WO2022127827A1 - Krasg12c protein mutation inhibitor and preparation method therefor, pharmaceutical composition and application thereof - Google Patents

Krasg12c protein mutation inhibitor and preparation method therefor, pharmaceutical composition and application thereof 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

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Abstract

A KRASG12C protein mutation inhibitor and a preparation method therefor, a pharmaceutical composition and an application thereof. Specifically disclosed are a compound as shown in formula I, a solvate thereof, a prodrug thereof, a metabolite thereof, or a pharmaceutically acceptable salt thereof. The compound has good KRASG12C protein mutation inhibition activity and can be used for treating or preventing cancers.

Description

KRAS G12C蛋白突变抑制剂、其制备方法、药物组合物及其应用 KRAS G12C protein mutation inhibitor, preparation method, pharmaceutical composition and application thereof
本申请要求申请日为2020年12月17日的中国专利申请2020114966198和申请日为2021年6月29日的中国专利申请2021107286137的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of Chinese patent application 2020114966198 with filing date on December 17, 2020 and Chinese patent application 2021107286137 with filing date on June 29, 2021. This application cites the full text of the above Chinese patent application.
技术领域technical field
本发明涉及一种KRAS G12C蛋白突变抑制剂、其制备方法、药物组合物及其应用。 The present invention relates to a KRAS G12C protein mutation inhibitor, its preparation method, pharmaceutical composition and its application.
背景技术Background technique
RAS(Rat sarcoma)蛋白包括KRAS，HRAS和NRAS，是小GTP酶(GTPase)家族的成员。RAS蛋白可以和鸟嘌呤三核苷酸磷酸(GTP)或者鸟嘌呤二核苷酸磷酸(GDP)结合，两种状态之间的转换受到鸟嘌呤核苷酸交换因子(GEFs)和GTP水解酶激活蛋白(GAP)的调控。当与GDP结合时，RAS蛋白处于“失活”状态；当与GTP结合时，RAS蛋白处于“活化”状态。在GTP结合状态下，RAS蛋白与多种下游效应蛋白直接相互作用并激活包括促分裂原活化蛋白激酶(MAPK)和磷脂酰肌醇3-激酶(PI3K)在内的信号通路，从而调节细胞生长，细胞运动或新陈代谢，以及细胞与其细胞外环境之间的相互作用。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. When bound to GDP, RAS protein is in an "inactive" state; when bound to GTP, RAS protein is in an "activated" state. In the GTP-bound state, 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.
RAS基因的过度活化突变是癌症中最常见的基因突变，大约30％的人类肿瘤中都携带某些突变的RAS基因。其中KRAS是最常见的突变癌基因，占到所有RAS突变的86％。多数RAS基因的突变可降低GAP与RAS蛋白的结合进而影响GAP催化GTP水解的能力，RAS蛋白内在GTP酶活性或同时降低这两者，从而导致GTP结合状态的RAS蛋白的增加，使RAS蛋白一直处于“活化”状态。活化的RAS蛋白持续的激活下游信号通路，最终导致细胞的持续增长和分化，进而导致肿瘤的发生。RAS突变是包括结直肠癌(CRC)，胰腺导管腺癌(PDAC)，肺腺癌(LUAD；非小细胞肺癌(NSCLC)的亚型)，黑色素瘤和某些血液学癌症在内的多种癌症类型的遗传驱动因素。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.
在KRAS突变肿瘤中，大多数致癌突变发生在12号密码子内，占到83％。G12C突变是KRAS基因突变中比较常见的一个亚型。KRAS G12C突变在肺腺癌中普遍存在，并存在胰腺癌和结直肠癌等其他肿瘤类型中。尽管有大量的药物发现工作，目前还没有针对KRAS G12C突变的上市药物。KRAS G12C的突变已被证明与癌症不良预后有关。因此，针对KRAS G12C突变抑制剂的开发具有重要的临床需求。Shokat及其同事报道的共价KRAS G12C抑制剂为治疗KRAS G12C突变肿瘤提供了可能性(Ostrem JM.,et al.Nature,2013,548-551)。 尽管已经公开了一系列关于KRASG12C抑制剂的专利(WO2014143659,WO2014152588,WO2015054572,WO2016049524,WO2017201161,WO2018119183等)，发现更有效的具有更好的药代动力学和药效学特性的KRAS抑制剂仍然非常重要。 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. 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.
发明内容SUMMARY OF THE INVENTION
本发明所要解决的技术问题是针对现有KRAS G12C蛋白突变抑制剂结构较为单一的缺陷，提供了一种KRAS G12C蛋白突变抑制剂、其制备方法、药物组合物及其应用，本发明化合物结构新颖，活性和选择性较好。 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.
本发明提供了一种如式I所示的化合物、其溶剂合物、其前药、其代谢产物、或它们(指前述如式I所示的化合物、其溶剂合物、其前药或其代谢产物)药学上可接受的盐：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:
Figure PCTCN2021138375-appb-000001
Figure PCTCN2021138375-appb-000001
环A为含2-4个N原子的4-12元脂杂环；所述的脂杂环为单环、桥环或螺环；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 1为-C(＝O)-C(R a)＝C(R b)(R c)、-C(＝O)-C≡CR c、-C(＝O)-C(＝O)-O-R d或-C(＝O)-R d； R 1 is -C(=O)-C(R a )=C(R b )(R c ), -C(=O)-C≡CR c , -C(=O)-C(=O) -OR d or -C(=O)-R d ;
R a为氢、卤素或C 1-6烷基； R a is hydrogen, halogen or C 1-6 alkyl;
R b和R c独立地为氢、C 1-6烷基或“被一个或多个R b-1取代的C 1-6烷基”； 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 ";
各R b-1独立地为卤素、C 1-6烷氧基或-NR b-2R b-3；R b-2和R b-3独立地为氢或C 1-6烷基，或者，R b-2、R b-3及与它们相连接的N共同形成“杂原子为N、或者N和O，杂原子数为1个或2个的4-10元杂环烷基”； 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为C 1-6烷基； R d is C 1-6 alkyl;
n为0、1、2或3；n is 0, 1, 2 or 3;
各R 4独立地为C 1-6烷基或“被一个或多个R 4-1取代的C 1-6烷基”； each R 4 is independently C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R 4-1 ";
各R 4-1独立地为卤素、氰基、羟基或C 1-6烷氧基； Each R 4-1 is independently halogen, cyano, hydroxyl or C 1-6 alkoxy;
R 2为-OR 2-1、-SR 2-2、-C(＝O)R 2-3、-S(＝O) 2R 2-4、-S(＝O)R 2-5、-(CR 1-1R 1-2) mR 2-6或NR 1- 3R 2-7； R 2 is -OR 2-1 , -SR 2-2 , -C(=O)R 2-3 , -S(=O) 2 R 2-4 , -S(=O)R 2-5 , - (CR 1-1 R 1-2 ) m R 2-6 or NR 1-3 R 2-7 ;
R 1-1、R 1-2和R 1-3独立地为氢或C 1-6烷基； R 1-1 , R 1-2 and R 1-3 are independently hydrogen or C 1-6 alkyl;
m为0、1、2或3，当m为0时，表示R 2-6通过单键直接与母体相连； m is 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和R 2-5独立地为C 1-6烷基、被一个或多个R e取代的C 1-6烷基、C 1-6烷氧基、“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、C 6-C 10芳基、被一个或多个R e-2取代的C 6-C 10芳基、“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、C 3- 10环烷基、或、被一个或多个R e-4取代的C 3-10环烷基； 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 , C 3-10 cycloalkyl, or, C 3-10 cycloalkyl substituted by one or more R e-4 ;
R 2-6为氢、CN、卤素、羟基、C 1-6烷基、被一个或多个R e取代的C 1-6烷基、C 1-6烷氧基、“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、C 6-C 10芳基、被一个或多个R e-2取代的C 6-C 10芳基、“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、C 3-10环烷基、或、被一个或多个R e-4取代的C 3-10环烷基； 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 or more C 3-10 cycloalkyl substituted by R e-4 ;
R 2-7为氢、C 1-6烷基、被一个或多个R e取代的C 1-6烷基、C 1-6烷氧基、“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、C 6-C 10芳基、被一个或多个R e-2取代的C 6-C 10芳基、“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、C 3-10环烷基、或、被一个或多个R e-4取代的C 3-10环烷基； 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 a substituted by one or more R e-4 C 3-10 cycloalkyl;
各R e独立地为“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、C 6-C 10芳基、被一个或多个R e-2取代的C 6-C 10芳基、“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、C 3-10环烷基、或、被一个或多个R e-4取代的C 3-10环烷基； 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-1、R e-2和R e-4独立地为卤素、C 1-6烷基、C 1-6烷氧基、-C(＝O)-C(R a)＝C(R b)(R c)或NR e-5R e-6；R e-5和R e-6独立地为氢或C 1-6烷基，或者，R e-5、R e-6及与它们相连接的N成共 同形成“杂原子为N、或者N和O，杂原子数为1个或2个的4-10元杂环烷基”； R e-1 , R e-2 and R e-4 are independently halogen, C 1-6 alkyl, C 1-6 alkoxy, -C(=O)-C(R a )=C(R b ) (R c ) or NR e-5 R e-6 ; 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";
各R e-3独立地为卤素、羟基、氰基、C 1-6烷基、被一个或多个R e-7取代的C 1-6烷基、C 1-6烷氧基、被一个或多个R e-8取代的C 1-6烷氧基、-C(＝O)-C(R a)＝C(R b)(R c)、NR e-5R e-6、-O(C＝O)NR e-13R e-14或-O(C＝O)OR e-15；R e-7和R e-8独立地为卤素、羟基、氰基、-COOH、C 1-6烷氧基或NR e-9R e-10，R e-9和R e-10独立地为氢、C 1-6烷基、-C(＝O)R e-11或-S(＝O) 2R e-12；R e-11和R e-12独立地为C 1-6烷基； Each R e-3 is independently halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R e-7 , C 1-6 alkoxy, or multiple R e-8 substituted C 1-6 alkoxy, -C(=O)-C(R a )=C(R b )(R c ), NR e-5 R e-6 , - O(C=O)NR e-13 R e-14 or -O(C=O)OR e-15 ; R e-7 and R e-8 are independently halogen, hydroxyl, cyano, -COOH, C 1-6 alkoxy or NR e-9 R e-10 , R e-9 and R e-10 are independently hydrogen, C 1-6 alkyl, -C(=O)R e-11 or -S (=O) 2 R e-12 ; R e-11 and R e-12 are independently C 1-6 alkyl;
R e-13和R e-14独立地为氢或C 1-6烷基，或者，R e-13、R e-14及与它们相连接的N共同形成“杂原子为N、或者N和O，杂原子数为1个或2个的4-10元杂环烷基”；R e-15为氢或C 1-6烷基； 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为氢、C 1-6烷基、被一个或多个R 3-1取代的C 1-6烷基，其中，各R 3-1独立地为C 1- 6烷基、C 1-6烷氧基、CN、卤素或OH； 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和Y独立地为O、NR 6或CR 7R 8；各R 6独立地为氢或C 1-6烷基；各R 7和R 8独立地为H或C 1-6烷基；Z为单键、O、NR 6或CR 7R 8；X、Y和Z不同时为O或不同时为NR 6； 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和Q独立地为N或CR 5； U, V, W and Q are independently N or CR5 ;
各R 5独立地为H、卤素、羟基、被一个或多个卤素取代的C 1-6烷基、被一个或多个卤素取代的C 1-6烷氧基、氰基、C 3-6环烷基、C 1-6烷基砜基、C 3-6环烷基砜基、C 1-6烷基或C 1-6烷氧基； 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;
带“*”碳原子为手性碳原子，为S构型、R构型或它们的混合物。The carbon atom with "*" is a chiral carbon atom, which is in S configuration, R configuration or a mixture thereof.
在本发明某些优选实施方案中，所述的如式I所示的化合物、其溶剂合物、其前药、其代谢产物、或它们药学上可接受的盐中的某些基团如下定义，未提及的基团同本发明任一方案所述(简称“在本发明某一方案中”)，In certain preferred embodiments of the present invention, 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"),
环A为含2-4个N原子的4-12元脂杂环；所述的脂杂环为单环、桥环或螺环；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 1为-C(＝O)-C(R a)＝C(R b)(R c)、-C(＝O)-C≡CR c、-C(＝O)-C(＝O)-O-R d或-C(＝O)-R d； R 1 is -C(=O)-C(R a )=C(R b )(R c ), -C(=O)-C≡CR c , -C(=O)-C(=O) -OR d or -C(=O)-R d ;
R a为氢、卤素或C 1-6烷基； R a is hydrogen, halogen or C 1-6 alkyl;
R b和R c独立地为氢、C 1-6烷基或“被一个或多个R b-1取代的C 1-6烷基”； 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 ";
各R b-1独立地为卤素、C 1-6烷氧基或-NR b-2R b-3；R b-2和R b-3独立地为氢或C 1-6烷基，或者，R b-2、R b-3及与它们相连接的N共同形成“杂原子为N、或者N和O，杂原子数为1个或2个的4-10元杂环烷基”； 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为C 1-6烷基； R d is C 1-6 alkyl;
n为0、1、2或3；n is 0, 1, 2 or 3;
各R 4独立地为C 1-6烷基或“被一个或多个R 4-1取代的C 1-6烷基”； each R 4 is independently C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R 4-1 ";
各R 4-1独立地为卤素、氰基、羟基或C 1-6烷氧基； Each R 4-1 is independently halogen, cyano, hydroxyl or C 1-6 alkoxy;
R 2为-OR 2-1、-SR 2-2、-C(＝O)R 2-3、-S(＝O) 2R 2-4、-S(＝O)R 2-5、-(CR 1-1R 1-2) mR 2-6或NR 1- 3R 2-7； R 2 is -OR 2-1 , -SR 2-2 , -C(=O)R 2-3 , -S(=O) 2 R 2-4 , -S(=O)R 2-5 , - (CR 1-1 R 1-2 ) m R 2-6 or NR 1-3 R 2-7 ;
R 1-1、R 1-2和R 1-3独立地为氢或C 1-6烷基； R 1-1 , R 1-2 and R 1-3 are independently hydrogen or C 1-6 alkyl;
m为0、1、2或3，当m为0时，表示R 2-6通过单键直接与母体相连； m is 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和R 2-5独立地为C 1-6烷基、被一个或多个R e取代的C 1-6烷基、C 1-6烷氧基、“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、C 6-C 10芳基、被一个或多个R e-2取代的C 6-C 10芳基、“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、C 3- 10环烷基、或、被一个或多个R e-4取代的C 3-10环烷基； 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 , C 3-10 cycloalkyl, or, C 3-10 cycloalkyl substituted by one or more R e-4 ;
R 2-6为氢、CN、卤素、羟基、C 1-6烷基、被一个或多个R e取代的C 1-6烷基、C 1-6烷氧基、“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、C 6-C 10芳基、被一个或多个R e-2取代的C 6-C 10芳基、“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、C 3-10环烷基、或、被一个或多个R e-4取代的C 3-10环烷基； 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 or more C 3-10 cycloalkyl substituted by R e-4 ;
R 2-7为氢、C 1-6烷基、被一个或多个R e取代的C 1-6烷基、C 1-6烷氧基、“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、C 6-C 10芳基、被一个或多个R e-2取代的C 6-C 10芳基、“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、C 3-10环烷基、或、被一个或多个R e-4取代的C 3-10环烷基； 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 a substituted by one or more R e-4 C 3-10 cycloalkyl;
各R e独立地为“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、C 6-C 10芳基、被一个或多个R e-2取代的C 6-C 10芳基、“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、被一个或多 个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、C 3-10环烷基、或、被一个或多个R e-4取代的C 3-10环烷基； 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-1、R e-2和R e-4独立地为卤素、C 1-6烷基、C 1-6烷氧基、-C(＝O)-C(R a)＝C(R b)(R c)或NR e-5R e-6；R e-5和R e-6独立地为氢或C 1-6烷基，或者，R e-5、R e-6及与它们相连接的N成共同形成“杂原子为N、或者N和O，杂原子数为1个或2个的4-10元杂环烷基”； R e-1 , R e-2 and R e-4 are independently halogen, C 1-6 alkyl, C 1-6 alkoxy, -C(=O)-C(R a )=C(R b ) (R c ) or NR e-5 R e-6 ; 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";
各R e-3独立地为卤素、羟基、氰基、C 1-6烷基、被一个或多个R e-7取代的C 1-6烷基、C 1-6烷氧基、被一个或多个R e-8取代的C 1-6烷氧基、-C(＝O)-C(R a)＝C(R b)(R c)、NR e-5R e-6、-O(C＝O)NR e-13R e-14或-O(C＝O)OR e-15；R e-7和R e-8独立地为卤素、羟基、氰基、-COOH、C 1-6烷氧基或NR e-9R e-10，R e-9和R e-10独立地为氢、C 1-6烷基、-C(＝O)R e-11或-S(＝O) 2R e-12；R e-11和R e-12独立地为C 1-6烷基； Each R e-3 is independently halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R e-7 , C 1-6 alkoxy, or multiple R e-8 substituted C 1-6 alkoxy, -C(=O)-C(R a )=C(R b )(R c ), NR e-5 R e-6 , - O(C=O)NR e-13 R e-14 or -O(C=O)OR e-15 ; R e-7 and R e-8 are independently halogen, hydroxyl, cyano, -COOH, C 1-6 alkoxy or NR e-9 R e-10 , R e-9 and R e-10 are independently hydrogen, C 1-6 alkyl, -C(=O)R e-11 or -S (=O) 2 R e-12 ; R e-11 and R e-12 are independently C 1-6 alkyl;
R e-13和R e-14独立地为氢或C 1-6烷基，或者，R e-13、R e-14及与它们相连接的N共同形成“杂原子为N、或者N和O，杂原子数为1个或2个的4-10元杂环烷基”；R e-15为氢或C 1-6烷基； 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为氢、C 1-6烷基、被一个或多个R 3-1取代的C 1-6烷基，其中，各R 3-1独立地为C 1- 6烷基、C 1-6烷氧基、CN、卤素或OH； 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和Y独立地为O、NR 6或CH 2；R 6为氢或C 1-6烷基；Z为单键、O、NR 6或CH 2；X、Y和Z不同时为O或不同时为NR 6； 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和Q独立地为N或CR 5； U, V, W and Q are independently N or CR5 ;
各R 5独立地为H、卤素、羟基、被一个或多个卤素取代的C 1-6烷基、被一个或多个卤素取代的C 1-6烷氧基、氰基、C 3-6环烷基、C 1-6烷基砜基、C 3-6环烷基砜基、C 1-6烷基或C 1-6烷氧基； 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;
带“*”碳原子为手性碳原子，为S构型、R构型或它们的混合物。The carbon atom with "*" is a chiral carbon atom, which is in S configuration, R configuration or a mixture thereof.
在本发明某一方案中，当环A为含2-4个N原子的4-12元脂杂环时，所述脂杂环为含2个N原子的6-10元脂杂环，例如
Figure PCTCN2021138375-appb-000002
为
Figure PCTCN2021138375-appb-000003
Figure PCTCN2021138375-appb-000004
In a certain embodiment of the present invention, when 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
Figure PCTCN2021138375-appb-000002
for
Figure PCTCN2021138375-appb-000003
Figure PCTCN2021138375-appb-000004
在本发明某一方案中，当R a为卤素时，所述卤素为氟、氯、溴或碘，例如氟。 In one embodiment of the invention, when Ra is halogen, the halogen is fluorine, chlorine, bromine or iodine, such as fluorine.
在本发明某一方案中，当R a为C 1-6烷基时，所述C 1-C 6烷基为C 1-C 3烷基，例如甲基。 In a certain embodiment of the present invention, when 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.
在本发明某一方案中，当R b和R c独立地为C 1-6烷基或“被一个或多个R b-1取代的C 1-6烷基”时，所述C 1-C 6烷基为C 1-C 3烷基，例如甲基。 In a certain embodiment of the present invention, when 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.
在本发明某一方案中，当各R b-1独立地为卤素时，所述卤素为氟、氯、溴或碘，例如氟。 In one embodiment of the present invention, when each R b-1 is independently halogen, the halogen is fluorine, chlorine, bromine or iodine, such as fluorine.
在本发明某一方案中，当各R b-1独立地为C 1-6烷氧基时，所述C 1-C 6烷氧基为C 1-C 3烷氧基，例如甲氧基。 In a certain embodiment of the present invention, when 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 .
在本发明某一方案中，当R b-2和R b-3独立地为C 1-6烷基时，所述C 1-C 6烷基为C 1-C 3烷基，例如甲基。 In a certain embodiment of the present invention, when R b-2 and R b-3 are independently C 1-6 alkyl groups, the C 1 -C 6 alkyl groups are C 1 -C 3 alkyl groups, such as methyl .
在本发明某一方案中，当R d为C 1-6烷基时，所述C 1-C 6烷基为C 1-C 3烷基，例如甲基。 In a certain embodiment of the present invention, when R d 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.
在本发明某一方案中，当各R 4独立地为C 1-6烷基或“被一个或多个R 4-1取代的C 1-6烷基”时，所述C 1-C 6烷基为C 1-C 3烷基，例如甲基。 In a certain embodiment of the present invention, when 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.
在本发明某一方案中，当各R 4-1独立地为卤素时，所述卤素为氟、氯、溴或碘，例如氟。 In one embodiment of the present invention, when each R4-1 is independently halogen, the halogen is fluorine, chlorine, bromine or iodine, such as fluorine.
在本发明某一方案中，当R 2-1、R 2-2、R 2-3、R 2-4和R 2-5独立地为C 1-6烷基或“被一个或多个R e取代的C 1-6烷基”时，所述C 1-C 6烷基为C 1-C 3烷基，例如甲基。 In a certain embodiment of the present invention, when 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.
在本发明某一方案中，当R 2-1、R 2-2、R 2-3、R 2-4和R 2-5独立地为C 1-6烷氧基时，所述C 1-C 6烷氧基为C 1-C 3烷氧基，例如甲氧基。 In a certain embodiment of the present invention, when 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.
在本发明某一方案中，当R 2-1、R 2-2、R 2-3、R 2-4和R 2-5独立地为“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”或“被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基””时，所述“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”为
Figure PCTCN2021138375-appb-000005
Figure PCTCN2021138375-appb-000006
In a certain scheme of the present invention, when 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
Figure PCTCN2021138375-appb-000005
Figure PCTCN2021138375-appb-000006
在本发明某一方案中，当R 2-1、R 2-2、R 2-3、R 2-4和R 2-5独立地为“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”或“被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基””时，所述“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”为
Figure PCTCN2021138375-appb-000007
Figure PCTCN2021138375-appb-000008
In a certain aspect of the present invention, when 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
Figure PCTCN2021138375-appb-000007
Figure PCTCN2021138375-appb-000008
在本发明某一方案中，当R 2-6为卤素时，所述卤素为氟、氯、溴或碘，例如氯。 In one embodiment of the present invention, when R 2-6 is halogen, the halogen is fluorine, chlorine, bromine or iodine, eg chlorine.
在本发明某一方案中，当R 2-6为C 1-6烷基或“被一个或多个R e取代的C 1-6烷基”时，所述C 1-C 6烷基为C 1-C 3烷基，例如甲基。 In a certain embodiment of the present invention, when 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.
在本发明某一方案中，当R 2-6为C 1-6烷氧基时，所述C 1-C 6烷氧基为C 1-C 3烷氧基，例如甲氧基。 In a certain embodiment of the present invention, when R 2-6 is C 1-6 alkoxy, the C 1 -C 6 alkoxy is C 1 -C 3 alkoxy, such as methoxy.
在本发明某一方案中，当R 2-6独立地为“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”或“被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基””时，所述“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”为
Figure PCTCN2021138375-appb-000009
In a certain scheme of the present invention, when 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, and the 5-12-membered heteroaryl group with 1-4 heteroatoms" is
Figure PCTCN2021138375-appb-000009
在本发明某一方案中，当R 2-6为“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”或“被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基””时，所述“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”为
Figure PCTCN2021138375-appb-000010
In a certain scheme of the present invention, when R 2-6 is "the heteroatom is selected from one or more of O and N, and the number of heteroatoms is 1-3 4-10-membered heterocycloalkyl" or " When "the heteroatom is selected from one or more of O and N, and the number of heteroatoms is 1-3 4-10-membered heterocycloalkyl group" substituted by one or more R e-3 , the said "The heteroatom is selected from one or more of O and N, and the 4-10-membered heterocycloalkyl with 1-3 heteroatoms" is
Figure PCTCN2021138375-appb-000010
在本发明某一方案中，当各R e独立地为“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”或“被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基””时，所述“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”为
Figure PCTCN2021138375-appb-000011
In a certain scheme of the present invention, when 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" Or "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, and the 5-12-membered heteroaryl with 1-4 heteroatoms" is
Figure PCTCN2021138375-appb-000011
在本发明某一方案中，当各R e独立地为“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”或“被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基””，所述“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”为
Figure PCTCN2021138375-appb-000012
例如
Figure PCTCN2021138375-appb-000013
In a certain aspect of the present invention, when 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
Figure PCTCN2021138375-appb-000012
E.g
Figure PCTCN2021138375-appb-000013
在本发明某一方案中，当R e-1、R e-2和R e-4独立地为C 1-C 6烷基时，为所述C 1-C 6烷基为C 1-C 3烷基，例如甲基。 In a certain embodiment of the present invention, when Re -1 , Re -2 and Re -4 are independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl is C 1 -C 3 Alkyl such as methyl.
在本发明某一方案中，R e-3独立地为卤素时，所述卤素为氟、氯、溴或碘，例如氟。 In one embodiment of the present invention, when R e-3 is independently halogen, the halogen is fluorine, chlorine, bromine or iodine, such as fluorine.
在本发明某一方案中，R e-3独立地为C 1-C 6烷基或“被一个或多个R e-7取代的C 1-6烷基”时，所述C 1-C 6烷基为C 1-C 3烷基，例如甲基。 In a certain embodiment of the present invention, when R e-3 is independently C 1 -C 6 alkyl or "C 1-6 alkyl substituted by one or more R e-7 ", the C 1 -C 6Alkyl is a C1 - C3 alkyl group such as methyl.
在本发明某一方案中，R e-3独立地为C 1-6烷氧基时，所述C 1-C 6烷氧基为C 1-C 3烷氧基，例如甲氧基。 In a certain embodiment of the present invention, when R e-3 is independently C 1-6 alkoxy, the C 1 -C 6 alkoxy is C 1 -C 3 alkoxy, such as methoxy.
在本发明某一方案中，当R e-5和R e-6独立地为C 1-C 6烷基时，为所述C 1-C 6烷基为C 1-C 3烷基，例如甲基或乙基。 In a certain embodiment of the present invention, when Re -5 and Re -6 are independently C 1 -C 6 alkyl groups, the C 1 -C 6 alkyl groups are C 1 -C 3 alkyl groups, for example methyl or ethyl.
在本发明某一方案中，当R 3为C 1-C 6烷基时，所述C 1-C 6烷基为C 1-C 3烷基，例如甲基。 In a certain embodiment of the present invention, when R 3 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is a C 1 -C 3 alkyl group, such as methyl.
在本发明某一方案中，当各R 5独立地为卤素时，所述卤素为氟、氯、溴或碘，例如氟、氯或溴，再例如氟或氯。 In one embodiment of the invention, when 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.
在本发明某一方案中，当各R 5独立地被一个或多个卤素取代的C 1-6烷基，所述被一个或多个卤素取代的C 1-6烷基为被一个或多个卤素取代的C 1-3烷基，例如为-CF 3。 In a certain embodiment of the present invention, when 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 A halogen-substituted C 1-3 alkyl group, for example -CF 3 .
在本发明某一方案中，当各R 5独立地为C 1-6烷基时，所述C 1-C 6烷基为C 1-C 3烷基，例如甲基。 In one embodiment of the present invention, when 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.
在本发明某一方案中，当各R 5独立地被一个或多个卤素取代的C 1-6烷氧基，所述被一个或多个卤素取代的C 1-6烷氧基为被一个或多个卤素取代的C 1-3烷氧基，例如为-OCF 3。 In a certain embodiment of the present invention, when 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 .
在本发明某一方案中，当各R 7和R 8独立地为C 1-6烷基时，所述C 1-C 6烷基为C 1-C 3烷基，例如甲基。 In one embodiment of the present invention, when each R7 and R8 is independently a C1-6 alkyl group, the C1 - C6 alkyl group is a C1 - C3 alkyl group, such as methyl.
在本发明某一方案中，环A为含2个N原子的6-10元脂杂环，所述的脂杂环为单环。In a certain embodiment of the present invention, ring A is a 6-10 membered alicyclic heterocyclic ring containing 2 N atoms, and the alicyclic heterocyclic ring is a monocyclic ring.
在本发明某一方案中，R 1为-C(＝O)-C(R a)＝C(R b)(R c)、-C(＝O)-C≡CCH 3、-C(＝O)-C(＝O)-OCH 3或-C(＝O)-CH 3；当R a为卤素或C 1-6烷基时，R b和R c为氢；当R b或R c为C 1-6烷基或“被一个或多个R b-1取代的C 1-6烷基”时，R a为氢。 In a certain aspect of the present invention, R 1 is -C(=O)-C(R a )=C(R b )(R c ), -C(=O)-C≡CCH 3 , -C(= O)-C(=O)-OCH 3 or -C(=O)-CH 3 ; when R a is halogen or C 1-6 alkyl, R b and R c are hydrogen; when R b or R c When C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R b-1 ", R a is hydrogen.
在本发明某一方案中，R a为氢或卤素。 In one embodiment of the present invention, Ra is hydrogen or halogen.
在本发明某一方案中，R b和R c独立地为氢、C 1-6烷基或“被一个或多个R b-1取代的C 1-6烷基”，且R b和R c至少有一个为氢。 In one embodiment of the invention, 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.
在本发明某一方案中，各R b-1独立地为卤素。 In one embodiment of the present invention, each R b-1 is independently halogen.
在本发明某一方案中，R b和R c独立地为氢或“被一个或多个卤素取代的C 1-6烷基”，且R b和R c至少有一个为氢。 In one embodiment of the present invention, 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.
在本发明某一方案中，n为0、1或2；优选为1或2。In a certain aspect of the present invention, n is 0, 1 or 2; preferably 1 or 2.
在本发明某一方案中，各R 4独立地为甲基、氰基取代的甲基、F取代的甲基或羟基取代的甲基；优选为氰基取代的甲基
Figure PCTCN2021138375-appb-000014
In a certain scheme of the present invention, each R 4 is independently methyl, cyano-substituted methyl, F-substituted methyl or hydroxy-substituted methyl; preferably cyano-substituted methyl
Figure PCTCN2021138375-appb-000014
在本发明某一方案中，R 2-1为氢、C 1-6烷基、被一个或多个R e取代的C 1-6烷基或“被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基””。 In a certain embodiment of the present invention, 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"".
在本发明某一方案中，R 2-2为C 1-6烷基或“被一个或多个R e取代的C 1-6烷基”。 In one embodiment of the present invention, R 2-2 is C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R e ".
在本发明某一方案中，R 2-5为被一个或多个R e取代的C 1-6烷基。 In one embodiment of the present invention, R 2-5 is C 1-6 alkyl substituted with one or more R e .
在本发明某一方案中，m为0。In a certain aspect of the present invention, m is 0.
在本发明某一方案中，R 2-6为氢、卤素、被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”或羟基。 In a certain scheme of the present invention, 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.
在本发明某一方案中，各R e独立地为“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”或“被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基””；较佳地，各R e独立地为“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”或“被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基””。 In a certain scheme of the present invention, 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 N Or more, 4-10 membered heterocycloalkyl "" with 1-3 heteroatoms.
在本发明某一方案中，R e-1独立地为C 1-6烷基。 In one embodiment of the present invention, R e-1 is independently C 1-6 alkyl.
在本发明某一方案中，各R e-3独立地为卤素、羟基、C 1-6烷基、C 1-6烷氧基、-C(＝O)-C(R a)＝C(R b)(R c)或NR e-5R e-6；较佳地，R a、R b和R c均为H。 In a certain embodiment of the present invention, each R e-3 is independently halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, -C(=O)-C(R a )=C( R b ) (R c ) or NR e-5 R e-6 ; preferably, Ra , R b and R c are all H.
在本发明某一方案中，R 2为-OR 2-1、-SR 2-2、-S(＝O)R 2-5或-(CR 1-1R 1-2) mR 2-6。 In a certain embodiment of the present invention, R 2 is -OR 2-1 , -SR 2-2 , -S(=O)R 2-5 or -(CR 1-1 R 1-2 ) m R 2-6 .
在本发明某一方案中，R 3为氢或C 1-6烷基。 In a certain embodiment of the present invention, R 3 is hydrogen or C 1-6 alkyl.
在本发明某一方案中，X为O或CR 7R 8，Y为CR 7R 8，Z为单键、O或CR 7R 8。 In one embodiment of the present invention, X is O or CR 7 R 8 , Y is CR 7 R 8 , and Z is a single bond, O or CR 7 R 8 .
在本发明某一方案中，X和Y为CH 2，Z为单键、O或CH 2。 In one embodiment of the present invention, X and Y are CH 2 , and Z is a single bond, O or CH 2 .
在本发明某一方案中，U、V、W和Q独立地为CR 5。 In one aspect of the invention, U, V, W and Q are independently CR5 .
在本发明某一方案中，各R 5独立地为H、卤素、被一个或多个卤素取代的C 1-6烷基、被一个或多个卤素取代的C 1-6烷氧基、氰基、C 3-6环烷基、C 1-6烷基或C 1-6烷氧基。 In a certain embodiment of the present invention, 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.
在本发明某一方案中，各R 5独立地为H、卤素或C 1-6烷基。 In one embodiment of the present invention, each R5 is independently H, halogen or C1-6 alkyl.
在本发明某一方案中，
Figure PCTCN2021138375-appb-000015
为
Figure PCTCN2021138375-appb-000016
In a certain aspect of the present invention,
Figure PCTCN2021138375-appb-000015
for
Figure PCTCN2021138375-appb-000016
在本发明某一方案中，R 1为
Figure PCTCN2021138375-appb-000017
Figure PCTCN2021138375-appb-000018
In a certain scheme of the present invention, R 1 is
Figure PCTCN2021138375-appb-000017
Figure PCTCN2021138375-appb-000018
在本发明某一方案中，R 2为-OR 2-1或-(CR 1-1R 1-2) mR 2-6，R 2-1为被一个或多个R e取代的C 1-6烷基，各R e独立地为被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”，R e中，各R e-3独立地为卤素、C 1-6烷基或C 1- 6烷氧基；m为0，R 2-6为被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”，R 2-6中，各R e-3独立地为NR e-5R e-6。 In a certain embodiment of the present invention, 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 .
在本发明某一方案中，
Figure PCTCN2021138375-appb-000019
为
Figure PCTCN2021138375-appb-000020
Figure PCTCN2021138375-appb-000021
Figure PCTCN2021138375-appb-000022
In a certain aspect of the present invention,
Figure PCTCN2021138375-appb-000019
for
Figure PCTCN2021138375-appb-000020
Figure PCTCN2021138375-appb-000021
Figure PCTCN2021138375-appb-000022
在本发明某一方案中，R 2为氢、羟基、氯、
Figure PCTCN2021138375-appb-000023
-OCH 3、-SCH 3、
Figure PCTCN2021138375-appb-000024
Figure PCTCN2021138375-appb-000025
In a certain scheme of the present invention, R 2 is hydrogen, hydroxyl, chlorine,
Figure PCTCN2021138375-appb-000023
-OCH 3 , -SCH 3 ,
Figure PCTCN2021138375-appb-000024
Figure PCTCN2021138375-appb-000025
在本发明某一方案中，
Figure PCTCN2021138375-appb-000026
为
Figure PCTCN2021138375-appb-000027
Figure PCTCN2021138375-appb-000028
In a certain aspect of the present invention,
Figure PCTCN2021138375-appb-000026
for
Figure PCTCN2021138375-appb-000027
Figure PCTCN2021138375-appb-000028
较佳地，所述的如式I所示的化合物为如下任一化合物：Preferably, the compound shown in the formula I is any of the following compounds:
Figure PCTCN2021138375-appb-000029
Figure PCTCN2021138375-appb-000029
Figure PCTCN2021138375-appb-000030
Figure PCTCN2021138375-appb-000030
Figure PCTCN2021138375-appb-000031
Figure PCTCN2021138375-appb-000031
Figure PCTCN2021138375-appb-000032
Figure PCTCN2021138375-appb-000032
Figure PCTCN2021138375-appb-000033
Figure PCTCN2021138375-appb-000033
Figure PCTCN2021138375-appb-000034
Figure PCTCN2021138375-appb-000034
Figure PCTCN2021138375-appb-000035
Figure PCTCN2021138375-appb-000035
Figure PCTCN2021138375-appb-000036
Figure PCTCN2021138375-appb-000036
Figure PCTCN2021138375-appb-000037
Figure PCTCN2021138375-appb-000037
较佳地，所述的如式I所示的化合物为如下任一化合物：Preferably, the compound shown in the formula I is any of the following compounds:
在下述条件下保留时间为1.21min的化合物，其为
Figure PCTCN2021138375-appb-000038
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 1.21 min under the following conditions is
Figure PCTCN2021138375-appb-000038
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为1.99min的化合物，其为
Figure PCTCN2021138375-appb-000039
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 1.99 min under the following conditions is
Figure PCTCN2021138375-appb-000039
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为0.93min的化合物，其为
Figure PCTCN2021138375-appb-000040
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 0.93 min under the following conditions is
Figure PCTCN2021138375-appb-000040
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为1.43min的化合物，其为
Figure PCTCN2021138375-appb-000041
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 1.43 min under the following conditions is
Figure PCTCN2021138375-appb-000041
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为1.24min的化合物，其为
Figure PCTCN2021138375-appb-000042
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 1.24 min under the following conditions is
Figure PCTCN2021138375-appb-000042
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为2.56min的化合物，其为
Figure PCTCN2021138375-appb-000043
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 2.56 min under the following conditions is
Figure PCTCN2021138375-appb-000043
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为1.01min的化合物，其为
Figure PCTCN2021138375-appb-000044
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； A compound with a retention time of 1.01 min under the following conditions is
Figure PCTCN2021138375-appb-000044
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为2.17min的化合物，其为
Figure PCTCN2021138375-appb-000045
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 2.17 min under the following conditions is
Figure PCTCN2021138375-appb-000045
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为4.74min的化合物，其为
Figure PCTCN2021138375-appb-000046
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 4.74 min under the following conditions is
Figure PCTCN2021138375-appb-000046
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为5.44min的化合物，其为
Figure PCTCN2021138375-appb-000047
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 5.44 min under the following conditions is
Figure PCTCN2021138375-appb-000047
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为4.08min的化合物，其为
Figure PCTCN2021138375-appb-000048
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 4.08 min under the following conditions is
Figure PCTCN2021138375-appb-000048
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为4.22min的化合物，其为
Figure PCTCN2021138375-appb-000049
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 4.22 min under the following conditions is
Figure PCTCN2021138375-appb-000049
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为1.42min的化合物，其为
Figure PCTCN2021138375-appb-000050
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 1.42 min under the following conditions is
Figure PCTCN2021138375-appb-000050
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为2.71min的化合物，其为
Figure PCTCN2021138375-appb-000051
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 2.71 min under the following conditions is
Figure PCTCN2021138375-appb-000051
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为1.11min的化合物，其为
Figure PCTCN2021138375-appb-000052
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 1.11 min under the following conditions is
Figure PCTCN2021138375-appb-000052
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为2.21min的化合物，其为
Figure PCTCN2021138375-appb-000053
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 2.21 min under the following conditions is
Figure PCTCN2021138375-appb-000053
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为3.88min的化合物，其为
Figure PCTCN2021138375-appb-000054
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 3.88 min under the following conditions is
Figure PCTCN2021138375-appb-000054
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为4.42min的化合物，其为
Figure PCTCN2021138375-appb-000055
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 4.42 min under the following conditions is
Figure PCTCN2021138375-appb-000055
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为1.254min的化合物，其为
Figure PCTCN2021138375-appb-000056
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 1.254 min under the following conditions is
Figure PCTCN2021138375-appb-000056
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为2.267min的化合物，其为
Figure PCTCN2021138375-appb-000057
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 2.267 min under the following conditions is
Figure PCTCN2021138375-appb-000057
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为4.473min的化合物，其为
Figure PCTCN2021138375-appb-000058
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound whose retention time is 4.473 min under the following conditions is
Figure PCTCN2021138375-appb-000058
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为4.688min的化合物，其为
Figure PCTCN2021138375-appb-000059
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 4.688 min under the following conditions is
Figure PCTCN2021138375-appb-000059
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为7.008min的化合物，其为
Figure PCTCN2021138375-appb-000060
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound whose retention time is 7.008 min under the following conditions is
Figure PCTCN2021138375-appb-000060
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为7.199min的化合物，其为
Figure PCTCN2021138375-appb-000061
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 7.199 min under the following conditions is
Figure PCTCN2021138375-appb-000061
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为4.735min的化合物，其为
Figure PCTCN2021138375-appb-000062
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 4.735 min under the following conditions is
Figure PCTCN2021138375-appb-000062
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为4.758min的化合物，其为
Figure PCTCN2021138375-appb-000063
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 4.758 min under the following conditions is
Figure PCTCN2021138375-appb-000063
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为7.198min的化合物，其为
Figure PCTCN2021138375-appb-000064
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 7.198 min under the following conditions is
Figure PCTCN2021138375-appb-000064
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为7.460min的化合物，其为
Figure PCTCN2021138375-appb-000065
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 7.460 min under the following conditions is
Figure PCTCN2021138375-appb-000065
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为4.249min的化合物，其为
Figure PCTCN2021138375-appb-000066
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound whose retention time is 4.249 min under the following conditions is
Figure PCTCN2021138375-appb-000066
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为4.333min的化合物，其为
Figure PCTCN2021138375-appb-000067
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound whose retention time is 4.333 min under the following conditions is
Figure PCTCN2021138375-appb-000067
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为6.961min的化合物，其为
Figure PCTCN2021138375-appb-000068
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound whose retention time is 6.961 min under the following conditions is
Figure PCTCN2021138375-appb-000068
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为7.133min的化合物，其为
Figure PCTCN2021138375-appb-000069
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound whose retention time is 7.133 min under the following conditions is
Figure PCTCN2021138375-appb-000069
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为4.903min的化合物，其为
Figure PCTCN2021138375-appb-000070
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound whose retention time is 4.903 min under the following conditions is
Figure PCTCN2021138375-appb-000070
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为5.508min的化合物，其为
Figure PCTCN2021138375-appb-000071
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 5.508 min under the following conditions is
Figure PCTCN2021138375-appb-000071
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为2.174min的化合物，其为
Figure PCTCN2021138375-appb-000072
中的一个立体异构体：色谱柱:CHIRALART Cellulose SB,2cm×25cm,5μm；流动相A:MtBE(0.5％2mM NH 3-MEOH)，流动相B:MeOH:DCM＝1:1； The compound with a retention time of 2.174 min under the following conditions is
Figure PCTCN2021138375-appb-000072
One stereoisomer in: chromatographic column: CHIRALART Cellulose SB, 2cm×25cm, 5μm; mobile phase A: MtBE (0.5% 2mM NH 3 -MEOH), mobile phase B: MeOH: DCM=1:1;
在下述条件下保留时间为2.950min的化合物，其为
Figure PCTCN2021138375-appb-000073
中的一个立体异构体：色谱柱:CHIRALART Cellulose SB,2cm×25cm,5μm；流动相A:MtBE(0.5％2mM NH 3-MEOH)，流动相B:MeOH:DCM＝1:1； The compound with a retention time of 2.950 min under the following conditions is
Figure PCTCN2021138375-appb-000073
One stereoisomer in: chromatographic column: CHIRALART Cellulose SB, 2cm×25cm, 5μm; mobile phase A: MtBE (0.5% 2mM NH 3 -MEOH), mobile phase B: MeOH: DCM=1:1;
在下述条件下保留时间为1.986min的化合物，其为
Figure PCTCN2021138375-appb-000074
中的一个立体异构体：色谱柱:CHIRALPAK IE,2cm×25cm,5μm；流动相A:MtBE(0.5％2mM NH 3-MEOH)，流动相B:MeOH:DCM＝1:1； The compound with a retention time of 1.986 min under the following conditions is
Figure PCTCN2021138375-appb-000074
One stereoisomer in: chromatographic column: CHIRALPAK IE, 2cm×25cm, 5μm; mobile phase A: MtBE (0.5% 2mM NH 3 -MEOH), mobile phase B:MeOH:DCM=1:1;
在下述条件下保留时间为2.919min的化合物，其为
Figure PCTCN2021138375-appb-000075
中的一个立体异构体：色谱柱:CHIRALPAK IE,2cm×25cm,5μm；流动相A:MtBE(0.5％2mM NH 3-MEOH)，流动相B:MeOH:DCM＝1:1； The compound with a retention time of 2.919 min under the following conditions is
Figure PCTCN2021138375-appb-000075
One stereoisomer in: chromatographic column: CHIRALPAK IE, 2cm×25cm, 5μm; mobile phase A: MtBE (0.5% 2mM NH 3 -MEOH), mobile phase B:MeOH:DCM=1:1;
在下述条件下保留时间为5.137min的化合物，其为
Figure PCTCN2021138375-appb-000076
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 5.137 min under the following conditions is
Figure PCTCN2021138375-appb-000076
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为5.370min的化合物，其为
Figure PCTCN2021138375-appb-000077
中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40； The compound with a retention time of 5.370 min under the following conditions is
Figure PCTCN2021138375-appb-000077
One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
在下述条件下保留时间为0.928min的化合物，其为
Figure PCTCN2021138375-appb-000078
中的一个立体异构体：色谱柱:CHIRALPAK IF,2cm×25cm,5μm；流动相A:MtBE(0.5％2mM NH 3-MEOH)，流动相B:MeOH:DCM＝1:1； The compound with a retention time of 0.928 min under the following conditions is
Figure PCTCN2021138375-appb-000078
One stereoisomer in: chromatographic column: CHIRALPAK IF, 2cm×25cm, 5μm; mobile phase A: MtBE (0.5% 2mM NH 3 -MEOH), mobile phase B:MeOH:DCM=1:1;
在下述条件下保留时间为1.411min的化合物，其为
Figure PCTCN2021138375-appb-000079
中的一个立体异构体：色谱柱:CHIRALPAK IF,2cm×25cm,5μm；流动相A:MtBE(0.5％2mM NH 3-MEOH)，流动相B:MeOH:DCM＝1:1； The compound with a retention time of 1.411 min under the following conditions is
Figure PCTCN2021138375-appb-000079
One stereoisomer in: chromatographic column: CHIRALPAK IF, 2cm×25cm, 5μm; mobile phase A: MtBE (0.5% 2mM NH 3 -MEOH), mobile phase B:MeOH:DCM=1:1;
在下述条件下保留时间为1.872min的化合物，其为
Figure PCTCN2021138375-appb-000080
中的一个立体异构体：色谱柱:CHIRALPAK IF,2cm×25cm,5μm；流动相A:MtBE，流动相B:MeOH:DCM＝1:1； The compound with a retention time of 1.872 min under the following conditions is
Figure PCTCN2021138375-appb-000080
One stereoisomer in: chromatographic column: CHIRALPAK IF, 2cm×25cm, 5μm; mobile phase A: MtBE, mobile phase B: MeOH: DCM=1:1;
在下述条件下保留时间为2.467min的化合物，其为
Figure PCTCN2021138375-appb-000081
中的一个立体异构体：色谱柱:CHIRALPAK IF,2cm×25cm,5μm；流动相A:MtBE，流动相B:MeOH:DCM＝1:1； The compound with a retention time of 2.467 min under the following conditions is
Figure PCTCN2021138375-appb-000081
One stereoisomer in: chromatographic column: CHIRALPAK IF, 2cm×25cm, 5μm; mobile phase A: MtBE, mobile phase B: MeOH: DCM=1:1;
在下述条件下保留时间为0.993min的化合物，其为
Figure PCTCN2021138375-appb-000082
中的一个立体异构体：色谱柱:CHIRALPAK IF,2cm×25cm,5μm；流动相A:MtBE(0.5％2mM NH 3-MEOH)，流动相B:MeOH:DCM＝1:1； The compound with a retention time of 0.993 min under the following conditions is
Figure PCTCN2021138375-appb-000082
One stereoisomer in: chromatographic column: CHIRALPAK IF, 2cm×25cm, 5μm; mobile phase A: MtBE (0.5% 2mM NH 3 -MEOH), mobile phase B:MeOH:DCM=1:1;
在下述条件下保留时间为2.596min的化合物，其为
Figure PCTCN2021138375-appb-000083
中的一个立体异构体：色谱柱:CHIRALPAK IF,2cm×25cm,5μm；流动相A:MtBE(0.5％2mM NH 3-MEOH)，流动相B:MeOH:DCM＝1:1。 The compound whose retention time is 2.596 min under the following conditions is
Figure PCTCN2021138375-appb-000083
One stereoisomer in: Chromatographic column: CHIRALPAK IF, 2 cm×25 cm, 5 μm; mobile phase A: MtBE (0.5% 2 mM NH 3 -MEOH), mobile phase B: MeOH: DCM=1:1.
以上保留时间的测试条件并非对化合物的限定，只要采用上述测试条件进行测定，得到的保留时间与上述记载的相同或在误差范围内，且该化合物为上述用保留时间限定的化合物中的一个立体异构体，则落入本发明的保护范围内。The 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.
本发明还提供了上述的如式I所示的化合物的制备方法，其包括以下步骤：The present invention also provides the above-mentioned preparation method of the compound shown in formula I, which comprises the following steps:
如式K-X所示的化合物和如式K-XIII所示的化合物进行取代反应，得如式I所示的化合物；The compound shown in formula K-X and the compound shown in formula K-XIII are subjected to substitution reaction to obtain the compound shown in formula I;
Figure PCTCN2021138375-appb-000084
Figure PCTCN2021138375-appb-000084
其中，“*”、n、环A、R 1、R 2、R 3、R 4、X、Y、Z、U、V、W和Q的定义如前任一项所述，L为卤素或羟基。 Wherein, "*", 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 .
所述取代反应的操作和条件可为本领域常规，较佳地，在碱(例如DIEA和/或TEA)的作用下进行。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).
所述如式I所示的化合物的制备方法中，还可包括以下步骤：In the preparation method of the compound shown in the formula I, the following steps may also be included:
如式K-IX所示的化合物经脱保护反应得如K-X所示的化合物；The compound represented by formula K-IX is subjected to deprotection reaction to obtain the compound represented by K-X;
Figure PCTCN2021138375-appb-000085
Figure PCTCN2021138375-appb-000085
其中，“*”、n、环A、R 2、R 3、R 4、X、Y、Z、U、V、W和Q的定义如前任一项所述，PG为氨基保护基。 Wherein, "*", 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.
式K-IX中，所述氨基保护基可为本领域常见的氨基保护基，较佳地，对叔丁氧羰基(Boc)或苄氧羰基(Cbz)。In formula K-IX, the amino protecting group can be a common amino protecting group in the art, preferably, p-tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Cbz).
所述的脱保护反应的操作和条件可为本领域常规，例如在酸(例如三氟乙酸和/或盐酸)的作用下进行。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).
本发明还提供了一种如式K-X所示的化合物：The present invention also provides a compound of formula K-X:
Figure PCTCN2021138375-appb-000086
Figure PCTCN2021138375-appb-000086
其中，“*”、n、环A、R 2、R 3、R 4、X、Y、Z、U、V、W和Q的定义如前任一项所述。 Wherein, the definitions of "*", n, ring A, R 2 , R 3 , R 4 , X, Y, Z, U, V, W and Q are as described in any of the preceding items.
较佳地，所述如式K-X所示的化合物为如下任一化合物：Preferably, the compound represented by the formula K-X is any of the following compounds:
Figure PCTCN2021138375-appb-000087
Figure PCTCN2021138375-appb-000087
Figure PCTCN2021138375-appb-000088
Figure PCTCN2021138375-appb-000088
Figure PCTCN2021138375-appb-000089
Figure PCTCN2021138375-appb-000089
Figure PCTCN2021138375-appb-000090
Figure PCTCN2021138375-appb-000090
Figure PCTCN2021138375-appb-000091
Figure PCTCN2021138375-appb-000091
本发明还提供了一种药物组合物，其包括上述的如式I所示的化合物、其溶剂合物、其前药、其代谢产物、或它们药学上可接受的盐，以及药用辅料。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.
本发明还提供了上述的如式I所示的化合物、其溶剂合物、其前药、其代谢产物、或它们药学上可接受的盐、或上述药物组合物在制备药物中的应用。所述的药物用于治疗癌症。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.
较佳地，所述癌症包括肺癌、结肠癌、胰腺癌、直肠癌、淋巴癌、食管癌、卵巢癌、脑胶质瘤、子宫颈癌、尿路上皮癌、胃癌、子宫内膜癌、肝癌、胆管癌、乳腺癌、白血病和黑色素瘤中的一种或多种。Preferably, 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.
本发明还提供了上述如式I所示的化合物、其溶剂合物、其前药、其代谢产物、或它们药学上可接受的盐、或上述药物组合物在制备KRAS G12C蛋白突变抑制剂中的应用。 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.
在所述的应用中，所述的KRAS G12C蛋白突变抑制剂可用于哺乳动物生物体内；也可用于生物体外，主要作为实验用途，例如：作为标准样或对照样提供比对，或按照本领域常规方法制成试剂盒，为KRAS G12C蛋白突变抑制效果提供快速检测。 In the application, 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.
如无特别说明，本发明所用术语具有如下含义：Unless otherwise specified, the terms used in the present invention have the following meanings:
本领域技术人员可以理解，根据本领域中使用的惯例，本发明描述基团的结构式中所使用的“”是指，相应的基团通过该位点与化合物中的其它片段、基团进行连接。本 发明用“”作为化学键与单键相连时，表示可以是R构型和S构型的混合。Those skilled in the art can understand that, according to the conventions used in the art, the "" used in the structural formula of the group described in the present invention means that the corresponding group is connected to other fragments and groups in the compound through this site. . In the present invention, when "" is used as a chemical bond to connect with a single bond, it means that it can be a mixture of R configuration and S configuration.
术语“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。The term "comprising" is an open-ended expression, that is, it includes the contents specified in the present invention, but does not exclude other aspects.
术语“多个”是指2个、3个、4个或5个，优选为2个或3个。The term "plurality" means 2, 3, 4 or 5, preferably 2 or 3.
术语“室温”是指20～30℃。The term "room temperature" refers to 20 to 30°C.
术语“药学上可接受的”是指盐、溶剂、辅料等一般无毒、安全，并且适合于患者使用。所述的“患者”优选哺乳动物，更优选为人类。The term "pharmaceutically acceptable" means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for patient use. The "patient" is preferably a mammal, more preferably a human.
术语“溶剂合物”是指本发明化合物与化学计量或非化学计量的溶剂结合形成的物质。溶剂合物中的溶剂分子可以有序或非有序排列的形式存在。所述的溶剂包括但不限于：水、甲醇、乙醇等。The term "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.
术语“前药”是指本发明化合物的衍生物，当对恒温动物(例如人)施用该衍生物时，该衍生物转化为本发明化合物(药物)。前药的典型实例包括在活性化合物的功能部分上具有生物学上易变的保护基团的化合物。前药包括可以通过氧化、还原、氨化、脱氨、羟基化、脱羟基、水解、脱水、烷基化、脱烷基、酰化、脱酰基、磷酸化、脱磷酸来产生活性化合物的化合物。The term "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 .
术语“代谢产物”是指本发明化合物通过一种或多种新陈代谢过程的降解产物，其发挥所期望的生物学活性。The term "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.
术语“药学上可接受的盐”是指本发明化合物、其溶剂合物、其前药或其代谢产物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于：锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸，所述无机酸包括但不限于：盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所述的药学上可接受的酸包括有机酸，所述有机酸包括但不限于：乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的化合物中含有相对酸性和相对碱性的官能 团时，可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。The term "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. When compounds of the present invention contain relatively acidic functional groups, 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. A salt. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine. When compounds 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 salt. The pharmaceutically acceptable acids 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. 4,4'-methylene-bis( 3-hydroxy-2-naphthoic acid), amino acids (eg, glutamic acid, arginine), and the like. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).
术语“化合物”、“溶剂合物”、“前药”、“代谢产物”和它们“药学上可接受的盐”可以以晶型或无定型的形式存在。术语“晶型”是指其中的离子或分子是按照一种确定的方式在三维空间作严格周期性排列，并具有间隔一定距离周期重复出现规律；因上述周期性排列的不同，可存在多种晶型，也即多晶型现象。术语“无定型”是指其中的离子或分子呈现杂乱无章的分布状态，即离子、分子间不具有周期性排列规律。The terms "compound", "solvate", "prodrug", "metabolite" and their "pharmaceutically acceptable salts" can exist in crystalline or amorphous form. The term "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. The term "amorphous" means that the ions or molecules are in a disordered distribution state, that is, there is no periodic arrangement between ions and molecules.
术语“化合物”、“溶剂合物”、“前药”、“代谢产物”和它们“药学上可接受的盐”如存在立体异构体，则可以以单一的立体异构体或它们的混合物(例如外消旋体)的形式存在。术语“立体异构体”是指顺反异构体或旋光异构体。这些立体异构体可以通过不对称合成方法或手性分离法(包括但不限于薄层色谱、旋转色谱、柱色谱、气相色谱、高压液相色谱等)分离、纯化及富集，还可以通过与其它手性化合物成键(化学结合等)或成盐(物理结合等)等方式进行手性拆分获得。术语“单一的立体异构体”是指本发明化合物的一种立体异构体相对于该化合物的所有立体异构体的质量含量不低于95％。The terms "compounds", "solvates", "prodrugs", "metabolites" and their "pharmaceutically acceptable salts", where stereoisomers exist, may be used as single stereoisomers or as mixtures thereof (eg racemate). The term "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.). The term "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%.
术语“化合物”、“溶剂合物”、“前药”、“代谢产物”和它们“药学上可接受的盐”如存在互变异构体，则可以以单一的互变异构体或它们的混合物的形式存在，较佳地以较稳定的互变异构体为主的形式存在。The terms "compounds", "solvates", "prodrugs", "metabolites" and their "pharmaceutically acceptable salts", if tautomers It exists in the form of a mixture, preferably in the form of a more stable tautomer.
术语“化合物”、“溶剂合物”、“前药”、“代谢产物”和它们“药学上可接受的盐”中的原子可以以其天然丰度或非天然丰度的形式存在。以氢原子为例，其天然丰度的形式是指其中约99.985％为氕、约0.015％为氘；其非天然丰度的形式是指其中约95％为氘。也即，术语“化合物”、“溶剂合物”、“前药”、“代谢产物”和它们“药学上可接受的盐”中的一个或多个原子可为以非天然丰度的形式存在的原子。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.
当任意变量(例如Re)在化合物的定义中多次出现时，该变量每一位置出现的定义与其余位置出现的定义无关，它们的含义互相独立、互不影响。因此，若某基团被1个、2个或3个Re基团取代，也就是说，该基团可能会被最多3个Re取代，该位置Re的定义与其余位置Re的定义是互相独立的。另外，取代基及/或变量的组合只有在该组合产生稳定的化合物时才被允许。When any variable (eg Re) appears multiple times in the definition of a compound, 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.
术语“烷基”是指具有指定的碳原子数的直链或支链烷基。The term "alkyl" refers to a straight or branched chain alkyl group having the indicated number of carbon atoms.
术语“烷氧基”是指基团-O-RX，其中，RX为如上文所定义的烷基。The term "alkoxy" refers to the group -O-RX, wherein RX is an alkyl group as defined above.
术语“环烷基”是指单价饱和的环状烷基，环烷基的示例为：环丙基、环丁基、环戊基或环己基等。The term "cycloalkyl" refers to a monovalent saturated cyclic alkyl group, exemplified by cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and the like.
术语“杂环烷基”是指具有杂原子的饱和的单环或多环基团。杂环烷基的示例为：吡咯烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢吡啶基、四氢吡咯基、氮杂环丁烷基、噻唑烷基、唑烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、氮杂环庚烷基、二氮杂环庚烷基、氧氮杂环庚烷基、等。The term "heterocycloalkyl" refers to a saturated monocyclic or polycyclic group having a heteroatom. Examples of heterocycloalkyl groups are: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl , piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, and the like.
术语“芳基”是指C6-C10芳基，例如苯基或萘基。The term "aryl" refers to a C6-C10 aryl group such as phenyl or naphthyl.
术语“杂芳基”是指含有杂原子的芳香基团，优选含有1个、2个或3个独立选自氮、氧和硫的芳族5-6元单环或9-10元双环，当为双环时，至少一个环具有芳香性。杂芳基的示例为：呋喃基、吡啶基、哒嗪基、嘧啶基、吡嗪基、噻吩基、异唑基、噁唑基、二唑基、咪唑基、吡咯基、吡唑基、三唑基、四唑基、噻唑基、异噻唑基、噻二唑基、苯并咪唑基、吲哚基、吲唑基、苯并噻唑基、苯并异噻唑基、苯并唑基、苯并异唑基、喹啉基、异喹啉基等。The term "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. Examples of 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.
在某些情况下，标准技术被用于化学合成、化学分析、发光器件性能检测。In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“…独立地为”应做广义理解，是指所描述的各个个体之间是相互独立的，可以独立地为相同或不同的具体基团。更详细地，描述方式“…独立地为”既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响；也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。In addition, it should be noted that, unless clearly stated otherwise, 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. In more detail, 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.
术语“药用辅料”是指生产药品和调配处方时使用的赋形剂和附加剂，是除活性成分以外，包含在药物制剂中的所有物质。可参见中华人民共和国药典(2015年版)四部、或、Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009 Sixth Edition)The term "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)
术语“治疗”指治疗性疗法。涉及具体病症时，治疗指：(1)缓解疾病或者病症的一种或多种生物学表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，(3)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或(4)减缓病症或者病症的一种或多种生物学表现发展。The term "treatment" refers to therapeutic therapy. In relation to a specific disorder, 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.
术语“预防”是指获得或发生疾病或障碍的风险降低。The term "prevention" refers to a reduced risk of acquiring or developing a disease or disorder.
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳化合物。On the basis of not violating common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain the preferred compounds of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
本发明的积极进步效果在于：本发明提供了一系列新型化合物，具有良好的KRAS G12C蛋白突变抑制活性，可用于治疗或预防癌症。 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.
本发明化合物对多种肿瘤细胞表现出较强的细胞毒性，例如，本发明所有化合物对NCI-H358、MIA PaCa-2等细胞表现出增殖抑制活性，其IC50值<100μM。The compounds of the present invention show strong cytotoxicity to a variety of tumor cells. For example, 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 μM.
附图说明Description of drawings
图1为中间体A27的X-Ray图。Figure 1 is an X-Ray image of intermediate A27.
具体实施方式Detailed ways
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further described below by way of examples, but the present invention is not limited to the scope of the described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.
以下实施例中，化合物采用以下流程进行制备得到：In the following examples, compounds were prepared by the following procedures:
Figure PCTCN2021138375-appb-000092
Figure PCTCN2021138375-appb-000092
以上化合物中，L为卤素(例如氯)或羟基，PG为常见的氨基保护基(例如叔丁氧羰基)，其余取代基的定义如前任一项所述。In the above compounds, L is halogen (such as chlorine) or hydroxyl, PG is a common amino protecting group (such as tert-butoxycarbonyl), and the definitions of the remaining substituents are as described in the previous one.
起始化合物K-I经取代反应得到K-II；K-II经卤化反应得到K-III；K-III与K-XI经取代反应得到K-IV；K-IV脱保护基团得到K-V；K-V经卤化反应得到K-VI；K-VI与K-XII经取代反应得到K-VII；K-VII再经过取代反应得到K-VIII；K-VIII经过还原氨解反应(或者再经过取代反应)得到K-IX；K-IX经脱保护基团得到K-X；K-X与K-XIII经取代或者酰化反应得到化合物I；化合物I经SFC手性拆分得到化合物Ia和化合物Ib。各步骤的操作和条件均可为本领域常规。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.
以下实施例中，化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶 剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。 In the following examples, the structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10&lt;&quot; 6 &gt; (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (TMS).
SHIMADZU LC系统(色谱柱：
Figure PCTCN2021138375-appb-000093
CSH TM Prep-C18，19*150mm，液体处理机LH-40，泵LC-20AP，检测器SPD-20A，系统控制器CBM-20A，溶剂系统：乙腈和0.05％三氟乙酸水溶液)。 SHIMADZU LC system (column:
Figure PCTCN2021138375-appb-000093
CSH ™ 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).
使用LC/MS(Agilent Technologies 1200Series)获得化合物的LC/MS光谱。LC/MS条件如下(运行时间为10分钟)：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):
酸性条件：A：0.05％三氟乙酸的水溶液；B：0.05％三氟乙酸的乙腈溶液；Acidic conditions: A: 0.05% trifluoroacetic acid in water; B: 0.05% trifluoroacetic acid in acetonitrile;
碱性条件：A：0.05％NH 3·H 2O的水溶液；B：乙腈 Basic conditions: A: 0.05% NH 3 ·H 2 O in water; B: acetonitrile
中性条件：A：10mM NH 4OAC的水溶液；B：乙腈 Neutral conditions: A: 10 mM NH4OAC in water; B: acetonitrile
如无特别说明，以下实施例中，中间体和最终化合物使用硅胶柱色谱法纯化、或使用
Figure PCTCN2021138375-appb-000094
CSH TM Prep-C18(5μm，OBD TM 19*150mm)色谱柱或XBridgeTM Prep Phenyl(5μm，OBD TM 30*100mm)在反相色谱柱上通过制备性HPLC纯化。 Unless otherwise specified, in the following examples, the intermediates and final compounds were purified by silica gel column chromatography, or used
Figure PCTCN2021138375-appb-000094
Purification by preparative HPLC on a CSH ™ Prep-C18 (5 μm, OBD ™ 19*150 mm) column or XBridge™ Prep Phenyl (5 μm, OBD ™ 30*100 mm) column on reversed phase chromatography.
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。The CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
薄层色谱法(TLC)硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层层析检测产品使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。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.
如无特别说明，以下实施例中，中间体或最终化合物经SFC进行分离，具体条件如下：设备：Waters SFC 150制备型色谱仪；色谱柱:CHIRAL ART Cellulose-SB,5cm×25cm,5μm或者Dr.maish Reprosil Chiral-JM，250x25mm，10μm；柱温:室温；流动相:乙醇在正己烷中或者CO 2/MeOH＝65/35；流速:70g/min；波长:214nm；背压:100bar。 Unless otherwise specified, in the following examples, intermediates or final compounds were separated by SFC, and the specific conditions were as follows: equipment: Waters SFC 150 preparative chromatograph; chromatographic column: CHIRAL ART Cellulose-SB, 5cm×25cm, 5μm or Dr. .maish Reprosil Chiral-JM, 250x25mm, 10 μm; column temperature: room temperature; mobile phase: ethanol in n-hexane or CO 2 /MeOH=65/35; flow rate: 70 g/min; wavelength: 214 nm; back pressure: 100 bar.
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG、Acros Organics、Aldrich Chemical Company、韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。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.
缩略词：AcOH：乙酸；ACN：乙腈；AcCl：乙酰氯；Acrylamide：丙-2-烯酰胺；AgF：氟化银；Ag 2O：氧化银；BH 3：硼烷；Boc 2O：碳酸叔丁氧基羰基叔丁酯；Boc：叔丁氧羰基；Conc.HCl：浓盐酸；C 2Br 2Cl 4：1,2-二溴四氯乙烷；Cbz：苄氧羰基；CH 3I：碘甲烷；Cs 2CO 3：碳酸铯；DAST：二乙胺基三氟化硫；DIEA：N,N-二异丙基乙胺；DMAP：4-二甲氨基吡啶；DCM：二氯甲烷；Dioxane：1,4-二氧六环；DMF：二甲基甲酰胺；DMA：二甲基乙酰胺；DMS：二甲亚砜；DCE：1,2-二氯乙烷；DMF-DMA：1,1-二甲氧基-N,N- 二甲基-甲胺；Dppf：双二苯基膦二茂铁；EDCI：1-乙基-3(3-二甲基丙胺)碳二亚胺；Ethyl propiolate：丙酸乙酯；EtOH：乙醇；Et 3N：三乙胺；H 2：氢气；HCOONH 4：甲酸铵；LAH：铝锂氢；LiHMDS：双(三甲基硅基)氨基锂；LDA：二异丙基氨基锂；LiOH：氢氧化锂；LiAlH 4：氢化铝锂；MeOH：甲醇；MsC：甲磺酰氯；MW：微波反应；m-CPBA：间氯过氧苯甲酸；n-BuLi：正丁基锂；NaH：氢化钠；NaHMDS：双(三甲基硅基)氨基钠；Ph 3PCH 2OMeCl：甲氧甲基三苯基氯化磷；Pd 2(dba) 3：三(二亚苄基丙酮)二钯；Pd(dppf)Cl 2：[1,1'-双(二苯基膦基)二茂铁]二氯化钯；PPA：多聚磷酸；POCl 3：三氯氧磷；Pd/C：钯碳；Pyrrolidine：吡咯烷；SOCl 2：氯化亚砜；t-BuOK：叔丁醇钾；t-butyl nitrite：亚硝酸叔丁酯；t-BuLi：叔丁基锂；Toluene：甲苯；TsOH：对甲苯磺酸；THF：四氢呋喃；TFA：三氟乙酸；TEA：三乙胺；Urea：尿素；Xphos：2-二环己基磷-2,4,6-三异丙基联苯；Xantphos：4,5-双(二苯基膦)-9,9-二甲基氧杂蒽；Zn/Cu：锌铜试剂；Zn：锌粉；Zn(CN) 2：氰化锌。 Abbreviations: AcOH: acetic acid; ACN: acetonitrile; AcCl: acetyl chloride; Acrylamide: prop-2-enamide; AgF: silver fluoride; Ag 2 O: silver oxide; BH 3 : borane; Boc 2 O: carbonic acid tert-Butoxycarbonyl tert-butyl ester; Boc: tert-butoxycarbonyl; Conc.HCl: concentrated hydrochloric acid; C 2 Br 2 Cl 4 : 1,2-dibromotetrachloroethane; Cbz: benzyloxycarbonyl; CH 3 I : iodomethane; Cs 2 CO 3 : cesium carbonate; DAST: diethylaminosulfur trifluoride; DIEA: N,N-diisopropylethylamine; DMAP: 4-dimethylaminopyridine; DCM: dichloromethane ; Dioxane: 1,4-dioxane; DMF: dimethylformamide; DMA: dimethylacetamide; DMS: dimethyl sulfoxide; DCE: 1,2-dichloroethane; DMF-DMA: 1,1-Dimethoxy-N,N-dimethyl-methylamine; Dppf: bisdiphenylphosphinoferrocene; EDCI: 1-ethyl-3(3-dimethylpropylamine)carbodiidene Amine; Ethyl propiolate: ethyl propionate; EtOH: ethanol; Et 3 N: triethylamine; H 2 : hydrogen; HCOONH 4 : ammonium formate; LAH: aluminum lithium hydrogen; LiHMDS: bis(trimethylsilyl)amino Lithium; LDA: lithium diisopropylamide; LiOH: lithium hydroxide; LiAlH 4 : lithium aluminum hydride; MeOH: methanol; MsC: methanesulfonyl chloride; MW: microwave reaction; m-CPBA: m-chloroperoxybenzoic acid; n-BuLi: n-butyllithium; NaH: sodium hydride; NaHMDS: sodium bis(trimethylsilyl)amide; Ph 3 PCH 2 OMeCl: methoxymethyltriphenylphosphonium chloride; Pd 2 (dba) 3 : tris(dibenzylideneacetone)dipalladium; Pd(dppf)Cl 2 : [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride; PPA: polyphosphoric acid; POCl 3 : phosphorus oxychloride; Pd/C: palladium carbon; Pyrrolidine: pyrrolidine; SOCl 2 : thionyl chloride; t-BuOK: potassium tert-butoxide; t-butyl nitrite: tert-butyl nitrite; t-BuLi: tert-butyllithium; Toluene: toluene; TsOH: p-toluenesulfonic acid; THF: tetrahydrofuran; TFA: trifluoroacetic acid; TEA: triethylamine; Urea: urea; Xphos: 2-dicyclohexylphosphorus-2,4,6 - Triisopropyl biphenyl; Xantphos: 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene; Zn/Cu: zinc-copper reagent; Zn: zinc powder; Zn(CN) 2 : Zinc cyanide.
制备例1中间体A1Preparation Example 1 Intermediate A1
4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)piperidine tert-Butyl oxazine-1-carboxylate
Figure PCTCN2021138375-appb-000095
Figure PCTCN2021138375-appb-000095
步骤1:4-(2-氯-6-甲基-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯的制备Step 1: Preparation of tert-butyl 4-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)piperazine-1-carboxylate
Figure PCTCN2021138375-appb-000096
Figure PCTCN2021138375-appb-000096
将2,4-二氯-6-甲基-5-硝基嘧啶(6克，28.8毫摩尔)溶于无水二氯甲烷(30毫升)中，在0℃时搅拌缓慢加入哌嗪-1-羧酸叔丁酯(10.75克，57.7毫摩尔)。滴完后，将反应混合物在0℃继续搅拌1小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体4-(2-氯-6-甲基-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯(6克，58％收率)。MS:358.1(M+H) +。 1H NMR(400MHz,Chloroform-d)δ3.54(s,8H),2.45(s,3H),1.49(s,9H)。 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 4-(2-chloro-6-methyl-5-nitropyrimidine as a yellow solid) -4-yl)piperazine-1-carboxylate tert-butyl ester (6 g, 58% yield). MS: 358.1 (M+H) + . 1 H NMR (400 MHz, Chloroform-d) δ 3.54 (s, 8H), 2.45 (s, 3H), 1.49 (s, 9H).
步骤2:4-(2-氯-6-甲基-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯的制备Step 2: Preparation of tert-butyl 4-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)piperazine-1-carboxylate
Figure PCTCN2021138375-appb-000097
Figure PCTCN2021138375-appb-000097
将4-(2-氯-6-甲基-5-硝基嘧啶-4-基)哌嗪-1-甲酸叔丁酯(1.8克，5.03毫摩尔)溶于无水四氢呋喃(40毫升)中，在-78℃时搅拌缓慢加入LDA(6.04毫摩尔)，并继续搅拌30分钟，然后将1,2-二溴-1,1,2,2-四氯乙烷(1.966克，6.04毫摩尔)的四氢呋喃(10毫升)溶液加到反应液中。滴完后，将反应混合物在-78℃继续搅拌0.5小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体4-(6-(溴甲基)-2-氯-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯(1克，45％收率)。MS:436.1&438.1(M+H) +。 4-(2-Chloro-6-methyl-5-nitropyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (1.8 g, 5.03 mmol) was dissolved in dry tetrahydrofuran (40 mL) , LDA (6.04 mmol) was slowly added with stirring at -78 °C, and stirring was continued for 30 minutes, then 1,2-dibromo-1,1,2,2-tetrachloroethane (1.966 g, 6.04 mmol) was added. ) in tetrahydrofuran (10 mL) was added to the reaction solution. After dropping, the reaction mixture was further stirred at -78°C for 0.5 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid 4-(6-(bromomethyl)-2-chloro-5- Nitropyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (1 g, 45% yield). MS: 436.1 & 438.1 (M+H) + .
步骤3:4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯的制备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
Figure PCTCN2021138375-appb-000098
Figure PCTCN2021138375-appb-000098
将1,2,3,4-四氢萘-1-羧酸甲酯(1.568克，8.24毫摩尔)溶于无水四氢呋喃(20毫升)中，在-78℃时搅拌缓慢加入LDA(5.50毫摩尔)，并在-78℃继续搅拌30分钟，然后将4-(6-(溴甲基)-2-氯-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯(1.2克，2.75毫摩尔)的四氢呋喃(10毫升)溶液加到反应液中。滴完后，将反应混合物在-78℃继续搅拌0.5小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯(300毫克，21％收率)。MS:546.1(M+H) +。 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. After dropping, the reaction mixture was further stirred at -78°C for 0.5 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid 4-(2-chloro-6-((1-(methoxycarbonyl) )-1,2,3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (300 mg, 21% yield ). MS: 546.1 (M+H) + .
制备例2中间体A2Preparation Example 2 Intermediate A2
(3S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(3S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4 -yl)-3-methylpiperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000099
Figure PCTCN2021138375-appb-000099
步骤1:(S)-4-(2-氯-6-甲基-5-硝基嘧啶-4-基)-3-甲基哌嗪-1-甲酸叔丁酯的制备Step 1: Preparation of (S)-4-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester
Figure PCTCN2021138375-appb-000100
Figure PCTCN2021138375-appb-000100
将2,4-二氯-6-甲基-5-硝基嘧啶(5.0克，24.04毫摩尔)溶于无水二氯甲烷(30毫升)中，在0℃时搅拌缓慢加入(S)-3-甲基哌嗪-1-甲酸叔丁酯(9.63克，48.1毫摩尔)。滴完后，将反应混合物在0℃继续搅拌1小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(S)-4-(2-氯-6-甲基-5-硝基嘧啶-4-基)-3-甲基哌嗪-1-甲酸叔丁酯(8克，90％收率)。MS:372.1(M+H) +。 2,4-Dichloro-6-methyl-5-nitropyrimidine (5.0 g, 24.04 mmol) was dissolved in dry dichloromethane (30 mL), and (S)- 3-Methylpiperazine-1-carboxylate tert-butyl ester (9.63 g, 48.1 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (S)-4-(2-chloro-6-methyl-5). -Nitropyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (8 g, 90% yield). MS: 372.1 (M+H) + .
步骤2:(S)-4-(6-(溴甲基)-2-氯-5-硝基嘧啶-4-基)-3-甲基哌嗪-1-甲酸叔丁酯的制备Step 2: Preparation of (S)-4-(6-(bromomethyl)-2-chloro-5-nitropyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester
Figure PCTCN2021138375-appb-000101
Figure PCTCN2021138375-appb-000101
将(S)-4-(2-氯-6-甲基-5-硝基嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(4克，10.76毫摩尔)溶于无水四氢呋喃(40毫升)中，在-65℃时搅拌缓慢加入LDA(12.91毫摩尔)，并继续搅拌40分钟，然后将1,2-二溴-1,1,2,2-四氯乙烷(4.20克，12.91毫摩尔)的四氢呋喃(10毫升)溶液加到反应液中。滴完后，将反应混合物在-65℃继续搅拌0.5小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(S)-4-(6-(溴甲基)-2-氯-5-硝基嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(1.0克，21％收率)。MS:450.1&452.1(M+H) +。 (S)-tert-butyl 4-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (4 g, 10.76 mmol) Dissolve in dry tetrahydrofuran (40 mL), slowly add LDA (12.91 mmol) with stirring at -65°C, and continue stirring for 40 minutes, then add 1,2-dibromo-1,1,2,2-tetrakis A solution of chloroethane (4.20 g, 12.91 mmol) in tetrahydrofuran (10 mL) was added to the reaction. After dropping, the reaction mixture was further stirred at -65°C for 0.5 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (S)-4-(6-(bromomethyl)-2- Chloro-5-nitropyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (1.0 g, 21% yield). MS: 450.1 & 452.1 (M+H) + .
步骤3:(3S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的制备Step 3: (3S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitro Preparation of pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000102
Figure PCTCN2021138375-appb-000102
将1,2,3,4-四氢萘-1-羧酸甲酯(169毫克，0.887毫摩尔)溶于无水四氢呋喃(20毫升)中，在-78℃时搅拌缓慢加入LDA(0.887毫摩尔)，并在-78℃继续搅拌30分钟，然后将(S)-4-(6-(6-溴甲基)-2-氯-5-硝基嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(200毫克，0.444毫摩尔)的四氢呋喃(10毫升)溶液加到反应液中。滴完后，将反应混合物在-78℃继续搅拌0.5小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(3S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(140毫克，56.3％收率)。MS:561.1(M+H) +。 Methyl 1,2,3,4-tetrahydronaphthalene-1-carboxylate (169 mg, 0.887 mmol) was dissolved in dry tetrahydrofuran (20 mL), and LDA (0.887 mmol) was added slowly with stirring at -78°C. mol) and continued stirring at -78°C for 30 minutes, then (S)-4-(6-(6-bromomethyl)-2-chloro-5-nitropyrimidin-4-yl)-3-methyl A solution of tert-butyl piperazine-1-carboxylate (200 mg, 0.444 mmol) in tetrahydrofuran (10 mL) was added to the reaction. After dropping, the reaction mixture was further stirred at -78°C for 0.5 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (3S)-4-(2-chloro-6-((1- (Methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (140 mg, 56.3% yield). MS: 561.1 (M+H) + .
制备例3中间体A3Preparation Example 3 Intermediate A3
(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4 -yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000103
Figure PCTCN2021138375-appb-000103
Figure PCTCN2021138375-appb-000104
Figure PCTCN2021138375-appb-000104
步骤1:2,4-双(苄氧基)-6-甲基-5-硝基嘧啶的制备Step 1: Preparation of 2,4-bis(benzyloxy)-6-methyl-5-nitropyrimidine
Figure PCTCN2021138375-appb-000105
Figure PCTCN2021138375-appb-000105
将2,4-二氯-6-甲基-5-硝基嘧啶(20克，96毫摩尔)和苯基甲醇(52.0克，481毫摩尔)溶于无水四氢呋喃(40毫升)中，在回流条件下搅拌加入叔丁醇钾(21.58克，192毫摩尔)。加完后，将反应混合物继续搅拌1小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到白色固体2，4-双(苄氧基)-6-甲基-5-硝基嘧啶(16克，47.4％收率)白色固体。MS:352.1(M+H) +。 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 2,4-bis(benzyloxy)-6-methyl-5 as a white solid - Nitropyrimidine (16 g, 47.4% yield) as a white solid. MS: 352.1 (M+H) + .
步骤2:2,4-双(苄氧基)-6-(溴甲基)-5-硝基嘧啶的制备Step 2: Preparation of 2,4-bis(benzyloxy)-6-(bromomethyl)-5-nitropyrimidine
Figure PCTCN2021138375-appb-000106
Figure PCTCN2021138375-appb-000106
将2,4-双(苄氧基)-6-甲基-5-硝基嘧啶(15克，42.7毫摩尔)溶于无水四氢呋喃(500毫升)中，在-78℃时搅拌缓慢加入LiHMDS(68.3毫摩尔)，并继续搅拌40分钟，然后将1,2-二溴-1,1,2,2-四氯乙烷(13.90克,42.7毫摩尔)的四氢呋喃(10毫升)溶液加到反应液中。滴完后，将反应混合物在-78℃继续搅拌0.5小时，然后加入冰水淬灭反 应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体2，4-双(苄氧基)-6-(溴甲基)-5-硝基嘧啶(12.8克，70％收率)。MS:430.1&432.1(M+H) +。 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. After dropping, the reaction mixture was further stirred at -78°C for 0.5 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 2,4-bis(benzyloxy)-6-(bromomethyl) as a yellow solid )-5-nitropyrimidine (12.8 g, 70% yield). MS: 430.1 & 432.1 (M+H) + .
步骤3:1-((2,6-双(苄氧基)-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯的制备Step 3: Methyl 1-((2,6-bis(benzyloxy)-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate preparation
Figure PCTCN2021138375-appb-000107
Figure PCTCN2021138375-appb-000107
将1,2,3,4-四氢萘-1-羧酸甲酯(6.63克，34.9毫摩尔)溶于无水四氢呋喃(150毫升)中，在-78℃时搅拌缓慢加入LDA(34.9毫摩尔)，并在-78℃继续搅拌30分钟，然后将2,4-双(苄氧基)-6-(溴甲基)-5-硝基嘧啶(5克，11.62毫摩尔)的四氢呋喃(15毫升)溶液加到反应液中。滴完后，将反应混合物在-78℃继续搅拌0.5小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到白色固体1-((2，6-双(苄氧基)-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(4.5克，72％收率)。MS:540.1(M+H) +。 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. After dropping, the reaction mixture was further stirred at -78°C for 0.5 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a white solid 1-((2,6-bis(benzyloxy)-5- Nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid methyl ester (4.5 g, 72% yield). MS: 540.1 (M+H) + .
步骤4:1-((2,6-二羟基-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯的制备Step 4: Preparation of methyl 1-((2,6-dihydroxy-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate
Figure PCTCN2021138375-appb-000108
Figure PCTCN2021138375-appb-000108
将1-((2,6-双(苄氧基)-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(1.0克，1.853毫摩尔)溶于三氟乙酸(5毫升)中。反应混合物在氮气的保护下缓慢升至100℃并微波条件搅拌1小时，然后反应混合液浓缩，并用乙酸乙酯萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体1-((2，6-二羟基-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(600毫克，90％收率)。MS:360.1(M+H) +。 Methyl 1-((2,6-bis(benzyloxy)-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (1.0 g, 1.853 mmol) in trifluoroacetic acid (5 mL). The reaction mixture was slowly warmed to 100°C under nitrogen and stirred under microwave conditions for 1 hour, then the reaction mixture was concentrated and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 1-((2,6-dihydroxy-5-nitropyrimidine- 4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid methyl ester (600 mg, 90% yield). MS: 360.1 (M+H) + .
步骤5:1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯的制备Step 5: Preparation of methyl 1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate
Figure PCTCN2021138375-appb-000109
Figure PCTCN2021138375-appb-000109
将1-((2,6-二羟基-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(2.2克，6.12毫摩尔)溶于三氯氧磷(15毫升)中，在0度时搅拌加入DIEA(791毫克，6.12毫摩尔)。反应混合物在氮气的保护下缓慢升至110℃并搅拌6小时，然后反应混合液浓缩，并用二氯甲烷稀释萃取并将溶液倒入饱和碳酸氢钠溶液中搅拌1小时。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色固体1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(2.2克，91％收率)。MS:397.2(M+H) +。 Methyl 1-((2,6-dihydroxy-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (2.2 g, 6.12 mM) mol) 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, extracted with dichloromethane and the solution was poured into saturated sodium bicarbonate solution and stirred for 1 hour. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give a yellow solid 1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-1,2, Methyl 3,4-tetrahydronaphthalene-1-carboxylate (2.2 g, 91% yield). MS: 397.2 (M+H) + .
步骤6:(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯的制备Step 6: (2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitro Preparation of tert-butyl pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate
Figure PCTCN2021138375-appb-000110
Figure PCTCN2021138375-appb-000110
将1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(1.5克，3.79毫摩尔)溶于无水二氯甲烷(30毫升)中，在0℃时搅拌缓慢加入(S)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(1.71克，7.57毫摩尔)。滴完后，将反应混合物在0℃继续搅拌1小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3，4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(1.0克，45％收率)。MS:586.1(M+H) +。 Methyl 1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (1.5 g, 3.79 mM mol) was dissolved in anhydrous dichloromethane (30 mL), and (S)-tert-butyl 2-(cyanomethyl)piperazine-1-carboxylate (1.71 g, 7.57 mL) was slowly added with stirring at 0°C Moore). 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2S)-4-(2-chloro-6-((1- (methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1- tert-Butyl carboxylate (1.0 g, 45% yield). MS: 586.1 (M+H) + .
制备例4中间体A4Preparation Example 4 Intermediate A4
(2R，6S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2,6-二甲基哌嗪-1-羧酸叔丁酯(2R,6S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine -4-yl)-2,6-dimethylpiperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000111
Figure PCTCN2021138375-appb-000111
将1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A3/步骤5,0.5克，1.3毫摩尔)溶于无水二氯甲烷(30毫升)中，在0℃时搅拌缓慢加入(2R，6S)-2，6-二甲基哌嗪-1-羧酸叔丁酯(0.57克，2.6毫摩尔)。滴完后，将反应混合物在0℃继续搅拌1小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2R，6S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2,6-二甲基哌嗪-1-羧酸叔丁酯(0.402克，54％收率)。MS:574.1(M+H) +。 Methyl 1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A3/step 5, 0.5 g, 1.3 mmol) was dissolved in anhydrous dichloromethane (30 mL) and slowly added with stirring at 0 °C (2R,6S)-2,6-dimethylpiperazine-1-carboxylic acid tertiary Butyl ester (0.57 g, 2.6 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2R,6S)-4-(2-chloro-6-(( 1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2,6-dimethylpiperazine-1 - tert-Butyl carboxylate (0.402 g, 54% yield). MS: 574.1 (M+H) + .
制备例5中间体A5Preparation Example 5 Intermediate A5
(2R，5S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(2R,5S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine -4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000112
Figure PCTCN2021138375-appb-000112
Figure PCTCN2021138375-appb-000113
Figure PCTCN2021138375-appb-000113
将1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A3/步骤5,0.5克，1.3毫摩尔)溶于无水二氯甲烷(30毫升)中，在0℃时搅拌缓慢加入(2R，5S)-2,5-二甲基哌嗪-1-甲酸叔丁酯(0.57克，2.6毫摩尔)。滴完后，将反应混合物在0℃继续搅拌1小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2R，5S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.342克，46％收率)。MS:574.1(M+H) +。 Methyl 1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A3/step 5, 0.5 g, 1.3 mmol) was dissolved in anhydrous dichloromethane (30 mL), and (2R,5S)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl was slowly added with stirring at 0 °C ester (0.57 g, 2.6 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2R,5S)-4-(2-chloro-6-(( 1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2,5-dimethylpiperazine-1 - tert-Butyl carboxylate (0.342 g, 46% yield). MS: 574.1 (M+H) + .
制备例6中间体A6Preparation Example 6 Intermediate A6
7-(2-氯-6-(((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯7-(2-Chloro-6-(((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl) -2,7-Diazaspiro[3.5]nonane-2-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000114
Figure PCTCN2021138375-appb-000114
将1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A3/步骤5,0.5克，1.3毫摩尔)溶于无水二氯甲烷(30毫升)中，在0℃时搅拌缓慢加入2,7- 二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(0.588克,2.6毫摩尔)。滴完后，将反应混合物在0℃继续搅拌1小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体7-(2-氯-6-(((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(0.388克，51％收率)。MS:587.1(M+H) +。 Methyl 1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A3/step 5, 0.5 g, 1.3 mmol) was dissolved in anhydrous dichloromethane (30 mL), and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate was slowly added with stirring at 0 °C (0.588 g, 2.6 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid 7-(2-chloro-6-(((1-(methoxyl carbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2- tert-Butyl carboxylate (0.388 g, 51% yield). MS: 587.1 (M+H) + .
制备例7中间体A7Preparation Example 7 Intermediate A7
(1R，5S)-3-(2-氯-6-((1-(甲氧基羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(1R,5S)-3-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitro pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000115
Figure PCTCN2021138375-appb-000115
将1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A3/步骤5,0.5克，1.3毫摩尔)溶于无水二氯甲烷(30毫升)中，在0℃时搅拌缓慢加入(1R，5S)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯(0.551克,2.6毫摩尔)。滴完后，将反应混合物在0℃继续搅拌1小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(1R，5S)-3-(2-氯-6-((1-(甲氧基羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(0.56克，75.1％收率)。MS:573.1(M+H) +。 Methyl 1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A3/step 5, 0.5 g, 1.3 mmol) was dissolved in anhydrous dichloromethane (30 mL), and (1R,5S)-3,8-diazabicyclo[3.2.1]octane was slowly added with stirring at 0°C tert-Butyl alkane-8-carboxylate (0.551 g, 2.6 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (1R,5S)-3-(2-chloro-6-(( 1-(Methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-3,8-diazabicyclo[3.2 .1] Octane-8-carboxylate tert-butyl ester (0.56 g, 75.1% yield). MS: 573.1 (M+H) + .
制备例8中间体A8Preparation Example 8 Intermediate A8
(1R，5S)-8-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶 -4-基)-3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(1R,5S)-8-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine -4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000116
Figure PCTCN2021138375-appb-000116
将1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A3/步骤5,0.5克，1.3毫摩尔)溶于无水二氯甲烷(30毫升)中，在0℃时搅拌缓慢加入(1R，5S)-3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(0.551克,2.6毫摩尔)。滴完后，将反应混合物在0℃继续搅拌1小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(1R，5S)-8-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(0.49克，65.9％收率)。MS:573.1(M+H) +。 Methyl 1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A3/step 5, 0.5 g, 1.3 mmol) was dissolved in anhydrous dichloromethane (30 mL), and (1R,5S)-3,8-diazabicyclo[3.2.1]octane was slowly added with stirring at 0 °C - tert-Butyl 3-carboxylate (0.551 g, 2.6 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (1R,5S)-8-(2-chloro-6-(( 1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-3,8-diazabicyclo[3.2. 1] Octane-3-carboxylate tert-butyl ester (0.49 g, 65.9% yield). MS: 573.1 (M+H) + .
制备例9中间体A9Preparation Example 9 Intermediate A9
(2R)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氟甲基)哌嗪-1-羧酸苄酯(2R)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4 -yl)-2-(fluoromethyl)piperazine-1-carboxylate benzyl ester
Figure PCTCN2021138375-appb-000117
Figure PCTCN2021138375-appb-000117
Figure PCTCN2021138375-appb-000118
Figure PCTCN2021138375-appb-000118
步骤1:(R)-3-(氟甲基)哌嗪-1-羧酸叔丁酯的制备Step 1: Preparation of (R)-3-(fluoromethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000119
Figure PCTCN2021138375-appb-000119
将(R)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(2克,9.25毫摩尔)溶于无水二氯甲烷(30毫升)中，在0℃时搅拌缓慢加入N-乙基-N-(三氟磺胺基)乙胺(1.79克,11.10毫摩尔,1.47毫升)的二氯甲烷(2毫升)溶液。滴完后，将反应混合物缓慢升至室温并继续搅拌3小时，反应完毕后，反应溶液直接用于下一步反应。(R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (2 g, 9.25 mmol) was dissolved in dry dichloromethane (30 mL) and added slowly with stirring at 0°C A solution of N-ethyl-N-(trifluorosulfonamido)ethylamine (1.79 g, 11.10 mmol, 1.47 mL) in dichloromethane (2 mL). After the dropping, the reaction mixture was slowly raised to room temperature and continued to be stirred for 3 hours. After the completion of the reaction, the reaction solution was directly used for the next reaction.
步骤2:4-(叔丁基)(R)-2-(氟甲基)哌嗪-1-苄基-1,4-二羧酸酯的制备Step 2: Preparation of 4-(tert-butyl)(R)-2-(fluoromethyl)piperazine-1-benzyl-1,4-dicarboxylate
Figure PCTCN2021138375-appb-000120
Figure PCTCN2021138375-appb-000120
在0℃时搅拌条件下，将N-乙基-N-异丙基-丙烷-2-胺(1.19克，9.21毫摩尔，1.60毫升)和2,5-二氧吡咯烷-1-羧酸苄酯(3.22克，13.81毫摩尔)缓慢加入到(R)-3-(氟甲基)哌嗪-1-羧酸叔丁酯(9.25毫摩尔)的二氯甲烷(30毫升)溶液中。滴完后，将反应混合物缓慢升至室温并继续搅拌3小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体4-(叔丁基)(R)-2-(氟甲基)哌嗪-1-苄基-1,4-二羧酸酯(1.02克,31.4％收率)。MS:353.1(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.41–7.29(m,5H),5.21–5.10(m,2H),4.55–4.35(m,3H),4.19–3.82(m,3H),3.16–2.98(m,3H),2.89(s,1H),1.47(s,9H)。 Mix N-ethyl-N-isopropyl-propan-2-amine (1.19 g, 9.21 mmol, 1.60 mL) and 2,5-dioxopyrrolidine-1-carboxylic acid with stirring at 0°C Benzyl ester (3.22 g, 13.81 mmol) was slowly added to a solution of (R)-tert-butyl 3-(fluoromethyl)piperazine-1-carboxylate (9.25 mmol) in dichloromethane (30 mL). After dropping, the reaction mixture was slowly warmed to room temperature and continued to stir for 3 hours, then ice water was added to quench the reaction, and the mixture was diluted with dichloromethane for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 4-(tert-butyl)(R)-2-(fluoromethyl) as a yellow solid ) piperazine-1-benzyl-1,4-dicarboxylate (1.02 g, 31.4% yield). MS: 353.1 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.41-7.29 (m, 5H), 5.21-5.10 (m, 2H), 4.55-4.35 (m, 3H), 4.19-3.82 (m, 3H), 3.16-2.98 (m, 3H), 2.89 (s, 1H), 1.47 (s, 9H).
步骤3:(R)-2-(氟甲基)哌嗪-1-羧酸苄酯的制备Step 3: Preparation of (R)-2-(fluoromethyl)piperazine-1-carboxylic acid benzyl ester
Figure PCTCN2021138375-appb-000121
Figure PCTCN2021138375-appb-000121
将4-(叔丁基)(R)-2-(氟甲基)哌嗪-1-苄基-1,4-二羧酸酯(300毫克,0.851毫摩尔)溶于二氯甲烷(5毫升)和TFA(2毫升)的混合溶液中，反应混合物在室温搅拌2小时。反应完毕后，反应溶液用乙酸乙酯稀释萃取，有机相用饱和碳酸钠水溶液，饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色油状物(R)-2-(氟甲基)哌嗪-1-羧酸苄酯(190毫克,88％yield)。MS:253.1(M+H) +。 4-(tert-Butyl)(R)-2-(fluoromethyl)piperazine-1-benzyl-1,4-dicarboxylate (300 mg, 0.851 mmol) was dissolved in dichloromethane (5 mL) and TFA (2 mL), the reaction mixture was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction solution was diluted with ethyl acetate and extracted, the organic phase was washed with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain (R)-2-(fluoromethyl) as a yellow oil. ) benzyl piperazine-1-carboxylate (190 mg, 88% yield). MS: 253.1 (M+H) + .
步骤4:(2R)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氟甲基)哌嗪-1-羧酸苄酯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
Figure PCTCN2021138375-appb-000122
Figure PCTCN2021138375-appb-000122
将1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A3/步骤5,0.3克，0.757毫摩尔)溶于无水二氯甲烷(10毫升)中，在0℃时搅拌缓慢加入(R)-2-(氟甲基)哌嗪-1-羧酸苄酯(191毫克,0.757毫摩尔)。滴完后，将反应混合物在0℃继续搅拌1小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2R)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氟甲基)哌嗪-1-羧酸苄酯(185毫克,39.9％收率)。MS:613.1(M+H) +。 Methyl 1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A3/step 5, 0.3 g, 0.757 mmol) was dissolved in anhydrous dichloromethane (10 mL), and (R)-benzyl 2-(fluoromethyl)piperazine-1-carboxylate ( 191 mg, 0.757 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2R)-4-(2-chloro-6-((1- (Methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(fluoromethyl)piperazine-1-carboxylate benzyl acid (185 mg, 39.9% yield). MS: 613.1 (M+H) + .
制备例10中间体A10Preparation Example 10 Intermediate A10
(3S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-3-(氰基甲基)哌嗪-1-羧酸叔丁酯(3S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4 -yl)-3-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000123
Figure PCTCN2021138375-appb-000123
步骤1:1-苄基4-(叔丁基)(R)-2-(羟甲基)哌嗪-1,4-二羧酸酯的制备Step 1: Preparation of 1-benzyl 4-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate
Figure PCTCN2021138375-appb-000124
Figure PCTCN2021138375-appb-000124
将(3R)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(5.2克,24.04毫摩尔)溶于二氯甲烷(20毫升)和水(20毫升)的混合溶液中，在0℃时搅拌加入NaHCO 3(6.1克,72.62毫摩尔)，然后缓慢加入氯甲酸苄酯(4.3克,25.21毫摩尔)的二氯甲烷(10毫升)溶液。滴完后，将反应混合物升至室温并继续搅拌18小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体1-苄基4-(叔丁基)(R)-2-(羟甲基)哌嗪-1,4-二羧酸酯(9.1克,108.0％收率)。MS:351.1&251.1(M+H) +。 (3R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (5.2 g, 24.04 mmol) was dissolved in a mixed solution of dichloromethane (20 mL) and water (20 mL), NaHCO3 (6.1 g, 72.62 mmol) was added with stirring at 0 °C, followed by slow addition of a solution of benzyl chloroformate (4.3 g, 25.21 mmol) in dichloromethane (10 mL). After dropping, the reaction mixture was warmed to room temperature and stirring was continued for 18 hours, then ice water was added to quench the reaction, and the mixture was diluted with dichloromethane for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 1-benzyl 4-(tert-butyl)(R)-2- as a yellow solid (Hydroxymethyl)piperazine-1,4-dicarboxylate (9.1 g, 108.0% yield). MS: 351.1 & 251.1 (M+H) + .
Step 2:1-苄基4-(叔丁基)(R)-2-(((甲基磺酰基)氧基)甲基)哌嗪-1,4-二羧酯的制备Step 2: Preparation of 1-benzyl 4-(tert-butyl)(R)-2-(((methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylate
Figure PCTCN2021138375-appb-000125
Figure PCTCN2021138375-appb-000125
将1-苄基4-(叔丁基)(R)-2-(羟甲基)哌嗪-1,4-二羧酸酯(5.3克,15.13毫摩尔)，DIEA(3.91克,30.25毫摩尔,5.27毫升)溶于无水二氯甲烷(30毫升)中，在0℃时搅拌缓慢加入MsCl(2.60克,22.69毫摩尔)的二氯甲烷(10毫升)溶液。滴完后，将反应混合物在0℃继续搅拌1小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物1-苄基4-(叔丁基)(R)-2-(((甲基磺酰基)氧基)甲基)哌嗪-1,4-二羧酯(5.3克,81.78％收率)。MS:429.1&329.1(M+H) +。 1-Benzyl 4-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (5.3 g, 15.13 mmol), DIEA (3.91 g, 30.25 mmol) mol, 5.27 mL) was dissolved in dry dichloromethane (30 mL), and a solution of MsCl (2.60 g, 22.69 mmol) in dichloromethane (10 mL) was slowly added with stirring at 0°C. 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 1-benzyl 4-(tert-butyl)(R)-2 as a yellow oil -(((methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylate (5.3 g, 81.78% yield). MS: 429.1 & 329.1 (M+H) + .
步骤3:1-苄基4-(叔丁基)(S)-2-(氰基甲基)哌嗪-1,4-二羧酸酯的制备Step 3: Preparation of 1-benzyl 4-(tert-butyl)(S)-2-(cyanomethyl)piperazine-1,4-dicarboxylate
Figure PCTCN2021138375-appb-000126
Figure PCTCN2021138375-appb-000126
将1-苄基4-(叔丁基)(R)-2-(((甲基磺酰基)氧基)甲基)哌嗪-1,4-二羧酯(5.3克,12.37毫摩尔)和氰化钾KCN(1.61克,24.72毫摩尔)溶于DMA(40毫升)中。反应混合物在氮气的保护下缓慢升至80℃并搅拌18小时，然后用水稀释并用乙酸乙酯萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物1-苄基4-(叔丁基)(S)-2-(氰基甲基)哌嗪-1,4-二羧酸酯(4克,89.9％收率)。MS:360.1&304.1(M+H) +。 1-Benzyl 4-(tert-butyl)(R)-2-(((methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylate (5.3 g, 12.37 mmol) and potassium cyanide KCN (1.61 g, 24.72 mmol) were dissolved in DMA (40 mL). The reaction mixture was slowly warmed to 80°C under nitrogen and stirred for 18 hours, then diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 1-benzyl 4-(tert-butyl)(S)-2 as a yellow oil - (cyanomethyl)piperazine-1,4-dicarboxylate (4 g, 89.9% yield). MS: 360.1 & 304.1 (M+H) + .
步骤4:(S)-3-(氰基甲基)哌嗪-1-羧酸叔丁酯的制备Step 4: Preparation of (S)-3-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000127
Figure PCTCN2021138375-appb-000127
将1-苄基4-(叔丁基)(S)-2-(氰基甲基)哌嗪-1,4-二羧酸酯(2.4克,6.68毫摩尔)溶于乙醇醇(5毫升)中，在搅拌条件下向反应混合物中加入钯碳(711毫克)。反应混合物在氢气作用下室温搅拌1小时，然后将混合物溶液过滤。将滤液真空浓缩，得到黄色固体(S)-3-(氰基甲基)哌嗪-1-羧酸叔丁酯(1.5克,100％收率)。MS:226.1(M+H) +。 1-Benzyl 4-(tert-butyl)(S)-2-(cyanomethyl)piperazine-1,4-dicarboxylate (2.4 g, 6.68 mmol) was dissolved in ethanol (5 mL) ), palladium on carbon (711 mg) was added to the reaction mixture with stirring. The reaction mixture was stirred at room temperature under the influence of hydrogen for 1 hour, and then the mixture solution was filtered. The filtrate was concentrated in vacuo to give (S)-tert-butyl 3-(cyanomethyl)piperazine-1-carboxylate (1.5 g, 100% yield) as a yellow solid. MS: 226.1 (M+H) + .
步骤5:(3S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-3-(氰基甲基)哌嗪-1-羧酸叔丁酯的制备Step 5: (3S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitro Preparation of pyrimidin-4-yl)-3-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000128
Figure PCTCN2021138375-appb-000128
将1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A3/步骤5,600毫克,1.514毫摩尔)溶于无水二氯甲烷(10毫升)中，在0℃时搅拌缓慢加入S)-3-(氰基甲基)哌嗪-1-羧酸叔丁酯(341毫克,1.514毫摩尔)。滴完后，将反应混合物在0℃继续搅拌1小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(3S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-3-(氰基甲基)哌嗪-1-羧酸叔丁酯(450毫克,50.8％收率)。MS:586.1(M+H) +。 Methyl 1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A3/step 5,600 mg, 1.514 mmol) was dissolved in anhydrous dichloromethane (10 mL), and S)-3-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (341) was slowly added with stirring at 0 °C. mg, 1.514 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (3S)-4-(2-chloro-6-((1- (methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-3-(cyanomethyl)piperazine-1- tert-Butyl carboxylate (450 mg, 50.8% yield). MS: 586.1 (M+H) + .
制备例11中间体A11Preparation Example 11 Intermediate A11
(2S)-2-(氰甲基)-4-(2-甲氧基-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯(2S)-2-(cyanomethyl)-4-(2-methoxy-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methan yl)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000129
Figure PCTCN2021138375-appb-000129
将(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4- 基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3,150毫克,0.256毫摩尔)溶于无水甲醇(5毫升)中，在0℃时搅拌缓慢加入甲醇钠(27.7毫克,0.513毫摩尔)。滴完后，将反应混合物升至室温并继续搅拌1小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-2-(氰甲基)-4-(2-甲氧基-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯(0.12克,100％收率)。MS:581.1(M+H) +。 (2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine- 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3, 150 mg, 0.256 mmol) was dissolved in dry methanol (5 mL) at 0 °C Sodium methoxide (27.7 mg, 0.513 mmol) was added slowly with stirring. After dropping, the reaction mixture was warmed to room temperature and stirring was continued for 1 hour, then ice water was added to quench the reaction, and the mixture was diluted with dichloromethane for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2S)-2-(cyanomethyl)-4-(2- Methoxy-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)piperazine-1 - tert-butyl carboxylate (0.12 g, 100% yield). MS: 581.1 (M+H) + .
制备例12中间体A12Preparation Example 12 Intermediate A12
(2S)-4-(2-氯-6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-5-nitropyrimidine-4- benzyl)-2-(cyanomethyl)piperazine-1-carboxylate
Figure PCTCN2021138375-appb-000130
Figure PCTCN2021138375-appb-000130
步骤1:2,3-二氢-1H-茚-1-羧酸甲酯的制备Step 1: Preparation of methyl 2,3-dihydro-1H-indene-1-carboxylate
Figure PCTCN2021138375-appb-000131
Figure PCTCN2021138375-appb-000131
将2,3-二氢-1H-茚-1-羧酸(11克,67.8毫摩尔)溶于无水甲醇(100毫升)中，在0℃时搅拌缓慢加入氯化亚砜(40.3克,339毫摩尔)。滴完后，将反应混合物缓慢升至70℃并继续搅拌1小时。反应完毕后，将反应混合物浓缩并用乙酸乙酯稀释萃取。有机相用饱和碳酸氢钠溶液，饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色油状物2,3-二氢-1H-茚-1-羧酸甲酯(11克,92.1％收率)。MS:177.1(M+H) +。 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. The organic phase was washed with saturated sodium bicarbonate solution, saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain crude product, which was purified by silica gel column chromatography to obtain 2,3-dihydro-1H- Indene-1-carboxylate methyl ester (11 g, 92.1% yield). MS: 177.1 (M+H) + .
步骤2:1-((2,6-双(苄氧基)-5-硝基嘧啶-4-基)甲基)-2,3-二氢-1H-茚-1-羧酸甲酯的制备Step 2: Methyl 1-((2,6-bis(benzyloxy)-5-nitropyrimidin-4-yl)methyl)-2,3-dihydro-1H-indene-1-carboxylate preparation
Figure PCTCN2021138375-appb-000132
Figure PCTCN2021138375-appb-000132
将2,3-二氢-1H-茚-1-羧酸甲酯(1.3克,6.97毫摩尔)溶于无水四氢呋喃(40毫升)中，在-78℃时搅拌缓慢加入LDA(6.97毫摩尔)，并在-78℃继续搅拌30分钟，然后将2,4-双(苄氧基)-6-(溴甲基)-5-硝基嘧啶(中间体A3-2,1.0克,2.32毫摩尔)的四氢呋喃(10毫升)溶液加到反应液中。滴完后，将反应混合物在-78℃继续搅拌0.5小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体1-((2,6-双(苄氧基)-5-硝基嘧啶-4-基)甲基)-2,3-二氢-1H-茚-1-羧酸甲酯(670毫克,55％收率)。MS:526.1(M+H) +。 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. After dropping, the reaction mixture was further stirred at -78°C for 0.5 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid 1-((2,6-bis(benzyloxy)-5- Nitropyrimidin-4-yl)methyl)-2,3-dihydro-1H-indene-1-carboxylic acid methyl ester (670 mg, 55% yield). MS: 526.1 (M+H) + .
步骤3:1-((2,6-二羟基-5-硝基嘧啶-4-基)甲基)-2,3-二氢-1H-茚-1-羧酸甲酯的制备Step 3: Preparation of methyl 1-((2,6-dihydroxy-5-nitropyrimidin-4-yl)methyl)-2,3-dihydro-1H-indene-1-carboxylate
Figure PCTCN2021138375-appb-000133
Figure PCTCN2021138375-appb-000133
将1-((2,6-双(苄氧基)-5-硝基嘧啶-4-基)甲基)-2,3-二氢-1H-茚-1-羧酸甲酯(2.0克,3.81毫摩尔)溶于三氟乙酸(5毫升)中。反应混合物在氮气的保护下缓慢升至100℃并微波条件搅拌1小时，然后反应混合液浓缩，并用乙酸乙酯萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体1-((2,6-二羟基-5-硝基嘧啶-4-基)甲基)-2,3-二氢-1H-茚-1-羧酸甲酯(1.3克, 99％收率)。MS:346.1(M+H) +。 Methyl 1-((2,6-bis(benzyloxy)-5-nitropyrimidin-4-yl)methyl)-2,3-dihydro-1H-indene-1-carboxylate (2.0 g , 3.81 mmol) in trifluoroacetic acid (5 mL). The reaction mixture was slowly warmed to 100°C under nitrogen and stirred under microwave conditions for 1 hour, then the reaction mixture was concentrated and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid 1-((2,6-dihydroxy-5-nitropyrimidine- 4-yl)methyl)-2,3-dihydro-1H-indene-1-carboxylic acid methyl ester (1.3 g, 99% yield). MS: 346.1 (M+H) + .
步骤4:1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-2,3-二氢-1H-茚-1-羧酸甲酯的制备Step 4: Preparation of methyl 1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-2,3-dihydro-1H-indene-1-carboxylate
Figure PCTCN2021138375-appb-000134
Figure PCTCN2021138375-appb-000134
将1-((2,6-二羟基-5-硝基嘧啶-4-基)甲基)-2,3-二氢-1H-茚-1-羧酸甲酯(600毫克,1.738毫摩尔)溶于三氯氧磷(15毫升)中，在0度时搅拌加入DIEA(225毫克，1.73毫摩尔)。反应混合物在氮气的保护下缓慢升至110℃并搅拌6小时，然后反应混合液浓缩，并用二氯甲烷稀释萃取并将溶液倒入饱和碳酸氢钠溶液中搅拌1小时。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色固体1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-2,3-二氢-1H-茚-1-羧酸甲酯(600毫克,90％收率)。MS:383.1(M+H) +。 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give a yellow solid 1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-2,3- Methyl dihydro-1H-indene-1-carboxylate (600 mg, 90% yield). MS: 383.1 (M+H) + .
步骤5:(S)-2-(氰甲基)哌嗪-1-羧酸苄酯的制备Step 5: Preparation of (S)-2-(cyanomethyl)piperazine-1-carboxylic acid benzyl ester
Figure PCTCN2021138375-appb-000135
Figure PCTCN2021138375-appb-000135
将1-苄基4-(叔丁基)(S)-2-(氰基甲基)哌嗪-1,4-二羧酸酯(中间体A10/步骤3,10.0克,27.85毫摩尔)溶于二氯甲烷(10毫升)和三氟乙酸(15毫升)中，反应混合物在室温搅拌2小时。将反应混合液浓缩蒸干，并用乙酸乙酯稀释萃取，有机相用饱和碳酸钠水溶液，饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色固体(S)-2-(氰甲基)哌嗪-1-羧酸苄酯(4.2克,58％收率)。MS:260.1(M+H) +。 1-Benzyl 4-(tert-butyl)(S)-2-(cyanomethyl)piperazine-1,4-dicarboxylate (Intermediate A10/Step 3, 10.0 g, 27.85 mmol) Dissolved in dichloromethane (10 mL) and trifluoroacetic acid (15 mL), the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and evaporated to dryness, diluted and extracted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a yellow solid (S)-2-(cyanomethyl) yl)piperazine-1-carboxylate benzyl ester (4.2 g, 58% yield). MS: 260.1 (M+H) + .
步骤6:(2S)-4-(2-氯-6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯的制备Step 6: (2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-5-nitropyrimidine Preparation of benzyl -4-yl)-2-(cyanomethyl)piperazine-1-carboxylate
Figure PCTCN2021138375-appb-000136
Figure PCTCN2021138375-appb-000136
将1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-2,3-二氢-1H-茚-1-羧酸甲酯(600毫克,1.570毫摩尔)溶于无水二氯甲烷(10毫升)中，在0℃时搅拌缓慢加入(S)-2-(氰甲基)哌嗪-1-羧酸苄酯(814毫克,3.14毫摩尔)。滴完后，将反应混合物在0℃继续搅拌1小时， 然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-4-(2-氯-6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(300毫克,31.6％收率)。MS:606.1(M+H) +。 Methyl 1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-2,3-dihydro-1H-indene-1-carboxylate (600 mg, 1.570 mmol ) was dissolved in dry dichloromethane (10 mL), and (S)-benzyl 2-(cyanomethyl)piperazine-1-carboxylate (814 mg, 3.14 mmol) was slowly added with stirring at 0°C. After dropping, the reaction mixture was further stirred at 0°C for 1 hour, then ice water was added to quench the reaction and diluted with dichloromethane for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2S)-4-(2-chloro-6-((1- (Methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate benzyl acid (300 mg, 31.6% yield). MS: 606.1 (M+H) + .
制备例13中间体A13Preparation Example 13 Intermediate A13
苄基(2S)-4-(2-氯-6-((4-(甲氧羰基)色满-4-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯Benzyl(2S)-4-(2-chloro-6-((4-(methoxycarbonyl)chroman-4-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyano tert-butyl methyl)piperazine-1-carboxylate
Figure PCTCN2021138375-appb-000137
Figure PCTCN2021138375-appb-000137
步骤1:苯并二氢吡喃-4-甲酸甲酯的制备Step 1: Preparation of methyl chroman-4-carboxylate
Figure PCTCN2021138375-appb-000138
Figure PCTCN2021138375-appb-000138
将苯并二氢吡喃-4-甲酸(1克,5.61毫摩尔)溶于无水甲醇(10毫升)中，在0℃时 搅拌缓慢加入氯化亚砜(1.335克,11.22毫摩尔)。滴完后，将反应混合物缓慢升至70℃并继续搅拌1小时。反应完毕后，将反应混合物浓缩并用乙酸乙酯稀释萃取。有机相用饱和碳酸氢钠溶液，饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色油状物苯并二氢吡喃-4-甲酸甲酯(0.6克,55.6％收率)。MS:193.1(M+H) +。 Chromodihydropyran-4-carboxylic acid (1 g, 5.61 mmol) was dissolved in anhydrous methanol (10 mL) and thionyl chloride (1.335 g, 11.22 mmol) was added slowly with stirring at 0°C. 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. The organic phase was washed with saturated sodium bicarbonate solution, saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain chroman-4- as a colorless oil. Methyl formate (0.6 g, 55.6% yield). MS: 193.1 (M+H) + .
步骤2:4-((2,6-二(苄氧基)-5-硝基嘧啶-4-基)甲基)苯并二氢吡喃-4-羧酸甲酯的制备Step 2: Preparation of methyl 4-((2,6-bis(benzyloxy)-5-nitropyrimidin-4-yl)methyl)chroman-4-carboxylate
Figure PCTCN2021138375-appb-000139
Figure PCTCN2021138375-appb-000139
将苯并二氢吡喃-4-甲酸甲酯(300毫克,1.561毫摩尔)溶于无水四氢呋喃(20毫升)中，在-78℃时搅拌缓慢加入LDA(1.87毫摩尔)，并在-78℃继续搅拌30分钟，然后将2,4-双(苄氧基)-6-(溴甲基)-5-硝基嘧啶(中间体A3-2,672毫克,1.561毫摩尔)的四氢呋喃(10毫升)溶液加到反应液中。滴完后，将反应混合物在-78℃继续搅拌0.5小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体4-((2,6-二(苄氧基)-5-硝基嘧啶-4-基)甲基)苯并二氢吡喃-4-羧酸甲酯(420毫克,50％收率)。MS:542.1(M+H) +。 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. After dropping, the reaction mixture was further stirred at -78°C for 0.5 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 4-((2,6-bis(benzyloxy)-5-) as a yellow solid Nitropyrimidin-4-yl)methyl)chroman-4-carboxylate methyl ester (420 mg, 50% yield). MS: 542.1 (M+H) + .
步骤3:4-((2,6-二羟基-5-硝基嘧啶-4-基)甲基)苯并二氢吡喃-4-羧酸甲酯的制备Step 3: Preparation of methyl 4-((2,6-dihydroxy-5-nitropyrimidin-4-yl)methyl)chroman-4-carboxylate
Figure PCTCN2021138375-appb-000140
Figure PCTCN2021138375-appb-000140
将4-((2,6-二(苄氧基)-5-硝基嘧啶-4-基)甲基)苯并二氢吡喃-4-羧酸甲酯(300毫克,0.554毫摩尔)溶于三氟乙酸(5毫升)中。反应混合物在氮气的保护下缓慢升至100℃并微波条件搅拌1小时，然后反应混合液浓缩，并用乙酸乙酯萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体4-((2,6-二羟基-5-硝基嘧啶-4-基)甲基)苯并二氢吡喃-4-羧酸甲酯(194毫克,97％收率)。MS:362.1(M+H) +。 Methyl 4-((2,6-bis(benzyloxy)-5-nitropyrimidin-4-yl)methyl)chroman-4-carboxylate (300 mg, 0.554 mmol) Dissolve in trifluoroacetic acid (5 mL). The reaction mixture was slowly warmed to 100°C under nitrogen and stirred under microwave conditions for 1 hour, then the reaction mixture was concentrated and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid 4-((2,6-dihydroxy-5-nitropyrimidine- 4-yl)methyl)chroman-4-carboxylic acid methyl ester (194 mg, 97% yield). MS: 362.1 (M+H) + .
步骤4:4-((2,6-二氯-5-硝基嘧啶-4-基)甲基)苯并二氢吡喃-4-羧酸甲酯的制备Step 4: Preparation of methyl 4-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)chroman-4-carboxylate
Figure PCTCN2021138375-appb-000141
Figure PCTCN2021138375-appb-000141
将4-((2,6-二羟基-5-硝基嘧啶-4-基)甲基)苯并二氢吡喃-4-羧酸甲酯(280毫克,0.775毫摩尔)溶于三氯氧磷(5毫升)中，在0度时搅拌加入DIEA(100毫克,0.775毫摩尔)。反应混合物在氮气的保护下缓慢升至110℃并搅拌6小时，然后反应混合液浓缩，并用二氯甲烷稀释萃取并将溶液倒入饱和碳酸氢钠溶液中搅拌1小时。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色固体4-((2,6-二氯-5-硝基嘧啶-4-基)甲基)苯并二氢吡喃-4-羧酸甲酯(309毫克,100％收率)。MS:399.1(M+H) +。 Methyl 4-((2,6-dihydroxy-5-nitropyrimidin-4-yl)methyl)chroman-4-carboxylate (280 mg, 0.775 mmol) was dissolved in trichloromethane DIEA (100 mg, 0.775 mmol) was added with stirring at 0 degrees to phosphorous oxide (5 mL). 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give 4-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)benzodihydropyridine as a yellow solid Methyl pyran-4-carboxylate (309 mg, 100% yield). MS: 399.1 (M+H) + .
步骤5:苄基(2S)-4-(2-氯-6-((4-(甲氧羰基)色满-4-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯的制备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
Figure PCTCN2021138375-appb-000142
Figure PCTCN2021138375-appb-000142
将4-((2,6-二氯-5-硝基嘧啶-4-基)甲基)苯并二氢吡喃-4-羧酸甲酯(309毫克,0.776毫摩尔)溶于无水二氯甲烷(10毫升)中，在0℃时搅拌缓慢加入(S)-2-(氰甲基)哌嗪-1-羧酸苄酯(中间体A12/步骤5,402毫克,1.55毫摩尔)。滴完后，将反应混合物在0℃继续搅拌1小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体苄基(2S)-4-(2-氯-6-((4-(甲氧羰基)色满-4-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(120毫克,24.9％收率)。MS:622.1(M+H) +。 Methyl 4-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)chroman-4-carboxylate (309 mg, 0.776 mmol) was dissolved in dry water In dichloromethane (10 mL), (S)-benzyl 2-(cyanomethyl)piperazine-1-carboxylate (Intermediate A12/Step 5, 402 mg, 1.55 mmol) was added slowly at 0 °C with stirring. 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid benzyl(2S)-4-(2-chloro-6-(( 4-(methoxycarbonyl)chroman-4-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (120 mg , 24.9% yield). MS: 622.1 (M+H) + .
制备例14中间体A14Preparation Example 14 Intermediate A14
(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4 -yl)-2-(cyanomethyl)piperazine-1-carboxylate benzyl ester
Figure PCTCN2021138375-appb-000143
Figure PCTCN2021138375-appb-000143
将1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A3/步骤5,1.5克,3.79毫摩尔)溶于无水二氯甲烷(30毫升)中，在0℃时搅拌缓慢加入(S)-2-(氰甲基)哌嗪-1-羧酸苄酯(中间体A12/步骤5,1.96克,7.57毫摩尔)。滴完后，将反应混合物在0℃继续搅拌1小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(1.35克,58％收率)。MS:620.1(M+H) +。 Methyl 1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A3/step 5, 1.5 g, 3.79 mmol) was dissolved in anhydrous dichloromethane (30 mL), and (S)-2-(cyanomethyl)piperazine-1-carboxylate benzyl ester ( Intermediate A12/step 5, 1.96 g, 7.57 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2S)-4-(2-chloro-6-((1- (Methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1- Benzyl carboxylate (1.35 g, 58% yield). MS: 620.1 (M+H) + .
制备例15中间体A15Preparation Example 15 Intermediate A15
(2R)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(羟甲基)哌嗪-1-羧酸叔丁酯(2R)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4 -yl)-2-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000144
Figure PCTCN2021138375-appb-000144
Figure PCTCN2021138375-appb-000145
Figure PCTCN2021138375-appb-000145
将1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A3/步骤5,200毫克,0.51毫摩尔)溶于无水二氯甲烷(5毫升)中，在0℃时搅拌缓慢加入(R)-2-(羟甲基)哌嗪-1-羧酸叔丁酯(164毫克,0.76毫摩尔)。滴完后，将反应混合物在0℃继续搅拌1小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色粉末(2R)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(羟甲基)哌嗪-1-羧酸叔丁酯(180毫克,62％收率)。MS:577.1(M+H) +。 Methyl 1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A3/step 5,200 mg, 0.51 mmol) was dissolved in anhydrous dichloromethane (5 mL), and (R)-2-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester (164) was slowly added with stirring at 0°C. mg, 0.76 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a colorless powder (2R)-4-(2-chloro-6-((1 -(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(hydroxymethyl)piperazine-1- tert-Butyl carboxylate (180 mg, 62% yield). MS: 577.1 (M+H) + .
制备例16中间体A16Preparation Example 16 Intermediate A16
6-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-2-羧酸叔丁酯6-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)- 2,6-Diazaspiro[3.4]octane-2-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000146
Figure PCTCN2021138375-appb-000146
将1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A3/步骤5,200毫克,0.51毫摩尔)溶于无水二氯甲烷(5毫升)中，在0℃时搅拌缓慢加入2,6-二氮杂螺[3.4]辛烷-2-羧酸叔丁酯(107毫克,0.505毫摩尔)。滴完后，将反应混合物在0℃继续搅拌1小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化 得到黄色油状物6-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-2-羧酸叔丁酯(145毫克,51.9％收率)。MS:573.1(M+H) +。 Methyl 1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A3/step 5,200 mg, 0.51 mmol) was dissolved in anhydrous dichloromethane (5 mL), and tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (107 mg, 0.505 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 6-(2-chloro-6-((1-(methoxyl) as a yellow oil. carbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2,6-diazaspiro[3.4]octane-2- tert-Butyl carboxylate (145 mg, 51.9% yield). MS: 573.1 (M+H) + .
制备例17中间体A17Preparation Example 17 Intermediate A17
7-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2,7-二氮杂螺[4.4]壬烷-2-羧酸叔丁酯7-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)- 2,7-Diazaspiro[4.4]nonane-2-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000147
Figure PCTCN2021138375-appb-000147
将1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A3/步骤5,200毫克,0.51毫摩尔)溶于无水二氯甲烷(5毫升)中，在0℃时搅拌缓慢加入2,7-二氮杂螺[4.4]壬烷-2-羧酸叔丁酯(114毫克,0.505毫摩尔)。滴完后，将反应混合物在0℃继续搅拌1小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物7-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2,7-二氮杂螺[4.4]壬烷-2-羧酸叔丁酯(145毫克,49％收率)。MS:587.1(M+H) +。 Methyl 1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A3/step 5,200 mg, 0.51 mmol) was dissolved in anhydrous dichloromethane (5 mL), and tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate (114) was slowly added with stirring at 0 °C. mg, 0.505 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain 7-(2-chloro-6-((1-(methoxyl) as a yellow oil. carbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2- tert-Butyl carboxylate (145 mg, 49% yield). MS: 587.1 (M+H) + .
制备例18中间体A18Preparation Example 18 Intermediate A18
(2S)-2-(氰基甲基)-4-(6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基-2-(吡啶-3-基)嘧啶-4-基)哌嗪-1-羧酸苄酯(2S)-2-(cyanomethyl)-4-(6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5- Benzyl nitro-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-1-carboxylate
Figure PCTCN2021138375-appb-000148
Figure PCTCN2021138375-appb-000148
将(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A14,600毫克,0.969毫摩尔)溶于1，4-二氧六环(10毫升)和水(1毫升)中，在25℃时搅拌缓慢加入吡啶-3-硼酸嚬哪醇酯(397毫克,1.93毫摩尔),Pd(Ph 3P) 4(112毫克,0.097毫摩尔),K 2CO 3(402毫克,2.91毫摩尔)。滴完后，将反应混合物缓慢升至80℃并搅拌3小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-2-(氰基甲基)-4-(6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基-2-(吡啶-3-基)嘧啶-4-基)哌嗪-1-羧酸苄酯(500毫克,78％收率)。MS:662.1(M+H) +。 (2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine- 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate benzyl ester (Intermediate A14, 600 mg, 0.969 mmol) dissolved in 1,4-dioxane (10 mL) and water (1 mL), slowly added with stirring at 25°C pyridine-3-boronic acid chonalyl ester (397 mg, 1.93 mmol), Pd(Ph 3 P) 4 (112 mg, 0.097 mmol), K 2 CO 3 (402 mg, 2.91 mmol). After dropping, the reaction mixture was slowly raised to 80°C and stirred for 3 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2S)-2-(cyanomethyl)-4-(6 -((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitro-2-(pyridin-3-yl)pyrimidin-4-yl ) benzyl piperazine-1-carboxylate (500 mg, 78% yield). MS: 662.1 (M+H) + .
制备例19中间体A19Preparation Example 19 Intermediate A19
(2S)-2-(氰基甲基)-4-(6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(2-甲基吡啶-3-基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯(2S)-2-(cyanomethyl)-4-(6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-2- (2-Methylpyridin-3-yl)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000149
Figure PCTCN2021138375-appb-000149
Figure PCTCN2021138375-appb-000150
Figure PCTCN2021138375-appb-000150
将(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A14,100毫克,0.162毫摩尔)溶于1，4-二氧六环(10毫升)和水(1毫升)中，在25℃时搅拌缓慢加入2-甲基-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶(71毫克,0.323毫摩尔),Pd(Ph 3P) 4(18.7毫克,0.016毫摩尔),K 2CO 3(67毫克,0.485毫摩尔)。滴完后，将反应混合物缓慢升至80℃并搅拌3小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-2-(氰基甲基)-4-(6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(2-甲基吡啶-3-基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯(100毫克,92％收率)。MS:676.1(M+H) +。 (2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine- 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate benzyl ester (Intermediate A14, 100 mg, 0.162 mmol) dissolved in 1,4-dioxane (10 mL) and water (1 mL), slowly add 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboropenan-2-yl)pyridine with stirring at 25°C (71 mg, 0.323 mmol), Pd(Ph3P )4 ( 18.7 mg, 0.016 mmol), K2CO3 ( 67 mg , 0.485 mmol). After dropping, the reaction mixture was slowly raised to 80°C and stirred for 3 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2S)-2-(cyanomethyl)-4-(6 -((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-2-(2-methylpyridin-3-yl)-5-nitropyrimidine -4-yl)piperazine-1-carboxylate tert-butyl ester (100 mg, 92% yield). MS: 676.1 (M+H) + .
制备例20中间体B1Preparation Example 20 Intermediate B1
2-氟丙烯酰氯2-Fluoroacryloyl chloride
Figure PCTCN2021138375-appb-000151
Figure PCTCN2021138375-appb-000151
将2-氟丙烯酸(50毫克,0.555毫摩尔)溶于无水二氯甲烷(3毫升)中，在0℃时搅拌缓慢加入草酰氯(106毫克,0.833毫摩尔)。滴完后，将反应混合物在0℃继续搅拌1小时，反应完毕后，将反应液直接用于下一步反应。2-Fluoroacrylic acid (50 mg, 0.555 mmol) was dissolved in dry dichloromethane (3 mL) and oxalyl chloride (106 mg, 0.833 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.
制备例21中间体B2Preparation Example 21 Intermediate B2
丁-2-炔酰氯But-2-ynoyl chloride
Figure PCTCN2021138375-appb-000152
Figure PCTCN2021138375-appb-000152
Figure PCTCN2021138375-appb-000153
Figure PCTCN2021138375-appb-000153
将丁-2-炔酸(300毫克,3.57毫摩尔)溶于无水二氯甲烷(3毫升)中，在0℃时搅拌缓慢加入草酰氯(679毫克,5.35毫摩尔)。滴完后，将反应混合物在0℃继续搅拌1小时，反应完毕后，将反应液直接用于下一步反应。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.
制备例22中间体B3Preparation Example 22 Intermediate B3
(E)-4,4,4-三氟丁-2-烯酰氯(E)-4,4,4-Trifluorobut-2-enoyl chloride
Figure PCTCN2021138375-appb-000154
Figure PCTCN2021138375-appb-000154
将(E)-4,4,4-三氟丁-2-烯酸(200毫克,1.428毫摩尔)溶于无水二氯甲烷(3毫升)中，在0℃时搅拌缓慢加入草酰氯(544毫克,4.28毫摩尔)。滴完后，将反应混合物在0℃继续搅拌1小时，反应完毕后，将反应液直接用于下一步反应。(E)-4,4,4-trifluorobut-2-enoic acid (200 mg, 1.428 mmol) was dissolved in dry dichloromethane (3 mL), and oxalyl chloride ( 544 mg, 4.28 mmol). 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.
制备例23中间体B4Preparation Example 23 Intermediate B4
(E)-4-甲氧基丁-2-烯酰氯(E)-4-Methoxybut-2-enoyl chloride
Figure PCTCN2021138375-appb-000155
Figure PCTCN2021138375-appb-000155
将(E)-4-甲氧基丁-2-烯酸(200毫克,1.722毫摩尔)溶于无水二氯甲烷(3毫升)中，在0℃时搅拌缓慢加入草酰氯(219毫克,1.722毫摩尔)。滴完后，将反应混合物在0℃继续搅拌1小时，反应完毕后，将反应液直接用于下一步反应。(E)-4-Methoxybut-2-enoic acid (200 mg, 1.722 mmol) was dissolved in dry dichloromethane (3 mL), and oxalyl chloride (219 mg, 1.722 mmol). 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.
制备例24中间体B5Preparation Example 24 Intermediate B5
(E)-4-氟丁-2-烯酰氯(E)-4-Fluorobut-2-enoyl chloride
Figure PCTCN2021138375-appb-000156
Figure PCTCN2021138375-appb-000156
Figure PCTCN2021138375-appb-000157
Figure PCTCN2021138375-appb-000157
步骤1:(E)-4-氟丁-2-烯酸甲酯的制备Step 1: Preparation of (E)-methyl 4-fluorobut-2-enoate
Figure PCTCN2021138375-appb-000158
Figure PCTCN2021138375-appb-000158
将氟化银(4.25克,33.5毫摩尔)溶于乙腈(20毫升)中，在0℃时搅拌缓慢加入(E)-4-溴丁-2-烯酸甲酯(2克,11.17毫摩尔)的乙腈(50毫升)溶液。滴完后，将反应混合物在20℃避光继续搅拌48小时，然后蒸干溶剂，并用二氯甲烷稀释萃取。有机相用饱和碳酸氢钠溶液，饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到(E)-4-氟丁-2-烯酸甲酯(1.2克,91％收率)。Silver fluoride (4.25 g, 33.5 mmol) was dissolved in acetonitrile (20 mL), and (E)-methyl 4-bromobut-2-enoate (2 g, 11.17 mmol) was added slowly with stirring at 0 °C ) in acetonitrile (50 mL). After dropping, the reaction mixture was further stirred at 20°C in the dark for 48 hours, then the solvent was evaporated to dryness, and the mixture was diluted with dichloromethane for extraction. The organic phase was washed with saturated sodium bicarbonate solution, saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give (E)-methyl 4-fluorobut-2-enoate (1.2 g, 91% yield).
步骤2:(E)-4-氟丁-2-烯酸的制备Step 2: Preparation of (E)-4-fluorobut-2-enoic acid
Figure PCTCN2021138375-appb-000159
Figure PCTCN2021138375-appb-000159
将(E)-4-氟丁-2-烯酸甲酯(1.2克,10.16毫摩尔)溶于四氢呋喃(30毫升)中，在0℃时搅拌缓慢加入氢氧化锂(1.217克,50.8毫摩尔)的水(30毫升)溶液。滴完后，将反应混合物在20℃继续搅拌4小时，然后蒸干溶剂，并用二氯甲烷稀释萃取。有机相用稀盐酸溶液，饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色固体(E)-4-氟丁-2-烯酸(560毫克,53％收率)。Methyl (E)-4-fluorobut-2-enoate (1.2 g, 10.16 mmol) was dissolved in tetrahydrofuran (30 mL), and lithium hydroxide (1.217 g, 50.8 mmol) was slowly added with stirring at 0 °C. ) in water (30 mL). After dropping, the reaction mixture was further stirred at 20°C for 4 hours, then the solvent was evaporated to dryness and extracted with dichloromethane. The organic phase was washed with dilute hydrochloric acid solution, saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give (E)-4-fluorobut-2-enoic acid (560 mg, 53% yield) as a yellow solid.
步骤3:(E)-4-氟丁-2-烯酰氯的制备Step 3: Preparation of (E)-4-fluorobut-2-enoyl chloride
Figure PCTCN2021138375-appb-000160
Figure PCTCN2021138375-appb-000160
将(E)-4-氟丁-2-烯酸(208毫克,2毫摩尔)溶于无水二氯甲烷(3毫升)中，在0℃时搅拌缓慢加入草酰氯(219毫克,1.722毫摩尔)。滴完后，将反应混合物在0℃继续搅拌1小时，反应完毕后，将反应液直接用于下一步反应。(E)-4-Fluorobut-2-enoic acid (208 mg, 2 mmol) was dissolved in dry dichloromethane (3 mL), and oxalyl chloride (219 mg, 1.722 mmol) was slowly added with stirring at 0°C Moore). After dropping, the reaction mixture was continued to be stirred at 0° C. for 1 hour, and after the completion of the reaction, the reaction solution was directly used for the next reaction.
制备例25中间体C1Preparation Example 25 Intermediate C1
((2S，4S)-4-氟-1-甲基吡咯烷-2-基)甲醇((2S,4S)-4-Fluoro-1-methylpyrrolidin-2-yl)methanol
Figure PCTCN2021138375-appb-000161
Figure PCTCN2021138375-appb-000161
Figure PCTCN2021138375-appb-000162
Figure PCTCN2021138375-appb-000162
将1-(叔丁基)2-甲基(2S，4S)-4-氟吡咯烷-1,2-二羧酸酯(10克,40.4毫摩尔)溶于无水四氢呋喃(100毫升)中，在0℃时搅拌缓慢加入LAH溶液(162毫摩尔)。滴完后，将反应混合物缓慢升至室温并继续搅拌16小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物((2S，4S)-4-氟-1-甲基吡咯烷-2-基)甲醇(2.2克,40％收率)。MS:134.1(M+H) +。 1-(tert-Butyl) 2-methyl(2S,4S)-4-fluoropyrrolidine-1,2-dicarboxylate (10 g, 40.4 mmol) was dissolved in dry tetrahydrofuran (100 mL) , LAH solution (162 mmol) was slowly added with stirring at 0°C. After dropping, the reaction mixture was slowly warmed to room temperature and continued to stir for 16 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain ((2S,4S)-4-fluoro-1-methylpyrrole as a yellow oil Alk-2-yl)methanol (2.2 g, 40% yield). MS: 134.1 (M+H) + .
制备例26中间体C2Preparation Example 26 Intermediate C2
((2S，4R)-4-甲氧基-1-甲基吡咯烷-2-基)甲醇((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methanol
Figure PCTCN2021138375-appb-000163
Figure PCTCN2021138375-appb-000163
步骤1:1-(叔丁基)2-甲基(2S，4R)-4-甲氧基吡咯烷-1,2-二羧酸酯的制备Step 1: Preparation of 1-(tert-butyl) 2-methyl(2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylate
Figure PCTCN2021138375-appb-000164
Figure PCTCN2021138375-appb-000164
将1-(叔丁基)2-甲基(2S，4R)-4-羟基吡咯烷-1,2-二羧酸酯(5克,20.39毫摩尔)溶于无水乙腈(130毫升)中，在0℃时搅拌缓慢加入氧化银(14.17克,61.2毫摩尔)和碘甲烷(28.9克,204毫摩尔)。滴完后，将反应混合物缓慢升至室温并继续搅拌24小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体1-(叔丁基)2-甲基(2S，4R)-4-甲氧基吡咯烷-1,2-二羧酸酯(3.1克,59.6％收率)。MS:260.1(M+H) +。 1-(tert-Butyl) 2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (5 g, 20.39 mmol) was dissolved in dry acetonitrile (130 mL) , Ag oxide (14.17 g, 61.2 mmol) and iodomethane (28.9 g, 204 mmol) were slowly added with stirring at 0 °C. After dropping, the reaction mixture was slowly warmed to room temperature and continued to be stirred for 24 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid 1-(tert-butyl)2-methyl(2S,4R)- 4-Methoxypyrrolidine-1,2-dicarboxylate (3.1 g, 59.6% yield). MS: 260.1 (M+H) + .
步骤2:((2S，4R)-4-甲氧基-1-甲基吡咯烷-2-基)甲醇的制备Step 2: Preparation of ((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methanol
Figure PCTCN2021138375-appb-000165
Figure PCTCN2021138375-appb-000165
将1-(叔丁基)2-甲基(2S，4R)-4-甲氧基吡咯烷-1,2-二羧酸酯(3.2克,12.34毫摩尔)溶于无水四氢呋喃(80毫升)中，在0℃时搅拌缓慢加入LAH溶液(62毫摩尔)。 滴完后，将反应混合物缓慢升至室温并继续搅拌16小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物(620毫克,24.6％收率)。MS:146.1(M+H) +。 1-(tert-Butyl) 2-methyl(2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylate (3.2 g, 12.34 mmol) was dissolved in dry tetrahydrofuran (80 mL) ), LAH solution (62 mmol) was slowly added with stirring at 0°C. After dropping, the reaction mixture was slowly warmed to room temperature and continued to stir for 16 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give a yellow oil (620 mg, 24.6% yield). MS: 146.1 (M+H) + .
制备例27中间体C3Preparation Example 27 Intermediate C3
((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇((2S,4R)-4-Fluoro-1-methylpyrrolidin-2-yl)methanol
Figure PCTCN2021138375-appb-000166
Figure PCTCN2021138375-appb-000166
将1-(叔丁基)2-甲基(2S，4R)-4-氟吡咯烷-1,2-二羧酸酯(10克,40.4毫摩尔)溶于无水四氢呋喃(100毫升)中，在0℃时搅拌缓慢加入LAH溶液(162毫摩尔)。滴完后，将反应混合物缓慢升至室温并继续搅拌16小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(4.3克,80％收率)。MS:134.1(M+H) +。 1-(tert-Butyl) 2-methyl(2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate (10 g, 40.4 mmol) was dissolved in dry tetrahydrofuran (100 mL) , LAH solution (162 mmol) was slowly added with stirring at 0°C. After dropping, the reaction mixture was slowly warmed to room temperature and continued to stir for 16 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain ((2S,4R)-4-fluoro-1-methylpyrrole as a yellow oil Alk-2-yl)methanol (4.3 g, 80% yield). MS: 134.1 (M+H) + .
制备例28中间体C4Preparation Example 28 Intermediate C4
(3R，4R)-4-甲氧基-1-甲基吡咯烷-3-醇(3R,4R)-4-methoxy-1-methylpyrrolidin-3-ol
Figure PCTCN2021138375-appb-000167
Figure PCTCN2021138375-appb-000167
将(3R，4R)-3-羟基-4-甲氧基吡咯烷-1-羧酸叔丁酯(500毫克,2.301毫摩尔)溶于无水四氢呋喃(10毫升)中，在0℃时搅拌缓慢加入LAH溶液(4.6毫摩尔)。滴完后，将反应混合物缓慢升至室温并继续搅拌16小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物(3R，4R)-4-甲氧基-1-甲基吡咯烷-3-醇(260毫克,86％收率)。MS:132.1(M+H) +。 (3R,4R)-tert-butyl 3-hydroxy-4-methoxypyrrolidine-1-carboxylate (500 mg, 2.301 mmol) was dissolved in dry tetrahydrofuran (10 mL) and stirred at 0 °C LAH solution (4.6 mmol) was added slowly. After dropping, the reaction mixture was slowly warmed to room temperature and continued to stir for 16 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain (3R, 4R)-4-methoxy-1-methyl as a yellow oil. Pyrrolidin-3-ol (260 mg, 86% yield). MS: 132.1 (M+H) + .
制备例29中间体C5Preparation Example 29 Intermediate C5
(S)-(1-甲基吡咯烷-2-基)甲硫醇(S)-(1-Methylpyrrolidin-2-yl)methanethiol
Figure PCTCN2021138375-appb-000168
Figure PCTCN2021138375-appb-000168
步骤1:(S)-(1-甲基吡咯烷-2-基)甲基磺酸甲酯的制备Step 1: Preparation of (S)-(1-methylpyrrolidin-2-yl)methyl methanesulfonate
Figure PCTCN2021138375-appb-000169
Figure PCTCN2021138375-appb-000169
将(S)-(1-甲基吡咯烷-2-基)甲醇(2克,17.36毫摩尔)和TEA(5.27克,52.1毫摩尔)溶于无水二氯甲烷(100毫升)中，在0℃时搅拌缓慢加入甲磺酰氯(2.387克,20.84毫摩尔)。滴完后，将反应混合物在0℃继续搅拌3小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物(S)-(1-甲基吡咯烷-2-基)甲基磺酸甲酯(3.1克,92％收率)。MS:194.1(M+H) +。 (S)-(1-Methylpyrrolidin-2-yl)methanol (2 g, 17.36 mmol) and TEA (5.27 g, 52.1 mmol) were dissolved in dry dichloromethane (100 mL) in Methanesulfonyl chloride (2.387 g, 20.84 mmol) was added slowly with stirring at 0°C. After dropping, the reaction mixture was further stirred at 0°C for 3 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain (S)-(1-methylpyrrolidin-2-yl) as a yellow oil. Methyl methanesulfonate (3.1 g, 92% yield). MS: 194.1 (M+H) + .
步骤2:(S)-S-((1-甲基吡咯烷-2-基)甲基)乙硫醇酸酯的制备Step 2: Preparation of (S)-S-((1-methylpyrrolidin-2-yl)methyl)ethanethiolate
Figure PCTCN2021138375-appb-000170
Figure PCTCN2021138375-appb-000170
将(S)-(1-甲基吡咯烷-2-基)甲基磺酸甲酯(3.2克,16.56毫摩尔)溶于无水DMF(10毫升)中，在20℃时加入硫代乙酸钾(2.08克,18.21毫摩尔)。滴完后，将反应混合物在65℃继续搅拌13小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到橙色油状物(S)-S-((1-甲基吡咯烷-2-基)甲基)乙硫醇酸酯(2.6克,91％收率)。MS:174.1(M+H) +。 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain an orange oil (S)-S-((1-methylpyrrolidine-2 -yl)methyl)ethanethiolate (2.6 g, 91% yield). MS: 174.1 (M+H) + .
步骤3:(S)-(1-甲基吡咯烷-2-基)甲硫醇的制备Step 3: Preparation of (S)-(1-methylpyrrolidin-2-yl)methanethiol
Figure PCTCN2021138375-appb-000171
Figure PCTCN2021138375-appb-000171
将(S)-S-((1-甲基吡咯烷-2-基)甲基)乙硫醇酸酯(2.6克,15.01毫摩尔)溶于甲醇(40毫升)中，在20℃时加入氢氧化钠(1.8克，45毫摩尔)。滴完后，将反应混合物在25℃继续搅拌13小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色油状物(S)-(1-甲基吡咯烷-2-基)甲硫醇(620毫克,31.5％收率)。MS:132.1(M+H) +。 (S)-S-((1-methylpyrrolidin-2-yl)methyl)ethanethiolate (2.6 g, 15.01 mmol) was dissolved in methanol (40 mL) and added at 20 °C Sodium hydroxide (1.8 g, 45 mmol). After dropping, the reaction mixture was further stirred at 25°C for 13 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give (S)-(1-methylpyrrolidin-2-yl)methanethiol (620 mg, 31.5% yield) as a yellow oil. . MS: 132.1 (M+H) + .
制备例30中间体A20Preparation Example 30 Intermediate A20
(2S，5R)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)-5-甲基哌嗪-1-羧酸苄酯(2S,5R)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine -4-yl)-2-(cyanomethyl)-5-methylpiperazine-1-carboxylate benzyl ester
Figure PCTCN2021138375-appb-000172
Figure PCTCN2021138375-appb-000172
步骤1:((苄氧基)羰基)-L-丝氨酸-L-丙氨酸甲酯的制备Step 1: Preparation of ((benzyloxy)carbonyl)-L-serine-L-alanine methyl ester
Figure PCTCN2021138375-appb-000173
Figure PCTCN2021138375-appb-000173
将D-丙氨酸甲酯(25克,179.11毫摩尔)和((苄氧基)羰基)-L-丝氨酸(42.8克,179.11毫摩尔)溶于二氯甲烷(780毫升)中，在0℃时搅拌缓慢加入EDCI(41.2克,214.93毫摩尔)和DIEA(109毫升,626.89毫摩尔)。滴完后，将反应混合物在10℃搅拌12小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到白色固体((苄氧基)羰基)-L-丝氨酸-L-丙氨酸甲酯(44.9克,77％收率)。MS:325.1(M+H) +。 D-Alanine methyl ester (25 g, 179.11 mmol) and ((benzyloxy)carbonyl)-L-serine (42.8 g, 179.11 mmol) were dissolved in dichloromethane (780 mL) at 0 EDCI (41.2 g, 214.93 mmol) and DIEA (109 mL, 626.89 mmol) were added slowly at °C with stirring. After completion of dropping, the reaction mixture was stirred at 10°C for 12 hours, then ice-water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give ((benzyloxy)carbonyl)-L-serine-L-alanine methyl ester (44.9 g, 77% yield) as a white solid . MS: 325.1 (M+H) + .
步骤2:(3S,6R)-3-(羟甲基)-6-甲基哌嗪-2,5-二酮的制备Step 2: Preparation of (3S,6R)-3-(hydroxymethyl)-6-methylpiperazine-2,5-dione
Figure PCTCN2021138375-appb-000174
Figure PCTCN2021138375-appb-000174
将((苄氧基)羰基)-L-丝氨酸-L-丙氨酸甲酯(22.4克,69.07毫摩尔)溶于甲醇(70毫升)和环己烯(45毫升)中，在搅拌条件下向反应混合物中加入钯碳(1.15克)。反应混合物在氢气作用下70℃搅拌12小时，然后将混合物溶液过滤。将滤液真空浓缩，得到灰色固体(3S,6R)-3-(羟甲基)-6-甲基哌嗪-2,5-二酮(7.9克,72.3％收率)。 1H NMR(400MHz,DMSO)δ8.09(s,1H),7.91(s,1H),5.12(t,J＝5.2Hz,1H),3.92–3.87(m,1H),3.74–3.70(m,1H),3.68–3.62(m,1H),3.52–3.48(m,1H),1.23–1.19(m,3H)。 ((benzyloxy)carbonyl)-L-serine-L-alanine methyl ester (22.4 g, 69.07 mmol) was dissolved in methanol (70 mL) and cyclohexene (45 mL) with stirring Palladium on carbon (1.15 g) was added to the reaction mixture. The reaction mixture was stirred at 70°C for 12 hours under the influence of hydrogen, and then the mixture solution was filtered. The filtrate was concentrated in vacuo to give (3S,6R)-3-(hydroxymethyl)-6-methylpiperazine-2,5-dione (7.9 g, 72.3% yield) as a grey solid. 1 H NMR(400MHz,DMSO)δ8.09(s,1H),7.91(s,1H),5.12(t,J=5.2Hz,1H),3.92-3.87(m,1H),3.74-3.70(m , 1H), 3.68–3.62 (m, 1H), 3.52–3.48 (m, 1H), 1.23–1.19 (m, 3H).
步骤3:((2R，5R)-5-甲基哌嗪-2-基)甲醇的制备Step 3: Preparation of ((2R,5R)-5-methylpiperazin-2-yl)methanol
Figure PCTCN2021138375-appb-000175
Figure PCTCN2021138375-appb-000175
将(3S,6R)-3-(羟甲基)-6-甲基哌嗪-2,5-二酮(7.9克,50毫摩尔)溶于无水四氢呋喃(150毫升)中，在0℃时搅拌缓慢加入硼烷的四氢呋喃溶液(1M,375毫升)。滴完后，将反应混合物缓慢升至70℃并继续搅拌16小时，然后加入甲醇淬灭反应，然后加入5M的盐酸水溶(27毫升)，将反应混合物缓慢升至70℃并继续搅拌2小时，冷却，析出固体，然后过滤，干燥得到灰色固体((2R,5R)-5-甲基哌嗪-2-基)甲醇(5.2克,80.8％收率)。 1H NMR(400MHz,DMSO)δ9.90(s,2H),5.61(s,1H),3.75–3.40(m,6H),3.18–3.02(m,2H),1.31–1.28(m,3H)。 (3S,6R)-3-(hydroxymethyl)-6-methylpiperazine-2,5-dione (7.9 g, 50 mmol) was dissolved in dry tetrahydrofuran (150 mL) at 0 °C A solution of borane in tetrahydrofuran (1 M, 375 mL) was added slowly with stirring. After dropping, the reaction mixture was slowly raised to 70°C and stirred for 16 hours, then methanol was added to quench the reaction, then 5M hydrochloric acid was added in water (27 mL), the reaction mixture was slowly raised to 70°C and stirred for 2 hours, Cool to precipitate a solid, then filter and dry to give ((2R,5R)-5-methylpiperazin-2-yl)methanol (5.2 g, 80.8% yield) as a grey solid. 1 H NMR(400MHz, DMSO)δ9.90(s,2H),5.61(s,1H),3.75-3.40(m,6H),3.18-3.02(m,2H),1.31-1.28(m,3H) .
步骤4:(2R，5R)-5-(羟甲基)-2-甲基哌嗪-1-羧酸叔丁酯的制备Step 4: Preparation of (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester
Figure PCTCN2021138375-appb-000176
Figure PCTCN2021138375-appb-000176
将((2R,5R)-5-甲基哌嗪-2-基)甲醇(6.1克,30.03毫摩尔)溶于甲醇(50毫升)中，在0℃时搅拌缓慢加入二乙胺(9.43克,93.21毫摩尔,13毫升)和Boc 2O(13.8克,63.23毫摩尔)。滴完后，将反应混合物在50℃并搅拌12小时，然后将反应液浓缩蒸干，浓缩物溶于乙醇(100毫升)中，将1.5M的NaOH水溶液(100毫升)加到上述溶液中，并在100℃搅拌12小时。将反应液冷却并用2M的盐酸溶液调pH值到9,并用二氯甲烷稀释萃取。有机相用饱和碳酸氢钠水溶液，饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色固体(2R，5R)-5-(羟甲基)-2-甲基哌嗪-1-羧酸叔丁酯(6克,86.5％收率)。MS:231.1(M+H) +。 ((2R,5R)-5-methylpiperazin-2-yl)methanol (6.1 g, 30.03 mmol) was dissolved in methanol (50 mL), and diethylamine (9.43 g) was slowly added with stirring at 0°C , 93.21 mmol, 13 mL) and Boc 2 O (13.8 g, 63.23 mmol). After dropping, the reaction mixture was stirred at 50°C for 12 hours, then the reaction solution was concentrated and evaporated to dryness, the concentrate was dissolved in ethanol (100 mL), and a 1.5M aqueous NaOH solution (100 mL) was added to the above solution, and stirred at 100°C for 12 hours. The reaction solution was cooled and adjusted to pH 9 with 2M hydrochloric acid solution, and extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium bicarbonate solution, saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give a yellow solid (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1- tert-Butyl carboxylate (6 g, 86.5% yield). MS: 231.1 (M+H) + .
步骤5:1-苄基4-(叔丁基)(2R，5R)-2-(羟甲基)-5-甲基哌嗪-1,4-二羧酸酯Step 5: 1-Benzyl 4-(tert-butyl)(2R,5R)-2-(hydroxymethyl)-5-methylpiperazine-1,4-dicarboxylate
Figure PCTCN2021138375-appb-000177
Figure PCTCN2021138375-appb-000177
将(2R，5R)-5-(羟甲基)-2-甲基哌嗪-1-羧酸叔丁酯(7.1克,30.8毫摩尔)溶于二氯甲烷(80毫升)中，在0℃时搅拌缓慢加入DIEA(4.38克,33.91毫摩尔,5.91毫升)和CbzCl(5.52克,32.37毫摩尔)。滴完后，将反应混合物在10℃搅拌12小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色油状物1-苄基4-(叔丁基)(2R，5R)-2-(羟甲基)-5-甲基哌嗪-1,4-二羧酸酯(8.9克,79.2％收率)。MS:265.1(M+H) +。 (2R,5R)-tert-butyl 5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate (7.1 g, 30.8 mmol) was dissolved in dichloromethane (80 mL) at 0 DIEA (4.38 g, 33.91 mmol, 5.91 mL) and CbzCl (5.52 g, 32.37 mmol) were slowly added with stirring at °C. After completion of dropping, the reaction mixture was stirred at 10°C for 12 hours, then ice-water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 1-benzyl 4-(tert-butyl) (2R, 5R) as a colorless oil. )-2-(hydroxymethyl)-5-methylpiperazine-1,4-dicarboxylate (8.9 g, 79.2% yield). MS: 265.1 (M+H) + .
步骤6:1-苄基4-(叔丁基)(2R，5R)-5-甲基-2-((甲基磺酰基)氧基)甲基)哌嗪-1,4-二羧酸酯的制备Step 6: 1-Benzyl 4-(tert-butyl)(2R,5R)-5-methyl-2-((methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylic acid Preparation of esters
Figure PCTCN2021138375-appb-000178
Figure PCTCN2021138375-appb-000178
将1-苄基4-(叔丁基)(2R，5R)-2-(羟甲基)-5-甲基哌嗪-1,4-二羧酸酯(8.9克,24.42毫摩尔)溶于二氯甲烷(30毫升)中，在0℃时搅拌缓慢加入DIEA(6.31克,48.84毫摩尔,8.51毫升)和MsCl(4.20克,36.63毫摩尔)。滴完后，将反应混合物在0℃搅拌2 小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色油状物1-苄基4-(叔丁基)(2R，5R)-5-甲基-2-((甲基磺酰基)氧基)甲基)哌嗪-1,4-二羧酸酯(10.8克,100％收率)。Dissolve 1-benzyl 4-(tert-butyl)(2R,5R)-2-(hydroxymethyl)-5-methylpiperazine-1,4-dicarboxylate (8.9 g, 24.42 mmol) In dichloromethane (30 mL), DIEA (6.31 g, 48.84 mmol, 8.51 mL) and MsCl (4.20 g, 36.63 mmol) were slowly added with stirring at 0 °C. After dropping, the reaction mixture was stirred at 0°C for 2 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give 1-benzyl 4-(tert-butyl)(2R,5R)-5-methyl-2-((methyl) as a yellow oil. Sulfonyl)oxy)methyl)piperazine-1,4-dicarboxylate (10.8 g, 100% yield).
步骤7:1-苄基4-(叔丁基)(2S,5R)-2-(氰基甲基)-5-甲基哌嗪-1,4-二羧酸酯的制备Step 7: Preparation of 1-benzyl 4-(tert-butyl)(2S,5R)-2-(cyanomethyl)-5-methylpiperazine-1,4-dicarboxylate
Figure PCTCN2021138375-appb-000179
Figure PCTCN2021138375-appb-000179
将1-苄基4-(叔丁基)(2R,5R)-5-甲基-2-((甲基磺酰基)氧基)甲基)哌嗪-1,4-二羧酸酯(10.8克,24.41毫摩尔)溶于DMA(100毫升)中，在20℃时搅拌缓慢加入氰化钾(4.77克,73.22毫摩尔)。加完后，将反应混合物在80℃搅拌12小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物1-苄基4-(叔丁基)(2S,5R)-2-(氰基甲基)-5-甲基哌嗪-1,4-二羧酸酯(5.0克,54.8％收率)。MS:374.1&318.1(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.36(dd,J＝10.3,4.6Hz,5H),5.25–5.07(m,2H),4.69–4.05(m,2H),4.05–3.68(m,2H),3.39–3.05(m,2H),2.79–2.44(m,2H),1.48(s,9H),1.15(s,3H)。 1-Benzyl 4-(tert-butyl)(2R,5R)-5-methyl-2-((methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylate ( 10.8 g, 24.41 mmol) was dissolved in DMA (100 mL) and potassium cyanide (4.77 g, 73.22 mmol) was added slowly with stirring at 20°C. After the addition was complete, the reaction mixture was stirred at 80°C for 12 hours, then quenched by the addition of ice water, and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 1-benzyl 4-(tert-butyl)(2S,5R) as a yellow oil. -2-(cyanomethyl)-5-methylpiperazine-1,4-dicarboxylate (5.0 g, 54.8% yield). MS: 374.1 & 318.1 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.36 (dd, J=10.3, 4.6 Hz, 5H), 5.25-5.07 (m, 2H), 4.69-4.05 (m, 2H), 4.05-3.68 (m, 2H) ), 3.39–3.05 (m, 2H), 2.79–2.44 (m, 2H), 1.48 (s, 9H), 1.15 (s, 3H).
步骤8:(2S，5R)-2-(氰甲基)-5-甲基哌嗪-1-羧酸苄酯的制备Step 8: Preparation of (2S,5R)-2-(cyanomethyl)-5-methylpiperazine-1-carboxylic acid benzyl ester
Figure PCTCN2021138375-appb-000180
Figure PCTCN2021138375-appb-000180
将1-苄基4-(叔丁基)(2S,5R)-2-(氰基甲基)-5-甲基哌嗪-1,4-二羧酸酯(2.5克,6.69毫摩尔)溶于二氧六环(10毫升)中，在0℃时搅拌缓慢加入二氧六环的氯化氢溶液(1.0M,10毫升)。加完后，将反应混合物在20℃搅拌2小时，然后将反应液浓缩蒸干，并用乙酸乙酯稀释萃取。有机相用饱和碳酸氢钠溶液，饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色油状物(2S，5R)-2-(氰甲基)-5-甲基哌嗪-1-羧酸苄酯(1.8克,100％收率)。MS:274.1(M+H) +。 1-Benzyl 4-(tert-butyl)(2S,5R)-2-(cyanomethyl)-5-methylpiperazine-1,4-dicarboxylate (2.5 g, 6.69 mmol) Dissolved in dioxane (10 mL), dioxane in hydrogen chloride (1.0 M, 10 mL) was slowly added with stirring at 0°C. After the addition, the reaction mixture was stirred at 20°C for 2 hours, then the reaction solution was concentrated and evaporated to dryness, and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give (2S,5R)-2-(cyanomethyl)-5-methylpiperazine-1 as a yellow oil - Benzyl carboxylate (1.8 g, 100% yield). MS: 274.1 (M+H) + .
步骤9:(2S，5R)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)-5-甲基哌嗪-1-羧酸苄酯的制备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
Figure PCTCN2021138375-appb-000181
Figure PCTCN2021138375-appb-000181
将1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A3/步骤5,200毫克,0.505毫摩尔)溶于无水二氯甲烷(10毫升)中，在0度时搅拌缓慢加入(2S，5R)-2-(氰甲基)-5-甲基哌嗪-1-羧酸苄酯(138毫克,0.505毫摩尔)。滴完后，将反应混合物在0度继续搅拌1小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S,5R)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)-5-甲基哌嗪-1-羧酸苄酯(200毫克,62.6％收率)。MS:633.1(M+H) +。 Methyl 1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A3/step 5,200 mg, 0.505 mmol) was dissolved in anhydrous dichloromethane (10 mL), and (2S,5R)-2-(cyanomethyl)-5-methylpiperazine-1- Benzyl carboxylate (138 mg, 0.505 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2S,5R)-4-(2-chloro-6-(( 1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)-5- Benzyl methylpiperazine-1-carboxylate (200 mg, 62.6% yield). MS: 633.1 (M+H) + .
制备例31中间体A21Preparation Example 31 Intermediate A21
(2S)-4-(2-氯-6-((7-氯-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((7-Chloro-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitro pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000182
Figure PCTCN2021138375-appb-000182
Figure PCTCN2021138375-appb-000183
Figure PCTCN2021138375-appb-000183
步骤1:(E)-7-氯-1-(甲氧基亚甲基)-1,2,3,4-四氢萘的制备Step 1: Preparation of (E)-7-chloro-1-(methoxymethylene)-1,2,3,4-tetrahydronaphthalene
Figure PCTCN2021138375-appb-000184
Figure PCTCN2021138375-appb-000184
将Ph 3PCH 2OMeCl(83.5克,243.6毫摩尔)溶于无水四氢呋喃(400毫升)中，在0度时搅拌缓慢加入叔丁醇钾(24.9克,221.5毫摩尔)。滴完后，将反应混合物在0度继续搅拌1小时，将6-氯-3,4-二氢萘-1(2H)-酮(20.0克,110.7毫摩尔)的四氢呋喃(100毫升)溶液加到上述反应液中，将反应混合物在20度继续搅拌12小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(E)-7-氯-1-(甲氧基亚甲基)-1,2,3,4-四氢萘(32克粗品)。 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (E)-7-chloro-1-(methoxymethylene )-1,2,3,4-tetrahydronaphthalene (32 g crude).
步骤2:7-氯-1,2,3,4-四氢萘-1-乙醛的制备Step 2: Preparation of 7-chloro-1,2,3,4-tetrahydronaphthalene-1-acetaldehyde
Figure PCTCN2021138375-appb-000185
Figure PCTCN2021138375-appb-000185
将(E)-7-氯-1-(甲氧基亚甲基)-1,2,3,4-四氢萘(32.0克,153.3毫摩尔)的甲酸(150毫升)溶液在25度时搅拌反应16小时，然后加入饱和碳酸氢钠溶液调pH值到7,并用 乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物7-氯-1,2,3,4-四氢萘-1-乙醛(13.7克,63.5％收率)。 1H NMR(400MHz,CHLOROFORM-d)δ9.59(d,J＝1.9Hz,1H),7.13-7.06(m,2H),7.04-6.98(m,1H),3.48(t,J＝5.5Hz,1H),2.66(t,J＝6.3Hz,2H),2.16(m,1H),1.90-1.78(m,1H),1.78-1.60(m,2H)。 A solution of (E)-7-chloro-1-(methoxymethylene)-1,2,3,4-tetrahydronaphthalene (32.0 g, 153.3 mmol) in formic acid (150 mL) at 25 degrees The reaction was stirred for 16 hours, then saturated sodium bicarbonate solution was added to adjust the pH to 7, and the extraction was diluted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 7-chloro-1,2,3,4-tetrahydronaphthalene- 1-acetaldehyde (13.7 g, 63.5% yield). 1 H NMR(400MHz, CHLOROFORM-d)δ9.59(d,J=1.9Hz,1H),7.13-7.06(m,2H),7.04-6.98(m,1H),3.48(t,J=5.5Hz) , 1H), 2.66(t, J=6.3Hz, 2H), 2.16(m, 1H), 1.90-1.78(m, 1H), 1.78-1.60(m, 2H).
步骤3:7-氯-1,2,3,4-四氢萘-1-羧酸甲酯的制备Step 3: Preparation of methyl 7-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxylate
Figure PCTCN2021138375-appb-000186
Figure PCTCN2021138375-appb-000186
将7-氯-1,2,3,4-四氢萘-1-乙醛(13.7克,70.4毫摩尔)溶于乙腈(300毫升)和甲醇(23.5克,731.9毫摩尔)中，在20度时搅拌缓慢加入NIS(47.5克,211.1毫摩尔)和碳酸钾(229.2克,211.1毫摩尔)。滴完后，将反应混合物在25度继续搅拌16小时，然后加入饱和碳酸氢钠溶液调pH值到9，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物7-氯-1,2,3,4-四氢萘-1-羧酸甲酯(6.5克,41.0％收率)。 1H NMR(400MHz,CHLOROFORM-d)δ7.18(d,J＝1.8Hz,1H),7.17-7.13(m,1H),7.07-7.03(m,1H),3.81(t,J＝5.5Hz,1H),3.77-3.73(m,3H),2.87-2.68(m,2H),2.21-2.10(m,1H),2.05-1.92(m,2H),1.83-1.72(m,1H)。 7-Chloro-1,2,3,4-tetrahydronaphthalene-1-acetaldehyde (13.7 g, 70.4 mmol) was dissolved in acetonitrile (300 mL) and methanol (23.5 g, 731.9 mmol) at 20 NIS (47.5 g, 211.1 mmol) and potassium carbonate (229.2 g, 211.1 mmol) were slowly added with stirring at 100°C. After dropping, the reaction mixture was further stirred at 25°C for 16 hours, then a saturated sodium bicarbonate solution was added to adjust the pH to 9, and the mixture was diluted and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 7-chloro-1,2,3,4-tetrahydronaphthalene- Methyl 1-carboxylate (6.5 g, 41.0% yield). 1 H NMR(400MHz, CHLOROFORM-d)δ7.18(d,J=1.8Hz,1H),7.17-7.13(m,1H),7.07-7.03(m,1H),3.81(t,J=5.5Hz) , 1H), 3.77-3.73 (m, 3H), 2.87-2.68 (m, 2H), 2.21-2.10 (m, 1H), 2.05-1.92 (m, 2H), 1.83-1.72 (m, 1H).
步骤4:1-((2,6-双(苄氧基)-5-硝基嘧啶-4-基)甲基)-7-氯-1,2,3,4-四氢萘-1-羧酸甲酯的制备Step 4: 1-((2,6-Bis(benzyloxy)-5-nitropyrimidin-4-yl)methyl)-7-chloro-1,2,3,4-tetrahydronaphthalene-1- Preparation of methyl carboxylate
Figure PCTCN2021138375-appb-000187
Figure PCTCN2021138375-appb-000187
将7-氯-1,2,3,4-四氢萘-1-羧酸甲酯(1253毫克,5.58毫摩尔)溶于无水四氢呋喃(10毫升)中，在-78度时搅拌缓慢加入LDA(6.97毫摩尔)，并在-78度继续搅拌30分钟，然后将2,4-双(苄氧基)-6-(溴甲基)-5-硝基嘧啶(中间体A3-2,2000毫克,4.65毫摩尔)的四氢呋喃(15毫升)溶液加到反应液中。滴完后，将反应混合物在-78度继续搅拌0.5小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到白色固体1-((2,6-双(苄氧基)-5-硝基嘧啶-4-基)甲基)-7-氯-1,2,3,4-四氢萘-1-羧酸甲酯(1.8克,68％收率)。MS:574.1(M+H) +。 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. After dropping, the reaction mixture was further stirred at -78°C for 0.5 hours, then ice water was added to quench the reaction, and the mixture was diluted and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a white solid 1-((2,6-bis(benzyloxy)-5- Nitropyrimidin-4-yl)methyl)-7-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid methyl ester (1.8 g, 68% yield). MS: 574.1 (M+H) + .
步骤5:7-氯-1-((2,6-二羟基-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯的制备Step 5: Methyl 7-chloro-1-((2,6-dihydroxy-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate preparation
Figure PCTCN2021138375-appb-000188
Figure PCTCN2021138375-appb-000188
将1-((2,6-双(苄氧基)-5-硝基嘧啶-4-基)甲基)-7-氯-1,2,3,4-四氢萘-1-羧酸甲酯(1.8克,3.14毫摩尔)溶于三氟乙酸(5毫升)中。反应混合物在氮气的保护下缓慢升至100度并微波条件搅拌1小时，然后反应混合液浓缩，并用乙酸乙酯萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体7-氯-1-((2,6-二羟基-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(1克，81％收率)。MS:394.1(M+H) +。 1-((2,6-Bis(benzyloxy)-5-nitropyrimidin-4-yl)methyl)-7-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid Methyl ester (1.8 g, 3.14 mmol) was dissolved in trifluoroacetic acid (5 mL). The reaction mixture was slowly raised to 100°C under nitrogen and stirred under microwave conditions for 1 hour, then the reaction mixture was concentrated and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid 7-chloro-1-((2,6-dihydroxy-5- Nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid methyl ester (1 g, 81% yield). MS: 394.1 (M+H) + .
步骤6:7-氯-1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯的制备Step 6: Methyl 7-chloro-1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate preparation
Figure PCTCN2021138375-appb-000189
Figure PCTCN2021138375-appb-000189
将7-氯-1-((2,6-二羟基-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(2200毫克,5.59毫摩尔)溶于三氯氧磷(15毫升)中，在0度时搅拌加入DIEA(791毫克,6.12毫摩尔)。反应混合物在氮气的保护下缓慢升至110度并搅拌6小时，然后反应混合液浓缩，并用二氯甲烷稀释萃取并将溶液倒入饱和碳酸氢钠溶液中搅拌1小时。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色固体7-氯-1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(2.2克,91％收率)。MS:397.1(M+H) +。 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give a yellow solid 7-chloro-1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)- Methyl 1,2,3,4-tetrahydronaphthalene-1-carboxylate (2.2 g, 91% yield). MS: 397.1 (M+H) + .
步骤7:(2S)-4-(2-氯-6-((7-氯-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯的制备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
Figure PCTCN2021138375-appb-000190
Figure PCTCN2021138375-appb-000190
将7-氯-1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(850毫克,1.974毫摩尔)溶于无水二氯甲烷(10毫升)中，在0度时搅拌缓慢加入(S)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(667毫克,2.96毫摩尔)。滴完后，将反应混合物在0度继续搅拌1小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-4-(2-氯-6-((7-氯-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(0.8克,66.7％收率)。MS:620.1(M+H) +。 Methyl 7-chloro-1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (850 mg, 1.974 mmol) was dissolved in anhydrous dichloromethane (10 mL), and (S)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (667) was slowly added with stirring at 0°C. mg, 2.96 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2S)-4-(2-chloro-6-((7- Chloro-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperidine tert-Butyl oxazine-1-carboxylate (0.8 g, 66.7% yield). MS: 620.1 (M+H) + .
制备例32中间体A22Preparation Example 32 Intermediate A22
(2S)-4-(2-氯-6-((5-氯-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((5-chloro-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitro pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000191
Figure PCTCN2021138375-appb-000191
中间体A22的合成参考中间体A21，通过使用5-氯-3,4-二氢萘-1(2H)-酮代替7-氯-3,4-二氢萘-1(2H)-酮制备得到中间体A22。MS:620.1(M+H) +。 Synthesis of Intermediate A22 Refers to Intermediate A21, prepared by using 5-chloro-3,4-dihydronaphthalene-1(2H)-one instead of 7-chloro-3,4-dihydronaphthalene-1(2H)-one Intermediate A22 is obtained. MS: 620.1 (M+H) + .
制备例33中间体A23Preparation Example 33 Intermediate A23
(2S)-4-(2-氯-6-((6-氯-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((6-chloro-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitro pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000192
Figure PCTCN2021138375-appb-000192
步骤1:(E)-6-氯-1-(甲氧基亚甲基)-1,2,3,4-四氢萘的制备Step 1: Preparation of (E)-6-chloro-1-(methoxymethylene)-1,2,3,4-tetrahydronaphthalene
Figure PCTCN2021138375-appb-000193
Figure PCTCN2021138375-appb-000193
将Ph 3PCH 2OMeCl(83.5克,243.6毫摩尔)溶于无水四氢呋喃(400毫升)中，在0度时搅拌缓慢加入叔丁醇钾(24.9克,221.5毫摩尔)。滴完后，将反应混合物在0度继续搅拌1小时，将6-氯-3,4-二氢萘-1(2H)-酮(20.0克,110.7毫摩尔)的四氢呋喃(100毫升)溶液加到上述反应液中，将反应混合物在20度继续搅拌12小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(E)-6-氯-1-(甲氧基亚甲基)-1,2,3,4-四氢萘(28.9克,75.1％收率)。MS:208.8(M+H) +。 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (E)-6-chloro-1-(methoxymethylene )-1,2,3,4-tetrahydronaphthalene (28.9 g, 75.1% yield). MS: 208.8 (M+H) + .
步骤2:6-氯-1,2,3,4-四氢萘-1-乙醛的制备Step 2: Preparation of 6-chloro-1,2,3,4-tetrahydronaphthalene-1-acetaldehyde
Figure PCTCN2021138375-appb-000194
Figure PCTCN2021138375-appb-000194
将(E)-6-氯-1-(甲氧基亚甲基)-1,2,3,4-四氢萘(27.3克,130.8毫摩尔)溶于1，4-二氧六环(270毫升)和水(27毫升)中，在20度时搅拌缓慢加入浓盐酸(12M,10.9毫升)。滴完后，将反应混合物在60度继续搅拌16小时，然后加入饱和碳酸氢钠溶液调pH值到9，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物6-氯-1,2,3,4-四氢萘-1-乙醛(11.2克,39.6％收率)。(E)-6-Chloro-1-(methoxymethylene)-1,2,3,4-tetrahydronaphthalene (27.3 g, 130.8 mmol) was dissolved in 1,4-dioxane ( 270 mL) and water (27 mL), slowly add concentrated hydrochloric acid (12M, 10.9 mL) with stirring at 20°C. After dropping, the reaction mixture was further stirred at 60°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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 6-chloro-1,2,3,4-tetrahydronaphthalene- 1-acetaldehyde (11.2 g, 39.6% yield).
步骤3:6-氯-1,2,3,4-四氢萘-1-羧酸甲酯的制备Step 3: Preparation of methyl 6-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxylate
Figure PCTCN2021138375-appb-000195
Figure PCTCN2021138375-appb-000195
将6-氯-1,2,3,4-四氢萘-1-乙醛(11.4克,58.6毫摩尔)溶于乙腈(270毫升)和甲醇(18.8克,585.7毫摩尔)中，在20度时搅拌缓慢加入NIS(39.5克,175.7毫摩尔)和碳酸钾(24.3克,175.7毫摩尔)。滴完后，将反应混合物在20度继续搅拌16小时，然后加入饱和碳酸氢钠溶液调pH值到9，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体6-氯-1,2,3,4-四氢萘-1-羧酸甲酯(7.6克,56.7％收率)。 1H NMR(400MHz,CHLOROFORM-d)δ7.01-7.18(m,3H),3.81(t,J＝5.90Hz,1H),3.72-3.75(m,3H),2.70-2.88(m,2H),2.11-2.22(m,1H),1.91-2.06(m,2H),1.73-1.83(m,1H)。 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 6-chloro-1,2,3,4-tetrahydronaphthalene-1 as a yellow solid - Methyl carboxylate (7.6 g, 56.7% yield). 1 H NMR(400MHz, CHLOROFORM-d)δ7.01-7.18(m,3H),3.81(t,J=5.90Hz,1H),3.72-3.75(m,3H),2.70-2.88(m,2H) , 2.11-2.22 (m, 1H), 1.91-2.06 (m, 2H), 1.73-1.83 (m, 1H).
步骤4:1-((2,6-双(苄氧基)-5-硝基嘧啶-4-基)甲基)-6-氯-1,2,3,4-四氢萘-1-羧酸甲酯的制备Step 4: 1-((2,6-Bis(benzyloxy)-5-nitropyrimidin-4-yl)methyl)-6-chloro-1,2,3,4-tetrahydronaphthalene-1- Preparation of methyl carboxylate
Figure PCTCN2021138375-appb-000196
Figure PCTCN2021138375-appb-000196
将6-氯-1,2,3,4-四氢萘-1-羧酸甲酯(1253毫克,5.58毫摩尔)溶于无水四氢呋喃(10毫升)中，在-78度时搅拌缓慢加入LDA(6.97毫摩尔)，并在-78度继续搅拌30分钟，然后将2,4-双(苄氧基)-6-(溴甲基)-5-硝基嘧啶(中间体A3-2,2000毫克,4.65毫摩 尔)的四氢呋喃(15毫升)溶液加到反应液中。滴完后，将反应混合物在-78度继续搅拌0.5小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到白色固体1-((2,6-双(苄氧基)-5-硝基嘧啶-4-基)甲基)-6-氯-1,2,3,4-四氢萘-1-羧酸甲酯(1.9克,73％收率)。MS:574.1(M+H) +。 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. After dropping, the reaction mixture was further stirred at -78°C for 0.5 hours, then ice water was added to quench the reaction, and the mixture was diluted and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a white solid 1-((2,6-bis(benzyloxy)-5- Nitropyrimidin-4-yl)methyl)-6-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid methyl ester (1.9 g, 73% yield). MS: 574.1 (M+H) + .
步骤5:6-氯-1-((2,6-二羟基-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯Step 5: Methyl 6-chloro-1-((2,6-dihydroxy-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate
Figure PCTCN2021138375-appb-000197
Figure PCTCN2021138375-appb-000197
将1-((2,6-双(苄氧基)-5-硝基嘧啶-4-基)甲基)-6-氯-1,2,3,4-四氢萘-1-羧酸甲酯(1.9克,3.3毫摩尔)溶于三氟乙酸(5毫升)中。反应混合物在氮气的保护下缓慢升至100度并微波条件搅拌1小时，然后反应混合液浓缩，并用乙酸乙酯萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体6-氯-1-((2,6-二羟基-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(1.1克,82％收率)。MS:394.1(M+H) +。 1-((2,6-Bis(benzyloxy)-5-nitropyrimidin-4-yl)methyl)-6-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid Methyl ester (1.9 g, 3.3 mmol) was dissolved in trifluoroacetic acid (5 mL). The reaction mixture was slowly raised to 100°C under nitrogen and stirred under microwave conditions for 1 hour, then the reaction mixture was concentrated and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid 6-chloro-1-((2,6-dihydroxy-5- Nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid methyl ester (1.1 g, 82% yield). MS: 394.1 (M+H) + .
步骤6:6-氯-1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯的制备Step 6: Methyl 6-chloro-1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate preparation
Figure PCTCN2021138375-appb-000198
Figure PCTCN2021138375-appb-000198
将6-氯-1-((2,6-二羟基-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(1.1克,2.8毫摩尔)溶于三氯氧磷(15毫升)中，在0度时搅拌加入DIEA(395毫克,3.03毫摩尔)。反应混合物在氮气的保护下缓慢升至110应并搅拌6小时，然后反应混合液浓缩，并用二氯甲烷稀释萃取并将溶液倒入饱和碳酸氢钠溶液中搅拌1小时。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色固体6-氯-1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(1克,90％收率)。MS:397.1(M+H) +。 Methyl 6-chloro-1-((2,6-dihydroxy-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (1.1 g, 2.8 mmol) was dissolved in phosphorus oxychloride (15 mL) and DIEA (395 mg, 3.03 mmol) was added with stirring at 0°C. The reaction mixture was slowly raised to 110 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give a yellow solid 6-chloro-1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)- Methyl 1,2,3,4-tetrahydronaphthalene-1-carboxylate (1 g, 90% yield). MS: 397.1 (M+H) + .
步骤7:(2S)-4-(2-氯-6-((6-氯-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯的制备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
Figure PCTCN2021138375-appb-000199
Figure PCTCN2021138375-appb-000199
将6-氯-1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(1克,2.5毫摩尔)溶于无水二氯甲烷(10毫升)中，在0度时搅拌缓慢加入(S)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(563毫克,1.78毫摩尔)。滴完后，将反应混合物在0度继续搅拌1小时，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-4-(2-氯-6-((6-氯-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(1.1克,89.2％收率)。MS:620.1(M+H) +。 Methyl 6-chloro-1-((2,6-dichloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (1 g, 2.5 mmol) was dissolved in anhydrous dichloromethane (10 mL), and (S)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (563) was slowly added with stirring at 0°C. mg, 1.78 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2S)-4-(2-chloro-6-((6- Chloro-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperidine tert-Butyl oxazine-1-carboxylate (1.1 g, 89.2% yield). MS: 620.1 (M+H) + .
制备例34中间体A24Preparation Example 34 Intermediate A24
(2S)-4-(2-氯-6-((7-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((7-fluoro-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitro pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000200
Figure PCTCN2021138375-appb-000200
中间体A24的合成参考中间体A21，通过使用7-氟-3,4-二氢萘-1(2H)-酮代替7-氯-3,4-二氢萘-1(2H)-酮制备得到中间体A24。MS:604.1(M+H) +。 Synthesis of Intermediate A24 Referring to Intermediate A21, prepared by using 7-fluoro-3,4-dihydronaphthalene-1(2H)-one instead of 7-chloro-3,4-dihydronaphthalene-1(2H)-one Intermediate A24 is obtained. MS: 604.1 (M+H) + .
制备例35中间体A25Preparation Example 35 Intermediate A25
(2S)-4-(2-氯-6-((6-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((6-fluoro-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitro pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000201
Figure PCTCN2021138375-appb-000201
中间体A25的合成参考中间体A21，通过使用6-氟-3,4-二氢萘-1(2H)-酮代替7-氯-3,4-二氢萘-1(2H)-酮制备得到中间体A25。MS:604.1(M+H) +。 Synthesis of Intermediate A25 Referring to Intermediate A21, prepared by using 6-fluoro-3,4-dihydronaphthalene-1(2H)-one in place of 7-chloro-3,4-dihydronaphthalene-1(2H)-one Intermediate A25 is obtained. MS: 604.1 (M+H) + .
制备例36中间体A26Preparation Example 36 Intermediate A26
(2S)-4-(2-氯-6-((1-(甲氧羰基)-7-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-7-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5- Nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000202
Figure PCTCN2021138375-appb-000202
中间体A26的合成参考中间体A21，通过使用7-甲基-3,4-二氢萘-1(2H)-酮代替7-氯-3,4-二氢萘-1(2H)-酮制备得到中间体A26。MS:600.1(M+H) +。 Synthesis of Intermediate A26 Reference to Intermediate A21 by using 7-methyl-3,4-dihydronaphthalene-1(2H)-one instead of 7-chloro-3,4-dihydronaphthalene-1(2H)-one Preparation of Intermediate A26. MS: 600.1 (M+H) + .
制备例37中间体A27和中间体A28Preparation Example 37 Intermediate A27 and Intermediate A28
(S)-1-((2,6-双(苄氧基)-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A27)和(R)-1-((2,6-双(苄氧基)-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A28)(S)-1-((2,6-bis(benzyloxy)-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate methyl Esters (Intermediate A27) and (R)-1-((2,6-bis(benzyloxy)-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydro Naphthalene-1-carboxylate methyl ester (Intermediate A28)
Figure PCTCN2021138375-appb-000203
Figure PCTCN2021138375-appb-000203
1-((2,6-双(苄氧基)-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(44克)经SFC手性拆分(柱型号：CHIRAL ART Cellulose-SB,5cm×25cm,5um column色谱柱，流动相：乙醇在正己烷中)得到均为淡黄色固体的第一个组分峰中间体A27(保留时间 为3.86分钟，20克)和第二个组分峰中间体A28(保留时间为4.11分钟，19克)。MS:540.1(M+H) +。中间体A27通过X射线晶体结构分析确定为(S)-构型，结果如图1所示。 Methyl 1-((2,6-bis(benzyloxy)-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (44 g ) by SFC chiral resolution (column type: CHIRAL ART Cellulose-SB, 5cm×25cm, 5um column, mobile phase: ethanol in n-hexane) to obtain the first component peak intermediate which is light yellow solid A27 (retention time 3.86 min, 20 g) and second component peak intermediate A28 (retention time 4.11 min, 19 g). MS: 540.1 (M+H) + . Intermediate A27 was identified as (S)-configuration by X-ray crystal structure analysis, and the results are shown in Figure 1.
制备例38中间体A29Preparation Example 38 Intermediate A29
(S)-4-(2-氯-6-(((S)-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(S)-4-(2-Chloro-6-(((S)-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitro pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000204
Figure PCTCN2021138375-appb-000204
中间体A29的合成参考中间体A3，通过使用(S)-1-((2,6-双(苄氧基)-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A27)代替1-((2,6-双(苄氧基)-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A3-3)制备得到中间体A29。MS:586.1(M+H) +。 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) + .
制备例39中间体A30Preparation Example 39 Intermediate A30
(S)-4-(2-氯-6-(((R)-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(S)-4-(2-Chloro-6-(((R)-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitro pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000205
Figure PCTCN2021138375-appb-000205
中间体A30的合成参考中间体A3，通过使用(R)-1-((2,6-双(苄氧基)-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A28)代替1-((2,6-双(苄氧基)-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A3-3)制备得到中间体A30。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) + .
制备例40中间体A31Preparation Example 40 Intermediate A31
(2S)-4-(2-氯-6-((1-(甲氧羰基)-6-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-6-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5- Nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000206
Figure PCTCN2021138375-appb-000206
中间体A31的合成参考中间体A21，通过使用6-甲基-3,4-二氢萘-1(2H)-酮代替7-氯-3,4-二氢萘-1(2H)-酮制备得到中间体A31。MS:600.1(M+H) +。 Synthesis of Intermediate A31 Refers to Intermediate A21 by using 6-methyl-3,4-dihydronaphthalen-1(2H)-one instead of 7-chloro-3,4-dihydronaphthalen-1(2H)-one Preparation of intermediate A31. MS: 600.1 (M+H) + .
制备例41中间体A32Preparation Example 41 Intermediate A32
(2S)-4-(2-氯-6-((5-氯-1-(甲氧羰基)-7-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(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
Figure PCTCN2021138375-appb-000207
Figure PCTCN2021138375-appb-000207
Figure PCTCN2021138375-appb-000208
Figure PCTCN2021138375-appb-000208
步骤1:4-(2-氯-4-甲基苯基)丁-3-炔-1-醇Step 1: 4-(2-Chloro-4-methylphenyl)but-3-yn-1-ol
Figure PCTCN2021138375-appb-000209
Figure PCTCN2021138375-appb-000209
将2-氯-1-碘-4-甲苯(40g,158mmol)溶于四氢呋喃(300毫升)中，在0升时搅拌缓慢加入丁-3-炔-1-醇(167g,2376mmol),CuI(0.603g,3.17mmol),Pd(PPh 3) 2Cl 2(3.34g,4.75mmol)和TEA(40.1g,396mmol)。滴完后，将反应混合物在60滴继续搅拌12小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物4-(2-氯-4-甲基苯基)丁-3-炔-1-醇(26g,84％收率)。MS:195.2(M+H) +。 2-Chloro-1-iodo-4-toluene (40 g, 158 mmol) was dissolved in tetrahydrofuran (300 mL), but-3-yn-1-ol (167 g, 2376 mmol), CuI ( 0.603 g, 3.17 mmol), Pd( PPh3 ) 2Cl2 (3.34 g , 4.75 mmol) and TEA (40.1 g, 396 mmol). After completion of dropping, the reaction mixture was further stirred at 60 drops for 12 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 4-(2-chloro-4-methylphenyl)butan- 3-yn-1-ol (26 g, 84% yield). MS: 195.2 (M+H) + .
步骤2:4-(2-氯-4-甲基苯基)丁烷-1-醇的制备Step 2: Preparation of 4-(2-Chloro-4-methylphenyl)butan-1-ol
Figure PCTCN2021138375-appb-000210
Figure PCTCN2021138375-appb-000210
将4-(2-氯-4-甲基苯基)丁-3-炔-1-醇(9g,45.3mmol)溶于乙酸乙酯(200毫升)中，在搅拌条件下向反应混合物中加入PtO 2(1克)。反应混合物在氢气作用下室温搅拌12小时，然后将混合物溶液过滤。将滤液真空浓缩，得到黄色油状物4-(2-氯-4-甲基苯基) 丁烷-1-醇(9g,98％收率)。MS:199.2(M+H) +。 4-(2-Chloro-4-methylphenyl)but-3-yn-1-ol (9 g, 45.3 mmol) was dissolved in ethyl acetate (200 mL) and added to the reaction mixture with stirring PtO2 (1 g). The reaction mixture was stirred at room temperature under the influence of hydrogen for 12 hours, and then the mixture solution was filtered. The filtrate was concentrated in vacuo to give 4-(2-chloro-4-methylphenyl)butan-1-ol as a yellow oil (9 g, 98% yield). MS: 199.2 (M+H) + .
步骤3:4-(2-氯-4-甲基苯基)丁酸的制备Step 3: Preparation of 4-(2-Chloro-4-methylphenyl)butanoic acid
Figure PCTCN2021138375-appb-000211
Figure PCTCN2021138375-appb-000211
将4-(2-氯-4-甲基苯基)丁烷-1-醇(8g,40.3mmol)溶于丙酮(30毫升)中，在0℃时搅拌缓慢加入Jone's reagent(10.41g,81mmol)。滴完后，将反应混合物在20℃继续搅拌反应2小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体4-(2-氯-4-甲基苯基)丁酸(3.8g,44.4％收率)。MS:213.2(M+H) +。 4-(2-Chloro-4-methylphenyl)butan-1-ol (8 g, 40.3 mmol) was dissolved in acetone (30 mL), and Jone's reagent (10.41 g, 81 mmol) was slowly added with stirring at 0°C ). After dropping, the reaction mixture was further stirred at 20° C. for 2 hours, then ice-water was added to quench the reaction, and the mixture was diluted and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered, and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 4-(2-chloro-4-methylphenyl)butyric acid as a yellow solid ( 3.8 g, 44.4% yield). MS: 213.2 (M+H) + .
步骤4:5-氯-7-甲基-3,4-二氢萘-1(2H)-酮的制备Step 4: Preparation of 5-Chloro-7-methyl-3,4-dihydronaphthalene-1(2H)-one
Figure PCTCN2021138375-appb-000212
Figure PCTCN2021138375-appb-000212
将4-(2-氯-4-甲基苯基)丁酸(3.8g,17.87mmol)溶于三氟甲磺酸(10毫升)中，并在0℃时搅拌反应3小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物5-氯-7-甲基-3,4-二氢萘-1(2H)-酮(2.2g,63.3％收率)。MS:195.2(M+H) +。 4-(2-Chloro-4-methylphenyl)butyric acid (3.8 g, 17.87 mmol) was dissolved in trifluoromethanesulfonic acid (10 mL) and the reaction was stirred at 0 °C for 3 hours, then ice was added The reaction was quenched with water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 5-chloro-7-methyl-3,4-dihydronaphthalene as a yellow oil -1(2H)-one (2.2 g, 63.3% yield). MS: 195.2 (M+H) + .
步骤5:(E)-5-氯-1-(甲氧基亚甲基)-7-甲基-1,2,3,4-四氢萘的制备Step 5: Preparation of (E)-5-chloro-1-(methoxymethylene)-7-methyl-1,2,3,4-tetrahydronaphthalene
Figure PCTCN2021138375-appb-000213
Figure PCTCN2021138375-appb-000213
中间体A32-5的合成参考中间体A21/步骤1，通过使用5-氯-7-甲基-3,4-二氢萘-1(2H)-酮(中间体A32-4)代替7-氯-3,4-二氢萘-1(2H)-酮制备得到中间体A32-5。The synthesis of 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.
步骤6:5-氯-7-甲基-1,2,3,4-四氢萘-1-甲醛的制备Step 6: Preparation of 5-chloro-7-methyl-1,2,3,4-tetrahydronaphthalene-1-carbaldehyde
Figure PCTCN2021138375-appb-000214
Figure PCTCN2021138375-appb-000214
将(E)-5-氯-1-(甲氧基亚甲基)-7-甲基-1,2,3,4-四氢萘(2.4g,10.78mmol)溶于二氯甲烷(20毫升)中，在-40℃时搅拌缓慢加入BBr 3(43.1mmol)。滴完后，将反应混合物在-40℃继续搅拌反应2小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物5-氯-7-甲基-1,2,3,4-四氢萘-1-甲醛(700mg,31.3％收率)。 (E)-5-Chloro-1-(methoxymethylene)-7-methyl-1,2,3,4-tetrahydronaphthalene (2.4 g, 10.78 mmol) was dissolved in dichloromethane (20 mL), BBr3 (43.1 mmol) was slowly added with stirring at -40°C. After dropping, the reaction mixture was further stirred at -40°C for 2 hours, then ice water was added to quench the reaction, and the mixture was diluted and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 5-chloro-7-methyl-1,2,3,4 as a yellow oil. - Tetrahydronaphthalene-1-carbaldehyde (700 mg, 31.3% yield).
步骤7:5-氯-7-甲基-1,2,3,4-四氢萘-1-羧酸甲酯的制备Step 7: Preparation of methyl 5-chloro-7-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylate
Figure PCTCN2021138375-appb-000215
Figure PCTCN2021138375-appb-000215
中间体A32-7的合成参考中间体A21/步骤3，通过使用5-氯-7-甲基-1,2,3,4-四氢萘-1-甲醛(中间体A32-6)代替7-氯-1,2,3,4-四氢萘-1-甲醛(中间体A21/步骤2)制备得到中间体A32-7。MS:239.2(M+H) +。 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) + .
步骤8:(2S)-4-(2-氯-6-((5-氯-1-(甲氧羰基)-7-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯的制备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
Figure PCTCN2021138375-appb-000216
Figure PCTCN2021138375-appb-000216
中间体A32的合成参考中间体A21，通过使用5-氯-7-甲基-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A32-7)代替7-氯-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A21/步骤3)制备得到中间体A32。MS:634.2(M+H) +。 Synthesis of Intermediate A32 was referred to Intermediate A21 by using methyl 5-chloro-7-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A32-7) in place of 7-chloro Methyl 1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A21/Step 3) was prepared to give Intermediate A32. MS: 634.2 (M+H) + .
制备例42中间体A33Preparation Example 42 Intermediate A33
(2S)-4-(2-氯-6-((5-氯-1-(甲氧羰基)-6-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((5-chloro-1-(methoxycarbonyl)-6-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl )-5-Nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000217
Figure PCTCN2021138375-appb-000217
中间体A33的合成参考中间体A32，通过使用2-氯-1-碘-3-甲苯代替2-氯-1-碘-4-甲苯制备得到中间体A33。MS:634.2(M+H) +。 Synthesis of Intermediate A33 Referring to Intermediate A32, Intermediate A33 was prepared by using 2-chloro-1-iodo-3-toluene instead of 2-chloro-1-iodo-4-toluene. MS: 634.2 (M+H) + .
制备例43中间体A34Preparation Example 43 Intermediate A34
(2S)-4-(2-氯-6-((5,6-二氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((5,6-difluoro-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)- 5-Nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000218
Figure PCTCN2021138375-appb-000218
Figure PCTCN2021138375-appb-000219
Figure PCTCN2021138375-appb-000219
步骤1:5,6-二氟-3,4-二氢萘-1(2H)-酮的制备(中间体A34-4)Step 1: Preparation of 5,6-difluoro-3,4-dihydronaphthalene-1(2H)-one (Intermediate A34-4)
中间体A34-4的合成参考中间体A32-4，通过使用1,2-二氟-3-碘苯代替2-氯-1-碘-4-甲苯制备得到中间体A34-4。MS:183.2(M+H) +。 Synthesis of Intermediate A34-4 Referring to Intermediate A32-4, Intermediate A34-4 was prepared by using 1,2-difluoro-3-iodobenzene instead of 2-chloro-1-iodo-4-toluene. MS: 183.2 (M+H) + .
步骤2:(2S)-4-(2-氯-6-((5,6-二氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯的制备(中间体A34)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)
中间体A34的合成参考中间体A23，通过使用5,6-二氟-3,4-二氢萘-1(2H)-酮(中间体A34-4)代替6-氯-3,4-二氢萘-1(2H)-酮制备得到中间体A34。MS:622.2(M+H) +。 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) + .
制备例44中间体A35Preparation Example 44 Intermediate A35
(2S)-4-(2-氯-6-((5-氯-6-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(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
Figure PCTCN2021138375-appb-000220
Figure PCTCN2021138375-appb-000220
Figure PCTCN2021138375-appb-000221
Figure PCTCN2021138375-appb-000221
步骤1:5-氯-6-氟-3,4-二氢萘-1(2H)-酮的制备(中间体A35-4)Step 1: Preparation of 5-chloro-6-fluoro-3,4-dihydronaphthalene-1(2H)-one (Intermediate A35-4)
Figure PCTCN2021138375-appb-000222
Figure PCTCN2021138375-appb-000222
中间体A35-4的合成参考中间体A32-4，通过使用2-氯-1-氟-3-碘苯代替2-氯-1-碘-4-甲苯制备得到中间体A35-4。MS:199.2(M+H) +。 Synthesis of Intermediate A35-4 Referring to Intermediate A32-4, Intermediate A35-4 was prepared by using 2-chloro-1-fluoro-3-iodobenzene in place of 2-chloro-1-iodo-4-toluene. MS: 199.2 (M+H) + .
步骤2:5-氯-6-氟-1-亚甲基-1,2,3,4-四氢萘的制备(中间体A35-5)Step 2: Preparation of 5-chloro-6-fluoro-1-methylene-1,2,3,4-tetrahydronaphthalene (Intermediate A35-5)
Figure PCTCN2021138375-appb-000223
Figure PCTCN2021138375-appb-000223
将甲基三苯基溴化鏻(27.3g,77mmol)溶于四氢呋喃(180毫升)中，在0℃时搅拌缓慢加入叔丁醇钾(8.59g,77mmol)并在0度搅拌1小时。然后将5-氯-6-氟-3,4-二氢萘-1(2H)-酮的制备(中间体A35-4，7.6g,38.3mmol)的四氢呋喃(50毫升)溶液在0度下加入到上述反应液中。滴完后，将反应混合物在20℃继续搅拌12小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色油状物5-氯-6-氟-1-亚甲基-1,2,3,4-四氢萘(中间体A35-5,6.4g,85％收率)。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. After dropping, the reaction mixture was further stirred at 20°C for 12 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 5-chloro-6-fluoro-1-methylene-1 as a colorless oil. , 2,3,4-tetrahydronaphthalene (Intermediate A35-5, 6.4 g, 85% yield).
步骤3:(5-氯-6-氟-1,2,3,4-四氢萘-1-基)甲醇的制备(中间体A35-6)Step 3: Preparation of (5-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-yl)methanol (Intermediate A35-6)
Figure PCTCN2021138375-appb-000224
Figure PCTCN2021138375-appb-000224
将5-氯-6-氟-1-亚甲基-1,2,3,4-四氢萘(中间体A35-5,6.4g,32.5mmol)溶于四氢呋喃(80毫升)中，在0℃时搅拌缓慢加入硼烷四氢呋喃溶液(65.1mmol)并在0度搅拌1小时。然后将NaOH(98mmol)和H 2O 2(521mmol)在0度下加入到上述反应液中。滴完后，将反应混合物在20℃继续搅拌12小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色油状物(5-氯-6-氟-1,2,3,4-四氢萘-1-基)甲醇(中间体A35-6,6.0g,86％收率)。 5-Chloro-6-fluoro-1-methylene-1,2,3,4-tetrahydronaphthalene (Intermediate A35-5, 6.4 g, 32.5 mmol) was dissolved in tetrahydrofuran (80 mL) at 0 A solution of borane in tetrahydrofuran (65.1 mmol) was slowly added with stirring at °C and stirred for 1 hour at 0°C. NaOH (98 mmol) and H2O2 (521 mmol) were then added to the above reaction at 0 degrees. After dropping, the reaction mixture was further stirred at 20°C for 12 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain a colorless oil (5-chloro-6-fluoro-1,2,3, 4-Tetrahydronaphthalen-1-yl)methanol (Intermediate A35-6, 6.0 g, 86% yield).
步骤4:5-氯-6-氟-1,2,3,4-四氢萘-1-甲醛(中间体A35-7)Step 4: 5-Chloro-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-carbaldehyde (Intermediate A35-7)
Figure PCTCN2021138375-appb-000225
Figure PCTCN2021138375-appb-000225
将(5-氯-6-氟-1,2,3,4-四氢萘-1-基)甲醇(中间体A35-6,6.0g,28.0mmol)溶于二氯甲烷(80毫升)中，在0℃时搅拌缓慢加入碳酸氢钠(4.70g,55.9mmol)和dess-martinperiodinane(23.71g,55.9mmol)并在0度搅拌1小时。然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到无色油状物5-氯-6-氟-1,2,3,4-四氢萘-1-甲醛(中间体A35-7,6.0g粗品)。(5-Chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)methanol (Intermediate A35-6, 6.0 g, 28.0 mmol) was dissolved in dichloromethane (80 mL) , Sodium bicarbonate (4.70 g, 55.9 mmol) and dess-martinperiodinane (23.71 g, 55.9 mmol) were slowly added with stirring at 0 °C and stirred at 0 °C for 1 hour. The reaction was then quenched by the addition of ice water, and the extraction was diluted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 5-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-carbaldehyde (Intermediate A35) as a colorless oil. -7,6.0g crude).
步骤5:5-氯-6-氟-1,2,3,4-四氢萘-1-羧酸甲酯的制备(中间体A35-8)Step 5: Preparation of methyl 5-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A35-8)
Figure PCTCN2021138375-appb-000226
Figure PCTCN2021138375-appb-000226
中间体A35-8的合成参考中间体A21/步骤3，通过使用5-氯-6-氟-1,2,3,4-四氢萘-1-甲醛(中间体A35-7)代替7-氯-1,2,3,4-四氢萘-1-甲醛(中间体A21/步骤2)制备得到中间 体A35-8。MS:243.2(M+H) +。 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) + .
步骤6:(2S)-4-(2-氯-6-((5-氯-6-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A35)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)
Figure PCTCN2021138375-appb-000227
Figure PCTCN2021138375-appb-000227
中间体A35的合成参考中间体A32，通过使用5-氯-6-氟-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A35-8)代替5-氯-7-甲基-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A32-7)制备得到中间体A35。MS:638.1(M+H) +。 Synthesis of Intermediate A35 Refers to Intermediate A32 by using methyl 5-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A35-8) in place of 5-chloro- 7-Methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid methyl ester (Intermediate A32-7) was prepared to give Intermediate A35. MS: 638.1 (M+H) + .
制备例45中间体A36Preparation Example 45 Intermediate A36
(2S)-4-(2-氯-6-((5-氯-7-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((5-chloro-7-fluoro-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl) -5-Nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000228
Figure PCTCN2021138375-appb-000228
Figure PCTCN2021138375-appb-000229
Figure PCTCN2021138375-appb-000229
步骤1:(E)-4-(2-氯-4-氟苯基)丁-3-烯酸的制备Step 1: Preparation of (E)-4-(2-chloro-4-fluorophenyl)but-3-enoic acid
Figure PCTCN2021138375-appb-000230
Figure PCTCN2021138375-appb-000230
将(2-羧乙基)三苯基溴化膦(79g,189mmol)溶于四氢呋喃(300毫升)中，在0℃时搅拌缓慢加入叔丁醇钾(53g,473mmol)并在0度搅拌10分钟。然后将2-氯-4-氟苯甲醛(25g,158mmol)的四氢呋喃(50毫升)溶液在0度下加入到上述反应液中。滴完后，将反应混合物在0℃继续搅拌5小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物(E)-4-(2-氯-4-氟苯基)丁-3-烯酸(20g,59.2％收率)。MS:215.2(M+H) +。 (2-Carboxyethyl)triphenylphosphine bromide (79 g, 189 mmol) was dissolved in tetrahydrofuran (300 mL), and potassium tert-butoxide (53 g, 473 mmol) was slowly added with stirring at 0 °C and stirred at 0 °C for 10 minute. A solution of 2-chloro-4-fluorobenzaldehyde (25 g, 158 mmol) in tetrahydrofuran (50 mL) was then added to the above reaction solution at 0 degrees. After dropping, the reaction mixture was further stirred at 0°C for 5 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain (E)-4-(2-chloro-4-fluorophenyl) as a yellow oil ) but-3-enoic acid (20 g, 59.2% yield). MS: 215.2 (M+H) + .
步骤2:4-(2-氯-4-氟苯基)丁酸的制备Step 2: Preparation of 4-(2-Chloro-4-fluorophenyl)butanoic acid
Figure PCTCN2021138375-appb-000231
Figure PCTCN2021138375-appb-000231
将(E)-4-(2-氯-4-氟苯基)丁-3-烯酸(15g,69.7mmol)溶于乙酸乙酯(200毫升)中，在搅拌条件下向反应混合物中加入PtO 2(1克)。反应混合物在氢气作用下室温搅拌12小时，然后将混合物溶液过滤。将滤液真空浓缩，得到黄色油状物4-(2-氯-4-氟苯基)丁酸(13.6g,90％收率)。MS:217.2(M+H) +。 (E)-4-(2-Chloro-4-fluorophenyl)but-3-enoic acid (15 g, 69.7 mmol) was dissolved in ethyl acetate (200 mL) and added to the reaction mixture with stirring PtO2 (1 g). The reaction mixture was stirred at room temperature under the influence of hydrogen for 12 hours, and then the mixture solution was filtered. The filtrate was concentrated in vacuo to give 4-(2-chloro-4-fluorophenyl)butyric acid (13.6 g, 90% yield) as a yellow oil. MS: 217.2 (M+H) + .
步骤3:5-氯-7-氟-3,4-二氢萘-1(2H)-酮的制备Step 3: Preparation of 5-chloro-7-fluoro-3,4-dihydronaphthalene-1(2H)-one
Figure PCTCN2021138375-appb-000232
Figure PCTCN2021138375-appb-000232
中间体A36-3的合成参考中间体A32-4，通过使用4-(2-氯-4-氟苯基)丁酸(中间体A36-2)代替4-(2-氯-4-甲基苯基)丁酸(Intermediate A32-3)制备得到中间体A36-3。MS:199.1(M+H) +。 Synthesis of 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. MS: 199.1 (M+H) + .
步骤4:(2S)-4-(2-氯-6-((5-氯-7-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯的制备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
Figure PCTCN2021138375-appb-000233
Figure PCTCN2021138375-appb-000233
中间体A36的合成参考中间体A23，通过使用5-氯-7-氟-3,4-二氢萘-1(2H)-酮(中间体A36-3)代替6-氯-3,4-二氢萘-1(2H)-酮制备得到中间体A36。MS:638.2(M+H) +。 Synthesis of intermediate A36 was done with reference to intermediate A23 by using 5-chloro-7-fluoro-3,4-dihydronaphthalen-1(2H)-one (intermediate A36-3) in place of 6-chloro-3,4- Dihydronaphthalene-1(2H)-one was prepared to give Intermediate A36. MS: 638.2 (M+H) + .
制备例46中间体A37Preparation Example 46 Intermediate A37
(2S)-4-(2-氯-6-((5,7-二氯-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((5,7-dichloro-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)- 5-Nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000234
Figure PCTCN2021138375-appb-000234
Figure PCTCN2021138375-appb-000235
Figure PCTCN2021138375-appb-000235
中间体A37的合成参考中间体A36，通过使用2,4-二氯苯甲醛代替2-氯-4-氟苯甲醛得到中间体A37。MS:654.1(M+H) +。 Synthesis of Intermediate A37 Referring to Intermediate A36, Intermediate A37 was obtained by using 2,4-dichlorobenzaldehyde in place of 2-chloro-4-fluorobenzaldehyde. MS: 654.1 (M+H) + .
制备例47中间体A38Preparation Example 47 Intermediate A38
(2S)-4-(2-氯-6-((5-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((5-fluoro-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitro pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000236
Figure PCTCN2021138375-appb-000236
中间体A38的合成参考中间体A34，通过使用1-氟-2-碘苯代替1,2-二氟-3-碘苯得到中间体A38。MS:604.1(M+H) +。 Synthesis of intermediate A38 Referring to intermediate A34, intermediate A38 was obtained by using 1-fluoro-2-iodobenzene in place of 1,2-difluoro-3-iodobenzene. MS: 604.1 (M+H) + .
制备例48中间体A39Preparation Example 48 Intermediate A39
(2S)-4-(2-氯-6-((1-(甲氧羰基)-5-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5- Nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000237
Figure PCTCN2021138375-appb-000237
中间体A39的合成参考中间体A34，通过使用1-碘-2-甲苯代替1,2-二氟-3-碘苯得到中间体A39。MS:600.1(M+H) +。 Synthesis of Intermediate A39 Referring to Intermediate A34, Intermediate A39 was obtained by using 1-iodo-2-toluene in place of 1,2-difluoro-3-iodobenzene. MS: 600.1 (M+H) + .
制备例49中间体A40Preparation Example 49 Intermediate A40
(2S)-4-(2-氯-6-((7-氟-1-(甲氧羰基)-5-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((7-fluoro-1-(methoxycarbonyl)-5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl )-5-Nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000238
Figure PCTCN2021138375-appb-000238
中间体A40的合成参考中间体A34，通过使用1-溴-4-氟-2-甲苯代替1,2-二氟-3-碘苯得到中间体A40。MS:618.1(M+H) +。 Synthesis of intermediate A40 Referring to intermediate A34, 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) + .
制备例50中间体A41Preparation Example 50 Intermediate A41
(2S)-4-(2-氯-6-((5-氟-1-(甲氧羰基)-6-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((5-fluoro-1-(methoxycarbonyl)-6-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl )-5-Nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000239
Figure PCTCN2021138375-appb-000239
中间体A41的合成参考中间体A34，通过使用1-溴-2-氟-3-甲苯代替1,2-二氟-3-碘苯得到中间体A41。MS:618.1(M+H) +。 Synthesis of intermediate A41 Referring to intermediate A34, 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) + .
制备例51中间体A42Preparation Example 51 Intermediate A42
(2S)-4-(2-氯-6-((1-(甲氧基羰基)-5-(三氟甲氧基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-5-(trifluoromethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl) Methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000240
Figure PCTCN2021138375-appb-000240
Figure PCTCN2021138375-appb-000241
Figure PCTCN2021138375-appb-000241
步骤1:5-(三氟甲氧基)-3,4-二氢萘-1(2H)-酮的制备Step 1: Preparation of 5-(trifluoromethoxy)-3,4-dihydronaphthalene-1(2H)-one
Figure PCTCN2021138375-appb-000242
Figure PCTCN2021138375-appb-000242
中间体A42-3的合成参考中间体A36-3，通过使用2-三氟甲氧基苯甲醛代替2-氯-4-氟苯甲醛制备得到中间体A42-3。MS:231.1(M+H) +。 Synthesis of Intermediate A42-3 With reference to Intermediate A36-3, Intermediate A42-3 was prepared by using 2-trifluoromethoxybenzaldehyde instead of 2-chloro-4-fluorobenzaldehyde. MS: 231.1 (M+H) + .
步骤2:(2S)-4-(2-氯-6-((1-(甲氧基羰基)-5-(三氟甲氧基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯的制备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
Figure PCTCN2021138375-appb-000243
Figure PCTCN2021138375-appb-000243
中间体A42的合成参考中间体A35，通过使用5-(三氟甲氧基)-3,4-二氢萘-1(2H)-酮(中间体42-3)代替5-氯-6-氟-3,4-二氢萘-1(2H)-酮(中间体A35-4)制备得到中间体A42。MS:670.1(M+H) +。 Intermediate A42 was synthesized with reference to Intermediate A35 by using 5-(trifluoromethoxy)-3,4-dihydronaphthalen-1(2H)-one (Intermediate 42-3) in place of 5-chloro-6- Fluoro-3,4-dihydronaphthalen-1(2H)-one (Intermediate A35-4) was prepared to give Intermediate A42. MS: 670.1 (M+H) + .
制备例52中间体A43Preparation Example 52 Intermediate A43
(2S)-4-(2-氯-6-((1-(甲氧羰基)-5-(三氟甲基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl) )-5-Nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000244
Figure PCTCN2021138375-appb-000244
中间体A43的合成参考中间体A34，通过使用1-碘-2-(三氟甲基)苯代替1,2-二氟-3-碘苯得到中间体A43。MS:654.1(M+H) +。 Synthesis of intermediate A43 Referring to intermediate A34, intermediate A43 was obtained by using 1-iodo-2-(trifluoromethyl)benzene in place of 1,2-difluoro-3-iodobenzene. MS: 654.1 (M+H) + .
制备例53中间体A51Preparation Example 53 Intermediate A51
(2S)-4-(2-氯-6-((6-氯-5-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((6-Chloro-5-fluoro-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl) -5-Nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000245
Figure PCTCN2021138375-appb-000245
中间体A51的合成参考中间体A32，通过使用1-氯-2-氟-3-碘苯代替2-氯-1-碘-4-甲苯得到中间体A51。MS:638.2(M+H) +。 Synthesis of Intermediate A51 Referring to Intermediate A32, Intermediate A51 was obtained by using 1-chloro-2-fluoro-3-iodobenzene instead of 2-chloro-1-iodo-4-toluene. MS: 638.2 (M+H) + .
制备例54中间体A44Preparation Example 54 Intermediate A44
(2S)-4-(2-氯-6-((5,7-二氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((5,7-difluoro-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)- 5-Nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000246
Figure PCTCN2021138375-appb-000246
中间体A44的合成参考中间体A35，通过使用2,4-二氟-1-碘苯代替2-氯-1-氟-3-碘苯制备得到中间体A44。MS:622.1(M+H) +。 Synthesis of Intermediate A44 Referring to Intermediate A35, Intermediate A44 was prepared by using 2,4-difluoro-1-iodobenzene instead of 2-chloro-1-fluoro-3-iodobenzene. MS: 622.1 (M+H) + .
制备例55中间体A46Preparation Example 55 Intermediate A46
(2S)-4-(2-氯-6-((5-氟-1-(甲氧羰基)-7-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸(2S)-4-(2-Chloro-6-((5-fluoro-1-(methoxycarbonyl)-7-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl )-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid
Figure PCTCN2021138375-appb-000247
Figure PCTCN2021138375-appb-000247
中间体A46的合成参考中间体A35，通过使用2-氟-1-碘-4-甲苯代替2-氯-1-氟-3-碘苯制备得到中间体A46。MS:618.1(M+H) +。 Synthesis of intermediate A46 Referring to intermediate A35, 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) + .
制备例56中间体A47Preparation Example 56 Intermediate A47
(2S)-4-(2-氯-6-((7-氯-1-(甲氧羰基)-5-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((7-Chloro-1-(methoxycarbonyl)-5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl )-5-Nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000248
Figure PCTCN2021138375-appb-000248
中间体A47的合成参考中间体A34，通过使用4-氯-1-碘-2-甲苯代替1,2-二氟-3-碘苯制备得到中间体A47。MS:634.1(M+H) +。 Synthesis of Intermediate A47 Referring to Intermediate A34, Intermediate A47 was prepared by using 4-chloro-1-iodo-2-toluene in place of 1,2-difluoro-3-iodobenzene. MS: 634.1 (M+H) + .
制备例57中间体A48Preparation Example 57 Intermediate A48
(2S)-4-(2-氯-6-((6-氟-1-(甲氧羰基)-5-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((6-fluoro-1-(methoxycarbonyl)-5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl )-5-Nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000249
Figure PCTCN2021138375-appb-000249
中间体A48的合成参考中间体A34，通过使用1-氟-3-碘-2-甲苯代替1,2-二氟-3-碘苯制备得到中间体A48。MS:618.1(M+H) +。 Synthesis of Intermediate A48 Referring to Intermediate A34, Intermediate A48 was prepared by using 1-fluoro-3-iodo-2-toluene in place of 1,2-difluoro-3-iodobenzene. MS: 618.1 (M+H) + .
制备例58中间体A45Preparation Example 58 Intermediate A45
(2S)-4-(6-((5-溴-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-氯-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(6-((5-Bromo-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-2-chloro-5-nitro pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000250
Figure PCTCN2021138375-appb-000250
中间体A45的合成参考中间体A35，通过使用5-溴-3,4-二氢萘-1(2H)-酮代替5-氯-6-氟-3,4-二氢萘-1(2H)-酮(中间体A35-4)制备得到中间体A45。MS:618.1(M+H) +。 Synthesis of Intermediate A45 Refers to Intermediate A35 by using 5-bromo-3,4-dihydronaphthalene-1(2H)-one instead of 5-chloro-6-fluoro-3,4-dihydronaphthalene-1(2H) )-ketone (Intermediate A35-4) was prepared to give Intermediate A45. MS: 618.1 (M+H) + .
制备例59中间体A49Preparation Example 59 Intermediate A49
(2S)-4-(2-氯-6-((4-氯-1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((4-Chloro-1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-5-nitro Pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000251
Figure PCTCN2021138375-appb-000251
中间体A49的合成参考中间体A34，通过使用4-氯-2,3-二氢-1H-茚-1-酮代替5,6-二氟-3,4-二氢萘-1(2H)-酮(中间体A34-4)制备得到中间体A49。MS:605.4(M+H) +。 Intermediate A49 was synthesized with reference to Intermediate A34 by using 4-chloro-2,3-dihydro-1H-inden-1-one instead of 5,6-difluoro-3,4-dihydronaphthalene-1(2H) - Ketone (Intermediate A34-4) was prepared to give Intermediate A49. MS: 605.4 (M+H) + .
制备例60中间体A52Preparation Example 60 Intermediate A52
(2S)-4-(2-氯-6-((1-(甲氧羰基)-4,4-二甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-yl)methyl) -5-Nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000252
Figure PCTCN2021138375-appb-000252
步骤1:中间体A52-1的制备Step 1: Preparation of Intermediate A52-1
将2-苯乙腈(5.00克,42.7毫摩尔)溶于无水四氢呋喃(100毫升)中，在0℃时搅拌缓慢加入钠氢(1.88克,47.0毫摩尔)。滴完后，将反应混合物在15℃并搅拌0.5小时，然后将1-溴-3-甲基-丁-2-烯加入到上述反应液中，并将反应混合物在15℃并搅拌16小时。然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物中间体A52-1(7.4克)。 1H NMR(400MHz,CDCl 3)δ7.42-7.33(m,5H),5.25-5.18(m,1H),3.79 (dd,J＝6.5,8.1Hz,1H),2.66-2.54(m,2H),1.77-1.72(m,3H),1.57(s,3H)。 2-Phenylacetonitrile (5.00 g, 42.7 mmol) was dissolved in dry tetrahydrofuran (100 mL) and sodium hydrogen (1.88 g, 47.0 mmol) was added slowly with stirring at 0°C. After completion of dropping, the reaction mixture was stirred at 15°C for 0.5 hours, then 1-bromo-3-methyl-but-2-ene was added to the above reaction solution, and the reaction mixture was stirred at 15°C for 16 hours. The reaction was then quenched by the addition of ice water, and the extraction was diluted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain Intermediate A52-1 (7.4 g) as a yellow oil. 1 H NMR (400MHz, CDCl 3 ) δ 7.42-7.33 (m, 5H), 5.25-5.18 (m, 1H), 3.79 (dd, J=6.5, 8.1 Hz, 1H), 2.66-2.54 (m, 2H) ), 1.77-1.72 (m, 3H), 1.57 (s, 3H).
步骤2:4,4-二甲基-1,2,3,4-四氢萘-1-羧酸的制备(中间体A52-2)Step 2: Preparation of 4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (Intermediate A52-2)
在60℃时搅拌下，将中间体A52-1(7.4克,39.9毫摩尔)缓慢加入硫酸(22.9克,139.8毫摩尔,12.4毫升,60％purity)溶液中。加完后，将反应混合物在130℃搅拌搅拌反应16小时。然后加入到冰水中淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物4,4-二甲基-1,2,3,4-四氢萘-1-羧酸(6.6克)。 1H NMR(400MHz,CDCl 3)δ11.45(br s,1H),7.30(d,J＝7.9Hz,1H),7.19-7.03(m,3H),3.79-3.68(m,1H),2.21-1.91(m,2H),1.86-1.72(m,1H),1.55-1.48(m,1H),1.26(s,3H),1.22-1.15(m,3H)。 Intermediate A52-1 (7.4 g, 39.9 mmol) was slowly added to a solution of sulfuric acid (22.9 g, 139.8 mmol, 12.4 mL, 60% purity) with stirring at 60°C. After the addition was complete, the reaction mixture was stirred at 130°C for 16 hours. The reaction was then quenched by addition to ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 4,4-dimethyl-1,2,3,4- Tetrahydronaphthalene-1-carboxylic acid (6.6 g). 1 H NMR (400MHz, CDCl 3 ) δ 11.45 (br s, 1H), 7.30 (d, J=7.9Hz, 1H), 7.19-7.03 (m, 3H), 3.79-3.68 (m, 1H), 2.21 -1.91(m, 2H), 1.86-1.72(m, 1H), 1.55-1.48(m, 1H), 1.26(s, 3H), 1.22-1.15(m, 3H).
步骤3:4,4-二甲基-1,2,3,4-四氢萘-1-羧酸甲酯的制备(中间体A52-3)Step 3: Preparation of methyl 4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A52-3)
将4,4-二甲基-1,2,3,4-四氢萘-1-羧酸(6.6克,32.3毫摩尔)溶于3.0M的盐酸甲醇(30毫升)溶液中。并将反应混合物在70℃搅拌搅拌反应16小时。然后浓缩，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色油状物4,4-二甲基-1,2,3,4-四氢萘-1-羧酸甲酯(5.9克)。 1H NMR(400MHz,CDCl 3)δ7.40(d,J＝7.8Hz,1H),7.28-7.21(m,1H),7.18-7.11(m,2H),3.88-3.81(m,1H),3.77(s,3H),2.23-2.13(m,1H),2.12-2.01(m,1H),1.87-1.82(m,1H),1.65-1.53(m,1H),1.36(s,3H),1.30(s,3H)。 4,4-Dimethyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (6.6 g, 32.3 mmol) was dissolved in a 3.0 M solution of hydrochloric acid in methanol (30 mL). The reaction mixture was stirred at 70°C for 16 hours. It was then concentrated and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 4,4-dimethyl-1,2,3,4 as a colorless oil. - Tetrahydronaphthalene-1-carboxylic acid methyl ester (5.9 g). 1 H NMR (400 MHz, CDCl 3 ) δ 7.40 (d, J=7.8 Hz, 1H), 7.28-7.21 (m, 1H), 7.18-7.11 (m, 2H), 3.88-3.81 (m, 1H), 3.77(s, 3H), 2.23-2.13(m, 1H), 2.12-2.01(m, 1H), 1.87-1.82(m, 1H), 1.65-1.53(m, 1H), 1.36(s, 3H), 1.30 (s, 3H).
步骤4:(2S)-4-(2-氯-6-((1-(甲氧羰基)-4,4-二甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯的制备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
中间体A52的合成参考中间体A35，通过使用4,4-二甲基-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A52-3)代替5-氯-6-氟-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A35-8)制备得到中间体A52。MS:614.1(M+H) +。 Synthesis of Intermediate A52 Reference to Intermediate A35 by using methyl 4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A52-3) in place of 5-chloro- Methyl 6-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylate (Intermediate A35-8) was prepared to give Intermediate A52. MS: 614.1 (M+H) + .
制备例61中间体C6Preparation Example 61 Intermediate C6
(S)-(4,4-二氟-1-甲基吡咯烷-2-基)甲醇(S)-(4,4-Difluoro-1-methylpyrrolidin-2-yl)methanol
Figure PCTCN2021138375-appb-000253
Figure PCTCN2021138375-appb-000253
中间体C6的合成参考中间体C3，通过使用1-(叔丁基)2-甲基(S)-4,4-二氟吡咯 烷-1,2-二羧酸酯代替1-(叔丁基)2-甲基(2S，4R)-4-氟吡咯烷-1,2-二羧酸酯制备得到中间体C6。MS:152.1(M+H) +。 Synthesis of 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) + .
制备例62中间体A53Preparation Example 62 Intermediate A53
(2S)-4-(2-氯-6-((5-氯-1-(甲氧羰基)异色-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((5-chloro-1-(methoxycarbonyl)isochrom-1-yl)methyl)-5-nitropyrimidin-4-yl)-2- (Cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000254
Figure PCTCN2021138375-appb-000254
步骤1:中间体A53-1的制备Step 1: Preparation of Intermediate A53-1
将2-(2-氯苯基)乙烷-1-醇(10克,63.9毫摩尔)溶于TFA(40毫升)中，在0℃时搅拌缓慢加入2,2-二羟基乙酸(8.82克,96毫摩尔)。滴完后，将反应混合物在100℃并搅拌48小时。然后浓缩，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物用二氯甲烷重结晶得到白色固体中间体A53-1(3.2克,23.5％)。2-(2-Chlorophenyl)ethane-1-ol (10 g, 63.9 mmol) was dissolved in TFA (40 mL) and 2,2-dihydroxyacetic acid (8.82 g) was added slowly with stirring at 0 °C. , 96 mmol). After completion of dropping, the reaction mixture was stirred at 100°C for 48 hours. It was then concentrated and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was recrystallized from dichloromethane to obtain a white solid Intermediate A53-1 (3.2 g, 23.5%).
步骤2:中间体A53-2的制备Step 2: Preparation of Intermediate A53-2
将中间体A53-1(3.5克,16.46毫摩尔)溶于甲醇(10毫升)溶液中,在0℃时搅拌缓慢加入氯化亚砜(9.79克,82毫摩尔)。滴加完后，将反应混合物在20℃搅拌搅拌反应2小时。然后浓缩，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色油状物中间体A53-2(2.6克,69.7％)。MS:227.1(M+H) +。 Intermediate A53-1 (3.5 g, 16.46 mmol) was dissolved in methanol (10 mL) solution, and thionyl chloride (9.79 g, 82 mmol) was slowly added with stirring at 0 °C. After the dropwise addition, the reaction mixture was stirred and reacted at 20°C for 2 hours. It was then concentrated and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain Intermediate A53-2 (2.6 g, 69.7%) as a colorless oil. MS: 227.1 (M+H) + .
步骤3:(2S)-4-(2-氯-6-((5-氯-1-(甲氧羰基)异色-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯的制备Step 3: (2S)-4-(2-Chloro-6-((5-chloro-1-(methoxycarbonyl)isochrom-1-yl)methyl)-5-nitropyrimidin-4-yl) - Preparation of tert-butyl 2-(cyanomethyl)piperazine-1-carboxylate
中间体A53的合成参考中间体A35，通过使用中间体A53-2代替5-氯-6-氟-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A35-8)制备得到中间体A53。MS:621.1(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. MS: 621.1 (M+H) + .
制备例63中间体C7Preparation Example 63 Intermediate C7
((2S,4R,5S)-4-氟-1,5-二甲基吡咯烷-2-基)甲醇((2S,4R,5S)-4-fluoro-1,5-dimethylpyrrolidin-2-yl)methanol
Figure PCTCN2021138375-appb-000255
Figure PCTCN2021138375-appb-000255
中间体C7的合成参考中间体C3，通过使用1-(叔丁基)2-甲基(2S,4R,5S)-4-氟-5-甲基吡咯烷-1,2-二甲酸酯代替1-(叔丁基)2-甲基(2S,4R)-4-氟吡咯烷-1,2-二羧酸酯制备得到中间体C7。MS:148.1(M+H) +。 The synthesis of intermediate C7 was referred to intermediate C3 by using 1-(tert-butyl)2-methyl(2S,4R,5S)-4-fluoro-5-methylpyrrolidine-1,2-dicarboxylate Prepared in place of 1-(tert-butyl)2-methyl(2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate, intermediate C7 was prepared. MS: 148.1 (M+H) + .
制备例64中间体A54Preparation Example 64 Intermediate A54
(2S)-4-(2-氯-6-((4-氯-6-氟-1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((4-Chloro-6-fluoro-1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)- 5-Nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000256
Figure PCTCN2021138375-appb-000256
步骤1:4-氯-6-氟-2,3-二氢-1H-茚-1-酮的制备(中间体A54-1)Step 1: Preparation of 4-chloro-6-fluoro-2,3-dihydro-1H-inden-1-one (Intermediate A54-1)
中间体A54-1的合成参考中间体A32-4，通过使用3-(2-氯-4-氟苯基)丙酸代替4-(2-氯-4-甲基苯基)丁酸(中间体A32-3)制备得到中间体A54-1。Synthesis of intermediate A54-1 was done with reference to intermediate A32-4 by using 3-(2-chloro-4-fluorophenyl)propionic acid in place of 4-(2-chloro-4-methylphenyl)butyric acid (intermediate body A32-3) was prepared to obtain intermediate A54-1.
步骤2:(2S)-4-(2-氯-6-((4-氯-6-氟-1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯的制备(中间体A54)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)
中间体A54的合成参考中间体A34，通过使用4-氯-6-氟-2,3-二氢-1H-茚-1-酮(中间体A54-1)代替5,6-二氟-3,4-二氢萘-1(2H)-酮(中间体A34-4)制备得到中间体A54。MS:623.4(M+H) +。 Synthesis of Intermediate A54 Refers to Intermediate A34 by using 4-chloro-6-fluoro-2,3-dihydro-1H-inden-1-one (Intermediate A54-1) in place of 5,6-difluoro-3 ,4-Dihydronaphthalene-1(2H)-one (Intermediate A34-4) was prepared to obtain Intermediate A54. MS: 623.4 (M+H) + .
制备例65中间体A55Preparation Example 65 Intermediate A55
(2S)-4-(2-氯-6-((5-氯-1-(乙氧羰基)-7-氟异色胺-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((5-chloro-1-(ethoxycarbonyl)-7-fluoroisotryptamine-1-yl)methyl)-5-nitropyrimidine-4- yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000257
Figure PCTCN2021138375-appb-000257
步骤1:2-(2-氯-4-氟苯乙氧基)-2-乙氧基乙酸乙酯的制备(中间体A55-1)Step 1: Preparation of ethyl 2-(2-chloro-4-fluorophenethoxy)-2-ethoxyacetate (Intermediate A55-1)
将2-(2-氯-4-氟苯基)乙烷-1-醇(25克,143毫摩尔)和2,2-二乙氧基乙酸乙酯(50.5克,286毫摩尔)溶于DCE(300毫升)溶液中,在0℃时搅拌缓慢加入三氟化硼乙醚(4.37克,14.32毫摩尔)。滴加完后，将反应混合物在20℃搅拌搅拌反应13小时。然后浓缩，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色油状物中间体A55-1(20克,45.8％)。2-(2-Chloro-4-fluorophenyl)ethan-1-ol (25 g, 143 mmol) and ethyl 2,2-diethoxyacetate (50.5 g, 286 mmol) were dissolved in To the DCE (300 mL) solution, boron trifluoride ether (4.37 g, 14.32 mmol) was slowly added with stirring at 0 °C. After the dropwise addition, the reaction mixture was stirred and reacted at 20°C for 13 hours. It was then concentrated and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain Intermediate A55-1 (20 g, 45.8%) as a colorless oil.
步骤2:中间体A55-2的制备Step 2: Preparation of Intermediate A55-2
将2-(2-氯-4-氟苯乙氧基)-2-乙氧基乙酸乙酯(中间体A55-1,19克,62.3毫摩尔)溶于DCE(100毫升)溶液中,在0℃时搅拌缓慢加入伊顿试剂(14.84克,62.3毫摩尔)。滴加完后，将反应混合物在20℃搅拌搅拌反应13小时。然后将反应液加入冰水中，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色油状物中间体A55-2(9.6克,59.5％)。MS:259.1(M+H) +。 Ethyl 2-(2-chloro-4-fluorophenethoxy)-2-ethoxyacetate (Intermediate A55-1, 19 g, 62.3 mmol) was dissolved in DCE (100 mL) solution in Eaton's reagent (14.84 g, 62.3 mmol) was slowly added with stirring at 0°C. After the dropwise addition, the reaction mixture was stirred and reacted at 20°C for 13 hours. The reaction solution was then added to ice water and diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain Intermediate A55-2 (9.6 g, 59.5%) as a colorless oil. MS: 259.1 (M+H) + .
步骤3:(2S)-4-(2-氯-6-((5-氯-1-(乙氧羰基)-7-氟异色胺-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯的制备Step 3: (2S)-4-(2-Chloro-6-((5-chloro-1-(ethoxycarbonyl)-7-fluoroisotryptamine-1-yl)methyl)-5-nitropyrimidine Preparation of -4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
中间体A55的合成参考中间体A35，通过使用中间体A55-2代替5-氯-6-氟-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A35-8)制备得到中间体A55。MS:653.4(M+H) +。 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) + .
制备例66中间体A56Preparation Example 66 Intermediate A56
(2S)-4-(2-氯-6-((5-氯-1-(乙氧羰基)-8-氟异色胺-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((5-chloro-1-(ethoxycarbonyl)-8-fluoroisotryptamine-1-yl)methyl)-5-nitropyrimidine-4- yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000258
Figure PCTCN2021138375-appb-000258
中间体A56的合成参考中间体A53，通过使用2-(2-氯-5-氟苯基)乙烷-1-醇代替2-(2-氯苯基)乙烷-1-醇制备得到中间体A56。MS:639.4(M+H) +。 Synthesis of Intermediate A56 Referring to Intermediate A53, intermediate was prepared by using 2-(2-chloro-5-fluorophenyl)ethane-1-ol in place of 2-(2-chlorophenyl)ethane-1-ol Body A56. MS: 639.4 (M+H) + .
制备例67中间体A57Preparation Example 67 Intermediate A57
5-氯-8-氟-1,2,3,4-四氢萘-1-羧酸甲酯Methyl 5-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylate
Figure PCTCN2021138375-appb-000259
Figure PCTCN2021138375-appb-000259
中间体A57的合成参考中间体A34-7，通过使用2-溴-1-氯-4-氟苯代替1,2-二氟-3-碘苯制备得到中间体A57。MS:242.4(M+H) +。 Synthesis of intermediate A57 Referring to intermediate A34-7, 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) + .
制备例68中间体A58Preparation Example 68 Intermediate A58
(2S)-4-(5-((叔丁氧羰基)氨基)-6-((5-氯-8-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(甲硫基)嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(5-((tert-butoxycarbonyl)amino)-6-((5-chloro-8-fluoro-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene -1-yl)methyl)-2-(methylthio)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000260
Figure PCTCN2021138375-appb-000260
步骤1:2,6-双(苄氧基)-5-硝基嘧啶-4-基)乙酸甲酯的制备(中间体A58-2)Step 1: Preparation of methyl 2,6-bis(benzyloxy)-5-nitropyrimidin-4-yl)acetate (Intermediate A58-2)
将2,4-双(苄基氧基)-6-(溴甲基)-5-硝基嘧啶(10克,23.24毫摩尔)溶于DMF(50毫升)中，在0℃时搅拌加入乙酸钾(3.42克,34.9毫摩尔)并在20度搅拌2小时。然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体2,6-双(苄氧基)-5-硝基嘧啶-4-基)乙酸甲酯(中间体A58-2,9.0克,95％)。MS:410.2(M+H) +。 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid 2,6-bis(benzyloxy)-5-nitropyrimidine- 4-yl) methyl acetate (Intermediate A58-2, 9.0 g, 95%). MS: 410.2 (M+H) + .
步骤2:(2,6-二羟基-5-硝基嘧啶-4-基)乙酸甲酯的制备(中间体A58-3)Step 2: Preparation of methyl (2,6-dihydroxy-5-nitropyrimidin-4-yl)acetate (Intermediate A58-3)
将2,6-双(苄氧基)-5-硝基嘧啶-4-基)乙酸甲酯(9克,21.98毫摩尔)溶于三氟乙酸(50毫升)中。反应混合物在氮气的保护下在50度搅拌反应12小时，然后反应混合液浓缩，并用乙酸乙酯萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2,6-二羟基-5-硝基嘧啶-4-基)乙酸甲酯(中间体A58-3,4.2克,83％)。MS:230.1(M+H) +。 Methyl 2,6-bis(benzyloxy)-5-nitropyrimidin-4-yl)acetate (9 g, 21.98 mmol) was dissolved in trifluoroacetic acid (50 mL). The reaction mixture was stirred at 50°C for 12 hours under nitrogen protection, then the reaction mixture was concentrated and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2,6-dihydroxy-5-nitropyrimidin-4-yl ) methyl acetate (Intermediate A58-3, 4.2 g, 83%). MS: 230.1 (M+H) + .
步骤3:(2,6-二氯-5-硝基嘧啶-4-基)乙酸甲酯的制备(中间体A58-4)Step 3: Preparation of methyl (2,6-dichloro-5-nitropyrimidin-4-yl)acetate (Intermediate A58-4)
将(2,6-二羟基-5-硝基嘧啶-4-基)乙酸甲酯(中间体A58-3,4.2克,18.33毫摩尔)溶于甲苯(50毫升)中，在0度时搅拌加入三氯氧磷(28.1克,183毫摩尔)和DIEA(7.11克,55.0毫摩尔)。反应混合物在氮气的保护下缓慢升至110℃并搅拌2小时，然后反应混合液浓缩，并用二氯甲烷稀释萃取并将溶液倒入饱和碳酸氢钠溶液中搅拌1小时。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色固体(2,6-二氯-5-硝基嘧啶-4-基)乙酸甲酯(中间体A58-4,3.1克,63.6％)。MS:266.1(M+H) +。 Methyl (2,6-dihydroxy-5-nitropyrimidin-4-yl)acetate (Intermediate A58-3, 4.2 g, 18.33 mmol) was dissolved in toluene (50 mL) and stirred at 0 degrees Phosphorus oxychloride (28.1 g, 183 mmol) and DIEA (7.11 g, 55.0 mmol) were added. The reaction mixture was slowly warmed to 110°C under nitrogen and stirred for 2 hours, then the reaction mixture was concentrated and extracted with dichloromethane and the solution was poured into saturated sodium bicarbonate solution and stirred for 1 hour. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give methyl (2,6-dichloro-5-nitropyrimidin-4-yl)acetate (Intermediate A58-4, 3.1) as a yellow solid grams, 63.6%). MS: 266.1 (M+H) + .
步骤4:(S)-4-(6-(乙酰氧基甲基)-2-氯-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯的制备(中间体A58-5)Step 4: Tertiary (S)-4-(6-(acetoxymethyl)-2-chloro-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid Preparation of Butyl Ester (Intermediate A58-5)
将(2,6-二氯-5-硝基嘧啶-4-基)乙酸甲酯(中间体A58-4,3.1克,11.65毫摩尔)溶于DCM(50毫升)中,在0度搅拌时向反应混合物中加入(S)-2-(哌嗪-2-基)乙腈(1.459克,11.65毫摩尔)并在20度搅拌反应1小时，然后在0度时将Boc 2O(5.09克,23.31毫摩尔)和DIEA(1.506克,11.65毫摩尔)加入到上述反应液中并在50度搅拌反应1小时。将反应混合液倒入冰水中并用乙酸乙酯萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(S)-4-(6-(乙酰氧基甲基)-2-氯-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A58-5,3.3克,62.3％)。MS:455.2(M+H) +。 Methyl (2,6-dichloro-5-nitropyrimidin-4-yl)acetate (Intermediate A58-4, 3.1 g, 11.65 mmol) was dissolved in DCM (50 mL) while stirring at 0 degrees To the reaction mixture was added (S)-2-(piperazin-2-yl)acetonitrile (1.459 g, 11.65 mmol) and the reaction was stirred at 20 degrees for 1 hour, then Boc 2 O (5.09 g, 23.31 mmol) and DIEA (1.506 g, 11.65 mmol) were added to the above reaction solution and the reaction was stirred at 50 degrees for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (S)-4-(6-(acetoxymethyl)- 2-Chloro-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A58-5, 3.3 g, 62.3%). MS: 455.2 (M+H) + .
步骤5:(S)-4-(6-(乙酰氧基甲基)-2-(甲硫基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯的制备(中间体A58-6)Step 5: (S)-4-(6-(Acetoxymethyl)-2-(methylthio)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1 - Preparation of tert-butyl carboxylate (Intermediate A58-6)
将(S)-4-(6-(乙酰氧基甲基)-2-氯-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A58-5,1.6克,3.52毫摩尔)和CH 3SNa(0.493克,7.04毫摩尔)的THF(10毫升)和水(5毫升)溶液在20度搅拌反应2小时。将反应混合液倒入冰水中并用乙酸乙酯萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(S)-4-(6-(乙酰氧基甲基)-2-(甲硫基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A58-6,1.3克,79％)。MS:467.2(M+H) +。 (S)-tert-butyl 4-(6-(acetoxymethyl)-2-chloro-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (Intermediate A58-5, 1.6 g, 3.52 mmol) and CH3SNa (0.493 g, 7.04 mmol) in THF (10 mL) and water (5 mL) were stirred at 20°C for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (S)-4-(6-(acetoxymethyl)- 2-(Methylthio)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A58-6, 1.3 g, 79%). MS: 467.2 (M+H) + .
步骤6:(S)-4-(6-(乙酰氧基甲基)-5-氨基-2-(甲硫基)嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯的制备(中间体A58-7)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)
将(S)-4-(6-(乙酰氧基甲基)-2-(甲硫基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A58-6,1.3克,2.79毫摩尔)溶于乙醇(15毫升)中，在0℃时搅拌加入铁粉(0.778克,13.93毫摩尔)和氯化铵水溶(3毫升)。滴完后，将反应混合物在85℃继续搅拌1小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和 盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(S)-4-(6-(乙酰氧基甲基)-5-氨基-2-(甲硫基)嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A58-7,1.0克,82％)。MS:437.2(M+H) +。 (S)-4-(6-(acetoxymethyl)-2-(methylthio)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-Butyl acid (Intermediate A58-6, 1.3 g, 2.79 mmol) was dissolved in ethanol (15 mL), and iron powder (0.778 g, 13.93 mmol) and ammonium chloride aqueous solution (3) were added with stirring at 0 °C. milliliters). After completion of dropping, the reaction mixture was further stirred at 85°C for 1 hour, then ice-water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (S)-4-(6-(acetoxymethyl)- 5-Amino-2-(methylthio)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A58-7, 1.0 g, 82%). MS: 437.2 (M+H) + .
步骤7:(S)-4-(6-(乙酰氧甲基)-5-((叔丁氧羰基)氨基)-2-(甲基硫基)嘧啶-4-基)-2-(氰基)哌嗪-1-羧酸叔丁酯的制备(中间体A58-8)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)
将(S)-4-(6-(乙酰氧基甲基)-5-氨基-2-(甲硫基)嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A58-7,1.0克,2.291毫摩尔),Boc 2O(5毫升)和DIEA(0.592克,4.58毫摩尔)的混合物在80℃继续搅拌12小时，然后加入冰水淬灭反应，并用DCM稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(S)-4-(6-(乙酰氧甲基)-5-((叔丁氧羰基)氨基)-2-(甲基硫基)嘧啶-4-基)-2-(氰基)哌嗪-1-羧酸叔丁酯(中间体A58-8,950毫克,77％)。MS:537.3(M+H) +。 (S)-4-(6-(acetoxymethyl)-5-amino-2-(methylthio)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid A mixture of tert-butyl ester (Intermediate A58-7, 1.0 g, 2.291 mmol), Boc 2 O (5 mL) and DIEA (0.592 g, 4.58 mmol) was stirred at 80 °C for a further 12 h, and then quenched with ice-water The reaction was quenched and extracted by dilution with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain crude product, which was purified by silica gel column chromatography to obtain yellow solid (S)-4-(6-(acetoxymethyl)-5 -((tert-Butoxycarbonyl)amino)-2-(methylthio)pyrimidin-4-yl)-2-(cyano)piperazine-1-carboxylate tert-butyl ester (Intermediate A58-8, 950 mg, 77%). MS: 537.3 (M+H) + .
步骤8:(S)-4-(5-((叔丁氧羰基)氨基)-6-(羟甲基)-2-(甲硫基)嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸的制备(中间体A58-9)Step 8: (S)-4-(5-((tert-butoxycarbonyl)amino)-6-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)-2-(cyanomethyl) ) Preparation of piperazine-1-carboxylic acid (Intermediate A58-9)
将(S)-4-(6-(乙酰氧甲基)-5-((叔丁氧羰基)氨基)-2-(甲基硫基)嘧啶-4-基)-2-(氰基)哌嗪-1-羧酸叔丁酯(中间体A58-8,950毫克,1.77毫摩尔),和氢氧化锂(212毫克,8.85毫摩尔)的THF(5毫升)和水(5毫升)混合物在20℃搅拌反应2小时。然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(S)-4-(5-((叔丁氧羰基)氨基)-6-(羟甲基)-2-(甲硫基)嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸(中间体A58-9,650毫克,74.2％)。MS:495.3(M+H) +。 (S)-4-(6-(acetoxymethyl)-5-((tert-butoxycarbonyl)amino)-2-(methylthio)pyrimidin-4-yl)-2-(cyano) A mixture of piperazine-1-carboxylate tert-butyl ester (Intermediate A58-8, 950 mg, 1.77 mmol), and lithium hydroxide (212 mg, 8.85 mmol) in THF (5 mL) and water (5 mL) at 20 The reaction was stirred for 2 hours. The reaction was then quenched by the addition of ice water, and the extraction was diluted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain (S)-4-(5-((tert-butoxycarbonyl)amino) as a yellow solid )-6-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid (Intermediate A58-9, 650 mg, 74.2%). MS: 495.3 (M+H) + .
步骤9:(S)-4-(6-(溴甲基)-5-((叔丁氧羰基)氨基)-2-(甲硫基)嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯的制备(中间体A58-10)Step 9: (S)-4-(6-(Bromomethyl)-5-((tert-butoxycarbonyl)amino)-2-(methylthio)pyrimidin-4-yl)-2-(cyanomethyl) ) Preparation of tert-butyl piperazine-1-carboxylate (Intermediate A58-10)
将(S)-4-(5-((叔丁氧羰基)氨基)-6-(羟甲基)-2-(甲硫基)嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸(中间体A58-9,650毫克,1.314毫摩尔)溶于DCM(10毫升)中，在0℃时搅拌加入Ph 3P(517毫克,1.971毫摩尔)和CBr 4(654毫克,1.971毫摩尔)。加完后，将反应混合物在20℃继续搅拌2小时，然后加入冰水淬灭反应，并用DCM稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(S)-4-(6-(溴甲基)-5-((叔丁氧羰基)氨基)-2-(甲硫基)嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A58-10,350毫克,47.8％)。MS:557.2&559.2(M+H) +。 (S)-4-(5-((tert-butoxycarbonyl)amino)-6-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)-2-(cyanomethyl)piperidine Zine-1-carboxylic acid (Intermediate A58-9, 650 mg, 1.314 mmol) was dissolved in DCM ( 10 mL), Ph3P (517 mg, 1.971 mmol) and CBr4 (654 mg) were added with stirring at 0 °C , 1.971 mmol). After the addition was complete, the reaction mixture was stirred for a further 2 hours at 20°C, then ice water was added to quench the reaction and diluted with DCM for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (S)-4-(6-(bromomethyl)-5- ((tert-Butoxycarbonyl)amino)-2-(methylthio)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A58-10, 350 mg, 47.8 %). MS: 557.2 & 559.2 (M+H) + .
步骤10:(2S)-4-(5-((叔丁氧羰基)氨基)-6-((5-氯-8-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(甲硫基)嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯的制备(中间体A58)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)
将5-氯-8-氟-1,2,3,4-四氢萘-1-羧酸甲酯(305毫克,1.256毫摩尔)溶于无水四氢呋喃(10毫升)中，在-78℃时搅拌缓慢加入LDA(1.25毫摩尔)，并在-20℃继续搅拌60分钟，然后将(S)-4-(6-(溴甲基)-5-((叔丁氧羰基)氨基)-2-(甲硫基)嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A58-10,350毫克,0.628毫摩尔)在-78℃加到上述反应液中。加完后，将反应混合物在-78℃继续搅拌1小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-4-(5-((叔丁氧羰基)氨基)-6-((5-氯-8-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(甲硫基)嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A58,220毫克,48.7％)。MS:719.4(M+H) +。 Methyl 5-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylate (305 mg, 1.256 mmol) was dissolved in dry tetrahydrofuran (10 mL) at -78 °C LDA (1.25 mmol) was added slowly while stirring, and stirring was continued at -20°C for 60 minutes, then (S)-4-(6-(bromomethyl)-5-((tert-butoxycarbonyl)amino)- 2-(Methylthio)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A58-10, 350 mg, 0.628 mmol) was added to the above at -78°C in the reaction solution. After the addition was complete, the reaction mixture was stirred for an additional 1 hour at -78°C, then quenched by the addition of ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain (2S)-4-(5-((tert-butoxycarbonyl)amino) as a yellow solid )-6-((5-Chloro-8-fluoro-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-2-(methylthio)pyrimidine -4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A58, 220 mg, 48.7%). MS: 719.4 (M+H) + .
制备例69中间体A59Preparation Example 69 Intermediate A59
(2S)-4-(2-氯-6-((4-氯-5-氟-1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(2S)-4-(2-Chloro-6-((4-Chloro-5-fluoro-1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)- 5-Nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000261
Figure PCTCN2021138375-appb-000261
中间体A59的合成参考中间体A54，通过使用3-(2-氯-3-氟苯基)丙酸代替3-(2-氯-4-氟苯基)丙酸制备得到中间体A59。MS:623.4(M+H) +。 Synthesis of Intermediate A59 Referring to Intermediate A54, Intermediate A59 was prepared by using 3-(2-chloro-3-fluorophenyl)propionic acid instead of 3-(2-chloro-4-fluorophenyl)propionic acid. MS: 623.4 (M+H) + .
制备例70中间体C8Preparation Example 70 Intermediate C8
((2R)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲醇((2R)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol
Figure PCTCN2021138375-appb-000262
Figure PCTCN2021138375-appb-000262
Figure PCTCN2021138375-appb-000263
Figure PCTCN2021138375-appb-000263
步骤1:中间体C8-1的制备Step 1: Preparation of Intermediate C8-1
将1-(叔丁基)2-甲基(2S，4R)-4-氟吡咯烷-1,2-二甲酸酯(20克,81毫摩尔)和HMPA(23.19克,129毫摩尔)溶于无水四氢呋喃(400毫升)中，在-70℃时搅拌缓慢加入LiHMDS(129毫升)，并在-70℃继续搅拌60分钟，然后将1-溴-3-氯丙烷(63.7克,404毫摩尔)的四氢呋喃(100毫升)溶液在-70℃加到上述反应液中。加完后，将反应混合物在-70℃继续搅拌2小时，并在室温继续搅拌2小时。然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物中间体C8-1(16克,61.1％)。MS:323.1&267.1(M+H) +。 Combine 1-(tert-butyl) 2-methyl(2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate (20 g, 81 mmol) and HMPA (23.19 g, 129 mmol) Dissolve in dry tetrahydrofuran (400 mL), slowly add LiHMDS (129 mL) with stirring at -70 °C, and continue stirring at -70 °C for 60 minutes, then add 1-bromo-3-chloropropane (63.7 g, 404 mmol) in tetrahydrofuran (100 mL) was added to the above reaction solution at -70°C. After the addition was complete, the reaction mixture was stirred for an additional 2 hours at -70°C and at room temperature for 2 hours. The reaction was then quenched by the addition of ice water, and the extraction was diluted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give Intermediate C8-1 (16 g, 61.1%) as a yellow oil. MS: 323.1 & 267.1 (M+H) + .
步骤2:中间体C8-2的制备Step 2: Preparation of Intermediate C8-2
将中间体C8-1(52克,161毫摩尔)溶于乙腈(100毫升)中，在0℃时搅拌缓慢加入氯化氢的二氧六环溶液(1.0M,200毫升),将反应混合物在室温搅拌3小时。将反应混合液浓缩蒸干，并用乙酸乙酯稀释萃取，有机相用饱和碳酸钠水溶液，饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色油状物中间体C8-2(36克,100％)。MS:224.1(M+H) +。 Intermediate C8-1 (52 g, 161 mmol) was dissolved in acetonitrile (100 mL), a solution of hydrogen chloride in dioxane (1.0 M, 200 mL) was added slowly with stirring at 0 °C, and the reaction mixture was allowed to cool at room temperature. Stir for 3 hours. The reaction mixture was concentrated and evaporated to dryness, diluted and extracted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a yellow oily intermediate C8-2 (36 g , 100%). MS: 224.1 (M+H) + .
步骤3:中间体C8-3的制备Step 3: Preparation of Intermediate C8-3
将中间体C8-2(36克,161毫摩尔)乙腈(50毫升)中，在0℃时搅拌缓慢加入NaHCO 3(67.6克，805毫摩尔)和碘化钾(2.67克，16.09毫摩尔)，然后将反应混合物在50℃继续搅拌12小时。然后冷却到室温，加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物中间体C8-3(21g,69.7％)。188.1(M+H) +。 Intermediate C8-2 (36 g, 161 mmol) acetonitrile (50 mL) was slowly added with stirring at 0 °C NaHCO3 (67.6 g, 805 mmol) and potassium iodide (2.67 g, 16.09 mmol), then The reaction mixture was stirred for a further 12 hours at 50°C. It was then cooled to room temperature, quenched by the addition of ice water, and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain crude product, which was purified by silica gel column chromatography to obtain intermediate C8-3 (21 g, 69.7%) as a yellow oil. 188.1(M+H) + .
步骤4:中间体C8的制备Step 4: Preparation of Intermediate C8
中间体C8的合成参考中间体C3，通过使用中间体C8-3代替1-(叔丁基)2-甲基 (2S,4R)-4-氟吡咯烷-1,2-二羧酸酯制备得到中间体C8。MS:160.1(M+H) +。 1H NMR(400MHz,CDCl 3):d 5.36-5.08(m,1H),3.51-3.29(m,3H),3.25-3.10(m,1H),3.04-2.93(m,1H),2.90-2.73(m,1H),2.71-2.59(m,1H),2.28-2.12(m,1H),1.95-1.73(m,4H),1.65-1.53(m,1H)。 Synthesis of Intermediate C8 Referenced to Intermediate C3, prepared by using Intermediate C8-3 in place of 1-(tert-butyl)2-methyl(2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate Intermediate C8 is obtained. MS: 160.1 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ): d 5.36-5.08 (m, 1H), 3.51-3.29 (m, 3H), 3.25-3.10 (m, 1H), 3.04-2.93 (m, 1H), 2.90-2.73 (m, 1H), 2.71-2.59 (m, 1H), 2.28-2.12 (m, 1H), 1.95-1.73 (m, 4H), 1.65-1.53 (m, 1H).
实施例1Example 1
化合物I-1：4’-(4-丙烯酰哌嗪-1-基)-2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮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
Figure PCTCN2021138375-appb-000264
Figure PCTCN2021138375-appb-000264
步骤1:4-(6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯的制备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
Figure PCTCN2021138375-appb-000265
Figure PCTCN2021138375-appb-000265
将(S)-(1-甲基吡咯烷-2-基)甲醇(105毫克,0.916毫摩尔)和4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯(中间体 A1,250毫克,0.458毫摩尔)溶于无水四氢呋喃(20毫升)中，在25℃时搅拌缓慢加入碳酸铯(448毫克,1.374毫摩尔)。滴完后，将反应混合物缓慢升至50℃并搅拌11小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物4-(6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯(200毫克,70％收率)。MS:625.1(M+H) +。 Combine (S)-(1-methylpyrrolidin-2-yl)methanol (105 mg, 0.916 mmol) and 4-(2-chloro-6-((1-(methoxycarbonyl)-1,2, 3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (Intermediate A1, 250 mg, 0.458 mmol) dissolved in To anhydrous tetrahydrofuran (20 mL), cesium carbonate (448 mg, 1.374 mmol) was slowly added with stirring at 25°C. After dropping, the reaction mixture was slowly raised to 50°C and stirred for 11 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 4-(6-((1-(methoxycarbonyl)-1) as a yellow oil ,2,3,4-Tetrahydronaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidine-4 -yl)piperazine-1-carboxylate tert-butyl ester (200 mg, 70% yield). MS: 625.1 (M+H) + .
步骤2:4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺[萘-1,7'-吡啶并[3,2-d]嘧啶]-4'-基)哌嗪-1-甲酸叔丁酯的制备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
Figure PCTCN2021138375-appb-000266
Figure PCTCN2021138375-appb-000266
将4-(6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯(300毫克,0.480毫摩尔)溶于乙酸乙酯(25毫升)和甲醇(5毫升)中，在搅拌条件下向反应混合物中加入钯碳(150毫克)。反应混合物在氢气条件下室温搅拌13小时，然后将混合物溶液过滤。将滤液真空浓缩，得到无色油状物4-(5-氨基-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-羧酸叔丁酯(286毫克,100％收率)。MS:595.1(M+H) +。 4-(6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidine -2-yl)methoxy)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (300 mg, 0.480 mmol) was dissolved in ethyl acetate (25 mL) and methanol ( 5 mL), palladium on carbon (150 mg) was added to the reaction mixture with stirring. The reaction mixture was stirred at room temperature under hydrogen for 13 hours, and then the mixture solution was filtered. The filtrate was concentrated in vacuo to give 4-(5-amino-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-2 as a colorless oil -(((S)-1-Methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (286 mg, 100% yield). MS: 595.1 (M+H) + .
将4-(5-氨基-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-羧酸叔丁酯(150毫克,0.252毫摩尔)溶于乙酸(2毫升)中，反应混合物在70度搅拌3小时。反应完毕后，反应溶液过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到白色固体4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺[萘-1,7'-吡啶并[3,2-d]嘧啶]-4'-基)哌嗪-1-甲酸叔丁酯(40毫克,28％收率)。MS:563.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.22–7.09(m,4H),4.70(t,J＝10.0Hz,1H),4.50(dt,J＝13.4,7.2Hz,1H),3.85(s,1H),3.77–3.45(m,8H),3.30(s,3H),3.12–2.92(m,4H),2.82(s,2H),2.37–2.30(m,1H),2.28–1.92(m,4H),1.83(s,3H),1.48(s,9H)。 4-(5-Amino-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-2-(((S)-1- Methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (150 mg, 0.252 mmol) was dissolved in acetic acid (2 mL) and the reaction mixture was heated at 70 Stir for 3 hours. After the reaction was completed, the reaction solution was filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a white solid 4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy) )-6'-oxo-3,4,5',8'-tetrahydro-2H, 6'H-spiro[naphthalene-1,7'-pyrido[3,2-d]pyrimidine]-4' -yl)piperazine-1-carboxylic acid tert-butyl ester (40 mg, 28% yield). MS: 563.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.22-7.09(m,4H),4.70(t,J=10.0Hz,1H),4.50(dt,J=13.4,7.2Hz,1H),3.85( s, 1H), 3.77–3.45 (m, 8H), 3.30 (s, 3H), 3.12–2.92 (m, 4H), 2.82 (s, 2H), 2.37–2.30 (m, 1H), 2.28–1.92 ( m, 4H), 1.83 (s, 3H), 1.48 (s, 9H).
步骤3:2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-4’-(哌嗪-1-基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮的制备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
Figure PCTCN2021138375-appb-000267
Figure PCTCN2021138375-appb-000267
将4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺[萘-1,7'-吡啶并[3,2-d]嘧啶]-4'-基)哌嗪-1-甲酸叔丁酯(50毫克,0.089毫摩尔)溶于二氯甲烷(5毫升)和6N盐酸甲醇(5毫升)中，反应混合物在室温搅拌1小时。将反应混合液浓缩蒸干，并用乙酸乙酯稀释萃取，有机相用饱和碳酸钠水溶液，饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色油状物2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-4’-(哌嗪-1-基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮(42毫克,100％收率)。MS:463.1(M+H) +。 4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxo-3,4,5',8'-tetrahydro-2H, 6'H-Spiro[naphthalene-1,7'-pyrido[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylic acid tert-butyl ester (50 mg, 0.089 mmol) was dissolved in In methyl chloride (5 mL) and 6N hydrochloric acid in methanol (5 mL), the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and evaporated to dryness, and was diluted and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain yellow oil 2'-(((S) -1-Methylpyrrolidin-2-yl)methoxy)-4'-(piperazin-1-yl)-3,4,5',8'-tetrahydro-2H,6'H-spiro [Naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-6'-one (42 mg, 100% yield). MS: 463.1 (M+H) + .
步骤4:4’-(4-丙烯酰哌嗪-1-基)-2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮的制备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
Figure PCTCN2021138375-appb-000268
Figure PCTCN2021138375-appb-000268
将2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-4’-(哌嗪-1-基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮(40毫克,0.086毫摩尔)和DIEA(33.5毫克,0.259毫摩尔)溶于二氯甲烷(5毫升)中，在0℃时搅拌缓慢加入丙烯酰氯(7.83毫克,0.086毫摩尔)。滴完后，将反应混合物在0℃并搅拌1小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经Pre-HPLC制备的到白色固体4’-(4-丙烯酰哌嗪-1-基)-2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮(16毫克,35.8％收率)。MS:517.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.17(dd,J＝20.2,13.2Hz,4H),6.88–6.68(m,1H),6.26(d,J＝16.7Hz,1H),5.79(d,J＝10.6Hz,1H),4.61–4.57(m,3H),3.88(s,3H),3.79–3.47(m,6H),3.34–3.28(m,2H),3.13–2.95(m,4H),2.83(s,2H),2.38(s,1H),2.10–1.96(m,4H),1.84(s,3H)。 2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4'-(piperazin-1-yl)-3,4,5',8'-tetrahydro -2H,6'H-Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-6'-one (40 mg, 0.086 mmol) and DIEA (33.5 mg, 0.259 mmol) Dissolve in dichloromethane (5 mL) and add acryloyl chloride (7.83 mg, 0.086 mmol) slowly with stirring at 0°C. After dropping, the reaction mixture was stirred at 0°C for 1 hour, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to a white solid 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 (16 mg, 35.8% yield). MS: 517.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.17(dd,J=20.2,13.2Hz,4H),6.88-6.68(m,1H),6.26(d,J=16.7Hz,1H),5.79( d, J=10.6Hz, 1H), 4.61–4.57 (m, 3H), 3.88 (s, 3H), 3.79–3.47 (m, 6H), 3.34–3.28 (m, 2H), 3.13–2.95 (m, 4H), 2.83(s, 2H), 2.38(s, 1H), 2.10–1.96(m, 4H), 1.84(s, 3H).
实施例2Example 2
化合物I-2:4'-(4-丙烯酰哌嗪-1-基)-5'-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮Compound 1-2: 4'-(4-Acryloylpiperazin-1-yl)-5'-methyl-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
Figure PCTCN2021138375-appb-000269
Figure PCTCN2021138375-appb-000269
步骤1:4-(5'-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯的制备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
Figure PCTCN2021138375-appb-000270
Figure PCTCN2021138375-appb-000270
将4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯(化合物I-1/步骤2，100毫克,0.178毫摩尔)DMF(5毫升)中，在0℃时搅拌缓慢加入钠氢(21.32毫克,0.533毫摩尔)。滴完后，将反应混合物在0℃并搅拌1小时，然后将碘甲烷(25.2毫克,0.178毫摩尔)加到反应液中，并继续搅拌1小时。反应完毕后，加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅 胶柱层析纯化得到黄色固体4-(5'-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯(80毫克,78％收率)。MS:577.1(M+H) +。 4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H, 6'H-Spiro[1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate tert-butyl ester (Compound I-1/Step 2, 100 mg, 0.178 mmol) DMF (5 mL) was slowly added sodium hydrogen (21.32 mg, 0.533 mmol) with stirring at 0°C. After completion of dropping, the 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. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid 4-(5'-methyl-2'-(((S) -1-Methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7 '-Pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate tert-butyl ester (80 mg, 78% yield). MS: 577.1 (M+H) + .
步骤2:5'-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-4'-(哌嗪-1-基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮的制备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
Figure PCTCN2021138375-appb-000271
Figure PCTCN2021138375-appb-000271
将4-(5'-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯(60毫克,0.104毫摩尔)溶于二氯甲烷(5毫升)和6N盐酸甲醇(5毫升)中，反应混合物在室温搅拌1小时。将反应混合液浓缩蒸干，并用乙酸乙酯稀释萃取，有机相用饱和碳酸钠水溶液，饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色油状物5'-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-4'-(哌嗪-1-基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮(50毫克,100％收率)。MS:477.1(M+H) +。 4-(5'-methyl-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4,5',8'-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate tert-butyl ester (60 mg, 0.104 mmol) in dichloromethane (5 mL) and 6N hydrochloric acid in methanol (5 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and evaporated to dryness, and was diluted and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain 5'-methyl-2' as a yellow oil. -(((S)-1-Methylpyrrolidin-2-yl)methoxy)-4'-(piperazin-1-yl)-3,4,5',8'-tetrahydro-2H, 6'H-Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-6'-one (50 mg, 100% yield). MS: 477.1 (M+H) + .
步骤3:4'-(4-丙烯酰哌嗪-1-基)-5'-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮的制备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
Figure PCTCN2021138375-appb-000272
Figure PCTCN2021138375-appb-000272
将5'-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-4'-(哌嗪-1-基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮(40毫克,0.084毫摩尔)和DIEA(33.5毫克,0.259毫摩尔)溶于二氯甲烷(5毫升)中，在0℃时搅拌缓慢加入丙烯酰氯(7.83毫克,0.086毫摩尔)。滴完后，将反应混合物在0℃并搅拌1小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经Pre-HPLC制备得到白色固体4'-(4-丙烯酰哌嗪-1-基)-5'-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮 (22毫克,50％收率)。MS:531.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.29–7.07(m,4H),6.81(dd,J＝16.8,10.6Hz,1H),6.26(dd,J＝16.8,1.9Hz,1H),5.80(dd,J＝10.6,1.9Hz,1H),4.83–4.67(m,1H),4.55–4.50(m,1H),3.89(s,3H),3.74–3.69(m,2H),3.65(m,2H),3.51–3.20(m,10H),3.08(s,2H),2.86–2.76(m,2H),2.40–2.37(m,1H),2.31–1.92(m,4H),1.76–1.68(m,3H)。 5'-methyl-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4'-(piperazin-1-yl)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-6'-one (40 mg, 0.084 mmol) and DIEA (33.5 mg, 0.259 mmol) was dissolved in dichloromethane (5 mL) and acryloyl chloride (7.83 mg, 0.086 mmol) was added slowly with stirring at 0°C. After dropping, the reaction mixture was stirred at 0°C for 1 hour, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was prepared by Pre-HPLC to obtain a white solid 4'-(4-acryloylpiperazin-1-yl)-5'-Methyl-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 (22 mg, 50% yield). MS: 531.1 (M+H) + . 1 H NMR (400MHz, Methanol-d 4 )δ7.29-7.07(m,4H),6.81(dd,J=16.8,10.6Hz,1H),6.26(dd,J=16.8,1.9Hz,1H), 5.80(dd,J=10.6,1.9Hz,1H),4.83-4.67(m,1H),4.55-4.50(m,1H),3.89(s,3H),3.74-3.69(m,2H),3.65( m, 2H), 3.51–3.20 (m, 10H), 3.08 (s, 2H), 2.86–2.76 (m, 2H), 2.40–2.37 (m, 1H), 2.31–1.92 (m, 4H), 1.76– 1.68 (m, 3H).
实施例3Example 3
化合物I-3：4’-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮Compound I-3: 4'-((S)-4-acryloyl-2-methylpiperazin-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
Figure PCTCN2021138375-appb-000273
Figure PCTCN2021138375-appb-000273
步骤1:(3S)-4-(6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-硝基嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的制备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
Figure PCTCN2021138375-appb-000274
Figure PCTCN2021138375-appb-000274
将(S)-(1-甲基吡咯烷-2-基)甲醇(0.339克,2.95毫摩尔)和(3S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(中间体A2,1.1克,1.964毫摩尔)溶于无水四氢呋喃(20毫升)中，在25℃时搅拌缓慢加入碳酸铯(1.280克,3.93毫摩尔)。滴完后，将反应混合物缓慢升至50℃并搅拌11小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(3S)-4-(6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-硝基嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(800毫克,63.8％收率)。MS:639.1(M+H) +。 Combine (S)-(1-methylpyrrolidin-2-yl)methanol (0.339 g, 2.95 mmol) and (3S)-4-(2-chloro-6-((1-(methoxycarbonyl)- 1,2,3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (Intermediate A2, 1.1 g, 1.964 mmol) was dissolved in dry tetrahydrofuran (20 mL), and cesium carbonate (1.280 g, 3.93 mmol) was slowly added with stirring at 25°C. After dropping, the reaction mixture was slowly raised to 50°C and stirred for 11 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (3S)-4-(6-((1-(methoxycarbonyl) )-1,2,3,4-Tetrahydronaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-nitro Pyrimidine-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (800 mg, 63.8% yield). MS: 639.1 (M+H) + .
步骤2:(3S)-3-甲基-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯的制备Step 2: (3S)-3-Methyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4, 5',8'-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate tert-butyl Preparation of esters
Figure PCTCN2021138375-appb-000275
Figure PCTCN2021138375-appb-000275
将(3S)-4-(6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-硝基嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(50毫克,0.078毫摩尔)和锌粉(51.2毫克,0.783毫摩尔)加到乙酸(5毫升)和水(1毫升)的混合溶液中，反应混合物在75度搅拌3小时。反应完毕后，反应溶液过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(3S)-3-甲基-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯(30毫克,66.5％收率)。MS:577.6(M+H) +。 (3S)-4-(6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-2-(((S)-1- Methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (50 mg, 0.078 mmol) and zinc powder (51.2 mg, 0.783 mmol) was added to a mixed solution of acetic acid (5 mL) and water (1 mL), and the reaction mixture was stirred at 75°C for 3 hours. After the completion of the reaction, the reaction solution was filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (3S)-3-methyl-4-(2'-(((S)-1-methylpyrrole) Alk-2-yl)methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3, 2-d]Pyrimidine]-4'-yl)piperazine-1-carboxylate tert-butyl ester (30 mg, 66.5% yield). MS: 577.6 (M+H) + .
步骤3:4’-((S)-2-甲基哌嗪-1-基)-2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮的制备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
Figure PCTCN2021138375-appb-000276
Figure PCTCN2021138375-appb-000276
将(3S)-3-甲基-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢 -2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯(100毫克,0.173毫摩尔)溶于盐酸的甲醇溶液(5毫升)中，反应混合物在室温搅拌12小时，然后将反应混合物溶液浓缩，并用乙酸乙酯稀释萃取。有机相用饱和碳酸钠水溶液，饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色油状物4’-((S)-2-甲基哌嗪-1-基)-2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮(83毫克,100％收率)。MS:477.6(M+H) +。 (3S)-3-methyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4,5',8'-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate tert-butyl ester ( 100 mg, 0.173 mmol) was dissolved in hydrochloric acid in methanol (5 mL), the reaction mixture was stirred at room temperature for 12 hours, then the reaction mixture solution was concentrated and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium carbonate solution, saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give 4'-((S)-2-methylpiperazin-1-yl)-2'- as a yellow oil. (((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 (83 mg, 100% yield). MS: 477.6 (M+H) + .
步骤4:4’-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮的制备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
Figure PCTCN2021138375-appb-000277
Figure PCTCN2021138375-appb-000277
将4’-((S)-2-甲基哌嗪-1-基)-2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮(100毫克,0.210毫摩尔)和DIEA(81毫克,0.629毫摩尔)溶于二氯甲烷(5毫升)中，在0℃时搅拌缓慢加入丙烯酰氯(18.99毫克,0.210毫摩尔)。滴完后，将反应混合物在0℃并搅拌1小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经Pre-HPLC制备的到白色固体4’-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮(40毫克,32.3％收率)。MS:531.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.16–6.97(m,4H),6.92–6.69(m,1H),6.38–6.18(m,1H),5.79(d,J＝10.6Hz,1H),4.43–4.17(m,3H),4.02–3.98(m,1H),3.90–3.70(m,1H),3.65–3.29(m,4H),3.20–2.92(m,3H),2.78–2.65(m,3H),2.49(s,3H),2.36–2.29(m,1H),2.16–1.61(m,8H),1.05–0.98(m,3H)。 4'-((S)-2-methylpiperazin-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 (100 mg, 0.210 mmol) and DIEA (81 mg, 0.629 mmol) was dissolved in dichloromethane (5 mL) and acryloyl chloride (18.99 mg, 0.210 mmol) was added slowly with stirring at 0°C. After dropping, the reaction mixture was stirred at 0°C for 1 hour, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to a white solid 4'-((S)-4-acryloyl-2-methyl) Piperazin-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 (40 mg, 32.3% yield). MS: 531.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.16-6.97(m,4H),6.92-6.69(m,1H),6.38-6.18(m,1H),5.79(d,J=10.6Hz,1H ), 4.43–4.17 (m, 3H), 4.02–3.98 (m, 1H), 3.90–3.70 (m, 1H), 3.65–3.29 (m, 4H), 3.20–2.92 (m, 3H), 2.78–2.65 (m, 3H), 2.49 (s, 3H), 2.36–2.29 (m, 1H), 2.16–1.61 (m, 8H), 1.05–0.98 (m, 3H).
化合物I-3a和I-3bCompounds I-3a and I-3b
(R)-4’-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮和(S)-4’-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮(R)-4'-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-2'-(((S)-1-methylpyrrolidin-2-yl)methyl oxy)-3,4,5',8'-tetrahydro-2H, 6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-6'-one and ( S)-4'-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy base)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-6'-one
Figure PCTCN2021138375-appb-000278
Figure PCTCN2021138375-appb-000278
将4’-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮(30毫克)经SFC手性拆分(柱型号：Dr.maish Reprosil Chiral-JM，250x25mm，10μm色谱柱，流动相：40％甲醇在二氧化碳中)得到均为白色固体的第一个组分峰化合物I-3a(保留时间为1.21分钟，8毫克)和第二个组分峰化合物I-3b(保留时间为1.99分钟，9毫克)。MS:531.1(M+H) +。 4'-((S)-4-Acryloyl-2-methylpiperazin-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 (30 mg) via SFC chiral resolution (column type: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm column, mobile phase: 40% methanol in carbon dioxide) gave the first component peak compound I-3a (all white solids) ( Retention time 1.21 min, 8 mg) and the second component peak compound 1-3b (retention time 1.99 min, 9 mg). MS: 531.1 (M+H) + .
化合物I-3a(保留时间为1.21分钟，8毫克): 1H NMR(400MHz,Methanol-d 4)δ7.16–6.96(m,4H),6.92–6.69(m,1H),6.38–6.18(m,1H),5.79(d,J＝10.6Hz,1H),4.43–4.17(m,3H),4.02–3.96(m,1H),3.90–3.70(m,1H),3.65–3.29(m,4H),3.20–2.92(m,3H),2.78–2.64(m,3H),2.49(s,3H),2.36–2.26(m,1H),2.16–1.61(m,8H),1.05–0.98(m,3H)。 Compound I-3a (retention time 1.21 min, 8 mg): 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.16–6.96 (m, 4H), 6.92–6.69 (m, 1H), 6.38–6.18 ( m, 1H), 5.79 (d, J=10.6Hz, 1H), 4.43–4.17 (m, 3H), 4.02–3.96 (m, 1H), 3.90–3.70 (m, 1H), 3.65–3.29 (m, 4H), 3.20–2.92 (m, 3H), 2.78–2.64 (m, 3H), 2.49 (s, 3H), 2.36–2.26 (m, 1H), 2.16–1.61 (m, 8H), 1.05–0.98 ( m, 3H).
化合物I-3b(保留时间为1.99分钟，9毫克): 1H NMR(400MHz,Methanol-d 4)δ7.16–6.90(m,4H),6.92–6.69(m,1H),6.38–6.18(m,1H),5.79(d,J＝10.6Hz,1H),4.43–4.17(m,3H),4.02–3.91(m,1H),3.90–3.75(m,1H),3.65–3.29(m,4H),3.20–2.91(m,3H),2.79–2.66(m,3H),2.49(s,3H),2.36–2.28(m,1H),2.16–1.61(m,8H),1.05–0.96(m,3H)。 Compound I-3b (retention time 1.99 min, 9 mg): 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.16–6.90 (m, 4H), 6.92–6.69 (m, 1H), 6.38–6.18 ( m, 1H), 5.79 (d, J=10.6Hz, 1H), 4.43–4.17 (m, 3H), 4.02–3.91 (m, 1H), 3.90–3.75 (m, 1H), 3.65–3.29 (m, 4H), 3.20–2.91 (m, 3H), 2.79–2.66 (m, 3H), 2.49 (s, 3H), 2.36–2.28 (m, 1H), 2.16–1.61 (m, 8H), 1.05–0.96 ( m, 3H).
实施例4Example 4
化合物I-4：4’-((S)-4-(2-氟丙烯酰)-2-甲基哌嗪-1-基)-2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮Compound I-4: 4'-((S)-4-(2-fluoroacryloyl)-2-methylpiperazin-1-yl)-2'-(((S)-1-methylpyrrolidine -2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]- 6'-keto
Figure PCTCN2021138375-appb-000279
Figure PCTCN2021138375-appb-000279
将4’-((S)-2-甲基哌嗪-1-基)-2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮(100毫克,0.210毫摩尔)和DIEA(81毫克,0.629毫摩尔)溶于二氯甲烷(5毫升)中，在0℃时搅拌缓慢加入2-氟丙烯酰氯(中间体B1,22.76毫克,0.210毫摩尔)。滴完后，将反应混合物在0℃并搅拌1小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经Pre-HPLC制备的到白色固体4’-((S)-4-(2-氟丙烯酰)-2-甲基哌嗪-1-基)-2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮(50毫克,43.5％收率)。MS:549.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.14–6.90(m,4H),5.44–5.08(m,2H),4.32–4.26(m,2H),4.08–3.97(m,2H),3.84–3.31(m,5H),3.18–2.92(m,2H),2.80–2.71(m,3H),2.50(s,3H),2.37–2.29(m,1H),2.06–1.89(m,2H),1.77–1.69(m,6H),1.29–1.19(m,4H)。 4'-((S)-2-methylpiperazin-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 (100 mg, 0.210 mmol) and DIEA (81 mg, 0.629 mmol) was dissolved in dichloromethane (5 mL) and 2-fluoroacryloyl chloride (Intermediate B1, 22.76 mg, 0.210 mmol) was added slowly with stirring at 0°C. After dropping, the reaction mixture was stirred at 0°C for 1 hour, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to a white solid 4'-((S)-4-(2-fluoroacryloyl) -2-Methylpiperazin-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 (50 mg, 43.5% yield). MS: 549.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.14-6.90(m,4H),5.44-5.08(m,2H),4.32-4.26(m,2H),4.08-3.97(m,2H),3.84 –3.31(m,5H), 3.18–2.92(m,2H), 2.80–2.71(m,3H), 2.50(s,3H), 2.37–2.29(m,1H), 2.06–1.89(m,2H) , 1.77–1.69 (m, 6H), 1.29–1.19 (m, 4H).
化合物I-4a和I-4bCompounds I-4a and I-4b
(R)-4’-((S)-4-(2-氟丙烯酰)-2-甲基哌嗪-1-基)-2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮和(S)-4’-((S)-4-(2-氟丙烯酰)-2-甲基哌嗪-1-基)-2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮(R)-4'-((S)-4-(2-fluoroacryloyl)-2-methylpiperazin-1-yl)-2'-(((S)-1-methylpyrrolidine- 2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-6 '-ketone and (S)-4'-((S)-4-(2-fluoroacryloyl)-2-methylpiperazin-1-yl)-2'-(((S)-1-methyl pyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d] Pyrimidine]-6'-one
Figure PCTCN2021138375-appb-000280
Figure PCTCN2021138375-appb-000280
4’-((S)-4-(2-氟丙烯酰)-2-甲基哌嗪-1-基)-2’-(((S)-1-甲基吡咯烷-2-基)甲氧 基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮(40毫克)经SFC手性拆分(柱型号：Dr.maish Reprosil Chiral-JM，250x25mm，10μm色谱柱，流动相：40％甲醇在二氧化碳中)得到均为白色固体的第一个组分峰化合物I-4a(保留时间为0.93分钟，12毫克)和第二个组分峰化合物I-4b(保留时间为1.43分钟，10毫克)。MS:549.1(M+H) +。 4'-((S)-4-(2-fluoroacryloyl)-2-methylpiperazin-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 ( 40 mg) was chiral resolved by SFC (column type: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm column, mobile phase: 40% methanol in carbon dioxide) to obtain the first component peak compounds as white solids 1-4a (RT 0.93 min, 12 mg) and the second component peak Compound 1-4b (RT 1.43 min, 10 mg). MS: 549.1 (M+H) + .
化合物I-4a(保留时间为0.93分钟，12毫克): 1H NMR(400MHz,Methanol-d 4)δ7.14–6.90(m,4H),5.44–5.08(m,2H),4.32–4.26(m,2H),4.08–3.97(m,2H),3.84–3.31(m,5H),3.18–2.92(m,2H),2.80–2.71(m,3H),2.50(s,3H),2.37–2.29(m,1H),2.06–1.89(m,2H),1.77–1.69(m,6H),1.29–1.19(m,4H)。 Compound I-4a (retention time 0.93 min, 12 mg): 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.14–6.90 (m, 4H), 5.44–5.08 (m, 2H), 4.32–4.26 ( m, 2H), 4.08–3.97 (m, 2H), 3.84–3.31 (m, 5H), 3.18–2.92 (m, 2H), 2.80–2.71 (m, 3H), 2.50 (s, 3H), 2.37– 2.29 (m, 1H), 2.06–1.89 (m, 2H), 1.77–1.69 (m, 6H), 1.29–1.19 (m, 4H).
化合物I-4b(保留时间为1.43分钟，10毫克): 1H NMR(400MHz,Methanol-d 4)δ7.14–6.90(m,4H),5.44–5.08(m,2H),4.32–4.26(m,2H),4.08–3.97(m,2H),3.84–3.31(m,5H),3.18–2.92(m,2H),2.80–2.71(m,3H),2.50(s,3H),2.37–2.29(m,1H),2.06–1.89(m,2H),1.77–1.69(m,6H),1.29–1.19(m,4H)。 Compound I-4b (retention time 1.43 min, 10 mg): 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.14–6.90 (m, 4H), 5.44–5.08 (m, 2H), 4.32–4.26 ( m, 2H), 4.08–3.97 (m, 2H), 3.84–3.31 (m, 5H), 3.18–2.92 (m, 2H), 2.80–2.71 (m, 3H), 2.50 (s, 3H), 2.37– 2.29 (m, 1H), 2.06–1.89 (m, 2H), 1.77–1.69 (m, 6H), 1.29–1.19 (m, 4H).
实施例5Example 5
化合物I-5：2-((2S)-1-丙烯酰-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound I-5: 2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy -3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-2 -base) acetonitrile
Figure PCTCN2021138375-appb-000281
Figure PCTCN2021138375-appb-000281
Figure PCTCN2021138375-appb-000282
Figure PCTCN2021138375-appb-000282
步骤1:(2S)-2-(氰基甲基)-4-(6-((1-(甲氧基羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯的制备Step 1: (2S)-2-(cyanomethyl)-4-(6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl Preparation of )-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
Figure PCTCN2021138375-appb-000283
Figure PCTCN2021138375-appb-000283
将(S)-(1-甲基吡咯烷-2-基)甲醇(413毫克,3.59毫摩尔)和(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3,700毫克,1.196毫摩尔)溶于无水四氢呋喃(2毫升)中，在25℃时搅拌缓慢加入碳酸铯(780毫克,2.393毫摩尔)。滴完后，将反应混合物缓慢升至50℃并搅拌11小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-2-(氰基甲基)-4-(6-((1-(甲氧基羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯(700毫克,88％收率)。MS:664.1(M+H) +。 Combine (S)-(1-methylpyrrolidin-2-yl)methanol (413 mg, 3.59 mmol) and (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)- 1,2,3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester ( Intermediate A3, 700 mg, 1.196 mmol) was dissolved in dry tetrahydrofuran (2 mL) and cesium carbonate (780 mg, 2.393 mmol) was slowly added with stirring at 25°C. After dropping, the reaction mixture was slowly raised to 50°C and stirred for 11 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2S)-2-(cyanomethyl)-4-(6 -((1-(Methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl )methoxy)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (700 mg, 88% yield). MS: 664.1 (M+H) + .
步骤2:(2S)-2-(氰甲基)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯的制备Step 2: (2S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-3 ,4,5',8'-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxy Preparation of tert-butyl acid
Figure PCTCN2021138375-appb-000284
Figure PCTCN2021138375-appb-000284
将(2S)-2-(氰基甲基)-4-(6-((1-(甲氧基羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯(700毫克,1.055毫摩尔)和锌粉(207毫克,3.16毫摩尔)加到乙酸(5毫升)和水(1毫升)的混合溶液中，反应混合物在75度搅拌3小时。反应完毕后，反应溶液过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-2-(氰甲基)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯(500毫克,78.7％收率)。MS:602.3(M+H) +。 (2S)-2-(cyanomethyl)-4-(6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)- 2-(((S)-1-Methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (700 mg, 1.055 mg mol) and zinc powder (207 mg, 3.16 mmol) were added to a mixed solution of acetic acid (5 mL) and water (1 mL), and the reaction mixture was stirred at 75°C for 3 hours. After completion of the reaction, the reaction solution was filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2S)-2-(cyanomethyl)-4-(2'-((((S)-1- Methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine [3,2-d]Pyrimidine]-4'-yl)piperazine-1-carboxylate tert-butyl ester (500 mg, 78.7% yield). MS: 602.3 (M+H) + .
步骤3:2-((2S)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈的制备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
Figure PCTCN2021138375-appb-000285
Figure PCTCN2021138375-appb-000285
将(2S)-2-(氰甲基)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯(350毫克,0.582毫摩尔)溶于二氯甲烷(5毫升)和6N盐酸甲醇(5毫升)中，反应混合物在室温搅拌1小时。将反应混合液浓缩蒸干，并用乙酸乙酯稀释萃取，有机相用饱和碳酸钠水溶液，饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色油状物2-((2S)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(292毫克,100％收率)。MS:502.3(M+H) +。 (2S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4 ,5',8'-Tetrahydro-2H,6'H-Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylic acid tert. Butyl ester (350 mg, 0.582 mmol) was dissolved in dichloromethane (5 mL) and 6N hydrochloric acid in methanol (5 mL) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and evaporated to dryness, diluted and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give 2-((2S)-4 as a yellow oil. -(2'-(((S)-1-Methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (292 mg, 100% yield). MS: 502.3 (M+H) + .
步骤4:2-((2S)-1-丙烯酰-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈的制备Step 4: 2-((2S)-1-Acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-3 ,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl ) Preparation of acetonitrile
Figure PCTCN2021138375-appb-000286
Figure PCTCN2021138375-appb-000286
将2-((2S)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(100毫克,0.199毫摩尔)和TEA(60.5毫克,0.598毫摩尔)溶于二氯甲烷(5毫升)中，在0℃时搅拌缓慢加入丙烯酰氯(18.04毫克,0.199毫摩尔)。滴完后，将反应混合物在0℃并搅拌1小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经Pre-HPLC制备得到白色固体2-((2S)-1-丙烯酰-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(55毫克,50％收率)。MS:556.1。(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.17–6.99(m,4H),6.79(s,1H),6.27(d,J＝16.7Hz,1H),5.81(d,J＝10.6Hz,1H),4.39–4.22(m,2H),4.20–3.68(m,3H),3.59–3.32(m,3H),3.15–2.67(m,8H),2.49(s,3H),2.37–2.34(m,1H),2.15–1.60(m,8H),1.29(s,1H)。 2-((2S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4,5',8 '-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (100 mg, 0.199 mmol) and TEA (60.5 mg, 0.598 mmol) were dissolved in dichloromethane (5 mL) and acryloyl chloride (18.04 mg, 0.199 mmol) was added slowly with stirring at 0°C. After dropping, the reaction mixture was stirred at 0°C for 1 hour, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was prepared by Pre-HPLC to obtain a white solid 2-((2S)-1-acryloyl-4-(2'- (((S)-1-Methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[ Naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (55 mg, 50% yield). MS: 556.1. (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.17-6.99(m,4H),6.79(s,1H),6.27(d,J=16.7Hz,1H),5.81(d,J=10.6Hz, 1H), 4.39–4.22 (m, 2H), 4.20–3.68 (m, 3H), 3.59–3.32 (m, 3H), 3.15–2.67 (m, 8H), 2.49 (s, 3H), 2.37–2.34 ( m, 1H), 2.15–1.60 (m, 8H), 1.29 (s, 1H).
化合物I-5a和化合物I-5bCompound I-5a and Compound I-5b
2-((S)-1-丙烯酰-4-((R)-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈和2-((S)-1-丙烯酰-4-((S)-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈2-((S)-1-Acryloyl-4-((R)-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy- 3,4,5',8'-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-2- yl)acetonitrile and 2-((S)-1-acryloyl-4-((S)-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6' -Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperidine oxazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000287
Figure PCTCN2021138375-appb-000287
Figure PCTCN2021138375-appb-000288
Figure PCTCN2021138375-appb-000288
2-((2S)-1-丙烯酰-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(50毫克)经SFC手性拆分(柱型号：Dr.maish Reprosil Chiral-JM，250x25mm，10μm色谱柱，流动相：40％甲醇在二氧化碳中)得到均为白色固体的第一个组分峰化合物I-5a(保留时间为1.24分钟，11毫克)和第二个组分峰化合物I-5b(保留时间为2.56分钟，8毫克)。MS:556.1(M+H) +。 2-((2S)-1-Acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4, 5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile ( 50 mg) was chiral resolved by SFC (column type: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm column, mobile phase: 40% methanol in carbon dioxide) to obtain the first component peak compounds as white solids 1-5a (retention time 1.24 min, 11 mg) and the second component peak compound 1-5b (retention time 2.56 min, 8 mg). MS: 556.1 (M+H) + .
化合物I-5a(保留时间为1.24分钟，11毫克)。 1H NMR(400MHz,Methanol-d 4)δ7.17–6.99(m,4H),6.79(s,1H),6.27(d,J＝16.7Hz,1H),5.81(d,J＝10.6Hz,1H),4.39–4.22(m,2H),4.20–3.68(m,3H),3.59–3.32(m,3H),3.15–2.67(m,8H),2.49(s,3H),2.37–2.34(m,1H),2.15–1.60(m,8H),1.29(s,1H)。 Compound 1-5a (retention time 1.24 min, 11 mg). 1 H NMR(400MHz,Methanol-d 4 )δ7.17-6.99(m,4H),6.79(s,1H),6.27(d,J=16.7Hz,1H),5.81(d,J=10.6Hz, 1H), 4.39–4.22 (m, 2H), 4.20–3.68 (m, 3H), 3.59–3.32 (m, 3H), 3.15–2.67 (m, 8H), 2.49 (s, 3H), 2.37–2.34 ( m, 1H), 2.15–1.60 (m, 8H), 1.29 (s, 1H).
化合物I-5b(保留时间为2.56分钟，8毫克)。 1H NMR(400MHz,Methanol-d 4)δ7.17–6.99(m,4H),6.79(s,1H),6.27(d,J＝16.7Hz,1H),5.81(d,J＝10.6Hz,1H),4.39–4.22(m,2H),4.20–3.68(m,3H),3.59–3.32(m,3H),3.15–2.67(m,8H),2.49(s,3H),2.37–2.34(m,1H),2.15–1.60(m,8H),1.29(s,1H)。 Compound 1-5b (retention time 2.56 min, 8 mg). 1 H NMR(400MHz,Methanol-d 4 )δ7.17-6.99(m,4H),6.79(s,1H),6.27(d,J=16.7Hz,1H),5.81(d,J=10.6Hz, 1H), 4.39–4.22 (m, 2H), 4.20–3.68 (m, 3H), 3.59–3.32 (m, 3H), 3.15–2.67 (m, 8H), 2.49 (s, 3H), 2.37–2.34 ( m, 1H), 2.15–1.60 (m, 8H), 1.29 (s, 1H).
实施例6Example 6
化合物I-6(481)：2-((2S)-1-(2-氟丙烯酰基)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound I-6(481): 2-((2S)-1-(2-fluoroacryloyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy base)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4 '-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000289
Figure PCTCN2021138375-appb-000289
将2-((2S)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(100毫克,0.199毫摩尔)和TEA(60.5毫克,0.598毫摩尔)溶于二氯甲烷(5毫升)中，在0℃时搅拌缓慢加入2-氟丙烯酰氯(中间体B1,21.63毫克,0.199毫摩尔)。滴完后，将反应混合物在0℃并搅拌1小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经Pre-HPLC制备得到白色固体2-((2S)-1-(2-氟丙烯酰基)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(55毫克,50％yield)。MS:574.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.26–7.06(m,4H),5.30–5.20(m,2H),4.48–4.27(m,2H),3.93–3.69(m,2H),3.52–3.41(m,1H),3.37–3.21(m,1H),3.17–2.67(m,9H),2.49(s,3H),2.35(m,1H),2.18–1.58(m,8H),1.29(s,2H)。 2-((2S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4,5',8 '-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (100 mg, 0.199 mmol) and TEA (60.5 mg, 0.598 mmol) were dissolved in dichloromethane (5 mL) and 2-fluoroacryloyl chloride (Intermediate B1, 21.63 mg, 0.199 mmol) was added slowly with stirring at 0°C. After dropping, the reaction mixture was stirred at 0°C for 1 hour, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was prepared by Pre-HPLC to obtain a white solid 2-((2S)-1-(2-fluoroacryloyl)-4 -(2'-(((S)-1-Methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (55 mg, 50% yield). MS: 574.1 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ7.26-7.06(m,4H),5.30-5.20(m,2H),4.48-4.27(m,2H),3.93-3.69(m,2H),3.52 –3.41(m,1H), 3.37–3.21(m,1H), 3.17–2.67(m,9H), 2.49(s,3H), 2.35(m,1H), 2.18–1.58(m,8H), 1.29 (s, 2H).
化合物I-6a和化合物I-6bCompound I-6a and Compound I-6b
2-((S)-1-(2-氟丙烯酰基)-4-((R)-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈和2-((S)-1-(2-氟丙烯酰基)-4-((S)-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈2-((S)-1-(2-Fluoroacryloyl)-4-((R)-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6 '-Oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperidine Azin-2-yl)acetonitrile and 2-((S)-1-(2-fluoroacryloyl)-4-((S)-2'-(((S)-1-methylpyrrolidine-2- yl)methoxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine ]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000290
Figure PCTCN2021138375-appb-000290
2-((2S)-1-(2-氟丙烯酰基)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(50毫克)经SFC手性拆分(柱型号：Dr.maish Reprosil Chiral-JM，250x25mm，10μm色谱柱，流动相：40％甲醇在二氧化碳中)得到均为白色固体的第一个组分峰化合物I-6a(保留时间为1.01分钟，13毫克)和第二个组分峰化合物I-6b保留时间为2.17分钟，9毫克)。MS:574.1(M+H) +。 2-((2S)-1-(2-Fluoroacryloyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy -3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-2 - base) acetonitrile (50 mg) by SFC chiral resolution (column type: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm column, mobile phase: 40% methanol in carbon dioxide) to give the first white solids The first component peak, Compound 1-6a (retention time 1.01 min, 13 mg) and the second component peak Compound 1-6b, retention time 2.17 min, 9 mg). MS: 574.1 (M+H) + .
化合物I-6a(保留时间为1.01分钟，13毫克)。 1H NMR(400MHz,Methanol-d 4)δ 7.26–7.06(m,4H),5.30–5.20(m,2H),4.48–4.27(m,2H),3.93–3.69(m,2H),3.52–3.41(m,1H),3.37–3.21(m,1H),3.17–2.67(m,9H),2.49(s,3H),2.35(m,1H),2.18–1.58(m,8H),1.29(s,2H)。 Compound 1-6a (retention time 1.01 min, 13 mg). 1 H NMR (400MHz, Methanol-d 4 )δ 7.26–7.06(m,4H), 5.30–5.20(m,2H), 4.48–4.27(m,2H), 3.93–3.69(m,2H), 3.52– 3.41 (m, 1H), 3.37–3.21 (m, 1H), 3.17–2.67 (m, 9H), 2.49 (s, 3H), 2.35 (m, 1H), 2.18–1.58 (m, 8H), 1.29 ( s, 2H).
化合物I-6b(保留时间为2.17分钟，9毫克)。 1H NMR(400MHz,Methanol-d 4)δ7.26–7.06(m,4H),5.30–5.20(m,2H),4.48–4.27(m,2H),3.93–3.69(m,2H),3.52–3.41(m,1H),3.37–3.21(m,1H),3.17–2.67(m,9H),2.49(s,3H),2.35(m,1H),2.18–1.58(m,8H),1.29(s,2H)。 Compound 1-6b (retention time 2.17 min, 9 mg). 1 H NMR(400MHz, Methanol-d 4 )δ7.26-7.06(m,4H),5.30-5.20(m,2H),4.48-4.27(m,2H),3.93-3.69(m,2H),3.52 –3.41(m,1H), 3.37–3.21(m,1H), 3.17–2.67(m,9H), 2.49(s,3H), 2.35(m,1H), 2.18–1.58(m,8H), 1.29 (s, 2H).
实施例7Example 7
化合物I-7：4'-((2S，5R)-4-丙烯酰-2,5-二甲基哌嗪-1-基)-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮Compound I-7: 4'-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-2'-(((S)-1-methylpyrrolidine -2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]- 6'-keto
Figure PCTCN2021138375-appb-000291
Figure PCTCN2021138375-appb-000291
化合物I-7的合成参考化合物I-5，通过使用(2R，5S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(中间体A5)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)制备得到化合物I-7。Synthesis of compound 1-7 Reference compound 1-5 by using (2R,5S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene) -1-yl)methyl)-5-nitropyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (Intermediate A5) instead of (2S)-4-( 2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-( Cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) was prepared to give compound 1-7.
化合物I-7(11.6毫克)。MS:545.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.29–7.06(m,4H),6.80(s,1H),6.15–6.98(m,1H),5.71–5.65(m,1H),4.78(s,1H),4.52–4.49(m,1H),4.46–4.28(m,2H),4.00–3.87(m,1H),3.76–3.65(m,2H),3.52-3.41(m,3H),3.21–3.02(m,2H),2.90–2.85(m,2H),2.81(s,1H),2.73(s,1H),2.41(s,3H),2.19(s,1H),2.02(s,1H),1.93–1.77(m,3H),1.74–1.67(m,1H),1.18–1.09(m,3H),1.00–0.89(m,3H)。 Compound 1-7 (11.6 mg). MS: 545.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ7.29-7.06(m, 4H), 6.80(s, 1H), 6.15-6.98(m, 1H), 5.71-5.65(m, 1H), 4.78(s ,1H),4.52-4.49(m,1H),4.46-4.28(m,2H),4.00-3.87(m,1H),3.76-3.65(m,2H),3.52-3.41(m,3H),3.21 –3.02(m, 2H), 2.90 – 2.85(m, 2H), 2.81(s, 1H), 2.73(s, 1H), 2.41(s, 3H), 2.19(s, 1H), 2.02(s, 1H) ), 1.93–1.77 (m, 3H), 1.74–1.67 (m, 1H), 1.18–1.09 (m, 3H), 1.00–0.89 (m, 3H).
实施例8Example 8
化合物I-8：4'-(2-丙烯酰-2,7-二氮杂螺[3.5]壬-7-基)-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮Compound I-8: 4'-(2-Acryloyl-2,7-diazaspiro[3.5]nonan-7-yl)-2'-(((S)-1-methylpyrrolidine-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-6'- ketone
Figure PCTCN2021138375-appb-000292
Figure PCTCN2021138375-appb-000292
化合物I-8的合成参考化合物I-5，通过使用7-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(中间体A6)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)制备得到化合物I-8。Synthesis of compound 1-8 Reference compound 1-5, by using 7-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methan (2S)-4-(2- Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyano Methyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) was prepared to give compound 1-8.
化合物I-8(10.6毫克)。MS:557.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)7.13–7.02(m,4H),6.32(dd,J＝17.0,10.3Hz,1H),6.10(d,J＝17.0Hz,1H),5.66–5.59(m,1H),4.58–4.36(m,2H),4.09–3.83(m,10H),3.68(s,1H),3.57(s,1H),3.43–3.38(m,3H),3.25(s,2H),3.15–3.05(m,1H),2.92–2.71(m,5H),2.21–2.16(m,1H),1.94(s,1H),1.86(s,1H),1.71(s,4H)。 Compound 1-8 (10.6 mg). MS: 557.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) 7.13-7.02 (m, 4H), 6.32 (dd, J=17.0, 10.3Hz, 1H), 6.10 (d, J=17.0Hz, 1H), 5.66-5.59 ( m, 1H), 4.58–4.36 (m, 2H), 4.09–3.83 (m, 10H), 3.68 (s, 1H), 3.57 (s, 1H), 3.43–3.38 (m, 3H), 3.25 (s, 2H), 3.15–3.05(m,1H), 2.92–2.71(m,5H), 2.21–2.16(m,1H), 1.94(s,1H), 1.86(s,1H), 1.71(s,4H) .
实施例9Example 9
化合物I-9：2-((2S)-1-(but-2-炔酰基)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-9: 2-((2S)-1-(but-2-alkynoyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy) -6'-Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4'- yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000293
Figure PCTCN2021138375-appb-000293
将2-((2S)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(50毫克,0.100毫摩尔)和TEA(60.5毫克,0.598毫摩尔)溶于二氯甲烷(5毫升)中，在0℃时搅拌缓慢加入丁-2-炔酰氯(中间体B2,10.63毫克,0.100毫摩尔)。滴完后，将反应混合物在0℃并搅拌1小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经Pre-HPLC制备得到白色固体2-((2S) -1-(丁-2-炔酰基)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(5毫克,10％yield)。MS:568.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.17–6.98(m,4H),4.64–4.56(m,3H),4.41–4.30(m,3H),4.19–3.70(m,2H),3.60–3.33(m,1H),3.17–2.74(m,7H),2.54–2.45(m,4H),2.32–1.60(m,9H),1.30–1.15(m,3H)。 2-((2S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4,5',8 '-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (50 mg, 0.100 mmol) and TEA (60.5 mg, 0.598 mmol) were dissolved in dichloromethane (5 mL) and but-2-ynoyl chloride (Intermediate B2, 10.63 mg, 0.100 mmol) was added slowly with stirring at 0°C. After dropping, the reaction mixture was stirred at 0°C for 1 hour, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was prepared by Pre-HPLC to give a white solid 2-((2S)-1-(but-2-ynoyl)- 4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6 'H-Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (5 mg, 10% yield). MS: 568.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.17-6.98(m,4H),4.64-4.56(m,3H),4.41-4.30(m,3H),4.19-3.70(m,2H),3.60 – 3.33 (m, 1H), 3.17 – 2.74 (m, 7H), 2.54 – 2.45 (m, 4H), 2.32 – 1.60 (m, 9H), 1.30 – 1.15 (m, 3H).
实施例10Example 10
化合物I-10a和I-10b：2-((S)-1-丙烯酰-4-((S)-2'-甲氧基-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈和2-((S)-1-丙烯酰-4-((R)-2'-甲氧基-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compounds I-10a and I-10b: 2-((S)-1-acryloyl-4-((S)-2'-methoxy-6'-oxy-3,4,5',8' -Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile and 2-((S )-1-Acryloyl-4-((R)-2'-methoxy-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene] -1,7'-Pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000294
Figure PCTCN2021138375-appb-000294
化合物I-10a和化合物I-10b的合成参考化合物I-5，通过使用(2S)-2-(氰基甲基)-4-(2-甲氧基-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯(中间体A11)代替(2S)-2-(氰基甲基)-4-(6-((1-(甲氧基羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯(化合物I-5/步骤1)制备得到化合物I-10a和化合物I-10b。Synthesis of compound 1-10a and compound 1-10b Reference compound 1-5, by using (2S)-2-(cyanomethyl)-4-(2-methoxy-6-((1-(methoxymethyl) carbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (Intermediate A11) instead of ( 2S)-2-(cyanomethyl)-4-(6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-2- (((S)-1-Methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (Compound 1-5/Step 1 ) to prepare compound I-10a and compound I-10b.
化合物I-10a(保留时间为4.74分钟,7.6毫克)。MS:473.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.15–6.97(m,4H),6.80(s,1H),6.28–6.01(m,1H),5.83–5.71(m,1H),5.24–4.86(m,1H),4.68–4.30(m,1H),4.03–3.88(m,4H),3.66–3.28(m,6H),3.13–2.88(m,2H),2.83–2.74(m,2H),2.20–1.72(m,4H)。 Compound 1-10a (retention time 4.74 min, 7.6 mg). MS: 473.1 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ7.15-6.97(m,4H),6.80(s,1H),6.28-6.01(m,1H),5.83-5.71(m,1H),5.24-4.86 (m, 1H), 4.68–4.30 (m, 1H), 4.03–3.88 (m, 4H), 3.66–3.28 (m, 6H), 3.13–2.88 (m, 2H), 2.83–2.74 (m, 2H) , 2.20–1.72 (m, 4H).
化合物I-10b(保留时间为5.44分钟,11.6毫克)。MS:473.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.15–6.97(m,4H),6.80(s,1H),6.28–6.01(m,1H),5.83–5.71(m,1H),5.24–4.86(m,1H),4.68–4.30(m,1H),4.03–3.88(m,4H),3.66–3.28(m,6H),3.13–2.88(m,2H),2.83–2.74(m,2H),2.20–1.72(m,4H)。 Compound I-10b (retention time 5.44 min, 11.6 mg). MS: 473.1 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ7.15-6.97(m,4H),6.80(s,1H),6.28-6.01(m,1H),5.83-5.71(m,1H),5.24-4.86 (m, 1H), 4.68–4.30 (m, 1H), 4.03–3.88 (m, 4H), 3.66–3.28 (m, 6H), 3.13–2.88 (m, 2H), 2.83–2.74 (m, 2H) , 2.20–1.72 (m, 4H).
实施例11Example 11
化合物I-11：2-((2S)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-((E)-4,4,4-三氟-2-烯基)哌嗪-2-基)乙腈Compound I-11: 2-((2S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4, 5',8'-Tetrahydro-2H,6'H-Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1-((E)-4 ,4,4-Trifluoro-2-enyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000295
Figure PCTCN2021138375-appb-000295
化合物I-11的合成参考化合物I-6，通过使用(E)-4,4,4-三氟-2-烯酰氯(中间体B3)代替2-氟丙烯酰氯(中间体B1)制备得到化合物I-11。Synthesis of compound 1-11 Reference compound 1-6, prepared by using (E)-4,4,4-trifluoro-2-enoyl chloride (intermediate B3) in place of 2-fluoroacryloyl chloride (intermediate B1) I-11.
化合物I-11(25.4毫克)。MS:625.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.54–7.35(m,1H),7.27–7.02(m,4H),6.84(dd,J＝15.6,7.6Hz,1H),5.05(s,1H),4.80(s,1H),4.58–4.48(m,1H),4.43(s,1H),3.75(s,2H),3.59–3.41(m,4H),3.36–3.20(m,1H),3.13(s,2H),2.99–2.95(m,1H),2.92–2.85(m,5H),2.76–2.53(m,2H),2.23(s,1H),2.04(s,2H),1.74–1.54(m,6H)。 Compound 1-11 (25.4 mg). MS: 625.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 7.54-7.35 (m, 1H), 7.27-7.02 (m, 4H), 6.84 (dd, J=15.6, 7.6Hz, 1H), 5.05 (s, 1H) ), 4.80(s, 1H), 4.58–4.48(m, 1H), 4.43(s, 1H), 3.75(s, 2H), 3.59–3.41(m, 4H), 3.36–3.20(m, 1H), 3.13(s,2H), 2.99–2.95(m,1H), 2.92–2.85(m,5H), 2.76–2.53(m,2H), 2.23(s,1H), 2.04(s,2H), 1.74– 1.54 (m, 6H).
实施例12Example 12
化合物I-12：4'-((R)-4-丙烯酰-3-(氟甲基)哌嗪-1-基)-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮Compound I-12: 4'-((R)-4-acryloyl-3-(fluoromethyl)piperazin-1-yl)-2'-(((S)-1-methylpyrrolidine-2 -yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-6' -ketone
Figure PCTCN2021138375-appb-000296
Figure PCTCN2021138375-appb-000296
化合物I-12的合成参考化合物I-5，通过使用(2R)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氟甲基)哌嗪-1-羧酸苄酯(中间体A9)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)制备得到化合物I-12。Synthesis of compound 1-12 Reference compound 1-5 by using (2R)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene-1 -yl)methyl)-5-nitropyrimidin-4-yl)-2-(fluoromethyl)piperazine-1-carboxylate benzyl ester (Intermediate A9) instead of (2S)-4-(2-chloro -6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl) yl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) was prepared to give compound 1-12.
化合物I-12(10.6毫克)。MS:549.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.27– 7.04(m,4H),6.81(dd,J＝16.4,10.6Hz,1H),6.15(d,J＝16.2Hz,1H),5.72–5.54(m,1H),4.92(s,1H),4.63(s,2H),4.40–4.13(m,2H),4.08–3.98(m,1H),3.89–3.66(m,2H),3.58–3.45(m,1H),3.16–3.08(m,2H),2.97–2.92(m,1H),2.89–2.61(m,4H),2.55(s,1H),2.34(s,3H),2.18(s,1H),2.01–1.48(m,8H)。 Compound 1-12 (10.6 mg). MS: 549.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.27– 7.04 (m, 4H), 6.81 (dd, J=16.4, 10.6 Hz, 1H), 6.15 (d, J=16.2 Hz, 1H), 5.72– 5.54 (m, 1H), 4.92 (s, 1H), 4.63 (s, 2H), 4.40–4.13 (m, 2H), 4.08–3.98 (m, 1H), 3.89–3.66 (m, 2H), 3.58– 3.45(m,1H), 3.16–3.08(m,2H), 2.97–2.92(m,1H), 2.89–2.61(m,4H), 2.55(s,1H), 2.34(s,3H), 2.18( s, 1H), 2.01–1.48 (m, 8H).
实施例13Example 13
化合物I-13：4'-((3R，5S)-4-丙烯酰-3,5-二甲基哌嗪-1-基)-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮Compound I-13: 4'-((3R,5S)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-2'-(((S)-1-methylpyrrolidine -2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]- 6'-keto
Figure PCTCN2021138375-appb-000297
Figure PCTCN2021138375-appb-000297
化合物I-13的合成参考化合物I-5，通过使用(2R，6S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2,6-二甲基哌嗪-1-羧酸叔丁酯(中间体A4)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)制备得到化合物I-13。Synthesis of compound 1-13 Reference compound 1-5, by using (2R,6S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene) -1-yl)methyl)-5-nitropyrimidin-4-yl)-2,6-dimethylpiperazine-1-carboxylate tert-butyl ester (Intermediate A4) instead of (2S)-4-( 2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-( Cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) was prepared to give compound 1-13.
化合物I-13(9.1毫克)。MS:545.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.18–7.06(m,4H),6.77(dd,J＝16.5,10.5Hz,1H),6.16(d,J＝16.6Hz,1H),5.73–5.68(m,1H),4.48–4.35(m,4H),4.19–3.99(m,1H),3.86(s,1H),3.42–3.26(m,2H),3.18–3.09(m,2H),2.91–2.85(m,3H),2.83–2.78(m 1H),2.74(s,3H),2.42(s,1H),2.23(s,1H),2.03(s,1H),1.89(s,3H),1.71(s,3H),1.32–1.25(m,3H),1.14–1.10(m,3H)。 Compound 1-13 (9.1 mg). MS: 545.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 7.18-7.06 (m, 4H), 6.77 (dd, J=16.5, 10.5Hz, 1H), 6.16 (d, J=16.6Hz, 1H), 5.73- 5.68 (m, 1H), 4.48–4.35 (m, 4H), 4.19–3.99 (m, 1H), 3.86 (s, 1H), 3.42–3.26 (m, 2H), 3.18–3.09 (m, 2H), 2.91–2.85(m, 3H), 2.83–2.78(m 1H), 2.74(s, 3H), 2.42(s, 1H), 2.23(s, 1H), 2.03(s, 1H), 1.89(s, 3H) ), 1.71 (s, 3H), 1.32–1.25 (m, 3H), 1.14–1.10 (m, 3H).
实施例14Example 14
化合物I-14：2-((2S)-1-丙烯酰-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-2,3,5',8'-四氢-6'H-螺环[茚-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound I-14: 2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxyl -2,3,5',8'-Tetrahydro-6'H-spiro[indene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl ) acetonitrile
Figure PCTCN2021138375-appb-000298
Figure PCTCN2021138375-appb-000298
Figure PCTCN2021138375-appb-000299
Figure PCTCN2021138375-appb-000299
步骤1:(2S)-2-(氰基甲基)-4-(6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸苄酯的制备Step 1: (2S)-2-(cyanomethyl)-4-(6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)- Preparation of 2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester
Figure PCTCN2021138375-appb-000300
Figure PCTCN2021138375-appb-000300
将(S)-(1-甲基吡咯烷-2-基)甲醇(114毫克,0.992毫摩尔)和(2S)-4-(2-氯-6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A12,200毫克,0.331毫摩尔)溶于无水四氢呋喃(5毫升)中，在25℃时搅拌缓慢加入碳酸铯(215毫克,0.661毫摩尔)。滴完后，将反应混合物缓慢升至50℃并搅拌11小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-2-(氰基甲基)-4-(6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸苄酯(113毫克,50％收率)。MS:684.1(M+H) +。 Combine (S)-(1-methylpyrrolidin-2-yl)methanol (114 mg, 0.992 mmol) and (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)- 2,3-Dihydro-1H-inden-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate benzyl ester (intermediate A12, 200 mg, 0.331 mmol) was dissolved in dry tetrahydrofuran (5 mL) and cesium carbonate (215 mg, 0.661 mmol) was slowly added with stirring at 25°C. After dropping, the reaction mixture was slowly raised to 50°C and stirred for 11 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2S)-2-(cyanomethyl)-4-(6 -((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methyl oxy)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate benzyl ester (113 mg, 50% yield). MS: 684.1 (M+H) + .
步骤2:(2S)-2-(氰甲基)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-2,3,5',8'-四氢-6'H-螺环[茚-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸苄酯的制备Step 2: (2S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-2 ,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate benzyl Preparation of esters
Figure PCTCN2021138375-appb-000301
Figure PCTCN2021138375-appb-000301
将((2S)-2-(氰基甲基)-4-(6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸苄酯(226毫克,0.331毫摩尔)和锌粉(103毫克,1.18毫摩尔)加到乙酸(5毫升)和水(1毫升)的混合溶液中，反应混合物在75度搅拌3小时。反应完毕后，反应溶液过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-2-(氰甲基)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-2,3,5',8'-四氢-6'H-螺环[茚-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸苄酯(120毫克,58.4％收率)。MS:622.1(M+H) +。 ((2S)-2-(cyanomethyl)-4-(6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-2 -(((S)-1-Methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate benzyl ester (226 mg, 0.331 mmol) And zinc powder (103 mg, 1.18 mmol) was added in the mixed solution of acetic acid (5 mL) and water (1 mL), and the reaction mixture was stirred at 75 degrees for 3 hours. After the completion of the reaction, the reaction solution was filtered and concentrated to obtain a crude product , the crude product was purified by silica gel column chromatography to give a yellow solid (2S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy )-6'-oxy-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl ) benzyl piperazine-1-carboxylate (120 mg, 58.4% yield). MS: 622.1 (M+H) + .
步骤3:2-((2S)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-2,3,5',8'-四氢-6'H-螺环[茚-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈的制备Step 3: 2-((2S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-2,3,5' Preparation of ,8'-tetrahydro-6'H-spiro[indene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000302
Figure PCTCN2021138375-appb-000302
将(2S)-2-(氰甲基)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-2,3,5',8'-四氢-6'H-螺环[茚-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸苄酯(210毫克,0.338毫摩尔)溶于乙醇醇(5毫升)中，在搅拌条件下向反应混合物中加入钯碳(711毫克)。反应混合物在氢气作用下室温搅拌2小时，然后将混合物溶液过滤。将滤液真空浓缩，得到黄色油状物2-((2S)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-2,3,5',8'-四氢-6'H-螺环[茚-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(160毫克,97％收率)。MS:488.1(M+H) +。 (2S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-2,3 ,5',8'-Tetrahydro-6'H-spiro[indene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate benzyl ester ( 210 mg, 0.338 mmol) was dissolved in ethanol alcohol (5 mL) and palladium on carbon (711 mg) was added to the reaction mixture with stirring. The reaction mixture was stirred at room temperature under the influence of hydrogen for 2 hours, and then the mixture solution was filtered. The filtrate was concentrated in vacuo to give 2-((2S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy- 2,3,5',8'-Tetrahydro-6'H-spiro[indene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl) Acetonitrile (160 mg, 97% yield). MS: 488.1 (M+H) + .
步骤4:2-((2S)-1-丙烯酰-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-2,3,5',8'-四氢-6'H-螺环[茚-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈的制备Step 4: 2-((2S)-1-Acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-2 ,3,5',8'-Tetrahydro-6'H-spiro[indene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile preparation
Figure PCTCN2021138375-appb-000303
Figure PCTCN2021138375-appb-000303
将2-((2S)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-2,3,5',8'-四氢-6'H-螺环[茚-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(90毫克,0.185毫摩尔)和TEA(56.0毫克,0.554毫摩尔)溶于二氯甲烷(5毫升)中，在0℃时搅拌缓慢加入丙烯酰氯(16.7毫克,0.185毫摩尔)。滴完后，将反应混合物在0℃并搅拌1小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经Pre-HPLC制备得到白色固体2-((2S)-1-丙烯酰-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-2,3,5',8'-四氢-6'H-螺环[茚-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(50毫克,50％收率)。MS:542.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.42–6.65(m,5H),6.28–6.15(m,1H),5.82–5.73(m,1H),5.06(s,1H),4.71–4.64(m,1H),4.52(s,1H),4.04–3.95(m,3H),3.78–3.67(m,2H),3.37–3.35(m,1H),3.34–2.69(m,13H),2.43–2.31(m,1H),2.11–1.96(m,5H)。 2-((2S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-2,3,5',8 '-Tetrahydro-6'H-spiro[indene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (90 mg, 0.185 mmol ) and TEA (56.0 mg, 0.554 mmol) were dissolved in dichloromethane (5 mL) and acryloyl chloride (16.7 mg, 0.185 mmol) was added slowly with stirring at 0°C. After dropping, the reaction mixture was stirred at 0°C for 1 hour, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was prepared by Pre-HPLC to obtain a white solid 2-((2S)-1-acryloyl-4-(2'- (((S)-1-Methylpyrrolidin-2-yl)methoxy)-6'-oxy-2,3,5',8'-tetrahydro-6'H-spiro[indene- 1,7'-Pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (50 mg, 50% yield). MS: 542.1 (M+H) + . 1 H NMR (400MHz, Methanol-d 4 )δ7.42-6.65(m,5H), 6.28-6.15(m,1H), 5.82-5.73(m,1H), 5.06(s,1H), 4.71-4.64 (m, 1H), 4.52 (s, 1H), 4.04–3.95 (m, 3H), 3.78–3.67 (m, 2H), 3.37–3.35 (m, 1H), 3.34–2.69 (m, 13H), 2.43 – 2.31 (m, 1H), 2.11 – 1.96 (m, 5H).
实施例15Example 15
化合物I-15：2-((2S)-4-丙烯酰-1-(2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6’-氧基-3,4,5’，8’-四氢-2H，6’H-螺环[萘-1,7’-吡啶[3,2-d]嘧啶]-4’-基)哌嗪-2-基)乙腈Compound I-15: 2-((2S)-4-acryloyl-1-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxyl -3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-2 -base) acetonitrile
Figure PCTCN2021138375-appb-000304
Figure PCTCN2021138375-appb-000304
化合物I-15的合成参考化合物I-5，通过使用(3S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-3-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A10)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)制备得到化合物I-15。Synthesis of compound 1-15 Reference compound 1-5 by using (3S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene-1 -yl)methyl)-5-nitropyrimidin-4-yl)-3-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A10) instead of (2S)-4-(2 -Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyano Compound 1-15 was prepared from tert-butyl methyl)piperazine-1-carboxylate (Intermediate A3).
化合物I-15(2.1毫克)。MS:556.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.13–7.02(m,4H),6.81–6.71(m,1H),6.45–6.07(m,1H),5.82–5.45(m,1H),4.57–4.21m,6H), 3.89–3.32(m,6H),3.09–2.58(m,5H),2.34–1.67(m,8H),1.30–1.21(m,4H)。 Compound 1-15 (2.1 mg). MS: 556.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.13-7.02(m,4H),6.81-6.71(m,1H),6.45-6.07(m,1H),5.82-5.45(m,1H),4.57 –4.21m, 6H), 3.89–3.32 (m, 6H), 3.09–2.58 (m, 5H), 2.34–1.67 (m, 8H), 1.30–1.21 (m, 4H).
实施例16Example 16
化合物I-16：4'-((1R，5S)-8-丙烯酰-3,8-二氮杂二环[3.2.1]辛烷-3-基)-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮Compound I-16: 4'-((1R,5S)-8-acryloyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-2'-((((S) -1-Methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3, 2-d]pyrimidin]-6'-one
Figure PCTCN2021138375-appb-000305
Figure PCTCN2021138375-appb-000305
化合物I-16的合成参考化合物I-5，通过使用(1R，5S)-3-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯(中间体A7)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)制备得到化合物I-16。Synthesis of compound 1-16 Reference compound 1-5 by using (1R,5S)-3-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene) -1-yl)methyl)-5-nitropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester (Intermediate A7) instead (2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4 -yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) was prepared to give compound 1-16.
化合物I-16(11.6毫克)。MS:543.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.14–6.95(m,4H),6.75(dd,J＝16.8,10.4Hz,1H),6.34(d,J＝16.7Hz,1H),5.80–5.45(m,1H),4.77–4.68(m,1H),4.61(s,1H),4.45–4.38(m,1H),4.32–4.13(m,2H),3.72–3.69(m,1H),3.66–3.50(m,1H),3.44–3.34(m,1H),3.23–3.05(m,2H),2.94–2.87(m,1H),2.81–2.61(m,3H),2.51(s,3H),2.38–2.34(m,1H),2.32–2.15(m,2H),2.13–1.63(m,8H)。 Compound 1-16 (11.6 mg). MS: 543.1 (M+H) + . 1 H NMR (400MHz, Methanol-d 4 )δ7.14-6.95(m,4H),6.75(dd,J=16.8,10.4Hz,1H),6.34(d,J=16.7Hz,1H),5.80- 5.45 (m, 1H), 4.77–4.68 (m, 1H), 4.61 (s, 1H), 4.45–4.38 (m, 1H), 4.32–4.13 (m, 2H), 3.72–3.69 (m, 1H), 3.66–3.50 (m, 1H), 3.44–3.34 (m, 1H), 3.23–3.05 (m, 2H), 2.94–2.87 (m, 1H), 2.81–2.61 (m, 3H), 2.51 (s, 3H) ), 2.38–2.34 (m, 1H), 2.32–2.15 (m, 2H), 2.13–1.63 (m, 8H).
实施例17Example 17
化合物I-17：4'-((1R，5S)-3-丙烯酰-3,8-二氮杂二环[3.2.1]辛烷-8-基)-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮Compound I-17: 4'-((1R,5S)-3-acryloyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-2'-((((S) -1-Methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3, 2-d]pyrimidin]-6'-one
Figure PCTCN2021138375-appb-000306
Figure PCTCN2021138375-appb-000306
化合物I-17的合成参考化合物I-5，通过使用(1R，5S)-8-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(中间体A8)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)制备得到化合物I-17。Synthesis of compound 1-17 Reference compound 1-5, by using (1R,5S)-8-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene) -1-yl)methyl)-5-nitropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester (Intermediate A8) instead of ( 2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4- yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A3) was prepared to give compound 1-17.
化合物I-17(15.7毫克)。MS:543.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.15–6.98(m,4H),6.81–6.63(m,1H),6.23–6.10(m,1H),5.76–5.65(m,1H),4.69(s,1H),4.55–4.49(m,1H),4.32–4.15(m,3H),4.02–3.42(m,3H),3.35–3.19(m,2H),3.11–2.99(m,1H),2.93–2.87(m 1H),2.80–2.75(m,3H),2.51(s,3H),2.39–2.34(m,1H),2.29–1.61(m,9H)。 Compound 1-17 (15.7 mg). MS: 543.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.15-6.98(m,4H),6.81-6.63(m,1H),6.23-6.10(m,1H),5.76-5.65(m,1H),4.69 (s, 1H), 4.55–4.49 (m, 1H), 4.32–4.15 (m, 3H), 4.02–3.42 (m, 3H), 3.35–3.19 (m, 2H), 3.11–2.99 (m, 1H) , 2.93–2.87 (m 1H), 2.80–2.75 (m, 3H), 2.51 (s, 3H), 2.39–2.34 (m, 1H), 2.29–1.61 (m, 9H).
实施例18Example 18
化合物I-18：2-((2S)-1-((E)-4-甲氧基-2-烯基)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-18: 2-((2S)-1-((E)-4-methoxy-2-enyl)-4-(2'-(((S)-1-methylpyrrolidine- 2-yl)methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2- d]Pyrimidine]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000307
Figure PCTCN2021138375-appb-000307
化合物I-18的合成参考化合物I-6，通过使用(E)-4-甲氧基-2-烯酰氯(中间体B4)代替2-氟丙烯酰氯(中间体B1)制备得到化合物I-18。Synthesis of compound 1-18 Reference compound 1-6, prepared by using (E)-4-methoxy-2-enoyl chloride (intermediate B4) in place of 2-fluoroacryloyl chloride (intermediate B1) to obtain compound 1-18 .
化合物I-18(20.4毫克)。MS:600.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.30–7.00(m,4H),6.67–6.45(m,2H),5.06(s,1H),4.62–4.24(m,4H),4.08(s,2H),3.72–3.59(m,6H),3.37(s,1H),3.30–3.27(m,3H),3.10–3.05(m,3H),2.97–2.94(m,1H),2.91(s,3H),2.75–2.69(m,3H),2.22(s,1H),2.04–1.95(m,2H),1.79–1.68(m,5H)。 Compound 1-18 (20.4 mg). MS: 600.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ7.30-7.00(m,4H),6.67-6.45(m,2H),5.06(s,1H),4.62-4.24(m,4H),4.08(s ,2H),3.72–3.59(m,6H),3.37(s,1H),3.30–3.27(m,3H),3.10–3.05(m,3H),2.97–2.94(m,1H),2.91(s , 3H), 2.75–2.69 (m, 3H), 2.22 (s, 1H), 2.04–1.95 (m, 2H), 1.79–1.68 (m, 5H).
实施例19Example 19
化合物I-19：4’-((R)-4-丙烯酰-2-(羟甲基)哌嗪-1-基)-2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮Compound I-19: 4'-((R)-4-acryloyl-2-(hydroxymethyl)piperazin-1-yl)-2'-(((S)-1-methylpyrrolidine-2 -yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-6' -ketone
Figure PCTCN2021138375-appb-000308
Figure PCTCN2021138375-appb-000308
步骤1:(R)-4-丙烯酰-2-(羟甲基)哌嗪-1-羧酸叔丁酯的制备Step 1: Preparation of (R)-4-Acryloyl-2-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000309
Figure PCTCN2021138375-appb-000309
将(R)-2-(羟甲基)哌嗪-1-羧酸叔丁酯(2.0克,9.26毫摩尔)和TEA(1.87克,18.52毫摩尔)溶于二氯甲烷(25毫升)中，在0℃时搅拌缓慢加入丙烯酰氯(922毫克,10.19毫摩尔)。滴完后，将反应混合物在0℃并搅拌1小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色油状物(R)-4-丙烯酰-2-(羟甲基)哌嗪-1-羧酸叔丁酯(1.8克,72％收率)。MS:271.3(M+H) +。 (R)-tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate (2.0 g, 9.26 mmol) and TEA (1.87 g, 18.52 mmol) were dissolved in dichloromethane (25 mL) , Acryloyl chloride (922 mg, 10.19 mmol) was slowly added with stirring at 0 °C. After dropping, the reaction mixture was stirred at 0°C for 1 hour, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain (R)-4-acryloyl-2-(hydroxymethyl) as a colorless oil. ) piperazine-1-carboxylate tert-butyl ester (1.8 g, 72% yield). MS: 271.3 (M+H) + .
步骤2:(R)-1-(3-(羟甲基)哌嗪-1-基)丙-2-烯-1-酮的制备Step 2: Preparation of (R)-1-(3-(hydroxymethyl)piperazin-1-yl)prop-2-en-1-one
Figure PCTCN2021138375-appb-000310
Figure PCTCN2021138375-appb-000310
将(R)-4-丙烯酰-2-(羟甲基)哌嗪-1-羧酸叔丁酯(1.8克,6.67毫摩尔)溶于二氯甲烷(15毫升)和三氟乙酸(10毫升)中，反应混合物在室温搅拌1小时。将反应混合液浓缩蒸干，并用乙酸乙酯稀释萃取，有机相用饱和碳酸钠水溶液，饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色油状物(R)-1-(3-(羟甲基)哌嗪-1-基)丙-2-烯-1-酮(1.7克,100％收率)。MS:171.3(M+H) +。 (R)-4-Acryloyl-2-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester (1.8 g, 6.67 mmol) was dissolved in dichloromethane (15 mL) and trifluoroacetic acid (10 mL), the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and evaporated to dryness, diluted and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a yellow oil (R)-1-(3 -(Hydroxymethyl)piperazin-1-yl)prop-2-en-1-one (1.7 g, 100% yield). MS: 171.3 (M+H) + .
步骤3:1-((6-((R)-4-丙烯酰-2-(羟甲基)哌嗪-1-基)-2-氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯的制备Step 3: 1-((6-((R)-4-Acryloyl-2-(hydroxymethyl)piperazin-1-yl)-2-chloro-5-nitropyrimidin-4-yl)methyl Preparation of )-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid methyl ester
Figure PCTCN2021138375-appb-000311
Figure PCTCN2021138375-appb-000311
将(R)-1-(3-(羟甲基)哌嗪-1-基)丙-2-烯-1-酮(120毫克,0.51毫摩尔)和1-((2,6-二氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(中间体A3-5,200毫克,0.51毫摩尔)溶于无水二氯甲烷(5毫升)中，在0℃时搅拌缓慢加入TEA(78毫克,0.76毫摩尔)。滴完后，将反应混合物继续搅拌1小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色油状物1-((6-((R)-4-丙烯酰-2-(羟甲基)哌嗪-1-基)-2-氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(150毫克,42％收率)。MS:530.2(M+H) +。 (R)-1-(3-(Hydroxymethyl)piperazin-1-yl)prop-2-en-1-one (120 mg, 0.51 mmol) and 1-((2,6-dichloro -5-Nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid methyl ester (Intermediate A3-5, 200 mg, 0.51 mmol) was dissolved in anhydrous dihydronaphthalene To methyl chloride (5 mL), TEA (78 mg, 0.76 mmol) was added slowly with stirring at 0 °C. After dropping, the reaction mixture was further stirred for 1 hour, then ice-water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 1-((6-((R)-4-acryloyl as a colorless oil). -2-(Hydroxymethyl)piperazin-1-yl)-2-chloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid Methyl ester (150 mg, 42% yield). MS: 530.2 (M+H) + .
步骤4:1-((6-((R)-4-丙烯酰-2-(羟甲基)哌嗪-1-基)-2-((S)-1-甲基吡咯烷-2-基)甲氧基)-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯的制备Step 4: 1-((6-((R)-4-Acryloyl-2-(hydroxymethyl)piperazin-1-yl)-2-((S)-1-methylpyrrolidine-2- Preparation of methyl)-methoxy)-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate
Figure PCTCN2021138375-appb-000312
Figure PCTCN2021138375-appb-000312
将(S)-(1-甲基吡咯烷-2-基)甲醇(54毫克,0.47毫摩尔)和1-((6-((R)-4-丙烯酰-2-(羟甲基)哌嗪-1-基)-2-氯-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(150毫克,0.28毫摩尔)溶于无水四氢呋喃(10毫升)中，在25℃时搅拌缓慢加入碳酸铯(153毫克,0.47毫摩尔)。滴完后，将反应混合物缓慢升至50℃并搅拌11小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到无色油状物1-((6-((R)-4-丙烯酰-2-(羟甲基)哌嗪-1-基)-2-((S)-1-甲基吡咯烷-2-基)甲氧基)-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(120毫克,70％收率)。MS:609.3(M+H) +。 Combine (S)-(1-methylpyrrolidin-2-yl)methanol (54 mg, 0.47 mmol) and 1-((6-((R)-4-acryloyl-2-(hydroxymethyl)) Piperazin-1-yl)-2-chloro-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (150 mg, 0.28 mg) mol) was dissolved in dry tetrahydrofuran (10 mL), and cesium carbonate (153 mg, 0.47 mmol) was slowly added with stirring at 25°C. After dropping, the reaction mixture was slowly raised to 50°C and stirred for 11 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 1-((6-((R)-4-acryloyl as a colorless oil). -2-(Hydroxymethyl)piperazin-1-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidin-4-yl)methyl yl)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid methyl ester (120 mg, 70% yield). MS: 609.3 (M+H) + .
步骤5:4’-((R)-4-丙烯酰-2-(羟甲基)哌嗪-1-基)-2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮的制备Step 5: 4'-((R)-4-Acryloyl-2-(hydroxymethyl)piperazin-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 preparation
Figure PCTCN2021138375-appb-000313
Figure PCTCN2021138375-appb-000313
将1-((6-((R)-4-丙烯酰-2-(羟甲基)哌嗪-1-基)-2-((S)-1-甲基吡咯烷-2-基)甲氧基)-5-硝基嘧啶-4-基)甲基)-1,2,3,4-四氢萘-1-羧酸甲酯(120毫克,0.20毫摩尔)和锌粉(30毫克,0.46毫摩尔)加到乙酸(5毫升)和水(1毫升)的混合溶液中，反应混合物在50度搅拌3小时。反应完毕后，反应溶液过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄白色固体4’-((R)-4-丙烯酰-2-(羟甲基)哌嗪-1-基)-2’-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮(20毫克,18.7％收率)。MS:547.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.14–6.95(m,4H),6.81(dd,J＝16.7,10.5Hz,1H),6.30(d,J＝16.7Hz,1H),5.94–5.79(m,1H),4.79–4.50(m,6H),4.05–3.45(m,8H),3.28–2.65(m,9H),2.49–1.78(m,6H)。 1-((6-((R)-4-Acryloyl-2-(hydroxymethyl)piperazin-1-yl)-2-((S)-1-methylpyrrolidin-2-yl) Methoxy)-5-nitropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (120 mg, 0.20 mmol) and zinc powder (30 mg, 0.46 mmol) was added to a mixed solution of acetic acid (5 mL) and water (1 mL), and the reaction mixture was stirred at 50°C for 3 hours. After the reaction was completed, the reaction solution was filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellowish white solid 4'-((R)-4-acryloyl-2-(hydroxymethyl)piperazine-1- base)-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 (20 mg, 18.7% yield). MS: 547.1 (M+H) + . 1 H NMR (400MHz, Methanol-d 4 )δ7.14-6.95 (m, 4H), 6.81 (dd, J=16.7, 10.5Hz, 1H), 6.30 (d, J=16.7Hz, 1H), 5.94- 5.79 (m, 1H), 4.79–4.50 (m, 6H), 4.05–3.45 (m, 8H), 3.28–2.65 (m, 9H), 2.49–1.78 (m, 6H).
实施例20Example 20
化合物I-20a和化合物I-20b：2-((S)-1-丙烯酰-4-((R)-2'-((2-甲基-1,2,3,4-四氢异喹啉-5-基)氧基)-6'-氧代-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈和2-((S)-1-丙烯酰-4-((S)-2'-((2-甲基-1,2,3,4-四氢异喹啉-5-基)氧基)-6'-氧代-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound I-20a and Compound I-20b: 2-((S)-1-acryloyl-4-((R)-2'-((2-methyl-1,2,3,4-tetrahydroiso quinolin-5-yl)oxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3, 2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile and 2-((S)-1-acryloyl-4-((S)-2'-((2-methyl- 1,2,3,4-Tetrahydroisoquinolin-5-yl)oxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[ Naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000314
Figure PCTCN2021138375-appb-000314
步骤1:(2S)-2-(氰基甲基)-4-(6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-((2-甲基-1,2,3,4-四氢异喹啉-5-基)氧基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯的制备Step 1: (2S)-2-(cyanomethyl)-4-(6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl) -2-((2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-5-nitropyrimidin-4-yl)piperazine-1-carboxylic acid tert. Preparation of butyl ester
Figure PCTCN2021138375-appb-000315
Figure PCTCN2021138375-appb-000315
将(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4- 基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3,200毫克,0.342毫摩尔)溶于无水四氢呋喃(5毫升)中，在25℃时搅拌缓慢加入2-甲基-1,2,3,4-四氢异喹啉-5-醇(55.8毫克,0.342毫摩尔)和氢氧化钠(13.67毫克,0.342毫摩尔)。滴完后，将反应混合物缓慢升至50℃并搅拌4小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-2-(氰基甲基)-4-(6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-((2-甲基-1,2,3,4-四氢异喹啉-5-基)氧基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯(197毫克,91％收率)。MS:712.1(M+H) +。 (2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine- 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3, 200 mg, 0.342 mmol) was dissolved in dry tetrahydrofuran (5 mL) at 25°C 2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-ol (55.8 mg, 0.342 mmol) and sodium hydroxide (13.67 mg, 0.342 mmol) were added slowly with stirring. After dropping, the reaction mixture was slowly raised to 50°C and stirred for 4 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2S)-2-(cyanomethyl)-4-(6 -((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-2-((2-methyl-1,2,3,4-tetrahydro Isoquinolin-5-yl)oxy)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (197 mg, 91% yield). MS: 712.1 (M+H) + .
步骤2:(2S)-2-(氰基甲基)-4-(2'-((2-甲基-1,2,3,4-四氢异喹啉-5-基)氧基)-6'-氧代-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯的制备Step 2: (2S)-2-(cyanomethyl)-4-(2'-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy) -6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4'- Preparation of tert-butyl)piperazine-1-carboxylate
Figure PCTCN2021138375-appb-000316
Figure PCTCN2021138375-appb-000316
将(2S)-2-(氰基甲基)-4-(6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-((2-甲基-1,2,3,4-四氢异喹啉-5-基)氧基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯(190毫克,0.267毫摩尔)和锌粉(87毫克,1.335毫摩尔)加到乙酸(5毫升)和水(1毫升)的混合溶液中，反应混合物在75度搅拌3小时。反应完毕后，反应溶液过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-2-(氰基甲基)-4-(2'-((2-甲基-1,2,3,4-四氢异喹啉-5-基)氧基)-6'-氧代-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯(200毫克,115％收率)。MS:550.1(M+H) +。 (2S)-2-(cyanomethyl)-4-(6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-2 -((2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (190 mg, 0.267 mmol) and zinc powder (87 mg, 1.335 mmol) were added to a mixed solution of acetic acid (5 mL) and water (1 mL), and the reaction mixture was stirred at 75°C for 3 hours. After the completion of the reaction, the reaction solution was filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2S)-2-(cyanomethyl)-4-(2'-((2-methyl- 1,2,3,4-Tetrahydroisoquinolin-5-yl)oxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[ Naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate tert-butyl ester (200 mg, 115% yield). MS: 550.1 (M+H) + .
步骤3:2-((2S)-4-(2'-((2-甲基-1,2,3,4-四氢异喹啉-5-基)氧基)-6'-氧代-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈的制备Step 3: 2-((2S)-4-(2'-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-6'-oxo -3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-2 -Preparation of acetonitrile
Figure PCTCN2021138375-appb-000317
Figure PCTCN2021138375-appb-000317
将(2S)-2-(氰基甲基)-4-(2'-((2-甲基-1,2,3,4-四氢异喹啉-5-基)氧基)-6'-氧代-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯(200毫克,0.308毫摩尔)溶于二氯甲烷(5毫升)和三氟乙酸(5毫升)中，反应混合物在室温搅拌2小时。将反应混合液浓缩蒸干，并用乙酸乙酯稀释萃取，有机相用饱和碳酸钠水溶液，饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色油状物2-((2S)-4-(2'-((2-甲基-1,2,3,4-四氢异喹啉-5-基)氧基)-6'-氧代-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(175毫克,103％收率)。MS:550.1(M+H) +。 (2S)-2-(cyanomethyl)-4-(2'-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-6 '-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl) Piperazine-1-carboxylate tert-butyl ester (200 mg, 0.308 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and evaporated to dryness, diluted and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give 2-((2S)-4 as a yellow oil. -(2'-((2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-6'-oxo-3,4,5',8'- Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (175 mg, 103% yield Rate). MS: 550.1 (M+H) + .
步骤4:2-((S)-1-丙烯酰-4-((R)-2'-((2-甲基-1,2,3,4-四氢异喹啉-5-基)氧基)-6'-氧代-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈和2-((S)-1-丙烯酰-4-((S)-2'-((2-甲基-1,2,3,4-四氢异喹啉-5-基)氧基)-6'-氧代-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈的制备Step 4: 2-((S)-1-Acryloyl-4-((R)-2'-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl) oxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]- 4'-yl)piperazin-2-yl)acetonitrile and 2-((S)-1-acryloyl-4-((S)-2'-((2-methyl-1,2,3,4) -Tetrahydroisoquinolin-5-yl)oxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'- Preparation of pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000318
Figure PCTCN2021138375-appb-000318
将2-((2S)-4-(2'-((2-甲基-1,2,3,4-四氢异喹啉-5-基)氧基)-6'-氧代-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(175毫克,0.318毫摩尔)和DIEA(82毫克,0.637毫摩尔)溶于二氯甲烷(5毫升)中，在0℃时搅拌缓慢加入丙烯酰氯(43.2毫克,0.478毫摩尔)。滴完后，将反应混合物在0℃并搅拌1小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经Pre-HPLC制备得到均为白色固体的化合物I-20a(保留时间为4.08分钟,3毫克)和化合物I-20b(保留时间为4.22分钟,4毫克)。MS:604.1(M+H) +。 2-((2S)-4-(2'-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-6'-oxo-3 ,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl ) acetonitrile (175 mg, 0.318 mmol) and DIEA (82 mg, 0.637 mmol) were dissolved in dichloromethane (5 mL) and acryloyl chloride (43.2 mg, 0.478 mmol) was added slowly with stirring at 0°C. After dropping, the reaction mixture was stirred at 0°C for 1 hour, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was prepared by Pre-HPLC to obtain Compound I-20a (retention time: 4.08 minutes, 3 mg) as white solids and Compound 1-20b (retention time 4.22 min, 4 mg). MS: 604.1 (M+H) + .
化合物I-20a(保留时间为4.08分钟,3毫克)。 1H NMR(400MHz,DMSO-d 6)δ7.12–6.98(m,5H),6.92–6.89(m,2H),6.81(s,1H),6.15–6.09(m,1H),5.73–5.61(m,1H),4.93(s,1H),4.65(s,1H),4.30(s,1H),3.65(s,2H),3.54-3.51(m,3H),3.41-3.25(m,2H),3.15(s,1H),2.90–2.79(m,3H),2.75–2.68(m,2H),2.32(s,3H),2.04–1.95(m,2H),1.76(s,3H),1.22(s,2H)。 Compound 1-20a (retention time 4.08 min, 3 mg). 1 H NMR (400MHz, DMSO-d 6 )δ7.12-6.98(m,5H), 6.92-6.89(m,2H), 6.81(s,1H), 6.15-6.09(m,1H), 5.73-5.61 (m, 1H), 4.93(s, 1H), 4.65(s, 1H), 4.30(s, 1H), 3.65(s, 2H), 3.54-3.51(m, 3H), 3.41-3.25(m, 2H) ), 3.15(s, 1H), 2.90–2.79(m, 3H), 2.75–2.68(m, 2H), 2.32(s, 3H), 2.04–1.95(m, 2H), 1.76(s, 3H), 1.22(s, 2H).
化合物I-20b(保留时间为4.22分钟,4毫克)。 1H NMR(400MHz,DMSO-d 6)δ7.12–6.98(m,5H),6.92–6.89(m,2H),6.81(s,1H),6.15–6.09(m,1H),5.73–5.61(m,1H),4.93(s,1H),4.65(s,1H),4.30(s,1H),3.65(s,2H),3.54-3.51(m,3H),3.41-3.25(m,2H),3.15(s,1H),2.90–2.79(m,3H),2.75–2.68(m,2H),2.32(s,3H),2.04–1.95(m,2H),1.76(s,3H),1.22(s,2H)。 Compound 1-20b (retention time 4.22 min, 4 mg). 1 H NMR (400MHz, DMSO-d 6 )δ7.12-6.98(m,5H), 6.92-6.89(m,2H), 6.81(s,1H), 6.15-6.09(m,1H), 5.73-5.61 (m, 1H), 4.93(s, 1H), 4.65(s, 1H), 4.30(s, 1H), 3.65(s, 2H), 3.54-3.51(m, 3H), 3.41-3.25(m, 2H) ), 3.15(s, 1H), 2.90–2.79(m, 3H), 2.75–2.68(m, 2H), 2.32(s, 3H), 2.04–1.95(m, 2H), 1.76(s, 3H), 1.22(s, 2H).
实施例21Example 21
化合物I-21:2-((2S)-1-(2-氟丙烯酰)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-2,3,5',8'-四氢-6'H-螺环[茚-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-21: 2-((2S)-1-(2-fluoroacryloyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)- 6'-Oxy-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperidine oxazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000319
Figure PCTCN2021138375-appb-000319
化合物I-21的合成参考化合物I-14，通过使用2-氟丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-21。Synthesis of Compound 1-21 Referring to compound 1-14, compound 1-21 was prepared by using 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride.
化合物I-21(46.5毫克)。MS:560.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.34–6.88(m,4H),5.32–5.18(m,2H),4.73–4.61(m,1H),4.53(s,1H),4.08–3.99(m,3H),3.79–3.64(m,2H),3.49–2.90(m,13H),2.43–2.21(m 1H),2.13–2.09(m,6H)。 Compound 1-21 (46.5 mg). MS: 560.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.34-6.88(m,4H),5.32-5.18(m,2H),4.73-4.61(m,1H),4.53(s,1H),4.08-3.99 (m, 3H), 3.79–3.64 (m, 2H), 3.49–2.90 (m, 13H), 2.43–2.21 (m 1H), 2.13–2.09 (m, 6H).
实施例22Example 22
化合物I-22:2-((2S)-1-丙烯酰-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-5'，8'-二氢-6'H-螺环[色满-4,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-22: 2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxo -5',8'-Dihydro-6'H-spiro[chroman-4,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000320
Figure PCTCN2021138375-appb-000320
化合物I-22的合成参考化合物I-14，通过使用苄基(2S)-4-(2-氯-6-((4-(甲氧 羰基)色满-4-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A13)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A12)制备得到化合物I-22。Synthesis of compound 1-22 Reference compound 1-14 by using benzyl(2S)-4-(2-chloro-6-((4-(methoxycarbonyl)chroman-4-yl)methyl)-5 -Nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A13) in place of (2S)-4-(2-chloro-6-((1 -(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1- Benzyl carboxylate (Intermediate A12) was prepared to give compound 1-22.
化合物I-22(4.6毫克)。MS:558.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.20–7.10(m,2H),7.01–6.69(m,2H),6.29–6.11(m,1H),5.83–5.76(m,1H),5.09(s,1H),4.58(s,3H),4.41–3.81(m,6H),3.64–3.51(m,1H),3.48–2.76(m,8H),2.49–1.66(m,6H),1.31–1.20(m,3H)。 Compound 1-22 (4.6 mg). MS: 558.1 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ7.20-7.10(m,2H),7.01-6.69(m,2H),6.29-6.11(m,1H),5.83-5.76(m,1H),5.09 (s, 1H), 4.58 (s, 3H), 4.41–3.81 (m, 6H), 3.64–3.51 (m, 1H), 3.48–2.76 (m, 8H), 2.49–1.66 (m, 6H), 1.31 -1.20 (m, 3H).
实施例23Example 23
化合物I-23：2-((2S)-1-(2-氟丙烯酰基)-4-(2'-((2-甲基-1,2,3,4-四氢异喹啉-5-基)氧基)-6'-氧代-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound I-23: 2-((2S)-1-(2-fluoroacryloyl)-4-(2'-((2-methyl-1,2,3,4-tetrahydroisoquinoline-5 -yl)oxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d] Pyrimidine]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000321
Figure PCTCN2021138375-appb-000321
化合物I-23的合成参考化合物I-20，通过使用2-氟丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-23。Synthesis of Compound 1-23 Referring to compound 1-20, compound 1-23 was prepared by using 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride.
化合物I-23(14.83毫克)。MS:622.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.39–7.19(m,2H),7.11(dq,J＝14.1,8.2,7.6Hz,5H),5.44–5.11(m,2H),4.54(d,J＝14.2Hz,1H),4.45–4.25(m,1H),4.02–3.43(m,6H),3.31–2.53(m,14H),2.14–1.57(m,4H)。 Compound 1-23 (14.83 mg). MS: 622.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ7.39-7.19(m, 2H), 7.11(dq, J=14.1, 8.2, 7.6Hz, 5H), 5.44-5.11(m, 2H), 4.54(d , J=14.2Hz, 1H), 4.45–4.25 (m, 1H), 4.02–3.43 (m, 6H), 3.31–2.53 (m, 14H), 2.14–1.57 (m, 4H).
实施例24Example 24
化合物I-24：4'-((R)-4-丙烯酰-3-(羟甲基)哌嗪-1-基)-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮Compound I-24: 4'-((R)-4-acryloyl-3-(hydroxymethyl)piperazin-1-yl)-2'-(((S)-1-methylpyrrolidine-2 -yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-6' -ketone
Figure PCTCN2021138375-appb-000322
Figure PCTCN2021138375-appb-000322
化合物I-24的合成参考化合物I-5，通过使用(2R)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(羟甲基)哌嗪-1-羧酸叔丁酯(中间体A15)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)制备得到化合物I-24。Synthesis of compound 1-24 Reference compound 1-5 by using (2R)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene-1 -yl)methyl)-5-nitropyrimidin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A15) instead of (2S)-4-(2- Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyano Methyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) was prepared to give compound 1-24.
化合物I-24(10.67毫克)。MS:547.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.15–6.96(m,4H),6.80(s,1H),6.25–6.01(m,1H),5.94–5.59(m,1H),4.82–4.41(m,3H),4.40–3.97(m,2H),3.95–3.36(m,3H),3.33–2.67(m,10H),2.51–1.77(m,9H),1.31–1.20(m,2H)。 Compound 1-24 (10.67 mg). MS: 547.1 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ7.15-6.96(m,4H),6.80(s,1H),6.25-6.01(m,1H),5.94-5.59(m,1H),4.82-4.41 (m, 3H), 4.40–3.97 (m, 2H), 3.95–3.36 (m, 3H), 3.33–2.67 (m, 10H), 2.51–1.77 (m, 9H), 1.31–1.20 (m, 2H) .
实施例25Example 25
化合物I-25：2-((2S)-1-乙酰基-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-2,3,5',8'-四氢-6'H-螺环[茚-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound I-25: 2-((2S)-1-acetyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy -2,3,5',8'-Tetrahydro-6'H-spiro[indene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl ) acetonitrile
Figure PCTCN2021138375-appb-000323
Figure PCTCN2021138375-appb-000323
化合物I-25的合成参考化合物I-14，通过使用乙酰氯代替丙烯酰氯制备得到化合物I-25。Synthesis of compound 1-25 Referring to compound 1-14, compound 1-25 was prepared by using acetyl chloride instead of acryloyl chloride.
化合物I-25(20毫克)。MS:530.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.34–6.86(m,4H),5.00–4.86(m,1H),4.61–4.43(m,4H),4.21–3.57(m,5H),3.43–2.84(m,11H),2.55–1.93(m,9H)。 Compound 1-25 (20 mg). MS: 530.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.34-6.86(m,4H),5.00-4.86(m,1H),4.61-4.43(m,4H),4.21-3.57(m,5H),3.43 – 2.84 (m, 11H), 2.55–1.93 (m, 9H).
实施例26Example 26
化合物I-26：2-((2S)-4-(2'-(((2S，4S)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌 嗪-2-基)乙腈Compound I-26: 2-((2S)-4-(2'-(((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-6'-oxygen base-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1- (2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000324
Figure PCTCN2021138375-appb-000324
化合物I-26的合成参考化合物I-14，通过使用(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A14)代替((2S)-4-(2-氯-6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A12)，((2S，4S)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C1)代替(S)-(1-甲基吡咯烷-2-基)甲醇，和2-氟丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-26。Synthesis of compound 1-26 Reference compound 1-14 by using (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene-1) -yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate benzyl ester (Intermediate A14) instead of ((2S)-4-(2 -Chloro-6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyano Methyl)piperazine-1-carboxylate benzyl ester (Intermediate A12), ((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate C1) instead of (S) -(1-Methylpyrrolidin-2-yl)methanol, and 2-fluoroacryloyl chloride (Intermediate B1) instead of acryloyl chloride were prepared to give compound 1-26.
化合物I-26(4.6毫克)。MS:592.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.29–7.02(m,4H),5.42–5.03(m,3H),4.26–4.19(m,1H),4.17–4.02(m,1H),3.81–3.47(m,2H),3.34–2.54(m,17H),2.31(s,4H),2.13–1.57(m,2H)。 Compound 1-26 (4.6 mg). MS: 592.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ7.29-7.02(m,4H), 5.42-5.03(m,3H), 4.26-4.19(m,1H), 4.17-4.02(m,1H), 3.81 – 3.47 (m, 2H), 3.34 – 2.54 (m, 17H), 2.31 (s, 4H), 2.13 – 1.57 (m, 2H).
实施例27Example 27
化合物I-27：2-((2S)-1-(2-氟丙烯酰)-4-(2'-(((2S，4R)-4-甲氧基-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-27: 2-((2S)-1-(2-fluoroacryloyl)-4-(2'-(((2S,4R)-4-methoxy-1-methylpyrrolidine-2 -yl)methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d ]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000325
Figure PCTCN2021138375-appb-000325
化合物I-27的合成参考化合物I-14，通过使用(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A14)代替((2S)-4-(2-氯-6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A12)，((2S，4R)-4-甲氧基-1-甲基吡咯烷-2-基)甲醇(中间体C2)代替(S)-(1-甲基吡咯烷-2-基)甲醇，和2-氟丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-27。Synthesis of compound 1-27 Reference compound 1-14 by using (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene-1) -yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate benzyl ester (Intermediate A14) instead of ((2S)-4-(2 -Chloro-6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyano Methyl)piperazine-1-carboxylate benzyl ester (Intermediate A12), ((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methanol (Intermediate C2) instead of ( S)-(1-methylpyrrolidin-2-yl)methanol, and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride were prepared to give compound 1-27.
化合物I-27(14.6毫克)。MS:604.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.31–7.04(m,4H),5.45–5.13(m,2H),4.64–4.38(m,2H),4.09(s,1H),3.89(s,1H),3.82–3.61(m,2H),3.59–2.65(m,19H),2.32(s,1H),2.07–1.59(m,5H)。 Compound 1-27 (14.6 mg). MS: 604.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ7.31-7.04(m,4H), 5.45-5.13(m,2H), 4.64-4.38(m,2H), 4.09(s,1H), 3.89(s , 1H), 3.82–3.61 (m, 2H), 3.59–2.65 (m, 19H), 2.32 (s, 1H), 2.07–1.59 (m, 5H).
实施例28Example 28
化合物I-28：2-((2S)-1-丙烯酰-4-(2'-(((2S，4S)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-28: 2-((2S)-1-acryloyl-4-(2'-(((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy) -6'-Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4'- yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000326
Figure PCTCN2021138375-appb-000326
化合物I-28的合成参考化合物I-14，通过使用(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A14)代替((2S)-4-(2-氯-6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A12)，((2S，4S)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C1)代替(S)-(1-甲基吡咯烷-2-基)甲醇制备得到化合物I-28。Synthesis of compound 1-28 Reference compound 1-14 by using (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene-1 -yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate benzyl ester (Intermediate A14) instead of ((2S)-4-(2 -Chloro-6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyano Methyl)piperazine-1-carboxylate benzyl ester (Intermediate A12), ((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate C1) instead of (S) -(1-Methylpyrrolidin-2-yl)methanol was prepared to give compound 1-28.
化合物I-28(14.6毫克)。MS:574.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.32–7.03(m,4H),6.84(s,1H),6.18(d,J＝16.7Hz,1H),5.77(d,J＝10.3Hz,1H),5.46(m,1H),5.16–4.68(m,1H),4.65–4.32(m,2H),4.20–3.44(m,9H),3.33–2.61(m,11H),2.21–1.60(m,5H)。 Compound 1-28 (14.6 mg). MS: 574.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ7.32-7.03(m, 4H), 6.84(s, 1H), 6.18(d, J=16.7Hz, 1H), 5.77(d, J=10.3Hz, 1H), 5.46 (m, 1H), 5.16–4.68 (m, 1H), 4.65–4.32 (m, 2H), 4.20–3.44 (m, 9H), 3.33–2.61 (m, 11H), 2.21–1.60 ( m, 5H).
实施例29Example 29
化合物I-29：2-((2S)-1-丙烯酰-4-(2'-(((2S，4R)-4-甲氧基-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-29: 2-((2S)-1-acryloyl-4-(2'-(((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methoxy base)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4 '-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000327
Figure PCTCN2021138375-appb-000327
化合物I-29的合成参考化合物I-14，通过使用(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A14)代替((2S)-4-(2-氯-6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A12)，((2S，4R)-4-甲氧基-1-甲基吡咯烷-2-基)甲醇(中间体C2)代替(S)-(1-甲基吡咯烷-2-基)甲醇制备得到化合物I-29。Synthesis of compound 1-29 Reference compound 1-14 by using (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene-1) -yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate benzyl ester (Intermediate A14) instead of ((2S)-4-(2 -Chloro-6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyano Methyl)piperazine-1-carboxylate benzyl ester (Intermediate A12), ((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methanol (Intermediate C2) instead of ( S)-(1-methylpyrrolidin-2-yl)methanol was prepared to give compound 1-29.
化合物I-29(11.6毫克)。MS:586.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.33–7.05(m,4H),6.84(s,1H),6.18(d,J＝16.7Hz,1H),5.77(d,J＝10.4Hz,1H),4.94–4.81(mz,1H),4.67–4.30(m,2H),4.16–3.42(m,9H),3.32–2.60(m,13H),2.39–1.59(m,6H)。 Compound 1-29 (11.6 mg). MS: 586.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 7.33-7.05 (m, 4H), 6.84 (s, 1H), 6.18 (d, J=16.7Hz, 1H), 5.77 (d, J=10.4Hz, 1H), 4.94–4.81 (mz, 1H), 4.67–4.30 (m, 2H), 4.16–3.42 (m, 9H), 3.32–2.60 (m, 13H), 2.39–1.59 (m, 6H).
实施例30Example 30
化合物I-30：2-((2S)-4-(2'-(((2S，4R)-4-甲氧基-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-((E)-4-甲氧基-2-烯基)哌嗪-2-基)乙腈Compound I-30: 2-((2S)-4-(2'-(((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methoxy)-6' -Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)- 1-((E)-4-Methoxy-2-enyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000328
Figure PCTCN2021138375-appb-000328
化合物I-30的合成参考化合物I-14，通过使用(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A14)代替((2S)-4-(2-氯-6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A12)，((2S，4R)-4-甲氧基-1-甲基吡咯烷-2-基)甲醇(中间体C2)代替(S)-(1-甲基吡咯烷-2-基)甲醇，和(E)- 4-甲氧基-2-烯酰氯(中间体B4)代替丙烯酰氯制备得到化合物I-30。Synthesis of compound 1-30 Reference compound 1-14 by using (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene-1) -yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate benzyl ester (Intermediate A14) instead of ((2S)-4-(2 -Chloro-6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyano Methyl)piperazine-1-carboxylate benzyl ester (Intermediate A12), ((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methanol (Intermediate C2) instead of ( S)-(1-methylpyrrolidin-2-yl)methanol, and (E)-4-methoxy-2-enoyl chloride (Intermediate B4) in place of acryloyl chloride were prepared to give compound 1-30.
化合物I-30(8.4毫克)。MS:630.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.26–7.04(m,4H),6.66–6.21(m,1H),5.06(s,1H),4.43–3.93(m,3H),3.89–3.43(m,9H),3.35–3.19(m,6H),3.16–3.14(m,3H),3.12–2.52(m,5H),2.29–2.21(m,3H),2.19–1.92(m,2H),1.92–1.64(m,5H)。 Compound 1-30 (8.4 mg). MS: 630.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ7.26-7.04(m,4H), 6.66-6.21(m,1H), 5.06(s,1H), 4.43-3.93(m,3H), 3.89-3.43 (m, 9H), 3.35–3.19 (m, 6H), 3.16–3.14 (m, 3H), 3.12–2.52 (m, 5H), 2.29–2.21 (m, 3H), 2.19–1.92 (m, 2H) , 1.92–1.64 (m, 5H).
实施例31Example 31
化合物I-31：2-((2S)-1-丙烯酰-4-(2'-((2-乙基吡啶-3-基)氧基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound I-31: 2-((2S)-1-acryloyl-4-(2'-((2-ethylpyridin-3-yl)oxy)-6'-oxo-3,4,5 ',8'-Tetrahydro-2H,6'H-Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000329
Figure PCTCN2021138375-appb-000329
步骤1:(2S)-2-(氰基甲基)-4-(2-((2-乙基吡啶-3-基)氧基)-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸苄酯的制备Step 1: (2S)-2-(cyanomethyl)-4-(2-((2-ethylpyridin-3-yl)oxy)-6-((1-(methoxycarbonyl)-1 Preparation of ,2,3,4-tetrahydronaphthalene-1-yl)methyl)-5-nitropyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester
Figure PCTCN2021138375-appb-000330
Figure PCTCN2021138375-appb-000330
将(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A14,600毫克,0.969毫摩尔)溶于无水四氢呋喃(5毫升)中，在25℃时搅拌缓慢加入2-乙基吡啶-3-醇(239毫克,1.938毫摩尔)和氢氧化钠(116毫克,2.91毫摩尔)。滴完后，将反应混合物在0℃并搅拌4小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-2-(氰基甲基)-4-(2-((2-乙基吡啶-3-基)氧基)-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸苄酯(580毫克,85％收率)。MS:706.1(M+H) +。 (2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine- Benzyl 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (Intermediate A14, 600 mg, 0.969 mmol) was dissolved in dry tetrahydrofuran (5 mL) and stirred at 25 °C 2-Ethylpyridin-3-ol (239 mg, 1.938 mmol) and sodium hydroxide (116 mg, 2.91 mmol) were added slowly. After completion of dropping, the reaction mixture was stirred at 0°C for 4 hours, then ice-water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain (2S)-2-(cyanomethyl)-4-(2 as a yellow solid. -((2-Ethylpyridin-3-yl)oxy)-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5 - Benzyl nitropyrimidin-4-yl)piperazine-1-carboxylate (580 mg, 85% yield). MS: 706.1 (M+H) + .
步骤2:(2S)-2-(氰基甲基)-4-(2'-((2-乙基吡啶-3-基)氧基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸苄酯的制备Step 2: (2S)-2-(cyanomethyl)-4-(2'-((2-ethylpyridin-3-yl)oxy)-6'-oxo-3,4,5' Preparation of ,8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylic acid benzyl ester
Figure PCTCN2021138375-appb-000331
Figure PCTCN2021138375-appb-000331
将(2S)-2-(氰基甲基)-4-(2-((2-乙基吡啶-3-基)氧基)-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸苄酯(580毫克,0.822毫摩尔)和锌粉(161毫克,2.46毫摩尔)加到乙酸(5毫升)和水(1毫升)的混合溶液中，反应混合物在75度搅拌3小时。反应完毕后，反应溶液过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-2-(氰基甲基)-4-(2'-((2-乙基吡啶-3-基)氧基)-6'-氧代-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸苄酯(280毫克,52.9％收率)。MS:644.1(M+H) +。 (2S)-2-(cyanomethyl)-4-(2-((2-ethylpyridin-3-yl)oxy)-6-((1-(methoxycarbonyl)-1,2 ,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate benzyl ester (580 mg, 0.822 mmol) and zinc powder (161 mg , 2.46 mmol) was added to a mixed solution of acetic acid (5 mL) and water (1 mL), and the reaction mixture was stirred at 75°C for 3 hours. After the completion of the reaction, the reaction solution was filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2S)-2-(cyanomethyl)-4-(2'-((2-ethylpyridine) -3-yl)oxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2- d]Pyrimidine]-4'-yl)piperazine-1-carboxylate benzyl ester (280 mg, 52.9% yield). MS: 644.1 (M+H) + .
步骤3:2-((2S)-4-(2'-((2-乙基吡啶-3-基)氧基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈的制备Step 3: 2-((2S)-4-(2'-((2-ethylpyridin-3-yl)oxy)-6'-oxo-3,4,5',8'-tetrahydro Preparation of -2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000332
Figure PCTCN2021138375-appb-000332
将(2S)-2-(氰基甲基)-4-(2'-((2-乙基吡啶-3-基)氧基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸苄酯(280毫克,0.435毫摩尔)溶 于乙醇(15毫升)中，在搅拌条件下向反应混合物中加入钯碳(231毫克)。反应混合物在氢气作用下室温搅拌12小时，然后将混合物溶液过滤。将滤液真空浓缩，得到黄色油状物2-((2S)-4-(2'-((2-乙基吡啶-3-基)氧基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(222毫克,100％收率)。MS:510.1(M+H) +。 (2S)-2-(cyanomethyl)-4-(2'-((2-ethylpyridin-3-yl)oxy)-6'-oxo-3,4,5',8 '-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate benzyl ester (280 mg, 0.435 mmol) in ethanol (15 mL) and palladium on carbon (231 mg) was added to the reaction mixture with stirring. The reaction mixture was stirred at room temperature under the influence of hydrogen for 12 hours, and then the mixture solution was filtered. The filtrate was concentrated in vacuo to give 2-((2S)-4-(2'-((2-ethylpyridin-3-yl)oxy)-6'-oxo-3,4,5' as a yellow oil ,8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (222 mg , 100% yield). MS: 510.1 (M+H) + .
步骤4:2-((2S)-1-丙烯酰-4-(2'-((2-乙基吡啶-3-基)氧基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈的制备Step 4: 2-((2S)-1-Acryloyl-4-(2'-((2-ethylpyridin-3-yl)oxy)-6'-oxo-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
Figure PCTCN2021138375-appb-000333
Figure PCTCN2021138375-appb-000333
将2-((2S)-4-(2'-((2-乙基吡啶-3-基)氧基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(100毫克,0.196毫摩尔)和TEA(19.86毫克,0.196毫摩尔)溶于二氯甲烷(5毫升)中，在0℃时搅拌缓慢加入丙烯酰氯(17.76毫克,0.196毫摩尔)。滴完后，将反应混合物在0℃并搅拌1小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经Pre-HPLC制备的到白色固体2-((2S)-1-丙烯酰-4-(2'-((2-乙基吡啶-3-基)氧基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(14毫克,7.3％收率)。MS:564.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.36–8.15(m,1H),7.61–7.57(m,1H),7.36–7.21(m,1H),7.17–7.89(m,5H),6.76(s,1H),6.25–6.10(m,1H),5.80–5.54(m,1H),4.69(s,4H),3.69(m,3H),3.24–2.94(m,2H),2.78(m,5H),2.15–1.78(m,4H),1.42–1.15(m,4H)。 2-((2S)-4-(2'-((2-ethylpyridin-3-yl)oxy)-6'-oxo-3,4,5',8'-tetrahydro-2H , 6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (100 mg, 0.196 mmol) and TEA ( 19.86 mg, 0.196 mmol) was dissolved in dichloromethane (5 mL) and acryloyl chloride (17.76 mg, 0.196 mmol) was added slowly with stirring at 0°C. After dropping, the reaction mixture was stirred at 0°C for 1 hour, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to a white solid 2-((2S)-1-acryloyl-4-(2'-((2-Ethylpyridin-3-yl)oxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-Pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (14 mg, 7.3% yield). MS: 564.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.36-8.15(m,1H),7.61-7.57(m,1H),7.36-7.21(m,1H),7.17-7.89(m,5H),6.76 (s, 1H), 6.25–6.10 (m, 1H), 5.80–5.54 (m, 1H), 4.69 (s, 4H), 3.69 (m, 3H), 3.24–2.94 (m, 2H), 2.78 (m , 5H), 2.15–1.78 (m, 4H), 1.42–1.15 (m, 4H).
实施例32Example 32
化合物I-32：2-((2S)-4-(2'-((2-乙基吡啶-3-基)氧基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound I-32: 2-((2S)-4-(2'-((2-ethylpyridin-3-yl)oxy)-6'-oxo-3,4,5',8'- Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl)piperazine-2- base) acetonitrile
Figure PCTCN2021138375-appb-000334
Figure PCTCN2021138375-appb-000334
化合物I-32的合成参考化合物I-31，通过使用2-氟丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-32。Synthesis of Compound 1-32 Referring to compound 1-31, compound 1-32 was prepared by using 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride.
化合物I-32(9.6毫克)。MS:582.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.52(d,J＝5.0Hz,1H),8.24–8.16(m,1H),7.75(dd,J＝8.4,5.7Hz,1H),7.26–7.07(m,4H),5.39–5.16(m,2H),4.82–4.58(m,3H),4.21–3.90(m,2H),3.78–3.61(m,1H),3.54–3.39(m,1H),3.23–3.18(m,1H),3.10–2.58(m,7H),2.15–1.76(m,4H),1.44–1.24(m,3H)。 Compound 1-32 (9.6 mg). MS: 582.1 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ8.52(d,J=5.0Hz,1H),8.24-8.16(m,1H),7.75(dd,J=8.4,5.7Hz,1H),7.26- 7.07 (m, 4H), 5.39–5.16 (m, 2H), 4.82–4.58 (m, 3H), 4.21–3.90 (m, 2H), 3.78–3.61 (m, 1H), 3.54–3.39 (m, 1H) ), 3.23–3.18 (m, 1H), 3.10–2.58 (m, 7H), 2.15–1.76 (m, 4H), 1.44–1.24 (m, 3H).
实施例33Example 33
化合物I-33：2-((2S)-1-乙酰基-4-(2'-((2-乙基吡啶-3-基)氧基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound I-33: 2-((2S)-1-acetyl-4-(2'-((2-ethylpyridin-3-yl)oxy)-6'-oxo-3,4,5 ',8'-Tetrahydro-2H,6'H-Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000335
Figure PCTCN2021138375-appb-000335
化合物I-33的合成参考化合物I-31，通过使用乙酰氯代替丙烯酰氯制备得到化合物I-33。Synthesis of compound 1-33 Referring to compound 1-31, compound 1-33 was prepared by using acetyl chloride instead of acryloyl chloride.
化合物I-33(9.6毫克)。MS:552.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.52(d,J＝5.6Hz,1H),8.27–8.10(m,1H),7.85–7.67(m,1H),7.28–7.04(m,4H),4.62–4.31(m,1H),3.88–3.79(m,2H),3.76–3.33(m,3H),3.25–2.47(m,9H),2.33–1.76(m,6H),1.31–1.21(m,4H)。 Compound 1-33 (9.6 mg). MS: 552.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.52(d,J=5.6Hz,1H),8.27-8.10(m,1H),7.85-7.67(m,1H),7.28-7.04(m,4H) ), 4.62–4.31 (m, 1H), 3.88–3.79 (m, 2H), 3.76–3.33 (m, 3H), 3.25–2.47 (m, 9H), 2.33–1.76 (m, 6H), 1.31–1.21 (m, 4H).
实施例34Example 34
化合物I-34：2-((2S)-1-(2-氟丙烯酰基)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲 氧基)-6'-氧基-5'，8'-二氢-6'H-螺环[色满-4,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-34: 2-((2S)-1-(2-fluoroacryloyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)- 6'-Oxy-5',8'-dihydro-6'H-spiro[chroman-4,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-2 -base) acetonitrile
Figure PCTCN2021138375-appb-000336
Figure PCTCN2021138375-appb-000336
化合物I-34的合成参考化合物I-22，通过使用2-氟丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-34。Synthesis of Compound 1-34 Referring to compound 1-22, compound 1-34 was prepared by using 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride.
化合物I-34(14.6毫克)。MS:576.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.28–7.11(m,2H),6.97–6.74(m,2H),5.32–5.09(m,2H),4.82–4.42(m,3H),4.36–3.55(m,9H),3.51–3.22(m,3H),3.15–2.81(m,5H),2.45–1.86(m,7H)。 Compound 1-34 (14.6 mg). MS: 576.1 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ7.28-7.11(m,2H),6.97-6.74(m,2H),5.32-5.09(m,2H),4.82-4.42(m,3H),4.36 – 3.55 (m, 9H), 3.51 – 3.22 (m, 3H), 3.15 – 2.81 (m, 5H), 2.45 – 1.86 (m, 7H).
实施例35Example 35
化合物I-35：2-((2S)-1-((E)-4-(二甲胺基)but-2-烯基)-4-(2’-((2S，4S)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6’-氧基-3,4,5',8'-四氢-2H，6’H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound I-35: 2-((2S)-1-((E)-4-(dimethylamino)but-2-enyl)-4-(2'-((2S,4S)-4- Fluoro-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1, 7'-Pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000337
Figure PCTCN2021138375-appb-000337
将2-((2S)-4-(2'-(((2S，4S)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(化合物I-28/步骤3,150毫克,0.289毫摩尔)和DIEA(112毫克,0.866毫摩尔)溶于二氯甲烷(5毫升)中，在0℃时搅拌缓慢加入(E)-4-溴代-2-烯酸(47.6毫克,0.289毫摩尔)和2-(3H-[1,2,3]三唑[4,5-b]吡啶-3-基)-1,1,3,3-四甲基尿铵六氟磷酸盐(V)(110毫克,0.289毫摩尔)。滴完后，将反应混合物在20℃搅拌1小时，然后二甲胺(0.866毫摩尔)加入到上述反应液中并在室温继续搅拌反应2小时。反应混合物用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经Pre-HPLC制备得到白色固 体2-((2S)-1-((E)-4-(二甲胺基)丁-2-烯基)-4-(2’-((2S，4S)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6’-氧基-3,4,5',8'-四氢-2H，6’H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(7.52毫克,4.3％收率)。MS:576.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.33–7.02(m,4H),6.65(s,2H),5.11–4.98(m,1H),4.42–4.21(m,1H),4.19–4.01(m,2H),3.83–3.42(m,10H),3.23–2.51(m,10H),2.45–2.13(m,10H),2.07–1.60(m,2H)。 2-((2S)-4-(2'-(((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-3, 4,5',8'-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl) Acetonitrile (compound 1-28/step 3, 150 mg, 0.289 mmol) and DIEA (112 mg, 0.866 mmol) were dissolved in dichloromethane (5 mL) and (E)-4-bromo was added slowly with stirring at 0 °C Sub-2-enoic acid (47.6 mg, 0.289 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3 - Tetramethyluridine hexafluorophosphate (V) (110 mg, 0.289 mmol). After dropping, the reaction mixture was stirred at 20°C for 1 hour, then dimethylamine (0.866 mmol) was added to the above reaction solution and the reaction was continued to be stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and extracted. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was prepared by Pre-HPLC to obtain a white solid 2-((2S)-1-((E)-4-(di Methylamino)but-2-enyl)-4-(2'-((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy -3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-2 -yl)acetonitrile (7.52 mg, 4.3% yield). MS: 576.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ7.33-7.02(m,4H), 6.65(s,2H), 5.11-4.98(m,1H), 4.42-4.21(m,1H), 4.19-4.01 (m, 2H), 3.83–3.42 (m, 10H), 3.23–2.51 (m, 10H), 2.45–2.13 (m, 10H), 2.07–1.60 (m, 2H).
实施例36Example 36
化合物I-36：2-((2S)-4-(2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-36: 2-((2S)-4-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-6'-oxygen base-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1- (2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000338
Figure PCTCN2021138375-appb-000338
化合物I-36的合成参考化合物I-14，通过使用(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A14)代替((2S)-4-(2-氯-6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A12)，((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇，和2-氟丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-36。Synthesis of compound 1-36 Reference compound 1-14 by using (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene-1 -yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate benzyl ester (Intermediate A14) instead of ((2S)-4-(2 -Chloro-6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyano Methyl)piperazine-1-carboxylate benzyl ester (Intermediate A12), ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate C3) instead of (S) -(1-Methylpyrrolidin-2-yl)methanol, and 2-fluoroacryloyl chloride (Intermediate B1) instead of acryloyl chloride were prepared to give compound 1-36.
化合物I-36(33毫克)。MS:592.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.30–7.02(m,4H),5.61–5.21(m,3H),4.75–4.50(m,2H),4.38–3.83(m,3H),3.82–3.24(m,8H),3.24–2.59(m,9H),2.52–1.74(m,5H)。 Compound 1-36 (33 mg). MS: 592.1 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ7.30-7.02(m,4H),5.61-5.21(m,3H),4.75-4.50(m,2H),4.38-3.83(m,3H),3.82 – 3.24 (m, 8H), 3.24 – 2.59 (m, 9H), 2.52 – 1.74 (m, 5H).
实施例37Example 37
化合物I-37Compound I-37
2-((2S)-1-丙烯酰-4-(2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈2-((2S)-1-Acryloyl-4-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy base-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine- 2-yl)acetonitrile
Figure PCTCN2021138375-appb-000339
Figure PCTCN2021138375-appb-000339
化合物I-37的合成参考化合物I-14，通过使用(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A14)代替((2S)-4-(2-氯-6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A12)，((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇制备得到化合物I-37。Synthesis of compound 1-37 Reference compound 1-14 by using (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene-1) -yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate benzyl ester (Intermediate A14) instead of ((2S)-4-(2 -Chloro-6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyano Methyl)piperazine-1-carboxylate benzyl ester (Intermediate A12), ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate C3) instead of (S) -(1-Methylpyrrolidin-2-yl)methanol was prepared to give compound 1-37.
化合物I-37(19.6毫克)。MS:574.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.17–6.98m,4H),6.81(s,1H),6.30–6.21(m,1H),5.84–5.76(m,1H),5.48–5.38(m,1H),4.72–3.83(m,8H),3.82–3.39(m,5H),3.24–2.59(m,9H),2.52–1.77(m,5H)。 Compound 1-37 (19.6 mg). MS: 574.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.17-6.98m,4H),6.81(s,1H),6.30-6.21(m,1H),5.84-5.76(m,1H),5.48-5.38( m, 1H), 4.72–3.83 (m, 8H), 3.82–3.39 (m, 5H), 3.24–2.59 (m, 9H), 2.52–1.77 (m, 5H).
实施例38Example 38
化合物I-38：2-((2S)-4-(2'-(((2S，4S)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-((E)-4-氟-2-烯基)哌嗪-2-基)乙腈Compound I-38: 2-((2S)-4-(2'-(((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-6'-oxygen base-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1- ((E)-4-Fluoro-2-enyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000340
Figure PCTCN2021138375-appb-000340
化合物I-38的合成参考化合物I-14，通过使用(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A14)代替((2S)-4-(2-氯-6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A12)，((2S，4S)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C1)代替(S)-(1-甲基吡咯烷-2-基)甲醇，和(E)-4-氟-2-烯酰氯(中间体B5)代替丙烯酰氯制备得到化合物I-38。Synthesis of compound 1-38 Reference compound 1-14, by using (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene-1) -yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate benzyl ester (Intermediate A14) instead of ((2S)-4-(2 -Chloro-6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyano Methyl)piperazine-1-carboxylate benzyl ester (Intermediate A12), ((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate C1) instead of (S) -(1-Methylpyrrolidin-2-yl)methanol, and (E)-4-fluoro-2-enoyl chloride (Intermediate B5) instead of acryloyl chloride were prepared to give compound 1-38.
化合物I-38(10.1毫克)。MS:606.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.29–7.01(m,4H),6.80–6.66(m,1H),5.45–5.35(m,1H),5.26–4.90(m,1H),4.46–4.21(m,2H),3.98–3.44(m,8H),3.30–2.61(m,13H),2.31–1.58(m,6H)。 Compound 1-38 (10.1 mg). MS: 606.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ7.29-7.01(m,4H),6.80-6.66(m,1H),5.45-5.35(m,1H),5.26-4.90(m,1H),4.46 – 4.21 (m, 2H), 3.98 – 3.44 (m, 8H), 3.30 – 2.61 (m, 13H), 2.31 – 1.58 (m, 6H).
实施例39Example 39
化合物II-1：2-((2S)-1-丙烯酰-4-(2'-(3-(二甲胺基)壬二酸-1-基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound II-1: 2-((2S)-1-acryloyl-4-(2'-(3-(dimethylamino)azelaic acid-1-yl)-6'-oxo-3,4 ,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000341
Figure PCTCN2021138375-appb-000341
步骤1:(2S)-2-(氰基甲基)-4-(2-(3-(二甲基氨基)氮杂环丁烷-1-基)-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯的制备Step 1: (2S)-2-(cyanomethyl)-4-(2-(3-(dimethylamino)azetidin-1-yl)-6-((1-(methoxy Preparation of carbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000342
Figure PCTCN2021138375-appb-000342
将(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4- 基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3,600毫克,1.026毫摩尔)和DIEA(1.4毫升,8.2毫摩尔)溶于无水二氯甲烷(10毫升)中，在25℃时搅拌缓慢加入N，N-二甲基氮杂环丁胺盐酸盐(355毫克,2.05毫摩尔)。滴完后，将反应混合物缓慢升至50℃并搅拌11小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-2-(氰基甲基)-4-(2-(3-(二甲基氨基)氮杂环丁烷-1-基)-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯(600毫克,90.2％收率)。MS:649.1(M+H) +。 (2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine- 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3, 600 mg, 1.026 mmol) and DIEA (1.4 mL, 8.2 mmol) were dissolved in anhydrous bismuth In methyl chloride (10 mL), N,N-dimethylazetidine hydrochloride (355 mg, 2.05 mmol) was slowly added with stirring at 25°C. After dropping, the reaction mixture was slowly raised to 50°C and stirred for 11 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain (2S)-2-(cyanomethyl)-4-(2 as a yellow solid. -(3-(Dimethylamino)azetidine-1-yl)-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methane (600 mg, 90.2% yield). MS: 649.1 (M+H) + .
步骤2:(2S)-2-(氰基甲基)-4-(2'-(3-(二甲基氨基)氮杂环丁烷-1-基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯的制备Step 2: (2S)-2-(cyanomethyl)-4-(2'-(3-(dimethylamino)azetidin-1-yl)-6'-oxo-3, 4,5',8'-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylic acid Preparation of tert-butyl ester
Figure PCTCN2021138375-appb-000343
Figure PCTCN2021138375-appb-000343
将(2S)-2-(氰基甲基)-4-(2-(3-(二甲基氨基)氮杂环丁烷-1-基)-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸叔丁酯(600毫克,0.925毫摩尔)和锌粉(181毫克,2.77毫摩尔)加到乙酸(10毫升)和水(1毫升)的混合溶液中，反应混合物在75度搅拌3小时。反应完毕后，反应溶液过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物(2S)-2-(氰基甲基)-4-(2'-(3-(二甲基氨基)氮杂环丁烷-1-基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯(480毫克,88％收率)。MS:587.1(M+H) +。 (2S)-2-(cyanomethyl)-4-(2-(3-(dimethylamino)azetidin-1-yl)-6-((1-(methoxycarbonyl) -1,2,3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (600 mg, 0.925 mmol) and Zinc powder (181 mg, 2.77 mmol) was added to a mixed solution of acetic acid (10 mL) and water (1 mL), and the reaction mixture was stirred at 75°C for 3 hours. After completion of the reaction, the reaction solution was filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow oil (2S)-2-(cyanomethyl)-4-(2'-(3-(dimethyl) amino)azetidin-1-yl)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine [3,2-d]Pyrimidine]-4'-yl)piperazine-1-carboxylate tert-butyl ester (480 mg, 88% yield). MS: 587.1 (M+H) + .
步骤3:2-((2S)-4-(2'-(3-(二甲胺基)氮杂环丁烷-1-基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈的制备Step 3: 2-((2S)-4-(2'-(3-(dimethylamino)azetidin-1-yl)-6'-oxo-3,4,5',8 Preparation of '-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000344
Figure PCTCN2021138375-appb-000344
将(2S)-2-(氰基甲基)-4-(2'-(3-(二甲基氨基)氮杂环丁烷-1-基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯(300毫克,0.511毫 摩尔)溶于二氯甲烷(5毫升)和三氟乙酸(5毫升)中，反应混合物在室温搅拌1小时。将反应混合液浓缩蒸干，并用乙酸乙酯稀释萃取，有机相用饱和碳酸钠水溶液，饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色油状物2-((2S)-4-(2'-(3-(二甲胺基)氮杂环丁烷-1-基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(250毫克,100％收率)。MS:487.1(M+H) +。 (2S)-2-(cyanomethyl)-4-(2'-(3-(dimethylamino)azetidin-1-yl)-6'-oxo-3,4, 5',8'-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate tert-butyl The ester (300 mg, 0.511 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and evaporated to dryness, diluted and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give 2-((2S)-4 as a yellow oil. -(2'-(3-(dimethylamino)azetidin-1-yl)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H- Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (250 mg, 100% yield). MS: 487.1 (M+H) + .
步骤4:2-((2S)-1-丙烯酰-4-(2'-(3-(二甲胺基)壬二酸-1-基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈的制备Step 4: 2-((2S)-1-Acryloyl-4-(2'-(3-(dimethylamino)azelaic acid-1-yl)-6'-oxo-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
Figure PCTCN2021138375-appb-000345
Figure PCTCN2021138375-appb-000345
将2-((2S)-4-(2'-(3-(二甲胺基)氮杂环丁烷-1-基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(100毫克,0.205毫摩尔)和TEA(20.79毫克,0.205毫摩尔)溶于二氯甲烷(5毫升)中，在0℃时搅拌缓慢加入丙烯酰氯(18.60毫克,0.205毫摩尔)。滴完后，将反应混合物在0℃并搅拌1小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经Pre-HPLC制备得到白色固体2-((2S)-1-丙烯酰-4-(2'-(3-(二甲胺基)壬二酸-1-基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(26毫克,24.8％收率)。MS:541.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.21–7.03(m,4H),6.79(s,1H),6.27(d,J＝16.6Hz,1H),5.81(d,J＝10.6Hz,1H),4.19–3.96(m,3H),3.97–3.68(m,4H),3.35–3.29(m,2H),3.24–2.92(m,7H),2.82–2.65(m,2H),2.21(s,6H),2.12–1.98(m,1H),1.87–1.71(m,3H)。 2-((2S)-4-(2'-(3-(dimethylamino)azetidin-1-yl)-6'-oxo-3,4,5',8'- Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (100 mg, 0.205 mmol ) and TEA (20.79 mg, 0.205 mmol) were dissolved in dichloromethane (5 mL) and acryloyl chloride (18.60 mg, 0.205 mmol) was added slowly with stirring at 0°C. After dropping, the reaction mixture was stirred at 0°C for 1 hour, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was prepared by Pre-HPLC to obtain a white solid 2-((2S)-1-acryloyl-4-(2'- (3-(Dimethylamino)azelaic acid-1-yl)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1, 7'-Pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (26 mg, 24.8% yield). MS: 541.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.21-7.03(m,4H),6.79(s,1H),6.27(d,J=16.6Hz,1H),5.81(d,J=10.6Hz, 1H), 4.19–3.96 (m, 3H), 3.97–3.68 (m, 4H), 3.35–3.29 (m, 2H), 3.24–2.92 (m, 7H), 2.82–2.65 (m, 2H), 2.21 ( s, 6H), 2.12–1.98 (m, 1H), 1.87–1.71 (m, 3H).
化合物II-1a和II-1b:2-((S)-1-丙烯酰-4-((R)-2'-(3-(二甲胺基)氮杂环丁烷-1-基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈和2-((S)-1-丙烯酰-4-((S)-2'-(3-(二甲胺基)氮杂环丁烷-1-基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compounds II-1a and II-1b: 2-((S)-1-acryloyl-4-((R)-2'-(3-(dimethylamino)azetidin-1-yl) -6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4'- yl)piperazin-2-yl)acetonitrile and 2-((S)-1-acryloyl-4-((S)-2'-(3-(dimethylamino)azetidine-1- base)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4 '-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000346
Figure PCTCN2021138375-appb-000346
2-((2S)-1-丙烯酰-4-(2'-(3-(二甲胺基)壬二酸-1-基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(20毫克)经SFC手性拆分(柱型号：Dr.maish Reprosil Chiral-JM，250x25mm，10μm色谱柱，流动相：40％甲醇在二氧化碳中)得到均为白色固体的第一个组分峰化合物II-1a(保留时间为1.42分钟,5毫克)和第二个组分峰化合物II-1b(保留时间为2.71分钟,7毫克)。MS:541.1(M+H) +。 2-((2S)-1-Acryloyl-4-(2'-(3-(dimethylamino)azelaic acid-1-yl)-6'-oxo-3,4,5',8 '-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (20 mg) via SFC chiral resolution (column type: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm column, mobile phase: 40% methanol in carbon dioxide) gave the first component peak compound II-1a (all white solids) ( retention time 1.42 min, 5 mg) and the second component peak compound II-1b (retention time 2.71 min, 7 mg). MS: 541.1 (M+H) + .
化合物II-1a(保留时间为1.42分钟,毫克)。 1H NMR(400MHz,Methanol-d 4)δ7.21–7.03(m,4H),6.79(s,1H),6.27(d,J＝16.6Hz,1H),5.81(d,J＝10.6Hz,1H),4.19–3.96(m,3H),3.97–3.68(m,4H),3.35–3.29(m,2H),3.24–2.92(m,7H),2.82–2.65(m,2H),2.21(s,6H),2.12–1.98(m,1H),1.87–1.65(m,3H)。 Compound II-1a (retention time 1.42 min, mg). 1 H NMR(400MHz,Methanol-d 4 )δ7.21-7.03(m,4H),6.79(s,1H),6.27(d,J=16.6Hz,1H),5.81(d,J=10.6Hz, 1H), 4.19–3.96 (m, 3H), 3.97–3.68 (m, 4H), 3.35–3.29 (m, 2H), 3.24–2.92 (m, 7H), 2.82–2.65 (m, 2H), 2.21 ( s, 6H), 2.12–1.98 (m, 1H), 1.87–1.65 (m, 3H).
化合物II-1b(保留时间为2.71分钟,7毫克)。 1H NMR(400MHz,Methanol-d 4)δ7.21–7.03(m,4H),6.79(s,1H),6.27(d,J＝16.6Hz,1H),5.81(d,J＝10.6Hz,1H),4.19–3.96(m,3H),3.97–3.68(m,4H),3.35–3.29(m,2H),3.24–2.92(m,7H),2.82–2.65(m,2H),2.21(s,6H),2.12–1.98(m,1H),1.87–1.65(m,3H)。 Compound II-1b (retention time 2.71 min, 7 mg). 1 H NMR(400MHz,Methanol-d 4 )δ7.21-7.03(m,4H),6.79(s,1H),6.27(d,J=16.6Hz,1H),5.81(d,J=10.6Hz, 1H), 4.19–3.96 (m, 3H), 3.97–3.68 (m, 4H), 3.35–3.29 (m, 2H), 3.24–2.92 (m, 7H), 2.82–2.65 (m, 2H), 2.21 ( s, 6H), 2.12–1.98 (m, 1H), 1.87–1.65 (m, 3H).
实施例40Example 40
化合物II-2：2-((2S)-4-(2'-(3-(二甲胺基)氮杂环丁烷-1-基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-甲基丙烯酰哌嗪-2-基)乙腈Compound II-2: 2-((2S)-4-(2'-(3-(dimethylamino)azetidin-1-yl)-6'-oxo-3,4,5' ,8'-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1-methacryloylpiperazine-2 -base) acetonitrile
Figure PCTCN2021138375-appb-000347
Figure PCTCN2021138375-appb-000347
化合物II-2的合成参考化合物II-1，通过使用2-氟丙烯酰氯(中间体B1)代替丙烯 酰氯制备得到化合物II-2。Synthesis of compound II-2 Referring to compound II-1, compound II-2 was prepared by using 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride.
化合物II-2(34.3毫克)。MS:559.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.12–6.91(m,4H),5.29–5.19(m,2H),4.23–3.96(m,3H),3.96–3.65(m,3H),3.42–2.91(m,11H),2.81(s,2H),2.20–2.15(m,6H),2.10–1.78(m,5H)。 Compound II-2 (34.3 mg). MS: 559.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.12-6.91(m,4H),5.29-5.19(m,2H),4.23-3.96(m,3H),3.96-3.65(m,3H),3.42 – 2.91(m, 11H), 2.81(s, 2H), 2.20 – 2.15(m, 6H), 2.10 – 1.78(m, 5H).
化合物II-2a和II-2b：2-((S)-4-((R)-2'-(3-(二甲胺基)氮杂环丁烷-1-基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈和2-((S)-4-((S)-2'-(3-(二甲胺基)氮杂环丁烷-1-基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compounds II-2a and II-2b: 2-((S)-4-((R)-2'-(3-(dimethylamino)azetidin-1-yl)-6'-oxo Substituted-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1- (2-Fluoroacryloyl)piperazin-2-yl)acetonitrile and 2-((S)-4-((S)-2'-(3-(dimethylamino)azetidine-1- base)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4 '-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000348
Figure PCTCN2021138375-appb-000348
2-((2S)-4-(2'-(3-(二甲胺基)氮杂环丁烷-1-基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-甲基丙烯酰哌嗪-2-基)乙腈(30毫克)经SFC手性拆分(柱型号：Dr.maish Reprosil Chiral-JM，250x25mm，10μm色谱柱，流动相：40％甲醇在二氧化碳中)得到均为白色固体的第一个组分峰化合物II-2a(保留时间为1.11分钟,10毫克)和第二个组分峰化合物II-2b(保留时间为2.21分钟,9毫克)。MS:559.1(M+H) +。 2-((2S)-4-(2'-(3-(dimethylamino)azetidin-1-yl)-6'-oxo-3,4,5',8'-tetra Hydrogen-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1-methacryloylpiperazin-2-yl)acetonitrile ( 30 mg) was chiral resolved by SFC (column type: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm column, mobile phase: 40% methanol in carbon dioxide) to obtain the first component peak compounds as white solids II-2a (retention time 1.11 min, 10 mg) and the second component peak compound II-2b (retention time 2.21 min, 9 mg). MS: 559.1 (M+H) + .
化合物II-2a(保留时间为1.11分钟,10毫克)。 1H NMR(400MHz,Methanol-d 4)δ7.12–6.90(m,4H),5.29–4.99(m,2H),4.23–3.96(m,3H),3.96–3.65(m,3H),3.42–2.91(m,11H),2.81(s,2H),2.20–2.12(m,6H),2.10–1.78(m,5H)。 Compound II-2a (retention time 1.11 min, 10 mg). 1 H NMR(400MHz,Methanol-d 4 )δ7.12-6.90(m,4H),5.29-4.99(m,2H),4.23-3.96(m,3H),3.96-3.65(m,3H),3.42 – 2.91 (m, 11H), 2.81 (s, 2H), 2.20 – 2.12 (m, 6H), 2.10 – 1.78 (m, 5H).
化合物II-2b(保留时间为2.21分钟,9毫克)。 1H NMR(400MHz,Methanol-d 4)δ7.12–6.90(m,4H),5.29–4.99(m,2H),4.23–3.96(m,3H),3.96–3.65(m,3H),3.42–2.91(m,11H),2.81(s,2H),2.20–2.12(m,6H),2.10–1.78(m,5H)。 Compound II-2b (retention time 2.21 min, 9 mg). 1 H NMR(400MHz,Methanol-d 4 )δ7.12-6.90(m,4H),5.29-4.99(m,2H),4.23-3.96(m,3H),3.96-3.65(m,3H),3.42 – 2.91 (m, 11H), 2.81 (s, 2H), 2.20 – 2.12 (m, 6H), 2.10 – 1.78 (m, 5H).
实施例41Example 41
化合物II-3：2-((2S)-1-丙烯酰-4-(2'-氯-6'-氧-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound II-3: 2-((2S)-1-acryloyl-4-(2'-chloro-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro Cyclo[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000349
Figure PCTCN2021138375-appb-000349
步骤1:(2S)-4-(2'-氯-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯的制备Step 1: (2S)-4-(2'-Chloro-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'- Preparation of pyrid[3,2-d]pyrimidin]-4'-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000350
Figure PCTCN2021138375-appb-000350
将(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3,250毫克,0.427毫摩尔)和锌粉(84毫克,1.28毫摩尔)加到乙酸(5毫升)和水(1毫升)的混合溶液中，反应混合物在75度搅拌3小时。反应完毕后，反应溶液过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-4-(2'-氯-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(130毫克,58.2％收率)。MS:524.1(M+H) +。 (2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine- 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3, 250 mg, 0.427 mmol) and zinc powder (84 mg, 1.28 mmol) were added to acetic acid ( 5 mL) and water (1 mL), the reaction mixture was stirred at 75°C for 3 hours. After completion of the reaction, the reaction solution was filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2S)-4-(2'-chloro-6'-oxo-3,4,5',8 '-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-2-(cyanomethyl)piperazine-1 - tert-butyl carboxylate (130 mg, 58.2% yield). MS: 524.1 (M+H) + .
步骤2:2-((2S)-4-(2'-氯-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈的制备Step 2: 2-((2S)-4-(2'-Chloro-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1, Preparation of 7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000351
Figure PCTCN2021138375-appb-000351
将(2S)-4-(2'-氯-6'-氧代-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(130毫克,0.248毫摩尔)溶于二氯甲烷(5毫升)和三氟乙酸(5毫升)中，反应混合物在室温搅拌11小时。将反应混合液浓缩蒸干，并用乙酸乙酯稀释萃取，有机相用饱和碳酸钠水溶液，饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色油状物2-((2S)-4-(2'-氯-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(106毫克,100％收率)。MS:424.1(M+H) +。 (2S)-4-(2'-Chloro-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[ 3,2-d]pyrimidin]-4'-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (130 mg, 0.248 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (5 mL), and the reaction mixture was stirred at room temperature for 11 hours. The reaction mixture was concentrated and evaporated to dryness, diluted and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give 2-((2S)-4 as a yellow oil. -(2'-Chloro-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d] Pyrimidine]-4'-yl)piperazin-2-yl)acetonitrile (106 mg, 100% yield). MS: 424.1 (M+H) + .
步骤3:2-((2S)-1-丙烯酰-4-(2'-氯-6'-氧-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈的制备Step 3: 2-((2S)-1-Acryloyl-4-(2'-chloro-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[ Preparation of naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000352
Figure PCTCN2021138375-appb-000352
将2-((2S)-4-(2'-氯-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(106毫克,0.205毫摩尔)和TEA(20.79毫克,0.205毫摩尔)溶于二氯甲烷(5毫升)中，在0℃时搅拌缓慢加入丙烯酰氯(18.60毫克,0.205毫摩尔)。滴完后，将反应混合物在0℃并搅拌1小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经Pre-HPLC制备得到白色固体2-((2S)-1-丙烯酰-4-(2'-氯-6'-氧-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(29.6毫克,24.8％收率)。MS:477.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.17–6.95(m,4H),6.80(s,1H),6.28–6.12(m,1H),5.83–5.69(m,1H),5.09(s,1H),4.81–4.44(m,1H),4.21–3.72(m,3H),3.55–3.49(m,1H),3.42–3.22(m,4H),3.18–2.96(m,1H),2.82–2.67(m,3H),2.13–1.70(m,3H)。 2-((2S)-4-(2'-chloro-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-Pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (106 mg, 0.205 mmol) and TEA (20.79 mg, 0.205 mmol) were dissolved in dichloromethane (5 mL), acryloyl chloride (18.60 mg, 0.205 mmol) was slowly added with stirring at 0 °C. After dropping, the reaction mixture was stirred at 0°C for 1 hour, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was prepared by Pre-HPLC to obtain a white solid 2-((2S)-1-acryloyl-4-(2'- Chloro-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4'- yl)piperazin-2-yl)acetonitrile (29.6 mg, 24.8% yield). MS: 477.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.17-6.95(m,4H),6.80(s,1H),6.28-6.12(m,1H),5.83-5.69(m,1H),5.09(s ,1H),4.81–4.44(m,1H),4.21–3.72(m,3H),3.55–3.49(m,1H),3.42–3.22(m,4H),3.18–2.96(m,1H),2.82 – 2.67 (m, 3H), 2.13 – 1.70 (m, 3H).
实施例42Example 42
化合物II-4：2-((2S)-1-丙烯酰-4-(2'-羟基-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound II-4: 2-((2S)-1-acryloyl-4-(2'-hydroxy-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H- Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000353
Figure PCTCN2021138375-appb-000353
步骤1:(2S)-2-(氰基甲基)-4-(2'-羟基-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯的制备Step 1: (2S)-2-(cyanomethyl)-4-(2'-hydroxy-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro Preparation of cyclo[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000354
Figure PCTCN2021138375-appb-000354
将(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3,250毫克,0.427毫摩尔)和锌粉(84毫克,1.28毫摩尔)加到乙酸(5毫升)和水(1毫升)的混合溶液中，反应混合物在75度搅拌3小时。反应完毕后，反应溶液过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化 得到黄色固体(2S)-2-(氰基甲基)-4-(2'-羟基-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯(60毫克,27.8％收率)。MS:505.1(M+H) +。 (2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine- 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3, 250 mg, 0.427 mmol) and zinc powder (84 mg, 1.28 mmol) were added to acetic acid ( 5 mL) and water (1 mL), the reaction mixture was stirred at 75°C for 3 hours. After completion of the reaction, the reaction solution was filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2S)-2-(cyanomethyl)-4-(2'-hydroxy-6'-oxyl) -3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1 - tert-butyl carboxylate (60 mg, 27.8% yield). MS: 505.1 (M+H) + .
步骤2:2-((2S)-4-(2'-羟基-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈的制备Step 2: 2-((2S)-4-(2'-Hydroxy-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1, Preparation of 7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000355
Figure PCTCN2021138375-appb-000355
将(2S)-2-(氰基甲基)-4-(2'-羟基-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯(60毫克,0.119毫摩尔)溶于二氯甲烷(5毫升)和三氟乙酸(5毫升)中，反应混合物在室温搅拌1小时。将反应混合液浓缩蒸干，并用乙酸乙酯稀释萃取，有机相用饱和碳酸钠水溶液，饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色油状物2-((2S)-4-(2'-羟基-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(50毫克,100％收率)。MS:405.1(M+H) +。 (2S)-2-(cyanomethyl)-4-(2'-hydroxy-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[ Naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate tert-butyl ester (60 mg, 0.119 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and evaporated to dryness, diluted and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give 2-((2S)-4 as a yellow oil. -(2'-Hydroxy-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d] Pyrimidine]-4'-yl)piperazin-2-yl)acetonitrile (50 mg, 100% yield). MS: 405.1 (M+H) + .
步骤3:2-((2S)-1-丙烯酰-4-(2'-羟基-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈的制备Step 3: 2-((2S)-1-Acryloyl-4-(2'-hydroxy-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro Preparation of [naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000356
Figure PCTCN2021138375-appb-000356
将2-((2S)-4-(2'-羟基-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(48毫克,0.119毫摩尔)和DIEA(33.5毫克,0.259毫摩尔)溶于二氯甲烷(5毫升)中，在0℃时搅拌缓慢加入丙烯酰氯(10.74毫克,0.119毫摩尔)。滴完后，将反应混合物在0℃并搅拌1小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经Pre-HPLC制备得到白色固体2-((2S)-1-丙烯酰-4-(2'-羟基-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(13.6毫克,25.1％收率)。MS: 459.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.15–6.92(m,4H),6.80(s,1H),6.27–6.04(m,1H),5.82–5.65(m,1H),4.13–3.99(m,2H),3.42–3.20(m,4H),3.16–2.69(m,5H),2.17–1.75(m,5H),1.28(s,1H)。 2-((2S)-4-(2'-hydroxy-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-Pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (48 mg, 0.119 mmol) and DIEA (33.5 mg, 0.259 mmol) in dichloromethane (5 mL), acryloyl chloride (10.74 mg, 0.119 mmol) was slowly added with stirring at 0 °C. After dropping, the reaction mixture was stirred at 0°C for 1 hour, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was prepared by Pre-HPLC to obtain a white solid 2-((2S)-1-acryloyl-4-(2'- Hydroxy-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4' -yl)piperazin-2-yl)acetonitrile (13.6 mg, 25.1% yield). MS: 459.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.15-6.92(m,4H),6.80(s,1H),6.27-6.04(m,1H),5.82-5.65(m,1H),4.13-3.99 (m, 2H), 3.42–3.20 (m, 4H), 3.16–2.69 (m, 5H), 2.17–1.75 (m, 5H), 1.28 (s, 1H).
实施例43Example 43
化合物II-5a和化合物II-5b：2-((S)-1-丙烯酰-4-((S)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈和2-((S)-1-丙烯酰-4-((R)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound II-5a and Compound II-5b: 2-((S)-1-acryloyl-4-((S)-6'-oxo-3,4,5',8'-tetrahydro-2H, 6'H-Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile and 2-((S)-1-acryloyl -4-((R)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d ]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000357
Figure PCTCN2021138375-appb-000357
步骤1:(2S)-4-(5-氨基-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯的制备Step 1: (2S)-4-(5-Amino-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)pyrimidin-4-yl Preparation of )-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester
Figure PCTCN2021138375-appb-000358
Figure PCTCN2021138375-appb-000358
将(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3,180毫克,0.308毫摩尔)溶于甲醇(5毫升)中，在搅拌条件下向反应混合物中加入钯碳(150毫克)。反应混合物在氢气作用下室温搅拌5小时，然后将混合物溶液过滤。将滤液真空浓缩，得到无色油状物(2S)-4-(5-氨基-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(130毫克,48.7％收率)。MS:522.1(M+H) +。 (2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine- 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3, 180 mg, 0.308 mmol) was dissolved in methanol (5 mL) and added to the reaction with stirring Palladium on carbon (150 mg) was added to the mixture. The reaction mixture was stirred at room temperature under the influence of hydrogen for 5 hours, and then the mixture solution was filtered. The filtrate was concentrated in vacuo to give (2S)-4-(5-amino-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methane) as a colorless oil (130 mg, 48.7% yield). MS: 522.1 (M+H) + .
步骤2:(2S)-2-(氰基甲基)-4-(6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯的制备Step 2: (2S)-2-(cyanomethyl)-4-(6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1 Preparation of ,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylic acid tert-butyl ester
Figure PCTCN2021138375-appb-000359
Figure PCTCN2021138375-appb-000359
将(2S)-4-(5-氨基-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(113毫克,0.065毫摩尔)和甲醇钠(0.436毫摩尔)溶于DMF(2毫升)中，反应混合物在50度搅拌1小时。反应完毕后，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-2-(氰基甲基)-4-(6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯(100毫克,94％收率)。MS:489.1(M+H) +。 (2S)-4-(5-amino-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)pyrimidin-4-yl)- 2-(Cyanomethyl)piperazine-1-carboxylate tert-butyl ester (113 mg, 0.065 mmol) and sodium methoxide (0.436 mmol) were dissolved in DMF (2 mL) and the reaction mixture was stirred at 50°C for 1 Hour. After the reaction was completed, ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2S)-2-(cyanomethyl)-4-(6 '-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl) Piperazine-1-carboxylate tert-butyl ester (100 mg, 94% yield). MS: 489.1 (M+H) + .
步骤3:2-((2S)-4-(6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈的制备Step 3: 2-((2S)-4-(6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[ Preparation of 3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000360
Figure PCTCN2021138375-appb-000360
将(2S)-2-(氰基甲基)-4-(6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯(100毫克,0.205毫摩尔)溶于二氯甲烷(5毫升)和三氟乙酸(5毫升)中，反应混合物在室温搅拌1小时。将反应混合液浓缩蒸干，并用乙酸乙酯稀释萃取，有机相用饱和碳酸钠水溶液，饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色油状物2-((2S)-4-(6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(80毫克,100％收率)。MS:389.1(M+H) +。 (2S)-2-(cyanomethyl)-4-(6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7 '-Pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate tert-butyl ester (100 mg, 0.205 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid ( 5 mL), the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and evaporated to dryness, diluted and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give 2-((2S)-4 as a yellow oil. -(6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4' -yl)piperazin-2-yl)acetonitrile (80 mg, 100% yield). MS: 389.1 (M+H) + .
步骤4:2-((S)-1-丙烯酰-4-((S)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈和2-((S)-1-丙烯酰-4-((R)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈的制备Step 4: 2-((S)-1-Acryloyl-4-((S)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[ Naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile and 2-((S)-1-acryloyl-4-(((R)) -6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4'- Preparation of yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000361
Figure PCTCN2021138375-appb-000361
将2-((2S)-4-(6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(150毫克,0.193毫摩尔)和DIEA(49.9毫克,0.386毫摩尔)溶于二氯甲烷(5毫升)中，在0℃时搅拌缓慢加入丙烯酰氯(26.2毫克,0.290毫摩尔)。滴完后，将反应混合物在0℃并搅拌1小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经Pre-HPLC制备得到均为白色固体的化合物II-5a(保留时间为3.88分钟,5毫克)和化合物II-5b(保留时间为4.42分钟,8毫克)。MS:443.1(M+H) +。 2-((2S)-4-(6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3, 2-d]Pyrimidine]-4'-yl)piperazin-2-yl)acetonitrile (150 mg, 0.193 mmol) and DIEA (49.9 mg, 0.386 mmol) were dissolved in dichloromethane (5 mL) in Acryloyl chloride (26.2 mg, 0.290 mmol) was added slowly with stirring at 0°C. After dropping, the reaction mixture was stirred at 0°C for 1 hour, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product. The crude product was prepared by Pre-HPLC to obtain Compound II-5a (retention time: 3.88 minutes, 5 mg) as white solids and Compound II-5b (retention time 4.42 min, 8 mg). MS: 443.1 (M+H) + .
化合物II-5a(保留时间为3.88分钟,5毫克)。 1H NMR(400MHz,DMSO-d 6)δ8.40(s,1H),7.11–6.90(m,4H),6.86(s,1H),6.22–6.13(m,1H),5.76–5.56(m,1H),5.06(s,1H),4.80(s,1H),4.36(s,1H),4.03(s,1H),3.59–3.49(m,2H),3.47–3.23(m,2H),3.06–2.99(m,2H),2.95(s,2H),2.77(s,2H),2.32(s,1H),1.77–1.56(m,2H)。 Compound II-5a (retention time 3.88 min, 5 mg). 1 H NMR (400MHz, DMSO-d 6 )δ8.40(s,1H),7.11-6.90(m,4H),6.86(s,1H),6.22-6.13(m,1H),5.76-5.56(m ,1H),5.06(s,1H),4.80(s,1H),4.36(s,1H),4.03(s,1H),3.59–3.49(m,2H),3.47–3.23(m,2H), 3.06–2.99 (m, 2H), 2.95 (s, 2H), 2.77 (s, 2H), 2.32 (s, 1H), 1.77–1.56 (m, 2H).
化合物II-5b(保留时间为4.42分钟,8毫克)。 1H NMR(400MHz,DMSO-d 6)δ8.40(s,1H),7.11–6.90(m,4H),6.86(s,1H),6.22–6.13(m,1H),5.76–5.56(m,1H),5.06(s,1H),4.80(s,1H),4.36(s,1H),4.03(s,1H),3.59–3.49(m,2H),3.47–3.23(m,2H),3.06–2.99(m,2H),2.95(s,2H),2.77(s,2H),2.32(s,1H),1.77–1.56(m,2H)。 Compound II-5b (retention time 4.42 min, 8 mg). 1 H NMR (400MHz, DMSO-d 6 )δ8.40(s,1H),7.11-6.90(m,4H),6.86(s,1H),6.22-6.13(m,1H),5.76-5.56(m ,1H),5.06(s,1H),4.80(s,1H),4.36(s,1H),4.03(s,1H),3.59–3.49(m,2H),3.47–3.23(m,2H), 3.06–2.99 (m, 2H), 2.95 (s, 2H), 2.77 (s, 2H), 2.32 (s, 1H), 1.77–1.56 (m, 2H).
实施例44Example 44
化合物II-6：2-((2S)-1-丙烯酰-4-(2'-(3-(二乙胺基)壬二酸-1-基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound II-6: 2-((2S)-1-acryloyl-4-(2'-(3-(diethylamino)azelaic acid-1-yl)-6'-oxo-3,4 ,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000362
Figure PCTCN2021138375-appb-000362
化合物II-6的合成参考化合物II-1，通过使用N，N-二乙基氮杂环丁胺盐酸盐代替N，N-二甲基氮杂环丁胺盐酸盐制备得到化合物II-6。Synthesis of compound II-6 Reference compound II-1, prepared by using N,N-diethylazetidine hydrochloride instead of N,N-dimethylazetidine hydrochloride to obtain compound II- 6.
化合物II-6(27.6毫克)。MS:570.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.24–7.01(m,4H),6.18–5.98(m,1H),5.76–5.69(m,1H),5.06(s,1H),4.78(s,1H),4.36–4.07(m,8H),3.69–3.45(m,5H),3.13–3.07(m,4H),2.96–2.86(m,2H),2.74–2.56(m,2H),1.74–1.56(m,3H),1.28–1.11(m,6H)。 Compound II-6 (27.6 mg). MS: 570.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ7.24-7.01(m,4H), 6.18-5.98(m,1H), 5.76-5.69(m,1H), 5.06(s,1H), 4.78(s ,1H),4.36–4.07(m,8H),3.69–3.45(m,5H),3.13–3.07(m,4H),2.96–2.86(m,2H),2.74–2.56(m,2H),1.74 –1.56(m,3H),1.28–1.11(m,6H).
实施例45Example 45
化合物I-94:2-((2S)-4-(6-氯-5-氟-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-94: 2-((2S)-4-(6-chloro-5-fluoro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6' -Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)- 1-(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000363
Figure PCTCN2021138375-appb-000363
化合物I-94的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((6-氯-5-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A51)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-94。Synthesis of compound 1-94 Reference compound 1-5 by using (2S)-4-(2-chloro-6-((6-chloro-5-fluoro-1-(methoxycarbonyl)-1,2,3 ,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A51) instead (2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4 -yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (intermediate A3) and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride were prepared to give compound I-94.
化合物I-94(35毫克)。MS:626.2(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.65(s,1H),7.38(s,1H),7.21–7.10(d,J＝8.6Hz,1H),5.43–5.10(m,2H),4.53–4.41(m,3H),3.78–3.65(m,3H),3.61–3.54(m,2H),3.46(s,1H),3.13(d,J＝11.8Hz,2H),3.05–2.93(m,2H),2.91(d,J＝4.7Hz,3H),2.86–2.77(m,1H),2.75–2.69(m,2H),2.28–2.17(m,1H),2.06–2.01(m,1H),1.74–1.57(m,8H)。 Compound 1-94 (35 mg). MS: 626.2 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.65(s,1H),7.38(s,1H),7.21-7.10(d,J=8.6Hz,1H),5.43-5.10(m,2H), 4.53–4.41 (m, 3H), 3.78–3.65 (m, 3H), 3.61–3.54 (m, 2H), 3.46 (s, 1H), 3.13 (d, J=11.8Hz, 2H), 3.05–2.93 ( m, 2H), 2.91 (d, J=4.7Hz, 3H), 2.86–2.77 (m, 1H), 2.75–2.69 (m, 2H), 2.28–2.17 (m, 1H), 2.06–2.01 (m, 1H), 1.74–1.57 (m, 8H).
实施例46Example 46
化合物I-39:4'-(2-丙烯酰-2,6-二氮杂螺[3.4]辛烷-6-基)-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮Compound 1-39: 4'-(2-Acryloyl-2,6-diazaspiro[3.4]octan-6-yl)-2'-(((S)-1-methylpyrrolidine-2 -yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-6' -ketone
Figure PCTCN2021138375-appb-000364
Figure PCTCN2021138375-appb-000364
化合物I-39的合成参考化合物I-5，通过使用6-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-2-羧酸叔丁酯(中间体A16)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)制备得到化合物I-39。Synthesis of compound 1-39 Reference compound 1-5 by using 6-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methan (2S)-4-(2- Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyano Methyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) was prepared to give compound 1-39.
化合物I-39(9.6毫克)。MS:543.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.16–6.90(m,4H),6.43–6.17(m,2H),5.75–5.65(m,1H),4.95–4.84(m,3H),4.65–4.50(m,1H),4.31–4.21(m,2H),4.18–3.66(m,7H),3.51–3.41(m,1H),3.23(s,1H),3.04(s,3H),2.94–2.87(m,1H),2.81–2.65(m,2H),2.47–2.28(m,1H),2.26–1.74(m,8H)。 Compound 1-39 (9.6 mg). MS: 543.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.16-6.90(m,4H),6.43-6.17(m,2H),5.75-5.65(m,1H),4.95-4.84(m,3H),4.65 –4.50(m,1H),4.31–4.21(m,2H),4.18–3.66(m,7H),3.51–3.41(m,1H),3.23(s,1H),3.04(s,3H),2.94 – 2.87 (m, 1H), 2.81 – 2.65 (m, 2H), 2.47 – 2.28 (m, 1H), 2.26 – 1.74 (m, 8H).
实施例47Example 47
化合物I-40:4'-(7-丙烯酰-2,7-二氮杂螺[4.4]壬-2-基)-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-6'-酮Compound I-40: 4'-(7-Acryloyl-2,7-diazaspiro[4.4]non-2-yl)-2'-(((S)-1-methylpyrrolidine-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-6'- ketone
Figure PCTCN2021138375-appb-000365
Figure PCTCN2021138375-appb-000365
化合物I-40的合成参考化合物I-5，通过使用7-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2,7-二氮杂螺[4.4]壬烷-2-羧酸叔丁酯(中间体A17)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)制备得到化合物I-40。Synthesis of compound 1-40 Reference compound 1-5 by using 7-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methan yl)-5-nitropyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester (Intermediate A17) instead of (2S)-4-(2- Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyano Methyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) was prepared to give compound 1-40.
化合物I-40(12.1毫克)。MS:557.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.14–6.90(m,4H),6.59–6.41(m,1H),6.27–6.15(m,1H),5.76–5.45(m,1H),4.77–4.51(m,2H),4.10(s,1H),3.99–3.40(m,10H),3.01–2.85(m,4H),2.81–2.64(m,2H),2.47–1.71(m,13H)。 Compound 1-40 (12.1 mg). MS: 557.1 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ7.14-6.90(m,4H),6.59-6.41(m,1H),6.27-6.15(m,1H),5.76-5.45(m,1H),4.77 –4.51(m, 2H), 4.10(s, 1H), 3.99 – 3.40(m, 10H), 3.01 – 2.85(m, 4H), 2.81 – 2.64(m, 2H), 2.47 – 1.71(m, 13H) .
实施例48Example 48
化合物I-41:2-((2S)-1-丙烯酰-4-(2'-((3R，4R)-3-羟基-4-甲氧基吡咯烷-1-基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-41: 2-((2S)-1-acryloyl-4-(2'-((3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl)-6'- Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine -2-yl)acetonitrile
Figure PCTCN2021138375-appb-000366
Figure PCTCN2021138375-appb-000366
化合物I-41的合成参考化合物I-14，通过使用(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A14)代替((2S)-4-(2-氯-6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A12)，(3R，4R)-4-甲氧基-1-甲基吡咯烷-3-醇(中间体C4)代替(S)-(1-甲基吡咯烷-2-基)甲醇制备得到化合物I-41。Synthesis of compound 1-41 Reference compound 1-14 by using (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene-1) -yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate benzyl ester (Intermediate A14) instead of ((2S)-4-(2 -Chloro-6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyano Methyl)piperazine-1-carboxylate benzyl ester (Intermediate A12), (3R,4R)-4-methoxy-1-methylpyrrolidin-3-ol (Intermediate C4) instead of (S)- (1-Methylpyrrolidin-2-yl)methanol was prepared to give compound 1-41.
化合物I-41(14.6毫克)。MS:558.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.28–7.05(m,4H),6.80(s,1H),6.38–6.24(m,1H),5.83(d,J＝10.2Hz,1H),5.19–4.61(m,2H),4.50–4.00(m,3H),3.99–3.43(m,5H),3.41(s,3H),3.37–2.74(m,9H),2.22–1.78(m,4H)。 Compound 1-41 (14.6 mg). MS: 558.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.28-7.05(m,4H),6.80(s,1H),6.38-6.24(m,1H),5.83(d,J=10.2Hz,1H), 5.19–4.61 (m, 2H), 4.50–4.00 (m, 3H), 3.99–3.43 (m, 5H), 3.41 (s, 3H), 3.37–2.74 (m, 9H), 2.22–1.78 (m, 4H) ).
实施例49Example 49
化合物I-42:2-((2S)-1-丙烯酰-4-(6'-氧基-2'-(吡啶-3-基)-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-42: 2-((2S)-1-Acryloyl-4-(6'-oxy-2'-(pyridin-3-yl)-3,4,5',8'-tetrahydro- 2H,6'H-Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000367
Figure PCTCN2021138375-appb-000367
化合物I-42的合成参考化合物I-14，通过使用(2S)-2-(氰基甲基)-4-(6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基-2-(吡啶-3-基)嘧啶-4-基)哌嗪-1-羧酸苄酯(中间体A18)代替(2S)-2-(氰基甲基)-4-(6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸苄酯(中间体A12/步骤1)制备得到化合物I-42。Synthesis of compound 1-42 Reference compound 1-14 by using (2S)-2-(cyanomethyl)-4-(6-((1-(methoxycarbonyl)-1,2,3,4- Tetrahydronaphthalen-1-yl)methyl)-5-nitro-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-1-carboxylate benzyl ester (Intermediate A18) in place of (2S) -2-(cyanomethyl)-4-(6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-2-((((S )-1-methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate benzyl ester (Intermediate A12/step 1) was prepared to give compound I- 42.
化合物I-42(19.1毫克)。MS:520.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ9.57(s,1H),9.18(s,1H),8.76(s,1H),7.91(d,J＝7.9Hz,1H),7.36–7.05(m,4H),6.83(s,1H),6.30(d,J＝16.6Hz,1H),5.84(d,J＝10.8Hz,1H),5.18–4.51(m,2H),3.94–3.87(m,3H),3.79–3.16(m,4H),3.16–2.73(m,4H),2.14–1.77(m,4H)。 Compound 1-42 (19.1 mg). MS: 520.1 (M+H) + . 1 H NMR (400MHz, Methanol-d 4 )δ9.57(s,1H),9.18(s,1H),8.76(s,1H),7.91(d,J=7.9Hz,1H),7.36-7.05( m, 4H), 6.83 (s, 1H), 6.30 (d, J=16.6Hz, 1H), 5.84 (d, J=10.8Hz, 1H), 5.18–4.51 (m, 2H), 3.94–3.87 (m , 3H), 3.79–3.16 (m, 4H), 3.16–2.73 (m, 4H), 2.14–1.77 (m, 4H).
实施例50Example 50
化合物I-43:2-((2S)-1-丙烯酰-4-(2'-(2-甲基吡啶-3-基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound I-43: 2-((2S)-1-acryloyl-4-(2'-(2-methylpyridin-3-yl)-6'-oxo-3,4,5',8' -Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000368
Figure PCTCN2021138375-appb-000368
化合物I-43的合成参考化合物I-14，通过使用2S)-2-(氰基甲基)-4-(6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(2-甲基吡啶-3-基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸苄酯(中间体A19)代替(2S)-2-(氰基甲基)-4-(6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸苄酯(中间体A12/步骤1)制备得到化合物I-43。Synthesis of compound 1-43 Reference compound 1-14 by using 2S)-2-(cyanomethyl)-4-(6-((1-(methoxycarbonyl)-1,2,3,4-tetrakis) Hydronaphthalen-1-yl)methyl)-2-(2-methylpyridin-3-yl)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate benzyl ester (Intermediate A19) instead (2S)-2-(cyanomethyl)-4-(6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-2-( Prepared from ((S)-1-methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate benzyl ester (Intermediate A12/Step 1) Compound 1-43.
化合物I-43(16.1毫克)。MS:534.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ9.14–8.98(m,1H),8.69(d,J＝4.5Hz,1H),7.91(d,J＝7.6Hz,1H),7.19–6.94(m,4H),6.82(s,1H),6.29–6.15(m,1H),5.84–5.64(m,1H),5.26–4.87(m,2H),4.26–3.35(m,4H),3.27–2.71(m,9H),2.16–1.78(m,5H)。 Compound 1-43 (16.1 mg). MS: 534.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ9.14-8.98(m,1H),8.69(d,J=4.5Hz,1H),7.91(d,J=7.6Hz,1H),7.19-6.94( m, 4H), 6.82 (s, 1H), 6.29–6.15 (m, 1H), 5.84–5.64 (m, 1H), 5.26–4.87 (m, 2H), 4.26–3.35 (m, 4H), 3.27– 2.71 (m, 9H), 2.16–1.78 (m, 5H).
实施例51Example 51
化合物I-44:2-((2S)-1-(2-氟丙烯酰基)-4-(2'-(2-甲基吡啶-3-基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-44: 2-((2S)-1-(2-fluoroacryloyl)-4-(2'-(2-methylpyridin-3-yl)-6'-oxo-3,4, 5',8'-Tetrahydro-2H,6'H-Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000369
Figure PCTCN2021138375-appb-000369
化合物I-44的合成参考化合物I-14，通过使用2S)-2-(氰基甲基)-4-(6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(2-甲基吡啶-3-基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸苄酯(中间体A19)代替(2S)-2-(氰基甲基)-4-(6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸苄酯(中间体A12/步骤1)和2-氟丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-44。Synthesis of compound 1-44 Reference compound 1-14 by using 2S)-2-(cyanomethyl)-4-(6-((1-(methoxycarbonyl)-1,2,3,4-tetrakis) Hydronaphthalen-1-yl)methyl)-2-(2-methylpyridin-3-yl)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate benzyl ester (Intermediate A19) instead (2S)-2-(cyanomethyl)-4-(6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-2-( ((S)-1-Methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate benzyl ester (Intermediate A12/Step 1) and 2 -Fluoroacryloyl chloride (Intermediate B1) was prepared in place of acryloyl chloride to give compound I-44.
化合物I-44(10.1毫克)。MS:552.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ9.09(dd,J＝15.4,8.1Hz,1H),8.70(d,J＝5.6Hz,1H),7.93(t,J＝7.1Hz,1H),7.37–7.11(m,4H),5.32–5.09(m,2H),4.12–4.09(m,1H),4.05–3.35(m,5H),3.30–2.74(m,9H),2.24–1.76(m,5H)。 Compound 1-44 (10.1 mg). MS: 552.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ9.09(dd,J=15.4,8.1Hz,1H),8.70(d,J=5.6Hz,1H),7.93(t,J=7.1Hz,1H) ,7.37–7.11(m,4H),5.32–5.09(m,2H),4.12–4.09(m,1H),4.05–3.35(m,5H),3.30–2.74(m,9H),2.24–1.76( m, 5H).
实施例52Example 52
化合物I-45:2-((2S)-1-(2-氟丙烯酰基)-4-(6'-氧基-2'-(吡啶-3-基)-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-45: 2-((2S)-1-(2-fluoroacryloyl)-4-(6'-oxy-2'-(pyridin-3-yl)-3,4,5',8 '-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000370
Figure PCTCN2021138375-appb-000370
化合物I-45的合成参考化合物I-14，通过使用(2S)-2-(氰基甲基)-4-(6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基-2-(吡啶-3-基)嘧啶-4-基)哌嗪-1-羧酸苄酯(中间体A18)代替(2S)-2-(氰基甲基)-4-(6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸苄酯(中间体A12/步骤1)和2-氟丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-45。Synthesis of compound 1-45 Reference compound 1-14 by using (2S)-2-(cyanomethyl)-4-(6-((1-(methoxycarbonyl)-1,2,3,4- Tetrahydronaphthalen-1-yl)methyl)-5-nitro-2-(pyridin-3-yl)pyrimidin-4-yl)piperazine-1-carboxylate benzyl ester (Intermediate A18) in place of (2S) -2-(cyanomethyl)-4-(6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-2-((((S )-1-Methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate benzyl ester (Intermediate A12/Step 1) and 2-fluoropropene The acid chloride (Intermediate B1) was prepared in place of acryloyl chloride to give compound 1-45.
化合物I-45(11.1毫克)。MS:538.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ9.45(s,1H),8.74(d,J＝8.1Hz,1H),8.59(d,J＝4.9Hz,1H),7.54(d,J＝7.1Hz,1H),7.30–7.07(m,4H),5.32–5.12(m,2H),4.41–3.33(m,6H),3.27–2.69(m,6H),2.30–1.74(m,5H)。 Compound 1-45 (11.1 mg). MS: 538.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ9.45(s,1H),8.74(d,J=8.1Hz,1H),8.59(d,J=4.9Hz,1H),7.54(d,J= 7.1Hz, 1H), 7.30–7.07 (m, 4H), 5.32–5.12 (m, 2H), 4.41–3.33 (m, 6H), 3.27–2.69 (m, 6H), 2.30–1.74 (m, 5H) .
实施例53Example 53
化合物I-46:2-((2S)-1-丙烯酰-4-(2'-((((S)-1-甲基吡咯烷-2-基)甲基)硫基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-46: 2-((2S)-1-acryloyl-4-(2'-((((S)-1-methylpyrrolidin-2-yl)methyl)sulfanyl)-6' -Oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperidine oxazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000371
Figure PCTCN2021138375-appb-000371
化合物I-46的合成参考化合物I-5，通过使用(S)-(1-甲基吡咯烷-2-基)甲硫醇(中间体C5)代替(S)-(1-甲基吡咯烷-2-基)甲醇制备得到化合物I-46。Synthesis of compound 1-46 Reference compound 1-5 by using (S)-(1-methylpyrrolidin-2-yl)methanethiol (intermediate C5) in place of (S)-(1-methylpyrrolidine -2-yl)methanol was prepared to give compound 1-46.
化合物I-46(11.7毫克)。MS:572.1(M+H) +。 1H NMR(400MHz,Methanol-d4)δ7.30–7.11(m,4H),6.81(s,1H),6.28–6.10(m,1H),5.83–5.65(m,1H),5.09(s,1H),4.21–3.43(m,6H),3.28–2.75(m,9H),2.54–2.37(m,1H),2.01–1.69(m,10H),1.29(s,2H) Compound 1-46 (11.7 mg). MS: 572.1 (M+H) + . 1 H NMR(400MHz,Methanol-d4)δ7.30–7.11(m,4H),6.81(s,1H),6.28–6.10(m,1H),5.83–5.65(m,1H),5.09(s, 1H), 4.21–3.43 (m, 6H), 3.28–2.75 (m, 9H), 2.54–2.37 (m, 1H), 2.01–1.69 (m, 10H), 1.29 (s, 2H)
实施例53Example 53
化合物I-47:2-((2S)-4-(2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-甲基丙烯酰哌嗪-2-基)乙腈Compound 1-47: 2-((2S)-4-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-6'-oxygen base-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1- Methacryloylpiperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000372
Figure PCTCN2021138375-appb-000372
化合物I-47的合成参考化合物I-14，通过使用(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A14)代替((2S)-4-(2-氯-6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A12)，((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和甲基丙烯酰氯代替丙烯酰氯制备得到化合物I-47。Synthesis of compound 1-47 Reference compound 1-14 by using (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene-1) -yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate benzyl ester (Intermediate A14) instead of ((2S)-4-(2 -Chloro-6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyano Methyl)piperazine-1-carboxylate benzyl ester (Intermediate A12), ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate C3) instead of (S) -(1-Methylpyrrolidin-2-yl)methanol and methacryloyl chloride in place of acryloyl chloride were prepared to give compound 1-47.
化合物I-47(19.6毫克)。MS:588.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.17(s,4H),5.37–5.01(m,3H),4.67–4.51(m,1H),4.35–3.82(m,4H),3.77–3.44(m,1H),2.92–2.57(m,14H),2.51–1.75(m,8H),1.38–1.24(m,2H)。 Compound 1-47 (19.6 mg). MS: 588.1 (M+H) + . 1 H NMR (400MHz, Methanol-d 4 )δ7.17(s,4H), 5.37-5.01(m,3H), 4.67-4.51(m,1H), 4.35-3.82(m,4H), 3.77-3.44 (m, 1H), 2.92–2.57 (m, 14H), 2.51–1.75 (m, 8H), 1.38–1.24 (m, 2H).
实施例54Example 54
化合物I-48:2-((2S)-1-((E)-but-2-烯基)-4-(2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-48: 2-((2S)-1-((E)-but-2-enyl)-4-(2'-(((2S,4R)-4-fluoro-1-methylpyrrole Alk-2-yl)methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3, 2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000373
Figure PCTCN2021138375-appb-000373
化合物I-48的合成参考化合物I-14，通过使用(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A14)代替((2S)-4-(2-氯-6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A12)，((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和(E)-丁-2-烯酰氯代替丙烯酰氯制备得到化合物I-48。Synthesis of compound 1-48 Reference compound 1-14 by using (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene-1 -yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate benzyl ester (Intermediate A14) instead of ((2S)-4-(2 -Chloro-6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyano Methyl)piperazine-1-carboxylate benzyl ester (Intermediate A12), ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate C3) instead of (S) -(1-Methylpyrrolidin-2-yl)methanol and (E)-but-2-enoyl chloride instead of acryloyl chloride were prepared to give compound 1-48.
化合物I-48(11.6毫克)。MS:588.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.34–7.11(m,4H),6.91(s,1H),6.51(s,1H),5.48–5.31(m,1H),4.82–4.53(m,3H),4.34–3.85(m,3H),3.54(m,3H),3.21–2.76(m,8H),2.65(s,1H),2.50–1.73(m,9H),1.33–1.24(m,2H)。 Compound 1-48 (11.6 mg). MS: 588.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.34-7.11(m,4H),6.91(s,1H),6.51(s,1H),5.48-5.31(m,1H),4.82-4.53(m ,3H),4.34–3.85(m,3H),3.54(m,3H),3.21–2.76(m,8H),2.65(s,1H),2.50–1.73(m,9H),1.33–1.24(m , 2H).
实施例55Example 55
化合物I-49:2-((2S)-2-(氰基甲基)-4-(2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-基)-2-氧代乙酸甲酯Compound 1-49: 2-((2S)-2-(cyanomethyl)-4-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl) Methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine] -4'-yl)piperazin-1-yl)-2-oxoacetate methyl ester
Figure PCTCN2021138375-appb-000374
Figure PCTCN2021138375-appb-000374
化合物I-49的合成参考化合物I-14，通过使用(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A14)代替((2S)-4-(2-氯-6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A12)，((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氯-2-氧代乙酸甲酯代替丙烯酰氯制备得到化合物I-49。Synthesis of compound 1-49 Reference compound 1-14 by using (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene-1) -yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate benzyl ester (Intermediate A14) instead of ((2S)-4-(2 -Chloro-6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyano Methyl)piperazine-1-carboxylate benzyl ester (Intermediate A12), ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate C3) instead of (S) -(1-Methylpyrrolidin-2-yl)methanol and 2-chloro-2-oxoacetate methyl ester instead of acryloyl chloride were prepared to give compound 1-49.
化合物I-49(21.6毫克)。MS:606.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.30–7.10(m,4H),5.47–5.31(m,1H),4.94(s,1H),4.77–4.69(m,1H),4.65–4.51(m,1H),4.47–4.17(m,2H),4.06–3.85(m,4H),3.77–3.33(m,3H),3.22–2.76(m,8H),2.65–2.54(m,1H),2.37–2.25(m,1H),2.15(s,3H),2.12–1.73(m,4H),1.29–1.23(m,2H)。 Compound 1-49 (21.6 mg). MS: 606.1 (M+H) + . 1 H NMR (400MHz, Methanol-d 4 )δ7.30-7.10(m,4H), 5.47-5.31(m,1H), 4.94(s,1H), 4.77-4.69(m,1H), 4.65-4.51 (m, 1H), 4.47–4.17 (m, 2H), 4.06–3.85 (m, 4H), 3.77–3.33 (m, 3H), 3.22–2.76 (m, 8H), 2.65–2.54 (m, 1H) , 2.37–2.25 (m, 1H), 2.15 (s, 3H), 2.12–1.73 (m, 4H), 1.29–1.23 (m, 2H).
实施例56Example 56
化合物I-50:2-((2S)-1-丙烯酰-4-(2'-(甲硫基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound I-50: 2-((2S)-1-acryloyl-4-(2'-(methylthio)-6'-oxy-3,4,5',8'-tetrahydro-2H, 6'H-Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000375
Figure PCTCN2021138375-appb-000375
步骤1:(2S)-2-(氰基甲基)-4-(6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(甲硫基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸苄酯的制备Step 1: (2S)-2-(cyanomethyl)-4-(6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl) - Preparation of benzyl 2-(methylthio)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate
Figure PCTCN2021138375-appb-000376
Figure PCTCN2021138375-appb-000376
将4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A14,300毫克,0.485毫摩尔)溶于无水四氢呋喃(20毫升)中，在25℃时搅拌缓慢加入甲硫醇钠(67.9毫克,0.969毫摩尔)。滴完后，将反应混合物缓慢升至50℃并搅拌4小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃 取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-2-(氰基甲基)-4-(6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(甲硫基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸苄酯(320毫克,105％收率)。MS:631.1(M+H) +。 4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl) - Benzyl 2-(cyanomethyl)piperazine-1-carboxylate (Intermediate A14, 300 mg, 0.485 mmol) was dissolved in dry tetrahydrofuran (20 mL), and methyl sulfide was added slowly with stirring at 25 °C Sodium alkoxide (67.9 mg, 0.969 mmol). After dropping, the reaction mixture was slowly raised to 50°C and stirred for 4 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2S)-2-(cyanomethyl)-4-(6 -((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-2-(methylthio)-5-nitropyrimidin-4-yl)piperidine Benzyl azine-1-carboxylate (320 mg, 105% yield). MS: 631.1 (M+H) + .
步骤2:(2S)-2-(氰基甲基)-4-(2'-(甲硫基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸苄酯的制备Step 2: (2S)-2-(cyanomethyl)-4-(2'-(methylthio)-6'-oxy-3,4,5',8'-tetrahydro-2H,6 Preparation of 'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate benzyl ester
Figure PCTCN2021138375-appb-000377
Figure PCTCN2021138375-appb-000377
将(2S)-2-(氰基甲基)-4-(6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(甲硫基)-5-硝基嘧啶-4-基)哌嗪-1-羧酸苄酯(300毫克,0.476毫摩尔)和锌粉(155毫克,2.378毫摩尔)加到乙酸(5毫升)和水(1毫升)的混合溶液中，反应混合物在65度搅拌3小时。反应完毕后，反应溶液过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-2-(氰基甲基)-4-(2'-(甲硫基)-6'-氧基-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸苄酯(180毫克,66.5％收率)。MS:569.1(M+H) +。 (2S)-2-(cyanomethyl)-4-(6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-2 -(Methylthio)-5-nitropyrimidin-4-yl)piperazine-1-carboxylate benzyl ester (300 mg, 0.476 mmol) and zinc dust (155 mg, 2.378 mmol) were added to acetic acid (5 mL) and water (1 mL), the reaction mixture was stirred at 65°C for 3 hours. After the completion of the reaction, the reaction solution was filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2S)-2-(cyanomethyl)-4-(2'-(methylthio)-6 '-Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl) Benzyl piperazine-1-carboxylate (180 mg, 66.5% yield). MS: 569.1 (M+H) + .
步骤3:2-((2S)-4-(2'-(甲硫基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈的制备Step 3: 2-((2S)-4-(2'-(methylthio)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[ Preparation of naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000378
Figure PCTCN2021138375-appb-000378
将(2S)-2-(氰基甲基)-4-(2'-(甲硫基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸苄酯(100毫克,0.176毫摩尔)乙酸(5毫升)和40％氢溴酸的乙酸溶液(1毫升)的混合溶液中，反应混合物在50度搅拌13小时。反应完毕后,反应溶液浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体2-((2S)-4-(2'-(甲硫基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(80毫克,105％收率)。MS:435.1(M+H) +。 (2S)-2-(cyanomethyl)-4-(2'-(methylthio)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H - Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate benzyl ester (100 mg, 0.176 mmol) acetic acid (5 mL) and In a mixed solution of 40% hydrobromic acid in acetic acid (1 mL), the reaction mixture was stirred at 50°C for 13 hours. After the completion of the reaction, the reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid 2-((2S)-4-(2'-(methylthio)-6'-oxy-3,4 ,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (80 mg, 105% yield). MS: 435.1 (M+H) + .
步骤4:2-((2S)-1-丙烯酰-4-(2'-(甲硫基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈的制备Step 4: 2-((2S)-1-Acryloyl-4-(2'-(methylthio)-6'-oxy-3,4,5',8'-tetrahydro-2H,6' Preparation of H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000379
Figure PCTCN2021138375-appb-000379
将2-((2S)-4-(2'-(甲硫基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(80毫克,0.184毫摩尔)和DIEA(23.79毫克,0.184毫摩尔)溶于二氯甲烷(5毫升)中，在0℃时搅拌缓慢加入丙烯酰氯(24.99毫克,0.276毫摩尔)。滴完后，将反应混合物在0℃并搅拌1小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经Pre-HPLC制备的到白色固体2-((2S)-1-丙烯酰-4-(2'-(甲硫基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(10.72毫克,11.9％收率)。MS:489.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.29–6.77(m,6H),6.17–5.98(m,1H),5.75–5.54(m 1H),4.93–4.87(m,1H),4.44–3.92(m,1H),3.76–3.44(m,6H),3.34–2.61(m,7H),1.88–1.64(m,4H)。 2-((2S)-4-(2'-(methylthio)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene- 1,7'-Pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (80 mg, 0.184 mmol) and DIEA (23.79 mg, 0.184 mmol) were dissolved in two To methyl chloride (5 mL) was slowly added acryloyl chloride (24.99 mg, 0.276 mmol) with stirring at 0°C. After dropping, the reaction mixture was stirred at 0°C for 1 hour, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to a white solid 2-((2S)-1-acryloyl-4-(2'-(Methylthio)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]Pyrimidine]-4'-yl)piperazin-2-yl)acetonitrile (10.72 mg, 11.9% yield). MS: 489.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ7.29-6.77(m,6H),6.17-5.98(m,1H),5.75-5.54(m1H),4.93-4.87(m,1H),4.44- 3.92 (m, 1H), 3.76–3.44 (m, 6H), 3.34–2.61 (m, 7H), 1.88–1.64 (m, 4H).
实施例57Example 57
化合物I-51:2-((2S)-1-丙烯酰-4-(2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-5'-甲基-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-51: 2-((2S)-1-acryloyl-4-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy) -5'-methyl-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d] Pyrimidine]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000380
Figure PCTCN2021138375-appb-000380
Figure PCTCN2021138375-appb-000381
Figure PCTCN2021138375-appb-000381
步骤1:(2S)-2-(氰基甲基)-4-(5'-甲基-2'-(甲硫基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸苄酯的制备Step 1: (2S)-2-(cyanomethyl)-4-(5'-methyl-2'-(methylthio)-6'-oxy-3,4,5',8'- Preparation of tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylic acid benzyl ester
Figure PCTCN2021138375-appb-000382
Figure PCTCN2021138375-appb-000382
将(2S)-2-(氰基甲基)-4-(2'-(甲硫基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸苄酯(化合物I-50/步骤2,400毫克,0.703毫摩尔)溶于四氢呋喃(10毫升)中，在0℃时搅拌缓慢加入钠氢(16.88毫克,0.703毫摩尔)。滴完后，将反应混合物在0℃并搅拌15分钟，将碘甲烷(300毫克,2.110毫摩尔)在0℃加到上述反应液中，并在0℃继续搅拌3小时。然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经Pre-HPLC制备的到黄色油状物(2S)-2-(氰基甲基)-4-(5'-甲基-2'-(甲硫基)-6'- 氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸苄酯(350毫克,85％收率)。MS:583.1(M+H) +。 (2S)-2-(cyanomethyl)-4-(2'-(methylthio)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H -Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate benzyl ester (Compound I-50/Step 2, 400 mg, 0.703 mmol) Dissolve in tetrahydrofuran (10 mL) and slowly add sodium hydrogen (16.88 mg, 0.703 mmol) with stirring at 0°C. After dropping, the reaction mixture was stirred at 0°C for 15 minutes, iodomethane (300 mg, 2.110 mmol) was added to the above reaction solution at 0°C, and stirring was continued at 0°C for 3 hours. The reaction was then quenched by the addition of ice water, and the extraction was diluted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to a yellow oil (2S)-2-(cyanomethyl)-4-( 5'-Methyl-2'-(methylthio)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'- Pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate benzyl ester (350 mg, 85% yield). MS: 583.1 (M+H) + .
步骤2:(2S)-2-(氰甲基)-4-(5'-甲基-2'-(甲基亚磺酰基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸苄酯的制备Step 2: (2S)-2-(cyanomethyl)-4-(5'-methyl-2'-(methylsulfinyl)-6'-oxo-3,4,5',8' - Preparation of benzyl tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate
Figure PCTCN2021138375-appb-000383
Figure PCTCN2021138375-appb-000383
将(2S)-2-(氰基甲基)-4-(5'-甲基-2'-(甲硫基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸苄酯(400毫克,0.686毫摩尔)溶于二氯甲烷(5毫升)中，在0℃时搅拌缓慢加入m-CPBA(118毫克,0.686毫摩尔)。滴完后，将反应混合物在0℃并搅拌15分钟，然后在室温继续搅拌3小时。然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色油状物(2S)-2-(氰甲基)-4-(5'-甲基-2'-(甲基亚磺酰基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸苄酯(411毫克,100％收率)，未经纯化直接用于下一步反应。MS:599.1(M+H) +。 (2S)-2-(cyanomethyl)-4-(5'-methyl-2'-(methylthio)-6'-oxy-3,4,5',8'-tetrahydro -2H,6'H-Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate benzyl ester (400 mg, 0.686 mmol) Dissolve in dichloromethane (5 mL) and add m-CPBA (118 mg, 0.686 mmol) slowly with stirring at 0°C. After completion of the dropwise addition, the reaction mixture was stirred at 0°C for 15 minutes and then continued to stir at room temperature for 3 hours. The reaction was then quenched by the addition of ice water, and the extraction was diluted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give a yellow oil (2S)-2-(cyanomethyl)-4-(5'-methyl-2'-(methylidene) Sulfonyl)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]- 4'-yl)piperazine-1-carboxylate benzyl ester (411 mg, 100% yield) was used in the next reaction without purification. MS: 599.1 (M+H) + .
步骤3:(2S)-2-(氰基甲基)-4-(2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-5'-甲基-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸苄酯的制备Step 3: (2S)-2-(cyanomethyl)-4-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)- 5'-Methyl-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine Preparation of ]-4'-yl)piperazine-1-carboxylic acid benzyl ester
Figure PCTCN2021138375-appb-000384
Figure PCTCN2021138375-appb-000384
将(2S)-2-(氰甲基)-4-(5'-甲基-2'-(甲基亚磺酰基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸苄酯(350毫克,0.585毫摩尔)和((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(156毫克,1.17毫摩尔)溶于无水四氢呋喃(5毫升)中，在25℃时搅拌缓慢加入碳酸铯(571毫克,1.75毫摩尔)。滴完后，将反应混合物缓慢升至50℃并搅拌11小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅 胶柱层析纯化得到黄色固体(2S)-2-(氰基甲基)-4-(2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-5'-甲基-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸苄酯(260毫克,66.6％收率)。MS:668.1(M+H) +。 (2S)-2-(cyanomethyl)-4-(5'-methyl-2'-(methylsulfinyl)-6'-oxo-3,4,5',8'-tetra Hydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate benzyl ester (350 mg, 0.585 mmol ) and ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (156 mg, 1.17 mmol) were dissolved in dry tetrahydrofuran (5 mL) and stirred slowly at 25°C Cesium carbonate (571 mg, 1.75 mmol) was added. After dropping, the reaction mixture was slowly raised to 50°C and stirred for 11 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain (2S)-2-(cyanomethyl)-4-(2) as a yellow solid '-(((2S,4R)-4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)-5'-methyl-6'-oxy-3,4,5',8 '-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate benzyl ester (260 mg, 66.6% yield). MS: 668.1 (M+H) + .
步骤4:2-((2S)-4-(2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-5'-甲基-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈的制备Step 4: 2-((2S)-4-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5'-methyl- 6'-Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl ) Preparation of piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000385
Figure PCTCN2021138375-appb-000385
将(2S)-2-(氰基甲基)-4-(2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-5'-甲基-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸苄酯(260毫克,0.389毫摩尔)溶于乙醇醇(5毫升)中，在搅拌条件下向反应混合物中加入钯碳(71毫克)。反应混合物在氢气作用下室温搅拌2小时，然后将混合物溶液过滤。将滤液真空浓缩，得到黄色油状物2-((2S)-4-(2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-5'-甲基-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(120毫克,57.7％收率)。MS:534.1(M+H) +。 (2S)-2-(cyanomethyl)-4-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5'-Methyl-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4'-yl)piperazine-1-carboxylate benzyl ester (260 mg, 0.389 mmol) was dissolved in ethanol alcohol (5 mL) and palladium on carbon (71 mg) was added to the reaction mixture with stirring. The reaction mixture was stirred at room temperature under the influence of hydrogen for 2 hours, and then the mixture solution was filtered. The filtrate was concentrated in vacuo to give 2-((2S)-4-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)- as a yellow oil 5'-Methyl-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine ]-4'-yl)piperazin-2-yl)acetonitrile (120 mg, 57.7% yield). MS: 534.1 (M+H) + .
步骤5:2-((2S)-1-丙烯酰-4-(2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-5'-甲基-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈的制备Step 5: 2-((2S)-1-Acryloyl-4-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5 '-Methyl-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine] Preparation of -4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000386
Figure PCTCN2021138375-appb-000386
将2-((2S)-4-(2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-5'-甲基-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(120毫克,0.225毫摩尔)和DIEA(0.12毫升,0.675毫摩尔)溶于二氯甲烷(5毫升)中，在0℃时搅拌缓慢加入丙烯酰氯(20.35毫克,0.225毫摩尔)。滴完后，将反应混合物在0℃并搅拌1小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经Pre-HPLC制备的到黄色固体2- ((2S)-1-丙烯酰-4-(2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-5'-甲基-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(40毫克,30.3％收率)。MS:588.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.29–7.10(m,4H),6.79(s,1H),6.27–6.11(m,1H),5.82–5.67(m,1H),5.48–5.21(m,1H),4.60(m,2H),4.12(m,2H),3.84–3.32(m,4H),3.22–2.22(m,14H),2.14–2.10(m,1H),2.08–1.63(m,4H),1.29–1.19(m,3H)。 2-((2S)-4-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5'-methyl-6'-Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperidine Azin-2-yl)acetonitrile (120 mg, 0.225 mmol) and DIEA (0.12 mL, 0.675 mmol) were dissolved in dichloromethane (5 mL), and acryloyl chloride (20.35 mg, 0.225 g) was added slowly with stirring at 0°C Millimoles). After dropping, the reaction mixture was stirred at 0°C for 1 hour, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to a yellow solid 2-((2S)-1-acryloyl-4-(2'-(((2S,4R)-4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)-5'-methyl-6'-oxo-3,4,5',8'-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (40 mg, 30.3% yield). MS: 588.1 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ7.29-7.10(m,4H),6.79(s,1H),6.27-6.11(m,1H),5.82-5.67(m,1H),5.48-5.21 (m, 1H), 4.60 (m, 2H), 4.12 (m, 2H), 3.84–3.32 (m, 4H), 3.22–2.22 (m, 14H), 2.14–2.10 (m, 1H), 2.08–1.63 (m, 4H), 1.29–1.19 (m, 3H).
实施例58Example 58
化合物I-52:2-((2S)-1-丙烯酰-4-(6'-氧基-2'-(吡啶-2-基甲氧基)-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound I-52: 2-((2S)-1-acryloyl-4-(6'-oxy-2'-(pyridin-2-ylmethoxy)-3,4,5',8'- Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000387
Figure PCTCN2021138375-appb-000387
化合物I-52的合成参考化合物I-14，通过使用(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A14)代替((2S)-4-(2-氯-6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A12)，吡啶-2-基甲醇代替(S)-(1-甲基吡咯烷-2-基)甲醇制备得到化合物I-52。Synthesis of compound 1-52 Reference compound 1-14 by using (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene-1) -yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate benzyl ester (Intermediate A14) instead of ((2S)-4-(2 -Chloro-6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyano Methyl)piperazine-1-carboxylate benzyl ester (Intermediate A12), pyridin-2-ylmethanol instead of (S)-(1-methylpyrrolidin-2-yl)methanol was prepared to give compound I-52.
化合物I-52(20.6毫克)。MS:550.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ8.66(d,J＝5.2Hz,1H),8.19(d,J＝8.8Hz,1H),7.83(t,J＝8.3Hz,1H),7.65(d,J＝6.7Hz,1H),7.31–7.06(m,5H),6.79(s,1H),6.28–6.15(m,1H),5.82–5.71(m,1H),5.60(s,2H),5.01(s,1H),4.26–3.43(m,2H),3.28–2.61(m,5H),2.26–1.68(m,6H),1.28–1.13(m,2H)。 Compound 1-52 (20.6 mg). MS: 550.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ8.66(d,J=5.2Hz,1H),8.19(d,J=8.8Hz,1H),7.83(t,J=8.3Hz,1H),7.65 (d, J=6.7Hz, 1H), 7.31–7.06 (m, 5H), 6.79 (s, 1H), 6.28–6.15 (m, 1H), 5.82–5.71 (m, 1H), 5.60 (s, 2H) ), 5.01 (s, 1H), 4.26–3.43 (m, 2H), 3.28–2.61 (m, 5H), 2.26–1.68 (m, 6H), 1.28–1.13 (m, 2H).
实施例59Example 59
化合物I-53:2-((2S)-1-丙烯酰-4-(2'-((((S)-1-甲基吡咯烷-2-基)甲基)亚磺酰基)-6'-氧代-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-53: 2-((2S)-1-acryloyl-4-(2'-((((S)-1-methylpyrrolidin-2-yl)methyl)sulfinyl)-6 '-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl) Piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000388
Figure PCTCN2021138375-appb-000388
步骤1:(2S)-2-(氰甲基)-4-(2'-((((S)-1-甲基吡咯烷-2-基)甲基)亚磺酰基)-6'-氧代-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯的制备Step 1: (2S)-2-(cyanomethyl)-4-(2'-((((S)-1-methylpyrrolidin-2-yl)methyl)sulfinyl)-6'- Oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine - Preparation of tert-butyl 1-carboxylate
Figure PCTCN2021138375-appb-000389
Figure PCTCN2021138375-appb-000389
将(2S)-2-(氰甲基)-4-(2'-((((S)-1-甲基吡咯烷-2-基)甲基)硫基)-6'-氧代-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯(化合物I-46/步骤2,300毫克,0.486毫摩尔)溶于无水二氯甲烷(10毫升)中，在0度时搅拌缓慢加入m-CPBA(94毫克,0.461毫摩尔)。滴完后，将反应混合物在0度继续搅拌15分钟，然后加入冰水淬灭反应，并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-2-(氰甲基)-4-(2'-((((S)-1-甲基吡咯烷-2-基)甲基)亚磺酰基)-6'-氧代-3,4,5',8'-四 氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯(210毫克,68.2％收率)。MS:634.1(M+H) +。 (2S)-2-(cyanomethyl)-4-(2'-((((S)-1-methylpyrrolidin-2-yl)methyl)sulfanyl)-6'-oxo- 3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1- tert-Butyl carboxylate (Compound I-46/Step 2, 300 mg, 0.486 mmol) was dissolved in dry dichloromethane (10 mL), and m-CPBA (94 mg, 0.461 mmol) was slowly added with stirring at 0°C . After dropping, the reaction mixture was further stirred at 0°C for 15 minutes, then ice water was added to quench the reaction, and the mixture was diluted with dichloromethane for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (2S)-2-(cyanomethyl)-4-(2'-((((S)-1-Methylpyrrolidin-2-yl)methyl)sulfinyl)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1-carboxylate tert-butyl ester (210 mg, 68.2% yield). MS: 634.1 (M+H) + .
步骤2:2-((2S)-4-(2’-((((S)-1-甲基吡咯烷-2-基)甲基)亚磺酰基)-6’-氧代-3,4,5’,8’-四氢-2H,6’H-螺环[萘-1,7’-吡啶[3,2-d]嘧啶]-4’-基)哌嗪-2-基)乙腈的制备Step 2: 2-((2S)-4-(2'-((((S)-1-methylpyrrolidin-2-yl)methyl)sulfinyl)-6'-oxo-3, 4,5',8'-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl) Preparation of acetonitrile
Figure PCTCN2021138375-appb-000390
Figure PCTCN2021138375-appb-000390
将(2S)-2-(氰甲基)-4-(2'-((((S)-1-甲基吡咯烷-2-基)甲基)亚磺酰基)-6'-氧代-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-1-羧酸叔丁酯(210毫克,0.331毫摩尔)溶于二氯甲烷(5毫升)和盐酸的1,4-二氧六环溶液(4.0M,1毫升)中，反应混合物在室温搅拌1小时。将反应混合液浓缩蒸干，并用乙酸乙酯稀释萃取，有机相用饱和碳酸钠水溶液，饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到黄色固体2-((2S)-4-(2’-((((S)-1-甲基吡咯烷-2-基)甲基)亚磺酰基)-6’-氧代-3,4,5’,8’-四氢-2H,6’H-螺环[萘-1,7’-吡啶[3,2-d]嘧啶]-4’-基)哌嗪-2-基)乙腈(160毫克,90％收率)。MS:543.3(M+H) +。 (2S)-2-(cyanomethyl)-4-(2'-((((S)-1-methylpyrrolidin-2-yl)methyl)sulfinyl)-6'-oxo -3,4,5',8'-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine-1 - tert-butyl carboxylate (210 mg, 0.331 mmol) was dissolved in dichloromethane (5 mL) and hydrochloric acid in 1,4-dioxane (4.0 M, 1 mL) and the reaction mixture was stirred at room temperature for 1 Hour. The reaction mixture was concentrated and evaporated to dryness, diluted and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a yellow solid 2-((2S)-4- (2'-((((S)-1-Methylpyrrolidin-2-yl)methyl)sulfinyl)-6'-oxo-3,4,5',8'-tetrahydro-2H ,6'H-Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (160 mg, 90% yield). MS: 543.3 (M+H) + .
步骤3:2-((2S)-1-丙烯酰-4-(2'-((((S)-1-甲基吡咯烷-2-基)甲基)亚磺酰基)-6'-氧代-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈的制备Step 3: 2-((2S)-1-Acryloyl-4-(2'-((((S)-1-methylpyrrolidin-2-yl)methyl)sulfinyl)-6'- Oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazine Preparation of -2-yl)acetonitrile
Figure PCTCN2021138375-appb-000391
Figure PCTCN2021138375-appb-000391
将2-((2S)-4-(2’-((((S)-1-甲基吡咯烷-2-基)甲基)亚磺酰基)-6’-氧代-3,4,5’,8’-四氢-2H,6’H-螺环[萘-1,7’-吡啶[3,2-d]嘧啶]-4’-基)哌嗪-2-基)乙腈(160毫克,0.300毫摩尔)溶于二氯甲烷(5毫升)中，在-50℃时搅拌缓慢加入碳酸钠(95毫克,0.899毫摩尔)和丙烯酰氯(27.1毫克,0.300毫摩尔)。滴完后，将反应混合物在-50℃并搅拌5分钟，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经Pre-HPLC制备的到黄色固体2-((2S) -1-丙烯酰-4-(2'-((((S)-1-甲基吡咯烷-2-基)甲基)亚磺酰基)-6'-氧代-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈(11.65毫克,5.8％收率)。MS:576.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.27–7.04(m,4H),6.81(s,1H),6.36–6.20(m,1H),5.83–5.69(m,1H),5.19–4.92(m,1H),4.22–3.74(m,3H),3.66–3.45(m,8H),3.11–2.76(m,5H),2.54–2.47(m,1H),2.15(s,9H),1.29(s,2H)。 2-((2S)-4-(2'-((((S)-1-methylpyrrolidin-2-yl)methyl)sulfinyl)-6'-oxo-3,4, 5',8'-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile ( 160 mg, 0.300 mmol) was dissolved in dichloromethane (5 mL), and sodium carbonate (95 mg, 0.899 mmol) and acryloyl chloride (27.1 mg, 0.300 mmol) were slowly added with stirring at -50°C. After dropping, the reaction mixture was stirred at -50°C for 5 minutes, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to a yellow solid 2-((2S)-1-acryloyl-4-(2'-((((S)-1-Methylpyrrolidin-2-yl)methyl)sulfinyl)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (11.65 mg, 5.8% yield). MS: 576.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.27-7.04(m,4H),6.81(s,1H),6.36-6.20(m,1H),5.83-5.69(m,1H),5.19-4.92 (m, 1H), 4.22–3.74 (m, 3H), 3.66–3.45 (m, 8H), 3.11–2.76 (m, 5H), 2.54–2.47 (m, 1H), 2.15 (s, 9H), 1.29 (s, 2H).
实施例60Example 60
化合物I-54:2-((2S，5R)-1-丙烯酰-5-甲基-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-54: 2-((2S,5R)-1-acryloyl-5-methyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy )-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4' -yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000392
Figure PCTCN2021138375-appb-000392
化合物I-54的合成参考化合物I-14，通过使用(2S，5R)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)-5-甲基哌嗪-1-羧酸苄酯(中间体A20)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A12)制备得到化合物I-54。Synthesis of compound 1-54 Reference compound 1-14 by using (2S,5R)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene) -1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)-5-methylpiperazine-1-carboxylate benzyl ester (Intermediate A20) in place of (2S )-4-(2-Chloro-6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-5-nitropyrimidin-4-yl) - Benzyl 2-(cyanomethyl)piperazine-1-carboxylate (Intermediate A12) was prepared to give compound 1-54.
化合物I-54(14.6毫克)。MS:570.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.28–7.02(m,4H),6.97–6.72(m,1H),6.30(d,J＝16.6Hz,1H),5.83(d,J＝10.7Hz,1H),4.78–4.25(m,2H),4.01–3.35(m,7H),3.24–2.72(m,9H),2.49–1.73(m,10H),1.26–0.89(m,3H)。 Compound 1-54 (14.6 mg). MS: 570.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.28-7.02(m,4H),6.97-6.72(m,1H),6.30(d,J=16.6Hz,1H),5.83(d,J=10.7 Hz, 1H), 4.78–4.25 (m, 2H), 4.01–3.35 (m, 7H), 3.24–2.72 (m, 9H), 2.49–1.73 (m, 10H), 1.26–0.89 (m, 3H).
实施例61Example 61
化合物I-55:2-((2S，5R)-1-(2-氟丙烯酰基)-5-甲基-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-55: 2-((2S,5R)-1-(2-fluoroacryloyl)-5-methyl-4-(2'-(((S)-1-methylpyrrolidine-2- yl)methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d] Pyrimidine]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000393
Figure PCTCN2021138375-appb-000393
化合物I-55的合成参考化合物I-14，通过使用(2S，5R)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)-5-甲基哌嗪-1-羧酸苄酯(中间体A20)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(中间体A12)和2-氟代丙烯酰氯代替丙烯酰氯制备得到化合物I-55。Synthesis of compound 1-55 Reference compound 1-14 by using (2S,5R)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene) -1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)-5-methylpiperazine-1-carboxylate benzyl ester (Intermediate A20) in place of (2S )-4-(2-Chloro-6-((1-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)methyl)-5-nitropyrimidin-4-yl) - Benzyl 2-(cyanomethyl)piperazine-1-carboxylate (Intermediate A12) and 2-fluoroacryloyl chloride instead of acryloyl chloride were prepared to give compound 1-55.
化合物I-55(20.6毫克)。MS:588.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.32–6.99(m,4H),5.31–5.21(m,2H),4.74–4.19(m,2H),3.95–3.36(m,7H),3.26–2.76(m,9H),2.45–1.75(m,10H),1.26–0.99(m,3H)。 Compound 1-55 (20.6 mg). MS: 588.1 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ7.32-6.99(m,4H),5.31-5.21(m,2H),4.74-4.19(m,2H),3.95-3.36(m,7H),3.26 – 2.76 (m, 9H), 2.45 – 1.75 (m, 10H), 1.26 – 0.99 (m, 3H).
实施例62Example 62
化合物I-56:2-((2S)-1-丙烯酰-4-(7-氯-2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-56: 2-((2S)-1-acryloyl-4-(7-chloro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl) Methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine] -4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000394
Figure PCTCN2021138375-appb-000394
化合物I-56的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((7-氯-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A21)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇制备得到化合物I-56。Synthesis of compound 1-56 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((7-chloro-1-(methoxycarbonyl)-1,2,3,4-tetrakis) Hydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A21) in place of (2S)- 4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)- 2-(Cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) and ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate A3) C3) was prepared in place of (S)-(1-methylpyrrolidin-2-yl)methanol to obtain compound 1-56.
化合物I-56(20.6毫克)。MS:608.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.34–7.09(m,3H),6.81(s,1H),6.29–6.09(m,1H),5.83–5.69(m,1H),5.48–5.35(m,1H),4.68 –3.86(m,8H),3.80–3.36(m,6H),3.24–2.76(m,6H),2.64–2.51(m,1H),2.38–2.28(m,1H),2.15(s,1H),2.11–1.96(m,1H),1.96–1.75(m,3H)。 Compound 1-56 (20.6 mg). MS: 608.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.34-7.09(m,3H),6.81(s,1H),6.29-6.09(m,1H),5.83-5.69(m,1H),5.48-5.35 (m,1H),4.68–3.86(m,8H),3.80–3.36(m,6H),3.24–2.76(m,6H),2.64–2.51(m,1H),2.38–2.28(m,1H) , 2.15 (s, 1H), 2.11–1.96 (m, 1H), 1.96–1.75 (m, 3H).
实施例63Example 63
化合物I-57:2-((2S)-1-丙烯酰-4-(5-氯-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-57: 2-((2S)-1-acryloyl-4-(5-chloro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6 '-Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl) Piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000395
Figure PCTCN2021138375-appb-000395
化合物I-57的合成参考化合物I-5，通过使用((2S)-4-(2-氯-6-((5-氯-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A22)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)制备得到化合物I-57。Synthesis of compound 1-57 Reference compound 1-5, by using ((2S)-4-(2-chloro-6-((5-chloro-1-(methoxycarbonyl)-1,2,3,4- Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A22) in place of (2S) -4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl) -2-(Cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) was prepared to give compound 1-57.
化合物I-57(10.6毫克)。MS:590.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.40–7.14(m,3H),6.82(s,1H),6.29(d,J＝16.8Hz,1H),5.84(d,J＝10.9Hz,1H),4.79–4.43(m,1H),4.39–3.38(m,5H),3.28–2.61(m,10H),2.52–1.78(m,11H),1.35–1.30(m,2H)。 Compound 1-57 (10.6 mg). MS: 590.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.40-7.14(m,3H),6.82(s,1H),6.29(d,J=16.8Hz,1H),5.84(d,J=10.9Hz, 1H), 4.79–4.43 (m, 1H), 4.39–3.38 (m, 5H), 3.28–2.61 (m, 10H), 2.52–1.78 (m, 11H), 1.35–1.30 (m, 2H).
实施例63Example 63
化合物I-58:2-((2S)-1-丙烯酰-4-(6-氯-2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-58: 2-((2S)-1-acryloyl-4-(6-chloro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl) Methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine] -4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000396
Figure PCTCN2021138375-appb-000396
化合物I-58的合成参考化合物I-5，通过使用((2S)-4-(2-氯-6-((6-氯-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A23)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇制备得到化合物I-58。Synthesis of compound 1-58 Reference compound 1-5, by using ((2S)-4-(2-chloro-6-((6-chloro-1-(methoxycarbonyl)-1,2,3,4- Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A23) in place of (2S) -4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl) - tert-butyl 2-(cyanomethyl)piperazine-1-carboxylate (Intermediate A3) and ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate A3) Compound 1-58 was prepared by replacing (S)-(1-methylpyrrolidin-2-yl)methanol with compound C3).
化合物I-58(12.6毫克)。MS:608.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.31–7.10(m,3H),6.81(s,1H),6.29(d,J＝16.6Hz,1H),5.83(d,J＝10.5Hz,1H),5.48–5.34(m,1H),4.78–3.40(m,8H),3.22–2.56(m,10H),2.45–2.15(m,5H),2.08–1.68(m,4H)。 Compound 1-58 (12.6 mg). MS: 608.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.31-7.10(m,3H),6.81(s,1H),6.29(d,J=16.6Hz,1H),5.83(d,J=10.5Hz, 1H), 5.48–5.34 (m, 1H), 4.78–3.40 (m, 8H), 3.22–2.56 (m, 10H), 2.45–2.15 (m, 5H), 2.08–1.68 (m, 4H).
实施例64Example 64
化合物I-59:2-((2S)-4-(5-氯-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-59: 2-((2S)-4-(5-chloro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy- 3,4,5',8'-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1-(2 -Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000397
Figure PCTCN2021138375-appb-000397
化合物I-59的合成参考化合物I-5，通过使用((2S)-4-(2-氯-6-((5-氯-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A22)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯代替丙烯酰氯制备得到化合物I-59。Synthesis of compound 1-59 Reference compound 1-5, by using ((2S)-4-(2-chloro-6-((5-chloro-1-(methoxycarbonyl)-1,2,3,4- Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A22) in place of (2S) -4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl) - 2-(Cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) and 2-fluoroacryloyl chloride instead of acryloyl chloride were prepared to give compound 1-59.
化合物I-59(21.6毫克)。MS:608.2(M+H) +. 1H NMR(400MHz,Methanol-d 4)δ7.36–7.14(m,3H),5.32–5.21(m,2H),4.78–4.45(m,2H),4.35–3.38(m,7H),3.28–2.64(m,8H),2.56–1.79(m,9H),1.37–1.31(m,3H)。 Compound 1-59 (21.6 mg). MS: 608.2(M+H) + . 1 H NMR (400MHz, Methanol-d 4 )δ7.36-7.14(m,3H),5.32-5.21(m,2H),4.78-4.45(m,2H), 4.35–3.38 (m, 7H), 3.28–2.64 (m, 8H), 2.56–1.79 (m, 9H), 1.37–1.31 (m, 3H).
化合物I-59a和化合物59b:2-((S)-4-((S)-5-氯-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟 丙烯酰基)哌嗪-2-基)乙腈和2-((S)-4-((R)-5-氯-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5'，8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-59a and Compound 59b: 2-((S)-4-((S)-5-chloro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy) -6'-Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4'- yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile and 2-((S)-4-((R)-5-chloro-2'-(((S)-1- Methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine [3,2-d]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000398
Figure PCTCN2021138375-appb-000398
将2-((2S)-4-(5-氯-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈(180毫克)经SFC手性拆分(柱型号：Dr.maish Reprosil Chiral-JM，250x25mm，10μm色谱柱，流动相：40％甲醇在二氧化碳中)得到均为白色固体的第一个组分峰化合物I-59a(保留时间为1.254分钟，60毫克)和第二个组分峰化合物I-59b(保留时间为2.267分钟，80毫克)。MS:608.2(M+H) +。 2-((2S)-4-(5-chloro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4, 5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl) ) piperazin-2-yl)acetonitrile (180 mg) was chiral resolved by SFC (column type: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm column, mobile phase: 40% methanol in carbon dioxide) to obtain all The first component peak Compound I-59a (retention time 1.254 minutes, 60 mg) and the second component peak Compound I-59b (retention time 2.267 minutes, 80 mg) were white solids. MS: 608.2 (M+H) + .
化合物I-59a(保留时间为1.254分钟)MS:608.2(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ9.78(s,1H),7.40–7.18(m,3H),7.05–7.01(m,2H),5.55–5.10(m,2H),4.60–4.36(m,2H),3.84–3.47(m,6H),3.12(d,J＝13.0Hz,3H),3.03–2.83(m,6H),2.80–2.58(m,2H),2.22–2.15(m,1H),2.04–2.01(m,1H),1.95–1.61(m,6H)。 Compound I-59a (retention time 1.254 min) MS: 608.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.78 (s, 1H), 7.40–7.18 (m, 3H), 7.05–7.01 (m, 2H), 5.55–5.10 (m, 2H), 4.60–4.36 (m, 2H), 3.84–3.47 (m, 6H), 3.12 (d, J=13.0Hz, 3H), 3.03– 2.83 (m, 6H), 2.80–2.58 (m, 2H), 2.22–2.15 (m, 1H), 2.04–2.01 (m, 1H), 1.95–1.61 (m, 6H).
化合物I-59b(保留时间为2.267分钟)MS:608.2(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ9.78(s,1H),7.40–7.18(m,3H),7.05–7.01(m,2H),5.55–5.10(m,2H),4.60–4.36(m,2H),3.84–3.47(m,6H),3.12(d,J＝13.0Hz,3H),3.03–2.83(m,6H),2.80–2.58(m,2H),2.22–2.15(m,1H),2.04–2.01(m,1H),1.95–1.61(m,6H)。 Compound I-59b (retention time 2.267 min) MS: 608.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.78 (s, 1H), 7.40–7.18 (m, 3H), 7.05–7.01 (m, 2H), 5.55–5.10 (m, 2H), 4.60–4.36 (m, 2H), 3.84–3.47 (m, 6H), 3.12 (d, J=13.0Hz, 3H), 3.03– 2.83 (m, 6H), 2.80–2.58 (m, 2H), 2.22–2.15 (m, 1H), 2.04–2.01 (m, 1H), 1.95–1.61 (m, 6H).
实施例65Example 65
化合物I-60:2-((2S)-4-(6-氯-2'-((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound I-60: 2-((2S)-4-(6-chloro-2'-((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-6 '-Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl) -1-(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000399
Figure PCTCN2021138375-appb-000399
化合物I-60的合成参考化合物I-5，通过使用((2S)-4-(2-氯-6-((6-氯-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A23)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯代替丙烯酰氯制备得到化合物I-60。Synthesis of compound 1-60 Reference compound 1-5, by using ((2S)-4-(2-chloro-6-((6-chloro-1-(methoxycarbonyl)-1,2,3,4- Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A23) in place of (2S) -4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl) - tert-butyl 2-(cyanomethyl)piperazine-1-carboxylate (Intermediate A3) and ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate A3) Compound I-60 was prepared by using compound C3) instead of (S)-(1-methylpyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride in place of acryloyl chloride.
化合物I-60(50.1毫克)。MS:626.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.32–7.14(m,3H),5.63–5.22(m,3H),4.82–4.54(m,2H),4.38–3.86(m,5H),3.80–3.45(m,5H),3.22–2.58(m,9H),2.53–1.77(m,6H)。 Compound 1-60 (50.1 mg). MS: 626.1 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ7.32-7.14(m,3H),5.63-5.22(m,3H),4.82-4.54(m,2H),4.38-3.86(m,5H),3.80 – 3.45 (m, 5H), 3.22 – 2.58 (m, 9H), 2.53 – 1.77 (m, 6H).
实施例66Example 66
化合物I-61:2-((S)-4-((S)-7-氯-2'-((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-61: 2-((S)-4-((S)-7-chloro-2'-((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy base)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4 '-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000400
Figure PCTCN2021138375-appb-000400
化合物I-61的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((7-氯-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A21)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和((2S，4R)-4-氟 -1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-61。Synthesis of compound 1-61 Reference compound 1-5 by using (2S)-4-(2-chloro-6-((7-chloro-1-(methoxycarbonyl)-1,2,3,4-tetrakis) Hydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A21) in place of (2S)- 4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)- 2-(Cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) and ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate A3) C3) in place of (S)-(1-methylpyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride to prepare compound I-61.
化合物I-61(51.1毫克)。MS:626.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.28–7.07(m,3H),5.59–5.22(m,3H),4.81–4.76(m,2H),4.57–4.45(m,1H),4.36–3.86(m,5H),3.79–3.33(m,7H),3.24–2.96(m,5H),2.81–2.71(m,2H),2.65–2.51(m,1H),2.38–2.19(m,1H),2.11–1.98(m,1H),1.96–1.78(m,3H)。 Compound 1-61 (51.1 mg). MS: 626.1 (M+H) + . 1 H NMR (400MHz, Methanol-d 4 )δ7.28-7.07(m,3H), 5.59-5.22(m,3H), 4.81-4.76(m,2H), 4.57-4.45(m,1H), 4.36 –3.86 (m, 5H), 3.79–3.33 (m, 7H), 3.24–2.96 (m, 5H), 2.81–2.71 (m, 2H), 2.65–2.51 (m, 1H), 2.38–2.19 (m, 1H), 2.11–1.98 (m, 1H), 1.96–1.78 (m, 3H).
实施例67Example 67
化合物I-62:2-((S)-1-丙烯酰-4-((S)-2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-62: 2-((S)-1-acryloyl-4-((S)-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl) Methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine] -4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000401
Figure PCTCN2021138375-appb-000401
化合物I-62的合成参考化合物I-5，通过使用(S)-4-(2-氯-6-(((S)-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A29)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇制备得到化合物I-62。Synthesis of compound 1-62 Reference compound 1-5 by using (S)-4-(2-chloro-6-(((S)-1-(methoxycarbonyl)-1,2,3,4-tetra Hydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A29) instead of (2S)- 4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)- 2-(Cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) and ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate A3) C3) was prepared in place of (S)-(1-methylpyrrolidin-2-yl)methanol to obtain compound I-62.
化合物I-62(21.1毫克)。MS:574.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.23–7.06(m,4H),6.82(s,1H),6.29(d,J＝16.7Hz,1H),5.83(d,J＝10.6Hz,1H),5.17–5.01(m,2H),4.57(s,1H),4.36–4.29(m,2H),4.25–4.01(m,2H),3.85–3.70(m,1H),3.65–3.42(m,3H),3.29–2.97(m,5H),2.92–2.79(m,2H),2.67–2.58(m,1H),2.54(s,3H),2.26–2.18(m,1H),2.14–1.82(m,5H)。 Compound 1-62 (21.1 mg). MS: 574.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.23-7.06(m,4H),6.82(s,1H),6.29(d,J=16.7Hz,1H),5.83(d,J=10.6Hz, 1H), 5.17–5.01(m,2H), 4.57(s,1H), 4.36–4.29(m,2H), 4.25–4.01(m,2H), 3.85–3.70(m,1H), 3.65–3.42( m, 3H), 3.29–2.97 (m, 5H), 2.92–2.79 (m, 2H), 2.67–2.58 (m, 1H), 2.54 (s, 3H), 2.26–2.18 (m, 1H), 2.14– 1.82 (m, 5H).
实施例68Example 68
化合物I-63:2-((S)-1-丙烯酰-4-((R)-2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-63: 2-((S)-1-acryloyl-4-((R)-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl) Methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine] -4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000402
Figure PCTCN2021138375-appb-000402
化合物I-63的合成参考化合物I-5，通过使用(S)-4-(2-氯-6-(((R)-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A30)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇制备得到化合物I-63。Synthesis of compound 1-63 Reference compound 1-5, by using (S)-4-(2-chloro-6-(((R)-1-(methoxycarbonyl)-1,2,3,4-tetrakis Hydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A30) instead of (2S)- 4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)- 2-(Cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) and ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate A3) C3) was prepared in place of (S)-(1-methylpyrrolidin-2-yl)methanol to obtain compound I-63.
化合物I-63(31.1毫克)。MS:574.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.32–7.05(m,4H),6.80(s,1H),6.27(d,J＝16.7Hz,1H),5.82(d,J＝10.6Hz,1H),5.16–4.98(m,2H),4.80–4.28(m,3H),4.15–3.74(m,3H),3.66–3.34(m,4H),3.17–2.58(m,7H),2.52(s,3H),2.25–2.20(m,1H),2.10–1.74(m,5H)。 Compound 1-63 (31.1 mg). MS: 574.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.32-7.05(m,4H),6.80(s,1H),6.27(d,J=16.7Hz,1H),5.82(d,J=10.6Hz, 1H), 5.16–4.98 (m, 2H), 4.80–4.28 (m, 3H), 4.15–3.74 (m, 3H), 3.66–3.34 (m, 4H), 3.17–2.58 (m, 7H), 2.52 ( s, 3H), 2.25–2.20 (m, 1H), 2.10–1.74 (m, 5H).
实施例69Example 69
化合物I-64:2-((S)-4-((R)-2'-((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-64: 2-((S)-4-((R)-2'-((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-6 '-Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl) -1-(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000403
Figure PCTCN2021138375-appb-000403
化合物I-64的合成参考化合物I-5，通过使用(S)-4-(2-氯-6-(((R)-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯 (中间体A30)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)，((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-64。Synthesis of compound 1-64 Reference compound 1-5, by using (S)-4-(2-chloro-6-(((R)-1-(methoxycarbonyl)-1,2,3,4-tetra Hydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A30) instead of (2S)- 4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)- 2-(Cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3), ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate A3) C3) in place of (S)-(1-methylpyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride was prepared to give compound 1-64.
化合物I-64(17.1毫克)。MS:592.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.17–6.90(m,4H),5.51–5.07(m,3H),4.37–4.24(m,2H),4.12–4.02(m,1H),3.87–3.71(m,1H),3.68–3.52(m,3H),3.40–2.99(m,8H),2.92–2.80(m,2H),2.76–2.61(m,1H),2.51(s,3H),2.26–2.15(m,1H),2.11–1.81(m,5H)。 Compound 1-64 (17.1 mg). MS: 592.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.17-6.90(m,4H),5.51-5.07(m,3H),4.37-4.24(m,2H),4.12-4.02(m,1H),3.87 –3.71 (m, 1H), 3.68–3.52 (m, 3H), 3.40–2.99 (m, 8H), 2.92–2.80 (m, 2H), 2.76–2.61 (m, 1H), 2.51 (s, 3H) , 2.26–2.15 (m, 1H), 2.11–1.81 (m, 5H).
实施例70Example 70
化合物I-65:2-((S)-4-((S)-2'-((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H，6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-65: 2-((S)-4-((S)-2'-((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-6 '-Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl) -1-(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000404
Figure PCTCN2021138375-appb-000404
化合物I-65的合成参考化合物I-5，通过使用(S)-4-(2-氯-6-(((S)-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A29)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)，((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-65。Synthesis of compound 1-65 Reference compound 1-5 by using (S)-4-(2-chloro-6-(((S)-1-(methoxycarbonyl)-1,2,3,4-tetra Hydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A29) instead of (2S)- 4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)- 2-(Cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3), ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate A3) C3) in place of (S)-(1-methylpyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride was prepared to give compound 1-65.
化合物I-65(19.1毫克)。MS:592.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.15–6.97(m,4H),5.49–5.05(m,3H),4.36–4.21(m,2H),4.14–4.01(m,1H),3.85–3.75(m,1H),3.61–3.42(m,3H),3.30–2.96(m,8H),2.90–2.83(m,2H),2.78–2.68(m,1H),2.54(s,3H),2.27–2.17(m,1H),2.12–1.80(m,5H)。 Compound 1-65 (19.1 mg). MS: 592.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.15-6.97(m,4H),5.49-5.05(m,3H),4.36-4.21(m,2H),4.14-4.01(m,1H),3.85 –3.75 (m, 1H), 3.61–3.42 (m, 3H), 3.30–2.96 (m, 8H), 2.90–2.83 (m, 2H), 2.78–2.68 (m, 1H), 2.54 (s, 3H) , 2.27–2.17 (m, 1H), 2.12–1.80 (m, 5H).
实施例71Example 71
化合物I-66:2-((2S)-1-丙烯酰-4-(7-氟-2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-66: 2-((2S)-1-acryloyl-4-(7-fluoro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl) Methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine] -4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000405
Figure PCTCN2021138375-appb-000405
化合物I-66的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((7-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A24)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇制备得到化合物I-66。Synthesis of compound 1-66 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((7-fluoro-1-(methoxycarbonyl)-1,2,3,4-tetrakis) Hydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A24) in place of (2S)- 4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)- 2-(Cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) and ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate A3) C3) was prepared in place of (S)-(1-methylpyrrolidin-2-yl)methanol to obtain compound 1-66.
化合物I-66(18.1毫克)。MS:592.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.15(dd,J＝8.6,6.0Hz,1H),7.06–6.89(m,2H),6.80(s,1H),6.28(dt,J＝16.8,1.9Hz,1H),5.83(d,J＝10.7Hz,1H),5.47–5.31(m,1H),4.82–4.74(m,3H),4.60–4.51(m,1H),4.37–3.84(m,4H),3.82–3.34(m,5H),3.22–2.75(m,8H),2.65–2.51(m,1H),2.36–2.21(m,1H),2.09–1.74(m,4H)。 Compound 1-66 (18.1 mg). MS: 592.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.15(dd,J=8.6,6.0Hz,1H),7.06-6.89(m,2H),6.80(s,1H),6.28(dt,J=16.8 ,1.9Hz,1H),5.83(d,J＝10.7Hz,1H),5.47-5.31(m,1H),4.82-4.74(m,3H),4.60-4.51(m,1H),4.37-3.84( m, 4H), 3.82–3.34 (m, 5H), 3.22–2.75 (m, 8H), 2.65–2.51 (m, 1H), 2.36–2.21 (m, 1H), 2.09–1.74 (m, 4H).
实施例72Example 72
化合物I-67:2-((2S)-4-(7-氟-2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-67: 2-((2S)-4-(7-fluoro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)- 6'-Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl )-1-(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000406
Figure PCTCN2021138375-appb-000406
化合物I-67的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((7-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A24)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3),((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-67。Synthesis of compound 1-67 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((7-fluoro-1-(methoxycarbonyl)-1,2,3,4-tetrakis) Hydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A24) instead of (2S)- 4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)- 2-(Cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3), ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate A3) C3) in place of (S)-(1-methylpyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride was prepared to give compound 1-67.
化合物I-67(30.1毫克)。MS:610.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.15(s,1H),7.05–6.85(m,2H),5.67–5.14(m,3H),4.81–4.50(m,4H),4.36–3.86(m,5H),3.81–3.32(m,5H),3.22–2.58(m,8H),2.53–2.25(m,1H),2.11–1.73(m,4H)。 Compound 1-67 (30.1 mg). MS: 610.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.15(s,1H),7.05-6.85(m,2H),5.67-5.14(m,3H),4.81-4.50(m,4H),4.36-3.86 (m, 5H), 3.81–3.32 (m, 5H), 3.22–2.58 (m, 8H), 2.53–2.25 (m, 1H), 2.11–1.73 (m, 4H).
实施例73Example 73
化合物I-68:2-((2S)-1-丙烯酰-4-(7-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-68: 2-((2S)-1-Acryloyl-4-(7-methyl-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)- 6'-Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl )piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000407
Figure PCTCN2021138375-appb-000407
化合物I-68的合成参考化合物I-5，通过使用2S)-4-(2-氯-6-((1-(甲氧羰基)-7-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A26)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)制备得到化合物I-68。Synthesis of compound 1-68 Reference compound 1-5, by using 2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-7-methyl-1,2,3,4-tetrakis) Hydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A26) instead of (2S)- 4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)- 2-(Cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) was prepared to give compound 1-68.
化合物I-68(18.1毫克)。MS:570.1(M+H) +。 1H NMR(400MHz,DMSO-d6)δ9.80–9.76(m,1H),7.21–6.58(m,4H),6.18–6.09(m,1H),5.96–5.64(m,1H),4.93–4.68(m,1H),4.09–3.98(m,2H),3.81–3.44(m,6H),3.22–2.56(m,9H),2.32(s,3H),2.24(s,1H),2.15(s,3H),2.05–1.49(m,7H)。 Compound 1-68 (18.1 mg). MS: 570.1 (M+H) + . 1 H NMR (400MHz, DMSO-d6)δ9.80-9.76(m,1H),7.21-6.58(m,4H),6.18-6.09(m,1H),5.96-5.64(m,1H),4.93- 4.68 (m, 1H), 4.09–3.98 (m, 2H), 3.81–3.44 (m, 6H), 3.22–2.56 (m, 9H), 2.32 (s, 3H), 2.24 (s, 1H), 2.15 ( s, 3H), 2.05–1.49 (m, 7H).
实施例74Example 74
化合物I-69:2-((2S)-1-(2-氟丙烯酰基)-4-(7-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-69: 2-((2S)-1-(2-fluoroacryloyl)-4-(7-methyl-2'-(((S)-1-methylpyrrolidin-2-yl) Methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine] -4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000408
Figure PCTCN2021138375-appb-000408
化合物I-69的合成参考化合物I-5，通过使用2S)-4-(2-氯-6-((1-(甲氧羰基)-7-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A26)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-69。Synthesis of compound 1-69 Reference compound 1-5, by using 2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-7-methyl-1,2,3,4-tetrakis) Hydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A26) instead of (2S)- 4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)- Compound 1-69 was prepared by tert-butyl 2-(cyanomethyl)piperazine-1-carboxylate (Intermediate A3) and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride.
化合物I-69(30.1毫克)。MS:588.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.81–9.75(m,1H),7.25–6.60(m,3H),5.76–5.15(m,2H),4.31–3.46(m,9H),3.20–2.57(m,9H),2.32(s,3H),2.24(s,1H),2.15(s,3H),2.07–1.48(m,7H)。 Compound 1-69 (30.1 mg). MS: 588.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.81-9.75(m,1H),7.25-6.60(m,3H),5.76-5.15(m,2H),4.31-3.46(m,9H),3.20 – 2.57(m, 9H), 2.32(s, 3H), 2.24(s, 1H), 2.15(s, 3H), 2.07 – 1.48(m, 7H).
实施例75Example 75
化合物I-70:2-((2S)-1-丙烯酰-4-(6-氟-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-70: 2-((2S)-1-acryloyl-4-(6-fluoro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6 '-Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl) Piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000409
Figure PCTCN2021138375-appb-000409
化合物I-70的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((6-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A25)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)制备得到化合物I-70。Synthesis of compound 1-70 Reference compound 1-5 by using (2S)-4-(2-chloro-6-((6-fluoro-1-(methoxycarbonyl)-1,2,3,4-tetrakis) Hydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A25) instead of (2S)- 4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)- 2-(Cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) was prepared to give compound 1-70.
化合物I-70(18.1毫克)。MS:574.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.84–9.76(m,1H),7.38–6.70(m,4H),6.18–6.06(m,1H),5.87–5.64(m,1H),4.91–4.86(m,1H),4.50–3.44(m,8H),3.24–2.53(m,8H),2.34(s,3H),2.00–1.58(m,9H)。 Compound 1-70 (18.1 mg). MS: 574.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.84-9.76(m,1H),7.38-6.70(m,4H),6.18-6.06(m,1H),5.87-5.64(m,1H),4.91 – 4.86 (m, 1H), 4.50 – 3.44 (m, 8H), 3.24 – 2.53 (m, 8H), 2.34 (s, 3H), 2.00 – 1.58 (m, 9H).
实施例76Example 76
化合物I-71:2-((2S)-4-(6-氟-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-71: 2-((2S)-4-(6-fluoro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy- 3,4,5',8'-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1-(2 -Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000410
Figure PCTCN2021138375-appb-000410
化合物I-71的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((6-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A25)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-71。Synthesis of compound 1-71 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((6-fluoro-1-(methoxycarbonyl)-1,2,3,4-tetrakis) Hydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A25) instead of (2S)- 4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)- Compound 1-71 was prepared by 2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride.
化合物I-71(19毫克)。MS:592.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.81–9.76(m,1H),7.45–6.79(m,4H),5.53–5.07(m,3H),4.31–3.37(m,6H),3.19–2.60(m,8H),2.31(s,3H),2.15–2.10(m,1H),2.03–1.50(m,10H)。 Compound 1-71 (19 mg). MS: 592.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.81-9.76(m,1H),7.45-6.79(m,4H),5.53-5.07(m,3H),4.31-3.37(m,6H),3.19 – 2.60(m, 8H), 2.31(s, 3H), 2.15 – 2.10(m, 1H), 2.03 – 1.50(m, 10H).
实施例77Example 77
化合物I-72:2-((2S)-1-(2-氟丙烯酰基)-4-(6-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-72: 2-((2S)-1-(2-fluoroacryloyl)-4-(6-methyl-2'-(((S)-1-methylpyrrolidin-2-yl) Methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine] -4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000411
Figure PCTCN2021138375-appb-000411
化合物I-72的合成参考化合物I-5，通过使用2S)-4-(2-氯-6-((1-(甲氧羰基)-6-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A31)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-72。Synthesis of compound 1-72 Reference compound 1-5 by using 2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-6-methyl-1,2,3,4-tetrakis) Hydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A31) instead of (2S)- 4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)- Compound 1-72 was prepared by 2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride.
化合物I-72(30.9毫克)。MS:588.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.90-9.80(m,1H),9.62(s,1H),7.13-6.85(m,3H),5.42-5.35(m,1H),5.32-5.15(m,1H),4.55-4.45(m,1H),4.44-4.36(m,1H),3.80-3.69(m,2H),3.55-3.25(m,6H),3.17-3.07(m,2H),3.05-2.87(m,5H),2.83-2.80(m,1H),2.75-2.65(m,3H),2.25-2.18(m,3H),2.08-1.98(m,2H),1.92-1.63(m,6H)。 Compound 1-72 (30.9 mg). MS: 588.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.90-9.80(m,1H), 9.62(s,1H), 7.13-6.85(m,3H), 5.42-5.35(m,1H), 5.32-5.15 (m,1H),4.55-4.45(m,1H),4.44-4.36(m,1H),3.80-3.69(m,2H),3.55-3.25(m,6H),3.17-3.07(m,2H) ,3.05-2.87(m,5H),2.83-2.80(m,1H),2.75-2.65(m,3H),2.25-2.18(m,3H),2.08-1.98(m,2H),1.92-1.63( m, 6H).
实施例78Example 78
化合物I-73:2-((2S)-1-(2-氟丙烯酰基)-4-(5-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-73: 2-((2S)-1-(2-fluoroacryloyl)-4-(5-methyl-2'-(((S)-1-methylpyrrolidin-2-yl) Methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine] -4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000412
Figure PCTCN2021138375-appb-000412
化合物I-73的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((1-(甲氧羰基)-5-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A39)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基) -5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-73。Synthesis of compound 1-73 Reference compound 1-5 by using (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-5-methyl-1,2,3,4- Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A39) in place of (2S) -4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl) -2-(Cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) and 2-fluoroacryloyl chloride (Intermediate B1) instead of acryloyl chloride were prepared to give compound I-73.
化合物I-73(40.1毫克)。MS:588.1(M+H) +。 1H NMR(400MHz,CD 3OD)δ7.09-7.03(m,3H),5.40-5.32(m,1H),5.30-5.22(m,1H),4.40-4.21(m,3H),4.11-4.08(m,1H),3.97-3.92(m,1H),3.86-3.78(m,1H),3.59-3.45(m,2H),3.34-3.30(m,1H),3.27-3.16(m,1H),3.14-3.04(m,2H),3.04-2.95(m,1H),2.89-2.82(m,1H),2.75-2.62(m,4H),2.48(s,3H),2.36-2.32(m,1H),2.26-2.23(m,3H),2.12-1.97(m,2H),1.92-1.77(m,5H),1.75-1.66(m,1H)。 Compound 1-73 (40.1 mg). MS: 588.1 (M+H) + . 1 H NMR (400MHz, CD 3 OD) δ 7.09-7.03 (m, 3H), 5.40-5.32 (m, 1H), 5.30-5.22 (m, 1H), 4.40-4.21 (m, 3H), 4.11- 4.08(m,1H),3.97-3.92(m,1H),3.86-3.78(m,1H),3.59-3.45(m,2H),3.34-3.30(m,1H),3.27-3.16(m,1H) ),3.14-3.04(m,2H),3.04-2.95(m,1H),2.89-2.82(m,1H),2.75-2.62(m,4H),2.48(s,3H),2.36-2.32(m , 1H), 2.26-2.23 (m, 3H), 2.12-1.97 (m, 2H), 1.92-1.77 (m, 5H), 1.75-1.66 (m, 1H).
实施例79Example 79
化合物I-74:2-((2S)-1-丙烯酰-4-(5-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-74: 2-((2S)-1-Acryloyl-4-(5-methyl-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)- 6'-Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl )piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000413
Figure PCTCN2021138375-appb-000413
化合物I-74的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((1-(甲氧羰基)-5-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A39)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)制备得到化合物I-74。Synthesis of compound 1-74 Reference compound 1-5 by using (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-5-methyl-1,2,3,4- Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A39) in place of (2S) -4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl) -2-(Cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) was prepared to give compound 1-74.
化合物I-74(2.1毫克)。MS:570.1(M+H) +。 Compound 1-74 (2.1 mg). MS: 570.1 (M+H) + .
实施例80Example 80
化合物I-75:2-((2S)-4-(5,6-二氟-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-75: 2-((2S)-4-(5,6-difluoro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'- Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1 -(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000414
Figure PCTCN2021138375-appb-000414
化合物I-75的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5,6-二氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A34)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-75。Synthesis of compound 1-75 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((5,6-difluoro-1-(methoxycarbonyl)-1,2,3, 4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A34) instead of ( 2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4- Compound 1-75 was prepared from tert-butyl)-2-(cyanomethyl)piperazine-1-carboxylate (Intermediate A3) and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride.
化合物I-75(40毫克)。MS:610.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.34–6.92(m,2H),5.51–5.12(m,2H),4.78–4.40(m,2H),4.31–4.12(m,1H),4.01(dt,J＝11.2,6.2Hz,1H),3.89–3.35(m,5H),3.28–2.55(m,8H),2.31(s,3H),2.15(q,J＝8.6Hz,1H),2.06–1.30(m,8H)。 Compound 1-75 (40 mg). MS: 610.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ7.34-6.92(m,2H),5.51-5.12(m,2H),4.78-4.40(m,2H),4.31-4.12(m,1H),4.01 (dt, J=11.2, 6.2Hz, 1H), 3.89–3.35 (m, 5H), 3.28–2.55 (m, 8H), 2.31 (s, 3H), 2.15 (q, J=8.6Hz, 1H), 2.06–1.30 (m, 8H).
实施例81Example 81
化合物I-76:2-((2S)-4-(5-氯-7-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-76: 2-((2S)-4-(5-chloro-7-methyl-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6 '-Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl) -1-(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000415
Figure PCTCN2021138375-appb-000415
化合物I-76的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氯-1-(甲氧羰基)-7-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A32)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲 基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-76。Synthesis of compound 1-76 Reference compound 1-5, by using (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 (Intermediate A32) In place of (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine- Compound 1-76 was prepared from tert-butyl 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (Intermediate A3) and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride.
化合物I-76(34毫克)。MS:622.3(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.33–6.77(m,2H),5.54–5.15(m,2H),4.65–4.35(m,2H),4.14–3.36(m,5H),3.23–2.61(m,11H),2.42–2.31(m,6H),2.23–2.17m,4H),2.09–1.57(m,4H)。 Compound 1-76 (34 mg). MS: 622.3 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ7.33-6.77(m,2H),5.54-5.15(m,2H),4.65-4.35(m,2H),4.14-3.36(m,5H),3.23 – 2.61 (m, 11H), 2.42 – 2.31 (m, 6H), 2.23 – 2.17m, 4H), 2.09 – 1.57 (m, 4H).
实施例82Example 82
化合物I-77:2-((2S)-1-丙烯酰-4-(5-氯-7-氟-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-77: 2-((2S)-1-acryloyl-4-(5-chloro-7-fluoro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy base)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4 '-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000416
Figure PCTCN2021138375-appb-000416
化合物I-77的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氯-7-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A36)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)制备得到化合物I-77。Synthesis of compound 1-77 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((5-chloro-7-fluoro-1-(methoxycarbonyl)-1,2,3 ,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A36) instead (2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4 -yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) was prepared to give compound 1-77.
化合物I-77(28毫克)。MS:608.2(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.86(s,1H),7.34(d,J＝7.9Hz,1H),7.33–7.11(m,1H),6.82(d,14.3Hz,1H),6.17(d,J＝16.7Hz,1H),5.76(s,1H),5.20–4.68(m,1H),4.44–3.96(m,4H),3.79–3.27(m,4H),3.12–2.54(m,9H),2.44–2.22(m,2H),2.05–1.44(m,9H)。 Compound 1-77 (28 mg). MS: 608.2 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.86(s,1H),7.34(d,J=7.9Hz,1H),7.33-7.11(m,1H),6.82(d,14.3Hz,1H) ,6.17(d,J＝16.7Hz,1H),5.76(s,1H),5.20-4.68(m,1H),4.44-3.96(m,4H),3.79-3.27(m,4H),3.12-2.54 (m, 9H), 2.44–2.22 (m, 2H), 2.05–1.44 (m, 9H).
实施例83Example 83
化合物I-78:2-((2S)-4-(5-氯-7-氟-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-78: 2-((2S)-4-(5-chloro-7-fluoro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6' -Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)- 1-(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000417
Figure PCTCN2021138375-appb-000417
化合物I-78的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氯-7-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A36)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-78。Synthesis of compound 1-78 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((5-chloro-7-fluoro-1-(methoxycarbonyl)-1,2,3 ,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A36) instead (2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4 -yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (intermediate A3) and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride were prepared to give compound 1-78.
化合物I-78(56毫克)。MS:626.2(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.72(s,1H),7.34(dt,J＝8.4,1.9Hz,2H),7.28(dd,J＝10.5,2.7Hz,1H),7.15(dd,J＝10.3,2.6Hz,1H),5.48–5.11(m,2H),4.12–3.95(m,2H),3.89–3.47(m,2H),3.19–2.60(m,9H),2.33(s,3H),2.18–1.39(m,11H)。 Compound 1-78 (56 mg). MS: 626.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.72 (s, 1H), 7.34 (dt, J=8.4, 1.9 Hz, 2H), 7.28 (dd, J=10.5, 2.7 Hz, 1H), 7.15 ( dd, J=10.3, 2.6Hz, 1H), 5.48–5.11 (m, 2H), 4.12–3.95 (m, 2H), 3.89–3.47 (m, 2H), 3.19–2.60 (m, 9H), 2.33 ( s, 3H), 2.18–1.39 (m, 11H).
实施例84Example 84
化合物I-79:2-((2S)-1-丙烯酰-4-(7-氟-5-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8’-四氢-2H,6’H-螺旋体[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-79: 2-((2S)-1-acryloyl-4-(7-fluoro-5-methyl-2'-(((S)-1-methylpyrrolidin-2-yl)methan oxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4 '-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000418
Figure PCTCN2021138375-appb-000418
化合物I-79的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((7-氟-1-(甲氧羰基)-5-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A40)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)制备得到化合物I-79。Synthesis of compound 1-79 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((7-fluoro-1-(methoxycarbonyl)-5-methyl-1,2, 3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A40) In place of (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine- 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) was prepared to give compound 1-79.
化合物I-79(21毫克)。MS:588.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.09–6.63(m,2H),6.29–5.63(m,2H),5.10-4.70(m,1H),4.48–3.95(m,4H),3.92–3.45(m,6H),3.14–2.74(m,6H),2.67–2.52(m,1H),2.32(s,3H),2.27–2.10(m,4H),1.97–1.51(m,8H)。 Compound 1-79 (21 mg). MS: 588.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ7.09-6.63(m,2H),6.29-5.63(m,2H),5.10-4.70(m,1H),4.48-3.95(m,4H),3.92 –3.45(m,6H), 3.14–2.74(m,6H), 2.67–2.52(m,1H), 2.32(s,3H), 2.27–2.10(m,4H), 1.97–1.51(m,8H) .
实施例85Example 85
化合物I-80:2-((2S)-1-(2-氟丙烯酰基)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-5-(三氟甲氧基)-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-80: 2-((2S)-1-(2-fluoroacryloyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)- 6'-Oxy-5-(trifluoromethoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2 -d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000419
Figure PCTCN2021138375-appb-000419
化合物I-80的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((1-(甲氧基羰基)-5-(三氟甲氧基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A42)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-80。Synthesis of compound 1-80 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-5-(trifluoromethoxy)-1, 2,3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A42) in place of (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitro Pyrimidine-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (intermediate A3) and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride were prepared to give compound I- 80.
化合物I-80(21毫克)。MS:658.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.79(s,1H),7.39–7.30(m,1H),7.29–7.17(m,2H),5.42–5.18(m,2H),4.59–4.36(m,2H),3.88–3.68(m,5H),3.48–3.40(m,2H),3.23–3.06(m,3H),3.06–2.93(m,2H),2.91–2.80(m,3H),2.78–2.60(m,3H),2.23–2.15(m,1H),2.05(m,1H),1.97–1.64(m,7H)。 Compound 1-80 (21 mg). MS: 658.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.79(s,1H), 7.39-7.30(m,1H), 7.29-7.17(m,2H), 5.42-5.18(m,2H), 4.59-4.36 (m, 2H), 3.88–3.68 (m, 5H), 3.48–3.40 (m, 2H), 3.23–3.06 (m, 3H), 3.06–2.93 (m, 2H), 2.91–2.80 (m, 3H) , 2.78–2.60 (m, 3H), 2.23–2.15 (m, 1H), 2.05 (m, 1H), 1.97–1.64 (m, 7H).
实施例86Example 86
化合物I-81:2-((2S)-4-(5-氯-6-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-81: 2-((2S)-4-(5-chloro-6-methyl-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6 '-Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl- 1-(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000420
Figure PCTCN2021138375-appb-000420
化合物I-81的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氯-1-(甲氧羰基)-6-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A33)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-81。Synthesis of compound 1-81 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((5-chloro-1-(methoxycarbonyl)-6-methyl-1,2, 3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A33) In place of (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine- 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) and 2-fluoroacryloyl chloride (Intermediate B1) instead of acryloyl chloride were prepared to give compound 1-81.
化合物I-81(26毫克)。MS:622.3(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.68(s,1H),7.20(s,1H),7.15–7.03(m,1H),5.42–5.30(m,2H),5.19(s,1H),4.61–4.35(m,4H),3.73(d,J＝10.9Hz,2H),3.42(m,1H),3.13–3.09(m,3H),3.07–2.94(m,2H),2.92–2.90(m,3H),2.82–2.68(m,3H),2.31–2.29(m,3H),2.27–2.18(m,1H),2.09–2.00–1.94(m,1H),1.90(s,1H),1.83–1.79(m,3H),1.77–1.63(m,4H)。 Compound 1-81 (26 mg). MS: 622.3 (M+H) + . 1 H NMR(400MHz, DMSO-d 6 )δ9.68(s,1H),7.20(s,1H),7.15-7.03(m,1H),5.42-5.30(m,2H),5.19(s,1H) ), 4.61–4.35 (m, 4H), 3.73 (d, J=10.9Hz, 2H), 3.42 (m, 1H), 3.13–3.09 (m, 3H), 3.07–2.94 (m, 2H), 2.92– 2.90(m,3H), 2.82–2.68(m,3H), 2.31–2.29(m,3H), 2.27–2.18(m,1H), 2.09–2.00–1.94(m,1H), 1.90(s,1H ), 1.83–1.79 (m, 3H), 1.77–1.63 (m, 4H).
实施例87Example 87
化合物I-82:2-((2S)-1-丙烯酰-4-(5-氯-6-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound I-82: 2-((2S)-1-acryloyl-4-(5-chloro-6-methyl-2'-(((S)-1-methylpyrrolidin-2-yl)methan oxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]- 4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000421
Figure PCTCN2021138375-appb-000421
化合物I-82的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氯-1-(甲氧羰基)-6-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A33)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲 基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)制备得到化合物I-82。Synthesis of compound 1-82 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((5-chloro-1-(methoxycarbonyl)-6-methyl-1,2, 3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A33) In place of (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine- 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) was prepared to give compound 1-82.
化合物I-82(23毫克)。MS:604.2(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.78(s,1H),7.20(s,1H),7.15–7.03(m,1H),6.88(s,1H),6.24–6.11(m,1H),5.83–5.70(m,1H),4.94(s,1H),4.58–4.39(m,3H),3.79–3.38(m,7H),3.10(d,J＝11.5Hz,2H),2.96(s,1H),2.93–2.89(m,3H),2.85–2.64(m,3H),2.31–2.24(m,3H),2.22–2.17(m,1H),2.12–1.99(m,1H),1.95–1.63(m,6H)。 Compound 1-82 (23 mg). MS: 604.2 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.78(s,1H), 7.20(s,1H), 7.15-7.03(m,1H), 6.88(s,1H), 6.24-6.11(m,1H) ), 5.83–5.70 (m, 1H), 4.94 (s, 1H), 4.58–4.39 (m, 3H), 3.79–3.38 (m, 7H), 3.10 (d, J=11.5Hz, 2H), 2.96 ( s,1H), 2.93–2.89(m,3H), 2.85–2.64(m,3H), 2.31–2.24(m,3H), 2.22–2.17(m,1H), 2.12–1.99(m,1H), 1.95–1.63 (m, 6H).
实施例88Example 88
化合物I-83:2-((2S)-4-(5-氟-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-83: 2-((2S)-4-(5-fluoro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy- 3,4,5',8'-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4'-1-(2-fluoropropene Acyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000422
Figure PCTCN2021138375-appb-000422
化合物I-83的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A38)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-83。Synthesis of compound 1-83 Reference compound 1-5 by using (2S)-4-(2-chloro-6-((5-fluoro-1-(methoxycarbonyl)-1,2,3,4-tetrakis) Hydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A38) instead of (2S)- 4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)- Compound 1-83 was prepared by 2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride.
化合物I-83(46毫克)。MS:592.1(M+H) +。 1H NMR(400MHz,CD 3OD)δ7.25-7.16(m,1H),7.13-7.06(m,1H),7.00-6.94(m,1H),5.39-5.34(m,1H),5.33-5.28(m,1H),4.81-4.72(m,1H),4.55-4.36(m,1H),4.09-3.83(m,3H),3.76-3.53(m,3H),3.48-3.32(m,4H),3.27-3.20(m,1H),3.15-3.02(m,6H),3.01-2.90(m,1H),2.87-2.70(m,1H),2.42-2.38(m,1H),2.25-2.15(m,1H),2.12-1.98(m,3H),1.96-1.78(m,3H)。 Compound 1-83 (46 mg). MS: 592.1 (M+H) + . 1 H NMR (400MHz, CD 3 OD) δ 7.25-7.16 (m, 1H), 7.13-7.06 (m, 1H), 7.00-6.94 (m, 1H), 5.39-5.34 (m, 1H), 5.33- 5.28(m,1H),4.81-4.72(m,1H),4.55-4.36(m,1H),4.09-3.83(m,3H),3.76-3.53(m,3H),3.48-3.32(m,4H ),3.27-3.20(m,1H),3.15-3.02(m,6H),3.01-2.90(m,1H),2.87-2.70(m,1H),2.42-2.38(m,1H),2.25-2.15 (m, 1H), 2.12-1.98 (m, 3H), 1.96-1.78 (m, 3H).
实施例89Example 89
化合物I-84:2-((2S)-1-丙烯酰-4-(5-氟-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-84: 2-((2S)-1-acryloyl-4-(5-fluoro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6 '-Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl) Piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000423
Figure PCTCN2021138375-appb-000423
化合物I-84的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A38)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-84。Synthesis of compound 1-84 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((5-fluoro-1-(methoxycarbonyl)-1,2,3,4-tetrakis) Hydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A38) instead of (2S)- 4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)- Compound 1-84 was prepared by 2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride.
化合物I-84(49毫克)。MS:574.1(M+H) +。 1H NMR(400MHz,CD 3OD)δ7.25-7.15(m,1H),7.12-7.05(m,1H),7.00-6.93(m,1H),6.85-6.75(m,1H),6.29(d,J＝16.6Hz,1H),5.84(d,J＝10.6Hz,1H),4.76-4.68(m,1H),4.56-4.49(m,1H),4.36-4.28(m,1H),4.08-4.00(m,1H),3.95-3.82(m,2H),3.76-3.68(m,1H),3.64-3.50(m,1H),3.45-3.41(m,1H),3.35-3.30(m,2H),3.27-3.19(m,1H),3.10-3.03(m,4H),3.01-2.88(m,2H),2.82-2.74(m,2H),2.42-2.33(m,1H),2.25-2.15(m,1H),2.12-1.97(m,3H),1.90-1.80(m,3H)。 Compound 1-84 (49 mg). MS: 574.1 (M+H) + . 1 H NMR(400MHz, CD 3 OD)δ7.25-7.15(m,1H),7.12-7.05(m,1H),7.00-6.93(m,1H),6.85-6.75(m,1H),6.29( d, J=16.6Hz, 1H), 5.84 (d, J=10.6Hz, 1H), 4.76-4.68 (m, 1H), 4.56-4.49 (m, 1H), 4.36-4.28 (m, 1H), 4.08 -4.00(m, 1H), 3.95-3.82(m, 2H), 3.76-3.68(m, 1H), 3.64-3.50(m, 1H), 3.45-3.41(m, 1H), 3.35-3.30(m, 2H), 3.27-3.19(m, 1H), 3.10-3.03(m, 4H), 3.01-2.88(m, 2H), 2.82-2.74(m, 2H), 2.42-2.33(m, 1H), 2.25- 2.15 (m, 1H), 2.12-1.97 (m, 3H), 1.90-1.80 (m, 3H).
实施例90Example 90
化合物I-85:2-((2S)-1-丙烯酰-4-(5,6-二氟-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-85: 2-((2S)-1-acryloyl-4-(5,6-difluoro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy )-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4' -yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000424
Figure PCTCN2021138375-appb-000424
化合物I-85的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5,6-二氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔 丁酯(中间体A34)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)制备得到化合物I-85。Synthesis of compound 1-85 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((5,6-difluoro-1-(methoxycarbonyl)-1,2,3, 4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A34) instead of ( 2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4- yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A3) was prepared to give compound 1-85.
化合物I-85(30.3毫克)。MS:592.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.32–6.99(m,2H),6.97-6.75(m,1H),6.18(d,J＝16.6Hz,1H),5.77(d,J＝10.3Hz,1H),5.17–4.26(m,4H),4.12–3.69(m,3H),3.68-3.59(m,3H),3.50–3.26(m,3H),3.23-3.06(m,2H),3.05–2.80(m,4H),2.80–2.52(m,3H),2.30-2.15(m,1H),2.11–1.56(m,6H)。 Compound 1-85 (30.3 mg). MS: 592.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 7.32-6.99 (m, 2H), 6.97-6.75 (m, 1H), 6.18 (d, J=16.6Hz, 1H), 5.77 (d, J=10.3 Hz, 1H), 5.17–4.26 (m, 4H), 4.12–3.69 (m, 3H), 3.68–3.59 (m, 3H), 3.50–3.26 (m, 3H), 3.23–3.06 (m, 2H), 3.05–2.80 (m, 4H), 2.80–2.52 (m, 3H), 2.30–2.15 (m, 1H), 2.11–1.56 (m, 6H).
实施例91Example 91
化合物I-86:2-((2S)-4-(7-氟-5-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-86: 2-((2S)-4-(7-Fluoro-5-methyl-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6 '-Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl) -1-(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000425
Figure PCTCN2021138375-appb-000425
化合物I-86的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((7-氟-1-(甲氧羰基)-5-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A40)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-86。Synthesis of compound 1-86 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((7-fluoro-1-(methoxycarbonyl)-5-methyl-1,2, 3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A40) In place of (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine- Compound 1-86 was prepared from tert-butyl 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (Intermediate A3) and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride.
化合物I-86(21毫克)。MS:606.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.06–6.78(m,2H),5.45–5.15(m,2H),5.05-4.60(m,2H),4.58–4.35(m,2H),3.70–3.43(m,6H),3.20-2.70(m,8H),2.65-2.53(m,2H),2.30-2.15(m,4H),2.13–1.59(m,8H)。 Compound 1-86 (21 mg). MS: 606.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ7.06-6.78(m,2H),5.45-5.15(m,2H),5.05-4.60(m,2H),4.58-4.35(m,2H),3.70 –3.43(m,6H), 3.20-2.70(m,8H), 2.65-2.53(m,2H), 2.30-2.15(m,4H), 2.13-1.59(m,8H).
实施例92Example 92
化合物I-87:2-((2S)-4-(5-氟-6-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-87: 2-((2S)-4-(5-fluoro-6-methyl-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6 '-Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl) -1-(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000426
Figure PCTCN2021138375-appb-000426
化合物I-87的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氟-1-(甲氧羰基)-6-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A41)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-87。Synthesis of compound 1-87 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((5-fluoro-1-(methoxycarbonyl)-6-methyl-1,2, 3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A41) In place of (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine- Compound 1-87 was prepared from tert-butyl 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (Intermediate A3) and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride.
化合物I-87(91毫克)。MS:606.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.14–6.89(m,3H),5.45–5.21(m,3H),4.79–4.66(m,2H),4.53(t,J＝10.0Hz,1H),4.28(d,J＝13.9Hz,1H),4.07–3.81(m,3H),3.83–3.65(m,1H),3.56–3.49(m,1H),3.44–3.19(m,3H),3.17–2.61(m,9H),2.49–1.95(m,8H),1.92–1.71(m,1H)。 Compound 1-87 (91 mg). MS: 606.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.14-6.89(m,3H),5.45-5.21(m,3H),4.79-4.66(m,2H),4.53(t,J=10.0Hz,1H ), 4.28(d, J=13.9Hz, 1H), 4.07–3.81 (m, 3H), 3.83–3.65 (m, 1H), 3.56–3.49 (m, 1H), 3.44–3.19 (m, 3H), 3.17–2.61 (m, 9H), 2.49–1.95 (m, 8H), 1.92–1.71 (m, 1H).
实施例93Example 93
化合物I-88:2-((2S)-1-丙烯酰-4-(5-氟-6-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-88: 2-((2S)-1-acryloyl-4-(5-fluoro-6-methyl-2'-(((S)-1-methylpyrrolidin-2-yl)methan oxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]- 4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000427
Figure PCTCN2021138375-appb-000427
化合物I-88的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氟-1-(甲氧羰基)-6-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A41)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-88。Synthesis of compound 1-88 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((5-fluoro-1-(methoxycarbonyl)-6-methyl-1,2, 3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A41) In place of (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine- Compound 1-88 was prepared from tert-butyl 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (Intermediate A3) and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride.
化合物I-88(71毫克)。MS:588.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.19–6.98(m,2H),6.85(d,J＝8.0Hz,1H),6.18(s,1H),5.77(d,J＝10.7Hz,1H),5.08(s,1H),4.68–4.37(m,2H),4.22–3.88(m,5H),3.74–3.05(m,14H),2.94–1.61(m,10H)。 Compound 1-88 (71 mg). MS: 588.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ7.19-6.98(m, 2H), 6.85(d, J=8.0Hz, 1H), 6.18(s, 1H), 5.77(d, J=10.7Hz, 1H), 5.08 (s, 1H), 4.68–4.37 (m, 2H), 4.22–3.88 (m, 5H), 3.74–3.05 (m, 14H), 2.94–1.61 (m, 10H).
实施例94Example 94
化合物I-89:2-((2S)-1-丙烯酰-4-(5-氯-6-氟-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-89: 2-((2S)-1-acryloyl-4-(5-chloro-6-fluoro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy base)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4 '-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000428
Figure PCTCN2021138375-appb-000428
化合物I-89的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氯-6-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A35)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)制备得到化合物I-89。Synthesis of compound 1-89 Reference compound 1-5 by using (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) instead (2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4 -yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) was prepared to give compound 1-89.
化合物I-89(7毫克)。MS:608.2(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.47–7.17(m,2H),6.97-6.6.75(m,1H),6.18(d,J＝16.6Hz,1H),5.76(t,J＝7.5Hz,1H),5.15–4.27(m,4H),4.12–3.60(m,6H),3.44–3.24(m,3H),3.22-3.05(m,2H),3.05–2.87(m,4H),2.86–2.56(m,3H),2.30-2.12(m,1H),2.11–1.98(m,1H),1.95-1.62(m,5H)。 Compound 1-89 (7 mg). MS: 608.2 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 7.47-7.17 (m, 2H), 6.97-6.6.75 (m, 1H), 6.18 (d, J=16.6Hz, 1H), 5.76 (t, J =7.5Hz,1H),5.15-4.27(m,4H),4.12-3.60(m,6H),3.44-3.24(m,3H),3.22-3.05(m,2H),3.05-2.87(m,4H ), 2.86–2.56 (m, 3H), 2.30–2.12 (m, 1H), 2.11–1.98 (m, 1H), 1.95–1.62 (m, 5H).
实施例95Example 95
化合物I-90:2-((2S)-4-(5-氯-6-氟-2'-(((S)-1-甲基吡咯烷-2-基甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound I-90: 2-((2S)-4-(5-chloro-6-fluoro-2'-(((S)-1-methylpyrrolidin-2-ylmethoxy)-6'- Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1 -(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000429
Figure PCTCN2021138375-appb-000429
化合物I-90的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氯-6-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A35)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-90。Synthesis of compound 1-90 Reference compound 1-5 by using (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) instead (2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4 -yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (intermediate A3) and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride were prepared to give compound I-90.
化合物I-90(97毫克)。MS:626.2(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.45–7.14(m,2H),5.50–5.09(m,2H),5.05–4.10(m,4H),3.79(4.05-3.70,4H),3.59–3.31(m,5H),3.25-3.02(m,2H),3.01-2.95(m,1H),2.94–2.82(m,3H),2.81–2.54(m,3H),2.30-2.15(m,1H),2.10-1.97(m,1H),1.95-1.60(m,5H)。 Compound 1-90 (97 mg). MS: 626.2 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 7.45-7.14 (m, 2H), 5.50-5.09 (m, 2H), 5.05-4.10 (m, 4H), 3.79 (4.05-3.70, 4H), 3.59 –3.31(m,5H),3.25-3.02(m,2H),3.01-2.95(m,1H),2.94-2.82(m,3H),2.81-2.54(m,3H),2.30-2.15(m, 1H), 2.10-1.97 (m, 1H), 1.95-1.60 (m, 5H).
实施例96Example 96
化合物I-91:2-((2S)-4-(5,7-二氯-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-91: 2-((2S)-4-(5,7-dichloro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'- Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1 -(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000430
Figure PCTCN2021138375-appb-000430
化合物I-91的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5,7-二氯-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A37)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲 基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-91。Synthesis of compound 1-91 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((5,7-dichloro-1-(methoxycarbonyl)-1,2,3, 4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A37) instead of ( 2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4- Compound 1-91 was prepared from tert-butyl)-2-(cyanomethyl)piperazine-1-carboxylate (Intermediate A3) and 2-fluoroacryloyl chloride (Intermediate B1) instead of acryloyl chloride.
化合物I-91(91毫克)。MS:642.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.56(s,1H),7.67–7.19(m,2H),5.58–5.16(m,2H),4.62–4.30(m,2H),3.97–3.47(m,5H),3.31–2.83(m,7H),2.79–2.57(m,5H),2.31–1.98(m,2H),1.99–1.62(m,8H)。 Compound 1-91 (91 mg). MS: 642.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.56(s,1H),7.67-7.19(m,2H),5.58-5.16(m,2H),4.62-4.30(m,2H),3.97-3.47 (m, 5H), 3.31–2.83 (m, 7H), 2.79–2.57 (m, 5H), 2.31–1.98 (m, 2H), 1.99–1.62 (m, 8H).
实施例97Example 97
化合物I-92:2-((2S)-1-丙烯酰-4-(5,7-二氯-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-92: 2-((2S)-1-acryloyl-4-(5,7-dichloro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy )-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4' -yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000431
Figure PCTCN2021138375-appb-000431
化合物I-92的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5,7-二氯-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A37)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)制备得到化合物I-92。Synthesis of compound 1-92 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((5,7-dichloro-1-(methoxycarbonyl)-1,2,3, 4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A37) instead of ( 2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4- yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A3) was prepared to give compound 1-92.
化合物I-92(23毫克)。MS:624.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.95(s,1H),7.54–7.33(m,2H),6.86–6.56(m,1H),6.18(dd,J＝16.4,2.5Hz,1H),5.77(d,J＝10.4Hz,1H),4.94–4.16(m,6H),3.81–3.48(m,5H),3.11(q,J＝9.2,7.9Hz,2H),3.03–2.83(m,4H),2.72–2.56(m,2H),2.14–2.06(m,2H),1.98–1.62(m,8H)。 Compound 1-92 (23 mg). MS: 624.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 7.54-7.33 (m, 2H), 6.86-6.56 (m, 1H), 6.18 (dd, J=16.4, 2.5Hz, 1H ), 5.77(d, J=10.4Hz, 1H), 4.94–4.16 (m, 6H), 3.81–3.48 (m, 5H), 3.11 (q, J=9.2, 7.9Hz, 2H), 3.03–2.83 ( m, 4H), 2.72–2.56 (m, 2H), 2.14–2.06 (m, 2H), 1.98–1.62 (m, 8H).
实施例98Example 98
化合物I-93:2-((2S)-1-(2-氟丙烯酰基)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-5-(三氟甲基)-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-93: 2-((2S)-1-(2-fluoroacryloyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)- 6'-Oxy-5-(trifluoromethyl)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2- d]Pyrimidine]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000432
Figure PCTCN2021138375-appb-000432
化合物I-93的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((1-(甲氧羰基)-5-(三氟甲基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A43)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-93。Synthesis of compound 1-93 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-5-(trifluoromethyl)-1,2, 3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A43) In place of (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine- 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) and 2-fluoroacryloyl chloride (Intermediate B1) instead of acryloyl chloride were prepared to give compound 1-93.
化合物I-93(45毫克)。MS:642.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.68(s,1H),7.56(dd,J＝31.0,8.1Hz,2H),7.38(dt,J＝16.0,7.8Hz,1H),5.52–5.11(m,2H),4.47–4.15(m,4H),3.95–3.35(m,5H),3.25–2.74(m,10H),2.31–1.64(m,10H)。 Compound 1-93 (45 mg). MS: 642.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.68 (s, 1H), 7.56 (dd, J=31.0, 8.1 Hz, 2H), 7.38 (dt, J=16.0, 7.8 Hz, 1H), 5.52– 5.11 (m, 2H), 4.47–4.15 (m, 4H), 3.95–3.35 (m, 5H), 3.25–2.74 (m, 10H), 2.31–1.64 (m, 10H).
实施例99Example 99
化合物I-94:2-((2S)-4-(6-氯-5-氟-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-94: 2-((2S)-4-(6-chloro-5-fluoro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6' -Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)- 1-(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000433
Figure PCTCN2021138375-appb-000433
化合物I-94的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((6-氯-5-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A51)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-94。Synthesis of compound 1-94 Reference compound 1-5 by using (2S)-4-(2-chloro-6-((6-chloro-5-fluoro-1-(methoxycarbonyl)-1,2,3 ,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A51) instead (2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4 -yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (intermediate A3) and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride were prepared to give compound I-94.
化合物I-94(35毫克)。MS:626.2(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.65(s,1H),7.38(s,1H),7.21–7.10(d,J＝8.6Hz,1H),5.43–5.10(m,2H),4.53–4.41(m,3H),3.78–3.65(m,3H),3.61–3.54(m,2H),3.46(s,1H),3.13(d,J＝11.8Hz,2H),3.05–2.93(m,2H),2.91(d,J＝4.7Hz,3H),2.86–2.77(m,1H),2.75–2.69(m,2H),2.28–2.17(m,1H),2.06–2.01(m,1H),1.74–1.57(m,8H)。 Compound 1-94 (35 mg). MS: 626.2 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.65(s,1H),7.38(s,1H),7.21-7.10(d,J=8.6Hz,1H),5.43-5.10(m,2H), 4.53–4.41 (m, 3H), 3.78–3.65 (m, 3H), 3.61–3.54 (m, 2H), 3.46 (s, 1H), 3.13 (d, J=11.8Hz, 2H), 3.05–2.93 ( m, 2H), 2.91 (d, J=4.7Hz, 3H), 2.86–2.77 (m, 1H), 2.75–2.69 (m, 2H), 2.28–2.17 (m, 1H), 2.06–2.01 (m, 1H), 1.74–1.57 (m, 8H).
实施例100Example 100
化合物I-95:2-((2S)-1-丙烯酰-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-5-(三氟甲基)-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-95: 2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy -5-(Trifluoromethyl)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]- 4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000434
Figure PCTCN2021138375-appb-000434
化合物I-95的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((1-(甲氧羰基)-5-(三氟甲基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A43)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)制备得到化合物I-95。Synthesis of compound 1-95 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-5-(trifluoromethyl)-1,2, 3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A43) In place of (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine- 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) was prepared to give compound 1-95.
化合物I-95(35毫克)。MS:624.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.82(s,1H),7.68–7.49(m,2H),7.39(dt,J＝16.4,7.9Hz,1H),7.03–6.73(m,1H),6.18(d,J＝16.7Hz,1H),5.77(d,J＝10.4Hz,1H),4.61–4.38(m,2H),3.99–3.44(m,9H),3.22–2.75(m,9H),2.34–1.66(m,9H)。 Compound 1-95 (35 mg). MS: 624.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.82 (s, 1H), 7.68-7.49 (m, 2H), 7.39 (dt, J=16.4, 7.9Hz, 1H), 7.03-6.73 (m, 1H) ), 6.18 (d, J=16.7Hz, 1H), 5.77 (d, J=10.4Hz, 1H), 4.61–4.38 (m, 2H), 3.99–3.44 (m, 9H), 3.22–2.75 (m, 9H), 2.34–1.66 (m, 9H).
实施例101Example 101
化合物I-96:2-((2S)-4-(5-氟-7-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-96: 2-((2S)-4-(5-fluoro-7-methyl-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6 '-Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl) -1-(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000435
Figure PCTCN2021138375-appb-000435
化合物I-96的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氟-1-(甲氧羰基)-7-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A46)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-96。Synthesis of compound 1-96 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((5-fluoro-1-(methoxycarbonyl)-7-methyl-1,2, 3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A46) In place of (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine- 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) and 2-fluoroacryloyl chloride (Intermediate B1) instead of acryloyl chloride were prepared to give compound 1-96.
化合物I-96(55毫克)。MS:606.2(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.71(s,1H),6.87(dd,J＝10.5,6.5Hz,1H),6.78(s,1H),5.37–5.28(m,2H),5.19(s,1H),4.54–4.48(m,1H),4.40(dd,J＝12.4,6.7Hz,1H),3.75(s,3H),3.57(d,J＝12.9Hz,2H),3.39–3.29(m,1H),3.13–3.01(m,2H),2.99(d,J＝4.9Hz,1H),2.90(d,J＝4.4Hz,4H),2.64–2.58(m,2H),2.26(s,1H),2.19(s,3H),2.09–1.91(m,3H),1.86–1.64(m,7H)。 Compound 1-96 (55 mg). MS: 606.2 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.71(s,1H),6.87(dd,J=10.5,6.5Hz,1H),6.78(s,1H),5.37-5.28(m,2H), 5.19(s, 1H), 4.54–4.48(m, 1H), 4.40(dd, J=12.4, 6.7Hz, 1H), 3.75(s, 3H), 3.57(d, J=12.9Hz, 2H), 3.39 –3.29(m,1H),3.13–3.01(m,2H),2.99(d,J=4.9Hz,1H),2.90(d,J=4.4Hz,4H),2.64–2.58(m,2H), 2.26 (s, 1H), 2.19 (s, 3H), 2.09–1.91 (m, 3H), 1.86–1.64 (m, 7H).
实施例102Example 102
化合物I-97:2-((2S)-4-(5-氟-2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-7-甲基-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-97: 2-((2S)-4-(5-fluoro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)- 7-Methyl-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine] -4'-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000436
Figure PCTCN2021138375-appb-000436
化合物I-97的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氟-1-(甲氧羰基)-7-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A46)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3),((2S，4R)- 4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-97。Synthesis of compound 1-97 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((5-fluoro-1-(methoxycarbonyl)-7-methyl-1,2, 3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A46) In place of (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine- 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3), ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl ) methanol (Intermediate C3) in place of (S)-(1-methylpyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride to prepare compound 1-97.
化合物I-97(58毫克)。MS:624.4(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.89(s,1H),6.90–6.85(m,1H),6.78(s,1H),5.55–5.16(m,2H),4.61–4.45(m,3H),4.07–3.90(m,4H),3.73(d,J＝13.6Hz,2H),3.53–3.42m,3H),3.12–3.01(m,1H),2.99(d,J＝4.5Hz,4H),2.84–2.76(m,1H),2.61–2.50(m,2H),2.26(s,2H),2.19(s,3H),1.85–1.60(m,6H)。 Compound 1-97 (58 mg). MS: 624.4 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.89(s,1H),6.90-6.85(m,1H),6.78(s,1H),5.55-5.16(m,2H),4.61-4.45(m ,3H),4.07–3.90(m,4H),3.73(d,J=13.6Hz,2H),3.53–3.42m,3H),3.12–3.01(m,1H),2.99(d,J=4.5Hz , 4H), 2.84–2.76 (m, 1H), 2.61–2.50 (m, 2H), 2.26 (s, 2H), 2.19 (s, 3H), 1.85–1.60 (m, 6H).
实施例103Example 103
化合物I-98a和化合物I-98b:2-((S)-1-丙烯酰-4-((S)-5,7-二氟-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈和2-((S)-1-丙烯酰-4-((R)-5,7-二氟-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-98a and Compound 1-98b: 2-((S)-1-acryloyl-4-((S)-5,7-difluoro-2'-(((S)-1-methylpyrrole Alk-2-yl)methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3, 2-d]Pyrimidine]-4'-yl)piperazin-2-yl)acetonitrile and 2-((S)-1-acryloyl-4-((R)-5,7-difluoro-2'- (((S)-1-Methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[ Naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000437
Figure PCTCN2021138375-appb-000437
化合物I-98a和化合物I-98b的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5,7-二氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A44)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)，并经SFC手性拆分(柱型号：Dr.maish Reprosil Chiral-JM，250x25mm，10μm色谱柱，流动相：40％甲醇在二氧化碳中)，制备得到化合物I-98a和化合物I-98b。Synthesis of compound 1-98a and compound 1-98b Reference compound 1-5 by using (2S)-4-(2-chloro-6-((5,7-difluoro-1-(methoxycarbonyl)-1) ,2,3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (intermediate body A44) instead of (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitro pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) and chiral resolved by SFC (column model: Dr.maish Reprosil Chiral-JM , 250x25mm, 10μm chromatographic column, mobile phase: 40% methanol in carbon dioxide) to prepare compound I-98a and compound I-98b.
化合物I-98a(保留时间4.473分钟,65毫克)。MS:592.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.73(s,1H),7.09(dd,J＝10.4,8.1Hz,1H),6.97(d,J＝10.2Hz,1H),6.93-6.77(m,1H),6.17(d,J＝16.6Hz,1H),5.76(d,J＝10.4Hz,1H),5.01–4.78(m,1H),4.21(dd,J＝10.8,5.2Hz,1H),4.12–3.94(m,2H),3.88-3.69(m,1H),3.67–3.56(m,1H),3.56–3.38(m, 3H),3.31–3.17(m,2H),3.07(d,J＝13.1Hz,1H),3.02-2.85(m,3H),2.84-2.55(m,3H),2.33(s,3H),2.16(d,J＝7.7Hz,1H),1.91–1.87(m,2H),1.81–1.49(m,5H)。 Compound 1-98a (retention time 4.473 min, 65 mg). MS: 592.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.73 (s, 1H), 7.09 (dd, J=10.4, 8.1 Hz, 1H), 6.97 (d, J=10.2 Hz, 1H), 6.93-6.77 ( m, 1H), 6.17 (d, J=16.6Hz, 1H), 5.76 (d, J=10.4Hz, 1H), 5.01–4.78 (m, 1H), 4.21 (dd, J=10.8, 5.2Hz, 1H) ), 4.12–3.94 (m, 2H), 3.88–3.69 (m, 1H), 3.67–3.56 (m, 1H), 3.56–3.38 (m, 3H), 3.31–3.17 (m, 2H), 3.07 (d , J＝13.1Hz, 1H), 3.02-2.85(m, 3H), 2.84-2.55(m, 3H), 2.33(s, 3H), 2.16(d, J＝7.7Hz, 1H), 1.91-1.87( m, 2H), 1.81–1.49 (m, 5H).
化合物I-98b(保留时间4.688分钟,55毫克)。MS:592.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.98(s,1H),7.18–7.02(m,2H),6.95-6.75(m,1H),6.17(s,J＝16.6Hz,1H),5.75(d,J＝10.4Hz,1H),5.08–4.86(m,1H),4.33–4.29(m,1H),4.26–4.16(m,1H),4.01(d,J＝11.7Hz,2H),3.74–3.63(m,2H),3.63–3.40(m,2H),3.05(t,J＝16.0Hz,1H),2.98-2.86(m,2H),2.81(d,J＝17.4Hz,1H),2.68-2.56(m,3H),2.32(s,3H),2.15(q,J＝8.8Hz,1H),1.95–1.79(m,2H),1.79–1.49(m,7H)。 Compound 1-98b (retention time 4.688 min, 55 mg). MS: 592.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.98(s,1H),7.18-7.02(m,2H),6.95-6.75(m,1H),6.17(s,J=16.6Hz,1H), 5.75(d,J＝10.4Hz,1H),5.08-4.86(m,1H),4.33-4.29(m,1H),4.26-4.16(m,1H),4.01(d,J＝11.7Hz,2H) ,3.74-3.63(m,2H),3.63-3.40(m,2H),3.05(t,J=16.0Hz,1H),2.98-2.86(m,2H),2.81(d,J=17.4Hz,1H) ), 2.68-2.56(m, 3H), 2.32(s, 3H), 2.15(q, J=8.8Hz, 1H), 1.95-1.79(m, 2H), 1.79-1.49(m, 7H).
实施例104Example 104
化合物I-99:2-((2S)-4-(5,7-二氟-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-99: 2-((2S)-4-(5,7-difluoro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'- Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1 -(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000438
Figure PCTCN2021138375-appb-000438
化合物I-99的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5,7-二氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A44)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯经Pre-HPLC制备得到化合物I-99。Synthesis of compound 1-99 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((5,7-difluoro-1-(methoxycarbonyl)-1,2,3, 4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A44) instead of ( 2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4- Compound I- 99.
化合物I-99(35毫克)。MS:610.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.73(s,1H),7.15–6.93(m,2H),5.49–5.06(m,2H),4.20–4.16(m,2H),4.11–3.96(m,2H),3.82–3.46(m,4H),3.14–2.76(m,6H),2.61(s,2H),2.32(s,3H),2.23–2.11(m,1H),2.01–1.49(m,9H)。 Compound 1-99 (35 mg). MS: 610.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.73(s,1H), 7.15-6.93(m,2H), 5.49-5.06(m,2H), 4.20-4.16(m,2H), 4.11-3.96 (m, 2H), 3.82–3.46 (m, 4H), 3.14–2.76 (m, 6H), 2.61 (s, 2H), 2.32 (s, 3H), 2.23–2.11 (m, 1H), 2.01–1.49 (m, 9H).
实施例105Example 105
化合物I-100a和化合物I-100b:2-((S)-4-((S)-2'-((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-5-(三氟甲基)-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈和2-((S)-4-((R)-2'-((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-5-(三氟甲基)-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-100a and Compound 1-100b: 2-((S)-4-((S)-2'-((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methan oxy)-6'-oxy-5-(trifluoromethyl)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[ 3,2-d]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile and 2-((S)-4-((R)-2'- ((2S,4R)-4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy-5-(trifluoromethyl)-3,4,5',8 '-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl)piperazine- 2-yl)acetonitrile
Figure PCTCN2021138375-appb-000439
Figure PCTCN2021138375-appb-000439
化合物I-100a和化合物I-100b的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((1-(甲氧羰基)-5-(三氟甲基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A43)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)，((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯，并经SFC手性拆分(柱型号：Dr.maish Reprosil Chiral-JM，250x25mm，10μm色谱柱，流动相：40％甲醇在二氧化碳中)制备得到化合物I-100a和化合物I-100b。Synthesis of Compound 1-100a and Compound 1-100b Reference compound 1-5 by using (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-5-(trifluoromethyl) -1,2,3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A43) in place of (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5 -Nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3), ((2S,4R)-4-fluoro-1-methylpyrrole Alk-2-yl)methanol (intermediate C3) in place of (S)-(1-methylpyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride (intermediate B1) in place of acryloyl chloride and purified by SFC The compound I-100a and the compound I-100b were prepared by sexual resolution (column type: Dr.maish Reprosil Chiral-JM, 250×25 mm, 10 μm column, mobile phase: 40% methanol in carbon dioxide).
化合物I-100a(保留时间7.008分钟,15毫克)。MS:660.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.60(d,J＝7.7Hz,1H),7.55(d,J＝8.0Hz,1H),7.37(t,J＝7.8Hz,1H),5.45–5.05(m,3H),4.44–4.28(m,2H),4.00–3.88(m,2H),3.62–3.35(m,5H),3.19–2.84(m,6H),2.65–2.58(m,1H),2.53(s,3H),2.26–2.19(m,1H),2.11–1.74(m,6H)。 Compound I-100a (retention time 7.008 min, 15 mg). MS: 660.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.60(d,J=7.7Hz,1H),7.55(d,J=8.0Hz,1H),7.37(t,J=7.8Hz,1H),5.45 –5.05(m,3H),4.44–4.28(m,2H),4.00–3.88(m,2H),3.62–3.35(m,5H),3.19–2.84(m,6H),2.65–2.58(m, 1H), 2.53 (s, 3H), 2.26–2.19 (m, 1H), 2.11–1.74 (m, 6H).
化合物I-100b(保留时间7.199分钟,25毫克)。MS:660.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.60(d,J＝7.7Hz,1H),7.55(d,J＝8.0Hz,1H),7.37(t,J＝7.8Hz,1H),5.45–5.05(m,3H),4.44–4.28(m,2H),4.00–3.88(m,2H),3.62–3.35(m,5H),3.19–2.84(m,6H),2.65–2.58(m,1H),2.53(s,3H),2.26–2.19(m,1H),2.11–1.74(m,6H)。 Compound I-100b (retention time 7.199 min, 25 mg). MS: 660.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.60(d,J=7.7Hz,1H),7.55(d,J=8.0Hz,1H),7.37(t,J=7.8Hz,1H),5.45 –5.05(m,3H),4.44–4.28(m,2H),4.00–3.88(m,2H),3.62–3.35(m,5H),3.19–2.84(m,6H),2.65–2.58(m, 1H), 2.53 (s, 3H), 2.26–2.19 (m, 1H), 2.11–1.74 (m, 6H).
实施例106Example 106
化合物I-101：2-((2S)-4-(7-氯-5-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound I-101: 2-((2S)-4-(7-chloro-5-methyl-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6 '-Oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl) -1-(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000440
Figure PCTCN2021138375-appb-000440
化合物I-101的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((7-氯-1-(甲氧羰基)-5-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A47)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-101。Synthesis of compound 1-101 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((7-chloro-1-(methoxycarbonyl)-5-methyl-1,2, 3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A47) In place of (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine- 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) and 2-fluoroacryloyl chloride (Intermediate B1) instead of acryloyl chloride were prepared to give compound 1-101.
化合物I-101(61毫克)。MS:622.4(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.80(s,1H),7.14(t,J＝2.7Hz,1H),7.07(d,J＝2.2Hz,1H),5.44–5.27(m,2H),5.20(s,1H),4.56–4.39(m,2H),3.86–3.53(m,6H),3.46(s,1H),3.13–3.1(m,2H),3.07–2.93(m,2H),2.91(d,J＝4.6Hz,3H),2.87–2.71(m,1H),2.64–2.52(m,3H),2.20(d,J＝3.5Hz,3H),2.09–1.99(m,1H),1.93–1.65(m,6H)。 Compound 1-101 (61 mg). MS: 622.4 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.80 (s, 1H), 7.14 (t, J=2.7Hz, 1H), 7.07 (d, J=2.2Hz, 1H), 5.44-5.27 (m, 2H), 5.20 (s, 1H), 4.56–4.39 (m, 2H), 3.86–3.53 (m, 6H), 3.46 (s, 1H), 3.13–3.1 (m, 2H), 3.07–2.93 (m, 2H), 2.91 (d, J=4.6Hz, 3H), 2.87–2.71 (m, 1H), 2.64–2.52 (m, 3H), 2.20 (d, J=3.5Hz, 3H), 2.09–1.99 (m , 1H), 1.93–1.65 (m, 6H).
实施例107Example 107
化合物I-102：2-((2S)-1-丙烯酰-4-(7-氯-5-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound I-102: 2-((2S)-1-acryloyl-4-(7-chloro-5-methyl-2'-(((S)-1-methylpyrrolidin-2-yl)methane oxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]- 4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000441
Figure PCTCN2021138375-appb-000441
化合物I-102的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((7-氯-1-(甲氧羰基)-5-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A47)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)制备得到化合物I-102。Synthesis of compound 1-102 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((7-chloro-1-(methoxycarbonyl)-5-methyl-1,2, 3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A47) In place of (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine- 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) was prepared to give compound 1-102.
化合物I-102(13毫克)。MS:604.2(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.83(s,1H),7.22(d,J＝2.2Hz,1H),7.14(t,J＝2.7Hz,1H),7.06(d,J＝2.1Hz,1H),6.19(dd,J＝16.6,2.8Hz,1H),5.77(d,J＝10.0Hz,1H),5.04(s,1H),4.80(s,1H),4.57–4.27(m,3H),4.03(s,1H),3.69–3.27(m,5H),3.14–3.05(m,2H),2.91(d,J＝4.7Hz,4H),2.87–2.75(m,1H),2.55(s,2H),2.20(d,J＝3.9Hz,4H),2.08–1.62(m,8H)。 Compound 1-102 (13 mg). MS: 604.2 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.83 (s, 1H), 7.22 (d, J=2.2 Hz, 1H), 7.14 (t, J=2.7 Hz, 1H), 7.06 (d, J= 2.1Hz, 1H), 6.19(dd, J＝16.6, 2.8Hz, 1H), 5.77(d, J＝10.0Hz, 1H), 5.04(s, 1H), 4.80(s, 1H), 4.57–4.27( m, 3H), 4.03 (s, 1H), 3.69–3.27 (m, 5H), 3.14–3.05 (m, 2H), 2.91 (d, J=4.7Hz, 4H), 2.87–2.75 (m, 1H) , 2.55(s, 2H), 2.20(d, J=3.9Hz, 4H), 2.08–1.62(m, 8H).
实施例108Example 108
化合物I-103a和化合物I-103b:2-((S)-4-((S)-6-氟-5-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈和2-((S)-4-((R)-6-氟-5-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-103a and Compound 1-103b: 2-((S)-4-((S)-6-fluoro-5-methyl-2'-(((S)-1-methylpyrrolidine-2 -yl)methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3,2-d ]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile and 2-((S)-4-((R)-6-fluoro-5-methyl) -2'-(((S)-1-Methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H -Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000442
Figure PCTCN2021138375-appb-000442
化合物I-103a和化合物I-103b的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((6-氟-1-(甲氧羰基)-5-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A48)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯，并经SFC手性拆分(柱型号：Dr.maish  Reprosil Chiral-JM，250x25mm，10μm色谱柱，流动相：40％甲醇在二氧化碳中)制备得到化合物I-103a和化合物I-103b。Synthesis of compound 1-103a and compound 1-103b Reference compound 1-5 by using (2S)-4-(2-chloro-6-((6-fluoro-1-(methoxycarbonyl)-5-methyl) -1,2,3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A48) in place of (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5 - nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride, and Compound I-103a and compound I-103b were prepared by SFC chiral resolution (column type: Dr.maish Reprosil Chiral-JM, 250×25 mm, 10 μm column, mobile phase: 40% methanol in carbon dioxide).
化合物I-103a(保留时间4.735分钟,41毫克)。MS:606.4(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.74(s,1H),7.02–6.85(m,2H),5.45–5.15(m,2H),4.77(s,2H),4.19(dd,J＝10.7,5.0Hz,1H),4.00(dd,J＝10.7,6.1Hz,1H),3.68–3.52(m,3H),3.10–3.07(m,1H),3.04–2.77(m,4H),2.74–2.54(m,2H),2.32(s,3H),2.24–1.98(m,4H),1.92–1.88(m,2H),1.80–1.79(s,2H),1.77–1.42(m,7H)。 Compound 1-103a (retention time 4.735 min, 41 mg). MS: 606.4 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.74(s,1H), 7.02-6.85(m,2H), 5.45-5.15(m,2H), 4.77(s,2H), 4.19(dd,J = 10.7, 5.0Hz, 1H), 4.00 (dd, J = 10.7, 6.1Hz, 1H), 3.68–3.52 (m, 3H), 3.10–3.07 (m, 1H), 3.04–2.77 (m, 4H), 2.74–2.54 (m, 2H), 2.32 (s, 3H), 2.24–1.98 (m, 4H), 1.92–1.88 (m, 2H), 1.80–1.79 (s, 2H), 1.77–1.42 (m, 7H) ).
化合物I-103b(保留时间4.758分钟,50毫克)。MS:606.4(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.74(s,1H),7.02–6.85(m,2H),5.45–5.15(m,2H),4.77(s,2H),4.19(dd,J＝10.7,5.0Hz,1H),4.00(dd,J＝10.7,6.1Hz,1H),3.68–3.52(m,3H),3.10–3.07(m,1H),3.04–2.77(m,4H),2.74–2.54(m,2H),2.32(s,3H),2.24–1.98(m,4H),1.92–1.88(m,2H),1.80–1.79(s,2H),1.77–1.42(m,7H)。 Compound 1-103b (retention time 4.758 min, 50 mg). MS: 606.4 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.74(s,1H), 7.02-6.85(m,2H), 5.45-5.15(m,2H), 4.77(s,2H), 4.19(dd,J = 10.7, 5.0Hz, 1H), 4.00 (dd, J = 10.7, 6.1Hz, 1H), 3.68–3.52 (m, 3H), 3.10–3.07 (m, 1H), 3.04–2.77 (m, 4H), 2.74–2.54 (m, 2H), 2.32 (s, 3H), 2.24–1.98 (m, 4H), 1.92–1.88 (m, 2H), 1.80–1.79 (s, 2H), 1.77–1.42 (m, 7H) ).
实施例109Example 109
化合物I-104a和化合物I-104b:2-((2S)-4-((1S)-7-氯-2'-((2S)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-5-甲基-6'-氧代-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈和2-((2S)-4-((1R)-7-氯-2'-((2S)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-5-甲基-6'-氧代-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-104a and Compound 1-104b: 2-((2S)-4-((1S)-7-chloro-2'-((2S)-4-fluoro-1-methylpyrrolidin-2-yl )Methoxy)-5-methyl-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[3, 2-d]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile and 2-((2S)-4-((1R)-7-chloro-2 '-((2S)-4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)-5-methyl-6'-oxo-3,4,5',8'-tetrahydro -2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl)piperazin-2-yl) Acetonitrile
Figure PCTCN2021138375-appb-000443
Figure PCTCN2021138375-appb-000443
化合物I-104a和化合物I-104b的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((7-氯-1-(甲氧羰基)-5-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A47)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)，((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2- 基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯，并经SFC手性拆分(柱型号：Dr.maish Reprosil Chiral-JM，250x25mm，10μm色谱柱，流动相：40％甲醇在二氧化碳中)制备得到化合物I-104a和化合物I-104b。Synthesis of compound 1-104a and compound 1-104b Reference compound 1-5 by using (2S)-4-(2-chloro-6-((7-chloro-1-(methoxycarbonyl)-5-methyl) -1,2,3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A47) in place of (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5 -Nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3), ((2S,4R)-4-fluoro-1-methylpyrrole Alk-2-yl)methanol (intermediate C3) in place of (S)-(1-methylpyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride (intermediate B1) in place of acryloyl chloride and purified by SFC The compound I-104a and the compound I-104b were prepared by sexual resolution (column type: Dr.maish Reprosil Chiral-JM, 250×25 mm, 10 μm column, mobile phase: 40% methanol in carbon dioxide).
化合物I-104a(保留时间7.198分钟,11毫克)。MS:640.4(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.75(s,1H),7.13(s,1H),7.05(s,1H),5.43–5.28(m,2H),5.21–5.18(m,2H),4.24–4.18(m,1H),4.11–4.07(m,1H),3.70–3.58(m,3H),3.44–3.28(m,3H),3.12–3.08(m,2H),3.03–2.79(m,5H),2.36(s,3H),2.19(s,3H),2.14–1.98(m,2H),1.96–1.67(m,6H)。 Compound I-104a (retention time 7.198 min, 11 mg). MS: 640.4 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.75(s,1H), 7.13(s,1H), 7.05(s,1H), 5.43-5.28(m,2H), 5.21-5.18(m,2H) ), 4.24–4.18 (m, 1H), 4.11–4.07 (m, 1H), 3.70–3.58 (m, 3H), 3.44–3.28 (m, 3H), 3.12–3.08 (m, 2H), 3.03–2.79 (m, 5H), 2.36 (s, 3H), 2.19 (s, 3H), 2.14–1.98 (m, 2H), 1.96–1.67 (m, 6H).
化合物I-104b(保留时间7.46分钟,20毫克)。MS:640.4(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.75(s,1H),7.13(s,1H),7.05(s,1H),5.43–5.28(m,2H),5.21–5.18(m,2H),4.24–4.18(m,1H),4.11–4.07(m,1H),3.70–3.58(m,3H),3.44–3.28(m,3H),3.12–3.08(m,2H),3.03–2.79(m,5H),2.36(s,3H),2.19(s,3H),2.14–1.98(m,2H),1.96–1.67(m,6H)。 Compound 1-104b (retention time 7.46 min, 20 mg). MS: 640.4 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.75(s,1H), 7.13(s,1H), 7.05(s,1H), 5.43-5.28(m,2H), 5.21-5.18(m,2H) ), 4.24–4.18 (m, 1H), 4.11–4.07 (m, 1H), 3.70–3.58 (m, 3H), 3.44–3.28 (m, 3H), 3.12–3.08 (m, 2H), 3.03–2.79 (m, 5H), 2.36 (s, 3H), 2.19 (s, 3H), 2.14–1.98 (m, 2H), 1.96–1.67 (m, 6H).
实施例110Example 110
化合物I-105a和化合物I-105b:2-((S)-1-丙烯酰-4-((S)-6-氟-5-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈和2-((S)-1-丙烯酰-4-((R)-6-氟-5-甲基-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧基-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)哌嗪-2-基)乙腈Compound 1-105a and Compound 1-105b: 2-((S)-1-acryloyl-4-((S)-6-fluoro-5-methyl-2'-(((S)-1-methyl) pyrrolidin-2-yl)methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine[ 3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile and 2-((S)-1-acryloyl-4-((R)-6-fluoro-5-methyl) -2'-(((S)-1-Methylpyrrolidin-2-yl)methoxy)-6'-oxy-3,4,5',8'-tetrahydro-2H,6'H -Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000444
Figure PCTCN2021138375-appb-000444
化合物I-105a和化合物I-105b的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((6-氟-1-(甲氧羰基)-5-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A48)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)， 并经SFC手性拆分(柱型号：Dr.maish Reprosil Chiral-JM，250x25mm，10μm色谱柱，流动相：40％甲醇在二氧化碳中)制备得到化合物I-105a和化合物I-105b。Synthesis of compound 1-105a and compound 1-105b Reference compound 1-5 by using (2S)-4-(2-chloro-6-((6-fluoro-1-(methoxycarbonyl)-5-methyl) -1,2,3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A48) in place of (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5 -Nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3), and chiral resolved by SFC (column model: Dr.maish Reprosil Chiral -JM, 250x25mm, 10μm column, mobile phase: 40% methanol in carbon dioxide) to prepare compound I-105a and compound I-105b.
化合物I-105a(保留时间4.249分钟,6毫克)。MS:588.5(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.89(s,1H),7.15(dd,J＝8.9,5.8Hz,1H),6.99(t,J＝9.0Hz,1H),6.94–6.73(m,1H),6.17(d,J＝16.3Hz,1H),5.75(d,J＝9.9Hz,1H),5.08(s,1H),4.46–4.12(m,2H),4.05–3.98(m,1H),3.86–3.80(m,1H),3.73–3.44(m,4H),3.11–2.85(m,3H),2.79–2.74(m,1H),2.60–2.54(m,2H),2.52(s,1H),2.32(s,3H),2.16–2.14(m,1H),2.10(d,J＝1.9Hz,3H),1.91(m,1H),1.85–1.48(m,7H)。 Compound I-105a (retention time 4.249 min, 6 mg). MS: 588.5 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 7.15 (dd, J=8.9, 5.8 Hz, 1H), 6.99 (t, J=9.0 Hz, 1H), 6.94-6.73 ( m, 1H), 6.17 (d, J=16.3Hz, 1H), 5.75 (d, J=9.9Hz, 1H), 5.08 (s, 1H), 4.46–4.12 (m, 2H), 4.05–3.98 (m ,1H),3.86–3.80(m,1H),3.73–3.44(m,4H),3.11–2.85(m,3H),2.79–2.74(m,1H),2.60–2.54(m,2H),2.52 (s, 1H), 2.32 (s, 3H), 2.16–2.14 (m, 1H), 2.10 (d, J=1.9Hz, 3H), 1.91 (m, 1H), 1.85–1.48 (m, 7H).
化合物I-105b(保留时间4.333分钟,9毫克)。MS:588.5(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.89(s,1H),7.15(dd,J＝8.9,5.8Hz,1H),6.99(t,J＝9.0Hz,1H),6.94–6.73(m,1H),6.17(d,J＝16.3Hz,1H),5.75(d,J＝9.9Hz,1H),5.08(s,1H),4.46–4.12(m,2H),4.05–3.98(m,1H),3.86–3.80(m,1H),3.73–3.44(m,4H),3.11–2.85(m,3H),2.79–2.74(m,1H),2.60–2.54(m,2H),2.52(s,1H),2.32(s,3H),2.16–2.14(m,1H),2.10(d,J＝1.9Hz,3H),1.91(m,1H),1.85–1.48(m,7H)。 Compound 1-105b (retention time 4.333 min, 9 mg). MS: 588.5 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 7.15 (dd, J=8.9, 5.8 Hz, 1H), 6.99 (t, J=9.0 Hz, 1H), 6.94-6.73 ( m, 1H), 6.17 (d, J=16.3Hz, 1H), 5.75 (d, J=9.9Hz, 1H), 5.08 (s, 1H), 4.46–4.12 (m, 2H), 4.05–3.98 (m ,1H),3.86–3.80(m,1H),3.73–3.44(m,4H),3.11–2.85(m,3H),2.79–2.74(m,1H),2.60–2.54(m,2H),2.52 (s, 1H), 2.32 (s, 3H), 2.16–2.14 (m, 1H), 2.10 (d, J=1.9Hz, 3H), 1.91 (m, 1H), 1.85–1.48 (m, 7H).
实施例111Example 111
化合物I-106a和化合物I-106b：2-((S)-4-((S)-5-溴-2'-((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H,6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈和2-((S)-4-((R)-5-溴-2'-((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H,6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈Compound 1-106a and Compound 1-106b: 2-((S)-4-((S)-5-bromo-2'-((2S,4R)-4-fluoro-1-methylpyrrolidine-2 -yl)methoxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridine[3,2-d] Pyrimidine]-4'-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile and 2-((S)-4-((R)-5-bromo-2'-(( 2S,4R)-4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro Cyclo[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000445
Figure PCTCN2021138375-appb-000445
Figure PCTCN2021138375-appb-000446
Figure PCTCN2021138375-appb-000446
化合物I-106a和化合物I-106b的合成参考化合物I-5，通过使用(2S)-4-(6-((5-溴-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-氯-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A45)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)，((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯，并经SFC手性拆分(柱型号：Dr.maish Reprosil Chiral-JM，250x25mm，10μm色谱柱，流动相：40％甲醇在二氧化碳中)制备得到化合物I-106a和化合物I-106b。Synthesis of Compound 1-106a and Compound 1-106b Reference compound 1-5, by using (2S)-4-(6-((5-bromo-1-(methoxycarbonyl)-1,2,3,4- Tetrahydronaphthalen-1-yl)methyl)-2-chloro-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A45) instead (2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4 -yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3), ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl) Methanol (Intermediate C3) in place of (S)-(1-methylpyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride and chiral resolution by SFC (column model : Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm column, mobile phase: 40% methanol in carbon dioxide) to prepare compound I-106a and compound I-106b.
化合物I-106a(保留时间6.961分钟,16毫克)。MS:670.2(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.51(d,J＝7.8Hz,1H),7.20(d,J＝7.8Hz,1H),7.09(t,J＝7.8Hz,1H),5.56–5.35(m,2H),5.34-5.17(m,1H),4.97–4.38(m,4H),4.24–3.77(m,5H),3.70–3.57(m,2H),3.44–3.37(m,1H),3.19–3.02(m,2H),3.01-2.87(m,4H),2.86–2.60(m,3H),2.37–2.03(m,2H),2.02-1.89(m,2H),1.86–1.66(m,3H)。 Compound I-106a (retention time 6.961 min, 16 mg). MS: 670.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.51 (d, J=7.8 Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 7.09 (t, J=7.8 Hz, 1H), 5.56 –5.35(m,2H),5.34-5.17(m,1H),4.97–4.38(m,4H),4.24–3.77(m,5H),3.70–3.57(m,2H),3.44–3.37(m, 1H), 3.19–3.02 (m, 2H), 3.01–2.87 (m, 4H), 2.86–2.60 (m, 3H), 2.37–2.03 (m, 2H), 2.02–1.89 (m, 2H), 1.86– 1.66 (m, 3H).
化合物I-106b(保留时间7.133分钟,18毫克)。MS:670.2(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.52(d,J＝7.8Hz,1H),7.35(d,J＝7.9Hz,1H),7.16(t,J＝7.9Hz,1H),5.58–5.23(m,2H),5.21-4.89(m,1H),4.70-4.43(m,2H),4.32–3.80(m,4H),3.77–3.64(m,3H),3.54-3.28(m,3H),3.21–3.08(m,1H),3.07–2.77(m,4H),2.74-2.56(m,2H),2.32-2.11(m,2H),1.90–1.56(m,6H)。 Compound 1-106b (retention time 7.133 min, 18 mg). MS: 670.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.52 (d, J=7.8 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.16 (t, J=7.9 Hz, 1H), 5.58 –5.23(m,2H),5.21-4.89(m,1H),4.70-4.43(m,2H),4.32-3.80(m,4H),3.77-3.64(m,3H),3.54-3.28(m, 3H), 3.21–3.08 (m, 1H), 3.07–2.77 (m, 4H), 2.74–2.56 (m, 2H), 2.32–2.11 (m, 2H), 1.90–1.56 (m, 6H).
实施例112Example 112
化合物I-107：4’-((S)-3-(氰甲基)-4-(2-氟丙烯酰)哌嗪-1-基)-2’-((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6’-氧代-3,4,5’,8’-四氢-2H,6’-螺环[萘-1,7’-吡啶[3,2-d]嘧啶]-5-碳腈Compound I-107: 4'-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-2'-((2S,4R)-4- Fluoro-1-methylpyrrolidin-2-yl)methoxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7 '-Pyridin[3,2-d]pyrimidine]-5-carbonitrile
Figure PCTCN2021138375-appb-000447
Figure PCTCN2021138375-appb-000447
步骤1:(2S)-4-(5-氰基-2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H,6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯的制备(中间体I-107-1)Step 1: (2S)-4-(5-cyano-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy Substituted-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-2-( Preparation of cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate I-107-1)
将(2S)-4-(5-溴-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5'，8'-四氢-2H，6'-H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体I-106-2,300毫克,0.220毫摩尔),氰化锌(129毫克,1.102毫摩尔),Pd 2dba 3(40.4毫克,0.044毫摩尔)和dppf(24.44毫克,0.044毫摩尔)的DMF(5毫升)溶液在100℃搅拌缓反应1.5小时。然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物(2S)-4-(5-氰基-2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H,6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(290毫克,84％收率)。MS:638.2(M+H) +。 (2S)-4-(5-bromo-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxo-3,4,5', 8'-Tetrahydro-2H,6'-H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-2-(cyanomethyl)piperazine- tert-Butyl 1-carboxylate (Intermediate I-106-2, 300 mg, 0.220 mmol), zinc cyanide (129 mg, 1.102 mmol), Pd 2 dba 3 (40.4 mg, 0.044 mmol) and dppf (24.44 mg, 0.044 mmol) in DMF (5 mL) at 100 °C for 1.5 h with stirring. The reaction was then quenched by the addition of ice water, and the extraction was diluted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain (2S)-4-(5-cyano-2'-( ((2S,4R)-4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'-Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (290 mg, 84 % yield). MS: 638.2 (M+H) + .
步骤2:4’-((S)-3-(氰甲基)-4-(2-氟丙烯酰)哌嗪-1-基)-2’-((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6’-氧代-3,4,5’,8’-四氢-2H,6’-螺环[萘-1,7’-吡啶[3,2-d]嘧啶]-5-碳腈的制备Step 2: 4'-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-2'-((2S,4R)-4-fluoro- 1-Methylpyrrolidin-2-yl)methoxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'- Preparation of pyridine[3,2-d]pyrimidine]-5-carbonitrile
化合物I-107的合成参考化合物I-5，通过使用(2S)-4-(5-氰基-2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H,6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体I-107-1)代替(2S)-2-(氰甲基)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5'，8'-四氢-2H，6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基]哌嗪-1-羧酸叔丁酯(中间体I-5/步骤2)，((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-107。Synthesis of compound 1-107 Reference compound 1-5 by using (2S)-4-(5-cyano-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidine-2- yl)methoxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine ]-4'-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate I-107-1) in place of (2S)-2-(cyanomethyl)-4-( 2'-(((S)-1-Methylpyrrolidin-2-yl)methoxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro Cyclo[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl]piperazine-1-carboxylate tert-butyl ester (Intermediate 1-5/Step 2), ((2S, 4R)-4-Fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate C3) in place of (S)-(1-methylpyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride ( Intermediate B1) was prepared in place of acryloyl chloride to give compound I-107.
化合物I-107(10毫克).MS:617.3(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.74–7.49(m,2H),7.44-7.29(m,1H),5.45–5.20(m,2H),5.19-5.05(m,1H),5.03-4.45(m,2H),4.32-4.20(m,1H),4.17-4.07(m,1H),4.05–3.74(m,2H),3.75–3.57(m,3H),3.47-3.43(m,2H),3.16–3.00(m,2H),2.99-2.91(m,2H),2.90-2.79(m,3H),2.42-2.32(m,3H),2.17–2.02(m,1H),1.97–1.64(m,5H)。 Compound 1-107 (10 mg). MS: 617.3 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ7.74-7.49(m,2H),7.44-7.29(m,1H),5.45-5.20(m,2H),5.19-5.05(m,1H),5.03 -4.45(m, 2H), 4.32-4.20(m, 1H), 4.17-4.07(m, 1H), 4.05-3.74(m, 2H), 3.75-3.57(m, 3H), 3.47-3.43(m, 2H), 3.16-3.00(m, 2H), 2.99-2.91(m, 2H), 2.90-2.79(m, 3H), 2.42-2.32(m, 3H), 2.17-2.02(m, 1H), 1.97- 1.64 (m, 5H).
实施例113Example 113
化合物I-108：2-((2S)-4-(5-环丙基-2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H,6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈Compound I-108: 2-((2S)-4-(5-cyclopropyl-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy )-6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4'- yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000448
Figure PCTCN2021138375-appb-000448
步骤1:(2S)-2-(氰甲基)-4-(5-环丙基-2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H,6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基]哌嗪-1-羧酸叔丁酯的制备(中间体I-108-1)Step 1: (2S)-2-(cyanomethyl)-4-(5-cyclopropyl-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl) Methoxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]- Preparation of 4'-yl]piperazine-1-carboxylate tert-butyl ester (Intermediate I-108-1)
将(2S)-4-(5-溴-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H,6'-H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体I-106-2,200毫克,0.147毫摩尔),Cs 2CO 3(144毫克,0.44毫摩尔),PdCl 2(dppf)(21.50毫克,0.029毫摩尔)和环丙基硼酸(76毫克,0.882毫摩尔)的DMF(5毫升)溶液在100℃搅拌缓反应1.5小时。然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色油状物(2S)-2-(氰甲基)-4-(5-环丙基-2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H,6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基]哌嗪-1-羧酸叔丁酯(200毫克,85％收率)。MS:638.0(M+H) +。 (2S)-4-(5-bromo-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6'-oxo-3,4,5', 8'-Tetrahydro-2H,6'-H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-2-(cyanomethyl)piperazine- tert-Butyl 1-carboxylate (Intermediate I-106-2, 200 mg, 0.147 mmol), Cs2CO3 ( 144 mg, 0.44 mmol), PdCl2 (dppf) (21.50 mg, 0.029 mmol) and cyclic A solution of propylboronic acid (76 mg, 0.882 mmol) in DMF (5 mL) was stirred slowly at 100 °C for 1.5 h. The reaction was then quenched by the addition of ice water, and the extraction was diluted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain (2S)-2-(cyanomethyl)-4-(5) as a yellow oil. -Cyclopropyl-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-6'-oxo-3,4,5',8 '-Tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl]piperazine-1-carboxylate tert-butyl ester (200 mg, 85% yield). MS: 638.0 (M+H) + .
步骤2:2-((2S)-4-(5-环丙基-2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H,6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈的制备Step 2: 2-((2S)-4-(5-cyclopropyl-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)- 6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl) - Preparation of 1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
化合物I-108的合成参考化合物I-5，通过使用(2S)-2-(氰甲基)-4-(5-环丙基-2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H,6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基]哌嗪-1-羧酸叔丁酯(中间体I-108-1)代替(2S)-2-(氰甲基)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5'，8'-四氢-2H，6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基]哌嗪-1-羧酸叔丁酯(中间体I-5/步骤2)，((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-108。Synthesis of compound 1-108 Reference compound 1-5 by using (2S)-2-(cyanomethyl)-4-(5-cyclopropyl-2'-(((2S,4R)-4-fluoro- 1-Methylpyrrolidin-2-yl)methoxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'- Pyridin[3,2-d]pyrimidin]-4'-yl]piperazine-1-carboxylate tert-butyl ester (Intermediate I-108-1) in place of (2S)-2-(cyanomethyl)-4- (2'-(((S)-1-Methylpyrrolidin-2-yl)methoxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'- Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl]piperazine-1-carboxylate tert-butyl ester (Intermediate 1-5/Step 2), ((2S , 4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (intermediate C3) in place of (S)-(1-methylpyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride (Intermediate B1) was prepared in place of acryloyl chloride to give compound I-108.
化合物I-108(30毫克)。MS:632.3(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.11-7.03(m,1H),7.03–6.84(m,2H),5.45-5.26(m,2H),5.22-5.08(m,1H),4.96-4.60(m,2H),4.28-4.22(m,1H),4.14-4.07(m,1H),3.71–3.55(m,5H),3.32(m,1H),3.11(m,1H),3.03-2.90(m,2H),2.89-2.69(m,4H),2.43-2.31(m,3H),2.16–1.98(m,2H),1.97-1.78(m,4H),1.77-1.61(m,2H),0.95–0.79(m,2H),0.66–0.48(m,2H)。 Compound 1-108 (30 mg). MS: 632.3 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 7.11-7.03 (m, 1H), 7.03-6.84 (m, 2H), 5.45-5.26 (m, 2H), 5.22-5.08 (m, 1H), 4.96 -4.60(m, 2H), 4.28-4.22(m, 1H), 4.14-4.07(m, 1H), 3.71-3.55(m, 5H), 3.32(m, 1H), 3.11(m, 1H), 3.03 -2.90(m, 2H), 2.89-2.69(m, 4H), 2.43-2.31(m, 3H), 2.16-1.98(m, 2H), 1.97-1.78(m, 4H), 1.77-1.61(m, 2H), 0.95–0.79 (m, 2H), 0.66–0.48 (m, 2H).
实施例114Example 114
化合物I-109a和化合物I-109b:2-((S)-4-((S)-5-氯-7-氟-2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H,6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈和2-((S)-4-((R)-5-氯-7-氟-2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H,6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-109a and Compound 1-109b: 2-((S)-4-((S)-5-chloro-7-fluoro-2'-(((2S,4R)-4-fluoro-1-methyl pyrrolidin-2-yl)methoxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridine[3 ,2-d]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile and 2-((S)-4-((R)-5-chloro- 7-Fluoro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-6'-oxo-3,4,5',8' -Tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl)piperazine-2- base) acetonitrile
Figure PCTCN2021138375-appb-000449
Figure PCTCN2021138375-appb-000449
化合物I-109a和化合物I-109b的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氯-7-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A36)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)，((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯，并经SFC手性拆分(柱型号：Dr.maish Reprosil Chiral-JM，250x25mm，10μm色谱柱，流动相：40％甲醇在二氧化碳中)制备得到化合物I-109a和化合物I-109b。Synthesis of Compound 1-109a and Compound 1-109b Reference compound 1-5, by using (2S)-4-(2-chloro-6-((5-chloro-7-fluoro-1-(methoxycarbonyl)- 1,2,3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (intermediate body A36) instead of (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitro pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3), ((2S,4R)-4-fluoro-1-methylpyrrolidine- 2-yl)methanol (intermediate C3) in place of (S)-(1-methylpyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride (intermediate B1) in place of acryloyl chloride and chiral resolved by SFC (Column type: Dr.maish Reprosil Chiral-JM, 250×25 mm, 10 μm chromatographic column, mobile phase: 40% methanol in carbon dioxide) to prepare compound I-109a and compound I-109b.
化合物I-109a(保留时间4.903分钟,36毫克)。MS:644.3(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.17(dd,J＝8.2,2.5Hz,1H),7.06(dd,J＝10.0,2.6Hz,1H),5.61–5.19(m,4H),4.85–4.48(m,4H),4.43–3.83(m,4H),3.80–3.33(m,3H),3.23–2.95(m,7H),2.89–2.58(m,3H),2.01(q,J＝7.7Hz,1H),1.87(d,J＝7.6Hz,4H)。 Compound I-109a (retention time 4.903 min, 36 mg). MS: 644.3 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.17(dd,J=8.2,2.5Hz,1H),7.06(dd,J=10.0,2.6Hz,1H),5.61-5.19(m,4H), 4.85–4.48 (m, 4H), 4.43–3.83 (m, 4H), 3.80–3.33 (m, 3H), 3.23–2.95 (m, 7H), 2.89–2.58 (m, 3H), 2.01 (q, J) = 7.7 Hz, 1H), 1.87 (d, J = 7.6 Hz, 4H).
化合物I-109b(保留时间5.508分钟,38毫克)。MS:644.3(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.17(dd,J＝8.2,2.5Hz,1H),7.10(dd,J＝10.0,2.6Hz,1H),5.43–5.19(m,3H),5.17–4.92(m,2H),4.47–4.34(m,2H),3.94–3.84(m,2H),3.66–3.35(m,4H),3.10–3.07(m,1H),3.05–2.57(m,6H),2.53(s,3H),2.26–2.19(m,1H),2.12–1.73(m,6H)。 Compound 1-109b (retention time 5.508 min, 38 mg). MS: 644.3 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.17(dd,J=8.2,2.5Hz,1H),7.10(dd,J=10.0,2.6Hz,1H),5.43-5.19(m,3H), 5.17–4.92 (m, 2H), 4.47–4.34 (m, 2H), 3.94–3.84 (m, 2H), 3.66–3.35 (m, 4H), 3.10–3.07 (m, 1H), 3.05–2.57 (m , 6H), 2.53 (s, 3H), 2.26–2.19 (m, 1H), 2.12–1.73 (m, 6H).
实施例115Example 115
化合物I-110:2-((2S)-4-(2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-4,4-二甲基-6'-氧代-3,4,5',8'-四氢-2H,6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈Compound I-110: 2-((2S)-4-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4,4- Dimethyl-6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4 '-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000450
Figure PCTCN2021138375-appb-000450
化合物I-110的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((1-(甲氧羰基)-4,4-二甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A52)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)，((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-110。Synthesis of compound 1-110 Reference compound 1-5 by using (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-4,4-dimethyl-1,2,3 ,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A52) instead of ( 2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4- yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3), ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate C3) in place of (S)-(1-methylpyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride were prepared to give compound 1-110.
化合物I-110(43毫克)。MS:620.1(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.43(d,J＝7.8Hz,1H),7.28–7.10(m,3H),5.60–5.22(m,3H),4.86–4.74(m,3H),4.59–4.49(m,1H),4.37–4.18(m,2H),3.97–3.87(m,2H),3.54–3.42(m,3H),3.22–2.83(m,7H),2.77–2.54(m,1H),2.38(m,1H),2.26–2.02(m,1H),1.98–1.63(m,4H),1.32–1.22(m,6H)。 Compound 1-110 (43 mg). MS: 620.1 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.43(d,J=7.8Hz,1H),7.28-7.10(m,3H),5.60-5.22(m,3H),4.86-4.74(m,3H) ), 4.59–4.49 (m, 1H), 4.37–4.18 (m, 2H), 3.97–3.87 (m, 2H), 3.54–3.42 (m, 3H), 3.22–2.83 (m, 7H), 2.77–2.54 (m, 1H), 2.38 (m, 1H), 2.26–2.02 (m, 1H), 1.98–1.63 (m, 4H), 1.32–1.22 (m, 6H).
实施例116Example 116
化合物I-111：2-((2S)-4-(4-氯-2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-2,3,5',8'-四氢-6'H-螺环[茚-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈Compound 1-111: 2-((2S)-4-(4-chloro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)- 6'-oxo-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)- 1-(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000451
Figure PCTCN2021138375-appb-000451
化合物I-111的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((4-氯-1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A49)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)，((2S，4R)-4-氟-1-甲基 吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-111。Synthesis of compound 1-111 Reference compound 1-5 by using (2S)-4-(2-chloro-6-((4-chloro-1-(methoxycarbonyl)-2,3-dihydro-1H- Inden-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A49) instead of (2S)-4- (2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2- (Cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3), ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate C3) Substitution of (S)-(1-methylpyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride gave compound 1-111.
化合物I-111(49毫克)。MS:612.4(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.31–7.18(m,2H),7.18–6.90(m,2H),5.61–5.19(m,4H),4.87–4.73(m,2H),4.59(m,1H),4.35–3.91(m,5H),3.51–3.34(m,2H),3.26–2.91(m,8H),2.82–2.58(m,2H),2.56–2.29(m,2H),2.12(m,1H)。 Compound 1-111 (49 mg). MS: 612.4 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ7.31-7.18(m,2H),7.18-6.90(m,2H),5.61-5.19(m,4H),4.87-4.73(m,2H),4.59 (m, 1H), 4.35–3.91 (m, 5H), 3.51–3.34 (m, 2H), 3.26–2.91 (m, 8H), 2.82–2.58 (m, 2H), 2.56–2.29 (m, 2H) , 2.12 (m, 1H).
化合物I-111a和化合物I-111bCompound I-111a and Compound I-111b
2-((S)-4-((S)-4-氯-2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-2,3,5',8'-四氢-6'H-螺环[茚-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈和2-((S)-4-((R)-4-氯-2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-2,3,5',8'-四氢-6'H-螺环[茚-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈2-((S)-4-((S)-4-Chloro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-6 '-Oxo-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1 -(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile and 2-((S)-4-((R)-4-chloro-2'-(((2S,4R)-4-fluoro- 1-Methylpyrrolidin-2-yl)methoxy)-6'-oxo-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-pyridine [3,2-d]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000452
Figure PCTCN2021138375-appb-000452
将2-((2S)-4-(4-氯-2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-2,3,5',8'-四氢-6'H-螺环[茚-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈(50毫克)经SFC手性拆分(CHIRALART Cellulose SB,2cm×25cm,5um column,流动相A:MtBE(0.5％2mM NH3-MEOH),流动相B:MeOH:DCM＝1:1)得到均为白色固体的第一个组分峰化合物I-111a(保留时间为2.174分钟,13毫克)和第二个组分峰化合物I-111b(保留时间为2.95分钟,20毫克)。2-((2S)-4-(4-chloro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy Substituted-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1-(2 -Fluoroacryloyl)piperazin-2-yl)acetonitrile (50 mg) was chiral resolved by SFC (CHIRALART Cellulose SB, 2cm × 25cm, 5um column, mobile phase A: MtBE (0.5% 2mM NH3-MEOH), mobile phase Phase B:MeOH:DCM=1:1) gave the first component peak Compound I-111a (retention time 2.174 min, 13 mg) and the second component peak Compound I-111b (retention time 2.174 min) both as white solids time of 2.95 minutes, 20 mg).
化合物I-111a(保留时间为2.174分钟,13毫克):MS:612.4(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.31–7.18(m,2H),7.18–6.90(m,2H),5.61–5.19(m,4H),4.87–4.73(m,2H),4.59(m,1H),4.35–3.91(m,5H),3.51–3.34(m,2H),3.26–2.91(m,8H),2.82–2.58(m,2H),2.56–2.29(m,2H),2.12(m,1H)。 Compound 1-111a (retention time 2.174 min, 13 mg): MS: 612.4 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ7.31-7.18(m,2H),7.18-6.90(m,2H),5.61-5.19(m,4H),4.87-4.73(m,2H),4.59 (m, 1H), 4.35–3.91 (m, 5H), 3.51–3.34 (m, 2H), 3.26–2.91 (m, 8H), 2.82–2.58 (m, 2H), 2.56–2.29 (m, 2H) , 2.12 (m, 1H).
化合物I-111b(保留时间为2.95分钟,20毫克):MS:612.4(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.31–7.18(m,2H),7.18–6.90(m,2H),5.61–5.19(m,4H),4.87–4.73 (m,2H),4.59(m,1H),4.35–3.91(m,5H),3.51–3.34(m,2H),3.26–2.91(m,8H),2.82–2.58(m,2H),2.56–2.29(m,2H),2.12(m,1H)。 Compound 1-111b (retention time 2.95 min, 20 mg): MS: 612.4 (M+H) + . 1 H NMR(400MHz, Methanol-d 4 )δ7.31-7.18(m,2H),7.18-6.90(m,2H),5.61-5.19(m,4H),4.87-4.73(m,2H),4.59 (m, 1H), 4.35–3.91 (m, 5H), 3.51–3.34 (m, 2H), 3.26–2.91 (m, 8H), 2.82–2.58 (m, 2H), 2.56–2.29 (m, 2H) , 2.12 (m, 1H).
实施例117Example 117
化合物I-112：2-((2S)-4-(5-氯-2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H,6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈Compound 1-112: 2-((2S)-4-(5-chloro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)- 6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl) -1-(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000453
Figure PCTCN2021138375-appb-000453
化合物I-112的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氯-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A22)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)，((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-112。Synthesis of compound 1-112 Reference compound 1-5 by using (2S)-4-(2-chloro-6-((5-chloro-1-(methoxycarbonyl)-1,2,3,4-tetrakis) Hydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A22) instead of (2S)-4 -(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2 -(Cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3), ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate C3 ) in place of (S)-(1-methylpyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride to prepare compound I-112.
化合物I-112(79毫克)。MS:626.4(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.96–9.93(m,1H),7.38–7.13(m,3H),5.58–5.13(m,4H),4.68–4.44(m,4H),4.14–3.38(m,6H),3.26–2.62(m,10H),2.32–1.91(m,2H),1.91–1.60(m,4H)。 Compound 1-112 (79 mg). MS: 626.4 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.96-9.93(m,1H),7.38-7.13(m,3H),5.58-5.13(m,4H),4.68-4.44(m,4H),4.14 – 3.38 (m, 6H), 3.26 – 2.62 (m, 10H), 2.32 – 1.91 (m, 2H), 1.91 – 1.60 (m, 4H).
化合物I-112a和化合物I-112bCompound I-112a and Compound I-112b
2-((S)-4-((R)-5-氯-2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H,6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈和2-((S)-4-((S)-5-氯-2'-((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H,6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈2-((S)-4-((R)-5-Chloro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-6 '-Oxo-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)- 1-(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile and 2-((S)-4-((S)-5-chloro-2'-((2S,4R)-4-fluoro- 1-Methylpyrrolidin-2-yl)methoxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'- Pyridin[3,2-d]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000454
Figure PCTCN2021138375-appb-000454
将2-((2S)-4-(5-氯-2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H,6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈(90毫克)经SFC手性拆分(CHIRALPAK IE,2cm×25cm,5um column,流动相A:MtBE(0.5％2mM NH 3-MEOH),流动相B:MeOH:DCM＝1:1)得到均为白色固体的第一个组分峰化合物I-112a(保留时间为1.986分钟,30毫克)和第二个组分峰化合物I-112b(保留时间为2.919分钟,25毫克)。 2-((2S)-4-(5-Chloro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-6'-oxy Substituted-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1-( 2-Fluoroacryloyl)piperazin-2-yl)acetonitrile (90 mg) was chiral resolved by SFC (CHIRALPAK IE, 2cm×25cm, 5um column, mobile phase A: MtBE (0.5% 2mM NH 3 -MEOH), Mobile phase B:MeOH:DCM=1:1) to obtain the first component peak Compound I-112a (retention time is 1.986 minutes, 30 mg) and the second component peak Compound I-112b ( Retention time 2.919 min, 25 mg).
化合物I-112a(保留时间为1.986分钟,30毫克):MS:626.4(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.96–9.93(m,1H),7.38–7.13(m,3H),5.58–5.13(m,4H),4.68–4.44(m,4H),4.14–3.38(m,6H),3.26–2.62(m,10H),2.32–1.91(m,2H),1.91–1.60(m,4H)。 Compound 1-112a (retention time 1.986 min, 30 mg): MS: 626.4 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.96-9.93(m,1H),7.38-7.13(m,3H),5.58-5.13(m,4H),4.68-4.44(m,4H),4.14 – 3.38 (m, 6H), 3.26 – 2.62 (m, 10H), 2.32 – 1.91 (m, 2H), 1.91 – 1.60 (m, 4H).
化合物I-112b(保留时间为2.919分钟,25毫克):MS:626.4(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.96–9.93(m,1H),7.38–7.13(m,3H),5.58–5.13(m,4H),4.68–4.44(m,4H),4.14–3.38(m,6H),3.26–2.62(m,10H),2.32–1.91(m,2H),1.91–1.60(m,4H)。 Compound 1-112b (retention time 2.919 min, 25 mg): MS: 626.4 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.96-9.93(m,1H),7.38-7.13(m,3H),5.58-5.13(m,4H),4.68-4.44(m,4H),4.14 – 3.38 (m, 6H), 3.26 – 2.62 (m, 10H), 2.32 – 1.91 (m, 2H), 1.91 – 1.60 (m, 4H).
实施例118Example 118
化合物I-113：2-((2S)-4-(6-氟-2'-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-5-甲基-6'-氧代-3,4,5',8'-四氢-2H,6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈Compound 1-113: 2-((2S)-4-(6-fluoro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)- 5-Methyl-6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]- 4'-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000455
Figure PCTCN2021138375-appb-000455
化合物I-113的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((6-氟-1-(甲氧羰基)-5-甲基-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A48)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)，((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-113。Synthesis of compound 1-113 Reference compound 1-5, by using (2S)-4-(2-chloro-6-((6-fluoro-1-(methoxycarbonyl)-5-methyl-1,2, 3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A48) instead (2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4 -yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3), ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl) Methanol (Intermediate C3) in place of (S)-(1-methylpyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride were prepared to give compound 1-113.
化合物I-113(72毫克)。MS:624.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.20–6.86(m,2H),5.57–5.12(m,3H),5.05-4.75(m,1H),4.67–4.45(m,2H),4.13-3.76(m,8H),3.63–3.34(m,5H),3.13–3.09(m,1H),3.04–2.79(m,5H),2.70-2.59(m,2H),2.13-2.06(m,3H),1.86–1.59(m,3H)。 Compound 1-113 (72 mg). MS: 624.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ7.20-6.86(m,2H),5.57-5.12(m,3H),5.05-4.75(m,1H),4.67-4.45(m,2H),4.13 -3.76(m, 8H), 3.63-3.34(m, 5H), 3.13-3.09(m, 1H), 3.04-2.79(m, 5H), 2.70-2.59(m, 2H), 2.13-2.06(m, 3H), 1.86–1.59 (m, 3H).
实施例119Example 119
化合物I-114:2-((2S)-4-(5-氯-2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-5',8'-二氢-6'H-螺环[异色烷-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈Compound 1-114: 2-((2S)-4-(5-chloro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)- 6'-oxo-5',8'-dihydro-6'H-spiro[isochroman-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1- (2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000456
Figure PCTCN2021138375-appb-000456
化合物I-114的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氯-1-(甲氧羰基)异色-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A53)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)，((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-114。Synthesis of compound 1-114 Reference compound 1-5 by using (2S)-4-(2-chloro-6-((5-chloro-1-(methoxycarbonyl)isochrom-1-yl)methyl) -5-Nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A53) in place of (2S)-4-(2-chloro-6-(( 1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine- 1-Carboxylic acid tert-butyl ester (Intermediate A3), ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate C3) instead of (S)-(1-methyl) pyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride (Intermediate B1) instead of acryloyl chloride were prepared to give compound 1-114.
化合物I-114(7毫克)。MS:628.1(M+H) +。 Compound 1-114 (7 mg). MS: 628.1 (M+H) + .
实施例120Example 120
化合物I-115a和化合物I-115b:2-((S)-4-((S)-5-氯-2'-(((S)-4,4-二氟-1-甲基吡咯烷-2-基)甲氧基)-7-氟-6'-氧代-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈和2-((S)-4-((R)-5-氯-2'-(((S)-4,4-二氟-1-甲基吡咯烷-2-基)甲氧基)-7-氟-6'-氧代-3,4,5',8'-四氢-2H,6'H-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-115a and Compound 1-115b: 2-((S)-4-((S)-5-chloro-2'-(((S)-4,4-difluoro-1-methylpyrrolidine -2-yl)methoxy)-7-fluoro-6'-oxo-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridine [3,2-d]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile and 2-((S)-4-((R)-5- Chloro-2'-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-fluoro-6'-oxo-3,4,5' ,8'-Tetrahydro-2H,6'H-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl)piperidine oxazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000457
Figure PCTCN2021138375-appb-000457
化合物I-115a和化合物I-115b的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氯-7-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A36)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)，(S)-(4,4-二氟-1-甲基吡咯烷-2-基)甲醇(中间体C6)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯，并经SFC手性拆分(柱型号：Dr.maish Reprosil Chiral-JM，250x25mm，10μm色谱柱，流动相：40％甲醇在二氧化碳中)制备得到化合物I-115a和化合物I-115b。Synthesis of Compound 1-115a and Compound 1-115b Reference compound 1-5, by using (2S)-4-(2-chloro-6-((5-chloro-7-fluoro-1-(methoxycarbonyl)- 1,2,3,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (intermediate body A36) instead of (2S)-4-(2-chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitro pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3), (S)-(4,4-difluoro-1-methylpyrrolidine -2-yl)methanol (intermediate C6) in place of (S)-(1-methylpyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride (intermediate B1) in place of acryloyl chloride and chiral by SFC Resolution (column type: Dr.maish Reprosil Chiral-JM, 250x25mm, 10μm column, mobile phase: 40% methanol in carbon dioxide) prepared compound I-115a and compound I-115b.
化合物I-115a(保留时间5.137分钟,6毫克)。MS:622.3(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.79(s,1H),7.35(dd,J＝8.5,2.5Hz,1H),7.17(dd,J＝10.2,2.6Hz,1H),5.38–5.31(m,1H),5.25–5.19(m,1H),4.82(s,2H),4.45–4.34(m,2H),3.87–3.74(m,2H),3.66–363(m,2H),3.60-3.54(m,5H),3.13–3.04(m,1H),3.01–2.97(m,2H),2.91–2.89(m,1H),2.84–2.59(m,6H),1.94–1.66(m,4H)。 Compound I-115a (retention time 5.137 min, 6 mg). MS: 622.3 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.79 (s, 1H), 7.35 (dd, J=8.5, 2.5Hz, 1H), 7.17 (dd, J=10.2, 2.6Hz, 1H), 5.38– 5.31 (m, 1H), 5.25–5.19 (m, 1H), 4.82 (s, 2H), 4.45–4.34 (m, 2H), 3.87–3.74 (m, 2H), 3.66–363 (m, 2H), 3.60-3.54(m,5H), 3.13-3.04(m,1H), 3.01-2.97(m,2H), 2.91-2.89(m,1H), 2.84-2.59(m,6H), 1.94-1.66(m , 4H).
化合物I-115b(保留时间5.37分钟,2毫克)。MS:622.3(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.79(s,1H),7.35(dd,J＝8.5,2.5Hz,1H),7.17(dd,J＝10.2,2.6Hz,1H),5.38–5.31(m,1H),5.25–5.19(m,1H),4.82(s,2H),4.45–4.34(m,2H),3.87–3.74(m,2H),3.66–363(m,2H),3.60-3.54(m,5H),3.13–3.04(m,1H),3.01–2.97(m,2H),2.91–2.89(m,1H),2.84–2.59(m,6H),1.94–1.66(m,4H)。 Compound 1-115b (retention time 5.37 min, 2 mg). MS: 622.3 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.79 (s, 1H), 7.35 (dd, J=8.5, 2.5Hz, 1H), 7.17 (dd, J=10.2, 2.6Hz, 1H), 5.38– 5.31 (m, 1H), 5.25–5.19 (m, 1H), 4.82 (s, 2H), 4.45–4.34 (m, 2H), 3.87–3.74 (m, 2H), 3.66–363 (m, 2H), 3.60-3.54(m,5H), 3.13-3.04(m,1H), 3.01-2.97(m,2H), 2.91-2.89(m,1H), 2.84-2.59(m,6H), 1.94-1.66(m , 4H).
实施例121Example 121
化合物I-116:2-((2S)-4-(5-氯-7-氟-2’-(((2S,4R,5S)-4-氟-1,5-二甲基吡咯烷-2-基)甲氧基)-6’-氧代-3,4,5’，8’-四氢-2H，6’-螺环[萘-1,7’-吡啶[3,2-d]嘧啶]-4’-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-116: 2-((2S)-4-(5-chloro-7-fluoro-2'-(((2S,4R,5S)-4-fluoro-1,5-dimethylpyrrolidine- 2-yl)methoxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridine[3,2-d ]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000458
Figure PCTCN2021138375-appb-000458
化合物I-116的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氯-7-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A36)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)，((2S,4R,5S)-4-氟-1,5-二甲基吡咯烷-2-基)甲醇(中间体C7)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-116。Synthesis of compound 1-116 Reference compound 1-5 by using (2S)-4-(2-chloro-6-((5-chloro-7-fluoro-1-(methoxycarbonyl)-1,2,3 ,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A36) instead of ( 2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4- yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3), ((2S,4R,5S)-4-fluoro-1,5-dimethylpyrrolidine- 2-yl)methanol (intermediate C7) in place of (S)-(1-methylpyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride (intermediate B1) in place of acryloyl chloride were prepared to give compound 1-116.
化合物I-116(3.6毫克)。MS:658.3(M+H) +。 Compound 1-116 (3.6 mg). MS: 658.3 (M+H) + .
实施例122Example 122
化合物I-117:2-((2S)-4-(4-氯-6-氟-2'-((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-2,3,5',8'-四氢-6'H-螺环[茚-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈Compound 1-117: 2-((2S)-4-(4-chloro-6-fluoro-2'-((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy base)-6'-oxo-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-pyridine[3,2-d]pyrimidine]-4'- yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000459
Figure PCTCN2021138375-appb-000459
化合物I-117的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((4-氯-6-氟-1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁 酯(中间体A54)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)，((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-117。Synthesis of compound 1-117 Reference compound 1-5 by using (2S)-4-(2-chloro-6-((4-chloro-6-fluoro-1-(methoxycarbonyl)-2,3-di) Hydrogen-1H-inden-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A54) in place of (2S )-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl )-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3), ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol ( Intermediate C3) in place of (S)-(1-methylpyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride (intermediate B1) in place of acryloyl chloride were prepared to give compound 1-117.
化合物I-117(76毫克)。MS:630.2(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ10.02(s,1H),7.33(d,J＝8.9Hz,1H),7.24(dd,J＝8.8,2.3Hz,1H),5.54–5.28(m,3H),4.66–4.43(m,4H),4.17–3.72(m,7H),3.52–4.38(m,2H),3.27–3.10(m,2H),3.00(s,3H),2.98–2.93(m,2H),2.83–2.78(m,2H),2.73–2.68(m,1H),2.32–2.22(m,1H),2.10–1.98(m,1H)。 Compound 1-117 (76 mg). MS: 630.2 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 10.02 (s, 1H), 7.33 (d, J=8.9Hz, 1H), 7.24 (dd, J=8.8, 2.3Hz, 1H), 5.54-5.28 ( m, 3H), 4.66–4.43 (m, 4H), 4.17–3.72 (m, 7H), 3.52–4.38 (m, 2H), 3.27–3.10 (m, 2H), 3.00 (s, 3H), 2.98– 2.93 (m, 2H), 2.83–2.78 (m, 2H), 2.73–2.68 (m, 1H), 2.32–2.22 (m, 1H), 2.10–1.98 (m, 1H).
实施例123Example 123
化合物I-118:2-((2S)-4-(5-氯-7-氟-2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-5'，8'-二氢-6'H-螺环[异色烷-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈Compound I-118: 2-((2S)-4-(5-chloro-7-fluoro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methan oxy)-6'-oxo-5',8'-dihydro-6'H-spiro[isochroman-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl )-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000460
Figure PCTCN2021138375-appb-000460
化合物I-118的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氯-1-(乙氧羰基)-7-氟异色胺-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A55)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)，((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-118。Synthesis of compound 1-118 Reference compound 1-5 by using (2S)-4-(2-chloro-6-((5-chloro-1-(ethoxycarbonyl)-7-fluoroisotryptamine-1- (2S)-4-(2-chloro)-methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate -6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl) yl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3), ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate C3) instead of (S) -(1-Methylpyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride (Intermediate B1) instead of acryloyl chloride were prepared to give compound 1-118.
化合物I-118(22毫克)。MS:646.3(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.46(dd,J＝8.5,2.5Hz,1H),7.36(dt,J＝9.8,2.6Hz,1H),5.57–5.15(m,4H),4.61–4.43(m,2H),4.06–3.68(m,7H),3.66-3.53(m,2H),3.18–3.05(m,2H),3.05–2.89(m,5H),2.83–2.59(m,4H),2.21-2.01(m,2H)。 Compound 1-118 (22 mg). MS: 646.3 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 7.46 (dd, J=8.5, 2.5Hz, 1H), 7.36 (dt, J=9.8, 2.6Hz, 1H), 5.57-5.15 (m, 4H), 4.61–4.43(m,2H), 4.06–3.68(m,7H), 3.66-3.53(m,2H), 3.18–3.05(m,2H), 3.05–2.89(m,5H), 2.83–2.59(m , 4H), 2.21-2.01 (m, 2H).
实施例124Example 124
化合物I-119:2-((2S)-4-(5-氯-7-氟-2'-((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-5',8'-二氢-6'H-螺环[异色烷-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈Compound 1-119: 2-((2S)-4-(5-chloro-7-fluoro-2'-((S)-1-methylpyrrolidin-2-yl)methoxy)-6'- Oxo-5',8'-dihydro-6'H-spiro[isochroman-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1-(2- Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000461
Figure PCTCN2021138375-appb-000461
化合物I-119的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氯-1-(乙氧羰基)-7-氟异色胺-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A55)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-119。Synthesis of compound 1-119 Reference compound 1-5 by using (2S)-4-(2-chloro-6-((5-chloro-1-(ethoxycarbonyl)-7-fluoroisotryptamine-1- (2S)-4-(2-chloro)-methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate -6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl) yl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride to prepare compound 1-119.
化合物I-119(12毫克)。MS:628.4(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.45(dd,J＝8.8,2.4Hz,1H),7.35(d,J＝10.1Hz,1H),5.41–5.24(m,2H),5.17-4.92(m,2H),4.55–4.49(m,1H),4.41-4.17(m,1H),3.96-3.87(m,2H),3.72-3.67(m,3H),3.62-3.47(m,4H),3.15-3.05(m,2H),3.01–2.87(m,4H),2.74–2.58(m,3H),2.26–2.16(m,1H),2.08–1.75(m,4H)。 Compound 1-119 (12 mg). MS: 628.4 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.45 (dd, J=8.8, 2.4 Hz, 1H), 7.35 (d, J=10.1 Hz, 1H), 5.41-5.24 (m, 2H), 5.17- 4.92(m, 2H), 4.55-4.49(m, 1H), 4.41-4.17(m, 1H), 3.96-3.87(m, 2H), 3.72-3.67(m, 3H), 3.62-3.47(m, 4H ), 3.15–3.05 (m, 2H), 3.01–2.87 (m, 4H), 2.74–2.58 (m, 3H), 2.26–2.16 (m, 1H), 2.08–1.75 (m, 4H).
实施例125Example 125
化合物I-120:2-((2S)-4-(5-氯-8-氟-2'-((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-5',8'-二氢-6'H-螺环[异色烷-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈Compound I-120: 2-((2S)-4-(5-chloro-8-fluoro-2'-((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy base)-6'-oxo-5',8'-dihydro-6'H-spiro[isochroman-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl) -1-(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000462
Figure PCTCN2021138375-appb-000462
化合物I-120的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氯-1-(乙氧羰基)-8-氟异色胺-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A56)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3),((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-120。Synthesis of compound 1-120 Reference compound 1-5 by using (2S)-4-(2-chloro-6-((5-chloro-1-(ethoxycarbonyl)-8-fluoroisotryptamine-1- (2S)-4-(2-chloro)-methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate -6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl) yl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3), ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate C3) instead of (S) -(1-Methylpyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride (Intermediate B1) instead of acryloyl chloride were prepared to give compound 1-120.
化合物I-120(62毫克)。MS:646.3(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.48(dd,J＝8.9,4.7Hz,1H),7.08(td,J＝9.5,8.6,1H),5.60–5.17(m,3H),4.90–4.79(m,2H),4.64–4.58(m,1H),4.45–4.16(m,2H),4.11–4.05(mz,3H),3.93–3.79(m,4H),3.76–3.37(m,3H),3.21–3.08(m,5H),3.01–2.77(m,3H),2.70–2.65(m,1H),2.46–2.38(m,1H)。 Compound 1-120 (62 mg). MS: 646.3 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.48(dd,J=8.9,4.7Hz,1H),7.08(td,J=9.5,8.6,1H),5.60-5.17(m,3H),4.90 –4.79(m,2H), 4.64–4.58(m,1H), 4.45–4.16(m,2H), 4.11–4.05(mz,3H), 3.93–3.79(m,4H), 3.76–3.37(m, 3H), 3.21–3.08 (m, 5H), 3.01–2.77 (m, 3H), 2.70–2.65 (m, 1H), 2.46–2.38 (m, 1H).
化合物I-120a和化合物I-120bCompound I-120a and Compound I-120b
2-((S)-4-((S)-5-氯-8-氟-2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-5',8'-二氢-6'H-螺环[异色烷-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈和2-((S)-4-(((R)-5-氯-8-氟-2'-((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-5',8'-二氢-6'H-螺环[异色烷-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈2-((S)-4-((S)-5-Chloro-8-fluoro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy base)-6'-oxo-5',8'-dihydro-6'H-spiro[isochroman-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl) -1-(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile and 2-((S)-4-(((R)-5-chloro-8-fluoro-2'-((2S,4R )-4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)-6'-oxo-5',8'-dihydro-6'H-spiro[isochroman-1, 7'-Pyridin[3,2-d]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000463
Figure PCTCN2021138375-appb-000463
将2-((2S)-4-(5-氯-8-氟-2'-((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-5',8'-二氢-6'H-螺环[异色烷-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈(50毫克)经SFC手性拆分(CHIRALPAK IF,2cm×25cm,5um column,流动相A:MTBE,流动相B:MeOH:DCM＝1:1)得到均为白色固体的第一个组分峰化合物I-120a(保留时间为0.928分钟,16毫克)和第二个组分峰化合物I-120b(保留时间为1.411分钟,20毫克)。2-((2S)-4-(5-Chloro-8-fluoro-2'-((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-6 '-Oxo-5',8'-dihydro-6'H-spiro[isochroman-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1-( 2-Fluoroacryloyl)piperazin-2-yl)acetonitrile (50 mg) was chiral resolved by SFC (CHIRALPAK IF, 2cm×25cm, 5um column, mobile phase A:MTBE, mobile phase B:MeOH:DCM=1 : 1) Obtain the first component peak compound I-120a (retention time is 0.928 minutes, 16 mg) and the second component peak compound I-120b (retention time is 1.411 minutes, 20 mg) as white solids .
化合物I-120a(保留时间为0.928分钟,16毫克)。MS:646.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.48(dd,J＝8.9,4.7Hz,1H),7.08(td,J＝9.5,8.6,1H),5.60–5.17(m, 3H),4.90–4.79(m,2H),4.64–4.58(m,1H),4.45–4.16(m,2H),4.11–4.05(mz,3H),3.93–3.79(m,4H),3.76–3.37(m,3H),3.21–3.08(m,5H),3.01–2.77(m,3H),2.70–2.65(m,1H),2.46–2.38(m,1H)。 Compound 1-120a (retention time 0.928 min, 16 mg). MS: 646.2 (M+H) + . 1 H NMR (400MHz, Methanol-d 4 ) δ 7.48 (dd, J=8.9, 4.7 Hz, 1H), 7.08 (td, J=9.5, 8.6, 1H), 5.60-5.17 (m, 3H), 4.90 –4.79(m,2H), 4.64–4.58(m,1H), 4.45–4.16(m,2H), 4.11–4.05(mz,3H), 3.93–3.79(m,4H), 3.76–3.37(m, 3H), 3.21–3.08 (m, 5H), 3.01–2.77 (m, 3H), 2.70–2.65 (m, 1H), 2.46–2.38 (m, 1H).
化合物I-120b(保留时间为1.411分钟,20毫克)。MS:646.2(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.48(dd,J＝8.9,4.7Hz,1H),7.08(td,J＝9.5,8.6,1H),5.60–5.17(m,3H),4.90–4.79(m,2H),4.64–4.58(m,1H),4.45–4.16(m,2H),4.11–4.05(mz,3H),3.93–3.79(m,4H),3.76–3.37(m,3H),3.21–3.08(m,5H),3.01–2.77(m,3H),2.70–2.65(m,1H),2.46–2.38(m,1H)。 Compound 1-120b (retention time 1.411 min, 20 mg). MS: 646.2 (M+H) + . 1 H NMR(400MHz,Methanol-d 4 )δ7.48(dd,J=8.9,4.7Hz,1H),7.08(td,J=9.5,8.6,1H),5.60-5.17(m,3H),4.90 –4.79(m,2H), 4.64–4.58(m,1H), 4.45–4.16(m,2H), 4.11–4.05(mz,3H), 3.93–3.79(m,4H), 3.76–3.37(m, 3H), 3.21–3.08 (m, 5H), 3.01–2.77 (m, 3H), 2.70–2.65 (m, 1H), 2.46–2.38 (m, 1H).
实施例126Example 126
化合物I-121:2-((2S)-4-(5-氯-8-氟-2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H，6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound I-121: 2-((2S)-4-(5-chloro-8-fluoro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methan oxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4 '-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000464
Figure PCTCN2021138375-appb-000464
步骤1:(2S)-4-(5-((叔丁氧羰基)氨基)-6-((5-氯-8-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(甲亚砜基)嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯的制备Step 1: (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-(methylsulfoxide)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate
将(2S)-4-(5-((叔丁氧羰基)氨基)-6-((5-氯-8-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(甲硫基)嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A58,220毫克,0.306毫摩尔)溶于DCM(5毫升)中,在0℃时搅拌缓慢加入mCPBA(63.3毫克,0.367毫摩尔)。滴加完后，将反应混合物在20℃搅拌搅拌反应2小时。然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-4-(5-((叔丁氧羰基)氨基)-6-((5-氯-8-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(甲亚砜基)嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(225毫克,98％)。MS:735.4(M+H) +。 (2S)-4-(5-((tert-butoxycarbonyl)amino)-6-((5-chloro-8-fluoro-1-(methoxycarbonyl)-1,2,3,4-tetrahydro Naphthalen-1-yl)methyl)-2-(methylthio)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A58, 220 mg, 0.306 mmol) was dissolved in DCM (5 mL) and mCPBA (63.3 mg, 0.367 mmol) was added slowly with stirring at 0 °C. After the dropwise addition, the reaction mixture was stirred and reacted at 20°C for 2 hours. The reaction was then quenched by the addition of ice water, and the extraction was diluted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain (2S)-4-(5-((tert-butoxycarbonyl)amino) as a yellow solid )-6-((5-Chloro-8-fluoro-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-2-(methylsulfoxide) Pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (225 mg, 98%). MS: 735.4 (M+H) + .
步骤2:(2S)-4-(5-((叔丁氧羰基)氨基)-6-((5-氯-8-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯的制备Step 2: (2S)-4-(5-((tert-butoxycarbonyl)amino)-6-((5-chloro-8-fluoro-1-(methoxycarbonyl)-1,2,3,4- Tetrahydronaphthalen-1-yl)methyl)-2-((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2-( Preparation of cyanomethyl)piperazine-1-carboxylate tert-butyl ester
将(2S)-4-(5-((叔丁氧羰基)氨基)-6-((5-氯-8-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-(甲亚砜基)嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(220毫克,0.299毫摩尔)溶于无水四氢呋喃(5毫升)中，在25℃时搅拌缓慢加入碳酸铯(146毫克,0.449毫摩尔)和((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(80毫克,0.598毫摩尔)。滴完后，将反应混合物缓慢升至60℃并搅拌12小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体(2S)-4-(5-((叔丁氧羰基)氨基)-6-((5-氯-8-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(150毫克,62.3％)。MS:804.4(M+H) +。 (2S)-4-(5-((tert-butoxycarbonyl)amino)-6-((5-chloro-8-fluoro-1-(methoxycarbonyl)-1,2,3,4-tetrahydro Naphthalen-1-yl)methyl)-2-(methylsulfoxide)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (220 mg, 0.299 mmol) Dissolved in anhydrous tetrahydrofuran (5 mL), cesium carbonate (146 mg, 0.449 mmol) and ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl were slowly added with stirring at 25°C ) methanol (80 mg, 0.598 mmol). After dropping, the reaction mixture was slowly raised to 60°C and stirred for 12 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain (2S)-4-(5-((tert-butoxycarbonyl)amino) as a yellow solid )-6-((5-Chloro-8-fluoro-1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-2-((2S,4R) -4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (150 mg, 62.3% ). MS: 804.4 (M+H) + .
步骤3:2-((2S)-4-(5-氯-8-氟-2’-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6’-氧代-3,4,5’,8’-四氢-2H,6’-螺环[萘-1,7’-吡啶[3,2-d]嘧啶]-4’-基)哌嗪-2-基)乙腈的制备Step 3: 2-((2S)-4-(5-Chloro-8-fluoro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy )-6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4'- Preparation of yl)piperazin-2-yl)acetonitrile
将(2S)-4-(5-((叔丁氧羰基)氨基)-6-((5-氯-8-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-2-((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(150毫克,0.186毫摩尔)的TFA(2毫升)溶液在20℃并搅拌反应2小时。将反应液浓缩得到粗产物，将粗产物和甲醇钠(30.2毫克,0.559毫摩尔)的DMF(2毫升)溶液在60度搅拌反应0.5小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经硅胶柱层析纯化得到黄色固体2-((2S)-4-(5-氯-8-氟-2’-(((2S,4R)-4-氟-1- 甲基吡咯烷-2-基)甲氧基)-6’-氧代-3,4,5’,8’-四氢-2H,6’-螺环[萘-1,7’-吡啶[3,2-d]嘧啶]-4’-基)哌嗪-2-基)乙腈(50毫克,46.9％)。MS:572.3(M+H) +。 (2S)-4-(5-((tert-butoxycarbonyl)amino)-6-((5-chloro-8-fluoro-1-(methoxycarbonyl)-1,2,3,4-tetrahydro Naphthalen-1-yl)methyl)-2-((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2-(cyanomethyl) A solution of tert-butyl)piperazine-1-carboxylate (150 mg, 0.186 mmol) in TFA (2 mL) was stirred at 20 °C for 2 h. The reaction solution was concentrated to obtain the crude product. The crude product and a solution of sodium methoxide (30.2 mg, 0.559 mmol) in DMF (2 mL) were stirred at 60°C for 0.5 h, and then quenched by adding ice water and diluted with ethyl acetate. extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 2-((2S)-4-(5-chloro-8-fluoro as a yellow solid) -2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-6'-oxo-3,4,5',8'-tetrahydro -2H,6'-Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)piperazin-2-yl)acetonitrile (50 mg, 46.9%). MS: 572.3 (M+H) + .
步骤4:2-((2S)-4-(5-氯-8-氟-2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H,6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的制备Step 4: 2-((2S)-4-(5-Chloro-8-fluoro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy )-6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]-4'- yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
将2-((2S)-4-(5-氯-8-氟-2’-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6’-氧代-3,4,5’,8’-四氢-2H,6’-螺环[萘-1,7’-吡啶[3,2-d]嘧啶]-4’-基)哌嗪-2-基)乙腈(50毫克,0.087毫摩尔)和2-氟丙烯酸(11.81毫克,0.131毫摩尔)溶于DMF(2毫升)中，在0℃时搅拌缓慢加入HATU(49.9毫克,0.131毫摩尔)和DIEA(22.59毫克,0.175毫摩尔)。滴完后，将反应混合物缓慢升至20℃并搅拌2小时，然后加入冰水淬灭反应，并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤，无水干燥硫酸钠干燥，然后过滤，浓缩得到粗产物，粗产物经Pre-HPLC纯化得到白色固体2-((2S)-4-(5-氯-8-氟-2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H,6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈(30毫克,35.5％)。MS:644.3(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ10.09(s,1H),9.71(s,1H),7.48-7.42(m,1H),7.17-7.07(m,1H),5.53-5.37(m,1H),5.37-5.18(m,1H),4.62-4.58(m,1H),4.52-4.48(m,1H),4.12-3.81(m,3H),3.71-3.68(m,1H),3.62-3.55(m,3H),3.35-3.30(m,2H),3.13-3.08(m,1H),3.05-2.95(m,7H),2.87-2.80(m,2H),2.69-2.56(m,2H),2.30-2.15(m,1H),1.92-1.85(m,1H),1.77-1.15(m,3H)。 2-((2S)-4-(5-Chloro-8-fluoro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)- 6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl) Piperazin-2-yl)acetonitrile (50 mg, 0.087 mmol) and 2-fluoroacrylic acid (11.81 mg, 0.131 mmol) were dissolved in DMF (2 mL) and HATU (49.9 mg, 0.131 mmol) and DIEA (22.59 mg, 0.175 mmol). After dropping, the reaction mixture was slowly raised to 20°C and stirred for 2 hours, then ice water was added to quench the reaction, and the mixture was diluted with ethyl acetate for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give the crude product, which was purified by Pre-HPLC to give a white solid 2-((2S)-4-(5-chloro-8-fluoro- 2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-6'-oxo-3,4,5',8'-tetrahydro- 2H,6'-Spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile ( 30 mg, 35.5%). MS: 644.3 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ10.09(s,1H), 9.71(s,1H), 7.48-7.42(m,1H), 7.17-7.07(m,1H), 5.53-5.37(m ,1H),5.37-5.18(m,1H),4.62-4.58(m,1H),4.52-4.48(m,1H),4.12-3.81(m,3H),3.71-3.68(m,1H),3.62 -3.55(m, 3H), 3.35-3.30(m, 2H), 3.13-3.08(m, 1H), 3.05-2.95(m, 7H), 2.87-2.80(m, 2H), 2.69-2.56(m, 2H), 2.30-2.15 (m, 1H), 1.92-1.85 (m, 1H), 1.77-1.15 (m, 3H).
实施例127Example 127
化合物I-122：2-((2S)-4-(5-氯-8-氟-2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-5',8'-二氢-6'H-螺环[异色烷-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈Compound 1-122: 2-((2S)-4-(5-chloro-8-fluoro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6' -Oxo-5',8'-dihydro-6'H-spiro[isochroman-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1-(2 -Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000465
Figure PCTCN2021138375-appb-000465
化合物I-122的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氯-1-(乙氧羰基)-8-氟异色胺-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间 体A56)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-122。Synthesis of compound 1-122 Reference compound 1-5 by using (2S)-4-(2-chloro-6-((5-chloro-1-(ethoxycarbonyl)-8-fluoroisotryptamine-1- (2S)-4-(2-chloro)-methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate -6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl) yl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3) and 2-fluoroacryloyl chloride (Intermediate B1) in place of acryloyl chloride to prepare compound 1-122.
化合物I-122(22毫克).MS:628.3(M+H) +。 1H NMR(400MHz,Methanol-d 4)δ7.47(dd,J＝8.8,4.7Hz,1H),7.07(t,J＝9.7Hz,1H),5.48–5.23(m,2H),4.79–4.68(m,1H),4.54–4.48(m,1H),4.33–4.28(m,1H),4.04–3.98(m,2H),3.95–3.65(m,5H),3.41–3.38(m,2H),3.27–3.01(m,7H),2.91–2.88(m,3H),2.50–2.33(m,1H),2.30–1.96(m,4H)。 Compound 1-122 (22 mg). MS: 628.3 (M+H) + . 1 H NMR (400MHz, Methanol-d 4 )δ7.47(dd,J=8.8,4.7Hz,1H),7.07(t,J=9.7Hz,1H),5.48-5.23(m,2H),4.79- 4.68 (m, 1H), 4.54–4.48 (m, 1H), 4.33–4.28 (m, 1H), 4.04–3.98 (m, 2H), 3.95–3.65 (m, 5H), 3.41–3.38 (m, 2H) ), 3.27–3.01 (m, 7H), 2.91–2.88 (m, 3H), 2.50–2.33 (m, 1H), 2.30–1.96 (m, 4H).
实施例128Example 128
化合物I-123:2-((2S)-4-(4-氯-5-氟-2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-2,3,5',8'-四氢-6'H-螺环[茚-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈Compound I-123: 2-((2S)-4-(4-chloro-5-fluoro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methan oxy)-6'-oxo-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-pyridine[3,2-d]pyrimidine]-4' -yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000466
Figure PCTCN2021138375-appb-000466
化合物I-123的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((4-氯-5-氟-1-(甲氧羰基)-2,3-二氢-1H-茚-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A59)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3),((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(中间体C3)代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-123。Synthesis of compound 1-123 Reference compound 1-5 by using (2S)-4-(2-chloro-6-((4-chloro-5-fluoro-1-(methoxycarbonyl)-2,3-di) Hydrogen-1H-inden-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A59) in place of (2S )-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl )-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A3), ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol ( Intermediate C3) in place of (S)-(1-methylpyrrolidin-2-yl)methanol and 2-fluoroacryloyl chloride (intermediate B1) in place of acryloyl chloride were prepared to give compound 1-123.
化合物I-123(112毫克)。MS:630.3(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.95–9.88(m,1H),7.28–7.18(m,2H),7.07–6.98(m,1H),6.82–6.68(m,1H),5.37–5.28(m,2H),5.26–5.06(m,3H),4.23–4.18(m,2H),4.11–4.08(m,2H),4.00–3.37(m,5H),3.24–2.59(m,8H),2.35–2.18(m,2H),2.18–1.98(m,3H),1.96–1.74(m,2H)。 Compound 1-123 (112 mg). MS: 630.3 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.95-9.88(m,1H),7.28-7.18(m,2H),7.07-6.98(m,1H),6.82-6.68(m,1H),5.37 –5.28(m,2H), 5.26–5.06(m,3H), 4.23–4.18(m,2H), 4.11–4.08(m,2H), 4.00–3.37(m,5H), 3.24–2.59(m, 8H), 2.35–2.18 (m, 2H), 2.18–1.98 (m, 3H), 1.96–1.74 (m, 2H).
化合物I-123a和化合物I-123b:2-((S)-4-((R)-4-氯-5-氟-2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-2,3,5',8'-四氢-6'H-螺环[茚-1,7'-吡啶[3,2-d]嘧啶]-4'- 基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈和2-((S)-4-((S)-4-氯-5-氟-2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-2,3,5',8'-四氢-6'H-螺环[茚-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-123a and Compound 1-123b: 2-((S)-4-((R)-4-chloro-5-fluoro-2'-(((2S,4R)-4-fluoro-1-methyl pyrrolidin-2-yl)methoxy)-6'-oxo-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-pyridine[3, 2-d]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile and 2-((S)-4-((S)-4-chloro-5 -Fluoro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-6'-oxo-2,3,5',8'- Tetrahydro-6'H-spiro[indene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl)piperazin-2-yl) Acetonitrile
Figure PCTCN2021138375-appb-000467
Figure PCTCN2021138375-appb-000467
将2-((2S)-4-(4-氯-5-氟-2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-6'-氧代-2,3,5',8'-四氢-6'H-螺环[茚-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈(110毫克)经SFC手性拆分(CHIRALPAK IF,2cm×25cm,5um column,流动相A:MTBE,流动相B:MeOH:DCM＝1:1)得到均为白色固体的第一个组分峰化合物I-123a(保留时间为1.872分钟,40毫克)和第二个组分峰化合物I-123b(保留时间为2.467分钟,25毫克)。2-((2S)-4-(4-chloro-5-fluoro-2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)- 6'-oxo-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)- 1-(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile (110 mg) was chiral resolved by SFC (CHIRALPAK IF, 2cm×25cm, 5um column, mobile phase A:MTBE, mobile phase B:MeOH: DCM=1:1) to obtain the first component peak Compound I-123a (retention time 1.872 minutes, 40 mg) and the second component peak Compound I-123b (retention time 2.467 minutes) as white solids, 25 mg).
化合物I-123a(保留时间为1.872分钟,40毫克)。MS:630.3(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.95–9.88(m,1H),7.28–7.18(m,2H),7.07–6.98(m,1H),6.82–6.68(m,1H),5.37–5.28(m,2H),5.26–5.06(m,3H),4.23–4.18(m,2H),4.11–4.08(m,2H),4.00–3.37(m,5H),3.24–2.59(m,8H),2.35–2.18(m,2H),2.18–1.98(m,3H),1.96–1.74(m,2H)。 Compound 1-123a (retention time 1.872 min, 40 mg). MS: 630.3 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.95-9.88(m,1H),7.28-7.18(m,2H),7.07-6.98(m,1H),6.82-6.68(m,1H),5.37 –5.28(m,2H), 5.26–5.06(m,3H), 4.23–4.18(m,2H), 4.11–4.08(m,2H), 4.00–3.37(m,5H), 3.24–2.59(m, 8H), 2.35–2.18 (m, 2H), 2.18–1.98 (m, 3H), 1.96–1.74 (m, 2H).
化合物I-123b(保留时间为2.467分钟,25毫克)。MS:630.3(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.95–9.88(m,1H),7.28–7.18(m,2H),7.07–6.98(m,1H),6.82–6.68(m,1H),5.37–5.28(m,2H),5.26–5.06(m,3H),4.23–4.18(m,2H),4.11–4.08(m,2H),4.00–3.37(m,5H),3.24–2.59(m,8H),2.35–2.18(m,2H),2.18–1.98(m,3H),1.96–1.74(m,2H)。 Compound 1-123b (retention time 2.467 min, 25 mg). MS: 630.3 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.95-9.88(m,1H),7.28-7.18(m,2H),7.07-6.98(m,1H),6.82-6.68(m,1H),5.37 –5.28(m,2H), 5.26–5.06(m,3H), 4.23–4.18(m,2H), 4.11–4.08(m,2H), 4.00–3.37(m,5H), 3.24–2.59(m, 8H), 2.35–2.18 (m, 2H), 2.18–1.98 (m, 3H), 1.96–1.74 (m, 2H).
实施例129Example 129
化合物I-124：2-((2S)-4-(5-氯-7-氟-2'-(((2R)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H,6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-124: 2-((2S)-4-(5-chloro-7-fluoro-2'-(((2R)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl) Methoxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridine[3,2-d]pyrimidine]- 4'-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2021138375-appb-000468
Figure PCTCN2021138375-appb-000468
化合物I-124的合成参考化合物I-5，通过使用(2S)-4-(2-氯-6-((5-氯-7-氟-1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸叔丁酯(中间体A36)代替(2S)-4-(2-氯-6-((1-(甲氧羰基)-1,2,3,4-四氢萘-1-基)甲基)-5-硝基嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(中间体A3)，中间体C8代替(S)-(1-甲基吡咯烷-2-基)甲醇和2-氟代丙烯酰氯(中间体B1)代替丙烯酰氯制备得到化合物I-124。Synthesis of compound 1-124 Reference compound 1-5 by using (2S)-4-(2-chloro-6-((5-chloro-7-fluoro-1-(methoxycarbonyl)-1,2,3 ,4-Tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate tert-butyl ester (Intermediate A36) instead of ( 2S)-4-(2-Chloro-6-((1-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-5-nitropyrimidine-4- (S)-(1-methylpyrrolidin-2-yl)methanol and 2 - Fluoroacryloyl chloride (Intermediate B1) was prepared in place of acryloyl chloride to give compound I-124.
化合物I-124(36毫克)。MS:670.3(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ10.85(s,1H),7.40–7.13(m,2H),5.64–5.14(m,3H),4.55–4.26(m,2H),4.18–3.22(m,14H),3.22–2.82(m,3H),2.79–2.54(m,2H),2.44–1.95(m,5H),1.92–1.59(m,3H)。 Compound 1-124 (36 mg). MS: 670.3 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ10.85(s,1H), 7.40-7.13(m,2H), 5.64-5.14(m,3H), 4.55-4.26(m,2H), 4.18-3.22 (m, 14H), 3.22–2.82 (m, 3H), 2.79–2.54 (m, 2H), 2.44–1.95 (m, 5H), 1.92–1.59 (m, 3H).
化合物I-124a和化合物I-124b:2-((2S)-4-((1R)-5-氯-7-氟-2'-(((2R)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)-6'-氧代-3,4,5'，8'-四氢-2H，6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈和2-((2S)-4-((1S)-5-氯-7-氟-2'-(((2R)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)-6'-氧代-3,4,5'，8'-四氢-2H，6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈Compound 1-124a and Compound 1-124b: 2-((2S)-4-((1R)-5-chloro-7-fluoro-2'-(((2R)-2-fluorotetrahydro-1H-pyrrole Lino-7a(5H)-yl)methoxy)-6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridine[ 3,2-d]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile and 2-((2S)-4-((1S)-5-chloro -7-Fluoro-2'-(((2R)-2-Fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)-6'-oxo-3,4,5', 8'-Tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl)-1-(2-fluoroacryloyl)piperazine- 2-yl)acetonitrile
Figure PCTCN2021138375-appb-000469
Figure PCTCN2021138375-appb-000469
将2-((2S)-4-(5-氯-7-氟-2'-(((2R)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)-6'-氧代-3,4,5',8'-四氢-2H,6'-螺环[萘-1,7'-吡啶[3,2-d]嘧啶]-4'-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈(90毫克)经SFC手性拆分(CHIRALPAK IE,2cm×25cm,5um column,流动 相A:MtBE(0.5％2mM NH3-MEOH),流动相B:MeOH:DCM＝1:1)得到均为白色固体的第一个组分峰化合物I-124a(保留时间为0.993分钟,30毫克)和第二个组分峰化合物I-124b(保留时间为2.596分钟,25毫克)。2-((2S)-4-(5-Chloro-7-fluoro-2'-(((2R)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy) -6'-oxo-3,4,5',8'-tetrahydro-2H,6'-spiro[naphthalene-1,7'-pyridin[3,2-d]pyrimidin]-4'-yl )-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile (90 mg) was chiral resolved by SFC (CHIRALPAK IE, 2cm×25cm, 5um column, mobile phase A: MtBE (0.5% 2mM NH3) -MEOH), mobile phase B:MeOH:DCM=1:1) to obtain the first component peak compound I-124a (retention time 0.993 minutes, 30 mg) and the second component peak compound as white solids I-124b (retention time 2.596 min, 25 mg).
化合物I-124a(保留时间为0.993分钟,30毫克)。MS:670.3(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ10.85(s,1H),7.40–7.13(m,2H),5.64–5.14(m,3H),4.55–4.26(m,2H),4.18–3.22(m,14H),3.22–2.82(m,3H),2.79–2.54(m,2H),2.44–1.95(m,5H),1.92–1.59(m,3H)。 Compound 1-124a (retention time 0.993 min, 30 mg). MS: 670.3 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.85 (s, 1H), 7.40–7.13 (m, 2H), 5.64–5.14 (m, 3H), 4.55– 4.26 (m, 2H), 4.18–3.22 (m, 14H), 3.22–2.82 (m, 3H), 2.79–2.54 (m, 2H), 2.44–1.95 (m, 5H), 1.92–1.59 (m, 3H) ).
化合物I-124b(保留时间为2.596分钟,25毫克)。MS:670.3(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ10.85(s,1H),7.40–7.13(m,2H),5.64–5.14(m,3H),4.55–4.26(m,2H),4.18–3.22(m,14H),3.22–2.82(m,3H),2.79–2.54(m,2H),2.44–1.95(m,5H),1.92–1.59(m,3H)。 Compound 1-124b (retention time 2.596 min, 25 mg). MS: 670.3 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.85 (s, 1H), 7.40–7.13 (m, 2H), 5.64–5.14 (m, 3H), 4.55– 4.26 (m, 2H), 4.18–3.22 (m, 14H), 3.22–2.82 (m, 3H), 2.79–2.54 (m, 2H), 2.44–1.95 (m, 5H), 1.92–1.59 (m, 3H) ).
效果实施例1 细胞水平药效评价Effect Example 1 Efficacy evaluation at the cellular level
本实验旨在验证本发明化合物对KRAS G12C突变的NCI-H358人非小细胞肺癌细胞和KRAS G12C突变的MIA PaCa-2人胰腺癌细胞的增殖抑制效果。 The purpose of this experiment is to verify the proliferation inhibitory effect of the compounds of the present invention on KRAS G12C -mutated NCI-H358 human non-small cell lung cancer cells and KRAS G12C -mutated MIA PaCa-2 human pancreatic cancer cells.
1.主要实验材料和仪器：1. Main experimental materials and instruments:
DMEM细胞培养基+GlutaMAXTM-I(Invitrogen)，RPMI 1640细胞培养基+L-Glutamine(Invitrogen)，胎牛血清(Corning)，二甲基亚砜DMSO(Sigma)，青霉素链霉素(Gibico)，杜氏磷酸盐缓冲液DPBS(Corning)，胰酶TryPLETM Express(Gibco)，96孔细胞培养板(Corning)，Cell titer
Figure PCTCN2021138375-appb-000470
(Promega)，TC-20细胞计数仪(Bio-rad)， DMEM cell culture medium + GlutaMAXTM-I (Invitrogen), RPMI 1640 cell culture medium + L-Glutamine (Invitrogen), fetal bovine serum (Corning), DMSO (Sigma), penicillin-streptomycin (Gibico), Dulbecco's Phosphate Buffered Saline DPBS (Corning), TryPLETM Express (Gibco), 96-well cell culture plate (Corning), Cell titer
Figure PCTCN2021138375-appb-000470
(Promega), TC-20 cell counter (Bio-rad),
多功能酶标仪Bio Synergy NEO2(Bio-tek)。Multifunctional microplate reader Bio Synergy NEO2 (Bio-tek).
人非小细胞肺癌细胞NCI-H358(ATCC)培养于培养于10％胎牛血清、100U青霉素和100μg/mL链霉素的RPMI 1640培养基中。Human non-small cell lung cancer cells NCI-H358 (ATCC) were cultured in RPMI 1640 medium cultured with 10% fetal bovine serum, 100 U penicillin and 100 μg/mL streptomycin.
人胰腺癌细胞MIA PaCa-2(ATCC)培养于10％胎牛血清、100U青霉素和100μg/mL链霉素的DMEM培养基中。Human pancreatic cancer cells MIA PaCa-2 (ATCC) were cultured in DMEM medium with 10% fetal bovine serum, 100 U penicillin and 100 μg/mL streptomycin.
2.实验步骤2. Experimental steps
将NCI-H358和MIA PaCa-2细胞种到96孔细胞培养板(NCI-H358每孔约800个细胞，MIA PaCa-2每孔约1200个细胞)，将种好细胞的96孔培养板移入37℃，5％CO 2培养箱中过夜培养。将测试化合物用DMSO配制为10mM母液。利用DMSO对待测定化合物按3.16倍进行梯度稀释，共9个浓度梯度，最高浓度为1mM，在第九个浓度之后设置DMSO对照。将梯度稀释的待测化合物和阳性化合物用细胞培养液稀释33.3倍，混 匀，然后转入40μL体积至96孔细胞培养板。将96孔细胞培养板移入到37℃，5％CO 2培养箱中孵育5天。取出细胞培养板，室温平衡30分钟。加入60ul的celltiter Glo试剂到含有120ul细胞培养试剂的96孔细胞培养板。在摇床上350rpm振动20min，使细胞充分裂解。利用Bio-TeK SYNERGY NEO2读取化合物发光信号值。酶标仪测定不同细胞数量下的化学发光值(Luminescent)，根据DMSO对照和培养基对照计算待测化合物的细胞毒性百分比，以化合物的浓度为横坐标，以化合物细胞毒力的百分比(cytotoxicity％)为纵坐标，利用GraphPad Prism拟合(fit)药物半数抑制浓度IC50，结果如表1所示。 Seed NCI-H358 and MIA PaCa-2 cells into a 96-well cell culture plate (about 800 cells per well for NCI-H358 and about 1200 cells per well for MIA PaCa-2), and transfer the seeded 96-well culture plate into Incubate overnight in a 37 °C, 5% CO 2 incubator. Test compounds were prepared as 10 mM stock solutions in DMSO. The compounds to be tested were serially diluted by 3.16 times in DMSO, with a total of 9 concentration gradients, the highest concentration being 1 mM, and a DMSO control was set after the ninth concentration. The serially diluted test compound and positive compound were diluted 33.3 times with cell culture medium, mixed well, and then transferred to a 40 μL volume to a 96-well cell culture plate. Transfer the 96-well cell culture plate to a 37 °C, 5% CO2 incubator and incubate for 5 days. Remove the cell culture plate and equilibrate at room temperature for 30 minutes. Add 60ul of celltiter Glo reagent to a 96-well cell culture plate containing 120ul of cell culture reagent. Shake at 350 rpm for 20 min on a shaker to fully lyse the cells. Compound luminescence signal values were read using Bio-TeK SYNERGY NEO2. The chemiluminescence value (Luminescent) under different cell numbers was measured by a microplate reader, and the cytotoxicity percentage of the compound to be tested was calculated according to the DMSO control and the medium control. ) is the ordinate, and GraphPad Prism was used to fit (fit) the IC50 of the drug's median inhibitory concentration. The results are shown in Table 1.
表1：本发明化合物对NCI-H358和MIA PaCa-2细胞毒性的测定IC 50值 Table 1: Determination of IC50 values for the cytotoxicity of the compounds of the present invention to NCI-H358 and MIA PaCa-2 cells
化合物编号Compound number NCI-H358 IC 50(μM) NCI-H358 IC 50 (μM) MIA PaCa-2 IC 50(μM) MIA PaCa-2 IC 50 (μM)
I-1I-1 1.241.24 1.561.56
I-3I-3 3.773.77 4.734.73
I-3bI-3b 1.221.22 1.281.28
I-5I-5 0.0070.007 0.010.01
I-5aI-5a 0.1860.186 0.4110.411
I-5bI-5b 0.0030.003 0.0080.008
I-6I-6 0.0510.051 0.0900.090
I-6bI-6b 0.0320.032 0.0620.062
I-7I-7 2.52.5 >10>10
I-9I-9 0.3580.358 1.841.84
I-10aI-10a 9.079.07 >10>10
I-10bI-10b 0.1080.108 0.3460.346
I-11I-11 0.0360.036 0.0690.069
I-14I-14 0.0570.057 0.1720.172
I-18I-18 0.3150.315 1.041.04
I-20bI-20b 0.9450.945 2.652.65
I-21I-21 0.3880.388 0.8770.877
I-22I-22 0.3440.344 0.7780.778
I-26I-26 0.0830.083 0.3040.304
I-27I-27 0.0430.043 0.1540.154
I-28I-28 0.0060.006 0.0130.013
I-29I-29 0.0030.003 0.0050.005
I-30I-30 0.290.29 0.6390.639
I-31I-31 1.751.75 5.765.76
I-35I-35 0.4610.461 0.8250.825
I-36I-36 0.0350.035 0.1530.153
I-37I-37 0.0030.003 0.0080.008
I-38I-38 1.0851.085 3.2383.238
II-1II-1 0.0520.052 0.2710.271
II-1aII-1a 0.4840.484 1.661.66
II-1bII-1b 0.0150.015 0.040.04
II-2II-2 1.131.13 4.234.23
II-2bII-2b 0.5040.504 1.611.61
II-3II-3 0.550.55 1.971.97
II-5bII-5b 0.2570.257 1.091.09
II-6II-6 0.0660.066 0.0690.069
I-46I-46 0.6790.679 1.8861.886
I-47I-47 1.5851.585 8.6258.625
I-48I-48 0.8030.803 2.2542.254
I-50I-50 0.3090.309 1.1771.177
I-51I-51 0.0310.031 0.1120.112
I-52I-52 0.2460.246 1.9171.917
I-54I-54 0.0070.007 0.0570.057
I-55I-55 0.1890.189 1.061.06
I-56I-56 0.00960.0096 0.01590.0159
I-57I-57 0.00120.0012 0.00070.0007
I-58I-58 0.0550.055 0.0630.063
I-59I-59 0.0080.008 0.0120.012
I-59aI-59a 0.5750.575 0.8430.843
I-59bI-59b 0.0050.005 0.0110.011
I-60I-60 0.8780.878 >1>1
I-61I-61 0.24890.2489 0.64140.6414
I-62I-62 0.05880.0588 0.08030.0803
I-63I-63 0.00060.0006 0.00050.0005
I-66I-66 0.00640.0064 0.01480.0148
I-67I-67 0.12430.1243 0.59090.5909
I-68I-68 0.00590.0059 0.03360.0336
I-69I-69 0.90350.9035 0.20990.2099
I-70I-70 0.03320.0332 0.10250.1025
I-71I-71 0.30480.3048 1.2091.209
I-72I-72 2.442.44 8.238.23
I-73I-73 0.0220.022 0.0740.074
I-74I-74 0.0050.005 0.0110.011
I-75I-75 0.2310.231 0.7460.746
I-76I-76 0.0890.089 0.1570.157
I-77I-77 0.0020.002 0.0080.008
I-78I-78 0.0160.016 0.0620.062
I-79I-79 0.0040.004 0.0140.014
I-80I-80 1.221.22 3.953.95
I-81I-81 0.2160.216 0.9840.984
I-82I-82 0.0140.014 0.0980.098
I-83I-83 0.0210.021 0.1080.108
I-84I-84 0.0050.005 0.0120.012
I-85I-85 0.0240.024 0.0620.062
I-86I-86 0.0720.072 0.1030.103
I-87I-87 1.1661.166 1.9871.987
I-88I-88 0.0660.066 0.1780.178
I-89I-89 0.0070.007 0.0130.013
I-90I-90 0.1010.101 0.1610.161
I-91I-91 0.1070.107 0.1130.113
I-92I-92 0.0040.004 0.0050.005
I-93I-93 0.2170.217 0.4450.445
I-94I-94 0.6220.622 0.7420.742
I-95I-95 0.0240.024 0.0410.041
I-96I-96 0.1410.141 0.5370.537
I-97I-97 0.0890.089 0.440.44
I-98aI-98a 0.2640.264 0.2580.258
I-98bI-98b 0.0010.001 0.0010.001
I-99I-99 0.0440.044 0.0560.056
I-100aI-100a 5.165.16 7.147.14
I-100bI-100b 0.0520.052 0.0860.086
I-101I-101 0.1530.153 0.1670.167
I-102I-102 0.0090.009 0.0100.010
I-103aI-103a 0.7600.760 0.5750.575
I-103bI-103b 0.0800.080 0.1010.101
I-104aI-104a 1.5131.513 3.3623.362
I-104bI-104b 0.0290.029 0.0520.052
I-105aI-105a 0.0280.028 0.0260.026
I-105bI-105b 0.0030.003 0.0050.005
I-106aI-106a 0.8990.899 0.6920.692
I-106bI-106b 0.0080.008 0.0040.004
I-107I-107 0.1010.101 0.0860.086
I-108I-108 0.6120.612 0.6940.694
I-109aI-109a 2.0922.092 1.4371.437
I-109bI-109b 0.0060.006 0.0030.003
I-110I-110 0.2560.256 0.4530.453
I-111I-111 0.0090.009 0.0170.017
I-111aI-111a 0.2270.227 0.7480.748
I-111bI-111b 0.0040.004 0.0050.005
I-112I-112 0.0090.009 0.0130.013
I-112aI-112a 0.0040.004 0.0050.005
I-112bI-112b 0.4400.440 0.5910.591
I-113I-113 0.140.14 0.270.27
I-114I-114 0.0020.002 0.0090.009
I-115aI-115a 0.0140.014 0.0610.061
I-115bI-115b 2.9692.969 4.2034.203
I-116I-116 0.1630.163 0.3850.385
I-117I-117 0.0160.016 0.0550.055
I-118I-118 0.01830.0183 0.0970.097
I-119I-119 0.0080.008 0.0100.010
I-120I-120 0.0120.012 0.0160.016
I-120aI-120a 0.0050.005 0.0080.008
I-120bI-120b 1.991.99 3.383.38
I-121I-121 0.0050.005 0.0110.011
I-122I-122 0.0050.005 0.0810.081
I-123I-123 0.0380.038 0.2770.277
I-123aI-123a 0.0290.029 0.0540.054
I-123bI-123b 0.3760.376 3.1463.146
I-124I-124 0.00260.0026 0.0060.006
I-124aI-124a 0.0020.002 0.0060.006
I-124bI-124b 0.8830.883 1.9261.926
结论：本发明化合物对NCI-H358和MIA PaCa-2细胞具有良好的抑制活性。Conclusion: The compounds of the present invention have good inhibitory activity on NCI-H358 and MIA PaCa-2 cells.
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes may be made to these embodiments without departing from the principle and essence of the present invention. Revise. Accordingly, the scope of protection of the present invention is defined by the appended claims.

Claims (17)

  1. 一种如式I所示的化合物、其溶剂合物、其前药、其代谢产物、或它们药学上可接受的盐：A compound shown in formula I, its solvate, its prodrug, its metabolite, or their pharmaceutically acceptable salt:
    Figure PCTCN2021138375-appb-100001
    Figure PCTCN2021138375-appb-100001
    环A为含2-4个N原子的4-12元脂杂环；所述的脂杂环为单环、桥环或螺环；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 1为-C(＝O)-C(R a)＝C(R b)(R c)、-C(＝O)-C≡CR c、-C(＝O)-C(＝O)-O-R d或-C(＝O)-R d； R 1 is -C(=O)-C(R a )=C(R b )(R c ), -C(=O)-C≡CR c , -C(=O)-C(=O) -OR d or -C(=O)-R d ;
    R a为氢、卤素或C 1-6烷基； R a is hydrogen, halogen or C 1-6 alkyl;
    R b和R c独立地为氢、C 1-6烷基或“被一个或多个R b-1取代的C 1-6烷基”； 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 ";
    各R b-1独立地为卤素、C 1-6烷氧基或-NR b-2R b-3；R b-2和R b-3独立地为氢或C 1-6烷基，或者，R b-2、R b-3及与它们相连接的N共同形成“杂原子为N、或者N和O，杂原子数为1个或2个的4-10元杂环烷基”； 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为C 1-6烷基； R d is C 1-6 alkyl;
    n为0、1、2或3；n is 0, 1, 2 or 3;
    各R 4独立地为C 1-6烷基或“被一个或多个R 4-1取代的C 1-6烷基”； each R 4 is independently C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R 4-1 ";
    各R 4-1独立地为卤素、氰基、羟基或C 1-6烷氧基； Each R 4-1 is independently halogen, cyano, hydroxyl or C 1-6 alkoxy;
    R 2为-OR 2-1、-SR 2-2、-C(＝O)R 2-3、-S(＝O) 2R 2-4、-S(＝O)R 2-5、-(CR 1-1R 1-2) mR 2-6或NR 1- 3R 2-7； R 2 is -OR 2-1 , -SR 2-2 , -C(=O)R 2-3 , -S(=O) 2 R 2-4 , -S(=O)R 2-5 , - (CR 1-1 R 1-2 ) m R 2-6 or NR 1-3 R 2-7 ;
    R 1-1、R 1-2和R 1-3独立地为氢或C 1-6烷基； R 1-1 , R 1-2 and R 1-3 are independently hydrogen or C 1-6 alkyl;
    m为0、1、2或3，当m为0时，表示R 2-6通过单键直接与母体相连； m is 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和R 2-5独立地为C 1-6烷基、被一个或多个R e取代的C 1-6烷基、C 1-6烷氧基、“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、C 6-C 10芳基、被一个或多个R e-2取代的C 6-C 10芳基、“杂原子选 自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、C 3- 10环烷基、或、被一个或多个R e-4取代的C 3-10环烷基； 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 , C 3-10 cycloalkyl, or, C 3-10 cycloalkyl substituted by one or more R e-4 ;
    R 2-6为氢、CN、卤素、羟基、C 1-6烷基、被一个或多个R e取代的C 1-6烷基、C 1-6烷氧基、“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、C 6-C 10芳基、被一个或多个R e-2取代的C 6-C 10芳基、“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、C 3-10环烷基、或、被一个或多个R e-4取代的C 3-10环烷基； 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 or more C 3-10 cycloalkyl substituted by R e-4 ;
    R 2-7为氢、C 1-6烷基、被一个或多个R e取代的C 1-6烷基、C 1-6烷氧基、“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、C 6-C 10芳基、被一个或多个R e-2取代的C 6-C 10芳基、“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、C 3-10环烷基、或、被一个或多个R e-4取代的C 3-10环烷基； 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 a substituted by one or more R e-4 C 3-10 cycloalkyl;
    各R e独立地为“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、C 6-C 10芳基、被一个或多个R e-2取代的C 6-C 10芳基、“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、C 3-10环烷基、或、被一个或多个R e-4取代的C 3-10环烷基； 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-1、R e-2和R e-4独立地为卤素、C 1-6烷基、C 1-6烷氧基、-C(＝O)-C(R a)＝C(R b)(R c)或NR e-5R e-6；R e-5和R e-6独立地为氢或C 1-6烷基，或者，R e-5、R e-6及与它们相连接的N成共同形成“杂原子为N、或者N和O，杂原子数为1个或2个的4-10元杂环烷基”； R e-1 , R e-2 and R e-4 are independently halogen, C 1-6 alkyl, C 1-6 alkoxy, -C(=O)-C(R a )=C(R b ) (R c ) or NR e-5 R e-6 ; 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";
    各R e-3独立地为卤素、羟基、氰基、C 1-6烷基、被一个或多个R e-7取代的C 1-6烷基、C 1-6烷氧基、被一个或多个R e-8取代的C 1-6烷氧基、-C(＝O)-C(R a)＝C(R b)(R c)、NR e-5R e-6、-O(C＝O)NR e-13R e-14或-O(C＝O)OR e-15；R e-7和R e-8独立地为卤素、羟基、氰基、-COOH、C 1-6烷氧基或NR e-9R e-10，R e-9和R e-10独立地为氢、C 1-6烷基、-C(＝O)R e-11或-S(＝O) 2R e-12；R e-11和R e-12独立地为C 1-6烷基； Each R e-3 is independently halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R e-7 , C 1-6 alkoxy, or multiple R e-8 substituted C 1-6 alkoxy, -C(=O)-C(R a )=C(R b )(R c ), NR e-5 R e-6 , - O(C=O)NR e-13 R e-14 or -O(C=O)OR e-15 ; R e-7 and R e-8 are independently halogen, hydroxyl, cyano, -COOH, C 1-6 alkoxy or NR e-9 R e-10 , R e-9 and R e-10 are independently hydrogen, C 1-6 alkyl, -C(=O)R e-11 or -S (=O) 2 R e-12 ; R e-11 and R e-12 are independently C 1-6 alkyl;
    R e-13和R e-14独立地为氢或C 1-6烷基，或者，R e-13、R e-14及与它们相连接的N共同形成“杂原子为N、或者N和O，杂原子数为1个或2个的4-10元杂环烷基”；R e-15为氢或C 1-6烷基； 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为氢、C 1-6烷基、被一个或多个R 3-1取代的C 1-6烷基，其中，各R 3-1独立地为C 1- 6烷基、C 1-6烷氧基、CN、卤素或OH； 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和Y独立地为O、NR 6或CR 7R 8；各R 6独立地为氢或C 1-6烷基；各R 7和R 8独立地为H或C 1-6烷基；Z为单键、O、NR 6或CR 7R 8；X、Y和Z不同时为O或不同时为NR 6； 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和Q独立地为N或CR 5； U, V, W and Q are independently N or CR5 ;
    各R 5独立地为H、卤素、羟基、被一个或多个卤素取代的C 1-6烷基、被一个或多个卤素取代的C 1-6烷氧基、氰基、C 3-6环烷基、C 1-6烷基砜基、C 3-6环烷基砜基、C 1-6烷基或C 1-6烷氧基； 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;
    带“*”碳原子为手性碳原子，为S构型、R构型或它们的混合物。The carbon atom with "*" is a chiral carbon atom, which is in S configuration, R configuration or a mixture thereof.
  2. 如权利要求1所述的如式I所示的化合物、其溶剂合物、其前药、其代谢产物、或它们药学上可接受的盐，其特征在于，环A为含2-4个N原子的4-12元脂杂环；所述的脂杂环为单环、桥环或螺环；The compound of formula I, its solvate, its prodrug, its metabolite, or their pharmaceutically acceptable salts as claimed in claim 1, wherein ring A contains 2-4 N 4-12-membered alicyclic heterocycle of atoms; said alicyclic heterocycle is monocyclic, bridged or spirocyclic;
    R 1为-C(＝O)-C(R a)＝C(R b)(R c)、-C(＝O)-C≡CR c、-C(＝O)-C(＝O)-O-R d或-C(＝O)-R d； R 1 is -C(=O)-C(R a )=C(R b )(R c ), -C(=O)-C≡CR c , -C(=O)-C(=O) -OR d or -C(=O)-R d ;
    R a为氢、卤素或C 1-6烷基； R a is hydrogen, halogen or C 1-6 alkyl;
    R b和R c独立地为氢、C 1-6烷基或“被一个或多个R b-1取代的C 1-6烷基”； 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 ";
    各R b-1独立地为卤素、C 1-6烷氧基或-NR b-2R b-3；R b-2和R b-3独立地为氢或C 1-6烷基，或者，R b-2、R b-3及与它们相连接的N共同形成“杂原子为N、或者N和O，杂原子数为1个或2个的4-10元杂环烷基”； 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为C 1-6烷基； R d is C 1-6 alkyl;
    n为0、1、2或3；n is 0, 1, 2 or 3;
    各R 4独立地为C 1-6烷基或“被一个或多个R 4-1取代的C 1-6烷基”； each R 4 is independently C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R 4-1 ";
    各R 4-1独立地为卤素、氰基、羟基或C 1-6烷氧基； Each R 4-1 is independently halogen, cyano, hydroxyl or C 1-6 alkoxy;
    R 2为-OR 2-1、-SR 2-2、-C(＝O)R 2-3、-S(＝O) 2R 2-4、-S(＝O)R 2-5、-(CR 1-1R 1-2) mR 2-6或NR 1- 3R 2-7； R 2 is -OR 2-1 , -SR 2-2 , -C(=O)R 2-3 , -S(=O) 2 R 2-4 , -S(=O)R 2-5 , - (CR 1-1 R 1-2 ) m R 2-6 or NR 1-3 R 2-7 ;
    R 1-1、R 1-2和R 1-3独立地为氢或C 1-6烷基； R 1-1 , R 1-2 and R 1-3 are independently hydrogen or C 1-6 alkyl;
    m为0、1、2或3，当m为0时，表示R 2-6通过单键直接与母体相连； m is 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和R 2-5独立地为C 1-6烷基、被一个或多个R e取代的C 1-6烷基、 C 1-6烷氧基、“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、C 6-C 10芳基、被一个或多个R e-2取代的C 6-C 10芳基、“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、C 3- 10环烷基、或、被一个或多个R e-4取代的C 3-10环烷基； 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 , C 3-10 cycloalkyl, or, C 3-10 cycloalkyl substituted by one or more R e-4 ;
    R 2-6为氢、CN、卤素、羟基、C 1-6烷基、被一个或多个R e取代的C 1-6烷基、C 1-6烷氧基、“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、C 6-C 10芳基、被一个或多个R e-2取代的C 6-C 10芳基、“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、C 3-10环烷基、或、被一个或多个R e-4取代的C 3-10环烷基； 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 or more C 3-10 cycloalkyl substituted by R e-4 ;
    R 2-7为氢、C 1-6烷基、被一个或多个R e取代的C 1-6烷基、C 1-6烷氧基、“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、C 6-C 10芳基、被一个或多个R e-2取代的C 6-C 10芳基、“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、C 3-10环烷基、或、被一个或多个R e-4取代的C 3-10环烷基； 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 a substituted by one or more R e-4 C 3-10 cycloalkyl;
    各R e独立地为“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、C 6-C 10芳基、被一个或多个R e-2取代的C 6-C 10芳基、“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、C 3-10环烷基、或、被一个或多个R e-4取代的C 3-10环烷基； 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-1、R e-2和R e-4独立地为卤素、C 1-6烷基、C 1-6烷氧基、-C(＝O)-C(R a)＝C(R b)(R c)或NR e-5R e-6；R e-5和R e-6独立地为氢或C 1-6烷基，或者，R e-5、R e-6及与它们相连接的N成共同形成“杂原子为N、或者N和O，杂原子数为1个或2个的4-10元杂环烷基”； R e-1 , R e-2 and R e-4 are independently halogen, C 1-6 alkyl, C 1-6 alkoxy, -C(=O)-C(R a )=C(R b ) (R c ) or NR e-5 R e-6 ; 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";
    各R e-3独立地为卤素、羟基、氰基、C 1-6烷基、被一个或多个R e-7取代的C 1-6烷基、C 1-6烷氧基、被一个或多个R e-8取代的C 1-6烷氧基、-C(＝O)-C(R a)＝C(R b)(R c)、NR e-5R e-6、 -O(C＝O)NR e-13R e-14或-O(C＝O)OR e-15；R e-7和R e-8独立地为卤素、羟基、氰基、-COOH、C 1-6烷氧基或NR e-9R e-10，R e-9和R e-10独立地为氢、C 1-6烷基、-C(＝O)R e-11或-S(＝O) 2R e-12；R e-11和R e-12独立地为C 1-6烷基； Each R e-3 is independently halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R e-7 , C 1-6 alkoxy, or multiple R e-8 substituted C 1-6 alkoxy, -C(=O)-C(R a )=C(R b )(R c ), NR e-5 R e-6 , - O(C=O)NR e-13 R e-14 or -O(C=O)OR e-15 ; R e-7 and R e-8 are independently halogen, hydroxyl, cyano, -COOH, C 1-6 alkoxy or NR e-9 R e-10 , R e-9 and R e-10 are independently hydrogen, C 1-6 alkyl, -C(=O)R e-11 or -S (=O) 2 R e-12 ; R e-11 and R e-12 are independently C 1-6 alkyl;
    R e-13和R e-14独立地为氢或C 1-6烷基，或者，R e-13、R e-14及与它们相连接的N共同形成“杂原子为N、或者N和O，杂原子数为1个或2个的4-10元杂环烷基”；R e-15为氢或C 1-6烷基； 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为氢、C 1-6烷基、被一个或多个R 3-1取代的C 1-6烷基，其中，各R 3-1独立地为C 1- 6烷基、C 1-6烷氧基、CN、卤素或OH； 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和Y独立地为O、NR 6或CH 2；R 6为氢或C 1-6烷基；Z为单键、O、NR 6或CH 2；X、Y和Z不同时为O或不同时为NR 6； 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和Q独立地为N或CR 5； U, V, W and Q are independently N or CR5 ;
    各R 5独立地为H、卤素、羟基、被一个或多个卤素取代的C 1-6烷基、被一个或多个卤素取代的C 1-6烷氧基、氰基、C 3-6环烷基、C 1-6烷基砜基、C 3-6环烷基砜基、C 1-6烷基或C 1-6烷氧基； 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;
    带“*”碳原子为手性碳原子，为S构型、R构型或它们的混合物。The carbon atom with "*" is a chiral carbon atom, which is in S configuration, R configuration or a mixture thereof.
  3. 如权利要求1-2中至少一项所述的如式I所示的化合物、其溶剂合物、其前药、其代谢产物、或它们药学上可接受的盐，其特征在于，当环A为含2-4个N原子的4-12元脂杂环时，所述脂杂环为含2个N原子的6-10元脂杂环；The compound represented by formula I, its solvate, its prodrug, its metabolite, or their pharmaceutically acceptable salts according to at least one of claims 1-2, characterized in that when Ring A When it is a 4-12-membered alicyclic heterocyclic ring containing 2-4 N atoms, the alicyclic heterocyclic ring is a 6-10-membered alicyclic heterocyclic ring containing 2 N atoms;
    和/或，当R a为卤素时，所述卤素为氟、氯、溴或碘； and/or, when Ra is halogen, the halogen is fluorine, chlorine, bromine or iodine;
    和/或，当R a为C 1-6烷基时，所述C 1-C 6烷基为C 1-C 3烷基； And/or, when R a is a C 1-6 alkyl group, the C 1 -C 6 alkyl group is a C 1 -C 3 alkyl group;
    和/或，当R b和R c独立地为C 1-6烷基或“被一个或多个R b-1取代的C 1-6烷基”时，所述C 1-C 6烷基为C 1-C 3烷基； and/or, when R b and R c are independently C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R b-1 ", the C 1 -C 6 alkyl is C 1 -C 3 alkyl;
    和/或，当各R b-1独立地为卤素时，所述卤素为氟、氯、溴或碘； and/or, when each R b-1 is independently halogen, the halogen is fluorine, chlorine, bromine or iodine;
    和/或，当各R b-1独立地为C 1-6烷氧基时，所述C 1-C 6烷氧基为C 1-C 3烷氧基； and/or, when 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;
    和/或，当R b-2和R b-3独立地为C 1-6烷基时，所述C 1-C 6烷基为C 1-C 3烷基； and/or, when R b-2 and R b-3 are independently C 1-6 alkyl, said C 1 -C 6 alkyl is C 1 -C 3 alkyl;
    和/或，当R d为C 1-6烷基时，所述C 1-C 6烷基为C 1-C 3烷基； And/or, when R d is C 1-6 alkyl, the C 1 -C 6 alkyl is C 1 -C 3 alkyl;
    和/或，当各R 4独立地为C 1-6烷基或“被一个或多个R 4-1取代的C 1-6烷基”时，所述C 1-C 6烷基为C 1-C 3烷基； and/or, when each R 4 is independently C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R 4-1 ", the C 1 -C 6 alkyl is C 1 -C 3 alkyl;
    和/或，当各R 4-1独立地为卤素时，所述卤素为氟、氯、溴或碘； and/or, when each R 4-1 is independently halogen, the halogen is fluorine, chlorine, bromine or iodine;
    和/或，当R 2-1、R 2-2、R 2-3、R 2-4和R 2-5独立地为C 1-6烷基或“被一个或多个R e取代的C 1-6烷基”时，所述C 1-C 6烷基为C 1-C 3烷基； and/or, when R 2-1 , R 2-2 , R 2-3 , R 2-4 and R 2-5 are independently C 1-6 alkyl or "C substituted with one or more R e 1-6 alkyl", the C 1 -C 6 alkyl is a C 1 -C 3 alkyl;
    和/或，当R 2-1、R 2-2、R 2-3、R 2-4和R 2-5独立地为C 1-6烷氧基时，所述C 1-C 6烷氧基为C 1-C 3烷氧基； and/or, when 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 -C 6 alkoxy The group is C 1 -C 3 alkoxy;
    和/或，当R 2-1、R 2-2、R 2-3、R 2-4和R 2-5独立地为“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”或“被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基””时，所述“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”为
    Figure PCTCN2021138375-appb-100002
    and/or, when 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 N, O and S, 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, heteroatoms When the number of 5-12-membered heteroaryl groups is 1-4"", the "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-4. 5-12 Yuan Heteroaryl" is
    Figure PCTCN2021138375-appb-100002
    和/或，当R 2-1、R 2-2、R 2-3、R 2-4和R 2-5独立地为“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”或“被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基””时，所述“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”为
    Figure PCTCN2021138375-appb-100003
    And/or, when 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, the heteroatoms The number of 4-10-membered heterocycloalkyl groups with 1-3 "or "substituted by one or more R e-3 " heteroatoms is selected from one or more of O and N, and the number of heteroatoms is 1 -3 4-10-membered heterocycloalkanes "", the "heteroatoms are selected from one or more of O and N, and the number of heteroatoms is 1-3 4-10-membered heterocycloalkanes. base" is
    Figure PCTCN2021138375-appb-100003
    和/或，当R 2-6为卤素时，所述卤素为氟、氯、溴或碘； and/or, when R 2-6 is halogen, the halogen is fluorine, chlorine, bromine or iodine;
    和/或，当R 2-6为C 1-6烷基或“被一个或多个R e取代的C 1-6烷基”时，所述C 1-C 6烷基为C 1-C 3烷基； and/or, when R 2-6 is C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R e ", the C 1 -C 6 alkyl is C 1 -C 3 alkyl;
    和/或，当R 2-6为C 1-6烷氧基时，所述C 1-C 6烷氧基为C 1-C 3烷氧基； And/or, when R 2-6 is C 1-6 alkoxy, the C 1 -C 6 alkoxy is C 1 -C 3 alkoxy;
    和/或，当R 2-6独立地为“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”或“被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基””时，所述“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”为
    Figure PCTCN2021138375-appb-100004
    And/or, when R 2-6 is independently "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-4 5-12-membered heteroaryl groups" or "are When one or more R e-1 is substituted "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"", the said "The heteroatom is selected from one or more of N, O and S, and the 5-12-membered heteroaryl group with 1-4 heteroatoms" is
    Figure PCTCN2021138375-appb-100004
    和/或，当R 2-6为“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”或“被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基””时，所述“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”为
    Figure PCTCN2021138375-appb-100005
    And/or, when R 2-6 is "heteroatoms selected from one or more of O and N, the number of heteroatoms is 1-3 4-10-membered heterocycloalkyl" or "by one or more When R e-3 is substituted "the heteroatom is selected from one or more of O and N, and the number of heteroatoms is 1-3 4-10-membered heterocycloalkyl"", the "heteroatom is selected from 1-3" A 4-10-membered heterocycloalkyl group with 1-3 heteroatoms selected from one or more of O and N" is
    Figure PCTCN2021138375-appb-100005
    和/或，当各R e独立地为“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”或“被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基””时，所述“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”为
    Figure PCTCN2021138375-appb-100006
    And/or, when each R e is independently "the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-4 of 5-12-membered heteroaryl" or "by a When "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-4, the 5-12-membered heteroaryl group" is substituted by more than one R e-1 , the " The heteroatom is selected from one or more of N, O and S, and the 5-12-membered heteroaryl with 1-4 heteroatoms "is
    Figure PCTCN2021138375-appb-100006
    和/或，当各R e独立地为“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”或“被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基””，所述“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”为
    Figure PCTCN2021138375-appb-100007
    And/or, when each R e is independently "the heteroatom is selected from one or more of O and N, the number of heteroatoms is 1-3 4-10-membered heterocycloalkyl" or "by one or Multiple R e-3 substituted "heteroatoms selected from one or more of O and N, and 4-10-membered heterocycloalkyl groups with 1-3 heteroatoms", the "heteroatoms selected from A 4-10-membered heterocycloalkyl group with 1-3 heteroatoms selected from one or more of O and N" is
    Figure PCTCN2021138375-appb-100007
    和/或，当R e-1、R e-2和R e-4独立地为C 1-C 6烷基时，为所述C 1-C 6烷基为C 1-C 3烷基； and/or, when Re -1 , Re -2 and Re -4 are independently C 1 -C 6 alkyl groups, the C 1 -C 6 alkyl groups are C 1 -C 3 alkyl groups;
    和/或，R e-3独立地为卤素时，所述卤素为氟、氯、溴或碘； And/or, when Re -3 is independently halogen, the halogen is fluorine, chlorine, bromine or iodine;
    和/或，R e-3独立地为C 1-C 6烷基或“被一个或多个R e-7取代的C 1-6烷基”时，所述C 1-C 6烷基为C 1-C 3烷基； And/or, when R e-3 is independently C 1 -C 6 alkyl or "C 1-6 alkyl substituted by one or more R e-7 ", the C 1 -C 6 alkyl is C 1 -C 3 alkyl;
    和/或，R e-3独立地为C 1-6烷氧基时，所述C 1-C 6烷氧基为C 1-C 3烷氧基； And/or, when R e-3 is independently C 1-6 alkoxy, the C 1 -C 6 alkoxy is C 1 -C 3 alkoxy;
    和/或，当R e-5和R e-6独立地为C 1-C 6烷基时，为所述C 1-C 6烷基为C 1-C 3烷基； and/or, when R e-5 and R e-6 are independently C 1 -C 6 alkyl groups, the C 1 -C 6 alkyl groups are C 1 -C 3 alkyl groups;
    和/或，当R 3为C 1-C 6烷基时，所述C 1-C 6烷基为C 1-C 3烷基； and/or, when R 3 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is a C 1 -C 3 alkyl group;
    和/或，当各R 5独立地为卤素时，所述卤素为氟、氯、溴或碘； and/or, when each R is independently halogen, the halogen is fluorine, chlorine, bromine or iodine;
    和/或，当各R 5独立地被一个或多个卤素取代的C 1-6烷基，所述被一个或多个卤素取代的C 1-6烷基为被一个或多个卤素取代的C 1-3烷基； and/or, when each R 5 is independently C 1-6 alkyl substituted with one or more halogens, the C 1-6 alkyl substituted with one or more halogens is a C 1-6 alkyl substituted with one or more halogens C 1-3 alkyl;
    和/或，当各R 5独立地为C 1-6烷基时，所述C 1-C 6烷基为C 1-C 3烷基； and/or, when 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;
    和/或，当各R 5独立地被一个或多个卤素取代的C 1-6烷氧基，所述被一个或多个卤素取代的C 1-6烷氧基为被一个或多个卤素取代的C 1-3烷氧基； And/or, when each R 5 is independently C 1-6 alkoxy substituted with one or more halogens, the C 1-6 alkoxy substituted with one or more halogens is a C 1-6 alkoxy substituted with one or more halogens Substituted C 1-3 alkoxy;
    和/或，当各R 7和R 8独立地为C 1-6烷基时，所述C 1-C 6烷基为C 1-C 3烷基。 And/or, when each R 7 and R 8 is independently a C 1-6 alkyl group, the C 1 -C 6 alkyl group is a C 1 -C 3 alkyl group.
  4. 如权利要求1-3中至少一项所述的如式I所示的化合物、其溶剂合物、其前药、其代谢产物、或它们药学上可接受的盐，其特征在于，
    Figure PCTCN2021138375-appb-100008
    为
    Figure PCTCN2021138375-appb-100009
    Figure PCTCN2021138375-appb-100010
    Figure PCTCN2021138375-appb-100011
    The compound represented by formula I, its solvate, its prodrug, its metabolite, or their pharmaceutically acceptable salts according to at least one of claims 1-3, characterized in that,
    Figure PCTCN2021138375-appb-100008
    for
    Figure PCTCN2021138375-appb-100009
    Figure PCTCN2021138375-appb-100010
    Figure PCTCN2021138375-appb-100011
    和/或，当R a为卤素时，所述卤素为氟； and/or, when Ra is halogen, the halogen is fluorine;
    和/或，当R a为C 1-6烷基时，所述C 1-C 6烷基为甲基； And/or, when R a is C 1-6 alkyl, the C 1 -C 6 alkyl is methyl;
    和/或，当R b和R c独立地为C 1-6烷基或“被一个或多个R b-1取代的C 1-6烷基”时，所述C 1-C 6烷基为甲基； and/or, when R b and R c are independently C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R b-1 ", the C 1 -C 6 alkyl is methyl;
    和/或，当各R b-1独立地为卤素时，所述卤素为氟； and/or, when each R b-1 is independently halogen, the halogen is fluorine;
    和/或，当各R b-1独立地为C 1-6烷氧基时，所述C 1-C 6烷氧基为甲氧基； and/or, when each R b-1 is independently a C 1-6 alkoxy group, the C 1 -C 6 alkoxy group is a methoxy group;
    和/或，当R b-2和R b-3独立地为C 1-6烷基时，所述C 1-C 6烷基为甲基； and/or, when R b-2 and R b-3 are independently C 1-6 alkyl, the C 1 -C 6 alkyl is methyl;
    和/或，当R d为C 1-6烷基时，所述C 1-C 6烷基为甲基； And/or, when R d is C 1-6 alkyl, the C 1 -C 6 alkyl is methyl;
    和/或，当各R 4独立地为C 1-6烷基或“被一个或多个R 4-1取代的C 1-6烷基”时，所述C 1-C 6烷基为甲基； And/or, when each R 4 is independently C 1-6 alkyl or "C 1-6 alkyl substituted with one or more R 4-1 ", the C 1 -C 6 alkyl is methyl base;
    和/或，当各R 4-1独立地为卤素时，所述卤素为氟； and/or, when each R 4-1 is independently halogen, the halogen is fluorine;
    和/或，当R 2-1、R 2-2、R 2-3、R 2-4和R 2-5独立地为C 1-6烷基或“被一个或多个R e取代的C 1-6烷基”时，所述C 1-C 6烷基为甲基； and/or, when R 2-1 , R 2-2 , R 2-3 , R 2-4 and R 2-5 are independently C 1-6 alkyl or "C substituted with one or more R e 1-6 alkyl", the C 1 -C 6 alkyl is methyl;
    和/或，当R 2-1、R 2-2、R 2-3、R 2-4和R 2-5独立地为C 1-6烷氧基时，所述C 1-C 6烷氧基为甲氧基； and/or, when 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 -C 6 alkoxy group is methoxy;
    和/或，当R 2-6为卤素时，所述卤素为氯； and/or, when R 2-6 is halogen, the halogen is chlorine;
    和/或，当R 2-6为C 1-6烷基或“被一个或多个R e取代的C 1-6烷基”时，所述C 1-C 6烷基为甲基； And/or, when 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 methyl;
    和/或，当R 2-6为C 1-6烷氧基时，所述C 1-C 6烷氧基为甲氧基； And/or, when R 2-6 is C 1-6 alkoxy, the C 1 -C 6 alkoxy is methoxy;
    和/或，当R e-1、R e-2和R e-4独立地为C 1-C 6烷基时，为所述C 1-C 6烷基为甲基； and/or, when Re -1 , Re -2 and Re -4 are independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl is methyl;
    和/或，R e-3独立地为卤素时，所述卤素为氟； and/or, when R e-3 is independently halogen, the halogen is fluorine;
    和/或，R e-3独立地为C 1-C 6烷基或“被一个或多个R e-7取代的C 1-6烷基”时，所述C 1-C 6烷基为甲基； And/or, when R e-3 is independently C 1 -C 6 alkyl or "C 1-6 alkyl substituted by one or more R e-7 ", the C 1 -C 6 alkyl is methyl;
    和/或，R e-3独立地为C 1-6烷氧基时，所述C 1-C 6烷氧基为甲氧基； And/or, when R e-3 is independently C 1-6 alkoxy, the C 1 -C 6 alkoxy is methoxy;
    和/或，当R e-5和R e-6独立地为C 1-C 6烷基时，为所述C 1-C 6烷基为甲基或乙基； And/or, when Re -5 and Re -6 are independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl is methyl or ethyl;
    和/或，当R 3为C 1-C 6烷基时，所述C 1-C 6烷基为甲基； And/or, when R 3 is C 1 -C 6 alkyl, the C 1 -C 6 alkyl is methyl;
    和/或，当各R 5独立地为卤素时，所述卤素为氟、氯或溴； and/or, when each R is independently halogen, the halogen is fluorine, chlorine or bromine;
    和/或，当各R 5独立地被一个或多个卤素取代的C 1-6烷基，所述被一个或多个卤素取代的C 1-6烷基为为-CF 3； And/or, when 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 -CF 3 ;
    和/或，当各R 5独立地为C 1-6烷基时，所述C 1-C 6烷基为甲基； and/or, when each R 5 is independently a C 1-6 alkyl group, the C 1 -C 6 alkyl group is methyl;
    和/或，当各R 5独立地被一个或多个卤素取代的C 1-6烷氧基，所述被一个或多个卤素取代的C 1-6烷氧基为-OCF 3； And/or, when each R 5 is independently C 1-6 alkoxy substituted with one or more halogens, the C 1-6 alkoxy substituted with one or more halogens is -OCF 3 ;
    和/或，当各R 7和R 8独立地为C 1-6烷基时，所述C 1-C 6烷基为甲基。 And/or, when each R 7 and R 8 is independently a C 1-6 alkyl group, the C 1 -C 6 alkyl group is a methyl group.
  5. 如权利要求1-4中至少一项所述的如式I所示的化合物、其溶剂合物、其前药、其代谢产物、或它们药学上可接受的盐，其特征在于，环A为含2个N原子的6-10元脂杂环，所述的脂杂环为单环；The compound represented by formula I, its solvate, its prodrug, its metabolite, or their pharmaceutically acceptable salts according to at least one of claims 1-4, wherein ring A is A 6-10-membered alicyclic heterocyclic ring containing 2 N atoms, the alicyclic heterocyclic ring is a single ring;
    和/或，R 1为-C(＝O)-C(R a)＝C(R b)(R c)、-C(＝O)-C≡CCH 3、-C(＝O)-C(＝O)-OCH 3或-C(＝O)-CH 3；当R a为卤素或C 1-6烷基时，R b和R c为氢；当R b或R c为C 1-6烷基或“被一个或多个R b-1取代的C 1-6烷基”时，R a为氢； And/or, R 1 is -C(=O)-C(R a )=C(R b )(R c ), -C(=O)-C≡CCH 3 , -C(=O)-C (=O)-OCH 3 or -C(=O)-CH 3 ; when R a is halogen or C 1-6 alkyl, R b and R c are hydrogen; when R b or R c is C 1- 6 alkyl or "C 1-6 alkyl substituted by one or more R b-1 ", R a is hydrogen;
    和/或，R a为氢或卤素； and/or, R a is hydrogen or halogen;
    和/或，R b和R c独立地为氢、C 1-6烷基或“被一个或多个R b-1取代的C 1-6烷基”，且R b和R c至少有一个为氢； and/or, 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 at least one of R b and R c is hydrogen;
    和/或，各R b-1独立地为卤素； and/or, each R b-1 is independently halogen;
    和/或，n为0、1或2；and/or, n is 0, 1 or 2;
    和/或，各R 4独立地为甲基、氰基取代的甲基、F取代的甲基或羟基取代的甲基； and/or, each R is independently methyl, cyano - substituted methyl, F-substituted methyl, or hydroxy-substituted methyl;
    和/或，R 2-1为氢、C 1-6烷基、被一个或多个R e取代的C 1-6烷基或“被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基””； And/or, R 2-1 is hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R e or "heteroatom substituted by one or more R e-1 ". From one or more of N, O and S, a 5-12-membered heteroaryl group with 1-4 heteroatoms "";
    和/或，R 2-2为C 1-6烷基或“被一个或多个R e取代的C 1-6烷基”； And/or, R 2-2 is C 1-6 alkyl or "C 1-6 alkyl substituted by one or more R e ";
    和/或，R 2-5为被一个或多个R e取代的C 1-6烷基； And/or, R 2-5 is C 1-6 alkyl substituted by one or more R e ;
    和/或，m为0；and/or, m is 0;
    和/或，R 2-6为氢、卤素、被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”、“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”或羟基； And/or, 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. -10-membered heterocycloalkyl", "heteroatoms selected from one or more of N, O and S, and 5-12-membered heteroaryl groups with 1-4 heteroatoms", by one or more R e-1 substituted "heteroatom selected from one or more of N, O and S, and a 5-12-membered heteroaryl group with 1-4 heteroatoms" or hydroxyl;
    和/或，各R e独立地为“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、被一个或多个R e-1取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”、“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”或“被一个或多个R e-3取代的“杂原子选自O和N中的一种或 多种，杂原子数为1-3个的4-10元杂环烷基””； And/or, 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", a group consisting of one or more R e-1 substituted "heteroatoms are selected from one or more of N, O and S, and 5-12-membered heteroaryl groups with 1-4 heteroatoms", "heteroatoms are selected from O and One or more of N, 4-10-membered heterocycloalkyl with 1-3 heteroatoms" or "substituted by one or more R e-3 " heteroatoms selected from O and N One or more 4-10-membered heterocycloalkyl "" with 1-3 heteroatoms;
    和/或，R e-1独立地为C 1-6烷基； and/or, R e-1 is independently C 1-6 alkyl;
    和/或，各R e-3独立地为卤素、羟基、C 1-6烷基、C 1-6烷氧基、-C(＝O)-C(R a)＝C(R b)(R c)或NR e-5R e-6； and/or, each R e-3 is independently halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, -C(=O)-C(R a )=C(R b )( R c ) or NR e-5 R e-6 ;
    和/或，R 2为-OR 2-1、-SR 2-2、-S(＝O)R 2-5或-(CR 1-1R 1-2) mR 2-6； and/or, R 2 is -OR 2-1 , -SR 2-2 , -S(=O)R 2-5 or -(CR 1-1 R 1-2 ) m R 2-6 ;
    和/或，R 3为氢或C 1-6烷基； And/or, R 3 is hydrogen or C 1-6 alkyl;
    和/或，X为O或CR 7R 8，Y为CR 7R 8，Z为单键、O或CR 7R 8； and/or, X is O or CR 7 R 8 , Y is CR 7 R 8 , and Z is a single bond, O or CR 7 R 8 ;
    和/或，U、V、W和Q独立地为CR 5； and/or, U, V, W and Q are independently CR5 ;
    和/或，各R 5独立地为H、卤素、被一个或多个卤素取代的C 1-6烷基、被一个或多个卤素取代的C 1-6烷氧基、氰基、C 3-6环烷基、C 1-6烷基或C 1-6烷氧基。 and/or, 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, C 3 -6cycloalkyl , C1-6alkyl or C1-6alkoxy .
  6. 如权利要求1-5中至少一项所述的如式I所示的化合物、其溶剂合物、其前药、其代谢产物、或它们药学上可接受的盐，其特征在于，R b和R c独立地为氢或“被一个或多个卤素取代的C 1-6烷基”，且R b和R c至少有一个为氢； The compound represented by formula I, its solvate, its prodrug, its metabolite, or their pharmaceutically acceptable salts according to at least one of claims 1-5, wherein R b and R c is 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;
    和/或，n为1或2；and/or, n is 1 or 2;
    和/或，各R 4独立地为氰基取代的甲基； and/or, each R is independently cyano - substituted methyl;
    和/或，各R e-3独立地为卤素、羟基、C 1-6烷基、C 1-6烷氧基、-C(＝O)-CH＝CH 2或NR e- 5R e-6； and/or, each R e-3 is independently halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, -C(=O)-CH=CH 2 or NR e- 5 R e- 6 ;
    和/或，各R e独立地为“杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-12元杂芳基”或“被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”； And/or, 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" or "a group consisting of one or more" Multiple R e-3 substituted "heteroatoms selected from one or more of O and N, 4-10-membered heterocycloalkyl with 1-3 heteroatoms";
    和/或，X和Y为CH 2，Z为单键、O或CH 2； and/or, X and Y are CH 2 , and Z is a single bond, O or CH 2 ;
    和/或，各R 5独立地为H、卤素或C 1-6烷基。 And/or, each R 5 is independently H, halogen or C 1-6 alkyl.
  7. 如权利要求1-6中至少一项所述的如式I所示的化合物、其溶剂合物、其前药、其代谢产物、或它们药学上可接受的盐，其特征在于，
    Figure PCTCN2021138375-appb-100012
    为
    Figure PCTCN2021138375-appb-100013
    Figure PCTCN2021138375-appb-100014
    The compound represented by formula I, its solvate, its prodrug, its metabolite, or their pharmaceutically acceptable salts according to at least one of claims 1-6, characterized in that,
    Figure PCTCN2021138375-appb-100012
    for
    Figure PCTCN2021138375-appb-100013
    Figure PCTCN2021138375-appb-100014
    和/或，R 1为
    Figure PCTCN2021138375-appb-100015
    Figure PCTCN2021138375-appb-100016
    and/or, R1 is
    Figure PCTCN2021138375-appb-100015
    Figure PCTCN2021138375-appb-100016
    和/或，R 2为-OR 2-1或-(CR 1-1R 1-2) mR 2-6，R 2-1为被一个或多个R e取代的C 1-6烷基，各R e独立地为被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”，R e中，各R e-3独立地为卤素、C 1-6烷基或C 1-6烷氧基；m为0，R 2-6为被一个或多个R e-3取代的“杂原子选自O和N中的一种或多种，杂原子数为1-3个的4-10元杂环烷基”，R 2-6中，各R e-3独立地为NR e-5R e-6。 And/or, R 2 is -OR 2-1 or -(CR 1-1 R 1-2 ) m R 2-6 , R 2-1 is C 1-6 alkyl substituted by one or more R e , each R e is independently a 4-10-membered heterocycloalkane with 1-3 heteroatoms substituted by one or more R e-3 "heteroatoms selected from O and N""base", 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 represented by 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 is NR e-5 R e-6 .
  8. 如权利要求1-7中至少一项所述的如式I所示的化合物、其溶剂合物、其前药、其代谢产物、或它们药学上可接受的盐，其特征在于，
    Figure PCTCN2021138375-appb-100017
    为
    Figure PCTCN2021138375-appb-100018
    Figure PCTCN2021138375-appb-100019
    The compound represented by formula I, its solvate, its prodrug, its metabolite, or their pharmaceutically acceptable salts according to at least one of claims 1-7, characterized in that,
    Figure PCTCN2021138375-appb-100017
    for
    Figure PCTCN2021138375-appb-100018
    Figure PCTCN2021138375-appb-100019
    Figure PCTCN2021138375-appb-100020
    Figure PCTCN2021138375-appb-100020
    和/或，R 2为氢、羟基、氯、
    Figure PCTCN2021138375-appb-100021
    -OCH 3、-SCH 3、
    Figure PCTCN2021138375-appb-100022
    Figure PCTCN2021138375-appb-100023
    and/or, R 2 is hydrogen, hydroxyl, chlorine,
    Figure PCTCN2021138375-appb-100021
    -OCH 3 , -SCH 3 ,
    Figure PCTCN2021138375-appb-100022
    Figure PCTCN2021138375-appb-100023
    和/或，
    Figure PCTCN2021138375-appb-100024
    为
    Figure PCTCN2021138375-appb-100025
    Figure PCTCN2021138375-appb-100026
    and / or,
    Figure PCTCN2021138375-appb-100024
    for
    Figure PCTCN2021138375-appb-100025
    Figure PCTCN2021138375-appb-100026
    Figure PCTCN2021138375-appb-100027
    Figure PCTCN2021138375-appb-100027
  9. 如权利要求1或2所述的如式I所示的化合物、其溶剂合物、其前药、其代谢产物、或它们药学上可接受的盐，其特征在于，所述的如式I所示的化合物为如下任一化合物：The compound shown in formula I, its solvate, its prodrug, its metabolite, or their pharmaceutically acceptable salts according to claim 1 or 2, wherein said compound shown in formula I The compound shown is any of the following compounds:
    Figure PCTCN2021138375-appb-100028
    Figure PCTCN2021138375-appb-100028
    Figure PCTCN2021138375-appb-100029
    Figure PCTCN2021138375-appb-100029
    Figure PCTCN2021138375-appb-100030
    Figure PCTCN2021138375-appb-100030
    Figure PCTCN2021138375-appb-100031
    Figure PCTCN2021138375-appb-100031
    Figure PCTCN2021138375-appb-100032
    Figure PCTCN2021138375-appb-100032
    Figure PCTCN2021138375-appb-100033
    Figure PCTCN2021138375-appb-100033
    Figure PCTCN2021138375-appb-100034
    Figure PCTCN2021138375-appb-100034
    Figure PCTCN2021138375-appb-100035
    Figure PCTCN2021138375-appb-100035
    Figure PCTCN2021138375-appb-100036
    Figure PCTCN2021138375-appb-100036
    Figure PCTCN2021138375-appb-100037
    Figure PCTCN2021138375-appb-100037
    Figure PCTCN2021138375-appb-100038
    Figure PCTCN2021138375-appb-100038
    Figure PCTCN2021138375-appb-100039
    Figure PCTCN2021138375-appb-100039
    Figure PCTCN2021138375-appb-100040
    Figure PCTCN2021138375-appb-100040
    Figure PCTCN2021138375-appb-100041
    Figure PCTCN2021138375-appb-100041
    Figure PCTCN2021138375-appb-100042
    Figure PCTCN2021138375-appb-100042
    Figure PCTCN2021138375-appb-100043
    Figure PCTCN2021138375-appb-100043
  10. 如权利要求1或2所述的如式I所示的化合物、其溶剂合物、其前药、其代谢产物、或它们药学上可接受的盐，其特征在于，所述的如式I所示的化合物为如下任一化合物：The compound shown in formula I, its solvate, its prodrug, its metabolite, or their pharmaceutically acceptable salts according to claim 1 or 2, wherein said compound shown in formula I The compound shown is any of the following compounds:
    在下述条件下保留时间为1.21min的化合物，其为
    Figure PCTCN2021138375-appb-100044
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 1.21 min under the following conditions is
    Figure PCTCN2021138375-appb-100044
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为1.99min的化合物，其为
    Figure PCTCN2021138375-appb-100045
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 1.99 min under the following conditions is
    Figure PCTCN2021138375-appb-100045
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为0.93min的化合物，其为
    Figure PCTCN2021138375-appb-100046
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 0.93 min under the following conditions is
    Figure PCTCN2021138375-appb-100046
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为1.43min的化合物，其为
    Figure PCTCN2021138375-appb-100047
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 1.43 min under the following conditions is
    Figure PCTCN2021138375-appb-100047
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为1.24min的化合物，其为
    Figure PCTCN2021138375-appb-100048
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 1.24 min under the following conditions is
    Figure PCTCN2021138375-appb-100048
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为2.56min的化合物，其为
    Figure PCTCN2021138375-appb-100049
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 2.56 min under the following conditions is
    Figure PCTCN2021138375-appb-100049
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为1.01min的化合物，其为
    Figure PCTCN2021138375-appb-100050
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     A compound with a retention time of 1.01 min under the following conditions is
    Figure PCTCN2021138375-appb-100050
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为2.17min的化合物，其为
    Figure PCTCN2021138375-appb-100051
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 2.17 min under the following conditions is
    Figure PCTCN2021138375-appb-100051
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为4.74min的化合物，其为
    Figure PCTCN2021138375-appb-100052
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 4.74 min under the following conditions is
    Figure PCTCN2021138375-appb-100052
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为5.44min的化合物，其为
    Figure PCTCN2021138375-appb-100053
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 5.44 min under the following conditions is
    Figure PCTCN2021138375-appb-100053
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为4.08min的化合物，其为
    Figure PCTCN2021138375-appb-100054
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 4.08 min under the following conditions is
    Figure PCTCN2021138375-appb-100054
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为4.22min的化合物，其为
    Figure PCTCN2021138375-appb-100055
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 4.22 min under the following conditions is
    Figure PCTCN2021138375-appb-100055
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为1.42min的化合物，其为
    Figure PCTCN2021138375-appb-100056
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 1.42 min under the following conditions is
    Figure PCTCN2021138375-appb-100056
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为2.71min的化合物，其为
    Figure PCTCN2021138375-appb-100057
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 2.71 min under the following conditions is
    Figure PCTCN2021138375-appb-100057
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为1.11min的化合物，其为
    Figure PCTCN2021138375-appb-100058
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 1.11 min under the following conditions is
    Figure PCTCN2021138375-appb-100058
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为2.21min的化合物，其为
    Figure PCTCN2021138375-appb-100059
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 2.21 min under the following conditions is
    Figure PCTCN2021138375-appb-100059
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为3.88min的化合物，其为
    Figure PCTCN2021138375-appb-100060
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 3.88 min under the following conditions is
    Figure PCTCN2021138375-appb-100060
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为4.42min的化合物，其为
    Figure PCTCN2021138375-appb-100061
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 4.42 min under the following conditions is
    Figure PCTCN2021138375-appb-100061
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为1.254min的化合物，其为
    Figure PCTCN2021138375-appb-100062
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 1.254 min under the following conditions is
    Figure PCTCN2021138375-appb-100062
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为2.267min的化合物，其为
    Figure PCTCN2021138375-appb-100063
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 2.267 min under the following conditions is
    Figure PCTCN2021138375-appb-100063
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为4.473min的化合物，其为
    Figure PCTCN2021138375-appb-100064
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound whose retention time is 4.473 min under the following conditions is
    Figure PCTCN2021138375-appb-100064
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为4.688min的化合物，其为
    Figure PCTCN2021138375-appb-100065
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 4.688 min under the following conditions is
    Figure PCTCN2021138375-appb-100065
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为7.008min的化合物，其为
    Figure PCTCN2021138375-appb-100066
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound whose retention time is 7.008 min under the following conditions is
    Figure PCTCN2021138375-appb-100066
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为7.199min的化合物，其为
    Figure PCTCN2021138375-appb-100067
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 7.199 min under the following conditions is
    Figure PCTCN2021138375-appb-100067
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为4.735min的化合物，其为
    Figure PCTCN2021138375-appb-100068
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 4.735 min under the following conditions is
    Figure PCTCN2021138375-appb-100068
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为4.758min的化合物，其为
    Figure PCTCN2021138375-appb-100069
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound whose retention time is 4.758 min under the following conditions is
    Figure PCTCN2021138375-appb-100069
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为7.198min的化合物，其为
    Figure PCTCN2021138375-appb-100070
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 7.198 min under the following conditions is
    Figure PCTCN2021138375-appb-100070
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为7.460min的化合物，其为
    Figure PCTCN2021138375-appb-100071
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 7.460 min under the following conditions is
    Figure PCTCN2021138375-appb-100071
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为4.249min的化合物，其为
    Figure PCTCN2021138375-appb-100072
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound whose retention time is 4.249 min under the following conditions is
    Figure PCTCN2021138375-appb-100072
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为4.333min的化合物，其为
    Figure PCTCN2021138375-appb-100073
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound whose retention time is 4.333 min under the following conditions is
    Figure PCTCN2021138375-appb-100073
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为6.961min的化合物，其为
    Figure PCTCN2021138375-appb-100074
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound whose retention time is 6.961 min under the following conditions is
    Figure PCTCN2021138375-appb-100074
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为7.133min的化合物，其为
    Figure PCTCN2021138375-appb-100075
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound whose retention time is 7.133 min under the following conditions is
    Figure PCTCN2021138375-appb-100075
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为4.903min的化合物，其为
    Figure PCTCN2021138375-appb-100076
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound whose retention time is 4.903 min under the following conditions is
    Figure PCTCN2021138375-appb-100076
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为5.508min的化合物，其为
    Figure PCTCN2021138375-appb-100077
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 5.508 min under the following conditions is
    Figure PCTCN2021138375-appb-100077
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为2.174min的化合物，其为
    Figure PCTCN2021138375-appb-100078
    中的一个立体异构体：色谱柱:CHIRALART Cellulose SB,2cm×25cm,5μm；流动相A:MtBE(0.5％2mM NH 3-MEOH)，流动相B:MeOH:DCM＝1:1；     The compound with a retention time of 2.174 min under the following conditions is
    Figure PCTCN2021138375-appb-100078
    One stereoisomer in: chromatographic column: CHIRALART Cellulose SB, 2cm×25cm, 5μm; mobile phase A: MtBE (0.5% 2mM NH 3 -MEOH), mobile phase B: MeOH: DCM=1:1;
    在下述条件下保留时间为2.950min的化合物，其为
    Figure PCTCN2021138375-appb-100079
    中的一个立体异构体：色谱柱:CHIRALART Cellulose SB,2cm×25cm,5μm；流动相A:MtBE(0.5％2mM NH 3-MEOH)，流动相B:MeOH:DCM＝1:1；     The compound with a retention time of 2.950 min under the following conditions is
    Figure PCTCN2021138375-appb-100079
    One stereoisomer in: chromatographic column: CHIRALART Cellulose SB, 2cm×25cm, 5μm; mobile phase A: MtBE (0.5% 2mM NH 3 -MEOH), mobile phase B: MeOH: DCM=1:1;
    在下述条件下保留时间为1.986min的化合物，其为
    Figure PCTCN2021138375-appb-100080
    中的一个立体异构体：色谱柱:CHIRALPAK IE,2cm×25cm,5μm；流动相A:MtBE(0.5％2mM NH 3-MEOH)，流动相B:MeOH:DCM＝1:1；     The compound with a retention time of 1.986 min under the following conditions is
    Figure PCTCN2021138375-appb-100080
    One stereoisomer in: chromatographic column: CHIRALPAK IE, 2cm×25cm, 5μm; mobile phase A: MtBE (0.5% 2mM NH 3 -MEOH), mobile phase B:MeOH:DCM=1:1;
    在下述条件下保留时间为2.919min的化合物，其为
    Figure PCTCN2021138375-appb-100081
    中的一个立体异构体：色谱柱:CHIRALPAK IE,2cm×25cm,5μm；流动相A:MtBE(0.5％2mM NH 3-MEOH)，流动相B:MeOH:DCM＝1:1；     The compound with a retention time of 2.919 min under the following conditions is
    Figure PCTCN2021138375-appb-100081
    One stereoisomer in: chromatographic column: CHIRALPAK IE, 2cm×25cm, 5μm; mobile phase A: MtBE (0.5% 2mM NH 3 -MEOH), mobile phase B:MeOH:DCM=1:1;
    在下述条件下保留时间为5.137min的化合物，其为
    Figure PCTCN2021138375-appb-100082
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound with a retention time of 5.137 min under the following conditions is
    Figure PCTCN2021138375-appb-100082
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为5.370min的化合物，其为
    Figure PCTCN2021138375-appb-100083
    中的一个立体异构体：色谱柱:Dr.maish Reprosil Chiral-JM，250 x 25mm，10μm；柱温:室温；流动相:CO 2/MeOH＝60/40；     The compound whose retention time is 5.370 min under the following conditions is
    Figure PCTCN2021138375-appb-100083
    One stereoisomer in: chromatographic column: Dr.maish Reprosil Chiral-JM, 250 x 25mm, 10 μm; column temperature: room temperature; mobile phase: CO 2 /MeOH=60/40;
    在下述条件下保留时间为0.928min的化合物，其为
    Figure PCTCN2021138375-appb-100084
    中的一个立体异构体：色谱柱:CHIRALPAK IF,2cm×25cm,5μm；流动相A:MtBE(0.5％2mM NH 3-MEOH)，流动相B:MeOH:DCM＝1:1；     The compound with a retention time of 0.928 min under the following conditions is
    Figure PCTCN2021138375-appb-100084
    One stereoisomer in: chromatographic column: CHIRALPAK IF, 2cm×25cm, 5μm; mobile phase A: MtBE (0.5% 2mM NH 3 -MEOH), mobile phase B:MeOH:DCM=1:1;
    在下述条件下保留时间为1.411min的化合物，其为
    Figure PCTCN2021138375-appb-100085
    中的一个立体异构体：色谱柱:CHIRALPAK IF,2cm×25cm,5μm；流动相A:MtBE(0.5％2mM NH 3-MEOH)，流动相B:MeOH:DCM＝1:1；     The compound with a retention time of 1.411 min under the following conditions is
    Figure PCTCN2021138375-appb-100085
    One stereoisomer in: chromatographic column: CHIRALPAK IF, 2cm×25cm, 5μm; mobile phase A: MtBE (0.5% 2mM NH 3 -MEOH), mobile phase B:MeOH:DCM=1:1;
    在下述条件下保留时间为1.872min的化合物，其为
    Figure PCTCN2021138375-appb-100086
    中的一个立体异构体：色谱柱:CHIRALPAK IF,2cm×25cm,5μm；流动相A:MtBE，流动相B:MeOH:DCM＝1:1；     The compound with a retention time of 1.872 min under the following conditions is
    Figure PCTCN2021138375-appb-100086
    One stereoisomer in: chromatographic column: CHIRALPAK IF, 2cm×25cm, 5μm; mobile phase A: MtBE, mobile phase B: MeOH: DCM=1:1;
    在下述条件下保留时间为2.467min的化合物，其为
    Figure PCTCN2021138375-appb-100087
    中的一个立体异构体：色谱柱:CHIRALPAK IF,2cm×25cm,5μm；流动相A:MtBE，流动相B:MeOH:DCM＝1:1；     The compound with a retention time of 2.467 min under the following conditions is
    Figure PCTCN2021138375-appb-100087
    One stereoisomer in: chromatographic column: CHIRALPAK IF, 2cm×25cm, 5μm; mobile phase A: MtBE, mobile phase B: MeOH: DCM=1:1;
    在下述条件下保留时间为0.993min的化合物，其为
    Figure PCTCN2021138375-appb-100088
    中的一个立体异构体：色谱柱:CHIRALPAK IF,2cm×25cm,5μm；流动相A:MtBE(0.5％2mM NH 3-MEOH)，流动相B:MeOH:DCM＝1:1；     The compound with a retention time of 0.993 min under the following conditions is
    Figure PCTCN2021138375-appb-100088
    One stereoisomer in: chromatographic column: CHIRALPAK IF, 2cm×25cm, 5μm; mobile phase A: MtBE (0.5% 2mM NH 3 -MEOH), mobile phase B:MeOH:DCM=1:1;
    在下述条件下保留时间为2.596min的化合物，其为
    Figure PCTCN2021138375-appb-100089
    中的一个立体异构体：色谱柱:CHIRALPAK IF,2cm×25cm,5μm；流动相A:MtBE(0.5％2mM NH 3-MEOH)，流动相B:MeOH:DCM＝1:1。     The compound whose retention time is 2.596 min under the following conditions is
    Figure PCTCN2021138375-appb-100089
    One stereoisomer in: Chromatographic column: CHIRALPAK IF, 2 cm×25 cm, 5 μm; mobile phase A: MtBE (0.5% 2 mM NH 3 -MEOH), mobile phase B: MeOH: DCM=1:1.
  11. 如权利要求1～10任一项所述的如式I所示的化合物的制备方法，其包括以下步骤：The preparation method of the compound shown in formula I as claimed in any one of claims 1 to 10, comprising the following steps:
    如式K-X所示的化合物和如式K-XIII所示的化合物进行取代反应，得如式I所示的化合物；The compound shown in formula K-X and the compound shown in formula K-XIII are subjected to substitution reaction to obtain the compound shown in formula I;
    Figure PCTCN2021138375-appb-100090
    Figure PCTCN2021138375-appb-100090
    其中，“*”、n、环A、R 1、R 2、R 3、R 4、X、Y、Z、U、V、W和Q的定义如权利要求1～10任一项所述，L为卤素或羟基； Wherein, the definitions of "*", n, ring A, R 1 , R 2 , R 3 , R 4 , X, Y, Z, U, V, W and Q are as described in any one of claims 1 to 10, L is halogen or hydroxyl;
    较佳地，所述如式I所示的化合物的制备方法中，还包括以下步骤：Preferably, in the preparation method of the compound shown in the formula I, it also comprises the following steps:
    如式K-IX所示的化合物经脱保护反应得如K-X所示的化合物；The compound represented by formula K-IX is subjected to deprotection reaction to obtain the compound represented by K-X;
    Figure PCTCN2021138375-appb-100091
    Figure PCTCN2021138375-appb-100091
    其中，“*”、n、环A、R 2、R 3、R 4、X、Y、Z、U、V、W和Q的定义如权利要求1～9任一项所述，PG为氨基保护基。 Wherein, "*", n, ring A, R 2 , R 3 , R 4 , X, Y, Z, U, V, W and Q are as defined in any one of claims 1 to 9, and PG is amino protecting groups.
  12. 一种如式K-X所示的化合物：A compound of formula K-X:
    Figure PCTCN2021138375-appb-100092
    Figure PCTCN2021138375-appb-100092
    其中，“*”、n、环A、R 2、R 3、R 4、X、Y、Z、U、V、W和Q的定义如权利要求1-10中至少一项所述。 Wherein, "*", n, ring A, R 2 , R 3 , R 4 , X, Y, Z, U, V, W and Q are defined as described in at least one of claims 1-10.
  13. 如权利要求12所述的如式K-X所示的化合物，其特征在于，所述如式K-X所 示的化合物为如下任一化合物：The compound shown in formula K-X as claimed in claim 12, wherein the compound shown in formula K-X is any of the following compounds:
    Figure PCTCN2021138375-appb-100093
    Figure PCTCN2021138375-appb-100093
    Figure PCTCN2021138375-appb-100094
    Figure PCTCN2021138375-appb-100094
    Figure PCTCN2021138375-appb-100095
    Figure PCTCN2021138375-appb-100095
    Figure PCTCN2021138375-appb-100096
    Figure PCTCN2021138375-appb-100096
    Figure PCTCN2021138375-appb-100097
    Figure PCTCN2021138375-appb-100097
    Figure PCTCN2021138375-appb-100098
    Figure PCTCN2021138375-appb-100098
    Figure PCTCN2021138375-appb-100099
    Figure PCTCN2021138375-appb-100099
  14. 一种药物组合物，其包括如权利要求1-10中至少一项所述的如式I所示的化合物、其溶剂合物、其前药、其代谢产物、或它们药学上可接受的盐，以及药用辅料。A pharmaceutical composition comprising the compound shown in formula I as described in at least one of claims 1-10, its solvate, its prodrug, its metabolite, or a pharmaceutically acceptable salt thereof , and pharmaceutical excipients.
  15. 如权利要求1-10中至少一项所述的如式I所示的化合物、其溶剂合物、其前药、其代谢产物、或它们药学上可接受的盐、或如权利要求14所述的药物组合物在制备药物中的应用。The compound of formula I, its solvate, its prodrug, its metabolite, or a pharmaceutically acceptable salt thereof as claimed in at least one of claims 1 to 10, or as claimed in claim 14 The application of the pharmaceutical composition in the preparation of medicine.
  16. 如权利要求15所述的应用，其特征在于，所述的药物用于治疗癌症；较佳地，所述癌症包括肺癌、结肠癌、胰腺癌、直肠癌、淋巴癌、食管癌、卵巢癌、脑胶质瘤、子宫颈癌、尿路上皮癌、胃癌、子宫内膜癌、肝癌、胆管癌、乳腺癌、白血病和黑色素瘤中的一种或多种。The application according to claim 15, wherein the medicine is used for the treatment of cancer; preferably, the cancer comprises lung cancer, colon cancer, pancreatic cancer, rectal cancer, lymphatic cancer, esophageal cancer, ovarian cancer, One or more of glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, leukemia and melanoma.
  17. 如权利要求1-10中至少一项所述的如式I所示的化合物、其溶剂合物、其前药、其代谢产物、或它们药学上可接受的盐、或如权利要求14所述的药物组合物在制备KRAS G12C蛋白突变抑制剂中的应用。 The compound of formula I, its solvate, its prodrug, its metabolite, or a pharmaceutically acceptable salt thereof as claimed in at least one of claims 1 to 10, or as claimed in claim 14 Application of the pharmaceutical composition in the preparation of KRAS G12C protein mutation inhibitor.
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