WO2023066371A1 - 含氮的四环化合物、其制备方法及其在医药上的应用 - Google Patents

含氮的四环化合物、其制备方法及其在医药上的应用 Download PDF

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WO2023066371A1
WO2023066371A1 PCT/CN2022/126650 CN2022126650W WO2023066371A1 WO 2023066371 A1 WO2023066371 A1 WO 2023066371A1 CN 2022126650 W CN2022126650 W CN 2022126650W WO 2023066371 A1 WO2023066371 A1 WO 2023066371A1
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general formula
alkyl
heterocyclyl
compound represented
pharmaceutically acceptable
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PCT/CN2022/126650
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English (en)
French (fr)
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李心
蔡国栋
陈阳
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CA3234517A priority Critical patent/CA3234517A1/en
Publication of WO2023066371A1 publication Critical patent/WO2023066371A1/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
    • A61K31/495—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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • C07D471/12—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 three 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • the disclosure belongs to the field of medicine, and relates to a nitrogen-containing tetracyclic compound, its preparation method and its application in medicine.
  • the present disclosure relates to a nitrogen-containing tetracyclic compound represented by the general formula (IM), its preparation method, a pharmaceutical composition containing the compound, and its use as a therapeutic agent, especially as a KRAS G12C inhibitor.
  • IM general formula
  • a pharmaceutical composition containing the compound especially as a KRAS G12C inhibitor
  • the RAS (Rat Sarcoma Viral Oncogene Homolog) family belongs to the small GTPase superfamily and is widely expressed in various eukaryotes. There are three RAS genes in humans (HRAS, KRAS, and NARS), which can be expressed as four highly related RAS small GTPases (HRAS, KRAS4A, KARS4B, and NRAS). It functions as a binary switch for GDP-GTP regulation. Normally, they have two forms: the GDP (guanosine diphosphate)-bound form in the inactive state and the GTP (guanosine triphosphate)-bound form in the activated state.
  • RAS protein regulates multiple downstream pathways including RAF-MEK-ERK, PI3K/Akt/mTOR by switching between two active states, thereby affecting cell growth, proliferation and differentiation (Nat Rev Cancer, 2007, 7, 295 -308).
  • the RAS gene has a high mutation rate in various tumors such as pancreatic cancer, colorectal cancer, and non-small cell lung cancer.
  • the activated mutant RAS protein will promote abnormal signal transduction, leading to the occurrence and development of cancer, as well as resistance to targeted drugs. Medicinal properties.
  • KRAS mutation is the gene with the highest mutation rate among human oncogenes, accounting for 20-30% of all tumors.
  • KRAS mutations are mainly point mutations, including 12, 13 and 61 amino acid mutations.
  • the mutation of glycine to cysteine (G12C) at position 12 is the most common, and this mutation has a large proportion (14%) in lung cancer, especially non-small cell lung cancer, and also in some colorectal cancer (4%), pancreatic cancer Expressed in cancer (2%) patients.
  • the incidence of mutations in this gene is even greater than the sum of mutations in ALK, RET, and TRK genes.
  • KRAS G12C small molecule inhibitor ARS-1620 can effectively inhibit tumor growth in a variety of KRAS G12C mutant tumor models, and even completely regress the tumor. Since KRAS G12C is a mutant protein in tumor cells, and wild-type KRAS does not have this mutation site, it provides a perfect tumor-selective target (Cell, 2018, 572, 578-589).
  • KRAS G12C has attracted many well-known new drug research and development companies at home and abroad to participate.
  • Amgen s fastest-growing small-molecule KRAS G12C inhibitor Sotorasib (AMG510) was approved by the FDA on May 28, 2021, it is used for patients with non-small cell lung cancer who have received at least one systemic therapy and carry a KRAS G12C mutation , but Eli Lilly's new generation KRAS G12C inhibitor LY3537982 has attracted more attention.
  • Eli Lilly reported the preclinical data of LY3537982 at the annual meeting of the American Association for Cancer Research (AACR) in April 2021. The data showed that LY3537982 inhibited cell activity more than 10 times higher than Sotorasib, and entered the clinic in July 2021 Phase one. It can be seen that highly selective, safe and effective KRAS G12C inhibitors are still needed clinically.
  • Patent applications for KRAS G12C inhibitors have been published, including WO2014152588A1, WO2015054572A1, WO2016164675A1, WO2017087528A1, WO2017201161A1, WO2018119183A2, WO2018206539A1, WO20181A1, WO4, WO4, WO4, WO4 019215203A1, WO2020081282A1, WO2020178282A1, WO2021118877A1, etc.
  • the object of the present disclosure is to provide a compound represented by general formula (IM) or a pharmaceutically acceptable salt thereof:
  • X is C(R a R b ) or C(R a R b )-C(R c R d );
  • Y is C(O) or CH 2 ;
  • Z is CR 5a or N
  • V is CR 5 or N
  • Ring A is aryl or heteroaryl
  • R a , R b , R c and R d are the same or different at each occurrence and are each independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl group, alkynyl group, hydroxyl group and cyano group;
  • R 1 is selected from cyano
  • Each R is the same or different, and is independently selected from a hydrogen atom, a halogen, a cyano group, an alkyl group, an alkoxy group, a hydroxyl group, and an amino group, wherein each of the alkyl and alkoxy groups is independently selected from One or more substituents in halogen, cyano, amino and hydroxyl;
  • R 3 , R 4 , R 5 and R 5a are the same or different, and each independently selected from hydrogen atom, halogen, cyano, alkyl, alkenyl, alkynyl, -NR 7a R 7b , -C(O)R 8 , -OR 8 , -S(O) p R 8 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Each group is independently selected from one or more of halogen, alkyl, haloalkyl, cyano, -NR 7c R 7d , -OR 8a , cycloalkyl, heterocyclyl, aryl and heteroaryl Substituents are substituted;
  • Each R 6 is the same or different, and each independently selected from hydrogen atom, halogen, cyano, alkyl, alkenyl, alkynyl, -NR 9a R 9b , -C(O)NR 9a R 9b , -C(O )R 10 , -C(O)OR 10 , -OC(O)R 10 , -OR 10 , -S(O) p R 10 , -S(O) p NR 9a R 9b , cycloalkyl, heterocycle radical, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, alkyl, haloalkyl, cyano, - NR 9c R 9d , -OR 10a , cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;
  • R 11 , R 12 , R 13 and R 14 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, -NR 15a R 15b , -OR 16 , cyano, cycloalkyl, heterocyclyl, Aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, haloalkyl, alkoxy One or more substituents in radical, haloalkoxy, cyano, -NR 15c R 15d , hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 8 , R 8a , R 10 , R 10a and R 16 are the same or different at each occurrence, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and Heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, alkyl, alkenyl, alkynyl, oxo, alkoxy One or more substituents in radical, haloalkyl, haloalkoxy, cyano, -NR 17a R 17b , hydroxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 7a , R 7b , R 7c , R 7d , R 9a , R 9b , R 9c , R 9d , R 15a , R 15b , R 15c , R 15d , R 17a and R 17b are identical or different at each occurrence, And each independently selected from hydrogen atom, alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Aryl groups are each independently optionally substituted by one or more substituents selected from halogen, oxo, hydroxy, cyano, alkyl, alkoxy, haloalkyl and haloalkoxy;
  • R 7a and R 7b together with the attached nitrogen atoms form a heterocyclyl, wherein the heterocyclyl is optionally selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano , amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;
  • R 7c and R 7d together with the attached nitrogen atom form a heterocyclyl, wherein the heterocyclyl is optionally selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano , amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;
  • R 9a and R 9b form a heterocyclic group together with the connected nitrogen atom, wherein the heterocyclic group is optionally selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano , amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;
  • R 9c and R 9d form a heterocyclic group together with the connected nitrogen atom, wherein the heterocyclic group is optionally selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano , amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;
  • R 15a and R 15b together with the attached nitrogen atoms form a heterocyclyl, wherein the heterocyclyl is optionally selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano , amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;
  • R 15c and R 15d together with the attached nitrogen atoms form a heterocyclyl, wherein the heterocyclyl is optionally selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano , amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;
  • R 17a and R 17b together with the attached nitrogen atoms form a heterocyclyl, wherein the heterocyclyl is optionally selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano , amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;
  • s 0, 1, 2, 3, 4, 5 or 6;
  • t 0, 1, 2, 3, 4 or 5;
  • p 0, 1 or 2.
  • the compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof:
  • X is C(R a R b ) or C(R a R b )-C(R c R d );
  • Y is C(O) or CH 2 ;
  • Z is CR 5a or N
  • Ring A is aryl or heteroaryl
  • R a , R b , R c and R d are the same or different at each occurrence and are each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkene group, alkynyl group, hydroxyl group and cyano group;
  • R 1 is selected from cyano
  • Each R is the same or different, and is independently selected from a hydrogen atom, a halogen, a cyano group, an alkyl group, an alkoxy group, a hydroxyl group, and an amino group, wherein each of the alkyl and alkoxy groups is independently selected from One or more substituents in halogen, cyano, amino and hydroxyl;
  • R 3 , R 4 , R 5 and R 5a are the same or different, and each independently selected from hydrogen atom, halogen, cyano, alkyl, alkenyl, alkynyl, -NR 7a R 7b , -C(O)R 8 , -OR 8 , -S(O) p R 8 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Each group is independently selected from one or more of halogen, alkyl, haloalkyl, cyano, -NR 7c R 7d , -OR 8a , cycloalkyl, heterocyclyl, aryl and heteroaryl Substituents are substituted;
  • Each R 6 is the same or different, and each independently selected from hydrogen atom, halogen, cyano, alkyl, alkenyl, alkynyl, -NR 9a R 9b , -C(O)NR 9a R 9b , -C(O )R 10 , -C(O)OR 10 , -OC(O)R 10 , -OR 10 , -S(O) p R 10 , -S(O) p NR 9a R 9b , cycloalkyl, heterocycle radical, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, alkyl, haloalkyl, cyano, - NR 9c R 9d , -OR 10a , cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;
  • R 11 , R 12 , R 13 and R 14 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, -NR 15a R 15b , -OR 16 , cyano, cycloalkyl, heterocyclyl, Aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, haloalkyl, alkoxy One or more substituents in radical, haloalkoxy, cyano, -NR 15c R 15d , hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 8 , R 8a , R 10 , R 10a and R 16 are the same or different at each occurrence, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and Heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, alkyl, alkenyl, alkynyl, oxo, alkoxy One or more substituents in radical, haloalkyl, haloalkoxy, cyano, -NR 17a R 17b , hydroxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 7a , R 7b , R 7c , R 7d , R 9a , R 9b , R 9c , R 9d , R 15a , R 15b , R 15c , R 15d , R 17a and R 17b are identical or different at each occurrence, And each independently selected from hydrogen atom, alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Aryl groups are each independently optionally substituted by one or more substituents selected from halogen, oxo, hydroxy, cyano, alkyl, alkoxy, haloalkyl and haloalkoxy;
  • R 7a and R 7b together with the attached nitrogen atoms form a heterocyclyl, wherein the heterocyclyl is optionally selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano , amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;
  • R 7c and R 7d together with the attached nitrogen atom form a heterocyclyl, wherein the heterocyclyl is optionally selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano , amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;
  • R 9a and R 9b form a heterocyclic group together with the connected nitrogen atom, wherein the heterocyclic group is optionally selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano , amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;
  • R 9c and R 9d form a heterocyclic group together with the connected nitrogen atom, wherein the heterocyclic group is optionally selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano , amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;
  • R 15a and R 15b together with the attached nitrogen atoms form a heterocyclyl, wherein the heterocyclyl is optionally selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano , amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;
  • R 15c and R 15d together with the attached nitrogen atoms form a heterocyclyl, wherein the heterocyclyl is optionally selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano , amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;
  • R 17a and R 17b together with the attached nitrogen atoms form a heterocyclyl, wherein the heterocyclyl is optionally selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano , amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;
  • s 0, 1, 2, 3, 4, 5 or 6;
  • t 0, 1, 2, 3, 4 or 5;
  • p 0, 1 or 2.
  • each R 2 is the same or different, and each independently selected from a hydrogen atom , halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl and amino, wherein said C 1-6 alkyl is optionally selected from one or more of halogen and cyano Substituents are substituted; preferably, each R 2 is the same or different, and each independently is a hydrogen atom or a C 1-6 alkyl group; more preferably, each R 2 is the same or different, and each independently is a hydrogen atom or a methyl group group; most preferably, R is a hydrogen atom.
  • the compound represented by general formula (IM), general formula (I) or a pharmaceutically acceptable salt thereof wherein s is 0, 1 or 2; preferably, s is 0 or 1; more preferably, s is 0.
  • the compound represented by general formula (IM), general formula (I) or a pharmaceutically acceptable salt thereof wherein each R 2 is the same or different, and each independently selected from halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl and amino, wherein the C 1-6 alkyl is optionally replaced by one or more substituents selected from halogen and cyano Substituted, and s is 0, 1 or 2; preferably, R 2 is C 1-6 alkyl, and s is 0 or 1; more preferably, R 2 is methyl, and s is 0 or 1.
  • the compound represented by the general formula (IM), the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof the salt:
  • Rings A, X, Z, R 1 , R 3 , R 4 , R 5 , R 6 and t are as defined in general formula (I).
  • the compound represented by general formula (IM), general formula (I), general formula (II) or a pharmaceutically acceptable salt thereof wherein ring A is a 6- to 10-membered aryl group or 5 to 10 membered heteroaryl; preferably, ring A is 5 to 10 membered heteroaryl; more preferably, ring A contains 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur in the ring 8 to 10 membered bicyclic heteroaryl; most preferably, ring A is benzothienyl or benzothiazolyl.
  • the compound represented by general formula (IM), general formula (I), general formula (II) or a pharmaceutically acceptable salt thereof wherein R a , R b , R c and R d are the same or different, and each independently selected from a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; preferably, R a , R b , R c and R d are all hydrogen atoms.
  • the compound represented by general formula (IM), general formula (I), general formula (II) or a pharmaceutically acceptable salt thereof is represented by general formula (III) Compound or its pharmaceutically acceptable salt:
  • W is C(CN) or N;
  • t 0, 1, 2 or 3;
  • the compound represented by general formula (IM), general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof is the general formula Compounds represented by (III-1) or pharmaceutically acceptable salts thereof:
  • W is C(CN) or N;
  • t 0, 1, 2 or 3;
  • the compound represented by general formula (IM), general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof is the general formula Compounds shown in (III-2) or pharmaceutically acceptable salts thereof:
  • W is C(CN) or N;
  • t 0, 1, 2 or 3;
  • the compound represented by the general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III-1) or its druggable is a compound represented by general formula (III-1-A) or a pharmaceutically acceptable salt thereof:
  • W is C(CN) or N;
  • t 0, 1, 2 or 3;
  • the compound represented by the general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III-1) or its druggable A useful salt which is a compound represented by general formula (III-1-B) or a pharmaceutically acceptable salt thereof:
  • W is C(CN) or N;
  • t 0, 1, 2 or 3;
  • the compound represented by general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III-2) or its druggable is a compound represented by general formula (III-2-A) or a pharmaceutically acceptable salt thereof:
  • W is C(CN) or N;
  • t 0, 1, 2 or 3;
  • the compound represented by general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III-2) or its druggable A useful salt which is a compound represented by general formula (III-2-B) or a pharmaceutically acceptable salt thereof:
  • W is C(CN) or N;
  • t 0, 1, 2 or 3;
  • the general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2) the compound shown in general formula (III-1-A), general formula (III-1-B), general formula (III-2-A), general formula (III-2-B) or its pharmaceutically acceptable A salt, wherein R 3 , R 4 , R 5 and R 5a are the same or different, and are each independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl.
  • the general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2) the compound shown in general formula (III-1-A), general formula (III-1-B), general formula (III-2-A), general formula (III-2-B) or its pharmaceutically acceptable Salt, wherein R 3 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; preferably, R 3 is hydrogen atom or halogen; more preferably, R 3 is hydrogen atom or F; most Preferably, R 3 is a hydrogen atom.
  • the general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2) the compound shown in general formula (III-1-A), general formula (III-1-B), general formula (III-2-A), general formula (III-2-B) or its pharmaceutically acceptable Salt, wherein R 4 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; preferably, R 4 is halogen; more preferably, R 4 is F.
  • the general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2) the compound shown in general formula (III-1-A), general formula (III-1-B), general formula (III-2-A), general formula (III-2-B) or its pharmaceutically acceptable Salt, wherein R is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; preferably, R is selected from hydrogen atom, halogen and C 1-6 alkyl; more preferably, R 5 is halogen or C 1-6 alkyl; most preferably, R 5 is Cl or methyl.
  • the general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2) the compound shown in general formula (III-1-A), general formula (III-1-B), general formula (III-2-A), general formula (III-2-B) or its pharmaceutically acceptable Salt, wherein R 5 is selected from hydrogen atom, F, Cl and methyl.
  • the general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2) the compound shown in general formula (III-1-A), general formula (III-1-B), general formula (III-2-A), general formula (III-2-B) or its pharmaceutically acceptable Salt, wherein R 5a is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; preferably, R 5a is hydrogen atom or C 1-6 alkyl; more preferably, R 5a is hydrogen atom or methyl.
  • the general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2) the compound shown in general formula (III-1-A), general formula (III-1-B), general formula (III-2-A), general formula (III-2-B) or its pharmaceutically acceptable Salt, wherein Z is CR 5a or N, and R 5a is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; preferably, Z is CR 5a or N, and R 5a is hydrogen atom or C 1-6 alkyl; more preferably, Z is N.
  • the compound represented by general formula (IM), general formula (I), general formula (II) or a pharmaceutically acceptable salt thereof wherein each R 6 is the same or different, and each independently selected from hydrogen atom, halogen, cyano, -NH 2 , C 1-6 alkyl and C 1-6 haloalkyl; preferably, each R 6 is the same or different, and each independently selected from hydrogen atom, halogen , cyano and -NH 2 .
  • each R 6 is the same or different, and each independently selected from hydrogen atom, halogen, cyano, -NH 2 , C 1-6 alkyl and C 1-6 haloalkyl; preferably, each R 6 is the same or different, and each independently is a hydrogen atom or halogen; More preferably, each R 6 is the same or different, and each independently is a hydrogen atom or F.
  • the general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2) the compound shown in general formula (III-1-A), general formula (III-1-B), general formula (III-2-A), general formula (III-2-B) or its pharmaceutically acceptable Salt, wherein R 11 is selected from hydrogen atom, halogen and C 1-6 alkyl; preferably, R 11 is hydrogen atom or halogen; more preferably, R 11 is hydrogen atom or F.
  • the general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2) the compound shown in general formula (III-1-A), general formula (III-1-B), general formula (III-2-A), general formula (III-2-B) or its pharmaceutically acceptable Salt, wherein R 12 is selected from a hydrogen atom, halogen and C 1-6 alkyl; preferably, R 12 is a hydrogen atom.
  • the general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2) the compound shown in general formula (III-1-A), general formula (III-1-B), general formula (III-2-A), general formula (III-2-B) or its pharmaceutically acceptable Salt, wherein R 13 is selected from a hydrogen atom, halogen and C 1-6 alkyl; preferably, R 13 is a hydrogen atom.
  • the compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof wherein V is CR 5 or N; X is C(R a R b ) or C(R a R b )-C(R c R d ); R a , R b , R c and R d are the same or different, and each independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkane Y is C(O); Z is CR 5a or N; Ring A is 5 to 10 membered heteroaryl; R 1 is R 3 , R 4 , R 5 and R 5a are the same or different, and are each independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 2 is C 1-6 alkyl, and s is 0 or 1; each R 6 is the same or different, and each independently selected from halogen, cyano, -NH 2 ,
  • the compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof wherein V is CR 5 or N; X is CH 2 or CH 2 -CH 2 ; Y is C (O); Z is CR 5a or N; R 5a is hydrogen atom or C 1-6 alkyl; R 1 is R 3 is hydrogen atom or halogen; R 4 is halogen; R 5 is selected from hydrogen atom, halogen and C 1-6 alkyl; R 2 is C 1-6 alkyl, and s is 0 or 1; for W is C(CN) or N; each R 6 is the same or different, and each independently selected from halogen, cyano, -NH 2 , C 1-6 alkyl and C 1-6 haloalkyl, and t is 0, 1, 2 or 3; R 11 is selected from hydrogen atom, halogen and C 1-6 alkyl; R 12 is selected from hydrogen atom, halogen and C 1-6 alkyl; and R 13 is selected from hydrogen
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof wherein X is C(R a R b ) or C(R a R b )-C(R c R d ); R a , R b , R c and R d are the same or different, and each independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; Y is C(O ); Z is CR 5a or N; Ring A is 5 to 10 membered heteroaryl; R 1 is R 3 , R 4 , R 5 and R 5a are the same or different, and are each independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 2 is C 1-6 alkyl, and s is 0 or 1; each R 6 is the same or different, and each independently selected from halogen, cyano, -NH 2 , C 1-6 alkyl and
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof wherein X is C(R a R b ) or C(R a R b )-C(R c R d ); R a , R b , R c and R d are the same or different, and each independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; Y is C(O ); Z is CR 5a or N; Ring A is 5 to 10 membered heteroaryl; R 1 is R 3 , R 4 , R 5 and R 5a are the same or different, and are each independently selected from a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; s is 0; each R 6 is the same or different , and each independently selected from halogen, cyano, -NH 2 , C 1-6 alkyl and C 1-6 haloalkyl,
  • the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof wherein ring A contains 1, 2 or 3 hetero Atoms of 8 to 10 membered bicyclic heteroaryl;
  • X is CH 2 or CH 2 -CH 2 ;
  • Z is CR 5a or N;
  • R 1 is R 3 , R 4 , R 5 and R 5a are the same or different, and are each independently selected from a hydrogen atom, halogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 6 is the same or different, and each is independently is selected from halogen, cyano, -NH 2 , C 1-6 alkyl and C 1-6 haloalkyl, and t is 0, 1, 2 or 3;
  • R 11 is a hydrogen atom or halogen;
  • R 12 is a hydrogen atom ;
  • R 13 is a hydrogen atom.
  • the general formula (III), general formula (III-1), general formula (III-2), general formula (III-1-A), general formula (III-1- B), a compound represented by general formula (III-2-A), general formula (III-2-B) or a pharmaceutically acceptable salt thereof wherein W is C (CN); Z is N; R is hydrogen Atom; R 4 is halogen; R 5 is selected from hydrogen atom, halogen and C 1-6 alkyl; R 11 is hydrogen atom or halogen; R 12 is hydrogen atom; R 13 is hydrogen atom; R 6 is halogen, and t is 0 or 1.
  • Typical compounds of the present disclosure include, but are not limited to:
  • Rings A, V, X, Y, Z, R2 , R3 , R4 , R6 , s and t are as defined in general formula (IM).
  • Rings A, X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 , s and t are as defined in general formula (I).
  • Rings A, X, Z, R 3 , R 4 , R 5 , R 6 and t are as defined in general formula (II).
  • W, Z, R 3 , R 4 , R 5 , R 6 and t are as defined in the general formula (III).
  • Another aspect of the present disclosure relates to a compound represented by general formula (III-1a) or a salt thereof:
  • W, Z, R 3 , R 4 , R 5 , R 6 and t are as defined in the general formula (III-1).
  • W, Z, R 3 , R 4 , R 5 , R 6 and t are as defined in the general formula (III-2).
  • W, Z, R 3 , R 4 , R 5 , R 6 and t are as defined in the general formula (III-1-A).
  • W, Z, R 3 , R 4 , R 5 , R 6 and t are as defined in the general formula (III-1-B).
  • W, Z, R 3 , R 4 , R 5 , R 6 and t are as defined in the general formula (III-2-A).
  • Another aspect of the present disclosure relates to a compound or a salt thereof represented by general formula (III-2-Ba):
  • W, Z, R 3 , R 4 , R 5 , R 6 and t are as defined in the general formula (III-2-B).
  • Typical intermediate compounds of the present disclosure include, but are not limited to:
  • R W2 is an amino protecting group; preferably, R W2 is tert-butoxycarbonyl;
  • Rings A, V, X, Y, Z, R2 , R3 , R4 , R6 , s and t are as defined in general formula (IMa).
  • R W1 and R W2 are the same or different, and each independently is an amino protecting group; preferably, both R W1 and R W2 are tert-butoxycarbonyl;
  • t 0, 1, 2 or 3;
  • V, X, Y, Z, R 2 , R 3 , R 4 , R 6 and s are as defined in general formula (IMa).
  • R W2 is an amino protecting group; preferably, R W2 is tert-butoxycarbonyl;
  • Rings A, X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 , s and t are as defined in general formula (Ia).
  • R W1 and R W2 are the same or different, and each independently is an amino protecting group; preferably, both R W1 and R W2 are tert-butoxycarbonyl;
  • t 0, 1, 2 or 3;
  • X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 and s are as defined in general formula (Ia).
  • R W2 is an amino protecting group; preferably, R W2 is tert-butoxycarbonyl;
  • Rings A, X, Z, R 3 , R 4 , R 5 , R 6 and t are as defined in general formula (IIa).
  • R W1 and R W2 are the same or different, and each independently is an amino protecting group; preferably, both R W1 and R W2 are tert-butoxycarbonyl;
  • t 0, 1, 2 or 3;
  • R W1 and R W2 are the same or different, and each independently is an amino protecting group; preferably, both R W1 and R W2 are tert-butoxycarbonyl;
  • W, Z, R 3 , R 4 , R 5 , R 6 and t are as defined in general formula (Ilia).
  • R W1 and R W2 are the same or different, and each independently is an amino protecting group; preferably, both R W1 and R W2 are tert-butoxycarbonyl;
  • W, Z, R 3 , R 4 , R 5 , R 6 and t are as defined in the general formula (III-1a).
  • R W1 and R W2 are the same or different, and each independently is an amino protecting group; preferably, both R W1 and R W2 are tert-butoxycarbonyl;
  • W, Z, R 3 , R 4 , R 5 , R 6 and t are as defined in the general formula (III-2a).
  • Typical intermediate compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IM) or a pharmaceutically acceptable salt thereof, comprising:
  • a compound represented by the general formula (IMa) or a salt thereof is reacted with a compound of the general formula (X) or a salt thereof to obtain a compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof;
  • L is halogen; preferably, L is Cl;
  • Rings A, V, X, Y, Z, R 2 , R 3 , R 4 , R 6 , R 11 , R 12 , R 13 , R 14 , s and t are as defined in general formula (IM).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, comprising:
  • the compound represented by general formula (Ia) or its salt reacts with the compound of general formula (X) or its salt to obtain the compound represented by general formula (I) or its pharmaceutically acceptable salt;
  • L is halogen; preferably, L is Cl;
  • Rings A, X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 , R 11 , R 12 , R 13 , R 14 , s and t are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, comprising:
  • the compound represented by general formula (IIa) or its salt reacts with the compound of general formula (X) or its salt to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt;
  • L is halogen; preferably, L is Cl;
  • Rings A, X, Z, R 3 , R 4 , R 5 , R 6 , R 11 , R 12 , R 13 , R 14 and t are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, comprising:
  • a compound represented by general formula (IIIa) or a salt thereof is reacted with a compound of general formula (XI) or a salt thereof to obtain a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof;
  • L is halogen; preferably, L is Cl;
  • W, Z, R 3 , R 4 , R 5 , R 6 , R 11 , R 12 , R 13 and t are as defined in the general formula (III).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, comprising:
  • a compound represented by general formula (III-1a) or a salt thereof is reacted with a compound represented by general formula (XI) or a salt thereof to obtain a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof;
  • L is halogen; preferably, L is Cl;
  • W, Z, R 3 , R 4 , R 5 , R 6 , R 11 , R 12 , R 13 and t are as defined in the general formula (III-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-2) or a pharmaceutically acceptable salt thereof, comprising:
  • a compound represented by general formula (III-2a) or a salt thereof is reacted with a compound represented by general formula (XI) or a salt thereof to obtain a compound represented by general formula (III-2) or a pharmaceutically acceptable salt thereof;
  • L is halogen; preferably, L is Cl;
  • W, Z, R 3 , R 4 , R 5 , R 6 , R 11 , R 12 , R 13 and t are as defined in the general formula (III-2).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1-A) and general formula (III-1-B) or a pharmaceutically acceptable salt thereof, comprising:
  • W, Z, R 3 , R 4 , R 5 , R 6 , R 11 , R 12 , R 13 and t are as defined in the general formula (III-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-2-A) and general formula (III-2-B) or a pharmaceutically acceptable salt thereof, comprising:
  • W, Z, R 3 , R 4 , R 5 , R 6 , R 11 , R 12 , R 13 and t are as defined in the general formula (III-2).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IMa) or a pharmaceutically acceptable salt thereof, comprising:
  • the compound shown in general formula (IMaa) or its salt removes R W2 and obtains the compound shown in general formula (IMa) or its pharmaceutically acceptable salt;
  • R W2 is an amino protecting group; preferably, R W2 is tert-butoxycarbonyl;
  • Rings A, V, X, Y, Z, R2 , R3 , R4 , R6 , s and t are as defined in general formula (IMa).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IMa) or a salt thereof, comprising:
  • the compound shown in general formula (IMaa) or its salt removes R W2 and obtains the compound or its salt shown in general formula (IMa);
  • R group contains a protecting group
  • the step of removing the protecting group on the R6 group is also included before, simultaneously or after the reaction;
  • R W2 is an amino protecting group; preferably, R W2 is tert-butoxycarbonyl;
  • Rings A, V, X, Y, Z, R2 , R3 , R4 , R6 , s and t are as defined in general formula (IMa).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (Ia) or a pharmaceutically acceptable salt thereof, comprising:
  • the compound shown in general formula (Iaa) or its salt removes R W2 and obtains the compound shown in general formula (Ia) or its pharmaceutically acceptable salt;
  • R W2 is an amino protecting group; preferably, R W2 is tert-butoxycarbonyl;
  • Rings A, X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 , s and t are as defined in general formula (Ia).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (Ia) or a salt thereof, comprising:
  • the compound shown in general formula (Iaa) or its salt removes R W2 and obtains the compound shown in general formula (Ia) or its salt;
  • the R group contains a protecting group
  • the step of removing the protecting group on the R6 group is also included before, simultaneously or after the reaction;
  • R W2 is an amino protecting group; preferably, R W2 is tert-butoxycarbonyl;
  • Rings A, X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 , s and t are as defined in general formula (Ia).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIa) or a pharmaceutically acceptable salt thereof, comprising:
  • the compound represented by the general formula (IIaa) or its salt is removed from R W2 to obtain the compound represented by the general formula (IIa) or its pharmaceutically acceptable salt;
  • R W2 is an amino protecting group; preferably, R W2 is tert-butoxycarbonyl;
  • Rings A, X, Z, R 3 , R 4 , R 5 , R 6 and t are as defined in general formula (IIa).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIa) or a salt thereof, comprising:
  • the compound shown in general formula (IIaa) or its salt removes R W2 and obtains the compound shown in general formula (IIa) or its salt;
  • the R group contains a protecting group
  • the step of removing the protecting group on the R6 group is also included before, simultaneously or after the reaction;
  • R W2 is an amino protecting group; preferably, R W2 is tert-butoxycarbonyl;
  • Rings A, X, Z, R 3 , R 4 , R 5 , R 6 and t are as defined in general formula (IIa).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIIa) or a pharmaceutically acceptable salt thereof, comprising:
  • Both R W1 and R W2 are amino protecting groups; preferably, R W1 and R W2 are both tert-butoxycarbonyl;
  • W, Z, R 3 , R 4 , R 5 , R 6 and t are as defined in general formula (Ilia).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1a) or a pharmaceutically acceptable salt thereof, comprising:
  • Both R W1 and R W2 are amino protecting groups; preferably, R W1 and R W2 are both tert-butoxycarbonyl;
  • W, Z, R 3 , R 4 , R 5 , R 6 and t are as defined in the general formula (III-1a).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-2a) or a pharmaceutically acceptable salt thereof, comprising:
  • Both R W1 and R W2 are amino protecting groups; preferably, R W1 and R W2 are both tert-butoxycarbonyl;
  • W, Z, R 3 , R 4 , R 5 , R 6 and t are as defined in the general formula (III-2a).
  • compositions which contains the general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III- 1), general formula (III-2), general formula (III-1-A), general formula (III-1-B), general formula (III-2-A), general formula (III-2-B) And the compound shown in Table A or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2), general formula (III-1 -A), general formula (III-1-B), general formula (III-2-A), general formula (III-2-B) and the compound shown in Table A or its pharmaceutically acceptable salt or containing it
  • the present disclosure further relates to general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2), general formula (III-1 -A), general formula (III-1-B), general formula (III-2-A), general formula (III-2-B) and the compound shown in Table A or its pharmaceutically acceptable salt or containing it
  • the present disclosure further relates to general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2), general formula (III-1 -A), general formula (III-1-B), general formula (III-2-A), general formula (III-2-B) and the compound shown in Table A or its pharmaceutically acceptable salt or containing it Use of the pharmaceutical composition in the preparation of medicines for treating and/or preventing tumors.
  • the present disclosure also relates to a method of inhibiting KRAS G12C, which comprises administering a therapeutically effective dose of the general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III) to the patient in need -1), general formula (III-2), general formula (III-1-A), general formula (III-1-B), general formula (III-2-A), general formula (III-2-B ) and a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it.
  • the present disclosure also relates to a method for treating and/or preventing a disease or condition mediated by KRAS G12C, which comprises administering a therapeutically effective amount of general formula (IM), general formula (I), general formula (II) to a patient in need , general formula (III), general formula (III-1), general formula (III-2), general formula (III-1-A), general formula (III-1-B), general formula (III-2- A), the compound shown in the general formula (III-2-B) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • general formula (IM), general formula (I), general formula (II) to a patient in need
  • the compound shown in the general formula (III-2-B) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure also relates to a method for treating and/or preventing tumors, which comprises administering a therapeutically effective dose of general formula (IM), general formula (I), general formula (II), general formula (III), general formula Formula (III-1), general formula (III-2), general formula (III-1-A), general formula (III-1-B), general formula (III-2-A), general formula (III- 2-B) and a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it.
  • IM general formula
  • general formula (I) general formula (II), general formula (II), general formula (III), general formula Formula (III-1), general formula (III-2), general formula (III-1-A), general formula (III-1-B), general formula (III-2-A), general formula (III- 2-B) and a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it.
  • the present disclosure further relates to a general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2), general formula (III) -1-A), general formula (III-1-B), general formula (III-2-A), general formula (III-2-B) and the compound shown in Table A or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it, for use as a medicament.
  • the present disclosure further relates to general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2), general formula (III-1 -A), general formula (III-1-B), general formula (III-2-A), general formula (III-2-B) and the compound shown in Table A or its pharmaceutically acceptable salt, or comprising A pharmaceutical composition thereof for use as a KRAS G12C inhibitor.
  • the present disclosure further relates to general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2), general formula (III-1 -A), general formula (III-1-B), general formula (III-2-A), general formula (III-2-B) and the compound shown in Table A or its pharmaceutically acceptable salt, or comprising A pharmaceutical composition thereof, which is used for treating and/or preventing diseases or conditions mediated by KRAS G12C.
  • the present disclosure further relates to general formula (IM), general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2), general formula (III-1 -A), general formula (III-1-B), general formula (III-2-A), general formula (III-2-B) and the compound shown in Table A or its pharmaceutically acceptable salt, or comprising A pharmaceutical composition thereof, which is used for treating and/or preventing tumors.
  • the tumor as described above in the present disclosure is preferably cancer; further preferably, the cancer is selected from lung cancer (such as non-small cell lung cancer and small cell lung cancer), pancreatic cancer, cervical cancer, esophageal cancer (also known as esophageal cancer), Endometrial cancer, ovarian cancer, bile duct cancer, colorectal cancer (such as colon and rectal cancer), liver cancer, breast cancer, prostate cancer, thyroid cancer, stomach cancer, urothelial cancer, testicular cancer, leukemia, skin cancer, squamous cell carcinoma Cell carcinoma, basal cell carcinoma, bladder cancer, head and neck cancer, renal cancer, nasopharyngeal carcinoma, bone cancer, lymphoma, melanoma, sarcoma, peripheral neuroepithelial tumor, glioma (such as astrocytoma and glioblastoma cell tumor), brain tumor and myeloma; more preferably, the cancer is selected from lung cancer, pancreatic cancer, cervical cancer,
  • the disease or disease mediated by KRAS G12C as described above in the present disclosure is preferably a tumor; further preferably, the tumor is cancer; more preferably, the cancer is selected from lung cancer (such as non-small cell lung cancer and small lung cancer), pancreatic cancer, cervical cancer, esophageal cancer (also known as oesophageal cancer), endometrial cancer, ovarian cancer, bile duct cancer, colorectal cancer (such as colon and rectal cancer), liver cancer, breast cancer, prostate cancer, Thyroid cancer, gastric cancer, urothelial cancer, testicular cancer, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, bladder cancer, head and neck cancer, kidney cancer, nasopharyngeal cancer, bone cancer, lymphoma, melanoma, sarcoma , peripheral neuroepithelial tumor, glioma (such as astrocytoma and glioblastoma), brain tumor and myeloma;
  • the active compounds of the present disclosure are preferably presented in unit dosage form, or in such a form that the patient can self-administer as a single dose.
  • a unit dosage form of a compound or composition of the present disclosure may be presented as a tablet, capsule, cachet, bottle, powder, granule, lozenge, suppository, reconstituted powder or liquid.
  • a suitable unit dosage may be from 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more excipients, which may be selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients. agent etc.
  • the compositions may contain from 0.1 to 99% by weight of active compound.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir.
  • Oral compositions can be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, To provide pleasing and palatable medicinal preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over an extended period of time.
  • Oral formulations can also be provided in soft gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, or where the active ingredient is mixed with a water-soluble carrier or an oil vehicle.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • Oily suspensions can be formulated by suspending the active ingredient in a vegetable or mineral oil.
  • the oily suspensions may contain a thickening agent.
  • Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oily phase may be vegetable oil, mineral oil or mixtures thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants.
  • Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase, and the injection or microemulsion can be injected into the patient's bloodstream by local bulk injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the disclosed compounds.
  • a continuous intravenous delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM. Model 5400 IV pump.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blended and fixed oil may be used.
  • fatty acids are also used in the preparation of injectables.
  • the disclosed compounds may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.
  • the dosage of the drug to be administered depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the state of health of the patient, the behavior of the patient , patient's diet, administration time, administration method, rate of excretion, combination of drugs, severity of disease, etc.; in addition, the optimal treatment mode such as the mode of treatment, the daily dosage of the compound or the content of the pharmaceutically acceptable saltkinds can be validated against traditional treatment regimens.
  • alkyl refers to a saturated linear or branched aliphatic hydrocarbon group having 1 to 20 (for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C 1-20 alkyl).
  • the alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (ie, a C 1-12 alkyl group), more preferably an alkyl group having 1 to 6 carbon atoms (ie, a C 1-6 alkyl group).
  • Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methyl
  • Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from deuterium atoms, halogen, alkoxy, haloalkyl, haloalkoxy, ring One or more of alkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkenyl refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as described above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (ie C 2-12 alkenyl).
  • the alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkenyl group).
  • Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like.
  • Alkenyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents being preferably selected from deuterium atoms, alkoxy, halogen, haloalkyl, haloalkoxy, ring One or more of alkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the definition of the alkyl group is as described above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (ie C 2-12 alkynyl).
  • the alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkynyl group).
  • Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents being preferably selected from deuterium atoms, alkoxy, halogen, haloalkyl, haloalkoxy, ring One or more of alkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, and butoxy, and the like. Alkoxy may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents being preferably selected from deuterium atoms, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic full carbocycle (ie monocyclic cycloalkyl) or polycyclic ring system (ie polycyclic cycloalkyl) having 3 to 20 (eg 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 3 to 20 membered cycloalkyl).
  • the cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e. a 3 to 12 membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e. a 3 to 8 membered cycloalkyl group). ), most preferably a cycloalkyl group having 3 to 6 ring atoms (ie a 3 to 6 membered cycloalkyl group).
  • Said monocyclic cycloalkyl non-limiting examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl , cycloheptatrienyl and cyclooctyl, etc.
  • the polycyclic cycloalkyl includes: spirocycloalkyl, condensed cycloalkyl and bridged cycloalkyl.
  • spirocycloalkyl refers to a polycyclic ring system that shares one carbon atom (called a spiro atom) between the rings, which may contain one or more double bonds in the ring, or may contain one or more rings selected from nitrogen, Oxygen and sulfur heteroatoms (the nitrogen may be optionally oxidized, i.e. form nitrogen oxides; the sulfur may be optionally oxo, i.e.
  • the spirocycloalkyl is preferably a spirocycloalkyl having 6 to 14 ring atoms (i.e.
  • spirocycloalkyl a 6 to 14 membered spirocycloalkyl, more preferably a spirocycloalkyl having 7 to 10 ring atoms (i.e. 7 to 10 member spirocycloalkyl).
  • the spirocycloalkyl group includes single spirocycloalkyl and polyspirocycloalkyl (such as double spirocycloalkyl, etc.), preferably single spirocycloalkyl or double spirocycloalkyl, more preferably 3-membered/4-membered, 3-membered Yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/ 6
  • connection point can be at any position
  • fused cycloalkyl refers to a polycyclic ring system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl to a heterocyclic
  • cyclic groups, aryl groups or heteroaryl groups are condensed, wherein the point of attachment is on the monocyclic cycloalkyl group, which can contain one or more double bonds in the ring, and have 5 to 20 (for example, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 5 to 20 membered fused cycloalkyl).
  • the condensed cycloalkyl group is preferably a condensed cycloalkyl group having 6 to 14 ring atoms (i.e. a 6 to 14 membered fused cycloalkyl group), more preferably a fused cycloalkyl group having 7 to 10 ring atoms (i.e. 7 to 10 fused cycloalkyl).
  • the fused cycloalkyl includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl , more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan , 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 y
  • bridged cycloalkyl refers to an all-carbon polycyclic ring system which shares two carbon atoms not directly connected between the rings, which may contain one or more double bonds in the ring, and has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie, 5 to 20 membered bridged cycloalkyl).
  • the bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (i.e. a 6 to 14 membered bridged cycloalkyl group), more preferably a bridged cycloalkyl group having 7 to 10 carbon atoms (i.e.
  • the bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (such as tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl .
  • Non-limiting examples include:
  • Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents being preferably selected from deuterium atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkane One of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or more.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic heterocycle (i.e. monocyclic heterocyclyl) or polycyclic heterocyclic ring system (i.e. polycyclic heterocyclyl) containing at least one (eg 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e. form nitrogen oxides; the sulfur may optionally be oxo, i.e.
  • the heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e. a 3 to 12 membered heterocyclic group); further preferably a heterocyclic group having 3 to 8 ring atoms (i.e.
  • a 3 to 8 membered heterocyclic group ); more preferably a heterocyclyl group having 3 to 6 ring atoms (ie, a 3- to 6-membered heterocyclyl group); most preferably a heterocyclyl group having 5 or 6 ring atoms (ie, a 5- or 6-membered heterocyclyl group).
  • Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl , Thiomorpholinyl and Homopiperazinyl, etc.
  • the polycyclic heterocyclic groups include spiro heterocyclic groups, condensed heterocyclic groups and bridged heterocyclic groups.
  • spiroheterocyclyl refers to a polycyclic heterocyclic ring system that shares one atom (called a spiro atom) between the rings, which may contain one or more double bonds in the ring, and at least one (such as 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo, i.e.
  • the condition is to contain at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 5 to 20 membered spiroheterocyclyl).
  • the spiroheterocyclyl is preferably a spiroheterocyclyl having 6 to 14 ring atoms (i.e.
  • the spiroheterocyclyl includes single spiroheterocyclyl and polyspiroheterocyclyl (such as double spiroheterocyclyl, etc.), preferably single spiroheterocyclyl or double spiroheterocyclyl, more preferably 3-membered/4-membered, 3-membered Yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/ 6 yuan,
  • fused heterocyclyl refers to a polycyclic heterocyclic ring system which shares two adjacent atoms between the rings, which may contain one or more double bonds, and which contains at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo, i.e.
  • sulfoxides or sulfones but not Including -O-O-, -O-S- or -S-S-), which is a monocyclic heterocyclic group fused with one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group with a cycloalkyl, aryl or heteroaryl
  • the fused heterocyclic group is preferably a fused heterocyclic group having 6 to 14 ring atoms (ie, a 6 to 14 membered fused heterocyclic group), more preferably a condensed heterocyclic group having 7 to 10 ring atoms (ie, 7 to 10 membered fused heterocyclyl).
  • the fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably bicyclic fused heterocyclic groups or tricyclic fused heterocyclic groups, more preferably 3 Yuan/4 Yuan, 3 Yuan/5 Yuan, 3 Yuan/6 Yuan, 4 Yuan/4 Yuan, 4 Yuan/5 Yuan, 4 Yuan/6 Yuan, 5 Yuan/3 Yuan, 5 Yuan/4 Yuan, 5 Yuan/ 5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan Or a 7-membered/6-membered bicyclic condensed heterocyclic group.
  • bridged heterocyclyl refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, and may contain one or more double bonds in the ring, and at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo, i.e.
  • the bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e. a 6 to 14 membered bridged heterocyclic group), more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e. 7 to 10 bridged heterocyclyl).
  • bicyclic bridged heterocyclic group and polycyclic bridged heterocyclic group such as tricyclic bridged heterocyclic group, tetracyclic bridged heterocyclic group, etc.
  • bicyclic bridged heterocyclic group or tricyclic bridged heterocyclic group base preferably bicyclic bridged heterocyclic group or tricyclic bridged heterocyclic group base.
  • Non-limiting examples include:
  • the heterocyclyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from deuterium atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkane One of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or more.
  • aryl refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aryl) or a polycyclic aromatic ring system (i.e., a polycyclic aryl) having a conjugated ⁇ -electron system, which has 6 to 14 (e.g., 6 , 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (ie 6 to 14 membered aryl).
  • the aryl group is preferably an aryl group having 6 to 10 ring atoms (ie, a 6 to 10 membered aryl group).
  • the monocyclic aryl group such as phenyl.
  • Non-limiting examples of the polycyclic aryl group include: naphthyl, anthracenyl, phenanthrenyl and the like.
  • the polycyclic aryl also includes the condensing of phenyl with one or more of heterocyclic or cycloalkyl, or the fused of naphthyl with one or more of heterocyclic or cycloalkyl, wherein the connection point On phenyl or naphthyl, and in this case, the number of ring atoms continues to mean the number of ring atoms in a polycyclic aromatic ring system, non-limiting examples include:
  • Aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents being preferably selected from deuterium atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy one or Multiple.
  • heteroaryl refers to a monocyclic heteroaryl ring (ie, monocyclic heteroaryl) or a polycyclic heteroaryl ring system (ie, polycyclic heteroaryl) having a conjugated ⁇ -electron system, which contains at least one (eg 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e. form nitrogen oxides; the sulfur may optionally be oxo, i.e.
  • the heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e. a 5 to 10 membered heteroaryl group), more preferably a monocyclic heteroaryl group having 5 or 6 ring atoms (i.e. a 5 or 6 membered heteroaryl group).
  • ring heteroaryl or bicyclic heteroaryl having 8 to 10 ring atoms (i.e.
  • 8 to 10 membered bicyclic heteroaryl most preferably containing 1, 2 or 3 heteroaryls selected from nitrogen, oxygen and sulfur in the ring
  • Non-limiting examples of the monocyclic heteroaryl include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl , pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (such as etc.), pyrazinyl, pyridazinyl, etc.
  • the polycyclic heteroaryl non-limiting examples include: indolyl, indazolyl, quinolinyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene group, quinazoline group, benzothiazolyl group, carbazolyl group, etc.
  • the polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aryls, wherein the point of attachment is on the aromatic ring, and in this case the number of ring atoms continues to represent the polycyclic heteroaryl The number of ring atoms in the system.
  • the polycyclic heteroaryl also includes monocyclic heteroaryl fused with one or more of cycloalkyl or heterocyclic, wherein the point of attachment is on the monocyclic heteroaryl ring, and in this case, the ring
  • the number of atoms continues to indicate the number of ring atoms in the polycyclic heteroaryl ring system.
  • Non-limiting examples include:
  • Heteroaryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from deuterium atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkane One or more of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • amino-protecting group refers to an easily detachable group introduced on an amino group in order to keep the amino group unchanged when other parts of the molecule are reacted.
  • Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methoxycarbonyl (Fmoc), allyl Oxycarbonyl (Alloc), Trimethylsilylethoxycarbonyl (Teoc), Methoxycarbonyl, Ethoxycarbonyl, Phthalyl (Pht), p-Toluenesulfonyl (Tos), Trifluoroacetyl (Tfa), Trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, etc.
  • hydroxyl protecting group refers to an easy-to-remove group introduced on the hydroxyl group, which is used to block or protect the hydroxyl group and react on other functional groups of the compound.
  • Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyl Diphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), methyl Acyl, acetyl, benzoyl, p-nitrobenzoyl, etc.
  • cycloalkyloxy refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • aryloxy refers to aryl-O-, wherein aryl is as defined above.
  • heteroaryloxy refers to heteroaryl-O-, wherein heteroaryl is as defined above.
  • alkylthio refers to alkyl-S-, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
  • deuteroalkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxyl refers to -OH.
  • mercapto refers to -SH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • carboxylate refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl and cycloalkyl are as defined above.
  • stereoisomer refers to isomers that are identical in structure but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (e.g. racemates, mixtures of diastereomers) . Substituents in compounds of the present disclosure may be present with additional asymmetric atoms.
  • Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (D)- and (L)-isomer Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (D)- and (L)-isomer.
  • An isomer of a certain compound in the present disclosure can be prepared by asymmetric synthesis or chiral auxiliary agent, or, when the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxyl), with appropriate optical Reactive acids or bases form diastereomeric salts, which are then resolved by conventional methods well known in the art to yield the pure isomers. Furthermore, separation of enantiomers and diastereomers is usually accomplished by chromatography.
  • the bond " in the chemical structures of the compounds described in this disclosure, the bond " "indicates that no configuration is specified, i.e. if chiral isomers exist in the chemical structure, the bond” “can be” “or” , or both “ “and” "Both configurations. For all carbon-carbon double bonds, even if only one configuration is named, Z and E are included.
  • tautomer or tautomeric form
  • tautomer refers to structural isomers that exist in equilibrium and are readily converted from one isomeric form to the other. It includes all possible tautomers, ie present as single isomers or as mixtures of said tautomers in any ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactam, and the like. An example of lactam-lactim equilibrium is shown below:
  • Atropisomers may contain atropisomers.
  • the term "atropisomer" is the result of hindered or greatly slowed rotation about a single bond in a molecule (due to steric interactions with the rest of the molecule and the asymmetry of the substituents at either end of the single bond) ) resulting in conformational stereoisomers whose interconversion is slow enough to allow separation and isolation under predetermined conditions.
  • certain compounds of the present disclosure may be present as a mixture of atropisomers (e.g., an equal mixture, a mixture enriched in one atropisomer, etc.) or as a purified atropisomer exist. Non-limiting examples include: wait.
  • isotopic derivatives refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass.
  • isotopes that may be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, etc., such as 2 H (deuterium, D), respectively, 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N , 17 O, 18 O, 32 p, 33 p, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I, and 131 I, etc., preferably deuterium.
  • deuterated drugs Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic and side effects, increasing drug stability, enhancing curative effect, and prolonging the biological half-life of drugs. All permutations of isotopic composition of the disclosed compounds, whether radioactive or not, are included within the scope of the present disclosure.
  • Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, wherein the replacement of deuterium may be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.
  • deuterium When a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (i.e. at least 15% deuterium incorporation) that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) .
  • Exemplary compounds having a natural abundance greater than deuterium can be at least 1000 times more abundant deuterium (i.e. at least 15% deuterium incorporation), at least 2000 times more abundant deuterium (i.e. at least 30% deuterium incorporation) , at least 3000 times the abundance of deuterium (i.e. at least 45% deuterium incorporation), at least 3340 times the abundance of deuterium (i.e.
  • deuterium incorporation at least 50.1% deuterium incorporation), at least 3500 times the abundance of deuterium (i.e. at least 52.5% deuterium incorporation), at least 4000-fold more abundant deuterium (i.e. at least 60% deuterium incorporation), at least 4500-fold more abundant deuterium (i.e. at least 67.5% deuterium incorporation), at least 5000-fold Deuterium in abundance (i.e. at least 75% deuterium incorporation), deuterium in at least 5500 times abundance (i.e. at least 82.5% deuterium incorporation), deuterium in at least 6000 times abundance (i.e. at least 90% deuterium incorporation deuterium incorporation), at least 6333.3 times the abundance of deuterium (i.e.
  • deuterium incorporation at least 95% deuterium incorporation
  • at least 6466.7 times the abundance of deuterium i.e. at least 97% deuterium incorporation
  • at least 6600 times the abundance of deuterium That is, at least 99% deuterium incorporation
  • at least 6633.3 times the abundance of deuterium ie, at least 99.5% deuterium incorporation
  • or higher abundance of deuterium at least 95% deuterium incorporation
  • C 1-6 alkyl optionally (optionally) substituted by halogen or cyano includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen or cyano.
  • Substituted or “substituted” means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. Possible or impossible substitutions can be determined (by experiment or theory) by those skilled in the art without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated bond such as an alkene.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a pharmaceutically acceptable salt thereof, and other chemical components, such as pharmaceutically acceptable carriers and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt” refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have proper biological activity. They can be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
  • the term "therapeutically effective amount” refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect.
  • the determination of the therapeutically effective dose varies from person to person, depending on the age and general condition of the subject, and also depends on the specific active substance. The appropriate therapeutically effective dose in individual cases can be determined by those skilled in the art according to routine experiments.
  • the term "pharmaceutically acceptable” means those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with patient tissues without undue toxicity, irritation, allergic reaction or Other problems or complications that have a reasonable benefit/risk ratio and are valid for the intended use.
  • the preparation method of the compound represented by the general formula (IM) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • a compound represented by the general formula (IMa) or a salt thereof and a compound represented by the general formula (X) or a salt thereof are reacted under alkaline conditions to obtain a compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof;
  • L is halogen; preferably, L is Cl;
  • Rings A, V, X, Y, Z, R 2 , R 3 , R 4 , R 6 , R 11 , R 12 , R 13 , R 14 , s and t are as defined in general formula (IM).
  • the preparation method of the compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • a compound represented by general formula (Ia) or a salt thereof and a compound represented by general formula (X) or a salt thereof are reacted under alkaline conditions to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof;
  • L is halogen; preferably, L is Cl;
  • Rings A, X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 , R 11 , R 12 , R 13 , R 14 , s and t are as defined in the general formula (I).
  • the preparation method of the compound represented by the general formula (II) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • a compound represented by general formula (IIa) or a salt thereof and a compound represented by general formula (X) or a salt thereof are reacted under alkaline conditions to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof;
  • L is halogen; preferably, L is Cl;
  • Rings A, X, Z, R 3 , R 4 , R 5 , R 6 , R 11 , R 12 , R 13 , R 14 and t are as defined in the general formula (II).
  • the preparation method of the compound represented by the general formula (III) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • a compound represented by general formula (IIIa) or a salt thereof and a compound represented by general formula (XI) or a salt thereof are reacted under alkaline conditions to obtain a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof;
  • L is halogen; preferably, L is Cl;
  • W, Z, R 3 , R 4 , R 5 , R 6 , R 11 , R 12 , R 13 and t are as defined in the general formula (III).
  • the preparation method of the compound represented by the general formula (III-1) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • L is halogen; preferably, L is Cl;
  • W, Z, R 3 , R 4 , R 5 , R 6 , R 11 , R 12 , R 13 and t are as defined in the general formula (III-1).
  • the preparation method of the compound represented by the general formula (III-2) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • L is halogen; preferably, L is Cl;
  • W, Z, R 3 , R 4 , R 5 , R 6 , R 11 , R 12 , R 13 and t are as defined in the general formula (III-2).
  • the preparation method of the compound represented by general formula (III-1-A) and general formula (III-1-B) or a pharmaceutically acceptable salt thereof of the present disclosure comprises the following steps:
  • the compound shown in general formula (III-1) or its pharmaceutically acceptable salt obtains the compound shown in general formula (III-1-A) and general formula (III-1-B) through HPLC preparative chromatography resolution A compound or a pharmaceutically acceptable salt thereof;
  • W, Z, R 3 , R 4 , R 5 , R 6 , R 11 , R 12 , R 13 and t are as defined in the general formula (III-1).
  • the preparation method of the compound represented by general formula (III-2-A) and general formula (III-2-B) or a pharmaceutically acceptable salt thereof of the present disclosure comprises the following steps:
  • the compound shown in general formula (III-2) or its pharmaceutically acceptable salt obtains the compound shown in general formula (III-2-A) and general formula (III-2-B) through HPLC preparative chromatography resolution A compound or a pharmaceutically acceptable salt thereof;
  • W, Z, R 3 , R 4 , R 5 , R 6 , R 11 , R 12 , R 13 and t are as defined in the general formula (III-2).
  • the preparation method of the compound represented by the general formula (IMa) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • RL is halogen; preferably, RL is Br;
  • R W2 is an amino protecting group; preferably, R W2 is tert-butoxycarbonyl;
  • R X selected from R is a hydrogen atom or a C 1-6 alkyl group
  • Rings A, V, X, Y, Z, R2 , R3 , R4 , R6 , s and t are as defined in general formula (IMa).
  • the preparation method of the compound or its salt represented by the general formula (IMa) of the present disclosure comprises the following steps:
  • RL is halogen; preferably, RL is Br;
  • R W2 is an amino protecting group; preferably, R W2 is tert-butoxycarbonyl;
  • R X selected from R is a hydrogen atom or a C 1-6 alkyl group
  • Rings A, V, X, Y, Z, R2 , R3 , R4 , R6 , s and t are as defined in general formula (IMa).
  • the preparation method of the compound represented by the general formula (Ia) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • RL is halogen; preferably, RL is Br;
  • R W2 is an amino protecting group; preferably, R W2 is tert-butoxycarbonyl;
  • R X selected from R is a hydrogen atom or a C 1-6 alkyl group
  • Rings A, X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 , s and t are as defined in general formula (Ia).
  • the preparation method of the compound represented by general formula (Ia) or its salt of the present disclosure comprises the following steps:
  • RL is halogen; preferably, RL is Br;
  • R W2 is an amino protecting group; preferably, R W2 is tert-butoxycarbonyl;
  • R X selected from R is a hydrogen atom or a C 1-6 alkyl group
  • Rings A, X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 , s and t are as defined in general formula (Ia).
  • the preparation method of the compound represented by the general formula (IIa) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • RL is halogen; preferably, RL is Br;
  • R W2 is an amino protecting group; preferably, R W2 is tert-butoxycarbonyl;
  • R X selected from R is a hydrogen atom or a C 1-6 alkyl group
  • Rings A, X, Z, R 3 , R 4 , R 5 , R 6 and t are as defined in general formula (IIa).
  • the preparation method of the compound represented by general formula (IIa) or its salt of the present disclosure comprises the following steps:
  • RL is halogen; preferably, RL is Br;
  • R W2 is an amino protecting group; preferably, R W2 is tert-butoxycarbonyl;
  • R X selected from R is a hydrogen atom or a C 1-6 alkyl group
  • Rings A, X, Z, R 3 , R 4 , R 5 , R 6 and t are as defined in general formula (IIa).
  • the preparation method of the compound represented by the general formula (IIIa) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • RL is halogen; preferably, RL is Br;
  • Both R W1 and R W2 are amino protecting groups; preferably, R W1 and R W2 are both tert-butoxycarbonyl;
  • R X selected from R is a hydrogen atom or a C 1-6 alkyl group
  • W, Z, R 3 , R 4 , R 5 , R 6 and t are as defined in general formula (Ilia).
  • the preparation method of the compound represented by the general formula (III-1a) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • RL is halogen; preferably, RL is Br;
  • Both R W1 and R W2 are amino protecting groups; preferably, R W1 and R W2 are both tert-butoxycarbonyl;
  • R X selected from R is a hydrogen atom or a C 1-6 alkyl group
  • W, Z, R 3 , R 4 , R 5 , R 6 and t are as defined in the general formula (III-1a).
  • the preparation method of the compound represented by the general formula (III-2a) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • RL is halogen; preferably, RL is Br;
  • Both R W1 and R W2 are amino protecting groups; preferably, R W1 and R W2 are both tert-butoxycarbonyl;
  • R X selected from R is a hydrogen atom or a C 1-6 alkyl group
  • W, Z, R 3 , R 4 , R 5 , R 6 and t are as defined in the general formula (III-2a).
  • the Suzuki coupling reaction is preferably carried out between a base (such as potassium carbonate, cesium carbonate) and a metal catalyst (such as bis(diphenylphosphine phenyl ether) palladium(II) dichloride, dichloro[1,1' - in the presence of bis(di-tert-butylphosphino)ferrocenepalladium(II)).
  • a base such as potassium carbonate, cesium carbonate
  • a metal catalyst such as bis(diphenylphosphine phenyl ether) palladium(II) dichloride, dichloro[1,1' - in the presence of bis(di-tert-butylphosphino)ferrocenepalladium(II)
  • the bases that provide basic conditions include organic bases and inorganic bases
  • the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropyl lithium amide, potassium acetate, sodium acetate, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, preferably triethylamine
  • the inorganic base includes but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, Potassium carbonate water, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide, preferably potassium carbonate or anhydrous potassium carbonate.
  • the acids providing acidic conditions include organic acids and inorganic acids
  • the organic acids include but not limited to trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, Me 3 SiCl and TMSOTf, preferably Trifluoroacetic acid
  • said inorganic acid includes but not limited to hydrogen chloride, hydrogen chloride in 1,4-dioxane solution, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.
  • the above synthesis scheme is preferably carried out in a solvent, and the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-Hexane, Dimethyl Sulfoxide, 1,4-Dioxane, Water, N,N-Dimethylformamide, N,N-Dimethylacetamide and mixtures thereof.
  • the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-Hexane, Dimethyl Sulfoxide, 1,4-Dioxane
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • MS uses Agilent 1200/1290DAD-6110/6120Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS); waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector); THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
  • HPLC High performance liquid chromatography
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the known starting materials of the present disclosure can be adopted or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui chemical companies.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.
  • the hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), the developer used for reaction, the eluent system of the column chromatography that purifies compound adopts and the developer system of thin-layer chromatography comprise: A: Petroleum ether/ethyl acetate system, B: dichloromethane/methanol system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • TLC thin-layer chromatography
  • Methyl 2-amino-4-bromo-5-fluoro-3-methylbenzoate 1a (2.7g, 10.3mmol, prepared by the method disclosed in step (iv) on page 103 of the specification in the patent application "WO2016020836A1" ) was dissolved in chloroform (50mL), acetic anhydride (3.16g, 30.9mmol) was added, the temperature was kept below 40°C, and potassium acetate (302mg, 3.08mmol) and tert-butyl nitrite (2.12g, 20.6mmol), reflux reaction for 14 hours.
  • reaction solution was cooled to room temperature, diluted with dichloromethane (50 mL), washed with water (30 mL), saturated sodium carbonate solution (10 mL), and saturated sodium chloride solution (10 mL) successively, and the organic phase was dried over anhydrous sodium sulfate, filtered, and The filtrate was concentrated under reduced pressure to obtain the crude title compound 1b (2.8 g), which was directly used in the next reaction without purification.
  • reaction solution was concentrated under reduced pressure to remove most of the solvent, added water, extracted with ethyl acetate (150mL ⁇ 6), combined the organic phases, washed with dilute hydrochloric acid and saturated sodium chloride solution successively, dried over anhydrous sodium sulfate, and filtered to remove the desiccant , the filtrate was concentrated under reduced pressure to obtain crude compound 1c (1.4 g), which was directly used in the next reaction without purification.
  • reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, saturated sodium carbonate solution, and saturated sodium chloride solution successively, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. Purification with eluent system A afforded the title compound If (600 mg, yield: 54.9%).
  • HPLC analysis retention time 1.12 minutes, purity: 99% (chromatographic column: ACQUITY BEH, C18, 1.7 ⁇ m, 2.1*50mm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • the crude compound 2c (382mg, 0.69mmol) was dissolved in 5mL N,N-dimethylformamide, sodium hydrogen (53mg, 1.38mmol, 60% purity) was added and stirred for 1 hour, and the reaction solution was quenched by adding saturated ammonium chloride solution. and extracted with ethyl acetate (5mL ⁇ 3), combined organic phases, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove desiccant, concentrated under reduced pressure, and the residue was washed by silica gel column chromatography. The title compound 2d (160 mg, yield: 50.7%) was obtained by purification of the stripping system A.
  • Embodiment 6-P1, 6-P2 Embodiment 6-P1, 6-P2
  • HPLC analysis retention time 2.29 minutes, purity: 95% (chromatographic column: ACQUITY BEH, C18, 1.7 ⁇ m, 2.1*50mm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • Embodiment 8-P1, 8-P2 Embodiment 8-P1, 8-P2
  • reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, saturated sodium carbonate solution, and saturated sodium chloride solution in turn, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 8b (1.5 g ), the product was directly used in the next step without purification.
  • the crude compound 8b (1.3 g, 2.65 mmol) was dissolved in 20 mL of tetrahydrofuran, and triphenylphosphine (1.39 g, 5.3 mmol), diethyl azodicarboxylate (1.07 g, 5.3mmol), kept the temperature and stirred for 30 minutes, the reaction solution was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate (15mL ⁇ 2), combined the organic phases, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate , filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 8c (200 mg, yield: 15.9%).
  • Crude compound 8e (100 mg, 140 ⁇ mol) was suspended in 2 mL of ethyl acetate, 1 mL of tetrahydrofuran and 2 mL of water, anhydrous potassium carbonate (100 mg, 723 ⁇ mol) was added, and acryloyl chloride (14 mg, 154 ⁇ mol) was added under ice cooling, reacted for 5 minutes and then used Extracted with ethyl acetate (5mL ⁇ 2), combined the organic phases, and concentrated under reduced pressure to obtain the crude compound 8, namely 4-((S)-10-acryloyl-2,4-difluoro-14-oxo-8, 8a,9,10,11,12-Hexahydro-7H,14H-pyrazino[1',2':5,6][1,5]diazacyclo[3,2,1-hi ]indazol-3-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (
  • HPLC analysis retention time 1.20 minutes, purity: 99% (chromatographic column: ACQUITY BEH, C18, 1.7 ⁇ m, 2.1*50mm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 1.23 minutes, purity: 99% (chromatographic column: ACQUITY BEH, C18, 1.7 ⁇ m, 2.1*50mm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • Methyl 2-amino-4-bromo-5-fluoro-3-iodobenzoate 9a was dissolved in N,N-Dimethylformamide (100mL), add bistriphenylphosphine palladium dichloride (1.87g, 2.67mmol), tributyl (1-ethoxyethylene) tin (5.79g, 16.04mmol, Shaoyuan, Shanghai), replaced with nitrogen, and reacted at 90°C for 12 hours.
  • reaction solution was cooled to room temperature, added 10% potassium fluoride aqueous solution, stirred for 30 minutes, filtered, the filtrate was separated, the organic phase was added with 10mL concentrated hydrochloric acid and stirred for 16 hours, and the pH was adjusted to neutral with saturated sodium carbonate solution, ethyl acetate (50mL ⁇ 3) extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered to remove the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 9b (1.8g, yield: 46.4%).
  • reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, saturated sodium carbonate solution, and saturated sodium chloride solution successively, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 9e (1.2g ), the product was directly used in the next step without purification.
  • the crude compound 9e (1.28g, 2.63mmol) was dissolved in 50mL of tetrahydrofuran, and triphenylphosphine (1.38g, 5.26mmol) and diethyl azodicarboxylate (1.06g, 5.26mmol), kept the temperature and stirred for 30 minutes, the reaction solution was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate (20mL ⁇ 2), combined organic phases, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate , filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 9f (650 mg, yield: 52.7%).
  • HPLC analysis retention time 1.17 minutes, purity: 99% (chromatographic column: ACQUITY BEH, C18, 1.7 ⁇ m, 2.1*50mm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 1.19 minutes, purity: 99% (chromatographic column: ACQUITY BEH, C18, 1.7 ⁇ m, 2.1*50mm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • Example 1-P1 and 1-P2 Using the synthetic route in Example 1-P1 and 1-P2, the third step raw material compound 1d was replaced by (2R,5S)-5-(2-hydroxyethyl)-2-methylpiperazine-1 formic acid tertiary Butyl ester 10a (prepared by the method disclosed in preparation 67 on page 80 of the patent application "WO2021118877A1") gave the title compound 10 (72 mg, yield: 62.2%).
  • HPLC analysis retention time 2.05 minutes, purity: 96% (chromatographic column: ACQUITY BEH, C18, 1.7 ⁇ m, 2.1*50mm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 2.10 minutes, purity: 97% (chromatographic column: ACQUITY BEH, C18, 1.7 ⁇ m, 2.1*50mm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • Example 1-P2 and 1-P2 Using the synthetic route in Example 1-P1 and 1-P2, the third step raw material compound 1d is replaced by (R)-3-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester 12a (using literature "Tetrahedron Letters, 2018, 59 (21), 2030-2033" published method preparation), to obtain the title compound 12-P2 (5mg, yield: 9.7%) and 12-P1 (1.5mg, yield: 2.9%) .
  • HPLC analysis retention time 2.42 minutes, purity: 99% (chromatographic column: C18, 2.7 ⁇ m, 3.0*30mm; mobile phase: water (1 ⁇ trifluoroacetic acid), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 2.45 minutes, purity: 92% (chromatographic column: C18, 2.7 ⁇ m, 3.0*30mm; mobile phase: water (1 ⁇ trifluoroacetic acid), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • the reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, saturated sodium carbonate solution, and saturated sodium chloride solution in turn, the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was prepared by HPLC Chromatographic purification (Waters-2545, chromatographic column: SharpSil-T C18, 30*150mm, 5 ⁇ m; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate : 30 mL/min) to obtain the title compound 14b (100 mg, yield: 10.1%).
  • reaction solution was quenched by adding a small amount of water, concentrated under reduced pressure, dissolved in 5mL N,N-dimethylformamide, added potassium carbonate (226mg, 1.6mmol), stirred and reacted at 80°C for 1 hour, and the reaction solution was cooled to room temperature After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 14c (30 mg, yield: 12.4%).
  • HPLC analysis retention time 1.27 minutes, purity: 99% (chromatographic column: ACQUITY BEH, C18, 1.7 ⁇ m, 2.1*50mm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 1.28 minutes, purity: 99% (chromatographic column: ACQUITY BEH, C18, 1.7 ⁇ m, 2.1*50mm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

Abstract

本公开涉及含氮的四环化合物、其制备方法及其在医药上的应用。具体而言，本公开涉及一种通式(IM)所示的含氮的四环化合物、其制备方法及含有该化合物的药物组合物以及其作为治疗剂的用途，特别是作为KRAS G12C抑制剂的用途和用于制备治疗和/或预防肿瘤的药物中的用途。

Description

含氮的四环化合物、其制备方法及其在医药上的应用 技术领域
本公开属于医药领域，涉及一种含氮的四环化合物、其制备方法及其在医药上的应用。具体而言，本公开涉及一种通式(IM)所示的含氮的四环化合物、其制备方法及含有该化合物的药物组合物以及其作为治疗剂的用途，特别是作为KRAS G12C抑制剂的用途和用于制备治疗和/或预防肿瘤的药物中的用途。
背景技术
RAS(Rat Sarcoma Viral Oncogene Homolog)家族属于小GTP酶超家族，广泛表达于各类真核生物。人体中有三种RAS基因(HRAS、KRAS和NARS)，可表达为四种高度相关的RAS小GTP酶(HRAS、KRAS4A、KARS4B和NRAS)。其作为GDP-GTP调控的二元开关发生作用。通常情况下它们有两种表现形式：非激活状态下的GDP(二磷酸鸟苷)结合形式和激活状态下的GTP(三磷酸鸟苷)结合形式。RAS蛋白通过在两种活性状态间切换，来调控包括RAF-MEK-ERK、PI3K/Akt/mTOR在内的多个下游通路，从而影响细胞的生长、增殖和分化(Nat Rev Cancer,2007,7,295-308)。RAS基因在胰腺癌、结直肠癌、非小细胞肺癌等多种肿瘤中突变率较高，激活的突变RAS蛋白会促进异常信号转导，从而导致癌症发生和发展，以及对靶向药产生耐药性。其中KRAS突变是人类致癌基因中突变率最高的基因，占所有肿瘤的20～30％。
对于KRAS蛋白的突变形式和信号通路研究，近年来分子生物学已取得重大进展，然而开发相关的靶向药物却依然挑战重重。在化学药开发方面，由于KRAS和GTP的亲和力非常高，达到60pM，而且细胞内GTP浓度在mM水平，因此这类直接竞争的分子对化合物亲和力要求极高，目前为止还没有成功的案例。在生物药开发方面，抗体药穿透细胞膜靶向KRAS蛋白，药物递送效率比较低下。所以不少研究者曾试图另辟蹊径，希望抑制KRAS下游信号通路中RAF、MEK和ERK等激酶的活性，达到抑制KRAS通路的目的。这类化合物有一定疗效，但是由于下游抑制剂不能完全阻断KRAS信号，而且靶点相关毒副作用很大，导致这些化合物在KRAS突变肿瘤上药效欠佳。因此，开发新作用机理的KRAS抑制剂有非常大的临床应用价值。
KRAS突变以点突变为主，包括12、13和61位氨基酸的突变。其中12位的甘氨酸突变成半胱氨酸(G12C)最为常见，该突变在肺癌、尤其是非小细胞肺癌中比例较大(14％)，此外还在一些结直肠癌(4％)、胰腺癌(2％)患者体内表达。在美国癌症人群中，该基因突变发生率甚至大于ALK、RET、TRK基因突变总和。
面对KRAS蛋白成药性的难点，加州大学旧金山分校Kevan M.Shokat教授率先验证了某些特殊的化合物可通过共价键绑定KRAS G12C突变蛋白。通过进一步 研究发现，这些共价化合物可与KRAS突变蛋白12位的半胱氨酸结合，并占据II号分子开关区域(switch-II regions)一个疏水别构调节口袋，被绑定的KRAS G12C突变体会被不可逆地锁定在失活状态，从而阻断依赖该蛋白的信号通路和癌细胞生存能力(Nature 2013,503,548-551)。KRAS G12C小分子抑制剂ARS-1620在多种KRAS G12C突变肿瘤模型上都能有效抑制肿瘤生长，甚至使肿瘤完全消退。由于KRAS G12C是肿瘤细胞中的突变蛋白，而野生型KRAS并没有这个突变位点，因此提供了一个完美的肿瘤选择性靶标(Cell,2018,572,578-589)。
KRAS G12C吸引了国内外众多知名的新药研发企业参与其中。虽然进展最快的安进的小分子KRAS G12C抑制剂Sotorasib(AMG510)已于2021年5月28日被FDA批准上市，用于至少接受过一次***治疗且携带KRAS G12C突变的非小细胞肺癌患者，但礼来的新一代KRAS G12C抑制剂LY3537982更加备受关注。礼来在2021年4月美国癌症研究协会(AACR)年会上报告了LY3537982的临床前数据，数据显示，LY3537982较Sotorasib的细胞活性抑制高出了10余倍，已于2021年7月进入临床一期。可见，临床上仍需高选择性、安全和有效的KRAS G12C抑制剂。
现已公开KRAS G12C抑制剂的专利申请包括WO2014152588A1、WO2015054572A1、WO2016164675A1、WO2017087528A1、WO2017201161A1、WO2018119183A2、WO2018206539A1、WO2018217651A1、WO2019099524A1、WO2019215203A1、WO2020081282A1、WO2020178282A1、WO2021118877A1等。
发明内容
本公开的目的在于提供一种通式(IM)所示的化合物或其可药用的盐：
Figure PCTCN2022126650-appb-000001
其中：
X为C(R aR b)或C(R aR b)-C(R cR d)；
Y为C(O)或CH 2；
Z为CR 5a或N；
V为CR 5或N；
环A为芳基或杂芳基；
R a、R b、R c和R d在每次出现时相同或不同，且各自独立地选自氢原子、卤素、 烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、羟基和氰基；
R 1选自氰基、
Figure PCTCN2022126650-appb-000002
各个R 2相同或不同，且各自独立地选自氢原子、卤素、氰基、烷基、烷氧基、羟基和氨基，其中所述的烷基和烷氧基各自独立地任选被选自卤素、氰基、氨基和羟基中的一个或多个取代基所取代；
R 3、R 4、R 5和R 5a相同或不同，且各自独立地选自氢原子、卤素、氰基、烷基、烯基、炔基、-NR 7aR 7b、-C(O)R 8、-OR 8、-S(O) pR 8、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、卤代烷基、氰基、-NR 7cR 7d、-OR 8a、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
各个R 6相同或不同，且各自独立地选自氢原子、卤素、氰基、烷基、烯基、炔基、-NR 9aR 9b、-C(O)NR 9aR 9b、-C(O)R 10、-C(O)OR 10、-OC(O)R 10、-OR 10、-S(O) pR 10、-S(O) pNR 9aR 9b、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、卤代烷基、氰基、-NR 9cR 9d、-OR 10a、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 11、R 12、R 13和R 14相同或不同，且各自独立地选自氢原子、卤素、烷基、-NR 15aR 15b、-OR 16、氰基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、氧代基、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、-NR 15cR 15d、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 8、R 8a、R 10、R 10a和R 16在每次出现时相同或不同，且各自独立地选自氢原子、烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、氧代基、烷氧基、卤代烷基、卤代烷氧基、氰基、-NR 17aR 17b、羟基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 7a、R 7b、R 7c、R 7d、R 9a、R 9b、R 9c、R 9d、R 15a、R 15b、R 15c、R 15d、R 17a和R 17b在每次出现时相同或不同，且各自独立地选自氢原子、烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、氧代基、羟基、氰基、烷基、烷氧基、卤代烷基和卤代烷氧基中的一个或多个取代基所取代；
或者R 7a和R 7b与相连的氮原子一起形成杂环基，其中所述杂环基任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或者R 7c和R 7d与相连的氮原子一起形成杂环基，其中所述杂环基任选被选自 卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或者R 9a和R 9b与相连的氮原子一起形成杂环基，其中所述杂环基任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或者R 9c和R 9d与相连的氮原子一起形成杂环基，其中所述杂环基任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或者R 15a和R 15b与相连的氮原子一起形成杂环基，其中所述杂环基任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或者R 15c和R 15d与相连的氮原子一起形成杂环基，其中所述杂环基任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或者R 17a和R 17b与相连的氮原子一起形成杂环基，其中所述杂环基任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
s为0、1、2、3、4、5或6；
t为0、1、2、3、4或5；且
p为0、1或2。
在本公开一些实施方案中，所述的通式(IM)所示的化合物或其可药用的盐，其中V为CR 5，R 5如通式(IM)中所定义。
在本公开一些实施方案中，所述的通式(IM)所示的化合物或其可药用的盐，其中V为N。
在本公开一些实施方案中，所述的通式(IM)所示的化合物或其可药用的盐，其为通式(I)所示的化合物或其可药用的盐：
Figure PCTCN2022126650-appb-000003
其中：
X为C(R aR b)或C(R aR b)-C(R cR d)；
Y为C(O)或CH 2；
Z为CR 5a或N；
环A为芳基或杂芳基；
R a、R b、R c和R d在每次出现时相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、羟基和氰基；
R 1选自氰基、
Figure PCTCN2022126650-appb-000004
各个R 2相同或不同，且各自独立地选自氢原子、卤素、氰基、烷基、烷氧基、羟基和氨基，其中所述的烷基和烷氧基各自独立地任选被选自卤素、氰基、氨基和羟基中的一个或多个取代基所取代；
R 3、R 4、R 5和R 5a相同或不同，且各自独立地选自氢原子、卤素、氰基、烷基、烯基、炔基、-NR 7aR 7b、-C(O)R 8、-OR 8、-S(O) pR 8、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、卤代烷基、氰基、-NR 7cR 7d、-OR 8a、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
各个R 6相同或不同，且各自独立地选自氢原子、卤素、氰基、烷基、烯基、炔基、-NR 9aR 9b、-C(O)NR 9aR 9b、-C(O)R 10、-C(O)OR 10、-OC(O)R 10、-OR 10、-S(O) pR 10、-S(O) pNR 9aR 9b、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、卤代烷基、氰基、-NR 9cR 9d、-OR 10a、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 11、R 12、R 13和R 14相同或不同，且各自独立地选自氢原子、卤素、烷基、-NR 15aR 15b、-OR 16、氰基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、氧代基、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、-NR 15cR 15d、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 8、R 8a、R 10、R 10a和R 16在每次出现时相同或不同，且各自独立地选自氢原子、烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、氧代基、烷氧基、卤代烷基、卤代烷氧基、氰基、-NR 17aR 17b、羟基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 7a、R 7b、R 7c、R 7d、R 9a、R 9b、R 9c、R 9d、R 15a、R 15b、R 15c、R 15d、R 17a和R 17b在每次出现时相同或不同，且各自独立地选自氢原子、烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、氧代基、羟基、氰基、烷基、烷氧基、卤代烷基和卤代烷氧基中的一个或多个取代基所取代；
或者R 7a和R 7b与相连的氮原子一起形成杂环基，其中所述杂环基任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或者R 7c和R 7d与相连的氮原子一起形成杂环基，其中所述杂环基任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或者R 9a和R 9b与相连的氮原子一起形成杂环基，其中所述杂环基任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或者R 9c和R 9d与相连的氮原子一起形成杂环基，其中所述杂环基任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或者R 15a和R 15b与相连的氮原子一起形成杂环基，其中所述杂环基任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或者R 15c和R 15d与相连的氮原子一起形成杂环基，其中所述杂环基任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或者R 17a和R 17b与相连的氮原子一起形成杂环基，其中所述杂环基任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
s为0、1、2、3、4、5或6；
t为0、1、2、3、4或5；且
p为0、1或2。
在本公开一些实施方案中，所述的通式(IM)、通式(I)所示的化合物或其可药用的盐，其中Y为C(O)。
在本公开一些实施方案中，所述的通式(IM)、通式(I)所示的化合物或其可药用的盐，其中各个R 2相同或不同，且各自独立地选自氢原子、卤素、氰基、C 1-6烷基、C 1-6烷氧基、羟基和氨基，其中所述的C 1-6烷基任选被选自卤素和氰基中的一个或多个取代基所取代；优选地，各个R 2相同或不同，且各自独立地为氢原子或C 1-6烷基；更优选地，各个R 2相同或不同，且各自独立地为氢原子或甲基；最优选地，R 2为氢原子。
在本公开一些实施方案中，所述的通式(IM)、通式(I)所示的化合物或其可药用的盐，其中s为0、1或2；优选地，s为0或1；更优选地，s为0。
在本公开一些实施方案中，所述的通式(IM)、通式(I)所示的化合物或其可药用的盐，其中各个R 2相同或不同，且各自独立地选自卤素、氰基、C 1-6烷基、C 1-6 烷氧基、羟基和氨基，其中所述的C 1-6烷基任选被选自卤素和氰基中的一个或多个取代基所取代，且s为0、1或2；优选地，R 2为C 1-6烷基，且s为0或1；更优选地，R 2为甲基，且s为0或1。
在本公开一些实施方案中，所述的通式(IM)、通式(I)所示的化合物或其可药用的盐，其为通式(II)所示的化合物或其可药用的盐：
Figure PCTCN2022126650-appb-000005
其中：
环A、X、Z、R 1、R 3、R 4、R 5、R 6和t如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)所示的化合物或其可药用的盐，其中环A为6至10元芳基或5至10元杂芳基；优选地，环A为5至10元杂芳基；更优选地，环A为环内含有1、2或3个选自氮、氧和硫的杂原子的8至10元双环杂芳基；最优选地，环A为苯并噻吩基或苯并噻唑基。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)所示的化合物或其可药用的盐，其中
Figure PCTCN2022126650-appb-000006
为
Figure PCTCN2022126650-appb-000007
W为C(CN)或N，t为0、1、2或3，R 6如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)所示的化合物或其可药用的盐，其中R 1为
Figure PCTCN2022126650-appb-000008
其中R 11、R 12、R 13和R 14如通式(I)中所定义；优选地，R 1为
Figure PCTCN2022126650-appb-000009
其中R 11、R 12和R 13如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)所示的化合物或其可药用的盐，其中X为C(R aR b)-C(R cR d)，R a、R b、R c和R d如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)所示的化合物或其可药用的盐，其中R a、R b、R c和R d相同或不同，且各自独立地选自氢原子、 卤素、C 1-6烷基和C 1-6卤代烷基；优选地，R a、R b、R c和R d均为氢原子。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)所示的化合物或其可药用的盐，其中X为CH 2或CH 2-CH 2；优选地，X为CH 2-CH 2。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)所示的化合物或其可药用的盐，其为通式(III)所示的化合物或其可药用的盐：
Figure PCTCN2022126650-appb-000010
其中：
W为C(CN)或N；
t为0、1、2或3；
Z、R 3、R 4、R 5、R 6、R 11、R 12和R 13如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其为通式(III-1)所示的化合物或其可药用的盐：
Figure PCTCN2022126650-appb-000011
其中：
W为C(CN)或N；
t为0、1、2或3；
Z、R 3、R 4、R 5、R 6、R 11、R 12和R 13如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其为通式(III-2)所示的化合物或其可药用的盐：
Figure PCTCN2022126650-appb-000012
其中：
W为C(CN)或N；
t为0、1、2或3；
Z、R 3、R 4、R 5、R 6、R 11、R 12和R 13如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-1)所示的化合物或其可药用的盐，其为通式(III-1-A)所示的化合物或其可药用的盐：
Figure PCTCN2022126650-appb-000013
其中：
W为C(CN)或N；
t为0、1、2或3；
Z、R 3、R 4、R 5、R 6、R 11、R 12和R 13如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-1)所示的化合物或其可药用的盐，其为通式(III-1-B)所示的化合物或其可药用的盐：
Figure PCTCN2022126650-appb-000014
其中：
W为C(CN)或N；
t为0、1、2或3；
Z、R 3、R 4、R 5、R 6、R 11、R 12和R 13如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-2)所示的化合物或其可药用的盐，其为通式(III-2-A)所示的化合物或其可药用的盐：
Figure PCTCN2022126650-appb-000015
其中：
W为C(CN)或N；
t为0、1、2或3；
Z、R 3、R 4、R 5、R 6、R 11、R 12和R 13如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-2)所示的化合物或其可药用的盐，其为通式(III-2-B)所示的化合物或其可药用的盐：
Figure PCTCN2022126650-appb-000016
其中：
W为C(CN)或N；
t为0、1、2或3；
Z、R 3、R 4、R 5、R 6、R 11、R 12和R 13如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)所示的化合物或其可药用的盐，其中W为C(CN)。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)所示的化合物或其可药用的盐，其中R 3、R 4、R 5和R 5a相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)所示的化合物或其可药用的盐，其中R 3选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；优选地，R 3为氢原子或卤素；更优选地，R 3为氢原子或F；最优选地，R 3 为氢原子。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)所示的化合物或其可药用的盐，其中R 4选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；优选地，R 4为卤素；更优选地，R 4为F。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)所示的化合物或其可药用的盐，其中R 5选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；优选地，R 5选自氢原子、卤素和C 1-6烷基；更优选地，R 5为卤素或C 1-6烷基；最优选地，R 5为Cl或甲基。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)所示的化合物或其可药用的盐，其中R 5选自氢原子、F、Cl和甲基。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)所示的化合物或其可药用的盐，其中R 5a选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；优选地，R 5a为氢原子或C 1-6烷基；更优选地，R 5a为氢原子或甲基。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)所示的化合物或其可药用的盐，其中Z为CR 5a或N，且R 5a选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；优选地，Z为CR 5a或N，且R 5a为氢原子或C 1-6烷基；更优选地，Z为N。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)所示的化合物或其可药用的盐，其中各个R 6相同或不同，且各自独立地选自氢原子、卤素、氰基、-NH 2、C 1-6烷基和C 1-6卤代烷基；优选地，各个R 6相同或不同，且各自独立地选自氢原子、卤素、氰基和-NH 2。
在本公开一些实施方案中，所述的通式(IM)、通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)所示的化合物或其可药用的盐，其中各个R 6相同或不同，且各自独立地选自氢原子、卤素、氰基、-NH 2、C 1-6烷基和C 1-6卤代烷基；优选地，各个R 6相同或不同，且各自独立地为氢原子或卤素；更优选地，各个R 6相同或不同，且各自独立地为氢原子或F。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)所示的化合物或其可药用的盐，其中R 11选自氢原子、卤素和C 1-6烷基；优选地，R 11为氢原子或卤素；更优选地，R 11为氢原子或F。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)、通式(III)、通 式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)所示的化合物或其可药用的盐，其中R 12选自氢原子、卤素和C 1-6烷基；优选地，R 12为氢原子。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)所示的化合物或其可药用的盐，其中R 13选自氢原子、卤素和C 1-6烷基；优选地，R 13为氢原子。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)所示的化合物或其可药用的盐，其中R 14选自氢原子、卤素和C 1-6烷基；优选地，R 14为氢原子。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)所示的化合物或其可药用的盐，其中t为0、1、2或3。
在本公开一些实施方案中，所述的通式(IM)、通式(I)、通式(II)所示的化合物或其可药用的盐，其中各个R 6相同或不同，且各自独立地选自卤素、氰基、-NH 2、C 1-6烷基和C 1-6卤代烷基，且t为0、1、2或3。
在本公开一些实施方案中，所述的通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)所示的化合物或其可药用的盐，其中t为0或1。
在本公开一些实施方案中，所述的通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)所示的化合物或其可药用的盐，其中R 6为卤素，且t为0或1。
在本公开一些实施方案中，所述的通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)所示的化合物或其可药用的盐，其中R 6为F，且t为0或1。
在本公开一些实施方案中，所述的通式(IM)所示的化合物或其可药用的盐，其中V为CR 5或N；X为C(R aR b)或C(R aR b)-C(R cR d)；R a、R b、R c和R d相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；Y为C(O)；Z为CR 5a或N；环A为5至10元杂芳基；R 1为
Figure PCTCN2022126650-appb-000017
R 3、R 4、R 5和R 5a相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 2为C 1-6烷基，且s为0或1；各个R 6相同或不同，且各自独立地选自卤素、氰基、-NH 2、C 1-6烷基和C 1-6卤代烷基，且t为0、1、2或3；R 11选自氢原子、卤素和C 1-6烷基；R 12选自氢原子、卤素和C 1-6烷基；R 13选自氢原子、卤素和C 1-6烷基；R 14选自氢原子、卤素和C 1-6烷基。
在本公开一些实施方案中，所述的通式(IM)所示的化合物或其可药用的盐，其中V为CR 5或N；X为CH 2或CH 2-CH 2；Y为C(O)；Z为CR 5a或N；R 5a为氢原子或C 1-6烷基；R 1为
Figure PCTCN2022126650-appb-000018
R 3为氢原子或卤素；R 4为卤素；R 5选自氢原子、卤素和C 1-6烷基；R 2为C 1-6烷基，且s为0或1；
Figure PCTCN2022126650-appb-000019
为
Figure PCTCN2022126650-appb-000020
W为C(CN)或N；各个R 6相同或不同，且各自独立地选自卤素、氰基、-NH 2、C 1-6烷基和C 1-6卤代烷基，且t为0、1、2或3；R 11选自氢原子、卤素和C 1-6烷基；R 12选自氢原子、卤素和C 1-6烷基；且R 13选自氢原子、卤素和C 1-6烷基。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中X为C(R aR b)或C(R aR b)-C(R cR d)；R a、R b、R c和R d相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；Y为C(O)；Z为CR 5a或N；环A为5至10元杂芳基；R 1为
Figure PCTCN2022126650-appb-000021
R 3、R 4、R 5和R 5a相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 2为C 1-6烷基，且s为0或1；各个R 6相同或不同，且各自独立地选自卤素、氰基、-NH 2、C 1-6烷基和C 1-6卤代烷基，且t为0、1、2或3；R 11选自氢原子、卤素和C 1-6烷基；R 12选自氢原子、卤素和C 1-6烷基；R 13选自氢原子、卤素和C 1-6烷基；R 14选自氢原子、卤素和C 1-6烷基。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中X为C(R aR b)或C(R aR b)-C(R cR d)；R a、R b、R c和R d相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；Y为C(O)；Z为CR 5a或N；环A为5至10元杂芳基；R 1为
Figure PCTCN2022126650-appb-000022
R 3、R 4、R 5和R 5a相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；s为0；各个R 6相同或不同，且各自独立地选自卤素、氰基、-NH 2、C 1-6烷基和C 1-6卤代烷基，且t为0、1、2或3；R 11选自氢原子、卤素和C 1-6烷基；R 12选自氢原子、卤素和C 1-6烷基；R 13选自氢原子、卤素和C 1-6烷基；R 14选自氢原子、卤素和C 1-6烷基。
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中环A为环内含有1、2或3个选自氮、氧和硫的杂原子的8至10元双环杂芳基； X为CH 2或CH 2-CH 2；Z为CR 5a或N；R 1为
Figure PCTCN2022126650-appb-000023
R 3、R 4、R 5和R 5a相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；各个R 6相同或不同，且各自独立地选自卤素、氰基、-NH 2、C 1-6烷基和C 1-6卤代烷基，且t为0、1、2或3；R 11为氢原子或卤素；R 12为氢原子；R 13为氢原子。
在本公开一些实施方案中，所述的通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)所示的化合物或其可药用的盐，其中W为C(CN)或N；Z为CR 5a或N；R 3、R 4、R 5和R 5a相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 11为氢原子或卤素；R 12为氢原子；R 13为氢原子；R 6为卤素，且t为0或1。
在本公开一些实施方案中，所述的通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)所示的化合物或其可药用的盐，其中W为C(CN)或N；Z为CR 5a或N，且R 5a为氢原子或C 1-6烷基；R 3为氢原子或卤素；R 4为卤素；R 5选自氢原子、卤素和C 1-6烷基；R 11为氢原子或卤素；R 12为氢原子；R 13为氢原子；R 6为卤素，且t为0或1。
在本公开一些实施方案中，所述的通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)所示的化合物或其可药用的盐，其中W为C(CN)；Z为N；R 3为氢原子；R 4为卤素；R 5选自氢原子、卤素和C 1-6烷基；R 11为氢原子或卤素；R 12为氢原子；R 13为氢原子；R 6为卤素，且t为0或1。
表A本公开的典型化合物包括但不限于：
Figure PCTCN2022126650-appb-000024
Figure PCTCN2022126650-appb-000025
Figure PCTCN2022126650-appb-000026
Figure PCTCN2022126650-appb-000027
Figure PCTCN2022126650-appb-000028
Figure PCTCN2022126650-appb-000029
Figure PCTCN2022126650-appb-000030
Figure PCTCN2022126650-appb-000031
Figure PCTCN2022126650-appb-000032
Figure PCTCN2022126650-appb-000033
Figure PCTCN2022126650-appb-000034
Figure PCTCN2022126650-appb-000035
Figure PCTCN2022126650-appb-000036
Figure PCTCN2022126650-appb-000037
Figure PCTCN2022126650-appb-000038
Figure PCTCN2022126650-appb-000039
Figure PCTCN2022126650-appb-000040
Figure PCTCN2022126650-appb-000041
Figure PCTCN2022126650-appb-000042
本公开的另一方面涉及通式(IMa)所示的化合物或其盐：
Figure PCTCN2022126650-appb-000043
其中：
环A、V、X、Y、Z、R 2、R 3、R 4、R 6、s和t如通式(IM)中所定义。
本公开的另一方面涉及通式(Ia)所示的化合物或其盐：
Figure PCTCN2022126650-appb-000044
其中：
环A、X、Y、Z、R 2、R 3、R 4、R 5、R 6、s和t如通式(I)中所定义。
本公开的另一方面涉及通式(IIa)所示的化合物或其盐：
Figure PCTCN2022126650-appb-000045
其中：
环A、X、Z、R 3、R 4、R 5、R 6和t如通式(II)中所定义。
本公开的另一方面涉及通式(IIIa)所示的化合物或其盐：
Figure PCTCN2022126650-appb-000046
其中：
W、Z、R 3、R 4、R 5、R 6和t如通式(III)中所定义。
本公开的另一方面涉及通式(III-1a)所示的化合物或其盐：
Figure PCTCN2022126650-appb-000047
其中：
W、Z、R 3、R 4、R 5、R 6和t如通式(III-1)中所定义。
本公开的另一方面涉及通式(III-2a)所示的化合物或其盐：
Figure PCTCN2022126650-appb-000048
其中：
W、Z、R 3、R 4、R 5、R 6和t如通式(III-2)中所定义。
本公开的另一方面涉及通式(III-1-Aa)所示的化合物或其盐：
Figure PCTCN2022126650-appb-000049
其中：
W、Z、R 3、R 4、R 5、R 6和t如通式(III-1-A)中所定义。
本公开的另一方面涉及通式(III-1-Ba)所示的化合物或其盐：
Figure PCTCN2022126650-appb-000050
其中：
W、Z、R 3、R 4、R 5、R 6和t如通式(III-1-B)中所定义。
本公开的另一方面涉及通式(III-2-Aa)所示的化合物或其盐：
Figure PCTCN2022126650-appb-000051
其中：
W、Z、R 3、R 4、R 5、R 6和t如通式(III-2-A)中所定义。
本公开的另一方面涉及通式(III-2-Ba)所示的化合物或其盐：
Figure PCTCN2022126650-appb-000052
其中：
W、Z、R 3、R 4、R 5、R 6和t如通式(III-2-B)中所定义。
表B本公开的典型中间体化合物包括但不限于：
Figure PCTCN2022126650-appb-000053
Figure PCTCN2022126650-appb-000054
Figure PCTCN2022126650-appb-000055
Figure PCTCN2022126650-appb-000056
Figure PCTCN2022126650-appb-000057
Figure PCTCN2022126650-appb-000058
Figure PCTCN2022126650-appb-000059
Figure PCTCN2022126650-appb-000060
Figure PCTCN2022126650-appb-000061
Figure PCTCN2022126650-appb-000062
Figure PCTCN2022126650-appb-000063
Figure PCTCN2022126650-appb-000064
本公开的通式(IMa)、通式(Ia)、通式(IIa)、通式(IIIa)、通式(III-1a)、通式(III-2a)、通式(III-1-Aa)、通式(III-1-Ba)、通式(III-2-Aa)、通式(III-2-Ba)所示的化合物或其盐，其中所述的盐优选二(2,2,2-三氟乙酸)盐。
本公开的另一方面涉及通式(IMaa)所示的化合物或其盐：
Figure PCTCN2022126650-appb-000065
其中：
R W2为氨基保护基；优选地，R W2为叔丁氧羰基；
环A、V、X、Y、Z、R 2、R 3、R 4、R 6、s和t如通式(IMa)中所定义。
本公开的另一方面涉及通式(IMaa)所示的化合物或其盐：
Figure PCTCN2022126650-appb-000066
其中：
Figure PCTCN2022126650-appb-000067
为
Figure PCTCN2022126650-appb-000068
R W1和R W2相同或不同，且各自独立地为氨基保护基；优选地，R W1和R W2均为叔丁氧羰基；
t为0、1、2或3；
V、X、Y、Z、R 2、R 3、R 4、R 6和s如通式(IMa)中所定义。
本公开的另一方面涉及通式(Iaa)所示的化合物或其盐：
Figure PCTCN2022126650-appb-000069
其中：
R W2为氨基保护基；优选地，R W2为叔丁氧羰基；
环A、X、Y、Z、R 2、R 3、R 4、R 5、R 6、s和t如通式(Ia)中所定义。
本公开的另一方面涉及通式(Iaa)所示的化合物或其盐：
Figure PCTCN2022126650-appb-000070
其中：
Figure PCTCN2022126650-appb-000071
为
Figure PCTCN2022126650-appb-000072
R W1和R W2相同或不同，且各自独立地为氨基保护基；优选地，R W1和R W2均为叔丁氧羰基；
t为0、1、2或3；
X、Y、Z、R 2、R 3、R 4、R 5、R 6和s如通式(Ia)中所定义。
本公开的另一方面涉及通式(IIaa)所示的化合物或其盐：
Figure PCTCN2022126650-appb-000073
其中：
R W2为氨基保护基；优选地，R W2为叔丁氧羰基；
环A、X、Z、R 3、R 4、R 5、R 6和t如通式(IIa)中所定义。
本公开的另一方面涉及通式(IIaa)所示的化合物或其盐：
Figure PCTCN2022126650-appb-000074
其中：
Figure PCTCN2022126650-appb-000075
为
Figure PCTCN2022126650-appb-000076
R W1和R W2相同或不同，且各自独立地为氨基保护基；优选地，R W1和R W2均为叔丁氧羰基；
t为0、1、2或3；
X、Z、R 3、R 4、R 5和R 6如通式(IIa)中所定义。
本公开的另一方面涉及通式(IIIaa)所示的化合物或其盐：
Figure PCTCN2022126650-appb-000077
其中：
R W1和R W2相同或不同，且各自独立地为氨基保护基；优选地，R W1和R W2均为叔丁氧羰基；
W、Z、R 3、R 4、R 5、R 6和t如通式(IIIa)中所定义。
本公开的另一方面涉及通式(III-1aa)所示的化合物或其盐：
Figure PCTCN2022126650-appb-000078
其中：
R W1和R W2相同或不同，且各自独立地为氨基保护基；优选地，R W1和R W2均为叔丁氧羰基；
W、Z、R 3、R 4、R 5、R 6和t如通式(III-1a)中所定义。
本公开的另一方面涉及通式(III-2aa)所示的化合物或其盐：
Figure PCTCN2022126650-appb-000079
其中：
R W1和R W2相同或不同，且各自独立地为氨基保护基；优选地，R W1和R W2均为叔丁氧羰基；
W、Z、R 3、R 4、R 5、R 6和t如通式(III-2a)中所定义。
表C本公开的典型中间体化合物包括但不限于：
Figure PCTCN2022126650-appb-000080
Figure PCTCN2022126650-appb-000081
Figure PCTCN2022126650-appb-000082
Figure PCTCN2022126650-appb-000083
Figure PCTCN2022126650-appb-000084
Figure PCTCN2022126650-appb-000085
Figure PCTCN2022126650-appb-000086
Figure PCTCN2022126650-appb-000087
本公开的另一方面涉及一种制备通式(IM)所示的化合物或其可药用的盐的方法，其包括：
Figure PCTCN2022126650-appb-000088
通式(IMa)所示的化合物或其盐和通式(X)化合物或其盐发生反应得到通式(IM)所示的化合物或其可药用的盐；
其中：
L为卤素；优选地，L为Cl；
R 1为
Figure PCTCN2022126650-appb-000089
环A、V、X、Y、Z、R 2、R 3、R 4、R 6、R 11、R 12、R 13、R 14、s和t如通式(IM)中所定义。
本公开的另一方面涉及一种制备通式(I)所示的化合物或其可药用的盐的方法，其包括：
Figure PCTCN2022126650-appb-000090
通式(Ia)所示的化合物或其盐和通式(X)化合物或其盐发生反应得到通式(I)所示的化合物或其可药用的盐；
其中：
L为卤素；优选地，L为Cl；
R 1为
Figure PCTCN2022126650-appb-000091
环A、X、Y、Z、R 2、R 3、R 4、R 5、R 6、R 11、R 12、R 13、R 14、s和t如通式(I)中所定义。
本公开的另一方面涉及一种制备通式(II)所示的化合物或其可药用的盐的方法，其包括：
Figure PCTCN2022126650-appb-000092
通式(IIa)所示的化合物或其盐和通式(X)化合物或其盐发生反应得到通式(II)所示的化合物或其可药用的盐；
其中：
L为卤素；优选地，L为Cl；
R 1为
Figure PCTCN2022126650-appb-000093
环A、X、Z、R 3、R 4、R 5、R 6、R 11、R 12、R 13、R 14和t如通式(II)中所定义。
本公开的另一方面涉及一种制备通式(III)所示的化合物或其可药用的盐的方法，其包括：
Figure PCTCN2022126650-appb-000094
通式(IIIa)所示的化合物或其盐和通式(XI)化合物或其盐发生反应得到通式(III)所示的化合物或其可药用的盐；
其中：
L为卤素；优选地，L为Cl；
W、Z、R 3、R 4、R 5、R 6、R 11、R 12、R 13和t如通式(III)中所定义。
本公开的另一方面涉及一种制备通式(III-1)所示的化合物或其可药用的盐的方法，其包括：
Figure PCTCN2022126650-appb-000095
通式(III-1a)所示的化合物或其盐和通式(XI)化合物或其盐发生反应得到通式(III-1)所示的化合物或其可药用的盐；
其中：
L为卤素；优选地，L为Cl；
W、Z、R 3、R 4、R 5、R 6、R 11、R 12、R 13和t如通式(III-1)中所定义。
本公开的另一方面涉及一种制备通式(III-2)所示的化合物或其可药用的盐的方法，其包括：
Figure PCTCN2022126650-appb-000096
通式(III-2a)所示的化合物或其盐和通式(XI)化合物或其盐发生反应得到通式(III-2)所示的化合物或其可药用的盐；
其中：
L为卤素；优选地，L为Cl；
W、Z、R 3、R 4、R 5、R 6、R 11、R 12、R 13和t如通式(III-2)中所定义。
本公开的另一方面涉及一种制备通式(III-1-A)和通式(III-1-B)所示的化合物或其可药用的盐的方法，其包括：
Figure PCTCN2022126650-appb-000097
通式(III-1)所示的化合物或其可药用的盐经拆分得到通式(III-1-A)和通式(III-1-B)所示的化合物或其可药用的盐；
其中：
W、Z、R 3、R 4、R 5、R 6、R 11、R 12、R 13和t如通式(III-1)中所定义。
本公开的另一方面涉及一种制备通式(III-2-A)和通式(III-2-B)所示的化合物或其可药用的盐的方法，其包括：
Figure PCTCN2022126650-appb-000098
通式(III-2)所示的化合物或其可药用的盐经拆分得到通式(III-2-A)和通式(III-2-B)所示的化合物或其可药用的盐；
其中：
W、Z、R 3、R 4、R 5、R 6、R 11、R 12、R 13和t如通式(III-2)中所定义。
本公开的另一方面涉及一种制备通式(IMa)所示的化合物或其可药用的盐的方法，其包括：
Figure PCTCN2022126650-appb-000099
通式(IMaa)所示的化合物或其盐脱去R W2得到通式(IMa)所示的化合物或其可药用的盐；
其中：
R W2为氨基保护基；优选地，R W2为叔丁氧羰基；
环A、V、X、Y、Z、R 2、R 3、R 4、R 6、s和t如通式(IMa)中所定义。
本公开的另一方面涉及一种制备通式(IMa)所示的化合物或其盐的方法，其包括：
Figure PCTCN2022126650-appb-000100
通式(IMaa)所示的化合物或其盐脱去R W2得到通式(IMa)所示的化合物或其盐；任选地，当R 6基团上含有保护基时，在所述脱保护反应之前、同时或之后还包括脱去R 6基团上的保护基的步骤；
其中：
R W2为氨基保护基；优选地，R W2为叔丁氧羰基；
环A、V、X、Y、Z、R 2、R 3、R 4、R 6、s和t如通式(IMa)中所定义。
本公开的另一方面涉及一种制备通式(Ia)所示的化合物或其可药用的盐的方法，其包括：
Figure PCTCN2022126650-appb-000101
通式(Iaa)所示的化合物或其盐脱去R W2得到通式(Ia)所示的化合物或其可药用的盐；
其中：
R W2为氨基保护基；优选地，R W2为叔丁氧羰基；
环A、X、Y、Z、R 2、R 3、R 4、R 5、R 6、s和t如通式(Ia)中所定义。
本公开的另一方面涉及一种制备通式(Ia)所示的化合物或其盐的方法，其包括：
Figure PCTCN2022126650-appb-000102
通式(Iaa)所示的化合物或其盐脱去R W2得到通式(Ia)所示的化合物或其盐；任 选地，当R 6基团上含有保护基时，在所述脱保护反应之前、同时或之后还包括脱去R 6基团上的保护基的步骤；
其中：
R W2为氨基保护基；优选地，R W2为叔丁氧羰基；
环A、X、Y、Z、R 2、R 3、R 4、R 5、R 6、s和t如通式(Ia)中所定义。
本公开的另一方面涉及一种制备通式(IIa)所示的化合物或其可药用的盐的方法，其包括：
Figure PCTCN2022126650-appb-000103
通式(IIaa)所示的化合物或其盐脱去R W2得到通式(IIa)所示的化合物或其可药用的盐；
其中：
R W2为氨基保护基；优选地，R W2为叔丁氧羰基；
环A、X、Z、R 3、R 4、R 5、R 6和t如通式(IIa)中所定义。
本公开的另一方面涉及一种制备通式(IIa)所示的化合物或其盐的方法，其包括：
Figure PCTCN2022126650-appb-000104
通式(IIaa)所示的化合物或其盐脱去R W2得到通式(IIa)所示的化合物或其盐；任选地，当R 6基团上含有保护基时，在所述脱保护反应之前、同时或之后还包括脱去R 6基团上的保护基的步骤；
其中：
R W2为氨基保护基；优选地，R W2为叔丁氧羰基；
环A、X、Z、R 3、R 4、R 5、R 6和t如通式(IIa)中所定义。
本公开的另一方面涉及一种制备通式(IIIa)所示的化合物或其可药用的盐的方法，其包括：
Figure PCTCN2022126650-appb-000105
通式(IIIaa)所示的化合物或其盐脱去R W1和R W2得到通式(IIIa)所示的化合物或其可药用的盐；
其中：
R W1和R W2均为氨基保护基；优选地，R W1和R W2均为叔丁氧羰基；
W、Z、R 3、R 4、R 5、R 6和t如通式(IIIa)中所定义。
本公开的另一方面涉及一种制备通式(III-1a)所示的化合物或其可药用的盐的方法，其包括：
Figure PCTCN2022126650-appb-000106
通式(III-1aa)所示的化合物或其盐脱去R W1和R W2得到通式(III-1a)所示的化合物或其可药用的盐；
其中：
R W1和R W2均为氨基保护基；优选地，R W1和R W2均为叔丁氧羰基；
W、Z、R 3、R 4、R 5、R 6和t如通式(III-1a)中所定义。
本公开的另一方面涉及一种制备通式(III-2a)所示的化合物或其可药用的盐的方法，其包括：
Figure PCTCN2022126650-appb-000107
通式(III-2aa)所示的化合物或其盐脱去R W1和R W2得到通式(III-2a)所示的化合物或其可药用的盐；
其中：
R W1和R W2均为氨基保护基；优选地，R W1和R W2均为叔丁氧羰基；
W、Z、R 3、R 4、R 5、R 6和t如通式(III-2a)中所定义。
本公开的另一方面涉及一种药物组合物，所述药物组合物含有本公开通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)以及表A所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开进一步涉及通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)以及表A所示的化合物或其可药用的盐或包含其的药物组合物在制备用于抑制KRAS G12C的药物中的用途。
本公开进一步涉及通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)以及表A所示的化合物或其可药用的盐或包含其的药物组合物在制备用于治疗和/或预防由KRAS G12C介导的疾病或病症的药物中的用途。
本公开进一步涉及通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)以及表A所示的化合物或其可药用的盐或包含其的药物组合物在制备用于治疗和/或预防肿瘤的药物中的用途。
本公开还涉及一种抑制KRAS G12C的方法，其包括给予所需患者治疗有效量的通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物。
本公开还涉及一种治疗和/或预防由KRAS G12C介导的疾病或病症的方法，其包括给予所需患者治疗有效量的通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物。
本公开还涉及一种治疗和/或预防肿瘤的方法，其包括给予所需患者治疗有效量的通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物。
本公开进一步涉及一种通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用作药物。
本公开进一步涉及通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用作KRAS G12C抑制剂。
本公开进一步涉及通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-1)、通式 (III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用于治疗和/或预防由KRAS G12C介导的疾病或病症。
本公开进一步涉及通式(IM)、通式(I)、通式(II)、通式(III)、通式(III-1)、通式(III-2)、通式(III-1-A)、通式(III-1-B)、通式(III-2-A)、通式(III-2-B)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用于治疗和/或预防肿瘤。
本公开中如上所述的肿瘤优选为癌症；进一步优选地，所述的癌症选自肺癌(如非小细胞肺癌和小细胞肺癌)、胰腺癌、***、食管癌(又称食道癌)、子宫内膜癌、卵巢癌、胆管癌、结直肠癌(如结肠癌和直肠癌)、肝癌、乳腺癌、***癌、甲状腺癌、胃癌、尿路上皮癌、睾丸癌、白血病、皮肤癌、鳞状细胞癌、基底细胞癌、膀胱癌、头颈癌、肾癌、鼻咽癌、骨癌、淋巴瘤、黑色素瘤、肉瘤、外周神经上皮瘤、胶质瘤(如星形细胞瘤和成胶质细胞瘤)、脑瘤和骨髓瘤；更优选地，所述的癌症选自肺癌、胰腺癌、***、食管癌、子宫内膜癌、卵巢癌、胆管癌和结直肠癌。
本公开中如上所述的由KRAS G12C介导的疾病或病症优选为肿瘤；进一步优选地，所述的肿瘤为癌症；更优选地，所述的癌症选自肺癌(如非小细胞肺癌和小细胞肺癌)、胰腺癌、***、食管癌(又称食道癌)、子宫内膜癌、卵巢癌、胆管癌、结直肠癌(如结肠癌和直肠癌)、肝癌、乳腺癌、***癌、甲状腺癌、胃癌、尿路上皮癌、睾丸癌、白血病、皮肤癌、鳞状细胞癌、基底细胞癌、膀胱癌、头颈癌、肾癌、鼻咽癌、骨癌、淋巴瘤、黑色素瘤、肉瘤、外周神经上皮瘤、胶质瘤(如星形细胞瘤和成胶质细胞瘤)、脑瘤和骨髓瘤；最优选地，所述的癌症选自肺癌、胰腺癌、***、食管癌、子宫内膜癌、卵巢癌、胆管癌和结直肠癌。
作为一般性指导，本公开活性化合物优选是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。合适的单位剂量可以是0.1～1000mg。
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料可选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。 这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水混悬液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使活性成分悬浮于植物油或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油、矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳，可通过局部大量注射将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、***的速率、药物的组合、疾病的严重性等；另外，最佳的治疗方式如治疗的模式、化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
术语说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和的直链或带有支链的脂肪族烃基，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或 20个)碳原子(即C 1-20烷基)。所述烷基优选具有1至12个碳原子的烷基(即C 1-12烷基)，更优选具有1至6个碳原子的烷基(即C 1-6烷基)。非限制性的实例包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自氘原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“烯基”指分子中含有至少一个碳碳双键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子(即C 2-12烯基)。所述烯基优选具有2至6个碳原子的烯基(即C 2-6烯基)。非限制性的实例包括：乙烯基、丙烯基、异丙烯基、丁烯基等。烯基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自氘原子、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“炔基”指分子中含有至少一个碳碳三键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子(即C 2-12炔基)。所述炔基优选具有2至6个碳原子的炔基(即C 2-6炔基)。非限制性的实例包括：乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。炔基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自氘原子、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。非限制性的实例包括：甲氧基、乙氧基、丙氧基和丁氧基等。烷氧基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自氘原子、卤素、 烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“环烷基”指饱和或部分不饱和的单环全碳环(即单环环烷基)或多环***(即多环环烷基)，其具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即3至20元环烷基)。所述环烷基优选具有3至12个环原子的环烷基(即3至12元环烷基)，更优选具有3至8个环原子的环烷基(即3至8元环烷基)，最优选具有3至6个环原子的环烷基(即3至6元环烷基)。
所述的单环环烷基，非限制性的实例包括：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基和环辛基等。
所述的多环环烷基包括：螺环烷基、稠环烷基和桥环烷基。
术语“螺环烷基”指环之间共用一个碳原子(称螺原子)的多环***，其环内可以含有一个或多个双键，或其环内可以含有一个或多个选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，条件是至少含有一个全碳环且连接点在该全碳环上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺环烷基)。所述螺环烷基优选具有6至14个环原子的螺环烷基(即6至14元螺环烷基)，更优选具有7至10个环原子的螺环烷基(即7至10元螺环烷基)。所述螺环烷基包括单螺环烷基和多螺环烷基(如双螺环烷基等)，优选单螺环烷基或双螺环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺环烷基。非限制性的实例包括：
Figure PCTCN2022126650-appb-000108
其连接点可在任意位置；
Figure PCTCN2022126650-appb-000109
等。
术语“稠环烷基”指环之间共享毗邻的两个碳原子的多环***，其为单环环烷基与一个或多个单环环烷基稠合，或者单环环烷基与杂环基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环环烷基上，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠环烷基)。所述稠环烷基优选具有6至14个环原子的稠环烷基(即6至14元稠环烷基)，更优选具有7至10个环原子的稠环烷基(即7至10元稠环烷基)。所述稠环烷基包括双环稠环烷基和多环稠 环烷基(如三环稠环烷基、四环稠环烷基等)，优选双环稠环烷基或三环稠环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠环烷基。非限制性的实例包括：
Figure PCTCN2022126650-appb-000110
其连接点可在任意位置；
Figure PCTCN2022126650-appb-000111
Figure PCTCN2022126650-appb-000112
等。
术语“桥环烷基”指环之间共用两个不直接连接的碳原子的全碳多环***，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即5至20元桥环烷基)。所述桥环烷基优选具有6至14个碳原子的桥环烷基(即6至14元桥环烷基)，更优选具有7至10个碳原子的桥环烷基(即7至10元桥环烷基)。所述桥环烷基包括双环桥环烷基和多环桥环烷基(如三环桥环烷基、四环桥环烷基等)，优选双环桥环烷基或三环桥环烷基。非限制性的实例包括：
Figure PCTCN2022126650-appb-000113
其连接点可在任意位置。
环烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自氘原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“杂环基”指饱和或部分不饱和的单环杂环(即单环杂环基)或多环杂环***(即多环杂环基)，其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，且具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即3至20元杂环基)。所述杂环基优选具有3至12个环原子的杂环基(即3至12元杂环基)；进一步优选具有3至8个环原子的杂环基(即3至8元杂环基)；更优选具有3至6个环原子的杂环基(即3至6元杂环基)；最优选具有5或6个环原子的杂环基(即5或6元杂环基)。
所述的单环杂环基，非限制性的实例包括：吡咯烷基、四氢吡喃基、1,2,3,6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基和高哌嗪基等。
所述的多环杂环基包括螺杂环基、稠杂环基和桥杂环基。
术语“螺杂环基”指环之间共用一个原子(称螺原子)的多环杂环***，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，条件是至少含有一个单环杂环基且连接点在该单环杂环基上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺杂环基)。所述螺杂环基优选具有6至14个环原子的螺杂环基(即6至14元螺杂环基)，更优选具有7至10个环原子的螺杂环基(即7至10元螺杂环基)。所述螺杂环基包括单螺杂环基和多螺杂环基(如双螺杂环基等)，优选单螺杂环基或双螺杂环基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺杂环基。非限制性的实例包括：
Figure PCTCN2022126650-appb-000114
等。
术语“稠杂环基”指环之间共享毗邻的两个原子的多环杂环***，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其为单环杂环基与一个或多个单环杂环基稠合，或者单环杂环基与环烷基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环杂环基上，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠杂环基)。所述稠杂环基优选具有6至14个环原子的稠杂环基(即6至14元稠杂环基)，更优选具有7至10个环原子的稠杂环基(即7至10元稠杂环基)。所述稠杂环基包括双环和多环稠杂环基(如三环稠杂环基、四环稠杂环基等)，优选双环稠杂环基或三环稠杂环基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠杂环基。非限制性的实例包括：
Figure PCTCN2022126650-appb-000115
Figure PCTCN2022126650-appb-000116
等。
术语“桥杂环基”指环之间共用两个不直接连接的原子的多环杂环***，其环内可以含有一个或多个双键，并且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元桥杂环基)。所述桥杂环基优选具有6至14个环原子的桥杂环基(即6至14元桥杂环基)，更优选具有7至10个环原子的桥杂环基(即7至10元桥杂环基)。根据组成环的数目可以分为双环桥杂环基和多环桥杂环基(如三环桥杂环基、四环桥杂环基等)，优选双环桥杂环基或三环桥杂环基。非限制性的实例包括：
Figure PCTCN2022126650-appb-000117
等。
杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自氘原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“芳基”指具有共轭的π电子体系的单环全碳芳环(即单环芳基)或多环芳环***(即多环芳基)，其具有6至14个(例如6、7、8、9、10、11、12、13或14个)环原子(即6至14元芳基)。所述芳基优选具有6至10个环原子的芳基(即6至10元芳基)。所述的单环芳基，例如苯基。所述的多环芳基，非限制性的实例包括：萘基、蒽基、菲基等。所述多环芳基还包括苯基与杂环基或环烷基中的一个或多个稠合，或萘基与杂环基或环烷基中的一个或多个稠合，其中连接点在苯基或萘基上，并且在这种情况下，环原子个数继续表示多环芳环***中的环原子个数，非限制性的实例包括：
Figure PCTCN2022126650-appb-000118
等。
芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自氘原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“杂芳基”指具有共轭的π电子体系的单环杂芳环(即单环杂芳基)或多环杂芳环***(即多环杂芳基)，其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其具有5至14个(例如5、6、7、8、9、10、11、12、13或14个)环原子(即5至14元杂芳基)。所述杂芳基优选具有5至10个环原子的杂芳基(即5至10元杂芳基)，更优选具有5或6个环原子的单环杂芳基(即5或6元单环杂芳基)或具有8至10个环原子的双环杂芳基(即8至10元双环杂芳基)，最优选环内含有1、2或3个选自氮、氧和硫的杂原子的5或6元单环杂芳基或环内含有1、2或3个选自氮、氧和硫的杂原子的8至10元双环杂芳基。
所述的单环杂芳基，非限制性的实例包括：呋喃基、噻吩基、噻唑基、异噻唑基、噁唑基、异噁唑基、噁二唑基、噻二唑基、咪唑基、吡唑基、***基、四唑基、呋咱基、吡咯基、N-烷基吡咯基、吡啶基、嘧啶基、吡啶酮基、N-烷基吡啶酮(如
Figure PCTCN2022126650-appb-000119
等)、吡嗪基、哒嗪基等。
所述的多环杂芳基，非限制性的实例包括：吲哚基、吲唑基、喹啉基、异喹啉基、喹喔啉基、酞嗪基、苯并咪唑基、苯并噻吩基、喹唑啉基、苯并噻唑基、咔唑基等。所述多环杂芳基还包括单环杂芳基与一个或多个芳基稠合，其中连接点在芳香环上，并且在这种情况下，环原子个数继续表示多环杂芳环***中的环原子个数。所述多环杂芳基还包括单环杂芳基与环烷基或杂环基中的一个或多个稠合，其中连接点在单环杂芳环上，并且在这种情况下，环原子个数继续表示多环杂芳环***中的环原子个数。非限制性的实例包括：
Figure PCTCN2022126650-appb-000120
Figure PCTCN2022126650-appb-000121
等。
杂芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自氘原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“氨基保护基”是指为了使分子其它部位进行反应时氨基保持不变，在氨基上引入的易于脱去的基团。非限制性的实例包括：(三甲基硅)乙氧基甲基、四氢吡喃基、叔丁氧羰基(Boc)、苄氧羰基(Cbz)、笏甲氧羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、甲氧羰基、乙氧羰基、邻苯二甲酰基(Pht)、对甲苯磺酰基(Tos)、三氟乙酰基(Tfa)、三苯甲基(Trt)、2,4-二甲氧基苄基(DMB)、乙酰基、苄基、烯丙基、对甲氧苄基等。
术语“羟基保护基”是指在羟基上引入的易于脱去的基团，用于阻断或保护羟基而在化合物的其它官能团上进行反应。非限制性的实例包括：三甲基硅基(TMS)、三乙基硅基(TES)、三异丙基硅基(TIPS)、叔丁基二甲基硅基(TBS)、叔丁基二苯基硅基(TBDPS)、甲基、叔丁基、烯丙基、苄基、甲氧基甲基(MOM)、乙氧基乙基、2-四氢吡喃基(THP)、甲酰基、乙酰基、苯甲酰基、对硝基苯甲酰基等。
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。
术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。
术语“芳基氧基”指芳基-O-，其中芳基如上所定义。
术语“杂芳基氧基”指杂芳基-O-，其中杂芳基如上所定义。
术语“烷硫基”指烷基-S-，其中烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。
术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如上所定义。
术语“卤素”指氟、氯、溴或碘。
术语“羟基”指-OH。
术语“巯基”指-SH。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代”或“氧代基”指“＝O”。
术语“羰基”指C＝O。
术语“羧基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)、-C(O)O(环烷基)、(烷基)C(O)O-或(环烷基)C(O)O-，其中烷基和环烷基如上所定义。
本公开化合物可以存在特定的立体异构体形式。术语“立体异构体”是指结构相同但原子在空间中的排列不同的异构体。其包括顺式和反式(或Z和E)异构体、(-)-和(+)-异构体、(R)-和(S)-对映异构体、非对映异构体、(D)-和(L)-异构体、 互变异构体、阻转异构体、构象异构体及其混合物(如外消旋体、非对映异构体的混合物)。本公开化合物中的取代基可以存在另外的不对称原子。所有这些立体异构体以及它们的混合物，均包括在本公开的范围内。可以通过手性合成、手性试剂或者其他常规技术制备光学活性的(-)-和(+)-异构体、(R)-和(S)-对映异构体以及(D)-和(L)-异构体。本公开某化合物的一种异构体，可以通过不对称合成或者手性助剂来制备，或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，得到纯的异构体。此外，对映异构体和非对映异构体的分离通常是通过色谱法完成。
本公开所述化合物的化学结构中，键“
Figure PCTCN2022126650-appb-000122
”表示未指定构型，即如果化学结构中存在手性异构体，键“
Figure PCTCN2022126650-appb-000123
”可以为“
Figure PCTCN2022126650-appb-000124
”或“
Figure PCTCN2022126650-appb-000125
”，或者同时包含“
Figure PCTCN2022126650-appb-000126
”和“
Figure PCTCN2022126650-appb-000127
”两种构型。对于所有的碳-碳双键，即使仅命名了一个构型，Z型和E型均包括在内。
本公开的化合物可以以不同的互变异构体形式存在，并且所有这样的形式包含在本公开的范围内。术语“互变异构体”或“互变异构体形式”是指平衡存在并且容易从一种异构形式转化为另一种异构形式的结构异构体。其包括所有可能的互变异构体，即以单一异构体的形式或以所述互变异构体的任意比例的混合物的形式存在。非限制性的实例包括：酮-烯醇、亚胺-烯胺、内酰胺-内酰亚胺等。内酰胺-内酰亚胺平衡实例如下所示：
Figure PCTCN2022126650-appb-000128
如当提及吡唑基时，应理解为包括如下两种结构中的任何一种或两种互变异构体的混合物：
Figure PCTCN2022126650-appb-000129
所有的互变异构形式在本公开的范围内，且化合物的命名不排除任何互变异构体。
本公开的化合物可包含阻转异构体。术语“阻转异构体”是由于围绕分子中单键的旋转受阻或大大减慢(这是由于与分子的其它部分的空间相互作用和在单键的两端处取代基是不对称的结果)而产生的构象立体异构体，其互变是足够慢的，以允许在预定条件下分开和分离。例如，某些本公开化合物可以以阻转异构体的混合物的形式(如等比例混合物、富集一种阻转异构体的混合物等)或经纯 化的一种阻转异构体的形式存在。非限制性的实例包括：
Figure PCTCN2022126650-appb-000130
Figure PCTCN2022126650-appb-000131
等。
本公开的化合物包括其化合物的所有合适的同位素衍生物。术语“同位素衍生物”是指至少一个原子被具有相同原子序数但原子质量不同的原子替代的化合物。可引入到本公开化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘等的稳定和放射性的同位素，例如分别为 2H(氘，D)、 3H(氚，T)、 11C、 13C、 14C、 15N、 17O、 18O、 32p、 33p、 33S、 34S、 35S、 36S、 18F、 36Cl、 82Br、 123I、 124I、 125I、 129I和 131I等，优选氘。
相比于未氘代药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。与碳原子连接的各个可用的氢原子可独立地被氘原子替换，其中氘的替换可以是部分或完全的，部分氘的替换是指至少一个氢被至少一个氘替换。
当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即至少15％的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘(即至少15％的氘掺入)、至少2000倍的丰度的氘(即至少30％的氘掺入)、至少3000倍的丰度的氘(即至少45％的氘掺入)、至少3340倍的丰度的氘(即至少50.1％的氘掺入)、至少3500倍的丰度的氘(即至少52.5％的氘掺入)、至少4000倍的丰度的氘(即至少60％的氘掺入)、至少4500倍的丰度的氘(即至少67.5％的氘掺入)、至少5000倍的丰度的氘(即至少75％的氘掺入)、至少5500倍的丰度的氘(即至少82.5％的氘掺入)、至少6000倍的丰度的氘(即至少90％的氘掺入)、至少6333.3倍的丰度的氘(即至少95％的氘掺入)、至少6466.7倍的丰度的氘(即至少97％的氘掺入)、至少6600倍的丰度的氘(即至少99％的氘掺入)、至少6633.3倍的丰度的氘(即至少99.5％的氘掺入)或更高丰度的氘。
“任选地”或“任选”是指随后所描述的事件或环境可以但不必然发生，其包括该事件或环境发生或不发生两种情形。例如“任选地(任选)被卤素或者氰 基取代的C 1-6烷基”包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。
“取代”或“取代的”指基团中的一个或多个氢原子，优选1～6个，更优选1～3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和键的碳原子(如烯)结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其可药用的盐与其他化学组分的混合物，以及其他组分例如药学上可接受的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用的盐”或“药学上可接受的盐”是指本公开化合物的盐，可选自无机盐或有机盐。这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。
针对药物或药理学活性剂而言，术语“治疗有效量”是指足以达到或至少部分达到预期效果的药物或药剂的用量。治疗有效量的确定因人而异，取决于受试者的年龄和一般情况，也取决于具体的活性物质，个案中合适的治疗有效量可以由本领域技术人员根据常规实验确定。
本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。
本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。
当将术语“约”应用于诸如pH、浓度、温度等参数时，表明该参数可以变化±10％，并且有时更优选地在±5％之内。如本领域技术人员将理解的，当参数不是关键时，通常仅出于说明目的给出数字，而不是限制。
本公开化合物的合成方法
为了完成本公开的目的，本公开采用如下技术方案：
方案一
本公开通式(IM)所示的化合物或其可药用的盐的制备方法，其包括以下步骤：
Figure PCTCN2022126650-appb-000132
通式(IMa)所示的化合物或其盐和通式(X)所示的化合物或其盐在碱性条件下发生反应得到通式(IM)所示的化合物或其可药用的盐；
其中：
L为卤素；优选地，L为Cl；
R 1为
Figure PCTCN2022126650-appb-000133
环A、V、X、Y、Z、R 2、R 3、R 4、R 6、R 11、R 12、R 13、R 14、s和t如通式(IM)中所定义。
方案二
本公开通式(I)所示的化合物或其可药用的盐的制备方法，其包括以下步骤：
Figure PCTCN2022126650-appb-000134
通式(Ia)所示的化合物或其盐和通式(X)所示的化合物或其盐在碱性条件下发生反应得到通式(I)所示的化合物或其可药用的盐；
其中：
L为卤素；优选地，L为Cl；
R 1为
Figure PCTCN2022126650-appb-000135
环A、X、Y、Z、R 2、R 3、R 4、R 5、R 6、R 11、R 12、R 13、R 14、s和t如通式(I)中所定义。
方案三
本公开通式(II)所示的化合物或其可药用的盐的制备方法，其包括以下步骤：
Figure PCTCN2022126650-appb-000136
通式(IIa)所示的化合物或其盐和通式(X)所示的化合物或其盐在碱性条件下发生反应得到通式(II)所示的化合物或其可药用的盐；
其中：
L为卤素；优选地，L为Cl；
R 1为
Figure PCTCN2022126650-appb-000137
环A、X、Z、R 3、R 4、R 5、R 6、R 11、R 12、R 13、R 14和t如通式(II)中所定义。
方案四
本公开通式(III)所示的化合物或其可药用的盐的制备方法，其包括以下步骤：
Figure PCTCN2022126650-appb-000138
通式(IIIa)所示的化合物或其盐和通式(XI)所示的化合物或其盐在碱性条件下发生反应得到通式(III)所示的化合物或其可药用的盐；
其中：
L为卤素；优选地，L为Cl；
W、Z、R 3、R 4、R 5、R 6、R 11、R 12、R 13和t如通式(III)中所定义。
方案五
本公开通式(III-1)所示的化合物或其可药用的盐的制备方法，其包括以下步骤：
Figure PCTCN2022126650-appb-000139
通式(III-1a)所示的化合物或其盐和通式(XI)所示的化合物或其盐在碱性条件下发生反应得到通式(III-1)所示的化合物或其可药用的盐；
其中：
L为卤素；优选地，L为Cl；
W、Z、R 3、R 4、R 5、R 6、R 11、R 12、R 13和t如通式(III-1)中所定义。
方案六
本公开通式(III-2)所示的化合物或其可药用的盐的制备方法，其包括以下步骤：
Figure PCTCN2022126650-appb-000140
通式(III-2a)所示的化合物或其盐和通式(XI)所示的化合物或其盐在碱性条件下发生反应得到通式(III-2)所示的化合物或其可药用的盐；
其中：
L为卤素；优选地，L为Cl；
W、Z、R 3、R 4、R 5、R 6、R 11、R 12、R 13和t如通式(III-2)中所定义。
方案七
本公开通式(III-1-A)和通式(III-1-B)所示的化合物或其可药用的盐的制备方法，其包括以下步骤：
Figure PCTCN2022126650-appb-000141
通式(III-1)所示的化合物或其可药用的盐经高效液相制备色谱法拆分得到通式(III-1-A)和通式(III-1-B)所示的化合物或其可药用的盐；
其中：
W、Z、R 3、R 4、R 5、R 6、R 11、R 12、R 13和t如通式(III-1)中所定义。
方案八
本公开通式(III-2-A)和通式(III-2-B)所示的化合物或其可药用的盐的制备方法，其包括以下步骤：
Figure PCTCN2022126650-appb-000142
通式(III-2)所示的化合物或其可药用的盐经高效液相制备色谱法拆分得到通 式(III-2-A)和通式(III-2-B)所示的化合物或其可药用的盐；
其中：
W、Z、R 3、R 4、R 5、R 6、R 11、R 12、R 13和t如通式(III-2)中所定义。
方案九-1
本公开通式(IMa)所示的化合物或其可药用的盐的制备方法，其包括以下步骤：
Figure PCTCN2022126650-appb-000143
(a)通式(IMaaa)所示的化合物或其盐和通式(Iaab)所示的化合物或其盐发生Suzuki偶联反应得到通式(IMaa)所示的化合物或其盐；
(b)通式(IMaa)所示的化合物或其盐在酸性条件下脱去R W2得到通式(IMa)所示的化合物或其可药用的盐；
其中：
R L为卤素；优选地，R L为Br；
R W2为氨基保护基；优选地，R W2为叔丁氧羰基；
R X选自
Figure PCTCN2022126650-appb-000144
R为氢原子或C 1-6烷基；
环A、V、X、Y、Z、R 2、R 3、R 4、R 6、s和t如通式(IMa)中所定义。
方案九-2
本公开通式(IMa)所示的化合物或其盐的制备方法，其包括以下步骤：
Figure PCTCN2022126650-appb-000145
(a)通式(IMaaa)所示的化合物或其盐和通式(Iaab)所示的化合物或其盐发生Suzuki偶联反应得到通式(IMaa)所示的化合物或其盐；
(b)通式(IMaa)所示的化合物或其盐在酸性条件下脱去R W2得到通式(IMa)所示的化合物或其盐；任选地，当R 6基团上含有保护基时，在所述脱保护反应之前、同时或之后还包括在酸性条件下脱去R 6基团上的保护基的步骤；
其中：
R L为卤素；优选地，R L为Br；
R W2为氨基保护基；优选地，R W2为叔丁氧羰基；
R X选自
Figure PCTCN2022126650-appb-000146
R为氢原子或C 1-6烷基；
环A、V、X、Y、Z、R 2、R 3、R 4、R 6、s和t如通式(IMa)中所定义。
方案十-1
本公开通式(Ia)所示的化合物或其可药用的盐的制备方法，其包括以下步骤：
Figure PCTCN2022126650-appb-000147
(a)通式(Iaaa)所示的化合物或其盐和通式(Iaab)所示的化合物或其盐发生Suzuki偶联反应得到通式(Iaa)所示的化合物或其可药用的盐；
(b)通式(Iaa)所示的化合物或其盐在酸性条件下脱去R W2得到通式(Ia)所示的化合物或其可药用的盐；
其中：
R L为卤素；优选地，R L为Br；
R W2为氨基保护基；优选地，R W2为叔丁氧羰基；
R X选自
Figure PCTCN2022126650-appb-000148
R为氢原子或C 1-6烷基；
环A、X、Y、Z、R 2、R 3、R 4、R 5、R 6、s和t如通式(Ia)中所定义。
方案十-2
本公开通式(Ia)所示的化合物或其盐的制备方法，其包括以下步骤：
Figure PCTCN2022126650-appb-000149
(a)通式(Iaaa)所示的化合物或其盐和通式(Iaab)所示的化合物或其盐发生Suzuki偶联反应得到通式(Iaa)所示的化合物或其盐；
(b)通式(Iaa)所示的化合物或其盐在酸性条件下脱去R W2得到通式(Ia)所示的化合物或其盐；任选地，当R 6基团上含有保护基时，在所述脱保护反应之前、同时或之后还包括在酸性条件下脱去R 6基团上的保护基的步骤；
其中：
R L为卤素；优选地，R L为Br；
R W2为氨基保护基；优选地，R W2为叔丁氧羰基；
R X选自
Figure PCTCN2022126650-appb-000150
R为氢原子或C 1-6烷基；
环A、X、Y、Z、R 2、R 3、R 4、R 5、R 6、s和t如通式(Ia)中所定义。
方案十一-1
本公开通式(IIa)所示的化合物或其可药用的盐的制备方法，其包括以下步骤：
Figure PCTCN2022126650-appb-000151
(a)通式(IIaaa)所示的化合物或其盐和通式(Iaab)所示的化合物或其盐发生Suzuki偶联反应得到通式(IIaa)所示的化合物或其可药用的盐；
(b)通式(IIaa)所示的化合物或其盐在酸性条件下脱去R W2得到通式(IIa)所示的化合物或其可药用的盐；
其中：
R L为卤素；优选地，R L为Br；
R W2为氨基保护基；优选地，R W2为叔丁氧羰基；
R X选自
Figure PCTCN2022126650-appb-000152
R为氢原子或C 1-6烷基；
环A、X、Z、R 3、R 4、R 5、R 6和t如通式(IIa)中所定义。
方案十一-2
本公开通式(IIa)所示的化合物或其盐的制备方法，其包括以下步骤：
Figure PCTCN2022126650-appb-000153
(a)通式(IIaaa)所示的化合物或其盐和通式(Iaab)所示的化合物或其盐发生Suzuki偶联反应得到通式(IIaa)所示的化合物或其盐；
(b)通式(IIaa)所示的化合物或其盐在酸性条件下脱去R W2得到通式(IIa)所示的化合物或其盐；任选地，当R 6基团上含有保护基时，在所述脱保护反应之前、同时或之后还包括在酸性条件下脱去R 6基团上的保护基的步骤；
其中：
R L为卤素；优选地，R L为Br；
R W2为氨基保护基；优选地，R W2为叔丁氧羰基；
R X选自
Figure PCTCN2022126650-appb-000154
R为氢原子或C 1-6烷基；
环A、X、Z、R 3、R 4、R 5、R 6和t如通式(IIa)中所定义。
方案十二
本公开通式(IIIa)所示的化合物或其可药用的盐的制备方法，其包括以下步骤：
Figure PCTCN2022126650-appb-000155
(a)通式(IIIaaa)所示的化合物或其盐和通式(IIIaab)所示的化合物或其盐发生Suzuki偶联反应得到通式(IIIaa)所示的化合物或其可药用的盐；
(b)通式(IIIaa)所示的化合物或其盐在酸性条件下脱去R W1和R W2得到通式(IIIa)所示的化合物或其可药用的盐；
其中：
R L为卤素；优选地，R L为Br；
R W1和R W2均为氨基保护基；优选地，R W1和R W2均为叔丁氧羰基；
R X选自
Figure PCTCN2022126650-appb-000156
R为氢原子或C 1-6烷基；
W、Z、R 3、R 4、R 5、R 6和t如通式(IIIa)中所定义。
方案十三
本公开通式(III-1a)所示的化合物或其可药用的盐的制备方法，其包括以下步骤：
Figure PCTCN2022126650-appb-000157
(a)通式(III-1aaa)所示的化合物或其盐和通式(IIIaab)所示的化合物或其盐发生Suzuki偶联反应得到通式(III-1aa)所示的化合物或其可药用的盐；
(b)通式(III-1aa)所示的化合物或其盐在酸性条件下脱去R W1和R W2得到通式(III-1a)所示的化合物或其可药用的盐；
其中：
R L为卤素；优选地，R L为Br；
R W1和R W2均为氨基保护基；优选地，R W1和R W2均为叔丁氧羰基；
R X选自
Figure PCTCN2022126650-appb-000158
R为氢原子或C 1-6烷基；
W、Z、R 3、R 4、R 5、R 6和t如通式(III-1a)中所定义。
方案十四
本公开通式(III-2a)所示的化合物或其可药用的盐的制备方法，其包括以下步骤：
Figure PCTCN2022126650-appb-000159
(a)通式(III-2aaa)所示的化合物或其盐和通式(IIIaab)所示的化合物或其盐发生Suzuki偶联反应得到通式(III-2aa)所示的化合物或其可药用的盐；
(b)通式(III-2aa)所示的化合物或其盐在酸性条件下脱去R W1和R W2得到通式(III-2a)所示的化合物或其可药用的盐；
其中：
R L为卤素；优选地，R L为Br；
R W1和R W2均为氨基保护基；优选地，R W1和R W2均为叔丁氧羰基；
R X选自
Figure PCTCN2022126650-appb-000160
R为氢原子或C 1-6烷基；
W、Z、R 3、R 4、R 5、R 6和t如通式(III-2a)中所定义。
上述合成方案中，Suzuki偶联反应优选在碱(例如碳酸钾、碳酸铯)和金属催化剂(例如双(二苯基膦苯基醚)二氯化钯(II)、二氯[1,1'-双(二叔丁基膦)二茂铁钯(II))的存在下进行。
上述合成方案中，提供碱性条件的碱包括有机碱和无机碱，所述的有机碱包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、乙酸钠、乙醇钠、叔丁醇钠或叔丁醇钾，优选三乙胺；所述的无机碱包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、无水碳酸钾、碳酸铯、氢氧化钠、氢氧化锂一水合物、氢氧化锂和氢氧化钾，优选为碳酸钾或无水碳酸钾。
上述合成方案中，提供酸性条件的酸包括有机酸和无机酸，所述的有机酸包括但不限于三氟乙酸、甲酸、乙酸、甲磺酸、对甲苯磺酸、Me 3SiCl和TMSOTf，优选三氟乙酸；所述的无机酸包括但不限于氯化氢、氯化氢的1,4-二氧六环溶液、盐酸、硫酸、硝酸和磷酸。
上述合成方案优选在溶剂中进行，所用溶剂包括但不限于：乙二醇二甲醚、醋酸、甲醇、乙醇、乙腈、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺及其混合物。
具体实施方式
以下结合实施例进一步描述本公开，但这些实施例并非限制着本公开的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪或Bruker AVANCE NEO 500M，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290DAD-6110/6120Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120Quadrupole MS)；waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)；THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC1200VWD和Waters HPLC e2695-2489高效液相色谱仪。
手性HPLC分析测定使用Agilent 1260DAD高效液相色谱仪。
高效液相制备使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应均能够在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或 HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：石油醚/乙酸乙酯体系，B：二氯甲烷/甲醇体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1-P1，1-P2
(R)-4-((S)-10-丙烯酰基-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈
1-P1
(S)-4-((S)-10-丙烯酰基-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈
1-P2
Figure PCTCN2022126650-appb-000161
第一步
4-溴-5-氟-1H-吲唑-7-甲酸甲酯1b
将2-氨基-4-溴-5-氟-3-甲基苯甲酸甲酯1a(2.7g，10.3mmol，采用专利申请“WO2016020836A1”中说明书第103页步骤(iv)公开的方法制备而得)溶于氯仿(50mL)中，加入醋酸酐(3.16g，30.9mmol)，温度保持40℃以下，搅拌反应90分钟后加入醋酸钾(302mg，3.08mmol)、亚硝酸叔丁酯(2.12g，20.6mmol)，回流反应14小时。反应液冷却至室温，用二氯甲烷(50mL)稀释，依次用水(30mL)、饱和碳酸钠溶液(10mL)、饱和氯化钠溶液洗涤(10mL)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得粗品标题化合物1b(2.8g)，产品不经纯化直接用于下步反应。
MS m/z(ESI)：272.9[M+1]。
第二步
4-溴-5-氟-1H-吲唑-7-甲酸1c
将粗品化合物1b(2.8g，10.25mmol)溶于四氢呋喃(20mL)、甲醇(10mL)和水(10mL)的混合溶剂中，加入氢氧化锂(2.15g，51.26mmol)，40℃搅拌反应1小时。反应液减压浓缩除去大部分溶剂，加入水，用乙酸乙酯(150mL×6)萃取，合并有机相，依次用稀盐酸、饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩得粗品化合物1c(1.4g)，产品不经纯化直接用于下步反应。
MS m/z(ESI)：259.0[M+1]。
第三步
(S)-4-(4-溴-5-氟-1H-吲唑-7-羰基)-3-(2-羟乙基)哌嗪-1-甲酸叔丁酯1f
将粗品化合物1c(600mg，2.32mmol)、(S)-3-(2-羟乙基)哌嗪-1-甲酸叔丁酯1d(586mg，2.54mmol，采用专利申请“WO2021118877A1”中说明书第80页的preparation 65公开的方法制备而得)溶于30mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(898mg，6.95mmol)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.05g，2.78mmol)，搅拌反应1小时。反应液减压浓缩后加入乙酸乙酯稀释，依次用水、饱和碳酸钠溶液、饱和氯化钠溶液洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1f(600mg，产率：54.9％)。
MS m/z(ESI):415.2[M-55]。
第四步
(S)-3-溴-2-氟-14-氧代-7,8,8a,9,11,12-六氢-10H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-10-甲酸叔丁酯1g
在氮气氛下，将化合物1f(600mg，1.27mmol)溶于36mL四氢呋喃中，冰浴下依次加入三苯基膦(667mg，2.54mmol)、偶氮二甲酸二乙酯(514mg，2.54mmol)，保持温度搅拌反应30分钟，反应液加入饱和氯化铵溶液淬灭，用乙酸乙酯萃取(15mL×2)，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1g(577mg， 产率：99.9％)。
MS m/z(ESI)：397.2[M-55]。
第五步
(8aS)-3-(2-((叔丁氧基羰基)氨基)-3-氰基-7-氟苯并[b]噻吩-4-基)-2-氟-14-氧代-7,8,8a,9,11,12-六氢-10H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-10-甲酸叔丁酯1i
将化合物1g(80mg，0.17mmol)、(3-氰基-4-(5,5-二甲基-1,3,2-二氧硼杂环己-2-基)-7-氟苯并[b]噻吩-2-基)氨基甲酸叔丁酯1h(107mg，0.26mmol，采用专利申请“WO2021118877A1”中说明书第50页的preparation 15公开的方法制备而得)溶于2mL的甲苯中，加入双(二苯基膦苯基醚)二氯化钯(II)(18mg，0.025mmol，上海泰坦)、碳酸铯(115mg，0.35mmol)，氮气置换，105℃搅拌反应6小时，反应液冷却至室温后过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1i(50mg，产率：42.6％)。
MS m/z(ESI):665.0[M+1]。
第六步
2-氨基-7-氟-4-((S)-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)苯并[b]噻吩-3-甲腈二(2,2,2-三氟乙酸)盐1j
将化合物1i(50mg，0.075mmol)溶于1mL二氯甲烷中，0℃加入1mL三氟乙酸，搅拌反应2小时，反应液减压浓缩得到粗品标题化合物1j(52mg)，产品不经纯化直接用于下步反应。
MS m/z(ESI):465.4[M+1]。
第七步
(R)-4-((S)-10-丙烯酰基-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈
1-P1
(S)-4-((S)-10-丙烯酰基-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈
1-P2
将化合物1j(52mg，0.075mmol)悬浮于2mL乙酸乙酯、1mL四氢呋喃和2mL水中，加入无水碳酸钾(52mg，0.37mmol)，冰浴下加入丙烯酰氯(7mg，0.077mmol)，反应5分钟后用乙酸乙酯(5mL×2)萃取，合并有机相，减压浓缩，得到粗品化合物1，即4-((S)-10-丙烯酰基-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈(39mg)，用高效液相制备色谱法(Waters-2545，色谱柱：YMC Triart-Exrs，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％， 流速：30mL/min)纯化，得到标题化合物1-P2(5mg，产率：12.7％)和1-P1(3mg，产率：7.6％)。
单一构型化合物(较短保留时间)1-P2(5mg，产率：12.7％)
MS m/z(ESI):519.3[M+1]。
HPLC分析：保留时间1.12分钟，纯度：99％(色谱柱:ACQUITY
Figure PCTCN2022126650-appb-000162
BEH,C18,1.7μm,2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。
1H NMR(500MHz,CD3OD):δ7.70(s,1H),7.66(d,1H),7.30(s,1H),7.08(dd,1H),6.82(dt,1H),6.34-6.25(m,1H),5.83(t,1H),4.75(d,3H),4.49-4.19(m,2H),4.16-3.93(m,1H),3.57-3.44(m,1H),3.22-3.06(m,2H),2.25(dd,1H),2.06-1.92(m,1H)。
单一构型化合物(较长保留时间)1-P1(3mg，产率：7.6％)
MS m/z(ESI):519.5[M+1]。
LCMS分析:保留时间1.13分钟，纯度：99％(色谱柱:ACQUITY
Figure PCTCN2022126650-appb-000163
BEH，C18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。
1H NMR(500MHz,CD3OD):δ7.65(s,1H),7.61(d,1H),7.38(dd,1H),7.13-6.99(m,1H),6.95-6.68(m,1H),6.35-6.28(m,1H),5.84(d,1H),4.75(d,4H),4.39-4.23(m,1H),4.16-3.98(m,1H),3.25-2.95(m,3H),2.24(d,1H),1.94(d,1H)。
实施例2
4-((S)-10-丙烯酰基-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲哚-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈2
Figure PCTCN2022126650-appb-000164
Figure PCTCN2022126650-appb-000165
第一步
(S)-4-(4-溴-5-氟-1H-吲哚-7-羰基)-3-(2-羟乙基)哌嗪-1-甲酸叔丁酯2b
将4-溴-5-氟-1H-吲哚-7-甲酸2a(180mg，0.69mmol，采用专利申请“US20190300526A1”中说明书第22页第[0152]段公开的方法制备而得)、化合物1d(160mg，0.69mmol)溶于3mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(270mg，2.0mmol)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(318mg，0.83mmol)，搅拌反应1小时。反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物2b(328mg，产率：99.9％)。
MS m/z(ESI):469.9[M+1]。
第二步
(S)-4-(4-溴-5-氟-1H-吲哚-7-羰基)-3-(2-((甲基磺酰基)氧基)乙基)哌嗪-1-甲酸叔丁酯2c
将化合物2b(328mg，0.69mmol)溶于5mL二氯甲烷中，加入N,N-二异丙基乙胺(216mg，1.67mmol)，冰浴下加入甲烷磺酰氯(119mg，1.04mmol)，搅拌2小时，反应液中加入水，用二氯甲烷(5mL×3)萃取，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩得到粗品标题化合物2c(382mg)，产品不经纯化直接用于下步反应。
MS m/z(ESI):392.3[M-55]。
第三步
(S)-3-溴-2-氟-14-氧代-7,8,8a,9,11,12-六氢-10H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲哚-10-甲酸叔丁酯2d
将粗品化合物2c(382mg，0.69mmol)溶于5mL N,N-二甲基甲酰胺中，加入 钠氢(53mg，1.38mmol，60％纯度)搅拌1小时，反应液加入饱和氯化铵溶液淬灭，用乙酸乙酯(5mL×3)萃取，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤除去干燥剂，液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物2d(160mg，产率：50.7％)。
MS m/z(ESI):452.0[M+1]。
第四步
(8aS)-3-(2-((叔丁氧基羰基)氨基)-3-氰基-7-氟苯并[b]噻吩-4-基)-2-氟-14-氧代-7,8,8a,9,11,12-六氢-10H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲哚-10-甲酸叔丁酯2e
将化合物2d(80mg，0.17mmol)、化合物1h(105mg，0.26mmol)溶于2mL的甲苯中，加入双(二苯基膦苯基醚)二氯化钯(II)(20mg，0.027mmol)、碳酸铯(115mg，0.35mmol，上海韶远)，氮气置换，加热至105℃搅拌反应6小时。反应液过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物2e(100mg，产率：85％)。
MS m/z(ESI):664.0[M+1]。
第五步
2-氨基-7-氟-4-((S)-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲哚-3-基)苯并[b]噻吩-3-甲腈二(2,2,2-三氟乙酸)盐2f
将化合物2e(100mg，0.15mmol)溶于1mL二氯甲烷中，0℃加入1mL三氟乙酸，搅拌反应2小时，反应液减压浓缩，得到粗品标题化合物2f(104mg)，产品不经纯化直接用于下步反应。
MS m/z(ESI):464.0[M+1]。
第六步
4-((S)-10-丙烯酰基-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲哚-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈2
将化合物2f(104mg，0.15mmol)悬浮于2mL乙酸乙酯、1mL四氢呋喃、2mL水的混合溶剂中，加入无水碳酸钾(85mg，0.65mmol)，冰浴下加入丙烯酰氯(13mg，0.14mmol)，保持温度反应5分钟，用乙酸乙酯(5mL×3)萃取，有机相减压浓缩，残余物用高效液相色谱法(Waters-2545，色谱柱：SharpSil-T C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)纯化得到标题化合物2(30mg，产率：38.5％)。
MS m/z(ESI):518.0[M+1]。
1H NMR(500MHz,CD3OD):δ7.37-7.24(m,2H),7.17(d,1H),7.01(t,1H),6.80(ddd,1H),6.29(dd,1H),6.11(d,1H),5.82(dd,1H),4.72(d,2H),4.36(d,2H),4.15-4.00(m,2H),3.46(d,1H),3.06(dd,2H),2.26-2.13(m,1H),1.86(d,1H)。
实施例3
(8aS)-10-丙烯酰基-3-(-2-氨基-7-氟苯并[d]噻唑-4-基)-2-氟-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲哚-14-酮3
Figure PCTCN2022126650-appb-000166
第一步
(8aS)-3-(2-((叔丁氧基羰基)氨基)-7-氟苯并[d]噻唑-4-基)-2-氟-14-氧代-7,8,8a,9,11,12-六氢-10H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲哚-10-甲酸叔丁酯3b
将化合物2d(30mg，0.07mmol)、(2-((叔丁氧羰基)氨基)-7-氟苯基[d]噻唑-4-基)硼酸3a(31mg，0.1mmol，采用专利申请“WO2021118877A1”中说明书第56-57页的preparation 25公开的方法制备而得)溶于1mL二氧六环和0.3mL水中，加入二氯[1,1'-双(二叔丁基膦)二茂铁钯(II)(4mg，0.006mmol，上海泰坦)、碳酸钾(14mg，0.1mmol)，氮气置换，加热至80℃搅拌反应1小时。反应液冷却至室温后过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物3b(42mg，产率：98.9％)。
MS m/z(ESI):640.0[M+1]。
第二步
(8aS)-3-(2-氨基-7-氟苯并[d]噻唑-4-基)-2-氟-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲哚-14-酮二(2,2,2-三氟乙酸)盐3c
将化合物3b(42mg，0.065mmol)溶于1mL二氯甲烷中，0℃加入1mL三氟乙酸，搅拌反应2小时，反应液减压浓缩，得到粗品标题化合物3c(50mg)，产品不经纯化直接用于下步反应。
MS m/z(ESI):440.4[M+1]。
第三步
(8aS)-10-丙烯酰基-3-(-2-氨基-7-氟苯并[d]噻唑-4-基)-2-氟-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲哚-14-酮3
将粗品化合物3c(50mg，0.075mmol)溶于1mL二氯甲烷中，-78℃加入三乙胺(36mg，0.35mmol)，加入丙烯酰氯(6mg，0.07mmol)，反应1小时，用二氯甲烷(5mL×2)萃取，有机相减压浓缩，残余物用高效液相色谱法(Waters-2545，色谱柱：SharpSil-T C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)纯化，得到标题化合物3(10mg，产率：30.7％。)。
MS m/z(ESI):494.3[M+1]。
1H NMR(500MHz,CD3OD):δ7.39-7.23(m,3H),7.00(q,1H),6.97-6.68(m,1H),6.30(d,1H),6.21-6.10(m,1H),5.83(t,1H),4.73(d,2H),4.38(q,2H),4.24-3.97(m,2H),3.49(d,1H),3.03(d,2H),2.21(t,1H),1.88(s,1H)。
实施例4
4-((S)-10-丙烯酰基-2-氟-5-甲基-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲哚-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈4
Figure PCTCN2022126650-appb-000167
第一步
4-溴-5-氟-2-甲基-1H-吲哚-7-甲酸4b
将4-溴-5-氟-2-甲基-1H-吲哚-7-甲酸甲酯4a(350mg，1.22mmol，采用专利申请“WO2018203302A1”中说明书第93-95页的example 9.1公开的方法制备而得)溶于4mL四氢呋喃、2mL甲醇和2mL水的混合溶剂中，加入氢氧化锂(260mg，6.19mmol)，40℃搅拌1小时，反应液减压除去大部分溶剂，用6M盐酸调pH至弱酸性后用乙酸乙酯(10mL×3)萃取，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品标题化合物4b(300mg)。
MS m/z(ESI):272.0[M+1]。
第二步
(S)-4-(4-溴-5-氟-2-甲基-1H-吲哚-7-羰基)-3-(2-羟乙基)哌嗪-1-甲酸叔丁酯4c
将粗品化合物4b(330mg，1.21mmol)、化合物1d(307mg，1.33mmol)溶于6mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(470mg，3.64mmol)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(553g，1.45mmol)，搅拌反应液1小时，反应液减压浓缩，残余物中加入乙酸乙酯稀释，依次用水，饱和碳酸钠溶液，饱和氯化钠溶液洗涤，有机相用无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物4c(250mg，产率：42.5％)。
MS m/z(ESI):484.2[M+1]。
第三步
(S)-3-溴-2-氟-5-甲基-14-氧代-7,8,8a,9,11,12-六氢-10H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲哚-10-甲酸叔丁酯4d
在氮气氛下，将化合物4c(249mg，0.51mmol)溶于5mL四氢呋喃中，冰浴下依次加入三苯基膦(269mg，1.02mmol)、偶氮二甲酸二乙酯(207mg，1.02mmol)，搅拌反应1小时。反应液中加入饱和氯化铵淬灭，用乙酸乙酯(10mL×3)萃取，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物4d(80mg，产率：33.3％)。
MS m/z(ESI):410.2[M-55]。
第四步
(8aS)-3-(2-((叔丁氧基羰基)氨基)-3-氰基-7-氟苯并[b]噻吩-4-基)-2-氟-5-甲基-14-氧代-7,8,8a,9,11,12-六氢-10H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲哚-10-甲酸叔丁酯4e
将化合物4d(32mg，0.07mmol)、化合物1h(41mg，0.1mmol)溶于1mL的甲苯中，加入双(二苯基膦苯基醚)二氯化钯(II)(8mg，0.011mmol)、碳酸铯(44mg,0.0.13mmol，上海韶远)，氮气置换，加热至105℃搅拌反应10小时，反应液冷却 至室温后过滤，滤液减压浓缩得到粗品标题化合物4e(40mg)，不经纯化直接用于下步反应。
MS m/z(ESI):678.6[M+1]。
第五步
2-氨基-7-氟-4-((S)-2-氟-5-甲基-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲哚-3-基)苯并[b]噻吩-3-甲腈二(2,2,2-三氟乙酸)盐4f
将化合物4e(40mg，0.059mmol)溶于0.5mL二氯甲烷中，0℃加入0.5mL三氟乙酸，搅拌反应2小时，反应液减压浓缩，得到粗品标题化合物4f(41.5mg)，不经纯化直接用于下步反应。
MS m/z(ESI):478.4[M+1]。
第六步
4-((S)-10-丙烯酰基-2-氟-5-甲基-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲哚-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈4
将化合物4f(41.5mg，0.059mmol)悬浮于2mL乙酸乙酯、1mL四氢呋喃和2mL水的混合溶剂中，加入无水碳酸钾(40mg，0.29mmol)，冰浴下加入丙烯酰氯(6mg，0.066mmol)，反应5分钟，用乙酸乙酯(5mL×2)萃取，有机相减压浓缩，残余物用高效液相色谱法(Waters-2545，色谱柱：SharpSil-T C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)纯化，得到标题化合物4(5mg，产率：15.8％)。
MS m/z(ESI):532.3[M+1]。
1H NMR(500MHz,CD3OD):δ7.22(d,2H),7.02(t,1H),6.93-6.69(m,1H),6.30(d,1H),5.92(s,1H),5.87-5.75(m,1H),4.71(d,2H),4.37(q,2H),4.17-3.83(m,2H),3.47(s,1H),3.20-2.91(m,2H),2.41(d,3H),2.05(d,1H),1.79(s,1H)。
实施例5
2-氨基-7-氟-4-((S)-2-氟-10-(2-氟丙烯酰基)-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲哚-3-基)苯并[b]噻吩-3-甲腈5
Figure PCTCN2022126650-appb-000168
采用实施例2中的合成路线，将第六步原料丙烯酰氯替换为2-氟丙烯酰氯(采用文献“Tetrahedron,2016,vol.72,32,p.4845-4853”公开的方法制备而得)得到标题化合物5(15mg，产率：40.4％)。
MS m/z(ESI):536.1[M+1]。
1H NMR(500MHz,CD3OD):δ7.36-7.26(m,2H),7.21(dd,1H),7.03(t,1H),6.12(d,1H),5.38-5.25(m,2H),4.75(d,2H),4.45-4.20(m,2H),4.20-4.03(m,2H),3.47(d,1H),3.12(t,2H),2.24(d,1H),1.88(t,1H)。
实施例6-P1，6-P2
(R)-2-氨基-7-氟-4-((S)-2-氟-10-(2-氟丙烯酰基)-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)苯并[b]噻吩-3-甲腈6-P1
(S)-2-氨基-7-氟-4-((S)-2-氟-10-(2-氟丙烯酰基)-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)苯并[b]噻吩-3-甲腈6-P2
Figure PCTCN2022126650-appb-000169
采用实施例1-P1和1-P2中的合成路线，将第七步原料丙烯酰氯替换为2-氟丙烯酰氯，得到粗品化合物6，即2-氨基-7-氟-4-((S)-2-氟-10-(2-氟丙烯酰基)-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)苯并[b]噻吩-3-甲腈(50mg)，用高效液相制备色谱法(Waters-2545，色谱柱：YMC Triart-Exrs,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)纯化，得到标题化合物6-P2(10mg，产率：15.4％)和6-P1(2mg，产率：3.8％)。
单一构型化合物(较短保留时间)6-P2(10mg，产率：15.4％)
(MS m/z(ESI):537.2M+1]。
制备HPLC分析：保留时间11.7分钟，纯度：99％(Waters-2545，色谱柱：YMC Triart-Exrs，Prep 30*150mm，5μm；C18，流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈34％-45％，流速：30mL/min)
1H NMR(500MHz,CD3OD):δ7.70(d,1H),7.66(dd,1H),7.29(dd,1H),7.12-7.04(m,1H),5.38-5.26(m,2H),4.80-4.66(m,3H),4.40-4.18(m,2H),4.10(s,1H),3.41(s,1H),3.19(td,2H),2.33(s,1H),1.96(ddd,1H)。
单一构型化合物(较长保留时间)6-P1(2mg，产率：3.8％)
MS m/z(ESI):537.2[M+1]。
制备HPLC分析：保留时间12.1分钟，纯度：99％(Waters-2545，色谱柱：YMC Triart-Exrs，Prep 30*150mm，5μm；C18，流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈34％-45％，流速：30mL/min)
1H NMR(500MHz,CD3OD):δ7.65(d,1H),7.61(d,1H),7.38(dd,1H),7.14-7.04(m,1H),5.32(s,2H),4.76(s,3H),4.33(t,2H),4.11(s,1H),3.47(s,1H),3.20(d,2H),2.33(s,1H),1.99-1.87(m,1H)。
实施例7-P1，7-P2
(R)-4-((S)-10-丙烯酰基-4-氯-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈7-P1
(S)-4-((S)-10-丙烯酰基-4-氯-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈7-P2
Figure PCTCN2022126650-appb-000170
第一步
(S)-3-溴-4-氯-2-氟-14-氧代-7,8,8a,9,11,12-六氢-10H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-10-甲酸叔丁基酯7a
将化合物1g(630mg，1.38mmol)溶于乙腈(6mL)中，加入N-氯代丁二酰亚胺(278mg，2.08mmol)，加热至60℃反应0.5小时，有固体析出，补加N-氯代丁二酰亚胺(100mg，0.75mmol)，继续反应20分钟，反应液冷却至室温，加入饱和碳 酸氢钠溶液，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物7a(380mg，产率：56％)。
MS m/z(ESI):487.1[M+1]。
第二步
(8aS)-3-(2-((叔丁氧基羰基)氨基)-3-氰基-7-氟苯并[b]噻吩-4-基)-4-氯-2-氟-14-氧代-7,8,8a,9,11,12-六氢-10H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-10-甲酸叔丁酯7b
将化合物7a(150mg，0.31mmol)、化合物1h(186mg，0.46mmol)溶于5mL的甲苯中，加入双(二苯基膦苯基醚)二氯化钯(II)(43mg，0.06mmol)、碳酸铯(300mg，0.92mmol)，氮气置换，105℃搅拌反应6小时，反应液冷却至室温后过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物7b(40mg，产率：18.6％)。
MS m/z(ESI):699.2[M+1]。
第三步
2-氨基-4-((S)-4-氯-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-7-氟苯并[b]噻吩-3-甲腈二(2,2,2-三氟乙酸)盐7c
将化合物7b(40mg，57.21μmol)溶于1mL二氯甲烷中，0℃下加入1mL三氟乙酸，搅拌反应2小时，反应液减压浓缩得到粗品标题化合物7c(41mg)，产品不经纯化直接用于下步反应。
MS m/z(ESI):499.2[M+1]。
第四步
(R)-4-((S)-10-丙烯酰基-4-氯-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈7-P1
(S)-4-((S)-10-丙烯酰基-4-氯-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈7-P2
将粗品化合物7c(41mg，56.4μmol)悬浮于2mL乙酸乙酯，1mL四氢呋喃和2mL水中，加入无水碳酸钾(24mg，173.6μmol)，冰浴下加入丙烯酰氯(5.4mg，59.6μmol)，反应5分钟后用乙酸乙酯(5mL×2)萃取，合并有机相，减压浓缩，得到粗品化合物7，即4-((S)-10-丙烯酰基-4-氯-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈(39mg)，用高效液相制备色谱法纯化(Waters-2545，色谱柱：SharpSil-T C18,30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)纯化得到标题化合物7-P2(5mg，产率：15.1％) 和7-P1(2mg，产率：6％)。
单一构型化合物(较短保留时间)7-P2(5mg，产率：15.1％)
MS m/z(ESI):553.2[M+1]。
HPLC分析：保留时间2.21分钟，纯度：99％(色谱柱:ACQUITY
Figure PCTCN2022126650-appb-000171
BEH，C18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。
1H NMR(500MHz,CD 3OD):δ7.67(d,1H),7.20(t,1H),7.02(dd,1H),6.87(dd,1H),6.72-6.28(m,1H),5.81(t,1H),4.74-4.67(m,1H),4.66-4.56(m,1H),4.41(d,1H),4.30(d,-1H),4.12-4.00(m,1H),3.96(d,1H),3.49(d,1H),3.09(dd,2H),2.26-2.16(m,1H),1.94(s,1H)。
单一构型化合物(较长保留时间)7-P1(2mg，产率：6％)
MS m/z(ESI):553.2[M+1]。
HPLC分析：保留时间2.29分钟，纯度：95％(色谱柱:ACQUITY
Figure PCTCN2022126650-appb-000172
BEH，C18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。
1H NMR(500MHz,CD 3OD):δ7.65(d,1H),7.20(t,1H),7.00(dd,1H),6.85(dd,1H),6.70-6.26(m,1H),5.81(t,1H),4.73-4.65(m,1H),4.66-4.56(m,1H),4.39(d,1H),4.30(d,1H),4.10-4.00(m,1H),3.92(d,1H),3.49(d,1H),3.12(dd,2H),2.24-2.16(m,1H),1.92(s,1H)。
实施例8-P1，8-P2
(R)-4-((S)-10-丙烯酰基-2,4-二氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈8-P1
(S)-4-((S)-10-丙烯酰基-2,4-二氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈8-P2
Figure PCTCN2022126650-appb-000173
Figure PCTCN2022126650-appb-000174
第一步
4-溴-3,5-二氟-1H-吲唑-7-甲酸8a
将化合物1c(1g，3.86mmol)溶于N,N-二甲基甲酰胺(15mL)中，加入1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(6.83g，19.3mmol，上海毕得)，微波100℃反应6小时，反应液冷却至室温，倒入冰水中，固体析出，过滤，收集固体，干燥后即得到粗品标题化合物8a(950mg，产率：88.8％)，产品不经纯化直接用于下步反应。
MS m/z(ESI):275.1[M-1]。
第二步
(S)-4-(4-溴-3,5-二氟-1H-吲唑-7-羰基)-3-(2-羟乙基)哌嗪-1-甲酸叔丁酯8b
将粗品化合物8a(900mg，3.24mmol)、化合物1d(897mg，3.89mmol)溶于30mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(1.62g，12.5mmol)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.48g，3.89mmol)，搅拌反应3小时。反应液减压浓缩后加入乙酸乙酯稀释，依次用水、饱和碳酸钠溶液、饱和氯化钠溶液洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品标题化合物8b(1.5g)，产品不经纯化直接用于下步反应。
MS m/z(ESI):433.2[M-55]。
第三步
(S)-3-溴-2,4-二氟-14-氧代-7,8,8a,9,11,12-六氢-10H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-10-甲酸叔丁酯8c
在氮气氛下，将粗品化合物8b(1.3g，2.65mmol)溶于20mL四氢呋喃中，冰 浴下依次加入三苯基膦(1.39g，5.3mmol)、偶氮二甲酸二乙酯(1.07g，5.3mmol)，保持温度搅拌反应30分钟，反应液加入饱和氯化铵溶液淬灭，用乙酸乙酯萃取(15mL×2)，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物8c(200mg，产率：15.9％)。
MS m/z(ESI):415.2[M-55]。
第四步
(8aS)-3-(2-((叔丁氧基羰基)氨基)-3-氰基-7-氟苯并[b]噻吩-4-基)-2,4-二氟-14-氧代-7,8,8a,9,11,12-六氢-10H,14H-吡嗪并[1,2:5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-10-甲酸叔丁酯8d
将化合物8c(80mg，169.7451μmol)、化合物1h(137mg，338.8μmol)溶于2mL的甲苯中，加入双(二苯基膦苯基醚)二氯化钯(II)(36mg，50.34μmol)、碳酸铯(165mg，506.4μmol)，氮气置换，105℃搅拌反应6小时，反应液冷却至室温后过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物8d(100mg，产率：86.2％)。
MS m/z(ESI):683.2[M+1]。
第五步
2-氨基-4-((S)-2,4-二氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-7-氟苯并[b]噻吩-3-甲腈二(2,2,2-三氟乙酸)盐8e
将化合物8d(100mg，146.4μmol)溶于1mL二氯甲烷中，0℃加入1mL三氟乙酸，搅拌反应2小时，反应液减压浓缩得到粗品标题化合物8e(100mg)，产品不经纯化直接用于下步反应。
MS m/z(ESI):483.2[M+1]。
第六步
(R)-4-((S)-10-丙烯酰基-2,4-二氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈8-P1
(S)-4-((S)-10-丙烯酰基-2,4-二氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈8-P2
将粗品化合物8e(100mg，140μmol)悬浮于2mL乙酸乙酯、1mL四氢呋喃和2mL水中，加入无水碳酸钾(100mg，723μmol)，冰浴下加入丙烯酰氯(14mg，154μmol)，反应5分钟后用乙酸乙酯(5mL×2)萃取，合并有机相，减压浓缩，得到粗品化合物8，即4-((S)-10-丙烯酰基-2,4-二氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈(70mg)，用高效液相制备色谱法纯化(Waters-2545，色谱柱：SharpSil-T C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)纯化，得到标题化合物8-P2(30mg，产率：38.3％) 和8-P1(13mg，产率：16.6％)。
单一构型化合物(较短保留时间)8-P2(30mg，产率：38.3％)
MS m/z(ESI):537.2[M+1]。
HPLC分析：保留时间1.20分钟，纯度：99％(色谱柱:ACQUITY
Figure PCTCN2022126650-appb-000175
BEH,C18,1.7μm,2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。
1H NMR(500MHz,CD 3OD):δ7.69(d,1H),7.27(d,1H),7.04(dd,1H),6.96-6.70(m,1H),6.30(dd,1H),5.83(t,1H),4.72(d,2H),4.51-4.25(m,3H),4.11(s,1H),3.57-3.39(m,1H),3.13(dt,2H),2.20(dd,1H),1.96(s,1H)。
单一构型化合物(较长保留时间)8-P1(13mg，产率：16.6％)
MS m/z(ESI):537.2[M+1]。
HPLC分析：保留时间1.23分钟，纯度：99％(色谱柱:ACQUITY
Figure PCTCN2022126650-appb-000176
BEH,C18,1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。
1H NMR(500MHz,CD 3OD):δ7.64(d,1H),7.36(dt,1H),7.06(t,1H),6.81(dt,1H),6.30(dd,1H),5.84(d,1H),4.72(d,2H),4.49-4.23(m,3H),4.12(s,1H),3.51(d,1H),3.08(dd,2H),2.26-2.18(m,1H),1.92(s,1H)。
实施例9-P1，9-P2
(R)-4-((S)-10-丙烯酰基-2-氟-4-甲基-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈9-P1
(S)-4-((S)-10-丙烯酰基-2-氟-4-甲基-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈9-P2
Figure PCTCN2022126650-appb-000177
Figure PCTCN2022126650-appb-000178
第一步
3-乙酰基-2-氨基-4-溴-5-氟苯甲酸甲酯9b
将2-氨基-4-溴-5-氟-3-碘苯甲酸甲酯9a(5g，13.37mmol，采用专利申请“WO2016020836A1”中说明书第103页的Intermediate 15公开的方法制备而得)溶于N,N-二甲基甲酰胺(100mL)，加入双三苯基膦二氯化钯(1.87g，2.67mmol)、三丁基(1-乙氧基乙烯)锡(5.79g，16.04mmol，上海韶远)，氮气置换，90℃反应12小时。反应液冷却至室温，加入10％氟化钾水溶液，搅拌30分钟，过滤，滤液分液，有机相加入10mL浓盐酸搅拌16小时，用饱和碳酸钠溶液调节pH至中性，乙酸乙酯(50mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物9b(1.8g，产率：46.4％)。
MS m/z(ESI):289.9[M+1]。
第二步
4-溴-5-氟-3-甲基-1H-吲唑-7-甲酸甲酯9c
将化合物9b(1g，3.44mmol)溶于浓盐酸(5mL)，冰浴下滴加亚硝酸钠(261mg，3.78mmol)的水溶液(2mL)，保持温度搅拌1小时后，滴加二水合氯化亚锡(1.71g，7.58mmol)的盐酸溶液(2mL)，继续搅拌30分钟，用饱和碳酸钾溶液调节pH至8，乙酸乙酯(30mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物9c(760mg，产率：76.7％)。
MS m/z(ESI):286.9[M+1]。
第三步
4-溴-5-氟-3-甲基-1H-吲唑-7-甲酸9d
将粗品化合物9c(760mg，2.6mmol)溶于四氢呋喃(5ml)、甲醇(5mL)和水(5mL)的混合溶剂中，加入氢氧化锂(555mg，13.2mmol)，40℃搅拌反应1小时，反应液减压浓缩除去大部分溶剂，加入水，用乙酸乙酯(150mL×6)萃取，合并有机相，依次用稀盐酸、饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，得粗品化合物9d(722mg)，产品不经纯化直接用于下步反应。
MS m/z(ESI):270.9[M-1]。
第四步
(S)-4-(4-溴-5-氟-3-甲基-1H-吲唑-7-羰基)-3-(2-羟乙基)哌嗪-1-甲酸叔丁酯9e
将粗品化合物9d(722mg，2.64mmol)、化合物1d(730mg，3.16mmol)溶于10mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(720mg，5.5mmol)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.2g，3.17mmol)，搅拌反应1小时。反应液减压浓缩后加入乙酸乙酯稀释，依次用水、饱和碳酸钠溶液、饱和氯化钠溶液洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品标题化合物9e(1.2g)，产品不经纯化直接用于下步反应。
MS m/z(ESI):429.2[M-55]。
第五步
(S)-3-溴-2-氟-4-甲基-14-氧代-7,8,8a,9,11,12-六氢-10H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-10-甲酸叔丁酯9f
在氮气氛下，将粗品化合物9e(1.28g，2.63mmol)溶于50mL四氢呋喃中，冰浴下依次加入三苯基膦(1.38g，5.26mmol)、偶氮二甲酸二乙酯(1.06g，5.26mmol)，保持温度搅拌反应30分钟，反应液加入饱和氯化铵溶液淬灭，用乙酸乙酯萃取(20mL×2)，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物9f(650mg，产率：52.7％)。
MS m/z(ESI):411.2[M-55]。
第六步
(8aS)-3-(2-((叔丁氧基羰基)氨基)-3-氰基-7-氟苯并[b]噻吩-4-基)-2-氟-4-甲基-14-氧代-7,8,8a,9,11,12-六氢-10H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-10-甲酸叔丁基酯9g
将粗品化合物9f(210mg，449.36μmol)、化合物1h(363mg，897μmol)溶于10mL的甲苯中，加入双(二苯基膦苯基醚)二氯化钯(II)(96mg，134.2μmol)、碳酸铯(439mg，1.34mmol)，氮气置换，105℃搅拌反应6小时，反应液冷却至室温后过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物9g(200mg，产率：65.6％)。
MS m/z(ESI):679.2[M+1]。
第七步
2-氨基-7-氟-4-((S)-2-氟-4-甲基-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)苯并[b]噻吩-3-甲腈二(2,2,2-三氟乙酸)盐9h
将化合物9g(200mg，294.6μmol)溶于2mL二氯甲烷中，0℃下加入2mL三氟乙酸，搅拌反应2小时，反应液减压浓缩得到粗品标题化合物9h(200mg)，产品不经纯化直接用于下步反应。
MS m/z(ESI):479.2[M+1]。
第八步
(R)-4-((S)-10-丙烯酰基-2-氟-4-甲基-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈9-P1
(S)-4-((S)-10-丙烯酰基-2-氟-4-甲基-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈9-P2
将化合物9h(200mg，283.2μmol)悬浮于2mL乙酸乙酯、1mL四氢呋喃和2mL水中，加入无水碳酸钾(202mg，1.46mmol)，冰浴下加入丙烯酰氯(29mg，320.4μmol)，反应5分钟后用乙酸乙酯(5mL×2)萃取，合并有机相，减压浓缩，得到粗品化合物9，即4-((S)-10-丙烯酰基-2-氟-4-甲基-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈(160mg)，用高效液相制备色谱法纯化(Waters-2545，色谱柱：SharpSil-TC18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)纯化得到标题化合物9-P2(50mg，产率：31.9％)和9-P1(50mg，产率：31.9％)。
单一构型化合物(较短保留时间)9-P2(50mg，产率：31.9％)
MS m/z(ESI):533.2[M+1]。
HPLC分析：保留时间1.17分钟，纯度：99％(色谱柱:ACQUITY
Figure PCTCN2022126650-appb-000179
BEH,C18,1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。
1H NMR(500MHz,CD 3OD):δ7.61(d,1H),7.21(t,1H),7.06(dd,1H),6.81(ddd,1H),6.30(d,1H),5.83(t,1H),4.80-4.51(m,3H),4.47-4.18(m,2H),4.05(t,1H),3.44(dd,1H),3.19-2.87(m,2H),2.32-2.15(m,1H),1.85(s,4H)。
单一构型化合物(较长保留时间)9-P1(50mg，产率：31.9％)
MS m/z(ESI):533.2[M+1]。
HPLC分析：保留时间1.19分钟，纯度：99％(色谱柱:ACQUITY
Figure PCTCN2022126650-appb-000180
BEH,C18,1.7μm,2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。
1H NMR(500MHz,CD 3OD):δ7.56(d,1H),7.34(dd,1H),7.08(dd,1H),6.96-6.65(m,1H),6.29(dd,1H),5.82(t,1H),4.67(dd,3H),4.40-4.27(m,1H),4.26-4.01(m,2H),3.48(d,1H),3.18-2.90(m,2H),2.22(d,1H),1.81(s,4H)。
实施例10
4-((8aS,11R)-10-丙烯酰基-2-氟-11-甲基-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈10
Figure PCTCN2022126650-appb-000181
采用实施例1-P1和1-P2中的合成路线，将第三步原料化合物1d替换为(2R,5S)-5-(2-羟乙基)-2-甲基哌嗪-1甲酸叔丁酯10a(采用专利申请“WO2021118877A1”中说明书第80页的preparation 67公开的方法制备而得)得到标题化合物10(72mg，产率：62.2％)。
MS m/z(ESI):533.2[M+1]。
1H NMR(500MHz,CD 3OD):δ7.73-7.64(m,2H),7.30(td,1H),7.08(ddd,1H),6.80(ddd,1H),6.27(ddd,1H),5.81(ddd,1H),4.74(dt,1H),4.62-4.55(m,2H),4.31(td,1H),4.15-4.00(m,1H),3.82-3.61(m,1H),3.24(ddd,2H),2.34(dt,1H),2.02-1.85(m,1H),1.37(dd,3H)。
实施例11-P1，11-P2
(R)-4-((S)-10-丙烯酰基-1,2-二氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈11-P1
(S)-4-((S)-10-丙烯酰基-1,2-二氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈11-P2
Figure PCTCN2022126650-appb-000182
第一步
(S)-3-溴-1,2-二氟-14-氧代-7,8,8a,9,11,12-六氢-10H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-10-甲酸叔丁酯11a
将化合物1g(500mg，1.10mmol)溶于四氢呋喃(6mL)，-78℃加入2M二异丙基氨基锂的四氢呋喃溶液(896μL)，保持温度搅拌反应40分钟，加入N-氟苯磺酰亚胺(417mg，1.32mmol，上海韶远)，搅拌反应20分钟后加入饱和氯化铵溶液淬灭，用乙酸乙酯(15mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物11a(400mg，产率：76.9％)。
MS m/z(ESI):471.1[M+1]。
后续采用实施例1-P1和1-P2中的合成路线，将第五步原料化合物1g替换为化合物11a，得到标题化合物11-P2(30mg，产率：33.3％)和11-P1(8mg，产率：8.9％)。
单一构型化合物(较短保留时间)11-P2(30mg，产率：33.3％)
MS m/z(ESI):537.2[M+1]。
HPLC分析：保留时间2.05分钟，纯度：96％(色谱柱:ACQUITY
Figure PCTCN2022126650-appb-000183
BEH,C18,1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。
1H NMR(500MHz,CD 3OD):δ7.70(d,1H),7.48-7.26(m,1H),7.10(q,1H),6.99-6.63(m,1H),6.30(d,1H),5.84(d,1H),4.72(d,2H),4.42(dd,1H),4.29-3.90(m,2H),3.45(d,2H),3.04(d,2H),2.42-2.15(m,1H),1.93(s,1H)。
单一构型化合物(较长保留时间)11-P1(8mg，产率：8.9％)
MS m/z(ESI):537.2[M+1]。
HPLC分析：保留时间2.10分钟，纯度：97％(色谱柱:ACQUITY
Figure PCTCN2022126650-appb-000184
BEH,C18,1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。
1H NMR(500MHz,CD 3OD):δ7.66(s,1H),7.41(dd,1H),7.11(t,1H),6.94-6.65(m,1H),6.30(dd,1H),5.84(d,1H),4.73-4.70(m,2H),4.37(d,1H),4.17(d,2H),3.36(d,2H),3.16-3.03(m,2H),2.30-2.21(m,2H)。
实施例12-P1，12-P2
(R)-4-((R)-10-丙烯酰基-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈12-P1
(S)-4-((R)-10-丙烯酰基-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈12-P2
Figure PCTCN2022126650-appb-000185
采用实施例1-P1和1-P2中的合成路线，将第三步原料化合物1d替换为(R)-3-(2-羟乙基)哌嗪-1-甲酸叔丁酯12a(采用文献“Tetrahedron Letters,2018,59(21),2030-2033”公开的方法制备)，得到标题化合物12-P2(5mg，产率：9.7％)和12-P1(1.5mg，产率：2.9％)。
单一构型化合物(较短保留时间)12-P2(5mg，产率：9.7％)
MS m/z(ESI):519.2[M+1]。
HPLC分析：保留时间2.42分钟，纯度：99％(色谱柱:
Figure PCTCN2022126650-appb-000186
C18,2.7μm，3.0*30mm；流动相：水(1‰三氟醋酸)，乙腈，梯度配比：乙腈10％-95％)。
1H NMR(500MHz,CD3OD):δ7.70(s,1H),7.66(d,1H),7.31(s,1H),7.08(d,1H),6.82(d,1H),6.30(dd,1H),5.83(t,1H),4.75(d,3H),4.33(d,2H),4.04(d,1H),3.51(d,1H),3.12(dd,2H),2.29(s,1H),2.05(t,1H)。
单一构型化合物(较长保留时间)12-P1(1.5mg，产率：2.9％)
MS m/z(ESI):519.2[M+1]。
HPLC分析：保留时间2.45分钟，纯度：92％(色谱柱:
Figure PCTCN2022126650-appb-000187
C18,2.7μm，3.0*30mm；流动相：水(1‰三氟醋酸)，乙腈，梯度配比：乙腈10％-95％)。
1H NMR(500MHz,CD3OD):δ7.65(s,1H),7.60(d,1H),7.38(ddd,1H),7.13-7.05(m,1H),6.92-6.75(m,1H),6.30(dt,1H),5.83(t,1H),4.82-4.69(m,3H),4.37(d,2H),4.10(s,1H),3.51(d,1H),3.10(dd,2H),2.26(d,1H),2.05(d,1H)。
实施例13-P1，13-P2
(R)-4-((S)-10-丙烯酰基-2,4-二氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲哚-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈13-P1
(S)-4-((S)-10-丙烯酰基-2,4-二氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲哚-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈13-P2
Figure PCTCN2022126650-appb-000188
第一步
(S)-3-溴-2,4-二氟-14-氧代-7,8,8a,9,11,12-六氢-10H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲哚-10-甲酸叔丁基13a
将化合物2d(300mg，0.66mmol)溶于乙腈(6mL)中，冰浴下加入1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(211mg，0.59mmol)，搅拌反应6小时，反应液中加入饱和碳酸氢钠溶液，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：SharpSil-T C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)纯化， 得到标题化合物13a(68mg，产率：21.8％)。
MS m/z(ESI):470.1[M+1]。
后续采用实施例1-P1和1-P2中的合成路线，将第五步原料化合物1g替换为化合物13a，得到标题化合物13-P2(5mg，产率：6.4％)和13-P1(5mg，产率：6.4％)。单一构型化合物(较短保留时间)13-P2(5mg，产率：6.4％)
MS m/z(ESI):536.2[M+1]。
制备HPLC分析：保留时间15.17分钟，纯度：99％(SharpSil-T C18，50*250mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈35％-42％，流速：80mL/min)。
1H NMR(500MHz,CD 3OD):δ7.35(d,2H),7.22(s,1H),7.00(dd,1H),6.87(d,1H),6.29(d,1H),5.82(s,1H),4.70(d,2H),4.37(d,1H),4.23(d,1H),4.06(s,2H),3.51(s,1H),3.07(s,2H),2.21(t,1H),2.05(d,1H)。
单一构型化合物(较长保留时间)13-P1(5mg，产率：6.4％)
MS m/z(ESI):536.2[M+1]。
制备HPLC分析：保留时间16.02分钟，纯度：99％(SharpSil-T C18，50*250mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈35％-42％，流速：80mL/min)。
1H NMR(500MHz,CD 3OD):δ7.34-7.26(m,2H),7.20(d,1H),7.01(dd,1H),6.80(dd,1H),6.29(dd,1H),5.82(t,1H),4.70(t,2H),4.35(dd,1H),4.25(s,1H),4.22-4.13(m,1H),4.01(s,1H),3.50(s,1H),3.06(dt,2H),2.24-2.15(m,1H),2.05(d,1H)。
实施例14
4-((R)-10-丙烯酰基-4-氟-6-氧代-8,9,10,11,11a,12-六氢-6H-吡嗪并[2',1':3,4][1,4]二氮杂庚环并[6,7,1-hi]吲唑-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈14
Figure PCTCN2022126650-appb-000189
Figure PCTCN2022126650-appb-000190
第一步
(R)-4-(4-溴-5-氟-1H-吲唑-7-羰基)-3-(羟甲基)哌嗪-1-甲酸叔丁酯14b
将粗品化合物1c(560mg，2.16mmol)、(R)-3-(羟甲基)哌嗪-1-羧酸叔丁酯14a(514mg，2.37mmol，上海韶远)溶于10mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(838mg，6.48mmol)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(986mg，2.59mmol)，搅拌反应1小时。反应液减压浓缩后加入乙酸乙酯稀释，依次用水、饱和碳酸钠溶液、饱和氯化钠溶液洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：SharpSil-T C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈35％-45％，流速：30mL/min)纯化，得到标题化合物14b(100mg，产率：10.1％)。
MS m/z(ESI):457.2[M+1]。
第二步
(R)-3-溴-4-氟-6-氧代-8,9,11a,12-四氢-6H-吡嗪并[2',1':3,4][1,4]二氮杂庚环并[6,7,1-hi]吲唑-10(11H)-甲酸叔丁酯14c
将化合物14b(250mg，546μmol)、三乙胺(166mg，1.6mmol)溶于5mL二氯甲烷中，冰浴下加入甲烷磺酰氯(187mg,1.6mmol)，搅拌反应2小时。反应液中加入少量水淬灭，减压浓缩，溶于5mL N,N-二甲基甲酰胺中，加入碳酸钾(226mg，1.6mmol)，80℃搅拌反应1小时，反应液降至室温后过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物14c(30mg，产率：12.4％)。
MS m/z(ESI):439.29[M+1]。
后续采用实施例1-P1和1-P2中的合成路线，将第五步原料化合物1g替换为化合物14c，得到标题化合物14(5mg产率：17.8％)。
MS m/z(ESI):505.2[M+1]。
1H NMR(500MHz,CD 3OD):δ8.05(d,1H),7.75(s,1H),7.31(d,1H),7.07(t,1H),6.78(ddd,1H),6.35-6.25(m,1H),5.82(dd,1H),4.79(s,1H),4.77-4.73(m,1H),4.73-4.65(m,1H),4.51(t,1H),4.41(ddd,1H),4.14(ddd,1H),4.02-3.96(m,1H),2.19 (t,1H),2.03(d,1H)。
实施例15-P1，15-P2
(R)-2-氨基-7-氟-4-((S)-2-氟-10-(2-氟丙烯酰基)-4-甲基-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)苯并[b]噻吩-3-甲腈15-P1
(S)-2-氨基-7-氟-4-((S)-2-氟-10-(2-氟丙烯酰基)-4-甲基-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)苯并[b]噻吩-3-甲腈15-P2
Figure PCTCN2022126650-appb-000191
采用实施例9-P1和9-P2中的合成路线，将第八步原料丙烯酰氯替换为2-氟丙烯酰氯，得到标题化合物15-P2(50mg，产率：24.9％)和15-P1(50mg，产率：24.9％)。
单一构型化合物(较短保留时间)15-P2(50mg，产率：24.9％)
MS m/z(ESI):551.3[M+1]。
HPLC分析：保留时间1.27分钟，纯度：99％(色谱柱:ACQUITY
Figure PCTCN2022126650-appb-000192
BEH,C18,1.7μm,2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。
1H NMR(500MHz,CD 3OD):δ7.62(d,1H),7.21(dd,1H),7.06(dd,1H),5.39-5.26(m,2H),4.76(d,1H),4.65-4.59(m,1H),4.38-3.96(m,3H),3.47(s,1H),3.21-2.99(m,2H),2.35-2.17(m,1H),2.05(d,1H),1.85(s,4H)。
单一构型化合物(较长保留时间)15-P1(50mg，产率：24.9％)
MS m/z(ESI):551.3[M+1]。
HPLC分析:保留时间1.28分钟，纯度：99％(色谱柱:ACQUITY
Figure PCTCN2022126650-appb-000193
BEH，C18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。
1H NMR(500MHz,CD 3OD):δ7.56(d,1H),7.35(dd,1H),7.08(dd,1H),5.42-5.22(m,2H),4.80-4.71(m,1H),4.69-4.59(m,1H),4.37-3.98(m,3H),3.55-3.36(m,1H),3.15(td,2H),2.32-2.02(m,2H),1.95-1.76(m,4H)。
实施例16-P1，16-P2
(R)-2-氨基-4-((S)-2,4-二氟-10-(2-氟丙烯酰基)-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-7-氟苯并[b]噻吩-3- 甲腈16-P1
(S)-2-氨基-4-((S)-2,4-二氟-10-(2-氟丙烯酰基)-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-7-氟苯并[b]噻吩-3-甲腈16-P2
Figure PCTCN2022126650-appb-000194
采用实施例8-P1和8-P2中的合成路线，将第六步原料丙烯酰氯替换为2-氟丙烯酰氯，得到标题化合物16-P2(40mg，产率：24.7％)和16-P1(10mg，产率：6.1％)。
单一构型化合物(较短保留时间)16-P2(40mg，产率：24.7％)
MS m/z(ESI):555.3[M+1]。
HPLC分析：保留时间1.31分钟，纯度：99％(色谱柱:ACQUITY
Figure PCTCN2022126650-appb-000195
BEH,C18,1.7μm,2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。
1H NMR(500MHz,CD 3OD):δ7.69(d,1H),7.27(dd,1H),7.04(dd,1H),5.42-5.22(m,2H),4.79-4.70(m,1H),4.60(s,1H),4.50(ddd,1H),4.39-3.88(m,3H),3.64-3.35(m,1H),3.29-2.87(m,2H),2.35-2.18(m,1H),2.02-1.89(m,1H)。
单一构型化合物(较长保留时间)16-P1(10mg，产率：6.1％)
MS m/z(ESI):555.3[M+1]。
HPLC分析：保留时间1.33分钟，纯度：96％(色谱柱:ACQUITY
Figure PCTCN2022126650-appb-000196
BEH，C18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。
1H NMR(500MHz,CD 3OD):δ7.64(d,1H),7.36(dd,1H),7.06(dd,1H),5.41-5.27(m,2H),4.74(d,1H),4.68-4.43(m,2H),4.37-3.97(m,3H),3.55-3.35(m,1H),3.24-2.87(m,2H),2.41-2.13(m,1H),2.00-1.78(m,1H)。
实施例17-P1，17-P2
(R)-2-氨基-4-((S)-4-氯-2-氟-10-(2-氟丙烯酰基)-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-7-氟苯并[b]噻吩-3-甲腈17-P1
(S)-2-氨基-4-((S)-4-氯-2-氟-10-(2-氟丙烯酰基)-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-7-氟苯并[b]噻吩-3-甲腈17-P2
Figure PCTCN2022126650-appb-000197
将化合物7c(299mg，599.2μmol)悬浮于2mL乙酸乙酯、1mL四氢呋喃和2mL水中，加入无水碳酸钾(414mg，2.99mmol)，冰浴下加入2-氟丙烯酰氯(322mg，2.98mmol)，反应5分钟后用乙酸乙酯(5mL×2)萃取，合并有机相，减压浓缩，得到粗品化合物17，即2-氨基-4-((S)-4-氯-2-氟-10-(2-氟丙烯酰基)-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲唑-3-基)-7-氟苯并[b]噻吩-3-甲腈(340mg)，用高效液相制备色谱法(Waters-2545，色谱柱：YMC Triart-Exrs，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)纯化，得到标题化合物17-P2(50mg，产率：14.6％)和17-P1(50mg，产率：14.6％)。
单一构型化合物(较短保留时间)17-P2(50mg，产率：14.6％)
MS m/z(ESI):571.2[M+1]。
HPLC分析：保留时间2.42分钟，纯度：99％(色谱柱:ACQUITY
Figure PCTCN2022126650-appb-000198
BEH,C18,1.7μm,2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。
1H NMR(500MHz,CD 3OD):δ7.67(d,1H),7.19(dd,1H),7.02(dd,1H),5.35(t,1H),5.26(s,1H),4.73(dt,2H),4.64(ddd,2H),4.30(ddd,2H),4.09(s,1H),3.20-3.10(m,2H),2.07-1.89(m,2H)。
单一构型化合物(较长保留时间)17-P1(50mg，产率：14.6％)
MS m/z(ESI):571.2[M+1]。
HPLC分析：保留时间2.47分钟，纯度：99％(色谱柱:ACQUITY
Figure PCTCN2022126650-appb-000199
BEH，C18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。
1H NMR(500MHz,CD 3OD):δ7.63(d,1H),7.31(dd,1H),7.04(dd,1H),5.35(d,1H),5.25(d,1H),4.72(dt,2H),4.64(ddd,2H),4.27(ddd,2H),4.10(s,1H),3.19-3.10(m,2H),1.95-1.83(m,2H)。
实施例18-P1，18-P2
(R)-4-((S)-10-丙烯酰基-2-氟-4-甲基-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲哚-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈18-P1
(S)-4-((S)-10-丙烯酰基-2-氟-4-甲基-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲哚-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈18-P2
Figure PCTCN2022126650-appb-000200
第一步
4-溴-5-氟-3-甲基-1H-吲哚-7-甲酸甲酯18b
将化合物18a(2.1g，7.95mmol，上海毕得)溶于无水四氢呋喃中(15mL)中，-40℃氮气氛下加入0.5M的1-丙烯基溴化镁四氢呋喃溶液(40mL，Sigma-Aldrich)，恢复室温反应5小时，反应液加入饱和氯化铵溶液淬灭，用乙酸乙酯(30mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物18b(200mg，产率：8.7％)。
MS m/z(ESI):285.9[M+1]。
后续采用实施例1-P1和1-P2中的合成路线，将第二步原料1b替换为化合物18b，得到标题化合物18-P2(3mg，产率：5.5％)和18-P1(10mg，产率：18.3％)。
单一构型化合物(较短保留时间)18-P2(3mg，产率：5.5％)
MS m/z(ESI):532.3[M+1]。
制备HPLC分析：保留时间12.30分钟，纯度：99％(SharpSil-T C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈35％-45％，流速：30mL/min)。
1H NMR(500MHz,CD 3OD):δ7.27(d,1H),7.13(s,1H),7.05-6.96(m,2H),6.81(ddd,1H),6.29(d,1H),5.86-5.78(m,1H),4.74-4.68(m,1H),4.45-4.22(m,2H),4.02(dq,3H),3.14-2.90(m,2H),2.24-2.02(m,2H),1.83(s,1H),1.58-1.55(m,3H)。
单一构型化合物(较长保留时间)18-P1(10mg，产率：18.3％)
MS m/z(ESI):532.3[M+1]。
制备LCMS分析:保留时间12.87分钟，纯度：99％(SharpSil-T C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈35％-45％， 流速：30mL/min)。
1H NMR(500MHz,CD 3OD):δ7.29(dd,1H),7.20(d,1H),7.07-7.00(m,2H),6.93-6.67(m,1H),6.29(dd,1H),5.82(dd,1H),4.70(d,1H),4.38-4.13(m,3H),4.0-3.86(m,2H),3.12-2.90(m,2H),2.18-2.12(m,1H),2.07-2.04(m,1H),1.79(d,1H),1.52(s,3H)。
实施例19-P1，19-P2
(R)-4-((S)-10-丙烯酰基-4-氯-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲哚-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈19-P1
(S)-4-((S)-10-丙烯酰基-4-氯-2-氟-14-氧代-8,8a,9,10,11,12-六氢-7H,14H-吡嗪并[1',2':5,6][1,5]二氮杂辛环并[3,2,1-hi]吲哚-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈19-P2
Figure PCTCN2022126650-appb-000201
采用实施例7-P1和7-P2中的合成路线，将第一步原料1g替换为化合物2d，得到标题化合物19-P2(5mg，产率：50％)和19-P1(5mg，产率：50％)(5mg，5mg，产率：50％，50％)。
单一构型化合物(较短保留时间)19-P2(5mg，产率：50％)
MS m/z(ESI):552.3[M+1]。
制备HPLC分析：保留时间12.30分钟，纯度：99％(色谱柱：Welch Xtimate Phenyl-hexyl，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈40％-55％，流速：30mL/min)。
1H NMR(500MHz,CD 3OD):δ7.38-7.35(m,2H),7.16(s,1H),6.99(dd,1H),6.92-6.70(m,1H),6.29(d,1H),5.88-5.78(m,1H),4.70(d,1H),4.45-4.30(m,2H),4.12-3.94(m,2H),3.52-3.46(m,1H),3.15-2.92(m,2H),2.27-2.15(m,1H),1.93-1.83(m,1H),0.96-0.88(m,1H)。
单一构型化合物(较长保留时间)19-P1(5mg，产率：50％)
MS m/z(ESI):552.3[M+1]。
制备HPLC分析：保留时间12.83分钟，纯度：99％(色谱柱：Welch Xtimate Phenyl-hexyl，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈40％-55％，流速：30mL/min)。
1H NMR(500MHz,CD 3OD):δ7.35(s,1H),7.34-7.25(m,2H),7.01(dd,1H),6.93-6.67(m,1H),6.29(dd,1H),5.82(t,1H),4.69(dd,1H),4.40-4.25(m,2H),4.16(d, 1H),4.02(s,1H),3.56-3.43(m,1H),3.16-2.91(m,2H),2.26-2.02(m,1H),1.93-1.83(m,1H),0.92(t,1H)。
实施例20-P1，20-P2
(R)-4-((S)-9-丙烯酰基-2-氟-12-氧代-7,7a,8,9,10,11-六氢-6H,12H-4,5,5a,9,11a-五氮杂苯并[5,6]辛环并[1,2,3-cd]茚-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈20-P1
(S)-4-((S)-9-丙烯酰基-2-氟-12-氧代-7,7a,8,9,10,11-六氢-6H,12H-4,5,5a,9,11a-五氮杂苯并[5,6]辛环并[1,2,3-cd]茚-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈20-P2
Figure PCTCN2022126650-appb-000202
第一步
2-乙酰氨基-4-溴-5-氟苯甲酸甲酯20b
将2-氨基-4-溴-5-氟苯甲酸甲酯20a(4g，16.12mmol，上海毕得)溶于醋酸酐(20mL)，90℃反应1小时，反应液减压浓缩，残余物加入二氯甲烷溶解，用饱和碳酸钠洗涤，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩得到粗品标题化合物20b(6.5g)，产品不经纯化直接用于下步反应。
MS m/z(ESI):289.9[M+1]。
第二步
2-乙酰氨基-4-溴-5-氟-3-硝基苯甲酸甲酯20c
将粗品化合物20b(6g，20.68mmol)溶于浓硫酸(30mL)，冰浴下逐滴加入硝酸(15mL)，保持温度反应1小时。将反应液倒入冰水中，用二氯甲烷萃取(10mL×3)，合并有机相，用饱和碳酸氢钠溶液洗涤，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩得到粗品标题化合物20c(1.5g)，产品不经纯化直接用于下步反应。
MS m/z(ESI):334.9[M+1]。
第三步
2-氨基-4-溴-5-氟-3-硝基苯甲酸甲酯20d
将粗品化合物20c(3.2g，9.5mmol)溶于乙醇(32mL)中，加入盐酸(32mL)，80℃反应3小时。反应液减压浓缩，加入饱和碳酸氢钠溶液(20mL)，用二氯甲烷萃取(20mL×3)，合并有机相，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，得到粗品标题化合物20d(6.5g)，产品不经纯化直接用于下步反应。
MS m/z(ESI):292.9[M+1]。
第四步
2,3-二氨基-4-溴-5-氟苯甲酸甲酯20e
将粗品化合物20d(500mg，1.7mmol)溶于乙醇(25mL)和水(5mL)中，加入氯化铵(910mg，17.01mmol)、铁粉(500mg，8.9mmol)，60℃反应1小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物20e(400mg，产率：89.1％)。
MS m/z(ESI):262.9[M+1]。
第五步
4-溴-5-氟-1H-苯并[d][1,2,3]***-7-甲酸甲酯20f
将粗品化合物20e(600mg，2.28mmol)溶于冰乙酸(6mL)，加入亚硝酸钠(188mg，2.72mmol)，反应30分钟，反应液过滤，滤饼用水洗涤，干燥后即得粗品标题化合物20f(600mg)，产品不经纯化直接用于下步反应。
MS m/z(ESI):273.9[M+1]。
后续采用实施例1-P1和1-P2中的合成路线，将第二步原料化合物1b替换为化合物20f，得到标题化合物20-P2(6mg，产率：27.4％)和20-P1(5mg，产率：22.8％)。
单一构型化合物(较短保留时间)20-P2(6mg，产率：27.4％)
MS m/z(ESI):519.2[M+1]。
HPLC分析：保留时间1.531分钟，纯度：99％(色谱柱:
Figure PCTCN2022126650-appb-000203
C18,2.7μm，3.0*30mm；流动相：水(5mM醋酸铵)，乙腈，梯度配比：乙腈10％-95％)。
1H NMR(500MHz,CDCl 3):δ7.92-7.83(m,1H),7.45(s,1H),7.09(br,1H),6.43(d,1H),5.84(br,1H),5.32-5.28(m,3H),4.91(br,1H),4.47(br,1H),4.10(br,1H),3.06(br,1H),2.24(br,1H),2.04(br,2H),1.65(br,1H),0.90(t,1H)。
单一构型化合物(较长保留时间)20-P1(5mg，产率：22.8％)
MS m/z(ESI):519.2[M+1]。
HPLC分析：保留时间1.545分钟，纯度：99％(色谱柱:
Figure PCTCN2022126650-appb-000204
C18,2.7μm，3.0*30mm；流动相：水(5mM醋酸铵)，乙腈，梯度配比：乙腈10％-95％)。
1H NMR(500MHz,CDCl 3):δ7.85(d,1H),7.53-7.48(m,1H),7.19-7.04(m,1H),6.73-6.35(m,2H),5.82(br,1H),5.33-5.11(m,3H),4.87(br,1H),4.56-4.34(m,1H),4.22-3.98(m,1H),3.52-2.87(m,2H),2.39(br,1H),2.10-1.95(m,1H),0.90(t,1H)。
实施例21-P1，21-P2
(R)-4-((S)-9-丙烯酰基-2-氟-12-氧代-7,7a,8,9,10,11-六氢-6H,12H-4,5a,9,11a-四氮杂苯并[5,6]辛环并[1,2,3-cd]茚-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈21-P1
(S)-4-((S)-9-丙烯酰基-2-氟-12-氧代-7,7a,8,9,10,11-六氢-6H,12H-4,5a,9,11a-四氮杂苯并[5,6]辛环并[1,2,3-cd]茚-3-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈21-P2
Figure PCTCN2022126650-appb-000205
第一步
4-溴-5-氟-1H-苯并[d]咪唑-7-甲酸甲酯21a
将化合物20e(500mg，1.9mmol)溶于原甲酸三乙酯(5mL)，加入4-对甲苯磺酸(98.1mg，569.6μmol)，搅拌反应5分钟，析出大量固体。反应液加入饱和碳酸氢钠水溶液，乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，得到粗品标题化合物21a(500mg)，产品不经纯化直接用于下步反应。
MS m/z(ESI):272.9[M+1]。
后续采用实施例1-P1和1-P2中的合成路线，将第二步原料化合物1b替换为化合物21a，得到标题化合物21-P2(3mg，产率：38.3％)和21-P1(2mg，产率：25.5％)。
单一构型化合物(较短保留时间)21-P2(3mg，产率：38.3％)
MS m/z(ESI):519.2[M+1]。
HPLC分析：保留时间1.455分钟，纯度：99％(色谱柱:
Figure PCTCN2022126650-appb-000206
C18,2.7μm，3.0*30mm；流动相：水(5mM醋酸铵)，乙腈，梯度配比：乙腈10％-95％)。
1H NMR(500MHz,DMSO-d 6):δ8.26(s,1H),7.36(d,1H),7.14(t,1H),6.87(s,1H),6.66(s,1H),6.18(d,1H),6.05(s,2H),5.74(d,1H),4.58(d,2H),4.24(s,1H),3.92(d,2H),3.63(s,2H),2.86(s,2H),2.15(s,1H),2.01(s,1H)。
单一构型化合物(较长保留时间)21-P1(2mg，产率：25.5％)
MS m/z(ESI):519.2[M+1]。
HPLC分析：保留时间1.465分钟，纯度：99％(色谱柱:
Figure PCTCN2022126650-appb-000207
C18,2.7μm，3.0*30mm；流动相：水(5mM醋酸铵)，乙腈，梯度配比：乙腈10％-95％)。
1H NMR(500MHz,DMSO-d 6):δ8.27(s,1H),7.94(s,2H),7.38(d,1H),7.27(dd,1H),7.12(t,1H),6.80(d,1H),6.18(t,1H),5.75(s,1H),4.56(s,2H),4.24(d,1H),4.03-3.89(m,2H),3.47(s,2H),3.09-2.93(m,2H),2.14(s,1H),1.79(s,1H)。
生物学评价
以下结合测试例进一步描述解释本公开，但这些测试例并非意味着限制本公开的范围。
测试例1：H358增殖试验
以下方法用来测定本公开化合物对H358细胞增殖的抑制活性，实验方法简述如下：
H358细胞(ATCC，CRL-5807)用含有10％胎牛血清(Corning，35-076-CV)的RPMI1640培养基(Hyclone，SH30809.01)(即完全培养基)进行培养。实验第一天，使用完全培养基将H358细胞以1200个细胞/孔的密度种于96孔板，每孔100μL细胞悬液，放置37℃，5％CO 2细胞培养箱培养过夜。第二天，每孔加入10μL用完全培养基配制的梯度稀释的待测化合物，化合物的终浓度是从10μM开始进行5倍梯度稀释的9个浓度点，设置含有0.5％DMSO的空白对照，孔板放置37℃，5％CO 2的细胞培养箱培养120小时。第七天，取出96孔细胞培养板，每孔加入50μL CellTiter-
Figure PCTCN2022126650-appb-000208
Luminescent Cell Viability Assay(Promega，G7573)，室温放置10分钟后，使用多功能微孔板酶标仪(PerkinElmer，
Figure PCTCN2022126650-appb-000209
2105)读取发光信号值，用Graphpad Prism软件计算化合物抑制活性的IC 50值。
表1本公开化合物对H358细胞增殖的抑制活性
化合物编号 IC 50(nM)
1-P2 0.93
1-P1 11.98
2 10.49
4 13.36
6-P2 5.73
6-P1 9.75
7-P2 0.74
8-P2 0.84
9-P2 0.52
10 0.8
11-P2 0.32
11-P1 2.25
13-P2 11.44
15-P2 4.21
15-P1 41.59
16-P2 8.00
17-P2 1.87
18-P2 9.57
19-P2 5.65
20-P2 7.90
20-P1 4.94
结论：本公开化合物对H358细胞增殖具有抑制作用。
测试例2：H358细胞ERK磷酸化抑制试验
以下方法用来测定本公开化合物对H358细胞ERK磷酸化的抑制作用。实验方法简述如下：
H358细胞(ATCC，CRL-5807)用含有10％胎牛血清(Corning，35-076-CV)的RPMI1640(Hyclone，SH30809.01)培养基(即完全培养基)进行培养。实验第一天，使用完全培养基将H358细胞以25,000个/孔的密度种于96孔板，每孔190μL细胞悬液，放置37℃，5％CO 2细胞培养箱培养过夜。第二天，每孔加入10μL用完全培养基配制的梯度稀释的待测化合物，化合物的终浓度是从10μM开始进行6倍梯度稀释的9个浓度点，设置含有0.5％DMSO的空白对照，孔板放置37℃，5％CO 2的细胞培养箱孵育3个小时。3小时后，取出96孔细胞培养板，吸掉培养基，每孔加入200μL PBS(上海源培生物科技股份有限公司，B320)洗一遍。吸掉PBS，每孔加入50μL含封闭剂(Cisbio，64KB1AAC)的裂解缓冲液(Cisbio，64KL1FDF)，孔板放置振荡器上室温震荡裂解30分钟。裂解后用移液器吹打混匀，每孔各转移16μL裂解液分别至两块HTRF 96孔检测板(Cisbio，66PL96100)中，之后两块板分别加入4μL预混的phospho-ERK1/2抗体溶液(Cisbio，64AERPEG)或4μL预混的total-ERK1/2抗体溶液(Cisbio，64NRKPEG)。微孔板用封板膜密封，在微孔板离心机中离心1分钟，室温避光孵育过夜。第三天，使用PHERAstar多功能酶标仪(BMG Labtech，PHERAstar FS)读取337nm波长激发、665nm和620nm波长发射的荧光值，用Graphpad Prism软件根据化合物浓度和pERK/total ERK的比值计算化合物抑制活性的IC 50值。
表2本公开化合物对H358细胞ERK磷酸化的抑制作用
化合物编号 IC 50(nM)
1-P2 0.07
1-P1 1.33
2 0.28
3 23.74
4 1.16
5 36.21
6-P2 0.35
6-P1 1.45
7-P2 0.13
8-P2 0.16
9-P2 0.06
9-P1 32.55
10 0.15
11-P2 0.09
11-P1 7.67
12-P2 11.32
13-P2 0.76
14 1.35
15-P2 3.94
15-P1 19.71
16-P2 1.06
17-P2 2.0
18-P2 1.09
19-P2 0.97
20-P2 0.88
20-P1 3.67
结论：本公开化合物对H358细胞ERK磷酸化具有抑制作用。
测试例3：MIA PaCa-2细胞增殖试验
以下方法用来测定本公开化合物对MIA PaCa-2细胞增殖的抑制活性。实验方法简述如下：
MIA PaCa-2细胞(ATCC，CRL-1420)用含有10％胎牛血清(Corning，35-076-CV)和2.5％马血清(碧云天生物技术，C0262)的DMEM/HIGH GLUCOSE(GE，SH30243.01)培养基(即完全培养基)进行培养。实验第一天，使用完全培养基将MIA PaCa-2细胞以500个细胞/孔的密度种于96孔板，每孔90μL细胞悬液，放置37℃，5％CO 2细胞培养箱培养过夜。第二天，每孔加入10μL用完全培养基配制的梯度稀释的待测化合物，化合物的终浓度是从10μM开始进行5倍梯度稀释的9个浓度点，设置含有0.5％DMSO的空白对照，孔板放置37℃、5％CO 2的细胞培养箱培养72小时。第五天，取出96孔细胞培养板，每孔加入50μL发光细胞活性检测试剂(CellTiter-
Figure PCTCN2022126650-appb-000210
Luminescent Cell Viability Assay)(Promega，G7573)，室温放置10分钟后，使用多功能微孔板酶标仪(PerkinElmer，EnVision2015)读取发光信号值。用Graphpad Prism软件计算化合物抑制活性的IC 50值。
表3本公开化合物对MIA PaCa-2细胞增殖的抑制活性
化合物编号 IC 50(nM)
1-P2 0.40
1-P1 2.79
2 5.87
4 11.15
6-P2 5.39
6-P1 13.87
7-P2 0.28
8-P2 0.19
9-P2 0.37
10 0.94
11-P2 0.46
11-P1 2.71
12-P2 35.29
13-P2 20.54
14 39.58
15-P2 7.75
15-P1 56.84
16-P2 4.56
17-P2 1.88
18-P2 9.16
19-P2 4.90
20-P2 1.21
20-P1 1.66
结论：本公开化合物对MIA PaCa-2细胞增殖具有抑制作用。

Claims (22)

  1. 一种通式(IM)所示的化合物或其可药用的盐：
    Figure PCTCN2022126650-appb-100001
    其中：
    X为C(R aR b)或C(R aR b)-C(R cR d)；
    Y为C(O)或CH 2；
    Z为CR 5a或N；
    V为CR 5或N；
    环A为芳基或杂芳基；
    R a、R b、R c和R d在每次出现时相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、羟基和氰基；
    R 1选自氰基、
    Figure PCTCN2022126650-appb-100002
    各个R 2相同或不同，且各自独立地选自氢原子、卤素、氰基、烷基、烷氧基、羟基和氨基，其中所述的烷基和烷氧基各自独立地任选被选自卤素、氰基、氨基和羟基中的一个或多个取代基所取代；
    R 3、R 4、R 5和R 5a相同或不同，且各自独立地选自氢原子、卤素、氰基、烷基、烯基、炔基、-NR 7aR 7b、-C(O)R 8、-OR 8、-S(O) pR 8、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、卤代烷基、氰基、-NR 7cR 7d、-OR 8a、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    各个R 6相同或不同，且各自独立地选自氢原子、卤素、氰基、烷基、烯基、炔基、-NR 9aR 9b、-C(O)NR 9aR 9b、-C(O)R 10、-C(O)OR 10、-OC(O)R 10、-OR 10、-S(O) pR 10、-S(O) pNR 9aR 9b、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、卤代烷基、氰基、-NR 9cR 9d、-OR 10a、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 11、R 12、R 13和R 14相同或不同，且各自独立地选自氢原子、卤素、烷基、-NR 15aR 15b、-OR 16、氰基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环 烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、氧代基、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、-NR 15cR 15d、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 8、R 8a、R 10、R 10a和R 16在每次出现时相同或不同，且各自独立地选自氢原子、烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、氧代基、烷氧基、卤代烷基、卤代烷氧基、氰基、-NR 17aR 17b、羟基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 7a、R 7b、R 7c、R 7d、R 9a、R 9b、R 9c、R 9d、R 15a、R 15b、R 15c、R 15d、R 17a和R 17b在每次出现时相同或不同，且各自独立地选自氢原子、烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、氧代基、羟基、氰基、烷基、烷氧基、卤代烷基和卤代烷氧基中的一个或多个取代基所取代；
    或者R 7a和R 7b与相连的氮原子一起形成杂环基，其中所述杂环基任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    或者R 7c和R 7d与相连的氮原子一起形成杂环基，其中所述杂环基任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    或者R 9a和R 9b与相连的氮原子一起形成杂环基，其中所述杂环基任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    或者R 9c和R 9d与相连的氮原子一起形成杂环基，其中所述杂环基任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    或者R 15a和R 15b与相连的氮原子一起形成杂环基，其中所述杂环基任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    或者R 15c和R 15d与相连的氮原子一起形成杂环基，其中所述杂环基任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    或者R 17a和R 17b与相连的氮原子一起形成杂环基，其中所述杂环基任选被选自卤素、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    s为0、1、2、3、4、5或6；
    t为0、1、2、3、4或5；且
    p为0、1或2。
  2. 根据权利要求1所述的通式(IM)所示的化合物或其可药用的盐，其为通式(I)所示的化合物或其可药用的盐：
    Figure PCTCN2022126650-appb-100003
    其中：
    环A、X、Y、Z、R 1、R 2、R 3、R 4、R 5、R 6、s和t如权利要求1中所定义。
  3. 根据权利要求1或2所述的通式(IM)所示的化合物或其可药用的盐，其中Y为C(O)。
  4. 根据权利要求1至3中任一项所述的通式(IM)所示的化合物或其可药用的盐，其中s为0或1。
  5. 根据权利要求1至4中任一项所述的通式(IM)所示的化合物或其可药用的盐，其为通式(II)所示的化合物或其可药用的盐：
    Figure PCTCN2022126650-appb-100004
    其中：
    环A、X、Z、R 1、R 3、R 4、R 5、R 6和t如权利要求1中所定义。
  6. 根据权利要求1至5中任一项所述的通式(IM)所示的化合物或其可药用的盐，其中环A为环内含有1、2或3个选自氮、氧和硫的杂原子的8至10元双环杂芳基。
  7. 根据权利要求1至6中任一项所述的通式(IM)所示的化合物或其可药用的盐，其中R 1为
    Figure PCTCN2022126650-appb-100005
    其中R 11、R 12和R 13如权利要求1中所定义。
  8. 根据权利要求1至7中任一项所述的通式(IM)所示的化合物或其可药用的盐，其中X为CH 2或CH 2-CH 2；优选地，X为CH 2-CH 2。
  9. 根据权利要求1至8中任一项所述的通式(IM)所示的化合物或其可药用的盐，其为通式(III)所示的化合物或其可药用的盐：
    Figure PCTCN2022126650-appb-100006
    其中：
    W为C(CN)或N；
    t为0、1、2或3；
    Z、R 3、R 4、R 5、R 6、R 11、R 12和R 13如权利要求1中所定义。
  10. 根据权利要求1至9中任一项所述的通式(IM)所示的化合物或其可药用的盐，其中R 3、R 4、R 5和R 5a相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基。
  11. 根据权利要求1至10中任一项所述的通式(IM)所示的化合物或其可药用的盐，其中各个R 6相同或不同，且各自独立地选自卤素、氰基、-NH 2、C 1-6烷基和C 1-6卤代烷基，且t为0、1、2或3。
  12. 根据权利要求1至11中任一项所述的通式(IM)所示的化合物或其可药用的盐，其中R 11为氢原子或卤素。
  13. 根据权利要求1至12中任一项所述的通式(IM)所示的化合物或其可药用的盐，其中R 12为氢原子。
  14. 根据权利要求1至13中任一项所述的通式(IM)所示的化合物或其可药用 的盐，其中R 13为氢原子。
  15. 根据权利要求1至14中任一项所述的通式(IM)所示的化合物或其可药用的盐，其选自以下化合物：
    Figure PCTCN2022126650-appb-100007
    Figure PCTCN2022126650-appb-100008
    Figure PCTCN2022126650-appb-100009
    Figure PCTCN2022126650-appb-100010
    Figure PCTCN2022126650-appb-100011
    Figure PCTCN2022126650-appb-100012
    Figure PCTCN2022126650-appb-100013
  16. 一种通式(IMa)所示的化合物或其盐：
    Figure PCTCN2022126650-appb-100014
    其中：
    环A、V、X、Y、Z、R 2、R 3、R 4、R 6、s和t如权利要求1中所定义。
  17. 一种化合物或其盐，其选自以下化合物：
    Figure PCTCN2022126650-appb-100015
    Figure PCTCN2022126650-appb-100016
    Figure PCTCN2022126650-appb-100017
    Figure PCTCN2022126650-appb-100018
    Figure PCTCN2022126650-appb-100019
    Figure PCTCN2022126650-appb-100020
    Figure PCTCN2022126650-appb-100021
  18. 一种制备通式(IM)所示的化合物或其可药用的盐的方法，其包括：
    Figure PCTCN2022126650-appb-100022
    通式(IMa)所示的化合物或其盐和通式(X)化合物或其盐发生反应得到通式(IM)所示的化合物或其可药用的盐；
    其中：
    L为卤素；优选地，L为Cl；
    R 1为
    Figure PCTCN2022126650-appb-100023
    环A、V、X、Y、Z、R 2、R 3、R 4、R 6、R 11、R 12、R 13、R 14、s和t如权利要求1中所定义。
  19. 一种药物组合物，所述药物组合物含有根据权利要求1至15中任一项所述的通式(IM)所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  20. 根据权利要求1至15中任一项所述的通式(IM)所示的化合物或其可药用的盐或根据权利要求19所述的药物组合物在制备用于抑制KRAS G12C的药物中的用途。
  21. 根据权利要求1至15中任一项所述的通式(IM)所示的化合物或其可药用的盐或根据权利要求19所述的药物组合物在制备用于治疗和/或预防肿瘤的药物中的用途。
  22. 根据权利要求21所述的用途，其中所述的肿瘤为癌症；优选地，所述的癌症选自肺癌、胰腺癌、***、食管癌、子宫内膜癌、卵巢癌、胆管癌、结直肠癌、肝癌、乳腺癌、***癌、甲状腺癌、胃癌、尿路上皮癌、睾丸癌、白血病、皮肤癌、鳞状细胞癌、基底细胞癌、膀胱癌、头颈癌、肾癌、鼻咽癌、骨癌、淋巴瘤、黑色素瘤、肉瘤、外周神经上皮瘤、胶质瘤、脑瘤和骨髓瘤；更优选地，所述的癌症选自肺癌、胰腺癌、***、食管癌、子宫内膜癌、卵巢癌、胆管癌和结直肠癌。
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