WO2022247919A1 - 作为bcr-abl抑制剂的化合物 - Google Patents

作为bcr-abl抑制剂的化合物 Download PDF

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WO2022247919A1
WO2022247919A1 PCT/CN2022/095436 CN2022095436W WO2022247919A1 WO 2022247919 A1 WO2022247919 A1 WO 2022247919A1 CN 2022095436 W CN2022095436 W CN 2022095436W WO 2022247919 A1 WO2022247919 A1 WO 2022247919A1
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compound
preparation
alkyl
membered
esi
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PCT/CN2022/095436
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English (en)
French (fr)
Inventor
张寅生
刘欣
秦慧
叶嘉炜
汪纪楠
吴松松
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正大天晴药业集团股份有限公司
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Application filed by 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to JP2023572243A priority Critical patent/JP2024519538A/ja
Priority to CN202280033493.1A priority patent/CN117295725A/zh
Priority to US18/561,553 priority patent/US20240262807A1/en
Priority to EP22810643.1A priority patent/EP4349829A1/en
Priority to CA3219641A priority patent/CA3219641A1/en
Priority to KR1020237044056A priority patent/KR20240014478A/ko
Priority to IL308614A priority patent/IL308614A/en
Priority to MX2023013650A priority patent/MX2023013650A/es
Priority to AU2022282316A priority patent/AU2022282316A1/en
Priority to BR112023024085A priority patent/BR112023024085A2/pt
Publication of WO2022247919A1 publication Critical patent/WO2022247919A1/zh

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
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    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the application belongs to the field of medicinal chemistry, and provides a compound as a BCR-ABL inhibitor, a preparation method thereof, a pharmaceutical composition containing the compound, and relates to its use in the preparation of medicines for treating BCR-ABL-related diseases.
  • Chronic myeloid leukemia is the main disease of chronic leukemia in my country, accounting for about 70% of chronic leukemia. More than 90% of the disease cases have chromosomal abnormalities, mainly the long arm translocation of chromosome 9 and chromosome 22, forming Bcr-Abl fusion gene and expressing protein p-210.
  • the tyrosine kinase activity of P-210 is much stronger than that of p-150 (the product of normal c-Abl gene expression), which causes abnormal proliferation and differentiation of hematopoietic stem cells, and finally causes CML.
  • Imatinib is the first Bcr-Abl targeted therapy drug on the market, and it is currently used as a first-line drug for the treatment of various stages of CML.
  • Nilotinib, dasatinib, and bosutinib (second-generation Bcr-Abl inhibitors) are approved for the treatment of imatinib-resistant or intolerant CML.
  • the second-generation Bcr-Abl inhibitors are more effective than imatinib, and are effective against almost all imatinib-resistant mutation types, but the problem of T315I (gatekeeper) mutation resistance has not yet been solved.
  • T315I mutation accounts for about 20%. The dilemma of being curable has become the only choice for patients who have failed the treatment of the first and second generation Bcr-Abl inhibitors.
  • ABL001 is a Bcr-Abl allosteric inhibitor developed by Novartis, which is disclosed in WO2013171639 and is currently in phase III clinical research.
  • ABL001 is a potent and selective BCR-ABL inhibitor, active against most mutants, such as T315I (Andrew A. Wylie et al. (2017) Nature 543, 733-737).
  • the application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • Q is selected from N or CH
  • R 1 is selected from which stated optionally substituted by one or more R a' ;
  • X, Y and Z are each independently selected from CH or N, and at least one of X, Y and Z is selected from CH;
  • Ring A is selected from 5-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S atoms;
  • Ring B is selected from 5-10 membered heterocyclic groups containing 1-3 heteroatoms selected from N, O or S atoms, or 5-8 membered heterocyclic groups containing 1-3 heteroatoms selected from N, O or S atoms Metaheteroaryl;
  • R 2 is selected from hydrogen, amino, C 1-6 alkyl, C 1-6 alkoxy, amino-C 1-6 alkyl-, 3-10 membered heterocyclyl or 5-6 membered heteroaryl, wherein The amino, C 1-6 alkyl, C 1-6 alkoxy, amino-C 1-6 alkyl-, 3-10 membered heterocyclic group or 5-6 membered heteroaryl group are optionally replaced by one or Multiple R b substitutions;
  • R 3 is selected from -OCF 2 H, wherein said -OCF 2 H is optionally substituted by halogen;
  • R a and R a' are each independently selected from hydroxyl, amino, cyano, halogen, C 1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 3-8 membered cycloalkyl-C 1-6 alkyl-, 3-8 membered heterocycloalkyl-C 1-6 alkyl-or C 1-6 alkyl substituted by one or more hydroxyl or halogen;
  • R b is selected from hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl-, C 1-6 alkyl-C(O)-NH- or by one or more C 1-6 alkyl substituted by hydroxyl or halogen.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (II) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from which stated optionally substituted by one or more R a' ;
  • X, Y and Z are each independently selected from CH or N, and at least one of X, Y and Z is selected from CH;
  • Ring A is selected from 5-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S atoms;
  • Ring B is selected from 5-10 membered heterocyclic groups containing 1-3 heteroatoms selected from N, O or S atoms, or 5-8 membered heterocyclic groups containing 1-3 heteroatoms selected from N, O or S atoms. Metaheteroaryl;
  • R 2 is selected from hydrogen, amino, C 1-6 alkyl, C 1-6 alkoxy, amino-C 1-6 alkyl-, 3-10 membered heterocyclyl or 5-6 membered heteroaryl, wherein The amino, C 1-6 alkyl, C 1-6 alkoxy, amino-C 1-6 alkyl-, 3-10 membered heterocyclic group or 5-6 membered heteroaryl group are optionally replaced by one or Multiple R b substitutions;
  • R 3 is selected from -OCF 2 H, wherein said -OCF 2 H is optionally substituted by halogen;
  • R a and R a' are each independently selected from hydroxyl, amino, cyano, halogen, C 1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 3-8 membered cycloalkyl-C 1-6 alkyl-, 3-8 membered heterocycloalkyl-C 1-6 alkyl-or C 1-6 alkyl substituted by one or more hydroxyl or halogen;
  • R b is selected from hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl-, C 1-6 alkyl-C(O)-NH- or by one or more C 1-6 alkyl substituted by hydroxyl or halogen.
  • R 1 is selected from which stated optionally substituted by one or more R a' ;
  • X, Y and Z are each independently selected from CH or N, and at least one of X, Y and Z is selected from CH;
  • R 2 is selected from hydrogen or a 3-10 membered heterocyclic group, wherein the 3-10 membered heterocyclic group is optionally substituted by one or more R b ;
  • R 3 is selected from -OCF 2 H, wherein said -OCF 2 H is optionally substituted by halogen;
  • R a and R a' are each independently selected from hydroxyl, amino, cyano, halogen, C 1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, or replaced by one or more C 1-6 alkyl substituted by hydroxyl or halogen;
  • R b is selected from hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkyl substituted by one or more hydroxyl groups or halogen.
  • the heterocyclyl or heterocycloalkyl comprises 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- or N, respectively; other Variables are as defined herein.
  • the heterocyclyl or heterocycloalkyl comprises 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH- or N, respectively; other variables are as described in the present application defined.
  • the heterocyclyl or heterocycloalkyl comprises 1 or 2 heteroatoms or heteroatom groups independently selected from -O-, -NH- or N, respectively; other variables are as defined herein.
  • the heterocyclyl or heterocycloalkyl mentioned in R 2 , R a or R a' contains 1, 2, 3 or 4 independently selected from -O-, -NH-, A heteroatom or heteroatom group of -S- or N; other variables are as defined herein.
  • the heterocyclyl or heterocycloalkyl mentioned in R 2 , R a or R a' contains 1, 2, 3 or 4 independently selected from -O-, -NH- or A heteroatom or heteroatom group of N; other variables are as defined herein.
  • the heterocyclyl or heterocycloalkyl mentioned in R 2 , R a or R a' respectively contains 1 or 2 heteroatoms independently selected from -O-, -NH- or N or a heteroatom group; other variables are as defined herein.
  • Q is selected from N, and other variables are as defined herein. In some embodiments, Q is selected from CH and other variables are as defined herein.
  • Q is selected from CH;
  • R 1 is selected from which stated is optionally substituted by one or more R a' ;
  • R a' is selected from halogen, C 1-6 alkyl or 3-6 membered cycloalkyl; Or, R a' is selected from fluorine, chlorine, Methyl, ethyl, isopropyl or cyclopropyl;
  • R2 is selected from which stated Optionally substituted by 1, 2 or 3 R b ;
  • R b is selected from hydroxyl or C 1-4 alkyl;
  • R 3 is selected from —OCF 2 H, wherein the —OCF 2 H is optionally substituted with halogen.
  • Q is selected from CH;
  • R 1 is selected from
  • R2 is selected from
  • R 3 is selected from —OCF 2 H, wherein the —OCF 2 H is optionally substituted with chlorine.
  • X, Y, and Z are all selected from CH; other variables are as defined herein.
  • one of X, Y, and Z is selected from N and the remainder is selected from CH; other variables are as defined herein.
  • X is selected from N and Y and Z are selected from CH; other variables are as defined herein.
  • Y is selected from N, and X and Z are selected from CH; other variables are as defined herein.
  • Z is selected from N, and X and Y are selected from CH; other variables are as defined herein.
  • one of X, Y, and Z is selected from CH and the remainder is selected from N; other variables are as defined herein.
  • Ring A is selected from 5-membered heteroaryls containing 1 or 2 heteroatoms selected from N, O, or S atoms; other variables are as defined herein.
  • Ring A is selected from 5-membered heteroaryls containing 1 or 2 heteroatoms selected from N or O atoms; other variables are as defined herein.
  • Ring A is selected from pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl, or isoxazolyl; other variables are as defined herein. In some embodiments, Ring A is selected from pyrrolyl, pyrazolyl, imidazolyl, or furyl; other variables are as defined herein.
  • ring B is selected from 5-8 membered heterocycloalkyls containing 1-3 heteroatoms selected from N or O atoms, or ring B containing 1-3 heteroatoms selected from N or O atoms 5-8 membered heteroaryl; other variables are as defined herein.
  • Ring B is selected from a 5-membered or 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from N or O atoms, or a heterocycloalkyl group containing 1 or 2 heteroatoms selected from N or O atoms.
  • 5- or 6-membered heteroaryl of heteroatoms; other variables are as defined herein.
  • Ring B is selected from a 5-membered or 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from N or O atoms, or a 5-membered heteroaryl group containing 1 or 2 N atoms. basis; other variables are as defined herein.
  • Ring B is selected from tetrahydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, or pyrazolyl; other variables are as defined herein. In some embodiments, Ring B is selected from tetrahydropyrrolidinyl, piperidinyl, morpholinyl, or imidazolyl; other variables are as defined herein.
  • R is selected from which stated optionally substituted with one or more R a' ; other variables are as defined herein.
  • R is selected from which stated optionally substituted with one or more R a' ; other variables are as defined herein.
  • R is selected from which stated optionally substituted with one or more R a' ; other variables are as defined herein.
  • R is selected from which stated optionally substituted with one or more R a' ; other variables are as defined herein.
  • R is selected from which stated optionally substituted with one or more R a' ; other variables are as defined herein.
  • R is selected from which stated optionally substituted with one or more R a' ; other variables are as defined herein.
  • R is selected from which stated optionally substituted with one or more R a' ; other variables are as defined herein.
  • R is selected from which stated optionally substituted with one or more R a' ; other variables are as defined herein.
  • R is selected from which stated optionally substituted with one or more R a' ; other variables are as defined herein.
  • R is selected from which stated optionally substituted with one or more R a' ; other variables are as defined herein.
  • R is selected from which stated optionally substituted with one or more R a' ; other variables are as defined herein.
  • R is selected from which stated optionally substituted with one or more R a' ; other variables are as defined herein.
  • R is selected from which stated optionally substituted with one or more R a' ; other variables are as defined herein.
  • R is selected from which stated is optionally substituted with one Ra ' ; other variables are as defined herein.
  • R is selected from Other variables are as defined herein.
  • Ra and Ra ' are each independently selected from halogen, C 1-6 alkyl, 3-6 membered cycloalkyl, 3-8 membered heterocycloalkyl-C 1-6 alkyl- or C 1-6 alkyl substituted by 1, 2 or 3 hydroxyl groups ; Other variables are as defined herein.
  • Ra and Ra ' are each independently selected from halogen, C 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl-C 1-4 alkyl- or C 1-4 alkyl substituted by 1, 2 or 3 hydroxyl groups ; Other variables are as defined herein.
  • Ra and Ra ' are each independently selected from hydroxyl, amino, cyano, halogen, C 1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, or C 1-6 alkyl substituted by one or more hydroxy or halogen; other variables are as defined herein.
  • each of Ra and Ra ' is independently selected from halogen, C 1-6 alkyl, 3-6 membered cycloalkyl, or C 1-6 substituted by 1, 2 or 3 hydroxyl groups Alkyl; other variables are as defined herein.
  • Ra and Ra ' are each independently selected from hydroxyl, amino, cyano, halogen, C 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, or C 1-4 alkyl substituted by one or more hydroxy or halogen; other variables are as defined herein.
  • each of Ra and Ra ' is independently selected from halogen, C 1-4 alkyl, 3-6 membered cycloalkyl, or C 1-4 substituted with 1, 2 or 3 hydroxyl groups Alkyl; other variables are as defined herein.
  • R a is selected from C 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl-C 1-4 alkyl- or replaced by 1, 2 or 3 C 1-4 alkyl substituted with a hydroxyl group; other variables are as defined in the application.
  • Ra is selected from methyl, ethyl, cyclopropyl, 2-hydroxyethyl, or Other variables are as defined herein.
  • R a is selected from C 1-4 alkyl, 3-6 membered cycloalkyl or C 1-4 alkyl substituted by 1, 2 or 3 hydroxyl groups; other variables are as described in the application definition.
  • Ra is selected from methyl, ethyl, cyclopropyl, or 2-hydroxyethyl; other variables are as defined herein.
  • Ra is selected from methyl; other variables are as defined herein.
  • R a' is selected from hydroxyl, amino, cyano, halogen, C 1-4 alkyl or 3-6 membered cycloalkyl; other variables are as defined in the present application.
  • R a' is selected from halogen, C 1-4 alkyl or 3-6 membered cycloalkyl; other variables are as defined in the present application.
  • Ra ' is selected from fluoro, chloro, bromo, iodo, Methyl, ethyl, isopropyl or cyclopropyl; other variables are as defined herein.
  • Ra ' is selected from fluoro, chloro, Methyl, ethyl or cyclopropyl; other variables are as defined herein.
  • Ra ' is selected from hydroxy, amino, cyano, or halo; other variables are as defined herein.
  • Ra ' is selected from halogen; other variables are as defined herein.
  • Ra ' is selected from fluoro or chloro; other variables are as defined herein.
  • R is selected from Other variables are as defined herein.
  • R is selected from Other variables are as defined herein.
  • R is selected from hydrogen, amino, C 1-4 alkoxy, amino-C 1-4 alkyl-, 3-10 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein The amino, C 1-4 alkoxy, amino-C 1-4 alkyl-, 3-0 membered heterocycloalkyl or 5-6 membered heterocyclic aryl are optionally substituted by one or more R b ; Other variables are as defined herein.
  • R is selected from hydrogen, amino, C 1-4 alkoxy, amino-C 1-4 alkyl-, 4-6 membered monoheterocycloalkyl, 6-9 membered bridged heterocycloalkane Base, 7-9 membered spiroheterocycloalkyl or 5-6 membered heteroaryl, wherein the amino, C 1-4 alkoxy, amino-C 1-4 alkyl-, 4-6 membered monoheterocycle
  • the alkyl, 6-9 membered bridged heterocycloalkyl, 7-9 membered spiroheterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted with one or more Rb ; other variables are as defined herein.
  • R is selected from amino, C 1-3 alkoxy, amino-C 1-3 alkyl-, 4-, 5-, or 6-membered monoheterocycloalkyl, 6-, 7-, or 8-membered bridged heterocycloalkyl, 7-membered, 8-membered or 9-membered spiroheterocycloalkyl, or 5-membered heteroaryl, wherein the amino, C 1-3 alkoxy, amino-C 1-3 alkyl -, 4-membered, 5-membered or 6-membered monoheterocycloalkyl, 6-membered, 7-membered or 8-membered bridged heterocycloalkyl, 7-membered, 8-membered or 9-membered spiroheterocycloalkyl, or 5-membered heteroaryl
  • R b eg, 1, 2, or 3
  • other variables are as defined herein.
  • R is selected from hydrogen or a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more R ; other variables are as defined herein.
  • R is selected from hydrogen or 3-10 membered heterocycloalkyl, wherein said 3-10 membered heterocycloalkyl is optionally substituted by one or more R ; other variables are as described herein definition.
  • R is selected from amino or 3-10 membered heterocycloalkyl, wherein said amino or 3-10 membered heterocycloalkyl is optionally substituted by one or more R ; other variables are as herein application defined.
  • the heterocycloalkyl group comprises 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- or N; other variables are as described in the present application defined. In some embodiments, the heterocycloalkyl group comprises 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH- or N, respectively; other variables are as defined herein. In some embodiments, the heterocycloalkyl group comprises 1 or 2 heteroatoms or heteroatom groups independently selected from -O-, -NH- or N, respectively; other variables are as defined herein.
  • the heterocycloalkyl mentioned in R 2 , R a or R a' contains 1, 2, 3 or 4 independently selected from -O-, -NH-, -S- or A heteroatom or heteroatom group of N; other variables are as defined herein.
  • the heterocycloalkyl mentioned in R 2 , R a or R a' contains 1, 2, 3 or 4 heteroatoms independently selected from -O-, -NH- or N, respectively or a heteroatom group; other variables are as defined herein.
  • the heterocycloalkyl mentioned in R 2 , R a or R a' respectively contains 1 or 2 heteroatoms or heteroatom groups independently selected from -O-, -NH- or N; Other variables are as defined herein.
  • R is selected from hydrogen, 4-6 membered monoheterocyclyl, 6-9 membered bridged heterocyclyl or 7-9 membered spiroheterocyclyl, wherein the 4-6 membered monoheterocyclyl , 6-9 membered bridged heterocyclyl or 7-9 membered spiroheterocyclyl are optionally substituted by one or more R b ; other variables are as defined herein.
  • R is selected from hydrogen, 4-6 membered monoheterocycloalkyl, 6-9 membered bridged heterocycloalkyl, or 7-9 membered spiroheterocycloalkyl, wherein the 4-6 membered mono
  • the heterocycloalkyl, 6-9 membered bridged heterocycloalkyl, or 7-9 membered spiroheterocycloalkyl is optionally substituted with one or more Rb ; other variables are as defined herein.
  • R is other than hydrogen; other variables are as defined herein.
  • R is selected from 4-, 5-, or 6-membered monoheterocycloalkyl, 6-, 7-, or 8-membered bridged heterocycloalkyl, or 7, 8, or 9-membered spiroheterocycloalkane group, wherein the 4-membered, 5-membered or 6-membered monoheterocycloalkyl group, 6-membered, 7-membered or 8-membered bridged heterocycloalkyl group or 7-membered, 8-membered or 9-membered spiroheterocycloalkyl group is optionally One or more Rb substitutions (eg, 1, 2, or 3); other variables are as defined herein.
  • R is selected from amino, methoxy, ethoxy, aminomethyl, pyrrolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, 1 ,4-dioxanyl, azetidinyl, piperazinyl, piperidinyl, 1,2,3,6-tetrahydropyridyl, tetrahydropyranyl, 3,4-dihydropyranyl Base, 3,6-dihydropyranyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 2-oxa-5-azabicyclo[2.2 .1]heptane, 3-azabicyclo[3.1.0]he
  • R is selected from amino, methoxy, ethoxy, aminomethyl, pyrrolidinyl, isoxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1, 4-dioxanyl, azetidinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 3-oxa-6-azabicyclo[3.1.1]heptane Base, 3-oxa-8-azabicyclo[3.2.1]octyl group, 8-oxa-3-azabicyclo[3.2.1]octyl group, 2-oxa-5-azabicyclo [2.2.1] Heptane, 3-azabicyclo[3.1.0]hexyl, 2-oxa-6-azaspiro[3.4]octane, 2-oxa-7-azaspiro[ 3.5] Nonyl, 2-oxa-6-azaspiro[3.3]heptanyl, pyrazolyl or imi
  • R is selected from pyrrolidinyl, isoxazolidinyl, morpholinyl, azetidinyl, piperazinyl, piperidinyl, 1,2,3,6-tetrahydropyridyl , tetrahydropyranyl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 3-oxa -6-Azabicyclo[3.1.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octane Alkyl, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexyl, 2-oxa-6-azaspiro[3.4]octane base, 2-oxa-7-azaspiro[3.5]nony
  • R is selected from pyrrolidinyl, isoxazolidinyl, morpholinyl, azetidinyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 3 -Oxa-6-azabicyclo[3.1.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.
  • R is selected from amino, methoxy, ethoxy, aminomethyl, Wherein said amino, methoxy, ethoxy, aminomethyl, Optionally substituted with 1, 2 or 3 Rb ; other variables are as defined herein.
  • R is selected from which stated Optionally substituted with 1, 2 or 3 Rb ; other variables are as defined herein.
  • R b is selected from hydroxyl, cyano, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl-, C 1-4 alkyl-C(O)-NH- or by one or more C 1-4 alkyl substituted by hydroxyl or halogen; other variables are as defined in the application.
  • R is selected from hydroxyl, cyano, fluoro, chloro, methyl, methoxy, hydroxymethyl, methoxyethyl, or acetamido; other variables are as defined herein.
  • R b is selected from hydroxyl, amino, cyano, halo, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkyl substituted by one or more hydroxy or halogen; other variables are as defined herein.
  • R b is selected from hydroxyl, cyano, halo, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkyl substituted by one or more hydroxy or halogen; other variables are as defined herein.
  • R b is selected from hydroxyl, cyano, halo, C 1-4 alkyl, C 1-4 alkoxy, or C 1-3 alkyl substituted by 1, 2 or 3 hydroxy groups; other variables are as defined herein.
  • R b is selected from hydroxyl, cyano, halo, C 1-3 alkyl, C 1-3 alkoxy, or C 1-3 alkyl substituted by one hydroxy; other variables are as defined herein.
  • R is selected from hydroxyl, cyano, fluoro, chloro, Methyl, methoxy, or hydroxymethyl; other variables are as defined herein.
  • R is selected from pyrrolidinyl, isoxazolidinyl, morpholinyl, azetidinyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 3 -Oxa-6-azabicyclo[3.1.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.
  • R is selected from amino, methoxy, ethoxy, aminomethyl, pyrrolidinyl, isoxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1, 4-dioxanyl, azetidinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 3-oxa-6-azabicyclo[3.1.1]heptane Base, 3-oxa-8-azabicyclo[3.2.1]octyl group, 8-oxa-3-azabicyclo[3.2.1]octyl group, 2-oxa-5-azabicyclo [2.2.1] Heptane, 3-azabicyclo[3.1.0]hexyl, 2-oxa-6-azaspiro[3.4]octane, 2-oxa-7-azaspiro[ 3.5] Nonyl, 2-oxa-6-azaspiro[3.3]heptanyl, pyrazolyl or imi
  • R is selected from methoxy, methoxyethoxy, methylamino, dimethylamino, Other variables are as defined herein.
  • R is selected from Other variables are as defined herein.
  • R is selected from methoxy, methoxyethoxy, methylamino, dimethylamino, Other variables are as defined herein.
  • R is selected from Other variables are as defined herein.
  • R3 is selected from -OCF2H , wherein said -OCF2H is optionally substituted with halogen; other variables are as defined herein.
  • R3 is selected from -OCF2H , wherein said -OCF2H is optionally substituted with fluorine, chlorine, bromine, iodine; other variables are as defined herein.
  • R 3 is selected from -OCF 2 Cl, -OCF 2 Br, -OCF 2 I, -OCF 3 .
  • R3 is selected from -OCF2Cl ; other variables are as defined herein.
  • R 1 is selected from which stated optionally substituted by one or more R a' ;
  • Ring A is selected from 5-membered heteroaryl groups containing 1 or 2 heteroatoms selected from N or O atoms;
  • Ring B is selected from a 5-membered or 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from N or O atoms, or a 5-membered heteroaryl group containing 1 or 2 N atoms;
  • R 2 is selected from 3-10 membered heterocycloalkyl groups, wherein the 3-10 membered heterocycloalkyl groups are optionally substituted by one or more R b , and the heterocycloalkyl groups contain 1, 2, 3 or 4 a heteroatom or heteroatom group independently selected from -O-, -NH- or N;
  • R 3 is selected from -OCF 2 Cl
  • R a' selected from C 1-6 alkyl, 3-8 membered cycloalkyl or C 1-6 alkyl substituted by one or more hydroxyl or halogen;
  • R b is selected from hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkyl substituted by one or more hydroxyl groups or halogen.
  • R 1 is selected from which stated optionally substituted by one or more R a' ;
  • X, Y and Z are each independently selected from CH or N, and at least one of X, Y and Z is selected from CH;
  • R 2 is selected from 3-10 membered heterocycloalkyl groups, wherein the 3-10 membered heterocycloalkyl groups are optionally substituted by one or more R b ;
  • R 3 is selected from -OCF 2 Cl
  • R a and R a' are each independently selected from halogen, C 1-6 alkyl, 3-6 membered cycloalkyl or C 1-6 alkyl substituted by 1, 2 or 3 hydroxyl groups;
  • R b is selected from hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkyl substituted by one or more hydroxyl or halogen;
  • the heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH- or N, respectively.
  • the "one or more” is selected from one, two, three, four, five or six. In some embodiments, the “one or more” is selected from one, two or three. In some embodiments, the “one or more” is selected from one or two.
  • the present application provides a compound of formula (III), a compound of formula (IV) or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are as defined above.
  • the present application provides a compound of formula (III-A), a compound of formula (III-B), a compound of formula (IV-A) or a pharmaceutically acceptable salt thereof,
  • R 2 , R a , R a' , X, Y, Z, ring A and ring B are as described above.
  • the application provides a compound of formula (V), a compound of formula (VI), a compound of formula (VII), a compound of formula (VIII), a compound of formula (IX), a compound of formula (X) or a pharmaceutically acceptable Salt,
  • R 2 , R a , R a' and ring B are as described above.
  • the present application also provides a pharmaceutical composition, which comprises the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present application further includes pharmaceutically acceptable excipients.
  • the present application also provides a method for treating and/or preventing BCR-ABL-related diseases, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application or its pharmaceutically acceptable amount to a mammal (preferably human) in need of the treatment Accepted salts, or pharmaceutical compositions thereof.
  • the present application also provides the use of the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating and/or preventing BCR-ABL related diseases.
  • the present application also provides the use of the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment and/or prevention of BCR-ABL related diseases.
  • the present application also provides the above-mentioned compound of the present application, its pharmaceutically acceptable salt, or its pharmaceutical composition for treating and/or preventing BCR-ABL related diseases.
  • the BCR-ABL-associated disease is selected from cancer, such as chronic myeloid leukemia.
  • the compound of the present application has good cell proliferation inhibitory activity (including K562 cells and T315I mutant cells), good in vivo pharmacokinetic properties, low toxicity, weak inhibitory effect on hERG potassium channel, and good safety.
  • the covalent bond in some structural units or groups in this application is not connected to specific atoms, it means that the covalent bond can be connected to any atom in the structural unit or group, as long as it does not violate the rules of valence bond connection .
  • substituted means that any one or more hydrogen atoms on the specified atom are replaced by a substituent, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • Optionally substituted means substituted or unsubstituted, for example, the ethyl group is "optionally” substituted by halogen, which means that the ethyl group can be unsubstituted (CH 2 CH 3 ), monosubstituted (such as CH 2 CH 2 F), polysubstituted (eg CHFCH 2 F, CH 2 CHF 2 etc.) or fully substituted (CF 2 CF 3 ). It will be appreciated by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or synthetically impossible substitution or substitution pattern is introduced.
  • C mn herein is that moiety has an integer number of carbon atoms in the given range mn.
  • C 1-6 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • C 1-3 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms.
  • variable e.g, R
  • R any variable
  • its definition is independent at each occurrence. So, for example, if a group is substituted by 2 R's, each R has independent options.
  • the substituent When a bond of a substituent crosses a bond between two atoms in a ring, the substituent may be bonded to any atom on the ring.
  • the structural unit It means that it can be substituted at any position on cyclohexyl or cyclohexadiene.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • hydroxyl refers to a -OH group.
  • amino refers to a -NH2 group.
  • cyano refers to a -CN group.
  • alkyl refers to a hydrocarbon group of the general formula CnH2n +1 .
  • the alkyl group may be linear or branched.
  • C 1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (such as methyl, ethyl, n - propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • alkyl portion ie, alkyl group
  • alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio has the same definition as above.
  • C 1-3 alkyl refers to an alkyl group containing 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, and isopropyl).
  • alkoxy refers to -O-alkyl
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring.
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl Alkyl, bicyclo[1.1.1]pent-1-yl, etc.
  • C 3-4 cycloalkyl includes cyclopropyl and cyclobutyl.
  • heterocyclyl refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and that can exist as a monocyclic, bridged, or spiro ring.
  • the heterocycle is typically a 3 to 10 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen, or a 4 to 6 membered ring ring.
  • heterocyclyl include, but are not limited to, oxiranyl, tetrahydrofuryl, dihydrofuryl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, 2-oxo Hetero-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.3]heptyl, 3-azabicyclo[3.1.0]hexyl, etc.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the heterocycle is typically a 3 to 10 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen, or a 4 to 6 membered ring ring.
  • 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thioethyl, cycloazaethyl
  • 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetyl, Cyclic, thiabutanyl
  • 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine , imidazolidinyl, tetrahydropyrazolyl
  • 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazin
  • heterocyclyl refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and that exists as only one ring.
  • the heterocycle is typically a 3 to 10 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen, or a 4 to 6 membered ring ring.
  • Non-limiting examples of monoheterocyclic groups include, but are not limited to, oxiranyl, tetrahydrofuryl, dihydrofuryl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, pyrrolidinyl , N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, etc.
  • monoheterocycloalkyl refers to a fully saturated monoheterocyclyl.
  • bridged heterocyclic group refers to a 5-14 membered polycyclic ring that is fully saturated or partially unsaturated, and two rings share two or more atoms, which may contain one or more double bonds, but no A ring has a fully conjugated ⁇ -electron system, wherein one or more ring atoms are heteroatoms selected from N, O, S(O) n (where n is 0, 1 or 2), and the remaining ring atoms are carbon.
  • it is 6-14 yuan, More preferably, it is 6-10 yuan.
  • the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic rings, preferably bicyclic or tricyclic, more preferably bicyclic.
  • bridged heterocycles include: Wait.
  • bridged heterocycloalkyl refers to a fully saturated bridged heterocyclyl.
  • spiroheterocyclyl refers to a fully saturated or partially unsaturated (but not fully unsaturated) spiro ring in which one or more ring atoms are selected from sulfur, oxygen and/or nitrogen heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 6 to 10 yuan.
  • the spiro heterocycle is divided into single spiro heterocycle, double spiro heterocycle or polyspiro heterocycle, preferably single spiro heterocycle or double spiro heterocycle, more preferably 4-membered/ 4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocycle.
  • Non-limiting examples of spiroheterocycles include Wait.
  • spiroheterocycloalkyl refers to a fully saturated spiroheterocyclyl.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring.
  • Preferred heteroaryls have a single 5 to 8 membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms.
  • heteroaryl include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolyl , tetrazolyl, triazolyl, triazinyl, benzofuryl, benzothienyl, indolyl, isoindolyl, etc.
  • the group Indicates that ring A and ring B form a bicyclic structure through a shared bond, where the shared bond can be a single bond or a double bond.
  • treating means administering a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes: preventing a disease or disease state from occurring in a mammal, especially when Such mammals are susceptible to the disease state, but have not been diagnosed as having the disease state.
  • terapéuticaally effective amount means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying The amount of a compound of the application for the onset of one or more symptoms of a particular disease, condition or disorder described herein.
  • the amount of a compound of the present application that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by a person skilled in the art according to its own knowledge and this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. .
  • composition refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable auxiliary materials.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • the compounds of the invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key and straight dashed keys
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen to form a deuterated drug.
  • d 3 -methyl means that all three hydrogen atoms on the methyl group are replaced by deuterium atoms. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • 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 changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • the present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature.
  • isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • Certain isotopically labeled compounds of the present application are useful in compound and/or substrate tissue distribution assays.
  • Tritiated (ie3H ) and carbon-14 (ie14C ) isotopes are especially preferred for their ease of preparation and detectability.
  • Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 18 F, can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the present application can generally be prepared by following procedures similar to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • substitution with heavier isotopes such as deuterium may confer certain therapeutic advantages resulting from greater metabolic stability (e.g. increased in vivo half-life or reduced dosage requirements), and thus in some cases
  • deuterium substitution may be partial or complete, partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium, and all such forms of compounds are included within the scope of the present application.
  • parameter values should be understood as being modified by the term "about”.
  • the term “about” indicates an error value exists, for example, it means a variation within ⁇ 5%, such as ⁇ 1% or ⁇ 0.1%, of a certain value.
  • Compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included as enantiomers and diastereomers.
  • the compounds of the present application containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administering a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present application can be produced by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, dragee-making methods, pulverizing methods, emulsifying methods, freeze-drying methods and the like.
  • Therapeutic dosages of the compounds of the present application may depend, for example, on the particular use for the treatment, the mode of administration of the compound, the health and state of the patient, and the judgment of the prescribing physician.
  • the ratio or concentration of the compounds of the present application in the pharmaceutical composition may vary, depending on various factors, including dosage, chemical properties (eg, hydrophobicity) and route of administration.
  • a compound of the present application may be provided for parenteral administration as an aqueous physiologically buffered solution containing about 0.1% w/v to 10% w/v of the compound.
  • Some typical dosages range from about 1 ⁇ g/kg to about 1 g/kg body weight per day.
  • the dosage range is from about 0.01 mg/kg to about 100 mg/kg body weight/day.
  • the dosage will likely depend on such variables as the type and extent of the disease or condition, the general health of the particular patient, the relative biological potency of the compound selected, the formulation of the excipient and its route of administration. Effective doses may be obtained by extrapolation from dose-response curves derived from in vitro or animal model test systems.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and equivalents well known to those skilled in the art Alternatives, preferred implementations include but are not limited to the examples of this application.
  • the compound of formula (I) of the present application can be prepared by the following routes by those skilled in the art of organic synthesis:
  • R 1 , R 2 and R 3 are as defined above, and R 2 is not hydrogen.
  • SOCl2 stands for thionyl chloride
  • TEA stands for triethylamine
  • DMSO stands for dimethylsulfoxide
  • THF stands for tetrahydrofuran.
  • Embodiment 1 the preparation of compound 1
  • Embodiment 2 the preparation of compound 2
  • step E of Example 1 compound 2-1 prepared in step A above was added to the reaction solution of compound 1-4 to react to obtain compound 2.
  • Embodiment 3 the preparation of compound 3
  • step E of Example 1 compound 3-1 prepared in step A above was added to the reaction solution of compound 1-4 to react to obtain compound 3.
  • Embodiment 4 the preparation of compound 4
  • step E of Example 1 compound 4-1 prepared in step A above was added to the reaction solution of compound 1-4 to react to obtain compound 4.
  • Embodiment 5 the preparation of compound 5
  • step E of Example 1 compound 5-1 prepared in the above step A was added to the reaction solution of compound 1-4 to react to obtain compound 5.
  • Embodiment 6 the preparation of compound 6
  • Step E of Example 1 the compound 6-1 prepared in the above step A was added to the reaction solution of compound 1-4 to react to obtain compound 6.
  • Embodiment 7 the preparation of compound 7
  • Embodiment 8 the preparation of compound 8
  • Embodiment 9 the preparation of compound 9
  • step D of Example 1 compound 9-1 was reacted with pinacol diboronate to obtain intermediate compound 9-2, which was directly used in the next step without separation and purification.
  • Embodiment 10 the preparation of compound 10
  • step D of Example 1 compound 1-3 was replaced by compound 10-1 prepared in the above step, and the reaction solution of compound 10-2 was obtained, which was directly used in the next reaction.
  • Embodiment 11 Preparation of compound 11
  • Step E of Example 1 the compound 11-1 prepared in the above step A was added to the reaction solution of compound 1-4 to react to obtain compound 11.
  • Embodiment 12 the preparation of compound 12
  • step D of Example 1 4-bromopyridin-2(1H)-one was reacted with pinacol diboronate to obtain a reaction solution of intermediate compound 12-1, which was directly used in the next step reaction.
  • step E of Example 1 the compound 13-1 prepared in the above step A was added to the reaction solution of compound 1-4 to react to obtain compound 13-2.
  • Embodiment 15 Preparation of compound 15
  • Step E of Example 1 the compound 15-1 prepared in the above step A was added to the reaction solution of compound 1-4 to react to obtain compound 15.
  • Embodiment 16 the preparation of compound 16
  • step E of Example 1 compound 16-1 prepared in step A above was added to the reaction solution of compound 1-4 to react to obtain compound 16.
  • Embodiment 17 the preparation of compound 17
  • step E of Example 1 compound 17-1 prepared in step A above was added to the reaction solution of compound 1-4 to react to obtain compound 17.
  • Embodiment 18 Preparation of compound 18
  • Step E of Example 1 the compound 18-1 prepared in the above step A was added to the reaction solution of compound 1-4 to react to obtain compound 18.
  • Embodiment 19 Preparation of compound 19
  • compound 19-1 was prepared by reacting compound 4-bromo-3-fluoropyridin-2(1H)-one with methyl iodide. MS(ESI,[M+H] + )m/z:208.02.
  • the reaction solution of compound 19-2 was obtained by reacting compound 19-1 with pinacol diboronate, which was directly used in the next reaction without purification.
  • step E of Example 1 compound 7-1 was added to the reaction solution of compound 19-2 prepared in step B above to react to obtain compound 19.
  • Embodiment 20 Preparation of Compound 20
  • step B of Example 1 compound 20-1 was prepared by reacting compound 1-1 with 3-oxa-6-azabicyclo[3.1.1]heptane hydrochloride. MS(ESI,[M+H] + )m/z:474.02.
  • step E of Example 1 compound 20-1 prepared in step A above was added to the reaction solution of compound 1-4 to react to obtain compound 20.
  • Embodiment 21 Preparation of Compound 21
  • step B of Example 1 compound 21-1 was prepared by reacting compound 1-1 with (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride. MS(ESI,[M+H] + )m/z:474.03.
  • step E of Example 1 compound 21-1 prepared in step A above was added to the reaction solution of compound 1-4 to react to obtain compound 21.
  • Embodiment 22 Preparation of compound 22
  • compound 22-1 was prepared by reacting compound 1-1 with (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride. MS(ESI,[M+H] + )m/z:474.03.
  • the compound 22-1 prepared in the above step A was added to the reaction solution of compound 1-4 to react to obtain compound 22.
  • Embodiment 23 Preparation of compound 23
  • step B of Example 1 compound 1-1 was reacted with 6-oxa-3-aza-bicyclo[3,1,1]heptane hydrochloride to obtain compound 23-1.
  • Step E of Example 1 the compound 23-1 prepared in the above step A was added to the reaction solution of compound 1-4 to react to obtain compound 23.
  • Embodiment 24 Preparation of Compound 24
  • step B of Example 1 compound 24-1 was prepared using compound 1-1 and 2-oxa-7-azaspiro[3.5]nonane as raw materials. MS(ESI,[M+H] + )m/z:502.10.
  • Step E of Example 1 the compound 24-1 prepared in the above step A was added to the reaction solution of compound 1-4 to react to obtain compound 24.
  • Embodiment 25 Preparation of compound 25
  • step B of Example 1 compound 25-1 was prepared using compound 1-1 and 3-acetonitrile cyclobutylamine as raw materials. MS(ESI,[M+H] + )m/z:457.02.
  • step E of Example 1 the compound 25-1 prepared in the above step A was added to the reaction solution of compound 1-4 to react to obtain compound 25.
  • Embodiment 26 Preparation of compound 26
  • step B of Example 1 compound 26-1 was prepared using compound 1-1 and 3-methyl-3-acridinol as raw materials. MS(ESI,[M+H] + )m/z:462.02.
  • step E of Example 1 the compound 26-1 prepared in the above step A was added to the reaction solution of compound 1-4 to react to obtain 26.
  • Embodiment 27 Preparation of compound 27
  • step B of Example 1 compound 27-1 was prepared by reacting compound 1-1 with (3S,4S)-4-fluoropyrrolidin-3-ol hydrochloride. MS(ESI,[M+H] + )m/z:480.02.
  • the compound 27-1 prepared in the above step A was added to the reaction solution of compound 1-4 to react to obtain compound 27.
  • Embodiment 28 Preparation of compound 28
  • compound 28-1 was prepared by reacting compound 1-1 with 3-azabicyclo[3.1.0]hexane hydrochloride. MS(ESI,[M+H] + )m/z:458.06.
  • the compound 28-1 prepared in the above step A was added to the reaction solution of compound 1-4 to react to obtain compound 28.
  • Embodiment 29 Preparation of Compound 29
  • compound 29-1 was prepared by reacting compound 1-1 with isoxazolidine hydrochloride. MS(ESI,[M+H] + )m/z:448.03.
  • step D of Example 1 To the reaction solution of compound 1-4 obtained in step D of Example 1, compound 29-1 (500 mg) obtained in step A above, potassium phosphate (710 mg), deionized water (3 mL) and dichloro[1,1' - Bis(di-tert-butylphosphine)ferrocenepalladium(II) (73mg); after the addition was completed, the reaction was carried out at room temperature for 6h after nitrogen replacement.
  • reaction was filtered, the mother liquor was collected, ethyl acetate (30 mL) was added to stir and wash and then separated to obtain an organic phase, which was added to saturated aqueous sodium chloride solution (30 mL) and stirred to wash and then separated, and purified by silica gel column chromatography to obtain a total of 280 mg of compound 29.
  • Embodiment 30 Preparation of compound 30
  • step B of Example 1 compound 30-1 was prepared by reacting compound 1-1 with (S)-pyrrolidine-3-carbonitrile hydrochloride.
  • the compound 30-1 prepared in the above step A was added to the reaction solution of compound 1-4 to react to obtain compound 30.
  • Embodiment 31 Preparation of compound 31
  • step B of Example 1 compound 31-1 was prepared by reacting compound 1-1 with (R)-3-fluoropyrrolidine hydrochloride.
  • step E of Example 1 the compound 31-1 prepared in the above step A was added to the reaction solution of compound 1-4 to react to obtain 31.
  • Embodiment 32 the preparation of compound 32
  • step E of Example 1 the compound 32-1 prepared in the above step A was added to the reaction solution of compound 1-4 to react to obtain compound 32.
  • Embodiment 33 Preparation of compound 33
  • step D Add compound 33-4 (200mg), morpholine (44.1mg), N,N-diisopropylethylamine (82mg) and N-methylpyrrolidone (5mL) obtained in step D to a 35mL microwave tube successively, nitrogen Purge the liquid surface for a while, cover and seal it, and use a microwave reactor to raise the temperature to 160°C for 2 hours; after the reaction liquid is cooled, add ethyl acetate (10 mL) to the system to dilute, add water (10 mL) to stir and wash, separate the liquid, and collect The organic layer was dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography to obtain 20 mg of compound 33.
  • Embodiment 34 Preparation of compound 34
  • step E of Example 1 the compound 34-1 prepared in the above step A was added to the reaction solution of compound 1-4 to react to obtain compound 34.
  • Embodiment 35 Preparation of compound 35
  • the compound 35-1 prepared in the above step A was added to the reaction solution of compound 1-4 to react to obtain compound 35.
  • Embodiment 36 Preparation of compound 36
  • Acetonitrile (80mL), 4-bromo-1H-pyrazole (10g) and cesium carbonate (44.3g) were added to a 250mL three-necked flask in sequence, under nitrogen protection, the reaction system was transferred to an ice-salt bath and cooled to 0°C, and (2- Bromoethoxy)(tert-butyl)dimethylsilane (19.53g) was dissolved in acetonitrile (40mL), and slowly added dropwise to the above reaction system. After the addition, the reaction system was naturally warmed up, and stirred overnight at room temperature.
  • N,N-Dimethylformamide (3.23g) was dissolved in anhydrous tetrahydrofuran (8mL), and slowly added dropwise to the above reaction system. After the addition was complete, the reaction system was stirred at -80°C for 3h. Isopropanol (5 mL) was added to the reaction system to quench the reaction, and the reaction system was transferred to room temperature and stirred. Add saturated ammonium chloride solution (40mL) and ethyl acetate (100mL) to the reaction solution, separate and collect the organic phase, dry the organic phase with anhydrous sodium sulfate, filter with suction, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 6g Compound 36-2. MS(ESI,[M+H] + )m/z: 333.1.
  • reaction solution obtained in the above step E was transferred to a 35 mL microwave tube, and compound 11-1 (250 mg), potassium carbonate (224 mg), tetrakis(triphenylphosphine) palladium (62.4 mg) and water ( 2.5mL) was added, sealed and placed in a microwave reactor after nitrogen protection, microwave reaction conditions: 150°C, 1h.
  • the reaction solution was filtered with celite, and the filtrate was collected. Ethyl acetate (50 mL) and saturated brine (25 mL) were added to the filtrate to wash and then separated. The organic phase was collected and purified by silica gel column chromatography to obtain 40 mg of compound 36.
  • Embodiment 37 Preparation of compound 37
  • compound 37-1 was prepared using compound 1-1 and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride.
  • Embodiment 38 Preparation of compound 38
  • compound 38-1 was prepared using compound 1-1 and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride.
  • Embodiment 39 Preparation of compound 39
  • step B of Example 1 compound 39-1 was prepared from compound 1-1 and 6-oxa-3-aza-bicyclo[3,1,1]heptane hydrochloride as raw materials. MS(ESI,[M+H] + )m/z:474.04/476.06.
  • Embodiment 40 Preparation of Compound 40
  • step B of Example 1 compound 40-1 was prepared from compound 1-1 and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride as raw materials .
  • step H of Example 1 compound 40 was prepared using compound 40-1 and compound 36-5.
  • Embodiment 41 Preparation of compound 41
  • step B of Example 1 compound 41-1 was prepared using compound 1-1 and (R)-3-methoxypyrrolidine hydrochloride.
  • Embodiment 42 Preparation of Compound 42
  • Embodiment 43 Preparation of Compound 43
  • compound 43-1 was prepared by reacting compound 1-1 with morpholine.
  • Embodiment 44 Preparation of Compound 44
  • compound 44-1 was prepared using compound 1-1 and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride.
  • Embodiment 45 Preparation of compound 45
  • reaction solution obtained in the above step B was transferred to a 35 mL microwave tube, and compound 15-1 (200 mg), cesium carbonate (146 mg), [2'-(amino)[1,1'-biphenyl ]-2-yl][[2',6'-bis(1-methylethoxy)[1,1'-biphenyl]-2-yl]dicyclohexylphosphine]palladium chloride (35mg), After adding 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (21mg) and water (2.5mL), it was sealed under nitrogen protection and placed in a microwave reactor. Reaction conditions: 140°C, 2h.
  • reaction solution was filtered with celite, and the filtrate was collected.
  • Ethyl acetate (50 mL) and saturated brine (25 mL) were added to the filtrate to wash and then separated.
  • the organic phase was collected and purified by silica gel column chromatography to obtain 15 mg of compound 45.
  • Embodiment 46 Preparation of compound 46
  • Embodiment 47 Preparation of Compound 47
  • step B Add toluene (20mL), compound 47-2 (800mg) and aluminum trichloride (2028mg) obtained in step B to a 50mL single-necked bottle in sequence, start stirring, and heat up the oil bath to 70°C for 2h after nitrogen replacement; Add saturated aqueous sodium bicarbonate solution (30mL) to the system to quench the reaction, add ethyl acetate for extraction (30mL x 2), and separate the layers to obtain an organic phase, add saturated aqueous sodium chloride solution (20mL) to it, stir and wash, and then separate the layers to obtain The organic phase was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography to obtain 300 mg of compound 47-3. MS(ESI,[MH] - )m/z:173.0.
  • Embodiment 48 Preparation of compound 48
  • Embodiment 49 Preparation of compound 49
  • Embodiment 50 the preparation of compound 50
  • Embodiment 51 Preparation of compound 51
  • Embodiment 52 Preparation of compound 52
  • Embodiment 53 Preparation of compound 53
  • Embodiment 54 Preparation of Compound 54
  • Embodiment 55 Preparation of compound 55
  • Embodiment 56 Preparation of compound 56
  • Embodiment 57 Preparation of compound 57
  • Step B Preparation of Compound 57
  • Step B of Example 48 Compound 57 was prepared by reacting Compound 45-2 with Compound 57-1.
  • Embodiment 58 Preparation of compound 58
  • Step B Preparation of Compound 58
  • Step B of Example 48 Compound 58 was prepared by reacting Compound 45-2 with Compound 58-1.
  • Embodiment 59 Preparation of Compound 59
  • Step B Preparation of compound 59-2
  • Embodiment 60 the preparation of compound 60
  • 5-bromopyrimidin-4-one (1 g) was dissolved in tetrahydrofuran (10 mL), cooled to 0° C., and sodium hydride (0.457 g) was added in batches. After addition, nitrogen replacement was performed three times. React for 1 hour. Under ice-cooling, methyl iodide (1.622 g) was added dropwise to the reaction solution with a syringe, and the reaction was continued overnight after the drop was completed.
  • step B of Example 45 compound 60-1 was reacted with pinacol diboronate to obtain compound 60-2, which was directly used in the next reaction without separation and purification.
  • Compound 60 was prepared by reacting Compound 7-1 with Compound 60-2.
  • Embodiment 61 the preparation of compound 61
  • Step A Preparation of compound 61-1
  • Step B Preparation of Compound 61
  • Step B of Example 48 Compound 61 was prepared by reacting Compound 45-2 with Compound 61-1.
  • Embodiment 62 the preparation of compound 62
  • Embodiment 63 the preparation of compound 63
  • step B of Example 62 compound 63-1 was prepared using compound 2-1 and neopentyl glycol diboronate. The reaction was not processed and used directly in the next reaction.
  • Step B Preparation of compound 63
  • Embodiment 64 the preparation of compound 64
  • Embodiment 65 the preparation of compound 65
  • compound 65 was prepared using compound 64-2 and R-prolinol.
  • Embodiment 66 the preparation of compound 66
  • Embodiment 67 the preparation of compound 67
  • step C of Example 64 compound 67 was prepared using compound 64-2 and thiomorpholine.
  • Embodiment 68 the preparation of compound 68
  • Embodiment 69 Preparation of compound 69
  • Compound 69-1 was prepared by reacting Compound 64-2 with 1-(2-tetrahydropyranyl)-1H-pyrazole-5-boronic acid pinadate. MS(ESI,[MH] - )m/z:555.14.
  • Step B Preparation of Compound 69
  • Embodiment 70 the preparation of compound 70
  • compound 70-1 was prepared by reacting compound 1-1 with ethylene glycol methyl ether. MS(ESI, [M+H] + )m/z:450.98.
  • Compound 70 was prepared by reacting Compound 45-2 with Compound 70-1.
  • Embodiment 71 Preparation of compound 71
  • Step A Preparation of Compound 71-1
  • Step B Preparation of Compound 71
  • Step B of Example 48 Compound 71 was prepared by reacting Compound 1-4 with Compound 25-1.
  • Embodiment 72 the preparation of compound 72
  • Compound 72-1 was prepared by reacting Compound 1-1 with 3,3-difluoroazetidine hydrochloride. MS(ESI,[M+H] + )m/z:467.91.
  • reaction solution of compound 72-2 was prepared by reacting compound 72-1 with neopentyl glycol diboronate, which was directly used in the next reaction without purification.
  • compound 72 should be prepared by using the reaction solution of compound 72-2 obtained in step B above and compound 45-1.
  • Embodiment 73 Preparation of compound 73
  • Embodiment 74 the preparation of compound 74
  • Embodiment 75 Preparation of Compound 75
  • Embodiment 76 the preparation of compound 76
  • Embodiment 77 the preparation of compound 77
  • Embodiment 78 Preparation of Compound 78
  • compound 78-1 was prepared by reacting 6-bromopyrimidin-4(3H)-one and 4-iodomethyltetrahydropyran. MS(ESI,[M+H] + )m/z:273.04.
  • Step B Preparation of compound 78-2
  • reaction solution of compound 78-2 was prepared by reacting compound 61-1 with neopentyl glycol bis-boronate, which was directly used in the next reaction without purification.
  • Step C of Example 62 Compound 78 was prepared by reacting the reaction solution of Compound 78-2 obtained in Step B above with Compound 78-1 obtained in Step A.
  • Embodiment 79 Preparation of Compound 79
  • Embodiment 80 Preparation of Compound 80
  • compound 80-1 was prepared using compound 1-1 and isoxazolidine hydrochloride.
  • Compound 80 was prepared by reacting Compound 45-2 with Compound 80-1.
  • Embodiment 81 the preparation of compound 81
  • Embodiment 82 the preparation of compound 82
  • N,N-dimethylformamide (10mL), 5-bromopyrazin-2(1H)-one (500mg) and cesium carbonate (1369mg) to a 50mL single-necked bottle in turn, after the addition is complete, start stirring, and Slowly add iodomethane (419mg/2mL) diluted with N,N-dimethylformamide dropwise to the system, after the addition is complete, react at room temperature for 4h; add purified water (10mL) and ethyl acetate (30mL) to the system, After stirring and washing, the liquids were separated, and the aqueous phase was then extracted once with ethyl acetate (20mL).
  • the reaction solution containing compound 82-2 was prepared by reacting compound 82-1 with pinacol bisboronate, cooled to room temperature, and directly used in subsequent reactions without separation and purification.
  • Embodiment 83 Preparation of compound 83
  • step B of Example 48 compound 83 was prepared by reacting compound 23-1 and compound 47-5.
  • Embodiment 84 Preparation of Compound 84
  • Step A Preparation of Compound 84-1
  • step D of Example 1 use 5-bromo-1-methylpyridin-2(1H)-one to react with biboronic acid pinacol ester to obtain the reaction solution of compound 84-1, without separation and purification, directly for the next reaction.
  • Step B Preparation of Compound 84
  • compound 84 was prepared by reacting the reaction solution of compound 84-1 with compound 7-1.
  • Embodiment 85 Preparation of Compound 85
  • the reaction liquid of compound 85-2 was obtained by reacting compound 85-1 with pinacol diborate, which was directly used in the next step reaction without separation and purification.
  • compound 85 was prepared by reacting the reaction solution of compound 85-2 with compound 7-1.
  • Embodiment 86 Preparation of Compound 86
  • Step A Preparation of Compound 86-1
  • compound 86-1 was prepared by reacting 3-bromopyridin-2(1H)-one with methyl iodide.
  • Step B of Example 48 Compound 86 was prepared by reacting the reaction solution containing Compound 86-2 with Compound 7-1.
  • Embodiment 87 the preparation of compound 87
  • Step A Preparation of Compound 87-1
  • Step B Preparation of Compound 87-2
  • Embodiment 88 Preparation of Compound 88
  • step B of Example 64 compound 88-1 was prepared by reacting compound 64-1 and compound 47-4. MS(ESI,[M+H] + )m/z:441.05.
  • Step B Preparation of Compound 88
  • compound 88 was prepared using compound 88-1 and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride.
  • Embodiment 89 Preparation of Compound 89
  • Embodiment 90 Preparation of Compound 90
  • Embodiment 91 Preparation of compound 91
  • compound 91 was prepared by using compound 88-1 and 8-oxo-3-azabicyclo[3,2,1]octane hydrochloride.
  • Embodiment 92 Preparation of compound 92
  • Step B of Example 48 Compound 92 was prepared by reacting Compound 20-1 with Compound 36-5.
  • Embodiment 93 Preparation of compound 93
  • Step B of Example 48 Compound 93 was prepared by reacting Compound 56-1 with Compound 36-5.
  • Embodiment 94 Preparation of compound 94
  • Step B Preparation of Compound 94-2
  • Step G Preparation of compound 94-7
  • Embodiment 95 Preparation of Compound 95
  • N,N-dimethylformamide (10mL) into a 25mL single-necked bottle, start stirring, and add 2-(7-azobenzotriazole)-N,N,N',N '-Tetramethyluronium hexafluorophosphate (488mg) and N,N-diisopropylethylamine (415mg), stirred for 5min, then added dropwise N,N-dimethylformamide (5mL) to the system to dissolve The N,N-dimethylformamide solution of compound 95-4 (390 mg) obtained in the above step D; after the addition, react at room temperature for 1 h; add ethyl acetate (30 mL) and purified water (10 mL) to the system, and stir and wash Separate the liquid, collect the organic phase, add ethyl acetate (10mL) to the aqueous phase to extract twice; combine the organic phase, add purified water (15mL) and saturated aqueous sodium chloride solution (15mL
  • compound 95-6 was prepared by reacting compound 11-1 with neopentyl glycol diboronate. The reaction product was used directly in the next step without treatment.
  • Embodiment 96 the preparation of compound 96
  • Step A Preparation of Compound 96-1
  • compound 96-1 was prepared by reacting ethyl 2-isocyanoacetate with N-Boc-aminopropyne.
  • step C of Example 94 compound 96-3 was prepared by reacting compound 96-2 with thionyl chloride. MS(ESI,[M+H] + )m/z:123.06.
  • Embodiment 97 the preparation of compound 97
  • step G of Example 94 compound 97-1 was prepared by reacting compound 94-3 with pinacol diboronate. MS(ESI,[M+H] + )m/z:263.23.
  • Step B Preparation of compound 97
  • Embodiment 98 Preparation of Compound 98
  • Embodiment 99 Preparation of Compound 99
  • Embodiment 100 Preparation of compound 100
  • Reaction system A At -30°C, under the protection of nitrogen, slowly add potassium tert-butoxide (3.50g) into tetrahydrofuran of 3-(tert-butoxy)-3-oxopropionic acid (5g) and magnesium chloride (2.97g) (200 mL) into the stirred solution, the dropwise addition was completed in 30 minutes, and the resulting mixture was stirred and reacted at room temperature for 5 h.
  • Reaction system B At -30°C, under nitrogen protection, add N,N'-carbonyldiimidazole (4.56g) into (tert-butoxycarbonyl)glycine (4.37g) in tetrahydrofuran (200mL) stirring solution, dropwise , The resulting mixture was stirred at room temperature for 3 h. At 0°C, the reaction system B was added dropwise to the reaction system A. After the dropwise addition, the reaction system was transferred to room temperature and stirred for 2 days.
  • Compound 100 was prepared by reacting Compound 95-6 with Compound 100-7.
  • Embodiment 101 Preparation of compound 101
  • Step C of Example 62 Compound 101 was prepared by reacting Compound 95-6 with Compound 101-7.
  • Embodiment 102 Preparation of compound 102

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Abstract

提供了一种作为BCR-ABL抑制剂的化合物，即式(I)化合物，或其药学上可接受的盐、其制备方法、含有该化合物的药物组合物，并涉及其在制备治疗BCR-ABL相关疾病的药物中的用途。

Description

作为BCR-ABL抑制剂的化合物
相关申请的引用
本申请要求于2021年05月28日、2021年09月17日和2021年12月31日向中华人民共和国国家知识产权局提交的申请号为202110592542.2、202111094508.9和202111661984.4的中国发明专利申请的权益和优先权，并在此将其全部内容以援引的方式整体并入本文中。
技术领域
本申请属于药物化学领域，提供了一种作为BCR-ABL抑制剂的化合物及其制备方法、含有该化合物的药物组合物，并涉及其在制备治疗BCR-ABL相关疾病的药物中的用途。
背景技术
慢性髓细胞白血病(CML)是我国慢性白血病的主要病种，约占慢性白血病的70％。该病病例中的90％以上存在染色体异常，主要为第9号和第22号染色体的长臂易位，形成Bcr-Abl融合基因，表达蛋白p-210。P-210的酪氨酸激酶活性远强于p-150(正常c-Abl基因表达产物)，引起造血干细胞增殖和分化异常，最终引发CML。
伊马替尼为首个上市的Bcr-Abl靶向治疗药物，目前作为一线治疗药物用于治疗各期CML。尼洛替尼、达沙替尼和博舒替尼(第二代Bcr-Abl抑制剂)被批准用于治疗伊马替尼耐药或不耐受的CML。第二代Bcr-Abl抑制剂的药效皆优于伊马替尼，且几乎对所有伊马替尼耐药突变类型有效，但仍未解决T315I(gatekeeper)的突变耐药问题。第一、二代Bcr-Abl抑制剂耐药的患者中，T315I突变占比约为20％，普纳替尼(第三代Bcr-Abl抑制剂)的上市缓解了T315I耐药突变患者无药可医的困境，成为第一、二代Bcr-Abl抑制剂治疗失败患者的唯一选择。
ABL001为诺华公司开发的Bcr-Abl变构抑制剂，其在WO2013171639中公开，目前处于III期临床研究。ABL001是一种有效的、选择性的BCR-ABL抑制剂，对多数突变型都具有活性，如T315I(Andrew A.Wylie等人(2017)Nature 543,733-737)。
Figure PCTCN2022095436-appb-000001
目前，尚未有BCR-ABL变构抑制剂上市，临床上亟需对T315I有效的高效、低毒Bcr-Abl抑制剂，有必要进一步研发新的BCR-ABL变构抑制剂。
发明内容
一方面，本申请提供了式(I)化合物或其药学上可接受的盐，
Figure PCTCN2022095436-appb-000002
其中，
Q选自N或CH；
R 1选自
Figure PCTCN2022095436-appb-000003
其中所述
Figure PCTCN2022095436-appb-000004
任选地被一个或多个R a’取代；
X、Y和Z各自独立地选自CH或N，且X、Y和Z中至少有一个选自CH；
环A选自含有1-3个选自N、O或S原子的杂原子的5元杂芳基；
环B选自含有1-3个选自N、O或S原子的杂原子的5-10元杂环基，或含有1-3个选自N、O或S原子的杂原子的5-8元杂芳基；
R 2选自氢、氨基、C 1-6烷基、C 1-6烷氧基、氨基-C 1-6烷基-、3-10元杂环基或5-6元杂芳基，其中所述氨基、C 1-6烷基、C 1-6烷氧基、氨基-C 1-6烷基-、3-10元杂环基或5-6元杂芳基任选地被一个或多个R b取代；
R 3选自-OCF 2H，其中所述-OCF 2H任选地被卤素取代；
R a和R a’各自独立地选自羟基、氨基、氰基、卤素、
Figure PCTCN2022095436-appb-000005
C 1-6烷基、3-8元环烷基、3-8元杂环烷基、3-8元环烷基-C 1-6烷基-、3-8元杂环烷基-C 1-6烷基-或被一个或多个羟基或卤素取代的C 1-6烷基；
R b选自羟基、氨基、氰基、卤素、
Figure PCTCN2022095436-appb-000006
C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基-、C 1-6烷基-C(O)-NH-或被一个或多个羟基或卤素取代的C 1-6烷基。
在一些实施方案中，式(I)化合物或其药学上可接受的盐选自式(II)化合物或其药学上可接受的盐，
Figure PCTCN2022095436-appb-000007
其中，
R 1选自
Figure PCTCN2022095436-appb-000008
其中所述
Figure PCTCN2022095436-appb-000009
任选地被一个或多个R a’取代；
X、Y和Z各自独立地选自CH或N，且X、Y和Z中至少有一个选自CH；
环A选自含有1-3个选自N、O或S原子的杂原子的5元杂芳基；
环B选自含有1-3个选自N、O或S原子的杂原子的5-10元杂环基，或含有1-3个选自N、O或S原子的杂原子的5～8元杂芳基；
R 2选自氢、氨基、C 1-6烷基、C 1-6烷氧基、氨基-C 1-6烷基-、3-10元杂环基或5-6元杂芳基，其中所述氨基、C 1-6烷基、C 1-6烷氧基、氨基-C 1-6烷基-、3-10元杂环基或5-6元杂芳基任选地被一个或多个R b取代；
R 3选自-OCF 2H，其中所述-OCF 2H任选地被卤素取代；
R a和R a’各自独立地选自羟基、氨基、氰基、卤素、
Figure PCTCN2022095436-appb-000010
C 1-6烷基、3-8元环烷基、3-8元杂环烷基、3-8元环烷基-C 1-6烷基-、3-8元杂环烷基-C 1-6烷基-或被一个或多个羟基或卤素取代的C 1-6烷基；
R b选自羟基、氨基、氰基、卤素、
Figure PCTCN2022095436-appb-000011
C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基-、C 1-6烷基-C(O)-NH-或被一个或多个羟基或卤素取代的C 1-6烷基。
在一些实施方案中，
R 1选自
Figure PCTCN2022095436-appb-000012
其中所述
Figure PCTCN2022095436-appb-000013
任选地被一个或多个R a’取代；
X、Y和Z各自独立地选自CH或N，且X、Y和Z中至少有一个选自CH；
R 2选自氢或3～10元杂环基，其中所述3～10元杂环基任选地被一个或多个R b取代；
R 3选自-OCF 2H，其中所述-OCF 2H任选地被卤素取代；
R a和R a’各自独立地选自羟基、氨基、氰基、卤素、C 1-6烷基、3～8元环烷基、3～8元杂环烷基、或被一个或多个羟基或卤素取代的C 1-6烷基；
R b选自羟基、氨基、氰基、卤素、
Figure PCTCN2022095436-appb-000014
C 1-6烷基、C 1-6烷氧基、或被一个或多个羟基或卤素取代的C 1-6烷基。
在一些实施方案中，所述杂环基或杂环烷基分别包含1、2、3或4个独立选自-O-、-NH-、-S-或N的杂原子或杂原子团；其他变量如本申请所定义。在一些实施方案中，所述杂环基或杂环烷基分别包含1、2、3或4个独立选自-O-、-NH-或N的杂原子或杂原子团；其他变量如本申请所定义。在一些实施方案中，所述杂环基或杂环烷基分别包含1或2个独立选自-O-、-NH-或N的杂原子或杂原子团；其他变量如本申请所定义。
在一些实施方案中，所述R 2、R a或R a’中提到的杂环基或杂环烷基分别包含1、2、3或4个独立选自-O-、-NH-、-S-或N的杂原子或杂原子团；其他变量如本申请所定义。在一些实施方案中，所述R 2、R a 或R a’中提到的杂环基或杂环烷基分别包含1、2、3或4个独立选自-O-、-NH-或N的杂原子或杂原子团；其他变量如本申请所定义。在一些实施方案中，所述R 2、R a或R a’中提到的杂环基或杂环烷基分别包含1或2个独立选自-O-、-NH-或N的杂原子或杂原子团；其他变量如本申请所定义。
在一些实施方案中，Q选自N，其他变量如本申请所定义。在一些实施方案中，Q选自CH，其他变量如本申请所定义。
在一些实施方案中，Q选自CH；
R 1选自
Figure PCTCN2022095436-appb-000015
其中所述
Figure PCTCN2022095436-appb-000016
Figure PCTCN2022095436-appb-000017
任选地被一个或多个R a’取代；R a’选自卤素、
Figure PCTCN2022095436-appb-000018
C 1-6烷基或3-6元环烷基；或者，R a’选自氟、氯、
Figure PCTCN2022095436-appb-000019
甲基、乙基、异丙基或环丙基；
R 2选自
Figure PCTCN2022095436-appb-000020
其中所述
Figure PCTCN2022095436-appb-000021
任选地被1个、2个或3个R b取代；R b选自羟基或C 1-4烷基；
R 3选自-OCF 2H，其中所述-OCF 2H任选地被卤素取代。
在一些实施方案中，Q选自CH；
R 1选自
Figure PCTCN2022095436-appb-000022
Figure PCTCN2022095436-appb-000023
R 2选自
Figure PCTCN2022095436-appb-000024
R 3选自-OCF 2H，其中所述-OCF 2H任选地被氯取代。
在一些实施方案中，X、Y和Z均选自CH；其他变量如本申请所定义。在一些实施方案中，X、Y和Z中有一个选自N，其余选自CH；其他变量如本申请所定义。在一些实施方案中，X选自N，Y和Z选自CH；其他变量如本申请所定义。在一些实施方案中，Y选自N，X和Z选自CH；其他变量如本申请所定义。在一些实施方案中，Z选自N，X和Y选自CH；其他变量如本申请所定义。在一些实施方案中，X、Y和Z中有一个选自CH，其余选自N；其他变量如本申请所定义。
在一些实施方案中，环A选自含有1个或2个选自N、O或S原子的杂原子的5元杂芳基；其他变量如本申请所定义。
在一些实施方案中，环A选自含有1个或2个选自N或O原子的杂原子的5元杂芳基；其他变量如本申请所定义。
在一些实施方案中，环A选自吡咯基、吡唑基、咪唑基、呋喃基、噻吩基、噻唑基、噁唑基或异噁唑基；其他变量如本申请所定义。在一些实施方案中，环A选自吡咯基、吡唑基、咪唑基或呋喃基；其他变量如本申请所定义。
在一些实施方案中，环B选自含有1-3个选自N或O原子的杂原子的5～8元杂环烷基、或含有1-3个选自N或O原子的杂原子的5～8元杂芳基；其他变量如本申请所定义。
在一些实施方案中，环B选自含有1个或2个选自N或O原子的杂原子的5元或6元杂环烷基、或 含有1个或2个选自N或O原子的杂原子的5元或6元杂芳基；其他变量如本申请所定义。
在一些实施方案中，环B选自含有1个或2个选自N或O原子的杂原子的5元或6元杂环烷基、或含有1个或2个N原子的5元杂芳基；其他变量如本申请所定义。
在一些实施方案中，环B选自四氢吡咯烷基、哌啶基、哌嗪基、吗啉基、咪唑基或吡唑基；其他变量如本申请所定义。在一些实施方案中，环B选自四氢吡咯烷基、哌啶基、吗啉基或咪唑基；其他变量如本申请所定义。
在一些实施方案中，R 1选自
Figure PCTCN2022095436-appb-000025
其中所述
Figure PCTCN2022095436-appb-000026
任选地被一个或多个R a’取代；其他变量如本申请所定义。
在一些实施方案中，R 1选自
Figure PCTCN2022095436-appb-000027
其中所述
Figure PCTCN2022095436-appb-000028
Figure PCTCN2022095436-appb-000029
任选地被一个或多个R a’取代；其他变量如本申请所定义。
在一些实施方案中，R 1选自
Figure PCTCN2022095436-appb-000030
Figure PCTCN2022095436-appb-000031
其中所述
Figure PCTCN2022095436-appb-000032
Figure PCTCN2022095436-appb-000033
任选地被一个或多个R a’取代；其他变量如本申请所定义。
在一些实施方案中，R 1选自
Figure PCTCN2022095436-appb-000034
其中所述
Figure PCTCN2022095436-appb-000035
任选地被一个或多个R a’取代；其他变量如本申请所定义。
在一些实施方案中，R 1选自
Figure PCTCN2022095436-appb-000036
其中所述
Figure PCTCN2022095436-appb-000037
任选地被一个或多个R a’取代；其他变量如本申请所定义。
在一些实施方案中，R 1选自
Figure PCTCN2022095436-appb-000038
Figure PCTCN2022095436-appb-000039
其中所述
Figure PCTCN2022095436-appb-000040
任选地被一个或多个R a’取代；其他变量如本申请所定义。
在一些实施方案中，R 1选自
Figure PCTCN2022095436-appb-000041
Figure PCTCN2022095436-appb-000042
其中所述
Figure PCTCN2022095436-appb-000043
Figure PCTCN2022095436-appb-000044
任选地被一个或多个R a’取代；其他变量如本申请所定义。
在一些实施方案中，R 1选自
Figure PCTCN2022095436-appb-000045
其中所述
Figure PCTCN2022095436-appb-000046
任选地被一个或多个R a’取代；其他变量如本申请所定义。
在一些实施方案中，R 1选自
Figure PCTCN2022095436-appb-000047
Figure PCTCN2022095436-appb-000048
其中所述
Figure PCTCN2022095436-appb-000049
Figure PCTCN2022095436-appb-000050
任选地被一个或多个R a’取代；其他变量如本申请所定义。
在一些实施方案中，R 1选自
Figure PCTCN2022095436-appb-000051
Figure PCTCN2022095436-appb-000052
Figure PCTCN2022095436-appb-000053
其中所述
Figure PCTCN2022095436-appb-000054
Figure PCTCN2022095436-appb-000055
Figure PCTCN2022095436-appb-000056
任选地被一个或多个R a’取代；其他变量如本申请所定义。
在一些实施方案中，R 1选自
Figure PCTCN2022095436-appb-000057
其中所述
Figure PCTCN2022095436-appb-000058
任选地被一个或多个R a’取代；其他变量如本申请所定义。
在一些实施方案中，R 1选自
Figure PCTCN2022095436-appb-000059
其中所述
Figure PCTCN2022095436-appb-000060
任选地被一个或多个R a’取代；其他变量如本申请所定义。
在一些实施方案中，R 1选自
Figure PCTCN2022095436-appb-000061
其中所述
Figure PCTCN2022095436-appb-000062
Figure PCTCN2022095436-appb-000063
任选地被一个或多个R a’取代；其他变量如本申请所定义。
在一些实施方案中，R 1选自
Figure PCTCN2022095436-appb-000064
其中所述
Figure PCTCN2022095436-appb-000065
Figure PCTCN2022095436-appb-000066
任选地被一个R a’取代；其他变量如本申请所定义。
在一些实施方案中，R 1选自
Figure PCTCN2022095436-appb-000067
其他变量如本申请所定义。
在一些实施方案中，R a和R a’各自独立地选自卤素、
Figure PCTCN2022095436-appb-000068
C 1-6烷基、3-6元环烷基、3-8元杂环烷基-C 1-6烷基-或被1个、2个或3个羟基取代的C 1-6烷基；其他变量如本申请所定义。
在一些实施方案中，R a和R a’各自独立地选自卤素、
Figure PCTCN2022095436-appb-000069
C 1-4烷基、3-6元环烷基、3-6元杂环烷基-C 1-4烷基-或被1个、2个或3个羟基取代的C 1-4烷基；其他变量如本申请所定义。
在一些实施方案中，R a和R a’各自独立地选自羟基、氨基、氰基、卤素、C 1-6烷基、3-8元环烷基、3-8元杂环烷基、或被一个或多个羟基或卤素取代的C 1-6烷基；其他变量如本申请所定义。
在一些实施方案中，R a和R a’各自独立地选自卤素、C 1-6烷基、3-6元环烷基或被1个、2个或3个羟基取代的C 1-6烷基；其他变量如本申请所定义。
在一些实施方案中，R a和R a’各自独立地选自羟基、氨基、氰基、卤素、C 1-4烷基、3-6元环烷基、3-6元杂环烷基、或被一个或多个羟基或卤素取代的C 1-4烷基；其他变量如本申请所定义。
在一些实施方案中，R a和R a’各自独立地选自卤素、C 1-4烷基、3-6元环烷基或被1个、2个或3个羟基取代的C 1-4烷基；其他变量如本申请所定义。
在一些实施方案中，R a选自C 1-4烷基、3-6元环烷基、3-6元杂环烷基-C 1-4烷基-或被1个、2个或3个羟基取代的C 1-4烷基；其他变量如本申请所定义。
在一些实施方案中，R a选自甲基、乙基、环丙基、2-羟基乙基或
Figure PCTCN2022095436-appb-000070
其他变量如本申请所定义。
在一些实施方案中，R a选自C 1-4烷基、3～6元环烷基或被1个、2个或3个羟基取代的C 1-4烷基；其他变量如本申请所定义。
在一些实施方案中，R a选自甲基、乙基、环丙基或2-羟基乙基；其他变量如本申请所定义。
在一些实施方案中，R a选自甲基；其他变量如本申请所定义。
在一些实施方案中，R a’选自羟基、氨基、氰基、卤素、
Figure PCTCN2022095436-appb-000071
C 1-4烷基或3～6元环烷基；其他变量如 本申请所定义。
在一些实施方案中，R a’选自卤素、
Figure PCTCN2022095436-appb-000072
C 1-4烷基或3～6元环烷基；其他变量如本申请所定义。
在一些实施方案中，R a’选自氟、氯、溴、碘、
Figure PCTCN2022095436-appb-000073
甲基、乙基、异丙基或环丙基；其他变量如本申请所定义。
在一些实施方案中，R a’选自氟、氯、
Figure PCTCN2022095436-appb-000074
甲基、乙基或环丙基；其他变量如本申请所定义。
在一些实施方案中，R a’选自羟基、氨基、氰基或卤素；其他变量如本申请所定义。
在一些实施方案中，R a’选自卤素；其他变量如本申请所定义。
在一些实施方案中，R a’选自氟或氯；其他变量如本申请所定义。
在一些实施方案中，R 1选自
Figure PCTCN2022095436-appb-000075
Figure PCTCN2022095436-appb-000076
Figure PCTCN2022095436-appb-000077
其他变量如本申请所定义。
在一些实施方案中，R 1选自
Figure PCTCN2022095436-appb-000078
Figure PCTCN2022095436-appb-000079
其他变量如本申请所定义。
在一些实施方案中，R 2选自氢、氨基、C 1-4烷氧基、氨基-C 1-4烷基-、3-10元杂环烷基或5-6元杂芳基，其中所述氨基、C 1-4烷氧基、氨基-C 1-4烷基-、3-0元杂环烷基或5-6元杂环芳基任选地被一个或多个R b取代；其他变量如本申请所定义。
在一些实施方案中，R 2选自氢、氨基、C 1-4烷氧基、氨基-C 1-4烷基-、4-6元单杂环烷基、6-9元桥杂环烷基、7-9元螺杂环烷基或5-6元杂芳基，其中所述氨基、C 1-4烷氧基、氨基-C 1-4烷基-、4-6元单杂环烷基、6-9元桥杂环烷基、7-9元螺杂环烷基或5-6元杂芳基任选地被一个或多个R b取代；其他变量如本申请所定义。
在一些实施方案中，R 2选自氨基、C 1-3烷氧基、氨基-C 1-3烷基-、4元、5元或6元单杂环烷基、6元、7元或8元桥杂环烷基、7元、8元或9元螺杂环烷基、或5元杂芳基，其中所述氨基、C 1-3烷氧基、氨基-C 1-3烷基-、4元、5元或6元单杂环烷基、6元、7元或8元桥杂环烷基、7元、8元或9元螺杂环烷基、或5元杂芳基任选地被一个或多个R b取代(例如，1个、2个或3个)；其他变量如本申请所定义。
在一些实施方案中，R 2选自氢或3-10元杂环基，其中所述3-10元杂环基任选地被一个或多个R b取代； 其他变量如本申请所定义。
在一些实施方案中，R 2选自氢或3-10元杂环烷基，其中所述3-10元杂环烷基任选地被一个或多个R b取代；其他变量如本申请所定义。
在一些实施方案中，R 2选自氨基或3-10元杂环烷基，其中所述氨基或3-10元杂环烷基任选地被一个或多个R b取代；其他变量如本申请所定义。
在一些实施方案中，所述杂环烷基分别包含1、2、3或4个独立选自-O-、-NH-、-S-或N的杂原子或杂原子团；其他变量如本申请所定义。在一些实施方案中，所述杂环烷基分别包含1、2、3或4个独立选自-O-、-NH-或N的杂原子或杂原子团；其他变量如本申请所定义。在一些实施方案中，所述杂环烷基分别包含1或2个独立选自-O-、-NH-或N的杂原子或杂原子团；其他变量如本申请所定义。
在一些实施方案中，所述R 2、R a或R a’中提到的杂环烷基分别包含1、2、3或4个独立选自-O-、-NH-、-S-或N的杂原子或杂原子团；其他变量如本申请所定义。在一些实施方案中，所述R 2、R a或R a’中提到的杂环烷基分别包含1、2、3或4个独立选自-O-、-NH-或N的杂原子或杂原子团；其他变量如本申请所定义。在一些实施方案中，所述R 2、R a或R a’中提到的杂环烷基分别包含1或2个独立选自-O-、-NH-或N的杂原子或杂原子团；其他变量如本申请所定义。在一些实施方案中，R 2选自氢、4-6元单杂环基、6-9元桥杂环基或7-9元螺杂环基，其中所述4-6元单杂环基、6-9元桥杂环基或7-9元螺杂环基任选地被一个或多个R b取代；其他变量如本申请所定义。
在一些实施方案中，R 2选自氢、4-6元单杂环烷基、6-9元桥杂环烷基或7-9元螺杂环烷基，其中所述4-6元单杂环烷基、6-9元桥杂环烷基或7-9元螺杂环烷基任选地被一个或多个R b取代；其他变量如本申请所定义。
在一些实施方案中，R 2不为氢；其他变量如本申请所定义。
在一些实施方案中，R 2选自4元、5元或6元单杂环烷基、6元、7元或8元桥杂环烷基或7元、8元或9元螺杂环烷基，其中所述4元、5元或6元单杂环烷基、6元、7元或8元桥杂环烷基或7元、8元或9元螺杂环烷基任选地被一个或多个R b取代(例如，1个、2个或3个)；其他变量如本申请所定义。
在一些实施方案中，R 2选自氨基、甲氧基、乙氧基、氨基甲基、吡咯烷基、噁唑烷基、异噁唑烷基、吗啉基、硫代吗啉基、1,4-二氧六环基、氮杂环丁基、哌嗪基、哌啶基、1,2,3,6-四氢吡啶基、四氢吡喃基、3,4-二氢吡喃基、3,6-二氢吡喃基、6-氧杂-3-氮杂双环[3.1.1]庚烷基、3-氧杂-6-氮杂双环[3.1.1]庚烷基、3-氧杂-8-氮杂双环[3.2.1]辛烷基、8-氧杂-3-氮杂双环[3.2.1]辛烷基、2-氧杂-5-氮杂双环[2.2.1]庚烷、3-氮杂双环[3.1.0]己烷基、2-氧杂-6-氮杂螺[3.4]辛烷基、2-氧杂-7-氮杂螺[3.5]壬烷基、2-氧杂-6-氮杂螺[3.3]庚烷基、吡唑基或咪唑基，其中所述氨基、甲氧基、乙氧基、氨基甲基、吡咯烷基、噁唑烷基、异噁唑烷基、吗啉基、硫代吗啉基、1,4-二氧六环基、氮杂环丁基、哌嗪基、哌啶基、1,2,3,6-四氢吡啶基、四氢吡喃基、3,4-二氢吡喃基、3,6-二氢吡喃基、6-氧杂-3-氮杂双环[3.1.1]庚烷基、3-氧杂-6-氮杂双环[3.1.1]庚烷基、3-氧杂-8-氮杂双环[3.2.1]辛烷基、8-氧杂-3-氮杂双环[3.2.1]辛烷基、2-氧杂-5-氮杂双环[2.2.1]庚烷、3-氮杂双环[3.1.0]己烷基、2-氧杂-6-氮杂螺[3.4]辛烷基、2-氧杂-7-氮杂螺[3.5]壬烷基、2-氧杂-6-氮杂螺[3.3]庚烷基、吡唑基或咪唑基任选地被一个或多个R b取代；其他变量如本申请所定义。
在一些实施方案中，R 2选自氨基、甲氧基、乙氧基、氨基甲基、吡咯烷基、异噁唑烷基、哌啶基、吗啉基、硫代吗啉基、1,4-二氧六环基、氮杂环丁基、6-氧杂-3-氮杂双环[3.1.1]庚烷基、3-氧杂-6-氮杂双环[3.1.1]庚烷基、3-氧杂-8-氮杂双环[3.2.1]辛烷基、8-氧杂-3-氮杂双环[3.2.1]辛烷基、2-氧杂-5-氮杂双环[2.2.1]庚烷、3-氮杂双环[3.1.0]己烷基、2-氧杂-6-氮杂螺[3.4]辛烷基、2-氧杂-7-氮杂螺[3.5]壬烷基、2-氧杂-6-氮杂螺[3.3]庚烷基、吡唑基或咪唑基，其中所述氨基、甲氧基、乙氧基、氨基甲基、吡咯烷基、异噁唑烷基、哌啶基、吗啉基、硫代吗啉基、1,4-二氧六环基、氮杂环丁基、6-氧杂-3-氮杂双环[3.1.1]庚烷基、3-氧杂-6-氮杂双环[3.1.1]庚烷基、3-氧杂-8-氮杂双环[3.2.1]辛烷基、8-氧杂-3-氮杂双环[3.2.1]辛烷基、2-氧杂-5-氮杂双环[2.2.1]庚烷、3-氮杂双环[3.1.0]己烷基、2-氧杂-6-氮杂螺[3.4]辛烷基、2-氧杂-7-氮杂螺[3.5]壬烷基、2-氧杂-6-氮杂螺[3.3]庚烷基、吡唑基或咪唑基任选地被一个或多个R b取代；其他变量如本申请所定义。
在一些实施方案中，R 2选自吡咯烷基、异噁唑烷基、吗啉基、氮杂环丁基、哌嗪基、哌啶基、1,2,3,6-四氢吡啶基、四氢吡喃基、3,4-二氢吡喃基、3,6-二氢吡喃基、6-氧杂-3-氮杂双环[3.1.1]庚烷基、3-氧杂-6-氮杂双环[3.1.1]庚烷基、3-氧杂-8-氮杂双环[3.2.1]辛烷基、8-氧杂-3-氮杂双环[3.2.1]辛烷基、2-氧杂-5-氮杂双环[2.2.1]庚烷、3-氮杂双环[3.1.0]己烷基、2-氧杂-6-氮杂螺[3.4]辛烷基、2-氧杂-7-氮杂螺[3.5]壬烷基或2-氧杂-6-氮杂螺[3.3]庚烷基，其中所述吡咯烷基、异噁唑烷基、吗啉基、氮杂环丁基、哌嗪基、哌啶基、1,2,3,6-四氢吡啶基、四氢吡喃基、3,4-二氢吡喃基、3,6-二氢吡喃基、6-氧杂-3-氮杂双环[3.1.1]庚烷基、3-氧杂-6-氮杂双环[3.1.1]庚烷基、3-氧杂-8-氮杂双环[3.2.1]辛烷基、8-氧杂-3-氮杂双环[3.2.1]辛烷基、2-氧杂-5-氮杂双环[2.2.1]庚烷、3-氮杂双环[3.1.0]己烷基、2-氧杂-6-氮杂螺[3.4]辛烷基、2-氧杂-7-氮杂螺[3.5]壬烷基或2- 氧杂-6-氮杂螺[3.3]庚烷基任选地被一个或多个R b取代；其他变量如本申请所定义。
在一些实施方案中，R 2选自吡咯烷基、异噁唑烷基、吗啉基、氮杂环丁基、6-氧杂-3-氮杂双环[3.1.1]庚烷基、3-氧杂-6-氮杂双环[3.1.1]庚烷基、3-氧杂-8-氮杂双环[3.2.1]辛烷基、8-氧杂-3-氮杂双环[3.2.1]辛烷基、2-氧杂-5-氮杂双环[2.2.1]庚烷、3-氮杂双环[3.1.0]己烷基、2-氧杂-6-氮杂螺[3.4]辛烷基、2-氧杂-7-氮杂螺[3.5]壬烷基或2-氧杂-6-氮杂螺[3.3]庚烷基，其中所述吡咯烷基、异噁唑烷基、吗啉基、氮杂环丁基、6-氧杂-3-氮杂双环[3.1.1]庚烷基、3-氧杂-6-氮杂双环[3.1.1]庚烷基、3-氧杂-8-氮杂双环[3.2.1]辛烷基、8-氧杂-3-氮杂双环[3.2.1]辛烷基、2-氧杂-5-氮杂双环[2.2.1]庚烷、3-氮杂双环[3.1.0]己烷基、2-氧杂-6-氮杂螺[3.4]辛烷基、2-氧杂-7-氮杂螺[3.5]壬烷基或2-氧杂-6-氮杂螺[3.3]庚烷基任选地被一个或多个R b取代；其他变量如本申请所定义。
在一些实施方案中，R 2选自氨基、甲氧基、乙氧基、氨基甲基、
Figure PCTCN2022095436-appb-000080
Figure PCTCN2022095436-appb-000081
Figure PCTCN2022095436-appb-000082
其中所述氨基、甲氧基、乙氧基、氨基甲基、
Figure PCTCN2022095436-appb-000083
Figure PCTCN2022095436-appb-000084
Figure PCTCN2022095436-appb-000085
任选地被1个、2个或3个R b取代；其他变量如本申请所定义。
在一些实施方案中，R 2选自
Figure PCTCN2022095436-appb-000086
Figure PCTCN2022095436-appb-000087
其中所述
Figure PCTCN2022095436-appb-000088
Figure PCTCN2022095436-appb-000089
任选地被1个、2个或3个R b取代；其他变量如本申请所定义。
在一些实施方案中，R b选自羟基、氰基、卤素、
Figure PCTCN2022095436-appb-000090
C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基-C 1-4烷基-、C 1-4烷基-C(O)-NH-或被一个或多个羟基或卤素取代的C 1-4烷基；其他变量如本申请所定义。
在一些实施方案中，R b选自羟基、氰基、氟、氯、
Figure PCTCN2022095436-appb-000091
甲基、甲氧基、羟基甲基、甲氧基乙基或乙酰氨基；其他变量如本申请所定义。
在一些实施方案中，R b选自羟基、氨基、氰基、卤素、
Figure PCTCN2022095436-appb-000092
C 1-6烷基、C 1-6烷氧基、或被一个或多个羟基或卤素取代的C 1-6烷基；其他变量如本申请所定义。
在一些实施方案中，R b选自羟基、氰基、卤素、
Figure PCTCN2022095436-appb-000093
C 1-6烷基、C 1-6烷氧基、或被一个或多个羟基或卤素取代的C 1-6烷基；其他变量如本申请所定义。
在一些实施方案中，R b选自羟基、氰基、卤素、
Figure PCTCN2022095436-appb-000094
C 1-4烷基、C 1-4烷氧基、或被1个、2个或3个羟基取代的C 1-3烷基；其他变量如本申请所定义。
在一些实施方案中，R b选自羟基、氰基、卤素、
Figure PCTCN2022095436-appb-000095
C 1-3烷基、C 1-3烷氧基、或被一个羟基取代的C 1-3烷基；其他变量如本申请所定义。
在一些实施方案中，R b选自羟基、氰基、氟、氯、
Figure PCTCN2022095436-appb-000096
甲基、甲氧基或羟基甲基；其他变量如本申请所定义。
在一些实施方案中，R 2选自吡咯烷基、异噁唑烷基、吗啉基、氮杂环丁基、6-氧杂-3-氮杂双环[3.1.1]庚烷基、3-氧杂-6-氮杂双环[3.1.1]庚烷基、3-氧杂-8-氮杂双环[3.2.1]辛烷基、8-氧杂-3-氮杂双环[3.2.1]辛烷基、2-氧杂-5-氮杂双环[2.2.1]庚烷、3-氮杂双环[3.1.0]己烷基、2-氧杂-6-氮杂螺[3.4]辛烷基、2-氧杂-7-氮杂螺[3.5]壬烷基或2-氧杂-6-氮杂螺[3.3]庚烷基，其中所述吡咯烷基任选地被1个或2个羟基、氰基、氟、氯或甲氧基取代，其中所述氮杂环丁基任选地被1个或2个羟基、氰基、氟、甲基或羟基甲基取代，其中所述2-氧杂-6-氮杂螺[3.4]辛烷基任选地被一个
Figure PCTCN2022095436-appb-000097
取代；其他变量如本申请所定义。
在一些实施方案中，R 2选自氨基、甲氧基、乙氧基、氨基甲基、吡咯烷基、异噁唑烷基、哌啶基、吗啉基、硫代吗啉基、1,4-二氧六环基、氮杂环丁基、6-氧杂-3-氮杂双环[3.1.1]庚烷基、3-氧杂-6-氮杂双环[3.1.1]庚烷基、3-氧杂-8-氮杂双环[3.2.1]辛烷基、8-氧杂-3-氮杂双环[3.2.1]辛烷基、2-氧杂-5-氮杂双环[2.2.1]庚烷、3-氮杂双环[3.1.0]己烷基、2-氧杂-6-氮杂螺[3.4]辛烷基、2-氧杂-7-氮杂螺[3.5]壬烷基、2-氧杂-6-氮杂螺[3.3]庚烷基、吡唑基或咪唑基，其中所述氨基任选地被1个或2个甲基、甲氧基乙基取代，其中所述乙氧基任选地被1个甲氧基取代，其中所述氨基甲基任选地被1个或2个甲基或甲氧基取代，其中所述吡咯烷基任选地被1个或2个羟基、氰基、氟、氯、甲氧基、羟基甲基或乙酰氨基取代，其中所述氮杂环丁基任选地被1个或2个羟基、氰基、氟、甲基或羟基甲基取代，其中所述2-氧杂-6-氮杂螺[3.4]辛烷基任选地被一个
Figure PCTCN2022095436-appb-000098
取代；其他变量如本申请所定义。
在一些实施方案中，R 2选自甲氧基、甲氧基乙氧基、甲基氨基、二甲基氨基、
Figure PCTCN2022095436-appb-000099
Figure PCTCN2022095436-appb-000100
Figure PCTCN2022095436-appb-000101
其他变量如本申请所定义。
在一些实施方案中，R 2选自
Figure PCTCN2022095436-appb-000102
Figure PCTCN2022095436-appb-000103
Figure PCTCN2022095436-appb-000104
其他变量如本申请所定义。
在一些实施方案中，R 2选自甲氧基、甲氧基乙氧基、甲基氨基、二甲基氨基、
Figure PCTCN2022095436-appb-000105
Figure PCTCN2022095436-appb-000106
Figure PCTCN2022095436-appb-000107
其他变量如本申请所定义。
在一些实施方案中，R 2选自
Figure PCTCN2022095436-appb-000108
Figure PCTCN2022095436-appb-000109
Figure PCTCN2022095436-appb-000110
其他变量如本申请所定义。
在一些实施方案中，R 3选自-OCF 2H，其中所述-OCF 2H任选地被卤素取代；其他变量如本申请所定义。
在一些实施方案中，R 3选自-OCF 2H，其中所述-OCF 2H任选地被氟、氯、溴、碘取代；其他变量如本申请所定义。例如，R 3选自-OCF 2Cl、-OCF 2Br、-OCF 2I、-OCF 3。
在一些实施方案中，R 3选自-OCF 2Cl；其他变量如本申请所定义。
在一些实施方案中，
R 1选自
Figure PCTCN2022095436-appb-000111
其中所述
Figure PCTCN2022095436-appb-000112
任选地被一个或多个R a’取代；
环A选自含有1个或2个选自N或O原子的杂原子的5元杂芳基；
环B选自含有1个或2个选自N或O原子的杂原子的5元或6元杂环烷基、或含有1个或2个N原子的5元杂芳基；
R 2选自3～10元杂环烷基，其中所述3～10元杂环烷基任选地被一个或多个R b取代，所述杂环烷基包含1、2、3或4个独立选自-O-、-NH-或N的杂原子或杂原子团；
R 3选自-OCF 2Cl；
R a’选自
Figure PCTCN2022095436-appb-000113
C 1-6烷基、3～8元环烷基或被一个或多个羟基或卤素取代的C 1-6烷基；
R b选自羟基、氨基、氰基、卤素、
Figure PCTCN2022095436-appb-000114
C 1-6烷基、C 1-6烷氧基或被一个或多个羟基或卤素取代的C 1-6烷基。
在一些实施方案中，
R 1选自
Figure PCTCN2022095436-appb-000115
其中所述
Figure PCTCN2022095436-appb-000116
任选地被一个或多个R a’取代；
X、Y和Z各自独立地选自CH或N，且X、Y和Z中至少有一个选自CH；
R 2选自3～10元杂环烷基，其中所述3～10元杂环烷基任选地被一个或多个R b取代；
R 3选自-OCF 2Cl；
R a和R a’各自独立地选自卤素、C 1-6烷基、3～6元环烷基或被1个、2个或3个羟基取代的C 1-6烷基；
R b选自羟基、氰基、卤素、
Figure PCTCN2022095436-appb-000117
C 1-6烷基、C 1-6烷氧基、或被一个或多个羟基或卤素取代的C 1-6烷基；
所述杂环烷基分别包含1、2、3或4个独立选自-O-、-NH-或N的杂原子或杂原子团。
在一些实施方案中，所述“一个或多个”选自一个、两个、三个、四个、五个或六个。在一些实施方案中，所述“一个或多个”选自一个、两个或三个。在一些实施方案中，所述“一个或多个”选自一个或两个。
本申请还有一些实施方案是由上述各变量任意组合而来。
另一方面，本申请提供了式(III)化合物、式(IV)化合物或其药学上可接受的盐，
Figure PCTCN2022095436-appb-000118
其中，
R 1以及R 2的定义如前所述。
另一方面，本申请提供了式(III-A)化合物、式(III-B)化合物、式(IV-A)化合物或其药学上可接受的盐，
Figure PCTCN2022095436-appb-000119
其中，
Figure PCTCN2022095436-appb-000120
任选地被一个R a’取代，
Figure PCTCN2022095436-appb-000121
任选地被一个或两个R a’取代；
R 2、R a、R a’、X、Y、Z、环A及环B的定义如前所述。
在一些实施方案中，
Figure PCTCN2022095436-appb-000122
的定义分别如前R 1所定义。
另一方面，本申请提供了式(V)化合物、式(VI)化合物、式(VII)化合物、式(VIII)化合物、式(IX)化合物、式(X)化合物或其药学上可接受的盐，
Figure PCTCN2022095436-appb-000123
其中，
R 2、R a、R a’以及环B的定义如前所述。
另一方面，本申请提供了以下化合物或其药学上可接受的盐，
Figure PCTCN2022095436-appb-000124
Figure PCTCN2022095436-appb-000125
Figure PCTCN2022095436-appb-000126
Figure PCTCN2022095436-appb-000127
Figure PCTCN2022095436-appb-000128
另一方面，本申请提供了以下化合物或其药学上可接受的盐，
Figure PCTCN2022095436-appb-000129
Figure PCTCN2022095436-appb-000130
Figure PCTCN2022095436-appb-000131
另一方面，本申请还提供药物组合物，其包含本申请的上述化合物或其药学上可接受的盐。在一些实施方案中，本申请的药物组合物还包括药学上可接受的辅料。
另一方面，本申请还提供一种治疗和/或预防BCR-ABL相关疾病的方法，包括对需要该治疗的哺乳动物(优选人类)给予治疗有效量的本申请的上述化合物或其药学上可接受的盐、或其药物组合物。
另一方面，本申请还提供了本申请的上述化合物或其药学上可接受的盐、或其药物组合物在制备治疗和/或预防BCR-ABL相关疾病的药物中的用途。
另一方面，本申请还提供了本申请的上述化合物或其药学上可接受的盐、或其药物组合物在治疗和/或预防BCR-ABL相关疾病中的用途。
另一方面，本申请还提供了一种用于治疗和/或预防BCR-ABL相关疾病的本申请的上述化合物、其药学上可接受的盐、或其药物组合物。
在一些实施方案中，所述BCR-ABL相关疾病选自癌症，例如慢性髓细胞白血病。
本申请的化合物具备良好的细胞增殖抑制活性(包括K562细胞以及T315I突变细胞)、良好的体内药代动力学性质，并且毒性小，对hERG钾通道抑制作用很弱，有较好的安全性。
定义
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
本申请中的某些结构单元或者基团中的共价键未与具体的原子连接时，表示该共价键可以与该结构单元或者基团中的任意原子连接，只要不违背价键连接规则。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。“任选被取代的”表示取代或未取代的，例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH 2CH 3)、单取代的(如CH 2CH 2F)、多取代的(如CHFCH 2F、CH 2CHF 2等)或完全被取代的(CF 2CF 3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
本文中的C m-n是该部分具有给定范围m-n中的整数个碳原子。例如“C 1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。例如C 1-3是指该基团可具有1个碳原子、2个碳原子、3个碳原子。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被2个R所取代，则每个R都有独立的选项。
当一个取代基的键交叉连接到一个环上的两个原子之间的连接键时，这种取代基可以与这个环上的任意原子相键合。例如，结构单元
Figure PCTCN2022095436-appb-000132
表示其可在环己基或者环己二烯上的任意一个位置发生取代。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“羟基”指-OH基团。
术语“氨基”指-NH 2基团。
术语“氰基”指-CN基团。
术语“烷基”是指通式为C nH 2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C 1- 6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。类似地，烷氧基、烷基氨基、二烷基氨基、烷基磺酰基和烷硫基的烷基部分(即烷基)具有上述相同定义。又例如，术语“C 1- 3烷基”指含有1至3个碳原子的烷基(例如甲基、乙基、丙基和异丙基)。
术语“烷氧基”指-O-烷基。
术语“环烷基”指完全饱和的并且可以以呈单环、桥环或螺环存在的碳环。除非另有指示，该碳环通常为3至10元环。环烷基非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、降冰片基(双 环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基、二环[1.1.1]戊-1-基等。例如，C 3-4环烷基包括环丙基和环丁基。
术语“杂环基”是指完全饱和的或部分不饱和的(但不是完全不饱和的杂芳族)并且可以以单环、桥环或螺环存在的非芳族环。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的3至10元环，或者4至6元环。杂环基的非限制性实例包括但不限于环氧乙烷基、四氢呋喃基、二氢呋喃基、3,4-二氢吡喃基、3,6-二氢吡喃基、吡咯烷基、N-甲基吡咯烷基、二氢吡咯基、哌啶基、哌嗪基、吡唑烷基、4H-吡喃基、吗啉基、硫代吗啉基、四氢噻吩基、2-氧杂-7-氮杂螺[3.5]壬烷基、2-氧杂-6-氮杂螺[3.3]庚烷基、3-氮杂双环[3.1.0]己烷基等。
术语“杂环烷基”是指完全饱和的并且可以以单环、桥环或螺环存在的环状基团。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的3至10元环，或者4至6元环。3元杂环烷基的实例包括但不限于环氧乙烷基、环硫乙烷基、环氮乙烷基，4元杂环烷基的非限制性实例包括但不限于吖丁啶基、噁丁环基、噻丁环基，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基、1,4-二噻烷基，7元杂环烷基的实例包括但不限于氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基。优选为具有4、5或6个环原子的单环杂环烷基。
术语“单杂环基”是指完全饱和的或部分不饱和的(但不是完全不饱和的杂芳族)并且仅以一个环存在的非芳族环。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的3至10元环，或者4至6元环。单杂环基的非限制性实例包括但不限于环氧乙烷基、四氢呋喃基、二氢呋喃基、3,4-二氢吡喃基、3,6-二氢吡喃基、吡咯烷基、N-甲基吡咯烷基、二氢吡咯基、哌啶基、哌嗪基、吡唑烷基、4H-吡喃基、吗啉基、硫代吗啉基、四氢噻吩基等。
术语“单杂环烷基”是指完全饱和的单杂环基。
术语“桥杂环基”是指完全饱和的或部分不饱和的，并且两个环共用两个或两个以上原子的5～14元多环，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子选自N、O、S(O) n(其中n为0、1或2)的杂原子，其余环原子为碳。优选为6～14元，更优选为6～10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环，优选为双环或三环，更优选为双环。桥杂环的非限制性实例包括：
Figure PCTCN2022095436-appb-000133
Figure PCTCN2022095436-appb-000134
等。
术语“桥杂环烷基”是指完全饱和的桥杂环基。
术语“螺杂环基”是指完全饱和的或部分不饱和的(但不是完全不饱和的)螺环中一个或多个环原子选自硫、氧和/或氮的杂原子(优选1或2个杂原子)，其余环原子为碳。优选为6至14元，更优选为6至10元。根据环与环之间共用螺原子的数目将螺杂环分为单螺杂环、双螺杂环或多螺杂环，优选为单螺杂环或双螺杂环，更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环。螺杂环的非限制性实例包括
Figure PCTCN2022095436-appb-000135
等。
术语“螺杂环烷基”是指完全饱和的螺杂环基。
术语“杂芳基”是指单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C，并且具有至少一个芳香环。优选的杂芳基具有单个5至8元环，或包含6至14个，尤其是6至10个环原子的多个稠合环。杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三唑基、三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基等。
在本申请中，基团
Figure PCTCN2022095436-appb-000136
表示环A和环B通过共用键形成双环结构，其中共用键可以是单键，也可以是双键。
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“药学上可接受的”是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2022095436-appb-000137
和楔形虚线键
Figure PCTCN2022095436-appb-000138
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022095436-appb-000139
和直形虚线键
Figure PCTCN2022095436-appb-000140
表示立体中心的相对构型，用波浪线
Figure PCTCN2022095436-appb-000141
表示楔形实线键
Figure PCTCN2022095436-appb-000142
或楔形虚线键
Figure PCTCN2022095436-appb-000143
或用波浪线
Figure PCTCN2022095436-appb-000144
表示直形实线键
Figure PCTCN2022095436-appb-000145
和直形虚线键
Figure PCTCN2022095436-appb-000146
可以通过手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。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，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)、碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，比如d 3-甲基表示甲基上的三个氢原子全部被氘原子取代，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，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。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
某些同位素标记的本申请化合物(例如用 3H及 14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即 3H)和碳-14(即 14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如 15O、 13N、 11C和 18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。
此外，用较重同位素(诸如氘(即 2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代，所有这样的形式的化合物包含于本申请的范围内。
在本文中，除非上下文另有明确规定，否则单数术语涵盖复数指代物，反之亦然。类似地，除非上下文另有明确指示，词语“或”意在包括“和”。
除非另有说明，在本文中，参数值应当被理解为由术语“约”修饰。当用术语“约”描述本申请的参数时，术语“约”表示存在的误差值，例如表示在某一特定值的±5％、例如±1％或±0.1％的范围内变化。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本文中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
本申请化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括如对映异构体和非对映异构体。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
本申请化合物的治疗剂量可根据例如以下而定：治疗的具体用途、给予化合物的方式、患者的健康和状态，以及签处方医师的判断。本申请化合物在药用组合物中的比例或浓度可不固定，取决于多种因素，它们包括剂量、化学特性(例如疏水性)和给药途径。例如可通过含约0.1％w/v～10％w/v该化合物的生理缓冲水溶液提供本申请化合物，用于肠胃外给药。某些典型剂量范围为约1μg/kg～约1g/kg体重/日。在某些实施方案中，剂量范围为约0.01mg/kg～约100mg/kg体重/日。剂量很可能取决于此类变量，如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。可通过由体外或动物模型试验系统导出的剂量-反应曲线外推，得到有效剂量。
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本领域合成路线规划中的一个重要考量因素是为反应性官能团(如本申请中的氨基)选择合适的保护基，例如，可参考Greene's Protective Groups in Organic Synthesis(4th Ed).Hoboken,New Jersey:John Wiley&Sons,Inc.
本申请式(I)的化合物可以由有机合成领域技术人员通过以下路线来制备：
Figure PCTCN2022095436-appb-000147
其中，
R 1、R 2以及R 3的定义如上所述，且R 2不为氢。
本申请采用下述缩略词：SOCl 2代表氯化亚砜；TEA代表三乙胺；DMSO代表二甲亚砜；THF代表四氢呋喃。
具体实施方式
为清楚起见，进一步用实施例来阐述本发明，但是实施例并非限制本申请的范围。对本领域的技术人员而言，在不脱离本发明精神和范围的情况下，针对本发明具体实施方式进行各种变化和改进将是显而易见的。本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。
实施例1：化合物1的制备
Figure PCTCN2022095436-appb-000148
步骤A：化合物1-1的制备
向500mL三口瓶中依次加入甲苯(300mL)和5-溴-6-氯烟酸(15.0g)，接着室温下向这一体系中滴加氯化亚砜(14.79g)，加毕，升温至70-80℃下反应4h，停止反应，减压浓缩后得褐色油状物；向其中加入二氯甲烷(300mL)，开启搅拌并向体系中滴加4-(氯二氟甲氧基)苯胺(12.28g)；滴毕，滴加三乙胺(12.58g)；滴毕，室温下反应4h。反应结束后，向上述反应液加入饱和碳酸氢钠水溶液(100mL)，搅拌10min后过滤并收集滤饼；将母液分液后得有机相，加饱和氯化钠水溶液(100mL)搅拌后分液，得有机相，将滤饼加入到有机相中一起减压浓缩得残余物，经硅胶柱层析纯化，获得20.44g化合物1-1。
步骤B：化合物1-2的制备
依次向50mL封管中加入异丙醇(10mL)、上述步骤A所得化合物1-1(1.0g)、(S)-3-甲氧基吡咯烷盐酸盐(0.334g)，N,N-二异丙基乙胺(1.004g)和磁子，封口后将封管置入微波反应器中140℃下反应1.5h。降至室温后，向反应液中加入乙酸乙酯(15mL)和饱和氯化钠水溶液(15mL)搅洗后分液，收集有机相，无水硫酸钠干燥，抽滤，减压浓缩，经硅胶柱层析纯化，得0.8g化合物1-2。MS(ESI,[M-H] -)m/z:474.0.
步骤C：化合物1-3的制备
依次向100mL三颈瓶中加入4-溴吡啶-2(1H)-酮(2.0g)和无水THF(20mL)，冰浴冷却至0℃后分批加入60％氢化钠(0.919g)，氮气置换3次后移至室温搅拌1h。冰浴下缓慢向反应液中加入碘甲烷(3.26g)，室温反应过夜。向反应液中加入水(10mL)淬灭反应，并加入乙酸乙酯(40mL)萃取，分出有机层，水层再用乙酸乙酯(20mL)萃取两次。将有机层合并，用饱和氯化钠洗涤，并用无水硫酸钠干燥。减压蒸除溶剂，得化合物1-3(1.82g)。MS(ESI,[M+H] +)m/z:188.0.
步骤D：化合物1-4的制备
依次向10mL微波管中加入1,4-二氧六环(5mL)、上述步骤C所得化合物1-3(142mg)、联硼酸频那醇酯(160mg)、乙酸钾(124mg)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(31mg)，加毕，氮气置换后升温至90℃下反应4h，停止反应并降至室温，得到的反应液不经分离纯化，直接用于下步反应。
步骤E：化合物1的制备
向上述步骤D所得反应液中，依次加入化合物1-2(200mg)、碳酸钾(174mg)、去离子水(1mL)，四(三苯基膦)钯(48mg)；加毕，氮气置换后将微波管封口，置于微波反应器中，升温至140℃下反应1.5h。降至室温后将上述反应过滤，收集母液，经硅胶柱层析纯化，得到123mg化合物1。
1H NMR(500MHz,DMSO-d 6)δ(ppm)10.20(s,1H),8.75(d,J＝2.3Hz,1H),8.06(d,J＝2.3Hz,1H),7.87(d,J＝8.9Hz,2H),7.75(d,J＝6.9Hz,1H),7.34(d,J＝8.6Hz,2H),6.39(s,1H),6.28(dd,J＝7.0,2.0Hz,1H),3.96(dd,J＝5.6,3.0Hz,1H),3.54–3.41(m,5H),3.37–3.34(m,1H),3.26(d,J＝12.0Hz,1H),3.20(s,3H),2.03–1.94(m,1H),1.94–1.85(m,1H).MS(ESI,[M+H] +)m/z:505.0.
实施例2：化合物2的制备
Figure PCTCN2022095436-appb-000149
步骤A：化合物2-1的制备
参照实施例1步骤B的制备方法，将化合物1-1与(R)-3-甲氧基吡咯烷盐酸盐反应得到中间体化合物2-1。MS(ESI,[M+H] +)m/z:476.1.
步骤B：化合物2的制备
参照实施例1步骤E的制备方法，将上述步骤A制备得到的化合物2-1加至化合物1-4的反应液中，反应得到化合物2。
1H NMR(500MHz,DMSO-d 6)δ(ppm)10.20(s,1H),8.75(d,J＝2.3Hz,1H),8.06(d,J＝2.3Hz,1H),7.91–7.82(m,2H),7.75(d,J＝6.9Hz,1H),7.35(d,J＝8.6Hz,2H),6.40(d,J＝2.0Hz,1H),6.28(dd,J＝6.9,2.0Hz,1H),4.01–3.93(m,1H),3.54–3.40(m,5H),3.26(d,J＝12.0Hz,1H),3.37–3.34(m,1H),3.20(s,3H),2.03–1.95(m,1H),1.95–1.85(m,1H).MS(ESI,[M+H] +)m/z:505.1.
实施例3：化合物3的制备
Figure PCTCN2022095436-appb-000150
步骤A：化合物3-1的制备
参照实施例1步骤B的制备方法，将化合物1-1与盐酸氮杂环丁烷反应得到中间体化合物3-1。MS(ESI,[M+H] +)m/z:431.9.
步骤B：化合物3的制备
参照实施例1步骤E的制备方法，将上述步骤A制备得到的化合物3-1加至化合物1-4的反应液中，反应得到化合物3。
1H NMR(500MHz,DMSO-d 6):δ10.22(s,1H),8.75(d,J＝2.0Hz,1H),8.02(d,J＝2.0Hz,1H),7.86(d,J＝9.0Hz,2H),7.75(d,J＝9.0Hz,1H),7.34(d,J＝9.0Hz,2H),6.42(d,J＝1.0Hz,1H),6.32(m,1H),3.89(t,J＝7.5Hz,4H),3.47(s,3H),2.22(m,2H).HRMS(ESI,[M+H] +)m/z:461.12323.
实施例4：化合物4的制备
Figure PCTCN2022095436-appb-000151
步骤A：化合物4-1的制备
参照实施例1步骤B的制备方法，将化合物1-1与(S)-3-氯吡咯烷盐酸盐反应得到中间体化合物4-1。MS(ESI,[M+H] +)m/z:480.00.
步骤B：化合物4的制备
参照实施例1步骤E的制备方法，将上述步骤A制备得到的化合物4-1加至化合物1-4的反应液中，反应得到化合物4。
1H NMR(500MHz,DMSO-d 6):δ10.24(s,1H),8.77(d,J＝2.5Hz,1H),8.09(d,J＝2.5Hz,1H),7.87(m,2H),7.77(d,J＝7.0Hz,1H),7.34(d,J＝9.0Hz,2H),6.43(s,1H),6.30(dd,J＝2.0Hz,7.0Hz,1H),4.80(t,J＝2.0Hz,1H),3.84(dd,J＝4.5Hz,13.0Hz,1H),3.68(m,1H),3.50(s,3H),3.41(m,2H),2.34(m,1H),2.11(m,1H).HRMS(ESI,[M+H] +)m/z:509.10003.
实施例5：化合物5的制备
Figure PCTCN2022095436-appb-000152
步骤A：化合物5-1的制备
参照实施例1步骤B的制备方法，将化合物1-1与2-氧杂-6-氮杂螺[3.3]庚烷盐酸盐反应得到中间体化合物5-1。MS(ESI,[M+H] +)m/z:474.1.
步骤B：化合物5的制备
参照实施例1步骤E的制备方法，将上述步骤A制备得到的化合物5-1加至化合物1-4的反应液中，反应得到化合物5。
1H NMR(500MHz,DMSO-d 6):δ10.22(s,1H),8.76(d,J＝2.5Hz,1H),8.03(d,J＝2.0Hz,1H),7.86(d,J＝9.5Hz,2H),7.76(d,J＝7.0Hz,1H),7.35(d,J＝9.0Hz,2H),6.42(d,J＝1.5Hz,1H),6.30(m,1H),4.64(s,4H),4.07(s,4H),3.49(s,3H).HRMS(ESI,[M+H] +)m/z:503.13412.
实施例6：化合物6的制备
Figure PCTCN2022095436-appb-000153
步骤A：化合物6-1的制备
参照实施例1步骤B的制备方法，将化合物1-1与3-氟氮杂环丁烷盐酸盐反应得到中间体化合物6-1。MS(ESI,[M+H] +)m/z:450.0.
步骤B：化合物6的制备
参照实施例1步骤E的制备方法，将上述步骤A制备得到的化合物6-1加至化合物1-4的反应液中，反应得到化合物6。
1H NMR(500MHz,DMSO-d 6)δ10.27(s,1H),8.78(s,1H),8.09(s,1H),7.86(d,J＝9.1Hz,2H),7.79(d,J＝6.9Hz,1H),7.35(d,J＝9.0Hz,2H),6.46(s,1H),6.34(d,J＝8.9Hz,1H),5.38(d,J＝55.1Hz,1H),4.18-4.25(m,2H),3.93-3.98(m,2H),3.48(s,3H).HRMS(ESI,[M+H] +)m/z:479.11256.
实施例7：化合物7的制备
Figure PCTCN2022095436-appb-000154
步骤A：化合物7-1的制备
参照实施例1步骤B的制备方法，将化合物1-1与吗啉反应得到中间体化合物7-1。MS(ESI,[M+H] +)m/z:462.0.
步骤B：化合物7的制备
参照实施例1步骤E的制备方法，将化合物7-1加至1-4的反应液中，反应得到7。
1H NMR(500MHz,DMSO-d 6)δ(ppm)10.37(s,1H),8.80(d,J＝2.3Hz,1H),8.17(d,J＝2.3Hz,1H),7.91–7.85(m,2H),7.78(d,J＝7.0Hz,1H),7.36(d,J＝8.6Hz,2H),6.68(d,J＝1.9Hz,1H),6.52(dd,J＝7.0,2.0Hz,1H),3.67–3.58(m,4H),3.47(s,3H),3.28(t,J＝4.6Hz,4H).MS(ESI,[M+H] +)m/z:491.1.
实施例8：化合物8的制备
Figure PCTCN2022095436-appb-000155
步骤A：化合物8-1的制备
参照实施例1步骤C的制备方法，将4-溴吡啶-2(1H)-酮与2-碘乙烷-1-醇反应得到中间体化合物8-1。
1H NMR(500MHz,DMSO-d 6)δ7.57(d,J＝7.2Hz,1H),6.70(d,J＝2.1Hz,1H),6.43(d,J＝7.2Hz,1H),4.88(t,J＝5.4Hz,1H),3.91(t,J＝5.4Hz,2H),3.59(q,J＝5.4Hz,2H).MS(ESI,[M+H] +)m/z:218.03.
步骤B：化合物8-2的制备
参照实施例1步骤D的制备方法，将化合物8-1与联硼酸频那醇酯反应得到中间体化合物8-2的反应液，不经分离纯化，直接用于下步反应。
步骤C：化合物8的制备
参照实施例1步骤E的制备方法，将化合物7-1加至化合物8-2的反应液中，反应得到化合物8。
1H NMR(500MHz,DMSO-d 6)δ10.33(s,1H),8.79(d,J＝2.2Hz,1H),8.17(d,J＝2.2Hz,1H),7.87(d,J＝9.0Hz,2H),7.68(d,J＝7.0Hz,1H),7.36(d,J＝8.8Hz,2H),6.70–6.61(m,1H),6.55–6.45(m,1H),4.89(t,J＝5.3Hz,1H),3.98(t,J＝5.4Hz,2H),3.70–3.65(m,2H),3.64–3.60(m,4H),3.28(t,J＝4.5Hz,4H).HRMS(ESI,[M+H] +)m/z:521.1423.
实施例9：化合物9的制备
Figure PCTCN2022095436-appb-000156
步骤A：化合物9-1的制备
依次向100mL三颈瓶中加入4-溴吡啶-2(1H)-酮(500mg)和无水四氢呋喃(10mL)，冰浴冷却至0℃后，分批加入60％氢化钠(230mg)，氮气置换3次后移至室温搅拌1h。冰浴下缓慢向反应液中加入碘乙烷(896mg)，油浴升温至70℃，反应6h。向反应液中加入水(10mL)淬灭反应，并加入乙酸乙酯(15mL)萃取，分出有机层，水层再用乙酸乙酯(15mL×2)萃取。将有机层合并，用饱和氯化钠洗涤，并用无水硫酸钠干燥。减压蒸除溶剂，得化合物9-1(200mg)。MS(ESI,[M+H] +)m/z:202.0.
步骤B：化合物9-2的制备
参照实施例1步骤D的制备方法，将化合物9-1与联硼酸频那醇酯反应得到中间体化合物9-2，不经分离纯化，直接用于下步反应。
步骤C：化合物9的制备
参照实施例1步骤E的制备方法，将化合物7-1加至化合物9-2的反应液中，反应得到化合物9。
1H NMR(500MHz,DMSO-d 6)δ10.32(s,1H),8.79(d,J＝2.3Hz,1H),8.17(d,J＝2.4Hz,1H),7.91–7.84(m,2H),7.78(d,J＝7.0Hz,1H),7.36(d,J＝8.7Hz,2H),6.66(d,J＝2.1Hz,1H),6.53(dd,J＝7.0,2.0Hz,1H),3.99–3.91(m,2H),3.68–3.58(m,4H),3.28(t,J＝4.6Hz,4H),1.24(t,J＝7.1Hz,3H).MS(ESI,[M+H] +)m/z:505.3.
实施例10：化合物10的制备
Figure PCTCN2022095436-appb-000157
步骤A：化合物10-1的制备
依次向50mL茄形瓶中加入4-溴吡啶-2(1H)-酮4-溴-2-羟基吡啶(500mg)、环丙基硼酸(494mg)、吡啶(1137mg)、醋酸铜(522mg)、碳酸铯(936mg)和甲苯(10mL)，空气下油浴升温至95℃反应过夜。次日，用乙酸乙酯(10mL)稀释反应液，硅藻土抽滤，滤液用水洗两次后用饱和氯化钠洗涤，无水硫酸钠干燥。减压蒸除溶剂，残留物经硅胶柱层析分离纯化，得化合物10-1(61mg)。MS(ESI,[M+H] +)m/z:214.0.
步骤B：化合物10-2的制备
参照实施例1步骤D的制备方法，将化合物1-3替换为上述步骤制备得到的化合物10-1，反应得到化合物10-2的反应液，直接用于下一步反应。
步骤C：化合物10的制备
参照实施例1步骤E的制备方法，将化合物7-1加至化合物10-2的反应液中，反应得到化合物10。
1H NMR(500MHz,DMSO-d 6)δ10.33(s,1H),8.78(s,1H),8.16(s,1H),7.86(d,J＝8.6Hz,2H),7.61(d,J＝7.2Hz,1H),7.36(d,J＝8.6Hz,2H),6.65(s,1H),6.48(d,J＝7.3Hz,1H),3.70–3.57(m,4H),3.38(s,1H),3.27(s,4H),1.11–0.95(m,2H),0.93–0.79(m,2H).HRMS(ESI,[M+H] +)m/z:517.1451.
实施例11：化合物11的制备
Figure PCTCN2022095436-appb-000158
步骤A：化合物11-1的制备
参照实施例1步骤B的制备方法，将化合物1-1与(R)-吡咯烷-3-醇盐酸盐反应得到中间体化合物11-1。
步骤B：化合物11的制备
参照实施例1步骤E的制备方法，将上述步骤A制备得到的化合物11-1加至化合物1-4的反应液中，反应得到化合物11。
1H NMR(500MHz,DMSO-d 6)δ10.20(s,1H),8.75(s,1H),8.05(d,J＝5.0Hz,1H),8.86(d,J＝10.0Hz,2H),7.75(d,J＝5.0Hz,1H),7.34(d,J＝10.0Hz,2H),6.38(s,1H),6.28-6.27(m,1H),4.91(s,1H),4.26(s,1H),3.57-3.56(m,1H),3.47(s,3H),3.44-3.41(m,1H),3.36-3.35(m,1H),3.06(d,J＝10.0Hz,1H)1.92-1.85(m,1H),1.80-1.77(m,1H).HRMS(ESI,[M+H] +)m/z:491.1302.
实施例12：化合物12的制备
Figure PCTCN2022095436-appb-000159
步骤A：化合物12-1的制备
参照实施例1步骤D的制备方法，4-溴吡啶-2(1H)-酮与联硼酸频那醇酯反应得到中间体化合物12-1的反应液，直接用于下一步反应。
步骤B：化合物12的制备
参照实施例1步骤E的制备方法，将化合物11-1加至化合物12-1的反应液中，反应得到化合物12。
1H NMR(500MHz,DMSO-d 6)δ11.21(br,1H),10.20(s,1H),8.75(s,1H),8.05(s,1H),7.87-7.86(m,2H),7.42(d,J＝10.0Hz,1H),7.34(d,J＝10.0Hz,2H),6.31(s,1H),6.22(d,J＝6.6Hz,1H),4.92(s,1H),4.26(s,1H),3.60-3.54(m,1H),3.50-3.43(m,1H),3.42-3.40(m,1H),3.06(d,J＝10.0Hz,1H),1.91-1.87(m,1H),1.80-1.78(m,1H).HRMS(ESI,[M+H] +)m/z:477.1139.
实施例13和14：化合物13和14的制备
Figure PCTCN2022095436-appb-000160
步骤A：化合物13-1的制备
参照实施例1步骤B的制备方法，将化合物1-1与氮杂环丁烷-2-基甲醇盐酸盐反应得到化合物13-1。MS(ESI,[M-H] -)m/z:460.0.
步骤B：化合物13-2的制备
参照实施例1步骤E的制备方法，将上述步骤A制备得到的化合物13-1加至化合物1-4的反应液中，反应得到化合物13-2。
步骤C：化合物13和14的制备
化合物13-2经超临界流体色谱仪(型号：waters SFC150G)拆分，分离柱：CHIRALART Cellulose-SC柱，流动相为：25vol％乙醇和75vol％二氧化碳，流速为：60mL/min，制备得到t R＝5.484min的化合物13；
1H NMR(500MHz,DMSO-d 6)δ10.23(s,1H),8.74(d,1H),8.04(d,J＝2.2Hz,1H),7.86(d,J＝9.1Hz,2H),7.76(d,J＝6.9Hz,1H),7.35(d,J＝8.9Hz,2H),6.46(s,1H),6.39(dd,J＝6.9,1.7Hz,1H),4.88(t,J＝5.8Hz,1H),4.60-4.43(m,1H),3.86-3.75(m,1H),3.73-3.65(m,1H),3.63-3.54(m,1H),3.48(s,3H),3.44-3.37(m,1H),2.28-2.10(m,2H).HRMS(ESI,[M+H] +)m/z:491.12806.
并且，制备得到t R＝9.467min的化合物14。
1H NMR(500MHz,DMSO-d 6)δ10.23(s,1H),8.74(d,1H),8.04(d,J＝2.2Hz,1H),7.86(d,J＝9.1Hz,2H),7.76(d,J＝6.9Hz,1H),7.35(d,J＝8.9Hz,2H),6.46(s,1H),6.39(dd,J＝6.9,1.7Hz,1H),4.88(t,J＝5.8Hz,1H),4.60-4.43(m,1H),3.86-3.75(m,1H),3.73-3.65(m,1H),3.63-3.54(m,1H),3.48(s,3H),3.44-3.37(m,1H),2.28-2.10(m,2H).HRMS(ESI,[M+H] +)m/z:491.12806.
实施例15：化合物15的制备
Figure PCTCN2022095436-appb-000161
步骤A：化合物15-1的制备
参照实施例1步骤B的制备方法，将化合物1-1与四氢吡咯反应得到中间体化合物15-1。
步骤B：化合物15的制备
参照实施例1步骤E的制备方法，将上述步骤A制备的化合物15-1加至化合物1-4的反应液中，反应得到化合物15。
1H NMR(500MHz,DMSO-d 6)δ10.19(s,1H),8.75(d,J＝2.1Hz,1H),8.04(d,J＝2.1Hz,1H),7.86(d,J＝9.0Hz,2H),7.73(d,J＝6.9Hz,1H),7.34(d,J＝8.8Hz,2H),6.39(d,J＝1.3Hz,1H),6.32–6.21(m,1H),3.47(s,3H),3.31(s,4H),1.82(s,4H).HRMS(ESI,[M+H] +)m/z:475.13331.
实施例16：化合物16的制备
Figure PCTCN2022095436-appb-000162
步骤A：化合物16-1的制备
参照实施例1步骤B的制备方法，将化合物1-1和(R)-3-氟吡咯烷盐酸盐反应制备得到化合物16-1。MS(ESI,[M+H] +)m/z:464.02.
步骤B：化合物16的制备
参照实施例1步骤E的制备方法，将上述步骤A制备的化合物16-1加至化合物1-4的反应液中，反应得到化合物16。
1H NMR(500MHz,DMSO-d 6)δ10.23(s,1H),8.77(d,J＝2.3Hz,1H),8.08(d,J＝2.3Hz,1H),7.87(d,J＝9.1Hz,2H),7.76(d,J＝6.9Hz,1H),7.35(d,J＝8.9Hz,2H),6.43(s,1H),6.29(dt,J＝10.9,5.4Hz,1H),5.35(d,J＝53.4Hz,1H),3.76–3.62(m,1H),3.54(tt,J＝13.9,6.9Hz,1H),3.48(s,3H),3.43(dt,J＝19.2,6.0Hz,2H),2.22–1.95(m,2H).MS(ESI,[M+H] +)m/z:493.29
实施例17：化合物17的制备
Figure PCTCN2022095436-appb-000163
步骤A：化合物17-1的制备
参照实施例1步骤B的制备方法，将化合物1-1和(S)-3-氟吡咯烷盐酸盐反应制备得到化合物17-1。MS(ESI,[M+H] +)m/z:464.02.
步骤B：化合物17的制备
参照实施例1步骤E的制备方法，将上述步骤A制备的化合物17-1加至化合物1-4的反应液中，反应得到化合物17。
1H NMR(500MHz,DMSO-d 6)δ10.23(s,1H),8.77(d,J＝2.3Hz,1H),8.08(d,J＝2.3Hz,1H),7.87(d,J＝9.1Hz,2H),7.76(d,J＝6.9Hz,1H),7.35(d,J＝8.9Hz,2H),6.43(s,1H),6.29(dt,J＝10.9,5.4Hz,1H),5.35(d,J＝53.4Hz,1H),3.76–3.62(m,1H),3.54(tt,J＝13.9,6.9Hz,1H),3.48(s,3H),3.43(dt,J＝19.2,6.0Hz,2H),2.22–1.95(m,2H).MS(ESI,[M+H] +)m/z:493.20.
实施例18：化合物18的制备
Figure PCTCN2022095436-appb-000164
步骤A：化合物18-1的制备
参照实施例1步骤B的制备方法，将化合物1-1和(R)-3-氯吡咯烷盐酸盐反应制备得到化合物18-1。MS(ESI,[M+H] +)m/z:479.98.
步骤B：化合物18的制备
参照实施例1步骤E的制备方法，将上述步骤A制备的化合物18-1加至化合物1-4的反应液中，反应得到化合物18。
1H NMR(500MHz,DMSO-d 6)δ10.24(s,1H),8.81(d,J＝2.0Hz,1H),8.13(d,J＝2.0Hz,1H),7.92(d,J＝9.0Hz,2H),7.78(d,J＝6.9Hz,1H),7.34(d,J＝8.7Hz,2H),6.45(s,1H),6.31(d,J＝6.7Hz,1H),4.80(s,1H),3.90(dd,J＝12.7,4.3Hz,1H),3.71(dt,J＝38.1,19.1Hz,1H),3.51(s,3H),3.46(dd,J＝22.1,11.0Hz,2H),2.36(dt,J＝13.2,11.4Hz,1H),2.15–1.97(m,1H).HRMS(ESI,[M+H] +)m/z:509.09537.
实施例19：化合物19的制备
Figure PCTCN2022095436-appb-000165
步骤A：化合物19-1的制备
参照实施例1步骤C的方法，将化合物4-溴-3-氟吡啶-2(1H)-酮与碘甲烷反应制备得到化合物19-1。MS(ESI,[M+H] +)m/z:208.02.
步骤B：化合物19-2的制备
参照实施例1步骤D的制备方法，使用化合物19-1和联硼酸频那醇酯反应得到化合物19-2的反应液，不经纯化直接用于下步反应。
步骤C：化合物19的制备
参照实施例1步骤E的制备方法，将化合物7-1加至上述步骤B制备得到的化合物19-2的反应液中，反应得到化合物19。
1H NMR(500MHz,DMSO-d 6)δ10.31(s,1H),8.83(d,J＝2.3Hz,1H),8.10(dd,J＝24.6,4.1Hz,2H),7.86(d,J＝9.1Hz,2H),7.36(d,J＝8.9Hz,2H),6.63(d,J＝7.1Hz,1H),3.66–3.54(m,4H),3.44(d,J＝8.9Hz,3H),3.39–3.34(m,4H).HRMS(ESI,[M+H] +)m/z:509.12021.
实施例20：化合物20的制备
Figure PCTCN2022095436-appb-000166
步骤A：化合物20-1的制备
参照实施例1步骤B的制备方法，将化合物1-1和3-氧杂-6-氮杂双环[3.1.1]庚烷盐酸盐反应制备得到化合物20-1。MS(ESI,[M+H] +)m/z:474.02.
步骤B：化合物20的制备
参照实施例1步骤E的制备方法，将上述步骤A制备的化合物20-1加至化合物1-4的反应液中，反 应得到化合物20。
1H NMR(500MHz,DMSO-d 6)δ10.27(d,J＝25.5Hz,1H),8.79(d,J＝2.3Hz,1H),8.05(t,J＝5.5Hz,1H),7.90–7.80(m,2H),7.75(d,J＝7.0Hz,1H),7.35(d,J＝9.0Hz,2H),6.51(d,J＝1.7Hz,1H),6.36(dd,J＝6.9,1.9Hz,1H),4.19(s,2H),3.97(s,2H),3.64(d,J＝10.1Hz,2H),3.45(s,3H),2.66(dd,J＝13.8,6.6Hz,1H),1.73(d,J＝8.1Hz,1H).HRMS(ESI,[M+H] +)m/z:503.12935.
实施例21：化合物21的制备
Figure PCTCN2022095436-appb-000167
步骤A：化合物21-1的制备
参照实施例1步骤B的制备方法，将化合物1-1和(1R,4R)-2-氧杂-5-氮杂双环[2.2.1]庚烷盐酸盐反应制备得到化合物21-1。MS(ESI,[M+H] +)m/z:474.03.
步骤B：化合物21的制备
参照实施例1步骤E的制备方法，将上述步骤A制备的化合物21-1加至化合物1-4的反应液中，反应得到化合物21。
1H NMR(500MHz,DMSO-d 6)δ10.25(s,1H),8.75(s,1H),8.07(s,1H),7.86(d,J＝8.6Hz,2H),7.73(d,J＝6.7Hz,1H),7.35(d,J＝8.3Hz,2H),6.51–6.22(m,2H),4.92(s,1H),4.53(s,1H),3.77(s,2H),3.46(s,3H),3.30(s,1H),2.80(d,J＝10.1Hz,1H),1.83(q,J＝9.3Hz,2H).HRMS(ESI,[M+H] +)m/z:503.12954.
实施例22：化合物22的制备
Figure PCTCN2022095436-appb-000168
步骤A：化合物22-1的制备
参照实施例1步骤B的制备方法，将化合物1-1和(1S,4S)-2-氧杂-5-氮杂双环[2.2.1]庚烷盐酸盐反应制备得到化合物22-1。MS(ESI,[M+H] +)m/z:474.03.
步骤B：化合物22的制备
参照实施例1步骤E的制备方法，将上述步骤A制备得到的化合物22-1加至化合物1-4的反应液中，反应得到化合物22。
1H NMR(500MHz,DMSO-d 6)δ10.25(s,1H),8.75(d,J＝2.3Hz,1H),8.07(d,J＝2.3Hz,1H),7.87(t,J＝9.1Hz,2H),7.73(d,J＝6.9Hz,1H),7.35(d,J＝8.9Hz,2H),6.45(s,1H),6.31(dd,J＝6.9,1.5Hz,1H),4.92(s,1H),4.53(s,1H),3.77(s,2H),3.47(d,J＝9.4Hz,3H),3.30(d,J＝3.4Hz,1H),2.80(d,J＝10.2Hz,1H),1.91–1.70(m,2H).HRMS(ESI,[M+H] +)m/z:503.12949.
实施例23：化合物23的制备
Figure PCTCN2022095436-appb-000169
步骤A：化合物23-1的制备
参照实施例1步骤B的制备方法，将化合物1-1和6-氧杂-3-氮杂-双环[3,1,1]庚烷烷盐酸盐反应制备得到化合物23-1。
MS(ESI,[M+H] +)m/z:474.06.
步骤B：化合物23的制备
参照实施例1步骤E的制备方法，将上述步骤A制备得到的化合物23-1加至化合物1-4的反应液中，反应得到化合物23。
1H NMR(500MHz,DMSO-d 6)δ10.26(s,1H),8.79(d,J＝2.3Hz,1H),8.08(d,J＝2.3Hz,1H),7.96–7.79(m,2H),7.74(d,J＝7.0Hz,1H),7.35(d,J＝9.0Hz,2H),6.52(d,J＝1.8Hz,1H),6.34(dd,J＝6.9,2.0Hz,1H),4.57(d,J＝6.3Hz,2H),3.80(d,J＝12.8Hz,2H),3.60(d,J＝12.7Hz,2H),3.46(s,3H),3.07–2.93(m,1H),1.79(d,J＝8.6Hz,1H).HRMS(ESI,[M+H] +)m/z:503.12984.
实施例24：化合物24的制备
Figure PCTCN2022095436-appb-000170
步骤A：化合物24-1的制备
参照实施例1步骤B的制备方法，以化合物1-1及2-氧杂-7-氮杂螺[3.5]壬烷为原料制备得到化合物24-1。MS(ESI,[M+H] +)m/z:502.10.
步骤B：化合物24的制备
参照实施例1步骤E的制备方法，将上述步骤A制备得到的化合物24-1加至化合物1-4的反应液中，反应得到化合物24。
1H NMR(500MHz,DMSO-d 6)δ10.29(s,1H),8.76(d,J＝2.3Hz,1H),8.12(d,J＝2.3Hz,1H),7.86(d,J＝9.1Hz,2H),7.76(d,J＝7.0Hz,1H),7.35(d,J＝8.8Hz,2H),6.65(d,J＝1.6Hz,1H),6.45(dd,J＝7.0,1.8Hz,1H),4.31(s,4H),3.47(s,3H),3.26–3.17(m,4H),1.84–1.76(m,4H).HRMS(ESI,[M+H] +)m/z:531.1332.
实施例25：化合物25的制备
Figure PCTCN2022095436-appb-000171
步骤A：化合物25-1的制备
参照实施例1步骤B的制备方法，以化合物1-1及3-乙腈环丁胺为原料制备得到化合物25-1。MS(ESI,[M+H] +)m/z:457.02.
步骤B：化合物25的制备
参照实施例1步骤E的制备方法，将上述步骤A制备得到的化合物25-1加至化合物1-4的反应液中，反应得到化合物25。
1H NMR(500MHz,DMSO-d 6)δ10.29(s,1H),8.79(d,J＝2.2Hz,1H),8.09(d,J＝2.3Hz,1H),7.86(d,J＝9.1Hz,2H),7.80(d,J＝6.9Hz,1H),7.35(d,J＝9.0Hz,2H),6.46(d,J＝1.8Hz,1H),6.34(dd,J＝6.9,1.9Hz,1H),4.17(t,J＝8.9Hz,2H),4.03(dd,J＝8.8,5.9Hz,2H),3.77(tt,J＝9.0,5.9Hz,1H),3.48(s,3H).HRMS(ESI,[M+H] +)m/z:486.1140.
实施例26：化合物26的制备
Figure PCTCN2022095436-appb-000172
步骤A：化合物26-1的制备
参照实施例1步骤B的制备方法，以化合物1-1及3-甲基-3-吖啶醇为原料制备得到化合物26-1。MS(ESI,[M+H] +)m/z:462.02.
步骤B：化合物26的制备
参照实施例1步骤E的制备方法，将上述步骤A制备得到的化合物26-1加至化合物1-4的反应液中， 反应得到26。
1H NMR(500MHz,DMSO-d 6)δ10.22(s,1H),8.76(d,J＝2.3Hz,1H),8.04(d,J＝2.3Hz,1H),7.90–7.83(m,2H),7.77(d,J＝6.9Hz,1H),7.35(d,J＝9.0Hz,2H),6.43(d,J＝1.9Hz,1H),6.32(dd,J＝6.9,2.0Hz,1H),5.51(s,1H),3.75(s,4H),3.48(s,3H),1.34(s,3H).HRMS(ESI,[M+H] +)m/z:491.1298.
实施例27：化合物27的制备
Figure PCTCN2022095436-appb-000173
步骤A：化合物27-1的制备
参照实施例1步骤B的制备方法，将化合物1-1和(3S,4S)-4-氟吡咯烷-3-醇盐酸盐反应制备得到化合物27-1。MS(ESI,[M+H] +)m/z:480.02.
步骤B：化合物27的制备
参照实施例1步骤E的制备方法，将上述步骤A制备得到的化合物27-1加至化合物1-4的反应液中，反应得到化合物27。
1H NMR(500MHz,DMSO-d 6)δ10.23(s,1H),8.83–8.70(m,1H),8.14–8.04(m,1H),7.86(d,J＝8.9Hz,2H),7.77(d,J＝6.9Hz,1H),7.34(d,J＝8.6Hz,2H),6.43(s,1H),6.28(d,J＝6.4Hz,1H),5.49(d,J＝3.1Hz,1H),4.98(d,J＝51.4Hz,1H),4.23(s,1H),3.83(dd,J＝42.0,13.4Hz,1H),3.62(d,J＝11.7Hz,1H),3.54–3.39(m,4H),3.18(d,J＝12.0Hz,1H).HRMS(ESI,[M+H] +)m/z:509.1248.
实施例28：化合物28的制备
Figure PCTCN2022095436-appb-000174
步骤A：化合物28-1的制备
参照实施例1步骤B的制备方法，将化合物1-1和3-氮杂双环[3.1.0]己烷盐酸盐反应制备得到化合物28-1。MS(ESI,[M+H] +)m/z:458.06.
步骤B：化合物28的制备
参照实施例1步骤E的制备方法，将上述步骤A制备得到的化合物28-1加至化合物1-4的反应液中，反应得到化合物28。
1H NMR(500MHz,DMSO-d 6)δ10.19(s,1H),8.71(d,J＝2.3Hz,1H),8.01(d,J＝2.3Hz,1H),7.85(d,J＝9.1Hz,2H),7.73(d,J＝6.9Hz,1H),7.34(d,J＝8.9Hz,2H),6.43(d,J＝1.8Hz,1H),6.25(dd,J＝6.9,1.9Hz,1H),3.67(d,J＝10.9Hz,2H),3.47(s,3H),3.34(d,J＝11.0Hz,2H),1.60–1.50(m,2H),0.58(td,J＝7.6,4.6Hz,1H),0.05(q,J＝4.0Hz,1H).HRMS(ESI,[M+H] +)m/z:487.1385.
实施例29：化合物29的制备
Figure PCTCN2022095436-appb-000175
步骤A：化合物29-1的制备
参照实施例1步骤B的制备方法，将化合物1-1和异噁唑烷盐酸盐反应制备得到化合物29-1。MS(ESI,[M+H] +)m/z:448.03.
步骤B：化合物29的制备
向实施例1步骤D所得化合物1-4的反应液中，依次加入上述步骤A所得化合物29-1(500mg)、磷酸钾(710mg)、去离子水(3mL)和二氯[1,1'-双(二叔丁基膦)二茂铁钯(II)(73mg)；加毕，氮气置换后，室温下反应6h。将反应过滤，收集母液，加入乙酸乙酯(30mL)搅洗后分液，得有机相，加入饱和氯化钠水溶液(30mL)搅洗后分液，经硅胶柱层析纯化，共得到280mg化合物29。
1H NMR(500MHz,DMSO-d 6)δ10.42(s,1H),8.81(d,J＝2.2Hz,1H),8.18(d,J＝2.2Hz,1H),7.86(d,J＝9.1Hz,2H),7.67(d,J＝7.0Hz,1H),7.36(d,J＝9.0Hz,2H),6.54(d,J＝1.8Hz,1H),6.42(dd,J＝7.0,1.9Hz,1H),3.78–3.73(m,2H),3.68(t,J＝7.3Hz,2H),3.45(s,3H),2.13(p,J＝7.3Hz,2H).HRMS(ESI,[M+H] +)m/z:477.1177.
实施例30：化合物30的制备
Figure PCTCN2022095436-appb-000176
步骤A：化合物30-1的制备
参照实施例1步骤B的制备方法，将化合物1-1和(S)-吡咯烷-3-甲腈盐酸盐反应制备得到化合物30-1。MS(ESI,[M+H] +)m/z:471.1.
步骤B：化合物30的制备
参照实施例1步骤E的制备方法，将上述步骤A制备得到的化合物30-1加至化合物1-4的反应液中，反应得到化合物30。
1H NMR(500MHz,DMSO-d 6)δ10.25(s,1H),8.78(d,J＝1.9Hz,1H),8.16–8.03(m,1H),7.87(d,J＝8.9Hz,2H),7.77(d,J＝6.9Hz,1H),7.35(d,J＝8.7Hz,2H),6.44(s,1H),6.30(dd,J＝6.9,2.1Hz,1H),3.73–3.64(m,1H),3.59–3.52(m,1H),3.48(s,3H),3.47–3.42(m,2H),3.42–3.36(m,1H),2.27–2.19(m,1H),2.19–2.09(m,1H).HRMS(ESI,[M+H] +)m/z:500.1312.
实施例31：化合物31的制备
Figure PCTCN2022095436-appb-000177
步骤A：化合物31-1的制备
参照实施例1步骤B的制备方法，将化合物1-1和(R)-3-氟吡咯烷盐酸盐反应制备得到化合物31-1。MS(ESI,[M+H] +)m/z:471.1.
步骤B：化合物31的制备
参照实施例1步骤E的制备方法，将上述步骤A制备得到的化合物31-1加至化合物1-4的反应液中，反应得到31。
1H NMR(500MHz,DMSO-d 6)δ10.25(s,1H),8.78(d,J＝2.2Hz,1H),8.10(d,J＝2.2Hz,1H),7.87(d,J＝9.0Hz,2H),7.77(d,J＝6.9Hz,1H),7.35(d,J＝8.8Hz,2H),6.44(d,J＝1.5Hz,1H),6.30(dd,J＝6.9,1.8Hz,1H),3.71–3.64(m,1H),3.59–3.52(m,1H),3.48(s,3H),3.47–3.43(m,2H),3.42–3.36(m,1H),2.29–2.20(m,1H),2.19–2.10(m,1H).HRMS(ESI,[M+H] +)m/z:500.1321.
实施例32：化合物32的制备
Figure PCTCN2022095436-appb-000178
步骤A：化合物32-1的制备
依次向35mL微波管中加入二氧六环(15mL)、化合物1-1(1g)、2-氧杂-6-氮杂螺[3.4]辛-7-酮(0.309g)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.140g)、三(二亚苄基丙酮)二钯(0.111g)以及磷酸三钾(1.030g)，氮气保护下，放入微波反应器中，加热至140℃反应4h。降至室温后将上述得到的反应液过滤，收集母液，经硅胶柱层析纯化，得到220mg化合物32-1。MS(ESI,[M+H] +)m/z:501.99.
步骤B：化合物32的制备
参照实施例1步骤E的制备方法，将上述步骤A制备得到的化合物32-1加至化合物1-4的反应液中，反应得到化合物32。
1H NMR(500MHz,DMSO-d 6)δ10.62(s,1H),8.99(d,J＝2.3Hz,1H),8.38(d,J＝2.3Hz,1H),7.88(d,J＝9.0Hz,2H),7.69(d,J＝7.0Hz,1H),7.39(d,J＝8.5Hz,2H),6.54(d,J＝2.1Hz,1H),6.23(dd,J＝7.1,2.1Hz,1H),4.71(d,J＝6.1Hz,2H),4.57(d,J＝6.1Hz,2H),4.35(s,2H),3.44(s,3H),2.74(s,2H).MS(ESI,[M+H] +)m/z:531.12415.
实施例33：化合物33的制备
Figure PCTCN2022095436-appb-000179
步骤A：化合物33-1的制备
依次向一个25mL单口瓶中加入纯化水(8mL)和4-溴-5-氯吡啶-2-氨基(500mg)，搅拌，降温至0-5℃下向体系中缓慢滴加98％w/w浓硫酸水溶液(1mL)，加毕，搅拌5min后向体系中滴加亚硝酸钠的水溶液(1mL，319mg/mL)；保温反应30min，过滤，滤饼加纯化水淋洗(10mL×2)，收集滤饼，置入真空干燥箱中50℃干燥至恒重，得到420mg化合物33-1。MS(ESI,[M-H] -)m/z:205.9.
步骤B：化合物33-2的制备
依次向一个25mL单口瓶中加入N,N-二甲基甲酰胺(5mL)、上述步骤A所得化合物33-1(200mg)、无水碳酸钾(199mg)，搅拌，降温至0-5℃下向体系中缓慢滴加无水N,N-二甲基甲酰胺的碘甲烷(1mL，136mg)溶液，加毕，保温反应2h；向前述体系中加入二氯甲烷(20mL)及纯化水(10mL)，搅拌后分液得有机相，无水硫酸钠干燥，过滤，减压浓缩得到160mg化合物33-2。MS(ESI,[M+H] +)m/z:222.0.
步骤C：化合物33-3的制备
依次向35mL微波管中加入1,4-二氧六环(10mL)、化合物1-1(500mg)、联硼酸频那醇酯(367mg)、乙酸钾(236mg)以及[1,1'-双(二苯基膦)二茂铁]二氯化钯(88mg)，加毕，氮气置换后升温至140℃下反应2h，停止反应并降至室温，不经分离纯化，直接用于下步反应。
步骤D：化合物33-4的制备
依次向上述步骤C所得反应液中加入化合物33-2(282mg)、磷酸三钾(639mg)、二氯[1,1'-双(二叔丁基膦)二茂铁钯(II)(78mg)以及纯化水(2mL)，加毕，氮气置换室温下反应4h；向体系中加入乙酸乙酯(20mL)搅洗后分液，收集有机相、无水硫酸钠干燥、抽滤、减压浓缩得残余物，经硅胶柱层析纯化得到300mg化合物33-4。MS(ESI,[M-H] -)m/z:472.0.
步骤E：化合物33的制备
依次向35mL微波管中加入上述步骤D所得化合物33-4(200mg)、吗啉(44.1mg)、N,N-二异丙基乙胺(82mg)以及N-甲基吡咯烷酮(5mL)，氮气吹扫液面片刻后加盖密封，使用微波反应仪升温至160℃反应2h；待反应液冷却后向体系中加入乙酸乙酯(10mL)稀释，加入水(10mL)搅洗后分液，收集有机层，无水硫酸钠干燥、抽滤、减压浓缩得残余物，经硅胶柱层析纯化得到20mg化合物33。
1H NMR(500MHz,DMSO-d 6)δ10.29(s,1H),8.82(d,J＝2.4Hz,1H),8.16(s,1H),8.02(d,J＝2.3Hz,1H),7.90–7.81(m,2H),7.35(d,J＝8.7Hz,2H),6.64(s,1H),3.66–3.53(m,4H),3.46–3.36(m,4H),3.48(s,3H).MS(ESI,[M-H] -)m/z:523.1.
实施例34：化合物34的制备
Figure PCTCN2022095436-appb-000180
步骤A：化合物4-1的制备
参照实施例1步骤B的制备方法，将化合物1-1与8-氧杂-3-氮杂双环[3.2.1]辛烷盐酸盐反应得到中间 体化合物34-1。MS(ESI,[M+H] +)m/z:488.04.
步骤B：化合物34的制备
参照实施例1步骤E的制备方法，将上述步骤A制备得到的化合物34-1加至化合物1-4的反应液中，反应得到化合物34。
1H NMR(500MHz,DMSO-d 6)δ10.31(s,1H),8.77(d,J＝2.3Hz,1H),8.10(d,J＝2.3Hz,1H),7.86(d,J＝9.1Hz,2H),7.80(d,J＝7.0Hz,1H),7.35(d,J＝8.9Hz,2H),6.57(d,J＝1.6Hz,1H),6.37(m,J＝6.9,1.8Hz,1H),4.29(s,2H),3.48(d,J＝10.9Hz,5H),3.04(d,J＝11.4Hz,2H),1.76(m,J＝11.0,8.0Hz,4H).HRMS(ESI,[M-H] -)m/z:517.1452.
实施例35：化合物35的制备
Figure PCTCN2022095436-appb-000181
步骤A：化合物35-1的制备
参照实施例1步骤B的制备方法，将化合物1-1与3-氧杂-8-氮杂双环[3.2.1]辛烷盐酸盐反应得到中间体化合物35-1。MS(ESI,[M+H] +)m/z:488.1.
步骤B：化合物35的制备
参照实施例1步骤E的制备方法，将上述步骤A制备得到的化合物35-1加至化合物1-4的反应液中，反应得到化合物35。
1H NMR(500MHz,DMSO-d 6)δ10.31(s,1H),8.76(d,J＝2.2Hz,1H),8.11(d,J＝2.2Hz,1H),7.86(d,J＝9.0Hz,2H),7.77(d,J＝7.0Hz,1H),7.35(d,J＝8.8Hz,2H),6.64(d,J＝1.5Hz,1H),6.55–6.41(m,1H),4.19(s,2H),3.66(d,J＝10.6Hz,2H),3.55–3.41(m,5H),1.98–1.64(m,4H).HRMS(ESI,[M+H] +)m/z:517.1452.
实施例36：化合物36的制备
Figure PCTCN2022095436-appb-000182
步骤A：化合物36-1的制备
依次向250mL三口瓶中加入乙腈(80mL)、4-溴-1H-吡唑(10g)和碳酸铯(44.3g)，氮气保护，反应体系转移至冰盐浴降温至0℃，将(2-溴乙氧基)(叔丁基)二甲基硅烷(19.53g)溶解在乙腈(40mL)中，缓慢滴加到上述反应体系中，加毕，反应体系自然升温，室温搅拌过夜。向反应体系中加入乙酸乙酯(50mL)以及水(20mL)，分液收集有机相，无水硫酸钠干燥，抽滤，减压浓缩，硅胶柱层析提纯得到13g的化合物36-1。
1H NMR(500MHz,DMSO-d 6):δ7.98(s,1H),7.62(s,1H),4.27(t,J＝5.0Hz,2H),3.96(t,J＝5.0Hz,2H),0.89(s,9H),0.00(s,6H).MS(ESI,[M-(CH 3) 3C] +)m/z:247.
步骤B：化合物36-2的制备
依次向250mL三口瓶中加入二异丙胺(3.98g)和无水四氢呋喃(20mL)，氮气保护。将反应体系转移至-80℃的低温槽中，向反应体系中滴加1.6M正丁基锂的正己烷溶液(23mL)，加毕，-80℃下搅拌30min。将化合物36-1(7.5g)溶解在无水四氢呋喃(15mL)中，并缓慢滴加到上述反应体系中，加毕，-80℃下搅拌30min。将N,N-二甲基甲酰胺(3.23g)溶解在无水四氢呋喃(8mL)中，缓慢滴加到上述反应体系中，加毕，反应体系在-80℃下搅拌3h。向反应体系中加入异丙醇(5mL)淬灭反应，并将反应体系转移至室温搅拌。向反应液中加入饱和氯化铵溶液(40mL)和乙酸乙酯(100mL)，分液收集有机相，有机相用无水硫酸钠干燥，抽滤，减压浓缩，硅胶柱层析提纯得到6g的化合物36-2。MS(ESI,[M+H] +)m/z: 333.1.
步骤C：化合物36-3的制备
依次向100mL的单口瓶中加入化合物36-2(4.8g)、2-甲基四氢呋喃(10mL)、水(10mL)以及三氟乙酸(18mL)，室温搅拌30min。用饱和碳酸氢钠水溶液调节体系pH至中性，有大量气体生成。向反应体系中加入二氯甲烷(100mL)，分液收集有机相，有机相用无水硫酸钠干燥，抽滤，减压浓缩得到3.8g化合物36-3。GCMS(EI,[M-e] +)m/z:218.
步骤D：化合物36-4的制备
依次向250mL的三口瓶中加入二氯甲烷(90mL)和化合物36-3(3.8g)，反应体系用冰盐浴降温到0℃，通过滴液漏斗依次滴入三乙基硅烷(6.05g)和三氟乙酸(11.87g)，反应体系室温搅拌过夜。用饱和碳酸氢钠水溶液调节体系pH至中性。向反应体系中加入二氯甲烷(100mL)，分液收集有机相，有机相用无水硫酸钠干燥，抽滤，减压浓缩，硅胶柱层析提纯得到的2.4g化合物36-4。
1H NMR(500MHz,DMSO-d 6):δ7.57(s,1H),4.71(s,2H),4.08(m,4H).GCMS(EI,[M-e] +)m/z:202.
步骤E：化合物36-5的制备
依次向25mL单口瓶中加入1,4-二氧六环(10mL)、化合物36-4(165mg)、联硼酸频那醇酯(247mg)、乙酸钾(159mg)以及[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(40mg)，加毕，氮气置换后升温至90℃下反应2h，停止反应并降至室温，不经分离纯化，直接用于下步反应。
步骤F：化合物36的制备
将上述步骤E所得反应液转移至35mL的微波管中，向微波管中依次加入化合物11-1(250mg)、碳酸钾(224mg)、四(三苯基膦)钯(62.4mg)和水(2.5mL)加毕，氮气保护后封闭放入微波反应器中，微波反应条件：150℃，1h。反应液硅藻土过滤，收集滤液，向滤液加入乙酸乙酯(50mL)和饱和食盐水(25mL)洗涤后分液，收集有机相，硅胶柱层析提纯，得到40mg的化合物36。
1H NMR(500MHz,DMSO-d 6):δ10.14(s,1H),8.68(s,1H),7.90(m,3H),7.59(s,1H),7.33(s,2H),4.85(s,1H),4.62(m,2H),4.14(m,5H),3.24(s,3H),2.96(s,1H),1.80(m,2H).HRMS(ESI,[M+H] +)m/z:506.1413.
实施例37：化合物37的制备
Figure PCTCN2022095436-appb-000183
步骤A：化合物37-1的制备
参照实施例1步骤B的方法，使用化合物1-1和3-氧杂-8-氮杂双环[3.2.1]辛烷盐酸盐制备化合物37-1。
步骤B：化合物37的制备
参照实施例1步骤H的方法，使用化合物37-1和化合物36-5制备化合物37。
1H NMR(500MHz,DMSO-d 6)δ10.29(s,1H),8.70(d,J＝2.2Hz,1H),7.94(d,J＝2.2Hz,1H),7.86(d,J＝9.0Hz,2H),7.71(s,1H),7.35(d,J＝8.8Hz,2H),4.81(s,2H),4.19(t,J＝4.9Hz,2H),4.10(dd,J＝15.8,9.5Hz,4H),3.62(d,J＝10.6Hz,2H),3.43(d,J＝10.4Hz,2H),1.88–1.81(m,2H),1.80–1.71(m,2H).HRMS(ESI,[M+H] +)m/z:532.15650.
实施例38：化合物38的制备
Figure PCTCN2022095436-appb-000184
步骤A：化合物38-1的制备
参照实施例1步骤B的方法，使用化合物1-1和(1R,4R)-2-氧杂-5-氮杂双环[2.2.1]庚烷盐酸盐制备化合物38-1。
步骤B：化合物38的制备
参照实施例1步骤H的方法，使用化合物38-1和化合物36-5制备化合物38。
1H NMR(500MHz,DMSO-d 6)δ10.21(s,1H),8.68(d,J＝2.4Hz,1H),7.96(d,J＝2.4Hz,1H),7.89–7.84(m,2H),7.61(s,1H),7.37–7.31(m,2H),4.85(s,1H),4.68–4.62(m,1H),4.60–4.53(m,1H),4.47(d,J＝2.3Hz,1H),4.20–4.14(m,2H),4.12–4.05(m,2H),3.83–3.78(m,1H),3.78–3.72(m,1H),2.93–2.86(m,1H),2.64–2.59(m,1H),1.88–1.82(m,1H),1.81–1.74(m,1H).MS(ESI,[M-H] -)m/z:516.1/518.1.
实施例39：化合物39的制备
Figure PCTCN2022095436-appb-000185
步骤A：化合物39-1的制备
参照实施例1步骤B的制备方法，以化合物1-1及6-氧杂-3-氮杂-双环[3,1,1]庚烷盐酸盐为原料制备得到化合物39-1。MS(ESI,[M+H] +)m/z:474.04/476.06.
步骤B：化合物39的制备
参照实施例1步骤H的方法，使用化合物39-1和化合物36-5制备化合物39。
1H NMR(500MHz,DMSO-d 6)δ10.25(s,1H),8.74(d,J＝2.2Hz,1H),7.97(d,J＝2.2Hz,1H),7.87(d,J＝9.0Hz,2H),7.63(s,1H),7.34(d,J＝8.8Hz,2H),4.69(s,2H),4.53(d,J＝6.2Hz,2H),4.18(t,J＝4.8Hz,2H),4.09(t,J＝5.0Hz,2H),3.66(d,J＝12.8Hz,2H),3.46(d,J＝12.8Hz,2H),3.07–2.96(m,1H),1.80(d,J＝8.6Hz,1H).HRMS(ESI,[M+H] +)m/z:518.1400.
实施例40：化合物40的制备
Figure PCTCN2022095436-appb-000186
步骤A：化合物40-1的制备
参照实施例1步骤B的制备方法，以化合物1-1及(1S,4S)-2-氧杂-5-氮杂双环[2.2.1]庚烷盐酸盐为原料制备得到化合物40-1。MS(ESI,[M+H] +)m/z:474.06/476.09.
步骤B：化合物40的制备
参照实施例1步骤H的方法，使用化合物40-1和化合物36-5制备化合物40。
1H NMR(500MHz,DMSO-d 6)δ10.21(s,1H),8.69(d,J＝2.3Hz,1H),7.96(d,J＝2.3Hz,1H),7.86(d,J＝9.1Hz,2H),7.62(s,1H),7.34(d,J＝8.9Hz,2H),4.86(s,1H),4.70–4.61(m,1H),4.61–4.53(m,1H),4.47(s,1H),4.17(t,J＝4.9Hz,2H),4.09(t,J＝5.5Hz,2H),3.84–3.74(m,2H),2.90(d,J＝9.3Hz,1H),2.61(d,J＝10.2Hz,1H),1.85(d,J＝9.7Hz,1H),1.79(d,J＝9.8Hz,1H).HRMS(ESI,[M+H] +)m/z:518.1405.
实施例41：化合物41的制备
Figure PCTCN2022095436-appb-000187
步骤A：化合物41-1的制备
参照实施例1步骤B的方法，使用化合物1-1和(R)-3-甲氧基吡咯烷盐酸盐制备化合物41-1。
步骤B：化合物41的制备
参照实施例1步骤H的方法，使用化合物41-1和化合物36-5制备化合物41。
1H NMR(500MHz,DMSO-d 6)δ(ppm)10.16(s,1H),8.68(d,J＝2.4Hz,1H),7.94(d,J＝2.4Hz,1H),7.90–7.82(m,2H),7.60(s,1H),7.33(d,J＝8.6Hz,2H),4.69–4.53(m,2H),4.21–4.15(m,2H),4.11–4.05(m,2H),3.95–3.91(m,1H),3.31–3.24(m,2H),3.22–3.13(m,5H),2.01–1.83(m,2H).MS(ESI,[M+H] +) m/z:520.2.
实施例42：化合物42的制备
Figure PCTCN2022095436-appb-000188
步骤A：化合物42的制备
参照实施例1步骤H的方法，使用化合物15-1和化合物36-5制备化合物42。
1H NMR(500MHz,DMSO-d 6)δ(ppm)10.14(s,1H),8.68(d,J＝2.4Hz,1H),7.92(d,J＝2.4Hz,1H),7.89–7.82(m,2H),7.58(s,1H),7.33(d,J＝8.6Hz,2H),4.62(s,2H),4.17(t,J＝5.1Hz,2H),4.09(t,J＝5.3Hz,2H),3.23–3.11(m,4H),1.85–1.71(m,4H).MS(ESI,[M+H] +)m/z:490.1.
实施例43：化合物43的制备
Figure PCTCN2022095436-appb-000189
步骤A：化合物43-1的制备
参照实施例1步骤B的方法，使用化合物1-1和吗啉反应制备化合物43-1。
步骤B：化合物43的制备
参照实施例1步骤H的方法，使用化合物43-1和化合物36-5制备化合物43。
1H NMR(500MHz,DMSO-d 6)δ10.31(s,1H),8.73(s,1H),7.97(s,1H),7.87(d,J＝10.0Hz,2H),7.80(s,1H),7.36(d,J＝10.0Hz,2H),4.83(s,2H),4.20-4.12(m,4H),3.63(t,J＝5.0Hz,4H),3.14(t,J＝5.0,4H).HRMS(ESI,[M+H] +)m/z:506.1605.
实施例44：化合物44的制备
Figure PCTCN2022095436-appb-000190
步骤A：化合物44-1的制备
参照实施例1步骤B的方法，使用化合物1-1和8-氧杂-3-氮杂双环[3.2.1]辛烷盐酸盐制备化合物44-1。
步骤B：化合物44的制备
参照实施例1步骤H的方法，使用化合物44-1和化合物36-5制备化合物44。
1H NMR(500MHz,DMSO-d 6)δ10.28(s,1H),8.71(d,J＝2.4Hz,1H),7.92(d,J＝2.4Hz,1H),7.88–7.83(m,2H),7.66(s,1H),7.35(d,J＝9.0Hz,2H),4.74(s,2H),4.25(s,2H),4.19(t,J＝5.1Hz,2H),4.11(t,J＝5.1Hz,2H),3.37(d,J＝12.3Hz,2H),2.95(d,J＝11.0Hz,2H),1.73(s,4H).HRMS(ESI,[M+H] +)m/z:532.15643.
实施例45：化合物45的制备
Figure PCTCN2022095436-appb-000191
Figure PCTCN2022095436-appb-000192
步骤A：化合物45-1的制备
依次向100mL三颈瓶中加入6-溴嘧啶-4(3H)-酮(2.0g)、N,N-二甲基甲酰胺(20mL)、碘甲烷(3.24g)和碳酸钾(4.74g)，氮气保护，反应体系加热到50℃反应3h。向反应液中加入水(10mL)淬灭反应，并加入乙酸乙酯(40mL)萃取，分出有机层，水层再用乙酸乙酯萃取(20mL×2)。将有机层合并，用饱和氯化钠洗涤，并用无水硫酸钠干燥，抽滤，减压浓缩，硅胶柱层析提纯得到1.4g的化合物45-1。MS(ESI,[M+H] +)m/z:189.01.
步骤B：化合物45-2的制备
依次向25mL单口瓶中加入1,4-二氧六环(10mL)、化合物45-2(127mg)、联硼酸频那醇酯(205mg)、乙酸钾(132mg)以及[1,1'-双(二苯基膦)二茂铁]二氯化钯(33mg)，加毕，氮气置换后升温至90℃下反应2h，停止反应并降至室温，所得反应液不经分离纯化，直接用于下步反应。
步骤C：化合物45的制备
将上述步骤B所得反应液转移至35mL的微波管中,向微波管中依次加入化合物15-1(200mg)、碳酸铯(146mg)、[2'-(氨基)[1,1'-联苯]-2-基][[2',6'-二(1-甲基乙氧基)[1,1'-联苯]-2-基]二环己基膦]氯化钯(35mg)、2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯(21mg)和水(2.5mL)加毕，氮气保护后封闭放入微波反应器中，微波反应条件：140℃，2h。反应液硅藻土过滤，收集滤液，向滤液加入乙酸乙酯(50mL)和饱和食盐水(25mL)洗涤后分液，收集有机相，硅胶柱层析提纯，得到15mg的化合物45。
1H NMR(500MHz,DMSO-d 6):δ10.21(s,1H),8.77(d,J＝2.0Hz,1H),8.53(s,1H),8.17(d,J＝2.0Hz,1H),7.86(d,J＝9.5Hz,2H),7.34(d,J＝9.0Hz,2H),6.47(s,1H),3.46(s,3H),3.32(s,4H),1.83(m,4H).HRMS(ESI,[M+H] +)m/z:476.13469.
实施例46：化合物46的制备
Figure PCTCN2022095436-appb-000193
步骤A：化合物46的制备
参照实施例45步骤C的制备方法，使用化合物11-1和化合物45-2反应，制备得到化合物46。
1H NMR(500MHz,DMSO-d 6)δ10.21(s,1H),8.77(d,J＝2.3Hz,1H),8.54(s,1H),8.17(d,J＝2.3Hz,1H),7.92–7.78(m,2H),7.34(d,J＝8.9Hz,2H),6.47(s,1H),4.90(d,J＝3.2Hz,1H),4.28(d,J＝1.9Hz,1H),3.66–3.53(m,1H),3.47(s,3H),3.44(d,J＝4.3Hz,1H),3.41–3.34(m,1H),3.08(d,J＝11.7Hz,1H),1.98–1.73(m,2H).HRMS(ESI,[M+H] +)m/z:492.1247.
实施例47：化合物47的制备
Figure PCTCN2022095436-appb-000194
步骤A：化合物47-1的制备
依次向一个50mL单口瓶中加入N-甲基吡咯烷酮(30mL)、4,5-二溴哒嗪-3-酮(4.0g)和碳酸铯(7.62g)，搅拌，室温下向体系中缓慢滴加溴苄(2.72g)，加毕，反应4h；过滤，收集滤液，向其中加入乙 酸乙酯(30mL)和纯化水(20mL)，搅洗后分液，收集有机相，减压浓缩得残余物，经硅胶柱层析纯化得到4.7g化合物47-1。MS(ESI,[M+H] +)m/z:342.9.
步骤B：化合物47-2的制备
依次向一个50mL单口瓶中加入无水四氢呋喃(30mL)、上述步骤A所得化合物47-1(4.7g)，开启搅拌，降温至-20℃后开始向体系中缓慢滴加2M的正丁基氯化镁的四氢呋喃溶液(6.9mL)，加毕，控温反应5min；将上述反应液倒入饱和氯化铵水溶液(20mL)中淬灭反应，并加入乙酸乙酯萃取(20mL×2)，合并有机相，以饱和食盐水搅洗后分液得有机相，减压浓缩得残余物，经硅胶柱层析纯化后得到1.05g化合物47-2。
1H NMR(500MHz,DMSO-d 6)δ8.14(d,J＝2.3Hz,1H),7.48(d,J＝2.3Hz,1H),7.37–7.30(m,2H),7.31–7.25(m,3H),5.22(s,2H).MS(ESI,[M+H] +)m/z:264.97.
步骤C：化合物47-3的制备
依次向一个50mL单口瓶中加入甲苯(20mL)、上述步骤B所得化合物47-2(800mg)和三氯化铝(2028mg)，开启搅拌，氮气置换后油浴升温至70℃下反应2h；向体系中加入饱和碳酸氢钠水溶液(30mL)淬灭反应，加入乙酸乙酯萃取(30mL x 2)，分液得有机相，向其中加入饱和氯化钠水溶液(20mL)搅洗后分液，得有机相并减压浓缩得残余物，经硅胶柱层析纯化得到300mg化合物47-3。MS(ESI,[M-H] -)m/z:173.0.
步骤D：化合物47-4的制备
依次向一个50mL单口瓶中加入N,N-二甲基甲酰胺(10mL)、上述步骤C所得化合物47-3(300mg)以及碳酸铯(838mg)，搅拌，室温下向体系中缓慢滴加2mL无水N,N-二甲基甲酰胺稀释的碘甲烷(257mg)，加毕，室温下反应4h；依次向体系中加入纯化水(10mL)和乙酸乙酯(30mL)，搅洗后分液，收集有机相，减压浓缩得残余物，经硅胶柱层析纯化得到250mg化合物47-4。MS(ESI,[M+H] +)m/z:189.0.
步骤E：化合物47-5的制备
依次向35mL微波管中加入1,4-二氧六环(15mL)、上述步骤D所得化合物47-4(93mg)、联硼酸频那醇酯(136mg)、乙酸钾(110mg)以及[1,1'-双(二苯基膦)二茂铁]二氯化钯(25mg)，加毕，氮气置换后升温至90℃下反应2h，停止反应并降至室温，不经分离纯化，直接用于下步反应。
步骤F：化合物47的制备
向上述步骤E所得反应液中，依次加入化合物15-1(200mg)、碳酸钾(154mg)、去离子水(1mL)以及四(三苯基膦)钯(30mg)，加毕，氮气置换后将微波管封口，置于微波反应器中，升温至140℃下反应1.5h。降至室温后将上述反应过滤，收集母液，经硅胶柱层析纯化，得到170mg化合物47。
1H NMR(500MHz,DMSO-d 6)δ10.17(s,1H),8.78(d,J＝2.3Hz,1H),8.13(d,J＝2.3Hz,1H),8.02(d,J＝2.2Hz,1H),7.89–7.83(m,2H),7.38–7.31(m,2H),6.90(d,J＝2.2Hz,1H),3.70(s,3H),3.30–3.25(m,4H),1.88–1.79(m,4H).MS(ESI,[M-H] -)m/z:474.09/475.99.
实施例48：化合物48的制备
Figure PCTCN2022095436-appb-000195
步骤A：化合物48-1的制备
依次向35mL的封管中加入异丙醇(10mL)、化合物1-1(1.0g)、3-羟基氮杂环丁烷盐酸盐(0.32g)，N,N-二异丙基乙胺(1.004g)和磁子，封口后将封管置入微波反应器中140℃下反应1.5h。降至室温后，向反应液中加入乙酸乙酯(15mL)和饱和氯化钠水溶液(15mL)搅洗后分液，收集有机相，无水硫酸钠干燥，抽滤，减压浓缩，经硅胶柱层析纯化，得0.8g化合物48-1。MS(ESI,[M+H] +)m/z:447.98.
步骤B：化合物48的制备
向35mL的微波管中依次加入化合物45-2、化合物48-1(500mg)、碳酸钾(424mg)、[2'-(氨基)[1,1'-联苯]-2-基][[2',6'-二(1-甲基乙氧基)[1,1'-联苯]-2-基]二环己基膦]氯化钯(80mg)、2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯(48mg)和水(2mL)，加毕，氮气保护下放入微波反应器中，微波反应条件：140℃，2h。反应液硅藻土过滤，收集滤液，向滤液加入乙酸乙酯(50mL)和饱和食盐水(25mL)洗涤后分液， 收集有机相，硅胶柱层析提纯，得到100mg的化合物48。
1H NMR(500MHz,DMSO-d 6)δ10.26(s,1H),8.78(d,J＝2.2Hz,1H),8.56(s,1H),8.20(d,J＝2.2Hz,1H),7.86(d,J＝9.1Hz,2H),7.34(d,J＝8.8Hz,2H),6.48(s,1H),5.63(d,J＝6.4Hz,1H),4.46(h,J＝6.5Hz,1H),4.16–4.05(m,2H),3.69(dd,J＝9.7,4.2Hz,2H),3.47(s,3H).HRMS(ESI,[M+H] +)m/z:478.10934.
实施例49：化合物49的制备
Figure PCTCN2022095436-appb-000196
参照实施例48步骤B的制备方法，使用化合物45-2与化合物35-1反应制备得到化合物49。
1H NMR(500MHz,DMSO-d 6)δ10.34(s,1H),8.78(d,J＝2.1Hz,1H),8.58(s,1H),8.28(d,J＝2.1Hz,1H),7.86(d,J＝9.0Hz,2H),7.35(d,J＝8.7Hz,2H),6.79(s,1H),4.22(s,2H),3.65(d,J＝10.7Hz,2H),3.50(d,J＝10.5Hz,2H),3.45(s,3H),1.83(dd,J＝45.3,5.8Hz,4H).HRMS(ESI,[M+H] +)m/z:518.14078.
实施例50：化合物50的制备
Figure PCTCN2022095436-appb-000197
参照实施例48步骤B的制备方法，使用化合物45-2与化合物34-1反应制备得到化合物50。
1H NMR(500MHz,DMSO-d 6)δ10.32(s,1H),8.77(d,J＝2.3Hz,1H),8.59(s,1H),8.25(d,J＝2.3Hz,1H),7.86(d,J＝9.1Hz,2H),7.35(d,J＝8.8Hz,2H),6.63(s,1H),4.29(s,2H),3.58(d,J＝12.6Hz,2H),3.46(s,3H),3.08(d,J＝11.6Hz,2H),1.73(s,4H).HRMS(ESI,[M+H] +)m/z:518.14054.
实施例51：化合物51的制备
Figure PCTCN2022095436-appb-000198
参照实施例48步骤B的制备方法，使用化合物45-2与化合物21-1反应制备得到化合物51。
1H NMR(500MHz,DMSO-d 6)δ10.27(s,1H),8.78(s,1H),8.53(s,1H),8.19(s,1H),7.86-7.87(m,2H),7.34-7.35(m,2H),6.52(s,1H),4.94(s,1H),4.55(s,1H),3.74-3.79(m,2H),3.45(s,3H),3.36(s,1H),2.80-2.82(m,1H),1.81-1.87(m,2H).HRMS(ESI,[M+H] +)m/z:504.12678.
实施例52：化合物52的制备
Figure PCTCN2022095436-appb-000199
参照实施例48步骤B的制备方法，使用化合物45-2与化合物23-1反应制备得到化合物52。
1H NMR(500MHz,DMSO-d 6)δ10.26(s,1H),8.80(d,J＝2.3Hz,1H),8.52(s,1H),8.17(d,J＝2.4Hz,1H),7.92–7.79(m,2H),7.34(d,J＝8.7Hz,2H),6.63(d,J＝0.8Hz,1H),4.57(d,J＝6.4Hz,2H),3.81(d,J＝12.8Hz,2H),3.64(d,J＝12.8Hz,2H),3.45(s,3H),3.08–2.98(m,1H),1.74(d,J＝8.6Hz,1H).HRMS(ESI,[M+H] +)m/z:504.12424.
实施例53：化合物53的制备
Figure PCTCN2022095436-appb-000200
参照实施例48步骤B的制备方法，使用化合物45-2与化合物16-1反应制备得到化合物53。
1H NMR(500MHz,DMSO-d 6)δ10.24(s,1H),8.79(d,J＝2.2Hz,1H),8.55(s,1H),8.19(d,J＝2.2Hz,1H),7.87(d,J＝9.1Hz,2H),7.34(d,J＝8.8Hz,2H),6.54(s,1H),5.54–5.17(m,1H),3.81–3.63(m,1H),3.63–3.48(m,2H),3.47(s,3H),3.45–3.40(m,1H),2.21–1.97(m,2H).HRMS(ESI,[M+H] +)m/z:494.1202.
实施例54：化合物54的制备
Figure PCTCN2022095436-appb-000201
参照实施例48步骤B的制备方法，使用化合物45-2与化合物7-1反应制备得到化合物54。
1H NMR(500MHz,DMSO-d 6)δ10.36(s,1H),8.80(d,J＝2.3Hz,1H),8.60(s,1H),8.35(d,J＝2.3Hz,1H),7.87(d,J＝9.0Hz,2H),7.35(d,J＝8.8Hz,2H),6.83(s,1H),3.67–3.59(m,4H),3.46(s,3H),3.40–3.33(m,4H).HRMS(ESI,[M+H] +)m/z:492.1249.
实施例55：化合物55的制备
Figure PCTCN2022095436-appb-000202
步骤A：化合物55-1的制备
参照实施例48步骤A的制备方法，将化合物1-1和2-甲氧基乙烷-1-胺反应制备得到化合物55-1。MS(ESI,[M-H] -)m/z:448.01.
步骤B：化合物55的制备
参照实施例48步骤B的制备方法，使用化合物45-2与化合物55-1反应制备得到化合物55。
1H NMR(500MHz,DMSO-d 6)δ10.19(s,1H),8.89(s,1H),8.75(s,1H),8.64(s,1H),8.44(s,1H),7.94–7.79(m,2H),7.43–7.29(m,2H),7.01(s,1H),3.76–3.60(m,2H),3.60–3.51(m,2H),3.48(s,3H),3.30(s,3H).HRMS(ESI,[M+H] +)m/z:480.12468.
实施例56：化合物56的制备
Figure PCTCN2022095436-appb-000203
步骤A：化合物56-1的制备
参照实施例48步骤A的制备方法，将化合物1-1和(R)-3-甲基吗啉盐酸盐反应制备得到化合物56-1。MS(ESI,[M+H] +)m/z:476.04.
步骤B：化合物56的制备
参照实施例48步骤B的制备方法，使用化合物45-2与化合物56-1反应制备得到化合物56。
1H NMR(500MHz,DMSO-d 6)δ10.36(s,1H),8.80(d,J＝2.4Hz,1H),8.59(s,1H),8.32(d,J＝2.4Hz,1H),7.90–7.83(m,2H),7.35(d,J＝8.6Hz,2H),6.81(s,1H),4.09(d,J＝6.4Hz,1H),3.78(d,J＝11.2Hz,1H),3.62–3.55(m,2H),3.50–3.42(m,4H),3.39–3.33(m,1H),3.31–3.24(m,1H),1.14(d,J＝6.7Hz,3H).HRMS(ESI,[M+H] +)m/z:506.1398.
实施例57：化合物57的制备
Figure PCTCN2022095436-appb-000204
步骤A：化合物57-1的制备
参照实施例48步骤A的制备方法，将化合物1-1和(S)-3-甲基吗啉盐酸盐反应制备得到化合物57-1。MS(ESI,[M+H] +)m/z:476.04.
步骤B：化合物57的制备
参照实施例48步骤B的制备方法，使用化合物45-2与化合物57-1反应制备得到化合物57。
1H NMR(500MHz,DMSO-d 6)δ10.36(s,1H),8.80(d,J＝2.4Hz,1H),8.59(s,1H),8.32(d,J＝2.4Hz,1H),7.87(d,J＝9.0Hz,2H),7.35(d,J＝8.6Hz,2H),6.81(s,1H),4.09(d,J＝6.6Hz,1H),3.78(d,J＝11.1Hz,1H),3.63–3.53(m,2H),3.52–3.40(m,4H),3.31–3.24(m,2H),1.14(d,J＝6.6Hz,3H).HRMS(ESI,[M+H] +)m/z:506.1404.
实施例58：化合物58的制备
Figure PCTCN2022095436-appb-000205
步骤A：化合物58-1的制备
参照实施例48步骤A的方法，使用化合物1-1和(S)-2-甲基氮杂环丁烷盐酸盐制备化合物58-1。MS(ESI,[M+H] +)m/z:446.02.
步骤B：化合物58的制备
参照实施例48步骤B的制备方法，使用化合物45-2与化合物58-1反应制备得到化合物58。
1H NMR(500MHz,CDCl 3)δ8.78(d,J＝2.2Hz,1H),8.25–8.09(m,2H),7.97(s,1H),7.69(d,J＝8.9Hz,2H),7.23(d,J＝8.7Hz,2H),6.53(s,1H),4.66–4.56(m,1H),4.16–4.02(m,1H),3.57(s,3H),3.45(dd,J＝15.3,8.8Hz,1H),2.51–2.39(m,1H),2.01–1.87(m,1H),1.38(d,J＝6.2Hz,3H).HRMS(ESI,[M+H] +)m/z:476.1314.
实施例59：化合物59的制备
Figure PCTCN2022095436-appb-000206
步骤A：化合物59-1的制备
参照实施例48步骤A的制备方法，将化合物1-1和(S)-吡咯烷-3-基氨基甲酸叔丁酯反应制备得到化合 物59-1。MS(ESI,[M+H] +)m/z:561.09.
步骤B：化合物59-2的制备
向一个50mL的茄形瓶中，依次加入化合物59-1(1g)、二氯甲烷(6mL)和三氟乙酸(4.00mL)，所得混合物室温下反应。待反应完全，减压浓缩除去溶剂。向残余物中加入二氯甲烷(10mL)，使用1M的氢氧化钠水溶液调节pH至8，分液，收集有机相。水相用乙酸乙酯(20mL)萃取两次，收集有机相，无水硫酸钠干燥，过滤，浓缩得到720mg化合物59-2。MS(ESI,[M+H] +)m/z:461.04.
步骤C：化合物59-3的制备
在一个50mL茄形瓶中，依次加入化合物59-2(0.7g)、N,N-二异丙基乙胺(0.588g)和二氯甲烷(6mL)，氮气保护下，加入乙酰氯(0.238g)，所得混合物室温下反应过夜。硅胶柱层析提纯，得到610mg的化合物59-3。MS(ESI,[M+H] +)m/z:503.05.
步骤D：化合物59的制备
参照实施例48步骤B的制备方法，使用化合物45-2与化合物59-3反应制备得到化合物59。
1H NMR(500MHz,DMSO-d 6)δ10.22(s,1H),8.79(s,1H),8.54(s,1H),8.19(s,1H),8.07(d,J＝6.0Hz,1H),7.87(d,J＝8.8Hz,2H),7.34(d,J＝8.5Hz,2H),6.47(s,1H),4.20(s,1H),3.43-3.53(m,6H),3.11-3.13(m,1H),2.05(s,1H),1.78(s,4H).HRMS(ESI,[M+H] +)m/z:533.15133.
实施例60：化合物60的制备
Figure PCTCN2022095436-appb-000207
步骤A：化合物60-1的制备
在一个50mL的反应瓶中，将5-溴嘧啶-4-酮(1g)用四氢呋喃(10mL)溶解，降温到0℃，分批加入氢化钠(0.457g)。加毕，氮气置换三次。反应1小时。冰浴下用注射器向反应液中滴加碘甲烷(1.622g)，滴完继续反应过夜。冰浴下滴加水(10mL)淬灭反应，加入乙酸乙酯(15mL)分液，再用乙酸乙酯(10mL)萃取两次，合并有机相，用无水硫酸钠干燥，过滤旋干得到0.8g化合物60-1。MS(ESI,[M+H] +)m/z:188.96.
步骤B：化合物60-2的制备
参照实施例45步骤B的制备方法，将化合物60-1与联硼酸频那醇酯反应制备得到化合物60-2，不经分离纯化，直接用于下步反应。
步骤D：化合物60的制备
参照实施例48步骤B的制备方法，使用化合物7-1与化合物60-2反应制备得到化合物60。
1H NMR(500MHz,DMSO-d 6)δ10.28(s,1H),8.78(s,1H),8.54(s,1H),8.15(s,1H),8.06(s,1H),7.85-7.87(m,2H),7.34-7.35(m,2H),3.55-3.56(m,4H),3.51(s,3H),3.28-3.29(m,4H).HRMS(ESI,[M+H] +)m/z:492.12730.
实施例61：化合物61的制备
Figure PCTCN2022095436-appb-000208
步骤A：化合物61-1的制备
参照实施例48步骤A的方法，使用化合物1-1和二甲胺盐酸盐制备化合物61-1。MS(ESI,[M+H] +)m/z:420.00.
步骤B：化合物61的制备
参照实施例48步骤B的制备方法，使用化合物45-2与化合物61-1反应制备得到化合物61。
1H NMR(500MHz,DMSO-d 6)δ10.25(s,1H),8.76(d,J＝2.3Hz,1H),8.56(s,1H),8.27(d,J＝2.3Hz, 1H),7.87(d,J＝9.0Hz,2H),7.34(d,J＝8.8Hz,2H),6.56(s,1H),3.46(s,3H),2.94(s,6H).HRMS(ESI,[M+H] +)m/z:450.1141.
实施例62：化合物62的制备
Figure PCTCN2022095436-appb-000209
步骤A：化合物62-1的制备
参照实施例48步骤A的方法，使用化合物1-1和甲胺盐酸盐制备化合物62-1。MS(ESI,[M+H] +)m/z:406.04.
步骤B：化合物62-2的制备
依次向一个15mL微波管中加入1,4-二氧六环(4mL)、化合物62-1(240mg)、联硼酸新戊二醇酯(200mg)、乙酸钾(174mg)、双三苯基膦二氯化钯(41.5mg)，加毕，氮气保护下，于微波反应仪120℃反应1h，停止反应并降至室温，不经分离纯化，直接用于下步反应。
步骤C：化合物62的制备
向上述步骤B所得反应液中依次加入化合物45-1(145mg)、无水碳酸钾(245mg)、四(三苯基膦)钯(68mg)和水(1mL)，加毕，氮气保护后封闭放入微波反应器中，微波反应条件：140℃，1.5h。向滤液加入乙酸乙酯(50mL)和饱和食盐水(25mL)洗涤后分液，收集有机相，硅胶柱层析提纯，得到60mg的化合物62。
1H NMR(500MHz,DMSO-d 6)δ10.18(s,1H),8.77(d,J＝2.2Hz,1H),8.61(s,1H),8.52–8.48(m,1H),8.39(d,J＝2.2Hz,1H),7.86(d,J＝9.1Hz,2H),7.35(d,J＝8.9Hz,2H),6.96(s,1H),3.48(s,3H),2.99(d,J＝4.7Hz,3H).HRMS(ESI,[M+H] +)m/z:436.1336.
实施例63：化合物63的制备
Figure PCTCN2022095436-appb-000210
步骤A：化合物63-1的制备
参照实施例62步骤B的方法，使用化合物2-1和联硼酸新戊二醇酯制备化合物63-1。反应未处理，直接用于下一步反应。
步骤B：化合物63的制备
参照实施例62步骤C的方法，使用化合物63-1和化合物45-1制备化合物63。
1H NMR(500MHz,DMSO-d 6)δ10.21(s,1H),8.77(d,J＝2.4Hz,1H),8.54(s,1H),8.17(d,J＝2.4Hz,1H),7.89–7.83(m,2H),7.38–7.30(m,2H),6.49(d,J＝0.9Hz,1H),4.00–3.94(m,1H),3.55–3.44(m,5H),3.37–3.33(m,1H),3.27(d,J＝12.2Hz,1H),3.20(s,3H),1.99(s,1H),1.94–1.86(m,1H).HRMS(ESI,[M+H] +)m/z:506.1471.
实施例64：化合物64的制备
Figure PCTCN2022095436-appb-000211
步骤A：化合物64-1的制备
依次向35mL的微波管中加入1,4-二氧六环(15mL)、化合物1-1(400mg)、联硼酸频那醇酯(370mg)、乙酸钾(191mg)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(79mg)，加毕，氮气保护下，于微波反应仪140℃反应1.5h，停止反应并降至室温，不经分离纯化，直接用于下步反应。
步骤B：化合物64-2的制备
向上述步骤A所得反应液中依次加入化合物45-1(150mg)、无水碳酸钾(90mg)、四(三苯基膦)钯(57mg)和水(2mL)，加毕，氮气保护70℃反应5小时。向反应液加入乙酸乙酯(50mL)和饱和食盐水(25mL)洗涤后分液，收集有机相，硅胶柱层析提纯，得到150mg的化合物64-2。MS(ESI,[M+H] +)m/z:441.02.
步骤C：化合物64的制备
向一个35mL的微波管中，依次加入化合物64-2(100mg)、4,4-二氟哌啶(30mg)、N,N-二异丙基乙胺(64mg)以及N-甲基吡咯烷酮(10mL)，180℃微波反应2h。向反应液加入乙酸乙酯(50mL)和饱和食盐水(25mL)洗涤后分液，收集有机相，硅胶柱层析提纯，得到75mg的化合物64。
1H NMR(500MHz,DMSO-d 6)δ10.38(s,1H),8.81(d,J＝2.4Hz,1H),8.62(s,1H),8.37(d,J＝2.4Hz,1H),7.91–7.84(m,2H),7.36(d,J＝8.7Hz,2H),6.85(s,1H),3.53–3.43(m,7H),2.03(td,J＝13.6,6.4Hz,4H).HRMS(ESI,[M+H] +)m/z:526.1279.
实施例65：化合物65的制备
Figure PCTCN2022095436-appb-000212
参照实施例64步骤C的方法，使用化合物64-2和R-脯氨醇制备化合物65。
1H NMR(500MHz,DMSO-d 6)δ10.26(s,1H),8.77(d,J＝2.4Hz,1H),8.55(s,1H),8.27(d,J＝2.4Hz,1H),7.91–7.83(m,2H),7.34(d,J＝8.8Hz,2H),6.42(d,J＝0.8Hz,1H),4.74(t,J＝5.5Hz,1H),4.47–4.39(m,1H),3.69–3.62(m,1H),3.61–3.51(m,1H),3.30–3.21(m,1H),2.85–2.74(m,1H),2.03–1.95(m,1H),1.94–1.84(m,2H),1.71–1.55(m,1H).HRMS(ESI,[M+H] +)m/z:506.1407.
实施例66：化合物66的制备
Figure PCTCN2022095436-appb-000213
在一个15mL微波管中加入化合物64-2(100mg)、咪唑(30.9mg)、叔丁醇钾(76mg)和二甲亚砜(4mL)。氮气保护下，微波反应，120℃反应15min。向反应体系加入乙酸乙酯(50mL)和饱和食盐水(25mL)洗涤后分液，收集有机相，硅胶柱层析提纯，得到50mg的化合物66。
1H NMR(500MHz,DMSO-d 6)δ10.75(s,1H),9.14(s,1H),8.66(s,1H),8.53(s,1H),7.96(s,1H),7.91(d,J＝9.1Hz,2H),7.42(d,J＝21.3Hz,3H),7.05(s,1H),6.56(s,1H),3.45(s,3H).HRMS(ESI,[M+H] +)m/z:473.09304.
实施例67：化合物67的制备
Figure PCTCN2022095436-appb-000214
参照实施例64步骤C的方法，使用化合物64-2和硫代吗啉制备化合物67。
1H NMR(500MHz,DMSO-d 6)δ10.37(s,1H),8.80(d,J＝2.3Hz,1H),8.61(s,1H),8.34(d,J＝2.3Hz,1H),7.87(d,J＝9.1Hz,2H),7.35(d,J＝8.9Hz,2H),6.80(s,1H),3.68–3.57(m,4H),3.46(s,3H),2.69–2.59(m,4H).HRMS(ESI,[M+H] +)m/z:508.1188.
实施例68：化合物68的制备
Figure PCTCN2022095436-appb-000215
向一个35mL的微波管中，依次加入化合物64-2(150mg)、二氧六环(10mL)、2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)乙-1-醇(97mg)、无水碳酸钾(94mg)、四(三苯基膦)钯(59mg)和水(1mL)。加毕，氮气保护后放入微波反应器中，微波反应条件：140℃，1.5h。向反应液中加入乙酸乙酯(50mL)和饱和食盐水(25mL)洗涤后分液，收集有机相，硅胶柱层析提纯，得到100mg的化合物68。
1H NMR(500MHz,DMSO-d 6)δ10.58(s,1H),9.12(d,J＝2.2Hz,1H),8.57(s,1H),8.25(d,J＝2.2Hz,1H),7.97(s,1H),7.93–7.86(m,2H),7.60(s,1H),7.38(d,J＝9.0Hz,2H),6.64(s,1H),4.90(t,J＝5.2Hz,1H),4.15(t,J＝5.6Hz,2H),3.72(q,J＝5.5Hz,2H),3.51(d,J＝7.6Hz,3H).HRMS(ESI,[M+H] +)m/z:517.1368.
实施例69：化合物69的制备
Figure PCTCN2022095436-appb-000216
步骤A：化合物69-1的制备
参照实施例68的制备方法，将化合物64-2和1-(2-四氢吡喃基)-1H-吡唑-5-硼酸频那酯反应制备得到化合物69-1。MS(ESI,[M-H] -)m/z:555.14.
步骤B：化合物69的制备
向一个25mL茄形瓶中，依次加入化合物69-1(330mg)和二氯甲烷(10mL)，将三氟乙酸(3mL)缓慢滴加至瓶中，加毕，室温下反应2h。将反应液浓缩除去溶剂，加入二氯甲烷(10mL)复溶，硅胶柱层析纯化，得到30mg化合物69。
1H NMR(500MHz,DMSO-d 6)δ13.05(s,1H),10.68(s,1H),9.19(d,J＝2.1Hz,1H),8.52(s,1H),8.36(d,J＝2.1Hz,1H),7.91(d,J＝9.1Hz,2H),7.70(s,1H),7.39(d,J＝8.9Hz,2H),6.58(d,J＝76.3Hz,2H),3.46(s,3H).HRMS(ESI,[M+H] +)m/z:473.09353.
实施例70：化合物70的制备
Figure PCTCN2022095436-appb-000217
步骤A：化合物70-1的制备
参照实施例48步骤A的制备方法，将化合物1-1和乙二醇甲醚反应制备得到化合物70-1。MS(ESI, [M+H] +)m/z:450.98.
步骤B：化合物70的制备
参照实施例48步骤B的制备方法，使用化合物45-2与化合物70-1反应制备得到化合物70。
1H NMR(500MHz,DMSO-d 6)δ10.59(s,1H),8.96(d,J＝2.5Hz,1H),8.85(d,J＝2.5Hz,1H),8.61(s,1H),7.89(d,J＝9.1Hz,2H),7.37(d,J＝9.0Hz,2H),7.27(s,1H),4.66–4.61(m,2H),3.80–3.73(m,2H),3.46(s,3H),3.34(s,3H).HRMS(ESI,[M+H] +)m/z:481.10819.
实施例71：化合物71的制备
Figure PCTCN2022095436-appb-000218
步骤A：化合物71-1的制备
依次向50mL反应瓶中加入化合物1-1(0.6g)、氢氧化钾(245mg)和甲醇(20mL)，氮气置换3次后微波60℃反应6h。将反应液浓缩，并加入乙酸乙酯(60mL)萃取，分出有机层，水层再用乙酸乙酯(40mL)萃取两次。合并有机层，用饱和氯化钠水溶液洗涤，并用无水硫酸钠干燥。减压蒸馏除去溶剂，硅胶柱层析得到0.5g的化合物71-1。MS(ESI,[M+H] +)m/z:406.9.
步骤B：化合物71的制备
参照实施例48步骤B的制备方法，使用化合物1-4与化合物25-1反应制备得到化合物71。
1H NMR(500MHz,DMSO-d 6)δ10.60(s,1H),8.93(d,J＝2.3Hz,1H),8.88(d,J＝2.4Hz,1H),8.61(s,1H),7.90(d,J＝9.0Hz,2H),7.38(d,J＝8.8Hz,2H),7.17(s,1H),4.09(s,3H),3.46(s,3H).HRMS(ESI,[M+H] +)m/z:437.08180.
实施例72：化合物72的制备
Figure PCTCN2022095436-appb-000219
步骤A：化合物72-1的制备
参照实施例48步骤A的制备方法，将化合物1-1和3,3-二氟吖丁啶盐酸盐反应制备得到化合物72-1。MS(ESI,[M+H] +)m/z:467.91.
步骤B：化合物72-2的制备
参照实施例62步骤B的制备方法，使用化合物72-1与联硼酸新戊二醇酯反应制备得到化合物72-2的反应液，不经纯化直接用于下步反应。
步骤C：化合物72的制备
参照实施例62步骤C的制备方法，使用上述步骤B所得化合物72-2的反应液与化合物45-1应制备得到化合物72。
1H NMR(500MHz,DMSO-d 6)δ10.36(s,1H),8.84(s,1H),8.57(s,1H),8.28(s,1H),7.87(d,J＝8.7Hz,2H),7.36(d,J＝8.4Hz,2H),6.61(s,1H),4.35(t,J＝12.4Hz,4H),3.47(s,3H).HRMS(ESI,[M+H] +)m/z:498.0951.
实施例73：化合物73的制备
Figure PCTCN2022095436-appb-000220
向一个50mL茄形瓶中，依次加入化合物64-2(330mg)、1,4-二氧六环(20mL)、1-甲基-1H-吡唑-5-硼酸频那醇酯(171mg)、碳酸钾(310mg)、去离子水(2mL)和双三苯基膦二氯化钯(53mg)，氮气置换三次，将反应置入油浴锅中升温至100℃反应8h。降至室温后将上述反应液过滤，收集母液，将反应液减压浓缩，得棕色残余物，加入乙酸乙酯(50mL)和水(30mL)，搅洗后分液，得有机相加入饱和氯化钠水溶液(30mL)搅洗后分液，经硅胶柱层析纯化，共得到43mg化合物73。
1H NMR(500MHz,DMSO-d 6)δ10.78(s,1H),9.27(d,J＝2.1Hz,1H),8.55(d,J＝2.1Hz,1H),8.52(s,1H),7.92(d,J＝9.0Hz,2H),7.45–7.37(m,3H),6.46(s,1H),6.19(d,J＝1.8Hz,1H),3.86(s,3H),3.42(s,3H).HRMS(ESI,[M+H] +)m/z:487.10835.
实施例74：化合物74的制备
Figure PCTCN2022095436-appb-000221
依次向30mL封管中加入化合物64-2(250mg)、N,N-二甲基甲酰胺(10mL)、1-甲基-5-(三正丁基锡)咪唑(275mg)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(45mg)，封口后将封管置入微波反应器中135℃下反应2h。降至室温后将上述反应液过滤，收集母液，将反应液减压浓缩，得棕色残余物，加入乙酸乙酯(50mL)和水(30mL)，搅洗后分液，得有机相加入饱和氯化钠水溶液(30mL)搅洗后分液，经硅胶柱层析纯化，共得到160mg化合物74。
1H NMR(500MHz,DMSO-d 6)δ10.70(s,1H),9.23(d,J＝2.2Hz,1H),8.54(s,1H),8.45(d,J＝2.2Hz,1H),7.91(d,J＝9.1Hz,2H),7.79(s,1H),7.39(d,J＝8.9Hz,2H),6.84(s,1H),6.54(s,1H),3.79(s,3H),3.45(s,3H).HRMS(ESI,[M+H] +)m/z:487.1080.
实施例75：化合物75的制备
Figure PCTCN2022095436-appb-000222
向一个35mL的微波管中，依次加入化合物64-2(400mg)、碳酸铯(591mg)、N,N-二甲基-1-(三氟-λ 4-硼烷基)甲胺钾盐(194mg)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(76mg)、2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯(85mg)、二氧六环(10mL)和水(1mL)。加完，吹氮气30s。将反应体系放置于微波反应器中，微波条件：120℃，90min。反应完成。硅藻土抽滤，硅胶柱层析纯化得到50mg的化合物75。
1H NMR(500MHz,DMSO-d 6)δ10.68(s,1H),9.09(d,J＝2.0Hz,1H),8.61(s,1H),8.42(d,J＝2.0Hz,1H),7.90(d,J＝9.0Hz,2H),7.39(d,J＝8.8Hz,2H),6.98(s,1H),3.77(s,2H),3.49(s,3H),2.13(s,6H).HRMS(ESI,[M+H] +)m/z:464.1294.
实施例76：化合物76的制备
Figure PCTCN2022095436-appb-000223
步骤A：化合物76-1的制备
参照实施例48步骤A的方法，使用化合物1-1和2-甲基氮杂环丁烷盐酸盐制备化合物76-1。MS(ESI,[M+H] +)m/z:446.02.
步骤B：化合物76-2的制备
参照实施例48步骤B的制备方法，使用化合物45-2与化合物76-1反应制备得到化合物76-2。MS(ESI,[M+H] +)m/z:476.15.
步骤C：化合物76的制备
将化合物76-2进行手性拆分，使用YMC高压制备色谱仪(CHIRALART Cellulose-SC柱，流速为40mL/min，流动相为(乙醇/正己烷＝2:3))最终得到化合物76。
1H NMR(500MHz,DMSO-d 6)δ10.28(s,1H),8.80(d,J＝2.3Hz,1H),8.57(s,1H),8.23(d,J＝2.3Hz,1H),7.87(d,J＝9.1Hz,2H),7.34(d,J＝8.9Hz,2H),6.47(s,1H),4.57–4.44(m,1H),4.01–3.87(m,1H),3.50–3.47(m,1H),3.46(s,3H),2.45–2.36(m,1H),1.93–1.84(m,1H),1.34(d,J＝6.2Hz,3H).HRMS(ESI,[M+H] +)m/z:476.13008.
实施例77：化合物77的制备
Figure PCTCN2022095436-appb-000224
向10mL微波管中依次加入化合物64-2(150mg)、二甲基亚砜(5mL)、叔丁醇钾(114mg)和吡唑(35mg)，加毕，氮气保护，于微波反应仪120℃反应0.5h，向反应液加入乙酸乙酯(50mL)和饱和食盐水溶液(25mL)洗涤后分液，收集有机相，硅胶柱层析提纯，得到70mg化合物77。
1H NMR(500MHz,DMSO-d 6)δ10.73(s,1H),9.10(d,J＝2.2Hz,1H),8.61(d,J＝2.2Hz,1H),8.51–8.43(m,2H),7.96–7.88(m,2H),7.69(d,J＝1.0Hz,1H),7.41(d,J＝8.9Hz,2H),6.59–6.50(m,1H),6.39(s,1H),3.44(s,3H).HRMS(ESI,[M+H] +)m/z:473.09397.
实施例78：化合物78的制备
Figure PCTCN2022095436-appb-000225
步骤A：化合物78-1的制备
参照实施例45步骤A的制备方法，将6-溴嘧啶-4(3H)-酮和4-碘甲基四氢吡喃反应制备得到化合物78-1。MS(ESI,[M+H] +)m/z:273.04.
步骤B：化合物78-2的制备
参照实施例62步骤B的制备方法，使用化合物61-1与联硼酸新戊二醇酯反应制备得到化合物78-2的反应液，不经纯化直接用于下步反应。
步骤C：化合物78的制备
参照实施例62步骤C的制备方法，使用上述步骤B所得化合物78-2的反应液与步骤A所得化合物78-1反应制备得到化合物78。
1H NMR(500MHz,DMSO-d 6)δ10.27(s,1H),8.81(d,J＝30.3Hz,2H),8.31(s,1H),7.87(d,J＝8.0Hz,2H),7.35(d,J＝7.5Hz,2H),7.11(s,1H),4.27(d,J＝5.5Hz,2H),3.88(d,J＝8.6Hz,2H),2.87(s,6H),2.06(s,1H),1.67(d,J＝11.7Hz,2H),1.46–1.23(m,2H).HRMS(ESI,[M+H] +)m/z:534.17145.
实施例79：化合物79的制备
Figure PCTCN2022095436-appb-000226
参照实施例64步骤C的方法，使用化合物64-2和(3R,4R)-3,4-二氟吡咯烷盐酸盐制备化合物79。
1H NMR(500MHz,DMSO-d 6)δ10.29(s,1H),8.81(d,J＝2.1Hz,1H),8.57(s,1H),8.22(d,J＝2.1Hz,1H),7.87(d,J＝9.0Hz,2H),7.35(d,J＝8.8Hz,2H),6.63(s,1H),5.51–5.39(m,1H),5.38–5.27(m,1H),3.96–3.84(m,1H),3.83–3.73(m,1H),3.61(dd,J＝26.2,14.1Hz,2H),3.47(s,3H).
HRMS(ESI,[M+H] +)m/z:512.11122.
实施例80：化合物80的制备
Figure PCTCN2022095436-appb-000227
步骤A：化合物80-1的制备
参照实施例48步骤A的方法，使用化合物1-1和异噁唑烷盐酸盐制备化合物80-1。
步骤B：化合物80的制备
参照实施例48步骤B的制备方法，使用化合物45-2与化合物80-1反应制备得到化合物80。
1H NMR(500MHz,DMSO-d 6)δ10.49(s,1H),8.85(s,1H),8.55(s,1H),8.35(s,1H),7.88(d,J＝8.9Hz,2H),7.37(d,J＝8.6Hz,2H),6.67(s,1H),3.80-3.83(m,2H),3.68-3.70(m,2H),3.47(s,3H),2.13-2.18(m,2H).HRMS(ESI,[M+H] +)m/z:478.10924.
实施例81：化合物81的制备
Figure PCTCN2022095436-appb-000228
在10mL微波管中，依次加入化合物64-2(150mg)、1,4-二氧六环(4mL)和二甲羟胺盐酸盐(663mg)。氮气吹扫液面片刻后加盖密封，微波反应，140℃反应6h。过硅胶柱提纯得到化合物81。
1H NMR(500MHz,DMSO-d 6)δ10.45(s,1H),8.85(s,1H),8.55(s,1H),8.16(s,1H),7.87(d,J＝9.0Hz,2H),7.36(d,J＝8.8Hz,2H),6.52(s,1H),3.47(s,3H),3.35(s,3H),3.19(s,3H).HRMS(ESI,[M+H] +)m/z:466.1083.
实施例82：化合物82的制备
Figure PCTCN2022095436-appb-000229
步骤A：化合物82-1的制备
依次向50mL单口瓶中加入N,N-二甲基甲酰胺(10mL)、5-溴吡嗪-2(1H)-酮(500mg)和碳酸铯(1369mg)，加毕，开启搅拌，室温下向体系中缓慢滴加N,N-二甲基甲酰胺稀释的碘甲烷(419mg/2mL)，加毕，室温下反应4h；向体系中加入纯化水(10mL)和乙酸乙酯(30mL)，搅洗后分液，水相接着加入乙酸乙酯(20mL)萃取一次，合并有机相，依次以纯化水(20mL)和饱和食盐水溶液(20mL)各搅拌洗涤2次；分液得有机相减压浓缩，所得粗品经硅胶柱层析得到120mg化合物82-1。MS(ESI,[M+H] +)m/z:188.97.
步骤B：化合物82-2的制备
参照实施例1步骤D的方法，使用化合物82-1与联硼酸频那醇酯反应制备含化合物82-2的反应液，降温至室温，不经分离纯化，直接用于后面反应。
步骤C：化合物82的制备
参照实施例48步骤B的方法，使用化合物7-1和化合物82-2反应制备得到化合物82。
1H NMR(500MHz,DMSO-d 6)δ10.39(s,1H),8.77(d,J＝2.3Hz,1H),8.25(d,J＝2.4Hz,1H),8.22(d,J＝1.1Hz,1H),8.14(d,J＝1.1Hz,1H),7.92–7.83(m,2H),7.41–7.29(m,2H),3.64(t,J＝4.5Hz,4H),3.53(s,3H),3.27(t,J＝4.6Hz,4H).HRMS(ESI,[M+H] +)m/z:492.12502.
实施例83：化合物83的制备
Figure PCTCN2022095436-appb-000230
参照实施例48步骤B的方法，使用化合物23-1和化合物47-5反应制备得到化合物83。
1H NMR(500MHz,DMSO-d 6)δ10.25(s,1H),8.83(d,J＝2.3Hz,1H),8.16(d,J＝2.4Hz,1H),8.09(d,J＝2.1Hz,1H),7.89–7.82(m,2H),7.40–7.30(m,2H),7.05(d,J＝2.2Hz,1H),4.57(d,J＝6.3Hz,2H),3.78(d,J＝12.7Hz,2H),3.70(s,3H),3.64–3.56(m,2H),3.08–2.99(m,1H),1.78(d,J＝8.7Hz,1H).HRMS(ESI,[M+H] +)m/z:504.12506.
实施例84：化合物84的制备
Figure PCTCN2022095436-appb-000231
步骤A：化合物84-1的制备
参照实施例1步骤D的制备方法，使用5-溴-1-甲基吡啶-2(1H)-酮与联硼酸频那醇酯反应得到化合物84-1的反应液，不经分离纯化，直接用于下一步反应。
步骤B：化合物84的制备
参照实施例48步骤B的制备方法，使用化合物84-1的反应液和化合物7-1反应制备得到化合物84。
1H NMR(500MHz,DMSO-d 6)δ10.36(s,1H),8.75(s,1H),8.06(d,J＝14.7Hz,2H),7.88(d,J＝8.6Hz,2H),7.79(d,J＝8.8Hz,1H),7.36(d,J＝8.4Hz,2H),6.50(d,J＝9.4Hz,1H),3.63(s,4H),3.51(s,3H),3.21(s,4H).HRMS(ESI,[M+H] +)m/z:491.1295.
实施例85：化合物85的制备
Figure PCTCN2022095436-appb-000232
步骤A：化合物85-1的制备
参照实施例82步骤A的方法，使用6-溴哒嗪-3(2H)-酮和碘甲烷反应制备得到化合物85-1。MS(ESI,[M+H] +)m/z:189.0.
步骤B：化合物85-2的制备
参照实施例1步骤D的制备方法，使用化合物85-1与联硼酸频那醇酯反应得到化合物85-2的反应液，不经分离纯化，直接用于下一步反应。
步骤C：化合物85的制备
参照实施例48步骤B的制备方法，使用化合物85-2的反应液和化合物7-1反应制备得到化合物85。
1H NMR(500MHz,DMSO-d 6)δ10.43(s,1H),8.86(d,J＝2.4Hz,1H),8.25(d,J＝2.4Hz,1H),7.91–7.84(m,3H),7.42–7.32(m,2H),7.05(d,J＝9.6Hz,1H),3.75(s,3H),3.67–3.60(m,4H),3.26–3.20(m,4H).HRMS(ESI,[M+H] +)m/z:492.12480.
实施例86：化合物86的制备
Figure PCTCN2022095436-appb-000233
步骤A：化合物86-1的制备
参照实施例1步骤C的方法，使用3-溴吡啶-2(1H)-酮和碘甲烷反应制备得到化合物86-1。
1H NMR(500MHz,DMSO-d 6)δ7.90(dd,J＝7.3,1.8Hz,1H),7.77(dd,J＝6.7,1.8Hz,1H),6.17(t,J＝7.0Hz,1H),3.50(s,3H).MS(ESI,[M+H] +)m/z:187.99.
步骤B：化合物86-2的制备
参照实施例1步骤D的制备方法，使用化合物86-1与联硼酸频那醇酯反应得到含化合物86-2的反应液，不经纯化直接用于下一步制备。
步骤C：化合物86的制备
参照实施例48步骤B的制备方法，使用含化合物86-2的反应液和化合物7-1反应制备得到化合物86。
1H NMR(500MHz,DMSO-d 6)δ10.28(s,1H),8.74(d,J＝2.2Hz,1H),8.05(d,J＝2.2Hz,1H),7.87(d,J＝9.0Hz,2H),7.79(dd,J＝6.7,1.7Hz,1H),7.63(dd,J＝6.9,1.7Hz,1H),7.34(d,J＝8.8Hz,2H),6.35(t,J＝6.8Hz,1H),3.59–3.54(m,4H),3.53(s,3H),3.29–3.23(m,4H).HRMS(ESI,[M+H] +)m/z:491.1307.
实施例87：化合物87的制备
Figure PCTCN2022095436-appb-000234
步骤A：化合物87-1的制备
参照实施例1步骤A的制备方法，使用5-溴烟酸与4-(氯二氟甲氧基)苯胺反应得到化合物87-1。MS(ESI,[M+H] +)m/z:377.0.
步骤B：化合物87-2的制备
参照实施例1步骤E的制备方法，使用化合物87-1和化合物1-4反应制备得到化合物87-2。MS(ESI,[M+H] +)m/z:406.17.
步骤C：化合物87的制备
向微波管中依次加入化合物87-2(100mg)、过氧化二苯甲酰(103mg)、三氟乙酸(36mg)和二氧六环(8mL)，加毕，氮气保护后封闭，放入微波反应器中，微波反应条件：100℃，2h。反应液硅藻土过滤，收集滤液，向滤液加入乙酸乙酯(50mL)和饱和食盐水溶液(25mL)洗涤后分液，收集有机相，硅胶柱层析提纯，得到26mg的化合物87。
1H NMR(500MHz,DMSO-d 6)δ10.69(s,1H),9.16(s,1H),8.70(s,1H),8.26(s,1H),7.90(d,J＝8.3Hz,2H),7.81(d,J＝6.6Hz,1H),7.36(d,J＝8.1Hz,2H),6.20(d,J＝6.6Hz,1H),4.60(d,J＝9.3Hz,1H),3.97–3.82(m,1H),3.76–3.63(m,1H),3.56–3.53(m,1H),3.50(s,3H),3.47–3.40(m,1H),3.37–3.20(m,2H).HRMS(ESI,[M+H] +)m/z:492.11330.
实施例88：化合物88的制备
Figure PCTCN2022095436-appb-000235
步骤A：化合物88-1的制备
参照实施例64步骤B的制备方法，使用化合物64-1和化合物47-4反应制备得到化合物88-1。MS(ESI,[M+H] +)m/z:441.05.
步骤B：化合物88的制备
参照实施例64步骤C的方法，使用化合物88-1和(1R,4R)-2-氧杂-5-氮杂双环[2.2.1]庚烷盐酸盐制备化合物88。
1H NMR(500MHz,DMSO-d 6)δ10.24(s,1H),8.79(d,J＝1.9Hz,1H),8.17(d,J＝1.9Hz,1H),8.07–7.99(m,1H),7.86(d,J＝9.0Hz,2H),7.35(d,J＝8.7Hz,2H),6.98(s,1H),4.95(s,1H),4.55(s,1H),3.79(s,2H),3.70(s,3H),3.23(d,J＝9.6Hz,1H),2.81(d,J＝9.9Hz,1H),1.90(d,J＝8.8Hz,1H),1.82(d,J＝9.8Hz, 1H).HRMS(ESI,[M+H] +)m/z:504.12449.
实施例89：化合物89的制备
Figure PCTCN2022095436-appb-000236
参照实施例64步骤C的方法，使用化合物88-1和3-氧杂-8-氮杂双环[3.2.1]辛烷盐酸盐制备化合物89。
1H NMR(500MHz,DMSO-d 6)δ10.32(s,1H),8.81(d,J＝2.2Hz,1H),8.20(dd,J＝10.7,2.1Hz,2H),7.86(d,J＝9.0Hz,2H),7.36(d,J＝8.8Hz,2H),7.18(d,J＝2.0Hz,1H),4.15(s,2H),3.69(s,3H),3.66(d,J＝10.7Hz,2H),3.50(d,J＝10.4Hz,2H),1.89–1.82(m,2H),1.79(dd,J＝13.8,8.8Hz,2H).HRMS(ESI,[M+H] +)m/z:518.14261.
实施例90：化合物90的制备
Figure PCTCN2022095436-appb-000237
向一个35mL的微波管中，依次加入化合物88-1(200mg)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑(113mg)、碳酸钾(63mg)、四(三苯基膦)钯(20mL)和二氧六环(15mL)，加毕，氮气保护后封闭放入微波反应器中，微波反应条件：140℃，2h。反应液硅藻土过滤，收集滤液，向滤液加入乙酸乙酯(50mL)和饱和食盐水溶液(25mL)洗涤后分液，收集有机相，硅胶柱层析提纯，得到100mg的化合物90。
1H NMR(500MHz,CDCl 3)δ9.06(s,1H),8.41(s,1H),8.19(s,1H),8.12(s,1H),7.80(s,1H),7.71(d,J＝8.7Hz,2H),7.40(s,1H),7.26(d,J＝6.6Hz,2H),6.58(s,1H),3.88(s,3H),3.57(s,3H).HRMS(ESI,[M+H] +)m/z:487.10909.
实施例91：化合物91的制备
Figure PCTCN2022095436-appb-000238
参照实施例64步骤C的方法，使用化合物88-1和8-氧代-3-杂氮二环[3,2,1]辛烷盐酸盐制备化合物91。
1H NMR(500MHz,DMSO-d 6)δ10.31(s,1H),8.82(d,J＝2.2Hz,1H),8.20(d,J＝2.2Hz,1H),8.09(d,J＝2.0Hz,1H),7.86(d,J＝9.0Hz,2H),7.36(d,J＝8.8Hz,2H),7.11(d,J＝2.0Hz,1H),4.30(s,2H),3.71(s,3H),3.45(d,J＝12.4Hz,2H),3.08(d,J＝11.6Hz,2H),1.74(s,4H).HRMS(ESI,[M+H] +)m/z:518.1404.
实施例92：化合物92的制备
Figure PCTCN2022095436-appb-000239
参照实施例48步骤B的制备方法，使用化合物20-1与化合物36-5反应制备得到化合物92。
1H NMR(500MHz,DMSO-d 6)δ10.26(s,1H),8.72(d,J＝2.3Hz,1H),7.95(d,J＝2.3Hz,1H),7.90–7.82(m,2H),7.66(s,1H),7.39–7.26(m,2H),4.69(s,2H),4.21–4.14(m,2H),4.13–4.06(m,2H),4.03–3.85(m,4H),3.61–3.51(m,2H),2.70–2.60(m,1H),1.70(d,J＝8.1Hz,1H).HRMS(ESI,[M+H] +)m/z:518.14062.
实施例93：化合物93的制备
Figure PCTCN2022095436-appb-000240
步骤A：化合物93的制备
参照实施例48步骤B的制备方法，使用化合物56-1与化合物36-5反应制备得到化合物93。
1H NMR(500MHz,DMSO-d 6)δ10.35(s,1H),8.74(d,J＝2.3Hz,1H),7.97(d,J＝2.3Hz,1H),7.87(d,J＝9.1Hz,2H),7.79(s,1H),7.35(d,J＝8.9Hz,2H),5.01(d,J＝15.1Hz,1H),4.68(d,J＝15.1Hz,1H),4.23–4.06(m,4H),3.77–3.64(m,2H),3.62(dd,J＝11.2,2.8Hz,1H),3.58–3.50(m,1H),3.46(dd,J＝11.3,3.4Hz,1H),3.21(ddd,J＝12.7,9.6,3.0Hz,1H),3.10(d,J＝13.4Hz,1H),0.99(d,J＝6.5Hz,3H).HRMS(ESI,[M+H] +)m/z:520.15643.
实施例94：化合物94的制备
Figure PCTCN2022095436-appb-000241
步骤A：化合物94-1的制备
在一个100mL的单口瓶中，依次加入2-异氰乙酸乙酯(1g)、无水二氧六环(10mL)、N-BOC-3-丁炔-1-胺(2.24g)和碳酸银(0.25g)，氮气保护，将所得混合物油浴加热至80℃反应过夜。待反应结束，向反应液中加入乙酸乙酯(50mL)和饱和食盐水溶液(25mL)洗涤后分液，收集有机相，硅胶柱层析提纯，得到1g的化合物94-1。MS(ESI,[M+Na] +)m/z:305.14.
步骤B：化合物94-2的制备
在一个50mL的单口瓶中，依次加入化合物94-1(1.2g)、甲醇(10mL)、2M的氢氧化锂水溶液(5mL)，50℃油浴条件下反应过夜。待反应完全，使用2M的稀盐酸调节pH至3～4，向反应液中加入乙酸乙酯(50mL)和饱和食盐水溶液(25mL)洗涤后分液，收集有机相，无水硫酸钠干燥，过滤、浓缩得到0.6g的化合物94-2。MS(ESI,[M-H] -)m/z:253.13.
步骤C：化合物94-3的制备
在一个50mL的单口瓶中，依次加入化合物94-2(0.47g)和二氯甲烷(10mL)，缓慢滴加二氯亚砜(0.27g)，加毕，室温搅拌2h。待反应完全，使用饱和碳酸钠水溶液调节pH至碱性，用乙酸乙酯(100mL)萃取5次，合并有机相，无水硫酸钠干燥，过滤，浓缩得到0.25g的化合物94-3。MS(ESI,[M+H] +)m/z:137.1.
步骤D：化合物94-4的制备
在一个100mL的单口瓶中，依次加入化合物94-3(0.22g)、二氯甲烷(10mL)、三乙胺(0.33g)、二碳酸二叔丁酯(0.36g)和4-二甲氨基吡啶(10mg)，氮气保护，混合物室温搅拌2h。待反应结束，向反应液中加入乙酸乙酯(50mL)和饱和食盐水溶液(25mL)洗涤后分液，收集有机相，硅胶柱层析提纯，得到0.13g的化合物94-4。MS(ESI,[M+H-C(CH 3) 3] +)m/z:181.10.
步骤E：化合物94-5的制备
在一个50mL的单口瓶中，依次加入化合物94-4(0.1g)、乙腈(10mL)、碘甲烷(0.1g)和碳酸铯(0.28g)，氮气保护，将所得混合物在80℃油浴条件下反应过夜。待反应结束，向反应液中加入乙酸乙酯(50mL)和饱和食盐水溶液(25mL)洗涤后分液，收集有机相，硅胶柱层析提纯，得到69mg的化合物94-5。MS(ESI,[M+H-C(CH 3) 3] +)m/z:195.10.
步骤F：化合物94-6的制备
在一个50mL的单口瓶中，依次加入化合物94-5(1g)和2M的盐酸二氧六环溶液(10mL)，氮气保护，混合物室温条件下搅拌2h。待反应结束，向反应体系中加入三乙胺(5mL)调节pH至碱性，向反应液中加入乙酸乙酯(50mL)和饱和食盐水溶液(25mL)洗涤后分液，收集有机相，硅胶柱层析提纯，得到0.5g的化合物94-6。MS(ESI,[M+H] +)m/z:151.06.
步骤G：化合物94-7的制备
在一个50mL的单口瓶中，依次加入化合物94-6(0.1g)、无水四氢呋喃(10mL)、联硼酸频那醇酯(0.25g)、3,4,7,8-四甲基-1,10-菲罗啉(10mg)以及甲氧基(环辛二烯)合铱二聚体(25mg)，氮气保护，将所得混合物油浴加热至70℃条件下回流4h。待反应完，减压浓缩除去溶剂。不经分离纯化，立即用于下步反应。MS(ESI,[M+H] +)m/z:277.18.
步骤H：化合物94的制备
向一个50mL的单口瓶中，依次加入化合物11-1(100mg)、二氧六环(10mL)、化合物94-7(72mg)、无水碳酸钾(30mg)、四(三苯基膦)钯(30mg)和水(1mL)。加毕，氮气保护后油浴100℃反应过夜。向反应液中加入乙酸乙酯(50mL)和饱和食盐水溶液(25mL)洗涤后分液，收集有机相，硅胶柱层析提纯，得到30mg的化合物94。
1H NMR(500MHz,DMSO-d 6)δ11.80(d,J＝1.6Hz,1H),10.14(s,1H),8.71(d,J＝2.4Hz,1H),8.05(d,J＝2.4Hz,1H),7.93–7.84(m,2H),7.33(d,J＝9.0Hz,2H),6.01(d,J＝2.0Hz,1H),4.87(d,J＝3.4Hz,1H),4.22(d,J＝2.4Hz,1H),3.58–3.49(m,2H),3.49–3.41(m,1H),3.30(dd,J＝6.9,4.5Hz,2H),2.99(d,J＝11.7Hz,1H),2.93(s,3H),2.78(t,J＝6.9Hz,2H),1.84(ddd,J＝12.6,8.6,4.3Hz,1H),1.78–1.70(m,1H).HRMS(ESI,[M+H] +)m/z:532.15638.
实施例95：化合物95的制备
Figure PCTCN2022095436-appb-000242
步骤A：化合物95-1的制备
向一个250mL单口瓶中加入无水N,N-二甲基甲酰胺(150mL)，开启搅拌接着向体系中加入4-甲基-5-咪唑甲酸乙酯(10.0g)，降至0℃后向体系中分批加入钠氢(3.11g,至含量为60％w/w)，加毕，保温搅拌30min后向体系中滴加2-(三甲基硅烷基)乙氧甲基氯(12.98g)，加毕，升温至室温下反应4h。向其中加入乙酸乙酯(100mL)和饱和氯化铵水溶液(100mL)，搅洗后分液，水相接着加入乙酸乙酯(100mL)萃取一次，合并有机相，向其中加入饱和氯化钠水溶液(150mL)搅洗后分液，有机相减压浓缩得残余物，经硅胶柱层析纯化得到13.18g化合物95-1。MS(ESI,[M+H] +)m/z:285.20.
步骤B：化合物95-2的制备
依次向250mL单口瓶中加入1,2-二氯乙烷(100mL)、化合物95-1(4.98g)、N-溴代丁二酰亚胺(6.48g)和偶氮二异丁腈(0.257g)，加毕，氮气置换后升温至70-80℃下反应6h。降温至室温后将反应液过滤，滤液减压浓缩得残余物，经硅胶柱层析纯化得到2.20g化合物95-2。MS(ESI,[M+Na] +)m/z:463.03.
步骤C：化合物95-3的制备
依次向100mL单口瓶中加入无水乙醇(50mL)、甲胺盐酸盐(1.527g)和N,N-二异丙基乙胺(5.85 g)，加毕搅拌30min，接着向体系中加入上述步骤B所得化合物95-2(2.0g)，加毕室温下反应过夜，将反应液减压浓缩，所得残余物经硅胶柱层析得到570mg化合物95-3。MS(ESI,[M+H] +)m/z:392.05.
步骤D：化合物95-4的制备
向一个100mL单口瓶中加入甲醇(30mL)，开启搅拌接着依次向体系中加入上述步骤C所得化合物95-3(570mg)、氢氧化锂(0.311g)和纯化水(10mL)，加毕室温下反应3h；将体系减压浓缩，向所得残余物中加入乙酸乙酯(20mL)及纯化水(10mL)，接着向体系中滴加1M的盐酸水溶液调节PH至6～7，体系变浑浊并析出固体，过滤，滤饼以纯化水(5mL)和乙酸乙酯(5mL)依次淋洗，收集滤饼置入真空干燥箱中，50℃下真空干燥至恒重，得到390mg化合物95-4。MS(ESI,[M+H] +)m/z:364.2.
步骤E：化合物95-5的制备
向一个25mL单口瓶中加入N,N-二甲基甲酰胺(10mL)，开启搅拌，依次向体系中加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(488mg)和N,N-二异丙基乙胺(415mg)，搅拌5min后向体系中滴加N,N-二甲基甲酰胺(5mL)溶解的上述步骤D所得化合物95-4(390mg)的N,N-二甲基甲酰胺溶液；加毕室温下反应1h；向体系中加入乙酸乙酯(30mL)及纯化水(10mL)，搅洗后分液，收集有机相，水相加入乙酸乙酯(10mL)萃取2次；合并有机相，分别加入纯化水(15mL)及饱和氯化钠水溶液(15mL)各搅洗2次，分液收集有机相，减压浓缩，所得残余物经硅胶柱层析得到200mg化合物95-5。MS(ESI,[M+H] +)m/z:346.1.
步骤F：化合物95-6的制备
参照实施例62步骤B的方法，使用化合物11-1和联硼酸新戊二醇酯反应制备化合物95-6。反应产物未处理，直接用于下一步反应。
步骤G：化合物95-7的制备
参照实施例62步骤C的制备方法，使用化合物95-6与化合物95-5反应制备得到化合物95-7。MS(ESI,[M-H] -)m/z:647.3.
步骤H：化合物95的制备
向一个25mL单口瓶中加入二氯甲烷(10mL)，开启搅拌，依次向体系中加入上述步骤G所得化合物95-7(90mg)和三氟乙酸(4467mg)，加毕室温下反应2h；将反应液减压浓缩，向所得残余物中加入乙酸乙酯(15mL)和饱和碳酸氢钠水溶液(10mL)搅洗后分液，得有机相接着加入饱和氯化钠水溶液(10mL)搅洗后分液，收集有机相减压浓缩得浓缩物，经反相色谱柱制备纯化得到化合物95(20mg)。
1H NMR(500MHz,DMSO-d 6)δ13.09(d,J＝115.1Hz,1H),10.23(d,J＝8.5Hz,1H),8.98–8.68(m,1H),8.19(d,J＝2.5Hz,1H),7.87(d,J＝8.7Hz,2H),7.33(d,J＝8.6Hz,2H),4.89(d,J＝3.2Hz,1H),4.33(t,J＝49.6Hz,3H),3.50–3.39(m,1H),3.27(s,1H),3.03(d,J＝11.5Hz,3H),2.92(d,J＝11.8Hz,1H),1.95–1.68(m,2H).HRMS(ESI,[M+H] +)m/z:519.13584.
实施例96：化合物96的制备
Figure PCTCN2022095436-appb-000243
步骤A：化合物96-1的制备
参照实施例94步骤A的方法，使用2-异氰乙酸乙酯和N-Boc-氨基丙炔反应制备化合物96-1。MS(ESI,[M+Na-Boc] +)m/z:191.1.
步骤B：化合物96-2的制备
参照实施例94步骤B的方法，使用化合物96-1在碱性条件下制备化合物96-2。MS(ESI,[M-H] -)m/z:239.214.
步骤C：化合物96-3的制备
参照实施例94步骤C的方法，使用化合物96-2与二氯亚砜反应制备化合物96-3。MS(ESI,[M+H] +)m/z:123.06.
步骤D：化合物96-4的制备
参照实施例94步骤G的方法，使用化合物96-3与联硼酸频那醇酯反应制备96-4。MS(ESI,[M+H] +)m/z:249.23.
步骤E：化合物96的制备
参照实施例94步骤H的方法，使用化合物7-1与化合物96-4反应制备化合物96。
1H NMR(500MHz,DMSO-d 6)δ11.99(s,1H),10.35(s,1H),8.72(d,J＝1.8Hz,1H),8.22(d,J＝1.8Hz,1H),8.06–7.74(m,3H),7.36(d,J＝8.7Hz,2H),6.52(s,1H),4.15(s,2H),3.65(s,4H),3.17(s,4H).HRMS(ESI,[M+H] +)m/z:504.12491.
实施例97：化合物97的制备
Figure PCTCN2022095436-appb-000244
步骤A：化合物97-1的制备
参照实施例94步骤G的方法，使用化合物94-3与联硼酸频那醇酯反应制备化合物97-1。MS(ESI,[M+H] +)m/z:263.23.
步骤B：化合物97的制备
参照实施例94步骤H的方法，使用化合物7-1与化合物97-1反应制备化合物97。
1H NMR(500MHz,DMSO-d 6)δ11.82(s,1H),10.32(s,1H),8.69(d,J＝2.2Hz,1H),8.26(d,J＝2.2Hz,1H),7.88(d,J＝9.1Hz,2H),7.36(d,J＝8.8Hz,2H),7.21(s,1H),6.44(d,J＝1.8Hz,1H),3.90–3.55(m,4H),3.43–3.35(m,2H),3.21–3.13(m,4H),2.71(t,J＝6.8Hz,2H).HRMS(ESI,[M+H] +)m/z:518.14061.
实施例98：化合物98的制备
Figure PCTCN2022095436-appb-000245
步骤A：化合物98的制备
参照实施例94步骤H的方法，使用化合物48-1与化合物97-1反应制备化合物98。
1H NMR(500MHz,DMSO-d 6)δ11.82(s,1H),10.17(s,1H),8.70(d,J＝2.2Hz,1H),8.08(d,J＝2.2Hz,1H),7.87(d,J＝9.1Hz,2H),7.34(d,J＝8.8Hz,2H),7.17(s,1H),6.07(d,J＝1.5Hz,1H),5.55(d,J＝5.8Hz,1H),4.42(dd,J＝10.7,5.1Hz,1H),4.01–3.89(m,2H),3.57(dd,J＝9.6,4.4Hz,2H),3.39(dd,J＝6.5,4.7Hz,2H),2.70(t,J＝6.7Hz,2H).HRMS(ESI,[M+H] +)m/z:504.12481.
实施例99：化合物99的制备
Figure PCTCN2022095436-appb-000246
步骤A：化合物99的制备
参照实施例94步骤H的方法，使用化合物11-1与化合物97-1反应制备化合物99。
1H NMR(500MHz,DMSO-d 6)δ11.80(s,1H),10.14(s,1H),8.71(d,J＝2.0Hz,1H),8.06(d,J＝2.0Hz,1H),7.87(d,J＝9.0Hz,2H),7.33(d,J＝8.7Hz,2H),7.13(s,1H),6.03(s,1H),4.88(d,J＝3.2Hz,1H),4.23(s,1H),3.47(dd,J＝17.5,9.7Hz,1H),3.39(t,J＝5.6Hz,2H),3.31(d,J＝5.2Hz,2H),2.99(d,J＝11.6Hz,1H),2.70(t,J＝6.7Hz,2H),1.89–1.79(m,1H),1.76(d,J＝3.5Hz,1H).HRMS(ESI,[M+H] +)m/z:518.14020.
实施例100：化合物100的制备
Figure PCTCN2022095436-appb-000247
步骤A：化合物100-1的制备
反应体系A：-30℃下，氮气保护下，将叔丁醇钾(3.50g)缓慢加入3-(叔丁氧基)-3-氧代丙酸(5g)和氯化镁(2.97g)的四氢呋喃(200mL)搅拌液中，30分钟滴加完毕，将所得混合物在室温搅拌反应5h。反应体系B：-30℃下，氮气保护下，将N,N'-羰基二咪唑(4.56g)加入(叔丁氧羰基)甘氨酸(4.37g)的四氢呋喃(200mL)搅拌液中，滴加完毕，将所得混合物在室温搅拌反应3h。0℃下，将反应体系B滴加入反应体系A，滴加完毕后将反应体系转移至室温搅拌2天。向反应体系中加入乙酸乙酯(500mL)萃取，有机相先后用1M的盐酸(200mL)、饱和碳酸氢钠水溶液(200mL)和水(200mL)洗涤。有机相用无水硫酸钠干燥后，减压蒸馏去除溶剂得到8g的化合物100-1。MS(ESI,[M+Na] +)m/z:296.21.
步骤B：化合物100-2的制备
向一个50mL的单口瓶中，依次加入化合物100-1(7g)、甲醇(6mL)、氨水(4.36g)、醋酸铵(19.74g)和2-氯乙醛(20.10g)，氮气保护下，将混合物加热至50℃反应3h。停止搅拌，反应液经硅胶柱层析纯化得到6.5g的化合物100-2。MS(ESI,[M+Na] +)m/z:319.25.
步骤C：化合物100-3的制备
0℃下，氮气保护下，将叔丁醇钠(4.22g)缓慢加入化合物100-2(6.5g)的四氢呋喃(10mL)搅拌液中，加完毕后，将所得混合物在室温搅拌反应1h。0℃下缓慢滴加4-对甲苯磺酰氯(5.02g)的四氢呋喃(10mL)溶液，10min滴加完毕，将混合物恢复至室温，搅拌反应过夜。停止搅拌，反应液中加入饱和氯化铵溶液(50mL)淬灭，加入乙酸乙酯(200mL)和水(200mL)萃取，分离有机相，水相再用乙酸乙酯(50mL)萃取两次，合并有机相，用饱和食盐水溶液(300mL)洗涤，无水硫酸钠干燥，过滤，滤液经硅胶柱层析纯化得到8.5g化合物100-3。MS(ESI,[M+Na] +)m/z:473.3.
步骤D：化合物100-4的制备
向一个50mL的茄形瓶中，依次加入化合物100-3(8.5g)和二氯甲烷(10mL)，氮气保护下，加入三氟醋酸(10mL)，混合物室温反应过夜。停止搅拌，将反应体系通过减压蒸馏蒸除溶剂得到5.6g的化合物100-4。MS(ESI,[M+H] +)m/z:295.11.
步骤E：化合物100-5的制备
向一个50mL的单口瓶中，依次加入四氢呋喃(5mL)、N,N-二异丙基乙胺(4.61g)以及化合物100-4(3.5g)，0℃下滴加1-丙基磷酸酐(4.54g)，氮气保护下，将混合物室温反应3h。经硅胶柱层析纯化得到3g的化合物100-5。MS(ESI,[M+H] +)m/z:277.13.
步骤F：化合物100-6的制备
向一个50mL单口瓶中，依次加入甲醇(5mL)、化合物100-5(1g)，碳酸钾(1.501g)，氮气保护下，将混合物室温反应过夜。减压浓缩至干，得到白色固体粗品，加入乙酸乙酯(50mL)稀释所述粗品，再加入水(30mL)洗涤，有机相用饱和氯化钠洗涤，得到300mg的化合物100-6。MS(ESI,[M+H] +)m/z:123.04.
步骤G：化合物100-7的制备
向一个25mL的单口瓶中，依次加入四氢呋喃(100mL)和化合物100-6(200mg)，加毕，搅拌下氮气置换后降温至-80℃，加入N-溴代丁二酰亚胺(357mg)，搅拌0.5h。反应结束，向反应体系中滴加1滴水，加入乙醇(5mL)，反应体系经硅胶柱层析纯化得到200mg的化合物100-7。MS(ESI,[M+H] +)m/z:201.06.
步骤H：化合物100的制备
参照实施例62步骤C的制备方法，使用化合物95-6与化合物100-7反应制备得到化合物100。
1H NMR(500MHz,DMSO-d 6)δ11.73(s,1H),10.18(s,1H),8.74(s,1H),8.08(s,1H),7.88(d,J＝8.8Hz,2H),7.54(s,1H),7.33(d,J＝8.6Hz,2H),6.17(s,1H),4.87(s,1H),4.23(s,3H),3.46-3.51(m,1H),3.30-3.31(m,2H),3.01-3.04(m,1H),1.76-1.86(m,2H).HRMS(ESI,[M+H] +)m/z:504.12477.
实施例101：化合物101的制备
Figure PCTCN2022095436-appb-000248
步骤A：化合物101-1的制备
0℃下，氮气保护下，将2-氯乙醛(24.53g)缓慢加入1,3-丙酮二羧酸二乙酯(31.6g)的乙腈(80mL)搅拌液中，加完毕后混合物在50℃搅拌反应3h。停止搅拌，反应液中加入饱和氯化铵溶液(50mL)淬灭反应，加入乙酸乙酯(200mL)和水(200mL)萃取，分离有机相，水相再用乙酸乙酯(50mL)萃取两次，合并有机相后用饱和食盐水溶液(300mL)洗涤，无水硫酸钠干燥，过滤，滤液经硅胶柱层析纯化得到22.6g的化合物101-1。MS(ESI,[M+H] +)m/z:227.2.
步骤B：化合物101-2的制备
向一个50mL的单口瓶中，依次加入乙腈(400mL)和化合物101-1(22g)。加毕，体系降温至0℃，加入N-溴代丁二酰亚胺(21.19g)，氮气置换后升温至室温下反应。过滤，收集母液，经硅胶柱层析纯化得到25g的化合物101-2。MS(ESI,[M+H] +)m/z:305.1.
步骤C：化合物101-3的制备
向一个50mL的单口瓶中，依次加入化合物101-2(24g)和乙醇(20mL)，降温至冰浴，随后加入硼氢化钠(8.93g)，将混合物室温搅拌3h。向反应体系加入饱和氯化铵水溶液(100mL)淬灭反应，再加入乙酸乙酯(50mL)萃取，有机相再用乙酸乙酯(50mL)萃取2次，合并有机相，经硅胶柱层析纯化得到7g化合物101-3。MS(ESI,[M+H] +)m/z:263.02.
步骤D：化合物101-4的制备
向一个50mL的三口瓶中，依次加入化合物101-3(6.5g)、邻苯二甲酰亚胺(4.36g)、三苯基膦(9.72g)及四氢呋喃(10mL)，氮气保护下，0℃条件下向其中滴加偶氮二甲酸二异丙酯(7.49g)，滴加完毕后移至室温搅拌反应过夜。向反应液中加入水和乙酸乙酯，萃取分液。有机相分别用水和饱和食盐水洗涤，无水硫酸钠干燥，经硅胶柱层析纯化得到8.5g的化合物101-4。MS(ESI,[M+H] +)m/z:392.14.
步骤E：化合物101-5的制备
向一个200mL的三口瓶中，依次加入化合物101-4(8g)及乙醇(600mL)，0℃下加入水合肼(2.403g)，加毕，将混合物加热至50℃反应过夜，硅胶柱层析纯化得到5g化合物101-5。MS(ESI,[M+H] +)m/z:262.09.
步骤F：化合物101-6的制备
向一个50mL的反应瓶中，依次加入化合物101-5(1g)、1,5,7-三叠氮双环(4.4.0)癸-5-烯(0.159g)及四氢呋喃(5mL)，将所得混合物75℃搅拌反应30min，硅胶柱层析纯化得到600mg的化合物101-6。MS(ESI,[M+H] +)m/z:216.03.
步骤G：化合物101-7的制备
参照实施例60步骤A的制备方法，使用化合物101-6与碘甲烷反应制备得到化合物101-7。MS(ESI,[M+H] +)m/z:230.0.
步骤H：化合物101的制备
参照实施例62步骤C的制备方法，使用化合物95-6与化合物101-7反应制备得到化合物101。
1H NMR(500MHz,DMSO-d 6)δ11.73(s,1H),10.18(s,1H),8.74(s,1H),8.08(s,1H),7.88(d,J＝8.8Hz,2H),7.54(s,1H),7.33(d,J＝8.6Hz,2H),6.17(s,1H),4.87(s,1H),4.23(s,3H),3.46-3.51(m,1H),3.30-3.31(m,2H),3.01-3.04(m,1H),1.76-1.86(m,2H).HRMS(ESI,[M+H] +)m/z:533.14074.
实施例102：化合物102的制备
Figure PCTCN2022095436-appb-000249
步骤A：化合物102-1的制备
向一个100mL单口瓶中加入N,N-二甲基甲酰胺(50mL)、3-溴-1H-吡唑-5-胺(3.0g)、碳酸铯(9.05g)、溴代乙醛缩二乙醇(4.01g)；加毕，氮气保护，升温至100℃，反应过夜。降至室温后向体系中加入乙酸乙酯(50mL)及纯化水(50mL)，搅洗后分液，收集有机相，水相接着加入乙酸乙酯(50mL)萃取2次，合并有机相，加入纯化水(50mL)及饱和氯化钠水溶液(50mL)各搅洗2次，分液收集有机相，减压浓缩得残余物，经硅胶柱层析纯化，得到3.15g化合物102-1。MS(ESI,[M+H] +)m/z:278.1.
步骤B：化合物102-2的制备
向一个100mL单口瓶中加入无水乙醇(50mL)、化合物102-1(3.0g)、1M的硫酸水溶液(7.5mL)；加毕，氮气保护，升温至80℃，反应4h。降至室温后将体系减压浓缩，向所得残余物中加入二氯甲烷(20mL)及饱和碳酸氢钠溶液(10mL)，搅洗后分液，得有机相加入饱和氯化钠溶液(10mL)，搅洗后分液收集有机相，减压浓缩得残余物，经硅胶柱层析纯化，得到500mg化合物102-2。MS(ESI,[M+H] +)m/z:186.0.
步骤C：化合物102-3的制备
依次向50mL单口瓶中加入二氯甲烷(10mL)、化合物102-3(200mg)、二碳酸二叔丁酯(258mg)、N,N-二异丙基乙胺(208mg)、4-二甲氨基吡啶(15mg)，加毕，室温下反应2h；向体系中依次加入1moL/L的盐酸水溶液(10mL)搅洗2次、饱和氯化钠水溶液搅洗1次，分液，收集有机相，减压浓缩得残余物，经硅胶柱层析纯化得到200mg化合物102-3。MS(ESI,[M+H] +)m/z:285.9.
步骤D：化合物102的制备
参照实施例62步骤C的制备方法，使用化合物95-6与化合物102-3反应制备得到化合物102。
1H NMR(500MHz,DMSO-d 6)δ11.09(s,1H),10.16(s,1H),8.72(d,J＝2.4Hz,1H),8.08(d,J＝2.5Hz,1H),7.97–7.81(m,2H),7.53(d,J＝2.2Hz,1H),7.32(d,J＝8.7Hz,2H),7.18(d,J＝2.2Hz,1H),5.79(s,1H),4.81(d,J＝3.3Hz,1H),4.25–4.11(m,1H),3.56–3.45(m,1H),3.08–2.97(m,1H),1.88–1.77(m,1H),1.77–1.64(m,1H).HRMS(ESI,[M+H] +)m/z:489.12628.
实施例103：化合物103的制备
Figure PCTCN2022095436-appb-000250
步骤A：化合物103-1的制备
参照实施例62步骤B的制备方法，使用化合物48-1与联硼酸新戊二醇酯反应制备得到化合物103-1。
步骤B：化合物103的制备
参照实施例62步骤C的制备方法，使用化合物103-1与化合物102-3反应制备得到化合物103。
1H NMR(500MHz,DMSO-d 6)δ11.10(s,1H),10.22(s,1H),8.71(d,J＝2.3Hz,1H),8.11(d,J＝2.4Hz,1H),7.92–7.84(m,2H),7.56(d,J＝1.8Hz,1H),7.36–7.29(m,2H),7.20(t,J＝2.4Hz,1H),5.82(s,1H),5.48(d,J＝5.9Hz,1H),4.41–4.34(m,1H),4.04–3.97(m,2H),3.63–3.55(m,2H).HRMS(ESI,[M+H] +)m/z:475.10915.
实施例104：化合物104的制备
Figure PCTCN2022095436-appb-000251
参照实施例94步骤H的制备方法，使用化合物48-1与化合物96-4反应制备得到化合物104。
1H NMR(500MHz,DMSO-d 6)δ11.94(s,1H),10.21(s,1H),8.73(d,J＝1.9Hz,1H),8.08(d,J＝1.8Hz,1H),7.87(d,J＝9.0Hz,2H),7.82(s,1H),7.34(d,J＝8.7Hz,2H),6.19(s,1H),5.55(d,J＝5.7Hz,1H),4.48–4.34(m,1H),4.15(s,2H),4.02–3.88(m,2H),3.57(dd,J＝9.4,4.3Hz,2H).HRMS(ESI,[M-H] -)m/z:488.09439.
实施例105：化合物105的制备
Figure PCTCN2022095436-appb-000252
步骤A：化合物105-1的制备
在一个35mL的微波管中，依次加入化合物96-3(0.1g)、无水四氢呋喃(10mL)、联硼酸频那醇酯(0.25g)、3,4,7,8-四甲基-1,10-菲罗啉(10mg)以及甲氧基(环辛二烯)合铱二聚体(25mg)，氮气保护，混合物放入微波反应器中，微波条件：100℃，2h。待反应完，减压浓缩除去溶剂。反应同时生成化合物96-4和化合物105-1。所得混合物不经分离纯化，立即用于下步反应。
步骤B：化合物105的制备
参照实施例94步骤H的制备方法，使用化合物48-1与上述步骤A得到的含化合物105-1的混合物反应，同时得到化合物104和化合物105的混合物，使用YMC高压制备色谱仪(Ultimate XB-Phenyl柱，流速为40mL/min，流动相为纯水/乙腈＝13:7)分离，最终得到化合物105。
1H NMR(500MHz,DMSO-d 6)δ11.89(s,1H),10.20(s,1H),8.66(s,1H),8.01(s,1H),7.94–7.82(m,3H),7.34(d,J＝8.1Hz,2H),7.25(s,1H),5.50(d,J＝5.4Hz,1H),4.39(s,1H),4.09(s,2H),3.97–3.74(m,2H),3.50(d,J＝4.7Hz,2H).HRMS(ESI,[M-H] -)m/z:488.09448.
实施例106：化合物106的制备
Figure PCTCN2022095436-appb-000253
参照实施例94步骤H的制备方法，使用化合物11-1与化合物96-4反应制备得到化合物106。
1H NMR(500MHz,DMSO-d 6)δ11.90(s,1H),10.17(s,1H),8.74(d,J＝2.4Hz,1H),8.08(d,J＝2.4Hz,1H),7.90–7.85(m,2H),7.79(s,1H),7.33(d,J＝9.0Hz,2H),6.16(d,J＝1.2Hz,1H),4.88(d,J＝3.1Hz,1H),4.22(s,1H),4.14(s,2H),3.47(dt,J＝9.4,7.3Hz,1H),3.32–3.26(m,2H),3.05–2.94(m,1H),1.85(ddd,J＝12.7,11.9,7.7Hz,1H),1.80–1.71(m,1H).HRMS(ESI,[M+H] +)m/z:504.12506
实施例107：化合物107的制备
Figure PCTCN2022095436-appb-000254
参照实施例94步骤H的制备方法，使用化合物48-1与化合物94-7反应制备得到化合物107。
1H NMR(500MHz,DMSO-d 6)δ11.82(s,1H),10.18(s,1H),8.69(d,J＝2.0Hz,1H),8.07(d,J＝1.9Hz,1H),7.87(d,J＝9.0Hz,2H),7.34(d,J＝8.7Hz,2H),6.05(s,1H),5.54(d,J＝5.5Hz,1H),4.47–4.35(m,1H),4.01–3.90(m,2H),3.62–3.49(m,4H),2.94(s,3H),2.79(t,J＝6.8Hz,2H).HRMS(ESI,[M+H] +)m/z:518.1399.
实施例108：化合物108的制备
Figure PCTCN2022095436-appb-000255
步骤A：化合物108-1的制备
参照实施例105步骤A的制备方法，使用化合物94-6与联硼酸频那醇酯反应制备得到含化合物108-1的粗品，不经分离纯化，立即用于下步反应。
步骤B：化合物108的制备
参照实施例94步骤H的制备方法，使用化合物48-1与上述步骤A得到的含化合物108-1的粗品反应，同时得到化合物107和化合物108的混合物，使用YMC高压制备色谱仪(Ultimate XB-Phenyl柱，流速为40mL/min，流动相为纯水/乙腈＝13:7)分离，最终得到化合物108。
1H NMR(500MHz,DMSO-d 6)δ11.80(s,1H),10.17(s,1H),8.73–8.59(m,1H),7.95–7.89(m,1H),7.87(d,J＝8.9Hz,2H),7.33(d,J＝8.6Hz,2H),7.00(d,J＝2.4Hz,1H),5.49(d,J＝5.9Hz,1H),4.37(h,J＝6.4Hz,1H),3.97–3.86(m,2H),3.58–3.46(m,4H),2.94(s,3H),2.63(t,J＝6.7Hz,2H).HRMS(ESI,[M+H] +)m/z:518.1408.
实施例109：化合物109的制备
Figure PCTCN2022095436-appb-000256
参照实施例94步骤H的制备方法，使用化合物61-1与化合物96-4反应制备得到化合物109。
1H NMR(500MHz,DMSO-d 6)δ11.90(s,1H),10.27(s,1H),8.71(d,J＝1.9Hz,1H),8.15(d,J＝1.9Hz,1H),7.88(d,J＝9.0Hz,2H),7.81(s,1H),7.34(d,J＝8.7Hz,2H),6.30(s,1H),4.14(s,2H),2.82(s,6H).HRMS(ESI,[M-H] -)m/z:460.10014.
实施例110：化合物110的制备
Figure PCTCN2022095436-appb-000257
参照实施例94步骤H的制备方法，使用化合物62-1与化合物96-4反应制备得到化合物110。
1H NMR(500MHz,DMSO-d 6)δ11.96(s,1H),10.14(s,1H),8.68(s,1H),8.05(s,1H),7.94–7.65(m,3H),7.34(d,J＝8.5Hz,2H),6.65(d,J＝4.3Hz,1H),6.43(s,1H),4.15(s,2H),2.92(d,J＝4.3Hz,3H).HRMS(ESI,[M-H] -)m/z:446.08408.
实施例111：化合物111的制备
Figure PCTCN2022095436-appb-000258
步骤A：化合物111-1的制备
向250mL的单口瓶中，依次加入N-Boc-氨基丙炔(10g)、无水N,N-二甲基甲酰胺(150mL)，冰浴条件下，分次加入氢化钠(1.5g)，之后加入碘甲烷(8g)，待反应完，缓慢加水淬灭反应，加入乙酸乙酯萃取(200mL x 3)，合并有机相，无水硫酸钠干燥，硅胶柱层析提纯，得到9g的化合物111-1。GC-MS(EI,[M-e] +)m/z:169.0.
步骤B：化合物111-2的制备
参照实施例94步骤A的方法，使用化合物111-1在碳酸银作用下制备化合物111-2。MS(ESI,[M+H] +)m/z:283.10.
步骤C：化合物111-3的制备
参照实施例94步骤B的方法，使用化合物111-2在氢氧化锂作用下水解制备化合物111-3。MS(ESI,[M-H] -)m/z:253.17.
步骤D：化合物111-4的制备
参照实施例94步骤C的方法，使用化合物111-3在二氯亚砜作用下制备化合物111-4。MS(ESI,[M+H] +)m/z:137.0.
步骤E：化合物111-5的制备
向50mL的单口瓶中，依次加入化合物111-4(0.5g)、无水四氢呋喃(30mL)，冰浴条件下，分次加入N-溴代琥珀酰亚胺(0.6g)，待反应完，硅胶柱层析提纯，得到0.2g化合物111-5。MS(ESI,[M+H] +)m/z:215.01
步骤F：化合物111的制备
参照实施例95步骤G的方法，使用化合物111-5、化合物95-6在四(三苯基膦)钯、碳酸钾作用下制备得到化合物111。
1H NMR(500MHz,DMSO-d 6)δ11.95(s,1H),10.17(s,1H),8.74(s,1H),8.06(s,1H),7.87(d,J＝8.5Hz,2H),7.33(d,J＝8.5Hz,2H),6.17(s,1H),4.87(s,1H),4.22(s,3H),3.46(q,J＝9.0Hz,1H),3.00(d,J＝12.0Hz,4H),1.95–1.66(m,2H),1.45–1.16(m,1H),0.84(s,1H).HRMS(ESI,[M-H] -)m/z:516.1256.
实施例112：化合物112的制备
Figure PCTCN2022095436-appb-000259
参照实施例95步骤G的方法，使用化合物103-1和化合物111-5在四(三苯基膦)钯和碳酸钾作用下制备得到化合物112。
1H NMR(500MHz,DMSO-d 6)δ11.99(d,J＝1.8Hz,1H),10.21(s,1H),8.73(d,J＝2.3Hz,1H),8.07(d,J＝2.4Hz,1H),7.92–7.84(m,2H),7.34(d,J＝8.6Hz,2H),6.20(d,J＝1.6Hz,1H),5.54(d,J＝5.5Hz,1H),4.41(q,J＝5.5Hz,1H),4.23(s,2H),3.95(dd,J＝9.6,6.6Hz,2H),3.56(dd,J＝9.8,4.5Hz,2H),3.01(s,3H).HRMS(ESI,[M-H] -)m/z:502.1112.
实施例113：化合物113的制备
Figure PCTCN2022095436-appb-000260
步骤A：化合物113-1的制备
在100mL的三口瓶中，将N-Boc-环丙胺(5g)溶解在四氢呋喃(50mL)中，抽排氮气三次，冰浴下分批加入氢化钠(1.908g)，加完抽排氮气1次，搅拌30分钟后，再滴加3-溴丙炔(4.54g)。滴完继续反应3小时，反应完成。滴加水(50mL)淬灭反应，用乙酸乙酯萃取三次(40mL×3)，有机相用饱和氯化钠洗涤(50mL)，无水硫酸钠干燥，过滤，旋干得到化合物20-1(6g)，没有进一步纯化，直接用于下一步。
步骤B：化合物113-2的制备
向250mL的单口瓶中依次加入化合物113-1(6g)、二氧六环(60mL)、异氰酸乙酯(3.13g)和碳酸银(1.695g)。加完，抽排氮气三次。升温到100℃反应过夜，反应完成。硅藻土滤去固体。滤液直接旋干，硅胶柱层析纯化得到化合物113-2(6g)。MS(ESI,[M+Na] +)m/z:331.2.
步骤C：化合物113-3的制备
向50mL的单口瓶中依次加入化合物113-2(1g)、甲醇(8mL)、水(4mL)和氢氧化钠(0.259g)。加完升温到55℃反应过夜。反应完成，冷却至室温，冰浴下滴加2M稀盐酸调节pH至6，直接旋干得到粗品(1.2g)，没有进一步纯化直接用于下一步。MS(ESI,[M-H] -)m/z:279.1.
步骤D：化合物113-4的制备
向50mL的单口瓶中依次加入化合物113-3(630mg)、二氧六环(8mL)和二氯亚砜(2673mg)，升温到60℃，反应3小时。反应完全，冷却至室温，旋去溶剂，用二氯甲烷和N,N-二甲基甲酰胺复溶，冰浴下滴加二异丙基乙胺(1452mg)，滴完室温反应30分钟。反应完成，直接旋去溶剂，硅胶柱层析制备得到化合物113-4(250mg)。MS(ESI,[M+H] +)m/z:163.0.
步骤E：化合物113-5的制备
向100mL的单口瓶中依次加入化合物113-4(310mg)和四氢呋喃(40mL)，降温至-60℃，滴加N-溴代琥珀酰亚胺(306mg)的四氢呋喃(10mL)溶液。滴完，继续保温1小时。自然升温到室温过夜。反应完成，直接室温旋干，用二氯甲烷溶解(2mL)，硅胶柱层析制备得到化合物113-5(160mg)。MS(ESI,[M+H] +)m/z:241.1.
步骤F：化合物113的制备
参照实施例95步骤G的方法，使用化合物113-5和化合物95-6在四(三苯基膦)钯、碳酸钾作用下制备得到化合物113。
1H NMR(500MHz,DMSO-d 6)δ11.94(s,1H),10.18(s,1H),8.74(d,J＝2.2Hz,1H),8.04(d,J＝2.2Hz,1H),7.87(d,J＝9.0Hz,2H),7.33(d,J＝8.8Hz,2H),6.14(s,1H),4.91(s,1H),4.19(d,J＝28.5Hz,3H),3.46(dd,J＝17.3,9.8Hz,1H),3.30–3.25(m,1H),2.99(d,J＝11.5Hz,1H),2.86–2.72(m,1H),1.82(ddd,J＝39.1,19.5,3.8Hz,2H),0.81–0.68(m,4H).HRMS(ESI,[M+H] +)m/z:544.1556.
实施例114：化合物114的制备
Figure PCTCN2022095436-appb-000261
参照实施例95步骤G的方法，使用化合物113-5和化合物103-1在四(三苯基膦)钯、碳酸铯作用下制备得到化合物114。
1H NMR(500MHz,DMSO-d 6)δ11.99(s,1H),10.22(s,1H),8.72(d,J＝1.8Hz,1H),8.05(d,J＝1.8Hz,1H),7.87(d,J＝8.9Hz,2H),7.34(d,J＝8.7Hz,2H),6.17(s,1H),5.55(s,1H),4.40(d,J＝4.6Hz,1H),4.16(s,2H),4.04–3.88(m,2H),3.56(dd,J＝9.4,4.3Hz,2H),2.80(dd,J＝8.6,4.6Hz,1H),0.82–0.68(m,4H).HRMS(ESI,[M+H] +)m/z:530.1397.
实施例115：化合物115的制备
Figure PCTCN2022095436-appb-000262
向一个50mL的单口瓶中，依次加入化合物7-1(100mg)、二氧六环(10mL)、化合物94-7(72mg)、无水碳酸钾(30mg)、四(三苯基膦)钯(30mg)和水(1mL)。加毕，氮气保护后油浴100℃反应过夜。向反应液中加入乙酸乙酯(50mL)和饱和食盐水(25mL)洗涤后分液，收集有机相，硅胶柱层析提纯，得到30mg的化合物115。
1H NMR(500MHz,Chloroform-d)δ10.32(s,1H),8.80(s,1H),8.67(s,1H),8.32–7.97(m,1H),7.92–7.53(m,2H),7.29–7.20(m,2H),6.36(s,1H),4.02–3.67(m,4H),3.66–3.43(m,2H),3.23–2.94(m,7H),2.94–2.69(m,2H).HRMS(ESI,[M+H] +)m/z:532.15640.
实施例116：化合物116制备
Figure PCTCN2022095436-appb-000263
步骤A：化合物116-1的制备
室温下向100mL的单口瓶中，依次加入4-三氟甲氧基苯甲酸(0.29g)、无水甲苯(20mL)和氯化亚砜(0.35g)，氮气保护，所得混合物油浴加热至80℃，反应过夜。待反应结束，浓缩除去溶剂后加入二氯甲烷(20mL)，搅拌并向体系中滴加3-溴-4-氟苯胺(0.3g)，滴完后滴加二异丙基乙胺(0.3g)，反应结束后，向反应液中加入乙酸乙酯(50mL)和饱和食盐水(25mL)洗涤，分液，收集有机相，硅胶柱层析提纯，得到0.5g的化合物116-1。MS(ESI,[M-H] -)m/z:392.053/394.06.
步骤B：化合物116-2的制备
依次向30mL微波管中加入化合物116-1(0.8g)、碳酸钾(560mg)和(R)-3-吡咯烷醇(2g)，氮气置换3次后微波160℃反应2h。向反应液中加入水(50mL)淬灭反应，并加入乙酸乙酯(60mL)萃取，分出有机层，水层再用乙酸乙酯萃取(40mL×2)。合并有机层，用饱和氯化钠洗涤，无水硫酸钠干燥。减压蒸除溶剂，硅胶柱层析得化合物116-2(0.7g)。MS(ESI,[M+H] +)m/z:461.1/463.0.
步骤C：化合物116的制备
向50mL的单口瓶中，依次加入化合物116-2(100mg)、乙二醇二甲醚(10mL)、化合物96-4(60mg)、无水碳酸钾(30mg)、四(三苯基膦)钯(30mg)和水(0.2mL)。加毕，氮气保护，油浴加热至100℃反应过夜。向反应液中加入乙酸乙酯(50mL)和饱和食盐水(25mL)洗涤后分液，收集有机相，硅胶柱层析提纯，得到30mg的化合物116。
1H NMR(500MHz,DMSO-d 6)δ11.77(s,1H),10.09(s,1H),7.97–7.83(m,4H),7.73(s,1H),7.31(d,J＝8.7Hz,2H),6.84(d,J＝8.7Hz,1H),6.12(s,1H),4.91–4.82(m,1H),4.27–4.18(m,1H),4.13(s,2H),3.30–3.25(m,1H),3.19–3.07(m,2H),2.84–2.74(m,1H),1.94–1.69(m,2H).HRMS(ESI,[M+H] +)m/z:503.1295.
实施例117：化合物117的制备
Figure PCTCN2022095436-appb-000264
步骤A：化合物117-1的制备
依次向30mL微波管中加入化合物116-1(0.8g)、碳酸钾(560mg)和氮杂环丁烷-3-醇(2g)，氮气置换3次后微波160℃反应2h。向反应液中加入水(50mL)淬灭反应，并加入乙酸乙酯(60mL)萃取，分出有机层，水层再用乙酸乙酯萃取(40mL×2)。将有机层合并，用饱和氯化钠洗涤，并用无水硫酸钠干燥。减压蒸除溶剂，硅胶柱层析得化合物117-1(0.7g)。MS(ESI,[M+H] +)m/z:447.1/449.0.
步骤B：化合物117的制备
向一个50mL的单口瓶中，依次加入化合物117-1(100mg)、乙二醇二甲醚(10mL)、化合物96-4(60mg)、无水碳酸钾(30mg)、四(三苯基膦)钯(30mg)和水(0.2mL)。加毕，氮气保护，油浴加热至100℃反应过夜。向反应液中加入乙酸乙酯(50mL)和饱和食盐水(25mL)洗涤，分液，收集有机相，硅胶柱层析提纯，得到30mg的化合物117。
1H NMR(500MHz,DMSO-d 6)δ11.81(s,1H),10.11(s,1H),7.88(d,J＝9.3Hz,4H),7.75(s,1H),7.32(d,J＝8.8Hz,2H),6.60(d,J＝9.0Hz,1H),6.12(s,1H),5.51(s,1H),4.40(q,J＝6.0,5.6Hz,1H),4.14(s,2H),3.81(t,J＝7.5Hz,2H),3.39(dd,J＝8.7,4.8Hz,2H).HRMS(ESI,[M+H] +)m/z:489.1143.
实施例118：化合物118的制备
Figure PCTCN2022095436-appb-000265
步骤A：化合物118-1的制备
参照实施例95步骤F的方法，使用化合物117-1与联硼酸新戊二醇酯反应制备得到化合物118-1。
步骤B：化合物118的制备
参照实施例95步骤G的方法，使用化合物118-1和化合物111-5在四(三苯基膦)钯和碳酸钾作用下制备得到化合物118。
1H NMR(500MHz,DMSO-d 6)δ11.85(s,1H),10.11(s,1H),7.97–7.79(m,4H),7.32(d,J＝8.6Hz,2H),6.60(d,J＝8.5Hz,1H),6.13(s,1H),5.49(d,J＝5.8Hz,1H),4.38(p,J＝5.6Hz,1H),4.22(s,2H),3.80(t,J＝7.5Hz,2H),3.38(dd,J＝8.7,4.8Hz,2H),3.01(s,3H).HRMS(ESI,[M-H] -)m/z:501.1147.
实施例119：化合物119的制备
Figure PCTCN2022095436-appb-000266
步骤A：化合物119-1的制备
参照实施例95步骤F的方法，使用化合物116-2与联硼酸新戊二醇酯反应制备得到化合物119-1。
步骤B：化合物119的制备
参照实施例95步骤G的方法，使用化合物119-1和化合物111-5在四(三苯基膦)钯和碳酸钾作用下制备化合物119。
1H NMR(500MHz,DMSO-d 6)δ11.81(s,1H),10.09(s,1H),7.88(q,J＝4.8,4.4Hz,4H),7.32(d,J＝8.6Hz,2H),6.84(d,J＝8.9Hz,1H),6.13(s,1H),4.86(d,J＝3.6Hz,1H),4.21(s,2H),3.30–3.24(m,1H),3.12 (ddt,J＝21.1,8.6,4.0Hz,2H),3.00(s,3H),2.79(d,J＝10.7Hz,1H),1.93–1.71(m,2H).HRMS(ESI,[M-H] -)515.1302.
实施例120：化合物120的制备
Figure PCTCN2022095436-appb-000267
参照实施例95步骤G的制备方法，使用化合物113-5和化合物118-1在四(三苯基膦)钯和碳酸钾作用下制备得到化合物120。
1H NMR(500MHz,DMSO-d 6)δ13.20–12.76(m,1H),10.22(s,1H),7.93–7.85(m,2H),7.83–7.51(m,2H),7.49–7.28(m,3H),6.54(d,J＝18.6Hz,1H),4.68–4.41(m,1H),4.18(s,2H),3.44–3.32(m,4H),2.91–2.69(m,2H).HRMS(ESI,[M+H] +)m/z:529.1446.
实施例121：化合物121的制备
Figure PCTCN2022095436-appb-000268
步骤A：化合物121-1的制备
参照实施例111步骤A的方法，使用N-Boc-氨基丙炔与碘代异丙烷反应制备得到化合物121-1.
步骤B：化合物121-2的制备
参照实施例94步骤A的方法，使用化合物121-1在碳酸银作用下制备化合物121-2。MS(ESI,[M+H-Boc] +)m/z:211.0.
步骤C：化合物121-3的制备
参照实施例94步骤B的方法，使用化合物121-2在氢氧化锂作用下水解制备121-3。MS(ESI,[M-H] -)m/z:281.13.
步骤D：化合物121-4的制备
参照实施例94步骤C的方法，使用化合物121-3在二氯亚砜作用下制备121-4。MS(ESI,[M+H] +)m/z:165.11.
步骤E：化合物121-5的制备
参照实施例111步骤E的方法，使用化合物121-4与N-溴代琥珀酰亚胺反应制备得到化合物121-5。MS(ESI,[M+H+2] +)m/z:245.05.
步骤F：化合物121的制备
参照实施例95步骤G的方法，使用化合物121-5、化合物77-2在四(三苯基膦)钯、碳酸钾作用下制备得到化合物121。
1H NMR(500MHz,DMSO-d 6)δ11.94(s,1H),10.18(s,1H),8.73(s,1H),8.07(s,1H),7.87(d,J＝8.8Hz, 2H),7.33(d,J＝8.5Hz,2H),6.19(s,1H),4.29-4.32(m,1H),4.23(s,1H),4.18(s,2H),3.50(s,1H),3.22-3.34(m,3H),3.00-3.02(m,1H),1.77-1.78(m,2H),1.20(d,J＝6.6Hz,6H).HRMS(ESI,[M+H] +)m/z:546.1715.
实施例122：化合物122的制备
Figure PCTCN2022095436-appb-000269
步骤A：化合物122的制备
参照实施例95步骤G的方法，使用化合物119-1和化合物121-5在四(三苯基膦)钯和碳酸钾作用下制备化合物122。
1H NMR(500MHz,DMSO-d 6)δ11.80(s,1H),10.07(s,1H),7.87-7.89(m,4H),7.31-7.33(m,2H),6.84-6.85(m,1H),6.14(s,1H),4.87(s,1H),4.33(s,1H),4.28-4.33(m,1H),4.17(s,2H),3.28-3.30(m,1H),3.12-3.19(m,2H),2.79-2.81(m,1H),1.78-1.91(m,2H),1.20(d,J＝6.7Hz,6H).HRMS(ESI,[M-H] -)m/z:545.1762.
实施例123：化合物123的制备
Figure PCTCN2022095436-appb-000270
参照实施例95步骤G的方法，使用化合物121-5和化合物103-1在四(三苯基膦)钯和碳酸钾作用下制备得到化合物123。
1H NMR(500MHz,DMSO-d 6)δ11.97(s,1H),10.20(s,1H),8.73(s,1H),8.06(s,1H),7.87(d,J＝9.1Hz,2H),7.34(d,J＝8.8Hz,2H),6.21(s,1H),5.54(s,1H),4.40-4.43(m,1H),4.30-4.32(m,1H),4.18(s,2H),3.94-3.98(m,2H),3.55-3.58(m,2H),1.20(d,J＝6.8Hz,6H).HRMS(ESI,[M-H] -)m/z:532.1564.
实施例124：化合物124的制备
Figure PCTCN2022095436-appb-000271
步骤A：化合物124的制备
参照实施例95步骤G的方法，使用化合物118-1和化合物121-5在四(三苯基膦)钯和碳酸钾作用下制备得到化合物124。
1H NMR(500MHz,DMSO-d 6)δ11.84(s,1H),10.10(s,1H),7.86-7.89(m,4H),7.32(d,J＝8.9Hz,2H),6.61(d,J＝8.6Hz,1H),6.14(s,1H),5.50(s,1H),4.38-4.41(m,1H),4.29-4.32(m,1H),4.17(s,2H),3.80-3.83(m,2H),3.38-3.40(m,2H),1.20(d,J＝6.8Hz,6H).HRMS(ESI,[M-H] -)m/z:531.1602.
试验例1化合物对K562细胞的增殖抑制作用
取处于指数生长期状态良好的K562细胞，收集细胞至离心管，低速台式离心机，1000转/min，离心5min，弃上清，用移液器加入5mL完全培养基(RPMI 1640基础培养基+10％FBS)进行细胞重悬。使用细胞计数仪计数，用完全培养基进行稀释，调整细胞密度至6×10 4个/mL，再加入等量的RPMI 1640基础培养基调整血清浓度为5％、细胞密度为3×10 4个/mL种板。使用多通道移液器接种于96孔板上，100μL/孔，置于37℃、含5％CO 2饱和湿度的细胞培养箱中培养。培养24h后，使用纳升加样仪进行化合物加样，每个化合物设置8个浓度(1000nM、250nM、63nM、16nM、3.9nM、0.98nM、0.24nM、0.061nM)，每一浓度设置2个复孔，以不加化合物的细胞作为阴性对照，以不加细胞的种板培养基作为空白对照。72小时后加CCK-8，10μL/孔，2小时后Envision酶标仪450nm处检测其吸光值，计算抑制率，抑制率(％) ＝(阴性对照组平均值-实验组平均值)/(阴性对照组平均值-空白组平均值)×100％，以化合物浓度对数为横坐标，抑制率为纵坐标，四参数分析，拟合量效曲线，计算IC 50，结果见表1。
表1
Figure PCTCN2022095436-appb-000272
试验例2化合物对BCR-ABL T315I转染的Ba/F3细胞的增殖抑制作用
取处于指数生长期状态良好的Ba/F3-BCR-ABL1-T315I-C3细胞，收集细胞至离心管，低速台式离心机， 1000转/min，离心5min，弃上清，用移液器加入5mL完全培养基(RPMI 1640基础培养基+10％FBS)进行细胞重悬。使用细胞计数仪计数，用完全培养基进行稀释，调整细胞密度至6×10 4个/mL，再加入等量的RPMI 1640基础培养基调整血清浓度为5％、细胞密度为3×10 4个/mL种板。使用多通道移液器接种于96孔板上，100μL/孔，置于37℃、含5％CO 2饱和湿度的细胞培养箱中培养。培养24h后，使用纳升加样仪进行化合物加样，每个化合物设置8个浓度(1000nM、250nM、63nM、16nM、3.9nM、0.98nM、0.24nM、0.061nM)，每一浓度设置2个复孔，以不加化合物的细胞作为阴性对照，以不加细胞的种板培养基作为空白对照。72小时后加CCK-8，10μL/孔，Ba/F3-BCR-ABL1T315I细胞加CCK-8之后置于37℃，1小时后用酶标仪检测450nm处检测其吸光值，计算抑制率，抑制率(％)＝(阴性对照组平均值-实验组平均值)/(阴性对照组平均值-空白组平均值)×100％，以化合物浓度对数为横坐标，抑制率为纵坐标，四参数分析，拟合量效曲线，计算IC 50，结果见表2。
表2
Figure PCTCN2022095436-appb-000273
试验例3小鼠体内药物代谢动力学评价
ICR小鼠(购自上海西普尔必凯实验动物有限公司)，体重18～22g，适应3～5天后，随机分组，每组9只，按10mg/kg剂量分别灌胃给予各化合物。受试动物(ICR小鼠)给药前禁食过夜，给药后4h给食物，实验前后和实验过程中均自由饮水。灌胃给药后，于0.25(15min)、0.5(30min)、1、2、3、4、6、8、10、24h眼眶取血0.1mL左右(每只小鼠采集3～4个时间点，每个时间点3只小鼠)，加入EDTA-K2 抗凝后，30min内转移到4℃、4000rpm、10min条件下离心分离血浆。收集全部血浆后立即于-20℃保存待测。
吸取30μL待测血浆样品和标准曲线样品，加入300μL含内标(地西泮20ng/mL)的乙腈溶液，振荡混匀5min，13000rpm离心10min，取上清70μL，加入70μL超纯水稀释，混匀，吸取1μL用于LC/MS/MS测定，记录色谱图。
通过小鼠体内药物动力学实验评估化合物的口服暴露量。采用DAS3.2.5软件拟合相关药代参数，其中绝对生物利用度F abs(％)＝(灌胃AUC*静注剂量)/(静注AUC*灌胃剂量)×100％，结果见表3。
表3
Figure PCTCN2022095436-appb-000274
试验例4化合物心脏安全性评估
细胞株来源于过表达hERG钾离子通道HEK-293细胞。细胞在37℃、5％CO 2培养箱中培养。当细胞密度达培养皿80％时，先用磷酸盐缓冲液(PBS)预清洗，然后用胰蛋白酶/EDTA消化细胞2-3分钟，加入细胞培养基停止消化，轻轻把细胞吹下来并转移到离心管中，1000转/分钟离心3分钟，上清液倒掉，加入细胞培养基，轻轻吹打将细胞混匀，随后转移到培养皿中进行传代培养，或将细胞滴于圆形玻片之上并置于培养皿中待细胞贴壁用于实验。
细胞培养基组成：DMEM、15％胎牛血清和1％100x青霉素-链霉素。
将稳转的细胞接种于玻片上，细胞密度低于50％，培养过夜。将实验用细胞转移到一个嵌于倒置显微镜平台的约1mL的浴槽中，灌流细胞外液，灌流速度为2.7mL/分钟。稳定5分钟后即可开始实验。采用HEKA EPC-10膜片钳放大器和PATCHMASTER采集系统记录膜电流(HEKA Instruments Inc.，D-67466 Lambrecht，Pfalz，Germany)，并采用Origin 8.5(OriginLab Corporation，Northampton，MA)软件以及Microsoft Excel进行分析和统计(结果见表4)。所有实验均在室温(22-24℃)下完成。实验中使用P-97微电极拉制仪(Sutter Instrument Company，One Digital Drive，Novato，CA 94949)拉直电极(BF150-110-10)。电极内径为1-1.5mm，充满内液后的入水电阻为2-4MΩ。
hERG钾通道的电生理刺激方案，是首先将膜电压钳制在-80mV，给予细胞持续2s、+20mV电压刺激，激活hERG钾通道，再复极化至-50mV、持续5s，产生外向尾电流，刺激频率每15s一次。电流值为尾电流的峰值。
实验中采用全细胞记录模式记录通道电流。首先灌流细胞外液(大约每分钟2mL)并持续记录，并等待电流稳定(5分钟内电流衰减(Run-Down)小于5％)，此时尾电流峰值即为对照电流值。接着灌流含待测药物的细胞外液并持续记录直到药物对hERG电流的抑制作用到达稳定状态，此时尾电流峰值即为加药后电流值。稳定状态的标准以最近的连续3个电流记录线是否重合来判断。达到稳定态势以后如果以细胞外液灌流冲洗后hERG电流回复或接近加药物之前的大小，则可以继续灌流测试其它浓度或药物。30μM Quinidine(奎尼丁)被用于实验中作为阳性对照以保证所使用的细胞反应正常。
表4
实施例 hERG IC 50(μM)
104 ﹥30
106 ﹥30
本领域技术人员将认识到，本公开的范围并不限于上文描述的各种具体实施方式和实施例，而是能够在不脱离本公开的精神和构思的情况下，进行各种修改、替换、或重新组合，这都落入了本公开的保护范围内。

Claims (15)

  1. 式(I)化合物或其药学上可接受的盐，
    Figure PCTCN2022095436-appb-100001
    其中，
    Q选自N或CH；
    R 1选自
    Figure PCTCN2022095436-appb-100002
    其中所述
    Figure PCTCN2022095436-appb-100003
    任选地被一个或多个R a’取代；
    X、Y和Z各自独立地选自CH或N，且X、Y和Z中至少有一个选自CH；
    环A选自含有1-3个选自N、O或S原子的杂原子的5元杂芳基；
    环B选自含有1-3个选自N、O或S原子的杂原子的5-10元杂环基，或含有1-3个选自N、O或S原子的杂原子的5-8元杂芳基；
    R 2选自氢、氨基、C 1-6烷基、C 1-6烷氧基、氨基-C 1-6烷基-、3-10元杂环基或5-6元杂芳基，其中所述氨基、C 1-6烷基、C 1-6烷氧基、氨基-C 1-6烷基-、3-10元杂环基或5-6元杂芳基任选地被一个或多个R b取代；
    R 3选自-OCF 2H，其中所述-OCF 2H任选地被卤素取代；
    R a和R a’各自独立地选自羟基、氨基、氰基、卤素、
    Figure PCTCN2022095436-appb-100004
    C 1-6烷基、3-8元环烷基、3-8元杂环烷基、3-8元环烷基-C 1-6烷基-、3-8元杂环烷基-C 1-6烷基-或被一个或多个羟基或卤素取代的C 1-6烷基；
    R b选自羟基、氨基、氰基、卤素、
    Figure PCTCN2022095436-appb-100005
    C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基-、C 1-6烷基-C(O)-NH-或被一个或多个羟基或卤素取代的C 1-6烷基。
  2. 如权利要求1所述的式(I)化合物或其药学上可接受的盐，其选自式(II)化合物或其药学上可接受的盐，
    Figure PCTCN2022095436-appb-100006
    其中，
    R 1选自
    Figure PCTCN2022095436-appb-100007
    其中所述
    Figure PCTCN2022095436-appb-100008
    任选地被一个或多个R a’取代；
    X、Y和Z各自独立地选自CH或N，且X、Y和Z中至少有一个选自CH；
    环A选自含有1-3个选自N、O或S原子的杂原子的5元杂芳基；
    环B选自含有1-3个选自N、O或S原子的杂原子的5-10元杂环基，或含有1-3个选自N、O或S原子的杂原子的5-8元杂芳基；
    R 2选自氢、氨基、C 1-6烷基、C 1-6烷氧基、氨基-C 1-6烷基-、3-10元杂环基或5-6元杂芳基，其中所述氨基、C 1-6烷基、C 1-6烷氧基、氨基-C 1-6烷基-、3-10元杂环基或5-6元杂芳基任选地被一个或多个R b取代；
    R 3选自-OCF 2H，其中所述-OCF 2H任选地被卤素取代；
    R a和R a’各自独立地选自羟基、氨基、氰基、卤素、
    Figure PCTCN2022095436-appb-100009
    C 1-6烷基、3-8元环烷基、3-8元杂环烷基、3-8元环烷基-C 1-6烷基-、3-8元杂环烷基-C 1-6烷基-或被一个或多个羟基或卤素取代的C 1-6烷基；
    R b选自羟基、氨基、氰基、卤素、
    Figure PCTCN2022095436-appb-100010
    C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基-、C 1-6烷基-C(O)-NH-或被一个或多个羟基或卤素取代的C 1-6烷基。
  3. 如权利要求1所述的式(I)化合物或其药学上可接受的盐，其中Q选自CH。
  4. 如权利要求1-3中任一项所述的式(I)化合物或其药学上可接受的盐，其中X、Y和Z均选自CH；或者，X、Y和Z中有一个选自N，其余选自CH；或者，X选自N，Y和Z选自CH；或者，Y选自N，X和Z选自CH；或者；Z选自N，X和Y选自CH；或者，X、Y和Z中有一个选自CH，其余选 自N。
  5. 如权利要求1-4中任一项所述的式(I)化合物或其药学上可接受的盐，其中环A选自含有1个或2个选自N或O原子的杂原子的5元杂芳基；或者，环A选自吡咯基、吡唑基、咪唑基、呋喃基、噻吩基、噻唑基、噁唑基或异噁唑基；或者，环A选自吡咯基、吡唑基、咪唑基或呋喃基。
  6. 如权利要求1-5中任一项所述的式(I)化合物或其药学上可接受的盐，其中环B选自含有1-3个选自N或O原子的杂原子的5～8元杂环烷基、或含有1-3个选自N或O原子的杂原子的5～8元杂芳基；或者，环B选自含有1个或2个选自N或O原子的杂原子的5元或6元杂环烷基、或含有1个或2个N原子的5元杂芳基；或者，环B选自四氢吡咯烷基、哌啶基、哌嗪基、吗啉基、咪唑基或吡唑基；或者，环B选自四氢吡咯烷基、哌啶基、吗啉基或咪唑基。
  7. 如权利要求1-6中任一项所述的式(I)化合物或其药学上可接受的盐，其中R 1选自
    Figure PCTCN2022095436-appb-100011
    其中所述
    Figure PCTCN2022095436-appb-100012
    任选地被一个或多个R a’取代；或者，R 1选自
    Figure PCTCN2022095436-appb-100013
    Figure PCTCN2022095436-appb-100014
    其中所述
    Figure PCTCN2022095436-appb-100015
    任选地被一个或多个R a’取代；或者，R 1选自
    Figure PCTCN2022095436-appb-100016
    其中所述
    Figure PCTCN2022095436-appb-100017
    任选地被一个或多个R a’取代；
    或者，R 1选自
    Figure PCTCN2022095436-appb-100018
    其中所述
    Figure PCTCN2022095436-appb-100019
    任选地被一个或多个R a’取代；或者，R 1选自
    Figure PCTCN2022095436-appb-100020
    Figure PCTCN2022095436-appb-100021
    其中所述
    Figure PCTCN2022095436-appb-100022
    Figure PCTCN2022095436-appb-100023
    任选地被一个或多个R a’取代；或者，R 1选自
    Figure PCTCN2022095436-appb-100024
    Figure PCTCN2022095436-appb-100025
    其中所述
    Figure PCTCN2022095436-appb-100026
    Figure PCTCN2022095436-appb-100027
    任选地被一个或多个R a’取代；或者，R 1选自
    Figure PCTCN2022095436-appb-100028
    Figure PCTCN2022095436-appb-100029
    其中所述
    Figure PCTCN2022095436-appb-100030
    Figure PCTCN2022095436-appb-100031
    Figure PCTCN2022095436-appb-100032
    任选地被一个或多个R a’取代。
  8. 如权利要求1-7中任一项所述的式(I)化合物或其药学上可接受的盐，其中R a和R a’各自独立地选自卤素、
    Figure PCTCN2022095436-appb-100033
    C 1-6烷基、3-6元环烷基、3-8元杂环烷基-C 1-6烷基-或被1个、2个或3个羟基取代的C 1-6烷基；或者，R a和R a’各自独立地选自卤素、
    Figure PCTCN2022095436-appb-100034
    C 1-4烷基、3-6元环烷基、3-6元杂环烷基-C 1-4烷基-或被1个、2个或3个羟基取代的C 1-4烷基；
    或者，R a选自C 1-4烷基、3-6元环烷基、3-6元杂环烷基-C 1-4烷基-或被1个、2个或3个羟基取代的C 1-4烷基；或者；R a选自甲基、乙基、环丙基、2-羟基乙基或
    Figure PCTCN2022095436-appb-100035
    或者，R a’选自卤素、
    Figure PCTCN2022095436-appb-100036
    C 1-4烷基或3-6元环烷基；或者，R a’选自氟、氯、
    Figure PCTCN2022095436-appb-100037
    甲基、乙基、异丙基或环丙基；或者，R a’选自氟、氯、
    Figure PCTCN2022095436-appb-100038
    甲基、乙基或环丙基。
  9. 如权利要求1-8中任一项所述的式(I)化合物或其药学上可接受的盐，其中R 1选自
    Figure PCTCN2022095436-appb-100039
    Figure PCTCN2022095436-appb-100040
    Figure PCTCN2022095436-appb-100041
    其中所述
    Figure PCTCN2022095436-appb-100042
    Figure PCTCN2022095436-appb-100043
    Figure PCTCN2022095436-appb-100044
    任选地被一个或多个R a’取代；或者，R 1选自
    Figure PCTCN2022095436-appb-100045
    Figure PCTCN2022095436-appb-100046
    Figure PCTCN2022095436-appb-100047
  10. 如权利要求1-9中任一项所述的式(I)化合物或其药学上可接受的盐，其中R 2选自氢、氨基、C 1-4烷氧基、氨基-C 1-4烷基-、3-10元杂环烷基或5-6元杂芳基，其中所述氨基、C 1-4烷氧基、氨基-C 1-4烷基-、3-10元杂环烷基或5-6元杂芳基任选地被一个或多个R b取代；或者，R 2选自氢、氨基、C 1-4烷氧基、氨基-C 1-4烷基-、4-6元单杂环烷基、6-9元桥杂环烷基、7-9元螺杂环烷基或5-6元杂芳基，其中所述氨基、C 1-4烷氧基、氨基-C 1-4烷基-、4-6元单杂环烷基、6-9元桥杂环烷基、7-9元螺杂环烷基或5-6元杂芳基任选地被一个或多个R b取代；或者，R 2选自氨基、甲氧基、乙氧基、氨基甲基、
    Figure PCTCN2022095436-appb-100048
    Figure PCTCN2022095436-appb-100049
    Figure PCTCN2022095436-appb-100050
    其中所述氨基、甲氧基、乙氧基、氨基甲基、
    Figure PCTCN2022095436-appb-100051
    Figure PCTCN2022095436-appb-100052
    Figure PCTCN2022095436-appb-100053
    任选地被1个、2个或3个R b取代；或者，R 2选自氨基、甲氧基、乙氧基、氨基甲基、吡咯烷基、异噁唑烷基、哌啶基、吗啉基、硫代吗啉基、1,4-二氧六环基、氮杂环丁基、6-氧杂-3-氮杂双环[3.1.1]庚烷基、3-氧杂-6-氮杂双环[3.1.1]庚烷基、3-氧杂-8-氮杂双环[3.2.1]辛烷基、8-氧杂-3-氮杂双环[3.2.1]辛烷基、2-氧杂-5-氮杂双环[2.2.1]庚烷、3-氮杂双环[3.1.0]己烷基、2-氧杂-6-氮杂螺[3.4]辛烷基、2-氧杂-7-氮杂螺[3.5]壬烷基、2-氧杂-6-氮杂螺[3.3]庚烷基、吡唑基或咪唑基，其中所述氨基任选地被1个或2个甲基、甲氧基乙基取代，其中所述乙氧基任选地被1个甲氧基取代，其中所述氨基甲基任选地被1个或2个甲基或甲氧基取代，其中所述吡咯烷基任选地被1个或2个羟基、氰基、氟、氯、甲氧基、羟基甲基或乙酰氨基取代，其中所述氮杂环丁基任选地被1个或2个羟基、氰基、氟、甲基或羟基甲基取代，其中所述2-氧杂-6-氮杂螺[3.4]辛烷基任选地被一个
    Figure PCTCN2022095436-appb-100054
    取代；或者，R 2选自甲氧基、甲氧基乙 氧基、甲基氨基、二甲基氨基、
    Figure PCTCN2022095436-appb-100055
    Figure PCTCN2022095436-appb-100056
    Figure PCTCN2022095436-appb-100057
    或者，R 2选自甲氧基、甲氧基乙氧基、甲基氨基、二甲基氨基、
    Figure PCTCN2022095436-appb-100058
    Figure PCTCN2022095436-appb-100059
  11. 如权利要求1-10中任一项所述的式(I)化合物或其药学上可接受的盐，其中R b选自羟基、氰基、 卤素、
    Figure PCTCN2022095436-appb-100060
    C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基-C 1-4烷基-、C 1-4烷基-C(O)-NH-或者被一个或多个羟基或卤素取代的C 1-4烷基；或者，R b选自羟基、氰基、氟、氯、
    Figure PCTCN2022095436-appb-100061
    甲基、甲氧基、羟基甲基、甲氧基乙基或乙酰氨基。
  12. 如权利要求1-11中任一项所述的式(I)化合物或其药学上可接受的盐，其中，所述式(I)化合物为式(III-A)化合物、式(III-B)化合物、式(IV-A)化合物、式(V)化合物、式(VI)化合物、式(VII)化合物、式(VIII)化合物、式(IX)化合物或式(X)化合物：
    Figure PCTCN2022095436-appb-100062
    R 2的定义同权利要求1，
    Figure PCTCN2022095436-appb-100063
    的定义同权利要求7；
    Figure PCTCN2022095436-appb-100064
    Figure PCTCN2022095436-appb-100065
    R 2、R a、R a，以及环B的定义同权利要求1。
  13. 如权利要求1-12中任一项所述的式(I)化合物或其药学上可接受的盐，其中，所述式(I)化合物或其药学上可接受的盐为以下化合物或其药学上可接受的盐：
    Figure PCTCN2022095436-appb-100066
    Figure PCTCN2022095436-appb-100067
    Figure PCTCN2022095436-appb-100068
    Figure PCTCN2022095436-appb-100069
    Figure PCTCN2022095436-appb-100070
    Figure PCTCN2022095436-appb-100071
    Figure PCTCN2022095436-appb-100072
  14. 药物组合物，其包含权利要求1-13中任一项所述的化合物或其药学上可接受的盐。
  15. 用于治疗和/或预防BCR-ABL相关疾病的权利要求1-13中任一项所述的化合物或其药学上可接受的盐、或权利要求14所述的药物组合物；优选地，所述疾病选自癌症；或者，所述疾病选自慢性髓细胞白血病。
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