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WO2017162133A1 - 一种具有突变型idh抑制活性的化合物、其制备方法及用途 - Google Patents

一种具有突变型idh抑制活性的化合物、其制备方法及用途 Download PDF

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Publication number
WO2017162133A1
WO2017162133A1 PCT/CN2017/077467 CN2017077467W WO2017162133A1 WO 2017162133 A1 WO2017162133 A1 WO 2017162133A1 CN 2017077467 W CN2017077467 W CN 2017077467W WO 2017162133 A1 WO2017162133 A1 WO 2017162133A1
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Prior art keywords
substituted
unsubstituted
compound
group
mmol
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PCT/CN2017/077467
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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
刘斐斐
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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Application filed by 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 filed Critical 上海海和药物研究开发有限公司
Priority to MX2018011592A priority Critical patent/MX380758B/es
Priority to CA3018602A priority patent/CA3018602C/en
Priority to AU2017239295A priority patent/AU2017239295B2/en
Priority to JP2019500718A priority patent/JP6718553B2/ja
Priority to KR1020187030355A priority patent/KR102245434B1/ko
Priority to ES17769410T priority patent/ES2870910T3/es
Priority to EA201892098A priority patent/EA037974B1/ru
Priority to EP17769410.6A priority patent/EP3434674B1/en
Priority to US16/087,556 priority patent/US10682352B2/en
Publication of WO2017162133A1 publication Critical patent/WO2017162133A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention belongs to the field of chemical synthesis, and in particular, the present invention relates to a compound having a mutant IDH inhibitory activity, a preparation method 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 divided into two distinct subclasses, one using NAD(+) and the other utilizing 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 a wide variety of cancer types including, but not limited to, glioma, glioblastoma, paraneoblastoma, acute leukemia, prostate cancer, thyroid cancer, colon cancer, cartilage Sarcoma, cholangiocarcinoma, peripheral T cell leukemia, melanoma, etc.
  • glioma glioblastoma, paraneoblastoma
  • acute leukemia prostate cancer
  • thyroid cancer colon cancer
  • cartilage Sarcoma cholangiocarcinoma
  • peripheral T cell leukemia melanoma
  • etc. see L. Deng, et al., Trends Mol. Med., 2010, 16, 387; T. shibata et al., Am. J. Pathol., 2011, 178(3), 1395; Gaal et al., J. Clin. Endocrinol. Metab. 2010; Hayden et al., Cell cycle, 2009
  • 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 the above normal function, it catalyzes 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 contributes to the formation and development of cancer (Dang, L et al, Nature 2009, 462: 739-44).
  • a high concentration of 2-HG was detected in an acute leukemia with an IDH mutation. (S. Gross et al., J. Exp. Med., 2010, 207(2), 339).
  • High concentrations of 2HG are highly correlated with oncogenes. Therefore, there is an urgent need in the art to develop mutant IDH inhibitors.
  • R 3 and R 4 are each independently selected from: H, D, substituted or unsubstituted C 1-4 alkyl;
  • R 3 and R 4 together with the C atom attached thereto form a substituted or unsubstituted C 3-6 cycloalkyl group, or R 3 and R 4 together with the C atom attached thereto form a substituted or unsubstituted C 3 -6 epoxyalkyl;
  • R 5 and R 6 are each independently selected from: H, a substituted or unsubstituted C 1-4 alkyl group, a substituted or unsubstituted C 6-10 aryl group, a substituted or unsubstituted C 3-6 cycloalkyl group;
  • R 5 and R 6 together with the C atom attached thereto form a substituted or unsubstituted C 3-6 cycloalkyl group
  • R 7 , R 8 are each independently selected from H, halogen, substituted or unsubstituted C 1-4 alkyl;
  • R 9 is selected from the group consisting of: H, substituted or unsubstituted C 1-4 alkyl;
  • R 10 is selected from the group consisting of: substituted or unsubstituted C 1-4 alkyl
  • R 9 and R 10 and C attached thereto form a substituted or unsubstituted C 3-6 cycloalkyl group
  • R 11 is selected from: a substituted or unsubstituted C 6-10 aryl group, a substituted or unsubstituted C 5-10 heteroaryl group; wherein the C 5-10 heteroaryl group contains 1-4 selected from N a hetero atom of O or S; and said "substituted” means having one or more (eg 1, 2, 3 or 4) substituents selected from Group A:
  • Group A substituents are selected from the group consisting of H, D, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-4 alkane Oxy, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 5-10 heteroaryl, substituted or unsubstituted C 6-10 aryloxy, -C(O)NHRa';
  • Ra' is selected from: a substituted or unsubstituted C 1-6 alkyl group, a substituted or unsubstituted C 3-8 cycloalkyl group;
  • R 12 is selected from the group consisting of: H, D, substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted 3-6 membered ring;
  • substituted means having one or more substituents selected from Group B;
  • Group B substituents are selected from the group consisting of H, D, halogen, substituted or unsubstituted C 1-6 alkyl, -OH, substituted or unsubstituted C 1-4 alkoxy, 3-8 membered cycloalkyl, Amino group, nitro group;
  • the "substituted" means having one or more (e.g., 1/2/3/4 or 5) substituents selected from the group consisting of D, halogen, C. 1-4 alkyl, trifluoromethyl, amino, nitro, -OH.
  • R 3 and R 4 together with C attached thereto form a substituted or unsubstituted C 3-6 cycloalkyl group.
  • R 3 and R 4 together with C attached thereto form a substituted or unsubstituted C 3-6 epoxyalkyl group.
  • R 3 is selected from the group consisting of H, D, and methyl.
  • R 4 is H, D, methyl.
  • R 5 is H, methyl
  • R 6 is H, a substituted or unsubstituted C 1-4 alkyl group, a substituted or unsubstituted C 6-10 aryl group, a substituted or unsubstituted C 3-6 cycloalkyl group.
  • R 6 is methyl, 1-hydroxyethyl, haloethyl, isopropyl, phenyl or cyclopropyl.
  • R 5 and R 6 together with the C atom attached thereto form a substituted or unsubstituted five-membered cycloalkyl group.
  • R 9 is H, methyl
  • R 10 is a methyl group.
  • R 9 and R 10 and C attached thereto form a substituted or unsubstituted 3-8 membered cycloalkyl or heterocyclic group, preferably a 3-6 membered cycloalkyl group, more preferably The ground is a three-membered ring.
  • the R 11 has the following structure:
  • A is selected from rings containing 1-3 hetero atoms substituted or unsubstituted C 5-10 heteroaryl
  • B is selected from ring containing 1-4 heteroatoms substituted or unsubstituted C 5-10 heteroaryl a base, wherein the hetero atom is selected from the group consisting of N, O and S;
  • R a is selected from the group consisting of: H, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-4 alkoxy, substituted or not Substituted C 6-10 aryl, substituted or unsubstituted C 5-10 heteroaryl, substituted or unsubstituted C 1-3 alkyl C 5-8 cycloalkyl, substituted or unsubstituted C 6-10 Aryloxy, -C(O)NHRa', Wherein Ra' is selected from: a substituted or unsubstituted C 1-6 alkyl group, a substituted or unsubstituted C 3-8 cycloalkyl group;
  • R b is selected from H, halogen, -CN, substituted or unsubstituted C 1-4 alkyl;
  • n 0, 1, 2 or 3.
  • the ring A is a six-membered heteroaryl group having from 1 to 3 hetero atoms.
  • the ring B is a five-membered heterocyclic group containing from 1 to 4 hetero atoms.
  • said R 11 is selected from the group consisting of substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 5-10 heteroaryl.
  • the R 11 is a 5-6 membered heterocyclic group having 1 to 3 hetero atoms.
  • the 5-6 membered heterocyclic group is unsaturated.
  • the 5-6 membered heterocyclic group is an aromatic heterocyclic group.
  • substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 5-10 heteroaryl group is each independently monocyclic, bicyclic or tricyclic.
  • R 11 is
  • Ra and Rb are as defined above, and n is 1, 2 or 3.
  • said R 11 is selected from the group consisting of substituted imidazolyl, substituted phenyl, substituted triazolyl, substituted pyridyl.
  • R 11 is In the formula, X is N, and the definitions of Ra, Rb and n are as described above.
  • the R11 is wherein, the definitions of Ra, Rb and n are as described above.
  • the R11 is wherein, the definitions of Ra, Rb and n are as described above.
  • the Group B substituent refers to a substituent having one or more (eg, 1-3) selected from the group consisting of H, halogen, C 1-3 alkyl, -OH, C. 1-3 alkoxy, 3-8 membered cycloalkyl, amino, nitro.
  • the C 6-10 aryl group is selected from the group consisting of phenyl, pyridyl, pyrazolyl, thiazolyl, imidazolyl, isoxazolyl or oxazolyl.
  • the compound is selected from the group consisting of:
  • a second aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the first aspect of the invention, a stereoisomer thereof, a racemate, or a pharmaceutically acceptable salt thereof, And a pharmaceutically acceptable excipient.
  • a method of preparing a compound according to the first aspect of the invention comprising the steps of:
  • the method further comprises, in the step (i), the step (i-1): in an inert solvent, the intermediate A and the intermediate B are subjected to a substitution reaction in the presence of a base to form an intermediate Body C,
  • R 3 - R 6 and R 12 are as defined above.
  • the inert solvent is selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, dioxane, DMF, acetonitrile, DMSO, NMP, THF, or a combination thereof.
  • the base includes an organic base and an inorganic base.
  • the organic base is selected from the group consisting of TEA, DIPEA, or a combination thereof.
  • the inorganic base is selected from the group consisting of sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, potassium t-butoxide, sodium t-butoxide, LiHMDS, LDA, butyl lithium, or a combination thereof.
  • the compound of formula I is a compound of formula J
  • R 5 -R 11 are as defined above.
  • step (i) the intermediate L and the intermediate D are subjected to a substitution reaction by heating in the absence of a solvent to form a compound of the formula J:
  • each group is as defined above.
  • the method further comprises the steps of step (i):
  • each group is as defined above.
  • a compound according to the first aspect of the present invention a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a composition according to the second aspect of the present invention, which is prepared for prevention and Use in a medicament for treating a disease associated with an IDH mutation, the use comprising:
  • the disease is a tumor associated with an IDH mutation.
  • the tumor is selected from the group consisting of glioma, acute myeloid leukemia, sarcoma, prostate cancer, melanoma, non-small cell lung cancer, articular chondrosarcoma, and cholangiocarcinoma.
  • a method for preventing and/or treating a disease associated with an IDH mutation in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of the compound of the first aspect of the invention, A construct, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition according to the second aspect of the invention of the invention.
  • the disease is a tumor associated with an IDH mutation.
  • the tumor is selected from the group consisting of glioma, acute myeloid leukemia, sarcoma, prostate cancer, melanoma, non-small cell lung cancer, articular chondrosarcoma, and cholangiocarcinoma.
  • the inventors discovered for the first time through extensive and in-depth research.
  • the present invention has been completed on this basis.
  • the term “about” means that the value can vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the terms "containing” or “including” may be open, semi-closed, and closed. In other words, the terms also include “consisting essentially of,” or “consisting of.”
  • 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 -CH 2 O- is equivalent to -OCH 2 -.
  • C1-C6 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 -NO 2 .
  • Amino means -NH 2 .
  • 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 means a fully saturated straight or branched hydrocarbon chain group, It consists solely of carbon atoms and hydrogen atoms, has, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and is bonded to the rest of the molecule by a single bond, for example including but 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, decyl and decyl.
  • alkyl means a fully saturated straight or branched hydrocarbon chain group, It consists solely of carbon atoms and hydrogen atoms, has, for example, 1 to 12 (preferably 1 to 8, more
  • 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.
  • 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 a fused ring. a 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 via any suitable
  • the carbon atom is attached to the rest of the molecule by a single bond. Unless otherwise specifically indicated in the specification, a carbon atom in a cyclic hydrocarbon group may be optionally oxidized.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indole Base, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzo Cycloheptene-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, Indenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bi
  • 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-benzoxazine-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, tetra Azyl, triazinyl, pyridazinyl, isodecyl, oxazolyl, isoxazolyl, indolyl, quinolyl, isoquinolyl, diazaphthyl, naphthyridyl, quinoxalinyl , pteridinyl, carbazolyl, porphyrinyl, phenanthryl, phenanthroline, acridinyl, phenazinyl, is
  • 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.
  • substituents described in the claims and the specification of the present invention are selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro
  • 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.
  • 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 A good biological reaction or in an undesirable manner interacts with any of the components contained in the composition.
  • pharmaceutically acceptable excipients include, but are not limited to, any adjuvants, carriers, excipients, glidants, supplements approved by the relevant government authorities for acceptable use by humans or domestic animals.
  • the "tumor” of the present invention includes, but is not limited to, glioma, sarcoma, melanoma, articular chondroma, cholangiocarcinoma, 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, melanin Tumor, kidney cancer, oral cancer and other diseases.
  • 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 a single The compound and at least one synergistic agent described herein are administered simultaneously to the patient in the form of a solid 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, a stereoisomer thereof, a racemate or a pharmaceutically acceptable salt thereof:
  • R 3 and R 4 are each independently selected from: H, D, substituted or unsubstituted C 1-4 alkyl;
  • R 3 and R 4 together with the C atom attached thereto form a substituted or unsubstituted C 3-6 cycloalkyl group, or R 3 and R 4 together with the C atom attached thereto form a substituted or unsubstituted C 3 -6 epoxyalkyl;
  • R 5 and R 6 are each independently selected from: H, a substituted or unsubstituted C 1-4 alkyl group, a substituted or unsubstituted C 6-10 aryl group, a substituted or unsubstituted C 3-6 cycloalkyl group;
  • R 5 and R 6 together with the C atom attached thereto form a substituted or unsubstituted C 3-6 cycloalkyl group
  • R 7 and R 8 are each independently selected from H, halogen, substituted or unsubstituted C 1-4 alkyl;
  • R 9 is selected from the group consisting of: H, substituted or unsubstituted C 1-4 alkyl;
  • R 10 is selected from the group consisting of: substituted or unsubstituted C 1-4 alkyl
  • R 9 and R 10 and C attached thereto form a substituted or unsubstituted C 3-6 cycloalkyl group
  • R 11 is selected from the group consisting of a substituted or unsubstituted C 6-10 aryl group, a substituted or unsubstituted C 5-10 heteroaryl group, wherein the C 5-10 heteroaryl group contains 1-4 selected from a hetero atom of N, O or S; and said "substituted” means having one or more (eg 1, 2, 3 or 4) substituents selected from Group A:
  • Group A substituents are selected from the group consisting of H, D, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-4 alkane Oxy, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 5-10 heteroaryl, substituted or unsubstituted C 6-10 aryloxy, -C(O)NHRa', Wherein Ra' is selected from: a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C3-8 cycloalkyl group;
  • substituted means having one or more (eg 1, 2, 3 or 4) substituents selected from Group B;
  • Group B substituents are selected from the group consisting of H, D, halogen, substituted or unsubstituted C 1-6 alkyl, -OH, substituted or unsubstituted C 1-4 alkoxy, 3-8 membered cycloalkyl, Amino group, nitro group;
  • the "substituted" means having one or more (eg 1, 2, 3, 4 or 5) substituents selected from the group consisting of D, halogen. , C 1-4 alkyl, trifluoromethyl, amino, nitro, -OH.
  • R 3 and R 4 together with C attached thereto form a substituted or unsubstituted C 3-6 cycloalkyl group.
  • R 3 is selected from the group consisting of H, D, and methyl.
  • R 4 is H, D, methyl.
  • R 5 is H, methyl
  • R 6 is H, a substituted or unsubstituted C 1-4 alkyl group, a substituted or unsubstituted C 6-10 aryl group, a substituted or unsubstituted C 3-6 cycloalkyl group.
  • R 6 is methyl, 1-hydroxyethyl, haloethyl, isopropyl, phenyl or cyclopropyl.
  • R 5 and R 6 together with the C atom attached thereto form a substituted or unsubstituted five-membered cycloalkyl group.
  • R 9 is H, methyl
  • R 10 is a methyl group.
  • R 9 and R 10 and C attached thereto form a substituted or unsubstituted 3-8 membered cycloalkyl or heterocyclic group, preferably a 3-6 membered cycloalkyl group, more preferably The ground is a three-membered ring.
  • the R 11 has the following structure:
  • ring A is selected from substituted or unsubstituted C 5-10 heteroaryl groups containing from 1 to 3 heteroatoms,
  • Ring B is selected from substituted or unsubstituted C 5-10 heteroaryl groups having from 1 to 4 heteroatoms, wherein the hetero atom is selected from N, O and S;
  • Ra is selected from: H, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-4 alkoxy, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 5-10 heteroaryl, substituted or unsubstituted C 1-3 alkyl C 5-8 cycloalkyl, substituted or unsubstituted C 6-10 aryl Baseoxy, -C(O)NHRa', Wherein Ra' is selected from: a substituted or unsubstituted C 1-6 alkyl group, a substituted or unsubstituted C 3-8 cycloalkyl group;
  • R b is selected from H, halogen, -CN, substituted or unsubstituted C 1-4 alkyl; n is 0, 1, 2 or 3.
  • the ring A is a six-membered heteroaryl group having from 1 to 3 hetero atoms.
  • the ring B is a five-membered heterocyclic group containing from 1 to 4 hetero atoms.
  • said R 11 is selected from the group consisting of substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 5-10 heteroaryl.
  • the R 11 is a 5-6 membered heterocyclic group having 1 to 3 hetero atoms.
  • the 5-6 membered heterocyclic group is unsaturated.
  • the 5-6 membered heterocyclic group is an aromatic heterocyclic group.
  • substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 5-10 heteroaryl each independently is monocyclic, bicyclic or tricyclic.
  • R 11 is
  • Ra and Rb are as defined above, and n is 1, 2 or 3.
  • said R 11 is selected from the group consisting of substituted imidazolyl, substituted phenyl, substituted triazolyl, substituted pyridyl.
  • R 11 is In the formula, X is N, and the definitions of Ra, Rb and n are as described above.
  • R11 is In the formula, the definitions of Ra, Rb and n are as described above.
  • R11 is In the formula, the definitions of Ra, Rb and n are as described above.
  • the Group B substituent refers to a substituent having one or more (eg, 1-3) selected from the group consisting of H, halogen, C 1-3 alkyl, -OH, C. 1-3 alkoxy, 3-8 membered cycloalkyl, amino, nitro.
  • the C 6-10 aryl group is selected from the group consisting of phenyl, pyridyl, pyrazolyl, thiazolyl, imidazolyl, isoxazolyl or oxazolyl.
  • reaction schemes exemplify a process for the preparation of a compound of formula I, a stereoisomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each group is as in the embodiment section of the compound of formula I above Said. It will be understood that in the following reaction schemes, combinations of substituents and/or variables in the formula are permissible only if such combinations result in stable compounds.
  • the present invention provides a method of preparing a compound of the present invention comprising the steps of:
  • the method further comprises, in the step (i), the step (i-1): in an inert solvent, the intermediate A and the intermediate B are subjected to a substitution reaction in the presence of a base to form an intermediate Body C,
  • R 3 - R 12 are as defined above.
  • the inert solvent is selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, dioxane, DMF, acetonitrile, DMSO, NMP, THF, or a combination thereof.
  • the base includes an organic base and an inorganic base.
  • the organic base is selected from the group consisting of TEA, DIPEA, or a combination thereof.
  • the inorganic base is selected from the group consisting of sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, potassium t-butoxide, sodium t-butoxide, LiHMDS, LDA, butyl lithium, or a combination thereof.
  • the compound of formula I is a compound of formula J
  • R 5 -R 11 are as defined above.
  • step (i) intermediate L is reacted with intermediate D to form a compound of formula J:
  • each group is as defined above.
  • the method further comprises the steps of step (i):
  • each group is as defined above.
  • Step 6 Synthesis of 2-chloro-N-cyclopentyl-4-(1-((R)-1,1-dimethylethylsulfonamide)ethyl)benzamide (A1-7)
  • Step 2 Synthesis of intermediate: (S)-N-((1-(4-chlorophenyl)-1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfenamide (A2-2)
  • Step 4 Synthesis of (S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethylamine (Intermediate A2)
  • the A3-2 can be obtained by using (R)-(+)-tert-butylsulfinamide in the first step. The same procedure can be used to obtain the intermediate A3.
  • Step 1 Synthesis of 1-(6-methoxynaphthalen-2-yl)ethanone oxime (A4-2)
  • Step 3 Add A8-3 (779 mg, 2.44 mmol), (4,4,5,5-tetramethyl-1,3,2-dioxaborolane) to a dry 100 ml three-necked flask. 2-yl)-2-(trifluoromethyl)pyridine (1 g, 3.66 mmol), sodium carbonate (517 mg, 4.88 mmol) and Pd(dppf)Cl 2 (89 mg, 0.12 mmol), 15 ml of 1,4-dioxane was added, and the reaction was carried out under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc EtOAc Product A8-4 (600 mg, yellow oil). Yield: 64%.
  • Step 4 Refer to the fourth step of the intermediate A2 to obtain A8.
  • Step 1 Synthesis of 4'-chloro-(1,1'-biphenyl)-4-carbonitrile (A9-1)
  • Step 2 1-(1-(4-chlorobenzyl)-1H-imidazol-4-yl)cyclopropan-1-amine was synthesized by the same procedure as in Intermediate A12.
  • Step 1 Add imidazole formaldehyde (3.0 g, 31.2 mmol), 1-bromo-3methylbutane (7.07 g) in a solution of 100 ml of N,N-dimethylformamide 250 ml round bottom flask at room temperature. , 46.8 mmol), potassium carbonate (8.6 g, 62.4 mmol). The reaction solution was heated to 60 ° C and reacted for 18 hours. After completion of the reaction, the reaction mixture was poured into water (300 mL) The organic phase was washed once with saturated aqueous sodium chloride (300 mL) andEtOAc. The filtrate was concentrated under reduced pressure and purified by silica gel elution eluting
  • Step 2 A53-1 (2.4 g, 14.4 mmol, 1.0 eq), (S)-tert-butylsulfinamide (2.1 mg, 17.3 mmol, 1.2 eq), cesium carbonate were added in a 100 mL round bottom flask at room temperature. (9.4 g, 28.9 mmol, 2.0 eq) and 1,2-dichloroethane (40 mL). The reaction solution was heated to 75 ° C and stirred for 18 hours. After completion of the reaction, the mixture was evaporated. mjjjjjjjjjj
  • Step 4 A53-3 (1.048 g, 3.67 mmol, 1.0 eq), methanol (10 mL) and concentrated hydrochloric acid (2.5 mL) were sequentially placed at room temperature in a 100 mL vial. Stir at room temperature for 1.5 hours. After the reaction was completed, the reaction liquid was distilled off under reduced pressure to remove methanol. The residue was diluted with water (20 mL) and taken to pH 10 with aqueous ammonia. It was extracted with ethyl acetate (40 mL ⁇ 3). The organic phase was washed once with aq. EtOAc (EtOAc)EtOAc.
  • Step 1 Add the compound imidazole-4-acetic acid methyl ester (1.00 g, 7.14 mmol) in a dry 100 ml single-necked flask at room temperature, dry N,N-dimethylformamide (12 ml), 1 -Chloro-4-iodobenzene (2.55 g, 10.71 mmol), (1R, 2R)-N1, N2-dimethylcyclohexane-1,2-diamine (0.10 g, 0.71 mmol), iodide Cuprous (0.14 g, 0.71 mmol) and potassium carbonate (0.99 g, 7.14 mmol). Pumping and ventilation for 3 times under nitrogen protection. Heat to 100 degrees Celsius for 16 hours.
  • Step 2 Add compound A55-1 (1.50 g, 5.98 mmol) and tetrahydrofuran (40 ml) in a dry 100 ml three-neck bottle at -70 ° C, and slowly add bis (trimethylsilane) under nitrogen protection. Sodium amide (17.94 ml, 17.94 mmol). Stir at -70 ° C and react for 1 hour. Methyl iodide (2.98 ML, 47.84 mmol) was added to the above reaction system at -70 °C. Stir at room temperature for 16 hours. After the reaction is completed, slowly pour into 50 water. It was extracted with ethyl acetate (40 ml ⁇ 2).
  • Step 4 Compound A55-3 (700 mg, 2.64 mmol) and tert-butanol (15 ml), triethylamine (1.10 mL, 7.92 mmol) and azide were added sequentially to dryness in a dry 50 ml. Diphenyl phosphate (0.74 mL, 3.43 mmol). Heat to 100 degrees Celsius for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure.
  • Step 1 In a dry 100 ml single-necked flask, add the compound p-chloroaniline (6.00 g, 47.03 mmol), 3 mol/ml aqueous hydrochloric acid (40 ml), and slowly add sodium nitrite at zero degrees Celsius. (3.25 g, 47.03 mmol) in water (20 mL). Stir at zero degrees Celsius for 5 minutes. Then, a solution of sodium hydrogencarbonate (51.36 g, 611.39 mmol) in water (500 ml) was slowly added at zero degrees Celsius. Stir for 8 minutes at zero degrees Celsius.
  • Step 2 Compound A59-1 (8.87 g, 35.24 mmol) and tetrahydrofuran (100 ml) were sequentially added to a dry 100 ml single-mouth flask at room temperature. After stirring at zero degrees Celsius, lithium tetrahydroaluminum (2.67 g, 70.48 mmol) was added in portions. Stir at room temperature and react for 1 hour. After the reaction is completed, slowly add 100 ml of water at zero degrees Celsius. It was extracted with ethyl acetate (80 ml ⁇ 2). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by chromatography (EtOAc:EtOAc:EtOAc) A59-2) (6.10 g, yellow solid), yield: 82.5%.
  • Step 3 Compound A59-2 (3.00 g, 14.31 mmol), dichloromethane (50 mL) and Dess-Martin Oxidant (9.11 g, 21.47 mmol) were added sequentially to a dry 50 ml. Stir at room temperature for 16 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was poured into 50 ml of saturated aqueous sodium hydrogen carbonate. Extract with dichloromethane (50 ml x 2). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and evaporated.
  • Step 4 Step 5 and Step 6: Similar to the operation of Intermediate A2.
  • Intermediate A59 is obtained: (S)-1-(1-(4-chlorophenyl)-1H-1,2,4-triazol-3-yl)ethylamine.
  • Step 1 A60-1 was obtained from m-bromoaniline as a starting material by the method of Step A59 of A59.
  • Step 3 Compound A60-2 (3.21 g, 11.97 mmol), dichloromethane (60 mL) and thionyl chloride (4.34 mL, 59.85 mmol) were added sequentially in a dry 100 mL round bottom flask at zero degrees Celsius. . Heat to 50 degrees Celsius and react for 2 hours.
  • the reaction mixture was concentrated with EtOAc EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Step 4 Compound (A60-3) (1.00 g, 3.74 mmol), tetrahydrofuran (10 ml), triethylamine (1.56 ml, 11.22 mmol) and trifluorobenzene were sequentially added to a dry 100 ml three-necked flask at room temperature. Acetic anhydride (0.74 mL, 5.61 mmol). Stir at room temperature for 16 hours. After completion of the reaction, 30 ml of water was slowly added, and extracted with ethyl acetate (30 ml ⁇ 2). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and evaporated.
  • Step 5 Compound A60-4 (970 mg, 3.89 mmol), toluene (20 mL), cyclopropylboronic acid (502 mg, 5.84 mmol), [1], in a dry 100 ml round bottom flask. , 1'-bis(diphenylphosphino)ferrocene]palladium dichloride (285 mg, 0.39 mmol) and cesium carbonate (2535 mg, 7.78 mmol). Heat to 100 degrees Celsius for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure.
  • Step 6 Compound A60-5 (610 mg, 2.90 mmol), toluene (12 ml) and diethyl ether (12 ml) were added sequentially in a dry 100 ml three-necked flask. Titanium isopropoxide (1.72 ml, 5.80 mmol) and ethyl magnesium bromide (2.90 ml, 8.70 mmol) were slowly added at -70 °C. Stir at -70 ° C for 15 minutes, warm to room temperature, and react for 1 hour. A boron trifluoride diethyl ether solution (1.06 ml, 8.70 mmol) was added, and the mixture was reacted at room temperature for 1.5 hours.
  • Step 1 Using Step A of Intermediate A12, A61-1 was obtained.
  • Step 2 In a 100 ml round bottom flask containing 40 ml of carbon tetrachloride, a compound A61-1 (1.0 g, 5.0 mmol), N-bromosuccinimide (0.89 g, 5.0 m) was sequentially added at room temperature. Mole) and azobisisobutyronitrile (0.246 g, 1.5 mmol). The gas was ventilated 3 times under the protection of nitrogen, and then heated to reflux for 8 hours. The system was cooled to room temperature and then washed with water. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated to give compound A61-2 (500 mg, yield: 34.7%).
  • Step 3 A61-2 (500 ml, 1.74 mmol, 1.0 eq), dry toluene and diethyl ether (15 mL + 15 mL) were then placed in a dry 50 mL three-necked flask. Under nitrogen protection, cool to -70 ° C, add tetraisopropyl titanate (988 mg, 3.48 mmol, 2.0 eq), then slowly add ethylmagnesium bromide in diethyl ether (3M, 1.74 mL, 4.8 mmol) , 3.0eq). After stirring at low temperature for 20 minutes, the mixture was warmed to room temperature and stirred for 2 hours. Boron trifluoride.
  • Step 1 Intermediate A61-1 (440 mg, 2.10 mmol), NBS (1.5 g, 8.4 mmol), NBS (1.5 g, 8.4 mmol) was added to a 20 ml round bottom flask containing 20 ml of acetic acid, and then heated to 70. After the reaction for 3 hours, the TLC detection reaction was almost complete. After the system was cooled to room temperature, the solvent was evaporated to dryness eluting with ethyl acetate. The mixture was diluted with EtOAc EtOAc EtOAc. Compound A63-1 (300 mg, yield: 50%).
  • Step 2 Using step A3 of A61, A63-1 is reacted to obtain A63.
  • Step 1 The intermediate A64-1 is obtained by reacting methyl imidazole-4-acetate with m-bromoiodobenzene using the procedure of Step A of Intermediate A55.
  • Step 2 Add sodium hydrogen (398 mg, 9.96 mmol) to a 100 ml three-neck round bottom flask containing 20 ml of N,N-dimethylformamide at room temperature, cool to 0 ° C, and slowly add to the middle.
  • a mixed solution of the compound A64-1 (1.4 g, 4.74 mmol) and 1,3-dibromopropane in N,N-dimethylformamide was reacted for 40 minutes, and the reaction was substantially complete by TLC.
  • the reaction was quenched by saturated ammonium chloride, diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to give intermediate A64-2 (650 mg, yield: 43%), the product is a yellow oil.
  • Step 3 A64-3 is obtained by the reaction of A64-2 using the method of Step A of Intermediate A55.
  • Step 4 A64-4 is obtained by the reaction of A64-3 using the method of Step A of Intermediate A55.
  • Step 5 Using the method of Step A of Intermediate A55, A64-4 is reacted to obtain A64.
  • Step 1 In a dry 100 mL three-necked flask, the compound 2,4-dichloropyrimidine (1.49 g, 10 mmoL), L-prolinamide hydrochloride (1.68 g, 11 mmoL) and tetrahydrofuran (25 mL) were sequentially added and stirred at room temperature. 5 minutes. Triethylamine (2.2 g, 22 mmol) was added and allowed to react at room temperature overnight at room temperature. After the reaction was completed, 100 mL of ethyl acetate was added. The organic phase was washed successively with water (20 mL ⁇ 1) and brine (20 mL ⁇ 2).
  • Step 2 Compound B1-1 (456 mg, 2.0 mmoL) and dichloromethane (10 mL) were sequentially added to a dry 25 mL one-necked flask, and stirred at zero degrees Celsius for 15 minutes. Then, triethylamine (606 mg, 6.0 mmoL) and triphosgene (297 mg, 1.0 mmoL) were successively added, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, 20 mL of dichloromethane was added. The organic phase was washed successively with water (20 mL ⁇ 1) and brine (20 mL ⁇ 1). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and evaporated.
  • Step 4 B1-3 (214 mg, 1.0 mmoL) and dichloromethane (5 mL) were added sequentially to a dry 50 mL single-necked flask and stirred at zero degrees Celsius for 15 minutes. Then, triethylamine (303 mg, 3.0 mmoL) and triphosgene (148 mg, 0.5 mmoL) were added in this order, and stirred at room temperature overnight. After the reaction was completed, 20 mL of dichloromethane was added. The organic phase was washed successively with water (20 mL ⁇ 1) and brine (20 mL ⁇ 1). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and evaporated.
  • dichloromethane 5 mL
  • Step 1 2,4-dichloropyrimidine (2.3 g, 15.64 mmol), (2S, 3R) was sequentially added to a 100 ml round bottom flask containing 40 ml of a tetrahydrofuran/water (5/1) mixed solvent at room temperature.
  • Methyl 2-amino-3-(tert-butoxy)butanoate (3.2 g, 14.2 mmol) and triethylamine (4 mL, 28.4 mmol) stirred at 60 ° C overnight, after TLC detection reaction, system Diluted with water, extracted with ethyl acetate. EtOAc (EtOAc m. Yield: 57%), product was a white solid.
  • Step 2 In a 100 ml round bottom flask containing 30 ml of N,N-dimethylformamide, B15-1 (2.2 g, 7.66 mmol), triethylamine (3.2 ml, 22.9 mmol) was added at room temperature. The ammonium chloride solid (811 mg, 15.32 mmol) and HATU (4.3 g, 11.5 mmol) were reacted at room temperature overnight and the reaction was essentially complete by TLC. The mixture was diluted with water and evaporated with ethyl acetate. EtOAc EtOAcjjjjjjjjj
  • Step 3 In a 100 ml three-neck round bottom flask containing 10 ml of dry dichloromethane solution, B15-2 (200 mg, 0.69 mmol) and triethylamine (0.3 ml, 2.09 mmol), nitrogen. After cooling to 0 ° C under the protection, a solution of triphosgene (103 mg, 0.34 mmol) in dichloromethane was added dropwise thereto, and after reacting for 3 hours, after the reaction was completed by TLC, the reaction mixture was diluted with dichloromethane, washed with water and organic. The mixture was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate.
  • B15-2 200 mg, 0.69 mmol
  • triethylamine 0.3 ml, 2.09 mmol
  • Step 4 Add LiAlH4 (61 mg, 1.6 mmol) to a 50 ml three-neck round bottom flask containing 10 ml of dry tetrahydrofuran solution. After cooling to 0 ° C under nitrogen atmosphere, add B15-3 (200 mg). After a solution of 0.64 mmol of tetrahydrofuran and stirring for 30 minutes, the reaction was completed by LCMS. The reaction mixture was quenched with 0.1 ml of water, 0.1 ml of 1N sodium hydroxide aqueous solution and 0.3 ml of water, dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give B15-4 (230 mg, crude).
  • Step 5 In a 50 ml round bottom flask containing 10 ml of N,N-dimethylformamide, B15-4 (230 mg, 0.84 mmol), DIEA (327 mg, 2.53 mmol) and CDI ( After the reaction was carried out for 2 hours at room temperature, the reaction was completed by LCMS. The reaction mixture was diluted with water and ethyl acetate. The organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. - TLC isolated to give B15-5 (140 mg, yield: 56%).
  • Step 6 Add NaH (38 mg, 0.94 mmol) to a 50 ml three-neck round bottom flask containing 8 ml of N,N-dimethylformamide. After cooling to 0 ° C, slowly add B15-5 to it. (140 mg, 0.47 mmol) of N,N-dimethylformamide solution, stirred at room temperature under nitrogen for 30 min, then added MeI (99 mg, 0.70 mmol), and reacted for 1 hour at room temperature, and then reacted by TLC Finished, reverse The solution was diluted with water, extracted with ethyl acetate.
  • Step 7 Add B15-6 (100 mg, 0.32 mmol) to a 50 ml round bottom flask containing 3 ml of dichloromethane. After cooling to 0 ° C, slowly add TFA (3 mL) and stir at room temperature 3 After the reaction was completed, the reaction was completed by TLC. The mixture was concentrated, ethyl acetate was evaporated, and the pH was adjusted to 8 with saturated sodium bicarbonate, and ethyl acetate was evaporated. The organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate After the filtrate was concentrated, prep-TLC was separated to give B15 (80 mg, yield: 98%).
  • Step 1 Fourteen aluminum lithium (500 mg, 12 mmol) was added to a dry 250 ml three-necked flask, three times with nitrogen, and 5 ml of anhydrous tetrahydrofuran was added at zero degrees Celsius. 10 ml of an intermediate B1-2 (1.25 g, 6 mmol) in anhydrous tetrahydrofuran was added at 0 °C. The reaction was carried out at zero degrees Celsius for 0.5 hour, 0.5 ml of water was added, 0.5 ml of a 15% sodium hydroxide solution was added, and 1.5 ml of water was added thereto, and an appropriate amount of anhydrous magnesium sulfate was added thereto, and the filtrate was concentrated under reduced pressure. Intermediate B16-1 (1.2 g, yellow solid) was obtained, yield: 93%.
  • Step 2 Add intermediate B16-1 (4.1 g, 19 mmol) to a 25 ml round bottom flask, add 100 ml of N,N-dimethylformamide, and add N,N-diisopropylethylamine. (7.3 g, 57 mmol) and N,N'-carbonyldiimidazole (4.6 g, 28 mmol) were stirred at room temperature for 3 hr. The mixture was stirred with EtOAc EtOAc.
  • Step 1 Compound B1-2 (10.00 g, 47.47 mmol), diethyl ether (100 ml) was added sequentially to a dry 500 ml three-necked flask. Methyllithium (1.6 M, 119 mL, 189.88 mmol) was slowly added to the above system at 0 ° C with nitrogen. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction was quenched by the addition of 100 ml of methanol and concentrated. Sodium borohydride (3.59 g, 94.94 mmol) was added portionwise at 0 ° C. Stir at room temperature and react for 4 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified using a reverse phase preparative column to afford two diasteromers.
  • Step 2 Add compound B18-1 or B19-1 (550 mg, 2.40 mmol), N,N-dimethylformamide (40 ml), N, N in a dry 100 ml single-mouth bottle at 0 ° C. Diisopropylethylamine (0.79 ml, 4.80 mmol) and N,N'-carbonyldiimidazole (584 mg, 3.60 mmol). The mixture was stirred at room temperature for 60 hours. After the reaction was completed, 400 ml of water was added. It was extracted with ethyl acetate (150 ml ⁇ 2). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified using a reverse preparative column to give the product.
  • Step 1 Hexachloride (3.75 g, 15.2 mmol) was weighed into a dry 250 ml three-necked flask, replaced with nitrogen, and solvent tetrahydrofuran (50 mL) was added. A solution of methyl lithium (28.5 mmol, 1.6 M, 18 mL) was added dropwise under dry ice acetone bath. After the dropwise addition was completed, the mixture was stirred at -78 ° C for 45 minutes. B1-2 (1.0 g, 4.75 mmol) was added to the system, and after stirring at this temperature for 10 minutes, it was returned to room temperature and stirred overnight. The reaction was quenched with 15 mL of EtOAc. The crude product was purified by silica gel column chromatography eluting elute The crude product was purified by prep-LC to afford B22-1 (200 mg, yield: 17%, orange solid).
  • Step 2 B22-1 (200 mg, 0.82 mmol) was added to a 25 ml round bottom flask, 10 ml of N,N-dimethylformamide was added, and N,N-diisopropylethylamine (423) was added. After stirring for 10 minutes, N,N'-carbonyldiimidazole (204 mg, 1.23 mmol) was added to the mixture and stirred at 35 ° C overnight. The mixture was stirred with EtOAc EtOAc. The crude product was purified by EtOAc EtOAcjjjjjjjjjjj
  • Step 1 Add 20 ml of a 1:1 mixture of toluene and diethyl ether to a 100 ml three-necked bottle, add B1-2 (1.4 g, 6.67 mmol) and cool to -78 ° C, then add titanic acid A solution of propyl ester (2.34 ml) and ethyl bromide in diethyl ether (3.0M, 7.7 ml), and then, after stirring for 20 min, then warmed to room temperature and stirred for 1 hour, then added boron trifluoride diethyl ether (3.3 ml) and stirred After 2 hours, after the TLC reaction was completed, the pH was adjusted to about 9 with 1N sodium hydroxide solution at room temperature, and extracted with ethyl acetate.
  • Step 2 B24-1 (230 mg, 0.96 mmol) and DIEA (371 mg, 2.88 mmol) were added to a 50 ml round bottom flask containing 10 mL of N,N-dimethylformamide and cooled. After 0 ° C, CDI (230 mg, 1.44 mmol) was slowly added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction was completed by TLC. After diluted with water, ethyl acetate was extracted and the organic phase was washed with saturated sodium chloride. The mixture was dried over sodium sulfate, filtered, and then filtered, and then evaporated, and then evaporated, and evaporated, and evaporated
  • Step 1 In a 100 ml round bottom flask containing 50 ml of anhydrous dichloromethane, compound B30-1 (4.0 g, 55.51 mmol), (S)-2-methylpropane-2- Sulfonamide (8.07 g, 66.61 mmol, Ti(OiPr) 4 (32.5 ml, 111.01 mmol), stirred at 40 ° C overnight, after TLC detection reaction was completed, the system was washed with saturated Na 2 CO 3 solution, washed with water, and extracted with dichloromethane. The mixture was washed with EtOAc (EtOAc m.
  • EtOAc EtOAc
  • Step 2 Add compound B30-2 (800 mg, 4.56 mmol) and Ti(OiPr) 4 (647 mg, 2.28 mmol) in a 100 ml single-neck round bottom flask containing 20 mL of dry dichloromethane. After stirring at room temperature for half an hour, the system was cooled to 0 ° C and TMSCN (905 mg, 9.13 mmol) was added dropwise. After reacting at room temperature overnight, the reaction was substantially complete by TLC.
  • Step 4 In a 100 ml single-neck round bottom flask containing 20 ml of dimethyl sulfoxide, B30-4 (640 mg, 2.58 mmol), 2,4-dichloropyrimidine (420 mg, 2.83 mmol) was sequentially added. And DIEA (998 mg, 7.74 mmol), stirring at 70 ° under nitrogen for overnight, after the reaction was completed by TLC, the reaction mixture was diluted with water, ethyl acetate was evaporated, and the organic phase was washed with water and brine It was dried, filtered, and purified with EtOAc EtOAcjjjjjjjj
  • Step 5 Add B30-5 (200 mg, in a 50 ml round bottom flask containing 3 ml of methanol solution. 0.56 mmol), hydrochloric acid (0.5 ml, 12.0 M) was added thereto at room temperature, and after reacting at 10 ° C for 3 hours, the reaction was completed by LCMS. The reaction mixture was diluted with water, extracted with ethyl acetate, and the aqueous phase was kept.
  • the compound 13 was obtained by the same procedure as in Example 1 using Intermediate A6 and Intermediate B4.
  • the compound 18 was obtained by the same procedure as in Example 1 using Intermediate A3 and Intermediate B8.
  • the compound 20 was obtained by the same procedure as in Example 1 using Intermediate A12 and Intermediate B1.
  • the compound 21 was obtained by the same procedure as in Example 1 using Intermediate A13 and Intermediate B1.
  • the compound 22 was obtained by the same procedure as in Example 1 using Intermediate A14 and Intermediate B1.
  • the compound 26 was obtained by the same procedure as in Example 1 using Intermediate A18 and Intermediate B8.
  • the compound 27 was obtained by the same procedure as in Example 1 using Intermediate A14 and Intermediate B8.
  • the compound 30 was obtained by the same procedure as in Example 1 using Intermediate A21 and Intermediate B8.
  • the compound 31 was obtained by the same procedure as in Example 1 using Intermediate A22 and Intermediate B8.
  • the compound 32 was obtained by the same procedure as in Example 1 using Intermediate A23 and Intermediate B8.
  • the compound 34 was obtained by the same procedure as in Example 1 using Intermediate A26 and Intermediate B8.
  • the compound 36 was obtained by the same procedure as in Example 1 using Intermediate A27 and Intermediate B8.
  • Step 2 Intermediate 42-1 (100 mg, 0.2 mmol), triethylamine (40 mg) and PdCl2 (dppf) 2 (20 mg) were sequentially added to a 100 ml single-mouth bottle containing 20 ml of methanol solution. The mixture was stirred at 70 ° C overnight, and after the reaction was completed by TLC, the system was concentrated and purified by chromatography (TFA) to afford compound 42 (80 mg, yield: 84%).
  • TFA chromatography
  • the compound 46 was obtained by the same procedure as in Example 1 using Intermediate A36 and Intermediate B27.
  • the compound 52 was obtained by the same procedure as in Example 1 using Intermediate A41 and Intermediate B8.
  • the compound 53 was obtained by the reaction of Compound 47 in the same manner as in Example 48.
  • the compound 56 was obtained by the same procedure as in Example 1 using Intermediate A44 and Intermediate B8.
  • the compound 58 was obtained by the same procedure as in Example 1 using Intermediate A46 and Intermediate B8.
  • the compound 60 was obtained by the same procedure as in Example 1 using Intermediate A48 and Intermediate B8.
  • the compound 61 was obtained by the same procedure as in Example 1 using Intermediate A49 and Intermediate B8.
  • the compound 62 was obtained by the same procedure as in Example 1 using Intermediate A50 and Intermediate B8.
  • the compound 63 was obtained by the same procedure as in Example 1 using Intermediate A51 and Intermediate B8.
  • Step 1 The same procedure as in Example 1 was carried out, using Intermediate A63 and Intermediate B27 to give Intermediate 69-1.
  • Step 2 Intermediate 69-1 (45 mg, 0.083 mmol), Zn(CN) 2 (98 mg, 0.838 mmol) were sequentially added to a microwave tube containing 4 ml of N,N-dimethylformamide. ), Zn powder (10 mg) and catalytic amount of PdCl 2 dppf, after nitrogen gas exchange for 3 times, heated to 140 ° C for microwave reaction for 2 hours, LCMS detection reaction was completed, filtration, high performance liquid phase separation to obtain compound 69 (20 mg) , yield: 50%), the product was a yellow solid.
  • Step 1 The same procedure as in Example 1 was carried out, using Intermediate A64 and Intermediate B27 to give Intermediate 71-1.
  • Step 2 Add intermediate 71-1 (60 mg, 0.117 mmol), cyclopropylboronic acid (25 mg, 0.294 mmol), cesium carbonate (95 mg, in a 50 ml round bottom flask containing 8 mL of toluene. 0.294 Millimol) and PdCl2 (dppf) were reacted overnight at 100 ° C under nitrogen atmosphere. The reaction was completed by LCMS. After purification by prep-HPLC, compound 71 (35 mg, yield: 64%) was obtained.

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Abstract

本发明提供了一种具有预防和治疗与IDH突变相关的疾病的化合物、其制备方法和用途。具体地，本发明提供了式(I)化合物、其立体异构体、外消旋体、或其药学上可接受的盐，并提供了其在制备用于预防和治疗与IDH突变相关的疾病的药物中的应用。

Description

一种具有突变型IDH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，具体地，本发明涉及一种具有突变型IDH抑制活性的化合物、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,这些酶可分为两种不同的亚类，一种利用NAD(+)，而另一种利用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2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，包括但不限于：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(见L.Deng,et al.,Trends Mol.Med.,2010,16,387；T.shibata et al.,Am.J.Pathol.,2011,178(3),1395；Gaal et al.,J.Clin.Endocrinol.Metab.2010；Hayden et al.,Cell cycle,2009；Balss et al.,Acta Neuropathol.,2008)。
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)。
而突变型的异柠檬酸脱氢酶失去了上述正常功能，反而催化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(Dang，L et al，Nature2009，462：739-44)。比如，在有IDH突变的急性白血病人检测到了高浓度2-HG。(S.Gross et al.,J.Exp.Med.,2010,207(2),339)。高浓度的2HG与致癌基因存在很大的关联性。因此，本领域急需研发突变型IDH抑制剂。
发明内容
本发明的目的在于提供一种式I化合物或其药学上可接受的盐，含有该化合物 或其药学上可接受的盐的药物组合物，以及该化合物或组合物在预防和治疗与IDH突变相关的疾病中的应用。
本发明第一方面，提供一种式I所示的化合物，其立体异构体、外消旋体或其药学上可接受的盐：
Figure PCTCN2017077467-appb-000001
其中，R3、R4各自独立地选自：H、D、取代或未取代的C1-4烷基；
或R3与R4和与之相连的C原子共同形成取代或未取代的C3-6环烷基,或R3与R4和与之相连的C原子共同形成取代或未取代的C3-6环氧烷基；
R5、R6各自独立地选自：H、取代或未取代的C1-4烷基、取代或未取代的C6-10芳基、取代或未取代的C3-6环烷基；
或R5与R6和与之相连的C原子共同形成取代或未取代的C3-6环烷基；
R7，R8各自独立的选自H、卤素、取代或未取代的C1-4烷基；
R9选自：H、取代或未取代的C1-4烷基；
R10选自：取代或未取代的C1-4烷基；
或R9与R10和与之相连的C形成取代或未取代的C3-6环烷基；
R11选自：取代或未取代的C6-10芳基、取代或未取代的C5-10杂芳基；其中，所述的C5-10杂芳基含有1-4个选自N、O或S的杂原子；并且所述的“取代”指具有选自A组的一个或多个(如1、2、3或4个)取代基：
A组取代基选自下组：H、D、卤素、取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基、取代或未取代的C1-4烷氧基、取代或未取代的C6-10芳基、取代或未取代的C5-10杂芳基、取代或未取代的C6-10芳基氧基、-C(O)NHRa’；
其中，Ra’选自：取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基；
R12选自：H、D、取代或未取代的C1-4烷基、取代或未取代的3-6元环；
对于R3-R12，所述的“取代”是指具有一个或多个选自B组的取代基；
B组取代基选自下组：H、D、卤素、取代或未取代的C1-6烷基、-OH、取代或未取代的C1-4烷氧基、3-8元环烃基、氨基、硝基；
并且，在所述A组和B组取代基中，所述“取代”指具有选自下组的一个或 多个(如1/2/3/4或5)取代基：D、卤素、C1-4烷基、三氟甲基、氨基、硝基、-OH。
在另一优选例中，R3与R4和与之相连的C共同形成取代或未取代的C3-6环烷基。
在另一优选例中，R3与R4和与之相连的C共同形成取代或未取代的C3-6环氧烷基。
在另一优选例中，R3选自H、D、甲基。
在另一优选例中，R4为H、D、甲基。
在另一优选例中，R5为H、甲基。
在另一优选例中，R6为H、取代或未取代的C1-4烷基、取代或未取代的C6-10芳基、取代或未取代的C3-6环烷基。
在另一优选例中，R6为甲基、1-羟基乙基、卤代乙基、异丙基、苯基或环丙基。
在另一优选例中，R5与R6和与之相连的C原子共同形成取代或未取代的五元环烷基。
在另一优选例中，R9为H、甲基。
在另一优选例中，R10为甲基。
在另一优选例中，R9与R10和与之相连的C形成取代或未取代的3-8元环烷基或杂环基，较佳地为3-6元环烷基，更佳地为三元环。
在另一优选例中，所述的R11具有如下结构：
Figure PCTCN2017077467-appb-000002
其中，环A选自含有1-3个杂原子的取代或未取代的C5-10杂芳基，环B选自含有1-4个杂原子的取代或未取代的C5-10杂芳基，其中所述杂原子选自N、O和S；
Ra选自：H、卤素、取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基、取代或未取代的C1-4烷氧基、取代或未取代的C6-10芳基、取代或未取代的C5-10杂芳基、取代或未取代的C1-3烷基C5-8环烷基、取代或未取代的C6-10芳基氧基、-C(O)NHRa’、
Figure PCTCN2017077467-appb-000003
其中，Ra’选自：取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基；
Rb选自H、卤素、-CN、取代或未取代的C1-4烷基；
n为0、1、2或3。
在另一优选例中，所述环A为含有1-3个杂原子的六元杂芳基。
在另一优选例中，所述环B是含有1-4个杂原子的五元杂环基。
在另一优选例中，所述的R11选自下组：取代或未取代的C6-10芳基、取代或未取代的C5-10杂芳基。
在另一优选例中，所述的R11为具有1-3个杂原子的5-6元杂环基。
在另一优选例中，所述的5-6元杂环基为不饱和的。
在另一优选例中，所述的5-6元杂环基为芳香杂环基。
在另一优选例中，所述的取代或未取代的C6-10芳基、取代或未取代的C5-10杂芳基各自独立地为单环、二环或三环。
在另一优选例中，R11为
Figure PCTCN2017077467-appb-000004
其中，Ra与Rb的定义如上所述，n为1、2或3。
在另一优选例中，所述的R11选自下组：取代的咪唑基、取代的苯基、取代三氮唑基、取代的吡啶基。
在另一优选例中，R11为
Figure PCTCN2017077467-appb-000005
式中，X为N，Ra、Rb和n的定义如上所述。
在另一优选例中，所述R11为
Figure PCTCN2017077467-appb-000006
式中，Ra、Rb和n的定义上所述。
在另一优选例中，所述R11为
Figure PCTCN2017077467-appb-000007
式中，Ra、Rb和n的定义上所述。
在另一优选例中，所述的B组取代基指具有一个或多个(如1-3个)选自下组的取代基：H、卤素、C1-3烷基、-OH、C1-3烷氧基、3-8元环烃基、氨基、硝基。
在另一优选例中，所述的C6-10芳基选自下组：苯基、吡啶基、吡唑基、噻唑基、咪唑基、异恶唑基或恶唑基。
在另一优选例中，所述的化合物选自下组：
Figure PCTCN2017077467-appb-000008
Figure PCTCN2017077467-appb-000009
Figure PCTCN2017077467-appb-000010
Figure PCTCN2017077467-appb-000011
Figure PCTCN2017077467-appb-000012
Figure PCTCN2017077467-appb-000013
Figure PCTCN2017077467-appb-000014
Figure PCTCN2017077467-appb-000015
本发明第二方面，提供一种药物组合物，其包含治疗有效量的如本发明第一方面所述的化合物、其立体异构体、外消旋体、或其药学上可接受的盐，以及药学上可接受的赋形剂。
本发明第三方面，提供一种制备如本发明第一方面所述化合物的方法，包括步骤：
(i)在无溶剂存在下，中间体C和中间体D经加热发生取代反应，生成化合物I，R3-R12的定义如上所述，X为卤素，
Figure PCTCN2017077467-appb-000016
在另一优选例中，所述方法在所述步骤(i)之前，还包括步骤(i-1)：在惰性溶剂中，中间体A和中间体B在碱存在下发生取代反应，形成中间体C，
Figure PCTCN2017077467-appb-000017
式中，R3-R6、R12的定义如上所述。
在另一优选例中，所述的惰性溶剂选自：二氯甲烷、氯仿、1,2-二氯乙烷、二氧六环、DMF、乙腈、DMSO、NMP、THF、或其组合。
在另一优选例中，所述的碱包括有机碱和无机碱。
在另一优选例中，所述的有机碱选自：TEA、DIPEA、或其组合。
在另一优选例中，所述的无机碱选自：氢化钠、碳酸钾、碳酸钠、碳酸铯、叔丁醇钾、叔丁醇钠、LiHMDS、LDA、丁基锂、或其组合。
在另一优选例中，所述的式I化合物为式J化合物
Figure PCTCN2017077467-appb-000018
其中R5-R11的定义如上所述。
在另一优选例中，在步骤(i)中，在无溶剂存在下，中间体L与中间体D经加热发生取代反应，从而形成式J化合物：
Figure PCTCN2017077467-appb-000019
式中，各基团定义如上所述。
在另一优选例中，所述的方法在步骤(i)之前，还包括步骤：
(i-1a)在惰性溶剂中，将式Q化合物与脱水剂(优选三光气、三氟乙酸酐、乙酸酐)进行反应，形成式P化合物，以及
(i-1b)在惰性溶剂中，将式P化合物与还原剂N(优选四氢铝锂、四氘铝锂、硼氢化钠、硼烷，氢气/钯碳、氘气/钯碳)进行反应，形成式M化合物，以及
(i-1c)在碱存在下，在惰性溶剂中，将式M化合物与三光气或者羰基二咪唑反应，形成式L化合物；
Figure PCTCN2017077467-appb-000020
，式中，各基团定义如上所述。
本发明第四方面，提供一种本发明第一方面所述的化合物、其立体异构体或其药学上可接受的盐，或本发明第二方面所述的组合物在制备用于预防和治疗与IDH突变相关的疾病的药物中的用途，所述用途包括：
(a)制备治疗与突变IDH酶活性或表达量相关的疾病的药物；
(b)制备突变IDH酶靶向抑制剂；
(c)体外非治疗性地抑制突变IDH酶的活性；
(d)体外非治疗性地抑制肿瘤细胞增殖；和/或
(e)治疗与突变IDH酶活性或表达量相关的疾病。
在另一优选例中，所述疾病为与IDH突变相关的肿瘤。
在另一优选例中，所述肿瘤选自下组：神经胶质瘤、急性骨髓性白血病、肉瘤、前列腺癌、黑色素瘤、非小细胞肺癌、关节软骨瘤、和胆管瘤。
本发明第五方面，提供一种预防和/或治疗哺乳动物中与IDH突变相关的疾病的方法，包括对需要的哺乳动物给予治疗有效量的本发明第一方面所述的化合物、其立体异构体、或其药学上可接受的盐，或给予治疗有效量的如本发明本发明第二方面所述的药物组合物。
在另一优选例中，所述疾病为与IDH突变相关的肿瘤。
在另一优选例中，所述肿瘤选自下组：神经胶质瘤、急性骨髓性白血病、肉瘤、前列腺癌、黑色素瘤、非小细胞肺癌、关节软骨瘤、和胆管瘤。
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
本发明人通过广泛而深入的研究，首次意外地发现。在此基础上完成了本发明。
术语说明
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
基团定义
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-C6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”是指完全饱和的直链或支链的烃链基，仅由碳原子和氢原子组成、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，例如包括但不限于甲基、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。就本发明而言，术语“烷基”指含有1至6个碳原子的烷基。
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“环烃基”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，环烃基中的碳原子可以任选地被氧化。环烃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，“任选地”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。本发明权利要求书和说明书部分所述的“任选地”的取代基选自烷基、烯基、炔基、卤素、卤代烷基、卤代烯基、卤代炔基、氰基、硝基、任选取代的芳基、任选取代的杂芳基、任选取代的环烃基、任选取代的杂环烃基。
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。
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，“药学上可接受的赋形剂”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”包括但不限于神经胶质瘤、肉瘤、黑色素瘤、关节软骨瘤、胆管瘤、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
本发明提供一种式I所示的化合物，其立体异构体、外消旋体或其药学上可接受的盐：
Figure PCTCN2017077467-appb-000021
其中，
R3、R4各自独立地选自：H、D、取代或未取代的C1-4烷基；
或R3与R4和与之相连的C原子共同形成取代或未取代的C3-6环烷基，或R3与R4和与之相连的C原子共同形成取代或未取代的C3-6环氧烷基；
R5、R6各自独立地选自：H、取代或未取代的C1-4烷基、取代或未取代的C6-10芳基、取代或未取代的C3-6环烷基；
或R5与R6和与之相连的C原子共同形成取代或未取代的C3-6环烷基；
R7、R8各自独立的选自H、卤素、取代或未取代的C1-4烷基；
R9选自：H、取代或未取代的C1-4烷基；
R10选自：取代或未取代的C1-4烷基；
或R9与R10和与之相连的C形成取代或未取代的C3-6环烷基；
R11选自：取代或未取代的C6-10芳基、取代或未取代的C5-10杂芳基、；其中，所述的C5-10杂芳基含有1-4个选自N、O或S的杂原子；并且所述的“取代”指具有选自A组的一个或多个(如1、2、3或4个)取代基：
A组取代基选自下组：H、D、卤素、取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基、取代或未取代的C1-4烷氧基、取代或未取代的C6-10芳基、取代或未取代的C5-10杂芳基、取代或未取代的C6-10芳基氧基、-C(O)NHRa’、；其中，Ra’选自：取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基；
对于R3-R12，所述的“取代”是指具有一个或多个(如1、2、3或4个)选自B组的取代基；
B组取代基选自下组：H、D、卤素、取代或未取代的C1-6烷基、-OH、取代或未取代的C1-4烷氧基、3-8元环烃基、氨基、硝基；
并且，在所述A组和B组取代基中，所述“取代”是指具有一个或多个(如1、2、3、4或5个)选自下组的取代基：D、卤素、C1-4烷基、三氟甲基、氨基、硝基、-OH。
在另一优选例中，R3与R4和与之相连的C共同形成取代或未取代的C3-6环烷基。
在另一优选例中，R3选自H、D、甲基。
在另一优选例中，R4为H、D、甲基。
在另一优选例中，R5为H、甲基。
在另一优选例中，R6为H、取代或未取代的C1-4烷基、取代或未取代的C6-10芳基、取代或未取代的C3-6环烷基。
在另一优选例中，R6为甲基、1-羟基乙基、卤代乙基、异丙基、苯基或环丙基。
在另一优选例中，R5与R6和与之相连的C原子共同形成取代或未取代的五元环烷基。
在另一优选例中，R9为H、甲基。
在另一优选例中，R10为甲基。
在另一优选例中，R9与R10和与之相连的C形成取代或未取代的3-8元环烷基或杂环基，较佳地为3-6元环烷基，更佳地为三元环。
在另一优选例中，所述的R11具有如下结构：
Figure PCTCN2017077467-appb-000022
其中，环A选自含有1-3个杂原子的取代或未取代的C5-10杂芳基，
环B选自含有1-4个杂原子的取代或未取代的C5-10杂芳基，其中所述杂原子选自N、O和S；
Ra选自：H、卤素、取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基、取代或未取代的C1-4烷氧基、取代或未取代的C6-10芳基、取代或未取代的C5-10杂芳基、取代或未取代的C1-3烷基C5-8环烷基、取代或未取代的C6-10芳基氧基、-C(O)NHRa’、
Figure PCTCN2017077467-appb-000023
其中，Ra’选自：取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基；
Rb选自H、卤素、-CN、取代或未取代的C1-4烷基；n为0、1、2或3。
在另一优选例中，所述环A为含有1-3个杂原子的六元杂芳基。
在另一优选例中，所述环B是含有1-4个杂原子的五元杂环基。
在另一优选例中，所述的R11选自下组：取代或未取代的C6-10芳基、取代或未取代的C5-10杂芳基。
在另一优选例中，所述的R11为具有1-3个杂原子的5-6元杂环基。
在另一优选例中，所述的5-6元杂环基为不饱和的。
在另一优选例中，所述的5-6元杂环基为芳香的杂环基。
在另一优选例中，所述的取代或未取代的C6-10芳基、取代或未取代的C5-10杂芳基、各自独立地为单环、二环或三环。
在另一优选例中，R11为
Figure PCTCN2017077467-appb-000024
其中，Ra与Rb的定义如上所述，n为1、2或3。
在另一优选例中，所述的R11选自下组：取代的咪唑基、取代的苯基、取代三氮唑基、取代的吡啶基。
在另一优选例中，R11为
Figure PCTCN2017077467-appb-000025
式中，X为N，Ra、Rb和n的定义如上所述。
在另一优选例中，R11为
Figure PCTCN2017077467-appb-000026
式中，Ra、Rb和n的定义如上所述。
在另一优选例中，R11为
Figure PCTCN2017077467-appb-000027
式中，Ra、Rb和n的定义如上所述。
在另一优选例中，所述的B组取代基指具有一个或多个(如1-3个)选自下组的取代基：H、卤素、C1-3烷基、-OH、C1-3烷氧基、3-8元环烃基、、氨基、硝基。
在另一优选例中，所述的C6-10芳基选自下组：苯基、吡啶基、吡唑基、噻唑基、咪唑基、异恶唑基或恶唑基。
式I化合物的制备
下列反应方案示例性的说明了制备式I化合物、其立体异构体或其混合物、或其药学上可接受的盐的方法，其中各基团均如在上文式I化合物的实施方案部分中所述。应理解在下列反应方案中，所述通式中取代基和/或变量的组合只有在这类组合导致稳定的化合物时才是可允许的。还应理解其他的通式，如通式(Ia)、(Ia-1)、(Ia-2)、(Ia-3)、(Ia-4)、(Ib)、(Ib-1)、(Ib-2)、(Ib-3)、(Ib-4)，以及本文中具体公开的其他式I化合物可由有机化学领域的技术人员通过本文公开的方法(通过应用适当取代的起始材料并利用本领域技术人员公知的方法根据需要修改合成参数)或已知方法进行制备。
本发明提供一种制备本发明所述化合物的方法，包括步骤：
(i)在无溶剂下，中间体C和中间体D经加热发生取代反应，生成化合物I， R3-R12的定义如上所述，X为卤素，
Figure PCTCN2017077467-appb-000028
在另一优选例中，所述方法在所述步骤(i)之前，还包括步骤(i-1)：在惰性溶剂中，中间体A和中间体B在碱存在下发生取代反应，形成中间体C，
Figure PCTCN2017077467-appb-000029
式中，R3-R12的定义如上所述。
在另一优选例中，所述的惰性溶剂选自：二氯甲烷、氯仿、1,2-二氯乙烷、二氧六环、DMF、乙腈、DMSO、NMP、THF、或其组合。
在另一优选例中，所述的碱包括有机碱和无机碱。
在另一优选例中，所述的有机碱选自：TEA、DIPEA、或其组合。
在另一优选例中，所述的无机碱选自：氢化钠、碳酸钾、碳酸钠、碳酸铯、叔丁醇钾、叔丁醇钠、LiHMDS、LDA、丁基锂、或其组合。
在另一优选例中，所述的式I化合物为式J化合物
Figure PCTCN2017077467-appb-000030
其中R5-R11的定义如上所述。
在另一优选例中，在步骤(i)中，中间体L与中间体D进行反应，从而形成式J化合物：
Figure PCTCN2017077467-appb-000031
式中，各基团定义如上所述。
在另一优选例中，所述的方法在步骤(i)之前，还包括步骤：
(i-1a)在在惰性溶剂中，将式Q化合物与脱水剂(优选三光气、三氟乙酸酐、乙酸酐)进行反应，形成式P化合物，以及
(i-1b)在惰性溶剂中，将式P化合物与还原剂N(优选四氢铝锂、四氘铝锂、硼氢化钠、硼烷，氢气/钯碳、氘气/钯碳)进行反应，形成式M化合物，以及
(i-1c)在碱存在下，在惰性溶剂中，将式M化合物与三光气或者羰基二咪唑反应，形成式L化合物；
Figure PCTCN2017077467-appb-000032
式中，各基团定义如上所述。
本发明的主要优点在于：
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用于预防和治疗与IDH突变相关的疾病的药物组合物。
3.提供了一种制备式I所示的化合物的简单高效方法。
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。
各实施例中：
LCMS仪器：Pump Agilent 1100 UV检测器：Agilent 1100 DAD
Mass Spectrometer API 3000
层析柱：Waters sunfire C18,4.6×50mm,5um
流动相：A—乙腈  B-H2O(0.1％FA)
中间体A1：4-(1-胺乙基)-2-氯-N-环戊基苯甲酰胺的合成
Figure PCTCN2017077467-appb-000033
步骤一：2-氯-4-(羟甲基)苯甲酸甲酯的合成(A1-2)
在干燥的氮气保护的50mL单口瓶中依次加入化合物A1-1(1.00g,4.67mmol)和20mL干燥的四氢呋喃，加入10mL硼烷四氢呋喃溶液(9.34mL,9.34mmol)。室温搅拌反应6小时。将反应体系冷至0摄氏度，缓慢加入5mL水萃灭反应，用乙酸乙酯萃取(3×20mL)，无水硫酸钠干燥，过滤，浓缩后通过硅胶柱纯化得到无色油状物化合物(A1-2)(756mg,产率：81.0％).
1H-NMR(CDCl3,400MHz):δ7.72(d,J＝8.0Hz,1H),7.37(s,1H),7.19(d,J＝8.0Hz,1H),4.63(s,2H),3.84 9s,3H).
步骤二：2-氯-4-(羟甲基)苯甲酸的合成(A1-3)
在25mL单口瓶中依次加入化合物A1-2(400mg，2.0mmol)和氢氧化钠(240mg,6mmol)以及10mL甲醇，加热到80摄氏度反应3个小时。反应完毕后，旋出溶剂，加入30mL2N HCl，用乙酸乙酯(30mL×2)萃取，合并有机相。无水硫酸钠干燥，过滤，滤液减压浓缩，得到浅黄色固体产物(A1-3)(350mg，产率：94.1％)。
1H-NMR(DMSO,400MHz):δ7.76(d,J＝8.0Hz,1H),7.46(s,1H),7.36(d,J＝8.0Hz,1H),6.53(brs,1H),5.44(brs,1H),4.55(s,2H)。
步骤三：2-氯-N-环戊基-4-(羟甲基)苯甲酰胺的合成(A1-4)
在干燥的50mL单口瓶中依次加入化合物A1-3(350mg，1.88mmol)，环戊基胺(80mg,1.88mmol)，HATU(859mg,2.26mmol)，三乙胺(380mg,3.76mmol)以及10mLN,N-二甲基甲酰胺，室温搅拌反应6小时。反应完毕后，加入10mL水中，用乙酸乙酯(30mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，柱层析纯化得到黄色油状物产物(A1-4)(390mg，产率：82.0％)。
LCMS:m/z 254.3[M+H]+；RT＝1.1min.
步骤四：2-氯-N-环戊基-4-甲醛基-苯甲酰胺的合成(A1-5)
在干燥的50mL单口瓶中依次加入化合物(A1-4)(390mg,1.54mmol)和10mL二氯甲烷以及Dess-Martin(784mg,1.85mmol)，室温搅拌反应4小时，过滤除去生成的固体，滤液浓缩后柱层析纯化得到淡黄色固体(A1-5)(300mg，收率：77.7％)。
LCMS:m/z 252.2[M+H]+；RT＝1.0min.
步骤五：(R,E)-4-((叔丁基亚磺酰亚胺)甲基)-2-氯-N-环戊基苯甲酰胺的合成(A1-6)
在干燥的50mL三口瓶中依次加入化合物A1-5(300mg，1.2mmol)，(R)-叔丁基亚磺酰胺(145mg，1.2mmol)，碳酸铯(780mg，2.4mmol)以及15mL1,2-二氯乙烷加热回流反应四小时。反应冷至室温后，加入5mL水后，分出有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，柱层析纯化得到白色色固体(A1-6)(339mg，产率：80.0％)。
LCMS:m/z 355.2[M+H]+；RT＝1.5min.
步骤六：2-氯-N-环戊基-4-(1-((R)-1,1-二甲基乙基磺酰胺)乙基)苯甲酰胺的合成(A1-7)
在干燥氮气保护的20mL三口瓶中依次加入化合物A1-6(339mg，0.95mmol)和5mL干燥的四氢呋喃，干冰丙酮浴冷至-70摄氏度，滴加甲基锂(0.7mL，1.14mmol)。低温反应1小时候后，加入5mL饱和氯化铵溶液萃灭反应，用乙酸乙酯(30mL×2)萃取，合并有机相。无水硫酸钠干燥，过滤，滤液减压浓缩，柱层析纯化得到黄色油状物产物A1-7(246mg，产率：69.9％)。
LCMS:m/z 370.2[M+H]+；RT＝1.7min.。
步骤七：4-(1-胺乙基)-2-氯-N-环戊基苯甲酰胺的合成(中间体A1)
在50mL单口瓶中依次加入化合物A1-7(246mg，0.66mmol)和5mL甲醇以及2mL浓盐酸，室温搅拌反应2小时，浓缩后加入15mL二氯甲烷和10mL 2N氢氧化钠水溶液。有机相无水硫酸钠干燥，过滤，滤液减压浓缩淡黄色液体(130mg，收率：74.2％).
LCMS:m/z 267.3[M+H]+；RT＝0.3min.
中间体A2：(S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙胺的合成
Figure PCTCN2017077467-appb-000034
步骤一：1-(4-氯苯基)-1H-咪唑-4-甲醛的合成(A2-1)
在干燥的250mL三口瓶中室温下依次加入1H-咪唑-4-甲醛(5.0g,52.03mmol,1.0eq)、1-氯-4-碘苯(18.6g,78.05mmol,1.5eq)、碳酸铯(34.0g,104.06mmol,2.0eq)、碘化亚铜(500mg,2.60mmol,0.05eq)、反-(1R,2R)-N,N’-二甲基1,2-环己烷二胺(1.5g,10.04mmol,0.2q)和N,N-二甲基甲酰胺(100mL),用氮气置换体系空气三次,在氮气保护下，110℃搅拌18小时。反应完毕后，反应液冷却至0℃，加入饱和氯化铵水溶液(500mL),用乙酸乙酯(1200mL)萃取,有机相用硫酸钠干燥，减压浓缩得到粗产品,粗产品用制备硅胶柱(石油醚:乙酸乙酯＝2:1)纯化得到产品1-(4-氯苯基)-1H-咪唑-4-甲醛(6.0g，黄色固体)，产率56％。
LCMS:m/z 207.2[M+H]+；RT＝1.327min；
步骤二：中间体：(S)-N-((1-(4-氯苯基)-1H-咪唑-4-基)亚甲基)-2-甲基丙烷-2-亚磺酰胺的合成(A2-2)
在干燥的100mL单口瓶中室温下依次加入中间体(A1-2)(1.0g,4.83mmol,1.0eq)、(S)-(+)-叔丁基亚磺酰胺(880.0mg,7.26mmol,1.5eq)、碳酸铯(3.67g,9.66mmol,3.0eq)和1,2-二氯乙烷(30mL),在氮气保护下，80℃搅拌18小时,反应完毕后，反应液冷却至0℃，加入饱和氯化铵水溶液(200mL),用二氯甲烷(300mL)萃取。有机相用硫酸钠干燥，减压浓缩得到粗产品。粗产品用制备硅胶柱(石油醚：乙酸乙酯＝2：1)纯化得到产品(R，Z)-N-((1-(4-氯苯基)-1H-咪唑-4-基)亚甲基)-2-甲基丙烷-2-亚磺酰胺(1.20g，黄色固体)，产率81％。
LCMS:m/z 310.1[M-43]+；RT＝1.61min；
1H NMR(D6-DMSO,400MHz)：δ8.55(s,1H),8.48(s,1H),8.40(s,1H),7.80(d,J＝8.8Hz,2H),7.63(d,J＝8.8Hz,2H),1.17(s,9H).
步骤三：(S)-N-((S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺的合成(A2-3)
在干燥的250mL三口瓶中室温下加入中间体(A1-3)(1.20g，3.29mmol,1.0eq)和二氯甲烷(50mL),用氮气置换体系空气三次,用干冰丙酮浴冷却至-78℃，缓慢加入甲基溴化镁(1.4M,11mL,16.45mmol,5.0eq),-78℃搅拌1.5小时。反应完毕后，加入饱和氯化铵水溶液(100mL)，用二氯甲烷(200mL)萃取。有机相用硫酸钠干燥，减压浓缩得到粗产品(S)-N-((S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺(1.5g，黄色油状液体)，产率100％。
LCMS:m/z 326.2[M-43]+；RT＝1.10min.
步骤四：(S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙胺的合成(中间体A2)
在100mL单口瓶中室温下依次加入中间体(A1-4)(15g，4.6mmol,1.0eq)、甲醇(10mL)和浓盐酸(5mL)，在室温下搅拌2小时，反应完毕后，反应液减压浓缩除掉甲醇，剩余物用水(30mL)稀释，用3M氢氧化钠水溶液调至PH值为10，用二氯甲烷(200mL)萃取，有机相用无水硫酸钠干燥，减压浓缩得到产品(S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙胺(900mg，黄色油状液体)，产率88％。
LCMS:m/z 205.2[M-NH2]+；RT＝0.86min.
使用如上方法，用类似的起始原料得到中间体A38，A41，A42，A43，A45，A46，A47，A48，A49，A50，A51，A52，A54，A57，A58。
Figure PCTCN2017077467-appb-000035
Figure PCTCN2017077467-appb-000036
Figure PCTCN2017077467-appb-000037
中间体A3：(R)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙胺的合成
参照中间体A2的合成方法，在第一步使用(R)-(+)-叔丁基亚磺酰胺可得A3-2.同样的操作步骤可得中间体A3。
LCMS:m/z 205.2[M-NH2]+；RT＝0.86min.
Figure PCTCN2017077467-appb-000038
中间体A4：1-(6-甲氧基萘-2-基)乙胺的合成
Figure PCTCN2017077467-appb-000039
步骤一：1-(6-甲氧基萘-2-基)乙酮肟的合成(A4-2)
在干燥的100mL的单口瓶中依次加入1-(6-甲氧基萘-2-基)乙酮(600mg,3.00mmol,1.0eq),盐酸羟胺(625mg,8.99mmol,3.0eq),甲醇(15mL)。在氮气保护条件下50℃搅拌4小时。TLC点板检测到产物生成后，将反应液倒入冰水(200mL)中,过滤，干燥，得到产品1-(6-甲氧基萘-2-基)乙酮肟(600mg,白色固体)，产率：93％。
步骤二：1-(6-甲氧基萘-2-基)乙胺的合成(中间体A4)
在干燥的100mL的单口瓶中依次加入1-(6-甲氧基萘-2-基)乙酮肟(600mg,2.79mmol,1.0eq),雷尼镍(2.0g),甲醇(15mL)。在氮气保护条件下80℃搅拌16小时。LCMS检测到产物生成后，将反应液过滤，滤液倒入水(200mL)中,用二氯甲烷(200mL)萃取，干燥，过滤，减压浓缩得到产品1-(6-甲氧基萘-2-基)乙胺(500mg,白色固体)，产率：89％。
LCMS:m/z 185.3[M-NH2]+；RT＝0.825min.
使用如上方法，用不同的酮作为起始原料得到中间体A5,A7。
Figure PCTCN2017077467-appb-000040
中间体A6:(1-(4-氯苯基)-1H-咪唑-4-基)环丙胺的合成
Figure PCTCN2017077467-appb-000041
步骤一：(4-氯苯基)-1H-咪唑-4-腈的合成(A6-1)
将化合物A2-1(1.236克，6mmoL)溶于吡啶(30mL)中，在室温下加入盐酸羟胺(626mg，9mmoL)反应1小时，然后加入醋酐(1.224克，12mmoL)，反应体系回流过夜。反应完毕后，加入30mL乙酸乙酯。有机相依次用水(50mL×1)，饱和食盐水(60mL×2)洗涤。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用柱层析法(乙酸乙酯:石油醚＝1:8)纯化得到产物1-(4-氯苯基)-1H-咪唑-4-腈(1.1克，白色固体)，产率：90.1％.
LCMS:m/z 204.1[M+H]+；RT＝0.63min.
步骤二：(1-(4-氯苯基)-1H-咪唑-4-基)环丙胺的合成(中间体A6)
将化合物A6-1(1.34克，6.6mmoL)溶于干燥的四氢呋喃(30mL)中，在室温下 加入钛酸四异丙酯(3.75克，13.2mmoL)，然后缓慢滴加乙基溴化镁(13.2mL，39.6mmoL)，室温下反应1小时。加入三氟化硼乙醚(1.6毫升，13.2毫摩尔)。室温反应1.5个小时。冰浴下加入1N的氢氧化钠水溶液至PH＝8。反应完毕后，加入50mL乙酸乙酯萃取。有机相依次用水(50mL×1)，饱和食盐水(60mL×2)洗涤。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用柱层析法(甲醇:二氯甲烷＝1:40)纯化得到产物1-(1-(4-氯苯基)-1H-咪唑-4-基)环丙胺(700mg，黄色液体)，产率：45％。
LCMS:m/z 234.1[M+H]+；RT＝1.07min.
中间体A8:(S)-1-(4-甲基-2’-(三氟甲基)-[3,4’-联吡啶]-6-基)乙胺的合成
Figure PCTCN2017077467-appb-000042
步骤一和步骤二，参照中间体A2的第二步和第三步方法得到A8-3.LCMS:m/z318.2/321.2[M+H]+；RT＝1.42min.
步骤三：在干燥的100毫升三口瓶中加入A8-3(779毫克，2.44毫摩尔)，(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-(三氟甲基)吡啶(1克，3.66毫摩尔)，碳酸钠(517毫克，4.88毫摩尔)和Pd(dppf)Cl2(89毫克，0.12毫摩尔)，加入1,4-二氧六环15毫升，氮气置换三次，在90摄氏度下反应过夜，加水适量，用乙酸乙酯萃取三次，有机相用无水硫酸钠干燥，减压浓缩。残渣用硅胶柱层层析法纯化，以石油醚比乙酸乙酯等于5：1洗脱。得产物A8-4(600毫克，黄色油状)，产率：64％。
LCMS:m/z 386.3[M+H]+；RT＝1.14min.
步骤四：参照中间体A2的第四步方法得到A8。LCMS:m/z 282.3[M+H]+；
RT＝0.72min.
使用如上方法，用类似的起始原料得到中间体A10
Figure PCTCN2017077467-appb-000043
中间体A9:4’-氯-(1,1’-联苯基)-4-环丙胺的合成
Figure PCTCN2017077467-appb-000044
步骤一：4’-氯-(1,1’-联苯基)-4-甲腈的合成(A9-1)
在干燥的100毫升圆底烧瓶中室温下依次加入对溴苯甲氰(2.18克，12毫摩尔)，对氯苯硼酸(2.8克，18毫摩尔)，[1,1’-双(二苯基膦基)二茂铁]二氯化钯(0.88克，1.2毫摩尔),碳酸钾(3.32克，24毫摩尔)，1,4-二氧六环(40毫升)和水(10毫升)。氮气保护下抽气换气3次，加热至90摄氏度，反应2个小时。反应完毕后，倒入100毫升水中，用乙酸乙酯(50毫升×2)萃取。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用层析柱(石油醚：乙酸乙酯＝10:1)纯化粗产品，得到产物4’-氯-(1,1’-联苯基)-4-甲腈(2克，白色固体)，产率：80％。
1H-NMR(CDCl3,400MHz):7.74(d,J＝8.4Hz,2H),7.65(d,J＝8.4Hz,2H),7.52(d,J＝8.4Hz,2H),7.46(d,J＝8.4Hz,2H).
步骤二：4’-氯-(1,1’-联苯基)-4-环丙胺的合成(A9)
在干燥的100毫升三口瓶中0摄氏度下依次加入化合物A9-1(400毫克，1.88 毫摩尔)，乙醚(10毫升)，四异丙氧基钛(568毫克，2毫摩尔)和乙基溴化镁(500毫克，3.76毫摩尔)。0摄氏度下搅拌反应15分钟。升温至室温，反应1个小时。加入三氟化硼乙醚(534毫克，3.76毫摩尔)，室温下反应1.5个小时。冰浴下加入1摩尔每升的氢氧化钠水溶液到PH＝8，用乙醚(50毫升)萃取。收集有机相，饱和食盐水(20毫升×1)洗涤，无水硫酸钠干燥，过滤，滤液加压浓缩。用层析柱(二氯甲烷：甲醇＝10:1)纯化粗产品，得到产物4’-氯-(1,1’-联苯基)-4-环丙胺(100毫克，黄色固体)，产率：22％。
LCMS:m/z 227.0[M-NH2]+；RT＝0.837min.
使用如上方法，用类似的起始原料得到中间体A11
Figure PCTCN2017077467-appb-000045
1-(2’-(trifluoromethyl)-[3,4’-bipyridin]-6-yl)cyclopropan-1-amine
中间体A12:1-(1-(对-甲苯基)-1H-咪唑-4-基)环丙胺的合成
Figure PCTCN2017077467-appb-000046
步骤一：1-(对-甲苯基)-1H-咪唑-4-甲腈的合成(A12-1)
在干燥的250毫升单口烧瓶瓶中室温下依次加入氰基咪唑(2.50克，26.86毫摩尔)，干燥的N,N-二甲基甲酰胺(40毫升)，1-碘-4-甲基苯(8.78克，40.29毫摩尔)，(1R，2R)-N1，N2-二甲基环己烷-1,2-二胺(0.38克，2.69毫摩尔)，碘化亚铜(0.51克，2.69毫摩尔)和碳酸铯(17.50克，53.72毫摩尔)。氮气保护下抽气换气3次。加热至100摄氏度，反应2个小时。反应完毕，反应液降到室温，倒入200毫升水中，用乙酸乙酯(150毫升×2)萃取。收集有机相，饱和食盐水(150毫升×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。用层析柱(石油醚：乙酸乙酯＝2：1)纯化粗产品，得到产物1-(对-甲苯基)-1H-咪唑-4-甲腈(2.20克，近白色固 体)，产率：44.7％。
1H-NMR(CDCl3,400MHz)：8.71(s,1H),8.47(s,1H),7.59-7.58(d,J＝6.8Hz,2H),7.44(d,J＝6.4Hz,2H).
步骤二：1-(1-(对-甲苯基)-1H-咪唑-4-基)环丙胺的合成(A12)
在干燥的100毫升三口瓶中-70摄氏度下依次加入化合物A12-1(500毫克，2.73毫摩尔)，甲苯(10毫升)，乙醚(10毫升)，四异丙氧基钛(0.97毫升，3.28毫摩尔)和乙基溴化镁(2.28毫升，6.83毫摩尔)。-70摄氏度下搅拌，反应15分钟。升温至20室温，反应1个小时。加入三氟化硼乙醚(0.67毫升，5.46毫摩尔)，室温下反应1.5个小时。冰浴下依次加入1N氢氧化钠水溶液至PH＝8。用乙酸乙酯(50毫升×2)萃取。收集有机相，，无水硫酸钠干燥，过滤，滤液减压浓缩。用层析柱(二氯甲烷：甲醇＝10:1)纯化粗产品，得到产物1-(1-(对-甲苯基)-1H-咪唑-4-基)环丙胺4(290毫克，黄色的油)，产率：49.8％。
LCMS:m/z 214.3[M+H]+；RT＝0.28min(2.00min).
使用如上方法，用类似的起始原料得到中间体A13，A14，A15，A16，A17，A18，A19，A20，A21，A22，A23，A26，A29，A31，A33，A34，A35，A37，A39，A40，A62。
Figure PCTCN2017077467-appb-000047
Figure PCTCN2017077467-appb-000048
Figure PCTCN2017077467-appb-000049
中间体A24:的合成
Figure PCTCN2017077467-appb-000050
步骤一:1-(4-氯苄基)-1H-咪唑-4-甲腈的合成(A24-1)
在干燥的100毫升单口烧瓶中室温下依次加入化合物氰基咪唑(1.00克，10.74毫摩尔)，N,N-二甲基甲酰胺(20毫升)，1-(溴甲基)-4-氯苯(2.65克，12.89毫摩尔)和碳酸铯(7.00克，21.48毫摩尔)。加热至100摄氏度，反应16个小时。反应完毕，反应液降到室温，倒入200毫升水中，用乙酸乙酯(80毫升×2)萃取。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用层析柱(石油醚：乙酸乙酯＝1：1)纯化粗产品，得到产物1-(4-氯苄基)-1H-咪唑-4-甲腈(0.80克，黄色的油)，产率：34.2％。
1H-NMR(CDCl3,400MHz):8.22(s,1H),8.04(s,1H),7.46-7.44(d,J＝8.4Hz,2H),7.35-7.33(d,J＝8.0Hz,2H),5.29(s,2H).
步骤二:使用中间体A12步骤二相同的方法，合成得到1-(1-(4-氯苄基)-1H-咪唑-4-基)环丙烷-1-胺。
LCMS:m/z248.2[M+H]+；RT＝0.658min.
使用如上方法，用类似的起始原料得到中间体A25，A27，A28，A32,A36.
Figure PCTCN2017077467-appb-000051
Figure PCTCN2017077467-appb-000052
中间体A53:(S)-1-(1-异戊基-1H-咪唑-4-基)乙胺的合成
Figure PCTCN2017077467-appb-000053
步骤一：在盛有100毫升N,N-二甲基甲酰胺250毫升圆底烧瓶中室温下依次加入咪唑甲醛(3.0克，31.2毫摩尔)，1-溴-3甲基丁烷(7.07克，46.8毫摩尔)，碳酸钾(8.6克，62.4毫摩尔)。反应液加热至60摄氏度，反应18小时。反应完毕后，将反应液倒入水(300mL)中，用乙酸乙酯(100mL)萃取三次。有机相用饱和氯化钠水溶液(300mL)洗涤一次，有机相用硫酸钠干燥，过滤。滤液减压浓缩，通过硅胶柱(石油醚：乙酸乙酯＝3:1)纯化得到产品黄色油状液体A53-1(2.402g,产率：46％)。
LCMS:m/z 167.3[M+H]+,t＝1.02min.
步骤二：在100mL圆底瓶中室温下依次加入A53-1(2.4g,14.4mmol,1.0eq)、(S)-叔丁基亚磺酰胺(2.1mg,17.3mmol,1.2eq)、碳酸铯(9.4g,28.9mmol,2.0eq)和1,2-二氯乙烷(40mL)。反应液加热至75℃，搅拌18小时。反应完毕后，减压浓缩，通过硅胶柱(石油醚：乙酸乙酯＝2:1)纯化得到产品黄色油状液体A53-2(2.80g,72％收率)。
LCMS:m/z 270.3[M+H]+,t＝1.19min.
步骤三：在干燥的250mL三口瓶中室温下加入A53-2(1.505g，5.59mmol,1.0eq)和四氢呋喃(50mL)。用氮气置换体系空气三次,用干冰丙酮浴冷却至-60℃以下。在-60℃以下氮气保护下，缓慢加入甲基溴化镁(3M,9.3mL),在-60℃搅拌2小时。反应完毕后，反应液-60℃下，加入水(10mL)，用乙酸乙酯(100mL)萃取三次。有机相用饱和氯化钠水溶液(300mL)洗涤一次，有机相用硫酸钠干燥，过滤，减压蒸馏得到粗产品。通过硅胶柱(二氯甲烷：甲醇＝20:1)纯化得到产品黄色油状液体A53-3(1.048g,66％收率)。
LCMS:m/z 286.3[M+H]+,t＝0.9min.
步骤四：在100mL单口瓶中室温下依次加入A53-3(1.048g，3.67mmol,1.0eq)、甲醇(10mL)和浓盐酸(2.5mL)。在室温下搅拌1.5小时。反应完毕后，反应液减压蒸馏除掉甲醇。剩余物用水(20mL)稀释，用氨水调至PH值为10。用乙酸乙酯(40mL×3)萃取。有机相用饱和氯化钠水溶液(100mL)洗涤一次，有机相用硫酸钠干燥，过滤，减压蒸馏得到粗产品A53(206mg，黄色油状液体)。
LCMS:m/z 165.4[M-NH2]+,t＝0.53min.
使用如上方法，用类似的起始原料得到中间体A44，A56：
Figure PCTCN2017077467-appb-000054
中间体A55:2-(1-(4-氯苯基)-1H-咪唑-4-基)丙-2-胺的合成
Figure PCTCN2017077467-appb-000055
步骤一：在干燥的100毫升单口烧瓶瓶中室温下依次加入化合物咪唑-4-乙酸甲酯(1.00克，7.14毫摩尔)，干燥的N,N-二甲基甲酰胺(12毫升)，1-氯-4-碘苯(2.55克，10.71毫摩尔)，(1R，2R)-N1，N2-二甲基环己烷-1,2-二胺(0.10克，0.71毫摩尔)，碘化亚铜(0.14克，0.71毫摩尔)和碳酸钾(0.99克，7.14毫摩尔)。氮气保护下抽气换气3次。加热至100摄氏度，反应16个小时。反应完毕，反应液降到室温，倒入120毫升水中，用乙酸乙酯(45毫升×2)萃取。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用层析柱(石油醚：乙酸乙酯＝1：1)纯化粗产品，得到产物2-(1-(4-氯苯基)-1H-咪唑-4-基)乙酸甲酯A55-1(1.00克，黄色固体)，产率：55.9％。
LCMS:m/z 251.1[M+H]+；RT＝1.335min.
步骤二：在干燥的100毫升三口瓶中-70摄氏度下依次加入化合物A55-1(1.50克，5.98毫摩尔)和四氢呋喃(40毫升)，在氮气保护下慢慢滴加双(三甲基硅基)氨基钠(17.94毫升，17.94毫摩尔)。-70摄氏度下搅拌，反应1小时。碘甲烷(2.98 毫升，47.84毫摩尔)在-70摄氏度下加入上述反应体系。室温搅拌，反应16个小时。反应完毕，慢慢倒入50水中。用乙酸乙酯(40毫升×2)萃取。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用层析柱(石油醚：乙酸乙酯＝1：1)纯化粗产品，得到产物2-(1-(4-氯苯基)-1H-咪唑-4-基)-2-甲基丙酸甲酯(A55-2)(1.07克，白色固体)，产率：64.1％。
LCMS:m/z 279.1[M+H]+；RT＝1.219min.
步骤三：在干燥的25毫升单口瓶中室温下依次加入化合物A55-2(1.07克，3.84毫摩尔)，四氢呋喃(10毫升)，水(2毫升)和一水合氢氧化锂(0.48克，11.52毫摩尔)。加热至50摄氏度，，反应16个小时。反应完毕，用2摩尔/毫升的盐酸水溶液调节至pH＝6。用乙酸乙酯(20毫升×2)萃取。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用层析柱(纯乙酸乙酯)纯化粗产品，得到产物2-(1-(4-氯苯基)-1H-咪唑-4-基)-2-甲基丙酸(A55-3)(0.70克，白色固体)，产率：68.6％。
1H-NMR(DMSO-d6,400MHz):12.12-12.10(m,1H),8.18(s,1H),7.72-7.68(m,2H),7.60-7.55(m,3H),1.47(s,6H).
步骤四：在干燥的50毫升单口瓶中室温下依次加入化合物A55-3(700毫克，2.64毫摩尔)和叔丁醇(15毫升)，三乙胺(1.10毫升，7.92毫摩尔)和叠氮磷酸二苯酯(0.74毫升，3.43毫摩尔)。加热至100摄氏度，反应16个小时。反应完毕，反应液减压浓缩。用层析柱(石油醚：乙酸乙酯＝1：1)纯化粗产品，得到产物叔丁基(2-(1-(4-氯苯基)-1H-咪唑-4-基)丙烷-2-基)甲酸酯A55-4(840毫克，白色固体)，产率：94.6％。
LCMS:m/z 336.1[M+H]+；RT＝1.155min.
步骤五：在干燥的50毫升单口瓶中室温下依次加入化合物A55-4(840毫克，2.50毫摩尔)，二氯甲烷(4毫升)和三氟乙酸(2毫升)。室温下搅拌，反应2小时。反应完毕，反应液减压浓缩。加入10毫升水，用乙醚(10毫升×2)萃取。水相用6摩尔每毫升的氢氧化钠水溶液调节至pH＝8。用乙酸乙酯(20毫升×2)萃取。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得到产物2-(1-(4-氯苯基)-1H-咪唑-4-基)丙-2-胺(A55)(500毫克，黄色固体)，产率：84.7％。
LCMS:m/z 219.3[M-NH2]+；RT＝1.046min.
中间体A59:(S)-1-(1-(4-氯苯基)-1H-1,2,4-三唑-3-基)乙胺的合成乙胺的合成：
Figure PCTCN2017077467-appb-000056
步骤一：在干燥的100毫升单口烧瓶瓶中室温下依次加入化合物对氯苯胺(6.00克，47.03毫摩尔)，3摩尔/毫升的盐酸水溶液(40毫升)，零摄氏度下慢慢加入亚硝酸钠(3.25克，47.03毫摩尔)的水(20毫升)溶液。零摄氏度下搅拌5分钟。然后零摄氏度下慢慢加入碳酸氢钠(51.36克，611.39毫摩尔)的水(500毫升)溶液中。零摄氏度下搅拌8分钟。零摄氏度下慢慢加入乙基2-异氰基乙酸酯(5.85克，51.73毫摩尔)的甲醇(40毫升)溶液。室温下搅拌，反应5个小时。反应完毕，用氯仿：甲醇(9：1，150毫升×2)萃取。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用层析柱(石油醚：乙酸乙酯＝1：1)纯化粗产品，得到产物1-(4-氯苯基)-1H-1,2,4-三唑-3-羧酸乙酯(A59-1)(8.87克，黄色固体)，产率：79.4％。
LCMS:m/z 252.2[M+H]+；RT＝1.410min.
步骤二：在干燥的100毫升单口瓶中室温下依次加入化合物A59-1(8.87克，35.24毫摩尔)和四氢呋喃(100毫升)。零摄氏度下搅拌，分批加入四氢铝锂(2.67克，70.48毫摩尔)。室温搅拌，反应1个小时。反应完毕，零摄氏度下慢慢加入100毫升水。用乙酸乙酯(80毫升×2)萃取。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用层析柱(石油醚：乙酸乙酯＝1：1)纯化粗产品，得到产物(1-(4-氯苯基)-1H-1,2,4-三唑-3-基)甲醇(A59-2)(6.10克，黄色固体)，产率：82.5％。
LCMS:m/z 210.1[M+H]+；RT＝1.009min.
步骤三：在干燥的50毫升单口瓶中室温下依次加入化合物A59-2(3.00克，14.31毫摩尔)，二氯甲烷(50毫升)和戴斯-马丁氧化剂(9.11克，21.47毫摩尔)。室温搅拌，反应16个小时。反应完毕，过滤反应液，滤液倒入50毫升饱和碳酸氢钠水溶液中。用二氯甲烷(50毫升×2)萃取。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用层析柱(石油醚：乙酸乙酯＝1：1)纯化粗产品，得到产物1-(4-氯苯基)-1H-1,2,4-三唑-3-甲醛(A59-3)(2.10克，黄色固体)，产率：70.7％。
LCMS:m/z 208.2[M+H]+；RT＝1.099/1.319min.
步骤四，步骤五和步骤六：与中间体A2的操作相似。得到中间体A59：(S)-1-(1-(4-氯苯基)-1H-1,2,4-三唑-3-基)乙胺。
LCMS:m/z 233.3[M-NH2]+；RT＝1.025min.
中间体A60：1-(1-(3-环丙基苯基)-1H-[1,2,4]-三唑-3-基)环丙基胺的合成
Figure PCTCN2017077467-appb-000057
步骤一：使用A59步骤一的方法，由间溴苯胺作为起始原料得到A60-1。
LCMS:m/z 298.1[M+H]+；RT＝1.322min.
步骤二：在干燥的100毫升单口烧瓶瓶中室温下依次加入化合物A60-1(3.61克，12.19毫摩尔)，四氢呋喃(50毫升)，水(25毫升)和氢氧化钠(1.46克，36.57毫摩尔)。室温搅拌，反应16个小时。反应完毕，用6摩尔/毫升的盐酸水溶液调节pH至pH＝6。用乙酸乙酯(50毫升×2)萃取。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用层析柱(二氯甲烷：甲醇＝10：1)纯化粗产品，得到产物1-(3-溴苯基)-1H-1,2,4-三唑-3-羧酸(A60-2)(3.21克，黄色固体)，产率：98.2％
LCMS:m/z 270.1[M+H]+；RT＝1.296min.
步骤三：在干燥的100毫升圆底烧瓶中零摄氏度下依次加入化合物A60-2(3.21克，11.97毫摩尔)，二氯甲烷(60毫升)和氯化亚砜(4.34毫升，59.85毫摩尔)。加热至50摄氏度，反应2个小时。反应液减压浓缩，用四氢呋喃(60毫升)溶解，慢慢加入氨水(0.46毫升，11.97毫摩尔)和三乙胺(3.33毫升，23.94毫摩尔)的四氢呋喃(60毫升)的溶液中。室温下搅拌，反应1个小时。反应完毕，反应液倒入100毫升水中。用乙酸乙酯(50毫升×2)萃取。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用层析柱(二氯甲烷：甲醇＝10：1)纯化粗产品，得到产物1-(3-溴苯基)-1H-1,2,4-三唑-3-甲酰胺(A60-3)(1.00克，黄色固体)，产率：31.3％。
LCMS:m/z 269.2[M+H]+；RT＝1.204min.
步骤四：在干燥的100毫升三口瓶中室温下依次加入化合物(A60-3)(1.00克，3.74毫摩尔)，四氢呋喃(10毫升)，三乙胺(1.56毫升，11.22毫摩尔)和三氟乙酸酐(0.74毫升，5.61毫摩尔)。室温下搅拌，反应16个小时。反应完毕，慢慢加入30毫升水，用乙酸乙酯(30毫升×2)萃取。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用层析柱(石油醚：乙酸乙酯＝1：1)纯化粗产品，得到产物1-(3-溴苯基)-1H-1,2,4-三唑-3-腈(A60-4)(0.93毫克，黄色固体)，产率：99.7％
LCMS:m/z 249.2[M+H]+；RT＝1.59min.
步骤五：在干燥的100毫升圆底烧瓶中室温下依次加入化合物A60-4(970毫克，3.89毫摩尔)，甲苯(20毫升)，环丙基硼酸(502毫克，5.84毫摩尔)，[1,1’-双(二苯基膦基)二茂铁]二氯化钯(285毫克，0.39毫摩尔)和碳酸铯(2535毫克，7.78毫摩尔)。加热至100摄氏度，反应16个小时。反应完毕，反应液减压浓缩。用层析柱(石油醚：乙酸乙酯＝1：1)纯化粗产品，得到产物1-(3-环丙基苯基)-1H-1,2,4-三唑-3-腈(A60-5)(610克，黄色固体)，产率：74.5％。
LCMS:m/z 211.2[M+H]+；RT＝1.63min.
步骤六：在干燥的100毫升三口瓶中室温下依次加入化合物A60-5(610毫克，2.90毫摩尔)，甲苯(12毫升)和乙醚(12毫升)。-70摄氏度依次慢慢加入四异丙氧基钛(1.72毫升，5.80毫摩尔)和乙基溴化镁(2.90毫升，8.70毫摩尔)。-70摄氏度下搅拌15分钟，升至室温，反应1个小时。加入三氟化硼乙醚溶液(1.06毫升，8.70毫摩尔)，室温反应1.5个小时。反应完毕，依次加入1摩尔/毫升的盐酸水溶液(12毫升)，乙醚(25毫升)和1摩尔/毫升的氢氧化钠水溶液(25毫升)。用乙酸 乙酯(50毫升×2)萃取。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用层析柱(二氯甲烷：甲醇＝10：1)纯化粗产品，得到产物1-(1-(3-环丙基苯基)-1H-[1,2,4]-三唑-3-基)环丙基胺(A60)(400毫克，黄色油状物)，产率：57.4％。
LCMS:m/z 241.3[M-NH2]+；RT＝0.90min.
中间体A61：1-(2-溴-1-(3-环丙基苯基)-1H-咪唑-4-基)环丙胺的合成
Figure PCTCN2017077467-appb-000058
步骤一：使用中间体A12步骤一方法，得到A61-1。
步骤二：在盛有40毫升四氯化碳的100毫升圆底烧瓶中室温下依次加入化合物A61-1(1.0克，5.0毫摩尔)，N-溴代琥珀酰亚胺(0.89克，5.0毫摩尔)和偶氮二异丁腈(0.246克，1.5毫摩尔)。在氮气的保护下换气3次，然后加热至回流反应8小时。体系冷却到室温后用水洗，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩后柱分离得到化合物A61-2(500毫克，收率：34.7％)，产品为黄色固体。
1H NMR(CDCl3-d4,400MHz):δ7.64(s,1H),7.41(t,J＝8.0Hz，1H),7.25(t,J＝6.4Hz，1H)，7.09(d,J＝8.0Hz，1H)，7.01(s,1H),2.87-2.97(m,1H),1.05-1.10(m,2H),0.73-0.77(m,2H)；
步骤三：在干燥的50mL三口瓶中室温下依次加入A61-2(500m g，1.74mmol,1.0eq)、干燥的甲苯和乙醚(15mL+15mL)。在氮气保护条件下，冷至-70摄氏度，加入钛酸四异丙酯(988mg，3.48mmol,2.0eq)，紧接着，缓慢加入乙基溴化镁的乙醚溶液(3M,1.74mL,4.8mmol，3.0eq)。低温搅拌20分钟后，升温至室温搅拌反应2小时。三氟化硼.乙醚(495mg,3.48mmmol)加入反应体系，搅拌反应1小时后，加入10mL 1N HCl，搅拌10分钟后，用2N NaOH调至碱性。过滤后，滤液用乙酸乙酯(30mL)萃取三次。有机相干燥，减压浓缩，通过硅胶柱纯化得到产品1-(2-溴-1-(3-环丙基苯基)-1H-咪唑-4-基)环丙胺(A61)(300mg，黄色固体)，产率54.2％。
LCMS:m/z 319.1[M+H]+；RT＝1.07min.
中间体A63：1-(5-溴-1-(3-环丙基苯基)-1H-咪唑-4-基)环丙胺的合成
Figure PCTCN2017077467-appb-000059
步骤一：在盛有20毫升醋酸100毫升圆底烧瓶中室温下依次加入中间体A61-1(440毫克，2.10毫摩尔)，NBS(1.5克，8.4毫摩尔)，然后加热至70摄 氏度，反应3个小时后TLC检测反应基本完全。体系冷却到室温后旋蒸除去溶剂用乙酸乙酯稀释，用饱和碳酸氢钠将pH值调至8，水洗，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩后柱分离得到化合物A63-1(,300毫克，收率：50％)，产品为白色固体。
1H-NMR(CDCl3,400MHz)：7.79(s,1H),7.73-7.69(m,2H),7.07-7.05(m,1H),6.93(s,1H).
步骤二：使用A61的步骤三，由A63-1反应得到A63.
LCMS:m/z 319.1[M+H]+；RT＝1.07min.
中间体A64：1-(1-(3-溴苯基)-1H-咪唑-4-基)环丁胺的合成
Figure PCTCN2017077467-appb-000060
步骤一：使用中间体A55步骤一的方法，由咪唑-4-乙酸甲酯与间溴碘苯反应得到中间体A64-1。
1H-NMR(CDCl3,400MHz):7.78(s,1H),7.55(s,1H),7.50-7.47(m,1H),7.34-7.33(m,2H),7.26(s,1H),3.75-3.63(m,5H).
步骤二：在盛有20毫升N,N-二甲基甲酰胺的100毫升三口圆底烧瓶中室温下加入钠氢(398毫克，9.96毫摩尔)，冷却到0摄氏度后，向其中缓慢加入中间体A64-1(1.4克,4.74毫摩尔)和1，3-二溴丙烷的N,N-二甲基甲酰胺混合溶液，反应40分钟后TLC检测反应基本完全。饱和氯化铵淬灭反应好，水稀释，乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩后柱分离得到中间体A64-2(650毫克，收率：43％)，产品为黄色油状物。
1H-NMR(CDCl3,400MHz):7.80(s,1H),7.56(s,1H),7.50-7.48(m,1H),7.34(d,J＝4.8Hz,2H),7.17(s,1H),3.75(s,3H),2.81-2.74(m,2H),2.58-2.52(m,2H),2.05-2.00(m,2H).
步骤三：使用中间体A55步骤三的方法，由A64-2反应得到A64-3。
1H-NMR(CDCl3,400MHz):7.87-7.84(m,1H),7.59-7.54(m,2H),7.39-7.34(m,2H),7.26-7.23(m,1H),2.90-2.87(m,2H),2.32(s,2H),2.11-2.04(m,2H).
步骤四：使用中间体A55步骤四的方法，由A64-3反应得到A64-4。
1H-NMR(CDCl3,400MHz):7.78(s,1H),7.56(s,1H),7.48-7.47(m,1H),7.36-7.33(m,2H),7.18(s,1H),2.64-2.62(m,4H),2.04-1.90(m,2H),1.42(s,9H).
步骤五：使用中间体A55步骤五的方法，由A64-4反应得到A64。
LCMS:m/z 275.1[M+H]+；RT＝0.83min.
中间体B1：(S)-1-(2-氯嘧啶-4-基)-5-异丙基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000061
步骤一：在干燥的100mL三口烧瓶中依次加入化合物2,4-二氯嘧啶(1.49克，10mmoL),L-缬氨酰胺盐酸盐(1.68g，11mmoL)和四氢呋喃(25mL)，室温下搅拌5分钟。加入三乙胺(2.2g，22mmoL)，室温下室温反应过夜。反应完毕后，加入100mL乙酸乙酯。有机相依次用水(20mL×1)，饱和食盐水(20mL×2)洗涤。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用柱层析法(乙酸乙酯:石油醚＝1:5)纯化得到产物(S)-2-((2-氯嘧啶-4-基)氨基)-3-甲基丁酰胺(B1-1)(1.1g，白色固体)，产率：48.2％
步骤二：在干燥的25mL单口烧瓶中依次加入化合物B1-1(456mg，2.0mmoL)和二氯甲烷(10mL)，在零摄氏度下搅拌15分钟。然后依次加入三乙胺(606mg，6.0mmoL)和三光气(297mg，1.0mmoL)，室温下搅拌3小时。反应完毕后，加入20mL二氯甲烷。有机相依次用水(20mL×1)，饱和食盐水(20mL×1)洗涤。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用柱层析法(乙酸乙酯:石油醚＝1:6)纯化得到产物(S)-1-((2-氯嘧啶-4-基)胺-3-甲基丁氰(B1-2)(410mg，白色固体)，产率：80.7％。
LCMS:m/z 211.2[M+H]+；RT＝0.89min.
1H NMR(d6-DMSO,400MHz)δ8.1(d,1H),7.3(d,1H),5.4(d,1H),4.9(s,1H),2.2(m,1H),1.21(m,6H).
步骤三：在干燥的100mL单口烧瓶中，将中间体B1-2(560mg，2.2mmoL)溶于四氢呋喃(15mL)溶液中，在0摄氏度下分批加入四氢锂铝(251mg，6.6mmoL)，然后室温反应1小时，反应完毕后，加入15mL乙酸乙酯。有机相依次用水(30mL×2)，饱和食盐水(20mL×1)洗涤。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品用柱层析法(二氯甲烷:甲醇＝10：1)纯化得到产物B1-3，产率：33.9％。
LCMS:m/z 215.2[M+H]+；RT＝1.04min.
步骤四：在干燥的50mL单口烧瓶中依次加入B1-3(214mg，1.0mmoL)和二氯甲烷(5mL)，在零摄氏度下搅拌15分钟。然后依次加入三乙胺(303mg，3.0mmoL)和三光气(148mg，0.5mmoL)，室温下搅拌过夜。反应完毕后，加入20mL二氯甲烷。有机相依次用水(20mL×1)，饱和食盐水(20mL×1)洗涤。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用柱层析法(乙酸乙酯:石油醚＝1:10)纯化得到产物(S)-1-(2-氯嘧啶-4-基)-5-异丙基咪唑烷-2-酮(B1)(160mg，白色固体)，产率：66.67％。
LCMS:m/z 241.2[M+H]+；RT＝1.22min.
使用如上方法，用类似的起始原料得到中间体B4，B5，B6，B7，B26。
Figure PCTCN2017077467-appb-000062
中间体B8：(S)-3-(2-氯嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮的合成
Figure PCTCN2017077467-appb-000063
实验步骤：在干燥的25毫升单口烧瓶中依次加入中间体B1(48毫克，0.2毫摩尔)和N,N-二甲基甲酰胺(5毫升)，在室温下搅拌5分钟。然后依次加入碳酸钾(41毫克，0.3毫摩尔)和碘甲烷(34毫克，0.24毫摩尔)，室温下搅拌过夜。反应完毕后，加入10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。用柱层析法(乙酸乙酯:石油醚＝1:6)纯化得到产物(S)-3-(2-氯嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮(B8)(35毫克，白色固体)，产率：68.9％。
LCMS:m/z 255.2[M+H]+；RT＝1.37min.
使用如上方法，用类似的起始原料得到中间体B9，B10，B12，B13，B14，B17，B20，B21，B23，B25。
Figure PCTCN2017077467-appb-000064
Figure PCTCN2017077467-appb-000065
Figure PCTCN2017077467-appb-000066
中间体B11：(S)-3-(2-氯嘧啶-4-基)-1-环丙基-4-异丙基咪唑烷-2-酮的合成
Figure PCTCN2017077467-appb-000067
在盛有20毫升二氯甲烷100毫升圆底烧瓶中室温下依次加入中间体B1(400毫克，1.66毫摩尔)，环丙基硼酸(285.2毫克，3.35毫摩尔)，醋酸铜(603.2毫克，3.32毫摩尔)和三乙胺(420毫克，4.15毫摩尔)。在室温下敞口搅拌24小时。反应完毕后，向体系中加入100mL水中，二氯甲烷(20mL×3)萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩后，通过硅胶柱(石油醚：乙酸乙酯＝3:1)纯化得到产品白色固体(S)-3-(2-氯嘧啶-4-基)-1-环丙基-4-异丙基咪唑烷-2-酮(B11)(163mg,产率：35％)。
LCMS:m/z 281.3[M+H]+；RT＝1.6min.
中间体B15：(R)-3-(2-氯嘧啶-4-基)-4-((R)-1-羟乙基)-1-甲基咪唑烷-2-酮的合成
Figure PCTCN2017077467-appb-000068
步骤一：在盛有40毫升四氢呋喃/水(5/1)混合溶剂的100毫升圆底烧瓶中室温下依次加入2,4-二氯嘧啶(2.3克，15.64毫摩尔),(2S，3R)-2-氨基-3-(叔丁氧基)丁酸甲酯(3.2克,14.2毫摩尔)和三乙胺(4毫升,28.4毫摩尔),60摄氏度搅拌过夜，TLC检测反应完全后,体系用水稀释,乙酸乙酯萃取,有机相依次用水,饱和氯化钠洗涤,无水硫酸钠干燥,过滤,浓缩,柱纯化(石油醚/乙酸乙酯＝3/1)得到2(2.4克， 收率：57％)，产品为白色固体。
1H-NMR(DMSO-d,400MHz):8.70(s,2H),4.23-4.00(m,1H),3.76(s,3H),1.13-1.11(m,1H),0.67-0.53(m,4H).
步骤二：在盛有30毫升的N,N-二甲基甲酰胺的100毫升圆底烧瓶中室温下加入B15-1(2.2克，7.66毫摩尔)，三乙胺(3.2毫升，22.9毫摩尔)，氯化铵固体(811毫克，15.32毫摩尔)和HATU(4.3克，11.5毫摩尔)，室温反应过夜后TLC检测反应基本完全。水稀释，乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩后得到化合物B15-2(1.0克，收率：48％)，产品为白色固体。
1H-NMR(DMSO-d,400MHz)：12.63-12.58(m,1H),8.17(d,J＝5.6Hz,1H),6.41(s,1H),3.75(s,1H),2.19(s,3H),1.23-1.12(m,1H),0.59-0.45(m,4H).
步骤三：在盛有10毫升干燥的二氯甲烷溶液的100毫升的三口圆底烧瓶中依次加入B15-2(200毫克，0.69毫摩尔)和三乙胺(0.3毫升，2.09毫摩尔)，氮气保护下冷却到0摄氏度后,向其中滴加三光气(103毫克，0.34毫摩尔)的二氯甲烷溶液，反应3小时后，TLC检测反应完全后，反应液用二氯甲烷稀释，水洗，有机相用饱和氯化钠水溶液洗，无水硫酸钠干燥后，过滤，滤液浓缩后柱纯化得到B15-3(170毫克，收率：80％)，产品为白色固体。
1H-NMR(CDCl3,400MHz):7.96(d,J＝6.0Hz,1H),7.47(s,1H),7.05(s,1H),6.43(s,1H),3.92-3.88(m,1H),2.17(s,3H),1.08-1.03(m,1H),0.52-0.33(m,4H).
步骤四：在盛有10毫升干燥的四氢呋喃溶液的50毫升三口圆底烧瓶中加入LiAlH4(61毫克，1.6毫摩尔),氮气保护下冷却到0摄氏度后，向其中滴加B15-3(200毫克，0.64毫摩尔)的四氢呋喃溶液并搅拌30分钟后，LCMS检测反应完毕，反应液依次用0.1毫升的水，0.1毫升的1N氢氧化钠的水溶液和0.3毫升的水淬灭，无水硫酸镁干燥后过滤，滤液浓缩后得到B15-4(230毫克，粗品)，产品为油状物。
LCMS:m/z 227.3[M+H]+；RT＝0.56min.
步骤五：在盛有10毫升N,N-二甲基甲酰胺的50毫升圆底烧瓶中依次加入B15-4(230毫克，0.84毫摩尔)，DIEA(327毫克，2.53毫摩尔)和CDI(202毫克，1.26毫摩尔),室温反应2小时后，LCMS检测反应完毕，反应液用水稀释，乙酸乙酯萃取，有机相用饱和氯化钠洗涤，无水硫酸钠干燥，过滤，滤液浓缩后prep-TLC分离得到B15-5(140毫克，收率：56％)，产品为白色固体。
LCMS:m/z 298.1[M+H]+；RT＝1.4min.
步骤六：在盛有8毫升N,N-二甲基甲酰胺的50毫升三口圆底烧瓶中加入NaH(38毫克，0.94毫摩尔),冷却到0摄氏度后，向其中缓慢滴加B15-5(140毫克，0.47毫摩尔)的N,N-二甲基甲酰胺溶液，氮气保护下室温搅拌30分钟后，滴加MeI(99毫克，0.70毫摩尔)，室温反应1小时后，TLC检测反应完毕，反 应液用水稀释，乙酸乙酯萃取，有机相用饱和氯化钠洗涤，无水硫酸钠干燥，过滤，滤液浓缩后prep-TLC分离得到B15-6(130毫克，收率：89％)，产品为白色固体。
1H-NMR(CDCl3,400MHz)：8.03(s,1H),4.97(s,1H),4.39-4.34(m,1H),3.69-3.65(m,1H),3.36-3.33(m,1H),2.46(s,3H),1.25-1.20(m,1H),0.91-0.87(m,1H),0.65-0.61(m,1H),0.52-0.48(m,1H),0.30-0.25(m,1H).
步骤七：在盛有3毫升二氯甲烷的50毫升圆底烧瓶中加入B15-6(100毫克，0.32毫摩尔),冷却到0摄氏度后，向其中缓慢加入TFA(3毫升),室温搅拌3小时后，TLC检测反应完毕，体系浓缩后,乙酸乙酯稀释,pH值用饱和碳酸氢钠溶液调节至8，乙酸乙酯萃取，有机相用饱和氯化钠洗涤，无水硫酸钠干燥，过滤，滤液浓缩后prep-TLC分离得到B15(80毫克，收率：98％)，产品为白色固体。
1H-NMR(CDCl3,400MHz):8.05(s,1H),4.27-4.22(m,1H),3.59-3.54(m,1H),3.27-3.24(m,1H),2.92(s,3H),2.44(s,3H),1.17-1.12(m,1H),0.90-0.85(m,1H),0.63-0.58(m,1H),0.52-0.45(m,1H),0.30-0.25(m,1H).
中间体B16：(S)-1-(2-氯嘧啶-4-基)-4,4-二氘-5-异丙基咪唑烷-2-酮的合成
Figure PCTCN2017077467-appb-000069
步骤一：在干燥的250毫升三口瓶中加入四氘铝锂(500毫克，12毫摩尔)，氮气置换三次，零摄氏度下加入无水四氢呋喃5毫升。零摄氏度下加入中间体B1-2(1.25克，6毫摩尔)的无水四氢呋喃溶液10毫升。零摄氏度下反应0.5小时，加入水0.5毫升，加15％的氢氧化钠溶液0.5毫升，再加入1.5毫升水，加无水硫酸镁适量，过滤，滤液减压浓缩。得到中间体B16-1(1.2克，黄色固体)，产率：93％。
LCMS:m/z 217.3[M+H]+；RT＝0.57min.
步骤二：在25毫升的圆底烧瓶中加入中间体B16-1(4.1克，19毫摩尔)，加入N,N-二甲基甲酰胺100毫升，加入N,N-二异丙基乙胺(7.3克，57毫摩尔)和N,N′-羰基二咪唑(4.6克，28毫摩尔)，室温下搅拌3小时。加水淬灭，加乙酸乙酯萃取，饱和食盐水洗涤，加无水硫酸钠干燥，减压浓缩。所得粗品用硅胶柱层析法纯化，以石油醚比乙酸乙酯等于3:1洗脱。得中间体B16：(S)-1-(2-氯嘧啶-4-基)-4,4-二 氘-5-异丙基咪唑烷-2-酮(3克,黄色固体)，产率：65％。
LCMS:m/z 243.3[M+H]+；RT＝1.321min(2.5min).
中间体B18和中间体B19：(单一物质，绝对构型未确证)
Figure PCTCN2017077467-appb-000070
步骤一：在干燥的500毫升三口瓶中室温下依次加入化合物B1-2(10.00克，47.47毫摩尔)，乙醚(100毫升)。将甲基锂(1.6M，119毫升，189.88毫摩尔)用氮气保护在0摄氏度下慢慢加入上述体系。室温下搅拌，反应16小时。反应完毕，加入100毫升甲醇淬灭反应，减压浓缩。加入100毫升甲醇，0摄氏度下分批加入硼氢化钠(3.59克，94.94毫摩尔)。室温搅拌，反应4个小时。反应液减压浓缩。用反相制备柱纯化粗产品，得到两个非对映异构体产物。
B18-1：(3S)-N3-(2-氯嘧啶-4-基)-4-甲基戊烷-2,3-二胺，产率：14.7％。LCMS:229.3[M+H]+；RT＝0.66min.
B19-1：(3S)-N3-(2-氯嘧啶-4-基)-4-甲基戊烷-2,3-二胺，产率：18.5％。LCMS:229.3[M+H]+；RT＝0.69min.
步骤二：在干燥的100毫升单口瓶中0摄氏度下依次加入化合物B18-1或者B19-1(550毫克，2.40毫摩尔)，N,N-二甲基甲酰胺(40毫升)，N,N-二异丙基乙胺(0.79毫升，4.80毫摩尔)和N,N’-羰基二咪唑(584毫克，3.60毫摩尔)。室温下搅拌，反应60小时。反应完毕，加入400毫升水。用乙酸乙酯(150毫升×2)萃取。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用反向制备柱纯化粗产品，得到产物。
B18：(5S)-1-(2-氯嘧啶-4-基)-5-异丙基-4-甲基咪唑烷-2-酮，产率：71.8％,LCMS:m/z 255.3[M+H]+；RT＝1.407min.
B19：(5S)-1-(2-氯嘧啶-4-基)-5-异丙基-4-甲基咪唑烷-2-酮
1H-NMR(CDCl3,400MHz):8.33(d,J＝6.0Hz,1H),8.23(d,J＝6.0Hz,1H),5.05(s,1H),4.27(s,1H),3.65(d,J＝6.4Hz,1H),2.58-2.56(m,1H),1.30(d,J＝6.4Hz,3H),0.99(d,J＝7.2Hz,3H),0.84(d,J＝6.8Hz,3H).
中间体B22：(S)-1-(2-氯嘧啶-4-基)-5-异丙基-4,4-二甲基咪唑烷-2-酮的合成
Figure PCTCN2017077467-appb-000071
步骤一：在干燥的250毫升三口瓶中称取三氯化铈(3.75g,15.2mmol),氮气置换，加入溶剂四氢呋喃(50mL)。在干冰丙酮浴条件下，滴加甲基锂(28.5mmol,1.6M,18mL)溶液。滴加完毕，在-78℃条件下，搅拌45分钟后。向体系加入B1-2(1.0g,4.75mmol)，在此温度下搅拌10分钟后，恢复至室温，搅拌过夜。加甲醇15毫升淬灭反应，减压浓缩，加入二氯甲烷，过滤，滤液旋干。所得粗品用硅胶柱层析法纯化，以二氯甲烷/甲醇/氨水等于500/10/0.5洗脱，得到粗产品。粗品通过prep-LC纯化得B22-1(200毫克，收率：17％，橙黄色固体)。
LCMS:m/z 243.4[M+H]+；RT＝0.96min.
步骤二：在25毫升的圆底烧瓶中加入B22-1(200毫克，0.82毫摩尔)，加入N,N-二甲基甲酰胺10毫升，加入N,N-二异丙基乙胺(423毫克，3.28毫摩尔)，搅拌10分钟后，向体系中加入N,N′-羰基二咪唑(204毫克，1.23毫摩尔)，35℃下搅拌过夜。加水淬灭，加乙酸乙酯萃取，饱和食盐水洗涤，加无水硫酸钠干燥，减压浓缩。所得粗品用硅胶柱层析法纯化，以石油醚比乙酸乙酯等于5:1洗脱，浓缩得中间体B22(114毫克,白色固体)，产率：52％。
LCMS:m/z 269.3[M+H]+；RT＝1.64min.
中间体B24：(S)-6-(2-氯嘧啶-4-基)-7-异丙基-4,6-二氮杂螺[2.4]庚-5-酮的合成
Figure PCTCN2017077467-appb-000072
步骤一：盛有20毫升的1:1的甲苯和乙醚的混合溶液的100毫升的三口瓶中加入B1-2(1.4克，6.67毫摩尔)并冷却到-78摄氏度后，依次加入钛酸异丙酯(2.34毫升)和乙基溴化镁的乙醚溶液(3.0M,7.7毫升)，搅拌20分钟后，迅速升到室温并搅拌1小时，然后加入三氟化硼乙醚(3.3毫升)并搅拌2小时，TLC检测反应完全后，在室温下用1N氢氧化钠溶液调节pH值到9左右，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩后柱层析纯化(二氯甲烷/甲醇＝20/1)得到B24-1(440毫克，收率：28％)，产品为黄色固体。
LCMS:m/z 241.4[M+H]+；RT＝0.98min.
步骤二：在盛有10毫升N,N-二甲基甲酰胺的50毫升圆底烧瓶中依次加入B24-1(230毫克，0.96毫摩尔)和DIEA(371毫克，2.88毫摩尔),冷却到0摄氏度后，向其中缓慢加入CDI(230毫克，1.44毫摩尔),室温搅拌1小时后，TLC检测反应完毕，体系水稀释后,乙酸乙酯萃取，有机相用饱和氯化钠洗涤，无水硫酸钠干燥，过滤，滤液浓缩后prep-TLC分离得到B24(70毫克，收率：27％)，产品为白色固体。
1H-NMR(CDCl3,400MHz):8.33(d,J＝6.0Hz,1H),8.20(d,J＝5.6Hz,1H),4.83(s,1H),4.57(s,1H),2.24-2.21(m,1H),1.29-1.25(m,1H),1.05-0.94(m,7H),0.78-0.74(m,1H).
中间体B27：(S)-3-(2-氯嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮的合成
Figure PCTCN2017077467-appb-000073
在干燥的50mL圆底烧瓶中依次加入(S)-3-(2-氯嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮(2.1克，8.1毫摩尔)，氟化钾(18.9克，325.1毫摩尔)和二甲基亚砜30 毫升，120摄氏度下冷凝回流反应48小时。加水100毫升，乙酸乙酯萃取5次，有机相用无水硫酸钠干燥，减压浓缩。残渣用硅胶柱层层析法纯化，以石油醚比乙酸乙酯等于5:1洗脱。得到产物(S)-3-(2-氟嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮(1.5克，黄色固体)，产率：77.7％。
1H-NMR(CDCL3,400MHz):8.32-8.30(q,J＝8.4Hz,1H),8.22-8.20(q,J＝10.4Hz,1H),4.61-4.57(m,1H),3.48(t,J＝19.2Hz,1H),3.28-3.25(q,J＝12.4Hz,1H),2.91(s,3H),2.64-2.60(m,1H),0.96(d,J＝6.8Hz,3H),0.78(d,J＝6.8Hz,3H).
使用如上方法，用类似的起始原料得到中间体B28，B29。
Figure PCTCN2017077467-appb-000074
中间体B30：(S)-3-(2-氯嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮的合成
Figure PCTCN2017077467-appb-000075
步骤一：在盛有50毫升无水二氯甲烷的100毫升圆底烧瓶中室温下依次加入化合物B30-1(4.0克，55.51毫摩尔),(S)-2-甲基丙烷-2-亚磺酰胺(8.07克， 66.61毫摩尔)，Ti(OiPr)4(32.5毫升，111.01毫摩尔)，40度搅拌过夜，TLC检测反应完全后,体系用饱和Na2CO3溶液洗涤，水洗,二氯甲烷萃取,有机相依次用水,饱和氯化钠洗涤,无水硫酸钠干燥,过滤,浓缩,柱纯化(石油醚/乙酸乙酯＝10/1)得到2(4.8克，收率：50％)，产品为黄色油状物。
1H-NMR(CDCl3,400MHz):5.81-5.77(m,1H),5.68-5.63(m,1H),5.50-5.42(m,2H),1.26(s,9H).
步骤二：在盛有20毫升干燥的二氯甲烷的100毫升单口圆底烧瓶中室温下加入化合物B30-2(800毫克，4.56毫摩尔)和Ti(OiPr)4(647毫克，2.28毫摩尔)，,室温搅拌半小时后，体系冷却到0摄氏度下滴加TMSCN(905毫克，9.13毫摩尔)，室温反应过夜后TLC检测反应基本完全。体系饱和食盐水洗，有机相用无水硫酸钠干燥，过滤，滤液浓缩后柱分离(石油醚/乙酸乙酯＝3/1)得到化合物B30-3(630毫克，收率：68％)，产品为黄色固体。
1H-NMR(CDCl3,400MHz)：5.08-5.05(m,2H),4.84(d,J＝7.2Hz,1H),4.76(d,J＝7.2Hz,1H),4.37-4.32(m,1H),1.29(s,9H).
步骤三：在盛有20毫升干燥乙醚的100毫升三口圆底烧瓶中室温下加入B30-3(500毫克，2.47毫摩尔)，氮气保护下0摄氏度向其中缓慢加入异丙基格式试剂(6.4毫升，12.36毫摩尔)，室温反应过夜后用甲醇淬灭反应，浓缩的固体溶解在甲醇中，0摄氏度下向其中加入NaBH4(187毫克，4.94毫摩尔)，室温反应2小时后，体系浓缩后柱纯化(DCM/MeOH＝20/1)得到化合物B30-4(390毫克，收率：63％)，产品为黄色油状物。
LCMS:m/z 249.4[M+H]+；RT＝0.66min.
步骤四：在盛有20毫升二甲亚砜的100毫升的单口圆底烧瓶中依次加入B30-4(640毫克，2.58毫摩尔)，2,4-二氯嘧啶(420毫克，2.83毫摩尔)和DIEA(998毫克，7.74毫摩尔)，氮气保护下70度搅拌过夜后，TLC检测反应完全后，反应液用水稀释，乙酸乙酯萃取，有机相用水，饱和食盐水依次洗涤，无水硫酸钠干燥，过滤，浓缩后柱纯化(DCM/MeOH＝20/1)得到B30-5(270毫克，收率：30％)，产品为黄色固体。
LCMS:m/z 361.3[M+H]+；RT＝1.003min
步骤五：盛有3毫升甲醇溶液的50毫升圆底烧瓶中加入B30-5(200毫克， 0.56毫摩尔),室温下向其中加入盐酸(0.5毫升，12.0M)，10摄氏度下反应3小时后，LCMS检测反应完毕，反应液用水稀释，乙酸乙酯萃取，保留水相，水相用饱和Na2CO3水溶液调至碱性后，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩后得到纯品B30-6(100毫克，收率：70％)，产品为黄色固体。
LCMS:m/z 257.4[M+H]+；RT＝0.443min.
步骤六：在盛有8毫升干燥DMF的100毫升圆底烧瓶中依次加入B30-6(80毫克，0.312毫摩尔)，DIEA(120毫克，0.936毫摩尔)和CDI(75毫克，0.468毫摩尔),60度反应过夜后，TLC检测反应完毕，反应液用水稀释，乙酸乙酯萃取，有机相用饱和氯化钠洗涤，无水硫酸钠干燥，过滤，滤液浓缩后Prep-TLC(石油醚/乙酸乙酯＝1/1)分离得到中间体B30(20毫克，收率：23％)，产品为白色固体。
1H-NMR(CDCl3,400MHz)：8.34(d,J＝6.4Hz,1H),8.12(d,J＝6.0Hz,1H),5.86-5.82(m,1H),5.21-5.14(m,1H),5.09-5.05(m,1H),4.86-4.80(m,1H),4.75-4.62(m,2H),2.42-2.36(m,1H),1.01-0.88(m,6H).
实施例1：化合物1的合成
2-氯-N-环戊基-4-(1-((4-((S)-5-异丙基-2-氧代咪唑烷-1-基)嘧啶-2-基)氨基)乙基)苯甲酰胺
Figure PCTCN2017077467-appb-000076
将中间体A1(40mg，0.14mmoL)和中间体B1(24mg，0.1mmoL)溶于二氯甲烷(2mL)中混合均匀，旋转蒸发二氯甲烷(或者缓慢升温至二氯甲烷蒸发)，接着在100摄氏度下无溶剂反应4小时。反应完毕后，将反应体系溶于甲醇(3mL)，用高效液相色谱柱纯化，得到产物2-氯-N-环戊基-4-(1-((4-((S)-5-异丙基-2-氧代咪唑烷-1-基)嘧啶-2-基)氨基)乙基)苯甲酰胺(9mg，黄色固体)，产率：19.1％
LCMS:m/z 471.5[M+H]+,RT＝1.27min.
1H-NMR(D6-DMSO,400MHz)δ7.97-8.66(t,1H),7.55-7.57(d,J＝8.0Hz,1H),7.44-7.46(dd,J1＝1.6Hz,J 2＝5.6Hz,1H),7.26-7.28(m,1H),7.21(s,1H), 6.06-6.10(m,1H),4.81(s,1H),4.63(s,1H),4.25-4.47(m,2H),3.20-3.38(m,1H),3.16-3.20(m,1H),1.97-2.20(m,2H),1.55-1.64(m,4H),1.39-1.48(m,5H),0.87-0.89(d,J＝8.0Hz,2H),0.74-0.82(m,6H).
使用类似方法可得到如下化合物：
实施例2：化合物2的合成
(S)-3-(2-(((S)-1-(5-(3-氯苯)吡啶-2-基)乙基)氨)嘧啶-4-基)-4-异丙基-1-甲基-咪唑烷-2-酮-5,5-二氘
Figure PCTCN2017077467-appb-000077
将中间体A66和中间体B17按照实施例1的方法合成得到化合物2。
LCMS:m/z 453.2[M+H]+；RT＝1.12min.
1H NMR(400MHz,CDCl3)δ8.75(d,J＝1.9Hz,1H),8.09(d,J＝5.9Hz,1H),7.78(dd,J＝8.1,2.3Hz,1H),7.57–7.49(m,2H),7.40(ddd,J＝7.7,7.0,4.8Hz,4H),5.71(s,1H),5.16(s,1H),4.46(s,1H),2.84(s,3H),1.69(s,1H),1.61(d,J＝7.0Hz,3H),0.62(m,6H).
实施例3：化合物3的合成
(R)-1-(2-(((S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-5-异丙基的咪唑烷-2-酮
Figure PCTCN2017077467-appb-000078
采用实施例1相同的方法，使用中间体A3和中间体B1进行反应后得到化合物3。
LCMS:m/z 426.2[M+H]+,RT＝1.23min；
1H-NMR(D6-DMSO,400MHz)δ8.02-8.04(d,J＝5.6Hz,1H),7.70(s,1H),7.42-7.44(d,J＝6.0Hz,1H),7.35-7.38(m,2H),7.22-7.26(m,2H),7.06(s,1H),5.33-5.35(d,J＝8.0Hz,1H),5.12-5.16(m,1H),4.78(s,1H),4.58-4.62(m,1H),3.37-3.42(t,1H),3.22-3.25(m,1H),2.54-2.57(m,1H),1.52-1.54(d,J＝6.8Hz,3H),0.85-0.87(d,J＝6.8Hz,3H),0.77-0.79(d,J＝6.8Hz,3H).
实施例4：化合物4的合成
(S)-1-(2-(((S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-5-异丙基的咪唑烷-2-酮
Figure PCTCN2017077467-appb-000079
采用实施例1相同的方法，使用中间体A2和中间体B1进行反应后得到化合物4。
LCMS:m/z 426.2[M+H]+,RT＝1.1min.
1H-NMR(CDCl3,400MHz)δ10.62(m,1H),8.35(s,1H),7.90(d,J＝7.2,1H),7.78(m,1H),7.52-7.54(m,3H),7.39(d,J＝8.4,2H)5.48(m,1H),5.08(s,2H),4.75(m,1H),3.36-3.62(m,2H),2.31(m,1H),1.91(m,3H),0.78-.89(m,6H).
实施例5：化合物5的合成
(S)-4-异丙基-1-甲基-3-(2-(((S)-1-(5-(3-(三氟甲基)苯基)吡啶-2-基)乙基)氨基)嘧啶-4-咪唑烷-2-酮-5,5-d2
Figure PCTCN2017077467-appb-000080
采用实施例1相同的方法，使用中间体A65和中间体B17进行反应后得到化合物5.
LCMS:m/z 487.3[M+H]+；RT＝1.09min.
1H NMR(400MHz,CDCl3)δ8.78(d,J＝2.1Hz,1H),8.10(d,J＝5.8Hz,1H),7.84–7.76(m,2H),7.73(d,J＝7.6Hz,1H),7.66(d,J＝7.6Hz,1H),7.63–7.57(m,1H),7.55(d,J＝5.9Hz,1H),7.41(d,J＝8.1Hz,1H),5.66(s,1H),5.17(s,1H),4.47 (s,1H),2.84(s,3H),2.17(s,1H),1.60(t,J＝9.0Hz,3H),0.64(m,6H).
实施例6：化合物6的合成
(S)-5-异丙基-1-(2-(((S)-1-(6-甲氧基萘-2-基)乙基)氨基)嘧啶-4-基)咪唑烷-2-酮
Figure PCTCN2017077467-appb-000081
采用实施例1相同的方法，使用中间体A4和中间体B1进行反应后得到化合物6。
LCMS:m/z 406.2[M+H]+；RT＝1.070min.
1H-NMR(CDCl3-d1,400MHz):δ10.49-10.51(m,1H),7.63-7.80(m,5H),7.45-7.50(m,1H),7.41--7.43(m,1H),7.11-7.15(m,2H),5.34-5.40(m,1H),5.16-5.20(m,1H),4.58-4.60(m,1H)3.91(s,3H),3.27-3.52(m,2H),1.78-1.79(m,3H),0.45-1.09(m,6H).
实施例7：化合物7的合成
(5S)-1-(2-((1-([1,1’-联苯]-4-基)乙基)氨基)嘧啶-4-基)-5-异丙基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000082
采用实施例1相同的方法，使用中间体A5和中间体B1进行反应后得到化合物7。
LCMS:m/z 402.0[M+H]+；RT＝0.860min.
1H-NMR(MeOD-d4,400MHz):δ7.99-7.95(m,1H),7.72-7.26(m,10H),6.00(s,1H),5.03(d,J＝36Hz,1H),4.56-4.11(m,1H),3.46-3.25(m,2H),2.04-2.01(m,1H),1.61-1.59(m,3H),1.00-0.86(m,3H),0.66-0.60(m,3H).
实施例8：化合物8的合成
(S)-1-(2-((1-(1-(4-氯苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-5-异丙基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000083
采用实施例1相同的方法，使用中间体A6和中间体B1进行反应后得到化合物8。
LCMS:m/z 438.2[M+H]+；RT＝1.12min(2min).
1H-NMR(MEOD-d4,400MHz):δ8.01-8.03(m,2H),7.48(s,5H),7.22(s,1H),4.52-4.58(m,1H),2.30(s,1H),1.38-1.50(m,3H),1.22-1.35(m,4H),0.65(s,6H).
实施例9：化合物9的合成
(5S)-5-异丙基-1-(2-((1-(4-苯氧基苯基)乙基)氨基)嘧啶-4-基)咪唑烷-2-酮
Figure PCTCN2017077467-appb-000084
采用实施例1相同的方法，使用中间体A7和中间体B1进行反应后得到化合物9。
1H-NMR(CDCl3-d1,400MHz):δ8.04-8.07(m,1H),7.47-7.50(m,1H),7.27-7.33(m,4H),7.00-7.08(m,1H),6.93-6.98(m,4H),5.49-5.52(m,1H),4.95-5.06(m,2H),4.43-4.61(m,1H),3.33-3.47(m,1H),3.26-3.28(m,1H),2.09-2.66(m,1H),1.25-1.64(m,3H),0.88-0.94(m,2H),0.80(s,4H).
LCMS:m/z 418.2[M+H]+；RT＝1.158min.
实施例10：化合物10的合成
(S)-1-(2-(((S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-5-苯基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000085
采用实施例1相同的方法，使用中间体A2和中间体B4进行反应后得到化合物10。
LCMS:m/z 460.1[M+H]+；RT＝0.911min.
1H-NMR(CDCl3-d1,400MHz):8.95(s,1H),8.00-8.06(m,2H),7.63-7.65(m,2H),7.57-7.59(m,2H),7.48(s,1H),7.18-7.20(m,2H),7.11-7.14(m,2H),6.96(s,1H),5.70-5.73(m,1H),5.14-5.16(s,1H),3.98-4.02(m,1H),3.17-3.30(m,1H),1.64-1.66(m,3H).
实施例11：化合物11的合成
(S)-1-(2-((1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-1,3-二氮杂螺[4.4]-2-酮
Figure PCTCN2017077467-appb-000086
采用实施例1相同的方法，使用中间体A2和中间体B5进行反应后得到化合物11。
LCMS:m/z 438.2[M+H]+；RT＝1.14min.
1H-NMR(MeOD-d4,400MHz):δ8.96(brs,1H),7.99(d,J＝7.6Hz,1H),7.89-7.91(m,2H),7.59-7.66(m,4H),5.35(brs,1H),3.37(s,2H),2.83-2.99(m,2H),2.63(brs,1H),1.91-1.92(m,1H),1.60-1.74(m,8H).
实施例12：化合物12的合成
(S)-1-(2-((1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-5,5-二甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000087
采用实施例1相同的方法，使用中间体A2和中间体B6进行反应后得到化合物12。
LCMS:m/z 412.3[M+H]+；RT＝1.08min.
1H-NMR(MeOD-d4,400MHz):δ9.15(brs,1H),8.00(d,J＝7.2Hz,2H),7.87(d,J＝7.2Hz,1H),7.60-7.68(m,4H),5.39(brs,1H),3.26(s,2H),1.67-1.76(m,6H),1.29(s,3H).
实施例13：化合物13的合成
(S)-1-(2-((1-(1-(4-氯苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-5-苯基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000088
采用实施例1相同的方法，使用中间体A6和中间体B4进行反应后得到化合物13。
LCMS:m/z 472.2[M+H]+；RT＝0.923min.
1H-NMR(MeOD-d4,400MHz):δ8.82-8.83(m,1H),8.02-8.07(m,2H),7.57-7.60(m,5H),7.37-7.42(m,1H),6.97-7.09(m,3H),6.93-6.97(m,1H),
5.65-5.66(m,1H),3.96-4.01(m,1H),3.12(s,1H),1.46-1.52(m,2H),1.25-1.30 (m,2H).
实施例14：化合物14的合成
(S)-1-(2-(((S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-5-环丙基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000089
采用实施例1相同的方法，使用中间体A2和中间体B7进行反应后得到化合物14。
LCMS:m/z 424.4[M+H]+；RT＝0.96min.
1H-NMR(MeOD-d4,400MHz):δ9.11(s,1H),7.97-8.03(m,2H),7.90-7.92(d,J＝7.6Hz,1H),7.60-7.70(m,4H),5.44(s,1H),4.69(s,1H),3.54-3.60(m,1H),3.13-3.19(m,1H),1.72-1.76(m,3H),1.15-1.19(m,1H),0.26-0.65(m,4H).
实施例15：化合物15的合成
(S)-1-(2-((1-(1-(4-氯苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-5-环丙基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000090
采用实施例1相同的方法，使用中间体A6和中间体B7进行反应后得到化合物15。
LCMS:m/z 436.4[M+H]+；RT＝1.11min.
1H-NMR(MeOD-d4,400MHz):δ8.49-8.94(m,1H),7.94-7.95(m,2H),7.59(s,5H),4.56(s,1H),3.56(s,1H),1.51-1.62(m,4H),1.28-1.36(m,2H),0.20-0.85(m,4H).
实施例16：化合物16的合成
(S)-1-(2-((1-(4’-氯-[1,1’-联苯]-4-基)环丙基)氨基)嘧啶-4-基)-5-异丙基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000091
采用实施例1相同的方法，使用中间体A9和中间体B1进行反应后得到化合物16。
LCMS:m/z 448.3[M+H]+；RT＝1.102min.
1H-NMR(CDCl3-d1,400MHz):δ8.10(d,J＝5.6Hz,1H),7.55(d,J＝5.6Hz,1H),7.48-7.37(m,6H),7.18(d,J＝8.0Hz,2H),6.10(br,1H),4.89(s,1H),4.46(s,1H),3.73(m,1H),3.20-3.18(m,1H),2.15-2.12(m,1H),1.39-1.23(m,6H),0.63-0.51(m,4H).
实施例17：化合物17的合成
(S)-3-(2-(((S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000092
采用实施例1相同的方法，使用中间体A2和中间体B8进行反应后得到化合物17。
LCMS:m/z 440.3[M+H]+；RT＝0.960min.
1H-NMR(CDCl3-d1,400MHz):δ8.01-7.99(d,J＝4.8Hz,1H),7.69(s,1H),7.47-7.46(d,J＝5.2Hz,1H),7.37-7.35(d,J＝7.6Hz,2H),7.00(s,1H),5.45(s,1 H),5.09(s,1H),4.47-4.45(d,J＝9.2Hz,1H),3.30-3.28(m,1H),3.10-3.08(m,1H),2.79(s,3H),2.34(s,1H),1.55-1.54(d,J＝6.4Hz,3H),0.87-0.85(d,J＝7.2Hz,3H),0.62-0.60(d,J＝5.6Hz,3H).
实施例18：化合物18的合成
(S)-3-(2-(((R)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000093
采用实施例1相同的方法，使用中间体A3和中间体B8进行反应后得到化合物18。
LCMS:m/z 440.3[M+H]+；RT＝0.993min.
1H-NMR(CDCl3-d1,400MHz):δ8.94(s,1H),7.96(s,1H),7.85-7.83(d,J＝5.6Hz,1H),7.66(s,1H),7.58-7.56(d,J＝7.6Hz,1H),7.49-7.47(d,J＝7.6Hz,2H),5.53(s,1H),4.63-4.62(d,J＝6.8Hz,1H),3.56-3.52(m,1H),3.26-3.24(m,1H),2.94(s,3H),2.22(s,1H),1.74-1.73(d,J＝4.8Hz,3H),0.85-0.84(d,J＝5.2Hz,3H),0.72-0.71(d,J＝6.0Hz,3H).
实施例19：化合物19的合成
(S)-3-(2-((1-(1-(4-氯苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000094
采用实施例1相同的方法，使用中间体A6和中间体B8进行反应后得到化合物19。
LCMS:m/z 452.2[M+H]+；RT＝1.20min.
1H-NMR(CDCl3-d1,400MHz):δ8.03(s,1H),7.58(s,1H),7.52-7.51(d,J＝4.8Hz,1H),7.34-7.24(d,J＝8.0Hz,2H),7.18-7.16(m,1H),6.91(s,1H),5.71(s,1H),4.34-4.33(d,J＝4.0Hz,1H),3.29-3.25(m,1H),3.06-3.05(m,1H),2.77(s,3H),2.31-2.26(m,1H),1.47-1.45(m,3H),0.82-0.77(m,2H),0.62-0.56(m,6H).
实施例20：化合物20的合成
(S)-5-异丙基-1-(2-((1-(1-(对甲苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)咪唑烷-2-酮
Figure PCTCN2017077467-appb-000095
采用实施例1相同的方法，使用中间体A12和中间体B1进行反应后得到化合物20。
LCMS:m/z 418.3[M+H]+；RT＝0.349and 0.873min.
1H-NMR(CDCl3-d1,400MHz):δ8.12(s,1H),7.78-7.58(m,2H),7.23-7.10(m,4H),7.00(s,1H),5.97(s,1H),5.07(s,1H),4.56(s,1H),3.45-3.25(m,2H),2.37(s,4H),1.53-1.50(m,2H),0.97-0.71(m,8H).
实施例21：化合物21的合成
(S)-1-(2-((1-(1-(4-乙基苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-5-异丙基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000096
采用实施例1相同的方法，使用中间体A13和中间体B1进行反应后得到化合物21。
LCMS:m/z 432.3[M+H]+；RT＝0.343and 0.919min.
1H-NMR(CDCl3-d1,400MHz):δ8.15(s,1H),7.86-7.71(m,2H),7.28(s,2H),7.23-7.21(d,J＝7.2Hz,2H),7.05(s,1H),6.27-6.22(m,1H),5.35(s,1H),4.54-4.53(d,J＝6.4Hz,1H),3.46-3.41(m,1H),3.26-3.24(m,1H),2.71-2.66(m 2H),2.39(s,1H),1.51(s,2H),1.25(s,3H),1.00-0.73(m,8H).
实施例22：化合物22的合成
(S)-5-异丙基-1-(2-((1-(1-(3-(三氟甲基)苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)咪唑烷-2-酮
Figure PCTCN2017077467-appb-000097
采用实施例1相同的方法，使用中间体A14和中间体B1进行反应后得到化合物22。
LCMS:m/z 472.1[M+H]+；RT＝0.935min.
1H-NMR(CDCl3-d1,400MHz):δ8.13(s,1H),7.92(s,1H),7.64(s,3H),7.59(s,2H),7.19(s,1H),5.54(s,1H),4.52(s,1H),3.48-3.44(m,1H),3.28-3.26(m,1H),2.40(s,1H),1.53(s,2H),0.99-0.73(m,8H).
实施例23：化合物23的合成
(S)-5-异丙基-1-(2-((1-(1-(间甲苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)咪唑烷-2-酮
Figure PCTCN2017077467-appb-000098
采用实施例1相同的方法，使用中间体A15和中间体B1进行反应后得到化合物23。
LCMS:m/z 418.3[M+H]+；RT＝0.864min.
1H-NMR(CDCl3-d1,400MHz):δ8.08-8.00(m,1H),7.75-7.65(m,1H),7.53-7.42(m,1H),7.25-7.22(m,1H),7.07-6.95(m,4H),6.13-6.05(m,1H),5.24-5.17(m,1H),4.48-4.46(d,J＝7.6Hz,1H),3.38-3.33(m,1H),3.18-3.16(d,J＝7.6Hz,1H),2.33-2.32(d,J＝6.0Hz,4H),1.46-1.43(m,2H),0.88-0.63(m,8H).
实施例24：化合物24的合成
(S)-3-(2-((1-(1-(3-氯-4-甲基苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000099
采用实施例1相同的方法，使用中间体A16和中间体B8进行反应后得到化合物24。
LCMS:m/z 466.2[M+H]+；RT＝1.036min.
1H-NMR(CDCl3-d1,400MHz):δ8.16(s,1H),7.94-7.71(m,2H),7.33-7.31(m,2H),7.15-7.13(d,J＝7.2Hz,2H),4.41-4.40(d,J＝6.0Hz,H),3.40-3.35(m,1H),3.16-3.14(d,J＝8.0Hz,1H),2.91(s,3H),40(s,4H),1.49(s,2H),0.96-0.87(m,2 H),0.80-0.66(m,6H).
实施例25：化合物25的合成
(S)-5-异丙基-1-(2-((1-(1-(5-甲基吡啶-2-基)-1H-咪唑-4-基)环丙基)氨基)-2-酮
Figure PCTCN2017077467-appb-000100
采用实施例1相同的方法，使用中间体A17和中间体B1进行反应后得到化合物25。
LCMS:m/z 419.2[M+H]+；RT＝0.350and 0.830min.
1H-NMR(CDCl3-d1,400MHz):δ8.52(s,1H),8.11(s,1H),7.72-7.66(m,1H),7.55-7.49(m,2H),7.27-7.22(m,1H),6.99(s.1H),5.99(d,J＝2.4Hz,1H),5.02(s,1H),4.56(s,1H),3.51-3.41(m,1H),3.25(s,1H),2.59(s,3H),2.39(s,1H),1.55-1.43(m,2H),1.00-0.98(m,2H),0.71(s,6H).
实施例26：化合物26的合成
(S)-3-(2-((1-(1-(3,5-二氯苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000101
采用实施例1相同的方法，使用中间体A18和中间体B8进行反应后得到化合物26。
LCMS:m/z 486.3[M+H]+；RT＝1.31min(2.00min).
1H-NMR(CDCl3-d1,400MHz):δ10.86(s,1H),8.20(s,1H),7.96(d,J＝6.8Hz, 1H),7.77(d,J＝7.2Hz,1H),7.42(s,1H),7.30(s,2H),7.18(s,1H),4.44-4.42(m,1H),3.47-3.42(m,1H),3.19(d,J＝10.0Hz,1H),2.90(s,3H),2.28-2.25(m,1H),1.64-1.40(m,4H),0.78-0.67(m,6H).
实施例27：化合物27的合成
(S)-4-异丙基-1-甲基-3-(2-((1-(1-(3-(三氟甲基)苯基)-1H-咪唑-4-基)环丙基)氨基))咪唑烷-2-酮
Figure PCTCN2017077467-appb-000102
采用实施例1相同的方法，使用中间体A14和中间体B8进行反应后得到化合物27。
LCMS:m/z 486.3[M+H]+；RT＝1.018min.
1H-NMR(CDCl3-d1,400MHz):δ9.40-9.27(m,1H),8.45-8.35(m,1H),7.97-7.95(d,J＝5.6Hz,1H),7.79(s,1H),7.76-7.74(d,J＝6.8Hz,1H),7.65(s,1H),7.55-7.52(m,3H),3.27-3.14(m,1H),2.97-2.95(d,J＝8.0Hz,1H),2.58(s,3H),1.83(s,1H),1.03-0.99(m,2H),0.69(s,1H),0.50(s,1H),0.23(s,6H).
实施例28：化合物28的合成
(S)-3-(2-((1-(1-(3-氯-4-氟苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-4-异丙基-1--甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000103
采用实施例1相同的方法，使用中间体A19和中间体B8进行反应后得到化合 物28。
LCMS:m/z 470.1[M+H]+；RT＝1.012min.
1H-NMR(CDCl3-d1,400MHz):δ8.00-7.95(m,1H),7.82-7.77(m,1H),7.58(s,1H),7.38-7.23(m,4H),4.49(s,1H),3.46(s,1H),3.21-3.18(m,1H),2.90(s,3H),2.28-2.26(m,1H),1.72-1.54(m,4H),0.95-0.69(m,6H).
实施例29：化合物29的合成
(S)-5-异丙基-1-(2-((1-(1-(6-甲基吡啶-3-基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-2-酮
Figure PCTCN2017077467-appb-000104
采用实施例1相同的方法，使用中间体A20和中间体B1进行反应后得到化合物29。
LCMS:m/z 419.2[M+H]+；RT＝0.830min.
1H-NMR(CDCl3-d1,400MHz):δ8.52(s,1H),8.11(s,1H),7.72-7.66(m,1H),7.55-7.49(m,2H),7.27-7.22(m,1H),6.99(s.1H),5.99(d,J＝2.4Hz,1H),5.02(s,1H),4.56(s,1H),3.51-3.41(m,1H),3.25(s,1H),2.59(s,3H),2.39(s,1H),1.55-1.43(m,2H),1.00-0.98(m,2H),0.71(s,6H).
实施例30：化合物30的合成
(S)-3-(2-((1-(1-(3-异丙基苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000105
采用实施例1相同的方法，使用中间体A21和中间体B8进行反应后得到化合物30。
LCMS:m/z 460.4[M+H]+；RT＝1.013min.
1H-NMR(CDCl3-d1,400MHz):δ11.0(s,1H),8.61(s,1H),7.97(d,J＝6.4Hz,1H),7.76(d,J＝7.2Hz,1H),7.46-7.18(m,5H),4.56-4.55(m,1H),3.49-3.45(m,1H),3.21-3.17(m,1H),3.02-2.90(m,1H),2.85(s,3H),2.24-2.21(m,1H),1.72-1.47(m,4H),1.29-1.25(m,6H),0.88-0.61(m,6H).
实施例31：化合物31的合成
(S)-3-(2-((1-(1-(3-氯苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000106
采用实施例1相同的方法，使用中间体A22和中间体B8进行反应后得到化合物31。
LCMS:m/z 452.2[M+H]+；RT＝1.001min.
1H-NMR(CDCl3-d1,400MHz):δ8.49(s,1H),7.98-7.97(d,J＝7.2Hz,1H),7.79-7.77(d,J＝7.2Hz,1H),7.53-7.30(m,5H),4.51-4.48(d,J＝8.8Hz,1H),3.49-3.44(m,1H),3.21-3.19(m,1H),2.91(s,3H),2.27-2.26(d,J＝2.4Hz,1H),1.68-1.45(m,4H),0.82-0.80(d,J＝6.8Hz,3H),0.70-0.68(d,J＝6.8Hz,3H).
实施例32：化合物32的合成
(S)-3-(2-((1-(1-(3,5-二氟-4-甲基苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000107
采用实施例1相同的方法，使用中间体A23和中间体B8进行反应后得到化合物32。
LCMS:m/z 468.3[M+H]+；RT＝1.015min(2.5min,Acid).
1H NMR(MeOD-d4,400MHz):δ8.55-8.62(m,1H),7.98-8.01(m,2H),7.64-7.73(m,1H),7.30-7.32(m,2H),4.37-4.40(m,1H),3.47-3.48(m,2H),2.88(s,3H),2.21(m,4H),1.41-1.58(m,4H),0.62-1.00(m,6H).
实施例33：化合物33的合成
(S)-3-(2-((1-(1-(环己基甲基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000108
采用实施例1相同的方法，使用中间体A25和中间体B8进行反应后得到化合物33。
LCMS:m/z 438.4[M+H]+；RT＝0.848min.
1H NMR(CDCl3-d1,400MHz):δ8.07-8.08(d,J＝5.2Hz,1H),7.54-7.55(d,J＝5.6Hz,1H),7.22(s,1H),6.58(s,1H),5.72(brs,1H),4.38(m,1H),3.59-3.60(d,J＝6.8Hz,2H),3.12-3.34(m,2H),2.84(s,3H),2.40(m,1H),0.80-1.70(m,21H).
实施例34：化合物34的合成
(S)-3-(2-((1-(1-(3-环丙基苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000109
采用实施例1相同的方法，使用中间体A26和中间体B8进行反应后得到化合物34。
LCMS:m/z 458.5[M+H]+；RT＝1.12min(2.0min).
1H-NMR(CDCl3-d1,400MHz):δ10.97(s,1H),8.72(s,1H),7.99(d,J＝7.2Hz,1H),7.78(d,J＝7.2Hz,1H),7.40(t,J＝8.0Hz,1H),7.31(s,1H),7.18-7.11(m,3H),4.55(d,J＝8.8Hz,1H),3.48-3.45(m,1H),3.20(d,J＝8.8Hz,1H),2.91(s,3H),2.25(s,1H),1.96-1.95(m,1H),1.72-1.49(m,4H),1.08-1.05(m,2H),0.84(d,J＝7.2Hz,2H),0.75(d,J＝4.4Hz,2H),0.70(d,J＝6.4Hz,2H).
实施例35：化合物35的合成
(S)-3-(2-((1-(1-(3-氯-4-甲基苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-4-异丙基-1--甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000110
采用实施例1相同的方法，使用中间体A16和中间体B8进行反应后得到化合物35。
LCMS:m/z 466.2[M+H]+；RT＝1.036min.
1H-NMR(CDCl3-d1,400MHz):δ8.16(s,1H),7.94-7.71(m,2H),7.33-7.31(m, 2H),7.15-7.13(d,J＝7.2Hz,2H),4.41-4.40(d,J＝6.0Hz,1H),3.40-3.35(m,1H),3.16-3.14(d,J＝8.0Hz,1H),2.91(s,3H),40(s,4H),1.49(s,2H),0.96-0.87(m,2H),0.80-0.66(m,6H).
实施例36：化合物36的合成
(S)-3-(2-((1-(1-(4,4-二氟环己基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000111
采用实施例1相同的方法，使用中间体A27和中间体B8进行反应后得到化合物36。
LCMS:m/z 460.2[M+H]+；RT＝0.878min.
1H NMR(MeOD-d4,400MHz):δ8.23(s,1H),7.62(m,1H),6.74-6.75(m,1H),6.13(m,1H),4.41(m,1H),4.00-4.02(m,1H),3.14-3.38(m,2H),2.87(s,3H),2.37(m,1H),1.85-2.08(m,8H),1.41-1.44(m,2H),0.86-0.93(m,2H),0.67-0.77(m,6H).
实施例37：化合物37的合成
(S)-4-异丙基-1-甲基-3-(2-((1-(1-(4-甲基环己基)-1H-咪唑-4-基)环丙基)氨基)-2-酮
Figure PCTCN2017077467-appb-000112
采用实施例1相同的方法，使用中间体A28和中间体B8进行反应后得到化合 物37。
LCMS:m/z 438.4[M+H]+；RT＝0.833min.
1H-NMR(CDCl3-d1,400MHz):δ8.41(s,1H),7.89-7.85(m,2H),6.92(s,1H),5.30(s,1H),4.40(d,J＝8.8Hz,1H),3.39-3.37(m,1H),3.18-3.16(m,1H),2.95(s,3H),2.41-2.39(m,1H),2.11-1.89(m,10H),1.78-1.77(m,3H),1.17-1.13(m,3H),0.99-0.93(m,6H).
实施例38：化合物38的合成
(S)-3-(2-((1-(1-(3-氯-5-甲氧基苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-4-异丙基-1--甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000113
采用实施例1相同的方法，使用中间体A29和中间体B8进行反应后得到化合物38。
LCMS:m/z 482.2[M+H]+；RT＝1.058min.
1H-NMR(CDCl3-d1,400MHz):δ8.09-8.07(d,J＝5.6Hz,1H),7.66(s,1H),7.59-7.58(d,J＝5.6Hz,1H),6.98(s,1H),6.89(s,1H),6.83(s,1H),6.71(s,1H),6.03(s,1H),4.41-4.40(d,J＝6.4Hz,1H),3.82(s,3H),3.36-3.32(m,1H),3.13-3.11(d,J＝6.8Hz,1H),2.84(s,3H),2.58-2.45(m,1H),1.55-1.48(m,2H),0.88-0.86(m,2H),0.69-0.63(m,6H).
实施例39：化合物39的合成
(S)-3-(2-((1-(1-(4-环丙基苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000114
采用实施例1相同的方法，使用中间体A31和中间体B8进行反应后得到化合物39。
LCMS:m/z 458.2[M+H]+；RT＝0.967min
1H-NMR(CDCl3-d1,400MHz):δ10.93(s,1H),8.71(s,1H),7.98(d,J＝6.8Hz,1H),7.78(d,J＝6.8Hz,1H),7.29-7.26(m,2H),7.20(d,J＝8.0Hz,3H),4.54(d,J＝8.0Hz,1H),3.47-3.45(m,1H),3.19(d,J＝9.6Hz,1H),2.91(s,3H),2.25(s,1H),1.96-1.95(m,1H),1.53-1.50(m,4H),1.07(d,J＝7.2Hz,2H),0.82(d,J＝6.8Hz,2H),0.74(d,J＝4.4Hz,3H),0.69(d,J＝6.8Hz,3H).
实施例40：化合物40的合成
(S)-3-(2-((1-(1-(环戊基甲基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000115
采用实施例1相同的方法，使用中间体A32和中间体B8进行反应后得到化合物40。
LCMS:m/z 424.4[M+H]+；RT＝0.953min.
1H-NMR(CDCl3-d1,400MHz):δ10.86(s,1H),8.63(s,1H),7.97-7.99(m,1H),7.77-7.79(m,1H),7.05(s,1H),4.50-4.52(m,1H),3.94-3.96(m,2H),3.45-3.47(m,1H),3.19-3.21(m,1H),2.91(s,3H),2.22-2.32(m,2H),1.61-1.74(m,8H),1.21-1.25(m,4H),0.82-0.84(m,3H),0.70-0.71(m,3H).
实施例41：化合物41的合成
采用实施例1相同的方法，使用中间体A22和中间体B29进行反应后得到化合物41。
(S)-1-(2-(1-(1-(3-氯苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-1-乙基-4--异丙基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000116
1H-NMR(CDCl3,400MHz):8.87(s,1H),8.02-8.01(d,J＝6.0Hz,1H),7.84-7.82(d,J＝6.8Hz,1H),7.50(s,3H),7.40(s,2H),4.51-4.49(d,J＝8.4Hz,1H),3.50-3.38(m,2H),3.35-3.21(m,2H),2.26(s,1H),1.70-1.54(m,4H),1.20-1.16(m,3H),0.83-0.81(d,J＝6.8Hz,3H),0.72-0.71(d,J＝6.8Hz,3H).
LCMS:m/z 466.1[M+H]+,RT＝1.040min.
实施例42：化合物42的合成
(S)-甲基3-(4-(1-((4-(5-异丙基-3-甲基-2-氧代咪唑啉-1-基)嘧啶-2-基)氨基)丙基)-1H-咪唑嗪-1-基)苯甲酸甲酯
Figure PCTCN2017077467-appb-000117
步骤一：采用实施例1相同的方法，使用中间体A62和中间体B27进行反应后得到中间体42-1:(S)-1-(2-(1-(1-(3-溴苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-1-甲基-4-异丙基咪唑烷-2-酮，LCMS:m/z 497.9[M+H]+,RT＝0.983min.
步骤二：在盛有20毫升的甲醇溶液的100毫升的单口瓶中依次加入中间体42-1(100毫克，0.2毫摩尔)，三乙胺(40毫克)和PdCl2(dppf)2(20毫克)，70摄氏度下搅拌过夜，TLC检测反应完全后，体系浓缩后高效制备色谱分离(TFA)得到化合物42(80毫克，收率：84％)，产品为白色固体。
1H-NMR(CDCl3,400MHz):10.94(s,1H),8.63(s,1H),8.16(d,J＝6.8Hz,1H),8.07(s,1H),7.99(s,J＝6.8Hz,1H),7.79(d,J＝6.0Hz,1H),7.63(s,2H),7.34(s,1H),4.52(d,J＝7.2Hz,1H),3.97(s,3H),3.50-3.45(m,1H),3.20(d,J＝9.6Hz,1H),2.91(s,3H),2.27(s,1H),1.71-1.50(m,4H),0.81(d,J＝6.4Hz,3H),0.69(d,J＝6.4Hz, 3H).
LCMS:m/z 476.2[M+H]+,RT＝0.91min
实施例43：化合物43的合成
采用实施例1相同的方法，使用中间体A34和中间体B27进行反应后得到化合物43。
(S)-3-(2-((1-(1-(苯并[d][1,3]二氧杂环戊烯-5-基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基硫代)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000118
1H-NMR(CDCl3,400MHz):8.09-8.07(d,J＝8.0Hz,1H),7.57-7.55(d,J＝8.0Hz,2H),6.90(s,1H),6.82-6.80(d,J＝8.0Hz,1H),6.75-6.71(m,2H),6.01(s,2H),5.69(s,1H),4.43-4.41(d,J＝8.0Hz,1H),3.36-3.31(m，1H)3.13-3.11(m,1H),4.34(m,1H),2.84(s,3H),2.37-2.35(s,1H),1.25-1.21(m,2H),1.19-1.14(m,2H),0.69-0.56(m,3H),0.06-0.00(m,3H).
LCMS:m/z 462.3[M+H]+,RT＝0.86min
实施例44：化合物44的合成
采用实施例1相同的方法，使用中间体A35和中间体B27进行反应后得到化合物44。
(S)-3-(2-((1-(1-(3-溴-5-氯苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000119
1H-NMR(CDCl3,400MHz):8.09(d,J＝6.0Hz,1H),7.66(s,1H),7.58(d,J＝2.4Hz,1H),7.45(s,1H),7.35(s,1H),7.24-7.26(m,1H),6.98(s,1H),5.70(s,1H),4.39-4.41(m,1H),3.32-3.36(m,1H),3.11-3.13(m,1H),2.84(s,3H),2.38(brs,1H),1.23-1.25(m,2H),0.81-0.84(m,3H),0.64-0.70(m,6H).
LCMS:m/z 532.1[M+H]+,RT＝1.3min.
实施例45：化合物45的合成
(S)-3-氯-5-(4-(1-((4-(5-异丙基-3-甲基咪唑烷-2-酮-1-基)嘧啶-2-基)胺基)环丙基)-1H-咪唑烷-1-基)苯氰
Figure PCTCN2017077467-appb-000120
在干燥的25mL的单口瓶中依次加入化合物44(80mg,0.15mmol,1.0eq)，氰化锌(75mg,1.5mmol,10.0eq),溶于N,N-二甲基甲酰胺(5mL)。氮气保护下,加入四三苯基膦钯(35毫克,0.03毫摩尔).加热至100摄氏度反应6小时。将反应液过滤,通过制备高效液相色谱仪纯化得到产品(S)-3-氯-5-(4-(1-((4-(5-异丙基-3-甲基咪唑烷-2-酮-1-基)嘧啶-2-基)胺基)环丙基)-1H-咪唑烷-1-基)苯氰(化合物45)(10mg,白色固体)，产率：14.1％。
1H-NMR(CDCl3,400MHz):8.03(d,J＝6.0Hz,1H),7.63(s,1H),7.46-7.53(m,3H),7.41(s,1H),6.95(s,1H),5.59(s,1H),4.39-4.41(m,1H),3.32-3.36(m,1H),3.11-3.13(m,1H),2.77(s,3H),2.38(brs,1H),1.23-1.25(m,1H),0.81-0.84(m,4H),0.64-0.70(m,6H).
LCMS:m/z 477.3[M+H]+,RT＝1.2min.
实施例46：化合物46的合成
采用实施例1相同的方法，使用中间体A36和中间体B27进行反应后得到化合物46。
(S)-3-(2-((1-(1-(4,4-二甲基环己基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000121
1H NMR(CDCl3-d1,400MHz)：δ8.08(d,J＝6.0Hz,1H),7.55(d,J＝6.0Hz,1H),7.35(s,1H),6.68(s,1H),5.68(s,1H),4.42-4.40(m,1H),3.72-3.69(m,1H),3.34(t,J＝9.6Hz,1H),3.14-3.11(m,1H),2.85(s,3H),2.32(m,1H),1.84-1.81(m,4H),1.51-1.27(m,6H),1.17(m,2H),0.95(s,6H),0.69-0.0.63(m,6H).
LCMS:m/z 454.2[M+H]+,RT＝0.97min.
实施例47：化合物47的合成
采用实施例1相同的方法，使用中间体A37和中间体B27进行反应后得到化合物47。
(S)-3-(2-((1-(1-(3-溴-5-氟苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000122
1H-NMR(CDCl3,400MHz):8.09(d,J＝6.0Hz,1H),7.67(s,1H),7.59(d,J＝2.8Hz,1H),7.19-7.26(m,2H),6.97-6.99(m,2H),5.77(s,1H),4.30-4.40(m,1H),3.32-3.36(m,1H),3.12-3.13(m,1H),2.84(s,3H),2.36-2.38(m,1H),1.51-1.59(m,2H),1.21-1.23(m,3H),0.57-0.65(m,6H).
LCMS:m/z 514.1[M+H]+,RT＝1.2min.
实施例48：化合物48的合成
((S)-3-(2-((1-(1-(3-氯-5-环丙基苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000123
在氮气保护的25mL的单口瓶中依次加入化合物54(100mg,0.189mmol,1.0eq)，环丙基硼酸(16mg,0.189mmol,1.0eq),1,1’-双二苯基膦二茂铁二氯化钯(14毫克,0.0189毫摩尔),碳酸钾(52毫克,0.378毫摩尔),以及1,4二氧六环(5毫升)和水(5毫升)。反应加热至100摄氏度反应8小时.反应冷至室温后,用乙酸乙酯萃取(2*10毫升)。有机相浓缩后,通过制备高效液相色谱仪纯化得到产品((S)-3-(2-((1-(1-(3-氯-5-环丙基苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮(化合物48)(35mg,白色固体)，产率：37.6％。
1H-NMR(CDCl3,400MHz):10.92(s,1H),8.44(s,1H),7.96(d,J＝6.0Hz 1H),7.77(d,J＝6.8Hz,1H),7.22(s,1H),7.15(s,1H),6.99(s,1H),6.83(s,1H),4.48-4.50(m,2H),3.44-3.48(m,1H),3.18-3.21(m,1H),2.90(s,3H),2.87-2.90(m,1H),1.92-1.93(m,1H),1.46-1.57(m,3H),1.08-1.10(m,1H),1.02-1.04(m,2H),0.62-0.81(m,8H)。
LCMS:m/z 492.2[M+H]+,RT＝1.1min.
实施例49：化合物49的合成
采用实施例1相同的方法，使用中间体A38和中间体B8进行反应后得到化合物49。
(S)-1-(2-(((S)-1-(1-(3-氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-5-异丙基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000124
1H-NMR(CDCl3,400MHz):1.08-8.07(m,1H),7.77(s,1H),7.55-7.54(m,1H),7.39-7.31(m,3H),7.23(m,1H)，7.09(s,1H),5.48-5.45(m,1H)5.14(m,1H),4.52(m,1H), 3.38(m,1H),3.17(m,1H),2.85(s,3H)2.40(s,1H)，1.62-1.59(m,3H),0.81-0.79(m,3H),0.70-0.68(m,3H).
LCMS:m/z 440.3[M+H]+,RT＝1.06min.
实施例50：化合物50的合成
采用实施例1相同的方法，使用中间体A39和中间体B27进行反应后得到化合物50。
(S)-3-(2-((1-(1-(5-氯-2-氟苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000125
1H NMR(CDCl3-d1,400MHz)：δ10.30(s,1H),8.80(s,1H),7.99-7.87(m,2H),7.52-7.49(m,2H),7.30(s,1H),4.48-4.47(m,1H),3.52-3.48(m,1H),3.23-3.21(m,1H)2.92(s,3H),2.25(m,1H),1.64-1.56(m,4H),0.82-0.71(m,6H).
LCMS:m/z 470.2[M+H]+,RT＝1.08min.
实施例51：化合物5的合成
采用实施例1相同的方法，使用中间体A40和中间体B27进行反应后得到化合物51。
(S)-3-(2-((1-(1-(2-氯苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000126
1H-NMR(CDCl3,400MHz)：8.02(s,1H),7.57(s,2H),7.46-7.44(m,1H),7.30(s,2H),7.20(s,1H),6.89(s,1H),4.35-4.33(d,J＝8.8Hz,1H),3.31-3.26(m,1H),3.09-3.07(m,1H),2.78(s,3H),2.36-2.30(m,1H),1.46-1.43(m,2H),1.18(s,2H),0.73(s,3H),0.62-0.60(d,J＝6.4Hz,3H).
LCMS:m/z 452.1[M+H]+,RT＝0.96min.
实施例52：化合物52的合成
采用实施例1相同的方法，使用中间体A41和中间体B8进行反应后得到化合物52。
(S)-3-(2-(((S)-1-(1-(3-环丙苯基)-1氢-咪唑-4-基)乙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000127
1H NMR(CDCl3-d1,400MHz)：δ8.07(d,J＝6.0Hz,1H),7.75(s,1H),7.53(d,J＝6.0Hz 1H),7.32-7.26(m,1H),7.08(d,J＝10Hz,2H),7.02(d,J＝2.0Hz,1H),5.42(d,J＝4.0Hz,1H),5.15(d,J＝6.4Hz,1H)4.55-4.53(m,1H),3.40-3.35(m,1H),3.17-3.14(m,1H),3.28(s,3H),2.44-2.43(m,1H),1.95-1.90(m,1H),1.51(s,3H),1.05-0.89(m,3H),0.88-0.76(m,3H),0.75-0.70(m,2H),0.69-0.60(m,3H).
LCMS:m/z 440.4[M+H]+,RT＝0.98min.
实施例53：化合物53的合成
采用实施例48相同的方法，由化合物47进行反应后得到化合物53。
(S)-3-(2-((1-(1-(3-氟-5-环丙基苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000128
1H-NMR(CDCl3,400MHz):8.06(s,1H),7.59-7.66(m,2H),7.00(s,1H),6.68-6.79(m,2H),6.66(s,1H),5.88(s,1H),4.39-4.41(m,1H),3.32-3.37(m,1H),3.12-3.14(m,1H),2.84(s,3H),2.45-2.48(m,1H),1.92-1.97(m,1H),1.45(s,3H),1.08-1.10(m,1H),1.04-1.06(m,2H),0.76-0.93(m,8H).
LCMS:m/z 476.6[M+H]+,RT＝1.32min.
实施例54：化合物54的合成
采用实施例1相同的方法，使用中间体A42和中间体B8进行反应后得到化合物54。
Figure PCTCN2017077467-appb-000129
1H NMR(400MHz,dmso)δ9.32(s,1H),9.19(s,1H),8.17(s,1H),8.00(s,1H),7.69(s,1H),7.54(s,1H),7.48(s,1H),7.34(s,1H),5.16(s,1H),4.40(d,J＝7.9Hz,1H),3.41(t,J＝9.3Hz,1H),3.23(d,J＝9.3Hz,1H),3.00-2.84(m,1H),2.76(s,3H),1.95(s,1H),1.59(d,J＝6.4Hz,3H),1.21(d,J＝6.7Hz,6H),0.86(d,J＝6.6Hz,1H),0.61(d,J＝21.0Hz,6H).
LCMS:m/z 448.3[M+H]+,RT＝1.38min.
实施例55：化合物55的合成
采用实施例1相同的方法，使用中间体A43和中间体B8进行反应后得到化合物55。
(S)-4-异丙基-1-甲基-3-(2-(((S)-1-(1-(对甲苯基)-1H-咪唑-4-基)甲基)胺)嘧啶-4-基)咪唑烷-2-酮
Figure PCTCN2017077467-appb-000130
1H-NMR(CDCl3,400MHz)：8.09-8.07(d,J＝6.4Hz,1H),7.74(s,1H),7.54-7.53(d,J＝6.4Hz,1H),7.24-7.20(m,4H),7.06(s,1H),5.48-5.40(m,1H),5.17-5.15(d,J＝7.2Hz,1H),4.55-4.53(m,1H),3.40-3.35(m,1H),3.18-3.14(m,1H),2.86(s,3H),2.39(s,4H),1.63(s,3H),0.81-0.79(d,J＝6.4Hz,3H),0.69-0.68(d,J＝6.4Hz,3H).
LCMS:m/z 420.2[M+H]+,RT＝0.90min.
实施例56：化合物56的合成
采用实施例1相同的方法，使用中间体A44和中间体B8进行反应后得到化合物56。
(S)-3-(2-(((S)-1-(1-(4,4-二甲基环己基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4- 基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000131
1H NMR(CDCl3-d1,400MHz)：δ8.05(d,J＝5.6Hz,1H),7.51(d,J＝5.6Hz,1H),7.49(s,1H),6.86(s,1H),5.47(br s,1H),5.16-5.12(m,1H),4.56-4.54(m,1H),3.83-3.77(m,1H)3.38(t,J＝9.2Hz,1H),3.20-3.17(m,1H),2.86(s,3H),2.63-2.60(m,1H),1.93-1.73(m,6H),1.54(d,J＝6.4Hz,3H),1.38-1.32(m,2H),0.99(s,3H),0.98(s,3H),0.92(d,J＝6.8Hz,3H),0.77(d,J＝6.8Hz,3H)
LCMS:m/z 440.4[M+H]+,RT＝1.00min.
实施例57：化合物57的合成
采用实施例1相同的方法，使用中间体A45和中间体B8进行反应后得到化合物57。
(S)-3-(2-(((S)-1-(1-(3-氯-5-氟苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000132
1H-NMR(CDCl3,400MHz)：8.09-8.08(d,J＝6.0Hz,1H),7.78(s,1H),7.55-7.54(d,J＝6.0Hz,1H),7.17(s,1H),7.08-7.07(m,2H),7.00-6.98(m,1H),5.37-5.35(d,J＝7.6Hz,1H),5.17-5.14(m,1H),4.56-4.52(m,1H),3.40-3.38(m,1H),3.18-3.15(m,1H),2.86(s,3H),2.41(s,1H),1.62-1.60(d,J＝6.8Hz,1H),0.81-0.80(d,J＝6.4Hz,3H),0.70-0.68(d,J＝6.8Hz,3H).
LCMS:m/z 458.2[M+H]+,RT＝0.97min.
实施例58：化合物58的合成
采用实施例1相同的方法，使用中间体A46和中间体B8进行反应后得到化合物58。
(S)-4-异丙基-1-甲基-3-(2-(((S)-1-(1-(4-三氟甲基)苯基)-1氢-咪唑-4-基)乙基) 氨基)嘧啶-4-基)甲基咪唑烷-2-酮的合成
Figure PCTCN2017077467-appb-000133
1H NMR(CDCl3-d1,400MHz)：δ10.52(s,1H),8.54(s,1H),7.93(d,J＝6.4Hz1H),7.82(d,J＝.2Hz,2H),7.76(d,J＝6.4Hz,1H),7.61(m,3H),5.45(s,1H),4.62(d,J＝7.6Hz,1H)3.53(t,J＝9.2Hz,1H),3.24(d,J＝10.0Hz,1H),2.93(s,3H),3.30(s,1H),1.71(d,J＝5.2Hz,3H),0.87(d,J＝6.0Hz,3H),0.71(d,J＝6.4Hz,3H).
LCMS:m/z 474.2[M+H]+,RT＝1.14min.
实施例59：化合物59的合成
采用实施例1相同的方法，使用中间体A47和中间体B8进行反应后得到化合物59。
(S)-4-异丙基-1-甲基-3-(2–((S)-1-(1-(3-三氟甲基苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-咪唑烷-2-酮
Figure PCTCN2017077467-appb-000134
1H NMR(CDCl3-d1,400MHz)：δ8.08(d,J＝5.6Hz,1H),7.82(s,1H),7.53-7.61(m,5H),7.14(s,1H),5.37-5.39(m,1H),5.16-5.18(m,1H),,4.53-4.55(m,1H),4.08-4.09(m,1H),3.35-3.38(m,1H),3.44(s,3H),1.62(d,J＝6.8Hz,3H),0.80(d,J＝6.8Hz,3H),0.68(d,J＝6.8Hz,3H)；
LCMS:m/z 474.2[M+H]+,RT＝1.154min.
实施例60：化合物60的合成
采用实施例1相同的方法，使用中间体A48和中间体B8进行反应后得到化合物60。
(S)-3-(2-(((S)-1-(1-(3,5-二氯苯基)-1氢-咪唑-4-基)乙基)氨基)嘧啶-4-yl)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000135
1H NMR(CDCl3-d1,400MHz)：δ10.46(t,J＝1.2Hz,1H),8.55(s,1H),7.94(d,J＝6.8Hz 1H),7.78(d,J＝7.2Hz,1H),7.61(s,1H),7.50(s,1H),7.42(s,1H),7.26(s 1H)5.46(t,J＝6.4Hz,1H),4.61(d,J＝8.8Hz,1H),3.54(t,J＝9.6Hz,1H),3.24(d,J＝9.6Hz,1H),2.94(s,3H),2.27(s,1H),1.70(d,J＝6.4Hz,3H),0.85(d,J＝6.4Hz,3H),0.71(d,J＝6.8Hz,3H).
LCMS:m/z 474.2[M+H]+,RT＝1.2min.
实施例61：化合物61的合成
采用实施例1相同的方法，使用中间体A49和中间体B8进行反应后得到化合物61。
Figure PCTCN2017077467-appb-000136
(S)-1-(2-(((S)-1-(1-(3,4-二氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-5-异丙基咪唑烷-2-酮
1H-NMR(CDCl3,400MHz):8.06(d,J＝6.0Hz,1H),7.75(s,1H),7.56-7.52(m,2H),7.46(s,1H),7.21-7.19(m,1H),7.07(s,1H),7.58-7.57(m,1H),5.57-5.58(brs,1H)，5.13-5.17(m,1H),4.51-4.55(m,1H),3.38(t,J＝6.4Hz,1H),3.15-3.18(m,1H)，2.86(s,3H),2.37-2.41(m,1H),1.60(d,J＝6.8Hz,3H),0.79(d,J＝6.8Hz,3H),0.68(d,J＝6.8Hz,3H).
LCMS:m/z 474.2[M+H]+,RT＝1.14min.
实施例62：化合物62的合成
采用实施例1相同的方法，使用中间体A50和中间体B8进行反应后得到化合物62。
(S)-3-(2-(((S)-1-(1-(4-环丙基苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000137
1H-NMR(CDCl3,400MHz)：8.05(d,J＝6.0Hz,1H),7.72(s,1H),7.54(d,J＝6.0Hz,1H),7.20(d,J＝8.4Hz,2H),7.12(d,J＝8.4Hz,2H),7.06(s,1H),5.67(s,1H),5.17-5.14(m,1H),4.56-4.53(m,1H),3.41-3.36(m,1H),3.18-3.15(m,1H),2.86(s,3H),2.42(brs,1H),1.95-1.89(m,1H),1.62(d,J＝6.8Hz,3H),1.03-0.99(m,2H),0.81-0.80(m,3H),0.73-0.68(m,5H).
LCMS:m/z 446.3[M+H]+,RT＝0.9min.
实施例63：化合物63的合成
采用实施例1相同的方法，使用中间体A51和中间体B8进行反应后得到化合物63。
(S)-1-(2-(((S)-1-(1-(3-氟-4-氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-5-异丙基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000138
1H-NMR(CDCl3,400MHz):8.07(s,1H),7.77(s,1H),7.53-7.49(m,2H),7.16-7.08(m,3H),5.42(s,1H)5.15(m,1H),4.54-4.53(m,1H),3.38(m,1H),3.17(m,1H),2.85(s,3H),2.38-2.40(m,1H),2.02(m,3H),0.80(m,3H),0.68(m,3H).
LCMS:m/z 458.2[M+H]+,RT＝1.1min.
实施例64：化合物64的合成
采用实施例1相同的方法，使用中间体A60和中间体B8进行反应后得到化合物64。
(S)-3-(2-((1-(1-(3-环丙基苯基)-1H-[1,2,4]-三唑-3-基)环丙基)氨基)-1-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000139
1H-NMR(CDCl3,400MHz)：8.32(s,1H),8.13-8.11(d,J＝6.0Hz,1H),7.59-7.57(d,J＝6.0Hz,1H),7.30-7.29(m,2H),7.26(s,1H),7.02-7.00(m,1H),5.83(s,1H),4.41-4.39(m,1H),3.33-3.28(m,1H),3.12-3.09(m,1H),2.82(s,3H),2.37-2.33(m,1H),1.97-1.90(m,1H),1.62(d,J＝2.8Hz,2H),1.38-1.31(m,2H),1.03-0.99(m,2H),0.74-0.70(m,5H),0.61-0.60(d,J＝6.0Hz,3H).
LCMS:m/z 459.3[M+H]+,RT＝1.0min.
实施例65：化合物65的合成
采用实施例1相同的方法，使用中间体A52和中间体B8进行反应后得到化合物65。
(S)-3-(2-(((S)-1-(1-(4-氯-3-甲氧基苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000140
1H NMR(CDCl3-d1,400MHz)：δ8.09(d,J＝6.0Hz,1H),7.75(s,1H),7.54-7.53(m,1H),7.44-7.42(m,1H),7.08(s,1H),6.89-6.86(m,2H),5.35-5.33(m,1H),5.18-5.14(m,1H),5.56-5.52(m,1H),3.94(s,3H),3.41-3.36(m,1H),3.18-3.15(m,1H),2.86(s,3H),2.43(s,1H),1.62(d,J＝6.8Hz,3H),0.81(d,J＝6.8Hz,3H),0.69(d,J＝6.8Hz,3H).
LCMS:m/z 470.2[M+H]+,RT＝0.93min.
实施例66：化合物66的合成
采用实施例1相同的方法，使用中间体A53和中间体B8进行反应后得到化合物66。
(S)-3-(2-(((S)-1-(1-异戊基-1H-咪唑-4-基)基)氨基)嘧啶-4-基)-4-异丙基-1-甲基 咪唑烷-2-酮
Figure PCTCN2017077467-appb-000141
1H NMR(CDCl3-d1,400MHz):δ8.06(s,1H),7.51-7.50(m,1H),7.39-7.38(m,1H),6.72-6.71(m 1H),5.38(s,1H),5.08(s,1H),4.53(s,1H),3.86-3.84(m,2H),3.40-3.36(m,1H),3.18-3.16(m,1H),2.85(d,J＝6.8Hz,3H),2.46(s,1H),1.57-1.55(m,3H),0.94-0.91(m,6H),0.83-0.70(m,9H).
LCMS:m/z 400.3[M+H]+,RT＝0.72min.
实施例67：化合物67的合成
采用实施例1相同的方法，使用中间体A61和中间体B8进行反应后得到化合物67。
Figure PCTCN2017077467-appb-000142
1HNMR(CDCl3,400MHz):δ8.05(s,1H),7.55(t,J＝6.4Hz,2H),7.24-7.32(m,1H),7.00-7.11(m,2H),6.84-6.93(m,2H),5.79(s,1H),4.44(s,1H),3.32-3.39(m,2H),3.14-3.16(m,1H),2.82(s,3H),2.32-2.37(m,1H),1.57-1.60(m,2H),1.18-1.20(m,3H),0.99-1.01(m,2H),0.67-0.85(m,8H)；
LCMS:m/z 536.2[M+H]+,RT＝1.34min.
实施例68：化合物68的合成
采用实施例1相同的方法，使用中间体A54和中间体B8进行反应后得到化合物68。
Figure PCTCN2017077467-appb-000143
1H NMR(400MHz,DMS0):8.08–8.02(m,1H),7.98(d,J＝5.7Hz,1H),7.44(dd,J＝14.7,8.5Hz,2H),7.30(dd,J＝6.9,4.7Hz,4H),6.90(s,1H),4.96(s,1H),4.40(dd,J＝6.4,3.4Hz,1H),3.36(dd,J＝11.7,7.3Hz,1H),3.15(d,J＝7.0Hz,1H),2.88(dd,J＝13.7,6.9Hz,1H),2.70(d,J＝4.1Hz,3H),2.02–1.90(m,1H),1.43(t,J＝7.9Hz,3H),1.17(dd,J＝6.9,2.3Hz,6H),0.67(dd,J＝54.0,47.1Hz,6H).
LCMS:m/z 448.3/1[M+H]+,RT＝1.89min.
实施例69：化合物69的合成
(S)-1-(3-环丙基苯基)-4-(1-((4-(5-异丙基-3-甲基-2-氧代咪唑烷-1-基)嘧啶-2-基)氨基)环丙基)-1H-咪唑-5-甲腈
Figure PCTCN2017077467-appb-000144
步骤一：采用实施例1相同的方法，使用中间体A63和中间体B27进行反应后得到中间体69-1。
LCMS:m/z 536.2[M+H]+,RT＝1.11min.
步骤二：在盛有4毫升N,N-二甲基甲酰胺干燥的微波管中依次加入中间体69-1(45毫克，0.083毫摩尔)，Zn(CN)2(98毫克，0.838毫摩尔),Zn粉(10毫克)和催化量的PdCl2dppf，氮气换气3次后加热到140摄氏度微波反应2小时后，LCMS检测反应完毕，过滤，高效液相制备分离得到化合物69(20毫克，收率：50％)，产品为黄色固体。
1H-NMR(CDCl3,400MHz):10.78(s,1H),8.44(s,1H),7.97(d,J＝5.2Hz,1H),7.79-7.72(m,2H),7.29-7.26(m,2H),6.97(s,1H),4.47(d,J＝7.2Hz,1H),3.45(t,J＝9.2Hz,1H),3.19(d,J＝9.2Hz,1H),2.91(s,3H),2.36-2.26(m,2H),1.65-1.45(m, 4H),1.27(d,J＝7.6Hz,2H),0.89(d,J＝4.4Hz,2H),0.79(d,J＝6.8Hz,3H),0.67(d,J＝6.4Hz,3H).
LCMS:m/z 483.2[M+H]+,RT＝1.03min.
实施例70：化合物70的合成
采用实施例1相同的方法，使用中间体A59和中间体B8进行反应后得到化合物70。
(S)-3-(2-(((S)-1-(1-(4-氯苯基)-1H-1,2,4-三唑-3-基)乙基)氨基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000145
1H-NMR(CDCl3,400MHz)：8.44(s,1H),8.10-8.08(d,J＝6.0Hz,1H),7.61-7.55(m,3H),7.47-7.45(d,J＝8.4Hz,2H),5.69(s,1H),5.36-5.33(m,1H),4.60-4.56(m,1H),3.42-3.38(m,1H),3.20-3.17(m,1H),2.86(s,3H),2.49(s,1H),1.68-1.66(d,J＝6.4Hz,3H),0.86-0.85(d,J＝7.2Hz,3H),0.61-0.60(d,J＝6.8Hz,3H).
LCMS:m/z 441.2[M+H]+,RT＝1.0min.
实施例71：化合物71的合成
(S)-3-(2-((1-(1-(3-环丙基苯基)-1H-咪唑-4-基)环丁基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000146
步骤一：采用实施例1相同的方法，使用中间体A64和中间体B27进行反应后得到中间体71-1。
LCMS:m/z 510.2[M+H]+,RT＝1.05min.
步骤二：在盛有8毫升甲苯的50毫升圆底瓶中加入中间体71-1(60毫克，0.117毫摩尔)，环丙基硼酸(25毫克，0.294毫摩尔)，碳酸铯(95毫克，0.294 毫摩尔)和PdCl2(dppf)，氮气保护下100摄氏度反应过夜，LCMS检测反应完毕，体系浓缩后prep-HPLC纯化得到化合物71(35毫克，收率：64％)，产品为白色固体。
1H-NMR(CDCl3,400MHz):10.87(s,1H),8.87(s,1H),7.93(d,J＝6.8Hz,1H),7.77(d,J＝6.4Hz,1H),7.42-7.38(m,1H),7.25(d,J＝6.8Hz,1H),7.19-7.12(m,3H),4.37(d,J＝7.2Hz,1H),3.43(t,J＝9.6Hz,1H),3.16(d,J＝9.6Hz,1H),2.88-2.78(m,7H),2.25-2.23(m,2H),1.97-1.95(m,2H),1.07(d,J＝6.8Hz,2H),0.82(d,J＝6.8Hz,3H),0.76(d,J＝4.8Hz,2H),0.64(d,J＝6.4Hz,3H).
LCMS:m/z 472.2[M+H]+,RT＝1.0min.
实施例72：化合物72的合成
采用实施例1相同的方法，使用中间体A55和中间体B8进行反应后得到化合物72。
(S)-3-(2-((2-(1-(4-氯苯基)-1H-咪唑-4-基)丙-2-基)氨基)嘧啶-4-基)-4-异丙基-1--甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000147
1H-NMR(CDCl3,400MHz):8.06-8.04(d,J＝6.0Hz,1H),7.72(s,1H),7.52-7.51(d,J＝6.0Hz,1H),7.43-7.41(d,J＝8.0Hz,2H),7.28-7.26(d,J＝5.6Hz,2H),7.01(s,1H),5.59(s,1H),4.38-4.35(m,1H),3.34-3.29(m,1H),3.13-3.10(m,1H),2.83(s,3H),2.24(s,1H),1.86(s,3H),1.76(s,3H),0.76-0.74(d,J＝6.8Hz,3H),0.64-0.62(d,J＝7.2Hz,3H).
LCMS:m/z 441.2[M+H]+,RT＝1.00min.
实施例73：化合物73的合成
采用实施例1相同的方法，使用中间体A2和中间体B11进行反应后得到化合物73。
(S)-3-(2-(((S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-4-异丙基-1-环丙基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000148
1H NMR(CDCl3-d1,400MHz):δ8.08(d,J＝6.0Hz,1H),7.75(s,1H),,7.55-7.53(m1H),7.44-7.42(m,2H),7.29-7.27(m,1H),7.06(s,1H),5.36-5.34(m,1H),5.16-5.15(m,1H),4.51-4.47(m,1H),3.39-3.35(m,1H),3.15-3.12(m,1H),2.55-2.50(m,1H),2.38(s,1H),1.62-1.61(m,3H),0.87-0.83(m,7H),0.80-0.64(m,4H).
LCMS:m/z 466.2[M+H]+,RT＝1.03min.
实施例74：化合物74的合成
采用实施例1相同的方法，使用中间体A2和中间体B9进行反应后得到化合物74。
(S)-3-(2-(((S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-1-乙基-4-异丙基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000149
1H-NMR(CDCl3,400MHz):10.33(s,1H),8.84(s,1H),7.97(d,J＝5.6Hz,1H),7.82(s,1H),7.66(s,1H),7.56(s,J＝8.0Hz,2H),7.46(d,J＝8.0Hz,2H),5.55(s,1H),4.64(d,J＝7.2Hz,1H),3.55-3.42(m,2H),3.40-3.26(m,2H),3.23(s,1H),1.73(d,J＝5.2Hz,3H),1.20(t,J＝14.4Hz,3H),0.86(d,J＝6.0Hz,3H),0.72(d,J＝6.4Hz,3H).
LCMS:m/z 454.2[M+H]+,RT＝0.95min.
实施例75：化合物75的合成
采用实施例1相同的方法，使用中间体A56和中间体B8进行反应后得到化合物75。
(S)-3-(2-(((S)-1-(1-(4,4-二氟环已基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000150
1H NMR(CDCl3,400MHz)：δ7.88(brs,1H),7.71-7.73(m,2H),7.52-7.54(m,1H),6.90(brs,1H),5.29(s,1H),4.48(s,1H),4.07(d,J＝6.8Hz,1H),3.40-3.44(m,1H),3.19-3.22(m,1H),2.87(s,3H),2.46(brs,1H),1.91-2.24(m,8H),0.99(d,J＝6.4Hz,3H),0.90-0.94(m,6H)；
LCMS:m/z 448.2[M+H]+,RT＝0.76min.
实施例76：化合物76的合成
采用实施例1相同的方法，使用中间体A57和中间体B8进行反应后得到化合物76。
Figure PCTCN2017077467-appb-000151
1H-NMR(CDCL3,400MHz):8.05(d,J＝6.0Hz 1H),7.52(d,J＝6.0Hz 1H),7.44-7.40(m,2H),7.19-7.15(m,2H),6.78(d,J＝5.2Hz,1H),5.40(t,J＝5.6Hz 1H),5.07(t,J＝3.6Hz 1H),4.55(t,J＝6.0Hz 1H),3.38(t,J＝9.6Hz 1H),3.17(t,J＝6.0Hz 1H),2.86(s,3H),2.45(s,1H),2.30(s,3H),1.70-1.35(m,3H),0.83-0.70(m,3H),0.05-0.10(m,3H).
LCMS:m/z 454.0[M+H]+,RT＝0.99min.
实施例77：化合物77的合成
采用实施例1相同的方法，使用中间体A58和中间体B10进行反应后得到化合物77。
(S)-3-(6-氯-2-(((S)-1-(1-(4-氟苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-4-环丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000152
1H-NMR(CDCl3,400MHz):7.71(s,1H),7.60(s,1H),7.33-7.30(m,2H),7.18-7.14(m,2H),7.08(s,1H),5.44-5.42(d,J＝8.0Hz,1H),5.8(s,1H),4.37(s,1H),3.48-3.43(m,1H),3.10-3.07(d,J＝8.8Hz,1H),2.87(s,3H),1.60-1.58(d,J＝7.6Hz,3H),1.15-1.13(m,1H),0.35-00.31(m,2H),0.16-0.15(m,2H).
LCMS:m/z 456.2[M+H]+,RT＝1.12min.
实施例78：化合物78的合成
采用实施例1相同的方法，使用中间体A2和中间体B12进行反应后得到化合物78。
(S)-3-(2-(((S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-4-异丙基-1-三氘代甲基咪唑-2-酮的合成
Figure PCTCN2017077467-appb-000153
1H NMR(CDCl3-d1,400MHz):δ8.80(d,J＝5.6Hz,1H),7.75(s,1H),7.52(d,J＝5.6Hz,1H),7.42(d,J＝8.4Hz,2H),7.26(d,J＝9.2Hz,1H),7.06(s,1H),5.33(d,J＝7.6Hz,1H),5.15(s,1H),4.54-4.52(m,1H),3.37(t,J＝9.2Hz,1H),3.17-3.14(m,1H),2.20(s,1H),1.61(d,J＝6.8Hz,3H),0.78(d,J＝6.0Hz,3H),0.67(d,J＝6.4Hz,3H).
LCMS:m/z 443.2[M+H]+,RT＝0.88min.
实施例79：化合物79的合成
采用实施例1相同的方法，使用中间体A2和中间体B13进行反应后得到化合物79。
(S)-3-(2-(((S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)-6-甲基嘧啶-4-基)环丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000154
1H-NMR(CDCl3,400MHz):10.63(s,1H),8.59(s,1H),7.72(s,1H),7.62(s,1H),7.54(d,J＝8.0Hz,2H),7.42(d,J＝8.4Hz,2H),5.57(s,1H),34.61-4.58(m,1H),3.62-3.58(m,1H),3.17(d,J＝9.2Hz,1H),2.94(s,3H),2.45(s,3H),1.69(d,J＝6.4Hz,3H),1.08(s,1H),0.30-0.19(m,4H).
LCMS:m/z 452.1[M+H]+,RT＝1.0min.
实施例80：化合物80的合成
采用实施例1相同的方法，使用中间体A2和中间体B14进行反应后得到化合物80。
(S)-3-(2-(((S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)-5-氟嘧啶-4-基)-1-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000155
1H-NMR(CDCl3,400MHz):8.13(s,1H),7.75(s,1H),7.45-7.43(d,J＝7.2Hz,2H),7.30-7.28(d,J＝6.8Hz,2H),7.08(s,1H),5.42-5.35(m,1H),5.15-5.05(m,1H),4.54(s,1H),3.40-3.6(m,1H),3.26-3.22(m,1H),2.87(s,3H),2.11-2.02(m,1H),1.58(s,3H),0.79-0.77(d,J＝5.6Hz,3H),0.74-0.73(d,J＝4.8Hz,3H).
LCMS:m/z 458.2[M+H]+,RT＝1.06min.
实施例81：化合物81的合成
采用实施例1相同的方法，使用中间体A2和中间体B15进行反应后得到化合物81。
(R)-3-(2–((S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-4-)-1-羟乙基)-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000156
1H-NMR(CDCl3,400MHz):10.63(s,1H),8.59(s,1H),7.72(s,1H),7.62(s,1H),7.54(d,J＝8.0Hz,2H),7.42(d,J＝8.4Hz,2H),5.57(s,1H),34.61-4.58(m,1H),3.62-3.58(m,1H),3.17(d,J＝9.2Hz,1H),2.94(s,3H),2.45(s,3H),1.69(d,J＝6.4Hz,3H),1.08(s,1H),0.30-0.19(m,4H).
LCMS:m/z 442.2[M+H]+,RT＝0.82min.
实施例82：化合物82的合成
(S)-1-(2-(((S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-4,4-二氘-5-异丙基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000157
采用实施例1相同的方法，使用中间体A2和中间体B16进行反应后得到化合物82。
LCMS:m/z 428.2[M+H]+；RT＝0.838min.
1H-NMR(CDCl3-d1,400MHz):δ8.08(d,J＝5.6Hz,1H),7.76(s,1H),7.48(d,J＝6.0Hz,1H),7.42(d,J＝8.8Hz,2H),7.27(d,J＝7.6Hz,2H),7.08(s,1H),5.51(d,J＝6.8Hz,1H),5.41(s,1H),5.18-5.14(m,1H),4.65(d,J＝3.2Hz,1H),2.43-2.42(m,1H),1.62(d,J＝6.8Hz,3H),0.79(d,J＝6.0Hz,3H),0.75(d,J＝6.8Hz,3H).
实施例83：化合物83的合成
(S)-1-(2-(((S)-1-(1-(4-(三氟甲基)苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-4,4-二氘-5-异丙基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000158
采用实施例1相同的方法，使用中间体A46和中间体B16进行反应后得到化合物83。
LCMS:m/z 462.2[M+H]+；RT＝0.922min.
1H-NMR(CDCl3-d1,400MHz):δ8.10(d,J＝5.6Hz,1H),7.85(s,1H),7.72(d,J＝8.4Hz,2H),7.50(d,J＝6.0Hz,1H),7.46(d,J＝8.0Hz,2H),7.16(s,1H),5.43(d,J＝7.2Hz,1H),5.19-5.16(m,1H),5.08(s,1H),4.65(d,J＝3.2Hz,1H),2.43-2.42(m,1H),1.63(d,J＝4.4Hz,3H),0.79(d,J＝6.8Hz,3H),0.75(d,J＝6.8Hz,3H).
实施例84：化合物84的合成
(S)-3-(2-(((S)-1-(1-(4-(三氟甲基)苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-5,5-二氘-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000159
采用实施例1相同的方法，使用中间体A46和中间体B17进行反应后得到化合物84。
LCMS:m/z 476.2[M+H]+；RT＝0.969min.
1H-NMR(CDCl3-d1,400MHz):δ8.07(d,J＝6.0Hz,1H),7.85(s,1H),7.72(d, J＝8.4Hz,2H),7.54(d,J＝5.6Hz,1H),7.46(d,J＝8.4Hz,2H),7.15(s,1H),5.48(d,J＝1.6Hz,1H),5.19-5.16(m,1H),4.52(d,J＝3.2Hz,1H),2.86(s,3H),2.43-2.42(m,1H),1.62(d,J＝6.8Hz,3H),0.79(d,J＝6.4Hz,3H),0.67(d,J＝6.4Hz,3H).
实施例85：化合物85的合成
(S)-3-(2-(((S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-5,5-二氘-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000160
采用实施例1相同的方法，使用中间体A2和中间体B17进行反应后得到化合物85。
LCMS:m/z 442.2[M+H]+；RT＝0.902min.
1H-NMR(CDCl3-d1,400MHz):δ8.08(d,J＝6.0Hz,1H),7.75(s,1H),7.53(d,J＝6.0Hz,1H),7.42(d,J＝8.8Hz,2H),7.27(d,J＝8.8Hz,2H),7.07(s,1H),5.32(d,J＝6.8Hz,1H),5.17-5.13(m,1H),4.52(d,J＝3.6Hz,1H),2.86(s,3H),2.43-2.40(m,1H),1.62(d,J＝3.2Hz,3H),0.79(d,J＝6.8Hz,3H),0.67(d,J＝6.8Hz,3H).
实施例86：化合物86和化合物87的合成
(5S)-1-(2-(((S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-5–异丙基-4-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000161
采用实施例1相同的方法，使用中间体A2和中间体B18进行反应后得到化合 物86(单一异构体)。
1H-NMR(CDCl3,400MHz):10.62(s,1H),8.45(s,1H),7.86(d,J＝7.2Hz,1H),7.77(d,J＝7.2Hz,1H),7.59-7.52(m,2H),7.44-7.38(m,2H),5.60-5.57(m,1H),5.22(s,1H),4.85(s,1H),4.16-4.13(m,1H),2.25-2.15(m,1H),1.71(d,J＝6.8Hz,3H),1.40(d,J＝6.8Hz,3H),0.93-0.81(m,6H).
LCMS:m/z 440.2[M+H]+；RT＝0.97min.
采用实施例1相同的方法，使用中间体A2和中间体B19进行反应后得到化合物87(单一异构体)。
1H NMR(CDCl3,400MHz)：δ8.110-8.096(m,1H),7.753-7.751(m,1H),7.488-7.473(m,1H),7.437-7.416(m,2H),7.281-7.264(m,2H),7.067(s,1H),5.367-5.347(m,1H),5.236-5.166(m,1H),4.725-4.696(m,2H),4.088-4.018(m,1H),2.183-2.173(m,1H),1.616(d,J＝7.2Hz,3H),1.34(d,J＝6.8Hz,3H),0.881-0.864(m,6H).
LCMS:m/z 440.2[M+H]+；RT＝0.89min.
实施例87：化合物88的合成
(S)-5-异丙基-1-(2-(((S)-1-(1-(4-(三氟甲基)苯基)-1H-咪唑-4-基)乙基)氨基))咪唑烷-2-酮
Figure PCTCN2017077467-appb-000162
采用实施例1相同的方法，使用中间体A46和中间体B1进行反应后得到化合物88。
1H-NMR(CDCl3,400MHz):8.12-8.11(d,J＝5.6Hz,1H),7.85(s,1H),7.75-7.73(d,J＝8.4Hz,2H),7.52-7.51(d,J＝5.6Hz,1H),7.48-7.46(d,J＝8.4Hz,2H),7.15(s,1H),5.36-5.34(d,J＝6.8Hz,1H),5.20-5.14(m,1H),4.70-4.65(m,2H),3.49-3.45(m,1H),3.30-3.27(m,1H),2.45-2.40(m,1H),1.64-1.63(d,J＝6.8Hz,3H),0.81-0.80(d, J＝5.2Hz,3H),0.77-0.75(d,J＝7.2Hz,3H).
LCMS:m/z 460.3[M+H]+；RT＝0.97min.
实施例88：化合物89的合成
(S)-3-(2-(((S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-5,5-二氘-4-异丙基-1-氘代甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000163
采用实施例1相同的方法，使用中间体A2和中间体B23进行反应后得到化合物89。
LCMS:m/z 445.3[M+H]+；RT＝0.883min.
1H-NMR(CDCl3-d1,400MHz):δ8.07(d,J＝6.0Hz,1H),7.75(s,1H),7.53(d,J＝5.60Hz,1H),7.42(d,J＝8.4Hz,2H),7.27(d,J＝8.4Hz,2H),7.07(s,1H),5.37(d,J＝7.2Hz,1H),5.17-5.15(m,1H),4.52(d,J＝3.6Hz,1H),2.43-2.40(m,1H),1.61(d,J＝6.8Hz,3H),0.79(d,J＝6.4Hz,3H),0.67(d,J＝6.8Hz,3H).
实施例89：化合物90和化合物91的合成
(5S)-1-(2-(((S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-5–异丙基-3，4-二甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000164
采用实施例1相同的方法，使用中间体A2和中间体B20进行反应后得到化合物90(单一异构体)。
LCMS:m/z 454.2[M+H]+；RT＝1.02min.
1H-NMR(CDCl3-d1,400MHz):δ10.57(s,1H),8.64-8.62(m,1H),7.94(d,J＝ 6.8Hz,1H),7.76(d,J＝6.0Hz,1H),7.63(s,1H),7.55(d,J＝8.0Hz,2H),7.43-7.38(m,2H),5.66(s,1H),4.87(d,J＝3.6Hz,1H),3.89-3.85(m,1H),2.85(s,3H),2.15(s,1H),1.72-1.66(m,3H),1.41-1.34(m,3H),0.82-0.69(m,3H).
采用实施例1相同的方法，使用中间体A2和中间体B21进行反应后得到化合物91(单一异构体)。
LCMS:m/z 454.2[M+H]+；RT＝0.94min.
1H-NMR(CDCl3-d1,400MHz):δ8.101-8.087(m,1H),7.749-7.747(m,1H),7.532-7.518(m,1H),7.436-7.414(m,2H),7.279-7.263(m,2H),7.059(s,1H),5.296-5.276(m,1H),5.240-5.170(m,1H),4.713-4.686(m,1H),3.727-3.657(m,1H),2.756(s,3H),2.126-2.118(m,1H),1.612(d,J＝6.8Hz,3H),1.34(d,J＝6.8Hz,3H),0.835-0.818(m,6H).
实施例90：化合物92和化合物93的合成
(5S)-1-(2-(((S)-1-(1-(4-三氟甲基苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-5–异丙基-4-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000165
采用实施例1相同的方法，使用中间体A46和中间体B18进行反应后得到化合物92(单一异构体)。
LCMS:m/z 474.3[M+H]+；RT＝0.94min.
1H-NMR(CDCl3-d1,400MHz):δ8.10(d,J＝5.6Hz,1H),7.85(s,1H),7.72(d,J＝8.4Hz,2H),7.53(d,J＝6.0Hz,1H),7.46(d,J＝8.4Hz,2H),7.15(s,1H),5.35(d,J＝8.0Hz,1H),5.20-5.18(m,1H),4.79(s,1H),4.19(s,1H),3.54-3.51(m,1H),2.41-2.38(m,1H),1.63(d,J＝7.2Hz,3H),1.23(d,J＝6.4Hz,3H),0.82(d,J＝6.4Hz,3H),0.73(d,J＝6.8Hz,3H).
采用实施例1相同的方法，使用中间体A46和中间体B19进行反应后得到化合物93(单一异构体)。
LCMS:m/z 474.3[M+H]+；RT＝0.95min.
1H-NMR(CDCl3-d1,400MHz):δ8.119-8.104(m,1H),7.848(s,1H),7.739-7.718(m,2H),7.499-7.448(m,3H),7.146(s,1H),5.346-5.326(m,1H),5.252-5.184(m,1H),4.724-4.697(m,1H),4.651(s,1H),4.090-4.020(m,1H),2.172(s,1H),1.626(d,J＝6.8Hz,3H),1.34(d,J＝6.8Hz,3H),0.880-0.863(m,6H).
实施例91：化合物94和化合物95的合成
(4S)-4–异丙基-1,5-甲基-3-(2-(((S)-1-(1-(4-三氟甲基苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)咪唑烷-2-酮
Figure PCTCN2017077467-appb-000166
采用实施例1相同的方法，使用中间体A46和中间体B20进行反应后得到化合物94(单一异构体)。
LCMS:m/z 488.3[M+H]+；RT＝1.00min.
1H-NMR(CDCl3-d1,400MHz):δ10.57(s,1H),8.90(s,1H),7.96(s,1H),7.89-7.83(m,3H),7.77(s,1H),7.68(d,J＝8.0Hz,2H),5.70-5.68(m,1H),4.87(d,J＝6.0Hz,1H),3.90-3.87(m,1H),2.85(s,3H),2.05(s,1H),1.72(d,J＝5.6Hz,3H),1.40(d,J＝6.8Hz,3H),0.83-0.78(m,6H).
采用实施例1相同的方法，使用中间体A46和中间体B21进行反应后得到化合物95(单一异构体)。
LCMS:m/z 488.3[M+H]+；RT＝1.01min.
1H-NMR(CDCl3-d1,400MHz):δ8.103-8.089(m,1H),7.847-7.844(m,1H),7.737-7.716(m,2H),7.542-7.527(m,1H),7.466-7.445(m,2H),7.142(s,1H),5.324-5.304(m,1H),5.257-5.187(m,1H),4.715-4.687(m,1H),3.731-3.661(m,1H),2.757(s,3H),2.132-2.125(m,1H),1.622(d,J＝6.8Hz,3H),1.34(d,J＝7.2Hz,3H),0.832-0.815(m,6H).
实施例92：化合物96的合成
(S)-3-(2-(((S)-1-(1-(4-三氟甲基苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-5,5-二氘-4-异丙基-1-三氘甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000167
采用实施例1相同的方法，使用中间体A46和中间体B23进行反应后得到化合物96。
LCMS:m/z 479.3[M+H]+；RT＝1.04min.
1H-NMR(CDCl3-d1,400MHz):δ8.07(d,J＝6.0Hz,1H),7.85(s,1H),7.72(d,J＝8.4Hz,2H),7.54(d,J＝5.6Hz,1H),7.46(d,J＝8.4Hz,2H),7.15(s,1H),5.32(d,J＝7.2Hz,1H),5.17-5.15(m,1H),4.52(d,J＝3.2Hz,1H),2.42-2.40(m,1H),1.62(d,J＝6.8Hz,3H),0.79(d,J＝6.0Hz,3H),0.67(d,J＝6.8Hz,3H).
实施例93：化合物97的合成
(S)-3-(2-((1-(1-(3-氯-5-氟苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-4-异丙基-1--甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000168
采用实施例1相同的方法，使用中间体A33和中间体B27进行反应后得到化合物97。
LCMS:m/z 470.1[M+H]+；RT＝1.07min.
1H-NMR(CDCl3-d1,400MHz):δ8.39(s,1H),7.98-7.97(d,J＝6.8Hz,1H),7.81-7.79(d,J＝7.2Hz,1H),7.25(s,2H),7.21-7.19(d,J＝7.6Hz,1H),7.09-7.07(d,J＝8.4Hz,1H),4.47-4.44(d,J＝8.8Hz,1H),3.48-3.44(m,1H),3.21-3.18(m,1H),2.91(s,3H),2.27-2.26(d,J＝2.8Hz,1H),1.65-1.43(m,4H),0.80-0.78(d,J＝6.8Hz,3H),0.69-0.68(d,J＝6.8Hz,3H).
实施例94：化合物98的合成
Figure PCTCN2017077467-appb-000169
采用实施例1相同的方法，使用中间体A2和中间体B22进行反应后得到化合物98。
LCMS:m/z 454.3[M+H]+；RT＝0.98min.
1H-NMR(CDCl3,400MHz):8.110-8.096(m,1H),7.759-7.756(m,1H),7.490-7.475(m,1H),7.439-7.417(m,2H),7.285-7.266(m,2H),7.076(s,1H),5.393-5.374(m,1H),5.220-5.186(m,1H),4.718(s,1H),4.424-4.416(m,1H),2.150-2.125(m,1H),1.618(d,J＝6.4Hz,3H),1.351(s,3H),1.270(s,3H),0.875-0.829(m,6H).
实施例95：化合物99的合成
(S)-6-(2-(((S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-7-异丙基-4，6-二氮杂螺[2.4]庚-5-酮
Figure PCTCN2017077467-appb-000170
采用实施例1相同的方法，使用中间体A2和中间体B24进行反应后得到化合物99。
LCMS:m/z 452.2[M+H]+；RT＝0.967min.
1H-NMR(CDCl3-d1,400MHz):δ10.68(d,J＝7.26Hz,1H),8.48(s,1H),7.90(d,J＝7.2Hz,1H),7.79(d,J＝7.2Hz,1H),7.58-7.53(m,3H),7.40(d,J＝8.8Hz,2H),5.61(s,1H),4.89(s,1H),4.63(s,1H),4.36(s,1H),2.12-2.08(m,1H),1.71(d,J＝6.8Hz,3H),1.29-1.25(m,1H),0.98-0.78(m,9H).
实施例96：化合物100的合成
(S)-6-(2-(((S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-7-异丙基-4-甲基-4,6-二氮杂螺[2.4]庚-5-酮
Figure PCTCN2017077467-appb-000171
采用实施例1相同的方法，使用中间体A2和中间体B25进行反应后得到化合物100。
LCMS:m/z 466.2[M+H]+；RT＝1.003min.
1H-NMR(CDCl3-d1,400MHz):δ10.61(d,J＝6.4Hz,1H),8.43(s,1H),7.94(d,J＝7.2Hz,1H),7.75(d,J＝7.6Hz,1H),7.56-7.52(m,3H),7.39(d,J＝8.8Hz,2H),5.60(s,1H),4.59(s,1H),2.62(s,3H),1.70(d,J＝6.4Hz,3H),1.20-1.16(m,2H),1.04-1.01(m,1H),0.92-0.86(m,4H),0.78-0.73(m,3H).
实施例97：化合物101的合成
(S)-5-异丙基-4,4-二甲基-1-(2-(((S)-1-(1-(4-(三氟甲基)苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)咪唑烷-2-酮
Figure PCTCN2017077467-appb-000172
采用实施例1相同的方法，使用中间体A46和中间体B22进行反应后得到化合物101。
LCMS:m/z 488.3[M+H]+；RT＝1.011min.
1H-NMR(CDCl3-d1,400MHz):δ8.122-8.108(m,1H),7.854-7.852(m,1H),7.741-7.720(m,2H),7.501-7.451(m,3H),7.152(s,1H),5.343-5.323(m,1H),5.257-5.185(m,1H),4.598(s,1H),4.423-4.416(m,1H),2.158-2.135(m,1H),1.628(d,J＝6.4Hz,3H),1.351(s,3H),1.273(s,3H),0.874-0.825(m,6H).
实施例98：化合物102的合成
(S)-7-异丙基-6-(2-(((S)-1-(1-(4-(三氟甲基)苯基)-1H-咪唑-4-基)乙基)氨基))-4,6-二氮杂螺[2.4]庚-5-酮
Figure PCTCN2017077467-appb-000173
采用实施例1相同的方法，使用中间体A46和中间体B24进行反应后得到化合物102。
LCMS:m/z 486.3[M+H]+；RT＝0.97min.
1H-NMR(CDCl3-d1,400MHz):δ10.59(d,J＝6.8Hz,1H),8.38(s,1H),7.89(d,J＝7.2Hz,1H),7.83-7.78(m,3H),7.62-7.58(m,2H),5.52(s,1H),5.04(s,1H),4.59(s,1H),2.12-2.10(m,1H),1.69(d,J＝6.4Hz,3H),1.32-1.29(m,1H), 1.02-0.99(m,1H),0.94-0.78(m,8H).
实施例99：化合物103的合成
(S)-7-异丙基-4-甲基-6-(2-(((S)-1-(1-(4-(三氟甲基)苯基)-1H-咪唑-4-基)乙基)氨基)-4-基)-4,6-二氮杂螺[2.4]庚-5-酮
Figure PCTCN2017077467-appb-000174
采用实施例1相同的方法，使用中间体A46和中间体B25进行反应后得到化合物103。
LCMS:m/z 500.2[M+H]+；RT＝1.012min.
1H-NMR(CDCl3-d1,400MHz):δ10.54(s,1H),8.52(s,1H),7.95(d,J＝6.8Hz,1H),7.84(d,J＝8.0Hz,2H),7.76(d,J＝6.8Hz,1H),7.68(s,1H),7.61(d,J＝4.0Hz,2H),5.59(s,1H),4.58(s,1H),2.62(s,3H),2.05-2.03(m,1H),1.70(d,J＝6.0Hz,3H),1.21-1.16(m,2H),0.92-0.87(m,4H),0.76(d,J＝6.0Hz,3H)。
实施例100：化合物104的合成
(S)-8-异丙基-7-(2-(((S)-1-(1-(4-氯苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-2-氧杂-5,7-二氮杂螺[3.4]辛-6-酮
采用实施例1相同的方法，使用中间体A2和中间体B30进行反应后得到化合物104。
Figure PCTCN2017077467-appb-000175
1H-NMR(CDCl3,400MHz):8.13(d,J＝6.0Hz,1H),7.78(d,J＝6.8Hz,1H),7.44-7.41(m,3H),7.32-7.27(m,2H),7.09(s,1H),5.88(s,1H),5.47(d,J＝8.0Hz,1H),5.23-5.17(m,2H),4.98(s,1H),4.79(d,J＝6.8Hz,1H),4.72-4.69(m,1H),4.63(d,J＝6.8Hz,1H),2.29-2.27(m,1H),1.63(d,J＝6.8Hz,3H),0.93(d,J＝6.4Hz,3H),0.78(s,3H).
LCMS:m/z 468.2[M+H]+；RT＝0.9min.
实施例101：化合物105的合成
(S)-8-异丙基-7-(2-(((S)-1-(1-(4-三氟甲基苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-2-氧杂-5,7-二氮杂螺[3.4]辛-6-酮
Figure PCTCN2017077467-appb-000176
采用实施例1相同的方法，使用中间体A46和中间体B30进行反应后得到化合物105。
1H-NMR(CDCl3,400MHz):8.13(d,J＝6.0Hz,1H),7.86(s,1H),7.75-7.70(m,2H),7.52-7.42(m,3H),7.016(s,1H),5.63(s,1H),5.41-5.37(m,1H),5.25-5.17(m,2H),4.98(s,1H),4.79(d,J＝7.2Hz,1H),4.70(d,J＝7.6Hz,1H),4.63(d,J＝7.2Hz,1H),2.31-2.28(m,1H),1.64(d,J＝6.8Hz,3H),0.94-0.83(m,3H),0.71(d,J＝6.4Hz,3H).
LCMS:m/z 502.2[M+H]+；RT＝1.0min.
实施例102：化合物106的合成
(S)-8-异丙基-5-甲基-7-(2-(((S)-1-(1-(4-三氟甲基苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-2-氧杂-5,7-二氮杂螺[3.4]辛-6-酮
Figure PCTCN2017077467-appb-000177
采用实施例1相同的方法，使用中间体A46和中间体B31进行反应后得到化合物106。
1H-NMR(CDCl3,400MHz):8.11(d,J＝6.0Hz,1H),7.86(s,1H),7.73(d,J＝8.4Hz,2H),7.47(d,J＝6.0Hz,3H),7.15(s,1H),5.34(d,J＝8.0Hz,1H),5.25-5.16(m,2H),4.95(s,1H),4.88(d,J＝8.4Hz,1H),4.78(d,J＝7.2Hz,1H),4.67(d,J＝7.2Hz,1H),3.13(s,3H),2.25-2.22(m,1H),1.63(d,J＝6.8Hz,3H),0.85(d,J＝6.8Hz,3H),0.73(d,J＝4.4Hz,3H).
LCMS:m/z 516.2[M+H]+；RT＝1.0min.
实施例103：化合物107的合成
(S)-8-异丙基-5-三氘甲基-7-(2-(((S)-1-(1-(4-三氟甲基苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-2-氧杂-5,7-二氮杂螺[3.4]辛-6-酮
Figure PCTCN2017077467-appb-000178
采用实施例1相同的方法，使用中间体A46和中间体B32进行反应后得到化合物107。
1H-NMR(CDCl3,400MHz):8.11(d,J＝6.0Hz,1H),7.86(s,1H),7.73(d,J＝8.4Hz,2H),7.47(d,J＝6.0Hz,3H),7.15(s,1H),5.36(d,J＝8.0Hz,1H),5.25-5.16(m,2H),4.95(s,1H),4.88(d,J＝8.0Hz,1H),4.77(d,J＝7.2Hz,1H),4.67(d,J＝7.2Hz, 1H),2.25-2.22(m,1H),1.64(d,J＝6.8Hz,3H),0.85(d,J＝6.8Hz,3H),0.72(br,3H).
LCMS:m/z 519.2[M+H]+；RT＝1.0min.
实施例104：化合物108的合成
(S)-4,4,-二氘-5-异丙基-1-(2-(((S)-1-(4-甲基-2’-(三氟甲基)-[3,4’-联吡啶]-6-基)乙基)氨基)嘧啶-4-基)咪唑烷-2-酮化合物
Figure PCTCN2017077467-appb-000179
采用实施例1相同的方法，使用中间体A8和中间体B16进行反应后得到化合物108。
1H-NMR(CDCl3,400MHz):8.82(d,J＝5.2Hz,1H),8.39(s,1H),8.11(d,J＝6.0Hz,1H),7.64(s,1H),7.52(d,J＝6.0Hz,1H),7.45(d,J＝4.8Hz,1H),7.26(s,1H),5.71(d,J＝6.8Hz,1H),5.16-5.15(m,1H),4.78(s,1H),4.62(s,1H),2.28(s,3H),2.18-2.05(m,1H),1.60(d,J＝6.8Hz,3H),0.73-0.67(m,3H).
LCMS:m/z 488.2[M+H]+；RT＝1.0min.
实施例105：化合物109的合成
((S)-4-异丙基-5,5-二氘-1-甲基-3-(2-(((S)-1-(4-甲基-2’-(三氟甲基)-[3,4’-联吡啶]-6-基)乙基)氨基)嘧啶-4-基)咪唑烷-2-酮
Figure PCTCN2017077467-appb-000180
采用实施例1相同的方法，使用中间体A8和中间体B17进行反应后得到化合物109。
1H-NMR(CDCl3,400MHz):8.82(d,J＝5.2Hz,1H),8.38(s,1H),8.09(d,J＝5.6Hz,1H),7.64(s,1H),7.55(d,J＝6.0Hz,1H),7.45(d,J＝4.0Hz,1H),7.27(s,1H),5.69(d,J＝6.8Hz,1H),5.16-5.15(m,1H),4.48(s,1H),2.85(s,3H),2.28(s,3H),2.18-2.05(m,1H),1.59(d,J＝6.8Hz,3H),0.73-0.64(m,3H).
LCMS:m/z 502.2[M+H]+；RT＝0.98min.
实施例106：化合物110的合成
(S)-3-(2-((1-(1-(3,5-二氯苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-5,5-二氘-4-异丙基-1-甲基咪唑烷-2-酮
Figure PCTCN2017077467-appb-000181
采用实施例1相同的方法，使用中间体A18和中间体B33进行反应后得到化合物110。
LCMS:m/z 488.2[M+H]+；RT＝2.08min.
1H NMR(400MHz,cdcl3)δ8.08(d,J＝5.9Hz,1H),7.65(d,J＝1.6Hz,1H),7.56(dd,J＝5.9,1.8Hz,1H),7.29–7.26(m,1H),7.24(s,1H),7.18(d,J＝1.8Hz,2H),6.97(s,1H),5.75(s,1H),4.36(s,1H),2.82(s,3H),2.35(s,1H),1.76(s,2H),1.50(dd,J＝4.7,2.5Hz,2H),0.63(s,6H).
实施例107：化合物111的合成
(S)-3-(2-((1-(1-(3-氯苯基)-1H-咪唑-4-基)环丙基)氨基)嘧啶-4-基)-5,5-二氘-4-异丙基-1-甲基咪唑烷-2酮
Figure PCTCN2017077467-appb-000182
采用实施例1相同的方法，使用中间体A22和中间体B33进行反应后得到化合物111。
LCMS:m/z 488.2[M+H]+；RT＝1.95min.
1H NMR(400MHz,cdcl3)δ8.08(d,J＝5.9Hz,1H),7.65(s,1H),7.56(d,J＝5.9Hz,1H),7.34(d,J＝8.7Hz,2H),7.28(s,2H),7.17(d,J＝6.6Hz,1H),6.98(s,1H),5.66(s,1H),4.38(s,1H),2.82(s,3H),2.35(s,1H),1.63(s,2H),1.51(d,J＝9.2Hz,2H),0.64(d,J＝21.4Hz,6H).
实施例108：化合物112的合成
采用实施例1相同的方法，使用中间体A46和中间体B12进行反应后得到化合物112。
(S)-3-(2-(((S)-1-(1-(4-三氟甲基苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-4-异丙基-1-三氘甲基咪唑-2-酮
Figure PCTCN2017077467-appb-000183
LCMS:m/z 477.1[M+H]+；RT＝2.01min.
1H NMR(400MHz,DMSO)δ8.30(s,1H),7.99(d,J＝5.7Hz,1H),7.82(s,4H),7.49(s,1H),7.30(d,J＝5.6Hz,1H),7.01(s,1H),4.94(s,1H),4.37(s,1H),3.35(t,J＝9.6Hz,1H),3.16(s,1H),2.25–2.08(m,1H),1.44(d,J＝6.9Hz,3H),0.85–0.36(m,6H).
实施例109：化合物113的合成
采用实施例1相同的方法，使用中间体A30和中间体B28进行反应后得到化合物113。
(S)-3-(2-(((S)-1-(1-(4-三氟甲基苯基)-1H-咪唑-4-基)乙基)氨基)嘧啶-4-基)-4-异丙基-1-三氘代甲基咪唑-2-酮
Figure PCTCN2017077467-appb-000184
1H NMR(CDCl3-d1,400MHz)：8.80(d,J＝4.8Hz,1H),8.76(s,1H),8.12(d,J＝6.0Hz,1H),7.84(s,1H),7.81-7.78(m,1H),7.66-7.61(m,2H),7.54(d,J＝8.0Hz,1H),5.75(s,1H),4.20-4.15(m,1H),3.29-3.27(m,1H),3.06-3.04(m,1H),2.82(s,3H),2.04-1.98(m,1H),1.83-1.77(m,3H),1.37-1.34(m,3H),0.56-0.47(m,4H)
LCMS:m/z 498.2[M+H]+,RT＝1.1min.
实施例110：化合物114的合成
采用实施例1相同的方法，使用中间体A10和中间体B16进行反应后得到化合物114。
(S)-1-(2-(((S)-1-(2’-(三氟甲基)-[3,4’-联吡啶]-6-基)乙基)氨基)-5,5-二氘-4-异丙基-咪唑烷-2-酮
Figure PCTCN2017077467-appb-000185
LCMS:m/z 474.2[M+H]+；RT＝1.77min.
1H NMR(400MHz,cdcl3)：8.85(d,J＝2.1Hz,1H),8.81(d,J＝5.0Hz,1H),8.09(d,J＝5.9Hz,1H),7.90(dd,J＝8.2,2.2Hz,1H),7.86(s,1H),7.68(d,J＝5.2Hz,1H),7.52–7.49(m,1H),7.47(d,J＝8.2Hz,1H),5.77(d,J＝6.5Hz,1H),5.13(s,1H),4.65(s,1H),4.37(s,1H),2.69–2.57(m,1H),1.58(d,J＝6.9Hz,3H),0.93(d,J＝7.0Hz,3H),0.83(d,J＝6.9Hz,3H).
实施例111：化合物115的合成
采用实施例1相同的方法，使用中间体A10和中间体B1进行反应后得到化合物115。
(S)-1-(2-(((S)-1-(2’-(三氟甲基)-[3,4’-联吡啶]-6-基)乙基)氨基)-4-异丙基-咪唑烷-2-酮
Figure PCTCN2017077467-appb-000186
LCMS:m/z 472.2[M+H]+；RT＝1.77min.
1H NMR(400MHz,cdcl3)δ8.84(d,J＝2.2Hz,1H),8.81(d,J＝5.1Hz,1H),8.09(d,J＝5.8Hz,1H),7.88(dd,J＝8.1,2.4Hz,1H),7.84(s,1H),7.66(dd,J＝5.0,1.5Hz,1H),7.51(d,J＝6.0Hz,1H),7.46(d,J＝8.1Hz,1H),5.72(d,J＝6.5Hz,1H),5.18(s,1H),4.75(s,1H),4.57(s,1H),3.43(t,J＝9.4Hz,1H),3.23(d,J＝7.6Hz,1H),1.59(s,3H),0.86(t,J＝6.9Hz,1H),0.65(s,6H).
实施例112：化合物116的合成
采用实施例1相同的方法，使用中间体A65和中间体B23进行反应后得到化合物116。
(S)-4-异丙基-1-三氘甲基-3-(2-(((S)-1-(5-(3-(三氟甲基)苯基)吡啶-2-基)乙基)氨基)嘧啶-4-咪唑烷-2-酮-5,5-二氘
Figure PCTCN2017077467-appb-000187
LCMS:m/z 490.3[M+H]+；RT＝1.09min.
1H NMR(400MHz,CDCl3)δ8.78(d,J＝2.1Hz,1H),8.10(d,J＝5.8Hz,1H), 7.84–7.76(m,2H),7.73(d,J＝7.6Hz,1H),7.66(d,J＝7.6Hz,1H),7.63–7.57(m,1H),7.55(d,J＝5.9Hz,1H),7.41(d,J＝8.1Hz,1H),5.66(s,1H),5.17(s,1H),4.47(s,1H),2.17(s,1H),1.60(t,J＝9.0Hz,3H),0.64(m,6H).
对照化合物：AG120，CAS:1448346-63-1,从上海蓝木化工有限公司购得。
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 PCTCN2017077467-appb-000188
 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1000nM以上
表一：
Figure PCTCN2017077467-appb-000189
Figure PCTCN2017077467-appb-000190
结果显示，本发明化合物在极低浓度(≤100nm)下，即可有效抑制IDH1的活性。
测试例2：本发明化合物对纤维肉瘤细胞株HT1080的2HG抑制测定
本实验采用如下方法测定了本发明化合物对纤维肉瘤细胞株HT1080的2HG浓度水平抑制活性。
细胞样品制备：将处于对数生长期的人成纤维肉瘤细胞HT-1080接种至6孔培养板，每孔2ml，过夜后，加入不同浓度的化合物作用48h。HT-1080细胞用胰酶消化后收集，500g离心5min，弃上清，用1ml PBS重悬细胞，于计数仪(Beckman coulter Z2，Beckman)计数后调整至每个样品细胞数一致，500g离心5min，弃上清，留细胞沉淀保存于-80℃冰箱用于2HG的检测。
2HG的检测：
样品处理：分别在样品管中加入含200μL维拉帕米(内标)的冰乙腈溶液，涡流1min，于4℃冰箱内静置20min将细胞裂解，100μL样品备份，取另外100μL裂解液于96孔板中氮吹仪吹干，加100μL水，涡旋混匀。
1.衍生化：加入100μL临苄基羟胺盐酸盐衍生化试剂，摇板机上震荡1h使得衍生化反应完全。
2.溶液萃取：分别加入300μL乙酸乙酯，摇板20min，1900rpm离心5min，置于-70℃冰箱放置40min，吸取全部的乙酸乙酯于另一块样品板中，氮吹仪下吹干，加入150μL MEOH/H2O(v/v,1/1)复溶。
3.生物分析：所有上述样品，经4000rpm离心10min后，进行LC-MS/MS(Waters ACQUITY H-Class System，Waters/AB6500，Sciex)分析。
抑制率及IC50的计算
样品的抑制率通过下列公式求得：
Figure PCTCN2017077467-appb-000191
IC50值采用GraphPad Prism软件计算求得。部分化合物对HT1080 2HG水平抑制活性列于表二.
表二：
Figure PCTCN2017077467-appb-000192
阳性药：AG120,IC50为30nM
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 (11)

  1. 一种式I所示的化合物，其立体异构体、外消旋体或其药学上可接受的盐：
    Figure PCTCN2017077467-appb-100001
    其中，
    R3、R4各自独立地选自：H、D、取代或未取代的C1-4烷基；
    或R3与R4和与之相连的C原子共同形成取代或未取代的C3-6环烷基，或R3与R4和与之相连的C原子共同形成取代或未取代的C3-6环氧烷基；
    R5、R6各自独立地选自：H、取代或未取代的C1-4烷基、取代或未取代的C6-10芳基、取代或未取代的C3-6环烷基；
    或R5与R6和与之相连的C原子共同形成取代或未取代的C3-6环烷基；
    R7和R8各自独立的选自：H、卤素、取代或未取代的C1-4烷基；
    R9选自：H、取代或未取代的C1-4烷基；
    R10选自：取代或未取代的C1-4烷基；或R9与R10和与之相连的C形成取代或未取代的C3-6环烷基；
    R11选自：取代或未取代的C6-10芳基、取代或未取代的C5-10杂芳基；其中，所述的C5-10杂芳基含有1-4个选自N、O或S的杂原子；并且所述的“取代”指具有选自A组的一个或多个(如1、2、3或4个)取代基：
    A组取代基选自下组：H、D、卤素、取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基、取代或未取代的C1-4烷氧基、取代或未取代的C6-10芳基、取代或未取代的C5-10杂芳基、取代或未取代的C6-10芳基氧基、-C(O)NHRa’；
    其中，Ra’选自：取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基；
    R12选自：H、D、取代或未取代的C1-4烷基、取代或未取代的3-6元环；
    对于R3-R12，所述的“取代”是指具有一个或多个选自B组的取代基；
    B组取代基选自下组：H、D、卤素、取代或未取代的C1-6烷基、-OH、取代或未取代的C1-4烷氧基3-8元环烃基、氨基、硝基；
    并且，在所述A组和B组取代基中，所述“取代”指具有选自下组的一个或多个(如1/2/3/4或5)取代基：D、卤素、C1-4烷基、三氟甲基、氨基、硝基、-OH。
  2. 如权利要求1所述的化合物，其立体异构体、外消旋体或其药学上可接受的盐，R3、R4分别独立地选自H、D或甲基。
  3. 如权利要求1所述的化合物，其立体异构体、外消旋体或其药学上可接受的盐，R5为H，R6为H、取代或未取代的C1-4烷基、取代或未取代的C6-10芳基、取代或未取代的C3-6环烷基。
  4. 如权利要求1所述的化合物，其立体异构体、外消旋体或其药学上可接受的盐，所述的R11具有如下结构：
    Figure PCTCN2017077467-appb-100002
    其中，环A选自含有1-3个杂原子的取代或未取代的C5-10杂芳基，
    环B选自含有1-4个杂原子的取代或未取代的C5-10杂芳基，其中所述杂原子选自N、O和S；
    Ra选自：H、卤素、取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基、取代或未取代的C1-4烷氧基、取代或未取代的C6-10芳基、取代或未取代的C5-10杂芳基、取代或未取代的C1-3烷基C5-8环烷基、取代或未取代的C6-10芳基氧基、-C(O)NHRa’、
    Figure PCTCN2017077467-appb-100003
    其中，Ra’选自：取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基；
    Rb选自H、卤素、-CN、取代或未取代的C1-4烷基；
    n为0、1、2或3。
  5. 如权利要求1所述的化合物，其立体异构体、外消旋体或其药学上可接受 的盐，所述R11为
    Figure PCTCN2017077467-appb-100004
    式中，X为N，Ra、Rb和n的定义如权利要求4所述。
  6. 如权利要求1所述的化合物，其立体异构体、外消旋体或其药学上可接受的盐，所述R11为
    Figure PCTCN2017077467-appb-100005
    式中，Ra、Rb和n的定义如权利要求4所述。
  7. 如权利要求1所述的化合物，其立体异构体、外消旋体或其药学上可接受的盐，所述R11为
    Figure PCTCN2017077467-appb-100006
    式中，Ra、Rb和n的定义如权利要求4所述。
  8. 如权利要求1所述的化合物，其立体异构体、外消旋体或其药学上可接受的盐，所述的化合物选自下组：
    Figure PCTCN2017077467-appb-100007
    Figure PCTCN2017077467-appb-100008
    Figure PCTCN2017077467-appb-100009
    Figure PCTCN2017077467-appb-100010
    Figure PCTCN2017077467-appb-100011
    Figure PCTCN2017077467-appb-100012
    Figure PCTCN2017077467-appb-100013
    Figure PCTCN2017077467-appb-100014
  9. 一种药物组合物，其包含治疗有效量的如权利要求1所述的化合物、其立体异构体、外消旋体、或其药学上可接受的盐，以及药学上可接受的赋形剂。
  10. 一种制备如权利要求1所述化合物的方法，包括如下步骤：
    在无溶剂存在下，中间体C和中间体D经加热发生取代反应，生成化合物I，
    Figure PCTCN2017077467-appb-100015
    其中，X为卤素，R3-R12的定义如上所述。
  11. 一种权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，或权利要求8所述的组合物在制备用于预防和治疗与IDH突变相关的疾病的药物中的用途，所述用途包括：
    (a)制备治疗与突变IDH酶活性或表达量相关的疾病的药物；
    (b)制备突变IDH酶靶向抑制剂；
    (c)体外非治疗性地抑制突变IDH酶的活性；
    (d)体外非治疗性地抑制肿瘤细胞增殖；和/或
    (e)治疗与突变IDH酶活性或表达量相关的疾病。
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