WO2022127827A1 - Inhibiteur de mutation de protéine krasg12c et son procédé de préparation, composition pharmaceutique et son application - Google Patents

Inhibiteur de mutation de protéine krasg12c et son procédé de préparation, composition pharmaceutique et son application Download PDF

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WO2022127827A1
WO2022127827A1 PCT/CN2021/138375 CN2021138375W WO2022127827A1 WO 2022127827 A1 WO2022127827 A1 WO 2022127827A1 CN 2021138375 W CN2021138375 W CN 2021138375W WO 2022127827 A1 WO2022127827 A1 WO 2022127827A1
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alkyl
heteroatoms
substituted
independently
compound
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唐国志
马大为
黄孟炜
刘永福
陈军利
李春水
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上海维申医药有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-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
    • A61K31/495—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
    • A61K31/527—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim spiro-condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems
    • 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

Definitions

  • the present invention relates to a KRAS G12C protein mutation inhibitor, its preparation method, pharmaceutical composition and its application.
  • RAS (Rat sarcoma) proteins include KRAS, HRAS and NRAS, and are members of the small GTPases (GTPase) family.
  • RAS protein can bind to guanine trinucleotide phosphate (GTP) or guanine dinucleotide phosphate (GDP), and the transition between the two states is activated by guanine nucleotide exchange factors (GEFs) and GTP hydrolase protein (GAP) regulation.
  • GTP guanine trinucleotide phosphate
  • GDP guanine dinucleotide phosphate
  • GAP GTP hydrolase protein
  • RAS proteins directly interact with multiple downstream effector proteins and activate signaling pathways including mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K), thereby regulating cell growth , cell movement or metabolism, and interactions between cells and their extracellular environment.
  • MAPK mitogen-activated protein kinase
  • PI3K phosphatidylinositol 3-kinase
  • Hyperactivating mutations in the RAS gene are the most common genetic mutations in cancer, and approximately 30% of human tumors carry some mutated RAS gene. Among them, KRAS is the most commonly mutated oncogene, accounting for 86% of all RAS mutations. Mutations in most RAS genes can reduce the binding of GAP to RAS protein and thus affect the ability of GAP to catalyze the hydrolysis of GTP. The intrinsic GTPase activity of RAS protein or both can be reduced, resulting in an increase in GTP-bound RAS protein, so that RAS protein has been maintained. in the "active" state. Activated RAS proteins continue to activate downstream signaling pathways, which ultimately lead to the continuous growth and differentiation of cells, which in turn leads to tumorigenesis.
  • RAS mutations are identified in a variety of cancers including colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), lung adenocarcinoma (LUAD; a subtype of non-small cell lung cancer (NSCLC)), melanoma, and certain hematological cancers Genetic drivers of cancer types.
  • CRC colorectal cancer
  • PDAC pancreatic ductal adenocarcinoma
  • LAD lung adenocarcinoma
  • NSCLC non-small cell lung cancer
  • KRAS-mutant tumors In KRAS-mutant tumors, the majority of oncogenic mutations occurred in codon 12, accounting for 83%. G12C mutation is a relatively common subtype of KRAS gene mutation. KRAS G12C mutations are prevalent in lung adenocarcinoma and in other tumor types such as pancreatic and colorectal cancer. Despite substantial drug discovery efforts, there are currently no marketed drugs targeting the KRAS G12C mutation. Mutations in KRAS G12C have been shown to be associated with poor cancer prognosis. Therefore, the development of inhibitors targeting the KRAS G12C mutation has an important clinical need.
  • KRAS G12C inhibitor The covalent KRAS G12C inhibitor reported by Shokat and colleagues offers the possibility to treat KRAS G12C mutant tumors (Ostrem JM., et al. Nature, 2013, 548-551). Although a series of patents on KRASG12C inhibitors have been published (WO2014143659, WO2014152588, WO2015054572, WO2016049524, WO2017201161, WO2018119183, etc.), it is still very important to find more effective KRAS inhibitors with better pharmacokinetic and pharmacodynamic properties important.
  • the technical problem to be solved by the present invention is to provide a KRAS G12C protein mutation inhibitor, a preparation method thereof, a pharmaceutical composition and an application thereof, aiming at the single defect of the existing KRAS G12C protein mutation inhibitor.
  • the compound of the present invention has a novel structure. , with better activity and selectivity.
  • the present invention provides a compound represented by formula I, its solvate, its prodrug, its metabolite, or their (referring to the aforementioned compound represented by formula I, its solvate, its prodrug or its metabolites) pharmaceutically acceptable salts:
  • Ring A is a 4-12-membered alicyclic heterocyclic ring containing 2-4 N atoms; the alicyclic heterocyclic ring is a monocyclic ring, a bridged ring or a spirocyclic ring;
  • R a is hydrogen, halogen or C 1-6 alkyl
  • R b and R c are independently hydrogen, C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R b-1 ";
  • Each R b-1 is independently halogen, C 1-6 alkoxy or -NR b-2 R b-3 ;
  • R b-2 and R b-3 are independently hydrogen or C 1-6 alkyl, or , R b-2 , R b-3 and the N connected to them together form "the heteroatom is N, or N and O, and the number of heteroatoms is 1 or 2 4-10-membered heterocycloalkyl";
  • R d is C 1-6 alkyl
  • n 0, 1, 2 or 3;
  • each R 4 is independently C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R 4-1 ";
  • Each R 4-1 is independently halogen, cyano, hydroxyl or C 1-6 alkoxy;
  • R 1-1 , R 1-2 and R 1-3 are independently hydrogen or C 1-6 alkyl
  • n 0, 1, 2 or 3, when m is 0, it means that R 2-6 is directly connected to the parent through a single bond;
  • R 2-1 , R 2-2 , R 2-3 , R 2-4 and R 2-5 are independently C 1-6 alkyl, C 1-6 alkyl substituted with one or more R e , C 1-6 alkoxy, "heteroatoms selected from one or more of N, O and S, 5-12-membered heteroaryl with 1-4 heteroatoms", surrounded by one or more R E-1 substituted "heteroatoms selected from one or more of N, O and S, and 5-12-membered heteroaryl groups with 1-4 heteroatoms", C 6 -C 10 aryl groups, C 6 -C 10 aryl substituted with one or more R e-2 , "heteroatoms selected from one or more of O and N, and 4-10-membered heterocycloalkanes with 1-3 heteroatoms "base", "heteroatoms selected from one or more of O and N, 4-10-membered heterocycloalkyl groups with 1-3 heteroatoms" substituted by one or more R e-3 ,
  • R 2-6 is hydrogen, CN, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R e , C 1-6 alkoxy, "heteroatom selected from N , one or more of O and S, a 5-12-membered heteroaryl group with 1-4 heteroatoms, "heteroatoms substituted by one or more R e-1 are selected from N, O and One or more of S, 5-12-membered heteroaryl with 1-4 heteroatoms, C 6 -C 10 aryl, C 6 -C substituted by one or more R e-2 10 Aryl, "heteroatoms selected from one or more of O and N, 4-10-membered heterocycloalkyl with 1-3 heteroatoms", substituted by one or more R e-3 "The heteroatom is selected from one or more of O and N, and the 4-10-membered heterocycloalkyl with 1-3 heteroatoms", C 3-10 cycloalkyl, or, by one
  • R 2-7 is hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R e , C 1-6 alkoxy, "heteroatom selected from N, O and S
  • One or more, 5-12-membered heteroaryl groups with 1-4 heteroatoms "heteroatoms substituted by one or more R e-1 are selected from one of N, O and S or
  • Various, 5-12-membered heteroaryl groups with 1-4 heteroatoms C 6 -C 10 aryl groups, C 6 -C 10 aryl groups substituted by one or more R e-2
  • "heteroaryl groups” Atoms are selected from one or more of O and N, 4-10-membered heterocycloalkyl with 1-3 heteroatoms
  • "heteroatoms substituted by one or more R e-3 are selected from O and one or more of N, a 4-10-membered heterocycloalkyl with 1-3 heteroatoms, a C 3-10 cycloalkyl, or
  • Each R e is independently "a 5-12-membered heteroaryl group with heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-4", which is replaced by one or more R e- 1 -substituted "heteroatoms selected from one or more of N, O and S, and 5-12-membered heteroaryl groups with 1-4 heteroatoms", C 6 -C 10 aryl groups, substituted by one or Multiple R e-2 substituted C 6 -C 10 aryl groups, "heteroatoms selected from one or more of O and N, and 4-10-membered heterocycloalkyl groups with 1-3 heteroatoms" , "4-10-membered heterocycloalkyl with 1-3 heteroatoms" substituted by one or more R e-3 , C 3- 10 cycloalkyl, or, C 3-10 cycloalkyl substituted by one or more R e-4 ;
  • R e-5 and R e-6 are independently hydrogen or C 1-6 alkyl, or, R e-5 , R e-6 and with The N to which they are connected together form a "4-10-membered heterocycloalkyl with the heteroatom being N, or N and O, and the number of heteroatoms being 1 or 2";
  • R e-11 and R e-12 are independently C 1-6 alkyl;
  • R e-13 and R e-14 are independently hydrogen or C 1-6 alkyl, or, R e-13 , R e-14 and the N to which they are attached together form "the heteroatom is N, or N and O, 4-10-membered heterocycloalkyl with 1 or 2 heteroatoms"; R e-15 is hydrogen or C 1-6 alkyl;
  • R 3 is hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 3-1 , wherein each R 3-1 is independently C 1-6 alkyl, C 1- 6 alkoxy, CN, halogen or OH;
  • X and Y are independently O, NR 6 or CR 7 R 8 ; each R 6 is independently hydrogen or C 1-6 alkyl; each R 7 and R 8 is independently H or C 1-6 alkyl; Z is a single bond, O, NR 6 or CR 7 R 8 ; X, Y and Z are not both O or NR 6 at the same time;
  • U, V, W and Q are independently N or CR5 ;
  • Each R 5 is independently H, halogen, hydroxy, C 1-6 alkyl substituted with one or more halogens, C 1-6 alkoxy substituted with one or more halogens, cyano, C 3-6 cycloalkyl, C 1-6 alkyl sulfone group, C 3-6 cycloalkyl sulfone group, C 1-6 alkyl group or C 1-6 alkoxy group;
  • the carbon atom with "*" is a chiral carbon atom, which is in S configuration, R configuration or a mixture thereof.
  • certain groups in the compound represented by formula I, its solvates, its prodrugs, its metabolites, or their pharmaceutically acceptable salts are defined as follows , the unmentioned groups are described in any scheme of the present invention (referred to as "in a certain scheme of the present invention"),
  • Ring A is a 4-12-membered alicyclic heterocyclic ring containing 2-4 N atoms; the alicyclic heterocyclic ring is a monocyclic ring, a bridged ring or a spirocyclic ring;
  • R a is hydrogen, halogen or C 1-6 alkyl
  • R b and R c are independently hydrogen, C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R b-1 ";
  • Each R b-1 is independently halogen, C 1-6 alkoxy or -NR b-2 R b-3 ;
  • R b-2 and R b-3 are independently hydrogen or C 1-6 alkyl, or , R b-2 , R b-3 and the N connected to them together form "the heteroatom is N, or N and O, and the number of heteroatoms is 1 or 2 4-10-membered heterocycloalkyl";
  • R d is C 1-6 alkyl
  • n 0, 1, 2 or 3;
  • each R 4 is independently C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R 4-1 ";
  • Each R 4-1 is independently halogen, cyano, hydroxyl or C 1-6 alkoxy;
  • R 1-1 , R 1-2 and R 1-3 are independently hydrogen or C 1-6 alkyl
  • n 0, 1, 2 or 3, when m is 0, it means that R 2-6 is directly connected to the parent through a single bond;
  • R 2-1 , R 2-2 , R 2-3 , R 2-4 and R 2-5 are independently C 1-6 alkyl, C 1-6 alkyl substituted with one or more R e , C 1-6 alkoxy, "heteroatoms selected from one or more of N, O and S, 5-12-membered heteroaryl with 1-4 heteroatoms", surrounded by one or more R E-1 substituted "heteroatoms selected from one or more of N, O and S, and 5-12-membered heteroaryl groups with 1-4 heteroatoms", C 6 -C 10 aryl groups, C 6 -C 10 aryl substituted with one or more R e-2 , "heteroatoms selected from one or more of O and N, and 4-10-membered heterocycloalkanes with 1-3 heteroatoms "base", "heteroatoms selected from one or more of O and N, 4-10-membered heterocycloalkyl groups with 1-3 heteroatoms" substituted by one or more R e-3 ,
  • R 2-6 is hydrogen, CN, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R e , C 1-6 alkoxy, "heteroatom selected from N , one or more of O and S, a 5-12-membered heteroaryl group with 1-4 heteroatoms, "heteroatoms substituted by one or more R e-1 are selected from N, O and One or more of S, 5-12-membered heteroaryl with 1-4 heteroatoms, C 6 -C 10 aryl, C 6 -C substituted by one or more R e-2 10 Aryl, "heteroatoms selected from one or more of O and N, 4-10-membered heterocycloalkyl with 1-3 heteroatoms", substituted by one or more R e-3 "The heteroatom is selected from one or more of O and N, and the 4-10-membered heterocycloalkyl with 1-3 heteroatoms", C 3-10 cycloalkyl, or, by one
  • R 2-7 is hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R e , C 1-6 alkoxy, "heteroatom selected from N, O and S
  • One or more, 5-12-membered heteroaryl groups with 1-4 heteroatoms "heteroatoms substituted by one or more R e-1 are selected from one of N, O and S or
  • Various, 5-12-membered heteroaryl groups with 1-4 heteroatoms C 6 -C 10 aryl groups, C 6 -C 10 aryl groups substituted by one or more R e-2
  • "heteroaryl groups” Atoms are selected from one or more of O and N, 4-10-membered heterocycloalkyl with 1-3 heteroatoms
  • "heteroatoms substituted by one or more R e-3 are selected from O and one or more of N, a 4-10-membered heterocycloalkyl with 1-3 heteroatoms, a C 3-10 cycloalkyl, or
  • Each R e is independently "a 5-12-membered heteroaryl group with heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-4", which is replaced by one or more R e- 1 -substituted "heteroatoms selected from one or more of N, O and S, and 5-12-membered heteroaryl groups with 1-4 heteroatoms", C 6 -C 10 aryl groups, substituted by one or Multiple R e-2 substituted C 6 -C 10 aryl groups, "heteroatoms selected from one or more of O and N, and 4-10-membered heterocycloalkyl groups with 1-3 heteroatoms" , "4-10-membered heterocycloalkyl with 1-3 heteroatoms" substituted by one or more R e-3 , C 3- 10 cycloalkyl, or, C 3-10 cycloalkyl substituted by one or more R e-4 ;
  • R e-5 and R e-6 are independently hydrogen or C 1-6 alkyl, or, R e-5 , R e-6 and with The N to which they are connected together form a "4-10-membered heterocycloalkyl with the heteroatom being N, or N and O, and the number of heteroatoms being 1 or 2";
  • R e-11 and R e-12 are independently C 1-6 alkyl;
  • R e-13 and R e-14 are independently hydrogen or C 1-6 alkyl, or, R e-13 , R e-14 and the N to which they are attached together form "the heteroatom is N, or N and O, 4-10-membered heterocycloalkyl with 1 or 2 heteroatoms"; R e-15 is hydrogen or C 1-6 alkyl;
  • R 3 is hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 3-1 , wherein each R 3-1 is independently C 1-6 alkyl, C 1- 6 alkoxy, CN, halogen or OH;
  • X and Y are independently O, NR 6 or CH 2 ;
  • R 6 is hydrogen or C 1-6 alkyl;
  • Z is a single bond, O, NR 6 or CH 2 ;
  • X, Y and Z are not simultaneously O or not At the same time, it is NR 6 ;
  • U, V, W and Q are independently N or CR5 ;
  • Each R 5 is independently H, halogen, hydroxy, C 1-6 alkyl substituted with one or more halogens, C 1-6 alkoxy substituted with one or more halogens, cyano, C 3-6 cycloalkyl, C 1-6 alkyl sulfone group, C 3-6 cycloalkyl sulfone group, C 1-6 alkyl group or C 1-6 alkoxy group;
  • the carbon atom with "*" is a chiral carbon atom, which is in S configuration, R configuration or a mixture thereof.
  • Ring A is a 4-12-membered alicyclic heterocycle containing 2-4 N atoms
  • the alicyclic heterocycle is a 6-10-membered alicyclic heterocyclic ring containing 2 N atoms, for example for
  • the halogen is fluorine, chlorine, bromine or iodine, such as fluorine.
  • R a is a C 1-6 alkyl group
  • the C 1 -C 6 alkyl group is a C 1 -C 3 alkyl group, such as methyl.
  • R b and R c are independently C 1-6 alkyl or "C 1-6 alkyl substituted by one or more R b-1 ", the C 1 - C6 alkyl is C1 - C3 alkyl, eg methyl.
  • each R b-1 is independently halogen
  • the halogen is fluorine, chlorine, bromine or iodine, such as fluorine.
  • each R b-1 is independently a C 1-6 alkoxy group
  • the C 1 -C 6 alkoxy group is a C 1 -C 3 alkoxy group, such as methoxy .
  • the C 1 -C 6 alkyl groups are C 1 -C 3 alkyl groups, such as methyl .
  • the C 1 -C 6 alkyl group is a C 1 -C 3 alkyl group, such as methyl.
  • each R 4 is independently C 1-6 alkyl or "C 1-6 alkyl substituted by one or more R 4-1 "
  • the C 1 -C 6 Alkyl is C1 - C3 alkyl, eg methyl.
  • each R4-1 is independently halogen
  • the halogen is fluorine, chlorine, bromine or iodine, such as fluorine.
  • R 2-1 , R 2-2 , R 2-3 , R 2-4 and R 2-5 are independently C 1-6 alkyl or "received by one or more R " e -substituted C 1-6 alkyl"
  • the C 1 -C 6 alkyl is a C 1 -C 3 alkyl, such as methyl.
  • R 2-1 , R 2-2 , R 2-3 , R 2-4 and R 2-5 are independently C 1-6 alkoxy
  • the C 1-6 C6alkoxy is C1 - C3alkoxy , for example methoxy.
  • R 2-1 , R 2-2 , R 2-3 , R 2-4 and R 2-5 are independently "heteroatoms are selected from one of N, O and S" or more, 5-12-membered heteroaryl with 1-4 heteroatoms" or “substituted by one or more R e-1 " heteroatoms are selected from one or more of N, O and S Species, 5-12-membered heteroaryl group with 1-4 heteroatoms "", the "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-4 The 5-12-membered heteroaryl" is
  • R 2-1 , R 2-2 , R 2-3 , R 2-4 and R 2-5 are independently "heteroatoms selected from one or more of O and N Species, 4-10-membered heterocycloalkyl with 1-3 heteroatoms" or “substituted by one or more R e-3 " heteroatoms are selected from one or more of O and N, heteroatoms 4-10-membered heterocycloalkyl with 1-3 atoms "", the "heteroatoms are selected from one or more of O and N, 4-10 with 1-3 heteroatoms membered heterocycloalkyl" is
  • R 2-6 when R 2-6 is halogen, the halogen is fluorine, chlorine, bromine or iodine, eg chlorine.
  • R 2-6 is C 1-6 alkyl or “C 1-6 alkyl substituted by one or more R e ”, the C 1 -C 6 alkyl is C 1 -C 3 alkyl, eg methyl.
  • the C 1 -C 6 alkoxy is C 1 -C 3 alkoxy, such as methoxy.
  • R 2-6 is independently "a heteroatom selected from one or more of N, O and S, and a 5-12-membered heteroaryl group with 1-4 heteroatoms "or "a 5-12-membered heteroaryl group with 1-4 heteroatoms substituted by one or more R e-1 "
  • the "heteroatoms are selected from one or more of N, O and S
  • the 5-12-membered heteroaryl group with 1-4 heteroatoms is
  • each R e is independently "a 5-12-membered heteroaryl group with a heteroatom selected from one or more of N, O and S, and the number of heteroatoms is 1-4"
  • a 5-12-membered heteroaryl group with 1-4 heteroatoms substituted by one or more R e-1 heteroatoms selected from one or more of N, O and S
  • the “heteroatoms are selected from one or more of N, O and S
  • the 5-12-membered heteroaryl with 1-4 heteroatoms is
  • each R e is independently "a 4-10-membered heterocycloalkyl group with 1-3 heteroatoms selected from one or more of O and N" or "A 4-10-membered heterocycloalkyl group substituted by one or more R e-3 ", the heteroatom is selected from one or more of O and N, and the number of heteroatoms is 1-3.
  • the heteroatom is selected from one or more of O and N, and the 4-10-membered heterocycloalkyl with 1-3 heteroatoms" is E.g
  • the C 1 -C 6 alkyl is C 1 -C 3 Alkyl such as methyl.
  • R e-3 when R e-3 is independently halogen, the halogen is fluorine, chlorine, bromine or iodine, such as fluorine.
  • the C 1 -C 6Alkyl is a C1 - C3 alkyl group such as methyl.
  • R e-3 is independently C 1-6 alkoxy
  • the C 1 -C 6 alkoxy is C 1 -C 3 alkoxy, such as methoxy.
  • the C 1 -C 6 alkyl groups are C 1 -C 3 alkyl groups, for example methyl or ethyl.
  • the C 1 -C 6 alkyl group is a C 1 -C 3 alkyl group, such as methyl.
  • each R5 is independently halogen
  • the halogen is fluorine, chlorine, bromine or iodine, such as fluorine, chlorine or bromine, further such as fluorine or chlorine.
  • each R 5 is independently C 1-6 alkyl substituted by one or more halogens
  • the C 1-6 alkyl substituted by one or more halogens is a C 1-6 alkyl substituted by one or more halogens
  • each R 5 is independently a C 1-6 alkyl group
  • the C 1 -C 6 alkyl group is a C 1 -C 3 alkyl group, such as methyl.
  • each R 5 is independently C 1-6 alkoxy substituted by one or more halogens
  • the C 1-6 alkoxy substituted by one or more halogens is a C 1-6 alkoxy substituted by one or more halogens or multiple halogen-substituted C 1-3 alkoxy groups such as -OCF 3 .
  • the C1 - C6 alkyl group is a C1 - C3 alkyl group, such as methyl.
  • ring A is a 6-10 membered alicyclic heterocyclic ring containing 2 N atoms, and the alicyclic heterocyclic ring is a monocyclic ring.
  • Ra is hydrogen or halogen
  • R b and R c are independently hydrogen, C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R b-1 ", and R b and R At least one of c is hydrogen.
  • each R b-1 is independently halogen.
  • R b and R c are independently hydrogen or "C 1-6 alkyl substituted with one or more halogens", and at least one of R b and R c is hydrogen.
  • n is 0, 1 or 2; preferably 1 or 2.
  • each R 4 is independently methyl, cyano-substituted methyl, F-substituted methyl or hydroxy-substituted methyl; preferably cyano-substituted methyl
  • R 2-1 is hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R e or "substituted by one or more R e-1 ""
  • the heteroatom is selected from one or more of N, O and S, and the 5-12-membered heteroaryl group with 1-4 heteroatoms"".
  • R 2-2 is C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R e ".
  • R 2-5 is C 1-6 alkyl substituted with one or more R e .
  • m is 0.
  • R 2-6 is hydrogen, halogen, "heteroatoms substituted by one or more R e-3 are selected from one or more of O and N, and the number of heteroatoms is 1- 3-membered 4-10-membered heterocycloalkyl", "heteroatoms selected from one or more of N, O and S, and 5-12-membered heteroaryl with 1-4 heteroatoms", One or more R e-1 substituted "heteroatoms selected from one or more of N, O and S, and a 5-12-membered heteroaryl group with 1-4 heteroatoms" or a hydroxyl group.
  • each R e is independently "a heteroatom selected from one or more of N, O and S, and a 5-12-membered heteroaryl group with 1-4 heteroatoms", "The heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-4 5-12-membered heteroaryl", "heteroatom” substituted by one or more R e-1 One or more selected from O and N, 4-10-membered heterocycloalkyl with 1-3 heteroatoms" or “substituted by one or more R e-3 " heteroatoms are selected from O and one or more of N, a 4-10-membered heterocycloalkyl with 1-3 heteroatoms ""; preferably, each R e is independently “heteroatoms selected from N, O and S One or more of, 5-12-membered heteroaryl with 1-4 heteroatoms" or “substituted by one or more R e-3 " heteroatoms are selected from one of O and
  • R e-1 is independently C 1-6 alkyl.
  • R 3 is hydrogen or C 1-6 alkyl.
  • X is O or CR 7 R 8
  • Y is CR 7 R 8
  • Z is a single bond, O or CR 7 R 8 .
  • X and Y are CH 2
  • Z is a single bond, O or CH 2 .
  • U, V, W and Q are independently CR5 .
  • each R 5 is independently H, halogen, C 1-6 alkyl substituted with one or more halogens, C 1-6 alkoxy substituted with one or more halogens, cyano group, C 3-6 cycloalkyl, C 1-6 alkyl or C 1-6 alkoxy.
  • each R5 is independently H, halogen or C1-6 alkyl.
  • R 1 is
  • R 2 is -OR 2-1 or -(CR 1-1 R 1-2 ) m R 2-6 , and R 2-1 is C 1 substituted by one or more R e -6 alkyl, each R e is independently substituted by one or more R e-3 "heteroatoms are selected from one or more of O and N, the number of heteroatoms is 1-3 4-10 "membered heterocycloalkyl", in R e , each R e-3 is independently halogen, C 1-6 alkyl or C 1-6 alkoxy; m is 0, R 2-6 is one or more R e-3 substituted "heteroatoms selected from one or more of O and N, 4-10-membered heterocycloalkyl with 1-3 heteroatoms", in R 2-6 , each R e -3 is independently NR e-5 R e-6 .
  • R 2 is hydrogen, hydroxyl, chlorine, -OCH 3 , -SCH 3 ,
  • the compound shown in the formula I is any of the following compounds:
  • the compound shown in the formula I is any of the following compounds:
  • test conditions of the above retention time are not limited to the compound, as long as the above test conditions are used for the measurement, the obtained retention time is the same as that described above or within the error range, and the compound is one of the compounds defined by the above retention time. Isomers fall within the protection scope of the present invention.
  • the present invention also provides the above-mentioned preparation method of the compound shown in formula I, which comprises the following steps:
  • n ring A, R 1 , R 2 , R 3 , R 4 , X, Y, Z, U, V, W and Q are as defined in any one of the preceding items, and L is halogen or hydroxyl .
  • the operation and conditions of the substitution reaction can be conventional in the art, preferably, it is carried out under the action of a base (eg DIEA and/or TEA).
  • a base eg DIEA and/or TEA.
  • n ring A, R 2 , R 3 , R 4 , X, Y, Z, U, V, W and Q are as defined in any one of the above, and PG is an amino protecting group.
  • the amino protecting group can be a common amino protecting group in the art, preferably, p-tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Cbz).
  • the operations and conditions of the deprotection reaction can be conventional in the art, for example, under the action of an acid (eg, trifluoroacetic acid and/or hydrochloric acid).
  • an acid eg, trifluoroacetic acid and/or hydrochloric acid.
  • the present invention also provides a compound of formula K-X:
  • the compound represented by the formula K-X is any of the following compounds:
  • the present invention also provides a pharmaceutical composition, which includes the above-mentioned compound represented by formula I, its solvate, its prodrug, its metabolite, or their pharmaceutically acceptable salts, and pharmaceutical excipients.
  • the present invention also provides the above-mentioned compounds represented by formula I, their solvates, their prodrugs, their metabolites, or their pharmaceutically acceptable salts, or the use of the above-mentioned pharmaceutical compositions in the preparation of medicines.
  • the medicament is used for the treatment of cancer.
  • the cancer includes lung cancer, colon cancer, pancreatic cancer, rectal cancer, lymphoma cancer, esophageal cancer, ovarian cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer , one or more of cholangiocarcinoma, breast cancer, leukemia and melanoma.
  • the present invention also provides the above-mentioned compounds shown in formula I, their solvates, their prodrugs, their metabolites, or their pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions in the preparation of KRAS G12C protein mutation inhibitors Applications.
  • the KRAS G12C protein mutation inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, such as: providing comparison as a standard sample or a control sample, or according to the art
  • the conventional method is used to make a kit to provide rapid detection of the inhibitory effect of KRAS G12C protein mutation.
  • plurality means 2, 3, 4 or 5, preferably 2 or 3.
  • room temperature refers to 20 to 30°C.
  • pharmaceutically acceptable means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for patient use.
  • patient is preferably a mammal, more preferably a human.
  • solvate refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent.
  • Solvent molecules in solvates can exist in ordered or non-ordered arrangements.
  • the solvent includes, but is not limited to, water, methanol, ethanol, and the like.
  • prodrug refers to a derivative of a compound of the present invention, which is converted to a compound of the present invention (drug) when administered to a warm-blooded animal (eg, a human).
  • Typical examples of prodrugs include compounds with biologically labile protecting groups on functional moieties of the active compound.
  • Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrated, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to yield the active compound .
  • metabolite refers to the degradation product of a compound of the present invention through one or more metabolic processes that exert a desired biological activity.
  • pharmaceutically acceptable salts refers to salts prepared from a compound of the present invention, a solvate thereof, a prodrug or metabolite thereof, and a relatively non-toxic, pharmaceutically acceptable acid or base.
  • base additions can be obtained by contacting neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine.
  • acids of the present invention contain relatively basic functional groups
  • acid additions can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.
  • a pharmaceutically acceptable acid include inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like.
  • Described pharmaceutically acceptable acid includes organic acid, described organic acid includes but is not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e.
  • crystal form means that the ions or molecules in it are arranged in a strictly periodic manner in three-dimensional space in a certain manner, and have the regularity of periodic repetition at a certain distance; crystal form, or polymorphism.
  • amorphous means that the ions or molecules are in a disordered distribution state, that is, there is no periodic arrangement between ions and molecules.
  • stereoisomer refers to a cis-trans isomer or an optical isomer. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, spin chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.) It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or forming salts (physical bonding, etc.).
  • single stereoisomer means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
  • Atoms in the terms “compound”, “solvate”, “prodrug”, “metabolite” and their “pharmaceutically acceptable salts” may exist in their natural or unnatural abundance. Taking a hydrogen atom as an example, its natural abundance means that about 99.985% of it is protium and about 0.015% is deuterium; its unnatural abundance means that about 95% of it is deuterium. That is, one or more atoms in the terms “compound”, “solvate”, “prodrug”, “metabolite” and their “pharmaceutically acceptable salts” may be present in unnatural abundance of atoms.
  • any variable eg Re
  • the definition that appears in each position of the variable has nothing to do with the definitions that appear in other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is substituted with 1, 2 or 3 Re groups, that is, the group may be substituted with up to 3 Re groups, the definition of Re at this position is independent of the definition of Re at the remaining positions of. Additionally, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • alkyl refers to a straight or branched chain alkyl group having the indicated number of carbon atoms.
  • alkoxy refers to the group -O-RX, wherein RX is an alkyl group as defined above.
  • cycloalkyl refers to a monovalent saturated cyclic alkyl group, exemplified by cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and the like.
  • heterocycloalkyl refers to a saturated monocyclic or polycyclic group having a heteroatom.
  • heterocycloalkyl groups are: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl , piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, and the like.
  • aryl refers to a C6-C10 aryl group such as phenyl or naphthyl.
  • heteroaryl refers to an aromatic group containing a heteroatom, preferably containing 1, 2 or 3 aromatic 5-6 membered monocyclic or 9-10 membered bicyclic rings independently selected from nitrogen, oxygen and sulfur, When bicyclic, at least one ring is aromatic.
  • heteroaryl groups are: furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl, pyrazolyl, tris azolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzoyl Isoxazolyl, quinolyl, isoquinolyl, etc.
  • the description mode "...independently” used in the present invention should be understood in a broad sense, meaning that the described individuals are independent of each other and may be independent of each other. are the same or different specific groups.
  • the description mode "...independently” can either mean that in different groups, the specific options expressed between the same symbols do not affect each other; it can also mean that in the same group, the same symbols are The specific options expressed between them do not affect each other.
  • pharmaceutical excipients refers to the excipients and additives used in the production of pharmaceuticals and the formulation of prescriptions, and are all substances contained in pharmaceutical preparations other than active ingredients. See Pharmacopoeia of the People's Republic of China (2015 edition) four, or, Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition)
  • treatment refers to therapeutic therapy.
  • treatment refers to: (1) ameliorating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade leading to or causing the disorder or (b) ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.
  • prevention refers to a reduced risk of acquiring or developing a disease or disorder.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention is that: the present invention provides a series of novel compounds, which have good KRAS G12C protein mutation inhibitory activity, and can be used for treating or preventing cancer.
  • the compounds of the present invention show strong cytotoxicity to a variety of tumor cells.
  • all the compounds of the present invention show proliferation inhibitory activity against NCI-H358, MIA PaCa-2 and other cells, and their IC50 values are ⁇ 100 ⁇ M.
  • Figure 1 is an X-Ray image of intermediate A27.
  • L is halogen (such as chlorine) or hydroxyl
  • PG is a common amino protecting group (such as tert-butoxycarbonyl)
  • the definitions of the remaining substituents are as described in the previous one.
  • the starting compound K-I is substituted to obtain K-II; K-II is halogenated to obtain K-III; K-III and K-XI are substituted to obtain K-IV; K-IV is deprotected to obtain K-V; K-V is obtained by Halogenation reaction to obtain K-VI; K-VI and K-XII are subjected to substitution reaction to obtain K-VII; K-VII is further subjected to substitution reaction to obtain K-VIII; K-VIII is obtained through reductive aminolysis reaction (or further substitution reaction) to obtain K-IX; K-IX is deprotected to obtain K-X; K-X and K-XIII are substituted or acylated to obtain compound I; Compound I is chiral resolved by SFC to obtain compound Ia and compound Ib.
  • the operation and conditions of each step can be conventional in the art.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • SHIMADZU LC system column: CSH TM Prep-C18, 19*150mm, liquid handler LH-40, pump LC-20AP, detector SPD-20A, system controller CBM-20A, solvent system: acetonitrile and 0.05% trifluoroacetic acid in water).
  • LC/MS spectra of compounds were obtained using LC/MS (Agilent Technologies 1200 Series). LC/MS conditions were as follows (run time was 10 min):
  • Acidic conditions A: 0.05% trifluoroacetic acid in water; B: 0.05% trifluoroacetic acid in acetonitrile;
  • the intermediates and final compounds were purified by silica gel column chromatography, or used Purification by preparative HPLC on a CSH TM Prep-C18 (5 ⁇ m, OBD TM 19*150 mm) column or XBridgeTM Prep Phenyl (5 ⁇ m, OBD TM 30*100 mm) column on reversed phase chromatography.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • Thin-layer chromatography (TLC) silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
  • the specifications of the silica gel plates used for TLC detection products are 0.15mm to 0.2mm, and the specifications for TLC separation and purification products are 0.4mm ⁇ 0.5mm.
  • the known starting materials of the present invention can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.
  • Step 1 Preparation of tert-butyl 4-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)piperazine-1-carboxylate
  • 2,4-Dichloro-6-methyl-5-nitropyrimidine (6 g, 28.8 mmol) was dissolved in dry dichloromethane (30 mL), and piperazine-1 was added slowly with stirring at 0 °C - tert-Butyl carboxylate (10.75 g, 57.7 mmol). After dropping, the reaction mixture was further stirred at 0°C for 1 hour, then ice water was added to quench the reaction, and the mixture was diluted with dichloromethane for extraction.
  • Step 2 Preparation of tert-butyl 4-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)piperazine-1-carboxylate
  • Step 3 4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4- Preparation of tert-butyl)piperazine-1-carboxylate
  • Methyl 1,2,3,4-tetrahydronaphthalene-1-carboxylate (1.568 g, 8.24 mmol) was dissolved in dry tetrahydrofuran (20 mL), and LDA (5.50 mmol) was added slowly with stirring at -78°C. mol) and continued stirring at -78°C for 30 minutes, then added tert-butyl 4-(6-(bromomethyl)-2-chloro-5-nitropyrimidin-4-yl)piperazine-1-carboxylate (1.2 g, 2.75 mmol) in tetrahydrofuran (10 mL) was added to the reaction.
  • Step 1 Preparation of (S)-4-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester
  • 2,4-Dichloro-6-methyl-5-nitropyrimidine (20 g, 96 mmol) and phenylmethanol (52.0 g, 481 mmol) were dissolved in dry tetrahydrofuran (40 mL), in Potassium tert-butoxide (21.58 g, 192 mmol) was added with stirring at reflux. After the addition was complete, the reaction mixture was stirred for an additional hour, then quenched by the addition of ice-water, and extracted by dilution with ethyl acetate.
  • 2,4-Bis(benzyloxy)-6-methyl-5-nitropyrimidine (15 g, 42.7 mmol) was dissolved in dry tetrahydrofuran (500 mL), and LiHMDS was added slowly with stirring at -78 °C (68.3 mmol) and stirring was continued for 40 minutes, then a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (13.90 g, 42.7 mmol) in tetrahydrofuran (10 mL) was added to in the reaction solution.
  • Step 3 Methyl 1-((2,6-bis(benzyloxy)-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate preparation
  • Methyl 1,2,3,4-tetrahydronaphthalene-1-carboxylate (6.63 g, 34.9 mmol) was dissolved in dry tetrahydrofuran (150 mL), and LDA (34.9 mmol) was slowly added with stirring at -78°C. mol), and stirring was continued for 30 min at -78°C, then 2,4-bis(benzyloxy)-6-(bromomethyl)-5-nitropyrimidine (5 g, 11.62 mmol) in tetrahydrofuran ( 15 mL) solution was added to the reaction solution.
  • Step 4 Preparation of methyl 1-((2,6-dihydroxy-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate
  • Step 5 Preparation of methyl 1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate
  • Step 4 (2R)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitro Benzyl pyrimidin-4-yl)-2-(fluoromethyl)piperazine-1-carboxylate
  • 2,3-Dihydro-1H-indene-1-carboxylic acid (11 g, 67.8 mmol) was dissolved in anhydrous methanol (100 mL), and thionyl chloride (40.3 g, 339 mmol). After the drop was completed, the reaction mixture was slowly raised to 70°C and stirring was continued for 1 hour. After completion of the reaction, the reaction mixture was concentrated and extracted with ethyl acetate.
  • Step 2 Methyl 1-((2,6-bis(benzyloxy)-5-nitropyrimidin-4-yl)methyl)-2,3-dihydro-1H-indene-1-carboxylate preparation
  • Methyl 2,3-dihydro-1H-indene-1-carboxylate (1.3 g, 6.97 mmol) was dissolved in dry tetrahydrofuran (40 mL), and LDA (6.97 mmol) was slowly added with stirring at -78°C. ) and continued stirring at -78°C for 30 minutes, then 2,4-bis(benzyloxy)-6-(bromomethyl)-5-nitropyrimidine (Intermediate A3-2, 1.0 g, 2.32 mM mol) in tetrahydrofuran (10 mL) was added to the reaction solution.
  • Step 3 Preparation of methyl 1-((2,6-dihydroxy-5-nitropyrimidin-4-yl)methyl)-2,3-dihydro-1H-indene-1-carboxylate
  • Step 4 Preparation of methyl 1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-2,3-dihydro-1H-indene-1-carboxylate
  • Methyl 1-((2,6-dihydroxy-5-nitropyrimidin-4-yl)methyl)-2,3-dihydro-1H-indene-1-carboxylate (600 mg, 1.738 mmol ) was dissolved in phosphorus oxychloride (15 mL) and DIEA (225 mg, 1.73 mmol) was added with stirring at 0°C. The reaction mixture was slowly raised to 110°C under nitrogen and stirred for 6 hours, then the reaction mixture was concentrated, extracted with dichloromethane and the solution was poured into saturated sodium bicarbonate solution and stirred for 1 hour.
  • Step 2 Preparation of methyl 4-((2,6-bis(benzyloxy)-5-nitropyrimidin-4-yl)methyl)chroman-4-carboxylate
  • Methyl chroman-4-carboxylate (300 mg, 1.561 mmol) was dissolved in dry tetrahydrofuran (20 mL), LDA (1.87 mmol) was slowly added with stirring at -78 °C, and at- Stirring was continued at 78°C for 30 minutes, then 2,4-bis(benzyloxy)-6-(bromomethyl)-5-nitropyrimidine (Intermediate A3-2, 672 mg, 1.561 mmol) in tetrahydrofuran (10 mL) was added. ) solution was added to the reaction solution.
  • Step 5 Benzyl(2S)-4-(2-chloro-6-((4-(methoxycarbonyl)chroman-4-yl)methyl)-5-nitropyrimidin-4-yl)-2 Preparation of -(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
  • But-2-ynoic acid (300 mg, 3.57 mmol) was dissolved in dry dichloromethane (3 mL) and oxalyl chloride (679 mg, 5.35 mmol) was added slowly with stirring at 0°C. After the dropping, the reaction mixture was continued to be stirred at 0° C. for 1 hour. After the completion of the reaction, the reaction solution was directly used for the next reaction.
  • Step 1 Preparation of 1-(tert-butyl) 2-methyl(2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylate
  • Methyl (S)-(1-methylpyrrolidin-2-yl)methanesulfonate (3.2 g, 16.56 mmol) was dissolved in dry DMF (10 mL) and thioacetic acid was added at 20°C Potassium (2.08 g, 18.21 mmol). After dropping, the reaction mixture was further stirred at 65°C for 13 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction.
  • Step 1 Preparation of ((benzyloxy)carbonyl)-L-serine-L-alanine methyl ester
  • Step 7 Preparation of 1-benzyl 4-(tert-butyl)(2S,5R)-2-(cyanomethyl)-5-methylpiperazine-1,4-dicarboxylate
  • Step 8 Preparation of (2S,5R)-2-(cyanomethyl)-5-methylpiperazine-1-carboxylic acid benzyl ester
  • Step 9 (2S,5R)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5- Preparation of benzyl nitropyrimidin-4-yl)-2-(cyanomethyl)-5-methylpiperazine-1-carboxylate
  • Ph3PCH2OMeCl (83.5 g , 243.6 mmol) was dissolved in dry tetrahydrofuran (400 mL) and potassium tert-butoxide (24.9 g, 221.5 mmol) was slowly added with stirring at 0 degrees. After dropping, the reaction mixture was further stirred at 0°C for 1 hour, and a solution of 6-chloro-3,4-dihydronaphthalen-1(2H)-one (20.0 g, 110.7 mmol) in tetrahydrofuran (100 mL) was added Into the above reaction solution, the reaction mixture was further stirred at 20 degrees for 12 hours, then ice water was added to quench the reaction, and the mixture was diluted and extracted with dichloromethane.
  • Step 3 Preparation of methyl 7-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxylate
  • Step 4 1-((2,6-Bis(benzyloxy)-5-nitropyrimidin-4-yl)methyl)-7-chloro-1,2,3,4-tetrahydronaphthalene-1- Preparation of methyl carboxylate
  • Methyl 7-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxylate (1253 mg, 5.58 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) and added slowly with stirring at -78°C LDA (6.97 mmol), and stirring was continued for 30 min at -78 degrees, then 2,4-bis(benzyloxy)-6-(bromomethyl)-5-nitropyrimidine (Intermediate A3-2, 2000 mg, 4.65 mmol) in tetrahydrofuran (15 mL) was added to the reaction solution.
  • Step 5 Methyl 7-chloro-1-((2,6-dihydroxy-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate preparation
  • Step 6 Methyl 7-chloro-1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate preparation
  • Methyl 7-chloro-1-((2,6-dihydroxy-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (2200 mg, 5.59 mmol) was dissolved in phosphorus oxychloride (15 mL) and DIEA (791 mg, 6.12 mmol) was added with stirring at 0 degrees. The reaction mixture was slowly raised to 110°C under nitrogen and stirred for 6 hours, then the reaction mixture was concentrated, diluted with dichloromethane for extraction and the solution was poured into saturated sodium bicarbonate solution and stirred for 1 hour.
  • Step 7 (2S)-4-(2-Chloro-6-((7-Chloro-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)- Preparation of 5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
  • Ph3PCH2OMeCl (83.5 g , 243.6 mmol) was dissolved in dry tetrahydrofuran (400 mL) and potassium tert-butoxide (24.9 g, 221.5 mmol) was slowly added with stirring at 0 degrees. After dropping, the reaction mixture was further stirred at 0°C for 1 hour, and a solution of 6-chloro-3,4-dihydronaphthalen-1(2H)-one (20.0 g, 110.7 mmol) in tetrahydrofuran (100 mL) was added Into the above reaction solution, the reaction mixture was further stirred at 20 degrees for 12 hours, then ice water was added to quench the reaction, and the mixture was diluted and extracted with dichloromethane.
  • Step 3 Preparation of methyl 6-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxylate
  • 6-Chloro-1,2,3,4-tetrahydronaphthalene-1-acetaldehyde (11.4 g, 58.6 mmol) was dissolved in acetonitrile (270 mL) and methanol (18.8 g, 585.7 mmol) at 20 NIS (39.5 g, 175.7 mmol) and potassium carbonate (24.3 g, 175.7 mmol) were slowly added with stirring at 100°C. After dropping, the reaction mixture was further stirred at 20°C for 16 hours, then a saturated sodium bicarbonate solution was added to adjust the pH to 9, and the mixture was diluted with ethyl acetate for extraction.
  • Step 4 1-((2,6-Bis(benzyloxy)-5-nitropyrimidin-4-yl)methyl)-6-chloro-1,2,3,4-tetrahydronaphthalene-1- Preparation of methyl carboxylate
  • Methyl 6-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxylate (1253 mg, 5.58 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) and added slowly with stirring at -78°C LDA (6.97 mmol), and stirring was continued for 30 min at -78 degrees, then 2,4-bis(benzyloxy)-6-(bromomethyl)-5-nitropyrimidine (Intermediate A3-2, 2000 mg, 4.65 mmol) in tetrahydrofuran (15 mL) was added to the reaction solution.
  • Step 5 Methyl 6-chloro-1-((2,6-dihydroxy-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate
  • Step 6 Methyl 6-chloro-1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate preparation
  • Step 7 (2S)-4-(2-Chloro-6-((6-Chloro-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)- Preparation of 5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
  • Intermediate A29 was synthesized with reference to Intermediate A3 by using (S)-1-((2,6-bis(benzyloxy)-5-nitropyrimidin-4-yl)methyl)-1,2,3 , 4-Tetrahydronaphthalene-1-carboxylate methyl ester (Intermediate A27) in place of 1-((2,6-bis(benzyloxy)-5-nitropyrimidin-4-yl)methyl)-1, 2,3,4-Tetrahydronaphthalene-1-carboxylic acid methyl ester (Intermediate A3-3) was prepared to give Intermediate A29. MS: 586.1 (M+H) + .
  • Intermediate A30 was synthesized with reference to Intermediate A3 by using (R)-1-((2,6-bis(benzyloxy)-5-nitropyrimidin-4-yl)methyl)-1,2,3 , 4-Tetrahydronaphthalene-1-carboxylate methyl ester (Intermediate A28) in place of 1-((2,6-bis(benzyloxy)-5-nitropyrimidin-4-yl)methyl)-1, 2,3,4-Tetrahydronaphthalene-1-carboxylic acid methyl ester (Intermediate A3-3) was prepared to obtain Intermediate A30. MS: 586.1 (M+H) + .
  • intermediate A32-5 was referred to intermediate A21/step 1 by using 5-chloro-7-methyl-3,4-dihydronaphthalen-1(2H)-one (intermediate A32-4) in place of 7- Chloro-3,4-dihydronaphthalene-1(2H)-one was prepared to give intermediate A32-5.
  • Step 7 Preparation of methyl 5-chloro-7-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylate
  • Intermediate A32-7 was synthesized with reference to Intermediate A21/Step 3 by using 5-chloro-7-methyl-1,2,3,4-tetrahydronaphthalene-1-carbaldehyde (Intermediate A32-6) in place of 7 -Chloro-1,2,3,4-tetrahydronaphthalene-1-carbaldehyde (Intermediate A21/Step 2) Prepared to give Intermediate A32-7. MS: 239.2 (M+H) + .
  • Step 8 (2S)-4-(2-Chloro-6-((5-Chloro-1-(methoxycarbonyl)-7-methyl-1,2,3,4-tetrahydronaphthalen-1-yl ) methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester preparation
  • Step 2 (2S)-4-(2-Chloro-6-((5,6-difluoro-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methan Preparation of tert-butyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (Intermediate A34)
  • Intermediate A34 was synthesized with reference to Intermediate A23 by using 5,6-difluoro-3,4-dihydronaphthalen-1(2H)-one (Intermediate A34-4) in place of 6-chloro-3,4-di Hydronaphthalene-1(2H)-one was prepared to provide intermediate A34. MS: 622.2 (M+H) + .
  • Step 1 Preparation of 5-chloro-6-fluoro-3,4-dihydronaphthalene-1(2H)-one (Intermediate A35-4)
  • Step 2 Preparation of 5-chloro-6-fluoro-1-methylene-1,2,3,4-tetrahydronaphthalene (Intermediate A35-5)
  • Methyltriphenylphosphonium bromide (27.3 g, 77 mmol) was dissolved in tetrahydrofuran (180 mL), and potassium tert-butoxide (8.59 g, 77 mmol) was slowly added with stirring at 0 °C and stirred at 0 °C for 1 hour.
  • the preparation of 5-chloro-6-fluoro-3,4-dihydronaphthalen-1(2H)-one (Intermediate A35-4, 7.6 g, 38.3 mmol) in tetrahydrofuran (50 mL) was then carried out at 0 degrees added to the above reaction solution.
  • Step 3 Preparation of (5-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-yl)methanol (Intermediate A35-6)
  • Step 4 5-Chloro-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-carbaldehyde (Intermediate A35-7)
  • Step 5 Preparation of methyl 5-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A35-8)
  • Intermediate A35-8 was synthesized with reference to Intermediate A21/Step 3 by using 5-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-carbaldehyde (Intermediate A35-7) in place of 7- Chloro-1,2,3,4-tetrahydronaphthalene-1-carbaldehyde (Intermediate A21/Step 2) was prepared to give Intermediate A35-8. MS: 243.2 (M+H) + .
  • Step 6 (2S)-4-(2-Chloro-6-((5-Chloro-6-fluoro-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl) Methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A35)
  • intermediate A36-3 was referred to intermediate A32-4 by using 4-(2-chloro-4-fluorophenyl)butyric acid (intermediate A36-2) in place of 4-(2-chloro-4-methyl) Phenyl)butyric acid (Intermediate A32-3) was prepared to give Intermediate A36-3.
  • Step 4 (2S)-4-(2-Chloro-6-((5-Chloro-7-fluoro-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl) Preparation of tert-butyl methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate
  • intermediate A38 was obtained by using 1-fluoro-2-iodobenzene in place of 1,2-difluoro-3-iodobenzene. MS: 604.1 (M+H) + .
  • intermediate A40 was obtained by using 1-bromo-4-fluoro-2-toluene in place of 1,2-difluoro-3-iodobenzene. MS: 618.1 (M+H) + .
  • intermediate A41 was obtained by using 1-bromo-2-fluoro-3-toluene in place of 1,2-difluoro-3-iodobenzene. MS: 618.1 (M+H) + .
  • Step 2 (2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-5-(trifluoromethoxy)-1,2,3,4-tetrahydronaphthalene-1) Preparation of -yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester
  • intermediate A43 was obtained by using 1-iodo-2-(trifluoromethyl)benzene in place of 1,2-difluoro-3-iodobenzene. MS: 654.1 (M+H) + .
  • intermediate A46 was prepared by using 2-fluoro-1-iodo-4-toluene in place of 2-chloro-1-fluoro-3-iodobenzene. MS: 618.1 (M+H) + .
  • Step 2 Preparation of 4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (Intermediate A52-2)
  • Step 3 Preparation of methyl 4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A52-3)
  • Step 4 (2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl) Preparation of tert-butyl methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate
  • intermediate C6 refers to intermediate C3 by using 1-(tert-butyl) 2-methyl(S)-4,4-difluoropyrrolidine-1,2-dicarboxylate in place of 1-(tert-butyl) base) 2-methyl(2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate was prepared to give intermediate C6. MS: 152.1 (M+H) + .
  • Intermediate A53 was synthesized with reference to Intermediate A35 by using Intermediate A53-2 in place of methyl 5-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A35-8 ) to prepare intermediate A53.
  • intermediate C7 was referred to intermediate C3 by using 1-(tert-butyl)2-methyl(2S,4R,5S)-4-fluoro-5-methylpyrrolidine-1,2-dicarboxylate
  • intermediate C7 was prepared. MS: 148.1 (M+H) + .
  • Step 1 Preparation of 4-chloro-6-fluoro-2,3-dihydro-1H-inden-1-one (Intermediate A54-1)
  • Step 2 (2S)-4-(2-Chloro-6-((4-Chloro-6-fluoro-1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methane Preparation of tert-butyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (Intermediate A54)
  • Step 1 Preparation of ethyl 2-(2-chloro-4-fluorophenethoxy)-2-ethoxyacetate (Intermediate A55-1)
  • Intermediate A55 was synthesized with reference to Intermediate A35 by using Intermediate A55-2 in place of methyl 5-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A35-8 ) to prepare intermediate A55. MS: 653.4 (M+H) + .
  • intermediate A57 was prepared by using 2-bromo-1-chloro-4-fluorobenzene in place of 1,2-difluoro-3-iodobenzene. MS: 242.4 (M+H) + .
  • Step 1 Preparation of methyl 2,6-bis(benzyloxy)-5-nitropyrimidin-4-yl)acetate (Intermediate A58-2)
  • 2,4-Bis(benzyloxy)-6-(bromomethyl)-5-nitropyrimidine (10 g, 23.24 mmol) was dissolved in DMF (50 mL) and acetic acid was added with stirring at 0 °C potassium (3.42 g, 34.9 mmol) and stirred at 20 degrees for 2 hours. The reaction was then quenched by the addition of ice water, and the extraction was diluted with ethyl acetate.
  • Step 6 (S)-4-(6-(acetoxymethyl)-5-amino-2-(methylthio)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1- Preparation of tert-butyl carboxylate (Intermediate A58-7)
  • Step 7 (S)-4-(6-(Acetoxymethyl)-5-((tert-butoxycarbonyl)amino)-2-(methylthio)pyrimidin-4-yl)-2-(cyano Preparation of tert-butyl)piperazine-1-carboxylate (Intermediate A58-8)
  • Step 8 (S)-4-(5-((tert-butoxycarbonyl)amino)-6-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)-2-(cyanomethyl) )
  • Step 10 (2S)-4-(5-((tert-butoxycarbonyl)amino)-6-((5-chloro-8-fluoro-1-(methoxycarbonyl)-1,2,3,4- Preparation of tert-butyl tetrahydronaphthalen-1-yl)methyl)-2-(methylthio)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (Intermediate A58)
  • Compound I-1 4'-(4-Acryloylpiperazin-1-yl)-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4, 5',8'-Tetrahydro-2H,6'H-Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-6'-one
  • Step 1 4-(6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-2-(((S)-1-methyl Preparation of pyrrolidin-2-yl)methoxy)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester
  • Step 2 4-(2'-(((S)-1-Methylpyrrolidin-2-yl)methoxy)-6'-oxo-3,4,5',8'-tetrahydro- Preparation of 2H,6'H-spiro[naphthalene-1,7'-pyrido[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylic acid tert-butyl ester
  • Step 3 2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4'-(piperazin-1-yl)-3,4,5',8'- Preparation of tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-6'-one
  • Step 4 4'-(4-Acryloylpiperazin-1-yl)-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5' Preparation of ,8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-6'-one
  • Step 1 4-(5'-Methyl-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4,5', Preparation of 8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate tert-butyl ester
  • reaction mixture was stirred at 0°C for 1 hour, then iodomethane (25.2 mg, 0.178 mmol) was added to the reaction solution and stirring was continued for 1 hour. After the reaction was completed, ice water was added to quench the reaction, and the mixture was diluted and extracted with ethyl acetate.
  • Step 2 5'-Methyl-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4'-(piperazin-1-yl)-3,4, Preparation of 5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-6'-one
  • Step 3 4'-(4-Acryloylpiperazin-1-yl)-5'-methyl-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)- Preparation of 3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-6'-one
  • Step 1 (3S)-4-(6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-2-(((S)- Preparation of 1-Methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester
  • Step 3 4'-((S)-2-Methylpiperazin-1-yl)-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3, Preparation of 4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-6'-one
  • Step 4 4'-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy yl)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-6'-one
  • Step 1 (2S)-2-(cyanomethyl)-4-(6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl
  • Step 3 2-((2S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4,5' Preparation of ,8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile

Abstract

L'invention concerne un inhibiteur de mutation de protéine KRASG12C et son procédé de préparation, une composition pharmaceutique et son application. L'invention divulgue spécifiquement est un composé tel que représenté dans la formule I, un solvate de celui-ci, un promédicament de celui-ci, un métabolite de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci. Le composé a une bonne activité d'inhibition de mutation de protéine KRASG12C et peut être utilisé pour le traitement ou la prévention de cancers.
PCT/CN2021/138375 2020-12-17 2021-12-15 Inhibiteur de mutation de protéine krasg12c et son procédé de préparation, composition pharmaceutique et son application WO2022127827A1 (fr)

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US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof

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Publication number Priority date Publication date Assignee Title
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof

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