WO2023138583A1 - Composé hétérocyclique, composition pharmaceutique et utilisation associée - Google Patents

Composé hétérocyclique, composition pharmaceutique et utilisation associée Download PDF

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WO2023138583A1
WO2023138583A1 PCT/CN2023/072654 CN2023072654W WO2023138583A1 WO 2023138583 A1 WO2023138583 A1 WO 2023138583A1 CN 2023072654 W CN2023072654 W CN 2023072654W WO 2023138583 A1 WO2023138583 A1 WO 2023138583A1
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ring
membered
substituted
alkyl
aliphatic
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肖贻崧
谷晓辉
赖焜民
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上海湃隆生物科技有限公司
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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • 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
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged 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 invention relates to a heterocyclic compound, a pharmaceutical composition and applications thereof.
  • KRAS The full name of the KRAS gene is Kirsten rat sarcoma viraloncogene homolog (Kristen rat sarcoma viral oncogene homolog).
  • KRAS plays a pivotal role in the signal regulation of cell growth.
  • the upstream cell surface receptors such as EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4, after receiving external signals, will pass the signal to the downstream through the RAS protein.
  • EGFR EGFR
  • HER2 HER2
  • ErbB3 and ErbB4 ErbB4
  • the KRAS protein When the KRAS protein is not activated, it is tightly bound to GDP (guanine nucleotide diphosphate).
  • the technical problem to be solved by the present invention is to provide a heterocyclic compound, a pharmaceutical composition and its application in view of the defect that the existing KRAS G12D inhibitor has a single structure.
  • the compound of the present invention has a novel structure, good activity and selectivity.
  • the present invention solves the above-mentioned technical problems through the following technical solutions.
  • the present invention provides a heterocyclic compound represented by formula I-0, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof (referring to the aforementioned heterocyclic compound represented by formula I-0, a pharmaceutically acceptable salt thereof or a stereoisomer thereof):
  • Ring K is an aromatic ring or a heteroaromatic ring
  • X1 is N, NR X1' or CR X1 ;
  • X2 is N or CR X2 ;
  • R X1 and R X2 Each independently is H, CN, halogen, C 1 -C 6 Alkyl, C substituted by one or more halogens 1 -C 6 Alkyl, substituted by one or more hydroxyl groups C 1 -C 6 Alkyl, PO(C 1 -C 6 alkyl) 2 ⁇ C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 6-14 membered aryl, 5-14 membered heteroaryl, one or more X 1-1 Substituted 3-6 membered heterocycloalkyl, replaced by one or more X 1-2 Substituted 5-14 membered heteroaryl, NO 2 , by one or more X 1-3 Substituted 3-6 membered heterocycloalkenyl,
  • X 3 is N or CR X3 , R X3 is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogenated (C 1 -C 6 alkyl), OR a , hydroxyl (C 1 -C 6 alkyl), cyano, nitro, -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a , 5-14 membered heteroaryl, 6-14 membered aryl;
  • R X1 and R X3 and the atoms connected to them together form a C 5 -C 8 cycloalkene structure
  • R X1' and R X3 and the atoms connected to them together form a 5-8 membered heteroaryl ring or a 5-8 membered heteroaryl ring substituted by one or more hydroxyl groups;
  • R 1-3 and R 1-4 are independently halogen
  • X 1 is CR X1 , wherein the C atom in X 1 is connected to the C atom in the aryl or heteroaryl group in R 1 through -O-(CH 2 ) n1 - * , * -NH-(CH 2 ) n2 -, -C ⁇ C-(CH 2 ) n3 -C ⁇ C- * or -(CH 2 ) n4 -O-(CH 2 ) n5 - * , wherein the * end is connected to the C atom in X 1 connected;
  • R 2 is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogenated (C 1 -C 6 alkyl), OR a , hydroxyl (C 1 -C 6 alkyl), cyano, nitro, -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a , 5-14 membered heteroaryl, 6-14 membered aryl;
  • L 2 represents absence, -O-(C 1 -C 6 alkylene) or -NR a -(C 1 -C 6 alkylene);
  • R 1' , R 2' , R 3' , R 4' , R 5' , R 6' , R 7' , R 8' , R 9' , R 10' , R 11' , R 12' Each independently represents hydrogen, halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -SO 3 R a , -NR a R b , -CO(C 1 -C 6 Alkyl) or -C(O)NR a R b ;
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl,
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl,
  • R 8' and R 9' together with the atoms connected to it form a C 3 -C 8 aliphatic ring, a C 3 -C 8 carbene ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbene ring, a substituted C 3 -C 8 aliphatic ring, a substituted C 3 -C 8 carbene ring, a substituted 3-8 membered aliphatic ring or a substituted 3-8 membered carbene ring;
  • the above substitution refers to being randomly 1-2 selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6 membered heterocycloalky
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl,
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • R 4 is L 1 -R 5 , L 1 means absent, CR a R b or NR a ;
  • R is any ring structure in the following formula (i), formula (ii) or formula (iii):
  • W 1 represents CR W1 R W2 or NR W1 ;
  • R c and R d together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens; or R d and R d' together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens;
  • R 1" , R 2" , R 3" , R 4" , R 5" , R 6" , R 7" , R 8" Each independently represents hydrogen, halogen, cyano, nitro, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a ⁇ -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a ;
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl,
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl,
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl,
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • R 5 is any ring structure in the following formula (i), formula (ii) or formula (iii):
  • W 2 is N, and when W 1 is NR W1 , R W1 is not H;
  • W 2 is N, W 1 is NR W1 , and when R W1 is H, Y is not ethylene;
  • X 1 is NR X1' , and R X1' and R X3 together with the atoms connected to them form a 5- to 8-membered heteroaromatic ring or are substituted by one or more hydroxyl groups 5-8 membered heteroaromatic rings;
  • X 1 is CR X1 , wherein the C atom in X 1 is connected to the C atom in the aryl or heteroaryl group in R 1 through -O-(CH 2 ) n1 - * , * -NH-(CH 2 ) n2 -, -C ⁇ C-(CH 2 ) n3 -C ⁇ C- * or -(CH 2 ) n4 -O-(CH 2 ) n5 - * , wherein the * terminal is connected to C in X 1 Atoms connected;
  • R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
  • R 1-3 and R 1-4 are independently halogen
  • the types of heteroatoms in the 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 5-14-membered heteroaryl, 3-8-membered heterocycloalkyl, 3-6-membered aliphatic heterocycle, 3-6-membered carboalkene ring, 5-8-membered heteroaryl ring, 3-8-membered aliphatic heterocycle, 3-8-membered carbazaene ring, 3-8-membered aliphatic heterocycle and 3-8-membered carbazaene ring are each independently selected from one, two or three of N, O and S;
  • X 1-2 is independently C 1 -C 6 alkyl.
  • X 1-4 is independently H, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted by one or more halogens;
  • X 1-7 is OH or C 1 -C 6 alkyl.
  • X 2 is N or CR X2
  • R X2 is CN
  • X 3 is N or CR X3
  • R X3 is H or C 1 -C 6 alkyl
  • R 2 is halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
  • L 2 represents -O-(C 1 -C 6 alkylene).
  • R3 is the following ring structure:
  • R 1' , R 2' , R 3' , R 4' , R 5' , R 6' , R 7' , R 8' , R 9' , R 10' , R 11' , R 12' each independently represent hydrogen or halogen;
  • R 3' and R 4' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 9' and R 10' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 3' and R 4' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring. Replaced by 1-2 halogens ;
  • R 4' and R 5' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 8' and R 9' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocycle, a substituted C 3 -C 8 aliphatic carbocycle or a 3-8 membered aliphatic heterocycle, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 2' and R 3' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 10' and R 11' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocycle, a substituted C 3 -C 8 aliphatic carbocycle or a 3-8 membered aliphatic heterocycle, and the substitution refers to being optionally substituted by 1-2 halogens.
  • R 4 is L 1 -R 5
  • L 1 represents absence or NR a
  • R a represents hydrogen or C 1 -C 6 alkyl.
  • R is any ring structure of the following formula (i), formula (ii) or formula (iii):
  • W 1 represents CR W1 R W2 or NR W1 ;
  • R a and R b each independently represent hydrogen or C 1 -C 6 alkyl
  • Y is methylene, ethylene, C 3 alkylene, C 2 -C 3 alkenylene, or R c and R d together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens; or R d and R d' together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens;
  • R 1" , R 2" , R 3" , R 4" , R 5" , R 6" , R 7" , R 8" each independently represent hydrogen or C 1 -C 6 alkyl
  • R 2" and R 3" together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring.
  • R 3" and R 4" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring with the atoms connected to it.
  • R 4" and R 5" together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring.
  • R 3" and R 4" together with the atom connected to it form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring.
  • ring K is an aromatic ring or a heteroaryl ring
  • X 1 is N, NR X1' or CR X1 ,
  • X 1-2 are independently C 1 -C 6 alkyl;
  • X 1-4 are independently H , C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted by one or more halogens;
  • X 1-7 is OH or C 1 -C 6 alkyl;
  • R X1' and R X3 and the atoms connected to them together form a 5-8 membered heteroaryl ring or a 5-8 membered heteroaryl ring substituted by one or more hydroxyl groups;
  • R 1 is a C 6 -C 14 aryl group, a C 6 -C 14 aryl group substituted by one or more R 1-1 , a 5-14 membered heteroaryl group or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
  • R 1-3 and R 1-4 are independently halogen
  • X 1 is CR X1 , wherein the C atom in X 1 is connected to the C atom in the aryl or heteroaryl group in R 1 through -O-(CH 2 ) n1 - * , * -NH-(CH 2 ) n2 -, -C ⁇ C-(CH 2 ) n3 -C ⁇ C- * or -(CH 2 ) n4 -O-(CH 2 ) n5 - * , wherein the * end is connected to the C atom in X 1 connected;
  • n1, n2, n3, n4 and n5 are each independently 1, 2, 3, 4, 5 or 6;
  • R 2 is halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy
  • R 3 is the following ring structure:
  • R 1' , R 2' , R 3' , R 4' , R 5' , R 6' , R 7' , R 8' , R 9' , R 10' , R 11' , R 12' each independently represent hydrogen or halogen;
  • R 3' and R 4' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 9' and R 10' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 3' and R 4' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, the substitution refers to being optionally substituted by 1-2 halogens ; Replaced by 1-2 halogens;
  • R 4' and R 5' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 8' and R 9' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocycle, a substituted C 3 -C 8 aliphatic carbocycle or a 3-8 membered aliphatic heterocycle, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 2' and R 3' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 4 is L 1 -R 5 , L 1 means absent or NR a ,
  • R is any ring structure in the following formula (i), formula (ii) or formula (iii):
  • W 1 represents CR W1 R W2 or NR W1 ;
  • R a and R b each independently represent hydrogen or C 1 -C 6 alkyl
  • W 2 represents CH or N
  • Y is methylene, ethylene, C 3 alkylene, C 2 -C 3 alkenylene, or R c and R d together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens; or R d and R d' together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens;
  • R 1" , R 2" , R 3" , R 4" , R 5" , R 6" , R 7" , R 8" each independently represent hydrogen or C 1 -C 6 alkyl
  • R 2" and R 3" together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring.
  • R 3" and R 4" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring with the atoms connected to it.
  • R 5" and R 6" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring with the atoms connected to it,
  • R 3" and R 4" together with the atoms connected to it form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring.
  • R 3 , R 3' and R 4' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 9' and R 10' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 3' and R 4' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring. Replaced by 1-2 halogens ;
  • R 4' and R 5' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocycle, a substituted C 3 -C 8 aliphatic carbocycle or a 3-8 membered aliphatic heterocycle, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 2' and R 3' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocycle, a substituted C 3 -C 8 aliphatic carbocycle or a 3-8 membered aliphatic heterocycle, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 10' and R 11' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocycle, a substituted C 3 -C 8 aliphatic carbocycle or a 3-8 membered aliphatic heterocycle, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 5 is any ring structure in the following formula (i), formula (ii) or formula (iii):
  • W 2 is N, and when W 1 is NR W1 , R W1 is not H;
  • W 2 is N, W 1 is NR W1 , and when R W1 is H, Y is not ethylene;
  • X 1 is NR X1' , and R X1' and R X3 together with the atoms connected to them form a 5-8 membered heteroaryl ring or a 5-8 membered heteroaryl ring substituted by one or more hydroxyl groups;
  • X 1 is CR X1 , wherein the C atom in X 1 and the C atom in the aryl or heteroaryl group in R 1 pass through -O-(CH 2 ) n1 - * , * -NH-(CH 2 ) n2 -, -C ⁇ C-(CH 2 ) n3 -C ⁇ C- * or -(CH 2 ) n4 -O-(CH 2 ) n5 - * is connected, where the * end is connected to the C atom in X 1 ;
  • R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
  • R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1
  • two adjacent R 1-1 and the atoms connected to it together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-3
  • R 1 is a 5- to 14-membered heteroaryl group substituted by one or more R 1-2
  • two adjacent R 1-2 and their connected atoms together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-4
  • R 1-3 and R 1-4 are independently halogen.
  • X 1-4 is independently C 1 -C 6 alkyl.
  • X 1-7 is C 1 -C 6 alkyl.
  • X 3 is CR X3
  • R X3 is H
  • R X1' and R X3 together with the atoms connected to them form a 5-8 membered heteroaromatic ring.
  • R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
  • R 2 is halogen
  • R3 is hour
  • ring A, ring B and ring C share one carbon atom with the parent structure, ring D and ring E share two atoms and one bond with the parent structure; ring A, ring B and ring C share one carbon atom with the parent structure, ring D and ring E share two atoms and one bond with the parent structure; ring A, ring B, ring C, ring D and ring E are each independently 3-8 membered aliphatic heterocyclic rings, C 3 -C 8 aliphatic carbocyclic rings, or C 3 -C substituted by one or more halogens 8 aliphatic carbon rings;
  • R 4 is formula (i), formula (ii) or formula (iii):
  • R 1" , R 2" , R 7" and R 8" are each independently hydrogen;
  • W 1 represents CR W1 R W2 or NR W1 ;
  • W 2 represents N;
  • R W1 is CR W1 R W2
  • R W1 and R W2 each independently represent H, a 3-8 membered heterocycloalkyl group or R W1 and R W2 together form a 3-8 membered aliphatic heterocycle together with the atoms connected to it;
  • R W1 is NR W1
  • R W1 is H
  • R 1" , R 2" , R 3" , R 4" , R 7" and R 8" are each independently hydrogen or C 1 -C 6 alkyl
  • R independently represents hydrogen or C 1 -C 6 alkyl
  • R 4 is
  • R 4-2 for C 1 -C 6 Alkyl, R 4-2 The number is one or more
  • R 4-3 and R 4-4 Each independently is H or 3-8 membered heterocycloalkyl, or R 4-3 and R 4-4
  • ring G, ring I and ring J share one carbon atom with the parent structure
  • ring F and ring H share two atoms and one bond with the parent structure
  • ring F, ring G, ring H, ring I and ring J are independently C 3 -C 8 Aliphatic carbon ring, 3-8 membered aliphatic heterocyclic ring, 5-8 membered lactam ring or one or more R e Substituted 3-8 membered
  • the halogens can be independently F, Cl, Br or I, such as Cl.
  • the C 1 -C 6 alkyl group can be independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.
  • the C 3 -C 6 cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.
  • the C 2 -C 6 alkenyl in R X1 , can be a C 2 -C 4 alkenyl, such as vinyl.
  • the C 2 -C 6 alkynyl can be a C 2 -C 4 alkynyl, such as ethynyl.
  • the 3-6 heterocycloalkyl groups can be independently tetrahydropyrrolyl, oxetanyl, tetrahydropyranyl or piperidinyl, more for example
  • the type of heteroatoms can be N, and the number of heteroatoms can be 2.
  • the 5-14 membered heteroaryl group can be a 5-6 membered heteroaryl group, such as pyrazolyl or imidazolyl, more for example
  • the type of heteroatoms in the 3-6 membered heterocycloalkenyl group, can be independently selected from N and O, and the number of heteroatoms can be independently 1.
  • the 3-6 membered heterocycloalkenyl groups can be independently 6-membered heterocycloalkenyl groups, for example, containing 1 O atom A 6-membered heterocycloalkenyl or a 6-membered heterocycloalkenyl containing 1 N atom, more for example
  • the C 1 -C 6 alkyl group can be independently a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl.
  • the C 3 -C 8 cycloalkyl can be a C 3 -C 6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl, cyclopentyl or cyclohexyl.
  • the 3-8 membered heterocycloalkyl group can be 3-6 membered heterocycloalkyl group, such as piperidinyl, morpholinyl or piperazinyl.
  • the C 5 -C 8 cycloalkene can be a C 5 -C 6 cycloalkene, such as cyclopentenone, at this time, Can be
  • the type of heteroatoms in the 5-8 membered heteroaromatic rings can be N independently, and the number of heteroatoms can be 2, 3 or 4 independently.
  • the 5-8 membered heteroaromatic ring can be independently a 5-membered heteroaromatic ring, such as a pyrazole ring, a triazole ring, a tetrazole ring or an oxadiazole ring, at this time, Can be
  • the C 6 -C 14 aryl groups can be independently phenyl or naphthyl, for example
  • the type of heteroatom in the 5- to 14-membered heteroaryl group in R 1 , can be independently N, and the number of heteroatom can be independently 1.
  • the 5-14 membered heteroaryl groups can be independently 5-12 membered heteroaryl groups, such as pyridyl, quinolinyl or isoquinolyl, more for example
  • the halogens can be independently F, Cl, Br or I, such as F or Cl.
  • the C 1 -C 6 alkyl group can be independently a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl.
  • the C 1 -C 10 alkyl group can be independently a C 1 -C 9 alkyl group, such as n-nonyl.
  • n2 is 6.
  • n3 is 4.
  • n4 is 1.
  • n5 is 1.
  • R is one or more R 1-1 substituted naphthyl, one or more R 1-1 substituted phenyl, one or more R 1-2 substituted pyridyl, one or more R 1-2 substituted quinolinyl or one or more R 1-2 substituted isoquinolinyl, for example
  • the C 1 -C 6 alkyl group can be a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • the C 1 -C 6 alkoxy group can be a C 1 -C 4 alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.
  • R 2 is F
  • the C 1 -C 6 alkylene group in L 2 , can be a C 1 -C 3 alkylene group, such as methylene, ethylene or propylene, preferably methylene.
  • the type of heteroatom in the 3-8 membered aliphatic heterocyclic ring, can be independently O, and the number of heteroatom can be independently 1.
  • the 3-8 membered aliphatic heterocyclic ring refers to all 3-8 membered aliphatic heterocyclic rings within the scope of the above definition of R 3 , such as the 3-8 membered aliphatic heterocyclic rings in ring A, ring B, ring C, ring D and ring E.
  • the 3-8 membered aliphatic heterocyclic rings can be independently 4-5 membered aliphatic heterocyclic rings, such as oxetane or tetrahydrofuran rings.
  • the 3-8 membered aliphatic heterocycles can be independently
  • the 3-8 membered aliphatic heterocyclic rings described in ring A, ring B and ring C can be independently
  • the 3-8 membered aliphatic heterocycles can be independently
  • the 3-8 membered aliphatic heterocycles can be independently
  • the C 3 -C 8 aliphatic carbocycles can be independently
  • the C 3 -C 8 aliphatic carbocyclic ring can be independently
  • the C 3 -C 8 aliphatic carbocycles can be independently
  • the C 3 -C 8 aliphatic carbocyclic ring can be independently
  • the halogen in the definition of R 3 , can be F, Cl, Br or I, such as F.
  • the halogen refers to all the halogens mentioned in the definition of R 3 above, such as the halogens in ring A, ring B, ring C, ring D and ring E.
  • the C 1 -C 10 alkyl group in R 4-1 , can be a C 1 -C 9 alkyl group, such as n-nonyl or isopropyl.
  • the type of heteroatoms can be independently selected from N and O, and the number of heteroatoms can be independently 1 or 2.
  • the 3-8 membered heterocycloalkyl groups can be independently 4-6 membered heterocycloalkyl groups, such as tetrahydropyrrolyl, morpholinyl or piperidinyl, more for example
  • the 3-8 membered aliphatic heterocyclic ring can be a 4-5 membered aliphatic heterocyclic ring, such as N-heterocyclobutane, more for example
  • the C 3 -C 8 aliphatic carbocycle can be independently a C 3 -C 6 aliphatic carbocycle, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclopropane, cyclobutane or cyclohexane.
  • the C 3 -C 8 aliphatic carbocycle refers to all C 3 -C 8 aliphatic carbocycles within the scope of the definition of R 4 above, such as C 3 -C 8 aliphatic carbocycles in ring F, ring G, ring H, ring I and ring J.
  • the C 3 -C 8 aliphatic carbocycles can be independently
  • the C 3 -C 8 aliphatic carbocyclic ring can be independently
  • the C 3 -C 8 aliphatic carbocycles can be independently
  • the C 3 -C 8 aliphatic carbocyclic ring can be independently
  • the 3-8 membered aliphatic heterocyclic rings can be independently 4-5 membered aliphatic heterocyclic rings, such as tetrahydropyrrole ring or N-heterocyclobutane.
  • the 3-8 membered aliphatic heterocyclic ring refers to all 3-8 membered aliphatic heterocyclic rings within the scope of the definition of R 4 above, such as the 3-8 membered aliphatic heterocyclic rings in ring F, ring G, ring H, ring I and ring J.
  • the 3-8 membered aliphatic heterocycles can be independently
  • the 3-8 membered aliphatic heterocycles can be independently
  • the 3-8 membered aliphatic heterocycles can be independently
  • the 3-8 membered aliphatic heterocycles can be independently
  • the 5- to 8-membered lactam rings may be independently 5-membered lactam rings.
  • the 5- to 8-membered lactam rings can be independently
  • the C 1 -C 6 alkyl group can be a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.
  • X can be F, Cl, Br or I, such as F or Br.
  • R3 is hour
  • X is N
  • Ring A is a 3-8 membered aliphatic heterocycle, a C 3 -C 8 aliphatic carbocycle or a C 3 -C 8 aliphatic carbocycle substituted by one or more halogens, such as oxetane, cyclopropane, or F-substituted cyclopropane, more for example
  • Ring D and ring E are each independently a C 3 -C 8 aliphatic carbocyclic ring, such as cyclopropane, more for example
  • X 1 is CR X1 ;
  • the 3-6 membered heterocycloalkyl is preferably oxetanyl or tetrahydropyrrolyl, for example
  • the 5-14 membered heteroaryl is preferably pyrazolyl, for example
  • Ring A is preferably a C 3 -C 8 aliphatic carbocyclic ring substituted by one or more halogens, such as cyclopropane substituted by F, more for example
  • R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
  • R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1
  • two adjacent R 1-1 and the atoms connected to it together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-3
  • R 1 is a 5- to 14-membered heteroaryl group substituted by one or more R 1-2
  • two adjacent R 1-2 and their connected atoms together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-4
  • R 1-3 and R 1-4 are independently halogen.
  • the heterocyclic compound shown in formula I-0 is a heterocyclic compound shown in formula I:
  • X 1 is N or CR X1 , R X1 is CN, halogen, CF 3 , SO 2 Me, POMe 2 or NH 2 ;
  • X 2 is N or CR X2 , R X2 is CN;
  • R 2 is halogen
  • R and R are selected from any of the following schemes:
  • R3 is hour
  • R3 is hour
  • certain groups in the heterocyclic compound represented by formula I, its pharmaceutically acceptable salts, its stereoisomers or their solvates are defined as follows, and the unmentioned groups are the same as those described in any scheme of the present application (referred to as "in a certain scheme of the present invention"), and X1 is N, C-CN, C-Cl, C- CF3 , C- SO2Me , C- POMe2 or C- NH2 .
  • X 2 is N or C-CN.
  • R 2 is F.
  • the compound shown in formula I-0 is a compound shown in formula I-1:
  • X 1 is NR X1' , and R X1' and R X3 together with the atoms connected to them form a 5-8 membered heteroaromatic ring or a 5-8 membered heteroaromatic ring substituted by one or more hydroxyl groups; the definitions of other substituents are as described in any scheme herein;
  • X 1 is CR X1 , wherein, the C atom in X 1 is connected to the C atom in the aryl or heteroaryl group in R 1 through -O-(CH 2 ) n1 - * , * -NH-(CH 2 ) n2 - , -C ⁇ C- (CH 2 ) n3 -C ⁇ C- * or -(CH 2 ) n4 -O-(CH 2 ) n5 - * , where the * end is connected to X 1 C atoms are connected; the definitions of other substituents and the definitions of n1, n2, n3, n4 and n5 are as described in any scheme herein;
  • R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1
  • two adjacent R 1-1 and the atoms connected to them together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-3
  • R 1 is a 5- to 14-membered heteroaryl group substituted by one or more R 1-2
  • two adjacent R 1-2 and their connected atoms together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-4
  • R 1-3 and R 1-4 are independently halogen
  • the compound shown in formula I-0 is a compound shown in formula I-2:
  • R3 is , wherein, Ring A, Ring B and Ring C share one carbon atom with the parent structure, Ring D and Ring E share two atoms and one bond with the parent structure; Ring A, Ring B, Ring C, Ring D and Ring E are each independently 3-8 membered aliphatic heterocyclic rings, C 3 -C 8 aliphatic carbocyclic rings, or C 3 -C 8 aliphatic carbocyclic rings substituted by one or more halogens;
  • the present invention also provides a heterocyclic compound as shown below, its pharmaceutically acceptable salt, its stereoisomer, or their solvate (referring to the aforementioned heterocyclic compound as shown below, its pharmaceutically acceptable salt or its stereoisomer):
  • the pharmaceutically acceptable salt of the heterocyclic compound is as follows:
  • the present invention also provides a heterocyclic compound as shown below, its pharmaceutically acceptable salt, its stereoisomer or their solvate (referring to the aforementioned heterocyclic compound as shown below, its pharmaceutically acceptable salt or its stereoisomer):
  • the compound whose retention time is 0.660min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 50% of B phase for 5 minutes, flow rate: 4 ml/min;
  • the compound whose retention time is 2.311min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase from 5% to 40% in 4 minutes, keep 40% B phase for 2.5 minutes, keep 5% B phase for 1.5 minutes, flow rate: 2.8 ml/min;
  • the compound whose retention time is 3.397min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase from 5% to 40% in 4 minutes, keep 40% B phase for 2.5 minutes, keep 5% B phase for 1.5 minutes, flow rate: 2.8 ml/min;
  • the compound whose retention time is 1.942min under the following conditions is One stereoisomer in: chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes, flow rate: 4 ml/min;
  • the compound whose retention time is 2.343min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes, flow rate: 4 ml/min;
  • the compound whose retention time is 3.004min under the following conditions is One stereoisomer in: chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes, flow rate: 4 ml/min;
  • the compound whose retention time is 2.414min under the following conditions is A stereoisomer in: Chromatographic column: Chiralpak IC-3, 100mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: 40% B phase, flow rate: 2.8 ml/min;
  • the compound whose retention time is 1.150min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep 40% of B phase, flow rate: 4 ml/min;
  • the compound whose retention time is 2.203min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep 40% of B phase, flow rate: 4 ml/min;
  • the compound whose retention time is 1.696min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes; flow rate: 4 ml/min;
  • the compound whose retention time is 2.137min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase is from 5% to 40% in 2 minutes, keep 40% B phase for 1.2 minutes, keep 5% B phase for 0.8 minutes; flow rate: 4 ml/min.
  • the compound whose retention time is 1.787min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes; flow rate: 4 ml/min;
  • the compound whose retention time is 2.089min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes; flow rate: 4 ml/min;
  • the compound whose retention time is 0.797min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep 40% of B phase; Flow rate: 4 ml/min;
  • the compound whose retention time is 1.943min under the following conditions is One stereoisomer in: Chromatographic column: ChiralPak AD-3, 150*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 40% of B phase; Flow rate: 2.5 ml/min;
  • the compound whose retention time is 3.400min under the following conditions is One stereoisomer in: Chromatographic column: ChiralPak AD-3, 150*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 40% of B phase; Flow rate: 2.5 ml/min;
  • the compound whose retention time is 6.088min under the following conditions is A mixture of stereoisomers in: chromatographic column: Chiralpak IG-3 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: maintain 40% phase B, flow rate: 2.8 ml/min;
  • the compound whose retention time is 8.998min under the following conditions is A mixture of stereoisomers in: Chromatographic column: Chiralpak IG-3 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, phase B 0.05% diethylamine/isopropanol; gradient: maintain 40% phase B, flow rate: 2.8 ml/min;
  • the compound whose retention time is 1.374min under the following conditions is Two stereoisomer mixtures in: Chromatographic column: Chiralpak IG-3, 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 40% of B phase, flow rate: 2.8 ml/min;
  • the compound whose retention time is 2.812min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 40% of B phase, flow rate: 2.8 ml/min;
  • the compound whose retention time is 6.215min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 40% of B phase, flow rate: 2.8 ml/min;
  • the compound whose retention time is 1.251min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: maintain 40% of B phase; Flow rate: 4 ml/min;
  • the compound whose retention time is 0.369min under the following conditions is Two stereoisomer mixtures in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep B phase at 40%; Flow rate: 4 ml/min;
  • the compound whose retention time is 0.752min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep B phase at 40%; Flow rate: 4 ml/min;
  • the compound whose retention time is 1.937min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, phase B is 0.05% Diethylamine/isopropanol; gradient: keep phase B at 40%; flow rate: 4 ml/min;
  • the compound whose retention time is 3.692min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 150mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase is maintained at 40%; Flow rate: 2.5 ml/min.
  • phase A is trifluoroacetic acid/water (1.5mL/4L)
  • phase B is trifluoroacetic acid/acetonitrile (0.75mL/4L)
  • gradient phase B from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% of phase B for 2 minutes, keep 1% of B phase for 2 minutes; flow rate: 1.2 ml/min):
  • the retention time is the compound of 3.539min, which is
  • the retention time is the compound of 3.539min, which is
  • the compound whose retention time is 3.754min under the following conditions is One stereoisomer in: Chromatographic column: ChiralCel OD-3, 150mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; keep 40% of B phase; flow rate: 2.5 ml/min;
  • the compound whose retention time is 3.131min under the following conditions is One stereoisomer in: Chromatographic column: ChiralCel OD-3, 150mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; keep 40% of B phase; flow rate: 2.5 ml/min;
  • the compound whose retention time is 1.653min under the following conditions is One stereoisomer in: Chromatographic column: ChiralCel OD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; 2min rises from 5% B phase to 40% B phase, maintains 40% B phase for 1.2min, then maintains 5% B phase for 0.8min; flow rate: 4 ml/min;
  • the compound whose retention time is 1.763min under the following conditions is One stereoisomer in: Chromatographic column: ChiralCel OD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; 2min rises from 5% B phase to 40% B phase, maintains 40% B phase for 1.2min, then maintains 5% B phase for 0.8min; flow rate: 4 ml/min;
  • the compound whose retention time is 1.343min under the following conditions is One stereoisomer in: Chromatographic column: Cellulose-2 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 50% of B phase; Flow rate: 2.8 ml/min;
  • Chromatographic column Cellulose-2 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
  • the compound whose retention time is 1.739min under the following conditions is A stereoisomer in: Chromatographic column: Cellulose-2 100*4.6mm ID3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 50% of B phase; Flow rate: 2.8 ml/min;
  • Chromatographic column Cellulose-2 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
  • Chromatographic column Cellulose 2 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/methanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
  • the compound whose retention time is 4.369min under the following conditions is One stereoisomer in: Chromatographic column: Cellulose 2 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/methanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
  • the compound whose retention time is 4.500min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IC-3 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
  • the compound whose retention time is 2.676min under the following conditions is One stereoisomer in: Chromatographic column: (S, S) Whelk-01 100 ⁇ 4.6mm ID, 5.0um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: B phase maintains 60%; Flow rate: 2.5 ml/min;
  • the compound whose retention time is 3.176min under the following conditions is One stereoisomer in: Chromatographic column: (S, S) Whelk-01 100 ⁇ 4.6mm ID, 5.0um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: B phase maintains 60%; Flow rate: 2.5 ml/min;
  • the compound whose retention time is 0.634min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3 50*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase maintains 40%; Flow rate: 4 ml/min;
  • test conditions of the above retention time are not limited to the compound, as long as the above test conditions are used to measure, the retention time obtained is the same as that described above or within the error range, and the compound is a stereoisomer in the above-mentioned compound limited by the retention time, it falls within the scope of protection of the present invention.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • heterocyclic compound as described in any one of the preceding items, its pharmaceutically acceptable salt, its stereoisomer or their solvate, and
  • the present invention also provides an application of substance A or the pharmaceutical composition in the preparation of a KRAS G12D inhibitor, wherein the substance A is the heterocyclic compound as described in any one of the preceding items, its pharmaceutically acceptable salt, its stereoisomer or their solvate.
  • the KRAS G12D inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample to provide comparison, or to prepare a kit according to conventional methods in the field to provide rapid detection of KRAS G12D inhibitory effect.
  • the present invention also provides a substance A or the application of the pharmaceutical composition in the preparation of medicines.
  • the substance A is a heterocyclic compound as described in any one of the preceding items, a pharmaceutically acceptable salt thereof, a stereoisomer or a solvate thereof, and the medicine is used for treating cancer, such as colorectal cancer, gastric cancer, pancreatic cancer, non-small cell lung cancer, prostate cancer, breast cancer, etc.
  • pharmaceutically acceptable means that salts, solvents, auxiliary materials, etc. are generally non-toxic, safe and suitable for use by patients.
  • the "patient” is preferably a mammal, more preferably a human.
  • pharmaceutically acceptable salt refers to a salt prepared from a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base either in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, diethanolamine salts.
  • solvate refers to a compound of the present invention in combination with a stoichiometric or non-stoichiometric amount of solvent.
  • the solvent molecules in a solvate may exist in an ordered or non-ordered arrangement.
  • the solvent includes but not limited to: water, methanol, ethanol and the like.
  • stereoisomer refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin-layer chromatography, rotational chromatography, column chromatography, gas chromatography, high-pressure liquid chromatography, etc.), and can also be obtained by chiral resolution through bond formation (chemical combination, etc.) or salt formation (physical combination, etc.) with other chiral compounds.
  • 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%.
  • tautomers in the terms “compound”, “pharmaceutically acceptable salt”, “solvate” and “solvate of pharmaceutically acceptable salt”, it may exist in the form of a single tautomer or a mixture thereof, preferably in the form of a relatively stable tautomer.
  • cycloalkyl refers to a cyclic, saturated monovalent hydrocarbon group having a specified number of carbon atoms (eg, C 3 -C 6 ). Cycloalkyl groups include, but are not limited to: wait.
  • cycloalkenyl refers to a cyclic, unsaturated monovalent hydrocarbon group with a specified number of carbon atoms (for example, C 3 to C 6 ), which has one or more (for example, 1, 2 or 3) carbon-carbon sp 2 double bonds, which is a single ring and does not have aromaticity.
  • (Monocyclic)cycloalkenyl groups include, but are not limited to: wait.
  • carrier ring satisfies any of the following conditions, and the remaining definitions are the same as the term “cycloalkenyl”: 1. It is connected to the rest of the molecule through more than two single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
  • alkenyl refers to a linear or branched, unsaturated, monovalent hydrocarbon group having a specified number of carbon atoms (eg, C2 - C6 ), which has one or more (eg, 1, 2 or 3) carbon-carbon sp2 double bonds.
  • Alkenyl groups include, but are not limited to: vinyl, wait.
  • alkynyl refers to a straight-chain or branched, unsaturated monovalent hydrocarbon group with a specified number of carbon atoms (for example, C 2 to C 6 ), which has one or more (for example, 1, 2 or 3) carbon-carbon sp 3 triple bonds.
  • Alkynyl includes, but is not limited to, ethynyl and the like.
  • heterocycloalkyl refers to a cyclic, saturated monovalent group having a specified number of ring atoms (for example, 3 to 8 members), a specified number of heteroatoms (for example, 1, 2 or 3), and a specified type of heteroatom (one or more of N, O and S), preferably a monocyclic ring.
  • a heterocycloalkyl group is attached to the rest of the molecule through a carbon atom or a heteroatom.
  • Heterocycloalkyl groups include, but are not limited to: wait.
  • cycloenone examples include, but are not limited to
  • heteroaryl ring satisfies any of the following conditions, and the remaining definitions are the same as the term “heteroaryl”: 1. It is connected to the rest of the molecule through more than two single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
  • aryl refers to a cyclic, unsaturated monovalent hydrocarbon group with a specified number of carbon atoms (for example, C 6 to C 14 ), which is monocyclic or polycyclic (for example, 2 or 3). When it is polycyclic, two atoms and one bond are shared between the single rings, and (at least one ring/each ring) is aromatic. An aryl group is attached to the rest of the molecule through a carbon atom in an aromatic ring.
  • Aryl groups include, but are not limited to: phenyl or naphthyl and the like.
  • aromatic ring satisfies any of the following conditions, and the remaining definitions are the same as the term “aryl”: 1. It is connected to the rest of the molecule through more than two single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
  • heteroalicyclic ring satisfies any of the following conditions, and the remaining definitions are the same as the term “heterocycloalkyl”: 1. It is connected to the rest of the molecule through more than two single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
  • aliphatic carbocycle satisfies any of the following conditions, and the remaining definitions are the same as the term “cycloalkyl”: 1. It is connected to the rest of the molecule through more than two single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
  • alkoxy refers to the group R x -O-, R x is defined the same as the term “alkyl”. Alkoxy includes, but is not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, and the like.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effect of the present invention is that the compound of the present invention has good cell proliferation inhibitory activity on KRAS G12D mutated gastric cancer AGS cell line and metastatic pancreatic adenocarcinoma AsPC-1 cells. It has good stability of liver microsomes, liver cells, plasma and whole blood, good PK properties, and significant tumor inhibitory effect.
  • HPLC analysis uses SHIMADZU 20A high performance liquid chromatograph.
  • SFC separation uses The Berger MG II, MG III, Sepiatec's Prep SFC 100 system, Waters Prep 80Q SFC SYSTEM, Prep 150 AP SFC SYSTEM, Prep 200 SFC SYSTEM, Prep 350 SFC SYSTEM.
  • Flash column chromatography was performed using a Biotage IsoleraOne flash preparative chromatograph.
  • the thin-layer chromatography silica gel plate uses GF254 acrylic adhesive silica gel plate from Anhui Liangchen Silicon Source Materials Co., Ltd.
  • the specification of the silica gel plate used for thin-layer chromatography (TLC) is 0.25mm, and the specification used for TLC separation and purification products is 0.5mm.
  • Microwave reactions were performed using a Biotage Initiator+ microwave synthesizer.
  • the glove box uses DELLIX custom glove box.
  • the first step N-bromosuccinimide (145g, 815mmol) and silver nitrate (12.6g, 74.2mmol) were slowly added to a solution of ethynyltriisopropylsilane (135g, 742mmol) in acetone (2000mL), and the reaction solution was stirred at 25°C for 16 hours.
  • the reaction solution was concentrated, the residue and petroleum ether (1500 mL) were stirred for 0.5 hours, filtered, and the filtrate was spin-dried to obtain the crude compound (bromoethynyl)triisopropylsilane (171 g) as a yellow oily liquid.
  • 1 H NMR 400MHz, CDCl 3
  • ⁇ ppm 1.13-0.84 m, 21H).
  • Step 2 Dissolve 2-(4-fluorophenyl)acetic acid (200g, 1.30mol), 2,2-dimethyl-1,3-dioxane-4,6-dione (205g, 1.42mol) and 4-dimethylaminopyridine (14g, 114mmol) in acetonitrile (600mL), cool down to 0°C and slowly add diisopropylethylamine (485mL) dropwise, and stir at 0°C for 15 minutes. Control reaction temperature below 30 °C, pivaloyl chloride (175mL) is slowly added dropwise to The reaction solution was stirred at room temperature for 30 minutes, then raised to 50°C and stirred for 16 hours.
  • Step 3 Dissolve 5-(2-(4-fluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (362 g, 1.29 mol) in tert-butanol (930 mL), heat to 90° C. and stir for 2 hours. The reaction solution was spin-dried to obtain the crude compound tert-butyl 4-(4-fluorophenyl)-3-oxobutanoate (280 g) as a yellow solid.
  • Step 4 tert-butyl 4-(4-fluorophenyl)-3-oxobutyrate (278g, 1.10mol) was dissolved in dichloromethane (2480mL), trifluoroacetic acid (575mL, 7.50mol) was added at 0°C, and the reaction was stirred at 25°C for 16 hours. After the reaction was completed, it was concentrated in vacuo to obtain the crude compound 4-(4-fluorophenyl)-3-oxobutanoic acid (231 g) as a white solid.
  • Step 5 4-(4-fluorophenyl)-3-oxobutanoic acid (231 g, 1.18 mol) was dissolved in trifluoromethanesulfonic acid (1230 mL, 13.9 mol), and the reaction was stirred at 25° C. for 24 hours. Slowly add ice water (10L) at 0°C, and extract the reaction solution with ethyl acetate (5L*3). The combined organic phases were washed with water (2 L) and saturated brine (2 L), dried over sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure.
  • Step 6 Mix 7-fluoronaphthalene-1,3-diol (88g, 494mmol), (bromoethynyl)triisopropylsilane (155g, 592mmol) and potassium acetate (98g, 1.0mol) in dioxane (640mL), add dichloro(p-methylisopropylphenyl)ruthenium(II) dimer (30.2g, 49.6mmol) under nitrogen, and the reaction solution is 110°C Stir for 2 hours.
  • Step 7 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (123g, 343mmol) was dissolved in dichloromethane (1230mL), lowered to 0°C, diisopropylethylamine (180mL, 1030mmol) and chloromethyl methyl ether (36.5g, 454mmol) were slowly added to the reaction solution, and the reaction was stirred at 20°C for 16 hours.
  • dichloromethane 1230mL
  • diisopropylethylamine 180mL, 1030mmol
  • chloromethyl methyl ether 36.5g, 454mmol
  • Step 8 Dissolve 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol (48.0g, 119mmol), diisopropylethylamine (62mL, 357mmol), 4-dimethylaminopyridine (3.00g, 24.5mmol) in dichloromethane (480mL), slowly add pivaloyl chloride (29mL, 238mL) at 0°C mmol), the reaction solution was stirred at 20°C for 2 hours.
  • Step 9 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ylpivalate (50g, 102mmol) was dissolved in N,N-dimethylformamide (916mL), cesium fluoride (167g, 1099mmol) was added, and the reaction was stirred at 20°C for 3 hours. After the reaction, the solvent was removed by concentration under reduced pressure. The crude product was dissolved in ethyl acetate (1000 mL) and water (2000 mL), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (1000 mL*2).
  • Step 11 Dissolve 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-ylpivalate (16g, 47.8mmol) in methanol (250mL), add potassium hydroxide (8.50g, 151mmol), and stir the reaction at 20°C for 2 hours.
  • reaction solution was adjusted to pH 6 with dilute hydrochloric acid (1M) at 0°C, extracted with ethyl acetate (200mL*3), combined the organic phases, washed with saturated brine (100ml), dried over sodium sulfate, filtered, and the filtrate was spin-dried, and the residue was purified by flash column chromatography (silica gel, 0-5% gradient ethyl acetate/petroleum ether) to obtain the compound 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-ol (11g, 43 .9 mmol, yield 92%), as a yellow solid.
  • Step 12 Dissolve 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-ol (11g, 43.9mmol) and diisopropylethylamine (23mL, 132mmol) in dichloromethane (220mL), slowly add trifluoromethanesulfonic anhydride (11mL, 67.1mmol) dropwise at -40°C, and stir the reaction at -40°C for 2 hours. After the reaction was completed, the reaction was quenched with ice water (200 mL), and extracted with dichloromethane (200 mL*2).
  • the thirteenth step 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl trifluoromethanesulfonate (15g, 39.2mmol), bis Alcohol borate (20g, 78.7mmol), potassium acetate (12g, 122mmol) were mixed in toluene (380mL), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (3.20g, 3.92mmol) was added under nitrogen, and the reaction was raised to 130°C and stirred for 16 hours. The reaction solution was filtered, and the filtrate was spin-dried.
  • Step 1 To a solution of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol (4.93 g, 12.2 mmol) and diisopropylethylamine (7 mL, 40.0 mmol) in dichloromethane (75 mL) was added trifluoromethanesulfonic anhydride (5.19 g, 18.4 mmol) at -40°C. The solution was stirred at -40°C for 1 hour, and the solution was concentrated.
  • Second step Add potassium acetate (3.31 g, 33.7 mmol) and 1, 1-Bis(diphenylphosphino)ferrocenepalladium chloride (0.92g, 1.13mmol). The suspension was stirred at 130°C for 3 hours. The suspension was filtered and concentrated to give a black crude product.
  • Step 1 Dissolve compound 7-fluoro-1-tetralone (18.0g, 109mmol) in acetic acid (300mL) and hydrobromic acid (33% acetic acid solution, 2.5mL), add liquid bromine (19.2g, 120mmol) at 0°C and dissolve in acetic acid (20mL). The reaction was stirred at 25°C for 3 hours. The reaction solution was diluted with dichloromethane (300 mL), washed with water (70 mL*3), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the crude product was dissolved in dimethylformamide (200 mL), lithium bromide (16.2 g, 186 mmol) and lithium carbonate (13.7 g, 186 mmol) were added, and the reaction was stirred at 160° C. for 3.5 hours.
  • the reaction solution was diluted with ethyl acetate (500 mL), dried with industrial brine (500 mL*2), sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Second step 7-fluoronaphthalen-1-ol (14.3g, 88.2mmol), (bromoethynyl)triisopropylsilane (27.6g, 105mmol), sodium acetate (1.45g, 17.6mmol) and potassium carbonate (12.2g, 88.2mmol) were dissolved in dichloroethane (192mL), and dichloro(p-methylisopropylphenyl) ruthenium (II) dimer ( 8.10 g, 13.2 mmol), and the reaction solution was stirred at 50° C. for 16 hours. After the reaction was completed, filter and spin the filtrate to dryness.
  • Step 3 Dissolve 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol (28.5g, 83.2mmol), diisopropylethylamine (59.0mL, 338mmol) in dichloromethane (500mL), slowly add trifluoromethanesulfonic anhydride (35.8g, 127mmol) dropwise at -40°C, and stir the reaction at -40°C for 2 hours. After the reaction was completed, it was quenched with ice water (500 mL), and extracted with DCM (200 mL*2).
  • Step 4 Dissolve 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl trifluoromethanesulfonate (5.20g, 10.9mmol), bis-diancol borate (4.17g, 16.4mmol), potassium acetate (6.18g, 21.9mmol) in toluene (100mL), and add [1,1-bis(diphenylphosphino)ferrocene]diferrocene under nitrogen Palladium chloride in dichloromethane (0.89g, 1.10mmol), the reaction was raised to 130°C and stirred for 3 hours. After the reaction, filter and spin the filtrate to dryness.
  • Step 1 To compound 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (4.00g, 15.84mmol) was added diisopropylethylamine (4mL, 23.77mmol), dichloromethane solution (140mL) and compound (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (3.87 g, 18.22mmol) and stirred at -40°C for 1 hour.
  • Second step To a mixture of compound (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (8.00 g, 18.6 mmol) and 2,2,2-trifluoroethanol (18.6 g, 186.7 mmol) was added diisopropylethylamine (5 mL , 28.0 mmol). The solution was stirred at 80°C for 16 hours.
  • the third step under the protection of nitrogen, the compound tert-butyl (1R, 5S)-3-(7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.00g, 18.3mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4 , 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (10.7 g, 20.9 mmol) in dioxane (200 mL) was added cesium carbonate solution (1.5 M in water, 43 mL) and chloro[(n-butylbis(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]
  • the first step compound tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (19.2g , 22.9 mmol) in dimethylformamide (250 mL) was added cesium fluoride (21.6 g, 142.5 mmol). The mixture was stirred at 25°C for 2 hours.
  • the second step under the protection of nitrogen, tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8.00g, 11.6mm ol) in ethyl acetate (200 mL) was added palladium carbon (5%, 4.00 g), and the reaction system was replaced with hydrogen. Stir the mixture at 25°C Stir for 16 hours.
  • Step 1 Compound 2-amino-4-bromo-3-fluorobenzoic acid (25.0g, 107mmol) was dissolved in N,N-dimethylformamide (100mL), N-iodosuccinimide (36.0g, 160mmol) was added, and the mixture was stirred at 80°C for 2 hours. After the reaction solution was cooled to room temperature, it was added to water (3 L), beaten at room temperature for 1 hour, filtered and washed with water (300 mL*3), and the filter cake was vacuum-dried to obtain compound 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (34.0 g, 94 mmol, yield 88%).
  • LCMS (ESI): [M+H] + 361.9.
  • the second step the compound 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (30.0 g, 83.3 mmol) and urea (50.0 g, 833 mmol) were added to the reaction flask.
  • the temperature of the reaction system was raised to 200° C. for 4 hours. Cool to room temperature, add water (300mL) and raise the temperature to 80°C for beating and stirring for half an hour, filter while hot, repeat the beating and filtering operation of the filter cake twice, and vacuum dry the filter cake to obtain 7-bromo-8-fluoro-6-iodoquinazoline-2,4-dihydroxyl (26.7g, 69.3mmol, yield 83%).
  • LCMS (ESI): [M+H] + 387.0.
  • the third step the compound 7-bromo-8-fluoro-6-iodoquinazoline-2,4-diol (24.7g, 64.1mmol) was added to phosphorus oxychloride (300mL), diisopropylethylamine (40mL, 224mmol) was added at 0°C, and stirred at 130°C for 4 hours.
  • the fourth step To compound 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (10.0g, 23.7mmol) in dichloromethane (100mL) solution, add (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester (5.54g, 26.1mmol) and triethylamine (10mL, 71mmol), the reaction solution in Stir at 20°C for 2 hours.
  • the fifth step the compound tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-Carboxylate (3.00 g, 5.00 mmol) was added to trifluoroethanol (15 mL), diisopropylethylamine (1560 uL, 8.94 mmol) was added, and the reaction solution was stirred at 50° C. for 3 hours.
  • the first step To the compound tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.00g, 5.02mmol) in N,N-dimethylacetamide (30mL) solution, add cuprous cyanide (4.50g, 50.2mmol) and zinc under nitrogen atmosphere powder (0.72g, 11.0mmol), and the reaction solution was stirred at 100°C for 16 hours.
  • the second step the compound (1R,5S)-3-(7-bromo-2-chloro-6-cyano-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.48g, 2.98mmol) was added to trifluoroethanol (15mL), diisopropylethylamine (1560uL, 8.94mmol) was added, and the reaction solution was stirred at 50°C 3 hours.
  • the first step Compound 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (0.50g, 1.51mmol) was dissolved in dichloromethane (10mL), added (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester (0.32g, 1.51mmol) and triethylamine (630uL, 4.54mmol), stirred at 20°C for 1 6 hours.
  • Second step compound (1R,5S)-3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (90% purity, 550mg, 0.98mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (173mg , 1.09mmol) was added to N,N-dimethylformamide (5mL) and tetrahydrofuran (5mL), cesium carbonate (1.06g, 3.26mmol) and triethylenediamine (24mg, 0.22mmol) were added.
  • the first step the compound 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (3.00g, 11.88mmol) and trifluoroethanol (1.43g, 14.2mmol) were dissolved in toluene (60mL), and sodium tert-butoxide (1.14g, 11.8mmol) was added at 0°C, and the mixture was stirred at 0°C for 2 hours.
  • the second step to compound ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (0.71g, 4.43mmol), diisopropylethylamine (0.79mL, 4.43mmol) and 4A molecular sieves (1g) in 2-methyltetrahydrofuran (10mL) suspension, 0 °C added 2,7-dichloro-8-fluoro-4-(2,2, 2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (70% purity, 1.00 g, 2.21 mmol). The temperature of the reaction system was raised to 25° C. for 1 hour.
  • the third step the compound 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (purity 75%, 2.75g, 4.69mmol) was added to dioxane (60mL), and ((2-fluoro-6-(methoxy Methoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (3.21g, 6.27mmol) and cesium carbonate (1.5M in water, 12.5mL, 18.80mmol), added chloro[(n-butylbis(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(I
  • Step 1 Diisopropylethylamine (21 mL, 126 mmol) was added to a solution of L-proline methyl ester hydrochloride (7.00 g, 42.2 mmol) and (3-(bromomethyl)oxetan-3-yl)methanol (10 g, 55.2 mmol) in N,N-dimethylacetamide (80 mL), and the mixture was heated to 50° C. and stirred for 12 hours under nitrogen protection. The reaction mixture was spin-dried.
  • Second step To ((3-(hydroxymethyl)oxetan-3-yl)methyl)-L-proline methyl ester (1.00g, 4.36mmol) and carbon tetrabromide (1.88g, 5.67mmol) in dichloromethane (25mL) solution at 0°C, triphenylphosphine (1831mg, 6.98mmol) was added in 3 batches, and then the mixture was stirred at 25°C for 3 hours under nitrogen protection. The reaction mixture was spin-dried.
  • the third step under nitrogen protection, ((3-(bromomethyl)oxetan-3-yl)methyl)-L-proline methyl ester (200mg, 0.68mmol) in N,N-dimethylformamide (5mL) and tetrahydrofuran (1mL) solution was cooled to -70°C, and hexamethyldisilazide potassium (1M solution in tetrahydrofuran, 958uL, 0.96mmol) was added at -60°C to -70°C, The mixture was then stirred at -60°C to -70°C for 30 minutes.
  • Step 4 To a solution of methyl dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazine]-7a'(5'H)-carboxylate (150 mg, 0.71 mmol) in tetrahydrofuran (3 mL) under nitrogen protection at -10°C was added lithium aluminum tetrahydride (81 mg, 2.13 mmol), and then the mixture was stirred at -10°C for 30 minutes.
  • Step 1 To a solution of (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (8.00 g, 33.16 mmol) and potassium carbonate (9.16 g, 66.3 mmol) in dimethylformamide (80 mL) was slowly added iodomethane (11.7 g, 82.8 mmol) at 0°C. The solution was stirred at 0°C for 1 hour, then the solution was stirred at 25°C for 12 hours. The reaction was quenched with sodium sulfite solution and then concentrated.
  • Step 2 Add 5-(tert-butyl)6-methyl(S)-5-azaspiro[2.4]heptane-5,6-dicarboxylate (8.00g, 29.8mmol) to a solution of lithium diisopropylamide (2M mixed solution of tetrahydrofuran-n-heptane, 16mL, 32mmol) in tetrahydrofuran (80mL) at -78°C and stir for 1 hour, then add 1-bromo at -78°C -3-Chloropropane (3 mL, 31.3 mmol) and stirred for 2 hours, then at 25 °C for 12 hours.
  • Li diisopropylamide 2M mixed solution of tetrahydrofuran-n-heptane, 16mL, 32mmol
  • 1-bromo at -78°C -3-Chloropropane 3 mL, 31.3 mmol
  • Step 4 Add potassium iodide (340 mg, 2.06 mmol) and potassium carbonate (8.53 g, 61.7 mmol) to a solution of methyl 6-(3-chloropropyl)-5-azaspiro[2.4]heptane-6-carboxylate (85% purity, 4.67 g, 17.1 mmol) in methanol (100 mL) at 25° C. The solution was stirred at 25°C for 16 hours.
  • Step 5 Add dihydro-1'H, 3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-methyl carboxylate (purity 85%, 2.00g, 8.72mmol) in tetrahydrofuran (0.50mL) to lithium aluminum hydride (0.58g, 15.3mmol) in tetrahydrofuran (10mL) under a nitrogen atmosphere at 0°C. Stir at 60°C for 4 hours. After cooling to room temperature, the mixture was sequentially quenched with water (600 uL), 15% sodium hydroxide (600 uL) and water (1800 uL).
  • Step 1 To a solution of compound 3-azabicyclo[3.1.0]hexane hydrochloride (15g, 125mmol) and triethylamine (35mL, 250mmol) in dichloromethane (150mL), di-tert-butyl dicarbonate (31.7mL, 137mmol) was added at 20°C. The reaction was stirred at 20°C for 16 hours.
  • the second step the compound tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate (20g, 108mmol) and tetramethylethylenediamine (9150uL, 61.3mmol) were dissolved in tetrahydrofuran (150mL), and sec-butyl lithium (1.3M n-hexane solution, 63mL, 81.9mmol) was added at -65°C under nitrogen protection. The reaction was stirred at -65°C for 3 hours. The nitrogen was replaced with carbon dioxide and the reaction was stirred at -65°C under a carbon dioxide balloon for 1 hour.
  • Step 3 Add iodomethane (5.2 mL, 84.4 mmol) to a suspension of compound 3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (80% purity, 12 g, 42.2 mmol) and potassium carbonate (17.6 g, 126 mmol) in acetone (150 mL) at 20° C. The reaction was stirred at 20°C for 16 hours. The reaction solution was concentrated under reduced pressure.
  • the reaction was stirred at -65°C for 2 hours and then warmed to 0°C, saturated ammonium chloride solution (200 mL) was added, then extracted with ethyl acetate (100 mL*2), the organic layer was dried over anhydrous magnesium sulfate, filtered, and the organic layer was concentrated under reduced pressure.
  • Step 5 Compound 3-(tert-butyl) 2-methyl 2-(3-chloropropyl)-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (purity 80%, 2.70g, 6.81mmol) was dissolved in dichloromethane (60mL), and hydrogen chloride (4M solution in dioxane, 15mL, 60 mmol). The reaction was stirred at 25°C for 16 hours. Concentration under reduced pressure gave crude compound 2-(3-chloropropyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester (1.72 g) as a yellow oil.
  • LCMS (ESI): [M+H] + 218.1.
  • Step 6 The compound 2-(3-chloropropyl)-3-azabicyclo[3.1.0]hexane-2-carboxylate methyl ester (1.72g, 6.81mmol) was dissolved in methanol (50mL), and potassium carbonate (8.57g, 62.0mmol) and potassium iodide (0.34g, 2.07mmol) were added at 20°C. The reaction was stirred at 20°C for 16 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to yield two intermediates.
  • Step 7 Dissolve lithium aluminum tetrahydride (35 mg, 0.91 mmol) in tetrahydrofuran (6 mL), and add trans-hexahydrocyclopropane[a]pyrrolazine-6a(4H)-methyl carboxylate (110 mg, 0.61 mmol) in tetrahydrofuran (0.5 mL) under a nitrogen atmosphere at -40°C. The reaction was stirred at -10°C for 1 hour. Water (110uL) and 15% aqueous sodium hydroxide solution (110uL) were added to the reaction solution at 0°C, and then water (330uL) was added.
  • Step 1 Add furan-2-carbaldehyde (50 g, 520 mmol) and ethyl azidoacetate (80.6 g, 624 mmol) to a solution of sodium ethoxide (44.2 g, 650 mmol) in ethanol (1000 mL) at 0°C. The reaction mixture was stirred at 25°C for 16 hours. The mixture was diluted with saturated ammonium chloride (1 L) and extracted with ethyl acetate (1 L*3).
  • the second step a toluene solution of ethyl 2-azido-3-(furan-2-yl)acrylate (24 g, 115 mmol) was stirred at 115° C. for 3 hours, and a large amount of gas was released during the reaction. After the reaction was completed, it was concentrated in vacuo to obtain ethyl 4H-furo[3,2-b]pyrrole-5-carboxylate (16 g, 89.3 mmol, yield 77%) as a brown solid compound.
  • LCMS (ESI): [M+H] + 180.1.
  • Step 3 To a solution of ethyl 4H-furo[3,2-b]pyrrole-5-carboxylate (16.5 g, 92.1 mmol) in acetonitrile (160 mL) was added 4-dimethylaminopyridine (1.07 g, 8.75 mmol) and di-tert-butyl dicarbonate (27.7 g, 127 mmol) at 0°C. The reaction was stirred at 25°C for 16 hours.
  • Step 4 To a solution of 4-(tert-butyl)5-ethyl 4H-furo[3,2-b]pyrrole-4,5-dicarboxylate (8 g, 28.6 mmol) in ethanol (200 mL) was added palladium on carbon (10% purity, 6.10 g, 5.73 mmol). The reaction was stirred at 60°C under 50 psi hydrogen atmosphere for 16 hours. The mixture was filtered, and the filtrate was concentrated in vacuo to obtain 4-(tert-butyl)5-ethylhexahydro-4H-furo[3,2-b]pyrrole-4,5-dicarboxylate (7.86 g, 27.5 mmol, yield 96%) as a yellow oil.
  • LCMS (ESI): [M+Na] + 308.1.
  • Step 6 To a solution of 4-(tert-butyl)5-ethyl 5-(3-chloropropyl)hexahydro-4H-furo[3,2-b]pyrrole-4,5-dicarboxylate (1.62 g, 4.48 mmol) in dichloromethane (16 mL) was added trifluoroacetic acid (4 mL) at 0°C. The reaction was stirred at 20°C for 2 hours. The mixture was concentrated in vacuo to afford crude compound ethyl 5-(3-chloropropyl)hexahydro-2H-furo[3,2-b]pyrrole-5-carboxylate (1.10 g) as a yellow oily liquid.
  • LCMS (ESI): [M+H] + 262.1.
  • Step 7 Potassium carbonate (1.74 g, 12.6 mmol) and potassium iodide (0.07 g, 0.42 mmol) were added to a solution of ethyl 5-(3-chloropropyl)hexahydro-2H-furo[3,2-b]pyrrole-5-carboxylate (1.10 g, 4.21 mmol) in ethanol (50 mL). The mixture was stirred at 25°C for 16 hours.
  • Step 8 To a solution of ethyl hexahydro-2H-furo[2,3-b]pyrrolazine-7a(5H)-carboxylate (0.86 g, 3.82 mmol) in THF (9.00 mL) was added lithium aluminum tetrahydrogen (156 mg, 4.12 mmol) at -40°C. The mixture was stirred at -10°C for 1 hour. Water (160uL) was slowly added to the mixture, then 15% sodium hydroxide solution (160uL) and water (480uL) were added, anhydrous sodium sulfate was added and stirred, filtered and the filter cake was washed with tetrahydrofuran.
  • Step 1 Add lithium bistrimethylsilylamide (1M solution in tetrahydrofuran) to a solution of (3R)-2-tert-butyl-3-ethyl-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (950mg, 3.72mmol) and 1-bromo-3-chloropropane (1.76g, 11.1mmol) in tetrahydrofuran (10mL) under a nitrogen atmosphere at -65°C. 7.44 mL, 7.44 mmol). The reaction was stirred at 25°C for 16 hours.
  • Second step To a solution of 2-tert-butyl-3-ethyl-3-(3-chloropropyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (610 mg, 1.84 mmol) in dichloromethane (6 mL) was added hydrogen chloride (4M in dioxane, 1.38 mL, 5.51 mmol). The reaction was stirred at 25°C for 16 hours. The mixture was concentrated in vacuo to afford crude compound ethyl 3-(3-chloropropyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate (60% purity, 690 mg) as a colorless oil.
  • LCMS (ESI): [M+H] + 232.2.
  • Step 3 To a solution of ethyl 3-(3-chloropropyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate (60% purity, 670 mg, 1.73 mmol) in ethanol (26 mL) was added potassium iodide (29 mg, 0.17 mmol) and potassium carbonate (719 mg, 5.20 mmol). The reaction was stirred at 25°C for 16 hours. The mixture was filtered and concentrated.
  • Step 4 To a solution of ethyl hexahydrocyclopropane[b]pyrrolazine-5a(3H)-carboxylate (95% purity, 310 mg, 1.50 mmol) in THF (3 mL) was added lithium aluminum tetrahydride (72 mg, 1.91 mmol) at -40°C. The mixture was stirred at -10°C for 1 hour. Water (72uL) and 15% aqueous sodium hydroxide solution (72uL) were added to the reaction, followed by water (216uL). Add anhydrous sodium sulfate to dry.
  • the first step Compound 1-(tert-butyl) 2-methyl(S)-4-methylenepyrrolidine-1,2-dicarboxylate (2.80g, 11.6mmol) and trimethyl(trifluoromethyl)silane (4.12g, 29.0mmol) were dissolved in tetrahydrofuran (100mL), and sodium iodide (0.87g, 5.81mmol) was added under nitrogen. The reaction was stirred at 60°C for 16 hours.
  • the second step the compound 5-(tert-butyl) 6-methyl(6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (purity 80%, 4.00g, 11.0mmol) was dissolved in tetrahydrofuran (65mL) and dropped to -70°C, and diisopropylamide lithium (2M tetrahydrofuran Heptane mixed solution, 10.3mL, 20.6mmol), the reaction was stirred at -70°C for 1 hour.
  • the third step the compound cis 5-(tert-butyl) 6-methyl-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (1.20g, 3.26mmol) was dissolved in dichloromethane (4mL), hydrogen chloride (4M solution in dioxane, 2mL, 9.78mmol) was added at 20°C, and the reaction solution was stirred at 20°C for 2 hours.
  • the fourth step the compound cis-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylate methyl ester (0.83g, 3.11mmol) was dissolved in methanol (2mL), and potassium iodide (62mg, 0.37mmol) and potassium carbonate (1.55g, 11.21mmol) were added at 25°C. The reaction was stirred at 25°C for 16 hours.
  • Step 5 The compound cis-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-methyl carboxylate (0.25g, 1.08mmol) was dissolved in tetrahydrofuran (4mL), and lithium aluminum tetrahydride (61mg, 1.62mmol) was added at 0°C. The reaction was stirred at 60°C for 2 hours.
  • Step 1 To a solution of (S)-1-(tert-butoxycarbonyl)-4-methylenepyrrolidine-2-carboxylic acid (90 g, 396 mmol) in dimethylformamide (1.8 L) was added cesium carbonate (168 g, 514 mmol) and benzyl bromide (88 g, 514 mmol) at 0°C. The suspension was stirred at 25°C for 16 hours.
  • reaction solution was diluted with water (1.8 L), extracted with ethyl acetate (1 L*3), the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-25% gradient tetrahydrofuran/petroleum ether) to obtain 2-benzyl 1-(tert-butyl)(S)-4-methylenepyrrolidine-1,2-dicarboxylate (120 g, 378 mmol, yield 95%) as a colorless oil.
  • Second step To a solution of 2-benzyl 1-(tert-butyl)(S)-4-methylenepyrrolidine-1,2-dicarboxylate (8.00 g, 25.2 mmol) and trimethyl(trifluoromethyl)silane (8.96 g, 63.0 mmol) in THF (300 mL) was added sodium iodide (1.89 g, 12.6 mmol) under nitrogen, and the mixture was stirred at 60° C. for 16 hours. The mixture was quenched with saturated ammonium chloride (50 mL), diluted with water (100 mL), extracted with ethyl acetate (50 mL*3).
  • Step 3 To a solution of 6-benzyl 5-(tert-butyl)(3R,6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (15g, 40.8mmol) in THF (150mL) was added potassium bis(trimethylsilyl)amide (2M solution in THF, 41mL, 82mmol) at -78°C under a nitrogen atmosphere. The reaction was stirred at -78°C for 1 hour. 1-Bromo-3-chloropropane (13 g, 81.6 mmol) was added to the solution and The solution was stirred at -78°C for 1 hour. It was then stirred at 25°C for 14 hours.
  • 2-benzyl 5-(tert-butyl)(3R,6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate 15g, 40.8mmol
  • Step 4 To a solution of compound 6-benzyl 5-(tert-butyl)(3R,6S)-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (6 g, 18.1 mmol) in dichloromethane (200 mL) was added hydrogen chloride (4M in dioxane, 100 mL, 400 mmol) at 25°C. The reaction was stirred at 25°C for 16 hours.
  • Step 5 To a methanol (500 mL) solution of compound (3R,6S)-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylate (16 g, 46.5 mmol) was added potassium iodide (0.77 g, 4.65 mmol) and potassium carbonate (19.3 g, 139 mmol) at 25°C. The solution was stirred at 25°C for 16 hours.
  • compound (3R,6S)-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylate (16 g, 46.5 mmol) was added potassium iodide (0.77 g, 4.65 mmol) and potassium carbonate (19.3 g, 139 mmol) at 25°C. The solution was stirred at 25°C for 16 hours.
  • Step 6 To a solution of benzyl (1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-carboxylate (350 mg, 1.14 mmol) in tetrahydrofuran (4 mL) was added lithium aluminum tetrahydride (259 mg, 6.83 mmol) at 0°C. The suspension was stirred at 60°C for 2 hours. The suspension was quenched sequentially with water (260 uL), 15% sodium hydroxide solution (260 uL) and water (780 uL).
  • Step 1 To a solution of 4-((tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinic acid (10.0g, 34.40mmol) in dichloromethane (50mL), hydrogen chloride (4M solution in dioxane, 172mL, 688mmol) was added at 0°C, and stirred at 20°C for 16 hours. The mixture was spin-dried to afford the crude compound 4-amino-6-chloro-5-fluoronicotinic acid (9.00 g) as a white solid.
  • LCMS (ESI): [M+H] + 191.0.
  • the second step 4-amino-6-chloro-5-fluoronicotinic acid (9.00g, 34.40mmol) was dissolved in phosphorus oxychloride (50mL), and the mixture was nitrogen Stir at 90°C for 2 hours under protection. Spin dry.
  • LCMS (ESI) of the methyl ester obtained by quenching with methanol during detection: [M+H] + 205.1.
  • Step 3 Ammonium thiocyanate (11.8 g, 155.02 mmol) was added to a solution of 4-amino-6-chloro-5-fluoronicotinoyl chloride (10.0 g, 34.40 mmol) in tetrahydrofuran (100 mL), and the mixture was stirred at 20° C. for 12 hours under nitrogen protection. Water (100 mL) was added, extracted with ethyl acetate (100 mL*3), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried.
  • Step 4 To a solution of 7-chloro-8-fluoro-2-thioxo-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one (5.60 g, 24.18 mmol) in N,N-dimethylformamide (56 mL), sodium methoxide (1.44 g, 26.59 mmol) and methyl iodide (3.26 g, 22.97 mmol) were added. The mixture was stirred at 20° C. for 2 hours under nitrogen protection.
  • Step 5 Dissolve 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (1.10 g, 4.48 mmol) in phosphorus oxychloride (10.0 mL), and add diisopropylethylamine (2.23 mL, 13.43 mmol). The mixture was stirred at 95 °C for 16 hours under nitrogen protection.
  • Step 1 To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (500mg, 1.68mmol) and diisopropylethylamine (350uL, 2.02mmol) in dichloromethane (5mL) at -40°C was added tert-butyl ((1R,5S,8S)-3-azabicyclo[3.2.1]octyl-8-yl)carbamate (381 mg, 1.68 mmol). The solution was stirred at -40°C for 1 hour.
  • Second step To a solution of tert-butyl ((1R,5S,8S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]oct-8-yl)carbamate (800 mg, 2.30 mmol) in dioxane (9 mL) was added (tetrahydro-1H-pyrrolazin-7a(5H)-yl) at 25°C Methanol (459 mg, 3.26 mmol) and diisopropylethylamine (850 mL, 4.88 mmol). The solution was stirred at 80°C for 16 hours.
  • the third step in a nitrogen atmosphere, to tert-butyl ((1R,5S,8S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-yl)carbamate (304mg, 0.56mmol), 2-(8- Ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (200mg, 0.56mmol), potassium phosphate (1.5M in water, 1120uL, 1.68mmol) in dioxane (4mL) was added [n-butylbis(1-adamantyl)phosphine](2-amino-1,1-biphenyl-2
  • the fourth step tert-butyl ((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]oct-8-yl)carbamate
  • Example 3 4-(4-(2,5-diazabicyclo[4.1.0]hept-2-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
  • the first step compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (150mg, 0.19 mmol) and diisopropylethylamine (113uL, 0.65mmol) were added to dimethylsulfoxide (1.2mL), 4-(pyrrolidin-1-yl)piperidine (30mg, 0.19mmol) was added, and stirred at 90°C for 3 hours.
  • the second step compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidine (13 0 mg, 0.15 mmol) was added to N,N-dimethylformamide (2 mL), cesium fluoride (234 mg, 1.54 mmol) was added, and stirred at 20°C for 1 hour.
  • the third step compound 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidine (100mg, 0.13mmol) was added into trifluoroacetic acid/dichloromethane (volume ratio 4:1, 2.5 mL), and stirred at 20°C for 2 hours.
  • Example 12 4-(4-([1,4'-bispiperidin]-1'-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Example 14 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((3aR,6aS))-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2 -alcohol formate
  • Example 16 4-(4-((1R,2R,4S,5S)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 2,4 ]non-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
  • Second step Benzoyl chloride (1.65 mL, 14.2 mmol) was added to a solution of compound (1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene (1.20 g, 3.55 mmol) and diisopropylethylamine (5.8 mL, 35.5 mmol) in dichloromethane (12 mL), and the reaction was stirred at 25° C. for 16 hours.
  • the third step the compound ((1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene-3,8-diyl)bis(phenyl ketone) (400mg, 1.25mmol), tetrabutylammonium bromide (40mg, 0.13mmol) was dissolved in toluene (5mL), and (bromodifluoromethyl)trimethylsilane (5.10g, 25.1mmol) was added under nitrogen protection. Stir at 110°C for 16 hours.
  • Step 4 The compound ((1R,2R,4S,5S)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane-7,9-diyl)bis(phenyl ketone) (200mg, 0.25mmol) was dissolved in 6M hydrochloric acid (2mL), and the reaction was stirred at 100°C for 16 hours.
  • Example 17 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,2R,4S,5S)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 2,4 ]non-7-yl)pyrido[4 ,3-d]pyrimidin-7-yl)naphthalene-2-ol
  • Second step Di-tert-butyl dicarbonate (5.00 mL, 23.1 mmol) was added to a solution of compound (1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene (1.20 g, 1.31 mmol) and diisopropylethylamine (5.36 mL, 38.4 mmol) in dichloromethane (12 mL), and the reaction was stirred at 25° C. for 16 hours.
  • Step 4 The compounds (1R, 2R, 4S, 5S) -3- (triangular silicon-based) -7,9-two-nitrogen miscellaneous three rings [3.3.1.0 2,4 ] mesexane-7,9-di-carboxylic acid two uncle (100 mg, 0.25 mmol), add hydrogen chloride (4m solution of 4m, 6m, 6, 6 30ul), stirred at 20 ° C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude compound (1R,2R,4S,5S)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane (dihydrochloride, 65mg) as a yellow oily liquid.
  • LCMS (ESI): [M+H] + 197.1.
  • Example 18 4-(4-((1R,5S)-8-Azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formate
  • the first step In the glove box, add 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (500mg, 1.89mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (825mg, 2.46 mmol) in 1,4-dioxane (15 mL), potassium phosphate (1.5 M in water, 3.16 mL, 4.73 mmol) and [n-butylbis(1-adamantyl)phosphine](2-amino-1,1-biphenyl-2-yl)palladium(II) methanesulfonate (69 mg, 0.09 mmol) were added.
  • the mixture was stirred at 50° C. for 16 hours under nitrogen protection.
  • the reaction solution was filtered, the filtrate was diluted with water (2 mL), extracted with ethyl acetate (10 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried.
  • the second step at -15°C, to a solution of tert-butyl (1S,5R)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (2.00g, 4.58mmol) in dichloromethane (120mL), add triethylsilane (4.40mL , 27.46mmol) and trifluoroacetic acid (6.80mL, 91.55mmol). The mixture was stirred at 25°C for 16 hours under nitrogen protection.
  • Step 3 To a solution of 4-((1R,3s,5S)-8-azabicyclo[3.2.1]oct-3-yl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (2.00g, 4.58mmol) in dichloromethane (20mL) was added triethylamine (1.97mL, 14.17mmol) and di-tert-butyl dicarbonate (2.0 3 mL, 8.85 mmol). The mixture was stirred at 20° C. for 16 hours under nitrogen protection, and then spin-dried.
  • Step 4 In a glove box, add tert-butyl (1R,3s,5S)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (500 mg, 1.14 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl -1,3,2-Dioxygen To a solution of xaboran-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (701 mg, 1.37 mmol) and cesium carbonate (1113 mg, 3.42 mmol) in dioxane (10 mL) and water (2 mL) was added chloro[(n-butylbis(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium
  • the mixture was stirred at 100° C. for 3 hours under nitrogen protection.
  • the reaction solution was filtered, the filtrate was diluted with water (4 mL), extracted with ethyl acetate (10 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried.
  • the fifth step to tert-butyl(1R,3s,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(methylthio))pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (400mg, 0.51mm ol) in dichloromethane (10 mL), add m-chloroperoxybenzoic acid (85% content, 257 mg, 1.27 mmol). The mixture was stirred at 25°C for 2 hours under nitrogen protection.
  • the sixth step at 25°C, to tert-butyl (1R,3s,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (600 mg, 0.73mmol) and diisopropylethylamine (510uL, 3.65mmol) in dioxane (6.00mL) were added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (357mg, 2.24mmol), and the mixture was stirred at 80°C for 4 hours.
  • the eighth step at 25°C, tert-butyl (1R,3s,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo [3.2.1] Octane-8-carboxylate (360 mg, 0.48 mmol) was dissolved in trifluoroacetic acid/dichloromethane (volume ratio 1/4, 4.00 mL), and stirred for 2 hours.
  • Example 19 (isobutyryloxy)methyl(1R,5S)-3-(2-((2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3, 8-Diazabicyclo[3.2.1]octane-8-carboxylate
  • the first step at 20°C, compound 4-nitrophenol (5.00g, 35.94mmol) was added to tetrahydrofuran (65.0mL), chloromethyl chloroformate (5.10g, 39.54mmol) was added, and N,N-diisopropylethylamine (6.91mL, 39.54mmol) was slowly added dropwise, and the reaction was stirred at 20°C for 2 hours.
  • the second step the compound (4-nitrophenyl) chloromethyl carbonate (5.00g, 21.59mmol) was added to acetone (100mL), sodium iodide (9.71g, 64.77mmol) and 4A molecular sieves (5.00g) were added at 20°C, and the reaction was stirred at 40°C for 16 hours. The reaction was cooled to room temperature and filtered through celite.
  • the third step add isobutyric acid (5.00g, 56.75mmol) into acetonitrile (200mL), add silver oxide (4.76 g, 34.05 mmol), stirred at 70°C for 6 hours in the dark. The mixture was cooled to ambient temperature and filtered through celite. The filtrate was freed of volatiles by vacuum to give the compound silver isobutyrate (1.00 g, 5.12 mmol, 9% yield) as a tan solid.
  • Step 4 Add the compound iodomethyl (4-nitrophenyl) carbonate (414 mg, 1.28 mmol) into toluene (7.00 mL), add silver isobutyrate (500 mg, 2.56 mmol), and stir at 55° C. for 16 hours. The reaction solution was cooled to room temperature and filtered through diatomaceous earth.
  • the fifth step at 25°C, to tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxy
  • Add ((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methanol (121mg, 0.59mmol) and sodium tert-butoxide (115mg, 0.89mmol) to a tetrahydrofuran (5.00mL) solution of acid ester (500m
  • Step 6 At 25°C, add tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl )naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350mg, 0.37mmol) in dimethylformamide (3.50mL) was added cesium fluoride (562mg, 3.70mmol), and the solution was stirred at 25°C for 2 hours.
  • cesium fluoride 562mg, 3.70m
  • the seventh step at 25°C, to tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoropyrido[ 4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50.0mg, 0.06mmol) in acetonitrile (1.00mL) was added hydrogen chloride (4M solution in dioxane, 317uL, 1.27mmol), and the solution was stirred at 20°C for 2 hours.
  • hydrogen chloride 4M solution in dioxane, 317uL
  • the eighth step at 20°C, add 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d ]Pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (purity 50%, 50.0mg, 0.04mmol) in dimethylformamide (1.00mL) was added (((4-nitrophenoxy)carbonyl)oxy)methyl isobutyrate (19.8mg, 0.07mmol), and the solution was stirred at 20°C for 2 hours.
  • Example 20 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)quinolin-2-ol
  • Example 21 7a'-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)tetrahydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazine]
  • the first step tert-butyl (1R,5S)-3-(7-chloro-2-((dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200mg, 0.
  • To azabicyclo[3.2.1]octane-8-carboxylate (220mg, 0.25mmol), add trifluoroacetic acid/dichloromethane 1:4 (4.4mL).
  • the third step 7a'-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl))naphthalene-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)tetrahydro-1'H,3'H-spiro[oxetane-3, 2'-Pyrrolazine] (200 mg, 0.25 mmol) in N,N dimethylformamide (2 mL) was added cesium fluoride (4468 mg, 26.1 mmol).
  • Example 22 7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline-6-carbonitrile
  • Step 1 To 6-bromo-4-methylpyridin-2-amine (1.00g, 5.35mmol) in N,N-dimethylformamide (17mL), add 60% sodium hydrogen (1.10g, 27.5mmol) at 0°C, stir at 25°C for 1 hour, then add 1-(chloromethyl)-4-methoxybenzene (1.90g, 12.1mmol) at 0°C, and place the mixture under nitrogen protection Stir at 25°C for 2 hours. Add saturated ammonium chloride solution (17 mL) to quench at 0°C, extract 5 times with ethyl acetate (25 mL), combine organic phases, wash with brine (50 mL), dry over anhydrous sodium sulfate, filter and spin dry.
  • the third step In the glove box, add tert-butyl(1R,5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (615mg, 1.10mmol), N,N-bis(4-methoxybenzyl)-4-methyl-6-(tributyltin To a solution of alkyl)pyridin-2-amines (1.40 g, 2.2 mmol), cuprous iodide (63 mg, 0.33 mmol) and lithium chloride (116 mg, 2.75 mmol) in 1,4-dioxane (18 mL) was added tetrakis(triphenylphosphine)palladium (254 mg, 0.22 mmol).
  • the fourth step acetonitrile (16 mL) solution, N-iodosuccinimide (1060 mg, 4.71 mmol) and p-toluenesulfonic acid (6 mg, 0.04 mmol) were added.
  • the mixture was stirred at 25 °C for 5 hours under nitrogen protection.
  • the mixture was spin-dried, added brine (10mL), extracted with ethyl acetate (20mL) Take 3 times, the combined organic phases are dried with anhydrous sodium sulfate, filtered and spin-dried.
  • the residue was purified by flash column chromatography (silica gel, gradient 0-20% tetrahydrofuran/petroleum ether).
  • the fifth step N to tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700mg, 0.73mmol) , To a solution of N-dimethylacetamide (17.5 mL), add methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (3525 mg, 18.3 mmol) and cuprous iodide (1677 mg, 8.81 mmol).
  • Step 6 To tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150mg, 0.17mm ol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (70mg, 0.44mmol) in tetrahydrofuran (3mL) was added sodium tert-butoxide (24mg, 0.25mmol).
  • the seventh step tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[ 3.2.1]
  • Octane-8-carboxylate (220mg, 0.16mmol) was dissolved in trifluoroacetic acid (3mL), and the mixture was stirred at 50°C for 2 hours under nitrogen protection. Then spin dry.
  • the first step under the protection of nitrogen, the compound tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300mg, 0.54 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-ol (176mg, 0.65mmol) in dioxane (5.00mL) were added potassium phosphate (1.5M in water, 1.09mL, 1.63mmol), methanesulfonic acid [n-butylbis(1-adamantyl)phosphine] (2-amino-1,1'-biphen
  • the fourth step at 25°C, to (4-(4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct)-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2 -yl) boronic acid (76.0 mg, 0.11 mmol) in acetonitrile (1600 uL) was added hydrogen chloride (4M in dioxane, 277 uL, 1.11 mmol).
  • Example 24 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)- Base) methoxy) -8-fluoro-quinazoline-6-carbonitrile
  • Example 24 was prepared by the synthetic route method of Example 22, using intermediates to tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane -8-carboxylates and intermediates (1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methanol A16-2A
  • Example 25 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-fluoronaphthalen-2-ol
  • Step 1 To a solution of 4-bromonaphthalene-2-ol (2.00 g, 8.96 mmol) in dichloromethane (30 mL) was added bis(benzenesulfonyl)fluoroamine (9.33 g, 29.59 mmol) and zirconium tetrachloride (0.10 g, 0.45 mmol) at 0°C. The solution was stirred at 25°C for 16 hours. The solution was concentrated and purified by flash column chromatography (silica gel, 0-20% gradient of petroleum ether/ethyl acetate) to give brown solid compound 4-bromo-1-fluoronaphthalen-2-ol (0.94 g, 3.50 mmol, yield 39%).
  • LCMS (ESI): [MH] + 240.8.
  • Step 2 Add bis(triphenylphosphine)palladium(II) chloride (44.0mg, 0.06mmol) to a solution of 4-bromo-1-fluoronaphthalen-2-ol (300mg, 1.24mmol), bis-pinacol borate (475mg, 1.87mmol) and potassium acetate (367mg, 3.73mmol) in dioxane (6000uL) at 25°C under nitrogen protection. The solution was stirred at 110°C for 3 hours.
  • the third step 1-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-ol (157mg, 0.54mmol) and tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl )methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150mg, 0.27mmol) in dioxane (3.00mL) was added potassium carbonate (2.0M in water, 409uL, 0.82mmol) and tetrakis(triphenylphosphine)palladium (32.0mg, 0.03mmol).
  • the fourth step at 25°C, to tert-butyl (1R,5S)-3-(8-fluoro-7-(4-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-
  • To a solution of the carboxylate (200 mg, 0.30 mmol) in acetonitrile (4000 uL) was added hydrogen chloride (4M in dioxane, 739 uL, 2.96 mmol).
  • Example 26 7-(3-amino-7,8-difluoroisoquinolin-1-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline-6-carbonitrile
  • Step 1 To a solution of 2-bromo-3,4-difluorobenzoic acid (25.0 g, 105.49 mmol) in tetrahydrofuran (100 mL) was added dropwise a solution of borane in tetrahydrofuran (422 mL, 422 mmol) at 0°C. Warm to room temperature and stir for 16 hours. The solution was cooled with an ice bath, and then 10% aqueous sodium carbonate solution (180 mL) was added slowly. The suspension was concentrated in vacuo to give a white solid. Acidify with 3 mol/L aqueous hydrochloric acid (600 mL), dilute with dichloromethane (300 mL), and filter the mixture through celite.
  • Step 3 To a solution of 2-bromo-3,4-difluorobenzyl methanesulfonate (29.0 g, 96.31 mmol) in acetonitrile (300 mL) was added potassium carbonate (26.0 g, 192 mmol) and trimethylsilyl cyanide (19.0 g, 192 mmol) at 0°C. The reaction was stirred at 80 °C for 16 hours. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL), the organic phase was washed with brine (200 mL), dried over anhydrous magnesium sulfate and filtered.
  • Step 7 To a solution of tert-butyl (1R,5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 0.45 mmol) in dioxane (5 mL) was added 7,8-difluoro-1-(tributyl Stannyl)isoquinolin-3-amine (251 mg, 0.54 mmol), cuprous iodide (25.5 mg, 0.13 mmol), lithium chloride (47 mg, 1.11 mmol) and tetrakis(triphenylphosphine)palladium (103 mg, 0.09 mmol).
  • Step 8 Add 4A molecular sieves to a solution of tert-butyl (1R,5S)-3-(7-(3-amino-7,8-difluoroisoquinolin-1-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60mg, 91umol) in tetrahydrofuran (1mL) (60 mg), sodium tert-butoxide (11 mg, 0.11 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (17 mg, 0.11 mmol).
  • the ninth step to tert-butyl (1R,5S)-3-(7-(3-amino-7,8-difluoroisoquinolin-1-yl)-6-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4 To a solution of 7.3 mg, 66 umol) in acetonitrile (1 mL) was added hydrogen chloride (4M in dioxane, 330 uL, 1.3 mmol).
  • Example 27 6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine
  • Example 29 6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(perfluoroethyl)pyridin-2-amine
  • the first step In the glove box, tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.40g, 2.85mmol), N,N-bis(4-methoxybenzyl)-4-methyl-6-( To a solution of tributylstannyl)pyridin-2-amine (3.27g, 5.12mmol), cuprous iodide (163mg, 0.85mmol) and lithium chloride (302mg, 7.12mmol) in dioxane (28mL) was added tetrakis(triphenylphosphine)palladium (657mg, 0.57mmol).
  • the second step Ethanol to tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy))pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500mg, 0.62mmol) To a solution of nitrile (10 mL), N-iodosuccinimide (700 mg, 3.11 mmol) and p-toluenesulfonic acid (4.30 mg, 0.02 mmol) were added.
  • the mixture was stirred under nitrogen protection at 25°C for 12 hours.
  • the mixture was spin-dried, brine (10 mL) was added, extracted with ethyl acetate (20 mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried.
  • the residue was purified by flash column chromatography (silica gel, gradient 0-30% ethyl acetate/petroleum ether) to give the crude product.
  • the third step tert-butyl(1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (290mg, 0.31mmol ) and cuprous iodide (178mg, 0.94mmol) in N,N-dimethylacetamide (7.2mL) solution, 2,2-difluoro-2-(fluorosulfonyl)acetate trimethylsilyl ester (468mg, 1.87mmol) was added at 0°C.
  • the fifth step tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diaze Heterobicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(perfluoroethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl
  • Example 27 (6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridine pyridin-2-amine) (43.98mg, 0.07mmol, yield 30%) as a white solid.
  • Example 29 (6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(perfluoroethyl)pyridine pyridin-2-amine) (5.26 mg, 8.2 umol, yield 3%) as a white solid.
  • LCMS(ESI):[M+H] + 641.2.
  • Example 28 N-(6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2- base) acetamide
  • the third step at 0°C, the compound tert-butyl (1R,5S)-3-(7-(6-acetylamino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8- Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (35.0 mg, 0.05 mmol) was dissolved in acetonitrile (1 mL), and hydrogen chloride (4M in dioxane, 239 u L, 0.96 mmol), and the reaction was stirred at 20°C for 2 hours.
  • Example 30 4-(4-(-3,8-diazabicyclo[3.2.1]oct-3-yl-2-((dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
  • the second step In the glove box, add tert-butyl-3-(7-chloro-2-((dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110mg, 0.19 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (83mg, 0.23mmol) in dioxane (2.2mL) were added potassium phosphate (1.5M in water, 386uL, 0.58mmol) and methanesulfonic acid [n-butylbis(1-adamanty
  • the third step to tert-butyl-3-(2-((dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1 ] To a solution of octane-8-carboxylate (110 mg, 0.14 mmol) in dichloromethane (1760 uL) was added trifluoroacetic acid (440 uL).
  • Example 31A and Example 31B 4-(4-((1R,5S)-(3,8-diazabicyclo[3.2.1]oct-3-yl-2-((dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-eth Base-6-fluoronaphthalen-2-ol, and
  • Example 30 was separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia water/ethanol; phase B was maintained at 50%; flow rate: 80 ml/min), and the target compound was obtained.
  • SFC column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia water/ethanol; phase B was maintained at 50%; flow rate: 80 ml/min), and the target compound was obtained.
  • Example 32 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((hexahydro-2H-furo[2,3-b]pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol dicarboxylate
  • the first step to tert-butyl(1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800mg, 1.16mmol) and (hexahydro- To a solution of 2H-furo[2,3-b]pyrrolazin-7a(5H)-yl)methanol (106 mg, 0.58 mmol) in tetrahydrofuran (5 mL) was added sodium tert-butoxide (375 mg, 2.90 mmol).
  • the second step at 0°C, add tert-butyl(1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((hexahydro-2H-furo[2,3-b]pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.
  • Example 33B cis-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((hexahydrocyclopropane[a]pyrrolazin-6a(4H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
  • Example 34 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2- Alcohol formate
  • Example 35 trans-4-(4-((1S,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrim Pyridin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol
  • Example 35A and Example 35B 4-(4-((1S,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3 -d] pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol, and
  • Example 36 cis-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrim Pyridin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol
  • Example 37 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((hexahydrocyclopropane[b]pyrrolazin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Step 1 To a solution of (1R,5S)-tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.47 mmol) in dioxane (5 mL) was added (hexahydrocyclopropane[b]pyrrolazin-5a(3H)-yl)methanol (85% purity, 257 mg, 1.40 mmol), diisopropylethylamine (0.39 mL, 2.33 mmol). The reaction was stirred at 80°C for 16 hours. The mixture was concentrated in vacuo.
  • the second step under nitrogen atmosphere, dioxane (2mL ) and water (0.40 mL) were added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (135mg, 0.26mmol), cesium carbonate (215mg, 0.66mmol) and [(bis(1-adamantyl)-N-butylphosphine)-2- (2-aminobiphenyl)palladium(II) chloride (14.72 mg, 0.02 mmol), and the mixture was stirred at 100° C.
  • the third step to tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-((hexahydrocyclopropane[b]pyrrolazin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] To a solution of octane-8-carboxylate (40 mg, 0.04 mmol) in dichloromethane (400 uL) was added trifluoroacetic acid (80 uL) at 0°C.
  • the fourth step to 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((hexahydrocyclopropane[b]pyrrolazin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol (40mg, 0 .05mmol) in dimethylformamide (400uL) was added cesium fluoride (162mg, 1.07mmol). The reaction was stirred at 20°C for 2 hours.
  • Example 38 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene- 2-ol
  • Example 40A 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidine- 7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • the third step tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy))naphthalene-1-yl)-8-fluoropyrido[4 ,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 79%, 370 mg, 0.37 mmol) was dissolved in trifluoroacetic acid/dichloromethane (volume ratio 1/4, 4 mL) and stirred for 2 hours.
  • Example 41 4-(2-((1'H, 3'H, 5'H-dithiacyclo[oxetane-3,2'-pyrrolidine-6', 3'-oxetane-7a'(7'H)-ylmethoxy)-4-((1R,5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidine-7- Base)-5-ethynyl-6-fluoronaphthalene-2-ol
  • Step 5 At 0°C, LiAlH4 (80mg, 2.24mmol) was added to a solution containing 1'H, 3'H, 5'H-ethyl dithiocyanate [oxetane-3,2'-pyrrolizine-6', 3'-oxetane]-7a'(7'H)-ethyl carboxylate (600mg, 2.24mmol) and THF (6mL), and the reaction solution was stirred at room temperature for 1 hour, Add excess sodium sulfate water to the reaction solution, stir for 30 minutes and then filter, and the filtrate is concentrated to obtain compound (1'H,3'H,5'H-dipyrrole[oxetane-3,2'-pyrrolidine-6',3'-oxetane]-7a'(7'H)-yl)methanol (210mg) as a yellow oily product.
  • LCMS (ESI): [M+H]+ 226.2.
  • the seventh step at 0°C, trifluoroacetic acid (0.5 mL) was added to the solution containing tert-butyl (1R, 5S)-3-(2-((1'H, 3'H, 5'H-bispiro[oxetane-3,2'-pyrrolizine-6', 3'-oxetane]-7a'(7'H)-ylmethoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalene-1-yl)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (50mg, 0.052mmol) and dichloromethane (3mL) in the reaction solution, the reaction solution was stirred at 0°C for 30 minutes, triethylamine (1mL)
  • Step 8 Containing 4-(2-((1'H, 3'H, 5'H-dithiacyclo[oxetane-3,2'-pyrrolidine-6', 3'-oxetane-7a'(7'H)-yl)methoxy)-4-((1R,5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidine-7-
  • a reaction solution of -6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol (30mg, 0.036mmol), cesium fluoride (28mg, 0.18mmol) and DMF (1mL) was stirred at 50°C for 2 hours, the reaction solution was poured into water (20mL) and extracted with EA (20mL x 3), the organic phase was dried over anhydrous Na2SO4, filtered and concentrated, and purified
  • Step 5 Under nitrogen protection at 20°C, triphenylphosphine (385mg, 1.47mmol) and carbon tetrabromide (491mg, 1.47mmol) were added to a solution of methyl 6- ⁇ [(hydroxymethyl)cyclopropyl]methyl ⁇ -6-azaspiro[2.4]heptane-5-carboxylate (270mg, 1.13mmol) in dichloromethane (5ml), and the reaction solution was stirred at 20°C for 2 hours.
  • triphenylphosphine 385mg, 1.47mmol
  • carbon tetrabromide 491mg, 1.47mmol
  • Step 6 Dissolve methyl 6- ⁇ [(bromomethyl)cyclopropyl]methyl ⁇ -6-azaspiro[2.4]heptane-5-carboxylate (300mg, 0.99mmol) in N,N-dimethylformamide (15mL) and tetrahydrofuran (5mL) at 20°C, replace with nitrogen three times, and cool to -70°C, dropwise add bis(trimethylsilyl)potassium amide (1.4mL, 1.39 mmol, 1M), and the reaction solution was stirred at this temperature for 50 minutes.
  • Step 7 Add lithium aluminum hydride (15mg, 0.39mmol) to 1'hydrogen, 3'hydrogen, 5'hydrogen-dispiro[cyclopropane-1,2'-pyrrolizine-6',1"-cyclopropanyl]-7a'(7'hydrogen)-methyl formate (30mg, 0.15mmol) in tetrahydrofuran (2mL) at 0°C, and stir the reaction solution at 0°C for 1 hour. Add to the reaction solution for 1 hour. Lithium aluminum hydride (15mg, 3eq) was added and stirred at 20°C for 1 hour. Water (30ul) and 15% sodium hydroxide solution (90uL) were added to the reaction solution, and stirred at 20°C for 10 minutes.
  • reaction solution was stirred at 20°C for 4 hours.
  • sodium tert-butoxide (2mg x 3) to the reaction solution 3 times, and stir at 60°C for 2 hours.
  • water (2mL) to the reaction solution and extract with ethyl acetate (2mL x 3).
  • the organic phase is dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue.
  • Step 9 Add cesium fluoride (61mg, 0.40mmol) to (1R,5S)-3-(2-((1'hydrogen,3'hydrogen,5'hydrogen-dispiro[cyclopropane-1,2'-pyrrolizine-6',1"-cyclopropanyl]-7a'(7'hydrogen)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(( Triisopropylsilyl)ethynyl)naphthalene-1-yl)pyridyl[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (37mg, 0.039mmol) in N,N-dimethylformamide (3mL).
  • reaction solution was stirred at 20°C for 1.5 hours.
  • the reaction solution was diluted with ethyl acetate (2mL) and diluted with water (1mL x 2 ) was washed.
  • the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, and the residue was purified by column chromatography (silica gel, 0-50% gradient ethyl acetate/petroleum ether, 0-5% gradient methanol/dichloromethane) to obtain a colorless viscous liquid (1R, 5S)-3-(2-((1'hydrogen, 3'hydrogen, 5'hydrogen-dispiro[cyclopropane-1,2'-pyrrolizine-6',1"-cyclopropanyl]-7a'( 7'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-
  • reaction solution was concentrated, diluted with acetonitrile (1mL), adjusted to pH 7 with triethylamine, and purified by reverse phase column chromatography (C18, 5- 95% acetonitrile/water gradient) to 4-(2-((1'hydrogen, 3'hydrogen, 5'hydrogen-dispiro[cyclopropane-1,2'-pyrrolizine-6',1"-ring Propanyl]-7a'(7'hydrogen)-yl)methoxy)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (1.80 mg, yield 32%).
  • LCMS (ESI): [M+H]+ 635.4.
  • Step 1 To a solution of 2-chloro-3-fluoroisonicotinic acid (100 g, 569 mmol) and triethylamine (158 mL, 1133 mmol) in toluene (500 mL) and tert-butanol (500 mL) under nitrogen atmosphere, di-tert-butyl dicarbonate (13 mL, 56.5 mmol) and diphenylphosphoryl azide (147 mL, 682 mmol) were added, and the solution was stirred at 80° C. for 16 hours. The mixture was concentrated and added with 500 mL of saturated brine, and extracted with 500 mL of ethyl acetate.
  • Second step A solution of tert-butyl (2-chloro-3-fluoropyridin-4-yl)carbamate (50 g, 202 mmol) and tetramethylethylenediamine (70.6 g, 608 mmol) in anhydrous methyl tert-butyl ether (500 mL) was cooled to -70°C. And n-butyllithium (2.5M in n-hexane, 203 mL, 506 mmol) was slowly added to the mixture.
  • Step 3 Triphosgene (7.45 g, 25.1 mmol) was added to a solution of 4-((tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinic acid (10 g, 34.4 mmol) in dioxane (100 mL), and the mixture was stirred at 100° C. for 4 hours. The reaction solution was concentrated in vacuo, and the residue was slurried with petroleum ether to obtain 7-chloro-8-fluoro-2H-pyrido[4,3-d][1,3]oxazine-2,4(1H)-dione (7.40 g, 34.4 mmol, yield 99%) as a white solid.
  • 1 H NMR 400MHz,DMSO-d 6 ) ⁇ ppm 12.84(br s,1H),8.73(s,1H).
  • Step 5 7-Chloro-8-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carbonitrile (5.80 g, 24.2 mmol) was carefully added to phosphorus oxychloride (50 mL, 536 mmol). The reaction was stirred at 90°C for 16 hours. The mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate (100ml), washed with saturated sodium bicarbonate (100ml), and the aqueous phase was extracted with ethyl acetate (50ml*3). The combined organic layers were dried over anhydrous magnesium sulfate and filtered.
  • Step 6 Under -70 ° C to 2,4,7-trigloin-8-fluorine -1,6-pyrimidine-3-metada (2.00g, 7.23 mmol) dichloromethane (30ml) solution (1R, 5S) -Ixin 3,8-two-nitrogen miscellaneous two-ring [3.2.1] Ectane-8-carboxylic acid ester (1.38g, 6.5 6.5, 6.5 1mmol) dichloromethane (10ml) solution. A solution of triethylamine (2.52 mL, 18.1 mmol) in dichloromethane (10 mL) was then added slowly. The reaction was stirred at -70°C for 0.5 hours.
  • Step 7 Add 4A molecular sieves (1.00 g) to a solution of tert-butyl (1R,5S)-3-(2,7-dichloro-3-cyano-8-fluoro-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 2.21 mmol) in tetrahydrofuran (20 mL), ((2R,7aS)-2-fluoro Tetrahydro-lH-pyrrolazin-7a(5H)-yl)methanol (0.35 g, 2.21 mmol) and sodium tert-butoxide (0.32 g, 3.32 mmol).
  • Step 8 In a nitrogen atmosphere, add tert-butyl(1R,5S)-3-(7-chloro-3-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500mg, 0.87 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (535 mg, 1.04 mmol) and cesium carbonate (850 mg, 2.61 mmol) in dioxane (5 mL) and water (1 mL) was added chloro[(n-
  • the ninth step to tert-butyl (1R,5S)-3-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-
  • diazabicyclo[3.2.1]octane-8-carboxylate 750 mg, 0.81 mmol
  • dimethylformamide 7.5 mL
  • cesium fluoride 2.40 g, 15.8 mmol
  • Step 10 To dichloromethane (7.20 mL) in trifluoroacetic acid (1.80 mL) was added tert-butyl(1R,5S)-3-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)- 1,6-Naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 0.59 mmol).
  • the first step to the compound tert-butyl (1R,5S)-3-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150mg, 0.19mmol) and (2-fluoro-6- Sodium carbonate (76mg, 0.72mmol) was added to a solution of hydroxyphenyl)boronic acid (59mg, 0.38mmol) in dioxane (3mL) and water (600uL), and (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (17mg, 0.02m
  • the second step compound tert-butyl (1R,5S)-3-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30.0mg, 0.03mmol ) was dissolved in dichloromethane/trifluoroacetic acid (volume ratio 4:1, 600uL), and the reaction solution was stirred at 20°C for 2 hours.
  • Example 45 4-(4-((1R,5S)-3,8-Diazabicyclo[3.2.1]oct-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol and
  • Example 46 1-(8 -(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-fluoro-6-hydroxynaphthalen-1-yl)ethan-1-one
  • Example 45 and Example 46 were prepared by the synthetic route method of Example 44, using intermediate ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane and intermediate tert-butyl (1R,5S)-3-(7-bromo-6-chloro-8-fluoro-2-(((2R, 7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • the third and fourth steps were combined into one step, and deprotected with TFA/DCM to obtain the main product 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1
  • Example 47 4-((1R,5S)-3,8-Diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-carbonitrile
  • the first step compound tert-butyl (1R,5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80% purity, 292mg, 0.57mmol) was added to dioxane (5mL) and water (1mL), and ((2-fluoro-6 -(Methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (200mg, 0.29mmol) and potassium phosphate (182mg, 0.86mmol), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl
  • the second step compound tert-butyl(1R,5S)-3-(6-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70% purity, 147 mg, 0.12mmol) into tetrahydrofuran (2mL), add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (57mg, 0.36mmol) and sodium tert-butoxide (17mg, 0.18mmol), and stir at 50°C for 2 hours.
  • the third step compound tert-butyl(1R,5S)-3-(6-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (66% purity, 156 mg, 0.11 mmol) was added to N,N-dimethylformamide (2 mL), cesium fluoride (169 mg, 1.11 mmol) was added, and stirred at 20°C for 1 hour.
  • the fourth step the compound tert-butyl (1R,5S)-3-(6-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-Carboxylate (60% purity, 135mg, 0.10mmol) was added to trifluoroacetic acid/dichloromethane (volume ratio 4:1, 2.5mL), stirred at 20°C Mix for 2 hours.
  • Examples 48A ⁇ 48D 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(R)-(8-ethynyl-7- Fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6-carbonitrile, 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(S
  • Example 50 4-(4-((1R,5S)-3,8-Diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)naphthalen-2-ol
  • the first step the compound tert-butyl(1R,5S)-3-(7-bromo-8-fluoro-6-iodo-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00g, 1.51mmol) was dissolved in N,N-dimethylformamide (15mL), in a nitrogen atmosphere, 2,2-difluoro - Methyl 2-(fluorosulfonyl)acetate (2.03g, 10.5mmol) and cuprous iodide (2.02g, 10.5mmol). The reaction was stirred at 60°C for 16 hours.
  • Second step To a solution of tert-butyl(1R,5S)-3-(7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.33 mmol) in THF (3 mL) was added 4-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-ol (107 mg, 0.40 mmol), potassium phosphate (1.5 M in water, 663 uL, 0.99 mmol), palladium (2-dicyclohexylphosphine-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl]methanesulfonate (28 mg, 0.03 mmol).
  • Step 3 Dissolve tert-butyl(1R,5S)-3-(8-fluoro-7-(3-hydroxynaphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170mg, 0.26mmol) in dichloromethane (3mL) to 0°C, and slowly pour into the reaction solution Diisopropylethylamine (133uL, 0.77mmol) and bromomethylmethyl ether (27uL, 0.33mmol) were added and the reaction was stirred at 25°C for 16 hours.

Abstract

La présente invention concerne un composé hétérocyclique, une composition pharmaceutique et son utilisation. L'invention concerne spécifiquement un composé hétérocyclique tel que représenté par la formule (I-0), un sel ou un stéréoisomère pharmaceutiquement acceptable du composé hétérocyclique, ou un solvate de celui-ci. Le composé de la présente invention a une nouvelle structure et une activité et une sélectivité relativement bonnes.
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