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WO2021228161A1 - Inhibiteur hétérocyclique substitué par alkyle, son procédé de préparation et son utilisation - Google Patents

Inhibiteur hétérocyclique substitué par alkyle, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2021228161A1
WO2021228161A1 PCT/CN2021/093444 CN2021093444W WO2021228161A1 WO 2021228161 A1 WO2021228161 A1 WO 2021228161A1 CN 2021093444 W CN2021093444 W CN 2021093444W WO 2021228161 A1 WO2021228161 A1 WO 2021228161A1
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Prior art keywords
substituted
alkyl
unsubstituted
group
alkoxy
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English (en)
Chinese (zh)
Inventor
吕彬华
崔大为
刘连军
韩涛
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Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
Original Assignee
Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
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Publication of WO2021228161A1 publication Critical patent/WO2021228161A1/fr
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Classifications

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

Definitions

  • the invention belongs to the field of medicine, and specifically relates to an alkoxyalkyl substituted heterocyclic group 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).
  • chemotherapeutic drugs mainly include gemcitabine, paclitaxel and platinum drugs, but these drugs generally have poor selectivity and high toxicity, which leads to relatively strong side effects.
  • molecular targeted drugs have gradually become research hotspots due to their high selectivity, relatively small side effects, and their obvious advantages such as precise treatment.
  • NSCLC molecular targeted drugs include EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Ocartinib, etc.) (Nil, etc.), and VEGFR inhibitors (Sorafenib, Regorafenib, Cabozantinib, Sunitinib, Donafenib, etc.) (Current Medicinal Chemistry, 2019, 26, 1-39).
  • EGFR inhibitors such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Pyrotinib, Rociletinib, Osimertin
  • KRAS mutations are frequently detected, accounting for about 32% of all oncogene mutations.
  • KRAS G12C mutation accounts for 44% of all oncogene mutations in NSCLC. So far, no drugs targeting KRAS G12C mutations have been approved on the market.
  • KRAS G12C target protein is pathologically related to a variety of diseases
  • KRAS G12C inhibitors for clinical treatment.
  • Highly selective and active KRAS G12C inhibitors can more effectively treat cancers and other diseases caused by KRAS G12C mutations, and reduce the potential for off-target effects, so they have more urgent clinical needs.
  • the purpose of the present invention is to provide a new class of compounds with selective inhibitory effect on KRAS G12C and/or better pharmacodynamic properties and uses thereof.
  • the first aspect of the present invention provides a compound represented by formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug:
  • a and B are the same or different, independently selected from CH or N;
  • X is selected from: a 4-14 membered saturated or unsaturated cycloalkyl or heterocyclic group, a C 6 -C 14 aryl group or a 5-14 membered heteroaryl group, wherein the saturated or unsaturated cycloalkyl group Or a heterocyclic group, an aryl group or a heteroaryl group may be optionally substituted by one or more R 8;
  • Y is selected from the following group: bond, O, S, NH, NR 5 , CR 5 R 6 , CONH, CONR 5 , SO 2 NH, SO 2 NR 5 , NHCO, NR 5 CO, NHSO 2 , NR 5 SO 2 ;
  • R 5 and R 6 are the same or different, and are each independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogen Substituted C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, amino , Hydroxyl, 4-20 membered heterocyclic group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group;
  • Z is selected from the following group: bond, C 1 -C 18 alkylene, deuterated C 1 -C 18 alkylene, halogenated C 1 -C 18 alkylene, C 3 -C 20 cycloalkylene, 4 -20-membered heterocyclylene, C 1 -C 18 alkyleneoxy, deuterated C 1 -C 18 alkyleneoxy, halogenated C 1 -C 18 alkyleneoxy;
  • R A is absent, or independently selected from: hydrogen, deuterium, fluoro, cyano or C 1 -C 3 alkyl;
  • Each R B is independently selected from: hydrogen, deuterium, cyano or C 1 -C 3 alkyl
  • the alkyl group in R A and R B may be substituted by one or more substituents selected from the following group: deuterium, halogen, cyano, amino, C 3 -C 7 cycloalkyl, 4-7 member Heterocyclic group, NHR 10 or NR 10 R 11 ; wherein R 10 and R 11 are each independently a C 1 -C 3 alkyl group;
  • R 2 is selected from the following group: -(CH 2 ) n , -(CH 2 ) n O(CH 2 ) q , -(CH 2 ) n S, -(CH 2 ) n CO, -(CH 2 ) n C (O)O, -(CH 2 ) n S(O) q , -(CH 2 ) n NR 5 , -(CH 2 ) n C(O)NR 5 , -(CH 2 ) n NR 5 C(O ), -(CH 2 ) n NR 5 C(O)NR 5 , -(CH 2 ) n S(O) q NR 5 , -(CH 2 ) n NR 5 S(O) q NR 5 , -(CH 2 ) n NR 5 S(O) q , -(CH 2 ) n NR 5 S(O) q , -(CH 2 ) n
  • L is selected from the following group: bond, -C(O)-, C 1 -C 3 alkylene;
  • R 4 is selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, amino, hydroxyl, 4-20 membered heterocyclic group, C 6 -C 14 aryl, 5-14 membered heteroaryl;
  • Ring C is a 4-20 membered heterocyclylene; wherein, the 4-20 membered heterocyclylene may be optionally substituted by one or more R 8;
  • R 7 is independently -R 12 -OR 13 , wherein R 12 is a substituted or unsubstituted C 1 -C 6 alkylene group, and R 13 is a substituted or unsubstituted C 1 -C 6 alkyl group, C 3- C 8 cycloalkyl;
  • R 8 is independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, 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, C 3 -C 20 cycloalkane Group, 4-20 membered heterocyclylene, 4-20 membered heterocyclic group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group;
  • R 9 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, C 6 -C 14 aryl, 5-14 member Heteroaryl, 4-20 membered heterocyclic group, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or ureido group;
  • 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, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea group;
  • n is an integer of 0, 1, 2 or 3;
  • n is an integer of 0, 1, 2, 3, 4 or 5;
  • p is an integer of 1 or 2;
  • q is an integer of 0, 1, 2, 3, 4 or 5;
  • s is an integer of 1, 2 or 3;
  • t is an integer of 0, 1, 2 or 3.
  • X is selected from: 4-14 membered saturated or unsaturated cycloalkyl or heterocyclic group, wherein the saturated or unsaturated cycloalkyl or heterocyclic group can be optionally One or more substituted or unsubstituted C 1 -C 18 alkyl groups, preferably substituted or unsubstituted C 1 -C 3 alkyl groups, wherein the substitution refers to substitution by cyano or halogen.
  • the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs have Structure shown in general formula (II-A) or (II-B):
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 9 , A, B, C, X, Y, Z, L, m, s, and t are as described above.
  • the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs are characterized by Is that it has the structure shown in formula (III):
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 9 , C, X, Y, Z, L, m, s, and t are as described above.
  • the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs have The structure shown in formula (IV):
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , C, Y, Z, L, m, s, and t are as described above.
  • the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs have The structure shown in formula (V):
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , C, Y, Z, m, s, and t are as described above.
  • the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs have The structure shown in formula (VI):
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , C, Z, m, s, and t are as described above.
  • the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs have The structure shown in formula (VII):
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , C, m, s, and t are as described above.
  • the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs R 4 Selected from substituted or unsubstituted groups from the following group: C 6 -C 14 aryl groups, 5-14 membered heteroaryl groups; wherein, the substitution refers to substitution by one or more groups selected from the following group: hydrogen , Deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterium Substituted 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 group, cyano group, ester group, amine
  • R 4 is selected from substituted or unsubstituted C 6 -C 10 aryl groups, preferably substituted or unsubstituted phenyl or naphthyl, wherein the substitution means being selected from the following group Substitution of one or more groups: 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, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic group , Halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea group.
  • R 4 is selected from substituted or unsubstituted 5-10 membered heteroaryl groups, preferably substituted or unsubstituted pyridine, benzopyrazole, benzimidazole, benzothiazole, benzoxazole Azoles, wherein the substitution refers to substitution by one or more groups selected from the following group: 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 group, 4-20 membered heterocyclic group, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or ureido group.
  • ring C is a 4-8 membered heterocyclylene, which may be optionally substituted with one or more R 8 , wherein R 8 is independently selected from the following group of substituted or unsubstituted groups : Hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, 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, C 3 -C 20 cycloalkylene, 4-20 membered heterocyclylene, 4-20 membered Heterocyclic group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group;
  • the substitution refers to substitution by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl , C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, halogen, nitro, hydroxyl, cyano , Ester group, amino group.
  • ring C is selected from the following group:
  • Y 1 and Y 2 are each independently selected from: O, CO, CS, S, SO, SO 2 , PO, NR 14 or CR 15 R 16 , f is 0, 1, 2 or 3;
  • R 15 and R 16 are each independently selected from: H, D, halogen, cyano, hydroxyl, substituted or unsubstituted C 1- C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C
  • 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 Alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, halogen, nitro, hydroxyl, Cyano groups, ester groups, amine groups.
  • R 3 is independently selected from the group consisting of hydrogen, deuterium, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, or C 3 -C 6 cycloalkyl.
  • R 3 is independently selected from the following group: deuterium, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, or C 3 -C 6 cycloalkyl.
  • R 7 is independently -R 12 -OR 13 , wherein R 12 is a substituted or unsubstituted C 1 -C 6 alkylene group, and R 13 is a substituted or unsubstituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl;
  • Ring C is selected from the following group: Wherein, Y 1 and Y 2 are each independently selected from: O, NR 14 or CR 15 R 16 , and f is 0, 1, 2 or 3; wherein, R 14 is selected from: H, substituted or unsubstituted C 1- C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 14 aryl, substituted or unsubstituted R 15 and R 16 are each independently selected from: H, D, halogen, cyano, hydroxyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1- C 6 alkoxy, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substitute
  • substitution refers to substitution by one or more groups selected from the following group: H, D, halogen, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl.
  • R 9 is independently selected from the following 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, C 6 -C 14 Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or ureido group;
  • R 7 is independently -R 12 -OR 13 , wherein R 12 is a substituted or unsubstituted C 1 -C 3 alkylene group, and R 13 is a substituted or unsubstituted C 1 -C 3 alkyl group, C 3- C 6 cycloalkyl;
  • Ring C is selected from the following group: Wherein, Y 1 and Y 2 are each independently selected from: NR 14 or CR 15 R 16 , and f is 0, 1, 2 or 3; wherein, R 14 is selected from: H, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 14 aryl, substituted or unsubstituted 5 -14 membered heteroaryl; R 15 and R 16 are each independently selected from: H, D, halogen, cyano, hydroxyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1- C 6 alkoxy, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 4-6 member
  • substitution refers to substitution by one or more groups selected from the following group: H, D, halogen, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl.
  • R 9 is independently H, C 1 -C 6 alkyl.
  • R 8 is independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 3 alkyl, deuterated C 1 -C 3 alkyl, C 1 -C 3 Alkoxy, deuterated C 1 -C 3 alkoxy, amino, and hydroxy; wherein, the substitution refers to substitution by one or more groups selected from the following group: halogen, cyano, amino, and hydroxy.
  • f is 1.
  • ring C is selected from:
  • ring C is wherein, Y 1 is NR 14 , Y 2 is CR 15 R 16 , and f is 0, 1 or 2; wherein, R 14 is selected from: H, substituted or unsubstituted C 1 -C 6 alkyl; R 15 and R 16 are each independently selected from: H, D, halogen, cyano, hydroxyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy.
  • X is a 6-11 membered bicyclic heterocyclic group, wherein the heterocyclic group may be substituted by R 8 ;
  • R 8 is independently selected from the following group of substituted or unsubstituted groups: hydrogen, Deuterium, C 1 -C 3 alkyl, deuterated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, deuterated C 1 -C 3 alkoxy; wherein the substitution refers to being selected from One or more of the following groups are substituted: halogen, cyano, amino, and hydroxyl.
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 9 , A, B, C, X, Y, Z, L, m, s, and t are each in the embodiment. Specific groups corresponding to specific compounds.
  • the compound is selected from the following group:
  • the compound is selected from the compounds shown in the examples.
  • the second aspect of the present invention provides a method for preparing a compound of formula (III), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs , which is characterized in that it includes the steps:
  • G is OH, F, Cl, -O-CO-R 1 , -O-CO-CH 2 CH(CH 3 ) 2 , -OBt,
  • Q is a leaving group, such as halogen, OH, -O-CO-R 4 -O-CO-CH 2 CH(CH 3 ) 2 , OMs, OTs, OTf, B(OH) 2 , B(OMe) 2 or Wait;
  • Rs and Rs' are protecting groups for amino, and the protecting groups are selected from: Boc, Bn, Cbz or Fmoc;
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 9 , A, B, C, L, X, Y, Z, m, s, and t are as defined above.
  • the base is TEA or DIPEA.
  • the inert solvent is selected from: DMSO.
  • the amino protecting agent is selected from: (Boc) 2 O, benzyl chloroformate, di-tert-butyl dicarbonate, phthaloyl chloride, benzyl chloride, triphenyl Methyl chloromethane, 9-fluorenyl methyl chloroformate, allyl chloroformate.
  • the deprotection agent is 1-chloroethyl chloroformate.
  • the inert solvent is selected from dichloromethane.
  • the inert solvent is selected from: dioxane.
  • the base is cesium carbonate.
  • the oxidizing agent is mCPBA.
  • the inert solvent is selected from ethyl acetate.
  • the base is sodium alkoxide, potassium alkoxide, NaH or LiHNMDS, preferably sodium tert-butoxide or potassium tert-butoxide.
  • the inert solvent is selected from toluene.
  • the acid is TFA.
  • the inert solvent is selected from dichloromethane.
  • the inert solvent is selected from: DMF.
  • the base is TEA or DIPEA.
  • the condensing agent is HATU.
  • the third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising one or more of the compounds described in the first aspect, their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrated Substances, solvates or prodrugs; and pharmaceutically acceptable carriers.
  • 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, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311 or biological analogues of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltu), CD20 antibodies
  • EGFR inhibitors e.g. Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Naquotinib, etc.
  • VEGFR inhibitors such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Cabozantinib, S unitinib, Donafenib, etc.
  • HDAC inhibitors such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.
  • CDK inhibitors such as Palbociclib
  • Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (e.g. Vistusertib, etc.), SHP2 inhibitors (Such as RMC-4630, JAB-3068, TNO155, etc.) or a combination thereof.
  • the fourth aspect of the present invention provides a compound of the first aspect, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, or
  • the use of the pharmaceutical composition described in the third aspect is to prepare a pharmaceutical composition for preventing and/or treating diseases related to the activity or expression of KRAS G12C.
  • the disease is a tumor or a disordered disease.
  • the disease is selected from the following group: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, gastric cancer, liver cancer, colorectal cancer, melanoma, lymphoma, blood cancer , Brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
  • the fifth aspect of the present invention provides a non-diagnostic and non-therapeutic method for inhibiting KRAS G12C , which comprises the steps of: administering an effective amount of the compound, its stereoisomers, and tautomers to the patient in need Constructs, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or administration of the above-mentioned pharmaceutical composition.
  • the inventors unexpectedly prepared a new type of KRAS G12C compound with selective inhibition and/or better pharmacodynamic properties. On this basis, the inventor completed the present invention.
  • alkyl refers to a straight or branched chain or cyclic alkane group containing 1-20 carbon atoms, such as 1-18 carbon atoms, especially 1-18 carbon atoms, preferably 1-10 carbon atoms
  • the carbon atom more preferably contains 1-6 carbon atoms.
  • alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, Pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and many more.
  • C1-C18 alkyl refers to straight or branched chain or cyclic alkyl, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17 or 18 carbon atoms, such as methyl, ethyl, propyl, isopropyl N-butyl, tert-butyl, isobutyl (e.g. ), n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl.
  • the alkyl group also includes a substituted alkyl group.
  • alkylene refers to a group formed by 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.
  • C1-C18 alkylene C3-C20 cycloalkylene or "C3-C20 cycloalkylene C1-C18 alkylene” has the same meaning and refers to the removal of cycloalkylalkyl or alkylcycloalkyl A group formed by two hydrogen atoms, such as Wait.
  • cycloalkyl refers to complete saturation containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms
  • the cyclic hydrocarbon group includes 1-4 rings, each of which contains 3-8 carbon atoms.
  • it is a C 3 -C 20 cycloalkyl group, more preferably a C 3 -C 18 cycloalkyl group, more preferably a C 3 -C 10 cycloalkyl group, more preferably a C 3 -C 6 cycloalkyl group .
  • “Substituted cycloalkyl” means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include spirocyclic, bridged or fused ring substituents, especially spirocyclic alkyl, spirocycloalkenyl, spirocyclic heterocycle (excluding heteroaromatic rings), bridged cycloalkyl, bridged cycloalkenyl, Bridged heterocyclic ring (excluding heteroaromatic ring), fused ring alkyl, fused ring alkenyl, fused ring heterocyclic group or fused ring aromatic ring group, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic group and heterocyclic aromatic The group can be optionally substituted.
  • C3-C20 cycloalkylene refers to a group formed by removing two hydrogen atoms from a cycloalkyl group, such as: Wait.
  • heterocyclyl refers to complete saturation containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms Or partially unsaturated cyclic groups (including but not limited to such as 3-7 membered monocyclic ring, 6-11 membered bicyclic ring, or 8-16 membered tricyclic ring system), in which at least one heteroatom is present in at least A ring of carbon atoms.
  • 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.
  • the nitrogen atom or sulfur atom can be oxidized, and the nitrogen atom 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.
  • 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,
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected to other groups through a single bond, or through a ring Any two or more of the above atoms are further connected to other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups; the heterocyclic group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxy, and carboxylate.
  • groups are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxy, and carboxylate.
  • the term "4-20 membered heterocyclylene” refers to a group formed by removing two or more hydrogen atoms from a heterocyclic group, such as: Wait.
  • the H of NH may be further substituted; when substituted, the substituent is preferably alkyl, deuterated alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl Group, alkoxyalkyl, hydroxyalkyl, aminoalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl.
  • aryl refers to an aromatic cyclic hydrocarbon compound group containing 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring carbon atoms, with 1-5 rings, especially 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, and alkoxy , Haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkane Sulfur group, oxo group, carboxyl group and carboxylate group.
  • C1-C18 alkoxy refers to a linear or branched or cyclic alkoxy group having 1 to 18 carbon atoms, including C1-C18 alkyl-O-, -C1-C6 alkyl-O-
  • the C1-C6 alkyl group includes, without limitation, methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like. It is preferably a C1-C8 alkoxy group, and more preferably a C1-C6 alkoxy group.
  • C1-C18 alkoxy refers to a group obtained by removing one hydrogen atom from the "C1-C18 alkoxy”.
  • 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 with 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.
  • amido 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.
  • sulfonamido refers to a group with the structure -SO 2 NRR', where R and R'can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, ring Alkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle are as defined above. R and R'may be the same or different in the dialkylamine segment.
  • ureido refers to a group with the structure -NRCONR'R", where R, R'and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl , Cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R'and R" may be the same or different in the dialkylamine segment.
  • alkylaminoalkyl refers to a group with the structure -RNHR', where R and R'can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, Cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle are as defined above. R and R'can be the same or different.
  • dialkylaminoalkyl refers to a group with the structure -RNHR'R", where R, R'and R" can independently represent alkyl or substituted alkyl, cycloalkyl or substituted Cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle are as defined above. R, R'and R" may be the same or different in the dialkylamine segment.
  • alkoxyalkyl refers to a group with the structure -ROR', where R and R'can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl Or substituted cycloalkenyl, aryl or substituted aryl.
  • heterocyclylalkyl refers to a group with the structure -RR', where R can independently represent an alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted Cycloalkenyl, aryl or substituted aryl; R'represents heterocycle or substituted heterocycle.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • the specific substituents are the substituents correspondingly described in the foregoing, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different in each position.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents such as (but not limited to): halogen, hydroxyl, cyano, carboxy (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, C1-C10 sulfonyl groups, and C1-C6 ureido and so on.
  • a substituent is a non-terminal substituent, it is a subunit of the corresponding group, for example, an alkyl group corresponds to an alkylene group, a cycloalkyl group corresponds to a cycloalkylene group, a heterocyclic group corresponds to a heterocyclylene group, and an alkoxy group corresponds to Alkyleneoxy and so on.
  • the term "plurality” means 2, 3, 4, 5 independently.
  • the terms "compounds of the present invention” or “active ingredients of the present invention” are used interchangeably and refer to compounds of formula (I), their stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable The salt, hydrate, solvate or prodrug of. The term also includes racemates and optical isomers.
  • the compound of formula (I) has the following structure:
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 9 , A, B, C, X, Y, Z, L, m, s, and t are as described above.
  • the compound of formula (I) has a structure represented by general formula (II-A) or (II-B):
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 9 , A, B, C, X, Y, Z, L, m, s, and t are as described above.
  • the compound of formula (I) has the structure shown in formula (III):
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 9 , C, X, Y, Z, L, m, s, and t are as described above.
  • the compound of formula (I) has the structure shown in formula (IV):
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , C, Y, Z, L, m, s, and t are as described above.
  • the compound of formula (I) has the structure shown in formula (V):
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , C, Y, Z, m, s, and t are as described above.
  • the compound of formula (I) has the structure shown in formula (VI):
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , C, Z, m, s, and t are as described above.
  • the compound of formula (I) has the structure shown in formula (VII):
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , C, m, s, and t are as described above.
  • R 4 is a substituted or unsubstituted C 6 -C 14 aryl group, a 5-14 membered heteroaryl group; more preferably a C6-C10 aryl group (such as substituted or unsubstituted Phenyl or naphthyl) or 5-10 membered heteroaryl (such as substituted or unsubstituted pyridine, benzopyrazole, benzimidazole, benzothiazole, benzoxazole), wherein the substitution refers to One or more group substitutions selected from the following group: 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 membere
  • ring C is a 4-8 membered heterocyclylene; preferably ring C is selected from the following group: Wherein, Y 1 , Y 2 , and f are as defined above, preferably Y 1 and Y 2 are each independently NR 14 or CR 15 R 16 , wherein R 14 is selected from: H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 14 aryl, substituted or Unsubstituted 5-14 membered heteroaryl; R 15 and R 16 are each independently selected from: H, D, halogen, cyano, hydroxyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alk
  • R 3 is independently selected from the group consisting of hydrogen, deuterium, C 1 -C 3 alkyl, halo C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl.
  • R 8 is independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 3 alkyl, deuterated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, deuterated C 1 -C 3 alkoxy, amino, hydroxy; wherein, the substitution refers to substitution by one or more groups selected from the following group: halogen, cyano, amino, Hydroxy.
  • R 9 is independently H, C 1 -C 6 alkyl.
  • R 4 is selected from the following group of substituted or unsubstituted groups: phenyl, naphthyl,
  • R 3 is independently selected from the group consisting of hydrogen, deuterium, C 1 -C 3 alkyl, halo C 1 -C 3 alkyl, or C 3 -C 6 cycloalkyl;
  • n 0 or 1
  • Ring C is wherein, Y 1 is NR 14 , Y 2 is CR 15 R 16 , and f is 0, 1 or 2; wherein, R 14 is selected from: H, substituted or unsubstituted C 1 -C 6 alkyl; R 15 and R 16 are each independently selected from: H, D, halogen, cyano, hydroxyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy;
  • R 7 is independently -R 12 -OR 13 , wherein R 12 is a substituted or unsubstituted C 1 -C 3 alkylene group, and R 13 is a substituted or unsubstituted C 1 -C 3 alkyl group, C 3- C 6 cycloalkyl;
  • R 8 is independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 3 alkyl, deuterated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, deuterated C 1 -C 3 alkoxy; wherein, the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano, amino, and hydroxy;
  • substitution refers to substitution by one or more groups selected from the following group: D, halogen, cyano, hydroxyl, C 1 -C 6 alkyl.
  • X is selected from: 6-11 membered bicyclic heterocyclic group, wherein the heterocyclic group may be substituted by R 8 ;
  • R 8 is independently selected from the following groups of substituted or unsubstituted: Hydrogen, deuterium, C 1 -C 3 alkyl, deuterated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, deuterated C 1 -C 3 alkoxy; wherein, the substitution refers to One or more group substitutions selected from the following group: halogen, cyano, amino, and hydroxyl.
  • 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, to salt out in the medium, or 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 Amine, 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 molecular 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 iodide), aralkyl halide (such as benzyl and phenyl bromide) and so on.
  • small molecular alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates E.g., dimethyl sulfate, diethy
  • prodrugs and solvates of the compounds of the present invention are also covered.
  • prodrug herein refers to a compound that undergoes metabolism or chemical transformation through a chemical process 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 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 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 the 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 that 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.
  • Tritium, which is 3 H and carbon-14, which is 14 C, is relatively easy to prepare and detect. It is the first choice among isotopes.
  • 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, and the resulting diastereomeric mixture is separated, and then the chiral adjuvant is removed. 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 enantiomer is obtained.
  • the compounds of the present invention can be combined with any number of substituents or functional groups to expand their scope of inclusion.
  • the general formula including substituents in the formula of the present invention refers to the replacement of hydrogen radicals with designated structural substituents.
  • 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 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, unless otherwise specified, can be purchased through commercial channels or synthesized according to reported literature.
  • the compound of formula (V-1) reacts with diamine-based compounds under the action of a base (such as TEA or DIPEA)
  • a base such as TEA or DIPEA
  • an amino protecting agent such as (Boc) 2 O, benzyl chloroformate, di-tert-butyl dicarbonate, phthaloyl chloride, benzyl chloride, triphenylchloromethane, chloroformic acid- 9-fluorenyl methyl ester and allyl chloroformate
  • an amino protecting agent such as (Boc) 2 O, benzyl chloroformate, di-tert-butyl dicarbonate, phthaloyl chloride, benzyl chloride, triphenylchloromethane, chloroformic acid- 9-fluorenyl methyl ester and allyl chloroformate
  • the V-2 compound is deprotected to generate intermediate V-3
  • an inert solvent such as two Oxane, tol
  • Q is a leaving group, such as halogen, OH, -O-CO-R 4 -O-CO-CH 2 CH(CH 3 ) 2 , OMs, OTs, OTf, B(OH) 2 , B(OMe) 2 or Wait;
  • reaction solvent reaction temperature, reaction time, catalyst, etc.
  • reaction time reaction time, catalyst, etc.
  • 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 several other known drugs at 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, cemipilimab, JS-001, SHR-120, BGB- A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, etc.) CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311 or biological analogues of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab,
  • 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 a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/agent, more preferably, 10-1000 mg of the compound of the present invention/agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween
  • wetting agents such as sodium lauryl sulfate
  • coloring agents such as sodium lauryl sulfate
  • flavoring agents such as pepperminophen, sorbitol, etc.
  • antioxidants
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycty
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such compositions 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 microcapsules 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 commonly 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 the mammal (such as a human) in need of treatment, wherein the dosage is the pharmaceutically effective dosage considered to be administered, and for a 60kg body weight, a day
  • 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, the patient's health status, etc., which are 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 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 was detected by Bruker AVANCE-400 nuclear magnetic instrument.
  • the solvent for measurement 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 mass spectrometry
  • Waters SQD2 mass spectrometer HPLC measurement uses Agilent1100 high pressure chromatograph (Microsorb 5 micron C18 100 x 3.0mm chromatographic column).
  • the thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, the TLC uses 0.15-0.20mm, and the preparative thin layer chromatography uses 0.4mm-0.5mm.
  • Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
  • the starting materials in the examples of the present invention are all known and commercially available, or can be synthesized by using or according to literature reported in the field.
  • reaction solution was quenched with water, and then extracted with ethyl acetate (3 x 100 mL). After all the organic phases were combined, washed once with saturated sodium chloride, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the target product (8.21 g, yield 73%).
  • reaction solution was stirred at 0°C for 10 min, and then quenched with sodium hyposulfite solution (50 mL).
  • the first step the preparation of 3-(tert-butyl-dimethyl-silyloxymethyl)-3-hydroxymethyl-azetidine-1-carboxylate tert-butyl ester
  • Step 2 Preparation of 3-(tert-butyl-dimethyl-silyloxymethyl)-3-methoxymethyl-azetidine-1-carboxylic acid tert-butyl ester
  • Example 5 1-(6-(7-(8-chloronaphthalene-1-yl)-2-((3-(methoxymethyl)-1-methylcyclobutylamine-3-yl)methoxy Yl)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)-2,6-diazaspiro[3.4]octane-2-yl)propan-2- En-1-one
  • Example 6 1-(7-(7-(8-chloronaphthalene-1-yl)-2-((3-(methoxymethyl)-1-methylcyclobutylamine-3-yl)methoxy Yl)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-yl)prop-2- En-1-one
  • the compound to be tested was 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 hétérocyclique substitué par alkyle, son procédé de préparation et son utilisation. Spécifiquement, le composé de la présente invention a une structure représentée par la formule (I). La présente invention concerne en outre un procédé de préparation du composé, et une utilisation du composé en tant qu'inhibiteur de KRASG12C. Le composé présente une excellente aptitude à inhiber sélectivement KRASG12C, de meilleures performances pharmacodynamiques et pharmacocinétiques, et des effets secondaires toxiques réduits.
PCT/CN2021/093444 2020-05-15 2021-05-12 Inhibiteur hétérocyclique substitué par alkyle, son procédé de préparation et son utilisation Ceased WO2021228161A1 (fr)

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WO2022235870A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras pour le traitement du cancer
WO2022235864A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
WO2023114954A1 (fr) 2021-12-17 2023-06-22 Genzyme Corporation Composés pyrazolopyrazine utilisés comme inhibiteurs de la shp2
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
EP4227307A1 (fr) 2022-02-11 2023-08-16 Genzyme Corporation Composés pyrazolopyrazine en tant qu'inhibiteurs de shp2
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
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WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024211712A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024211663A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024216048A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'inhibiteurs de ras, compositions les contenant et leurs procédés d'utilisation
WO2024216016A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'un inhibiteur de ras
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US11932633B2 (en) 2018-05-07 2024-03-19 Mirati Therapeutics, Inc. KRas G12C inhibitors
US12208099B2 (en) 2018-09-10 2025-01-28 Mirati Therapeutics, Inc. Combination therapies
US12336995B2 (en) 2018-09-10 2025-06-24 Mirati Therapeutics, Inc. Combination therapies
US12377101B2 (en) 2018-12-05 2025-08-05 Mirati Therapeutics, Inc. Combination therapies
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
US11964989B2 (en) 2019-08-29 2024-04-23 Mirati Therapeutics, Inc. KRas G12D inhibitors
US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
US12485122B2 (en) 2019-09-09 2025-12-02 Mirati Therapeutics, Inc. Combination of palbociclib and adagrasib for lung cancer
US11890285B2 (en) 2019-09-24 2024-02-06 Mirati Therapeutics, Inc. Combination therapies
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
US12304915B2 (en) 2019-12-20 2025-05-20 Mirati Therapeutics, Inc. SOS1 inhibitors
US12281113B2 (en) 2020-09-11 2025-04-22 Mirati Therapeutics, Inc. Crystalline forms of a KRas G12C inhibitor
US12286431B2 (en) 2020-09-11 2025-04-29 Mirati Therapeutics, Inc. Crystalline forms of a KRas G12C inhibitor
US12162893B2 (en) 2020-09-23 2024-12-10 Erasca, Inc. Tricyclic pyridones and pyrimidones
US12398154B2 (en) 2020-12-15 2025-08-26 Mirati Therapeutics, Inc. Azaquinazoline pan-KRas inhibitors
US12421253B2 (en) 2020-12-16 2025-09-23 Mirati Therapeutics, Inc. Tetrahydropyridopyrimidine pan-KRas inhibitors
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2022235864A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras
WO2022235870A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras pour le traitement du cancer
WO2023114954A1 (fr) 2021-12-17 2023-06-22 Genzyme Corporation Composés pyrazolopyrazine utilisés comme inhibiteurs de la shp2
EP4227307A1 (fr) 2022-02-11 2023-08-16 Genzyme Corporation Composés pyrazolopyrazine en tant qu'inhibiteurs de shp2
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024211663A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024211712A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024216016A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'un inhibiteur de ras
WO2024216048A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'inhibiteurs de ras, compositions les contenant et leurs procédés d'utilisation
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

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