WO2021143927A1 - Compound acting as bcr-abl inhibitor - Google Patents

Compound acting as bcr-abl inhibitor Download PDF

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Publication number
WO2021143927A1
WO2021143927A1 PCT/CN2021/072699 CN2021072699W WO2021143927A1 WO 2021143927 A1 WO2021143927 A1 WO 2021143927A1 CN 2021072699 W CN2021072699 W CN 2021072699W WO 2021143927 A1 WO2021143927 A1 WO 2021143927A1
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compound
alkyl
amino
preparation
membered
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PCT/CN2021/072699
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French (fr)
Chinese (zh)
Inventor
张寅生
陆鹏
李久香
杨加举
秦慧
叶嘉炜
诸丽娟
汪纪楠
施伟
王晓金
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正大天晴药业集团股份有限公司
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Priority to CN202180006423.2A priority Critical patent/CN114728943A/en
Publication of WO2021143927A1 publication Critical patent/WO2021143927A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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 two hetero rings
    • C07D401/10—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 two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This application belongs to the field of medicinal chemistry, and provides a compound as a BCR-ABL inhibitor, a preparation method thereof, and a pharmaceutical composition containing the compound, and relates to its use in the preparation of drugs for treating BCR-ABL-related diseases.
  • Chronic myeloid leukemia is the main type 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 chromosomes 9 and 22, forming the Bcr-Abl fusion gene, expressing the protein p-210. The tyrosine kinase activity of p-210 is much stronger than that of p-150 (normal c-Abl gene expression product), which causes abnormal proliferation and differentiation of hematopoietic stem cells, and ultimately leads to CML.
  • Imatinib is the first Bcr-Abl targeted therapy to be marketed, and it is currently used as a first-line therapy for the treatment of various stages of CML.
  • Nilotinib, dasatinib, and bosutinib (second-generation Bcr-Abl inhibitors) are approved for the treatment of CML that is resistant or intolerant to imatinib.
  • the second-generation Bcr-Abl inhibitors are more effective than imatinib, and are effective for almost all imatinib-resistant mutation types, but the problem of mutation resistance of T315I (gatekeeper) has not been solved yet. T315I mutations accounted for about 20% of patients with resistance to first and second generation Bcr-Abl inhibitors.
  • Pranatinib third-generation Bcr-Abl inhibitor
  • the curable dilemma is 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 inhibitor of BCR-ABL, which is 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,
  • R 1 is selected from or
  • R 2 is selected from hydrogen, amino, or 3-10 membered heterocyclyl, wherein said 3-10 membered heterocyclyl group or an amino group optionally substituted with one or more substituents R a;
  • R a is selected from hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, di (C 1-6 alkyl) amino, or one or more hydroxy or C 1-6 alkoxy substituted C 1-6 alkyl;
  • R 3 is selected from -OCF 2 H, wherein the -OCF 2 H is optionally substituted by halogen;
  • R 4 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-10 membered heterocyclic group, wherein C 1-6 alkyl, C 3-6 cycloalkyl or 3-10 membered heterocyclic group The cyclic group is optionally substituted with one or more R b ;
  • R b is selected from deuterium, hydroxyl, C 1-6 alkoxy, C 1-6 alkyl, amino, mono(C 1-6 alkyl)amino or di(C 1-6 alkyl)amino;
  • R 5 is selected from C 1-6 alkyl
  • Ring A is selected from 5-6 membered heteroaryl or phenyl.
  • R a is selected from hydroxy, halogen, C 1-6 alkyl, di(C 1-6 alkyl)amino, or C 1-6 alkyl substituted with one or more hydroxy groups;
  • R b It is selected from hydroxyl, C 1-6 alkoxy, C 1-6 alkyl, amino, mono(C 1-6 alkyl)amino or di(C 1-6 alkyl)amino.
  • R 1 is selected from Other variables are as defined in this application.
  • R 1 is selected from Other variables are as defined in this application.
  • R 2 is selected from hydrogen, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, or amino, wherein the 3-10 membered heterocycloalkyl, 3-10 membered heterocycle alkenyl group or an amino group optionally substituted with one or more substituents R a; the other variables are as defined herein.
  • R 2 is selected from hydrogen, 4-6 membered heterocyclyl, 7-9 membered spiroheterocyclyl or amino, wherein the 4-6 membered heterocyclyl, 7-9 membered spiroheterocyclyl or amino optionally substituted with one or more substituents R a; the other variables are as defined herein.
  • R 2 is selected from hydrogen, 4-6 membered heterocyclyl or amino group, wherein the 4-6 membered heterocyclyl or amino optionally substituted with one or more substituents R a; the other variables are as this As defined by the application.
  • R 2 is selected from hydrogen, 4-6 membered heterocycloalkyl, 6 membered heterocycloalkenyl, 7 or 9 membered spiroheterocycloalkyl, or amino, wherein the 4-6 membered heterocycloalkane group, a 6-membered heterocycloalkenyl, 7, or 9-membered spirocyclic heterocycloalkyl or amino optionally substituted with one or more substituents R a; the other variables are as defined herein.
  • R 2 is selected from hydrogen, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 1,2,3,6-tetrahydropyridyl, tetrahydropyridine Pyryl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro [3.3] Heptyl or amino, wherein the pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 1,2,3,6-tetrahydropyridyl, tetrahydropyridine Pyryl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro [3.3] heptyl or amino
  • R 2 is selected from hydrogen, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 3,4-dihydropyranyl, or amino, wherein the pyrrole alkyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 3,4-dihydropyran or an amino group optionally substituted with one or more R a; the other variables are as herein definition.
  • R 2 is selected from hydrogen, Or amino, where the Or amino optionally substituted with one or more substituents R a; the other variables are as defined herein.
  • R a is selected from hydroxy, cyano, halogen, C 1-4 alkyl, C 1-3 alkoxy, di(C 1-3 alkyl)amino or C 1-4 alkyl substituted with one or more hydroxy groups or C 1-3 alkoxy; others
  • the variables are as defined in this application.
  • R a is selected from hydroxy, halo, C 1-3 alkyl, di (C 1-3 alkyl) amino, or by one or more hydroxy-substituted C 1-3 alkyl; other variables As defined in this application.
  • R a is selected from hydroxy, cyano, fluorine, Methyl, methoxy, 2-hydroxyethyl, 2-methoxyethyl, 2-methyl-2-hydroxypropyl, bis(methyl)amino or hydroxymethyl; other variables are as defined in this application .
  • R a is selected from hydroxy, fluoro, methyl, 2-hydroxyethyl, di (methyl) amino or hydroxyl group; the other variables are as defined herein.
  • R 2 is selected from hydrogen, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 1,2,3,6-tetrahydropyridyl, tetrahydropyridine Pyryl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro [3.3] Heptyl or amino, wherein the pyrrolidinyl group is optionally substituted by a hydroxyl group, cyano group, fluorine, Methoxy or bis(methyl)amino substitution, wherein the piperazinyl, piperidinyl or morpholinyl is optionally substituted by one or two hydroxy groups or methyl groups, wherein the azetidinyl group is optionally substituted Ground is substituted with one or two hydroxy, fluoro, cyano, methyl
  • R 2 is selected from hydrogen, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 3,4-dihydropyranyl, or amino, wherein the pyrrole
  • the alkyl group is optionally substituted with a hydroxy, fluoro or bis(methyl)amino group, wherein the piperazinyl or piperidinyl group is optionally substituted with a methyl group, and wherein the azetidinyl group is optionally substituted by One hydroxy or hydroxymethyl substitution, wherein the amino group is optionally substituted with one or more 2-hydroxyethyl or methyl; other variables are as defined in this application.
  • R 2 is selected from hydrogen
  • Other variables are as defined in this application.
  • R 2 is selected from hydrogen
  • Other variables are as defined in this application.
  • R 3 is selected from -OCF 3 or -OCF 2 Cl; other variables are as defined in this application.
  • R 4 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or 3-10 membered heterocycloalkyl, wherein C 1-6 alkyl, C 3-6 cycloalkane
  • the group or 3-10 membered heterocycloalkyl group is optionally substituted with one or more R b ; other variables are as defined in this application.
  • R 4 is selected from hydrogen, C 1-5 alkyl, C 3-6 cycloalkyl, or 4-6 membered heterocycloalkyl, wherein C 1-5 alkyl, C 3-6 cycloalkane
  • the radical or 4-6 membered heterocycloalkyl is optionally substituted with one or more R b ; other variables are as defined in this application.
  • R 4 is selected from hydrogen, C 1-5 alkyl, cyclopropyl or 6-membered heterocycloalkyl, wherein C 1-5 alkyl, cyclopropyl or 6-membered heterocycloalkyl is optionally Ground is replaced by one or more R b ; other variables are as defined in this application.
  • R 4 is selected from hydrogen, methyl, ethyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, tetrahydropyranyl or piperidinyl, wherein methyl, Ethyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, tetrahydropyranyl or piperidinyl is optionally substituted with one or more R b ; other variables are as defined in this application.
  • R 4 is selected from hydrogen, methyl, ethyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, Among them, methyl, ethyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, Optionally substituted by one or more R b ; other variables are as defined in this application.
  • R b is selected from deuterium, hydroxyl, C 1-3 alkoxy, C 1-3 alkyl, amino, mono(C 1-3 alkyl)amino, or di(C 1-3 alkyl ) Amino; other variables are as defined in this application.
  • R b is selected from hydroxyl, C 1-3 alkoxy, C 1-3 alkyl, amino, mono(C 1-3 alkyl)amino, or di(C 1-3 alkyl)amino ; Other variables are as defined in this application.
  • R b is selected from deuterium, hydroxyl, methoxy, methyl, or di(ethyl)amino; other variables are as defined in this application.
  • R b is selected from hydroxyl, methoxy, methyl, or di(ethyl)amino; other variables are as defined in this application.
  • R 4 is selected from hydrogen, methyl, ethyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, tetrahydropyranyl, or piperidinyl, wherein methyl is any Optionally substituted by three deuteriums, wherein the ethyl group is optionally substituted by a hydroxy, methoxy or di(ethyl)amino group, and wherein the 2-methylpropyl or 3-methylbutyl group is optionally substituted by a hydroxy group Substitution, where the piperidinyl group is optionally substituted with a methyl group; other variables are as defined in this application.
  • R 4 is selected from hydrogen, methyl, d 3 -methyl, cyclopropyl, Other variables are as defined in this application.
  • R 4 is selected from hydrogen; other variables are as defined in this application.
  • R 4 is selected from methyl or cyclopropyl; other variables are as defined in this application.
  • R 5 is selected from C 1-3 alkyl; other variables are as defined in this application.
  • R 5 is selected from methyl; other variables are as defined in this application.
  • ring A is selected from 5-6 membered nitrogen-containing heteroaryl or phenyl; other variables are as defined in this application.
  • ring A is selected from pyrrolyl, pyridyl, or phenyl; other variables are as defined in this application.
  • ring A is selected from pyrrolyl; other variables are as defined in this application.
  • the structural unit Selected from Other variables are as defined in this application.
  • the structural unit Selected from Further selected from Other variables are as defined in this application.
  • R 1 is selected from or
  • R 2 is selected from hydrogen, amino, or 3-10 membered heterocyclyl, wherein said 3-10 membered heterocyclyl group or an amino group optionally substituted with one or more substituents R a;
  • R a is selected from hydroxy, halo, C 1-6 alkyl, di (C 1-6 alkyl) amino or by one or more hydroxy-substituted C 1-6 alkyl;
  • R 3 is selected from -OCF 2 H, wherein the -OCF 2 H is optionally substituted with halogen;
  • R 4 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-10 membered heterocyclic group, wherein C 1-6 alkyl, C 3-6 cycloalkyl or 3-10 membered heterocyclic group The cyclic group is optionally substituted with one or more R b ;
  • R b is selected from hydroxyl, C 1-6 alkoxy, C 1-6 alkyl, amino, mono(C 1-6 alkyl)amino or di(C 1-6 alkyl)amino;
  • R 5 is selected from C 1-6 alkyl
  • Ring A is selected from 5-6 membered heteroaryl or phenyl.
  • the present application provides a compound of formula (II) or a pharmaceutically acceptable salt thereof,
  • R 3 is selected from -OCF 3 or -OCF 2 Cl;
  • R 4 and R a and R b are as previously defined R.
  • the present application provides a compound of formula (III) or a pharmaceutically acceptable salt thereof,
  • R 3 is selected from -OCF 3 or -OCF 2 Cl;
  • R 2 and R a is defined above.
  • the application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 is selected from or
  • R 2 is selected from hydrogen, a 4-10 membered heterocyclic group or amino group containing 1-3 heteroatoms selected from N or O or S, wherein the 4-10 membered heterocyclic group or amino group is optionally substituted by one or a plurality of substituents R a;
  • R a is selected from hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, di (C 1-6 alkyl) amino, or one or more hydroxy or C 1-6 alkoxy substituted C 1-6 alkyl;
  • R 3 is selected from -OCF 3 , -OCF 2 Cl or -OCF 2 Br;
  • R 4 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or a 5-7 membered heterocyclic group containing 1-3 heteroatoms selected from N or O or S, wherein C 1- 6 alkyl, C 3-6 cycloalkyl or 5-7 membered heterocyclic group is optionally substituted by one or more R b;
  • R b is selected from deuterium, hydroxyl, C 1-6 alkoxy, C 1-6 alkyl;
  • R 5 is selected from C 1-6 alkyl
  • Ring A is selected from 5-6 membered heteroaryl or phenyl containing 1-3 heteroatoms selected from N or O or S.
  • the application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 is selected from or
  • R 2 is selected from hydrogen, a 4-9 membered heterocyclic group or amino group containing 1-3 (for example, 1, 2 or 3) heteroatoms selected from N or O or S (preferably N or O), wherein the 4-9 membered heterocyclic group or an amino group optionally substituted with one or two R a;
  • R a is selected from hydroxy, cyano, halogen (preferably F.), C 1-3 alkyl (preferably methyl, ethyl), C 1-3 alkoxy (preferably methoxy, ethoxy), two (C 1-6 alkyl) amino, or by a hydroxyl or C C 1-4 alkyl substituted with 1-3 alkoxy (preferably methoxy, ethoxy);
  • R 3 is selected from -OCF 3 or -OCF 2 Cl;
  • R 4 is selected from hydrogen, C 1-4 alkyl, C 3 cycloalkyl, or a 6-membered heterocyclic group containing 1-2 (preferably 1) heteroatoms selected from N, O or S, wherein C 1 -4 alkyl, C 3 cycloalkyl or 6-membered heterocyclic group is optionally substituted with one or more R b ;
  • R b is selected from deuterium, hydroxyl and C 1-3 alkoxy (e.g. methoxy, ethoxy, propoxy);
  • R 5 is selected from C 1-3 alkyl (e.g. methyl, ethyl, propyl);
  • Ring A is selected from 5-6 membered heteroaryl or phenyl containing 1-2 (preferably 1) N heteroatoms.
  • the application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 is selected from or
  • R 2 is selected from hydrogen, a 4-9 membered heterocyclic group or amino group containing 1-3 (for example, 1, 2 or 3) heteroatoms selected from N or O or S (preferably N or O), wherein the 4-9 membered heterocyclic group or an amino group optionally substituted with one or two R a;
  • R a is selected from hydroxy, cyano, halogen (preferably F.), C 1-3 alkyl (preferably methyl, ethyl), C 1-3 alkoxy (preferably methoxy, ethoxy), two (C 1-6 alkyl) amino, or by a hydroxyl or C C 1-4 alkyl substituted with 1-3 alkoxy (preferably methoxy, ethoxy);
  • R 3 is -OCF 2 Cl
  • R 4 is selected from hydrogen, C 1-3 alkyl (preferably methyl, ethyl), C 3 cycloalkyl, or a 6-membered heterocyclic ring containing 1 heteroatom selected from N or O (preferably O heteroatom) Group, wherein C 1-3 alkyl is optionally substituted with one or more R b ;
  • R b is selected from deuterium
  • R 5 is selected from C 1-3 alkyl (preferably methyl, ethyl);
  • Ring A is a 5-membered heteroaryl or phenyl group containing 1-2 (preferably 1) N heteroatoms.
  • the application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 is selected from or
  • R 2 is selected from
  • R 3 is selected from -OCF 3 or -OCF 2 Cl;
  • R 4 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxy2-methylpropyl, methoxymethyl, methoxyethyl , Methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, Wherein methyl, ethyl and propyl are optionally substituted with one or more deuterium;
  • R 5 is selected from methyl, ethyl and propyl
  • Ring A is selected from pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl or phenyl.
  • the application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
  • R 1 is selected from or
  • R 2 is selected from
  • R 3 is -OCF 2 Cl
  • R 4 is selected from hydrogen, methyl, d 3 -methyl, cyclopropyl or
  • R 5 is selected from methyl
  • Ring A is selected from pyrrolyl or phenyl.
  • 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.
  • this application also provides a method for treating and/or preventing BCR-ABL related diseases, which comprises administering a therapeutically effective amount of the above-mentioned compound of this application or a pharmaceutically acceptable compound thereof to a mammal in need, preferably a human. Salt or its pharmaceutical composition.
  • the application also provides the use of the above-mentioned compound of the application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicine for the treatment and/or prevention of BCR-ABL-related diseases.
  • the application also provides the use of the above-mentioned compound of the 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 a compound of the present application, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the treatment and/or prevention of BCR-ABL-related diseases.
  • the BCR-ABL-related disease is selected from cancer, such as leukemia (such as chronic myeloid leukemia).
  • the compound of the present application or a pharmaceutically acceptable salt thereof can exhibit a proliferation inhibitory effect on K562 cells and BCR-ABL T315I transfected Ba/F3 cells, has good cell activity, and can exhibit good in vivo pharmacokinetics. Kinetic properties.
  • the covalent bond in some structural unit or group in this application is not connected to a specific atom, 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 valence bond connection rule .
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence of the specific atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are replaced, and the oxo will not occur on the aromatic group.
  • C mn in this context means that the part has an integer number of carbon atoms in a given range.
  • 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, or 3 carbon atoms.
  • any variable such as R
  • its definition in each case is independent. So, for example, if a group is replaced by 2 Rs, then each R has independent options.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a covalent bond.
  • the substituent can be bonded to any atom on the ring.
  • the structural unit It means that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • hydroxy refers to the -OH group.
  • amino refers to the -NH 2 group.
  • cyano refers to the -CN group.
  • alkyl refers to a hydrocarbon group of the general formula C n H 2n+1.
  • the alkyl group may be linear or branched.
  • C 1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (e.g., 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 moiety ie, alkyl
  • alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio have the same definition as described above.
  • C 1-3 alkyl refers to an alkyl group containing 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, and isopropyl).
  • alkoxy refers to -O-alkyl
  • alkylamino refers to -NH-alkyl
  • dialkylamino refers to -N(alkyl) 2 .
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the carbocyclic ring is usually a 3- to 10-membered ring, such as a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, or a 10-membered ring.
  • Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, diamond 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 may exist as a single ring, bridged ring, or spiro ring.
  • the heterocyclic ring is generally 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, for example, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, or 9-membered ring.
  • heterocyclic groups include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, 2-oxy Hetero-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.3]heptanyl, etc.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the heterocyclic ring is generally 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. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, sulfidene, and azaethylenyl.
  • Non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetin
  • Examples of cyclic group, thiabutanyl, 5-membered heterocycloalkyl include but are not limited to tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine
  • 6-membered heterocycloalkyl groups include but are not limited to piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, Examples of 4-thiaxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, and 7-membered heterocycloalkyl include But it is not limited
  • heterocycloalkenyl refers to a non-aromatic ring that is partially unsaturated (but not fully unsaturated heteroaromatic) and may exist as a single ring, bridged ring, or spiro ring.
  • the heterocyclic ring is generally 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.
  • heterocyclenyl include, but are not limited to, dihydrofuranyl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, dihydropyrrolyl, 4H-pyranyl, and the like.
  • spiroheterocyclyl refers to a fully saturated or partially unsaturated (but not fully saturated) spiro ring with one or more ring atoms selected from sulfur, oxygen and/or nitrogen heteroatoms (preferably 1 or 2 Heteroatoms), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 6 to 10 yuan.
  • the spiro heterocyclic ring is divided into a single spiro heterocyclic ring, a dispiro heterocyclic ring or a polyspiro heterocyclic ring, preferably a single spiro heterocyclic ring or a dispiro heterocyclic ring, and more preferably a 4-membered/ 4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic ring.
  • spiro heterocycles include
  • spiroheterocycloalkyl refers to a fully saturated spiroheterocyclic group.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system, which contains at least one (for example, 1-4, 1-3 or 1-2, for example, 1, 2, or 3) selected from The heteroatoms of N, O, and S are used as ring atoms, and the rest of the ring atoms are C and have at least one aromatic ring.
  • Preferred heteroaryl groups have a single 5- to 8-membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , Tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.
  • treatment means administering the compound or formulation described in this application to ameliorate or eliminate a disease or one or more symptoms related to the disease, and includes:
  • prevention means administering the compound or preparation described in this application to prevent a disease or one or more symptoms related to the disease, and includes: preventing the occurrence of a disease or disease state 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) treatment or prevention of a particular disease, condition or disorder, (ii) reduction, amelioration or elimination of one or more symptoms of a particular disease, condition or disorder, or (iii) prevention or delay
  • the amount of the compound of the present application that constitutes a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but it can be routinely determined by those skilled in the art. Determined by its own knowledge and this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reactions or other problems or complications of the disease are 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. can be mentioned. .
  • pharmaceutical composition refers to a mixture of one or more of the compounds of the application or their salts and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound of the present application to the organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not damage the biological activity and performance of the active compound.
  • Suitable auxiliary materials 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 present invention may exist in specific 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 mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
  • wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a three-dimensional center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dashed key Or use wavy lines Represents a straight solid line key And straight dashed key
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with an appropriate optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • radioisotopes such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • heavy hydrogen can be substituted for 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 between deuterium and carbon is stronger than the bond between 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 efficacy, and prolonging the biological half-life of drugs. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention. "Optional” or “optionally” means that the event or condition described later may but not necessarily occur, and the description includes a situation in which the event or condition occurs and a situation in which the event or condition does not occur.
  • the present application also includes compounds of the present application that are the same as those described herein, but have one or more atoms replaced by an isotope-labeled atom having an atomic weight or mass number different from the atomic weight or mass number commonly found in nature.
  • isotopes that can be bound to 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.
  • isotope-labeled compounds of the application can be used in compound and/or substrate tissue distribution analysis. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are especially preferred due to their ease of preparation and detectability. Positron emission 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.
  • PET positron emission tomography
  • the isotopically-labeled compounds of the present application can be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by replacing non-isotopically-labeled reagents with isotope-labeled reagents.
  • substitution with heavier isotopes can provide certain therapeutic advantages resulting from higher metabolic stability (for example, increased in vivo half-life or reduced dosage requirements), and therefore in certain situations
  • the following may be preferred, wherein the deuterium substitution may be partial or complete.
  • Partial deuterium substitution refers to the substitution of at least one hydrogen with at least one deuterium. All compounds in such forms are included in the scope of the present application.
  • the compounds of the application may be asymmetric, for example, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, for example, enantiomers and diastereomers.
  • the compound containing asymmetric carbon atoms of the present application can be isolated in an optically pure form or a racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using chiral raw materials or chiral reagents.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , Granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes for administering the compound of the present application or a pharmaceutically acceptable salt or pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method, etc.
  • the pharmaceutical composition is in an oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These auxiliary materials enable the compound of the present application to be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • the solid oral composition can be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or the core of the dragee.
  • suitable excipients include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • the pharmaceutical composition may also be suitable for parenteral administration, such as a sterile solution, suspension or lyophilized product in a suitable unit dosage form.
  • the therapeutic dose of the compound of the present application may be determined according to, for example, the following: the specific use of the treatment, the way of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the ratio or concentration of the compound of the present application in the pharmaceutical composition may not be fixed, depending on various factors, including dosage, chemical properties (for example, hydrophobicity), and route of administration.
  • the compound of the present application can be provided by a physiologically buffered aqueous solution containing about 0.1-10% w/v of the compound for parenteral administration. Some typical dosage ranges are from about 1 ⁇ g/kg to about 1 g/kg body weight/day.
  • the dosage range is from about 0.01 mg/kg to about 100 mg/kg body weight/day.
  • the dosage is likely to depend on such variables, such as the type and degree of development of the disease or condition, the general health status of the specific patient, the relative biological efficacy of the selected compound, the excipient formulation and its route of administration.
  • the effective dose can be obtained by extrapolating the dose-response curve derived from the in vitro or animal model test system.
  • 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 those well known to those skilled in the art Equivalent replacement manners, preferred implementation manners include but are not limited to the embodiments of the present application.
  • R 2 and R 3 are as described above, and R 2 is not hydrogen.
  • R 3 is as described above, and R 2 is hydrogen.
  • R 4 , R 5 and ring A are as described above.
  • R 2 , R 3 , R 4 , R 5 and ring A are as described above.
  • SOCl 2 stands for thionyl chloride; TEA stands for triethylamine; Oxone stands for potassium hydrogen persulfate complex salt; NBS stands for N-bromosuccinimide; Pd(PPh 3 ) 4 stands for tetrakis(triphenylphosphine) palladium ; PdCl 2 (dppf) stands for 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; DCM stands for dichloromethane; DMSO stands for dimethyl sulfoxide; DMF stands for N,N-dimethyl ⁇ Formamide.
  • the compound 1-2 obtained in the above step B (163 mg), potassium carbonate (146 mg), deionized water (1.5 mL), and tetrakis (triphenylphosphine) palladium (10 mg) were sequentially added; After nitrogen replacement, the temperature was raised to 80-90°C and reacted for 4 hours. After cooling to room temperature, the above reaction was filtered, the mother liquor was collected, 15 mL of ethyl acetate was added, and the mixture was washed and then separated. The organic phase was obtained by adding 15 mL of saturated sodium chloride aqueous solution, followed by stirring, and then separation. Purified by column chromatography, a total of 60 mg of compound 1 was obtained. .
  • step E in Example 1 the compound 2-2 obtained in step B was used to prepare a reaction solution containing compound 2-3, which was cooled to room temperature, and was directly used in the next step without separation and purification.
  • step F of Example 1 using the reaction solution obtained in step C above and compound 1-2 obtained in step B of Example 1, compound 2 was prepared.
  • step F in Example 1 compound 3 was prepared using compound 1-2 obtained in step B of Example 1 and 3-methanesulfonylphenylboronic acid.
  • step B in Example 1 compound 1-1 is reacted with N-methylpiperazine to prepare compound 4-1.
  • step F in Example 1 the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 4-1 in step A to prepare compound 4.
  • step B in Example 1 compound 1-1 is reacted with morpholine to prepare compound 5-1.
  • step F in Example 1 the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 5-1 in step A above to prepare compound 5.
  • step B in Example 1 Referring to the preparation method of step B in Example 1, compound 1-1 and (R)-3-dimethylaminopyrrolidine are reacted to prepare compound 6-1.
  • step F in Example 1 the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 6-1 in step A to prepare compound 6.
  • step B in Example 1 compound 1-1 is reacted with azetidine to prepare compound 7-1.
  • step F in Example 1 the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 7-1 in step A above to prepare compound 7.
  • step B in Example 1 compound 8-1 was prepared by reacting compound 1-1 with tetrahydropyrrole.
  • step F of Example 1 With reference to the preparation method of step F of Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 8-1 of step A above to prepare compound 8.
  • step A compound 9-1 was prepared using 5-bromo-6-chloronicotinic acid and 4-trifluoromethoxyaniline.
  • step B of Example 1 compound 9-2 was prepared using compound 9-1 obtained in step A above and (R)-3-pyrrolidinol.
  • step F in Example 1 With reference to the method of step F in Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 and compound 9-2 obtained in step B above were used to prepare compound 9.
  • step B in Example 2 With reference to the preparation method of step B in Example 2, the ethanol solution of methylamine (30%-35%, m/m) was used to replace the isopropanol solution of ammonia (2mol/L) to prepare compound 10-2.
  • step E in Example 1 the compound 10-2 obtained in step A was used to prepare a reaction solution containing compound 10-3, which was cooled to room temperature, and was directly used in the next step without separation and purification.
  • step F of Example 1 With reference to the method in step F of Example 1, using the reaction solution containing compound 10-3 obtained in step B above and compound 1-2 obtained in step B of Example 1, compound 10 was prepared.
  • step E in Example 1 With reference to the method of step E in Example 1, the compound 11-1 obtained in step A was used to prepare a reaction solution containing compound 11-2, which was cooled to room temperature, and was directly used in the next step without separation and purification.
  • step F in Example 1 using the reaction solution containing compound 11-2 obtained in step B above and compound 1-2 obtained in step B of Example 1, compound 11 was prepared.
  • step F in Example 1 using the reaction solution containing compound 2-3 obtained in step C of Example 2 and compound 12-1 obtained in step A above, compound 12 was prepared.
  • step E in Example 1 With reference to the method of step E in Example 1, the compound 13-1 obtained in step A was used to prepare a reaction solution containing compound 13-2, which was cooled to room temperature, and was directly used in the next step without separation and purification.
  • step F in Example 1 With reference to the method of step F in Example 1, the reaction solution containing compound 13-2 obtained in step B above and compound 12-1 obtained in step A of Example 12 were used to prepare compound 13.
  • the compound 14-1 was prepared by referring to the method of step A in Example 13, using the raw material ethanolamine instead of 2-methoxyethylamine.
  • step E in Example 1 With reference to the method of step E in Example 1, the compound 14-1 obtained in step A was used to prepare a reaction solution containing compound 14-2, which was cooled to room temperature, and was directly used in the next step without separation and purification.
  • step F in Example 1 With reference to the method of step F in Example 1, the reaction solution containing compound 14-2 obtained in step B above and compound 12-1 obtained in step A of Example 12 were used to prepare compound 14.
  • step A in Example 13 the starting material 1-amino-2-methyl-2-propanol was substituted for 2-methoxyethylamine to prepare compound 15-1.
  • step E in Example 1 With reference to the method of step E in Example 1, the compound 15-1 obtained in step A was used to prepare a reaction solution containing compound 15-2, which was cooled to room temperature, and was directly used in the next step without separation and purification.
  • step F in Example 1 using the reaction solution containing compound 15-2 obtained in step B above and compound 12-1 obtained in step A of Example 12, compound 15 was prepared.
  • the compound 16-1 was prepared by using 4-aminotetrahydropyran as the starting material instead of 2-methoxyethylamine.
  • step E in Example 1 the compound 16-1 obtained in step A was used to prepare a reaction solution containing compound 16-2, which was cooled to room temperature, and was directly used in the next step without separation and purification.
  • step F in Example 1 With reference to the method of step F in Example 1, the reaction solution containing compound 16-2 obtained in step B above and compound 12-1 obtained in step A of Example 12 were used to prepare compound 16.
  • the compound 17-1 was prepared by using 3-hydroxyazetidine hydrochloride as the raw material instead of (R)-3-pyrrolidinol.
  • step F in Example 1 the reaction solution containing compound 11-2 obtained in step B of Example 11 and the reaction solution containing compound 17-1 obtained in step A above were used to prepare compound 17.
  • step B in Example 1 compound 18-1 was prepared by using morpholine as the raw material instead of (R)-3-pyrrolidinol.
  • step F in Example 1 With reference to the method of step F in Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 and the reaction solution containing compound 18-1 obtained in step A above were used to prepare compound 18.
  • step F in Example 1 using the reaction solution containing compound 10-3 obtained in step B of Example 10 and compound 17-1 obtained in step A of Example 17, compound 19 was prepared.
  • the compound 20-1 was prepared by using the starting material 2-oxa-7-azaspiro[3.5]nonane instead of (R)-3-pyrrolidinol.
  • step F in Example 1 With reference to the method of step F in Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 and the reaction solution containing compound 20-1 obtained in step A above were used to prepare compound 20.
  • step B in Example 1 compound 1-1 is reacted with 2-oxa-6-aza-spiro[3.3]heptane to obtain compound 21-1.
  • step F in Example 1 the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 21-1 obtained in step A above to prepare compound 21.
  • step B in Example 1 compound 1-1 is reacted with 3-cyanoazetidine hydrochloride to prepare compound 22-1.
  • step F in Example 1 the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 22-1 obtained in step A above to prepare compound 22.
  • step F in Example 1 the reaction solution containing compound 11-2 obtained in step B of Example 11 was reacted with compound 22-1 obtained in step A of Example 22 to prepare compound 23.
  • step B in Example 1 compound 1-1 is reacted with 3-methoxyazetidine to prepare compound 24-1.
  • step F in Example 1 With reference to the method of step F in Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 24-1 obtained in step A above to prepare compound 24.
  • step B in Example 1 compound 1-1 and 2-methoxyethylamine are reacted to prepare compound 25-1.
  • step F in Example 1 the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 25-1 obtained in step A above to prepare compound 25.
  • step B in Example 1 compound 1-1 is reacted with 1-amino-2-methyl-2-propanol to prepare compound 26-1.
  • step F in Example 1 the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 26-1 obtained in step A above to prepare compound 26.
  • step B of Example 1 compound 1-1 is reacted with N-methyl-2-hydroxyethylamine to obtain compound 27-1.
  • step F in Example 1 the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 27-1 obtained in step A above to prepare compound 27.
  • step B in Example 1 compound 1-1 is reacted with azetidine hydrochloride to obtain compound 28-1.
  • step F of Example 1 the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 28-1 obtained in step A above to prepare compound 28.
  • step B in Example 1 compound 1-1 is reacted with 3-fluoroazetidine hydrochloride to obtain compound 29-1.
  • step F of Example 1 the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 29-1 obtained in step A above to prepare compound 29.
  • step F in Example 1 the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 28-1 obtained in step A of Example 28 to prepare compound 30.
  • step F in Example 1 the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 29-1 obtained in step A of Example 29 to prepare compound 31.
  • step F of Example 1 the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 8-1 obtained in step A of Example 8 to prepare compound 32.
  • step B in Example 1 compound 1-1 is reacted with (S)-3-hydroxymethyltetrahydropyrrole hydrochloride to obtain compound 33-1.
  • step F of Example 1 the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 33-1 obtained in the above step to prepare compound 33.
  • step F in Example 1 the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 33-1 obtained in step A of Example 33 to prepare compound 34.
  • step F of Example 1 the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 35-1 obtained in the above step to prepare compound 35.
  • step F of Example 1 the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 35-1 obtained in step A of Example 35 to prepare compound 36.
  • step B in Example 1 compound 1-1 is reacted with ethyl 4-aminobutyrate hydrochloride to prepare compound 37-1.
  • step B Add compound 37-2 (600 mg), DMF (20 mL), and triethylamine (162 mg) prepared in step B above to a 50 mL single-neck bottle, and add DMF with pentafluorophenyl diphenyl phosphate (482 mg) dropwise at room temperature (5mL) The solution was heated to 50°C for reaction, after the reaction was completed. Add 150 mL of water, extract three times with ethyl acetate, combine the organic phases, and wash the organic phases with saturated aqueous sodium chloride three times. The organic phase was dried with anhydrous sodium sulfate and concentrated. The crude product obtained was purified by column chromatography to obtain 489 mg of compound 37-3.
  • step F of Example 1 the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 37-3 obtained in the above step to prepare compound 37.
  • step B in Example 1 compound 1-1 is reacted with (R)-3-methoxypyrrolidine to obtain compound 38-1.
  • step F in Example 1 the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 38-1 obtained in step A above to prepare compound 38.
  • step F of Example 1 the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 38-1 obtained in step 38 of Example 38 to prepare compound 39.
  • step B in Example 1 compound 1-1 is reacted with (R)-3-cyanopyrrolidine to obtain compound 40-1.
  • step F in Example 1 the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 40-1 obtained in step A above to prepare compound 40.
  • step F of Example 1 the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 40-1 obtained in step A of Example 40 to prepare compound 41.
  • step B in Example 42 the compound 42-1 obtained in step A of Example 42 was reacted with 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester to prepare compound 43.
  • step B in Example 42 the compound 44-1 obtained in step A was reacted with 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester to prepare compound 44-2.
  • step B in Example 1 compound 1-1 is reacted with 4-hydroxypiperidine to prepare compound 45-1.
  • step F in Example 1 the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 45-1 obtained in step A to prepare compound 45.
  • step F in Example 1 the reaction solution containing compound 11-2 obtained in step B of Example 11 was reacted with compound 45-1 obtained in step A of Example 45 to prepare compound 46.
  • step B in Example 1 compound 1-1 is reacted with 3-methylhydroxyazetidine hydrochloride to obtain compound 47-1.
  • step F in Example 1 the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 47-1 obtained in step A above to prepare compound 47.
  • step F in Example 1 the reaction solution containing compound 11-2 obtained in step B of Example 11 was reacted with compound 47-1 obtained in step A of Example 47 to prepare compound 48.
  • step B in Example 1 compound 49-1 was prepared by reacting compound 1-1 with cis-2,6-dimethylmorpholine.
  • step F in Example 1 the reaction solution containing compound 10-3 obtained in step B of Example 10 is reacted with compound 49-1 obtained in step A above to prepare compound 49.
  • step B in Example 1 compound 1-1 and 3-methyl-3-acridol hydrochloride are reacted to prepare compound 50-1.
  • step F in Example 1 With reference to the preparation method of step F in Example 1, the reaction solution containing compound 11-2 obtained in step B of Example 11 was reacted with compound 50-1 obtained in step A to prepare compound 50.
  • step B in Example 1 the compound 51-1 containing compound 51-1 obtained in step A above and compound 1-1 are reacted to prepare compound 51-2.
  • step F in Example 1 the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 51-2 of step B above to prepare compound 51.
  • step B in Example 1 the compound 52-1 obtained in the above step A is reacted with compound 1-1 to prepare compound 52-2.
  • step F in Example 1 the reaction solution containing compound 10-3 obtained in step B of Example 10 is reacted with compound 52-2 obtained in step B above to prepare compound 52.
  • step B in Example 1 compound 1-1 is reacted with (R)-3-fluoropyrrolidine to obtain compound 53-1.
  • step F in Example 1 the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 53-1 obtained in step A above to prepare compound 53.
  • step F in Example 1 the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 53-1 obtained in step A of Example 53 to prepare compound 54.
  • step B in Example 1 compound 1-1 is reacted with (S)-3-fluoropyrrolidine to prepare compound 55-1.
  • step F of Example 1 With reference to the preparation method of step F of Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 55-1 of step A above to prepare compound 55.
  • step F in Example 1 the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 55-1 obtained in step A of Example 55 to prepare compound 56.
  • step A of Example 2 Add 10 mL of absolute ethanol, compound 2-1 (400 mg), diisopropylethylamine (428 mg), and deuterated methylamine hydrochloride (97 mg) obtained in step A of Example 2 to a 50 mL single-necked flask, and add to room temperature. The reaction was continued for 6 hours; the reaction solution was concentrated under reduced pressure; the resulting residue was subjected to column chromatography to obtain compound 57-1.
  • Step B Preparation of compound 57-2
  • step E in Example 1 With reference to the method of step E in Example 1, the compound 57-1 obtained in step A was used to prepare a reaction solution containing compound 57-2, which was cooled to room temperature, and was directly used in the next step without separation and purification.
  • step F in Example 1 With reference to the method of step F in Example 1, the reaction solution containing compound 57-2 obtained in step B above and compound 33-1 obtained in step A of Example 33 were used to prepare compound 57.
  • step F in Example 1 the compound 5-1 obtained in step A of Example 5 was reacted with (3-(methylsulfonyl)phenyl)boronic acid to prepare compound 58.
  • Step B Preparation of compound 59-2
  • step B in Example 1 With reference to the method of step B in Example 1, the compound 1-1 and 2-(methylamino)ethan-1-ol obtained in step A of Example 1 were used to prepare the standard compound 60-1.
  • step F in Example 1 compound 60 was prepared by reacting compound 60-1 obtained in step A above with the reaction solution containing compound 2-3 obtained in step C of embodiment 2.
  • Step A Preparation of compound 61-1
  • step A in Example 13 using 1-tert-butoxycarbonyl-4-aminopiperidine instead of 2-methoxyethylamine to react with compound 2-1 to prepare compound 61-1.
  • step E in Example 1 the compound 61-1 obtained in step A was used to prepare a reaction solution containing compound 61-2, which was cooled to room temperature, and was directly used in the next step without separation and purification.
  • step F in Example 1 With reference to the method of step F in Example 1, the reaction solution containing compound 61-2 obtained in step B above and compound 12-1 obtained in step A of Example 12 were used to prepare compound 61-3.
  • step A Add compound 61-3 (430mg), dichloromethane (10mL) and 6M hydrogen chloride-dioxane solution (2.5mL) obtained in step A to a 50mL round bottom flask, stir overnight at room temperature, and concentrate the reaction after the reaction is complete. Then, ethyl acetate (10 mL) was added and stirred at room temperature for 4 h. Filter and wash the filter cake with ethyl acetate. The filter cake was collected and dried to obtain 60 mg of compound 61.
  • Test Example 1 The compound's inhibitory effect on the proliferation of K562 cells
  • Test Example 2 The compound's inhibitory effect on the proliferation of BCR-ABL T315I transfected Ba/F3 cells
  • ICR mice purchased from Shanghai Xipuerbikai Experimental Animal Co., Ltd., weighing 18-22 g, were used for 3 to 5 days and then randomly divided into groups, 9 mice in each group, and each compound was administered by intragastric administration at a dose of 10 mg/kg.
  • the test animals were fasted overnight before the administration, and were given food 4 hours after the administration, and they were free to drink water before and after the experiment and during the experiment.
  • the oral exposure of the compound was evaluated by pharmacokinetic experiments in mice.
  • the DAS 3.2.5 software was used to fit the relevant pharmacokinetic parameters, and the results are shown in Table 2.

Abstract

A compound used as a BCR-ABL inhibitor in the field of pharmaceutical chemistry, that is, a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, a preparation method therefor, and a pharmaceutical composition comprising the compound. The present invention also relates to a use thereof in the preparation of a drug for treating BCR-ABL related diseases.

Description

作为BCR-ABL抑制剂的化合物Compounds that act as inhibitors of BCR-ABL
相关申请的引用References to related applications
本申请要求于2020年01月19日向中华人民共和国知识产权局提交的申请号为202010062317.3的中国发明专利申请的权益和优先权，以及于2020年11月10日向中华人民共和国知识产权局提交的申请号为202011246125.4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。This application claims the rights and priority of the Chinese invention patent application with the application number 202010062317.3 filed with the Intellectual Property Office of the People's Republic of China on January 19, 2020, and the application filed with the Intellectual Property Office of the People's Republic of China on November 10, 2020 The rights and priority of the Chinese invention patent application No. 202011246125.4, and the entire content of which is incorporated herein by reference.
技术领域Technical field
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。This application belongs to the field of medicinal chemistry, and provides a compound as a BCR-ABL inhibitor, a preparation method thereof, and a pharmaceutical composition containing the compound, and relates to its use in the preparation of drugs for treating BCR-ABL-related diseases.
背景技术Background technique
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。Chronic myeloid leukemia (CML) is the main type 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 chromosomes 9 and 22, forming the Bcr-Abl fusion gene, expressing the protein p-210. The tyrosine kinase activity of p-210 is much stronger than that of p-150 (normal c-Abl gene expression product), which causes abnormal proliferation and differentiation of hematopoietic stem cells, and ultimately leads to 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，为第一、二代Bcr-Abl抑制剂治疗失败患者的唯一选择。Imatinib is the first Bcr-Abl targeted therapy to be marketed, and it is currently used as a first-line therapy for the treatment of various stages of CML. Nilotinib, dasatinib, and bosutinib (second-generation Bcr-Abl inhibitors) are approved for the treatment of CML that is resistant or intolerant to imatinib. The second-generation Bcr-Abl inhibitors are more effective than imatinib, and are effective for almost all imatinib-resistant mutation types, but the problem of mutation resistance of T315I (gatekeeper) has not been solved yet. T315I mutations accounted for about 20% of patients with resistance to first and second generation Bcr-Abl inhibitors. The launch of Pranatinib (third-generation Bcr-Abl inhibitor) alleviated the absence of drugs in patients with T315I resistance mutations. The curable dilemma is the only choice for patients who have failed the treatment of the first and second generation Bcr-Abl inhibitors.
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)。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 inhibitor of BCR-ABL, which is active against most mutants, such as T315I. (Andrew A. Wylie et al. (2017) Nature 543,733-737).
Figure PCTCN2021072699-appb-000001
Figure PCTCN2021072699-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。At present, there is no BCR-ABL allosteric inhibitor on the market. There is an urgent need for effective and low-toxic Bcr-Abl inhibitors for T315I in clinical practice. It is necessary to further develop new BCR-ABL allosteric inhibitors.
发明内容Summary of the invention
一方面，本申请提供了式(I)化合物或其药学上可接受的盐，In one aspect, the application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2021072699-appb-000002
Figure PCTCN2021072699-appb-000002
其中，in,
R 1选自
Figure PCTCN2021072699-appb-000003
或者
Figure PCTCN2021072699-appb-000004
R 1 is selected from
Figure PCTCN2021072699-appb-000003
or
Figure PCTCN2021072699-appb-000004
R 2选自氢、3-10元杂环基或氨基，其中所述3-10元杂环基或氨基任选地被一个或多个R a取代； R 2 is selected from hydrogen, amino, or 3-10 membered heterocyclyl, wherein said 3-10 membered heterocyclyl group or an amino group optionally substituted with one or more substituents R a;
R a选自羟基、氰基、卤素、
Figure PCTCN2021072699-appb-000005
C 1-6烷基、C 1-6烷氧基、二(C 1-6烷基)氨基、或被一个或多个羟基或C 1-6烷氧基取代的C 1-6烷基； R a is selected from hydroxyl, cyano, halogen,
Figure PCTCN2021072699-appb-000005
C 1-6 alkyl, C 1-6 alkoxy, di (C 1-6 alkyl) amino, or one or more hydroxy or C 1-6 alkoxy substituted C 1-6 alkyl;
R 3选自-OCF 2H，其中所述-OCF 2H任选地被卤素取代； R 3 is selected from -OCF 2 H, wherein the -OCF 2 H is optionally substituted by halogen;
R 4选自氢、C 1-6烷基、C 3-6环烷基或3-10元杂环基，其中C 1-6烷基、C 3-6环烷基或3-10元杂环基任选 地被一个或多个R b取代； R 4 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-10 membered heterocyclic group, wherein C 1-6 alkyl, C 3-6 cycloalkyl or 3-10 membered heterocyclic group The cyclic group is optionally substituted with one or more R b ;
R b选自氘、羟基、C 1-6烷氧基、C 1-6烷基、氨基、单(C 1-6烷基)氨基或二(C 1-6烷基)氨基； R b is selected from deuterium, hydroxyl, C 1-6 alkoxy, C 1-6 alkyl, amino, mono(C 1-6 alkyl)amino or di(C 1-6 alkyl)amino;
R 5选自C 1-6烷基； R 5 is selected from C 1-6 alkyl;
环A选自5-6元杂芳基或苯基。Ring A is selected from 5-6 membered heteroaryl or phenyl.
在一些实施方案中，R a选自羟基、卤素、C 1-6烷基、二(C 1-6烷基)氨基、或被一个或多个羟基取代的C 1-6烷基；R b选自羟基、C 1-6烷氧基、C 1-6烷基、氨基、单(C 1-6烷基)氨基或二(C 1-6烷基)氨基。 In some embodiments, R a is selected from hydroxy, halogen, C 1-6 alkyl, di(C 1-6 alkyl)amino, or C 1-6 alkyl substituted with one or more hydroxy groups; R b It is selected from hydroxyl, C 1-6 alkoxy, C 1-6 alkyl, amino, mono(C 1-6 alkyl)amino or di(C 1-6 alkyl)amino.
在一些实施方案中，R 1选自
Figure PCTCN2021072699-appb-000006
其他变量如本申请所定义。 In some embodiments, R 1 is selected from
Figure PCTCN2021072699-appb-000006
Other variables are as defined in this application.
在一些实施方案中，R 1选自
Figure PCTCN2021072699-appb-000007
其他变量如本申请所定义。 In some embodiments, R 1 is selected from
Figure PCTCN2021072699-appb-000007
Other variables are as defined in this application.
在一些实施方案中，R 2选自氢、3-10元杂环烷基、3-10元杂环烯基或氨基，其中所述3-10元杂环烷基、3-10元杂环烯基或氨基任选地被一个或多个R a取代；其他变量如本申请所定义。 In some embodiments, R 2 is selected from hydrogen, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, or amino, wherein the 3-10 membered heterocycloalkyl, 3-10 membered heterocycle alkenyl group or an amino group optionally substituted with one or more substituents R a; the other variables are as defined herein.
在一些实施方案中，R 2选自氢、4-6元杂环基、7-9元螺杂环基或氨基，其中所述4-6元杂环基、7-9元螺杂环基或氨基任选地被一个或多个R a取代；其他变量如本申请所定义。 In some embodiments, R 2 is selected from hydrogen, 4-6 membered heterocyclyl, 7-9 membered spiroheterocyclyl or amino, wherein the 4-6 membered heterocyclyl, 7-9 membered spiroheterocyclyl or amino optionally substituted with one or more substituents R a; the other variables are as defined herein.
在一些实施方案中，R 2选自氢、4-6元杂环基或氨基，其中所述4-6元杂环基或氨基任选地被一个或多个R a取代；其他变量如本申请所定义。 In some embodiments, R 2 is selected from hydrogen, 4-6 membered heterocyclyl or amino group, wherein the 4-6 membered heterocyclyl or amino optionally substituted with one or more substituents R a; the other variables are as this As defined by the application.
在一些实施方案中，R 2选自氢、4-6元杂环烷基、6元杂环烯基、7或9元螺杂环烷基或氨基，其中所述4-6元杂环烷基、6元杂环烯基、7或9元螺杂环烷基或氨基任选地被一个或多个R a取代；其他变量如本申请所定义。 In some embodiments, R 2 is selected from hydrogen, 4-6 membered heterocycloalkyl, 6 membered heterocycloalkenyl, 7 or 9 membered spiroheterocycloalkyl, or amino, wherein the 4-6 membered heterocycloalkane group, a 6-membered heterocycloalkenyl, 7, or 9-membered spirocyclic heterocycloalkyl or amino optionally substituted with one or more substituents R a; the other variables are as defined herein.
在一些实施方案中，R 2选自氢、吡咯烷基、吗啉基、哌嗪基、氮杂环丁基、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、2-氧杂-7-氮杂螺[3.5]壬烷基、2-氧杂-6-氮杂螺[3.3]庚烷基或氨基，其中所述吡咯烷基、吗啉基、哌嗪基、氮杂环丁基、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、2-氧杂-7-氮杂螺[3.5]壬烷基、2-氧杂-6-氮杂螺[3.3]庚烷基或氨基任选地被一个或多个R a取代；其他变量如本申请所定义。 In some embodiments, R 2 is selected from hydrogen, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 1,2,3,6-tetrahydropyridyl, tetrahydropyridine Pyryl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro [3.3] Heptyl or amino, wherein the pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 1,2,3,6-tetrahydropyridyl, tetrahydropyridine Pyryl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro [3.3] heptan-alkyl or amino optionally substituted with one or more substituents R a; the other variables are as defined herein.
在一些实施方案中，R 2选自氢、吡咯烷基、吗啉基、哌嗪基、氮杂环丁基、哌啶基、3,4-二氢吡喃基或氨基，其中所述吡咯烷基、吗啉基、哌嗪基、氮杂环丁基、哌啶基、3,4-二氢吡喃基或氨基任选地被一个或多个R a取代；其他变量如本申请所定义。 In some embodiments, R 2 is selected from hydrogen, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 3,4-dihydropyranyl, or amino, wherein the pyrrole alkyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 3,4-dihydropyran or an amino group optionally substituted with one or more R a; the other variables are as herein definition.
在一些实施方案中，R 2选自氢、
Figure PCTCN2021072699-appb-000008
Figure PCTCN2021072699-appb-000009
或氨基，其中所述
Figure PCTCN2021072699-appb-000010
Figure PCTCN2021072699-appb-000011
或氨基任选地被一个或多个R a取代；其他变量如本申请所定义。 In some embodiments, R 2 is selected from hydrogen,
Figure PCTCN2021072699-appb-000008
Figure PCTCN2021072699-appb-000009
Or amino, where the
Figure PCTCN2021072699-appb-000010
Figure PCTCN2021072699-appb-000011
Or amino optionally substituted with one or more substituents R a; the other variables are as defined herein.
在一些实施方案中，R a选自羟基、氰基、卤素、
Figure PCTCN2021072699-appb-000012
C 1-4烷基、C 1-3烷氧基、二(C 1-3烷基)氨基或被一个或多个羟基或C 1-3烷氧基取代的C 1-4烷基；其他变量如本申请所定义。 In some embodiments, R a is selected from hydroxy, cyano, halogen,
Figure PCTCN2021072699-appb-000012
C 1-4 alkyl, C 1-3 alkoxy, di(C 1-3 alkyl)amino or C 1-4 alkyl substituted with one or more hydroxy groups or C 1-3 alkoxy; others The variables are as defined in this application.
在一些实施方案中，R a选自羟基、卤素、C 1-3烷基、二(C 1-3烷基)氨基、或被一个或多个羟基取代的C 1-3烷基；其他变量如本申请所定义。 In some embodiments, R a is selected from hydroxy, halo, C 1-3 alkyl, di (C 1-3 alkyl) amino, or by one or more hydroxy-substituted C 1-3 alkyl; other variables As defined in this application.
在一些实施方案中，R a选自羟基、氰基、氟、
Figure PCTCN2021072699-appb-000013
甲基、甲氧基、2-羟基乙基、2-甲氧基乙基、2-甲基-2-羟基丙基、二(甲基)氨基或羟基甲基；其他变量如本申请所定义。 In some embodiments, R a is selected from hydroxy, cyano, fluorine,
Figure PCTCN2021072699-appb-000013
Methyl, methoxy, 2-hydroxyethyl, 2-methoxyethyl, 2-methyl-2-hydroxypropyl, bis(methyl)amino or hydroxymethyl; other variables are as defined in this application .
在一些实施方案中，R a选自羟基、氟、甲基、2-羟基乙基、二(甲基)氨基或羟基甲基；其他变量如本申请所定义。 In some embodiments, R a is selected from hydroxy, fluoro, methyl, 2-hydroxyethyl, di (methyl) amino or hydroxyl group; the other variables are as defined herein.
在一些实施方案中，R 2选自氢、吡咯烷基、吗啉基、哌嗪基、氮杂环丁基、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、2-氧杂-7-氮杂螺[3.5]壬烷基、2-氧杂-6-氮杂螺[3.3]庚烷基或氨基，其中所述吡咯烷基任选地被一个羟基、氰基、氟、
Figure PCTCN2021072699-appb-000014
甲氧基或二(甲基)氨基取代，其中所述哌嗪基、哌啶基或吗啉基任选地被一个或两个羟基或甲基取代，其中所述氮杂环丁基任选地被一个或两个羟基、氟、氰基、甲基、甲氧基或羟基甲基取代，其中所述氨基任选地被一个或多个2-羟基乙基、甲基、2-甲氧基乙基或2-甲基-2-羟基丙基取代；其他变量如本申请所定义。 In some embodiments, R 2 is selected from hydrogen, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 1,2,3,6-tetrahydropyridyl, tetrahydropyridine Pyryl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro [3.3] Heptyl or amino, wherein the pyrrolidinyl group is optionally substituted by a hydroxyl group, cyano group, fluorine,
Figure PCTCN2021072699-appb-000014
Methoxy or bis(methyl)amino substitution, wherein the piperazinyl, piperidinyl or morpholinyl is optionally substituted by one or two hydroxy groups or methyl groups, wherein the azetidinyl group is optionally substituted Ground is substituted with one or two hydroxy, fluoro, cyano, methyl, methoxy or hydroxymethyl, wherein the amino group is optionally substituted with one or more 2-hydroxyethyl, methyl, 2-methoxy Ethyl or 2-methyl-2-hydroxypropyl substitution; other variables are as defined in this application.
在一些实施方案中，R 2选自氢、吡咯烷基、吗啉基、哌嗪基、氮杂环丁基、哌啶基、3,4-二氢吡喃基或氨基，其中所述吡咯烷基任选地被一个羟基、氟或二(甲基)氨基取代，其中所述哌嗪基或哌啶基任选地被一个甲基取代，其中所述氮杂环丁基任选地被一个羟基或羟基甲基取代，其中所述氨基任选地被一个或多个2-羟基乙基或甲基取代；其他变量如本申请所定义。 In some embodiments, R 2 is selected from hydrogen, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 3,4-dihydropyranyl, or amino, wherein the pyrrole The alkyl group is optionally substituted with a hydroxy, fluoro or bis(methyl)amino group, wherein the piperazinyl or piperidinyl group is optionally substituted with a methyl group, and wherein the azetidinyl group is optionally substituted by One hydroxy or hydroxymethyl substitution, wherein the amino group is optionally substituted with one or more 2-hydroxyethyl or methyl; other variables are as defined in this application.
在一些实施方案中，R 2选自氢、
Figure PCTCN2021072699-appb-000015
Figure PCTCN2021072699-appb-000016
Figure PCTCN2021072699-appb-000017
其他变量如本申请所定义。 In some embodiments, R 2 is selected from hydrogen,
Figure PCTCN2021072699-appb-000015
Figure PCTCN2021072699-appb-000016
Figure PCTCN2021072699-appb-000017
Other variables are as defined in this application.
在一些实施方案中，R 2选自氢、
Figure PCTCN2021072699-appb-000018
Figure PCTCN2021072699-appb-000019
Figure PCTCN2021072699-appb-000020
其他变量如本申请所定义。 In some embodiments, R 2 is selected from hydrogen,
Figure PCTCN2021072699-appb-000018
Figure PCTCN2021072699-appb-000019
Figure PCTCN2021072699-appb-000020
Other variables are as defined in this application.
在一些实施方案中，R 3选自-OCF 3或-OCF 2Cl；其他变量如本申请所定义。 In some embodiments, R 3 is selected from -OCF 3 or -OCF 2 Cl; other variables are as defined in this application.
在一些实施方案中，R 4选自氢、C 1-6烷基、C 3-6环烷基或3-10元杂环烷基，其中C 1-6烷基、C 3-6环烷 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。 In some embodiments, R 4 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or 3-10 membered heterocycloalkyl, wherein C 1-6 alkyl, C 3-6 cycloalkane The group or 3-10 membered heterocycloalkyl group is optionally substituted with one or more R b ; other variables are as defined in this application.
在一些实施方案中，R 4选自氢、C 1-5烷基、C 3-6环烷基或4-6元杂环烷基，其中C 1-5烷基、C 3-6环烷基或4-6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。 In some embodiments, R 4 is selected from hydrogen, C 1-5 alkyl, C 3-6 cycloalkyl, or 4-6 membered heterocycloalkyl, wherein C 1-5 alkyl, C 3-6 cycloalkane The radical or 4-6 membered heterocycloalkyl is optionally substituted with one or more R b ; other variables are as defined in this application.
在一些实施方案中，R 4选自氢、C 1-5烷基、环丙基或6元杂环烷基，其中C 1-5烷基、环丙基或6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。 In some embodiments, R 4 is selected from hydrogen, C 1-5 alkyl, cyclopropyl or 6-membered heterocycloalkyl, wherein C 1-5 alkyl, cyclopropyl or 6-membered heterocycloalkyl is optionally Ground is replaced by one or more R b ; other variables are as defined in this application.
在一些实施方案中，R 4选自氢、甲基、乙基、2-甲基丙基、3-甲基丁基、环丙基、四氢吡喃基或哌啶基，其中甲基、乙基、2-甲基丙基、3-甲基丁基、环丙基、四氢吡喃基或哌啶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。 In some embodiments, R 4 is selected from hydrogen, methyl, ethyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, tetrahydropyranyl or piperidinyl, wherein methyl, Ethyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, tetrahydropyranyl or piperidinyl is optionally substituted with one or more R b ; other variables are as defined in this application.
在一些实施方案中，R 4选自氢、甲基、乙基、2-甲基丙基、3-甲基丁基、环丙基、
Figure PCTCN2021072699-appb-000021
Figure PCTCN2021072699-appb-000022
其中甲基、乙基、2-甲基丙基、3-甲基丁基、环丙基、
Figure PCTCN2021072699-appb-000023
任选地被一个或多个R b取代；其他变量如本申请所定义。 In some embodiments, R 4 is selected from hydrogen, methyl, ethyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl,
Figure PCTCN2021072699-appb-000021
Figure PCTCN2021072699-appb-000022
Among them, methyl, ethyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl,
Figure PCTCN2021072699-appb-000023
Optionally substituted by one or more R b ; other variables are as defined in this application.
在一些实施方案中，R b选自氘、羟基、C 1-3烷氧基、C 1-3烷基、氨基、单(C 1-3烷基)氨基或二(C 1-3烷基)氨基；其他变量如本申请所定义。 In some embodiments, R b is selected from deuterium, hydroxyl, C 1-3 alkoxy, C 1-3 alkyl, amino, mono(C 1-3 alkyl)amino, or di(C 1-3 alkyl ) Amino; other variables are as defined in this application.
在一些实施方案中，R b选自羟基、C 1-3烷氧基、C 1-3烷基、氨基、单(C 1-3烷基)氨基或二(C 1-3烷基)氨基；其他变量如本申请所定义。 In some embodiments, R b is selected from hydroxyl, C 1-3 alkoxy, C 1-3 alkyl, amino, mono(C 1-3 alkyl)amino, or di(C 1-3 alkyl)amino ; Other variables are as defined in this application.
在一些实施方案中，R b选自氘、羟基、甲氧基、甲基或二(乙基)氨基；其他变量如本申请所定义。 In some embodiments, R b is selected from deuterium, hydroxyl, methoxy, methyl, or di(ethyl)amino; other variables are as defined in this application.
在一些实施方案中，R b选自羟基、甲氧基、甲基或二(乙基)氨基；其他变量如本申请所定义。 In some embodiments, R b is selected from hydroxyl, methoxy, methyl, or di(ethyl)amino; other variables are as defined in this application.
在一些实施方案中，R 4选自氢、甲基、乙基、2-甲基丙基、3-甲基丁基、环丙基、四氢吡喃基或哌啶基，其中甲基任选地被三个氘取代，其中乙基任选地被一个羟基、甲氧基或二(乙基)氨基取代，其中2-甲基丙基或3-甲基丁基任选地被一个羟基取代，其中哌啶基任选地被一个甲基取代；其他变量如本申请所定义。 In some embodiments, R 4 is selected from hydrogen, methyl, ethyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, tetrahydropyranyl, or piperidinyl, wherein methyl is any Optionally substituted by three deuteriums, wherein the ethyl group is optionally substituted by a hydroxy, methoxy or di(ethyl)amino group, and wherein the 2-methylpropyl or 3-methylbutyl group is optionally substituted by a hydroxy group Substitution, where the piperidinyl group is optionally substituted with a methyl group; other variables are as defined in this application.
在一些实施方案中，R 4选自氢、甲基、d 3-甲基、环丙基、
Figure PCTCN2021072699-appb-000024
Figure PCTCN2021072699-appb-000025
其他变量如本申请所定义。 In some embodiments, R 4 is selected from hydrogen, methyl, d 3 -methyl, cyclopropyl,
Figure PCTCN2021072699-appb-000024
Figure PCTCN2021072699-appb-000025
Other variables are as defined in this application.
在一些实施方案中，R 4选自氢；其他变量如本申请所定义。 In some embodiments, R 4 is selected from hydrogen; other variables are as defined in this application.
在一些实施方案中，R 4选自甲基或环丙基；其他变量如本申请所定义。 In some embodiments, R 4 is selected from methyl or cyclopropyl; other variables are as defined in this application.
在一些实施方案中，R 5选自C 1-3烷基；其他变量如本申请所定义。 In some embodiments, R 5 is selected from C 1-3 alkyl; other variables are as defined in this application.
在一些实施方案中，R 5选自甲基；其他变量如本申请所定义。 In some embodiments, R 5 is selected from methyl; other variables are as defined in this application.
在一些实施方案中，环A选自5-6元含氮的杂芳基或苯基；其他变量如本申请所定义。In some embodiments, ring A is selected from 5-6 membered nitrogen-containing heteroaryl or phenyl; other variables are as defined in this application.
在一些实施方案中，环A选自吡咯基、吡啶基或苯基；其他变量如本申请所定义。In some embodiments, ring A is selected from pyrrolyl, pyridyl, or phenyl; other variables are as defined in this application.
在一些实施方案中，环A选自吡咯基；其他变量如本申请所定义。In some embodiments, ring A is selected from pyrrolyl; other variables are as defined in this application.
在一些实施方案中，结构单元
Figure PCTCN2021072699-appb-000026
选自
Figure PCTCN2021072699-appb-000027
Figure PCTCN2021072699-appb-000028
其他变量如本申请所定义。 In some embodiments, the structural unit
Figure PCTCN2021072699-appb-000026
Selected from
Figure PCTCN2021072699-appb-000027
Figure PCTCN2021072699-appb-000028
Other variables are as defined in this application.
在一些实施方案中，结构单元
Figure PCTCN2021072699-appb-000029
选自
Figure PCTCN2021072699-appb-000030
进一步选自
Figure PCTCN2021072699-appb-000031
Figure PCTCN2021072699-appb-000032
其他变量如本申请所定义。 In some embodiments, the structural unit
Figure PCTCN2021072699-appb-000029
Selected from
Figure PCTCN2021072699-appb-000030
Further selected from
Figure PCTCN2021072699-appb-000031
Figure PCTCN2021072699-appb-000032
Other variables are as defined in this application.
在一些实施方案中，R 1选自
Figure PCTCN2021072699-appb-000033
或者
Figure PCTCN2021072699-appb-000034
In some embodiments, R 1 is selected from
Figure PCTCN2021072699-appb-000033
or
Figure PCTCN2021072699-appb-000034
R 2选自氢、3-10元杂环基或氨基，其中所述3-10元杂环基或氨基任选地被一个或多个R a取代； R 2 is selected from hydrogen, amino, or 3-10 membered heterocyclyl, wherein said 3-10 membered heterocyclyl group or an amino group optionally substituted with one or more substituents R a;
R a选自羟基、卤素、C 1-6烷基、二(C 1-6烷基)氨基或被一个或多个羟基取代的C 1-6烷基； R a is selected from hydroxy, halo, C 1-6 alkyl, di (C 1-6 alkyl) amino or by one or more hydroxy-substituted C 1-6 alkyl;
R 3选自-OCF 2H，其中所述-OCF 2H任选地被卤素取代； R 3 is selected from -OCF 2 H, wherein the -OCF 2 H is optionally substituted with halogen;
R 4选自氢、C 1-6烷基、C 3-6环烷基或3-10元杂环基，其中C 1-6烷基、C 3-6环烷基或3-10元杂环基任选地被一个或多个R b取代； R 4 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-10 membered heterocyclic group, wherein C 1-6 alkyl, C 3-6 cycloalkyl or 3-10 membered heterocyclic group The cyclic group is optionally substituted with one or more R b ;
R b选自羟基、C 1-6烷氧基、C 1-6烷基、氨基、单(C 1-6烷基)氨基或二(C 1-6烷基)氨基； R b is selected from hydroxyl, C 1-6 alkoxy, C 1-6 alkyl, amino, mono(C 1-6 alkyl)amino or di(C 1-6 alkyl)amino;
R 5选自C 1-6烷基； R 5 is selected from C 1-6 alkyl;
环A选自5-6元杂芳基或苯基。Ring A is selected from 5-6 membered heteroaryl or phenyl.
另一方面，本申请提供了式(II)化合物或其药学上可接受的盐，In another aspect, the present application provides a compound of formula (II) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2021072699-appb-000035
Figure PCTCN2021072699-appb-000035
其中，in,
R 3选自-OCF 3或-OCF 2Cl； R 3 is selected from -OCF 3 or -OCF 2 Cl;
R 2、R 4以及R a和R b的定义如前所述。 2, R 4 and R a and R b are as previously defined R.
另一方面，本申请提供了式(III)化合物或其药学上可接受的盐，In another aspect, the present application provides a compound of formula (III) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2021072699-appb-000036
Figure PCTCN2021072699-appb-000036
其中，in,
结构单元
Figure PCTCN2021072699-appb-000037
选自
Figure PCTCN2021072699-appb-000038
Structural units
Figure PCTCN2021072699-appb-000037
Selected from
Figure PCTCN2021072699-appb-000038
R 3选自-OCF 3或-OCF 2Cl； R 3 is selected from -OCF 3 or -OCF 2 Cl;
R 2以及R a的定义如前所述。 R 2 and R a is defined above.
在一些实施方案中，本申请提供了式(I)化合物或其药学上可接受的盐，其中，In some embodiments, the application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
R 1选自
Figure PCTCN2021072699-appb-000039
或者
Figure PCTCN2021072699-appb-000040
R 1 is selected from
Figure PCTCN2021072699-appb-000039
or
Figure PCTCN2021072699-appb-000040
R 2选自氢、含有1-3个选自N或O或S的杂原子的4-10元杂环基或氨基，其中所述4-10元杂环基或氨基任选地被一个或多个R a取代； R 2 is selected from hydrogen, a 4-10 membered heterocyclic group or amino group containing 1-3 heteroatoms selected from N or O or S, wherein the 4-10 membered heterocyclic group or amino group is optionally substituted by one or a plurality of substituents R a;
R a选自羟基、氰基、卤素、
Figure PCTCN2021072699-appb-000041
C 1-6烷基、C 1-6烷氧基、二(C 1-6烷基)氨基、或被一个或多个羟基或C 1-6烷氧基取代的C 1-6烷基； R a is selected from hydroxyl, cyano, halogen,
Figure PCTCN2021072699-appb-000041
C 1-6 alkyl, C 1-6 alkoxy, di (C 1-6 alkyl) amino, or one or more hydroxy or C 1-6 alkoxy substituted C 1-6 alkyl;
R 3选自-OCF 3、-OCF 2Cl或-OCF 2Br； R 3 is selected from -OCF 3 , -OCF 2 Cl or -OCF 2 Br;
R 4选自氢、C 1-6烷基、C 3-6环烷基、或含有1-3个选自N或O或S的杂原子的5-7元杂环基，其中C 1-6烷基、C 3-6环烷基或5-7元杂环基任选地被一个或多个R b取代； R 4 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or a 5-7 membered heterocyclic group containing 1-3 heteroatoms selected from N or O or S, wherein C 1- 6 alkyl, C 3-6 cycloalkyl or 5-7 membered heterocyclic group is optionally substituted by one or more R b;
R b选自氘、羟基、C 1-6烷氧基、C 1-6烷基； R b is selected from deuterium, hydroxyl, C 1-6 alkoxy, C 1-6 alkyl;
R 5选自C 1-6烷基； R 5 is selected from C 1-6 alkyl;
环A选自含有1-3个选自N或O或S的杂原子的5-6元杂芳基或苯基。Ring A is selected from 5-6 membered heteroaryl or phenyl containing 1-3 heteroatoms selected from N or O or S.
在一些实施方案中，本申请提供了式(I)化合物或其药学上可接受的盐，其中，In some embodiments, the application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
R 1选自
Figure PCTCN2021072699-appb-000042
或者
Figure PCTCN2021072699-appb-000043
R 1 is selected from
Figure PCTCN2021072699-appb-000042
or
Figure PCTCN2021072699-appb-000043
R 2选自氢、含有1-3个(例如1个、2个或3个)选自N或O或S(优选N或O)的杂原子的4-9元杂环基或氨基，其中所述4-9元杂环基或氨基任选地被1个或2个R a取代； R 2 is selected from hydrogen, a 4-9 membered heterocyclic group or amino group containing 1-3 (for example, 1, 2 or 3) heteroatoms selected from N or O or S (preferably N or O), wherein the 4-9 membered heterocyclic group or an amino group optionally substituted with one or two R a;
R a选自羟基、氰基、卤素(优选F)、
Figure PCTCN2021072699-appb-000044
C 1-3烷基(优选甲基、乙基)、C 1-3烷氧基(优选甲氧基、乙氧基)、二(C 1-6烷基)氨基、或被一个羟基或C 1-3烷氧基(优选甲氧基、乙氧基)取代的C 1-4烷基； R a is selected from hydroxy, cyano, halogen (preferably F.),
Figure PCTCN2021072699-appb-000044
C 1-3 alkyl (preferably methyl, ethyl), C 1-3 alkoxy (preferably methoxy, ethoxy), two (C 1-6 alkyl) amino, or by a hydroxyl or C C 1-4 alkyl substituted with 1-3 alkoxy (preferably methoxy, ethoxy);
R 3选自-OCF 3或-OCF 2Cl； R 3 is selected from -OCF 3 or -OCF 2 Cl;
R 4选自氢、C 1-4烷基、C 3环烷基、或含有1-2个(优选1个)选自N或O或S的杂原子的6元杂环基，其中C 1-4烷基、C 3环烷基或6元杂环基任选地被一个或多个R b取代； R 4 is selected from hydrogen, C 1-4 alkyl, C 3 cycloalkyl, or a 6-membered heterocyclic group containing 1-2 (preferably 1) heteroatoms selected from N, O or S, wherein C 1 -4 alkyl, C 3 cycloalkyl or 6-membered heterocyclic group is optionally substituted with one or more R b ;
R b选自氘、羟基和C 1-3烷氧基(例如甲氧基、乙氧基、丙氧基)； R b is selected from deuterium, hydroxyl and C 1-3 alkoxy (e.g. methoxy, ethoxy, propoxy);
R 5选自C 1-3烷基(例如甲基、乙基、丙基)； R 5 is selected from C 1-3 alkyl (e.g. methyl, ethyl, propyl);
环A选自含有1-2个(优选1个)N杂原子的5-6元杂芳基或苯基。Ring A is selected from 5-6 membered heteroaryl or phenyl containing 1-2 (preferably 1) N heteroatoms.
在一些实施方案中，本申请提供了式(I)化合物或其药学上可接受的盐，其中，In some embodiments, the application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
R 1选自
Figure PCTCN2021072699-appb-000045
或者
Figure PCTCN2021072699-appb-000046
R 1 is selected from
Figure PCTCN2021072699-appb-000045
or
Figure PCTCN2021072699-appb-000046
R 2选自氢、含有1-3个(例如1个、2个或3个)选自N或O或S(优选N或O)的杂原子的4-9元杂环基或氨基，其中所述4-9元杂环基或氨基任选地被1个或2个R a取代； R 2 is selected from hydrogen, a 4-9 membered heterocyclic group or amino group containing 1-3 (for example, 1, 2 or 3) heteroatoms selected from N or O or S (preferably N or O), wherein the 4-9 membered heterocyclic group or an amino group optionally substituted with one or two R a;
R a选自羟基、氰基、卤素(优选F)、
Figure PCTCN2021072699-appb-000047
C 1-3烷基(优选甲基、乙基)、C 1-3烷氧基(优选甲氧基、乙氧基)、二(C 1-6烷基)氨基、或被一个羟基或C 1-3烷氧基(优选甲氧基、乙氧基)取代的C 1-4烷基； R a is selected from hydroxy, cyano, halogen (preferably F.),
Figure PCTCN2021072699-appb-000047
C 1-3 alkyl (preferably methyl, ethyl), C 1-3 alkoxy (preferably methoxy, ethoxy), two (C 1-6 alkyl) amino, or by a hydroxyl or C C 1-4 alkyl substituted with 1-3 alkoxy (preferably methoxy, ethoxy);
R 3为-OCF 2Cl； R 3 is -OCF 2 Cl;
R 4选自氢、C 1-3烷基(优选甲基、乙基)、C 3环烷基、或含有1个选自N或O的杂原子(优选O杂原子)的6元杂环基，其中C 1-3烷基任选地被一个或多个R b取代； R 4 is selected from hydrogen, C 1-3 alkyl (preferably methyl, ethyl), C 3 cycloalkyl, or a 6-membered heterocyclic ring containing 1 heteroatom selected from N or O (preferably O heteroatom) Group, wherein C 1-3 alkyl is optionally substituted with one or more R b ;
R b选自氘； R b is selected from deuterium;
R 5选自C 1-3烷基(优选甲基、乙基)； R 5 is selected from C 1-3 alkyl (preferably methyl, ethyl);
环A为含有1-2个(优选1个)N杂原子的5元杂芳基或苯基。Ring A is a 5-membered heteroaryl or phenyl group containing 1-2 (preferably 1) N heteroatoms.
在一些实施方案中，本申请提供了式(I)化合物或其药学上可接受的盐，其中，In some embodiments, the application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
R 1选自
Figure PCTCN2021072699-appb-000048
或者
Figure PCTCN2021072699-appb-000049
R 1 is selected from
Figure PCTCN2021072699-appb-000048
or
Figure PCTCN2021072699-appb-000049
R 2选自
Figure PCTCN2021072699-appb-000050
Figure PCTCN2021072699-appb-000051
Figure PCTCN2021072699-appb-000052
R 2 is selected from
Figure PCTCN2021072699-appb-000050
Figure PCTCN2021072699-appb-000051
Figure PCTCN2021072699-appb-000052
R 3选自-OCF 3或-OCF 2Cl； R 3 is selected from -OCF 3 or -OCF 2 Cl;
R 4选自氢、甲基、乙基、丙基、环丙基、羟基甲基、羟基乙基、羟基丙基、羟基2-甲基丙基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、丙氧基甲基、丙氧基乙基、丙氧基丙基、
Figure PCTCN2021072699-appb-000053
其中甲基、乙基和丙基任选地被一个或多个氘取代； R 4 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxy2-methylpropyl, methoxymethyl, methoxyethyl , Methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl,
Figure PCTCN2021072699-appb-000053
Wherein methyl, ethyl and propyl are optionally substituted with one or more deuterium;
R 5选自甲基、乙基和丙基； R 5 is selected from methyl, ethyl and propyl;
环A选自吡咯基、咪唑基、吡唑基、吡啶基、嘧啶基、吡嗪基或苯基。Ring A is selected from pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl or phenyl.
在一些实施方案中，本申请提供了式(I)化合物或其药学上可接受的盐，其中，In some embodiments, the application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
R 1选自
Figure PCTCN2021072699-appb-000054
或者
Figure PCTCN2021072699-appb-000055
R 1 is selected from
Figure PCTCN2021072699-appb-000054
or
Figure PCTCN2021072699-appb-000055
R 2选自
Figure PCTCN2021072699-appb-000056
Figure PCTCN2021072699-appb-000057
R 2 is selected from
Figure PCTCN2021072699-appb-000056
Figure PCTCN2021072699-appb-000057
R 3为-OCF 2Cl； R 3 is -OCF 2 Cl;
R 4选自氢、甲基、d 3-甲基、环丙基或
Figure PCTCN2021072699-appb-000058
R 4 is selected from hydrogen, methyl, d 3 -methyl, cyclopropyl or
Figure PCTCN2021072699-appb-000058
R 5选自甲基； R 5 is selected from methyl;
环A选自吡咯基或苯基。Ring A is selected from pyrrolyl or phenyl.
在本申请还有一些实施方案是由上述各变量任意组合而来。In this application, there are still some implementations that are arbitrarily combined with the above-mentioned variables.
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，On the other hand, this application provides the following compounds or pharmaceutically acceptable salts thereof,
Figure PCTCN2021072699-appb-000059
Figure PCTCN2021072699-appb-000059
Figure PCTCN2021072699-appb-000060
Figure PCTCN2021072699-appb-000060
Figure PCTCN2021072699-appb-000061
Figure PCTCN2021072699-appb-000061
Figure PCTCN2021072699-appb-000062
Figure PCTCN2021072699-appb-000062
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，On the other hand, this application provides the following compounds or pharmaceutically acceptable salts thereof,
Figure PCTCN2021072699-appb-000063
Figure PCTCN2021072699-appb-000063
Figure PCTCN2021072699-appb-000064
Figure PCTCN2021072699-appb-000064
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。On the other hand, the present application also provides a pharmaceutical composition, which comprises the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present application further includes pharmaceutically acceptable excipients.
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，包括对有需要的哺乳动物、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。On the other hand, this application also provides a method for treating and/or preventing BCR-ABL related diseases, which comprises administering a therapeutically effective amount of the above-mentioned compound of this application or a pharmaceutically acceptable compound thereof to a mammal in need, preferably a human. Salt or its pharmaceutical composition.
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。On the other hand, the application also provides the use of the above-mentioned compound of the application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicine for the treatment and/or prevention of BCR-ABL-related diseases.
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。On the other hand, the application also provides the use of the above-mentioned compound of the application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment and/or prevention of BCR-ABL related diseases.
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。On the other hand, the present application also provides a compound of the present application, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the treatment and/or prevention of BCR-ABL-related diseases.
在一些实施方案中，所述BCR-ABL相关疾病选自癌症，例如白血病(如慢性髓细胞白血病)。In some embodiments, the BCR-ABL-related disease is selected from cancer, such as leukemia (such as chronic myeloid leukemia).
技术效果Technical effect
本申请的化合物或其药学上可接受的盐能够表现出对K562细胞和BCR-ABL T315I转染的Ba/F3细胞的增殖抑制作用，具有良好的细胞活性，同时能够表现出良好的体内药代动力学性质。The compound of the present application or a pharmaceutically acceptable salt thereof can exhibit a proliferation inhibitory effect on K562 cells and BCR-ABL T315I transfected Ba/F3 cells, has good cell activity, and can exhibit good in vivo pharmacokinetics. Kinetic properties.
定义definition
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。Unless otherwise specified, the following terms used in this application have the following meanings. A specific term should not be considered uncertain or unclear without a special definition, but should be understood according to the ordinary meaning in the field. When a trade name appears in this article, it is meant to refer to its corresponding commodity or its active ingredient.
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。When the covalent bond in some structural unit or group in this application is not connected to a specific atom, 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 valence bond connection rule .
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。The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence of the specific atom is normal and the substituted compound is stable. When the substituent is oxo (ie =O), it means that two hydrogen atoms are replaced, and the oxo will not occur on the aromatic group.
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。当某一基团“任选地”被取代时，其意味着该基团可以为未被取代的或被取代的，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。 The term "optional" or "optionally" means that the event or situation described later can occur or not occur, and the description includes occurrence of said event or situation and non-occurrence of said event or situation. When a group is "optionally" substituted, it means that the group can be unsubstituted or substituted. For example, the ethyl group is "optionally" substituted by halogen, meaning that the ethyl group can be unsubstituted. Substituted (CH 2 CH 3 ), monosubstituted (such as CH 2 CH 2 F), polysubstituted (such as CHFCH 2 F, CH 2 CHF 2 etc.) or completely substituted (CF 2 CF 3 ). Those skilled in the art can understand that for any group containing one or more substituents, any substitution or substitution pattern that is impossible to exist in space and/or cannot be synthesized will not be introduced.
本文中的C m-n，是该部分具有给定范围中的整数个碳原子。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。 C mn in this context means that the part has an integer number of carbon atoms in a given range. For example, "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. For example, C 1-3 means that the group can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.
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。When any variable (such as R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. So, for example, if a group is replaced by 2 Rs, then each R has independent options.
当一个连接基团的数量为0时，比如-(CH 2) 0-，表示该连接基团为共价键。 When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a covalent bond.
当其中一个变量选自共价键时，表示其连接的两个基团直接相连，比如A-L’-Z中L’代表共价键时表示该结构实际上是A-Z。When one of the variables is selected from a covalent bond, it means that the two connected groups are directly connected. For example, when L'in A-L'-Z represents a covalent bond, it means that the structure is actually A-Z.
当一个取代基的键交叉连接到一个环上的两个原子时，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 PCTCN2021072699-appb-000065
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。 When the bond of a substituent is cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. For example, the structural unit
Figure PCTCN2021072699-appb-000065
It means that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
术语“卤”或“卤素”是指氟、氯、溴和碘。The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
术语“羟基”指-OH基团。The term "hydroxy" refers to the -OH group.
术语“氨基”指-NH 2基团。 The term "amino" refers to the -NH 2 group.
术语“氰基”指-CN基团。The term "cyano" refers to the -CN group.
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)。 The term "alkyl" refers to a hydrocarbon group of the general formula C n H 2n+1. The alkyl group may be linear or branched. For example, the term "C 1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., 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.). Similarly, the alkyl moiety (ie, alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio have the same definition as described above. As another example, the term "C 1-3 alkyl" refers to an alkyl group containing 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, and isopropyl).
术语“烷氧基”指-O-烷基。The term "alkoxy" refers to -O-alkyl.
术语“烷基氨基”指-NH-烷基。The term "alkylamino" refers to -NH-alkyl.
术语“二烷基氨基”指-N(烷基) 2。 The term "dialkylamino" refers to -N(alkyl) 2 .
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，例如3元环、4元环、5元环、6元环、7元环、8元环、9元环或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。 The term "cycloalkyl" refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the carbocyclic ring is usually a 3- to 10-membered ring, such as a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, or a 10-membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, diamond Alkyl, bicyclo[1.1.1]pent-1-yl, etc. For example, C 3-4 cycloalkyl includes cyclopropyl and cyclobutyl.
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，例如4元环、5元环、6元环、7元环、8元环或9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]庚烷基等。The term "heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the heterocyclic ring is generally 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, for example, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, or 9-membered ring. Non-limiting examples of heterocyclic groups include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, 2-oxy Hetero-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.3]heptanyl, etc.
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5或6个环原子的单环杂环烷基。The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the heterocyclic ring is generally 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. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, sulfidene, and azaethylenyl. Non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetin Examples of cyclic group, thiabutanyl, 5-membered heterocycloalkyl include but are not limited to tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine Examples of 6-membered heterocycloalkyl groups include but are not limited to piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, Examples of 4-thiaxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, and 7-membered heterocycloalkyl include But it is not limited to azepanyl, oxepanyl, and thieppanyl. Preferably, it is a monocyclic heterocycloalkyl group having 5 or 6 ring atoms.
术语“杂环烯基”是指部分不饱和的(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。杂环烯基的非限制性实例包括但不限于二氢呋喃基、3,4-二氢吡喃基、3,6-二氢吡喃基、二氢吡咯基、4H-吡喃基等。The term "heterocycloalkenyl" refers to a non-aromatic ring that is partially unsaturated (but not fully unsaturated heteroaromatic) and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the heterocyclic ring is generally 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 heterocyclenyl include, but are not limited to, dihydrofuranyl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, dihydropyrrolyl, 4H-pyranyl, and the like.
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 PCTCN2021072699-appb-000066
The term "spiroheterocyclyl" refers to a fully saturated or partially unsaturated (but not fully saturated) spiro ring with one or more ring atoms selected from sulfur, oxygen and/or nitrogen heteroatoms (preferably 1 or 2 Heteroatoms), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 6 to 10 yuan. According to the number of shared spiro atoms between the ring and the ring, the spiro heterocyclic ring is divided into a single spiro heterocyclic ring, a dispiro heterocyclic ring or a polyspiro heterocyclic ring, preferably a single spiro heterocyclic ring or a dispiro heterocyclic ring, and more preferably a 4-membered/ 4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic ring. Non-limiting examples of spiro heterocycles include
Figure PCTCN2021072699-appb-000066
术语“螺杂环烷基”是指完全饱和的螺杂环基。The term "spiroheterocycloalkyl" refers to a fully saturated spiroheterocyclic group.
术语“杂芳基”是指单环或稠合多环体系，其中含有至少一个(例如1-4个、1-3个或1-2个，例如1个、2个或3个)选自N、O、S的杂原子作为环原子，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。The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system, which contains at least one (for example, 1-4, 1-3 or 1-2, for example, 1, 2, or 3) selected from The heteroatoms of N, O, and S are used as ring atoms, and the rest of the ring atoms are C and have at least one aromatic ring. Preferred heteroaryl groups have a single 5- to 8-membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , Tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.
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：The term "treatment" means administering the compound or formulation described in this application to ameliorate or eliminate a disease or one or more symptoms related to the disease, and includes:
(i)抑制疾病或疾病状态，即遏制其发展；(i) Suppress the disease or disease state, that is, curb its development;
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。(ii) Alleviate the disease or disease state, even if the disease or disease state subsides.
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。The term "prevention" means administering the compound or preparation described in this application to prevent a disease or one or more symptoms related to the disease, and includes: preventing the occurrence of a disease or disease state in a mammal, especially when Such mammals are susceptible to the disease state, but have not been diagnosed as having the disease state.
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。The term "therapeutically effective amount" means (i) treatment or prevention of a particular disease, condition or disorder, (ii) reduction, amelioration or elimination of one or more symptoms of a particular disease, condition or disorder, or (iii) prevention or delay The amount of the compound of the present application for the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of the compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but it can be routinely determined by those skilled in the art. Determined by its own knowledge and this disclosure.
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。The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reactions or other problems or complications of the disease are commensurate with a reasonable benefit/risk ratio.
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。As pharmaceutically acceptable 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. can be mentioned. .
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。The term "pharmaceutical composition" refers to a mixture of one or more of the compounds of the application or their salts and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound of the present application to the organism.
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。The term "pharmaceutically acceptable excipients" refers to those excipients that have no obvious stimulating effect on the organism and will not damage the biological activity and performance of the active compound. Suitable auxiliary materials 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.
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising或等同物应理解为开放的、非排他性的意义，即“包括但不限于”，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。The word "comprise" or "comprise" and its English variants such as comprises or comprising or equivalents should be understood in an open, non-exclusive meaning, that is, "including but not limited to", meaning except for the listed In addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included.
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。The compounds of the present invention may exist in specific 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 mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
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。Unless otherwise specified, "(D)" or "(+)" means dextrorotation, "(L)" or "(-)" means levorotatory, and "(DL)" or "(±)" means racemic.
除非另有说明，用楔形实线键
Figure PCTCN2021072699-appb-000067
和楔形虚线键
Figure PCTCN2021072699-appb-000068
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2021072699-appb-000069
和直形虚线键
Figure PCTCN2021072699-appb-000070
表示立体中心的相对构型，用波浪线
Figure PCTCN2021072699-appb-000071
表示楔形实线键
Figure PCTCN2021072699-appb-000072
或楔形虚线键
Figure PCTCN2021072699-appb-000073
或用波浪线
Figure PCTCN2021072699-appb-000074
表示直形实线键
Figure PCTCN2021072699-appb-000075
和直形虚线键
Figure PCTCN2021072699-appb-000076
Unless otherwise specified, use wedge-shaped solid line keys
Figure PCTCN2021072699-appb-000067
And wedge-shaped dashed key
Figure PCTCN2021072699-appb-000068
Represents the absolute configuration of a three-dimensional center, with a straight solid line key
Figure PCTCN2021072699-appb-000069
And straight dashed key
Figure PCTCN2021072699-appb-000070
Indicates the relative configuration of the three-dimensional center, using wavy lines
Figure PCTCN2021072699-appb-000071
Represents a wedge-shaped solid line key
Figure PCTCN2021072699-appb-000072
Or wedge-shaped dashed key
Figure PCTCN2021072699-appb-000073
Or use wavy lines
Figure PCTCN2021072699-appb-000074
Represents a straight solid line key
Figure PCTCN2021072699-appb-000075
And straight dashed key
Figure PCTCN2021072699-appb-000076
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)。The optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with an appropriate optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
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。“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。 The compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). For another example, heavy hydrogen can be substituted for hydrogen to form a deuterated drug. For example, d 3 -methyl means that all three hydrogen atoms on the methyl group are replaced by deuterium atoms. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic and side effects, increasing drug stability, enhancing efficacy, and prolonging the biological half-life of drugs. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention. "Optional" or "optionally" means that the event or condition described later may but not necessarily occur, and the description includes a situation in which the event or condition occurs and a situation in which the event or condition does not occur.
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。 The present application also includes compounds of the present application that are the same as those described herein, but have one or more atoms replaced by an isotope-labeled atom having an atomic weight or mass number different from the atomic weight or mass number commonly found in nature. Examples of isotopes that can be bound to 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.
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。 Certain isotope-labeled compounds of the application (such as those labeled with 3 H and 14 C) can be used in compound and/or substrate tissue distribution analysis. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are especially preferred due to their ease of preparation and detectability. Positron emission 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. Generally, the isotopically-labeled compounds of the present application can be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by replacing non-isotopically-labeled reagents with isotope-labeled reagents.
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。 In addition, substitution with heavier isotopes (such as deuterium (ie 2 H)) can provide certain therapeutic advantages resulting from higher metabolic stability (for example, increased in vivo half-life or reduced dosage requirements), and therefore in certain situations The following may be preferred, wherein the deuterium substitution may be partial or complete. Partial deuterium substitution refers to the substitution of at least one hydrogen with at least one deuterium. All compounds in such forms are included in the scope of the present application.
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。The compounds of the application may be asymmetric, for example, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, for example, enantiomers and diastereomers. The compound containing asymmetric carbon atoms of the present application can be isolated in an optically pure form or a racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using chiral raw materials or chiral reagents.
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。The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , Granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
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。Typical routes for administering the compound of the present application or a pharmaceutically acceptable salt or pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
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。The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method, etc.
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These auxiliary materials enable the compound of the present application to be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。The solid oral composition can be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or the core of the dragee. Suitable excipients include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。The pharmaceutical composition may also be suitable for parenteral administration, such as a sterile solution, suspension or lyophilized product in a suitable unit dosage form.
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0.1～10％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。The therapeutic dose of the compound of the present application may be determined according to, for example, the following: the specific use of the treatment, the way of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compound of the present application in the pharmaceutical composition may not be fixed, depending on various factors, including dosage, chemical properties (for example, hydrophobicity), and route of administration. For example, the compound of the present application can be provided by a physiologically buffered aqueous solution containing about 0.1-10% w/v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg/kg to about 1 g/kg body weight/day. In certain embodiments, the dosage range is from about 0.01 mg/kg to about 100 mg/kg body weight/day. The dosage is likely to depend on such variables, such as the type and degree of development of the disease or condition, the general health status of the specific patient, the relative biological efficacy of the selected compound, the excipient formulation and its route of administration. The effective dose can be obtained by extrapolating the dose-response curve derived from the in vitro or animal model test system.
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。In this article, unless the context clearly dictates otherwise, singular terms encompass plural referents and vice versa.
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。For the purpose of description and disclosure, all patents, patent applications and other established publications are expressly incorporated herein by reference. These publications are only provided because their publication is earlier than the filing date of this application. All statements regarding the dates of these documents or the representation of the contents of these documents are based on the information available to the applicant and do not constitute any recognition of the correctness of the dates of these documents or the contents of these documents. Moreover, in any country, any reference to these publications in this article does not constitute an endorsement that the publication has become part of the common general knowledge in the field.
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上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。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 those well known to those skilled in the art Equivalent replacement manners, preferred implementation manners include but are not limited to the embodiments of the present application.
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。The chemical reaction in the specific embodiment of the application is completed in a suitable solvent, and the solvent must be suitable for the chemical change of the application and the required reagents and materials. In order to obtain the compound of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the existing embodiments.
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.An important consideration in the planning of synthetic routes in this field is to select suitable protective groups for reactive functional groups (such as amino groups in this application). For example, refer to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley&Sons, Inc.
本申请通式(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：The compound of general formula (I) of the present application can be prepared by a person skilled in the art of organic synthesis through the following route:
中间体的合成(一)：Synthesis of intermediates (1):
Figure PCTCN2021072699-appb-000077
Figure PCTCN2021072699-appb-000077
其中，in,
R 2、R 3的定义如上所述，且R 2不为氢。 The definitions of R 2 and R 3 are as described above, and R 2 is not hydrogen.
中间体的合成(二)：Synthesis of intermediates (two):
Figure PCTCN2021072699-appb-000078
Figure PCTCN2021072699-appb-000078
其中，in,
R 3的定义如上所述，R 2为氢。 The definition of R 3 is as described above, and R 2 is hydrogen.
中间体的合成(三)：Synthesis of intermediates (3):
方案一：Option One:
Figure PCTCN2021072699-appb-000079
Figure PCTCN2021072699-appb-000079
方案二：Option II:
Figure PCTCN2021072699-appb-000080
Figure PCTCN2021072699-appb-000080
其中，in,
R 4、R 5以及环A的定义如上所述。 The definitions of R 4 , R 5 and ring A are as described above.
目标化合物的制备：Preparation of target compound:
Figure PCTCN2021072699-appb-000081
Figure PCTCN2021072699-appb-000081
其中，in,
R 2、R 3、R 4、R 5以及环A的定义如上所述。 The definitions of R 2 , R 3 , R 4 , R 5 and ring A are as described above.
本申请采用下述缩略词：This application uses the following acronyms:
SOCl 2代表氯化亚砜；TEA代表三乙胺；Oxone代表过硫酸氢钾复合盐；NBS代表N-溴代丁二酰亚胺；Pd(PPh 3) 4代表四(三苯基膦)钯；PdCl 2(dppf)代表1,1'-双(二苯基膦基)二茂铁]二氯化钯；DCM代表二氯甲烷；DMSO代表二甲亚砜；DMF代表N,N-二甲基甲酰胺。 SOCl 2 stands for thionyl chloride; TEA stands for triethylamine; Oxone stands for potassium hydrogen persulfate complex salt; NBS stands for N-bromosuccinimide; Pd(PPh 3 ) 4 stands for tetrakis(triphenylphosphine) palladium ; PdCl 2 (dppf) stands for 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; DCM stands for dichloromethane; DMSO stands for dimethyl sulfoxide; DMF stands for N,N-dimethyl基Formamide.
具体实施方式Detailed ways
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。For the sake of clarity, examples are further used to illustrate the present invention, but the examples do not limit the scope of the application. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. All reagents used in this application are commercially available and can be used without further purification.
实施例1：化合物1的制备Example 1: Preparation of Compound 1
Figure PCTCN2021072699-appb-000082
Figure PCTCN2021072699-appb-000082
Figure PCTCN2021072699-appb-000083
Figure PCTCN2021072699-appb-000083
步骤A：化合物1-1的制备Step A: Preparation of compound 1-1
向500mL三口瓶中依次加入300mL甲苯、5-溴-6-氯烟酸(15.0g)，接着室温下向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)；滴毕接着滴加三乙胺(12.58g)；滴毕室温下反应4h。向上述反应液加入100mL饱和碳酸氢钠水溶液，搅拌10min后过滤并收集滤饼；将母液分液后得有机相，加100mL饱和氯化钠水溶液搅拌后分液，得有机相，将滤饼加入到有机相中一起减压浓缩得残余物，经柱层析纯化，获得20.44g化合物1-1。Add 300mL of toluene and 5-bromo-6-chloronicotinic acid (15.0g) to a 500mL three-necked flask, and then add thionyl chloride (14.79g) dropwise to the system at room temperature. After the addition, the temperature is raised to 70-80℃ After reacting for 4 hours, the reaction was stopped, and a brown oil was obtained after concentration under reduced pressure; dichloromethane (300mL) was added to it, stirring was turned on, and 4-(chlorodifluoromethoxy)aniline (12.28g) was added dropwise to the system; After dripping, triethylamine (12.58g) was added dropwise; after dripping, the reaction was carried out at room temperature for 4 hours. Add 100 mL of saturated sodium bicarbonate aqueous solution to the above reaction solution, stir for 10 min, filter and collect the filter cake; separate the mother liquor to obtain the organic phase, add 100 mL of saturated sodium chloride aqueous solution and stir and then separate the layers to obtain the organic phase. Add the filter cake The organic phase was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography to obtain 20.44 g of compound 1-1.
步骤B：化合物1-2的制备Step B: Preparation of compound 1-2
依次向50mL封管中加入异丙醇(10mL)、步骤A所得化合物1-1(2.0g)、(R)-3-吡咯烷醇(0.498g)，N,N-二异丙基乙胺(1.229g)和磁子，封口后将封管置入微波反应器中130℃下反应30min。将反应液减压浓缩，得棕色残余物，向其中加入无水乙醇(4mL)打浆10min，抽滤，滤饼用少量无水乙醇淋洗，收集滤饼；将滤饼置入真空干燥箱中50℃下真空干燥至恒重，得1.744g化合物1-2。Add isopropanol (10mL), the compound 1-1 obtained in step A (2.0g), (R)-3-pyrrolidinol (0.498g), and N,N-diisopropylethylamine in sequence to the 50mL sealed tube (1.229g) and magnets, after sealing, put the sealed tube into a microwave reactor at 130°C for 30 min. Concentrate the reaction solution under reduced pressure to obtain a brown residue. Add absolute ethanol (4mL) to the residue for 10 minutes, and filter with suction. The filter cake is rinsed with a small amount of absolute ethanol, and the filter cake is collected; the filter cake is placed in a vacuum drying oven Vacuum drying at 50°C to constant weight, 1.744 g of compound 1-2 was obtained.
MS(ESI,[M+H] +)m/z:462.0/464.0. MS(ESI,[M+H] + )m/z:462.0/464.0.
步骤C：化合物1-3的制备Step C: Preparation of Compound 1-3
依次向25mL单口瓶中加入二甲亚砜(5mL)、2,5-二溴吡啶(100mg)、2-甲基-2-疏基硫酸脲(120mg)，碳酸铯(550mg)，加毕，升温至75-85℃下反应4h。降至室温后过滤，得淡黄色母液，加入20mL水并用10mL二氯甲烷萃取2次，合并有机相后加10mL饱和氯化钠水溶液搅洗后分液，得有机相，无水硫酸钠干燥，抽滤，减压浓缩得153mg化合物1-3；不经纯化，直接用于下步反应。Add dimethyl sulfoxide (5mL), 2,5-dibromopyridine (100mg), 2-methyl-2-mercaptourea sulfate (120mg), and cesium carbonate (550mg) to a 25mL single-necked flask in turn. After the addition, The temperature was raised to 75-85°C and reacted for 4h. After being cooled to room temperature, it was filtered to obtain a pale yellow mother liquor. 20 mL of water was added and extracted twice with 10 mL of dichloromethane. The organic phases were combined and 10 mL of saturated sodium chloride aqueous solution was added to stir and wash the liquids to obtain the organic phase, which was dried with anhydrous sodium sulfate. Filtration with suction, and concentration under reduced pressure to obtain 153 mg of compound 1-3; without purification, it was directly used in the next reaction.
MS(ESI,[M+H] +)m/z:203.9. MS(ESI,[M+H] + )m/z: 203.9.
步骤D：化合物1-4的制备Step D: Preparation of Compound 1-4
依次向250mL三口瓶中加入异丙醇(90mL)和水(30mL)，开启搅拌向体系中加入按照步骤C中方法制得的5-溴-2-(甲硫基)吡啶(3.2g)，然后分批加入Oxone(过硫酸氢钾复合盐，22.17g)。加毕，保持在室温下反应。降至室温后过滤，得白色母液，减压浓缩；加入50mL乙酸乙酯、30mL水洗涤，再用50mL乙酸乙酯萃取水相1次，合并有机相后加30mL饱和氯化钠水溶液洗涤后分液，得有机相，减压浓缩，得3.70g化合物1-4。Sequentially add isopropanol (90mL) and water (30mL) into a 250mL three-necked flask, turn on the stirring and add 5-bromo-2-(methylthio)pyridine (3.2g) prepared according to the method in step C into the system, Then Oxone (potassium hydrogen persulfate composite salt, 22.17g) was added in batches. After the addition, keep the reaction at room temperature. After cooling to room temperature, it was filtered to obtain a white mother liquor, which was concentrated under reduced pressure; 50 mL ethyl acetate and 30 mL water were added to wash, and the aqueous phase was extracted once with 50 mL ethyl acetate. The organic phases were combined and washed with 30 mL saturated sodium chloride aqueous solution and then separated. The organic phase was obtained, which was concentrated under reduced pressure to obtain 3.70 g of compound 1-4.
MS(ESI,[M+H] +)m/z:224.1. MS(ESI,[M+H] + )m/z:224.1.
步骤E：化合物1-5的制备Step E: Preparation of compound 1-5
依次向25mL三口瓶中加入1,4-二氧六环(10mL)、上述步骤D所得5-溴-2-甲砜基吡啶(100mg)、联硼酸频那醇酯(164mg)、乙酸钾(85mg)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(10mg)，加毕，氮气置换后升温至80-90℃下反应4h，停止反应并降至室温，不经分离纯化，直接用于下步反应。Add 1,4-dioxane (10mL), 5-bromo-2-methylsulfonylpyridine (100mg) obtained in step D above, pinacol diborate (164mg), potassium acetate ( 85mg), [1,1'-bis(diphenylphosphine)ferrocene]dichloride palladium dichloromethane complex (10mg), after the addition, after nitrogen replacement, the temperature is increased to 80-90°C and reacted for 4h, The reaction was stopped and cooled to room temperature, without separation and purification, it was directly used in the next reaction.
步骤F：化合物1的制备Step F: Preparation of Compound 1
向上述步骤E所得反应液中，依次加入上述步骤B所得化合物1-2(163mg)、碳酸钾(146mg)、去离子水(1.5mL)、四(三苯基膦)钯(10mg)；加毕，氮气置换后升温至80-90℃下反应4h。降至室温后将上述反应过滤，收集母液，加入15mL乙酸乙酯搅洗后分液，得有机相加入15mL饱和氯化钠水溶液搅洗后分液，经柱层析纯化，共得到60mg化合物1。To the reaction solution obtained in the above step E, the compound 1-2 obtained in the above step B (163 mg), potassium carbonate (146 mg), deionized water (1.5 mL), and tetrakis (triphenylphosphine) palladium (10 mg) were sequentially added; After nitrogen replacement, the temperature was raised to 80-90°C and reacted for 4 hours. After cooling to room temperature, the above reaction was filtered, the mother liquor was collected, 15 mL of ethyl acetate was added, and the mixture was washed and then separated. The organic phase was obtained by adding 15 mL of saturated sodium chloride aqueous solution, followed by stirring, and then separation. Purified by column chromatography, a total of 60 mg of compound 1 was obtained. .
1H NMR(500MHz,DMSO-d 6)δ10.22(s,1H),8.88(m,1H),8.81(d,J＝2.3Hz,1H),8.17-8.11(m,3H),7.93–7.82(m,2H),7.35(d,J＝8.8Hz,2H),4.91(d,J＝3.5Hz,1H),4.27–4.18(m,1H),3.46–3.37(m,1H),3.36(s,3H),3.28–3.19(m,2H),2.86(d,J＝11.4Hz,1H),1.91–1.81(m,1H),1.81–1.71(m,1H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.22 (s, 1H), 8.88 (m, 1H), 8.81 (d, J = 2.3 Hz, 1H), 8.17-8.11 (m, 3H), 7.93- 7.82(m,2H),7.35(d,J=8.8Hz,2H), 4.91(d,J=3.5Hz,1H), 4.27–4.18(m,1H), 3.46–3.37(m,1H), 3.36 (s,3H), 3.28–3.19(m,2H), 2.86(d,J=11.4Hz,1H), 1.91–1.81(m,1H), 1.81–1.71(m,1H).
MS(ESI,[M+H] +)m/z:539.2/541.1. MS(ESI,[M+H] + )m/z:539.2/541.1.
实施例2：化合物2的制备Example 2: Preparation of Compound 2
Figure PCTCN2021072699-appb-000084
Figure PCTCN2021072699-appb-000084
步骤A：化合物2-1的制备Step A: Preparation of compound 2-1
依次向50mL单口瓶中加入三氟甲基苯(30mL)、5-溴-2-甲基烟酸乙酯(3.0g)、N-溴代丁二酰亚胺(2.62g)、偶氮二异丁氰(0.395g)，加毕，氮气置换后升温至70-80℃下反应6h。降至室温后将反应液过滤，滤液减压浓缩得残余物，经柱层析纯化得到1.731g化合物2-1。Add trifluoromethylbenzene (30mL), 5-bromo-2-methylnicotinic acid ethyl ester (3.0g), N-bromosuccinimide (2.62g), azobis Isobutyl cyanide (0.395g), after the addition is completed, the temperature is increased to 70-80°C for 6h after nitrogen replacement. After cooling to room temperature, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography to obtain 1.731 g of compound 2-1.
MS(ESI,[M+H] +)m/z:321.9/323.9. MS(ESI,[M+H] + )m/z:321.9/323.9.
步骤B：化合物2-2的制备Step B: Preparation of compound 2-2
依次向100mL单口瓶中加入30mL氨的异丙醇溶液(2mol/L)，上述步骤A所得化合物2-1(1.484g)，加毕室温下反应6h；将反应液减压浓缩；所得残余物经柱层析得到768mg化合物2-2。Add 30mL of ammonia in isopropanol solution (2mol/L) to a 100mL single-necked flask in turn, the compound 2-1 (1.484g) obtained in the above step A, and react at room temperature for 6h after the addition; the reaction solution is concentrated under reduced pressure; the resulting residue Through column chromatography, 768 mg of compound 2-2 was obtained.
1H NMR(500MHz,DMSO-d 6):δ8.93(s,1H),8.87(s,1H),8.28(s,1H),4.39(s,2H). 1 H NMR (500MHz, DMSO-d 6 ): δ 8.93 (s, 1H), 8.87 (s, 1H), 8.28 (s, 1H), 4.39 (s, 2H).
步骤C：化合物2-3的制备Step C: Preparation of Compound 2-3
参照实施例1步骤E的方法，使用步骤B所得化合物2-2制备含化合物2-3的反应液，降至室温，不经分离纯化，直接用于下步反应。Referring to the method of step E in Example 1, the compound 2-2 obtained in step B was used to prepare a reaction solution containing compound 2-3, which was cooled to room temperature, and was directly used in the next step without separation and purification.
步骤D：化合物2的制备Step D: Preparation of Compound 2
参照实施例1步骤F的方法，使用上述步骤C所得反应液和实施例1步骤B所得化合物1-2制备得到化合物2。Referring to the method in step F of Example 1, using the reaction solution obtained in step C above and compound 1-2 obtained in step B of Example 1, compound 2 was prepared.
1H NMR(500MHz,DMSO-d 6)δ10.19(s,1H),8.92(s,1H),8.81-8.76(m,2H),8.11–8.05(m,2H),7.86(d,J＝8.8Hz,2H),7.33(d,J＝8.6Hz,2H),4.87(d,J＝3.4Hz,1H),4.51(s,2H),4.21–4.16(m,1H),3.41–3.39(m,1H),3.25–3.15(m,2H),2.88(d,J＝11.4Hz,1H),1.87–1.79(m,1H),1.76–1.69(m,1H). 1 H NMR(500MHz,DMSO-d 6 )δ10.19(s,1H),8.92(s,1H),8.81-8.76(m,2H),8.11-8.05(m,2H),7.86(d,J =8.8Hz,2H),7.33(d,J=8.6Hz,2H), 4.87(d,J=3.4Hz,1H),4.51(s,2H),4.21–4.16(m,1H),3.41–3.39 (m,1H), 3.25–3.15(m,2H), 2.88(d,J=11.4Hz,1H), 1.87–1.79(m,1H), 1.76–1.69(m,1H).
MS(ESI,[M+H] +)m/z:516.2/518.2. MS(ESI,[M+H] + )m/z:516.2/518.2.
实施例3：化合物3的制备Example 3: Preparation of Compound 3
Figure PCTCN2021072699-appb-000085
Figure PCTCN2021072699-appb-000085
参照实施例1步骤F的方法，使用实施例1步骤B所得化合物1-2和3-甲磺酰基苯硼酸制备化合物3。Referring to the method of step F in Example 1, compound 3 was prepared using compound 1-2 obtained in step B of Example 1 and 3-methanesulfonylphenylboronic acid.
1H NMR(500MHz,DMSO-d 6)δ10.23(s,1H),8.78(d,J＝2.3Hz,1H),8.06(d,J＝2.4Hz,1H),7.96–7.91(m,2H),7.90–7.84(m,2H),7.79–7.73(m,2H),7.34(d,J＝8.7Hz,2H),4.86(d,J＝3.3Hz,1H),4.19(q,J＝3.6Hz,1H),3.45–3.36(m,1H),3.29(s,3H),3.27–3.22(m,1H),3.21–3.14(m,1H),2.85(d,J＝11.4Hz,1H),1.88–1.79(m,1H),1.77–1.70(m,1H). 1 H NMR(500MHz,DMSO-d 6 )δ10.23(s,1H), 8.78(d,J=2.3Hz,1H), 8.06(d,J=2.4Hz,1H), 7.96–7.91(m, 2H),7.90–7.84(m,2H),7.79–7.73(m,2H), 7.34(d,J=8.7Hz,2H), 4.86(d,J=3.3Hz,1H), 4.19(q,J =3.6Hz,1H), 3.45–3.36(m,1H), 3.29(s,3H), 3.27–3.22(m,1H), 3.21–3.14(m,1H), 2.85(d,J=11.4Hz, 1H), 1.88-1.79 (m, 1H), 1.77-1.70 (m, 1H).
MS(ESI,[M+H] +)m/z:538.1/540.1. MS(ESI,[M+H] + )m/z:538.1/540.1.
实施例4：化合物4的制备Example 4: Preparation of Compound 4
Figure PCTCN2021072699-appb-000086
Figure PCTCN2021072699-appb-000086
步骤A：化合物4-1的制备Step A: Preparation of compound 4-1
参照实施例1步骤B的制备方法，将化合物1-1和N-甲基哌嗪反应制备得到化合物4-1。Referring to the preparation method of step B in Example 1, compound 1-1 is reacted with N-methylpiperazine to prepare compound 4-1.
MS(ESI,[M+H] +)m/z:475.1/477.1. MS(ESI,[M+H] + )m/z:475.1/477.1.
步骤B：化合物4的制备Step B: Preparation of compound 4
参照实施例1步骤F的制备方法，使用实施例2步骤C所得含化合物2-3的反应液与上述步骤A的化合物4-1反应制备得到化合物4。Referring to the preparation method of step F in Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 4-1 in step A to prepare compound 4.
1H NMR(500MHz,DMSO-d 6)δ10.37(s,1H),9.05(s,1H),8.94(s,1H),8.83(d,J＝1.8Hz,1H),8.35(s,1H),8.23(s,1H),7.90(d,J＝8.9Hz,2H),7.39(d,J＝8.7Hz,2H),4.54(s,2H),3.17(t,J＝4.7Hz,4H),2.28(t,J＝4.7Hz,4H),2.17(s,3H). 1 H NMR(500MHz,DMSO-d 6 )δ10.37(s,1H),9.05(s,1H),8.94(s,1H),8.83(d,J=1.8Hz,1H),8.35(s, 1H), 8.23 (s, 1H), 7.90 (d, J = 8.9 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 4.54 (s, 2H), 3.17 (t, J = 4.7 Hz, 4H), 2.28 (t, J = 4.7Hz, 4H), 2.17 (s, 3H).
MS(ESI,[M+H] +)m/z:529.3. MS(ESI,[M+H] + )m/z:529.3.
实施例5：化合物5的制备Example 5: Preparation of Compound 5
Figure PCTCN2021072699-appb-000087
Figure PCTCN2021072699-appb-000087
步骤A：化合物5-1的制备Step A: Preparation of compound 5-1
参照实施例1步骤B的制备方法，将化合物1-1和吗啉反应制备得到化合物5-1。Referring to the preparation method of step B in Example 1, compound 1-1 is reacted with morpholine to prepare compound 5-1.
MS(ESI,[M+H] +)m/z:462.0/464.0. MS(ESI,[M+H] + )m/z:462.0/464.0.
步骤B：化合物5的制备Step B: Preparation of compound 5
参照实施例1步骤F的制备方法，使用实施例2步骤C所得含化合物2-3的反应液与上述步骤A的化合物5-1反应制备得到化合物5。Referring to the preparation method of step F in Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 5-1 in step A above to prepare compound 5.
1H NMR(500MHz,DMSO-d 6)δ10.29(s,1H),8.98(s,1H),8.85(s,1H),8.75(s,1H),8.28(s,1H),8.15(s,1H),7.80(d,J＝8.5Hz,2H),7.29(d,J＝8.6Hz,2H),4.44(s,2H),3.63–3.36(m,4H),3.18–2.89(m,4H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.29 (s, 1H), 8.98 (s, 1H), 8.85 (s, 1H), 8.75 (s, 1H), 8.28 (s, 1H), 8.15 ( s, 1H), 7.80 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.6 Hz, 2H), 4.44 (s, 2H), 3.63–3.36 (m, 4H), 3.18–2.89 (m ,4H).
MS(ESI,[M+H] +)m/z:516.2. MS(ESI,[M+H] + )m/z:516.2.
实施例6：化合物6的制备Example 6: Preparation of Compound 6
Figure PCTCN2021072699-appb-000088
Figure PCTCN2021072699-appb-000088
步骤A：化合物6-1的制备Step A: Preparation of compound 6-1
参照实施例1步骤B的制备方法，将化合物1-1和(R)-3-二甲氨基吡咯烷反应制备得到化合物6-1。Referring to the preparation method of step B in Example 1, compound 1-1 and (R)-3-dimethylaminopyrrolidine are reacted to prepare compound 6-1.
MS(ESI,[M+H] +)m/z:489.3/491.3. MS(ESI,[M+H] + )m/z:489.3/491.3.
步骤B：化合物6的制备Step B: Preparation of compound 6
参照实施例1步骤F的制备方法，使用实施例2步骤C所得含化合物2-3的反应液与上述步骤A的化合物6-1反应制备得到化合物6。Referring to the preparation method of step F in Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 6-1 in step A to prepare compound 6.
1H NMR(500MHz,DMSO-d 6)δ10.23(s,1H),8.92(s,1H),8.86–8.74(m,2H),8.18–8.06(m,2H),7.87(d,J＝9.0Hz,2H),7.34(d,J＝8.7Hz,2H),4.51(s,2H),3.26–3.09(m,2H),3.09–2.93(m,1H),2.77–2.60(m,1H),2.12(s,6H),2.03–1.94(m,1H),1.72–1.59(m,2H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.23 (s, 1H), 8.92 (s, 1H), 8.86-8.74 (m, 2H), 8.18-8.06 (m, 2H), 7.87 (d, J =9.0Hz,2H),7.34(d,J=8.7Hz,2H),4.51(s,2H),3.26–3.09(m,2H),3.09–2.93(m,1H),2.77–2.60(m, 1H), 2.12(s, 6H), 2.03-1.94(m, 1H), 1.72-1.59(m, 2H).
MS(ESI,[M+H] +)m/z:543.3. MS(ESI,[M+H] + )m/z: 543.3
实施例7：化合物7的制备Example 7: Preparation of Compound 7
Figure PCTCN2021072699-appb-000089
Figure PCTCN2021072699-appb-000089
步骤A：化合物7-1的制备Step A: Preparation of compound 7-1
参照实施例1步骤B的制备方法，将化合物1-1和氮杂环丁烷反应制备得到化合物7-1。Referring to the preparation method of step B in Example 1, compound 1-1 is reacted with azetidine to prepare compound 7-1.
MS(ESI,[M+H] +)m/z:448.1/450.1. MS(ESI,[M+H] + )m/z:448.1/450.1.
步骤B：化合物7的制备Step B: Preparation of compound 7
参照实施例1步骤F的制备方法，使用实施例2步骤C所得含化合物2-3的反应液与上述步骤A的化合物7-1反应制备得到化合物7。Referring to the preparation method of step F in Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 7-1 in step A above to prepare compound 7.
1H NMR(500MHz,DMSO-d 6)δ10.24(s,1H),8.93(s,1H),8.83(s,1H),8.79(s,1H),8.17–8.07(m,2H),7.87(d,J＝8.4Hz,2H),7.35(d,J＝8.2Hz,2H),5.57(d,J＝5.8Hz,1H),4.52(s,2H),4.45–4.31(m,1H),3.94–3.81(m,2H),3.53–3.43(m,2H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.24 (s, 1H), 8.93 (s, 1H), 8.83 (s, 1H), 8.79 (s, 1H), 8.17-8.07 (m, 2H), 7.87(d,J=8.4Hz,2H),7.35(d,J=8.2Hz,2H), 5.57(d,J=5.8Hz,1H),4.52(s,2H),4.45-4.31(m,1H ), 3.94-3.81(m,2H),3.53-3.43(m,2H).
MS(ESI,[M+H] +)m/z:502.1. MS(ESI,[M+H] + )m/z:502.1.
实施例8：化合物8的制备Example 8: Preparation of Compound 8
Figure PCTCN2021072699-appb-000090
Figure PCTCN2021072699-appb-000090
步骤A：化合物8-1的制备Step A: Preparation of compound 8-1
参照实施例1步骤B的制备方法，将化合物1-1和四氢吡咯反应制备得到化合物8-1。Referring to the preparation method of step B in Example 1, compound 8-1 was prepared by reacting compound 1-1 with tetrahydropyrrole.
MS(ESI,[M+H] +)m/z:446.0/448.0. MS(ESI,[M+H] + )m/z:446.0/448.0.
步骤B：化合物8的制备Step B: Preparation of compound 8
参照实施例1步骤F的制备方法，使用实施例2步骤C所得含化合物2-3的反应液与上述步骤A的化合物8-1反应制备得到化合物8。With reference to the preparation method of step F of Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 8-1 of step A above to prepare compound 8.
1H NMR(500MHz,DMSO-d 6)δ10.17(s,1H),8.90(s,1H),8.79(d,J＝2.5Hz,1H),8.78(d,J＝2.4Hz,1H),8.12–8.05(m,2H),7.92–7.77(m,2H),7.33(d,J＝8.6Hz,2H),4.50(s,2H),3.19–3.04(m,4H),1.85–1.65(m,4H). 1 H NMR(500MHz,DMSO-d 6 )δ10.17(s,1H), 8.90(s,1H), 8.79(d,J=2.5Hz,1H), 8.78(d,J=2.4Hz,1H) ,8.12–8.05(m,2H),7.92–7.77(m,2H),7.33(d,J=8.6Hz,2H),4.50(s,2H),3.19–3.04(m,4H),1.85–1.65 (m,4H).
MS(ESI,[M-H] -)m/z:498.1/500.1. MS(ESI,[MH] - )m/z:498.1/500.1.
实施例9：化合物9的制备Example 9: Preparation of Compound 9
Figure PCTCN2021072699-appb-000091
Figure PCTCN2021072699-appb-000091
步骤A：化合物9-1的制备Step A: Preparation of compound 9-1
参照实施例1步骤A的方法，使用5-溴-6-氯烟酸和4-三氟甲氧基苯胺制备化合物9-1。According to the method of Example 1, step A, compound 9-1 was prepared using 5-bromo-6-chloronicotinic acid and 4-trifluoromethoxyaniline.
MS(ESI,[M-H] -)m/z:393.0. MS(ESI,[MH] - )m/z:393.0.
步骤B：化合物9-2的制备Step B: Preparation of compound 9-2
参照实施例1步骤B的方法，使用上述步骤A所得化合物9-1和(R)-3-吡咯烷醇制备化合物9-2。Referring to the method of step B of Example 1, compound 9-2 was prepared using compound 9-1 obtained in step A above and (R)-3-pyrrolidinol.
MS(ESI,[M+H] +)m/z:446.1. MS(ESI,[M+H] + )m/z: 446.1.
步骤C：化合物9的制备Step C: Preparation of compound 9
参照实施例1步骤F的方法，使用实施例2步骤C所得含化合物2-3的反应液与上述步骤B所得化合物9-2制备得到化合物9。With reference to the method of step F in Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 and compound 9-2 obtained in step B above were used to prepare compound 9.
1H NMR(500MHz,DMSO-d 6)δ10.18(s,1H),8.92(s,1H),8.86–8.72(m,2H),8.16–8.01(m,2H),7.86(d,J＝8.7Hz,2H),7.35(d,J＝8.4Hz,2H),4.94–4.82(m,1H),4.52(s,2H),4.19(s,1H),3.44–3.37(m,1H),3.28–3.15(m,2H),2.95–2.83(m,1H),1.90–1.79(m,1H),1.79–1.67(m,1H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.18 (s, 1H), 8.92 (s, 1H), 8.86-8.72 (m, 2H), 8.16-8.01 (m, 2H), 7.86 (d, J =8.7Hz,2H),7.35(d,J=8.4Hz,2H), 4.94–4.82(m,1H),4.52(s,2H),4.19(s,1H),3.44–3.37(m,1H) , 3.28-3.15(m,2H), 2.95-2.83(m,1H), 1.90-1.79(m,1H), 1.79-1.67(m,1H).
MS(ESI,[M+H] +)m/z:500.2. MS(ESI,[M+H] + )m/z:500.2.
实施例10：化合物10的制备Example 10: Preparation of Compound 10
Figure PCTCN2021072699-appb-000092
Figure PCTCN2021072699-appb-000092
步骤A：化合物10-2的制备Step A: Preparation of compound 10-2
参照实施例2步骤B的制备方法，用甲胺的乙醇溶液(30％-35％，m/m)替代氨的异丙醇溶液(2mol/L)制备可得化合物10-2。With reference to the preparation method of step B in Example 2, the ethanol solution of methylamine (30%-35%, m/m) was used to replace the isopropanol solution of ammonia (2mol/L) to prepare compound 10-2.
MS(ESI,[M+H] +)m/z:227.1/229.1. MS(ESI,[M+H] + )m/z:227.1/229.1.
步骤B：化合物10-3的制备Step B: Preparation of compound 10-3
参照实施例1步骤E的方法，使用步骤A所得化合物10-2制备含化合物10-3的反应液，降至室温，不经分离纯化，直接用于下步反应。Referring to the method of step E in Example 1, the compound 10-2 obtained in step A was used to prepare a reaction solution containing compound 10-3, which was cooled to room temperature, and was directly used in the next step without separation and purification.
步骤C：化合物10的制备Step C: Preparation of compound 10
参照实施例1步骤F的方法，使用上述步骤B所得含化合物10-3的反应液和实施例1步骤B所得化合物1-2制备得到化合物10。With reference to the method in step F of Example 1, using the reaction solution containing compound 10-3 obtained in step B above and compound 1-2 obtained in step B of Example 1, compound 10 was prepared.
1H NMR(500MHz,DMSO-d 6)δ10.18(s,1H),8.78(d,J＝2.4Hz,1H),8.76(d,J＝2.1Hz,1H),8.07(d,J＝2.4Hz,1H),8.05(d,J＝2.1Hz,1H),7.97–7.80(m,2H),7.34(d,J＝8.7Hz,2H),4.86(d,J＝3.5Hz,1H),4.53(s,2H),4.21–4.15(m,1H),3.34(s,3H),3.25–3.13(m,2H),3.07–2.95(m,1H),2.87(d,J＝11.3Hz,1H),1.88–1.78(m,1H),1.76–1.68(m,1H). 1 H NMR(500MHz,DMSO-d 6 )δ10.18(s,1H), 8.78(d,J=2.4Hz,1H), 8.76(d,J=2.1Hz,1H), 8.07(d,J= 2.4Hz, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.97-7.80 (m, 2H), 7.34 (d, J = 8.7 Hz, 2H), 4.86 (d, J = 3.5 Hz, 1H) ,4.53(s,2H),4.21–4.15(m,1H), 3.34(s,3H), 3.25–3.13(m,2H),3.07–2.95(m,1H), 2.87(d,J=11.3Hz) ,1H), 1.88-1.78(m,1H), 1.76-1.68(m,1H).
MS(ESI,[M+H] +)m/z:530.2/532.2. MS(ESI,[M+H] + )m/z:530.2/532.2
实施例11：化合物11的制备Example 11: Preparation of Compound 11
Figure PCTCN2021072699-appb-000093
Figure PCTCN2021072699-appb-000093
步骤A：化合物11-1的制备Step A: Preparation of compound 11-1
依次向100mL单口瓶中加入20mL无水乙醇、环丙胺(532mg)、和以实施例2中步骤A的方法制 备所得的化合物2-1(600mg)。室温下反应6h后，将反应液减压浓缩，所得残余物经柱层析得到405mg化合物11-1。20 mL of absolute ethanol, cyclopropylamine (532 mg), and the obtained compound 2-1 (600 mg) prepared by the method of step A in Example 2 were sequentially added to a 100 mL single-necked flask. After reacting at room temperature for 6 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to column chromatography to obtain 405 mg of compound 11-1.
1H NMR(500MHz,DMSO-d 6)δ8.86(d,J＝2.3Hz,1H),8.27(d,J＝2.1Hz,1H),4.43(s,2H),3.01–2.93(m,1H),0.91–0.85(m,2H),0.85–0.77(m,2H). 1 H NMR(500MHz,DMSO-d 6 )δ8.86(d,J=2.3Hz,1H), 8.27(d,J=2.1Hz,1H), 4.43(s,2H), 3.01–2.93(m, 1H), 0.91-0.85 (m, 2H), 0.85-0.77 (m, 2H).
MS(ESI,[M+H] +)m/z:253.0/255.0. MS(ESI,[M+H] + )m/z:253.0/255.0.
步骤B：化合物11-2的制备Step B: Preparation of compound 11-2
参照实施例1步骤E的方法，使用上述步骤A所得化合物11-1制备含化合物11-2的反应液，降至室温，不经分离纯化，直接用于下步反应。With reference to the method of step E in Example 1, the compound 11-1 obtained in step A was used to prepare a reaction solution containing compound 11-2, which was cooled to room temperature, and was directly used in the next step without separation and purification.
步骤C：化合物11的制备Step C: Preparation of compound 11
参照实施例1步骤F的方法，使用上述步骤B所得含化合物11-2的反应液和实施例1步骤B所得化合物1-2制备得到化合物11。Referring to the method of step F in Example 1, using the reaction solution containing compound 11-2 obtained in step B above and compound 1-2 obtained in step B of Example 1, compound 11 was prepared.
1H NMR(500MHz,DMSO-d 6)δ10.19(s,1H),8.78(d,J＝2.4Hz,1H),8.77(d,J＝2.1Hz,1H),8.08(d,J＝2.4Hz,1H),8.06(d,J＝2.1Hz,1H),7.93–7.80(m,2H),7.34(d,J＝8.6Hz,2H),4.86(d,J＝3.5Hz,1H),4.60(s,2H),4.21–4.15(m,1H),3.41–3.35(m,1H),3.36-3.30(m,2H),3.24–3.16(m,2H),3.16-3.11(m,3H),2.87(d,J＝11.3Hz,1H),1.88–1.77(m,1H),1.76–1.68(m,1H). 1 H NMR(500MHz,DMSO-d 6 )δ10.19(s,1H), 8.78(d,J=2.4Hz,1H), 8.77(d,J=2.1Hz,1H), 8.08(d,J= 2.4Hz, 1H), 8.06 (d, J = 2.1 Hz, 1H), 7.93-7.80 (m, 2H), 7.34 (d, J = 8.6 Hz, 2H), 4.86 (d, J = 3.5 Hz, 1H) ,4.60(s,2H),4.21–4.15(m,1H),3.41–3.35(m,1H),3.36-3.30(m,2H), 3.24–3.16(m,2H),3.16-3.11(m, 3H), 2.87(d,J=11.3Hz,1H), 1.88–1.77(m,1H), 1.76–1.68(m,1H).
MS(ESI,[M+H] +)m/z:556.3/558.2. MS(ESI,[M+H] + )m/z:556.3/558.2.
实施例12：化合物12的制备Example 12: Preparation of Compound 12
Figure PCTCN2021072699-appb-000094
Figure PCTCN2021072699-appb-000094
步骤A：化合物12-1的制备Step A: Preparation of compound 12-1
参照实施例1步骤A的方法，将5-溴-6-氯烟酸替换为5-溴烟酸，得到化合物12-1Refer to the method of step A in Example 1, replacing 5-bromo-6-chloronicotinic acid with 5-bromonicotinic acid to obtain compound 12-1
1H NMR(500MHz,DMSO-d 6)δ10.68(s,1H),9.07(d,J＝1.9Hz,1H),8.92(d,J＝2.2Hz,1H),8.55(t,J＝2.1Hz,1H),7.96–7.83(m,2H),7.44–7.33(m,2H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.68 (s, 1H), 9.07 (d, J = 1.9 Hz, 1H), 8.92 (d, J = 2.2 Hz, 1H), 8.55 (t, J = 2.1Hz, 1H), 7.96-7.83 (m, 2H), 7.44-7.33 (m, 2H).
MS(ESI,[M+H] +)m/z:377.0/379.0/381.0. MS(ESI,[M+H] + )m/z: 377.0/379.0/381.0.
步骤B:化合物12的制备Step B: Preparation of compound 12
参照实施例1步骤F的方法，使用实施例2步骤C所得含化合物2-3的反应液和上述步骤A所得化合物12-1制备得到化合物12。Referring to the method of step F in Example 1, using the reaction solution containing compound 2-3 obtained in step C of Example 2 and compound 12-1 obtained in step A above, compound 12 was prepared.
1H NMR(500MHz,DMSO-d 6)δ10.68(s,1H),9.28–9.21(m,2H),9.13(s,1H),8.93(s,1H),8.74(s,1H),8.56(s,1H),7.91(d,J＝8.6Hz,2H),7.40(d,J＝8.6Hz,2H),4.52(s,2H). 1 H NMR(500MHz,DMSO-d 6 )δ10.68(s,1H), 9.28-9.21(m,2H), 9.13(s,1H), 8.93(s,1H), 8.74(s,1H), 8.56(s,1H),7.91(d,J=8.6Hz,2H),7.40(d,J=8.6Hz,2H),4.52(s,2H).
MS(ESI,[M-H] -)m/z:429.0/431.0. MS(ESI,[MH] - )m/z: 429.0/431.0.
实施例13：化合物13的制备Example 13: Preparation of Compound 13
Figure PCTCN2021072699-appb-000095
Figure PCTCN2021072699-appb-000095
步骤A：化合物13-1的制备Step A: Preparation of compound 13-1
依次向25mL单口瓶中加入5mL无水乙醇、实施例2中步骤A制备的化合物2-1(0.15g)以及2-甲氧基乙胺(0.18g)，室温条件下反应6h。将反应液减压浓缩，所得残余物经柱层析得到0.12g化合物13-1。5mL of absolute ethanol, compound 2-1 (0.15g) prepared in step A in Example 2 and 2-methoxyethylamine (0.18g) were sequentially added to a 25mL single-necked flask, and reacted for 6h at room temperature. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to column chromatography to obtain 0.12 g of compound 13-1.
MS(ESI,[M+H] +)m/z:271.0. MS(ESI,[M+H] + )m/z:271.0.
步骤B：化合物13-2的制备Step B: Preparation of compound 13-2
参照实施例1步骤E的方法，使用上述步骤A所得化合物13-1制备含化合物13-2的反应液，降至室温，不经分离纯化，直接用于下步反应。With reference to the method of step E in Example 1, the compound 13-1 obtained in step A was used to prepare a reaction solution containing compound 13-2, which was cooled to room temperature, and was directly used in the next step without separation and purification.
步骤C：化合物13的制备Step C: Preparation of compound 13
参照实施例1步骤F的方法，使用上述步骤B所得含化合物13-2的反应液和实施例12步骤A所得化合物12-1制备得到化合物13。With reference to the method of step F in Example 1, the reaction solution containing compound 13-2 obtained in step B above and compound 12-1 obtained in step A of Example 12 were used to prepare compound 13.
1H NMR(500MHz,DMSO-d 6)δ10.69(s,1H),9.25(s,2H),9.14(s,1H),8.75(s,1H),8.58(s,1H),7.92(d,J＝9.0Hz,2H),7.41(d,J＝8.8Hz,2H),4.67(s,2H),3.76-3.78(m,2H),3.61-3.64(m,2H),3.30(s,3H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.69 (s, 1H), 9.25 (s, 2H), 9.14 (s, 1H), 8.75 (s, 1H), 8.58 (s, 1H), 7.92 ( d,J=9.0Hz,2H),7.41(d,J=8.8Hz,2H),4.67(s,2H),3.76-3.78(m,2H),3.61-3.64(m,2H),3.30(s ,3H).
MS(ESI,[M+H] +)m/z:489.2. MS(ESI,[M+H] + )m/z:489.2.
实施例14：化合物14的制备Example 14: Preparation of compound 14
Figure PCTCN2021072699-appb-000096
Figure PCTCN2021072699-appb-000096
步骤A：化合物14-1的制备Step A: Preparation of compound 14-1
参照实施例13步骤A的方法，用原料乙醇胺替代2-甲氧基乙胺制备化合物14-1。The compound 14-1 was prepared by referring to the method of step A in Example 13, using the raw material ethanolamine instead of 2-methoxyethylamine.
MS(ESI,[M+H] +)m/z:257.2/259.2. MS(ESI,[M+H] + )m/z:257.2/259.2.
步骤B：化合物14-2的制备Step B: Preparation of compound 14-2
参照实施例1步骤E的方法，使用上述步骤A所得化合物14-1制备含化合物14-2的反应液，降至室温，不经分离纯化，直接用于下步反应。With reference to the method of step E in Example 1, the compound 14-1 obtained in step A was used to prepare a reaction solution containing compound 14-2, which was cooled to room temperature, and was directly used in the next step without separation and purification.
步骤C：化合物14的制备Step C: Preparation of compound 14
参照实施例1步骤F的方法，使用上述步骤B所得含化合物14-2的反应液和实施例12步骤A所得化合物12-1制备得到化合物14。With reference to the method of step F in Example 1, the reaction solution containing compound 14-2 obtained in step B above and compound 12-1 obtained in step A of Example 12 were used to prepare compound 14.
1H NMR(500MHz,DMSO-d 6)δ10.69(s,1H),9.25(s,2H),9.14(s,1H),8.75(s,1H),8.58(s,1H),7.92(d,J＝9.1Hz,2H),7.41(d,J＝9.0Hz,2H),4.87-4.89(m,1H),4.69(s,2H),3.66-3.69(m,4H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.69 (s, 1H), 9.25 (s, 2H), 9.14 (s, 1H), 8.75 (s, 1H), 8.58 (s, 1H), 7.92 ( d, J = 9.1Hz, 2H), 7.41 (d, J = 9.0Hz, 2H), 4.87-4.89 (m, 1H), 4.69 (s, 2H), 3.66-3.69 (m, 4H).
MS(ESI,[M+H] +)m/z:475.1. MS(ESI,[M+H] + )m/z:475.1.
实施例15：化合物15的制备Example 15: Preparation of Compound 15
Figure PCTCN2021072699-appb-000097
Figure PCTCN2021072699-appb-000097
Figure PCTCN2021072699-appb-000098
Figure PCTCN2021072699-appb-000098
步骤A：化合物15-1的制备Step A: Preparation of compound 15-1
参照实施例13步骤A的方法，用原料1-氨基-2-甲基-2-丙醇替代2-甲氧基乙胺制备化合物15-1。Referring to the method of step A in Example 13, the starting material 1-amino-2-methyl-2-propanol was substituted for 2-methoxyethylamine to prepare compound 15-1.
MS(ESI,[M+H] +)m/z:285.0/287.0. MS(ESI,[M+H] + )m/z:285.0/287.0.
步骤B：化合物15-2的制备Step B: Preparation of compound 15-2
参照实施例1步骤E的方法，使用上述步骤A所得化合物15-1制备含化合物15-2的反应液，降至室温，不经分离纯化，直接用于下步反应。With reference to the method of step E in Example 1, the compound 15-1 obtained in step A was used to prepare a reaction solution containing compound 15-2, which was cooled to room temperature, and was directly used in the next step without separation and purification.
步骤C：化合物15的制备Step C: Preparation of compound 15
参照实施例1步骤F的方法，使用上述步骤B所得含化合物15-2反应液和实施例12步骤A所得化合物12-1制备得到化合物15。Referring to the method of step F in Example 1, using the reaction solution containing compound 15-2 obtained in step B above and compound 12-1 obtained in step A of Example 12, compound 15 was prepared.
1H NMR(500MHz,DMSO-d 6):δ10.69(s,1H),9.25(s,2H),9.14(s,1H),8.76(s,1H),8.59(s,1H),7.93(d,J＝8.5Hz,2H),7.41(d,J＝8.5Hz,2H),4.80(s,2H),4.74(s,1H),3.53(s,2H),1.16(s,6H). 1 H NMR (500MHz, DMSO-d 6 ): δ 10.69 (s, 1H), 9.25 (s, 2H), 9.14 (s, 1H), 8.76 (s, 1H), 8.59 (s, 1H), 7.93 (d,J=8.5Hz,2H),7.41(d,J=8.5Hz,2H),4.80(s,2H),4.74(s,1H),3.53(s,2H),1.16(s,6H) .
MS(ESI,[M-H] -)m/z:501.1. MS(ESI,[MH] - )m/z:501.1.
实施例16：化合物16的制备Example 16: Preparation of Compound 16
Figure PCTCN2021072699-appb-000099
Figure PCTCN2021072699-appb-000099
步骤A：化合物16-1的制备Step A: Preparation of compound 16-1
参照实施例13步骤A的方法，用原料4-氨基四氢吡喃替代2-甲氧基乙胺制备化合物16-1。Referring to the method of step A in Example 13, the compound 16-1 was prepared by using 4-aminotetrahydropyran as the starting material instead of 2-methoxyethylamine.
MS(ESI,[M+H] +)m/z:297.0/299.0. MS(ESI,[M+H] + )m/z:297.0/299.0.
步骤B：化合物16-2的制备Step B: Preparation of compound 16-2
参照实施例1步骤E的方法，使用上述步骤A所得化合物16-1制备含化合物16-2的反应液，降至室温，不经分离纯化，直接用于下步反应。Referring to the method of step E in Example 1, the compound 16-1 obtained in step A was used to prepare a reaction solution containing compound 16-2, which was cooled to room temperature, and was directly used in the next step without separation and purification.
步骤C：化合物16的制备Step C: Preparation of compound 16
参照实施例1步骤F的方法，使用上述步骤B所得含化合物16-2的反应液和实施例12步骤A所得化合物12-1制备得到化合物16。With reference to the method of step F in Example 1, the reaction solution containing compound 16-2 obtained in step B above and compound 12-1 obtained in step A of Example 12 were used to prepare compound 16.
1H NMR(500MHz,DMSO-d 6):δ11.21(s,1H),9.44(m,2H),9.33(s,1H),9.17(m,1H),8.73(d,J＝2.0Hz,1H),8.05(d,J＝9.0Hz,2H),7.47(d,J＝8.5Hz,2H),4.72(s,2H),4.42(m,1H),4.03(m,2H),3.53(m,2H),1.95(m,2H),1.79(m,2H). 1 H NMR (500MHz, DMSO-d 6 ): δ 11.21 (s, 1H), 9.44 (m, 2H), 9.33 (s, 1H), 9.17 (m, 1H), 8.73 (d, J = 2.0 Hz ,1H),8.05(d,J=9.0Hz,2H),7.47(d,J=8.5Hz,2H),4.72(s,2H),4.42(m,1H),4.03(m,2H),3.53 (m, 2H), 1.95 (m, 2H), 1.79 (m, 2H).
MS(ESI,[M-H] -)m/z:513.1. MS(ESI,[MH] - )m/z: 513.1.
实施例17：化合物17的制备Example 17: Preparation of Compound 17
Figure PCTCN2021072699-appb-000100
Figure PCTCN2021072699-appb-000100
步骤A：化合物17-1的制备Step A: Preparation of compound 17-1
参照实施例1步骤B的方法，用原料3-羟基氮杂环丁烷盐酸盐替代(R)-3-吡咯烷醇制备化合物17-1。According to the method of step B of Example 1, the compound 17-1 was prepared by using 3-hydroxyazetidine hydrochloride as the raw material instead of (R)-3-pyrrolidinol.
步骤B：化合物17的制备Step B: Preparation of compound 17
参照实施例1步骤F的方法，使用实施例11步骤B所得含化合物11-2的反应液和上述步骤A所得含化合物17-1的反应液制备得到化合物17。Referring to the method of step F in Example 1, the reaction solution containing compound 11-2 obtained in step B of Example 11 and the reaction solution containing compound 17-1 obtained in step A above were used to prepare compound 17.
1H NMR(500MHz,DMSO-d 6)δ10.23(s,1H),8.79(d,J＝4.8Hz,2H),8.07(s,2H),7.86(d,J＝8.8Hz,2H),7.35(d,J＝8.5Hz,2H),5.54(d,J＝6.1Hz,1H),4.53(s,2H),4.36-4.37(m,1H),3.84-3.88(m,2H),3.45-3.48(m,2H),3.02(s,1H),0.82-0.84(m,4H). 1 H NMR(500MHz,DMSO-d 6 )δ10.23(s,1H), 8.79(d,J=4.8Hz,2H), 8.07(s,2H), 7.86(d,J=8.8Hz,2H) ,7.35(d,J=8.5Hz,2H),5.54(d,J=6.1Hz,1H),4.53(s,2H),4.36-4.37(m,1H),3.84-3.88(m,2H), 3.45-3.48 (m, 2H), 3.02 (s, 1H), 0.82-0.84 (m, 4H).
MS(ESI,[M+H] +)m/z:542.1. MS(ESI,[M+H] + )m/z:542.1.
实施例18：化合物18的制备Example 18: Preparation of Compound 18
Figure PCTCN2021072699-appb-000101
Figure PCTCN2021072699-appb-000101
步骤A：化合物18-1的制备Step A: Preparation of compound 18-1
参照实施例1步骤B的方法，用原料吗啉替代(R)-3-吡咯烷醇制备化合物18-1。Referring to the method of step B in Example 1, compound 18-1 was prepared by using morpholine as the raw material instead of (R)-3-pyrrolidinol.
步骤B：化合物18的制备Step B: Preparation of compound 18
参照实施例1步骤F的方法，使用实施例10步骤B所得含化合物10-3的反应液和上述步骤A所得含化合物18-1的反应液制备得到化合物18。With reference to the method of step F in Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 and the reaction solution containing compound 18-1 obtained in step A above were used to prepare compound 18.
1H NMR(500MHz,DMSO-d 6)δ10.36(s,1H),9.02(d,J＝2.0Hz,1H),8.82(s,1H),8.34(s,1H),8.21(s,1H),7.87(d,J＝9.1Hz,2H),7.36(d,J＝9.0Hz,2H),4.60(s,2H),3.52-3.53(m,4H),3.14(s,3H),3.13-3.14(m,4H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.36 (s, 1H), 9.02 (d, J = 2.0 Hz, 1H), 8.82 (s, 1H), 8.34 (s, 1H), 8.21 (s, 1H), 7.87 (d, J = 9.1Hz, 2H), 7.36 (d, J = 9.0Hz, 2H), 4.60 (s, 2H), 3.52-3.53 (m, 4H), 3.14 (s, 3H), 3.13-3.14(m,4H).
MS(ESI,[M+H] +)m/z:530.1. MS(ESI,[M+H] + )m/z:530.1.
实施例19：化合物19的制备Example 19: Preparation of Compound 19
Figure PCTCN2021072699-appb-000102
Figure PCTCN2021072699-appb-000102
步骤A：化合物19的制备Step A: Preparation of compound 19
参照实施例1步骤F的方法，使用实施例10步骤B所得含化合物10-3的反应液和实施例17步骤A所得化合物17-1制备得到化合物19。Referring to the method of step F in Example 1, using the reaction solution containing compound 10-3 obtained in step B of Example 10 and compound 17-1 obtained in step A of Example 17, compound 19 was prepared.
1H NMR(500MHz,DMSO-d 6)δ10.23(s,1H),8.78-8.80(m,2H),8.09(s,2H),7.85-7.87(m,2H),7.34-7.36(m,2H),5.54(d,J＝6.2Hz,1H),4.60(s,2H),4.33-4.39(m,1H),3.85-3.88(m,2H),3.44-3.48(m,2H), 3.15(s,3H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.23 (s, 1H), 8.78-8.80 (m, 2H), 8.09 (s, 2H), 7.85-7.87 (m, 2H), 7.34-7.36 (m ,2H),5.54(d,J=6.2Hz,1H),4.60(s,2H),4.33-4.39(m,1H),3.85-3.88(m,2H),3.44-3.48(m,2H), 3.15(s,3H).
MS(ESI,[M+H] +)m/z:516.1. MS(ESI,[M+H] + )m/z: 516.1.
实施例20：化合物20的制备Example 20: Preparation of Compound 20
Figure PCTCN2021072699-appb-000103
Figure PCTCN2021072699-appb-000103
步骤A：化合物20-1的制备Step A: Preparation of compound 20-1
参照实施例1步骤B的方法，用原料2-氧杂-7-氮杂螺[3.5]壬烷替代(R)-3-吡咯烷醇制备化合物20-1。According to the method of step B in Example 1, the compound 20-1 was prepared by using the starting material 2-oxa-7-azaspiro[3.5]nonane instead of (R)-3-pyrrolidinol.
步骤B：化合物20的制备Step B: Preparation of compound 20
参照实施例1步骤F的方法，使用实施例10步骤B所得含化合物10-3的反应液和上述步骤A所得含化合物20-1的反应液制备得到化合物20。With reference to the method of step F in Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 and the reaction solution containing compound 20-1 obtained in step A above were used to prepare compound 20.
1H NMR(500MHz,DMSO-d 6)δ10.33(s,1H),8.99(s,1H),8.79(s,1H),8.30(s,1H),8.18(s,1H),7.86(d,J＝8.9Hz,2H),7.36(d,J＝8.7Hz,2H),4.61(s,2H),4.27(s,4H),3.14(s,3H),3.07(s,4H),1.70(s,4H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.33 (s, 1H), 8.99 (s, 1H), 8.79 (s, 1H), 8.30 (s, 1H), 8.18 (s, 1H), 7.86 ( d,J=8.9Hz,2H),7.36(d,J=8.7Hz,2H),4.61(s,2H),4.27(s,4H),3.14(s,3H),3.07(s,4H), 1.70(s,4H).
MS(ESI,[M+H] +)m/z:570.2. MS(ESI,[M+H] + )m/z:570.2.
实施例21：化合物21的制备Example 21: Preparation of Compound 21
Figure PCTCN2021072699-appb-000104
Figure PCTCN2021072699-appb-000104
步骤A：化合物21-1的制备Step A: Preparation of compound 21-1
参照实施例1步骤B的制备方法，将化合物1-1和2-氧杂-6-氮杂-螺[3.3]庚烷反应制备得到化合物21-1。Referring to the preparation method of step B in Example 1, compound 1-1 is reacted with 2-oxa-6-aza-spiro[3.3]heptane to obtain compound 21-1.
MS(ESI,[M+H] +)m/z:474.1. MS(ESI,[M+H] + )m/z:474.1.
步骤B：化合物21的制备Step B: Preparation of compound 21
参照实施例1步骤F的方法，使用实施例10步骤B所得含化合物10-3的反应液与上述步骤A所得化合物21-1反应制备得到化合物21。Referring to the method of step F in Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 21-1 obtained in step A above to prepare compound 21.
1H NMR(500MHz,DMSO-d 6)δ10.23(s,1H),8.79(s,2H),8.08(s,2H),7.86(d,J＝8.0Hz,2H),7.35(d,J＝7.7Hz,2H),4.62(s,2H),4.57(s,4H),3.88(s,4H),3.16(s,3H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.23 (s, 1H), 8.79 (s, 2H), 8.08 (s, 2H), 7.86 (d, J = 8.0 Hz, 2H), 7.35 (d, J=7.7Hz, 2H), 4.62 (s, 2H), 4.57 (s, 4H), 3.88 (s, 4H), 3.16 (s, 3H).
MS(ESI,[M+H] +)m/z:542.3/544.2. MS(ESI,[M+H] + )m/z:542.3/544.2.
实施例22：化合物22的制备Example 22: Preparation of Compound 22
Figure PCTCN2021072699-appb-000105
Figure PCTCN2021072699-appb-000105
步骤A：化合物22-1的制备Step A: Preparation of compound 22-1
参照实施例1步骤B的制备方法，将化合物1-1和3-氰基氮杂环丁烷盐酸盐反应制备得到化合物22-1。Referring to the preparation method of step B in Example 1, compound 1-1 is reacted with 3-cyanoazetidine hydrochloride to prepare compound 22-1.
MS(ESI,[M-H] -)m/z:455.0/457.0. MS(ESI,[MH] - )m/z:455.0/457.0.
步骤B：化合物22的制备Step B: Preparation of compound 22
参照实施例1步骤F的方法，使用实施例10步骤B所得含化合物10-3的反应液与上述步骤A所得化合物22-1反应制备得到化合物22。Referring to the method of step F in Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 22-1 obtained in step A above to prepare compound 22.
1H NMR(500MHz,DMSO-d 6)δ10.30(s,1H),8.90–8.74(m,2H),8.19–8.06(m,2H),7.86(d,J＝8.7 Hz,2H),7.35(d,J＝8.6Hz,2H),4.60(s,2H),3.96(t,J＝8.8Hz,2H),3.88–3.81(m,2H),3.74–3.66(m,1H),3.15(s,3H). 1 H NMR(500MHz,DMSO-d 6 )δ10.30(s,1H), 8.90–8.74(m,2H), 8.19–8.06(m,2H), 7.86(d,J=8.7 Hz,2H), 7.35(d,J=8.6Hz,2H),4.60(s,2H),3.96(t,J=8.8Hz,2H),3.88–3.81(m,2H),3.74–3.66(m,1H),3.15 (s,3H).
MS(ESI,[M-H] -)m/z:523.2.0/525.2. MS(ESI,[MH] - )m/z:523.2.0/525.2.
实施例23：化合物23的制备Example 23: Preparation of Compound 23
Figure PCTCN2021072699-appb-000106
Figure PCTCN2021072699-appb-000106
步骤A：化合物23的制备Step A: Preparation of compound 23
参照实施例1步骤F的方法，使用实施例11步骤B所得含化合物11-2的反应液与实施例22步骤A所得化合物22-1反应制备得到化合物23。Referring to the method of step F in Example 1, the reaction solution containing compound 11-2 obtained in step B of Example 11 was reacted with compound 22-1 obtained in step A of Example 22 to prepare compound 23.
1H NMR(500MHz,DMSO-d 6)δ10.30(s,1H),9.01–8.70(m,2H),8.29–8.00(m,2H),7.86(d,J＝8.7Hz,2H),7.35(d,J＝8.6Hz,2H),4.53(s,2H),3.96(t,J＝8.8Hz,2H),3.84(t,J＝7.1Hz,2H),3.76–3.64(m,1H),3.09–2.93(m,1H),0.99–0.89(m,2H),0.88–0.77(m,2H). 1 H NMR(500MHz,DMSO-d 6 )δ10.30(s,1H), 9.01–8.70(m,2H), 8.29–8.00(m,2H), 7.86(d,J=8.7Hz,2H), 7.35(d,J=8.6Hz,2H),4.53(s,2H),3.96(t,J=8.8Hz,2H),3.84(t,J=7.1Hz,2H),3.76-3.64(m,1H ), 3.09-2.93 (m, 1H), 0.99-0.89 (m, 2H), 0.88-0.77 (m, 2H).
MS(ESI,[M-H] -)m/z:549.2/551.1. MS(ESI,[MH] - )m/z:549.2/551.1.
实施例24：化合物24的制备Example 24: Preparation of Compound 24
Figure PCTCN2021072699-appb-000107
Figure PCTCN2021072699-appb-000107
步骤A：化合物24-1的制备Step A: Preparation of compound 24-1
参照实施例1步骤B的制备方法，将化合物1-1和3-甲氧基氮杂环丁烷反应制备得到化合物24-1。Referring to the preparation method of step B in Example 1, compound 1-1 is reacted with 3-methoxyazetidine to prepare compound 24-1.
MS(ESI,[M-H] -)m/z:460.1/462.1. MS(ESI,[MH] - )m/z:460.1/462.1.
步骤B：化合物24的制备Step B: Preparation of compound 24
参照实施例1步骤F的方法，使用实施例10步骤B所得含化合物10-3的反应液与上述步骤A所得化合物24-1反应制备得到化合物24。With reference to the method of step F in Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 24-1 obtained in step A above to prepare compound 24.
1H NMR(500MHz,DMSO-d 6)δ10.25(s,1H),8.90–8.71(m,2H),8.19–8.05(m,2H),7.86(d,J＝8.6Hz,2H),7.35(d,J＝8.6Hz,2H),4.60(s,2H),4.16–4.07(m,1H),3.92–3.79(m,2H),3.58–3.46(m,2H),3.14(s,3H),3.12(s,3H). 1 H NMR(500MHz,DMSO-d 6 )δ10.25(s,1H),8.90–8.71(m,2H),8.19–8.05(m,2H),7.86(d,J=8.6Hz,2H), 7.35(d,J=8.6Hz,2H), 4.60(s,2H), 4.16–4.07(m,1H), 3.92–3.79(m,2H), 3.58–3.46(m,2H), 3.14(s, 3H), 3.12(s, 3H).
MS(ESI,[M-H] -)m/z:527.91/529.90. MS(ESI,[MH] - )m/z:527.91/529.90.
实施例25：化合物25的制备Example 25: Preparation of Compound 25
Figure PCTCN2021072699-appb-000108
Figure PCTCN2021072699-appb-000108
步骤A：化合物25-1的制备Step A: Preparation of compound 25-1
参照实施例1步骤B的制备方法，将化合物1-1和2-甲氧基乙胺反应制备得到化合物25-1。Referring to the preparation method of step B in Example 1, compound 1-1 and 2-methoxyethylamine are reacted to prepare compound 25-1.
MS(ESI,[M-H] -)m/z:448.08/450.05. MS(ESI,[MH] - )m/z:448.08/450.05.
步骤B：化合物25的制备Step B: Preparation of compound 25
参照实施例1步骤F的方法，使用实施例10步骤B所得含化合物10-3的反应液与上述步骤A所得化合物25-1反应制备得到化合物25。Referring to the method of step F in Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 25-1 obtained in step A above to prepare compound 25.
1H NMR(500MHz,DMSO-d 6)δ10.15(s,1H),8.78(d,J＝2.0Hz,1H),8.74(d,J＝2.3Hz,1H),8.09(d,J＝2.1Hz,1H),7.93(d,J＝2.4Hz,1H),7.90–7.80(m,2H),7.33(d,J＝8.7Hz,2H),6.70(t,J＝5.6Hz,1H),4.60(s,2H),3.55(q,J＝5.9Hz,2H),3.47(t,J＝6.0Hz,2H),3.25(s,3H),3.15(s,3H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.15 (s, 1H), 8.78 (d, J = 2.0 Hz, 1H), 8.74 (d, J = 2.3 Hz, 1H), 8.09 (d, J = 2.1Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.90-7.80 (m, 2H), 7.33 (d, J = 8.7 Hz, 2H), 6.70 (t, J = 5.6 Hz, 1H) ,4.60(s,2H),3.55(q,J=5.9Hz,2H), 3.47(t,J=6.0Hz,2H), 3.25(s,3H), 3.15(s,3H).
MS(ESI,[M-H] -)m/z:516.2/518.2. MS(ESI,[MH] - )m/z:516.2/518.2.
实施例26：化合物26的制备Example 26: Preparation of Compound 26
Figure PCTCN2021072699-appb-000109
Figure PCTCN2021072699-appb-000109
步骤A：化合物26-1的制备Step A: Preparation of compound 26-1
参照实施例1步骤B的制备方法，将化合物1-1和1-氨基-2-甲基-2-丙醇反应制备得到化合物26-1。Referring to the preparation method of step B in Example 1, compound 1-1 is reacted with 1-amino-2-methyl-2-propanol to prepare compound 26-1.
MS(ESI,[M-H] -)m/z:462.0. MS(ESI,[MH] - )m/z:462.0.
步骤B：化合物26的制备Step B: Preparation of compound 26
参照实施例1步骤F的方法，使用实施例10步骤B所得含化合物10-3的反应液与上述步骤A所得化合物26-1反应制备得到化合物26。Referring to the method of step F in Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 26-1 obtained in step A above to prepare compound 26.
1H NMR(500MHz,DMSO-d 6)δ10.16(s,1H),8.85(d,J＝2.1Hz,1H),8.71(d,J＝2.4Hz,1H),8.17(d,J＝2.1Hz,1H),7.96(d,J＝2.4Hz,1H),7.89–7.78(m,2H),7.33(d,J＝8.7Hz,2H),6.22(t,J＝5.8Hz,1H),4.69(s,1H),4.61(s,2H),3.42(d,J＝5.8Hz,2H),3.15(s,3H),1.10(s,6H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.16 (s, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.17 (d, J = 2.1Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.89–7.78 (m, 2H), 7.33 (d, J = 8.7 Hz, 2H), 6.22 (t, J = 5.8 Hz, 1H) ,4.69(s,1H),4.61(s,2H),3.42(d,J=5.8Hz,2H),3.15(s,3H),1.10(s,6H).
MS(ESI,[M-H] -)m/z:530.3/532.3. MS(ESI,[MH] - )m/z:530.3/532.3.
实施例27：化合物27的制备Example 27: Preparation of Compound 27
Figure PCTCN2021072699-appb-000110
Figure PCTCN2021072699-appb-000110
步骤A：化合物27-1的制备Step A: Preparation of compound 27-1
参照实施例1步骤B的制备方法，将化合物1-1和N-甲基-2-羟基乙胺反应制备得到化合物27-1。Referring to the preparation method in step B of Example 1, compound 1-1 is reacted with N-methyl-2-hydroxyethylamine to obtain compound 27-1.
1H NMR(500MHz,DMSO-d 6)δ10.68(s,1H),9.00(d,J＝2.3Hz,1H),8.98(d,J＝2.0Hz,1H),8.95(s,1H),8.53(d,J＝2.3Hz,1H),8.34(d,J＝2.0Hz,1H),7.88(d,J＝9.1Hz,2H),7.40(d,J＝8.9Hz,2H),4.55(s,2H). 1 H NMR(500MHz,DMSO-d 6 )δ10.68(s,1H), 9.00(d,J=2.3Hz,1H), 8.98(d,J=2.0Hz,1H), 8.95(s,1H) , 8.53 (d, J = 2.3 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 9.1 Hz, 2H), 7.40 (d, J = 8.9 Hz, 2H), 4.55 (s,2H).
步骤B：化合物27的制备Step B: Preparation of compound 27
参照实施例1步骤F的方法，使用实施例10步骤B所得含化合物10-3的反应液与上述步骤A所得化合物27-1反应制备得到化合物27。Referring to the method of step F in Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 27-1 obtained in step A above to prepare compound 27.
1H NMR(500MHz,DMSO-d 6)δ10.25(s,1H),8.85(s,1H),8.76(s,1H),8.17(s,1H),8.12(s,1H),7.86(d,J＝8.7Hz,2H),7.35(d,J＝8.4Hz,2H),4.66(t,J＝4.7Hz,1H),4.59(s,2H),3.53(t,J＝5.7Hz,2H),3.43(t,J＝6.0Hz,2H),3.14(s,3H),2.71(s,3H). 1 H NMR(500MHz,DMSO-d 6 )δ10.25(s,1H), 8.85(s,1H), 8.76(s,1H), 8.17(s,1H), 8.12(s,1H), 7.86( d,J=8.7Hz,2H),7.35(d,J=8.4Hz,2H),4.66(t,J=4.7Hz,1H),4.59(s,2H),3.53(t,J=5.7Hz, 2H), 3.43 (t, J = 6.0 Hz, 2H), 3.14 (s, 3H), 2.71 (s, 3H).
MS(ESI,[M-H] -)m/z:516.2/518.1. MS(ESI,[MH] - )m/z:516.2/518.1.
实施例28：化合物28的制备Example 28: Preparation of Compound 28
Figure PCTCN2021072699-appb-000111
Figure PCTCN2021072699-appb-000111
步骤A：化合物28-1的制备Step A: Preparation of compound 28-1
参照实施例1步骤B的制备方法，将化合物1-1和氮杂环丁烷盐酸盐反应制备得到化合物28-1。Referring to the preparation method of step B in Example 1, compound 1-1 is reacted with azetidine hydrochloride to obtain compound 28-1.
1H NMR(500MHz,DMSO-d 6)δ10.24(s,1H),8.68(d,J＝2.0Hz,1H),8.29(d,J＝2.0Hz,1H),7.85(d,J＝9.1Hz,2H),7.34(d,J＝9.0Hz,2H),4.31(t,J＝7.6Hz,4H),2.27(p,J＝7.6Hz,2H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.24 (s, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 9.1Hz, 2H), 7.34 (d, J = 9.0 Hz, 2H), 4.31 (t, J = 7.6 Hz, 4H), 2.27 (p, J = 7.6 Hz, 2H).
步骤B：化合物28的制备Step B: Preparation of compound 28
参照实施例1步骤F的方法，使用实施例2步骤C所得含化合物2-3的反应液与上述步骤A所得化合物28-1反应制备得到化合物28。Referring to the method in step F of Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 28-1 obtained in step A above to prepare compound 28.
1H NMR(500MHz,DMSO-d 6)δ8.96(d,J＝1.9Hz,1H),8.76(d,J＝2.1Hz,1H),8.50(d,J＝2.1Hz,1H), 8.31(d,J＝1.9Hz,1H),7.96(d,J＝9.1Hz,2H),7.37(d,J＝8.9Hz,2H),5.59(s,4H),4.56(s,2H),2.56(p,J＝1.9Hz,1H). 1 H NMR(500MHz,DMSO-d 6 )δ8.96(d,J=1.9Hz,1H), 8.76(d,J=2.1Hz,1H), 8.50(d,J=2.1Hz,1H), 8.31 (d,J=1.9Hz,1H),7.96(d,J=9.1Hz,2H),7.37(d,J=8.9Hz,2H),5.59(s,4H),4.56(s,2H),2.56 (p,J=1.9Hz,1H).
MS(ESI,[M-H] -)m/z:484.16/486.14. MS(ESI,[MH] - )m/z:484.16/486.14.
实施例29：化合物29的制备Example 29: Preparation of Compound 29
Figure PCTCN2021072699-appb-000112
Figure PCTCN2021072699-appb-000112
步骤A：化合物29-1的制备Step A: Preparation of compound 29-1
参照实施例1步骤B的制备方法，将化合物1-1和3-氟氮杂环丁烷盐酸盐反应制备得到化合物29-1。Referring to the preparation method of step B in Example 1, compound 1-1 is reacted with 3-fluoroazetidine hydrochloride to obtain compound 29-1.
步骤B：化合物29制备Step B: Preparation of compound 29
参照实施例1步骤F的方法，使用实施例2步骤C所得含化合物2-3的反应液与上述步骤A所得化合物29-1反应制备得到化合物29。Referring to the method in step F of Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 29-1 obtained in step A above to prepare compound 29.
1H NMR(500MHz,DMSO-d 6)δ10.28(s,1H),8.94(s,1H),8.86(d,J＝2.0Hz,1H),8.82(d,J＝2.2Hz,1H),8.15(d,J＝2.2Hz,1H),8.14(d,J＝2.0Hz,1H),7.88(d,J＝9.1Hz,2H),7.36(d,J＝8.9Hz,2H),5.47–5.16(m,1H),4.52(s,2H),4.10–3.96(m,2H),3.83–3.68(m,2H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.28 (s, 1H), 8.94 (s, 1H), 8.86 (d, J = 2.0 Hz, 1H), 8.82 (d, J = 2.2 Hz, 1H) , 8.15 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 9.1 Hz, 2H), 7.36 (d, J = 8.9 Hz, 2H), 5.47 --5.16 (m, 1H), 4.52 (s, 2H), 4.10 - 3.96 (m, 2H), 3.83 - 3.68 (m, 2H).
MS(ESI,[M-H] -)m/z:502.20/504.25. MS(ESI,[MH] - )m/z:502.20/504.25.
实施例30：化合物30的制备Example 30: Preparation of Compound 30
Figure PCTCN2021072699-appb-000113
Figure PCTCN2021072699-appb-000113
步骤A：化合物30的制备Step A: Preparation of compound 30
参照实施例1步骤F的方法，使用实施例10步骤B所得含化合物10-3的反应液与实施例28步骤A所得化合物28-1反应制备得到化合物30。Referring to the method of step F in Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 28-1 obtained in step A of Example 28 to prepare compound 30.
1H NMR(500MHz,DMSO-d 6)δ10.69(s,1H),9.25(d,J＝2.1Hz,1H),9.14(d,J＝2.0Hz,1H),8.75(t,J＝2.1Hz,1H),8.57(d,J＝2.1Hz,1H),7.92(d,J＝9.1Hz,2H),7.41(d,J＝9.0Hz,2H),4.64(s,2H),3.70–3.60(m,2H),3.43–3.37(m,2H),3.25(s,3H),1.95–1.84(m,2H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.69 (s, 1H), 9.25 (d, J = 2.1 Hz, 1H), 9.14 (d, J = 2.0 Hz, 1H), 8.75 (t, J = 2.1Hz, 1H), 8.57 (d, J = 2.1 Hz, 1H), 7.92 (d, J = 9.1 Hz, 2H), 7.41 (d, J = 9.0 Hz, 2H), 4.64 (s, 2H), 3.70 --3.60 (m, 2H), 3.43 - 3.37 (m, 2H), 3.25 (s, 3H), 1.95 - 1.84 (m, 2H).
MS(ESI,[M-H] -)m/z:498.14/500.10. MS(ESI,[MH] - )m/z:498.14/500.10.
实施例31：化合物31的制备Example 31: Preparation of Compound 31
Figure PCTCN2021072699-appb-000114
Figure PCTCN2021072699-appb-000114
步骤A：化合物31的制备Step A: Preparation of compound 31
参照实施例1步骤F的方法，使用实施例10步骤B所得含化合物10-3的反应液与实施例29步骤A所得化合物29-1反应制备得到化合物31。Referring to the method of step F in Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 29-1 obtained in step A of Example 29 to prepare compound 31.
1H NMR(500MHz,DMSO-d 6)δ10.28(s,1H),8.83(d,J＝2.0Hz,1H),8.82(d,J＝2.2Hz,1H),8.14(d,J＝2.2Hz,1H),8.12(d,J＝2.0Hz,1H),7.87(d,J＝9.1Hz,2H),7.36(d,J＝8.9Hz,2H),5.41–5.22(m,1H),4.61(s,2H),4.11–3.96(m,2H),3.81–3.67(m,2H),3.15(s,3H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.28 (s, 1H), 8.83 (d, J = 2.0 Hz, 1H), 8.82 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 2.2Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 9.1 Hz, 2H), 7.36 (d, J = 8.9 Hz, 2H), 5.41-5.22 (m, 1H) , 4.61 (s, 2H), 4.11-3.96 (m, 2H), 3.81-3.67 (m, 2H), 3.15 (s, 3H).
MS(ESI,[M-H] -)m/z:516.13/518.11. MS(ESI,[MH] - )m/z:516.13/518.11.
实施例32：化合物32的制备Example 32: Preparation of Compound 32
Figure PCTCN2021072699-appb-000115
Figure PCTCN2021072699-appb-000115
步骤A：化合物32的制备Step A: Preparation of compound 32
参照实施例1步骤F的方法，使用实施例10步骤B所得含化合物10-3的反应液与实施例8步骤A所得化合物8-1反应制备得到化合物32。Referring to the method in step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 8-1 obtained in step A of Example 8 to prepare compound 32.
1H NMR(500MHz,DMSO-d 6)δ10.19(s,1H),8.78(d,J＝2.3Hz,1H),8.77(d,J＝2.0Hz,1H),8.08(d,J＝2.2Hz,1H),8.07(d,J＝1.9Hz,1H),7.87(d,J＝9.1Hz,2H),7.34(d,J＝8.8Hz,2H),4.59(s,2H),3.14(s,3H),3.13–3.04(m,4H),1.82–1.67(m,4H). 1 H NMR(500MHz,DMSO-d 6 )δ10.19(s,1H), 8.78(d,J=2.3Hz,1H), 8.77(d,J=2.0Hz,1H), 8.08(d,J= 2.2Hz, 1H), 8.07 (d, J = 1.9 Hz, 1H), 7.87 (d, J = 9.1 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 4.59 (s, 2H), 3.14 (s,3H),3.13-3.04(m,4H),1.82-1.67(m,4H).
MS(ESI,[M-H] -)m/z:512.20/514.16. MS(ESI,[MH] - )m/z:512.20/514.16.
实施例33：化合物33的制备Example 33: Preparation of Compound 33
Figure PCTCN2021072699-appb-000116
Figure PCTCN2021072699-appb-000116
步骤A：化合物33-1的制备Step A: Preparation of compound 33-1
参照实施例1步骤B的制备方法，将化合物1-1和(S)-3-羟甲基四氢吡咯盐酸盐反应制备得到化合物33-1。Referring to the preparation method of step B in Example 1, compound 1-1 is reacted with (S)-3-hydroxymethyltetrahydropyrrole hydrochloride to obtain compound 33-1.
1H NMR(500MHz,DMSO-d 6)δ10.23(s,1H),8.69(d,J＝2.1Hz,1H),8.35(d,J＝2.1Hz,1H),7.86(d,J＝9.1Hz,2H),7.34(d,J＝9.0Hz,2H),3.78–3.66(m,4H),1.97–1.83(m,4H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.23 (s, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.35 (d, J = 2.1 Hz, 1H), 7.86 (d, J = 9.1Hz, 2H), 7.34 (d, J = 9.0Hz, 2H), 3.78-3.66 (m, 4H), 1.97-1.83 (m, 4H).
步骤B：化合物33的制备Step B: Preparation of compound 33
参照实施例1步骤F的方法，使用实施例10步骤B所得含化合物10-3的反应液与上述步骤所得化合物33-1反应制备得到化合物33。Referring to the method in step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 33-1 obtained in the above step to prepare compound 33.
1H NMR(500MHz,DMSO-d 6)δ10.20(s,1H),8.79(d,J＝1.9Hz,1H),8.78–8.74(m,1H),8.10(d,J＝1.9Hz,1H),8.08(d,J＝2.1Hz,1H),7.87(d,J＝9.0Hz,2H),7.34(d,J＝8.7Hz,2H),4.60(s,2H),3.94–3.80(m,1H),3.31–3.25(m,1H),3.25–3.17(m,2H),3.16(s,3H),3.15(s,3H),3.12–3.06(m,1H),1.95–1.88(m,1H),1.88–1.79(m,1H). 1 H NMR(500MHz,DMSO-d 6 )δ10.20(s,1H), 8.79(d,J=1.9Hz,1H), 8.78–8.74(m,1H), 8.10(d,J=1.9Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.87 (d, J = 9.0 Hz, 2H), 7.34 (d, J = 8.7 Hz, 2H), 4.60 (s, 2H), 3.94-3.80 ( m,1H),3.31–3.25(m,1H), 3.25–3.17(m,2H), 3.16(s,3H), 3.15(s,3H), 3.12–3.06(m,1H), 1.95–1.88( m,1H),1.88-1.79(m,1H).
MS(ESI,[M-H] -)m/z:542.19/544.20. MS(ESI,[MH] - )m/z:542.19/544.20.
实施例34：化合物34的制备Example 34: Preparation of Compound 34
Figure PCTCN2021072699-appb-000117
Figure PCTCN2021072699-appb-000117
步骤A：化合物34的制备Step A: Preparation of compound 34
参照实施例1步骤F的方法，使用实施例2步骤C所得含化合物2-3的反应液与实施例33步骤A所得化合物33-1反应制备得到化合物34。Referring to the method of step F in Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 33-1 obtained in step A of Example 33 to prepare compound 34.
1H NMR(500MHz,DMSO-d 6)δ10.20(s,1H),8.92(s,1H),8.82–8.76(m,2H),8.11(d,J＝2.3Hz,1H),8.10–8.07(m,1H),7.87(d,J＝9.1Hz,2H),7.35(d,J＝8.9Hz,2H),4.51(s,2H),3.90(p,J＝4.8,2.3Hz,1H),3.31–3.26(m,1H),3.26–3.17(m,2H),3.16(s,3H),3.13–3.05(m,1H),1.96–1.89(m,1H),1.89–1.77(m,1H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.20 (s, 1H), 8.92 (s, 1H), 8.82-8.76 (m, 2H), 8.11 (d, J = 2.3 Hz, 1H), 8.10- 8.07(m,1H),7.87(d,J=9.1Hz,2H),7.35(d,J=8.9Hz,2H),4.51(s,2H),3.90(p,J=4.8,2.3Hz,1H ), 3.31–3.26(m,1H), 3.26–3.17(m,2H), 3.16(s,3H), 3.13–3.05(m,1H), 1.96–1.89(m,1H), 1.89–1.77(m ,1H).
MS(ESI,[M-H] -)m/z:528.18/530.22. MS(ESI,[MH] - )m/z:528.18/530.22.
实施例35：化合物35的制备Example 35: Preparation of Compound 35
Figure PCTCN2021072699-appb-000118
Figure PCTCN2021072699-appb-000118
步骤A：化合物35-1的制备Step A: Preparation of compound 35-1
参照实施例1步骤B的制备方法，将化合物1-1和(S)-3-氰基吡咯烷盐酸盐应制备得到化合物35-1。With reference to the preparation method of step B in Example 1, compound 1-1 and (S)-3-cyanopyrrolidine hydrochloride should be prepared to obtain compound 35-1.
1H NMR(500MHz,DMSO-d 6)δ10.30(s,1H),8.72(d,J＝1.9Hz,1H),8.41(d,J＝1.9Hz,1H),7.87(d,J＝9.0Hz,2H),7.35(d,J＝8.8Hz,2H),4.05–3.97(m,1H),3.95–3.86(m,2H),3.85–3.77(m,1H),3.53(p,J＝6.4Hz,1H),2.38–2.28(m,1H),2.27–2.16(m,1H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.30 (s, 1H), 8.72 (d, J = 1.9 Hz, 1H), 8.41 (d, J = 1.9 Hz, 1H), 7.87 (d, J = 9.0Hz,2H),7.35(d,J=8.8Hz,2H),4.05-3.97(m,1H),3.95-3.86(m,2H),3.85-3.77(m,1H),3.53(p,J =6.4Hz,1H), 2.38–2.28(m,1H), 2.27–2.16(m,1H).
步骤B：化合物35的制备Step B: Preparation of compound 35
参照实施例1步骤F的方法，使用实施例10步骤B所得含化合物10-3的反应液与上述步骤所得化合物35-1反应制备得到化合物35。Referring to the method of step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 35-1 obtained in the above step to prepare compound 35.
1H NMR(500MHz,DMSO-d 6)δ10.26(s,1H),8.81(d,J＝2.3Hz,1H),8.79(d,J＝2.0Hz,1H),8.14(d,J＝2.3Hz,1H),8.12(d,J＝2.0Hz,1H),7.87(d,J＝9.1Hz,2H),7.35(d,J＝8.9Hz,2H),4.61(s,2H),3.57–3.48(m,1H),3.46–3.36(m,2H),3.26–3.17(m,2H),3.15(s,3H),2.23–2.13(m,1H),2.11–2.02(m,1H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.26 (s, 1H), 8.81 (d, J = 2.3 Hz, 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 2.3Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 9.1 Hz, 2H), 7.35 (d, J = 8.9 Hz, 2H), 4.61 (s, 2H), 3.57 --3.48(m,1H), 3.46–3.36(m,2H), 3.26–3.17(m,2H), 3.15(s,3H), 2.23–2.13(m,1H), 2.11–2.02(m,1H) .
MS(ESI,[M-H] -)m/z:537.18/539.19. MS(ESI,[MH] - )m/z:537.18/539.19.
实施例36：化合物36的制备Example 36: Preparation of Compound 36
Figure PCTCN2021072699-appb-000119
Figure PCTCN2021072699-appb-000119
步骤A：化合物36的制备Step A: Preparation of compound 36
参照实施例1步骤F的方法，使用实施例2步骤C所得含化合物2-3的反应液与实施例35步骤A所得化合物35-1反应制备得到化合物36。Referring to the method in step F of Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 35-1 obtained in step A of Example 35 to prepare compound 36.
1H NMR(500MHz,DMSO-d 6)δ10.25(s,1H),8.93(s,1H),8.81(d,J＝2.1Hz,2H),8.17–8.12(m,2H),7.87(d,J＝9.1Hz,2H),7.35(d,J＝8.9Hz,2H),4.52(s,2H),3.58–3.50(m,1H),3.47–3.37(m,2H),3.28–3.12(m,2H),2.25–2.13(m,1H),2.13–2.03(m,1H). 1 H NMR(500MHz,DMSO-d 6 )δ10.25(s,1H),8.93(s,1H),8.81(d,J=2.1Hz,2H),8.17–8.12(m,2H),7.87( d,J=9.1Hz,2H),7.35(d,J=8.9Hz,2H),4.52(s,2H),3.58–3.50(m,1H),3.47–3.37(m,2H),3.28–3.12 (m,2H),2.25-2.13(m,1H),2.13-2.03(m,1H).
MS(ESI,[M-H] -)m/z:523.18/525.18. MS(ESI,[MH] - )m/z:523.18/525.18.
实施例37：化合物37的制备Example 37: Preparation of Compound 37
Figure PCTCN2021072699-appb-000120
Figure PCTCN2021072699-appb-000120
步骤A：化合物37-1的制备Step A: Preparation of compound 37-1
参照实施例1步骤B的制备方法，将化合物1-1和4-氨基丁酸乙酯盐酸盐反应制备得到化合物37-1。Referring to the preparation method of step B in Example 1, compound 1-1 is reacted with ethyl 4-aminobutyrate hydrochloride to prepare compound 37-1.
1H NMR(500MHz,DMSO-d 6)δ10.19(s,1H),8.70–8.62(m,1H),8.29(d,J＝2.0Hz,1H),7.86(d,J＝9.1Hz,2H),7.34(d,J＝8.9Hz,2H),7.08(t,J＝5.8Hz,1H),4.05(q,J＝7.1Hz,2H),3.47(q,J＝6.6Hz,2H), 2.34(t,J＝7.4Hz,2H),1.84(q,J＝7.1Hz,2H),1.17(t,J＝7.1Hz,3H). 1 H NMR(500MHz,DMSO-d 6 )δ10.19(s,1H), 8.70–8.62(m,1H), 8.29(d,J=2.0Hz,1H), 7.86(d,J=9.1Hz, 2H), 7.34 (d, J = 8.9 Hz, 2H), 7.08 (t, J = 5.8 Hz, 1H), 4.05 (q, J = 7.1 Hz, 2H), 3.47 (q, J = 6.6 Hz, 2H) , 2.34 (t, J = 7.4 Hz, 2H), 1.84 (q, J = 7.1 Hz, 2H), 1.17 (t, J = 7.1 Hz, 3H).
步骤B：化合物37-2的制备Step B: Preparation of compound 37-2
向50mL单口瓶中加入上述步骤A制得的化合物37-1(660mg)、1M氢氧化钠水溶液(10mL)，加热至80℃反应2h。用6M稀盐酸调pH至5，并加入10mL水稀释，用乙酸乙酯萃取3次。合并有机相，用无水硫酸钠干燥后浓缩，得600mg化合物37-2。Add compound 37-1 (660 mg) prepared in step A above and 1M aqueous sodium hydroxide solution (10 mL) to a 50 mL single-neck flask, and heat to 80° C. to react for 2 h. Adjust the pH to 5 with 6M dilute hydrochloric acid, dilute with 10 mL of water, and extract 3 times with ethyl acetate. The organic phases were combined, dried with anhydrous sodium sulfate and concentrated to obtain 600 mg of compound 37-2.
1H NMR(500MHz,DMSO-d 6)δ12.06(s,1H),10.20(s,1H),8.66(d,J＝2.0Hz,1H),8.29(d,J＝2.0Hz,1H),7.86(d,J＝9.1Hz,2H),7.34(d,J＝8.9Hz,2H),7.08(t,J＝5.7Hz,1H),3.46(q,J＝6.6Hz,2H),2.27(t,J＝7.4Hz,2H),1.81(p,J＝7.2Hz,2H). 1 H NMR (500MHz, DMSO-d 6 ) δ 12.06 (s, 1H), 10.20 (s, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H) ,7.86(d,J=9.1Hz,2H), 7.34(d,J=8.9Hz,2H), 7.08(t,J=5.7Hz,1H), 3.46(q,J=6.6Hz,2H), 2.27 (t,J=7.4Hz,2H),1.81(p,J=7.2Hz,2H).
步骤C：化合物37-3的制备Step C: Preparation of compound 37-3
向50mL单口瓶中加入上述步骤B制得的化合物37-2(600mg)、DMF(20mL)、三乙胺(162mg)，室温下滴加五氟苯基二苯基磷酸酯(482mg)的DMF(5mL)溶液，加热至50℃反应，反应完毕后。加入150mL水，用乙酸乙酯萃取三次，合并有机相，有机相用饱和氯化钠水溶液洗涤三次。有机相用无水硫酸钠干燥后浓缩，所得粗品经柱层析纯化后得489mg化合物37-3。Add compound 37-2 (600 mg), DMF (20 mL), and triethylamine (162 mg) prepared in step B above to a 50 mL single-neck bottle, and add DMF with pentafluorophenyl diphenyl phosphate (482 mg) dropwise at room temperature (5mL) The solution was heated to 50°C for reaction, after the reaction was completed. Add 150 mL of water, extract three times with ethyl acetate, combine the organic phases, and wash the organic phases with saturated aqueous sodium chloride three times. The organic phase was dried with anhydrous sodium sulfate and concentrated. The crude product obtained was purified by column chromatography to obtain 489 mg of compound 37-3.
1H NMR(500MHz,DMSO-d 6)δ10.68(s,1H),8.97(d,J＝1.8Hz,1H),8.66(d,J＝1.8Hz,1H),7.88(d,J＝9.0Hz,2H),7.39(d,J＝8.8Hz,2H),3.90(t,J＝6.9Hz,2H),2.49(d,J＝8.1Hz,2H),2.18(p,J＝7.4Hz,2H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.68 (s, 1H), 8.97 (d, J = 1.8 Hz, 1H), 8.66 (d, J = 1.8 Hz, 1H), 7.88 (d, J = 9.0Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 3.90 (t, J = 6.9 Hz, 2H), 2.49 (d, J = 8.1 Hz, 2H), 2.18 (p, J = 7.4 Hz ,2H).
步骤D：化合物37的制备Step D: Preparation of compound 37
参照实施例1步骤F的方法，使用实施例10步骤B所得含化合物10-3的反应液与上述步骤所得化合物37-3反应制备得到化合物37。Referring to the method in step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 37-3 obtained in the above step to prepare compound 37.
1H NMR(500MHz,DMSO-d 6)δ10.63(s,1H),9.01(d,J＝2.2Hz,1H),8.84(d,J＝1.9Hz,1H),8.49–8.42(m,1H),8.20(d,J＝2.0Hz,1H),7.89(d,J＝9.1Hz,2H),7.40(d,J＝8.9Hz,2H),4.59(s,2H),4.14(t,J＝6.8Hz,2H),3.14(s,3H),2.18(t,J＝7.7Hz,2H),2.07(p,J＝8.0,7.4Hz,2H). 1 H NMR (500MHz, DMSO-d 6 ) δ10.63 (s, 1H), 9.01 (d, J = 2.2 Hz, 1H), 8.84 (d, J = 1.9 Hz, 1H), 8.49–8.42 (m, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 9.1 Hz, 2H), 7.40 (d, J = 8.9 Hz, 2H), 4.59 (s, 2H), 4.14 (t, J = 6.8Hz, 2H), 3.14 (s, 3H), 2.18 (t, J = 7.7 Hz, 2H), 2.07 (p, J = 8.0, 7.4 Hz, 2H).
MS(ESI,[M+H] +)m/z:528.3/530.2. MS(ESI,[M+H] + )m/z:528.3/530.2.
实施例38：化合物38的制备Example 38: Preparation of Compound 38
Figure PCTCN2021072699-appb-000121
Figure PCTCN2021072699-appb-000121
步骤A：化合物38-1的制备Step A: Preparation of compound 38-1
参照实施例1步骤B的制备方法，将化合物1-1和(R)-3-甲氧基吡咯烷反应制备得到化合物38-1。Referring to the preparation method of step B in Example 1, compound 1-1 is reacted with (R)-3-methoxypyrrolidine to obtain compound 38-1.
步骤B：化合物38的制备Step B: Preparation of compound 38
参照实施例1步骤F的方法，使用实施例2步骤C所得含化合物2-3的反应液与上述步骤A所得化合物38-1反应制备得到化合物38。Referring to the method of step F in Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 38-1 obtained in step A above to prepare compound 38.
1H NMR(500MHz,DMSO-d 6)δ10.20(s,1H),8.92(s,1H),8.79(d,J＝2.5Hz,2H),8.10(m,2H),7.86(d,J＝8.0Hz,2H),7.53(d,J＝7.5Hz,2H),4.51(s,2H),3.89(s,1H),3.25(m,3H),3.17(s,3H),3.10(m,1H),1.85(m,2H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.20 (s, 1H), 8.92 (s, 1H), 8.79 (d, J = 2.5 Hz, 2H), 8.10 (m, 2H), 7.86 (d, J = 8.0Hz, 2H), 7.53 (d, J = 7.5Hz, 2H), 4.51 (s, 2H), 3.89 (s, 1H), 3.25 (m, 3H), 3.17 (s, 3H), 3.10 ( m, 1H), 1.85 (m, 2H).
MS(ESI,[M+H] +)m/z:530.1. MS(ESI,[M+H] + )m/z:530.1.
实施例39：化合物39的制备Example 39: Preparation of Compound 39
Figure PCTCN2021072699-appb-000122
Figure PCTCN2021072699-appb-000122
步骤A：化合物39的制备Step A: Preparation of compound 39
参照实施例1步骤F的方法，使用实施例10步骤B所得含化合物10-3的反应液与实施例38步骤所得化合物38-1反应制备得到化合物39。Referring to the method in step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 38-1 obtained in step 38 of Example 38 to prepare compound 39.
1H NMR(500MHz,DMSO-d 6)δ10.20(s,1H),8.78(m,2H),8.08(m,2H),7.86(d,J＝9.0Hz,2H),7.34(d, J＝8.5Hz,2H),4.60(s,2H),3.89(s,1H),3.25(m,3H),3.20(s,3H),3.18(s,3H),3.12(m,1H),1.85(m,2H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.20 (s, 1H), 8.78 (m, 2H), 8.08 (m, 2H), 7.86 (d, J = 9.0 Hz, 2H), 7.34 (d, J=8.5Hz, 2H), 4.60 (s, 2H), 3.89 (s, 1H), 3.25 (m, 3H), 3.20 (s, 3H), 3.18 (s, 3H), 3.12 (m, 1H), 1.85(m,2H).
MS(ESI,[M+H] +)m/z:544.2. MS(ESI,[M+H] + )m/z:544.2.
实施例40：化合物40的制备Example 40: Preparation of Compound 40
Figure PCTCN2021072699-appb-000123
Figure PCTCN2021072699-appb-000123
步骤A：化合物40-1的制备Step A: Preparation of compound 40-1
参照实施例1步骤B的制备方法，将化合物1-1和(R)-3-氰基吡咯烷反应制备得到化合物40-1。Referring to the preparation method of step B in Example 1, compound 1-1 is reacted with (R)-3-cyanopyrrolidine to obtain compound 40-1.
步骤B：化合物40的制备Step B: Preparation of compound 40
参照实施例1步骤F的方法，使用实施例2步骤C所得含化合物2-3的反应液与上述步骤A所得化合物40-1反应制备得到化合物40。Referring to the method of step F in Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 40-1 obtained in step A above to prepare compound 40.
1H NMR(500MHz,DMSO-d 6)δ10.25(s,1H),8.92(s,1H),8.81(s,2H),8.14(d,J＝1.5Hz,2H),7.86(d,J＝8.5Hz,2H),7.35(d,J＝8.5Hz,2H),4.52(s,2H),3.52(m,1H),3.39(m,2H),3.18(m,2H),2.12(m,2H). 1 H NMR(500MHz,DMSO-d 6 )δ10.25(s,1H), 8.92(s,1H), 8.81(s,2H), 8.14(d,J=1.5Hz,2H), 7.86(d, J = 8.5Hz, 2H), 7.35 (d, J = 8.5Hz, 2H), 4.52 (s, 2H), 3.52 (m, 1H), 3.39 (m, 2H), 3.18 (m, 2H), 2.12 ( m,2H).
HRMS(ESI,[M+H] +)m/z:525.1. HRMS(ESI,[M+H] + )m/z:525.1.
实施例41:化合物41的制备Example 41: Preparation of Compound 41
Figure PCTCN2021072699-appb-000124
Figure PCTCN2021072699-appb-000124
步骤A：化合物41的制备Step A: Preparation of compound 41
参照实施例1步骤F的方法，使用实施例10步骤B所得含化合物10-3的反应液与实施例40步骤A所得化合物40-1反应制备得到化合物41。Referring to the method in step F of Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 40-1 obtained in step A of Example 40 to prepare compound 41.
1H NMR(500MHz,DMSO-d 6)δ10.26(s,1H),8.79(d,J＝5.0Hz,2H),8.12(d,J＝8.0Hz,2H),7.86(d,J＝8.5Hz,2H),7.34(d,J＝8.5Hz,2H),4.61(s,2H),3.52(s,1H),3.40(d,J＝7.0Hz,2H),3.18(m,2H),3.15(s,3H),2.12(m,2H). 1 H NMR(500MHz,DMSO-d 6 )δ10.26(s,1H), 8.79(d,J=5.0Hz,2H), 8.12(d,J=8.0Hz,2H), 7.86(d,J= 8.5Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 4.61 (s, 2H), 3.52 (s, 1H), 3.40 (d, J = 7.0 Hz, 2H), 3.18 (m, 2H) , 3.15 (s, 3H), 2.12 (m, 2H).
HRMS(ESI,[M+H] +)m/z:539.1418. HRMS(ESI,[M+H] + )m/z:539.1418.
实施例42：化合物42的制备Example 42: Preparation of Compound 42
Figure PCTCN2021072699-appb-000125
Figure PCTCN2021072699-appb-000125
步骤A：化合物42-1的制备Step A: Preparation of compound 42-1
向25mL的三口瓶中，依次加入实施例2步骤B所得化合物2-2(0.931g)、1,4-二氧六环(20mL)、联硼酸频那醇酯(1.664g)、PdCl 2(dppf)(0.266g)、乙酸钾(1.072g)，加毕，N 2保护后，升温至90℃反应2h。待反应完全后，将反应体系降温至室温，向体系中依次加入实施例1步骤A所得化合物1-1(1.5g)、碳酸钾(1.509g)、Pd(Ph 3P) 4(0.421g)、水(5mL)，加毕，氮气置换后升温至110℃下反应2h。待反应完全，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，有机相经无水硫酸钠干燥后浓缩。所得粗品经柱层析纯化得0.5g化合物42-1。 Into a 25mL three-necked flask, sequentially add compound 2-2 (0.931g) obtained in step B of Example 2, 1,4-dioxane (20mL), pinacol diborate (1.664g), PdCl 2 ( dppf) (0.266g), potassium acetate (1.072g), after the addition is completed, after N 2 protection, the temperature is raised to 90° C. and the reaction is carried out for 2 hours. After the reaction is complete, the reaction system is cooled to room temperature, and compound 1-1 (1.5g) obtained in step A of Example 1 (1.5g), potassium carbonate (1.509g), and Pd(Ph 3 P) 4 (0.421g) are sequentially added to the system. , Water (5mL), after the addition is completed, the temperature is increased to 110°C for 2h after nitrogen replacement. After the reaction is complete, filter, collect the filtrate, add ethyl acetate (50 mL) and saturated brine (25 mL) to the filtrate to wash and separate the layers, and the organic phase is dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by column chromatography to obtain 0.5 g of compound 42-1.
1H NMR(500MHz,DMSO-d 6)δ10.68(s,1H),9.00(d,J＝2.3Hz,1H),8.98(d,J＝2.0Hz,1H),8.95(s,1H),8.53(d,J＝2.3Hz,1H),8.34(d,J＝2.0Hz,1H),7.88(d,J＝9.1Hz,2H),7.40(d,J＝8.9Hz,2H),4.55(s,2H). 1 H NMR(500MHz,DMSO-d 6 )δ10.68(s,1H), 9.00(d,J=2.3Hz,1H), 8.98(d,J=2.0Hz,1H), 8.95(s,1H) , 8.53 (d, J = 2.3 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 9.1 Hz, 2H), 7.40 (d, J = 8.9 Hz, 2H), 4.55 (s,2H).
MS(ESI,[M+H] -)m/z:463.1. MS(ESI,[M+H] - )m/z:463.1.
步骤B：化合物42-2的制备Step B: Preparation of compound 42-2
向35mL的微波管中，依次加入化合物42-2(0.3g)、1,4-二氧六环(20mL)、4-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(0.199g)、双(三叔丁基膦)钯(0)(0.033g)、碳酸铯(0.420g)和水(4.00mL)，将反应体系置于微波反应器中，微波条件：150℃，30min。待反应完全，向反应液中加入50mL乙酸乙酯以及20mL水，分液收集有机相，并以20mL饱和氯化钠水溶液洗涤有机相三次，有机相经无水硫酸钠干燥后浓缩。所得粗品经柱层析纯化得210mg化合物42-2。Into a 35mL microwave tube, sequentially add compound 42-2 (0.3g), 1,4-dioxane (20mL), 4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-tert-butyl carboxylate (0.199g), bis(tri-tert-butylphosphine)palladium(0)(0.033 g), cesium carbonate (0.420g) and water (4.00mL), put the reaction system in a microwave reactor, microwave conditions: 150°C, 30min. When the reaction is complete, add 50 mL of ethyl acetate and 20 mL of water to the reaction solution, separate and collect the organic phase, and wash the organic phase with 20 mL of saturated sodium chloride aqueous solution three times, and the organic phase is dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by column chromatography to obtain 210 mg of compound 42-2.
1H NMR(500MHz,DMSO-d 6)δ10.62(s,1H),9.12(d,J＝2.5Hz,1H),8.90(s,1H),8.83(d,J＝2.0Hz,1H),8.40(d,J＝2.5Hz,1H),8.24(d,J＝2.0Hz,1H),7.89(m,2H),7.39(d,J＝8.5Hz,2H),5.63(s,1H),4.50(s,2H),4.28(s,2H),3.35(s,2H),1.98(s,2H),1.41(s,9H). 1 H NMR(500MHz,DMSO-d 6 )δ10.62(s,1H), 9.12(d,J=2.5Hz,1H), 8.90(s,1H), 8.83(d,J=2.0Hz,1H) ,8.40(d,J=2.5Hz,1H),8.24(d,J=2.0Hz,1H),7.89(m,2H),7.39(d,J=8.5Hz,2H),5.63(s,1H) , 4.50(s, 2H), 4.28(s, 2H), 3.35(s, 2H), 1.98(s, 2H), 1.41(s, 9H).
MS(ESI,[M+Na] +)m/z:634.3. MS(ESI,[M+Na] + )m/z:634.3.
步骤C：化合物42的制备Step C: Preparation of Compound 42
向25mL的单口瓶中，依次加入上述步骤所得化合物42-2(50mg)以及4M氯化氢的1,4-二氧六环溶液(5mL)，将混合物室温搅拌1h。待反应完，将反应液浓缩除去溶剂，所得粗品经柱层析纯化得40mg化合物42。Into a 25 mL single-neck flask, compound 42-2 (50 mg) obtained in the above steps and 4M 1,4-dioxane solution (5 mL) of hydrogen chloride were sequentially added, and the mixture was stirred at room temperature for 1 h. After the reaction is complete, the reaction solution is concentrated to remove the solvent, and the obtained crude product is purified by column chromatography to obtain 40 mg of compound 42.
1H NMR(500MHz,DMSO-d 6)δ10.87(s,1H),9.48(s,2H),9.15(d,J＝2.0Hz,1H),8.94(s,2H),8.47(d,J＝2.0Hz,1H),8.33(d,J＝2.0Hz,1H),7.94(d,J＝8.5Hz,2H),7.39(d,J＝8.5Hz,2H),5.66(s,1H),5.51(s,2H),4.15(s,2H),3.11(d,J＝4.0Hz,2H),2.17(s,2H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.87 (s, 1H), 9.48 (s, 2H), 9.15 (d, J = 2.0 Hz, 1H), 8.94 (s, 2H), 8.47 (d, J = 2.0Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 5.66 (s, 1H) , 5.51 (s, 2H), 4.15 (s, 2H), 3.11 (d, J = 4.0 Hz, 2H), 2.17 (s, 2H).
MS(ESI,[M+H] +)m/z:512.1. MS(ESI,[M+H] + )m/z:512.1.
实施例43：化合物43的制备Example 43: Preparation of Compound 43
Figure PCTCN2021072699-appb-000126
Figure PCTCN2021072699-appb-000126
参照实施例42步骤B的方法，使用实施例42步骤A所得化合物42-1与3,6-二氢-2H-吡喃-4-硼酸频哪醇酯反应制备得到化合物43。Referring to the method of step B in Example 42, the compound 42-1 obtained in step A of Example 42 was reacted with 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester to prepare compound 43.
1H NMR(500MHz,DMSO-d 6)δ10.62(s,1H),9.12(d,J＝2.0Hz,1H),8.91(s,1H),8.83(d,J＝1.5Hz,1H),8.39(d,J＝1.5Hz,1H),8.21(d,J＝1.5Hz,1H),7.89(d,J＝8.0Hz,2H),7.39(d,J＝7.5Hz,2H),5.64(s,1H),4.52(s,2H),3.95(d,J＝2.0Hz,2H),3.72(t,J＝5.5Hz,2H),2.45(s,2H). 1 H NMR(500MHz,DMSO-d 6 )δ10.62(s,1H), 9.12(d,J=2.0Hz,1H), 8.91(s,1H), 8.83(d,J=1.5Hz,1H) , 8.39 (d, J = 1.5 Hz, 1H), 8.21 (d, J = 1.5 Hz, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 7.5 Hz, 2H), 5.64 (s, 1H), 4.52 (s, 2H), 3.95 (d, J = 2.0 Hz, 2H), 3.72 (t, J = 5.5 Hz, 2H), 2.45 (s, 2H).
HRMS(ESI,[M+H] +)m/z:513.1174. HRMS(ESI,[M+H] + )m/z:513.1174.
实施例44：化合物44的制备Example 44: Preparation of Compound 44
Figure PCTCN2021072699-appb-000127
Figure PCTCN2021072699-appb-000127
步骤A：化合物44-1的制备Step A: Preparation of compound 44-1
参照实施例42步骤A的方法，使用实施例1步骤A所得化合物1-1与实施例10步骤A所得化合物10-2反应制备得到化合物44-1。Referring to the method of Step A in Example 42, the compound 1-1 obtained in Step A of Example 1 was reacted with the compound 10-2 obtained in Step A of Example 10 to prepare compound 44-1.
1H NMR(500MHz,DMSO-d 6)δ10.69(s,1H),8.97(m,2H),8.56(d,J＝2.0Hz,1H),8.32(d,J＝2.0Hz,1H),7.86(d,J＝9.5Hz,2H),7.05(d,J＝9.0Hz,2H),4.64(s,2H),3.15(s,3H). 1 H NMR(500MHz,DMSO-d 6 )δ10.69(s,1H),8.97(m,2H),8.56(d,J=2.0Hz,1H), 8.32(d,J=2.0Hz,1H) ,7.86(d,J=9.5Hz,2H), 7.05(d,J=9.0Hz,2H), 4.64(s,2H), 3.15(s,3H).
MS(ESI,[M+H] +)m/z:479.2. MS(ESI,[M+H] + )m/z:479.2.
步骤B：化合物44-2的制备Step B: Preparation of compound 44-2
参照实施例42步骤B的方法，使用上述步骤A所得化合物44-1与3,6-二氢-2H-吡喃-4-硼酸频哪醇酯反应制备得到化合物44-2。Referring to the method of step B in Example 42, the compound 44-1 obtained in step A was reacted with 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester to prepare compound 44-2.
MS(ESI,[M+H] +)m/z:527.3. MS(ESI,[M+H] + )m/z:527.3.
步骤C：化合物44的制备Step C: Preparation of compound 44
向100mL的单口瓶中，依次加入上述步骤所得化合物44-2(150mg)、甲醇(20mL)，加入Pd/C(1.671mg)，氢气置换三次，室温搅拌过夜。待反应完全后过滤，浓缩滤液所得粗品经柱层析纯化得88mg化合物44。To a 100 mL single-neck flask, add compound 44-2 (150 mg) and methanol (20 mL) obtained in the above steps in sequence, add Pd/C (1.671 mg), replace with hydrogen three times, and stir overnight at room temperature. After the reaction was completed, it was filtered, and the crude product obtained by concentrating the filtrate was purified by column chromatography to obtain 88 mg of compound 44.
1H NMR(500MHz,DMSO-d 6)δ10.59(s,1H),9.15(d,J＝2.0Hz,1H),8.83(d,J＝1.5Hz,1H),8.19(m,2H),7.88(d,J＝9.0Hz,2H),7.38(d,J＝8.5Hz,2H),4.64(s,2H),3.86(dd,J＝3.5Hz,11Hz,2H),3.22(t,J＝11.5Hz,2H),3.16(s,3H),3.00(m,1H),1.95(m,2H),1.60(d,J＝12.5Hz,2H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.59 (s, 1H), 9.15 (d, J = 2.0 Hz, 1H), 8.83 (d, J = 1.5 Hz, 1H), 8.19 (m, 2H) ,7.88(d,J=9.0Hz,2H),7.38(d,J=8.5Hz,2H),4.64(s,2H),3.86(dd,J=3.5Hz,11Hz,2H),3.22(t, J = 11.5Hz, 2H), 3.16 (s, 3H), 3.00 (m, 1H), 1.95 (m, 2H), 1.60 (d, J = 12.5 Hz, 2H).
MS(ESI,[M+H] +)m/z:529.1. MS(ESI,[M+H] + )m/z:529.1.
实施例45：化合物45的制备Example 45: Preparation of Compound 45
Figure PCTCN2021072699-appb-000128
Figure PCTCN2021072699-appb-000128
步骤A：化合物45-1的制备Step A: Preparation of compound 45-1
参照实施例1步骤B的制备方法，将化合物1-1和4-羟基哌啶反应制备得到化合物45-1。Referring to the preparation method of step B in Example 1, compound 1-1 is reacted with 4-hydroxypiperidine to prepare compound 45-1.
MS(ESI,[M+H] +)m/z:476.1/478.1. MS(ESI,[M+H] + )m/z:476.1/478.1.
步骤B：化合物45的制备Step B: Preparation of compound 45
参照实施例1步骤F的制备方法，使用实施例10步骤B所得含化合物10-3的反应液与上述步骤A所得化合物45-1反应制备得到化合物45。Referring to the preparation method of step F in Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 45-1 obtained in step A to prepare compound 45.
1H NMR(500MHz,DMSO-d 6)δ10.31(s,1H),8.98(d,J＝1.6Hz,1H),8.78(d,J＝2.1Hz,1H),8.32–8.24(m,1H),8.16(d,J＝2.0Hz,1H),7.86(d,J＝9.0Hz,2H),7.35(d,J＝8.7Hz,2H),4.67(d,J＝4.0Hz,1H),4.60(s,2H),3.58(dq,J＝8.3,4.1Hz,1H),3.44(d,J＝13.1Hz,2H),3.14(s,3H),2.86(t,J＝10.5Hz,2H),1.63(d,J＝9.8Hz,2H),1.28(d,J＝9.5Hz,2H). 1 H NMR (500MHz, DMSO-d 6 ) δ10.31 (s, 1H), 8.98 (d, J = 1.6 Hz, 1H), 8.78 (d, J = 2.1 Hz, 1H), 8.32-8.24 (m, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 9.0 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 4.67 (d, J = 4.0 Hz, 1H) ,4.60(s,2H),3.58(dq,J=8.3,4.1Hz,1H), 3.44(d,J=13.1Hz,2H), 3.14(s,3H), 2.86(t,J=10.5Hz, 2H), 1.63 (d, J = 9.8 Hz, 2H), 1.28 (d, J = 9.5 Hz, 2H).
MS(ESI,[M+H] +)m/z:544.1. MS(ESI,[M+H] + )m/z:544.1.
实施例46：化合物46的制备Example 46: Preparation of Compound 46
Figure PCTCN2021072699-appb-000129
Figure PCTCN2021072699-appb-000129
步骤A：化合物46的制备Step A: Preparation of compound 46
参照实施例1步骤F的制备方法，使用实施例11步骤B所得含化合物11-2的反应液与实施例45步骤A所得化合物45-1反应制备得到化合物46。Referring to the preparation method of step F in Example 1, the reaction solution containing compound 11-2 obtained in step B of Example 11 was reacted with compound 45-1 obtained in step A of Example 45 to prepare compound 46.
1H NMR(500MHz,DMSO-d 6)δ10.31(s,1H),8.99(d,J＝1.8Hz,1H),8.78(d,J＝2.2Hz,1H),8.27(d,J＝1.7Hz,1H),8.15(d,J＝2.1Hz,1H),7.86(d,J＝9.0Hz,2H),7.35(d,J＝8.8Hz,2H),4.67(d,J＝4.0Hz,1H),4.53(s,2H),3.58(dq,J＝8.4,4.2Hz,1H),3.45(d,J＝13.1Hz,2H),3.01(tt,J＝7.4,4.0Hz,1H),2.86(t,J＝10.5Hz,2H),1.64(d,J＝9.9Hz,2H),1.29(d,J＝9.5Hz,2H),0.92(d,J＝3.3Hz,2H),0.83(d,J＝5.3Hz,2H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.31 (s, 1H), 8.99 (d, J = 1.8 Hz, 1H), 8.78 (d, J = 2.2 Hz, 1H), 8.27 (d, J = 1.7Hz, 1H), 8.15 (d, J = 2.1 Hz, 1H), 7.86 (d, J = 9.0 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 4.67 (d, J = 4.0 Hz ,1H),4.53(s,2H),3.58(dq,J＝8.4,4.2Hz,1H),3.45(d,J＝13.1Hz,2H),3.01(tt,J＝7.4,4.0Hz,1H) , 2.86 (t, J = 10.5 Hz, 2H), 1.64 (d, J = 9.9 Hz, 2H), 1.29 (d, J = 9.5 Hz, 2H), 0.92 (d, J = 3.3 Hz, 2H), 0.83 (d,J=5.3Hz,2H).
MS(ESI,[M+H] +)m/z:570.2. MS(ESI,[M+H] + )m/z:570.2.
实施例47：化合物47的制备Example 47: Preparation of Compound 47
Figure PCTCN2021072699-appb-000130
Figure PCTCN2021072699-appb-000130
步骤A：化合物47-1的制备Step A: Preparation of compound 47-1
参照实施例1步骤B的制备方法，将化合物1-1和3-甲羟基氮杂环丁烷盐酸盐反应制备得到化合物47-1。Referring to the preparation method of step B in Example 1, compound 1-1 is reacted with 3-methylhydroxyazetidine hydrochloride to obtain compound 47-1.
MS(ESI,[M-H] -)m/z:460.0/462.0. MS(ESI,[MH] - )m/z:460.0/462.0.
步骤B：化合物47的制备Step B: Preparation of compound 47
参照实施例1步骤F的制备方法，使用实施例10步骤B所得含化合物10-3的反应液与上述步骤A所得化合物47-1反应制备得到化合物47。Referring to the preparation method of step F in Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 47-1 obtained in step A above to prepare compound 47.
1H NMR(500MHz,Methanol-d 4)δ8.82(d,J＝1.9Hz,1H),8.78(d,J＝2.2Hz,1H),8.17(d,J＝1.9Hz,1H),8.05(d,J＝2.2Hz,1H),7.79(d,J＝9.0Hz,2H),7.27(d,J＝8.9Hz,2H),4.62(s,2H),3.84(t,J＝8.6Hz,2H),3.64–3.53(m,4H),3.26(s,3H),2.70(p,J＝8.0Hz,1H). 1 H NMR(500MHz,Methanol-d 4 )δ8.82(d,J＝1.9Hz,1H), 8.78(d,J＝2.2Hz,1H), 8.17(d,J＝1.9Hz,1H), 8.05 (d,J=2.2Hz,1H), 7.79(d,J=9.0Hz,2H), 7.27(d,J=8.9Hz,2H), 4.62(s,2H), 3.84(t,J=8.6Hz ,2H), 3.64–3.53(m,4H), 3.26(s,3H), 2.70(p,J=8.0Hz,1H).
MS(ESI,[M+H] +)m/z:530.1. MS(ESI,[M+H] + )m/z:530.1.
实施例48：化合物48的制备Example 48: Preparation of Compound 48
Figure PCTCN2021072699-appb-000131
Figure PCTCN2021072699-appb-000131
步骤A：化合物48的制备Step A: Preparation of compound 48
参照实施例1步骤F的制备方法，使用实施例11步骤B所得含化合物11-2的反应液与实施例47步骤A所得化合物47-1反应制备得到化合物48。Referring to the preparation method of step F in Example 1, the reaction solution containing compound 11-2 obtained in step B of Example 11 was reacted with compound 47-1 obtained in step A of Example 47 to prepare compound 48.
1H NMR(500MHz,DMSO-d 6)δ10.21(s,1H),8.78(d,J＝8.4Hz,2H),8.06(d,J＝15.2Hz,2H),7.86(d,J＝8.6Hz,2H),7.34(d,J＝8.3Hz,2H),4.68(s,1H),4.53(s,2H),3.69(t,J＝7.9Hz,2H),3.43(dd,J＝11.6,6.0Hz,4H),3.01(s,1H),2.61(s,1H),0.92(s,2H),0.83(d,J＝5.5Hz,2H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.21 (s, 1H), 8.78 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 15.2 Hz, 2H), 7.86 (d, J = 8.6Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 4.68 (s, 1H), 4.53 (s, 2H), 3.69 (t, J = 7.9 Hz, 2H), 3.43 (dd, J = 11.6, 6.0 Hz, 4H), 3.01 (s, 1H), 2.61 (s, 1H), 0.92 (s, 2H), 0.83 (d, J = 5.5 Hz, 2H).
MS(ESI,[M+H] +)m/z:556.2. MS(ESI,[M+H] + )m/z:556.2.
实施例49：化合物49的制备Example 49: Preparation of Compound 49
Figure PCTCN2021072699-appb-000132
Figure PCTCN2021072699-appb-000132
步骤A：化合物49-1的制备Step A: Preparation of compound 49-1
参照实施例1步骤B的制备方法，将化合物1-1和顺-2,6-二甲基吗啉反应制备得到化合物49-1。Referring to the preparation method of step B in Example 1, compound 49-1 was prepared by reacting compound 1-1 with cis-2,6-dimethylmorpholine.
MS(ESI,[M+H] +)m/z:490.0/492.0. MS(ESI,[M+H] + )m/z:490.0/492.0.
步骤B：化合物49的制备Step B: Preparation of compound 49
参照实施例1步骤F的制备方法，使用实施例10步骤B所得含化合物10-3的反应液与上述步骤A所得化合物49-1反应制备得到化合物49。Referring to the preparation method of step F in Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 is reacted with compound 49-1 obtained in step A above to prepare compound 49.
1H NMR(500MHz,DMSO-d 6)δ10.35(s,1H),8.99(d,J＝1.8Hz,1H),8.80(d,J＝2.2Hz,1H),8.30(d,J＝1.8Hz,1H),8.20(d,J＝2.2Hz,1H),7.87(d,J＝9.1Hz,2H),7.36(d,J＝8.8Hz,2H),4.61(s,2H),3.50(d,J＝16.4Hz,2H),3.44(d,J＝12.6Hz,2H),3.15(s,3H),2.48–2.40(m,2H),0.96(d,J＝6.2Hz,6H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.35 (s, 1H), 8.99 (d, J = 1.8 Hz, 1H), 8.80 (d, J = 2.2 Hz, 1H), 8.30 (d, J = 1.8Hz, 1H), 8.20 (d, J = 2.2 Hz, 1H), 7.87 (d, J = 9.1 Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H), 4.61 (s, 2H), 3.50 (d,J=16.4Hz,2H),3.44(d,J=12.6Hz,2H),3.15(s,3H),2.48–2.40(m,2H),0.96(d,J=6.2Hz,6H) .
MS(ESI,[M+H] +)m/z:558.2. MS(ESI,[M+H] + )m/z:558.2.
实施例50：化合物50的制备Example 50: Preparation of Compound 50
Figure PCTCN2021072699-appb-000133
Figure PCTCN2021072699-appb-000133
步骤A：化合物50-1的制备Step A: Preparation of compound 50-1
参照实施例1步骤B的制备方法，将化合物1-1和3-甲基-3-吖啶醇盐酸盐反应制备得到化合物50-1。Referring to the preparation method of step B in Example 1, compound 1-1 and 3-methyl-3-acridol hydrochloride are reacted to prepare compound 50-1.
MS(ESI,[M+H] -)m/z:460.0/462.0. MS(ESI,[M+H] - )m/z:460.0/462.0.
步骤B：化合物50的制备Step B: Preparation of compound 50
参照实施例1步骤F的制备方法，使用实施例11步骤B所得含化合物11-2的反应液与上述步骤A所得化合物50-1反应制备得到化合物50。With reference to the preparation method of step F in Example 1, the reaction solution containing compound 11-2 obtained in step B of Example 11 was reacted with compound 50-1 obtained in step A to prepare compound 50.
1H NMR(500MHz,DMSO-d 6)δ10.23(s,1H),8.79(dd,J＝7.3,1.9Hz,2H),8.07(dd,J＝4.7,2.0Hz,2H),7.86(d,J＝9.0Hz,2H),7.34(d,J＝8.8Hz,2H),5.48(s,1H),4.53(s,2H),3.62–3.48(m,4H),3.01(tt,J＝7.4,3.9Hz,1H),1.27(s,3H),0.92(d,J＝3.3Hz,2H),0.84(d,J＝5.3Hz,2H). 1 H NMR (500MHz, DMSO-d 6 ) δ10.23 (s, 1H), 8.79 (dd, J = 7.3, 1.9 Hz, 2H), 8.07 (dd, J = 4.7, 2.0 Hz, 2H), 7.86 ( d,J=9.0Hz,2H),7.34(d,J=8.8Hz,2H),5.48(s,1H),4.53(s,2H),3.62–3.48(m,4H),3.01(tt,J =7.4,3.9Hz,1H),1.27(s,3H),0.92(d,J=3.3Hz,2H),0.84(d,J=5.3Hz,2H).
MS(ESI,[M+H] +)m/z:556.2. MS(ESI,[M+H] + )m/z:556.2.
实施例51：化合物51的制备Example 51: Preparation of Compound 51
Figure PCTCN2021072699-appb-000134
Figure PCTCN2021072699-appb-000134
步骤A：化合物51-1的制备Step A: Preparation of compound 51-1
氮气保护下，依次向50mL封管中加入(S)-(-)-2-羧基环丁胺(200mg)、四氢呋喃(10mL)、硼烷四氢呋喃络合物(425mg)，封口后将封管置入油浴锅中加热至中72℃下搅拌反应过夜。向反应液中加入甲醇(5mL)搅拌10min，将反应液减压浓缩，得淡黄色残余物51-1，不经分离纯化，直接用于下步反应。Under the protection of nitrogen, add (S)-(-)-2-carboxycyclobutylamine (200mg), tetrahydrofuran (10mL), borane tetrahydrofuran complex (425mg) to the 50mL sealed tube in sequence, and place the sealed tube after sealing. Put it into an oil bath and heat to medium 72°C and stir to react overnight. Methanol (5 mL) was added to the reaction solution and stirred for 10 min, and the reaction solution was concentrated under reduced pressure to obtain a pale yellow residue 51-1, which was directly used in the next reaction without separation and purification.
步骤B：化合物51-2的制备Step B: Preparation of compound 51-2
参照实施例1步骤B的制备方法，将上述步骤A所得含化合物51-1和化合物1-1反应制备得到化合物51-2。Referring to the preparation method of step B in Example 1, the compound 51-1 containing compound 51-1 obtained in step A above and compound 1-1 are reacted to prepare compound 51-2.
MS(ESI,[M-H] -)m/z:460.0/462.0. MS(ESI,[MH] - )m/z:460.0/462.0.
步骤C：化合物51的制备Step C: Preparation of compound 51
参照实施例1步骤F的制备方法，使用实施例10步骤B所得含化合物10-3的反应液与上述步骤B化合物51-2反应制备得到化合物51。Referring to the preparation method of step F in Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 51-2 of step B above to prepare compound 51.
1H NMR(500MHz,DMSO-d 6)δ10.22(s,1H),8.85(d,J＝2.0Hz,1H),8.76(d,J＝2.3Hz,1H),8.14(d,J＝2.1Hz,1H),8.08(d,J＝2.3Hz,1H),7.86(d,J＝9.1Hz,2H),7.34(d,J＝9.0Hz,2H),4.88(s,1H),4.59(s,2H),4.44(tt,J＝7.5,4.1Hz,1H),3.69(dt,J＝10.6,5.1Hz,1H),3.55(dt,J＝11.2,5.7Hz,1H),3.19(q,J＝7.9Hz,1H),3.14(s,3H),2.12(q,J＝7.6Hz,2H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.22 (s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.76 (d, J = 2.3 Hz, 1H), 8.14 (d, J = 2.1Hz, 1H), 8.08 (d, J = 2.3 Hz, 1H), 7.86 (d, J = 9.1 Hz, 2H), 7.34 (d, J = 9.0 Hz, 2H), 4.88 (s, 1H), 4.59 (s, 2H), 4.44 (tt, J = 7.5, 4.1 Hz, 1H), 3.69 (dt, J = 10.6, 5.1 Hz, 1H), 3.55 (dt, J = 11.2, 5.7 Hz, 1H), 3.19 ( q,J=7.9Hz,1H), 3.14(s,3H), 2.12(q,J=7.6Hz,2H).
MS(ESI,[M-H] -)m/z:528.2. MS(ESI,[MH] - )m/z:528.2.
实施例52：化合物52的制备Example 52: Preparation of Compound 52
Figure PCTCN2021072699-appb-000135
Figure PCTCN2021072699-appb-000135
步骤A：化合物52-1的制备Step A: Preparation of compound 52-1
参照实施例51步骤A的制备方法，将(R)-(-)-2-羧基环丁胺和硼烷四氢呋喃络合物反应制备得到化合物52-1。Referring to the preparation method of step A in Example 51, (R)-(-)-2-carboxycyclobutylamine and borane tetrahydrofuran complex were reacted to prepare compound 52-1.
步骤B：化合物52-2的制备Step B: Preparation of compound 52-2
参照实施例1步骤B的制备方法，将上述步骤A所得含化合物52-1和化合物1-1反应制备得到化合物52-2。Referring to the preparation method of step B in Example 1, the compound 52-1 obtained in the above step A is reacted with compound 1-1 to prepare compound 52-2.
MS(ESI,[M+H] +)m/z:462.1/464.1. MS(ESI,[M+H] + )m/z:462.1/464.1.
步骤C：化合物52的制备Step C: Preparation of compound 52
参照实施例1步骤F的制备方法，使用实施例10步骤B所得含化合物10-3的反应液与上述步骤B所得化合物52-2反应制备得到化合物52。Referring to the preparation method of step F in Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 is reacted with compound 52-2 obtained in step B above to prepare compound 52.
1H NMR(500MHz,DMSO-d 6)δ10.22(s,1H),8.85(d,J＝2.0Hz,1H),8.76(d,J＝2.3Hz,1H),8.14(d,J＝2.1Hz,1H),8.08(d,J＝2.4Hz,1H),7.89–7.83(m,2H),7.34(d,J＝9.0Hz,2H),4.90(t,J＝5.8Hz,1H),4.59(s,2H),4.44(tt,J＝7.5,4.2Hz,1H),3.69(dt,J＝10.6,5.1Hz,1H),3.60–3.50(m,1H),3.19(q,J＝8.0Hz,1H),3.14(s,3H),2.12(q,J＝7.6Hz,2H). 1 H NMR (500MHz, DMSO-d 6 ) δ 10.22 (s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.76 (d, J = 2.3 Hz, 1H), 8.14 (d, J = 2.1Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.89-7.83 (m, 2H), 7.34 (d, J = 9.0 Hz, 2H), 4.90 (t, J = 5.8 Hz, 1H) , 4.59 (s, 2H), 4.44 (tt, J = 7.5, 4.2 Hz, 1H), 3.69 (dt, J = 10.6, 5.1 Hz, 1H), 3.60-3.50 (m, 1H), 3.19 (q, J =8.0Hz,1H),3.14(s,3H),2.12(q,J=7.6Hz,2H).
MS(ESI,[M+H] +)m/z:530.3. MS(ESI,[M+H] + )m/z:530.3.
实施例53：化合物53的制备Example 53: Preparation of Compound 53
Figure PCTCN2021072699-appb-000136
Figure PCTCN2021072699-appb-000136
步骤A：化合物53-1的制备Step A: Preparation of compound 53-1
参照实施例1步骤B的制备方法，将化合物1-1和(R)-3-氟吡咯烷反应制备得到化合物53-1。Referring to the preparation method of step B in Example 1, compound 1-1 is reacted with (R)-3-fluoropyrrolidine to obtain compound 53-1.
MS(ESI,[M+H] +)m/z:464.0/466.0. MS(ESI,[M+H] + )m/z:464.0/466.0.
步骤B：化合物53制备Step B: Preparation of Compound 53
参照实施例1步骤F的制备方法，使用实施例2步骤C所得含化合物2-3的反应液与上述步骤A所得化合物53-1反应制备得到化合物53。Referring to the preparation method of step F in Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 53-1 obtained in step A above to prepare compound 53.
1H NMR(500MHz,DMSO-d 6)δ10.23(s,1H),8.93(s,1H),8.82(d,J＝1.7Hz,1H),8.81(d,J＝2.3Hz,1H),8.13(d,J＝2.3Hz,1H),8.13–8.11(m,1H),7.88(s,1H),7.86(s,1H),7.36(s,1H),7.34(s,1H),5.41–5.16(m,1H),4.52(s,2H),3.54–3.42(m,1H),3.34–3.22(m,3H),2.14–1.91(m,2H). 1 H NMR(500MHz,DMSO-d 6 )δ10.23(s,1H),8.93(s,1H),8.82(d,J=1.7Hz,1H),8.81(d,J=2.3Hz,1H) ,8.13(d,J=2.3Hz,1H),8.13-8.11(m,1H),7.88(s,1H),7.86(s,1H),7.36(s,1H),7.34(s,1H), 5.41--5.16(m,1H), 4.52(s,2H), 3.54--3.42(m,1H), 3.34--3.22(m,3H), 2.14--1.91(m,2H).
MS(ESI,[M-H] -)m/z:516.16/518.20. MS(ESI,[MH] - )m/z:516.16/518.20.
实施例54：化合物54的制备Example 54: Preparation of Compound 54
Figure PCTCN2021072699-appb-000137
Figure PCTCN2021072699-appb-000137
步骤A：化合物54制备Step A: Preparation of compound 54
参照实施例1步骤F的制备方法，使用实施例10步骤B所得含化合物10-3的反应液与实施例53步骤A所得化合物53-1反应制备得到化合物54。Referring to the preparation method of step F in Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 53-1 obtained in step A of Example 53 to prepare compound 54.
1H NMR(500MHz,DMSO-d 6)δ10.23(s,1H),8.80(s,2H),8.11(d,J＝11.2Hz,2H),7.87(d,J＝8.8Hz,2H),7.35(d,J＝8.5Hz,2H),5.39–5.18(m,1H),4.60(s,2H),3.54–3.40(m,1H),3.33–3.19(m,3H),3.15(s,3H),2.14–1.89(m,2H). 1 H NMR(500MHz,DMSO-d 6 )δ10.23(s,1H),8.80(s,2H),8.11(d,J=11.2Hz,2H),7.87(d,J=8.8Hz,2H) ,7.35(d,J=8.5Hz,2H),5.39–5.18(m,1H),4.60(s,2H),3.54–3.40(m,1H),3.33–3.19(m,3H),3.15(s ,3H),2.14-1.89(m,2H).
MS(ESI,[M-H] -)m/z:530.16/532.14. MS(ESI,[MH] - )m/z:530.16/532.14.
实施例55：化合物55的制备Example 55: Preparation of Compound 55
Figure PCTCN2021072699-appb-000138
Figure PCTCN2021072699-appb-000138
步骤A：化合物55-1的制备Step A: Preparation of compound 55-1
参照实施例1步骤B的制备方法，将化合物1-1和(S)-3-氟吡咯烷反应制备得到化合物55-1。Referring to the preparation method of step B in Example 1, compound 1-1 is reacted with (S)-3-fluoropyrrolidine to prepare compound 55-1.
MS(ESI,[M+H] +)m/z:464.3/466.3. MS(ESI,[M+H] + )m/z:464.3/466.3.
步骤B：化合物55制备Step B: Preparation of compound 55
参照实施例1步骤F的制备方法，使用实施例2步骤C所得含化合物2-3的反应液与上述步骤A化合物55-1反应制备得到化合物55。With reference to the preparation method of step F of Example 1, the reaction solution containing compound 2-3 obtained in step C of Example 2 was reacted with compound 55-1 of step A above to prepare compound 55.
1H NMR(500MHz,DMSO-d 6)δ10.23(s,1H),8.93(s,1H),8.81(s,2H),8.24–8.03(m,2H),7.87(d,J＝7.8Hz,2H),7.35(d,J＝7.6Hz,2H),5.40–5.16(m,1H),4.52(s,2H),3.57–3.41(m,1H),3.33–3.15(m,3H),2.20–1.87(m,2H). 1 H NMR(500MHz,DMSO-d 6 )δ10.23(s,1H),8.93(s,1H),8.81(s,2H),8.24-8.03(m,2H),7.87(d,J=7.8 Hz,2H),7.35(d,J=7.6Hz,2H),5.40–5.16(m,1H),4.52(s,2H),3.57–3.41(m,1H),3.33–3.15(m,3H) ,2.20-1.87(m,2H).
MS(ESI,[M+H] +)m/z:518.3/520.3. MS(ESI,[M+H] + )m/z:518.3/520.3.
实施例56：化合物56的制备Example 56: Preparation of Compound 56
Figure PCTCN2021072699-appb-000139
Figure PCTCN2021072699-appb-000139
步骤A：化合物56制备Step A: Preparation of compound 56
参照实施例1步骤F的制备方法，使用实施例10步骤B所得含化合物10-3的反应液与实施例55步骤A所得化合物55-1反应制备得到化合物56。Referring to the preparation method of step F in Example 1, the reaction solution containing compound 10-3 obtained in step B of Example 10 was reacted with compound 55-1 obtained in step A of Example 55 to prepare compound 56.
1H NMR(500MHz,DMSO-d 6)δ10.23(s,1H),8.86–8.76(m,2H),8.13(d,J＝2.3Hz,1H),8.12–8.06(m,1H),7.87(d,J＝9.1Hz,2H),7.35(d,J＝8.9Hz,2H),5.37–5.18(m,1H),4.60(s,2H),3.55–3.40(m,1H),3.34–3.19(m,3H),3.15(s,3H),2.17–1.88(m,2H). 1 H NMR(500MHz,DMSO-d 6 )δ10.23(s,1H), 8.86–8.76(m,2H), 8.13(d,J=2.3Hz,1H), 8.12–8.06(m,1H), 7.87(d,J=9.1Hz,2H),7.35(d,J=8.9Hz,2H),5.37–5.18(m,1H),4.60(s,2H),3.55–3.40(m,1H),3.34 --3.19(m,3H),3.15(s,3H),2.17-1.88(m,2H).
MS(ESI,[M+H] +)m/z:532.3/534.2. MS(ESI,[M+H] + )m/z:532.3/534.2.
实施例57：化合物57的制备Example 57: Preparation of Compound 57
Figure PCTCN2021072699-appb-000140
Figure PCTCN2021072699-appb-000140
步骤A：化合物57-1的制备Step A: Preparation of compound 57-1
依次向50mL单口瓶中加入10mL无水乙醇、实施例2步骤A所得化合物2-1(400mg)、二异丙基乙胺(428mg)、氘代甲胺盐酸盐(97mg)，加毕室温下反应6h；将反应液减压浓缩；所得残余物经柱层析得化合物57-1。Add 10 mL of absolute ethanol, compound 2-1 (400 mg), diisopropylethylamine (428 mg), and deuterated methylamine hydrochloride (97 mg) obtained in step A of Example 2 to a 50 mL single-necked flask, and add to room temperature. The reaction was continued for 6 hours; the reaction solution was concentrated under reduced pressure; the resulting residue was subjected to column chromatography to obtain compound 57-1.
MS(ESI,[M+H] +)m/z:230.1/231.9. MS(ESI,[M+H] + )m/z:230.1/231.9.
步骤B：化合物57-2的制备Step B: Preparation of compound 57-2
参照实施例1步骤E的方法，使用上述步骤A所得化合物57-1制备含化合物57-2的反应液，降至室温，不经分离纯化，直接用于下步反应。With reference to the method of step E in Example 1, the compound 57-1 obtained in step A was used to prepare a reaction solution containing compound 57-2, which was cooled to room temperature, and was directly used in the next step without separation and purification.
步骤C：化合物57的制备Step C: Preparation of compound 57
参照实施例1步骤F的方法，使用上述步骤B所得含化合物57-2的反应液和实施例33步骤A所得化合物33-1制备得到化合物57。With reference to the method of step F in Example 1, the reaction solution containing compound 57-2 obtained in step B above and compound 33-1 obtained in step A of Example 33 were used to prepare compound 57.
1H NMR(500MHz,DMSO-d 6)δ10.20(s,1H),8.78(d,J＝2.4Hz,1H),8.77(d,J＝2.2Hz,1H),8.09(d,J＝2.3Hz,1H),8.07(d,J＝2.1Hz,1H),7.90–7.82(m,2H),7.34(d,J＝8.6Hz,2H),4.59(s,2H),3.93–3.85(m,1H),3.30–3.16(m,2H),3.15(s,3H),3.09(d,J＝11.9Hz,1H),1.95–1.78(m,2H). 1 H NMR(500MHz,DMSO-d 6 )δ10.20(s,1H), 8.78(d,J=2.4Hz,1H), 8.77(d,J=2.2Hz,1H), 8.09(d,J= 2.3Hz, 1H), 8.07 (d, J = 2.1 Hz, 1H), 7.90-7.82 (m, 2H), 7.34 (d, J = 8.6 Hz, 2H), 4.59 (s, 2H), 3.93-3.85 ( m,1H), 3.30–3.16(m,2H), 3.15(s,3H), 3.09(d,J=11.9Hz,1H), 1.95–1.78(m,2H).
MS(ESI,[M-H] -)m/z:545.2/547.2. MS(ESI,[MH] - )m/z:545.2/547.2.
实施例58：化合物58的制备Example 58: Preparation of Compound 58
Figure PCTCN2021072699-appb-000141
Figure PCTCN2021072699-appb-000141
步骤A：化合物58的制备Step A: Preparation of compound 58
参照实施例1步骤F的方法，使用实施例5中步骤A所得化合物5-1与(3-(甲基磺酰基)苯基)硼酸反应制备得化合物58。Referring to the method of step F in Example 1, the compound 5-1 obtained in step A of Example 5 was reacted with (3-(methylsulfonyl)phenyl)boronic acid to prepare compound 58.
1H NMR(500MHz,DMSO-d 6)δ10.42(s,1H),8.82(d,J＝2.3Hz,1H),8.27(s,1H),8.18(d,J＝2.3Hz,1H),8.04(d,J＝7.7Hz,1H),7.95(d,J＝7.8Hz,1H),7.88(d,J＝9.1Hz,2H),7.81(t,J＝7.8Hz,1H),7.36(d,J＝8.8Hz,2H),3.58–3.54(m,4H),3.30(s,3H),3.19–3.08(m,4H). 1 H NMR(500MHz,DMSO-d 6 )δ10.42(s,1H), 8.82(d,J=2.3Hz,1H), 8.27(s,1H), 8.18(d,J=2.3Hz,1H) ,8.04(d,J=7.7Hz,1H),7.95(d,J=7.8Hz,1H),7.88(d,J=9.1Hz,2H),7.81(t,J=7.8Hz,1H),7.36 (d,J=8.8Hz,2H), 3.58–3.54(m,4H), 3.30(s,3H), 3.19–3.08(m,4H).
MS(ESI,[M+H] +)m/z:538.3/540.2. MS(ESI,[M+H] + )m/z:538.3/540.2.
实施例59：化合物59的制备Example 59: Preparation of Compound 59
Figure PCTCN2021072699-appb-000142
Figure PCTCN2021072699-appb-000142
步骤A：化合物59-1的制备Step A: Preparation of compound 59-1
向20mL微波管中依次加入1,4-二氧六环(15mL)、1-叔丁氧羰基-吡咯-2-硼酸(423mg)、实施例1步骤B所得化合物1-2(700mg)、碳酸钾(626mg)、四(三苯基膦)钯(87mg)、纯化水(3mL)和磁子，氮气吹扫后置入微波反应器中，130℃反应1.5h；减压浓缩，所得粗品经柱层析纯化得500mg化合物59-1。Add 1,4-dioxane (15mL), 1-tert-butoxycarbonyl-pyrrole-2-boronic acid (423mg), compound 1-2 (700mg) obtained in step B of Example 1 to a 20mL microwave tube in turn, carbonic acid Potassium (626mg), tetrakis (triphenylphosphine) palladium (87mg), purified water (3mL) and magneton, purged with nitrogen, placed in a microwave reactor, reacted at 130°C for 1.5h; concentrated under reduced pressure, the crude product obtained Purified by column chromatography, 500 mg of compound 59-1 was obtained.
MS(ESI,[M-H] -)m/z:447.16/449.14. MS(ESI,[MH] - )m/z:447.16/449.14.
步骤B：化合物59-2的制备Step B: Preparation of compound 59-2
向100mL单口瓶中加入超干四氢呋喃(15mL)、步骤A所得化合物59-1(400mg)和偶氮二异丁腈(21mg)，加毕，在氮气保护条件下降温至-78℃；开始向体系中分批加入二溴海因(94mg)，加毕保温反应2h。减压浓缩，所得粗品经柱层析纯化得370mg化合物59-2。Add ultra-dry tetrahydrofuran (15mL), compound 59-1 (400mg) obtained in step A, and azobisisobutyronitrile (21mg) to a 100mL single-necked flask. After the addition, the temperature is reduced to -78℃ under nitrogen protection; Dibromohydantoin (94mg) was added to the system in batches, and the reaction was kept for 2h after the addition. Concentrated under reduced pressure, and the obtained crude product was purified by column chromatography to obtain 370 mg of compound 59-2.
MS(ESI,[M-H] -)m/z:525.1/527.1. MS(ESI,[MH] - )m/z:525.1/527.1.
步骤C：化合物59-3的制备Step C: Preparation of compound 59-3
向20mL微波管中加入1,4-二氧六环(15mL)、步骤B所得化合物59-2(370mg)、N,N-二异丙基乙胺(94mg)、甲硫醇钠(51.0mg)、三(二亚苄-BASE丙酮)二钯(50mg)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(63mg)和磁子，氮气吹扫后置入微波反应器中130℃反应2h。减压浓缩，所的粗品经柱层析纯化得250mg化合物59-3。Add 1,4-dioxane (15mL), compound 59-2 (370mg) obtained in step B, N,N-diisopropylethylamine (94mg), sodium methyl mercaptan (51.0mg) to a 20mL microwave tube ), tris(dibenzylidene-BASE acetone) dipalladium (50mg), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (63mg) and magneton, purge with nitrogen and put in React at 130°C for 2h in a microwave reactor. After concentration under reduced pressure, the crude product was purified by column chromatography to obtain 250 mg of compound 59-3.
MS(ESI,[M-H] -)m/z:493.2/495.2. MS(ESI,[MH] - )m/z:493.2/495.2.
步骤D：化合物59的制备Step D: Preparation of compound 59
向25mL单口瓶中依次加入异丙醇(5mL)、纯化水(1.5mL)、步骤C所得化合物59-3(230mg)和过氧单磺酸钾(195mg)，加毕室温下反应0.5h。向反应体系中加入乙酸乙酯萃取3次，合并有机相，并依次用饱和亚硫酸钠水溶液和饱和食盐水各洗2次。收集有机相，用无水硫酸钠干燥后减压浓缩，所得粗品经柱层析纯化得20mg化合物59。Isopropanol (5 mL), purified water (1.5 mL), compound 59-3 (230 mg) obtained in step C, and potassium peroxymonosulfonate (195 mg) were sequentially added to a 25 mL single-neck flask, and reacted at room temperature for 0.5 h after addition. Ethyl acetate was added to the reaction system to extract 3 times, the organic phases were combined, and washed with saturated sodium sulfite aqueous solution and saturated brine twice in turn. The organic phase was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography to obtain 20 mg of compound 59.
1H NMR(500MHz,DMSO-d 6)δ12.50(s,1H),10.18(s,1H),8.76(d,J＝2.4Hz,1H),8.08(d,J＝2.4Hz,1H),7.93–7.81(m,2H),7.40–7.28(m,2H),6.80(dd,J＝3.6,2.4Hz,1H),6.28(dd,J＝3.7,2.3Hz,1H),4.88(d,J＝3.4Hz,1H),4.23(s,1H),3.52–3.42(m,1H),3.21(s,3H),2.97(d,J＝11.6Hz,1H),1.90–1.81(m,1H),1.80–1.72(m,1H). 1 H NMR (500MHz, DMSO-d 6 ) δ 12.50 (s, 1H), 10.18 (s, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H) ,7.93-7.81(m,2H),7.40-7.28(m,2H), 6.80(dd,J=3.6,2.4Hz,1H), 6.28(dd,J=3.7,2.3Hz,1H), 4.88(d ,J=3.4Hz,1H),4.23(s,1H),3.52–3.42(m,1H),3.21(s,3H),2.97(d,J=11.6Hz,1H),1.90–1.81(m, 1H), 1.80-1.72 (m, 1H).
MS(ESI,[M-H] -)m/z:525.2/527.2. MS(ESI,[MH] - )m/z:525.2/527.2.
实施例60：化合物60的制备Example 60: Preparation of Compound 60
Figure PCTCN2021072699-appb-000143
Figure PCTCN2021072699-appb-000143
步骤A：化合物60-1的制备Step A: Preparation of compound 60-1
参照实施例1中步骤B的方法，使用实施例1中步骤A所得化合物1-1和2-(甲氨基)乙-1-醇制备标化合物60-1。With reference to the method of step B in Example 1, the compound 1-1 and 2-(methylamino)ethan-1-ol obtained in step A of Example 1 were used to prepare the standard compound 60-1.
1H NMR(500MHz,DMSO-d 6)δ10.68(s,1H),9.00(d,J＝2.3Hz,1H),8.98(d,J＝2.0Hz,1H),8.95(s,1H),8.53(d,J＝2.3Hz,1H),8.34(d,J＝2.0Hz,1H),7.88(d,J＝9.1Hz,2H),7.40(d,J＝8.9Hz,2H),4.55(s,2H). 1 H NMR(500MHz,DMSO-d 6 )δ10.68(s,1H), 9.00(d,J=2.3Hz,1H), 8.98(d,J=2.0Hz,1H), 8.95(s,1H) , 8.53 (d, J = 2.3 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 9.1 Hz, 2H), 7.40 (d, J = 8.9 Hz, 2H), 4.55 (s,2H).
步骤B：化合物60的制备Step B: Preparation of compound 60
参照实施例1步骤F的方法，使用上述步骤A所得化合物60-1与实施例2步骤C所得含化合物2-3的反应液反应制备得化合物60。With reference to the method of step F in Example 1, compound 60 was prepared by reacting compound 60-1 obtained in step A above with the reaction solution containing compound 2-3 obtained in step C of embodiment 2.
1H NMR(500MHz,DMSO-d 6)δ10.25(s,1H),8.91(s,1H),8.88(s,1H),8.76(s,1H),8.19(s,1H),8.14(s,1H),7.87(d,J＝8.8Hz,2H),7.35(d,J＝8.5Hz,2H),4.66(t,J＝4.9Hz,1H),4.51(s,2H),3.54(q,J＝5.7Hz,2H),3.44(t,J＝6.0Hz,2H),2.71(s,3H). 1 H NMR(500MHz,DMSO-d 6 )δ10.25(s,1H), 8.91(s,1H), 8.88(s,1H), 8.76(s,1H), 8.19(s,1H), 8.14( s, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 4.66 (t, J = 4.9 Hz, 1H), 4.51 (s, 2H), 3.54 ( q,J=5.7Hz,2H), 3.44(t,J=6.0Hz,2H), 2.71(s,3H).
MS(ESI,[M+H] +)m/z:504.2/506.2. MS(ESI,[M+H] + )m/z:504.2/506.2.
实施例61：化合物61的制备Example 61: Preparation of Compound 61
Figure PCTCN2021072699-appb-000144
Figure PCTCN2021072699-appb-000144
步骤A：化合物61-1的制备Step A: Preparation of compound 61-1
参照实施例13步骤A的方法，用1-叔丁氧羰基-4-氨基哌啶替代2-甲氧基乙胺与化合物2-1反应制备化合物61-1。According to the method of step A in Example 13, using 1-tert-butoxycarbonyl-4-aminopiperidine instead of 2-methoxyethylamine to react with compound 2-1 to prepare compound 61-1.
步骤B：化合物61-2的制备Step B: Preparation of compound 61-2
参照实施例1步骤E的方法，使用上述步骤A所得化合物61-1制备含化合物61-2的反应液，降至室温，不经分离纯化，直接用于下步反应。Referring to the method of step E in Example 1, the compound 61-1 obtained in step A was used to prepare a reaction solution containing compound 61-2, which was cooled to room temperature, and was directly used in the next step without separation and purification.
步骤C：化合物61-3的制备Step C: Preparation of compound 61-3
参照实施例1步骤F的方法，使用上述步骤B所得含化合物61-2的反应液和实施例12步骤A所得化合物12-1制备得到化合物61-3。With reference to the method of step F in Example 1, the reaction solution containing compound 61-2 obtained in step B above and compound 12-1 obtained in step A of Example 12 were used to prepare compound 61-3.
MS(ESI,[M-H] -)m/z:612.29/614.30. MS(ESI,[MH] - )m/z:612.29/614.30.
步骤D：化合物61的制备Step D: Preparation of compound 61
向50mL的圆底烧瓶中，加入上述步骤A所得化合物61-3(430mg)、二氯甲烷(10mL)、6M氯化氢-二氧六环溶液(2.5mL)，室温搅拌过夜，反应完毕后浓缩反应液，随后加入乙酸乙酯(10mL)室温搅拌4h。过滤，滤饼用乙酸乙酯洗涤。收集滤饼并干燥，得60mg化合物61。Add compound 61-3 (430mg), dichloromethane (10mL) and 6M hydrogen chloride-dioxane solution (2.5mL) obtained in step A to a 50mL round bottom flask, stir overnight at room temperature, and concentrate the reaction after the reaction is complete. Then, ethyl acetate (10 mL) was added and stirred at room temperature for 4 h. Filter and wash the filter cake with ethyl acetate. The filter cake was collected and dried to obtain 60 mg of compound 61.
1H NMR(500MHz,DMSO-d 6)δ9.50–9.45(m,1H),9.41(s,1H),9.38(d,J＝6.7Hz,1H),9.34(s,1H),8.74(s,1H),8.02(d,J＝9.0Hz,2H),7.40(d,J＝8.5Hz,2H),4.64(s,2H),4.41(d,J＝11.7Hz,1H),3.37(d,J＝12.1Hz,2H),3.07(t,J＝11.7Hz,2H),2.14(d,J＝13.3Hz,2H),1.95(d,J＝12.3Hz,2H). 1 H NMR(500MHz,DMSO-d 6 )δ9.50–9.45(m,1H), 9.41(s,1H), 9.38(d,J=6.7Hz,1H), 9.34(s,1H), 8.74( s, 1H), 8.02 (d, J = 9.0 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 4.64 (s, 2H), 4.41 (d, J = 11.7 Hz, 1H), 3.37 ( d, J = 12.1 Hz, 2H), 3.07 (t, J = 11.7 Hz, 2H), 2.14 (d, J = 13.3 Hz, 2H), 1.95 (d, J = 12.3 Hz, 2H).
MS(ESI,[M+H] +)m/z:514.3/516.4. MS(ESI,[M+H] + )m/z:514.3/516.4.
试验例1 化合物对K562细胞的增殖抑制作用Test Example 1 The compound's inhibitory effect on the proliferation of K562 cells
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，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。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。 Take the K562 cells that are in good condition in the exponential growth phase, collect the cells into a centrifuge tube, low-speed benchtop centrifuge, 1000 rpm, centrifuge for 5 minutes, discard the supernatant, add 5 mL complete medium (RPMI 1640 basal medium + 10% FBS) for cell resuspension. Count with a cell counter, dilute the complete medium, adjust the cell density to 6×10 4 cells/mL, add the same amount of RPMI 1640 basal medium to adjust the serum concentration to 5%, and the cell density to 3×10 4 cells/mL mL. Use a multi-channel pipette to inoculate a 96-well plate, 100 μL/well, and place it in a cell incubator at 37°C and 5% CO 2 saturated humidity. After culturing for 24 hours, use a nanoliter sampler to add compounds, each compound set 8 concentrations (1000nM, 250nM, 63nM, 16nM, 3.9nM, 0.98nM, 0.24nM, 0.061nM), each concentration set 2 Repeat wells with cells without compound as a negative control, and medium without cells as a blank control. After 72 hours, add CCK-8, 10μL/well. After 2 hours, detect the absorbance at 450nm by Envision microplate reader, calculate the inhibition rate, the inhibition rate (%)=(average of negative control group-average of experimental group)/( the average value of negative control group - average blank group) × 100%, a concentration of the compound number as abscissa, ordinate inhibition rate, a four-parameter analysis of dose-response curve fitting to calculate IC 50, the results shown in Table 1.
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Test Example 2 The compound's inhibitory effect on the proliferation of BCR-ABL T315I transfected Ba/F3 cells
取处于指数生长期状态良好的Ba/F3-BCR-ABL1-T315I细胞(购自南京科佰生物科技有限公司)，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(RPMI1640基础培养基+10％FBS)进行细胞重悬。使用细胞计数仪计数，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。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，以不加细胞的培养基作为空白对照。72小时后加CCK-8，10μL/孔，Ba/F3-BCR-ABL1-T315I细胞加CCK8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1。 Take Ba/F3-BCR-ABL1-T315I cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) that are in good condition in the exponential growth phase, collect the cells into a centrifuge tube, low-speed benchtop centrifuge, 1000 rpm, centrifuge for 5 min, discard Supernatant, add 5mL complete medium (RPMI1640 basal medium + 10% FBS) with a pipette to resuspend the cells. Count with a cell counter, dilute the complete medium, adjust the cell density to 6×10 4 cells/mL, add the same amount of RPMI 1640 basal medium to adjust the serum concentration to 5%, and the cell density to 3×10 4 cells/mL mL. Use a multi-channel pipette to inoculate a 96-well plate, 100 μL/well, and place it in a cell incubator at 37°C and 5% CO 2 saturated humidity. After culturing for 24 hours, use a nanoliter sampler to add compounds, each compound set 8 concentrations (1000nM, 250nM, 63nM, 16nM, 3.9nM, 0.98nM, 0.24nM, 0.061nM), each concentration set 2 Repeat wells with cells without compound as a negative control, and medium without cells as a blank control. After 72 hours, add CCK-8, 10μL/well, add CCK8 to Ba/F3-BCR-ABL1-T315I cells and place them at 37℃. After 1 hour, use a microplate reader to detect the absorbance at 450nm, calculate the inhibition rate, and inhibit Rate (%)=(average value of negative control group-average value of experimental group)/(average value of negative control group-average value of blank group)×100%, the logarithm of compound concentration is taken as abscissa, and the inhibition rate is ordinate, four Parameter analysis, fitting the dose-response curve, and calculating IC 50 , the results are shown in Table 1.
表1Table 1
Figure PCTCN2021072699-appb-000145
Figure PCTCN2021072699-appb-000145
Figure PCTCN2021072699-appb-000146
Figure PCTCN2021072699-appb-000146
试验例3 小鼠体内药代动力学评价Test Example 3 Evaluation of pharmacokinetics in mice
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0.25h(15min)、0.5h(30min)、1h、2h、3h、4h、6h、8h、10h、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)，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。ICR mice (purchased from Shanghai Xipuerbikai Experimental Animal Co., Ltd.), weighing 18-22 g, were used for 3 to 5 days and then randomly divided into groups, 9 mice in each group, and each compound was administered by intragastric administration at a dose of 10 mg/kg. The test animals (ICR mice) were fasted overnight before the administration, and were given food 4 hours after the administration, and they were free to drink water before and after the experiment and during the experiment. After intragastric administration, take about 0.1 mL of blood from the orbit at 0.25h (15min), 0.5h (30min), 1h, 2h, 3h, 4h, 6h, 8h, 10h, and 24h (3 to 4 samples per mouse Time points, 3 mice per time point), after EDTA-K2 anticoagulation, transfer to 4°C, 4000rpm, 10min conditions for centrifugal separation of plasma within 30min. After collecting all the plasma, store it immediately at -20°C for testing.
吸取30μL待测血浆样品和标曲样品，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。Aspirate 30μL of plasma sample to be tested and standard curve sample, add 300μL of acetonitrile solution containing internal standard (diazepam 20ng/mL), shake and mix for 5min, centrifuge at 13000rpm for 10min, take 70μL of supernatant, add 70μL of ultrapure water to dilute and mix Evenly, draw 1μL for LC/MS/MS determination, and record the chromatogram.
通过小鼠体内药代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，结果见表2。The oral exposure of the compound was evaluated by pharmacokinetic experiments in mice. The DAS 3.2.5 software was used to fit the relevant pharmacokinetic parameters, and the results are shown in Table 2.
表2Table 2
Figure PCTCN2021072699-appb-000147
Figure PCTCN2021072699-appb-000147

Claims (15)

  1. 式(I)化合物或其药学上可接受的盐，The compound of formula (I) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2021072699-appb-100001
    Figure PCTCN2021072699-appb-100001
    其中，in,
    R 1选自
    Figure PCTCN2021072699-appb-100002
    或者
    Figure PCTCN2021072699-appb-100003
    R 1 is selected from
    Figure PCTCN2021072699-appb-100002
    or
    Figure PCTCN2021072699-appb-100003
    R 2选自氢、3-10元杂环基或氨基，其中所述3-10元杂环基或氨基任选地被一个或多个R a取代； R 2 is selected from hydrogen, amino, or 3-10 membered heterocyclyl, wherein said 3-10 membered heterocyclyl group or an amino group optionally substituted with one or more substituents R a;
    R a选自羟基、氰基、卤素、
    Figure PCTCN2021072699-appb-100004
    C 1-6烷基、C 1-6烷氧基、二(C 1-6烷基)氨基、或被一个或多个羟基或C 1-6烷氧基取代的C 1-6烷基；     R a is selected from hydroxyl, cyano, halogen,
    Figure PCTCN2021072699-appb-100004
    C 1-6 alkyl, C 1-6 alkoxy, di (C 1-6 alkyl) amino, or one or more hydroxy or C 1-6 alkoxy substituted C 1-6 alkyl;
    R 3选自-OCF 2H，其中所述-OCF 2H任选地被卤素取代； R 3 is selected from -OCF 2 H, wherein the -OCF 2 H is optionally substituted with halogen;
    R 4选自氢、C 1-6烷基、C 3-6环烷基或3-10元杂环基，其中C 1-6烷基、C 3-6环烷基或3-10元杂环基任选地被一个或多个R b取代； R 4 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-10 membered heterocyclic group, wherein C 1-6 alkyl, C 3-6 cycloalkyl or 3-10 membered heterocyclic group The cyclic group is optionally substituted with one or more R b ;
    R b选自氘、羟基、C 1-6烷氧基、C 1-6烷基、氨基、单(C 1-6烷基)氨基或二(C 1-6烷基)氨基； R b is selected from deuterium, hydroxyl, C 1-6 alkoxy, C 1-6 alkyl, amino, mono(C 1-6 alkyl)amino or di(C 1-6 alkyl)amino;
    R 5选自C 1-6烷基； R 5 is selected from C 1-6 alkyl;
    环A选自5-6元杂芳基或苯基。Ring A is selected from 5-6 membered heteroaryl or phenyl.
  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，其中R 2选自氢、4-6元杂环基、7-9元螺杂环基或氨基，其中所述4-6元杂环基、7-9元螺杂环基或氨基任选地被一个或多个R a取代；或者，R 2选自氢、4-6元杂环基或氨基，其中所述4-6元杂环基或氨基任选地被一个或多个R a取代；或者，R 2选自氢、4-6元杂环烷基、6元杂环烯基、7或9元螺杂环烷基或氨基，其中所述4-6元杂环烷基、6元杂环烯基、7或9元螺杂环烷基或氨基任选地被一个或多个R a取代；或者，R 2选自氢、吡咯烷基、吗啉基、哌嗪基、氮杂环丁基、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、2-氧杂-7-氮杂螺[3.5]壬烷基、2-氧杂-6-氮杂螺[3.3]庚烷基或氨基，其中所述吡咯烷基、吗啉基、哌嗪基、氮杂环丁基、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、2-氧杂-7-氮杂螺[3.5]壬烷基、2-氧杂-6-氮杂螺[3.3]庚烷基或氨基任选地被一个或多个R a取代；或者，R 2选自氢、
    Figure PCTCN2021072699-appb-100005
    Figure PCTCN2021072699-appb-100006
    Figure PCTCN2021072699-appb-100007
    The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is selected from hydrogen, 4-6 membered heterocyclic group, 7-9 membered spiro heterocyclic group or amino group, wherein said 4-6 membered heterocyclyl, 7-9 membered spiro-heterocyclyl or amino optionally substituted with one or more R a; or, R 2 is selected from hydrogen, 4-6 membered heterocyclyl or amino, wherein said 4-6 membered heterocyclic group or an amino group optionally substituted with one or more substituents R a; or, R 2 is selected from hydrogen, 4-6 membered heterocycloalkyl, 6-membered heterocycloalkenyl, 7, or 9-membered heterocycloalkyl or spiro-amino group, wherein the 4-6 membered heterocycloalkyl, 6-membered heterocycloalkenyl, 7 or 9 membered heterocycloalkyl or spiro amino group optionally substituted with one or more substituents R a; Alternatively, R 2 is selected from hydrogen, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, 3 ,4-Dihydropyranyl, 3,6-dihydropyranyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.3]heptan Alkyl or amino, wherein the pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, 1,2,3,6-tetrahydropyridyl, tetrahydropyranyl, 3 ,4-Dihydropyranyl, 3,6-dihydropyranyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.3]heptan alkyl or amino optionally substituted with one or more substituents R a; or, R 2 is selected from hydrogen,
    Figure PCTCN2021072699-appb-100005
    Figure PCTCN2021072699-appb-100006
    Figure PCTCN2021072699-appb-100007
  3. 如权利要求1或2所述的式(I)化合物或其药学上可接受的盐，其中R a选自羟基、卤素、C 1-6烷基、二(C 1-6烷基)氨基或被一个或多个羟基取代的C 1-6烷基；或者，R a选自羟基、氰基、卤素、
    Figure PCTCN2021072699-appb-100008
    C 1-4烷基、C 1-3烷氧基、二(C 1-3烷基)氨基或被一个或多个羟基或C 1-3烷氧基取代的C 1-4烷基；或者，R a选自羟基、卤素、C 1-3烷基、二(C 1-3烷基)氨基或被一个或多个羟基取代的C 1-3烷基；或者，R a选自羟基、氰基、氟、
    Figure PCTCN2021072699-appb-100009
    甲基、甲氧基、2-羟基乙基、2-甲氧基乙基、2-甲基-2-羟基丙基、二(甲基)氨基或羟基甲基。     Of formula (I) or a pharmaceutically acceptable salt of a compound of claim 1 or claim 2, wherein R a is selected from hydroxy, halo, C 1-6 alkyl, di (C 1-6 alkyl) amino, or C 1-6 alkyl substituted by one or more hydroxy groups; or, R a is selected from hydroxy, cyano, halogen,
    Figure PCTCN2021072699-appb-100008
    C 1-4 alkyl, C 1-3 alkoxy, di(C 1-3 alkyl)amino or C 1-4 alkyl substituted with one or more hydroxy groups or C 1-3 alkoxy; or , R a is selected from hydroxy, halo, C 1-3 alkyl, di (C 1-3 alkyl) amino group or by one or more hydroxy-substituted C 1-3 alkyl; alternatively, R a is selected from hydroxy, Cyano, fluorine,
    Figure PCTCN2021072699-appb-100009
    Methyl, methoxy, 2-hydroxyethyl, 2-methoxyethyl, 2-methyl-2-hydroxypropyl, bis(methyl)amino or hydroxymethyl.
  4. 如权利要求1-3任一项所述的式(I)化合物或其药学上可接受的盐，其中R 3选自-OCF 3或-OCF 2Cl。 The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 3 is selected from -OCF 3 or -OCF 2 Cl.
  5. 如权利要求1-4任一项所述的式(I)化合物或其药学上可接受的盐，其中R 4选自氢、C 1-5烷基、C 3-6环烷基或4-6元杂环烷基，其中C 1-5烷基、C 3-6环烷基或4-6元杂环烷基任选地被一个或多个R b取代；或者，R 4选自氢、C 1-5烷基、环丙基或6元杂环烷基，其中C 1-5烷基、环丙基或6元杂环烷基任选地被一个或多个R b取代；或者，R 4选自氢、甲基、乙基、2-甲基丙基、3-甲基丁基、环丙基、四氢吡喃基或哌啶基，其中甲基、乙基、2-甲基丙基、3-甲基丁基、环丙基、四氢吡喃基或哌啶基任选地被一个或多个R b取代；或者，R 4选自氢、甲基、d 3-甲基、环丙基、
    Figure PCTCN2021072699-appb-100010
    Figure PCTCN2021072699-appb-100011
    The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 4 is selected from hydrogen, C 1-5 alkyl, C 3-6 cycloalkyl or 4- 6-membered heterocycloalkyl, wherein C 1-5 alkyl, C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with one or more R b ; or, R 4 is selected from hydrogen , C 1-5 alkyl, cyclopropyl or 6-membered heterocycloalkyl, wherein C 1-5 alkyl, cyclopropyl or 6-membered heterocycloalkyl is optionally substituted with one or more R b ; or , R 4 is selected from hydrogen, methyl, ethyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, tetrahydropyranyl or piperidinyl, wherein methyl, ethyl, 2- Methylpropyl, 3-methylbutyl, cyclopropyl, tetrahydropyranyl or piperidinyl is optionally substituted with one or more R b ; or, R 4 is selected from hydrogen, methyl, d 3 -Methyl, cyclopropyl,
    Figure PCTCN2021072699-appb-100010
    Figure PCTCN2021072699-appb-100011
  6. 如权利要求1-5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、C 1-6烷氧基、C 1-6烷基、氨基、单(C 1-6烷基)氨基或二(C 1-6烷基)氨基；或者，R b选自氘、羟基、C 1-3烷氧基、C 1-3烷基、氨基、单(C 1-3烷基)氨基或二(C 1-3烷基)氨基；或者，R b选自羟基、C 1-3烷氧基、C 1-3烷基、氨基、单(C 1-3烷基)氨基或二(C 1-3烷基)氨基；或者，R b选自氘、羟基、甲氧基、甲基或二(乙基)氨基。 The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R b is selected from the group consisting of hydroxy, C 1-6 alkoxy, C 1-6 alkyl, amino, Mono(C 1-6 alkyl)amino or di(C 1-6 alkyl)amino; alternatively, R b is selected from deuterium, hydroxyl, C 1-3 alkoxy, C 1-3 alkyl, amino, mono (C 1-3 alkyl) amino or di(C 1-3 alkyl) amino; alternatively, R b is selected from hydroxyl, C 1-3 alkoxy, C 1-3 alkyl, amino, mono(C 1 -3 alkyl)amino or di(C 1-3 alkyl)amino; alternatively, R b is selected from deuterium, hydroxyl, methoxy, methyl or di(ethyl)amino.
  7. 如权利要求1-6任一项所述的式(I)化合物或其药学上可接受的盐，其中R 5选自C 1-3烷基；或者，R 5选自甲基。 The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R 5 is selected from C 1-3 alkyl; or, R 5 is selected from methyl.
  8. 如权利要求1-7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5-6元含氮的杂芳基或苯基；或者，环A选自吡咯基、吡啶基或苯基。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein ring A is selected from 5-6 membered nitrogen-containing heteroaryl or phenyl; alternatively, ring A is selected from From pyrrolyl, pyridyl or phenyl.
  9. 如权利要求1-8任一项所述的式(I)化合物或其药学上可接受的盐，其中结构单元
    Figure PCTCN2021072699-appb-100012
    选自
    Figure PCTCN2021072699-appb-100013
    或者，结构单元
    Figure PCTCN2021072699-appb-100014
    选自
    Figure PCTCN2021072699-appb-100015
    进一步选自
    Figure PCTCN2021072699-appb-100016
    The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein the structural unit
    Figure PCTCN2021072699-appb-100012
    Selected from
    Figure PCTCN2021072699-appb-100013
    Or, structural unit
    Figure PCTCN2021072699-appb-100014
    Selected from
    Figure PCTCN2021072699-appb-100015
    Further selected from
    Figure PCTCN2021072699-appb-100016
  10. 如权利要求1-9任一项所述的式(I)化合物或其药学上可接受的盐，式(I)化合物为式(II)化合物或式(III)化合物，The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein the compound of formula (I) is a compound of formula (II) or a compound of formula (III),
    Figure PCTCN2021072699-appb-100017
    Figure PCTCN2021072699-appb-100017
    其中，in,
    R 3选自-OCF 3或-OCF 2Cl；或者 R 3 is selected from -OCF 3 or -OCF 2 Cl; or
    Figure PCTCN2021072699-appb-100018
    Figure PCTCN2021072699-appb-100018
    其中，in,
    结构单元
    Figure PCTCN2021072699-appb-100019
    选自
    Figure PCTCN2021072699-appb-100020
    Structural units
    Figure PCTCN2021072699-appb-100019
    Selected from
    Figure PCTCN2021072699-appb-100020
    R 3选自-OCF 3或-OCF 2Cl。 R 3 is selected from -OCF 3 or -OCF 2 Cl.
  11. 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，The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein:
    R 1选自
    Figure PCTCN2021072699-appb-100021
    或者
    Figure PCTCN2021072699-appb-100022
    R 1 is selected from
    Figure PCTCN2021072699-appb-100021
    or
    Figure PCTCN2021072699-appb-100022
    R 2选自氢、含有1-3个选自N或O或S的杂原子的4-10元杂环基或氨基，其中所述4-10元杂环基或氨基任选地被一个或多个R a取代； R 2 is selected from hydrogen, a 4-10 membered heterocyclic group or amino group containing 1-3 heteroatoms selected from N or O or S, wherein the 4-10 membered heterocyclic group or amino group is optionally substituted by one or a plurality of substituents R a;
    R a选自羟基、氰基、卤素、
    Figure PCTCN2021072699-appb-100023
    C 1-6烷基、C 1-6烷氧基、二(C 1-6烷基)氨基、或被一个或多个羟基或C 1-6烷氧基取代的C 1-6烷基；     R a is selected from hydroxyl, cyano, halogen,
    Figure PCTCN2021072699-appb-100023
    C 1-6 alkyl, C 1-6 alkoxy, di (C 1-6 alkyl) amino, or one or more hydroxy or C 1-6 alkoxy substituted C 1-6 alkyl;
    R 3选自-OCF 3、-OCF 2Cl或-OCF 2Br； R 3 is selected from -OCF 3 , -OCF 2 Cl or -OCF 2 Br;
    R 4选自氢、C 1-6烷基、C 3-6环烷基、或含有1-3个选自N或O或S的杂原子的5-7元杂环基，其中C 1-6烷基、C 3-6环烷基或5-7元杂环基任选地被一个或多个R b取代； R 4 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or a 5-7 membered heterocyclic group containing 1-3 heteroatoms selected from N or O or S, wherein C 1- 6 alkyl, C 3-6 cycloalkyl or 5-7 membered heterocyclic group is optionally substituted by one or more R b;
    R b选自氘、羟基、C 1-6烷氧基、C 1-6烷基； R b is selected from deuterium, hydroxyl, C 1-6 alkoxy, C 1-6 alkyl;
    R 5选自C 1-6烷基； R 5 is selected from C 1-6 alkyl;
    环A选自含有1-3个选自N或O或S的杂原子的5-6元杂芳基或苯基。Ring A is selected from 5-6 membered heteroaryl or phenyl containing 1-3 heteroatoms selected from N or O or S.
  12. 如权利要求1-11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)化合物选自：The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-11, wherein the compound of formula (I) is selected from:
    Figure PCTCN2021072699-appb-100024
    Figure PCTCN2021072699-appb-100024
    Figure PCTCN2021072699-appb-100025
    Figure PCTCN2021072699-appb-100025
    Figure PCTCN2021072699-appb-100026
    Figure PCTCN2021072699-appb-100026
    Figure PCTCN2021072699-appb-100027
    Figure PCTCN2021072699-appb-100027
  13. 如权利要求1-12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)化合物选自：The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-12, wherein the compound of formula (I) is selected from:
    Figure PCTCN2021072699-appb-100028
    Figure PCTCN2021072699-appb-100028
    Figure PCTCN2021072699-appb-100029
    Figure PCTCN2021072699-appb-100029
  14. 药物组合物，其包含权利要求1-13任一项所述的化合物或其药学上可接受的盐。A pharmaceutical composition comprising the compound according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof.
  15. 权利要求1-13任一项所述的化合物或其药学上可接受的盐、权利要求14所述的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；任选地，所述疾病选自癌症；或者，所述疾病选自白血病；或者，所述疾病选自慢性髓细胞白血病。Use of the compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition of claim 14 in the preparation of a medicament for the treatment and/or prevention of BCR-ABL related diseases; optionally Preferably, the disease is selected from cancer; or, the disease is selected from leukemia; or, the disease is selected from chronic myelogenous leukemia.
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