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WO2023179629A1 - 取代桥环类抑制剂及其制备方法和应用 - Google Patents

取代桥环类抑制剂及其制备方法和应用 Download PDF

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Publication number
WO2023179629A1
WO2023179629A1 PCT/CN2023/082908 CN2023082908W WO2023179629A1 WO 2023179629 A1 WO2023179629 A1 WO 2023179629A1 CN 2023082908 W CN2023082908 W CN 2023082908W WO 2023179629 A1 WO2023179629 A1 WO 2023179629A1
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alkyl
cycloalkyl
group
substituted
membered
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PCT/CN2023/082908
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English (en)
French (fr)
Inventor
吕彬华
崔大为
张青
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苏州泽璟生物制药股份有限公司
上海泽璟医药技术有限公司
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Priority claimed from CN202210288030.1A external-priority patent/CN116813646A/zh
Priority claimed from CN202211015208.1A external-priority patent/CN117659049A/zh
Priority claimed from CN202310059893.6A external-priority patent/CN118344386A/zh
Application filed by 苏州泽璟生物制药股份有限公司, 上海泽璟医药技术有限公司 filed Critical 苏州泽璟生物制药股份有限公司
Publication of WO2023179629A1 publication Critical patent/WO2023179629A1/zh
Priority to PCT/CN2024/072124 priority Critical patent/WO2024149389A1/zh

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • 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

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a substituted bridged ring inhibitor and its preparation method and application.
  • KRAS mutations account for 85% of all RAS mutations. KRAS mutations are found in nearly 90% of pancreatic cancers, 30-40% of colon cancers, and 15-20% of lung cancers (mainly non-small cell lung cancers).
  • the most important mutations among KRAS mutations are G12C and G12D mutations. G12C mutations mainly occur in HSCLC, while G12D mutations mainly occur in pancreatic cancer. So far, there are still no drugs on the market approved for the KRAS G12D mutation.
  • pancreatic cancer Current clinical conventional treatment options for pancreatic cancer include gemcitabine monotherapy, gemcitabine combined with albumin-paclitaxel, and FOLFIRINOX regimen (oxaliplatin + irinotecan + 5-FU/LV).
  • gemcitabine monotherapy gemcitabine combined with albumin-paclitaxel
  • FOLFIRINOX regimen oxaliplatin + irinotecan + 5-FU/LV.
  • liposomal irinotecan is suitable for use in combination with fluorouracil and folinic acid to treat patients with advanced pancreatic cancer who have failed gemcitabine chemotherapy (second-line therapy).
  • second-line therapy second-line therapy
  • the current effective treatments for pancreatic cancer are limited, and the overall survival time of patients does not exceed 1 year.
  • KRAS G12D target protein is pathologically associated with various diseases, especially pancreatic cancer
  • novel KRAS G12D inhibitors are currently needed for clinical treatment.
  • Highly selective and active KRAS G12D inhibitors can more effectively treat cancer and other diseases caused by KRAS G12D mutations, as well as have the potential to reduce off-target effects, so they have a more urgent clinical need.
  • the purpose of the present invention is to provide a new class of compounds with selective inhibitory effects on KRAS G12D and/or better pharmacodynamic properties and their uses.
  • the present invention provides a compound of formula (A0), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs:
  • Ring C is selected from the following groups:
  • Y is selected from: bond, O, NH, N (C 1 -C 3 alkyl);
  • Z is a substituted or unsubstituted C 1 -C 6 alkylene group; wherein the substitution means substitution by one or more R;
  • W is selected from: substituted or unsubstituted C 3 -C 14 cycloalkyl, or substituted or unsubstituted 4-14 membered saturated or unsaturated heterocyclyl; wherein the substitution refers to one or more R replace;
  • X is selected from: N, CH, CD, CF, C(CN);
  • R 1 is selected from: -L 1 -QL 2 -L 3 ;
  • L 1 is selected from: substituted or unsubstituted C 1 -C 6 alkylene; wherein said substitution means substitution by one or more R;
  • Q is selected from: O, S, SO 2 , NH, or N (C 1 -C 3 alkyl);
  • L 2 is selected from: none, substituted or unsubstituted C 1 -C 6 alkylene; wherein, the substitution means substitution by one or more R;
  • L 3 is selected from the following substituted or unsubstituted groups: -C 1 -C 6 alkyl, -C 3 -C 6 cycloalkyl, -C 4 -C 6 heterocyclyl, -C 1 -C 6 sub- Alkyl (C 3 -C 6 cycloalkyl), -C 1 -C 6 alkylene (C 4 -C 6 heterocyclyl), -C 1 -C 6 alkylene (C 1 -C 6 alkoxy base), -C 1 -C 6 alkylene (C 3 -C 6 cycloalkyloxy), or -C 1 -C 6 alkylene (C 4 -C 6 heterocyclyloxy); wherein, The substitution means substitution by one or more R;
  • n is an integer of 0, 1, 2, 3, 4, 5 or 6; the qualification is that when W is a single ring or a double ring, n is not 0;
  • R 10 is selected from the following substituted or unsubstituted groups: C 6 -C 14 aryl, 5-14 membered heteroaryl; wherein, the substitution means substitution by one or more Ra;
  • R 11 is each independently selected from the following group of substituted or unsubstituted groups: H, deuterium, halogen, cyano, ester, amine, amido, sulfone, ureido, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 1 -C 6 alkyloxy, C 3 -C 6 ring Alkyloxy, 4-6 membered heterocyclyloxy; wherein, the substitution means substitution by one or more R;
  • Ra is each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, NH 2 , OH, CONH 2 , NHCO (C 1 -C 6 alkyl), NHCO (C 3 -C 6 Cycloalkyl), SONH 2 , SO 2 NH 2 , NHSO 2 (C 1 -C 6 alkyl), NHSO 2 (C 3 -C 6 cycloalkyl), C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 20 cycloalkyl, 4- 20-membered heterocycle, C 3 -C 20 cycloalkyloxy group, 4-20 membered heterocyclyloxy group; wherein, the substitution means substitution by one or more R;
  • n is an integer of 0, 1, 2, 3, 4, 5 or 6;
  • Each R is the same or different, and each is independently selected from: deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, (C 3 -C 18 cycloalkyl base) C 1 -C 18 alkyl, (4-20 membered heterocyclyl) C 1 -C 18 alkyl, (C 1 -C 18 alkoxy) C 1 -C 18 alkyl, (C 3 -C 18 cycloalkyloxy)C 1 -C 18 alkyl, (4-20 membered heterocyclyloxy)C 1 -C 18 alkyl, vinyl, ethynyl, (C 1 -C 6 alkyl)ethylene base, deuterated (C 1 -C 6 alkyl) vinyl, halogenated (C 1 -C 6 alkyl) vinyl, (C 1 -C 6 alkyl) ethynyl, deuterated Substituted (C
  • the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has the formula (A) The structure shown:
  • Y is selected from: bond, O, NH, N (C 1 -C 3 alkyl);
  • Z is a substituted or unsubstituted C 1 -C 6 alkylene group; wherein the substitution means substitution by one or more R;
  • W is selected from: substituted or unsubstituted C 3 -C 14 cycloalkyl, or substituted or unsubstituted 4-14 membered saturated or unsaturated heterocyclyl; wherein the substitution refers to one or more R replace;
  • X is selected from: N, CH, CD, CF, C(CN);
  • R 1 is selected from: -L 1 -QL 2 -L 3 ;
  • L 1 is selected from: substituted or unsubstituted C 1 -C 6 alkylene; wherein said substitution means substitution by one or more R;
  • Q is selected from: O, S, SO 2 , NH, or N (C 1 -C 3 alkyl);
  • L 2 is selected from: none, substituted or unsubstituted C 1 -C 6 alkylene; wherein, the substitution means substitution by one or more R;
  • L 3 is selected from the following substituted or unsubstituted groups: -C 1 -C 6 alkyl, -C 3 -C 6 cycloalkyl, -C 4 -C 6 heterocyclyl, -C 1 -C 6 sub- Alkyl (C 3 -C 6 cycloalkyl), -C 1 -C 6 alkylene (C 4 -C 6 heterocyclyl), -C 1 -C 6 alkylene (C 1 -C 6 alkoxy base), -C 1 -C 6 alkylene (C 3 -C 6 cycloalkyloxy), or -C 1 -C 6 alkylene (C 4 -C 6 heterocyclyloxy); wherein, The substitution means substitution by one or more R;
  • n is an integer of 0, 1, 2, 3, 4, 5 or 6; the qualification is that when W is a single ring or a double ring, n is not 0;
  • R 10 is selected from the following substituted or unsubstituted groups: C 6 -C 14 aryl, 5-14 membered heteroaryl; wherein, the substitution means substitution by one or more Ra;
  • R 11 is each independently selected from the following group of substituted or unsubstituted groups: H, deuterium, halogen, cyano, ester, amine, amido, sulfone, ureido, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 yuan Heterocyclyl, C 1 -C 6 alkyloxy, C 3 -C 6 cycloalkyloxy, 4-6 membered heterocyclyloxy;
  • Ra is each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, NH 2 , OH, CONH 2 , NHCO (C 1 -C 6 alkyl), NHCO (C 3 -C 6 Cycloalkyl), SONH 2 , SO 2 NH 2 , NHSO 2 (C 1 -C 6 alkyl), NHSO 2 (C 3 -C 6 cycloalkyl), C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 20 cycloalkyl, 4- 20-membered heterocyclyl, C 3 -C 20 cycloalkyloxy, 4-20-membered heterocyclyloxy; wherein, the substitution means substitution by one or more R;
  • n is an integer of 0, 1, 2, 3, 4, 5 or 6;
  • Each R is the same or different, and each is independently selected from: deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, (C 3 -C 18 cycloalkyl base) C 1 -C 18 alkyl, (4-20 membered heterocyclyl) C 1 -C 18 alkyl, (C 1 -C 18 alkoxy) C 1 -C 18 alkyl, (C 3 -C 18 cycloalkyloxy)C 1 -C 18 alkyl, (4-20 membered heterocyclyloxy)C 1 -C 18 alkyl, vinyl, ethynyl, (C 1 -C 6 alkyl)ethylene base, deuterated (C 1 -C 6 alkyl) vinyl, halo (C 1 -C 6 alkyl) vinyl, (C 1 -C 6 alkyl) ethynyl, deuterated (C 1 -C 6 Al
  • Ra is each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, OH, SONH 2 , NHSO 2 CH 3 , C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 20 cycloalkyl , 4-20 membered heterocyclyl; wherein, the substitution means substitution by one or more R; R is as defined above.
  • the compound has the structure shown by A'
  • n, Y, Z, W, L 1 , L 2 , L 3 , Q, R 10 , R 11 , m, and ring A are as defined above.
  • the compound has a structure represented by formula A”'
  • R 2 and R 3 are the same or different, and are each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy; wherein, the substitution means substitution by one or more R;
  • X, Y, Z, W, R 1 , n and R 10 are defined as above.
  • R 3 is selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 - C 6 haloalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, 4-6-membered heterocyclyl, 4-6-membered heterocyclyloxy; wherein, the substitution means substitution by one or more R.
  • R 10 is selected from: the following groups selected from substituted or unsubstituted groups: phenyl, naphthyl, 5-6 membered monocyclic heteroaryl (such as pyridyl), 9-10 membered bicyclic Heteroaryl (such as indazolyl, benzothiazole, benzothiophene, benzofuran), wherein the substitution is by one or more groups selected from the group consisting of: halogen, hydroxyl, cyano, NH 2.
  • R 10 is selected from:
  • R 8 is selected from: NH 2 , OH, SONH 2 , NHSO 2 CH 3 .
  • R 10 is
  • U is selected from: N, CH, CD, CF;
  • R 4 is selected from the following substituted or unsubstituted groups: halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl;
  • R 5 , R 6 , R 7 , R 9 are the same or different, each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy; wherein, the substitution means substitution by one or more R;
  • R 8 is selected from: NH 2 , OH, SONH 2 , NHSO 2 CH 3 .
  • R 10 is Preferably, R 10 is Preferably, R 10 is
  • U' is selected from: O, or S;
  • U is selected from: N, or C(CN);
  • R 7' , R 8' , R 9' are the same or different, each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy; wherein, the substitution means substitution by one or more R;
  • R 5' is selected from: H, D, halogen, CN, NH 2 , OH, CONH 2 , NHCO (C 1 -C 6 alkyl), NHCO (C 3 -C 6 cycloalkyl), SONH 2 , SO 2 NH 2 , NHSO 2 (C 1 -C 6 alkyl), NHSO 2 (C 3 -C 6 cycloalkyl), C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy.
  • R 10 is wherein, V 1 , V 2 , V 3 , V 4 and V 5 are each independently selected from: N, or CR v ; R v is the same or different, each is independently selected from: H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated C 1 -C 3 alkyl, halogenated C 3 -C 6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO)-C 1 -C 3 alkyl, (HO)-C 3 -C 6 ring Alkyl, (NH 2 )-C 1 -C 3 alkyl, (NH 2 )-C 3 -C 6 cycloalkyl, halogen, CN, -C ⁇ CH, OH,
  • R 10 is Among them, R v1 , R v2 , R v3 , R v4 and R v5 are each independently selected from: H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated C 1 -C 3 alkyl (such as CF 3 , CF 2 CF 3 ), halo Substituted C 3 -C 6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO)-C 1 -C 3 alkyl, (HO)-C 3 -C 6 cycloalkyl, (NH 2 )- C 1 -C 3 alkyl, (NH 2 )-C 3 -C 6 cycloalkyl, halogen, CN, -C
  • R v5 is selected from: halogenated C 1 -C 3 alkyl (such as CF 3 , CF 2 CF 3 ).
  • R v1 is selected from: H.
  • R v1 is selected from: NH 2 .
  • U is selected from: N, CH, CD, CF;
  • U’ is selected from: O, or S;
  • U is selected from: N, or C(CN);
  • X is selected from: N, CH, CD, CF, C(CN);
  • Y is selected from: bond, O, NH, N (C 1 -C 3 alkyl);
  • Z is a substituted or unsubstituted C 1 -C 6 alkylene group; wherein the substitution means substitution by one or more R;
  • W is selected from: substituted or unsubstituted C 3 -C 14 cycloalkyl, or substituted or unsubstituted 4-14 membered saturated or unsaturated heterocyclyl; wherein the substitution refers to one or more R replace;
  • R 1 is selected from: -L 1 -QL 2 -L 3 ; where:
  • L 1 is selected from: substituted or unsubstituted C 1 -C 6 alkylene; wherein said substitution means substitution by one or more R;
  • Q is selected from: O, S, SO 2 , NH, or N (C 1 -C 3 alkyl);
  • L 2 is selected from: none, substituted or unsubstituted C 1 -C 6 alkylene; wherein, the substitution means substitution by one or more R;
  • L 3 is selected from the following substituted or unsubstituted groups: -C 1 -C 6 alkyl, -C 3 -C 6 cycloalkyl, -C 4 -C 6 heterocyclyl, -C 1 -C 6 sub- Alkyl (C 3 -C 6 cycloalkyl), -C 1 -C 6 alkylene (C 4 -C 6 heterocyclyl), -C 1 -C 6 alkylene (C 1 -C 6 alkoxy base), -C 1 -C 6 alkylene (C 3 -C 6 cycloalkyloxy), or -C 1 -C 6 alkylene (C 4 -C 6 heterocyclyloxy); wherein, The substitution means substitution by one or more R;
  • n is an integer of 1, 2, 3, 4, 5 or 6;
  • R 2 and R 3 are the same or different, and are each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy; wherein, the substitution means substitution by one or more R;
  • R 4 is selected from the following substituted or unsubstituted groups: halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; wherein, the substitution means by one or Multiple R substitutions;
  • R 8 is selected from: OH, SONH 2 , NHSO 2 CH 3 ;
  • R 5 , R 6 , R 7 , R 9 , R 7' , R 8' , and R 9' are the same or different, and each is independently selected from substituted or unsubstituted lower groups.
  • R 5' is selected from: H, D, halogen, CN, NH 2 , OH, CONH 2 , NHCO (C 1 -C 6 alkyl), NHCO (C 3 -C 6 cycloalkyl), SONH 2 , SO 2 NH 2 , NHSO 2 (C 1 -C 6 alkyl), NHSO 2 (C 3 -C 6 cycloalkyl), C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy;
  • Each R is the same or different, and each is independently selected from: deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, (C 3 -C 18 cycloalkyl base) C 1 -C 18 alkyl, (4-20 membered heterocyclyl) C 1 -C 18 alkyl, (C 1 -C 18 alkoxy) C 1 -C 18 alkyl, (C 3 -C 18 cycloalkyloxy)C 1 -C 18 alkyl, (4-20 membered heterocyclyloxy)C 1 -C 18 alkyl, vinyl, ethynyl, (C 1 -C 6 alkyl)ethylene base, deuterated (C 1 -C 6 alkyl) vinyl, halo (C 1 -C 6 alkyl) vinyl, (C 1 -C 6 alkyl) ethynyl, deuterated (C 1 -C 6 Al
  • each R is the same or different, and each is independently selected from: deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, ( C 3 -C 18 cycloalkyl) C 1 -C 18 alkyl, (4-20 membered heterocyclyl) C 1 -C 18 alkyl, (C 1 -C 18 alkoxy) C 1 -C 18 alkyl base, (C 3 -C 18 cycloalkyloxy) C 1 -C 18 alkyl, (4-20 membered heterocyclyloxy) C 1 -C 18 alkyl, vinyl, ethynyl, (C 1 -C 6 alkyl) vinyl, deuterated (C 1 -C 6 alkyl) vinyl, halo (C 1 -C 6 alkyl) vinyl, (C 1 -C 6 alkyl) ethynyl, deuterated Substituted
  • each R is the same or different, and each is independently selected from: deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, ( C 3 -C 10 cycloalkyl) C 1 -C 6 alkyl, (4-10 membered heterocyclyl) C 1 -C 6 alkyl, (C 1 -C 6 alkoxy) C 1 -C 6 alkyl base, (C 3 -C 6 cycloalkyloxy) C 1 -C 6 alkyl, (4-20 membered heterocyclyloxy) C 1 -C 18 alkyl, vinyl, ethynyl, (C 1 -C 6 alkyl) vinyl, deuterated (C 1 -C 6 alkyl) vinyl, halo (C 1 -C 6 alkyl) vinyl, (C 1 -C 6 alkyl) ethynyl, deuterated Substituted
  • the compound of formula I has the structure represented by formula (I'A) or formula (I'B)
  • n, U, U', U", X, Y, Z, W, L 1 , L 2 , L 3 , Q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 5' , R 7' , R 8' , R 9' are as defined above.
  • the compound has a structure represented by formula (IIA) or formula (IIB):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 5' , R 7' , R 8' , R 9 ' , U, U', U", X, Z, W and n are defined as above.
  • the compound has a structure represented by formula (IIIA) or formula (IIIB):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 5' , R 7' , R 8' , R 9 ' , U, U', U", Z, W and n are defined as above.
  • R 3 is selected from: H, D, F, Cl, Br, CN, methyl, ethyl, propyl, isopropyl, deuterated methyl, CH 2 F, CHF 2 , CF 3. Methoxy, ethoxy, propoxy, OCH 2 F, OCHF 2 , OCF 3 .
  • the compound has a structure represented by formula (IVA) or formula (IVB):
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 5' , R 7 ' , R 8' , R 9' , U, U', U", Z, W and n are defined as above.
  • the compound has a structure represented by formula (VA) or formula (VB):
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 9 , R 7' , R 8' , R 9' , U, U', U", Z, W and n are defined as above .
  • the compound has a structure represented by formula (VIA) or formula (VIB):
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 9 , R 7′ , R 8′ , R 9′ , U′′, Z, W and n are defined as above.
  • the compound has a structure represented by formula (VIIA) or formula (VIIB):
  • R 1 , R 4 , R 5 , R 7′ , R 8′ , R 9′ , Z, W and n are defined as above.
  • the compound has a structure represented by formula (VIIIA) or formula (VIIIB):
  • R 1 , R 4 , R 5 , R 7′ , R 9′ , Z, W and n are defined as above.
  • W substitutes or unsubstitutes the following groups: C 3 -C 6 monocyclic cycloalkyl, C 7 -C 10 bicyclic or C 7 -C 11 tricyclic cycloalkyl, 4-6 One-membered saturated or unsaturated monocyclic heterocyclyl, 7-10-membered bicyclic or 7-11-membered tricyclic heterocyclyl; preferably, W is selected from: substituted or unsubstituted 7-10-membered saturated or unsaturated bridged ring Heterocyclyl, substituted or unsubstituted 7-10 membered saturated or unsaturated fused ring heterocyclyl.
  • W is selected from:
  • n' is an integer of 0, 1, 2, 3, 4, 5, or 6; R is defined as above, and R can be substituted on any ring of a polycyclic ring (such as a bridged ring or a spiro ring).
  • W is selected from:
  • n' can be 1 or 2, more preferably, n' is 1, R is defined as above, and R can be substituted on any ring of a polycyclic ring (such as a bridged ring or a spiro ring).
  • W is selected from:
  • n' can be 0, 1 or 2
  • R is defined as above, and R can be substituted on any ring of a polycyclic ring (such as a bridged ring or a spiro ring).
  • W is selected from:
  • n' can be 0, 1 or 2
  • R is defined as above, and R can be substituted on any ring of a polycyclic ring (such as a bridged ring or a spiro ring).
  • R is selected from: deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, (C 3 -C 6 cycloalkyl )C 1 -C 18 alkyl, (4-6 membered heterocyclyl) C 1 -C 6 alkyl, (C 1 -C 6 alkoxy) C 1 -C 6 alkyl, (C 3 -C 6 cycloalkyl oxide Base) C 1 -C 6 alkyl, (4-6 membered heterocyclyloxy) C 1 -C 6 alkyl, vinyl, ethynyl, (C 1 -C 6 alkyl) vinyl, deuterated ( C 1 -C 6 alkyl) vinyl, halogenated (C 1 -C 6 alkyl) vinyl, (C 1 -C 6 alkyl) ethynyl, deuterated (C 1 -C 6 alkyl) e
  • Z is a substituted or unsubstituted C 1 -C 3 alkylene group, preferably methylene, ethylene, or propylene.
  • Z is CD 2 .
  • the compound has a structure represented by formula (IX):
  • n’ is an integer of 0, 1, 2, 3, 4, 5, or 6;
  • R 5 , R, L 1 , Q, L 2 , L 3 and n are defined as above.
  • R 4 is selected from the following substituted or unsubstituted groups: halogen, methyl, ethyl, propyl, vinyl, propenyl, allyl, butenyl, ethynyl, propyl Alkynyl, butynyl.
  • the compound has a structure represented by formula (X):
  • V 1 , V 2 , V 3 , V 4 and V 5 are each independently selected from: N, or CR v ;
  • R v is the same or different, each is independently selected from: H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated C 1 - C 3 alkyl, halogenated C 3 -C 6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO)-C 1 -C 3 alkyl, (HO)-C 3 -C 6 cycloalkyl , (NH 2 )-C 1 -C 3 alkyl, (NH 2 )-C 3 -C 6 cycloalkyl, halogen, CN, -C ⁇ CH, OH, NH 2 , CONH
  • R 2 and R 3 are the same or different, and are each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy; wherein, the substitution means substitution by one or more R;
  • Rings C, R, X, Z, W and n are defined as above.
  • the compound has a structure represented by formula (XI):
  • V 1 , V 2 , V 3 , V 4 , and V 5 are each independently selected from: N, or CR v ;
  • R v is the same or different, and each is independently selected from: H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated C 1 - C 3 alkyl, halogenated C 3 -C 6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO)-C 1 -C 3 alkyl, (HO)-C 3 -C 6 cycloalkyl , (NH 2 )-C 1 -C 3 alkyl, (NH 2 )-C 3 -C 6 cycloalkyl, halogen, CN, -C ⁇ CH, OH, NH 2
  • R 2 and R 3 are the same or different, and are each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy; wherein, the substitution means substitution by one or more R;
  • R, R 1 , X, Z, W and n are defined as above.
  • the compound has a structure represented by formula (XII):
  • V 1 , V 2 , V 3 , V 4 , and V 5 are each independently selected from: N, or CR v ;
  • R v is the same or different, and each is independently selected from: H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated C 1 - C 3 alkyl, halogenated C 3 -C 6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO)-C 1 -C 3 alkyl, (HO)-C 3 -C 6 cycloalkyl , (NH 2 )-C 1 -C 3 alkyl, (NH 2 )-C 3 -C 6 cycloalkyl, halogen, CN, -C ⁇ CH, OH, NH 2
  • R 3 is selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy; wherein, the substitution means substitution by one or more R;
  • R, R 1 , X, Z, W and n are defined as above.
  • the compound has a structure represented by formula (XIII):
  • V 1 , V 2 , V 3 , V 4 , and V 5 are each independently selected from: N, or CR v ;
  • R v is the same or different, and each is independently selected from: H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated C 1 - C 3 alkyl, halogenated C 3 -C 6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO)-C 1 -C 3 alkyl, (HO)-C 3 -C 6 cycloalkyl , (NH 2 )-C 1 -C 3 alkyl, (NH 2 )-C 3 -C 6 cycloalkyl, halogen, CN, -C ⁇ CH, OH, NH 2
  • R 3 is selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy; wherein, the substitution means substitution by one or more R;
  • R, R 1 , Z, W and n are defined as above.
  • R v is each independently selected from: H, halogen, CN, -C ⁇ CH, or NH 2 .
  • L 1 is selected from: substituted or unsubstituted methylene or substituted or unsubstituted ethylene; Q is selected from: O; L 2 is selected from: none, or substituted or unsubstituted ethylene.
  • Methyl; L 3 is selected from the following substituted or unsubstituted groups: -C 1 -C 6 alkyl, -C 3 -C 6 cycloalkyl, -C 4 -C 6 heterocyclyl, -C 1 - C 6 alkylene (C 3 -C 6 cycloalkyl), -C 1 -C 6 alkylene (C 4 -C 6 heterocyclyl), -C 1 -C 6 alkylene (C 1 -C 6 alkoxy), -C 1 -C 6 alkylene (C 3 -C 6 cycloalkyloxy), or -C 1 -C 6 alkylene (C 4 -C 6 heterocyclyloxy) ; Wherein, the substitution refers to substitution with one or more groups selected from the following group: deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl Base, vinyl, ethy
  • -L 1 -QL 2 -L 3 is selected from:
  • n' is an integer of 0, 1, 2, 3, 4, 5 or 6;
  • R, R 1 and n are defined as above, R and R 1 can be substituted in polycyclic rings (such as bridged rings or spiro rings) on any ring of ;
  • n' is an integer of 0, 1, 2, 3, 4, 5 or 6; R is defined as above, and R can be substituted on any ring of a polycyclic ring (such as a bridged ring or a spiro ring).
  • W is selected from:
  • W is selected from:
  • W is selected from:
  • the prodrug of the compound has a structure represented by the following formula (XIV):
  • C' is selected from:
  • PG selected from:
  • Y, Z, W, ring A, R 1 , R 10 , R 11 , m and n are as defined above.
  • m, A ring, n, U, X, Y, Z, W, L 1 , L 2 , L 3 , Q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 have groups corresponding to each specific compound in the examples.
  • V 1 , V 2 , V 3 , V 4 , V 5 , ring C, and PG have the values corresponding to each specific compound in the embodiment. Should group.
  • the compound is selected from the following group:
  • the compound is preferably the compound prepared in the embodiment.
  • the present invention provides a method for preparing a compound of formula (A0), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, Among them, it includes steps (taking formula IA as an example):
  • the compound of formula V-7 removes the protecting group PG1 under the action of acid (such as TFA, HCl, etc.) or Pd catalyzed hydrogenation conditions to obtain the compound of formula (IA);
  • X 1 , X 2 and X 3 are each independently selected from: OH, halogen, OTf, OTs or OMs;
  • PG1 is selected from: Boc, Cbz, or Bn;
  • LG1 is selected from: -B(OH) 2 , -B(KBF 3 ), -Sn( n Bu) 3 ,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , U, X, Y, Z, W and n are defined as above.
  • the third aspect of the present invention provides a pharmaceutical composition, which contains one or more compounds described in the first aspect, their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, a hydrate, solvate or prodrug; and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises a drug selected from the following group: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI- 308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzuma
  • the fourth aspect of the present invention provides a compound described in the first aspect, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, or
  • the use of the pharmaceutical composition described in the third aspect is used to prepare drugs for preventing and/or treating diseases related to the activity or expression level of KRAS G12D .
  • the disease is a tumor or disorder.
  • the disease is selected from the following group: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, gastric cancer, liver cancer, colorectal cancer, melanoma, lymphoma, blood cancer , brain tumors, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
  • the fourth aspect of the present invention provides a non-diagnostic and non-therapeutic method for inhibiting KRAS G12D , which includes the steps of: administering to a desired subject an effective amount of a compound as described in the first aspect, and its stereoisomers , tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or administer a pharmaceutical composition as described above.
  • the subject is a mammal, preferably a human.
  • the fifth aspect of the present invention provides a method for inhibiting KRAS G12D activity in vitro, including the steps of: combining the compound described in the first aspect, its stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable Salts, hydrates, solvates or prodrugs, or pharmaceutical compositions as described above, contact proteins or cells, thereby inhibiting the activity of KRAS G12D .
  • the cells are selected from the following group: macrophages, intestinal cells (including intestinal stem cells, intestinal epithelial cells), or combinations thereof.
  • the cells are from rodents (such as mice, rats) or primates (such as humans).
  • the inventor unexpectedly prepared a new class of compounds with selective inhibitory effects on KRAS G12D and/or better pharmacodynamic properties. On this basis, the inventor completed the present invention.
  • alkyl refers to a straight or branched chain alkyl hydrocarbon radical, containing 1 to 20 carbon atoms, such as 1 to 18 carbon atoms, especially 1 to 18 carbon atoms, preferably containing 1 to 10 carbon atoms ( C1-C10), more preferably containing 1-6 carbon atoms (C1-C6).
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, Pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl etc.
  • alkyl groups also include substituted alkyl groups. "Substituted alkyl” means that one or more positions in the alkyl group are substituted, especially 1 to 4 substituents, which can be substituted at any position.
  • alkylene refers to a group formed by removing a hydrogen atom from "alkyl or substituted alkyl", such as methylene, ethylene, propylene, isopropylene (such as ), butylene (such as ), pentylene (such as ), Ethylene (such as ), heptylene (such as ), wait.
  • the term also includes an alkylene group (such as C1-C18 alkylene) in which one methylene group is replaced by a cycloalkylene group (such as C3-C20 cycloalkylene), such as "C1-C18 alkylene C3-C20""Cycloalkylene” or "C3-C20 cycloalkylene C1-C18 alkylene".
  • alkylene group such as C1-C18 alkylene
  • cycloalkylene group such as C3-C20 cycloalkylene
  • C1-C18 alkylene C3-C20 cycloalkylene or "C3-C20 cycloalkylene C1-C18 alkylene” have the same meaning and refer to cycloalkylalkyl or alkylcycloalkyl off A group formed by two hydrogen atoms, such as wait.
  • alkenyl means a straight or branched hydrocarbon group containing one or more double bonds and usually having a length of 2 to 20 carbon atoms.
  • the alkenyl group is preferably a C2-C6 alkenyl group, and more preferably a C2-C4 alkenyl group.
  • Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
  • alkenyl includes substituted alkenyl.
  • alkynyl refers to a straight or branched hydrocarbon group containing one or more triple bonds and usually having a length of 2 to 20 carbon atoms.
  • the alkynyl group is preferably a C2-C6 alkynyl group, and more preferably a C2-C4 alkynyl group.
  • Alkynyl groups include, but are not limited to, ethynyl, propynyl or similar groups.
  • alkynyl groups also include substituted alkynyl groups, and the substituents may be halogenated, hydroxyl, cyano, nitro, etc.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon group, including 1 to 4 rings, each ring containing 3 to 8 carbon atoms.
  • C 3 -C 20 refers to a ring containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms Alkyl.
  • Cycloalkyl is preferably C 3 -C 14 cycloalkyl, more preferably C 3 -C 10 cycloalkyl, more preferably C 3 -C 6 monocyclic cycloalkyl, C 7 -C 10 bicyclic or Tricyclic cycloalkyl.
  • Substituted cycloalkyl means that one or more positions in the cycloalkyl are substituted, especially 1 to 4 substituents, which can be substituted at any position.
  • cycloalkyl includes substituted cycloalkyl.
  • the typical substituents described above may be optionally substituted.
  • Typical substitutions also include spiro, bridged or condensed ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spiroheterocycle (excluding heteroaromatic rings), bridged cycloalkyl, bridged cycloalkenyl, Bridged ring heterocycle (excluding heteroaryl ring), fused ring alkyl, fused ring alkenyl, fused ring heterocyclyl or fused ring aromatic ring, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclyl and heterocyclic aromatic
  • the groups may be optionally substituted.
  • Examples of cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like.
  • C3-C20 cycloalkylene refers to a group formed by removing two hydrogen atoms from a cycloalkyl group, such as: wait.
  • heterocyclyl refers to a fully saturated or partially unsaturated cyclic group (including but not limited to 3-7 membered monocyclic ring, 4-7 membered monocyclic ring, 6-11 membered bicyclic ring). or 8-16 membered tricyclic or polycyclic ring systems) in which at least one heteroatom is present in a ring with at least one carbon atom.
  • the term “4-20 membered heterocyclyl” refers to a group containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms. Heterocyclyl. "Heterocyclyl” has the same meaning as "saturated or unsaturated heterocyclyl".
  • Heterocyclyl is preferably a 4-14 membered heterocyclyl (including but not limited to a 4-6 membered monocyclic ring, a 7-10 membered bicyclic ring or an 8-14 membered tricyclic or polycyclic ring system), more preferably 4-12 membered heterocyclyl, more preferably 4-10 membered heterocyclyl, such as 4-6 membered monocyclic heterocyclyl, 7-10 membered bicyclic or tricyclic heterocyclyl, more preferably 4-8
  • a membered heterocyclyl group is more preferably a 4- to 6-membered heterocyclyl group.
  • Each heterocyclic ring containing heteroatoms can have 1, 2, 3 or 4 heteroatoms.
  • heteroatoms are selected from nitrogen atoms, oxygen atoms or sulfur atoms.
  • the nitrogen atoms or sulfur atoms can be oxidized, and the nitrogen atoms can also be Be quaternized.
  • the heterocyclic group may be attached to any heteroatom or residue of a carbon atom of the ring or ring system molecule, preferably to an N or C atom of the ring or ring system molecule.
  • Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidine base, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepine Gene base, 4-piperidinone group, tetrahydropyranyl group, morpholinyl group, thiomorpholinyl group, thiomorpholine sulfoxide group, thiomorpholine sulfone group, 1,3-dioxanyl group and Tetrahydro-1,1-dioxythiophene, etc.
  • Polycyclic heterocyclyl groups include spirocyclic, fused-cyclic and bridged-cyclic heterocyclyl groups; the involved spirocyclic, fused-cyclic and bridged-cyclic heterocyclyl groups are optionally connected to other groups through a single bond, or through a ring. Any two or more atoms on are further connected to other cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups; the heterocyclic group can be substituted or unsubstituted.
  • the substituents are preferably one or more substituents independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate groups.
  • C4-C20 heterocyclylene refers to a group formed by removing two hydrogen atoms from a heterocyclyl group, such as: wait.
  • aryl refers to an aromatic cyclic hydrocarbon group having 1 to 5 rings, especially monocyclic and bicyclic groups.
  • C 6 -C 14 aryl refers to an aromatic cyclic hydrocarbon compound group containing 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring carbon atoms.
  • Aryl groups include phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be connected by single bonds (such as biphenyl), or fused (such as naphthalene, anthracene, etc.).
  • the typical substituents described above may be optionally substituted.
  • Typical substitutions also include condensed ring substituents, especially condensed ring alkyl, condensed ring alkenyl, condensed ring heterocyclyl or condensed ring aromatic ring groups.
  • condensed ring substituents especially condensed ring alkyl, condensed ring alkenyl, condensed ring heterocyclyl or condensed ring aromatic ring groups.
  • the above-mentioned cycloalkyl, cycloalkenyl, heterocyclyl and heterocyclic aromatic groups The groups may be optionally substituted.
  • heteroaryl refers to an aromatic cyclic hydrocarbon group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur.
  • heteroaryl refers to a heteroaromatic system containing 1-4 heteroatoms and 5-14 ring atoms.
  • the heteroaryl group is preferably a 5- to 10-membered ring, more preferably a 5- or 6-membered ring, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazazinyl, triazolyl and tetrazolyl, etc.
  • “Heteroaryl” may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy , haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyl Thio, oxo, carboxyl and carboxylate groups.
  • groups are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy , haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyl Thio, oxo, carb
  • alkoxy refers to a straight-chain or branched alkoxy group, including alkyl-O-, alkyl-O-alkyl, where "C 1 -C 18 alkoxy” is Refers to a straight-chain or branched alkoxy group with 1 to 18 carbon atoms, including C 1 -C 18 alkyl-O-, -C 1 -C 6 alkyl-OC 1 -C 6 alkyl, non-limiting Ground includes methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably it is a C 1 -C 8 alkoxy group, more preferably a C 1 -C 6 alkoxy group.
  • cycloalkyloxy refers to cycloalkyl-O-, where "C 3 -C 20 cycloalkyloxy” refers to C 3 -C 20 cycloalkyl -O-, where, C 3 -C 20 cycloalkyl is defined as above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein "4-20-membered heterocyclyloxy” refers to 4-20-membered heterocyclyl-O-, wherein 4 -
  • the 20-membered heterocyclyl group is as defined above.
  • C 1 -C 18 alkyleneoxy refers to a group obtained by removing one hydrogen atom from "C 1 -C 18 alkoxy”.
  • halogen refers to chlorine, bromine, fluorine, and iodine.
  • halo means substituted by halogen.
  • deuterated means substituted by deuterium.
  • hydroxyl refers to a group with the structure OH.
  • nitro refers to a group with the structure NO2 .
  • cyano refers to a group with the structure CN.
  • ester group refers to a group with the structure -COOR, where R represents hydrogen, alkyl or substituted alkyl. radical, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle.
  • the ester group is preferably -COO C 1 -C 6 alkyl.
  • amino refers to a group with the structure -NRR', where R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' may be the same or different in the dialkylamine moiety.
  • the amine group is preferably NH 2 , NH C 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 .
  • amide group refers to a group with the structure -CONRR' or -NRCOR', where R and R' can each independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl , cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above.
  • the amide group is preferably CONH 2 , NHCO (C 1 -C 6 alkyl), NHCO (C 3 -C 6 cycloalkyl).
  • sulfonamido refers to a group with the structure -S 2 ONRR' or -NRSO 2 R', where R and R' can each independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or Substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above.
  • the sulfonamide group is preferably SO 2 NH 2 , NHSO 2 (C 1 -C 6 alkyl), NHSO 2 (C 3 -C 6 cycloalkyl).
  • sulfone refers to a group having the structure -SO 2 R, where R may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted Cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above.
  • ureido refers to a group with the structure -NRCONR'R", where R, R' and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl , cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R" may be the same or different in the dialkylamine moiety.
  • alkylaminoalkyl refers to a group having the structure -RNHR', where R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, Cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' may be the same or different.
  • dialkylaminoalkyl refers to a group with the structure -RNHR'R", where R, R' and R" can independently represent alkyl or substituted alkyl, cycloalkyl or substituted Cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R" may be the same or different in the dialkylamine moiety.
  • heterocyclylalkyl refers to a group with the structure -RR', where R may independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl; R' represents heterocycle or substituted heterocycle.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • Specific substituents are the substituents described accordingly in the foregoing text, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents include, but are not limited to, In): halogen, hydroxyl, cyano group, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic group, Aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amine group, C1-C6 alkoxy group, C1-C10 sulfonyl group, and C1-C6 urea group, etc.
  • any heteroatom that is not satisfied with its valence is assumed to have enough hydrogen atoms to supplement its valence.
  • an alkyl group corresponds to an alkylene group
  • a cycloalkyl group corresponds to a cycloalkylene group
  • a heterocyclyl group corresponds to a heterocyclylene group
  • an alkoxy group corresponds to Alkyleneoxy etc.
  • compounds of the present invention refer to compounds represented by Formula I, and also include stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates of compounds of Formula I.
  • salts formed by the compounds in the present invention also belong to the scope of the present invention. Unless otherwise stated, compounds in the present invention are understood to include salts thereof.
  • the term "salt” as used herein refers to an acidic or basic salt formed from an inorganic or organic acid and a base.
  • the compound of the present invention contains a basic moiety, which includes but is not limited to pyridine or imidazole, and when it contains an acidic moiety, including but is not limited to carboxylic acid, the zwitterion (“inner salt”) that may be formed is included in Within the scope of the term "salt”.
  • salts are preferred, although other salts are also useful, for example, in isolation or purification steps during preparation.
  • the compounds of the present invention may form salts, for example, compound I can be obtained by reacting with a certain amount of, for example, an equivalent amount of acid or base, salting out in a medium, or by freeze-drying in an aqueous solution.
  • the compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids.
  • Typical acids that can form salts include acetates (eg, with acetic acid or trihaloacetic acids, such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, and benzoates.
  • benzenesulfonate hydrogen sulfate, borate, butyrate, citrate, camphor salt, camphor sulfonate, cyclopentane propionate, diglycolate, dodecyl sulfate, Ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, enanthate, caproate, hydrochloride, hydrobromide, hydroiodide, glycolate (e.g., 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalic acid Salt, pectate, persulfate, phenylpropionate (such as 3-phenylpropionate), phosphate, picrate, pivalate, propionate, sal
  • Certain compounds of the invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases.
  • Typical salts formed with bases include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (such as organic amines), such as benzathine, dicyclohexyl Amine, hepamine (salt with N,N-bis(dehydroabidyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butyl amines, and salts formed with amino acids such as arginine, lysine, etc.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl ester and dipentyl ester), long chain halides (such as decyl, dodecyl, tetradecyl and tetradecyl chlorides, bromides and iodide), aralkyl halides (such as benzyl and phenyl bromide), etc.
  • small halides such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl
  • dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl este
  • Prodrugs and solvates of the compounds of the present invention are also within the scope of the invention.
  • the term "prodrug” here refers to a compound that undergoes chemical transformation through metabolism or chemical processes to produce the compound, salt, or solvate of the present invention when treating related diseases.
  • Compounds of the present invention include solvates, such as hydrates.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All such tautomers are part of the present invention.
  • All stereoisomers of the compounds are contemplated by the present invention.
  • the compounds of the invention may be independent stereoisomers that do not exist simultaneously with other isomers (e.g., have a specific activity as a pure or substantially pure optical isomer), or they may be mixtures, e.g. Racemates, or mixtures with all other stereoisomers or portions thereof.
  • the chiral center of the present invention has two configurations: S or R, which are defined as recommended by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974.
  • Racemic forms can be resolved by physical methods, such as fractional crystallization, or by fractional crystallization by derivatization to diastereoisomers, or by chiral column chromatography.
  • Individual optical isomers can be obtained from the racemate by suitable methods, including but not limited to traditional methods, such as salt formation with an optically active acid followed by recrystallization.
  • the weight content of the compounds in the present invention obtained by sequential preparation, separation and purification is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compounds), as described in the text List. Such "very pure” compounds of the invention are here also included as part of the invention.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, elimination Spin mixtures and other mixtures.
  • asymmetric carbon atoms can represent substituents, such as alkyl groups. All isomers, as well as mixtures thereof, are included in the present invention.
  • the mixture of isomers may contain the isomers in various ratios.
  • a mixture of only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: All ratios of isomers 2, 99:1, or 100:0 are within the scope of the invention. Similar ratios, as well as ratios for more complex mixtures of isomers that are readily understood by those of ordinary skill in the art, are also within the scope of the present invention.
  • the present invention also includes isotopically labeled compounds that are equivalent to the original compounds disclosed herein. In practice, however, it often occurs that one or more atoms are replaced by atoms with a different atomic weight or mass number.
  • isotopes of compounds that may be included in the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O respectively. , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • the compounds of the present invention or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotope atoms of the above compounds are within the scope of the present invention.
  • Certain isotopically labeled compounds of the present invention such as radioactive isotopes of 3 H and 14 C, are also included and are useful in tissue distribution experiments of drugs and substrates. Tritium, or 3H , and carbon-14, or 14C , are relatively easy to prepare and detect. It is the first choice among isotopes.
  • heavier isotope substitutions such as deuterium, i.e.
  • Isotopically labeled compounds can be prepared by general methods by replacing readily available isotopically labeled reagents with non-isotopic reagents, using the protocols disclosed in the Examples.
  • a synthesis of a specific enantiomer of the compound of the present invention it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, and the resulting diastereomeric mixture is separated and then the chiral auxiliary is removed. Pure enantiomer.
  • a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then through separation, crystallization or chromatography, etc. After separation by conventional means, the pure enantiomers are obtained.
  • the compounds of the present invention may be provided with any number of substituents or functional groups to broaden their encompassing scope.
  • substituents or functional groups in general, whether the term “substituted” appears before or after the term “optional”, the general formula of the substituent included in the formulation of the present invention means that the substituent of the specified structure is used in place of the hydrogen radical. When multiple positions in a specific structure are substituted by multiple specific substituents, the substituents may be the same or different at each position.
  • substitution as used herein includes all permissible substitutions of organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • heteroatoms such as nitrogen may have hydrogen substituents or any of the permissible organic compounds described above to supplement their valence.
  • this invention is not intended to be limited in any way to the permitted substituted organic compounds.
  • the present invention contemplates that combinations of substituents and variable groups may be advantageous in the form of stable compounds for the treatment of diseases, such as infectious or proliferative diseases.
  • stable refers to a compound that is stable, detectable over a long enough period of time to maintain the structural integrity of the compound, and preferably effective over a long enough period of time, and is used herein for the above purposes.
  • prodrug refers to a drug obtained by modifying the chemical structure to introduce an easy-leaving group, which is inactive or has little activity in vitro, but is in vivo through the participation of enzymes (such as hydrolases, oxidases, etc.) or Compounds that undergo non-enzymatic transformation (such as pH, light, radiation, etc.) to release active drugs and exert medicinal effects.
  • the prodrugs include, but are not limited to, carboxylic acid esters, phosphate esters, carbamate esters, carbonic acid esters, etc.
  • Easy-leaving group structures include (but are not limited to):
  • the preparation method of the compound of formula (A0) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention can also be optionally prepared by combining various synthetic methods described in the specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
  • the preparation process of the compounds of the present invention is as follows.
  • the raw materials and reagents used therein can be purchased through commercial channels unless otherwise specified.
  • the compound of the present invention is prepared by the following method (taking formula IA as an example)
  • the compound of formula V-7 removes the protecting group PG1 under the action of acid (such as TFA, HCl, etc.) or Pd catalyzed hydrogenation conditions to obtain the compound of formula (IA);
  • X 1 , X 2 and X 3 are each independently selected from: OH, halogen, OTf, OTs or OMs;
  • PG1 is selected from: Boc, Cbz, or Bn;
  • LG1 is selected from: -B(OH) 2 , -B(KBF 3 ), -Sn( n Bu) 3 ,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , U, X, Y, Z, W and n are defined as above.
  • compositions and methods of administration are provided.
  • the pharmaceutical composition of the present invention is used to prevent and/or treat the following diseases: inflammation, cancer, cardiovascular diseases, infections, immune diseases, and metabolic diseases.
  • the compound of general formula (A0) can be used in combination with other drugs known to treat or improve similar conditions. When co-administered, the original administration mode and dosage of the drug can remain unchanged, while the compound of formula I is administered simultaneously or subsequently. When the compound of formula (A0) is taken simultaneously with one or several other drugs, a pharmaceutical composition containing one or several known drugs and the compound of formula I can be preferably used. Drug combinations also include administration of a compound of formula (A0) with one or more other known drugs during overlapping time periods. When the compound of formula (A0) is used in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of them alone.
  • Drugs or active ingredients that can be combined with the compound described in general formula (A0) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB- A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumuma
  • Dosage forms of the pharmaceutical composition of the present invention include (but are not limited to): Injections, tablets, capsules, aerosols, suppositories, films, pills, topical liniments, controlled-release or sustained-release or nano-preparations.
  • the pharmaceutical composition of the present invention contains a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier within a safe and effective amount.
  • the “safe and effective dose” refers to the amount of compound that is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, it contains 10-1000 mg of the compound of the present invention/dose.
  • the "dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility” here means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • solid lubricants such as
  • administration mode of the compounds or pharmaceutical compositions of the present invention is not particularly limited.
  • Representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) Humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarder, such as paraffin; (f) Absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl mono
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active compounds can also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 ,3-D Diols, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 ,3-D Diols, dimethylformamide and oils, especially cotton
  • compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions may contain, in addition to the active compound, suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
  • compositions for parenteral injection may contain physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.
  • the treatment method of the present invention can be administered alone or in combination with other treatment methods or therapeutic drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, and the dosage when administered is a pharmaceutically effective dosage.
  • a mammal such as a human
  • the daily dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.
  • the present invention also provides a method for preparing a pharmaceutical composition, which includes the steps of: combining a pharmaceutically acceptable carrier with the compound of general formula (A0) of the present invention or its crystal form, pharmaceutically acceptable salt, hydrate or The solvates are mixed to form a pharmaceutical composition.
  • the present invention also provides a treatment method, which includes the step of: administering the compound of general formula (A0) described in the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate to a subject in need of treatment. , or administering the pharmaceutical composition of the invention for selectively inhibiting KRAS G12D .
  • the present invention has the following main advantages:
  • the compound has a very good selective inhibitory effect on KRAS G12D ;
  • the compound has better pharmacodynamics, pharmacokinetic properties and lower toxic and side effects.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) and liquid mass spectrometry (LC-MS).
  • NMR NMR was detected using a Bruker AVANCE-400 nuclear magnetic instrument.
  • the measurement solvents included deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated acetone (CD 3 COCD 3 ), deuterated chloroform (CDCl 3 ) and deuterated methanol ( CD 3 OD), etc.
  • the internal standard is tetramethylsilane (TMS), and the chemical shift is measured in parts per million (ppm).
  • LC-MS Liquid mass spectrometry
  • the thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, TLC uses 0.15-0.20mm, and preparative thin layer chromatography uses 0.4mm-0.5mm.
  • Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as the carrier.
  • the starting materials in the examples of the present invention are all known and commercially available, or can be adopted or synthesized according to literature data reported in the field.
  • 3-(hydroxymethyl)tetrahydro-1H-double-condensed pyrrolidine-7a(5H)-formic acid methyl ester was chirally resolved to obtain cis-3-(hydroxymethyl)tetrahydro-1H-double-condensed pyrrolidine- 7a(5H)-formic acid methyl ester and trans-3-(hydroxymethyl)tetrahydro-1H-bis-condensed pyrrolidine-7a(5H)-formic acid methyl ester.
  • Step 5 Preparation of: (3-(methoxymethyl)tetrahydro-1H-bis-condensed pyrrolidin-7a(5H)-yl)methanol
  • Step 3 Preparation of 1-(tert-butyl)2-methyl 2-((1-((benzyloxy)methyl)cyclopropyl)methyl)pyrrolidine-1,2-dicarboxylate
  • Step 4 Preparation of 1-(tert-butyl)2-methyl 2-((1-(hydroxymethyl)cyclopropyl)methyl)pyrrolidine-1,2-dicarboxylate
  • Step 5 Preparation of 1-(tert-butyl)2-methyl 2-((1-(bromomethyl)cyclopropyl)methyl)pyrrolidine-1,2-dicarboxylate
  • Step 6 Preparation of 2-((1-(bromomethyl)cyclopropyl)methyl)pyrrolidine-2-carboxylic acid methyl ester
  • Step 7 Preparation of dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-formic acid methyl ester
  • Step 8 Preparation of: (dihydro-1'H,3'H-spiro[cyclopropane-1,2'-biscondensed pyrrolidine]-7a'(5'H)-yl)methanol
  • Step 2 ((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-biscondensed pyrrolidine]-7a'(5'H) -yl)methanol and ((cis)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bifused pyrrolidine]-7a'(5'H )-yl)methanol
  • Step 1 (trans)-2,2-difluoro-5'-oxydihydro-1'H,3'H-spiro[cyclopropane-1,2'-bifused pyrrolidine]-7a'( 5'H)-Ethyl formate and (cis)-2,2-difluoro-5'-oxydihydro-1'H,3'H-spiro[cyclopropane-1,2'-biscondensed pyrrolidine Preparation of ]-7a'(5'H)-ethyl formate (intermediate 1-11-IA and intermediate 1-11-IB)
  • Intermediate 1-11-I (6g) was isolated by silica gel column chromatography ( 40g Silica Flash Column, eluent: 0 ⁇ 50% THF/petroleum ether 40mL/min) to obtain intermediate I-11-IA (2.80g, 10.8mmol, 47% yield) and intermediate I-11-IB (2.40g) ,9.26mmol, 40% yield).
  • Step 2 ((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-biscondensed pyrrolidine]-7a'(5'H) -yl)methanol and ((cis)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bifused pyrrolidine]-7a'(5'H )-base) Preparation of methanol (intermediate 1-11-A and intermediate 1-11-B)
  • Isomer 1-11A was separated through chiral resolution to obtain isomer 1-11A-1(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane- 1,2'-Bisfused pyrrolidine]-7a'(5'H)-yl)methanol) and isomer 1-11A-2(((1R,7a'R)-2,2-difluorodihydrogen -1'H,3'H-spiro[cyclopropane-1,2'-bisfused pyrrolidine]-7a'(5'H)-yl)methanol).
  • Step 2 Preparation of intermediate 1-11A-1 and intermediate 1-11A-2
  • Step 1 Preparation of: (S)-5-(((tert-butylmethylsilyl)oxy)methyl)pyrrolin-2-one
  • the obtained mixture was reacted at 25°C for 16 h, then quenched by adding saturated NH 4 Cl aqueous solution (1000 mL) at 0-10°C under nitrogen protection, and then extracted with EtOAc (1000 mL*2). The combined organic phases were washed with saturated brine (1000 mL), dried over anhydrous MgSO 4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (122 g, 382 mmol, 87.6% yield).
  • Step 3 Preparation of: (S)-4-benzyl-5-(((tert-butylmethylsilyl)oxy)methyl)-4-azaspiro[2.4]heptane
  • Ti(OiPr) 4 (224g, 789mmol, 2.25eq) was added to a solution of TiCl 4 (49.9g, 263mmol, 0.750eq) in toluene (263mL) at 0°C.
  • the reaction solution was reacted at 25°C for 2 h, and then MeLi (1.60M, 657mL, 3.00eq) was added dropwise at 0°C.
  • Step 6 Preparation of: (S)-5-(hydroxymethyl)-azaspiro[2.4]heptane-4-carboxylic acid tert-butyl ester
  • Step 7 Preparation of: (S)-4-(tert-butyloxycarbonyl)-4-azaspiro[2.4]heptane-5-carboxylic acid
  • Step 8 Preparation of: (S)-4-(tert-butyloxycarbonyl)-4-azaspiro[2.4]heptane-5-carboxylic acid methyl ester
  • Step 9 Preparation of 4-(tert-butyl)5-methyl5-(3-chloropropyl)-4-azaspiro[2.4]heptane-4,5-dicarboxylate
  • Step 11 Preparation of tetrahydrospiro[cyclopropane-1,3'-bifused pyrrolidine]-7a'(5'H)-formic acid methyl ester
  • Step 12 (Preparation of tetrahydrospiro[cyclopropane-1,3'-bifused pyrrolidine]-7a'(5'H)-yl)methanol
  • Step 1 Preparation of: (3R,6R,7aS)-3-(tert-butyl)-6-fluorotetrahydro-1H,3H-pyrrole[1,2-c]oxazol-1-one
  • Step 3 Preparation of: (2R,7aS)-2-fluoro-6-methenyltetrahydro-1H-bis-condensed pyrrolidine-7a(5H)-formic acid methyl ester
  • Step 4 (1S,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-biscondensed pyrrolidine]- 7a'(5'H)-Methyl formate and (1R,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2 Preparation of '-bis-condensed pyrrolidine]-7a'(5'H)-formic acid methyl ester
  • Step 5 Intermediates 1-16A and 1-16B ((1S,6'R,7a'S)-2,2,6'-trifluorodihydrogen-1'H,3'H-spiro[cyclopropane-1 ,2'-Bisfused pyrrolidine]-7a'(5'H)-yl)methanol and ((1R,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3 Preparation of 'H-spiro[cyclopropane-1,2'-bis-condensed pyrrolidine]-7a'(5'H)-yl)methanol
  • Step 1 Preparation of 1-(2-ethoxy-2-oxyethyl)-2-oxocyclopropane-1-carboxylic acid methyl ester
  • Step 4 Preparation of 3a-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methylhexahydrocyclopentane[b]pyrrole-2(1H)-one
  • Step 5 3a-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methylhexahydro-1H-spiro[cyclopentane[b]pyrrole-2,1'-cyclopropane ]
  • Step 6 Preparation of: (1-methyltetrahydro-1H-spiro[cyclopentane[b]pyrrole-2,1'-cyclopropane]-3a(3H)-yl)methanol 3a-((tert-butyl MeOH of diphenylsilyloxy)methyl)-1-methylhexahydro-1H-spiro[cyclopentane[b]pyrrole-2,1'-cyclopropane] (190 mg, 453 ⁇ mol, 1.00 eq) (5mL) solution was added KHF 2 (707mg, 9.05mmol, 298 ⁇ L, 20.0eq). The reaction solution was reacted at 70°C for 16 hours and then concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the target product (72.6 mg, 360 ⁇ mol, 79.6% yield).
  • Step 1 Preparation of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol
  • Step 2 Preparation of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol
  • Step 3 Preparation of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl trifluoromethanesulfonate
  • Step 4 ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborocyclopentane-2) Preparation of -yl)naphthalen-1-yl)ethynyl)triisopropylsilane
  • reaction solution was reacted at 130°C for 8 hours and then filtered.
  • the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (3.5 g, 6.49 mmol, 69.3% yield).
  • Step 2 Preparation of 4-amino-6-chloro-5-fluoronicotinic acid ethyl ester
  • Step 1 (1R,5S)-3-(7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl) Preparation of -3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
  • Step 2 (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene base-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]
  • reaction solution was reacted at 100°C for 1 hour, then quenched with H 2 O (50 mL) and extracted with EtOAc (100 mL*3). The combined organic phases were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (14.8 g, 17.6 mmol, 96.10% yield).
  • Example 1 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(methoxy) Methyl)tetrahydro-1H-bifused pyrrolidin-7a(5H)-yl)methoxy)pyridine[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2 -Preparation of alcohol
  • Step 1 (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene -1- base)-2-((3-(methoxymethyl)tetrahydro-1H-bifused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl
  • reaction solution was reacted at 25°C for 16 hours, then quenched with H 2 O (10 mL) and extracted with EtOAc (30 mL*3). The combined organic phases were washed with saturated experimental water (100 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (723 mg, 257 umol, 21.7% yield, 33.0% purity). It was used directly in the next reaction without purification.
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(methoxy methyl)tetrahydro-1H-bifused pyrrolidin-7a(5H)-yl)methoxymethyl)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-(( Preparation of triisopropylsilyl)ethynyl)naphthalene-2-ol
  • Step 3 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(methoxy (Methyl)tetrahydro-1H-diffused pyrrolidin-7a(5H)-yl)methoxy)pyridine[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene- Preparation of 2-alcohols
  • the isomer 1 of Example 1 (11.3 mg, 17.6 umol, 10.8% yield) and the isomer 2 of Example 1 (19.2 mg, 29.9 umol, 18.3% yield) were separated by chiral SFC.
  • Example 1 Isomer 1 and Example 1 Isomer 2 were separated again by SFC to obtain Example 1 Isomer 1A, Example 1 Isomer 1B, Example 1 Isomer 2A and Example 1 Isomer 2B: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3S,7aR)-(3 -(Methoxymethyl)tetrahydro-1H-bifused pyrrolidin-7a(5H)-yl)methoxy)pyridine[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Fluoronaphth-2-ol, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3R ,7aS)-(3-(methoxymethyl)tetrahydro
  • Example 4 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-((cyclopropyl methyloxy)methyl)tetrahydro-1H-bifused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl- Preparation of 6-fluoronaphthalene-2-ol
  • Example 6 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R)-2- Fluoro-5-(methoxymethyl)tetrahydro-1H-bifused pyrrolidin-7a(5H)-yl)methoxy)pyridine[4,3-d]pyrimidin-7-yl)-5-ethyne methyl-6-fluoronaphthalene-2-ol
  • isomer 6A and isomer 6B were obtained: cis-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)- 8-Fluoro-2-(((2R)-2-fluoro-5-(methoxymethyl)tetrahydro-1H-bifused pyrrolidine-7a(5H)-yl)methoxy)pyridine[4, 3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol and trans-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.
  • Example 7 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R)-5-(cyclopropoxy) (methylmethyl)-2-fluorotetrahydro-1H-bis-condensed pyrrolidin-7a(5H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5- Ethynyl-6-fluoronaphthalene-2-ol
  • Example 8A and Example 8B cis 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(( 3-(trifluoromethoxymethyl)tetrahydro-1H-bifused pyrrolidin-7a(5H)-yl)methoxy)pyridine[4,3-d]pyrimidin-7-yl)-5-ethyne yl-6-fluoronaphthalen-2-ol and trans-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2 -((3-(trifluoromethoxymethyl)tetrahydro-1H-bispyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)- 5-ethynyl-6-fluoronaphthalene
  • Example 10 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((6'R) -6'-Fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridine[4, 3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Example 10 obtained isomers 10A and 10B through chiral resolution: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8 -Fluoro-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5 'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol and 4-(4-((1R,5S)- 3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-1'H ,3'H-spiro[cyclopropane-1,
  • Example 11 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((tetrahydrospiro[cyclopropane- 1,3'-Bisfused pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2 -alcohol
  • Examples 12A and 12B were synthesized using intermediates 1-13A and 1-13B as raw materials respectively: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3- base)-8-fluoro-2-(((trans)-6'-fluorotetrahydrospiro[cyclopropane-1,3'-bis-condensed pyrrolidine]-7a'(5'H)-yl)methoxy yl)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol and 4-(4-((1R,5S)-3,8-diazabicyclo [3.2.1]oct-3-yl)-8-fluoro-2-(((cis)-6'-fluorotetrahydrospiro[cyclopropane-1,3'-bifused pyrrolidine]-7a'( 5'H)-yl)me
  • Example 13 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((7',7'-difluorotetrahydro- 3'-H-spiro[cyclopropane-1,2'-bifused pyrrolidine]-8a'(1'H)-yl)methoxy)-8-fluoropyridine[4,3d]pyrimidine-7- methyl)-5-ethynyl-6-fluoronaphthalene-2-ol trifluoroacetate
  • Example 14 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((6',6'-difluorotetrahydro- 3'-H-spiro[cyclopropane-1,2'-bifused pyrrolidine]-8a'(1'H)-yl)methoxy)-8-fluoropyridine[4,3d]pyrimidine-7- methyl)-5-ethynyl-6-fluoronaphthalene-2-ol
  • Examples 16A and 16B 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((cis)-2,2 -Difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol and 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.
  • Example 16A 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((cis)-2,2-di Fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[4, 3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Example 16B 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-(((trans)-2,2-di Fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[4, 3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Example 16B-1 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2, 2-Difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine [4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Example 16B-2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)- 2,2-Difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8- Fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Example 17 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((trans)-2,2- Difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
  • Example 17A 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2 -Difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine [4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
  • LCMS m/z 649 (M+H) + .
  • Example 17B 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2 ,2-Difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8- Fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
  • Example 18 6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((trans)-2,2-di Fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[ 4,3d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine
  • Example 19 6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((trans)-2,2-di Fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[ 4,3d]pyrimidin-7-yl)-4-methyl-5-(pentafluoroethyl)pyridin-2-amine
  • Example 20 4-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bifused pyrrolidine] -7a'(5'H)-yl)methoxy)-8-fluoro-4-(1-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridine[4 ,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthol-2-ol
  • Example 21 (1S,7a'S)-7a'-(((4-(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyne (7-fluoronaphthol-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorodihydro-1'H, 3'H-Spiro[cyclopropane-1,2'-bifused pyrrolidine]
  • Example 22 (1S,7a'S)-7a'-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7 -(6-Fluoro-5-methyl-1H-indazol-4-yl)pyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorodihydro- 1'H,3'H-Spiro[cyclopropane-1,2'-biscondensed pyrrolidine]
  • Example 23 4-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-7-fluorobenzo[d]thiazol-2-amine
  • Example 24 4-(4-((1R,5S)-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluoro Dihydro-1'H,3'H-spiro[cyclopropane-1,2'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[4,3 -d]pyrimidin-7-yl)-2-amino-7-fluorobenzene[b]thiophene-3-carbonitrile
  • Example 25 2-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-4,6-dichloro-3-fluoroaniline
  • Example 26 3-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-2-fluoro-5-methyl-4-(trifluoromethyl)aniline
  • Example 27 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2- difluorodihydrogen -1'H,3'H-spiro[cyclopropane-1,2'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[4,3- d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)aniline
  • Example 28 4-(4-(3,9-diazabicyclo[4.2.1]nonan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1) 'H,3'H-spiro[cyclopropane-1,2'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[4,3-d] Pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Example 29 4-(4-(3-amino-3-methylpiperidin-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3 'H-spiro[cyclopropane-1,2'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[4,3-d]pyrimidine-7- methyl)-5-ethynyl-6-fluoronaphthalene-2-ol
  • Example 31 3-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-methoxy Pyridine[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)aniline
  • Example 32 4-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-2-amino-6-fluorobenzo[b]thiophene-3-carbonitrile
  • Example 33 (1S,7a'S)-7a'-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7 -(5-(trifluoromethyl)-1H-indazol-4-yl)pyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorotetrahydro-1 'H,3'H-spiro[cyclopropane-1,2'-bifused pyrrolidine]
  • Example 34 3-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-5-chloro-2-fluoro-4-(trifluoromethyl)aniline
  • Example 35 3-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-2,5-dichloro-4-(trifluoromethyl)aniline
  • Example 36 3-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-2- Chloro-5-fluoro-4-(trifluoromethyl)aniline
  • Example 37 3-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-2,4-dichloro-5-fluoroaniline
  • Example 38 N-(3-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8- Fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenyl)acetamide
  • Example 39 N-(3-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8- Fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenyl)methanesulfonamide
  • Example 40 3-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl))-5-chloro-4-(trifluoromethyl)phenol
  • Example 41 5-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-3-chloro-2-fluoro-4-(trifluoromethyl)aniline
  • Example 42 5-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-2-fluoro-3-methyl-4-(trifluoromethyl)aniline
  • Example 43 3-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-5-amino-2-(trifluoromethyl)benzonitrile
  • Example 44 3-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-5-fluoro-4-(trifluoromethyl)aniline
  • Example 45 3-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-4- Chloro-5-(trifluoromethyl)aniline
  • Example 46 3-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-5-chloro-4-fluoroaniline
  • Example 47 3-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-4,5-dichloroaniline
  • Example 48 3-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-5- Amino-2-chlorobenzonitrile
  • Example 49 2-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-4-amino-6-chlorobenzonitrile
  • Example 50 2-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-4-amino-6-(trifluoromethyl)benzonitrile
  • Example 51 2-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-6- Amino-3-chlorobenzonitrile
  • Example 52 5-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-6-(trifluoromethyl)pyridin-3-amine
  • Example 53 5-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)pyridin-3-amine
  • Example 54 5-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-4-methyl-6-(trifluoromethyl)pyridin-3-amine
  • Example 55 4-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine
  • Example 56 4-(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'-bifused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridine[ 4,3-d]pyrimidin-7-yl)-2-chloro-3-(trifluoromethyl)aniline
  • Example D01 4-(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'-bicondensed pyrrolidine]-7a'(5'H)-yl-5',5'-d2)methoxy Base-d2)-8-fluoropyridine [4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Example D02 4-(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'-bifused pyrrolidine]-7a'(5'H)-yl-5',5'-d2) Methoxy-d2)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Example D03 3-(4-((1R,5S)-3,8-diaza Bicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2' -Bisfused pyrrolidine]-7a'(5'H)-yl)methoxy-d2)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4-(tri Fluoromethyl)aniline
  • Example E01 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-methyltetrahydro) -1H-spiro[cyclopentane[b]pyrrole-2,1'-cyclopropane]-3a(3H)-yl)methoxy)pyridine[4,3-d]pyrimidin-7-yl)-5- Ethynyl-6-fluoronaphthalene-2-ol
  • Example P01 ((1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2 '-Bisfused pyrrolidine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido Preparation of [4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)methylisobutyrate trifluoroacetate
  • Example 16B-1 (100 mg, 0.155 mmol) was dissolved in THF (5 mL), and 2,6-lutidine (83 mg, 0.775 mmol) and iodomethyl isobutyrate (189 mg, 0.775 mmol) were added in sequence. After the addition was completed, the mixture was stirred at room temperature for 16 h, then acetonitrile was added to dissolve the solution, and the target product (28 mg) was directly separated by preparative HPLC.
  • Example P02 (1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-Pyrrolizine]-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-carboxylic acid isopropyl ester
  • Example P03 ((1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2 '-Pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[ 4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-yl)methylisopropyl carbonate
  • Example P04 and Example P05 1-(isobutyryloxy)ethyl(1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H ,3'H-spiro[cyclopropane-1,2'-pyrrozine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-( ((1-(isobutyryloxy)ethoxy)carbonyl)oxy)naphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- Diazabicyclo[3.2.1]octane-8-carboxylate and 1-(isobutyryloxy)ethyl(1R,5S)-3-(2-(((1S,7a'S)-2, 2-Difluorodihydro-1'H,3'H-spiro[cyclo
  • Step 1 1-(isobutyryloxy)ethyl(1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H) -Spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(((1- (isobutyryloxy)ethoxy)carbonyl)oxy)naphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo [3.2.1] Preparation of octane-8-carboxylate
  • Example 16B-1 Dissolve Example 16B-1 (100 mg, 0.155 mmol) in DCM (4 mL), add DIPEA (100 mg, 0.775 mmol), and add 1-(((4-nitrophenoxy)carbonyl)oxy)isobutyl Ethyl acid ester (184 mg, 0.62 mmol) was added and stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness, acetonitrile was added to dissolve the solution, and the target product (65 mg) was directly separated by preparative HPLC.
  • Step 1 1-(isobutyryloxy)ethyl(1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H) -Spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-
  • Example P04 Dissolve Example P04 (105 mg, 0.109 mmol) in acetonitrile (4 mL), add ammonia water (10 drops), and stir at room temperature for 2 hours after the addition. After the reaction was completed, the reaction solution was concentrated to dryness, acetonitrile was added to dissolve the solution, and the target product (65 mg) was directly separated by preparative HPLC.
  • Example P06 1-(isobutyryloxy)ethyl(1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-( ((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-yl)methyl Oxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • TR-FRET technology was used to detect the binding ability of compounds to KRAS G12D protein. Negative biotin-labeled GDP KRAS G12D- loaded recombinant human protein was incubated with Cy5-labeled tracer, europium-labeled streptavidin, and compounds (2% DMSO final concentration) in buffer (HEPES (pH 7.5), MgCl 2 , Tween-20 and DTT) . After incubation for 60 minutes at 22°C, the reaction activity was detected by the dual-wavelength technology of the EnVision multifunctional microplate reader, and the protein binding capacity (POC) was calculated using the ratiometric emission factor.
  • 100POC means no compound; 0POC means that the control compound completely inhibits the binding of the tracer to KRAS G12D at this concentration.
  • the POC value is fitted using a four-parameter Logistic model curve, and IC 50 represents the 50POC concentration value.
  • Seed KRAS G12D mutant cells (such as GP2D, AGS, etc.) in a 384-well plate and culture overnight in a 37°C, 5% CO2 incubator.
  • IR (%) (1 – (RLU compound – RLU blank control) / (RLU vehicle control – RLU blank control)) * 100%.
  • mice Male ICR mice, weighing 22-24 g, were orally administered with a solution of 30 mg/kg of the compound of the present invention or the control compound [10% DMSO+60% PEG400+30% aqueous solution] after overnight fasting. Blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0 and 24 hours after administration of the compound of the present invention, and the concentration of the compound of the present invention or the control compound in the plasma was measured using LC/MS/MS.
  • mice 100uL of tumor cell suspension containing 5x10 6 AsPC-1 was subcutaneously inoculated into the right rear abdomen of nude mice. Mice health was monitored daily and measurements were started when tumors grew to palpable size.
  • the tumor volume calculation formula adopts: 0.5xLxW 2 , where L and W represent the tumor length and width respectively.
  • mice were randomized into groups. Mice were given corresponding doses of compounds by intraperitoneal injection or oral administration every day, and their general status was monitored at the same time. Tumors were measured three times a week and body weight was measured twice a week.

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Abstract

本发明涉及取代的桥环类抑制剂及其制备方法和应用。具体地，本发明化合物具有式(A0)所示结构，本发明还公开了所述化合物的制备方法及其作为KRASG12D抑制剂的用途，对KRASG12D具有很好的选择性抑制作用且具有更好的药效学、药代动力学性能和更低的毒副作用。

Description

取代桥环类抑制剂及其制备方法和应用 技术领域
本发明属于药物领域，具体涉及一种取代桥环类抑制剂及其制备方法和应用。
背景技术
在所有人类肿瘤中约四分之一是由RAS突变引起，每年有近一百万人因此而失去生命。在RAS家族中，KRAS突变占到了所有RAS突变的85％。在近90％的胰腺癌、30-40％的结肠癌中、以及15-20％的肺癌中(主要为非小细胞肺癌)中发现KRAS突变。在KRAS突变中最主要的突变时G12C和G12D突变，其中G12C突变主要发生在HSCLC中，而G12D突变主要发生在胰腺癌中。到目前为止，市场上仍然没有针对KRASG12D突变的药物被批准上市。
目前临床上胰腺癌常规治疗方案包括吉西他滨单药疗法、吉西他滨联合白蛋白紫杉醇、以及FOLFIRINOX方案(奥沙利铂+伊立替康+5-FU/LV)等。其中脂质体伊立替康适用于与氟尿嘧啶和亚叶酸联用治疗经吉西他滨化疗效果不佳的晚期胰腺癌患者(二线疗法)。但是总的来说，目前胰腺癌有效的治疗手段有限，患者总生存时间不超过1年。虽然针对晚期胰腺癌患者的药物探索在持续不断开展，但到现在为止研究进展仍较为缓慢。
由于KRASG12D靶蛋白在病理学上与多种疾病相关，尤其胰腺癌，因此目前需要新型的KRASG12D抑制剂用于临床治疗。高选择性高活性的KRASG12D抑制剂可以对KRASG12D突变导致的癌症等疾病更有效治疗，以及减少脱靶效应的潜力，因而具有更迫切的临床需求。
发明内容
本发明的目的在于提供一类新型的对KRASG12D有选择性抑制作用和/或更好药效学性能的化合物及其用途。
本发明第一方面，提供一种式(A0)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药：
环C选自下组基团：
Y选自：键、O、NH、N(C1-C3烷基)；
Z为取代或未取代的C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
W选自：取代或未取代的C3-C14环烷基、或者取代或未取代的4-14元饱和或不饱和的杂环基；其中，所述取代是指被一个或多个R取代；
选自下组基团： 其中，X选自：N、CH、CD、CF、C(CN)；
R1选自：-L1-Q-L2-L3；
其中：
L1选自：取代或未取代的C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
Q选自：O、S、SO2、NH、或N(C1-C3烷基)；
L2选自：无、或者取代或未取代的C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
L3选自取代或未取代的下组基团：-C1-C6烷基、-C3-C6环烷基、-C4-C6杂环基、-C1-C6亚烷基(C3-C6环烷基)、-C1-C6亚烷基(C4-C6杂环基)、-C1-C6亚烷基(C1-C6烷氧基)、-C1-C6亚烷基(C3-C6环烷基氧基)、或-C1-C6亚烷基(C4-C6杂环基氧基)；其中，所述取代是指被一个或多个R取代；
n为0、1、2、3、4、5或6的整数；限定条件是当W为单环或双环时，n不为0；
R10选自取代或未取代的下组基团：C6-C14芳基、5-14元杂芳基；其中，所述取代是指被一个或多个Ra取代；
R11各自独立地选自取代或未取代的下组基团：H、氘、卤素、氰基、酯基、胺基、酰胺基、砜基、脲基、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C3-C6环烷基、4-6元杂环基、C1-C6烷基氧基、C3-C6环烷基氧基、4-6元杂环基氧基；其中，所述取代是指被一个或多个R取代；
Ra各自独立地选自取代或未取代的下组基团：H、D、卤素、CN、NH2、OH、CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基)、SONH2、SO2NH2、NHSO2(C1-C6烷基)、NHSO2(C3-C6环烷基)、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C20环烷基、4-20元杂环、C3-C20环烷基氧基、4-20元杂环基氧基；其中，所述取代是指被一个或多个R取代；
m为0、1、2、3、4、5或6的整数；
各R相同或不同，各自独立地选自：氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、(C3-C18环烷基)C1-C18烷基、(4-20元杂环基)C1-C18烷基、(C1-C18烷氧基)C1-C18烷基、(C3-C18环烷基氧基)C1-C18烷基、(4-20元杂环基氧基)C1-C18烷基、乙烯基、乙炔基、(C1-C6烷基)乙烯基、氘代(C1-C6烷基)乙烯基、卤代(C1-C6烷基)乙烯基、(C1-C6烷基)乙炔基、氘 代(C1-C6烷基)乙炔基、卤代(C1-C6烷基)乙炔基、(C3-C14环烷基)乙炔基、(4-14元杂环基)乙炔基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、4-20元杂环基C(O)、C3-C20环烷基、4-20元杂环基、C6-C14芳基、5-14元杂芳基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基、砜基或脲基。
在另一优选例中，所述化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有式(A)所示的结构：
Y选自：键、O、NH、N(C1-C3烷基)；
Z为取代或未取代的C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
W选自：取代或未取代的C3-C14环烷基、或者取代或未取代的4-14元饱和或不饱和的杂环基；其中，所述取代是指被一个或多个R取代；
选自下组基团： 其中，X选自：N、CH、CD、CF、C(CN)；
R1选自：-L1-Q-L2-L3；
其中：
L1选自：取代或未取代的C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
Q选自：O、S、SO2、NH、或N(C1-C3烷基)；
L2选自：无、或者取代或未取代的C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
L3选自取代或未取代的下组基团：-C1-C6烷基、-C3-C6环烷基、-C4-C6杂环基、-C1-C6亚烷基(C3-C6环烷基)、-C1-C6亚烷基(C4-C6杂环基)、-C1-C6亚烷基(C1-C6烷氧基)、-C1-C6亚烷基(C3-C6环烷基氧基)、或-C1-C6亚烷基(C4-C6杂环基氧基)；其中，所述取代是指被一个或多个R取代；
n为0、1、2、3、4、5或6的整数；限定条件是当W为单环或双环时，n不为0；
R10选自取代或未取代的下组基团：C6-C14芳基、5-14元杂芳基；其中，所述取代是指被一个或多个Ra取代；
R11各自独立地选自取代或未取代的下组基团：H、氘、卤素、氰基、酯基、胺基、酰胺基、砜基、脲基、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C3-C6环烷基、4-6元 杂环基、C1-C6烷基氧基、C3-C6环烷基氧基、4-6元杂环基氧基；
Ra各自独立地选自取代或未取代的下组基团：H、D、卤素、CN、NH2、OH、CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基)、SONH2、SO2NH2、NHSO2(C1-C6烷基)、NHSO2(C3-C6环烷基)、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C20环烷基、4-20元杂环基、C3-C20环烷基氧基、4-20元杂环基氧基；其中，所述取代是指被一个或多个R取代；
m为0、1、2、3、4、5或6的整数；
各R相同或不同，各自独立地选自：氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、(C3-C18环烷基)C1-C18烷基、(4-20元杂环基)C1-C18烷基、(C1-C18烷氧基)C1-C18烷基、(C3-C18环烷基氧基)C1-C18烷基、(4-20元杂环基氧基)C1-C18烷基、乙烯基、乙炔基、(C1-C6烷基)乙烯基、氘代(C1-C6烷基)乙烯基、卤代(C1-C6烷基)乙烯基、(C1-C6烷基)乙炔基、氘代(C1-C6烷基)乙炔基、卤代(C1-C6烷基)乙炔基、(C3-C14环烷基)乙炔基、(4-14元杂环基)乙炔基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、4-20元杂环基C(O)、C3-C20环烷基、4-20元杂环基、C6-C14芳基、5-14元杂芳基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基、砜基或脲基。
在另一优选例中，Ra各自独立地选自取代或未取代的下组基团：H、D、卤素、CN、OH、SONH2、NHSO2CH3、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C20环烷基、4-20元杂环基；其中，所述取代是指被一个或多个R取代；R的定义如上所述。
在另一优选例中，所述化合物具有A’所示的结构
优选地，具有A”所示的结构
式中，n、Y、Z、W、L1、L2、L3、Q、R10、R11、m、环A的定义如上所述。
在另一优选例中，选自下组基团：
在另一优选例中，所述化合物具有式A”’所示的结构
R2和R3相同或不同，各自独立地选自取代或未取代的下组基团：H、D、卤素、CN、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基；其中，所述取代是指被一个或多个R取代；
X、Y、Z、W、R1、n和R10的定义如上所述。
在另一优选例中，R3选自取代或未取代的下组基团：H、D、卤素、CN、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、C3-C6环烷基氧基、4-6元杂环基、4-6元杂环基氧基；其中，所述取代是指被一个或多个R取代。
在另一优选例中，R10选自：选自取代或未取代的下组基团：苯基、萘基、5-6元单环杂芳基(如吡啶基)、9-10元双环杂芳基(如吲唑基、苯并噻唑、苯并噻吩、苯并呋喃)，其中所述取代是被被选自下组的一个或多个基团取代：卤素、羟基、氰基、NH2、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C2-C6烯基、C2-C6炔基：优选地，R10选自：
在另一优选例中，R8选自：NH2、OH、SONH2、NHSO2CH3。
在另一优选例中，R10为
在另一优选例中，U选自：N、CH、CD、CF；
R4选自取代或未取代的下组基团：卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基；
R5、R6、R7、R9相同或不同，各自独立地选自取代或未取代的下组基团：H、D、卤素、CN、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基；其中，所述取代是指被一个或多个R取代；
R8选自：NH2、OH、SONH2、NHSO2CH3。
在另一优选例中，R10为优选地，R10为优选地，R10为
在另一优选例中，U’选自：O、或S；
U”选自：N、或C(CN)；
R7’、R8’、R9’相同或不同，各自独立地选自取代或未取代的下组基团：H、D、卤素、CN、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基；其中，所述取代是指被一个或多个R取代；
R5’选自：H、D、卤素、CN、NH2、OH、CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基)、SONH2、SO2NH2、NHSO2(C1-C6烷基)、NHSO2(C3-C6环烷基)、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基。
在另一优选例中，R10为其中，V1、V2、V3、V4和V5各自独立地选自：N、或CRv；Rv相同或不同，各自独立地选自：H、C1-C3烷基、C3-C6环烷基、4-6元杂环基、C1-C3烷氧基、C3-C6环烷基氧基、4-6元杂环基氧基、卤代C1-C3烷基、卤代C3-C6环烷基、卤代4-6元杂环基、(HO)-C1-C3烷基、(HO)-C3-C6环烷基、(NH2)-C1-C3烷基、(NH2)-C3-C6环烷基、卤素、CN、-C≡CH、OH、NH2、CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基)、SO2NH2、NHSO2(C1-C6烷基)、NHSO2(C3-C6环烷基)，其中，所述杂环基任选地被一个或多个氧代基(＝O)取代。
在另一优选例中，R10为其中，Rv1、Rv2、Rv3、Rv4和Rv5各自独立地选自：H、C1-C3烷基、C3-C6环烷基、4-6元杂环基、C1-C3烷氧基、C3-C6环烷基氧基、4-6元杂环基氧基、卤代C1-C3烷基(如CF3、CF2CF3)、卤代C3-C6环烷基、卤代4-6元杂环基、(HO)-C1-C3烷基、(HO)-C3-C6环烷基、(NH2)-C1-C3烷基、(NH2)-C3-C6环烷基、卤素、CN、-C≡CH、OH、NH2、CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基、SO2NH2、NHSO2(C1-C6烷基)、NHSO2(C3-C6环烷基)H、C1-C3烷基、C3-C6环烷基、4-6元杂环基、C1-C3烷氧基、C3-C6环烷基氧基、4-6元杂环基氧基、卤代C1-C3烷基、卤代C3-C6环烷基、卤代4-6元杂环基、(HO)-C1-C3烷基、(HO)-C3-C6环烷基、(NH2)-C1-C3烷基、(NH2)-C3-C6环烷基、卤素、CN、-C≡CH、OH、NH2、CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基)、SO2NH2、NHSO2(C1-C6烷基)、NHSO2(C3-C6环烷基)，所述杂环基任选地被一个或多个氧代基(＝O)取代。
在另一优选例中，Rv5选自：卤代C1-C3烷基(如CF3、CF2CF3)。
在另一优选例中，Rv1选自：H。
在另一优选例中，Rv1选自：NH2。
在另一优选例中，提供一种式(IA)或式(IB)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药：
式中，
U选自：N、CH、CD、CF；
U’选自：O、或S；
U”选自：N、或C(CN)；
X选自：N、CH、CD、CF、C(CN)；
Y选自：键、O、NH、N(C1-C3烷基)；
Z为取代或未取代的C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
W选自：取代或未取代的C3-C14环烷基、或者取代或未取代的4-14元饱和或不饱和的杂环基；其中，所述取代是指被一个或多个R取代；
R1选自：-L1-Q-L2-L3；其中：
L1选自：取代或未取代的C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
Q选自：O、S、SO2、NH、或N(C1-C3烷基)；
L2选自：无、或者取代或未取代的C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
L3选自取代或未取代的下组基团：-C1-C6烷基、-C3-C6环烷基、-C4-C6杂环基、-C1-C6亚烷基(C3-C6环烷基)、-C1-C6亚烷基(C4-C6杂环基)、-C1-C6亚烷基(C1-C6烷氧基)、-C1-C6亚烷基(C3-C6环烷基氧基)、或-C1-C6亚烷基(C4-C6杂环基氧基)；其中，所述取代是指被一个或多个R取代；
n为1、2、3、4、5或6的整数；
R2和R3相同或不同，各自独立地选自取代或未取代的下组基团：H、D、卤素、CN、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基；其中，所述取代是指被一个或多个R取代；
R4选自取代或未取代的下组基团：卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基；其中，所述取代是指被一个或多个R取代；
R8选自：OH、SONH2、NHSO2CH3；
R5、R6、R7、R9、R7’、R8’、R9’相同或不同，各自独立地选自取代或未取代的下组基 团：H、D、卤素、CN、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基；其中，所述取代是指被一个或多个R取代；
R5’选自：H、D、卤素、CN、NH2、OH、CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基)、SONH2、SO2NH2、NHSO2(C1-C6烷基)、NHSO2(C3-C6环烷基)、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基；
各R相同或不同，各自独立地选自：氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、(C3-C18环烷基)C1-C18烷基、(4-20元杂环基)C1-C18烷基、(C1-C18烷氧基)C1-C18烷基、(C3-C18环烷基氧基)C1-C18烷基、(4-20元杂环基氧基)C1-C18烷基、乙烯基、乙炔基、(C1-C6烷基)乙烯基、氘代(C1-C6烷基)乙烯基、卤代(C1-C6烷基)乙烯基、(C1-C6烷基)乙炔基、氘代(C1-C6烷基)乙炔基、卤代(C1-C6烷基)乙炔基、(C3-C14环烷基)乙炔基、(4-14元杂环基)乙炔基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、C3-C20环烷基、4-20元杂环基、C6-C14芳基、5-14元杂芳基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基、砜基或脲基。
在另一优选例中，各R相同或不同，各自独立地选自：氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、(C3-C18环烷基)C1-C18烷基、(4-20元杂环基)C1-C18烷基、(C1-C18烷氧基)C1-C18烷基、(C3-C18环烷基氧基)C1-C18烷基、(4-20元杂环基氧基)C1-C18烷基、乙烯基、乙炔基、(C1-C6烷基)乙烯基、氘代(C1-C6烷基)乙烯基、卤代(C1-C6烷基)乙烯基、(C1-C6烷基)乙炔基、氘代(C1-C6烷基)乙炔基、卤代(C1-C6烷基)乙炔基、(C3-C14环烷基)乙炔基、(4-14元杂环基)乙炔基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、C3-C20环烷基、4-20元杂环基、C6-C14芳基、5-14元杂芳基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、砜基或脲基。
在另一优选例中，各R相同或不同，各自独立地选自：氘、C1-C6烷基、氘代C1-C6烷基、卤代C1-C6烷基、(C3-C10环烷基)C1-C6烷基、(4-10元杂环基)C1-C6烷基、(C1-C6烷氧基)C1-C6烷基、(C3-C6环烷基氧基)C1-C6烷基、(4-20元杂环基氧基)C1-C18烷基、乙烯基、乙炔基、(C1-C6烷基)乙烯基、氘代(C1-C6烷基)乙烯基、卤代(C1-C6烷基)乙烯基、(C1-C6烷基)乙炔基、氘代(C1-C6烷基)乙炔基、卤代(C1-C6烷基)乙炔基、(C3-C10环烷基)乙炔基、(4-10元杂环基)乙炔基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、C3-C10环烷基、4-10元杂环基、C6-C10芳基、5-10元杂芳基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基、砜基或脲基。
在另一优选例中，式I化合物具有式(I’A)或式(I’B)所示的结构
优选地，具有式(I”A)或式(I”B)所示的结构
其中，n、U、U’、U”、X、Y、Z、W、L1、L2、L3、Q、R2、R3、R4、R5、R6、R7、R8、R9、R5’、R7’、R8’、R9’、的定义如上所述。
在另一优选例中，所述化合物具有式(IIA)或式(IIB)所示的结构：
其中，R1、R2、R3、R4、R5、R6、R7、R8、R9、R5’、R7’、R8’、R9’、U、U’、U”、X、Z、W和n的定义如上所述。
在另一优选例中，所述化合物具有式(IIIA)或式(IIIB)所示结构：
其中，R1、R2、R3、R4、R5、R6、R7、R8、R9、R5’、R7’、R8’、R9’、U、U’、U”、Z、W和n的定义如上所述。
在另一优选例中，R3选自：H、D、F、Cl、Br、CN、甲基、乙基、丙基、异丙基、氘代甲基、CH2F、CHF2、CF3、甲氧基、乙氧基、丙氧基、OCH2F、OCHF2、OCF3。
在另一优选例中，所述化合物具有式(IVA)或式(IVB)所示结构：
其中，R1、R4、R5、R6、R7、R8、R9、R5’、R7’、R8’、R9’、U、U’、U”、Z、W和n的定义如上所述。
在另一优选例中，所述化合物具有式(VA)或式(VB)所示结构：
其中，R1、R4、R5、R6、R7、R9、R7’、R8’、R9’、U、U’、U”、Z、W和n的定义如上所述。
在另一优选例中，所述化合物具有式(VIA)或式(VIB)所示结构：
其中，R1、R4、R5、R6、R7、R9、R7’、R8’、R9’、U”、Z、W和n的定义如上所述。
在另一优选例中，所述化合物具有式(VIIA)或式(VIIB)所示结构：
其中，R1、R4、R5、R7’、R8’、R9’、Z、W和n的定义如上所述。
在另一优选例中，所述化合物具有式(VIIIA)或式(VIIIB)所示结构：
其中，R1、R4、R5、R7’、R9’、Z、W和n的定义如上所述。
在另一优选例中，W取代或未取代的下组基团：C3-C6单环环烷基、C7-C10双环或C7-C11三环环烷基、4-6元饱和或不饱和单环杂环基、7-10元双环或7-11元三环杂环基；优选地，W选自：取代或未取代的7-10元饱和或不饱和的桥环杂环基、取代或未取代的7-10元饱和或不饱和的稠环杂环基。
在另一优选例中，W选自：
其中，n’为0、1、2、3、4、5、或6的整数；R的定义如上所述，R可以取代在多环(如桥环或螺环)的任意一个环上。
在另一优选例中，当W选自：
时，n’可以为1或2，更优选的，n’为1，R的定义如上所述，R可以取代在多环(如桥环或螺环)的任意一个环上。
在另一优选例中，当W选自：
时，n’可以为0、1或2，R的定义如上所述，R可以取代在多环(如桥环或螺环)的任意一个环上。
在另一优选例中，当W选自：
时，n’可以为0、1或2，R的定义如上所述，R可以取代在多环(如桥环或螺环)的任意一个环上。
在另一优选例中，R选自：氘、C1-C6烷基、氘代C1-C6烷基、卤代C1-C6烷基、(C3-C6环烷基)C1-C18烷基、(4-6元杂环基)C1-C6烷基、(C1-C6烷氧基)C1-C6烷基、(C3-C6环烷基氧 基)C1-C6烷基、(4-6元杂环基氧基)C1-C6烷基、乙烯基、乙炔基、(C1-C6烷基)乙烯基、氘代(C1-C6烷基)乙烯基、卤代(C1-C6烷基)乙烯基、(C1-C6烷基)乙炔基、氘代(C1-C6烷基)乙炔基、卤代(C1-C6烷基)乙炔基、(C3-C6环烷基)乙炔基、(4-6元杂环基)乙炔基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、4-6元杂环基C(O)、C3-C6环烷基、4-6元杂环基、C6-C10芳基、5-10元杂芳基(优选5-6元)、卤素、硝基、羟基、氧代基、氰基、COOC1-C6烷基、NH2、NHC1-C6烷基、N(C1-C6烷基)2、CONH2、CONHC1-C6烷基、CON(C1-C6烷基)2、SO2C1-C6烷基、-NHCONH2、-NHCO NHC1-C6烷基、-NHCON(C1-C6烷基)2。
在另一优选例中，Z为取代或未取代的C1-C3亚烷基，优选地为亚甲基、亚乙基、亚丙基。
在另一优选例中，Z为CD2。
在另一优选例中，所述化合物具有式(IX)所示结构：
其中，n’为0、1、2、3、4、5、或6的整数；
R5、R、L1、Q、L2、L3和n的定义如上所述。
在另一优选例中，R4选自取代或未取代的下组基团：卤素、甲基、乙基、丙基、乙烯基、丙烯基、烯丙基、丁烯基、乙炔基、丙炔基、丁炔基。
在另一优选例中，选自：
在另一优选例中，所述化合物具有式(X)所示的结构：
V1、V2、V3、V4和V5各自独立地选自：N、或CRv；Rv相同或不同，各自独立地选自：H、C1-C3烷基、C3-C6环烷基、4-6元杂环基、C1-C3烷氧基、C3-C6环烷基氧基、4-6元杂环基氧基、卤代C1-C3烷基、卤代C3-C6环烷基、卤代4-6元杂环基、(HO)-C1-C3烷基、(HO)-C3-C6环烷基、(NH2)-C1-C3烷基、(NH2)-C3-C6环烷基、卤素、CN、-C≡CH、OH、NH2、CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基)、SO2NH2、NHSO2(C1-C6烷基)、NHSO2(C3-C6环烷基)，其中，所述杂环基任选地被一个或多个氧代基(＝O)取代；
R2和R3相同或不同，各自独立地选自取代或未取代的下组基团：H、D、卤素、CN、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基；其中，所述取代是指被一个或多个R取代；
环C、R、X、Z、W和n的定义如上所述。
在另一优选例中，所述化合物具有式(XI)所示的结构：
V1、V2、V3、V4、V5各自独立地选自：N、或CRv；Rv相同或不同，各自独立地选自：H、C1-C3烷基、C3-C6环烷基、4-6元杂环基、C1-C3烷氧基、C3-C6环烷基氧基、4-6元杂环基氧基、卤代C1-C3烷基、卤代C3-C6环烷基、卤代4-6元杂环基、(HO)-C1-C3烷基、(HO)-C3-C6环烷基、(NH2)-C1-C3烷基、(NH2)-C3-C6环烷基、卤素、CN、-C≡CH、OH、NH2、CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基)、SO2NH2、NHSO2(C1-C6烷基)、NHSO2(C3-C6环烷基)，其中，所述杂环基任选地被一个或多个氧代基(＝O)取代；
R2和R3相同或不同，各自独立地选自取代或未取代的下组基团：H、D、卤素、CN、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基；其中，所述取代是指被一个或多个R取代；
其中，R、R1、X、Z、W和n的定义如上所述。
在另一优选例中，所述化合物具有式(XII)所示的结构：
V1、V2、V3、V4、V5各自独立地选自：N、或CRv；Rv相同或不同，各自独立地选自：H、C1-C3烷基、C3-C6环烷基、4-6元杂环基、C1-C3烷氧基、C3-C6环烷基氧基、4-6元杂环基氧基、卤代C1-C3烷基、卤代C3-C6环烷基、卤代4-6元杂环基、(HO)-C1-C3烷基、(HO)-C3-C6环烷基、(NH2)-C1-C3烷基、(NH2)-C3-C6环烷基、卤素、CN、-C≡CH、OH、NH2、CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基)、SO2NH2、NHSO2(C1-C6烷基)、NHSO2(C3-C6环烷基)，其中，所述杂环基任选地被一个或多个氧代基(＝O)取代；
R3选自取代或未取代的下组基团：H、D、卤素、CN、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基；其中，所述取代是指被一个或多个R取代；
其中，R、R1、X、Z、W和n的定义如上所述。
在另一优选例中，所述化合物具有式(XIII)所示的结构：
V1、V2、V3、V4、V5各自独立地选自：N、或CRv；Rv相同或不同，各自独立地选自：H、C1-C3烷基、C3-C6环烷基、4-6元杂环基、C1-C3烷氧基、C3-C6环烷基氧基、4-6元杂环基氧基、卤代C1-C3烷基、卤代C3-C6环烷基、卤代4-6元杂环基、(HO)-C1-C3烷基、(HO)-C3-C6环烷基、(NH2)-C1-C3烷基、(NH2)-C3-C6环烷基、卤素、CN、-C≡CH、OH、NH2、CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基)、SO2NH2、NHSO2(C1-C6烷基)、NHSO2(C3-C6环烷基)，其中，所述杂环基任选地被一个或多个氧代基(＝O)取代；
R3选自取代或未取代的下组基团：H、D、卤素、CN、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基；其中，所述取代是指被一个或多个R取代；
其中，R、R1、Z、W和n的定义如上所述。
在另一优选例中，Rv各自独立地选自：H、卤素、CN、-C≡CH、或NH2。
在另一优选例中，L1选自：取代或未取代的亚甲基或取代或未取代的亚乙基；Q选自：O；L2选自：无、或者取代或未取代的亚甲基；L3选自取代或未取代的下组基团：-C1-C6烷基、-C3-C6环烷基、-C4-C6杂环基、-C1-C6亚烷基(C3-C6环烷基)、-C1-C6亚烷基(C4-C6杂环基)、-C1-C6亚烷基(C1-C6烷氧基)、-C1-C6亚烷基(C3-C6环烷基氧基)、或-C1-C6亚烷基(C4-C6杂环基氧基)；其中，所述取代是指被选自下组的一个或多个基团取代：氘、C1-C6烷基、氘代C1-C6烷基、卤代C1-C6烷基、乙烯基、乙炔基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C6-C14芳基、5-14元杂芳基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、砜基或脲基。
在另一优选例中，-L1-Q-L2-L3选自：
在另一优选例中，为优选地为
在另一优选例中，为优选地为
在另一优选例中，选自：
或者选自：
其中，n’为0、1、2、3、4、5或6的整数；R、R1和n的定义如上所述，R、R1可以取代在多环(如桥环或螺环)的任意一个环上；
或者选自：
其中，n’为0、1、2、3、4、5或6的整数；R的定义如上所述，R可以取代在多环(如桥环或螺环)的任意一个环上。
在另一优选例中，选自：
在另一优选例中，W选自：
在另一优选例中，W选自：
在另一优选例中，W选自：
在另一优选例中，所述化合物的前药具有如下式(XIV)所示的结构：
C’选自：
PG选自：
Y、Z、W、环A、R1、R10、R11、m和n的定义如上所述。
在另一优选例中，m、A环、n、U、X、Y、Z、W、L1、L2、L3、Q、R2、R3、R4、R5、R6、R7、R8、R9、R10和R11具有实施例中各具体化合物所对应基团。
在另一优选例中，V1、V2、V3、V4、V5、环C、PG具有实施例中各具体化合物所对 应基团。
在另一优选例中，所述化合物选自下组：






或者选自：
或者选自：
或者选自：
或者选自：



或者选自：
或者选自：
或者选自：

在另一优选例中，所述化合物优选为实施例中所制备的化合物。
本发明第二方面，提供一种制备式(A0)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药的方法，其中，包括步骤(以式IA为例)：
(i)在惰性溶剂中，碱存在下，有或者没有Pd催化剂，有或者没有缩合剂存在下，式V-1化合物与式V-2化合物反应，得到式V-3化合物；
(ii)在惰性溶剂中，碱存在下，有或者没有Pd催化剂存在下，式V-3化合物与式V-4化合物反应，得到式V-5化合物；
(iii)在惰性溶剂中，碱存在下，在Pd催化剂存在下，式V-5化合物与式V-6化合物反应，得到式V-7化合物；
(iv)式V-7化合物在酸(如TFA、HCl等)作用或者Pd催化氢化条件下脱去保护基PG1，得到式(IA)化合物；
式中，
X1、X2和X3各自独立地选自：OH、卤素、OTf、OTs或OMs；
PG1选自：Boc、Cbz、或Bn；
LG1选自：-B(OH)2、-B(KBF3)、-Sn(nBu)3、
R1、R2、R3、R4、R5、R6、R7、R8、R9、U、X、Y、Z、W和n的定义如上所述。
本发明第三方面，提供一种药物组合物，其包含一种或多种第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药；和药学上可接受的载体。
在另一优选例中，所述药物组合物还包含选自下组的药物：PD-1抑制剂(如nivolumab、pembrolizumab、pidilizumab、cemiplimab、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10,BAT 1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如durvalumab、atezolizumab、avelumab、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如rituximab、obinutuzumab、ofatumumab、veltuzumab、tositumomab、131I-tositumomab、ibritumomab、90Y-ibritumomab、90In-ibritumomab、ibritumomab tiuxetan等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如Ceritinib、Alectinib、Brigatinib、Lorlatinib、奥卡替尼)、PI3K抑制剂(如Idelalisib、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如Ibrutinib、Tirabrutinib、Acalabrutinib、Zanubrutinib、Vecabrutinib等)、EGFR抑制剂(如Afatinib、Gefitinib、Erlotinib、Lapatinib、Dacomitinib、Icotinib、Canertinib、Sapitinib、Naquotinib、Pyrotinib、Rociletinib、Osimertinib等)、VEGFR抑制剂(如Sorafenib、Pazopanib、Regorafenib、Sitravatinib、Ningetinib、Cabozantinib、Sunitinib、多纳非尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、Vorinostat、Fimepinostat、Droxinostat、Entinostat、Dacinostat、Quisinostat、Tacedinaline等)、CDK抑制剂(如Palbociclib、Ribociclib、Abemaciclib、Milciclib、Trilaciclib、Lerociclib等)、MEK抑制剂(如Selumetinib(AZD6244)、Trametinib(GSK1120212)、PD0325901、U0126、Pimasertib(AS-703026)、PD184352(CI-1040)等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)或其组合。
本发明第四方面，提供一种第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或第三方面所述的药物组合物的用途，其用于制备预防和/或治疗与KRASG12D的活性或表达量相关的疾病的药物。
在另一优选例中，所述的疾病为肿瘤或失调性疾病。
在另一优选例中，所述疾病选自下组：肺癌、乳腺癌、前列腺癌、食道癌、结直肠癌、骨癌、肾癌、胃癌、肝癌、大肠癌、黑色素瘤、淋巴瘤、血癌、脑瘤、骨髓瘤、软组织肉瘤、胰腺癌、皮肤癌。
本发明第四方面，提供了一种非诊断性、非治疗性地抑制KRASG12D的方法，其包括步骤：向所需对象施用有效量的如第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或施用如上所述的药物组合物。
在另一优选例中，所述的对象为哺乳动物，较佳地为人。
本发明第五方面，提供一种体外抑制KRASG12D活性的方法，包括步骤：将如第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或如上所述的药物组合物与蛋白或者细胞接触，从而抑制KRASG12D的活性。
在另一优选例中，所述的细胞选自下组：巨噬细胞、肠道细胞(包括肠干细胞、肠上皮细胞)、或其组合。
在另一优选例中，所述的细胞来自啮齿动物(如小鼠、大鼠)、或灵长动物(如人)。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，意外地制备了一类新型的KRASG12D有选择性抑制作用和/或更好药效学性能的化合物。在此基础上，发明人完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
术语“烷基”是指直链或支链烷烃基，包含1-20个碳原子，如1-18个碳原子，尤其指1-18个碳原子，优选地包含1-10个碳原子(C1-C10)，更优选地包含1-6个碳原子(C1-C6)。典型的“烷基”包括甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、戊基、异戊基、庚基、4,4–二甲基戊基、辛基、2,2,4-三甲基戊基、壬基、癸基、十一烷基，十二烷基等等。本发明中，烷基还包括取代烷基。“取代烷基”是指烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl3的烷基)、氰基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、ORa、SRa、S(＝O)Re、S(＝O)2Re、P(＝O)2Re、S(＝O)2ORe,P(＝O)2ORe、NRbRc、NRbS(＝O)2Re、NRbP(＝O)2Re、S(＝O)2NRbRc、P(＝O)2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)ORe,NRdC(＝O)NRbRc、NRdS(＝O)2NRbRc、NRdP(＝O)2NRbRc、NRbC(＝O)Ra、或NRbP(＝O)2Re，其中在此出现的Ra可以独立表示氢、氘、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C3-C6环烯基、C2-C6炔基、5-14元杂环或C6-C14芳环，Rb、Rc和Rd可以独立表示氢、氘、C1-C6烷基、C3-C8环烷基、5-14元杂环或C6-C14芳环，或者说Rb和Rc与N原子一起可以形成杂环；Re可以独立表示氢、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C3-C6环烯基、C2-C6炔基、5-14元杂环或C6-C14芳环。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。
术语“亚烷基”是指“烷基或取代的烷基”再脱掉一个氢原子所形成的基团，如亚甲基、亚乙基、亚丙基、亚异丙基(如)、亚丁基(如)、亚戊基(如)、亚己基(如)、亚庚基(如)、等。此外，所述术 语还包括亚烷基(如C1-C18亚烷基)的一个亚甲基被一个亚环烷基(如C3-C20亚环烷基)所替换，例如“C1-C18亚烷基C3-C20亚环烷基”或“C3-C20亚环烷基C1-C18亚烷基”。
术语“C1-C18亚烷基C3-C20亚环烷基”或“C3-C20亚环烷基C1-C18亚烷基”具有相同含义，是指环烷基烷基或烷基环烷基脱掉两个氢原子所形成的基团，如 等。
本发明中，术语“烯基”表示含一个或多个双键且通常长度为2至20个碳原子的直链或支链的烃基。烯基优选C2-C6烯基，更优选C2-C4烯基。烯基包括但不限于例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基等。本发明中，烯基包括取代的烯基。
术语“炔基”表示含一个或多个三键且通常长度为2至20个碳原子的直链或支链的烃基。炔基优选C2-C6炔基，更优选C2-C4炔基。炔基包括但不限于乙炔基、丙炔基或类似基团。本发明中，炔基还包括取代炔基，取代基可以为卤代、羟基、氰基、硝基等。
本发明中，术语“环烷基”是指完全饱和的环状烃类化合物基团，包括1-4个环，每个环中含有3-8个碳原子。术语“C3-C20”是指包含3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个碳原子环烷基的。环烷基优选地为C3-C14环烷基，更优选地为C3-C10环烷基，更优选地为C3-C6单环环烷基、C7-C10双环或三环环烷基。“取代环烷基”是指环烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。本发明中，“环烷基”包含取代环烷基，典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl3的烷基)、氰基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、ORa、SRa、S(＝O)Re、S(＝O)2Re、P(＝O)2Re、S(＝O)2ORe、P(＝O)2ORe、NRbRc、NRbS(＝O)2Re、NRbP(＝O)2Re、S(＝O)2NRbRc、P(＝O)2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)ORe、NRdC(＝O)NRbRc、NRdS(＝O)2NRbRc、NRdP(＝O)2NRbRc、NRbC(＝O)Ra、或NRbP(＝O)2Re，其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说Rb和Rc与N原子一起可以形成杂环；Re可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括螺环、桥环或稠环取代基，尤其是螺环烷基、螺环烯基、螺环杂环(不包括杂芳环)、桥环烷基、桥环烯基、桥环杂环(不包括杂芳环)、稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。环烷基的实例包括但不限于：环丙基、环丁基、环戊基、环己基、金刚烷基等。
术语“C3-C20亚环烷基”是指环烷基脱掉两个氢原子所形成的基团，如：等。
本发明中，术语“杂环基”是指完全饱和的或部分不饱和的的环状基团(包含但不限于如3-7元单环、4-7元单环、6-11元双环或8-16元三环或多环系统)，其中至少有一个杂原子存在于至少有一个碳原子的环中。术语“4-20元杂环基”是指包含4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个环原子的杂环基。“杂环基”与“饱和或不饱和的杂环基”具有相同含义。“杂环基”优选地为4-14元杂环基(包含但不限于如4-6元单环、7-10元双环或8-14元三环或多环系统)，更优选地为4-12元杂环基，更优选地为4-10元杂环基，如4-6元单环杂环基、7-10元双环或三环杂环基，更优选地为4-8元杂环基，更优选地为4-6元杂环基。每个含有杂原子的杂环可以带有1，2，3或4个杂原子，这些杂原子选自氮原子、氧原子或硫原子，其中氮原子或硫原子可以被氧化，氮原子也可以被季铵化。杂环基团可以连接到环或环系分子的任何杂原子或碳原子的残基上，优选连接到环或环系分子上的N或C原子。典型的单环杂环包括但不限于氮杂环丁烷基、吡咯烷基、氧杂环丁烷基、吡唑啉基、咪唑啉基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、六氢吖庚因基、4-哌啶酮基、四氢吡喃基、吗啡啉基、硫代吗啡啉基、硫代吗啡啉亚砜基、硫代吗啡啉砜基、1,3-二噁烷基和四氢-1,1-二氧噻吩等。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接；杂环基团可以是取代的或者未取代的，当被取代时，取代基优选为一个或多个一下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。
术语“C4-C20亚杂环基”是指杂环基脱掉两个氢原子所形成的基团，如： 等。
本发明中，术语“芳基”是指芳香环状烃基团，具有1-5个环，尤其指单环和双环基团。其中，“C6-C14芳基”是指包含6、7、8、9、10、11、12、13或14个环碳原子的芳香环状烃类化合物基团。芳基包括苯基、联苯基或萘基。凡含有两个或两个以上芳香环(双环等)，芳基基团的芳香环可由单键联接(如联苯)，或稠合(如萘、蒽等等)。“取代芳基”是指芳基中的一个或多个位置被取代，尤其是1-3个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl3的烷基)、氰基、硝基、氧代基(如＝O)、三氟甲基、 三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、ORa、SRa、S(＝O)Re、S(＝O)2Re、P(＝O)2Re、S(＝O)2ORe,P(＝O)2ORe、NRbRc、NRbS(＝O)2Re、NRbP(＝O)2Re、S(＝O)2NRbRc、P(＝O)2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)ORe,NRdC(＝O)NRbRc、NRdS(＝O)2NRbRc、NRdP(＝O)2NRbRc、NRbC(＝O)Ra、或NRbP(＝O)2Re，其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说Rb和Rc与N原子一起可以形成杂环；Re可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括稠环取代基，尤其是稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。
术语“杂芳基”指包含1-4个杂原子芳香环状烃基团，其中杂原子选自氧、氮和硫的。其中，“5-14元杂芳基”指包含1-4个杂原子、5-14个环原子的杂芳族体系。杂芳基优选5至10元环，更优选为5元或6元，例如吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三氮嗪基、三氮唑基及四氮唑基等。“杂芳基”可以是取代的或者未取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。
本发明中，术语“烷氧基”是指具有直链或支链烷氧基，包含烷基-O-、烷基-O-烷基，其中，“C1-C18烷氧基”是指具有1至18个碳原子的直链或支链烷氧基，包含C1-C18烷基-O-、-C1-C6烷基-O-C1-C6烷基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C8烷氧基，更优选C1-C6烷氧基。
本发明中，术语“环烷基氧基”是指环烷基-O-，其中，“C3-C20环烷基氧基”是指C3-C20环烷基-O-，其中，C3-C20环烷基的定义如上所述。
本发明中，术语“杂环基氧基”是指杂环基-O-，其中，“4-20元杂环基氧基”是指4-20元杂环基-O-，其中，4-20元杂环基的定义如上所述。
本发明中，术语“C1-C18亚烷氧基”是指“C1-C18烷氧基”脱掉一个氢原子所得基团。
本发明中，术语“卤素”或“卤”是指氯、溴、氟、碘。
本发明中，术语“卤代”是指被卤素取代。
本发明中，术语“氘代”是指被氘取代。
本发明中，术语“羟基”是指带有结构OH的基团。
本发明中，术语“硝基”是指带有结构NO2的基团。
本发明中，术语“氰基”是指带有结构CN的基团。
本发明中，术语“酯基”是指带有结构-COOR的基团，其中R代表氢、烷基或取代的烷 基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环。酯基优选地为-COO C1-C6烷基。
术语“胺基”是指带有结构-NRR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。胺基优选地为NH2、NH C1-C6烷基、N(C1-C6烷基)2。
术语“酰胺基”是指带有结构-CONRR'或者-NRCOR'的基团，其中R和R'可以各自独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。酰胺基优选地为CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基)。
术语“磺酰胺基”是指带有结构-S2ONRR'或者-NRSO2R'的基团，其中R和R'可以各自独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。磺酰胺基优选地为SO2NH2、NHSO2(C1-C6烷基)、NHSO2(C3-C6环烷基)。
术语“砜基”是指带有结构-SO2R的基团，其中R可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。
术语“脲基”是指带有结构-NRCONR'R"的基团，其中R、R'和R"可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R、R'和R"在二烷基胺片段中可以相同或不同。
术语"烷基胺基烷基"是指带有结构-RNHR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'可以相同或不同。
术语"二烷基胺基烷基"是指带有结构-RNHR'R"的基团，其中R、R'和R"可以独立的代表烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R、R'和R"在二烷基胺片段中可以相同或不同。
术语"杂环基烷基"是指带有结构-RR'的基团，其中R可以独立的代表烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基；R'代表杂环或取代的杂环。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限 于)：卤素、羟基、氰基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、胺基、C1-C6烷氧基、C1-C10磺酰基、及C1-C6脲基等。
除非另外说明，假定任何不满价态的杂原子有足够的氢原子补充其价态。
当取代基为非末端取代基时，其为相应基团的亚基，例如烷基对应于亚烷基、环烷基对应亚环烷基、杂环基对亚杂环基、烷氧基对应亚烷氧基等。
本发明中，多个是指2、3、4、5。
活性成分
如本文所用，“本发明化合物”指式I所示的化合物，并且还包括及式I化合物的立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物。
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明，本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”，指用无机或有机酸和碱形成酸式或碱式的盐。此外，当本发明中的化合物含一个碱性片段时，它包括但不限于吡啶或咪唑，含一个酸性片段时，包括但不限于羧酸，可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒，生理可接受的)盐是首选，虽然其他盐类也有用，例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐，例如，化合物I与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。
本发明中的化合物含有的碱性片段，包括但不限于胺或吡啶或咪唑环，可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸，如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如，2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如，2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等。
本发明的某些化合物可能含有的酸性片段，包括但不限于羧酸，可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐，碱土金属盐如钙、镁盐，和有机碱形成的盐(如有机胺)，如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺，以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐，如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物)，二烷基硫酸盐(如，硫酸二甲酯、二乙酯，二丁酯和二戊酯)，长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物)，芳烷基卤化物(如苄基和苯基溴化物)等等。
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物，在治疗相关疾病时，经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂合物。本发明的化合物包括溶剂合物，如水合物。
本发明中的化合物、盐或溶剂合物，可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。
所有化合物的立体异构体(例如，那些由于对各种取代可能存在的不对称碳原子)，包括其对映体形式和非对映形式，都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如，作为一个纯的或者实质上是纯的光学异构体具有特殊的活性)，或者也可能是混合物，如消旋体，或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型，由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决，例如分步结晶，或通过衍生为非对映异构体分离结晶，或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到，包括但不限于传统的方法，例如与光学活性酸成盐后再结晶。
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。
本发明的化合物所有的构型异构体都在涵盖的范围之内，无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体，以及碳环和杂环的顺式和反式异构体。
在整个说明书中，基团和取代基可以被选择以提供稳定的片段和化合物。
特定官能团和化学术语定义都详细介绍如下。对本发明来说，化学元素与Periodic Table of the Elements,CAS version,Handbook of Chemistry and Physics,75th Ed.中定义的一致。特定官能团的定义也在其中描述。此外，有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,也有说明，其全部内容纳入参考文献之列。
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物，包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基，如烷基。所有异构体以及它们的混合物，都包涵在本发明中。
按照本发明，同分异构体的混合物含有异构体的比率可以是多样的。例如，在只有两个异构体的混合物可以有以下组合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1，或100:0，异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率，及为更复杂的异构体的混合物的比率也在本发明范围之内。
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如3H和14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即3H和碳-14，即14C，它们的制备和检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用批露在示例中的方案可以制备。
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。
如本文所述，本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常，术语“取代”不论在术语“可选”前面或后面出现，在本发明配方中包括取代基的通式，是指用指定结构取代基，代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。在本发明中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的，例如传染病或增生性疾病。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。
本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。在本发明中，术语“前药”指药物经过化学结构修饰引入易离去基团后得到的在体外无活性或活性较小，但是在体内经过酶(如水解酶、氧化酶等)参与或非酶参与(如pH、光照、辐射等)的转化释放出活性药物而发挥药效的化合物。所述前药例如(但并不限于)：羧酸酯、磷酸酯、氨基甲酸酯、碳酸酯等。易离去基团结构如(但并不限于)：
制备方法
下面更具体地描述本发明式(A0)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
典型地，本发明化合物的制备工艺流程如下，其中所用原料和试剂如无特殊说明，均可通过商业途径购买。
优选地，本发明化合物采用如下方法制备(以式IA为例)
(i)在惰性溶剂中，碱存在下，有或者没有Pd催化剂，有或者没有缩合剂存在下，式V-1化合物与式V-2化合物反应，得到式V-3化合物；
(ii)在惰性溶剂中，碱存在下，有或者没有Pd催化剂存在下，式V-3化合物与式V-4化合物反应，得到式V-5化合物；
(iii)在惰性溶剂中，碱存在下，在Pd催化剂存在下，式V-5化合物与式V-6化合物反应，得到式V-7化合物；
(iv)式V-7化合物在酸(如TFA、HCl等)作用或者Pd催化氢化条件下脱去保护基PG1，得到式(IA)化合物；
式中，
X1、X2和X3各自独立地选自：OH、卤素、OTf、OTs或OMs；
PG1选自：Boc、Cbz、或Bn；
LG1选自：-B(OH)2、-B(KBF3)、-Sn(nBu)3、
R1、R2、R3、R4、R5、R6、R7、R8、R9、U、X、Y、Z、W和n的定义如上所述。
药物组合物和施用方法
本发明所述的药物组合物用于预防和/或治疗以下疾病：炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。
通式(A0)所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时，原来药物的给药方式和剂量可以保持不变，而同时或随后服用式I的化合物。当式(A0)化合物与其它一种或几种药物同时服用时，可以优选使用同时含有一种或几种已知药物和式I化合物的药用组合物。药物联用也包括在重叠的时间段服用式(A0)化合物与其它一种或几种已知药物。当式(A0)化合物与其它一种或几种药物进行药物联用时，式I化合物或已知药物的剂量可能比它们单独用药的剂量低。
可以与通式(A0)所述化合物进行药物联用的药物或活性成分包括但不局限为：PD-1抑制剂(如nivolumab、pembrolizumab、pidilizumab、cemiplimab、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10,BAT 1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如durvalumab、atezolizumab、avelumab、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如rituximab、obinutuzumab、ofatumumab、veltuzumab、tositumomab、131I-tositumomab、ibritumomab、90Y-ibritumomab、90In-ibritumomab、ibritumomab tiuxetan等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如Ceritinib、Alectinib、Brigatinib、Lorlatinib、奥卡替尼)、PI3K抑制剂(如Idelalisib、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如Ibrutinib、Tirabrutinib、Acalabrutinib、Zanubrutinib、Vecabrutinib等)、EGFR抑制剂(如Afatinib、Gefitinib、Erlotinib、Lapatinib、Dacomitinib、Icotinib、Canertinib、Sapitinib、Naquotinib、Pyrotinib、Rociletinib、Osimertinib等)、VEGFR抑制剂(如Sorafenib、Pazopanib、Regorafenib、Sitravatinib、Ningetinib、Cabozantinib、Sunitinib、多纳非尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、Vorinostat、Fimepinostat、Droxinostat、Entinostat、Dacinostat、Quisinostat、Tacedinaline等)、CDK抑制剂(如Palbociclib、Ribociclib、Abemaciclib、Milciclib、Trilaciclib、Lerociclib等)、MEK抑制剂(如Selumetinib(AZD6244)、Trametinib(GSK1120212)、PD0325901、U0126、Pimasertib(AS-703026)、PD184352(CI-1040)等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)或其组合。本发明所述药物组合物的剂型包括(但并不限于)： 注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用擦剂、控释型或缓释型或纳米制剂。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁 二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明还提供了一种药物组合物的制备方法，包括步骤：将药学上可接受的载体与本发明所述通式(A0)化合物或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合，从而形成药物组合物。
本发明还提供了一种治疗方法，它包括步骤：给需要治疗的对象施用本发明中所述通式(A0)化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物，或施用本发明所述的药物组合物，用于选择性地抑制KRASG12D。
与现有技术相比，本发明具有以下主要优点：
(1)所述化合物对KRASG12D具有很好的选择性抑制作用；
(2)所述化合物具有更好的药效学、药代动力学性能和更低的毒副作用。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所 述的较佳实施方法与材料仅作示范之用。
本发明的化合物结构是通过核磁共振(NMR)和液质联用色谱(LC-MS)来确定的。
NMR是使用Bruker AVANCE-400核磁仪检测的，测定溶剂包含氘代二甲亚砜(DMSO-d6)、氘代丙酮(CD3COCD3)、氘代氯仿(CDCl3)及氘代甲醇(CD3OD)等，内标采用四甲基硅烷(TMS)，化学位移以百万分之一(ppm)的单位计量。
液质联用色谱(LC-MS)是使用Waters SQD2质谱仪检测的。HPLC的测定使用Agilent 1100高压色谱仪(Microsorb 5 micron C18 100 x 3.0mm色谱柱)。
薄层层析硅胶板使用青岛GF254硅胶板，TLC采用的是0.15-0.20mm，制备薄层色谱采用的是0.4mm-0.5mm。柱层析一般使用青岛硅胶200-300目硅胶作为载体。
本发明实施例中的起始原料都是已知并有市售的，或者可以采用或按照本领域已报道的文献资料合成的。
除特殊说明外，本发明所有反应均在干燥的惰性气体(如氮气或氩气)保护下通过连续磁力搅拌进行，反应温度均为摄氏度。
实施例
中间体1-1(3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇的制备
第一步：1-苄基2-甲基2-(丁-3-烯-1-基)吡咯啉-1,2-二甲酸酯的制备
氮气保护下，在-70℃ 1-苄基2-甲基(S)-吡咯啉-1,2-二甲酸酯(50.0g,190mmol,1.00eq)的THF(100mL)溶液滴加到LiHMDS(1.00M,285mL,1.50eq)中。得到的反应液在-70℃反应2h，随后滴加4-溴丁-1-烯(51.2g,380mmol,38.6mL,2.00eq)。得到的反应液升温至25℃并反应16h随后用饱和NH4Cl(200mL)水溶液淬灭，然后用EtOAc(100mL*3)萃取。合并的有机相用饱和食盐水(200mL)洗涤后用无水硫酸钠干燥后过滤。滤液减压浓缩得到目标产物(38.0g,120mmol,63.1％产率)。
1H NMR(400MHz,CDCl3)δ7.33(m,5H)5.77(m,1H)5.07(m,4H)3.72(m,3H)3.48(m,2H)2.01(m,8H)
第二步：1-苄基2-甲基2-(2-(环氧丙烷-2-基)乙基)吡咯啉-1,2-二甲酸酯的制备
在0℃下，1-苄基2-甲基2-(丁-3-烯-1-基)吡咯啉-1,2-二甲酸酯(37.5g,118mmol,1.00eq)的DCM(650mL)溶液中分批加入m-CPBA(60.0g,295mmol,85.0％purity,2.50eq)。得到的反应液在25℃反应16h，然后用饱和Na2SO3(300mL*3)洗涤。有机相用无水硫酸钠干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物 (29.0g,87.0mmol,73.6％产率)。
1H NMR(400MHz,CDCl3)δ7.33(br d,J＝7.88Hz,5H)5.11(m,2H)3.70(m,3H)3.48(m,2H)2.73(m,2H)2.36(m,2H)1.98(m,5H)1.50(m,2H)
第三步：3-(羟甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯的制备
1-苄基2-甲基2-(2-(环氧丙烷-2-基)乙基)吡咯啉-1,2-二甲酸酯(28.0g,84.0mmol,1.00eq)的MeOH(600mL)溶液中加入Pd/C(6.00g,10.0％wt)。在氢气氛围下，反应物在25℃反应16h然后过滤。滤液减压浓缩得到目标产物(16.8g)。无需纯化直接用于下一步反应。
3-(羟甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯经手性拆分得到顺式-3-(羟甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯和反式3-(羟甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯。
第四步：3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯的制备
氮气保护下，在0℃下3-(羟甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯(1.00g,5.02mmol,1.00eq)的THF(20mL)溶液中加入NaH(602mg,15.1mmol,60.0％wt,3.00eq)。反应液在25℃反应0.5h，随后加入MeI(1.42g,10.0mmol,625uL,2.00eq)。得到的反应液在25℃反应3h，然后在0℃下用H2O(10mL)淬灭后用EtOAc(30mL*2)萃取。合并的有机相用无水硫酸镁干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(1.0g,1.88mmol,37.5％产率)。
1H NMR(400MHz,CDCl3)δ3.66-3.72(m,3H)3.30-3.33(m,3H)2.22-2.43(m,1H)1.83-2.12(m,6H)1.56-1.72(m,1H)。
以顺式-3-(羟甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯和反式3-(羟甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯为起始原料分别得到顺式-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯和反式3-3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯。
第五步：(3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇的制备
氮气保护下，在0℃下3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯(1.00g,4.69mmol,1.00eq)的THF(10mL)溶液中加入LiAlH4(356mg,9.38mmol,2.00eq)。反应液在25℃反应1h，随后在0℃下依次加入H2O(10mL)、15％NaOH(10mL)和H2O(30mL)淬灭，再用EtOAc(50mL*2)萃取。合并的有机相用无水硫酸镁干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(1.1g)。
LC-MS：m/z 186(M+H)+。1H NMR(400MHz,CDCl3)δ4.39(dd,J＝10.54,9.03Hz,1H)4.26(br d,J＝6.53Hz,1H)3.97-4.06(m,1H)3.80-3.96(m,2H)3.68-3.76(m,2H)3.50(s,3H)2.04-2.40(m,6H)1.78-1.93(m,2H)
按中间体1-1同样的合成方法以不同起始原料合成以下化合物：
中间体1-1A和中间体1-1B顺式-(3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇和反式-(3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇
中间体1-1A
LC-MS：m/z 186(M+H)+。
中间体1-1B
LC-MS：m/z 186(M+H)+。
中间体1-2(3-((乙氧基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇
LC-MS：m/z 200(M+H)+。
中间体1-3(3-((异丙氧基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇
LC-MS：m/z 214(M+H)+。
中间体1-4(3-((环丙基甲氧基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇
LC-MS：m/z 226(M+H)+。
中间体1-5(3-(环丙氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇
LC-MS：m/z 212(M+H)+。
中间体1-6((2R)-2-氟-5-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇
LC-MS：m/z 204(M+H)+。
中间体1-7((2R)-2-氟-5-(环丙氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇
LC-MS：m/z 230(M+H)+。
中间体1-8(二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇的制备
第一步：(1-((苄氧)甲基)环丙基)甲醇的制备
0℃下，环丙烷-1,1-二甲醇(25.0g,245mmol,1.00eq)的THF(500mL)溶液中加入NaH(9.79g,245mmol,60.0％wt,1.00eq)。混合物在25℃搅拌30min，随后加入BnBr(41.9g,245mmol,29.1mL,1.00eq)。得到的反应液在25℃反应18h，然后用饱和NH4Cl水溶液(50mL)淬灭，再用EtOAc(50mL*3)萃取。合并的有机相用饱和食盐水(20mL*3)洗涤后用无水硫酸镁干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(26.00g,108mmol,44.1％产率)。
1H NMR(400MHz,CDCl3)δ7.35(s,5H),4.56(s,2H),3.58(s,2H),3.47(s,2H),0.64-0.44(m,4H)
第二步：(((1-(溴甲基)环丙基)甲氧基)甲基)苯的制备
0℃下，(1-((苄氧)甲基)环丙基)甲醇(26.0g,135mmol,1.00eq)的DCM(300mL)溶液中加入PPh3(39.0g,149mmol,1.10eq)和NBS(26.5g,148mmol,1.10eq)。反应液在25℃反应16h，然后减压浓缩。残余物用硅胶柱层析分离得到目标产物(24.0g,84.7mmol,62.6％产率)。
1H NMR(400MHz,CDCl3)δ7.27(s,5H),4.47(s,2H),3.49(s,2H),3.38(s,2H),0.54-0.27(m,4H)
第三步：1-(叔丁基)2-甲基2-((1-((苄氧基)甲基)环丙基)甲基)吡咯啶-1,2-二甲酸酯的制备
-70℃下，1-(叔丁基)2-甲基吡咯啶-1,2-二甲酸酯(15.0g,65.4mmol,1.00eq)的THF(150mL)中滴加LiHMDS(1.00M,78.5mL,1.20eq)。得到的反应液在当前温度下反应2h，随后加入(((1-(溴甲基)环丙基)甲氧基)甲基)苯(21.7g,85.1mmol,1.30eq)和HMPA(44.5g,249mmol,43.7mL,3.80eq)。得到的反应液在25℃反应16h，然后用水(100mL)淬灭后用EtOAc(100mL*2)萃取。合并的有机相用饱和食盐水(50mL*2)洗涤后用无水硫酸钠干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(12.0g,26.8mmol,40.9％产率)。
1H NMR(400MHz,CD3OD)δ7.46-7.21(m,5H),4.68-4.35(m,2H),3.79-3.56 (m,4H),3.45-3.26(m,3H),2.59-2.38(m,2H),2.09-1.82(m,4H),1.47-1.37(m,9H),0.54-0.42(m,4H)。
第四步：1-(叔丁基)2-甲基2-((1-(羟甲基)环丙基)甲基)吡咯啶-1,2-二甲酸酯的制备
氮气保护下，1-(叔丁基)2-甲基2-((1-((苄氧基)甲基)环丙基)甲基)吡咯啶-1,2-二甲酸酯(11.0g,27.3mmol,1.00eq)的MeOH(100mL)溶液中加入Pd/C(10％wt,1.50g)。得到的反应液在氢气氛围(15psi)下在25℃反应16h。反应液过滤，滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(10.0g,25.5mmol,93.6％产率)。
1H NMR(400MHz,CD3OD)δ3.73-3.60(m,4H),3.37(s,5H),2.08-1.90(m,4H),1.48-1.42(m,9H),0.59-0.36(m,4H)。
第五步：1-(叔丁基)2-甲基2-((1-(溴甲基)环丙基)甲基)吡咯啶-1,2-二甲酸酯的制备
1-(叔丁基)2-甲基2-((1-(羟甲基)环丙基)甲基)吡咯啶-1,2-二甲酸酯(5.00g,16.0mmol,1.00eq)的DCM(50mL)溶液中加入CBr4(7.94g,23.9mmol,1.50eq)和PPh3(6.11g,23.3mmol,1.46eq)。得到的混合物在25℃反应16h，然后减压浓缩。残余物用硅胶柱层析分离得到目标产物(0.50g,1.20mmol,7.50％产率)。
1H NMR(400MHz,CDCl3)δ3.80-3.70(m,5H),3.52-3.42(m,1H),3.19-3.02(m,1H),2.82(dd,J＝7.0,15.6Hz,1H),2.45-2.20(m,1H),2.13-1.89(m,4H),1.49-1.44(m,9H),1.00-0.51(m,4H)。
第六步：2-((1-(溴甲基)环丙基)甲基)吡咯啶-2-甲酸甲酯的制备
1-(叔丁基)2-甲基2-((1-(溴甲基)环丙基)甲基)吡咯啶-1,2-二甲酸酯(1.40g,3.72mmol,1.00eq)的DCM(14mL)溶液中加入TFA(64.7g,567.3mmol,42.0mL,152eq)。反应在0℃反应2h然后减压浓缩得到目标产物(0.60g,1.74mmol,46.7％产率)。无需纯化直接用于下一步反应。
第七步：二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯啶]-7a'(5'H)-甲酸甲酯的制备
2-((1-(溴甲基)环丙基)甲基)吡咯啶-2-甲酸甲酯(0.60g,2.17mmol,1.00eq)的DMF(10mL)溶液中加入K2CO3(1.20g,8.69mmol,4.00eq)。得到的反应液在25℃反应16h然后减压浓缩，残余物用硅胶柱层析分离得到目标产物(0.60g,1.84mmol,84.9％产率)。
1H NMR(400MHz,CDCl3)δ3.75(s,3H),3.31-3.18(m,1H),3.01(d,J＝10.0Hz,1H),2.81(s,1H),2.71(d,J＝10.0Hz,1H),2.28-2.22(m,2H),1.94-1.84(m,4H),0.64-0.45(m,4H)。
第八步：(二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇的制备
氮气保护下，二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯啶]-7a'(5'H)-甲酸甲酯(0.60g,3.07mmol,1.00eq)的THF(1mL)溶液中加入LAH(174.9mg,4.61mmol,1.50eq)。得到的反应液在0℃反应4h，然后加入水(0.3mL)淬灭，然后加入MgSO4(2g)。得 到的反应液在室温搅拌30min然后过滤。滤液减压浓缩，得到目标产物(0.200g,1.08mmol,35.0％产率)。
LC-MS：m/z 168(M+H)+。1H NMR(400MHz,CDCl3)δ3.50-3.43(m,1H),3.39-3.31(m,1H),3.10-3.03(m,1H),2.90(d,J＝10.3Hz,1H),2.80(td,J＝6.3,10.5Hz,1H),2.69(d,J＝10.5Hz,1H),1.98-1.82(m,6H),0.62-0.46(m,4H)。
按中间体1-8同样合成方法以不同起始原料合成以下化合物：
中间体1-9((6'R)-6'-氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇
LC-MS：m/z 186(M+H)+。1H NMR(400MHz,CDCl3)δ7.00(s,1H),5.44-4.99(m,1H),3.60-3.25(m,3H),3.23-2.95(m,3H),2.88-2.51(m,1H),2.36-2.03(m,4H),1.96-1.57(m,1H),1.43-1.25(m,1H),0.67-0.38(m,4H)
中间体1-10((6'S)-6'-氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇
LC-MS：m/z 186(M+H)+。1H NMR(400MHz,CDCl3)δ5.15-5.43(m,1H)3.41-3.54(m,3H)3.00-3.14(m,3H)2.56(d,J＝11.22Hz,1H)2.22-2.36(m,1H)2.00-2.17(m,1H)1.94(d,J＝12.98Hz,1H)1.64(d,J＝12.76Hz,1H)0.44-0.69(m,4H).
中间体1-11A((反式)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇和1-11B及((顺式)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇制备路线一
第一步：2,2-二氟-5'-氧二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-甲酸乙酯(中间体1-11-I)的制备
2-亚甲基-5-氧四氢-1H-双稠吡咯啶-7a(5H)-甲酸乙酯(4.8g,22.9mmol,1.00eq)的甲苯(75mL)溶液中加入TBAB(222mg,688umol,0.03eq)和[溴(二氟)甲基]-三甲基-硅(14.0g,68.8mmol,3.00eq)。反应液在110℃反应16h，然后减压浓缩。残余物用硅胶柱层析分离得到目标产物(5.2g,87.6％收率)。
LC-MS：m/z 260(M+H)+。
第二步：((反式)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇及((顺式)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇 (中间体1-11A和1-11B)的制备
0℃下，2,2-二氟-5'-氧二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-甲酸乙酯(2.40g,9.26mmol,1.00eq)的THF(40mL)溶液中加入LAH(2.1g,57.6mmol,6.00eq)。反应液在60℃反应2h然后0℃下用Na2SO4.10H2O(20g)淬灭反应后过滤。滤饼用THF(40mL)洗涤。滤液减压浓缩得到中间体1-11((2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇)。
LC-MS：m/z 204(M+H)+。
中间体1-11用硅胶柱层析(DCM:MeOH:NH3.H2O＝20:1:0.05)分离得到((反式)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇及((顺式)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇。
异构体1-11A((反式)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇(0.50g)：
LC-MS：m/z 204(M+H)+。1H NMR(400MHz,CDCl3)δ3.44-3.35(m,2H),3.19-3.13(m,2H),2.83(d,J＝12.1Hz,1H),2.73-2.59(m,1H),2.73-2.59(m,1H),2.05(dd,J＝6.3,13.3Hz,1H),1.93-1.84(m,3H),1.83-1.74(m,1H),1.74-1.63(m,1H),1.36(ddd,J＝4.0,8.1,12.1Hz,1H),1.28(ddd,J＝4.2,8.1,12.4Hz,1H)。
异构体1-11B((顺式)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇(0.64g)：
LC-MS：m/z 204(M+H)+。1H NMR(400MHz,CDCl3)δ3.32(d,J＝2.0Hz,2H),3.24(d,J＝11.0Hz,1H),3.12-3.02(m,1H),2.83-2.71(m,2H),2.05(d,J＝13.2Hz,1H),1.98-1.89(m,2H),1.89-1.81(m,1H),1.81-1.70(m,2H),1.36-1.28(m,2H)。
中间体1-11A((反式)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇及和1-11B((顺式)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇制备路线二
第一步：(反式)-2,2-二氟-5'-氧二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-甲酸乙酯和(顺式)-2,2-二氟-5'-氧二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-甲酸乙酯(中间体1-11-IA和中间体1-11-IB)的制备
中间体1-11-I(6g)通过硅胶柱层析分离(40gSilica Flash  Column,洗脱剂：0～50％THF/石油醚40mL/min)依次得到中间体I-11-IA(2.80g,10.8mmol,47％产率)和中间体I-11-IB(2.40g,9.26mmol,40％产率)。
第二步：((反式)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇及((顺式)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇(中间体1-11-A和中间体1-11-B)的制备
按照制备路线一同样方法以中间体I-11-IA合成中间体1-11A。
按照制备路线一同样方法以中间体I-11-IB合成中间体1-11B。
异构体1-11A通过手性拆分得到异构体1-11A-1(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇)和异构体1-11A-2(((1R,7a'R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇)。
第一步：中间体1-11A-I1和中间体1-11A-I2的制备
中间体1-11A(9.00g,44.3mmol,1.00eq)的DMF(100mL)溶液中加入咪唑(6.03g,88.6mmol,2.00eq)和TBDPSCl(14.6g,53.1mmol,13.6mL,1.20eq)。反应液在25℃反应16h然后减压浓缩。残余物硅胶柱层析得到目标产物中间体1-11A-I(20.0g,41.7mmol,94.1％产率)。
LC-MS：m/z 442(M+H)+。1H NMR(400MHz,CDCl3)δ7.77-7.62(m,4H),7.53-7.34(m,6H),3.51(s,2H),3.14-3.02(m,2H),2.79(d,J＝12.0Hz,1H),2.65-2.54(m,1H),2.13-1.99(m,2H),1.90(d,J＝13.3Hz,1H),1.86-1.77(m,1H),1.72-1.61(m,2H),1.23-1.16(m,2H),1.10(s,9H)。
中间体1-11A-I通过SFC手性分离(column:DAICEL CHIRALPAK IC(250mm*50mm,10um)；mobile phase:[CO2-EtOH(0.1％NH3H2O)]；15％B isocratic elution mode)得到两个异构体：
中间体1-11A-I1(4.50g,10.2mmol,45.0％产率)：RT 1.931min.LC-MS：m/z 442(M+H)+。
中间体1-11A-I2(4.20g,9.51mmol,42.0％产率)：RT 2.412min.LC-MS：m/z 442(M+H)+。
第二步：中间体1-11A-1和中间体1-11A-2的制备
中间体1-11A-I1(4.50g,10.2mmol,1.00eq)的MeOH(50mL)溶液中加入KHF2(15.9g,203mmol,6.72mL,20.0eq)。反应液在25℃反应16h然后减压浓缩。残余物 用硅胶柱层析(20gSilica Flash Column,洗脱剂：0～25％MeOH/DCM@40mL/min)分离得到目标产物1-11A-1(1.71g,7.98mmol,78.3％产率)。LC-MS：m/z 204(M+H)+。1H NMR(400MHz,CDCl3)δ3.40-3.16(m,2H),3.03(dd,J＝7.4,12.1Hz,2H),2.73(d,J＝12.1Hz,1H),2.66-2.43(m,1H),2.00-1.86(m,1H),1.84-1.73(m,3H),1.72-1.54(m,2H),1.33-1.10(m,2H)。
按照同样方法合成中间体1-11A-2(1.79g,8.38mmol,88.1％产率)：
LC-MS：m/z 204(M+H)+。1H NMR(400MHz,CDCl3)δ3.35-3.20(m,2H),3.10-2.96(m,2H),2.73(d,J＝12.1Hz,1H),2.63-2.49(m,1H),1.97-1.87(m,1H),1.84-1.74(m,3H),1.72-1.53(m,2H),1.31-1.11(m,2H)。
按照同样的中间体1-11A-1和中间体1-11A-2的同样方法合成了中间体D-1-11A-1(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基-5',5'-d2)甲烷-d2-醇)和中间体D-1-11A-2(((1R,7a'R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基-5',5'-d2)甲烷-d2-醇)。
中间体D-1-11A-1。LC-MS：m/z 208(M+H)+。1H NMR(400MHz,CDCl3)δ2.81-3.08(m,2H)2.73(d,J＝12.13Hz,1H)1.92(dd,J＝13.26,6.13Hz,1H)1.73-1.83(m,3H)1.52-1.71(m,2H)1.08-1.33(m,2H)。
中间体D-1-11A-2。LC-MS：m/z 208(M+H)+。1H NMR(400MHz,CDCl3)δ3.03(dd,J＝12.13,7.25Hz,2H)2.73(d,J＝12.13Hz,1H)1.92(dd,J＝13.26,6.25Hz,1H)1.74-1.83(m,3H)1.53-1.70(m,2H)1.13-1.32(m,2H)。
中间体1-12(四氢螺[环丙烷-1,3'-双稠吡咯啶]-7a'(5'H)-基)甲醇的制备
第一步：(S)-5-(((叔丁基甲基硅基)氧)甲基)吡咯啉-2-酮的制备
(S)-5-(羟甲基)吡咯啉-2-酮(50.0g,434mmol,1.00eq)和咪唑(59.1g,868mmol, 2.00eq)的DCM(1000mL)溶液中分批加入TBSCl(78.6g,521mmol,63.9mL,1.20eq)。反应液在25℃反应2h，然后再0℃滴加H2O(1000mL)，再加入DCM(1000mL)稀释。混合液用饱和食盐水洗涤后用无水硫酸镁干燥后过滤。滤液减压浓缩得到目标产物。无需纯化直接用于下一步反应。
1H NMR(400MHz,CDCl3)δ6.43(br s,1H)3.71(m,1H)3.57(m,1H)3.44(m,1H)2.30(m,2H)2.13(m,1H)1.74(m,1H)0.85(s,9H)0.02(m,6H)。
第二步：(S)-1-苄基-5-(((叔丁基甲基硅基)氧)甲基)吡咯啉-2-酮的制备
氮气保护下，在0℃(S)-5-(((叔丁基甲基硅基)氧)甲基)吡咯啉-2-酮(100g,436mmol,1.00eq)的THF(1250mL)溶液中2h分批加入NaH(72.7g,1.82mol,60.0％wt,4.17eq)。混合物在0℃反应0.5h，随后加入BnBr(112g,654mmol,77.7mL,1.50eq)。得到的混合物在25℃反应16h，随后在氮气保护下，在0-10℃加入饱和NH4Cl水溶液淬灭(1000mL)，再用EtOAc(1000mL*2)萃取。合并的有机相用饱和食盐水(1000mL)洗涤后用无水MgSO4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(122g,382mmol,87.6％产率)。
1H NMR(400MHz,CDCl3)δ7.29(m,5H)5.02(d,J＝14.97Hz,1H)4.06(d,J＝14.97Hz,1H)3.69(m,1H)3.54(m,2H)2.55(m,1H)2.38(m,1H)2.05(m,1H)1.91(m,1H)0.89(s,9H)0.04(s,6H)
第三步：(S)-4-苄基-5-(((叔丁基甲基硅基)氧基)甲基)-4-氮杂螺[2.4]庚烷的制备
氮气保护下，在0℃ TiCl4(49.9g,263mmol,0.750eq)的甲苯(263mL)溶液中加入Ti(OiPr)4(224g,789mmol,2.25eq)。反应液在25℃反应2h，随后在0℃滴加MeLi(1.60M,657mL,3.00eq)。得到的化合物在25℃反应1h，随后加入(S)-1-苄基-5-(((叔丁基甲基硅基)氧)甲基)吡咯啉-2-酮(112g,351mmol,1.00eq)的THF(560mL)溶液，随后在0℃在2h内滴加EtMgBr(3.00M,400mL,3.42eq)。得到的混合物在25℃反应2h，随后在0℃滴加水(700mL)淬灭反应后过滤。滤饼用EtOAc(1000mL)洗涤。合并的有机相用饱和食盐水(500mL*2)洗涤后用无水MgSO4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(19.0g,57.3mmol,16.4％产率)。
1H NMR(400MHz,CDCl3)δ7.29(m,5H)3.75(d,J＝13.82Hz,1H)3.54(d,J＝13.82Hz,1H)3.40(m,2H)3.03(m,1H)2.07(m,1H)1.95(dt,J＝11.80,8.22Hz,1H)1.78(m,1H)1.55(ddd,J＝12.01,8.04,4.40Hz,1H)0.84(s,9H)0.79(m,1H)0.56(m,1H)0.48(m,1H)0.41(m,1H)-0.06(d,J＝9.17Hz,6H)
第四步：(S)-(4-苄基-4-氮杂螺[2.4]庚烷-5-基)甲醇的制备
(S)-4-苄基-5-(((叔丁基甲基硅基)氧基)甲基)-4-氮杂螺[2.4]庚烷(19.0g,57.3mmol,1.00eq)的THF(300mL)溶液中加入TBAF(1.00M,57.3mL,1.00eq)。混合物在25℃反应16h，随后加入EtOAc(500mL)稀释。得到的混合物依次用H2O(100mL)和饱和食盐水(100mL)后用无水MgSO4干燥后过滤。滤液减压浓缩，残余物用硅胶柱 层析分离得到目标产物(5.30g,24.4mmol,42.6％产率)。
1H NMR(400MHz,CDCl3)δ7.28(m,4H)7.20(m,1H)4.14(br t,J＝5.39Hz,1H)3.67(d,J＝14.09Hz,1H)3.50(d,J＝14.08Hz,1H)3.24(m,1H)3.14(m,1H)2.91(m,1H)1.96(m,2H)1.65(m,1H)1.49(ddd,J＝11.50,8.20,3.41Hz,1H)0.80(m,1H)0.45(m,2H)0.37(m,1H)。
第五步：(S)-(4-氮杂螺[2.4]庚烷-5-基)甲醇盐酸盐的制备
氮气保护下，(S)-(4-苄基-4-氮杂螺[2.4]庚烷-5-基)甲醇(5.00g,23.0mmol,1.00eq)的MeOH(50.0mL)溶液加入Pd/C(500mg,10.0％wt)和HCl(12.0M,8.00mL,4.17eq)。混合物在氢气氛围下在30℃反应3days然后过滤，滤液减压浓缩得到目标产物(4.50g,粗品)。无需进一步纯化直接用于下一步反应。
1H NMR(400MHz,CDCl3)δ9.67(br s,1H)8.97(br s,1H)3.60(m,3H)2.07(m,1H)1.92(m,2H)1.79(m,1H)1.14(m,2H)0.77(m,2H)。
第六步：(S)-5-(羟甲基)-氮杂螺[2.4]庚烷-4-甲酸叔丁酯的制备
(S)-(4-氮杂螺[2.4]庚烷-5-基)甲醇盐酸盐(4.50g,27.5mmol,1.00eq)的DCM(90.0mL)溶液中加入TEA(3.34g,33.0mmol,4.59mL,1.20eq)和Boc2O(7.20g,33.0mmol,7.58mL,1.20eq)。混合物在25℃反应16h，然后在0℃加入水(50mL)淬灭后再用DCM(50mL*2)萃取。合并的有机相用饱和食盐水(50mL)洗涤后再用无水MgSO4干燥后过滤。滤液减压浓缩得到目标产物(5.90g,26.0mmol,94.4％产率)。
1H NMR(400MHz,CDCl3)δ3.85(br d,J＝5.94Hz,1H)3.52(ddd,J＝9.96,5.56,3.85Hz,1H)3.25(ddd,J＝10.12,8.58,5.94Hz,1H)2.14(m,1H)1.85(m,2H)1.50(br s,1H)1.35(s,9H)1.15(m,1H)0.84(m,1H)0.39(m,2H)。
第七步：(S)-4-(叔丁基氧基羰基)-4-氮杂螺[2.4]庚烷-5-甲酸的制备
0℃下，NaIO4(11.7g,54.7mmol,3.03mL,2.54eq)的H2O(18.0mL)溶液中加入(S)-5-(羟甲基)-氮杂螺[2.4]庚烷-4-甲酸叔丁酯(4.90g,21.6mmol,1.00eq)的ACN(12.0mL)和CCl4(12.0mL)混合溶液，随后加入RuCl3.H2O(206mg,912μmol,0.0423eq)。混合物在25℃反应16h，然后0℃下滴加入水(30mL)淬灭反应，再用DCM(50mL*2)萃取。合并的有机相用饱和食盐水(50mL)洗涤后用无水MgSO4干燥后过滤。滤液减压浓缩得到目标产物(4.70g,粗品)。无需进一步纯化直接用于下一步反应。
LC-MS：m/z 242(M+H)+。
第八步：(S)-4-(叔丁基氧基羰基)-4-氮杂螺[2.4]庚烷-5-甲酸甲酯的制备
0℃下，(S)-4-(叔丁基氧基羰基)-4-氮杂螺[2.4]庚烷-5-甲酸(4.70g,19.5mmol,1.00eq)的丙酮(50.0mL)溶液中加入MeI(5.53g,39.0mmol,2.43mL,2.00eq)和K2CO3(8.08g,58.4mmol,3.00eq)。混合物在25℃反应16h，然后0℃下滴加入水(30mL)淬灭反应，再用DCM(50mL*2)萃取。合并的有机相用饱和食盐水(50mL)洗涤后用无水MgSO4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产 物(1.10g,4.31mmol,22.1％产率)。
1H NMR(400MHz,CDCl3)δ4.33(br dd,J＝8.44,3.79Hz,1H)3.65(m,3H)2.20(m,1H)1.81(m,3H)1.39(m,1H)1.30(br s,9H)0.86(m,1H)0.48(br s,2H)。
第九步：4-(叔丁基)5-甲基5-(3-氯丙基)-4-氮杂螺[2.4]庚烷-4,5-二甲酸酯的制备
氮气保护下，在-70℃(S)-4-(叔丁基氧基羰基)-4-氮杂螺[2.4]庚烷-5-甲酸甲酯(1.00g,3.92mmol,1.00eq)的THF(10.0mL)溶液中加入LiHMDS(1.00M,5.88mL,1.50eq)。反应液在-70℃反应1h，随后加入1-氯-3-碘-丙烷(2.40g,11.8mmol,1.26mL,3.00eq)。得到的混合物在-70℃反应1h，然后在25℃反应40h。在-0℃混合物用饱和NH4Cl(20mL)淬灭再用EtOAc(30mL*2)萃取。合并的有机相用饱和食盐水(50mL)洗涤后用无水MgSO4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(767mg,2.31mmol,59.0％产率)。
1H NMR(400MHz,CDCl3)δ3.73(s,3H)3.59(br t,J＝6.27Hz,2H)2.39(m,1H)2.07(m,4H)1.89(m,1H)1.74(m,2H)1.44(m,1H)1.39(m,9H)0.90(br dd,J＝14.97,7.04Hz,1H)0.50(m,2H)。
第十步：5-甲基5-(3-氯丙基)-4-氮杂螺[2.4]庚烷-5-甲酸酯盐酸盐的制备
4-(叔丁基)5-甲基5-(3-氯丙基)-4-氮杂螺[2.4]庚烷-4,5-二甲酸酯(700mg,2.11mmol,1.00eq)的DCM(8.00mL)溶液中加入HCl/dioxane(4.00M,4.00mL,7.58eq)。混合物在25℃反应1h，然后减压浓缩得到目标产物(698mg,crude)。无需进一步纯化直接用于下一步反应。
LC-MS：m/z 232(M+H)+。
第十一步：四氢螺[环丙烷-1,3'-双稠吡咯啶]-7a'(5'H)-甲酸甲酯的制备
5-甲基5-(3-氯丙基)-4-氮杂螺[2.4]庚烷-5-甲酸酯盐酸盐(698mg,2.60mmol,1.00eq)的ACN(8.00mL)溶液中加入K2CO3(1.08g,7.81mmol,3.00eq)。混合物在25℃反应16h过滤，滤液减压浓缩得到目标产物(412mg,2.11mmol,81.1％产率)。无需进一步纯化直接用于下一步反应。
1H NMR(400MHz,CDCl3)δ3.74(m,3H)3.15(dt,J＝9.24,4.62Hz,1H)2.73(m,1H)2.45(m,2H)2.13(td,J＝11.55,7.92Hz,1H)1.94(m,1H)1.77(m,4H)1.31(m,2H)0.97(m,1H)0.66(m,2H)0.37(m,1H)
第十二步：(四氢螺[环丙烷-1,3'-双稠吡咯啶]-7a'(5'H)-基)甲醇的制备
氮气保护下，在0℃四氢螺[环丙烷-1,3'-双稠吡咯啶]-7a'(5'H)-甲酸甲酯(412mg,1.78mmol,1.00eq)的THF(4.00mL)溶液中加入LiAlH4(135mg,3.56mmol,2.00eq)。反应液在25℃反应1h，然后依次加入H2O(0.04mL)、NaOH水溶液(15％wt,0.04mL)和H2O(0.12mL)淬灭。混合物经无水硫酸镁干燥后过滤，滤液减压浓缩得到目标产物(263mg,1.57mmol)。
LC-MS：m/z 168(M+H)+。1H NMR(400MHz,CDCl3)δ3.40(d,J＝10.15Hz,1H) 3.28(d,J＝10.15Hz,1H)2.99(m,1H)2.73(m,1H)2.19(m,1H)1.91(m,2H)1.69(m,4H)1.26(m,2H)0.86(m,1H)0.61(dt,J＝9.81,5.73Hz,1H)0.50(dt,J＝10.18,5.00Hz,1H)0.38(ddd,J＝9.90,6.05,4.10Hz,1H)。
以中间体1-12同样方法合成了中间体1-13A和13B：((顺式)-6'-氟四氢螺[环丙烷-1,3'-双稠吡咯啶]-7a'(5'H)-基)甲醇和((反式)-6'-氟四氢螺[环丙烷-1,3'-双稠吡咯啶]-7a'(5'H)-基)甲醇
中间体1-13A
LC-MS：m/z 186(M+H)+。1H NMR(400MHz,CDCl3)δ5.26-5.02(m,1H),3.48(d,J＝10.8Hz,1H),3.42-3.13(m,3H),2.96-2.57(m,1H),2.52-2.29(m,2H),2.18-1.94(m,2H),1.87-1.74(m,1H),1.40-1.29(m,1H),0.95-0.82(m,1H),0.76-0.59(m,2H),0.53-0.38(m,1H),0.53-0.38(m,1H)。
中间体1-13B
LC-MS：m/z 186(M+H)+。1H NMR(400MHz,CDCl3)δ5.30-5.06(m,1H),3.57-3.41(m,2H),3.33(br dd,J＝12.4,18.8Hz,1H),3.07-2.86(m,1H),2.82-2.42(m,1H),2.40-2.27(m,1H),2.25-2.12(m,1H),2.11-1.93(m,2H),1.73(ddd,J＝2.0,8.8,12.5Hz,1H),1.34(ddd,J＝1.8,7.8,12.2Hz,1H),0.92-0.81(m,1H),0.77-0.57(m,2H),0.44(ddd,J＝3.8,5.9,9.6Hz,1H)。
按照中间体1-8同样方法以不同起始原料合成中间体1-14：(7',7'-二氟二氢-3'H-螺[环丙烷-1,2'-吲嗪]-8a'(1'H)-基)甲醇
LC-MS：m/z 218(M+H)+。1H NMR(400MHz,CDCl3)δ3.66(dd,J＝10.88,2.32Hz,1H)3.24(d,J＝10.88Hz,1H)2.97(m,4H)2.26(d,J＝11.62Hz,1H)1.95(m,6H)0.58(m,4H)。
按照中间体1-8同样方法以不同起始原料合成中间体1-15：(6',6'-二氟二氢-3'H-螺[环丙烷-1,2'-吲嗪]-8a'(1'H)-基)甲醇
LC-MS：m/z 218(M+H)+。1H NMR(400MHz,CDCl3)δ3.68(d,J＝10.39Hz,1H)3.29(m,2H)2.96(m,4H)2.04(m,6H)0.55(m,4H)。
中间体1-16A和1-16B((1S,6'R,7a'S)-2,2,6'-三氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇和((1R,6'R,7a'S)-2,2,6'-三氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯 啶]-7a'(5'H)-基)甲醇的制备
第一步：(3R,6R,7aS)-3-(叔丁基)-6-氟四氢-1H,3H-吡咯[1,2-c]恶唑-1-酮的制备
(2S,4R)-4-氟吡咯啶-2-甲酸(13.3g,100mmol,1.00eq)的THF(40mL)溶液中加入2,2-二甲基丙醛(17.3g,200mmol,22.1mL,2.00eq)、三甲氧基甲烷(31.9g,300mmol,32.9mL,3.00eq)和TFA(1.14g,10.0mmol,744μL,0.100eq)。混合物在57℃反应16h然后减压浓缩得到目标产物(22.0g,粗品)。无需纯化直接用于下一步反应。
1H NMR(400MHz,CDCl3)δppm 5.27(m,1H)4.52(s,1H)4.09(t,J＝8.14Hz,1H)3.56(m,1H)2.94(m,1H)2.54(m,1H)2.20(m,1H)0.96(m,9H)。
第二步：(3R,6R,7aS)-3-(叔丁基)-7a-(2-(氯甲基)丙烯基)-6-氟四氢-1H,3H-吡咯[1,2-c]恶唑-1-酮的制备
氮气保护下，在-70℃(3R,6R,7aS)-3-(叔丁基)-6-氟四氢-1H,3H-吡咯[1,2-c]恶唑-1-酮(22.0g,109mmol,1.00eq)的THF(220mL)溶液中滴加入LDA(2.00M,82.0mL,1.50eq)和DMPU(28.0g,219mmol,26.3mL,2.00eq)。混合物在-70℃反应2h，随后加入3-氯-2-(氯甲基)丙-1-烯(17.8g,142mmol,16.5mL,1.30eq)。得到的混合物在25℃反应16h，然后在0℃滴加饱和NH4Cl水溶液(250mL)淬灭后用EtOAc(250mL*2)萃取。合并的有机相用饱和食盐水(250mL)洗涤后用无水MgSO4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(16.7g,57.6mmol,52.7％产率)。
1H NMR(400MHz,CDCl3)δ5.37(m,1H)5.33(s,1H)5.24(m,1H)5.17(s,1H)4.21(m,3H)3.43(m,1H)3.23(m,1H)2.72(s,2H)2.37(m,1H)2.12(m,1H)0.91(s,9H)。
第三步：(2R,7aS)-2-氟-6-甲烯基四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯的制备
(3R,6R,7aS)-3-(叔丁基)-7a-(2-(氯甲基)丙烯基)-6-氟四氢-1H,3H-吡咯[1,2-c]恶唑-1-酮(11.2g,38.7mmol,1.00eq)的MeOH(56mL)溶液加入NaI(6.95g,46.4mmol,1.20eq)。混合物在68℃反应16h，然后过滤。滤液减压浓缩。残余物用丙酮(12mL)在25℃打浆30min后过滤。固体加入ACN(70mL)和K2CO3(12g)，然后在25℃反应3 h后过滤。滤液减压浓缩，残余物加入THF(70mL)后过滤，滤液减压浓缩得到目标产物(3.50g,17.6mmol,45.5％产率)。无需纯化，直接用于下一步反应。
1H NMR(400MHz,CDCl3)δ5.29(m,1H)4.97(dt,J＝11.44,1.87Hz,2H)3.82(br d,J＝13.86Hz,1H)3.72(m,3H)3.59(br d,J＝13.86Hz,1H)3.26(m,2H)3.04(br d,J＝16.07Hz,1H)2.81(br d,J＝16.07Hz,1H)2.56(m,1H)2.30(m,1H)。
第四步：(1S,6'R,7a'S)-2,2,6'-三氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-甲酸甲酯和(1R,6'R,7a'S)-2,2,6'-三氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-甲酸甲酯的制备
氮气保护下(2R,7aS)-2-氟-6-甲烯基四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯(2.00g,10.0mmol,1.00eq)的THF(20mL)溶液中加入NaI(752mg,5.02mmol,0.500eq)和TMSCF3(3.57g,25.1mmol,2.50eq)。反应液在80℃反应16h，然后减压浓缩。残余物用硅胶柱层析(20gSilica Flash Column,洗脱剂：10.3％THF/PE@60mL/min)依次得到异构体A(269mg,1.08mmol,10.8％产率)和异构体B(372mg,1.49mmol,14.9％产率)。
异构体A:1H NMR(400MHz,CDCl3)δ5.33(m,1H)3.78(s,3H)3.49(d,J＝9.90Hz,1H)3.27(m,3H)2.45(m,4H)1.37(m,2H)。
异构体B:1H NMR(400MHz,CDCl3)δ5.26(m,1H)3.78(m,3H)3.31(m,4H)2.54(m,2H)2.35(m,2H)1.36(m,2H)。
第五步：中间体1-16A和1-16B((1S,6'R,7a'S)-2,2,6'-三氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇和((1R,6'R,7a'S)-2,2,6'-三氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇的制备
氮气保护下，在0℃上一步得到的异构体A(269mg,1.08mmol,1.00eq)的THF(3mL)溶液中加入LAH(81.9mg,2.16mmol,2.00eq)。混合物在25℃反应1h，然后在0℃依次加入H2O(0.03mL)、NaOH水溶液(15％wt、0.03mL)和H2O(0.09mL)。得到的混合物经无水硫酸镁干燥后过滤，滤液减压浓缩得到目标产物中间体1-16A(193mg,871μmol,80.7％产率)。无需进一步纯化直接用于下一步反应。
LC-MS：m/z 222(M+H)+。1H NMR(400MHz,CDCl3)δ5.34(br s,1H)5.21(br d,J＝2.64Hz,1H)3.24(m,5H)2.77(br s,1H)2.19(m,3H)1.88(d,J＝12.98Hz,1H)1.33(m,2H)。
用上一步得到的异构体B以同样方法合成了中间体1-16B。
LC-MS：m/z 222(M+H)+。1H NMR(400MHz,CDCl3)δ5.28(m,1H)5.14(m,1H)3.27(m,5H)2.80(m,1H)2.20(m,3H)1.82(br dd,J＝13.31,4.73Hz,1H)1.30(m,2H)。
以中间体1-16A和1-16B同样的方法以不同起始原料合成了以下化合物：
中间体1-16C和1-16D：((1S,6'R,7a'R)-2,2,6'-三氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇和((1R,6'R,7a'R)-2,2,6'-三氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠 吡咯啶]-7a'(5'H)-基)甲醇
中间体1-16C
LC-MS：m/z 222(M+H)+。1H NMR(400MHz,CDCl3)δ5.31(m,1H)5.17(m,1H)3.56(m,1H)3.43(m,2H)3.21(dd,J＝12.53,7.52Hz,1H)2.78(d,J＝12.59Hz,2H)2.10(m,4H)1.29(s,2H)。
中间体1-16D
LC-MS：m/z 222(M+H)+。1H NMR(400MHz,CDCl3)δ5.38(br t,J＝4.95Hz,1H)5.24(m,1H)3.75(m,1H)3.42(m,2H)3.06(m,1H)2.68(m,2H)2.26(m,3H)1.82(m,1H)1.34(m,2H)。
中间体1-16E和1-16F：((1S,6'S,7a'S)-2,2,6'-三氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇和((1R,6'S,7a'S)-2,2,6'-三氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇
中间体1-16E
LC-MS：m/z 222(M+H)+。1H NMR(400MHz,CDCl3)δ5.31(m,1H)5.18(t,J＝4.29Hz,1H)3.57(d,J＝11.00Hz,1H)3.45(m,2H)3.21(dd,J＝12.54,7.48Hz,1H)2.83(m,2H)2.10(m,4H)1.34(m,2H)。
中间体1-16F
LC-MS：m/z 222(M+H)+。1H NMR(400MHz,CDCl3)δ5.36(m,1H)5.22(br d,J＝4.40Hz,1H)3.74(m,1H)3.42(m,2H)3.03(m,1H)2.72(m,2H)2.35(m,1H)2.13(m,2H)1.78(dd,J＝13.53,6.05Hz,1H)1.33(m,2H)。
中间体1-16G和1-16H：((1S,6'S,7a'R)-2,2,6'-三氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇和((1R,6'S,7a'R)-2,2,6'-三氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇
中间体1-16G
LC-MS：m/z 222(M+H)+。1H NMR(400MHz,CDCl3)δ5.35(br s,1H)5.18(m,1H)3.73(m,1H)3.28(m,5H)2.25(m,3H)1.87(m,1H)1.32(m,2H)。
中间体1-16H
LC-MS：m/z 222(M+H)+。1H NMR(400MHz,CDCl3)δ5.05(m,1H)3.48(m,1H) 3.06(m,5H)2.03(m,3H)1.62(m,1H)1.08(m,2H)。
中间体1-17(1-甲基四氢-1H-螺[环戊烷[b]吡咯-2,1'-环丙烷]-3a(3H)-基)甲醇的制备
第一步：1-(2-乙氧基-2-氧乙基)-2-氧环丙烷-1-甲酸甲酯的制备
2-氧环戊烷-1-甲酸甲酯(20.0g,141mmol,17.5mL,1.00eq)和2-溴乙酸乙酯(25.9g,15.5mmol,17.1mL,1.10eq)的ACN(200mL)溶液中加入K2CO3(29.2g,211mmol,1.50eq)。反应液在70℃反应16h，然后过滤，滤液减压浓缩得到目标产物(32.0g)。无需进一步纯化直接用于下一步反应。
1H NMR(400MHz,CDCl3)δ4.16-4.06(m,2H),3.71(s,3H),3.03-2.76(m,2H),2.65-2.53(m,1H),2.51-2.35(m,1H),2.51-2.35(m,1H),2.17-1.95(m,1H),2.17-1.95(m,2H),1.26-1.20(m,1H),1.26-1.20(m,1H),1.24(t,J＝7.2Hz,1H)。
第二步：1-甲基-2-氧六氢环戊烷[b]吡咯-3a(1H)-甲酸甲酯的制备
1-(2-乙氧基-2-氧乙基)-2-氧环丙烷-1-甲酸甲酯(5.00g,21.9mmol,1.00eq)的MeOH(50mL)溶液中加入甲胺甲醇溶液(2.0M,16.4mL,1.50eq)、AcOH(1.32g,21.9mmol,1.25mL,1.00eq)和NaBH3CN(1.79g,28.5mmol,1.30eq)。反应液在80℃反应24h，然后减压浓缩。残余物用3.0M HCl(50mL)洗涤后用DCM(500mL x 3)萃取。合并的有机相用无水硫酸镁干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(700mg,3.02mmol,13.8％产率)。
1H NMR(400MHz,CDCl3)δ4.15(d,J＝5.6Hz,1H),3.76-3.74(m,3H),3.10(d,J＝17.9Hz,1H),2.81(s,3H),2.39(d,J＝17.9Hz,1H),2.23-2.11(m,1H),1.91-1.73(m,4H),1.70-1.57(m,1H)。
第三步：3a-(羟甲基)-1-甲基六氢环戊烷[b]吡咯-2(1H)-酮的制备
0℃下，1-甲基-2-氧六氢环戊烷[b]吡咯-3a(1H)-甲酸甲酯(650mg,3.30mmol,1.00eq)的MeOH(10mL)中加入NaBH4(277mg,3.29mmol,2.20eq)的MeOH(10mL)。反应液在25℃反应4h，然后加入2mL 1M HCl淬灭后减压浓缩。残余物用DCM(200mL)稀释后无水硫酸镁干燥后过滤，滤液减压浓缩得到目标产物(390mg)。无需进一步纯化直接用于下一步反应。
LC-MS：m/z 170(M+H)+。
第四步：3a-(((叔丁基二苯基硅基)氧)甲基)-1-甲基六氢环戊烷[b]吡咯-2(1H)-酮的制备
室温下，3a-(羟甲基)-1-甲基六氢环戊烷[b]吡咯-2(1H)-酮(360mg,2.13mmol,1.00eq)的DCM(5mL)溶液中加入TBDPSCl(702mg,2.55mmol,1.20eq)和咪唑(290mg,4.25mmol,2.00eq)。反应液在室温反应2h，然后减压浓缩。残余物用硅胶柱层析分离得到目标产物(540mg,1.19mmol,56.04％产率)。
1H NMR(400MHz,CDCl3)δ7.70-7.59(m,4H),7.52-7.37(m,6H),3.64-3.46(m,2H),2.80(s,3H),2.61(d,J＝17.5Hz,1H),2.25(d,J＝17.5Hz,1H),2.08-1.84(m,1H),1.83-1.75(m,1H),1.74-1.65(m,2H),1.65-1.51(m,3H),1.08(s,9H)。
第五步：3a-(((叔丁基二苯基硅基)氧)甲基)-1-甲基六氢-1H-螺[环戊烷[b]吡咯-2,1'-环丙烷]的制备
氮气保护下，在0℃在3a-(((叔丁基二苯基硅基)氧)甲基)-1-甲基六氢环戊烷[b]吡咯-2(1H)-酮(500mg,1.23mmol,1.00eq)的THF(10mL)溶液中加入MeTi(OiPr)3(1.0M,3.07mL,2.50eq)和EtMgBr(3.0M,2.45mL,6.00eq)。反应液在25℃反应16h，然后加入水(10mL)稀释后用EtOAc(100mL*2)萃取。合并的有机相用饱和食盐水(50mL)洗涤后用无水硫酸钠干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(190mg,385μmol,31.4％产率)。
1H NMR(400MHz,CDCl3)δ7.68(br t,J＝5.7Hz,4H),7.54-7.35(m,6H),3.73-3.42(m,2H),2.77-2.50(m,1H),2.12-1.39(m,11H),1.09(s,9H),0.96--0.27(m,1H),0.96--0.31(m,1H)。
第六步：(1-甲基四氢-1H-螺[环戊烷[b]吡咯-2,1'-环丙烷]-3a(3H)-基)甲醇的制备3a-(((叔丁基二苯基硅基)氧)甲基)-1-甲基六氢-1H-螺[环戊烷[b]吡咯-2,1'-环丙烷](190mg,453μmol,1.00eq)的MeOH(5mL)溶液中加入KHF2(707mg,9.05mmol,298μL,20.0eq)。反应液在70℃反应16h然后减压浓缩。残余物用硅胶柱层析分离得到目标产物(72.6mg,360μmol,79.6％产率)。
1H NMR(400MHz,CDCl3)δ3.70-3.44(m,3H),3.70-3.44(m,1H),2.97-2.70(m,2H),2.21-1.94(m,3H),1.87(br d,J＝13.4Hz,3H),1.73-1.50(m,3H),1.37(t,J＝7.6Hz,1H),1.11-1.00(m,1H),0.99-0.73(m,1H),0.58-0.13(m,1H)。
中间体2-1((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼环戊烷-2-基)萘-1-基)乙炔基)三异丙基硅烷的制备
第一步：7-氟-8-((三异丙基硅基)乙炔基)萘-1,3-二醇的制备
氮气保护下，在室温下7-氟萘-1,3-二醇(5g,28.1mmol,1eq)、(溴乙炔)三异丙基硅烷(7.33g,28.1mmol,1eq)、和醋酸钾(5.51g,56.1mmol,2eq)的dioxane(120mL)溶液中加入二氯化钌1-异丙基-4-甲基-苯(1.20g,1.96mmol,0.07eq)。反应液在110℃反应16h然后过滤。滤饼用EtOAc(200mL*2)洗涤。合并的有机相减压浓缩。残余物用硅胶柱层析分离得到目标产物(8g,22.3mmol,79.5％产率)。
1H NMR(400MHz,CDCl3)δ9.19(m,1H)7.60(dd,J＝9.17,5.62Hz,1H)7.18(m,1H)6.73(m,2H)5.29(br s,1H)1.22(m,21H)
第二步：7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-醇的制备
0℃下7-氟-8-((三异丙基硅基)乙炔基)萘-1,3-二醇(7g,19.5mmol,1eq)和DIEA(5.05g,39.0mmol,6.80mL,2eq)的DCM(100mL)溶液中加入MOMCl(1.66g,20.6mmol,1.57mL,1.06eq)。得到的反应液在25℃反应1.5h然后用H2O(200mL)淬灭，再用1N HCl调节pH 6-7，再用DCM(80.0mLx 2)萃取。合并的有机相用饱和食盐水(200mL)洗涤，再用无水硫酸钠干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(4.2g,10.4mmol,53.4％产率)。
1H NMR(400MHz,DMSO-d6)δ8.94-9.20(m,1H)8.93-9.13(m,1H)7.58(dd,J＝9.07,5.69Hz,1H)7.10(t,J＝8.82Hz,1H)6.89(d,J＝2.50Hz,1H)6.73(d,J＝1.88Hz,1H)5.12-5.24(m,2H)3.43(s,3H)1.09-1.13(m,21H)
第三步：7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-基三氟甲烷磺酸酯的制备
-40℃下7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-醇(4g,9.94mmol,1eq)的DCM(40mL)溶液中加入DIEA(3.85g,29.8mmol,5.19mL,3eq)和Tf2O(4.21g,14.9mmol,2.46mL,1.5eq)。得到的反应液在-40℃反应0.5h，然后用H2O(20mL)稀释后再用DCM(50mL*2)萃取。合并的有机相用饱和食盐水(100mL)洗涤，再用无水硫酸钠干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到黄色油状目标产物(5g,8.88mmol,89.4％产率,95％纯度).
1H NMR(400MHz,CDCl3)δ7.72(dd,J＝9.03,5.27Hz,1H)7.44(d,J＝2.26Hz,1H)7.36-7.39(m,1H)7.31-7.35(m,1H)5.20-5.37(m,2H)3.46-3.63(m,3H)1.17-1.33(m,17H)
第四步：((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼环戊烷-2-基)萘-1-基)乙炔基)三异丙基硅烷的制备
氮气保护下，7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-基三氟甲烷磺酸酯(5g,9.35mmol,1eq),4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧硼环戊烷-2-基)-1,3,2-二氧硼环戊烷(4.75g,18.70mmol,2eq)、AcOK(2.75g,28.06mmol,3eq)的toluene(100mL)溶液中加入Pd(dppf)Cl2(684mg,935umol,0.1eq)。得到的反应液在130℃反应8h然后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(3.5g,6.49mmol,69.3％产率)。
1H NMR(400MHz,CDCl3)δ7.68(dd,J＝8.93,5.62Hz,1H)7.52(d,J＝2.45Hz,1H)7.39(d,J＝2.57Hz,1H)7.24(t,J＝8.80Hz,1H)5.18-5.39(m,2H)3.43-3.58(m,3H)1.45(s,12H)1.15-1.21(m,20H)
中间体3-1(1R,5S)-3-(2,7-二氯-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯的制备
第一步：2-氯-3-氟-5-碘吡啶-4-胺的制备
2-氯-3-氟吡啶-4-胺(10g,68.5mmol)和NIS(18.5g,82.2mmol,1.2eq)的乙腈(50mL)溶液中加入对甲苯磺酸单水合物(0.65g,3.43mmol,0.05eq)。反应液在70℃搅拌16小时，然后用水(30mL)和EtOAc(200mL)稀释。分离的有机相依次用S.aq.Na2CO3、S.aq.Na2SO3和饱和食盐水洗涤,经无水硫酸钠干燥后过滤。滤液减压浓缩得到目标产物(16.6g,61mmol,产率：89％)。无需纯化，直接用于下一步反应。
LC-MS：m/z 273(M+H)+。
第二步：4-氨基-6-氯-5-氟烟酸乙酯的制备
氮气氛围下，2-氯-3-氟-5-碘吡啶-4-胺(8.2g,30mmol,1.0eq)的EtOH(150mL)溶液中加入Pd(PPh3)2Cl2(2.1g,3mmol,0.1eq)和TEA(11.1g,0.11mmol,3.6eq)，得到的反应液在CO2氛围下，在80℃反应15小时，然后过滤。滤液减压浓缩至原体积的70-80％然后再次过滤。滤饼收集合并后真空干燥，得到目标产物(定量收率)。无需纯化，直接用于下一步反应。
LC-MS：m/z 219(M+H)+。
第三步：7-氯-8-氟吡啶[4,3-d]嘧啶-2,4-二醇的制备
在0℃下，在上述得到的4-氨基-6-氯-5-氟烟酸乙酯(657mg，3mmol)的THF(7mL)溶液中加入三氯乙酰基异氰酸酯(673mg,3.6mmol，1.2eq)。反应液在rt反应30min然后减压浓缩。残余物中加入MeOH(15mL),并冷却到0℃，随后加入NH3甲醇溶液(7M in MeOH,15mL,105mmol)。得到的反应液在rt反应16小时然后过滤。滤饼用甲醇洗涤然后真空干燥得到目标产物(定量收率)。无需纯化，直接用于下一步反应。
LC-MS：m/z 216(M+H)+。
第四步：2,4,7-三氯-8-氟吡啶[4,3-d]嘧啶的制备
7-氯-8-氟吡啶[4,3-d]嘧啶-2,4-二醇(500mg,2.4mmol)和DIPEA(1.55g,12mmol,5.0eq)的POCl3(5mL)溶液在100℃反应1小时，然后减压浓缩，得到目标化合物(定量收率)。无需纯化，直接用于下一步反应。
LC-MS：m/z 252(M+H)+。
第五步：(1R,5S)-3-(2,7-二氯-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯的制备
在-40℃下，在上述得到的2,4,7-三氯-8-氟吡啶[4,3-d]嘧啶和DIPEA(2g,15.5mmol)的DCM(2mL)溶液中加入3,8-二氮杂双环[3.2.l]辛烷-8-甲酸叔丁酯(500mg,2.4mmol)。得到的反应液在当前温度下反应0.5h，然后用水(2mL)稀释后再用DCM(2x 2mL)萃取。有机相分离后用饱和食盐水洗涤,再经无水硫酸钠干燥后过滤。滤液减压浓缩，得到目标产物(400mg，粗产率：38.9％)。无需纯化，直接用于下一步反应。
LC-MS：m/z 428(M+H)+。
中间体4-1(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘基-1-基)-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯的制备
第一步：(1R,5S)-3-(7-氯-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯的制备
(1R,5S)-3-(2,7-二氯-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(8.00g,18.7mmol,1.00eq)和2,2,2-三氟乙醇(56.1g,560mmol,40.3mL,30.0eq)加入DIEA(7.24g,56.0mmol,9.76mL,3.00eq)。得到的反应液在70℃反应2h然后减压浓缩。残余物用H2O(100mL)稀释然后用EtOAc(100mL*3)萃取。合并的有机相用饱和实验水洗涤(100mL)再用无水硫酸镁干燥后过滤。滤液减压浓缩得到目标产物(9g,18.3mmol,97.9％产率)。
LC-MS：m/z 492(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),4.82(q, J＝8.4Hz,2H),4.44(br d,J＝12.0Hz,2H),4.31(br s,2H),3.63(br s,2H),1.95-1.83(m,2H),1.68-1.58(m,2H),1.45(s,9H)
第二步：(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘基-1-基)-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯的制备
氮气氛围下，(1R,5S)-3-(7-氯-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(9.00g,18.3mmol,1.00eq)、((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼环戊烷-2-基)萘-1-基)乙炔基)三异丙基硅烷(9.85g,19.2mmol,1.05eq)和Cs2CO3(11.9g,36.6mmol,2.00eq)的H2O(20.0mL)和dioxane(100mL)的混合溶液中加入CataCXium Pd G2(611mg,915umol,0.05eq)。得到的反应液在100℃反应1h，然后用H2O(50mL)淬灭再用EtOAc(100mL*3)萃取。合并的有机相用无水硫酸镁干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(14.8g,17.6mmol,96.10％产率)。
LC-MS：m/z 842(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.25(s,1H),8.11(dd,J＝5.9,9.2Hz,1H),7.75(d,J＝2.5Hz,1H),7.57(t,J＝8.9Hz,1H),7.35(d,J＝2.4Hz,1H),5.76(s,1H),5.46-5.27(m,2H),5.21-4.91(m,2H),4.81(d,J＝12.4Hz,1H),4.38-4.17(m,3H),3.81(d,J＝12.0Hz,1H),3.60-3.52(m,1H),3.43(s,3H),1.63(d,J＝7.4Hz,1H),1.46(s,9H),0.80(t,J＝7.8Hz,20H),0.57-0.38(m,3H).
按中间体4-1的合成方法，以不同起始原料合成以下化合物：
中间体4-2(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 872(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.15(s,1H),7.17(br d,J＝8.4Hz,4H),6.88(br d,J＝8.4Hz,4H),6.82(s,1H),5.08(q,J＝8.9Hz,2H),4.69(br s,4H),4.55(br d,J＝12.1Hz,2H),4.27(br s,2H),3.73(s,6H),3.70-3.62(m,2H),2.39(br s,3H),1.85-1.76(m,2H),1.68(br d,J＝7.5Hz,2H),1.47(s,9H).
中间体4-3(1R,5S)-3-(7-(2-((叔丁氧羰基)氨基)-7-氟苯并[d]噻唑-4-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 724(M+H)+。
中间体4-4(1R,5S)-3-(7-(2-((叔丁氧羰基)氨基)-3-氰基-7-氟苯并[b]噻吩-4-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 748(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.79(s,1H),9.21(s,1H),7.61(dd,J＝5.3,8.4Hz,1H),7.42(t,J＝8.8Hz,1H),5.11(q,J＝9.1Hz,2H),4.57(br d,J＝12.5Hz,2H),4.28(br s,2H),3.78-3.67(m,2H),1.82(br d,J＝4.8Hz,2H),1.61(br d,J＝7.5Hz,2H),1.52(s,9H),1.48(s,9H)。
中间体4-5(1R,5S)-3-(8-氟-7-(6-氟-5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 690(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.29(s,1H)7.75-7.81(m,2H)5.86(dd,J＝9.68,1.98Hz,1H)5.12(q,J＝9.17Hz,2H)4.51-4.72(m,2H)4.29(br s,2H)3.91(br d,J＝11.88Hz,1H)3.76-3.84(m,1H)3.62-3.75(m,2H)2.32-2.47(m,1H)2.16-2.24(m,1H)2.19(s,2H)1.94-2.08(m,2H)1.83(br d,J＝3.30Hz,2H)1.70(br d,J＝7.48Hz,3H)1.59(br s,2H)1.48(s,9H)。
中间体4-6(1R,5S)-3-(8-氟-7-(7-氟-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 782(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.26(s,1H)8.24(m,2H)7.66(m,3H)5.08(m,2H)4.83(br d,J＝12.59Hz,1H)4.34(m,3H)3.83(br d,J＝11.86Hz,1H)3.41(m,1H)1.91(br d,J＝8.44Hz,2H)1.82(m,1H)1.65(m,1H)1.48(s,9H)0.82(m,18H)0.50(m,3H)。
中间体4-7(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 690(M+H)+。1H NMR(400MHz,CDCl3)δ9.08(s,1H)7.71(dd,J＝9.01,5.88Hz,1H)7.55(d,J＝2.63Hz,1H)7.28(s,1H)7.23(d,J＝2.50Hz,1H)5.31(d,J＝2.13Hz,2H)4.94(q,J＝8.38Hz,2H)4.54-4.67(m,2H)4.44(br s,2H)3.60-3.90(m,2H)3.53(s,3H)2.51(br dd,J＝13.95,7.07Hz,1H)2.23(ddd,J＝14.32,7.32,2.75Hz,1H)2.00-2.06(m,2H)1.81(br d,J＝8.38Hz,2H)1.26(s,9H)0.85(t,J＝7.44Hz,3H)。
中间体4-8 3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘基-1-基)-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,9-二氮杂双环[4.2.1]壬烷-9-甲酸叔丁酯
LC-MS：m/z 856(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.15-9.32(m,1H)8.05-8.19(m,1H)7.76(br d,J＝2.32Hz,1H)7.50-7.64(m,1H)7.14-7.46(m,1H)5.28-5.43(m,2H)4.94-5.20(m,2H)4.08-4.51(m,4H)3.49-3.80(m,1H)3.39-3.48(m,3H)3.29-3.34(m,3H)2.01-2.21(m,2H)1.50-1.77(m,2H)1.44(s,3H)1.20(s,3H)0.94-1.06(m,3H)0.81(t,J＝6.48Hz,18H)0.40-0.61(m,3H)。
中间体4-9(1-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘基-1-基)-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-基)氨基甲酸叔丁酯
LC-MS：m/z 842(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.01-9.27(m,1H)8.12(dd,J＝9.17,5.87Hz,1H)7.73-7.80(m,1H)7.58(t,J＝8.93Hz,1H)7.35-7.41(m,1H)7.12-7.20(m,1H)6.41-6.65(m,1H)5.32-5.42(m,2H)5.08-5.19(m,1H)4.92-5.05(m,1H)4.40(br d,J＝12.35Hz,1H)3.63-3.74(m,1H)3.44(s,3H)3.35-3.41(m,1H)3.28-3.34(m,2H)2.01-2.14(m,1H)1.84-1.95(m,1H)1.50-1.83(m,2H)1.30-1.41(m,3H)1.21-1.27(m,2H)1.12(s,6H)0.72-0.88(m,18H)0.34-0.58(m,3H)
中间体4-10(1R,5S)-3-(7-(3-((双叔丁基氧基羰基)氨基)-2-氟-5-甲基-6-(三氟甲基)苯基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 849(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.24(s,1H)7.82(d,J＝9.26Hz,1H)5.11(q,J＝9.01Hz,2H)4.57(br d,J＝12.38Hz,2H)4.29(br s,2H)3.69(br d,J＝12.26Hz,2H)2.28(br s,3H)1.82(br d,J＝4.13Hz,2H)1.66(br d,J＝7.50Hz,2H)1.47(s,9H)1.38(s,18H)。
中间体4-11(1R,5S)-3-(7-(2-((双叔丁氧羰基)氨基)-3,5-二氯-6-氟苯基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 835(M+H)+。1H NMR(400MHz,CDCl3)δ9.00(s,1H)7.68(d,J＝7.09Hz,1H)4.81-5.01(m,2H)4.64-4.77(m,1H)4.34-4.49(m,3H)3.59-3.89(m,2H)2.02(br d,J＝1.47Hz,2H)1.79-1.86(m,4H)1.78-1.86(m,1H)1.53-1.59(m,10H)1.43-1.51(m,9H)1.16-1.27(m,8H)。
中间体4-12(1R,5S)-3-(7-(5-((双叔丁氧羰基)氨基)-3-氯-2-(三氟甲基)苯基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 851(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.06(br s,1H)7.52(s,1H)7.20(br s,1H)4.92(br d,J＝7.46Hz,2H)4.44(br s,4H)3.74(br s,2H)2.02(br s,2H)1.78(br s,2H)1.55(s,9H)1.48(s,18H)。
中间体4-13(1R,5S)-3-(7-(3-(双(4-甲氧基苄基)氨基)-2-氟-5-甲基-6-(三氟甲基)苯基)-8-甲氧基-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 901(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.99-9.10(m,1H)7.26-7.45(m,1H)7.02-7.23(m,4H)6.75-6.96(m,4H)4.98-5.21(m,2H)4.47-4.55(m,2H)4.21-4.29(m,2H)4.04-4.13(m,4H)3.81-3.88(m,3H)3.71-3.78(m,6H)3.60-3.69(m,2H)2.00-2.12(m,3H)1.77-1.87(m,2H)1.62-1.71(m,2H)1.41-1.51(m,9H)。
中间体4-14(1R,5S)-3-(7-(5-(双(叔丁基羰基)胺基)-3-氯-2-(三氟甲基)苯基)-8-基氧基-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 863(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),7.88(s,1H),7.37-7.27(m,1H),5.09(br d,J＝9.0Hz,2H),4.65-4.39(m,2H),4.28(br s,2H),3.95-3.87(m,3H),3.76-3.53(m,2H),1.82(br s,2H),1.74-1.57(m,2H),1.47(s,9H),1.42-1.39(m,18H)
中间体4-15(1R,5S)-3-(7-(3-乙酰氨基-5-氯-2-氟-6-(三氟甲基)苯基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 711(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),9.24(s,1H),8.68(br d,J＝6.9Hz,1H),5.10(q,J＝9.0Hz,2H),4.56(br d,J＝8.6Hz,2H),4.29(br s,2H),3.69(br t,J＝12.2Hz,2H),2.19(s,3H),1.82(br s,2H),1.71(br d,J＝9.6Hz,2H),1.47(s,9H)。
中间体4-16(1R,5S)-3-(7-(3-乙酰氨基-2,5-二氯-6-(三氟甲基)苯基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 727(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.99(s,1H)9.25(s,1H)8.51(s,1H)4.98-5.20(m,2H)4.54(br d,J＝11.66Hz,2H)4.29(br s,2H)3.68(br d,J＝7.48Hz,2H)2.21(s,3H)1.82(br d,J＝3.30Hz,2H)1.70(br d,J＝7.92Hz,2H)1.46(s,9H)。
中间体4-17(1R,5S)-3-(7-(3-乙酰氨基-2-氯-5-氟-6-(三氟甲基)苯基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 711(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.98(s,1H)9.26(s,1H)8.34(d,J＝13.63Hz,1H)5.11(q,J＝8.84Hz,2H)4.48-4.62(m,2H)4.22-4.36(m,2H)3.59-3.79(m,1H)3.69(br t,J＝12.82Hz,1H)2.18-2.26(m,3H)1.79-1.88(m,2H)1.71(br d,J＝7.75Hz,2H)1.42-1.51(m,9H)。
中间体4-18(1R,5S)-3-(7-(3-氨基-2,6-二氯-5-氟苯基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 635(M+H)+。
中间体4-19(1R,5S)-3-(7-(5-乙酰氨基-3-氯-2-(三氟甲基)苯基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 693(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),9.19(s,1H),8.09-7.97(m,1H),7.73(s,1H),5.10(q,J＝9.1Hz,2H),4.56(br s,2H),4.28(br s,2H),3.76-3.63(m,2H),2.11(s,3H),1.82(br s,2H),1.73-1.63(m,2H),1.47(s,9H)。
中间体4-20(1R,5S)-3-(7-(3-氯-5-(甲基磺酰胺基)-2-(三氟甲基)苯基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 729(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),9.20(s,1H),7.58(d,J＝1.8Hz,1H),7.22(d,J＝1.9Hz,1H),5.10(q,J＝9.0Hz,2H),4.56(br s,2H),4.28(br s,2H),3.69(br d,J＝12.5Hz,2H),3.23(s,3H),1.81(br s,2H),1.68(br d,J＝7.3Hz,2H),1.47(s,9H)。
中间体4-21(1R,5S)-3-(7-(5-(双叔丁氧甲酰基氨基)-3-氯-4-氟-2-(三氟甲基)苯基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 869(M+H)+。1H NMR(400MHz,CDCl3)δ9.03(br s,1H),7.26-7.21(m,1H),4.90(br d,J＝6.8Hz,2H),4.66-4.34(m,4H),3.85-3.59(m,2H),2.00(br s,2H),1.76(br s,2H),1.52(s,9H),1.45(s,18H)
中间体4-22(1R,5S)-3-(7-(5-(双(4-甲氧基苄基)氨基)-3-甲基-4-氟-2-(三氟甲基)苯基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 889(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.93-8.86(m,1H),7.10-7.02(m,4H),6.85-6.71(m,4H),6.66-6.53(m,1H),4.94-4.76(m,2H),4.57-4.29(m,4H),4.26(s,4H),3.72(s,6H),3.68-3.55(m,2H),2.47-2.32(m,3H),1.95-1.87(m,2H),1.68(br d,J＝7.9Hz,2H),1.45(s,9H)。
中间体4-23(1R,5S)-3-(7-(5-氨基-3-氟-2-(三氟甲基)苯基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 635(M+H)+。
中间体4-24(1R,5S)-3-(7-(5-氨基-3-氰基-2-(三氟甲基)苯基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 642(M+H)+。1H NMR(400MHz,CDCl3)δ9.39-8.96(m,1H),7.41(br s,1H),6.91-6.73(m,1H),6.62(br s,2H),5.24-4.96(m,2H),4.54(br s,2H),4.28(br s,2H),3.68(br d,J＝10.4Hz,2H),1.81(br s,2H),1.68(br s,2H),1.55-1.36(m,9H)。
中间体4-25(1R,5S)-3-(7-(5-氨基-3-氯-2-氟苯基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 601(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.20(s,1H),6.82(m,2H),5.50(s,2H),5.11(q,J＝9.0Hz,2H),4.57(d,J＝12.5Hz,2H),4.28(s,2H),3.68(d,J＝12.3Hz,2H),1.80(s,2H),1.68(d,J＝7.3Hz,2H),1.44(s,9H).
中间体4-26(1R,5S)-3-(7-(5-氨基-3-氯-2-氰基苯基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 608(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),6.87(d,J＝2.1Hz,1H),6.80(d,J＝1.8Hz,1H),5.10(q,J＝9.0Hz,2H),4.56(d,J＝12.1Hz,2H),4.28(s,2H),3.68(d,J＝12.2Hz,2H),1.81(s,2H),1.68(d,J＝7.4Hz,2H),1.47(s,9H).
中间体4-27(1R,5S)-3-(7-(5-氨基-2-氯-3-(三氟甲基)苯基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 651(M+H)+。
中间体4-28(1R,5S)-3-(7-(5-氨基-2-氰基-3-(三氟甲基)苯基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 642(M+H)+。
中间体4-29(1R,5S)-3-(7-(5-氨基-2-氯-3-氰基苯基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 608(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),7.14(d,J＝2.7Hz,1H),7.02(d,J＝2.7Hz,1H),5.10(dt,J＝9.1,7.0Hz,2H),4.56(s,2H),4.29(s,2H),3.68(d,J＝12.2Hz,2H),1.81(s,2H),1.69(d,J＝7.5Hz,2H),1.48(s,11H).
中间体4-30(1R,5S)-3-(7-(5-氨基-2,3-二氯苯基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 617(M+H)+。
中间体4-31(1R,5S)-3-(7-(3-氨基-6-氯-2-氰基苯基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 608(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.27(s,1H),7.53(d,J＝9.1Hz,1H),6.97(d,J＝9.1Hz,1H),6.46(s,2H),5.10(q,J＝9.0Hz,2H),4.64(d,J＝12.3Hz, 1H),4.47(d,J＝11.9Hz,1H),4.28(s,2H),3.76(d,J＝11.4Hz,1H),3.59(s,1H),1.83–1.64(m,4H),1.47(s,8H).
中间体4-32(1R,5S)-3-(7-(5-(苄氧基)-3-氯-2-(三氟甲基)苯基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 742(M+H)+。
中间体4-33(1R,5S)-3-(7-(5-氨基-2-(三氟甲基)吡啶-3-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 618(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.18(s,1H)8.12(d,J＝2.20Hz,1H)6.87(s,1H)6.32(br d,J＝4.18Hz,2H)5.09(q,J＝9.17Hz,2H)4.55(br d,J＝12.10Hz,2H)4.27(br s,2H)3.67(br d,J＝11.44Hz,2H)1.93(br s,2H)1.80(br s,2H)1.35(s,9H)。
中间体4-34(1R,5S)-3-(7-(5-氨基-4-(三氟甲基)吡啶-3-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 618(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.38(s,1H),7.73(s,1H),6.26(s,2H),5.09(q,J＝9.0Hz,2H),4.55(br d,J＝11.6Hz,2H),4.28(br s,2H),3.67(br d,J＝10.3Hz,2H),1.82(br s,2H),1.67(br d,J＝7.5Hz,2H),1.47(s,9
H)。
中间体4-35(1R,5S)-3-(7-(5-氨基-4-甲基-2-(三氟甲基)吡啶-3-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 632(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.23(s,1H)8.12(s,1H) 6.02-6.16(m,2H)5.00-5.21(m,2H)4.55(br t,J＝14.42Hz,2H)4.30(br s,2H)3.60-3.80(m,2H)2.40-2.48(m,3H)1.83(br d,J＝1.76Hz,2H)1.70(br d,J＝7.92Hz,2H)1.47(s,9H)。
中间体4-36(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-2-甲基-3-(三氟甲基)吡啶-4-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 872(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.12(s,1H),7.26–7.11(m,4H),6.89(d,J＝8.4Hz,4H),6.50(s,1H),5.07(q,J＝9.0Hz,2H),4.85–4.68(m,4H),4.59–4.43(m,2H),4.32–4.21(m,2H),3.73(s,6H),3.70–3.60(m,2H),2.60(s,3H),1.85–1.76(m,2H),1.69–1.60(m,2H),1.46(s,9H).
中间体4-37(1R,5S)-3-(8-氟-7-(1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吲唑-4-基)-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
LC-MS：m/z 726(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.27(d,J＝5.0Hz,1H),8.12(d,J＝8.9Hz,1H),7.91(d,J＝8.2Hz,2H),6.09-5.93(m,1H),5.21-5.02(m,2H),4.59(t,J＝12.0Hz,2H),4.45-4.18(m,2H),3.92(d,J＝7.8Hz,1H),3.85-3.54(m,3H),2.38(dd,J＝22.2,12.9Hz,1H),2.03(d,J＝6.9Hz,2H),1.94-1.66(m,5H),1.61(s,2H),1.47(s,9H).
实施例1 4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的制备
第一步：(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1- 基)-2-((3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯的制备
(3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇(1.01g,5.45mmol,4.59eq)和(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘基-1-基)-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(1.00g,1.19mmol,1.00eq)的THF(20mL)溶液中加入t-BuONa(913mg,9.50mmol,8.00eq)。反应液在25℃反应16h，然后用H2O(10mL)淬灭后用EtOAc(30mL*3)萃取。合并的有机相用饱和实验水洗涤(100mL)再用无水硫酸镁干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(723mg,257umol,21.7％产率,33.0％纯度)。无需纯化直接用于下一步反应。
第二步：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基甲基)吡啶[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-醇的制备
(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-((3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(670mg,238μmol,33.0％纯度,1.00eq)的DCM(6mL)溶液中加入HCl/dioxane(4.00M,945μL,15.8eq)。反应液在25℃反应2h，然后减压浓缩得到目标产物(430mg,crude)。无需纯化直接用于下一步反应。
第三步：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的制备
4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基甲基)吡啶[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-醇(400mg,163μmol,32.0％纯度,1.00eq)的DMF(6mL)溶液中加入CsF(497mg,3.27mmol,121uL,20.0eq)。反应液在25℃反应16h，然后过滤。滤液减压浓缩，残余物用prep-HPLC分离得到目标产物(63.0mg)。
LC-MS：m/z 627(M+H)+。
经手性SFC分离得到实施例1异构体1(11.3mg,17.6umol,10.8％产率)和实施例1异构体2(19.2mg,29.9umol,18.3％产率)。
实施例1异构体1
LC-MS：m/z 627(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.17(br s,1H)9.03(s,1H)7.98(dd,J＝9.16,5.90Hz,1H)7.47(t,J＝8.91Hz,1H)7.39(d,J＝2.51Hz,1H)7.18(d,J＝2.26Hz,1H)4.48(br d,J＝11.80Hz,1H)4.31(br d,J＝12.30Hz,1H)3.95-4.08(m,2H)3.94(s,1H)3.64(br d,J＝12.05Hz,1H)3.57(br s,3H)3.17-3.28(m,5H)2.79-2.94(m,2H)2.65-2.70(m,1H)1.90-2.06(m,2H)1.78(br d,J＝4.52Hz,3H)1.51-1.69(m,8H).
实施例1异构体2
LC-MS：m/z 627(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.17(br s,1H)9.04(s,1H)7.98(dd,J＝9.16,5.90Hz,1H)7.47(t,J＝9.03Hz,1H)7.40(d,J＝2.51Hz,1H)7.18(d,J＝2.26Hz,1H)4.49(br d,J＝12.05Hz,1H)4.32(br d,J＝12.30Hz,1H)3.96-4.10(m,2H)3.94(s,1H)3.65(br d,J＝14.31Hz,1H)3.56-3.62(br s,3H)3.17-3.28(m,5H)2.80-2.95(m,2H)2.68(br d,J＝1.76Hz,1H)1.90-2.03(m,2H)1.78(br s,3H)1.51-1.72(m,8H).
实施例1异构体1和实施例1异构体2再次经SFC分离得到实施例1异构体1A、实施例1异构体1B、实施例1异构体2A和实施例1异构体2B：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((3S,7aR)-(3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇、4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((3R,7aS)-(3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇、4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((3R,7aR)-(3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇、4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((3S,7aS)-(3-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
实施例1异构体1A
LC-MS：m/z 627(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),9.03(s,1H),7.98(dd,J＝9.20,5.92Hz,1H),7.46(t,J＝9.00Hz,1H),7.39(d,J＝2.64Hz,1H),7.17(d,J＝2.56Hz,1H),4.47(d,J＝12.44Hz,1H),4.30(d,J＝12.32Hz,1H),3.97-4.07(m,2H),3.92(s,1H),3.56-3.66(m,4H),3.17-3.27(m,5H),2.79-2.92(m,2H),2.63-2.69(m,1H),1.51–2.03(m,13H)。
实施例1异构体1B
LC-MS：m/z 627(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.14(s,1H)，9.03(s,1H),7.98(dd,J＝9.24,5.92Hz,1H),7.46(t,J＝9.00Hz,1H),7.39(d,J＝2.56Hz,1H),7.17(d,J＝2.60Hz,1H),4.47(d,J＝12.32Hz,1H),4.30(d,J＝12.24Hz,1H),3.97-4.07(m,2H),3.92(s,1H)，3.56-3.66(m,4H),3.17-3.27(m,5H),2.80-2.92(m,2H),2.63-2.68(m,1H),1.51–2.04(m,13H)。
实施例1异构体2A
LC-MS：m/z 627(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.03(s,1H),7.99-7.95(m,1H),7.46(t,J＝8Hz,1H),7.39(s,1H),7.18(s,1H),4.47(d,J＝8Hz,1H), 4.30(d,J＝8Hz,1H),4.11(d,J＝4Hz,1H),4.01(d,J＝4Hz,1H),3.93(s,1H),3.63(d,J＝8Hz,1H),3.57-3.53(m,3H),3.44-3.40(m,1H),3.25(s,3H),3.19(s,2H),2.72-2.64(m,2H),2.05-1.97(m,2H),1.71-1.56(m,9H),1.52-1.44(m,1H)。
实施例1异构体2B
LC-MS：m/z 627(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.04(s,1H),7.96(m,1H),7.46(t,J＝8Hz,1H),7.39(m,1H),7.18(m,1H),4.65-4.56(m,1H),4.48-4.39(m,1H),4.30(d,J＝8Hz,1H),4.15-4.06(m,1H),4.02(t,J＝4Hz,1H),3.93(s,1H),3.85-3.75(m,1H),3.63(d,J＝4Hz,1H),3.58-3.54(m,3H),3.44-3.40(m,2H),3.25(s,3H),3.18(s,2H),2.72-2.66(m,2H),2.07-2.02(m,3H),1.71-1.57(m,7H),1.51-1.44(m,1H)。
按照实施例1的方法以不同的起始原料合成了以下实施例：
实施例2 4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((3-((乙氧基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的制备
LCMS:m/z 641(M+H)+.
实施例3 4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((3-((异丙氧基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的制备
LCMS:m/z 655(M+H)+.
实施例4 4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((3-((环丙基甲基氧基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的制备
LCMS:m/z 667(M+H)+.
实施例5 4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-((3-(环丙氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LCMS:m/z 653(M+H)+.
实施例6 4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-(((2R)-2-氟-5-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LCMS:m/z 645(M+H)+.
经手性分离得到异构体6A和异构体6B：顺式-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-(((2R)-2-氟-5-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇和反式-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-(((2R)-2-氟-5-(甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
异构体6A
LCMS:m/z 645(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.03(s,1H),7.97(q,J＝8Hz,1H),7.47(t,J＝8Hz,1H),7.39(s,1H),7.18(d,J＝4Hz,1H),5.47-5.32(m,1H),4.50(d,J＝8Hz,1H),4.31(d,J＝8Hz,1H),4.07(s,2H),3.96(s,1H),3.66(d,J＝12Hz,1H),3.56(s,3H),3.28-3.21(m,6H),3.00-2.85(m,3H),2.36-2.24(m,1H),2.087-1.92(m,3H),1.86-1.82(m,1H),1.73-1.58(m,6H)。
异构体6B
LCMS:m/z 645(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),9.03(s,1H),7.98(dd,J＝5.92Hz,9.20Hz,1H),7.46(t,J＝9.00Hz,1H),7.38(d,J＝2.52Hz,1H),7.17(d,J＝2.48Hz,1H),5.34(m,0.5H),5.20(m,0.5H),4.47(m,1H),4.29(m,1H),4.18(m,1H),4.10(m,1H),3.94(d,J＝5.28Hz,1H),3.63(m,1H),3.48(m,5H),3.26(s,3H),3.00(m,2H),2.29(m,1H),1.72(m,9H)。
实施例7 4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((2R)-5-(环丙氧基甲基)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LCMS:m/z 671(M+H)+.
实施例8A和实施例8B顺式4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((3-(三氟甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇和反式4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((3-(三氟甲氧基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
实施例8A
LCMS:m/z 681(M+H)+.
实施例8B
LCMS:m/z 681(M+H)+.
实施例9 4-(4-(1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-2-(二氢-1'H,3'H-螺环[1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟-萘-2-醇
LCMS:m/z 609(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.03(m,1H),7.97(t,J＝8Hz,1H),7.46(t,J＝8Hz,1H),7.39(d,J＝4Hz,1H),7.18-7.17(m,1H),4.47(t,J＝8Hz,1H),4.34-4.21(m,2H),4.08-4.04(m,1H),3.94(d,J＝4Hz,1H),3.63(t,J＝8Hz,1H),3.55(s,3H),2.99-2.94(m,1H),2.74-2.61(m,3H),2.03-1.85(m,3H),1.83-1.76(m,3H),1.71-1.66(m,4H),0.49-0.45(m,4H)。
实施例10 4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((6'R)-6'-氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LCMS:m/z 627(M+H)+.
实施例10经手性拆分得到异构体10A和10B：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((6'R,7a'S)-6'-氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇和4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((6'R,7a'R)-6'-氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
异构体10A：
LCMS:m/z 627(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),9.06(s,1H),7.99(dd,J＝5.92,9.24Hz,1H),7.48(t,J＝9.00Hz,1H),7.40(d,J＝2.56Hz,1H),7.19(m,1H),5.41(m,0.5H),5.28(m,0.5H),4.49(m,1H),4.35(m,2H),4.09(d,J＝10.24Hz,1H),3.95(m,1H),3.58(m,4H),3.27(m,2H),3.11(m,3H),2.70(m,1H),2.16(m,3H),1.68(m,4H),0.51(m,4H)。
异构体10B：
LCMS:m/z 627(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),7.99(dd,J＝5.96,9.16Hz,1H),7.48(t,J＝9.04Hz,1H),7.40(d,J＝2.52Hz,1H),7.16(m,1H),5.48(m,0.5H),5.35(m,0.5H),4.48(m,1H),4.30(m,2H),4.12(m,1H),3.93(s,1H),3.58(m,4H),3.26(m,2H),3.01(m,0.5H),2.89(m,0.5H),2.80(d,J＝9.92Hz,1H),2.62(d,J＝9.92Hz,1H),2.32(m,1H),2.03(m,2H),1.82(m,3H),1.65(m,3H),0.48(m,4H)。
实施例11 4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((四氢螺[环丙烷-1,3'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)吡啶并[4,3d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LCMS:m/z 609(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.03(m,1H),7.95(dd,J＝6.00,9.28Hz,1H),7.45(t,J＝9.00Hz,1H),7.37(d,J＝2.56Hz,1H),7.18(m,1H),4.49(m,2H),4.32(m,1H),4.14(m,2H),3.92(m,1H),3.76(m,1H),3.62(m,1H),3.58(m,1H),2.90(m,1H),2.63(m,1H),2.04(m,7H),1.63(m,6H),1.24(m,1H),0.75(m,1H),0.58(m,1H), 0.43(m,1H),0.33(m,1H)。
以中间体1-13A和1-13B分别为原料合成了实施例12A和12B：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((反式)-6'-氟四氢螺[环丙烷-1,3'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇和4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((顺式)-6'-氟四氢螺[环丙烷-1,3'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
实施例12A
LCMS:m/z 627(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.04(s,1H),7.99-7.95(m,1H),7.46(t,J＝8Hz,1H),7.39(d,J＝4Hz 1H),7.18(d,J＝4Hz 1H),5.25(d,J＝4Hz,1H),4.49(d,J＝12Hz,1H),4.32(d,J＝12Hz,1H),4.25-4.17(m,2H),3.94(s,1H),3.65(d,J＝12Hz,1H),3.57(d,J＝8Hz,3H),3.26-3.14(m,1H),3.05-2.96(m,1H),2.39-2.22(m,2H),2.15-2.05(m,1H),2.00-1.95(m,2H),1.65(s,4H),1.34-1.23(m,1H),0.85-0.75(m,1H),0.61-0.55(m,1H),0.45-0.37(m,2H)。
实施例12B
LCMS:m/z 627(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),9.03(s,1H),7.99-7.95(m,1H),7.46(t,J＝8Hz,1H),7.39(d,J＝4Hz 1H),7.18(d,J＝4Hz 1H),5.34(d,J＝4Hz,1H),4.50(d,J＝12Hz,1H),4.31-4.27(m,1H),4.27-4.16(m,2H),3.95(d,J＝4Hz,1H),3.66(d,J＝12Hz,1H),3.57(d,J＝12Hz,3H),3.23-3.15(m,1H),2.99-2.85(m,1H),2.40-2.31(m,1H),2.17-2.09(m,1H),2.05-1.86(m,3H),1.65(s,4H),1.34-1.23(m,2H),0.81-0.76(m,1H),0.64-0.58(m,1H),0.52-0.46(m,1H),0.38-0.33(m,1H)。
实施例13 4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-((7',7'-二氟四氢-3'-H-螺环[环丙烷-1,2'-双稠吡咯啶]-8a'(1'H)-基)甲氧基)-8-氟吡啶[4,3d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇三氟乙酸盐
LCMS:m/z 659(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.25(br,1H),9.42(m,1H),9.15(m,2H),8.00(dd,J＝6.00,9.20Hz,1H),7.47(t,J＝9.20Hz,1H),7.42(d,J＝2.40Hz,1H),7.19(m,1H),4.63(m,5H),4.23(s,2H),3.91(m,4H),3.52(m,1H),3.39(m,4H),3.52(m,1H),3.39(m,1H),2.53(m,1H),1.97(m,5H),0.74(m,4H)。
实施例14 4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-((6',6'-二氟四氢-3'-H-螺环[环丙烷-1,2'-双稠吡咯啶]-8a'(1'H)-基)甲氧基)-8-氟吡啶[4,3d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LCMS:m/z 645(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.05(s,1H),7.97(dd,J＝5.92,9.24Hz,1H),7.46(t,J＝9.00Hz,1H),7.39(d,J＝2.60Hz,1H),7.18(s,1H),4.64(dd,J＝2.92,10.88Hz,1H),4.47(d,J＝12.64Hz,1H),4.35(m,2H),3.93(m,1H),3.60(m,4H),3.10(m,4H),2.81(dd,J＝3.96,8.68Hz,1H),2.84(m,1H),2.02(m,1H),1.91(m,3H),1.68(m,5H),0.52(m,4H)。
以中间体1-16A和1-16B按照实施例1的方法合成实施例15A、15B：
4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-(((1S,6'R,7a'S)-2,2,6'-三氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇和4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-(((1R,6'R,7a'S)-2,2,6'-三氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
实施例15A
LCMS:m/z 663(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),9.05(s,1H),7.98(dd,J＝5.92,9.16Hz,1H),7.47(t,J＝9.04Hz,1H),7.40(d,J＝2.64Hz,1H),7.18(m,1H),5.43(m,0.5H),5.29(m,0.5H),4.51(t,J＝12.16Hz,1H),4.31(m,1H),4.05(m,2H),3.94(d,J＝4.16Hz,1H),3.61(m,4H),3.12(m,4H),2.22(m,5H),1.69(s,4H),1.54(m,2H)。
实施例15B
LCMS:m/z 663(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.06(s,1H),7.98(dd,J＝5.92,9.12Hz,1H),7.47(t,J＝9.00Hz,1H),7.40(d,J＝2.68Hz,1H),7.18(m,1H),5.35(m,0.5H),521(m,0.5H),4.48(m,1H),4.31(m,2H),4.18(m,1H),3.94(s,1H),3.61(m,4H),3.21(m,2H),3.01(m,2H),2.16(m,5H),1.69(s,4H),1.54(m,2H)。
以中间体1-16C和1-16D按照实施例1的方法合成实施例15C、15D
4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-(((1S,6'R,7a'R)-2,2,6'-三氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇和4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟 -2-(((1R,6'R,7a'R)-2,2,6'-三氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
实施例15C
LCMS:m/z 663(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),9.05(s,1H),7.98(dd,J＝5.92,9.28Hz,1H),7.48(t,J＝8.96Hz,1H),7.40(d,J＝2.52Hz,1H),7.19(d,J＝2.52Hz,1H),5.45(m,0.5H),5.32(m,0.5H),4.48(d,J＝11.56Hz,1H),4.30(m,3H),3.96(d,J＝2.88Hz,1H),3.59(m,4H),3.31(m,2H),3.01(m,2H),2.16(m,5H),1.69(s,4H),1.54(m,2H)。
实施例15D
LCMS:m/z 663(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),9.04(s,1H),7.98(dd,J＝6.00,9.28Hz,1H),7.48(t,J＝9.04Hz,1H),7.40(d,J＝2.44Hz,1H),7.19(m,1H),5.51(m,0.5H),5.37(m,0.5H),4.50(m,1H),4.30(m,1H),4.16(m,1H),3.98(m,2H),3.61(m,4H),3.28(m,1H),3.07(m,1H),2.79(m,1H),2.21(m,5H),1.59(s,6H)。
以中间体1-16E和1-16F按照实施例1的方法合成实施例15E、15F
4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-(((1S,6'S,7a'S)-2,2,6'-三氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇和4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-(((1R,6'S,7a'S)-2,2,6'-三氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
实施例15E
LCMS:m/z 663(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.15(s,1H)，9.05(s,1H)，7.97(dd,J＝5.92,9.16Hz,1H)，7.46(t,J＝9.00Hz,1H)，7.39(d,J＝2.52Hz,1H)，7.17(d,J＝2.52Hz,1H)，5.44(m,0.5H)，5.30(m,0.5H)，4.48(d,J＝11.72Hz,1H)，4.30(m,3H)，3.93(d,J＝2.84Hz,1H)，3.61(m,4H)，3.16(m,2H)，2.77(m,2H)，2.14(m,5H)，1.61(s,6H)。
实施例15F
LCMS:m/z 663(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.16(s,1H)，9.04(s,1H)，7.97(dd,J＝5.92,9.16Hz,1H)，7.46(t,J＝8.96Hz,1H)，7.39(d,J＝2.60Hz,1H)，7.18(m,1H)， 5.50(m,0.5H)，5.36(m,0.5H)，4.50(m,1H)，4.29(m,1H)，4.14(m,1H)，4.01(m,1H)，3.94(s,1H)，3.60(m,4H)，3.28(m,1H)，3.03(m,2H)，2.78(m,1H)，2.16(m,5H)，1.65(s,6H)。
以中间体1-16G和1-16H按照实施例1的方法合成实施例15G、15H：
4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-(((1S,6'S,7a'R)-2,2,6'-三氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇和4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-(((1R,6'S,7a'R)-2,2,6'-三氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
实施例15G
LCMS:m/z 663(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.17(s,1H)，9.04(s,1H)，7.97(dd,J＝5.96,9.20Hz,1H)，7.46(t,J＝9.00Hz,1H)，7.39(d,J＝2.56Hz,1H)，7.17(m,1H)，5.42(m,0.5H)，5.28(m,0.5H)，4.49(m,1H)，4.29(m,1H)，4.04(m,2H)，3.93(m,1H)，3.62(m,4H)，3.09(m,4H)，2.11(m,5H)，1.56(s,6H)。
实施例15H
LCMS:m/z 663(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.01(s,1H)，7.66(m,1H)，7.21(m,1H)，7.01(m,2H)，5.34(m,0.5H)，5.20(m,0.5H)，4.28(m,4H)，3.75(m,1H)，3.58(m,3H)，3.17(m,3H)，2.99(m,2H)，2.19(m,5H)，1.56(s,6H)。
以中间体1-11A和1-11B为起始原料，按照实施例1的方法合成了以下实施例：
实施例16A和16B 4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((顺式)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇及4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((反式)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
实施例16A 4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((顺式)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LCMS:m/z 645(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),9.03(s,1H),7.99-7.95(m,1H),7.46(t,J＝8Hz,1H),7.39(s,1H),7.18(t,J＝4Hz,1H),4.49(t,J＝12Hz,1H),4.31(t,J＝12Hz,1H),4.09(d,J＝12Hz,1H),3.98(d,J＝4Hz,1H),3.95-3.93(m,1H),3.65(t,J＝8Hz,1H),3.59-3.56(m,3H),3.06(d,J＝12Hz,1H),3.00-2.95(m,1H),2.80-2.76(m,1H),2.71-2.65(m,1H),2.14-2.10(m,1H),1.96-1.87(m,3H),1.84-1.75(m,2H),1.66(s,4H),1.56-1.51(m,2H)。
实施例16B 4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((反式)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LCMS:m/z 645(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.04(s,1H),7.99-7.95(m,1H),7.46(t,J＝8Hz,1H),7.39(s,1H),7.18(d,J＝4Hz,1H),4.49(t,J＝12Hz,1H),4.33(d,J＝12Hz,1H),4.22-4.15(m,2H),3.92(s,1H),3.95-3.93(m,1H),3.65(d,J＝12Hz,1H),3.58-3.56(m,3H),3.12-3.08(m,1H),3.04-3.00(m,1H),2.73(d,J＝12Hz,1H),2.56-2.54(m,1H),2.10-2.05(m,1H),2.01-1.97(m,1H),1.92(d,J＝16Hz,1H),1.84-1.75(m,2H),1.66-1.44(m,7H)。
实施例16B经手性HPLC(SFC-150(Waters)，柱:IG 20*250mm,10um(Daicel)，柱温:35℃，流动相:CO2/EtOH[0.5％NH3(7M in MeOH)]＝120/40)拆分得到异构体实施例16B-1和实施例16B-2。
实施例16B-1 4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
RT：15.079min。LCMS:m/z 645(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),7.93-7.89(m,1H),7.41(d,J＝8Hz,1H),7.32(s,1H),7.17(s,1H),4.49(d,J＝12Hz,1H),4.35(d,J＝12Hz,1H),4.20-4.16(m,2H),3.89(s,1H),3.64-3.55(m,5H),3.13-3.09(m,1H),3.05-3.00(m,1H),2.74(d,J＝12Hz,1H),2.57-2.55(m,1H),2.11-2.06(m,1H),2.02-1.98(m,1H),1.92(d,J＝12Hz,1H),1.84-1.75(m,3H),1.66-1.47(m,8H)。
实施例16B-2 4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((1R,7a'R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
RT：20.572min。LCMS:m/z 645(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),7.95-7.99(m,1H),7.46(t,J＝8Hz,1H),7.39(s,1H),7.18(s,1H),4.49(d,J＝12Hz,1H),4.35(d,J＝12Hz,1H),4.20-4.18(m,2H),392(s,1H),3.65-3.56(m,5H),3.13-3.09(m,1H),3.05-3.00(m,1H),2.74(d,J＝12Hz,1H),2.57-2.55(m,1H),2.11-2.06(m,1H),2.02-1.98(m,1H),1.92(d,J＝12Hz,1H),1.84-1.74(m,3H),1.67-1.45(m,8H)。
以中间体1-11A为起始原料，按照实施例1的方法合成了以下实施例：
实施例17：4-(4-(1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-2-(((反式)-2,2-二氟二氢-1'H,3'H-螺环[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]并嘧啶-7-基)-5-乙基-6-氟萘-2-醇
LCMS:m/z 649(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),9.10(s,1H),7.77(q,J＝4Hz,1H),7.38(d,J＝8Hz,1H),7.34(d,J＝4Hz,1H),7.03(d,J＝4Hz,1H),4.44(d,J＝12Hz,2H),4.26-4.17(m,2H),3.62(t,J＝12Hz,2H),3.55(s,2H),3.13(q,J＝8Hz,1H),3.04-2.99(m,1H),2.74(d,J＝12Hz,1H),2.57-2.55(m,1H),2.39-2.34(m,1H),2.15(t,J＝8Hz,1H),2.12-2.06(m,1H),2.02-1.98(m,1H),1.92(d,J＝12Hz,1H),1.80-1.73(m,2H),1.63-1.44(m,7H),7.38(t,J＝8Hz,3H)。
经手性HPLC拆分得到两个异构体：
实施例17A：4-(4-(1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺环[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]并嘧啶-7-基)-5-乙基-6-氟萘-2-醇
RT：14.093min(U3000(ThermoFisher)；柱:CHIRALPAK IF-3 4.6mm*150mm,3um；柱温:40℃；流动相:正己烷：乙醇-二乙胺＝85/15-0.1％)。LCMS:m/z 649(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.11(s,1H),7.77(q,J＝4Hz,1H),7.38(d,J＝8Hz,1H),7.34(s,1H),7.04(d,J＝4Hz,1H),4.44(d,J＝12Hz,2H),4.26-4.17(m,2H),3.65-3.56(m,4H),3.13(q,J＝8Hz,1H),3.04-2.99(m,1H),2.74(d,J＝12Hz,1H),2.57-2.54(m,1H),2.39-2.34(m, 1H),2.17-2.00(m,2H),2.00-1.98(m,1H),1.92(d,J＝12Hz,1H),1.82-1.44(m,10H),0.73(t,J＝8Hz,3H)。
实施例17B：4-(4-(1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-2-(((1R,7a'R)-2,2-二氟二氢-1'H,3'H-螺环[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]并嘧啶-7-基)-5-乙基-6-氟萘-2-醇
RT：14.840min(U3000(ThermoFisher)；柱:CHIRALPAK IF-3 4.6mm*150mm,3um；柱温:40℃；流动相:正己烷：乙醇-二乙胺＝85/15-0.1％)。LCMS:m/z 649(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),9.11(s,1H),7.77(q,J＝4Hz,1H),7.38(d,J＝8Hz,1H),7.34(s,1H),7.03(d,J＝4Hz,1H),4.45(d,J＝16Hz,2H),4.26-4.17(m,2H),3.65-3.55(m,4H),3.13(q,J＝8Hz,1H),3.04-2.99(m,1H),2.74(d,J＝12Hz,1H),2.57-2.54(m,1H),2.39-2.34(m,1H),2.17-2.00(m,2H),2.00-1.98(m,1H),1.92(d,J＝12Hz,1H),1.80-1.44(m,10H),0.73(t,J＝8Hz,3H)。
实施例18：6-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((反式)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3d]嘧啶-7-基)-4-甲基-5-(三氟甲基)吡啶-2-胺
LCMS:m/z 635(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.01(s,1H),6.78(s,1H),4.36(d,J＝9.20Hz,1H),4.17(m,2H),3.55(m,4H),3.09(m,1H),2.99(m,1H),2.70(m,2H),2.54(m,1H),2.36(m,3H),2.05(m,1H),1.97(m,1H),1.99(m,1H),1.79(m,2H),1.56(m,7H)。
实施例19：6-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((反式)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3d]嘧啶-7-基)-4-甲基-5-(五氟乙基)吡啶-2-胺
LCMS:m/z 685(M+H)+.
以中间体1-11A-1为起始原料，按照实施例1的方法合成了以下实施例：
实施例20：4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(1-甲基-3,8-二氮杂双环[3.2.1]辛-3-基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘酚-2-醇
LCMS:m/z 659(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.20(br,1H),9.06(s,1H),7.98(dd,J＝5.88Hz,J＝9.20Hz,1H),7.48(t,J＝9.00Hz,1H),7.40(d,J＝2.64Hz,1H),7.19(s,1H),4.30(m,4H),3.94(s,1H),3.58(m,2H),3.11(m,1H),3.02(m,1H),2.71(d,J＝11.96Hz,1H),2.55(m,1H),2.06(m,2H),1.71(m,10H),1.25(m,5H)。
经手性拆分(SFC-150(Waters)；柱:OD 20*250mm,10um(Daicel))得到异构体20A和20B：4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-((1S,5R)-1-甲基-3,8-二氮杂双环[3.2.1]辛-3-基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘酚-2-醇和4-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-((1R,5S)-1-甲基-3,8-二氮杂双环[3.2.1]辛-3-基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘酚-2-醇
异构体20A
RT:0.905min。LCMS:m/z 659(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),9.07(s,1H),8.01-7.97(m,1H),7.48(t,J＝8Hz,1H),7.40(d,J＝4Hz,1H),7.19(s,1H),4.44(t,J＝12Hz,1H),4.35-4.15(m,3H),3.94(s,1H),3.60-3.57(m,2H),3.38(s,1H),3.13-3.09(m,1H),3.05-3.00(m,1H),2.74(d,J＝12Hz,1H),2.57-2.55(m,1H),2.11-1.99(m,2H),1.93(d,J＝16Hz,1H),1.84-1.46(m,9H),1.38-1.32(m,1H),1.26(s,3H)。
异构体20B
RT:1.419min。LCMS:m/z 659(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),9.07(s,1H),8.01-7.97(m,1H),7.48(t,J＝8Hz,1H),7.40(d,J＝4Hz,1H),7.20(s,1H),4.49-4.35(m,2H),4.31(d,J＝12Hz,1H),4.20(s,2H),3.95(s,1H),3.64-3.56(m,2H),3.43(d,J＝16Hz,1H),3.13-3.09(m,1H),3.04-3.00(m,1H),2.74(d,J＝12Hz,1H),2.57-2.55(m,1H), 2.11-2.07(m,1H),2.02-1.99(m,1H),1.82-1.35(m,10H),1.29-1.24(m,3H)。
实施例21：(1S,7a'S)-7a'-(((4-(1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟萘酚-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]
LC-MS：m/z 609(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.25(d,J＝8Hz,1H),8.22(d,J＝8Hz,1H),7.79-7.60(m,3H),4.51(d,J＝12Hz,1H),4.38(d,J＝12Hz,1H),4.24-4.19(m,2H),4.02(s,1H),3.67-3.62(m,4H),3.14-3.09(m,1H),3.05-3.00(m,1H),2.74(d,J＝12Hz,1H),2.57-2.55(m,1H),2.11-2.06(m,1H),2.02-1.90(m,2H),1.82-1.45(m,9H)。
实施例22：(1S,7a'S)-7a'-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-7-(6-氟-5-甲基-1H-吲唑-4-基)吡啶[4,3-d]嘧啶-2-基)氧基)甲基)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]
LC-MS：m/z 609(M+H)+。1H NMR(400MHz,DMSO-d6)δ13.21(s,1H),9.20(s,1H),7.74(s,1H),7.50(d,J＝8Hz,1H),4.47(s,2H),4.25-4.19(m,2H),3.64-3.58(m,3H),3.14(q,J＝7Hz,J＝5Hz,1H),3.05-3.00(m,1H),2.74(d,J＝12Hz,1H),2.57-2.55(m,4H),2.19(s,2H),2.12-1.45(m,8H)。
实施例23：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-7-氟苯并[d]噻唑-2-胺
LC-MS：m/z 627(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.08(s,1H),7.91(s,1H),7.42(dd,J＝5.80,8.48Hz,1H),7.07(t,J＝8.88Hz,1H),4.38(d,J＝12.12Hz,2H),4.19(m,2H),3.57(m,4H),3.09(m,1H),3.01(m,1H),2.70(d,J＝11.84Hz,1H),2.54(m,1H),2.08(m,1H),1.98(m,1H),1.88(d,J＝13.32Hz,1H),1.63(m,9H)。
实施例24：4-(4-((1R,5S)-二氮杂二环[3.2.1]辛烷-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-2-氨基-7-氟苯[b]噻吩-3-甲腈
LC-MS：m/z 651(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.10(s,2H),7.44-7.40(m,1H),7.15(t,J＝8Hz,1H),4.43(d,J＝12Hz,2H),4.23-4.17(m,2H),3.63(d,J＝12Hz,2H),3.53(s,2H),3.13-3.09(m,1H),3.05-3.00(m,1H),2.74(d,J＝12Hz,1H),2.57-2.55(m,1H),2.12-2.07(m,1H),2.03-1.97(m,1H),1.92-1.89(m,2H),1.86-1.71(m,2H),1.64-1.44(m,7H)。
实施例25：2-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-4,6-二氯-3-氟苯胺
LC-MS：m/z 638(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),9.59(s,1H),9.36(s,1H),9.25(s,1H),7.71(d,J＝7.56Hz,1H),5.76(s,2H),4.67(m,4H),4.21(m,2H),3.64(m,2H),3.13(m,1H),2.47(m,1H),2.28(m,4H),1.88(m,9H)。
实施例26：3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-2-氟-5-甲基-4-(三氟甲基)苯胺
LC-MS：m/z 652(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),7.31(d,J＝11.76Hz,1H),5.86(s,1H),4.42(d,J＝11.40Hz,2H),4.19(d,J＝3.24Hz,2H),3.61(m,4H),3.11(m,1H),3.02(m,1H),2.71(d,J＝11.84Hz,1H),2.55(m,1H),2.17(s,3H),2.09(m,1H),2.00(m,1H),1.88(d,J＝13.32Hz,1H),1.64(m,10H)。
实施例27：3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢 -1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯胺
LC-MS：m/z 654(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),6.89(s,1H),6.48(s,1H),6.34(s,1H),4.39(d,J＝12.08Hz,2H),4.20(m,2H),3.59(m,4H),3.10(m,1H),3.02(m,1H),2.71(d,J＝11.88Hz,1H),2.56(m,1H),2.07(m,1H),1.99(m,1H),1.88(d,J＝13.32Hz,1H),1.62(m,10H)。
实施例28：4-(4-(3,9-二氮杂双环[4.2.1]壬-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LC-MS：m/z 659(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),9.09(d,J＝16Hz,1H),8.00-7.95(m,1H),7.47(t,J＝8Hz,1H),7.40(s,1H),7.22-7.19(m,1H),4.71(d,J＝12Hz,1H),4.42(d,J＝12Hz,1H),4.25-4.15(m,2H),4.09-3.99(m,2H),3.92-3.82(m,2H),3.73-3.67(m,2H),3.13-3.08(m,1H),3.04-3.00(m,1H),2.74(d,J＝12Hz,1H),2.57-2.55(m,1H),2.11-1.95(m,3H),1.92-1.89(m,3H),1.84-1.72(m,3H),1.65-1.45(m,5H)。
实施例29：4-(4-(3-氨基-3-甲基哌啶-1-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LC-MS：m/z 647(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.16(s,2H),9.25(d,J＝56Hz,1H),7.99-7.96(m,1H),7.46(t,J＝8Hz,1H),7.40(d,J＝4Hz,1H),7.22-7.20(m,1H),4.24-4.16(m,2H),4.10(m,1H),4.03-4.00(d,J＝12Hz,1H),3.95(s,1H),3.89(d,J＝12Hz,1H),3.73-3.65(m,1H),3.60-3.47(m,2H),3.13-2.99(m,2H),2.73(d,J＝12Hz,1H),2.56-2.54 (m,1H),2.10-2.05(m,1H),2.02-1.97(m,2H),1.92(s,1H),1.89(s,1H),1.83-1.74(m,3H),1.64-1.44(m,5H),1.10(d,J＝4Hz,3H)。
实施例30 3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-甲氧基吡啶[4,3-d]嘧啶-7-基)-2-氟-5-甲基-4-(三氟甲基)苯胺
LC-MS：m/z 664(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.96(s,1H)，7.18(d,J＝11.68Hz,1H)，5.67(s,2H)，4.35(d,J＝12.40Hz,2H)，4.20(m,2H)，3.85(s,3H)，3.53(m,4H)，3.11(m,1H)，3.02(m,1H)，2.71(m,1H)，1.73(m,17H)。
实施例31：3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-甲氧基吡啶[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯胺
LC-MS：m/z 666(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.92(s,1H)，6.82(d,J＝2.24Hz,1H)，6.36(d,J＝2.28Hz,1H)，6.19(s,2H)，4.36(m,2H)，4.20(m,2H)，3.89(s,3H)，3.57(m,4H)，3.09(m,1H)，3.00(m,1H)，2.70(m,1H)，2.55(m,1H)，1.64(m,13H)。
实施例32：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-2-氨基-6-氟苯并[b]噻吩-3-甲腈
LC-MS：m/z 651(M+H)+。1H NMR(400MHz,DMSO-d6)δδ9.07(s,1H),7.82-7.80(m,2H),7.28-7.25(m,1H),4.42(d,J＝12Hz,2H),4.22-4.16(m,2H),3.62(d,J＝12Hz,2H),3.51(s,2H),3.12-3.08(m,1H),3.04-2.99(m,1H),2.73(d,J＝12Hz,1H),2.56-2.54(m,1H), 2.11-2.06(m,1H),2.02-1.96(m,1H),1.91-1.71(m,4H),1.63-1.45(m,7H)。
实施例33：(1S,7a'S)-7a'-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-7-(5-(三氟甲基)-1H-吲唑-4-基)吡啶[4,3-d]嘧啶-2-基)氧)甲基)-2,2-二氟四氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]
LC-MS：m/z 645(M+H)+。1H NMR(400MHz,DMSO-d6)δ13.71(s,1H),9.17(s,1H),7.86(m,3H)，4.46(m,2H)，4.21(m,2H)，3.63(m,4H)，3.10(m,1H)，3.02(m,1H)，2.71(m,1H)，2.55(m,1H)，2.08(m,1H)，2.00(m,1H)，1.89(m,1H)，1.67(m,10H)。
实施例34：3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-氯-2-氟-4-(三氟甲基)苯胺
LC-MS：m/z 672(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),7.09(d,J＝7.92Hz,1H),6.48(s,2H),4.39(m,2H),4.20(m,2H),3.61(m,4H),3.10(m,1H),3.00(m,1H),2.70(m,1H),2.54(m,1H),2.06(m,1H),1.99(m,1H),1.88(m,1H),1.64(m,10H)。
实施例35：3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-2,5-二氯-4-(三氟甲基)苯胺
LC-MS：m/z 688(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.12(s,1H),7.15(s,1H),6.64(s,2H),4.39(m,2H),4.20(m,2H),3.59(m,4H),3.10(m,1H),3.00(m,1H),2.70(m,1H),2.54(m,1H),2.06(m,1H),1.97(m,1H),1.88(m,1H),1.64(m,10H)。
实施例36：3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-2- 氯-5-氟-4-(三氟甲基)苯胺
LC-MS：m/z 672(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),6.86(d,J＝13.68Hz,1H),6.68(s,2H),4.38(d,J＝12.32Hz,2H),4.19(m,2H),3.58(m,4H),3.10(m,1H),3.00(m,1H),2.71(m,1H),2.53(m,1H),2.07(m,1H),2.00(m,1H),1.89(m,1H),1.65(m,10H)。
实施例37：3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-2,4-二氯-5-氟苯胺
LC-MS：m/z 638(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),6.94(d,J＝12Hz,1H),6.05(s,2H),4.49(d,J＝12Hz,2H),4.25-4.18(m,2H),3.78(s,2H),3.71(d,J＝16Hz,2H),3.12-3.08(m,1H),3.04-2.99(m,1H),2.74(d,J＝12Hz,1H),2.57-2.55(m,1H),2.10-2.05(m,1H),2.02-1.95(m,1H),1.92(d,J＝16Hz,1H),1.84-1.70(m,6H),1.65-1.44(m,4H)。
实施例38：N-(3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯基)乙酰胺
LC-MS：m/z 696(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.50(s,1H),9.09(s,1H),8.03(s,1H),7.70(s,1H),4.43-4.40(m,2H),4.22-4.15(m,2H),3.58(m,4H),3.12-3.07(m,1H),3.03-2.98(m,1H),2.73(d,J＝12Hz,1H),2.55-2.53(m,1H),2.10(s,3H),2.08-1.95(m,2H),1.91-1.70(m,3H),1.63-1.44(m,8H)。
实施例39：N-(3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯基)甲磺酰胺
LC-MS：m/z 732(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.03(s,1H),7.33(s,1H),6.99(s,1H),4.51(t,J＝12Hz,2H),4.25-4.19(m,2H),3.85(s,2H),3.75-3.65(m,2H),3.14-3.09(m,1H),3.05-3.01(m,1H),2.99(s,3H),2.75(d,J＝12Hz,1H),2.58-2.55(m,1H),2.11-2.05(m,1H),2.03-1.97(m,1H),1.92(d,J＝12Hz,1H),1.83-1.78(m,6H),1.65-1.45(m,4H)。
实施例40：3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基))-5-氯-4-(三氟甲基)苯酚
LC-MS：m/z 655(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.08(s,1H),7.20(d,J＝2.44Hz,1H),6.80(d,J＝2.40Hz,1H),4.40(d,J＝12.04Hz,2H),4.20(m,2H),3.59(m,4H),3.10(m,1H),3.01(m,1H),2.71(m,1H),2.55(m,1H),2.07(m,1H),1.99(m,1H),1.87(m,1H),1.64(m,10H)。
实施例41：5-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-3-氯-2-氟-4-(三氟甲基)苯胺
LC-MS：m/z 672(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),6.69(d,J＝8.28Hz,1H),6.49(s,2H),4.38(d,J＝12.44Hz,2H),4.18(m,2H),3.57(m,4H),3.09(m,1H),3.00(m,1H),2.70(m,1H),2.53(m,1H),2.06(m,1H),1.99(m,1H),1.87(m,1H),1.61(m,10H)。
实施例42：5-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-2-氟-3-甲基-4-(三氟甲基)苯胺
LC-MS：m/z 652(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),6.57(d,J＝8Hz,1H),6.02(s,2H),4.43(d,J＝12Hz,2H),4.21-4.15(m,2H),3.62-3.59(m,4H),3.12-3.07(m,1H),3.03-2.98(m,1H),2.73(d,J＝12Hz,1H),2.56-2.54(m,1H),2.34(s,3H),2.09-2.04(m,1H),2.01-1.95(m,1H),1.91(d,J＝16Hz,1H),1.83-1.70(m,3H),1.65-1.44(m,7H).
实施例43：3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-氨基-2-(三氟甲基)苯腈
LC-MS：m/z 645(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),7.22(d,J＝2.40Hz,1H),6.83(d,J＝2.32Hz,1H),6.61(s,2H),4.39(m,2H),4.20(m,2H),3.58(m,4H),3.10(m,1H),3.00(m,1H),2.71(m,1H),2.55(m,1H),2.07(m,1H),2.00(m,1H),1.88(m,1H),1.64(m,10H)。
实施例44：3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-氟-4-(三氟甲基)苯胺
LC-MS：m/z 638(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),6.60(d,J＝16Hz,1H),6.39(d,J＝4Hz,3H),4.42(d,J＝12Hz,2H),4.22-4.16(m,2H),3.62(s,1H),3.59(s,3H),3.13-3.08(m,1H),3.04-2.99(m,1H),2.74(d,J＝12Hz,1H),2.57-2.54(m,1H),2.10-2.05(m,1H),2.02-1.95(m,1H),1.92(d,J＝16Hz,1H),1.83-1.71(m,3H),1.63-1.44(m,7H)。
实施例45：3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-4- 氯-5-(三氟甲基)苯胺
LC-MS：m/z 654(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),7.17(d,J＝4Hz,1H),6.91(d,J＝4Hz,1H),5.95(s,2H),4.44(d,J＝12Hz,2H),4.24-4.18(m,2H),3.62(s,1H),3.59(s,3H),3.13-3.08(m,1H),3.04-3.00(m,1H),2.74(d,J＝12Hz,1H),2.58-2.54(m,1H),2.11-2.05(m,1H),2.02-1.96(m,1H),1.92(d,J＝12Hz,1H),1.84-1.73(m,3H),1.67-1.45(m,7H)。
实施例46：3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-氯-4-氟苯胺
LC-MS：m/z 604(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.10(s,1H),6.85-6.82(m,1H),6.78-6.75(m,1H),5.47(s,2H),4.42(d,J＝12Hz,2H),4.23-4.17(m,2H),3.60(d,J＝12Hz,2H),3.53(s,2H),3.13-3.08(m,1H),3.04-3.00(m,1H),2.74(d,J＝12Hz,1H),2.57-2.55(m,1H),2.11-2.06(m,1H),2.02-1.97(m,1H),1.92(d,J＝12Hz,1H),1.85-1.71(m,3H),1.64-1.45(m,7H)。
实施例47：3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-4,5-二氯苯胺
LC-MS：m/z 620(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.08(s,1H),6.89(d,J＝2.60Hz,2H),6.65(d,J＝2.68Hz,2H),5.74(s,2H),4.38(d,J＝11.84Hz,2H),4.18(m,2H),3.54(m,4H),3.10(m,1H),3.00(m,1H),2.70(m,1H),2.53(m,1H),2.06(m,1H),1.98(m,1H),1.87(m,1H),1.58(m,10H)。
实施例48：3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5- 氨基-2-氯苯腈
LC-MS：m/z 611(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),7.13(d,J＝2.72Hz,1H),7.01(d,J＝2.76Hz,1H),6.01(s,2H),4.40(d,J＝12.00Hz,2H),4.20(m,2H),3.60(m,4H),3.10(m,1H),3.01(m,1H),2.70(m,1H),2.54(m,1H),2.09(m,1H),1.99(m,1H),1.88(m,1H),1.61(m,10H)。
实施例49：2-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-4-氨基-6-氯苯腈
LC-MS：m/z 611(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),6.86(d,J＝4Hz,1H),6.79(d,J＝4Hz,1H),6.71(s,2H),4.42(d,J＝12Hz,2H),4.23-4.17(m,2H),3.62(d,J＝12Hz,1H),3.55(s,3H),3.12-3.07(m,1H),3.03-2.99(m,1H),2.73(d,J＝12Hz,1H),2.56-2.54(m,1H),2.10-2.05(m,1H),2.02-1.96(m,1H),1.91(d,J＝12Hz,1H),1.83-1.70(m,3H),1.65-1.44(m,7H)。
实施例50：2-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-4-氨基-6-(三氟甲基)苯腈
LC-MS：m/z 645(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.14(s,1H),7.17(d,J＝4Hz,1H),7.02(d,J＝4Hz,1H),6.95(s,2H),4.45(d,J＝12Hz,2H),4.25-4.19(m,2H),3.65(s,1H),3.62(s,3H),3.13-3.09(m,1H),3.05-3.00(m,1H),2.74(d,J＝12Hz,1H),2.57-2.55(m,1H),2.13-2.05(m,1H),2.03-1.97(m,1H),1.92(d,J＝12Hz,1H),1.83-1.76(m,3H),1.65-1.45(m,7H)。
实施例51：2-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-6- 氨基-3-氯苯腈
LC-MS：m/z 611(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.17(s,1H),7.51(d,J＝9.04Hz,1H),6.95(d,J＝9.04Hz,1H),6.45(s,2H),4.50(m,1H),4.34(m,1H),4.20(m,2H),3.64(m,4H),3.09(m,1H),3.01(m,1H),2.70(m,1H),2.56(m,1H),2.07(m,1H),1.99(m,1H),1.91(m,1H),1.67(m,10H)。
实施例52：5-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-6-(三氟甲基)吡啶-3-胺
LC-MS：m/z 621(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.13(d,J＝4Hz,1H),6.97(d,J＝4Hz,1H),6.31(s,2H),4.51(d,J＝12Hz,2H),4.25-4.19(m,2H),3.83(s,2H),3.73(d,J＝12Hz,2H),3.13-3.09(m,1H),3.04-3.00(m,1H),2.75(d,J＝12Hz,1H),2.58-2.55(m,1H),2.11-2.06(m,1H),2.02-1.96(m,1H),1.93(d,J＝12Hz,1H),1.84-1.74(m,3H),1.65-1.45(m,7H)。
实施例53：5-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-4-(三氟甲基)吡啶-3-胺
LC-MS：m/z 621(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.38(s,1H),7.14(s,1H),6.24(s,2H),4.42(d,J＝12.24Hz,2H),4.19(m,2H),3.62(m,4H),3.10(m,1H),3.01(m,1H),2.71(m,1H),2.55(m,1H),2.07(m,1H),1.98(m,1H),1.89(m,1H),1.64(m,10H)。
实施例54：5-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-4-甲基-6-(三氟甲基)吡啶-3-胺
LC-MS：m/z 635(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.10(s,1H),6.06(s,2H),4.41(d,J＝12Hz,2H),4.23-4.15(m,2H),3.63(d,J＝12Hz,1H),3.57(s,3H),3.12-3.07(m,1H),3.03-2.98(m,1H),2.73(d,J＝12Hz,1H),2.56-2.54(m,1H),2.09-2.05(m,1H),2.01-1.95(m,1H),1.91(d,J＝12Hz,1H),1.83-1.76(m,6H),1.64-1.43(m,7H)。
实施例55：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-6-甲基-5-(三氟甲基)吡啶-2-胺
LC-MS：m/z 635(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.10(s,1H),6.69(s,2H),6.26(s,1H),4.51(d,J＝13.00Hz,2H),4.21(m,2H),3.94(m,2H),3.79(d,J＝13.16Hz,2H),3.10(m,1H),3.03(m,1H),2.72(m,1H),2.54(m,1H),2.49(m,3H),2.08(m,1H),1.99(m,1H),1.89(m,1H),1.65(m,10H)。
实施例56：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-2-氯-3-(三氟甲基)苯胺
LC-MS：m/z 654(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.12(s,1H),7.47(d,J＝8Hz,1H),7.14(d,J＝8Hz,1H),6.09(s,2H),4.48(d,J＝12Hz,2H),4.24-4.19(m,2H),3.69-3.65(m,4H),3.13-3.08(m,1H),3.04-2.99(m,1H),2.74(d,J＝12Hz,1H),2.57-2.54(m,1H),2.12-2.05(m,1H),2.01-1.97(m,1H),1.92(d,J＝16Hz,1H),1.83-1.44(m,10H).
以中间体D-1-11A-1为起始原料，按照实施例1的方法合成了以下实施例：
实施例D01：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基-5',5'-d2)甲氧基-d2)-8-氟吡啶 [4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LC-MS：m/z 649(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.15(s,1H)，9.05(s,1H)，7.98(dd,J＝5.92,9.24Hz,1H)，7.47(t,J＝9.04Hz,1H)，7.40(d,J＝2.60Hz,1H)，7.18(d,J＝2.64Hz,1H)，4.47(d,J＝12.36Hz,1H)，4.31(m,1H)，3.94(s,1H)，3.63(m,4H)，3.29(m,1H)，3.10(m,1H)，2.71(d,J＝11.72Hz,1H)，2.07(m,1H)，1.99(m,1H)，1.89(m,1H)，1.67(m,1H)。
以中间体D-1-11A-2为起始原料，按照实施例1的方法合成了以下实施例：
实施例D02：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基-5',5'-d2)甲氧基-d2)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LC-MS：m/z 649(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.15(s,1H)，9.05(s,1H)，7.98(dd,J＝5.96,9.20Hz,1H)，7.47(t,J＝9.04Hz,1H)，7.40(d,J＝2.60Hz,1H)，7.18(d,J＝2.56Hz,1H)，4.47(d,J＝12.20Hz,1H)，4.32(m,1H)，3.94(s,1H)，3.63(m,4H)，3.29(m,1H)，3.10(m,1H)，2.71(d,J＝11.72Hz,1H)，2.07(m,1H)，1.99(m,1H)，1.89(m,1H)，1.67(m,1H)。
以中间体D‐1‐11A‐1为起始原料，按照实施例1的方法合成了以下实施例：实施例D03：3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基-d2)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯胺
LC-MS：m/z 658(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),6.90(d,J＝4Hz,1H),6.48(d,J＝4Hz,1H),6.34(s,2H),4.46(d,J＝12Hz,2H),3.69-3.63(m,4H),3.13-3.08(m,1H),2.74(d,J＝12Hz,1H),2.10-2.05(m,1H),2.02-1.95(m,1H),1.92(d,J＝16Hz,1H),1.84-1.73(m,3H),1.69-1.45(m,7H).
以中间体1-17为起始原料，按照实施例1的方法合成了以下实施例：
实施例E01：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((1-甲基四氢-1H-螺[环戊烷[b]吡咯-2,1'-环丙烷]-3a(3H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LC-MS：m/z 623(M+H)+。
实施例P01：((1R,5S)-3-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-基)甲基异丁酸酯三氟乙酸盐的制备
将实施例16B-1(100mg,0.155mmol)溶于THF(5mL)中,依次加入2,6-二甲基吡啶(83mg,0.775mmol)和异丁酸碘甲酯(189mg,0.775mmol)。加完后室温搅拌16h,随后加入乙腈溶清后直接用制备HPLC分离得到目标产物(28mg)。
LC-MS：m/z 745(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),9.45(d,J＝9.64Hz,1H),9.19(m,2H),8.00(dd,J＝5.96,9.20Hz,1H),7.49(t,J＝9.04Hz,1H),7.43(d,J＝2.52Hz,1H),7.18(d,J＝2.60Hz,1H),5.59(m,2H),4.95(s,2H),4.72(m,1H),4.56(m,1H),4.25(s,2H),4.12(m,1H),3.88(m,5H),3.73(m,2H),2.70(m,2H),2.40(m,2H),2.22(m,3H),1.98(m,7H),1.15(m,6H)。
按照实施例P01同样方法合成以下化合物：
实施例P02：(1R,5S)-3-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-吡咯里嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸异丙酯
LC-MS：m/z 731(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),7.97(dd,J＝5.96,9.24Hz,1H),7.46(t,J＝9.04Hz,1H),7.39(d,J＝2.56Hz,1H),7.18(d,J＝2.48Hz,1H),4.87(m, 1H),4.56(m,1H),4.41(m,3H),4.20(m,2H),3.92(s,1H),3.64(m,2H),3.10(m,1H),3.01(m,1H),2.70(d,J＝11.84Hz,1H),2.54(m,1H),2.06(m,1H),1.99(m,1H),1.81(m,7H),1.61(m,3H),1.24(d,J＝6.48Hz,6H)。
实施例P03：((1R,5S)-3-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-吡咯里嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基异丙基碳酸酯
LC-MS：m/z 761(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),9.57(s,1H),9.29(s,1H),9.19(s,1H),8.01(t,J＝8Hz,1H),7.52-7.44(m,2H),7.19(s,1H),5.65-5.56(m,2H),4.95(s,2H),4.87-4.74(m,2H),4.60(d,J＝12Hz,1H),4.25(s,2H),4.18(d,J＝12Hz,1H),3.93-3.86(m,5H),3.77-3.74(m,2H),2.70-2.66(m,2H),2.60(s,1H),2.43-2.34(m,2H),2.25-2.18(m,3H),1.99-1.90(m,6H),1.25-1.24(m,6H)。
实施例P04和实施例P05：1-(异丁酰氧基)乙基(1R,5S)-3-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(((1-(异丁酰氧基)乙氧基)羰基)氧基)萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸酯和1-(异丁酰氧基)乙基(1R,5S)-3-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸酯的制备
第一步：1-(异丁酰氧基)乙基(1R,5S)-3-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(((1-(异丁酰氧基)乙氧基)羰基)氧基)萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸酯的制备
将实施例16B-1(100mg,0.155mmol)溶于DCM(4mL)中，加入DIPEA(100mg,0.775mmol)，加入1-(((4-硝基苯氧基)羰基)氧基)异丁酸乙酯(184mg,0.62mmol)，加完后室温搅拌16h。反应结束后，反应液浓缩干，加入乙腈溶清后直接用制备HPLC分离得到目标产物(65mg)。
LC-MS：m/z 961(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.25(dd,J＝5.92Hz,9.28Hz,1H),8.15(d,J＝2.52Hz,1H),7.68(t,J＝9.00Hz,1H),7.62(m,1H),6.75(m,2H),4.46(m,4H),4.20(m,2H),4.08(s,1H),3.68(m,2H),3.09(m,1H),3.00(m,1H),2.07(d,J＝11.84Hz,1H),2.61(m,3H),2.09(m,1H),1.99(m,1H),1.85(m,7H),1.57(m,9H),1.09(m,12H)。
第一步：1-(异丁酰氧基)乙基(1R,5S)-3-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸酯的制备
将实施例P04(105mg,0.109mmol)溶于乙腈(4mL)中，加入氨水(10滴)，加完后室温搅拌2h。反应结束后，反应液浓缩干，加入乙腈溶清后直接用制备HPLC分离得到目标产物(65mg)。
LC-MS：m/z 803(M+H)+。1H NMR(400MHz,DMSO-d6):10.16(s,1H)，9.06(s,1H),7.98(dd,J＝5.92,9.24Hz,1H),7.47(t,J＝9.00Hz,1H),7.40(d,J＝2.60Hz,1H),7.18(d,J＝2.52Hz,1H),6.74(m,1H),4.59(m,1H),4.39(m,3H),4.22(m,2H),3.93(s,1H),3.67(m,2H),3.11(m,2H),2.71(d,J＝11.84Hz,1H),2.55(m,1H),1.98(m,10H),1.56(m,6H),1.08(d,J＝7.16Hz,6H)。
按照实施例P05同样方法合成以下化合物：
实施例P06：1-(异丁酰氧基)乙基(1R,5S)-3-(7-(5-氨基-3-氯-2-(三氟甲基)苯基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺并[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸酯
LC-MS：m/z 812(M+H)+。1H NMR(400MHz,DMSO-d6):9.07(s,1H)，6.89(d,J＝2.20Hz,1H)，6.73(dd,J＝5.32Hz,J＝10.76Hz,1H)，6.47(d,J＝2.28Hz,1H)，6.35(s,2H)，4.53(m,2H)，4.36(m,2H)，4.23(m,2H)，3.67(m,2H)，3.10(m,1H)，3.01(m,1H)，2.71(m,1H)，2.55(m,1H)，2.09(m,1H)，1.98(m,1H)，1.65(m,14H)。
生物学测试例
以下生物学测试例进一步描述解释本发明，但这些实例并非意味着限制本发明的范围。
KRASGl2D结合抑制实验
实验步骤
采用TR-FRET技术检测化合物与KRASG12D蛋白的结合能力。将生物素标记的GDP负 载KRASG12D重组人蛋白与Cy5标记的示踪剂、铕标记链亲和素、化合物(2％DMSO终浓度)在缓冲液(HEPES(pH 7.5),MgCl2,Tween-20和DTT)中共孵育。22℃下孵育60min后，反应活性通过EnVision多功能酶标仪双波长技术进行检测，蛋白结合量(POC)采用ratiometric emission factor计算。
100POC表示不含有化合物；0POC表示对照化合物该浓度下完全抑制示踪剂与KRASG12D的结合。POC值采用四参数Logistic模型曲线拟合，IC50表示50POC浓度值。
结果表明，本发明实施例化合物对于KRASG12D显示出了很好的抑制活性。
ERK磷酸化抑制实验
实验步骤
在384孔板中种入KRASG12D突变细胞(如GP2D、AGS等)，37℃,5％CO2培养箱中培养过夜。
用Echo 500加入200nL稀释好的化合物，DMSO终浓度为0.5％，在37℃，5％CO2培养箱中培养1小时。加入hEGF作用10分钟。
移去培养基，加入细胞固定液，固定细胞
PBS洗1次，冷的100％甲醇孵育，
移去甲醇，加入PBS洗1次。
移去PBS,每孔加入Li-Cor封闭缓冲液，室温封闭1hr。
移去封闭液，每孔加入一抗混合液，4℃室温孵育过夜。
移去一抗混合液，加入PBST洗3次。
加入二抗混合液，室温避光孵育45min。
移去二抗混合液，加入PBST洗3次,最后吸出PBST,倒扣离心，1000rpm离心1min。
Odyssey CLx读数。测试结果如下表1和表2所示。
参照化合物MRTX1133结构如下：
表1 GP2D ERK磷酸化抑制实验结果
表2 AGS ERK磷酸化抑制实验结果

结果表明，本发明实施例化合物对于KRASG12D突变细胞ERK磷酸化显示出了很好的抑制活性。
化合物对KRAS G12D突变细胞增殖的抑制实验
实验步骤
1.细胞培养
(a)复苏细胞于T75细胞培养瓶中：
(b)当细胞融合度达到80-90％，对细胞进行传代。
2.细胞增殖检测
实验步骤
利用纳升移液系统将稀释好的待测化合物加入384孔细胞培养板中,设置复孔。阳性对照组加入等体积的培养基；阴性对照组加入等体积的DMSO，1000rpm室温离心1min。
将细胞接种到a)384培养板中，阴性对照组加入等量等体积细胞，阳性对照组仅加入等体积的培养基。1000rpm室温离心1min，最终化合物的DMSO终浓度为0.5％，放置于37℃，5％CO2恒温培养箱孵育7天。
加入20μL/well的3D至b)384孔细胞培养板中，避光320rpm震荡20min，避光室温孵育2hrs。
用Envision多功能酶标仪读取发光值。
3.数据分析
用下列公式来计算检测化合物的抑制率(Inhibition rate，IR)：IR(％)＝(1–(RLU化合物–RLU空白对照)/(RLU溶媒对照–RLU空白对照))*100％。在Excel中计算不同浓度化合物的抑制率，然后用GraphPad Prism软件作抑制曲线图和计算相关参数，包括最小抑制率，最大抑制率及IC50。实验结果如表3所示。
表3本发明中实施例化合物细胞增殖抑制活性


药代动力学测试评价
雄性ICR小鼠，体重22-24g，禁食过夜后，口服给予30mg/kg本发明化合物或对照化合物的溶液[10％DMSO+60％PEG400+30％水溶液]。分别在给于本发明化合物后0.25，0.5，1.0，2.0，4.0，6.0，8.0，12.0和24h采血，用LC/MS/MS测定血浆中本发明化合物或对照化合物的浓度。
表4血浆中的主要药代动力学参数
BLOQ:低于最低检测限；NA：未得到
由检测结果看出，本发明化合物具有良好的口服药代动力学特性。
药代动力学测试评价
雄性SD大鼠，体重220g左右，禁食过夜后，口服给予30mg/kg本发明化合物或对照化合物的溶液[10％DMSO+60％PEG400+30％水溶液]。分别在给于本发明化合物后0.25，0.5，1.0，2.0，4.0，6.0，8.0，12.0和24h采血，用LC/MS/MS测定血浆中本发明化合物或对照化合物的浓度。
由检测结果看出，本发明化合物具有良好的药代动力学特性。
抗肿瘤活性药效学测试评价(AsPC-1CDX肿瘤模型)
将100uL含5x106AsPC-1肿瘤细胞悬液皮下接种到裸鼠右后侧腹部。每天监测小鼠健康状况，当肿瘤生长至可触及时开始测量。肿瘤体积计算公式采用:0.5xLxW2，其中L、W分别代表肿瘤长、宽。肿瘤长至～200mm3，对小鼠进行随机分组。小鼠每天腹腔注射或者口服给予相应剂量化合物，同时对其一般状态进行监测。肿瘤每周测量3次，体重每周测量两次。
由检测结果看出，本发明化合物具有良好的抗肿瘤效果。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (16)

  1. 式(A0)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药：
    环C选自下组基团：
    Y选自：键、O、NH、N(C1-C3烷基)；
    Z为取代或未取代的C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
    W选自：取代或未取代的C3-C14环烷基、或者取代或未取代的4-14元饱和或不饱和的杂环基；其中，所述取代是指被一个或多个R取代；
    选自下组基团： 其中，X选自：N、CH、CD、CF、C(CN)；
    R1选自：-L1-Q-L2-L3；
    其中：
    L1选自：取代或未取代的C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
    Q选自：O、S、SO2、NH、或N(C1-C3烷基)；
    L2选自：无、或者取代或未取代的C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
    L3选自取代或未取代的下组基团：-C1-C6烷基、-C3-C6环烷基、-C4-C6杂环基、-C1-C6亚烷基(C3-C6环烷基)、-C1-C6亚烷基(C4-C6杂环基)、-C1-C6亚烷基(C1-C6烷氧基)、-C1-C6亚烷基(C3-C6环烷基氧基)、或-C1-C6亚烷基(C4-C6杂环基氧基)；其中，所述取代是指被一个或多个R取代；
    n为0、1、2、3、4、5或6的整数；限定条件是当W为单环或双环时，n不为0；
    R10选自取代或未取代的下组基团：C6-C14芳基、5-14元杂芳基；其中，所述取代是指被一个或多个Ra取代；
    R11各自独立地选自取代或未取代的下组基团：H、氘、卤素、氰基、酯基、胺基、酰胺基、砜基、脲基、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C3-C6环烷基、4-6元杂环基、C1-C6烷基氧基、C3-C6环烷基氧基、4-6元杂环基氧基；其中，所述取代是指被一 个或多个R取代；
    Ra各自独立地选自取代或未取代的下组基团：H、D、卤素、CN、NH2、OH、CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基)、SONH2、SO2NH2、NHSO2(C1-C6烷基)、NHSO2(C3-C6环烷基)、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C20环烷基、4-20元杂环基、C3-C20环烷基氧基、4-20元杂环基氧基；其中，所述取代是指被一个或多个R取代；
    m为0、1、2、3、4、5或6的整数；
    各R相同或不同，各自独立地选自：氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、(C3-C18环烷基)C1-C18烷基、(4-20元杂环基)C1-C18烷基、(C1-C18烷氧基)C1-C18烷基、(C3-C18环烷基氧基)C1-C18烷基、(4-20元杂环基氧基)C1-C18烷基、乙烯基、乙炔基、(C1-C6烷基)乙烯基、氘代(C1-C6烷基)乙烯基、卤代(C1-C6烷基)乙烯基、(C1-C6烷基)乙炔基、氘代(C1-C6烷基)乙炔基、卤代(C1-C6烷基)乙炔基、(C3-C14环烷基)乙炔基、(4-14元杂环基)乙炔基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、4-20元杂环基C(O)、C3-C20环烷基、4-20元杂环基、C6-C14芳基、5-14元杂芳基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基、砜基或脲基。
  2. 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(A)所示的结构：
    Y选自：键、O、NH、N(C1-C3烷基)；
    Z为取代或未取代的C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
    W选自：取代或未取代的C3-C14环烷基、或者取代或未取代的4-14元饱和或不饱和的杂环基；其中，所述取代是指被一个或多个R取代；
    选自下组基团： 其中，X选自：N、CH、CD、CF、C(CN)；
    R1选自：-L1-Q-L2-L3；
    其中：
    L1选自：取代或未取代的C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
    Q选自：O、S、SO2、NH、或N(C1-C3烷基)；
    L2选自：无、或者取代或未取代的C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
    L3选自取代或未取代的下组基团：-C1-C6烷基、-C3-C6环烷基、-C4-C6杂环基、-C1-C6亚烷基(C3-C6环烷基)、-C1-C6亚烷基(C4-C6杂环基)、-C1-C6亚烷基(C1-C6烷氧基)、-C1-C6亚烷基(C3-C6环烷基氧基)、或-C1-C6亚烷基(C4-C6杂环基氧基)；其中，所述取代是指被一个或多个R取代；
    n为0、1、2、3、4、5或6的整数；限定条件是当W为单环或双环时，n不为0；
    R10选自取代或未取代的下组基团：C6-C14芳基、5-14元杂芳基；其中，所述取代是指被一个或多个Ra取代；
    R11各自独立地选自取代或未取代的下组基团：H、氘、卤素、氰基、酯基、胺基、酰胺基、砜基、脲基、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C3-C6环烷基、4-6元杂环基、C1-C6烷基氧基、C3-C6环烷基氧基、4-6元杂环基氧基；
    Ra各自独立地选自取代或未取代的下组基团：H、D、卤素、CN、NH2、OH、CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基)、SONH2、SO2NH2、NHSO2(C1-C6烷基)、NHSO2(C3-C6环烷基)、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C20环烷基、4-20元杂环基、C3-C20环烷基氧基、4-20元杂环基氧基；其中，所述取代是指被一个或多个R取代；
    m为0、1、2、3、4、5或6的整数；
    各R相同或不同，各自独立地选自：氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、(C3-C18环烷基)C1-C18烷基、(4-20元杂环基)C1-C18烷基、(C1-C18烷氧基)C1-C18烷基、(C3-C18环烷基氧基)C1-C18烷基、(4-20元杂环基氧基)C1-C18烷基、乙烯基、乙炔基、(C1-C6烷基)乙烯基、氘代(C1-C6烷基)乙烯基、卤代(C1-C6烷基)乙烯基、(C1-C6烷基)乙炔基、氘代(C1-C6烷基)乙炔基、卤代(C1-C6烷基)乙炔基、(C3-C14环烷基)乙炔基、(4-14元杂环基)乙炔基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、4-20元杂环基C(O)、C3-C20环烷基、4-20元杂环基、C6-C14芳基、5-14元杂芳基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基、砜基或脲基。
  3. 如权利要求1-2中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(IA)或式(IB)所示的结构：
    式中，
    U选自：N、CH、CD、CF；
    U’选自：O、或S；
    U”选自：N、或C(CN)；
    X选自：N、CH、CD、CF、C(CN)；
    Y选自：键、O、NH、N(C1-C3烷基)；
    Z为取代或未取代的C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
    W选自：取代或未取代的C3-C14环烷基、或者取代或未取代的4-14元饱和或不饱和的杂环基；其中，所述取代是指被一个或多个R取代；
    R1选自：-L1-Q-L2-L3；其中：
    L1选自：取代或未取代的C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
    Q选自：O、S、SO2、NH、或N(C1-C3烷基)；
    L2选自：无、或者取代或未取代的C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
    L3选自取代或未取代的下组基团：-C1-C6烷基、-C3-C6环烷基、-C4-C6杂环基、-C1-C6亚烷基(C3-C6环烷基)、-C1-C6亚烷基(C4-C6杂环基)、-C1-C6亚烷基(C1-C6烷氧基)、-C1-C6亚烷基(C3-C6环烷基氧基)、或-C1-C6亚烷基(C4-C6杂环基氧基)；其中，所述取代是指被一个或多个R取代；
    n为1、2、3、4、5或6的整数；
    R2和R3相同或不同，各自独立地选自取代或未取代的下组基团：H、D、卤素、CN、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基；其中，所述取代是指被一个或多个R取代；
    R4选自取代或未取代的下组基团：卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基；其中，所述取代是指被一个或多个R取代；
    R8选自：OH、SONH2、NHSO2CH3；
    R5、R6、R7、R9、R7’、R8’、R9’相同或不同，各自独立地选自取代或未取代的下组基团：H、D、卤素、CN、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基；其中，所述取代是指被一个或多个R取代；
    R5’选自：H、D、卤素、CN、NH2、OH、CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基)、SONH2、SO2NH2、NHSO2(C1-C6烷基)、NHSO2(C3-C6环烷基)、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基；
    各R相同或不同，各自独立地选自：氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、(C3-C18环烷基)C1-C18烷基、(4-20元杂环基)C1-C18烷基、(C1-C18烷氧基)C1-C18烷基、(C3-C18环烷基氧基)C1-C18烷基、(4-20元杂环基氧基)C1-C18烷基、乙烯基、乙炔基、(C1-C6 烷基)乙烯基、氘代(C1-C6烷基)乙烯基、卤代(C1-C6烷基)乙烯基、(C1-C6烷基)乙炔基、氘代(C1-C6烷基)乙炔基、卤代(C1-C6烷基)乙炔基、(C3-C14环烷基)乙炔基、(4-14元杂环基)乙炔基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、C3-C20环烷基、4-20元杂环基、C6-C14芳基、5-14元杂芳基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基、砜基或脲基。
  4. 如权利要求1-3中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(IIA)或式(IIB)所示的结构：
    其中，R1、R2、R3、R4、R5、R6、R7、R8、R9、R5’、R7’、R8’、R9’、U、U’、U”、X、Z、W和n的定义如权利要求3所述。
  5. 如权利要求1-4中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(VA)或式(VB)所示结构：
    其中，R1、R4、R5、R6、R7、R9、R7’、R8’、R9’、U、U’、U”、Z、W和n的定义如权利要求3所述。
  6. 如权利要求1-5中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(VIA)或式(VIB)所示结构：
    其中，R1、R4、R5、R6、R7、R9、R7’、R8’、R9’、U”、Z、W和n的定义如权利要求3 所述。
  7. 如权利要求1-6中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(VIIA)或式(VIIB)所示结构：
    其中，R1、R4、R5、R7’、R8’、R9’、Z、W和n的定义如权利要求3所述。
  8. 如权利要求1-7中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(VIIIA)或式(VIIIB)所示结构：
    其中，R1、R4、R5、R7’、R9’、Z、W和n的定义如权利要求3所述。
  9. 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(IXA)或式(IXB)所示结构：
    其中，n’为0、1、2、3、4、5、或6的整数；
    R5、R、R7、R9、R7’、R9’、L1、Q、L2、L3和n的定义如权利要求3所述。
  10. 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(X)所示的结构：
    其中，
    V1、V2、V3、V4和V5各自独立地选自：N、或CRv；Rv相同或不同，各自独立地选自：H、C1-C3烷基、C3-C6环烷基、4-6元杂环基、C1-C3烷氧基、C3-C6环烷基氧基、4-6元杂环基氧基、卤代C1-C3烷基、卤代C3-C6环烷基、卤代4-6元杂环基、(HO)-C1-C3烷基、(HO)-C3-C6环烷基、(NH2)-C1-C3烷基、(NH2)-C3-C6环烷基、卤素、CN、-C≡CH、OH、NH2、CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基)、SO2NH2、NHSO2(C1-C6烷基)、NHSO2(C3-C6环烷基)，其中，所述杂环基任选地被一个或多个氧代基(＝O)取代；
    R2和R3相同或不同，各自独立地选自取代或未取代的下组基团：H、D、卤素、CN、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基；其中，所述取代是指被一个或多个R取代；
    环C、R、R1、X、Z、W和n的定义如权利要求1所述；
    优选地，所述化合物具有式(XI)所示的结构：
    V1、V2、V3、V4、V5各自独立地选自：N、或CRv；Rv相同或不同，各自独立地选自：H、C1-C3烷基、C3-C6环烷基、4-6元杂环基、C1-C3烷氧基、C3-C6环烷基氧基、4-6元杂环基氧基、卤代C1-C3烷基、卤代C3-C6环烷基、卤代4-6元杂环基、(HO)-C1-C3烷基、(HO)-C3-C6环烷基、(NH2)-C1-C3烷基、(NH2)-C3-C6环烷基、卤素、CN、-C≡CH、OH、NH2、CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基)、SO2NH2、NHSO2(C1-C6烷基)、NHSO2(C3-C6环烷基)，其中，所述杂环基任选地被一个或多个氧代基(＝O)取代；
    R2和R3相同或不同，各自独立地选自取代或未取代的下组基团：H、D、卤素、CN、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基；其中，所述取代是指被一个或多个R取代；
    其中，R、R1、X、Z、W和n的定义如权利要求1所述；
    优选地，所述化合物具有式(XII)所示的结构：
    V1、V2、V3、V4、V5各自独立地选自：N、或CRv；Rv相同或不同，各自独立地选自：H、C1-C3烷基、C3-C6环烷基、4-6元杂环基、C1-C3烷氧基、C3-C6环烷基氧基、4-6元杂环基氧基、卤代C1-C3烷基、卤代C3-C6环烷基、卤代4-6元杂环基、(HO)-C1-C3烷基、(HO)-C3-C6环烷基、(NH2)-C1-C3烷基、(NH2)-C3-C6环烷基、卤素、CN、-C≡CH、OH、NH2、CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基)、SO2NH2、NHSO2(C1-C6烷基)、NHSO2(C3-C6环烷基)，其中，所述杂环基任选地被一个或多个氧代基(＝O)取代；
    R3选自取代或未取代的下组基团：H、D、卤素、CN、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基；其中，所述取代是指被一个或多个R取代；
    其中，R、R1、X、Z、W和n的定义如权利要求1所述；
    优选地，所述化合物具有式(XIII)所示的结构：
    V1、V2、V3、V4、V5各自独立地选自：N、或CRv；Rv相同或不同，各自独立地选自：H、C1-C3烷基、C3-C6环烷基、4-6元杂环基、C1-C3烷氧基、C3-C6环烷基氧基、4-6元杂环基氧基、卤代C1-C3烷基、卤代C3-C6环烷基、卤代4-6元杂环基、(HO)-C1-C3烷基、(HO)-C3-C6环烷基、(NH2)-C1-C3烷基、(NH2)-C3-C6环烷基、卤素、CN、-C≡CH、OH、NH2、CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基)、SO2NH2、NHSO2(C1-C6烷基)、NHSO2(C3-C6环烷基)，其中，所述杂环基任选地被一个或多个氧代基(＝O)取代；
    R3选自取代或未取代的下组基团：H、D、卤素、CN、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基；其中，所述取代是指被一个或多个R取代；
    其中，R、R1、Z、W和n的定义如权利要求1所述。
  11. 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，R10为优选地，R10为 其中，Rv1、Rv2、Rv3、Rv4和Rv5各自独立地选自：H、C1-C3烷基、C3-C6环烷基、4-6元杂环基、C1-C3烷氧基、C3-C6环烷基氧基、4-6元杂环基氧基、卤代C1-C3烷基(如CF3、CF2CF3)、卤代C3-C6环烷基、卤代4-6元杂环基、(HO)-C1-C3烷基、(HO)-C3-C6环烷基、(NH2)-C1-C3烷基、(NH2)-C3-C6环烷基、卤素、CN、-C≡CH、OH、NH2、CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基、SO2NH2、NHSO2(C1-C6烷基)、NHSO2(C3-C6环烷基)H、C1-C3烷基、C3-C6环烷基、4-6元杂环基、C1-C3烷氧基、C3-C6环烷基氧基、4-6元杂环基氧基、卤代C1-C3烷基、卤代C3-C6环烷基、卤代4-6元杂环基、(HO)-C1-C3烷基、(HO)-C3-C6环烷基、(NH2)-C1-C3烷基、(NH2)-C3-C6环烷基、卤素、CN、-C≡CH、OH、NH2、CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基)、SO2NH2、NHSO2(C1-C6烷基)、NHSO2(C3-C6环烷基)，所述杂环基任选地被一个或多个氧代基(＝O)取代。
  12. 如权利要求1-10中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，R10选自取代或未取代的下组基团：苯基、萘基、5-6元单环杂芳基(如吡啶基)、9-10元双环杂芳基(如吲唑基、苯并噻唑、苯并噻吩、苯并呋喃)，其中所述取代是被被选自下组的一个或多个基团取代：卤素、羟基、氰基、NH2、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C2-C6烯基、C2-C6炔基；优选地，R10选自：
  13. 如权利要求1-12中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，W选自：

    其中，n’为0、1、2、3、4、5、或6的整数；优选地，当W选自：
    时，n’可以为0、1或2，R的定义如权利要求1所述，R可以取代在多环(如桥环或螺环)的任意一个环上。
  14. 如权利要求1-13中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，所述化合物选自下组：






    或者选自：
    或者选自：
    或者选自：
    或者选自：



    或者选自：

    或者选自：
    或者选自：


  15. 一种药物组合物，其特征在于，包含一种或多种权利要求1-14中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药；和药学上可接受的载体。
  16. 一种权利要求1-14中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或权利要求15所述的药物组合物的用途，其特征在于，用于制备预防和/或治疗与KRASG12D的活性或表达量相关的疾病的药物。
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