. 53, S-26, (1996) ). However, MPA is characterized by undesirable pharmacological properties, such as gastrointestinal toxicity. (L.M. Shaw, et. al., Therapeutic Drug Monitoring. 17, pp. 690-699, (1995) ).
Mycophenolate mofetil, a prodrug which quickly liberates free MPA in vivo, was recently approved to prevent acute allograft rejection following kidney transplantation (i.e. renal allograft failure) and heart transplantation. (L.M. Shaw, et. al., Therapeutic Drug Monitoring. 17, pp. 690-699, (1995); H.W. Sollinger, Transplantation. 60, pp. 225-232, (1995); J. Kobashigawa Transplant. 66, pp. 507, (1998) ). Mycophenolate mofetil has also been used for the treatment of rheumatoid arthritis. The experimental use of mycophenolate mofetil in the treatment of systemic lupus erythematosus, lupus nephritis, myasthenia gravis, inflammatory eye disease, autoimmune and inflammatory skin disorders (including psoriasis) and glomerular disease has also been described (R. Bentley, Chem. Rev.. 100, pp. 3801-3825, (2000)). Mycophenolate mofetil has also been postulated to be of use for the treatment of atopic dermatitis (Grundmann-Kollman M et al, Archives of Dermatology. 137 (7), pp. 870-873, (2001) ) and has been shown to be effective in predictive animal models of multiple sclerosis (Tran G.T et al, International Immunopharmacoloov. 1 (9-10) pp. 1709-1723, (2001) ). Several clinical observations, however, limit the therapeutic potential of this drug. (L.M. Shaw, et. al., Therapeutic Drug Monitoring. 17, pp. 690-699, (1995) ).
Nucleoside analogues such as tiazofurin, bavirin and mizoribine also inhibit IMPDH (L. Hedstrom, et. al., Biochemistry. 29, pp. 849-854, (1990) ). These nucleoside analogues are competitive inhibitors of IMPDH, but also inhibit other NAD dependant enzymes. This lack of specificity limits the therapeutic application of these compounds. New agents with improved selectivity for IMPDH would represent a significant improvement over these nucleoside analogues. Mizorbine (Bredinin®) has been approved in Japan for multiple indications in transplantation and autoimmune diseases including prevention of rejection after renal transplantation, idiopathic glomerulonephritis, lupus nephritis and rheumatoid arthritis.
Vertex has recently disclosed a series of novel IMPDH inhibitors (WO 97/40028), of which VX-497 has been evaluated for the treatment of psoriasis.
It is also known that IMPDH plays a role in other metabolic events. Increased IMPDH activity has been observed in rapidly proliferating human leukemic cell lines and other tumour cell lines, indicating IMPDH as a target for anti-cancer as well as immunosuppressive chemotherapy (M. Nagai et. al., Cancer Res.. 51 , pp. 3886-3890, (1991), Pankiewicz K.W., Exp. Opin. Ther. Patents. 11 , pp. 1161-1170, (2001) ). IMPDH has also been shown to play a role in the proliferation of smooth muscle cells, indicating that inhibitors of IMPDH may be useful in preventing restenosis or other hyperproliferative vascular diseases (CR. Gregory et. al., Transplantation. 59, pp. 655-61 , (1995); PCT publication WO 94/12184; and PCT publication WO 94/ 01105).
Additionally, IMPDH has been shown to play a role in viral replication in some virus-infected cell lines. (S.F. Carr, J. Biol. Chem.. 268, pp. 27286-27290, (1993) ). VX-497 is currently being evaluated for the treatment of hepatitis C in humans. Thus, there remains a need for potent IMPDH inhibitors with improved pharmacological properties. Such inhibitors would have therapeutic potential as immunosuppressants, anti-cancer agents, anti-inflammatory agents, antipsoriatic and anti-viral agents.
WO98/56770 generally discloses the synthesis of a class of substituted quinazolinediones. However, these are not disclosed for use as IMPDH inhibitors.
The present inventors disclose new potent IMPDH inhibitors based on substituted quinazolinedione derivatives.
Thus according to one aspect of the invention we provide a compound of formula (1 ):
Figure imgf000005_0001
wherein:
X and Y, which may be the same or different, is each an O or S atom; R1 is an aliphatic, cycloaliphatic or cycloalkyl-alkyl- group; R2 is an optionally substituted heteroaromatic group; R3 is the group -Alk1-L1-Alk2-R4 in which Alk1 is a covalent bond or an optionally substituted aliphatic or heteroaliphatic chain, L1 is a covalent bond or a linker atom or group, Alk2 is a covalent bond or an optionally substituted aliphatic or heteroaliphatic chain and R4 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group; and the salts, solvates, hydrates, tautomers, isomers or N-oxides thereof.
It will be appreciated that certain compounds of formula (1 ) may exist as geometric isomers (E or Z isomers). The compounds may also have one or more chiral centres, and exist as enantiomers or diastereomers. The invention is to be understood to extend to all such geometric isomers, enantiomers, diastereomers and mixtures thereof, including racemates. Formula (1) and the formulae hereinafter are intended to represent all individual isomers and mixtures thereof, unless stated or shown otherwise. In addition, compounds of formula (1) may exist as tautomers, for example keto (CH2C=0) - enol (CH=CHOH) tautomers. Quinazolinediones may also exist as tautomers, one possible example is illustrated below:
Figure imgf000006_0001
Formula (1 ) and the formulae hereinafter are intended to represent all individual tautomers and mixtures thereof, unless stated otherwise.
It will also be appreciated that where desired the compounds of the invention may be administered in a pharmaceutically acceptable pro-drug form, for example, as a protected carboxylic acid derivative, e.g. as an acceptable ester. It will be further appreciated that the pro-drugs may be converted in vivo to the active compounds of formula (1), and the invention is intended to extend to such pro-drugs. Such prodrugs are well known in the literature, see for example International Patent Application No. WO 00/23419, Bodor N. (Alfred Benson Symposium, 1982, 17, 156-177), Singh G. et al (J. Sci. Ind. Res., 1996, 55, 497-510) and Bundgaard H. (Design of Prodrugs, 1985, Elsevier, Amsterdam).
In the compounds of the invention as represented by formula (1) and the more detailed description hereinafter certain of the general terms used in relation to substituents are to be understood to include the following atoms or groups unless specified otherwise.
The term "aliphatic group" is intended to include optionally substituted straight or branched CMoalkyl, e.g. C 1-6 alkyl, C2-ιoalkenyl e.g. C^-ealkenyl or C-2-10 alkynyi e.g. C2-6alkynyl groups. Optional substituents when present on these groups include those optional substituents mentioned hereinafter.
Thus as used herein the term "alkyl", whether present as a group or part of a group includes straight or branched d-ioalkyl groups, for example Ci-βalkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl or neopentyl groups. Optional substituents when present on those groups include those optional substituents mentioned hereinafter.
The terms "alkenyl" or "alkynyi" are intended to mean straight or branched C2- 10 alkenyl or C-2-ιoalkynyl groups such as
Figure imgf000007_0001
or C2-6alkynyl groups such as -CHCH2, -CHCHCH3, -CH2CHCHCH3, -CCH, -CH2CCH and -CH2CCCH3 groups. Such groups may be substituted by those optional substituents mentioned hereinafter.
Particular examples of aliphatic groups include optionally substituted Cι-6 alkyl groups such as -CH3, -CH2CH3, -CH(CH3)2, -(CH2)2CH3, -(CH2)3CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)2> - CH2C(CH3)3, -C(CH3)3, -(CH2)4CH3, -(CH2)5CH3, or
Figure imgf000007_0002
or C2-6alkynyl groups such as -CHCH2, -CHCHCH3, -CH2CHCH2, -CHCHCH2CH3, -CH2CHCHCH3, -(CH2)2CHCH2, -CCH, -CCCH3, -CH2CCH, -CCCH2CH3, -CH2CCCH3, or -(CH2)2CCH groups.
The term "aliphatic chain" is intended to include those alkyl, alkenyl or alkynyi groups as just described where a terminal hydrogen atom is replaced by a covalent bond to give a divalent chain.
Examples of aliphatic chains include optionally substituted Ci-6 alkylene chains such as -CH2-, -CH2CH2-, -CH(CH3)CH2-,-(CH2)2CH2-, -(CH2)3CH2-,
-CH(CH3)(CH2)2CH2-, -CH2CH(CH3)CH2-, -C(CH3)2-, -C(CH3)2CH2-, -CH2C(CH3)2CH2-, -(CH2)2CH(CH3)CH2-, -CH(CH3)CH2CH2-,
-CH(CH3)CH2CH(CH3)CH2-, -CH2CH(CH3)CH2CH2-, -(CH2)2C(CH3)2CH2-, -(CH2)4CH2-, -(CH2)sCH2 or
Figure imgf000007_0003
or C2-6alkynylene chains such as -CHCH-, -CHCHCH2 -CH2CHCH-, -CHCHCH2CH2-, -CH2CHCHCH2-, -(CH2)2CHCH-, -CC-, -CCCH2, -CH2CC-, -CCCH2CH2-, -CH2CCCH2- or -(CH2)2CCH- chains. More particular examples include optionally substituted d-3 alkylene chains selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)CH2-, -C(CH3)2- and -CH2CH(CH3)- chains.
Heteroaliphatic chains represented by Alk1 or Alk2 in the compounds of formula (1) include the aliphatic chains just described but with each additionally containing one, two, three or four heteroatoms or heteroatom-containing groups. Particular heteroatoms or groups include atoms or groups L3 where L3 is a linker atom or group. Each L3 atom or group may interrupt the aliphatic group, or may be positioned at its terminal carbon atom to connect the group to an adjoining atom or group. Particular examples include optionally substituted -L3CH2-, -CH2L3-, -L3CH(CH3)-, -CH(CH3)L3-, -CH2L3CH2-, -L3CH2CH2-, -L3CH2CH(CH3)-, -CH(CH3)CH2L3-, -CH2CH2L3-, -CH2L3CH2CH2-, -CH2L3CH2CH2L3-, -(CH2)2L3CH2-, -(CH2)3L3CH2-, -L3(CH2)2CH2-, -L3CH2CHCH-, -CHCHCH2L3-, -(CH2)2L3CH2CH2-, -(CH2)3L3- and -L3CH2L3CH2CH2- chains.
When L3 is present in heteroaliphatic chains as a linker atom or group it may be any divalent linking atom or group. Particular examples include -O- or -S- atoms or -C(O)-, -C(S)-, -S(O)-, -S(0)2-, -C(O)0-, -OC(O)-, -N(R5)- [where R5 is a hydrogen atom or a straight or branched Chalky! group], -N(R5)O-, -N(R5)N-, -CON(R5)-, -OC(0)N(R5)-, -CSN(R5)-, -N(R5)CO-, -N(R5)C(0)O-, -N(R5)CS-, -S(O)2N(R5)-, -N(R5)S(0)2-, -N(R5)CON(R5)-, -N(R5)CSN(R5)-, -N(R5)SO2N(R5)-, -C(=NOR5)- or -C(R5a)=NO- [where R5a is a straight or branched Cι-6alkyl group] groups. Where L3 contains two R5 groups these may be the same or different.
The term "cycloaliphatic group" includes optionally substituted non-aromatic cyclic or multicyclic, saturated or partially saturated C3-ιo ring systems, such as, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, adamantyl, norbomyl, norbomenyl, bicyclo[2.2.1]heptanyl or bicyclo[2.2.1]heptenyl. Particular examples include optionally substituted C3-6 cycloalkyl ring systems such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. Optional substituents present on those groups include those substituents mentioned hereinafter.
The term "cycloalkyl-alkyl- group" refers to a Cι-6 alkyl group (as described herein) where a terminal hydrogen atom is replaced by a C3-6 cycloalkyl ring (as described herein). Examples include -(CH2)ι-6-cyclopropyl, -(CH2)1-6- cyclobutyl, -(CH2)ι-6-cyclopentyl or -(CH2)ι-6-cyclohexyl.
The term "heterocycloaliphatic group" refers to an optionally substituted 3 to 10 membered saturated or partially saturated monocyclic or saturated or partially saturated multicyclic hydrocarbon ring system containing one, two, three or four L2 linker atoms or groups. Particular examples of suitable L2 atoms or groups include -O- or -S- atoms or -C(O)-, -C(0)O-, -OC(O)-, -C(S)-,
-S(O)-, -S(0)2-, -N(R5)- [where R5 is a hydrogen atom or a Cι-6 alkyl group], -N(R5)N(R5), -N(R5)0-, -ON(R5)-, -CON(RS)-, -OC(0)N(R5)-, -CSN(RS)-,
-N(R5)CO-, -N(R5)C(O)0-, -N(R5)CS-, -S(0)2N(R5)-, -N(R5)S(0)2-,
-N(R5)CON(R5)-, -N(R5)CSN(R5)-, -N(R5)S02N(R5)- groups. Where the linker group contains two R5 substituents, these may be the same or different.
Optional substituents present on the heterocycloaliphatic groups include those substituents mentioned hereinafter.
Particular examples of heterocycloaliphatic groups include optionally substituted cyclobutanonyl, cyclopentanonyl, cyclohexanonyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolinyl, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, oxazolidinyl, oxazolidinonyl, dioxolanyl, e.g. 1 ,3- dioxolanyl, imidazolinyl, e.g. 2-imidazolinyl, imidazolidinyl, pyrazolinyl, e.g. 2- pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, e.g. 2- or 4-pyranyl, pyranonyl, piperidinyl, piperidinonyl, quinuclidinyl, 1 ,4-dioxanyl, morpholinyl, morpholinonyl, 1 ,4-dithianyl, thiomorpholinyl, piperazinyl, Λ/-Cι-6 alkylpiperazinyl, Λ/-Cι-6 alkylpyrrolidinyl, Λ/-C1-6 alkylpiperidinyl, Λ/-C1-6 alkylmorpholinyl, homopiperazinyl, dihydrofuran-2-onyl, tetrahydropyran-2- onyl, isothiazolidinyl 1 ,1-dioxide, [1 ,2]thiazinanyl 1 ,1-dioxide, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyrazolidin-3-onyl, tetrahydrothiopyranyl 1 ,1-dioxide, tetrahydrothiophenyl 1 ,1-dioxide, 1 ,3,5- trithianyl, oxazinyl, e.g. 2H-1 ,3-, 6H-1 ,3-, 6H-1 ,2-, 2H-1 ,2- or 4H-1 ,4- oxazinyl, 1 ,2,5-oxathiazinyl, isoxazinyl, e.g. o- or p-isoxazinyl, oxathiazinyl, e.g. 1 ,2,5 or 1 ,2,6-oxathiazinyl, or 1 ,3,5,-oxadiazinyl groups.
Cycloaliphatic groups may be linked to the remainder of the compound of formula (1) by any available ring carbon atom. Heterocycloaliphatic groups may be linked to the remainder of the compound of formula (1) by any available ring carbon or, where available, ring nitrogen atom.
When R4 in compounds of formula (1) is an optionally substituted heterocycloaliphatic or cycloaliphatic ring, these may optionally be fused to an optionally substituted monocyclic C6-12aromatic group, such as phenyl or an optionally substituted monocyclic C1-9heteroaromatic group, such as a 5 or 6 membered heteroaromatic group, containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms.
The optional substituents which may be present on the aliphatic, alkyl, alkenyl, alkynyi, cycloaliphatic or heterocycloaliphatic groups, described above and generally herein include one, two, three or more substituents, which each may be the same or different, selected from halogen atoms, or alkoxy, haloalkyl, haloalkoxy, hydroxy (-OH), thiol (-SH), alkylthio, amino(-NH2), substituted amino, optionally substituted C6-12arylamino, -CN, -C02H, -CO2R6 (where R6 is an optionally substituted C-ι-6 alkyl group), -SO3H, -SOR7 (where R7 is a C1- 6 alkyl group) -SO2R7, -S03R7, -OC02R7, -C(0)H, -C(O)R7, -OC(0)R7, -C(S)R7, -C(O)N(R8)(R9) (where R8 and R9, which may be the same or different is each a hydrogen atom or a Cι-6 alkyl group), -OC(0)N(R8)(R9), -N(Rβ)C(0)R9, -CSN(R8)(R9), -N(R8)C(S)(R9), -S02N(R8)(R9), -N(R8)S02R9, -N(R8)C(O)N(R9)(R10) (where R10 is a hydrogen atom or a Cι-6 alkyl group), -N(R8)C(S)N(R9)(R10), -N(R8)S02N(R9)(R1°), or an optionally substituted aromatic or heteroaromatic group or a Cι-6alkyl group optionally substituted by one, two, three or more of the same or different halogen atoms, or alkoxy, haloalkyl, haloalkoxy, hydroxy (-OH), thiol (-SH), alkylthio, amino (-NH2), substituted amino, optionally substituted C6-12arylamino, -CN, -C02H, -C02R6, -SO3H, -SOR7, -SO2R7, -SO3R7, -OCO2R7, -C(0)H, -C(0)R7, -0C(O)R7, -C(S)R7, -C(0)N(R8)(R9), -OC(0)N(R8)(R9), -N(R8)C(O)R9, -CSN(R8)(R9), -N(R8)C(S)(R9), -S02N(R8)(R9), -N(R8)SO2R9, -N(R8)C(0)N(R9)(R1°), -N(R8)C(S)N(R9)(R10), -N(R8)SO2N(R9)(R °), or optionally substituted aromatic or heteroaromatic groups. Substituted amino groups include -NHR7 and -N(R7)(R8) groups.
The optional substituents which may be present on aliphatic or heteroaliphatic chains represented by Alk1or Alk2 include one, two, three or more substituents where each substituent may be the same or different and is selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or -OH, -CN,
-CO2H, -C02R11 [where R11 is an optionally substituted straight or branched
C1-6alkyl group] e.g -CO2CH3 or -CO2C(CH3)3; -CONHR11, e.g. -CONHCH3; -CON(R11)2, e.g. -CON(CH3)2; -COR11, e.g. -COCH3; Cι-6alkoxy, e.g. methoxy or ethoxy; haloCi-βalkoxy, e.g. trifluoromethoxy or difluoromethoxy; thiol (-SH); -S(0)R11, e.g. -S(O)CH3; -S(O)2R11, e.g. -S(0)2CH3; Cι-6alkylthio e.g. methylthio or ethylthio; amino; -NHR11, e.g. -NHCH3 or -N(R11)2, e.g.
-N(CH3)2 groups. Where two R11 groups are present in any of the above substituents these may be the same or different.
When L1 is present in compounds of formula (1) as a linker atom or group it may be any such atom or group as hereinbefore described in relation to L3 linker atoms and groups. When Alk1 in compounds of formula (1) is a covalent bond then L1, when present, is a -C(O)-, -C(S)-, -S(0)2-, -CON(R5)-, -CSN(R5)- or -S(0)2N(R5)- group, where R5 is as herein defined.
When R5, R5a, R7, R8, R9 or R10 is present as a Cι-6alkyl group it may be a straight or branched Cι-6 alkyl group e.g. a Cι-3 alkyl group such as methyl, ethyl or /-propyl. Optional substituents which may be present on R11 include for example one, two or three substituents which may be the same or different selected from fluorine, chlorine, bromine or iodine atoms or hydroxy or Cι-6 alkoxy e.g. methoxy or ethoxy groups. The term "halogen atom" is intended to include fluorine, chlorine, bromine or iodine atoms.
The term "haloalkyl" is intended to include the alkyl groups just mentioned substituted by one, two or three of the halogen atoms just described. Particular examples of such groups include -CF3) -CCI3, -CHF2, -CHCI2, -CH2F, and -CH2CI groups.
The term "alkoxy" as used herein is intended to include straight or branched CM0alkoxy for example C1-6alkoxy such as methoxy, ethoxy, π-propoxy, /-propoxy and f-butoxy. "Haloalkoxy" as used herein includes any of those alkoxy groups substituted by one, two or three halogen atoms as described above. Particular examples include -OCF3, -OCCI3, -OCHF2, -OCHCI2, -OCH2F and -OCH2CI groups.
As used herein the term "alkylthio" is intended to include straight or branched C1-10alkylthio, e.g. C1-6alkylthio such as methylthio or ethylthio groups.
The terms "aromatic group" and "aryl group" are intended to include for example optionally substituted monocyclic ring C6-12 aromatic groups, such as phenyl, or bicyclic fused ring C6-12 aromatic groups, such as, 1- or 2-naphthyl groups.
The terms "heteroaromatic group" and "heteroaryl group" are intended to include for example optionally substituted C-ι-9 heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulfur or nitrogen atoms (or oxidised versions thereof). In general, the heteroaromatic groups may be for example monocyclic or bicyclic fused ring heteroaromatic groups. Monocyclic heteroaromatic groups include for example five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulfur or nitrogen atoms. Bicyclic heteroaromatic groups include for example eight- to thirteen- membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
Each of these aromatic or heteroaromatic groups may be optionally substituted by one, two, three or more R12 atoms or groups as defined below.
Particular examples of monocyclic ring heteroaromatic groups of this type include pyrrolyl, furyl, thienyl, imidazolyl, N-C1-6alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, triazinyl, pyridyl-N-oxide, dihydropyrazolonyl or imidazolonyl.
Particular examples of bicyclic ring heteroaromatic groups of this type include benzofuryl, benzothienyl, benzotriazolyl, indolyl, indazolinyl, benzimidazolyl, imidazo[1 ,2-a]pyridyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzopyranyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]-pyridyl, quinolinyl, isoquinolinyl or phthalazinyl.
The R2 or R4 heteroaromatic groups may be attached to the remainder of the compound of formula (1) by any carbon or hetero e.g. nitrogen atom as appropriate.
Optional substituents which may be present on the aromatic or heteroaromatic groups include one, two, three or more substituents, each selected from an atom or group R12 in which R12 is -R12a or -Alk3(R12a)f, where R12a is a halogen atom, or an amino (-NH2), substituted amino, nitro, cyano, hydroxyl (-OH), substituted hydroxyl, amidino, formyl, carboxyl (-CO2H), esterified carboxyl, thiol (-SH), substituted thiol, -COR13 [where R13 is an -Alk3(R1 a)f, heterocycloaliphatic, cycloaliphatic, aryl or heteroaryl group], -CSR13, -S03H, -SOR13, -S02R13, -S03R13, -SO2NH2, -S02NHR13, S02N(R13)2, -CONH2, -CSNH2, -CONHR13, -CSNHR13, -C0N(R13)2, -CSN(R13)2, -N(R14)S02R13, [where R14 is a hydrogen atom or a Cι-6 alkyl group] -N(S02R13)2, -N(R14)SO2NH2, -N(R1 )SO2NHR13, -N(R 3)S02N(R1 )2, -N(R14)COR13, -N(R14)CONH2, -N(R14)CONHR13, -N(R1 )CON(R13)2> -N(R 4)CSNH2, -N(R14)CSNHR13, -N(R1 )CSN(R13)2, -N(R14)CSR13, -N(R )C(O)OR13, -S02NHet1 [where -NHet1 is an optionally substituted C4-7heterocycloaliphatic group optionally containing one or more other -O- or -S- atoms or -N(R14)-, -C(0 or -C(S)- groups], -CONHet1, -CSNHet1, -N(R1 )SO2NHet1, -N(R1 )CONHetι, -N(R14)CSNHet1, -SO2N(R )Het2 [where Het2 is an optionally substituted monocyclic C3-7cycloaliphatic group optionally containing one or more -O- or -S- atoms or -N(R14)-, -C(O)- or -C(S)- groups], -Het2, -CON(R14)Het2, -CSN(R1 )Het2, -N(R1 )CON(R14)Het2,
-N(R14)CSN(R14)Het2, aryl or heteroaryl group; Alk3 is a straight or branched C1-6alkylene, C2-6alkenylene or C2-6alkynylene chain, optionally interrupted by one, two or three -O- or -S- atoms or -S(O)g- [where g is an integer 1 or 2] or -N(R14)- groups; and f is zero or an integer 1 , 2 or 3. It will be appreciated that when two R13 or R14 groups are present in one of the above substituents, the R13 or R groups may be the same or different.
When in the group -Alk3(R12a)t f is an integer 1 , 2 or 3, it is to be understood that the substituent or substituents R12a may be present on any suitable carbon atom in -Alk3. Where more than one R12a substituent is present these may be the same or different and may be present on the same or different atom in -Alk3. Clearly, when f is zero and no substituent R12a is present the chain represented by Alk3 becomes a corresponding group.
When R1 a is a substituted amino group it may be for example a group -NHR13 [where R13 is as defined above] or a group -N(R13)2 wherein each R13 group is the same or different.
When R1 a is a substituted hydroxyl or substituted thiol group it may be for example a group -OR13 or a -SR13 group respectively.
Esterified carboxyl groups represented by the group R12a include groups of formula -CO2Alk4 wherein Alk4 is an optionally substituted C1-6 alkyl group. When Alk3 is present in or as a substituent it may be for example a methylene, ethylene, n-propylene, /-propylene, n-butylene, /-butylene, s-butylene, t- butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three -O- or -S-, atoms or -S(O)-, -S(0)2- or -N(R15)- groups. When f is the integer 1 , 2 or 3 more particular examples include Cι-3alkylene chains, especially -CH2- or -CH2CH2.
When -NHet1 or -Het2 forms part of a substituent R 2 each may be for example an optionally substituted 2- or 3-pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperazinyl, imidazolinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, oxazolidinyl or thiazolidinyl group. Additionally Het2 may represent for example, an optionally substituted cyclopentyl or cyclohexyl group. Optional substituents which may be present on -NHet1 or -Het2 include those substituents described above in relation to aromatic groups.
Particularly useful atoms or groups represented by R12 include fluorine, chlorine, bromine or iodine atoms, or C -6alkyl, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl, optionally substituted phenyl, pyridyl, pyrimidinyl, pyrrolyl, furyl, thiazolyl, thienyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl or piperidinyl, C^ehydroxyalkyl, e.g. hydroxymethyl or hydroxyethyl, carboxyC1-6alkyl, e.g. carboxyethyl, C -6alkylthio e.g. methylthio or ethylthio, carboxyC1-6alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3- carboxypropylthio, C1-6alkoxy, e.g. methoxy or ethoxy, hydroxyC^alkoxy, e.g. 2-hydroxyethoxy, optionally substituted phenoxy, pyridyloxy, thiazolyoxy, phenylthio or pyridylthio, C5-7cycloalkoxy, e.g. cyclopentyloxy, haloC^alkyl, e.g. trifluoromethyl, haloC1-6alkoxy, e.g. thfluoromethoxy, C1-6alkylamino, e.g. methylamino or ethylamino, amino (-NH2), aminoC1-6alkyl, e.g. aminomethyl or aminoethyl, C1-6dialkylamino, e.g. dimethylamino or diethylamino, aminoC1-6 alkylamino e.g. aminoethylamino, Het1NCι-6alkylamino e.g. morpholinopropylamino, C1-6alkylaminoC1-6alkyl, e.g. ethylaminoethyl, C1-6 dialkylaminoC1-6alkyl, e.g. diethylaminoethyl, aminoC1-6alkoxy, e.g. aminoethoxy, C1-6alkylaminoC1-6alkoxy, e.g. methylaminoethoxy, C1-6 dialkylaminoCi-βalkoxy, e.g. dimethylaminoethoxy, diethylaminoethoxy, diisopropylaminoethoxy, or dimethylaminopropoxy, hydroxyC1-6alkylamino e.g. hydroxyethylamino, imido, such as phthalimido or naphthalimido, e.g. 1 ,8- naphthalimido, nitro, cyano, amidino, formyl [HC(O)-], carboxyl (-C02H), -Cθ2Alk4 [where Alk4 is as defined above], C-|.6alkanoyl e.g. acetyl, optionally substituted benzoyl, thiol (-SH), thioCi-βalkyl, e.g. thiomethyl or thioethyl, -SC(=NH)NH2, sulphonyl (-SO3H), -S03R13, C1-6alkylsulphinyl e.g. methylsulphinyl, C1-6alkylsulphonyl, e.g. methylsulphonyl, aminosulphonyl
(-S02NH2), C1-6alkylaminosulphonyl, e.g. methylamino-sulphonyl or ethylaminosulphonyl, C1-6dialkylaminosulphonyl, e.g. dimethyl-aminosulphonyl or diethylaminosulphonyl, optionally substituted phenylamino-sulphonyl, carboxamido (-CONH2), C1-6alkylaminocarbonyl, e.g. methylamino-carbonyl or ethylaminocarbonyl, C -6dialkylaminocarbonyl, e.g. dimethyl-aminocarbonyl or diethylaminocarbonyl, aminoC βalkylaminocarbonyl, e.g. aminoethylaminocarbonyl, C1-6dialkylaminoC1-6alkylaminocarbonyl, e.g. diethylaminoethylaminocarbonyl, aminocarbonylamino, C1-6alkylamino- carbonylamino, e.g. methylaminocarbonylamino or ethylaminocarbonylamino, Ci-6dialkylaminocarbonylamino, e.g. dimethylaminocarbonylamino or diethyl- aminocarbonylamino, C1-6alkylaminocabonylC1-6alkylamino, e.g. methylamino- carbonylmethylamino, aminothiocarbonylamino, C1-6alkylaminothiocarbonyl- amino, e.g. methylaminothiocarbonylamino or ethylaminothiocarbonylamino, Cι.6dialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino, Ci-ealkylaminothiocarbonylC^βalkylamino, e.g. ethylaminothiocarbonylmethylamino, -CONHC(=NH)NH2, Ci-βalkyl- sulphonylamino, e.g. methylsulphonylamino or ethylsulphonylamino, C1-6dialkyl sulphonylamino, e.g. dimethylsulphonylamino or diethylsulphonyl-amino, optionally substituted phenylsulphonylamino, aminosulphonylamino (-NHSO2NH2), C^alkylaminosulphonylamino, e.g. methylamino sulphonylamino or ethylaminosulphonylamino, C1-6dialkylamino sulphonylamino, e.g. dimethylaminosulphonylamino or diethylamino sulphonylamino, optionally substituted morpholinesulphonylamino or morpholinesulphonylCι.6alkylamino, optionally substituted phenylamino sulphonylamino, C1-6alkanoylamino, e.g. acetylamino, aminoC1-6alkanoylamino e.g. aminoacetylamino, C1-6dialkyl-aminoCι-6alkanoylamino, e.g. dimethylaminoacetylamino,
Figure imgf000017_0001
e.g. acetylaminomethyl, C1-6alkanoylaminoC1-6alkylamino, e.g. acetamidoethylamino, C1-6alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino or optionally substituted benzyloxy, benzylamino, pyridylmethoxy, thiazolylmethoxy, benzyloxy- carbonylamino, benzyloxycarbonylaminoC1-6alkyl e.g. benzyloxycarbonyl- aminoethyl, thiobenzyl, pyridylmethylthio or thiazolylmethylthio groups.
Where desired, two adjacent R12 substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C^alkylenedioxy group such as methylenedioxy or ethylenedioxy or a C3-6 cycloalkyl or 3-10 membered monocylic heterocycloaliphatic group as defined herein.
It will be appreciated that where two or more R12 substituents are present, these need not necessarily be the same atoms and/or groups. In general, the substituent(s) may be present at any available ring position in the aromatic or heteroaromatic group.
The presence of certain substituents in the compounds of formula (1) may enable salts of the compounds to be formed. Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.
Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isothionates, arylsulphonates, e.g. p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
Examples of optionally substituted alkyl groups present in ester groups of formulae -C02R6 and -C02Alk4 include Cι-6 alkyl groups as herein described, in particular Cι-3 alkyl groups. Optional substituents, which may be present on these alkyl groups, include optionally substituted cycloaliphatic, aromatic or heteroaromatic groups as herein defined. Particular examples include optionally substituted C3-6 cycloalkyl wherein the optional substituents include for example one, two or three substituents which may be the same or different selected from fluorine, chlorine, bromine or iodine atoms or hydroxy or Ci-e alkoxy e.g. methoxy or ethoxy groups; or optionally substituted phenyl or five or six membered heteroaryl groups wherein the optional substituents include for example one, two or three substituents which may be the same or different selected from fluorine, chlorine, bromine, straight or branched Ci-β alkyl, methoxy, OCF3, OCF2H, CF3, CN, NHCH3, N(CH3)2, CONH2, CONHCH3, CON(CH3)2, CO2CH3) C02CH2CH3, -CO2C(CH3)3) or -COCH3, -NHCOCH3, -N(CH3)COCH3 or CO2H.
One useful group of compounds of the invention has the formula (1) wherein both X and Y is each a S atom. A particularly preferred group of compounds has the formula (1) wherein X is an O atom and Y is a S atom. Another preferred group of compounds has the formula (1) wherein both X and Y is each an O atom. Examples of aliphatic groups, which may represent R1 include Cι-6 alkyl groups as herein described. More particular examples include Cι-3 alkyl groups, such as -CH3, -CH2CH3, -CH2CH2CH3 or -CH(CH3)CH3. Examples of cycloaliphatic groups which may represent R1 include C3-6 cycloalkyl groups, such as those described previously. Examples of cycloalkyl-alkyl- groups which may represent R1 include Cι-3 alkyl groups (as described herein) where a terminal hydrogen atom is replaced by a C3-6 cycloalkyl ring (as described herein), for example, cyclopropylCH2-.
In one group of compounds of formula (1) R1 is in particular a Ci-e alkyl group. Especially preferred is when R1 is a Cι-3 alkyl group. Most especially preferred is when R1 is a methyl group.
In another group of compounds of formula (1) R1 is in particular a haloalkyl group. Especially preferred is when R1 is a CHF2 or CH2F group.
A particularly preferred group of compounds of the invention has the formula (1) wherein R2 is an optionally substituted monocyclic heteroaromatic group, especially a five-membered heteroaromatic group containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Particular preferred heteroaromatic groups which may represent R2 include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, N-C1-6alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl or pyrazolyl. Especially preferred is when R2 is an oxazolyl group.
In compounds of formula (1) R3 is preferably represented by the groups -Alk1- L1-Alk2-R4, -Alk1-L1-R4, -Alk1-R4, -L1-Alk2-R4, -L1-R4 or -R4 wherein Alk1, L1, Alk2 and R4 are as herein defined.
A particularly preferred group of compounds of the invention has the formula (1) wherein R3 is the group -Alk1-L1-R4. Another group of compounds of the invention has the formula (1) wherein R3 is the group -Alk1-L1-Alk2-R4. One group of compounds of the invention has the formula (1) wherein Alk1 is a covalent bond or an optionally substituted aliphatic chain, in particular a Cι-6 alkylene chain, especially an optionally substituted -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)CH2- or -CH2CH(CH3)- chain, most especially a Cι-3 alkylene chain such as -CH2-, -CH2CH2- or -CH2CH2CH2-.
Alk2, when present in compounds of formula (1), is preferably a Cι-3 alkyl chain as defined herein.
One particular group of compounds of the invention has the formula (1 ) wherein Alk2 is a covalent bond.
Particular examples of L1, when present in compounds of formula (1), include -O- or -S- atoms or -C(0>, -C(S)-, -S(O)-, -S(O)2-, -C(0)0-, -OC(O)-, -N(R5)- [where R5 is as defined hereinbefore], -CON(R5)-, -CSN(R5)-, -N(R5)CO-, -N(R5)CS-, -S(0)2N(R5)- or -N(R5)S(O)2- groups. R5 is especially a hydrogen atom or a Cι-3 alkyl group, particularly a methyl group.
R4, in one particular group of compounds of formula (1 ), is a hydrogen atom or an optionally substituted C3-6 cycloalkyl, 3 to 10 membered saturated monocyclic heterocycloaliphatic, especially 3 to 6 membered, phenyl or 5 to 6 membered heteroaromatic group. More particular examples include a hydrogen atom or an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, Λ/-Cι-6 alkylpiperazinyl, especially N- methylpiperazinyl, Λ/-Cι-6 alkylpyrrolidinyl, especially Λ/-methylpyrrolidinyl, N- Ci-6 alkylpiperidinyl, especially Λ/-methylpiperidinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, N-C^ 6alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, triazinyl, pyridyl-N-oxide, dihydropyrazolonyl or imidazolonyl group. R3 in one group of compounds of formula (1) is a hydrogen atom.
One group of compounds of the invention has the formula (1) wherein R3 is the group -Alk1-L1-R4 in which Alk1 is an optionally substituted aliphatic chain, L1 is a covalent bond and R4 is a hydrogen atom. Alk1 in compounds of this type preferably forms an optionally substituted straight or branched Cι-6 alkyl chain such as those as herein defined, especially optionally substituted -CH2-, -CH2CH2-, -(CH2)2CH2-, -(CH2)3CH2- or -CH2C(CH3)2-. Optional substituents which may be present on these groups include those as herein defined for Alk1 substituents, especially -CN, -C02H, -CO2R11 [where R11 is as herein defined] -CONHR11, -CON(R11)2, -COR11, Cι-6 alkoxy, particularly methoxy or ethoxy; haloCι-6alkoxy, particularly trifluoromethoxy or difluoromethoxy; -S(O)R11, -S(O)2R11, amino, -NHR11 or -N(R11)2, groups. R11 is in particular a Cι-3 alkyl group. One particular group of compounds of this type is where Alk1 is an optionally substituted -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2- chain and the optional substituent is a -NH(CH3) or -N(CH3)2 group, especially a -N(CH3)2 group. Further preferred substituents include -CN, -CO2H, -C02CH3, -CO2CH2CH3, -C02C(CH3)3, -CONH2, -CONHCH3 or -CON(CH3)2. R3 in another particular group of compounds of this type is a -CH3, -CH2CH3, -CH2CH2CH3 or - CH2C(CH3)3 group, especially a -CH3 group.
Another group of compounds of the invention has the formula (1) wherein R3 is the group -Alk1-L1-R4 in which Alk1 is an optionally substituted aliphatic chain, L1 is a covalent bond and R4 is an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group especially an optionally substituted heterocycloaliphatic, aromatic or heteroaromatic group. Alk1 in compounds of this type is in particular a Cι-3 alkyl chain, especially -CH2-, CH2CH2- or -CH2CH2CH2-. R4 in compounds of this type is especially an optionally substituted 3-10 membered saturated monocyclic heterocycloaliphatic, phenyl or monocyclic heteroaromatic group. Particular R4 examples include optionally substituted azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, Λ/-C1-6 alkylpiperazinyl, especially Λ/-methylpiperazinyl, Λ/-Cι-6 alkylpyrrolidinyl, especially Λ/-methylpyrrolidinyl, Λ/-C1-6 alkylpiperidinyl, especially N- methylpiperidinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, /-C1-6alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, triazinyl, pyridyl-Λ/-oxide, dihydropyrazolonyl or imidazolonyl. In one group of compounds R4 is a morpholinyl, pyrrolidinonyl, Λ/-methylpiperazinyl, tetrahydropyranyl, imidazolyl, pyridyl, pyrrolidinyl, pyrazolyl, piperidinyl or N- methylpyrrolidinyl group.
R3 in another group of compounds of formula (1) is the group -Alk1-L1-R4 in which Alk1 is a covalent bond or an optionally substituted aliphatic chain, L1 is a linker group and R4 is an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group. L1 in compounds of this type is especially a -C(O)-, -C(S)- or -S(0)2 group or a -CON(R5)- or - N(R5)CO- group. One preferred group of compounds of this type is where R4 is an optionally substituted phenyl or monocyclic heteroaromatic group, especially a 5 to 6 membered heteroaromatic group. In compounds of this type R4 is in particular an optionally substituted phenyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl group.
In one group of compounds of the invention R3 is the group -Alk1-L1-Alk2-R4 in which Alk1 is an optionally substituted aliphatic chain, L1 is a linker atom or group, Alk2 is a covalent bond or an optionally substituted aliphatic or heteroaliphatic chain and R4 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group. Alk1 in compounds of this type preferably forms an optionally substituted straight or branched Cι-6 alkylene chain such as those as herein defined, especially optionally substituted -CH2-, -CH2CH2-, -(CH2)2CH2-, -(CH2)3CH2- or -CH2C(CH3)2-; L1 is preferably -O-, -C(O)-, -C(S)-, -S(O)0-2-, -N(R5)- [where R5 is a hydrogen atom or a straight or branched C1-6 alkyl group, especially methyl], -CON(R5)-, -CSN(R5)-, -N(R5)CO-, -N(R5)CS-, -S(0)2N(R5)- or -N(R5)S(O)2-; Alk2 is preferably a covalent bond or an optionally substituted straight or branched Cι-6 alkylene chain as defined herein for Alk1 or a -CH2L3- [where L3 is as defined herein], -CH(CH3)L3-, -CH2L3CH2-, -CH(CH3)CH2L3-, -CH2CH2L3-, -CH2L3CH2CH2-, -(CH2)2L3CH2-, -(CH2)3L3CH2- or -(CH2)3L3- chain and R4 is preferably a hydrogen atom or an optionally substituted C3-6 cycloalkyl, 3-10 membered saturated monocyclic heterocycloaliphatic, especially 5 to 6 membered, phenyl or monocyclic heteroaromatic group, especially 5 to 6 membered. Alk1 is most preferably a Cι-3 alkylene chain, especially -CH2-, CH2CH2- or -CH2CH2CH2-; L1 is most preferably -O-, - N(R5)-, -CON(R5)- or -N(R5)CO- [where R5 is especially a hydrogen atom or a methyl group] and Alk2 is most preferably a covalent bond or an optionally substituted Cι-3 alkylene chain, especially -CH2-, CH2CH2- or -CH2CH2CH2-. Optional substituents which may in particular be present on Alk2 include -CN, -C02H, -C02R11 [where R11 is as herein defined] -CONHR11, -CON(R11)2, -COR11, d-βalkoxy, particularly methoxy or ethoxy; haloCι.6alkoxy, particularly trifluoromethoxy or difluoromethoxy; -S(O)R11, -S(O)2R11, amino, -NHR11 or -N(R11)2, groups. R11 is in particular a C1-3 alkyl group.
One group of optional substituents which may be present on cycloaliphatic or heterocycloaliphatic groups in compounds of formula (1) and in particular on the group R4, are one, two, three or more groups selected from Ci-3 alkoxy, OCF3, OCF2H, CF3, Ci-3 alkylthio, -CN, NHCH3, N(CH3)2, CONH2, CONHCH3, CON(CH3)2, C02CH3, CO2CH2CH3, -CO2C(CH3)3, or -COCH3, -NHCOCH3, -N(CH3)COCH3> CO2H or optionally substituted straight or branched C1-3 alkyl, wherein the optional alkyl substituent is in particular a CN, Cι-3 alkoxy, NHCH3, N(CH3)2, CONH2, CONHCH3, CON(CH3)2, C02CH3, CO2CH2CH3, -C02C(CH3)3, -COCH3, -NHCOCH3, -N(CH3)COCH3> C02H or an optionally substituted phenyl or monocyclic heteroaromatic group, wherein the optional substituent is in particular selected from one, two, three or more atoms or groups selected from fluorine, chlorine, straight or branched C1-6 alkyl, methoxy, OCF3, OCF2H, CF3, CN, NHCH3, N(CH3)2, CONH2, CONHCH3, CON(CH3)2, C02CH3, C0 CH2CH3, -CO2C(CH3)3, or -COCH3, -NHCOCH3, -N(CH3)COCH3, -SCH3, -SO2CH3 or CO2H.
One group of optional substituents which may be present on aromatic or heteroaromatic groups in compounds of formula (1) and in particular in R4 aromatic or heteroaromatic groups, are one, two, three or more atoms or groups selected from fluorine, chlorine, bromine, straight or branched Cι-6 alkyl, methoxy, OCF3, OCF2H, CF3, CN, NHCH3, N(CH3)2, CONH2, CONHCH3, CON(CH3)2> C02CH3, C02CH2CH3, -CO2C(CH3)3, or -COCH3, - NHCOCH3, -N(CH3)COCH3, -SCH3, -SO2CH3, C02H or optionally substituted morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, wherein the optional substituent is in particular selected from one, two, three or more atoms or groups selected from straight or branched Cι-3 alkyl, methoxy, OCF3, OCF2H, CF3, C1-3 alkylthio, -CN, NHCH3, N(CH3)2, CONH2, CONHCH3, CON(CH3)2, C02CH3, C02CH2CH3, -CO2C(CH3)3, or -COCH3, -NHCOCH3, -N(CH3)COCH3ι CO2H, especially Cι-3 alkyl.
Particular compounds of the invention include:
7-Methoxy-3-methyl-6-oxazol-5-yl-7H-quinazoline-2,4-dione; 7-Methoxy-6-oxazol-5-yl-3-(2-pyridin-2-yl-ethyl)-7H-quinazoline-2,4-dione;
7-Methoxy-6-oxazol-5-yl-3-(tetrahydro-pyran-2-ylmethyl)- 7/--quinazoline-2,4- dione;
7-Methoxy-6-oxazol-5-yl-3-(2-pyridin-4-yl-ethyl)- 7H-quinazoline-2,4-dione;
3-(2-lmidazol-1-yl-ethyl)-7-methoxy-6-oxazol-5-yl- 7H-quinazoline-2,4-dione; hydrochloride;
7-Methoxy-3-[3-(5-methyl- 7H-pyrazol-4-yl)-propyl]-6-oxazol-5-yl- 7 -- quinazoline-3,4-dione; and the salts, solvates, hydrates, tautomers, isomers or Λ/-oxides thereof.
Compounds of formula (1) are potent inhibitors of IMPDH. The ability of the compounds to act in this way may be simply determined by employing tests such as those described in the Examples hereinafter. Thus the compounds of the invention may be used in the treatment of IMPDH- associated disorders. The invention extends to such a use and in general to the use of the compounds of formula (1) for the manufacture of a medicament for treating such diseases and disorders.
"IMPDH-associated disorders" refers to any disorder or disease state in which inhibition of the enzyme IMPDH (inosine monphosphate dehydrogenase, EC1.1.1.205, of which there are presently two known isozymes referred to as IMPDH type 1 and IMPDH type 2) would modulate the activity of cells (such as lymphocytes or other cells) and thereby ameliorate or reduce the symptoms or modify the underlying cause(s) of that disorder or disease. There may or may not be present in the disorder or disease an abnormality associated directly with the IMPDH enzyme. Examples of IMPDH-associated disorders include transplant rejection and autoimmune disorders, such as rheumatoid arthritis, lupus, multiple sclerosis, juvenile diabetes, asthma, and inflammatory bowel disease, as well as inflammatory disorders, cancer and tumors, T-cell mediated hypersensitivity diseases, ischemic or reperfusion injury, viral replication diseases, proliferative disorders and vascular diseases.
Use of the compounds of the present invention is exemplified by, but is not limited to, treating a range of disorders such as: treatment of transplant rejection (e.g. kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts (such as employed in burn treatment), heart valve xenografts, serum sickness, and graft vs. host disease, in the treatment of autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, juvenile diabetes, asthma, inflammatory bowel disease (such as Crohn's disease and ulcerative colitus), pyoderma gangrenum, lupus (systemic lupus erythematosis), myasthenia gravis, psoriasis, eczema, dermatitis, dermatomyosis, atopic dermatitis; multiple sclerosis, seborrhoea, pulmonary inflammation, eye uveitis, hepatitis, Grave's disease, Hashimoto's thyroiditis, autoimmune thyroiditis, Behcet's or Sjorgen's syndrome (dry eyes/mouth), pernicious or immunohaemolytic anaemia, Addison's disease (autoimmune disease of the adrenal glands), idiopathic adrenal insufficiency, autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome) glomerulonephritis, scleroderma, morphea, lichen planus, viteligo (depigmentation of the skin), alopecia areata, autoimmune alopecia, autoimmune hypopituatarism, cicatricial pemphigoid, Gullivan-Barre syndrome, and alveolitis; in the treatment of T-cell mediated hypersensitivity diseases, including contact hypersensitivity, delayed-type hypersensitivity, contact dermatitis (including that due to poison ivy), urticaria, skin allergies, respiratory allergies (hayfever, allergic rhinitis) and gluten-sensitive enteropathy (Celiac disease); in the treatment of inflammatory diseases such as osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, acute respiratory distress syndrome, Sezary's syndrome and vascular diseases which have an inflammatory and or a proliferatory component such as restenosis, stenosis and artherosclerosis; in the treatment of cancer and tumor disorders, such as solid tumors, lymphomas and leukemia; in the treatment of fungal infections such as mycosis fungoides; in protection from ischemic or reperfusion injury such as ischemic or reperfusion injury that may have been incurred during organ transplantation, myocardial infarction, stroke or other causes; in the treatment of DNA or RNA viral replication diseases, such as herpes simplex type 1 (HSV-1), herpes simplex type 2 (HSV-2), hepatitis (including hepatitis B and hepatitis C) cytomegalovirus, Epstein-Barr, human immundeficiency virus (HIV) and influenza.
Additionally, IMPDH is also known to be present in bacteria and thus may regulate bacterial growth. As such, the IMPDH-inhibitor compounds of the present invention may be useful in treatment or prevention of bacterial infection, alone or in combination with other antibiotic agents.
In a particular embodiment, the compounds of the present invention are useful for the treatment of the afore mentioned exemplary disorders irrespective of their etiology, for example, for the treatment of lupus, psoriasis, inflammatory bowl disease, multiple sclerosis, atopic dermatitis, transplant rejection or rheumatoid arthritis. In another particular embodiment the compounds of the present invention are of particular use for the treatment of DNA or RNA viral replication diseases, such as hepatitis (including hepatitis B and hepatitis C) cytomegalovirus, human immundeficiency virus (HIV) and influenza.
In an additional particular embodiment the compounds of the present invention are of particular use for the treatment of cancer and tumour disorders, such as solid tumors, lymphoma, leukemia and other forms of cancer.
The compounds of formula (1) can be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, anti-inflammatory agents, antibiotics, anticancer agents and immunosuppressants.
For the prophylaxis or treatment of disease the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
Alternate compositions of this invention comprise a compound formula (1) or a salt thereof; an additional agent selected from an immunosuppressant, an anti-cancer agent, an anti-viral agent, anti-inflammatory agent, anti-fungal agent, anti-vascular hyperproliferation agent or an antibiotic agent; and any pharmaceutically acceptable carrier, adjuvant or vehicle.
Thus, for example, additional immunosuppression agents include, but are not limited to, cyclosporin A, FK506, rapamycin, leflunomide, deoxyspergualin, prednisone, azathioprine, OKT3, ATAG, interferon and mizoribine. Additional anti-cancer agents include, but are not limited to, cis-platin, actinomycin D, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, tenipaside, taxol, colchicine, cyclosporin A, phenothiazines, interferon and thioxantheres. Additional anti-viral agents include, but are not limited to, Cytovene, Ganiclovir, trisodium phosphonoformate, Ribavirin, d4T, ddl, AZT and acyclovir. Additional anti-vascular hyperproliferative agents include, but are not limited to, HMG Co-A reductase inhibitors such as lovastatin, thromboxane A2 synthetase inhibitors, eicosapentanoic acid, ciprostene, trapidil, ACE inhibitors, low molecular weight heparin, and rapamycin.
The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physician's Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, vaginal or rectal administration, or a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well-known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives. The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds for formula (1) may be formulated for parenteral administration by injection e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen- free water, before use. For particle mediated administration the compounds of formula (1) may be coated on particles such as microscopic gold particles.
In addition to the formulations described above, the compounds of formula (1) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
For nasal administration or administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichloro- fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
For vaginal or rectal administration the compounds of formula (1) may be formulated as a suppository. These formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is a solid at room temperature but liquid at the body temperature. Such materials include for example cocoa butter and polyethylene glycols.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.
The quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen, and the condition of the patient to be treated. In general, however, daily dosages may range from around 100ng/kg to 100mg/kg e.g. around 0.01 mg/kg to 40mg/kg body weight for oral or buccal administration, from around 10ng/kg to 50mg/kg body weight for parenteral administration and around 0.05mg to around 1000mg e.g. around 0.5mg to around 1000mg for nasal administration or administration by inhalation or insufflation.
The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. Many of the reactions described are well-known standard synthetic methods which may be applied to a variety of compounds and as such can be used not only to generate compounds of the invention, but also where necessary the intermediates thereto.
In the following process description, the symbols R1-R3 when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (1) unless otherwise indicated. In the reactions described below, it may be necessary to protect reactive functional groups, for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W. in "Protective Groups in Organic Synthesis", John Wiley and Sons, (1999) and the examples herein]. In some instances, deprotection may be the final step in the synthesis of a compound of formula (1) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups. Compounds of formula (1 ) in which X is O and Y is S may be prepared according to one of several general methods, including the methods shown in Scheme B and Scheme C. The starting materials for these routes are the amines of formula (ii).
Amines of general formula (ii) may be prepared in a variety of ways. For example, the amine of formula (ii) where R1 is a methyl group and R2 is an oxazole group may be prepared using methods known in the literature, (CAS 198821-79-3).
Alternatively amines of formula (ii), where R2 is an optionally substituted heteroaromatc group, may be prepared using the route as shown in Scheme A:
1) Pd R2— W
R,-OX -R 2) Reduce or
(iii) FV Deprotect -"r (ϋ)x
Z=CI, Br or OTf R=R'=H or R=R'=0 or R=H, R'=Protecting group Scheme A
For example, a compound of formula (iii), where Z is a halogen atom e.g. CI or Br or a suitable leaving group e.g. trifluoromethylsulfonyloxy (OTf) and - NRR' is a nitro group or an amine group (which may be suitably protected), may be reacted with a derivative of the desired heteroaromatic group (R2-W, where W is as described below) utilising a palladium catalysed cross coupling reaction. The following literature methodology may be used to perform this coupling reaction according to the nature of the W group; e.g. when W is a hydrogen atom (Heterpcycles, 31 , pp. 1951-1958, (1990)); the zinc species (W=ZnCI) (J Organomet. Chem.. 390, pp. 389-398, (1990); Tetrahedron. 53, pp. 7237-7254, (1997) ); the mercury species (W=HgBr) (Chem. Heterocvcl. Compd.. 19, pp. 1159-1162, (1983) ) or a boron derivative (W=B(OH)2, W=BEt2) (J. Med. Chem.. 40, pp. 3542-3550, (1997); J. Pro. Chem.. 63, pp. 8295-8303, (1998) ). The resulting coupled product may require further manipulation, depending on the nature of the -NRR' group, in order to obtain an amine of formula (ii). For example, when -NRR' is a nitro group this may be reduced to an amine using standard techniques, or when -NRR' is a protected amine the protecting group may be removed using standard methodology. It will be appreciated that the various R2-W derivatives are either commercially available or may be prepared using methods known to those skilled in the art. In a similar manner the compounds of formula (iii) are either commercially available or may be prepared using methods known to those skilled in the art. For example, the compound of formula (iii) may be prepared by alkylation of the phenol precursor of (iii) using standard techniques.
One method for the synthesis of compounds of formula (1) in which X = O and Y = S is depicted in Scheme B. Amines of formula (ii) may be converted into bromides of formula (iv) using any standard procedure known to those skilled in the art. For example, amines of formula (ii) may be treated with a halogenating agent e.g. Λ/-bromosuccinimide in an appropriate solvent, such as acetonitrile, at a suitable temperature, such as -20°C. Bromides of formula (iv) may be converted into nitriles of formula (v) using any appropriate procedure known to those skilled in the art. For example, bromides of formula (iv) may be treated with zinc cyanide in the presence of a suitable catalyst, e.g. a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0), in an appropriate solvent, such as DMF (Λ/,Λ/-dimethylformamide). It may be appropriate to carry out such a reaction at elevated temperature, such as 100°C. Nitriles of formula (v) may be converted into amides of formula (vi) by hydrolysis, for example using sodium perborate tetrahydrate in aqueous methanol at elevated temperature, for example 50°C. Thioureas of formula (vii) may be obtained from amides of formula (vi) by treatment with an isothiocyanate of formula (viii) in a suitable solvent, such as acetone, at an appropriate temperature, such as reflux temperature. Thioureas of formula (vii) may be converted into compounds of formula (1) by cyclisation. Cyclisation may be achieved using an adaptation of the method described by Chan and Shish (Heterocycles, 1987, 26, 3193). Thus, heating a thiourea of formula (vii) with sodium hydroxide in aqueous ethanol provides a compound of formula (1). When Ra in a thiourea of formula (vii) is an acyl group, such as p-tolylmethanoyl, it is lost during the reaction and a compound of formula (1) in which R3 is H will be produced. When Ra is not an acyl group, it is retained during the reaction and the product of formula (1) will have R3 = Ra. Amides of formula (vi) may be prepared using a variety of alternative procedures known to those skilled in the art, including the methods described in a recent patent application, WO0181340. Standard functional group interconversions known to those skilled in the art may be employed.
Figure imgf000033_0001
(ιι) (iv)
Figure imgf000033_0002
S ch e m e B
Figure imgf000033_0003
(1 )
An alternative method for the synthesis of compounds of formula (1) in which
X =0 and Y = S is shown in Scheme C. An ester of formula (ix) may be treated with thiophosgene in the presence of a suitable base, such as triethylamine, in an appropriate solvent such as dichloromethane to provide an isothiocyanate of formula (x). Heating an isothiocyanate of formula (x) with an amine of formula (xi) in an appropriate solvent, such as THF, at a suitable temperature, such as reflux temperature, provides a compound of formula (1). Esters of formula (ix) may be prepared by any suitable method known to those skilled in the art, including the methods described in a recent patent application, WO0181340. Amines of formula (xi) may be commercially available, previously described compounds, or prepared using any standard method known to those skilled in the art.
Figure imgf000034_0001
( 1 )
Compounds of formula (1) in which X is O and Y is O may be prepared according to one of several general methods, including the methods shown in Scheme D, E and F.
Thus amines of formula (ix) may be treated with triphosgene in the presence of a suitable base such as triethylamine in an appropriate solvent such as dichloromethane to afford intermediate isocyanate (xii). This may be reacted, without isolating, with an amine of formula (xi) to yield ureas of formula (xiii). The urea thus formed may then be heated to reflux in a mixture of ethanol and water in the presence of sodium hydroxide to afford the desired quinazolinedione of general formula (1). Alternatively the ureas of formula (xiii) may be heated to reflux in a solvent such as ethylene glycol dimethyl ether with a non-nucleophilic, non-hydrolysing base such as 1 ,5- diazabicyclo[4.3.0]non-5-ene to yield the diones of formula (1 ).
Figure imgf000035_0001
Scheme D
Alternatively, In route E, adapted from the method of Smith et al (Bioorganic & Medicinal Chemistry Letter, 6 (1996), 1483-1486), amines of formula (xiv) may be treated with a commercially available chloroformate of formula (xv) using a suitable base such as di/sopropylethylamine in an appropriate solvent such as dichloromethane to give a carbamate of formula (xvi). The free acid in compounds of formula (xvi) may then be coupled with amines of formula (xi) using standard conditions known to those skilled in the art to give an amide of formula (xvii). Appropriate coupling conditions may involve the use of a coupling reagent such as pyBOP® (benzotriazol-1-yloxytris (pyrrolidino)phosphonium hexafluorophosphate) in the presence of suitable base such as diisopropylethylamine in a suitable solvent such as dichloromethane. The amides of formula (xv) may then be heated in an appropriate solvent such as DMF to afford the desired quinazolinediones of general formula (1).
Figure imgf000036_0001
S c h e m e E
Figure imgf000036_0002
Alternatively a catch-and-release variant of this method, as shown in route F, adapted in part from the method of Dressman et al. (Tetrahedron Letters, 37(7), (1996), 937-940) may be used. Thus, amines of formula (xiv) may be reacted with an acylating reagent attached to an inert support (represented by the black circle in Scheme F), such as a polystyrene resin, employing for example hydroxymethyl polystyrene p-nitrophenylcarbonate (xviii) and N- methylmorpholine (NMM) in DCM, to give an intermediate resin-bound carbamate (xix). The free acids (xix) may then coupled with amines of formula (xi) using standard conditions such as PyBOP in the presence of a suitable base such as di-/so-propylethylamine in a suitable solvent such as dichloromethane or Λ/-methylpyrrolidinone to give resin-bound amides of formula (xx). Heating compounds of formula (xx) in an appropriate solvent such as DMF cleaves the desired quinazolinediones of formula (1) from the resin.
Figure imgf000037_0001
(1 )
Scheme F
Compounds of formula (1) in which X is S, Y is S and R3 is H may be prepared as shown in scheme G according to the method of Chem et al (J. Med. Chem. 1993, 36, 2196-2207). Thus an amine of formula (v) may be heated at reflux in pyridine with carbon disulphide to afford a quinazolinedithiones of general formula (1).
Figure imgf000038_0001
It will be appreciated that compounds of formula (1) or any preceding intermediates may be further derivatised by one or more standard synthetic methods employing substitution, oxidation, reduction or cleavage reactions.
Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, thioacylation, halogenation, sulphonylation, nitration, formylation and coupling procedures. It will be appreciated that these methods may also be used to obtain or modify other compounds of any of formula (1) or any preceding intermediates where appropriate functional groups exist in these compounds.
For example, ester groups such as -C02R6, -C02R11 or -C02Alk4 in the compounds may be converted to the corresponding acid [-CO2H] by acid- or base-catalysed hydrolysis depending on the nature of the groups R6, R 1 or Alk4. Acid- or base- catalysed hydrolysis may be achieved for example by treatment with an organic or inorganic acid, e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxan or an alkali metal hydroxide, e.g. lithium hydroxide in an aqueous alcohol, e.g. aqueous methanol. Similarly an acid [-CO2H] may be prepared by hydrolysis of the corresponding nitrile [-CN], using for example a base such as sodium hydroxide in a refluxing alcoholic solvent, such as ethanol.
In another example, -OH groups may be generated from the corresponding ester [e.g. CO2Alk4 or C02R11] or aldehyde [-CHO] by reduction, using for example a complex metal hydride such as lithium aluminium hydride or sodium borohydride in a solvent such as methanol. Alternatively an alcohol may be prepared by reduction of the corresponding acid [-C02H], using for example lithium aluminium hydride in a solvent such as tetrahydrofuran. Alcohol groups may be converted into leaving groups, such as halogen atoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g. trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g. p-toluenesulfonyloxy group using conditions known to those skilled in the art. For example, an alcohol may be reacted with thionyl chloride in a halogenated hydrocarbon e.g., dichloromethane to yield the corresponding chloride. A base e.g., triethylamine may also be used in the reaction.
In another example, alcohol or phenol groups may be converted to ether groups groups by coupling a phenol with an alcohol in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate. Alternatively ether groups may be prepared by deprotonation of an alcohol, using a suitable base e.g. sodium hydride followed by subsequent addition of an alkylating agent, such as an alkylhalide.
Aldehyde [-CHO] groups may be obtained by oxidation of a corresponding alcohol using well known conditions. For example using an oxidising agent such as a periodinane e.g. Dess Martin, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane. An alternative oxidation may be suitably activating dimethyl sulfoxide using for example, oxalyl chloride, followed by addition of an alcohol, and subsequent quenching of the reaction by the addition of an amine base, such as triethylamine. Suitable conditions for this reaction may be using an appropriate solvent, for example, a halogenated hydrocarbon, e.g. dichloromethane at -78°C followed by subsequent warming to room temperature.
In a further example primary amine (-NH2) or secondary amine (-NH-) groups may be alkylated using a reductive alkylation process employing an aldehyde and a borohydride, for example sodium triacetoxyborohyride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, a ketone such as acetone, or an alcohol, e.g. ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature. In a further example, amine [-NH2] groups may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e.g. ethanol at ambient temperature.
In another example, a nitro [-N02] group may be reduced to an amine [-NH2], for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol e.g. methanol, or by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid.
In a further example amine (-CH2NH2) groups may be obtained by reduction of nitriles (-CN), for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon, or Raney nickel, in a solvent such as an ether e.g. a cyclic an ether, e.g. a cyclic ether such as tetrahydrofuran, at a temperature from -78°C to the reflux temperature.
Aromatic halogen substituents in the compounds may be subjected to halogen- metal exchange by treatment with a base, for example a lithium base such as n-butyl or t- butyl lithium, optionally at a low temperature, e.g. around -78°C, in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent. Thus, for example, a formyl group may be introduced by using dimethylformamide as the electrophile; a thiomethyl group may be introduced by using dimethyldisulphide as the electrophile. Aromatic halogen substituents may also be subjected to palladium catalysed reactions, to introduce, for example, acid, ester, cyano or amino substituents.
In another example, sulphur atoms in the compounds, for example when present in a linker group L1, L2 or L3 may be oxidised to the corresponding sulphoxide or sulphone using an oxidising agent such as a peroxy acid, e.g. 3- chloroperoxybenzoic acid, in an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane, at around ambient temperature.
N-oxides of compounds of formula (1) may be prepared for example by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70°C to 80°C, or alternatively by reaction with a peracid such as peracetic acid in a solvent, e.g. dichloromethane, at ambient temperature.
Salts of compounds of formula (1) may be prepared by reaction of a compound of formula (1) with an appropriate base or acid in a suitable solvent or mixture of solvents e.g. an organic solvent such as an ether e.g. diethylether, or an alcohol, e.g. ethanol or an aqueous solvent using conventional procedures. Salts of compounds of formula (1) may be exchanged for other salts by use of conventional ion-exchange chromatography procedures.
Where it is desired to obtain a particular enantiomer of a compound of formula (1) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers.
Thus for example diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (1) e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base. The diastereomers may then be separated by any convenient means, for example by crystallisation and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
In another resolution process a racemate of formula (1) may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.
The following Examples illustrate the invention. All temperatures are in °C. Where experimental detail is not given for the preparation of a reagent it is either commercially available, or it is known in the literature, for which the CAS number is quoted. The compounds are named with the aid of Beilstein Autonom supplied by MDL Information Systems GmbH, Theodor-Heuss-Allee 108, D-60486 Frankfurt, Germany.
1H NMR spectra were obtained at 300MHz or 400MHz unless otherwise indicated.
The following LCMS conditions were used to obtained the retention times (RT) as described herein: LCMS conditions:
HP1100 (Diode Array) linked to a Finnigan LC-Q Mass Spectrometer, ESI mode with Pos/Neg ionization
Column: Luna C18(2) 100x4.6mm, 5μm particle size Analytical column Column Temp: 35°C
Mobile Phase: A: Water + 0.08% formic acid
B: Acetonitrile + 0.1% formic acid
Flow rate: 3ml/min
Gradient: Time (mins): % Composition B: 0 5
4.4 95 5.30 95 5.32 5
6.5 5 6.6
Run time: 6.5 mins
Typical Injection Vol: 5μl
Detector Wavelength: DAD 205-330nm
Preparative LC conditions:
Gilson 215 liquid handler setup.
Column: Luna C18(2) 250x21.2mm, 5μn particle size PREP column Column Temp: Ambient Mobile Phase: A: Water + 0.08% formic acid B: Acetonitrile + 0.1% formic acid Gradient: Variable - depends on retention of sample in LCMS screen
Run Time: 20 mins Flow rate: 20ml/min
Typical Injection Vol: 750μl of 25mg/ml solution
Detector Wavelength: 210 and 254nm
Abbreviations: PyBOP Benzo-triazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate CDCI3 Chloroform-d DCM Dichloromethane
DBN 1 ,8-Diazabicyclo[4.3.0]non-5-ene Et20 Diethyl ether EDC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride DIPEA Di- so-propylethylamine DMAPDimethylaminopyridine DMF Λ/,Λ/-Dimethylformamide EtOH Ethanol d6-DMSO Dimethyl-d6sulphoxide EtOAc Ethyl acetate
DME Ethylene glycol dimethyl ether HOBT 1-Hydroxybenzotriazole
MeOH Methanol d4-MeOH Methanol-d4
NMP Λ/-Methylpyrrolidinone THF Tetrahydrofuran TEA Triethylamine
Intermediate 1. 2-Bromo-5-methoxy-4-oxazol-5-yl-phenylamine
To a solution/suspension of 3-methoxy-4-oxazol-5-yl-phenylamine (CAS 198821-79-3) (3.0g) in dry acetonitrile (120ml) under nitrogen cooled to -20°C was added portionwise Λ/-bromosuccinimide (3.1 g). The reaction mixture was stirred at -20°C for 15 mins. Water (50ml) was added and the mixture extracted with EtOAc (200ml). The organic layer was washed with water (50ml), washed with brine (50ml), separated, dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by column chromatography eluting with 40% EtOAc/hexane to afford the title compound as a pale yellow solid (2.1 g, 49%). TLC Rf 0.33 (50% EtOAc/hexane). 1H NMR 300MHz (CDCI3) 7.83 (1 H, s), 7.79 (1 H, s), 7.35 (1 H, s), 6.38 (1 H, s), 4.17-4.32 (2H, s, br), 3.88 (3H, s). Intermediate 2. 2-Amino-4-methoxy-5-oxazol-5-yl-benzonitrile A mixture of Intermediate 1 (2.8g), zinc cyanide (1.8g) and tetrakis(triphenylphosphine)palladium(0) (0.60g) in dry DMF (30ml) under nitrogen was heated at 100°C for 96 hours. Water (30ml) was added and the mixture extracted with EtOAc (200ml). The organic layer was washed with water (6 x 30ml), washed with brine (30ml), separated, dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by column chromatography eluting with 60-80% EtOAc/hexane to afford the title compound as a pale yellow solid (1.6g, 71%). TLC Rf 0.17 (50% EtOAc/hexane). 1H NMR 300MHz (CDCI3) 7.86 (1 H, s), 7.80 (1 H, s), 7.37 (1 H, s), 6.29 (1 H, s), 4.48-4.66 (2H, s, br), 3.96 (3H, s). Intermediate 3. 2- Am i no-4-methox v-5-oxazol-5-yl-benzam ide To a mixture of Intermediate 2 (50mg) and sodium perborate tetrahydrate (106mg) in water (10ml) heated to 50°C was added dropwise MeOH (10ml). Heating was continued overnight. The MeOH was removed in vacuo and the aqueous residue extracted with DCM (3 x 50ml). The organic layers were combined, dried over MgS0 ) filtered and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 70% EtOAc/heptane to afford the title compound as a yellow solid (16mg, 30%). TLC Rf 0.38 (EtOAc). 1H NMR 300MHz (d4-MeOH) 8.04 (1 H, s), 7.87 (1 H, s), 7.17 (1 H, s), 6.31 (1 H, s), 3.83 (3H, s). Intermediate 4. 4-methoxy-5-oxazol-5-yl-2-r3-(1-p-tolyl-methanoyl)- thioureidol-benzamide
A mixture of Intermediate 3 (50mg) and 4-methylbenzoyl isothiocyanate (0.03ml) in acetone (10ml) was heated at reflux for 30 mins. The resulting solid was filtered off and dried in vacuo to yield the title compound as a pale yellow solid (62mg, 70%). TLC Rf 0.58 (EtOAc). 1H NMR 300MHz (d6- DMSO) 13.56-13.74 (1 H, s, br), 11.50-11.60 (1 H, s, br), 8.66 (1 H, s), 8.47 (1H, s), 8.30-8.40 (1 H, s, br), 8.15 (1 H, s), 8.03-8.05 (2H, d), 7.75 (1 H, s), 7.63-7.72 (1 H, s, br), 7.48-7.50 (2H, d), 4.14 (3H, s), 2.55 (3H, s). Intermediate 5. 2-lsothiocvanato-4-methoxy-5-oxazol-5-yl-benzoic acid methyl ester To a solution of 2-amino-4-methoxy-5-oxazol-5-yl-benzoic acid methyl ester (CAS 371251-37-5) (1.0g) in dry DCM (60ml) under nitrogen cooled to -78°C was added TEA (1.2ml) followed by thiophosgene (0.34ml) dropwise. The reaction mixture was allowed to warm to 0°C and stirred for 30 mins. The solvent was removed in vacuo and the residue purified by column chromatography on silica eluting with 40% EtOAc/hexane to yield the title compound as a mustard yellow solid (0.59g, 50%). TLC Rf 0.46 (50% EtOAc/hexane). 1H NMR 300MHz (CDCI3) 8.44 (1 H, s), 7.95 (1 H, s), 7.58 (1 H, s), 7.55 (1 H, s), 6.85 (1 H, s), 4.04 (3H, s), 3.98 (3H, s).
Intermediate 6. 2-r3-(2,2-Dimethylpropyl)-ureidol-4-methoxy-5-oxazol-
5-yl-benzoic acid methyl ester To a solution of 2-amino-4-methoxy-5-oxazol-5-yl-benzoic acid methyl ester (CAS 371251-37-5) (120mg) in dry DCM (10ml) cooled to -78°C was added TEA (0.14ml) followed by triphosgene (50mg). The reaction mixture was allowed to warm to 0°C and stirred for 30mins. Terf-amylamine (0.07ml) was added dropwise and the reaction mixture stirred at 0°C for 60mins. The solvent was removed in vacuo and the residue purified by flash chromatography on silica eluting with 40% EtOAc/hexane to afford the title compound as an off-white solid (103mg, 59%). TLC R 0.39 (50% EtOAc/hexane). 1H NMR 300MHz (CDCI3) 10.60-10.68 (1 H, s, br), 8.44 (1 H, s), 8.39 (1 H, s), 7.87 (1 H, s), 7.46 (1 H, s), 4.80-4.90 (1 H, m), 4.04 (3H, s), 3.93 (3H, s), 3.10-3.13 (2H, d), 0.97 (9H, s). Intermediate 7. 4-Methoxy-2-(3-methylureido)-5-oxazol-5-yl-benzoic acid methyl ester
To a solution of 2-amino-4-methoxy-5-oxazol-5-yl-benzoic acid methyl ester (100mg) in dry DCM (10ml) under nitrogen cooled to -78°C was added TEA (0.11 ml) followed by triphosgene (42mg). The reaction mixture was allowed to warm to 0°C and stirred for 30mins. Methylamine hydrochloride (41 mg) was added in a single portion followed by TEA (0.08ml). The mixture was stirred at 0°C for 90mins, after which the solvent was removed in vacuo. Purification by flash chromatography on silica eluting with 50-100% EtOAc/hexane afforded the title compound as a cream solid (87mg, 71%). TLC Rf 0.11 (50% EtOAc/hexane). 1H NMR 300MHz (CDCI3) 10.60-10.75 (1 H, s, br), 8.44 (1 H, s), 8.39 (1 H, s), 7.88 (1 H, s), 7.46 (1 H, s), 4.70-4.80 (1 H, m), 4.04 (3H, s), 3.92 (3H, s), 2.91-2.93 (3H, d).
Intermediate 8. 4-Methoxy-5-oxazol-5-yl-2-r3-(2-pyridin-2-ylethvD- ureidol-benzoic acid methyl ester To a solution of 2-amino-4-methoxy-5-oxazol-5-yl-benzoic acid methyl ester (100mg) in dry DCM (10ml) under nitrogen cooled to -78°C was added triphosgene (42mg) followed by triethylamine (0.11 ml) dropwise. The mixture was allowed to warm to 0°C and stirred for 30mins. 2-(2-Aminoethyl)pyridine (0.05ml) was added dropwise and the mixture stirred at 0°C for 30mins. A precipitate resulted. The solvent was removed in vacuo and the residue triturated in DCM/Et2O and in water to afford the title compound as a white solid (57mg, 36%). TLC Rf 0.16 (EtOAc). 1H NMR 300MHz (d6-DMSO) 10.10-10.20 (1 H, s, br), 8.48-8.54 (1 H, m), 8.38 (2H, s), 8.24 (1 H, s), 7.80- 7.88 (1 H, m), 7.57-7.65 (1 H, m), 7.35 (1 H, s), 7.19-7.21 (2H, m), 3.96 (3H, s), 3.87 (3H, s), 3.41-3.51 (2H, m), 2.88-2.97 (2H, m).
Intermediates 9 and 10 were prepared in a similar manner to method of intermediate 8:-
Intermediate 9. 4-Methoxy-2-r3-(2-morpholin-4-yl-ethyl)-ureido1-5- oxazol-5-yl-benzoic acid methyl ester From 2-amino-4-methoxy-5-oxazol-5-yl-benzoic acid methyl ester (150mg) and 4-(2-aminoethyl)morpholine (0.09ml). Purification by flash chromatography on silica eluting with 5-10% MeOH/DCM afforded the title compound as an off-white solid (172mg, 70%). TLC Rf 0.40 (10% MeOH/DCM). 1H NMR 300MHz (d6-DMSO) 10.13 (1 H, s), 8.41 (2H, s), 8.26 (1H, s), 7.65-7.67 (1 H, s, br), 7.44 (1 H, s), 3.94 (3H, s), 3.86 (3H, s), 3.56-3.60 (4H, tr), 3.18-3.26 (2H, q), 2.36-2.42 (6H, m). Intermediate 10. 2-r3-(3-lmidazol-1-yl-propyl)-ureido1-4-methoxy-5- oxazol-5-yl-benzoic acid methyl ester From 2-amino-4-methoxy-5-oxazol-5-yl-benzoic acid methyl ester (150mg) and 1-(3-aminopropyl)-imidazole (0.08ml). Purification by thturation in DCM / Et20 and in water afforded the title compound as an off-white solid (149mg, 62%). TLC Rf 0.34 (10% MeOH/DCM). 1H NMR 300MHz (d6-DMSO) 10.16- 10.27 (1 H, s, br), 8.42 (2H, s), 8.26 (1 H, s), 7.78-7.88 (1 H, s, br), 7.71 (1 H, s), 7.47 (1 H, s), 7.24 (1 H, s), 6.94 (1 H, s), 4.01-4.08 (2H, m), 3.97 (3H, s), 3.92 (3H, s), 3.04-3.13 (2H, m), 1.84-2.00 (2H, m). Intermediate 11. 4-Methoxy-5-oxazol-5-yl-2-r3-(tetrahvdro-pyran-2- ylmethvD-ureidol-benzoic acid methyl ester
To a solution of 2-amino-4-methoxy-5-oxazol-5-yl-benzoic acid methyl ester (200mg) in dry DCM (20ml) under nitrogen cooled to -78°C was added triphosgene (84mg) followed by triethylamine (0.23ml) dropwise. The reaction mixture was allowed to warm to 0°C and stirred for 30mins. 2-(Aminomethyl)tetrahydropyran (CAS 6628-83-7) (112mg) was then added and the mixture stirred at 0°C for 30mins. The solvent was removed in vacuo. Purification by trituration in Et20 followed by trituration in aqueous citric acid afforded the title compound as a pale yellow solid (104mg. 33%). TLC Rf 0.44 (EtOAc). LCMS 390 [M+1]\ RT 3.26 mins. 1H NMR 300MHz (CDCI3) 10.61 (1 H, s, br), 8.44 (1 H, s), 8.39 (1 H, s), 7.89 (1 H, s), 7.57 (1 H, s), 5.28-5.20 (1 H, s, br), 4.04 (3H, s), 4.04-3.94 (1 H, m), 3.94 (3H, s), 3.60-3.40 (3H, m), 3.16- 3.06 (1 H, m), 1.90-1.82 (1 H, m), 1.68-1.18 (5H, m).
Intermediate 12 was prepared in a similar manner to the method of intermediate 11 :-
I ntermed iate 12. 2-(3-r3-(2.5-Dioxopyrrolidin-1-yl)propynureido -4- methoxy-5-oxazol-5-ylbenzoic acid methyl ester
From 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid methyl ester (115mg) and 1-(3-aminopropyl)pyrrolidine-2,5-dione (CAS 54052-99-2) (134mg). Purification by flash chromatography on silica eluting with 5% MeOH/DCM afforded the title compound as a pale orange solid (142mg, 72%). TLC Rf 0.26 (5% MeOH/DCM). LCMS 431 [M+1]+, RT 2.68 mins.
Intermediate 13. 4-Methoxy-5-oxazol-5-yl-2-r3-(2-pyridin-4-ylethyl)- ureidolbenzoic acid methyl ester To a solution of 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid methyl ester (125mg) in dry DCM (30ml) under nitrogen cooled to -78°C was added TEA (0.14ml) followed by triphosgene (52mg). The reaction mixture was allowed to warm to 0°C and stirred for 2 hours. 4-(2-Aminoethyl)pyridine (0.140 ml) was added dropwise and the reaction mixture stirred at 0°C for 2 hours. The solvent was removed in vacuo. Purification by flash chromatography on silica eluting with 6% MeOH/DCM afforded the title compound as a white solid (133mg, 67%). TLC Rf 0.31 (6% MeOH/DCM). LCMS 397 [M+1]+, RT 1.79 mins. 1H NMR 300MHz (d6-DMSO) 10.14 (1 H, s, br), 8.51-8.49 (2H, d), 8.43 (1 H, s), 8.41 (1 H, s), 8.27 (1 H, s), 7.80-7.73 (1 H, s, br), 7.57 (1 H, s), 7.31-7.29 (2H, d), 3.97 (3H, s), 3.90 (3H, s), 3.44-3.37 (2H, q), 2.83-2.79 (2H, tr).
Intermediates 14-16 were prepared in a similar manner to the method of intermediate 13:-
Intermediate 14. 2-(3-Cvanomethylureido)-4-methoxy-5-oxazol-5- ylbenzoic acid methyl ester
From 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid methyl ester (110mg) and aminoacetonitrile (62mg). Purification by flash chromatography on silica eluting with 3% MeOH/DCM afforded the title compound as a yellow solid (87mg, 60%). TLC R, 0.20 (3% MeOH/DCM). LCMS 331 [M+1]+, RT 2.80 mins. Intermediate 15. 2-(3-r2-(1 H-lmidazol-4-yl)ethyllureido>-4-methoxy-5- oxazol-5-ylbenzoic acid methyl ester From 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid methyl ester (125mg) and histamine (84mg). Purification by flash chromatography on silica eluting with 8-10% MeOH/DCM (containing concentrated aqueous ammonium hydroxide (c. NH3)) afforded the title compound as a white solid (87mg, 45%). TLC Rf 0.31 (8% MeOH/DCM + c. NH3). LCMS 386 [M+1]+, RT 1.77 mins. Intermediate 16 2-r3-(2-Acetylaminoethv0ureido1-4-methoxy-5-oxazol- 5-ylbenzoic acid methyl ester
From 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid methyl ester (200mg) and Λ/-acetylethylenediamine (123mg). Purification by trituration with EtOAc afforded the title compound as an off-white solid (223mg, 73%). LCMS 377 [M+1]+, RT 2.35 mins. Intermediate 17. 2-r3-(2-lmidazol-1-ylethyl)ureido1-4-methoxy-5-oxazol-
5-ylbenzoic acid methyl ester To a stirred solution of 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid methyl ester (200mg) in dry DCM (20ml) under nitrogen cooled to -78°C was added TEA (0.22ml) followed by triphosgene (84mg). The reaction mixture was allowed to warm to 0°C and stirred for 30mins. TEA (0.28ml) was added followed by 1-(2-aminoethyl)imidazole dihydrochloride (CAS 93668-43-0) (178mg). The mixture was stirred at 0°C for 60mins and at room temperature for 90mins. The reaction mixture was diluted with 1 N HCI (50ml) and washed with EtOAc (2 x 200ml). The aqueous layer was basified with aqueous Na2CO3 and extracted with EtOAc (2 x 200ml). The organic layer was separated, dried over MgSO4, filtered and the solvent removed in vacuo. Purification by trituration with MeOH/Et2O (1 :6) afforded the title compound as a white solid (111 mg, 36%). LCMS 386 [M+1]\ RT 1.71 mins. 1H NMR 300MHz (de-DMSO) 10.12 (1 H, s, br), 8.36 (1 H, s), 8.35 (1 H, s), 8.23 (1 H, s), 7.92-7.85 (1 H, s, br), 7.59 (1 H, s), 7.44 (1 H, s), 7.15 (1 H, s), 6.87 (1 H, s), 4.06-4.02 (2H, tr), 3.93 (3H, s), 3.87 (3H, s), 3.43-3.37 (2H, q).
Intermediates 18-19 were prepared in a similar manner to the method of intermediate 17 :-
Intermediate 18. 2-r3-(4-fe/t-Butoxycarbonylaminobutyl)ureido1-4- methoxy-5-oxazol-5-ylbenzoic acid methyl ester From 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid methyl ester (700mg) and Λ/-te/ -butoxycarbonyl-1 ,4-diaminobutane (530mg). Purification by flash chromatography on silica eluting with 50-100% EtOAc/heptane afforded the title compound as an off-white solid (1.27g, 98%). TLC Rf 0.78 (EtOAc). LCMS 463 [M+1]+, RT 3.47 mins. Intermediate 19. 2-l3-r2-(fe/t-Butoxycarbonylmethylamino)ethyll- ureido)-4-methoxy-5-oxazol-5-ylbenzoic acid methyl ester From 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid methyl ester (379mg) and Λ/-tert-butoxycarbonyl-Λ/-methylethylenediamine (0.41 ml). Purification by flash chromatography on silica eluting with 3% MeOH/DCM afforded the title compound as an orange solid (571 mg, 83%). TLC Rf 0.28 (3% MeOH/DCM). LCMS 449 [M+1]+, RT 3.56 mins. Intermediate 20. 2-Chloro-M-r2-(7-methoxy-β-oxazol-5-yl-2.4-dioxo-1.4- dihvdro-2H-quinazolin-3-yl)ethyll/V-methylacetamide
A suspension of example 65 (198mg) in DCM (20ml) was treated with chloroacetyl chloride (0.100ml), followed by 1 M aqueous Na2C03 solution (1.5ml), and the mixture stirred at room temperature for 30 mins. The reaction mixture was then washed with water (20ml), 1% citric acid solution (20ml), water (20ml), saturated NaHCO3 solution (20ml), saturated brine (20ml), dried over Na2S04, filtered and concentrated in vacuo to provide the title compound as a brown solid (85mg, 39%). TLC Rf 0.26 (5% MeOH/ DCM + c. NH4OH). LCMS 393,395[M+1]+, RT 2.35 mins.
Example 1. 7-Methoxy-6-oxazol-5-yl-2-thioxo-2.3-dihvdro-7 - quinazolin-4-one
To a suspension of Intermediate 4 (50mg) in ethanol (5ml) was added a solution of sodium hydroxide (24mg) in water (2.5ml). The mixture was heated at reflux for 2 hours. The ethanol was removed in vacuo and the aqueous residue acidified to pH2 with 2M HCI. The resulting solid was filtered off and purified by column chromatography on silica eluting with 5-10% MeOH/DCM to yield the title compound as cream solid (10mg, 30%). TLC Rf 0.09 (5% MeOH/DCM). LCMS 276 [M+1]+, RT 1.41 mins. 1H NMR 300MHz (d6- DMSO) 12.38-12.90 (2H, s, br), 8.52 (1 H, s), 8.19 (1 H, s), 7.64 (1 H, s), 7.03 (1 H, s), 4.04 (3H, s).
Example 2. 7-Methoxy-6-oxazol-5-yl-3-pyridin-3-yl-2-thioxo-2.3- dihvdro- 7H-αuinazolin-4-one A solution of Intermediate 5 (25mg) and 3-aminopyridine (8mg) in dry THF (5ml) was heated at reflux for 18 hours. The solvent was removed in vacuo. The residue was triturated in DCM, filtered off and dried in vacuo to afford the title compound as a brown solid (16mo. 53%). TLC Rf 0.15 (EtOAc). LCMS 353 [M+1]+, RT 2.31 mins. 1H NMR 300MHz (d6-DMSO) 13.10-13.27 (1 H, s, br), 8.59-8.62 (1 H, dd), 8.50-8.52 (1 H, d), 8.19 (1 H, s), 7.76-7.83 (1 H, ddd), 7.63 (1 H, s), 7.53-7.57 (1 H, dd), 7.12 (1 H, s), 4.04 (3H, s).
The compounds of Examples 3-24 were prepared in a similar manner to the compound of Example 2:- Example 3. 3-(2.2-Dimethyl-propyl)-7-methoxy-6-oxazol-5-yl-2- thioxo-2.3-dihvdro-7H-quinazolin-4-one
From Intermediate 5 (40mg) and fe/t-amylamine (0.02ml). Triturating in Et2O afforded the title compound as an off-white solid (23mg, 48%). TLC Rf 0.67 (EtOAc). LCMS 346 [M+1]+ , RT 3.84 mins. 1H NMR 300MHz (d6-DMSO) 12.72-12.88 (1 H, s, br), 8.47 (1 H, s), 8.16 (1 H, s), 7.59 (1 H, s), 7.02 (1 H, s), 4.42-4.53 (1 H, s, br), 4.00 (3H, s). Example 4. 7-Methoxy-3-methyl-6-oxazol-5-yl-2-thioxo-2.3-dihvdro- H- quinazolin-4-one
From Intermediate 5 (40mg) and methylamine hydrochloride (28mg) and TEA (0.06ml). Triturating in Et2O and water afforded the title compound as an off- white solid (19mg, 48%). 1H NMR 300MHz (d6-DMSO) 13.11-13.34 (1 H, s, br), 8.75 (1 H, s), 8.45 (1 H, s), 7.86 (1 H, s), 7.31 (1 H, s), 4.29 (3H, s), 3.93 (3H, s). LCMS 290 [M+1]+ , RT 2.75 mins.
Example 5. 7-Methoxy-3-(3-morpholin-4-yl-propyl)-6-oxazol-5-yl-
2-thioxo-2,3-dihvdro-7H-quinazolin-4-one From Intermediate 5 (40mg) and 4-(3-aminopropyl)morpholine (0.02ml). Triturating in DCM afforded the title compound as an off-white solid (20mg, 36%). 1H NMR 300MHz (d6-DMSO) 12.70-12.891 (1 H, s, br), 8.48 (1 H, s), 8.19 (1 H, s), 7.58 (1 H, s), 7.02 (1 H, s), 4.41-4.49 (2H, tr), 4.00 (3H, s), 3.41- 3.54 (4H, m), 2.26-2.43 (6H, m), 1.80-1.95 (2H, m). LCMS 403 [M+1]+, RT 1.54 mins. Example 6. 7-Methoxy-6-oxazol-5-yl-3-(2-pyridin-2-yl-ethyl)-2-thioxo-2.3- dihvdro- 7H-quinazolin-4-one
From Intermediate 5 (40mg) and 2-(2-aminoethyl)-pyridine (0.02ml). Triturating in DCM afforded the title compound as a cream solid (14mg, 27%). 1H NMR 300MHz (d6-DMSO) 11.4-12.1 (1 H, s, br), 8.42-8.48 (2H, m), 8.13 (1 H, s), 7.67-7.74 (1 H, dd), 7.56 (1 H, s), 7.25-7.31 (1 H, d), 7.17-7.25 (1 H, dd), 7.00 (1 H, s), 4.66-4.76 (2H, tr), 3.97 (3H, s), 3.06-3.15 (2H, tr). LCMS 381 [M+1]+, RT 1.78 mins.
Example 7. 3-(3-lmidazol-1-yl)-7-methoxy-6-oxazol-5-yl-2-thioxo-
2.3-dihvdro- 7H-quinazolin-4-one From Intermediate 5 (40mg) and 1-(3-aminopropyl)imidazole (0.016ml). Triturating in DCM afforded the title compound as an off-white solid (20mg, 38%). 1H NMR 300MHz (d6-DMSO) 8.48 (1 H, s), 8.19 (1 H, s), 7.65 (1 H, s), 7.61 (1 H, s), 7.19 (1 H, s), 7.02 (1 H, s), 6.86 (1 H, s), 4.38-4.44 (2H, tr), 4.03- 4.09 (2H, tr), 4.00 (3H, s), 2.08-2.20 (2H, trtr). LCMS 384 [M+1]+, RT 1.61 mins. Example 8. 3-(2-Dimethyiamino-ethyl)-7-methoxy-6-oxazol-5-yl-2- thioxo-2,3-dihvdro-7H-quinazolin-4-one From Intermediate 5 (40mg) and Λ/,Λ/-dimethylethylenediamine (0.015ml). Triturating in Et20 afforded the title compound as an off-white solid (30mg, 63%).
1H NMR 300MHz (d6-DMSO) 8.49 (1 H, s), 8.16 (1 H, s), 7.79 (1 H, s), 7.00 (1 H, s), 4.44-4.54 (2H, m), 3.98 (3H, s), 3.26-3.40 (2H, m), 2.21 (6H, s). LCMS 347 [M+1]+, RT 1.52 mins. Example 9. 7-Methoxy-3-(2-morpholin-4-yl-ethyl)-6-oxazol-5-yl-2- thioxo-2,3-dihvdro-7H-quinazolin-4-one From Intermediate 5 (40mg) and 4-(2-aminoethyl)morpholine (0.02ml). Triturating in Et20 afforded the title compound as a pale yellow solid (49mg, 92%). 1H NMR 300MHz (d6-DMSO) 12.40-13.06 (1 H, s, br), 8.53 (1 H, s), 8.19 (1 H, s), 7.62 (1 H, s), 7.04 (1 H, s), 4.54-4.59 (2H, tr), 4.06 (3H, s), 3.33- 3.43 (4H, m), 2.48-2.63 (6H, m). LCMS 389 [M+1]+, RT 1.51 mins. Example 10. 7-Methoxy-β-oxazol-5-yl-3-r3-(2-oxo-pyrrolidin-1-vD- propyll-2-thioxo-2,3-dihvdro-7H-quinazolin-4-one From Intermediate 5 (40mg) and 1-(3-aminopropyl)-2-pyrrolidinone (0.02ml). Triturating in DCM afforded the title compound as an off-white solid (25mg, 45%). 1H NMR 300MHz (DLCMSO-d6) 8.48 (1 H, s), 8.16 (1 H, s), 7.54 (1 H, s), 6.93 (1 H, s), 4.33-4.41 (2H, tr), 3.98 (3H, s), 3.16-3.45 (4H, m), 2.18-2.25 (2H, tr), 1.80-2.00 (4H, m). LCMS 401 [M+1]+, RT 2.47 mins. Example 11. 7-Methoxy-3-r3-(4-methyl-piperazin-1-yl)-propyπ-6- oxazol-5-yl-2-thioxo-2,3-dihydro-7H-quinazolin-4-one
From Intermediate 5 (40mg) and 1-(3-aminopropyl)-4-methyl-piperazine (0.03ml). Triturating in Et2O afforded the title compound as a yellow solid (36mg, 63%). 1H NMR 300MHz (d6-DMSO) 12.1-12.8 (1 H, s, br), 8.48 (1 H, s), 8.20 (1 H, s), 7.60 (1 H, s), 7.02 (1 H, s), 4.40-4.46 (2H, tr), 3.99 (3H, s), 1.80-2.45 (15H, m). LCMS 416 [M+1 ]+, RT 1.41 mins. Example 12. 7-Methoxy-6-oxazol-5-yl-3-pyridin-4-ylmethyl-2- thioxo-2.3-dihvdro-7H-quinazolin-4-one From Intermediate 5 (40mg) and 4-(aminomethyl)pyridine (0.016ml). Triturating in Et20 afforded the title compound as a cream solid (36mg, 71%). 1H NMR 300MHz (d6-DMSO) 12.20-12.84 (1 H, s, br), 8.44-8.50 (3H, m), 8.18 (1 H, s), 7.60 (1 H, s), 7.23-7.26 (2H, d), 7.06 (1 H, s), 5.65 (2H, s), 4.04 (3H, s). LCMS 367 [M+1]+, RT 1.73 mins. Example 13. (7-Methoxy-6-oxazol-5-yl-4-oxo-2-thioxo-1 ,4-dihvdro-
2H-quinazolin-3-yl)-acetic acid methyl ester From Intermediate 5 (205mg), glycine methyl ester hydrochloride (89mg) and TEA (0.2ml). Triturating with water and purification by flash chromatography eluting with EtOAc afforded the title compound as a pale yellow solid (89mg, 36%). 1H NMR 300MHz (d6-DMSO) 13.2 (1 H, s, br), 8.4 (1 H, s), 8.2 (1 H, s), 7.65 (1 H, s), 7.05 (1 H, s), 5.2 (2H, s), 4.05 (3H, s), 3.7 (3H, s). LCMS 348 [M+1]+, RT 2.84 mins. Example 14. 4-(7-Methoxy-6-oxazol-5-yl-4-oxo-2-thioxo-1.4- dihvdro-2H-quinazolin-3-yl)-butyric acid ethyl ester From Intermediate 5 (300mg), ethyl 4-aminobutyrate hydrochloride (173mg) and TEA (0.29ml). Triturating with water afforded the title compound as an off- white solid (369mg, 92%). 1H NMR 300MHz (d6-DMSO) 12.95 (1 H, s, br), 8.55 (1 H, s), 8.2 (1 H, s), 7.65 (1 H, s), 7.05 (1 H, s), 4.45 (2H, t), 4.1-4.0 (5H, m), 2.4 (2H, t), 2.05-1.95 (2H, m), 1.2 (3H, t). LCMS 390 [M+1]+, RT 3.25 mins.
Example 15. 3-(7-Methoxy-β-oxazol-5-yl-4-oxo-2-thioxo-1.4- dihvdro-,2/-/-quinazolin-3-vD-propionic acid ethyl ester From Intermediate 5 (300mg), β-alanine ethyl ester hydrochloride (158mg) and TEA (0.29ml). Triturating with water afforded the title compound as an off- white solid (361 mg, 93%). 1H NMR 300MHz (d6-DMSO) 12.95 (1 H, s, br), 8.5 (1 H, s), 8.2 (1 H, s), 7.6 (1 H, s), 7.05 (1 H, s), 4.6 (2H, t), 4.1-4.0 (5H, m), 2.7 (2H, t), 1.15 (3H, t). LCMS 376 [M+1]+, RT 3.16 mins. Example 16. 3-Ethyl-7-methoxy-β-oxazol-5-yl-2-thioxo-2.3-dihvdro-
7H-quiazolin-4-one
From Intermediate 5 (40mg) and ethylamine (2M in THF) (0.14ml). Triturating with Et20 afforded the title compound as an off-white solid (28mg). 1H NMR 300MHz (de-DMSO) 12.85 (1 H, s, br), 8.5 (1 H, s), 8.15 (1 H, s), 7.6 (1 H, s), 7.0 (1 H, s), 4.45 (2H, q), 4.0 (3H, s), 1.2 (3H, t). LCMS 304 [M+1]+, RT 3.03 mins. Example 17. 7-Methoxy-6-oxazol-5-yl-3-propyl-2-thioxo-2.3- dihvdro-7H-quinazolin-4-one From Intermediate 5 (40mg) and propylamine (0.1 ml). Triturating with Et2O afforded the title compound as an off-white solid (25mg). 1H NMR 300MHz (de-DMSO) 12.85 (1 H, s, br), 8.5 (1 H, s), 8.15 (1 H, s), 7.6 (1 H, s), 7.0 (1 H, s), 4.35 (2H, q), 4.0 (3H, s), 1.7 (2H, m), 0.9 (3H, t). LCMS 318 [M+1]\ RT 3.32 mins. Example 18. 7-Methoxy-6-oxazol-5-yl-3-pyridin-2-ylmethyl-2- thioxo-2.3-dihvdro-7H-quinazolin-4-one
From Intermediate 5 (40mg) and 2-(aminomethyl)pyridine (15mg). Triturating with Et20 afforded the title compound as a tan solid (29mg). 1H NMR 300MHz (d6-DMSO) 8.55-8.4 (2H, m), 8.2 (1 H, s), 7.8-7.6 (2H, m), 7.3-7.2 (2H, m), 7.1 (1 H, s), 5.75 (2H, s), 4.1 (3H, s). LCMS 367 [M+1]+, RT 2.28 mins.
Example 19. 7-Methoxy-6-oxazol-5-yl-3-(2-pyridin-3-yl-ethyl)-2- thioxo-2,3-dihvdro-7H-quinazolin-4-one From Intermediate 5 (40mg) and 3-(aminoethyl)pyridine (17mg). Triturating with Et20 then with DCM afforded the title compound as an off-white solid (25mg). 1H NMR 300MHz (d6-DMSO) 8.55-8.45 (4H, m), 8.2 (1 H, s), 7.8-7.7 (1 H, m), 7.65 (1 H, s), 7.4-7.3 (1 H, m), 7.05 (1 H, s), 4.7-4.6 (2H, m), 4.05 (3H, s), 3.1-3.0 (2H, m). LCMS 381 [M+1]\ RT 1.76 mins. Example 20. 7-Methoxy-6-oxazol-5-yl-3-(2-Pyridin-4-vi-ethylι-2- thioxo-2,3-dihvdro-7H-quinazolin-4-one From Intermediate 5 (40mg) and 4-(aminoethyl)pyridine (17mg). Triturating with Et20 then with DCM afforded the title compound as an off-white solid (15mg). 1H NMR 300MHz (d6-DMSO) 10-9.3 (1 H, s, br), 8.45 (3H, m), 8.15 (1 H, s), 7.55 (1 H, s), 7.3-7.2 (3H, m), 7.0 (1 H, s), 4.65-4.55 (2H, m), 4.0 (3H, s), 3.05-2.95 (2H, m). LCMS 381 [M+1]+, RT 1.69 mins. Example 21. 7-Methoxy-3-r3-(5-methyl-7H-pyrazol-4-vn-propyn-β- oxazol-5-yl-2-thioxo-2,3-dihvdro-7H-quinazolin-4-one
From Intermediate 5 (40mg) and 3-(5-methyl- 7 --pyrazol-4-yl)-propylamine (27mg). Triturating with THF/Et20 afforded the title compound as a pale yellow solid (30mg). 1H NMR 300MHz (d6-DMSO) 12.66-13.15 (1 H, br, s), 12.00-12.40 (1 H, br, s), 8.52 (1 H, s), 8.21 (1 H, s), 7.63 (1 H, s), 7.20-7.52 (1 H, br, s), 7.04 (1 H, s), 4.38-4.44 (2H, tr), 4.03 (3H, s), 2.41-2.47 (2H, m), 2.15 (3H, s), 1.86-1.99 (2H, m). LCMS 398 [M+1]\ RT 2.45 mins. Example 22. (7-Methoxy-6-oxazol-5-yl-4-oxo-2-thioxo-1.4-dihvdro- 2H-quinazolin-3-yl)-acetonitrile
From Intermediate 5 (40mg), aminoacetonitrile.HCI (13mg) and TEA (0.04ml). Triturating with water and then purification by preparative HPLC afforded the title compound as an off-white solid (9mg). 1H NMR 300MHz (d6-DMSO) 8.5 (1 H, s), 8.2 (1 H, s), 7.65 (1 H, s), 7.05 (1 H, s), 5.4 (2H, s), 4.05 (3H, s). LCMS 315 [M+1]+, RT 2.73 mins.
Example 23. r2-(7-Methoxy-6-oxazol-5-yl-4-oxo-2-thioxo-1.4- dihvdro-2H-quinazolin-3-yl)-ethylamino1-acetic acid ethyl ester From Intermediate 5 (40mg), Λ/-β-aminoethylglycine ethyl ester.2HCI (30mg) and TEA (0.1 ml). Triturating with water and then purification by preparative HPLC afforded the title compound as an off-white solid (2mg). 1H NMR 300MHz (de-DMSO) 8.3 (1 H, s), 8.15 (1 H, s), 7.45 (1 H, s), 6.75 (1 H, s), 4.1 (2H, q), 3.95 (3H, s), 3.7 (2H, s), 3.3 (2H, t), 1.15 (3H, t). LCMS 405 [M+1]+, RT 1.62 mins. Example 24. r3-(7-Methoxy-6-oxazol-5-yl-4-oxo-2-thioxo-1.4- dihvdro-2H-quinazolin-3-yl)-propyll-carbamic acid tert-butyl ester From Intermediate 5 (150mg) and terf-butyl Λ/-(3-aminopropyl)-carbamate (0.11ml). Triturating with DCM/Et20 afforded the title compound as an off- white solid (190mg, 85%). 1H NMR 300MHz (d6-DMSO) 13.03-12.84 (1 H, s, br), 8.54 (1 H, s), 8.21 (1 H, s), 7.64 (1 H, s), 7.06 (1 H, s), 6.89-6.84 (1 H, tr, br), 4.06 (3H, s), 3.06-2.96 (2H, m), 1.90-1.76 (2H, m), 1.42 (9H, s). LCMS 431 [M-1]+, RT 3.33 mins. Example 25. (7-Methoxy-β-oxazol-5-yl-4-oxo-2-thioxo-1.4-dihvdro-
2H-quinazolin-3-yl)-acetic acid
Example 13 (87mg), lithium hydroxide hydrate (21 mg), water (1 ml), THF (2ml) and MeOH (2ml) were combined and stirred at room temperature for 16 hrs. Then heated to reflux for 6 hrs. The solvents were then removed in vacuo and the residue triturated with aqueous 1 N HCI to give the title compound as an off-white solid (82mg, 98%). 1H NMR 300MHz (d6-DMSO) 13.15 (1 H, s, br), 8.5 (1 H, s), 8.2 (1 H, s), 7.6 (1 H, s), 7.1 (1 H, s), 5.1 (2H, s), 4.05 (3H, s). LCMS 334 [M+1 ]+, RT 2.33 mins.
The compounds of Examples 26-27 were prepared in a similar manner to the compound of Example 25:-
Example 26. 3-(7-Methoxy-6-oxazol-5-yl-4-oxo-2-thioxo-1.4- dihvdro-2H-quinazolin-3-yl)-propionic acid
From Example 15 (339mg), and lithium hydroxide (76mg). Triturating with aqueous 1 N HCI gave the title compound as an off-white solid (343mg, 100%). 1H NMR 300MHz (d6-DMSO) 12.95 (1 H, s, br), 8.5 (1 H, s), 8.2 (1 H, s), 7.6 (1H, s), 7.05 (1 H, s), 4.5 (2H, t), 4.0 (3H, s), 2.65 (2H, t). LCMS 348 [M+1]+, RT 2.36 mins. Example 27.4-(7-Methoxy-6-oxazol-5-yl-4-oxo-2-thioxo-1.4-dihvdro-2H- quinazolin-3-yl)-butyric acid From Example 14 (348mg), and lithium hydroxide (76mg). Triturating with aqueous 1 N HCI gave the title compound as an off-white solid (323mg, 96%). 1H NMR 300MHz (d6-DMSO) 12.9 (1 H, s, br), 8.5 (1 H, s), 8.2 (1 H, s), 7.6 (1 H, s), 7.0 (1 H, s), 4.4 (2H, t), 4.0 (3H, s), 2.3 (2H, t), 1.95 (2H, m). LCMS 362 [M+1]+, RT 2.49 mins. Example 28. 2-(7-Methoxy-6-oxazol-5-yl-4-oxo-2-thioxo-1.4- dihvdro-2H-quinazolin-3-yl)-n-pyridin-4-yl-acetamide
Example 25 (20mg), 4-aminopyridine (6mg), TEA (10 drops), EDC (12mg), DMAP (1mg) and DMF (3ml) were combined and stirred at room temperature for 2 days. The reaction was then evaporated to dryness and purified by preparative HPLC to give the title compound as an off-white solid (2mg). 1H NMR 300MHz (d6-DMSO) 8.25 (3H, m), 8.15 (3H, m), 7.5 (2H, d), 7.4 (1 H, s), 6.75 (1 H, s), 5.25 (2H, s), 3.95 (3H, s). LCMS 410 [M+1]+, RT 1.59 mins. Example 29. 3-(3-Amino-propyh-7-methoxy-6-oxazol-5-yl-2-thioxo-
2,3-dihvdro-7H-quinazolin-4-one: trifluoro-acetic acid salt
To a suspension/solution of Example 24 (100mg) in DCM (20ml) was added trifluoroacetic acid (5ml) and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue triturated in DCM/Et2O to afford the title compound as an off-white solid (97mg, 95%). 1H NMR 300MHz (d6-DMSO) 12.98 (1 H, s), 8.50 (1 H, s), 8.18 (1 H, s), 7.85-7.66 (2H, s, br), 7.60 (1 H, s), 7.04 (1 H, s), 4.46-4.42 (2H, tr), 4.03 (3H, s), 2.96-2.80 (2H, m), 2.08-1.92 (2H, m). LCMS 333 [M+1- F3CC02H]+, RT 1.52 mins. Example 30. ΛH3-(7-Methoxy-6-oxazol-5-yl-4-oxo-2-thioxo-1.4- dihvdro-2H-qinazolin-3-yl)-propyll-nicotinamide
To a suspension of Example 29 (50mg) in dry DCM (10ml) was added TEA (0.02ml) followed by nicotinic acid (14mg), EDC (26mg) and HOBT (18mg). DMF (5ml) was added and the mixture stirred at room temperature overnight. Trituration in water followed by trituration in DCM afforded the title compound as an off-white solid (28mg, 57%). 1H NMR 300MHz (d6-DMSO) 12.75 (1 H, s), 9.00 (1 H, s), 8.74-8.65 (2H, m), 8.50 (1 H, s), 8.20 (1 H, s), 8.19-8.16 (1 H, d), 7.60 (1 H, s), 7.52-7.47 (1 H, m), 7.05 (1 H, s), 4.53-4.46 (2H, tr), 4.04 (3H, s), 3.43-3.34 (2H, m), 2.06-1.92 (2H, m). LCMS 438 [M+1]+, RT 2.23 mins. Example 31. 7-Methoxy-6-oxazol-5-yl-7A quinazoline-2,4-dione To a solution of 2-amino-4-methoxy-5-oxazol-5-yl-benzoic acid methyl ester (CAS 371251-37-5) (100mg) in dry DCM (10ml) cooled to -78°C was added TEA (0.14ml) followed by triphosgene (50mg). The reaction mixture was allowed to warm to 0°C and stirred for 30 mins. A solution of ammonia (0.5M in dioxane) (8.1 ml) was added slowly and the reaction mixture stirred at 0°C for 30 mins. The solvent was removed in vacuo to give a pale yellow solid. This was resuspended in EtOH (10ml) and a solution of NaOH (48mg) in water (2ml) added. The mixture was heated at reflux for 90 mins. After cooling to room temperature, the organic solvent was removed in vacuo and the aqueous residue acidified to pH1 with 2M HCI. The resulting solid was filtered off, washed with water, washed with DCM and dried in vacuo. Purification by flash chromatography on silica eluting with 0-5% MeOH/EtOAc afforded the title compound as an off-white solid (5mg, 5%). TLC Rf 0.33 (EtOAc). 1H NMR 300MHz (d6-DMSO) 11.26 (1 H, s), 11.20 (1 H, s), 8.42 (1 H, s), 8.12 (1 H, s), 7.51 (1 H, s), 6.79 (1 H, s), 3.96 (3H, s). LCMS 260 [M+1 ]+, RT 1.82 mins. Example 32. 3-(2,2-Dimethyl-propyl)-7-methoxy-β-oxazol-5-yl-7H- quinazoline-2,4-dione To a solution of Intermediate 6 (100mg) in EtOH (10ml) was added a solution of NaOH (33mg) in water (2ml) and the reaction mixture heated at reflux for 2 hours. The ethanol was removed in vacuo and the aqueous residue acidified to pH1 with aqueous 2M HCI. The resulting solid was filtered off and dried in vacuo to afford the title compound as a white solid (69mg, 76%). TLC Rf 0.23 (50% EtOAc/hexane). 1H NMR 300MHz (d6-DMSO) 11.46 (1 H, s), 8.45 (1 H, s), 8.18 (1 H, s), 7.52 (1 H, s), 6.80 (1 H, s), 4.00 (3H, s), 3.82 (2H, s), 0.91 (9H, s). LCMS 330 [M+1]+, RT 3.17 mins. Example 33. 7-Methoxy-3-methyl-β-oxazol-5-yl-7H-quinazoline-2.4- dione To a solution of Intermediate 7 (80mg) in ethanol (10ml) was added NaOH (31 mg) in H20 (2ml) and the reaction mixture heated at reflux for 90mins. The ethanol was removed in vacuo and the aqueous residue acidified to pH1 with aqueous 2M HCI. The resulting solid was filtered off, washed with H2O, washed with Et2O and dried in vacuo to afford the title compound as a white solid (35mg, 49%). TLC Rf 0.19 (EtOAc). H NMR 300MHz (d6-DMSO) 11.55 (1 H, s), 8.45 (1H, s), 8.17 (1 H, s), 7.53 (1 H, s), 6.81 (1 H, s), 3.99 (3H, s), 3.24 (3H, s). LCMS 274 [M+1]+, RT 2.16 mins. Example 34. 7-Methoxy-6-oxazol-5-yl-3-(2-pyridin-2-yl-ethyl)-7M- quinazoline-2,4-dione To a solution of Intermediate 8 (55mg) in EtOH/water (10ml/1 ml) was added NaOH (17mg) in water (1 ml). The mixture was heated at reflux for 3 hours. The EtOH was removed in vacuo and the aqueous residue acidified to pH7 with aqueous 2M HCI. The resulting precipitate was filtered off, washed with water, washed with Et20 to afford the title compound as a white solid (41 mg, 81%). 1H NMR 400MHz (d6-DMSO) 11.23-11.48 (1 H, s, br), 8.44-8.46 (1 H, m), 8.38 (1 H, s), 8.18 (1 H, s), 7.65-7.69 (1 H, m), 7.50 (1 H, s), 7.25-7.27 (1 H, d), 7.17-7.21 (1 H, m), 6.81 (1 H, s), 4.24-4.27 (2H, tr), 4.04 (3H, s), 3.02-3.06 (2H, tr). LCMS 365 [M+1]+, RT 1.56 mins.
The compounds of Examples 35-36 were prepared in a similar manner to the compound of Example 34:-
Example 35. 7-Methoxy-3-(2-morpholin-4-yl-ethyl)-6-oxazol-5-yl-
7H-quinazoline-2,4-dione From Intermediate 9 (160mg). Acidification to pH7 and isolation of the resulting precipitate afforded the title compound as a white solid (127mg, 86%). 1H NMR 300MHz (d6-DMSO) 11.37-11.44 (1 H, s, br), 8.45 (1 H, s), 8.14 (1 H, s), 7.50 (1 H, s), 6.75 (1 H, s), 4.02-3.95 (2H, m), 3.77 (3H, s), 3.48- 3.54 (4H, m), 2.38-2.44 (6H, m). LCMS 373 [M+1]+, RT 1.40 mins. Example 36. 3-(3-lmidazol-1-yl-propyl)-7-methoxy-6-oxazol-5-yl-7H- quinazoline-2,4-dione From Intermediate 10 (130mg). Acidification to pH7 and isolation of the resulting precipitate afforded the title compound as a white solid (103mg, 86%). 1H NMR 300MHz (d6-DMSO) 11.54 (1 H, s), 8.48 (1 H, s), 8.22 (1 H, s), 7.67 (1 H, s), 7.56 (1 H, s), 7.23 (1 H, s), 6.89 (1 H, s), 6.81 (1 H, s), 4.01-4.06 (2H, m), 4.03 (3H, s), 3.87-3.93 (2H, tr), 2.01-2.06 (2H, m). LCMS 368 [M+1]+, RT 1.45 mins.
Example 37. 7-Methoxy-6-oxazol-5-yl-3-(tetrahvdro-pyran-2- ylmethyl)-7H-quinazoline-2.4-dione To a solution/suspension of Intermediate 11 (104mg) in EtOH/water (15ml/2ml) was added NaOH in water (2ml). The resulting clear solution was heated at reflux for 3 hours. The EtOH was removed in vacuo and the aqueous residue acidified to pH7 with aqueous 2M HCI. The resulting precipitate was filtered off and dried in vacuo to yield by the title compound as a yellow solid (72mg, 75%). TLC Rf 0.27 (EtOAc). 1H NMR 300MHz (de- DMSO) 11.52 (1 H, s), 8.46 (1 H, s), 8.18 (1 H, s), 7.56 (1 H, s), 6.83 (1 H, s), 4.13-3.94 (1 H, m), 4.02 (3H, s), 3.85-3.68 (2H, m), 3.67-3.43 (1 H, m), 3.40- 3.13 (1 H, m), 1.81-1.68 (1 H, m), 1.60-1.13 (5H, m). LCMS 274 [M+1]+, RT 2.16 mins. Example 38. 3-r3-(2,5-Dioxo-pyrrolidin-1-v0-propyπ-7-methoxy-6- oxazol-5-yl-7H-quinazoline-2,4-dione
A mixture of Intermediate 12 (136mg) and DBN (0.04ml) in DME (20ml) was heated at reflux overnight. The mixture was allowed to cool and the resulting precipitate filtered off, washed with DME and washed with Et20 to yield the title compound as a white solid (66mg, 52%). TLC Rf 0.28 (5% MeOH/DCM). 1H NMR 300MHz (d6-DMSO) 11.52 (1 H, s, br), 8.46 (1 H, s), 8.16 (1 H, s), 7.52 (1 H, s), 6.80 (1 H, s), 4.00 (3H, s), 3.88-3.83 (2H, m), 3.40-3.35 (2H, m), 3.60 (4H, s), 1.85-1.73 (2H, m). LCMS 399 [M+1]+, RT 2.10 mins. Example 39. 7-Methoxy-β-oxazol-5-yl-3-(2-pyridin-4-yl-ethyl)-7H- quinazoline-2,4-dione A mixture of Intermediate 13 (121 mg) and DBN (0.045ml) in DME (20ml) was heated at reflux overnight. The mixture was allowed to cool and the resulting precipitate was filtered off, washed with DME and washed with Et2O to yield the title compound as a white solid (95mg, 84%). TLC Rf 0.29 (7% MeOH/DCM). 1H NMR 300MHz (d6-DMSO) 11.55 (1 H, s, br), 8.50-8.46 (3H, m), 8.18 (1 H, s), 7.55 (1 H, s), 7.29-7.26 (2H, m), 6.81 (1 H, s), 4.19-4.13 (2H, tr), 4.05 (3H, s), 2.96-2.90 (2H, tr). LCMS 365 [M+1]+, RT 1.54 mins.
The compounds of Examples 40-42 were prepared in a similar manner to the compound of Example 39:-
Example 40. (7-Methoxy-6-oxazol-5-yl-2,4-dioxo-1,4-dihvdro-2H- quinazolin-3-yl)-acetonitrile From Intermediate 14 (98mg) and DBN (0.044ml). The resulting precipitate was filtered off, washed with DME and washed with Et20 to yield the title compound as a white solid (56mg, 63%). TLC Rf 0.40 (5% MeOH/DCM). 1H NMR 300MHz (d6-DMSO) 11.92-11.80 (1 H, s, br), 8.48 (1 H, s), 8.22 (1 H, s), 7.52 (1 H, s), 6.84 (1 H, s), 3.92 (2H, s), 4.04 (3H, s). LCMS 299 [M+1]+, RT 2.31 mins.
Example 41. 3-[2-(7H-lmidazol-4-yl)-ethyl]-7-methoxy-6-oxazol-5-yl-
7H-quinazoline-2,4-dione From Intermediate 15 (84mg) and DBN (0.032ml). The resulting precipitate was filtered off, washed with DME and washed with Et20 to yield the title compound as a white solid (70mg, 90%). TLC Rf 0.32 (10% MeOH/DCM + cNH3). H NMR 300MHz (d6-DMSO) 12.00-11.90 (1 H, s, br), 11.54 (1 H, s), 8.49 (1 H, s), 8.22 (1 H, s), 7.59 (1 H, s), 7.56 (1 H, s), 6.85 (1 H, s), 6.83 (1 H, s), 4.17-4.11 (2H, tr), 4.04 (3H, s), 3.87-3.80 (2H, tr). LCMS 354 [M+1]+, RT 1.52 mins.
Example 42. ΛH7-Methoxy-6-oxazol-5-yl-2.4-dioxo-1.4-dihvdro-2H- quinazolin-3-yl)-ethyll-acetamide From Intermediate 16 (220mg) and DBN (0.086ml). The resulting precipitate was filtered off and triturated in hot MeOH to afford the title compound as a solid (175mg, 87%). TLC Rf 0.29 (EtOAc).1 H NMR 300MHz (d6-DMSO) 8.45 (1 H,s), 8.16 (1 H,s), 7.93 (1 H.tr), 7.55 (1 H, s), 6.80 (1 H, s), 4.00 (3H, s), 3.95 (2H, tr), 3.30 (2H, m), 1.72 (3H,s). LCMS 344 [M+1]\ RT 1.90 mins. Example 43. 3-(2-lmidazol-1 -yl-ethyl)-7-methoxy-6-oxazol-5-yl- 1H- quinazoline-2.4-dione: hydrochloride A mixture of Intermediate 17 (111 mg) and DBN (0.043ml) in DME (20ml) was heated at reflux overnight. The mixture was allowed to cool and the resulting precipitate was filtered off and washed with EtOAc. The solid was dissolved in MeOH and aqueous HCI and the solvent removed in vacuo. The residue was washed with DCM, EtOAc and MeOH to afford the title compound as a solid (31 mg, 30%). 1H NMR 300MHz (d4-MeOH) 9.10 (1 H, s), 8.40 (1 H, s), 8.39 (1 H, s), 7.75 (1 H, m), 7.60 (1 H, s), 7.59 (1 H, m), 6.85 (1 H, s), 4.65 (2H, m), 4.55 (2H,m), 4.15 (3H, s). LCMS 354 [M+1]+, RT 1.45 mins.
The compounds of Examples 44-45 were prepared in a similar manner to the compound of Example 43:-
Example 44. r4-(7-Methoxy-6-oxazol-5-yl-2.4-dioxo-1.4-dihvdro-2tf- quinazolin-3-yl)-butyll-carbamic acid terf-butyl ester
From Intermediate 18 (1.27g) and DBN (0.341 ml). The solvent was removed in vacuo and the residue washed with Et20, EtOAc and MeOH to afford the title compound as a solid (597mg, 50%). TLC Rf 0.51 (EtOAc). 1H NMR 300MHz (de-DMSO) 1 1.47 (1 H, s, br), 8.48 (1 H, s), 8.20 (1 H, s), 7.55 (1 H, s), 6.80 (1 H, s), 6.795 (1 H, s, br), 4.00 (3H, s), 3.89 (2H, m), 2.92 (2H, m), 1.55 (2H, m), 1.40 (2H, m), 1.38 (9H, s). LCMS 354 [M+1 ]+, RT 2.98 mins. Example 45 r2-(7-Methoxy-6-oxazol-5-yl-2.4-dioxo-1.4-dihvdro-2H- quinazolin-3-yl)-ethyll-carbamic acid tert-butyl ester
From Intermediate 19 (569mg) and DBN (0.188ml). The solvent was removed in vacuo. The residue was dissolved in DCM (40ml), washed with 1% citric acid solution (20ml), water (20ml), saturated brine (20ml), dried over MgS04 and the solvent removed in vacuo to yield the title compound as an orange solid (545mg, 100%). TLC Rf 0.20 (10%MeOH/DCM). 1H NMR 400MHz, 50°C (CDCI3) 9.22 (1 H, s, br), 8.49 (1 H,s), 7.90 (1 H,s), 7.49 (1 H, s), 6.58 (1 H, s), 4.25 (2H,tr), 4.02 (3H,s), 3.60 (2H, tr), 2.94 (3H, s), 1.29 (9H, s). LCMS 439 [M+Na]+, RT 2.86 mins.
Example 46 7-Methoxy-3-r3-(5-methyl-7H-pyrazol-4-yl)-propyπ-6- oxazol-5-yl-7H-quinazoline-3.4-dione To a solution of 2-amino-4-methoxy-5-oxazol-5-yl-benzoic acid methyl ester (CAS 371251-37-5) (200mg) in dry THF (20ml) under nitrogen cooled to -78°C was added triphosgene (84mg) followed by TEA (0.23ml) dropwise. The reaction mixture was allowed to warm to 0°C and stirred for 30 mins. 3- (5-Methyl- H-pyrazole-4-yl) propylamine (135mg) in THF (3ml) was added dropwise and the mixture stirred at 0°C for 90 mins. The solvent was removed in vacuo and the residue triturated with Et20 and water to give a bright yellow solid (188mg). A mixture of the solid (188mg) and DBN (0.07ml) in DME (15ml) was heated at reflux overnight. The solvent was removed in vacuo and the residue was purified by preparative HPLC to afford the title compound as a white solid (9.5mg, 5.4%). TLC Rf 0.42 (10%MeOH/DCM). 1H NMR 400MHz 130°C (d6-DMSO) 8.24 (1 H, s), 8.24 (1 H, s), 7.45 (1 H, s), 7.29 (1 H, s), 6.90 (1 H, s), 4.01 (3H, s), 3.98 (2H, tr), 2.45 (2H, tr), 2.15 (3H,s), 1.90 (2H, m). LCMS 381 [M+1]+, RT 2.09 mins.
The compounds of Examples 47-50 were prepared in a similar manner to the compound of Example 46:-
Example 47. 7-Methoxy-3-r2-(3-methyl-3H-imidazol-4-yl)-ethvM-6- oxazol-5-yl-7H-quinazoline-3,4-dione
From 2-amino-4-methoxy-5-oxazol-5-yl-benzoic acid methyl ester (CAS 371251-37-5) (104mg), 3-methylhistidine (100mg), TEA (0.23ml) and triphosgene (44mg) in dry DCM (20ml). The reaction was allowed to warm to room temperature and stirred for 2 days. The solvent was removed in vacuo and the residue partitioned between EtOAc (50ml) and water (30ml). The aqueous was extracted with EtOAc (3 x 50ml), the organic layers were combined, dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by column chromatography on silica eluting with 5-10% MeOH/DCM to give a white solid. A mixture of the solid (10mg) and DBN (0.007ml) in DME (10ml) was heated at reflux overnight. The solvent was removed in vacuo and the residue triturated with MeOH to afford the title compound as a white solid (0.7mg, 6%). 1H NMR 400MHz (d4-MeOH) 8.44 (1 H, s), 8.27 (1 H, s), 7.55 (1 H, s), 7.55 (1 H, s), 6.80 (1 H,s), 6.73 (1 H, s), 4.27 (2H,tr), 4.10 (3H,s), 3.80 (3H,s), 3.05 (2H,tr). LCMS 367 [M+1]+, RT 1.50 mins. Example 48. 3-Benzyl-7-methoxy-6-oxazol-5-yl-7H-quinazoline-2,4- dione
From 2-amino-4-methoxy-5-oxazol-5-yl-benzoic acid methyl ester (CAS 371251-37-5) (200mg), benzylamine (0.11 ml), TEA (0.23ml) and triphosgene (84mg) in DCM (20ml). The solvent was removed in vacuo and the residue purified by trituration with Et20 and water to yield a yellow solid (132mg). A mixture of the solid (132mg) and DBN (0.05ml) in DME (20ml) was heated at reflux overnight. The solvent was removed in vacuo, MeOH (5ml) added to the residue, the resulting precipitate filtered off and washed with Et2O and water to afford the title compound as a pale yellow solid (55mg, 45%). TLC Rf 0.48 (10%MeOH/DCM). 1H NMR 400MHz 130°C (d6-Acetone) 8.40 (1 H, s), 8.22 (1 H, s), 7.54 (1 H, s), 7.45 (2H, m), 7.29 (3H, m), 7.00 (1 H, s), 5.19 (2H, s), 4.11 (3H, s). LCMS 349 [M+1]+, RT 3.05 mins. Example 49. 3-(4-Dimethylamino-butyl)-7-methoxy-6-oxazol-5-yl-
7H-quinazoline-2,4-dione: formate salt From 2-amino-4-methoxy-5-oxazol-5-yl-benzoic acid methyl ester (CAS 371251-37-5) (200mg), 4-dimethylamino butylamine (112mg), TEA (0.23ml) and triphosgene (84mg) in DCM (20ml). The solvent was removed in vacuo and the residue combined with DBN (0.12ml) in DME (20ml) and heated at reflux overnight. The solvent was removed in vacuo, and the residue purified by preparative HPLC to afford the title compound as a yellow solid, (65mg, 20%). TLC R, 0.06 (10% MeOH/DCM). 1H NMR 400MHz 130°C (d6-DMSO) 8.25 (1 H, s), 8.00 (1 H, s), 7.94 (1 H, s), 7.35 (1 H, s), 6.62 (1 H, s), 3.80 (3H, s), 3.72 (2H, tr), 2.88 (2H, m), 2.35 (3H, s), 2.30 (3H, s), 1.45 (2H, m), 1.45 (2H, m). LCMS 358 [M+1]+, RT 1.56 mins. Example 50. 7-Methoxy-6-oxazol-5-yl-3-(4-pyrrolidin-1-yl-butvh-7H- quinazoline-2,4-dione From 2-amino-4-methoxy-5-oxazol-5-yl-benzoic acid methyl ester (CAS 371251-37-5) (200mg), 4-pyrrolidinobutylamine (138mg), TEA (0.23ml) and triphosgene (84mg) in DCM (20ml). The solvent was removed in vacuo and the residue combined with DBN (0.12ml) in DME (20ml) and heated at reflux overnight. The solvent was removed in vacuo, and the residue purified by crystallisation from a combination of hot EtOAc/DCM/MeOH to afford the title compound as a yellow solid, (11 mg, 3%). 1H NMR 300MHz (d4-MeOH) 8.4 (1 H, s), 8.30 (1 H, s), 7.55 (1 H, s), 6.80 (1H, s), 4.09 (3H, s), 4.08 (2H, m), 3.22 (4H, m), 3.14 (2H, m), 2.04 (4H, m),1.79 (2H, m), 1.79 (2H, m). LCMS 384 [M+1]+, RT 3.85 mins. Example 51. 7-Methoxy-3-r2-(1-methyl-pyrrolidin-2-yl)-ethvπ
-6-oxazol-5-yl-7H-quinazoline-3,4-dione To a solution of 2-amino-4-methoxy-5-oxazol-5-yl-benzoic acid methyl ester (CAS 371251-37-5) (200mg) in dry DCM (20ml) under nitrogen cooled to -78°C was added TEA (0.23ml) dropwise followed by triphosgene (84mg) dropwise. The reaction mixture was allowed to warm to 0°C and stirred for 30 mins. 2-(2-Aminoethyl)-1-methyl-pyrrolidine (0.14ml) was added and the reaction mixture allowed to warm to RT and heated at reflux overnight. The solvent was removed in vacuo and the residue dissolved in a mixture of MeOH/hexane/water from which it was precipitated out, filtered off and triturated in turn with Et20, EtOAc and water to afford the title compound as a bright yellow solid (6.2mg, 2%). TLC R» 0.22 (20% MeOH/DCM). 1H NMR 300MHz (d4-MeOH) 8.42 (1 H,s), 8.33 (1 H, s), 7.55 (1 H,s), 6.81 (1 H, s), 4.10 (3H, s), 4.10 (2H, m), 3.40 (1 H, m), 2.88(1 H, m), 2.78 (1 H, m), 2.70 (3H, s), 2.40 (1 H, m), 2.25 (1 H, m), 2.01 (1 H, m), 1.82 (1 H, m). LCMS 370 [M+1]+, RT 1.56 mins. Example 52. 7-Methoxy-3-r2-(2-methyl-5-nitroimidazol-1-yl)ethvn-β- oxazol-5-yl-1 H-quinazoline-2.4-dione
Hydroxymethylpolystyrene resin (10.2g, 100-2— mesh, 0.98gmol"1) was suspended in anhydrous DCM (120ml), treated with Λ/-Methylmorpholine (2.20ml) and cooled in an ice-bath. 4-Nitrophenylchloroformate (4.03g) was added in one portion and the mixture stirred in the ice bath for 5 minutes, then at room temperature for 18 hours. The resin was filtered under a nitrogen atmosphere, washed with DCM (4 x 40ml), and dried overnight in a vacuum desiccator. The resultant pale pink resin (12.3g) was placed in a round-bottomed flask. DIPEA (10.5ml), HOBT (4.05g) and 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid (CAS 371251-38-6) (11.71g) were dissolved in a 1 :1 mixture of anhydrous DCM/DMF (200ml) and transferred onto the resin via cannular. After stirring at room temperature for 18 hours, the mixture was filtered, and the resin was washed with DMF (4 x 30ml) followed by DCM (4 x 30ml), then dried in a vacuum desiccator to constant weight, as a beige solid (11.56 g).
In a fritted polypropylene tube, was placed a portion of the loaded resin (116mg), followed by NMP (0.5ml) to swell the resin. PyBOP (172mg), HOBT (45mg) and DIPEA (0.116ml) were dissolved in NMP (0.5ml), added to the resin, and the mixture shaken at 500-600 rpm. A solution of 1 -(2-aminoethyl)- 2-methyl-5-nitroimidazole dihydrochlohde monohydrate (131 mg) and DIPEA (0.174ml) in NMP (1.0ml) was then added to the reaction mixture, which was shaken at 600 rpm for 4 hours. The solution was drained through the frit and the resin was charged as before with PyBOP (172mg), HOBT (45mg) and DIPEA (0.116ml) in NMP (0.5ml), then with 1-(2-aminoethyl)-2-methyl-5- nitroimidazole dihydrochlohde monohydrate (13 mg) and DIPEA (0.174ml) in NMP (1.0ml). The reaction mixture was shaken as before for 18 hours and the solution drained off and the resin was washed with NMP (2 x 4ml), DCM (3 x 4ml), heptane (4ml) then dried at the filter.
The resin thus produced was placed in a glass tube with DMF (1 ml), and heated to 125°C under an atmosphere of nitrogen for 16 hours. The reaction mixture was then filtered into a tared flask, and the resin washed with DMF (2 x 2ml), then 1 :1 MeOH/DCM (3 x 2ml). Evaporation of the filtrate yielded the title compound as beige solid (4.6mg, 11%). 1H NMR 300MHz (d6-DMSO) 11.45 (1 H, s, br), 8.40 (1 H, s), 7.96 (1 H, s), 7.82 (1 H, s), 7.40 (1 H, s), 6.62 (1 H, s), 4.45 (2H, m), 4.17 (2H, m), 3.85 (3H, s), 2.15 (3H, s). LCMS 413 [M+1]+, RT 2.48 mins.
The compounds of Examples 53-62 were prepared in a similar manner to the compound of Example 52:-
Example 53. 3-Furan-2-ylmethyl-7-methoxy-6-oxazol-5-yl-1H- quinazoline-2,4-dione
From the 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid loaded resin (116mg), and furfurylamine (98mg). The title compound was obtained as a cream solid
(4.9 mg, 14%). 1H NMR 300MHz (d6-DMSO) 11.65 (1 H, s, br), 8.58 (1 H, s), 8.22 (1 H, s), 7.57 (2H, m), 6.84 (1 H, s), 6.42 (1 H, m), 6.33 (1 H, m), 5.09 (2H, s), 4.02 (3H, s). LCMS 340 [M+1]+, RT 2.85 mins.
Example 54. 3-r2-(3.4-Dihvdroχyphenyl)ethvπ-7-methoxy-6-oxazol-
5-vi-1 H-quinazoline-2,4-dione
From the 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid loaded resin (116mg), and 3-hydroxytyramine hydrobromide (234mg). The title compound was obtained as an off-white solid (4.0mg, 10%). LCMS 396 [M+1]+, RT 2.44 mins.
Example 55. 3-Cvclopropylmethyl-7-methoxy-6-oxazol-5-yl-1 H- quinazoline-2.4-dione From the 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid loaded resin (116mg), and aminomethylcyclopropane (71 mg). The title compound was obtained as an off-white solid (5.8mg, 19%). LCMS 314 [M+1]+, RT 2.86 mins.
Example 56. 3-(1-HvdroxycvclohexylmethvO-7-methoxy-6-oxazol-
5-yl-1 H-quinazoline-2.4-dione From the 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid loaded resin (116mg), and 1-aminomethyl-1-cyclohexanol (166mg). The title compound was obtained as an off-white solid (5.3mg, 14%). LCMS 372 [M+1]+, RT 2.96 mins.
Example 57. 7-Methoxy-3-r2-(6-methoxy-1 H-indol-3-ylιethvn-6- oxazol-5-yl-1 H-quinazoline-2.4-dione From the 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid loaded resin (116mg), and 6-methoxytryptamine (190mg). The title compound was obtained as an off-white solid (7.4mg, 17%). LCMS 433 [M+1]+, RT 3.08 mins. Example 58. 7-Methoxy-3-(2-methoxyethylj-6-oxazol-5-yl-1 H- quinazoline-2.4-dione
From the 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid loaded resin (116mg), and methoxyethylamine (75mg). The title compound was obtained as an off- white solid (6.1 mg, 19%).LCMS 318 [M+1]+, RT 2.31 mins. Example 59. 3-(2-Hvdroxy-2-phenylethyl)-7-methoxy-6-oxazol-5-yl- 1 H-quinazoline-2,4-dione
From the 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid loaded resin (116mg), and (+/-)-2-amino-1-phenylethanol (137mg). The title compound was obtained as an off-white solid (6.6mg, 17%). LCMS 380 [M+1]+, RT 2.73 mins. Example 60. 7-Methoxy-6-oxazol-5-yl-3-(2-oxo-2-phenylethyl)-1 tf- quinazoline-2.4-dione
From the 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid loaded resin (116mg), and phenacylamine hydrochloride (172mg). The title compound was obtained as an off-white solid (5.0mg, 13%). LCMS 378 [M+1]+, RT 2.96 mins. Example 61. 7-Methoxy-3-(2-methylsulfanylethyl)-6-oxazol-5-yl-1 H- quinazoline-2.4-dione
From the 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid loaded resin (116mg), and 2-(methylthio)ethylamine (91 mg). The title compound was obtained as an off-white solid (6.7mg, 20%). LCMS 334 [M+1]+, RT 2.76 mins. Example 62. 3-(6-Fluoro-4H-benzoH.31dioxin-8-ylmethyl)-7- methoxy-6-oxazol-5-yl-1H-quinazoline-2,4-dione
From the 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid loaded resin (116mg), and (6-fluoro-4H-1 ,3-benzodioxin-8-yl)methylamine (183mg). The title compound was obtained as an off-white solid (7.1 mg, 17%). LCMS 426 [M+1]\ RT 3.08 mins.
Example 63. 7-Methoxy-6-oxazol-5-yl-3-(2H-tetrazol-5-ylmethyl)-7f*- quinazoline-2.4-dione
To a solution of Example 40 (20mg) in dry DMF (3ml) was added sodium azide (5mg) and ammonium chloride (4mg). The mixture was heated at 120°C overnight. The solvent was removed in vacuo and the residue taken up in aqueous Na2CO3 (20ml) and washed with EtOAc (20ml). The aqueous layer was acidified with aqueous 1N HCI and extracted with EtOAc (2 x 30ml). The combined organic layers were died over MgS04, filtered and the solvent removed in vacuo to afford the title compound as a solid (10mg, 44%). 1H NMR 300MHz (d6-DMSO) 11.77 (1 H, s, br), 8.48 (1 H, s), 8.21 (1 H, s), 7.59 (1 H, s), 6.85 (1 H, s), 5.39 (2H, s), 4.05 (3H, s). LCMS 342 [M+1]+, RT 1.92 mins. Example 64. 3-(4-Amino-butyl)-7-methoxy-6-oxazol-5-yl-7W- quinazoline-2.4-dione
A solution of Example 44 (315mg) in formic acid (8ml) was stirred at room temperature for 4 hours. The mixture was taken up in water (20ml) and washed with Et20 (20ml). The aqueous layer was basified with solid Na2C03 and washed with EtOAc (20ml). The aqueous layer was acidified to pH7 with aqueous 1 N HCI and the resulting solid filtered off and dried in vacuo to yield the title compound as a solid (150mg, 62%). TLC Rf 0.03 (10% MeOH/DCM). 1H NMR 300MHz (d4-MeOH) 8.37 (1 H, s), 8.29 (1 H, s), 7.53 (1 H, s), 6.76 (1 H, s), 4.08 (3H, s), 4.08-4.03 (2H, tr), 2.82-2.87 (2H, tr), 1.81-1.70 (2H, m), 1.68- 1.57 (2H, m). LCMS 331 [M+1]+, RT 1.46 mins. Example 65. 7-(Methoxy-3-(2-methylamino-ethyl)-6-oxazol-5-yl-7W- quinazoline-2,4-dione; hydrochloride salt To a solution of Example 45 (479mg) in DCM (30ml) was added a 1.0M solution of HCI in Et2O (5.8ml). MeOH (5ml) was added and the mixture stirred room temperature overnight. More HCI in Et20 (6ml) and MeOH were added and the mixture stirred at room temperature overnight. The solvents were removed in vacuo and the residue triturated in DCM to afford the title compound as a pale yellow solid (488mg, quantitative). TLC Rf 0.11 (10% MeOH/DCM + cNH3). 1H NMR 300MHz (d6-DMSO) 11.73 (1 H, s), 8.70-8.58 (2H, s, br), 8.49 (1 H, s), 8.22 (1 H, s), 7.57 (1 H, s), 6.93 (1 H, s), 4.22-4.17 (2H, tr), 4.04 (3H, s), 3.25-3.15 (2H, tr), 2.60-2.55 (3H, m). LCMS 317 [M-HCI+1]+, RT 1.36 mins.
Example 66. N-Ϊ4-17-Methox v-6-oxazo l-5-yl-2.4-d ioxo-1.4-d i h vdro-
2H-quinazolin-3-vh-butvπ-acetamide To a solution of Example 64 (60mg) in dry DMF (10ml) under nitrogen was added acetyl chloride (14mg) and DMAP (2mg). The mixture was heated at 90°C overnight. The mixture was concentrated in vacuo and the residue dissolved in EtOAc (50ml), washed with aqueous 1 N HCI (20ml), the organic layer separated, dried over MgS04 and concentrated in vacuo. Trituration with MeOH afforded the title compound as solid (15mg, 22%). TLC Rf 0.39 (10% MeOH/DCM). 1H NMR 300MHz (d6-DMSO) 11.55 (1 H, s), 8.45 (1 H, s), 8.20 (1 H, s), 7.99 (1 H, s, br), 7.55 (1 H, s), 6.81 (1 H, s), 4.02 (3H, s), 3.99-3.82 (2H, m), 3.40-3.30 (1 H, m), 3.15-3.05 (1 H, m), 1.65-1.35 (4H, m). LCMS 371 [M- 1]+, RT 2.05 mins.
Example 67. ΛH4-(7-Methoxy-6-oxazol-5-yl-2.4-dioxo-1.4-dihvdro-
2H-quinazolin-3-yl)-butvπ-methanesulphonamide To a solution of Example 64 (60mg) in dry DMF (10ml) under nitrogen was added methyl sulphonyl chloride (0.2ml) and TEA (0.2ml). The mixture was heated at 60°C for 5 hours. The mixture was concentrated in vacuo and the residue dissolved in EtOAc (50ml), washed with aqueous 1 N HCI, the organic layer was separated, dried over MgS04, filtered and the solvent removed in vacuo. Purification by preparative HPLC afforded the title compound as a solid (1 mg, 1%). 1H NMR 300MHz (d6-DMSO) 11.40-11.00 (1 H, s, br), 8.46 (1 H, s), 8.20 (1 H, s), 7.54 (1 H, s), 7.01 -6.94 (1 H, s, br), 6.82 (1 H, s), 4.02 (3H, s), 3.94-3.85 (2H, m), 3.00-2.91 (2H, m), 2.88 (3H, s), 1.69-1.43 (4H, m). LCMS 317 [M-HCI+1]\ RT 1.36 mins.
Example 68. r4-(7-Methoxy-6-oxazol-5-yl-2.4-dioxo-1.4-dihvdro-2/-f- quinazolin-3-yl)-butvπ-carbamic acid (SHtetrahvdro- furan-3-yl) ester
To a solution of Example 64 (56mg) in dry DCM / DMF (15ml / 3ml) under nitrogen was added TEA (0.04ml). The mixture was cooled to 0°C and carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester (3S)-tetrahydro-furan-3-yl ester (CAS 138499-08-8) (43mg) was added in a single portion. The reaction mixture was allowed to warm to room temperature and stirred over the weekend. The solvents were removed in vacuo. Trituration in Et20, trituration in MeOH, followed by purification by preparative HPLC afforded the title compound as a white solid (6.8mg, 9%). TLC Rf 0.52 (10% MeOH/DCM). 1H NMR 300MHz (d6-DMSO) 11.54-11.39 (1 H, s, br), 8.42 (1 H, s), 8.15 (1 H, s), 7.50 (1 H, s), 7.18-7.11 (1 H, tr), 6.76 (1 H, s), 5.06-5.00 (1 H, m), 3.98 (3H, s), 3.86-3.81 (2H, tr), 3.72-3.56 (4H, m), 2.08-1.96 (1 H, m), 1.85-1.73 (1 H, m), 1.59-1.47 (2H, m), 1.43-1.28 (2H, m). LCMS 445 [M+1]+, RT 2.46 mins. Example 69. ΛH2-(7-Methoxy-6-oxazol-5-yl-2.4-dioxo-1,4-dihvdro-
2H-quinazolin-3-yl)-ethyl-Λ/-methyl-2-morpholin-4-yl- acetamide To a solution of Intermediate 20 (80mg) in dry DMF (5ml) under nitrogen was added TEA (0.034ml) followed by morpholine (0.05ml) and sodium iodide (5mg). The reaction mixture was stirred at room temperature for 3 days. The solvent was removed in vacuo. Purification by column chromatography on silica eluting with 9% MeOH/DCM followed by trituration with MeOH/Et2O afforded the title compound as a cream solid (25mg, 28%). TLC Rf 0.35 (9% MeOH/DCM). 1H NMR 400MHz 130°C (d6-DMSO) 8.26 (1 H, s), 8.23 (1 H, s), 7.48 (1 H, s), 6.92 (1 H, s), 4.20-4.16 (2H, tr), 4.03 (3H, s), 3.76-3.64 (8H, m), 3.01 (3H, s), 2.94-2.64 (4H, m). LCMS 444 [M+1]+, RT 1.57 mins. Example 70. Λ 2-(7-Methoxy-6-oxazol-5-yl-2.4-dioxo-1.4-dihvdro-
2H-quinazolin-3-yl)-ethyll-N-methyl-2-π .2.4ltriazol-1 - yl-acetamide To a solution of Intermediate 20 (40mg) in dry DMF (2ml) under nitrogen was added 1 ,2,4-thazole, sodium salt (21 mg) and the mixture stirred at room temperature overnight. The mixture was diluted with 5% MeOH/DCM (30ml) and washed with saturated brine (5ml). The organic layer was separated, dried over MgS04, filtered and concentrated in vacuo to yield the title compound as a solid (30mg, 69%). 1H NMR 400MHz 130°C (d6-DMSO) 8.26 (1 H, s), 8.23 (1 H, s), 7.48 (1 H, s), 6.92 (1 H, s), 4.20-4.16 (2H, tr), 4.03 (3H, s), 3.76-3.64 (8H, m), 3.01 (3H, s), 2.94-2.64 (4H, m). LCMS 444 [M+1]+, RT 1.57 mins. Example 71. 7-Methoxy-6-oxazol-5-yl-7W-quinazoline-2.4-dithione To a solution of Intermediate 2 (130mg) in dry pyridine (1 ml) was added dry carbon disulphide (1 ml). The mixture was heated at reflux for 18 hours. A yellow precipitate resulted. The solvent was removed in vacuo and the solid washed with DCM and dried in vacuo to afford the title compound as a yellow solid (155mg, 88%).TLC Rf 0.41 (EtOAc). 1H NMR 400MHz 130°C 8.26 (1 H, s), 8.24 (1 H, s), 8.23 (1 H, s), 7.79 (1 H, s), 7.48 (1 H, s), 6.92 (1 H, s), 5.12 (2H, s), 4.20-4.16 (2H, tr), 4.04 (3H, s), 3.70-3.66 (2H, tr), 3.07 (3H, s). LCMS 426 [M+1]\ RT 2.03 mins.
The ability of the compounds of the invention to inhibit the IMPDH enzymes may be determined using the following assays:
Abbreviatons used:
IMPDH Inosine 5'monophosphate dehydrogenase IMP Inosine 5'monophosphate
XMP Xanthosine δ'-monophosphate
NAD β- Nicotinamide adenine dinucleotide
NADH β- Nicotinamide adenine dinucleotide, reduced form
MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
Assay Protocol 1
IMPDH catalyses the NAD dependent oxidation of IMP to XMP with concomitant reduction of the cofactor. IMPDH activity was determined by monitoring the production of the fluorescent product, NADH. Assays were performed in a final volume of 200/yl containing IMPDH (2/yg), NAD (100 /M), IMP (100/yM), 1% DMSO, 30mM KCl and 100mM Tris/HCI, pH7.5. Fluorescence (excitation 340nm / emission 465nm) was read continuously at 25°C for 30 minutes. From this data, initial rates (i.e. change in fluorescence intensity per minute) were calculated. To determine the IC50 values, test compounds were prepared at an initial concentration of 1.0mM in 100% DMSO, then diluted in assay buffer to 0.2mM. Further dilutions were made in assay buffer containing 20% DMSO, prior to diluting 20-fold into the assay, to allow testing across the range 0.3nM to 10 M.
The functional effect of the compounds of the invention may be demonstrated using the following assay: PBMC Proliferation Assay
Peripheral blood mononuclear cells were isolated from freshly taken human blood using standard procedures. Cells were plated out in RPMI medium containing 5% human serum in the presence and absence of inhibitor. PHA (25μl of 30μg/ml solution to each well) was added and the plates were incubated at 37°C in an atmosphere of 95% air/5% C0 for 48 hours. O.δμCi of tritiated thymidine was added to each well and the plates were incubated for a further 18 hours. The contents of the plate were transferred to a filter plate and the cells washed with saline. The plates were dried, microscintillation fluid was added to each well and the plate was counted on a scintillation counter. IC50 values were calculated by plotting inhibitor concentration versus %inhibition.
The assay described above can be carried out using anti-CD3 (40μl of 3750ng/ml concentration to each well) stimulation instead of PHA.

Claims

1. A compound of formula (1):
Figure imgf000073_0001
wherein:
X and Y, which may be the same or different, is each an O or S atom; R1 is an aliphatic, cycloaliphatic or cycloalkyl-alkyl- group; R2 is an optionally substituted heteroaromatic group; R3 is the group -Alk1-L1-Alk2-R4 in which Alk1 is a covalent bond or an optionally substituted aliphatic or heteroaliphatic chain, L1 is a covalent bond or a linker atom or group, Alk2 is a covalent bond or an optionally substituted aliphatic or heteroaliphatic chain and R4 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group; and the salts, solvates, hydrates, tautomers, isomers or Λ/-oxides thereof.
2. A compound according to Claim 1 wherein R1 is a Cι-6 alkyl group.
3. A compound according to Claim 1 or 2 wherein R1 is a methyl group.
4. A compound according to any one of Claims 1 to 3 wherein R2 is a five- membered heteroaromatic group containing one, two, three or four heteroatoms selected from oxygen, sulfur or nitrogen.
5. A compound according to any one of Claims 1 to 4 wherein R2 is an oxazolyl group.
6. A compound according to any one of Claims 1 to 5 wherein X is an O atom and Y is a S atom.
7. A compound according to any one of Claims 1 to 5 wherein X and Y is each an O atom.
8. A compound according to any one of Claims 1 to 7 wherein Alk1 is a covalent bond or an optionally substituted aliphatic group.
9. A compound according to Claim 8 wherein Alk1 is a Cι-6 alkylene chain.
10. A compound according to any one of Claims 1 to 9 wherein L1 is a -O- or - S- atom or a -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -C(O)0-, -OC(O)-, -N(R5)- [where R5 is a hydrogen atom or a straight or branched d-βalkyl group], - CON(R5)-, -CSN(R5)-, -N(R5)CO-, -N(R5)CS-, -S(0)2N(R5)- or - N(R5)S(0)2- group.
11. A compound according to any one of Claims 1 to 10 wherein R4 is a hydrogen atom or an optionally substituted C3-6 cycloalkyl, 3 to 10 membered saturated monocyclic heterocycloaliphatic, phenyl or 5 to 6 membered heteroaromatic group.
12. A compound according to any one of Claims 1 to 11 wherein R3 is the group -Alk1-L1-R4.
13. A compound according to Claim 1 or Claim 12 wherein Alk1 is an optionally substituted aliphatic chain, L1 and Alk2 are each a covalent bond and R4 is a hydrogen atom.
14. A compound according to Claim 13 wherein Alk1 is an optionally substituted -CH2-, -CH2CH2-, -CH2CH2CH2-, -(CH2)3CH2- or
-CH2C(CH3)2-, chain.
15. A compound according to Claim 14 wherein Alk1 is an optionally substituted -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2- chain.
16. A compound according to any one of Claims 13 to 15 wherein Alk1 is substituted with a -N(CH3)2, -CN, -CO2H, -C02CH3, -C02CH2CH3,
-C02C(CH3)3, -CONH2, -CONHCH3 or -CON(CH3)2 group.
17. A compound according to Claim 1 or Claim 12 wherein Alk1 is an optionally substituted aliphatic chain, L1 and Alk2 are each a covalent bond and R4 is an optionally substituted heterocycloaliphatic, aromatic or heteroaromatic group.
18. A compound according to Claim 17 wherein Alk1 is a -CH2-, -CH2CH2- or - CH2CH2CH2- chain.
19. A compound according to Claim 17 or Claim 18 wherein R4 is an optionally substituted azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, N-Cι-6 alkylpiperazinyl, especially N- methylpiperazinyl, N-Cι-6 alkylpyrrolidinyl, especially N-methylpyrrolidinyl, N-Cι-6 alkylpiperidinyl, especially N-methylpiperidinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, N-Ci. 6alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, triazinyl, pyridyl-N-oxide, dihydropyrazolonyl or imidazolonyl group.
20. A compound according to any one of Claims 17 to 19 wherein R4 is an optionally substituted morpholinyl, pyrrolidinonyl, N-methylpiperazinyl, tetrahydropyranyl, imidazolyl, pyridyl, pyrrolidinyl, pyrazolyl, piperidinyl or N-methylpyrrolidinyl group.
21. A compound according to Claim 1 or Claim 12 wherein Alk1 is covalent bond or an optionally substituted aliphatic chain, L1 is a linker atom or group, Alk2 is a covalent bond and R4 is an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group.
22. A compound which is
7-Methoxy-3-methyl-6-oxazol-5-yl- 7H-quinazoline-2,4-dione;
7-Methoxy-6-oxazol-5-yl-3-(2-pyridin-2-yl-ethyl)- 7H-quinazoline-2,4-dione;
7-Methoxy-6-oxazol-5-yl-3-(tetrahydro-pyran-2-ylmethyl)- 7 --quinazoline-
2,4-dione; 7-Methoxy-6-oxazol-5-yl-3-(2-pyridin-4-yl-ethyl)- 7/-/-quinazoline-2,4-dione;
3-(2-lmidazol-1-yl-ethyl)-7-methoxy-6-oxazol-5-yl- 7/-/-quinazoline-2,4- dione; hydrochloride;
7-Methoxy-3-[3-(5-methyl- 7H-pyrazol-4-yl)-propyl]-6-oxazol-5-yl- 7H- quinazoline-3,4-dione; and the salts, solvates, hydrates, tautomers, isomers or Λ/-oxides thereof.
23. A pharmaceutical composition comprising a compound according to any of Claims 1 to 22 together with one or more pharmaceutically acceptable carriers, excipients or diluents.
24. A compound according to any of Claims 1 to 22 for use in the treatment of cancer, inflammatory disorders, autoimmune disorders, psoriatic disorders and viral disorders.
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WO2008128982A1 (en) * 2007-04-18 2008-10-30 Probiodrug Ag Thioxoquinazolinone derivatives as glutaminyl cyclase inhibitors
JP2009523748A (en) * 2006-01-18 2009-06-25 シエナ ビオテク ソシエタ ペル アチオニ Modulators of α7 nicotinic acetylcholine receptors and their use in therapy
JP2009531309A (en) * 2006-03-08 2009-09-03 タケダ サン ディエゴ インコーポレイテッド Glucokinase activator
EP2181704A2 (en) 2002-12-30 2010-05-05 Angiotech International Ag Drug delivery from rapid gelling polymer composition
WO2015006100A1 (en) 2013-07-08 2015-01-15 Bristol-Myers Squibb Company Aryl amide kinase inhibitors
CN104379568A (en) * 2012-04-24 2015-02-25 中外制药株式会社 Quinazolinedione derivative
EP2886120A1 (en) * 2010-10-29 2015-06-24 Emory University Quinazoline derivatives, compositions and uses related thereto
WO2015189595A1 (en) * 2014-06-11 2015-12-17 University Of Dundee Treatment of chagas disease
US9695118B2 (en) 2012-04-24 2017-07-04 Chugai Seiyaku Kabushiki Kaisha Benzamide derivative
US10005739B2 (en) 2013-10-23 2018-06-26 Chugai Seiyaku Kabushiki Kaisha Quinazolinone and isoquinolinone derivative
JP2018520195A (en) * 2015-07-22 2018-07-26 アラクセス ファーマ エルエルシー Substituted quinazoline compounds and their use as inhibitors of G12C mutant KRAS, HRAS and / or NRAS proteins
US10919850B2 (en) 2013-03-15 2021-02-16 Araxes Pharma Llc Covalent inhibitors of KRas G12C
US10927125B2 (en) 2013-10-10 2021-02-23 Araxes Pharma Llc Substituted cinnolines as inhibitors of KRAS G12C
US10975071B2 (en) 2015-09-28 2021-04-13 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US11021470B2 (en) 2015-11-16 2021-06-01 Araxes Pharma Llc 2-substituted quinazoline compounds comprising a substituted heterocyclic group and methods of use thereof
US11059819B2 (en) 2017-01-26 2021-07-13 Janssen Biotech, Inc. Fused hetero-hetero bicyclic compounds and methods of use thereof
CN113354592A (en) * 2021-06-30 2021-09-07 赣南师范大学 2-thioquinazolinone compound and preparation method and application thereof
US11136308B2 (en) 2017-01-26 2021-10-05 Araxes Pharma Llc Substituted quinazoline and quinazolinone compounds and methods of use thereof
US11274093B2 (en) 2017-01-26 2022-03-15 Araxes Pharma Llc Fused bicyclic benzoheteroaromatic compounds and methods of use thereof
US11279689B2 (en) 2017-01-26 2022-03-22 Araxes Pharma Llc 1-(3-(6-(3-hydroxynaphthalen-1-yl)benzofuran-2-yl)azetidin-1 yl)prop-2-en-1-one derivatives and similar compounds as KRAS G12C modulators for treating cancer
US11358959B2 (en) 2017-01-26 2022-06-14 Araxes Pharma Llc Benzothiophene and benzothiazole compounds and methods of use thereof
US11377441B2 (en) 2017-05-25 2022-07-05 Araxes Pharma Llc Covalent inhibitors of KRAS
US11639346B2 (en) 2017-05-25 2023-05-02 Araxes Pharma Llc Quinazoline derivatives as modulators of mutant KRAS, HRAS or NRAS
US12134620B2 (en) 2018-08-01 2024-11-05 Araxes Pharma Llc Heterocyclic spiro compounds and methods of use thereof for the treatment of cancer

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EP2181704A2 (en) 2002-12-30 2010-05-05 Angiotech International Ag Drug delivery from rapid gelling polymer composition
JP2009523748A (en) * 2006-01-18 2009-06-25 シエナ ビオテク ソシエタ ペル アチオニ Modulators of α7 nicotinic acetylcholine receptors and their use in therapy
US8034822B2 (en) * 2006-03-08 2011-10-11 Takeda San Diego, Inc. Glucokinase activators
JP2009531309A (en) * 2006-03-08 2009-09-03 タケダ サン ディエゴ インコーポレイテッド Glucokinase activator
US9034907B2 (en) 2007-04-18 2015-05-19 Probiodrug Ag Inhibitors of glutaminyl cyclase
JP2010524894A (en) * 2007-04-18 2010-07-22 プロビオドルグ エージー Thioxoquinazolinone derivatives as glutaminyl cyclase inhibitors
WO2008128982A1 (en) * 2007-04-18 2008-10-30 Probiodrug Ag Thioxoquinazolinone derivatives as glutaminyl cyclase inhibitors
EP2886120A1 (en) * 2010-10-29 2015-06-24 Emory University Quinazoline derivatives, compositions and uses related thereto
US9868728B2 (en) 2010-10-29 2018-01-16 Emory University Quinazoline derivatives, compositions, and uses related thereto
CN104379568A (en) * 2012-04-24 2015-02-25 中外制药株式会社 Quinazolinedione derivative
US9567304B2 (en) 2012-04-24 2017-02-14 Chugai Seiyaku Kabushiki Kaisha Quinazolinedione derivative
US9695118B2 (en) 2012-04-24 2017-07-04 Chugai Seiyaku Kabushiki Kaisha Benzamide derivative
US10919850B2 (en) 2013-03-15 2021-02-16 Araxes Pharma Llc Covalent inhibitors of KRas G12C
WO2015006100A1 (en) 2013-07-08 2015-01-15 Bristol-Myers Squibb Company Aryl amide kinase inhibitors
US11878985B2 (en) 2013-10-10 2024-01-23 Araxes Pharma Llc Substituted quinazolines as inhibitors of KRAS G12C
US10927125B2 (en) 2013-10-10 2021-02-23 Araxes Pharma Llc Substituted cinnolines as inhibitors of KRAS G12C
US10005739B2 (en) 2013-10-23 2018-06-26 Chugai Seiyaku Kabushiki Kaisha Quinazolinone and isoquinolinone derivative
WO2015189595A1 (en) * 2014-06-11 2015-12-17 University Of Dundee Treatment of chagas disease
JP2018520195A (en) * 2015-07-22 2018-07-26 アラクセス ファーマ エルエルシー Substituted quinazoline compounds and their use as inhibitors of G12C mutant KRAS, HRAS and / or NRAS proteins
US10975071B2 (en) 2015-09-28 2021-04-13 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US11021470B2 (en) 2015-11-16 2021-06-01 Araxes Pharma Llc 2-substituted quinazoline compounds comprising a substituted heterocyclic group and methods of use thereof
US11274093B2 (en) 2017-01-26 2022-03-15 Araxes Pharma Llc Fused bicyclic benzoheteroaromatic compounds and methods of use thereof
US11136308B2 (en) 2017-01-26 2021-10-05 Araxes Pharma Llc Substituted quinazoline and quinazolinone compounds and methods of use thereof
US11279689B2 (en) 2017-01-26 2022-03-22 Araxes Pharma Llc 1-(3-(6-(3-hydroxynaphthalen-1-yl)benzofuran-2-yl)azetidin-1 yl)prop-2-en-1-one derivatives and similar compounds as KRAS G12C modulators for treating cancer
US11358959B2 (en) 2017-01-26 2022-06-14 Araxes Pharma Llc Benzothiophene and benzothiazole compounds and methods of use thereof
US11059819B2 (en) 2017-01-26 2021-07-13 Janssen Biotech, Inc. Fused hetero-hetero bicyclic compounds and methods of use thereof
US11377441B2 (en) 2017-05-25 2022-07-05 Araxes Pharma Llc Covalent inhibitors of KRAS
US11639346B2 (en) 2017-05-25 2023-05-02 Araxes Pharma Llc Quinazoline derivatives as modulators of mutant KRAS, HRAS or NRAS
US12134620B2 (en) 2018-08-01 2024-11-05 Araxes Pharma Llc Heterocyclic spiro compounds and methods of use thereof for the treatment of cancer
CN113354592A (en) * 2021-06-30 2021-09-07 赣南师范大学 2-thioquinazolinone compound and preparation method and application thereof
CN113354592B (en) * 2021-06-30 2022-06-21 赣南师范大学 2-thioquinazolinone compound and preparation method and application thereof

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