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WO2021098859A1 - 氮杂七元环类抑制剂及其制备方法和应用 - Google Patents

氮杂七元环类抑制剂及其制备方法和应用 Download PDF

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Publication number
WO2021098859A1
WO2021098859A1 PCT/CN2020/130641 CN2020130641W WO2021098859A1 WO 2021098859 A1 WO2021098859 A1 WO 2021098859A1 CN 2020130641 W CN2020130641 W CN 2020130641W WO 2021098859 A1 WO2021098859 A1 WO 2021098859A1
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group
alkyl
alkoxy
deuterated
substituted
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PCT/CN2020/130641
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English (en)
French (fr)
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吕彬华
崔大为
刘连军
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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 WO2021098859A1 publication Critical patent/WO2021098859A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention belongs to the field of medicine, and specifically relates to an aza seven-membered ring 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.
  • EGFR inhibitors such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, pirotinib, and Role (Tinib, osimertinib, etc.), ALK inhibitors (such as ceritinib, alectinib, brigatinib, loratinib, okatinib, etc.), and VEGFR inhibitors (sorafil (Current Medicinal Chemistry, 2019, 26, 1-39).
  • EGFR inhibitors such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, pirotinib, and Role (Tinib, osimertinib, etc.)
  • ALK inhibitors such as ceritinib, alectinib, brigatinib, loratini
  • 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 first aspect of the present invention provides an aza seven-membered ring compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, and hydrates , Solvate or prodrug:
  • a and B are the same or different, and each is independently selected from: CH, CR 5 or N;
  • C, D, E, and F are the same or different, and are each independently selected from the following group: O, S, SO, SO 2 , CO, CH, CR 3a R 3b , N, NH, NR 3a ; C, D, E , N, F and the two adjacent carbons on the pyrimidine ring to which they are connected form a seven-membered ring; wherein R 3a and R 3b are each independently selected from the following group: hydrogen, deuterium, oxygen, halogen, hydroxyl, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; or R 3a and R 3b and the connected carbon atoms form a C 3 -C 6 cycloalkyl or 4-6 membered heterocyclic group; wherein, the The seven-membered ring can be further substituted;
  • Y is independently selected from the 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 independently 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 , 4-20 membered heterocyclylene, C 1 -C 18 alkyleneoxy, deuterated C 1 -C 18 alkyleneoxy, halogenated C 1 -C 18 alkyleneoxy;
  • W is independently 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, NHSO 2 NR 5 , NR 5 SO 2 NR 6 ;
  • R 1 is independently selected from: among them, Represents a double bond or a triple bond;
  • R 1 is independently selected from: among them, Represents a double bond or a triple bond;
  • R A is not present, or is independently selected from the following group: hydrogen, deuterium, fluorine, cyano or C 1 -C 3 alkyl
  • R B is independently selected from the following group: hydrogen, deuterium, cyano or C 1- C 3 alkyl; wherein, the C 1 -C 3 alkyl can be substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, amine, 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;
  • R 7 is selected From the following group: substituted or unsubstituted C 1 -C 18 alkyl, substituted or unsubstituted C 3 -C 20 cycloalkyl, or substituted or unsubstituted 4-20 membered heterocyclic group;
  • R 4 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, halo 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 Alkyl, 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, 4-20 membered heterocyclic group, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or ureido group;
  • n is an integer of 0, 1, 2, 3, 4 or 5;
  • q is an integer of 0, 1, 2, 3, 4, or 5.
  • C, D, E, and F are the same or different, and are each independently selected from the following group: O, S, SO, SO 2 , CO, CH, CR 3a R 3b , N, NH, NR 3a ; C, D, E, N, F and two adjacent carbons on the pyrimidine ring to which they are connected form a 7-membered heterocyclic group; wherein R 3a and R 3b are each independently selected from the following group: hydrogen, deuterium, Oxygen, halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; or R 3a and R 3b and the connected carbon atoms form a C 3 -C 6 cycloalkyl or 4- A 6-membered heterocyclic group; wherein, the 7-membered heterocyclic group may be further substituted; wherein, the substitution refers to being substituted by one or more groups selected from the following group: hydrogen, deuterium, C 1 -
  • E is SO 2 .
  • D is SO 2 .
  • E is CO
  • C is CR 3a R 3b , and R 3a and R 3b and the connected carbon atoms form a C 3 -C 6 cycloalkyl group or a C 4 -C 6 heterocyclic group.
  • L is a bond
  • Y is O.
  • R 8 is independently selected from the following substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1- C 6 alkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, amino, hydroxyl, 4-7 membered heterocyclic group, C 6 -C 14 aryl, 5-14 membered heteroaryl; the substitution is selected from the following group: halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or ureido.
  • R 8 is independently selected from the following substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 3 alkyl, deuterated C 1 -C 3 alkyl, halo C 1- C 3 alkyl, C 1 -C 3 alkoxy, deuterated C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkoxy, amino, hydroxyl, 4-7 membered heterocyclic group, phenyl , Pyrimidinyl, pyridyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl; the substitution is selected from the following group: halogen, nitro, hydroxyl, cyano, ester, Amine group, amide group, sulfonamide group or urea group.
  • Z is independently selected from the following group: bond, C 1 -C 6 alkylene, deuterated C 1 -C 6 alkylene, halogenated C 1 -C 6 alkylene, C 3 -C 6 azacycloalkyl, 4-7 membered heterocyclylene, C 1 -C 6 alkyleneoxy, deuterated C 1 -C 6 alkyleneoxy, halogenated C 1 -C 6 alkylene Oxy.
  • R 5 and R 6 are the same or different, and are each independently selected from substituted or unsubstituted Group of groups: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo 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, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclic group, C 6- C 14 aryl, 5-14 membered heteroaryl; wherein, the substitution refers to substitution by one or more groups selected from the following group: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, deuterated C 1 -C 6 alky
  • R 2 is independently 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 or -(CH 2 ) n NR 5 S(O) q NR 5 R 7
  • the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has the general formula (II The structure shown in -A) or (II-B):
  • R 1 , R 2 , R 4 , A, B, X, Y, Z, L, W, C, D, E, and F are as described above.
  • the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has the general formula (III ) Shows the structure:
  • R 1 , R 2 , R 4 , X, Y, Z, L, W, C, D, E, and F are as described above.
  • the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has the general formula (IV -A) shows the structure:
  • R 1 , R 2 , R 3a , R 3b , R 4 , X, Y, Z, L, and W are as described above.
  • R 1 , R 2 , R 4 , X, Y, Z, L, and W are as described above.
  • R 1 , R 2 , R 4 , X, Z, W, C, D, E, and F are as described above.
  • the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has the general formula (VI ) Shows the structure:
  • R 1 , R 2 , R 4 , R 8 , Y, Z, L, W, C, D, E, and F are as described above.
  • the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has the general formula (VII ) Shows the structure:
  • R 1 , R 2 , R 4 , R 8 , Y, Z, W, C, D, E, and F are as described above.
  • the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has the general formula (VIII ) Shows the structure:
  • R 1 , R 2 , R 4 , R 8 , Z, W, C, D, E, and F are as described above.
  • R 1 , R 2 , R 4 , R 8 , C, D, E, and F are as described above.
  • the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has the general formula (IX The structure shown in -A) or (IX-B):
  • R 1 , R 2 , R 4 , R 5 , R 8 , Z, C, D, E, and F are as described above.
  • the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug is selected from the following group:
  • the compound of formula I is the compound shown in the embodiment.
  • an aza seven-membered ring compound of the general formula (IV-B) structure in the second aspect of the present invention, there is provided an aza seven-membered ring compound of the general formula (IV-B) structure, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts,
  • the method of hydrate, solvate or prodrug includes the steps:
  • R and Rs' are protecting groups for amino groups, and the protecting groups are selected from: Boc, Bn, Cbz or Fmoc;
  • the deprotection agent is selected from: (Boc) 2 O, benzyl chloroformate, di-tert-butyl dicarbonate, phthaloyl chloride, benzyl chloride, triphenylchloromethane, 9-fluorenyl methyl chloroformate , Allyl chloroformate.
  • R 1 , R 2 , R 4 , L, X, Y, Z, and W are as described above.
  • the first base is TEA or DIPEA.
  • the second base is sodium alkoxide, potassium alkoxide, NaH or LiHNMDS, preferably sodium tert-butoxide or potassium tert-butoxide.
  • the acid in the step (v), 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, cemipilimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10 , BAT1306, AK105, LZM 009 or biological analogues of the above drugs, etc.
  • PD-L1 inhibitors such as duvacizumab, atezolizumab, avelumab, 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, obin utuzumab, Ofatumumab, veltuzumab, tositumomab, 131
  • MEK inhibitors such as simetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, Pim asertib (AS-703026), PD184352 (CI-1040), etc.
  • mTOR inhibitors such as Vistusertib, etc.
  • SHP2 inhibitors such as RMC-4630, JAB-3068,
  • 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 an aza seven-membered ring compound having the structure of general formula (I) as described in the first aspect, its stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable
  • the use of the salt, hydrate, solvate or prodrug, or the pharmaceutical composition of the third aspect is used 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 method for inhibiting the inhibition of KRAS G12C in vitro, which comprises the steps of: combining the compound described in the first aspect, its stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable salts , Hydrate, solvate or prodrug or the composition of the third aspect, contacting somatic cells.
  • the somatic cells are derived from primates (such as humans).
  • the sixth aspect of the present invention provides a method for preventing and/or treating diseases related to the activity or expression level of KRAS G12C , which comprises the steps of: administering an effective amount of a compound of general formula (I) as described above to the patient in need , Its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or administration of the above-mentioned pharmaceutical composition.
  • alkyl refers to straight or branched chain or cyclic alkyl, such as methyl, ethyl, propyl, isopropyl N-butyl, tert-butyl, isobutyl (e.g. ), n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl.
  • Substituted alkyl means that one or more positions in the alkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.
  • alkylene refers to a group formed by the removal of a hydrogen atom from the “alkyl” group, such as methylene, ethylene, propylene, isopropylene (such as ), butylene (e.g. ), pentylene (e.g. ), hexyl (e.g. ), Heptyl (e.g. )Wait.
  • cycloalkyl refers to a fully saturated or partially saturated cyclic hydrocarbon compound group, including 1-4 rings, each ring containing 3-8 carbon atoms.
  • the cycloalkyl group is preferably a C3-20 cycloalkyl group, more preferably a C3-12 cycloalkyl group, more preferably a C3-8 cycloalkyl group, and more preferably a C5-6 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.
  • cycloalkylene refers to a group formed by removing two hydrogen atoms from a cycloalkyl group, such as: Wait.
  • heterocyclyl refers to a fully saturated or partially unsaturated cyclic group (including but not limited to, for example, 3-7 membered monocyclic ring, 6-11 membered bicyclic ring, or 8-16 membered tricyclic ring system), At least one 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. Among them, nitrogen atoms or sulfur atoms can be oxidized, and nitrogen atoms can also be Is quaternized.
  • the heterocyclic group can be attached to any heteroatom or carbon atom residue of the ring or ring system molecule.
  • the heterocyclic group is preferably a 3-20 membered heterocyclic group, more preferably a 3-12 membered heterocyclic group, more preferably a 3-8 membered heterocyclic group, and more preferably a 5-6 membered heterocyclic group.
  • 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, fused and bridged heterocyclic groups; among them, the involved spiro, fused and bridged heterocyclic groups are optionally connected to other groups through single bonds, or through Any two or more atoms on the ring are further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups in parallel; the heterocyclic group may be substituted or unsubstituted, when substituted ,
  • the substituent is preferably one or more lower 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.
  • even-membered ring includes seven-membered cycloalkyl and seven-membered heterocyclyl, wherein cycloalkyl and heterocyclyl are as defined above.
  • 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 with 1-5 rings, especially monocyclic 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.
  • alkoxy refers to a straight or branched chain or cyclic alkoxy group, preferably a C1-C8 alkoxy group, more preferably a C1-C6 alkoxy group, more preferably a C1-C3 alkyleneoxy group, without limitation Properties include methoxy, ethoxy, propoxy, isopropoxy and butoxy. .
  • alkyleneoxy refers to a group obtained by removing one hydrogen atom from the "alkoxy”. It is preferably a C1-C6 alkyleneoxy group, and more preferably a C1-C3 alkyleneoxy group.
  • 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.
  • 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, 3-12 membered heterocyclic group, C6-C10 aryl group, 5-14 membered heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, C1-C6 alkoxy group, C1 -C10 sulfonyl, and C1-C6 ureido, etc.
  • 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 terms "compounds of the present invention” or “active ingredients of the present invention” are used interchangeably and refer to compounds of formula I, or pharmaceutically acceptable salts, hydrates, solvates, isotopic compounds (such as deuterated Compound) or prodrug.
  • the term also includes racemates and optical isomers.
  • the compound of formula I has the following structure:
  • X is independently a 4-14 membered saturated or unsaturated nitrogen heterocyclic ring, wherein the saturated or unsaturated nitrogen heterocyclic ring may be optionally substituted by one or more R 8 , R 8 independently Ground is 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, C 1 -C 6 Alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, amino, hydroxyl, 4-7 membered heterocyclic group, C 6 -C 14 aryl, 5-14 membered Heteroaryl; the substitution is selected from the following group: halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or ureido.
  • the compound of formula I has a structure represented by the general formula (II-A) or (II-B):
  • R 1 , R 2 , R 4 , A, B, X, Y, Z, L, W, C, D, E, and F are as described above.
  • the compound of formula I has a structure represented by general formula (III):
  • R 1 , R 2 , R 4 , X, Y, Z, L, W, C, D, E, and F are as described above.
  • the compound of formula I has a structure represented by the general formula (IV-A):
  • R 1 , R 2 , R 3a , R 3b , R 4 , X, Y, Z, L, and W are as described above.
  • the compound of formula I has a structure represented by the general formula (IV-B):
  • R 1 , R 2 , R 4 , X, Y, Z, L, and W are as described above.
  • the compound of formula I has a structure represented by general formula (V):
  • R 1 , R 2 , R 4 , X, Z, W, C, D, E, and F are as described above.
  • the compound of formula I has a structure represented by general formula (VI):
  • R 1 , R 2 , R 4 , R 8 , Y, Z, L, W, C, D, E, and F are as described above.
  • the compound of formula I has a structure represented by general formula (VII):
  • R 1 , R 2 , R 4 , R 8 , Y, Z, W, C, D, E, and F are as described above.
  • the compound of formula I has a structure represented by general formula (VIII):
  • R 1 , R 2 , R 4 , R 8 , Z, W, C, D, E, and F are as described above.
  • the compound of formula I has a structure represented by general formula (XII):
  • R 1 , R 2 , R 4 , R 8 , C, D, E, and F are as described above.
  • the compound of formula I has a structure represented by the general formula (IX-A) or (IX-B):
  • R 1 , R 2 , R 4 , R 5 , R 8 , Z, C, D, E, and F are as described above.
  • R 3a and R 3b are as described above.
  • Z is independently selected from the following group: bond, C 1 -C 6 alkylene, deuterated C 1 -C 6 alkylene, halogenated C 1 -C 6 alkylene, C 3 -C 6 azacycloalkylene, 4-7 membered heterocyclylene, C 1 -C 6 alkyleneoxy, deuterated C 1 -C 6 alkyleneoxy, halogenated C 1 -C 6 alkylene Alkoxy.
  • 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, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, amino, hydroxyl, 4-7 membered heterocyclic group, C 6 -C 14 aryl, 5-14 membered heteroaryl; more preferably, R 8 is independently selected from the following substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 3 alkyl, deuterated C 1- C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, deuterated C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkoxy, amino, Hydroxy, 4
  • substitution is selected from the group consisting of halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea.
  • R 4 is independently 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 alkane Group, C 3 -C 12 cycloalkyl 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, 4-12 Membered heterocyclic group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group; wherein, the substitution refers to substitution by one or more groups selected from the following group: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C
  • R 2 is independently 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 or -(CH 2 ) n NR 5 S(O)
  • R 7 is selected from: substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted 4-7 membered heterocyclic group;
  • R 5 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, halo 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, C 3 -C 6 cycloalkyl , 4-7 membered heterocyclic group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group;
  • substitution refers to substitution by one or more groups selected from the following group: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkane Group, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-7 membered heterocyclic group, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or ureido group;
  • R 1 is a group corresponding to each specific compound in the embodiment.
  • 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 coverage.
  • 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.
  • each position of the substituents may be the same or different.
  • substitution as used herein includes all permissible substitution of organic compounds. Broadly speaking, 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 (X-1) generates intermediate general formula (X-2) under the action of a base (such as TEA or DIPEA); then the intermediate (X-3) is obtained through substitution reaction; the deprotection group Rs generates intermediate ( X-4); Compound (X-4) obtains intermediate (X-5) through coupling or substitution or acylation reaction; deprotection group Rs' generates intermediate (X-6); then through substitution or acylation reaction
  • the general formula (IV-B) of the target product is obtained; wherein, R 1 , R 2 , R 4 , Y, Z, W, X and L are as defined above, and Rs and Rs' are amino protecting groups (such as Boc, Bn , Cbz or Fmoc).
  • 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.
  • 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, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biological analogues of the above drugs, etc.), PD-L1 inhibitors (such as Vavazumab, atezizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311 or the above drugs Biosimilar drugs, etc.), CD20 antibodies (such as rituximab, obin utuzumab, ofatum
  • BTK inhibitors e.g. Ibrutinib, Tirabrutinib, Akatinib, Zambu Tinib, Vecabrutinib, etc.
  • EGFR inhibitors such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, canetinib, shaproti) Ni, Naquotinib, pyrrotinib, rollotinib, osimertinib, etc.
  • VEGFR inhibitors such as sorafenib, pazopanib, regorafenib, stritinib, Ningetinib, cabozinib, etc. Ni, sunitinib, don
  • 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 Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • 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) humectant, 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, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycyl
  • 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 the general formula (I) of the present invention, or a crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, 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 Waters SQD2 mass spectrometer.
  • HPLC measurement uses Agilent 1100 high pressure chromatograph (Microsorb 5micron C18 100x3.0mm 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.
  • Step 1 Preparation of 5-(benzyl-ethoxycarbonylmethyl-amino)-pentanoic acid ethyl ester
  • the third step preparation of 8-benzyl-6,7,8,9-tetrahydro-5H-pyrimidine[4,5-c]azazep-2,4-diol
  • Step 6 4-(8-Benzyl-2-chloro-6,7,8,9-tetrahydro-5H-pyrimidine[4,5-c]azazid-4-yl)-2-cyano Preparation of tert-butyl methyl-piperazine-1-carboxylate
  • the seventh step 4-(8-benzyl-2-(((S)-1-methyl-pyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H- Preparation of pyrimidinyl[4,5-c]azazid-4-yl)-2-cyanomethylpiperazine-1-carboxylic acid tert-butyl ester
  • the first step 2-(cyanomethyl)-4-(8-(8-methylnaphthalene-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy Yl)-6,7,8,9-tetrahydro-5H-pyrimidine[4,5-c]azazid-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • reaction liquid was replaced with nitrogen three times, it was heated to 72° C. and stirred for 16 h.
  • acetonitrile (1 mL) was added to the reaction, and then filtered.
  • the second step 2-(4-(8-(8-methylnaphthalene-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6, Preparation of 7,8,9-tetrahydro-5H-pyrimidine[4,5-c]azazid-4-yl)piperazin-2-yl)acetonitrile
  • the third step 2-(1-acryloyl-4-(8-(8-methylnaphthalene-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy (Base)-6,7,8,9-tetrahydro-5H-pyrimidine[4,5-c]azepine-4-yl)piperazin-2-yl)acetonitrile
  • reaction solution was raised to room temperature and stirred for 1 h, and then quenched by adding 1 mL of methanol.
  • the compounds to be tested were diluted in a gradient, each compound was diluted in 10 concentration gradients (diluted from 50 ⁇ M to 0.003 ⁇ M) and 100 nL was added to the corresponding wells of the microplate. After adding the drug, add 40 ⁇ L of phosphate buffer to each well in rows A, P and columns 1, 24, and then place the microtiter plate in a carbon dioxide incubator for 5 days.
  • the compounds of the examples of the present invention show good cell anti-proliferation activity against KRAS G12C mutant NCI-H358 cells, and at the same time have weak anti-proliferative activity against KRAS G12S mutant A549 cells, showing high selectivity.

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Abstract

氮杂七元环类抑制剂及其制备方法和应用。具体地，化合物具有式(I)所示结构，所述化合物的制备方法及其作为KRAS G12C抑制剂的用途，对KRAS G12C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

氮杂七元环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，具体涉及一种氮杂七元环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(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、埃克替尼、吡咯替尼、罗乐替尼、奥希替尼等)，ALK抑制剂(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼等)，以及VEGFR抑制剂(索拉非尼、瑞戈替尼、卡博替尼、舒尼替尼、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
本发明第一方面，提供了一种具有通式(I)结构的氮杂七元环类化合物、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 PCTCN2020130641-appb-000001
式中：
A、B相同或者不同，且各自独立地选自：CH、CR 5或N；
C、D、E、F相同或者不同，且各自独立地选自下组：O、S、SO、SO 2、CO、CH、CR 3aR 3b、N、NH、NR 3a；C、D、E、N、F和其连接的嘧啶环上相邻的两个碳形成七元环；其中，R 3a和R 3b各自独立地选自下组：氢、氘、氧、卤素、羟基、氰基、C 1-C 6烷基、C 1-C 6烷氧基；或者R 3a和R 3b及相连的碳原子形成C 3-C 6环烷基或4-6元杂环基；其中，所述七元环可进一步被取代；
X独立地选自下组：4-14元饱和或不饱和的氮杂环或杂环基、C 6-C 14芳基或者5-14元杂芳基，其中，所述的饱和或不饱和的氮杂环或杂环基、芳基或者杂芳基可以任选地被一个或多个R 8所取代；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；
Y独立地选自下组：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独立地选自下组：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、4-20元亚杂环基、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独立地选自下组：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、NHSO 2NR 5、NR 5SO 2NR 6；
当B为N时，R 1独立地选自：
Figure PCTCN2020130641-appb-000002
其中，
Figure PCTCN2020130641-appb-000003
表示双键或三键；
当B选自CH或CR 5，R 1独立地选自：
Figure PCTCN2020130641-appb-000004
Figure PCTCN2020130641-appb-000005
其中，
Figure PCTCN2020130641-appb-000006
表示双键或三键；
R A为不存在，或者独立地选自下组：氢、氘、氟、氰基或者C 1-C 3烷基；R B独立地选自下组：氢、氘、氰基或者C 1-C 3烷基；其中，所述C 1-C 3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；
R 2独立地选自下组：-(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或-(CH 2) nNR 5S(O) qNR 5R 7，其中，CH 2中的H可以被取代；R 7选自下组：取代或未取代的C 1-C 18烷基、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；
L选自下组：键、-C(O)-、C 1-C 3亚烷基；
R 4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、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、卤素、氨基、羟基、氰基、胺基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基；
其中，所述取代是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；
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。
在另一优选例中，C、D、E、F相同或者不同，且各自独立地选自下组：O、S、SO、SO 2、CO、CH、CR 3aR 3b、N、NH、NR 3a；C、D、E、N、F和其连接的嘧啶环上相邻的两个碳形成7元杂环基；其中，R 3a和R 3b各自独立地选自下组：氢、氘、氧、卤素、羟基、氰基、C 1-C 6烷基、C 1-C 6烷氧基；或者R 3a和R 3b及相连的碳原子形成C 3-C 6的环烷基或4-6元的杂环基；其中，所述7元杂环基可进一步被取代；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 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、C 6-C 10芳基、5-10元杂芳基、4-6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，E为SO 2。
在另一优选例中，D为SO 2。
在另一优选例中，E为CO。
在另一优选例中，C为CR 3aR 3b，且R 3a和R 3b及相连的碳原子形成C 3-C 6的环烷基或C 4-C 6的杂环基。
在另一优选例中，L为键。
在另一优选例中，Y为O。
在另一优选例中，X独立地为4-14元饱和或不饱和的氮杂环，其中，所述的饱和或不饱和的氮杂环可以任选地被一个或多个R 8所取代，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、4-7元杂环基、C 6-C 14芳基、5-14元杂芳基；所述取代选自下组：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，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、4-7元杂环基、C 6-C 14芳基、5-14元杂芳基；所述取代选自下组：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，R 8独立地选自取代或未取代的下组基团：氢、氘、C 1-C 3烷基、氘代C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基、氘代C 1-C 3烷氧基、卤代C 1-C 3烷氧基、氨基、羟基、4-7元杂环基、苯基、嘧啶基、吡啶基、呋喃基、噻吩基、咪唑基、吡唑基、恶唑基、异恶唑基；所述取代选自下组：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，Y独立地选自下组：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；R 5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 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、C 3-C 6环烷基、4-7元杂环基、C 6-C 14芳基、5-14元杂芳基；其中，所述取代是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 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、C 6-C 10芳基、5-14元杂芳基、4-7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，Z独立地选自下组：键、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 6亚氮杂环烷基、4-7元亚杂环基、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。
在另一优选例中，W独立地选自下组：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、NHSO 2NR 5、NR 5SO 2NR 6；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 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、C 3-C 6环烷基、4-7元杂环基、C 6-C 14芳基、5-14元杂芳基；其中，所述 取代是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 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、C 6-C 14芳基、5-14元杂芳基、4-7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，R 4独立地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 12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、胺基、羟基、4-12元杂环基、C 6-C 14芳基、5-14元杂芳基；其中，所述取代是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 3-C 12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、苯基、嘧啶基、吡啶基、呋喃基、噻吩基、咪唑基、吡唑基、恶唑基、异恶唑基、4-12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，R 2独立地选自下组：-(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或-(CH 2) nNR 5S(O) qNR 5R 7，其中，CH 2中的H可以被取代；且R 7选自：取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 6环烷基或取代或未取代的4-7元杂环基；其中，CH 2中的H可以被取代；R 7选自下组：取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 6环烷基，或取代或未取代的4-7元杂环基；R 5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 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、C 3-C 6环烷基、4-7元杂环基、C 6-C 14芳基、5-14元杂芳基；其中，所述取代是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-C6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、C 6-C 14芳基、5-14元杂芳基、4-7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；n为0、1、2、3、4或5的整数；q为0、1、2、3、4或5的整数。
在另一优选例中，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(II-A)或(II-B)所示的结构：
Figure PCTCN2020130641-appb-000007
式中：
R 1、R 2、R 4、A、B、X、Y、Z、L、W、C、D、E、F的定义如上所述。
在另一优选例中，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(III)所示结构：
Figure PCTCN2020130641-appb-000008
R 1、R 2、R 4、X、Y、Z、L、W、C、D、E、F的定义如上所述。
在另一优选例中，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(IV-A)所示结构：
Figure PCTCN2020130641-appb-000009
R 1、R 2、R 3a、R 3b、R 4、X、Y、Z、L、W的定义如上所述。
在另一优选例中，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(IV-B)所示结构：
Figure PCTCN2020130641-appb-000010
R 1、R 2、R 4、X、Y、Z、L、W的定义如上所述。
在另一优选例中，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，具有通式(V)所示结构：
Figure PCTCN2020130641-appb-000011
R 1、R 2、R 4、X、Z、W、C、D、E、F的定义如上所述。
在另一优选例中，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(VI)所示结构：
Figure PCTCN2020130641-appb-000012
式中：
R 1、R 2、R 4、R 8、Y、Z、L、W、C、D、E、F的定义如上所述。
在另一优选例中，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(VII)所示结构：
Figure PCTCN2020130641-appb-000013
式中：
R 1、R 2、R 4、R 8、Y、Z、W、C、D、E、F的定义如上所述。
在另一优选例中，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 PCTCN2020130641-appb-000014
式中：
R 1、R 2、R 4、R 8、Z、W、C、D、E、F的定义如上所述。
在另一优选例中，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(XII)所示结构：
Figure PCTCN2020130641-appb-000015
其中，R 1、R 2、R 4、R 8、C、D、E、F的定义如上所述。
在另一优选例中，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(IX-A)或(IX-B)所示的结构：
Figure PCTCN2020130641-appb-000016
式中：
R 1、R 2、R 4、R 5、R 8、Z、C、D、E、F的定义如上所述。
在另一优选例中，
Figure PCTCN2020130641-appb-000017
部分为
Figure PCTCN2020130641-appb-000018
在另一优选例中，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，其选自下组：
Figure PCTCN2020130641-appb-000019
Figure PCTCN2020130641-appb-000020
Figure PCTCN2020130641-appb-000021
Figure PCTCN2020130641-appb-000022
Figure PCTCN2020130641-appb-000023
Figure PCTCN2020130641-appb-000024
Figure PCTCN2020130641-appb-000025
Figure PCTCN2020130641-appb-000026
Figure PCTCN2020130641-appb-000027
Figure PCTCN2020130641-appb-000028
Figure PCTCN2020130641-appb-000029
Figure PCTCN2020130641-appb-000030
Figure PCTCN2020130641-appb-000031
Figure PCTCN2020130641-appb-000032
Figure PCTCN2020130641-appb-000033
Figure PCTCN2020130641-appb-000034
Figure PCTCN2020130641-appb-000035
Figure PCTCN2020130641-appb-000036
Figure PCTCN2020130641-appb-000037
Figure PCTCN2020130641-appb-000038
在另一优选例中，所述式I化合物为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(IV-B)结构的氮杂七元环类化合物、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 PCTCN2020130641-appb-000039
(i)在第一个碱作用下，式X-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X-2化合物；
(ii)在第二个碱作用下，式X-2化合物通过反应生成式X-3化合物；
(iii)在脱保护剂的作用下，式X-3化合物脱保护生成式X-4化合物；
(iv)式X-4化合物通过偶联、取代或酰化反应得到式X-5化合物；
(v)在酸作用下，式X-5化合物脱保护生成式X-6化合物；
(vii)式X-6通过取代或者酰化反应得到式(IV-B)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；
所述脱保护剂选自：(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。
R 1、R 2、R 4、L、X、Y、Z、W的定义如上所述。
在另一优选例中，所述步骤(i)中，第一种碱为TEA或DIPEA。
在另一优选例中，所述步骤(ii)中，第二种碱为醇钠、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(v)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(如纳武单抗、派姆单抗、pidilizumab、cemiplimab、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如度伐单抗、阿特珠单抗、阿维鲁单抗(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(如利妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、veltuzumab,托西莫单抗、131I-托西莫单抗、替伊莫单抗、90Y-替伊莫单抗、90In-替伊莫单抗、替伊莫单抗(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(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼)、PI3K抑制剂(如艾代拉里斯、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如依鲁替尼、Tirabrutinib、阿卡替尼、赞布替尼、Vecabrutinib等)、EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、埃克替尼、卡奈替尼、沙普替尼、Naquotinib、吡咯替尼、罗乐替尼、奥希替尼等)、VEGFR抑制剂(如索拉非尼、帕唑帕尼、瑞戈非尼、司曲替尼、Ningetinib、卡博替尼、舒尼替尼、多纳非尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、伏立诺他、Fimepinostat、Droxinostat、恩替诺特、达西司特、Quisinostat、泰克地那林等)、CDK抑制剂(如帕博西尼、瑞博西尼、Abemaciclib、Milciclib、Trilaciclib、Lerociclib等)、MEK抑制剂(如司美替尼(AZD6244)、曲美替尼(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，提供一种第一方面所述的具有通式(I)结构的氮杂七元环类化合物、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，提供一种体外抑制抑制KRAS G12C的方法，包括步骤：将第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药或第三方面所述的组合物，与体细胞接触。
在另一优选例中，所述体细胞体细胞来自灵长动物(如人)。
本发明第六方面，提供了一种预防和/或治疗与KRAS G12C的活性或表达量相关疾病的方法，它包括步骤：向所需患者施用有效量的如上所述的通式(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，或施用如上所述的药物组合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过广泛而深入的研究，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”指的是直链或支链或环状烷基，如甲基、乙基、丙基、异丙基
Figure PCTCN2020130641-appb-000040
正丁基、叔丁基、异丁基(如
Figure PCTCN2020130641-appb-000041
)、正戊基、异戊基、正己基、异己基、正庚基、异庚基。“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、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、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，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”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 PCTCN2020130641-appb-000042
)、亚丁基(如
Figure PCTCN2020130641-appb-000043
)、亚戊基(如
Figure PCTCN2020130641-appb-000044
)、亚己基(如
Figure PCTCN2020130641-appb-000045
)、亚庚基(如
Figure PCTCN2020130641-appb-000046
)等。
术语“环烷基”是指完全饱和或部分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。环烷基优选C3-20环烷基，更优选C3-12环烷基，更优选C3-8环烷基，更优选C5-6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。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“亚环烷基”是指环烷基脱掉两个氢原子所形成的基团，如：
Figure PCTCN2020130641-appb-000047
等。
术语“杂环基”是指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，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。杂环基团优选3-20元杂环基，更优选3-12元杂环基，更优选3-8元杂环基，更优选5-6元杂环基。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“七元环”包括七元环烷基、七元杂环基，其中环烷基、杂环基定义如上所述。
术语“亚杂环基”是指杂环基脱掉两个氢原子所形成的基团，如：
Figure PCTCN2020130641-appb-000048
等。
术语“芳基”是指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“烷氧基”是指直链或支链或环状烷氧基，优选为C1-C8烷氧基，更优选C1-C6烷氧基，更优选C1-C3亚烷氧基，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。。
术语“亚烷氧基”是指“烷氧基”脱掉一个氢原子所得基团。优选C1-C6亚烷氧基，更优选C1-C3亚烷氧基。
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“多个”是指两个或两个以上。
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、3-12元杂环基、C6-C10芳基、5-14元杂芳基、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，术语“本发明的化合物”或“本发明的活性成分”可互换使用，指式I化合物、或其药学上可接受的盐、水合物、溶剂化物、同位素化合物(如氘代化合物)或前药。该术语还包括外消旋体、光学异构体。
所述的式I化合物具有如下结构：
Figure PCTCN2020130641-appb-000049
式中：
A、B、C、D、E、F、X、Y、Z、W、L、R 1、R 2、R 4的定义如上所述。
优选地，X独立地为4-14元饱和或不饱和的氮杂环，其中，所述的饱和或不饱和的氮杂环可以任选地被一个或多个R 8所取代，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、4-7元杂环基、C 6-C 14芳基、5-14元杂芳基；所述取代选自下组：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，所述的式I化合物具有通式(II-A)或(II-B)所示的结构：
Figure PCTCN2020130641-appb-000050
式中：
R 1、R 2、R 4、A、B、X、Y、Z、L、W、C、D、E、F的定义如上所述。
优选地，所述的式I化合物具有通式(III)所示结构：
Figure PCTCN2020130641-appb-000051
R 1、R 2、R 4、X、Y、Z、L、W、C、D、E、F的定义如上所述。
优选地，所述的式I化合物具有通式(IV-A)所示结构：
Figure PCTCN2020130641-appb-000052
R 1、R 2、R 3a、R 3b、R 4、X、Y、Z、L、W的定义如上所述。
优选地，所述的式I化合物具有通式(IV-B)所示结构：
Figure PCTCN2020130641-appb-000053
R 1、R 2、R 4、X、Y、Z、L、W的定义如上所述。
优选地，所述的式I化合物具有通式(V)所示结构：
Figure PCTCN2020130641-appb-000054
R 1、R 2、R 4、X、Z、W、C、D、E、F的定义如上所述。
优选地，所述的式I化合物具有通式(VI)所示结构：
Figure PCTCN2020130641-appb-000055
式中：
R 1、R 2、R 4、R 8、Y、Z、L、W、C、D、E、F的定义如上所述。
优选地，所述的式I化合物具有通式(VII)所示结构：
Figure PCTCN2020130641-appb-000056
式中：
R 1、R 2、R 4、R 8、Y、Z、W、C、D、E、F的定义如上所述。
优选地，所述的式I化合物具有通式(VIII)所示结构：
Figure PCTCN2020130641-appb-000057
式中：
R 1、R 2、R 4、R 8、Z、W、C、D、E、F的定义如上所述。
优选地，所述的式I化合物具有通式(XII)所示结构：
Figure PCTCN2020130641-appb-000058
其中，R 1、R 2、R 4、R 8、C、D、E、F的定义如上所述。
优选地，所述的式I化合物具有通式(IX-A)或(IX-B)所示的结构：
Figure PCTCN2020130641-appb-000059
式中：
R 1、R 2、R 4、R 5、R 8、Z、C、D、E、F的定义如上所述。
优选地，上述各式中，
Figure PCTCN2020130641-appb-000060
部分为
Figure PCTCN2020130641-appb-000061
优选地为
Figure PCTCN2020130641-appb-000062
其中R 3a、R 3b的定义如上所述。
优选地，上述各式中，Z独立地选自下组：键、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 6亚氮杂环烷基、4-7元亚杂环基、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。
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、4-7元杂环基、C 6-C 14芳基、5-14元杂芳基；更优选地，R 8独立地选自取代或未取代的下组基团：氢、氘、C 1-C 3烷基、氘代C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基、氘代C 1-C 3烷氧基、卤代C 1-C 3烷氧基、氨基、羟基、4-7元杂环基、苯基、嘧啶基、吡啶基、呋喃基、噻吩基、咪唑基、吡唑基、恶唑基、异恶唑基；
所述取代选自下组：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，上述各式中，R 4独立地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 12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、胺基、羟基、4-12元杂环基、C 6-C 14芳基、5-14元杂芳基；其中，所述取代是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 3-C 12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、苯基、嘧啶基、吡啶基、呋喃基、噻吩基、咪唑基、吡唑基、恶唑基、异恶唑基、4-12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。
优选地，上述各式中，R 2独立地选自下组：-(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或-(CH 2) nNR 5S(O) qNR 5R 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 1-C 6烷基、取代或未取代的C 3-C 6环烷基或取代或未取代的4-7元杂环基；
R 5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 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、C 3-C 6环烷基、4-7元杂环基、C 6-C 14芳基、5-14元杂芳基；
其中，所述取代是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-C6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、C 6-C 14芳基、5-14元杂芳基、4-7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；
n为0、1、2、3、4或5的整数；q为0、1、2、3、4或5的整数。
优选地，上述各式中，R 1为实施例中各具体化合物所对应基团。
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(VI)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 PCTCN2020130641-appb-000063
通式(X-1)化合物在碱(如TEA或DIPEA)作用下生成中间体通式(X-2)；然后通过取代反应得到中间体(X-3)；脱保护基Rs生成中间体(X-4)；化合物(X-4)通过偶联或取代或酰化反应得到中间体(X-5)；脱保护基Rs’生成中间体(X-6)；然后通过取代或者酰化反应得到目标产物通式(IV-B)；其中，R 1、R 2、R 4、Y、Z、W、X和L定义如上文所述，Rs和Rs'为氨基保护基(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(如纳武单抗、派姆单抗、pidilizumab、cemiplimab、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如度伐单抗、阿特珠单抗、阿维鲁单抗(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(如利妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、veltuzumab,托西莫单抗、131I-托西莫单抗、替伊莫单抗、90Y-替伊莫单抗、90In-替伊莫单抗、替伊莫单抗(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(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼)、PI3K抑制剂(如艾代拉里斯、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如依鲁替尼、Tirabrutinib、阿卡替尼、赞布替尼、Vecabrutinib等)、EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、埃克替尼、卡奈替尼、沙普替尼、Naquotinib、吡咯替尼、罗乐替尼、奥希替尼等)、VEGFR抑制剂(如索拉非尼、帕唑帕尼、瑞戈非尼、司曲替尼、Ningetinib、卡博替尼、舒尼替尼、多纳非尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、伏立诺他、Fimepinostat、Droxinostat、恩替诺特、达西司特、Quisinostat、泰克地那林等)、CDK抑制剂(如帕博西尼、瑞博西尼、Abemaciclib、Milciclib、Trilaciclib、Lerociclib等)、MEK抑制剂(如司美替尼(AZD6244)、曲美替尼(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
Figure PCTCN2020130641-appb-000064
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Agilent 1100高压色谱仪(Microsorb 5micron C18 100x3.0mm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-氰基甲基-4-[2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7,8,9-四氢-5H-嘧啶基[4,5-c]氮杂卓-4-基]-哌嗪-1-羧酸叔丁酯的制备
Figure PCTCN2020130641-appb-000065
第一步:5-(苄基-乙氧基羰基甲基-氨基)-戊酸乙酯的制备
将苄基氨基乙酸乙酯(50g，259mmol)、5-溴戊酸乙酯(65g，311mmol)和碳酸钾(79g，570mmol)加入到600毫升乙腈中。反应液在85度回流16小时，然后抽滤除去碳酸钾。滤液减压浓缩，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝100/1到20/1)，得到目标产物(65g,收率：78％)。
LC-MS：m/z 322(M+H) +. 1H NMR(300MHz,CDCl 3)δ7.40-7.20(m,5H),4.22-4.11(m,4H),3.80(s,2H),3.32(s,2H),2.68(t,J＝7.2Hz,2H),2.31(t,J＝ 7.2Hz,2H),1.72-1.52(m,4H),1.32-1.25(m,6H).
第二步:1-苄基-3-氧代-氮杂环庚烷-4-羧酸乙酯的制备
将5-(苄基-乙氧基羰基甲基-氨基)-戊酸乙酯(65g，202mmol)溶于650毫升无水四氢呋喃中，然后在冰浴和氮气流下分批次加入钠氢(60％wt，16g，404mmol)。得到的反应液于70度回流16小时，然后将反应液置于冰裕中，用500毫升饱和氯化铵淬灭。得到的混合物用500毫升乙酸乙酯萃取3次。合并乙酸乙酯层，然后以500毫升盐水洗涤后用无水硫酸男干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝100/1到40/1)，得到目标产物(20.8g，收率：37％)。
LC-MS：m/z 276(M+H) +. 1H NMR(300MHz,CDCl 3)δ7.44-7.32(m,5H),4.32-4.20(m,2H),3.93(t,J＝6.6Hz,1H),3.79-3.67(m,2H),3.45-3.27(m,2H),2.70-2.60(m,2H),2.22-2.10(m,1H),2.09-1.95(m,1H),1.90-1.80(m,1H),1.80-1.70(m,1H),1.28(t,J＝7.2Hz,3H).
第三步:8-苄基-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-2,4-二醇的制备
将1-苄基-3-氧代-氮杂环庚烷-4-羧酸乙酯(20.8g，75.6mmol)溶于310毫升乙醇中，然后加入尿素(22.7g，378.2mmol)和甲醇钠(10.2g，189.1mmol)。反应液于90度回流16小时，然后减压浓缩。残留物溶于400毫升水中，不溶性黏稠状物抽滤除去。滤液以6M的盐酸将pH调到5～6之间，有白色固体析出，继续搅拌1小时后抽滤。得到的固体以30毫升水洗涤，然后冷冻干燥，得到目标产物(9.5g，收率：46％)。
LC-MS：m/z 272(M+H) +. 1H NMR(300MHz,DMSO-d 6)δ10.98(s,1H),10.58(s,1H),7.35-7.24(m,5H),5.40(brs,2H),3.67(s,2H),3.63(s,2H),2.81(t,J＝5.1Hz,2H),2.50(overlap,2H),1.52-1.50(m,2H).
第四步:8-苄基-2,4-二氯-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓的制备
将8-苄基-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-2,4-二醇(1g，3.7mmol)加入到12毫升三氯氧磷中，然后小心加入6毫升N,N-二异丙基乙胺。得到的反应液于110度加热搅拌16小时，然后减压浓缩除去多余的溶剂。残留物缓慢滴加到100毫升水中，然后以6M的氢氧化钠溶液调节pH大于8。得到的混合物以80毫升乙酸乙酯萃取3次。乙酸乙酯层合并后以50毫升盐水洗涤，然后用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(洗脱剂：石油醚/乙酸乙酯＝50/1到20/1)，得到目标产物(420mg，收率：37％)。
LC-MS：m/z 308(M+H) +. 1H NMR(400MHz,CDCl 3)δ7.33-7.23(m,5H),4.02(s,2H),3.67(s,2H),3.07(t,J＝5.6Hz,2H),2.96(t,J＝5.6Hz,2H),1.86-1.79(m,2H).
第五步:2-(4-(8-苄基-2-氯-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4- 基)pipera哌嗪-2-基)乙腈的制备
将8-苄基-2,4-二氯-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓(385mg，1.25mmol)、哌嗪-2-基乙腈盐酸盐(260mg，1.32mmol)和N,N-二异丙基乙胺(1mL，6.27mmol)加入到5毫升DMF中。得到的反应液在室温搅拌16小时，然后加入25毫升水，再用20毫升乙酸乙酯萃取3次。乙酸乙酯层合并后以15毫升盐水洗涤3次，然后经干燥、减压浓缩，得到目标产物。无需纯化直接用于下一步反应。
LC-MS：m/z 397(M+H) +.
第六步:4-(8-苄基-2-氯-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)-2-氰基甲基-哌嗪-1-甲酸叔丁酯的制备
将上一步得到的2-(4-(8-苄基-2-氯-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)pipera哌嗪-2-基)乙腈溶于2.7g二碳酸二叔丁酯中。得到的反应液在室温搅拌2小时，然后以硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1到2/1)，得到目标产物(490mg，两步收率：79％)。
LC-MS：m/z 497(M+H) +. 1H NMR(400MHz,CDCl 3)δ7.40-7.20(m,5H),4.61(brs,1H),4.10-4.00(m,1H),3.95-3.80(m,3H),3.79-3.60(m,3H),3.30-3.10(m,2H),3.05-2.96(m,1H),2.95-2.60(m,6H),1.90-1.70(m,2H),1.51(s,9H).
第七步:4-(8-苄基-2-(((S)-1-甲基-吡咯烷-2-基)甲氧基)-6,7,8,9-四氢-5H-嘧啶基[4,5-c]氮杂卓-4-基)-2-氰基甲基哌嗪-1-羧酸叔丁酯的制备
将(S)-(1-甲基-吡咯烷-2-基)甲醇(288mg，2.5mmol)溶于5毫升无水四氢呋喃中，冰裕下加入钠氢(60％wt，80mg，2.0mmol)。得到的反应液在氮气保护下继续搅拌30分钟，然后将4-(8-苄基-2-氯-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)-2-氰基甲基-哌嗪-1-甲酸叔丁酯(490mg，1.0mmol)的5毫升无水四氢呋喃溶液滴加到上述混合物中。得到的反应液于70度回流16小时，然后以20毫升饱和氯化铵淬灭，再以20毫升乙酸乙酯萃取3次。乙酸乙酯层合并后，经干燥后减压浓缩。残余物用硅胶柱纯化纯化(洗脱剂：二氯甲烷/甲醇＝30/1到10/1)，得到目标产物(350mg，收率：60％)。
LC-MS：m/z 576(M+H) +. 1H NMR(400MHz,CDCl 3)δ7.30-7.20(m,5H),4.60(brs,1H),4.39(dd,J＝10.8Hz,4.8Hz,1H),4.17-4.11(m,1H),4.04(brs,1H),3.88(s,2H),3.73(d,J＝14.4Hz,1H),3.68(s,2H),3.58(d,J＝12.8Hz,1H),3.20-3.11(m,3H),2.95-2.85(m,3H),2.80-2.65(m,5H),2.49(s,3H),2.35-2.27(m,1H),2.10-2.00(m,2H),1.90-1.80(m,4H),1.51(s,9H).
第八步:2-氰基甲基-4-[2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7,8,9-四氢-5H-嘧啶基[4,5-c]氮杂卓-4-基]-哌嗪-1-羧酸叔丁酯的制备
将4-(8-苄基-2-(((S)-1-甲基-吡咯烷-2-基)甲氧基)-6,7,8,9-四氢-5H-嘧啶基[4,5-c]氮杂卓-4-基)-2-氰基甲基哌嗪-1-羧酸叔丁酯(340mg，0.6mmol)溶于 15毫升7M的氨-甲醇溶液，然后加入10％Pd/C(100mg)。得到的反应液经氢气置换3次后在40度加热搅拌16小时。得到的混合物抽滤除去催化剂，滤液浓缩。得到的残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇/＝5/1，1.5‰氨水做添加剂)，得到目标产物(230mg，收率：80％)。
LC-MS：m/z 486(M+H) +. 1H NMR(400MHz,CDCl 3)δ4.59(brs,1H),4.45(dd,J＝10.8Hz,4.8Hz,1H),4.19(dd,J＝10.4Hz,6.4Hz,1H),4.02(brs,1H),3.96(s,2H),3.71(d,J＝13.2Hz,1H),3.56(d,J＝12.8Hz,1H),3.23-3.10(m,5H),2.95-2.65(m,6H),2.54(s,3H),2.40-2.35(m,1H),2.10-1.90(m,7H),1.50(s,9H).
实施例1 2-(1-丙烯酰-4-(8-(8-甲基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020130641-appb-000066
第一步:2-(氰甲基)-4-(8-(8-甲基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)哌嗪-1-甲酸叔丁酯的制备
将2-氰基甲基-4-[2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7,8,9-四氢-5H-嘧啶基[4,5-c]氮杂卓-4-基]-哌嗪-1-羧酸叔丁酯(50mg，0.10mmol)、1-溴-8-甲基萘(55mg，0.25mmol)、碳酸铯(98mg，0.30mmol)和二氧六环(2mL)加入反应瓶中，经氮气置换三次后加入Ruphos G3pd(25mg，0.03mmol)。得到的反应液经氮气置换三次后，加热至72℃搅拌16h。反应结束后，反应也中加入乙腈(1mL)，然后过滤。滤液用制备色谱纯化(乙腈:0.05％TFA水溶液＝0％到50％)，得到目标产物(18mg)。
LC-MS：m/z 626(M+H) +.
第二步:2-(4-(8-(8-甲基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)哌嗪-2-基)乙腈的制备
将2-(氰甲基)-4-(8-(8-甲基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7,8,9- 四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)哌嗪-1-甲酸叔丁酯(12mg)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，然后减压浓缩干，得到目标产物(18mg)。无需提纯直接用于下一步反应。
LC-MS：m/z 526(M+H) +.
第三步:2-(1-丙烯酰-4-(8-(8-甲基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)哌嗪-2-基)乙腈的制备
将上步得到的2-(4-(8-(8-甲基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)哌嗪-2-基)乙腈(18mg，0.024mmol)中加入二氯甲烷(1.5mL)和N,N-二异丙基乙胺(20mg，0.144mmol)，在氮气保护下降温至-40℃；随后滴加丙烯酰氯(5mg，0.048mmol)。滴加完后，反应液升至室温搅拌1h，然后加入1mL甲醇淬灭。得到的混合物减压浓缩干，残余物用制备色谱纯化(乙腈/0.05％碳酸氢铵水溶液＝5％到85％，10v)，得到目标产物(4.5mg)。
LC-MS：m/z 580(M+H) +. 1H NMR(400MHz,CDCl 3)δ7.55(m,2H),7.28(m,2H),7.13(m,2H),6.52(m,1H),6.34(d,J＝16.8Hz,1H),5.77(d,J＝10.4Hz,1H),5.04(brs,0.5H),4.53(brs,0.5H),4.33(m,2H),4.23(m,1H)，4.10(m,1H)，3.79(m,3H),3.08(m,14H),2.42(s,3H),2.28(m,1H),1.95(m,3H),1.69(m,3H)。
化合物经手性制备分离得到
2-((S)-1-丙烯酰-4-(8-(8-甲基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)哌嗪-2-基)乙腈(A)和2-((R)-1-丙烯酰-4-(8-(8-甲基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)哌嗪-2-基)乙腈(B)
Figure PCTCN2020130641-appb-000067
实施例1A 2-((S)-1-丙烯酰-4-(8-(8-甲基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)哌嗪-2-基)乙腈
LC-MS：m/z 580(M+H) +.
实施例1B 2-((R)-1-丙烯酰-4-(8-(8-甲基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)哌嗪-2-基)乙腈
LC-MS：m/z 580(M+H) +.
按照实施例1的方法，以不同的起始原料合成了以下化合物：
实施例2 2-(1-丙烯酰-4-(2-(2-(环丁基(甲基)胺基)乙氧基)-8-(8-甲基萘-1-
基)-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020130641-appb-000068
LC-MS：m/z 594(M+H) +.
实施例3 2-(1-丙烯酰-4-(2-(2-((环丙甲基)(甲基)胺基)乙氧基)-8-(8-甲基萘-1-基)-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)哌嗪-2-基)乙腈的制备
Figure PCTCN2020130641-appb-000069
LC-MS：m/z 594(M+H) +.
实施例4 2-(1-丙烯酰-4-(8-(2-甲基-3-氟苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020130641-appb-000070
LC-MS：m/z 548(M+H) +. 1H NMR(400MHz,CDCl 3)δ7.19–7.06(m,1H),6.84(d,J＝8.0Hz,1H),6.76(t,J＝8.6Hz,1H),6.61(brs,1H),6.40(d,J＝16.7Hz,1H),5.84(d,J＝10.5Hz,1H),5.31(m,1H),5.08(brs,0.5H),4.72–4.47(m,1.5H),4.37–3.50(m,7H),3.47–3.21(m,3H),3.20–2.66(m,9H),2.45–2.27(m,2H),2.26–1.98(m,8H).
实施例5 2-(1-丙烯酰-4-(8-(2-氟-3-甲基苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020130641-appb-000071
LC-MS：m/z 548(M+H) +.
实施例6 2-(1-丙烯酰-4-(8-(2-氟苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020130641-appb-000072
LC-MS：m/z 534(M+H) +.
实施例7 2-(1-丙烯酰-4-(8-(2,3-二甲基苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020130641-appb-000073
LC-MS：m/z 544(M+H) +. 1H NMR(400MHz,CDCl 3)δ7.06(t,J＝7.7Hz,1H),6.94(d,J＝7.8Hz,1H),6.89(d,J＝7.4Hz,1H),6.59(brs,1H),6.38(d,J＝16.7Hz,1H),5.82(d,J＝10.6Hz,1H),5.09(brs,0.5H),4.68(brs,1.5H),4.31(brs,1H),4.23–4.07(m,2H),4.05–3.67(m,3H),3.64–3.15(m,5H),3.15–2.90(m,3H),2.76(m,6H),2.25(s,3H),2.20–1.80(m,10H).
实施例8 2-(1-丙烯酰-4-(8-(2-氟-6-羟基苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020130641-appb-000074
LC-MS：m/z 550(M+H) +.
实施例9 2-(1-丙烯酰-4-(8-(5-甲基-1H-吲唑-4-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020130641-appb-000075
LC-MS：m/z 570(M+H) +.
实施例10 2-(1-丙烯酰-4-(8-(5,6-二甲基-1H-吲唑-4-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020130641-appb-000076
LC-MS：m/z 584(M+H) +.
实施例11 2-(1-丙烯酰-4-(8-苄基-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7,8,9-四氢-5H-嘧啶[4,5-c]氮杂卓-4-基)哌嗪-2-基)乙腈
Figure PCTCN2020130641-appb-000077
LC-MS：m/z 530(M+H) +.
实施例12 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 0.36 /
实施例4 0.28 8.2
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。
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)结构的氮杂七元环类化合物、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 PCTCN2020130641-appb-100001
    式中：
    A、B相同或者不同，且各自独立地选自：CH、CR 5或N；
    C、D、E、F相同或者不同，且各自独立地选自下组：O、S、SO、SO 2、CO、CH、CR 3aR 3b、N、NH、NR 3a；C、D、E、N、F和其连接的嘧啶环上相邻的两个碳形成七元环；其中，R 3a和R 3b各自独立地选自下组：氢、氘、氧、卤素、羟基、氰基、C 1-C 6烷基、C 1-C 6烷氧基；或者R 3a和R 3b及相连的碳原子形成C 3-C 6环烷基或4-6元杂环基；其中，所述七元环可进一步被取代；
    X独立地选自下组：4-14元饱和或不饱和的氮杂环或杂环基、C 6-C 14芳基或者5-14元杂芳基，其中，所述的饱和或不饱和的氮杂环或杂环基、芳基或者杂芳基可以任选地被一个或多个R 8所取代；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；
    Y独立地选自下组：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独立地选自下组：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、4-20元亚杂环基、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独立地选自下组：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、NHSO 2NR 5、NR 5SO 2NR 6；
    当B为N时，R 1独立地选自：
    Figure PCTCN2020130641-appb-100002
    其中，
    Figure PCTCN2020130641-appb-100003
    表示双键或三键；
    当B选自CH或CR 5，R 1独立地选自：
    Figure PCTCN2020130641-appb-100004
    Figure PCTCN2020130641-appb-100005
    其中，
    Figure PCTCN2020130641-appb-100006
    表示双键或三键；
    R A为不存在，或者独立地选自下组：氢、氘、氟、氰基或者C 1-C 3烷基；R B独立地选自下组：氢、氘、氰基或者C 1-C 3烷基；其中，所述C 1-C 3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；
    R 2独立地选自下组：-(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或-(CH 2) nNR 5S(O) qNR 5R 7，其中，CH 2中的H可以被取代；R 7选自下组：取代或未取代的C 1-C 18烷基、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；
    L选自下组：键、-C(O)-、C 1-C 3亚烷基；
    R 4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、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、卤素、氨基、羟基、氰基、胺基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基；
    其中，所述取代是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；
    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。
  2. 如权利要求1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，其特征在于，其具有通式(V)所示结构：
    Figure PCTCN2020130641-appb-100007
    R 1、R 2、R 4、X、Z、W、C、D、E、F的定义如权利要求1所述。
  3. 如权利要求1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，其特征在于，其具有通式(VI)所示结构：
    Figure PCTCN2020130641-appb-100008
    式中：
    R 1、R 2、R 4、R 8、Y、Z、L、W、C、D、E、F的定义如权利要求1所述。
  4. 如权利要求1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，其特征在于，其具有通式(VII)所示结构：
    Figure PCTCN2020130641-appb-100009
    式中：
    R 1、R 2、R 4、R 8、Y、Z、W、C、D、E、F的定义如权利要求1所述。
  5. 如权利要求1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，其特征在于，其具有通式(VIII)所示结构：
    Figure PCTCN2020130641-appb-100010
    式中：
    R 1、R 2、R 4、R 8、Z、W、C、D、E、F的定义如权利要求1所述。
  6. 如权利要求1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，其特征在于，其具有通式(IX-A)或(IX-B)所示的结构：
    Figure PCTCN2020130641-appb-100011
    式中：
    R 1、R 2、R 4、R 5、R 8、Z、C、D、E、F的定义如权利要求1所述。
  7. 如权利要求1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，其特征在于，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、4-7元杂环基、C 6-C 14芳基、5-14元杂芳基；所述取代选自下组：卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。
  8. 如权利要求1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，其特征在于，其具有通式(IV-A)所示结构：
    Figure PCTCN2020130641-appb-100012
    式中，
    R 1、R 2、R 3a、R 3b、R 4、X、Y、Z、L、W的定义如权利要求1所述。
  9. 如权利要求1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，其特征在于，Z独立地选自下组：键、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 6亚氮杂环烷基、4-7元亚杂环基、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。
  10. 如权利要求1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，其特征在于，R 4独立地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 12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、胺基、羟基、4-12元杂环基、C 6-C 14芳基、5-14元杂芳基；其中，所述取代是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 3-C 12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、苯基、嘧啶基、吡啶基、呋喃基、噻吩基、咪唑基、吡唑基、恶唑基、异恶唑基、4-12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，R 2独立地选自下组：-(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或-(CH 2) nNR 5S(O) qNR 5R 7，其中，CH 2中的H可以被取代；
    R 7选自下组：取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 6环烷基，或取 代或未取代的4-7元杂环基；
    R 5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 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、C 3-C 6环烷基、4-7元杂环基、C 6-C 14芳基、5-14元杂芳基；
    其中，所述取代是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-C6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、C 6-C 14芳基、5-14元杂芳基、4-7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；
    n为0、1、2、3、4或5的整数；
    q为0、1、2、3、4或5的整数。
  12. 如权利要求1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，其特征在于，所述化合物选自下组：
    Figure PCTCN2020130641-appb-100013
    Figure PCTCN2020130641-appb-100014
    Figure PCTCN2020130641-appb-100015
    Figure PCTCN2020130641-appb-100016
    Figure PCTCN2020130641-appb-100017
    Figure PCTCN2020130641-appb-100018
    Figure PCTCN2020130641-appb-100019
    Figure PCTCN2020130641-appb-100020
    Figure PCTCN2020130641-appb-100021
    Figure PCTCN2020130641-appb-100022
    Figure PCTCN2020130641-appb-100023
    Figure PCTCN2020130641-appb-100024
    Figure PCTCN2020130641-appb-100025
    Figure PCTCN2020130641-appb-100026
    Figure PCTCN2020130641-appb-100027
    Figure PCTCN2020130641-appb-100028
    Figure PCTCN2020130641-appb-100029
    Figure PCTCN2020130641-appb-100030
    Figure PCTCN2020130641-appb-100031
    Figure PCTCN2020130641-appb-100032
  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)结构的氮杂七元环类化合物、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8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. 一种体外抑制抑制KRAS G12C的方法，其特征在于，包括步骤：将权利要求1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、溶剂合物或前药或权利要求8所述的组合物，与体细胞接触。
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US11697657B2 (en) 2019-10-28 2023-07-11 Merck Sharp & Dohme Llc Small molecule inhibitors of KRAS G12C mutant
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US12065430B2 (en) 2018-10-26 2024-08-20 Taiho Pharmaceutical Co., Ltd. Indazole compound or salt thereof
US11697657B2 (en) 2019-10-28 2023-07-11 Merck Sharp & Dohme Llc Small molecule inhibitors of KRAS G12C mutant
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