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WO2021098859A1 - Inhibiteur à cycle aza à sept chaînons, et son procédé de préparation et utilisation associée - Google Patents

Inhibiteur à cycle aza à sept chaînons, et son procédé de préparation et utilisation associée 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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Chinese (zh)
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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/fr

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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

La présente invention concerne un inhibiteur à cycle aza à sept chaînons, et son procédé de préparation et une utilisation associée. Plus particulièrement, le composé possède une structure représentée par la formule (I). L'invention concerne en outre un procédé de préparation du composé et son utilisation en tant qu'inhibiteur de KRASG12C. Le composé présente un bon effet d'inhibition sélective sur KRASG12C, et présente de meilleures performances pharmacodynamiques et pharmacocinétiques et une toxicité inférieure et moins d'effets secondaires.
PCT/CN2020/130641 2019-11-21 2020-11-20 Inhibiteur à cycle aza à sept chaînons, et son procédé de préparation et utilisation associée WO2021098859A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022266206A1 (fr) 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras
US11697657B2 (en) 2019-10-28 2023-07-11 Merck Sharp & Dohme Llc Small molecule inhibitors of KRAS G12C mutant
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2024081674A1 (fr) 2022-10-11 2024-04-18 Aadi Bioscience, Inc. Polythérapies pour le traitement du cancer
US12065430B2 (en) 2018-10-26 2024-08-20 Taiho Pharmaceutical Co., Ltd. Indazole compound or salt thereof
US12162893B2 (en) 2020-09-23 2024-12-10 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2025067459A2 (fr) 2023-09-29 2025-04-03 D3 Bio (Wuxi) Co., Ltd. Thérapies pour le traitement du cancer

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CN114616232A (zh) * 2019-09-06 2022-06-10 正大天晴药业集团南京顺欣制药有限公司 氮杂环庚烷并嘧啶类衍生物及其医药用途
WO2024002373A1 (fr) * 2022-07-01 2024-01-04 苏州泽璟生物制药股份有限公司 Inhibiteur de cycle fusionné de pyrimidine substitué, son procédé de préparation et son utilisation

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WO2019099524A1 (fr) * 2017-11-15 2019-05-23 Mirati Therapeutics, Inc. Inhibiteurs de kras g12c
CN109843856A (zh) * 2016-05-18 2019-06-04 米拉蒂治疗股份有限公司 Kras g12c抑制剂
WO2020047192A1 (fr) * 2018-08-31 2020-03-05 Mirati Therapeutics, Inc. Inhibiteurs de kras g12c

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JP7289839B2 (ja) * 2018-01-19 2023-06-12 メッドシャイン ディスカバリー インコーポレイテッド Ｋｒａｓｇ１２ｃ突然変異タンパク質阻害剤としてのピリドン－ピリミジン系誘導体
CN112430234B (zh) * 2019-08-26 2023-04-28 信达生物制药(苏州)有限公司 一种新型kras g12c蛋白抑制剂及其制备方法和用途

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CN109843856A (zh) * 2016-05-18 2019-06-04 米拉蒂治疗股份有限公司 Kras g12c抑制剂
WO2019099524A1 (fr) * 2017-11-15 2019-05-23 Mirati Therapeutics, Inc. Inhibiteurs de kras g12c
WO2020047192A1 (fr) * 2018-08-31 2020-03-05 Mirati Therapeutics, Inc. Inhibiteurs de kras g12c

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US12162893B2 (en) 2020-09-23 2024-12-10 Erasca, Inc. Tricyclic pyridones and pyrimidones
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2022266206A1 (fr) 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras
WO2024081674A1 (fr) 2022-10-11 2024-04-18 Aadi Bioscience, Inc. Polythérapies pour le traitement du cancer
WO2025067459A2 (fr) 2023-09-29 2025-04-03 D3 Bio (Wuxi) Co., Ltd. Thérapies pour le traitement du cancer

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