WO2021078312A1 - 环烷基类和杂环烷基类抑制剂及其制备方法和应用 - Google Patents

环烷基类和杂环烷基类抑制剂及其制备方法和应用 Download PDF

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WO2021078312A1
WO2021078312A1 PCT/CN2020/138142 CN2020138142W WO2021078312A1 WO 2021078312 A1 WO2021078312 A1 WO 2021078312A1 CN 2020138142 W CN2020138142 W CN 2020138142W WO 2021078312 A1 WO2021078312 A1 WO 2021078312A1
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group
alkyl
cycloalkyl
substituted
compound
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French (fr)
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吕彬华
崔大为
刘连军
韩涛
王润卿
倪沛钟
盛泽林
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苏州泽璟生物制药股份有限公司
上海泽璟医药技术有限公司
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Publication of WO2021078312A1 publication Critical patent/WO2021078312A1/zh
Priority to US17/303,762 priority Critical patent/US11459327B1/en
Priority to US17/805,092 priority patent/US20230105745A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a cycloalkyl and heterocycloalkyl inhibitor, and a preparation method and application thereof.
  • Lung cancer is one of the important causes of human cancer deaths.
  • lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • the global NSCLC market was approximately US$20.9 billion in 2016, of which the US market accounted for half, followed by Japan, Germany and China.
  • the non-small cell lung cancer market has maintained continuous growth, and the global market is expected to reach 54 billion U.S. dollars in 2023 (Nature, 2018; 553(7689):446-454).
  • the main treatment drugs for NSCLC are divided into chemotherapy drugs, molecular targeted drugs and tumor immunotherapy.
  • chemotherapeutic drugs mainly include gemcitabine, paclitaxel and platinum drugs, but these drugs generally have poor selectivity and high toxicity, which leads to relatively strong side effects.
  • molecular targeted drugs have gradually become research hotspots due to their high selectivity, relatively small side effects, and their obvious advantages such as precise treatment.
  • NSCLC molecular targeted drugs include EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Ocarti Nigra, etc.), and VEGFR inhibitors (Sorafenib, Regorafenib, Cabozantinib, Sunitinib, Donafenib, etc.) (Current Medicinal Chemistry, 2019, 26, 1-39).
  • EGFR inhibitors such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Pyrotinib, Rociletinib, Osimertinib, etc.
  • KRAS mutations are frequently detected, accounting for about 32% of all oncogene mutations.
  • KRAS G12C mutation accounts for 44% of all oncogene mutations in NSCLC. So far, no drugs targeting the KRAS G12C mutation have been approved on the market.
  • KRAS G12C target protein is pathologically related to a variety of diseases
  • KRAS G12C inhibitors for clinical treatment.
  • Highly selective and active KRAS G12C inhibitors can more effectively treat cancers and other diseases caused by KRAS G12C mutations, and reduce the potential for off-target effects, so they have more urgent clinical needs.
  • the purpose of the present invention is to provide a new type of compound with selective inhibitory effect on KRAS G12C and/or better pharmacodynamic performance and its use.
  • the first aspect of the present invention provides a cycloalkyl and heterocycloalkyl compound having a structure of general formula (I), its stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable
  • a and B are the same or different, independently selected from CH or N;
  • X is selected from: a 4-14 membered saturated or unsaturated cycloalkyl or heterocyclic group, a C 6 -C 14 membered aryl group or a 5-14 membered heteroaryl group, wherein the saturated or unsaturated cycloalkane A group or a heterocyclic group, an aryl group or a heteroaryl group may be optionally substituted by one or more R 8;
  • Y is selected from the following group: bond, O, S, NH, NR 5 , CR 5 R 6 , CONH, CONR 5 , SO 2 NH, SO 2 NR 5 , NHCO, NR 5 CO, NHSO 2 , NR 5 SO 2 ;
  • Z is selected from the following group: bond, C 1 -C 18 alkylene, deuterated C 1 -C 18 alkylene, halogenated C 1 -C 18 alkylene, C 3 -C 20 cycloalkylene, C 4- C 20 heterocyclylene, C 1 -C 18 alkyleneoxy, deuterated C 1 -C 18 alkyleneoxy, halogenated C 1 -C 18 alkyleneoxy;
  • W is selected from the following group: bond, O, NH, NR 5 , CONH, CONR 5 , SO 2 NH, SO 2 NR 5 , NHCO, NHSO 2 , NHCONH, NR 5 CONH, NHCONR 5 , NR 5 CONR 6 , NHSO 2 NH, NR 5 SO 2 NH, NH SO 2 NR 5 , NR 5 SO 2 NR 6 ;
  • R 1 is selected from the following group:
  • R 2 is selected from the following group: -(CH 2 ) n R 7 , -(CH 2 ) n O(CH 2 ) q R 7 , -(CH 2 ) n SR 7 , -(CH 2 ) n COR 7 ,- (CH 2 ) n C(O)OR 7 , -(CH 2 ) n S(O) q R 7 , -(CH 2 ) n NR 5 R 7 , -(CH 2 ) n C(O)NR 5 R 7 , -(CH 2 ) n NR 5 C(O)R 7 , -(CH 2 ) n NR 5 C(O)NR 5 R 7 , -(CH 2 ) n S(O) q NR 5 R 7 , -(CH 2 ) n NR 5 S(O) q R 7 , -(CH 2 ) n NR 5 S(O) q R 7 , -(CH 2
  • R 3 is independently selected from the following group: hydrogen, deuterium, oxygen, C 1 -C 3 alkyl or halo C 1 -C 3 alkyl;
  • L is selected from the following group: bond, -C(O)-, C 1 -C 3 alkylene;
  • R 4 is selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, amino, hydroxyl, 4-20 membered heterocyclic group, C 6 -C 14 aryl, 5-14 membered heteroaryl;
  • R 5 and R 6 are the same or different, and are each independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, amino, hydroxyl , 4-20 membered heterocyclic group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group;
  • R 7 is selected from: substituted or unsubstituted C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl or 4-20 membered heterocyclic group;
  • R 8 is independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, amino, hydroxyl, 4-20 membered heterocyclic group, C 6 -C 14 aryl, 5-14 membered heteroaryl;
  • substitution refers to substitution by one or more groups selected from the following group: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkane Group, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl group, 4-20 membered heterocyclic group, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or ureido group;
  • R A is absent, or independently selected from: hydrogen, deuterium, fluoro, cyano or C 1 -C 3 alkyl;
  • R B is independently selected from: hydrogen, deuterium, cyano or C 1 -C 3 alkyl
  • alkyl group may be substituted by one or more substituents selected from the following group: deuterium, halogen, cyano, amino, C 3 -C 7 cycloalkyl, 4-7 membered heterocyclic group, NHR 9 Or NR 9 R 10 ;
  • R 9 and R 10 are each independently selected from C 1 -C 3 alkyl groups
  • n is an integer of 0, 1, 2 or 3;
  • n is an integer of 0, 1, 2, 3, 4 or 5;
  • p is an integer of 1 or 2;
  • q is an integer of 0, 1, 2, 3, 4 or 5;
  • a and B are N at the same time, and X is a 4-14 membered heterocyclic group, Y is selected from the following group: bond, O, S, NH or NR 5 , and R 5 is C 1 -C 18 alkane In the case of the group, Z is selected from substituted or unsubstituted C 3 -C 20 cycloalkylene groups;
  • Y is selected from the following group: bond, O, S, NH or NR 5 , W is selected from bond, and R 5 is C 1 -C 18
  • R 7 needs to be selected from substituted or unsubstituted C 3 -C 20 cycloalkyl groups;
  • Y is selected from the following group: bond, O, S, NH or NR 5
  • W is selected from the following group: NH or NR 5
  • R 7 When it is a C 1 -C 18 alkyl group, R 7 needs to be selected from a substituted or unsubstituted C 3 -C 20 cycloalkyl group or a substituted or unsubstituted 4-20 membered heterocyclic group.
  • R 1 , R 2 , R 3 , R 4 , A, B, X, Y, Z, L, W, and m are as described above.
  • cycloalkyl and heterocycloalkyl compounds having the structure of general formula (I), their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, Hydrates, solvates or prodrugs, which have the structure represented by the general formula (III):
  • R 1 , R 2 , R 3 , R 4 , X, Y, Z, L, W, and m are as described above.
  • R 1 , R 2 , R 3 , R 4 , R 8 , Y, Z, L, W, and m are as described above.
  • R 1 , R 2 , R 3 , R 4 , R 8 , Y, Z, W, and m are as described above.
  • R 1 , R 2 , R 3 , R 4 , R 8 , Z, W, and m are as described above.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , Z, and m are as described above.
  • the compound described in formula I-VI its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug,
  • W is the key
  • R 2 is -(CH 2 ) n R 7 , where H in CH 2 may be substituted;
  • R 7 is selected from: substituted or unsubstituted C 3 -C 20 cycloalkyl or 4-20 membered heterocyclic group; wherein, the substitution refers to substitution by one or more groups selected from the following group: C 1- C 18 alkyl group, deuterated C 1 -C 18 alkyl group; the alkyl group may be substituted by one or more substituents selected from the following group: deuterium, halogen, cyano, amine, C 3 -C 7 ring Alkyl group, 4-7 membered heterocyclic group, NHR 9 or NR 9 R 10 ; R 9 and R 10 are each independently a C 1 -C 3 alkyl group;
  • n 1, 2, or 3;
  • R 1 , R 3 , R 4 , R 8 , and m are as described above.
  • the compound is represented by formula VI, and in the formula:
  • W is the key
  • R 2 is -(CH 2 ) n R 7 ;
  • R 7 is selected from: substituted or unsubstituted C 3 -C 8 cycloalkyl; wherein, the substitution refers to substitution by one or more groups selected from the following group: C 1 -C 6 alkyl, deuterated C 1- C 6 alkyl; the alkyl group may be substituted by one or more substituents selected from the group consisting of 4-7 membered heterocyclyl, NHR 9 or NR 9 R 10 ; R 9 and R 10 are each independently Is a C 1 -C 3 alkyl group;
  • n 1, or 2;
  • R 1 , R 3 , R 4 , R 8 , and m are as described above.
  • the compound is represented by formula VI, and in the formula:
  • W is the key
  • R 2 is -(CH 2 ) n R 7 ;
  • R 7 is selected from: substituted or unsubstituted C 3 -C 6 cycloalkyl; wherein, the substitution refers to substitution by one or more groups selected from the following group: C 1 -C 3 alkyl, deuterated C 1- C 3 alkyl; the alkyl group may be substituted by one or more substituents selected from the group consisting of 4-7 membered heterocyclic group, NHR 9 or NR 9 R 10 ; R 9 , R 10 are each independently Is a C 1 -C 3 alkyl group;
  • n 1, or 2;
  • R 1 , R 3 , R 4 , R 8 and m are as described above.
  • the compound described in formula I-VI, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug It has the structure shown in general formula (VIII):
  • R 11 and R 12 are the same or different, and are each independently selected from: hydrogen, deuterium, C 1 -C 18 alkyl, and deuterated C 1 -C 18 alkyl;
  • Ring A is a substituted or unsubstituted C 3 -C 20 cycloalkyl group or a 4-20 membered heterocyclic group;
  • L 1 is a C 1 -C 18 alkyl group or a deuterated C 1 -C 18 alkyl group
  • Q is a C 3 -C 7 cycloalkyl group, a 4-7 membered heterocyclic group, NHR 9 or NR 9 R 10 ;
  • R 9 and R 10 are each independently a C 1 -C 3 alkyl group.
  • the compound described in formula I-VI its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein ,
  • Z is C 1 -C 18 alkylene C 3 -C 20 cycloalkylene
  • W is the key
  • R 2 is -(CH 2 ) n NR 5 R 7 ; wherein, H in CH 2 can be substituted;
  • n is an integer of 0, 1, 2, 3, 4 or 5;
  • R 5 is selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, amino, hydroxyl, 4-20 membered heterocyclic group, C 6 -C 14 aryl, 5-14 membered heteroaryl;
  • R 7 is selected from: substituted or unsubstituted C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl or 4-20 membered heterocyclic group;
  • alkyl group may be substituted by one or more substituents selected from the following group: deuterium, halogen, cyano, amino, C 3 -C 7 cycloalkyl, 4-7 membered heterocyclic group, NHR 9 Or NR 9 R 10 ;
  • R 9 and R 10 are each independently a C 1 -C 3 alkyl group
  • the substitution refers to substitution by one or more groups selected from the following group: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkane Group, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl group, 4-20 membered heterocyclic group, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea group.
  • the compound is represented by formula VI, and in the formula:
  • Z is CH 2 C 3 -C 6 cycloalkylene
  • W is the key
  • R 2 is -(CH 2 ) n R 7 ;
  • R 7 is selected from: substituted or unsubstituted C 3 -C 8 cycloalkyl; wherein, the substitution refers to substitution by one or more groups selected from the following group: C 1 -C 6 alkyl, deuterated C 1- C 6 alkyl; the alkyl group may be substituted by one or more substituents selected from the group consisting of 4-7 membered heterocyclyl, NHR 9 or NR 9 R 10 ; R 9 and R 10 are each independently Is a C 1 -C 3 alkyl group;
  • n 1, or 2;
  • R 1 , R 3 , R 4 , R 8 and m are as described above.
  • the compound is represented by formula VI, and in the formula:
  • Z is CH 2 C 3 -C 6 cycloalkylene
  • W is the key
  • R 2 is -(CH 2 ) n R 7 ;
  • R 7 is selected from: substituted or unsubstituted C 3 -C 6 cycloalkyl; wherein, the substitution refers to substitution by one or more groups selected from the following group: C 1 -C 3 alkyl, deuterated C 1- C 3 alkyl; the alkyl group may be substituted by one or more substituents selected from the group consisting of 4-7 membered heterocyclic group, NHR 9 or NR 9 R 10 ; R 9 , R 10 are each independently Is a C 1 -C 3 alkyl group;
  • n 1, or 2;
  • R 1 , R 3 , R 4 , R 8 , and m are as described above.
  • R 1 , R 2 , R 3 , R 4 , R 11 , R 12 , A, B, L, L 1 , X, Y, Z, W, Q, ring A And m are specific groups corresponding to each specific compound in the examples.
  • the cycloalkyl and heterocycloalkyl compounds with the structure of general formula (I), their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrated Compounds, solvates or prodrugs, the compounds are selected from the following group:
  • the compound of formula I is selected from the compounds shown in the examples.
  • the second aspect of the present invention provides a preparation of cycloalkyl and heterocycloalkyl compounds of the general formula (I) structure, its stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable
  • the method of salt, hydrate, solvate or prodrug includes the steps:
  • Rs and Rs' are protecting groups for amino, and the protecting groups are selected from: Boc, Bn, Cbz or Fmoc;
  • R 1 , R 2 , R 3 , R 4 , L, X, Y, Z, W and m are as defined above.
  • the base is TEA or DIPEA.
  • the amino protecting agent is selected from: (Boc) 2 O, benzyl chloroformate, di-tert-butyl dicarbonate, phthaloyl chloride, benzyl chloride, triphenyl Methyl chloride, 9-fluorenyl methyl chloroformate, allyl chloroformate.
  • the deprotection agent is 1-chloroethyl chloroformate.
  • the oxidizing agent is mCPBA.
  • the base is sodium alkoxide, potassium alkoxide, NaH or LiHNMDS, preferably sodium tert-butoxide or potassium tert-butoxide.
  • the acid is TFA.
  • the third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising one or more of the compounds of the general formula (I) described in the first aspect, its stereoisomers, tautomers, crystal forms, pharmaceuticals Above acceptable salt, hydrate, solvate or prodrug; and pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises a drug selected from the following group:
  • PD-1 inhibitors such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM009 or biosimilars of the above drugs, etc.
  • PD-L1 inhibitors such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405 , MSB2311 or biological analogues of the above drugs, etc.
  • CD20 antibodies such as rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tosit
  • VEGFR inhibitors e.g. Sorafenib, Pazopanib, Regorafenib, Sitravatinib, No.
  • HDAC inhibitors such as Gi vinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.
  • CDK inhibitors e.g. Palbociclib, Ribociclib, Abemaciclib, Milciclib, Trilaciclib, Lerociclib, etc.
  • MEK inhibitors e.g.
  • SelfetinDel4 (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) or Its combination.
  • a method for preparing a pharmaceutical composition which includes the steps of: combining a pharmaceutically acceptable carrier with the compound of general formula (I), stereoisomers, tautomers, The crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs are mixed to form a pharmaceutical composition.
  • the fourth aspect of the present invention provides a cycloalkyl and heterocycloalkyl compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable salts , Hydrate, solvate or prodrug, or the use of the pharmaceutical composition of the third aspect to prepare a pharmaceutical composition for preventing and/or treating diseases related to the activity or expression of KRAS G12C.
  • the disease is a tumor or a disordered disease.
  • the disease is selected from the following group: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, gastric cancer, liver cancer, colorectal cancer, melanoma, lymphoma, blood cancer , Brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
  • the fifth aspect of the present invention provides a non-diagnostic and non-therapeutic method for inhibiting KRAS G12C , which comprises the steps of: administering an effective amount of the compound of general formula (I) described in the first aspect, and its Stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or administration of the pharmaceutical composition described in the third aspect.
  • the compound is preferably the compound prepared in the embodiment.
  • Figure 1 is a graph of blood drug concentration-time.
  • Figure 2 shows the tumor volume-time curve in the MIA PaCa-2 CDX tumor model.
  • Figure 3 shows the tumor volume-time curve in the H358 CDX tumor model.
  • the inventors unexpectedly prepared a new type of KRAS G12C compound with selective inhibition and/or better pharmacodynamic properties. On this basis, the inventor completed the present invention.
  • alkyl refers to a straight or branched chain or cyclic alkane group containing 1-20 carbon atoms, such as 1-18 carbon atoms, especially 1-18 carbon atoms, preferably 1-10 carbon atoms
  • the carbon atom more preferably contains 1-6 carbon atoms.
  • alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, Pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and many more.
  • C1-C18 alkyl refers to straight or branched chain or cyclic alkyl, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17 or 18 carbon atoms, such as methyl, ethyl, propyl, isopropyl N-butyl, tert-butyl, isobutyl (e.g. ), n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl.
  • the alkyl group also includes a substituted alkyl group.
  • alkylene refers to a group formed by removing a hydrogen atom from an "alkyl or substituted alkyl” group, such as methylene, ethylene, propylene, isopropylene (such as ), butylene (e.g. ), pentylene (e.g. ), hexyl (e.g. ), Heptyl (e.g. ), Wait.
  • the term also includes the replacement of a methylene group of an alkylene group (such as C1-C18 alkylene) by a cycloalkylene group (such as C3-C20 cycloalkylene), such as "C1-C18 alkylene Group C3-C20 cycloalkylene” or "C3-C20 cycloalkylene C1-C18 alkylene".
  • C1-C18 alkylene C3-C20 cycloalkylene or "C3-C20 cycloalkylene C1-C18 alkylene” has the same meaning and refers to the removal of cycloalkylalkyl or alkylcycloalkyl A group formed by two hydrogen atoms, such as Wait.
  • cycloalkyl refers to complete saturation containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms
  • the cyclic hydrocarbon group includes 1-4 rings, and each ring contains 3-8 carbon atoms. It is preferably a C 3 -C 20 cycloalkyl group, more preferably a C 3 -C 18 cycloalkyl group, more preferably a C 3 -C 10 cycloalkyl group, more preferably a C 3 -C 6 cycloalkyl group .
  • “Substituted cycloalkyl” means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include spirocyclic, bridged or fused ring substituents, especially spirocyclic alkyl, spirocycloalkenyl, spirocyclic heterocycle (excluding heteroaromatic rings), bridged cycloalkyl, bridged cycloalkenyl, Bridged heterocyclic ring (excluding heteroaromatic ring), fused ring alkyl, fused ring alkenyl, fused ring heterocyclic group or fused ring aromatic ring group, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic group and heterocyclic aromatic The group can be optionally substituted.
  • C3-C20 cycloalkylene refers to a group formed by removing two hydrogen atoms from a cycloalkyl group, such as: Wait.
  • heterocyclyl refers to complete saturation containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms Or partially unsaturated cyclic groups (including but not limited to such as 3-7 membered monocyclic ring, 4-7 membered monocyclic ring, 6-11 membered bicyclic ring, or 8-16 membered tricyclic ring system), of which at least A heteroatom is present in a ring with at least one carbon atom.
  • Each heterocyclic ring containing heteroatoms can have 1, 2, 3 or 4 heteroatoms, these heteroatoms are selected from nitrogen atoms, oxygen atoms or sulfur atoms, wherein nitrogen atoms or sulfur atoms can be oxidized, and nitrogen atoms can also be Is quaternized.
  • the heterocyclic group may be attached to any heteroatom or carbon atom residue of the ring or ring system molecule, and is preferably attached to the N or C atom on the ring or ring system molecule.
  • Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidine Group, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepine Inyl group, 4-piperidinone group, tetrahydropyranyl group, morpholino group, thiomorpholino group, thiomorpholine sulfoxide group, thiomorpholine sulfone group, 1,3-dioxanyl group and Tetrahydro-1,1-dioxythiophene, etc.
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups involved are optionally connected to other groups through a single bond, or through a ring Any two or more atoms above are further connected to other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups; the heterocyclic group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxy, and carboxylate.
  • groups are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxy, and carboxylate.
  • C4-C20 heterocyclylene refers to a group formed by removing two hydrogen atoms from a heterocyclic group, such as: Wait.
  • aryl refers to an aromatic cyclic hydrocarbon compound group containing 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring carbon atoms, with 1-5 rings, especially single ring And bicyclic groups such as phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic, etc.), the aromatic ring of the aryl group can be connected by a single bond (such as biphenyl) or condensed (such as naphthalene, anthracene, etc.). "Substituted aryl” means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which can be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include fused ring substituents, especially fused ring alkyl, fused ring alkenyl, fused ring heterocyclic group or fused ring aromatic ring group, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic group and heterocyclic aromatic The group can be optionally substituted.
  • heteroaryl refers to a heteroaromatic system containing 1-4 heteroatoms and 5-14 ring atoms, where the heteroatoms are selected from oxygen, nitrogen and sulfur.
  • the heteroaryl group is preferably a 5- to 10-membered ring, more preferably 5-membered or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , Furyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazole and tetrazolyl, etc.
  • Heteroaryl may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy , Haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkane Sulfur group, oxo group, carboxyl group and carboxylate group.
  • C1-C18 alkoxy refers to a linear or branched or cyclic alkoxy group having 1 to 18 carbon atoms, including C1-C18 alkyl-O-, -C1-C6 alkyl-O-
  • the C1-C6 alkyl group includes, without limitation, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like. It is preferably a C1-C8 alkoxy group, and more preferably a C1-C6 alkoxy group.
  • C1-C18 alkoxy refers to a group obtained by removing one hydrogen atom from the "C1-C18 alkoxy”.
  • 4-7 membered heterocyclic group refers to a heterocyclic ring having 1, 2, 3 or 4 (preferably 1, 2 or 3, more preferably 1 or 2) selected from N, O and S heteroatoms Groups, preferably, the 4-7 membered heterocyclic group contains at least 1 N heteroatom, more preferably the 4-7 membered heterocyclic group is connected to other moieties through the N atom or C atom on the ring Connected.
  • halogen refers to chlorine, bromine, fluorine, and iodine.
  • halo refers to substitution by halogen.
  • deuterated refers to substitution by deuterium.
  • hydroxyl refers to a group with the structure OH.
  • nitro refers to a group bearing the structure NO 2.
  • cyano refers to a group bearing the structure CN.
  • ester group refers to a group with the structure -COOR, where R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aromatic Group or substituted aryl, heterocycle or substituted heterocycle.
  • amino refers to a group with the structure -NRR', where R and R'can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle are as defined above. R and R'may be the same or different in the dialkylamine segment.
  • amide group refers to a group with the structure -CONRR', where R and R'can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle are as defined above. R and R'may be the same or different in the dialkylamine segment.
  • sulfonamide group refers to a group with the structure -SO 2 NRR', where R and R'can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, ring Alkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle are as defined above. R and R'may be the same or different in the dialkylamine segment.
  • ureido refers to a group with the structure -NRCONR'R", where R, R'and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl , Cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R'and R" may be the same or different in the dialkylamine segment.
  • alkylaminoalkyl refers to a group with the structure -RNHR', where R and R'can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, Cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle are as defined above. R and R'can be the same or different.
  • dialkylaminoalkyl refers to a group with the structure -RNHR'R", where R, R'and R" can independently represent alkyl or substituted alkyl, cycloalkyl or substituted Cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle are as defined above. R, R'and R" may be the same or different in the dialkylamine segment.
  • heterocyclylalkyl refers to a group with the structure -RR', where R can independently represent an alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted Cycloalkenyl, aryl or substituted aryl; R'represents heterocycle or substituted heterocycle.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • the specific substituents are the substituents correspondingly described in the foregoing, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different in each position.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents such as (but not limited to): halogen, hydroxyl, cyano, carboxy (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic group, aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, C1-C6 alkoxy group, C1-C10 sulfonyl group, and C1-C6 ureido and so on.
  • a substituent is a non-terminal substituent, it is a subunit of the corresponding group, for example, an alkyl group corresponds to an alkylene group, a cycloalkyl group corresponds to a cycloalkylene group, a heterocyclic group corresponds to a heterocyclylene group, and an alkoxy group corresponds to Alkyleneoxy and so on.
  • the compound of the present invention refers to the compound represented by Formula I, and also includes stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates of the compound of Formula I.
  • the compound of formula I has the following structure:
  • R 1 , R 2 , R 3 , R 4 , A, B, L, X, Y, Z, W, and m are as defined above.
  • the compound of formula I has a structure represented by the general formula (II-A) or (II-B):
  • R 1 , R 2 , R 3 , R 4 , A, B, X, Y, Z, L, W, and m are as described above.
  • the compound of formula I has a structure represented by general formula (III):
  • R 1 , R 2 , R 3 , R 4 , X, Y, Z, L, W, and m are as described above.
  • the compound of formula (I) has the structure shown in general formula (IV):
  • R 1 , R 2 , R 3 , R 4 , R 8 , Y, Z, L, W, and m are as described above.
  • the compound of formula (I) has a structure represented by general formula (V):
  • R 1 , R 2 , R 3 , R 4 , R 8 , Y, Z, W, and m are as described above.
  • the compound of formula (I) has a structure represented by general formula (VI):
  • R 1 , R 2 , R 3 , R 4 , R 8 , Z, W, and m are as described above.
  • the compound of formula (I) has a structure represented by general formula (VII-A) or (VII-B):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , Z, and m are as described above.
  • R A is selected from: hydrogen, deuterium, fluoro, cyano or C 1 -C 3 alkyl;
  • R B is selected from: hydrogen, deuterium, cyano or C 1 -C 3 alkyl
  • the alkyl group may be substituted by one or more substituents selected from the following group: deuterium, halogen, cyano, amino, C 3 -C 7 cycloalkyl, 4-7 membered heterocyclic group, NHR 9 Or NR 9 R 10 ; wherein R 9 and R 10 are each independently a C 1 -C 3 alkyl group.
  • Z is C 1 -C 18 alkylene C 3 -C 20 cycloalkylene, preferably CH 2 C 3 -C 20 cycloalkylene, more preferably CH 2 C 3- C 6 cycloalkylene.
  • Z is a bond or C 1 -C 18 alkylene C 3 -C 20 cycloalkylene
  • W is a bond
  • R 2 is -(CH 2 )R 7 or -(CH 2 ) n NR 5 R 7
  • n is 1, 2 or 3, preferably 1 or 2;
  • R 5 and R 7 are as described above.
  • Z is a bond or CH 2 C 3 -C 6 cycloalkylene
  • W is a bond
  • R 2 is -(CH 2 ) n R 7 or -(CH 2 ) n NR 5 R 7
  • N is 1, 2 or 3, preferably 1 or 2;
  • R 5 is selected from the following group of substituted or unsubstituted groups: C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl , C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, amino, hydroxyl, 3-7 membered heterocyclic group, C 6 -C 14 aromatic Group, 5-14 membered heteroaryl group;
  • R 7 is selected from: substituted or unsubstituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-7 membered heterocyclic group;
  • substitution refers to substitution by one or more groups selected from the following group: deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, halogen, nitro, hydroxyl, cyano, ester, amine, amide, Sulfonamide group or urea group.
  • the compound of formula (I) has the structure shown in (VIII):
  • R 1 , R 4 , R 8 , R 11 , R 12 , ring A, L 1 , Q, and m are as described above.
  • ring A is a substituted or unsubstituted group of the following group: C 3 -C 6 cycloalkyl or 4-6 membered heterocyclic group, wherein the substitution refers to a group selected from the group One or more group substitutions: deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 1 -C 18 alkoxy, deuterated C 1- C 18 alkoxy, halogenated C 1 -C 18 alkoxy, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide, or urea.
  • Q is a 4-7 membered heterocyclic group, NHR 9 or NR 9 R 10 ; more preferably, Q is NR 9 R 10 ; R 9 and R 10 are each independently C 1- C 3 alkyl.
  • R 8 is independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, deuterated C 1 -C 6 alkoxy group, halogenated C 1 -C 6 alkoxy group, amino group, hydroxyl group; wherein, the substitution refers to being selected from Substitution of one or more groups from the following group: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy Group, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, halogen, nitro, hydroxyl, cyano, ester, amine, amide, s
  • Z is selected from the group consisting of C 1 -C 6 alkylene, deuterated C 1 -C 6 alkylene, halogenated C 1 -C 6 alkylene, C 3 -C 8 Cycloalkylene, C 4 -C 8 heterocyclylene, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy.
  • Salts that may be formed by the compounds of the present invention also belong to the scope of the present invention. Unless otherwise specified, the compounds in the present invention are understood to include their salts.
  • the term "salt” as used herein refers to a salt formed into an acid or basic form with an inorganic or organic acid and a base.
  • the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and when it contains an acidic fragment, including but not limited to carboxylic acid, the zwitterion (“internal salt") that may be formed is contained in Within the scope of the term "salt”.
  • salts are preferred, although other salts are also useful, for example, they can be used in separation or purification steps in the preparation process.
  • the compound of the present invention may form a salt.
  • the compound I can be obtained by reacting with a certain amount of acid or base, such as an equivalent amount of acid or base, and salting out in the medium, or by freeze-drying in an aqueous solution.
  • the basic fragments contained in the compounds of the present invention may form salts with organic or inorganic acids.
  • Typical acids that can form salts include acetate (such as acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, and benzoate.
  • Benzene sulfonate hydrogen sulfate, borate, butyrate, citrate, camphor salt, camphor sulfonate, cyclopentane propionate, diglycolate, dodecyl sulfate, Ethane sulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, isethionate (E.g. 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g.
  • 2-naphthalenesulfonate nicotinate, nitrate, oxalic acid Salt, pectinate, persulfate, phenylpropionate (such as 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, Sulfate (such as formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate such as p-toluenesulfonate, dodecanoate, etc.
  • the acidic fragments that some compounds of the present invention may contain, including but not limited to carboxylic acids, may form salts with various organic or inorganic bases.
  • Typical salts formed by bases include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed by organic bases (such as organic amines) such as benzathine and bicyclohexyl.
  • Hypamine a salt formed with N,N-bis(dehydroabietyl)ethylenediamine
  • N-methyl-D-glucamine N-methyl-D-glucamide
  • tert-butyl Base amines and salts with amino acids such as arginine, lysine, etc.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (E.g., dimethyl sulfate, diethyl, dibutyl and dipentyl sulfate), long chain halides (such as chlorides and bromides of decyl, dodecyl, tetradecyl and tetradecyl) And iodides), aralkyl halides (such as benzyl and phenyl bromides) and so on.
  • alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates E.g., dimethyl sulfate, diethyl, dibutyl
  • prodrugs and solvates of the compounds of the present invention are also within the scope of coverage.
  • prodrug herein refers to a compound that undergoes metabolic or chemical transformation to produce the compound, salt, or solvate of the present invention when treating related diseases.
  • the compounds of the present invention include solvates, such as hydrates.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imine ethers). All these tautomers are part of the invention.
  • All stereoisomers of compounds (for example, those asymmetric carbon atoms that may exist due to various substitutions), including their enantiomeric forms and diastereomeric forms, fall within the scope of the present invention.
  • the independent stereoisomers of the compound in the present invention may not coexist with other isomers (for example, as a pure or substantially pure optical isomer with special activity), or may be a mixture, such as Racemates, or mixtures with all other stereoisomers or part of them.
  • the chiral center of the present invention has two configurations, S or R, defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974.
  • racemic form can be resolved by physical methods, such as fractional crystallization, or separation of crystallization by derivatization into diastereomers, or separation by chiral column chromatography.
  • Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to traditional methods, such as salt formation with an optically active acid and then recrystallization.
  • the weight content of the compound obtained by successive preparation, separation and purification is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), as described in the text Listed.
  • very pure compounds of the invention are also part of the invention.
  • All configuration isomers of the compounds of the present invention are within the scope of coverage, whether in mixture, pure or very pure form.
  • the definition of the compound of the present invention includes two olefin isomers, cis (Z) and trans (E), as well as cis and trans isomers of carbocyclic and heterocyclic rings.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, and exogenous Spin mixtures and other mixtures.
  • the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and their mixtures are included in the present invention.
  • the ratio of the mixture of isomers containing isomers can be varied.
  • a mixture of only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: 2, 99:1, or 100:0, all ratios of isomers are within the scope of the present invention. Similar ratios, which are easily understood by those skilled in the art, and ratios that are mixtures of more complex isomers are also within the scope of the present invention.
  • the present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. In practice, however, it usually occurs when one or more atoms are replaced by atoms whose atomic weight or mass number is different.
  • isotopes that can be classified as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, and 18 O, respectively. , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • the compounds of the present invention or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are all within the scope of the present invention.
  • Certain isotope-labeled compounds of the present invention such as radioisotopes of 3 H and 14 C, are also among them, which are useful in tissue distribution experiments of drugs and substrates.
  • Isotopically-labeled compounds can be prepared by general methods by replacing readily available isotope-labeled reagents with non-isotopic reagents, using the protocol disclosed in the example.
  • a specific enantiomer of the compound of the present invention can be prepared by asymmetric synthesis, or derivatized with a chiral adjuvant, separating the resulting diastereomeric mixture, and then removing the chiral adjuvant. Pure enantiomer.
  • a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then through separation crystallization or chromatography, etc. After separation by conventional means, the pure enantiomers are obtained.
  • the compounds of the present invention can be combined with any number of substituents or functional groups to expand their scope of inclusion.
  • substituents or functional groups Generally, whether the term “substituted” appears before or after the term “optional”, the general formula including substituents in the formula of the present invention means that the substituents of the specified structure are substituted for hydrogen radicals. When a plurality of positions in a specific structure are substituted by a plurality of specific substituents, each position of the substituents may be the same or different.
  • substitution as used herein includes all permissible substitution of organic compounds.
  • the permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • the heteroatom nitrogen may have a hydrogen substituent or any permitted organic compound as described above to supplement its valence.
  • the present invention is not intended to limit the permitted substitution of organic compounds in any way.
  • the present invention believes that the combination of substituents and variable groups is good in the treatment of diseases in the form of stable compounds, such as infectious diseases or proliferative diseases.
  • stable here refers to a compound that is stable and can be tested for a long enough time to maintain the structural integrity of the compound, preferably for a long enough time to be effective, and is used herein for the above purpose.
  • the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.
  • the compound of general formula (V-1) generates intermediate general formula (V-2) under the action of a base (such as TEA or DIPEA), and then deprotects to produce intermediate (V-3); compound (V-3) is coupled by coupling Or substitution or acylation reaction to obtain intermediate (V-4), and then generate intermediate (V-5) under the action of oxidant (such as mCPBA); compound (V-5) acts on alkali (such as NaH, LiHNMDS or tBuOK)
  • oxidant such as mCPBA
  • compound (V-5) acts on alkali (such as NaH, LiHNMDS or tBuOK)
  • the following generates intermediate formula (V-6); compound (V-6) is deprotected to generate intermediate (V-7), which is then substituted or acylated to obtain the target product formula (III); wherein, R 1 , R 2 , R 3 , R 4 , L, X, Y, Z, W, and m are as described above; Rs and Rs' are protecting groups
  • the pharmaceutical composition of the present invention is used to prevent and/or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.
  • the compound of general formula (I) can be used in combination with other drugs known to treat or improve similar conditions.
  • the mode of administration and dosage of the original drug can be kept unchanged, while the compound of formula I is administered at the same time or subsequently.
  • a pharmaceutical composition containing one or more known drugs and the compound of formula I can be preferably used.
  • the combination of drugs also includes taking the compound of formula I and one or more other known drugs in overlapping time periods.
  • the dose of the compound of formula I or the known drug may be lower than the dose of the compound used alone.
  • the drugs or active ingredients that can be used in combination with the compound of general formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemipilimab, JS-001, SHR-120, BGB- A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, etc.) CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofat
  • Ibrutinib Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.
  • EGFR inhibitors e.g. Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib Osimertinib, etc.
  • VEGFR inhibitors such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Caboza ntinib, Sunitinib, Donafenib, etc.
  • HDAC inhibitors such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.
  • CDK inhibitors such as Palbociclib, Ribociclib, Abemacic
  • the dosage form of the pharmaceutical composition of the present invention includes (but is not limited to): injection, tablet, capsule, aerosol, suppository, film, dripping pill, external liniment, controlled release or sustained release or nano preparation.
  • the pharmaceutical composition of the present invention contains the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/agent, more preferably, 10-1000 mg of the compound of the present invention/agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as emulsifiers
  • wetting agents such as sodium lauryl sulfate
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited.
  • Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycty
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into a microcapsule form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage forms of the compound of the present invention for topical administration include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the treatment method of the present invention can be administered alone or in combination with other treatment means or therapeutic drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment.
  • the administered dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also consider factors such as the route of administration and the patient's health status, which are all within the skill range of a skilled physician.
  • the present invention also provides a method for preparing a pharmaceutical composition, which comprises the steps of: combining a pharmaceutically acceptable carrier with the compound of general formula (I) of the present invention or its crystal form, pharmaceutically acceptable salt, hydrate or The solvates are mixed to form a pharmaceutical composition.
  • the present invention also provides a treatment method, which comprises the steps of: administering the compound of general formula (I) of the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, to a subject in need of treatment , Or administer the pharmaceutical composition of the present invention for selectively inhibiting KRAS G12C .
  • the present invention has the following main advantages:
  • the compound has a very good selective inhibitory effect on KRAS G12C;
  • the compound has better pharmacodynamics, pharmacokinetic properties and lower toxic and side effects.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) and liquid mass spectrometry (LC-MS).
  • NMR is detected by Bruker AVANCE-400 nuclear magnetic instrument.
  • the solvent for determination includes deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated acetone (CD 3 COCD 3 ), deuterated chloroform (CDCl 3 ) and deuterated methanol ( CD 3 OD), etc.
  • the internal standard uses tetramethylsilane (TMS), and the chemical shift is measured in units of parts per million (ppm).
  • LC-MS Liquid chromatography mass spectrometry
  • Waters SQD2 mass spectrometer The measurement of HPLC uses Agilent1100 high pressure chromatograph (Microsorb 5micron C18 100x 3.0mm chromatographic column).
  • the thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, the TLC uses 0.15-0.20mm, and the preparative thin layer chromatography uses 0.4mm-0.5mm.
  • Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
  • the starting materials in the examples of the present invention are all known and commercially available, or can be synthesized by using or according to literature reported in the field.
  • the first step Preparation of 7-benzyl-2-(methylthio)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidine-4-hydroxyl
  • the third step 4-(7-benzyl-2-(methylthio)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)-2-(cyano (Methyl) piperazine-1-carboxylic acid tert-butyl ester preparation
  • reaction solution was quenched with water, and then extracted with ethyl acetate (3 x 100 mL). After all the organic phases were combined, washed once with saturated sodium chloride, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (8.21 g, yield 73%).
  • the fifth step 2-(cyanomethyl)-4-(7-(8-methylnaphthalene-1-yl)-2-(methylthio)-5,6,7,8-tetrahydropyridine [ Preparation of 3,4-d)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • reaction solution was stirred at 0°C for 10 min, and then quenched with sodium hyposulfite solution (50 mL).
  • Step 1 Preparation of tert-butyl 3-((2-hydroxyethyl)(methyl)amino)azetidine-1-carboxylate
  • the target product (4.3 g, yield 56%) was obtained.
  • the target product (1.6 g, yield 50%) was obtained.
  • Step 1 Preparation of cis-4-(dimethylamino)tetrahydrofuran-3-yl 4-nitrobenzoate
  • Step 1 Preparation of (R)-2-tert-butoxycarbonylamino-3-methoxypropionic acid methyl ester
  • the third step preparation of 2-[(2,2-difluoro-cyclopropylmethyl)-methylamino]-ethanol
  • N-(2-(benzyloxy)ethyl)-N,1-dimethylcyclobutylamine 700 mg, 3 mmol was added to hydrobromic acid (30%) acetic acid solution (10 mL) and stirred at room temperature overnight.
  • the reaction solution was concentrated to remove acetic acid, then diluted with 2M sodium hydroxide solution (pH>10), extracted with ethyl acetate (40mL) 3 times, the combined organic phases were concentrated, and then diluted with methanol (10mL), sodium hydroxide ( 240 mg), stirred at room temperature for 30 minutes, concentrated to remove methanol to obtain a crude product.
  • N-methylcyclopropylamine hydrochloride (3.2 g, 29.6 mmol) was dissolved in methanol (60 mL), and while stirring, water (1.1 mL, 59.1 mmol) and sodium hydroxide (2.4 g, 59.1 mmol) were added. The mixture was placed in an ice salt bath, and a tetrahydrofuran solution of ethylene oxide (3mol/L, 30mL, 90.0mmol) was added. The reaction solution was slowly raised to room temperature, and after stirring for 16 hours, it was concentrated in vacuo to remove the solvent. Water (30 mL) and potassium carbonate (5 g) were added to the residue, and then extracted with ethyl acetate (30 mL x 4).
  • the first step the preparation of (S)-(2-hydroxypropyl) carboxylate tert-butyl ester
  • the first step the preparation of 2,2'-(cyclopropylazanediyl)bis(ethane-1-ol)
  • the first step the preparation of 1-fluorocyclopropane-1-formyl chloride
  • the second step the preparation of 1-fluoro-N-(2-hydroxyethyl)-N-methylcyclopropane-1-carboxamide
  • the third step preparation of 2-(((1-fluorocyclopropyl)methyl)(methyl)amino)ethane-1-ol
  • Step 2 (S)-(1-cyclopropylethyl)(2-hydroxyethyl) tert-butyl carbamate
  • the third step preparation of (S)-2-((1-cyclopropylethyl)(methyl)amino)ethane-1-ol
  • the first step 2-(cyanomethyl)-4-(2-((R)-2-(cyclobutyl(methyl)amino)-3-methoxypropoxy)-7-(8 -Methylnaphthalene-1-yl)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • the second step 2-(4-(-(2-((R)-2-(cyclobutyl(methyl)amino)-3-methoxypropoxy)-7-(8-methylnaphthalene) -1-yl)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
  • reaction solution was warmed to room temperature Stir for 1 h, then add methanol (1 mL) for quenching.
  • methanol (1 mL) for quenching.
  • the obtained mixture is concentrated, and the obtained residue is prepared in a liquid phase to obtain the target product (13 mg, yield 35%).
  • the first step tert-butyl 4-(2-((1-((tert-butoxycarbonyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7-(8-chloronaphthalene-1 -Yl)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate
  • the second step 2-(4-(7-(8-chloronaphthalene-1-yl)-2-((1-((methylamino)methyl)cyclopropyl)methoxy)-5,6 ,7,8-Tetrahydropyridine[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
  • the third step tert-butyl ((1-((7-(8-chloronaphthalene-1-yl)-4-(3-(cyanomethyl)piperazin-1-yl)-5,6,7 ,8-Tetrahydropyridine [3,4-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)(methyl)carbamate
  • the fourth step tert-butyl ((1-((4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8-chloronaphthalene-1-yl)-5 ,6,7,8-Tetrahydropyridine[3,4-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)(methyl)carbamate
  • reaction solution was raised to room temperature and stirred for 1 h, and then quenched by adding methanol (1 mL).
  • methanol 1 mL
  • the fifth step 2-(1-acryloyl-4-(7-(8-chloronaphthalene-1-yl)-2-((1-((methylamino)methyl)cyclopropyl)methoxy )-5,6,7,8-Tetrahydropyridine[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
  • reaction solution was stirred at room temperature for 0.5 h, then saturated sodium bicarbonate solution (10 mL) was added to destroy it, and then extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed once with saturated sodium chloride solution, then dried over anhydrous sodium sulfate and filtered. After the filtrate was concentrated, the target product (20 mg, yield: 29%) was obtained by liquid phase preparation.
  • reaction solution was quenched with water, and then extracted with ethyl acetate (3 x 100 mL). After all the organic phases were combined, washed once with saturated sodium chloride, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the target product (8.0 g, yield 71%).
  • (2S)-4-(7-(8-chloronaphthalene-1-yl)-2-(methylsulfone)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidine-4 -Yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (1.16g, 2.00mmol) was added to the reaction flask, followed by toluene (12mL) and (1-((dimethylamino)methyl Cyclopropyl)methanol (517 mg, 4.00 mmol), and then sodium tert-butoxide (577 mg, 6.00 mmol) was added under stirring in an ice-water bath.
  • the resulting reaction solution was stirred for 0.5 h in an ice-water bath, then quenched by adding water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated with a medium pressure preparative column to obtain the target product (730 mg, yield 60%).
  • reaction solution was concentrated and then adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, and then extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed once with saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness to obtain a crude product. Without further purification, it was directly used in the next reaction.
  • the seventh step (S)-2-(4-(7-(8-chloronaphthalene-1-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy )-5,6,7,8-Tetrahydropyridine[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
  • reaction solution was stirred for 0.5 h under the protection of nitrogen, then quenched by adding water (100 mL), and then extracted with ethyl acetate (3 x 60 mL). The combined organic phase was washed 4 times with saturated sodium chloride solution, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by preparative chromatography to obtain the target product (162 mg, two-step yield 25%).
  • Example 28 was synthesized according to the method of Example 27 with different starting materials:
  • Example 29 Obtained four isomers through chiral resolution Example 29A, 29B, 29C and 29D
  • Example 39 1-(7-(7-(8-chloronaphthalene-1-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-5,6 ,7,8-Tetrahydropyridine[3,4-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-yl)prop-2-en-1-one preparation
  • Example 40 1-(6-(7-(8-chloronaphthalene-1-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-5,6 ,7,8-Tetrahydropyridine[3,4-d]pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one preparation
  • Example 41 1-(4-(7-(8-chloronaphthalene-1-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-5,6 ,7,8-Tetrahydropyridine[3,4-d]pyrimidin-4-yl)-2-(trifluoromethyl)piperazin-1-yl)prop-2-en-1-one
  • Example 44 1-(6-(7-(8-chloronaphthalene-1-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-5,6 ,7,8-Tetrahydropyridine[3,4-d]pyrimidin-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)prop-2-en-1-one preparation
  • Example 47 Obtained two isomers through chiral resolution
  • Example 47A, 47B
  • Example 53 Obtained two isomers through chiral resolution
  • Example 53A, 53B
  • the first step 2-(cyanomethyl)-4-(2-(cyclopropyl(methyl)amino)ethoxy)-7-(8-methylnaphthalene-1-yl)-5,6 ,7,8-Tetrahydropyridine[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • the second step 2-(4-(2-(2-(cyclopropyl(methyl)amino)ethoxy)-7-(8-methylnaphthalene-1-yl)-5,6,7, Preparation of 8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
  • reaction solution was raised to room temperature and stirred for 1 h, and then quenched by adding methanol (1 mL).
  • methanol 1 mL
  • the obtained mixture was concentrated, and the obtained residue was reversed-phase purified with a C18 column to obtain the target product (12 mg, yield 36%).
  • the compound was prepared by chiral separation to obtain 2-((S)-1-acryloyl-4-(2-((S)-2-(cyclobutyl(methyl)amino)propoxy)-7-(8 -Methylnaphthyl-1-yl)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (A) and 2-( (R)-1-acryloyl-4-(2-((S)-2-(cyclobutyl(methyl)amino)propoxy)-7-(8-methylnaphthyl-1-yl )-5,6,7,8-Tetrahydropyridine[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (B)

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Abstract

一种环烷基类和杂环烷基类抑制剂及其制备方法和应用。具有式（I）所示结构，还公开了所述化合物的制备方法及其作为KRASG12C抑制剂的用途，对KRASG12C具有很好的选择性抑制作用且具有更好的药效学、药代动力学性能和更低的毒副作用。

Description

环烷基类和杂环烷基类抑制剂及其制备方法和应用 技术领域
本发明属于药物领域，具体涉及一种环烷基类和杂环烷基类抑制剂及其制备方法和应用。
背景技术
肺癌是人类癌症致死的重要原因之一。按照细胞类型肺癌可以分为小细胞肺癌(SCLC)和非小细胞肺癌(NSCLC)，其中NSCLC占所有肺癌患者的85％。据统计2016年全球NSCLC的市场约为209亿美元，其中美国市场占据一半，其次是日本、德国和中国。从现有趋势来看，非小细胞肺癌市场保持着持续增长，预计2023年全球市场将达到540亿美元(Nature，2018；553(7689):446-454)。
目前NSCLC的主要治疗用药分为化疗药物、分子靶向药物以及肿瘤免疫疗法等。其中化疗药物主要包括吉西他滨、紫杉醇以及铂类药物等，但是这类药物普遍具有选择性差、毒性大从而导致比较强烈的毒副作用。近年来，分子靶向药物因其选择性较高、毒副作用相对较小，能够实现精准治疗等明显优势从而逐渐成为研究热点。现有的NSCLC分子靶向药物包括EGFR抑制剂(如Afatinib、Gefitinib、Erlotinib、Lapatinib、Dacomitinib、Icotinib、Pyrotinib、Rociletinib、Osimertinib等)，ALK抑制剂(如Ceritinib、Alectinib、Brigatinib、Lorlatinib、奥卡替尼等)，以及VEGFR抑制剂(Sorafenib、Regorafenib、Cabozantinib、Sunitinib、多纳非尼等)(Current Medicinal Chemistry,2019,26,1-39)。
在肺癌病患里面，经常检测到KRAS突变，约占所有致癌基因突变的32％。其中KRAS G12C突变在NSCLC里面占所有致癌基因突变的44％。到目前为止，市场上仍然没有针对KRAS G12C突变的药物被批准上市。
由于KRAS G12C靶蛋白在病理学上与多种疾病相关，因此目前还需要新型的KRAS G12C抑制剂用于临床治疗。高选择性高活性的KRAS G12C抑制剂可以对KRAS G12C突变导致的癌症等疾病更有效治疗，以及减少脱靶效应的潜力，因而具有更迫切的临床需求。
发明内容
本发明的目的在于提供一类新型的对KRAS G12C有选择性抑制作用和/或更好药效学性能的化合物及其用途。
本发明的第一方面，提供了一种具有通式(I)结构的环烷基类和杂环烷基类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药：
Figure PCTCN2020138142-appb-000001
式中：
A，B相同或者不同，独立地选自CH或N；
X选自：4-14元饱和或不饱和的环烷基或杂环基、C 6-C 14元芳基或者5-14元杂芳基，其中，所述的饱和或不饱和的环烷基或杂环基、芳基或者杂芳基可以任选地被一个或多个R 8所取代；
Y选自下组：键、O、S、NH、NR 5、CR 5R 6、CONH、CONR 5、SO 2NH、SO 2NR 5、NHCO、NR 5CO、NHSO 2、NR 5SO 2；
Z选自下组：键、C 1-C 18亚烷基、氘代C 1-C 18亚烷基、卤代C 1-C 18亚烷基、C 3-C 20亚环烷基、C 4-C 20亚杂环基、C 1-C 18亚烷氧基、氘代C 1-C 18亚烷氧基、卤代C 1-C 18亚烷氧基；
W选自下组：键、O、NH、NR 5、CONH、CONR 5、SO 2NH、SO 2NR 5、NHCO、NHSO 2、NHCONH、NR 5CONH、NHCONR 5、NR 5CONR 6、NHSO 2NH、NR 5SO 2NH、NH SO 2NR 5、NR 5SO 2NR 6；
R 1选自下组：
Figure PCTCN2020138142-appb-000002
R 2选自下组：-(CH 2) nR 7、-(CH 2) nO(CH 2) qR 7、-(CH 2) nSR 7、-(CH 2) nCOR 7、-(CH 2) nC(O)OR 7、-(CH 2) nS(O) qR 7、-(CH 2) nNR 5R 7、-(CH 2) nC(O)NR 5R 7、-(CH 2) nNR 5C(O)R 7、-(CH 2) nNR 5C(O)NR 5R 7、-(CH 2) nS(O) qNR 5R 7、-(CH 2) nNR 5S(O) qR 7、-(CH 2) nNR 5S(O) qNR 5R 7，其中，CH 2中的H可以被取代；
R 3独立地选自下组：氢、氘、氧、C 1-C 3烷基或卤代C 1-C 3烷基；
L选自下组：键、-C(O)-、C 1-C 3的亚烷基；
R 4选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、胺基、羟基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基；
R 5和R 6相同或不同，且各自独立地选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、氨基、羟基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基；
R 7选自：取代或未取代的C 1-C 18烷基、C 3-C 20环烷基或4-20元杂环基；
R 8独立地选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、氨基、羟基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基；
其中，所述取代指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；
Figure PCTCN2020138142-appb-000003
可以是双键“＝”或三键“≡”；
R A为不存在，或者独立地选自：氢、氘、氟、氰基或者C 1-C 3烷基；
R B独立地选自：氢、氘、氰基或者C 1-C 3烷基；
其中，所述烷基可以被选自下组的一个或多个取代基取代：氘、卤素、氰基、胺基、C 3-C 7环烷基、4-7元杂环基、NHR 9或NR 9R 10；
R 9，R 10各自独立地选自C 1-C 3烷基；
m为0、1、2或3的整数；
n为0、1、2、3、4或5的整数；
p为1或2的整数；
q为0、1、2、3、4或5的整数；
限定条件是：当A和B同时为N，且X为4-14元杂环基，Y选自下组：键、O、S、NH或NR 5，且R 5为C 1-C 18烷基时，Z选自取代或未取代的C 3-C 20亚环烷基；
或，
当A和B同时为N，且X为4-14元杂环基，Y选自下组：键、O、S、NH或NR 5，W选自键，且R 5为C 1-C 18烷基时，R 7需选自取代或未取代的C 3-C 20环烷基；
或，
当A和B同时为N，且X为4-14元杂环基，Y选自下组：键、O、S、NH或NR 5，W选自下组：NH或NR 5，且R 5为C 1-C 18烷基时，R 7需选自取代或未取代的C 3-C 20环烷基或取代或未取代的4-20元杂环基。
在另一优选例中，具有通式(I)结构的环烷基类和杂环烷基类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有通式(II-A)或(II-B)所示的结构：
Figure PCTCN2020138142-appb-000004
式中：
R 1、R 2、R 3、R 4、A、B、X、Y、Z、L、W、m的定义如上所述。
在另一优选例中，具有通式(I)结构的环烷基类和杂环烷基类化合物化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有通式(III)所示结构：
Figure PCTCN2020138142-appb-000005
其中，R 1、R 2、R 3、R 4、X、Y、Z、L、W、m的定义如上所述。
在另一优选例中，具有通式(I)结构的环烷基类和杂环烷基类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有通式(IV)所示结构：
Figure PCTCN2020138142-appb-000006
式中：
R 1、R 2、R 3、R 4、R 8、Y、Z、L、W、m的定义如上所述。
在另一优选例中，具有通式(I)结构的环烷基类和杂环烷基类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有通式(V)所示结构：
Figure PCTCN2020138142-appb-000007
式中：
R 1、R 2、R 3、R 4、R 8、Y、Z、W、m的定义如上所述。
在另一优选例中，具有通式(I)结构的环烷基类和杂环烷基类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有通式(VI)所示结构：
Figure PCTCN2020138142-appb-000008
式中：
R 1、R 2、R 3、R 4、R 8、Z、W、m的定义如上所述。
在另一优选例中，具有通式(I)结构的环烷基类和杂环烷基类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有通式(VII-A)或(VII-B)所示的结构：
Figure PCTCN2020138142-appb-000009
式中：
R 1、R 2、R 3、R 4、R 5、R 8、Z、m的定义如上所述。
在另一优选例中，式I-VI中所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，
式中：
Z为键；
W为键；
R 2为-(CH 2) nR 7，其中，CH 2中的H可以被取代；
R 7选自：取代或未取代的C 3-C 20环烷基或4-20元杂环基；其中，所述取代指被选自下 组的一个或多个基团取代：C 1-C 18烷基、氘代C 1-C 18烷基；所述烷基可以被选自下组的一个或多个取代基取代：氘、卤素、氰基、胺基、C 3-C 7环烷基、4-7元杂环基、NHR 9或NR 9R 10；R 9，R 10各自独立地为C 1-C 3烷基；
n为1、2、或3；
R 1、R 3、R 4、R 8、m的定义如上所述。
在另一优选例中，所述化合物如式VI所示，并且式中：
Z为键；
W为键；
R 2为-(CH 2) nR 7；
R 7选自：取代或未取代的C 3-C 8环烷基；其中，所述取代指被选自下组的一个或多个基团取代：C 1-C 6烷基、氘代C 1-C 6烷基；所述烷基可以被选自下组的一个或多个取代基取代：4-7元杂环基、NHR 9或NR 9R 10；R 9，R 10各自独立地为C 1-C 3烷基；
n为1、或2；
R 1、R 3、R 4、R 8、m的定义如上所述。
在另一优选例中，所述化合物如式VI所示，并且式中：
Z为键；
W为键；
R 2为-(CH 2) nR 7；
R 7选自：取代或未取代的C 3-C 6环烷基；其中，所述取代指被选自下组的一个或多个基团取代：C 1-C 3烷基、氘代C 1-C 3烷基；所述烷基可以被选自下组的一个或多个取代基取代：4-7元杂环基、NHR 9或NR 9R 10；R 9，R 10各自独立地为C 1-C 3烷基；
n为1、或2；
R 1、R 3、R 4、R 8、m的定义如上所述。
在另一优选例中，式I-VI中所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有通式(VIII)所示结构：
Figure PCTCN2020138142-appb-000010
R 11、R 12相同或不同，各自独立地选自：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基；
环A为取代或未取代的C 3-C 20环烷基或4-20元杂环基；
L 1为C 1-C 18烷基、氘代C 1-C 18烷基；
Q为C 3-C 7环烷基、4-7元杂环基、NHR 9或NR 9R 10；R 9，R 10各自独立地为C 1-C 3烷基。
在另一优选例中，式I-VI中所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其中，
Z为C 1-C 18亚烷基C 3-C 20亚环烷基；
W为键；
R 2为-(CH 2) nNR 5R 7；其中，CH 2中的H可以被取代；
n为0、1、2、3、4或5的整数；
R 5选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、氨基、羟基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基；
R 7选自：取代或未取代的C 1-C 18烷基、C 3-C 20环烷基或4-20元杂环基；
其中，所述烷基可以被选自下组的一个或多个取代基取代：氘、卤素、氰基、胺基、C 3-C 7环烷基、4-7元杂环基、NHR 9或NR 9R 10；
R 9，R 10各自独立地为C 1-C 3烷基；
其中，所述取代指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。
在另一优选例中，所述化合物如式VI所示，并且式中：
Z为CH 2C 3-C 6亚环烷基；
W为键；
R 2为-(CH 2) nR 7；
R 7选自：取代或未取代的C 3-C 8环烷基；其中，所述取代指被选自下组的一个或多个基团取代：C 1-C 6烷基、氘代C 1-C 6烷基；所述烷基可以被选自下组的一个或多个取代基取代：4-7元杂环基、NHR 9或NR 9R 10；R 9，R 10各自独立地为C 1-C 3烷基；
n为1、或2；
R 1、R 3、R 4、R 8、m的定义如上所述。
在另一优选例中，所述化合物如式VI所示，并且式中：
Z为CH 2C 3-C 6亚环烷基；
W为键；
R 2为-(CH 2) nR 7；
R 7选自：取代或未取代的C 3-C 6环烷基；其中，所述取代指被选自下组的一个或多个基团取代：C 1-C 3烷基、氘代C 1-C 3烷基；所述烷基可以被选自下组的一个或多个取代基取代：4-7元杂环基、NHR 9或NR 9R 10；R 9，R 10各自独立地为C 1-C 3烷基；
n为1、或2；
R 1、R 3、R 4、R 8、m的定义如上所述。
在另一优选例中，式I中，R 1、R 2、R 3、R 4、R 11、R 12、A、B、L、L 1、X、Y、Z、W、Q、环A和m为实施例中各具体化合物相对应的具体基团。
在另一优选例中，具有通式(I)结构的环烷基类和杂环烷基类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，所述化合物选自下组：
Figure PCTCN2020138142-appb-000011
Figure PCTCN2020138142-appb-000012
Figure PCTCN2020138142-appb-000013
Figure PCTCN2020138142-appb-000014
Figure PCTCN2020138142-appb-000015
Figure PCTCN2020138142-appb-000016
Figure PCTCN2020138142-appb-000017
Figure PCTCN2020138142-appb-000018
Figure PCTCN2020138142-appb-000019
Figure PCTCN2020138142-appb-000020
Figure PCTCN2020138142-appb-000021
Figure PCTCN2020138142-appb-000022
Figure PCTCN2020138142-appb-000023
Figure PCTCN2020138142-appb-000024
Figure PCTCN2020138142-appb-000025
Figure PCTCN2020138142-appb-000026
Figure PCTCN2020138142-appb-000027
Figure PCTCN2020138142-appb-000028
Figure PCTCN2020138142-appb-000029
Figure PCTCN2020138142-appb-000030
Figure PCTCN2020138142-appb-000031
Figure PCTCN2020138142-appb-000032
Figure PCTCN2020138142-appb-000033
Figure PCTCN2020138142-appb-000034
Figure PCTCN2020138142-appb-000035
Figure PCTCN2020138142-appb-000036
Figure PCTCN2020138142-appb-000037
Figure PCTCN2020138142-appb-000038
Figure PCTCN2020138142-appb-000039
Figure PCTCN2020138142-appb-000040
Figure PCTCN2020138142-appb-000041
Figure PCTCN2020138142-appb-000042
Figure PCTCN2020138142-appb-000043
Figure PCTCN2020138142-appb-000044
Figure PCTCN2020138142-appb-000045
Figure PCTCN2020138142-appb-000046
Figure PCTCN2020138142-appb-000047
Figure PCTCN2020138142-appb-000048
Figure PCTCN2020138142-appb-000049
Figure PCTCN2020138142-appb-000050
Figure PCTCN2020138142-appb-000051
Figure PCTCN2020138142-appb-000052
Figure PCTCN2020138142-appb-000053
Figure PCTCN2020138142-appb-000054
Figure PCTCN2020138142-appb-000055
Figure PCTCN2020138142-appb-000056
Figure PCTCN2020138142-appb-000057
Figure PCTCN2020138142-appb-000058
Figure PCTCN2020138142-appb-000059
Figure PCTCN2020138142-appb-000060
Figure PCTCN2020138142-appb-000061
Figure PCTCN2020138142-appb-000062
Figure PCTCN2020138142-appb-000063
Figure PCTCN2020138142-appb-000064
Figure PCTCN2020138142-appb-000065
Figure PCTCN2020138142-appb-000066
Figure PCTCN2020138142-appb-000067
Figure PCTCN2020138142-appb-000068
Figure PCTCN2020138142-appb-000069
Figure PCTCN2020138142-appb-000070
Figure PCTCN2020138142-appb-000071
Figure PCTCN2020138142-appb-000072
在另一优选例中，所述式I化合物选自实施例中所示化合物。
本发明第二方面，提供了一种制备通式(I)结构的环烷基类和杂环烷基类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药的方法，包括步骤：
Figure PCTCN2020138142-appb-000073
(i)在碱存在下，式V-1化合物与二胺基类化合物分子中的一个胺基反应，然后与氨基保护剂反应，生成式V-2化合物；
(ii)在脱保护剂的存在下，式V-2化合物脱保护，生成式V-3化合物；
(iii)式V-3化合物通过偶联、取代或酰化反应，得到式V-4化合物；
(iv)式V-4化合物与氧化剂反应，生成式V-5化合物；
(v)在碱存在下，式V-5化合物通过反应，生成式V-6化合物；
(vi)在酸存在下，式V-6化合物脱保护，生成式V-7化合物；
(vii)式V-7通过取代或者酰化反应，得到式(III)化合物；
式中，
Rs和Rs'为氨基的保护基，所述保护基选自：Boc、Bn、Cbz或Fmoc；
R 1、R 2、R 3、R 4、L、X、Y、Z、W和m定义如上所述。
在另一优选例中，所述步骤(i)中，碱为TEA或DIPEA。
在另一优选例中，所述步骤(i)中，氨基保护剂选自：(Boc) 2O、氯甲酸苄酯、二碳酸二叔丁酯、邻苯二甲酰氯、氯苄、三苯基氯甲烷、氯甲酸-9-芴基甲酯、氯甲酸烯丙酯。
在另一优选例中，所述步骤(ii)中，脱保护剂为氯甲酸-1-氯乙酯。
在另一优选例中，所述步骤(iv)中，氧化剂为mCPBA。
在另一优选例中，所述步骤(v)中，碱为醇钠、醇钾、NaH或LiHNMDS，优选叔丁醇钠或叔丁醇钾。
在另一优选例中，所述步骤(vi)中，酸为TFA。
本发明第三方面，提供了一种药物组合物，包含一种或多种第一方面所述通式(I)结构的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药；和药学上可接受的载体。
在另一优选例中，所述药物组合物还包含选自下组的药物：
PD-1抑制剂(如nivolumab,pembrolizumab,pidilizumab,cemiplimab，JS-001，SHR-120，BGB-A317，IBI-308，GLS-010，GB-226，STW204，HX008,HLX10,BAT 1306,AK105,LZM009或上述药物的生物类似药等)、PD-L1抑制剂(如durvalumab,atezolizumab,avelumab，CS1001，KN035,HLX20,SHR-1316，BGB-A333，JS003,CS1003,KL-A167,F 520,GR1405,MSB2311或上述药物的生物类似药等)、CD20抗体(如rituximab,obinutuzumab,ofatumumab,veltuzumab,tositumomab,131I-tositumomab,ibritumomab,90Y-ibritumomab,90In-ibritumomab,ibritumomab tiuxetan等)、CD47抗体(如Hu5F9-G4，CC-90002，TTI-621，TTI-622,OSE-172，SRF-231，ALX-148，NI-1701，SHR-1603，IBI188，IMM01)、ALK抑制剂(如Ceritinib、Alectinib、Brigatinib、Lorlatinib、奥卡替尼)、PI3K抑制剂(如Idelalisib、 Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如Ibrutinib、Tirabrutinib、Acalabrutinib、Zanubrutinib、Vecabrutinib等)、EGFR抑制剂(如Afatinib、Gefitinib、Erlotinib、Lapatinib、Dacomitinib、Icotinib、Canertinib、Sapitinib、Naquotinib、Pyrotinib、Rociletinib、Osimertinib等)、VEGFR抑制剂(如Sorafenib、Pazopanib、Regorafenib、Sitravatinib、Ningetinib、Cabozantinib、Sunitinib、多纳非尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、Vorinostat、Fimepinostat、Droxinostat、Entinostat、Dacinostat、Quisinostat、Tacedinaline等)、CDK抑制剂(如Palbociclib、Ribociclib、Abemaciclib、Milciclib、Trilaciclib、Lerociclib等)、MEK抑制剂(如Selumetinib(AZD6244)、Trametinib(GSK1120212)、PD0325901、U0126、Pimasertib(AS-703026)、PD184352(CI-1040)等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)或其组合。
在另一优选例中，提供一种药物组合物的制备方法，包括步骤：将药学上可接受的载体与本发明所述通式(I)化合物、立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药进行混合，从而形成药物组合物。
本发明第四方面，提供一种具有通式(I)结构的环烷基类和杂环烷基类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或第三方面所述的药物组合物的用途，用于制备预防和/或治疗与KRAS G12C的活性或表达量相关的疾病的药物组合物。
在另一优选例中，所述的疾病是的肿瘤或失调性疾病。
在另一优选例中，所述疾病选自下组：肺癌、乳腺癌、前列腺癌、食道癌、结直肠癌、骨癌、肾癌、胃癌、肝癌、大肠癌、黑色素瘤、淋巴瘤、血癌、脑瘤、骨髓瘤、软组织肉瘤、胰腺癌、皮肤癌。
本发明第五方面，提供了一种非诊断性、非治疗性地抑制KRAS G12C的方法，它包括步骤：向所需患者施用有效量的第一方面所述的通式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或施用第三方面所述的药物组合物.
在另一优选例中，所述化合物优选为实施例中所制备的化合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图简要说明
图1为血药浓度-时间曲线图。
图2为MIA PaCa-2 CDX肿瘤模型中肿瘤体积-时间曲线。
图3为H358 CDX肿瘤模型中肿瘤体积-时间曲线。
具体实施方式
本发明人经过长期而深入的研究，意外地制备了一类新型的KRAS G12C有选择性抑制作用和/或更好药效学性能的化合物。在此基础上，发明人完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
术语“烷基”是指直链或支链或环状烷烃基，包含1-20个碳原子，如1-18个碳原子，尤其指1-18个碳原子，优选地包含1-10个碳原子，更优选地包含1-6个碳原子。典型的“烷基”包括 甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、
Figure PCTCN2020138142-appb-000074
戊基、异戊基、庚基、4,4–二甲基戊基、辛基、2,2,4-三甲基戊基、壬基、癸基、十一烷基，十二烷基等等。
术语“C1-C18烷基”指的是直链或支链或环状烷基，包括1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个碳原子，如甲基、乙基、丙基、异丙基
Figure PCTCN2020138142-appb-000075
正丁基、叔丁基、异丁基(如
Figure PCTCN2020138142-appb-000076
)、正戊基、异戊基、正己基、异己基、正庚基、异庚基。本发明中，烷基还包括取代烷基。“取代烷基”是指烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C3-C6环烯基、C2-C6炔基、5-14元杂环或C6-C14芳环，R b、R c和R d可以独立表示氢、氘、C1-C6烷基、C3-C8环烷基、5-14元杂环或C6-C14芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C3-C6环烯基、C2-C6炔基、5-14元杂环或C6-C14芳环。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。
术语“亚烷基”是指“烷基或取代的烷基”再脱掉一个氢原子所形成的基团，如亚甲基、亚乙基、亚丙基、亚异丙基(如
Figure PCTCN2020138142-appb-000077
)、亚丁基(如
Figure PCTCN2020138142-appb-000078
)、亚戊基(如
Figure PCTCN2020138142-appb-000079
)、亚己基(如
Figure PCTCN2020138142-appb-000080
)、亚庚基(如
Figure PCTCN2020138142-appb-000081
)、
Figure PCTCN2020138142-appb-000082
等。此外，所述术语还包括亚烷基(如C1-C18亚烷基)的一个亚甲基被一个亚环烷基(如C3-C20亚环烷基)所替换，例如“C1-C18亚烷基C3-C20亚环烷基”或“C3-C20亚环烷基C1-C18亚烷基”。
术语“C1-C18亚烷基C3-C20亚环烷基”或“C3-C20亚环烷基C1-C18亚烷基”具有相同含义，是指环烷基烷基或烷基环烷基脱掉两个氢原子所形成的基团，如
Figure PCTCN2020138142-appb-000083
Figure PCTCN2020138142-appb-000084
等。
术语“环烷基”是指包含3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个碳原子的完全饱和的环状烃类化合物基团，包括1-4个环，每个环中含有3-8个碳原子。优选地为C 3-C 20环烷基，更优选地为C 3-C 18环烷基，更优选地为C 3-C 10环烷基，更优选地为C 3-C 6环烷基。“取代环烷基”是指环烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。本发明中，“环烷基”包含取代环烷基，典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括螺环、桥环或稠环取代基，尤其是螺环烷基、螺环烯基、螺环杂环(不包括杂芳环)、桥环烷基、桥环烯基、桥环杂环(不包括杂芳环)、稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。
术语“C3-C20亚环烷基”是指环烷基脱掉两个氢原子所形成的基团，如：
Figure PCTCN2020138142-appb-000085
等。
术语“杂环基”是指包含3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个环原子的完全饱和的或部分不饱和的的环状基团(包含但不限于如3-7元单环，4-7元单环，6-11元双环，或8-16元三环系统)，其中至少有一个杂原子存在于至少有一个碳原子的环中。每个含有杂原子的杂环可以带有1，2，3或4个杂原子，这些杂原子选自氮原子、氧原子或硫原子，其中氮原子或硫原子可以被氧化，氮原子也可以被季铵化。杂环基团可以连接到环或环系分子的任何杂原子或碳原子的残基上，优选连接到环或环系分子上的N或C原子。典型的单环杂环包括但不限于氮杂环丁烷基、吡咯烷基、氧杂环丁烷基、吡唑啉基、咪唑啉基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、六氢吖庚因基、4-哌啶酮基、四氢吡喃基、吗啡啉基、硫代吗啡啉基、硫代吗啡啉亚砜基、硫代吗啡啉砜基、1,3-二噁烷基和四氢-1,1-二氧噻吩等。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接；杂环基团可以是取代的或者未取代的，当被取代时，取代基优选为一个或多个一下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。
术语“C4-C20亚杂环基”是指杂环基脱掉两个氢原子所形成的基团，如：
Figure PCTCN2020138142-appb-000086
等。
术语“芳基”是指包含6、7、8、9、10、11、12、13或14个环碳原子的芳香环状烃类化合物基团，具有1-5个环，尤其指单环和双环基团，如苯基、联苯基或萘基。凡含有两个或两个以上芳香环(双环等)，芳基基团的芳香环可由单键联接(如联苯)，或稠合(如萘、蒽等等)。“取代芳基”是指芳基中的一个或多个位置被取代，尤其是1-3个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括稠环取代基，尤其是稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。
术语“杂芳基”指包含1-4个杂原子、5-14个环原子的杂芳族体系，其中杂原子选自氧、氮和硫。杂芳基优选5至10元环，更优选为5元或6元，例如吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三氮嗪基、三氮唑基及四氮唑基等。“杂芳基”可以是取代的或者未取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。
术语“C1-C18烷氧基”是指具有1至18个碳原子的直链或支链或环状烷氧基，包含C1-C18烷基-O-、-C1-C6烷基-O-C1-C6烷基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C8烷氧基，更优选C1-C6烷氧基。
术语“C1-C18亚烷氧基”是指“C1-C18烷氧基”脱掉一个氢原子所得基团。
术语“4-7元杂环基”指具有1，2，3或4个(较佳地1、2或3个，更佳地1或2)选自N、O和S的杂原子杂环基团，较佳地，所述的4-7元杂环基含有至少1个N杂原子，更佳地4-7元杂环基通过环上的N原子或C原子与其他部分(moiety)相连。
术语“卤素”或“卤”是指氯、溴、氟、碘。
术语“卤代”是指被卤素取代。
术语“氘代”是指被氘取代。
术语“羟基”是指带有结构OH的基团。
术语“硝基”是指带有结构NO 2的基团。
术语“氰基”是指带有结构CN的基团。
术语“酯基”是指带有结构-COOR的基团，其中R代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环。
术语“胺基”是指带有结构-NRR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。
术语“酰胺基”是指带有结构-CONRR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。
术语“磺酰胺基”是指带有结构-SO 2NRR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。
术语“脲基”是指带有结构-NRCONR'R"的基团，其中R、R'和R"可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R、R'和R"在二烷基胺片段中可以相同或不同。
术语"烷基胺基烷基"是指带有结构-RNHR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'可以相同或不同。
术语"二烷基胺基烷基"是指带有结构-RNHR'R"的基团，其中R、R'和R"可以独立的代表烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R、R'和R"在二烷基胺片段中可以相同或不同。
术语"杂环基烷基"是指带有结构-RR'的基团，其中R可以独立的代表烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基；R'代表杂环或取代的杂环。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：卤素、羟基、氰基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、胺基、C1-C6烷氧基、C1-C10磺酰基、及C1-C6脲基等。
除非另外说明，假定任何不满价态的杂原子有足够的氢原子补充其价态。
当取代基为非末端取代基时，其为相应基团的亚基，例如烷基对应于亚烷基、环烷基对应亚环烷基、杂环基对亚杂环基、烷氧基对应亚烷氧基等。
活性成分
如本文所用，“本发明化合物”指式I所示的化合物，并且还包括及式I化合物的立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物。
所述式I化合物具有如下结构：
Figure PCTCN2020138142-appb-000087
其中，R 1、R 2、R 3、R 4、A、B、L、X、Y、Z、W和m的定义如上所述。
优选地，所述式I化合物具有通式(II-A)或(II-B)所示的结构：
Figure PCTCN2020138142-appb-000088
式中：
R 1、R 2、R 3、R 4、A、B、X、Y、Z、L、W、m的定义如上所述。
优选地，所述式I化合物具有通式(III)所示的结构：
Figure PCTCN2020138142-appb-000089
其中，R 1、R 2、R 3、R 4、X、Y、Z、L、W、m的定义如上所述。
优选地，式(I)化合物具有通式(IV)所示结构：
Figure PCTCN2020138142-appb-000090
式中：
R 1、R 2、R 3、R 4、R 8、Y、Z、L、W、m的定义如上所述。
优选地，所述式(I)化合物具有通式(V)所示结构：
Figure PCTCN2020138142-appb-000091
式中：
R 1、R 2、R 3、R 4、R 8、Y、Z、W、m的定义如上所述。
优选地，所述式(I)化合物具有通式(VI)所示结构：
Figure PCTCN2020138142-appb-000092
式中：
R 1、R 2、R 3、R 4、R 8、Z、W、m的定义如上所述。
优选地，所述式(I)化合物具有通式(VII-A)或(VII-B)所示的结构：
Figure PCTCN2020138142-appb-000093
式中：
R 1、R 2、R 3、R 4、R 5、R 8、Z、m的定义如上所述。
优选地，上述各式中，R 1为
Figure PCTCN2020138142-appb-000094
其中，
Figure PCTCN2020138142-appb-000095
为双键“＝”；R A选自：氢、氘、氟、氰基或者C 1-C 3烷基；
R B选自：氢、氘、氰基或者C 1-C 3烷基；
其中，所述烷基可以被选自下组的一个或多个取代基取代：氘、卤素、氰基、胺基、C 3-C 7环烷基、4-7元杂环基、NHR 9或NR 9R 10；其中，R 9，R 10各自独立地为C 1-C 3烷基。
优选地，上述各式中，Z为C 1-C 18亚烷基C 3-C 20亚环烷基，优选地为CH 2C 3-C 20亚环烷基，更优选地为CH 2C 3-C 6亚环烷基。
优选地，上述各式中，Z为键或C 1-C 18亚烷基C 3-C 20亚环烷基，W为键；R 2为-(CH 2)R 7或-(CH 2) nNR 5R 7；n为1、2或3，优选地为1或2；
R 5、R 7的定义如上所述。
优选地，上述各式中，Z为键或CH 2C 3-C 6亚环烷基，W为键；R 2为-(CH 2) nR 7或-(CH 2) nNR 5R 7；n为1、2或3，优选地为1或2；
R 5选自取代或未取代的下组基团：C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、氨基、羟基、3-7元杂环基、C 6-C 14芳基、5-14元杂芳基；
R 7选自：取代或未取代的C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基；
其中，所述取代指被选自下组的一个或多个基团取代：氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。
优选地，所述式(I)化合物具有(VIII)所示结构：
Figure PCTCN2020138142-appb-000096
R 1、R 4、R 8、R 11、R 12、环A、L 1、Q、m的定义如上所述。
优选地，式(VIII)中，环A为取代或未取代的下组基团：C 3-C 6环烷基或4-6元杂环基，其中所述取代指被选自下组的一个或多个基团取代：氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。
优选地，式(VIII)中，Q为4-7元杂环基、NHR 9或NR 9R 10；更优选地，Q为NR 9R 10；R 9，R 10各自独立地为C 1-C 3烷基。
优选地，上述各式中，R 8独立地选自取代或未取代的下组基团：氢、氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、氨基、羟基；其中，所述取代指被选自下组的一个或多个基团取代：氢、氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；优选地R 8为亚甲基氰基。
优选地，上述各式中，Z选自下组：C 1-C 6亚烷基、氘代C 1-C 6亚烷基、卤代C 1-C 6亚烷基、C 3-C 8亚环烷基、C 4-C 8亚杂环基、C 1-C 6亚烷氧基、氘代C 1-C 6亚烷氧基、卤代C 1-C 6亚烷氧基。
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明，本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”，指用无机或有机酸和碱形成酸式或碱式的盐。此外，当本发明中的化合物含一个碱性片段时，它包括但不限于吡啶或咪唑，含一个酸性片段时，包括但不限于羧酸，可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒，生理可接受的)盐是首选，虽然其他盐类也有用，例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐，例如，化合物I与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。
本发明中的化合物含有的碱性片段，包括但不限于胺或吡啶或咪唑环，可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸，如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如，2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如，2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等。
本发明的某些化合物可能含有的酸性片段，包括但不限于羧酸，可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐，碱土金属盐如钙、镁盐，和有机碱形成的盐(如有机胺)，如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙 二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺，以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐，如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物)，二烷基硫酸盐(如，硫酸二甲酯、二乙酯，二丁酯和二戊酯)，长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物)，芳烷基卤化物(如苄基和苯基溴化物)等等。
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物，在治疗相关疾病时，经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂合物。本发明的化合物包括溶剂合物，如水合物。
本发明中的化合物、盐或溶剂合物，可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。
所有化合物的立体异构体(例如，那些由于对各种取代可能存在的不对称碳原子)，包括其对映体形式和非对映形式，都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如，作为一个纯的或者实质上是纯的光学异构体具有特殊的活性)，或者也可能是混合物，如消旋体，或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型，由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决，例如分步结晶，或通过衍生为非对映异构体分离结晶，或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到，包括但不限于传统的方法，例如与光学活性酸成盐后再结晶。
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。
本发明的化合物所有的构型异构体都在涵盖的范围之内，无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体，以及碳环和杂环的顺式和反式异构体。
在整个说明书中，基团和取代基可以被选择以提供稳定的片段和化合物。
特定官能团和化学术语定义都详细介绍如下。对本发明来说，化学元素与Periodic Table of the Elements,CAS version,Handbook of Chemistry and Physics,75 th Ed.中定义的一致。特定官能团的定义也在其中描述。此外，有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,也有说明，其全部内容纳入参考文献之列。
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物，包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基，如烷基。所有异构体以及它们的混合物，都包涵在本发明中。
按照本发明，同分异构体的混合物含有异构体的比率可以是多样的。例如，在只有两个异构体的混合物可以有以下组合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1，或100:0，异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率，及为更复杂的异构体的混合物的比率也在本发明范围之内。
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物 同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如 3H和 14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即 3H和碳-14，即 14C，它们的制备和检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即 2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用批露在示例中的方案可以制备。
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。
如本文所述，本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常，术语“取代”不论在术语“可选”前面或后面出现，在本发明配方中包括取代基的通式，是指用指定结构取代基，代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。在本发明中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的，例如传染病或增生性疾病。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。
本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。
制备方法
下面更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
典型地，本发明化合物的制备工艺流程如下，其中所用原料和试剂如无特殊说明，均可通过商业途径购买。
Figure PCTCN2020138142-appb-000097
通式(V-1)化合物在碱(如TEA或DIPEA)作用下生成中间体通式(V-2)，然后脱保护生成中间体(V-3)；化合物(V-3)通过偶联或取代或酰化反应得到中间体(V-4),然后在氧化剂(如mCPBA)作用下生成中间体(V-5)；化合物(V-5)在碱(如NaH、LiHNMDS或tBuOK)作用下生成中间体通式(V-6)；化合物(V-6)脱保护生成中间体(V-7)，然后通过取代或者酰化反应得到目标产物通式(III)；其中，R 1、R 2、R 3、R 4、L、X、Y、Z、W和m如上文所述；Rs和Rs'为氨基的保护基(如Boc、Bn、Cbz或Fmoc)。
药物组合物和施用方法
本发明所述的药物组合物用于预防和/或治疗以下疾病：炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。
通式(I)所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时，原来药物的给药方式和剂量可以保持不变，而同时或随后服用式I的化合物。当式I化合物与其它一种或几种药物同时服用时，可以优选使用同时含有一种或几种已知药物和式I化合物的药用组合物。药物联用也包括在重叠的时间段服用式I化合物与其它一种或几种已知药物。当式I化合物与其它一种或几种药物进行药物联用时，式I化合物或已知药物的剂量可能比它们单独用药的剂量低。
可以与通式(I)所述化合物进行药物联用的药物或活性成分包括但不局限为：PD-1抑制剂(如nivolumab,pembrolizumab,pidilizumab,cemiplimab，JS-001，SHR-120，BGB-A317，IBI-308，GLS-010，GB-226，STW204，HX008,HLX10,BAT 1306,AK105,LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如durvalumab,atezolizumab,avelumab，CS1001，KN035,HLX20,SHR-1316，BGB-A333，JS003,CS1003,KL-A167,F 520,GR1405,MSB2311或上述药物的生物类似药等)、CD20抗体(如rituximab,obinutuzumab,ofatumumab,veltuzumab,tositumomab,131I-tositumomab,ibritumomab,90Y-ibritumomab,90In-ibritumomab,ibritumomab tiuxetan等)、CD47抗体(如Hu5F9-G4，CC-90002，TTI-621，TTI-622,OSE-172，SRF-231，ALX-148，NI-1701，SHR-1603，IBI188，IMM01)、ALK抑制剂(如Ceritinib、Alectinib、Brigatinib、Lorlatinib、奥卡替尼)、PI3K抑制剂(如Idelalisib、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如Ibrutinib、Tirabrutinib、Acalabrutinib、Zanubrutinib、Vecabrutinib等)、EGFR抑制剂(如Afatinib、Gefitinib、Erlotinib、Lapatinib、Dacomitinib、Icotinib、Canertinib、Sapitinib、Naquotinib、Pyrotinib、Rociletinib、Osimertinib等)、VEGFR抑制剂(如Sorafenib、Pazopanib、Regorafenib、Sitravatinib、Ningetinib、Cabozantinib、Sunitinib、多纳非尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、Vorinostat、Fimepinostat、Droxinostat、Entinostat、Dacinostat、Quisinostat、Tacedinaline等)、CDK抑制 剂(如Palbociclib、Ribociclib、Abemaciclib、Milciclib、Trilaciclib、Lerociclib等)、MEK抑制剂(如Selumetinib(AZD6244)、Trametinib(GSK1120212)、PD0325901、U0126、Pimasertib(AS-703026)、PD184352(CI-1040)等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)或其组合。
本发明所述药物组合物的剂型包括(但并不限于)：注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用擦剂、控释型或缓释型或纳米制剂。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2020138142-appb-000098
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨 醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明还提供了一种药物组合物的制备方法，包括步骤：将药学上可接受的载体与本发明所述通式(I)化合物或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合，从而形成药物组合物。
本发明还提供了一种治疗方法，它包括步骤：给需要治疗的对象施用本发明中所述通式(I)化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物，或施用本发明所述的药物组合物，用于选择性地抑制KRAS G12C。
与现有技术相比，本发明具有以下主要优点：
(1)所述化合物对KRAS G12C具有很好的选择性抑制作用；
(2)所述化合物具有更好的药效学、药代动力学性能和更低的毒副作用。
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，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，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。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
本发明的化合物结构是通过核磁共振(NMR)和液质联用色谱(LC-MS)来确定的。
NMR是使用Bruker AVANCE-400核磁仪检测的，测定溶剂包含氘代二甲亚砜(DMSO-d 6)、氘代丙酮(CD 3COCD 3)、氘代氯仿(CDCl 3)及氘代甲醇(CD 3OD)等，内标采用四甲基硅烷(TMS)，化学位移以百万分之一(ppm)的单位计量。
液质联用色谱(LC-MS)是使用Waters SQD2质谱仪检测的。HPLC的测定使用Agilent1100高压色谱仪(Microsorb 5micron C18 100x 3.0mm色谱柱)。
薄层层析硅胶板使用青岛GF254硅胶板，TLC采用的是0.15-0.20mm，制备薄层色谱采用的是0.4mm-0.5mm。柱层析一般使用青岛硅胶200-300目硅胶作为载体。
本发明实施例中的起始原料都是已知并有市售的，或者可以采用或按照本领域已报道的文献资料合成的。
除特殊说明外，本发明所有反应均在干燥的惰性气体(如氮气或氩气)保护下通过连续磁力搅拌进行，反应温度均为摄氏度。
实施例
中间体1 2-(哌嗪-2-基)乙腈二盐酸盐的制备
Figure PCTCN2020138142-appb-000099
第一步：4-溴-丁-2-烯腈的制备
在10℃下，将溴素(119.2g，0.745mol,1.0eq)和叔丁醇(75mL)的溶液滴加到烯丙基腈(50g,0.745mol，1.0eq)的叔丁醇(75mL)和石油醚(250mL)的混合溶液中。滴加完毕，反应液搅拌30min，随后加入乙醇钠(50.7g,0.745mol,1.0eq)的乙醇(250mL)溶液。得到的混合物在室温反应2h，然后过滤。滤液浓缩，残余物通过硅胶柱层析得到目标产物(72.7g,收率67％)。
第二步：2-(1,4-二苯基哌嗪-2-基)乙腈的制备
在0℃下，将4-溴-丁-2-烯腈(58.16g,0.4mol,1.0eq)滴加到N,N'-二苄基乙二胺(95.9g,0.4mol，1.0eq)和三乙胺(80.9g,0.8mol,2.0eq)的甲苯(360mL)溶液中。得到的混合物室温反应过夜，然后过滤。滤液浓缩，残余物通过硅胶柱层析得到目标产物(65.3g，收率54％)。
LC-MS：m/z 306(M+H) +。
第三步：2-(哌嗪-2-基)乙腈二盐酸盐的制备
在0℃下，将1-氯乙基氯甲酸酯(142g,1.096mol,6.0eq)滴加到2-(1,4-二苯基哌嗪-2-基)乙腈(55.8g,0.1827mol，1.0eq)的1,2-二氯乙烷(250mL)中。滴加完毕，反应液在90℃反应50h，然后减压浓缩。残余物中加入甲醇(550mL)，得到的混合物在80℃反应1h，然后减压浓缩。残余物用甲基叔丁基醚打浆，过滤得到目标产物(36g,定量收率)。
LC-MS：m/z 126(M+H) +。 1H NMR(400MHz,D 2O)δ4.01-3.96(m,1H),3.81-3.67(m,3H),3.46-3.27(m,3H),3.09(d,J＝6.0HZ,2H)。
中间体2 2-(氰甲基)-4-(7-(8-甲基萘-1-yl)-2-(甲亚砜基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯的制备
Figure PCTCN2020138142-appb-000100
第一步：7-苄基-2-(甲硫基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-羟基的制备
将金属钠(11.0g，478.35mmol)分批加入至甲醇(500ml)中，冰水浴冷却搅拌溶清后，依次加入1-苄基-3-氧哌啶-4-羧酸乙酯(25.0g，95.67mmol)和S-甲基异硫脲硫酸盐(47.9g，172.2mmol)。得到的混合物在氮气保护下，于室温搅拌16h。反应结束后，反应液用2M盐酸水溶液调节pH为6。得到的混合物减压浓缩除去甲醇。残余物中加入100ml水，搅拌后过滤。滤饼依次用水(50mL)和乙酸乙酯(50mL)各淋洗一次，然后50℃真空干燥，得到目标产物(25.68g，收率93％)。
LC-MS：m/z 288(M+H) +。
第二步：7-苄基-4-氯-2-(甲硫基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶的制备
将7-苄基-2-(甲硫基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-羟基(25.68g，89.36mmol)加入到三氯氧磷(310mL)中。得到的反应液在80℃搅拌3h。反应结束后，反应液减压浓缩除去大部分三氯氧磷，然后加入乙酸乙酯(500mL)。得到的混合物用饱和碳酸氢钠水溶液调节pH为6。水相分离后，用乙酸乙酯(3 x 100mL)萃取。所有的有机相合并后，用饱和氯化钠洗涤，然后经无水硫酸钠干燥后，过滤。滤液减压浓缩，得到的残余物用硅胶柱层析分离，得到目标产物(13.3g，收率49％)。
LC-MS：m/z 306(M+H) +。
第三步：4-(7-苄基-2-(甲硫基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-2-(氰基甲基)哌嗪-1-甲酸叔丁酯的制备
将7-苄基-4-氯-2-(甲硫基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶(7.0g，22.89mmol)、2-(哌嗪-2-基)乙腈二盐酸盐(5.44g，27.47mmol)、N,N-二异丙基乙胺(22.8mL，137.34mmol)和DMSO加入反应瓶中。反应液在氮气保护下，加热至80℃搅拌3h，然后加入二碳酸二叔丁酯(26.3mL，114.45mmol)。待反应结束后，反应液用水淬灭，然后用乙酸乙酯萃取(3 x 100mL)。所有有机相合并以后，用饱和氯化钠洗一次，然后经无水硫酸钠干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离，得到目标产物(8.21g，收率73％)。
LC-MS：m/z 495(M+H) +。
第四步：2-(氰基甲基)-4-(2-(甲硫基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁 酯的制备
将4-(7-苄基-2-(甲硫基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-2-(氰基甲基)哌嗪-1-甲酸叔丁酯(8.21g，16.6mmol)加入到二氯甲烷(160mL)中，随后在0℃下，滴加氯甲酸-1-氯乙酯(3.58mL，33.2mmol)。加完后，反应液在15℃下，搅拌3h。得到的混合物减压浓缩除去溶剂，然后加入甲醇(160mL)。得到的混合物在70℃下搅拌1.5h，然后冷却至室温，随后加入饱和碳酸氢钠溶液(300mL)。得到的混合物用乙酸乙酯(3 x 100mL)萃取。所有有机相合并以后，用饱和氯化钠洗一次，然后经无水硫酸钠干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离(洗脱剂：DCM/MeOH＝100/1至30/1)，得到目标产物(4.9g，收率73％)。
LC-MS：m/z 405(M+H) +。 1HNMR(400M,CDCl 3)4.52(s,1H),3.93(m,2H),3.78(d,J＝12.4Hz,1H),3.34(m,1H),3.24(m,3H),2.73(m,5H),2.42(s,3H),1.43(s,9H)。
第五步：2-(氰基甲基)-4-(7-(8-甲基萘-1-基)-2-(甲硫基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯的制备
将2-(氰基甲基)-4-(2-(甲硫基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯(2g，4.94mmol)、1-溴-8-甲基萘(2.73g，12.35mmol)、碳酸铯(4.83g，14.82mmol)和二氧六环(80mL)加入反应瓶中，然后用氮气置换三次，随后加入Ruphos Pd G3(1.24g，1.48mmol)。得到的混合物经氮气置换三次后加热至72℃，搅拌16h。得到的混合物加入水(100mL)，然后用乙酸乙酯(3 x 100mL)萃取。所有有机相合并以后，用饱和氯化钠洗一次，然后经无水硫酸钠干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析(洗脱剂：PE/EA＝1/0至5/1)分离，得到目标产物(863mg，收率32％)。
LC-MS：m/z 545(M+H) +。1HNMR(400M,CD 3OD)7.54(m,2H),7.28(m,1H),7.17(m,3H),4.55(s,1H),4.48(s,1H),3.98(m,4H),3.56(m,1H),3.38(m,1H),3.27(m,1H),3.02(m,3H),2.86(s,1H),2.79(s,3H),2.57(m,2H),2.40(s,3H),1.41(s,9H)。
第六步：2-(氰基甲基)-4-(7-(8-甲基萘-1-基)-2-(甲基亚砜基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯的制备
将2-(氰基甲基)-4-(7-(8-甲基萘-1-基)-2-(甲硫基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯(340mg，0.62mmol)溶于乙酸乙酯(6mL)中，然后用冰盐浴降温至0℃；随后滴加间氯过氧苯甲酸(216mg，1.25mmol)的乙酸乙酯(3mL)溶液。加完后，反应液在0℃，搅拌10min，然后用低亚硫酸钠溶液(50mL)淬灭。得到的混合物加入水(30mL)，然后用乙酸乙酯(3 x 30mL)萃取。所有有机相合并以后，用饱和氯化钠洗一次，然后经无水硫酸钠干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析(PE:EA＝1:0至0:1)，得到目标产物(186mg，收率53％)。
LC-MS：m/z 561(M+H) +。 1HNMR(400M,CDCl 3)δ7.61(m,2H),7.32(m,2H),7.17(m,2H),4.53(s,1H),3.97(m,5H),3.68(m,1H),3.24(m,6H),2.84(m,6H),2.64(m,2H),1.44(s,9H)。
中间体3 2-(甲基(氧杂环丁-3-基)氨基)乙醇的制备
Figure PCTCN2020138142-appb-000101
将2-(甲胺基)乙醇(5g,67mmol)加入甲醇(50mL)中，再加入3-氧杂环丁酮2(5.8g,80mmol)、氰基硼氢化钠(12.6g,200mmol)和醋酸(1mL)。然后反应液升温60度搅拌2小时，降 温，倒入饱和碳酸钾水溶液中，乙酸乙酯(50mLx 2)萃取，有机相干燥，浓缩，硅胶柱层析(洗脱剂：DCM/MeOH＝20/1)，得到目标产物(6.7g，收率：77％)。
1H NMR(400MHz,CDCl 3)δ4.67(t,J＝6.8Hz,2H),4.60-4.56(m,2H),3.70-3.60(m,3H),2.41(t,J＝5.6Hz,2H),2.16(s,3H).
中间体4 2-(甲基(1-甲基氮杂环丁烷-3-基)氨基)乙醇的制备
Figure PCTCN2020138142-appb-000102
第一步:3-((2-羟乙基)(甲基)氨基)氮杂环丁烷-1-甲酸叔丁酯的制备
将2-(甲胺基)乙醇(5g,67mmol)加入甲醇(50mL)中，再加入1-叔丁氧羰基-3-氮杂环丁酮(11.4g,67mmol)、氰基硼氢化钠(12.6g,200mmol)和醋酸(1mL)。然后反应液升温60度搅拌2小时，降温，倒入饱和碳酸钾溶液中，乙酸乙酯(50mLx 2)萃取，有机相干燥，浓缩硅胶柱层析(洗脱剂：DCM/MeOH＝20/1)，得到目标产物(8g，收率：53％)。
第二步:2-(甲基(1-甲基氮杂环丁烷-3-基)氨基)乙醇的制备
将3-((2-羟乙基)(甲基)氨基)氮杂环丁烷-1-甲酸叔丁酯(4g,17mmol)加入四氢呋喃(50mL)中，再加入氢化铝锂(2.6g,70mmol)。然后反应液升温回流搅拌过夜，降温，用十水硫酸钠淬灭，过滤，浓缩，硅胶柱层析(洗脱剂：DCM/MeOH＝10/1)，得到目标产物(600mg，收率：24％)。
1H NMR(400MHz,CDCl 3)δ3.71-3.67(m,2H),3.59(t,J＝5.2Hz,2H),3.23-3.17(m,1H),3.08-3.04(m,2H),2.49(s,3H),2.41(t,J＝5.2Hz,2H),2.14(s,3H).
中间体5 (R)-2-((环丁基甲基)(甲基)氨基)丙-1-醇的制备
Figure PCTCN2020138142-appb-000103
第一步:(R)-2-((环丁基甲基)氨基)丙-1-醇的制备
将(R)-2-氨基丙-1-醇(3g,40mmol)、环丁酮(2.8g,40mmol)和醋酸(240mg,4mmol)加入到甲醇(25mL)中，室温搅拌半个小时。然后将反应液冷却至零度，缓慢加入氰基硼氢化钠(7.56g,120mmol)，反应液在室温下搅拌过夜，TLC显示有新的点出现。将反应液浓缩除去甲醇，得到粗产品，粗产品用饱和碳酸钾溶液稀释，用乙酸乙酯萃取3次，合并有机相浓缩过硅胶柱(洗脱剂：二氯甲烷/甲醇＝10/1)得到目标产物(4.3g，收率56％)。
LCMS:m/z 129.9(M+H) +.
第二步:(R)-2-((环丁基甲基)(甲基)氨基)丙-1-醇的制备
将(R)-2-((环丁基甲基)氨基)丙-1-醇(2.9g,22.48mmol)、多聚甲醛(2.02g,67.44mmol)和醋酸(138mg,2.3mmol)加入到甲醇(40mL)中，室温搅拌半个小时。然后将反应液冷却至零度，缓慢加入氰基硼氢化钠(12.6g,200mmol)，反应液在室温下搅拌过夜，TLC显示有新的点出现。将反应液浓缩除去甲醇，得到粗产品，粗产品用饱和碳酸钾溶液稀释，用乙酸乙酯萃取3次，合并有机相浓缩过硅胶柱(洗脱剂：二氯甲烷/甲醇＝10/1)得到目标产物(1.6g，收 率50％)。
1H NMR(400MHz,CDCl 3)δ3.37-3.33(m,2H),3.25(t,J＝10.0Hz,1H),3.14-3.10(m,1H),2.89-2.85(m,1H),2.06-1.98(m,5H),1.86-1.73(m,2H),1.69-1.61(m,2H),0.80(d,J＝6.8Hz,3H).
中间体6 反式-2-(二甲氨基)环戊醇的制备
Figure PCTCN2020138142-appb-000104
第一步:(S)-2-((1-环丙基乙基)氨基)乙烷-1-醇
将6-恶唑环[3.1.0]己烷(2g，23.8mmol)加入到二甲胺水溶液(含量大于33％，10mL)中，得到的反应液在室温搅拌过夜。将反应液浓缩旋干，残余物用硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇＝20/1)得到目标产物(1.63g，收率：53％)。
中间体31 顺式-2-(二甲基氨基)环戊醇的制备
Figure PCTCN2020138142-appb-000105
第一步:顺式-2-(二甲基氨基)环戊基4-硝基苯甲酸酯的制备
将反式-2-(二甲基氨基)环戊醇(3.0g，23.3mmol)、4-硝基苯甲酸(4.66g，27.9mmol)和三苯基膦(7.9g，30.2mmol)悬浮于50毫升无水四氢呋喃中，氮气置换3次，冷却至0度。向该混合物中缓慢滴加偶氮二甲酸二异丙酯(6.1g，30.2mmol)，滴加过程中控制温度不超过10度。反应液室温搅拌16小时，旋干，硅胶柱分离(洗脱剂：二氯甲烷/甲醇＝30/1，)得目标产物(粗品)。
第二步:顺式-2-(二甲基氨基)环戊醇的制备
将顺式-2-(二甲基氨基)环戊基4-硝基苯甲酸酯2(粗品)溶于50毫升甲醇中，加入一水合氢氧化锂(1.95g，46.52mmol)的水(10mL)溶液。反应液室温搅拌16小时，然后浓缩除去甲醇，以50毫升水稀释，用50毫升乙酸乙酯萃取2次，合并有机层干燥，浓缩，硅胶柱分离(二氯甲烷：甲醇＝50：1到10：1)得目标产物(2g)，两步收率：67％。
1H NMR(400MHz,CDCl 3)δ4.30-4.27(m,1H),2.91-2.87(m,1H),2.53(s,6H)2.03-1.93(m,2H),1.77-1.60(m,4H).
中间体7 反式-4-(二甲氨基)四氢呋喃-3-醇的制备
Figure PCTCN2020138142-appb-000106
将二甲胺水溶液(含量大于33％，20mL)于50度加热搅拌，向其滴加3,4-环氧四氢呋喃(5g，58mmol)。然后反应液在50度继续搅拌16小时。反应液旋干，硅胶柱分离(洗脱剂：二氯甲烷/甲醇＝10/1，洗脱剂添加1‰的氨水)得目标产物(7g，收率：92％)。
1H NMR(400MHz,CDCl 3)δ4.33-4.29(m,1H),4.04(dd,J＝9.6Hz,6.8Hz,1H),3.95(dd,J＝10.0Hz,5.6Hz,1H),3.70(dd,J＝10.0Hz,3.2Hz,1H),3.65(dd,J＝9.6Hz,6.8Hz,1H), 2.76-2.71(m,1H),2.29(s,6H).
中间体8 顺式-4-(二甲氨基)四氢呋喃-3-醇的制备
Figure PCTCN2020138142-appb-000107
第一步:顺式-4-(二甲基氨基)四氢呋喃-3-基4-硝基苯甲酸酯的制备
将反式-4-(二甲氨基)四氢呋喃-3-醇(3.0g，22.9mmol)、4-硝基苯甲酸(4.6g，27.5mmol)和三苯基膦(7.8g，29.8mmol)悬浮于60毫升无水四氢呋喃中，氮气置换3次，冷却至0度。向该混合物中缓慢滴加偶氮二甲酸二异丙酯(6.0g，29.8mmol)，滴加过程中控制温度不超过10度。反应液室温搅拌16小时，旋干，硅胶柱分离(二氯甲烷：甲醇＝30：1)得目标产物(粗品)。
第二步:顺式-4-(二甲氨基)四氢呋喃-3-醇的制备
将顺式-4-(二甲基氨基)四氢呋喃-3-基4-硝基苯甲酸酯(粗品)溶于150毫升甲醇中，加入一水合氢氧化锂(5.6g，133.6mmol)的水(50mL)溶液。反应液室温搅拌16小时，然后浓缩除去甲醇，以100毫升水稀释，再以6摩的盐酸调节pH到2。该混合物以200毫升乙酸乙酯洗涤2次，水相以固体碳酸钾调节pH大于12，再以二氯甲烷/异丙醇(10:1，150mL)萃取10次。合并二氯甲烷层干燥，浓缩，硅胶柱分离(洗脱剂：二氯甲烷/甲醇＝50/1到10/1)得目标产物(1.8g，两步收率：51％)。
1H NMR(400MHz,CDCl 3)δ4.33-4.30(m,1H),4.07-4.02(m,1H),3.95(dd,J＝10.0Hz,5.6Hz,1H),3.71(dd,J＝10.0Hz,2.8Hz,1H),3.64(dd,J＝9.2Hz,6.4Hz,1H),2.75-2.70(m,1H),2.29(s,6H).
中间体9 (S)-2-(环丁基甲胺基)-3-甲氧基-1-丙醇的制备
Figure PCTCN2020138142-appb-000108
第一步:(R)-2-叔丁氧羰基氨基-3-甲氧基丙酸甲酯的制备
将(R)-2-叔丁氧羰基氨基-3-甲氧基丙酸(9g，41.1mol)溶于无水四氢呋喃(90mL)中，在冰浴下，加入碳酸钾(8.5g，61.7mol)和碘甲烷(8.8g，61.7mol)，加毕，室温搅拌反应过夜。乙酸乙酯(400mL)和水(300mL)加入到反应液中淬灭反应，有机相用水(200mL)洗两次，饱和食盐水(100mL)洗一次，无水硫酸钠干燥，过滤，旋干，得到目标产物(9.9g)，黄色油状物，收率93％。
LCMS:m/z 256(M+H) +.
第二步:(S)-3-甲氧基-2-甲氨基-1-醇的制备
将(R)-2-叔丁氧羰基氨基-3-甲氧基丙酸甲酯(8.9g，38.2mmol)溶于无水四氢呋喃(150mL)中，在冰浴下，分批次加入锂铝氢(5.8g，153mmol)，加毕，回流反应过夜。反应液在冰浴 下慢慢加入十水硫酸钠(15g)淬灭反应，过滤，滤液旋干，硅胶柱分离(洗脱剂：二氯甲烷/甲醇＝15/1)得到目标产物，收率56％。
LCMS:m/z 120(M+H) +.
第三步:(S)-2-(环丁基甲胺基)-3-甲氧基-1-丙醇的制备
将(S)-3-甲氧基-2-甲氨基-1-醇(2.5g，21mmol)、环丁酮(2.2g，31.5mmol)和醋酸(1.3g，21mmol)加入到甲醇(50mL)中，将反应液冷却至零度，缓慢加入氰基硼氢化钠(3.3g,52.5mmol)，然后反应液在室温下搅拌过夜，LCMS显示原料消失，产物生成。将反应液浓缩除去甲醇，得到粗产品，粗产品用1mol/L的碳酸钾水溶液调至弱碱性，用乙酸乙酯(200mL)萃取两次。合并有机相，用饱和食盐水(100mL)洗一次，无水硫酸钠干燥，旋干，硅胶柱分离(洗脱剂：二氯甲烷/甲醇＝15/1)得到目标产物(700mg，收率：19％)。
1H NMR(400MHz,CDCl 3)δ3.52-3.44(m,2H),3.33-3.23(m,5H),3.22-3.15(m,1H),2.96-2.86(m,1H),2.12(s,3H),2.08-1.98(m,2H),1.85-1.75(m,2H),1.68-1.54(m,2H).
中间体10 (1-((二甲氨基)甲基)环丙基)甲醇的制备
Figure PCTCN2020138142-appb-000109
将(1-(氨基甲基)环丙基)甲醇(800mg，7.92mmol)、多聚甲醛(1.43g，47.52mmol)和醋酸(48mg，0.8mmol)加入到甲醇(10mL)中，室温搅拌半个小时。将反应液冷却至零度，缓慢加入氰基硼氢化钠(3.0g，47.52mmol)，反应液在室温下搅拌过夜，TLC显示有新的点出现。将反应液浓缩除去甲醇，得到粗产品，粗产品用饱和碳酸钾溶液稀释，用乙酸乙酯萃取3次，合并有机相干燥，浓缩，过硅胶柱(洗脱剂：二氯甲烷/甲醇＝10/1)得到目标产物(273mg)，收率：27％。
LCMS:m/z 130(M+H) +.
1H NMR(400MHz,CDCl 3)δ4.76(brs,1H),3.53(d,J＝6.0Hz 2H),2.42(s,2H),2.31(s,6H),0.51-0.48(m,2H),0.37-0.34(m,2H).
以不同的起始原料按照中间体10同样的方法合成了以下化合物：
中间体11 (1-((二甲基氨基)甲基)环丁基)甲醇的制备
Figure PCTCN2020138142-appb-000110
LCMS:m/z 144(M+H) +. 1H NMR(400MHz,CDCl 3)δ4.90(brs,1H),3.79(s,2H),2.50(s,2H),2.24(s,6H),1.83-1.80(m,6H).
中间体12 (3-((二甲基氨基)甲基)氧杂环丁烷-3-基)甲醇的制备
Figure PCTCN2020138142-appb-000111
LCMS:m/z 146(M+H) +. 1H NMR(400MHz,CDCl 3)δ5.20(brs,1H),4.50-4.48(m,2H),4.41-4.39(m,2H),4.07(s,2H),2.77(s,2H),2.24(s,6H).
中间体13 2-(环丁基(2-甲氧基乙基)氨基)乙醇的制备
Figure PCTCN2020138142-appb-000112
第一步.2-(环丁基氨基)乙醇的制备
将2-溴乙醇(10g，57.14mmol)、环丁胺(4.06g，57.14mmol)和碳酸钾(11.83g，85.71mmol)加入到乙腈(500mL)中，室温搅拌搅拌过夜，TLC显示有新的点出现。将反应液过滤，滤液浓缩过硅胶柱(洗脱剂：二氯甲烷/甲醇＝10/1)得到目标产物(1.5g，收率：23％)。
MS:m/z 116(M+H) +.
第二步.(2-(环丁基(2-甲氧基乙基)氨基)乙醇的制备
将2-(环丁基氨基)乙醇(500mg,4.34mmol)、碳酸钾(1.2g,8.69mmol)和碘化钾(71mg，0.43mmol)加入到乙腈(20mL)中，然后将1-溴-2-甲氧基乙烷(725mg,5.22mmol)加入到反应液中，反应液在室温下搅拌过夜。TLC显示有新的点出现。将反应液过滤，滤液浓缩过硅胶柱(洗脱剂：二氯甲烷/甲醇＝10/1)得到目标产物(618mg，收率：86％)。
MS:m/z 174(M+H) +. 1H NMR(400MHz,CDCl 3)δ3.58(t,J＝5.6Hz,2H),3.46(t,J＝6.0Hz,2H),3.39-3.25(m,5H),2.73-2.64(m,4H),2.09-1.92(m,4H),1.70-1.57(m,2H).
中间体14 2-[(2,2-二氟-环丙基甲基)-甲基氨基]-乙醇
Figure PCTCN2020138142-appb-000113
第一步:2,2-二氟环丙烷酰氯的制备
将2,2-二氟环丙烷羧酸(2.5g，20.5mmol)溶于无水二氯甲烷(25mL)中，在冰浴下，慢慢加入草酰氯(2.1mL，24.6mmol)和N，N-二甲基甲酰胺(5滴)，加毕，室温搅拌反应两小时。反应液直接用于下一步反应。
第二步:2,2-二氟环丙烷羧酸(2-羟乙基)-甲酰胺的制备
将2-甲基氨基乙醇(2.3g，31mmol)溶于二氯甲烷(28mL)中，在冰浴下，加入三乙胺(10.5g，102mmol)和第一步的反应液，加毕，室温反应过夜。然后，浓缩除去二氯甲烷，残渣中加入乙酸乙酯(200mL)和水(100mL)，分出有机相，用饱和食盐水(50mL)洗一次，无水硫酸钠干燥，旋干，硅胶柱分离(洗脱剂：石油醚/乙酸乙酯＝2/1)得到目标产物(2.0g，收率38％)。
MS:m/z 180(M+H) +.
第三步:2-[(2,2-二氟-环丙基甲基)-甲基氨基]-乙醇的制备
将2,2-二氟环丙烷羧酸(2-羟乙基)-甲酰胺(1.9g，10.6mmol)溶于无水四氢呋喃(30mL)中，在冰浴下，分批次加入锂铝氢(0.8g，21.2mmol)，加毕，室温反应过夜。反应液在冰浴下慢慢加入十水硫酸钠(3g)淬灭反应，过滤，旋干，硅胶柱分离(洗脱剂：二氯甲烷/甲醇＝20/1)得到目标产物(750mg，收率43％)。
1H NMR(400MHz,CDCl 3)δ3.60(t,J＝5.2Hz,2H),2.76-2.67(m,1H),2.66-2.43(m,4H),2.32(s,3H),1.76-1.62(m,1H),1.52-1.40(m,1H),1.05-0.95(m,1H).
中间体15 (S)-2-(环丁基甲胺基)-3-甲基丁醇的制备
Figure PCTCN2020138142-appb-000114
第一步:(S)-2-环丁胺基-3-甲基丁醇
将(S)-2-氨基-3-甲基丁醇1(3.1g，30mmol)、环丁酮(2.7g，39mmol)和醋酸(0.18g，0.1mmol)加入到甲醇(100mL)中，将反应液冷却至零度，缓慢加入氰基硼氢化钠(5.7g,90mmol)，然后反应液在室温下搅拌过夜，LCMS显示原料消失，产物生成。将反应液浓缩除去甲醇，得到粗产品，粗产品用1mol/L的碳酸钾水溶液调至弱碱性，用乙酸乙酯(200mL)萃取两次。合并有机相，用饱和食盐水(100mL)洗一次，无水硫酸钠干燥，旋干，硅胶柱分离(洗脱剂：石油醚/乙酸乙酯＝2/1)得到目标产物(1.4g，收率：30％)。
MS:m/z 158(M+H) +.
第二步:(S)-2-(环丁基甲胺基)-3-甲基丁醇的制备
将(S)-2-环丁胺基-3-甲基丁醇2(1.2g，7.6mmol)、多聚甲醛(0.69g，22.9mmol)和醋酸(46mg，0.76mmol)加入到甲醇(25mL)中，将反应液冷却至零度，缓慢加入氰基硼氢化钠(1.4g,22.9mmol)，然后反应液在室温下搅拌过夜，LCMS显示原料消失，产物生成。将反应液浓缩除去甲醇，得到粗产品，粗产品用1mol/L的碳酸钾水溶液调至弱碱性，用乙酸乙酯(200mL)萃取两次。合并有机相，用饱和食盐水(100mL)洗一次，无水硫酸钠干燥，旋干，硅胶柱分离(洗脱剂：石油醚/乙酸乙酯＝2/1)得到目标产物(1.1g，收率：74％)。
1H NMR(400MHz,CDCl 3)δ3.52-3.47(m,1H),3.45-3.34(m,1H),3.12(t,J＝10.0Hz,1H),2.43-2.34(m,1H),2.17(s,3H),2.12-1.95(m,2H),1.86-1.50(m,5H),0.96(d,J＝6.4Hz,3H),0.81(d,J＝7.2Hz,3H).
中间体16 (S)-2-(环丁基(甲基)氨基)丁-1-醇的制备
Figure PCTCN2020138142-appb-000115
第一步:(S)-2-(环丁基氨基)丁-1-醇的制备
将(S)-2-氨基丁-1-醇(3g,33.7mmol)、环丁酮(2.83g,40.45mmol)和醋酸(204mg,3.4mmol)加入到甲醇(30mL)中，室温搅拌半个小时。然后将反应液冷却至零度，缓慢加入氰基硼氢化钠(6.37g,101.1mmol)，反应液在室温下搅拌过夜，TLC显示有新的点出现。将反应液浓缩除去甲醇，得到粗产品，粗产品用饱和碳酸钾溶液稀释，用乙酸乙酯萃取3次，合并有机相干燥，浓缩，过硅胶柱(洗脱剂：二氯甲烷/甲醇＝10/1)得到目标产物(2.4g，收率：50％)。
MS:m/z 144(M+H) +.
第二步:(S)-2-(环丁基(甲基)氨基)丁-1-醇的制备
将(S)-2-(环丁基氨基)丁-1-醇(2.4g,16.78mmol)、多聚甲醛(1.5g,50.35mmol)和醋酸(102mg,1.7mmol)加入到甲醇(30mL)中，室温搅拌半个小时。然后将反应液冷却至零度，缓慢加入氰基硼氢化钠(3.17g,50.35mmol)，反应液在室温下搅拌过夜，TLC显示有新的点出现。将反应液浓缩除去甲醇，得到粗产品，粗产品用饱和碳酸钾溶液稀释，用乙酸乙酯萃取3次，合并有机相干燥，浓缩，过硅胶柱(洗脱剂：二氯甲烷/甲醇＝10/1)得到目标产物(1.66g，收率：63％)。
1H NMR(400MHz,CDCl 3)δ3.83(s,1H),3.55-3.51(m,1H),3.28-3.17(m,2H),2.66-2.59(m,1H),2.07-2.00(m,5H),1.87-1.77(m,2H),1.71-1.50(m,3H),1.16-1.08(m,1H),0.80(t,J＝8.0Hz,3H).
中间体17 2-(环丁基(2,2,2-三氟乙基)氨基)乙醇的制备
Figure PCTCN2020138142-appb-000116
将2-(环丁基氨基)乙醇(450mg,3.9mmol)和三乙胺(788mg,7.8mmol)加入到二氯甲烷(10mL)中，然后将2,2,2-三氟乙基三氟甲磺酸酯(1.09g,4.7mmol)加入到反应液中，反应液在室温下搅拌过夜。TLC显示有新的点出现。将反应液浓缩，过硅胶柱，(洗脱剂：二氯甲烷/甲醇＝10/1)得到目标产物(555mg，收率：72％)。
MS:m/z 198(M+H) +. 1H NMR(400MHz,CDCl 3)δ3.59(d,J＝4.8Hz,2H),3.39-3.35(m,1H),3.13-3.06(m,2H),2.77(t,J＝5.6Hz,2H),2.38(s,1H),2.11-2.04(m,2H),1.89-1.84(m,2H),1.69-1.58(m,2H).
中间体18 N-(2-羟乙基)-N-甲基乙酰胺的制备
Figure PCTCN2020138142-appb-000117
将2-(甲胺基)乙醇(10g,130mmol)加入氧化铝(20g,200mmol)中，再加入醋酐(15g,150mmol)。然后反应液室温搅拌0.5小时，过滤，硅胶柱层析(DCM:MeOH＝20:1)，得到目标产物(11g，收率：70％)。
1H NMR(400MHz,CDCl 3)δ4.00(brs,1H),3.78-3.75(m,2H),3.55-3.44(m,2H),3.08-2.95(m,3H),2.15-2.05(m,3H).
中间体19 2-(甲基(1-甲基环丁基)氨基)乙醇的制备
Figure PCTCN2020138142-appb-000118
第一步.N-(2-(苄氧基)乙基)-1-甲基环丁胺的制备
将2-(苄氧基)乙醛(717mg，4.78mmol)、1-甲基环丁胺盐酸盐(530mg，4.34mmol)和醋酸(24mg，0.4mmol)加入到甲醇(10mL)中，室温搅拌半个小时。然后将反应液冷却至零度，缓慢加入氰基硼氢化钠(820mg，13.02mmol)，然后反应液在室温下搅拌过夜。将反应液浓缩除去甲醇，得到粗产品。粗产品用饱和碳酸钾溶液(40mL)稀释，用乙酸乙酯(40mL)萃取2次，合并有机相干燥，浓缩。残余物用硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇＝10/1)得到目标产物(610mg，收率：58％)。
MS:m/z 220(M+H) +。
第二步.N-(2-(苄氧基)乙基)-N，1-二甲基环丁胺的制备
将N-(2-(苄氧基)乙基)-1-甲基环丁胺(890mg，4.06mmol)，多聚甲醛(244mg,8.13mmol)和醋酸(24mg,0.4mmol)加入到甲醇(10mL)中，室温搅拌半个小时。然后将反应液冷却至零度，缓慢加入氰基硼氢化钠(767mg，12.18mmol)然后反应液在室温下搅拌过夜。将反应液浓缩除去甲醇，得到粗产品。粗产品用饱和碳酸钾溶液(40mL)稀释，用乙酸乙酯(40mL)萃取3次，合并有机相干燥，浓缩。残余物用硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇＝10/1)得到目标产物(800mg，收率：84％)。
MS:m/z 234(M+H) +。
第三步.2-(甲基(1-甲基环丁基)氨基)乙醇的制备
将N-(2-(苄氧基)乙基)-N，1-二甲基环丁胺(700mg，3mmol)加入到氢溴酸(30％)醋酸溶液(10mL)中，室温搅拌过夜。将反应液浓缩除去醋酸，然后用2M氢氧化钠溶液稀释(pH>10)，用乙酸乙酯(40mL)萃取3次，合并有机相浓缩，然后用甲醇(10mL)稀释，加入氢氧化钠(240mg)，室温搅拌30分钟，浓缩除去甲醇得到粗产品。粗产品用饱和碳酸钾(40mL)稀释，乙酸乙酯(40mL)萃取2次，有机相干燥，浓缩。残余物用硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇＝10/1)得到目标产物(100mg，收率：23％)。
MS:m/z 144(M+H) +. 1H NMR(400MHz,CDCl 3)δ3.53(t,J＝5.6Hz,2H),3.0(brs,1H),2.39(t,J＝5.6Hz,2H),2.07(s,3H),1.96-1.88(m,2H),1.77-1.68(m,4H),1.11(s,3H).
按照中间体19的方法以不同的起始原料合成了中间体20：
中间体20 2-(甲基(3-甲基氧杂环丁烷-3-基)氨基)乙烷-1-醇的制备
Figure PCTCN2020138142-appb-000119
MS:m/z 146(M+H) +. 1H NMR(400MHz,CD 3OD)δ3.84-3.76(m,1H),3.75-3.62(m,3H),3.52-3.42(m,2H),2.85-2.77(m,1H),2.75-2.67(m,1H),2.40(s,3H),1.10(s,3H).
中间体3-1 2-(环丙基(甲基)氨基)乙烷-1-醇的制备
Figure PCTCN2020138142-appb-000120
第一步：2-(环丙基(甲基)氨基)乙烷-1-醇的制备
将N-甲基环丙胺盐酸盐(3.2g，29.6mmol)溶于甲醇(60mL)中，搅拌下，加入水(1.1mL，59.1mmol)和氢氧化钠(2.4g，59.1mmol)。将该混合物置于冰盐浴中，加入环氧乙烷的四氢呋喃溶液(3mol/L，30mL，90.0mmol)。反应液缓慢升至室温，搅拌16小时后，真空浓缩，除去溶剂。残余物中加入水(30mL)和碳酸钾(5g)，然后用乙酸乙酯(30mL x4)萃取。合并的有机相干燥后,过滤，并真空浓缩。残余物通过硅胶柱纯化(洗脱剂：二氯甲烷/甲醇＝100/1至50/1，洗脱剂中添加1‰氨水)，得到目标产物(1g，收率：29％)。
1H NMR(400MHz,CDCl 3)δ3.59(t,J＝5.6Hz,2H),2.71(t,J＝5.6Hz,2H),2.51(brs,1H),2.34(s,3H),1.76-1.70(m,1H),0.50-0.46(m,2H),0.42-0.38(m,2H).
中间体4-1 2-(环丁基(甲基)氨基)乙烷-1-醇的制备
Figure PCTCN2020138142-appb-000121
第一步：2-(环丁基(甲基)氨基)乙烷-1-醇的制备
将2-甲氨基乙醇(1.2g，16mmol)、环丁酮(1.68g，24mmol)和醋酸(96mg，1.6mmol)加入到甲醇(12mL)中，然后将反应液冷却至0℃，缓慢加入氰基硼氢化钠(5.04g，80mmol)。得到的反应液在室温下搅拌过夜，然后浓缩除去甲醇得到粗产品。粗产品用碳酸钾水溶液(1M)稀释，然后用乙酸乙酯萃取5次。有机相合并后干燥浓缩，残余物通过硅胶柱纯化(洗脱剂：二氯甲烷/甲醇＝5/1，Rf＝0.3)，得到目标产物(838mg，收率：41％)。
MS：m/z 130(M+H) +。 1H NMR(400MHz,CDCl 3)δ3.62-3.60(m,2H),3.00-2.91(m,1H),2.45(t,J＝5.2Hz,2H),2.16(s,3H),2.10-2.04(m,2H),1.91-1.86(m,2H),1.72-1.62(m,2H).
以不同的起始原料按照中间体5同样的方法合成了以下化合物：
中间体5-1 2-(环戊基(甲基)氨基)乙烷-1-醇的制备
Figure PCTCN2020138142-appb-000122
MS：m/z 144(M+H) +。 1H NMR(400MHz,CDCl 3)δ3.74(t,J＝5.6Hz),3.15-3.11(m,1H),2.83(t,J＝4.2Hz,2H),2.49(s,3H),1.96-1.92(m,2H),1.77-1.70(m,2H),1.64-1.54(m,4H).
中间体6-1 2-(环己基(甲基)氨基)乙烷-1-醇的制备
Figure PCTCN2020138142-appb-000123
MS：m/z 158(M+H) +。 1H NMR(400MHz,CDCl 3)δ3.72(t,J＝4.2Hz,2H),2.87(t,J＝4.2Hz,2H),2.78-2.72(m,1H),2.51(s,3H),1.90-1.85(m,4H),1.69-1.66(m,1H),1.29-1.24(m,4H),1.13-1.11(m,1H)。
中间体7-1 2-(环丁基(乙基)氨基)乙烷-1-醇
Figure PCTCN2020138142-appb-000124
MS：m/z 144(M+H) +。 1H NMR(400MHz,CDCl 3)δ3.52(t,J＝5.6Hz,2H),3.15(m,1H),2.86(brs,1H),2.57-2.53(m,4H),2.04-1.99(m,2H),1.88-1.83(m,2H),1.65-1.58(m,2H),0.97(t,J＝7.2Hz,3H).
中间体8-1 2-(环丁甲基(甲基)氨基)乙烷-1-醇的制备
Figure PCTCN2020138142-appb-000125
第一步：2-(环丁甲基(甲基)氨基)乙烷-1-醇的制备
将乙腈(30mL)加入封管，随后加入2-(甲基氨基)乙醇(5g，67mmol)与溴甲基环丁烷(5g，33.5mmol)，然后继续加入K 2CO 3(5g，37mmol)。得到的混合液加热至45～50℃，搅拌48h。体系降至室温，加入乙酸乙酯(100mL)和水(100mL)分层。水层分离后用乙酸乙酯(30mL)萃取两次。合并的有机层依次用水(50mL×2)和饱和氯化钠(50mL×2)洗涤，然后用无水Na 2SO 4干燥后，过滤。滤液真空浓缩，得目标产物(3.7g，收率：78％)。
MS：m/z 144(M+H) +。 1H NMR(400MHz,CDCl 3)δ3.56(t,J＝4.8Hz,2H),2.56-2.46(m,3H),2.42(d,J＝7.2Hz,2H),2.21(s,3H),2.09-2.02(m,2H),1.94-1.78(m,2H),1.70-1.63(m,2H).
以不同的起始原料按照中间体8同样的方法合成了以下化合物：
中间体9-1 2-(环丙甲基(甲基)氨基)乙烷-1-醇的制备
Figure PCTCN2020138142-appb-000126
MS：m/z 130(M+H) +。 1H NMR(400MHz,CDCl 3)δ3.49(t,J＝5.4Hz,2H),2.90(brs,1H),2.48(t,J＝5.4Hz,2H),2.27–2.14(m,5H),0.84–0.64(m,1H),0.49–0.32(m,2H),0.01(q,J＝4.7Hz,2H).
中间体10-1 (S)-2-((环丙甲基)(甲基)氨基)丙烷-1-醇的制备
Figure PCTCN2020138142-appb-000127
第一步：(S)-2-((环丙甲基)氨基)丙烷-1-醇的制备
将(S)-2-氨基丙-1-醇(10g，126.6mmol)、环丙醛(9.3g，132.9mmol)和醋酸(760mg，12.6mmol)加入到甲醇(500mL)中，然后将反应液冷却至0℃，随后缓慢加入醋酸硼氢化钠(53.7g，253.2mmol)。反应液在室温下，搅拌过夜，然后真空浓缩除去甲醇。得到的粗产品经硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝5/1，Rf＝0.3)，得到目标产物(6.9g)，收率：42％。
MS：m/z 130(M+H) +。
第二步：(S)-2-((环丙甲基)(甲基)氨基)丙烷-1-醇的制备
将(S)-2-((环丙基甲基)氨基)丙-1-醇(2.35g，18.2mmol)、多聚甲醛(1.1g，36.4mmol)和醋酸(110mg，1.82mmol)加入到甲醇(45mL)中。将反应液冷却至0℃，随后缓慢加入氰基硼氢化钠(3.45g,54.6mmol)。反应液在室温下搅拌过夜，然后减压浓缩除去甲醇。得到的粗产品经硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝5/1，Rf＝0.3)，得到目标产物(937mg，收率：37％)。
MS：m/z 144(M+H) +。 1H NMR(400MHz,CDCl 3)δ3.73-3.69(m,1H),3.58-3.53(m,1H),3.45-3.41(m,1H),2.82-3.2.77(m,1H),2.65-2.60(m,1H),2.57(s,3H),1.08-1.02(m,4H),0.70-0.67(m,2H),0.34-0.26(m,2H).
以不同的起始原料按照中间体10同样的方法合成了以下化合物：
中间体11-1 (R)-2-((环丙甲基)(甲基)氨基)丙烷-1-醇的制备
Figure PCTCN2020138142-appb-000128
MS：m/z 144(M+H) +。 1H NMR(400MHz,CDCl 3)δ3.65-3.61(m,1H),3.51-3.41(m,1H),3.33-3.29(m,1H),2.70-2.65(m,1H),2.55-2.49(m,4H),1.02-1.00(m,4H),0.66-0.62(m,2H),0.29-0.21(m,2H).
中间体12-1 (S)-2-(环丁基(甲基)氨基)丙烷-1-醇
Figure PCTCN2020138142-appb-000129
MS：m/z 144(M+H) +。 1H NMR(400MHz,CDCl 3)δ3.47-3.43(m,1H),3.35-3.30(m,1H),3.25-3.22(m,1H),3.02-2.97(m,1H),2.13(s,3H),2.10-2.05(m,2H),1.99-1.87(m,2H),1.74-1.64(m,2H),089(d,J＝6.4Hz,3H).
中间体13-1 (R)-2-(环丁基(甲基)氨基)丙烷-1-醇
Figure PCTCN2020138142-appb-000130
MS：m/z 144(M+H) +。
中间体14-1 (S)-1-((环丙甲基)(甲基)氨基)丙烷-2-醇的制备
Figure PCTCN2020138142-appb-000131
第一步：(S)-(2-羟基丙基)甲酸叔丁酯的制备
将(S)-1-氨基丙-2-醇(10g，0.13mol)和三乙胺(26.9g，0.27mol)溶于无水四氢呋喃(150mL)中。在冰浴下，慢慢加入二碳酸二叔丁酯(34.8g，0.16mol)。加毕，反应液在室温搅拌，反应过夜，然后减压浓缩。残余物用硅胶柱纯化(洗脱剂：石油醚/乙酸乙酯＝1/1)，得到目标产物(21.7g，收率93％)。
第二步：(S)-1-(甲氨基)丙烷-2-醇的制备
将(S)-(2-羟基丙基)甲酸叔丁酯(21.7g，0.12mol)溶于无水四氢呋喃(300mL)中，在冰浴下，分批次加入锂铝氢(9.4g，0.25mol)。加毕，反应液回流反应过夜。得到的反应液在冰浴下，慢慢加入十水硫酸钠(40g)淬灭反应，然后过滤。滤液旋干，残余物用硅胶柱纯化(洗脱剂：二氯甲烷/甲醇＝5/1)，得到目标产物(6g，收率54％)。
1H NMR(400MHz,CDCl 3)δ3.90-3.80(m,1H),2.66(dd,J＝12.0Hz,3.2Hz,1H),2.51-2.43(m,4H),1.17(d,J＝6.0Hz,3H).
第三步：(S)-1-((环丙甲基)(甲基)氨基)丙烷-2-醇的制备
将(S)-1-(甲氨基)丙烷-2-醇(3g，33.7mmol)溶于乙腈(100mL)中，室温下，加入碳酸钾(5.6g，40.5mmol)和(溴甲基)环丙烷(4.6g，33.7mmol)。加毕，反应液升温至60℃反应2h。得到的反应液降至室温，加入乙酸乙酯(150mL)和水(100mL)淬灭反应。有机相收集后依次用水(100mL)洗两次、饱和食盐水(50mL)洗一次，然后用无水硫酸钠干燥后,过滤。滤液真空浓缩,得到目标产物(2g，收率42％)。
MS：m/z 144(M+H) +。 1H NMR(400MHz,CDCl 3)δ3.81-3.73(m,1H),2.40-2.21(m,7H),1.12(d,J＝6.0Hz,3H),0.90-0.81(m,1H),0.56-0.45(m,2H),0.14-0.06(m,2H).
以不同的起始原料按照中间体14-1同样的方法合成了以下化合物：
中间体15-1 (R)-1-((环丙甲基)(甲基)氨基)丙烷-2-醇的制备
Figure PCTCN2020138142-appb-000132
MS：m/z 144(M+H) +。 1H NMR(400MHz,CDCl 3)δ3.81-3.73(m,1H),2.40-2.21(m,7H),1.12(d,J＝6.4Hz,3H),0.90-0.81(m,1H),0.56-0.45(m,2H),0.14-0.06(m,2H).
中间体16-1 (S)-1-(环丁基(甲基)氨基)丙烷-2-醇
Figure PCTCN2020138142-appb-000133
MS：m/z 144(M+H) +。 1H NMR(400MHz,CDCl 3)δ3.78-3.76(m,1H),2.89-2.85(m,1H),2.27-2.23(m,1H),2.21(s,3H),2.10-1.95(m,3H),1.83-1.76(m,2H),1.68-1.59(m,2H),1.11(d,J＝6.4Hz,3H).
中间体17-1 (R)-1-(环丁基(甲基)氨基)丙烷-2-醇
Figure PCTCN2020138142-appb-000134
MS：m/z 144(M+H) +。 1H NMR(400MHz,CDCl 3)δ3.77-3.76(m,1H),2.89-2.85(m,1H),2.27-2.22(m,1H),2.21(s,3H),2.05-1.95(m,3H),1.84-1.79(m,2H),1.69-1.60(m,2H),1.11(d,J＝6.4Hz,3H).
中间体18-1 2,2'-(环丙基氮烷二基)双(乙烷-1-醇)的制备
Figure PCTCN2020138142-appb-000135
第一步：2,2'-(环丙基氮烷二基)双(乙烷-1-醇)的制备
将环丙胺(550mg，9.7mmol)溶于甲醇(20mL)中，冰盐浴搅拌下，加入环氧乙烷的四氢呋喃溶液(3mol/L，19.3mL，57.9mmol)。反应液缓慢升至室温，搅拌16h。得到的反应液浓缩除去溶剂，残余物经硅胶柱纯化(洗脱剂：二氯甲烷/甲醇＝100/1到80/1，洗脱剂中添加1‰氨水)，得到目标化合物(700mg，收率：50％)。
MS：m/z 146(M+H) +。 1H NMR(400MHz,CDCl 3)δ3.68(t,J＝5.6Hz,4H),2.82(t,J＝5.6Hz,4H),1.91-1.85(m,1H),0.56-0.49(m,2H),0.48-0.43(m,2H).
中间体19-1 (S)-1-(双(环丙甲基)氨基)丙烷-2-醇的制备
Figure PCTCN2020138142-appb-000136
将(S)-1-氨基丙-2-醇9a(2g，26.7mmol)、环丙醛(4.1g,58.7mmol)和醋酸(162mg,2.7mmol)溶于甲醇(80mL)中，然后将反应液冷却至0℃，随后分批次加入醋酸硼氢化钠(17g,80.1mmol)。加毕，反应液室温搅拌过夜。将反应液真空浓缩，得到粗品经硅胶柱纯化(洗脱剂：二氯甲烷/甲醇＝10/1)，得到目标产物(2.3g，收率：47％)。
MS：m/z 184(M+H) +。 1H NMR(400MHz,CDCl 3)δ3.80-3.68(m,1H),2.53-2.35(m,6H),1.12(d,J＝6.4Hz,3H),0.93-0.80(m,2H),0.58-0.41(m,4H),0.16-0.05(m,4H).
中间体20-1 2-(((3,3-二氟环丁基)甲基)(甲基)氨基)乙烷-1-醇的制备
Figure PCTCN2020138142-appb-000137
第一步:3,3-二氟环丁烷-1-甲酰氯的制备
将3,3-二氟环丁烷-1-甲酸(4g，29.4mmol)溶于无水二氯甲烷(50mL)中，在冰浴下，慢慢加入草酰氯(4.5g，35.3mmol)和N，N-二甲基甲酰胺(5滴)。加毕，反应液在室温搅拌反应2h，然后直接用于下一步反应。
第二步:3,3-二氟-N-(2-羟乙基)-N-甲基环丁烷-1-甲酰胺的制备
将2-甲基氨基乙烷-1-醇(3.3g，44.1mmol)溶于二氯甲烷(50mL)中，在冰浴下，加入三乙胺(14.7g，147mmol)和上一步得到的反应液。加毕，反应液在室温反应过夜，然后减压 浓缩除去二氯甲烷。残留物中加入乙酸乙酯(200mL)和水(100mL)。有机相分分离，然后用饱和食盐水(50mL)洗一次，再经无水硫酸钠干燥后,过滤。滤液减压浓缩，残余物经硅胶柱层析纯化(洗脱液：二氯甲烷/甲醇＝20/1)，得到目标产物(3.9g，收率68％)。
MS：m/z 194(M+H) +。
第三步:2-(((3,3-二氟环丁基)甲基)(甲基)氨基)乙烷-1-醇的制备
将3,3-二氟-N-(2-羟乙基)-N-甲基环丁烷-1-甲酰胺(3.9g，20.2mmol)溶于无水四氢呋喃(60mL)中，在冰浴下，分批次加入锂铝氢(2.2g，60.9mmol)。加毕，反应液在室温反应过夜。得到的混合物在冰浴下，慢慢加入十水硫酸钠(4g)淬灭反应，然后过滤。滤液减压浓缩，得到目标产物(3.1g，收率86％)。
MS：m/z 184(M+H) +。 1H NMR(400MHz,CDCl 3)δ3.58(t,J＝5.2Hz,2H),2.73-2.60(m,2H),2.56-2.50(m,4H),2.40-2.13(m,7H).
中间体21-1 (S)-2-(环丙基(甲基)氨基)丙烷-1-醇的制备
Figure PCTCN2020138142-appb-000138
第一步：(R)-2-((三氟甲基)磺酰)氧基)丙酸甲酯的制备
将(R)-2-羟基丙酸甲酯(20.8g，0.2mol)加入到无水二氯甲烷(800ml)中。反应液冷却至0℃，在氮气保护下，加入三氟甲烷磺酸酐(35.3mL，0.21mol)和2,6-二甲基吡啶(24.4mL，0.21mmol)，然后在0℃下，搅拌20min。得到的混合物减压浓缩。残余物经硅胶柱纯化(洗脱剂：二氯甲烷)，得到目标产物(42.3g，收率89％)。
第二步：(S)-2-(环丙氨基)丙酸甲酯的制备
将环丙胺(9.3g，0.163mol)和三乙胺(49.4g,0.489mol)加入到二氯甲烷(400mL)溶液中。将混合物在0℃下，搅拌10min，然后加入(R)-2-((三氟甲基)磺酰)氧基)丙酸甲酯(42.3g，0.179mol)。将反应混合物在室温下，搅拌2h，然后用饱和碳酸氢钠(200mL)将反应淬灭。得到的混合物用二氯甲烷萃取(2 x 100mL)。合并的有机相用无水硫酸钠干燥后，过滤。滤液减压浓缩，得到的残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝2/1)纯化，得到目标产物(17.5g，收率75％)。
第三步：(S)-2-(环丙基(甲基)氨基)丙酸甲酯的制备
将化合物(S)-2-(环丙氨基)丙酸甲酯(11.9g，83.22mmol)溶于乙腈(200mL)中，在0℃下，加入钠氢(60％wt，5.0g，124.83mmol)和碘化钾(138mg，0.832mmol)。反应液在0℃下，搅拌30min，然后加入碘甲烷(12.4g，87.38mmol)。得到的混合物升至室温搅拌4小时，然后用水(100mL)淬灭，再用二氯甲烷(200mL)萃取。合并的有机相用无水硫酸钠干燥后,过滤。滤液减压浓缩，得到的残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝2/1)纯化，得到目标产物(4.3g，收率33％)。
第四步：(S)-2-(环丙基(甲基)氨基)丙烷-1-醇的制备
将锂铝氢(2.08g，54.78mmol)悬浮到四氢呋喃(50mL)中，冷却到0℃，然后缓慢滴加(S)-2-(环丙基(甲基)氨基)丙酸甲酯(4.3g，27.39mmol)的四氢呋喃(30mL)溶液。反应液在0 ℃下，搅拌30min。然后在0℃，依次加入2mL水、2mL15％氢氧化钠溶液和6mL水。得到的混合物搅拌30min，然后过滤。滤液干燥后，减压浓缩，得到目标产物(1.97g，收率56％)。
MS：m/z 130(M+H) +。 1H NMR(400MHz,CDCl 3)δ3.35-3.31(m,1H),3.24(t,J＝10.4Hz,1H),3.02-2.96(m,1H),2.74(brs,1H),2.22(s,3H),1.94-1.90(m,1H),0.94(d,J＝6.4Hz,3H),0.52-0.32(m,3H),0.31-0.27(m,1H)。
以不同的起始原料按照中间体21同样的方法合成了以下化合物：
中间体22-1 (R)-2-(环丙基(甲基)氨基)丙烷-1-醇的制备
Figure PCTCN2020138142-appb-000139
MS：m/z 130(M+H) +。 1H NMR(400MHz,CDCl 3)δ3.34-3.30(m,1H),3.23(t,J＝10Hz,1H),3.02-2.95(m,1H),2.81(brs,1H),2.20(s,3H),1.94-1.89(m,1H),0.93(d,J＝6.8Hz,3H),0.51-0.31(m,3H),0.30-0.25(m,1H).
中间体23-1 2-(((1-氟环丙基)甲基)(甲基)氨基)乙烷-1-醇的制备
Figure PCTCN2020138142-appb-000140
第一步:1-氟环丙烷-1-甲酰氯的制备
将1-氟环丙烷-1-甲酸(1.7g，16.3mmol)溶于无水二氯甲烷(30mL)中，在冰浴下，慢慢加入草酰氯(2.5g，19.6mmol)和N，N-二甲基甲酰胺(5drops)。加毕，反应液在室温搅拌，反应2h，然后直接用于下一步反应。
第二步:1-氟-N-(2-羟乙基)-N-甲基环丙烷-1-甲酰胺的制备
将2-(甲基氨基)乙烷-1-醇(1.8g，24.5mmol)溶于二氯甲烷(40mL)中，在冰浴下，加入三乙胺(8g，81.5mmol)和上一步得到的反应液。加毕，反应液在室温反应过夜，然后减压浓缩除去二氯甲烷。残余物中加入乙酸乙酯(200mL)和水(100mL)。有机相分离后，用饱和食盐水(50mL)洗一次，然后经无水硫酸钠干燥后，过滤。滤液减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝40/1)，得到目标产物(1.9g，收率73％)。
MS：m/z 162(M+H) +。
第三步:2-(((1-氟环丙基)甲基)(甲基)氨基)乙烷-1-醇的制备
将1-氟-N-(2-羟乙基)-N-甲基环丙烷-1-甲酰胺(1.9g，11.8mmol)溶于无水四氢呋喃(40mL)中，在冰浴下，分批次加入锂铝氢(0.87g，23.6mmol)。加毕，反应液在室温反应过夜，然后在冰浴下，慢慢加入十水硫酸钠(2g)淬灭反应，然后过滤。滤液减压浓缩,得到的残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝40/1)，得到目标产物(0.64g，收率38％)。
MS：m/z 148(M+H) +。 1H NMR(400MHz,CDCl 3)δ3.61(t,J＝5.6Hz,2H),2.82(d,J＝19.2Hz,2H),2.70(t,J＝5.6Hz,2H),2.43(s,3H),1.13-1.02(m,2H),0.65-0.57(m,2H).
中间体24-1 (S)-2-((1-环丙基乙基)(甲基)氨基)乙烷-1-醇的制备
Figure PCTCN2020138142-appb-000141
第一步:(S)-2-((1-环丙基乙基)氨基)乙烷-1-醇
将(S)-1-环丙乙烷-1-胺(3.4g，40mmol)、溴乙醇(5g，40mmol)和碳酸钾(8.3g，60mmol)加入到乙腈(50mL)中，然后将反应加热到50℃过夜。得到的反应混合物无需纯化，直接用于下一步。
第二步:(S)-(1-环丙基乙基)(2-羟乙基)氨基甲酸叔丁酯
将二碳酸二叔丁酯(9.3g，43mmol)和碳酸钾(10.7g,78mmol)加入上一步反应液中。得到的反应液在室温下，搅拌过夜，然后过滤。滤液减压浓缩，得到的残余物经硅胶柱层析纯化，得到目标产物(1.9g，收率21％)。
第三步:(S)-2-((1-环丙基乙基)(甲基)氨基)乙烷-1-醇的制备
将(S)-(1-环丙基乙基)(2-羟乙基)氨基甲酸叔丁酯(1.9g，8.3mmol)和氢化铝锂(1.26g,33mmol)加入四氢呋喃中。得到的反应液升温回流，搅拌过夜，然后降温后，用十水硫酸钠淬灭。得到的混合物过滤，滤液减压浓缩。残余物经硅胶柱层析纯化，得到目标产物(420mg，收率35％)。
MS：m/z 144(M+H) +。 1H NMR(400MHz,CDCl 3)δ3.57(t,J＝4.8Hz,2H),2.72-2.64(m,2H),2.33(s,3H),1.97-1.93(m,1H),1.09(d,J＝6.8Hz,3H),0.83-0.78(m,1H),0.54-0.47(m,2H),0.30-0.27(m,1H),0.10-0.06(m,1H).
以不同的起始原料按照中间体24-1同样的方法合成了以下化合物：
中间体25-1 (R)-2-((1-环丙基乙基)(甲基)氨基)乙烷-1-醇的制备
Figure PCTCN2020138142-appb-000142
MS：m/z 144(M+H) +。 1H NMR(400MHz,CDCl 3)δ3.57(t,J＝4.8Hz,2H),2.72-2.66(m,2H),2.32(s,3H),1.96-1.91(m,1H),1.09(d,J＝6.8Hz,3H),0.83-0.77(m,1H),0.55-0.46(m,2H),0.32-0.26(m,1H),0.10-0.04(m,1H).
中间体26-1 2-((3,3-二氟环丁基)(甲基)氨基)乙烷-1-醇的制备
Figure PCTCN2020138142-appb-000143
MS：m/z 166(M+H) +。 1H NMR(400MHz,CDCl 3)δ(t,J＝4.2Hz,2H),2.87-2.85(m,1H),2.73-2.65(m,2H),2.48-2.33(m,4H),2.18(s,3H)。
中间体27-1 反式-2-(二甲氨基)环戊醇的制备
Figure PCTCN2020138142-appb-000144
第一步:(S)-2-((1-环丙基乙基)氨基)乙烷-1-醇
将6-恶唑环[3.1.0]己烷(2g，23.8mmol)加入到二甲胺水溶液(含量大于33％，10mL)中， 得到的反应液在室温搅拌过夜。将反应液浓缩旋干，残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)，得到目标产物(1.63g，收率：53％)。实施例1 2-(1-丙烯酰-4-(2-((R)-2-(环丁基(甲基)氨基)-3-甲氧基丙氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000145
第一步：2-(氰基甲基)-4-(2-((R)-2-(环丁基(甲基)氨基)-3-甲氧基丙氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯的制备
将2-(氰基甲基)-4-(7-(8-甲基萘-1-基)-2-(甲基亚砜基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-1-甲酸酸叔丁酯(72mg，0.128mmol)加入反应瓶中，随后依次加入甲苯(0.8mL)、(S)-2-(环丁基(甲基)氨基)-3-甲氧基丙基-1-醇(45mg，0.256mmol)和叔丁醇钠(37mg，0.384mmol)。反应液在冰水浴下，搅拌0.5h，随后加入水(50mL)，然后用乙酸乙酯萃取(3 x 30mL)。所有有机相合并，用饱和氯化钠溶液洗一次，然后经无水硫酸钠干燥后，过滤。滤液减压浓缩，得到的残余物用制备板分离(洗脱剂：DCM/MeOH＝20/1)，得到目标产物(43mg，产率50％)。
LC-MS：m/z 670(M+H) +。
第二步：2-(4-(-(2-((R)-2-(环丁基(甲基)氨基)-3-甲氧基丙氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
将2-(氰基甲基)-4-(2-((R)-2-(环丁基(甲基)氨基)-3-甲氧基丙氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯(40mg，0.059mmol)溶于二氯甲烷(1mL)中，随后加入三氟乙酸(0.5mL)。反应液在室温搅拌0.5h，然后减压浓缩至干，得到目标产物，无需纯化直接用于下一步反应。
LC-MS：m/z 570(M+H) +。
第三步 2-(1-丙烯酰-4-(2-((R)-2-(环丁基(甲基)氨基)-3-甲氧基丙氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
将上一步得到的2-(4-(-(2-((R)-2-(环丁基(甲基)氨基)-3-甲氧基丙氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈中加入N,N-二异丙基乙胺(42mg，0.324mmol)的二氯甲烷(2mL)溶液中。反应液在氮气保护，在-40℃下，滴加丙烯酰氯(10mg，0.108 mmol)。滴加完后，反应液升至室温搅拌1h，然后加入甲醇(1mL)淬灭。得到的混合物浓缩，得到的残余物用液相制备得到目标产物(13mg，产率35％)。
LCMS:m/z 624(M+H) +. 1HNMR(400MHz,CDCl 3)δ7.66(m,2H),7.40(m,2H),7.24(m,2H),6.58(m,1H),6.41(d,J＝16.8Hz,1H),5.84(d,J＝10.4Hz,1H),5.07(brs,0.5H),4.60(brs,0.5H),4.41(m,1H),4.24(m,5H),3.55(m,5H),3.33(m,4H),3.15(m,5H),2.91(s,3H),2.68(m,2H),2.27(s,3H),1.87(m,5H),1.57(m,2H).
按照实施例1的方法以不同的起始原料合成了实施例2-24：
实施例2 2-(1-丙烯酰-4-(7-(8-氯萘-1-基)-2-((1-((二甲氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000146
LCMS:m/z 600(M+H) +. 1HNMR(400MHz,CDCl 3)δ7.76(m,1H),7.62(m,1H),7.52(m,1H),7.44(m,1H),7.33(m,1H),7.23(m,1H),6.58(m,1H),6.41(d,J＝16.8Hz,1H),5.84(d,J＝10.4Hz,1H),5.08(brs,0.5H),4.61(brs,0.5H),4.41(m,1H),4.05(m,6H),3.56(m,1H),3.42(m,1H),3.14(m,4H),2.40(m,11H),0.72(m,2H),0.54(m,2H).
实施例3 2-(1-丙烯酰-4-(7-(8-氯萘-1-基)-2-((1-((二甲氨基)甲基)环丁基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000147
LCMS:m/z 614(M+H) +. 1H NMR(400MHz,CDCl 3)δ7.68(d,J＝8.0Hz,1H),7.54(dd,J＝8.0,3.2Hz,1H),7.40(m,2H),7.26(t,J＝7.8Hz,1H),7.15(m,1H),6.52(brs,1H),6.31(d,J＝16.4Hz,1H),5.74(d,J＝10.5Hz,1H),5.00(brs,0.5H),4.69(m,2.5H),4.50–4.19(m,2H),3.91(m,2H),3.49(m,2H),3.16(m,6H),2.92(m,1H),2.78(m,7H),2.53(m,1H),2.24–1.81(m,7H).
实施例4 2-(1-丙烯酰-4-(2-(2-((1-氟环丙基)甲基)(甲基)氨基)乙氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000148
LCMS:m/z 598(M+H) +. 1HNMR(400MHz,CDCl 3)δ7.60(m,2H),7.29(m,2H),7.17(m, 2H),6.49(m,1H),6.34(d,J＝17.2Hz,1H),5.77(d,J＝10.0Hz,1H),4.99(brs,0.5H),4.59(m,2.5H),2.88(m,5H),3.46(m,2H),3.09(m,8H),2.84(s,3H),2.69(m,6H),1.1 2(m,2H),0.81(m,2H).
实施例5 2-(1-丙烯酰-4-(7-(8-氯萘-1-基)-2-(环丁基(2-甲氧基乙基)氨基)乙氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000149
LCMS:m/z 644(M+H) +. 1HNMR(400MHz,CDCl 3)δ7.76(m,1H),7.61(m,1H),7.53(m,1H),7.45(m,1H),7.33(m,1H),7.24(m,1H),6.58(m,1H),6.41(d,J＝16.8Hz,1H),5.83(d,J＝10.4Hz,1H),5.07(brs,0.5H),4.62(brs,0.5H),4.41(m,3H),3.91(m,4H),3.48(m,4H),3.32(m,3H),2.93(m,4H),2.40(m,12H),2.03(m,4H),1.58(m,2H).
实施例6 2-(1-丙烯酰-4-(7-(8-氯萘-1-基)-2-(2-((2,2-二氟环丙基)甲基)(甲基)氨基)乙氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000150
LCMS:m/z 636(M+H) +. 1HNMR(400MHz,CDCl 3)δ7.76(m,1H),7.61(m,1H),7.53(m,1H),7.45(m,1H),7.33(m,1H),7.24(m,1H),6.58(m,1H),6.41(d,J＝16.8Hz,1H),5.83(d,J＝10.4Hz,1H),5.07(brs,0.5H),4.61(brs,0.5H),4.42(m,3H),3.82(m,4H),3.53(m,2H),3.21(m,4H),2.82(m,5H),2.55(m,2H),2.40(s,3H),1.45(m,1H),1.30(m,1H),1.00(m,1H).
实施例7 2-(1-丙烯酰-4-(2-(2-(甲基(环丁氧-3-基)胺基)乙氧)-7-(8-甲基萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000151
LC-MS:m/z 582(M+H) +。 1H NMR(400MHz，CDCl 3)δ7.71–7.63(m,2H),7.44–7.32(m,2H),7.25–7.19(m,2H),6.62–6.55(m,1H),6.42–6.38(m,1H),5.83(d,J＝10.4Hz,1H),5.11–4.99(m,0.5H),4.67-4.63(m,4.5H),4.44–4.37(m,2H),4.27–4.06(m,3H),3.92–3.84(m,1H),3.78–3.68(m,2H),3.56–3.42(m,2H),3.22–2.97(m,4H),2.91(s,3H),2.86–2.60(m,5H),2.28(s,3H).
实施例8 2-(1-丙烯酰-4-(7-(8-氯萘-1-基)-2-((S)-2-(环丁基(甲基)氨基)丁氧)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000152
LC-MS:m/z 628(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.73(dd,J＝14.4,5.3Hz,1H),7.61(t,J＝7.2Hz,1H),7.52(d,J＝7.4Hz,1H),7.44(dt,J＝12.1,7.8Hz,1H),7.33(t,J＝7.8Hz,1H),7.26–7.17(m,1H),6.59(m,1H),6.39(d,J＝16.7Hz,1H),5.82(d,J＝10.5Hz,1H),5.08(brs,0.5H),4.63(brs,0.5H),4.50–3.76(m,7H),3.75–2.47(m,12H),2.22(m,3H),2.00(m,3H),1.67(m,4H),0.97(m,3H).
实施例9 2-(1-丙烯酰-4-(7-(8-氯萘-1-基)-2-((S)-2-(环丁基(甲基)氨基)-3-甲基丁氧)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000153
LC-MS:m/z 642(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.70(d,J＝7.7Hz,1H),7.56(m,1H),7.46(d,J＝7.3Hz,1H),7.43–7.35(m,1H),7.27(t,J＝7.8Hz,1H),7.14(d,J＝7.4Hz,1H),6.52(m,1H),6.33(d,J＝16.5Hz,1H),5.76(d,J＝10.0Hz,1H),4.93(brs,0.5H),4.65–4.20(m,3.5H),4.17–3.63(m,4H),3.61–2.90(m,8H),2.63(m,7H),2.25–1.79(m,4H),1.29–1.00(m,8H).
实施例10 2-(1-丙烯酰-4-(7-(8-氯萘-1-基)-2-(2-(环丁基(2,2,2-三氟乙基)胺基)乙氧)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000154
LC-MS:m/z 668(M+H) +。 1H NMR(400MHz，CDCl 3)δ7.76(d,J＝8.0Hz,1H),7.62(t,J＝6.4Hz,1H),7.52(d,J＝7.2Hz,1H),7.48–7.41(m,1H),7.34(t,J＝8.0Hz,1H),7.26–7.20(m,1H),6.63–6.55(m,1H),6.42–6.385(m,1H),5.83(d,J＝10.4Hz,1H),5.12–4.98(m,0.6H),4.67-4.41(m,3.4H),4.22–3.73(m,4H),3.60–3.41(m,3H),3.26–2.99(m,8H),2.87–2.56(m,3H),2.16–2.06(m,3H),1.72–1.53(m,3H).
实施例11 2-(4-(7-(8-氯萘-1-基)-2-(2-(环丁基(甲基)胺基)乙氧)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000155
LC-MS:m/z 618(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.69(d,J＝8.1Hz,1H),7.59–7.51(m,1H),7.45(d,J＝7.4Hz,1H),7.38(dd,J＝17.3,7.9Hz,1H),7.27(t,J＝7.8Hz,1H),7.19–7.11(m,1H),5.34(d,J＝47.4Hz,1H),5.24–5.12(m,1H),4.74(brs,1H),4.42–3.68(m,5H),3.47(d,J＝32.7Hz,3H),3.29–2.93(m,5H),2.93–2.40(m,8H),2.15(m,2H),1.88(m,1H),1.76–1.60(m,2H),1.35–1.09(m,2H).
实施例12 2-(4-(7-(8-氯萘-1-基)-2-((S)-2-(环丙基(甲基)氨基)丙氧)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000156
LC-MS:m/z 632(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.69(t,J＝7.6Hz,1H),7.56(dd,J＝12.8,8.2Hz,1H),7.45(d,J＝7.2Hz,1H),7.42–7.33(m,1H),7.27(dd,J＝14.4,7.0Hz,1H),7.19–7.09(m,1H),5.35(m,1H),5.17(m,1H),4.65(brs,1H),4.52–3.32(m,9H),3.32–2.96(m,5H),2.96–2.36(m,8H),2.14(d,J＝7.5Hz,2H),2.02–1.79(m,1H),1.72–1.59(m,1H),1.39(d,J＝6.2Hz,2H),1.31–1.13(m,2H).
实施例13 2-(4-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000157
LC-MS:m/z 618(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.68(d,J＝8.1Hz,1H),7.57–7.51(m,1H),7.44(d,J＝7.4Hz,1H),7.37(dt,J＝10.3,7.8Hz,1H),7.26(t,J＝7.8Hz,1H),7.18–7.11(m,1H),5.32(d,J＝47.5Hz,1H),5.16(dd,J＝16.9,3.5Hz,1H),4.75(brs,0.5H),4.44–4.24(m,2.5H),4.23–3.69(m,5H),3.48(m,1H),3.36(m,1H),2.89(m,15H),0.83(m,2H),0.70(m,2H).
实施例14 2-(4-(7-(8-氯-7-氟萘-1-基)-2-(2-(环丁基(甲基)氨基)乙氧)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000158
LCMS:m/z 636(M+H) +. 1H NMR(400MHz,CDCl 3)δ7.81–7.67(m,1H),7.65–7.49(m,1H),7.42(dt,J＝12.2,7.8Hz,1H),7.35–7.21(m,2H),5.41(m,1H),5.23(m,1H),4.85(brs,1H),4.36(m,3H),4.23–3.97(m,2H),3.96–3.73(m,1H),3.50(m,2H),3.13(m,3H),3.00–2.51(m,5H),2.24(s,3H),2.02(m,5H),1.80–1.55(m,2H),1.29(m,2H).
实施例15 2-(1-丙烯酰-4-(7-(8-氯萘-1-基)-2-(((顺式)-2-(二甲基氨基)环戊基)氧)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000159
LCMS:m/z 600(M+H) +. 1H NMR(400MHz,CDCl 3)δ7.69(d,J＝8.1Hz,1H),7.56(t,J＝7.6Hz,1H),7.46(d,J＝7.4Hz,1H),7.38(dt,J＝12.4,7.7Hz,1H),7.27(t,J＝7.8Hz,1H),7.19–7.09(m,1H),6.50(m,1H),6.32(d,J＝16.7Hz,1H),5.76(d,J＝10.6Hz,1H),5.54(m,1H),4.98(brs,0.5H),4.59(brs,0.5H),4.42–4.16(m,2H),4.16–3.48(m,9H),3.47–3.28(m,2H),3.29–2.87(m,5H),2.85–2.33(m,10H).
实施例16 2-(1-丙烯酰-4-(7-(8-氯萘-1-基)-2-(((反式)-2-(二甲基氨基)环戊基)氧)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000160
LCMS:m/z 600(M+H) +.
实施例17 2-(1-丙烯酰-4-(7-(8-氯萘-1-基)-2-(((顺式)-4-(二甲基氨基)四氢呋喃-3-基)氧)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000161
LCMS:m/z 602(M+H) +.
实施例18 2-(1-丙烯酰-4-(7-(8-氯萘-1-基)-2-(((反式)-4-(二甲基氨基)四氢呋喃-3-基)氧)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000162
LCMS:m/z 602(M+H) +.
实施例19 2-(1-丙烯酰-4-(7-(8-氯萘-1-基)-2-((3-((二甲基氨基)甲基)氧杂环丁烷-3-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000163
LCMS:m/z 616(M+H) +. 1H NMR(400MHz,CDCl 3)δ7.68(d,J＝8.1Hz,1H),7.54(dd,J＝7.8,4.8Hz,1H),7.45(d,J＝7.4Hz,1H),7.37(dd,J＝16.7,8.0Hz,1H),7.26(t,J＝7.8Hz,1H),7.15(dd,J＝15.9,7.3Hz,1H),6.52(m,1H),6.32(d,J＝16.7Hz,1H),5.75(d,J＝10.6Hz,1H),5.01(brs,0.5H),4.79–4.44(m,6.5H),4.35(m,1H),4.29–3.70(m,4H),3.47(m,2H),3.29–2.88(m,6H),2.89–2.60(m,2H),2.48(m,7H).
实施例20 2-(1-丙烯酰-4-(7-(8-氯萘-1-基)-2-((1-(甲氧基甲基)环丙基)甲氧基)-5,6,7,8-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000164
LCMS:m/z 587(M+H) +. 1H NMR(400MHz,CDCl 3)δ7.68(d,J＝8.2Hz,1H),7.54(t,J＝7.1Hz,1H),7.44(d,J＝7.4Hz,1H),7.36(dt,J＝11.9,7.8Hz,1H),7.26(t,J＝7.8Hz,1H),7.19–7.09(m,1H),6.61–6.43(m,1H),6.32(d,J＝16.7Hz,1H),5.75(d,J＝10.7Hz,1H),4.97(brs,0.5H),4.80–4.32(m,1.5H),4.23–3.97(m,4H),3.85(m,2H),3.71–3.25(m,8H),3.23–2.86(m,4H),2.77(m,1H),2.53(m,1H),0.65–0.44(m,4H).
实施例21 2-(1-丙烯酰-4-(2-(2-(环丁基(甲基)氨基)乙氧基)-7-(7-氟-8-甲基萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000165
LCMS:m/z 598(M+H) +. 1H NMR(400MHz,CDCl 3)δ7.67(m,2H),7.38(m,1H),7.22(m, 2H),6.57(m,1H),6.67(m,1H),5.86(d,J＝12Hz,1H),4.90(m,3H),4.57(m,1H),4.32(m,2H),4.12-3.86(m,3H),3.56(m,5H),3.19(m，3H)，3.00-2.88(m,1H),2.80-2.73(m,7H),2.57(m,2H),2.30(m,3H),1.96-1.74(m,2H)
实施例22 2-(4-(2-(2-(环丁基(甲基)氨基)乙氧基)-7-(7-氟-8-甲基萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000166
LCMS:m/z 616(M+H) +.1H NMR(400MHz,CDCl 3)δ7.77–7.46(m,3H),7.36(m,1H),7.24–7.18(m,1H),5.42(m,1H),5.24(m,1H),4.61(m,2H),4.07(m,5H),3.53(m,2H),3.35–2.73(m,11H),2.71–2.05(m,5H),1.71(m,3H),1.44(m,1H),1.30(m,3H).
实施例23 2-(1-丙烯酰-4-(7-(8-氯萘-1-基)-2-(2-(甲基(1-甲基环丁基)氨基)乙氧)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000167
LCMS:m/z 614(M+H) +. 1H NMR(400MHz,CDCl 3)δ7.66(t,J＝11.3Hz,1H),7.54(t,J＝7.3Hz,1H),7.45(d,J＝7.3Hz,1H),7.37(dt,J＝12.3,7.8Hz,1H),7.26(t,J＝7.8Hz,1H),7.19–7.09(m,1H),6.52(m,1H),6.31(d,J＝16.7Hz,1H),5.75(d,J＝10.5Hz,1H),4.99(brs,0.5H),4.70–4.20(m,3.5H),4.17–3.58(m,4H),3.57–3.27(m,2H),3.27–2.45(m,10H),2.45–2.08(m,4H),1.88–1.48(m,5H),1.16(m,2H).
实施例24 2-(1-丙烯酰-4-(7-(8-氯萘-1-基)-2-(2-(甲基(3-甲基氧杂环丁烷-3-基)氨基)乙氧)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000168
LCMS:m/z 616(M+H) +.
实施例25 2-(4-(7-(8-氯萘-1-基)-2-((3-((二甲基氨基)甲基)氧杂环丁烷-3-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000169
LCMS:m/z 634(M+H) +. 1H NMR(400MHz,CDCl 3)δ7.77(d,J＝8.1Hz,1H),7.63(dd,J＝7.8,5.0Hz,1H),7.54(d,J＝7.3Hz,1H),7.46(dd,J＝16.7,8.1Hz,1H),7.35(t,J＝7.8Hz,1H),7.24(dd,J＝16.3,7.5Hz,1H),5.43(m,1H),5.31–5.17(m,1H),4.90(brs,0.5H),4.80–4.51(m,6.5H),4.50–4.24(m,2H),4.20–3.79(m,3H),3.55(m,2H),3.35–2.75(m,8H),2.59(m,1H),2.30(s,6H).
实施例26 2-(1-丙烯酰-4-(7-(8-氯萘-1-基)-2-((1-((甲胺基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000170
第一步：叔丁基4-(2-((1-((叔丁氧羰基)(甲基)氨基)甲基)环丙基)甲氧基)-7-(8-氯萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸盐的制备
将4-(7-(8-氯萘-1-基)-2-(甲基亚砜基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(155mg，0.267mmol)加入反应瓶中，依次加入甲苯(1.5mL)、叔丁基((1-(羟甲基)环丙基)甲基)(甲基)氨基甲酸酯(115mg，0.533mmol)和叔丁醇钠(77mg，0.800mmol)。反应液在冰水浴下搅拌0.5h，然后加入水(50mL)淬灭后用乙酸乙酯萃取(30mL x 3)。合并的有机相用饱和氯化钠溶液洗一次，再由无水硫酸钠干燥后过滤。滤液浓缩，然后用TLC板分离(洗脱剂：EA/PE＝1.5/1)得到目标化合物(210mg，收率97％)。
LC-MS:m/z 732.7(M+H) +。
第二步：2-(4-(7-(8-氯萘-1-基)-2-((1-((甲胺基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
将叔丁基4-(2-((1-((叔丁氧羰基)(甲基)氨基)甲基)环丙基)甲氧基)-7-(8-氯萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸盐(210mg,0.287mmol)溶于 二氯甲烷(4mL)中，加入三氟乙酸(2mL)。反应液在室温搅拌0.5h，然后浓缩干得到目标化合物(粗产品150mg)，无需纯化直接用于下一步反应。
LC-MS:m/z 532.4(M+H) +。
第三步：叔丁基((1-((7-(8-氯萘-1-基)-4-(3-(氰基甲基)哌嗪-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-2-基)氧基)甲基)环丙基)甲基)(甲基)氨基甲酸酯的制备
将上一步得到的2-(4-(7-(8-氯萘-1-基)-2-((1-((甲胺基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈(150mg)加入反应瓶中，依次加入二氯甲烷(4mL)和N,N-二异丙基乙胺(364mg，2.82mmol)。将反应液降温至0℃，慢慢滴加二碳酸二叔丁酯(49mg，0.226mmol)。得到的混合物在冰水浴下搅拌1h，然后加入水(50mL)后用乙酸乙酯萃取(30mL x 3)。合并的有机相用饱和氯化钠溶液洗一次，然后用无水硫酸钠干燥后过滤。滤液浓缩干得到目标化合物(粗产品150mg)，无需纯化直接用于下一步反应。
LC-MS:m/z 632.6(M+H) +。
第四步：叔丁基((1-((4-(4-丙烯酰-3-(氰甲基)哌嗪-1-基)-7-(8-氯萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-2-基)氧基)甲基)环丙基)甲基)(甲基)氨基甲酸酯的制备
将上一步得到的叔丁基((1-((7-(8-氯萘-1-基)-4-(3-(氰基甲基)哌嗪-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-2-基)氧基)甲基)环丙基)甲基)(甲基)氨基甲酸酯(150mg)中加入二氯甲烷(5mL)和N,N-二异丙基乙胺(200mg，1.55mmol)。反应液在氮气保护，降温至-40℃，随后滴加丙烯酰氯(60mg，0.663mmol)。加完后反应液升至室温搅拌1h，然后加入甲醇(1mL)淬灭。得到的混合物浓缩干，然后用TLC板分离(洗脱剂：EA/PE＝3/2)得到目标化合物(80mg)。
LC-MS:m/z 686.9(M+H) +。
第五步：2-(1-丙烯酰-4-(7-(8-氯萘-1-基)-2-((1-((甲胺基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
将叔丁基((1-((4-(4-丙烯酰-3-(氰甲基)哌嗪-1-基)-7-(8-氯萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-2-基)氧基)甲基)环丙基)甲基)(甲基)氨基甲酸酯(80mg，0.117mmol)中加入乙酸乙酯(2mL)和盐酸的乙酸乙酯溶液(4N，4mL)。加完后反应液在室温搅拌0.5h，然后加入饱和碳酸氢钠溶液(10mL)摧灭后用乙酸乙酯萃取(30mL x 3)。合并的有机相用饱和氯化钠溶液洗一次，然后用无水硫酸钠干燥后过滤。滤液浓缩后用液相制备得到目标产物(20mg，产率：29％)。
LC-MS:m/z 586.6(M+H) +. 1H NMR(400MHz,CDCl 3)δ7.76(d,J＝8.4Hz,1H),7.62(t,J＝6.8Hz,1H),7.52(d,J＝7.6Hz,1H),7.48–7.41(m,1H),7.33(t,J＝8.0Hz,1H),7.24–7.19(m,1H),6.64–6.53(m,1H),6.41–6.37(m,1H),5.82(d,J＝10.4Hz,1H),5.11–4.96(brs,0.5H),4.67–4.56(brs,0.5H),4.39(dd,J＝15.2,2.8Hz,1H),4.28–4.20(m,2H),4.12–3.78(m,4H),3.61–3.57(m,1H),3.48–3.35(m,1H),3.26–3.01(m,4H),2.88–2.73(m,4H),2.62–2.50(m,5H),0.71–0.60(m,4H).
实施例27 (S)-2-(4-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000171
第一步：(S)-4-(7-苄基-2-(甲硫基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-2-(氰基甲基)哌嗪-1-甲酸叔丁酯的制备
将7-苄基-4-氯-2-(甲硫基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶(7.0g，22.89mmol)、(S)-2-(哌嗪-2-基)乙腈二盐酸盐(5.44g，27.47mmol)、N,N-二异丙基乙胺(22.8mL，137.34mmol)和DMSO加入反应瓶中。反应液在氮气保护下，加热至80℃搅拌3h，然后加入二碳酸二叔丁酯(26.3mL，114.45mmol)。待反应结束后，反应液用水淬灭，然后用乙酸乙酯萃取(3 x 100mL)。所有有机相合并以后，用饱和氯化钠洗一次，然后经无水硫酸钠干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析纯化，得到目标产物(8.0g，收率71％)。
LC-MS：m/z 495(M+H) +。
第二步：(S)-2-(氰基甲基)-4-(2-(甲硫基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯的制备
将(S)-4-(7-苄基-2-(甲硫基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-2-(氰基甲基)哌嗪-1-甲酸叔丁酯(7.5g，15.2mmol)、DIPEA(5.9g，45.6mmol)和DCM(150mL)加入反应瓶中，降温至0℃,随后滴加1-氯乙基氯甲酸酯(4.4g，30.4mmol)。滴加完毕反应液在15℃搅拌3h，随后减压浓缩干。残余物加入甲醇(150mL)，随后在70℃搅拌1.5h。反应结束后，反应液浓缩，随后加入饱和碳酸氢钠溶液(50mL)，再用乙酸乙酯萃取(3 x 25mL)。合并的有机相用饱和氯化钠溶液洗一次，再无水硫酸钠干燥后过滤，滤液浓缩后用中压制备柱分离得到目标产物(2.25g，收率36.9％)。
LC-MS：m/z 405(M+H) +。
第三步：(S)-4-(7-(8-氯萘-1-基)-2-(甲硫基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-2-(氰甲基)哌嗪-1-甲酸叔丁酯的制备
将(S)-2-(氰基甲基)-4-(2-(甲硫基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯(4.50g，11.12mmol)、1-溴-8-氯萘(3.22g，13.35mmol)、碳酸铯(10.87g，33.36mmol)和二氧六环(90mL)加入反应瓶中，氮气置换三次后加入Ruphos G3pd(2.79g，3.34mmol)，再氮气置 换三次后加热至72℃搅拌16h。反应结束后加入水(100mL)，然后用乙酸乙酯萃取(3 x 100mL)。合并的有机相，用饱和氯化钠溶液(100mL)洗一次，无水硫酸钠干燥后过滤。滤液浓缩后用柱层析分离(EA/PE＝0to 20％)得到目标产物(2.4g,收率38.7％)。
LC-MS：m/z 565(M+H) +。
第四步：(2S)-4-(7-(8-氯萘-1-基)-2-(甲砜基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-2-(氰甲基)哌嗪-1-甲酸叔丁酯的制备
将(S)-4-(7-(8-氯萘-1-基)-2-(甲硫基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-2-(氰甲基)哌嗪-1-甲酸叔丁酯(2.32g，4.12mmol)溶于乙酸乙酯(45mL)中，用冰盐浴降温至0℃，随后滴加间氯过氧苯甲酸(1.71g，9.89mmol)的乙酸乙酯溶液(15mL)。加完后反应液保持温度搅拌10min，随后用饱和低亚硫酸钠溶液(100mL)淬灭，再加入水(50mL)稀释后，用乙酸乙酯萃取(3 x 50mL)。合并的有机相，用饱和氯化钠溶液(50mL)洗一次，再用无水硫酸钠干燥后过滤。滤液浓缩后用柱层析分离(EA/PE＝0to 100％)得到目标产物(1.2g，收率51％)。
LC-MS：m/z 581(M+H) +。
第五步：(S)-4-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-2-(氰甲基)哌嗪-1-甲酸叔丁酯的制备
将(2S)-4-(7-(8-氯萘-1-基)-2-(甲砜基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-2-(氰甲基)哌嗪-1-甲酸叔丁酯(1.16g，2.00mmol)加入反应瓶中，依次加入甲苯(12mL)和(1-((二甲基氨基)甲基)环丙基)甲醇(517mg，4.00mmol)，随后在冰水浴搅拌下加入叔丁醇钠(577mg，6.00mmol)。得到的反应液在冰水浴下搅拌0.5h，随后加入水(100mL)淬灭后用乙酸乙酯萃取(3 x 50mL)。合并的有机相，用饱和氯化钠溶液洗一次，再用无水硫酸钠干燥后过滤。滤液浓缩后用中压制备柱分离后得到目标产物(730mg，产率60％)。
LC-MS：m/z 646(M+H) +。
第六步：(S)-2-(4-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
将(S)-4-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-2-(氰甲基)哌嗪-1-甲酸叔丁酯(678mg，1.05mmol)加入反应瓶中，依次加入DCM(5mL)及三氟乙酸(5mL)，然后在室温搅拌2h。反应结束后，反应液浓缩然后用饱和碳酸氢钠水溶液调节pH为8，然后用乙酸乙酯萃取(3 x 50mL)。合并的有机相用饱和氯化钠水溶液洗一次，然后用无水硫酸钠干燥后过滤。滤液浓缩干得到粗品。无需进一步纯化，直接用于下一步反应。
LC-MS：m/z 546(M+H) +。
第七步：(S)-2-(4-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的制备
将上一步得到的(S)-2-(4-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈粗品加入到DMF(12mL)中，随后依次加入DIPEA(1.40g，10.80mmol)、2-氟丙烯酸(575mg，6.38mmol)、及HATU(2.05g，5.4mmol)。反应液在氮气保护下搅拌0.5h，然后加入水(100mL)淬灭，然后用乙酸乙酯(3 x 60mL)萃取。合并的有机相用饱和氯化钠溶液洗4次，然后用无水硫酸钠干燥后过滤。滤液浓缩后制备色谱分离得到目标产物(162mg，两步产率25％)。
LC-MS：m/z 618(M+H) +。 1H NMR(400MHz,DMSO)δ7.92(d,J＝8.1Hz,1H),7.74(dd, J＝7.9,3.3Hz,1H),7.55(m,2H),7.45(t,J＝7.8Hz,1H),7.33(m,1H),5.33(m,2H),4.86(brs,1H),4.26–3.65(m,8H),3.57–3.43(m,2H),3.26–2.60(m,7H),2.37–2.05(m,7H),0.58(s,2H),0.39(s,2H).
按照实施例27的方法以不同的起始原料合成了实施例28：
实施例28 (S)-2-(4-(7-(8-氯-7-氟萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000172
LC-MS：m/z 636(M+H) +。 1H NMR(400MHz,DMSO)δ8.02(dd,J＝8.9,5.9Hz,1H),7.79(dd,J＝7.8,2.7Hz,1H),7.65–7.49(m,2H),7.42(m,1H),5.50–5.16(m,2H),4.87(brs,1H),4.27–3.66(m,7H),3.55–3.43(m,2H),3.28–2.62(m,7H),2.33–2.06(m,8H),0.57(s,2H),0.40(s,2H).
实施例29 2-(1-丙烯酰基-4-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-6-甲基-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000173
LC-MS:m/z 614(M+H) +。
实施例29经手性拆分得到四个异构体实施例29A、29B、29C及29D
Figure PCTCN2020138142-appb-000174
异构体29A:LC-MS:m/z 614(M+H) +； 1HNMR(CDCl 3)7.76(d,J＝7.2Hz,1H),7.70(d,J＝8.0Hz,0.6H),7.58(d,J＝8.0Hz,0.4H),7.54–7.42(m,2H),7.34–7.31(m,2H),6.66–6.53(m,1H),6.41–6.36(m,1H),5.83–5.80(m,1H),5.13–5.02(m,0.5H),4.66–4.50(m,0.5H),4.36–4.32(m,1H),4.21–4.13(m,2H),4.05–3.87(m,3H),3.68–3.62(m,1H),3.45–2.97(m,4H),2.87–2.76(m,2H),2.60–2.56(m,1H),2.35–2.20(m,9H),1.08(d,J＝6.0Hz,2.5H),0.80(d,J＝6.4Hz,0.5H),0.69–0.59(m,2H),0.47–0.41(m,2H).
异构体29B:LC-MS:m/z 614(M+H) +； 1HNMR(CDCl 3)7.75(d,J＝8.4Hz,1H),7.67(d,J＝8.0Hz,0.6H),7.58(d,J＝8.0Hz,0.4H),7.54–7.50(m,1H),7.45(t,J＝7.6Hz,1H),7.34–7.31(m,2H),6.66–6.53(m,1H),6.41–6.35(m,1H),5.82–5.80(m,1H),5.11–5.02(m,0.5H), 4.65–4.53(m,0.5H),4.43–3.94(m,7H),3.85–3.74(m,1H),3.48–3.44(m,1H),3.25–2.72(m,14H),1.13(d,J＝6.4Hz,2H),0.93–0.86(m,2H),0.81–0.72(m,3H).
异构体29C:LC-MS:m/z 614(M+H) +； 1HNMR(CDCl 3)7.75(d,J＝8.0Hz,1H),7.68(d,J＝8.0Hz,1H),7.58(d,J＝8.4Hz,0.4H),7.54–7.49(m,1H),7.44(t,J＝7.6Hz,1H),7.33(td,J＝7.6,2.0Hz,1H),7.25–7.21(m,1H),6.64–6.53(m,1H),6.41–6.36(m,1H),5.82–5.79(m,1H),5.11–5.01(m,0.5H),4.71–4.53(m,0.5H),4.41–3.72(m,8H),3.50–3.43(m,1H),3.23–2.33(m,14H),1.13(d,J＝6.4Hz,2.5H),0.80–0.79(m,2.5H),0.68–0.56(m,2H).
异构体29D:LC-MS:m/z 614(M+H) +； 1HNMR(CDCl 3)7.76(d,J＝7.6Hz,1H),7.70(d,J＝7.6Hz,1H),7.58(d,J＝8.0Hz,1H),7.54–7.42(m,2H),7.34–7.30(m,2H),6.56–6.54(m,1H),6.39–6.35(m,1H),5.79(d,J＝10.4Hz,1H),5.15–5.07(m,0.5H),4.69–4.59(m,0.5H),4.43–3.93(m,8H),3.72–3.65(m,1H),3.44–2.76(m,13H),2.62–2.58(m,1H),1.09(d,J＝6.0Hz,2.5H),0.96–0.90(m,2H),20.83–0.75(m,2.5H).
实施例30 2-(1-丙烯酰-4-(7-(8-氯萘-1-基)-2-((1-(二甲基氨基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000175
LC-MS:m/z 586(M+H) +； 1H NMR(400MHz,CDCl 3)δ7.69(d,J＝8.1Hz,1H),7.55(t,J＝7.1Hz,1H),7.47–7.33(m,2H),7.26(t,J＝7.8Hz,1H),7.18–7.09(m,1H),6.50(m,1H),6.32(d,J＝16.7Hz,1H),5.75(d,J＝10.4Hz,1H),5.01(brs,0.5H),4.51(brs,0.5H),4.33(m,3H),4.21–3.69(m,4H),3.67–2.86(m,7H),2.76(m,2H),2.54(s,6H),0.90(s,2H),0.75(s,2H).
实施例31 2-(丙烯酰-4-(7-(8-氯萘-1-基)-2-(2-((1-(甲氧基甲基)环丁基)(甲基)氨基)乙氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000176
LC-MS:m/z 644(M+H) +； 1H NMR(400MHz,CDCl 3)δ7.68(d,J＝8.1Hz,1H),7.54(t,J＝7.2Hz,1H),7.45(d,J＝7.4Hz,1H),7.37(m,1H),7.26(t,J＝7.8Hz,1H),7.15(m,1H),6.51(m,1H),6.31(d,J＝16.7Hz,1H),5.75(d,J＝10.4Hz,1H),5.27(brs,0.5H),4.99(brs,0.5H),4.29(m,3H),4.17–3.68(m,4H),3.67–3.33(m,5H),3.32–3.24(m,3H),3.23–2.86(m,7H),2.83–2.42(m,4H),2.37(m,3H),2.04(m,2H),1.35(t,J＝8.6Hz,4H).
实施例32 2-(1-丙烯酰-4-(7-(8-氯萘-1-基)-2-((3-((环丙基(甲基)氨基)甲基)氧杂环丁烷-3-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000177
LC-MS:m/z 642(M+H) +； 1H NMR(400MHz,CDCl 3)δ7.77(d,J＝8.2Hz,1H),7.70–7.59(m,1H),7.54(d,J＝7.4Hz,1H),7.46(dt,J＝10.1,7.8Hz,1H),7.35(t,J＝7.8Hz,1H),7.27–7.19(m,1H),6.61(m,1H),6.41(d,J＝16.7Hz,1H),5.85(d,J＝10.4Hz,1H),5.11(brs,0.5H),4.78–4.35(m,7.5H),4.30–3.81(m,4H),3.81–3.36(m,3H),3.18(m,7H),2.74(m,3H),2.24(s,2H),0.40(s,2H),0.27(s,2H).
实施例33 2-(4-(7-(8-氯-7-氟萘-1-基)-2-(2-(甲基(1-甲基环丁基)氨基)乙氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000178
LC-MS:m/z 650(M+H) +； 1H NMR(400MHz,CDCl 3)δ7.61(m,1H),7.48(t,J＝7.2Hz,1H),7.30(m,1H),7.24–7.16(m,1H),7.12(d,J＝7.5Hz,1H),5.29(d,J＝47.3Hz,1H),5.11(dt,J＝21.5,10.7Hz,1H),4.68(brs,0.5H),4.24(m,3.5H),4.11–3.61(m,4H),3.52–3.21(m,2H),3.19–2.83(m,4H),2.82–2.35(m,5H),2.20–1.91(m,5H),1.57(m,4H),1.03(s,3H).
实施例34 1-((2S,5R)-4-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-基)丙-2-烯-1-酮的制备
Figure PCTCN2020138142-appb-000179
LC-MS:m/z 589(M+H) +； 1H NMR(400MHz,DMSO)δ9.46(brs,1H),7.94(d,J＝8.2Hz,1H),7.69(m,1H),7.56(m,2H),7.47(t,J＝7.8Hz,1H),7.40–7.26(m,1H),6.80(m,1H),6.17(m,1H),5.74(m,1H),5.44–3.88(m,7H),3.88–3.28(m,4H),3.28–3.00(m,4H),2.93–2.71(m,7H),1.36–0.99(m,6H),0.81(m,4H).
实施例35 (S)-2-(4-(2-((1-((二甲基氨基)甲基)环丙基)甲氧基-7-(5-甲基-1H-吲唑-4-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000180
LC-MS:m/z 588(M+H) +； 1H NMR(400MHz,CDCl 3)δ10.50(brs,1H),8.09(s,1H),7.45–7.08(m,2H),5.42(d,J＝47.6Hz,1H),5.32–5.18(m,1H),4.92(brs,1H),4.30(m,4H),4.20(m,1H),3.99(m,1H),3.53(t,J＝5.1Hz,2H),3.33(d,J＝12.3Hz,1H),3.21–2.94(m,2H),2.81(m,4H),2.71–2.30(m,11H),0.77(s,2H),0.59(s,2H).
实施例36 (S)-2-(4-(2-((1-((双(甲基-d3)氨基)甲基)环丙基)甲氧基)-7-(5-甲基-1H-吲唑-4-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000181
LC-MS:m/z 594(M+H) +； 1H NMR(400MHz,CDCl 3)δ10.35(brs,1H),8.00(d,J＝13.6Hz,1H),7.31–6.99(m,2H),5.33(d,J＝46.7Hz,1H),5.17(dd,J＝16.9,3.5Hz,1H),4.79(brs,1H),4.33–3.82(m,8H),3.42(m,2H),3.25(m,1H),2.98(m,2H),2.85–2.45(m,5H),2.33(s,3H),0.72(s,2H),0.54(s,2H).
实施例37 1-((1R,5S)-3-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)丙-2-烯-1-酮的制备
Figure PCTCN2020138142-appb-000182
LC-MS:m/z 587(M+H) +； 1H NMR(400MHz,DMSO)δ7.92(d,J＝7.4Hz,1H),7.74(d,J＝7.9Hz,1H),7.58(d,J＝6.5Hz,1H),7.53(t,J＝7.8Hz,1H),7.45(t,J＝7.8Hz,1H),7.33(d,J＝7.5Hz,1H),6.83–6.69(m,1H),6.21(d,J＝16.6Hz,1H),5.73(d,J＝9.5Hz,1H),4.65(m,2H),4.11(m,4H),3.80–3.61(m,2H),3.48(d,J＝10.6Hz,1H),3.28–2.78(m,3H),1.97(m,6H),1.26(m,8H),0.58(s,2H),0.39(s,2H).
实施例38 1-(5-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)六氢吡咯[3,4-c]吡咯基-2(1H)-yl)丙-2-烯-1-酮的制备
Figure PCTCN2020138142-appb-000183
LC-MS:m/z 587(M+H) +； 1H NMR(400MHz,DMSO)δ7.91(d,J＝7.8Hz,1H),7.72(d,J＝8.1Hz,1H),7.61–7.49(m,2H),7.44(t,J＝7.8Hz,1H),7.31(d,J＝7.5Hz,1H),6.56(ddd,J＝16.8,10.3,6.4Hz,1H),6.13(d,J＝16.7Hz,1H),5.66(dd,J＝12.5,2.3Hz,1H),4.14–3.41(m,11H),3.24(m,2H),3.09–2.75(m,5H),2.12(m,8H),0.55(s,2H),0.35(s,2H).
实施例39 1-(7-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡 啶[3,4-d]嘧啶-4-基)-4,7-二氮杂螺[2.5]辛烷-4-基)丙-2-烯-1-酮的制备
Figure PCTCN2020138142-appb-000184
LC-MS:m/z 587(M+H) +； 1H NMR(400MHz,DMSO)δ7.92(d,J＝7.4Hz,1H),7.74(d,J＝7.9Hz,1H),7.61–7.49(m,2H),7.45(t,J＝7.8Hz,1H),7.32(d,J＝7.0Hz,1H),6.88(m,1H),6.14(dd,J＝16.8,2.2Hz,1H),5.73(d,J＝10.4Hz,1H),4.16(d,J＝17.4Hz,1H),4.05(s,2H),3.70(m,3H),3.49(m,2H),3.21–2.96(m,2H),2.16(m,7H),2.00(m,1H),1.23(m,4H),0.96(m,4H),0.56(t,J＝4.7Hz,2H),0.36(t,J＝4.9Hz,2H).
实施例40 1-(6-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-2,6-二氮杂螺[3.3]庚烷-2-基)丙-2-烯-1-酮的制备
Figure PCTCN2020138142-appb-000185
LC-MS:m/z 573(M+H) +； 1H NMR(400MHz,DMSO)δ7.91(d,J＝7.4Hz,1H),7.72(d,J＝7.9Hz,1H),7.60–7.48(m,2H),7.44(t,J＝7.8Hz,1H),7.31(d,J＝7.2Hz,1H),6.29(dd,J＝17.0,10.3Hz,1H),6.10(dd,J＝17.0,2.2Hz,1H),5.67(dd,J＝10.3,2.2Hz,1H),4.50–4.26(m,6H),4.16–3.91(m,5H),3.68(d,J＝16.8Hz,1H),3.47(d,J＝10.6Hz,1H),3.17–2.88(m,2H),2.58(d,J＝14.9Hz,1H),2.55–2.45(m,1H),2.25–2.07(m,7H),0.62–0.47(m,2H),0.35(t,J＝4.9Hz,2H).
实施例41 1-(4-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-2-(三氟甲基)哌嗪-1-基)丙-2-烯-1-酮的制备
Figure PCTCN2020138142-appb-000186
LC-MS:m/z 629(M+H) +； 1H NMR(400MHz,DMSO)δ7.92(d,J＝8.0Hz,1H),7.74(t,J＝9.7Hz,1H),7.61–7.23(m,4H),6.88(dd,J＝16.8,10.4Hz,1H),6.25(t,J＝16.6Hz,1H),5.90–5.77(m,1H),5.49–5.15(m,1H),4.57–3.39(m,9H),2.94(m,5H),2.24–2.06(m,8H),0.57(s,2H),0.37(d,J＝4.6Hz,2H).
实施例42 1-(5-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)丙-2-烯-1-酮的制备
Figure PCTCN2020138142-appb-000187
LC-MS:m/z 573(M+H) +； 1H NMR(400MHz,DMSO)δ7.90(dd,J＝7.7,4.1Hz,1H),7.71(dd,J＝13.9,8.1Hz,1H),7.59–7.21(m,4H),6.74(dt,J＝18.3,9.2Hz,1H),6.44(m,1H),6.15(dd,J＝18.6,1.9Hz,1H),5.67(dd,J＝10.2,2.3Hz,1H),5.18–4.78(m,2H),4.16–3.38(m,8H),3.25–2.55(m,3H),2.19(m,8H),2.07–1.76(m,2H),0.56(s,2H),0.36(s,2H).
实施例43 1-(5-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)丙-2-烯-1-酮的制备
Figure PCTCN2020138142-appb-000188
LC-MS:m/z 587(M+H) +； 1H NMR(400MHz,DMSO)δ7.91(d,J＝8.1Hz,1H),7.73(d,J＝8.0Hz,1H),7.61–7.49(m,2H),7.44(td,J＝7.8,2.3Hz,1H),7.32(t,J＝8.3Hz,1H),6.85–6.53(m,1H),6.27–6.06(m,1H),5.71(m,1H),4.60(m,2H),4.20–3.38(m,8H),2.97(m,5H),2.01(m,8H),0.54(m,4H).
实施例44 1-(6-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-2-基)丙-2-烯-1-酮的制备
Figure PCTCN2020138142-appb-000189
LC-MS:m/z 587(M+H) +； 1H NMR(400MHz,DMSO)δ7.91(d,J＝8.0Hz,1H),7.72(d,J＝8.1Hz,1H),7.60–7.38(m,3H),7.32(d,J＝7.4Hz,1H),6.31(m,1H),6.11(dd,J＝17.0,2.0Hz,1H),5.67(d,J＝10.3Hz,1H),4.36–3.80(m,9H),3.80–3.59(m,3H),3.46(s,1H),3.24(m,1H),3.04(dm,1H),2.82(m,1H),2.36–1.91(m,10H),0.47(m,4H).
实施例45 (S)-2-(4-(2-((1-((双(甲基-d3)氨基)甲基)环丙基)甲氧基)-7-(8-氯萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000190
LC-MS:m/z 624(M+H) +； 1H NMR(400MHz,CDCl 3)δ7.68(d,J＝8.1Hz,1H),7.54(t,J＝6.9Hz,1H),7.44(d,J＝7.4Hz,1H),7.37(dt,J＝11.2,7.8Hz,1H),7.26(t,J＝7.8Hz,1H),7.14(dd,J＝19.3,7.4Hz,1H),5.33(d,J＝48.0Hz,1H),5.15(dt,J＝24.2,12.1Hz,1H),4.84(brs,1H),4.48–3.69(m,6H),3.59–3.24(m,2H),3.23–2.68(m,5H),2.62–2.33(m,3H),1.23(m,2H),0.65(s,2H),0.47(s,2H).
实施例46 (S)-2-(4-(7-(8-氯萘-1-基)-2-((3-(甲氧基甲基)-1-甲基氮杂环丁胺-3-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000191
LC-MS:m/z 634(M+H) +； 1H NMR(400MHz,CDCl 3)δ7.68(d,J＝8.1Hz,1H),7.55(dd,J＝7.8,4.7Hz,1H),7.45(d,J＝7.4Hz,1H),7.37(dd,J＝17.0,7.9Hz,1H),7.26(t,J＝7.8Hz,1H),7.15(dd,J＝16.1,7.5Hz,1H),5.34(d,J＝47.8Hz,1H),5.18(dd,J＝16.8,3.3Hz,1H),4.80(brs,1H),4.57–3.45(m,16H),3.00(m,8H),2.47(m,2H),1.28–1.14(m,2H).
实施例47 2-((2S)-4-(7-(8-氯萘-1-基)-2-((1-(1-(二甲基氨基)乙基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000192
LC-MS:m/z 632(M+H) +； 1H NMR(400MHz,DMSO)δ7.93(d,J＝8.1Hz,1H),7.75(dd,J＝8.1,3.0Hz,1H),7.56(m,2H),7.46(t,J＝7.8Hz,1H),7.35(dd,J＝14.8,7.4Hz,1H),5.40(m,2H),5.22(brs,1H),4.97–4.45(m,2H),4.33–3.40(m,7H),3.01(m,8H),2.20(s,6H),1.28–0.92(m,3H),0.70–0.34(m,4H).
实施例47经手性拆分得到两个异构体实施例47A、47B
Figure PCTCN2020138142-appb-000193
实施例47A：LC-MS:m/z 632(M+H) +； 1H NMR(400MHz,DMSO)δ7.92(d,J＝8.1Hz,1H),7.74(dd,J＝7.9,3.3Hz,1H),7.62–7.49(m,2H),7.45(t,J＝7.8Hz,1H),7.34(dd,J＝14.8,7.5Hz,1H),5.51–5.11(m,2H),4.86(brs,1H),3.91(m,9H),3.25–2.65(m,8H),2.21(s,6H),1.22(m,3H),0.69–0.31(m,4H).
实施例47B：LC-MS:m/z 632(M+H) +； 1H NMR(400MHz,DMSO)δ7.92(d,J＝8.1Hz,1H),7.74(dd,J＝8.0,3.3Hz,1H),7.55(dt,J＝22.4,7.5Hz,2H),7.45(t,J＝7.8Hz,1H),7.34(dd,J＝14.9,7.3Hz,1H),5.34(m,2H),4.86(brs,1H),4.29–3.43(m,9H),3.26–2.63(m,8H),2.28(s,6H),1.29–1.20(m,3H),0.72–0.30(m,4H).
实施例48 (S)-2-(4-(2-((1-(氮杂环丁胺-1-基甲基)环丙基)甲氧基)-7-(8-氯萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000194
LC-MS:m/z 630(M+H) +； 1H NMR(400MHz,CDCl 3)δ7.68(d,J＝8.2Hz,1H),7.54(t,J＝7.1Hz,1H),7.44(d,J＝7.4Hz,1H),7.37(dt,J＝11.9,7.8Hz,1H),7.26(t,J＝7.8Hz,1H),7.15(dd,J＝20.9,7.3Hz,1H),5.34(d,J＝48.3Hz,1H),5.16(dt,J＝23.4,11.7Hz,1H),4.81(brs,0.5H),4.43–1.99(m,21.5H),1.22(m,3H),0.52(m,4H).
实施例49 (S)-2-(1-(丁-2-炔酰基)-4-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000195
LC-MS:m/z 612(M+H) +； 1H NMR(400MHz,DMSO)δ7.93(d,J＝8.1Hz,1H),7.75(dd,J＝7.9,3.2Hz,1H),7.62–7.50(m,2H),7.46(t,J＝7.8Hz,1H),7.34(dd,J＝14.5,7.3Hz,1H),4.89(s,1H),4.38–3.43(m,9H),3.26–2.64(m,8H),2.23(m,7H),2.13–1.96(m,3H),0.59(s,2H),0.40(s,2H).
实施例50 (S)-1-(4-(7-(8-氯萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-3-甲基哌嗪-1-基)丙-2-烯-1-酮的制备
Figure PCTCN2020138142-appb-000196
LC-MS:m/z 575(M+H) +； 1H NMR(400MHz,DMSO)δ7.92(d,J＝8.1Hz,1H),7.74(d,J＝8.2Hz,1H),7.62–7.51(m,2H),7.45(t,J＝7.8Hz,1H),7.33(t,J＝6.5Hz,1H),6.95–6.74(m,1H),6.17(dd,J＝16.5,6.7Hz,1H),5.73(d,J＝11.4Hz,1H),4.49–3.41(m,10H),3.28–2.80(m,4H),2.17(m,8H),1.34–1.15(m,2H),1.13–0.93(m,2H),0.57(s,2H),0.39(s,2H).
实施例51 (S)-2-(4-(7-(8-氯萘-1-基)-2-((1-((二甲氨基甲基)甲基-d2)环丙基)甲氧基-d2)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000197
LC-MS:m/z 622(M+H) +； 1H NMR(400MHz,DMSO)δ7.91(t,J＝8.5Hz,1H),7.74(dd,J＝7.8,3.3Hz,1H),7.62–7.40(m,3H),7.33(dd,J＝15.0,7.1Hz,1H),5.46–5.16(m,2H),4.86(brs,1H),4.29–3.44(m,8H),3.26–2.58(m,6H),2.17(s,6H),0.57(s,2H),0.38(s,2H).
实施例52 (S)-2-(4-(7-(8-氯萘-1-基)-2-((1-(2-(二甲基氨基)乙基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000198
LC-MS:m/z 632(M+H) +； 1H NMR(400MHz,DMSO)δ7.92(d,J＝8.0Hz,1H),7.74(dd,J＝7.9,3.4Hz,1H),7.54(dt,J＝21.4,6.9Hz,2H),7.45(t,J＝7.8Hz,1H),7.34(dd,J＝14.5,7.2Hz,1H),5.49–5.12(m,2H),4.84(brs,1H),4.32–3.46(m,8H),3.29–2.62(m,8H),2.37(m,2H),2.14(s,6H),1.62–1.44(m,2H),0.48(s,2H),0.42(s,2H).
实施例53 2-((2S)-4-(7-(8-氯萘-1-基)-2-(1-(1-((二甲基氨基)乙基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000199
LC-MS:m/z 632(M+H) +.
实施例53经手性拆分得到两个异构体实施例53A、53B
Figure PCTCN2020138142-appb-000200
实施例53A LC-MS:m/z 632(M+H) +； 1H NMR(400MHz,DMSO)δ7.93(d,J＝7.3Hz,1H),7.75(d,J＝8.2Hz,1H),7.48(m,4H),5.45–5.18(m,3H),4.87(brs,1H),3.90(m,8H),3.04(m,9H),2.33–1.80(m,8H),0.59(d,J＝6.1Hz,2H),0.28(m,2H).
实施例53B LC-MS:m/z 632(M+H) +； 1H NMR(400MHz,DMSO)δ7.93(d,J＝8.2Hz,1H),7.75(dd,J＝7.8,5.0Hz,1H),7.62–7.31(m,4H),5.52–5.13(m,3H),4.87(brs,1H),4.31–3.44(m,8H),3.27–2.60(m,9H),2.40–1.91(m,8H),0.63(m,2H),0.33(m,2H).
实施例54 (S)-2-(4-(7-(8-氯萘-1-基)-2-((1-((乙基(甲基)氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000201
LC-MS:m/z 632(M+H) +. 1H NMR(400MHz,DMSO)δ7.92(d,J＝8.1Hz,1H),7.74(dd,J＝7.8,3.2Hz,1H),7.55(dt,J＝22.3,7.5Hz,2H),7.45(t,J＝7.8Hz,1H),7.34(dd,J＝14.6,7.0Hz,1H),5.39(dd,J＝18.0,4.0Hz,1H),5.35–5.13(m,1H),4.86(brs,1H),4.28–3.43(m,9H),3.28–2.60(m,7H),2.23(m,7H),0.94(m,3H),0.57(s,2H),0.39(s,2H).
实施例55 (S)-2-(4-(2-(2-(双环[1.1.1]戊烷-1-基(甲基)氨基)乙氧基)-7-(8-氯萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000202
LC-MS:m/z 630(M+H) +. 1H NMR(400MHz,DMSO)δ7.92(d,J＝8.0Hz,1H),7.74(dd,J＝7.9,3.4Hz,1H),7.55(dt,J＝15.1,7.4Hz,2H),7.45(t,J＝7.8Hz,1H),7.34(dd,J＝15.0,7.3Hz,1H),5.39(dd,J＝18.0,4.0Hz,1H),5.28(d,J＝49.5Hz,1H),4.86(brs,1H),4.37–3.42(m,9H),3.28–2.84(m,6H),2.55–2.45(m,3H),2.35(s,1H),2.19(s,3H),1.71(s,6H).
实施例56 (S)-2-(4-(7-(8-氯萘-1-基)-2-((1-((异丙基(甲基)氨基)甲基)环丙基)甲氧基-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000203
LC-MS:m/z 646(M+H) +. 1H NMR(400MHz,DMSO)δ7.92(d,J＝8.0Hz,1H),7.74(dd,J＝7.9,3.1Hz,1H),7.55(dt,J＝14.5,7.5Hz,2H),7.45(t,J＝7.8Hz,1H),7.34(dd,J＝14.1,7.1Hz,1H),5.38(dt,J＝10.1,5.1Hz,1H),5.27(d,J＝49.9Hz,1H),4.86(brs,1H),4.24–3.42(m,9H),3.26–2.62(m,8H),2.33(s,2H),2.11(m 3H),0.89(d,J＝4.7Hz,6H),0.54(s,2H),0.37(s,2H).
实施例57 (S)-2-(4-(7-(8-氯萘-1-基)-2-((1-((甲砜基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000204
LC-MS:m/z 653(M+H) +. 1H NMR(400MHz,DMSO)δ7.92(d,J＝8.0Hz,1H),7.74(dd,J＝7.9,3.0Hz,1H),7.62–7.50(m,2H),7.44(dd,J＝17.1,9.4Hz,1H),7.34(dd,J＝14.3,7.1Hz,1H),5.39(dd,J＝18.0,4.0Hz,1H),5.34–5.16(m,1H),4.85(brs,1H),4.33–3.44(m,9H),3.32–3.04(m,7H),3.01(d,J＝10.2Hz,3H),2.96–2.63(m,2H),0.86–0.76(m,2H),0.74(s,2H).
实施例58 (S)-2-(4-(2-((1-(氮杂环丁烷-1-基甲基)环丙基)甲氧基)-7-(8-氯-7-氟萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000205
LC-MS:m/z 648(M+H) +. 1H NMR(400MHz,DMSO)δ8.02(dd,J＝9.0,5.9Hz,1H),7.79(dd,J＝7.9,3.3Hz,1H),7.65–7.49(m,2H),7.42(dd,J＝16.5,7.5Hz,1H),5.39(dd,J＝18.0,4.0Hz,1H),5.34–5.16(m,1H),4.87(brs,1H),4.23–3.41(m,9H),3.26–2.60(m,10H),2.33(s,2H),1.93(p,J＝6.4Hz,2H),0.44(s,2H),0.38(s,2H).
实施例59 (S)-2-(4-(7-(8-氯-7-氟萘-1-基)-2-((1-((3,3-二氟-氮杂环丁烷-1-基甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000206
LC-MS:m/z 684(M+H) +. 1H NMR(400MHz,DMSO)δ8.02(dd,J＝9.0,5.9Hz,1H),7.79(dd,J＝7.9,3.3Hz,1H),7.65–7.49(m,2H),7.42(dd,J＝16.2,7.6Hz,1H),5.39(dd,J＝18.0,4.0Hz,1H),5.34–5.13(m,1H),4.86(brs,1H),4.35–3.40(m,14H),3.28–2.60(m,7H),1.16(d,J＝26.6Hz,1H),0.47(d,J＝13.1Hz,4H).
实施例60 (S)-2-(4-(7-(8-氯-7-氟萘-1-基)-2-((1-((二乙基氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000207
LC-MS:m/z 664(M+H) +. 1H NMR(400MHz,DMSO)δ8.02(dd,J＝9.0,5.9Hz,1H),7.84–7.75(m,1H),7.56(dt,J＝14.4,8.2Hz,2H),7.42(dd,J＝14.1,7.6Hz,1H),5.39(dt,J＝9.5,4.8Hz,1H),5.28(d,J＝50.1Hz,1H),4.86(brs,1H),4.35–3.69(m,11H),3.30–2.64(m,10H),1.21–1.06(m,1H),1.05–0.79(m,6H),0.57(s,2H),0.43(s,2H).
实施例61 (S)-2-(4-(7-(8-氯-7-氟萘-1-基)-2-((1-((异丙基(甲基)氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000208
LC-MS:m/z 664(M+H) +. 1H NMR(400MHz,DMSO)δ8.02(dd,J＝8.8,5.9Hz,1H),7.80(d,J＝7.9Hz,1H),7.66–7.49(m,2H),7.42(dd,J＝14.9,7.5Hz,1H),5.39(dd,J＝18.0,3.8Hz,1H),5.27(d,J＝50.3Hz,1H),4.85(brs,1H),4.26–3.46(m,9H),3.27–2.61(m,8H),2.13(m,5H),0.90(s,6H),0.55(s,2H),0.39(s,2H).
实施例62 (S)-2-(4-(7-(8-氯-7-氟萘-1-基)-2-((1-((乙基(甲基)氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000209
LC-MS:m/z 650(M+H) +. 1H NMR(400MHz,DMSO)δ8.02(dd,J＝9.0,5.9Hz,1H),7.79(dd,J＝7.8,3.0Hz,1H),7.65–7.49(m,2H),7.42(dd,J＝15.4,7.5Hz,1H),5.39(dd,J＝18.0,4.0Hz,1H),5.24(d,J＝21.3Hz,1H),4.86(brs,1H),4.29–3.68(m,8H),3.56–3.39(m,1H),3.28–2.62(m,7H),2.45–2.24(m,4H),2.12(m,3H),1.00–0.85(m,3H),0.54(s,2H),0.40(s,2H).
实施例63 (S)-2-(4-(2-((1-((双(甲基-d3)氨基)甲基)环丙基)甲氧基)-7-(8-氯-7-氟萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000210
LC-MS:m/z 642(M+H) +. 1H NMR(400MHz,DMSO)δ8.02(dd,J＝9.0,5.9Hz,1H),7.79(dd,J＝7.9,3.2Hz,1H),7.66–7.49(m,2H),7.42(dd,J＝16.0,7.5Hz,1H),5.39(dd,J＝18.0,4.0Hz,1H),5.35–5.13(m,1H),4.86(brs,1H),4.30–3.65(m,7H),3.47(m,2H),3.27–2.59(m,7H),2.24–2.13(m,2H),0.54(s,2H),0.37(s,2H).
实施例64 (S)-2-(4-(7-(8-氯-7-氟萘-1-基)-2-((1-((3-甲氧基氮杂环丁基-1-基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000211
LC-MS:m/z 678(M+H) +. 1H NMR(400MHz,DMSO)δ8.02(dd,J＝9.0,5.9Hz,1H),7.79(dd,J＝7.9,3.2Hz,1H),7.66–7.51(m,2H),7.46–7.34(m,1H),5.40(dd,J＝18.0,3.9Hz,1H),5.36–5.18(m,1H),4.86(brs,1H),4.25–3.65(m,8H),3.46(m,4H),3.27–2.60(m,12H),2.39(s,2H),0.45(s,2H),0.40(s,2H).
实施例65 (S)-2-(4-(7-(8-氯-7-氟萘-1-基)-2-((1-((3-氟氮杂环丁烷-1-基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000212
LC-MS:m/z 666(M+H) +. 1H NMR(400MHz,DMSO)δ8.02(dd,J＝8.9,5.9Hz,1H),7.79(dd,J＝7.8,3.2Hz,1H),7.66–7.49(m,2H),7.42(dd,J＝16.5,7.4Hz,1H),5.48–4.98(m,3H),4.85(brs,1H),4.24–3.65(m,8H),3.54(m,4H),3.27–2.60(m,8H),2.44(s,2H),0.44(m,4H).
实施例66 (S)-2-(1-(2-氟丙烯酰基)-4-(2-((1-((3-氟氮杂环丁烷-1-基)甲基)环丙基)甲氧基)-7-(7-氟萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000213
LC-MS:m/z 632(M+H) +. 1H NMR(400MHz,DMSO)δ8.04(dd,J＝9.0,6.0Hz,1H),7.80(d,J＝9.1Hz,1H),7.71(d,J＝8.2Hz,1H),7.46(t,J＝7.7Hz,2H),7.31(d,J＝7.4Hz,1H),5.49–4.99(m,3H),4.87(brs,1H),4.24–3.45(m,12H),3.05(m,8H),2.45(s,2H),0.46(m,4H).
实施例67 (S)-2-(4-(7-(8-氯-7-氟萘-1-基)-2-((1-((3-甲基氮杂环丁烷-1-基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000214
LC-MS:m/z 662(M+H) +. 1H NMR(400MHz,DMSO)δ8.02(dd,J＝8.9,5.9Hz,1H),7.79(dd,J＝7.9,3.2Hz,1H),7.66–7.49(m,2H),7.42(dd,J＝16.3,7.6Hz,1H),5.39(dt,J＝9.5,4.7Hz,1H),5.35–5.15(m,1H),4.85(brs,1H),4.20–3.68(m,7H),3.47(m,2H),3.26–2.58(m,11H),2.41(m,1H),2.35(m,2H),1.06(d,J＝6.6Hz,3H),0.43(s,2H),0.38(s,2H).
实施例68 (S)-2-(4-(7-(8-氯-7-氟萘-1-基)-2-((1-((3-羟基氮杂环丁烷-1-基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000215
LC-MS:m/z 664(M+H) +. 1H NMR(400MHz,DMSO)δ8.02(dd,J＝8.9,5.9Hz,1H),7.79(dd,J＝7.9,3.1Hz,1H),7.66–7.49(m,2H),7.42(dd,J＝16.3,7.5Hz,1H),5.47–5.10(m,3H),4.85(brs,1H),4.28–3.45(m,13H),3.25–2.59(m,9H),2.41(s,2H),0.44(s,2H),0.41(s,2H).
实施例69 (S)-2-(4-(7-(8-氯-7-氟萘-1-基)-2-((1-(((2-甲氧基乙基)(甲基)氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000216
LC-MS:m/z 664(M+H) +. 1H NMR(400MHz,CDCl 3)δ7.77(d,J＝8.2Hz,1H),7.67–7.60(m,1H),7.57–7.51(m,1H),7.46(dt,J＝11.3,7.8Hz,1H),7.35(t,J＝7.8Hz,1H),7.24(dd,J＝19.2,7.5Hz,1H),5.43(d,J＝48.4Hz,1H),5.27(dd,J＝16.8,3.4Hz,1H),4.92(brs,1H),4.52–2.32(m,25H),1.73(m,3H),0.66(m,4H).
实施例70 2-(1-丙烯酰-4-(2-(2-((环丙基)(甲基)胺基)乙氧基)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000217
第一步：2-(氰基甲基)-4-(2-(环丙基(甲基)氨基)乙氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯的制备
将2-(氰基甲基)-4-(7-(8-甲基萘-1-基)-2-(甲基亚砜基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-1-甲酸酸叔丁酯(72mg，0.128mmol)加入反应瓶中，随后依次加入甲苯(0.8mL)、2-(环丙基(甲基)氨基)乙烷-1-醇(30mg，0.256mmol)和叔丁醇钠(37mg，0.384mmol)。反应液在冰水浴下，搅拌0.5h，随后加入水(50mL)，然后用乙酸乙酯萃取(3 x 30mL)。所有有机相合并，用饱和氯化钠溶液洗一次，然后经无水硫酸钠干燥后，过滤。滤液减压浓缩，得到的残余物用制备板纯化(洗脱剂：DCM/MeOH＝20/1)，得到目标产物(36mg，产率46％)。
LC-MS：m/z 612(M+H) +。
第二步：2-(4-(2-(2-(环丙基(甲基)氨基)乙氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
将2-(氰基甲基)-4-(2-(环丙基(甲基)氨基)乙氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯(36mg，0.059mmol)溶于二氯甲烷(1mL)中，随后加入三氟乙酸(0.5mL)。反应液在室温搅拌0.5h，然后减压浓缩至干，得到目标产物(40mg)，无需纯化直接用于下一步反应。
LC-MS：m/z 512(M+H) +。
第三步 2-(1-丙烯酰-4-(2-(2-((环丙基)(甲基)胺基)乙氧基)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
将上一步得到的2-(4-(2-(2-(环丙基(甲基)氨基)乙氧基)-7-(8-甲基萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈(40mg，0.054mmol)中加入N,N-二异丙基乙胺(42mg，0.324mmol)的二氯甲烷(2mL)溶液中。反应液在氮气保护，在-40℃下，滴加丙烯酰氯(10mg，0.108mmol)。滴加完后，反应液升至室温搅拌1h，然后加入甲醇(1mL)淬灭。得到的混合物浓缩，得到的残余物用C18柱反相纯化，得到目标产物(12mg，产率36％)。
LC-MS：m/z 566(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.66(m,2H),7.38(m,2H),7.24(m,2H),6.56(m,1H),6.41(d,J＝16.8Hz,1H),5.84(d,J＝10.4Hz,1H),5.06(brs,0.5H),4.63(brs,0.5H),4.44(m,2H),4.01(m,5H),3.52(m,2H),3.08(m,6H),2.91(s,3H),2.70(m,3H),2.45(d,J＝3.6Hz,3H),1.77(m,1H),0.48(m,4H)。
按照实施例70的方法以不同的起始原料合成了以下化合物：
实施例71 2-(1-丙烯酰-4-(2-((S)-2-(环丙基(甲基)胺基)丙氧基)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000218
LC-MS：m/z 580(M+H) +。 1HNMR(400M,CDCl 3)δ7.66(m,2H),7.38(m,2H),7.24(m,2H),6.55(m,1H),6.41(d,J＝16.8Hz,1H),5.83(d,J＝10.0Hz,1H),5.08(brs,0.5H),4.63(brs,0.5H),4.45(m,1H),3.87(m,7H),3.12(m,5H),2.91(s,3H),2.70(m,3H),2.39(s,3H),1.95(s,1H),1.87(s,1H)，1.83(m,3H)，0.46(m,4H)。
实施例72 2-(1-丙烯酰-4-(2-((R)-2-(环丙基(甲基)胺基)丙氧基)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000219
LC-MS：m/z 580(M+H) +。 1HNMR(400M,CDCl 3)δ7.66(m,2H),7.38(m,2H),7.24(m,2H),6.58(m,1H),6.42(d,J＝16.4Hz,1H),5.84(d,J＝10.4Hz,1H),5.07(brs,0.5H),4.63(brs,0.5H),4.48(m,1H),4.08(m,5H),3.16(m,7H),2.91(s,3H),2.72(m,3H),2.43(s,3H),2.01(m,1H),1.74(m,1H)，1.22(s,3H)，0.50(s,4H)。
实施例73 2-(1-丙烯酰-4-(2-(2-((环丙基甲基)(甲基)胺基)乙氧基)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000220
LC-MS：m/z 580(M+H) +。 1HNMR(400M,CDCl 3)δ7.66(m,2H),7.38(m,2H),7.24(m,2H),6.58(m,1H),6.41(d,J＝16.8Hz,1H),5.84(d,J＝10.4Hz,1H),5.05(brs,0.5H),4.62(brs,0.5H),4.44(m,2H),4.08(m,5H),3.52(m,2H)，2.91(m,12H),2.43(m,5H),0.90(m,1H),0.52(m,2H)，0.14(m,2H)。
实施例74 2-(1-丙烯酰-4-(2-((S)-2-((环丙基甲基)(甲基)胺基)丙氧基)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000221
LC-MS：m/z 594(M+H) +。 1HNMR(400M,CDCl 3)δ7.66(m,2H),7.37(m,2H),7.24(m,2H),6.58(m,1H),6.40(m,1H),5.83(d,J＝10.4Hz,1H),5.02(brs,0.5H),4.60(s,0.5H),4.42(m,1H),4.07(m,6H),3.29(m,7H),2.91(s,3H),2.75(m,3H),2.40(m,5H),1.13(m,3H),0.86(m,1H)，0.50(m,2H)，0.12(m,2H)。
实施例75 2-(1-丙烯酰-4-(2-((R)-2-((环丙基甲基)(甲基)胺基)丙氧基)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000222
LC-MS：m/z 594(M+H)+。 1HNMR(400M,CDCl 3)δ7.66(m,2H),7.38(m,2H),7.24(m,2H),6.58(m,1H),6.41(d,J＝16Hz,1H),5.83(d,J＝8Hz,1H),5.05(brs,0.5H),4.63(brs,0.5H),4.42(m,1H),4.27-3.74(m,6H),3.52(m,2H),3.31(brs，1H)，3.20-2.94(m,4H),2.91(s,3H),2.84-2.59(m,3H),2.41(m,5H),1.13(m,3H),0.88(m,1H),0.53(m,2H),0.12(m,2H)。
实施例76 2-(1-丙烯酰-4-(2-(((S)-1-((环丙基甲基)(甲基)胺基)丙烷-2-基)氧)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000223
LC-MS：m/z 594(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.79–7.58(m,2H),7.50–7.32(m,2H),7.29–7.18(m,2H),6.61(m,1H),6.41(d,J＝16.6Hz,1H),5.84(d,J＝10.5Hz,1H),5.08(brs,0.5H),4.68(brs,0.5H),4.34–3.65(m,5H),3.65–2.38(m,20H),1.42(d,J＝4.2Hz,3H),1.08(m,1H),0.66(m,2H),0.28(m,2H).
实施例77 2-(1-丙烯酰-4-(2-(((R)-1-((环丙基甲基)(甲基)胺基)丙烷-2-基)氧)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000224
LC-MS：m/z 594(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.78–7.58(m,2H),7.49–7.31(m,2H),7.26–7.13(m,2H),6.57(m,1H),6.39(d,J＝16.7Hz,1H),5.82(d,J＝10.4Hz,1H),5.07(brs,0.5H),4.63(brs,0.5H),4.35–3.81(m,4H),3.81–2.88(m,11H),2.73(m,5H),2.39(m,5H),1.34(m,3H),0.87(m,1H),0.50(m,2H),0.10(m,2H).
实施例78 2-(1-丙烯酰-4-(2-(2-(((S)-1-环丙基甲基)(甲基)胺基)乙氧)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000225
LC-MS：m/z 594(M+H) +。 1HNMR(400M,CDCl 3)δ7.66(m,2H),7.38(m,2H),7.24(m,2H),6.58(m,1H),6.41(d,J＝16.8Hz,1H),5.84(d,J＝10.8Hz,1H),5.05(brs,0.5H),4.65(brs,0.5H),4.43(m,2H),4.08(m,5H),3.46(m,2H),3.06(m,6H),2.91(s,3H),2.72(m,3H),2.47(m,3H),2.02(m,1H),1.13(m,3H),0.80(s,1H)，0.48(m,3H)，0.06(m,1H)。
实施例79 2-(1-丙烯酰-4-(2-(2-(((R)-1-环丙基甲基)(甲基)胺基)乙氧)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000226
LC-MS：m/z 594(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.66(m,2H),7.38(m,2H),7.24(m,2H),6.58(m,1H),6.41(d,J＝16Hz,1H),5.83(d,J＝8Hz,1H),5.06(brs,0.5H),4.61(brs,0.5H),4.38(m,2H),4.27-3.76(m,5H),3.52(m,2H),3.20-2.94(m,6H),2.91(s,3H),2.84-2.63(d,3H),2.43(d,J＝4Hz,3H),1.96(m,1H),1.10(m,3H),0.78(m,1H),0.53-0.43(m,2H),0.30(m,1H),0.04(m,1H)。
实施例80 2-(1-丙烯酰-4-(2-(2-(((1-氟环丙基)甲基)(甲基)胺基)乙氧基)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000227
LC-MS：m/z 598(M+H) +。
实施例81 2-(1-丙烯酰-4-(2-(2-((环丁基)(甲基)胺基)乙氧基)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000228
LC-MS：m/z 580(M+H) +。 1HNMR(400M,CDCl 3)δ7.66(m,2H),7.38(m,2H),7.24(m,2H),6.56(m,1H),6.41(d,J＝16.8Hz,1H),5.84(d,J＝10.4Hz,1H),5.06(brs,0.5H),4.61(brs,0.5H),4.38(m,2H),4.08(m,5H),3.16(m,6H),2.91(s,3H),2.70(m,5H),2.21(m,3H),2.05(m,2H),1.90(m,3H),1.63(m,2H)。
实施例82 2-(1-丙烯酰-4-(2-(2-((环丁基甲基)(甲基)胺基)乙氧基)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000229
LC-MS：m/z 594(M+H) +。 1HNMR(400M,CDCl 3)δ7.66(m,2H),7.38(m,2H),7.24(m,2H),6.57(m,1H),6.40(d,J＝16.4Hz,1H),5.83(d,J＝10.4Hz,1H),5.05(brs,0.5H),4.58(brs,0.5H),4.39(m,2H),3.90(m,5H),3.49(m,2H),3.02(m,7H),2.65(m,8H),2.31(m,3H),2.05(m,2H),1.85(m,2H)，1.67(m,2H)。
实施例83 2-(1-丙烯酰-4-(2-(2-(((3,3-二氟环丁基)甲基)(甲基)胺基)乙氧基)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000230
LC-MS：m/z 630(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.76–7.59(m,2H),7.37(m,2H),7.26–7.14(m,2H),6.70–6.49(m,1H),6.39(d,J＝16.7Hz,1H),5.82(d,J＝10.5Hz,1H),5.06(brs,0.5H),4.57(brs,0.5H),4.39(m,2H),4.32–4.00(m,3H),3.80(m,2H),3.62–2.96(m,7H),2.92(s,3H),2.87–2.74(m,3H),2.72–2.51(m,5H),2.33(d,J＝4.0Hz,4H),2.26–2.13(m,2H).
实施例84 2-(1-丙烯酰-4-(2-(((S)-1-(双(环丙甲基)氨基)丙烷-2-基)氧)-7-(8-甲基萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000231
LC-MS：m/z 634(M+H) +。
实施例85 2-(1-丙烯酰-4-(2-(2-((3,3-二氟环丁基)(甲基)胺基)乙氧基)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000232
LC-MS：m/z 616(M+H) +。
实施例86 2-(1-丙烯酰-4-(2-(2-((环戊基)(甲基)胺基)乙氧基)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000233
LC-MS：m/z 594(M+H) +。
实施例86 2-(1-丙烯酰-4-(2-(2-((环己基)(甲基)胺基)乙氧基)-7-(8-甲甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000234
LC-MS：m/z 608(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.76–7.60(m,2H),7.37(m,2H),7.26–7.14(m,2H),6.58(s,1H),6.39(d,J＝16.7Hz,1H),5.82(d,J＝10.5Hz,1H),5.06(brs,0.5H),4.61(brs,0.5H),4.43(m,2H),4.32–3.63(m,5H),3.61–3.37(m,2H),3.31–2.86(m,9H),2.86–2.56(m,3H),2.46(d,J＝36.3Hz,4H),1.84(d,J＝33.8Hz,3H),1.67–1.55(m,1H),1.37–1.16(m,5H),1.09(m,1H).
实施例88 2-(1-丙烯酰-4-(2-(2-((环丁基)(乙基)胺基)乙氧基)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000235
LC-MS：m/z 594(M+H) +。
实施例89 2-(1-丙烯酰-4-(2-(((S)-1-((环丁基)(甲基)胺基)丙烷-2-基)氧)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000236
LC-MS：m/z 594(M+H) +。
实施例90 2-(1-丙烯酰-4-(2-(((R)-1-((环丁基)(甲基)胺基)丙烷-2-基)氧)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000237
LC-MS：m/z 594(M+H) +。
实施例91 2-(1-丙烯酰-4-(2-((S)-2-(环丁基(甲基)胺基)丙氧基)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000238
LC-MS：m/z 594(M+H) +。
化合物经手性制备分离得到2-((S)-1-丙烯酰-4-(2-((S)-2-(环丁基(甲基)胺基)丙氧基)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈(A)和2-((R)-1-丙烯酰-4-(2-((S)-2-(环丁基(甲基)胺基)丙氧基)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈(B)
Figure PCTCN2020138142-appb-000239
异构体91A
LC-MS：m/z 594(M+H) +。
异构体91B
LC-MS：m/z 594(M+H) +。
实施例92 2-(1-丙烯酰-4-(2-((R)-2-(环丁基(甲基)胺基)丙氧基)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000240
LC-MS：m/z 594(M+H) +。
实施例93 2-(1-丙烯酰-4-(2-(2-环丙氧基乙基氧基)-7-(8-甲基萘基-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000241
LC-MS：m/z 553(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.68–7.52(m,2H),7.37–7.22(m,2H),7.19–7.08(m,2H),6.65–6.40(m,1H),6.32(d,J＝16.7Hz,1H),5.76(d,J＝10.5Hz,1H),4.96(brs,0.5H),4.54(brs,0.5H),4.39(m,2H),4.31–3.68(m,7H),3.54–3.24(m,3H),3.09(s,3H),3.01–2.47(m,7H),0.53(m,2H),0.40(m,2H).
实施例94 2-(1-丙烯酰-4-(2-(((顺式)-2-(二甲基氨基)环戊基)氧)-7-(8-甲基萘-1-基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020138142-appb-000242
LC-MS：m/z 580(M+H) +。
实施例95 1-(4-(2-(2-((环丙甲基)(甲基)氨基)乙氧)-7-(3-氟-2-(三氟甲基)苯基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮
Figure PCTCN2020138142-appb-000243
LC-MS：m/z 563(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.27(dd,J＝14.4,8.1Hz,1H),6.86(d,J＝8.2Hz,1H),6.80–6.67(m,1H),6.39(dd,J＝16.8,10.5Hz,1H),6.14(dd,J＝16.8,1.4Hz,1H),5.55(dd,J＝10.5,1.4Hz,1H),4.30(t,J＝6.0Hz,2H),3.88(m,2H),3.52(m,2H),3.50(m,2H),3.37(m,3H),2.99(t,J＝4.7Hz,2H),2.84(t,J＝6.0Hz,3H),2.54(s,2H),2.33(d,J＝6.8Hz,5H),0.75(m,1H),0.38(q,J＝5.3Hz,2H),-0.01(q,J＝5.0Hz,2H).
按照实施例27的方法以不同的起始原料合成了实施例96A和96B：
2-((S)-4-((S)-7-(8-氯-7-氟萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-6-甲基-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈和2-((S)-4-((R)-7-(8-氯-7-氟萘-1-基)-2-((1-((二甲基氨基)甲基)环丙基)甲氧基)-6-甲基-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈
Figure PCTCN2020138142-appb-000244
实施例96A(异构体A)
LC-MS：m/z 650(M+H) +。 1HNMR(400M,DMSO-d 6)：8.02(m,1H),7.87(m,0.68H),7.75(m,0.32H),7.55(m,3H),5.37(m,2H),4.82(brs,1H),3.97(m,7H),3.57(m,2H),2.93(m,6H),2.17(m,8H),1.00(d,J＝8.0Hz,2.06H),0.73(d,J＝8.0Hz,0.93H),0.58(m,2H),0.39(m,2H).
实施例96B(异构体B)
LC-MS：m/z 650(M+H) +。 1HNMR(400M,DMSO-d 6)：8.03(m,1H),7.90(m,0.79H),7.77(m,0.24H),7.56(m,3H),5.37(m,2H),4.85(brs,1H),3.98(m,7H),3.53(m,2H),2.94(m,6H),2.15(m,8H),1.00(d,J＝8.0Hz,2.3H),0.73(d,J＝8.0Hz,0.66H),0.57(m,2H),0.38(m,2H).
实施例97 生物学测试例
生物学测试评价
以下生物学测试例进一步描述解释本发明，但这些实例并非意味着限制本发明的范围。
化合物对NCI-H358(KRAS G12C突变)细胞和A549(KRAS G12S突变)细胞的抗增殖活性的 细胞实验。
实验步骤
向384微孔板的外围孔中加入40μL磷酸盐缓冲液，随后向其他孔中加入40μL待测细胞悬浮液，然后将微孔板置于二氧化碳培养箱中培养过夜。
对待测化合物进行梯度稀释，将每个化合物稀释10个浓度梯度(从50μM稀释到0.003μM)并分别加100nL到微孔板的对应孔中。加药以后，在A、P行及1、24列每孔加入40μL磷酸盐缓冲液，然后将微孔板置于二氧化碳培养箱中培养5天。
向微孔板每孔中加入20μL的Promega CellTiter-Glo试剂，随后在室温震荡10min使发光信号稳定，然后采用PekinElmer Envision多标记分析仪读数。
最后应用GraphPad Prism软件计算化合物的IC 50值，并绘出拟合曲线。
本发明中实施例化合物对NCI-H358(KRAS G12C突变)细胞和A549(KRAS G12S突变)细胞的抗增殖活性见表1。
表1 本发明中实施例化合物抗增殖活性
IC 50 NCI-H358(μM) A549(μM)
实施例1 0.22 7.1
实施例2 0.0078 4.3
实施例3 0.039 7.1
实施例4 0.21 9.5
实施例5 0.06 7.1
实施例6 0.11 9.9
实施例7 0.072 8.2
实施例8 0.13 7.04
实施例9 0.16 17.67
实施例10 6.5 17.42
实施例11 0.11 3.2
实施例12 0.14 2.3
实施例13 0.055 6.0
实施例14 0.090 6.2
实施例15 0.090 13.5
实施例19 0.0046 8.9
实施例20 0.87 7.7
实施例21 0.027 7.8
实施例22 0.091 2.2
实施例23 0.013 -
实施例25 0.059 -
实施例26 0.062 -
实施例27 0.014 -
实施例28 0.008 -
实施例29A 0.36 -
实施例29B 0.053 -
实施例29C 0.1 -
实施例29D 0.006 -
实施例30 0.041 -
实施例31 0.073 -
实施例32 0.12 -
实施例33 0.066 -
实施例34 1.9 -
实施例35 0.31 -
实施例36 0.25 -
实施例37 1.4 -
实施例38 4.9 -
实施例39 2.5 -
实施例40 0.30 -
实施例41 1.4 -
实施例42 5.5 -
实施例43 0.83 -
实施例44 3.3 -
实施例45 0.049 -
实施例46 0.037 -
实施例47A 0.1 -
实施例47B 0.071 -
实施例48 0.065 -
实施例49 0.043 -
实施例50 0.30 -
实施例52 0.54 -
实施例53A 1.4 -
实施例53B 1.3 -
实施例54 0.047 -
实施例55 0.87 -
实施例56 0.061 -
实施例57 1.3 -
实施例58 0.065 -
实施例59 0.81 -
实施例60 0.092 -
实施例61 0.11 -
实施例62 0.036 -
实施例63 0.007 -
实施例65 0.045 -
实施例66 0.18 -
实施例67 0.051 -
实施例68 0.086 -
实施例69 0.059 -
实施例70 0.17 11.5
实施例71 0.15 11.5
实施例72 0.18 10.6
实施例73 0.06 3.7
实施例74 0.08 2.6
实施例75 0.09 2.8
实施例76 0.86 3.5
实施例77 1.80 2.7
实施例78 0.05 2.8
实施例79 0.04 3.1
实施例80 <0.1 /
实施例81 0.04 7.5
实施例82 0.16 6.6
实施例85 <0.1 /
实施例91A <0.03 /
实施例91B <1  
实施例92 <0.1 /
实施例93 0.31 7.8
实施例95 6.26 /
实施例96A 0.191 /
实施例96B 0.005 /
从表1可以看出：
本发明实施例化合物对于KRAS G12C突变型NCI-H358细胞显示出了很好的细胞抗增殖活性，同时对于KRAS G12S突变型A549细胞抗增殖活性较弱，体现出了高选择性。
药代动力学测试评价
雄性SD大鼠，体重220g左右，禁食过夜后，灌胃给予15mg/kg本发明化合物或对照化合物的溶液[10％皮质醇(captisol)和50mM柠檬酸钠(sodium citrate),pH 5为载体]。分别在给于本发明化合物后0.5，1.0，2.0，4.0，6.0，8.0，12.0和24h采血，用LC/MS/MS测定血浆中本发明化合物或对照化合物的浓度。
对照化合物结构如下：
Figure PCTCN2020138142-appb-000245
药代动力学测试结果
实施例13、14和对照化合物的血药浓度-时间曲线如图1所示，药代动力学参数如表2所示：
表2 药代动力学参数总结：(n＝4，均值)
Figure PCTCN2020138142-appb-000246
Figure PCTCN2020138142-appb-000247
综上，从表2和图1中可以看出，相对于对照化合物，本发明化合物实施例13在大鼠体内体现出更好的代谢性质，最大血药浓度(Cmax)和血浆暴露量AUC更高。结果表明，实施例13具有优异的生物利用度和药效。
抗肿瘤活性药效学测试评价(MIA PaCa-2CDX肿瘤模型)
将100uL含5x10 6MIA PaCa-2肿瘤细胞悬液皮下接种到裸鼠右后侧腹部。每天监测小鼠健康状况，当肿瘤生长至可触及时开始测量。肿瘤体积计算公式采用:0.5xLxW 2，其中L、W分别代表肿瘤长、宽。肿瘤长至～200mm 3，对小鼠进行随机分组。小鼠每天灌胃给予相应剂量(7.5mg/Kg)化合物的CMC-Na悬液，同时对其一般状态进行监测。肿瘤每周测量3次，体重每周测量两次。由检测结果如表3和图2所示。
表3 抗肿瘤活性药效学测试评价
Figure PCTCN2020138142-appb-000248
抗肿瘤活性药效学测试评价(H358CDX肿瘤模型)
将100uL含5x10 6NCI-H358肿瘤细胞悬液皮下接种到裸鼠右后背部。每天监测小鼠健康状况，当肿瘤生长至可触及时开始测量。肿瘤体积计算公式采用:0.5xLxW2，其中L、W分别代表肿瘤长、宽。肿瘤长至～200mm 3，对小鼠进行随机分组。小鼠每天灌胃给予相应剂量(30mg/Kg)化合物的溶液，同时对其一般状态进行监测。肿瘤每周测量2次，体重每周测量两次。测量结果如表4和图3所示。
表4 抗肿瘤活性药效学测试评价
Figure PCTCN2020138142-appb-000249
上述检测结果表明，相较于空白对照，本发明化合物能够明显减小肿瘤体积，具有良好的抗肿瘤效果。
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 (15)

  1. 具有通式(I)结构的环烷基类和杂环烷基类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药：
    Figure PCTCN2020138142-appb-100001
    式中：
    A，B相同或者不同，独立地选自CH或N；
    X选自：4-14元饱和或不饱和的环烷基或杂环基、C 6-C 14元芳基或者5-14元杂芳基，其中，所述的饱和或不饱和的环烷基或杂环基、芳基或者杂芳基可以任选地被一个或多个R 8所取代；
    Y选自下组：键、O、S、NH、NR 5、CR 5R 6、CONH、CONR 5、SO 2NH、SO 2NR 5、NHCO、NR 5CO、NHSO 2、NR 5SO 2；
    Z选自下组：键、C 1-C 18亚烷基、氘代C 1-C 18亚烷基、卤代C 1-C 18亚烷基、C 3-C 20亚环烷基、C 4-C 20亚杂环基、C 1-C 18亚烷氧基、氘代C 1-C 18亚烷氧基、卤代C 1-C 18亚烷氧基；
    W选自下组：键、O、NH、NR 5、CONH、CONR 5、SO 2NH、SO 2NR 5、NHCO、NHSO 2、NHCONH、NR 5CONH、NHCONR 5、NR 5CO NR 6、NHSO 2NH、NR 5SO 2NH、NH SO 2NR 5、NR 5SO 2NR 6；
    R 1选自下组：
    Figure PCTCN2020138142-appb-100002
    R 2选自下组：-(CH 2) nR 7、-(CH 2) nO(CH 2) qR 7、-(CH 2) nSR 7、-(CH 2) nCOR 7、-(CH 2) nC(O)OR 7、-(CH 2) nS(O) qR 7、-(CH 2) nNR 5R 7、-(CH 2) nC(O)NR 5R 7、-(CH 2) nNR 5C(O)R 7、-(CH 2) nNR 5C(O)NR 5R 7、-(CH 2) nS(O) qNR 5R 7、-(CH 2) nNR 5S(O) qR 7、-(CH 2) nNR 5S(O) qNR 5R 7，其中，CH 2中的H可以被取代；
    R 3独立地选自下组：氢、氘、氧、C 1-C 3烷基或卤代C 1-C 3烷基；
    L选自下组：键、-C(O)-、C 1-C 3的亚烷基；
    R 4选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、胺基、羟基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基；
    R 5和R 6相同或不同，且各自独立地选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、氨基、羟基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基；
    R 7选自：取代或未取代的C 1-C 18烷基、C 3-C 20环烷基或4-20元杂环基；
    R 8独立地选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、氨基、羟基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基；
    其中，所述取代指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18 烷基、卤代C 1-C 18烷基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；
    Figure PCTCN2020138142-appb-100003
    可以是双键
    Figure PCTCN2020138142-appb-100004
    或三键
    Figure PCTCN2020138142-appb-100005
    R A为不存在，或者独立地选自：氢、氘、氟、氰基或者C 1-C 3烷基；
    R B独立地选自：氢、氘、氰基或者C 1-C 3烷基；
    其中，所述烷基可以被选自下组的一个或多个取代基取代：氘、卤素、氰基、胺基、C 3-C 7环烷基、4-7元杂环基、NHR 9或NR 9R 10；
    R 9，R 10各自独立地为C 1-C 3烷基；
    m为0、1、2或3的整数；
    n为0、1、2、3、4或5的整数；
    p为1或2的整数；
    q为0、1、2、3、4或5的整数；
    限定条件是：当A和B同时为N，且X为4-14元杂环基，Y选自下组：键、O、S、NH或NR 5，且R 5为C 1-C 18烷基时，Z选自取代或未取代的C 3-C 20亚环烷基；
    或，
    当A和B同时为N，且X为4-14元杂环基，Y选自下组：键、O、S、NH或NR 5，W选自键，且R 5为C 1-C 18烷基时，R 7需选自取代或未取代的C 3-C 20环烷基；
    或，
    当A和B同时为N，且X为4-14元杂环基，Y选自下组：键、O、S、NH或NR 5，W选自下组：NH或NR 5，且R 5为C 1-C 18烷基时，R 7需选自取代或未取代的C 3-C 20环烷基或取代或未取代的4-20元杂环基。
  2. 如权利要求1所述的具有通式(I)结构的环烷基类和杂环烷基类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有通式(II-A)或(II-B)所示的结构：
    Figure PCTCN2020138142-appb-100006
    式中：
    R 1、R 2、R 3、R 4、A、B、X、Y、Z、L、W、m的定义如权利要求1所述。
  3. 如权利要求1所述的具有通式(I)结构的环烷基类和杂环烷基类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有通式(III)所示结构：
    Figure PCTCN2020138142-appb-100007
    R 1、R 2、R 3、R 4、X、Y、Z、L、W、m的定义如权利要求1所述。
  4. 如权利要求1所述的具有通式(I)结构的环烷基类和杂环烷基类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有通式(IV)所示结构：
    Figure PCTCN2020138142-appb-100008
    式中：
    R 1、R 2、R 3、R 4、R 8、Y、Z、L、W、m的定义如权利要求1所述。
  5. 如权利要求1所述的具有通式(I)结构的环烷基类和杂环烷基类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有通式(V)所示结构：
    Figure PCTCN2020138142-appb-100009
    式中：
    R 1、R 2、R 3、R 4、R 8、Y、Z、W、m的定义如权利要求1所述。
  6. 如权利要求1所述的具有通式(I)结构的环烷基类和杂环烷基类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有通式(VI)所示结构：
    Figure PCTCN2020138142-appb-100010
    式中：
    R 1、R 2、R 3、R 4、R 8、Z、W、m的定义如权利要求1所述。
  7. 如权利要求1所述的具有通式(I)结构的环烷基类和杂环烷基类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有通式(VII-A)或(VII-B)所示的结构：
    Figure PCTCN2020138142-appb-100011
    式中：
    R 1、R 2、R 3、R 4、R 5、R 8、Z、m的定义如权利要求1所述。
  8. 如权利要求1-6中任一项所述的具有通式(I)结构的环烷基类和杂环烷基类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，式中：
    Z为键；
    W为键；
    R 2为-(CH 2) nR 7，其中，CH 2中的H可以被取代；
    R 7选自：取代或未取代的C 3-C 20环烷基或4-20元杂环基；其中，所述取代指被选自下组的一个或多个基团取代：C 1-C 18烷基、氘代C 1-C 18烷基；所述烷基可以被选自下组的一个或多个取代基取代：氘、卤素、氰基、胺基、C 3-C 7环烷基、4-7元杂环基、NHR 9或NR 9R 10；R 9，R 10各自独立地为C 1-C 3烷基；
    n为1、2、或3；
    R 1、R 3、R 4、R 8、m的定义如权利要求1所述。
  9. 如权利要求8所述的具有通式(I)结构的环烷基类和杂环烷基类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有通式(VIII)所示结构：
    Figure PCTCN2020138142-appb-100012
    R 11、R 12相同或不同，各自独立地选自：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基；
    环A为取代或未取代的C 3-C 20环烷基或4-20元杂环基；
    L 1为C 1-C 18烷基、氘代C 1-C 18烷基；
    Q为C 3-C 7环烷基、4-7元杂环基、NHR 9或NR 9R 10；R 9，R 10各自独立地为C 1-C 3烷基。
  10. 如权利要求1-6中任一项所述的具有通式(I)结构的环烷基类和杂环烷基类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，
    Z为C 1-C 18亚烷基C 3-C 20亚环烷基；
    W为键；
    R 2为-(CH 2) nNR 5R 7；其中，CH 2中的H可以被取代；
    n为0、1、2、3、4或5的整数；
    R 5选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、氨基、羟基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基；
    R 7选自：取代或未取代的C 1-C 18烷基、C 3-C 20环烷基或4-20元杂环基；
    其中，所述烷基可以被选自下组的一个或多个取代基取代：氘、卤素、氰基、胺基、C 3-C 7环烷基、4-7元杂环基、NHR 9或NR 9R 10；
    R 9，R 10各自独立地为C 1-C 3烷基；
    其中，所述取代指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。
  11. 如权利要求1所述的具有通式(I)结构的环烷基类和杂环烷基类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，所述化合物选自下组：
    Figure PCTCN2020138142-appb-100013
    Figure PCTCN2020138142-appb-100014
    Figure PCTCN2020138142-appb-100015
    Figure PCTCN2020138142-appb-100016
    Figure PCTCN2020138142-appb-100017
    Figure PCTCN2020138142-appb-100018
    Figure PCTCN2020138142-appb-100019
    Figure PCTCN2020138142-appb-100020
    Figure PCTCN2020138142-appb-100021
    Figure PCTCN2020138142-appb-100022
    Figure PCTCN2020138142-appb-100023
    Figure PCTCN2020138142-appb-100024
    Figure PCTCN2020138142-appb-100025
    Figure PCTCN2020138142-appb-100026
    Figure PCTCN2020138142-appb-100027
    Figure PCTCN2020138142-appb-100028
    Figure PCTCN2020138142-appb-100029
    Figure PCTCN2020138142-appb-100030
    Figure PCTCN2020138142-appb-100031
    Figure PCTCN2020138142-appb-100032
    Figure PCTCN2020138142-appb-100033
    Figure PCTCN2020138142-appb-100034
    Figure PCTCN2020138142-appb-100035
    Figure PCTCN2020138142-appb-100036
    Figure PCTCN2020138142-appb-100037
    Figure PCTCN2020138142-appb-100038
    Figure PCTCN2020138142-appb-100039
    Figure PCTCN2020138142-appb-100040
    Figure PCTCN2020138142-appb-100041
    Figure PCTCN2020138142-appb-100042
    Figure PCTCN2020138142-appb-100043
    Figure PCTCN2020138142-appb-100044
    Figure PCTCN2020138142-appb-100045
    Figure PCTCN2020138142-appb-100046
    Figure PCTCN2020138142-appb-100047
    Figure PCTCN2020138142-appb-100048
    Figure PCTCN2020138142-appb-100049
    Figure PCTCN2020138142-appb-100050
    Figure PCTCN2020138142-appb-100051
    Figure PCTCN2020138142-appb-100052
    Figure PCTCN2020138142-appb-100053
    Figure PCTCN2020138142-appb-100054
    Figure PCTCN2020138142-appb-100055
    Figure PCTCN2020138142-appb-100056
    Figure PCTCN2020138142-appb-100057
    Figure PCTCN2020138142-appb-100058
    Figure PCTCN2020138142-appb-100059
    Figure PCTCN2020138142-appb-100060
    Figure PCTCN2020138142-appb-100061
    Figure PCTCN2020138142-appb-100062
    Figure PCTCN2020138142-appb-100063
    Figure PCTCN2020138142-appb-100064
    Figure PCTCN2020138142-appb-100065
    Figure PCTCN2020138142-appb-100066
    Figure PCTCN2020138142-appb-100067
    Figure PCTCN2020138142-appb-100068
    Figure PCTCN2020138142-appb-100069
    Figure PCTCN2020138142-appb-100070
    Figure PCTCN2020138142-appb-100071
    Figure PCTCN2020138142-appb-100072
    Figure PCTCN2020138142-appb-100073
    Figure PCTCN2020138142-appb-100074
    Figure PCTCN2020138142-appb-100075
  12. 一种制备通式(I)结构的环烷基类和杂环烷基类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药的方法，其特征在于，包括步骤：
    Figure PCTCN2020138142-appb-100076
    (i)在碱存在下，式V-1化合物与二胺基类化合物分子中的一个胺基反应，然后与氨基保护剂反应，生成式V-2化合物；
    (ii)在脱保护剂的存在下，式V-2化合物脱保护，生成式V-3化合物；
    (iii)式V-3化合物通过偶联、取代或酰化反应，得到式V-4化合物；
    (iv)式V-4化合物与氧化剂反应，生成式V-5化合物；
    (v)在碱存在下，式V-5化合物通过反应，生成式V-6化合物；
    (vi)在酸存在下，式V-6化合物脱保护，生成式V-7化合物；
    (vii)式V-7通过取代或者酰化反应，得到式(III)化合物；
    式中，
    Rs和Rs'为氨基的保护基，所述保护基选自：Boc、Bn、Cbz或Fmoc；
    R 1、R 2、R 3、R 4、L、X、Y、Z、W和m定义如权利要求1所述。
  13. 一种药物组合物，其特征在于，包含一种或多种权利要求1所述通式(I)结构的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药；和药学上可接受的载体。
  14. 一种权利要求1所述的具有通式(I)结构的环烷基类和杂环烷基类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或权利要求13所述的药物组合物的用途，其特征在于，用于制备预防和/或治疗与KRAS G12C的活性或表达量相关的疾病的药物组合物。
  15. 提供了一种非诊断性、非治疗性地抑制KRAS G12C的方法，它包括步骤：向所需患者施用有效量的权利要求1所述的通式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或施用权利要求13所述的药物组合物。
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