WO2015192760A1 - 作为pi3k抑制剂的吡啶并[1,2-a]嘧啶酮类似物 - Google Patents

作为pi3k抑制剂的吡啶并[1,2-a]嘧啶酮类似物 Download PDF

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WO2015192760A1
WO2015192760A1 PCT/CN2015/081518 CN2015081518W WO2015192760A1 WO 2015192760 A1 WO2015192760 A1 WO 2015192760A1 CN 2015081518 W CN2015081518 W CN 2015081518W WO 2015192760 A1 WO2015192760 A1 WO 2015192760A1
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group
alkyl
compound
reaction
cycloalkyl
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PCT/CN2015/081518
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English (en)
French (fr)
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吴成德
于涛
陈曙辉
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南京明德新药研发股份有限公司
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Priority claimed from CN201410271282.9A external-priority patent/CN105461711B/zh
Priority to US15/319,726 priority Critical patent/US9856256B2/en
Priority to KR1020177000523A priority patent/KR102495840B1/ko
Priority to EA201790016A priority patent/EA032642B1/ru
Priority to AU2015276699A priority patent/AU2015276699B2/en
Application filed by 南京明德新药研发股份有限公司 filed Critical 南京明德新药研发股份有限公司
Priority to EP15810067.7A priority patent/EP3159341B8/en
Priority to ES15810067T priority patent/ES2754264T3/es
Priority to JP2017518397A priority patent/JP6680774B2/ja
Priority to CN201580027396.1A priority patent/CN106470992B/zh
Priority to CA2951971A priority patent/CA2951971A1/en
Publication of WO2015192760A1 publication Critical patent/WO2015192760A1/zh

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D519/00Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a pyrido[1,2-a]pyrimidinone analog as a PI3K inhibitor, and in particular, the present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • the PI3K pathway is the most frequently mutated part of human cancer cells, which can lead to cell proliferation, activation, and amplification of signals.
  • PI3K kinase (phosphatidylinositol 3-kinase, PI3Ks) belongs to the family of lipid kinases and is capable of phosphorylating the 3'-OH end of the inositol ring of phosphatidylinositol.
  • Phosphatidylinositol-3-kinase (PI3K) is a lipid kinase composed of the regulatory subunit p85 or p101 and the catalytic subunit p110, which catalyzes the phosphatidylinositol by phosphatidylinositol.
  • PIP2 phosphatidylinositol 3,4,5-trisphosphate
  • PIP3 phosphatidylinositol 3,4,5-trisphosphate
  • PTEN phosphatase and stretching homolog deleted on chromosome ten dephosphorylates PIP3 to form PIP2, thereby achieving negative regulation of PI3K/Akt signaling pathway, inhibiting cell proliferation and promoting apoptosis.
  • the frequent occurrence of PI3K gene mutation and amplification in cancer and the loss of PTEN in cancer suggest a close relationship between PI3K and tumorigenesis.
  • E is selected from C 1-6 alkyl, 3 to 10 membered cycloalkyl or heterocycloalkyl optionally substituted by 1, 2 or 3 R 3 ;
  • A, T are each independently selected from N or C(R t );
  • X, Y, Z is selected from N, and the rest is selected from C(R t );
  • n 1 is independently selected from 0, 1 , 2 or 3;
  • D 2 is selected from -C(R d1 )(R d2 )-;
  • R 4 is selected from H or is selected from a C 1-10 alkyl or heteroalkyl group optionally substituted by R 01 , a 3 to 10 membered cycloalkyl or heterocycloalkyl group, and is substituted by a 3 to 10 membered cycloalkyl or heterocycloalkyl group.
  • n is selected from 1, 2, 3, 4, 5 or 6;
  • R 01 is selected from the group consisting of F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, R 02 ;
  • R 02 is selected from C 1-10 alkyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkoxy, C 1-10 alkanoyl, C 1 -10 alkoxycarbonyl, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkoxy, C 3-10 cycloalkyl acyl, C 3-10 cycloalkoxycarbonyl, C 3-10 cycloalkylsulfonyl, C 3-10 cycloalkylsulfinyl, 5- a 6-membered unsaturated heterocyclic group, a 6-12 membered aryl group or a heteroaryl group;
  • R d3 - d9 are each independently selected from H, OH, NH 2 , R 02 ;
  • R 02 is optionally substituted by R 001 ;
  • R 001 is selected from the group consisting of F, Cl, Br, I, CN, OH, N(CH 3 ) 2 , NH(CH 3 ), NH 2 , CHO, COOH, trifluoromethyl, aminomethyl, hydroxymethyl, A Base, methoxy, formyl, methoxycarbonyl, methylsulfonyl, methylsulfinyl;
  • the numbers of R 01 and R 001 are each independently selected from 0, 1, 2 or 3, and the number of hetero atoms or heteroatoms is independently selected from 1, 2 or 3.
  • the above E is selected from the R 3 substituted C 1-6 alkyl or C 3-6 cycloalkyl, R 3 is selected from the number 1, 2 or 3, or E is selected from
  • G 1 to 5 0, 1, 2 or 3 of G 1 to 5 is selected from N, and the remainder is selected from C(R 3 );
  • G 7 to 9 0, 1 or 2 of G 7 to 9 is selected from N, and the remainder is selected from C(R 3 );
  • G 10 to 16 0, 1, 2, 3 or 4 of G 10 to 16 is selected from N, and the remainder is selected from C(R 3 );
  • G 17 is selected from N or C(R 3 );
  • the above E is selected from the group consisting of methyl, ethyl, propyl optionally substituted by 1, 2 or 3 R 3 ,
  • the above E is selected from
  • 0 or 1 of the above X, Y, and Z is selected from N, and the remainder is selected from the group consisting of CH, C(CH 3 ), C(CF 3 ), CCl, and CF.
  • the above A and T are each independently selected from N, CH, C(CH 3 ), C(CF 3 ), CCl, CF; or, B is selected from NH, N(CH 3 ) or N (CF 3 ).
  • R 1-3 is selected from the group consisting of The remainder is selected from the group consisting of H, F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, OR a , N(R b )(R c ), C 1-3 optionally substituted by R d Alkyl or cyclopropyl;
  • D 2 is selected from -C(R a )(R a )-;
  • n is selected from 1, 2, 3, 4, 5 or 6;
  • R a , R b , R c are each independently selected from H, optionally R d -substituted C 1-6 alkyl or C 3-6 cycloalkyl;
  • R e is selected from H, optionally R d -substituted C 1-6 alkyl or alkoxy, optionally R d -substituted C 3-6 cycloalkyl or cycloalkoxy;
  • R d is selected from the group consisting of F, Cl, Br, I, CN, OH, CHO, COOH, CH 3 , CF 3 , CH 3 O, CH 3 CH 2 O, and the number of Rd is selected from 0, 1, 2 or 3;
  • any two R 1 , between R a and R a in the same D 2 , between two D 2 , or between R a and D 2 are co-bonded to the same carbon atom or oxygen
  • One or two 3, 4, 5 or 6 membered carbocyclic or oxo rings are formed on the atom, wherein the number of oxygen atoms is 1 or 2.
  • a ring formed between any two of R 1 , between R a and R a in the same D 2 , between two D 2 , or between R a and D 2 It is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, and 1,3-dioxopentacyclyl.
  • one of the above R 1-3 is selected from the group consisting of The rest are selected from the group consisting of H, F, Cl, Br, I, CN, OH, NH 2 , methyl, ethyl, propyl, methoxy, ethoxy, propoxymethylamino, dimethylamino, halo Base, haloethyl, halopropyl, aminomethyl, aminoethyl, aminopropyl, cyclopropyl.
  • the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of Compounds 1 to 25 and Compounds 27 to 99.
  • C 1-10 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 and C 10 ;
  • C 3-10 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 and C 10 .
  • C 1-10 alkyl or heteroalkyl, C 3-10 cyclo or heterocycloalkyl, C 1-10 alkyl or heteroalkyl substituted by C 3-10 cycloalkyl or heterocycloalkyl includes, but is not limited to:
  • pharmaceutically acceptable as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention. Certain compounds of the invention may exist in polycrystalline or amorphous form.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a salt of a diastereomer is formed with a suitable optically active acid or base, followed by stepping as is known in the art.
  • the diastereomeric resolution is carried out by crystallization or chromatography, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on the vector, refer to Remington: The Science and Practice of Pharmacy, 21 St Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are substituted.
  • Ketone substitution does not occur on the aryl group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • a structural unit It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • substituents When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring.
  • substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • alkyl and heteroalkyl radicals (including what are commonly referred to as alkylene, alkenyl, heteroalkyl, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl)
  • R', R", R"', R"" and R""' are each independently preferably hydrogen, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group (for example, an aryl group substituted by 1 to 3 halogens), a substituted or unsubstituted alkyl group, an alkoxy group, or a thioalkyl group Oxyl a group or an aralkyl group.
  • each R group is independently selected, as when more than one R', R", R"' Each of these groups, R"" and R""' groups.
  • R' and R" When R' and R" are attached to the same nitrogen atom, they can form a 5-, 6- or 7-member with the nitrogen atom. ring.
  • -NR'R is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • alkyl is intended to include carbon.
  • a group bonded to a non-hydrogen group such as a haloalkyl group (e.g., -CF 3 , -CH 2 CF 3 ) and an acyl group (e.g., -C(O)CH 3 , -C(O)CF 3 ,- C(O)CH 2 OCH 3 , etc.).
  • a non-hydrogen group such as a haloalkyl group (e.g., -CF 3 , -CH 2 CF 3 ) and an acyl group (e.g., -C(O)CH 3 , -C(O)CF 3 ,- C(O)CH 2 OCH 3 , etc.).
  • Two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -TC(O)-(CRR')qU-, wherein T and U are independently selected From -NR-, -O-, CRR'- or a single bond, q is an integer from 0 to 3.
  • two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein A and B are independently selected From -CRR'-, -O-, -NR-, -S-, -S(O)-, S(O) 2 -, -S(O) 2 NR'- or a single bond, r is 1 to 4 The integer.
  • a single bond on the new ring thus formed can be replaced with a double bond.
  • two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein s and d are each independently An integer selected from 0 to 3, X is -O-, -NR', -S-, -S(O)-, -S(O) 2 - or -S(O) 2 NR'-.
  • the substituents R, R', R" and R"' are each independently preferably selected from hydrogen and substituted or unsubstituted (C 1 -C 6 )alkyl.
  • halo or halogen
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • Alkoxy represents the above alkyl group having a specified number of carbon atoms attached through an oxygen bridge.
  • the C 1-6 alkoxy group includes a C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • Cycloalkyl includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl.
  • the 3-7 cycloalkyl group includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl groups.
  • Alkenyl includes hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds, such as vinyl and propylene groups, are present at any stable site on the chain.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • N nitrogen
  • S sulfur
  • Si silicon
  • Ge germanium
  • Al aluminum
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 impurities. atom.
  • 5- to 7-membered ring includes, for example, phenylpyridine and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed one.
  • Bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means straight-chain, branched or cyclic
  • the hydrocarbon radical or a combination thereof may be fully saturated, unitary or polyunsaturated, may be monosubstituted, disubstituted or polysubstituted, and may include divalent or polyvalent radicals having a specified number of carbon atoms (eg, C 1 -C 10 represents 1 to 10 carbons).
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • alkyl refers to a straight or branched chain of atoms or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated alkyl group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). ), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and Structure.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroatoms B, O, N and S can be located at any internal position of the heterohydrocarbyl group (including where the hydrocarbyl group is attached to the rest of the molecule).
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • alkoxy alkylamino and “alkylthio” (or thioalkoxy) are customary expressions and refer to those alkane which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Base group alkoxy
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, which may be monocyclic or polycyclic (preferably 1 to 3 rings), They are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, indolyl, 2-benzimidazolyl, 5-indenyl
  • aryl groups when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the present invention employs the following abbreviations: aq for water; HATU for O-7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for carbonyl Diimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl and is an amine protecting group; BOC
  • Figure 1-1 shows the experimental results of the in vivo pharmacodynamic study of the human colon cancer CO-04-0032 subcutaneous xenograft tumor model.
  • mice in each group is 5;
  • Dosing volume 10 ⁇ l/g based on the body weight of the mouse. If the weight loss exceeds 15%, the dosage regimen should be adjusted accordingly;
  • BKM120 solvent is: 10% NMP + 90% PEG300, PO, QD x 5 Weeks;
  • the solvent of Compound 11 is: water, PO, QD x 5 Weeks.
  • Figure 1-2a is the experimental results of the in vivo pharmacodynamic study of the test drug on human colon cancer CO-04-0032 subcutaneous xenograft tumor model, wherein:
  • mice in each group is 6;
  • Dosing volume 10 ⁇ l/g based on the body weight of the mouse. If the weight loss exceeds 15%, the dosage regimen should be adjusted accordingly;
  • BKM120 solvent is: 10% NMP + 90% PEG300, PO, QD x 4 weeks;
  • the compound 25, 27, 32 solvent was: 5% DMSO + 60% PEG 400 + 35% water.
  • Figure 1-2b is the experimental results of the in vivo pharmacodynamic study of the test drug on human colon cancer CO-04-0032 subcutaneous xenograft tumor model, wherein:
  • mice in each group is 6;
  • Dosing volume 10 ⁇ l/g based on the body weight of the mouse. If the weight loss exceeds 15%, the dosage regimen should be adjusted accordingly;
  • BKM120 solvent is: 10% NMP + 90% PEG300, PO, QD x 4 weeks;
  • the compound 25, 27, 32 solvent was: 5% DMSO + 60% PEG 400 + 35% water.
  • Figure 2-1 shows the results of an in vivo pharmacodynamic study of a test drug on a subcutaneous xenograft mouse model of human gastric cancer ST-02-0013, in which:
  • mice in each group is 5;
  • Dosing volume 10 ⁇ l/g based on the body weight of the mouse. If the weight loss exceeds 15%, the dosage regimen should be adjusted accordingly;
  • BKM120 solvent is: 10% NMP + 90% PEG300, PO, QD x 18 days;
  • Figure 2-2 shows the results of the in vivo pharmacodynamic study of the test drug on human gastric cancer ST-02-0013 subcutaneous xenograft mouse model, in which:
  • mice in each group is 8;
  • Dosing volume 10 ⁇ l/g based on the body weight of the mouse. If the weight loss exceeds 15%, the dosage regimen should be adjusted accordingly;
  • Reaction conditions a) tert-butyldimethylsilyl chloride, 1 hydrogen-imidazole; b) 1-tert-butoxy-N,N,N',N'-tetramethyldiaminomethane, heating; c) 2-amino-5-bromopyridine, acetic acid, heating; d) acetic acid, microwave; e) potassium carbonate, DMF, heating; f) R boron ester (boric acid), 1,1'-bis(diphenylphosphine) Ferrocene palladium chloride, potassium carbonate, dioxane, water, heating.
  • Reaction conditions a) 2-morpholine ethanol, dibromotriphenylphosphine, dichloromethane; b) 7-bromo-3-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one, carbonic acid Potassium, N,N-dimethylformamide; c) 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborophen-2-yl)pyridine --3-amine, 1,1'-bis(diphenylphosphino)ferrocene palladium chloride, potassium carbonate, dioxane, water, heating; d) R-sulfonyl chloride, pyridine.
  • Dibromotriphenylphosphine (15.45 g, 36.59 mmol) was added portionwise to a solution of 2-morpholineethanol (4 g, 30.49 mmol) in dichloromethane (80 mL). The mixture was stirred at 15 degrees for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and then filtered and evaporated.
  • Reaction conditions a) methanesulfonyl chloride, triethylamine, dichloromethane; b) potassium carbonate, N,N-dimethylformamide; c) N-(2-methoxy-5-(4,4, 5,5-t tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-dimethylthiazole-5-sulfonamide, palladium, potassium carbonate , dioxane, water, heating.
  • Reaction conditions a) 1,2-dibromoethane, potassium carbonate, DMF, heating; b) 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide, 1,1'-bis(diphenylphosphino)ferrocene palladium chloride, Potassium carbonate, dioxane, water, heating; c) 1H-pyrazole, cesium carbonate, acetonitrile, heating.
  • Reaction conditions a) methanesulfonyl chloride, triethylamine, dichloromethane, 0 degree to room temperature; b) potassium carbonate, DMF, heating; c) R boron ester (boric acid), 1,1 '-bis (diphenyl Phosphorus) ferrocene palladium chloride, potassium carbonate, dioxane, water, heating; d) hydrochloric acid - ethyl acetate, ethyl acetate, room temperature.
  • Reaction conditions a) 5-bromo-2-chloro-3-nitropyridine, R alcohol, potassium hydroxide, potassium carbonate, 2-(2-methoxyethoxy)-N,N-di[2- (2-methoxyethoxy)ethyl]ethylamine, toluene; b) 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1,3,2-dioxaborane, 1,1'-bis(diphenylphosphino)ferrocene palladium chloride, potassium acetate, dioxane Hexacyclic, heating; c) Pd/C, methanol; d) 7-bromo-3-chloro-pyrido[1,2-a]pyrimidin-4-one, 1,1'-bis(diphenylphosphine) Ferrocene palladium chloride, potassium carbonate, dioxane, water,
  • Reaction conditions a) diethyl ethoxymethylene malonate, ethanol, heating; b) phosphorus oxybromide, heating; c) DIBAL-H, tetrahydrofuran, -5-0 degrees; d) manganese dioxide, Dioxane, heating; e) morpholine, sodium borohydride, acetic acid, methanol, heating; f) N-[2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-yl]-2,4-dimethyl-5-sulfonamide, 1,1'-bis(diphenylphosphine) ferrocene Iron palladium chloride, potassium carbonate, dioxane, water, heated.
  • N-(2-Hydroxypropyl)morphinphyrin (404 mg, 3.08 mmol) was dissolved in tetrahydrofuran (5 mL) in a 50 mL round bottom flask and sodium hydrogen (308 mg, 7.71 mmol, 60% purity) was added at 0. The reaction was stirred for 30 minutes, and 7-bromo-2-(2-morpholineethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one (200 mg, 770 umol) was added dropwise. The reaction solution was raised to 15 degrees, and the reaction was stirred for 3 hours. TLC showed the reaction was complete. The reaction mixture was slowly poured into ice water (50 mL), evaporated, evaporated. The crude product was purified by EtOAcjjjjjjjj
  • Reaction conditions a) triphosgene, triethylamine, 2,4-dimethyl-5-aminothiazole, 0 degree; anhydrous dichloromethane, room temperature; b) 1,1'-bis(diphenylphosphine) Ferrocene palladium chloride, potassium acetate, bis-pinacol borate, anhydrous dioxane, heating; c) 1-(2-methoxy-5-bromopyridin-3-yl)- 3-(2,4-Dimethylthiazol-5-yl)urea, 1,1'-bis(di-tert-butylphosphine)ferrocene palladium dichloride, potassium phosphate trihydrate, tetrahydrofuran, water, heated.
  • Reaction conditions a) thionyl chloride, dichloromethane, room temperature; b) 7-(5-amino-6-methoxypyridin-3-yl)-3-(2-morpholineethoxy)-4H Pyridine[1,2-a]pyrimidin-4-one, DMF, heated.
  • Reaction conditions a) triethylamine, diphenylphosphoryl azide, tert-butanol, heating; b) hydrochloric acid-ethyl acetate, room temperature; c) chlorosulfonic acid, heating; d) pyridine, 2,4-dimethyl 5-aminothiazole, dioxane, heating; e) sodium nitrite, concentrated hydrochloric acid, ice bath; f) sodium methoxide, methanol, heating; g) bis-colonol borate, 1,1' - bis(diphenylphosphino)ferrocene palladium chloride, potassium acetate, dioxane, heating; h) (3-(2-morpholineethoxy)-4-oxo-4H-pyrido[ 1,2-a]pyrimidin-7-yl)boronic acid, 1,1'-bis(diphenylphosphino)ferrocene palladium chloride, potassium carbonate, di
  • the title compound (30.00 mg, 28.48%) was obtained.
  • Reaction conditions a) carbonyl diimidazole, acetonitrile, heating; b) 4-(2-chloroethyl)morpholine, cesium carbonate, dimethyl sulfoxide, heating; c) 2,4-difluoro -N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboro-2-yl)pyridin-3-yl)benzenesulfonamide, [1,1'-bis(diphenylphosphino)ferrocene] palladium chloride, potassium carbonate, dioxane, water, heating.
  • Reaction conditions a) ethyl formate, sodium hydrogen, ethylene glycol dimethyl ether, heating; b) 5-bromopyridin-2-amine, ammonium acetate, heating; c) phosphorus oxybromide, heating; d) cesium carbonate , acetonitrile, heating; e) R boric acid (borate), 1,1'-bis(diphenylphosphino)ferrocene palladium chloride, potassium carbonate, dioxane, water, heating.
  • the mixture was placed under microwave reaction conditions for 100 hours for 1 hour. Liquid phase mass spectrometry showed the reaction was complete.
  • the reaction solution was concentrated by filtration to give a crude material.
  • the crude product was purified by silica gel column chromatography and preparative chromatography.
  • Reaction conditions a) 2-bromo-1,1-diethoxy-ethane, potassium carbonate, heating; b) concentrated hydrochloric acid, heating; c) triethyl orthoformate, 2,2-dimethyl-1 , 3-dioxane-4,6-dione, heating; EtOH, heating; d) diphenyl ether, reflux; e) concentrated sulfuric acid, nitric acid; f) Fe powder, ammonium chloride, ethanol, water , heating; g) 3-amino-7-bromo-4H-pyrido[1,2-a]pyrimidin-4-one, dichloromethane, 4A powdered molecular sieve, acetic acid, sodium borohydride; h) 2- Chloro-4-fluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-2-yl)pyridin-3-yl) Benzenesulfonamide, dio
  • Morpholine (2.21 g, 25.37 mmol, 1.00 Eq) and 2-bromo-1,1-diethoxy-ethane (5.00 g, 25.37 mmol, 1.00 Eq) were placed in a three-neck round bottom flask, and potassium carbonate was added. (7.01 g, 50.73 mmol, 2.00 Eq), and the mixture was stirred at 80 ° C for 2 hr. The reaction mixture was cooled to EtOAc EtOAc EtOAc m. The crude product was used directly in the next reaction.
  • Triethyl orthoformate 25.8 g, 0.174 mol
  • 2,2-dimethyl-1,3-dioxane-4,6-dione (25.1 g, 0.174 mol) were placed in three necks
  • the reaction was stirred at 60 °C for 2 hours in a round bottom flask.
  • a solution of 2-amino-5-bromopyridine (30 g, 0.174 mol) in ethanol (150 mL) was added dropwise to the mixture.
  • the reaction solution was stirred at 60 °C for 2 hours.
  • the mixture was cooled to 25 ° C.
  • EtOAc EtOAc
  • Reaction conditions a) Raney nickel, tetrahydrofuran, tert-butoxy anhydride, hydrogen, heating; b) 7-bromo-3-(2-morpholineethoxy)pyrido[1,2-a] Pyrimidine-4-one, dioxane, potassium carbonate, water, [1,1'-bis(diphenylphosphino)ferrocene]palladium chloride, heating; c) dichloromethane, hydrogen chloride, dioxane Ring solution; d) 2-chloro-4-fluoro-benzenesulfonyl chloride, pyridine.
  • PI3K (p110 ⁇ ) kinase activity was tested in all of the examples of the present invention by the following two test methods.
  • Reaction buffer HEPES 50 mM (pH 7.0), NaN 30.02%, BSA 0.01%, Orthovanadate 0.1 mM, 1% DMSO Detection buffer: HEPES 10 mM (pH 7.0), BSA 0.02%, KF 0.16M, EDTA 4 mM
  • Reaction substrate 10 ⁇ M PIP2 substrate (PI(4,5)P2)
  • test compound was diluted 3 times in a total of 10 concentration points (10000 nM to 0.5 nM).
  • the IC50 (Model 205, XL-fit, iDBS) was calculated using a standard 4-parameter fit method.
  • the mTOR kinase activity was tested in the following test methods in all of the examples of the present invention.
  • Reaction buffer 20 mM Hepes (pH 7.5), 10 mM MgCl 2 , 2 mM MnCl 2 , 1 mM EGTA, 0.02% Brij 35, 0.02 mg/ml BSA, 0.1 mM Na 3 VO 4 , 2 mM DTT, 2% DMSO.
  • a ⁇ 1 nM; 1 nM ⁇ B ⁇ 50 nM; 50 nM ⁇ C ⁇ 200 nM; 200 nM ⁇ D; NT means untested.
  • MCF-7 cells were seeded into 96-well plates at a density of 2.5 ⁇ 10 4 per well (the culture medium used was a complete medium containing 10% FBS).
  • the culture medium in the well was removed the next day, and a certain concentration (primary screening) or a series of concentrations (IC 50 test) of the compound was dissolved in the serum-free medium, and the cells were added to the 96-well plate. hour.
  • Enhancer Solution needs to be removed from the refrigerator in advance.
  • Enhancer solution (Enhancer Solution) was diluted 10-fold with 5X Lysis Buffer to prepare a concentrated lysate.
  • the culture solution in the well was aspirated and rinsed once with PBS.
  • the antibody mixture is prepared by mixing the medium antibody reagent and the enzyme-labeled antibody reagent in equal proportions. Note that when preparing the antibody mixture, do not vortex)
  • the substrate mixture should be used as needed. One hundred microliters of the substrate mixture was added to each well, and the microplate was sealed with tin foil paper and incubated on a microplate shaker for 10 minutes at room temperature.
  • the compound of the present invention has a significant inhibitory effect on PI3K, but has a weak inhibitory effect on mTOR.
  • test drug was tested for its in vivo efficacy in the animal model of human colon cancer CO-04-0032 and the animal model of gastric cancer ST-02-0013.
  • the descriptions of animal feeding, feed ingredients, experimental observations, experimental indicators, experimental termination and data analysis are as follows:
  • Animal feeding After the animals arrive, they can be started in the experimental environment for 3-7 days. Animals were housed in an IVC (independent air supply system) cage at the SPF level animal house (5 per cage). All cages, litter and drinking water must be sterilized before use. The sterilization and disinfection records are shown in the annex. All laboratory personnel should wear protective clothing and latex gloves when operating in the animal room. The animal information card for each cage should indicate the number of animals in the cage, gender, strain, date of receipt, dosing schedule, experiment number, group, and start date of the experiment. Cage, feed and drinking water are changed twice a week. The feeding environment and lighting conditions are as follows:
  • ⁇ Lighting cycle 12 hours of light, 12 hours of no light
  • ⁇ Feed ingredients The feed meets the animal food identification criteria.
  • the maximum content of pollutants is within the controllable range and is inspected by the manufacturer.
  • Drinking water is autoclaved drinking water.
  • Animal grouping Animals were weighed prior to dosing and tumor volume was measured. Randomly grouped according to tumor volume (random block design).
  • TGI tumor growth inhibition
  • TGI (%) [1-(Ti-T0) / (Vi-V0)] ⁇ 100, where Ti is the average tumor volume of a certain administration group on a certain day, and T0 is given for this purpose.
  • Tumor weights were measured after the end of the experiment and the percentage of T/C was calculated.
  • T and C represent the tumor weights of the drug-administered group and the vehicle control group, respectively.
  • the mean volume of the tumor in the control group reached 2,000 mm 3 and the experiment was terminated.
  • Human-transplantation tumor model establishment The human colon cancer CO-04-0032 model was originally derived from tumor samples excised during clinical surgery. The collection of specimens is strictly in accordance with national, hospital and company ethical laws and regulations, including patients. Informed consent. The model building process is strictly in accordance with the company's internal SOP. The passage naming rule is that the tumor sample is inoculated into nude mice and then P0 generation, and the passage is continued to P1 generation. By analogy, the recovered specimen is named FP. The tumor tissue used in this experiment was FP4 generation.
  • ⁇ tumor inoculation The volume of about 30mm 3 CO-04-0032 tumor blocks were subcutaneously inoculated on the right back of each mouse group average tumor volume reached approximately the start of administration 100-200mm 3.
  • ⁇ Human-transplantation tumor model establishment The PDX model of ST-02-0013 was originally derived from a surgically removed clinical sample, which was defined as P0 generation in nude mice. The next generation of implanted P0 tumors is defined as the P1 generation, and subsequent progeny transplantation in mice, and so on. FP2 generation tumor resuscitation resulted in FP3 tumors. FP3 generation tumors were passaged to obtain FP4 tumors. FP4 tumor tissue will be used for this study.
  • ⁇ tumor inoculation The volume of about 30mm 3 ST-02-0013FP4 generation of tumor tissue were inoculated subcutaneously to the right back of each mouse group average tumor volume reached approximately the start of administration 150-200mm 3.

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Abstract

公开了一类作为PI3K抑制剂的吡啶并[1,2-a]嘧啶酮类似物,具体涉及式(I)所示化合物或其药学上可接受的盐。

Description

作为PI3K抑制剂的吡啶并[1,2-a]嘧啶酮类似物 技术领域
本发明涉及一类作为PI3K抑制剂的吡啶并[1,2-a]嘧啶酮类似物,具体地,本发明涉及式(I)所示化合物或其药学上可接受的盐。
背景技术
PI3K通路是人体癌细胞中最常发生变异的地方,可导致细胞的增殖,活化,放大信号。
PI3K激酶(磷脂酰肌醇3-激酶,PI3Ks)属于脂质激酶家族,能够磷酸化磷脂酰肌醇的肌醇环3’-OH端。磷脂酰肌醇3-激酶(phosphatidylinositol-3-kinase,PI3K)为一种由调节亚单位p85或p101和催化亚单位p110组成的脂激酶,通过催化磷脂酰肌醇4,5-二磷酸(phosphatidylinositol 4,5-bisphosphate,PIP2)磷酸化为磷脂酰肌醇3,4,5-三磷酸(phosphatidylinositol 3,4,5-trisphosphate,PIP3)而激活下游的Akt等从而对细胞的增殖、生存和代谢等起关键作用。因此抑制磷酸酯酰肌醇3激酶,可以影响PI3K通路,从而抑制癌细胞的增殖与活化。
肿瘤抑制基因PTEN(phosphatase and tension homolog deleted on chromosome ten)使PIP3去磷酸化生成PIP2,从而实现PI3K/Akt信号通路的负性调节,抑制细胞增殖和促进细胞凋亡。PI3K基因突变和扩增在癌症中频繁发生以及PTEN在癌症中缺失等都提示PI3K与肿瘤发生的密切关系。
发明内容
本发明的目的在于提供式(I)所示化合物或其药学上可接受的盐,
Figure PCTCN2015081518-appb-000001
其中,
可将结构单元
Figure PCTCN2015081518-appb-000002
替换为
Figure PCTCN2015081518-appb-000003
Figure PCTCN2015081518-appb-000004
E选自任选被1、2或3个R3取代的C1-6烷基、3~10元环烃基或杂环烃基;
L和Q中,一个选自-C(Rd1)(Rd2)-、-C(=O)N(Rd3)-、-N(Rd4)-、-C(=NRd5)-、-S(=O)2N(Rd6)-、-S(=O)N(Rd7)-、-O-、-S-、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-或-N(Rd8)C(=O)N(Rd9)-,另一个选自单键或 -C(Rd1)(Rd2)-;
A、T分别独立地选自N或C(Rt);
X、Y、Z中的0或1个选自N,其余选自C(Rt);
B选自-C(Rd1)(Rd2)-、-C(=O)N(Rd3)-、-N(Rd4)-、-C(=NRd5)-、-S(=O)2N(Rd6)-、-S(=O)N(Rd7)-、-O-、-S-、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-或-N(Rd8)C(=O)N(Rd9)-;
杂原子或杂原子团分别独立地选自-C(=O)N(Rd3)-、-N(Rd4)-、-C(=NRd5)-、-S(=O)2N(Rd6)-、-S(=O)N(Rd7)-、-O-、-S-、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-和/或-N(Rd8)C(=O)N(Rd9)-;
m1分别独立地选自0、1、2或3;
R1-3中的一个选自
Figure PCTCN2015081518-appb-000005
其余选自H、F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH,或选自任选被R01取代的C1-10烷基或杂烷基、3~10元环烃基或杂环烃基、被3~10元环烃基或杂环烃基取代的C1-10烷基或杂烷基、3~10元环烃基或杂环烃基-O-、3~10元环烃基或杂环烃基-氨基-;D1选自单键、-C(Rd1)(Rd2)-、-C(=O)N(Rd3)-、-N(Rd4)-、-C(=NRd5)-、-S(=O)2N(Rd6)-、-S(=O)N(Rd7)-、-O-、-S-、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-或-N(Rd8)C(=O)N(Rd9)-;
D2选自-C(Rd1)(Rd2)-;
D3选自-N(Rd4)-、-C(=O)N(Rd4)-、-N(Rd4)C(=O)-、-N(Rd4)C(=O)O-、-N(Rd4)OC(=O)-、-N(Rd4)C(=O)N(Rd4)-、-S(=O)-、-S(=O)2-、-S(=O)2N(Rd6)-、-S(=O)N(Rd7)-;
R4选自H,或选自任选被R01取代的C1-10烷基或杂烷基、3~10元环烃基或杂环烃基、被3~10元环烃基或杂环烃基取代的C1-10烷基或杂烷基;
n选自1、2、3、4、5或6;
任选地,任意两个R1之间、同一个D2中的Rd1与Rd2之间、两个D2之间、R4与一个D2之间或者R4与D3之间共同连接到同一碳原子或杂原子上形成一个或两个3、4、5或6元碳环或杂环;
Rt、Rd1、Rd2分别独立地选自H、F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH、C(=O)NH2、S(=O)NH2、S(=O)2NH2,或选自任选被R01取代的C1-10烷基或杂烷基、3~10元环烃基或杂环烃基、被3~10元环烃基或杂环烃基取代的C1-10烷基或杂烷基;
R01选自F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH、R02
R02选自C1-10烷基、C1-10烷氨基、N,N-二(C1-10烷基)氨基、C1-10烷氧基、C1-10烷酰基、C1-10烷氧羰基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基、C3-10环烷氨基、C3-10杂环烷氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧羰基、C3-10环烷基磺酰基、C3-10环烷基亚磺酰基、5-6元不饱和杂环基、6-12元芳基或杂芳基;
杂原子或杂原子团分别独立地选自-C(=O)N(Rd3)-、-N(Rd4)-、-C(=NRd5)-、-S(=O)2N(Rd6)-、-S(=O)N(Rd7)-、-O-、-S-、=O、=S、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-和/或-N(Rd8)C(=O)N(Rd9)-;
Rd3-d9分别独立地选自H、OH、NH2、R02
R02任选地被R001取代;
R001选自F、Cl、Br、I、CN、OH、N(CH3)2、NH(CH3)、NH2、CHO、COOH、三氟甲基、氨甲基、羟 甲基、甲基、甲氧基、甲酰基、甲氧羰基、甲磺酰基、甲基亚磺酰基;
上述任意一种情况下,R01、R001数目分别独立地选自0、1、2或3,杂原子或杂原子团的数目分别独立地选自1、2或3。本发明的一个方案中,上述E选自被R3取代的C1-6烷基或C3-6环烷基,R3的数目选自0、1、2或3,或者E选自
Figure PCTCN2015081518-appb-000006
Figure PCTCN2015081518-appb-000007
其中,
G1~5中的0、1、2或3个选自N,其余选自C(R3);
G6选自-C(R3)(R3)-、-C(=O)N(R3a)-、-N(R3a)-、-C(=NR3a)-、-S(=O)2N(R3a)-、-S(=O)N(R3a)-、-O-、-S-、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-或-N(R3a)C(=O)N(R3a)-;
G7~9中的0、1或2个选自N,其余选自C(R3);
G10~16中的0、1、2、3或4个选自N,其余选自C(R3);
G17选自N或者C(R3);
G18~22中的0、1、2或3个选自-C(=O)N(R3a)-、-N(R3a)-、-C(=NR3a)-、-S(=O)2N(R3a)-、-S(=O)N(R3a)-、-O-、-S-、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-或-N(R3a)C(=O)N(R3a)-,其余选自-C(R3)(R3)-;R3a选自C1-10烷基、C1-10烷基酰基、C1-10烷氧羰基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基、C3-10环烷基酰基、C3-10环烷氧羰基、C3-10环烷基磺酰基、C3-10环烷基亚磺酰基、5-6元不饱和杂环基、6-10元芳基或杂芳基。
本发明的一个方案中,上述E选自任选被1、2或3个R3取代的甲基、乙基、丙基、
Figure PCTCN2015081518-appb-000008
Figure PCTCN2015081518-appb-000009
本发明的一个方案中,上述E选自任选被1、2、或3个卤素、OH、OC1-3烷基、CN、NH2、NH(C1-3 烷基)、N(C1-3烷基)2、C1-3烷基、三氟甲基、三氟乙基、C(=O)NH2、C1-3烷基C(=O)、C1-3烷基C(=O)NH、C1-3烷基S(=O)、C1-3烷基S(=O)NH、C1-3烷基S(=O)2或C1-3烷基S(=O)2NH所取代的:
Figure PCTCN2015081518-appb-000010
Figure PCTCN2015081518-appb-000011
Figure PCTCN2015081518-appb-000012
C1-3烷基。
本发明的一个方案中,上述E选自
Figure PCTCN2015081518-appb-000013
Figure PCTCN2015081518-appb-000014
Figure PCTCN2015081518-appb-000015
本发明的一个方案中,上述L和Q中,一个选自-S(=O)2NH-、-S(=O)2-、-NH-、-NHC(=O)NH-,另一个选自单键、-CH2-。
本发明的一个方案中,上述X、Y、Z中的0或1个选自N,其余选自CH、C(CH3)、C(CF3)、CCl、CF。
本发明的一个方案中,上述A、T分别独立地选自N、CH、C(CH3)、C(CF3)、CCl、CF;或者,B选自NH、N(CH3)或N(CF3)。
本发明的一个方案中,上述任意两个R1之间、同一个D2中的Rd1与Rd2之间、两个D2之间、R4与一个D2之间或者R4与D3之间所成的环选自任选被1、2、或3个卤素、OH、OC1-3烷基、CN、NH2、NH(C1-3烷基)、N(C1-3烷基)2、C1-3烷基、三氟甲基、三氟乙基、C(=O)NH2、C1-3烷基C(=O)、C1-3烷基C(=O)NH、C1-3烷基S(=O)、C1-3烷基S(=O)NH、C1-3烷基S(=O)2或C1-3烷基S(=O)2NH所取代的:
Figure PCTCN2015081518-appb-000016
本发明的一个方案中,上述任意两个R1之间、同一个D2中的Rd1与Rd2之间、两个D2之间、R4与一个D2之间或者R4与D3之间所成的环选自:
Figure PCTCN2015081518-appb-000017
本发明的一个方案中,上述R1-3中的一个选自
Figure PCTCN2015081518-appb-000018
其余选自H、F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH、ORa、N(Rb)(Rc)、任选被Rd取代的C1-3烷基或环丙基;D1选自单键、-C(Re)(Re)-、-C(=O)N(Ra)-、-N(Ra)-、-C(=NRa)-、-S(=O)2N(Ra)-、-S(=O)N(Ra)-、-O-、-S-、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-或-N(Ra)C(=O)N(Ra)-;
D2选自-C(Ra)(Ra)-;
n选自1、2、3、4、5或6;
Ra、Rb、Rc分别独立地选自H、任选Rd取代的C1-6烷基或C3-6环烷基;
Re选自H、任选Rd取代的C1-6烷基或烷氧基、任选Rd取代的C3-6环烷基或环烷氧基;
Rd选自F、Cl、Br、I、CN、OH、CHO、COOH、CH3、CF3、CH3O、CH3CH2O,Rd的数目选自0、1、2或3;
任选地,任意两个R1之间、同一个D2中的Ra与Ra之间、两个D2之间、或Ra与一个D2之间共同连接到同一碳原子或氧原子上形成一个或两个3、4、5或6元碳环或氧杂环,其中氧原子的数目为1或2。
本发明的一个方案中,上述任意两个R1之间、同一个D2中的Ra与Ra之间、两个D2之间、或Ra与一个D2之间所成的环选自环丙基、环丁基、环戊基、环己基、氧杂环丁基、1,3-二氧五环基。
本发明的一个方案中,上述R1-3中的一个选自
Figure PCTCN2015081518-appb-000019
Figure PCTCN2015081518-appb-000020
Figure PCTCN2015081518-appb-000021
Figure PCTCN2015081518-appb-000022
其余选自H、F、Cl、Br、I、CN、OH、NH2、甲基、乙基、丙基、甲氧基、乙氧基、丙氧基甲氨基、二甲氨基、卤代甲基、卤代乙基、卤代丙基、氨甲基、氨乙基、氨丙基、环丙基。
本发明的一个方案中,上述化合物或其药学上可接受的盐,其选自化合物1~25、化合物27~99。
相关定义:
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。
C1-10选自C1、C2、C3、C4、C5、C6、C7、C8、C9和C10;C3-10选自C3、C4、C5、C6、C7、C8、C9和C10
C1-10烷基或杂烷基、C3-10环基或杂环烃基、被C3-10环烃基或杂环烃基取代的C1-10烷基或杂烷基包括但不限于:
C1-10烷基、C1-10烷氨基、N,N-二(C1-10烷基)氨基、C1-10烷氧基、C1-10烷酰基、C1-10烷氧羰基、C1-10 烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基、C3-10环烷氨基、C3-10杂环烷氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷基氧羰基、C3-10环烷基磺酰基、C3-10环烷基亚磺酰基;
甲基、乙基、正丙基、异丙基、-CH2C(CH3)(CH3)(OH)、环丙基、环丁基、丙基亚甲基、环丙酰基、苄氧基、三氟甲基、氨甲基、羟甲基、甲氧基、甲酰基、甲氧羰基、甲磺酰基、甲基亚磺酰基、乙氧基、乙酰基、乙磺酰基、乙氧羰基、二甲基氨基、二乙基氨基、二甲基氨基羰基、二乙基氨基羰基;
N(CH3)2,NH(CH3),-CH2CF3,-CH2CH2CF3,-CH2CH2F,-CH2CH2S(=O)2CH3,-CH2CH2CN,
Figure PCTCN2015081518-appb-000023
Figure PCTCN2015081518-appb-000024
-CH2CH(OH)(CH3)2,-CH2CH(F)(CH3)2,-CH2CH2F,-CH2CF3,-CH2CH2CF3,-CH2CH2NH2,-CH2CH2OH,-CH2CH2OCH3,-CH2CH2CH2OCH3,-CH2CH2N(CH3)2,-S(=O)2CH3,-CH2CH2S(=O)2CH3,
Figure PCTCN2015081518-appb-000025
Figure PCTCN2015081518-appb-000026
Figure PCTCN2015081518-appb-000027
Figure PCTCN2015081518-appb-000028
苯基、噻唑基、联苯基、萘基、环戊基、呋喃基、3-吡咯啉基、吡咯烷基、1,3-氧五环基、吡唑基、2-吡唑啉基、吡唑烷基、咪唑基、恶唑基、噻唑基、1,2,3-唑基、1,2,3-三唑基、1,2,4-三唑基、1,3,4-噻二唑基、4H-吡喃基、吡啶基、哌啶基、1,4-二氧六环基、吗啉基、哒嗪基、嘧啶基、吡嗪基、哌嗪基、1,3,5-三噻烷基、1,3,5-三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、苯并咪唑基、苯并噻唑基、嘌呤基、喹啉基、异喹啉基、噌啉基或喹喔啉基;
甲基、乙基、丙基、甲氧基、乙氧基、甲氨基、二甲氨基、卤代甲基、卤代乙基、卤代丙基、氨甲基、氨乙基、氨丙基、环丙基;和
Figure PCTCN2015081518-appb-000029
Figure PCTCN2015081518-appb-000030
这里所采用的术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐,由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐,所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸,碳酸氢根,磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等;以及有机酸盐,所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸;还包括氨基酸(如精氨酸等)的盐,以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团,从而可以被转换成任一碱或酸加成盐。
优选地,以常规方式使盐与碱或酸接触,再分离母体化合物,由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质,例如在极性溶剂中的溶解度不同。
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物,其中,通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于:碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐,例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐,所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬 脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地,优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
除了盐的形式,本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外,前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在,包括水合物形式。一般而言,溶剂化形式与非溶剂化的形式相当,都包含在本发明的范围之内。本发明的某些化合物可以以多晶或无定形形式存在。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
本文中消旋体、ambiscalemic and scalemic或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。1985年,62:114-120。除非另有说明,用楔形键和虚线键表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心,除非另有规定,它们包括E、Z几何异构体。同样地,所有的互变异构形式均包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物,包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体,及其外消旋混合物和其他混合物,例如对映异构体或非对映体富集的混合物,所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物,均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体,可以通过不对称合成或者具有手性助剂的衍生作用来制备,其中将所得非对映体混合物分离,并且辅助基团裂开以提供纯的所需对映异构体。或者,当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时,与适当的光学活性的酸或碱形成非对映异构体的盐,然后通过本领域所公知的分步结晶法或色谱法进行非对映异构体拆分,然后回收得到纯的对映体。此外,对映异构体和非对映异构体的分离通常是通过使用色谱法完成的,所述色谱法采用手性固定相,并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氚(3H),碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息,可以参考Remington:The Science and Practice of  Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005),该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言,术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型,组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异,取决于受体的年龄和一般情况,也取决于具体的活性物质,个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”,“活性物质”或“活性剂”是指一种化学实体,它可以有效地治疗目标紊乱、疾病或病症。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代,包括重氢和氢的变体,只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即=O)时,意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代,也可以不被取代,除非另有规定,取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当其中一个变量选自单键时,表示其连接的两个基团直接相连,比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时,其在每一种情况下的定义都是独立的。因此,例如,如果一个基团被0-2个R所取代,则所述基团可以任选地至多被两个R所取代,并且每种情况下的R都有独立的选项。此外,取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。例如,结构单元
Figure PCTCN2015081518-appb-000031
表示其可在环己基或者环己二烯上的任意一个位置发生取代。
当一个取代基的键可以交叉连接到一个环上的两个原子时,这种取代基可以与这个环上的任意原子相键合。当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时,这种取代基可以通过其任何原子相键合。取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
烷基和杂烷基原子团(包括通常被称为亚烷基、链烯基、亚杂烷基、杂烯基、炔基、环烷基、杂环烷基、环烯基和杂环烯基的那些基团)的取代基一般被称为“烷基取代基”,它们可以选自但不限于下列基团中的一个或多个:-R’、-OR’、=O、=NR’、=N-OR’、-NR’R”、-SR’、卤素、-SiR’R”R”’、OC(O)R’、-C(O)R’、-CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、NR’C(O)NR”R”’、-NR”C(O)2R’、-NR””’-C(NR’R”R”’)=NR””、NR””C(NR’R”)=NR”’、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、NR”SO2R’、-CN、–NO2、-N3、-CH(Ph)2和氟代(C1-C4)烷基,取代基的数目为0~(2m’+1),其中m’是这类原子团中碳原子的总数。R'、R”、R”'、R””和R””’各自独立地优选氢、被取代或未被取代的杂烷基、被取代或未被取代的芳基(例如被1~3个卤素取代芳基)、被取代或未被取代的烷基、烷氧基、硫代烷氧基基团或芳烷基。当本发明的化合物包括一个以上的R基团时,例如,每一个R基团是独立地加以选择的,如同当存在一个以上的R'、R”、R”'、R””和R””’基团时的每个这些基团。当R'和R”附着于同一个氮原子时,它们可与该氮原子结合形成5-,6-或7-元环。例如,-NR'R“意在包括但不仅限于1-吡咯烷基和4-吗啉基。根据上述关于取代基的讨论中,本领域技术人员可以理解,术语“烷基”意在包括碳原子键合于非氢 基团所构成的基团,如卤代烷基(例如-CF3、-CH2CF3)和酰基(例如-C(O)CH3、-C(O)CF3、-C(O)CH2OCH3等)。
与烷基原子团所述取代基相似,芳基和杂芳基取代基一般统称为“芳基取代基”,选自例如-R’、-OR’、-NR’R”、-SR’、-卤素,-SiR’R”R”’、OC(O)R’、-C(O)R’、-CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、NR’C(O)NR”R”’、-NR”C(O)2R’、-NR””’-C(NR’R”R”’)=NR””、NR””C(NR’R”)=NR”’、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、NR”SO2R’、-CN、–NO2、-N3、-CH(Ph)2、氟(C1-C4)烷氧基和氟(C1-C4)烷基等,取代基的数量为0到芳香环上开放化合价的总数之间;其中R’、R”、R”’、R””和R””’独立地优选自氢、被取代或未被取代的烷基、被取代或未被取代的杂烷基、被取代或未被取代的芳基和被取代或未被取代的杂芳基。当本发明的化合物包括一个以上的R基团时,例如,每个R基团是独立地加以选择的,如同当存在一个以上R’、R”、R”’、R””和R””’基团时的每个这些基团。
芳基或杂芳基环的相邻原子上的两个取代基可以任选地被通式为–T-C(O)-(CRR’)q-U-的取代基所取代,其中T和U独立地选自-NR-、-O-、CRR'-或单键,q是0到3的整数。作为替代选择,芳基或杂芳基环的相邻原子上的两个取代基可以任选地被通式为–A(CH2)r B-的取代基所取代,其中A和B独立的选自–CRR’-、-O-、-NR-、-S-、-S(O)-、S(O)2-、-S(O)2NR’-或单键,r是1~4的整数。任选地,由此形成的新环上的一个单键可以替换为双键。作为替代选择,芳基或杂芳基环的相邻原子上的两个取代基可以任选地被通式为–A(CH2)r B-的取代基所取代,其中s和d分别独立的选自0~3的整数,X是–O-、-NR’、-S-、-S(O)-、-S(O)2-或–S(O)2NR’-。取代基R、R’、R”和R”’分别独立地优选自氢和被取代或未被取代的(C1-C6)烷基。
除非另有规定,术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外,术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如,术语“卤代(C1-C4)烷基”意在包括但不仅限于三氟甲基、2,2,2-三氟乙基、4-氯丁基和3-溴丙基等等。
卤代烷基的实例包括但不仅限于:三氟甲基、三氯甲基、五氟乙基,和五氯乙基。“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基。C1-6烷氧基包括C1、C2、C3、C4、C5和C6的烷氧基。烷氧基的例子包括但不限于:甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。“环烷基”包括饱和环基,如环丙基、环丁基或环戊基。3-7环烷基包括C3、C4、C5、C6和C7环烷基。“链烯基”包括直链或支链构型的烃链,其中该链上任何的稳定位点上存在一个或多个碳-碳双键,例如乙烯基和丙烯基。
术语“卤”或“卤素”是指氟、氯、溴和碘。
除非另有规定,术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团),包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团,例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、=O、=S、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)、-S(=O)2-,以及任选被被取代的-C(=O)N(H)-、-N(H)-、-C(=NH)-、-S(=O)2N(H)-或-S(=O)N(H)-。
除非另有规定,“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数,例如,“5~7元环”是指环绕排列5~7个原子。除非另有规定,该环任选地包含1~3个杂 原子。因此,“5~7元环”包括例如苯基吡啶和哌啶基;另一方面,术语“5~7元杂环烷基环”包括吡啶基和哌啶基,但不包括苯基。术语“环”还包括含有至少一个环的环系,其中的每一个“环”均独立地符合上述定义。
除非另有规定,术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环,它们可以是饱和的、部分不饱和的或不饱和的(芳族的),它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子,其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p)。氮原子可以是被取代的或未取代的(即N或NR,其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的,本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是,当杂环中S及O原子的总数超过1时,这些杂原子彼此不相邻。另一个优选方案是,杂环中S及O原子的总数不超过1。如本文所用,术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环,它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR,其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p)。值得注意的是,芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于:一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是,一个桥总是将单环转换成三环。桥环中,环上的取代基也可以出现在桥上。
杂环化合物的实例包括但不限于:吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、isatino基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基,八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基,6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基。还包括稠环和螺环化合物。
除非另有规定,术语“烃基”或者其下位概念(比如烷基、烯基、炔基、苯基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合,可以是完全饱和的、单元或多元不饱和的,可以是单取代、二取代或多取代的,可以包括二价或多价原子团,具有指定数量的碳原子(如 C1-C10表示1至10个碳)。“烃基”包括但不限于脂肪烃基和芳香烃基,所述脂肪烃基包括链状和环状,具体包括但不限于烷基、烯基、炔基,所述芳香烃基包括但不限于6-12元的芳香烃基,例如苯、萘等。在一些实施例中,术语“烷基”表示直链的或支链的原子团或它们的组合,可以是完全饱和的、单元或多元不饱和的,可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基,以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烷基具有一个或多个双键或三键,其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)、乙炔基、1-和3-丙炔基,3-丁炔基,以及更高级的同系物和异构体。
除非另有规定,术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合,有一定数目的碳原子和至少一个杂原子组成。在一些实施例中,术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物,有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中,杂原子选自B、O、N和S,其中氮和硫原子任选地被氧化,氮杂原子任选地被季铵化。杂原子B、O、N和S可以位于杂烃基的任何内部位置(包括该烃基附着于分子其余部分的位置)。实例包括但不限于-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH=CH-O-CH3、-CH2-CH=N-OCH3和–CH=CH-N(CH3)-CH3。至多两个杂原子可以是连续的,例如-CH2-NH-OCH3
术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达,是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。
除非另有规定,术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外,就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言,杂原子可以占据该杂环附着于分子其余部分的位置。环烷基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基,3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基,1-哌嗪基和2-哌嗪基。
除非另有规定,术语“芳基”表示多不饱和的芳族烃取代基,可以是单取代、二取代或多取代的,它可以是单环或多环(优选1至3个环),它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中,杂原子选自B、N、O和S,其中氮和硫原子任选地被氧化,氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
为简便起见,芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此,术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等),包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基,例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如,代表性的离去基团包括三氟甲磺酸酯;氯、溴、碘;磺酸酯基,如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等;酰氧基,如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于:甲酰基;酰基,例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基);烷氧基羰基,如叔丁氧基羰基(Boc);芳基甲氧羰基,如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc);芳基甲基,如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基;甲硅烷基,如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于:烷基,如甲基、乙基和叔丁基;酰基,例如链烷酰基(如乙酰基);芳基甲基,如苄基(Bn),对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基,DPM);甲硅烷基,如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
本发明所使用的所有溶剂是市售的,无需进一步纯化即可使用。反应一般是在惰性氮气下、无水溶剂中进行的。质子核磁共振数据记录在Bruker Avance III 400(400MHz)分光仪上,化学位移以四甲基硅烷低场处的(ppm)表示。质谱是在安捷伦1200系列加6110(&1956A)上测定。LC/MS或Shimadzu MS包含一个DAD:SPD-M20A(LC)和Shimadzu Micromass 2020检测器。质谱仪配备有一个正或负模式下操作的电喷雾离子源(ESI)。
本发明采用下述缩略词:aq代表水;HATU代表O-7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐;EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐;m-CPBA代表3-氯过氧苯甲酸;eq代表当量、等量;CDI代表羰基二咪唑;DCM代表二氯甲烷;PE代表石油醚;DIAD代表偶氮二羧酸二异丙酯;DMF代表N,N-二甲基甲酰胺;DMSO代表二甲亚砜;EtOAc代表乙酸乙酯;EtOH代表乙醇;MeOH代表甲醇;CBz代表苄氧羰基,是一种胺保护基团;BOC代表叔丁基羰基是一种胺保护基团;HOAc代表乙酸;NaCNBH3代表氰基硼氢化钠;r.t.代表室温;O/N代表过夜;THF代表四氢呋喃;Boc2O代表二-叔丁基二碳酸酯;TFA代表三氟乙酸;DIPEA代表二异丙基乙基胺;SOCl2代表氯化亚砜;CS2代表二硫化碳;TsOH代表对甲苯磺酸;NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺;NCS代表1-氯吡咯烷-2,5-二酮;n-Bu4NF代表氟化四丁基铵;iPrOH代表2-丙醇;mp代表熔点。
化合物经手工或者
Figure PCTCN2015081518-appb-000032
软件命名,市售化合物采用供应商目录名称。
附图说明
图1-1是受试药对人源结肠癌CO-04-0032皮下异种移植肿瘤模型的体内药效学研究实验一的实验结果,
其中:
1)每组小鼠数目为5只;
2)给药容积:根据小鼠体重10μl/g。如果体重下降超过15%,给药方案应做出相应调整;
3)BKM120溶媒为:10%NMP+90%PEG300,PO,QD x 5Weeks;
4)化合物11溶媒为:水,PO,QD x 5Weeks。
图1-2a是受试药对人源结肠癌CO-04-0032皮下异种移植肿瘤模型的体内药效学研究实验二的实验结果,其中:
1)每组小鼠数目为6只;
2)给药容积:根据小鼠体重10μl/g。如果体重下降超过15%,给药方案应做出相应调整;
3)BKM120溶媒为:10%NMP+90%PEG300,PO,QD x 4周;
4)化合物11溶媒为:水,PO,QD x 4周;
5)化合物25,27,32溶媒为:5%DMSO+60%PEG400+35%water。
图1-2b是受试药对人源结肠癌CO-04-0032皮下异种移植肿瘤模型的体内药效学研究实验二的实验结果,其中:
1)每组小鼠数目为6只;
2)给药容积:根据小鼠体重10μl/g。如果体重下降超过15%,给药方案应做出相应调整;
3)BKM120溶媒为:10%NMP+90%PEG300,PO,QD x 4周;
4)化合物11溶媒为:水,PO,QD x 4周;
5)化合物25,27,32溶媒为:5%DMSO+60%PEG400+35%water。
图2-1是受试药对人胃癌ST-02-0013皮下异种移植小鼠模型的体内药效学研究实验一的实验结果,其中:
1)每组小鼠数目为5只;
2)给药容积:根据小鼠体重10μl/g。如果体重下降超过15%,给药方案应做出相应调整;
3)BKM120溶媒为:10%NMP+90%PEG300,PO,QD x 18天;
4)化合物11溶媒为:水,PO,QD x 18天;
5)化合物15溶媒为:1%MC,PO,QD x 18天。
图2-2是受试药对人胃癌ST-02-0013皮下异种移植小鼠模型的体内药效学研究实验二的实验结果,其中:
1)每组小鼠数目为8只;
2)给药容积:根据小鼠体重10μl/g。如果体重下降超过15%,给药方案应做出相应调整;
3)化合物25,27,32溶媒为:5%DMSO+60%PEG400+35%water。
具体实施方式
为了更详细地说明本发明,给出下列实例,但本发明的范围并非限定于此。
流程1:
Figure PCTCN2015081518-appb-000033
反应条件:a)叔丁基二甲基硅氯,1氢-咪唑;b)1-叔丁氧基-N,N,N',N'-四甲基二胺基甲烷,加热;c)2-胺基-5-溴吡啶,醋酸,加热;d)醋酸,微波;e)碳酸钾,DMF,加热;f)R硼脂(硼酸),1,1’-双(二苯基膦)二茂铁氯化钯,碳酸钾,二氧六环,水,加热。g)甲磺酰氯,三乙胺,二氯甲烷,0度;h)4,4-二氟哌啶,二异丙基乙胺,乙腈,加热。
实施例1
N-(5-(3-(2-(4,4-二氟-1-哌啶基)乙氧基)-4-氧代-吡啶并[1,2-a]嘧啶-7-基]-2-甲氧基吡啶-3-]-2,4-二甲基噻唑-5-磺酰胺
Figure PCTCN2015081518-appb-000034
a)2-((叔丁基二甲基硅)氧)乙酸乙酯
将乙醇酸乙酯(100g,961mmol)和1氢-咪唑(130g,1.9mol)溶于二氯甲烷(1L)置于三口圆底烧瓶中,0度下加入叔丁基二甲基硅氯(158g,1mol),混合物在室温下搅拌8小时,水洗(1L*3),硫酸钠干燥浓缩得到黄色油状标题化合物(195g,93%)。
1H NMR(400MHz,CDCl3)ppmδ4.14-4.09(m,4H),1.20-1.16(t,3H),0.83(s,9H),0.01(s,6H).
b)(Z)-乙基2-((叔丁基二甲基硅)氧)-3-(二甲胺基)丙烯酸酯
将2-((叔丁基二甲基硅)氧)乙酸乙酯(96g,0.44mol)和1-叔丁氧基-N,N,N',N'-四甲基二胺基甲烷(91.9g,0.53mol)在回流状态下搅拌24小时。浓缩混合物,残留液用硅胶柱色谱纯化得到黄色油状标题化合物(80g,66.6%)。
1H NMR(400MHz,CDCl3)ppmδ6.68(s,1H),4.13-4.11(q,2H),2.96(s,6H),1.28-1.24(t,3H),0.95(s,9H),0.14(s,6H).
c)(Z)-乙基3-((5-溴吡啶-2-基)胺基)-2-((叔丁基二甲基硅)氧)丙烯酸酯
将(Z)-乙基3-((5-溴吡啶-2-基)胺基)-2-((叔丁基二甲基硅)氧)丙烯酸酯(80g,293mmol)和2-胺基-5-溴吡啶(50.6g,293mmol)溶于乙酸(800mL)中,80度下搅拌2小时。浓缩混合物,残留物溶于乙酸乙酯(500mL)中,用碳酸钠溶液(500mL)和饱和食盐水(500mL)洗,硫酸钠干燥、浓缩,所得残留物用硅胶柱色谱纯化得到黄色油状标题化合物(74g,63.0%)。
1H NMR(400MHz,CDCl3)ppmδ8.24(s,1H),7.75-7.72(d,1H),7.63-7.60(d,1H),6.75-6.72(d,1H),6.57-6.54(d,1H),4.25-4.20(q,2H),1.34-1.30(t,3H),1.02(s,9H),0.22(s,6H).
d)7-溴-3-羟基-4氢-吡啶并[1,2-a]嘧啶-4-酮
将(Z)-乙基3-((5-溴吡啶-2-基)胺基)-2-((叔丁基二甲基硅)氧)丙烯酸酯(2g*34,169mmol)溶于乙酸(13mL*34)中,微波140度下搅拌4小时。浓缩混合物,残留物溶于乙醇(50mL*34)中,过滤得到标题化合物(20.4g,50%)。
1H NMR(400MHz,CDCl3)ppmδ8.98(s,1H),8.14(s,1H),8.00-7.98(d,1H),7.79-7.77(d,1H).
e)7-溴-3-(2-羟乙基)-4H-吡啶并[1,2-a]嘧啶-4-酮
将2-溴乙醇(933mg,7.47mmol),7-溴-3-羟基-4H-吡啶并[1,2-a]嘧啶-4-酮(600mg,2.49mmol)和碳酸钾(1.03g,7.47mmol)溶于N,N-二甲基甲酰胺(10mL)中,氮气保护下110度搅拌反应1小时。LCMS显示反应完全。将反应液浓缩后得到粗品。粗品直接用于下一步。
f)N-(5-(3-(2-羟乙基)-4-氧代4H-吡啶并[1,2-a]嘧啶-7-基)-2-甲氧基吡啶-3-基)-2,4-二甲基噻唑-5-磺酰胺
将7-溴-3-(2-羟乙基)-4H-吡啶并[1,2-a]嘧啶-4-酮(704mg,2.49mmol)溶解在二氧六环(10mL)和水(2mL)中,加入N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)吡啶-3-基)-2,4-二甲基噻唑-5-磺酰胺(1.06g,2.49mmol),碳酸钾(687mg,4.97mmol)和1,1’-双(二苯基膦)二茂铁氯化钯(50mg)。反应液在100度下搅拌反应3小时。LCMS显示反应完全。将反应液过滤浓缩后得到粗品,粗品用制备高效液相色谱法纯化得到白色固体状标题产物(500mg,40%)。
1H NMR(400MHz,CDCl3)ppmδ9.09(s,1H),8.24(s,1H),8.18(d,1H),8.01(d,1H),7.80-7.67(m,1H),4.28-4.22(m,2H),4.01-3.92(m,5H),2.65(s,3H),2.56(s,3H).
g)2-((7-(5-(2,4-二甲基噻唑2,4-二甲基噻唑-5-磺酰胺基)-6-甲氧基吡啶-3-基)-4-氧代-4H-吡啶并[1,2-a]
嘧啶-3-基)氧基)乙基甲磺酸酯
将N-(5-(3-(2-羟基乙氧基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)-2,4-二甲基噻唑-5-磺酰胺(50.00mg,99.30umol)和三乙胺(20.10mg,198.60umol)溶解在二氯甲烷中,0度下加入甲烷磺酰氯(13.65mg,119.16umol)。0度下搅拌反应1小时。TLC显示反应完全,向反应液中加入二氯甲烷(10mL)和水(8mL)。有机相用饱和食盐水(10mL)洗,无水硫酸钠干燥,过滤,浓缩得到粗品。粗品用硅胶柱色谱法纯化得到淡黄色固体状标题化合物(55mg,95.2%)。
1H NMR(400MHz,CDCl3)ppm 9.08(d,J=1.10Hz,1H),8.54(d,J=2.43Hz,1H),8.21(s,1H),7.67-7.79(m,3H),4.58-4.66(m,2H),4.43-4.50(m,2H),4.01(s,3H),3.17(s,3H),2.74(s,3H),2.46(s,3H).
h)N-(5-(3-(2-(4,4-二氟-1-哌啶基)乙氧基)-4-氧代-吡啶并[1,2-a]嘧啶-7-基]-2-甲氧基吡啶-3-]-2,4-二甲基噻唑-5-磺酰胺
将2-((7-(5-(2,4-二甲基噻唑2,4-二甲基噻唑-5-磺酰胺基)-6-甲氧基吡啶-3-基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-3-基)氧基)乙基甲磺酸酯(50.00mg,85.96umol)和4,4-二氟哌啶(12.50mg,103.16umol)溶解在乙腈(2mL)中,加入二异丙基乙胺(22.22mg,171.93umol)。50度搅拌反应12小时。液相质谱显示反应完全。将反应液过滤浓缩后得到粗品。粗品用制备高效液相色谱法纯化得到淡黄色固体状标题产物(15.00mg,28.77%)。
1H NMR(400MHz,CD3OD)ppm 9.11(d,J=1.51Hz,1H),8.30(d,J=2.26Hz,1H),8.27(s,1H),8.01-8.11(m,2H),7.74(d,J=9.29Hz,1H),4.35(t,J=5.40Hz,2H),3.89(s,3H),2.94-2.97(m,2H),2.78(d,J=5.02Hz,4H),2.64(s,3H),2.49(s,3H),1.98-2.05(m,4H).
参照化合物1的制备方法还合成了以下5个化合物:
Figure PCTCN2015081518-appb-000035
流程2:
Figure PCTCN2015081518-appb-000036
反应条件:a)2-吗啡啉乙醇,二溴三苯基膦,二氯甲烷;b)7-溴-3-羟基-4H-吡啶并[1,2-a]嘧啶-4-酮,碳酸钾,N,N-二甲基甲酰胺;c)2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶)-3-胺,1,1’-双(二苯基膦)二茂铁氯化钯,碳酸钾,二氧六环,水,加热;d)R基磺酰氯,吡啶。
实施例7
2,4-二甲基-N-(2-甲氧基-5-(3-(2-吗啡啉乙氧基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-4-酮-7-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2015081518-appb-000037
a)4-(2-溴乙基)吗啡啉氢溴酸盐
在氮气保护下,0度下向溶有2-吗啡啉乙醇(4g,30.49mmol)的二氯甲烷(80mL)溶液中分批加入二溴三苯基膦(15.45g,36.59mmol)。混合液在15度下搅拌18小时。反应完全后,反应液过滤,滤饼用二氯甲烷洗涤后减压干燥得到近白色固体(5.1g,60.8%)。
1H NMR(400MHz,CDCl3)ppmδ4.06(d,J=12.2Hz,2H),3.89-3.75(m,4H),3.71-3.63(m,2H),3.56(d,J=12.5Hz,2H),3.28-3.18(m,2H)
b)7-溴-3-(2-吗啉乙氧基)-4H-吡啶并[1,2-a]嘧啶-4-酮
在氮气保护下,将7-溴-3-羟基-4H-吡啶并[1,2-a]嘧啶-4-酮(1g,4.15mmol),4-(2-溴乙基)吗啡啉氢溴酸盐(1.14g,4.15mmol)和碳酸钾(1.72g,12.45mmol)置于N,N-二甲基甲酰胺(80mL)中并在120度下搅拌2小时。反应完成后,反应液浓缩除去N,N-二甲基甲酰胺。浓缩液中加入二氯甲烷并过滤。将滤液浓缩后得到呈棕色的固体产品(1.3g,88.4%)。
1H NMR(400MHz CDCl3)ppmδ9.03(d,J=1.7Hz,1H),8.07(s,1H),7.51(dd,J=2.2,9.5Hz,1H),7.45-7.29(m,1H),4.24(t,J=5.7Hz,2H),3.75-3.56(m,4H),2.78(t,J=5.6Hz,2H),2.62-2.47(m,4H)
c)7-(5-氨基-6-甲氧基吡啶-3-基)-3-(2-吗啡啉乙氧基)-4H-吡啶并[1,2-a]嘧啶-4-酮
在氮气保护下,向溶有7-溴-3-(2-吗啉乙氧基)-4H-吡啶并[1,2-a]嘧啶-4-酮(100mg,0.28mmol),2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶)-3-胺(46mg,0.31mmol)和碳酸钾(117mg,0.85mmol)的二氧六环(5mL)混合液中加入1,1’-双(二苯基膦)二茂铁氯化钯(8mg,0.008mmol)和水(1mL)。此混合液在氮气保护下于90度下搅拌18小时。反应完成后,反应液用二氯甲烷萃取。有机相经无水硫酸钠干 燥后浓缩。所得粗产品经制备级薄层色谱法和制备级液相色谱法纯化得到近白色固体(23.82mg,22.06%)。
1H NMR(400MHz,CDCl3)ppmδ9.13(d,J=1.5Hz,1H),8.46(d,J=2.5Hz,1H),8.19(s,1H),7.86(dd,J=2.5,8.5Hz,1H),7.79(dd,J=2.0,9.0Hz,1H),7.72-7.64(m,1H),6.89(d,J=8.5Hz,1H),4.33(t,J=5.5Hz,2H),4.01(s,3H),3.82-3.66(m,4H),2.87(t,J=5.8Hz,2H),2.62(br.s.,4H)
d)2,4-二甲基-N-(2-甲氧基-5-(3-(2-吗啡啉乙氧基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-4-酮-7-基)吡啶-3-基)苯磺酰胺
向溶有7-(5-氨基-6-甲氧基吡啶-3-基)-3-(2-吗啡啉乙氧基)-4H-吡啶并[1,2-a]嘧啶-4-酮(100.00mg,251.62umol)的吡啶(3mL)溶液中滴加2-甲基-4-氟苯磺酰氯(61.8mg,301.94umol)。反应液在18度下搅拌18小时。反应结束后,吡啶减压蒸除。残余物溶于二氯甲烷并用水和饱和食盐水洗涤。有机相经无水硫酸钠干燥后浓缩得到粗产品。此粗产品经制备级液相色谱法纯化得到呈黄色的固体产品(23.16mg,16.11%)。
1H NMR(400MHz,CDCl3)ppmδ8.97(s,1H),8.16(s,1H),8.03(d,J=2.2Hz,1H),7.91(d,J=8.1Hz,1H),7.82(d,J=2.0Hz,1H),7.65(d,J=1.0Hz,2H),7.16(d,J=8.1Hz,1H),7.10(s,1H),4.31(t,J=5.6Hz,2H),3.99(s,3H),3.82-3.66(m,4H),2.86(t,J=5.6Hz,2H),2.64(s,3H),2.61(d,J=4.2Hz,4H),2.33(s,3H).
参照化合物7的制备方法还合成了以下13个化合物:
Figure PCTCN2015081518-appb-000038
Figure PCTCN2015081518-appb-000039
Figure PCTCN2015081518-appb-000040
流程3:
Figure PCTCN2015081518-appb-000041
反应条件:a)甲烷磺酰氯,三乙胺,二氯甲烷;b)碳酸钾,N,N-二甲基甲酰胺;c)N-(2-甲氧基-5-(4,4,5,5-t四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-3-基)-2,4-二甲基噻唑-5-磺酰胺,钯,碳酸钾,二氧六环,水,加热。
实施例21
N-(2-甲氧基-5-(4-氧代-3-(2-(2-氧代吡咯烷-1-基)乙氧基)-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)-2,4-二甲基噻唑-5-磺酰胺
Figure PCTCN2015081518-appb-000042
a)2-(2-氧代吡咯烷-1-基)乙基甲烷磺酸酯
在0度下,向溶有1-(2-羟基乙基)吡咯烷-2-酮(500.00mg,3.87mmol)和三乙胺(1.17g,11.61mmol)的二氯甲烷(5mL)溶液中加入甲烷磺酰氯(531.97mg,4.64mmol)。反应液在0度下搅拌1小时。反应完成后,反应液用水和盐水洗涤。有机相经无水硫酸钠干燥后浓缩得到黄色油状粗产品(470.00mg,58.60%)。
1H NMR(400MHz,CDCl3)δ4.35(t,J=5.1Hz,2H),3.62(t,J=5.1Hz,2H),3.51(t,J=7.1Hz,2H),3.03(s,3H),2.40(t,J=8.1Hz,2H),2.06(quin,J=7.6Hz,2H)
b)7-溴-3-(2-(2-氧代吡咯烷-1-基)乙氧基)-4H-吡啶并[1,2-a]嘧啶-4-酮
在氮气保护下,将加有7-溴-3-羟基-4H-吡啶并[1,2-a]嘧啶-4-酮(100.00mg,414.87umol),2-(2-氧代吡咯烷-1-基)乙基甲烷磺酸酯(257.94mg,1.24mmol)和碳酸钾(229.36mg,1.66mmol)的N,N-二甲基甲酰胺(10mL)混合液在120度下搅拌18小时。反应完成后,反应液浓缩。浓缩物经硅胶色谱柱纯化后得到黄色油状产品(210.00mg,79.05%,纯度:55%)。
1H NMR(400MHz,CDCl3)δ9.02(d,J=1.7Hz,1H),8.03(s,1H),7.51(dd,J=2.1,9.4Hz,1H),7.44-7.37(m,1H),4.23(t,J=5.1Hz,2H),3.67(s,2H),3.62(t,J=7.0Hz,2H),2.34(t,J=8.0Hz,2H),2.10-1.86(m,2H).
c)N-(2-甲氧基-5-(4-氧代-3-(2-(2-氧代吡咯烷-1-基)乙氧基)-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)-2,4-二甲基噻唑-5-磺酰胺
在氮气保护下,向加有7-溴-3-(2-(2-氧代吡咯烷-1-基)乙氧基)-4H-吡啶并[1,2-a]嘧啶-4-酮(210.00mg,327.96umol),N-(2-甲氧基-5-(4,4,5,5-t四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-3-基)-2,4-二甲基噻唑-5-磺酰胺(145.19mg,327.96umol)和碳酸钾(135.98mg,983.87umol)的二氧六环(5mL)混合液中加入1,1'-双(二苯基磷)二茂铁氯化钯(2.40mg,3.28umol)和水(1mL)。在氮气保护下,混合液在90度下搅拌18小时。反应完成后,反应液浓缩。浓缩残余物经制备级薄层色谱法纯化得到黄色固体状目标化合物(60.07mg,30.41%)。
1H NMR(400MHz,CDCl3)δ8.98(s,1H),8.20-8.06(m,3H),7.92(d,J=2.2Hz,1H),7.68(d,J=1.1Hz,2H),7.58(s,1H),7.28(d,J=2.4Hz,1H),7.20-7.09(m,1H),4.32(t,J=5.1Hz,2H),4.00(s,3H),3.84-3.65(m,4H),2.42(t,J=8.0Hz,2H),2.08(quin,J=7.6Hz,2H)
参照化合物21的制备方法还合成了以下15个化合物:
Figure PCTCN2015081518-appb-000043
Figure PCTCN2015081518-appb-000044
Figure PCTCN2015081518-appb-000045
流程4:
Figure PCTCN2015081518-appb-000046
反应条件:a)1,2-二溴乙烷,碳酸钾,DMF,加热;b)2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)吡啶-3-基)苯磺酰胺,1,1’-双(二苯基膦)二茂铁氯化钯,碳酸钾,二氧六环,水,加热;c)1H-吡唑,碳酸铯,乙腈,加热。
实施例37
2,4-二氟-N-(2-甲氧基-5-(4-氧代-3-(2-吡唑-1-乙氧基)吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2015081518-appb-000047
a)7-溴-3-(2-溴乙氧基)吡啶并[1,2-a]嘧啶-4-酮
将7-溴-3-羟基-吡啶并[1,2-a]嘧啶-4-酮(600.00mg,2.49mmol)和1,2-二溴乙烷(1.40g,7.47mmol)溶解在DMF(10mL)中,加入碳酸钾(1.03g,7.47mmol)。100度搅拌反应1.5小时。TLC显示反应完全,将反应液冷却至室温。用硅胶柱色谱法纯化得到棕色固体状标题化合物(550.00mg,63.5%)。
1H NMR(400MHz,CDCl3)ppm 9.10(s,1H),8.20(s,1H),7.61(dd,J=9.54,1.71Hz,1H),7.49(d,J=9.54Hz,1H),4.49(t,J=6.36Hz,2H),3.66(t,J=6.36Hz,2H).
b)N-(5-(3-(2-溴乙氧基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺
将7-溴-3-(2-溴乙氧基)吡啶并[1,2-a]嘧啶-4-酮(550.00mg,1.58mmol)溶解在二氧六环(15mL)和水(2mL)中,在氮气保护下加入2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)吡啶-3-基)苯磺酰胺(673.67mg,1.58mmol),碳酸钾(436.74mg,3.16mmol)和1,1’-双(二苯基磷)二茂铁氯化钯(117.20mg,158.00umol)。90度搅拌反应1.5小时。液相质谱显示反应完全。将反应液过滤浓缩后得到粗品。粗品用硅胶柱色谱法纯化得到淡黄色固体状标题产物(250.00mg,27.89%)。
1H NMR(400MHz,CDCl3)ppm 9.03(s,1H),8.24(s,1H),8.12(d,J=2.20Hz,1H),7.89-7.98(m,2H),7.68-7.76(m,2H),7.32(br.s.,1H),6.99-7.06(m,1H),6.90-6.98(m,1H),4.52(t,J=6.24Hz,2H),3.98(s,3H),3.69(t,J=6.36Hz,2H).
c)2,4-二氟-N-(2-甲氧基-5-(4-氧代-3-(2-吡唑-1-乙氧基)吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
将N-(5-(3-(2-溴乙氧基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺(50.00mg,88.13umol)和1H-吡唑(9.00mg,132.20umol)溶解在乙腈(0.5mL)中,加入碳酸铯(57.43mg,176.26umol)。70度搅拌反应2小时。液相质谱显示反应完全。将反应液过滤浓缩后得到粗品。粗品用制备高效液相色谱法纯化得到黄色固体状标题产物(15.00mg,30.69%)。
1H NMR(400MHz,CDCl3)ppm 9.00(d,J=0.98Hz,1H),8.11(d,J=2.20Hz,1H),7.87-7.99(m,3H),7.61-7.73(m,3H),7.49-7.57(m,1H),7.34(br.s.,1H),6.98-7.06(m,1H),6.90-6.98(m,1H),6.26(t,J=1.96Hz,1H),4.57(dd,J=10.88,4.28Hz,4H),3.97(s,3H).
参照化合物37的制备方法还合成了以下3个化合物:
Figure PCTCN2015081518-appb-000048
流程5:
Figure PCTCN2015081518-appb-000049
反应条件:a)甲烷磺酰氯,三乙胺,二氯甲烷,0度到室温;b)碳酸钾,DMF,加热;c)R硼脂(硼酸),1,1’-双(二苯基磷)二茂铁氯化钯,碳酸钾,二氧六环,水,加热;d)盐酸-乙酸乙酯,乙酸乙酯,室温。
实施例41
2,4-二氟-N-(2-甲氧基-5-(4-氧代-3-(哌啶-4-氧基)-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2015081518-appb-000050
a)叔丁基4-((甲磺酰)氧)哌啶-1-羧酸酯
将叔丁基4-羟基哌啶-1-羧酸酯(1g,4.97mmol)和三乙胺(1g,9.95mmol)溶于二氯甲烷(4mL)中,0度下滴加甲烷磺酰氯(1g,8.72mmol)。滴加完后将反应液升至室温下搅拌反应2小时。将反应液倒入冰水中淬灭,用二氯甲烷萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,过滤,将滤液浓缩后得到红色固体状标题化合物(1.6g,粗品)。
b)叔丁基4-((7-溴-4-氧代-4H-吡啶并[1,2-a]嘧啶-3-基)氧)哌啶-1-羧酸酯
将叔丁基4-((甲磺酰)氧)哌啶-1-羧酸酯(200mg,0.72mmol),7-溴-3-羟基-4H-吡啶并[1,2-a]嘧啶-4-酮(115mg,0.48mmol)和碳酸钾(198mg,1.43mmol)溶于N,N-二甲基甲酰胺(2mL)中,氮气保护下120度搅拌反应2小时。将水加入到反应液中,用乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,过滤,将滤液浓缩后得到粗品。粗品用硅胶柱色谱法纯化得到红色固体状标题化合物(170mg,84%)。
1H NMR(400MHz,CDCl3)ppm 9.14-9.10(m,1H),8.17(s,1H),7.65-7.59(m,1H),7.53-7.47(m,1H),4.90-4.88(m,1H),3.85(m,2H),3.71-3.70(m,2H),1.95(s,3H),1.47(s,9H).
c)叔丁基4-((7-(5-(2,4-二氟苯磺酰胺)-6-甲氧基吡啶-3-基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-3-基)氧)哌啶-1-羧酸酯
将叔丁基4-((7-溴-4-氧代-4H-吡啶并[1,2-a]嘧啶-3-基)氧)哌啶-1-羧酸酯(130mg,0.3mmol),2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)吡啶-3-基)苯磺酰胺(130mg,0.3mmol),碳酸钾(85mg,0.61umol)和1,1’-双(二苯基磷)二茂铁氯化钯(22mg,0.03mmol)溶解在二氧六环(2mL)和水(0.4mL)中。反应液在氮气保护微波条件下100度搅拌反应2小时。粗品用硅胶柱色谱法纯化得到红色油状标题化合物(80mg,30%)。
d)2,4-二氟-N-(2-甲氧基-5-(4-氧代-3-(哌啶-4-氧基)-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺盐酸盐
将叔丁基4-((7-(5-(2,4-二氟苯磺酰胺)-6-甲氧基吡啶-3-基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-3-基)氧)哌啶-1-羧酸酯(28mg,0.043mmol)溶解在乙酸乙酯(2mL)中,加入盐酸/乙酸乙酯(15mL)。反应液室温下度搅拌反应1小时。将反应液过滤,固体旋干后得到棕色固体状标题产物(7.4mg,29%)。
1H NMR(400MHz,CD3OD)ppm 9.24(s,1H),8.47-8.46(m,2H),8.37(s,1H),8.13(s,1H),7.97-7.86(m,2H),7.26-7.21(m,1H),7.12-7.08(m,1H),4.85-4.84(m,1H),3.86(s,1H),3.55-3.50(m,2H),3.31-3.25(m,2H),2.19(s,4H).
参照化合物41的制备方法还合成了以下3个化合物:
Figure PCTCN2015081518-appb-000051
Figure PCTCN2015081518-appb-000052
流程6:
Figure PCTCN2015081518-appb-000053
反应条件:a)5-溴-2-氯-3-硝基吡啶,R醇,氢氧化钾,碳酸钾,2-(2-甲氧基乙氧基)-N,N-二[2-(2-甲氧基乙氧基)乙基]乙胺,甲苯;b)4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1,3,2-二氧杂硼烷,1,1'-双(二苯基磷)二茂铁氯化钯,醋酸钾,二氧六环,加热;c)Pd/C,甲醇;d)7-溴-3-氯-吡啶并[1,2-a]嘧啶-4-酮,1,1'-双(二苯基磷)二茂铁氯化钯,碳酸钾,二氧六环,水,加热;e)2,4-二氟苯磺酰氯,吡啶;f)盐酸/二氧六环,二氧六环。
实施例45
N-[5-(3-氯-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)-2-(3-(甲基氨基)丙氧基)吡啶-3-基]-2,4-二氟-苯磺酰胺
Figure PCTCN2015081518-appb-000054
a)(3-((5-溴-3-硝基吡啶-2-基)氧)丙基)(甲基)氨基甲酸叔丁酯
向加有氢氧化钾(723mg,12.89mmol)和碳酸钾(1.78g,12.89mmol)的甲苯(30mL)混合液中加入5-溴-2-氯-3-硝基吡啶(1.8g,7.58mmol),(3-羟基丙基)(甲基)氨基甲酸叔丁酯(1.72g,9.1mmol)和2-(2-甲氧基乙氧基)-N,N-二[2-(2-甲氧基乙氧基)乙基]乙胺(245mg,0.758mmol)。混合液在氮气保护下于15度搅拌18小时。反应完后,反应液过滤,滤液浓缩后经硅胶色谱柱纯化(PE:EA=20:1-4:1)得到黄色油状目标化合物(1.5g,50%)。
1H NMR(400MHz,CDCl3)ppmδ8.40(d,J=2.0Hz,1H),8.36(d,J=2.2Hz,1H),4.47(t,J=6.1Hz,2H),3.40(t,J=6.8Hz,2H),2.87(s,3H),2.03(s,2H),1.41(s,9H)
b)甲基(3-((3-硝基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-2-基)氧)丙基)氨基甲酸叔丁酯
在氮气保护下,向加有(3-((5-溴-3-硝基吡啶-2-基)氧)丙基)(甲基)氨基甲酸叔丁酯(1.5g,3.84mmol),4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1,3,2-二氧杂硼烷(1.17g,4.61mmol)和醋酸钾(1.13g,11.53mmol)的二氧六环(30mL)混合液中加入1,1'-双(二苯基磷)二茂铁氯化钯(97mg,0.11mmol)。此混合液在氮气保护下于80度搅拌18小时。反应经检测完成后,反应液过滤,滤液浓缩后经硅胶色谱法纯化得到黄色油状粗产品(0.9g,53%)。
1H NMR(400MHz,CDCl3)ppm 8.65(d,J=1.5Hz,1H),8.55(d,J=1.5Hz,1H),4.52(t,J=5.7Hz,2H),3.41(t,J=6.8Hz,2H),2.87(s,3H),2.04(br.s.,2H),1.41(s,9H),1.33(s,12H).
c)(3-((3-氨基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-2-基)氧)丙基)(甲基)氨基甲酸叔丁酯
向溶有甲基(3-((3-硝基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-2-基)氧)丙基)氨基甲酸叔丁酯(900mg,2.06mmol)的甲醇(10mL)溶液中加入Pd/C(90.00mg)。混合液在氢气氛围下于15度搅拌4小时。反应经检测完成后,反应液过滤,滤液浓缩后得到黄色油状粗产品(870mg,95%)。
1H NMR(400MHz,CDCl3)ppmδ7.93(s,1H),7.21(s,1H),4.41(t,J=6.0Hz,2H),3.39(br.s.,2H),2.85(br.s.,3H),2.00(br.s.,2H),1.41(br.s.,9H),1.31(s,12H).
d)(3-((3-氨基-5-(3-氯-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-2-基)氧)丙基)(甲基)氨基甲酸叔丁酯
在氮气保护下,于室温向加有7-溴-3-氯-吡啶并[1,2-a]嘧啶-4-酮(503mg,1.94mmol),(3-((3-氨基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-2-基)氧)丙基)(甲基)氨基甲酸叔丁酯(790mg,1.94mmol)和碳酸钠(1M,4.85mL,4.85mmol)的二氧六环(10mL)混合液中加入1,1'-双(二苯基磷)二茂铁氯化钯(17mg,0.019mmol)。此混合液在氮气保护下于80度搅拌18小时。反应经检测完成后,反应液过滤,滤液经无水硫酸钠干燥后减压浓缩。残余物经硅胶色谱柱纯化后得到黄色固体状目标化合物(600mg,67%)。
1H NMR(400MHz,CDCl3)δ9.18(d,J=1.7Hz,1H),8.48(s,1H),7.97(dd,J=2.1,9.2Hz,1H),7.84-7.66 (m,2H),7.13(d,J=1.7Hz,1H),4.45(br.s.,2H),3.43(br.s.,2H),2.88(br.s.,3H),2.05(t,J=6.5Hz,2H),1.43(s,9H).
e)(3-((5-(3-氯-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)-3-(2,4-二氟苯磺酰胺)吡啶-2-基)氧)丙基)(甲基)氨基甲酸叔丁酯
向加有(3-((3-氨基-5-(3-氯-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-2-基)氧)丙基)(甲基)氨基甲酸叔丁酯(600mg,1.3mmol)的吡啶(5mL)混合液中加入2,4-二氟苯磺酰氯(333mg,1.57mmol)。混合液在15度下反应18小时。反应完成后,反应液浓缩。残余物溶于二氯甲烷并用水、盐水洗涤。有机相经无水硫酸钠干燥后浓缩。所得物经硅胶色谱法纯化得到黄色固体状目标化合物(404mg,48%)。
f)N-[5-(3-氯-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)-2-(3-(甲基氨基)丙氧基)吡啶-3-基]-2,4-二氟-苯磺酰胺
向(3-((5-(3-氯-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)-3-(2,4-二氟苯磺酰胺)吡啶-2-基)氧)丙基)(甲基)氨基甲酸叔丁酯(450mg,0.43mmol)的二氧六环(30mL)溶液中加入盐酸/二氧六环溶液(4mL).混合液在15度下搅拌3小时。反应完成后,反应液浓缩。向浓缩残余物中加入碳酸氢钠水溶液。沉淀物滤出抽干,并用二氯甲烷洗涤得到浅黄色固体状目标产品(175.56mg,75.9%)。
1H NMR(400MHz,DMSO-d6)δ8.81(d,J=1.5Hz,1H),8.56(s,1H),8.13(dd,J=2.0,9.3Hz,1H),8.02-7.89(m,1H),7.85-7.73(m,2H),7.47(d,J=2.2Hz,1H),7.33-7.21(m,1H),7.19-7.09(m,1H),4.29(t,J=5.4Hz,2H),3.20-3.08(m,2H),2.72(s,3H),2.08(m,2H).
参照化合物45的制备方法还合成了以下5个化合物:
Figure PCTCN2015081518-appb-000055
Figure PCTCN2015081518-appb-000056
流程7:
Figure PCTCN2015081518-appb-000057
反应条件:a)乙氧基甲叉丙二酸二乙酯,乙醇,加热;b)三溴氧磷,加热;c)DIBAL-H,四氢呋喃,-5-0度;d)二氧化锰,二氧六环,加热;e)吗啡啉,醋酸硼氢化钠,醋酸,甲醇,加热;f)N-[2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)吡啶-3-基]-2,4-二甲基-5-磺酰胺,1,1’-双(二苯基膦)二茂铁氯化钯,碳酸钾,二氧六环,水,加热。
实施例51
N-(2-甲氧基-5-(3-(吗啡啉甲基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)-2,4-二甲基噻唑-5-磺酰胺
Figure PCTCN2015081518-appb-000058
a)2-(((5-溴吡啶-2-基)氨基)亚甲基)丙二酸二乙酯
将2-胺基-5-溴吡啶(1.72g,9.94mmol)和乙氧基甲叉丙二酸二乙酯(4.51g,20.87mmol)置于圆底烧瓶中,130度搅拌反应2小时。TLC显示反应完全,将混合物冷却至25度,过滤,滤饼用石油醚(20mL*3)淋洗后得到白色固体状标题化合物(3.14g,92%)。
1H NMR(400MHz,CDCl3)ppm 11.10(d,J=12.47Hz,1H),9.06(d,J=12.72Hz,1H),8.38(d,J=2.20Hz,1H),7.74(dd,J=8.56,2.45Hz,1H),6.76(d,J=8.56Hz,1H),4.21-4.34(m,4H),1.35(dt,J=16.02,7.15Hz,6H).
b)7-溴-4-氧代-4H-吡啶并[1,2-a]嘧啶-3-羧酸乙酯
将2-(((5-溴吡啶-2-基)氨基)亚甲基)丙二酸二乙酯(21.76g,63.41mmol)和三溴氧磷(54.54g,190.23mmol)置于圆底烧瓶中,80度搅拌反应4小时。TLC显示反应完全,将混合物冷却至25度,缓慢加入到冰水中。向混合物中加入碳酸钠水溶液,调节pH至8左右。用二氯甲烷(300mL*3)萃取,有机相用饱和食盐水(200mL*2)洗,无水硫酸钠干燥,过滤,浓缩后得到白色固体状标题化合物(18.8g,99.8%)。
1H NMR(400MHz,CDCl3)ppm 9.36(d,J=1.98Hz,1H),9.03(s,1H),7.97(dd,J=9.26,1.98Hz,1H),7.67(d,J=9.26Hz,1H),4.42(q,J=7.06Hz,2H),1.41(t,J=7.06Hz,3H).
c)7-溴-3-(羟甲基)-4H-吡啶并[1,2-a]嘧啶-4-酮
将7-溴-4-氧代-4H-吡啶并[1,2-a]嘧啶-3-羧酸乙酯(5.00g,16.83mmol)溶解在四氢呋喃(150mL)置于三颈圆底烧瓶中,在-5度下向上述混合物中滴加DIBAL-H(50.49mmol)的甲苯(50mL)溶液。将反应液0度下搅拌2小时。TLC显示反应完全,向反应液中缓慢加入饱和氯化铵水溶液,用乙酸乙酯(200mL*3)萃取,用饱和食盐水(200mL*2)洗,无水硫酸钠干燥,过滤,浓缩得到粗品。粗品用硅胶柱色谱法纯化得到砖红色固体状标题化合物(1.1g,25.6%)。
1H NMR(400MHz,CDCl3)ppm 9.15(d,J=1.96Hz,1H),8.39(s,1H),7.98(dd,J=9.54,2.20Hz,1H),7.59(d,J=9.29Hz,1H),4.64(s,2H).
d)7-溴-4-氧代-4H-吡啶并[1,2-a]嘧啶-3-甲醛
将7-溴-3-(羟甲基)-4H-吡啶并[1,2-a]嘧啶-4-酮(0.7g,2.74mmol)溶解于二氧六环(15mL)置于50mL圆底烧瓶中,加入二氧化锰(2.39g,27.44mmol)。80度搅拌反应3小时。TLC显示反应完全,将反应液冷却至室温。反应液用二氯甲烷(50mL)稀释,过滤。将滤液浓缩得到黄色固体状标题化合物(0.6g,86.5%)。
1H NMR(400MHz,CDCl3)ppm 10.38(s,1H),9.39(d,J=2.21Hz,1H),8.90(s,1H),8.06(dd,J=9.26,2.21Hz,1H),7.73(d,J=9.26Hz,1H).
e)7-溴-3-(吗啡啉甲基)-4H-吡啶并[1,2-a]嘧啶-4-酮
将7-溴-4-氧代-4H-吡啶并[1,2-a]嘧啶-3-甲醛(88.00mg,347.75umol)溶于甲醇(4mL)置于10mL母指瓶中,加入吗啡啉(45.44mg,521.63umol)和AcOH(41.77mg,695.51umol)。50度搅拌2小时。向上述反应液中加入醋酸硼氢化钠(294.81mg,1.39mmol),在50度下继续搅拌12小时。TLC显示反应完全,将反应液冷却至室温。用硅胶柱色谱法纯化得到黄色固体状标题化合物(45mg,40%)。
1H NMR(400MHz,CDCl3)ppm 9.13(d,J=1.71Hz,1H),8.38(s,1H),7.70(dd,J=9.41,2.08Hz,1H),7.49(d,J=9.29Hz,1H),3.68-3.73(m,4H),3.62(s,2H),2.57(br.s.,4H).
f)N-(2-甲氧基-5-(3-(吗啡啉甲基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)-2,4-二甲基噻唑-5-磺酰胺
将7-溴-3-(吗啡啉甲基)-4H-吡啶并[1,2-a]嘧啶-4-酮(60.00mg,185.09umol)溶解在二氧六环(3mL)和水(0.5mL)中,在氮气保护下加入N-[2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)吡啶-3-基]-2,4-二甲基噻唑-5-磺酰胺(86.60mg,203.60umol),碳酸钾(51.16mg,370.18umol)和1,1’-双(二苯基磷)二茂铁氯化钯(13.54mg,18.51umol)。80度搅拌反应2小时。液相质谱显示反应完全。将反应液过滤浓缩后得到粗品。粗品用制备高效液相色谱法纯化得到黄色固体状标题产物(50.00mg,50%)。
1H NMR(400MHz,CDCl3)ppm 9.23(s,1H),8.42(s,1H),8.20(d,J=1.76Hz,1H),8.06(s,1H),7.90(dd,J=9.04,1.76Hz,1H),7.77(d,J=9.04Hz,1H),4.00(s,3H),3.76(t,J=4.41Hz,4H),3.65(s,2H),2.66(s,3H),2.59(s,7H).
参照化合物51的制备方法还合成了以下1个化合物:
Figure PCTCN2015081518-appb-000059
流程8:
Figure PCTCN2015081518-appb-000060
条件:a)丙二酰氯,二氯甲烷,室温;b)三氯氧磷,回流;c)N-(2-羟丙基)吗啡啉,钠氢,四氢呋喃,0 度到室温;d)R硼脂(硼酸),1,1’-双(二苯基膦)二茂铁氯化钯,碳酸钾,二氧六环,水,加热。
实施例53
2-氯-4-氟-N-(2-甲氧基-5-(2-(2-吗啡啉乙氧基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2015081518-appb-000061
a)7-溴-2-羟基-4H-吡啶并[1,2-a]嘧啶-4-酮
将2-氨基-5-溴吡啶(1.0g,5.7mmol)溶于二氯甲烷(10mL)置于50mL圆底烧瓶中,0度下滴加丙二酰氯(977mg,6.9mmol)。滴加完后将反应液升至15度,反应在15度搅拌反应48小时。LCMS显示反应完全。将反应液过滤,滤饼用二氯甲烷(20mL)淋洗后得到黄色固体状标题化合物(1.4g,100%)。
b)7-溴-2-氯-4H-吡啶并[1,2-a]嘧啶-4-酮
将7-溴-2-羟基-4H-吡啶并[1,2-a]嘧啶-4-酮(900mg,3.73mmol)溶于三氯氧磷(8mL)置于50mL圆底烧瓶中,110度搅拌反应18小时。LCMS显示反应完全。将反应液冷却至室温,缓慢倒入常温水(50mL)中淬灭,用乙酸乙酯(20mL*3)萃取,有机相用无水硫酸钠干燥,过滤,将滤液浓缩后得到粗品。粗品用硅胶柱色谱法纯化得到黄色固体状标题化合物(300mg,31%)。
1H NMR(400MHz,DMSO-d6)ppm 8.99(d,1H),8.21(dd,1H),7.65(d,1H),6.56(s,1H).
c)7-溴-2-(2-吗啡啉乙氧基)-4H-吡啶并[1,2-a]嘧啶-4-酮
将N-(2-羟丙基)吗啡啉(404mg,3.08mmol)溶于四氢呋喃(5mL)置于50mL圆底烧瓶中,0度下加入钠氢(308mg,7.71mmol,60%纯度),0度下搅拌反应30分钟,滴加7-溴-2-(2-吗啡啉乙氧基)-4H-吡啶并[1,2-a]嘧啶-4-酮(200mg,770umol)。将反应液升至15度,搅拌反应3小时。TLC显示反应完全。将反应液缓慢倒入冰水(50mL)中淬灭,用乙酸乙酯(20mL*3)萃取,有机相用无水硫酸钠干燥,过滤,将滤液浓缩后得到粗品。粗品用制备薄层层析法纯化得到标题化合物(40mg,14%)。
d)2-氯-4-氟-N-(2-甲氧基-5-(2-(2-吗啡啉乙氧基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
将7-溴-2-(2-吗啡啉乙氧基)-4H-吡啶并[1,2-a]嘧啶-4-酮(70mg,197umol)溶解在二氧六环(5mL)和水(1mL)中,加入2-氯-4-氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)吡啶-3-基苯磺酰胺(87mg,197umol),碳酸钾(54mg,395umol)和1,1’-双(二苯基膦)二茂铁氯化钯(7mg)。反应液在氮气保护下100度搅拌反应3小时。LCMS显示反应完全。将反应液浓缩后得到粗品。粗品用制备高效液相色谱法纯化得到白色固体状标题产物(50mg,42%)。
1H NMR(400MHz,CDCl3)ppm 9.08(d,1H),8.14(dd,1H),8.09(d,1H),7.90(d,1H),7.87(dd,1H),7.58(d,2H),7.28(d,1H),7.19-7.12(m,1H),5.86(s,1H),4.58-4.48(m,2H),3.99(s,3H),3.76(br.s.,4H),2.85(br.s.,2H),2.62(br.s.,3H).
流程9:
Figure PCTCN2015081518-appb-000062
反应条件:a)三光气,三乙胺,2,4-二甲基-5-胺基噻唑,0度;无水二氯甲烷,室温;b)1,1’-双(二苯基膦)二茂铁氯化钯,醋酸钾,双联频哪醇硼酸酯,无水二氧六环,加热;c)1-(2-甲氧基-5-溴吡啶-3-基)-3-(2,4-二甲基噻唑-5-基)脲,1,1'-双(二叔丁基膦)二茂铁二氯化钯,三水合磷酸钾,四氢呋喃,水,加热。
实施例54
1-(2,4-二甲基噻唑-5-基)-3-(2-甲氧基-5-(3-(2-吗啉代乙基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)脲
Figure PCTCN2015081518-appb-000063
a)1-(2-甲氧基-5-溴吡啶-3-基)-3-(2,4-二甲基噻唑-5-基)脲
将2-甲氧基-3-胺基-5溴吡啶(100.00mg,492.52umol)、三乙胺(498.38mg,4.93mmol)和无水二氯甲烷(5mL)置于10mL三颈圆底烧瓶中,在0度、氮气保护下缓慢滴加三光气(438.47mg,1.48mmol)二氯甲烷溶液(1mL),室温搅拌反应2小时。在0度、氮气保护下加入2,4-二甲基-5-氨基噻唑(162.20mg,985.04umol),室温搅拌反应过夜。液相质谱显示反应完全,向混合物中加入水(50mL),用二氯甲烷(50mL*3)萃取,合并有机相,用饱和食盐水(50mL*2)洗涤,无水硫酸钠干燥,过滤,浓缩,用硅胶色谱法得到标题化合物(85.00mg,48%)。
1H NMR(400MHz,CD3OD)ppmδ8.57(d,1H),7.82(d,1H),4.02(s,3H),2.56(s,3H),2.26(s,3H).
b)(3-(2-吗啉代乙基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)硼酸
将7-溴-3-(2-吗啉代乙基)-4H-吡啶并[1,2-a]嘧啶-4-酮(200.00mg,564.65umol)置于10mL长颈圆底烧瓶中,在室温下溶解于二氧六环(3mL)中,然后在氮气保护下加入双联频哪醇硼酸酯(430.16mg,1.69mmol),醋酸钾(221.57mg,2.26mmol),1,1'-双(二苯基膦基)二茂铁二氯化钯(41.32mg,56.47umol)。将混合物置于100度反应2小时。液相质谱显示反应完全。将反应液用乙酸乙酯(20mL)稀释,并用水(20mL*3)萃取,水相合并浓缩得标题化合物(120.00mg,粗品),粗品未经纯化直接用作下一步反应。
c)1-(2,4-二甲基噻唑-5-基)-3-(2-甲氧基-5-(3-(2-吗啉代乙基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)脲
向3-(2-吗啉代乙基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)硼酸(120.00mg,粗品)四氢呋喃(4mL)和水(1mL)的溶液中加入1-(2-甲氧基-5-溴吡啶-3-基)-3-(2,4-二甲基噻唑-5-基)脲(30.00mg,83.98umol),三水 合磷酸钾(38.68mg,167.96umol),1,1'-双(二叔丁基膦)二茂铁二氯化钯(5.47mg,8.40umol),混合物在80度反应5小时。液相质谱显示反应完全。将反应液过滤浓缩后得到粗品。粗品用制备高效液相色谱法纯化得到标题产物(24.00mg,52%)。
1H NMR(400MHz,DMSO-d6)ppmδ8.92(d,1H),8.73(d,1H),8.18(s,1H),8.13(d,1H),8.01–8.03(m,1H),7.66(d,1H),4.19–4.22(m,2H),4.01(s,3H),3.54–3.56(m,4H),2.67–2.70(m,2H),2.45–2.49(m,7H),2.23(s,3H).
参照化合物54的制备方法还合成了以下1个化合物:
Figure PCTCN2015081518-appb-000064
流程10:
Figure PCTCN2015081518-appb-000065
反应条件:a)氯化亚砜,二氯甲烷,室温;b)7-(5-氨基-6-甲氧基吡啶-3-基)-3-(2-吗啡啉乙氧基)-4H-吡啶并[1,2-a]嘧啶-4-酮,DMF,加热。
实施例56
氮-(2-甲氧基-5-(3-(2-吗啉代乙氧基)-4-氧代-4氢吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)-2,4-二甲基噻唑-5-甲酰胺
Figure PCTCN2015081518-appb-000066
a)2,4-二甲基噻唑-5-甲酰氯
将2,4-二甲基噻唑-5-羧酸(50.0mg,0.318mmol)和二氯甲烷(2mL)置于10mL圆底烧瓶中,在0度下加入二氯亚砜(378.43mg,3.18mmol)室温下搅拌反应1小时。TLC显示反应完全。将混合物浓缩后得到黑色固体状标题化合物,不经纯化,直接进行下一步反应。
b)氮-(2-甲氧基-5-(3-(2-吗啉代乙氧基)-4-氧代-4氢吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)-2,4-二甲基噻唑-5-甲酰胺
将2,4-二甲基噻唑-5-甲酰氯(50.0mg,0.284mmol),7-(5-氨基-6-甲氧基吡啶-3-基)-3-(2-吗啉代乙氧基)-4氢-吡啶并[1,2-a]嘧啶-4-酮(113.1mg,0.284mmol),DMF(0.5mL)置于10mL圆底烧瓶中,60度搅拌反应0.5小时。TLC显示反应完全,将反应液冷却至室温,用制备薄层层析板纯化得到标题化合物(10g,80%)。
1H NMR(400MHz,CD3OD)ppmδ9.19(s,1H),8.82(d,1H),8.35-8.37(m,1H),8.16-8.19(m,1H),7.81(d,1H),4.50-4.52(m,2H),4.13(s,3H),3.97(s,4H),3.59(s,1H),3.49(s,1H),2.73(d,1H).
参照化合物56的制备方法还合成了以下1个化合物:
Figure PCTCN2015081518-appb-000067
流程11:
Figure PCTCN2015081518-appb-000068
反应条件:a)三乙胺,叠氮磷酸二苯酯,叔丁醇,加热;b)盐酸-乙酸乙酯,室温;c)氯磺酸,加热;d)吡啶,2,4-二甲基-5-氨基噻唑,二氧六环,加热;e)亚硝酸钠,浓盐酸,冰浴;f)甲醇钠,甲醇,加热;g)双联嚬哪醇硼酸酯,1,1’-双(二苯基膦)二茂铁氯化钯,醋酸钾,二氧六环,加热;h)(3-(2-吗啡啉乙氧基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)硼酸,1,1’-双(二苯基膦)二茂铁氯化钯,碳酸钾,二氧六环,水,加热。
实施例58
N-(2,4-二甲基噻唑-5-基)-2-甲氧基-5-(3-(2-吗啡啉乙氧基)-4-氧代-4H-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-磺酰胺
Figure PCTCN2015081518-appb-000069
a)叔丁基(2,4-二甲基噻唑-5-基)氨基甲酸酯
将2,4-二甲基噻唑-5-羧酸(700.00mg,4.45mmol),叠氮磷酸二苯酯(1.65g,6.00mmol),三乙胺(1.13g,11.13mmol)和叔丁醇(35mL)置于100mL圆底单口烧瓶中,85度搅拌反应4小时.TLC显示反应完全,将反应液冷却至室温,向其中加入H2O(20mL),乙酸乙酯萃取三次,合并有机相,无水硫酸钠干燥,过滤,滤液旋干,得到的粗品用硅胶柱色谱法纯化得到标题化合物(900.00mg,88.54%)。
1H NMR(400MHz,DMSO-d6)δ9.46(br.s.,1H),2.46(s,3H),2.14(s,3H),1.43(s,9H).
b)2,4-二甲基-5-氨基噻唑盐酸盐
将叔丁基(2,4-二甲基噻唑-5-基)氨基甲酸酯溶解在盐酸-乙酸乙酯(10mL)中,室温搅拌1小时后旋干,得到的粗品用乙酸乙酯打浆得到标题化合物(700mg)。
1H NMR(400MHz,DMSO-d6)δ2.66(s,3H),2.19(s,3H).
c)2-氨基-5-溴-3-磺酰氯吡啶
将氯磺酸(136.18g,57.80mmol)置于250mL圆底三颈瓶中,冷至-15度,氮气保护下,向其中滴加2-氨基-5-溴吡啶(10.00g,57.80mmol)。滴加完毕后,将其油浴中逐渐升温至160度加热搅拌5小时。反应结束后,冷至室温,将其缓慢倒入冰中,待冰融化完,析出的固体经过滤,冰水洗涤得到标题化合物(10.00g,63.72%)
1H NMR(400MHz,DMSO-d6)δ8.27(d,J=2.3Hz,1H),8.08(d,J=2.0Hz,1H).
d)2-氨基-5-溴-N-(2,4-二甲基噻唑-5-基)吡啶-3-磺酰胺
将含有2-氨基-5-溴-3-磺酰氯吡啶(164.90mg,607.33mmol)的二氧六环(3mL)溶液置于50mL圆底三颈烧瓶中,冷至0度,向其中加入吡啶(196.00mg,2.48mmol)和2,4-二甲基-5-氨基噻唑盐酸盐(100.00mg,607.33mmol)。反应溶液逐渐升至室温搅拌2小时,然后加热到50度反应1小时。反应结束后,冷至室温将其溶解在二氯甲烷和甲醇的混合溶液中(二氯甲烷:甲醇=20:1),搅拌30分钟后过滤,得到的滤液旋干,得到的粗品用硅胶柱色谱法纯化得到标题化合物(60.00mg,27.20%)。
1H NMR(400MHz,CD3OD)δ8.27(d,J=2.5Hz,1H),7.81(d,J=2.5Hz,1H),2.56(s,3H),2.06(s,3H).
e)2-氯-5-溴-N-(2,4-二甲基噻唑-5-基)吡啶-3-磺酰胺
将2-氨基-5-溴-N-(2,4-二甲基噻唑-5-基)吡啶-3-磺酰胺(100.00mg,275.29umol)置于25mL的圆底烧瓶中,冷至0度,向其中加入浓盐酸(7mL)。然后在0度条件下向其中滴加亚硝酸钠的水溶液(855.00mg,12.39mmol,1.5mL)。滴加完毕后,将其升至室温搅拌1小时,过滤,滤液用饱和的碳酸氢钠溶液调pH值至8。所得溶液旋干后,溶于二氯甲烷和甲醇的混合溶液中(二氯甲烷:甲醇=10:1),搅拌30分钟后过滤,得到的滤液旋干,得到的粗品用薄层色谱法纯化得到标题化合物(30.00mg,28.48%)。
1H NMR(400MHz,CD3OD)δ8.76(d,J=2.3Hz,1H),8.40(d,J=2.5Hz,1H),2.55(s,3H),2.17(s,3H).
f)2-甲氧基-5-溴-N-(2,4-二甲基噻唑-5-基)吡啶-3-磺酰胺
将含有2-氯-5-溴-N-(2,4-二甲基噻唑-5-基)吡啶-3-磺酰胺(30.00mg,78.39umol)和甲醇钠(10.00mg,185.19umol)的甲醇溶液置于密闭的微波管中,加热至110度搅拌3小时。反应完毕后,将其冷至室温,向其中加入饱和碳酸氢钠(5mL),二氯甲烷萃取三次,合并有机相,无水硫酸钠干燥,过滤旋干得到标题化合物(20.00mg,67.45%)。
1H NMR(400MHz,CD3OD)δ8.24(d,J=2.5Hz,1H),8.10(d,J=2.5Hz,1H),3.97(s,3H),2.44(s,3H),2.06(s,3H).
g)(3-(2-吗啡啉乙氧基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)硼酸
将含有7-溴-3-(2-吗啡啉乙氧基)-4H-4-氧代吡啶并[1,2-a]嘧啶(80.00mg,225.86umol),双联嚬哪醇硼酸酯(172.06mg,677.58umol),1,1’-双(二苯基膦)二茂铁氯化钯(49.58mg,67.76umol)和醋酸钾(66.50mg,677.58umol)的二氧六环(3mL)溶液置于50mL的圆底单口烧瓶中,氮气保护下加热至80度搅拌1小时。反应结束后,向其中加入水(5mL),乙酸乙酯萃取三次,水相旋干,得到的粗品用二氯甲烷和甲醇的混合溶液打浆(二氯甲烷:甲醇=20:1),过滤得到标题化合物(60.00mg,83.24%)。
1H NMR(400MHz,CD3OD)δ9.00(br.s.,1H),8.23(s,1H),8.00(d,J=7.8Hz,1H),7.53(d,J=8.3Hz,1H),4.31(br.s.,2H),3.73(br.s.,4H),2.87(br.s.,2H),2.65(br.s.,4H),1.22(s,4H).
h)N-(2,4-二甲基噻唑-5-基)-2-甲氧基-5-(3-(2-吗啡啉乙氧基)-4-氧代-4H-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-磺酰胺
将2-甲氧基-5-溴-N-(2,4-二甲基噻唑-5-基)吡啶-3-磺酰胺(20.00mg,52.87umol),(3-(2-吗啡啉乙氧基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)硼酸(60.00mg,188.02umol),1,1’-双(二苯基膦)二茂铁氯化钯(3.87mg,5.29umol)和碳酸钾(21.92mg,158.61umol)溶于二氧六环(3mL)和水(0.3mL)中,氮气保护下,将反应液加热至80度搅拌1小时。反应结束后,将溶液旋干,得到的粗品制备高效液相色谱法纯化得到标题化合物(5.00mg,16.51%)。
1H NMR(400MHz,CD3OD)δ9.14(s,1H),8.64(s,1H),8.39(d,J=2.5Hz,1H),8.26(s,1H),8.03(d,J=11.3Hz,1H),7.74(d,J=9.3Hz,1H),4.35(t,J=5.4Hz,2H),4.10(s,3H),3.76-3.69(m,4H),2.88(t,J=5.5Hz,2H),2.66(br.s.,4H),2.44(s,3H),2.11(s,3H);MS(ESI)m/z:573(M+H+).
流程12:
Figure PCTCN2015081518-appb-000070
反应条件:a)羰基二咪唑,乙腈,加热;b)4-(2-氯乙基)吗啡啉,碳酸铯,二甲亚砜,加热;c)2,4-二氟 -N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧代硼-2-基)吡啶-3-基)苯磺酰胺,[1,1’-双(二苯基膦)二茂铁]氯化钯,碳酸钾,二氧六环,水,加热。
实施例59
2,4-二氟-N-(2-甲氧基-5-(2-(2-吗啡啉乙基)-3-氧代-2,3-二氢-[1,2,4]三氮唑[4,3-a]吡啶-6-基)嘧啶-3-基)苯磺酰胺
Figure PCTCN2015081518-appb-000071
a)6-溴-[1,2,4]三氮唑[4,3-a]吡啶-3(2H)-酮
将5-溴-2-亚联氨基-1,2-二氢吡啶(5.00g,26.59mmol)和乙腈(100mL)置于250mL的圆底单口烧瓶中,然后在氮气保护的条件下加入羰基二咪唑(4.75g,29.29mmol)。将反应溶液置于80度反应2小时。过滤析出固体,然后加入乙腈(20mL)打浆纯化,过滤得到标题化合物(3.90g,68.53%)。
1H NMR(400MHz,DMSO-d6)δ12.63(br.s.,1H),8.07(s,1H),7.28-7.19(m,2H)
b)6-溴-2-(2-吗啡啉乙基)-[1,2,4]三氮唑[4,3-a]吡啶-3(2H)-酮
将6-溴-[1,2,4]三氮唑[4,3-a]吡啶-3(2H)-酮(1.00g,4.67mmol)溶解在二甲亚砜(10mL)中,加入碳酸铯(3.80g,11.68mmol)和4-(2-氯乙基)吗啡(1.40g,9.34mmol,),得到溶液室温搅拌16小时。反应结束后过滤,滤液中加入水(10mL)然后用乙酸乙酯萃取三次,合并有机相,无水硫酸钠干燥,过滤,旋干,粗品用柱色谱分离纯化得到标题化合物(500.00mg,32.72%)
1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),7.38-7.19(m,2H),4.02(t,J=6.5Hz,2H),3.53-3.49(m,4H),2.68(t,J=6.3Hz,2H),2.41(br.s.,4H).
c)2,4-二氟-N-(2-甲氧基-5-(2-(2-吗啡啉乙基)-3-氧代-2,3-二氢-[1,2,4]三氮唑[4,3-a]吡啶-6-基)嘧啶-3-基)苯磺酰胺
将6-溴-2-(2-吗啡啉乙基)-[1,2,4]三氮唑[4,3-a]吡啶-3(2H)-酮(100.00mg,305.64umol),2,4-二氟-N-[2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼烷基-2-基)-3-吡啶基]苯磺酰胺(130.28mg,305.64umol),碳酸钾(42.24mg,305.64umol)和1,1’-双(二苯基膦)二茂铁氯化钯(223.64mg,305.64umol)溶解在二氧六环(1.5mL)和水(0.3mL)中。在氮气保护的条件下,将上述反应液置于80度反应2小时。反应结束后,旋干,得到粗品用制备高效液相色谱法纯化得到标题化合物(50.00mg,29.93%)。
1H NMR(400MHz,CD3OD)δ7.99-7.92(m,1H),7.84(s,1H),7.75(d,J=2.0Hz,1H),7.60(d,J=2.0Hz,1H),7.50-7.43(m,1H),7.27(d,J=9.5Hz,1H),7.08-6.95(m,2H),4.18(t,J=6.3Hz,2H),3.88(s,3H),3.71-3.64(m,4H),2.88-2.83(m,2H),2.58(br.s.,4H).
流程13:
Figure PCTCN2015081518-appb-000072
反应条件:a)甲酸乙酯,钠氢,乙二醇二甲醚,加热;b)5-溴吡啶-2-胺,醋酸铵,加热;c)三溴氧磷,加热;d)碳酸铯,乙腈,加热;e)R硼酸(硼酸酯),1,1’-双(二苯基膦)二茂铁氯化钯,碳酸钾,二氧六环,水,加热。
实施例60
2-氯-4-氟-N-(2-甲氧基-5-(3-(2-乙基吗啡啉)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2015081518-appb-000073
a)(E)-(2-氧代二氢呋喃-3(2H)-亚烯基)甲醇钠
将钠氢(0.93g,23.23mmol)缓慢分批加入装有乙二醇二甲醚(96mL)的500mL圆底烧瓶中。搅拌状态下向上述混合物中滴加二氢呋喃-2(3H)-酮(2g,23.23mmol)和甲酸乙酯(1.72g,23.23mmol)的乙二醇二甲醚(12mL)溶液,然后再加入乙醇(0.15mL)。反应液在60度搅拌反应16小时。将混合物冷却至25度,过滤,滤饼用乙酸乙酯(20mL*3)淋洗后得到黄绿色固体状标题化合物(2.1g,66%)。
1H NMR(400MHz,D2O)ppmδ8.45-8.31(m,1H),4.27(t,2H),2.71(t,2H).
b)(E)-3-(((5-溴吡啶-2-基)氨基)亚甲烯基)二氢呋喃-2(3H)-酮
将(E)-(2-氧代二氢呋喃-3(2H)-亚烯基)甲醇钠(1.42g,10.4mmol),5-溴吡啶-2-胺(1.2g,6.94mmol)和醋酸铵(2.67g,34.68mmol)置于50mL圆底烧瓶中,120度搅拌反应1小时。液相质谱显示反应完全,将反应液冷却至室温,缓慢倒入冰水中,有固体析出,过滤,滤饼用水(20mL*3)淋洗后得到粗品固体标题化合物,然后再用石油醚(30mL)打浆得到灰色标题化合物(1.4g,75%)。
1H NMR(400MHz,CDCl3)ppmδ8.29(d,1H),8.02(d,1H),7.74(dd,1H),6.79(d,1H),4.44(t,2H),2.90(dt,2H).
c)7-溴-3-(2-溴乙基)-4H-吡啶并[1,2-a]嘧啶-4-酮
将(E)-3-(((5-溴吡啶-2-基)氨基)亚甲烯基)二氢呋喃-2(3H)-酮(1.4g,5.2mmol)和三溴氧磷(6.98g,24.35mmol)置于50mL圆底烧瓶中,80度搅拌反应1.5小时。液相质谱显示反应完全,将反应液冷却至室温,缓慢倒入冰水中,调节pH值到8,用二氯甲烷(20mL*3)萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,浓缩得到黄色固体状标题化合物(1.2g,69%)。
1H NMR(400MHz,CDCl3)ppmδ9.17(d,1H),8.27(s,1H),7.74(dd,1H),7.54(d,1H),3.73(t,2H),3.21(t,2H).
d)7-溴-3-(2-乙基吗啡啉)-4H-吡啶并[1,2-a]嘧啶-4-酮
将7-溴-3-(2-溴乙基)-4H-吡啶并[1,2-a]嘧啶-4-酮(0.2g,0.6mmol),吗啡啉(78.73mg,0.9mmol)和碳酸铯(0.59g,1.81mmol)置于50mL圆底烧瓶中,70度搅拌反应12小时。液相质谱显示反应完全,将反应液冷却至室温,加水,用二氯甲烷(20mL*3)萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,浓缩得到油状粗品标题化合物,直接用于下一步反应。
e)2-氯-4-氟-N-(2-甲氧基-5-(3-(2-乙基吗啡啉)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
将7-溴-3-(2-乙基吗啡啉)-4H-吡啶并[1,2-a]嘧啶-4-酮(0.59mmol)溶解在二氧六环(2mL)和水(0.4mL)中,在氮气保护下加入2-氯-4-氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)吡啶-3-基)苯磺酰胺(0.59mmol),碳酸钾(1.18mmol)和1,1’-双(二苯基磷)二茂铁氯化钯(22mg)。将混合物置于微波反应条件下100度反应1小时。液相质谱显示反应完全。将反应液过滤浓缩后得到粗品。粗品用硅胶柱色谱和制备高效液相色谱法纯化得到标题产物。
1H NMR(400MHz,CDCl3)ppmδ9.08(s,1H),8.29(s,1H),8.17-8.09(m,2H),7.94(d,1H),7.85-7.77(m,1H),7.75-7.68(m,1H),7.28(d,1H),7.18-7.12(m,1H),4.00(s,3H),3.79(br.s.,3H),2.93(br.s.,1H).
参照化合物1的制备方法还合成了以下1个化合物
Figure PCTCN2015081518-appb-000074
参照化合物7的制备方法还合成了以下3个化合物
Figure PCTCN2015081518-appb-000075
Figure PCTCN2015081518-appb-000076
参照化合物21的制备方法还合成了以下31个化合物
Figure PCTCN2015081518-appb-000077
Figure PCTCN2015081518-appb-000078
Figure PCTCN2015081518-appb-000079
Figure PCTCN2015081518-appb-000080
Figure PCTCN2015081518-appb-000081
参照化合物45的制备方法还合成了以下2个化合物
Figure PCTCN2015081518-appb-000082
Figure PCTCN2015081518-appb-000083
流程14:
Figure PCTCN2015081518-appb-000084
反应条件:a)2-溴-1,1-二乙氧基-乙烷,碳酸钾,加热;b)浓盐酸,加热;c)原甲酸三乙酯,2,2-二甲基-1,3-二氧杂环己烷-4,6-二酮,加热;EtOH,加热;d)二苯醚,回流;e)浓硫酸,硝酸;f)Fe粉,氯化铵,乙醇,水,加热;g)3-氨基-7-溴-4H-吡啶并[1,2-a]嘧啶-4-酮,二氯甲烷,4A粉末状分子筛,乙酸,乙酸硼氢化钠;h)2-氯-4-氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-3-基)苯磺酰胺,二氧六环,[1,1’-双(二苯基膦)二茂铁]氯化钯,碳酸钾,水,加热;。
实施例98
2-氯-4-氟-N-(2-甲氧基-5-(3-((2-吗啡啉乙基)氨基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2015081518-appb-000085
a)4-(2,2-二乙氧基乙基)吗啡啉
将吗啡啉(2.21g,25.37mmol,1.00Eq)和2-溴-1,1-二乙氧基-乙烷(5.00g,25.37mmol,1.00Eq)置于三口圆底烧瓶中,加入碳酸钾(7.01g,50.73mmol,2.00Eq),混合物在80℃下搅拌2小时。将反应混合物冷却至室温,加入20mL水,用二氯甲烷(20mL x 2)萃取,无水硫酸钠干燥浓缩的到黄色油状标题化合物(3.50g,67.87%)。粗品直接用于下一步反应。
1H NMR(400MHz,CDCl3)δ4.62-4.65(m,1H),4.61(s,1H),3.66(t,J=4.6Hz,4H),3.45-3.59(m,3H),3.33(d,J=5.6Hz,2H),2.49(d,J=5.1Hz,4H),1.19-1.22(m,5H),1.18(s,2H)
b)2-吗啡啉乙醛
将4-(2,2-二乙氧基乙基)吗啡啉(800.00mg,3.94mmol,1.00Eq)溶于浓盐酸(4mL)置于三口圆底烧瓶中。混合物在80℃下搅拌3小时。冷却至室温,用饱和碳酸氢钠水溶液调pH至10后,用二氯甲烷萃取DCM(50mL x 3),无水硫酸钠干燥浓缩的到无色油状标题化合物(350.00mg,67.87%)。粗品直接用于下一步反应。
1H NMR(400MHz,CDCl3)δ9.69(s,1H),3.62-3.67(m,4H),3.18(s,2H),2.54-2.60(m,4H)
c)(E)-5-(((5-溴吡啶-2-基)亚胺基)甲基)-2,2-二甲基-1,3-二氧杂环乙烷-4,6-二酮
将原甲酸三乙酯(25.8g,0.174mol)和2,2-二甲基-1,3-二氧杂环乙烷-4,6-二酮(25.1g,0.174mol)置于三颈圆底烧瓶中,60度搅拌反应2小时。向上述混合物中滴加2-胺基-5-溴吡啶(30g,0.174mol)的乙醇(150mL)溶液。反应液60度搅拌反应2小时。将混合物冷却至25度,过滤,滤饼用乙醇(200mL*3)淋洗后得到白色固体状标题化合物(40g,70%)。
1H NMR(400MHz,CDCl3)δ1.77(s,6H),6.93-7.04(m,1H),8.44-8.53(m,1H),7.85-7.91(m,1H),9.31-9.42(m,1H),11.28-11.40(m,1H).
d)7-溴-4H-吡啶并[1,2-a]嘧啶-4-酮
将(E)-5-(((5-溴吡啶-2-基)亚胺基)甲基)-2,2-二甲基-1,3-二氧杂环乙烷-4,6-二酮(18g,0.056mmol),二苯醚(180mL)置于250mL圆底烧瓶中,220度搅拌反应1小时。TLC显示反应完全,将反应液冷却至室温,用硅胶柱色谱法纯化得到标题化合物(10g,80%)。
1H NMR(400MHz,CDCl3)δ6.46(d,1H),7.53(d,1H),7.75(dd,1H),8.27(d,1H),9.19(d,1H).
e)7-溴-3-硝基-4H-吡啶并[1,2-a]嘧啶-4-酮
将7-溴-4H-吡啶并[1,2-a]嘧啶-4-酮(5g,22.2mmol)置于100mL三颈圆底烧瓶中,加入浓硫酸(11.2mL),5~10度下滴加硝酸(5.2mL)。混合物在20度反应3小时。将反应液慢慢倒入冰水中,用1N氢氧 化钠调节pH=8,过滤,收集滤饼,减压旋干得到黄色标题产物(4.0g,66.7%)。
1H NMR(400MHz,CDCl3)δ9.47(d,1H),9.35(s,1H),8.14(dd,1H),7.81(d,1H).
f)3-氨基-7-溴-4H-吡啶并[1,2-a]嘧啶-4-酮
将7-溴-3-硝基-4H-吡啶并[1,2-a]嘧啶-4-酮(4.0g,14.7mmol,1.0eq),氯化铵(11.8g,220.54mmol,15.0eq)置于250mL圆底烧瓶,加入乙醇(50mL)和水(10mL)。室温条件下分批加入铁粉(1.32g,220.54mmol,15.0eq)。混合物置于70℃油浴,搅拌反应12小时。反应液冷却至室温,过滤。滤饼用二氯甲烷(50mL)淋洗。合并有机相,有机相用水(30mL*2),饱和食盐水(30mL*2)洗。有机相用无水硫酸钠干燥。过滤,滤液减压浓缩得黄色固体粗产品(3.29g,93%)。
1H NMR(400MHz,CDCl3)δ4.13(br.s,2H)7.39(d,J=0.98Hz,2H)7.96(s,1H)9.00(s,1H)
g)7-溴-3-((2-吗啡啉乙基)氨基)-4H-吡啶并[1,2-a]嘧啶-4-酮
将2-吗啡啉乙醛(80.70mg,624.84umol,3.00Eq)和3-氨基-7-溴-4H-吡啶并[1,2-a]嘧啶-4-酮(50.00mg,208.28umol,1.00Eq)溶于二氯甲烷(5mL)置于三口圆底烧瓶中,加入4A粉末状分子筛,反应混合物在25度下搅拌1小时。加入乙酸(15.01mg,249.94umol,1.20Eq)和乙酸硼氢化钠(52.97mg,249.94umol,1.20Eq),25度下搅拌1小时。反应液由黄色变成红色。用0.5mL甲醇淬灭反应,过滤,滤饼用10mL二氯甲烷洗涤,滤液浓缩,通过制备级硅胶色谱层析板纯化得到棕色固体标题化合物。(32.00mg,43.50%)。
h)2-氯-4-氟-N-(2-甲氧基-5-(3-((2-吗啡啉乙基)氨基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
将7-溴-3-((2-吗啡啉乙基)氨基)-4H-吡啶并[1,2-a]嘧啶-4-酮(40.00mg,90.60umol,1.00Eq)和2-氯-4-氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-3-基)苯磺酰胺(48.13mg,108.72umol,1.20Eq)溶于二氧六环(3mL)置于三口圆底烧瓶中,加入[1,1’-双(二苯基膦)二茂铁]氯化钯(3.31mg,4.53umol,0.05Eq),碳酸钾(37.56mg,271.79umol,3.00Eq)和水(1mL)。氮气保护下80度搅拌2小时。液相质谱检测反应已完毕。将反应液过滤且浓缩得到粗品产物。该粗品经制备级液相色谱分离得到白色固体标题化合物(5.70mg,10.25%)。
1H NMR(400MHz,CDCl3)δ8.83(s,1H),8.06-8.15(m,2H),7.90(d,J=2.2Hz,1H),7.71(s,1H),7.54(d,J=9.3Hz,1H),7.38(dd,J=9.4,1.8Hz,1H),7.26(d,J=2.4Hz,1H),7.09-7.17(m,1H),5.17(br.s.,1H),3.97(s,3H),3.74(t,J=4.4Hz,4H),3.29(d,J=5.4Hz,2H),2.72(t,J=5.9Hz,2H),2.51(br.s.,4H)
流程15:
Figure PCTCN2015081518-appb-000086
反应条件:a)雷尼镍,四氢呋喃,叔丁氧基甲酸酐,氢气,加热;b)7-溴-3-(2-吗啡啉乙氧基)吡啶并[1,2-a] 嘧啶-4-酮,二氧六环,碳酸钾,水,[1,1’-双(二苯基膦)二茂铁]氯化钯,加热;c)二氯甲烷,氯化氢的二氧六环溶液;d)2-氯-4-氟-苯磺酰氯,吡啶。
实施例99
2-氯-4-氟-N-((2-甲氧基-5-(3-(2-吗啡啉乙氧基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)甲基)苯磺酰胺
Figure PCTCN2015081518-appb-000087
a)叔丁基((2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-3-基)甲基)甲酰胺
将雷尼镍(9.88mg,115.34umol)加入到充满氮气的单口圆底烧瓶中,加入四氢呋喃(10.00mL),加入2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-3-氰基(150.00mg,576.70umol)和叔丁氧基甲酸酐(151.04mg,692.04umol)。40psi氢气中80度下搅拌2小时。LCMS显示反应完全。反应液通过硅藻土过滤,滤液旋干后得到黄色标题化合物(200.00mg,69.50%),直接用于下一步反应。
b)叔丁基((2-甲氧基-5-(3-(2-吗啡啉乙氧基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)甲基)甲酰胺
将叔丁基((2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-3-基)甲基)甲酰胺(200.00mg,400.83umol),7-溴-3-(2-吗啡啉乙氧基)吡啶并[1,2-a]嘧啶-4-酮(141.98mg,400.83umol)溶于二氧六环(10.00mL),加入碳酸钾(110.80mg,801.67umol)的水(3.00mL)溶液。加入[1,1’-双(二苯基膦)二茂铁]氯化钯(14.66mg,20.04umol)。氮气保护下80度搅拌2小时。LCMS显示反应完全。反应液浓缩,用5mL水洗涤,通过p-TLC(二氯甲烷:甲醇=20:1)纯化得到黄色标题化合物(100.00mg,46.33%)。
1H NMR(400MHz,CDCl3)δ9.11(s,1H),8.35(d,J=2.0Hz,1H),8.17(s,1H),7.74-7.83(m,2H),7.64-7.71(m,1H),4.32(t,J=5.5Hz,4H),4.04(s,3H),3.73-3.76(m,4H),2.85-2.89(m,2H),2.62(br.s.,4H),1.45(s,9H)
c)7-(5-(胺甲基)-6-甲氧基吡啶-3-基)-3-(2-吗啡啉乙氧基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-4-酮
将叔丁基((2-甲氧基-5-(3-(2-吗啡啉乙氧基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)甲基)甲酰胺(80.00mg,148.56umol)溶于二氯甲烷(10.00mL),0度滴加氯化氢的二氧六环溶液(4M,2.00mL)。升至室温(25度)搅拌1小时。LCMS显示反应完全。加入碳酸钾(1.12g),搅拌30分钟,过滤,滤饼用二氯甲烷(10mL)洗涤,滤液旋干得到黄色粗品标题化合物(70.00mg)。直接用于下一步反应。
d)2-氯-4-氟-N-((2-甲氧基-5-(3-(2-吗啡啉乙氧基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)甲基)苯磺酰胺
将7-(5-(胺甲基)-6-甲氧基吡啶-3-基)-3-(2-吗啡啉乙氧基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-4-酮(70.00mg,119.09umol)溶于吡啶(3.00mL),滴加2-氯-4-氟-苯磺酰氯(30.01mg,131.00umol)。25度下搅拌1小时。LCMS显示反应完全。反应液浓缩,经过p-TLC(二氯甲烷:甲醇=10:1)纯化,甲醇重结晶(3mL),得到白色固体标题化合物(26.00mg,36.14%)。
1H NMR(400MHz,CDCl3)δ8.95(s,1H),8.26(d,J=2.5Hz,1H),8.19(s,1H),8.02(dd,J=8.3,5.8Hz,1H),7.62-7.72(m,2H),7.46(d,J=2.0Hz,1H),7.01-7.11(m,2H),5.87(t,J=6.5Hz,1H),4.34(t,J=5.5 Hz,2H),4.25(d,J=6.5Hz,2H),4.02(s,3H),3.75(t,J=4.5Hz,4H),2.89(t,J=5.5Hz,2H),2.63(br.s.,4H)。
实验例1体外酶活性测试
本发明所有实施例中对PI3K(p110α)激酶活性分别通过以下两种测试方法进行测试。
方法一:
反应缓冲液:HEPES 50mM(pH7.0),NaN30.02%,BSA 0.01%,Orthovanadate 0.1mM,1%DMSO Detection buffer:HEPES 10mM(pH7.0),BSA 0.02%,KF 0.16M,EDTA 4mM
反应用酶:在昆虫细胞中表达的N-末端带His标记的人源重组全长PI3K p110α亚基(分子量=128.4kDa)和不带标记的p85α亚基(分子量=83.6kDa)
反应用底物:10μM PIP2底物(PI(4,5)P2)
反应条件:10μM PI(4,5)P2和10μM ATP
反应步骤:
1.在新鲜配置的反应液里准备好底物。
2.将激酶加入底物反应液中,轻柔地混合。
3.利用Acoustic技术(Echo550;nanoliter rang)将溶解在100%DMSO的化合物转移入激酶反应液中,在室温下孵育10分钟
4.在反应体系中加入合适浓度的ATP。
5.30℃孵育半个小时
6.加入终止液终止反应。
7.加入检测混合物并孵育过夜。
8.利用均相时间分辨荧光(HTRF)方法进行检测。(激发波长320nm,测量在615nm和665nm发射波长读数的比例)。
方法二:
ADP-Glo实验方法
化合物稀释:
3倍梯度稀释待测化合物,共10个浓度点(10000nM到0.5nM)。
实验方法:
转移50nL化合物至反应板(PerkinElmer#6007299)中,加入3uL酶/底物混合物(0.33nM PI3Kalpha,Millipore#14-602-K/166.5uM PIP2),孵育20min后加入2uL ATP溶液(100uM)起始反应,室温反应2小时后,加入5uL ADP-Glo试剂终止激酶反应,室温孵育60分钟完全消化剩余未反应ATP,加入10uL激酶检测试剂,室温孵育40分钟后,在Envision上读取荧光。PIP2,ATP,ADP-Glo试剂及激酶检测试剂均来自ADP-Glo激酶检测试剂盒(Promega#V1792)。
数据分析:
采用标准4参数拟合法计算IC50(Model205,XL-fit,iDBS)。
本发明所有实施例中对mTOR激酶活性分别通过以下测试方法进行测试。
反应缓冲液:20mM Hepes(pH 7.5),10mM MgCl2,2mM MnCl2,1mM EGTA,0.02%Brij35,0.02mg/ml BSA,0.1mM Na3VO4,2mM DTT,2%DMSO.
反应用酶:在昆虫细胞中表达的N-末端带GST标记的人源重组mTOR片段(氨基酸1360-2549,分子量=163.9kDa)
反应用底物:在细菌中表达的N-末端带His标记的人源重组全长4EBP1(分子量=13.6kDa)
反应条件:3μM 4EBP1和10μM ATP
反应步骤:
1.在新鲜制备的反应缓冲液中加入反应底物和其它反应因子。
2.将激酶加入底物反应液中,轻柔地混合。
3.利用Acoustic技术(Echo550;nanoliter rang)将溶解在100%DMSO的化合物转移入激酶反应液中,在室温下孵育20分钟。
4.在反应体系中加入合适浓度的32P-ATP。
5.室温中孵育两个小时。
6.利用P81filter-binding方法检测激酶活性。
实验结果见表3:
表3体外酶活性测试结果
化合物 PI3K(p110α)酶活性_IC50 mTOR酶活性_IC50 PI3K测试方法
1 A C 方法一
2 A C 方法一
3 A D 方法一
4 A NT 方法二
5 A NT 方法二
6 A D 方法一
7 A D 方法一
8 A D 方法一
9 A D 方法一
10 A D 方法一
11 A D 方法一
12 A C 方法一
13 A D 方法一
14 A D 方法一
15 A C 方法一
16 A C 方法一
20 A C 方法一
21 A NT 方法二
22 A NT 方法二
23 A NT 方法二
25 A D 方法二
27 A C 方法二
32 A C 方法二
33 A NT 方法二
34 A NT 方法二
35 A C 方法一
36 A D 方法一
37 A C 方法一
38 B NT 方法二
39 B NT 方法二
40 B NT 方法二
41 B D 方法一
42 A D 方法一
43 A D 方法一
44 A D 方法一
51 B NT 方法二
52 B NT 方法二
54 D NT 方法二
56 D NT 方法二
58 D NT 方法二
61 A NT 方法二
62 A NT 方法二
63 A NT 方法二
64 A NT 方法二
65 A NT 方法二
66 B NT 方法二
67 B NT 方法二
68 A NT 方法二
70 B NT 方法二
71 B NT 方法二
73 B NT 方法二
74 B NT 方法二
75 A NT 方法二
77 B NT 方法二
78 B NT 方法二
79 A NT 方法二
80 A NT 方法二
81 A NT 方法二
82 A NT 方法二
83 B NT 方法二
84 B NT 方法二
85 B NT 方法二
86 A NT 方法二
87 A NT 方法二
88 A NT 方法二
89 A NT 方法二
90 A NT 方法二
92 A NT 方法二
93 A NT 方法二
95 B NT 方法二
注:A≤1nM;1nM<B≤50nM;50nM<C≤200nM;200nM<D;NT表示未测。
实验例2体外细胞活性测试
实验步骤和方法:
1.将MCF-7细胞以每孔2.5×104个的密度种进96孔板中(使用的培养液需为含10%FBS的完整培养液)。
2.第二天将孔中的培养液抽走,将某一个浓度(初步筛选)或一系列浓度(IC50测试)的化合物溶解在不含血清的培养液中,加入96孔板培养细胞2小时。
3.把胰岛素溶解在不含血清的培养液中,加入细胞培养30分钟,胰岛素终浓度为10微克/毫升。
4.等待反应时,按如下方法准备裂解液:
a)增强液(Enhancer Solution)需要提前从冰箱里取出融化。
b)将增强液(Enhancer Solution)用5X的裂解缓冲液(Lysis Buffer)稀释10倍,制备成浓缩裂解液。
c)将浓缩裂解液用双蒸水稀释5倍,制成裂解液。
5.将孔内的培养液吸净,并用PBS迅速的润洗一次。
6.每个孔加入150微升新鲜制备的裂解液,然后室温震荡10分钟。
7.确认所有细胞都已脱落后,将裂解液同细胞碎片一起转移到1.5毫升管内。
8.涡旋几次,使裂解液和细胞完全混合,然后将混合液在4℃用12000g离心10分钟。
9.计算出需要的ELISA-one微板条的数目。把多出的微板条从框架上取下,放回储存袋中密封好。使用微板条之前,先用200微升双蒸水润洗一下每个孔,以除去上面的防腐剂。
10.往每个孔中加入50微升的抗体混合液。(抗体混合液是通过将媒介抗体试剂和酶标抗体试剂等比例混合而成,注意制备抗体混合液时不要涡旋)
11.向ELISA-One微板的每个孔中加入25微升细胞裂解产物。用粘性封口膜盖住微板,室温下在微板震荡仪上孵育1小时。
12.每个孔用150微升1X清洗缓冲液洗3次。最后一次洗完后,将孔内的清洗缓冲液抽净。如果需要,可让1X清洗缓冲液在微板中停留最长30分钟,以留出时间准备底物混合液。
13.底物混合液应随用随配。向每个孔内加入100微升底物混合液,然后用锡箔纸封住微板,室温下在微板震荡仪上孵育10分钟。
14.向每个孔内加入10微升终止液,然后在微板震荡仪上稍微(5-10秒)混匀一下。
15.装配好相应的ELISA-One滤镜组,读出荧光信号强度。
实验结果见表4:
表4体外细胞活性测试结果
化合物 细胞活性
1 A
2 A
3 D
4 B
5 D
7 A
8 B
9 C
10 B
11 A
12 D
14 A
15 A
16 C
20 A
21 A
22 C
23 B
25 A
27 B
28 A
29 D
30 D
32 B
33 D
34 B
35 A
36 A
37 C
42 C
43 B
62 C
63 A
65 A
66 A
68 A
69 A
70 C
72 A
75 D
76 D
77 D
78 D
79 C
81 D
82 C
85 B
88 B
89 A
90 B
91 A
94 D
95 A
注:A≤50nM;50nM<B≤100nM;100nM<C≤250nM;D>250nM。
结论:本发明化合物对PI3K抑制作用显著,但对mTOR有较弱的抑制作用。
体内药效实验部分:
研究受试药物在人源结肠癌CO-04-0032动物模型以及胃癌ST-02-0013动物模型是否具有体内药效。有关实验中对动物饲养,饲料成分,实验观察,实验指标,实验终止以及数据分析的描述如下:
■动物饲养:动物到达后在实验环境饲养3-7天后方能开始实验。动物在SPF级动物房以IVC(独立送风系统)笼具饲养(每笼5只)。所有笼具、垫料及饮水在使用前均需灭菌,灭菌消毒记录见附件。所有实验人员在动物房操作时应穿着防护服和乳胶手套。每笼动物信息卡应注明笼内动物数目,性别,品系,接收日期,给药方案,实验编号,组别以及实验开始日期。笼具、饲料及饮水每周更换两次。饲养环境及光照情况如下:
√温度:20~26℃
√湿度:40~70%
√光照周期:12小时光照,12小时无光照
■饲料成分:饲料符合实验动物食物鉴定标准。污染物最高含量在可控范围内并由生产厂家负责例检。饮水采用高压灭菌的饮用水。
■动物分组:给药前称重动物,测量瘤体积。根据瘤体积随机分组(随机区组设计)。
■观察:本实验方案的拟定及任何修改将在上海药明康德实验动物伦理委员会(IACUC)进行评估核准后方可实行。实验动物的使用及福利将遵照国际实验动物评估和认可委员会(AAALAC)的规则执 行。每天监测动物的健康状况及死亡情况,例行检查包括观察肿瘤生长和药物治疗对动物日常行为表现的影响如行为活动,摄食摄水量,体重变化(每周测量两次体重),外观体征或其它不正常情况。基于各组动物数量记录组内动物死亡数和副作用,相关记录见附件。
■实验指标:实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为:V=0.5a×b2,a和b分别表示肿瘤的长径和短径。化合物的抑瘤疗效(TGI)用T-C(天)和T/C(%)评价。T-C(天)反映肿瘤生长延迟指标,T表示用药组肿瘤达到预先设定体积(如1,000mm3)所用的平均天数,C表示对照组肿瘤达到相同体积所用的平均天数。T/C(%)的百分比值反映肿瘤生长抑制率,T和C分别表示给药组和对照组在某一天的瘤重(瘤体积)。
肿瘤生长抑制率用下列公式计算:TGI(%)=[1-(Ti-T0)/(Vi-V0)]×100,其中Ti为某一天某给药组的平均肿瘤体积,T0为此给药组在开始给药时的平均肿瘤体积;Vi为某一天(与Ti同一天)溶媒对照组的平均肿瘤体积,V0为溶媒对照组在给开始药时的平均肿瘤体积。在实验结束后将检测肿瘤重量,并计算T/C百分比,T和C分别表示给药组和溶媒对照组的瘤重。
■实验终止:若动物健康状况持续恶化,或瘤体积超过2,000mm3,或有严重疾病,或疼痛,须处以安乐死。有以下情况者,通知兽医并处以安乐死:
√明显消瘦,体重降低大于20%;
√不能自由取食和饮水;
√对照组瘤体积平均值达到2,000mm3,实验终止。
√动物出现以下临床表现且持续恶化:
○立毛
○弓背
○耳、鼻、眼或足色发白
○呼吸仓促
○抽搐
○连续腹泻
○脱水
○行动迟缓
○发声
■数据分析:三组或多组间比较用one-way ANOVA。如果F值有显著性差异,应在ANOVA分析之后再进行多重比较。用SPSS 17.0进行所有数据分析。p<0.05认为有显著性差异。
受试药对人源结肠癌CO-04-0032皮下异种移植肿瘤模型的体内药效学研究:
实验设计:
■人源移植肿瘤模型建立:人源结肠癌CO-04-0032模型最初来源于临床外科手术中切除的肿瘤样本,标本的采集使用严格遵守国家、医院以及公司有关伦理的法律法规,包括病人的知情同意。模型建立流程严格按照公司内部SOP。传代命名规则为肿瘤样本接种于裸鼠后为P0代,继续传代为P1代,以此类推,复苏的标本命名为FP。本次实验中使用的肿瘤组织是FP4代。
■动物:BALB/c裸小鼠,雌性,6-8周龄,体重18-20克。由上海西普尔-必凯实验动物有限公司提供。
■肿瘤接种:将体积约30mm3CO-04-0032肿瘤块皮下接种于每只小鼠的右后背,肿瘤平均体积达到约100-200mm3时开始分组给药。
药效实验结果:见图1-1、图1-2a和图1-2b。
受试药对人胃癌ST-02-0013皮下异种移植小鼠模型的体内药效学研究
实验设计:
■人源移植肿瘤模型建立:ST-02-0013的PDX模型最初来源于外科手术割除的临床样本,植入裸鼠体内定义为P0代。下一代植入P0代肿瘤被定义为P1代,以及之后在小鼠体内的持续代代移植,可依此类推。FP2代肿瘤复苏得到FP3代肿瘤。FP3代肿瘤传代得到FP4代肿瘤。FP4代肿瘤组织将用于该研究。
■动物:BALB/c裸小鼠,雌性,6-8周龄,体重18-22克。由上海灵畅生物科技有限公司提供。
■肿瘤接种:将体积约30mm3ST-02-0013FP4代肿瘤组织皮下接种于每只小鼠的右后背,肿瘤平均体积达到约150-200mm3时开始分组给药。
药效实验结果:见图2-1和图2-2。

Claims (12)

  1. 式(I)所示化合物或其药学上可接受的盐,
    Figure PCTCN2015081518-appb-100001
    其中,
    可将结构单元
    Figure PCTCN2015081518-appb-100002
    替换为
    Figure PCTCN2015081518-appb-100003
    Figure PCTCN2015081518-appb-100004
    E选自任选被1、2或3个R3取代的C1-6烷基、3~10元环烃基或杂环烃基;
    L和Q中,一个选自-C(Rd1)(Rd2)-、-C(=O)N(Rd3)-、-N(Rd4)-、-C(=NRd5)-、-S(=O)2N(Rd6)-、-S(=O)N(Rd7)-、-O-、-S-、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-或-N(Rd8)C(=O)N(Rd9)-,另一个选自单键或-C(Rd1)(Rd2)-;
    A、T分别独立地选自N或C(Rt);
    X、Y、Z中的0或1个选自N,其余选自C(Rt);
    B选自-C(Rd1)(Rd2)-、-C(=O)N(Rd3)-、-N(Rd4)-、-C(=NRd5)-、-S(=O)2N(Rd6)-、-S(=O)N(Rd7)-、-O-、-S-、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-或-N(Rd8)C(=O)N(Rd9)-;
    杂原子或杂原子团分别独立地选自-C(=O)N(Rd3)-、-N(Rd4)-、-C(=NRd5)-、-S(=O)2N(Rd6)-、-S(=O)N(Rd7)-、-O-、-S-、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-和/或-N(Rd8)C(=O)N(Rd9)-;
    m1分别独立地选自0、1、2或3;
    R1-3中的一个选自
    Figure PCTCN2015081518-appb-100005
    其余选自H、F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH,或选自任选被R01取代的C1-10烷基或杂烷基、3~10元环烃基或杂环烃基、被3~10元环烃基或杂环烃基取代的C1-10烷基或杂烷基、3~10环烃基或杂环烃基-O-、3~10元环烃基或杂环烃基-氨基-;
    D1选自单键、-C(Rd1)(Rd2)-、-C(=O)N(Rd3)-、-N(Rd4)-、-C(=NRd5)-、-S(=O)2N(Rd6)-、-S(=O)N(Rd7)-、-O-、-S-、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-或-N(Rd8)C(=O)N(Rd9)-;
    D2选自-C(Rd1)(Rd2)-;
    D3选自-N(Rd4)-、-C(=O)N(Rd4)-、-N(Rd4)C(=O)-、-N(Rd4)C(=O)O-、-N(Rd4)OC(=O)-、-N(Rd4)C(=O)N(Rd4)-、-S(=O)-、-S(=O)2-、-S(=O)2N(Rd6)-、-S(=O)N(Rd7)-;
    R4选自H,或选自任选被R01取代的C1-10烷基或杂烷基、3~10元环烃基或杂环烃基、被3~10元环烃基或杂环烃基取代的C1-10烷基或杂烷基;
    n选自1、2、3、4、5或6;
    任选地,任意两个R1之间、同一个D2中的Rd1与Rd2之间、两个D2之间、R4与一个D2之间或者R4与D3之间共同连接到同一碳原子或杂原子上形成一个或两个3、4、5或6元碳环或杂环;
    Rt、Rd1、Rd2分别独立地选自H、F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH、C(=O)NH2、S(=O)NH2、S(=O)2NH2,或选自任选被R01取代的C1-10烷基或杂烷基、3~10环烃基或杂环烃基、被3~10元环烃基或杂环烃基取代的C1-10烷基或杂烷基;
    R01选自F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH、R02
    R02选自C1-10烷基、C1-10烷氨基、N,N-二(C1-10烷基)氨基、C1-10烷氧基、C1-10烷酰基、C1-10烷氧羰基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基、C3-10环烷氨基、C3-10杂环烷氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧羰基、C3-10环烷基磺酰基、C3-10环烷基亚磺酰基、5-6元不饱和杂环基、6-12元芳基或杂芳基;
    杂原子或杂原子团分别独立地选自-C(=O)N(Rd3)-、-N(Rd4)-、-C(=NRd5)-、-S(=O)2N(Rd6)-、-S(=O)N(Rd7)-、-O-、-S-、=O、=S、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-和/或-N(Rd8)C(=O)N(Rd9)-;
    Rd3-d9分别独立地选自H、OH、NH2、R02
    R02任选地被R001取代;
    R001选自F、Cl、Br、I、CN、OH、N(CH3)2、NH(CH3)、NH2、CHO、COOH、三氟甲基、氨甲基、羟甲基、甲基、甲氧基、甲酰基、甲氧羰基、甲磺酰基、甲基亚磺酰基;
    上述任意一种情况下,R01、R001数目分别独立地选自0、1、2或3,杂原子或杂原子团的数目分别独立地选自1、2或3。
  2. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐,其中,E选自被R3取代的C1-6烷基或C3-6环烷基,R3的数目选自0、1、2或3,或者E选自
    Figure PCTCN2015081518-appb-100006
    Figure PCTCN2015081518-appb-100007
    其中,
    G1~5中的0、1、2或3个选自N,其余选自C(R3);
    G6选自-C(R3)(R3)-、-C(=O)N(R3a)-、-N(R3a)-、-C(=NR3a)-、-S(=O)2N(R3a)-、-S(=O)N(R3a)-、-O-、-S-、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-或-N(R3a)C(=O)N(R3a)-;
    G7~9中的0、1或2个选自N,其余选自C(R3);
    G10~16中的0、1、2、3或4个选自N,其余选自C(R3);
    G17选自N或者C(R3);
    G18~22中的0、1、2或3个选自-C(=O)N(R3a)-、-N(R3a)-、-C(=NR3a)-、-S(=O)2N(R3a)-、-S(=O)N(R3a)-、-O-、-S-、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-或-N(R3a)C(=O)N(R3a)-,其余选自-C(R3)(R3)-;R3a选自C1-10烷基、C1-10烷基酰基、C1-10烷氧羰基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基、C3-10环烷基酰基、C3-10环烷氧羰基、C3-10环烷基磺酰基、C3-10环烷基亚磺酰基、5-6元不饱和杂环基、6-10元芳基或杂芳基;
    其余变量如权利要求1所定义。
  3. 根据权利要求2所述的式(I)所示化合物或其药学上可接受的盐,其中,E选自任选被1、2或3个R3取代的甲基、乙基、丙基、
    Figure PCTCN2015081518-appb-100008
    Figure PCTCN2015081518-appb-100009
  4. 根据权利要求3所述的式(I)所示化合物或其药学上可接受的盐,其中,E选自任选被1、2、或3个卤素、OH、OC1-3烷基、CN、NH2、NH(C1-3烷基)、N(C1-3烷基)2、C1-3烷基、三氟甲基、三氟乙基、C(=O)NH2、C1-3烷基C(=O)、C1-3烷基C(=O)NH、C1-3烷基S(=O)、C1-3烷基S(=O)NH、C1-3烷基S(=O)2或C1-3烷基S(=O)2NH所取代的:
    Figure PCTCN2015081518-appb-100010
    Figure PCTCN2015081518-appb-100011
    C1-3烷基;
    任选地,E选自:
    Figure PCTCN2015081518-appb-100012
  5. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐,其中,L和Q中,一个选自-S(=O)2NH-、-S(=O)2-、-NH-、-NHC(=O)NH-,另一个选自单键、-CH2-。
  6. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐,其中,X、Y、Z中的0或1个选自N,其余选自CH、C(CH3)、C(CF3)、CCl、CF。
  7. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐,其中,A、T分别独立地选自N、CH、C(CH3)、C(CF3)、CCl、CF;或者,B选自NH、N(CH3)或N(CF3)。
  8. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐,其中,任意两个R1之间、同一个D2中的Rd1与Rd2之间、两个D2之间、R4与一个D2之间或者R4与D3之间所成的环选自任选被1、2、或3个卤素、OH、OC1-3烷基、CN、NH2、NH(C1-3烷基)、N(C1-3烷基)2、C1-3烷基、三氟甲基、三氟乙基、C(=O)NH2、C1-3烷基C(=O)、C1-3烷基C(=O)NH、C1-3烷基S(=O)、C1-3烷基S(=O)NH、C1-3烷基S(=O)2或C1-3烷基S(=O)2NH所取代的:
    Figure PCTCN2015081518-appb-100013
    任选地,所成的环选自:
    Figure PCTCN2015081518-appb-100014
    Figure PCTCN2015081518-appb-100015
  9. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐,其中,R1-3中的一个选自
    Figure PCTCN2015081518-appb-100016
    其余选自H、F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH、ORa、N(Rb)(Rc)、任选被Rd取代的C1-3烷基或环丙基;
    D1选自单键、-C(Re)(Re)-、-C(=O)N(Ra)-、-N(Ra)-、-C(=NRa)-、-S(=O)2N(Ra)-、-S(=O)N(Ra)-、-O-、-S-、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-或-N(Ra)C(=O)N(Ra)-;
    D2选自-C(Ra)(Ra)-;
    n选自1、2、3、4、5或6;
    Ra、Rb、Rc分别独立地选自H、任选Rd取代的C1-6烷基或C3-6环烷基;
    Re选自H、任选Rd取代的C1-6烷基或烷氧基、任选Rd取代的C3-6环烷基或环烷氧基;
    Rd选自F、Cl、Br、I、CN、OH、NH2、CHO、COOH、CH3、CF3、CH3O、CH3CH2O,Rd的数目选自0、1、2或3;
    任选地,任意两个R1之间、同一个D2中的Ra与Ra之间、两个D2之间、或Ra与一个D2之间共同连接到同一碳原子或氧原子上形成一个或两个3、4、5或6元碳环或氧杂环,其中氧原子的数目为1或2。
  10. 根据权利要求9所述的式(I)所示化合物或其药学上可接受的盐,其中,任意两个R1之间、同一个D2中的Ra与Ra之间、两个D2之间、或Ra与一个D2之间所成的环选自环丙基、环丁基、环戊基、环己基、氧杂环丁基、1,3-二氧五环基。
  11. 根据权利要求1~10任意一项所述的式(I)所示化合物或其药学上可接受的盐,其中,R1-3中的一个选自
    Figure PCTCN2015081518-appb-100017
    Figure PCTCN2015081518-appb-100018
    Figure PCTCN2015081518-appb-100019
    其余选自H、F、Cl、Br、I、CN、OH、NH2、甲基、乙基、丙基、甲氧基、乙氧基、丙氧基、甲氨基、二甲氨基、卤代甲基、卤代乙基、卤代丙基、氨甲基、氨乙基、氨丙基、环丙基。
  12. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐,其选自化合物1~25、化合物27~99。
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WO2017101847A1 (zh) * 2015-12-16 2017-06-22 正大天晴药业集团股份有限公司 吡啶并[1,2-a]嘧啶酮类似物、其晶型、其中间体及其制备方法
KR102731762B1 (ko) 2015-12-16 2024-11-18 치아타이 티안큉 파마수티컬 그룹 주식회사 피리도[1,2-a]피리미돈 유사체, 이의 결정형, 이의 중간체 및 이의 제조방법
JP7037483B2 (ja) 2015-12-16 2022-03-16 チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッド ピリド[1,2-a]ピリミドン類似体、それらの結晶形、それらの中間体、及びそれらの製造方法
US11725010B2 (en) 2019-12-02 2023-08-15 Storm Therapeutics Limited Polyheterocyclic compounds as METTL3 inhibitors
WO2021160147A1 (zh) 2020-02-10 2021-08-19 正大天晴药业集团股份有限公司 吡啶并[1,2-a]嘧啶酮化合物的治疗淋巴瘤的用途
WO2021180111A1 (zh) 2020-03-10 2021-09-16 正大天晴药业集团股份有限公司 包括吡啶并[1,2-a]嘧啶酮化合物的药物组合
WO2022057812A1 (zh) 2020-09-15 2022-03-24 正大天晴药业集团股份有限公司 吡啶并[1,2-a]嘧啶酮化合物的治疗外周T细胞淋巴瘤的用途
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WO2023169488A1 (zh) * 2022-03-09 2023-09-14 正大天晴药业集团股份有限公司 包括吡啶并[1,2-a]嘧啶酮化合物和EGFR抑制剂的药物组合

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