WO2018001332A1 - 具有突变型异柠檬酸脱氢酶抑制活性的化合物、其制备方法及用途 - Google Patents

具有突变型异柠檬酸脱氢酶抑制活性的化合物、其制备方法及用途 Download PDF

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WO2018001332A1
WO2018001332A1 PCT/CN2017/090909 CN2017090909W WO2018001332A1 WO 2018001332 A1 WO2018001332 A1 WO 2018001332A1 CN 2017090909 W CN2017090909 W CN 2017090909W WO 2018001332 A1 WO2018001332 A1 WO 2018001332A1
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compound
group
unsubstituted
substituted
alkyl
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PCT/CN2017/090909
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English (en)
French (fr)
Inventor
江磊
耿美玉
郑乾刚
黄敏
万惠新
唐帅
付贤磊
兰小晶
曹建华
丁健
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上海海和药物研究开发有限公司
中国科学院上海药物研究所
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Publication of WO2018001332A1 publication Critical patent/WO2018001332A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides

Definitions

  • the invention belongs to the field of chemical synthesis, and particularly relates to a compound having a mutant IDH inhibitory activity, a preparation method thereof and use thereof.
  • Isocitrate dehydrogenase catalyzes the oxidative decarboxylation of isocitrate to 2-oxoglutarate (alpha-ketoglutarate) while producing carbon dioxide and NADPH/NADH. This process plays an important role in the metabolism of cells. Depending on the electron acceptor, these enzymes can be distinguished into two different subclasses, one using NAD(+) and the other using NADP(+).
  • isocitrate dehydrogenases Of the five isocitrate dehydrogenases that have been reported, three are NAD(+)-dependent isocitrate dehydrogenases, mainly present in the mitochondrial matrix; the other two are NADP(+)-dependent, ie different Citric acid ester dehydrogenase 1 and isocitrate dehydrogenase 2. Isocitrate dehydrogenase 1 is mainly present in the cytoplasm, while isocitrate dehydrogenase 2 is mainly present in the mitochondria.
  • Mutations of isocitrate dehydrogenase occur in many types of cancer, such as, but not limited to, glioma, glioblastoma, paraneoblastoma, acute leukemia, prostate cancer, thyroid cancer, colon cancer , chondrosarcoma, cholangiocarcinoma, peripheral T cell leukemia, melanoma, etc.
  • Non-mutated IDH1 catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate, thereby reducing NAD+(NADP+) to NADP (NADPH) in the following forward reactions:
  • the mutant isocitrate dehydrogenase loses this normal function and has the new ability to catalyze the NAPH-dependent reduction of ⁇ -ketoglutarate to R(-)-2-hydroxyglutarate ( 2HG).
  • the level of 2HG in normal cells is very low.
  • the production of high concentrations of 2HG will help the formation and development of cancer.
  • a high concentration of 2-HG was detected in an acute leukemia with an IDH mutation.
  • High concentrations of 2HG are well correlated with oncogenes.
  • inhibition of mutated IDH and its novel activity is a potential therapeutic treatment for cancer.
  • a compound of formula I or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate thereof , polymorph or prodrug,
  • W 1 and W 2 are each independently selected from N or CR b ;
  • W and W' are each independently selected from CR a R b ;
  • R a is selected from H, C 1 -C 6 alkyl
  • R b is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halogen, cyano, phenyl, C 1 -C 6 alkoxy;
  • R 1 is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl-C1-C4 alkyl group, a substituted or unsubstituted 4-8 membered heterocyclic group, substituted or unsubstituted a 4-8 membered carbocyclic group, a substituted or unsubstituted C5-20 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group; wherein said heterocyclic group or heteroaryl group comprises 1-3 selected From the following group of heteroatoms: N, O, S or P;
  • R 2 is a substituted or unsubstituted C 5 -C 20 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group, a substituted or unsubstituted 5-10 membered arylheterocyclyl group, wherein the heteroaryl group
  • the base comprises 1-3 heteroatoms selected from the group consisting of N, O or S; the arylheterocyclyl containing 1-3 heteroatoms selected from the group consisting of N, O or S;
  • R 3 is halogen, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, substituted or unsubstituted 5-10 membered aryl;
  • R 4 is -(CH 2 ) m R 11 ;
  • n is an integer from 0 to 5; preferably an integer from 0 to 3;
  • R 11 is a substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 5-10 membered heterocyclic group; wherein; X is selected from O, N or S; An integer from 0 to 5; Rc is selected from H, a substituted or unsubstituted 5-10 membered heteroaryl, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted 5-10 membered aryl group; and Rd is selected from H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkylcarbonyl group; or Rc bonded to Rd to form a 4-8 membered saturated or unsaturated heterocyclic group or heteroaryl group;
  • the heteroaryl group contains from 1 to 4 heteroatoms selected from N
  • any of the above “substituted” means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of -D, halogen, -OH, -NO 2 , -NH 2 , -N (unsubstituted C1-C6 alkyl) 2 , -CN, unsubstituted or halogenated C1-C8 alkyl, unsubstituted or halogenated C1-C8 alkoxy-C1-C8 alkyl, unsubstituted or halogenated C3- a C8 cycloalkyl group, an unsubstituted or halogenated C3-C8 cycloalkyl-C1-C8 alkyl group, an unsubstituted or halogenated C1-C8 alkoxy group, an unsubstituted or halogenated C1-C6 alkylcarbonyl group, Unsubstituted or halogen
  • W is CR a R b and n is preferably an integer from 1 to 4.
  • W' is CR a R b and n' is preferably 1.
  • R 2 is selected from the group consisting of Wherein Rm is selected from the group consisting of H, D, halogen, C1-C6 alkyl, C1-C6 alkoxy.
  • R 4 is -(CH 2 ) m R 11 ; m is preferably 0, 1, or 2.
  • R 11 is selected from the group consisting of Wherein X is O or N; V1, V2 and V3 are each selected from CRa or N; m is an integer from 0 to 4; Ra is selected from H, C 1 -C 6 alkyl, halogen, cyano; Rc is selected from H , substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-10 membered aryl; Rd selected from H, substituted or unsubstituted C1-C6 alkyl a substituted or unsubstituted C1-C6 alkylcarbonyl group; wherein said heteroaryl group comprises from 1 to 4 heteroatoms selected from N, O or S; said heterocyclic group contains from 1 to 4 A hetero atom selected from the group consisting of N, O or S.
  • R 4 is -(CH 2 ) m R 11 ; m is preferably 0 or 1.
  • R 11 is preferably Wherein m is an integer from 0 to 4; Rc is selected from H, a substituted or unsubstituted 5-10 membered heteroaryl group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted 5-10 membered aryl group; Rd is selected from H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkylcarbonyl group; wherein the heteroaryl group contains 1-4 heteroatoms selected from the group consisting of N, O Or S; the heterocyclic group contains 1-4 heteroatoms selected from the group consisting of N, O or S.
  • Rc is selected from the group consisting of: Wherein, R 'or R "are each independently selected from -CN, -OH, hydroxamic acid groups, C1-C6 alkylcarbonyl group, -NO 2, halogen, or halo-substituted C1-C6 alkyl, C1-C6 Alkoxy.
  • the compound has the structure shown in the following formula I-1:
  • the compound has the structure shown in the following formula I-2:
  • the compound is selected from the group consisting of compounds 1-133.
  • each group is as defined in the second aspect of the invention.
  • the reaction is carried out in a solvent
  • the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, Tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof.
  • the mutant IDH-related disease is selected from the group consisting of cancer; preferably leukemia, glioma, cholangiocarcinoma, cartilage joint sarcoma, fibrosarcoma, intrahepatic cholangiocarcinoma, rectal cancer .
  • the mutant IDH is selected from the group consisting of IDH1, IDH2, or a combination thereof.
  • a pharmaceutical composition comprising:
  • a fifth aspect of the invention provides a method of inhibiting an IDH mutation, the method comprising the steps of: administering to a subject, inhibiting an effective amount of a compound of formula I according to the first aspect of the invention, or a pharmaceutically acceptable thereof, A salt, or an inhibitory effective amount of a pharmaceutical composition according to the third aspect of the invention, is administered to the subject.
  • the inventors have conducted a long-term and intensive study to prepare a compound having the structure of the formula I, and found that it has a mutant IDH inhibitory activity. Moreover, the compound has an inhibitory effect on a series of mutant IDHs at a very low concentration (as low as ⁇ 100 nmol/L), and the inhibitory activity is quite excellent, and thus can be used for treating diseases associated with mutant IDH such as tumors. . Based on the above findings, the inventors completed the present invention.
  • reaction can be carried out and purified using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in the present invention.
  • the above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification.
  • group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left.
  • substituent -CH2O- is equivalent to -OCH2-.
  • C1-6 alkyl refers to an alkyl group as defined below having a total of from 1 to 6 carbon atoms.
  • the total number of carbon atoms in the simplified symbol does not include carbon that may be present in the substituents of the group.
  • halogen means fluoro, chloro, bromo or iodo.
  • Haldroxy means an -OH group.
  • Hydroalkyl means an alkyl group as defined below which is substituted by a hydroxy group (-OH).
  • Niro means -NO2.
  • Amino means -NH2.
  • Substituted amino means an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkyl Amido, aralkylamino, heteroarylalkylamino.
  • Carboxyl means -COOH.
  • alkyl group means consisting only of carbon atoms and hydrogen atoms, and is not unsaturated.
  • a bond a straight or branched hydrocarbon chain group having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and attached to the remainder of the molecule by a single bond.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, ⁇ , etc.
  • alkenyl as a group or part of another group means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10) And more preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group attached to the remainder of the molecule by a single bond, such as, but not limited to, vinyl, propenyl, allyl, butyl- 1-Alkenyl, but-2-enyl, pent-1-enyl, pentane-1,4-dienyl and the like.
  • alkynyl as a group or part of another group means consisting solely of carbon atoms and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having for example 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group bonded to the remainder of the molecule by a single bond, such as, but not limited to, an ethynyl group , prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl and the like.
  • cycloalkyl as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, which may include condensing a ring system, a bridged ring system or a spiro ring system having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and may be suitably employed
  • the carbon atom is connected to the rest of the molecule by a single bond.
  • a carbon atom in a cycloalkyl group may be optionally oxidized.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene And cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl , fluorenyl, bicyclo [2.2.1] heptyl, 7,7-dimethyl-bicyclo[2.2.1]hept
  • heterocyclyl as a group or part of another group means consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur.
  • a heterocyclic group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include a fused ring system, a bridged ring system or a spiro ring system;
  • the nitrogen, carbon or sulfur atom may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated.
  • the heterocyclic group may be attached to the remainder of the molecule via a carbon atom or a hetero atom and through a single bond.
  • one or more of the rings may be an aryl or heteroaryl group as defined hereinafter, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • the heterocyclic group is preferably a stable 4 to 11 membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocyclic groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]fluorene.
  • Alkan-7-yl 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza Cyclobutane, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, quinazolinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indanyl, octahydroindenyl, octahydroisodecyl, pyrrolidinyl, pyrazolidinyl , phthalimido and the like.
  • aryl as a group or part of another group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms.
  • an aryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atoms on the aromatic ring are connected to the rest of the molecule by a single bond.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, anthracenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4- Benzooxazine-3(4H)-one-7-yl and the like.
  • arylalkyl refers to an alkyl group as defined above substituted with an aryl group as defined above.
  • heteroaryl as a group or part of another group means having from 1 to 15 carbon atoms (preferably having from 1 to 10 carbon atoms) and from 1 to 6 selected from nitrogen in the ring. a 5- to 16-membered conjugated ring system of a hetero atom of oxygen and sulfur. Unless otherwise specifically indicated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that The aryl group is attached to the remainder of the molecule via a single bond through an atom on the aromatic ring.
  • the nitrogen, carbon or sulfur atom in the heteroaryl group can be optionally oxidized; the nitrogen atom can optionally be quaternized.
  • the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably from 1 to 4 selected
  • heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, fluorenyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, isodecyl, oxazolyl, isoxazolyl , fluorenyl, quinolyl, isoquinolyl, diaza naphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, oxazolyl, porphyrin, phenanthryl, phenanthroline, acridine Base, phenazinyl
  • heteroarylalkyl refers to an alkyl group as defined above which is substituted by a heteroaryl group as defined above.
  • optionally or “optionally” means that the subsequently described event or condition may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or condition.
  • optionally substituted aryl means that the aryl group is substituted or unsubstituted, and the description includes both the substituted aryl group and the unsubstituted aryl group.
  • a chemical moiety refers to a particular fragment or functional group in a molecule.
  • a chemical moiety is generally considered to be a chemical entity that is embedded or attached to a molecule.
  • Stepoisomer refers to a compound composed of the same atoms bonded by the same bond but having a different three-dimensional structure.
  • the invention will cover various stereoisomers and mixtures thereof.
  • the compounds of the present invention are intended to include E- and Z-geometric isomers unless otherwise stated.
  • Tautomer refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention will also be embraced within the scope of the invention.
  • the compounds of the invention may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the invention is intended to include all possible isomers, as well as racemic and optically pure forms thereof.
  • the preparation of the compounds of the invention may employ racemates, diastereomers or enantiomers as starting materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as by crystallization and chiral chromatography.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” means a salt formed with an inorganic or organic acid which retains the bioavailability of the free base without any other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate , trifluoroacetate, propionate, hexanoate, octoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, hexane Acid salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, me
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic or organic base which is capable of retaining the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines, and basic ion exchange resins.
  • ammonia isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclo Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, hydrazine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin, and the like.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • Polymorph refers to a different solid crystalline phase of certain compounds of the invention resulting from the presence of two or more different molecular arrangements in a solid state. Certain compounds of the invention may exist in more than one crystal form, and the invention is intended to include various crystal forms and mixtures thereof.
  • solvate refers to an aggregate comprising one or more molecules of the compound of the invention and one or more solvent molecules.
  • the solvent may be water, and the solvate in this case is a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms.
  • the compounds of the invention may form true solvates, but in some cases, it is also possible to retain only a defined amount of water or a mixture of water plus a portion of the indefinite solvent.
  • the compound of the present invention can be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.
  • the invention also includes prodrugs of the above compounds.
  • prodrug means a compound which can be converted into a biologically active compound of the invention under physiological conditions or by solvolysis.
  • prodrug refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention.
  • Prodrugs may be inactive when administered to an individual in need thereof, but are converted in vivo to the active compound of the invention.
  • Prodrugs are typically rapidly converted in vivo to produce the parent compound of the invention, for example by hydrolysis in blood.
  • Prodrug compounds generally provide the advantage of solubility, tissue compatibility or sustained release in mammalian organisms.
  • Prodrugs include known amino protecting groups and carboxy protecting groups.
  • pharmaceutical composition refers to a formulation of a compound of the invention and a medium generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human.
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, thereby facilitating the absorption of the active ingredient and thereby exerting biological activity.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable organisms. The reaction or in an undesirable manner interacts with any of the components contained in the composition.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government authorities for acceptable use by humans or livestock. , diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • tumor include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, Lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc. disease.
  • preventing include the possibility of reducing the occurrence or progression of a disease or condition by a patient.
  • treatment and other similar synonyms as used herein includes the following meanings:
  • an "effective amount,” “therapeutically effective amount,” or “pharmaceutically effective amount,” as used herein, refers to at least one agent or compound that, after administration, is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent. The amount. The result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired change in the biological system.
  • an "effective amount” for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic.
  • An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.
  • administering refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration.
  • parenteral injections including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical administration and rectal administration.
  • the techniques of administration of the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, those discussed in Pa.
  • the compounds and compositions discussed herein are administered orally.
  • pharmaceutical combination means a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, It includes both fixed and unfixed combinations of active ingredients.
  • fixed combination refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form.
  • unfixed combination refers to the simultaneous administration, combination or sequential administration of at least one of the compounds described herein and at least one synergistic formulation to the patient in the form of separate entities. These are also applied to cocktail therapy, for example the administration of three or more active ingredients.
  • the intermediate compound functional groups may need to be protected by a suitable protecting group.
  • suitable protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, and the like.
  • Suitable protecting groups for amino, mercapto and fluorenyl include t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable mercapto protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T. W. and P. G. M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymeric resin.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph thereof Or a prodrug,
  • the W, W', W 1 , W 2 , n, n', R 1 , R 2 , R 3 , R 4 , m, R 11 , X, Rc, and Rd are each independently
  • the ground is a group corresponding to the following compounds.
  • the compound of the formula I provided by the present invention can be produced by the following method 1) or 2):
  • each group is as defined above.
  • the reaction is carried out in a solvent
  • the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, Tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof.
  • novel mutant IDH inhibitor having a novel structure and a preparation and use thereof, wherein the inhibitor has high inhibitory activity against mutant IDH.
  • a class of pharmaceutical compositions for treating diseases associated with mutant IDH is provided.
  • the solvent can be replaced with toluene or dioxane or other inert solvent.
  • A2 A3, A4, A5, A6, A8, A9, A10, A16, A28, A29, A31, A33, A34, A35 were used in the next reaction without purification; A19, A20, A21, A22, A26 were purified by column chromatography.
  • the intermediate structure is as follows:
  • the imine intermediates A7, A11, A13, A14 are obtained by reacting a substituted or unsubstituted (hetero)arylcycloalkyl ketone compound with a substituted or unsubstituted aniline or a heterocyclic aromatic amine using the above procedure.
  • titanium tetrachloride can be replaced with other Lewis acids (boron trifluoride etherate, aluminum trichloride, etc.), and the solvent can be replaced by toluene or dioxane.
  • Lewis acids boron trifluoride etherate, aluminum trichloride, etc.
  • the imine intermediate A32 was obtained by the reaction of 7-chlorofluorenone and 3,5-difluoroaniline using the above procedure.
  • Step 1 In a clean 250 ml sealed tube, add B1-1 (25 g, 175 mmol) and 140 ml of ethyl formate, and add triethylamine (53 g, 525 mmol) under stirring, and stir at 110 ° C in an oil bath overnight to cool. The mixture was filtered and the mixture was washed with EtOAc EtOAc EtOAc (EtOAc)
  • Step 2 In a dry 1 L single-mouth bottle, compound B1-2 (22 g, 163 mmol), triphenylphosphine (47 g, 179 mmol), carbon tetrachloride (25 g, 163 mmol), triethylamine (16.5 g) were sequentially added. , 163 mmol) and 500 ml of dichloromethane, refluxed at 45 ° C overnight, vortexed in a cold water bath, and then added with 500 ml of diethyl ether for 1 hour, filtered, washed with diethyl ether, the filtrate was mixed with silica gel, and dried in a cold water bath. The title compound (11.8 g, 62%) was obtained.
  • Step 1 The compound L-valine methyl ester hydrochloride (4.98 g, 30 mmol, CAS: 2133-40-6) and 2-bromo-4-cyanopyridine (2.28 g, 20 mmol) were dissolved.
  • Xantphos (5.78 g, 10 mmol) and cesium carbonate (19.56 g, 60 mmol), in 1 dioxane (80 ml), Pd2(dba)3 (1.83 g, The mixture was reacted for 12 hours under a nitrogen atmosphere at 00 ° C.
  • Step 2 Dissolve C1-1 (460 mg, 2 mmol) in tetrahydrofuran/water (15 ml / 8 ml), add lithium hydroxide (84 mg, 2 mmol) at room temperature and react at room temperature 4 hour. After completion of the reaction, the pH was adjusted to 2 with dilute hydrochloric acid, and 15 ml of ethyl acetate was added. The organic phase was washed with water (20 ml ⁇ 1) and brine (20 ml ⁇ 1). The organic phase was collected, dried over anhydrous sodium sulfate and filtered and evaporated ), yield: 78.3%.
  • Step 1 Compound C2-1 (1 g, 8.5 mmol), sodium acetate (1.4 g, 17 mmol), ethyl bromoacetate (1.7 g, 10 mmol) and 30 ml of ethanol were successively added to a dry 50 ml single-necked flask, and refluxed for 36 hours. The solvent was evaporated to dryness, EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH
  • Step 2 In a dry 50 ml single-mouth bottle, add compound C2-2 (300 mg, 1.47 mmol), sodium hydroxide (118 mg, 2.94 mmol), water 3 ml and 12 ml methanol, stir at room temperature for 3 hours, spin dry solvent, dilute Hydrochloric acid was adjusted to a pH of about 5, and a white solid C2 (120 mg, yield: 46.3%) was isolated.
  • Step 1 In a dry 50 ml sealed tube, compound C3-1 (3 g, 16.7 mmol, CAS23284-84-6), methyl iodide (7.1 g, 50 mmol), 20 ml of toluene, stirred at 80 ° C overnight, cooled, added 30 ml. Water, extracted with ethyl acetate (50 ml * 2), dried over anhydrous sodium sulfate, EtOAc (EtOAc m. (Methyl(phenyl)amino)ethyl acetate (C3-2) 1.2 g. Yield: 37%. LCMS: m/z 194.3 (M-1).
  • Step 2 In a dry 25 ml single-mouth bottle, a compound C3-2 (1.2 g, 6.2 mmol) sodium hydroxide (0.62 g, 15 mmol) and 5 ml of water, 15 ml of methanol were added successively, stirred at room temperature for three hours, and the organic solvent was rotated to adjust The pH is about 4, and it is extracted with ethyl acetate (50 ml*2), dried over anhydrous sodium sulfate, and evaporated to dryness to give benzene (2-(methylphenyl)amino)acetic acid (C3) 420 mg (yield: 41%) .
  • C3 benzene (2-(methylphenyl)amino)acetic acid
  • Step 1 L-Serine (10.0 g, 95.2 mmol, 1.0 eq), sodium bicarbonate (20 g, 238.0 mmol, 2.5 eq) and water (30 mL) were added sequentially in a dry 500 mL single-necked flask. Benzyl chloroformate (2.0 mL, 142.8 mmol, 1.5 eq) was added at 0 ° C and stirred at room temperature for 18 h. After completion of the reaction, the reaction solution was poured into water (200), and the mixture was extracted with ethyl acetate (300 mL).
  • Step 2 C5-1 (2.5 g, 10.45 mmol, 1.0 eq), water (10 mL) and sodium hydroxide (0.84 g, 20.91 mmol, 2.0 eq) were added sequentially at room temperature in a 100 mL vial at 0 °C. Stir at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into water (20), and the mixture was extracted with diethyl ether (300 mL). The aqueous phase was acidified to pH 1 with concentrated aqueous HCl and extracted with ethyl acetate (300 mL). The product (S)-2-oxooxazolidine-4-carboxylic acid (600 mg, white solid) was obtained.
  • Step 1 Add 30 ml of anhydrous tetrahydrofuran to a dry 100 ml three-necked flask, ventilate, protect with nitrogen, cool to 0 ° C, slowly add 2 mol / L LDA (10.5 ml, 22.7 mmol) and tributyltin hydride (5.64 ml).
  • Step 1 Add intermediate A1, L-pyroglutamic acid (260 mg, 2 mmol) to a microwave reaction tube, dissolve in 2 mL of anhydrous methanol, stir at room temperature for 15 minutes, add intermediate B1 (240 mg, 2 mmol), and seal the tube. It was then reacted overnight in a 40 ° C oil bath. After adding 10 mL of water, it was extracted three times with ethyl acetate (3*10 mL), and the combined ethyl acetate phase was washed several times with saturated brine, dried over anhydrous sodium sulfate and then evaporated to dryness.
  • intermediate A1 L-pyroglutamic acid
  • Step 2 Add the intermediate 1-1 (140 mg, 0.3 mmol) obtained in the first step to a microwave reaction tube, cesium carbonate (145 mg, 0.45 mmol), Pd 2 (dba) 3 (14 mg, 0.015 mmol), Xant-phos (9 mg, 0.015 mmol) and 2-chloro-4-cyanopyridine (50 mg, 0.36 mmol) were poured into 5 mL of anhydrous 1,4-dioxane, and the mixture was sealed at 70 ° C for 3 h.
  • cesium carbonate 145 mg, 0.45 mmol
  • Pd 2 (dba) 3 14 mg, 0.015 mmol
  • Xant-phos 9 mg, 0.015 mmol
  • 2-chloro-4-cyanopyridine 50 mg, 0.36 mmol
  • the product obtained by the reaction of the imine intermediate A2, the isocyanide intermediate B1 and the L-pyroglutamic acid was carried out in the same manner as in Example 1, and then reacted with 2-chloropyrazine to obtain a compound 50 and a compound 51. .
  • Example 27 Compound 56 and Compound 57
  • Example 28 Compound 58 and Compound 59
  • Example 28 Compound 60 and Compound 61
  • Compound 72 (S)-N-(3,4-difluorophenyl)-1-(4-cyanopyridin-2-yl)-N-((R)-1-((3,3-di) Fluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-indol-1-yl)-5-oxopyrrole-2-carboxamide
  • Example 35 Compound 73 and Compound 74
  • Example 36 Compound 75 and Compound 76
  • Compound 80 (S)-N-((R)-4-chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-indole-1- 1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide
  • Example 51 Compound 105 and Compound 106
  • Example 52 Compound 107 and Compound 108
  • Example 55 Compound 113 and Compound 114
  • Example 58 Compound 117 and Compound 118
  • Example 59 Compound 119 and Compound 120
  • Compound 120 (S)-N-((R)-7-chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-indole-1- 3-(4-cyanopyrimidin-2-yl)-N-(3-fluorophenyl)-2-oxooxazolidine-4-carboxamide
  • Step 1 Weigh chloroacetic acid (190mg, 2mmol) in a microwave reaction tube, dissolve Schiff base in 1mL anhydrous methanol and inject into the microwave tube, stir for 30 minutes, then add cyclohexyl isocyanide (220mg, 2mmol), seal the microwave tube The reaction was carried out at 30 ° C overnight. The reaction was quenched by the addition of EtOAc (EtOAc) (EtOAc) Methane: 50:1) Intermediate 5-1 (200 mg, white solid) was isolated, yield 23.3%.
  • Step 2 Intermediate 5-1 (100 mg, 0.23 mmol) and 100 mL reaction flask were added with 2-methylimidazole (19 mg, 0.23 mmol), triethylamine (46 mg, 0.46 mmol) and 5 mL of dichloromethane. The reaction was heated to reflux under a nitrogen atmosphere overnight. The reaction mixture was filtered over EtOAc (EtOAc)EtOAc.
  • Compound 5 N-cyclohexyl-1-(N-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)acetamide)-2,3-dihydro-1H- ⁇ -1-carboxamide.
  • Example 54 The same procedure as in Example 54 was carried out using the imine intermediate A3, cyclohexyl isocyanide and chloroacetic acid. The obtained product was subjected to a substitution reaction with 2-methylimidazole to obtain Compound 6.
  • Example 62 The same procedure as in Example 62 was carried out, and the reaction was carried out using the imine intermediate A1, the isocyanide intermediate B2 and the acid intermediate C4.
  • Test Example 1 Effect of the compound of the present invention on the activity of IDH1 enzyme at the molecular level
  • the enzyme used in the experiment was purchased from cayman.
  • the substrates ⁇ -KG, NADPH and Diaphorase were purchased from Sigma; Resazurin was purchased from BEHRINGER; the remaining reagents were purchased from Sinopharm Chemical Reagent Co., Ltd.
  • the reaction microplate (6008260) was purchased from PerkinElmer.
  • the experimental plate reader is a PerkinElmer product using a multi-function microplate reader, model: EnVison.
  • the experimental water is distilled water produced by Sinopharm Group.
  • Compound preparation Compound 12000g was centrifuged for 5min, added with DMSO to prepare 10 mM stock solution, vortexed evenly, then sonicated for 10 minutes, and stored at -40 °C. The test was first diluted with DMSO to a solution of 10 ⁇ M and then diluted 3 ⁇ times to a different test solubility.
  • Test method The enzyme activity of IDH1 to convert ⁇ -KG to 2HG was measured by the consumption of NADPH. After the end of the enzymatic reaction, a catalytic excess of diaphorase and reazurin is added and the resulting fluorescent signal reflects the amount of remaining NADPH.
  • Detection reaction 5 ⁇ L of 1 ⁇ detection buffer diluted 0.01unit diaphroase and 5 ⁇ M resazurin were added to each well, and incubated at room temperature for 10 min in the dark. Reading board: with PerkinElmer At Ex 544Em 590. Test board. IC 50 values calculated using GraphPad Prism software determined.
  • Table 1 shows the IC 50 values of some of the compounds of the present invention.
  • the letter A represents an IC 50 of less than 100 nm
  • the letter B represents an IC 50 of from 100 nm to 1000 nm;
  • the letter C represents an IC 50 of 1 uM to 10 uM
  • the letter D represents an IC 50 of 10 uM or more.
  • Test Example 2 Inhibition of proliferation of malignant glioma cell line U87 by the compound of the present invention
  • the proliferation inhibitory activity of the compound of the present invention against malignant glioma cell line U87 was measured by the following method.
  • Test compound 1-133 was determined to have an inhibitory effect on malignant glioma cell line U87.
  • Test Example 3 Determination of proliferation inhibitory activity of the compound of the present invention against tumor cell lines other than malignant glioma cell line U87
  • the present invention also determined the proliferation inhibitory activity of some of the compounds against other tumor cell lines other than Test Example 2, such as HT1080, MCF-7, T47D, ZR-75, MAD-MB-468, etc. .
  • Test compound 1-133 was determined to have inhibitory effects on different tumor cell lines HT1080, MCF-7, T47D, ZR-75, and MAD-MB-468.

Abstract

具有突变型异柠檬酸脱氢酶抑制活性的化合物、其制备方法及用途，具体的为一种式I所示的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其中，各基团的定义如说明书中所述。所述的化合物对突变型IDH具有较高的抑制活性，因此可以用于治疗与突变型IDH相关的疾病。

Description

具有突变型异柠檬酸脱氢酶抑制活性的化合物、其制备方法及用途 技术领域
本发明属于化学合成领域，具体涉及一种具有突变型IDH抑制活性的化合物、其制备方法和用途。
背景技术
异柠檬酸脱氢酶(IDH)催化异柠檬酸酯氧化性脱羧至2-氧代戊二酸酯(α-酮戊二酸酯)，同时产生二氧化碳和NADPH/NADH。这一过程在细胞的代谢过程中起了重要的作用。根据电子接受剂的不同，这些酶可区分为两种不同的亚类，一种利用NAD(+)而另外一种利用NADP(+)。已经报道的5种异柠檬酸酯脱氢酶中，3种是NAD(+)依赖性异柠檬酸酯脱氢酶，主要存在于线粒体基质；另外两种是NADP(+)依赖性，即异柠檬酸酯脱氢酶1和异柠檬酸酯脱氢酶2。异柠檬酸脱氢酶1主要存在于细胞质里，而异柠檬酸脱氢酶2主要存在于线粒体里。异柠檬酸脱氢酶的突变发生于很多种类型的癌症，比如但不局限于如下，脑胶质瘤，胶质母细胞瘤，副神经细胞瘤，急性白血病，前列腺癌，甲状腺癌，结肠癌，软骨肉瘤，胆管上皮癌，外周T细胞白血病，黑色素瘤等。
异柠檬酸脱氢酶1的突变位点一般位于R100，R132，H133和A134；异柠檬酸脱氢酶2的突变位点一般位于R140和R172。非突变IDH1催化异柠檬酸酯氧化性脱羧成α-酮戊二酸酯，从而在下列正向反应中还原NAD+(NADP+)至NADP(NADPH)：
异柠檬酸酯+NAD+(NADP+)→α-酮戊二酸酯+CO2+NADH(NADPH)。
突变型的异柠檬酸脱氢酶失去了这种正常功能，而具有新的能力，能催化α-酮戊二酸酯NAPH-依赖性还原成R(-)-2-羟基戊二酸酯(2HG)。正常细胞里面2HG的浓度水平非常低。而高浓度2HG的产生会帮助癌症的形成和发展。比如，在有IDH突变的急性白血病人检测到了高浓度2-HG。高浓度的2HG与致癌基因存在很好的关联性。因此，突变的IDH及其新活性的抑制是用于癌症的潜在治疗性疗法。
综上所述，本领域急需开发突变的IDH抑制剂。
发明内容
本发明的目的是提供一种突变型IDH的抑制剂，特别是IDH1、IDH2突变型抑制剂。
本发明的第一方面，提供了一种式I所示的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，
Figure PCTCN2017090909-appb-000001
其中，
W1、W2各自独立地选自N或CRb；
W和W'分别独立地选自CRaRb；
Ra选自H、C1-C6烷基；
Rb选自H、C1-C6烷基、C1-C6卤代烷基、卤素、氰基、苯基、C1-C6烷氧基；
n为1、2、3、4或5；n’为0或1；
R1为取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基-C1-C4烷基、取代或未取代的4-8元杂环基、取代或未取代的4-8元碳环基、取代或未取代的C5-20芳基、取代或未取代的5-10元杂芳基；其中，所述的杂环基或杂芳基包含1-3个选自下组的杂原子：N、O、S或P；
R2为取代或未取代的C5-C20芳基、取代或未取代的5-10元杂芳基、取代或未取代的5-10元芳基并杂环基，其中，所述的杂芳基包含1-3个选自下组的杂原子：N、O或S；所述的芳基并杂环基包含1-3个选自下组的杂原子：N、O或S；
R3为卤素、取代或未取代的C1-C6烷基，C1-C6烷氧基、氰基、羟基、取代或未取代的5-10元芳基；
R4为-(CH2)mR11；
其中，m为0-5的整数；优选为0-3的整数；
R11为
Figure PCTCN2017090909-appb-000002
取代或未取代的5-10元杂芳基、取代或未取代的5-10元芳基、取代或未取代的5-10元杂环基；其中；X选自O、N或S；m为0-5的整数；Rc选自H、取代或未取代的5-10元杂芳基、取代或未取代C1-C6烷基、取代或未取代的5-10元芳基；Rd选自H、取代或未取代C1-C6烷基、取代或未取代的C1-C6烷基羰基；或者Rc与Rd相连形成4-8元饱和或不饱和的杂环基或杂芳基；其中，所述的杂芳基包含1-4个选自如下的杂原子：N、O、S或P；所述的杂环基包含1-4个选自下组的杂原子：N、O、S或P；
上述的任一“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：-D、卤素、-OH、-NO2、-NH2、-N(未取代的C1-C6烷基)2、-CN、未取代或卤代的C1-C8烷基、未取代或卤代的C1-C8烷氧基-C1-C8烷基、未取代或卤代的C3-C8环烷基、未取代或卤代的C3-C8环烷基-C1-C8烷基、未取代或卤代的C1-C8烷氧基、未取代或卤代的C1-C6烷基羰基、未取代或卤代的C1-C6烷氧基羰基、异羟肟酸基、未取代或卤代的5～8元芳基、未取代或卤代的5～8元杂芳基、未取代或卤代的4～8元饱和杂环或碳环；其中，所述的杂芳基包含1-4个选自下组的杂原子：N、O或S，所述的杂环包含1-4个选自下组的杂原子：N、O或S；
在另一优选例中，W为CRaRb，且n优选为1-4的整数。
在另一优选例中，W’为CRaRb，且n’优选为1。
在另一优选例中，R2选自下组：
Figure PCTCN2017090909-appb-000003
其中Rm选自H、D、卤素、C1-C6烷基、C1-C6烷氧基。
在另一优选例中，R4为-(CH2)mR11；m优选为0、1或2。
在另一优选例中，R11选自下组：
Figure PCTCN2017090909-appb-000004
Figure PCTCN2017090909-appb-000005
其中，X为O或N；V1、V2和V3分别选自CRa或N； m为0-4的整数；Ra选自H、C1-C6烷基、卤素、氰基；Rc选自H、取代或未取代的5-10元杂芳基、取代或未取代C1-C6烷基、取代或未取代的5-10元芳基；Rd选自H、取代或未取代C1-C6烷基、取代或未取代的C1-C6烷基羰基；其中，所述的杂芳基包含1-4个选自如下的杂原子：N、O或S；所述的杂环基包含1-4个选自下组的杂原子：N、O或S。
在另一优选例中，R4为-(CH2)mR11；m优选为0或1。
在另一优选例中，R11优选为
Figure PCTCN2017090909-appb-000006
Figure PCTCN2017090909-appb-000007
其中，m为0-4的整数；Rc选自H、取代或未取代的5-10元杂芳基、取代或未取代C1-C6烷基、取代或未取代的5-10元芳基；Rd选自H、取代或未取代C1-C6烷基、取代或未取代的C1-C6烷基羰基；其中，所述的杂芳基包含1-4个选自如下的杂原子：N、O或S；所述的杂环基包含1-4个选自下组的杂原子：N、O或S。
在另一优选例中，Rc选自下组：
Figure PCTCN2017090909-appb-000008
其中，R'或R″各自独立的选自-CN、-OH、异羟肟酸基、C1-C6烷基羰基、-NO2、卤素、取代或卤代C1-C6烷基、C1-C6烷氧基。
在另一优选例中，所述的化合物具有如下式I-1所示的结构：
Figure PCTCN2017090909-appb-000009
其中，各基团的定义如上文中所述。
在另一优选例中，所述的化合物具有如下式I-2所示的结构：
Figure PCTCN2017090909-appb-000010
其中，各基团的定义如上文中所述。
在另一优选例中，所述的化合物选自化合物1-133。
本发明的第二方面，提供了一种制备如本发明第一方面所述的式I化合物的方法，所述方法包括如下步骤1)或2)：
1)化合物1a与化合物
Figure PCTCN2017090909-appb-000011
和
Figure PCTCN2017090909-appb-000012
在惰性溶剂的反应条件下进行偶联，从而形成式I化合物；
Figure PCTCN2017090909-appb-000013
式中，各基团的定义如本发明第二方面中所述；
2)化合物1a与化合物
Figure PCTCN2017090909-appb-000014
和
Figure PCTCN2017090909-appb-000015
在惰性溶剂的反应条件下进行偶联，然后再与
Figure PCTCN2017090909-appb-000016
反应生成式I化合物；
Figure PCTCN2017090909-appb-000017
式中，各基团的定义如本发明第二方面中所述。
在另一优选例中，所述反应在溶剂中进行，且所述溶剂选自下组：水、甲醇、乙醇、异丙醇、乙二醇、N-甲基吡咯烷酮、二甲基亚砜，四氢呋喃、甲苯、二氯甲烷、1，2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氧六环，或其组合物。
本发明的第三方面，提供了一种如本发明第一方面所述的式I化合物的用途，用于：
(a)制备治疗与突变型IDH相关的疾病的药物；
(b)制备突变型IDH抑制剂；
(c)体外非治疗性地抑制IDH突变；
(d)体外非治疗性地抑制肿瘤细胞增殖；和/或
(e)治疗与突变型IDH相关的疾病。
在另一优选例中，所述的突变型IDH相关的疾病选自下组：癌症；优选为白血病、脑胶质瘤，胆管上皮癌，软骨关节肉瘤，纤维肉瘤，肝内胆管癌，直肠癌。
在另一优选例中，所述突变型IDH选自下组：IDH1、IDH2，或其组合。
本发明的第四方面，提供了一种药物组合物，所述的药物组合物包括：
(i)有效量的式I化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药；和
(ii)药学上可接受的载体。
本发明的第五方面，提供了一种抑制IDH突变的方法，所述方法包括步骤：对抑制对象施用抑制有效量的如本发明第一方面所述的式I化合物或其药学上可接受的盐，或对抑制对象施用抑制有效量的如本发明第三方面所述的药物组合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，制备了一类具有式I所示结构的化合物，并发现其具有突变型IDH抑制活性。且所述的化合物在极低浓度(可低至≤100nmol/L)下，即对一系列突变型IDH产生抑制作用，抑制活性相当优异，因而可以用于治疗与突变型IDH相关的疾病如肿瘤。基于上述发现，发明人完成了本发明。
术语
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人 员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4TH ED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH2O-等同于-OCH2-。
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C1-6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。
在本申请中，术语“卤素”是指氟、氯、溴或碘。
“羟基”是指-OH基团。
“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基。
“羰基”是指-C(＝O)-基团。
“硝基”是指-NO2。
“氰基”是指-CN。
“氨基”是指-NH2。
“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳烷基、杂芳烷基取代的氨基，例如，单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基。
“羧基”是指-COOH。
在本申请中，作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中)，术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至12个(优选为1至8个，更优选为1至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、 仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。
在本申请中，作为基团或是其它基团的一部分，术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个(优选为2至10个，更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。
在本申请中，作为基团或是其它基团的一部分，术语“炔基”意指仅由碳原子和氢原子组成、含有至少一个三键和任选的一个或多个双键、具有例如2至14个(优选为2至10个，更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙炔基、丙-1-炔基、丁-1-炔基、戊-1-烯-4-炔基等。
在本申请中，作为基团或是其它基团的一部分，术语“环烷基”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基，其可包括稠合环体系、桥环体系或螺环体系，具有3至15个碳原子，优选具有3至10个碳原子，更优选具有3至8个碳原子，且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明，环烷基中的碳原子可以任选地被氧化。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯基等。
在本申请中，作为基团或是其它基团的一部分，术语“杂环基”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系、桥环体系或螺环体系；其杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中，一个或多个环可以是下文所定义的芳基或杂芳基，条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言，杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团，更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于：吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。
在本申请中，作为基团或是其它基团的一部分，术语“芳基”意指具有6至18个碳原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本发明的目的而言，芳基可以为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4- 苯并噁嗪-3(4H)-酮-7-基等。
在本申请中，术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。
在本申请中，作为基团或是其它基团的一部分，术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明，否则杂芳基可为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化。就本发明的目的而言，杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团，更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、三唑基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]三唑并[4,3-b]哒嗪、[1,2,4]三唑并[4,3-a]吡嗪、[1,2,4]三唑并[4,3-c]嘧啶、[1,2,4]三唑并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。
在本申请中，术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。
在本申请中，“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。
“立体异构体”是指由相同原子组成，通过相同的键键合，但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。
当本发明的化合物中含有烯双键时，除非另有说明，否则本发明的化合物旨在包含E-和Z-几何异构体。
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子，且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in  Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。
在本申请中，术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
“多晶型物”是指本发明的某些化合物在固体状态下由于存在两种或两种以上不同分子排列而产生的不同固体结晶相。本发明的某些化合物可以存在多于一种晶型，本发明旨在包括各种晶型及其混合物。
通常，结晶化作用会产生本发明化合物的溶剂化物。本发明中使用的术语“溶剂化物”是指包含一个或多个本发明化合物分子与一个或多个溶剂分子的聚集体。溶剂可以是水，该情况下的溶剂化物为水合物。或者，溶剂可以是有机溶剂。因此，本发明的化合物可以以水合物存在，包括单水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等，以及相应的溶剂化形式。本发明化合物可形成真实的溶剂化物，但在某些情况下，也可以仅保留不定的水或者水加上部分不定溶剂的混合物。本发明的化合物可以在溶剂中反应或者从溶剂中沉淀析出或结晶出来。本发明化合物的溶剂化物也包含在本发明的范围之内。
本发明还包括上述化合物的前药。在本申请中，术语“前药”表示可在生理学条件下或通过溶剂分解而被转化成本发明的生物活性化合物的化合物。因此，术语“前药”是指本发明的化合物的药学上可接受的代谢前体。当被给予有需要的个体时，前药可以不具有活性，但在体内被转化成本发明的活性化合物。前药通常在体内迅速转化，而产生本发明的母体化合物，例如通过在血液中水解来实现。前药化合物通常在哺乳动物生物体内提供溶解度、组织相容性或缓释的优点。前药包括已知的氨基保护基和羧基保护基。 具体的前药制备方法可参照Saulnier,M.G.,et al.,Bioorg.Med.Chem.Lett.1994,4,1985-1990；Greenwald,R.B.,et al.,J.Med.Chem.2000,43,475。
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中，“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明所述“肿瘤”，“细胞增殖异常相关疾病”等包括但不限于白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。
本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
本文所用的术语“治疗”和其它类似的同义词包括以下含义：
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington’s,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi Synthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
式I化合物
本发明提供了一种式I所示的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，
Figure PCTCN2017090909-appb-000018
在另一优选例中，所述的W、W’、W1、W2、n、n’、R1、R2、R3、R4、m、R11、X、Rc、Rd各自独立地为如下化合物所对应的基团。
Figure PCTCN2017090909-appb-000019
Figure PCTCN2017090909-appb-000020
Figure PCTCN2017090909-appb-000021
Figure PCTCN2017090909-appb-000022
Figure PCTCN2017090909-appb-000023
式I化合物的制备
本发明提供的所述式I化合物，可以通过如下的方法1)或2)从而制备：
1)化合物1a与化合物
Figure PCTCN2017090909-appb-000024
和
Figure PCTCN2017090909-appb-000025
在惰性溶剂的反应条件下进行偶联，从而形成式I化合物；
Figure PCTCN2017090909-appb-000026
式中，各基团的定义如上文中所述；
2)化合物1a与化合物
Figure PCTCN2017090909-appb-000027
和
Figure PCTCN2017090909-appb-000028
在惰性溶剂的反应条件下进行偶联，然后再与
Figure PCTCN2017090909-appb-000029
反应生成式I化合物；
Figure PCTCN2017090909-appb-000030
式中，各基团的定义如上文中所述。
在另一优选例中，所述反应在溶剂中进行，且所述溶剂选自下组：水、甲醇、乙醇、异丙醇、乙二醇、N-甲基吡咯烷酮、二甲基亚砜，四氢呋喃、甲苯、二氯甲烷、1，2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氧六环，或其组合物。
本发明的主要优点包括：
1.提供了一种如式I所示的化合物。
2.提供了一种结构新颖的突变型IDH抑制剂及其制备和应用，所述的抑制剂对突变型IDH具有较高的抑制活性。
3.提供了一类治疗与突变型IDH相关疾病的药物组合物。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
中间体A1：N-(2,3-二氢-1H-茚-1-基)-3-氟苯胺的合成
Figure PCTCN2017090909-appb-000031
在干燥的50ml的单口瓶中依次加入1-茚酮(2g,15mmol)，间氟苯胺(2.2g，19.7mmol)，活化过的4A分子筛(20g)，干燥的1,2-二氯乙烷40ml，在氮气保护下回流36h，TLC监测，生成产物60％-70％，有原料剩余，过滤，收集滤液旋干得产品2.3g。粗品未经纯化直接使用。
使用如上方法，用取代或未取代的(杂)芳环并环烷基酮，和取代或未取代的苯胺、杂环芳香胺反应，溶剂可以替换为甲苯或者二氧六环或者其他惰性溶剂，得到亚胺中间体A2,A3,A4,A5,A6,A8,A9,A10,A16,A19,A20,A21,A22,A26,A28,A29,A31,A33,A34和A35.其中A2,A3,A4,A5,A6,A8,A9,A10,A16,A28,A29,A31,A33,A34,A35未经纯化直接用于下一步反应；A19,A20,A21,A22,A26经柱层析纯化。
所述中间体结构如下：
Figure PCTCN2017090909-appb-000032
Figure PCTCN2017090909-appb-000033
中间体A19:N-(2,3-二氢-1H-茚-1-基)-3氟-4氯苯胺
Figure PCTCN2017090909-appb-000034
1H-NMR(d6-DMSO,400MHz)：δ7.91-7.75(dd,J1＝7.6Hz,J2＝13.6Hz 1H),7.61-7.57(m,1H),7.49-7.32(m,3H),6.74-6.65(dd,J1＝8.4Hz,J2＝24.8Hz 1H),3.16-3.07(m,2H),2.71-2.64-(m,2H).
中间体A20:N-(2,3-二氢-1H-茚-1-基)苯胺
Figure PCTCN2017090909-appb-000035
LCMS:m/z 208.2(M+H)+,RT＝1.5min.
中间体A21:N-(2,3-二氢-1H-茚-1-基)-2,5-二氟苯胺
Figure PCTCN2017090909-appb-000036
LCMS:m/z 244.1(M+H)+,RT＝1.7min.
中间体A22:N-(2,3-二氢-1H-茚-1-基)-3,5-二氟苯胺
Figure PCTCN2017090909-appb-000037
1H-NMR(CDCl3,400MHz)：δ7.88(d,J＝7.6Hz,1H),7.51-7.37(m,3H),6.56-6.43(m,3H),3.09(t,J＝6.4Hz,2H),2.67(t,J＝6.4Hz,2H)。
中间体A26:(N-(2,3-二氢-1H-茚-1-基)-2,5-二氟苯胺
Figure PCTCN2017090909-appb-000038
1H-NMR(CDCl3,400MHz):δ7.93(d,J＝8.0Hz,1H),7.51-7.36(m,3H),7.06-7.03(m,1H),6.76-6.69(m,2H),3.10(t,J＝6.4Hz,2H),2.65(t,J＝6.4Hz,2H)
中间体A11：N-(5-氯-2,3-二氢-1H-茚-1-基)-5-氟-3-吡啶胺
Figure PCTCN2017090909-appb-000039
5-氯-1-茚酮(333mg,2mmol)及3-氨基-5-氟吡啶(222mg,2mmol)于10mL的反应瓶试管中，封管氮气保护下加热到120℃反应。TLC/LCMS检测至产物不再增加时，加入二氯甲烷溶解，加入无水硫酸钠干燥，过滤，旋干得到席夫碱粗品待用。
使用如上方法，用取代或未取代的(杂)芳基并环烷基酮类化合物，和取代或未取代的苯胺、杂环芳香胺反应，得到亚胺中间体A7,A11,A13,A14,A15,A17,A18,A23,A24,A25,A27,A30。
中间体A12：N-(7-氯-2,3-二氢-1H-茚-1-基)-3-氟苯胺
Figure PCTCN2017090909-appb-000041
在干燥的50ml的单口瓶中依次加入7-氯茚酮(2.5g，15mmol)，间氟苯胺(2.2g，19.7mmol)，活化过的4A分子筛(20g)，干燥的1,2-二氯乙烷40ml，滴入四氯化钛(142mg,0.05equiv)催化，在氮气保护下回流，TLC监测至产物不再增多，过滤，滤液旋干得粗产品2.5g直接用于下一步反应。
以上方法，四氯化钛可以替换成其他的路易斯酸(三氟化硼乙醚、三氯化铝等)，溶剂可替换为甲苯，二氧六环。
使用如上方法，用7-氯茚酮和3,5-二氟苯胺反应，得到亚胺中间体A32。
Figure PCTCN2017090909-appb-000042
中间体B1:1,1-二氟-3-环丁基异氰的合成
Figure PCTCN2017090909-appb-000043
步骤一：在干净的250ml封管中，加入B1-1(25g,175mmol)和甲酸乙酯140ml，搅拌状态下加入三乙胺(53g，525mmol)，在油浴110℃下，搅拌过夜，冷却到室温，过滤，滤饼用乙酸乙酯洗涤2-3遍，滤液用饱和食盐水洗涤2遍，旋干，得到化合物2(22g,yield:93％)。
1H-NMR(DMSO 400MHz):δ8.51(s,1H),8.00(s,2H),4.10(s,1H),2.90-2.88(m,2H),2.57-2.55(m,2H)。
步骤二：在干燥的1L的单口瓶中，依次加入化合物B1-2(22g,163mmol)，三苯基磷(47g,179mmol)，四氯化碳(25g,163mmol)，三乙胺(16.5g,163mmol)和500ml的二氯甲烷，在45℃下回流过夜，在冷水浴下旋干，加入500ml乙醚打浆1小时，过滤，用乙醚洗涤，滤液用硅胶拌样，在冷水浴下旋干，通过硅胶柱(乙醚)纯化得目标化合物(11.8g,62％)。
1H-NMR(DMSO 400MHz):δ4.28-4.26(m,1H),3.19-3.08(m,2H),2.97-2.87(m,2H)。
使用如上方法，用不同的胺做成不同的异氰中间体B2,B3,B5,B6,B7。
中间体B2:1,1-二氟-3-环已基异氰
Figure PCTCN2017090909-appb-000044
1H-NMR(CDCl 400MHz):δ3.84(s,1H),1.93-2.17(m,8H)
中间体B3：4-异氰-四氢吡喃
Figure PCTCN2017090909-appb-000045
1H NMR(CDCl3-d1,400MHz)：δ3.94-3.85(m,3H),3.61-3.56(m,2H),1.99-1.98(m,2H),1.86-1.83(m,2H).
中间体B5：4,4-二甲基环己基异氰
Figure PCTCN2017090909-appb-000046
1H-NMR(CDCl3,400MHz):1.82-1.76(m,2H),1.53-1.51(m,1H),1.28-1.24(m,6H),0.92(s,6H).
中间体B6：乙醚浓液未旋干，不分离中间体,直接用于下一步反应。
Figure PCTCN2017090909-appb-000047
中间体B7：乙醚浓液未旋干，不分离中间体，直接用于下一步反应。
Figure PCTCN2017090909-appb-000048
中间体B4:苯基异氰的合成
Figure PCTCN2017090909-appb-000049
在干燥的500mL三口瓶中室温下依次加入苯胺(5.0g,53.69mmol,1.0eq)、四丁基硫酸氢铵(1.82g,5.37mmol,0.1eq)、二氯甲烷(160mL)、氢氧化钠水溶液(50％，80mL)。在0℃下缓慢滴加三氯甲烷(9.61g，80.54mmol，1.5eq)，室温搅拌18小时。反应完毕后，将反应液倒入水(500mL)中，用二氯甲烷(500mL)萃取。有机相用硫酸钠干燥，减压浓缩。通过硅胶柱得到产品苯基异氰(3.0g，黄色油状液体)，产率55％。
1H NMR(CDCl3-d1,400MHz)：δ7.39(m,5H).
中间体C1：(S)-1-(4-氰基吡啶-2-基)吡咯烷-2-羧酸的合成
Figure PCTCN2017090909-appb-000050
步骤一：将化合物L-脯氨酸甲酯盐酸盐(4.98克，30毫摩尔，CAS:2133-40-6)和2-溴-4-氰基吡啶(2.28克，20毫摩尔)溶于尔),Xantphos(5.78克，10毫摩尔)和碳酸铯(19.56克，60毫摩尔)，在1二氧六环(80毫升)中，在室温下加入Pd2(dba)3(1.83克，2毫摩00摄氏度氮气保护下反应12小时。反应完毕后，加入50毫升乙酸乙酯。有机相依次用水(20毫升×1)，饱和食盐水(20毫升×1)洗涤。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。过柱子(石油醚：乙酸乙酯＝20：1，10：1)纯化，得到产物(S)-甲基1-(4-氰基吡啶-2-基)吡咯烷-2-羧酸(1.34克，黄色固体)，产率：29％。LCMS:m/z 232.1(M+H)+；RT＝1.387min。
步骤二：将C1-1(460毫克，2毫摩尔)溶于四氢呋喃/水(15毫升/8毫升)中，在室温下加入氢氧化锂(84毫克，2毫摩尔),在室温下反应4小时。反应完毕后，加入用稀盐酸调节pH至2，加入15毫升乙酸乙酯。有机相依次用水(20毫升×1)，饱和食盐水(20毫升×1)洗涤。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到产物C1：(S)-1-(4-氰基吡啶-2-基)吡咯烷-2-羧酸(310毫克，黄色固体)，产率：78.3％。
LCMS:m/z 218.1(M+H)+；RT＝1.076min.
中间体C2：2-((4-氰基苯基)氨基)乙酸的合成
Figure PCTCN2017090909-appb-000051
步骤一：在干燥的50ml单口瓶中依次加入化合物C2-1(1g，8.5mmol)，醋酸钠(1.4g，17mmol)，溴乙酸乙酯(1.7g，10mmol)和30ml乙醇，回流36小时，旋干溶剂，加入50ml乙酸乙酯，用饱和食盐水洗涤，无水硫酸钠干燥，过滤旋干，用(石油醚：乙酸乙酯＝2:1)过硅胶柱纯化得中间体C2-2(300mg，收率：17.4％)LCMS:m/z 205.2(M+H)+,RT＝1.37min。
步骤二：在干燥的50ml单口瓶中依次加入化合物C2-2(300mg，1.47mmol)，氢氧化钠(118mg，2.94mmol)，水3ml和12ml甲醇，室温搅拌3小时，旋干溶剂，用稀盐酸调节PH约等于5，通过制备分离得白色固体C2(120mg，收率：46.3％)。
LCMS:m/z＝175.2(M-1)-,RT＝1.07min。
中间体C4:2-((2-氟吡啶-3-基)氨基)乙酸
使用与中间体C2相同的方法制备中间体C4.
Figure PCTCN2017090909-appb-000052
1H NMR(CDCl3-d1,400MHz)：δ7.64-7.65(m,1H),7.43-7.44(m,1H),7.30(m,2H),7.24(m,2H),7.14(m,1H),6.89-6.92(m,2H),6.49-6.54(m,1H),5.34-5.45(m,2H),3.93(m,1H),3.49(s,2H),2.66-2.77(m,2H),2.22-2.30(m,5H),1.79-1.86(m,3H).
LCMS:m/z 541.2(M+H)+；RT＝1.678min.
中间体C3：2-(甲基(苯基)氨基)乙酸的合成
Figure PCTCN2017090909-appb-000053
步骤一：在干燥的50ml封管中依次加入化合物C3-1(3g，16.7mmol，CAS23284-84-6)，碘甲烷(7.1g，50mmol)，20ml甲苯，80摄氏度搅拌过夜，冷却，加入30ml水，用乙酸乙酯萃取(50ml*2)，无水硫酸钠干燥，饱和食盐水洗涤，旋干，粗品通过硅胶柱用(石油醚：乙酸乙酯＝20:1)得黄色油状产物2-(甲基(苯基)氨基)乙酸乙酯(C3-2)1.2g.收率：37％。LCMS:m/z 194.3(M-1)R＝1.616。
步骤二：在干燥的25ml单口瓶中依次加入化合物C3-2(1.2g，6.2mmol)氢氧化钠(0.62g，15mmol)和5ml水，15ml甲醇，室温搅拌三小时，旋掉有机溶剂，调节PH约等于4，用乙酸乙酯萃取(50ml*2)，无水硫酸钠干燥，旋干得黄色油状物2-(甲基(苯基)氨基)乙酸(C3)420mg，收率：41％。
LCMS:m/z 166.3(M-1)-,RT＝1.2min.
中间体C5：(S)-2-氧代恶唑烷-4-羧酸的合成
Figure PCTCN2017090909-appb-000054
步骤一：在干燥的500mL单口瓶中室温下依次加入L-丝氨酸(10.0g,95.2mmol,1.0eq)、碳酸氢钠(20g,238.0mmol,2.5eq)和水(30mL)。在0℃下加入氯甲酸苄酯(2.0mL，142.8mmol,1.5eq)，室温搅拌18小时。反应完毕后，将反应液倒入水(200)中，用乙酸乙酯(300mL)萃取杂质。水相用浓盐酸酸化至PH值为1，再用乙酸乙酯(300mL)萃取3次。有机相旋干，剩余物用乙酸乙酯洗涤打浆，过滤，得到产品C5-1：(S)-2-(((苄氧基)羰基)氨基)-3-羟基丙酸(10g，白色固体)，产率45％。LCMS:m/z 238.2(M-H)-；RT＝1.047min
步骤二：在0℃下，100mL单口瓶中室温下依次加入C5-1(2.5g,10.45mmol,1.0eq)、水(10mL)和氢氧化钠(0.84g,20.91mmol,2.0eq)。在室温下搅拌1小时。反应完毕后，将反应液倒入水(20)中，用乙醚(300mL)萃取杂质。水相用浓盐酸酸化至PH值为1，再用乙酸乙酯(300mL)萃取5次。得到产品(S)-2-氧代恶唑烷-4-羧酸(600mg，白色固体)，产率86％。
1H NMR(DMSO-d6,400MHz):δ13.30(br s,1H),8.15(s,1H),4.46-4.51(m,1H),4.28-4.36(m,2H).
中间体D1:2-甲基-1H-咪唑并[4，3-b]吡嗪的合成
Figure PCTCN2017090909-appb-000055
在干燥的50ml单口瓶中依次加入2,3-二氨基哌嗪(200mg，1.82mmol)，乙酸酐(445.4mg，4.36mmol)，在140℃下反应2小时，冷却到室温，旋干乙酸酐，加入热的10N的NaOH溶液1ml，加入2ml乙酸，放冰箱静置过夜，析出固体，过滤，用水洗涤，干燥得棕色色固体产物90mg。
LCMS:m/z 135.2(M+H)+；RT＝0.53min.
中间体D2：2-(2-甲基-1H-咪唑-5-基)嘧啶的合成
Figure PCTCN2017090909-appb-000056
步骤一：在干燥的100ml三口瓶中加入30ml无水四氢呋喃，换气，氮气保护，降温到0℃，缓慢加入2mol/L的LDA(10.5ml，22.7mmol)和三丁基氢化锡(5.64ml，22.7mmol)，在0℃下搅拌15分钟，然后降温至-78℃，滴加2-氯嘧啶(2g，17.5mmol)的四氢呋喃溶液(20ml)，加完缓慢升到室温，搅拌过夜，加入30ml水，用乙酸乙酯萃取(50mlx3)，无水硫酸钠干燥，旋干，粗品通过硅胶柱(PE:EA＝10：1)纯化得到黄色油状液体产物D2-1：2.15g(收率：35％)。
步骤二：在干燥的100ml单口瓶中，加入5-溴-2-甲基-1H-咪唑(CAS:16265-11-5,1g,6.25mmol)，和四氢呋喃20ml，降温到0℃，分批加入NaH(0.375g，9.4mmol)，缓慢升到室温，搅拌1小时，加入SEM-Cl(1.25g，7.5mmol)，室温搅拌过夜，用水淬灭，乙酸乙酯萃取(50mlx3)，饱和食盐水洗涤，无水硫酸钠干燥，旋干，粗品通过硅胶柱(PE:EA＝1:1)纯化得到淡黄色油状产品D2-2:1.4g(收率：78％)。LCMS:m/z 293.1[M+H]+,RT＝1.34min。
步骤三：在干燥的50ml单口瓶中依次加入D2-2(1g,3.43mmol),D2-1(1.18g,4.12mmol)和四三苯基膦钯(300mg),加入干燥的DMF 20ml，换气三次，氮气保护，在120℃下搅拌4小时，用油泵拉干溶剂，加20ml水，用乙酸乙酯萃取，无水硫酸钠干燥，旋干，粗品通过硅胶柱(PE:EA＝1：1)得红色固体D2-3:0.97g(收率：95％)。LCMS:m/z 291.2[M+H]+,RT＝0.980min。
步骤四：在干燥的50ml单口瓶中加入D2-3(500mg，1.72mmol)加入20ml DCM，和10ml三氟乙酸，室温搅拌过夜，旋干溶剂，用饱和碳酸氢钠水溶液洗涤，乙酸乙酯萃取，旋干，粗品通过硅胶柱(PE:EA＝1：1)得红色固体产物D2:160mg(收率58％).
LCMS:m/z 161.2[M+H]+,RT＝0.445min。
中间体D3：2-(2-甲基-1H-咪唑-5-基)吡嗪
使用上述方法，用2-氯吡嗪出发得到2-(2-甲基-1H-咪唑-5-基)吡嗪。
实施例1：化合物1和化合物2
Figure PCTCN2017090909-appb-000057
步骤一：在微波反应管中加入中间体A1，L-焦谷氨酸(260mg,2mmol)，注入2mL无水甲醇溶解后于室温搅拌15分钟，加入中间体B1(240mg,2mmol)，封管后于40℃油浴中反应过夜。加入10mL水后用乙酸乙酯萃取三次(3*10mL),合并乙酸乙酯相用饱和食盐水洗涤数次，用无水硫酸钠干燥后旋干得到反应粗品，使用正相柱色谱(二氯甲烷/甲醇＝95/5)分离得到浅棕色固体即为(2S)-N-(1-(3,3-二氟环丁基甲酰基)-2,3-二氢-1H-茚基)-N-3-氟苯基-5-氧代-吡咯烷-2-甲酰胺(中间体1-1,140mg,yield＝15％),
LCMS:m/z 943.4(2M+H)+,RT＝1.64min.
步骤二：在微波反应管中加入步骤一得到的中间体1-1(140mg，0.3mmol)，碳酸铯(145mg,0.45mmol),Pd2(dba)3(14mg,0.015mmol),Xant-phos(9mg,0.015mmol)以及2-氯-4-氰基吡啶(50mg,0.36mmol)，注入5mL无水1,4-二氧六环，封管后置于70℃下反应3h。过滤，滤液旋干后使用层析柱分离(石油醚/乙酸乙酯＝4/1)分离得到化合物1和化合物2的粗品，后使用高效液相制备液相色谱分别对其进一步纯化得到目标化合物1和2。
化合物1：(S)-1-(4-氰基吡啶-2-基)-N-((S)-1-((3,3-二氟环丁基)甲酰基)-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000058
1H NMR(400MHz,CDCl3):δ8.77(s,1H),8.23-8.18(m,1H),7.53–7.29(m,5H),7.29–7.07(m,2H),6.98–6.78(m,1H),5.55–5.45(m,1H),4.67-4.60(m,1H),4.13-4.03(m,1H),2.96–2.68(m,4H),2.65–2.50(m,2H),2.39–2.18(m,4H),2.10–1.90(m,2H).
LCMS:m/z 574.1(M+H)+,RT＝1.84min.
化合物2：(S)-1-(4-氰基吡啶-2-基)-N-((R)-1-((3,3-二氟环丁基)甲酰基)-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000059
1H NMR(400MHz,CDCl3):δ8.73(d,J＝0.9Hz,1H),8.56-8.51(m,1H),7.33–7.11(m,7H),7.08–6.94(m,2H),5.83–5.71(m,1H),4.72–4.62(m,1H),4.18-4.08(m,1H),2.98-2.84(m,5H),2.65–2.07(m,6H),2.03–1.90(m,1H).
LCMS:m/z 574.1(M+H)+,RT＝1.84min.
实施例2：化合物3和化合物4
采用与实施例1相同的方法，使用亚胺中间体A2，异氰中间体B1和L-焦谷氨酸进行反应得到的产物，再和2-氯-4-氰基吡啶进行反应，纯化得到化合物3和化合物4。
化合物3：(S)-1-(4-氰基吡啶-2-基)-N-((S)-1-((3,3-二氟环丁基)羰基)-2,3-二氢-1H-茚-1-基)-N-(5-氟吡啶-3-基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000060
1H NMR(400MHz,CDCl3):δ8.75(s,1H),8.55-8.25(m,3H),7.81–7.42(m,1H),7.31–6.95(m,5H),5.82(dd,J＝34.3,6.2Hz,1H),4.64–4.47(m,1H),4.25-4.10(m,1H),3.14–2.77(m,6H),2.60–1.91(m,6H).
LCMS:m/z 575.2(M+H)+,RT＝1.74min.
化合物4：(S)-1-(4-氰基吡啶-2-基)-N-((R)-1-((3,3-二氟环丁基)羰基)-2,3-二氢-1H-茚-1-基)-N-(5-氟吡啶-3-基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000061
1H NMR(400MHz,CDCl3):δ8.76(d,J＝7.9Hz,1H),8.65–8.16(m,3H),7.77–7.32(m,3H),7.32–7.07(m,3H),5.60-5.54(m,1H),4.59-4.52(m,1H),4.16-4.05(m,1H),2.97–2.71(m,4H),2.68–2.47(m,2H),2.45–2.14(m,4H),2.12–1.83(m,2H).
LCMS:m/z 575.2(M+H)+,RT＝1.74min.
实施例3：化合物7和化合物8
采用与实施例1相同的方法，使用亚胺中间体A2，异氰中间体B2和L-焦谷氨酸进行反应得到的产物，再和2-氯-4-氰基吡啶进行反应，纯化得到化合物7和化合物8。
化合物7：(S)-1-(4-氰基吡啶-2-基)-N-((S)-1-((4,4-二氟环己烷)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-N-(5-氟吡啶-3-基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000062
1H NMR(400MHz,CDCl3):δ8.79-8.53(m,2H),8.42–8.09(m,2H),7.52–7.06(m,6H),5.46–5.12(m,1H),4.62–4.36(m,1H),3.90-3.75(m,1H),3.17–2.44(m,5H),2.40–2.15(m,3H),2.16–1.75(m,8H).
LCMS:m/z 603.3(M+H)+,RT＝1.79min.
化合物8：(S)-1-(4-氰基吡啶-2-基)-N-((R)-1-((4,4-二氟环己烷)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-N-(5-氟吡啶-3-基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000063
1H NMR(400MHz,CDCl3):δ8.75(s,1H),8.59–8.18(m,2H),7.81–7.69(m,1H),7.45-7.15(m,5H),7.06-6.93(m,1H),5.53-5.42(m,1H),4.67–4.46(m,1H),3.94–3.74 (m,1H),3.11–2.83(m,2H),2.65–2.35(m,2H),2.30–2.13(m,2H),2.10-1.78(m,10H).
LCMS:m/z 603.3(M+H)+,RT＝1.79min.
实施例4：化合物9和化合物10
采用与实施例1相同的方法，使用亚胺中间体A4，环己基异氰和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，纯化得到化合物9和化合物10。
化合物9：(S)-1-(4-氰基吡啶-2-基)-N-((S)-1-(环己基甲酰基)-1，2，3，4-四氢萘-1-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000064
1H NMR(400MHz,CDCl3)δ8.75(s,1H),8.59–8.50(m,1H),7.36–7.30(m,1H),7.25–7.07(m,4H),7.07–7.01(m,1H),7.01–6.89(m,2H),6.89–6.82(m,1H),5.41–5.30(m,1H),4.72(dd,J＝9.2,3.1Hz,1H),3.85–3.63(m,1H),3.08–2.74(m,5H),2.58–2.44(m,1H),2.40–2.09(m,3H),2.03–1.77(m,6H),1.43–1.34(m,1H),1.17–0.98(m,2H),0.98–0.78(m,2H).
LCMS:m/z 580.3[M+H]+,RT＝2.0min.
化合物10：(S)-1-(4-氰基吡啶-2-基)-N-((R)-1-(环己基甲酰基)-1，2，3，4-四氢萘-1-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000065
1H NMR(400MHz,CDCl3)δ8.78(s,1H),8.48–8.39(m,1H),7.72–7.61(m,1H),7.49–7.39(m,1H),7.37–7.30(m,1H),7.14–7.08(m,2H),7.08–6.99(m,2H),6.95–6.89(m,1H),6.88–6.79(m,1H),5.04–4.96(m,1H),4.63–4.54(m,1H),3.71–3.60(m,1H),3.04–2.91(m,1H),2.84–2.50(m,4H),2.44–2.34(m,1H),2.32–2.20(m,1H),2.23–1.95(m,2H),1.56–1.42(m,4H),1.23–1.11(m,2H),1.09–0.79(m,5H).
LCMS:m/z 580.3[M+H]+,RT＝2.01min.
实施例5：化合物12和化合物13
采用实施例1相同的方法，使用亚胺中间体A1，异氰中间体B2和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，纯化得到化合物12和化合物13。
化合物12：(S)-1-(4-氰基吡啶-2-基)-N-((S)-1-((4,4-二氟环己烷)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000066
1H NMR(400MHz,CDCl3):δ8.74(s,1H),8.52(dd,J＝13.0,5.1Hz,1H),7.24–6.92(m,9H),5.44(dd,J＝7.6,4.1Hz,1H),4.70–4.61(m,1H),3.99-3.77(m,1H),3.01–2.78(m,3H),2.73–2.32(m,3H),2.25-2.13(m,1H),2.09–1.66(m,7H),1.45-1.22(m,2H).
LCMS:m/z 602.2(M+H)+,RT＝1.88min.
化合物13：(S)-1-(4-氰基吡啶-2-基)-N-((R)-1-((4,4-二氟环己烷)氨基甲酰基)-2,3- 二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000067
1H NMR(400MHz,CDCl3):δ8.79–8.73(m,1H),8.21-8.16(m,1H),7.50–7.28(m,4H),7.25-7.06(m,4H),6.98–6.82(m,1H),5.26-5.20(m,1H),4.68–4.56(m,1H),3.86-3.76(m,1H),2.95–2.68(m,2H),2.64–2.46(m,2H),2.34–2.19(m,2H),2.07–1.67(m,8H),1.38-1.24(m,2H).
LCMS:m/z 602.2(M+H)+,RT＝1.88min.
实施例6：化合物14和化合物15
采用实施例1相同的方法，使用亚胺中间体A1，环己基异氰和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物14和化合物15。
化合物14：(S)-1-(4-氰基吡啶-2-基)-N-((R)-1-(环己基氨基甲酰基)-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000068
1H NMR(400MHz,CDCl3):δ8.73(s,1H),8.51(dd,J＝11.9,5.0Hz,1H),7.37–7.06(m,6H),7.04–6.88(m,3H),5.42(d,J＝7.8Hz,1H),4.68-4.64(m,1H),3.76-3.64(m,1H),3.05–2.80(m,3H),2.78–2.11(m,4H),2.07–1.58(m,5H),1.43–0.81(m,6H).
LCMS:m/z 566.2(M+H)+,RT＝1.95min.
化合物15：(S)-1-(4-氰基吡啶-2-基)-N-((S)-1-(环己基氨基甲酰基)-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000069
1H NMR(400MHz,CDCl3):δ8.76(s,1H),8.18(dd,J＝8.1,5.0Hz,1H),7.51–7.41(m,3H),7.35–6.86(m,6H),5.24–5.15(m,1H),4.66-4.61(m,1H),3.74–3.59(m,1H),2.98–2.68(m,2H),2.63–2.41(m,2H),2.39–2.17(m,2H),2.09–1.69(m,5H),1.54(s,2H),1.30-1.26(m,1H),1.15-0.66(m,4H).
LCMS:m/z 566.2(M+H)+,RT＝1.95min.
实施例7：化合物19和化合物20
采用实施例1相同的方法，使用亚胺中间体A31，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物19和化合物20。
化合物19：(S)-1-(4-氰基吡啶-2-基)-N-((S)-1-((3,3-二氟环丁基)氨基甲酰基)-4-甲基-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000070
1H NMR(400MHz,CDCl3):δ8.73(s,1H),8.55(dd,J＝11.9,5.0Hz,1H),7.30-7.23(m,1H),7.25–6.94(m,7H),5.74(d,J＝6.1Hz,1H),4.69-4.65(m,J＝9.1,3.4Hz,1H),4.13-4.09(m,1H),2.93–2.77(m,5H),2.58–2.28(m,5H),2.24(d,J＝3.5Hz,3H),2.17-2.11(m,1H),2.00–1.92(m,1H).
LCMS:m/z 588.2(M+H)+,RT＝1.91min.
化合物20：(S)-1-(4-氰基吡啶-2-基)-N-((R)-1-((3,3-二氟环丁基)氨基甲酰基)-4-甲基-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000071
1H NMR(400MHz,CDCl3):δ8.76(s,1H),8.24–8.17(m,1H),7.50–7.43(m,1H),7.42–7.27(m,2H),7.24–7.19(m,1H),7.18–7.10(m,2H),7.03(dd,J＝7.6,4.8Hz,1H),6.93((d,J＝9.1Hz,0.5H),6.81(d,J＝9.1Hz,0.5H),5.53(t,J＝5.6Hz,1H),4.68–4.56(m,1H),4.12-4.08(m,1H),2.93-2.82(m,3H),2.71–2.29(m,7H),2.26(2,3H),2.11–1.90(m,2H).
LCMS:m/z 588.2(M+H)+,RT＝1.91min.
实施例8：化合物21
采用实施例1相同的方法，使用亚胺中间体A22，异氰中间体B2和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基嘧啶进行反应，得到化合物21。
化合物21：(2S)-1-(4-氰基嘧啶-2-基)-N-(1-((4,4-二氟环己基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-N-(3，5-二氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000072
1H NMR(400MHz,CDCl3):δ9.0-8.9(m,1H),7.6(d,1H),7.3–7.4(m,3H),7.2(d,1H),6.8-7.0(m,2H),6.7(dd,1H),5.5-5.3(m,1H),4.6(m,2H),3.7-3.9(m,2H),2.8-3.2(m,4H),2.4–2.7(m,2H),2.3(m,2H),1.7–2.1(m,4H),1.3–1.5(m,2H).
LCMS:m/z 621.0(M+H)+,RT＝1.61min.
实施例9：化合物22
采用实施例1相同的方法，使用亚胺中间体A16，异氰中间体B1和酸中间体C5进行反应后得到的产物，再和2-氯-4-氰基嘧啶进行反应，得到化合物22。
化合物22：(2S)-3-(4-氰基嘧啶-2-基)-N-(1–(3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-N-(3,5-二氟苯基)-2-氧代噁唑烷-4-甲酰胺
Figure PCTCN2017090909-appb-000073
1H NMR(400MHz,CDCl3):δ9.0-8.9(m,1H),7.3–7.6(m,3H),6.9-7.2(m,3H),6.7-6.9(m,2H),5.5-5.7(m,1H),4.8(m,1H),4.4(m,1H),4.1-4.3(m,2H),2.7-3.2(m,4H),2.2–2.6(m,4H).
LCMS:m/z 595.1(M+H)+,RT＝1.45min.
实施例10：化合物23
采用实施例1相同的方法，使用亚胺中间体A6，异氰中间体B2和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物23。
化合物23：(2S)-1-(4-氰基吡啶-2-基)-N-(7-((4,4-二氟环己烷)氨基甲酰基)二环[4.2.0]辛-1(6)，2,4-三烯-7-基)-N-(5-氟吡啶-3-基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000074
1H NMR(400MHz,CDCl3):δ8.76(d,J＝6.0Hz,1H),8.69–8.44(m,3H),8.28-8.02(m,2H),7.40-7.28(m,1H),7.26-7.15(m,3H),5.75-5.50(m,1H),4.90-4.73(m,1H),3.79(s,1H),3.09–2.36(m,4H),2.31–1.19(m,10H).
LCMS:m/z 561.1(M+H)+,RT＝1.72min.
实施例11：化合物27
采用实施例1相同的方法，使用亚胺中间体A1，异氰中间体B3和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物27。
化合物27：(2S)-1-(4-氰基吡啶-2-基)-N-(3-氟苯基)-5-氧代-N-(1-((四氢-2H-吡喃-4-基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)吡咯烷-2-甲酰胺。
Figure PCTCN2017090909-appb-000075
1H NMR(MeOD-d4,400MHz)：δ8.74-8.76(m,1H),8.16-8.54(m,1H),7.41-7.48(m,2H),7.32-7.33(m,2H),6.84-7.21(m,5H),5.24-5.47(m,1H),4.62-4.68(m,1H),3.82-3.95(m,4H),3.39-3.45(m,2H),2.50-2.95(m,5H),2.22-2.1(m,2H),1.99-2.04(m,3H).
LCMS:m/z 568.3(M+H)+,RT＝1.526min.
实施例12：化合物28和化合物29
采用实施例1相同的方法，使用亚胺中间体A7，异氰中间体B2和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物28和化合物29。
化合物28：(S)-1-(4-氰基吡啶-2-基)-N-((S)-1-((4,4-二氟环己基)氨基甲酰基)-6-氟-2,3-二氢-1H-茚-1基)-N-(5-氟吡啶-3-基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000076
1H NMR(400MHz,CDCl3):δ8.75(s,1H),8.56-8.25(m,4H),7.82–7.47(m,2H),7.24-6.76(m,2H),5.49(dd,J＝44.3,7.8Hz,1H),4.59-4.51(m,1H),3.87(s,1H),3.10–2.74(m,4H),2.66–2.38(m,3H),2.26–2.17(m,3H),2.11–1.94(m,6H).
LCMS:m/z 621.2(M+H)+,RT＝1.79min.
化合物29：(S)-1-(4-氰基吡啶-2-基)-N-((R)-1-((4,4-二氟环己基)氨基甲酰基)-6-氟-2,3-二氢-1H-茚-1基)-N-(5-氟吡啶-3-基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000077
1H NMR(400MHz,CDCl3):δ8.80–8.55(m,2H),8.37–7.70(m,2H),7.34–7.01(m,5H),5.20(t,J＝8.5Hz,1H),4.59-4.51(m,1H),3.81(s,1H),2.96–2.14(m,4H),2.11–1.55(m,4H),1.48–1.10(m,8H).
LCMS:m/z 621.2(M+H)+,RT＝1.79min.
实施例13：化合物30
采用实施例1相同的方法，使用亚胺中间体A8，异氰中间体B2和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物30。
化合物30：(2S)-1-(4-氰基吡啶-2-基)-N-(1-(4，4–二氟环己基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-5-氧代-N-(3-甲氧基苯基)吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000078
1H-NMR(CDCl3,400MHz):8.72(s,1H),8.12(s,1H),7.51-7.35(m,3H),7.26-7.11(m,4H),6.95-6.93(m,1H),6.61-6.52(m,1H),5.47-5.43(m,1H),4.70-4.66(m,1H),3.86(s,3H),3.64(s,1H),2.92-2.46(m,4H),2.34-1.67(m,9H),1.41-1.32(m,3H).
LCMS:m/z 614(M+H)+,RT＝1.558min.
实施例14：化合物31
采用实施例1相同的方法，使用亚胺中间体A9，异氰中间体B2和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物31。
化合物31：(2S)-1-(4-氰基吡啶-2-基)-N-(1-(4，4–二氟环己基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-5-氧代-N-(3-甲苯基)吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000079
1H-NMR(CDCl3 400MHz):8.74-8.75(m,1H),8.14-8.71(m,1H),7.31-7.49(m,3H),7.02-7.21(m,5H),6.87(s,1H),5.32-5.55(m,1H),4.63-4.71(m,1H),3.82-3.84(m,1H)2.83-2.89(m,3H)，2.34-2.54(m，4H)，2.20-2.33(m，5H),1.63-1.67(m，4H),1.29-1.34(m,2H)。
LCMS:m/z 598.2(M+H)+,RT＝1.76min.
实施例14：化合物32和化合物33
采用实施例1相同的方法，使用亚胺中间体A2，叔丁基异氰和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物32和化合物33。
化合物32：(S)-N-((S)-1-(叔丁基甲酰基)-2,3-二氢-1H-茚-1-基)-1-(4-氰基吡啶-2-基)-N-(5-氟吡啶-3-基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000080
1H NMR(400MHz,CDCl3)δ8.74(d,J＝7.3Hz,1H),8.59(s,1H),8.54–8.48(m,1H),8.29–8.24(m,1H),7.98–7.89(m,1H),7.30–7.27(m,1H),7.25–7.16(m,2H),7.16–7.07(m,1H),7.06–6.93(m,1H),5.59–5.44(m,1H),4.62–4.53(m,1H),3.17– 2.94(m,1H),2.94–2.79(m,3H),2.62–2.47(m,1H),2.43–2.31(m,1H),2.32–2.18(m,1H),2.04–1.88(m,1H),1.31(s,5H),1.23(s,4H).
LCMS:m/z 541.1[M+H]+,RT＝1.81min.
化合物33：(S)-N-((R)-1-(叔丁基甲酰基)-2,3-二氢-1H-茚-1-基)-1-(4-氰基吡啶-2-基)-N-(5-氟吡啶-3-基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000081
1H NMR(400MHz,CDCl3)δ8.74(d,J＝6.5Hz,1H),8.55–8.51(m,1H),8.31–8.26(m,1H),8.23–8.17(m,1H),7.92–7.85(m,1H),7.50–7.39(m,1H),7.34–7.28(m,1H),7.25–7.17(m,2H),7.13–7.06(m,1H),5.30–5.21(m,1H),4.57–4.48(m,1H),2.95–2.70(m,2H),2.63–2.46(m,2H),2.38–2.19(m,2H),2.08–1.87(m,2H),1.21(s,4H),1.21(s,5H).
LCMS:m/z 541.1[M+H]+,RT＝1.8min.
实施例15：化合物34
采用实施例1相同的方法，使用亚胺中间体A2，异氰中间体B2和L-焦谷氨酸进行反应后得到的产物，再和2-氯嘧啶进行反应，得到化合物34。
化合物34：(2S)-N-(1-(4,4-二氟环己基)甲酰基)-2,3-二氢-1H-茚-1基)-N-(5-氟吡啶-3-基)-5-氧代-1-(嘧啶-2-基)吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000082
1H NMR(400MHz,CDCl3)δ8.74–8.60(m,1H),8.59–8.51(m,2H),8.43–8.25(m,1H),7.86–7.75(m,1H),7.55–7.43(m,1H),7.38–7.28(m,1H),7.25–6.92(m,3H),5.61–5.31(m,1H),4.54–4.43(m,1H),3.93–3.77(m,1H),3.00–2.77(m,2H),2.67–2.49(m,2H),2.47–2.15(m,2H),2.11–1.67(m,8H),1.45–1.23(m,2H).
LCMS:m/z 579.2[M+H]+,RT＝1.61min.
实施例16：化合物35
采用实施例1相同的方法，使用亚胺中间体A2，异氰中间体B2和L-焦谷氨酸进行反应后得到的产物，再和3-氯苯氰进行反应，得到化合物35。
化合物35：(2S)-1-(3-氰基苯基)-N-(1-(N-(4,4-二氟环己基)甲酰基)-2,3-二氢-1H-茚-1基)-N-(5-氟-3-吡啶基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000083
1H NMR(400MHz,CDCl3)δ8.63–8.36(m,1H),8.18–7.93(m,1H),7.80–7.56(m,2H),7.53–7.38(m,2H),7.37–7.27(m,2H),7.23–7.16(m,1H),7.15–7.03(m,1H),7.02–6.94(m,1H),5.51–5.24(m,1H),4.35–4.18(m,1H),4.00–3.63(m,1H),3.04–2.62(m,2H),2.60–2.41(m,1H),2.41–2.15(m,2H),2.13–1.92(m,4H),1.94–1.69(m,4H),1.46–1.20(m,3H).
LCMS:m/z 602.2[M+H]+,RT＝1.74min.
实施例17：化合物36和化合物37
采用实施例1相同的方法，使用亚胺中间体A10，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物36和化合物37。
化合物36：(S)-N-((S)-1-((4,4-二氟环丁基)甲酰基)-2,3-二氢-1H-茚-1-基)-1-(4-氰基吡啶-2-基)-N-(3-氯苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000084
1H-NMR(CDCl3,400MHz):8.74(s,1H),8.54(dd,J＝4.8Hz,J＝24Hz,1H),7.44(d,J＝14Hz,1H),7.25-7.14(m,6H),7.06(d,J＝2.8Hz,1H),5.77(t,J＝5.2Hz,1H),4.66(d,J＝6.8Hz,1H),4.15-4.10(m,1H),2.95-2.86(m,5H),2.58-2.48(m,2H),2.44-2.27(m,3H),2.18-2.12(m,1H),2.10-1.93(m,1H).
LCMS:m/z 590.1(M+H)+,RT＝1.59min.
化合物37：(S)-N-((R)-1-((4,4-二氟环丁基)甲酰基)-2,3-二氢-1H-茚-1-基)-1-(4-氰基吡啶-2-基)-N-(3-氯苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000085
1H-NMR(CDCl3,400MHz):8.77(s,1H),8.21(dd,J＝4.8Hz,J＝23.2Hz,1H),7.52-7.04(m,9H),5.51(s,1H),4.62(d,J＝6.8Hz,1H),4.15-4.10(m,1H),2.89-2.74(m,4H),2.61-2.51(m,2H),2.39-2.14(m,4H),2.07-1.96(m,2H).
LCMS:m/z 590.1(M+H)+,RT＝1.606min.
实施例18：化合物39
采用实施例1相同的方法，使用亚胺中间体A2，异氰中间体B2和L-焦谷氨酸进行反应后得到的产物，再和2-氟吡啶进行反应，得到化合物39。
化合物39：(2S)-N-(1-((4,4-二氟环己基)甲酰基)-2,3-二氢-1H-茚-1-基)-1-(4-氟吡啶-2-基)-N-(5-氟吡啶-3-基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000086
1H NMR(400MHz,CDCl3)δ8.63–8.49(m,1H),8.39–8.18(m,2H),8.05–7.98(m,1H),7.83–7.69(m,1H),7.46–7.37(m,1H),7.36–7.28(m,1H),7.24–7.07(m,1H),7.04–6.90(m,1H),6.83–6.75(m,1H),5.62–5.21(m,1H),4.60–4.47(m,1H),3.98–3.68(m,1H),3.15–2.75(m,2H),2.62–2.49(m,2H),2.47–2.29(m,1H),2.26–2.12(m,1H),2.10–1.68(m,8H),1.39–1.22(m,2H).
LCMS:m/z 596.2[M+H]+.
实施例19：化合物40
采用实施例1相同的方法，使用亚胺中间体A11，异氰中间体B1和L-焦谷氨酸进 行反应后得到的产物，再和2-氯吡啶进行反应，得到化合物40。
化合物40：(2S)-N-(5-氯-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-1-(4-氰基吡啶-2-基)-N-(5-氟吡啶-3-基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000087
1H NMR(400MHz,CDCl3)δ8.76(s,1H),8.64–8.43(m,2H),8.41–8.20(m,2H),7.81–7.52(m,1H),7.42–7.30(m,1H),7.05-7.22(m,2H),5.95–5.42(m,1H),4.69–4.39(m,1H),4.05-4.22(m,1H),3.00–2.74(m,4H),2.66–1.75(m,8H).
LCMS:m/z 609.2[M+H]+,RT＝1.81min.
实施例20：化合物41和化合物42
采用实施例1相同的方法，使用亚胺中间体A2，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-溴-4-氯吡啶进行反应，得到化合物41和化合物42。
化合物41：(S)-1-(4-氯吡啶-2-基)-N-((S)-1((3,3-二氟环丁基)甲酰基)-2,3-二氢-1H-茚-1-基)-1-N-(5-氟吡啶-3-基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000088
1H NMR(500MHz,CDCl3)δ8.60–8.54(m,1H),8.52(s,1H),8.43–8.34(m,1H),8.24(d,J＝5.2Hz,1H),7.79–7.73(m,1H),7.25–7.21(m,2H),7.20–7.14(m,1H),7.11–7.07(m,1H),7.02–6.95(m,1H),5.96–5.85(m,1H),4.67–4.52(m,1H),4.23-4.21(m,1H),3.18–2.83(m,5H),2.67–2.41(m,3H),2.37–2.27(m,1H),2.25–2.14(m,1H),2.10–1.88(m,1H),1.72–1.57(m,1H).
LCMS:m/z 584.1[M+H]+,RT＝1.81min.
化合物42：(S)-1-(4-氯吡啶-2-基)-N-((R)-1((3,3-二氟环丁基)甲酰基)-2,3-二氢-1H-茚-1-基)-1-N-(5-氟吡啶-3-基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000089
1H NMR(500MHz,CDCl3)δ8.65–8.56(m,1H),8.54(s,1H),8.53–8.33(m,1H),7.98(d,J＝5.2Hz,1H),7.76–7.70(m,1H),7.50–7.40(m,1H),7.39–7.33(m,1H),7.34–7.30(m,1H),7.18–7.11(m,1H),7.09–7.02(m,1H),5.69–5.47(m,1H),4.65–4.49(m,1H),4.19–4.05(m,1H),3.02–2.75(m,4H),2.66–2.49(m,2H),2.45–2.14(m,4H),2.10–1.94(m,2H).
LCMS:m/z 584.1[M+H]+,RT＝1.81min.
实施例21：化合物43和化合物44
采用实施例1相同的方法，使用亚胺中间体A12，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯吡啶进行反应，得到化合物43和化合物44。
化合物43：(S)-N-((S)-7-氯-1-((3,3-二氟环丁基)甲酰基)-2,3-二氢-1H-茚-1基)-1-(4- 氰基吡啶-2-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000090
1H NMR(400MHz,CDCl3)δ8.76(s,1H),8.51–8.41(m,1H),7.55–7.46(m,1H),7.34–7.27(m,1H),7.24–7.20(m,1H),7.16–7.11(m,1H),7.08–7.02(m,1H),7.00–6.92(m,1H),6.90–6.84(m,1H),6.83–6.70(m,1H),6.02–5.90(m,1H),4.69(dd,J＝6.3,3.0Hz,1H),4.36–4.20(m,1H),3.41–3.25(m,1H),3.23–3.10(m,1H),3.10–2.99(m,1H),2.99–2.84(m,3H),2.72–2.49(m,3H),2.48–2.17(m,3H),2.10–1.87(m,1H).
LCMS:m/z 608.2[M+H]+,RT＝1.84min.
化合物44：(S)-N-((R)-7-氯-1-((3,3-二氟环丁基)甲酰基)-2,3-二氢-1H-茚-1基)-1-(4-氰基吡啶-2-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000091
1H NMR(400MHz,CDCl3)δ8.72(s,1H),8.57–8.49(m,1H),7.57–7.38(m,1H),7.31–7.26(m,1H),7.25–7.19(m,1H),7.15–7.05(m,3H),7.05–6.98(m,1H),6.96–6.82(m,1H),6.81–6.72(m,1H),4.73–4.62(m,1H),4.04–3.93(m,1H),3.27–3.14(m,1H),3.09–2.94(m,2H),2.91–2.79(m,3H),2.77–2.65(m,1H),2.62–2.48(m,1H),2.40–2.18(m,2H),2.16–2.01(m,1H),1.90–1.74(m,1H).
LCMS:m/z 608.2[M+H]+,RT＝1.84min.
实施例22：化合物46和化合物47
采用实施例1相同的方法，使用亚胺中间体A13，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯吡啶进行反应，得到化合物46和化合物47。
化合物46：(S)-N-((S)-6-氯-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-1-(4-氰基吡啶-2-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000092
1H NMR(400MHz,CDCl3):δ8.73(s,1H),8.53(dd,J＝9.1,5.2Hz,1H),7.38–7.01(m,8H),5.82(d,J＝6.3Hz,1H),4.69-4.63(m,1H),4.15-4.11(m,1H),3.01–2.79(m,5H),2.62–2.25(m,5H),2.20–1.90(m,2H).
LCMS:m/z 608.2(M+H)+,RT＝1.90min.
化合物47：(S)-N-((R)-6-氯-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-1-(4-氰基吡啶-2-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000093
1H NMR(400MHz,CDCl3):δ8.77(s,1H),8.33(dd,J＝5.0,2.5Hz,1H),7.53–7.23(m,5H),7.23–7.11(m,2H),6.92(dd,J＝49.4,8.7Hz,1H),5.41(d,J＝4.0Hz,1H),4.69–4.59(m,1H),4.13–3.99(m,1H),2.80-2.70(m,4H),2.63–2.49(m,2H),2.44–2.16(m,4H),2.07-1.90(m,2H).
LCMS:m/z 608.2(M+H)+,RT＝1.88min.
实施例23：化合物48和化合物49
采用实施例1相同的方法，使用亚胺中间体A14，异氰中间体B1和L-焦谷氨酸进行反应后经纯化得到的产物，再和2-氯吡啶进行反应，得到化合物48和化合物49。
化合物48：(S)-N-((S)-5-氯-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-1-(4-氰基吡啶-2-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000094
1H NMR(400MHz,CDCl3):δ8.73(s,1H),8.53(dd,J＝14.9,5.0Hz,1H),7.38–6.97(m,8H),5.85–5.73(m,1H),4.72–4.59(m,1H),4.14-4.10(m,1H),3.03–2.79(m,5H),2.63–1.86(m,7H).
LCMS:m/z 608.2(M+H)+,RT＝1.90min.
化合物49：(S)-N-((R)-5-氯-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-1-(4-氰基吡啶-2-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000095
1H NMR(400MHz,CDCl3):δ8.76(s,1H),8.23(dd,J＝11.7,5.1Hz,1H),7.52–7.29(m,4H),7.25–7.21(m,1H),7.19–7.05(m,2H),6.91(dd,J＝40.0,8.6Hz,1H),5.46(s,1H),4.63(dd,J＝6.6,2.8Hz,1H),4.09(s,1H),2.96–2.71(m,4H),2.65–2.18(m,6H),2.08–1.92(m,2H).
LCMS:m/z 608.2(M+H)+,RT＝1.90min.
实施例24：化合物50和化合物51
采用实施例1相同的方法，使用亚胺中间体A2，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯吡嗪进行反应，得到化合物50和化合物51。
化合物50：(S)-N-((S)-1-((3,3-二氟环丁基)甲酰基)2,3-二氢-1H-茚-1-基)-N-(5-氟吡啶-3-基)-5-氧代-1-(吡嗪-2-基)吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000096
1H NMR(400MHz,CDCl3)δ9.73(s,1H),8.64–8.57(m,1H),8.34–8.25(m,2H),8.08(s,1H),7.85–7.76(m,1H),7.50–7.42(m,1H),7.30–7.26(m,1H),7.20–7.11(m,1H),7.02–6.95(m,1H),6.00–5.70(m,1H),4.55–4.44(m,1H),4.26–4.04(m,1H),3.03–2.75(m,4H),2.64–2.51(m,2H),2.39–2.18(m,3H),2.16–1.90(m,3H).
LCMS:m/z 551.1[M+H]+,RT＝1.62min.
化合物51：(S)-N-((R)-1-((3,3-二氟环丁基)甲酰基)2,3-二氢-1H-茚-1-基)-N-(5-氟吡啶-3-基)-5-氧代-1-(吡嗪-2-基)吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000097
1H NMR(400MHz,CDCl3)δ9.73(s,1H),8.64–8.57(m,1H),8.45–8.33(m,2H),8.08(s,1H),7.85–7.76(m,1H),7.50–7.42(m,1H),7.41–7.33(m,1H),7.20–7.11(m,1H),7.09–7.02(m,1H),5.65–5.56(m,1H),4.55–4.44(m,1H),4.26–4.04(m,1H),3.07–2.79(m,4H),2.65–2.51(m,3H),2.22–2.18(m,2H),2.16–1.90(m,3H).
LCMS:m/z 551.1[M+H]+,RT＝1.62min.
实施例25：化合物52和化合物53
采用实施例1相同的方法，使用亚胺中间体A1，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-三氟甲基吡啶进行反应，得到化合物52和化合物53
化合物52：(S)-N-((S)-1-(N-(3，3-二氟环丁基)甲酰基)-2,3-二氢-1H-茚-1基)-N-(3-氟苯基)-5-氧代-1-(4-三氟甲基吡啶-2-基)-吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000098
1H NMR(400MHz,CDCl3)δ8.71(s,1H),8.57-8.52(m,1H),7.31–7.27(m,1H),7.25–7.09(m,6H),7.05–6.92(m,2H),5.85–5.77(m,1H),4.74–4.63(m,1H),4.21–3.95(m,1H),2.99–2.79(m,5H),2.68–2.48(m,2H),2.46–2.27(m,3H),2.20–2.09(m,1H),2.02–1.91(m,1H).
LCMS:m/z 617.2[M+H]+,RT＝1.93min.
化合物53：(S)-N-((R)-1-(N-(3，3-二氟环丁基)甲酰基)-2,3-二氢-1H-茚-1基)-N-(3-氟苯基)-5-氧代-1-(4-三氟甲基吡啶-2-基)-吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000099
1H NMR(400MHz,CDCl3)δ8.74(s,1H),8.34–8.10(m,1H),7.51–7.40(m,2H),7.40–7.26(m,3H),7.25–7.20(m,1H),7.17–7.09(m,2H),7.04–6.86(m,1H),5.63–5.42(m,1H),4.73–4.62(m,1H),4.17–3.90(m,1H),2.96–2.82(m,3H),2.81–2.68(m,1H),2.65–2.45(m,2H),2.38–2.17(m,4H),2.11–1.89(m,2H).
LCMS:m/z 617.2[M+H]+,RT＝1.95min.
实施例26：化合物54和化合物55
采用实施例1相同的方法，使用亚胺中间体A1，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-甲氧基吡啶进行反应，得到化合物54和化合物55。
化合物54：(S)-N-((S)-1-((3,3,-二氟环丁基)甲酰基)-2,3-二氢-1H-茚-1-基)-N-(3-氟苯 基)-1-(4-甲氧基吡啶-2-基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000100
1H NMR(400MHz,CDCl3)δ8.25–8.09(m,1H),7.97(s,1H),7.39–7.27(m,1H),7.24–7.08(m,4H),7.07–6.92(m,3H),6.69–6.62(m,1H),6.10–5.90(m,1H),4.74–4.64(m,1H),4.21–4.06(m,1H),3.88(s,3H),2.91–2.80(m,5H),2.62–2.40(m,3H),2.37–2.22(m,2H),2.13–1.97(m,1H),1.96–1.81(m,1H).
LCMS:m/z 579.2[M+H]+,RT＝1.84min.
化合物55：(S)-N-((R)-1-((3,3,-二氟环丁基)甲酰基)-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-1-(4-甲氧基吡啶-2-基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000101
1H NMR(400MHz,CDCl3)δ8.06(d,J＝2.1Hz,1H),7.97–7.87(m,1H),7.46–7.26(m,4H),7.24–7.19(m,1H),7.14–6.96(m,3H),6.67–6.53(m,1H),5.73–5.54(m,1H),4.70–4.60(m,1H),4.15–4.00(m,1H),3.87(s,3H),2.95–2.75(m,4H),2.68–2.58(m,1H),2.56–2.45(m,1H),2.45–2.35(m,1H),2.35–2.23(m,2H),2.20–2.10(m,1H),2.07–1.89(m,2H).
LCMS:m/z 579.2[M+H]+,RT＝1.84min.
实施例27：化合物56和化合物57
采用实施例1相同的方法，使用亚胺中间体A15，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物56和化合物57。
化合物56:(S)-1-(4-氰基吡啶-2-基)-N-((S)-1-((3,3,-二氟环丁基)甲酰基)-4-氯-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000102
1H NMR(400MHz,CDCl3):δ8.73(s,1H),8.62-8.47(m,1H),7.35-7.27(m,2H),7.25-7.17(m,2H),7.17-7.08(m,2H),7.08-6.96(m,2H),5.88-5.69(m,1H),4.74-4.58(m,1H),4.21-4.01(m,1H),3.07-2.77(m,5H),2.65-2.42(m,3H),2.41-2.22(m,2H),2.20-2.04(m,1H),2.00-1.89(m,1H).
LCMS:m/z 609.2[M+H]+；RT＝1.89min.
化合物57:(S)-1-(4-氰基吡啶-2-基)-N-((R)-1-((3,3,-二氟环丁基)甲酰基)-4-氯-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000103
1H NMR(400MHz,CDCl3):δ8.7(d,J＝1.1Hz,1H),8.38-8.08(m,1H),7.53-7.29(m,4H),7.25-7.20(m,1H),7.18-7.12(m,1H),7.11-7.04(m,1H),6.96-6.82(m,1H),5.49(d,J＝6.1Hz,1H),4.62(dd,J＝9.3,3.0Hz,1H),4.18-3.97(m,1H),2.98-2.81(m,3H),2.72-2.59(m,1H),2.61-2.48(m,1H),2.47-2.15(m,4H),2.13-1.92(m,2H).
LCMS:m/z 609.2[M+H]+；RT＝1.89min
实施例28：化合物58和化合物59
采用实施例1相同的方法，使用亚胺中间体A16，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物58和化合物59。
化合物58:(S)-1-(4-氰基吡啶-2-基)-N-((S)-1-((3,3,-二氟环丁基)甲酰基)-2,3-二氢-1H-茚-1-基)-N-(3-氯-5-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000104
1H-NMR(CDCl3 400MHz):δ8.74(m,1H),8.54-8.50(m,1H),7.30(m,1H),7.24-7.13(m,4H),7.10-7.01(m,3H),5.76(m,1H),4.67-4.65(m,1H),4.30-4.12(m,1H),2.95-2.87(m,2H),2.57-2.55(m,2H),2.44-2.37(m,2H),2.18-2.13(m,1H),2.04-2.00(m,1H),1.59-1.27(m,2H),0.98-0.85(m,2H).
LCMS:m/z 608.2[M+H]+,RT＝1.748min.
化合物59:(S)-1-(4-氰基吡啶-2-基)-N-((R)-1-((3,3,-二氟环丁基)甲酰基)-2,3-二氢-1H-茚-1-基)-N-(3-氯-5-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000105
1H-NMR(CDCl3 400MHz):δ8.77(s,1H),8.23-8.18(m,1H),7.48-7.39(m,1H),7.38-7.29(m,3H),7.23-7.10(m,3H),5.49(m,1H),4.65-4.63(m,1H),4.08(s,1H),2.92-2.77(m,2H),2.65-2.54(m,2H),2.31-2.27(m,2H),2.08-1.97(m,2H),1.27-1.25(m,2H),0.98-0.85(m,2H).
LCMS:m/z 608.2[M+H]+,RT＝1.75min.
实施例28：化合物60和化合物61
采用实施例1相同的方法，使用亚胺中间体A1，异氰中间体B4和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物60和化合物61。
化合物60:(S)-1-(4-氰基吡啶-2-基)-N-((S)-1-(苯基氨基甲酰基)-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000106
1H NMR(MeOD-d4,400MHz):δ8.73(s,1H),8.58-8.54(m,1H),7.41-7.29(m,9H),7.08-7.01(m,6H),4.73-4.71(m,1H),2.98-2.88(m,3H),2.61-2.55(m,3H),2.17-1.98(m,2H).
LCMS:m/z 560.2(M+H)+；RT＝1.72min.
化合物61:(S)-1-(4-氰基吡啶-2-基)-N-((R)-1-(苯基氨基甲酰基)-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000107
1H NMR(MeOD-d4,400MHz):δ8.76s,1H),8.22-8.21(m,1H),7.58-7.33(m,6H),7.24-7.01(m,9H),4.68-4.67(m,1H),2.91-2.24(m,2H),2.57-2.01(m,6H).
LCMS:m/z 560.2(M+H)+；RT＝1.72min.
实施例29：化合物62和化合物63
采用实施例1相同的方法，使用亚胺中间体A1，异氰中间体B1和酸中间体C5进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物62和化合物63。
化合物62:(S)-3-(4-氰基吡啶-2-基)-N-((S)-1-(3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)2-氧代噁唑烷-4-甲酰胺
Figure PCTCN2017090909-appb-000108
1H NMR(MeOD-d4,400MHz):δ8.52-8.4(m,2H),7.32-7.01(m,9H),5.77(m,1H),4.83-4.82(m,1H),4.41-4.13(m,3H),2.96-2.29(m,8H).
LCMS:m/z 576.2(M+H)+；RT＝1.66min.
化合物63:(S)-3-(4-氰基吡啶-2-基)-N-((R)-1-(3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-2-氧代噁唑烷-4-甲酰胺
Figure PCTCN2017090909-appb-000109
1H NMR(MeOD-d4,400MHz):δ8.56(s,1H),8.21-8.17(m,1H),7.49-6.83(m,9H),5.52(m,1H),4.83-4.79(m,1H),4.49-4.1(m,3H),2.96-1.98(m,8H).
LCMS:m/z 576.2(M+H)+；RT＝1.66min.
实施例30：化合物64和化合物65
采用实施例1相同的方法，使用亚胺中间体A17，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物64和化合物65。
化合物64:(S)-1-(4-氰基吡啶-2-基)-N-((S)-1-((3,3-二氟环丁基)氨基甲酰基)-6-氟-2,3-二氢-1H-茚-1-基-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000110
1H NMR(400MHz,CDCl3):δ8.73(s,1H),8.53(dd,J＝9.8,5.1Hz,1H),7.35-6.93(m,8H),5.81(d,J＝6.0Hz,1H),4.66(dd,J＝8.6,2.8Hz,1H),4.12(d,J＝7.1Hz,1H), 2.95-2.83(m,5H),259-2.25(m,5H),2.18-1.85(m,2H).
LCMS:m/z 592.2(M+H)+；RT＝1.83min.
化合物65:(S)-1-(4-氰基吡啶-2-基)-N-((R)-1-((3,3-二氟环丁基)氨基甲酰基)-6-氟-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000111
1H NMR(400MHz,CDCl3):δ8.71(s,1H),8.25(dd,J＝7.4,5.2Hz,1H),7.47-7.27(m,2H),7.24-7.21(m,1H),7.19-7.07(m,3H),7.04-6.97(m,1H),6.89(dd,J＝43.0,8.6Hz,1H),5.57(d,J＝5.7Hz,1H),4.67-4.60(m,1H),4.17-3.94(m,1H),2.95-2.62(m,4H),2.59-2.13(m,5H),2.05-1.83(m,3H).
LCMS:m/z 592.2(M+H)+；RT＝1.84min.
实施例31：化合物66
采用实施例1相同的方法，使用亚胺中间体A18，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物66。
化合物66:(2S)-1-(4-氰基吡啶-2-基)-N-(1-((3,3-二氟环丁基)氨基甲酰基)-4-(三氟甲基)-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000112
1H NMR(400MHz,CDCl3):δ8.82-8.67(m,1H),8.57-8.15(m,1H),7.76-7.57(m,1H),7.53-6.79(m,7H),5.94-5.38(m,1H),4.63(dd,J＝9.3,3.1Hz,1H),4.10(s,1H),3.22-2.70(m,4H),2.62-1.81(m,8H).
LCMS:m/z 642.2(M+H)+；RT＝1.92min.
实施例32：化合物67和化合物68
采用实施例1相同的方法，使用亚胺中间体A19，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物67和化合物68。
化合物67:(S)-N-(4-氯-3-氟苯基)-1-(4-氰基吡啶-2-基)-N-((S)-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-5-氧代吡咯-2-甲酰胺
Figure PCTCN2017090909-appb-000113
1H-NMR(DMSO-d6,400MHz):δ8.74(s,1H),8.53-8.48(dd,J 1＝4.8Hz,J 2＝15.2Hz1H),7.37-7.30(m,1H),7.23-7.18(m,6H),7.07(s,1H),5.75(s,1H),4.66-4.64(d,J＝6.8Hz,1H),4.11(s,1H),2.95-2.84(m,5H),2.62-2.52(m,2H),2.43-2.27(m,3H),2.16-2.11(m,1H),2.02-1.94(m,1H).
LCMS:m/z 608.2(M+H)+,RT＝1.75min.
化合物68:(S)-N-(4-氯-3-氟苯基)-1-(4-氰基吡啶-2-基)-N-((R)-1-((3,3-二氟环丁基)氨 基甲酰基)-2,3-二氢-1H-茚-1-基)-5-氧代吡咯-2-甲酰胺
Figure PCTCN2017090909-appb-000114
1H-NMR(DMSO-d6,400MHz)：δ8.77(s,1H),8.20-8.16(dd,J 1＝4.0Hz,J 2＝12.8Hz 1H),7.53-7.47(m,1H),7.42-7.35(m,3H),7.23-7.22(m,2H),7.12(s,1H),6.95(t,1H),5.49(s,1H),4.64-4.62(m,1H),4.08(s,1H),2.88-2.77(m,4H),2.60-2.57(m,2H),2.38-2.24(m,4H),2.03-1.98(m,2H).
LCMS:m/z 608.2(M+H)+；RT＝1.76min.
实施例33：化合物69和化合物70
采用实施例1相同的方法，使用亚胺中间体A20，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物69和化合物70。
化合物69:(S)-1-(4-氰基吡啶-2-基)-N-((S)-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-5-氧代-N-苯基吡咯-2-甲酰胺
Figure PCTCN2017090909-appb-000115
1H-NMR(DMSO-d6,400MHz):δ8.72(s,1H),8.56-8.54(d,J＝4.8Hz,1H),7.41(s,1H),7.30-7.28(m,6H),7.19(s,2H),7.04(s,1H),5.81-5.80(d,J＝5.6Hz,1H),4.68-4.66(d,J＝6.0Hz,1H),4.11(s,1H),2.91-2.83(m,5H),2.55-2.26(m,1H),2.16-2.10(m,1H),1.98-1.88(m,1H).
LCMS:m/z 556.2(M+H)+；RT＝1.64min.
化合物70:(S)-1-(4-氰基吡啶-2-基)-N-((R)-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-5-氧代-N-苯基吡咯-2-甲酰胺
Figure PCTCN2017090909-appb-000116
1H-NMR(DMSO-d6,400MHz):δ8.76(s,1H),8.20-8.21(d,J＝4.0Hz,1H),7.58-7.60(d,J＝6.8Hz,1H),7.47-7.48(d,J＝7.2Hz,2H),7.40(t,1H),7.31-7.33(d,J＝6.4Hz,2H),7.20-7.23(m,2H),7.11(s,2H),5.53-5.54(d,J＝4.8Hz,1H),4.62-4.64(d,J＝8.4Hz,1H),4.09(m,1H),2.82-2.88(m,3H),2.71-2.78(m,1H),2.54-2.55(m,2H),2.27-2.37(m,4H),1.95-2.04(m,2H).
LCMS:m/z 556.2(M+H)+；RT＝1.66min.
实施例34：化合物71和化合物72
采用实施例1相同的方法，使用亚胺中间体A21，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物71和化合物72。
化合物71:(S)-N-(3,4-二氟苯基)-1-(4-氰基吡啶-2-基)-N-((S)-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-5-氧代吡咯-2-甲酰胺
Figure PCTCN2017090909-appb-000117
1H NMR(MeOD-d4,400MHz):δ8.74(s,1H),8.54-8.48(m,1H),7.40-6.97(m,8H),5.79-5.78(m,1H),4.67-4.65(d,J＝8.8Hz,1H),4.1(m,1H),2.9-2.8(m,5H),2.7-2.2(m,6H),1.9(m,1H).
LCMS:m/z 592.2(M+H)+；RT＝1.69min.
化合物72:(S)-N-(3,4-二氟苯基)-1-(4-氰基吡啶-2-基)-N-((R)-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-5-氧代吡咯-2-甲酰胺
Figure PCTCN2017090909-appb-000118
1H NMR(MeOD-d4,400MHz)：δ8.77(s,1H),8.21-8.17(m,1H),7.42-6.96(m,8H),5.52(m,1H),4.64-4.62(m,1H),4.08(m,1H),2.9-2.8(m,4H),2.6-2.5(m,2H),2.5-2.2(m,4H),2.1-1.9(m,2H).
LCMS:m/z 592.2(M+H)+；RT＝1.691min.
实施例35：化合物73和化合物74
采用实施例1相同的方法，使用亚胺中间体A22，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物73和化合物74。
化合物73(S)-1-(4-氰基吡啶-2-基)-N-((S)-1-(3,3-二氟环丁基胺基甲酰)-2,3-二氢-1H-茚-1-基)-N-(3,5-二氟苯基)-5-氧吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000119
1H-NMR(CDCl3,400MHz):δ8.74(s,1H),8.52(d,J＝4.8Hz,1H),7.26-7.20(m,5H),7.07-7.05(m,2H),6.91-6.89(m,1H),6.76-6.72(m,1H),5.77(m,1H),4.67-4.69(m,1H),4.14-4.09(m,1H),2.98-2.85(m,5H),2.61-2.54(m,2H),2.45-2.40(m,3H),2.38-2.30(m,1H).
LCMS:m/z 5921[M+H]+；RT＝1.8min.
化合物74:(S)-1-(4-氰基吡啶-2-基)-N-((R)-1-(3,3-二氟环丁基胺基甲酰)-2,3-二氢-1H-茚-1-基)-N-(3,5-二氟苯基)-5-氧吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000120
1H-NMR(CDCl3,400MHz):δ8.77(s,1H),8.20(d,J＝4.8Hz,1H),7.42-7.21(m,5H)7.13-7.10(m,1H),6.93-6.92(m,1H),6.74-6.72(m,1H),5.49(s,1H),4.67-4.64(m,1H),4.08(s,1H),2.77-2.85(m,4H),2.65-2.54(m,2H),2.38-2.26(m,3H),2.11-1.98(m,2H).
LCMS:m/z 5921[M+H]+；RT＝1.7min.
实施例36：化合物75和化合物76
采用实施例1相同的方法，使用亚胺中间体A23，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物75和化合物76。
化合物75:(S)-1-(4-氰基吡啶-2-基)-N-((S)-1-((3,3,-二氟环丁基)甲酰基)-5-氟-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000121
1H NMR(400MHz,CDCl3)δ8.73(d,J＝1.0Hz,1H),8.52(dd,J＝13.5,5.1Hz,1H),7.35-7.27(m,1H),7.25-7.08(m,4H),7.06-6.97(m,1H),6.92-6.85(m,1H),6.76-6.69(m,1H),5.89-5.77(m,1H),4.70-4.60(m,1H),4.20-4.04(m,1H),3.01-2.77(m,5H),2.69-2.41(m,3H),2.40-2.24(m,2H),2.18-2.08(m,1H),2.03-1.89(m,1H).
LCMS:m/z 592.1[M+H]+；RT＝1.85min.
化合物76:(S)-1-(4-氰基吡啶-2-基)-N-((R)-1-((3,3,-二氟环丁基)甲酰基)-5-氟-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000122
1H NMR(400MHz,CDCl3)δ8.76(s,1H),8.31-8.20(m,1H),7.53-7.31(m,3H),7.25-7.08(m,2H),7.02-6.75(m,3H),5.74-5.44(m,1H),4.79-4.46(m,1H),4.22-3.94(m,1H),3.00-2.67(m,4H),2.66-2.47(m,2H),2.40-2.18(m,4H),2.10-1.94(m,2H).
LCMS:m/z 592.1[M+H]+；RT＝1.86min.
实施例37：化合物77和化合物78
采用实施例1相同的方法，使用亚胺中间体A24，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物77和化合物78。
化合物77:(S)-1-(4-氰基吡啶-2-基)-N-((S)-1-((3,3-二氟环丁基)氨基甲酰基-4-氟-2,3-二氢-1H-茚-1-基-)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000123
1H NMR(400MHz,CDCl3):δ8.73(s,1H),8.54(dd,J＝15.8,4.4Hz,1H),7.35-6.84(m,8H),5.85-5.74(m,1H),4.70-4.61(m,1H),4.11(s,1H),3.06-2.80(m,5H),2.65-1.89(m,7H).
LCMS:m/z 592.2[M+H]+；RT＝1.86min.
化合物78:(S)-1-(4-氰基吡啶-2-基)-N–((R)-1-((3,3-二氟环丁基)氨基甲酰基)-4-氟-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000124
1H NMR(400MHz,CDCl3):δ8.76(s,1H),8.19(dd,J＝17.6,5.1Hz,1H),7.48(dd,J＝14.4,8.1Hz,1H),7.43-7.01(m,6H),6.90(dd,J＝39.4,8.5Hz,1H),5.52(d,J＝6.0Hz,1H),4.62(dd,J＝9.3,2.8Hz,1H),4.10(s,1H),2.95-2.50(m,6H),2.47-2.18(m,4H),2.13-1.90(m,2H).
LCMS:m/z 592.1[M+H]+；RT＝1.87min.
实施例37：化合物79和化合物80
采用实施例1相同的方法，使用亚胺中间体A25，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物79和化合物80。
化合物79:(S)-N-((S)-4-氯-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-1-(4-氰基吡啶-2-基)-N-(5-氟吡啶-3-基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000125
1H NMR(400MHz,CDCl3):δ8.75(s,1H),8.48(dd,J＝30.3,3.8Hz,2H),8.38-8.22(m,1H),7.62(dd,J＝96.1,8.5Hz,1H),7.31-7.24(m,1H),7.21-7.13(m,1H),7.10-6.90(m,2H),5.84(m,1H),4.63-4.49(m,1H),4.22-4.15(m,1H),3.11-2.82(m,5H),2.63-2.45(m,2H),2.26-2.20(m,2H),2.08-1.96(m,2H).
LCMS:m/z 609.1[M+H]+；RT＝1.80min.
化合物80:(S)-N-((R)-4-氯-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-1-(4-氰基吡啶-2-基)-N-(5-氟吡啶-3-基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000126
1H NMR(400MHz,CDCl3):δ8.76(d,J＝8.5Hz,1H),8.64-8.27(m,2H),8.20(dd,J＝10.3,5.0Hz,1H),7.79-7.34(m,2H),7.34-7.20(m,2H),7.10(t,J＝7.9Hz,1H),5.53(m,1H),4.53(t,J＝9.4Hz,1H),4.13-4.09(m,1H),2.96-2.77(m,4H),2.56-2.62(m,2H),2.45-2.19(m,4H),1.94-2.13(m,2H).
LCMS:m/z 609.1[M+H]+；RT＝1.81min.
实施例39：化合物81和化合物82
采用实施例1相同的方法，使用亚胺中间体A26，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物81和化合物82。化合物81:(S)-1-(4-氰基吡啶-2-基)-N-((S)-1-(3,3-二氟环丁基胺基甲酰)-2,3-二氢-1H-茚-1-基)-N-(2,5-二氟苯基)-5-氧吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000127
1H-NMR(CDCl3,400MHz):δ8.72(s,1H),8.48-8.40(m,1H),7.39-7.10(m,5H),6.99-6.94(m,3H),6.68-6.67(m,1H),5.90(s,1H),4.68-4.64(m,1H),4.20-4.19(m,1H),3.05-2.88(m,5H),2.62-2.56(m,1H),2.45-2.39(m,3H),2.38-2.31(m,1H).
LCMS:m/z 592.1[M+H]+；RT＝1.8min.
化合物82:(S)-1-(4-氰基吡啶-2-基)-N-((R)-1-(3,3-二氟环丁基胺基甲酰)-2,3-二氢-1H-茚-1-基)-N-(2,5-二氟苯基)-5-氧吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000128
1H-NMR(CDCl3,400MHz):δ8.75(s,1H),8.32-8.24(m,1H),7.33-6.96(m,9H),5.73(s,1H),4.67-4.63(m,1H),4.11(s,1H),2.89-2.80(m,4H),2.58-2.53(m,2H),2.34-2.29(m,3H).
LCMS:m/z 592.1[M+H]+；RT＝1.82min.
实施例40：化合物83
采用实施例1相同的方法，使用亚胺中间体A27，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物83。
化合物83:(S)-1-(4-氰基吡啶-2-基)-N-((S)-1-((3,3,-二氟环丁基)甲酰基)-7-氟-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000129
1H NMR(400MHz,CDCl3):δ8.75(s,1H),8.44(dd,J＝10.1,5.1Hz,1H),7.39-7.32(m,1H),7.25-7.08(m,2H),7.03-6.93(m,2H),6.92-6.78(m,1H),6.62-6.47(m,1H),6.13-5.98(m,1H),5.45-5.25(m,1H),4.70-4.61(m,1H),4.34-4.22(m,1H),3.14-3.08(m,2H),2.96-2.88(m,3H),2.64-2.51(m,1H),2.39-2.28(m,3H),2.24-2.19(m,1H),2.12-2.00(m,2H).
LCMS:m/z 592.1[M+H]+；RT＝1.83min.
实施例40：化合物84和化合物85
采用实施例1相同的方法，使用亚胺中间体A28，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物84和化合物85。
化合物84:(S)-1-(4-氰基吡啶-2-基)-N-((S)-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-N-(2,3-二氟苯基)-5-氧代吡咯-2-甲酰胺
Figure PCTCN2017090909-appb-000130
1H-NMR(DMSO-d6,400MHz):δ8.74-8.72(d,J＝5.2Hz,1H),8.47-8.43(dd,J 1＝4.8Hz,J 2＝8.8Hz 1H),7.38(s,1H),7.27-6.90(m,7H),6.59-5.89(m,1H),4.69-4.60(m, 1H),4.20(s,1H),3.18-2.87(m,6H),2.77-2.15(m,6H).
LCMS:m/z 592.2[M+H]+；RT＝1.67min.
化合物85:(S)-1-(4-氰基吡啶-2-基)-N-((R)-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-N-(2,3-二氟苯基)-5-氧代吡咯-2-甲酰胺
Figure PCTCN2017090909-appb-000131
1H-NMR(DMSO-d6,400MHz):δ8.75(s,1H),8.35-8.22(dd,J 1＝4.8Hz,J 2＝9.6Hz1H),7.32-7.29(m,2H),7.21(s,3H),7.13-7.03(m,3H),6.01-5.73(m,1H),4.66-4.64(d,J＝8.8Hz,1H),4.11(s,1H),2.93-2.82(m,4H),2.67-2.54(m,2H),2.34-2.02(m,6H).
LCMS:m/z 592.2[M+H]+；RT＝1.67min.
实施例41：化合物88和化合物89
采用实施例1相同的方法，使用亚胺中间体A29，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物88和化合物89。
化合物88:(S)-1-(4-氰基吡啶-2-基)-N-((S)-1-((3,3-二氟环丁基)氨基甲酰基)-4-甲氧基-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧代吡咯-2-甲酰胺
Figure PCTCN2017090909-appb-000132
1H-NMR(DMSO-d6,400MHz):δ8.72(s,1H),8.56-8.51(dd,J1＝4.4Hz,J2＝13.6Hz,1H),7.29(s,1H),7.22-7.12(m,3H),7.05-6.99(dd,J1＝8.0Hz,J2＝16.4Hz,2H),6.85(t,1H),6.71(t,1H),5.75-5.74(d,J＝4.8Hz,1H),4.67-4.65(d,J＝8.8Hz,1H),4.11(s,1H),3.82(s,3H),2.90-2.77(m,5H),2.57-2.28(m,5H),2.15-2.10(m,1H),2.01-1.95(m,1H).
LCMS:m/z 604.2[M+H]+；RT＝1.64min.
化合物89:(S)-1-(4-氰基吡啶-2-基)-N-((R)-1-((3,3-二氟环丁基)氨基甲酰基)-4-甲氧基-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧代吡咯-2-甲酰胺
Figure PCTCN2017090909-appb-000133
1H-NMR(DMSO-d6,400MHz):δ8.76(s,1H),8.22-8.18(dd,J1＝4.4Hz,J2＝12.0Hz,1H),7.47-7.29(m,2H),7.21(t,1H),7.15-7.02(m,3H),6.96-6.83(d,J＝8.4Hz,2H),5.57(s,1H),4.63-4.61(m,1H),4.09(s,1H),3.85(s,3H),2.88-2.82(m,3H),2.66-2.51(m,3H),2.40-2.26(m,4H),2.04-1.97(m,2H).
LCMS:m/z 604.2[M+H]+；RT＝1.65min.
实施例42：化合物90
采用实施例1相同的方法，使用亚胺中间体A22，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基嘧啶进行反应，得到化合物90。
化合物90:(S)-1-(4-腈基嘧啶-2-基)-N-((S)-1-(3,3-二氟环丁基胺基甲酰)-2,3-二氢 -1H-茚-1-基)-N-(3,5-二氟苯基)-5-氧吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000134
1H-NMR(CDCl3,400MHz):δ8.90(s,1H),7.29-6.85(m,7H),6.65-6.63(m,1H),5.73(s,1H),4.52-4.49(m,1H),4.09(s,1H),2.9-2.6(m,5H),2.51-1.98(m,7H).
LCMS:m/z 593.3[M+H]+；RT＝1.3min.
实施例43：化合物91
采用实施例1相同的方法，使用亚胺中间体A22，异氰中间体B1和酸中间体C5进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物91。
化合物91:(S)-3-(4-氰基吡啶-2-基)-N-((S)-1-(3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-N-(3,5-二氟苯基)-2-氧代噁唑烷-4-甲酰胺
Figure PCTCN2017090909-appb-000135
1H NMR(MeOD-d4,400MHz)：δ8.5(s,1H),8.49-8.47(m,1H),6.74-7.22(m,8H),5.75(m,1H),4.85-4.82(m,1H),4.44-4.41(m,1H),4.27-4.15(m,2H),3.00-2.29(m,8H).
LCMS:m/z 594.2[M+H]+；RT＝1.7min.
实施例44：化合物92和化合物93
采用实施例1相同的方法，使用亚胺中间体A30，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物92和化合物93。
化合物92:(S)-N-((S)-4-氯-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-1-(4-氰基吡啶-2-基)-N-(3,5-二氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000136
1H NMR(400MHz,CDCl3):δ8.74(s,1H),8.53(d,J＝5.0Hz,1H),7.28(dd,J＝5.1,1.2Hz,1H),7.24(d,J＝7.9Hz,1H),7.14(d,J＝7.6Hz,1H),7.04(t,J＝7.8Hz,2H),6.93(d,J＝9.1Hz,1H),6.78(t,J＝8.7Hz,1H),5.77(d,J＝6.3Hz,1H),4.67(dd,J＝9.1,3.5Hz,1H),4.14-4.11(m,1H),3.06-2.82(m,5H),2.61-2.53(m,2H),2.51-2.02(m,5H).
LCMS:m/z 626.1[M+H]+；RT＝1.91min.
化合物93:(S)-N-((R)-4-氯-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-1-(4-氰基吡啶-2-基)-N-(3,5-二氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000137
1H NMR(400MHz,CDCl3):δ8.77(s,1H),8.20(d,J＝5.1Hz,1H),7.36(t,J＝7.4Hz,2H),7.23(dt,J＝9.3,4.7Hz,2H),7.09(t,J＝7.9Hz,1H),6.97-6.89(m,1H),6.73(d,J＝8.3 Hz,1H),5.45(d,J＝6.1Hz,1H),4.64(dd,J＝9.3,3.0Hz,1H),4.10-4.09(m,1H),2.97-2.68(m,5H),2.61-2.55(m,1H),2.46-2.19(m,4H),2.11-1.96(m,2H).
LCMS:m/z 626.2[M+H]+；RT＝1.93min.
实施例44：化合物96和化合物97
采用实施例1相同的方法，使用亚胺中间体A1，异氰中间体B6和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物96和化合物97。
化合物96:(S)-1-(4-腈基吡啶-2-基)-N-((S)-1-(环丙基甲基胺基甲酰)-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000138
1H NMR(400MHz,CDCl3):δ8.8(s,1H),8.40(d,J＝5.1Hz,1H),7.3-7.1(m,6H),7.1(m,1H),7.0-6.9(m,2H),5.6(d,J＝6.1Hz,1H),4.6(dd,J＝9.3,3.0Hz,1H),3.2-2.8(m,4H),2.7-2.3(m,4H),2.2(m,1H),1.9(m,1H),1.5(m,1H),0.8(m,1H),0.4(m,2H),0.1(m,2H).
LCMS:m/z 538.6(M+H)+；RT＝1.79min.
化合物97:(S)-1-(4-腈基吡啶-2-基)-N-((R)-1-(环丙基甲基胺基甲酰)-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000139
1H NMR(400MHz,CDCl3):δ8.7(s,1H),8.10(d,J＝5.1Hz,1H),7.4(m,3H),7.4-7.0(m,5H),7.0-6.7(m,1H),5.4(d,J＝6.1Hz,1H),4.6(dd,J＝9.3,3.0Hz,1H),3.2(m,1H)2.9-2.6(m,4H),2.5(m,2H),2.2(m,1H),1.9(m,1H),1.7(m,1H),0.7(m,1H),0.3(m,2H),0.0(m,2H).
LCMS:m/z 538.6[M+H]+；RT＝1.81min.
实施例46：化合物98和化合物99
采用实施例1相同的方法，使用亚胺中间体A1，异氰中间体B5和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物98和化合物99。
化合物98:(S)-1-(4-腈基吡啶-2-基)-N-(3-氟苯基)-N-((S)-1-(4,4-二甲基环已基甲酰基)-2,3-二氢-1H-茚-1-基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000140
1H-NMR(CDCl3,400MHz):δ8.73(s,1H),8.53-8.49(m,1H),7.30-6.91(m,8H),5.43(s,1H),4.65(s,1H),3.64(s,1H),3.50-3.47(m,1H),3.00-2.90(m,3H),2.56-2.48(m,3H),2.47-2.44(m,1H),2.01-1.98(m,1H),1.97-1.95(m,1H),1.75-1.59(m,6H),1.24(s,3H),1.22(s,3H).
LCMS:m/z 594.2[M+H]+；RT＝1.83min.
化合物99:(S)-1-(4-腈基吡啶-2-基)-N-(3-氟苯基)-N-((R)-1-(4,4-二甲基环已基甲酰基)-2,3-二氢-1H-茚-1-基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000141
1H-NMR(CDCl3,400MHz):δ8.76(s,1H),8.20-8.17(m,1H),7.47-6.88(m,8H),5.22(s,1H),4.65-4.63(m,1H),3.64-3.62(m,1H),2.91-2.73(m,2H),2.60-2.55(m,2H),2.34-2.24(m,2H),2.03-1.95(m,2H),1.73-1.70(m,1H),1.20-1.11(m,7H),0.85(s,3H),0.77(s,3H).
LCMS:m/z 594.2[M+H]+；RT＝1.86min.
实施例47：化合物100
采用实施例1相同的方法，使用亚胺中间体A12，异氰中间体B1和酸中间体C5进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物100。
化合物100:(S)-1-(4-氰基吡啶-2-基)-N-((S)-1-((3,3,-二氟环丁基)甲酰基)-7-氯-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-2-氧代恶唑烷-4-甲酰胺
Figure PCTCN2017090909-appb-000142
1H NMR(400MHz,DMSO):δ8.73(dd,J＝23.0,4.9Hz,1H),8.28(s,1H),8.16(d,J＝6.6Hz,1H),7.65-7.56(m,1H),7.55-7.48(m,1H),7.40-7.24(m,2H),7.21-7.02(m,2H),6.89-6.80(m,1H),6.73-6.53(m,1H),4.65-4.53(m,2H),4.40-4.22(m,1H),4.21-4.08(m,1H),3.30-3.20(m,1H),3.17-3.05(m,1H),3.02-2.92(m,1H),2.91-2.77(m,2H),2.74-2.50(m,3H).
LCMS:m/z＝611.1[M+H]+；RT＝1.84min.
实施例48：化合物101
采用实施例1相同的方法，使用亚胺中间体A1，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基嘧啶进行反应，得到化合物101(一对非对映混合物未分开)。
化合物101:(2S)-N-(1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-1-(4-氰基嘧啶啶-2-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000143
1H-NMR(CDCl3,400MHz):δ8.90(s,1H),7.6(d,1H),7.2-7.4(m,7H),7.0(m,1H),5.5-5.7(m,1H),4.6(m,1H),4.2(m,1H),3.2-2.7(m,4H),2.6-2.5(m,2H),2.4-2.3(m,4H),2.1-2.0(m,2H).
LCMS:m/z 575.6[M+H]+；RT＝1.44min.
实施例49：化合物102和化合物103
采用实施例1相同的方法，使用亚胺中间体A12，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基嘧啶进行反应，得到化合物102和化合物103.
化合物102:(S)-1-(4-氰基嘧啶-2-基)-N-((S)-1-((3,3,-二氟环丁基)甲酰基)-7-氯-2,3- 二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000144
1H NMR(400MHz,CDCl3):δ8.94(d,J＝4.3Hz,1H),7.62-7.46(m,1H),7.35-7.28(m,1H),7.25-7.17(m,1H),7.13-7.02(m,2H),6.99-6.90(m,1H),6.90-6.77(m,2H),6.03-5.84(m,1H),4.53(d,J＝8.3Hz,1H),4.40-4.18(m,1H),3.52-3.24(m,2H),3.15-2.78(m,4H),2.71-2.23(m,5H),2.13-1.91(m,1H).
LCMS:m/z＝610.2[M+H]+；RT＝1.81min.
化合物103:(S)-1-(4-氰基嘧啶-2-基)-N-((R)-1-((3,3,-二氟环丁基)甲酰基)-7-氯-2,3-二氢-1H-茚-1-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000145
1H NMR(400MHz,CDCl3):δ8.94(d,J＝4.2Hz,1H),7.72-7.57(m,1H),7.56-7.46(m,1H),7.39-7.28(m,1H),7.19-6.98(m,4H),6.78-6.69(m,1H),4.66-4.55(m,1H),4.01-3.86(m,1H),3.40-3.29(m,1H),3.09-2.96(m,2H),2.93-2.79(m,3H),2.77-2.51(m,2H),2.41-2.05(m,4H),1.88-1.75(m,1H).
LCMS:m/z＝610.2[M+H]+；RT＝1.81min.
实施例50：化合物104
采用实施例1相同的方法，使用亚胺中间体A30，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基嘧啶进行反应，得到化合物104。
化合物104：(S)-N–(S)-4-氯-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-1-(4-氨基嘧啶-2-基)-N-(3,5-二氟苯基)-5-氧代吡咯烷-2-甲酰胺环丁基
Figure PCTCN2017090909-appb-000146
1H NMR(400MHz,CDCl3)δ8.96(dd,J＝16.2,4.7Hz,1H),7.49–7.31(m,2H),7.25–7.15(m,2H),7.13–6.99(m,1H),6.92(dd,J＝34.9,8.9Hz,1H),6.78(t,J＝8.7Hz,1H),5.88-5.47(m,1H),4.62–4.50(m,1H),4.12(s,1H),3.16–3.00(m,1H),2.97–2.54(m,5H),2.50-2.0(m 5H),2.10–1.97(m,1H).
LCMS:m/z 627.0[M+H]+；RT＝1.80min.
实施例51：化合物105和化合物106
采用实施例1相同的方法，使用亚胺中间体A2，异氰中间体B1和酸中间体C5进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物105和化合物106。
化合物105:(S)-3-(4-氰基吡啶-2-基)-N-((S)-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-N-(5-氟吡啶-3-基)-2-氧代恶唑烷-4-甲酰胺
Figure PCTCN2017090909-appb-000147
1H-NMR(CDCl3 400MHz):δ8.51-8.38(m,4H),7.88(m,1H),7.27-7.17(m,2H),7.05-6.96(m,3H),5.99-5.89(m,1H),4.73-4.72(m,1H),4.47(s,1H),4.26-4.12(m,2H),2.99-2.88(m,2H),2.62-2.61(m,3H),2.03(m,1H),1.23-1.27(m,1H),0.85-0.87(m,1H).
LCMS:m/z577.3[M+H]+；RT＝1.70min.
化合物106:(S)-3-(4-氰基吡啶-2-基)-N-((R)-1-((3,3-二氟环丁烷)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-N-(5-氟吡啶-3-基)-2-氧代恶唑烷-4-甲酰胺
Figure PCTCN2017090909-appb-000148
1H-NMR(CDCl3 400MHz):δ8.59-8.53(m,2H),8.29-8.17(m,1H),7.48-7.46(m,1H),7.40-7.36(m,2H),7.30-7.28(m,2H),7.27-7.25(m,1H),7.23-7.15(m,1H),5.62(m,1H),4.47(m,1H),4.31-4.27(m,1H),4.14-4.12(m,1H),4.11(m,1H),2.91-2.90(m,2H),2.53-2.51(m,1H),2.39-2.29(m,2H),2.04(m,1H),1.76m,1H),1.27-1.24(m,1H).
LCMS:m/z 577.3[M+H]+；RT＝1.69min.
实施例52：化合物107和化合物108
采用实施例1相同的方法，使用亚胺中间体A22，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-硝基吡啶进行反应，得到化合物107和化合物108。
化合物107:(S)-1-(4-硝基吡啶-2-基)-N-((S)-1-(3,3-二氟环丁基胺基甲酰)-2,3-二氢-1H-茚-1-基)-N-(3,5-二氟苯基)-5-氧吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000149
1H-NMR(CDCl3,400MHz):δ9.18(s,1H),8.60(d,J＝6.4Hz,1H),7.76(d,J＝3.2Hz,1H),7.26-7.21(m,3H),7.07-7.05(m,2H),6.95-6.92(m,1H),6.77-6.75(m,1H),5.73(s,1H),4.74-4.71(m,1H),4.12(s,1H),2.98-2.85(m,5H),2.44-2.40(m,3H),2.12-2.04(m,1H),2.02-1.98(m,1H).
LCMS:m/z 612.2[M+H]+；RT＝1.60min.
化合物108:(S)-1-(4-硝基吡啶-2-基)-N-((R)-1-(3,3-二氟环丁基胺基甲酰)-2,3-二氢-1H-茚-1-基)-N-(3,5-二氟苯基)-5-氧吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000150
1H-NMR(CDCl3,400MHz):δ9.21(s,1H),8.29(d,J＝5.6Hz,1H),7.74(d,J＝3.6Hz,1H),7.41-7.21(m,4H),7.13-7.10(m,1H),7.09-6.94(m,1H),6.76-6.74(m,1H),5.47(s,1H),4.71-4.68(m,1H),4.08(s,1H),2.93-2.86(m,4H),2.60-2.79(m,2H),2.38-2.10(m,4H),2.06-2.01(m,2H).
LCMS:m/z 612.2[M+H]+；RT＝1.61min.
实施例53：化合物109和化合物110
采用实施例1相同的方法，使用亚胺中间体A33，异氰中间体B1和酸L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基嘧啶进行反应，得到化合物109和化合物110。
化合物109:(S)-1-(4-氰基嘧啶-2-基)-N-((S)-1-(3,3-二氟环丁基胺基甲酰)-7-甲基-2,3-二氢-1H-茚-1-基)-N-(3,5-二氟苯基)-5-氧吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000151
1H-NMR(CDCl3,400MHz):δ8.9(s,1H),7.3(m,2H),7.2-7.1(m,2H),6.7(m,2H),6.4(m,1H),5.7(d,1H),4.4(d,1H),4.3(m,1H),3.4-3.3(m,2H),3.2-2.8(m,4H),2.8-2.3(m,5H),2.10(m,1H),1.9(s,3H).
LCMS:m/z＝607.6[M+H]+；RT＝1.52min.
化合物110:(S)-1-(4-氰基嘧啶-2-基)-N-((R)-1-(3,3-二氟环丁基胺基甲酰)-7-甲基-2,3-二氢-1H-茚-1-基)-N-(3,5-二氟苯基)-5-氧吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000152
1H-NMR(CDCl3,400MHz):δ9.0(s,1H),7.7(d,1H),7.5(d,1H),7.4(m,1H),7.3(m,2H),6.7(m,1H),6.3(d,1H),5.9(d,1H),4.7(m,1H),4.3(m,1H),3.1-2.8(m,6H),2.6-2.5(m,2H),2.4-2.3(m,2H),2.10(m,1H),1.9(s,3H).
LCMS:m/z＝607.6[M+H]+；RT＝1.51min.
实施例54：化合物111和化合物112
采用实施例1相同的方法，使用亚胺中间体A35，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物111和化合物112。
化合物111：(S)-7-((S)-1-(4-氰基吡啶-2-基)-N-(3,5-二氟苯基)-5-氧代吡咯烷-2-甲酰胺)-N-(3,3-二氟环丁基)-6,7-二氢-5H-环戊烷并吡啶-7-甲酰胺
Figure PCTCN2017090909-appb-000153
1H-NMR(CDCl3,400MHz):δ8.7(s,1H),8.45(d,1H),8.3(d,1H),7.5(d,1H),7.22(d,1H),7.2-6.9(m,3H),6.8(m,1H),4.7(m,1H),4.05(m,1H),3.4(m,1H),3.1-2.8(m,6H),2.6-2.5(m,2H),2.4-2.3(m,2H),2.10(m,1H).
LCMS:m/z＝593.0[M+H]+；RT＝1.59min.
化合物112：(R)-7-((S)-1-(4-氰基吡啶-2-基)-N-(3,5-二氟苯基)-5-氧代吡咯烷-2-甲酰胺)-N-(3,3-二氟环丁基)-6,7-二氢-5H-环戊烷并吡啶-7-甲酰胺
Figure PCTCN2017090909-appb-000154
1H-NMR(CDCl3,400MHz):δ8.7(s,1H),8.45(d,1H),8.3(d,1H),7.5(d,1H),7.22(d, 1H),7.2(m,2H),7.0(m,1H),6.8(m,1H),4.7(m,1H),3.9(m,1H),3.35(m,1H),2.9(m,2H),2.85-2.7(m,3H),2.6-2.4(m,2H),2.25(m,1H),2.10(m,3H).
LCMS:m/z＝593.0[M+H]+；RT＝1.58min.
实施例55：化合物113和化合物114
采用实施例1相同的方法，使用亚胺中间体A32，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物113和化合物114。
化合物113：(S)-N-((S)-7-氯-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-(4-氰基吡啶-2-基)-N-(3,5-二氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000155
1H NMR(400MHz,CDCl3)δ8.77(s,1H),8.45(d,J＝5.1Hz,1H),7.39(d,J＝9.1Hz,1H),7.24(s,2H),7.16(t,J＝7.7Hz,1H),6.91(d,J＝7.7Hz,1H),6.72(t,J＝8.6Hz,1H),6.46(d,J＝8.2Hz,1H),5.80(d,J＝6.9Hz,1H),4.66(dd,J＝9.3,2.7Hz,1H),4.34(s,1H),3.39(dd,J＝12.8,5.8Hz,1H),3.20–2.92(m,5H),2.63–2.31(m,5H),2.13–1.97(m,1H).
LCMS:m/z＝626.2[M+H]+；RT＝1.85min.
化合物114：(S)-N-((R)-7-氯-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-(4-氰基吡啶-2-基)-N-(3,5-二氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000156
1H NMR(400MHz,CDCl3)δ8.73(s,1H),8.53(d,J＝5.1Hz,1H),7.40–7.27(m,2H),7.16(d,J＝6.3Hz,1H),7.06(s,1H),6.85(s,1H),6.68-6.57(m,2H),5.34(s,1H),4.80–4.60(m,1H),4.11–3.93(m,1H),3.2-2.58(m,6H),2.40–1.90(m,6H).
LCMS:m/z＝626.2[M+H]+；RT＝1.85min.
实施例56：化合物115
采用实施例1相同的方法，使用亚胺中间体A22，异氰中间体B7和L-焦谷氨酸进行反应后得到的产物，再和2-氯-4-氰基吡啶进行反应，得到化合物115(一对非对映混合物未分开)。
化合物115：(2S)-1-(4-氰基吡啶-2-基)-N-(3,5-二氟苯基)-5-氧代-N-1-((3,3,3-三氟丙基)胺基甲酰)-2,3-二氢-1H-茚-1-基)吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000157
1H NMR(400MHz,CDCl3)δ8.80(s,1H),8.2(d,J＝5.1Hz,1H),7.70(m,1H),7.52(m,1H),7.40-7.32(m,2H),7.26-7.20(m,1H),7.10(m,1H),6.94(m,1H),6.85(m,1H),5.6(m,1H),4.65–4.60(m,1H),4.11–3.93(m,1H),2.90-2.70(m,3H),2.60-2.55(m,3H),2.40–2.2(m,5H),2.10–1.98(m,1H).LCMS:m/z＝598.0[M+H]+；RT＝1.74min.
实施例57：化合物116
采用实施例1相同的方法，使用亚胺中间体A12，异氰中间体B1和L-焦谷氨酸进行反应后得到的产物，再和2-氯嘧啶进行反应，得到化合物116
化合物116：(S)-N-((S)-7-氯-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-(嘧啶-2-基)-N-(3-氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000158
1H NMR(400MHz,CDCl3)δ8.70(s,1H),7.5(t,1H),7.40(m,1H),7.25(m,1H),7.10-6.8(m,5H),6.7(m,1H),6.05(d 1H),4.65–4.60(m,1H),4.35–4.3(m,1H),3.4-3.3(m,1H),3.2-3.1(m,1H),2.9-2.8(m,1H),2.70-2.3(m,8H),2.0(m,1H).
LCMS:m/z＝584.0[M+H]+；RT＝1.67min
实施例58：化合物117和化合物118
采用实施例1相同的方法，使用亚胺中间体A22，异氰中间体B1和D-焦谷氨酸进行反应后得到的产物，再和4-氰基-2-氯吡啶进行反应，得到化合物117和化合物118。
化合物117：(R)-1-(4-氨基吡啶-2-基)-N-((S)-1-((3,3-二氟环丁烷)氨基甲酰基)-2,3-1H-茚-1-基)-N-(3,5-二氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000159
1H NMR(400MHz,CDCl3)δ8.75(s,1H),8.52(d,J＝5.0Hz,1H),7.30–7.18(m,4H),7.09-7.04(m,2H),6.91(d,J＝8.6Hz,1H),6.78-6.72(m,1H),5.75(d,J＝6.2Hz,1H),4.68(dd,J＝9.2,3.4Hz,1H),4.18-4.09(m,1H),3.00–2.82(m,5H),2.62–2.52(m,2H),2.45–2.25(m,3H),2.22-2.14(m,1H),2.09–1.97(m,1H).
LCMS:m/z 592.1(M+H)+,RT＝1.80min.
化合物118：(R)-1-(4-氨基吡啶-2-基)-N-((R)-1-((3,3-二氟环丁烷)氨基甲酰基)-2,3-1H-茚-1-基)-N-(3,5-二氟苯基)-5-氧代吡咯烷-2-甲酰胺
Figure PCTCN2017090909-appb-000160
1H NMR(400MHz,CDCl3)δ8.74(s,1H),8.52(d,J＝5.1Hz,1H),7.31–7.17(m,4H),7.07(s,2H),6.91(d,J＝8.9Hz,1H),6.74(t,J＝8.7Hz,1H),5.75(d,J＝6.1Hz,1H),4.68(dd,J＝9.1,3.3Hz,1H),4.13(s,1H),3.01–2.84(m,6H),2.63-2.52(m,2H),2.43–2.26(m,3H),2.06–1.98(m,1H).
LCMS:m/z 592.1(M+H)+,RT＝1.80min.
实施例59：化合物119和化合物120
采用实施例1相同的方法，使用亚胺中间体A12，异氰中间体B1和酸中间体C5进行反应后得到的产物，再和4-氰基-2-氯嘧啶进行反应，得到化合物119和化合物120。
化合物119：(S)-N-((S)-7-氯-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-3-(4-氰基嘧啶-2-基)-N-(3-氟苯基)-2-氧代恶唑烷-4-甲酰胺
Figure PCTCN2017090909-appb-000161
1H NMR(400MHz,CDCl3)δ8.90(s,1H),7.6(m,1H),7.40(m,2H),7.25-7.10(m,4H),6.9-6.8(m,1H),6.6(m,1H),4.82(m,1H),4.60(m,1H),4.40(m,1H),3.95(m,1H),3.40(m,1H),3.0(m,2H),2.9-2.7(m,3H),2.25(m,1H),1.75(m,1H).
LCMS:m/z＝611.1[M+H]+；RT＝1.74min
化合物120：(S)-N-((R)-7-氯-1-((3,3-二氟环丁基)氨基甲酰基)-2,3-二氢-1H-茚-1-基)-3-(4-氰基嘧啶-2-基)-N-(3-氟苯基)-2-氧代恶唑烷-4-甲酰胺
Figure PCTCN2017090909-appb-000162
1H NMR(400MHz,CDCl3)δ8.90(s,1H),7.6(m,1H),7.40(m,1H),7.25-7.10(m,4H),6.8(m,1H),6.6(m,1H),5.75(m,1H),4.75-4.60(m,2H),4.40-4.20(m,2H),3.65(m,1H),3.40(m,1H),3.1(m,1H),3.0(m,2H),2.60-2.35(m,3H).
LCMS:m/z＝611.1[M+H]+；RT＝1.74min
实施例60：化合物5
Figure PCTCN2017090909-appb-000163
步骤一：称取氯乙酸(190mg,2mmol)于微波反应管，以1mL无水甲醇溶解席夫碱并注入微波管中，搅拌30分钟后加入环己基异腈(220mg,2mmol)，密封微波管于30℃下反应过夜。加入10mL水淬灭反应并用乙酸乙酯萃取(3*15mL)，合并的乙酸乙酯用盐水洗数次后用无水硫酸钠干燥，过滤，滤液旋干后柱层析(洗脱剂二氯甲烷：50:1)分离得到中间体5-1(200mg，白色固体)，产率23.3％.
1H NMR(DMSO-d6,400MHz):δ7.39-7.33(m,1H),7.27-7.22(m,2H),7.12-7.03(m,6H),3.90-3.82(m,2H),3.81-3.49(m,3H),3.07-3.00(m,2H),1.72-1.68(m,4H),1.59-1.54(m,1H),1.31-1.07(m,5H).
LCMS:m/z 451.3[M+Na]+；RT＝2.0min.
步骤二：中间体5-1(100mg,0.23mmol)与100mL反应瓶中，分别加入2-甲基咪唑(19mg,0.23mmoL),三乙胺(46mg,0.46mmol)及5mL的二氯甲烷后在氮气的保护下加热回流反应过夜。反应液用硅藻土过滤，滤液旋干后使用柱层析(洗脱剂二氯甲烷：20:1)分离得到化合物5(80mg,白色固体)，产率73％。化合物5：N-环己基-1-(N-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙酰胺)-2,3-二氢-1H-茚-1-甲酰胺。
1H NMR(600MHz,MeOD):δ7.40-7.35(m,1H),7.30-7.03(m,5H),7.01-6.93(m,1H),6.88(s,2H),6.77(d,J＝1.3Hz,1H),5.50-5.49(m,1H),4.51-4.35(m,2H),3.75-3.61(m,1H),2.86-2.57(m,2H),2.22(s,3H),1.87-1.58(m,6H),1.40-1.28(m,4H),1.27-1.05(m,2H).
LCMS:m/z 475.3(M+H)+；RT＝1.64min.
实施例61：化合物6
采用实施例54相同的方法，使用亚胺中间体A3，环己基异氰和氯乙酸进行反应后 得到的产物，再和2-甲基咪唑进行取代反应，得到化合物6。
化合物6:N-环己基-2-(N-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙酰胺)-2,3-二氢-1H-茚-2-甲酰胺
Figure PCTCN2017090909-appb-000164
1HNMR(400MHz,DMSO):δ7.44-7.37(m,1H),7.30-7.24(m,1H),7.23-7.07(m,6H),7.06-7.00(m,2H),6.84(d,J＝1.1Hz,1H),6.63(d,J＝1.1Hz,1H),4.29(q,J＝17.3Hz,3H),3.62-3.47(m,3H),3.10-3.01(m,2H),2.05(s,3H),1.69-1.44(m,5H),1.30-1.11(m,5H).
LCMS:m/z 475.2(M+H)+；RT＝1.65min.
实施例62：化合物11
采用实施例54相同的方法，使用亚胺中间体A5，环己基异氰和氯乙酸进行反应后得到的产物，再和2-甲基咪唑进行取代反应，得到化合物11。
化合物11:N-环己基-7-(N-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙酰胺)二环[4.2.0]辛-1(6),2,4-三烯-7-甲酰胺
Figure PCTCN2017090909-appb-000165
1HNMR(400MHz,CDCl3):δ7.30-7.16(m,7H),6.99(t,J＝7.3Hz,1H),6.89(d,J＝1.1Hz,1H),6.66(d,J＝1.1Hz,1H),6.47(d,J＝7.4Hz,1H),4.50(s,2H),4.12-3.98(m,1H),3.61-3.50(m,1H),3.34(s,1H),2.12(s,3H),1.75-1.42(m,5H),1.40-0.96(m,5H).
LCMS:m/z 461.2[M+H]+；RT＝1.58min.
实施例63：化合物16
采用实施例54相同的方法，使用亚胺中间体A1，异氰中间体B2和氯乙酸进行反应后得到的产物，再和哌啶进行取代反应，得到化合物16。
化合物16:N-(4,4-二氟环已基)-1-(N-3-氟苯基)-2-(哌啶-1-基)乙酰氨基)-2,3-二氢-1H-茚-1-甲酰胺
Figure PCTCN2017090909-appb-000166
1H-NMR(MeOD 400MHz):δ7.47-7.36(m,1H),7.24-6.93(m,6H),6.81(d,1H)3.88(s,1H),3.76-3.61(m,2H),3.52-3.45(m,2H),3.01-2.79(m,6H),2.02-.199(m,2H),1.88-1.50(m,9H),1.47-1.43(m,4H).
LCMS:m/z 514.2[M+H]+；RT＝1.057min.
实施例64：化合物25
采用实施例54相同的方法，使用亚胺中间体A1，异氰中间体B2和氯乙酸进行反应后得到的产物，再和二甲基苯并咪唑进行取代反应，得到化合物25。
化合物25:N-(4,4-二氟环已基)-1-(N-3-氟苯基)2-(2-甲基-1H-苯并咪唑-1-基)乙酰氨基)-2,3-二氢-1H-茚-1-甲酰胺
Figure PCTCN2017090909-appb-000167
1H-NMR(MeOD 400MHz):δ7.90-7.88(m,1H),7.49-7.42(m,5H),7.35-7.32(m,3H),7.23-7.17(m,2H),6.98-6.93(m,1H),5.40-5.39(m,1H),4.60-4.54(m,2H),3.82(s,1H),2.82-2.73(m,3H),2.71-2.67(m,2H),2.33-2.29(m,2H),1.96-1.72(m,6H),1.39-1.29(m,2H).
LCMS:m/z 561.2[M+H]+；RT＝1.124min.
实施例65：化合物28
采用实施例54相同的方法，使用亚胺中间体A2，异氰中间体B1和氯乙酸进行反应后得到的产物，再和2-甲基咪唑进行取代反应，得到化合物28。
化合物28:N-(4,4-二氟环丁基)-1-(N-(5-吡啶-3-基)-2–(2-甲基咪唑-1-基)乙酰氨基)-2,3-二氢-1H-茚-1基-甲酰胺
Figure PCTCN2017090909-appb-000168
1H-NMR(MeOD 400MHz):δ8.70-8.42(m,1H),8.38-8.04(m,1H),7.42-739(m,3H),7.26-7.16(m,2H),6.95-6.87(m,2H),4.90-4.75(m,2H),4.25(m,1H),3.07-3.05(m,2H),2.93-2.86(m,4H),2.74-2.59(m,1H),2.57(s,3H),2.56-2.50(m,1H).
LCMS:m/z 484.3[M+H]+；RT＝0.937min.
实施例66：化合物45
采用实施例54相同的方法，使用亚胺中间体A1，异氰中间体B1和氯乙酸进行反应后得到的产物，再和中间体D1进行取代反应，得到化合物45。
化合物45：N-(4,4-二氟环已基)-1-(N-3-氟苯基)2-(2-甲基-1H-咪唑并[4，5-b]吡嗪-1-基)乙酰氨基)-2,3-二氢-1H-茚-1-甲酰胺
Figure PCTCN2017090909-appb-000169
1H-NMR(MeOD 400MHz):δ8.45(s,1H),8.34(s,1H),7.45-7.43(m,1H),7.26-7.15(m,2H),7.09-6.96(m,5H),4.92(m,1H),4.81(m,1H),4.10-4.08(m,1H),2.98(m,2H),2.86-2.79(m,4H),2.74(s,3H),2.69-2.46(m,2H).
LCMS:m/z 535.2[M+H]+；RT＝1.44min.
实施例67：化合物86
采用实施例54相同的方法，使用亚胺中间体A1，异氰中间体B2和氯乙酸进行反应后得到的产物，再和中间体D2进行取代反应，得到化合物86。
化合物86:N-(3,3-二氟环丁基)-1-(N-(3-氟苯基)-2-(2-甲基-4-(嘧啶-2-基)-1H-咪唑-1-基)乙酰胺基)-2,3-二氢-1H-茚-1-基甲酰胺
Figure PCTCN2017090909-appb-000170
H-NMR(CDCl3 400MHz):δ8.74(m,1H),7.65(m,1H),7.57-7.45(m,2H),7.38-7.33(m, 3H),7.28(m,1H),7.23-7.19(m,2H),6.89-6.82(m,1H),5.50(m,1H),4.51-4.44(m,2H),3.88-3.87(m,1H),2.81-2.77(m,2H),2.69(s,3H),2.33-2.32(m,1H),1.98-1.73(m,6H),1.44-1.37(m,2H).
LCMS:m/z 589.2[M+H]+；RT＝1.056min.
实施例68：化合物87
采用实施例54相同的方法，使用亚胺中间体A2，异氰中间体B2和氯乙酸进行反应后得到的产物，再和2-甲基咪唑进行取代反应，得到化合物87。
化合物87:N-(4,4-二氟环己基)-1-(N-(5-氟吡啶-3-基)-2-(2-甲基咪唑-1-基)乙酰氨基)-2,3-二氢-1H-茚-1-基甲酰胺
Figure PCTCN2017090909-appb-000171
1H-NMR(CDCl3 400MHz):δ8.56-8.48(m,1H),8.37-8.34(m,1H),7.65-7.63(m,1H),7.40-7.28(m,2H),7.21-7.08(m,3H),7.03-7.00(m,1H),5.80-5.63(m,1H),4.48-4.40(m,2H),3.88-3.84(m,1H),2.92-2.72(m,2H),2.56(s,3H),2.38(s,1H),2.01-1.74(m,7H),1.50-1.41(m,2H).
LCMS:m/z 512.3[M+H]+；RT＝0.944min.
实施例69：化合物18
N-(4,4-二氟环己基)-1-(N-(3-氟苯基)-2-(甲基(苯基)氨基)乙酰氨基)-2,3-二氢-1-茚-1-甲酰胺
Figure PCTCN2017090909-appb-000172
在干燥的25ml单口瓶中依次加入化合物C3(165mg,1mmol),A1(225mg,1mmol),和2ml无水甲醇，室温搅拌4小时后，加入B2(145mg,1mmol)继续搅拌过夜，通过分离制备得到灰色固体产物N-(4,4-二氟环己基)-1-(N-(3-氟苯基)-2-(甲基(苯基)氨基)乙酰氨基)-2,3-二氢-1-茚-1-甲酰胺19mg,收率：3.6％。
1H-NMR(CDCl3 400MHz):δ7.23-7.19(m,1H),7.15-7.05(m,5H),7.03-6.86(m,4H),6.78-6.68(m,3H),3.89-3.78(m,2H),3.06(s,3H),2.94-2.79(m,2H),2.58-2.56(m,1H),2.02-1.59(m,7H),1.48-1.44(m,3H).
LCMS:m/z 536.2[M+H]+；RT＝1.84min.
实施例70：化合物17
采用实施例62相同的方法，使用亚胺中间体A1，异氰中间体B2和酸中间体C3进行反应后得到化合物17。
化合物17:1-(2-((4-氰基苯基)氨基)-N-(3-氟苯基)乙酰氨基)-N-(4,4-二氟环己基)-2,3-二氢-1-茚-1-甲酰胺
Figure PCTCN2017090909-appb-000173
1H-NMR(CDCl3 400MHz):δ7.49-7.45(m,2H),7.25(s,1H),7.12-7.07(m,4H), 6.99-6.93(m,3H),6.75(s,2H),6.56(d,1H),3.41-3.78(m,3H),2.91-3.27(m,4H),2.09-1.82(m,4H),1.69-1.52(m,4H).
LCMS:m/z 569.2[M+2]+；RT＝1.71min.
实施例71：化合物24
采用实施例62相同的方法，使用亚胺中间体A1，异氰中间体B2和4-吡啶乙酸进行反应后得到化合物24。
化合物24:N-(4,4-二氟环己基)-1-(N-(3-氟苯基)-2-(吡啶-4-基)乙酰氨基)-2,3-二氢-1H-茚-1-甲酰胺
Figure PCTCN2017090909-appb-000174
1H-NMR(CDCl3 400MHz):δ8.74(s,2H),7.64-7.58(m,3H),7.36-7.29(m,3H),7.23-7.13(m,3H),6.72-6.68(m,1H),5.46-5.44(m,1H),3.91-3.90(m,1H),3.59-3.55(m,2H),2.76(m,1H),2.61(m,1H),2.28(s,2H),2.00-1.78(m,6H),1.45-1.37(m,2H).
LCMS:m/z 508.2[M+H]+；RT＝1.116min.
实施例72：化合物26
采用实施例62相同的方法，使用亚胺中间体A1，异氰中间体B2和酸中间体C4进行反应后得到化合物26。
化合物26:N-(4,4-二氟环己基)-1–(N-(3-氟苯基)-2-((2-氟吡啶-3-基)氨基)乙酰氨基)-2,3-二氢-1H-茚-1-甲酰胺
Figure PCTCN2017090909-appb-000175
1H NMR(CDCl3-d1,400MHz):δ7.65-7.64(m,1H),7.44-7.43(m,1H),7.30(m,2H),7.24(m,2H),7.14(m,1H),692-6.89(m,2H),6.54-6.49(m,1H),5.45-5.34(m,2H),3.93(m,1H),3.49(s,2H),2.77-2.66(m,2H),2.30-2.22(m,5H),1.86-1.79(m,3H).
LCMS:m/z 541.2[M+H]+；RT＝1.678min.
对照化合物AGI-5198，CAS:1355326-35-0,从Selleck公司购得。
Figure PCTCN2017090909-appb-000176
测试例1本发明化合物在分子水平对IDH1酶活性的影响
试剂、耗材与仪器：
实验中所用酶购自cayman公司。
底物α-KG，NADPH和Diaphorase均购自Sigma；Resazurin购自百灵威；其余所用试剂均购自国药集团化学试剂有限公司。
反应微孔板(6008260)购自PerkinElmer公司。
实验读板用多功能酶标仪为PerkinElmer公司产品，型号：EnVison。
实验用水为国药集团产蒸馏水。
化合物配制：化合物12000g离心5min，加入DMSO配制成10mM储液,涡旋均匀后超声10min待用，-40℃保存。测试时首先用DMSO稀释至10μM的溶液，然后再梯度稀释3×倍至不同的测试溶度。
试验方法：IDH1转换α-KG至2HG的酶活功能用NADPH的消耗来测量。在酶促反应结束后，加入催化过量的diaphorase和reazurin,产生的荧光信号能够反映出剩余的NADPH的量。384孔板中，加入5μL酶体系(150mM NaCl,20mM Tris pH＝7.5,10mM MgCl2,0.05％(w/v)bovine serum albumin、0.012μL酶)，2.5μL化合物，2.5μL的底物α-KG和NADPH的混合液(底物α-KG终浓度1mM，NADPH终浓度4μM)，室温避光孵育60min。检测反应：每孔加入5μL 1×detection buffer稀释的0.01unit diaphroase和5μM resazurin，室温避光孵育10min。读板：用PerkinElmer 
Figure PCTCN2017090909-appb-000177
 at Ex 544Em 590.测板。IC50值采用GraphPad Prism软件计算求得。
结果
表1显示了本发明部分化合物的IC50值。
字母A代表IC50小于100nm；
字母B代表IC50为100nm至1000nm；
字母C代表IC50为1uM至10uM；
字母D代表IC50为10uM以上。
表1 本发明部分化合物的IC50值
Figure PCTCN2017090909-appb-000178
Figure PCTCN2017090909-appb-000179
结果显示，本发明化合物在极低浓度(≤10uM，优选地≤100nm)下，即可有效抑制IDH1的活性。
测试例2：本发明化合物对恶性胶质瘤细胞株U87的增殖抑制测定
本实验采用如下方法测定了本发明化合物对恶性胶质瘤细胞株U87的增殖抑制活性。
测定方法：首先将U87细胞(中国科学院典型培养物保藏委员会细胞库)以适宜细胞浓度2000个/孔接种在96孔培养板上，每孔90μL培养基，在二氧化碳恒温箱内37℃培养过夜后，加入不同浓度的受试化合物作用96小时，并设定溶剂对照组(阴性对照)。96小时后，可用CCK8(Cell Counting Kit-8)方法进行测试化合物对于抑制细胞增殖活性。IC50值可通过一系列不同浓度下，受试化合物对于细胞的抑制数值进行计算。
经测定，受试化合物1-133对于恶性胶质瘤细胞株U87均具有抑制作用。
测试例3：本发明化合物对恶性胶质瘤细胞株U87以外的肿瘤细胞株的增殖抑制活性的测定
采用与测试例2相同的方法，本发明还测定了部分化合物对测试例2以外的其他肿瘤细胞株的增殖抑制活性，比如HT1080、MCF-7,T47D,ZR-75,MAD-MB-468等。
细胞株名称 肿瘤细胞类型
HT1080 人纤维肉瘤细胞
MCF-7 人乳腺癌细胞
T47D 人乳腺癌细胞株
ZR-75 人乳腺癌细胞株
MAD-MB-468 人乳腺癌细胞株
经测定，受试化合物1-133对于不同的肿瘤细胞株HT1080、MCF-7,T47D,ZR-75,MAD-MB-468均具有抑制作用。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种式I所示的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，
    Figure PCTCN2017090909-appb-100001
    其中，
    W1、W2各自独立地选自N或CRb；
    W和W'分别独立地选自CRaRb；
    Ra选自H、C1-C6烷基；
    Rb选自H、C1-C6烷基、C1-C6卤代烷基、卤素、氰基、苯基、C1-C6烷氧基；
    n为1、2、3、4或5；n’为0或1；
    R1为取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基-C1-C4烷基、取代或未取代的4-8元杂环基、取代或未取代的4-8元碳环基、取代或未取代的C5-20芳基、取代或未取代的5-10元杂芳基；其中，所述的杂环基或杂芳基包含1-3个选自下组的杂原子：N、O、S或P；
    R2为取代或未取代的C5-C20芳基、取代或未取代的5-10元杂芳基、取代或未取代的5-10元芳基并杂环基，其中，所述的杂芳基包含1-3个选自下组的杂原子：N、O或S；所述的芳基并杂环基包含1-3个选自下组的杂原子：N、O或S；
    R3为卤素、取代或未取代的C1-C6烷基，C1-C6烷氧基、氰基、羟基、取代或未取代的5-10元芳基；
    R4为-(CH2)mR11；
    其中，m为0、1、2、3、4或5；优选为0、1、2或3；
    R11为
    Figure PCTCN2017090909-appb-100002
    取代或未取代的5-10元杂芳基、取代或未取代的5-10元芳基、取代或未取代的5-10元杂环基；其中；X选自O、N或S；m为0、1、2、3、4或5；Rc选自H、取代或未取代的5-10元杂芳基、取代或未取代C1-C6烷基、取代或未取代的5-10元芳基；Rd选自H、取代或未取代C1-C6烷基、取代或未取代的C1-C6烷基羰基；或者Rc与Rd相连形成4-8元饱和或不饱和的杂环基或杂芳基；其中，所述的杂芳基包含1-4个选自如下的杂原子：N、O、S或P；所述的杂环基包含1-4个选自下组的杂原子：N、O、S或P；
    上述的任一“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：-D、卤素、-OH、-NO2、-NH2、-N(未取代的C1-C6烷基)2、-CN、未取代或卤代的C1-C8烷基、未取代或卤代的C1-C8烷氧基-C1-C8烷基、未取代或卤代的C3-C8环烷基、未取代或卤代的C3-C8环烷基-C1-C8烷基、未取代或卤代的C1-C8烷氧基、未取代或卤代的C1-C6烷基羰基、未取代或卤代的C1-C6烷氧基羰基、异羟肟酸基、未取代或卤代的5～8元芳基、未取代或卤代的5～8元杂芳基、未取代或卤代的4～8元饱和杂环或碳环；其中， 所述的杂芳基包含1-4个选自下组的杂原子：N、O或S，所述的杂环包含1-4个选自下组的杂原子：N、O或S。
  2. 如权利要求1所述的式I化合物，其特征在于，R2选自下组：
    Figure PCTCN2017090909-appb-100003
    Figure PCTCN2017090909-appb-100004
    其中Rm选自H、D、卤素、C1-C6烷基、C1-C6烷氧基。
    在另一优选例中，R4为-(CH2)mR11；m优选为0、1或2。
  3. 如权利要求1所述的式I化合物，其特征在于，R11选自下组：
    Figure PCTCN2017090909-appb-100005
    Figure PCTCN2017090909-appb-100006
    其中，X为O或N；V1、V2和V3分别选自CRa或N；m为0、1、2、3或4；Ra选自H、C1-C6烷基、卤素、氰基；Rc选自H、取代或未取代的5-10元杂芳基、取代或未取代C1-C6烷基、取代或未取代的5-10元芳基；Rd选自H、取代或未取代C1-C6烷基、取代或未取代的C1-C6烷基羰基；其中，所述的杂芳基包含1-4个选自如下的杂原子：N、O或S；所述的杂环基包含1-4个选自下组的杂原子：N、O或S。
  4. 如权利要求1所述的式I化合物，其特征在于，Rc选自下组：
    Figure PCTCN2017090909-appb-100007
    Figure PCTCN2017090909-appb-100008
    其中，R'或R”各自独立的选自-CN、-OH、异羟肟酸基、C1-C6烷基羰基、-NO2、卤素、取代或卤代C1-C6烷基、C1-C6烷氧基。
  5. 如权利要求1所述的式I化合物，其特征在于，所述的化合物选自如下结构：
    Figure PCTCN2017090909-appb-100009
    Figure PCTCN2017090909-appb-100010
    Figure PCTCN2017090909-appb-100011
    Figure PCTCN2017090909-appb-100012
    Figure PCTCN2017090909-appb-100013
  6. 一种制备如权利要求1-5任一所述的式I化合物的方法，其特征在于，所述方法包括如下步骤1)或2)：
    1)化合物1a与化合物
    Figure PCTCN2017090909-appb-100014
    在惰性溶剂的反应条件下进行偶联，从而形成式I化合物；
    Figure PCTCN2017090909-appb-100015
    式中，各基团的定义如权利要求1-5任一中所述；
    2)化合物1a与化合物
    Figure PCTCN2017090909-appb-100016
    在惰性溶剂的反应条件下进行偶联，然后再与
    Figure PCTCN2017090909-appb-100017
    反应生成式I化合物；
    Figure PCTCN2017090909-appb-100018
    式中，各基团的定义如权利要求1-5任一中所述。
  7. 如权利要求1所述的式I化合物的用途，其特征在于，用于：
    (a)制备治疗与突变型IDH相关的疾病的药物；
    (b)制备突变型IDH抑制剂；
    (c)体外非治疗性地抑制IDH突变；
    (d)体外非治疗性地抑制肿瘤细胞增殖；和/或
    (e)治疗与突变型IDH相关的疾病。
  8. 如权利要求7所述的用途，其特征在于，所述突变型IDH选自下组：IDH1、IDH2，或其组合。
  9. 一种药物组合物，其特征在于，所述的药物组合物包括：
    (i)有效量的式I化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药；和
    (ii)药学上可接受的载体。
  10. 一种抑制IDH突变的方法，其特征在于，包括步骤：对抑制对象施用抑制有效量的如权利要求1所述的式I化合物或其药学上可接受的盐，或对抑制对象施用抑制有效量的如权利要求7所述的药物组合物。
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021028643A1 (en) * 2019-08-09 2021-02-18 Artios Pharma Limited Heterocyclic compounds for use in the treatment of cancer
WO2021028670A1 (en) * 2019-08-09 2021-02-18 Artios Pharma Limited Deuterated compounds for use in the treatment of cancer
WO2022262784A1 (zh) * 2021-06-15 2022-12-22 微境生物医药科技(上海)有限公司 Idh突变体抑制剂及其用途
WO2023169573A1 (zh) * 2022-03-11 2023-09-14 武汉人福创新药物研发中心有限公司 一种Polθ抑制剂

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103304572A (zh) * 2012-03-09 2013-09-18 上海医药集团股份有限公司 一类3-氰基喹啉类化合物及其药用组合物和应用
WO2014147586A1 (en) * 2013-03-22 2014-09-25 Novartis Ag 1-(2-(ethylamino)pyrimidin-4-yl)pyrrolidin-2-ones as inhibitors of mutant idh
WO2015010297A1 (en) * 2013-07-25 2015-01-29 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
CN104822373A (zh) * 2012-10-15 2015-08-05 安吉奥斯医药品有限公司 治疗性化合物和组合物
CN105492435A (zh) * 2013-07-11 2016-04-13 安吉奥斯医药品有限公司 作为idh2突变体抑制剂用于癌症治疗的n,6-双(芳基或杂芳基)-1,3,5-三嗪-2,4-二胺化合物
CN105593215A (zh) * 2013-07-11 2016-05-18 安吉奥斯医药品有限公司 用于治疗癌症的作为idh2突变体抑制剂的2,4-或4,6-二氨基嘧啶化合物

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5421374B2 (ja) * 2008-09-03 2014-02-19 ザ・ジョンズ・ホプキンス・ユニバーシティー 悪性神経膠腫におけるイソクエン酸デヒドロゲナーゼ遺伝子および他の遺伝子の遺伝子変化
WO2012173682A2 (en) * 2011-03-29 2012-12-20 The Broad Institute, Inc. Compounds and methods for the treatment of isocitrate dehydrognase related diseases
CA2939021C (en) * 2014-02-11 2022-07-12 Bayer Pharma Aktiengesellschaft Benzimidazol-2-amines as midh1 inhibitors
AR101976A1 (es) * 2014-09-19 2017-01-25 Forma Therapeutics Inc Derivados de piridin-2(1h)-on quinolinona como inhibidores de isocitrato deshidrogenasa mutante
US10532047B2 (en) * 2018-05-16 2020-01-14 Forma Therapeutics, Inc. Solid forms of ((S)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile
CN111825674A (zh) * 2019-04-22 2020-10-27 上海仕谱生物科技有限公司 嘧啶并五元杂环类化合物及其作为突变型idh2抑制剂的用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103304572A (zh) * 2012-03-09 2013-09-18 上海医药集团股份有限公司 一类3-氰基喹啉类化合物及其药用组合物和应用
CN104822373A (zh) * 2012-10-15 2015-08-05 安吉奥斯医药品有限公司 治疗性化合物和组合物
WO2014147586A1 (en) * 2013-03-22 2014-09-25 Novartis Ag 1-(2-(ethylamino)pyrimidin-4-yl)pyrrolidin-2-ones as inhibitors of mutant idh
CN105492435A (zh) * 2013-07-11 2016-04-13 安吉奥斯医药品有限公司 作为idh2突变体抑制剂用于癌症治疗的n,6-双(芳基或杂芳基)-1,3,5-三嗪-2,4-二胺化合物
CN105593215A (zh) * 2013-07-11 2016-05-18 安吉奥斯医药品有限公司 用于治疗癌症的作为idh2突变体抑制剂的2,4-或4,6-二氨基嘧啶化合物
WO2015010297A1 (en) * 2013-07-25 2015-01-29 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021028643A1 (en) * 2019-08-09 2021-02-18 Artios Pharma Limited Heterocyclic compounds for use in the treatment of cancer
WO2021028670A1 (en) * 2019-08-09 2021-02-18 Artios Pharma Limited Deuterated compounds for use in the treatment of cancer
WO2022262784A1 (zh) * 2021-06-15 2022-12-22 微境生物医药科技(上海)有限公司 Idh突变体抑制剂及其用途
WO2023169573A1 (zh) * 2022-03-11 2023-09-14 武汉人福创新药物研发中心有限公司 一种Polθ抑制剂

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