WO2023011629A1 - Pyrrolidone derivative and use thereof in medicine - Google Patents

Pyrrolidone derivative and use thereof in medicine Download PDF

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Publication number
WO2023011629A1
WO2023011629A1 PCT/CN2022/110534 CN2022110534W WO2023011629A1 WO 2023011629 A1 WO2023011629 A1 WO 2023011629A1 CN 2022110534 W CN2022110534 W CN 2022110534W WO 2023011629 A1 WO2023011629 A1 WO 2023011629A1
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membered
alkyl
cycloalkyl
membered heterocycloalkyl
group
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PCT/CN2022/110534
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French (fr)
Chinese (zh)
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朱钰沁
魏用刚
楚洪柱
叶飞
孙毅
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成都百裕制药股份有限公司
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Priority to CN202280032997.1A priority Critical patent/CN117279907A/en
Publication of WO2023011629A1 publication Critical patent/WO2023011629A1/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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/495—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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/14—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
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D515/04—Ortho-condensed systems

Definitions

  • the invention relates to a pyrrolidone derivative or its stereoisomer and its application in medicine.
  • Adenosine diphosphate-ribosylation is a protein post-transcriptional modification process, in which single or multiple adenosine diphosphate-ribose (ADP-ribose) groups are embedded in amino acid residues of proteins.
  • ADP-ribosylation is a reversible process involved in physiological regulation of cell signal transduction, DNA damage repair, transcription, regulation of gene expression, and apoptosis.
  • ADP-ribose is derived from a redox cofactor: Nicotinamide adenine dinucleotide (NAD+), and the enzyme that mediates the insertion modification of ADP-ribose is ADP-ribosylase.
  • NAD+ Nicotinamide adenine dinucleotide
  • ADP-ribosylases can perform two types of modifications: mono-ADP ribosylation and poly-ADP ribosylation.
  • PARP1 When DNA is damaged or cells are stressed, PARP is activated, resulting in an increase in the amount of poly ADP-ribose and a decrease in the amount of NAD+.
  • PARP1 was thought to be the only poly-ADP-ribose polymerase in mammalian cells and thus the most studied enzyme.
  • scientists have identified 17 different PARPs.
  • MonoPARP occupies the majority of the PARP family and mediates important biological functions and various stress responses, such as: unfolded protein response, NF- ⁇ B signaling, antiviral response, and cytokine signaling.
  • TCDD 2,3,7,8-Tetrachlorodibenzo-p-dioxin
  • PARP-7 2,3,7,8-Tetrachlorodibenzo-p-dioxin
  • TCDD 2,3,7,8-Tetrachlorodibenzo-p-dioxin
  • AHR AHR
  • a ligand-activated transcription factor that mediates the toxic activity of many environmental xenobiotics.
  • AHR up-regulates the expression of PARP-7, and PARP-7 interacts with the kinase TBK1 and makes it ADP-ribosylated, leading to the inhibition of TBK1 activity and the down-regulation of IFN-I (type I interferon) response, which in turn leads to the body's antiviral and tumor immune responses are suppressed.
  • IFN-I type I interferon
  • the object of the present invention is to provide a selective PARP7 inhibitor or its stereoisomer, its pharmaceutical composition, and its application in medicine.
  • One or more embodiments of the present application provide a compound represented by general formula (I) or its stereoisomer, pharmaceutically acceptable salt or deuterated product:
  • the C 1-6 alkylene, 3- to 10-membered heterocycloalkyl monocyclic or polycyclic ring is further 1 or more substituents selected from the following substituents: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C
  • L 1 is R 17 is H, D or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • X3 is C or N
  • B is a cycloalkyl group with 3 to 10 members, a heterocycloalkyl group with 3 to 10 members, an aryl group with 6 to 12 members, and a heteroaryl group with 5 to 12 members, and the heterocycle and heteroaryl ring contain at least 1 to 3 a heteroatom selected from N, O and S;
  • R a4 and R a5 , R b4 and R b5 , R c4 and R c5 , R d4 and R d5 , R x4 and R x5 each independently form a 4- to 7-membered heterocycle together with the N atom to which they are attached, and the heterocycle
  • R f1 , R f2 , R f3 , R f4 , R f5 , R f6 , Re1 , Re2 , Re3 , Re4 , Re5 , Re6 , R g1 , R g2 , R g3 , R g4 , R g5 , R g6 are each independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl group, 3 to 10 membered heterocycloalkyl group, the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-10 cycloalkyl group, C 6-12 aryl group, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of H
  • n 0, 1, 2 or 3;
  • n 0, 1, 2, 3 or 4;
  • o 0 or 1
  • p 1, 2 or 3.
  • One or more embodiments of the present application provide a compound represented by general formula (I) or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein:
  • R 14a is OH, C 1-6 alkyl, C 3-5 cycloalkyl, said C 1-6 alkyl, C 3-5 cycloalkyl are optionally substituted by 1 to 3 halogens;
  • X 1 is NR x1 , O, S, a monocyclic or polycyclic ring of 3 to 10 membered heterocycloalkyl, and the heterocycloalkyl is further substituted by 1 or more substituents selected from the group consisting of H, halogen, CN , OH, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 3-7 cycloalkyl, 5 to 10 membered heteroaryl or 3 to 10 membered heterocycloalkyl,
  • the C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 3-7 cycloalkyl, 5 to 10 membered heteroaryl, 3 to 10 membered heterocycloalkyl are each independently is substituted by 1 or more substituents selected from H, halogen, CN or OH, and the heteroaryl or heterocycloalkyl contains 1, 2, 3 or 4 substituents independently selected from O, N and S heteroatoms;
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from H, D, halogen, NR a4 R a5 , OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkane base, 5 to 10 membered heteroaryl or 3 to 10 membered heterocycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 5 to 10 membered heteroaryl group, 3- to 10-membered heterocycloalkyl group are each independently substituted by 1 or more substituents selected from the group consisting of: H, halogen, OH, NR a4 R a5 , C 1-6 alkyl, C 1-6 alkoxy group, C 3-7 cycloalkyl group, 5 to 10 membered heteroaryl group, 3 to 10 membered heterocycloalkyl group; or R 1 and R 2 , R 3 and R 4 , R 1 and R 3 each independently together with
  • R a4 and R a5 are each independently H or C 1-6 alkyl, or each of R a4 and R a5 independently form a 5 to 6-membered heterocycloalkyl together with the atoms they are connected to; the 5 to 6-membered Heterocycloalkyl comprises 1 to 3 heteroatoms selected from O, N and S;
  • L 1 is R 17 is H, D or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • the alkyl group contains 1 to 3 heteroatoms selected from N, O
  • X3 is C or N
  • B is a cycloalkyl group with 3 to 10 members, a heterocycloalkyl group with 3 to 10 members, an aryl group with 6 to 12 members, and a heteroaryl group with 5 to 12 members, and the heterocycle and heteroaryl ring contain at least 1 to 3 a heteroatom selected from N, O and S;
  • R 13 is C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN or CF 3 , the C 3-10 cycloalkane radical, 3 to 10 membered heterocycloalkyl, 6 to 12 membered aryl, 5 to 12 membered heteroaryl are further substituted by 1 or more substituents selected from the group consisting of: H, halogen, CN, OH, NH 2.
  • R x1 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1- 6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H, OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, CN, NH 2 , NO 2 , N 3 , COOH ;
  • the 5-12 membered heteroaryl, 3-10 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, S;
  • n 0, 1, 2 or 3;
  • n 0, 1, 2, 3 or 4;
  • o 0 or 1
  • p 1, 2 or 3.
  • One or more embodiments of the present application provide a compound represented by general formula (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product:
  • R 14a is OH, C 1-6 alkyl, C 3-5 cycloalkyl, said C 1-6 alkyl, C 3-5 cycloalkyl are optionally substituted by 1 to 3 halogens;
  • X 1 is NR x1 , O, S, or
  • R 18 , R 19 , R 20 , R 21 , R 22 and R 23 are each independently selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl C 3-7 cycloalkyl, 5 to 10 membered heteroaryl or 3 to 10 membered heterocycloalkyl , the C 1-6 alkyl, C 1-6 alkoxy , C 6-10 aryl , C 3-7 cycloalkyl, 5 to 10 membered heteroaryl, 3 to 10 membered heterocycloalkyl are each independently substituted by 1 or more substituents selected from the group consisting of: H, halogen, CN, OH, all The 5 to 10 membered heteroaryl, 3 to 10 membered heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms independently selected from O, N and S;
  • C is 5 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10 membered aromatic ring or 5 to 10 membered aromatic heterocyclic ring; the 5 to 10 membered heterocyclic ring and 5 to 10 membered aromatic heterocyclic ring include 1 to 3 heteroatoms selected from O, N and S;
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from H, D, halogen, NR a4 R a5 , OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkane base, 5 to 10 membered heteroaryl or 3 to 10 membered heterocycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 5 to 10 membered heteroaryl group, 3- to 10-membered heterocycloalkyl group are each independently substituted by 1 or more substituents selected from the group consisting of: H, halogen, OH, NR a4 R a5 , C 1-6 alkyl, C 1-6 alkoxy group, C 3-7 cycloalkyl group, 5 to 10 membered heteroaryl group, 3 to 10 membered heterocycloalkyl group; or R 1 and R 2 , R 3 and R 4 , R 1 and R 3 each independently together with
  • R a4 and R a5 are each independently H or C 1-6 alkyl, or each of R a4 and R a5 independently form a 5 to 6-membered heterocycloalkyl together with the atoms they are connected to; the 5 to 6-membered Heterocycloalkyl comprises 1 to 3 heteroatoms selected from O, N and S;
  • L 1 is R 17 is H, D or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • B is a cycloalkyl group with 3 to 10 members, a heterocycloalkyl group with 3 to 10 members, an aryl group with 6 to 12 members, and a heteroaryl group with 5 to 12 members, and the heterocycle and heteroaryl ring contain at least 1 to 3 a heteroatom selected from N, O and S;
  • R 13 is C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN or CF 3 , the C 3-10 cycloalkane radical, 3 to 10 membered heterocycloalkyl, 6 to 12 membered aryl, 5 to 12 membered heteroaryl are further substituted by 1 or more substituents selected from the group consisting of: H, halogen, CN, OH, NH 2.
  • R x1 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1- 6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H, OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, CN, NH 2 ; said 5 to 12 membered heteroaryl Aryl, 3 to 10 membered heterocycloalkyls contain 1 to 3 heteroatoms selected from N, O, S;
  • n 0, 1, 2, 3 or 4;
  • o 0 or 1
  • p 1, 2 or 3;
  • q 1, 2 or 3.
  • One or more embodiments of the present application provide a compound represented by general formula (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein:
  • R 14 is C 1-6 alkyl, C 3-5 cycloalkyl or halogen, and the C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • X 1 is NH, O, or
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from H, D, and C 1-6 alkyl groups, and R 1 and R 2 , R 3 and R 4 , R 1 and R 3 are each independently selected from the group consisting of The attached carbon atoms form a 3 to 6 membered cycloalkyl group;
  • X 5 , X 6 , and X 7 are each independently selected from CH, CH 2 , N, NH, O or S;
  • D is selected from 5 to 10 membered carbocyclic rings, 5 to 10 membered heterocyclic rings, 6 to 10 membered aromatic rings or 5 to 10 membered aromatic heterocyclic rings;
  • the 10-membered aromatic ring and the 5-10-membered aromatic heterocycle are further substituted by 1 or more substituents selected from the group consisting of: C 3-10 cycloalkyl, C 6-12 aryl, 5-12-membered heteroaryl, 3 to 10 membered heterocycloalkyl;
  • the 5 to 10 membered heterocycle, 5 to 10 membered aromatic heterocycle, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl contain 1 to 3 members selected from N, Heteroatoms of O and S;
  • R 13 is C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN or CF 3 , the C 3-10 cycloalkane radical, 3 to 10 membered heterocycloalkyl, 6 to 12 membered aryl, 5 to 12 membered heteroaryl are further substituted by 1 or more substituents selected from the group consisting of: H, halogen, CN, OH, NH 2.
  • R x1 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl is optionally substituted by 1 to more substituents selected from the group consisting of H, OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, CN, NH 2 ; the 5 to 12 membered heteroaryl, The 3 to 10 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, S;
  • n 0, 1, 2, 3 or 4;
  • o 0 or 1.
  • One or more embodiments of the present application provide a compound represented by general formula (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein:
  • X1 is NH, or
  • R 1 , R 2 , R 3 , R 4 are each independently selected from H, D, C 1-6 alkyl;
  • X 5 and X 6 are each independently selected from CH, CH 2 , N, NH, O or S;
  • D is selected from 5 to 10 membered carbocyclic rings, 5 to 10 membered heterocyclic rings, 6 to 10 membered aromatic rings or 5 to 10 membered aromatic heterocyclic rings;
  • the 10-membered aromatic ring and the 5-10-membered aromatic heterocycle are further substituted by 1 or more substituents selected from the group consisting of: C 3-10 cycloalkyl, C 6-12 aryl, 5-12-membered heteroaryl, 3 to 10 membered heterocycloalkyl;
  • the 5 to 10 membered heterocycle, 5 to 10 membered aromatic heterocycle, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl contain 1 to 3 members selected from N, Heteroatoms of O and S;
  • R 13 is C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN or CF 3 , the C 3-10 cycloalkane radical, 3 to 10 membered heterocycloalkyl, 6 to 12 membered aryl, 5 to 12 membered heteroaryl are further substituted by 1 or more substituents selected from the group consisting of: H, halogen, CN, OH, NH 2.
  • R 13 is CN or CF 3
  • R 3 and R 4 are D.
  • R x1 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1- 6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H, OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, CN, NH 2 ; the 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, contain 1 to 3 Heteroatoms selected from N, O, S;
  • n 0, 1, 2, 3 or 4;
  • o 0 or 1.
  • One or more embodiments of the present application provide a compound represented by general formula (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein:
  • X1 is NH, or
  • R 1 and R 2 are each independently selected from H, D or C 1-6 alkyl
  • R 3 and R 4 are each independently selected from H or D;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, D, halogen, OH, C 1-6 alkyl;
  • R 13 is C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN or CF 3 , the C 3-10 cycloalkane radical, 3 to 10 membered heterocycloalkyl, 6 to 12 membered aryl, 5 to 12 membered heteroaryl are further substituted by 1 or more substituents selected from the group consisting of: H, halogen, CN, OH, NH 2.
  • R 13 is CN or CF 3
  • R 3 and R 4 are D.
  • R x1 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1- 6 alkyl C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H , OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, CN, NH 2 said 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl containing 1 to 3 members selected from N , O, S heteroatoms;
  • n 0, 1, 2, 3 or 4;
  • o 0 or 1.
  • One or more embodiments of the present application provide a compound represented by general formula (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein:
  • X1 is NH, or
  • R 1 and R 2 are each independently selected from H, D or C 1-6 alkyl
  • R 3 and R 4 are each independently selected from H or D;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, D, halogen, OH, C 1-6 alkyl;
  • R 13 is C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN or CF 3 , the C 3-10 cycloalkane radical, 3 to 10 membered heterocycloalkyl, 6 to 12 membered aryl, 5 to 12 membered heteroaryl are further substituted by 1 or more substituents selected from the group consisting of: H, halogen, CN, OH, NH 2.
  • R 13 is CN or CF 3
  • R 3 and R 4 are D.
  • the monocyclic or polycyclic ring of the 3 to 10 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, S;
  • R x1 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1- 6 alkyl C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H , OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, CN, NH 2 said 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl containing 1 to 3 members selected from N , O, S heteroatoms;
  • n 0, 1, 2, 3 or 4;
  • o 0 or 1.
  • One or more embodiments of the present application provide a compound represented by general formula (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein:
  • X1 is NH, or
  • R 1 and R 2 are each independently selected from H, D or C 1-6 alkyl
  • R 3 and R 4 are each independently selected from H or D;
  • X2 is O
  • R 5 and R 6 are each independently selected from H, D or C 1-6 alkyl
  • R 7 and R 8 are each independently selected from H or D;
  • R 9 and R 10 are each independently selected from H, D, OH or C 1-6 alkyl
  • R 11 and R 12 are each independently selected from H or D;
  • R 13 is
  • R 13a and R 13b are each independently selected from H, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl or NH 2 ;
  • R x1 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1- 6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H, OH, halogen CN, NH 2 , or COOH; the 5-12 membered heteroaryl, 3-10 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, S;
  • n 0, 1, 2, 3 or 4;
  • o 0 or 1.
  • One or more embodiments of the present application provide a compound represented by general formula (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein:
  • X1 is NH, or
  • R 1 and R 2 are each independently selected from H, D or C 1-6 alkyl
  • R 3 and R 4 are each independently selected from H or D;
  • X2 is O
  • R 5 and R 6 are each independently selected from H or D;
  • R 7 and R 8 are each independently selected from H or D;
  • R 9 and R 10 are each independently selected from H, D or OH;
  • R 11 and R 12 are each independently selected from H or D;
  • R 13 is
  • R 13a and R 13b are selected from H, halogen, CF 3 ;
  • n 0, 1, 2, 3 or 4;
  • o 0 or 1.
  • One or more embodiments of the present application provide a compound represented by general formula (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein:
  • X1 is NH, or
  • R 1 and R 2 are each independently selected from H, D or C 1-6 alkyl
  • R 3 and R 4 are each independently selected from H or D;
  • X2 is O
  • R 5 and R 6 are each independently selected from H or D;
  • R 7 and R 8 are each independently selected from H or D;
  • R 9 and R 10 are each independently selected from H, D or OH;
  • R 11 and R 12 are each independently selected from H or D;
  • R 13 is,
  • R 13a and R 13b are selected from H, halogen, CF 3 ;
  • n 0, 1, 2, 3 or 4;
  • o 0 or 1.
  • One or more embodiments of the present application provide a compound represented by general formula (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein:
  • X1 is NH, or
  • R 1 and R 2 are each independently selected from H, D or C 1-6 alkyl
  • R 3 and R 4 are each independently selected from H or D;
  • X2 is O
  • R 5 and R 6 are each independently selected from H or D;
  • R 7 and R 8 are each independently selected from H or D;
  • R 9 and R 10 are each independently selected from H, D or OH;
  • R 11 and R 12 are each independently selected from H or D;
  • R 13 is
  • R 13a is selected from H, halogen, CF 3 ;
  • n 0, 1, 2, 3 or 4;
  • o 0 or 1.
  • One or more embodiments of the present application provide a compound represented by general formula (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein:
  • X1 is NH, or
  • R 1 and R 2 are each independently selected from H, D or C 1-6 alkyl
  • R 3 and R 4 are each independently selected from D;
  • X2 is O
  • R 5 and R 6 are each independently selected from H or D;
  • R 7 and R 8 are each independently selected from H or D;
  • R 9 and R 10 are each independently selected from H, D or OH;
  • R 11 and R 12 are each independently selected from H or D;
  • R 13 is CN or CF 3 .
  • n 0, 1, 2, 3 or 4;
  • o 0 or 1.
  • One or more embodiments of the present application provide a compound or its stereoisomer, pharmaceutically acceptable salt or deuterated substance, which is selected from the following structures:
  • One or more embodiments of the present application provide an intermediate compound for the preparation of a compound of general formula (I), (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product or its stereo Isomers, pharmaceutically acceptable salts or deuterated substances, which have compounds represented by general formula (II) or (III):
  • the C 1-6 alkylene, 3 to 10 membered heterocycloalkyl ring or polycyclic ring is further selected from 1 or more
  • the following substituents are substituted: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl,
  • X 4 is NHR x1 , OH, SH or a bond
  • L 1 is R 17 is H, D or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • X3 is C or N
  • B is a cycloalkyl group with 3 to 10 members, a heterocycloalkyl group with 3 to 10 members, an aryl group with 6 to 12 members, and a heteroaryl group with 5 to 12 members, and the heterocycle and heteroaryl ring contain at least 1 to 3 a heteroatom selected from N, O and S;
  • R a4 and R a5 , R b4 and R b5 , R c4 and R c5 , R d4 and R d5 , R x4 and R x5 each independently form a 4- to 7-membered heterocycle together with the N atom to which they are attached, and the heterocycle
  • R f1 , R f2 , R f3 , R f4 , R f5 , R f6 , R e1 , R e2 , R e3 , R e4 , R e5 , R e6 are each independently selected from C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1-6 alkane C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl optionally Substituted by 1 to more substituents selected from : H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C
  • n 0, 1, 2 or 3;
  • n 0, 1, 2, 3 or 4;
  • o 0 or 1
  • p 1, 2 or 3.
  • the intermediate compound or its stereoisomer or pharmaceutically acceptable salt has the following structure or its stereoisomer or pharmaceutically acceptable salt:
  • One or more embodiments of the present application provide an intermediate compound for the preparation of a compound of general formula (I), (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product or its stereo Isomers, pharmaceutically acceptable salts or deuterated substances, which have compounds represented by general formula (IV) or (V):
  • R 17 is H, D or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • X 3 is CH 2 or NH
  • R 20 and R 21 are each independently selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 3-7 cycloalkyl, 5 to 10-membered heteroaryl or 3 to 10-membered heterocycloalkyl, the C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 3-7 cycloalkyl, 5 to 10 Member heteroaryl, 3 to 10 member heterocycloalkyl are each independently substituted by 1 to 3 substituents selected from the following: H, halogen, CN, OH; the heteroaryl or heterocycloalkyl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, N and S; C is a 5- to 10-membered carbocyclic ring, a 5- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered aromatic heterocyclic ring.
  • R b1 , R b2 , R b3 , R b4 , R b5 or R b6 are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 ring Alkyl, C6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl or TBS, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H, OH , halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocyclo
  • R f1 , R f2 , R f3 , R f4 , R f5 , R f6 , R e1 , R e2 , R e3 , R e4 , R e5 , R e6 are each independently selected from C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1-6 alkane C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl optionally Substituted by 1 to more substituents selected from : H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C
  • p 1, 2 or 3.
  • the intermediate compound or its stereoisomer or pharmaceutically acceptable salt has the following structure or its stereoisomer or pharmaceutically acceptable salt:
  • One or more embodiments of the present application provide the use of the compound of the present application or its stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition of the present application in the preparation of antitumor drugs.
  • said tumor formation is associated with PARP.
  • the PARP is PARP-7.
  • One or more embodiments of the present application provide the use of the compound of the present application or its stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition of the present application in the preparation of a PARP inhibitor.
  • the PARP is PARP-7.
  • One or more embodiments of the present application provide the compound of the present application or its stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition of the present application for use as a medicament.
  • One or more embodiments of the present application provide the compound of the present application or its stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition of the present application, which is used in the method of treating tumor.
  • said tumor formation is associated with PARP.
  • the PARP is PARP-7.
  • One or more embodiments of the present application provide the compound of the present application or its stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition of the present application, which is used as a PARP inhibitor, such as a PARP-7 inhibitor.
  • One or more embodiments of the present application provide a method for treating tumors, which includes administering the compound of the present application or its stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition of the present application to a subject in need thereof.
  • One or more embodiments of the present application provide a method for inhibiting PARP, which includes administering the compound of the present application or its stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition of the present application.
  • the PARP is PARP-7.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, and I involved in the groups and compounds of the present invention include their isotopes, and the carbon involved in the groups and compounds of the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D, Also called heavy hydrogen), tritium (T, also called super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, the isotopes of fluorine include 17 F and 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, and the isotopes of bromine include 79 Br and 81 Br.
  • the isotopes of carbon include 12 C, 13 C and 14
  • Alkyl means 1 to 20 carbon atoms (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms) straight-chain or branched saturated aliphatic hydrocarbon group, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, further preferably 1 to 4 Alkyl group of carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl And its various branched isomers; when the alkyl group is substituted, it may be optionally further substituted by one or more substituents.
  • Aryl refers to a substituted or unsubstituted aromatic ring, which can be a 5 to 8 membered (eg 5, 6, 7, 8 membered) monocyclic ring, a 5 to 12 membered (eg 5, 6, 7 , 8, 9, 10, 11, 12 member) bicyclic ring or 10 to 15 member (eg 10, 11, 12, 13, 14, 15 member) tricyclic ring system, which can be a bridge ring or a spiro ring, non-limiting implementation Examples include phenyl, naphthyl, The aryl group may be optionally further substituted by one or more substituents.
  • Heteroaryl refers to a substituted or unsubstituted aromatic ring, which can be a 5 to 8 membered (eg 5, 6, 7, 8 membered) monocyclic ring, a 5 to 12 membered (eg 5, 6, 7, 8 membered) 8, 9, 10, 11, 12 member) bicyclic ring or 10 to 15 member (eg 10, 11, 12, 13, 14, 15 member) tricyclic ring system, and contains 1 to 6 (eg 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably 3 to 8-membered (eg 3, 4, 5, 6, 7, 8-membered) heterocyclic group, optional in the ring of the heterocyclic group Substituted N and S can be oxidized into various oxidation states.
  • N and S can be oxidized into various oxidation states.
  • the heterocyclic group can be connected to a heteroatom or a carbon atom, and the heterocyclic group can be a bridge ring or a spiro ring.
  • Non-limiting examples include cyclopyridyl, furyl, thienyl, oxazolyl, pyranyl, pyrrolyl , pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl benzimidazolyl, benzopyridyl, pyrrolopyridyl, pyrazolopiperazinyl, triazolopiperazinyl, imidazo Piperazinyl, imidazopyrazinyl, pyrazolopyrimidinyl, benzopyrimidinyl, When heteroaryl is substituted, it may be optionally further substituted with one or more substituents.
  • Heterocyclic group or “heterocyclic ring” refers to a saturated or unsaturated heteroaromatic or non-heteroaromatic ring. When selected from a heteroaromatic ring, its definition is the same as the definition of "heteroaryl"above; In the case of an aromatic ring, it can be a monocyclic ring with 3 to 10 members (for example, 3, 4, 5, 6, 7, 8, 9, 10 members), a 4 to 12 member (for example, 4, 5, 6, 7, 8, 9, 10, 11, 12) bicyclic or 10 to 15 (e.g. 10, 11, 12, 13, 14, 15) tricyclic ring system, and contains 1 to 4 (e.g.
  • 1, 2, 3, 4 is a heteroatom selected from N, O or S, preferably a 3- to 8-membered heterocyclic group.
  • the selectively substituted N and S in the ring of "heterocyclic group” or “heterocyclic ring” can be oxidized to various oxidation states;
  • heterocyclic group” or “heterocyclic ring” can be connected to a heteroatom or a carbon atom;
  • a “heterocyclyl” or “heterocycle” may be a bridged ring or a spiro ring.
  • heterocyclyl or “heterocycle” include oxiranyl, epoxypropyl, aziridyl, oxetanyl, azetidinyl, thietanyl , 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, oxepyl, thiepanyl, oxygen Azepine, diazepine, thiazepine, pyridyl, piperidyl, homopiperidyl, furyl, thienyl, pyryl, N-alkylpyrrolyl, pyrimidyl, pyrimidyl Azidinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, piperidinyl, morpholin
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated non-aromatic ring group, which may be 3 to 8 membered (eg 3, 4, 5, 6, 7 or 8 membered) monocyclic, 4 to 12 membered (e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12 members) bicyclic rings or 10 to 15 membered (e.g. 10, 11, 12, 13, 14, 15 members) tricyclic ring systems, and comprising 1, 2 or 3 heteroatoms selected from N, O or S, eg 3 to 8 membered heterocyclyl.
  • 3 to 8 membered eg 3, 4, 5, 6, 7 or 8 membered
  • 4 to 12 membered e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12 members
  • bicyclic rings e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12 members
  • 10 to 15 membered e.g. 10, 11, 12, 13, 14, 15 members
  • heterocycloalkyl can be oxidized into various oxidation states; “heterocycloalkyl” can be connected to a heteroatom or carbon atom; “heterocycloalkyl” can be a bridge ring or spiral.
  • heterocycloalkyl include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-di Oxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl , tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonyl, oxa Tricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl,
  • Carbocyclyl or “carbocycle” refers to a saturated or unsaturated aromatic or non-aromatic ring. When selected from an aromatic ring, its definition is the same as the definition of "aryl”above; when selected from a non-aromatic ring, it can be a 3-10-membered monocyclic ring, a 4-12-membered bicyclic ring, or a 10-15-membered tricyclic ring system , can be bridged or spiro, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1 -Cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cyclohepty
  • “Pharmaceutical composition” refers to a mixture of one or more compounds described in the present invention, their pharmaceutically acceptable salts or prodrugs and other active components, wherein “other active components” refers to pharmaceutically acceptable acceptable carrier, excipient and/or one or more other therapeutic agents.
  • Carrier refers to a material that does not produce significant irritation to an organism and that does not abrogate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of the compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders agents and disintegrants.
  • Stepoisomer refers to isomers produced by different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” means that the compound of the present invention maintains the biological effectiveness and characteristics of free acid or free base, and the free acid is mixed with a non-toxic inorganic base or Organic base, the salt obtained by reacting the free base with a non-toxic inorganic acid or organic acid.
  • Optional or “optionally” or “optional” or “optionally” means that the subsequently described event or circumstance may, but need not, occur, and that the description includes the circumstances in which the event or circumstance occurs and the circumstances in which it is not what happened.
  • heterocyclyl optionally substituted with an alkyl group means that the alkyl group may but need not be present, and the description includes cases where the heterocyclyl group is substituted with an alkyl group, and cases where the heterocyclyl group is not substituted with an alkyl group.
  • TBS tert-butyldimethylsilyl.
  • compound 2B was obtained as a white solid (100 mg, yield 74%).
  • compound 2 was obtained as a white solid (50 mg, yield 60%).
  • compound 3A was obtained as a colorless oil (464 mg, yield 64%).
  • compound 3B was obtained as a white solid (487 mg, yield 60%).
  • compound 3 was obtained as a white solid (211 mg, yield 53%).
  • compound 4A was obtained as a colorless oil (130 mg, yield 62%).
  • compound 4B was obtained as a white solid (159 mg, yield 72%).
  • compound 5B was obtained as a white solid (853 mg, yield 83%).
  • compound 6A was obtained as a colorless oil (622 mg, yield 63%).
  • compound 6B was obtained as a white solid (771 mg, yield 71%).
  • compound 7B was obtained as a light yellow solid (352 mg, yield 76%).
  • Blocking add Blocking buffer 100 ⁇ L/well, and block for 90 minutes.
  • Compound dilution Dilute the compound to 8 concentrations at a ratio of 1:3, and the initial concentration is 1000nM.
  • IC 50 refers to the compound concentration at which PARP enzyme activity is inhibited by 50%.
  • the compound was prepared into 10 mM stock solution with DMSO, and diluted with 1640 medium to 8 concentrations (1:5), the final concentrations were 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128 nM.
  • IC 50 refers to the compound concentration at which cell proliferation is inhibited by 50%.
  • A IC 50 ⁇ 50nM
  • B 50nM ⁇ IC 50 ⁇ 100nM.

Abstract

Provided are a pyrrolidone derivative or a stereoisomer thereof, and the use thereof in medicine.

Description

吡咯烷酮衍生物及其在医药上的应用Pyrrolidone derivatives and their application in medicine 技术领域technical field
本发明涉及一种吡咯烷酮衍生物或者其立体异构体及其在医药上的应用。The invention relates to a pyrrolidone derivative or its stereoisomer and its application in medicine.
背景技术Background technique
二磷酸腺苷核糖基化(ADP-ribosylation，ADP-核糖基化)是蛋白质转录后修饰过程，将单个或多个二磷酸腺苷核糖(ADP核糖)基团嵌入蛋白质的氨基酸残基上。ADP-核糖基化是可逆过程，涉及细胞信号转导、DNA损伤修复、转录、基因表达调控和细胞凋亡等生理调控。ADP-核糖来源于氧化还原辅因子：烟酰胺腺嘌呤二核苷酸(Nicotinamide adenine dinucleotide，NAD+)，介导ADP核糖嵌入修饰的酶为ADP-核糖基化酶。在该生理反应调节中，连接ADP-核糖分子和烟酰胺(nicotinamide)基团的NAD+的N-糖苷键发生裂解，随后其与靶蛋白相应氨基酸残基捕捉成键。ADP-核糖基酶可以进行两种类型的修饰：单-ADP核糖基化和聚-ADP核糖基化。当DNA损伤或细胞受到压力应激时，PARP会被激活，导致聚ADP-核糖量增加，而NAD+量减少。十多年来，人们一直认为PARP1是哺乳动物细胞中唯一的聚ADP-核糖聚合酶，因此对该酶的研究最多。迄今为止，科学家已经鉴定出17个不同的PARP。MonoPARP占据了PARP家族的大部分，并介导重要的生物学功能和各种应激反应，例如：未折叠的蛋白质反应、NF-κB信号传导、抗病毒反应和细胞因子信号传导。2,3,7,8-四氯二苯并-对二恶英(TCDD)诱导型聚(ADP-核糖)聚合酶(PARP-7)是MonoPARP家族成员之一，其表达受TCDD激活芳烃受体(AHR)的调节，AHR是一种配体激活的转录因子，可介导许多环境异源生物的毒性活性。AHR上调PARP-7的表达，PARP-7通过与激酶TBK1相互作用并使其ADP-核糖基化，导致TBK1活性受抑制、IFN-I(Ⅰ型干扰素)反应的下调，进而导致机体抗病毒和肿瘤免疫应答受到抑制。Adenosine diphosphate-ribosylation (ADP-ribosylation, ADP-ribosylation) is a protein post-transcriptional modification process, in which single or multiple adenosine diphosphate-ribose (ADP-ribose) groups are embedded in amino acid residues of proteins. ADP-ribosylation is a reversible process involved in physiological regulation of cell signal transduction, DNA damage repair, transcription, regulation of gene expression, and apoptosis. ADP-ribose is derived from a redox cofactor: Nicotinamide adenine dinucleotide (NAD+), and the enzyme that mediates the insertion modification of ADP-ribose is ADP-ribosylase. In this physiological response regulation, the N-glycosidic bond of NAD+ connecting the ADP-ribose molecule and the nicotinamide group is cleaved, and then it is captured and bonded with the corresponding amino acid residue of the target protein. ADP-ribosylases can perform two types of modifications: mono-ADP ribosylation and poly-ADP ribosylation. When DNA is damaged or cells are stressed, PARP is activated, resulting in an increase in the amount of poly ADP-ribose and a decrease in the amount of NAD+. For more than a decade, PARP1 was thought to be the only poly-ADP-ribose polymerase in mammalian cells and thus the most studied enzyme. To date, scientists have identified 17 different PARPs. MonoPARP occupies the majority of the PARP family and mediates important biological functions and various stress responses, such as: unfolded protein response, NF-κB signaling, antiviral response, and cytokine signaling. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP-ribose) polymerase (PARP-7) is a member of the MonoPARP family, and its expression is activated by TCDD. Regulation of AHR (AHR), a ligand-activated transcription factor that mediates the toxic activity of many environmental xenobiotics. AHR up-regulates the expression of PARP-7, and PARP-7 interacts with the kinase TBK1 and makes it ADP-ribosylated, leading to the inhibition of TBK1 activity and the down-regulation of IFN-I (type I interferon) response, which in turn leads to the body's antiviral and tumor immune responses are suppressed.
发明内容Contents of the invention
本发明的目的是提供一种选择性PARP7抑制剂或者其立体异构体、其药物组合物，以及其在医药上的应用。The object of the present invention is to provide a selective PARP7 inhibitor or its stereoisomer, its pharmaceutical composition, and its application in medicine.
本申请的一个或多个实施方式提供了通式(I)所示的化合物或者其立体异构体、药学上可接受的盐或氘代物：One or more embodiments of the present application provide a compound represented by general formula (I) or its stereoisomer, pharmaceutically acceptable salt or deuterated product:
Figure PCTCN2022110534-appb-000001
Figure PCTCN2022110534-appb-000001
其中：in:
A为
Figure PCTCN2022110534-appb-000002
R 14为OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、CN、C(＝O)R 14a、C(＝O)OR 14b、SR 14c或OR 14c，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、任选地被1至3个卤素取代； A is
Figure PCTCN2022110534-appb-000002
R 14 is OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, CN, C(=O)R 14a , C(=O ) OR 14b , SR 14c or OR 14c , the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, optionally replaced by 1 to 3 halogen replace;
X 1、X 2和L 2各自独立地选自O、S、C 1-6亚烷基、3至10元杂环烷基的单环或多环、-NR x1-、-C(＝O)-、-C(＝O)O-、-C(＝O)NR x1-、-S(＝O)-、-S(＝O) 2-、-S(＝O)NR x1-、-S(＝O) 2NR x1-、-NR x1C(＝O)NR x1-或键，所述C 1-6亚烷基、3至10元杂环烷基的单环或多环进一步被1或多个选自以下的取代基取代：H、OH、 卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR x2、SR x2、C(＝O)R x3、C(＝O)NR x4R x5、C(＝O)OR x2、OC(＝O)R x3、OC(＝O)NR x4R x5、NR x4R x5、NR x4C(＝O)R x3、NR x4OC(＝O)R x3、NR x4C(＝O)NR x4R x5、C(＝NR x6)R x3、C(＝NR x6)NR x4R x5、NR x4C(＝NR x6)NR x4R x5、NR x4S(＝O)R x2、NR x4S(＝O) 2R x2、NR x4S(＝O) 2NR x4R x5、S(＝O)R x2、S(＝O)NR x4R x5、S(＝O) 2NR x4R x5、P(＝O)(R x4) 2或P(＝O) 2；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR x2、SR x2、C(＝O)R x3、C(＝O)NR x4R x5、C(＝O)OR x2、OC(＝O)R x3、OC(＝O)NR x4R x5、NR x4R x5、NR x4C(＝O)R x3、NR x4OC(＝O)R x3、NR x4C(＝O)NR x4R x5、C(＝NR x6)R x3、C(＝NR x6)NR x4R x5、NR x4C(＝NR x6)NR x4R x5、NR x4S(＝O)R x2、NR x4S(＝O) 2R x2、NR x4S(＝O) 2NR x4R x5、S(＝O)R x2、S(＝O)NR x4R x5或S(＝O) 2NR x4R x5；所述3至10元杂环烷基的单环或多环、5至12元杂芳基、3至10元杂环烷基包含1、2、3或4个独立地选自O、N和S的杂原子； X 1 , X 2 and L 2 are each independently selected from O, S, C 1-6 alkylene, monocyclic or polycyclic rings of 3 to 10 membered heterocycloalkyl, -NR x1 -, -C(=O )-, -C(=O)O-, -C(=O)NR x1 -, -S(=O)-, -S(=O) 2 -, -S(=O)NR x1 -, - S(=O) 2 NR x1 -, -NR x1 C(=O)NR x1 - or a bond, the C 1-6 alkylene, 3- to 10-membered heterocycloalkyl monocyclic or polycyclic ring is further 1 or more substituents selected from the following substituents: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C6-12 Aryl, 5- to 12-membered heteroaryl, 3- to 10-membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR x2 , SR x2 , C(=O)R x3 , C(=O)NR x4 R x5 , C(=O)OR x2 , OC(=O)R x3 , OC(=O)NR x4 R x5 , NR x4 R x5 , NR x4 C(=O)R x3 , NR x4 OC(=O)R x3 , NR x4 C(=O)NR x4 R x5 , C(=NR x6 )R x3 , C(=NR x6 )NR x4 R x5 , NR x4 C(=NR x6 )NR x4 R x5 , NR x4 S(=O)R x2 , NR x4 S(=O) 2 R x2 , NR x4 S(=O) 2 NR x4 R x5 , S(=O)R x2 , S( =O)NR x4 R x5 , S(=O) 2 NR x4 R x5 , P(=O)(R x4 ) 2 or P(=O) 2 ; the C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally selected from 1 to more of the following Substituent substitution: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10-membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR x2 , SR x2 , C(=O)R x3 , C(=O)NR x4 R x5 , C(= O)OR x2 , OC(=O)R x3 , OC(=O)NR x4 R x5 , NR x4 R x5 , NR x4 C(=O)R x3 , NR x4 OC(=O)R x3 , NR x4 C(=O)NR x4 R x5 , C(=NR x6 )R x3 , C( =NR x6 )NR x4 R x5 , NR x4 C(=NR x6 )NR x4 R x5 , NR x4 S(=O)R x2 , NR x4 S(=O) 2 R x2 , NR x4 S(=O) 2 NR x4 R x5 , S(=O)R x2 , S(=O)NR x4 R x5 or S(=O) 2 NR x4 R x5 ; the monocyclic or polycyclic ring of the 3 to 10-membered heterocycloalkyl ring, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from O, N and S;
R 1、R 2、R 3、R 4、R 15各自独立地选自H、D、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元杂芳基、3至10元杂环烷基、CN、NH 2、NO 2、N 3、COOH、OR a2、SR a2、C(＝O)R a3、C(＝O)NR a4R a5、C(＝O)OR a2、OC(＝O)R a3、OC(＝O)NR a4R a5、NR a4R a5、NR a4C(＝O)R a3、NR a4OC(＝O)R a3、NR a4C(＝O)NR a4R a5、C(＝NR a6)R a3、C(＝NR a6)NR a4R a5、NR a4C(＝NR a6)NR a4R a5、NR a4S(＝O)R a2、NR a4S(＝O) 2R a2、NR a4S(＝O) 2NR a4R a5、S(＝O)R a2、S(＝O)NR a4R a5或S(＝O) 2NR a4R a5；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR a2、SR a2、C(＝O)R a3、C(＝O)NR a4R a5、C(＝O)OR a2、OC(＝O)R a3、OC(＝O)NR a4R a5、NR a4R a5、NR a4C(＝O)R a3、NR a4OC(＝O)R a3、NR a4C(＝O)NR a4R a5、C(＝NR a6)R a3、C(＝NR a6)NR a4R a5、NR a4C(＝NR a6)NR a4R a5、NR a4S(＝O)R a2、NR a4S(＝O) 2R a2、NR a4S(＝O) 2NR a4R a5、S(＝O)R a2、S(＝O)NR a4R a5或S(＝O) 2NR a4R a5；或R 1和R 2、R 3和R 4、R 1和R 3各自独立地连同其所连接的碳原子形成3至6元环烷基或5至10元杂环烷基，所述环烷基、杂环烷基任选地被1或多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR a2、SR a2、C(＝O)R a3、C(＝O)NR a4R a5、C(＝O)OR a2、OC(＝O)R a3、OC(＝O)NR a4R a5、NR a4R a5、NR a4C(＝O)R a3、NR a4OC(＝O)R a3、NR a4C(＝O)NR a4R a5、C(＝NR a6)R a3、C(＝NR a6)NR a4R a5、NR a4C(＝NR a6)NR a4R a5、NR a4S(＝O)R a2、NR a4S(＝O) 2R a2、NR a4S(＝O) 2NR a4R a5、S(＝O)R a2、S(＝O)NR a4R a5或S(＝O) 2NR a4R a5；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R 1 , R 2 , R 3 , R 4 , and R 15 are each independently selected from H, D, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -10 cycloalkyl, C6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, CN, NH 2 , NO 2 , N 3 , COOH, OR a2 , SR a2 , C( =O)R a3 , C(=O)NR a4 R a5 , C(=O)OR a2 , OC(=O)R a3 , OC(=O)NR a4 R a5 , NR a4 R a5 , NR a4 C (=O)R a3 , NR a4 OC(=O)R a3 , NR a4 C(=O)NR a4 R a5 , C(=NR a6 )R a3 , C(=NR a6 )NR a4 R a5 , NR a4 C(=NR a6 )NR a4 R a5 , NR a4 S(=O)R a2 , NR a4 S(=O) 2 R a2 , NR a4 S(=O) 2 NR a4 R a5 , S(=O )R a2 , S(=O)NR a4 R a5 or S(=O) 2 NR a4 R a5 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -10 cycloalkyl, C6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkane group, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR a2 , SR a2 , C(=O)R a3 , C(=O)NR a4 R a5 , C(=O)OR a2 , OC(=O)R a3 , OC(=O)NR a4 R a5 , NR a4 R a5 , NR a4 C(=O)R a3 , NR a4 OC(=O)R a3 , NR a4 C(=O) NR a4 R a5 , C(=NR a6 )R a3 , C(=NR a6 )NR a4 R a5 , NR a4 C(=NR a6 )NR a4 R a5 , NR a4 S (=O)R a2 , NR a4 S(=O) 2 R a2 , NR a4 S(=O) 2 NR a4 R a5 , S(=O)R a2 , S(=O)NR a4 R a5 or S(=O) 2 NR a4 R a5 or R 1 and R 2 , R 3 and R 4 , R 1 and R 3 each independently together with their The attached carbon atoms form a 3 to 6 membered cycloalkyl group or a 5 to 10 membered heterocycloalkyl group, which are optionally substituted by 1 or more substituents selected from the group consisting of: H , OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10-membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR a2 , SR a2 , C(=O)R a3 , C(=O)NR a4 R a5 , C( =O)OR a2 , OC(=O)R a3 , OC(=O)NR a4 R a5 , NR a4 R a5 , NR a4 C(=O)R a3 , NR a4 OC(=O)R a3 , NR a4 C(=O)NR a4 R a5 , C(=NR a6 )R a3 , C(=NR a6 )NR a4 R a5 , NR a4 C(=NR a6 )NR a4 R a5 , NR a4 S(=O )R a2 , NR a4 S(=O) 2 R a2 , NR a4 S(=O) 2 NR a4 R a5 , S(=O)R a2 , S(=O)NR a4 R a5 or S(=O ) 2 NR a4 R a5 ; the 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, S;
L 1为
Figure PCTCN2022110534-appb-000003
R 17为H、D或C 1-6烷基,所述C 1-6烷基任选地被1至3个卤素取代；L 2选自C 1-6亚烷基、3至10元杂环烷基的单环或多环、-C(＝O)-、-C(＝O)O-、-C(＝O)或键，所述C 1-6亚烷基、3至10元杂环烷基的单环或多环进一步被1或多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、 C 6-12芳基、C 3-10杂环烷基、5-12元杂芳基、4-10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR x2、SR x2、C(＝O)R x3、C(＝O)NR x4R x5、C(＝O)OR x2、OC(＝O)R x3、OC(＝O)NR x4R x5、NR x4R x5、NR x4C(＝O)R x3、NR x4OC(＝O)R x3、NR x4C(＝O)NR x4R x5、C(＝NR x6)R x3、C(＝NR x6)NR x4R x5、NR x4C(＝NR x6)NR x4R x5、NR x4S(＝O)R x2、NR x4S(＝O) 2R x2、NR x4S(＝O) 2NR x4R x5、S(＝O)R x2、S(＝O)NR x4R x5、S(＝O) 2NR x4R x5、P(＝O)(R x4) 2或P(＝O) 2；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、C 3-10杂环烷基、5-12元杂芳基、4-10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 3-10杂环烷基、5-12元杂芳基、4-10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR x2、SR x2、C(＝O)R x3、C(＝O)NR x4R x5、C(＝O)OR x2、OC(＝O)R x3、OC(＝O)NR x4R x5、NR x4R x5、NR x4C(＝O)R x3、NR x4OC(＝O)R x3、NR x4C(＝O)NR x4R x5、C(＝NR x6)R x3、C(＝NR x6)NR x4R x5、NR x4C(＝NR x6)NR x4R x5、NR x4S(＝O)R x2、NR x4S(＝O) 2R x2、NR x4S(＝O) 2NR x4R x5、S(＝O)R x2、S(＝O)NR x4R x5或S(＝O) 2NR x4R x5； L 1 is
Figure PCTCN2022110534-appb-000003
R 17 is H, D or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by 1 to 3 halogens; L 2 is selected from C 1-6 alkylene, 3 to 10 membered hetero Cycloalkyl monocyclic or polycyclic, -C(=O)-, -C(=O)O-, -C(=O) or bond, said C 1-6 alkylene, 3 to 10 membered The monocyclic or polycyclic ring of the heterocycloalkyl group is further substituted by 1 or more substituents selected from: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 cycloalkyl, C 6-12 aryl, C 3-10 heterocycloalkyl, 5-12 membered heteroaryl, 4-10 membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR x2 , SR x2 , C(=O)R x3 , C(=O)NR x4 R x5 , C(=O)OR x2 , OC(=O)R x3 , OC( =O)NR x4 R x5 , NR x4 R x5 , NR x4 C(=O)R x3 , NR x4 OC(=O)R x3 , NR x4 C(=O)NR x4 R x5 , C(=NR x6 )R x3 , C(=NR x6 )NR x4 R x5 , NR x4 C(=NR x6 )NR x4 R x5 , NR x4 S(=O)R x2 , NR x4 S(=O) 2 R x2 , NR x4 S(=O) 2 NR x4 R x5 , S(=O)R x2 , S(=O)NR x4 R x5 , S(=O) 2 NR x4 R x5 , P(=O)(R x4 ) 2 or P(=O) 2 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, C 3- 10 heterocycloalkyl, 5-12 membered heteroaryl, 4-10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, 5-12 membered heteroaryl, 4-10 membered heterocycloalkyl, =O , CN, NH 2 , NO 2 , N 3 , COOH, OR x2 , SR x2 , C(=O)R x3 , C(=O)NR x4 R x5 , C(=O)OR x2 , OC(=O )R x3 , OC(=O)NR x4 R x5 , NR x4 R x5 , NR x4 C(=O)R x3 , NR x4 OC(=O)R x3 , NR x4 C(=O)NR x4 R x5 , C(=NR x6 )R x3 , C(=NR x6 )NR x4 R x5 , NR x4 C(=N R x6 )NR x4 R x5 , NR x4 S(=O)R x2 , NR x4 S(=O) 2 R x2 , NR x4 S(=O) 2 NR x4 R x5 , S(=O)R x2 , S ( = O) NRx4Rx5 or S(=O) 2NRx4Rx5 ;
X 3为C或N； X3 is C or N;
R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、D、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、CN、NH 2、NO 2、N 3、COOH、OR b2、SR b2、C(＝O)R b3、C(＝O)NR b4R b5、C(＝O)OR b2、OC(＝O)R b3、OC(＝O)NR b4R b5、NR b4R b5、NR b4C(＝O)R b3、NR b4OC(＝O)R b3、NR b4C(＝O)NR b4R b5、C(＝NR b6)R b3、C(＝NR b6)NR b4R b5、NR b4C(＝NR b6)NR b4R b5、NR b4S(＝O)R b2、NR b4S(＝O) 2R b2、NR b4S(＝O) 2NR b4R b5、S(＝O)R b2、S(＝O)NR b4R b5或S(＝O) 2NR b4R b5；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR b2、SR b2、C(＝O)R b3、C(＝O)NR b4R b5、C(＝O)OR b2、OC(＝O)R b3、OC(＝O)NR b4R b5、NR b4R b5、NR b4C(＝O)R b3、NR b4OC(＝O)R b3、NR b4C(＝O)NR b4R b5、C(＝NR b6)R b3、C(＝NR b6)NR b4R b5、NR b4C(＝NR b6)NR b4R b5、NR b4S(＝O)R b2、NR b4S(＝O) 2R b2、NR b4S(＝O) 2NR b4R b5、S(＝O)R b2、S(＝O)NR b4R b5或S(＝O) 2NR b4R b5；或R 5和R 6、R 7和R 8、R 9和R 10、R 11和R 12各自独立地连同其所连接的碳原子形成＝O；或R 5和R 7、R 5和R 9、R 5和R 11、R 7和R 9、R 7和R 11、R 9和R 11相连；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, D, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, CN, NH 2 , NO 2 , N 3 , COOH, OR b2 , SR b2 , C(=O)R b3 , C(=O)NR b4 R b5 , C(=O)OR b2 , OC(=O)R b3 , OC(=O)NR b4 R b5 , NR b4 R b5 , NR b4 C(=O)R b3 , NR b4 OC(=O)R b3 , NR b4 C(=O)NR b4 R b5 , C(=NR b6 )R b3 , C( =NR b6 )NR b4 R b5 , NR b4 C(=NR b6 )NR b4 R b5 , NR b4 S(=O)R b2 , NR b4 S(=O) 2 R b2 , NR b4 S(=O) 2 NR b4 R b5 , S(=O)R b2 , S(=O)NR b4 R b5 or S(=O) 2 NR b4 R b5 ; the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally selected from 1 to more of the following Substituent substitution: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 members Heteroaryl, 3- to 10-membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR b2 , SR b2 , C(=O)R b3 , C(=O)NR b4 R b5 , C(=O)OR b2 , OC(=O)R b3 , OC(=O)NR b4 R b5 , NR b4 R b5 , NR b4 C(=O)R b3 , NR b4 OC(=O )R b3 , NR b4 C(=O)NR b4 R b5 , C(=NR b6 )R b3 , C(=NR b6 )NR b4 R b5 , NR b4 C(=NR b6 )NR b4 R b5 , NR b4 S(=O)R b2 , NR b4 S(=O) 2 R b2 , NR b4 S(=O) 2 NR b4 R b5 , S(=O)R b2 , S(=O)NR b4 R b5 or S(=O) 2 NR b4 R b5 ; or R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 each independently form =O together with the carbon atom to which they are attached; or R 5 and R 7 , R 5 and R 9 , R 5 and R 11 , R 7 and R 9 , R 7 and R 11 , R 9 and R 11 are connected; the 5-12 membered heteroaryl, 3-10 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, S;
B为3至10元的环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基，所述杂环、杂芳环包含至少1至3个选自N、O和S的杂原子；B is a cycloalkyl group with 3 to 10 members, a heterocycloalkyl group with 3 to 10 members, an aryl group with 6 to 12 members, and a heteroaryl group with 5 to 12 members, and the heterocycle and heteroaryl ring contain at least 1 to 3 a heteroatom selected from N, O and S;
R 13为C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基、CN或CF 3，所述C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基进一步被1或多个选自以下的取代基取代：H、D、卤素、CN、OH、NO 2、OR g2、SR g2、C(＝O)R g3、C(＝O)NR g4R g5、C(＝O)OR g2、OC(＝O)R g3、OC(＝O)NR g4R g5、NR g4R g5、NR g4C(＝O)R g3、NR g4OC(＝O)R g3、NR g4C(＝O)NR g4R g5、C(＝NR g6)R g3、C(＝NR g6)NR g4R g5、NR g4C(＝NR g6)NR g4R g5、NR g4S(＝O)R g2、NR g4S(＝O) 2R g2、NR g4S(＝O) 2NR g4R g5、S(＝O)R g2、S(＝O)NR g4R g5或S(＝O) 2NR g4R g5；所述3至10元的杂环烷基、5至12元杂芳基包含1至3个选自N、O、S的杂原子； R 13 is C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN or CF 3 , the C 3-10 cycloalkane radical, 3 to 10 membered heterocycloalkyl, 6 to 12 membered aryl, 5 to 12 membered heteroaryl are further substituted by 1 or more substituents selected from the group consisting of: H, D, halogen, CN, OH , NO 2 , OR g2 , SR g2 , C(=O)R g3 , C(=O)NR g4 R g5 , C(=O)OR g2 , OC(=O)R g3 , OC(=O)NR g4 R g5 , NR g4 R g5 , NR g4 C(=O)R g3 , NR g4 OC(=O)R g3 , NR g4 C(=O)NR g4 R g5 , C(=NR g6 )R g3 , C(=NR g6 )NR g4 R g5 , NR g4 C(=NR g6 )NR g4 R g5 , NR g4 S(=O)R g2 , NR g4 S(=O) 2 R g2 , NR g4 S(= O) 2 NR g4 R g5 , S(=O)R g2 , S(=O)NR g4 R g5 or S(=O) 2 NR g4 R g5 ; the 3 to 10-membered heterocycloalkyl, 5 to 12 membered heteroaryls containing 1 to 3 heteroatoms selected from N, O, S;
条件是：当R 13为CN或CF 3时，R 3和R 4为D； The condition is: when R 13 is CN or CF 3 , R 3 and R 4 are D;
R 14a选自H、OH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元杂芳基、3至10元杂环烷基、OR c2、SR c2、C(＝O)R c3、C(＝O)NR c4R c5、C(＝O)OR c2、OC(＝O)R c3、OC(＝O)NR c4R c5、NR c4R c5、NR c4C(＝O)R c3、 NR c4OC(＝O)R c3、NR c4C(＝O)NR c4R c5、C(＝NR c6)R c3、C(＝NR c6)NR c4R c5、NR c4C(＝NR c6)NR c4R c5、NR c4S(＝O)R c2、NR c4S(＝O) 2R c2、NR c4S(＝O) 2NR c4R c5、S(＝O)R c2、S(＝O)NR c4R c5或S(＝O) 2NR c4R c5；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR c2、SR c2、C(＝O)R c3、C(＝O)NR c4R c5、C(＝O)OR c2、OC(＝O)R c3、OC(＝O)NR c4R c5、NR c4R c5、NR c4C(＝O)R c3、NR c4OC(＝O)R c3、NR c4C(＝O)NR c4R c5、C(＝NR c6)R c3、C(＝NR c6)NR c4R c5、NR c4C(＝NR c6)NR c4R c5、NR c4S(＝O)R c2、NR c4S(＝O) 2R c2、NR c4S(＝O) 2NR c4R c5、S(＝O)R c2、S(＝O)NR c4R c5、S(＝O) 2NR c4R c5、P(＝O)(R c4) 2或P(＝O) 2；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R 14a is selected from H, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl , 3- to 10-membered heterocycloalkyl, OR c2 , SR c2 , C(=O)R c3 , C(=O)NR c4 R c5 , C(=O)OR c2 , OC(=O)R c3 , OC(=O)NR c4 R c5 , NR c4 R c5 , NR c4 C(=O)R c3 , NR c4 OC(=O)R c3 , NR c4 C(=O)NR c4 R c5 , C(= NR c6 )R c3 , C(=NR c6 )NR c4 R c5 , NR c4 C(=NR c6 )NR c4 R c5 , NR c4 S(=O)R c2 , NR c4 S(=O) 2 R c2 , NR c4 S(=O) 2 NR c4 R c5 , S(=O)R c2 , S(=O)NR c4 R c5 or S(=O) 2 NR c4 R c5 ; the C 1-6 alkane C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl optionally Substituted by 1 to more substituents selected from H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 5 to 12 Membered heteroaryl, 3- to 10-membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR c2 , SR c2 , C(=O)R c3 , C(=O)NR c4 R c5 , C(=O)OR c2 , OC(=O)R c3 , OC(=O)NR c4 R c5 , NR c4 R c5 , NR c4 C(=O)R c3 , NR c4 OC(= O)R c3 , NR c4 C(=O)NR c4 R c5 , C(=NR c6 )R c3 , C(=NR c6 )NR c4 R c5 , NR c4 C(=NR c6 )NR c4 R c5 , NR c4 S(=O)R c2 , NR c4 S(=O) 2 R c2 , NR c4 S(=O) 2 NR c4 R c5 , S(=O)R c2 , S(=O)NR c4 R c5 , S(=O) 2 NR c4 R c5 , P(=O)(R c4 ) 2 or P(=O) 2 ; the 5 to 12-membered heteroaryl, 3 to 10-membered heterocycloalkyl comprises 1 to 3 heteroatoms selected from N, O, S;
R 14b、R 14c、R 16各自独立地H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6- 12芳基、5至12元杂芳基、3至10元杂环烷基、COOH、OR d2、SR d2、C(＝O)R d3、C(＝O)NR d4R d5、C(＝O)OR d2、C(＝NR d6)R d3或C(＝NR d6)NR d4R d5；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR d2、SR d2、C(＝O)R d3、C(＝O)NR d4R d5、C(＝O)OR d2、OC(＝O)R d3、OC(＝O)NR d4R d5、NR d4R d5、NR d4C(＝O)R d3、NR d4OC(＝O)R d3、NR d4C(＝O)NR d4R d5、C(＝NR d6)R d3、C(＝NR d6)NR d4R d5、NR d4C(＝NR d6)NR d4R d5、NR d4S(＝O)R d2、NR d4S(＝O) 2R d2、NR d4S(＝O) 2NR d4R d5、S(＝O)R d2、S(＝O)NR d4R d5或S(＝O) 2NR d4R d5；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R 14b , R 14c , and R 16 are each independently H, C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12-membered heteroaryl, 3 to 10-membered heterocycloalkyl, COOH, OR d2 , SR d2 , C(=O)R d3 , C(=O)NR d4 R d5 , C(=O)OR d2 , C(=NR d6 )R d3 or C(=NR d6 )NR d4 R d5 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl , C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl optionally substituted by 1 to more substituents selected from the group consisting of H, OH, halogen, C 1-6 alkane radical, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR d2 , SR d2 , C(=O)R d3 , C(=O)NR d4 R d5 , C(=O)OR d2 , OC(=O)R d3 , OC(= O)NR d4 R d5 , NR d4 R d5 , NR d4 C(=O)R d3 , NR d4 OC(=O)R d3 , NR d4 C(=O)NR d4 R d5 , C(=NR d6 ) R d3 , C(=NR d6 )NR d4 R d5 , NR d4 C(=NR d6 )NR d4 R d5 , NR d4 S(=O)R d2 , NR d4 S(=O) 2 R d2 , NR d4 S(=O) 2 NR d4 R d5 , S(=O)R d2 , S(=O)NR d4 R d5 or S(=O) 2 NR d4 R d5 ; the 5 to 12-membered heteroaryl, The 3 to 10 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, S;
R a1、R a2、R a3、R a4、R a5、R a6、R b1、R b2、R b3、R b4、R b5、R b6、R c1、R c2、R c3、R c4、R c5、R c6、R d1、R d2、R d3、R d4、R d5、R d6、R x1、R x2、R x3、R x4、R x5或R x6、各自独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元杂芳基、3至10元杂环烷基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR e2、SR e2、C(＝O)R e3、C(＝O)NR e4R e5、C(＝O)OR e2、OC(＝O)R e3、OC(＝O)NR e4R e5、NR e4R e5、NR e4C(＝O)R e3、NR e4OC(＝O)R e3、NR e4C(＝O)NR e4R e5、C(＝NR e6)R e3、C(＝NR e6)NR e4R e5、NR e4C(＝NR e6)NR e4R e5、NR e4S(＝O)R e2、NR e4S(＝O) 2R e2、NR e4S(＝O) 2NR e4Re 5、S(＝O)R e2、S(＝O)NR e4R e5或S(＝O) 2NR e4R e5；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R x1 , R x2 , R x3 , R x4 , R x5 or R x6 , each independently selected from H, C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, all C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heteroaryl Cycloalkyl is optionally substituted with 1 to more substituents selected from the group consisting of H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cyclo Alkyl, 5- to 12-membered heteroaryl, 3- to 10-membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR e2 , SR e2 , C(=O)R e3 , C(=O)NR e4 R e5 , C(=O)OR e2 , OC(=O)R e3 , OC(=O)NR e4 R e5 , NR e4 R e5 , NR e4 C(=O)R e3 , NR e4 OC(=O)R e3 , NR e4 C(=O)NR e4 R e5 , C(=NR e6 )R e3 , C(=NR e6 )NR e4 R e5 , NR e4 C(=NR e6 )NR e4 R e5 , NR e4 S(=O)R e2 , NR e4 S(=O) 2 R e2 , NR e4 S(=O) 2 NR e4 Re 5 , S(=O)R e2 , S( =O) NR e4 R e5 or S(=O) 2 NR e4 R e5 ; the 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl contains 1 to 3 selected from N, O, S heteroatom;
R a4和R a5、R b4和R b5、R c4和R c5、R d4和R d5、R x4和R x5各自独立地连同其所连接的N原子形成4至7元杂环，所述杂环进一步被1或多个选自以下的取代基取代：卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、CN、OR f2、SR f2、C(＝O)R f3、C(＝O)NR f4R f5、C(＝O)OR f2、OC(＝O)R f3、OC(＝O)NR f4R f5、NR f4R f5、NR f4C(＝O)R f3、NR f4OC(＝O)R f3、NR f4C(＝O)NR f4R f5、C(＝NR f6)R f3、C(＝NR f6)NR f4R f5、NR f4C(＝NR f6)NR f4R f5、NR f4S(＝O)R f2、NR f4S(＝O) 2R f2、NR f4S(＝O) 2NR f4R f5、S(＝O)R f2、S(＝O)NR f4R f5或S(＝O) 2NR f4R f5；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R a4 and R a5 , R b4 and R b5 , R c4 and R c5 , R d4 and R d5 , R x4 and R x5 each independently form a 4- to 7-membered heterocycle together with the N atom to which they are attached, and the heterocycle The ring is further substituted by 1 or more substituents selected from the group consisting of halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, OR f2 , SR f2 , C(=O )R f3 , C(=O)NR f4 R f5 , C(=O)OR f2 , OC(=O)R f3 , OC(=O)NR f4 R f5 , NR f4 R f5 , NR f4 C(= O)R f3 , NR f4 OC(=O)R f3 , NR f4 C(=O)NR f4 R f5 , C(=NR f6 )R f3 , C(=NR f6 )NR f4 R f5 , NR f4 C (=NR f6 )NR f4 R f5 , NR f4 S(=O)R f2 , NR f4 S(=O) 2 R f2 , NR f4 S(=O) 2 NR f4 R f5 , S(=O)R f2 , S(=O)NR f4 R f5 or S(=O) 2 NR f4 R f5 ; the 5 to 12-membered heteroaryl, 3 to 10-membered heterocycloalkyl contains 1 to 3 members selected from N, Heteroatoms of O and S;
R f1、R f2、R f3、R f4、R f5、R f6、R e1、R e2、R e3、R e4、R e5、R e6、R g1、R g2、R g3、R g4、R g5、R g6各自独立地选自C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3- 10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R f1 , R f2 , R f3 , R f4 , R f5 , R f6 , Re1 , Re2 , Re3 , Re4 , Re5 , Re6 , R g1 , R g2 , R g3 , R g4 , R g5 , R g6 are each independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl group, 3 to 10 membered heterocycloalkyl group, the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-10 cycloalkyl group, C 6-12 aryl group, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 5-12 membered heteroaryl, 3-10 membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH; the 5-12 membered heteroaryl, 3-10 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, S;
m为0、1、2或者3；m is 0, 1, 2 or 3;
n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
o为0或者1；o is 0 or 1;
p为1、2或者3。p is 1, 2 or 3.
本申请的一个或多个实施方式提供了通式(I)所示的化合物或者其立体异构体、药学上可接受的盐或氘代物，其中：One or more embodiments of the present application provide a compound represented by general formula (I) or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein:
A为
Figure PCTCN2022110534-appb-000004
R 14为C 1-6烷基、C 3-5环烷基、C 2-6烯基、卤素、CN或C(＝O)R 14a，所述C 1-6烷基、C 3-5环烷基、C 2-6烯基任选地被1至3个卤素取代； A is
Figure PCTCN2022110534-appb-000004
R 14 is C 1-6 alkyl, C 3-5 cycloalkyl, C 2-6 alkenyl, halogen, CN or C(=O)R 14a , the C 1-6 alkyl, C 3-5 Cycloalkyl, C 2-6 alkenyl are optionally substituted by 1 to 3 halogens;
R 14a为OH、C 1-6烷基、C 3-5环烷基，所述C 1-6烷基、C 3-5环烷基任选地被1至3个卤素取代； R 14a is OH, C 1-6 alkyl, C 3-5 cycloalkyl, said C 1-6 alkyl, C 3-5 cycloalkyl are optionally substituted by 1 to 3 halogens;
X 1为NR x1、O、S、3至10元杂环烷基的单环或多环,所述杂环烷基进一步被1或多个选自以下的取代基取代：H、卤素、CN、OH、C 1-6烷基、C 1-6烷氧基、C 6-10芳基、C 3-7环烷基、5至10元杂芳基或3至10元杂环烷基，所述C 1-6烷基、C 1-6烷氧基、C 6-10芳基、C 3-7环烷基、5至10元杂芳基、3至10元杂环烷基各自独立地被1或多个选自以下的取代基取代：H、卤素、CN或OH，所述杂芳基或杂环烷基包含1、2、3或4个独立地选自O、N和S的杂原子； X 1 is NR x1 , O, S, a monocyclic or polycyclic ring of 3 to 10 membered heterocycloalkyl, and the heterocycloalkyl is further substituted by 1 or more substituents selected from the group consisting of H, halogen, CN , OH, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 3-7 cycloalkyl, 5 to 10 membered heteroaryl or 3 to 10 membered heterocycloalkyl, The C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 3-7 cycloalkyl, 5 to 10 membered heteroaryl, 3 to 10 membered heterocycloalkyl are each independently is substituted by 1 or more substituents selected from H, halogen, CN or OH, and the heteroaryl or heterocycloalkyl contains 1, 2, 3 or 4 substituents independently selected from O, N and S heteroatoms;
X 2为NR x1、O、S、-C(＝O)-、-C(＝O)O-、-C(＝O)NR x1-、-S(＝O)-、-S(＝O) 2-、-S(＝O)NR x1-、-S(＝O) 2NR x1-、-NR x1C(＝O)NR x1-或键； X 2 is NR x1 , O, S, -C(=O)-, -C(=O)O-, -C(=O)NR x1 -, -S(=O)-, -S(=O ) 2 -, -S(=O)NR x1 -, -S(=O) 2 NR x1 -, -NR x1 C(=O)NR x1 - or a bond;
R 1、R 2、R 3、R 4各自独立地选自H、D、卤素、NR a4R a5、OH、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、5至10元杂芳基或3至10元杂环烷基，所述C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、5至10元杂芳基、3至10元杂环烷基各自独立地被1或多个选自以下的取代基取代：H、卤素、OH、NR a4R a5、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、5至10元杂芳基、3至10元杂环烷基；或R 1和R 2、R 3和R 4、R 1和R 3各自独立地连同其所连接的碳原子形成3至6元环烷基或5至10元杂环烷基，所述环烷基、杂环烷基任选地被1或多个选自以下的取代基取代：H、卤素、OH、NR a4R a5、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、5至10元杂芳基、3至10元杂环烷基；所述5至10元杂芳基、3至10元杂环烷基包含1至3个选自O、N和S的杂原子； R 1 , R 2 , R 3 , and R 4 are each independently selected from H, D, halogen, NR a4 R a5 , OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkane base, 5 to 10 membered heteroaryl or 3 to 10 membered heterocycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 5 to 10 membered heteroaryl group, 3- to 10-membered heterocycloalkyl group are each independently substituted by 1 or more substituents selected from the group consisting of: H, halogen, OH, NR a4 R a5 , C 1-6 alkyl, C 1-6 alkoxy group, C 3-7 cycloalkyl group, 5 to 10 membered heteroaryl group, 3 to 10 membered heterocycloalkyl group; or R 1 and R 2 , R 3 and R 4 , R 1 and R 3 each independently together with their The attached carbon atoms form a 3 to 6 membered cycloalkyl group or a 5 to 10 membered heterocycloalkyl group, which are optionally substituted by 1 or more substituents selected from the group consisting of: H , halogen, OH, NR a4 R a5 , C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 5 to 10 membered heteroaryl, 3 to 10 membered heterocycloalkyl; The 5- to 10-membered heteroaryl group and the 3- to 10-membered heterocycloalkyl group contain 1 to 3 heteroatoms selected from O, N and S;
R a4、R a5各自独立的地为H或C 1-6烷基，或者R a4和R a5各自独立地连同其所连接的原子形成5至6元杂环烷基；所述5至6元杂环烷基包含1至3个选自O、N和S的杂原子； R a4 and R a5 are each independently H or C 1-6 alkyl, or each of R a4 and R a5 independently form a 5 to 6-membered heterocycloalkyl together with the atoms they are connected to; the 5 to 6-membered Heterocycloalkyl comprises 1 to 3 heteroatoms selected from O, N and S;
L 1为
Figure PCTCN2022110534-appb-000005
R 17为H、D或C 1-6烷基,所述C 1-6烷基任选地被1至3个卤素取代； L 1 is
Figure PCTCN2022110534-appb-000005
R 17 is H, D or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
L 2选自C 1-6亚烷基、3至10元杂环烷基的单环或多环、-C(＝O)-、-C(＝O)O-、-C(＝O)NR x1-或键，所述C 1-6亚烷基、3至10元杂环烷基的单环或多环进一步被1或多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷 基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH；所述3至10元杂环烷基的单环或多环、5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； L2 is selected from C 1-6 alkylene, 3 to 10 membered heterocycloalkyl rings or polycyclic rings, -C(=O)-, -C(=O)O-, -C(=O) NR x1 - or a bond, the C 1-6 alkylene, 3 to 10 membered heterocycloalkyl ring or polycyclic ring is further substituted by 1 or more substituents selected from the following: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycle Alkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH; monocyclic or polycyclic, 5 to 12 membered heteroaryl, 3 to 10 membered heterocyclic The alkyl group contains 1 to 3 heteroatoms selected from N, O, S;
X 3为C或N； X3 is C or N;
R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、D、卤素、OH、C(＝O)NH 2、C 1-6烷基，所述C 1-6烷基任选地被1至3个卤素取代；或R 5和R 6、R 7和R 8、R 9和R 10、R 11和R 12各自独立地连同其所连接的碳原子形成3至6元环烷基；或R 5和R 6、R 7和R 8、R 9和R 10、R 11和R 12各自独立地连同其所连接的碳原子形成＝O；或R 5和R 7、R 5和R 9、R 5和R 11、R 7和R 9、R 7和R 11、R 9和R 11相连； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, D, halogen, OH, C(=O)NH 2 , C 1-6 alkyl , the C 1-6 alkyl group is optionally substituted by 1 to 3 halogens; or R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 are each independently together with their The attached carbon atoms form a 3 to 6-membered cycloalkyl group; or R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 each independently together with the carbon atoms to which they are attached form =O ; or R 5 and R 7 , R 5 and R 9 , R 5 and R 11 , R 7 and R 9 , R 7 and R 11 , R 9 and R 11 are connected;
B为3至10元的环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基，所述杂环、杂芳环包含至少1至3个选自N、O和S的杂原子；B is a cycloalkyl group with 3 to 10 members, a heterocycloalkyl group with 3 to 10 members, an aryl group with 6 to 12 members, and a heteroaryl group with 5 to 12 members, and the heterocycle and heteroaryl ring contain at least 1 to 3 a heteroatom selected from N, O and S;
R 13为C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基、CN或CF 3，所述C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基进一步被1或多个选自以下的取代基取代：H、卤素、CN、OH、NH 2、C 1-6烷基、C 1-6卤代烷基或C 3-10环烷基；所述3至10元的杂环烷基、5至12元杂芳基包含1至3个选自N、O、S的杂原子； R 13 is C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN or CF 3 , the C 3-10 cycloalkane radical, 3 to 10 membered heterocycloalkyl, 6 to 12 membered aryl, 5 to 12 membered heteroaryl are further substituted by 1 or more substituents selected from the group consisting of: H, halogen, CN, OH, NH 2. C 1-6 alkyl, C 1-6 haloalkyl or C 3-10 cycloalkyl; the 3 to 10 membered heterocycloalkyl, 5 to 12 membered heteroaryl contains 1 to 3 members selected from N, O, S heteroatoms;
条件是：当R 13为CN或CF 3时，R 3和R 4为D； The condition is: when R 13 is CN or CF 3 , R 3 and R 4 are D;
R x1选自H、C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基，所述C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、CN、NH 2、NO 2、N 3、COOH；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R x1 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1- 6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H, OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, CN, NH 2 , NO 2 , N 3 , COOH ; The 5-12 membered heteroaryl, 3-10 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, S;
m为0、1、2或者3；m is 0, 1, 2 or 3;
n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
o为0或者1；o is 0 or 1;
p为1、2或者3。p is 1, 2 or 3.
本申请的一个或多个实施方式提供了通式(I-1)所示的化合物或者其立体异构体、药学上可接受的盐或氘代物：One or more embodiments of the present application provide a compound represented by general formula (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product:
Figure PCTCN2022110534-appb-000006
Figure PCTCN2022110534-appb-000006
其中：in:
A为
Figure PCTCN2022110534-appb-000007
R 14为C 1-6烷基、C 3-5环烷基、C 2-6烯基、卤素、CN或C(＝O)R 14a，所述C 1-6烷基、C 3-5环烷基、C 2-6烯基任选地被1至3个卤素取代； A is
Figure PCTCN2022110534-appb-000007
R 14 is C 1-6 alkyl, C 3-5 cycloalkyl, C 2-6 alkenyl, halogen, CN or C(=O)R 14a , the C 1-6 alkyl, C 3-5 Cycloalkyl, C 2-6 alkenyl are optionally substituted by 1 to 3 halogens;
R 14a为OH、C 1-6烷基、C 3-5环烷基，所述C 1-6烷基、C 3-5环烷基任选地被1至3个卤素取代； R 14a is OH, C 1-6 alkyl, C 3-5 cycloalkyl, said C 1-6 alkyl, C 3-5 cycloalkyl are optionally substituted by 1 to 3 halogens;
X 1为NR x1、O、S、
Figure PCTCN2022110534-appb-000008
或者
Figure PCTCN2022110534-appb-000009
X 1 is NR x1 , O, S,
Figure PCTCN2022110534-appb-000008
or
Figure PCTCN2022110534-appb-000009
X 2为NR x1、O、S、-C(＝O)-、-C(＝O)O-、-C(＝O)NR x1-、-S(＝O)-、-S(＝O) 2-、-S(＝O)NR x1-、-S(＝O) 2NR x1-、-NR x1C(＝O)NR x1-或键； X 2 is NR x1 , O, S, -C(=O)-, -C(=O)O-, -C(=O)NR x1 -, -S(=O)-, -S(=O ) 2 -, -S(=O)NR x1 -, -S(=O) 2 NR x1 -, -NR x1 C(=O)NR x1 - or a bond;
R 18、R 19、R 20、R 21、R 22和R 23各自独立地选自H、卤素、CN、OH、C 1-6烷基、C 1-6烷氧基、C 6-10芳基、C 3-7环烷基、5至10元杂芳基或3至10元杂环烷基，所述C 1- 6烷基、C 1-6烷氧基、C 6-10芳基、C 3-7环烷基、5至10元杂芳基、3至10元杂环烷基各自独立地被1或多个选自以下的取代基取代：H、卤素、CN、OH，所述5至10元杂芳基、3至10元杂环烷基包含1、2、3或4个独立地选自O、N和S的杂原子； R 18 , R 19 , R 20 , R 21 , R 22 and R 23 are each independently selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl C 3-7 cycloalkyl, 5 to 10 membered heteroaryl or 3 to 10 membered heterocycloalkyl , the C 1-6 alkyl, C 1-6 alkoxy , C 6-10 aryl , C 3-7 cycloalkyl, 5 to 10 membered heteroaryl, 3 to 10 membered heterocycloalkyl are each independently substituted by 1 or more substituents selected from the group consisting of: H, halogen, CN, OH, all The 5 to 10 membered heteroaryl, 3 to 10 membered heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms independently selected from O, N and S;
C为5至10元碳环、5至10元杂环、6至10元芳环或者5至10元芳杂环；所述5至10元杂环、5至10元芳杂环包含1至3个选自O、N和S的杂原子；C is 5 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10 membered aromatic ring or 5 to 10 membered aromatic heterocyclic ring; the 5 to 10 membered heterocyclic ring and 5 to 10 membered aromatic heterocyclic ring include 1 to 3 heteroatoms selected from O, N and S;
R 1、R 2、R 3、R 4各自独立地选自H、D、卤素、NR a4R a5、OH、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、5至10元杂芳基或3至10元杂环烷基，所述C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、5至10元杂芳基、3至10元杂环烷基各自独立地被1或多个选自以下的取代基取代：H、卤素、OH、NR a4R a5、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、5至10元杂芳基、3至10元杂环烷基；或R 1和R 2、R 3和R 4、R 1和R 3各自独立地连同其所连接的碳原子形成3至6元环烷基或5至10元杂环烷基，所述环烷基、杂环烷基任选地被1或多个选自以下的取代基取代：H、卤素、OH、NR a4R a5、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、5至10元杂芳基、3至10元杂环烷基；所述5至10元杂芳基、3至10元杂环烷基包含1至3个选自O、N和S的杂原子； R 1 , R 2 , R 3 , and R 4 are each independently selected from H, D, halogen, NR a4 R a5 , OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkane base, 5 to 10 membered heteroaryl or 3 to 10 membered heterocycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 5 to 10 membered heteroaryl group, 3- to 10-membered heterocycloalkyl group are each independently substituted by 1 or more substituents selected from the group consisting of: H, halogen, OH, NR a4 R a5 , C 1-6 alkyl, C 1-6 alkoxy group, C 3-7 cycloalkyl group, 5 to 10 membered heteroaryl group, 3 to 10 membered heterocycloalkyl group; or R 1 and R 2 , R 3 and R 4 , R 1 and R 3 each independently together with their The attached carbon atoms form a 3 to 6 membered cycloalkyl group or a 5 to 10 membered heterocycloalkyl group, which are optionally substituted by 1 or more substituents selected from the group consisting of: H , halogen, OH, NR a4 R a5 , C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 5 to 10 membered heteroaryl, 3 to 10 membered heterocycloalkyl; The 5- to 10-membered heteroaryl group and the 3- to 10-membered heterocycloalkyl group contain 1 to 3 heteroatoms selected from O, N and S;
R a4、R a5各自独立的地为H或C 1-6烷基，或者R a4和R a5各自独立地连同其所连接的原子形成5至6元杂环烷基；所述5至6元杂环烷基包含1至3个选自O、N和S的杂原子； R a4 and R a5 are each independently H or C 1-6 alkyl, or each of R a4 and R a5 independently form a 5 to 6-membered heterocycloalkyl together with the atoms they are connected to; the 5 to 6-membered Heterocycloalkyl comprises 1 to 3 heteroatoms selected from O, N and S;
L 1为
Figure PCTCN2022110534-appb-000010
R 17为H、D或C 1-6烷基，所述C 1-6烷基任选地被1至3个卤素取代； L 1 is
Figure PCTCN2022110534-appb-000010
R 17 is H, D or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
L 2选自C 1-6亚烷基、3至10元杂环烷基的单环或多环、--C(＝O)-、-C(＝O)O-、-C(＝O)NR x1-或键，所述C 1-6亚烷基、3至10元杂环烷基的单环或多环进一步被1或多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2；所述3至10元杂环烷基的单环或多环、5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； L2 is selected from C 1-6 alkylene, 3 to 10 membered heterocycloalkyl rings or polycyclic rings, --C(=O)-, -C(=O)O-, -C(=O ) NR x1 - or a bond, the C 1-6 alkylene, 3 to 10 membered heterocycloalkyl ring or polycyclic ring is further substituted by 1 or more substituents selected from the following: H, OH, halogen , C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, =O, CN, NH 2 ; 3 to 10 membered heterocycloalkyl monocyclic or polycyclic, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl contain 1 to 3 heteroatoms selected from N, O and S;
R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、D、卤素、C(＝O)NH 2、OH、C 1-6烷基，所述C 1-6烷基任选地被1至3个卤素取代；或R 5和R 6、R 7和R 8、R 9和R 10、R 11和R 12各自独立地连同其所连接的碳原子形成3至6元环烷基；或R 5和R 6、R 7和R 8、R 9和R 10、R 11和R 12各自独立地连同其所连接的碳原子形成＝O；或R 5和R 7、R 5和R 9、R 5和R 11、R 7和R 9、R 7和R 11、R 9和R 11相连； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, D, halogen, C(=O)NH 2 , OH, C 1-6 alkyl , the C 1-6 alkyl group is optionally substituted by 1 to 3 halogens; or R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 are each independently together with their The attached carbon atoms form a 3 to 6-membered cycloalkyl group; or R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 each independently together with the carbon atoms to which they are attached form =O ; or R 5 and R 7 , R 5 and R 9 , R 5 and R 11 , R 7 and R 9 , R 7 and R 11 , R 9 and R 11 are connected;
B为3至10元的环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基，所述杂环、杂芳环包含至少1至3个选自N、O和S的杂原子；B is a cycloalkyl group with 3 to 10 members, a heterocycloalkyl group with 3 to 10 members, an aryl group with 6 to 12 members, and a heteroaryl group with 5 to 12 members, and the heterocycle and heteroaryl ring contain at least 1 to 3 a heteroatom selected from N, O and S;
R 13为C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基、CN或CF 3，所述C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基进一步被1或多个选自以下的取代基取代：H、卤素、CN、OH、NH 2、C 1-6烷基、C 1-6卤代烷基或C 3-10环烷基；所述3至10元的杂环烷基、5至12元杂芳基包含1至3个选自N、O、S的杂原子；条件是：当R 13为CN或CF 3时，R 3和R 4为D； R 13 is C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN or CF 3 , the C 3-10 cycloalkane radical, 3 to 10 membered heterocycloalkyl, 6 to 12 membered aryl, 5 to 12 membered heteroaryl are further substituted by 1 or more substituents selected from the group consisting of: H, halogen, CN, OH, NH 2. C 1-6 alkyl, C 1-6 haloalkyl or C 3-10 cycloalkyl; the 3 to 10 membered heterocycloalkyl, 5 to 12 membered heteroaryl contains 1 to 3 members selected from Heteroatoms of N, O, S; condition is: when R 13 is CN or CF 3 , R 3 and R 4 are D;
R x1选自H、C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂 环烷基，所述C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、CN、NH 2；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R x1 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1- 6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H, OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, CN, NH 2 ; said 5 to 12 membered heteroaryl Aryl, 3 to 10 membered heterocycloalkyls contain 1 to 3 heteroatoms selected from N, O, S;
n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
o为0或者1；o is 0 or 1;
p为1、2或者3；p is 1, 2 or 3;
q为1、2或者3。q is 1, 2 or 3.
本申请的一个或多个实施方式提供了通式(I-1)所示的化合物或者其立体异构体、药学上可接受的盐或氘代物，其中：One or more embodiments of the present application provide a compound represented by general formula (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein:
A为
Figure PCTCN2022110534-appb-000011
R 14为C 1-6烷基、C 3-5环烷基或卤素，所述C 1-6烷基任选地被1至3个卤素取代； A is
Figure PCTCN2022110534-appb-000011
R 14 is C 1-6 alkyl, C 3-5 cycloalkyl or halogen, and the C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
X 1为NH、O、
Figure PCTCN2022110534-appb-000012
或者
Figure PCTCN2022110534-appb-000013
X 1 is NH, O,
Figure PCTCN2022110534-appb-000012
or
Figure PCTCN2022110534-appb-000013
X 2为NH、O、S、-C(＝O)-、-C(＝O)O-、-C(＝O)NH-、-S(＝O)-、-S(＝O) 2-、-S(＝O)NH-、-S(＝O) 2NH-、-NHC(＝O)NH-或键； X 2 is NH, O, S, -C(=O)-, -C(=O)O-, -C(=O)NH-, -S(=O)-, -S(=O) 2 -, -S(=O)NH-, -S(=O) 2NH- , -NHC(=O)NH- or a bond;
R 1、R 2、R 3、R 4各自独立地选自H、D、C 1-6烷基，R 1和R 2、R 3和R 4、R 1和R 3各自独立地连同其所连接的碳原子形成3至6元环烷基； R 1 , R 2 , R 3 , and R 4 are each independently selected from H, D, and C 1-6 alkyl groups, and R 1 and R 2 , R 3 and R 4 , R 1 and R 3 are each independently selected from the group consisting of The attached carbon atoms form a 3 to 6 membered cycloalkyl group;
L 1为
Figure PCTCN2022110534-appb-000014
L 1 is
Figure PCTCN2022110534-appb-000014
L 2选自C 1-6亚烷基、3至10元杂环烷基的单环或多环、-C(＝O)-、-C(＝O)O-、-C(＝O)NR x1-或键，所述C 1-6亚烷基、3至10元杂环烷基的单环或多环进一步被1或多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2；所述3至10元杂环烷基的单环或多环、5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； L2 is selected from C 1-6 alkylene, 3 to 10 membered heterocycloalkyl rings or polycyclic rings, -C(=O)-, -C(=O)O-, -C(=O) NR x1 - or a bond, the C 1-6 alkylene, 3 to 10 membered heterocycloalkyl ring or polycyclic ring is further substituted by 1 or more substituents selected from the following: H, OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, =O, CN, NH 2 ; the 3 Monocyclic or polycyclic, 5- to 12-membered heteroaryl, 3- to 10-membered heterocycloalkyl to 10-membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, and S;
R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、D、卤素、OH、C 1-6烷基，所述C 1-6烷基任选地被1至3个卤素取代；或R 5和R 6、R 9和R 10各自独立地连同其所连接的碳原子形成3至6元环烷基；或R 11和R 12与其所连接的碳原子形成＝O；或R 5和R 9、R 5和R 11、R 7和R 9、R 7和R 11相连； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, D, halogen, OH, C 1-6 alkyl, said C 1-6 alkane The group is optionally substituted by 1 to 3 halogens; or R 5 and R 6 , R 9 and R 10 each independently form a 3 to 6-membered cycloalkyl group together with the carbon atom to which they are attached; or R 11 and R 12 are combined with The attached carbon atoms form =O; or R 5 and R 9 , R 5 and R 11 , R 7 and R 9 , R 7 and R 11 are linked;
B为
Figure PCTCN2022110534-appb-000015
Figure PCTCN2022110534-appb-000016
Figure PCTCN2022110534-appb-000017
B for
Figure PCTCN2022110534-appb-000015
Figure PCTCN2022110534-appb-000016
Figure PCTCN2022110534-appb-000017
X 5、X 6、X 7各自独立的选自CH、CH 2、N、NH、O或S； X 5 , X 6 , and X 7 are each independently selected from CH, CH 2 , N, NH, O or S;
Figure PCTCN2022110534-appb-000018
为双键或单键；
Figure PCTCN2022110534-appb-000018
is a double bond or a single bond;
D选自5至10元碳环、5至10元杂环、6至10元芳环或者5至10元芳杂环；所述5至10元碳环、5至10元杂环、6至10元芳环、5至10元芳杂环进一步被1或多个选自以下的取代基取代：C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基；所述5至10元杂环、5至10元芳杂环、5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； D is selected from 5 to 10 membered carbocyclic rings, 5 to 10 membered heterocyclic rings, 6 to 10 membered aromatic rings or 5 to 10 membered aromatic heterocyclic rings; The 10-membered aromatic ring and the 5-10-membered aromatic heterocycle are further substituted by 1 or more substituents selected from the group consisting of: C 3-10 cycloalkyl, C 6-12 aryl, 5-12-membered heteroaryl, 3 to 10 membered heterocycloalkyl; the 5 to 10 membered heterocycle, 5 to 10 membered aromatic heterocycle, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl contain 1 to 3 members selected from N, Heteroatoms of O and S;
R 13为C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基、CN或CF 3，所述C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基进一步被1或多个选自以下的取代基取代：H、卤素、CN、OH、NH 2、C 1-6烷基、C 1-6卤代烷基或C 3-10环烷基；所述3至10元的杂环烷基、5至12元杂芳基包含1至3个选自N、O、S的杂原子；条件是：当R 13为CN或CF 3时，R 3和R 4为D。 R 13 is C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN or CF 3 , the C 3-10 cycloalkane radical, 3 to 10 membered heterocycloalkyl, 6 to 12 membered aryl, 5 to 12 membered heteroaryl are further substituted by 1 or more substituents selected from the group consisting of: H, halogen, CN, OH, NH 2. C 1-6 alkyl, C 1-6 haloalkyl or C 3-10 cycloalkyl; the 3 to 10 membered heterocycloalkyl, 5 to 12 membered heteroaryl contains 1 to 3 members selected from Heteroatoms of N, O, S; with the proviso that: when R 13 is CN or CF 3 , R 3 and R 4 are D.
R x1选自H、C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1- 6烷基、C 3-10环烷基、CN、NH 2；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R x1 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl is optionally substituted by 1 to more substituents selected from the group consisting of H, OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, CN, NH 2 ; the 5 to 12 membered heteroaryl, The 3 to 10 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, S;
n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
o为0或者1。o is 0 or 1.
本申请的一个或多个实施方式提供了通式(I-1)所示的化合物或者其立体异构体、药学上可接受的盐或氘代物，其中：One or more embodiments of the present application provide a compound represented by general formula (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein:
A为
Figure PCTCN2022110534-appb-000019
A is
Figure PCTCN2022110534-appb-000019
X 1为NH、
Figure PCTCN2022110534-appb-000020
或者
Figure PCTCN2022110534-appb-000021
 X1 is NH,
Figure PCTCN2022110534-appb-000020
or
Figure PCTCN2022110534-appb-000021
X 2为NH、O、S、-C(＝O)-、-C(＝O)O-、-C(＝O)NH-或键； X2 is NH, O, S, -C(=O)-, -C(=O)O-, -C(=O)NH- or a bond;
R 1、R 2、R 3、R 4各自独立地选自H、D、C 1-6烷基； R 1 , R 2 , R 3 , R 4 are each independently selected from H, D, C 1-6 alkyl;
L 1为
Figure PCTCN2022110534-appb-000022
L 1 is
Figure PCTCN2022110534-appb-000022
L 2选自C 1-6亚烷基、3至10元杂环烷基的单环或多环、-C(＝O)-、-C(＝O)O-、-C(＝O)NR x1-或键，所述C 1-6亚烷基、3至10元杂环烷基的单环或多环进一步被1或多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2；所述3至10元杂环烷基的单环或多环、5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； L2 is selected from C 1-6 alkylene, 3 to 10 membered heterocycloalkyl rings or polycyclic rings, -C(=O)-, -C(=O)O-, -C(=O) NR x1 - or a bond, the C 1-6 alkylene, 3 to 10 membered heterocycloalkyl ring or polycyclic ring is further substituted by 1 or more substituents selected from the following: H, OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, =O, CN, NH 2 ; the 3 Monocyclic or polycyclic, 5- to 12-membered heteroaryl, 3- to 10-membered heterocycloalkyl to 10-membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, and S;
R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、D、卤素、OH、C 1-6烷基，所述C 1-6烷基任选地被1至3个卤素取代；或R 5和R 6、R 9和R 10各自独立地连同其所连接的碳原子形成3至6元环烷基；或R 11和R 12与其所连接的碳原子形成＝O；或R 5和R 9、R 5和R 11、R 7和R 9、R 7和R 11相连； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, D, halogen, OH, C 1-6 alkyl, said C 1-6 alkane The group is optionally substituted by 1 to 3 halogens; or R 5 and R 6 , R 9 and R 10 each independently form a 3 to 6-membered cycloalkyl group together with the carbon atom to which they are attached; or R 11 and R 12 are combined with The attached carbon atoms form =O; or R 5 and R 9 , R 5 and R 11 , R 7 and R 9 , R 7 and R 11 are linked;
B为
Figure PCTCN2022110534-appb-000023
Figure PCTCN2022110534-appb-000024
B for
Figure PCTCN2022110534-appb-000023
Figure PCTCN2022110534-appb-000024
X 5、X 6各自独立的选自CH、CH 2、N、NH、O或S； X 5 and X 6 are each independently selected from CH, CH 2 , N, NH, O or S;
Figure PCTCN2022110534-appb-000025
为双键或单键；
Figure PCTCN2022110534-appb-000025
is a double bond or a single bond;
D选自5至10元碳环、5至10元杂环、6至10元芳环或者5至10元芳杂环；所述5至10元碳环、5至10元杂环、6至10元芳环、5至10元芳杂环进一步被1或多个选自以下的取代基取代：C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基；所述5至10元杂环、5至10元芳杂环、5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； D is selected from 5 to 10 membered carbocyclic rings, 5 to 10 membered heterocyclic rings, 6 to 10 membered aromatic rings or 5 to 10 membered aromatic heterocyclic rings; The 10-membered aromatic ring and the 5-10-membered aromatic heterocycle are further substituted by 1 or more substituents selected from the group consisting of: C 3-10 cycloalkyl, C 6-12 aryl, 5-12-membered heteroaryl, 3 to 10 membered heterocycloalkyl; the 5 to 10 membered heterocycle, 5 to 10 membered aromatic heterocycle, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl contain 1 to 3 members selected from N, Heteroatoms of O and S;
R 13为C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基、CN或CF 3，所述C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基进一步被1或多个选自以下的取代基取代：H、卤素、CN、OH、NH 2、C 1-6烷基、C 1-6卤代烷基或C 3-10环烷基；所述3至10元的杂环烷基、5至12元杂芳基包含1至3个选自N、O、S的杂原子； R 13 is C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN or CF 3 , the C 3-10 cycloalkane radical, 3 to 10 membered heterocycloalkyl, 6 to 12 membered aryl, 5 to 12 membered heteroaryl are further substituted by 1 or more substituents selected from the group consisting of: H, halogen, CN, OH, NH 2. C 1-6 alkyl, C 1-6 haloalkyl or C 3-10 cycloalkyl; the 3 to 10 membered heterocycloalkyl, 5 to 12 membered heteroaryl contains 1 to 3 members selected from N, O, S heteroatoms;
条件是：当R 13为CN或CF 3时，R 3和R 4为D。 Provided that: when R 13 is CN or CF 3 , R 3 and R 4 are D.
R x1选自H、C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基，所述C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 3-10环烷基、CN、NH 2；所述5至12元杂芳基、3至10元杂环烷基、包含1至3个选自N、O、S的杂原子； R x1 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1- 6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H, OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, CN, NH 2 ; the 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, contain 1 to 3 Heteroatoms selected from N, O, S;
n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
o为0或者1。o is 0 or 1.
本申请的一个或多个实施方式提供了通式(I-1)所示的化合物或者其立体异构体、药学上可接受的盐或氘代物，其中：One or more embodiments of the present application provide a compound represented by general formula (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein:
A为
Figure PCTCN2022110534-appb-000026
A is
Figure PCTCN2022110534-appb-000026
X 1为NH、
Figure PCTCN2022110534-appb-000027
或者
Figure PCTCN2022110534-appb-000028
 X1 is NH,
Figure PCTCN2022110534-appb-000027
or
Figure PCTCN2022110534-appb-000028
X 2为NH、O、S、-C(＝O)NH-或键； X 2 is NH, O, S, -C(=O)NH- or a bond;
R 1、R 2各自独立地选自H、D或者C 1-6烷基； R 1 and R 2 are each independently selected from H, D or C 1-6 alkyl;
R 3、R 4各自独立地选自H或者D； R 3 and R 4 are each independently selected from H or D;
L 1为
Figure PCTCN2022110534-appb-000029
L 1 is
Figure PCTCN2022110534-appb-000029
L 2选自C 1-6亚烷基、3至10元杂环烷基的单环或多环、-C(＝O)-、-C(＝O)O-、-C(＝O)NR x1-或键，所述C 1-6亚烷基、3至10元杂环烷基的单环或多环进一步被1或多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2；所述3至10元杂环烷基的单环或多环、5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； L2 is selected from C 1-6 alkylene, 3 to 10 membered heterocycloalkyl rings or polycyclic rings, -C(=O)-, -C(=O)O-, -C(=O) NR x1 - or a bond, the C 1-6 alkylene, 3 to 10 membered heterocycloalkyl ring or polycyclic ring is further substituted by 1 or more substituents selected from the following: H, OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, =O, CN, NH 2 ; the 3 Monocyclic or polycyclic, 5- to 12-membered heteroaryl, 3- to 10-membered heterocycloalkyl to 10-membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, and S;
R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、D、卤素、OH、C 1-6烷基； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, D, halogen, OH, C 1-6 alkyl;
B为
Figure PCTCN2022110534-appb-000030
Figure PCTCN2022110534-appb-000031
B for
Figure PCTCN2022110534-appb-000030
Figure PCTCN2022110534-appb-000031
R 13为C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基、CN或CF 3，所述C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基进一步被1或多个选自以下的取代基取代：H、卤素、CN、OH、NH 2、C 1-6烷基、C 1-6卤代烷基或C 3-10环烷基；所述3至10元的杂环烷基、5至12元杂芳基包含1 至3个选自N、O、S的杂原子； R 13 is C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN or CF 3 , the C 3-10 cycloalkane radical, 3 to 10 membered heterocycloalkyl, 6 to 12 membered aryl, 5 to 12 membered heteroaryl are further substituted by 1 or more substituents selected from the group consisting of: H, halogen, CN, OH, NH 2. C 1-6 alkyl, C 1-6 haloalkyl or C 3-10 cycloalkyl; the 3 to 10 membered heterocycloalkyl, 5 to 12 membered heteroaryl contains 1 to 3 members selected from N, O, S heteroatoms;
条件是：当R 13为CN或CF 3时，R 3和R 4为D。 Provided that: when R 13 is CN or CF 3 , R 3 and R 4 are D.
R x1选自H、C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基，所述C 1-6烷基C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 3-10环烷基、CN、NH 2所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R x1 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1- 6 alkyl C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H , OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, CN, NH 2 said 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl containing 1 to 3 members selected from N , O, S heteroatoms;
n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
o为0或者1。o is 0 or 1.
本申请的一个或多个实施方式提供了通式(I-1)所示的化合物或者其立体异构体、药学上可接受的盐或氘代物，其中：One or more embodiments of the present application provide a compound represented by general formula (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein:
A为
Figure PCTCN2022110534-appb-000032
A is
Figure PCTCN2022110534-appb-000032
X 1为NH、
Figure PCTCN2022110534-appb-000033
或者
Figure PCTCN2022110534-appb-000034
 X1 is NH,
Figure PCTCN2022110534-appb-000033
or
Figure PCTCN2022110534-appb-000034
R 1、R 2各自独立地选自H、D或者C 1-6烷基； R 1 and R 2 are each independently selected from H, D or C 1-6 alkyl;
R 3、R 4各自独立地选自H或者D； R 3 and R 4 are each independently selected from H or D;
X 2为NH、O、S、-C(＝O)NH-或键； X 2 is NH, O, S, -C(=O)NH- or a bond;
L 1为
Figure PCTCN2022110534-appb-000035
L 1 is
Figure PCTCN2022110534-appb-000035
R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、D、卤素、OH、C 1-6烷基； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, D, halogen, OH, C 1-6 alkyl;
B为
Figure PCTCN2022110534-appb-000036
Figure PCTCN2022110534-appb-000037
B for
Figure PCTCN2022110534-appb-000036
Figure PCTCN2022110534-appb-000037
R 13为C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基、CN或CF 3，所述C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基进一步被1或多个选自以下的取代基取代：H、卤素、CN、OH、NH 2、C 1-6烷基、C 1-6卤代烷基或C 3-10环烷基；所述3至10元的杂环烷基、5至12元杂芳基包含1至3个选自N、O、S的杂原子； R 13 is C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN or CF 3 , the C 3-10 cycloalkane radical, 3 to 10 membered heterocycloalkyl, 6 to 12 membered aryl, 5 to 12 membered heteroaryl are further substituted by 1 or more substituents selected from the group consisting of: H, halogen, CN, OH, NH 2. C 1-6 alkyl, C 1-6 haloalkyl or C 3-10 cycloalkyl; the 3 to 10 membered heterocycloalkyl, 5 to 12 membered heteroaryl contains 1 to 3 members selected from N, O, S heteroatoms;
条件是：当R 13为CN或CF 3时，R 3和R 4为D。 Provided that: when R 13 is CN or CF 3 , R 3 and R 4 are D.
L 2选自C 1-6亚烷基、3至10元杂环烷基的单环或多环、-C(＝O)-、-C(＝O)O-、-C(＝O)NR x1-或键；所述3至10元杂环烷基的单环或多环包含1至3个选自N、O、S 的杂原子； L 2 is selected from C 1-6 alkylene, 3 to 10 membered heterocycloalkyl rings or polycyclic rings, -C(=O)-, -C(=O)O-, -C(=O) NR x1 -or bond; The monocyclic or polycyclic ring of the 3 to 10 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, S;
R x1选自H、C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基，所述C 1-6烷基C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 3-10环烷基、CN、NH 2所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R x1 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1- 6 alkyl C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H , OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, CN, NH 2 said 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl containing 1 to 3 members selected from N , O, S heteroatoms;
n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
o为0或者1。o is 0 or 1.
本申请的一个或多个实施方式提供了通式(I-1)所示的化合物或者其立体异构体、药学上可接受的盐或氘代物，其中：One or more embodiments of the present application provide a compound represented by general formula (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein:
A为
Figure PCTCN2022110534-appb-000038
A is
Figure PCTCN2022110534-appb-000038
X 1为NH、
Figure PCTCN2022110534-appb-000039
或者
Figure PCTCN2022110534-appb-000040
 X1 is NH,
Figure PCTCN2022110534-appb-000039
or
Figure PCTCN2022110534-appb-000040
R 1、R 2各自独立地选自H、D或者C 1-6烷基； R 1 and R 2 are each independently selected from H, D or C 1-6 alkyl;
R 3、R 4各自独立地选自H或者D； R 3 and R 4 are each independently selected from H or D;
X 2为O； X2 is O;
L 1为
Figure PCTCN2022110534-appb-000041
L 1 is
Figure PCTCN2022110534-appb-000041
R 5、R 6各自独立地选自H、D或C 1-6烷基； R 5 and R 6 are each independently selected from H, D or C 1-6 alkyl;
R 7、R 8各自独立地选自H或D； R 7 and R 8 are each independently selected from H or D;
R 9、R 10各自独立地选自H、D、OH或C 1-6烷基； R 9 and R 10 are each independently selected from H, D, OH or C 1-6 alkyl;
R 11和R 12各自独立地选自H或D； R 11 and R 12 are each independently selected from H or D;
B为
Figure PCTCN2022110534-appb-000042
Figure PCTCN2022110534-appb-000043
B for
Figure PCTCN2022110534-appb-000042
Figure PCTCN2022110534-appb-000043
R 13为
Figure PCTCN2022110534-appb-000044
Figure PCTCN2022110534-appb-000045
Figure PCTCN2022110534-appb-000046
R 13 is
Figure PCTCN2022110534-appb-000044
Figure PCTCN2022110534-appb-000045
Figure PCTCN2022110534-appb-000046
R 13a、R 13b各自独立地选自H、卤素、CN、C 1-6烷基、C 1-6卤代烷基或NH 2； R 13a and R 13b are each independently selected from H, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl or NH 2 ;
L 2选自C 1-6亚烷基、3至10元杂环烷基的单环或多环、-C(＝O)-、-C(＝O)O-、-C(＝O)NR x1-或键；所述3至10元杂环烷基的单环或多环包含1至3个选自N、O、S的杂原子； L 2 is selected from C 1-6 alkylene, 3 to 10 membered heterocycloalkyl rings or polycyclic rings, -C(=O)-, -C(=O)O-, -C(=O) NR x1 -or a bond; the monocyclic or polycyclic ring of the 3 to 10 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, S;
R x1选自H、C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基，所述C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素CN、NH 2、或COOH；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R x1 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1- 6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H, OH, halogen CN, NH 2 , or COOH; the 5-12 membered heteroaryl, 3-10 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, S;
n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
o为0或者1。o is 0 or 1.
本申请的一个或多个实施方式提供了通式(I-1)所示的化合物或者其立体异构体、药学上可接受的盐或氘代物，其中：One or more embodiments of the present application provide a compound represented by general formula (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein:
A为
Figure PCTCN2022110534-appb-000047
A is
Figure PCTCN2022110534-appb-000047
X 1为NH、
Figure PCTCN2022110534-appb-000048
或者
Figure PCTCN2022110534-appb-000049
 X1 is NH,
Figure PCTCN2022110534-appb-000048
or
Figure PCTCN2022110534-appb-000049
R 1、R 2各自独立地选自H、D或者C 1-6烷基； R 1 and R 2 are each independently selected from H, D or C 1-6 alkyl;
R 3、R 4各自独立地选自H或者D； R 3 and R 4 are each independently selected from H or D;
X 2为O； X2 is O;
L 1为
Figure PCTCN2022110534-appb-000050
L 1 is
Figure PCTCN2022110534-appb-000050
R 5、R 6各自独立地选自H或D； R 5 and R 6 are each independently selected from H or D;
R 7、R 8各自独立地选自H或D； R 7 and R 8 are each independently selected from H or D;
R 9、R 10各自独立地选自H、D或OH； R 9 and R 10 are each independently selected from H, D or OH;
R 11和R 12各自独立地选自H或D； R 11 and R 12 are each independently selected from H or D;
B为
Figure PCTCN2022110534-appb-000051
或者
Figure PCTCN2022110534-appb-000052
B for
Figure PCTCN2022110534-appb-000051
or
Figure PCTCN2022110534-appb-000052
R 13为
Figure PCTCN2022110534-appb-000053
Figure PCTCN2022110534-appb-000054
Figure PCTCN2022110534-appb-000055
R 13 is
Figure PCTCN2022110534-appb-000053
Figure PCTCN2022110534-appb-000054
Figure PCTCN2022110534-appb-000055
R 13a、R 13b选自H、卤素、CF 3； R 13a and R 13b are selected from H, halogen, CF 3 ;
L 2选自-C(＝O)-、-C(＝O)O-、-C(＝O)NH-或键； L is selected from -C(=O)-, -C(=O)O-, -C(=O)NH- or a bond;
n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
o为0或者1。o is 0 or 1.
本申请的一个或多个实施方式提供了通式(I-1)所示的化合物或者其立体异构体、药学上可接受的盐或氘代物，其中：One or more embodiments of the present application provide a compound represented by general formula (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein:
A为
Figure PCTCN2022110534-appb-000056
A is
Figure PCTCN2022110534-appb-000056
X 1为NH、
Figure PCTCN2022110534-appb-000057
或者
Figure PCTCN2022110534-appb-000058
 X1 is NH,
Figure PCTCN2022110534-appb-000057
or
Figure PCTCN2022110534-appb-000058
R 1、R 2各自独立地选自H、D或者C 1-6烷基； R 1 and R 2 are each independently selected from H, D or C 1-6 alkyl;
R 3、R 4各自独立地选自H或者D； R 3 and R 4 are each independently selected from H or D;
X 2为O； X2 is O;
L 1为
Figure PCTCN2022110534-appb-000059
L 1 is
Figure PCTCN2022110534-appb-000059
R 5、R 6各自独立地选自H或D； R 5 and R 6 are each independently selected from H or D;
R 7、R 8各自独立地选自H或D； R 7 and R 8 are each independently selected from H or D;
R 9、R 10各自独立地选自H、D或OH； R 9 and R 10 are each independently selected from H, D or OH;
R 11和R 12各自独立地选自H或D； R 11 and R 12 are each independently selected from H or D;
B为
Figure PCTCN2022110534-appb-000060
或者
Figure PCTCN2022110534-appb-000061
B for
Figure PCTCN2022110534-appb-000060
or
Figure PCTCN2022110534-appb-000061
R 13为、
Figure PCTCN2022110534-appb-000062
Figure PCTCN2022110534-appb-000063
Figure PCTCN2022110534-appb-000064
R 13 is,
Figure PCTCN2022110534-appb-000062
Figure PCTCN2022110534-appb-000063
Figure PCTCN2022110534-appb-000064
R 13a、R 13b选自H、卤素、CF 3； R 13a and R 13b are selected from H, halogen, CF 3 ;
L 2选自-C(＝O)-、-C(＝O)O-、-C(＝O)NH-或键； L is selected from -C(=O)-, -C(=O)O-, -C(=O)NH- or a bond;
n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
o为0或者1。o is 0 or 1.
本申请的一个或多个实施方式提供了通式(I-1)所示的化合物或者其立体异构体、药学上可接受的盐或氘代物，其中：One or more embodiments of the present application provide a compound represented by general formula (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein:
A为
Figure PCTCN2022110534-appb-000065
A is
Figure PCTCN2022110534-appb-000065
X 1为NH、
Figure PCTCN2022110534-appb-000066
或者
Figure PCTCN2022110534-appb-000067
 X1 is NH,
Figure PCTCN2022110534-appb-000066
or
Figure PCTCN2022110534-appb-000067
R 1、R 2各自独立地选自H、D或者C 1-6烷基； R 1 and R 2 are each independently selected from H, D or C 1-6 alkyl;
R 3、R 4各自独立地选自H或者D； R 3 and R 4 are each independently selected from H or D;
X 2为O； X2 is O;
L 1为
Figure PCTCN2022110534-appb-000068
L 1 is
Figure PCTCN2022110534-appb-000068
R 5、R 6各自独立地选自H或D； R 5 and R 6 are each independently selected from H or D;
R 7、R 8各自独立地选自H或D； R 7 and R 8 are each independently selected from H or D;
R 9、R 10各自独立地选自H、D或OH； R 9 and R 10 are each independently selected from H, D or OH;
R 11和R 12各自独立地选自H或D； R 11 and R 12 are each independently selected from H or D;
B为
Figure PCTCN2022110534-appb-000069
或者
Figure PCTCN2022110534-appb-000070
B for
Figure PCTCN2022110534-appb-000069
or
Figure PCTCN2022110534-appb-000070
R 13为
Figure PCTCN2022110534-appb-000071
R 13 is
Figure PCTCN2022110534-appb-000071
R 13a选自H、卤素、CF 3； R 13a is selected from H, halogen, CF 3 ;
L 2选自-C(＝O)-、-C(＝O)O-、-C(＝O)NH-或键； L is selected from -C(=O)-, -C(=O)O-, -C(=O)NH- or a bond;
n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
o为0或者1。o is 0 or 1.
本申请的一个或多个实施方式提供了通式(I-1)所示的化合物或者其立体异构体、药学上可接受的盐或氘代物，其中：One or more embodiments of the present application provide a compound represented by general formula (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein:
A为
Figure PCTCN2022110534-appb-000072
A is
Figure PCTCN2022110534-appb-000072
X 1为NH、
Figure PCTCN2022110534-appb-000073
或者
Figure PCTCN2022110534-appb-000074
 X1 is NH,
Figure PCTCN2022110534-appb-000073
or
Figure PCTCN2022110534-appb-000074
R 1、R 2各自独立地选自H、D或者C 1-6烷基； R 1 and R 2 are each independently selected from H, D or C 1-6 alkyl;
R 3、R 4各自独立地选自D； R 3 and R 4 are each independently selected from D;
X 2为O； X2 is O;
L 1为
Figure PCTCN2022110534-appb-000075
L 1 is
Figure PCTCN2022110534-appb-000075
L 2选自-C(＝O)-、-C(＝O)O-、-C(＝O)NH-或键； L is selected from -C(=O)-, -C(=O)O-, -C(=O)NH- or a bond;
R 5、R 6各自独立地选自H或D； R 5 and R 6 are each independently selected from H or D;
R 7、R 8各自独立地选自H或D； R 7 and R 8 are each independently selected from H or D;
R 9、R 10各自独立地选自H、D或OH； R 9 and R 10 are each independently selected from H, D or OH;
R 11和R 12各自独立地选自H或D； R 11 and R 12 are each independently selected from H or D;
B为
Figure PCTCN2022110534-appb-000076
或者
Figure PCTCN2022110534-appb-000077
B for
Figure PCTCN2022110534-appb-000076
or
Figure PCTCN2022110534-appb-000077
R 13为CN或CF 3。 R 13 is CN or CF 3 .
n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
o为0或1。o is 0 or 1.
本申请的一个或多个实施方式提供了化合物或者其立体异构体、药学上可接受的盐或氘代物，其选自以下结构：One or more embodiments of the present application provide a compound or its stereoisomer, pharmaceutically acceptable salt or deuterated substance, which is selected from the following structures:
Figure PCTCN2022110534-appb-000078
Figure PCTCN2022110534-appb-000079
Figure PCTCN2022110534-appb-000080
或者
Figure PCTCN2022110534-appb-000081
Figure PCTCN2022110534-appb-000078
Figure PCTCN2022110534-appb-000079
Figure PCTCN2022110534-appb-000080
or
Figure PCTCN2022110534-appb-000081
本申请一个或多个实施方式提供了用于制备通式(I)、(I-1)一种化合物或者其立体异构体，药学上可接受的盐或氘代物的中间体化合物或者其立体异构体，药学上可接受的盐或氘代物，其具有通式(II)或(III)所示的化合物：One or more embodiments of the present application provide an intermediate compound for the preparation of a compound of general formula (I), (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product or its stereo Isomers, pharmaceutically acceptable salts or deuterated substances, which have compounds represented by general formula (II) or (III):
Figure PCTCN2022110534-appb-000082
Figure PCTCN2022110534-appb-000082
其中：in:
X 1选自OH、SH、C 1-6烷基、3至10元杂环烷基的单环或多环、-NHR x1、-C(＝O)H、-C(＝O)OH、-C(＝O)NR x1H、-S(＝O)H、-S(＝O) 2H、-S(＝O)NR x1H、-S(＝O) 2NR x1H、-NR x1C(＝O)NR x1H或键，所述C 1-6亚烷基、3至10元杂环烷基的单环或多环进一步被1或多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR x2、SR x2、C(＝O)R x3、C(＝O)NR x4R x5、C(＝O)OR x2、OC(＝O)R x3、OC(＝O)NR x4R x5、NR x4R x5、NR x4C(＝O)R x3、NR x4OC(＝O)R x3、NR x4C(＝O)NR x4R x5、C(＝NR x6)R x3、C(＝NR x6)NR x4R x5、NR x4C(＝NR x6)NR x4R x5、NR x4S(＝O)R x2、NR x4S(＝O) 2R x2、NR x4S(＝O) 2NR x4R x5、S(＝O)R x2、S(＝O)NR x4R x5、S(＝O) 2NR x4R x5、P(＝O)(R x4) 2或P(＝O) 2；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR x2、SR x2、C(＝O)R x3、C(＝O)NR x4R x5、C(＝O)OR x2、OC(＝O)R x3、OC(＝O)NR x4R x5、NR x4R x5、NR x4C(＝O)R x3、NR x4OC(＝O)R x3、NR x4C(＝O)NR x4R x5、C(＝NR x6)R x3、C(＝NR x6)NR x4R x5、NR x4C(＝NR x6)NR x4R x5、NR x4S(＝O)R x2、 NR x4S(＝O) 2R x2、NR x4S(＝O) 2NR x4R x5、S(＝O)R x2、S(＝O)NR x4R x5或S(＝O) 2NR x4R x5；所述3至10元杂环烷基的单环或多环、5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； X 1 is selected from OH, SH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl monocyclic or polycyclic, -NHR x1 , -C(=O)H, -C(=O)OH, -C(=O)NR x1 H, -S(=O)H, -S(=O) 2 H, -S(=O)NR x1 H, -S(=O) 2 NR x1 H, -NR x1 C(=O)NR x1 H or a bond, the C 1-6 alkylene, 3 to 10 membered heterocycloalkyl ring or polycyclic ring is further substituted by 1 or more substituents selected from the following: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 cycloalkyl, C6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10-membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR x2 , SR x2 , C(=O)R x3 , C(=O)NR x4 R x5 , C( =O)OR x2 , OC(=O)R x3 , OC(=O)NR x4 R x5 , NR x4 R x5 , NR x4 C(=O)R x3 , NR x4 OC(=O)R x3 , NR x4 C(=O)NR x4 R x5 , C(=NR x6 )R x3 , C(=NR x6 )NR x4 R x5 , NR x4 C(=NR x6 )NR x4 R x5 , NR x4 S(=O )R x2 , NR x4 S(=O) 2 R x2 , NR x4 S(=O) 2 NR x4 R x5 , S(=O)R x2 , S(=O)NR x4 R x5 , S(=O ) 2 NR x4 R x5 , P(=O)(R x4 ) 2 or P(=O) 2 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, =O, CN , NH 2 , NO 2 , N 3 , COOH, OR x2 , SR x2 , C(=O)R x3 , C(=O)NR x4 R x5 , C(=O)OR x2 , OC(=O)R x3 , OC(=O)NR x4 R x5 , NR x4 R x5 , NR x4 C(=O)R x3 , NR x4 OC(=O)R x3 , NR x4 C(=O)NR x4 R x5 , C (=NR x6 )R x3 , C(=NR x6 )NR x4 R x5 , NR x4 C(=NR x6 )NR x4 R x5 , NR x4 S(=O)R x2 , NR x4 S(=O) 2 R x2 , NR x4 S(=O) 2 NR x4 R x5 , S(=O)R x2 , S(=O)NR x4 R x5 or S(=O) 2 NR x4 R x5 ; monocyclic or polycyclic, 5- to 12-membered heterocycloalkyls of the 3- to 10-membered Heteroaryl, 3 to 10 membered heterocycloalkyls contain 1 to 3 heteroatoms selected from N, O, S;
X 2和L 2选自O、S、C 1-6亚烷基、3至10元杂环烷基的单环或多环、-NR x1-、-C(＝O)-、-C(＝O)O-、-C(＝O)NR x1-、-S(＝O)-、-S(＝O) 2-、-S(＝O)NR x1-、-S(＝O) 2NR x1-、-NR x1C(＝O)NR x1-或键，所述C 1-6亚烷基、3至10元杂环烷基的单环或多环进一步被1或多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR x2、SR x2、C(＝O)R x3、C(＝O)NR x4R x5、C(＝O)OR x2、OC(＝O)R x3、OC(＝O)NR x4R x5、NR x4R x5、NR x4C(＝O)R x3、NR x4OC(＝O)R x3、NR x4C(＝O)NR x4R x5、C(＝NR x6)R x3、C(＝NR x6)NR x4R x5、NR x4C(＝NR x6)NR x4R x5、NR x4S(＝O)R x2、NR x4S(＝O) 2R x2、NR x4S(＝O) 2NR x4R x5、S(＝O)R x2、S(＝O)NR x4R x5、S(＝O) 2NR x4R x5、P(＝O)(R x4) 2或P(＝O) 2；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR x2、SR x2、C(＝O)R x3、C(＝O)NR x4R x5、C(＝O)OR x2、OC(＝O)R x3、OC(＝O)NR x4R x5、NR x4R x5、NR x4C(＝O)R x3、NR x4OC(＝O)R x3、NR x4C(＝O)NR x4R x5、C(＝NR x6)R x3、C(＝NR x6)NR x4R x5、NR x4C(＝NR x6)NR x4R x5、NR x4S(＝O)R x2、NR x4S(＝O) 2R x2、NR x4S(＝O) 2NR x4R x5、S(＝O)R x2、S(＝O)NR x4R x5或S(＝O) 2NR x4R x5；所述3至10元杂环烷基的单环或多环、5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； X 2 and L 2 are selected from O, S, C 1-6 alkylene, monocyclic or polycyclic rings of 3 to 10 membered heterocycloalkyl groups, -NR x1 -, -C(=O)-, -C( =O)O-, -C(=O)NR x1 -, -S(=O)-, -S(=O) 2 -, -S(=O)NR x1 -, -S(=O) 2 NR x1 -, -NR x1 C(=O)NR x1 - or a bond, the C 1-6 alkylene, 3 to 10 membered heterocycloalkyl ring or polycyclic ring is further selected from 1 or more The following substituents are substituted: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12-membered heteroaryl, 3- to 10-membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR x2 , SR x2 , C(=O)R x3 , C(=O) NR x4 R x5 , C(=O)OR x2 , OC(=O)R x3 , OC(=O)NR x4 R x5 , NR x4 R x5 , NR x4 C(=O)R x3 , NR x4 OC( =O)R x3 , NR x4 C(=O)NR x4 R x5 , C(=NR x6 )R x3 , C(=NR x6 )NR x4 R x5 , NR x4 C(=NR x6 )NR x4 R x5 , NR x4 S(=O)R x2 , NR x4 S(=O) 2 R x2 , NR x4 S(=O) 2 NR x4 R x5 , S(=O)R x2 , S(=O)NR x4 R x5 , S(=O) 2 NR x4 R x5 , P(=O)(R x4 ) 2 or P(=O) 2 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkane base, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR x2 , SR x2 , C(=O)R x3 , C(=O)NR x4 R x5 , C(=O)OR x2 , OC(=O)R x3 , OC(=O)NR x4 R x5 , NR x4 R x5 , NR x4 C(=O)R x3 , NR x4 OC(=O)R x3 , NR x4 C(=O) NR x4 R x5 , C(=NR x6 )R x3 , C(=NR x6 )NR x4 R x5 , NR x4 C(=NR x6 )NR x4 R x5 , NR x4 S(=O)R x2 , NR x4 S(=O) 2 R x2 , NR x4 S(=O) 2 NR x4 R x5 , S(=O)R x2 , S(=O)NR x4 R x5 or S(=O) 2 NR x4 R x5 ; the monocyclic or polycyclic, 5 to 12 Member heteroaryl, 3 to 10 member heterocycloalkyl contain 1 to 3 heteroatoms selected from N, O, S;
X 4为NHR x1、OH、SH或键； X 4 is NHR x1 , OH, SH or a bond;
R 1、R 2、R 3、R 4、R 15各自独立地选自H、D、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元杂芳基、3至10元杂环烷基、CN、NH 2、NO 2、N 3、COOH、OR a2、SR a2、C(＝O)R a3、C(＝O)NR a4R a5、C(＝O)OR a2、OC(＝O)R a3、OC(＝O)NR a4R a5、NR a4R a5、NR a4C(＝O)R a3、NR a4OC(＝O)R a3、NR a4C(＝O)NR a4R a5、C(＝NR a6)R a3、C(＝NR a6)NR a4R a5、NR a4C(＝NR a6)NR a4R a5、NR a4S(＝O)R a2、NR a4S(＝O) 2R a2、NR a4S(＝O) 2NR a4R a5、S(＝O)R a2、S(＝O)NR a4R a5或S(＝O) 2NR a4R a5；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR a2、SR a2、C(＝O)R a3、C(＝O)NR a4R a5、C(＝O)OR a2、OC(＝O)R a3、OC(＝O)NR a4R a5、NR a4R a5、NR a4C(＝O)R a3、NR a4OC(＝O)R a3、NR a4C(＝O)NR a4R a5、C(＝NR a6)R a3、C(＝NR a6)NR a4R a5、NR a4C(＝NR a6)NR a4R a5、NR a4S(＝O)R a2、NR a4S(＝O) 2R a2、NR a4S(＝O) 2NR a4R a5、S(＝O)R a2、S(＝O)NR a4R a5或S(＝O) 2NR a4R a5；或R 1和R 2、R 3和R 4、R 1和R 3各自独立地连同其所连接的碳原子形成3至6元环烷基或5至10元杂环烷基，所述环烷基、杂环烷基任选地被1或多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR a2、SR a2、C(＝O)R a3、C(＝O)NR a4R a5、C(＝O)OR a2、OC(＝O)R a3、OC(＝O)NR a4R a5、NR a4R a5、NR a4C(＝O)R a3、NR a4OC(＝O)R a3、NR a4C(＝O)NR a4R a5、C(＝NR a6)R a3、C(＝NR a6)NR a4R a5、NR a4C(＝NR a6)NR a4R a5、NR a4S(＝O)R a2、NR a4S(＝O) 2R a2、NR a4S(＝O) 2NR a4R a5、S(＝O)R a2、S(＝O)NR a4R a5或S(＝O) 2NR a4R a5；所述5至12元杂芳基、5至10元杂环烷基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R 1 , R 2 , R 3 , R 4 , and R 15 are each independently selected from H, D, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -10 cycloalkyl, C6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, CN, NH 2 , NO 2 , N 3 , COOH, OR a2 , SR a2 , C( =O)R a3 , C(=O)NR a4 R a5 , C(=O)OR a2 , OC(=O)R a3 , OC(=O)NR a4 R a5 , NR a4 R a5 , NR a4 C (=O)R a3 , NR a4 OC(=O)R a3 , NR a4 C(=O)NR a4 R a5 , C(=NR a6 )R a3 , C(=NR a6 )NR a4 R a5 , NR a4 C(=NR a6 )NR a4 R a5 , NR a4 S(=O)R a2 , NR a4 S(=O) 2 R a2 , NR a4 S(=O) 2 NR a4 R a5 , S(=O )R a2 , S(=O)NR a4 R a5 or S(=O) 2 NR a4 R a5 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkane group, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR a2 , SR a2 , C(=O)R a3 , C(=O)NR a4 R a5 , C(=O)OR a2 , OC(=O)R a3 , OC(=O)NR a4 R a5 , NR a4 R a5 , NR a4 C(=O)R a3 , NR a4 OC(=O)R a3 , NR a4 C(=O) NR a4 R a5 , C(=NR a6 )R a3 , C(=NR a6 )NR a4 R a5 , NR a4 C(=NR a6 )NR a4 R a5 , NR a4 S (=O)R a2 , NR a4 S(=O) 2 R a2 , NR a4 S(=O) 2 NR a4 R a5 , S(=O)R a2 , S(=O)NR a4 R a5 or S(=O) 2 NR a4 R a5 or R 1 and R 2 , R 3 and R 4 , R 1 and R 3 each independently together with their The attached carbon atoms form a 3 to 6 membered cycloalkyl group or a 5 to 10 membered heterocycloalkyl group, which are optionally substituted by 1 or more substituents selected from the group consisting of: H , OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10-membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR a2 , SR a2 , C(=O)R a3 , C(=O)NR a4 R a5 , C( =O)OR a2 , OC(=O)R a3 , OC(=O)NR a4 R a5 , NR a4 R a5 , NR a4 C(=O)R a3 , NR a4 OC(=O)R a3 , NR a4 C(=O)NR a4 R a5 , C(=NR a6 )R a3 , C(=NR a6 )NR a4 R a5 , NR a4 C(=NR a6 )NR a4 R a5 , NR a4 S(=O )R a2 , NR a4 S(=O) 2 R a2 , NR a4 S(=O) 2 NR a4 R a5 , S(=O)R a2 , S(=O)NR a4 R a5 or S(=O ) 2 NR a4 R a5 ; the 5 to 12 membered heteroaryl, 5 to 10 membered heterocycloalkyl, 3 to 10 membered heterocycloalkyl contain 1 to 3 heteroatoms selected from N, O and S;
L 1为
Figure PCTCN2022110534-appb-000083
R 17为H、D或C 1-6烷基,所述C 1-6烷基任选地被1至3个卤素取代； L 1 is
Figure PCTCN2022110534-appb-000083
R 17 is H, D or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
X 3为C或N； X3 is C or N;
R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、D、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、CN、NH 2、NO 2、N 3、COOH、OR b2、SR b2、C(＝O)R b3、C(＝O)NR b4R b5、C(＝O)OR b2、OC(＝O)R b3、OC(＝O)NR b4R b5、NR b4R b5、NR b4C(＝O)R b3、NR b4OC(＝O)R b3、NR b4C(＝O)NR b4R b5、C(＝NR b6)R b3、C(＝NR b6)NR b4R b5、NR b4C(＝NR b6)NR b4R b5、NR b4S(＝O)R b2、NR b4S(＝O) 2R b2、NR b4S(＝O) 2NR b4R b5、S(＝O)R b2、S(＝O)NR b4R b5或S(＝O) 2NR b4R b5；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR b2、SR b2、C(＝O)R b3、C(＝O)NR b4R b5、C(＝O)OR b2、OC(＝O)R b3、OC(＝O)NR b4R b5、NR b4R b5、NR b4C(＝O)R b3、NR b4OC(＝O)R b3、NR b4C(＝O)NR b4R b5、C(＝NR b6)R b3、C(＝NR b6)NR b4R b5、NR b4C(＝NR b6)NR b4R b5、NR b4S(＝O)R b2、NR b4S(＝O) 2R b2、NR b4S(＝O) 2NR b4R b5、S(＝O)R b2、S(＝O)NR b4R b5或S(＝O) 2NR b4R b5；或R 5和R 6、R 7和R 8、R 9和R 10、R 11和R 12各自独立地连同其所连接的碳原子形成＝O；或R 5和R 7、R 5和R 9、R 5和R 11、R 7和R 9、R 7和R 11、R 9和R 11相连；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, D, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, CN, NH 2 , NO 2 , N 3 , COOH, OR b2 , SR b2 , C(=O)R b3 , C(=O)NR b4 R b5 , C(=O)OR b2 , OC(=O)R b3 , OC(=O)NR b4 R b5 , NR b4 R b5 , NR b4 C(=O)R b3 , NR b4 OC(=O)R b3 , NR b4 C(=O)NR b4 R b5 , C(=NR b6 )R b3 , C( =NR b6 )NR b4 R b5 , NR b4 C(=NR b6 )NR b4 R b5 , NR b4 S(=O)R b2 , NR b4 S(=O) 2 R b2 , NR b4 S(=O) 2 NR b4 R b5 , S(=O)R b2 , S(=O)NR b4 R b5 or S(=O) 2 NR b4 R b5 ; the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally selected from 1 to more of the following Substituent substitution: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 members Heteroaryl, 3- to 10-membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR b2 , SR b2 , C(=O)R b3 , C(=O)NR b4 R b5 , C(=O)OR b2 , OC(=O)R b3 , OC(=O)NR b4 R b5 , NR b4 R b5 , NR b4 C(=O)R b3 , NR b4 OC(=O )R b3 , NR b4 C(=O)NR b4 R b5 , C(=NR b6 )R b3 , C(=NR b6 )NR b4 R b5 , NR b4 C(=NR b6 )NR b4 R b5 , NR b4 S(=O)R b2 , NR b4 S(=O) 2 R b2 , NR b4 S(=O) 2 NR b4 R b5 , S(=O)R b2 , S(=O)NR b4 R b5 or S(=O) 2 NR b4 R b5 ; or R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 each independently form =O together with the carbon atom to which they are attached; or R 5 and R 7 , R 5 and R 9 , R 5 and R 11 , R 7 and R 9 , R 7 and R 11 , R 9 and R 11 are connected; the 5-12 membered heteroaryl, 3-10 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, S;
B为3至10元的环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基，所述杂环、杂芳环包含至少1至3个选自N、O和S的杂原子；B is a cycloalkyl group with 3 to 10 members, a heterocycloalkyl group with 3 to 10 members, an aryl group with 6 to 12 members, and a heteroaryl group with 5 to 12 members, and the heterocycle and heteroaryl ring contain at least 1 to 3 a heteroatom selected from N, O and S;
R 13为C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基、CN或CF 3，所述C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基进一步被1或多个选自以下的取代基取代：H、D、卤素、CN、OH、NO 2、OR g2、SR g2、C(＝O)R g3、C(＝O)NR g4R g5、C(＝O)OR g2、OC(＝O)R g3、OC(＝O)NR g4R g5、NR g4R g5、NR g4C(＝O)R g3、NR g4OC(＝O)R g3、NR g4C(＝O)NR g4R g5、C(＝NR g6)R g3、C(＝NR g6)NR g4R g5、NR g4C(＝NR g6)NR g4R g5、NR g4S(＝O)R g2、NR g4S(＝O) 2R g2、NR g4S(＝O) 2NR g4R g5、S(＝O)R g2、S(＝O)NR g4R g5或S(＝O) 2NR g4R g5；所述3至10元的杂环烷基、5至12元杂芳基包含1至3个选自N、O、S的杂原子； R 13 is C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN or CF 3 , the C 3-10 cycloalkane radical, 3 to 10 membered heterocycloalkyl, 6 to 12 membered aryl, 5 to 12 membered heteroaryl are further substituted by 1 or more substituents selected from the group consisting of: H, D, halogen, CN, OH , NO 2 , OR g2 , SR g2 , C(=O)R g3 , C(=O)NR g4 R g5 , C(=O)OR g2 , OC(=O)R g3 , OC(=O)NR g4 R g5 , NR g4 R g5 , NR g4 C(=O)R g3 , NR g4 OC(=O)R g3 , NR g4 C(=O)NR g4 R g5 , C(=NR g6 )R g3 , C(=NR g6 )NR g4 R g5 , NR g4 C(=NR g6 )NR g4 R g5 , NR g4 S(=O)R g2 , NR g4 S(=O) 2 R g2 , NR g4 S(= O) 2 NR g4 R g5 , S(=O)R g2 , S(=O)NR g4 R g5 or S(=O) 2 NR g4 R g5 ; the 3 to 10-membered heterocycloalkyl, 5 to 12 membered heteroaryls containing 1 to 3 heteroatoms selected from N, O, S;
条件是：当R 13为CN或CF 3时，R 3和R 4为D； The condition is: when R 13 is CN or CF 3 , R 3 and R 4 are D;
R a1、R a2、R a3、R a4、R a5、R a6、R b1、R b2、R b3、R b4、R b5、R b6、R c1、R c2、R c3、R c4、R c5、R c6、R d1、R d2、R d3、R d4、R d5、R d6、R x1、R x2、R x3、R x4、R x5或R x6、各自独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元杂芳基、3至10元杂环烷基或TBS，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR e2、SR e2、C(＝O)R e3、C(＝O)NR e4R e5、C(＝O)OR e2、OC(＝O)R e3、OC(＝O)NR e4R e5、NR e4R e5、NR e4C(＝O)R e3、NR e4OC(＝O)R e3、NR e4C(＝O)NR e4R e5、C(＝NR e6)R e3、C(＝NR e6)NR e4R e5、NR e4C(＝NR e6)NR e4R e5、NR e4S(＝O)R e2、NR e4S(＝O) 2R e2、NR e4S(＝O) 2NR e4Re 5、S(＝O)R e2、S(＝O)NR e4R e5或S(＝O) 2NR e4R e5；所述5至12元杂芳基、3至10 元杂环烷基包含1至3个选自N、O、S的杂原子； R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R x1 , R x2 , R x3 , R x4 , R x5 or R x6 , each independently selected from H, C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl or TBS , the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 Membered heterocycloalkyl is optionally substituted by 1 to more substituents selected from the group consisting of H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR e2 , SR e2 , C(=O)R e3 , C(=O)NR e4 R e5 , C(=O)OR e2 , OC(=O)R e3 , OC(=O)NR e4 R e5 , NR e4 R e5 , NR e4 C(=O) R e3 , NR e4 OC(=O)R e3 , NR e4 C(=O)NR e4 R e5 , C(=NR e6 )R e3 , C(=NR e6 )NR e4 R e5 , NR e4 C(= NR e6 ) NR e4 R e5 , NR e4 S(=O)R e2 , NR e4 S(=O) 2 R e2 , NR e4 S(=O) 2 NR e4 Re 5 , S(=O)R e2 , S(=O)NR e4 R e5 or S(=O) 2 NR e4 R e5 ; the 5 to 12-membered heteroaryl, 3 to 10-membered heterocycloalkyl contains 1 to 3 members selected from N, O, S heteroatoms;
R a4和R a5、R b4和R b5、R c4和R c5、R d4和R d5、R x4和R x5各自独立地连同其所连接的N原子形成4至7元杂环，所述杂环进一步被1或多个选自以下的取代基取代：卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、CN、OR f2、SR f2、C(＝O)R f3、C(＝O)NR f4R f5、C(＝O)OR f2、OC(＝O)R f3、OC(＝O)NR f4R f5、NR f4R f5、NR f4C(＝O)R f3、NR f4OC(＝O)R f3、NR f4C(＝O)NR f4R f5、C(＝NR f6)R f3、C(＝NR f6)NR f4R f5、NR f4C(＝NR f6)NR f4R f5、NR f4S(＝O)R f2、NR f4S(＝O) 2R f2、NR f4S(＝O) 2NR f4R f5、S(＝O)R f2、S(＝O)NR f4R f5或S(＝O) 2NR f4R f5；所述4至7元杂环包含1至3个选自N、O、S的杂原子； R a4 and R a5 , R b4 and R b5 , R c4 and R c5 , R d4 and R d5 , R x4 and R x5 each independently form a 4- to 7-membered heterocycle together with the N atom to which they are attached, and the heterocycle The ring is further substituted by 1 or more substituents selected from the group consisting of halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, OR f2 , SR f2 , C(=O )R f3 , C(=O)NR f4 R f5 , C(=O)OR f2 , OC(=O)R f3 , OC(=O)NR f4 R f5 , NR f4 R f5 , NR f4 C(= O)R f3 , NR f4 OC(=O)R f3 , NR f4 C(=O)NR f4 R f5 , C(=NR f6 )R f3 , C(=NR f6 )NR f4 R f5 , NR f4 C (=NR f6 )NR f4 R f5 , NR f4 S(=O)R f2 , NR f4 S(=O) 2 R f2 , NR f4 S(=O) 2 NR f4 R f5 , S(=O)R f2 , S(=O)NR f4 R f5 or S(=O) 2 NR f4 R f5 ; the 4 to 7-membered heterocyclic ring contains 1 to 3 heteroatoms selected from N, O, S;
R f1、R f2、R f3、R f4、R f5、R f6、R e1、R e2、R e3、R e4、R e5、R e6各自独立地选自C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1- 6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R f1 , R f2 , R f3 , R f4 , R f5 , R f6 , R e1 , R e2 , R e3 , R e4 , R e5 , R e6 are each independently selected from C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1-6 alkane C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl optionally Substituted by 1 to more substituents selected from : H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3- 10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH; the 5 to 12 membered heteroaryl, 3 to The 10-membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, S;
m为0、1、2或者3；m is 0, 1, 2 or 3;
n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
o为0或1；o is 0 or 1;
p为1、2或者3。p is 1, 2 or 3.
在一个或多个实施方式中，中间体化合物或者其立体异构体或药学上可接受的盐具有以下结构或者其立体异构体或药学上可接受的盐：In one or more embodiments, the intermediate compound or its stereoisomer or pharmaceutically acceptable salt has the following structure or its stereoisomer or pharmaceutically acceptable salt:
Figure PCTCN2022110534-appb-000084
Figure PCTCN2022110534-appb-000085
或者
Figure PCTCN2022110534-appb-000086
Figure PCTCN2022110534-appb-000084
Figure PCTCN2022110534-appb-000085
or
Figure PCTCN2022110534-appb-000086
本申请一个或多个实施方式提供了用于制备通式(I)、(I-1)一种化合物或者其立体异构体，药学上可接受的盐或氘代物的中间体化合物或者其立体异构体，药学上可接受的盐或氘代物，其具有通式(IV)或(V)所示的化合物：One or more embodiments of the present application provide an intermediate compound for the preparation of a compound of general formula (I), (I-1) or its stereoisomer, pharmaceutically acceptable salt or deuterated product or its stereo Isomers, pharmaceutically acceptable salts or deuterated substances, which have compounds represented by general formula (IV) or (V):
Figure PCTCN2022110534-appb-000087
Figure PCTCN2022110534-appb-000087
其中：in:
R 17为H、D或C 1-6烷基,所述C 1-6烷基任选地被1至3个卤素取代； R 17 is H, D or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
X 3为CH 2或NH； X 3 is CH 2 or NH;
R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、D、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、CN、NH 2、NO 2、N 3、COOH、OR b2、SR b2、C(＝O)R b3、C(＝O)NR b4R b5、C(＝O)OR b2、OC(＝O)R b3、OC(＝O)NR b4R b5、NR b4R b5、NR b4C(＝O)R b3、NR b4OC(＝O)R b3、NR b4C(＝O)NR b4R b5、C(＝NR b6)R b3、C(＝NR b6)NR b4R b5、NR b4C(＝NR b6)NR b4R b5、NR b4S(＝O)R b2、NR b4S(＝O) 2R b2、NR b4S(＝O) 2NR b4R b5、S(＝O)R b2、S(＝O)NR b4R b5或S(＝O) 2NR b4R b5；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR b2、SR b2、C(＝O)R b3、C(＝O)NR b4R b5、C(＝O)OR b2、OC(＝O)R b3、OC(＝O)NR b4R b5、NR b4R b5、NR b4C(＝O)R b3、NR b4OC(＝O)R b3、NR b4C(＝O)NR b4R b5、C(＝NR b6)R b3、C(＝NR b6)NR b4R b5、NR b4C(＝NR b6)NR b4R b5、NR b4S(＝O)R b2、NR b4S(＝O) 2R b2、NR b4S(＝O) 2NR b4R b5、S(＝O)R b2、S(＝O)NR b4R b5或S(＝O) 2NR b4R b5；或R 5和R 6、R 7和R 8、R 9和R 10、R 11和R 12各自独立地连同其所连接的碳原子形成＝O；或R 5和R 7、R 5和R 9、R 5和R 11、R 7和R 9、R 7和R 11、R 9和R 11相连；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, D, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, CN, NH 2 , NO 2 , N 3 , COOH, OR b2 , SR b2 , C(=O)R b3 , C(=O)NR b4 R b5 , C(=O)OR b2 , OC(=O)R b3 , OC(=O)NR b4 R b5 , NR b4 R b5 , NR b4 C(=O)R b3 , NR b4 OC(=O)R b3 , NR b4 C(=O)NR b4 R b5 , C(=NR b6 )R b3 , C( =NR b6 )NR b4 R b5 , NR b4 C(=NR b6 )NR b4 R b5 , NR b4 S(=O)R b2 , NR b4 S(=O) 2 R b2 , NR b4 S(=O) 2 NR b4 R b5 , S(=O)R b2 , S(=O)NR b4 R b5 or S(=O) 2 NR b4 R b5 ; the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally selected from 1 to more of the following Substituent substitution: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 members Heteroaryl, 3- to 10-membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR b2 , SR b2 , C(=O)R b3 , C(=O)NR b4 R b5 , C(=O)OR b2 , OC(=O)R b3 , OC(=O)NR b4 R b5 , NR b4 R b5 , NR b4 C(=O)R b3 , NR b4 OC(=O )R b3 , NR b4 C(=O)NR b4 R b5 , C(=NR b6 )R b3 , C(=NR b6 )NR b4 R b5 , NR b4 C(=NR b6 )NR b4 R b5 , NR b4 S(=O)R b2 , NR b4 S(=O) 2 R b2 , NR b4 S(=O) 2 NR b4 R b5 , S(=O)R b2 , S(=O)NR b4 R b5 or S(=O) 2 NR b4 R b5 ; or R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 each independently form =O together with the carbon atom to which they are attached; or R 5 and R 7 , R 5 and R 9 , R 5 and R 11 , R 7 and R 9 , R 7 and R 11 , R 9 and R 11 are connected; the 5-12 membered heteroaryl, 3-10 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, S;
R 20、R 21各自独立地选自H、卤素、CN、OH、C 1-6烷基、C 1-6烷氧基、C 6-10芳基、C 3-7环烷基、5至10元杂芳基或3至10元杂环烷基，所述C 1-6烷基、C 1-6烷氧基、C 6-10芳基、C 3-7环烷基、5至10元杂芳基、3至10元杂环烷基各自独立地被1至3个选自以下的取代基取代：H、卤素、CN、OH；所述杂芳基或杂环烷基包含1、2、3或4个独立地选自O、N和S的杂原子；C为5至10元碳环、5至10元杂环、6至10元芳环或者5至10元芳杂环。所述5至10元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R 20 and R 21 are each independently selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 3-7 cycloalkyl, 5 to 10-membered heteroaryl or 3 to 10-membered heterocycloalkyl, the C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 3-7 cycloalkyl, 5 to 10 Member heteroaryl, 3 to 10 member heterocycloalkyl are each independently substituted by 1 to 3 substituents selected from the following: H, halogen, CN, OH; the heteroaryl or heterocycloalkyl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, N and S; C is a 5- to 10-membered carbocyclic ring, a 5- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered aromatic heterocyclic ring. The 5- to 10-membered heteroaryl group and the 3- to 10-membered heterocycloalkyl group contain 1 to 3 heteroatoms selected from N, O, and S;
R b1、R b2、R b3、R b4、R b5或R b6各自独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元杂芳基、3至10元杂环烷基或TBS，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR e2、SR e2、C(＝O)R e3、C(＝O)NR e4R e5、C(＝O)OR e2、OC(＝O)R e3、OC(＝O)NR e4R e5、NR e4R e5、NR e4C(＝O)R e3、NR e4OC(＝O)R e3、NR e4C(＝O)NR e4R e5、C(＝NR e6)R e3、C(＝NR e6)NR e4R e5、NR e4C(＝NR e6)NR e4R e5、NR e4S(＝O)R e2、NR e4S(＝O) 2R e2、NR e4S(＝O) 2NR e4Re 5、S(＝O)R e2、S(＝O)NR e4R e5或S(＝O) 2NR e4R e5；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R b1 , R b2 , R b3 , R b4 , R b5 or R b6 are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 ring Alkyl, C6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl or TBS, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H, OH , halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, = O, CN, NH 2 , NO 2 , N 3 , COOH, OR e2 , SR e2 , C(=O)R e3 , C(=O)NR e4 R e5 , C(=O)OR e2 , OC(= O)R e3 , OC(=O)NR e4 R e5 , NR e4 R e5 , NR e4 C(=O)R e3 , NR e4 OC(=O)R e3 , NR e4 C(=O)NR e4 R e5 , C(=NR e6 )R e3 , C(=NR e6 )NR e4 R e5 , NR e4 C(=NR e6 )NR e4 R e5 , NR e4 S (=O)R e2 , NR e4 S(= O) 2 R e2 , NR e4 S(=O) 2 NR e4 Re 5 , S(=O)R e2 , S(=O)NR e4 R e5 or S(=O) 2 NR e4 R e5 ; the 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl contain 1 to 3 heteroatoms selected from N, O and S;
R b4和R b5连同其所连接的N原子形成4至7元杂环，所述杂环进一步被1或多个选自以下的取代基取代：卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、CN、OR f2、SR f2、C(＝O)R f3、C(＝O)NR f4R f5、C(＝O)OR f2、OC(＝O)R f3、OC(＝O)NR f4R f5、NR f4R f5、NR f4C(＝O)R f3、NR f4OC(＝O)R f3、NR f4C(＝O)NR f4R f5、C(＝NR f6)R f3、C(＝NR f6)NR f4R f5、NR f4C(＝NR f6)NR f4R f5、NR f4S(＝O)R f2、NR f4S(＝O) 2R f2、NR f4S(＝O) 2NR f4R f5、S(＝O)R f2、S(＝O)NR f4R f5或S(＝O) 2NR f4R f5；所述4至7元杂环包含1至3个选自N、O、S的杂原子； R b4 and R b5 form a 4 to 7-membered heterocyclic ring together with the N atom to which they are attached, and the heterocyclic ring is further substituted by 1 or more substituents selected from the group consisting of: halogen, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, CN, OR f2 , SR f2 , C(=O)R f3 , C(=O)NR f4 R f5 , C(=O)OR f2 , OC(=O) R f3 , OC(=O)NR f4 R f5 , NR f4 R f5 , NR f4 C(=O)R f3 , NR f4 OC(=O)R f3 , NR f4 C(=O)NR f4 R f5 , C(=NR f6 )R f3 , C(=NR f6 )NR f4 R f5 , NR f4 C(=NR f6 )NR f4 R f5 , NR f4 S(=O)R f2 , NR f4 S (=O) 2 R f2 , NR f4 S(=O) 2 NR f4 R f5 , S(=O)R f2 , S(=O)NR f4 R f5 or S(=O) 2 NR f4 R f5 ; the 4 to The 7-membered heterocycle contains 1 to 3 heteroatoms selected from N, O, S;
R f1、R f2、R f3、R f4、R f5、R f6、R e1、R e2、R e3、R e4、R e5、R e6各自独立地选自C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳 基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1- 6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R f1 , R f2 , R f3 , R f4 , R f5 , R f6 , R e1 , R e2 , R e3 , R e4 , R e5 , R e6 are each independently selected from C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1-6 alkane C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl optionally Substituted by 1 to more substituents selected from : H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3- 10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH; the 5 to 12 membered heteroaryl, 3 to The 10-membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, S;
p为1、2或者3。p is 1, 2 or 3.
在一个或多个实施方式中，中间体化合物或者其立体异构体或药学上可接受的盐具有以下结构或者其立体异构体或药学上可接受的盐：In one or more embodiments, the intermediate compound or its stereoisomer or pharmaceutically acceptable salt has the following structure or its stereoisomer or pharmaceutically acceptable salt:
Figure PCTCN2022110534-appb-000088
或者
Figure PCTCN2022110534-appb-000089
Figure PCTCN2022110534-appb-000088
or
Figure PCTCN2022110534-appb-000089
本申请的一个或多个实施方式提供了药物组合物，其包含：One or more embodiments of the present application provide a pharmaceutical composition comprising:
(1)本申请的化合物，或者其立体异构体或药学上可接受的盐；(1) The compound of the present application, or its stereoisomer or pharmaceutically acceptable salt;
(2)任选的一种或者多种其他活性成分；以及(2) Optional one or more other active ingredients; and
(3)药学上可接受的载体和/或赋形剂。(3) Pharmaceutically acceptable carriers and/or excipients.
本申请的一个或多个实施方式提供了本申请的化合物或者其立体异构体或药学上可接受的盐或者本申请的药物组合物在制备抗肿瘤药物中的用途。One or more embodiments of the present application provide the use of the compound of the present application or its stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition of the present application in the preparation of antitumor drugs.
在一个或多个实施方式中，所述肿瘤的形成与PARP相关。In one or more embodiments, said tumor formation is associated with PARP.
在一个或多个实施方式中，所述PARP为PARP-7。In one or more embodiments, the PARP is PARP-7.
本申请的一个或多个实施方式提供了本申请的化合物或者其立体异构体或药学上可接受的盐或者本申请的药物组合物在制备PARP抑制剂中的用途。One or more embodiments of the present application provide the use of the compound of the present application or its stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition of the present application in the preparation of a PARP inhibitor.
在一个或多个实施方式中，所述PARP为PARP-7。In one or more embodiments, the PARP is PARP-7.
本申请的一个或多个实施方式提供了本申请的化合物或者其立体异构体或药学上可接受的盐或者本申请的药物组合物，其用作药物。One or more embodiments of the present application provide the compound of the present application or its stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition of the present application for use as a medicament.
本申请的一个或多个实施方式提供了本申请的化合物或者其立体异构体或药学上可接受的盐或者本申请的药物组合物，其用于***的方法中。在一个或多个实施方式中，所述肿瘤的形成与PARP相关。在一个或多个实施方式中，所述PARP为PARP-7。One or more embodiments of the present application provide the compound of the present application or its stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition of the present application, which is used in the method of treating tumor. In one or more embodiments, said tumor formation is associated with PARP. In one or more embodiments, the PARP is PARP-7.
本申请的一个或多个实施方式提供了本申请的化合物或者其立体异构体或药学上可接受的盐或者本申请的药物组合物，其用作PARP抑制剂，例如PARP-7抑制剂。One or more embodiments of the present application provide the compound of the present application or its stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition of the present application, which is used as a PARP inhibitor, such as a PARP-7 inhibitor.
本申请的一个或多个实施方式提供了***的方法，其包括将本申请的化合物或者其立体异构体或药学上可接受的盐或者本申请的药物组合物给予有此需要的对象。One or more embodiments of the present application provide a method for treating tumors, which includes administering the compound of the present application or its stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition of the present application to a subject in need thereof.
本申请的一个或多个实施方式提供了抑制PARP的方法，其包括给予本申请的化合物或者其立体异构体或药学上可接受的盐或者本申请的药物组合物。在一个或多个实施方式中，所述PARP为PARP-7。One or more embodiments of the present application provide a method for inhibiting PARP, which includes administering the compound of the present application or its stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition of the present application. In one or more embodiments, the PARP is PARP-7.
发明详述Detailed description of the invention
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括 12C、 13C和 14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括 16O、 17O和 18O，硫的同位素包括 32S、 33S、 34S和 36S，氮的同位素包括 14N和 15N，氟的同位素包括 17F和 19F，氯的同位素包括 35Cl和 37Cl，溴的同位素包括 79Br和 81Br。 The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, and I involved in the groups and compounds of the present invention include their isotopes, and the carbon involved in the groups and compounds of the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D, Also called heavy hydrogen), tritium (T, also called super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, the isotopes of fluorine include 17 F and 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, and the isotopes of bromine include 79 Br and 81 Br.
“烷基”是指1至20个碳原子(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个碳原子)的直链或支链饱和脂肪族烃基，优选为1至8个碳原子的烷基，更优选为1至6个碳原子的烷基，进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；当烷基被取代基时，可以任选进一步被1个或者多个取代基所取代。"Alkyl" means 1 to 20 carbon atoms (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms) straight-chain or branched saturated aliphatic hydrocarbon group, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, further preferably 1 to 4 Alkyl group of carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl And its various branched isomers; when the alkyl group is substituted, it may be optionally further substituted by one or more substituents.
“芳基”是指是指取代的或未取代的芳香环，其可以是5至8元(例如5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，其可以是桥环或者螺环，非限制性实施例包括苯基、萘基、
Figure PCTCN2022110534-appb-000090
Figure PCTCN2022110534-appb-000091
Figure PCTCN2022110534-appb-000092
所述的芳基可以任选进一步被1个或者多个取代基所取代。 "Aryl" refers to a substituted or unsubstituted aromatic ring, which can be a 5 to 8 membered (eg 5, 6, 7, 8 membered) monocyclic ring, a 5 to 12 membered (eg 5, 6, 7 , 8, 9, 10, 11, 12 member) bicyclic ring or 10 to 15 member (eg 10, 11, 12, 13, 14, 15 member) tricyclic ring system, which can be a bridge ring or a spiro ring, non-limiting implementation Examples include phenyl, naphthyl,
Figure PCTCN2022110534-appb-000090
Figure PCTCN2022110534-appb-000091
Figure PCTCN2022110534-appb-000092
The aryl group may be optionally further substituted by one or more substituents.
“杂芳基”是指取代的或未取代的芳香环，其可以是5至8元(例如5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1至6个(例如1、2、3、4、5、6个)选自N、O或S的杂原子，优选3至8元(例如3、4、5、6、7、8元)杂环基，杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂环基可以是桥环或者螺环，非限制性实施例包括环吡啶基、呋喃基、噻吩基、噁唑基、吡喃基、吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基苯并咪唑基、苯并吡啶基、吡咯并吡啶基、吡唑并哌嗪基、三氮唑并哌嗪基、咪唑并哌嗪基、咪唑并吡嗪基、吡唑并嘧啶基、苯并嘧啶基、
Figure PCTCN2022110534-appb-000093
Figure PCTCN2022110534-appb-000094
Figure PCTCN2022110534-appb-000095
当杂芳基被取代时，可以任选进一步被1个或多个取代基所取代。 "Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be a 5 to 8 membered (eg 5, 6, 7, 8 membered) monocyclic ring, a 5 to 12 membered (eg 5, 6, 7, 8 membered) 8, 9, 10, 11, 12 member) bicyclic ring or 10 to 15 member (eg 10, 11, 12, 13, 14, 15 member) tricyclic ring system, and contains 1 to 6 (eg 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably 3 to 8-membered (eg 3, 4, 5, 6, 7, 8-membered) heterocyclic group, optional in the ring of the heterocyclic group Substituted N and S can be oxidized into various oxidation states. The heterocyclic group can be connected to a heteroatom or a carbon atom, and the heterocyclic group can be a bridge ring or a spiro ring. Non-limiting examples include cyclopyridyl, furyl, thienyl, oxazolyl, pyranyl, pyrrolyl , pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl benzimidazolyl, benzopyridyl, pyrrolopyridyl, pyrazolopiperazinyl, triazolopiperazinyl, imidazo Piperazinyl, imidazopyrazinyl, pyrazolopyrimidinyl, benzopyrimidinyl,
Figure PCTCN2022110534-appb-000093
Figure PCTCN2022110534-appb-000094
Figure PCTCN2022110534-appb-000095
When heteroaryl is substituted, it may be optionally further substituted with one or more substituents.
“杂环基”或“杂环”是指饱和或不饱和的杂芳环或者非杂芳环，当选自杂芳环时，其 定义与上文“杂芳基”定义相同；当选自非杂芳环时，其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1至4个(例如1、2、3、4个)选自N、O或S的杂原子，优选3至8元杂环基。“杂环基”或“杂环”的环中选择性取代的N、S可被氧化成各种氧化态；“杂环基”或“杂环”可以连接在杂原子或者碳原子上；“杂环基”或“杂环”可以为桥环或者螺环。“杂环基”或“杂环”的非限制性实施例包括环氧乙基、环氧丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、硫杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、氧杂环庚基、硫杂环庚基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、吡啶基、哌啶基、高哌啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、高哌嗪基、咪唑基、吡唑基、噁唑基、异噁唑基、哌啶基、吗啉基、硫代吗啉基、噻噁烷基、1,3-二噻烷基、二氢呋喃基、二噻戊环基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、3H-吲哚基喹嗪基、N-吡啶基尿素、1,1-二氧硫代吗啉基、氮杂二环[3.2.1]辛烷基、
Figure PCTCN2022110534-appb-000096
Figure PCTCN2022110534-appb-000097
Figure PCTCN2022110534-appb-000098
氮杂二环[5.2.0]壬烷基、氧杂 三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的“杂环基”或“杂环”可以任选进一步被0个或者多个取代基所取代。 "Heterocyclic group" or "heterocyclic ring" refers to a saturated or unsaturated heteroaromatic or non-heteroaromatic ring. When selected from a heteroaromatic ring, its definition is the same as the definition of "heteroaryl"above; In the case of an aromatic ring, it can be a monocyclic ring with 3 to 10 members (for example, 3, 4, 5, 6, 7, 8, 9, 10 members), a 4 to 12 member (for example, 4, 5, 6, 7, 8, 9, 10, 11, 12) bicyclic or 10 to 15 (e.g. 10, 11, 12, 13, 14, 15) tricyclic ring system, and contains 1 to 4 (e.g. 1, 2, 3, 4 ) is a heteroatom selected from N, O or S, preferably a 3- to 8-membered heterocyclic group. The selectively substituted N and S in the ring of "heterocyclic group" or "heterocyclic ring" can be oxidized to various oxidation states; "heterocyclic group" or "heterocyclic ring" can be connected to a heteroatom or a carbon atom; " A "heterocyclyl" or "heterocycle" may be a bridged ring or a spiro ring. Non-limiting examples of "heterocyclyl" or "heterocycle" include oxiranyl, epoxypropyl, aziridyl, oxetanyl, azetidinyl, thietanyl , 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, oxepyl, thiepanyl, oxygen Azepine, diazepine, thiazepine, pyridyl, piperidyl, homopiperidyl, furyl, thienyl, pyryl, N-alkylpyrrolyl, pyrimidyl, pyrimidyl Azidinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaxyl , 1,3-Dithianyl, Dihydrofuranyl, Dithiapentyl, Tetrahydrofuryl, Tetrahydrothiophenyl, Tetrahydropyranyl, Tetrahydrothiopyranyl, Tetrahydropyrrolyl, Tetrahydroimidazolyl , tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, indoline Base, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolyl, pyrazolinyl, dithianyl, dithianolyl, dihydrothienyl, Pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0] Heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinazinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl alkyl,
Figure PCTCN2022110534-appb-000096
Figure PCTCN2022110534-appb-000097
Figure PCTCN2022110534-appb-000098
Azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl. The "heterocyclic group" or "heterocycle" may be optionally further substituted by 0 or more substituents.
“杂环烷基”是指取代的或未取代的饱和非芳香环基，其可以是3至8元(例如3、4、5、6、7或8元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1、2或3个选自N、O或S的杂原子，例如3至8元杂环基。“杂环烷基”的环中选择性取代的N、S可被氧化成各种氧化态；“杂环烷基”可以连接在杂原子或者碳原子上；“杂环烷基”可以为桥环或者螺环。“杂环烷基”非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻烷基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基、
Figure PCTCN2022110534-appb-000099
Figure PCTCN2022110534-appb-000100
"Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic ring group, which may be 3 to 8 membered (eg 3, 4, 5, 6, 7 or 8 membered) monocyclic, 4 to 12 membered (e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12 members) bicyclic rings or 10 to 15 membered (e.g. 10, 11, 12, 13, 14, 15 members) tricyclic ring systems, and comprising 1, 2 or 3 heteroatoms selected from N, O or S, eg 3 to 8 membered heterocyclyl. The N and S selectively substituted in the ring of "heterocycloalkyl" can be oxidized into various oxidation states; "heterocycloalkyl" can be connected to a heteroatom or carbon atom; "heterocycloalkyl" can be a bridge ring or spiral. Non-limiting examples of "heterocycloalkyl" include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-di Oxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl , tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonyl, oxa Tricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl,
Figure PCTCN2022110534-appb-000099
Figure PCTCN2022110534-appb-000100
“碳环基”或“碳环”是指饱和或者不饱和的芳香环或者非芳香环。当选自芳香环时，其定义与上文“芳基”的定义相同；当选自非芳香环时，其可以是3至10元的单环、4至12元双环或者10至15元三环体系，可以是桥环或者螺环，非限制性实施例包括环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、环己二烯基、环庚基、环辛基、 环壬基、环癸基、环十一烷基、环十二烷基、
Figure PCTCN2022110534-appb-000101
Figure PCTCN2022110534-appb-000102
所述的“碳环基”或“碳环”可以任选进一步被1个或者多个取代基所取代。 "Carbocyclyl" or "carbocycle" refers to a saturated or unsaturated aromatic or non-aromatic ring. When selected from an aromatic ring, its definition is the same as the definition of "aryl"above; when selected from a non-aromatic ring, it can be a 3-10-membered monocyclic ring, a 4-12-membered bicyclic ring, or a 10-15-membered tricyclic ring system , can be bridged or spiro, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1 -Cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl Cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl,
Figure PCTCN2022110534-appb-000101
Figure PCTCN2022110534-appb-000102
The "carbocyclyl" or "carbocycle" may be optionally further substituted by one or more substituents.
当上文所述的“烷基”、“芳基”、“杂芳基”、“杂环”、“杂环基”、“杂环烷基”、“碳环”、“碳环基”被取代时，可以任选进一步被0、1、2、3、4、5、6、7、8、9或者10个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、C 1-6烷基氨基、＝O、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、-NR q4R q5、＝NR q6、-C(＝O)OC 1-6烷基、-OC(＝O)C 1-6烷基、-C(＝O)NR q4R q5、C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基、C 5-10杂芳基、-C(＝O)OC 6-10芳基、-OC(＝O)C 6-10芳基、-OC(＝O)C 5-10杂芳基、-C(＝O)OC 5-10杂芳基、-OC(＝O)C 3-8杂环烷基、-C(＝O)OC 3-8杂环烷基、-OC(＝O)C 3-8环烷基、-C(＝O)OC 3-8环烷基、-NHC(＝O)C 3-8杂环烷基、-NHC(＝O)C 6-10芳基、-NHC(＝O)C 5-10杂芳基、-NHC(＝O)C 3-8环烷基、-NHC(＝O)C 3-8杂环烷基、-NHC(＝O)C 2-6烯基或者-NHC(＝O)C 2-6炔基的取代基所取代，且其中所述的取代基C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基、C 5-10杂芳基、-NHC(＝O)C 6-10芳基、-NHC(＝O)C 5-10杂芳基、-NHC(＝O)C 3-8杂环烷基或者-NHC(＝O)C 3-8环烷基任选进一步被1至3个选自OH、F、Cl、Br、I、C 1-6烷基、C 1-6烷氧基、-NR q4R q5或者＝O的取代基所取代；R q1选自C 1-6烷基、C 1-6烷氧基或者C 6-10芳基；R q2、R q3选自H或者C 1-6烷基；R q4、R q5选自H、C 1-6烷基、-NH(C＝NR q1)NR q2R q3、-S(＝O) 2NR q2R q3、-C(＝O)R q1或者-C(＝O)NR q2R q3，其中所述的C 1-6烷基任选进一步被1个或者多个选自OH、F、Cl、Br、I、C 1-6烷基、C 1-6烷氧基、C 6-10芳基、C 5-10杂芳基、C 3-8环烷基或者C 3-8杂环烷基的取代基所取代；或者R q4与R q5及N原子形成一个3至8元杂环，所述的环可以含有1个或者多个选自N、O或者S的杂原子。 When the above-mentioned "alkyl", "aryl", "heteroaryl", "heterocycle", "heterocyclyl", "heterocycloalkyl", "carbocycle", "carbocyclyl" When substituted, it can optionally be further 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano , amino, C 1-6 alkylamino, =O, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -NR q4 R q5 , = NR q6 , -C(=O)OC 1-6 alkyl, -OC(=O)C 1-6 alkyl, -C(=O)NR q4 R q5 , C 3-8 cycloalkyl, C 3 -8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, -C(=O)OC 6-10 aryl, -OC(=O)C 6-10 aryl, -OC (=O)C 5-10 heteroaryl, -C(=O)OC 5-10 heteroaryl, -OC(=O)C 3-8 heterocycloalkyl, -C(=O)OC 3- 8 Heterocycloalkyl, -OC(=O)C 3-8 Cycloalkyl, -C(=O)OC 3-8 Cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, - NHC(=O)C 6-10 aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC (=O) C 2-6 alkenyl or -NHC (= O) C 2-6 alkynyl is substituted by substituents, and wherein the substituent C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, C 5-10 Heteroaryl, -NHC(=O)C 6-10 aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 heterocycloalkyl or -NHC(= O) C 3-8 cycloalkyl is optionally further replaced by 1 to 3 selected from OH, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, -NR q4 R q5 or =O substituent; R q1 is selected from C 1-6 alkyl, C 1-6 alkoxy or C 6-10 aryl; R q2 , R q3 are selected from H or C 1-6 alkyl; R q4 and R q5 are selected from H, C 1-6 alkyl, -NH(C=NR q1 )NR q2 R q3 , -S(=O) 2 NR q2 R q3 , -C(=O)R q1 or -C(=O)NR q2 R q3 , wherein the C 1-6 alkyl is optionally further replaced by one or more selected from OH, F, Cl, Br, I, C 1-6 alkyl, C Substituents of 1-6 alkoxy, C 6-10 aryl, C 5-10 heteroaryl, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; or R q4 , R q5 and N atoms form a 3-8 membered heterocyclic ring, and the ring may contain one or more heteroatoms selected from N, O or S.
“药物组合物”是指一种或多种本发明所述的化合物、其药学上可接受的盐或前药和其它活性组分形成的混合物，其中，“其它活性组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。"Pharmaceutical composition" refers to a mixture of one or more compounds described in the present invention, their pharmaceutically acceptable salts or prodrugs and other active components, wherein "other active components" refers to pharmaceutically acceptable acceptable carrier, excipient and/or one or more other therapeutic agents.
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。"Carrier" refers to a material that does not produce significant irritation to an organism and that does not abrogate the biological activity and properties of the administered compound.
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。"Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders agents and disintegrants.
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。"Stereoisomer" refers to isomers produced by different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means that the compound of the present invention maintains the biological effectiveness and characteristics of free acid or free base, and the free acid is mixed with a non-toxic inorganic base or Organic base, the salt obtained by reacting the free base with a non-toxic inorganic acid or organic acid.
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生，该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如，“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在，该描述包括其中杂环基被烷基取代的情况，及其中杂环基未被烷基取代的情况。"Optional" or "optionally" or "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes the circumstances in which the event or circumstance occurs and the circumstances in which it is not what happened. For example, "heterocyclyl optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and the description includes cases where the heterocyclyl group is substituted with an alkyl group, and cases where the heterocyclyl group is not substituted with an alkyl group. Condition.
TBS:叔丁基二甲基硅烷基。TBS: tert-butyldimethylsilyl.
具体实施方式Detailed ways
以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于 此。The following examples describe technical solutions of the present invention in detail, but protection scope of the present invention includes but is not limited to this.
中间体1Intermediate 1
5-氯-2-(4-甲氧基苄基)-4-(三氟甲基)哒嗪-3(2H)-酮(中间体1)5-Chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Intermediate 1)
5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022110534-appb-000103
Figure PCTCN2022110534-appb-000103
第一步：first step:
4,5-二溴-2-(4-甲氧基苄基)哒嗪-3(2H)-酮(1b)4,5-Dibromo-2-(4-methoxybenzyl)pyridazin-3(2H)-one (1b)
4,5-dibromo-2-(4-methoxybenzyl)pyridazin-3(2H)-one4,5-dibromo-2-(4-methoxybenzyl)pyridazin-3(2H)-one
在0-10℃下，向4,5-二溴-2,3-二氢哒嗪-3-酮(1a,50g，196.94mmol，1.0equiv)的N,N-二甲基-甲酰胺(500mL)溶液中，分批次加入氢化钠(11.82g，295.41mmol，1.5equiv，60％)，随后在0℃下加入1-(氯甲基)-4-甲氧基苯(46.06g，294.11mmol，1.49equiv)。加毕，将反应混合于室温下搅拌3h。待反应完全后将反应液缓慢倾倒入1.0L冰水混合物中淬灭，并用二氯甲烷(2×500mL)萃取。合并有机层并浓缩。用甲醇(500mL×2)洗涤固体，得化合物1b,黄色固体(48.4g,产率66％)。To 4,5-dibromo-2,3-dihydropyridazin-3-one (1a, 50 g, 196.94 mmol, 1.0 equiv) in N,N-dimethyl-formamide ( 500mL) solution, sodium hydride (11.82g, 295.41mmol, 1.5equiv, 60%) was added in batches, followed by 1-(chloromethyl)-4-methoxybenzene (46.06g, 294.11 mmol, 1.49 equiv). After the addition was complete, the reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, the reaction solution was slowly poured into 1.0L ice-water mixture to quench, and extracted with dichloromethane (2×500 mL). The organic layers were combined and concentrated. The solid was washed with methanol (500 mL×2) to obtain compound 1b as a yellow solid (48.4 g, yield 66%).
LC-MS m/z(ESI)＝375.00[M+1]。LC-MS m/z (ESI) = 375.00 [M+1].
第二步：Step two:
4-溴-5-甲氧基-2-(4-甲氧基苄基)哒嗪-3(2H)-酮(1c)4-Bromo-5-methoxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one (1c)
4-bromo-5-methoxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one4-bromo-5-methoxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one
将化合物1b(48.4g，129.40mmol，1.0equiv)，氢氧化钾(21.78g，388.30mmol，3.00equiv)溶解于甲醇(417mL)中，反应液于室温下搅拌2h。将所得反应混合物浓缩至80mL，过滤得粗品。将所得滤饼在水(160mL)中制浆1h，过滤得化合物1c,白色固体(38.72g，产率92％)。Compound 1b (48.4g, 129.40mmol, 1.0equiv), potassium hydroxide (21.78g, 388.30mmol, 3.00equiv) were dissolved in methanol (417mL), and the reaction solution was stirred at room temperature for 2h. The resulting reaction mixture was concentrated to 80 mL and filtered to obtain a crude product. The resulting filter cake was slurried in water (160 mL) for 1 h and filtered to obtain compound 1c as a white solid (38.72 g, 92% yield).
LC-MS m/z(ESI)＝326.30[M+1]。LC-MS m/z (ESI) = 326.30 [M+1].
第三步：third step:
5-甲氧基-2-(4-甲氧基苄基)-4-(三氟甲基)哒嗪-3(2H)-酮(1d)5-methoxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (1d)
5-methoxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one5-methoxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one
称取化合物1c(14g，43.04mmol，1.0equiv)和CuI(4.10g，21.52mmol，0.50equiv)与250mL反应烧瓶中，以N-甲基吡咯烷酮(72mL)溶解，随后缓慢加入2,2-二氟-2-(氟磺酰基)乙酸甲酯(16.4mL，129.11mmol，3.0equiv)。加毕，将反应置于100℃油浴中搅拌反应3h。待反应完全后，向反应液中加入90mL水淬灭。二氯甲烷(3×60mL)萃取所得溶液。合并有机层，无水硫酸钠干燥，真空浓缩，将残留物通过柱层析(石油醚:乙酸乙酯＝1:1)纯化得化合物1d，白色固体(12.1g，产 率89％)。Weigh compound 1c (14g, 43.04mmol, 1.0equiv) and CuI (4.10g, 21.52mmol, 0.50equiv) into a 250mL reaction flask, dissolve it with N-methylpyrrolidone (72mL), then slowly add 2,2-bis Methyl fluoro-2-(fluorosulfonyl)acetate (16.4 mL, 129.11 mmol, 3.0 equiv). After the addition was complete, the reaction was placed in an oil bath at 100°C and stirred for 3h. After the reaction was complete, 90 mL of water was added to the reaction solution to quench it. The resulting solution was extracted with dichloromethane (3 x 60 mL). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 1d as a white solid (12.1 g, yield 89%).
LC-MS m/z(ESI)＝315.10[M+1]。LC-MS m/z (ESI) = 315.10 [M+1].
第四步：the fourth step:
5-羟基-2-(4-甲氧基苄基)-4-(三氟甲基)哒嗪-3(2H)-酮(1e)5-Hydroxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (1e)
5-hydroxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one5-hydroxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one
在室温下，向化合物1d(12.1g，38.52mmol，1.0equiv)的N,N-二甲基-甲酰胺(60mL)溶液中，逐滴加入三甲基碘硅烷(9.97g，50.07mmol，1.3equiv)。所得反应液在85℃下搅拌20h。待反应完毕，向反应混合物中加入60mL水淬灭反应，随后二氯甲烷(3×60mL)萃取所得溶液。合并有机相，无水硫酸钠干燥，真空浓缩，残留物柱层析(石油醚:乙酸乙酯＝1:1)纯化得化合物1e，白色固体(10.4g，产率90％)。To a solution of compound 1d (12.1 g, 38.52 mmol, 1.0 equiv) in N,N-dimethyl-formamide (60 mL) was added dropwise iodotrimethylsilane (9.97 g, 50.07 mmol, 1.3 equiv). The resulting reaction solution was stirred at 85 °C for 20 h. After the reaction was completed, 60 mL of water was added to the reaction mixture to quench the reaction, and then the resulting solution was extracted with dichloromethane (3×60 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 1e as a white solid (10.4 g, yield 90%).
LC-MS m/z(ESI)＝301.07[M+1]。LC-MS m/z (ESI) = 301.07 [M+1].
第五步：the fifth step:
5-氯-2-(4-甲氧基苄基)-4-(三氟甲基)哒嗪-3(2H)-酮(中间体1)5-Chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Intermediate 1)
5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one
在0℃下，向化合物1e(10.4g，34.66mmol，1.0equiv)的N,N-二甲基-甲酰胺(52mL)溶液中，缓慢滴加草酰二氯(8.79g，69.32mmol，2.0equiv)。加毕，将反应混合液于室温下搅拌8h。待反应完全，向反应液中加入550mL水淬灭。过滤混合液，得中间体1，白色固体(11.04g，99％)。To a solution of compound 1e (10.4 g, 34.66 mmol, 1.0 equiv) in N,N-dimethyl-formamide (52 mL) at 0°C, oxalyl dichloride (8.79 g, 69.32 mmol, 2.0 equiv). After the addition was complete, the reaction mixture was stirred at room temperature for 8 h. After the reaction was complete, 550 mL of water was added to the reaction solution to quench it. The mixture was filtered to obtain Intermediate 1 as a white solid (11.04 g, 99%).
LC-MS m/z(ESI)＝319.68[M+1]。LC-MS m/z (ESI) = 319.68 [M+1].
中间体2Intermediate 2
(R)-2-(2,2-二甲基-5-氧代-1,3-二氧戊环-4-基)乙醛(中间体2)(R)-2-(2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (Intermediate 2)
(R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde(R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde
Figure PCTCN2022110534-appb-000104
Figure PCTCN2022110534-appb-000104
第一步：first step:
(R)-5-(2-羟乙基)-2,2-二甲基-1,3-二氧戊环-4-酮(2b)(R)-5-(2-Hydroxyethyl)-2,2-dimethyl-1,3-dioxolan-4-one (2b)
(R)-5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolan-4-one(R)-5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolan-4-one
称取中间体2a(3.5g，20mmol，1.0equiv)溶于四氢呋喃(20mL)中。冰浴下滴加硼烷四氢呋喃络合物(26mL，26.0mmol，1.3equiv)。滴毕，室温反应2.5h。待反应完全后，加入甲醇(10mL)淬灭，室温搅拌10min，浓缩，得化合物2b，黄色油状物(3.0g，产率94％)。Intermediate 2a (3.5 g, 20 mmol, 1.0 equiv) was weighed and dissolved in THF (20 mL). Borane tetrahydrofuran complex (26 mL, 26.0 mmol, 1.3 equiv) was added dropwise under ice cooling. After dropping, react at room temperature for 2.5h. After the reaction was complete, it was quenched by adding methanol (10 mL), stirred at room temperature for 10 min, and concentrated to obtain compound 2b as a yellow oil (3.0 g, yield 94%).
第二步：Step two:
(R)-2-(2,2-二甲基-5-氧代-1,3-二氧戊环-4-基)乙醛(中间体2)(R)-2-(2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (Intermediate 2)
(R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde(R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde
称取化合物2b(2.6g，18mmol，1.0equiv)溶于二氯甲烷(50mL)中，缓慢加入氯铬 酸吡啶盐(19.4g，90mmol，5.0equiv)。加毕，室温反应2h。待反应完毕，硅藻土抽滤，乙酸乙酯洗滤饼，滤液中加入活性炭，放置30min。再次硅藻土抽滤，旋干滤液，得中间体2，褐色油状物(1.1g,产率42％)，冰箱保存。Compound 2b (2.6g, 18mmol, 1.0equiv) was weighed and dissolved in dichloromethane (50mL), and pyridinium chlorochromate (19.4g, 90mmol, 5.0equiv) was slowly added. After the addition, react at room temperature for 2h. After the reaction is complete, filter with diatomaceous earth, wash the filter cake with ethyl acetate, add activated carbon to the filtrate, and let it stand for 30 minutes. Suction filtration with diatomaceous earth again, and the filtrate was spin-dried to obtain Intermediate 2, a brown oil (1.1 g, yield 42%), which was stored in a refrigerator.
中间体3Intermediate 3
(R)-3-((S)-2-氨基丙氧基)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)吡咯烷-2-酮(中间体3)(R)-3-((S)-2-aminopropoxy)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidine-4 -yl)pyrrolidin-2-one (intermediate 3)
(R)-3-((S)-2-aminopropoxy)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)pyrrolidin-2-one(R)-3-((S)-2-aminopropoxy)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)pyrrolidin-2-one
Figure PCTCN2022110534-appb-000105
Figure PCTCN2022110534-appb-000105
第一步：first step:
叔丁基((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)氨基甲酸酯(3b)tert-Butyl ((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)carbamate (3b)
tert-butyl((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)carbamatetert-butyl((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)carbamate
称取化合物3a(500mg，2.3mmol，1.0equiv)溶于N,N-二甲基-甲酰胺(5.0mL)中。随后，依次加入N,N-二异丙基-乙胺(1.8mL，11.5mmol，5.0equiv)和2-氯-5-环丙基嘧啶(320mg，2.1mmol，0.9equiv)。将混合物于100℃下搅拌反应4h。待反应完全后，真空浓缩，将残留物通过柱层析(石油醚:乙酸乙酯＝1:1)纯化得化合物3b，黄色固体(600mg，产率78％)。Compound 3a (500 mg, 2.3 mmol, 1.0 equiv) was weighed and dissolved in N,N-dimethyl-formamide (5.0 mL). Subsequently, N,N-diisopropyl-ethylamine (1.8 mL, 11.5 mmol, 5.0 equiv) and 2-chloro-5-cyclopropylpyrimidine (320 mg, 2.1 mmol, 0.9 equiv) were added sequentially. The mixture was stirred at 100 °C for 4 h. After the reaction was complete, it was concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 3b as a yellow solid (600 mg, yield 78%).
LC-MS m/z(ESI)＝335.10[M+1]。LC-MS m/z (ESI) = 335.10 [M+1].
第二步：Step two:
(3R，4R)-4-氨基-1-(5-环丙基嘧啶-2-基)哌啶-3-醇(3c)(3R,4R)-4-Amino-1-(5-cyclopropylpyrimidin-2-yl)piperidin-3-ol (3c)
(3R,4R)-4-amino-1-(5-cyclopropylpyrimidin-2-yl)piperidin-3-ol(3R,4R)-4-amino-1-(5-cyclopropylpyrimidin-2-yl)piperidin-3-ol
称取化合物3b(1.1g，3.3mmol，1.0equiv)，溶于盐酸二氧六环溶液中(4M,8mL)。反应于25℃下搅拌1h。随后，旋干反应液，得到化合物3c，白色固体(770mg，产率99％)。Compound 3b (1.1 g, 3.3 mmol, 1.0 equiv) was weighed and dissolved in dioxane hydrochloride solution (4M, 8 mL). The reaction was stirred at 25 °C for 1 h. Subsequently, the reaction solution was spin-dried to obtain compound 3c as a white solid (770 mg, yield 99%).
LC-MS m/z(ESI)＝235.10[M+1]。LC-MS m/z (ESI) = 235.10 [M+1].
第三步：third step:
(3R，4R)-3-((叔丁基二甲基硅)氧基)-1-(5-环丙基嘧啶-2-基)哌啶-4-胺(3d)(3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-amine (3d)
(3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(5-cyclopropylpyrimidin-2-yl)piperidin-4- amine(3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-amine
称取化合物3c(700mg，3.3mmol，1.0equiv)溶于乙腈(30mL)中。随后，依次加入咪唑(2.2g，33mmol，10.0equiv)和叔丁基二甲基氯硅烷(3.0g，19.8mmol，6.0equiv)。将混合物于60℃下搅拌反应24h。待反应完全后，真空浓缩，将残留物通过柱层析(石油醚:乙酸乙酯＝1:1)纯化得化合物3d，黄色固体(1.0g，产率87％)。Compound 3c (700 mg, 3.3 mmol, 1.0 equiv) was weighed and dissolved in acetonitrile (30 mL). Subsequently, imidazole (2.2 g, 33 mmol, 10.0 equiv) and tert-butyldimethylchlorosilane (3.0 g, 19.8 mmol, 6.0 equiv) were added sequentially. The mixture was stirred at 60 °C for 24 h. After the reaction was complete, it was concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain compound 3d as a yellow solid (1.0 g, yield 87%).
LC-MS m/z(ESI)＝349.10[M+1]。LC-MS m/z (ESI) = 349.10 [M+1].
第四步：the fourth step:
(R)-1-((3R，4R)-3-((叔丁基二甲基硅)氧基)-1-(5-环丙基嘧啶-2-基)哌啶-4-基)-3-羟基吡咯烷-2-酮(3e)(R)-1-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-yl) -3-Hydroxypyrrolidin-2-one (3e)
(R)-1-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-yl)-3-hydroxypyrrolidin-2-one(R)-1-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-yl)-3-hydroxypyrrolidin-2-one
称取化合物3d(118mg，0.34mmol，1.0equiv)溶于二氯甲烷(2.0mL)中。随后，依次加入中间体2(188mg，1.2mmol，3.5equiv)和冰乙酸(38.8μL，0.64mmol，2.0equiv)，室温反应1h后，加入三乙酰氧基硼氢化钠(216mg，1.02mmol，3.0equiv)。室温反应24h。待反应完全后，饱和碳酸氢钠淬灭反应，二氯甲烷萃取，浓缩有机相，将残留物通过柱层析(石油醚:乙酸乙酯＝1:1)纯化得化合物3e，黄色固体(62mg，产率42％)。Compound 3d (118 mg, 0.34 mmol, 1.0 equiv) was weighed and dissolved in dichloromethane (2.0 mL). Subsequently, Intermediate 2 (188mg, 1.2mmol, 3.5equiv) and glacial acetic acid (38.8μL, 0.64mmol, 2.0equiv) were added successively, and after reacting at room temperature for 1h, sodium triacetoxyborohydride (216mg, 1.02mmol, 3.0 equiv). Reaction at room temperature for 24h. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate, extracted with dichloromethane, the organic phase was concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 3e, a yellow solid (62mg , yield 42%).
第五步：the fifth step:
(R)-3-((S)-2-氨基丙氧基)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)吡咯烷-2-酮(中间体3)(R)-3-((S)-2-aminopropoxy)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidine-4 -yl)pyrrolidin-2-one (intermediate 3)
(R)-3-((S)-2-aminopropoxy)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)pyrrolidin-2-one(R)-3-((S)-2-aminopropoxy)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)pyrrolidin-2-one
向50mL反应瓶中，加入化合物3e(600mg，1.38mmol，1.0equiv)，无水N,N-二甲基甲酰胺(7mL)溶解。N 2保护，0℃下分批加入氢化钠(99mg，4.14mmol，3.0equiv)，加毕，于该温度下继续搅拌10min。随后，向反应体系中缓慢滴加(S)-4-甲基-1,2,3-氧杂噻唑烷-3-羧酸叔丁酯2,2-二氧化物的N,N-二甲基甲酰胺溶液(394mg于7mL)，保持滴加过程温度为0℃并继续搅拌2h。待反应完全，盐酸溶液(2M)调节反应体系至pH＝3，并室温搅拌0.5h。反应混合物以乙酸乙酯(3×120mL)的萃取。合并有机层，无水硫酸钠干燥，真空浓缩，得粗品，柱层析(二氯甲烷:甲醇＝20:1)纯化得中间体3，为白色固体(217mg，产率42％)。 Into a 50 mL reaction flask, add compound 3e (600 mg, 1.38 mmol, 1.0 equiv) and dissolve in anhydrous N,N-dimethylformamide (7 mL). Under N 2 protection, sodium hydride (99 mg, 4.14 mmol, 3.0 equiv) was added in portions at 0° C., after the addition was complete, stirring was continued at this temperature for 10 min. Subsequently, slowly drop (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2,2-dioxide in N,N-dimethyl Dimethyl formamide solution (394mg in 7mL), keep the dropwise addition process temperature at 0°C and continue to stir for 2h. After the reaction was complete, the reaction system was adjusted to pH=3 with hydrochloric acid solution (2M), and stirred at room temperature for 0.5 h. The reaction mixture was extracted with ethyl acetate (3 x 120 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol=20:1) to obtain intermediate 3 as a white solid (217 mg, yield 42%).
LC-MS m/z(ESI)＝377.10[M+1]。LC-MS m/z (ESI) = 377.10 [M+1].
实施例1Example 1
5-(((S)-1-(((R)-1-((3R,4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-2-氧代吡咯烷-3-基)氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物1)5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl) -2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 1)
5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin- 3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022110534-appb-000106
Figure PCTCN2022110534-appb-000106
Figure PCTCN2022110534-appb-000107
Figure PCTCN2022110534-appb-000107
第一步：first step:
5-(((S)-1-(((R)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-2-氧吡咯烷-3-基)氧基)丙烷-2-基)氨基)-2-(4-甲氧基苄基)-4-(三氟甲基)哒嗪-3(2H)-酮(1A)5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl) -2-Oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazine-3(2H) - Ketone (1A)
5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin- 3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one
称取中间体3(188mg，0.5mmol，1.0equiv)与中间体1(160mg，0.5mmol，1.0equiv)于10mL反应瓶中，并加入N,N-二甲基-甲酰胺(3.0mL)溶解。随后，依次加入N,N-二异丙基-乙胺(0.3mL，2.0mmol，4.0equiv)。将混合物于100℃下搅拌反应4h。待反应完全后，真空浓缩，将残留物通过柱层析(石油醚:乙酸乙酯＝1:1.5)纯化得化合物1A，白色固体(200mg，产率60％)。Weigh Intermediate 3 (188mg, 0.5mmol, 1.0equiv) and Intermediate 1 (160mg, 0.5mmol, 1.0equiv) in a 10mL reaction bottle, and add N,N-dimethyl-formamide (3.0mL) to dissolve . Subsequently, N,N-diisopropyl-ethylamine (0.3 mL, 2.0 mmol, 4.0 equiv) was added sequentially. The mixture was stirred at 100 °C for 4 h. After the reaction was complete, it was concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether:ethyl acetate=1:1.5) to obtain Compound 1A as a white solid (200 mg, yield 60%).
LC-MS m/z(ESI)＝658.10[M+1]。LC-MS m/z (ESI) = 658.10 [M+1].
第二步：Step two:
5-(((S)-1-(((R)-1-((3R,4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-2-氧代吡咯烷-3-基)氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物1)5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl) -2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 1)
5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin- 3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
向称有化合物1A(200mg，0.3mmol，1.0equiv)的10mL反应烧瓶中依次加入三氟乙酸(2.0mL)和三氟甲磺酸(0.2mL，2.4mmol，8.0equiv)。加毕，反应于25℃下搅拌1h。待反应完毕，向反应液中加入15mL水淬灭。所得溶液用乙酸乙酯(3×15mL)萃取。通过碳酸钾水溶液将有机层的pH值调节至8到9。合并有机层，真空浓缩，残留物经C18反相色谱法(水:乙腈＝1:1)纯化得化合物1，白色固体(110mg，产率68％)。To a 10 mL reaction flask weighing compound 1A (200 mg, 0.3 mmol, 1.0 equiv) was added trifluoroacetic acid (2.0 mL) and trifluoromethanesulfonic acid (0.2 mL, 2.4 mmol, 8.0 equiv) sequentially. After the addition was complete, the reaction was stirred at 25 °C for 1 h. After the reaction was complete, 15 mL of water was added to the reaction solution to quench it. The resulting solution was extracted with ethyl acetate (3 x 15 mL). The pH of the organic layer was adjusted to 8-9 by aqueous potassium carbonate. The organic layers were combined and concentrated in vacuo, and the residue was purified by C18 reverse phase chromatography (water:acetonitrile=1:1) to obtain compound 1 as a white solid (110 mg, yield 68%).
LC-MS m/z(ESI)＝538.10[M+1]。LC-MS m/z (ESI) = 538.10 [M+1].
1H NMR(400MHz,DMSO-d 6)δ12.47(s,1H),8.16(s,2H),7.96(s,1H),6.35(dd,1H),5.15(d,1H),4.89–4.70(m,1H),4.61(d,1H),4.15–4.11(m,2H),3.83–3.79(m,1H),3.77–3.70(m,1H),3.59(dd,1H),3.54–3.46(m,1H),3.29–3.26(m,1H),3.54–3.46(m,1H),2.88–2.75(m,1H),2.62(dd,1H),2.25–2.21(m,1H),1.83–1.65(m,2H),1.56–1.46(m,2H),1.17(d,3H),0.93–0.78(m,2H),0.68–0.56(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ12.47(s,1H),8.16(s,2H),7.96(s,1H),6.35(dd,1H),5.15(d,1H),4.89– 4.70(m,1H),4.61(d,1H),4.15–4.11(m,2H),3.83–3.79(m,1H),3.77–3.70(m,1H),3.59(dd,1H),3.54– 3.46(m,1H),3.29–3.26(m,1H),3.54–3.46(m,1H),2.88–2.75(m,1H),2.62(dd,1H),2.25–2.21(m,1H), 1.83–1.65(m,2H), 1.56–1.46(m,2H), 1.17(d,3H), 0.93–0.78(m,2H), 0.68–0.56(m,2H).
实施例2Example 2
5-(((S)-1-(((R)-1-((3R,4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-2-氧代吡咯烷-3- 基)氧基)丁-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物2)5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl) -2-oxopyrrolidin-3-yl)oxy)but-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 2)
5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)butan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin- 3-yl)oxy)butan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022110534-appb-000108
Figure PCTCN2022110534-appb-000108
第一步：first step:
(R)-3-((S)-2-氨基丁氧基)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)吡咯烷-2-酮(2A)(R)-3-((S)-2-aminobutoxy)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidine-4 -yl)pyrrolidin-2-one (2A)
(R)-3-((S)-2-aminobutoxy)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxy piperidin-4-yl)pyrrolidin-2-one(R)-3-((S)-2-aminobutoxy)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxy piperidin-4-yl)pyrrolidin-2- one
参考中间体3第五步类似的合成方法，得化合物2A,为无色油状物(120mg，产率30％)。Referring to the similar synthesis method of the fifth step of Intermediate 3, Compound 2A was obtained as a colorless oil (120 mg, yield 30%).
LC-MS m/z(ESI)＝390.55[M+1]。LC-MS m/z (ESI) = 390.55 [M+1].
第二步：Step two:
5-(((S)-1-(((R)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-2-氧吡咯烷-3-基)氧基)丁烷-2-基)氨基)-2-(4-甲氧基苄基)-4-(三氟甲基)哒嗪-3(2H)-酮(2B)5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl) -2-Oxypyrrolidin-3-yl)oxy)butan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazine-3(2H )-ketone (2B)
5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)butan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin- 3-yl)oxy)butan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one
参考化合物1A类似的合成方法，得化合物2B,为白色固体(100mg，产率74％)。Referring to the similar synthesis method of compound 1A, compound 2B was obtained as a white solid (100 mg, yield 74%).
LC-MS m/z(ESI)＝672.70[M+1]。LC-MS m/z (ESI) = 672.70 [M+1].
第三步：third step:
5-(((S)-1-(((R)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-2-氧吡咯烷-3-基)氧基)丁烷-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物2)5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl) -2-Oxypyrrolidin-3-yl)oxy)butan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 2)
5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)butan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin- 3-yl)oxy)butan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
参考化合物1第二步类似的合成方法，得化合物2,为白色固体(50mg，产率 60％)。Referring to the similar synthesis method of the second step of compound 1, compound 2 was obtained as a white solid (50 mg, yield 60%).
LC-MS m/z(ESI)＝552.60[M+1]。LC-MS m/z (ESI) = 552.60 [M+1].
1H NMR(400MHz,DMSO-d 6)δ12.46(s,1H),8.16(s,2H),7.98(s,1H),6.33–6.23(m,1H),5.15(d,1H),4.77(d,1H),4.62(d,1H),4.12(t,1H),4.00(s,1H),3.86(dd,1H),3.80–3.69(m,1H),3.61(dd,1H),3.53–3.47(m,1H),3.30–3.24(m,1H),3.12(q,1H),2.81(t,1H),2.62(dd,1H),2.24(d,1H),1.77–1.71(m,2H),1.64–1.42(m,6H),0.95–0.83(m,5H),0.66–0.51(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ12.46(s,1H),8.16(s,2H),7.98(s,1H),6.33–6.23(m,1H),5.15(d,1H), 4.77(d,1H),4.62(d,1H),4.12(t,1H),4.00(s,1H),3.86(dd,1H),3.80–3.69(m,1H),3.61(dd,1H) ,3.53–3.47(m,1H),3.30–3.24(m,1H),3.12(q,1H),2.81(t,1H),2.62(dd,1H),2.24(d,1H),1.77–1.71 (m,2H), 1.64–1.42(m,6H), 0.95–0.83(m,5H), 0.66–0.51(m,2H).
实施例3Example 3
5-(((S)-1-(((R)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-2-氧吡咯烷-3-基)氧基)丙烷-2-基)氧基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物3)5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl) -2-Oxypyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 3)
5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin- 3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022110534-appb-000109
Figure PCTCN2022110534-appb-000109
第一步：first step:
(R)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-3-(S)-2-羟丙氧基)吡咯烷-2-酮(3A)(R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-3-(S)-2-hydroxypropoxy base) pyrrolidin-2-one (3A)
(R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-3-((S)-2-hydroxy propoxy)pyrrolidin-2-one(R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-3-((S)-2-hydroxy proxy)pyrolidin-2- one
参考中间体3第五步类似的合成方法，得化合物3A,为无色油状物(464mg，产率64％)。Referring to the similar synthesis method of the fifth step of intermediate 3, compound 3A was obtained as a colorless oil (464 mg, yield 64%).
LC-MS m/z(ESI)＝377.50[M+1]。LC-MS m/z (ESI) = 377.50 [M+1].
第二步：Step two:
5-(((S)-1-(((R)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-2-氧吡咯烷-3-基)氧基)丙烷-2-基)氧基)-2-(4-甲氧基苄基)-4-(三氟甲基)哒嗪-3(2H)-酮(3B)5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl) -2-Oxypyrrolidin-3-yl)oxy)propan-2-yl)oxy)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazine-3(2H )-ketone (3B)
5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin- 3-yl)oxy)propan-2-yl)oxy)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one
参考化合物1A类似的合成方法，得化合物3B,为白色固体(487mg，产率60％)。Referring to the similar synthesis method of compound 1A, compound 3B was obtained as a white solid (487 mg, yield 60%).
LC-MS m/z(ESI)＝659.70[M+1]。LC-MS m/z (ESI) = 659.70 [M+1].
第三步：third step:
5-(((S)-1-(((R)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-2-氧吡咯烷-3-基)氧基)丙烷-2-基)氧基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物3)5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl) -2-Oxypyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 3)
5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin- 3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one
参考化合物1第二步类似的合成方法，得化合物3,为白色固体(211mg，产率53％)。Referring to the similar synthesis method of the second step of compound 1, compound 3 was obtained as a white solid (211 mg, yield 53%).
LC-MS m/z(ESI)＝539.52[M+1]。LC-MS m/z (ESI) = 539.52 [M+1].
1H NMR(400MHz,DMSO-d 6)δ12.47(s,1H),8.16(s,2H),8.01(s,1H),5.14(d,1H),4.88–4.70(m,1H),4.60(d,1H),4.16–4.12(m,2H),3.82–3.80(m,1H),3.76–3.69(m,1H),3.60–3.58(m,1H),3.54–3.46(m,1H),3.30–3.27(m,1H),3.53–3.47(m,1H),2.88–2.75(m,1H),2.62(dd,1H),2.24–2.20(m,1H),1.83–1.65(m,2H),1.56–1.46(m,2H),1.17(d,3H),0.92–0.77(m,2H),0.68–0.56(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ12.47(s,1H),8.16(s,2H),8.01(s,1H),5.14(d,1H),4.88–4.70(m,1H), 4.60(d,1H),4.16–4.12(m,2H),3.82–3.80(m,1H),3.76–3.69(m,1H),3.60–3.58(m,1H),3.54–3.46(m,1H ),3.30–3.27(m,1H),3.53–3.47(m,1H),2.88–2.75(m,1H),2.62(dd,1H),2.24–2.20(m,1H),1.83–1.65(m ,2H), 1.56–1.46(m,2H), 1.17(d,3H), 0.92–0.77(m,2H), 0.68–0.56(m,2H).
实施例4Example 4
5-((S)-2-((((R)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-2-氧吡咯烷-3-基)氧基)甲基)吡咯烷-1-基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物4)5-((S)-2-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl) -2-Oxypyrrolidin-3-yl)oxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 4)
5-((S)-2-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one5-((S)-2-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin- 3-yl)oxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022110534-appb-000110
Figure PCTCN2022110534-appb-000110
第一步：first step:
(R)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-3-((S)-吡咯烷-2-基)甲氧基)吡咯烷-2-酮(4A)(R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-3-((S)-pyrrolidin-2 -yl)methoxy)pyrrolidin-2-one (4A)
(R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-3-(((S)- pyrrolidin-2-yl)methoxy)pyrrolidin-2-one(R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-3-(((S)-pyrrolidin-2-yl)methoxy) pyrrolidin-2-one
参考中间体3第五步类似的合成方法，得化合物4A,为无色油状物(130mg，产率62％)。Referring to the similar synthesis method of the fifth step of intermediate 3, compound 4A was obtained as a colorless oil (130 mg, yield 62%).
LC-MS m/z(ESI)＝402.50[M+1]。LC-MS m/z (ESI) = 402.50 [M+1].
第二步：Step two:
5-((S)-2-((((R)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-2-氧吡咯烷-3-基)氧基)甲基)吡咯烷-1-基)-2-(4-甲氧基苄基)-4-(三氟甲基)哒嗪-3(2H)-酮(4B)5-((S)-2-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl) -2-Oxypyrrolidin-3-yl)oxy)methyl)pyrrolidin-1-yl)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazine-3( 2H)-Kone (4B)
5-((S)-2-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)methyl)pyrrolidin-1-yl)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one5-((S)-2-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin- 3-yl)oxy)methyl)pyrrolidin-1-yl)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one
参考化合物1A类似的合成方法，得化合物4B,为白色固体(159mg，产率72％)。Referring to the similar synthesis method of compound 1A, compound 4B was obtained as a white solid (159 mg, yield 72%).
LC-MS m/z(ESI)＝684.71[M+1]。LC-MS m/z (ESI) = 684.71 [M+1].
第三步：third step:
5-((S)-2-((((R)-1-(3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-2-氧吡咯烷-3-基)氧基)甲基)吡咯烷-1-基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物4)5-((S)-2-((((R)-1-(3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)- 2-Oxypyrrolidin-3-yl)oxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 4)
5-((S)-2-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one5-((S)-2-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin- 3-yl)oxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one
参考化合物1第二步类似的合成方法，得化合物4,为白色固体(70mg，产率53％)。Referring to the similar synthesis method of the second step of compound 1, compound 4 was obtained as a white solid (70 mg, yield 53%).
LC-MS m/z(ESI)＝564.60[M+1]。LC-MS m/z (ESI) = 564.60 [M+1].
1H NMR(400MHz,DMSO-d 6)δ12.39(s,1H),8.19–8.15(m,2H),8.10(s,1H),4.81–4.71(m,1H),4.60(d,2H),4.57–4.48(m,1H),4.06(t,2H),3.82(dd,1H),3.76–3.70(m,1H),3.61(dd,1H),3.53–3.47(m,2H),3.32–3.19(m,2H),3.14–3.05(m,1H),2.87–2.76(m,1H),2.62(dd,1H),2.27–2.15(m,1H),1.89(d,,1H),1.79–1.60(m,4H),1.55–1.49(m,2H),0.92–0.81(m,2H),0.68–0.58(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ12.39(s,1H),8.19–8.15(m,2H),8.10(s,1H),4.81–4.71(m,1H),4.60(d,2H ),4.57–4.48(m,1H),4.06(t,2H),3.82(dd,1H),3.76–3.70(m,1H),3.61(dd,1H),3.53–3.47(m,2H), 3.32–3.19(m,2H),3.14–3.05(m,1H),2.87–2.76(m,1H),2.62(dd,1H),2.27–2.15(m,1H),1.89(d,,1H) ,1.79–1.60(m,4H),1.55–1.49(m,2H),0.92–0.81(m,2H),0.68–0.58(m,2H).
实施例5Example 5
5-((S)-1-((((R)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-2-氧吡咯烷-3-基)甲基)异吲哚-2-基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物5)5-((S)-1-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl) -2-Oxypyrrolidin-3-yl)methyl)isoindol-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 5)
5-((S)-1-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one5-((S)-1-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin- 3-yl)oxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022110534-appb-000111
Figure PCTCN2022110534-appb-000111
Figure PCTCN2022110534-appb-000112
Figure PCTCN2022110534-appb-000112
第一步：first step:
(3R)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-3-(异吲哚啉-1-基甲氧基)吡咯烷-2-酮(5A)(3R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-3-(isoindoline-1-yl Methoxy)pyrrolidin-2-one (5A)
(3R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-3-(isoindolin-1-ylmethoxy)pyrrolidin-2-one(3R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-3-(isoindolin-1-ylmethoxy)pyrrolidin-2-one
参考中间体3第五步类似的合成方法，得化合物5A,为无色油状物(631mg，产率69％)。Referring to the similar synthesis method in the fifth step of Intermediate 3, Compound 5A was obtained as a colorless oil (631 mg, yield 69%).
LC-MS m/z(ESI)＝450.55[M+1]。LC-MS m/z (ESI) = 450.55 [M+1].
第二步：Step two:
5-(1-((((R)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-2-氧吡咯烷-3-基)氧基)甲基)异吲哚-2-基)-2-(4-甲氧基苄基)-4-(三氟甲基)哒嗪-3(2H)-酮(5B)5-(1-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxo Pyrrolidin-3-yl)oxy)methyl)isoindol-2-yl)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazine-3(2H)- Ketone (5B)
5-(1-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)methyl)isoindolin-2-yl)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(1-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin-3-yl) oxy)methyl)isoindolin-2-yl)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one
参考化合物1A类似的合成方法，得化合物5B,为白色固体(853mg，产率83％)。Referring to the similar synthesis method of compound 1A, compound 5B was obtained as a white solid (853 mg, yield 83%).
LC-MS m/z(ESI)＝732.80[M+1]。LC-MS m/z (ESI) = 732.80 [M+1].
第三步：third step:
5-(1-((((R)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-2-氧吡咯烷-3-基)氧基)甲基)异吲哚-2-基)-4-(三氟甲基)哒嗪-3(2H)-酮(5C)5-(1-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxo Pyrrolidin-3-yl)oxy)methyl)isoindol-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (5C)
5-(1-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(1-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin-3-yl) oxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one
参考化合物1第二步类似的合成方法，得化合物5C,为白色固体(405mg，产率57％)。Referring to the similar synthesis method of the second step of compound 1, compound 5C was obtained as a white solid (405 mg, yield 57%).
LC-MS m/z(ESI)＝611.64[M+1]。LC-MS m/z (ESI) = 611.64 [M+1].
第四步：the fourth step:
5-((S)-1-((((R)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-2-氧吡咯烷-3-基)甲基)异吲哚-2-基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物5-I)5-((S)-1-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl) -2-Oxypyrrolidin-3-yl)methyl)isoindol-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 5-I)
5-((S)-1-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one5-((S)-1-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin- 3-yl)oxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one
5-((R)-1-((((R)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-2-氧吡咯烷-3-基)甲基)异吲哚-2-基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物5-II)5-((R)-1-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl) -2-Oxypyrrolidin-3-yl)methyl)isoindol-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 5-II)
5-((R)-1-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one5-((R)-1-((((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin- 3-yl)oxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one
化合物5C通过SFC拆分得到化合物5-I(136mg，收率34％，RT＝6.454min,100％ee)和化合物5-II(145mg，产率36％，RT＝8.355min,100％ee)。手性HPLC(AS)流动相:正己烷/乙醇＝90/10；柱温:35℃；柱压:80bar；流速:1mL/min；检测器信号通道:[email protected]；二极管阵列检测器起止波长:200～400nm。Compound 5C was resolved by SFC to obtain compound 5-I (136mg, yield 34%, RT=6.454min, 100%ee) and compound 5-II (145mg, yield 36%, RT=8.355min, 100%ee) . Chiral HPLC (AS) mobile phase: n-hexane/ethanol = 90/10; column temperature: 35°C; column pressure: 80bar; flow rate: 1mL/min; detector signal channel: [email protected]; diode array detector start-stop Wavelength: 200~400nm.
化合物5-I: 1H NMR(400MHz,DMSO-d 6)δ12.36(s,1H),8.81(s,2H),8.01(s,1H),7.90–7.87(m,2H),7.82(dd,1H),7.80(dd,1H),5.15(d,1H),4.99(s,2H),4.59–4.48(m,1H),4.41(d,1H),4.19–4.15(m,2H),3.87–3.82(m,1H),3.79–3.72(m,1H),3.62(dd,1H),3.55–3.48(m,1H),3.30–3.27(m,1H),3.53–3.45(m,1H),2.89–2.76(m,1H),2.63(dd,1H),2.26–2.22(m,1H),1.84–1.66(m,2H),1.57–1.47(m,2H),0.94–0.78(m,2H),0.68–0.57(m,2H)。 Compound 5-I: 1 H NMR (400MHz, DMSO-d 6 )δ12.36(s,1H),8.81(s,2H),8.01(s,1H),7.90–7.87(m,2H),7.82( dd,1H),7.80(dd,1H),5.15(d,1H),4.99(s,2H),4.59–4.48(m,1H),4.41(d,1H),4.19–4.15(m,2H) ,3.87–3.82(m,1H),3.79–3.72(m,1H),3.62(dd,1H),3.55–3.48(m,1H),3.30–3.27(m,1H),3.53–3.45(m, 1H),2.89–2.76(m,1H),2.63(dd,1H),2.26–2.22(m,1H),1.84–1.66(m,2H),1.57–1.47(m,2H),0.94–0.78( m,2H), 0.68–0.57(m,2H).
化合物5-II： 1H NMR(400MHz,DMSO-d 6)δ12.36(s,1H),8.81(s,2H),8.01(s,1H),7.90–7.87(m,2H),7.82(dd,1H),7.80(dd,1H),5.15(d,1H),4.99(s,2H),4.59–4.48(m,1H),4.41(d,1H),4.19–4.15(m,2H),3.87–3.82(m,1H),3.79–3.72(m,1H),3.62(dd,1H),3.55–3.48(m,1H),3.30–3.27(m,1H),3.53–3.45(m,1H),2.89–2.76(m,1H),2.63(dd,1H),2.26–2.22(m,1H),1.84–1.66(m,2H),1.57–1.47(m,2H),0.94–0.78(m,2H),0.68–0.57(m,2H)。 Compound 5-II: 1 H NMR (400MHz, DMSO-d 6 ) δ12.36(s, 1H), 8.81(s, 2H), 8.01(s, 1H), 7.90–7.87(m, 2H), 7.82( dd,1H),7.80(dd,1H),5.15(d,1H),4.99(s,2H),4.59–4.48(m,1H),4.41(d,1H),4.19–4.15(m,2H) ,3.87–3.82(m,1H),3.79–3.72(m,1H),3.62(dd,1H),3.55–3.48(m,1H),3.30–3.27(m,1H),3.53–3.45(m, 1H),2.89–2.76(m,1H),2.63(dd,1H),2.26–2.22(m,1H),1.84–1.66(m,2H),1.57–1.47(m,2H),0.94–0.78( m,2H), 0.68–0.57(m,2H).
实施例6Example 6
5-(((S)-1-(((R)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-2-氧吡咯烷-3-基)氧基)丙烷-2-基-1,1-d 2)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物6) 5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl) -2-oxopyrrolidin-3-yl)oxy)propan-2-yl-1,1-d 2 )amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 6 )
5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl-1,1-d 2)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin- 3-yl)oxy)propan-2-yl-1,1-d 2 )amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022110534-appb-000113
Figure PCTCN2022110534-appb-000113
Figure PCTCN2022110534-appb-000114
Figure PCTCN2022110534-appb-000114
第一步：first step:
(R)-3-((S)-2-氨基丙氧基-1,1-d2)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)吡咯烷-2-酮(6A)(R)-3-((S)-2-aminopropoxy-1,1-d2)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3 -Hydroxypiperidin-4-yl)pyrrolidin-2-one (6A)
(R)-3-((S)-2-aminopropoxy-1,1-d2)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)pyrrolidin-2-one(R)-3-((S)-2-aminopropoxy-1,1-d2)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl ) pyrrolidin-2-one
参考中间体3第五步类似的合成方法，得化合物6A,为无色油状物(622mg，产率63％)。Referring to the similar synthesis method of the fifth step of intermediate 3, compound 6A was obtained as a colorless oil (622 mg, yield 63%).
LC-MS m/z(ESI)＝378.50[M+1]。LC-MS m/z (ESI) = 378.50 [M+1].
第二步：Step two:
5-(((S)-1-(((R)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-2-氧吡咯烷-3-基)氧基)丙烷-2-基-1,1-d 2)氨基)-2-(4-甲氧基苄基)-4-(三氟甲基)哒嗪-3(2H)-酮 5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl) -2-Oxypyrrolidin-3-yl)oxy)propan-2-yl-1,1-d 2 )amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl) Pyridazin-3(2H)-one
5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl-1,1-d 2)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one 5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin- 3-yl)oxy)propan-2-yl-1,1-d 2 )amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one
参考化合物1A类似的合成方法，得化合物6B,为白色固体(771mg，产率71％)。Referring to the similar synthesis method of compound 1A, compound 6B was obtained as a white solid (771 mg, yield 71%).
LC-MS m/z(ESI)＝660.70[M+1]。LC-MS m/z (ESI) = 660.70 [M+1].
第三步：third step:
5-(((S)-1-((R)-1-((3R，4R)-1-(5-环丙基嘧啶-2-基)-3-羟基哌啶-4-基)-2-氧吡咯烷-3-基)氧基)丙烷-2-基-1,1-d 2)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮 5-(((S)-1-((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)- 2-Oxypyrrolidin-3-yl)oxy)propan-2-yl-1,1- d2 )amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl-1,1-d 2)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 5-(((S)-1-(((R)-1-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-oxopyrrolidin- 3-yl)oxy)propan-2-yl-1,1-d 2 )amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
参考化合物1第二步类似的合成方法，得化合物6,为白色固体(328mg，产率61％)。Referring to the similar synthesis method of the second step of compound 1, compound 6 was obtained as a white solid (328 mg, yield 61%).
LC-MS m/z(ESI)＝540.54[M+1]。LC-MS m/z (ESI) = 540.54 [M+1].
1H NMR(400MHz,DMSO-d 6)12.60(s,1H),8.23(s,2H),7.99(s,1H),6.37(dd,1H),5.17(d,1H),4.90-4.71(m,1H),4.60(d,1H),4.16-4.12(m,2H),3.58(dd,1H),3.55-3.47(m,1H),3.30-3.25(m,1H),3.53-3.47(m,1H),2.84-2.62(m,2H),2.25-2.22(m,1H),1.82-1.64(m,2H),1.57-1.45(m,2H),1.19(d,3H),0.93-0.79(m,2H),0.69-0.57(m,2H)。 1 H NMR (400MHz, DMSO-d 6 ) 12.60(s,1H), 8.23(s,2H), 7.99(s,1H), 6.37(dd,1H), 5.17(d,1H), 4.90-4.71( m,1H),4.60(d,1H),4.16-4.12(m,2H),3.58(dd,1H),3.55-3.47(m,1H),3.30-3.25(m,1H),3.53-3.47( m,1H),2.84-2.62(m,2H),2.25-2.22(m,1H),1.82-1.64(m,2H),1.57-1.45(m,2H),1.19(d,3H),0.93- 0.79(m,2H),0.69-0.57(m,2H).
实施例7Example 7
6-((3R，4R)-3-羟基-4-((R)-2-氧代-3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基-1,1-d 2)吡咯烷-1-基)哌啶-1-基)烟腈(化合物7) 6-((3R,4R)-3-Hydroxy-4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4-yl)amino)propoxy-1,1- d2 )pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (Compound 7)
6-((3R,4R)-3-hydroxy-4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydro pyridazin-4-yl)amino)propoxy-1,1-d 2)pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile 6-((3R,4R)-3-hydroxy-4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydro pyridazin-4-yl)amino)propoxy-1,1-d 2 )pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrole
Figure PCTCN2022110534-appb-000115
Figure PCTCN2022110534-appb-000115
第一步：first step:
6-((3R，4R)-3-((叔丁基二甲基硅)氧基)-4-((R)-3-羟基-2-氧吡咯烷-1-基)哌啶-1-基)烟腈(7A)6-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1 -yl) nicotinonitrile (7A)
6-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile6-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile
参照中间体3b类似的合成方法，得化合物7A，为白色固体(420mg，产率：83％)。Referring to the similar synthesis method of intermediate 3b, compound 7A was obtained as a white solid (420 mg, yield: 83%).
LC-MS m/z(ESI)＝417.65[M+1]。LC-MS m/z (ESI) = 417.65 [M+1].
第二步：Step two:
6-((3R，4R)-4-((R)-3-((S)-2-氨基丙氧基)-2-氧吡咯烷-1-基)-3-((叔丁基二甲基硅氧基)哌啶-1-基)烟腈(7B)6-((3R,4R)-4-((R)-3-((S)-2-aminopropoxy)-2-oxopyrrolidin-1-yl)-3-((tert-butyldi Methylsilyloxy)piperidin-1-yl)nicotinonitrile (7B)
6-((3R,4R)-4-((R)-3-((S)-2-aminopropoxy)-2-oxopyrrolidin-1-yl)-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)nicotinonitrile6-((3R,4R)-4-((R)-3-((S)-2-aminopropoxy)-2-oxopyrrolidin-1-yl)-3-((tert-butyldimethylsilyl)oxy)piperidin-1 -yl)nicotinonitrole
参考中间体3第五步类似的合成方法，得化合物7B,为白色固体(341mg，产率72％)。Referring to the similar synthesis method of the fifth step of intermediate 3, compound 7B was obtained as a white solid (341 mg, yield 72%).
LC-MS m/z(ESI)＝474.70[M+1]。LC-MS m/z (ESI) = 474.70 [M+1].
第三步：third step:
6-((3R，4R)-3-羟基-4-((R)-3-((S)-2-((1-(4-甲氧基苄基)-6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基-1,1-d 2)-2-氧吡咯烷-1-基)哌啶-1-基)烟腈(7C) 6-((3R,4R)-3-hydroxy-4-((R)-3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5- (Trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy-1,1-d 2 )-2-oxopyrrolidin-1-yl)piperidin-1-yl ) nicotinonitrile (7C)
6-((3R,4R)-3-hydroxy-4-((R)-3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy-1,1-d 2)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile 6-((3R,4R)-3-hydroxy-4-((R)-3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1 ,6-dihydropyridazin-4-yl)amino)propoxy-1,1-d 2 )-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrole
参考化合物1A类似的合成方法，得化合物7B,为淡黄色固体(352mg，产率76％)。Referring to the similar synthesis method of compound 1A, compound 7B was obtained as a light yellow solid (352 mg, yield 76%).
LC-MS m/z(ESI)＝644.65[M+1]。LC-MS m/z (ESI) = 644.65 [M+1].
第四步：the fourth step:
6-((3R，4R)-3-羟基-4-((R)-2-氧代-3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基-1,1-d 2)吡咯烷-1-基)哌啶-1-基)烟腈(化合物7) 6-((3R,4R)-3-Hydroxy-4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4-yl)amino)propoxy-1,1- d2 )pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (Compound 7)
6-((3R,4R)-3-hydroxy-4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy-1,1-d 2)pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile 6-((3R,4R)-3-hydroxy-4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin -4-yl)amino)propoxy-1,1-d 2 )pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrole
参考化合物1第二步类似的合成方法，得化合物7,为白色固体(253mg，产率89％)。Referring to the similar synthesis method of the second step of compound 1, compound 7 was obtained as a white solid (253 mg, yield 89%).
LC-MS m/z(ESI)＝524.41[M+1]。LC-MS m/z (ESI) = 524.41 [M+1].
1H NMR(400MHz,DMSO-d 6)δ12.47(s,1H),8.59(d,1H),8.00(dd,1H),7.91(s,1H),7.17(d,1H),6.37(dd,1H),5.19(d,1H),4.91-4.70(m,1H),4.62(d,1H),4.17-4.13(m,2H),3.59(dd,1H),3.56-3.47(m,1H),3.31-3.27(m,1H),3.53-3.48(m,1H),2.85-2.63(m,2H),2.26-2.21(m,1H),1.83-1.64(m,2H),1.58-1.46(m,2H),1.20(d,3H),0.93-0.79(m,2H),0.68-0.59(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ12.47(s,1H),8.59(d,1H),8.00(dd,1H),7.91(s,1H),7.17(d,1H),6.37( dd,1H),5.19(d,1H),4.91-4.70(m,1H),4.62(d,1H),4.17-4.13(m,2H),3.59(dd,1H),3.56-3.47(m, 1H),3.31-3.27(m,1H),3.53-3.48(m,1H),2.85-2.63(m,2H),2.26-2.21(m,1H),1.83-1.64(m,2H),1.58- 1.46 (m, 2H), 1.20 (d, 3H), 0.93-0.79 (m, 2H), 0.68-0.59 (m, 2H).
生物学试验biological test
PARP酶学生化试验方案：PARP Enzyme Biochemical Test Protocol:
1、包被：1×histone mixture(25μL/孔)过夜包被。1. Coating: 1×histone mixture (25 μL/well) was coated overnight.
2、封闭：加入Blocking buffer 100μL/孔，封闭90min。2. Blocking: add Blocking buffer 100 μL/well, and block for 90 minutes.
3、化合物稀释：将化合物按照1:3比例稀释8个浓度，起始浓度为1000nM。3. Compound dilution: Dilute the compound to 8 concentrations at a ratio of 1:3, and the initial concentration is 1000nM.
4、向包含10×PARP buffer、10×PARP Assay mixture、5×Activated DNA、蒸馏水的12.5μL混合物中，加入2.5μL不同浓度化合物、10μL酶(1-2ng/μL)，室温孵育1h。4. To the 12.5μL mixture containing 10×PARP buffer, 10×PARP Assay mixture, 5×Activated DNA, and distilled water, add 2.5μL of different concentrations of compounds and 10μL of enzyme (1-2ng/μL), and incubate at room temperature for 1h.
5、加入稀释Streptavidin-HRP孵育30min，加入显色液进行显色。5. Add diluted Streptavidin-HRP and incubate for 30 minutes, then add color developing solution for color development.
6、用酶标仪进行化学发光读数。6. Perform chemiluminescence readings with a microplate reader.
IC 50：是指PARP酶活性受到50％抑制时的化合物浓度。 IC 50 : refers to the compound concentration at which PARP enzyme activity is inhibited by 50%.
结果表明，本发明化合物对PARP-7靶蛋白具有显著的生物抑制活性。The results show that the compound of the present invention has significant biological inhibitory activity on PARP-7 target protein.
NCI-H1373细胞增殖抑制实验方案：NCI-H1373 cell proliferation inhibition experimental protocol:
1.1将NCI-H1373细胞接种于96孔细胞培养板中(1500个/孔)，每孔体积为80μL。置于37℃、5％CO 2培养箱孵育过夜。 1.1 Inoculate NCI-H1373 cells in a 96-well cell culture plate (1500 cells/well), with a volume of 80 μL per well. Incubate overnight in a 37°C, 5% CO 2 incubator.
1.2将化合物用DMSO配制成10mM母液，用1640培养基稀释8个浓度(1:5)，终浓度分别为10000，2000，400，80，16，3.2，0.64，0.128nM。1.2 The compound was prepared into 10 mM stock solution with DMSO, and diluted with 1640 medium to 8 concentrations (1:5), the final concentrations were 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128 nM.
1.3以未经药物处理的细胞为对照组，其余细胞分别接受各药物浓度处理，同时设立无细胞的培养孔作为空白调零组，每组设2个平行孔，放入37℃、5％CO 2培养箱培养。 1.3 Take the cells without drug treatment as the control group, and the remaining cells are treated with different drug concentrations respectively. At the same time, set up culture wells without cells as the blank zero-adjustment group. Set up 2 parallel wells for each group and put them in 37°C, 5% CO 2 incubator culture.
1.4培养6天后，从培养箱中取出96孔板，每孔加入100μL Cell Titer Blue工作液，震荡2min，孵育10min。1.4 After culturing for 6 days, take out the 96-well plate from the incubator, add 100 μL Cell Titer Blue working solution to each well, shake for 2 minutes, and incubate for 10 minutes.
1.5用酶标仪进行化学发光读数。1.5 Perform chemiluminescence readings with a microplate reader.
1.6计算细胞存活率＝(处理组荧光强度/对照组荧光强度)×100％，通过曲线拟合计算半抑制浓度(half maximal inhibitory concentration,IC 50)。 1.6 Calculation of cell viability=(fluorescence intensity of treatment group/fluorescence intensity of control group)×100%, and half maximal inhibitory concentration (IC 50 ) was calculated by curve fitting.
IC 50：是指细胞增殖受到50％抑制时的化合物浓度。 IC 50 : refers to the compound concentration at which cell proliferation is inhibited by 50%.
表1.抗NCI-H1373细胞增殖活性Table 1. Anti-NCI-H1373 cell proliferation activity
化合物编号Compound number IC 50(nM) IC 50 (nM)
化合物1Compound 1 AA
化合物2Compound 2 BB
化合物3Compound 3 AA
化合物4Compound 4 BB
化合物5Compound 5 BB
化合物6Compound 6 AA
化合物7Compound 7 BB
注：A：IC 50＜50nM；B：50nM＜IC 50＜100nM。 Note: A: IC 50 <50nM; B: 50nM<IC 50 <100nM.
结果表明，本发明化合物对NCI-H1373细胞增殖具有抑制效果。The results show that the compound of the present invention has an inhibitory effect on the proliferation of NCI-H1373 cells.
本发明说明书对具体实施方案进行了详细描述，本领域技术人员应认识到，上述实施方案是示例性的，不能理解为对本发明的限制，对于本领域技术人员来说，在不脱离本发明原理的前提下，通过对本发明进行若干改进和修饰，这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。The description of the present invention has described specific implementations in detail, and those skilled in the art should recognize that the above-mentioned implementations are exemplary and cannot be construed as limitations on the present invention. Under the premise of the present invention, several improvements and modifications are made to the present invention, and the technical solutions obtained by these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims (19)

  1. 一种通式(I)所示的化合物或者其立体异构体、药学上可接受的盐或氘代物：A compound represented by general formula (I) or its stereoisomer, pharmaceutically acceptable salt or deuterated product:
    Figure PCTCN2022110534-appb-100001
    Figure PCTCN2022110534-appb-100001
    其中：in:
    A为
    Figure PCTCN2022110534-appb-100002
    R 14为OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、CN、C(＝O)R 14a、C(＝O)OR 14b、SR 14c或OR 14c，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、任选地被1至3个卤素取代；     A is
    Figure PCTCN2022110534-appb-100002
    R 14 is OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, CN, C(=O)R 14a , C(=O ) OR 14b , SR 14c or OR 14c , the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, optionally replaced by 1 to 3 halogen replace;
    X 1、X 2和L 2各自独立地选自O、S、C 1-6亚烷基、3至10元杂环烷基的单环或多环、-NR x1-、-C(＝O)-、-C(＝O)O-、-C(＝O)NR x1-、-S(＝O)-、-S(＝O) 2-、-S(＝O)NR x1-、-S(＝O) 2NR x1-、-NR x1C(＝O)NR x1-或键，所述C 1-6亚烷基、3至10元杂环烷基的单环或多环进一步被1或多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR x2、SR x2、C(＝O)R x3、C(＝O)NR x4R x5、C(＝O)OR x2、OC(＝O)R x3、OC(＝O)NR x4R x5、NR x4R x5、NR x4C(＝O)R x3、NR x4OC(＝O)R x3、NR x4C(＝O)NR x4R x5、C(＝NR x6)R x3、C(＝NR x6)NR x4R x5、NR x4C(＝NR x6)NR x4R x5、NR x4S(＝O)R x2、NR x4S(＝O) 2R x2、NR x4S(＝O) 2 NR x4R x5、S(＝O)R x2、S(＝O)NR x4R x5、S(＝O) 2NR x4R x5、P(＝O)(R x4) 2或P(＝O) 2；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR x2、SR x2、C(＝O)R x3、C(＝O)NR x4R x5、C(＝O)OR x2、OC(＝O)R x3、OC(＝O)NR x4R x5、NR x4R x5、NR x4C(＝O)R x3、NR x4OC(＝O)R x3、NR x4C(＝O)NR x4R x5、C(＝NR x6)R x3、C(＝NR x6)NR x4R x5、NR x4C(＝NR x6)NR x4R x5、NR x4S(＝O)R x2、NR x4S(＝O) 2R x2、NR x4S(＝O) 2 NR x4R x5、S(＝O)R x2、S(＝O)NR x4R x5或S(＝O) 2NR x4R x5；所述3至10元杂环烷基的单环或多环、5至12元杂芳基、3至10元杂环烷基包含1、2、3或4个独立地选自O、N和S的杂原子； X 1 , X 2 and L 2 are each independently selected from O, S, C 1-6 alkylene, monocyclic or polycyclic rings of 3 to 10 membered heterocycloalkyl, -NR x1 -, -C(=O )-, -C(=O)O-, -C(=O)NR x1 -, -S(=O)-, -S(=O) 2 -, -S(=O)NR x1 -, - S(=O) 2 NR x1 -, -NR x1 C(=O)NR x1 - or a bond, the C 1-6 alkylene, 3- to 10-membered heterocycloalkyl monocyclic or polycyclic ring is further 1 or more substituents selected from the following substituents: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C6-12 Aryl, 5- to 12-membered heteroaryl, 3- to 10-membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR x2 , SR x2 , C(=O)R x3 , C(=O)NR x4 R x5 , C(=O)OR x2 , OC(=O)R x3 , OC(=O)NR x4 R x5 , NR x4 R x5 , NR x4 C(=O)R x3 , NR x4 OC(=O)R x3 , NR x4 C(=O)NR x4 R x5 , C(=NR x6 )R x3 , C(=NR x6 )NR x4 R x5 , NR x4 C(=NR x6 )NR x4 R x5 , NR x4 S(=O)R x2 , NR x4 S(=O) 2 R x2 , NR x4 S(=O) 2 NR x4 R x5 , S(=O)R x2 , S( =O)NR x4 R x5 , S(=O) 2 NR x4 R x5 , P(=O)(R x4 ) 2 or P(=O) 2 ; the C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally selected from 1 to more of the following Substituent substitution: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10-membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR x2 , SR x2 , C(=O)R x3 , C(=O)NR x4 R x5 , C(= O)OR x2 , OC(=O)R x3 , OC(=O)NR x4 R x5 , NR x4 R x5 , NR x4 C(=O)R x3 , NR x4 OC(=O)R x3 , NR x4 C(=O)NR x4 R x5 , C(=NR x6 )R x3 , C(= NR x6 )NR x4 R x5 , NR x4 C(=NR x6 )NR x4 R x5 , NR x4 S(=O)R x2 , NR x4 S(=O) 2 R x2 , NR x4 S(=O) 2 NR x4 R x5 , S(=O)R x2 , S(=O)NR x4 R x5 or S(=O) 2 NR x4 R x5 ; monocyclic or polycyclic rings of the 3- to 10-membered heterocycloalkyl , 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from O, N and S;
    R 1、R 2、R 3、R 4、R 15各自独立地选自H、D、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元杂芳基、3至10元杂环烷基、CN、NH 2、NO 2、N 3、COOH、OR a2、SR a2、C(＝O)R a3、C(＝O)NR a4R a5、C(＝O)OR a2、OC(＝O)R a3、OC(＝O)NR a4R a5、NR a4R a5、NR a4C(＝O)R a3、NR a4OC(＝O)R a3、NR a4C(＝O)NR a4R a5、C(＝NR a6)R a3、C(＝NR a6)NR a4R a5、NR a4C(＝NR a6)NR a4R a5、NR a4S(＝O)R a2、NR a4S(＝O) 2R a2、NR a4S(＝O) 2 NR a4R a5、S(＝O)R a2、S(＝O)NR a4R a5或S(＝O) 2NR a4R a5；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR a2、SR a2、C(＝O)R a3、 C(＝O)NR a4R a5、C(＝O)OR a2、OC(＝O)R a3、OC(＝O)NR a4R a5、NR a4R a5、NR a4C(＝O)R a3、NR a4OC(＝O)R a3、NR a4C(＝O)NR a4R a5、C(＝NR a6)R a3、C(＝NR a6)NR a4R a5、NR a4C(＝NR a6)NR a4R a5、NR a4S(＝O)R a2、NR a4S(＝O) 2R a2、NR a4S(＝O) 2 NR a4R a5、S(＝O)R a2、S(＝O)NR a4R a5或S(＝O) 2NR a4R a5；或R 1和R 2、R 3和R 4、R 1和R 3各自独立地连同其所连接的碳原子形成3至6元环烷基或5至10元杂环烷基，所述环烷基、杂环烷基任选地被1或多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR a2、SR a2、C(＝O)R a3、C(＝O)NR a4R a5、C(＝O)OR a2、OC(＝O)R a3、OC(＝O)NR a4R a5、NR a4R a5、NR a4C(＝O)R a3、NR a4OC(＝O)R a3、NR a4C(＝O)NR a4R a5、C(＝NR a6)R a3、C(＝NR a6)NR a4R a5、NR a4C(＝NR a6)NR a4R a5、NR a4S(＝O)R a2、NR a4S(＝O) 2R a2、NR a4S(＝O) 2 NR a4R a5、S(＝O)R a2、S(＝O)NR a4R a5或S(＝O) 2NR a4R a5；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R 1 , R 2 , R 3 , R 4 , and R 15 are each independently selected from H, D, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -10 cycloalkyl, C6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, CN, NH 2 , NO 2 , N 3 , COOH, OR a2 , SR a2 , C( =O)R a3 , C(=O)NR a4 R a5 , C(=O)OR a2 , OC(=O)R a3 , OC(=O)NR a4 R a5 , NR a4 R a5 , NR a4 C (=O)R a3 , NR a4 OC(=O)R a3 , NR a4 C(=O)NR a4 R a5 , C(=NR a6 )R a3 , C(=NR a6 )NR a4 R a5 , NR a4 C(=NR a6 )NR a4 R a5 , NR a4 S(=O)R a2 , NR a4 S(=O) 2 R a2 , NR a4 S(=O) 2 NR a4 R a5 , S(=O )R a2 , S(=O)NR a4 R a5 or S(=O) 2 NR a4 R a5 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -10 cycloalkyl, C6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkane group, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR a2 , SR a2 , C(=O)R a3 , C(=O)NR a4 R a5 , C(=O)OR a2 , OC(=O)R a3 , OC(=O)NR a4 R a5 , NR a4 R a5 , NR a4 C(=O)R a3 , NR a4 OC(=O)R a3 , NR a4 C(=O) NR a4 R a5 , C(=NR a6 )R a3 , C(=NR a6 )NR a4 R a5 , NR a4 C(=NR a6 )NR a4 R a5 , NR a4 S (=O)R a2 , NR a4 S(=O) 2 R a2 , NR a4 S(=O) 2 NR a4 R a5 , S(=O)R a2 , S(=O)NR a4 R a5 or S(=O) 2 NR a4 R a5 or R 1 and R 2 , R 3 and R 4 , R 1 and R 3 each independently together with The carbon atoms connected to it form a 3-6 membered cycloalkyl group or a 5-10 membered heterocycloalkyl group, and the cycloalkyl group and heterocycloalkyl group are optionally substituted by 1 or more substituents selected from the following groups: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3- to 10-membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR a2 , SR a2 , C(=O)R a3 , C(=O)NR a4 R a5 , C (=O)OR a2 , OC(=O)R a3 , OC(=O)NR a4 R a5 , NR a4 R a5 , NR a4 C(=O)R a3 , NR a4 OC(=O)R a3 , NR a4 C(=O)NR a4 R a5 , C(=NR a6 )R a3 , C(=NR a6 )NR a4 R a5 , NR a4 C(=NR a6 )NR a4 R a5 , NR a4 S(= O)R a2 , NR a4 S(=O) 2 R a2 , NR a4 S(=O) 2 NR a4 R a5 , S(=O)R a2 , S(=O)NR a4 R a5 or S(= O) 2 NR a4 R a5 ; the 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, S;
    L 1为
    Figure PCTCN2022110534-appb-100003
    R 17为H、D或C 1-6烷基,所述C 1-6烷基任选地被1至3个卤素取代；L 2选自C 1-6亚烷基、3至10元杂环烷基的单环或多环、-C(＝O)-、-C(＝O)O-、-C(＝O)或键，所述C 1-6亚烷基、3至10元杂环烷基的单环或多环进一步被1或多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、C 3-10杂环烷基、5-12元杂芳基、4-10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR x2、SR x2、C(＝O)R x3、C(＝O)NR x4R x5、C(＝O)OR x2、OC(＝O)R x3、OC(＝O)NR x4R x5、NR x4R x5、NR x4C(＝O)R x3、NR x4OC(＝O)R x3、NR x4C(＝O)NR x4R x5、C(＝NR x6)R x3、C(＝NR x6)NR x4R x5、NR x4C(＝NR x6)NR x4R x5、NR x4S(＝O)R x2、NR x4S(＝O) 2R x2、NR x4S(＝O) 2 NR x4R x5、S(＝O)R x2、S(＝O)NR x4R x5、S(＝O) 2NR x4R x5、P(＝O)(R x4) 2或P(＝O) 2；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、C 3-10杂环烷基、5-12元杂芳基、4-10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 3-10杂环烷基、5-12元杂芳基、4-10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR x2、SR x2、C(＝O)R x3、C(＝O)NR x4R x5、C(＝O)OR x2、OC(＝O)R x3、OC(＝O)NR x4R x5、NR x4R x5、NR x4C(＝O)R x3、NR x4OC(＝O)R x3、NR x4C(＝O)NR x4R x5、C(＝NR x6)R x3、C(＝NR x6)NR x4R x5、NR x4C(＝NR x6)NR x4R x5、NR x4S(＝O)R x2、NR x4S(＝O) 2R x2、NR x4S(＝O) 2NR x4R x5、S(＝O)R x2、S(＝O)NR x4R x5或S(＝O) 2NR x4R x5；     L 1 is
    Figure PCTCN2022110534-appb-100003
    R 17 is H, D or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by 1 to 3 halogens; L 2 is selected from C 1-6 alkylene, 3 to 10 membered hetero Cycloalkyl monocyclic or polycyclic, -C(=O)-, -C(=O)O-, -C(=O) or bond, said C 1-6 alkylene, 3 to 10 membered The monocyclic or polycyclic ring of the heterocycloalkyl group is further substituted by 1 or more substituents selected from: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 cycloalkyl, C 6-12 aryl, C 3-10 heterocycloalkyl, 5-12 membered heteroaryl, 4-10 membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR x2 , SR x2 , C(=O)R x3 , C(=O)NR x4 R x5 , C(=O)OR x2 , OC(=O)R x3 , OC( =O)NR x4 R x5 , NR x4 R x5 , NR x4 C(=O)R x3 , NR x4 OC(=O)R x3 , NR x4 C(=O)NR x4 R x5 , C(=NR x6 )R x3 , C(=NR x6 )NR x4 R x5 , NR x4 C(=NR x6 )NR x4 R x5 , NR x4 S(=O)R x2 , NR x4 S(=O) 2 R x2 , NR x4 S(=O) 2 NR x4 R x5 , S(=O)R x2 , S(=O)NR x4 R x5 , S(=O) 2 NR x4 R x5 , P(=O)(R x4 ) 2 or P(=O) 2 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, C 3- 10 heterocycloalkyl, 5-12 membered heteroaryl, 4-10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, 5-12 membered heteroaryl, 4-10 membered heterocycloalkyl, =O , CN, NH 2 , NO 2 , N 3 , COOH, OR x2 , SR x2 , C(=O)R x3 , C(=O)NR x4 R x5 , C(=O)OR x2 , OC(=O )R x3 , OC(=O)NR x4 R x5 , NR x4 R x5 , NR x4 C(=O)R x3 , NR x4 OC(=O)R x3 , NR x4 C(=O)NR x4 R x5 , C(=NR x6 )R x3 , C(=NR x6 )NR x4 R x5 , NR x4 C(=NR x4 x6 )NR x4 R x5 , NR x4 S(=O)R x2 , NR x4 S(=O) 2 R x2 , NR x4 S(=O) 2 NR x4 R x5 , S(=O)R x2 , S ( =O ) NRx4Rx5 or S(=O) 2NRx4Rx5 ;
    X 3为C或N； X3 is C or N;
    R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、D、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、CN、NH 2、NO 2、N 3、COOH、OR b2、SR b2、C(＝O)R b3、C(＝O)NR b4R b5、C(＝O)OR b2、OC(＝O)R b3、OC(＝O)NR b4R b5、NR b4R b5、NR b4C(＝O)R b3、NR b4OC(＝O)R b3、NR b4C(＝O)NR b4R b5、C(＝NR b6)R b3、C(＝NR b6)NR b4R b5、NR b4C(＝NR b6)NR b4R b5、NR b4S(＝O)R b2、NR b4S(＝O) 2R b2、NR b4S(＝O) 2 NR b4R b5、S(＝O)R b2、S(＝O)NR b4R b5或S(＝O) 2NR b4R b5；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR b2、SR b2、C(＝O)R b3、C(＝O)NR b4R b5、C(＝O)OR b2、OC(＝O)R b3、OC(＝O)NR b4R b5、 NR b4R b5、NR b4C(＝O)R b3、NR b4OC(＝O)R b3、NR b4C(＝O)NR b4R b5、C(＝NR b6)R b3、C(＝NR b6)NR b4R b5、NR b4C(＝NR b6)NR b4R b5、NR b4S(＝O)R b2、NR b4S(＝O) 2R b2、NR b4S(＝O) 2NR b4R b5、S(＝O)R b2、S(＝O)NR b4R b5或S(＝O) 2NR b4R b5；或R 5和R 6、R 7和R 8、R 9和R 10、R 11和R 12各自独立地连同其所连接的碳原子形成＝O；或R 5和R 7、R 5和R 9、R 5和R 11、R 7和R 9、R 7和R 11、R 9和R 11相连；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, D, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, CN, NH 2 , NO 2 , N 3 , COOH, OR b2 , SR b2 , C(=O)R b3 , C(=O)NR b4 R b5 , C(=O)OR b2 , OC(=O)R b3 , OC(=O)NR b4 R b5 , NR b4 R b5 , NR b4 C(=O)R b3 , NR b4 OC(=O)R b3 , NR b4 C(=O)NR b4 R b5 , C(=NR b6 )R b3 , C( =NR b6 )NR b4 R b5 , NR b4 C(=NR b6 )NR b4 R b5 , NR b4 S(=O)R b2 , NR b4 S(=O) 2 R b2 , NR b4 S(=O) 2 NR b4 R b5 , S(=O)R b2 , S(=O)NR b4 R b5 or S(=O) 2 NR b4 R b5 ; the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally selected from 1 to more of the following Substituent substitution: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 members Heteroaryl, 3- to 10-membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR b2 , SR b2 , C(=O)R b3 , C(=O)NR b4 R b5 , C(=O)OR b2 , OC(=O)R b3 , OC(=O)NR b4 R b5 , NR b4 R b5 , NR b4 C(=O)R b3 , NR b4 OC(=O )R b3 , NR b4 C(=O)NR b4 R b5 , C(=NR b6 )R b3 , C(=NR b6 )NR b4 R b5 , NR b4 C(=NR b6 )NR b4 R b5 , NR b4 S(=O)R b2 , NR b4 S(=O) 2 R b2 , NR b4 S(=O) 2 NR b4 R b5 , S(=O)R b2 , S(=O)NR b4 R b5 or S(=O) 2 NR b4 R b5 ; or R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 each independently form =O together with the carbon atom to which they are attached; or R 5 and R 7 , R 5 and R 9 , R 5 and R 11 , R 7 and R 9 , R 7 and R 11 , R 9 and R 11 are connected; the 5-12 membered heteroaryl, 3-10 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, S;
    B为3至10元的环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基，所述杂环、杂芳环包含至少1至3个选自N、O和S的杂原子；B is a cycloalkyl group with 3 to 10 members, a heterocycloalkyl group with 3 to 10 members, an aryl group with 6 to 12 members, and a heteroaryl group with 5 to 12 members, and the heterocycle and heteroaryl ring contain at least 1 to 3 a heteroatom selected from N, O and S;
    R 13为C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基、CN或CF 3，所述C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基进一步被1或多个选自以下的取代基取代：H、D、卤素、CN、OH、NO 2、OR g2、SR g2、C(＝O)R g3、C(＝O)NR g4R g5、C(＝O)OR g2、OC(＝O)R g3、OC(＝O)NR g4R g5、NR g4R g5、NR g4C(＝O)R g3、NR g4OC(＝O)R g3、NR g4C(＝O)NR g4R g5、C(＝NR g6)R g3、C(＝NR g6)NR g4R g5、NR g4C(＝NR g6)NR g4R g5、NR g4S(＝O)R g2、NR g4S(＝O) 2R g2、NR g4S(＝O) 2NR g4R g5、S(＝O)R g2、S(＝O)NR g4R g5或S(＝O) 2NR g4R g5；所述3至10元的杂环烷基、5至12元杂芳基包含1至3个选自N、O、S的杂原子； R 13 is C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN or CF 3 , the C 3-10 cycloalkane radical, 3 to 10 membered heterocycloalkyl, 6 to 12 membered aryl, 5 to 12 membered heteroaryl are further substituted by 1 or more substituents selected from the group consisting of: H, D, halogen, CN, OH , NO 2 , OR g2 , SR g2 , C(=O)R g3 , C(=O)NR g4 R g5 , C(=O)OR g2 , OC(=O)R g3 , OC(=O)NR g4 R g5 , NR g4 R g5 , NR g4 C(=O)R g3 , NR g4 OC(=O)R g3 , NR g4 C(=O)NR g4 R g5 , C(=NR g6 )R g3 , C(=NR g6 )NR g4 R g5 , NR g4 C(=NR g6 )NR g4 R g5 , NR g4 S(=O)R g2 , NR g4 S(=O) 2 R g2 , NR g4 S(= O) 2 NR g4 R g5 , S(=O)R g2 , S(=O)NR g4 R g5 or S(=O) 2 NR g4 R g5 ; the 3 to 10-membered heterocycloalkyl, 5 to 12 membered heteroaryls containing 1 to 3 heteroatoms selected from N, O, S;
    条件是：当R 13为CN或CF 3时，R 3和R 4为D； The condition is: when R 13 is CN or CF 3 , R 3 and R 4 are D;
    R 14a选自H、OH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元杂芳基、3至10元杂环烷基、OR c2、SR c2、C(＝O)R c3、C(＝O)NR c4R c5、C(＝O)OR c2、OC(＝O)R c3、OC(＝O)NR c4R c5、NR c4R c5、NR c4C(＝O)R c3、NR c4OC(＝O)R c3、NR c4C(＝O)NR c4R c5、C(＝NR c6)R c3、C(＝NR c6)NR c4R c5、NR c4C(＝NR c6)NR c4R c5、NR c4S(＝O)R c2、NR c4S(＝O) 2R c2、NR c4S(＝O) 2 NR c4R c5、S(＝O)R c2、S(＝O)NR c4R c5或S(＝O) 2NR c4R c5；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR c2、SR c2、C(＝O)R c3、C(＝O)NR c4R c5、C(＝O)OR c2、OC(＝O)R c3、OC(＝O)NR c4R c5、NR c4R c5、NR c4C(＝O)R c3、NR c4OC(＝O)R c3、NR c4C(＝O)NR c4R c5、C(＝NR c6)R c3、C(＝NR c6)NR c4R c5、NR c4C(＝NR c6)NR c4R c5、NR c4S(＝O)R c2、NR c4S(＝O) 2R c2、NR c4S(＝O) 2NR c4R c5、S(＝O)R c2、S(＝O)NR c4R c5、S(＝O) 2NR c4R c5、P(＝O)(R c4) 2或P(＝O) 2；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R 14a is selected from H, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl , 3- to 10-membered heterocycloalkyl, OR c2 , SR c2 , C(=O)R c3 , C(=O)NR c4 R c5 , C(=O)OR c2 , OC(=O)R c3 , OC(=O)NR c4 R c5 , NR c4 R c5 , NR c4 C(=O)R c3 , NR c4 OC(=O)R c3 , NR c4 C(=O)NR c4 R c5 , C(= NR c6 )R c3 , C(=NR c6 )NR c4 R c5 , NR c4 C(=NR c6 )NR c4 R c5 , NR c4 S(=O)R c2 , NR c4 S(=O) 2 R c2 , NR c4 S(=O) 2 NR c4 R c5 , S(=O)R c2 , S(=O)NR c4 R c5 or S(=O) 2 NR c4 R c5 ; the C 1-6 alkane C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl optionally Substituted by 1 to more substituents selected from H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 5 to 12 Membered heteroaryl, 3- to 10-membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR c2 , SR c2 , C(=O)R c3 , C(=O)NR c4 R c5 , C(=O)OR c2 , OC(=O)R c3 , OC(=O)NR c4 R c5 , NR c4 R c5 , NR c4 C(=O)R c3 , NR c4 OC(= O)R c3 , NR c4 C(=O)NR c4 R c5 , C(=NR c6 )R c3 , C(=NR c6 )NR c4 R c5 , NR c4 C(=NR c6 )NR c4 R c5 , NR c4 S(=O)R c2 , NR c4 S(=O) 2 R c2 , NR c4 S(=O) 2 NR c4 R c5 , S(=O)R c2 , S(=O)NR c4 R c5 , S(=O) 2 NR c4 R c5 , P(=O)(R c4 ) 2 or P(=O) 2 ; the 5 to 12-membered heteroaryl, 3 to 10-membered heterocycloalkyl comprises 1 to 3 heteroatoms selected from N, O, S;
    R 14b、R 14c、R 16各自独立地H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6- 12芳基、5至12元杂芳基、3至10元杂环烷基、COOH、OR d2、SR d2、C(＝O)R d3、C(＝O)NR d4R d5、C(＝O)OR d2、C(＝NR d6)R d3或C(＝NR d6)NR d4R d5；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR d2、SR d2、C(＝O)R d3、C(＝O)NR d4R d5、C(＝O)OR d2、OC(＝O)R d3、OC(＝O)NR d4R d5、NR d4R d5、NR d4C(＝O)R d3、NR d4OC(＝O)R d3、NR d4C(＝O)NR d4R d5、C(＝NR d6)R d3、C(＝NR d6)NR d4R d5、NR d4C(＝NR d6)NR d4R d5、NR d4S(＝O)R d2、NR d4S(＝O) 2R d2、NR d4S(＝O) 2 NR d4R d5、S(＝O)R d2、S(＝O)NR d4R d5或S(＝O) 2NR d4R d5；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R 14b , R 14c , and R 16 are each independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12-membered heteroaryl, 3 to 10-membered heterocycloalkyl, COOH, OR d2 , SR d2 , C(=O)R d3 , C(=O)NR d4 R d5 , C(=O)OR d2 , C(=NR d6 )R d3 or C(=NR d6 )NR d4 R d5 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl , C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl optionally substituted by 1 to more substituents selected from the group consisting of H, OH, halogen, C 1-6 alkane radical, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR d2 , SR d2 , C(=O)R d3 , C(=O)NR d4 R d5 , C(=O)OR d2 , OC(=O)R d3 , OC(= O)NR d4 R d5 , NR d4 R d5 , NR d4 C(=O)R d3 , NR d4 OC(=O)R d3 , NR d4 C(=O)NR d4 R d5 , C(=NR d6 ) R d3 , C(=NR d6 )NR d4 R d5 , NR d4 C(=NR d6 )NR d4 R d5 , NR d4 S(=O)R d2 , NR d4 S(=O) 2 R d2 , NR d4 S(=O) 2 NR d4 R d5 , S(=O)R d2 , S(=O)NR d4 R d5 or S(=O) 2 NR d4 R d5 ; the 5 to 12-membered heteroaryl, The 3 to 10 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, S;
    R a1、R a2、R a3、R a4、R a5、R a6、R b1、R b2、R b3、R b4、R b5、R b6、R c1、R c2、R c3、R c4、R c5、R c6、R d1、R d2、R d3、R d4、R d5、R d6、R x1、R x2、R x3、R x4、R x5或R x6、各自独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元 杂芳基、3至10元杂环烷基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR e2、SR e2、C(＝O)R e3、C(＝O)NR e4R e5、C(＝O)OR e2、OC(＝O)R e3、OC(＝O)NR e4R e5、NR e4R e5、NR e4C(＝O)R e3、NR e4OC(＝O)R e3、NR e4C(＝O)NR e4R e5、C(＝NR e6)R e3、C(＝NR e6)NR e4R e5、NR e4C(＝NR e6)NR e4R e5、NR e4S(＝O)R e2、NR e4S(＝O) 2R e2、NR e4S(＝O) 2 NR e4Re 5、S(＝O)R e2、S(＝O)NR e4R e5或S(＝O) 2NR e4R e5；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R x1 , R x2 , R x3 , R x4 , R x5 or R x6 , each independently selected from H, C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, all C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heteroaryl Cycloalkyl is optionally substituted with 1 to more substituents selected from the group consisting of H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cyclo Alkyl, 5- to 12-membered heteroaryl, 3- to 10-membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR e2 , SR e2 , C(=O)R e3 , C(=O)NR e4 R e5 , C(=O)OR e2 , OC(=O)R e3 , OC(=O)NR e4 R e5 , NR e4 R e5 , NR e4 C(=O)R e3 , NR e4 OC(=O)R e3 , NR e4 C(=O)NR e4 R e5 , C(=NR e6 )R e3 , C(=NR e6 )NR e4 R e5 , NR e4 C(=NR e6 )NR e4 R e5 , NR e4 S(=O)R e2 , NR e4 S(=O) 2 R e2 , NR e4 S(=O) 2 NR e4 Re 5 , S(=O)R e2 , S( =O) NR e4 R e5 or S(=O) 2 NR e4 R e5 ; the 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl contains 1 to 3 selected from N, O, S heteroatom;
    R a4和R a5、R b4和R b5、R c4和R c5、R d4和R d5、R x4和R x5各自独立地连同其所连接的N原子形成4至7元杂环，所述杂环进一步被1或多个选自以下的取代基取代：卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、CN、OR f2、SR f2、C(＝O)R f3、C(＝O)NR f4R f5、C(＝O)OR f2、OC(＝O)R f3、OC(＝O)NR f4R f5、NR f4R f5、NR f4C(＝O)R f3、NR f4OC(＝O)R f3、NR f4C(＝O)NR f4R f5、C(＝NR f6)R f3、C(＝NR f6)NR f4R f5、NR f4C(＝NR f6)NR f4R f5、NR f4S(＝O)R f2、NR f4S(＝O) 2R f2、NR f4S(＝O) 2 NR f4R f5、S(＝O)R f2、S(＝O)NR f4R f5或S(＝O) 2NR f4R f5；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R a4 and R a5 , R b4 and R b5 , R c4 and R c5 , R d4 and R d5 , R x4 and R x5 each independently form a 4- to 7-membered heterocycle together with the N atom to which they are attached, and the heterocycle The ring is further substituted by 1 or more substituents selected from the group consisting of halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, OR f2 , SR f2 , C(=O )R f3 , C(=O)NR f4 R f5 , C(=O)OR f2 , OC(=O)R f3 , OC(=O)NR f4 R f5 , NR f4 R f5 , NR f4 C(= O)R f3 , NR f4 OC(=O)R f3 , NR f4 C(=O)NR f4 R f5 , C(=NR f6 )R f3 , C(=NR f6 )NR f4 R f5 , NR f4 C (=NR f6 )NR f4 R f5 , NR f4 S(=O)R f2 , NR f4 S(=O) 2 R f2 , NR f4 S(=O) 2 NR f4 R f5 , S(=O)R f2 , S(=O)NR f4 R f5 or S(=O) 2 NR f4 R f5 ; the 5 to 12-membered heteroaryl, 3 to 10-membered heterocycloalkyl contains 1 to 3 members selected from N, Heteroatoms of O and S;
    R f1、R f2、R f3、R f4、R f5、R f6、R e1、R e2、R e3、R e4、R e5、R e6、R g1、R g2、R g3、R g4、R g5、R g6各自独立地选自C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3- 10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R f1 , R f2 , R f3 , R f4 , R f5 , R f6 , Re1 , Re2 , Re3 , Re4 , Re5 , Re6 , R g1 , R g2 , R g3 , R g4 , R g5 , R g6 are each independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl group, 3 to 10 membered heterocycloalkyl group, the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-10 cycloalkyl group, C 6-12 aryl group, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 5-12 membered heteroaryl, 3-10 membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH; the 5-12 membered heteroaryl, 3-10 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, S;
    m为0、1、2或者3；m is 0, 1, 2 or 3;
    n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
    o为0或者1；o is 0 or 1;
    p为1、2或者3。p is 1, 2 or 3.
  2. 根据权利要求1所述的化合物或者其立体异构体、药学上可接受的盐或氘代物，其中：The compound or its stereoisomer, pharmaceutically acceptable salt or deuterated product according to claim 1, wherein:
    A为
    Figure PCTCN2022110534-appb-100004
    R 14为C 1-6烷基、C 3-5环烷基、C 2-6烯基、卤素、CN或C(＝O)R 14a，所述C 1-6烷基、C 3-5环烷基、C 2-6烯基任选地被1至3个卤素取代；     A is
    Figure PCTCN2022110534-appb-100004
    R 14 is C 1-6 alkyl, C 3-5 cycloalkyl, C 2-6 alkenyl, halogen, CN or C(=O)R 14a , the C 1-6 alkyl, C 3-5 Cycloalkyl, C 2-6 alkenyl are optionally substituted by 1 to 3 halogens;
    R 14a为OH、C 1-6烷基、C 3-5环烷基，所述C 1-6烷基、C 3-5环烷基任选地被1至3个卤素取代； R 14a is OH, C 1-6 alkyl, C 3-5 cycloalkyl, said C 1-6 alkyl, C 3-5 cycloalkyl are optionally substituted by 1 to 3 halogens;
    X 1为NR x1、O、S、3至10元杂环烷基的单环或多环,所述杂环烷基进一步被1或多个选自以下的取代基取代：H、卤素、CN、OH、C 1-6烷基、C 1-6烷氧基、C 6-10芳基、C 3-7环烷基、5至10元杂芳基或3至10元杂环烷基，所述C 1-6烷基、C 1-6烷氧基、C 6-10芳基、C 3-7环烷基、5至10元杂芳基、3至10元杂环烷基各自独立地被1或多个选自以下的取代基取代：H、卤素、CN或OH，所述杂芳基或杂环烷基包含1、2、3或4个独立地选自O、N和S的杂原子； X 1 is NR x1 , O, S, a monocyclic or polycyclic ring of 3 to 10 membered heterocycloalkyl, and the heterocycloalkyl is further substituted by 1 or more substituents selected from the group consisting of H, halogen, CN , OH, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 3-7 cycloalkyl, 5 to 10 membered heteroaryl or 3 to 10 membered heterocycloalkyl, The C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 3-7 cycloalkyl, 5 to 10 membered heteroaryl, 3 to 10 membered heterocycloalkyl are each independently is substituted by 1 or more substituents selected from H, halogen, CN or OH, and the heteroaryl or heterocycloalkyl contains 1, 2, 3 or 4 substituents independently selected from O, N and S heteroatoms;
    X 2为NR x1、O、S、-C(＝O)-、-C(＝O)O-、-C(＝O)NR x1-、-S(＝O)-、-S(＝O) 2-、-S(＝O)NR x1-、-S(＝O) 2NR x1-、-NR x1C(＝O)NR x1-或键； X 2 is NR x1 , O, S, -C(=O)-, -C(=O)O-, -C(=O)NR x1 -, -S(=O)-, -S(=O ) 2 -, -S(=O)NR x1 -, -S(=O) 2 NR x1 -, -NR x1 C(=O)NR x1 - or a bond;
    R 1、R 2、R 3、R 4各自独立地选自H、D、卤素、NR a4R a5、OH、C 1-6烷基、C 1-6烷 氧基、C 3-7环烷基、5至10元杂芳基或3至10元杂环烷基，所述C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、5至10元杂芳基、3至10元杂环烷基各自独立地被1或多个选自以下的取代基取代：H、卤素、OH、NR a4R a5、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、5至10元杂芳基、3至10元杂环烷基；或R 1和R 2、R 3和R 4、R 1和R 3各自独立地连同其所连接的碳原子形成3至6元环烷基或5至10元杂环烷基，所述环烷基、杂环烷基任选地被1或多个选自以下的取代基取代：H、卤素、OH、NR a4R a5、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、5至10元杂芳基、3至10元杂环烷基；所述5至10元杂芳基、3至10元杂环烷基包含1至3个选自O、N和S的杂原子； R 1 , R 2 , R 3 , and R 4 are each independently selected from H, D, halogen, NR a4 R a5 , OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkane base, 5 to 10 membered heteroaryl or 3 to 10 membered heterocycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 5 to 10 membered heteroaryl group, 3- to 10-membered heterocycloalkyl group are each independently substituted by 1 or more substituents selected from the group consisting of: H, halogen, OH, NR a4 R a5 , C 1-6 alkyl, C 1-6 alkoxy group, C 3-7 cycloalkyl group, 5 to 10 membered heteroaryl group, 3 to 10 membered heterocycloalkyl group; or R 1 and R 2 , R 3 and R 4 , R 1 and R 3 each independently together with their The attached carbon atoms form a 3 to 6 membered cycloalkyl group or a 5 to 10 membered heterocycloalkyl group, which are optionally substituted by 1 or more substituents selected from the group consisting of: H , halogen, OH, NR a4 R a5 , C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 5 to 10 membered heteroaryl, 3 to 10 membered heterocycloalkyl; The 5- to 10-membered heteroaryl group and the 3- to 10-membered heterocycloalkyl group contain 1 to 3 heteroatoms selected from O, N and S;
    R a4、R a5各自独立的地为H或C 1-6烷基，或者R a4和R a5各自独立地连同其所连接的原子形成5至6元杂环烷基；所述5至6元杂环烷基包含1至3个选自O、N和S的杂原子； R a4 and R a5 are each independently H or C 1-6 alkyl, or each of R a4 and R a5 independently form a 5 to 6-membered heterocycloalkyl together with the atoms they are connected to; the 5 to 6-membered Heterocycloalkyl comprises 1 to 3 heteroatoms selected from O, N and S;
    L 1为
    Figure PCTCN2022110534-appb-100005
    R 17为H、D或C 1-6烷基,所述C 1-6烷基任选地被1至3个卤素取代；     L 1 is
    Figure PCTCN2022110534-appb-100005
    R 17 is H, D or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
    L 2选自C 1-6亚烷基、3至10元杂环烷基的单环或多环、-C(＝O)-、-C(＝O)O-、-C(＝O)NR x1-或键，所述C 1-6亚烷基、3至10元杂环烷基的单环或多环进一步被1或多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH；所述3至10元杂环烷基的单环或多环、5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； L2 is selected from C 1-6 alkylene, 3 to 10 membered heterocycloalkyl rings or polycyclic rings, -C(=O)-, -C(=O)O-, -C(=O) NR x1 - or a bond, the C 1-6 alkylene, 3 to 10 membered heterocycloalkyl ring or polycyclic ring is further substituted by 1 or more substituents selected from the following: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycle Alkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH; monocyclic or polycyclic, 5 to 12 membered heteroaryl, 3 to 10 membered heterocyclic The alkyl group contains 1 to 3 heteroatoms selected from N, O, S;
    X 3为C或N； X3 is C or N;
    R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、D、卤素、OH、C(＝O)NH 2、C 1-6烷基，所述C 1-6烷基任选地被1至3个卤素取代；或R 5和R 6、R 7和R 8、R 9和R 10、R 11和R 12各自独立地连同其所连接的碳原子形成3至6元环烷基；或R 5和R 6、R 7和R 8、R 9和R 10、R 11和R 12各自独立地连同其所连接的碳原子形成＝O；或R 5和R 7、R 5和R 9、R 5和R 11、R 7和R 9、R 7和R 11、R 9和R 11相连； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, D, halogen, OH, C(=O)NH 2 , C 1-6 alkyl , the C 1-6 alkyl group is optionally substituted by 1 to 3 halogens; or R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 are each independently together with their The attached carbon atoms form a 3 to 6-membered cycloalkyl group; or R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 each independently together with the carbon atoms to which they are attached form =O ; or R 5 and R 7 , R 5 and R 9 , R 5 and R 11 , R 7 and R 9 , R 7 and R 11 , R 9 and R 11 are connected;
    B为3至10元的环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基，所述杂环、杂芳环包含至少1至3个选自N、O和S的杂原子；B is a cycloalkyl group with 3 to 10 members, a heterocycloalkyl group with 3 to 10 members, an aryl group with 6 to 12 members, and a heteroaryl group with 5 to 12 members, and the heterocycle and heteroaryl ring contain at least 1 to 3 a heteroatom selected from N, O and S;
    R 13为C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基、CN或CF 3，所述C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基进一步被1或多个选自以下的取代基取代：H、卤素、CN、OH、NH 2、C 1-6烷基、C 1-6卤代烷基或C 3-10环烷基；所述3至10元的杂环烷基、5至12元杂芳基包含1至3个选自N、O、S的杂原子； R 13 is C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN or CF 3 , the C 3-10 cycloalkane radical, 3 to 10 membered heterocycloalkyl, 6 to 12 membered aryl, 5 to 12 membered heteroaryl are further substituted by 1 or more substituents selected from the group consisting of: H, halogen, CN, OH, NH 2. C 1-6 alkyl, C 1-6 haloalkyl or C 3-10 cycloalkyl; the 3 to 10 membered heterocycloalkyl, 5 to 12 membered heteroaryl contains 1 to 3 members selected from N, O, S heteroatoms;
    条件是：当R 13为CN或CF 3时，R 3和R 4为D； The condition is: when R 13 is CN or CF 3 , R 3 and R 4 are D;
    R x1选自H、C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基，所述C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、CN、NH 2、NO 2、N 3、COOH；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R x1 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1- 6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H, OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, CN, NH 2 , NO 2 , N 3 , COOH ; The 5-12 membered heteroaryl, 3-10 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, S;
    m为0、1、2或者3；m is 0, 1, 2 or 3;
    n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
    o为0或者1；o is 0 or 1;
    p为1、2或者3。p is 1, 2 or 3.
  3. 据权利要求1、2所述的化合物或者其立体异构体、药学上可接受的盐或氘代物，所述化合物或者其立体异构体，药学上可接受的盐或氘代物具有式(I-1)所示的结构：According to the compound or its stereoisomer, pharmaceutically acceptable salt or deuterated substance according to claim 1 and 2, said compound or its stereoisomer, pharmaceutically acceptable salt or deuterated substance has the formula (I -1) The structure shown:
    Figure PCTCN2022110534-appb-100006
    Figure PCTCN2022110534-appb-100006
    其中：in:
    A为
    Figure PCTCN2022110534-appb-100007
    R 14为C 1-6烷基、C 3-5环烷基、C 2-6烯基、卤素、CN或C(＝O)R 14a，所述C 1-6烷基、C 3-5环烷基、C 2-6烯基任选地被1至3个卤素取代；     A is
    Figure PCTCN2022110534-appb-100007
    R 14 is C 1-6 alkyl, C 3-5 cycloalkyl, C 2-6 alkenyl, halogen, CN or C(=O)R 14a , the C 1-6 alkyl, C 3-5 Cycloalkyl, C 2-6 alkenyl are optionally substituted by 1 to 3 halogens;
    R 14a为OH、C 1-6烷基、C 3-5环烷基，所述C 1-6烷基、C 3-5环烷基任选地被1至3个卤素取代； R 14a is OH, C 1-6 alkyl, C 3-5 cycloalkyl, said C 1-6 alkyl, C 3-5 cycloalkyl are optionally substituted by 1 to 3 halogens;
    X 1为NR x1、O、S、
    Figure PCTCN2022110534-appb-100008
    或者
    Figure PCTCN2022110534-appb-100009
    X 1 is NR x1 , O, S,
    Figure PCTCN2022110534-appb-100008
    or
    Figure PCTCN2022110534-appb-100009
    X 2为NR x1、O、S、-C(＝O)-、-C(＝O)O-、-C(＝O)NR x1-、-S(＝O)-、-S(＝O) 2-、-S(＝O)NR x1-、-S(＝O) 2NR x1-、-NR x1C(＝O)NR x1-或键； X 2 is NR x1 , O, S, -C(=O)-, -C(=O)O-, -C(=O)NR x1 -, -S(=O)-, -S(=O ) 2 -, -S(=O)NR x1 -, -S(=O) 2 NR x1 -, -NR x1 C(=O)NR x1 - or a bond;
    R 18、R 19、R 20、R 21、R 22和R 23各自独立地选自H、卤素、CN、OH、C 1-6烷基、C 1-6烷氧基、C 6-10芳基、C 3-7环烷基、5至10元杂芳基或3至10元杂环烷基，所述C 1- 6烷基、C 1-6烷氧基、C 6-10芳基、C 3-7环烷基、5至10元杂芳基、3至10元杂环烷基各自独立地被1或多个选自以下的取代基取代：H、卤素、CN、OH，所述5至10元杂芳基、3至10元杂环烷基包含1、2、3或4个独立地选自O、N和S的杂原子； R 18 , R 19 , R 20 , R 21 , R 22 and R 23 are each independently selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl C 3-7 cycloalkyl, 5 to 10 membered heteroaryl or 3 to 10 membered heterocycloalkyl , the C 1-6 alkyl, C 1-6 alkoxy , C 6-10 aryl , C 3-7 cycloalkyl, 5 to 10 membered heteroaryl, 3 to 10 membered heterocycloalkyl are each independently substituted by 1 or more substituents selected from the group consisting of: H, halogen, CN, OH, all The 5 to 10 membered heteroaryl, 3 to 10 membered heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms independently selected from O, N and S;
    C为5至10元碳环、5至10元杂环、6至10元芳环或者5至10元芳杂环；所述5至10元杂环、5至10元芳杂环包含1至3个选自O、N和S的杂原子；C is 5 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10 membered aromatic ring or 5 to 10 membered aromatic heterocyclic ring; the 5 to 10 membered heterocyclic ring and 5 to 10 membered aromatic heterocyclic ring include 1 to 3 heteroatoms selected from O, N and S;
    R 1、R 2、R 3、R 4各自独立地选自H、D、卤素、NR a4R a5、OH、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、5至10元杂芳基或3至10元杂环烷基，所述C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、5至10元杂芳基、3至10元杂环烷基各自独立地被1或多个选自以下的取代基取代：H、卤素、OH、NR a4R a5、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、5至10元杂芳基、3至10元杂环烷基；或R 1和R 2、R 3和R 4、R 1和R 3各自独立地连同其所连接的碳原子形成3至6元环烷基或5至10元杂环烷基，所述环烷基、杂环烷基任选地被1或多个选自以下的取代基取代：H、卤素、OH、NR a4R a5、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、5至10元杂芳基、3至10元杂环烷基；所述5至10元杂芳基、3至10元杂环烷基包含1至3个选自O、N和S的杂原子； R 1 , R 2 , R 3 , and R 4 are each independently selected from H, D, halogen, NR a4 R a5 , OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkane base, 5 to 10 membered heteroaryl or 3 to 10 membered heterocycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 5 to 10 membered heteroaryl group, 3- to 10-membered heterocycloalkyl group are each independently substituted by 1 or more substituents selected from the group consisting of: H, halogen, OH, NR a4 R a5 , C 1-6 alkyl, C 1-6 alkoxy group, C 3-7 cycloalkyl group, 5 to 10 membered heteroaryl group, 3 to 10 membered heterocycloalkyl group; or R 1 and R 2 , R 3 and R 4 , R 1 and R 3 each independently together with their The attached carbon atoms form a 3 to 6 membered cycloalkyl group or a 5 to 10 membered heterocycloalkyl group, which are optionally substituted by 1 or more substituents selected from the group consisting of: H , halogen, OH, NR a4 R a5 , C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 5 to 10 membered heteroaryl, 3 to 10 membered heterocycloalkyl; The 5- to 10-membered heteroaryl group and the 3- to 10-membered heterocycloalkyl group contain 1 to 3 heteroatoms selected from O, N and S;
    R a4、R a5各自独立的地为H或C 1-6烷基，或者R a4和R a5各自独立地连同其所连接的原子形成5至6元杂环烷基；所述5至6元杂环烷基包含1至3个选自O、N和S的杂原子； R a4 and R a5 are each independently H or C 1-6 alkyl, or each of R a4 and R a5 independently form a 5 to 6-membered heterocycloalkyl together with the atoms they are connected to; the 5 to 6-membered Heterocycloalkyl comprises 1 to 3 heteroatoms selected from O, N and S;
    L 1为
    Figure PCTCN2022110534-appb-100010
    R 17为H、D或C 1-6烷基，所述C 1-6烷基任选地被1至3个卤素取代；     L 1 is
    Figure PCTCN2022110534-appb-100010
    R 17 is H, D or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
    L 2选自C 1-6亚烷基、3至10元杂环烷基的单环或多环、--C(＝O)-、-C(＝O)O-、-C(＝O)NR x1-或键，所述C 1-6亚烷基、3至10元杂环烷基的单环或多环进一步被1或多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2；所述3至10元杂环烷基的单环或多环、5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； L2 is selected from C 1-6 alkylene, 3 to 10 membered heterocycloalkyl rings or polycyclic rings, --C(=O)-, -C(=O)O-, -C(=O ) NR x1 - or a bond, the C 1-6 alkylene, 3 to 10 membered heterocycloalkyl ring or polycyclic ring is further substituted by 1 or more substituents selected from the following: H, OH, halogen , C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, =O, CN, NH 2 ; 3 to 10 membered heterocycloalkyl monocyclic or polycyclic, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl contain 1 to 3 heteroatoms selected from N, O and S;
    R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、D、卤素、C(＝O)NH 2、OH、C 1-6烷基，所述C 1-6烷基任选地被1至3个卤素取代；或R 5和R 6、R 7和R 8、R 9和R 10、R 11和R 12各自独立地连同其所连接的碳原子形成3至6元环烷基；或R 5和R 6、R 7和R 8、R 9和R 10、R 11和R 12各自独立地连同其所连接的碳原子形成＝O；或R 5和R 7、R 5和R 9、R 5和R 11、R 7和R 9、R 7和R 11、R 9和R 11相连； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, D, halogen, C(=O)NH 2 , OH, C 1-6 alkyl , the C 1-6 alkyl group is optionally substituted by 1 to 3 halogens; or R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 are each independently together with their The attached carbon atoms form a 3 to 6-membered cycloalkyl group; or R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 each independently together with the carbon atoms to which they are attached form =O ; or R 5 and R 7 , R 5 and R 9 , R 5 and R 11 , R 7 and R 9 , R 7 and R 11 , R 9 and R 11 are connected;
    B为3至10元的环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基，所述杂环、杂芳环包含至少1至3个选自N、O和S的杂原子；B is a cycloalkyl group with 3 to 10 members, a heterocycloalkyl group with 3 to 10 members, an aryl group with 6 to 12 members, and a heteroaryl group with 5 to 12 members, and the heterocycle and heteroaryl ring contain at least 1 to 3 a heteroatom selected from N, O and S;
    R 13为C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基、CN或CF 3，所述C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基进一步被1或多个选自以下的取代基取代：H、卤素、CN、OH、NH 2、C 1-6烷基、C 1-6卤代烷基或C 3-10环烷基；所述3至10元的杂环烷基、5至12元杂芳基包含1至3个选自N、O、S的杂原子；条件是：当R 13为CN或CF 3时，R 3和R 4为D； R 13 is C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN or CF 3 , the C 3-10 cycloalkane radical, 3 to 10 membered heterocycloalkyl, 6 to 12 membered aryl, 5 to 12 membered heteroaryl are further substituted by 1 or more substituents selected from the group consisting of: H, halogen, CN, OH, NH 2. C 1-6 alkyl, C 1-6 haloalkyl or C 3-10 cycloalkyl; the 3 to 10 membered heterocycloalkyl, 5 to 12 membered heteroaryl contains 1 to 3 members selected from Heteroatoms of N, O, S; condition is: when R 13 is CN or CF 3 , R 3 and R 4 are D;
    R x1选自H、C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基，所述C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、CN、NH 2；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R x1 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1- 6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H, OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, CN, NH 2 ; said 5 to 12 membered heteroaryl Aryl, 3 to 10 membered heterocycloalkyls contain 1 to 3 heteroatoms selected from N, O, S;
    n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
    o为0或者1；o is 0 or 1;
    p为1、2或者3；p is 1, 2 or 3;
    q为1、2或者3。q is 1, 2 or 3.
  4. 根据权利要求要求1至3所述的化合物或者其立体异构体、药学上可接受的盐或氘代物，其中：The compound or its stereoisomer, pharmaceutically acceptable salt or deuterated product according to claims 1 to 3, wherein:
    A为
    Figure PCTCN2022110534-appb-100011
    R 14为C 1-6烷基、C 3-5环烷基或卤素，所述C 1-6烷基任选地被1至3个卤素取代；     A is
    Figure PCTCN2022110534-appb-100011
    R 14 is C 1-6 alkyl, C 3-5 cycloalkyl or halogen, and the C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
    X 1为NH、O、
    Figure PCTCN2022110534-appb-100012
    或者
    Figure PCTCN2022110534-appb-100013
    X 1 is NH, O,
    Figure PCTCN2022110534-appb-100012
    or
    Figure PCTCN2022110534-appb-100013
    X 2为NH、O、S、-C(＝O)-、-C(＝O)O-、-C(＝O)NH-、-S(＝O)-、-S(＝O) 2-、- S(＝O)NH-、-S(＝O) 2NH-、-NHC(＝O)NH-或键； X 2 is NH, O, S, -C(=O)-, -C(=O)O-, -C(=O)NH-, -S(=O)-, -S(=O) 2 -, -S(=O)NH-, -S(=O) 2NH- , -NHC(=O)NH- or a bond;
    R 1、R 2、R 3、R 4各自独立地选自H、D、C 1-6烷基，R 1和R 2、R 3和R 4、R 1和R 3各自独立地连同其所连接的碳原子形成3至6元环烷基； R 1 , R 2 , R 3 , and R 4 are each independently selected from H, D, and C 1-6 alkyl groups, and R 1 and R 2 , R 3 and R 4 , R 1 and R 3 are each independently selected from the group consisting of The attached carbon atoms form a 3 to 6 membered cycloalkyl group;
    L 1为
    Figure PCTCN2022110534-appb-100014
    L 1 is
    Figure PCTCN2022110534-appb-100014
    L 2选自C 1-6亚烷基、3至10元杂环烷基的单环或多环、-C(＝O)-、-C(＝O)O-、-C(＝O)NR x1-或键，所述C 1-6亚烷基、3至10元杂环烷基的单环或多环进一步被1或多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2；所述3至10元杂环烷基的单环或多环、5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； L2 is selected from C 1-6 alkylene, 3 to 10 membered heterocycloalkyl rings or polycyclic rings, -C(=O)-, -C(=O)O-, -C(=O) NR x1 - or a bond, the C 1-6 alkylene, 3 to 10 membered heterocycloalkyl ring or polycyclic ring is further substituted by 1 or more substituents selected from the following: H, OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, =O, CN, NH 2 ; the 3 Monocyclic or polycyclic, 5- to 12-membered heteroaryl, 3- to 10-membered heterocycloalkyl to 10-membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, and S;
    R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、D、卤素、OH、C 1-6烷基，所述C 1-6烷基任选地被1至3个卤素取代；或R 5和R 6、R 9和R 10各自独立地连同其所连接的碳原子形成3至6元环烷基；或R 11和R 12与其所连接的碳原子形成＝O；或R 5和R 9、R 5和R 11、R 7和R 9、R 7和R 11相连； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, D, halogen, OH, C 1-6 alkyl, said C 1-6 alkane The group is optionally substituted by 1 to 3 halogens; or R 5 and R 6 , R 9 and R 10 each independently form a 3 to 6-membered cycloalkyl group together with the carbon atom to which they are attached; or R 11 and R 12 are combined with The attached carbon atoms form =O; or R 5 and R 9 , R 5 and R 11 , R 7 and R 9 , R 7 and R 11 are linked;
    B为
    Figure PCTCN2022110534-appb-100015
    Figure PCTCN2022110534-appb-100016
    B for
    Figure PCTCN2022110534-appb-100015
    Figure PCTCN2022110534-appb-100016
    X 5、X 6、X 7各自独立的选自CH、CH 2、N、NH、O或S； X 5 , X 6 , and X 7 are each independently selected from CH, CH 2 , N, NH, O or S;
    Figure PCTCN2022110534-appb-100017
    为双键或单键；
    Figure PCTCN2022110534-appb-100017
    is a double bond or a single bond;
    D选自5至10元碳环、5至10元杂环、6至10元芳环或者5至10元芳杂环；所述5至10元碳环、5至10元杂环、6至10元芳环、5至10元芳杂环进一步被1或多个选自以下的取代基取代：C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基；所述5至10元杂环、5至10元芳杂环、5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； D is selected from 5 to 10 membered carbocyclic rings, 5 to 10 membered heterocyclic rings, 6 to 10 membered aromatic rings or 5 to 10 membered aromatic heterocyclic rings; The 10-membered aromatic ring and the 5-10-membered aromatic heterocycle are further substituted by 1 or more substituents selected from the group consisting of: C 3-10 cycloalkyl, C 6-12 aryl, 5-12-membered heteroaryl, 3 to 10 membered heterocycloalkyl; the 5 to 10 membered heterocycle, 5 to 10 membered aromatic heterocycle, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl contain 1 to 3 members selected from N, Heteroatoms of O and S;
    R 13为C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基、CN或CF 3，所述C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂 芳基进一步被1或多个选自以下的取代基取代：H、卤素、CN、OH、NH 2、C 1-6烷基、C 1-6卤代烷基或C 3-10环烷基；所述3至10元的杂环烷基、5至12元杂芳基包含1至3个选自N、O、S的杂原子；条件是：当R 13为CN或CF 3时，R 3和R 4为D。 R 13 is C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN or CF 3 , the C 3-10 cycloalkane radical, 3 to 10 membered heterocycloalkyl, 6 to 12 membered aryl, 5 to 12 membered heteroaryl are further substituted by 1 or more substituents selected from the group consisting of: H, halogen, CN, OH, NH 2. C 1-6 alkyl, C 1-6 haloalkyl or C 3-10 cycloalkyl; the 3 to 10 membered heterocycloalkyl, 5 to 12 membered heteroaryl contains 1 to 3 members selected from Heteroatoms of N, O, S; with the proviso that: when R 13 is CN or CF 3 , R 3 and R 4 are D.
    R x1选自H、C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1- 6烷基、C 3-10环烷基、CN、NH 2；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R x1 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl is optionally substituted by 1 to more substituents selected from the group consisting of H, OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, CN, NH 2 ; the 5 to 12 membered heteroaryl, The 3 to 10 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, S;
    n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
    o为0或者1。o is 0 or 1.
  5. 根据权利要求1至4所述的化合物或者其立体异构体、药学上可接受的盐或氘代物，其中：The compound or its stereoisomer, pharmaceutically acceptable salt or deuterated product according to claims 1 to 4, wherein:
    A为
    Figure PCTCN2022110534-appb-100018
    A is
    Figure PCTCN2022110534-appb-100018
    X 1为NH、
    Figure PCTCN2022110534-appb-100019
    或者
    Figure PCTCN2022110534-appb-100020
     X1 is NH,
    Figure PCTCN2022110534-appb-100019
    or
    Figure PCTCN2022110534-appb-100020
    X 2为NH、O、S、-C(＝O)-、-C(＝O)O-、-C(＝O)NH-或键； X2 is NH, O, S, -C(=O)-, -C(=O)O-, -C(=O)NH- or a bond;
    R 1、R 2、R 3、R 4各自独立地选自H、D、C 1-6烷基； R 1 , R 2 , R 3 , R 4 are each independently selected from H, D, C 1-6 alkyl;
    L 1为
    Figure PCTCN2022110534-appb-100021
    L 1 is
    Figure PCTCN2022110534-appb-100021
    L 2选自C 1-6亚烷基、3至10元杂环烷基的单环或多环、-C(＝O)-、-C(＝O)O-、-C(＝O)NR x1-或键，所述C 1-6亚烷基、3至10元杂环烷基的单环或多环进一步被1或多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2；所述3至10元杂环烷基的单环或多环、5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； L2 is selected from C 1-6 alkylene, 3 to 10 membered heterocycloalkyl rings or polycyclic rings, -C(=O)-, -C(=O)O-, -C(=O) NR x1 - or a bond, the C 1-6 alkylene, 3 to 10 membered heterocycloalkyl ring or polycyclic ring is further substituted by 1 or more substituents selected from the following: H, OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, =O, CN, NH 2 ; the 3 Monocyclic or polycyclic, 5- to 12-membered heteroaryl, 3- to 10-membered heterocycloalkyl to 10-membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, and S;
    R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、D、卤素、OH、C 1-6烷基，所述C 1-6烷基任选地被1至3个卤素取代；或R 5和R 6、R 9和R 10各自独立地连同其所连接的碳原子形成3至6元环烷基；或R 11和R 12与其所连接的碳原子形成＝O；或R 5和R 9、R 5和R 11、R 7和R 9、R 7和R 11相连； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, D, halogen, OH, C 1-6 alkyl, said C 1-6 alkane The group is optionally substituted by 1 to 3 halogens; or R 5 and R 6 , R 9 and R 10 each independently form a 3 to 6-membered cycloalkyl group together with the carbon atom to which they are attached; or R 11 and R 12 are combined with The attached carbon atoms form =O; or R 5 and R 9 , R 5 and R 11 , R 7 and R 9 , R 7 and R 11 are linked;
    B为
    Figure PCTCN2022110534-appb-100022
    Figure PCTCN2022110534-appb-100023
    Figure PCTCN2022110534-appb-100024
    B for
    Figure PCTCN2022110534-appb-100022
    Figure PCTCN2022110534-appb-100023
    Figure PCTCN2022110534-appb-100024
    X 5、X 6各自独立的选自CH、CH 2、N、NH、O或S； X 5 and X 6 are each independently selected from CH, CH 2 , N, NH, O or S;
    Figure PCTCN2022110534-appb-100025
    为双键或单键；
    Figure PCTCN2022110534-appb-100025
    is a double bond or a single bond;
    D选自5至10元碳环、5至10元杂环、6至10元芳环或者5至10元芳杂环；所述5至10元碳环、5至10元杂环、6至10元芳环、5至10元芳杂环进一步被1或多个选自以下的取代基取代：C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基；所述5至10元杂环、5至10元芳杂环、5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； D is selected from 5 to 10 membered carbocyclic rings, 5 to 10 membered heterocyclic rings, 6 to 10 membered aromatic rings or 5 to 10 membered aromatic heterocyclic rings; The 10-membered aromatic ring and the 5-10-membered aromatic heterocycle are further substituted by 1 or more substituents selected from the group consisting of: C 3-10 cycloalkyl, C 6-12 aryl, 5-12-membered heteroaryl, 3 to 10 membered heterocycloalkyl; the 5 to 10 membered heterocycle, 5 to 10 membered aromatic heterocycle, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl contain 1 to 3 members selected from N, Heteroatoms of O and S;
    R 13为C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基、CN或CF 3，所述C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基进一步被1或多个选自以下的取代基取代：H、卤素、CN、OH、NH 2、C 1-6烷基、C 1-6卤代烷基或C 3-10环烷基；所述3至10元的杂环烷基、5至12元杂芳基包含1至3个选自N、O、S的杂原子； R 13 is C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN or CF 3 , the C 3-10 cycloalkane radical, 3 to 10 membered heterocycloalkyl, 6 to 12 membered aryl, 5 to 12 membered heteroaryl are further substituted by 1 or more substituents selected from the group consisting of: H, halogen, CN, OH, NH 2. C 1-6 alkyl, C 1-6 haloalkyl or C 3-10 cycloalkyl; the 3 to 10 membered heterocycloalkyl, 5 to 12 membered heteroaryl contains 1 to 3 members selected from N, O, S heteroatoms;
    条件是：当R 13为CN或CF 3时，R 3和R 4为D。 Provided that: when R 13 is CN or CF 3 , R 3 and R 4 are D.
    R x1选自H、C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基，所述C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 3-10环烷基、CN、NH 2；所述5至12元杂芳基、3至10元杂环烷基、包含1至3个选自N、O、S的杂原子； R x1 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1- 6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H, OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, CN, NH 2 ; the 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, contain 1 to 3 Heteroatoms selected from N, O, S;
    n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
    o为0或者1。o is 0 or 1.
  6. 根据权利要求1至5所述的化合物或者其立体异构体、药学上可接受的盐或氘代物，其中：The compound or its stereoisomer, pharmaceutically acceptable salt or deuterated product according to claims 1 to 5, wherein:
    A为
    Figure PCTCN2022110534-appb-100026
    A is
    Figure PCTCN2022110534-appb-100026
    X 1为NH、
    Figure PCTCN2022110534-appb-100027
    或者
    Figure PCTCN2022110534-appb-100028
     X1 is NH,
    Figure PCTCN2022110534-appb-100027
    or
    Figure PCTCN2022110534-appb-100028
    X 2为NH、O、S、-C(＝O)NH-或键； X 2 is NH, O, S, -C(=O)NH- or a bond;
    R 1、R 2各自独立地选自H、D或者C 1-6烷基； R 1 and R 2 are each independently selected from H, D or C 1-6 alkyl;
    R 3、R 4各自独立地选自H或者D； R 3 and R 4 are each independently selected from H or D;
    L 1为
    Figure PCTCN2022110534-appb-100029
    L 1 is
    Figure PCTCN2022110534-appb-100029
    L 2选自C 1-6亚烷基、3至10元杂环烷基的单环或多环、-C(＝O)-、-C(＝O)O-、-C(＝O)NR x1-或键，所述C 1-6亚烷基、3至10元杂环烷基的单环或多环进一步被1或多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2；所述3至10元杂环烷基的单环或多环、5至12元杂芳基、3至10元杂环烷基包含1至3个 选自N、O、S的杂原子； L2 is selected from C 1-6 alkylene, 3 to 10 membered heterocycloalkyl rings or polycyclic rings, -C(=O)-, -C(=O)O-, -C(=O) NR x1 - or a bond, the C 1-6 alkylene, 3 to 10 membered heterocycloalkyl ring or polycyclic ring is further substituted by 1 or more substituents selected from the following: H, OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, =O, CN, NH 2 ; the 3 Monocyclic or polycyclic, 5- to 12-membered heteroaryl, 3- to 10-membered heterocycloalkyl to 10-membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, and S;
    R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、D、卤素、OH、C 1-6烷基； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, D, halogen, OH, C 1-6 alkyl;
    B为
    Figure PCTCN2022110534-appb-100030
    Figure PCTCN2022110534-appb-100031
    B for
    Figure PCTCN2022110534-appb-100030
    Figure PCTCN2022110534-appb-100031
    R 13为C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基、CN或CF 3，所述C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基进一步被1或多个选自以下的取代基取代：H、卤素、CN、OH、NH 2、C 1-6烷基、C 1-6卤代烷基或C 3-10环烷基；所述3至10元的杂环烷基、5至12元杂芳基包含1至3个选自N、O、S的杂原子； R 13 is C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN or CF 3 , the C 3-10 cycloalkane radical, 3 to 10 membered heterocycloalkyl, 6 to 12 membered aryl, 5 to 12 membered heteroaryl are further substituted by 1 or more substituents selected from the group consisting of: H, halogen, CN, OH, NH 2. C 1-6 alkyl, C 1-6 haloalkyl or C 3-10 cycloalkyl; the 3 to 10 membered heterocycloalkyl, 5 to 12 membered heteroaryl contains 1 to 3 members selected from N, O, S heteroatoms;
    条件是：当R 13为CN或CF 3时，R 3和R 4为D。 Provided that: when R 13 is CN or CF 3 , R 3 and R 4 are D.
    R x1选自H、C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基，所述C 1-6烷基C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 3-10环烷基、CN、NH 2所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R x1 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1- 6 alkyl C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H , OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, CN, NH 2 said 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl containing 1 to 3 members selected from N , O, S heteroatoms;
    n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
    o为0或者1。o is 0 or 1.
  7. 根据权利要求1至6所述的化合物或者其立体异构体、药学上可接受的盐或氘代物，其中：The compound or its stereoisomer, pharmaceutically acceptable salt or deuterated product according to claims 1 to 6, wherein:
    A为
    Figure PCTCN2022110534-appb-100032
    A is
    Figure PCTCN2022110534-appb-100032
    X 1为NH、
    Figure PCTCN2022110534-appb-100033
    或者
    Figure PCTCN2022110534-appb-100034
     X1 is NH,
    Figure PCTCN2022110534-appb-100033
    or
    Figure PCTCN2022110534-appb-100034
    R 1、R 2各自独立地选自H、D或者C 1-6烷基； R 1 and R 2 are each independently selected from H, D or C 1-6 alkyl;
    R 3、R 4各自独立地选自H或者D； R 3 and R 4 are each independently selected from H or D;
    X 2为NH、O、S、-C(＝O)NH-或键； X 2 is NH, O, S, -C(=O)NH- or a bond;
    L 1为
    Figure PCTCN2022110534-appb-100035
    L 1 is
    Figure PCTCN2022110534-appb-100035
    R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、D、卤素、OH、C 1-6烷基； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, D, halogen, OH, C 1-6 alkyl;
    B为
    Figure PCTCN2022110534-appb-100036
    Figure PCTCN2022110534-appb-100037
    B for
    Figure PCTCN2022110534-appb-100036
    Figure PCTCN2022110534-appb-100037
    R 13为C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基、CN或CF 3，所述C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基进一步被1或多个选自以下的取代基取代：H、卤素、CN、OH、NH 2、C 1-6烷基、C 1-6卤代烷基或C 3-10环烷基；所述3至10元的杂环烷基、5至12元杂芳基包含1至3个选自N、O、S的杂原子； R 13 is C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN or CF 3 , the C 3-10 cycloalkane radical, 3 to 10 membered heterocycloalkyl, 6 to 12 membered aryl, 5 to 12 membered heteroaryl are further substituted by 1 or more substituents selected from the group consisting of: H, halogen, CN, OH, NH 2. C 1-6 alkyl, C 1-6 haloalkyl or C 3-10 cycloalkyl; the 3 to 10 membered heterocycloalkyl, 5 to 12 membered heteroaryl contains 1 to 3 members selected from N, O, S heteroatoms;
    条件是：当R 13为CN或CF 3时，R 3和R 4为D。 Provided that: when R 13 is CN or CF 3 , R 3 and R 4 are D.
    L 2选自C 1-6亚烷基、3至10元杂环烷基的单环或多环、-C(＝O)-、-C(＝O)O-、-C(＝O)NR x1-或键；所述3至10元杂环烷基的单环或多环包含1至3个选自N、O、S的杂原子； L2 is selected from C 1-6 alkylene, 3 to 10 membered heterocycloalkyl rings or polycyclic rings, -C(=O)-, -C(=O)O-, -C(=O) NR x1 -or a bond; the monocyclic or polycyclic ring of the 3 to 10 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, S;
    R x1选自H、C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基，所述C 1-6烷基C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 3-10环烷基、CN、NH 2所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R x1 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1- 6 alkyl C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H , OH, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, CN, NH 2 said 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl containing 1 to 3 members selected from N , O, S heteroatoms;
    n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
    o为0或者1。o is 0 or 1.
  8. 根据权利要求1至7所述的化合物或者其立体异构体、药学上可接受的盐或氘代物，其中：The compound or its stereoisomer, pharmaceutically acceptable salt or deuterated product according to claims 1 to 7, wherein:
    A为
    Figure PCTCN2022110534-appb-100038
    A is
    Figure PCTCN2022110534-appb-100038
    X 1为NH、
    Figure PCTCN2022110534-appb-100039
    或者
    Figure PCTCN2022110534-appb-100040
     X1 is NH,
    Figure PCTCN2022110534-appb-100039
    or
    Figure PCTCN2022110534-appb-100040
    R 1、R 2各自独立地选自H、D或者C 1-6烷基； R 1 and R 2 are each independently selected from H, D or C 1-6 alkyl;
    R 3、R 4各自独立地选自H或者D； R 3 and R 4 are each independently selected from H or D;
    X 2为O； X2 is O;
    L 1为
    Figure PCTCN2022110534-appb-100041
    L 1 is
    Figure PCTCN2022110534-appb-100041
    R 5、R 6各自独立地选自H、D或C 1-6烷基； R 5 and R 6 are each independently selected from H, D or C 1-6 alkyl;
    R 7、R 8各自独立地选自H或D； R 7 and R 8 are each independently selected from H or D;
    R 9、R 10各自独立地选自H、D、OH或C 1-6烷基； R 9 and R 10 are each independently selected from H, D, OH or C 1-6 alkyl;
    R 11和R 12各自独立地选自H或D； R 11 and R 12 are each independently selected from H or D;
    B为
    Figure PCTCN2022110534-appb-100042
    Figure PCTCN2022110534-appb-100043
    B for
    Figure PCTCN2022110534-appb-100042
    Figure PCTCN2022110534-appb-100043
    R 13为
    Figure PCTCN2022110534-appb-100044
    Figure PCTCN2022110534-appb-100045
    R 13 is
    Figure PCTCN2022110534-appb-100044
    Figure PCTCN2022110534-appb-100045
    Figure PCTCN2022110534-appb-100046
    Figure PCTCN2022110534-appb-100046
    R 13a、R 13b各自独立地选自H、卤素、CN、C 1-6烷基、C 1-6卤代烷基或NH 2； R 13a and R 13b are each independently selected from H, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl or NH 2 ;
    L 2选自C 1-6亚烷基、3至10元杂环烷基的单环或多环、-C(＝O)-、-C(＝O)O-、-C(＝O)NR x1-或键；所述3至10元杂环烷基的单环或多环包含1至3个选自N、O、S的杂原子； L2 is selected from C 1-6 alkylene, 3 to 10 membered heterocycloalkyl rings or polycyclic rings, -C(=O)-, -C(=O)O-, -C(=O) NR x1 -or a bond; the monocyclic or polycyclic ring of the 3 to 10 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, S;
    R x1选自H、C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基，所述C 1-6烷基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素CN、NH 2、或COOH；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R x1 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1- 6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H, OH, halogen CN, NH 2 , or COOH; the 5- to 12-membered heteroaryl, 3- to 10-membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, and S;
    n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
    o为0或者1。o is 0 or 1.
  9. 根据权利要求1至8所述的化合物或者其立体异构体、药学上可接受的盐或氘代物，其中：The compound or its stereoisomer, pharmaceutically acceptable salt or deuterated product according to claims 1 to 8, wherein:
    A为
    Figure PCTCN2022110534-appb-100047
    A is
    Figure PCTCN2022110534-appb-100047
    X 1为NH、
    Figure PCTCN2022110534-appb-100048
    或者
    Figure PCTCN2022110534-appb-100049
     X1 is NH,
    Figure PCTCN2022110534-appb-100048
    or
    Figure PCTCN2022110534-appb-100049
    R 1、R 2各自独立地选自H、D或者C 1-6烷基； R 1 and R 2 are each independently selected from H, D or C 1-6 alkyl;
    R 3、R 4各自独立地选自H或者D； R 3 and R 4 are each independently selected from H or D;
    X 2为O； X2 is O;
    L 1为
    Figure PCTCN2022110534-appb-100050
    L 1 is
    Figure PCTCN2022110534-appb-100050
    R 5、R 6各自独立地选自H或D； R 5 and R 6 are each independently selected from H or D;
    R 7、R 8各自独立地选自H或D； R 7 and R 8 are each independently selected from H or D;
    R 9、R 10各自独立地选自H、D或OH； R 9 and R 10 are each independently selected from H, D or OH;
    R 11和R 12各自独立地选自H或D； R 11 and R 12 are each independently selected from H or D;
    B为
    Figure PCTCN2022110534-appb-100051
    或者
    Figure PCTCN2022110534-appb-100052
    B for
    Figure PCTCN2022110534-appb-100051
    or
    Figure PCTCN2022110534-appb-100052
    R 13为
    Figure PCTCN2022110534-appb-100053
    Figure PCTCN2022110534-appb-100054
    R 13 is
    Figure PCTCN2022110534-appb-100053
    Figure PCTCN2022110534-appb-100054
    R 13a、R 13b选自H、卤素、CF 3； R 13a and R 13b are selected from H, halogen, CF 3 ;
    L 2选自-C(＝O)-、-C(＝O)O-、-C(＝O)NH-或键； L is selected from -C(=O)-, -C(=O)O-, -C(=O)NH- or a bond;
    n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
    o为0或者1。o is 0 or 1.
  10. 根据权利要求1至9所述的化合物或者其立体异构体、药学上可接受的盐或氘代物，其中：The compound or its stereoisomer, pharmaceutically acceptable salt or deuterated product according to claims 1 to 9, wherein:
    A为
    Figure PCTCN2022110534-appb-100055
    A is
    Figure PCTCN2022110534-appb-100055
    X 1为NH、
    Figure PCTCN2022110534-appb-100056
    或者
    Figure PCTCN2022110534-appb-100057
     X1 is NH,
    Figure PCTCN2022110534-appb-100056
    or
    Figure PCTCN2022110534-appb-100057
    R 1、R 2各自独立地选自H、D或者C 1-6烷基； R 1 and R 2 are each independently selected from H, D or C 1-6 alkyl;
    R 3、R 4各自独立地选自H或者D； R 3 and R 4 are each independently selected from H or D;
    X 2为O； X2 is O;
    L 1为
    Figure PCTCN2022110534-appb-100058
    L 1 is
    Figure PCTCN2022110534-appb-100058
    R 5、R 6各自独立地选自H或D； R 5 and R 6 are each independently selected from H or D;
    R 7、R 8各自独立地选自H或D； R 7 and R 8 are each independently selected from H or D;
    R 9、R 10各自独立地选自H、D或OH； R 9 and R 10 are each independently selected from H, D or OH;
    R 11和R 12各自独立地选自H或D； R 11 and R 12 are each independently selected from H or D;
    B为
    Figure PCTCN2022110534-appb-100059
    或者
    Figure PCTCN2022110534-appb-100060
    B for
    Figure PCTCN2022110534-appb-100059
    or
    Figure PCTCN2022110534-appb-100060
    R 13为
    Figure PCTCN2022110534-appb-100061
    Figure PCTCN2022110534-appb-100062
    R 13 is
    Figure PCTCN2022110534-appb-100061
    Figure PCTCN2022110534-appb-100062
    R 13a、R 13b选自H、卤素、CF 3； R 13a and R 13b are selected from H, halogen, CF 3 ;
    L 2选自-C(＝O)-、-C(＝O)O-、-C(＝O)NH-或键； L is selected from -C(=O)-, -C(=O)O-, -C(=O)NH- or a bond;
    n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
    o为0或者1。o is 0 or 1.
  11. 根据权利要求1至10所述的化合物或者其立体异构体、药学上可接受的盐或氘代物，其中：The compound or its stereoisomer, pharmaceutically acceptable salt or deuterated product according to claims 1 to 10, wherein:
    A为
    Figure PCTCN2022110534-appb-100063
    A is
    Figure PCTCN2022110534-appb-100063
    X 1为NH、
    Figure PCTCN2022110534-appb-100064
    或者
    Figure PCTCN2022110534-appb-100065
     X1 is NH,
    Figure PCTCN2022110534-appb-100064
    or
    Figure PCTCN2022110534-appb-100065
    R 1、R 2各自独立地选自H、D或者C 1-6烷基； R 1 and R 2 are each independently selected from H, D or C 1-6 alkyl;
    R 3、R 4各自独立地选自H或者D； R 3 and R 4 are each independently selected from H or D;
    X 2为O； X2 is O;
    L 1为
    Figure PCTCN2022110534-appb-100066
    L 1 is
    Figure PCTCN2022110534-appb-100066
    R 5、R 6各自独立地选自H或D； R 5 and R 6 are each independently selected from H or D;
    R 7、R 8各自独立地选自H或D； R 7 and R 8 are each independently selected from H or D;
    R 9、R 10各自独立地选自H、D或OH； R 9 and R 10 are each independently selected from H, D or OH;
    R 11和R 12各自独立地选自H或D； R 11 and R 12 are each independently selected from H or D;
    B为
    Figure PCTCN2022110534-appb-100067
    或者
    Figure PCTCN2022110534-appb-100068
    B for
    Figure PCTCN2022110534-appb-100067
    or
    Figure PCTCN2022110534-appb-100068
    R 13为
    Figure PCTCN2022110534-appb-100069
    R 13 is
    Figure PCTCN2022110534-appb-100069
    R 13a选自H、卤素、CF 3； R 13a is selected from H, halogen, CF 3 ;
    L 2选自-C(＝O)-、-C(＝O)O-、-C(＝O)NH-或键； L is selected from -C(=O)-, -C(=O)O-, -C(=O)NH- or a bond;
    n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
    o为0或者1。o is 0 or 1.
  12. 根据权利要求1至7所述的化合物或者其立体异构体、药学上可接受的盐或氘代物，其中：The compound or its stereoisomer, pharmaceutically acceptable salt or deuterated product according to claims 1 to 7, wherein:
    A为
    Figure PCTCN2022110534-appb-100070
    A is
    Figure PCTCN2022110534-appb-100070
    X 1为NH、
    Figure PCTCN2022110534-appb-100071
    或者
    Figure PCTCN2022110534-appb-100072
     X1 is NH,
    Figure PCTCN2022110534-appb-100071
    or
    Figure PCTCN2022110534-appb-100072
    R 1、R 2各自独立地选自H、D或者C 1-6烷基； R 1 and R 2 are each independently selected from H, D or C 1-6 alkyl;
    R 3、R 4各自独立地选自D； R 3 and R 4 are each independently selected from D;
    X 2为O； X2 is O;
    L 1为
    Figure PCTCN2022110534-appb-100073
    L 1 is
    Figure PCTCN2022110534-appb-100073
    L 2选自-C(＝O)-、-C(＝O)O-、-C(＝O)NH-或键； L is selected from -C(=O)-, -C(=O)O-, -C(=O)NH- or a bond;
    R 5、R 6各自独立地选自H或D； R 5 and R 6 are each independently selected from H or D;
    R 7、R 8各自独立地选自H或D； R 7 and R 8 are each independently selected from H or D;
    R 9、R 10各自独立地选自H、D或OH； R 9 and R 10 are each independently selected from H, D or OH;
    R 11和R 12各自独立地选自H或D； R 11 and R 12 are each independently selected from H or D;
    B为
    Figure PCTCN2022110534-appb-100074
    或者
    Figure PCTCN2022110534-appb-100075
    B for
    Figure PCTCN2022110534-appb-100074
    or
    Figure PCTCN2022110534-appb-100075
    R 13为CN或CF 3。 R 13 is CN or CF 3 .
    n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
    o为0或1。o is 0 or 1.
  13. 一种化合物或者其立体异构体，药学上可接受的盐或氘代物，其中所述化合物或者其立体异构体，药学上可接受的盐或氘代物选自以下结构：A compound or its stereoisomer, pharmaceutically acceptable salt or deuterated substance, wherein said compound or its stereoisomer, pharmaceutically acceptable salt or deuterated substance is selected from the following structures:
    Figure PCTCN2022110534-appb-100076
    Figure PCTCN2022110534-appb-100077
    或者
    Figure PCTCN2022110534-appb-100078
    Figure PCTCN2022110534-appb-100076
    Figure PCTCN2022110534-appb-100077
    or
    Figure PCTCN2022110534-appb-100078
  14. 用于制备通式(I)、(I-1)一种化合物或者其立体异构体，药学上可接受的盐或氘代物的中间体化合物或者其立体异构体，药学上可接受的盐或氘代物，其具有通式(II)或(III)所示的化合物：For the preparation of a compound of general formula (I), (I-1) or its stereoisomer, a pharmaceutically acceptable salt or an intermediate compound of a deuterated product or its stereoisomer, a pharmaceutically acceptable salt Or deuterium, it has the compound shown in general formula (II) or (III):
    Figure PCTCN2022110534-appb-100079
    Figure PCTCN2022110534-appb-100079
    其中：in:
    X 1选自OH、SH、C 1-6烷基、3至10元杂环烷基的单环或多环、-NHR x1、-C(＝O)H、-C(＝O)OH、-C(＝O)NR x1H、-S(＝O)H、-S(＝O) 2H、-S(＝O)NR x1H、- S(＝O) 2NR x1H、-NR x1C(＝O)NR x1H或键，所述C 1-6亚烷基、3至10元杂环烷基的单环或多环进一步被1或多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR x2、SR x2、C(＝O)R x3、C(＝O)NR x4R x5、C(＝O)OR x2、OC(＝O)R x3、OC(＝O)NR x4R x5、NR x4R x5、NR x4C(＝O)R x3、NR x4OC(＝O)R x3、NR x4C(＝O)NR x4R x5、C(＝NR x6)R x3、C(＝NR x6)NR x4R x5、NR x4C(＝NR x6)NR x4R x5、NR x4S(＝O)R x2、NR x4S(＝O) 2R x2、NR x4S(＝O) 2NR x4R x5、S(＝O)R x2、S(＝O)NR x4R x5、S(＝O) 2NR x4R x5、P(＝O)(R x4) 2或P(＝O) 2；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR x2、SR x2、C(＝O)R x3、C(＝O)NR x4R x5、C(＝O)OR x2、OC(＝O)R x3、OC(＝O)NR x4R x5、NR x4R x5、NR x4C(＝O)R x3、NR x4OC(＝O)R x3、NR x4C(＝O)NR x4R x5、C(＝NR x6)R x3、C(＝NR x6)NR x4R x5、NR x4C(＝NR x6)NR x4R x5、NR x4S(＝O)R x2、NR x4S(＝O) 2R x2、NR x4S(＝O) 2 NR x4R x5、S(＝O)R x2、S(＝O)NR x4R x5或S(＝O) 2NR x4R x5；所述3至10元杂环烷基的单环或多环、5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； X 1 is selected from OH, SH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl monocyclic or polycyclic, -NHR x1 , -C(=O)H, -C(=O)OH, -C(=O)NR x1 H, -S(=O)H, -S(=O) 2 H, -S(=O)NR x1 H, -S(=O) 2 NR x1 H, -NR x1 C(=O)NR x1 H or a bond, the C 1-6 alkylene, 3 to 10 membered heterocycloalkyl ring or polycyclic ring is further substituted by 1 or more substituents selected from the following: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3- to 10-membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR x2 , SR x2 , C(=O)R x3 , C(=O)NR x4 R x5 , C (=O)OR x2 , OC(=O)R x3 , OC(=O)NR x4 R x5 , NR x4 R x5 , NR x4 C(=O)R x3 , NR x4 OC(=O)R x3 , NR x4 C(=O)NR x4 R x5 , C(=NR x6 )R x3 , C(=NR x6 )NR x4 R x5 , NR x4 C(=NR x6 )NR x4 R x5 , NR x4 S(= O)R x2 , NR x4 S(=O) 2 R x2 , NR x4 S(=O) 2 NR x4 R x5 , S(=O)R x2 , S(=O)NR x4 R x5 , S(= O) 2 NR x4 R x5 , P(=O)(R x4 ) 2 or P(=O) 2 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted with 1 to more substituents selected from the group consisting of: H, OH, halogen , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR x2 , SR x2 , C(=O)R x3 , C(=O)NR x4 R x5 , C(=O)OR x2 , OC(=O) R x3 , OC(=O)NR x4 R x5 , NR x4 R x5 , NR x4 C(=O)R x3 , NR x4 OC(=O)R x3 , NR x4 C(=O)NR x4 R x5 , C(=NR x6 )R x3 , C(=NR x6 )NR x4 R x5 , NR x4 C(=NR x6 )NR x4 R x5 , NR x4 S(=O)R x2 , NR x4 S(=O) 2 R x2 , NR x4 S(=O) 2 NR x4 R x5 , S(=O)R x2 , S(=O)NR x4 R x5 or S(=O) 2 NR x4 R x5 ; the monocyclic or polycyclic, 5 to 12 Member heteroaryl, 3 to 10 member heterocycloalkyl contain 1 to 3 heteroatoms selected from N, O, S;
    X 2和L 2选自O、S、C 1-6亚烷基、3至10元杂环烷基的单环或多环、-NR x1-、-C(＝O)-、-C(＝O)O-、-C(＝O)NR x1-、-S(＝O)-、-S(＝O) 2-、-S(＝O)NR x1-、-S(＝O) 2NR x1-、-NR x1C(＝O)NR x1-或键，所述C 1-6亚烷基、3至10元杂环烷基的单环或多环进一步被1或多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR x2、SR x2、C(＝O)R x3、C(＝O)NR x4R x5、C(＝O)OR x2、OC(＝O)R x3、OC(＝O)NR x4R x5、NR x4R x5、NR x4C(＝O)R x3、NR x4OC(＝O)R x3、NR x4C(＝O)NR x4R x5、C(＝NR x6)R x3、C(＝NR x6)NR x4R x5、NR x4C(＝NR x6)NR x4R x5、NR x4S(＝O)R x2、NR x4S(＝O) 2R x2、NR x4S(＝O) 2 NR x4R x5、S(＝O)R x2、S(＝O)NR x4R x5、S(＝O) 2NR x4R x5、P(＝O)(R x4) 2或P(＝O) 2；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR x2、SR x2、C(＝O)R x3、C(＝O)NR x4R x5、C(＝O)OR x2、OC(＝O)R x3、OC(＝O)NR x4R x5、NR x4R x5、NR x4C(＝O)R x3、NR x4OC(＝O)R x3、NR x4C(＝O)NR x4R x5、C(＝NR x6)R x3、C(＝NR x6)NR x4R x5、NR x4C(＝NR x6)NR x4R x5、NR x4S(＝O)R x2、NR x4S(＝O) 2R x2、NR x4S(＝O) 2 NR x4R x5、S(＝O)R x2、S(＝O)NR x4R x5或S(＝O) 2NR x4R x5；所述3至10元杂环烷基的单环或多环、5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； X 2 and L 2 are selected from O, S, C 1-6 alkylene, monocyclic or polycyclic rings of 3 to 10 membered heterocycloalkyl groups, -NR x1 -, -C(=O)-, -C( =O)O-, -C(=O)NR x1 -, -S(=O)-, -S(=O) 2 -, -S(=O)NR x1 -, -S(=O) 2 NR x1 -, -NR x1 C(=O)NR x1 - or a bond, the C 1-6 alkylene, 3 to 10 membered heterocycloalkyl ring or polycyclic ring is further selected from 1 or more The following substituents are substituted: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12-membered heteroaryl, 3- to 10-membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR x2 , SR x2 , C(=O)R x3 , C(=O) NR x4 R x5 , C(=O)OR x2 , OC(=O)R x3 , OC(=O)NR x4 R x5 , NR x4 R x5 , NR x4 C(=O)R x3 , NR x4 OC( =O)R x3 , NR x4 C(=O)NR x4 R x5 , C(=NR x6 )R x3 , C(=NR x6 )NR x4 R x5 , NR x4 C(=NR x6 )NR x4 R x5 , NR x4 S(=O)R x2 , NR x4 S(=O) 2 R x2 , NR x4 S(=O) 2 NR x4 R x5 , S(=O)R x2 , S(=O)NR x4 R x5 , S(=O) 2 NR x4 R x5 , P(=O)(R x4 ) 2 or P(=O) 2 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkane base, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR x2 , SR x2 , C(=O)R x3 , C(=O)NR x4 R x5 , C(=O)OR x2 , OC(=O)R x3 , OC(=O)NR x4 R x5 , NR x4 R x5 , NR x4 C(=O)R x3 , NR x4 OC(=O)R x3 , NR x4 C(=O) NR x4 R x5 , C(=NR x6 )R x3 , C(=NR x6 )NR x4 R x5 , NR x4 C(=NR x6 )NR x4 R x5 , NR x4 S(=O)R x2 , NR x4 S(=O) 2 R x2 , NR x4 S(=O) 2 NR x4 R x5 , S(=O)R x2 , S(=O)NR x4 R x5 or S(=O) 2 NR x4 R x5 ; the monocyclic or polycyclic, 5 to 12 Member heteroaryl, 3 to 10 member heterocycloalkyl contain 1 to 3 heteroatoms selected from N, O, S;
    X 4为NHR x1、OH、SH或键； X 4 is NHR x1 , OH, SH or a bond;
    R 1、R 2、R 3、R 4、R 15各自独立地选自H、D、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元杂芳基、3至10元杂环烷基、CN、NH 2、NO 2、N 3、COOH、OR a2、SR a2、C(＝O)R a3、C(＝O)NR a4R a5、C(＝O)OR a2、OC(＝O)R a3、OC(＝O)NR a4R a5、NR a4R a5、NR a4C(＝O)R a3、NR a4OC(＝O)R a3、NR a4C(＝O)NR a4R a5、C(＝NR a6)R a3、C(＝NR a6)NR a4R a5、NR a4C(＝NR a6)NR a4R a5、NR a4S(＝O)R a2、NR a4S(＝O) 2R a2、NR a4S(＝O) 2 NR a4R a5、S(＝O)R a2、S(＝O)NR a4R a5或S(＝O) 2NR a4R a5；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元杂芳基、3 至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR a2、SR a2、C(＝O)R a3、C(＝O)NR a4R a5、C(＝O)OR a2、OC(＝O)R a3、OC(＝O)NR a4R a5、NR a4R a5、NR a4C(＝O)R a3、NR a4OC(＝O)R a3、NR a4C(＝O)NR a4R a5、C(＝NR a6)R a3、C(＝NR a6)NR a4R a5、NR a4C(＝NR a6)NR a4R a5、NR a4S(＝O)R a2、NR a4S(＝O) 2R a2、NR a4S(＝O) 2 NR a4R a5、S(＝O)R a2、S(＝O)NR a4R a5或S(＝O) 2NR a4R a5；或R 1和R 2、R 3和R 4、R 1和R 3各自独立地连同其所连接的碳原子形成3至6元环烷基或5至10元杂环烷基，所述环烷基、杂环烷基任选地被1或多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR a2、SR a2、C(＝O)R a3、C(＝O)NR a4R a5、C(＝O)OR a2、OC(＝O)R a3、OC(＝O)NR a4R a5、NR a4R a5、NR a4C(＝O)R a3、NR a4OC(＝O)R a3、NR a4C(＝O)NR a4R a5、C(＝NR a6)R a3、C(＝NR a6)NR a4R a5、NR a4C(＝NR a6)NR a4R a5、NR a4S(＝O)R a2、NR a4S(＝O) 2R a2、NR a4S(＝O) 2 NR a4R a5、S(＝O)R a2、S(＝O)NR a4R a5或S(＝O) 2NR a4R a5；所述5至12元杂芳基、5至10元杂环烷基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R 1 , R 2 , R 3 , R 4 , and R 15 are each independently selected from H, D, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -10 cycloalkyl, C6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, CN, NH 2 , NO 2 , N 3 , COOH, OR a2 , SR a2 , C( =O)R a3 , C(=O)NR a4 R a5 , C(=O)OR a2 , OC(=O)R a3 , OC(=O)NR a4 R a5 , NR a4 R a5 , NR a4 C (=O)R a3 , NR a4 OC(=O)R a3 , NR a4 C(=O)NR a4 R a5 , C(=NR a6 )R a3 , C(=NR a6 )NR a4 R a5 , NR a4 C(=NR a6 )NR a4 R a5 , NR a4 S(=O)R a2 , NR a4 S(=O) 2 R a2 , NR a4 S(=O) 2 NR a4 R a5 , S(=O )R a2 , S(=O)NR a4 R a5 or S(=O) 2 NR a4 R a5 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -10 cycloalkyl, C6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkane group, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR a2 , SR a2 , C(=O)R a3 , C(=O)NR a4 R a5 , C(=O)OR a2 , OC(=O)R a3 , OC(=O)NR a4 R a5 , NR a4 R a5 , NR a4 C(=O)R a3 , NR a4 OC(=O)R a3 , NR a4 C(=O) NR a4 R a5 , C(=NR a6 )R a3 , C(=NR a6 )NR a4 R a5 , NR a4 C(=NR a6 )NR a4 R a5 , NR a4 S (=O)R a2 , NR a4 S(=O) 2 R a2 , NR a4 S(=O) 2 NR a4 R a5 , S(=O)R a2 , S(=O)NR a4 R a5 or S(=O) 2 NR a4 R a5 or R 1 and R 2 , R 3 and R 4 , R 1 and R 3 each independently together with The carbon atoms connected to it form a 3-6 membered cycloalkyl group or a 5-10 membered heterocycloalkyl group, and the cycloalkyl group and the heterocycloalkyl group are optionally substituted by 1 or more substituents selected from the following groups: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3- to 10-membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR a2 , SR a2 , C(=O)R a3 , C(=O)NR a4 R a5 , C (=O)OR a2 , OC(=O)R a3 , OC(=O)NR a4 R a5 , NR a4 R a5 , NR a4 C(=O)R a3 , NR a4 OC(=O)R a3 , NR a4 C(=O)NR a4 R a5 , C(=NR a6 )R a3 , C(=NR a6 )NR a4 R a5 , NR a4 C(=NR a6 )NR a4 R a5 , NR a4 S(= O)R a2 , NR a4 S(=O) 2 R a2 , NR a4 S(=O) 2 NR a4 R a5 , S(=O)R a2 , S(=O)NR a4 R a5 or S(= O) 2 NR a4 R a5 ; the 5 to 12 membered heteroaryl, 5 to 10 membered heterocycloalkyl, 3 to 10 membered heterocycloalkyl contain 1 to 3 heteroatoms selected from N, O, S ;
    L 1为
    Figure PCTCN2022110534-appb-100080
    R 17为H、D或C 1-6烷基,所述C 1-6烷基任选地被1至3个卤素取代；     L 1 is
    Figure PCTCN2022110534-appb-100080
    R 17 is H, D or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
    X 3为C或N； X3 is C or N;
    R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、D、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、CN、NH 2、NO 2、N 3、COOH、OR b2、SR b2、C(＝O)R b3、C(＝O)NR b4R b5、C(＝O)OR b2、OC(＝O)R b3、OC(＝O)NR b4R b5、NR b4R b5、NR b4C(＝O)R b3、NR b4OC(＝O)R b3、NR b4C(＝O)NR b4R b5、C(＝NR b6)R b3、C(＝NR b6)NR b4R b5、NR b4C(＝NR b6)NR b4R b5、NR b4S(＝O)R b2、NR b4S(＝O) 2R b2、NR b4S(＝O) 2 NR b4R b5、S(＝O)R b2、S(＝O)NR b4R b5或S(＝O) 2NR b4R b5；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR b2、SR b2、C(＝O)R b3、C(＝O)NR b4R b5、C(＝O)OR b2、OC(＝O)R b3、OC(＝O)NR b4R b5、NR b4R b5、NR b4C(＝O)R b3、NR b4OC(＝O)R b3、NR b4C(＝O)NR b4R b5、C(＝NR b6)R b3、C(＝NR b6)NR b4R b5、NR b4C(＝NR b6)NR b4R b5、NR b4S(＝O)R b2、NR b4S(＝O) 2R b2、NR b4S(＝O) 2NR b4R b5、S(＝O)R b2、S(＝O)NR b4R b5或S(＝O) 2NR b4R b5；或R 5和R 6、R 7和R 8、R 9和R 10、R 11和R 12各自独立地连同其所连接的碳原子形成＝O；或R 5和R 7、R 5和R 9、R 5和R 11、R 7和R 9、R 7和R 11、R 9和R 11相连；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, D, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, CN, NH 2 , NO 2 , N 3 , COOH, OR b2 , SR b2 , C(=O)R b3 , C(=O)NR b4 R b5 , C(=O)OR b2 , OC(=O)R b3 , OC(=O)NR b4 R b5 , NR b4 R b5 , NR b4 C(=O)R b3 , NR b4 OC(=O)R b3 , NR b4 C(=O)NR b4 R b5 , C(=NR b6 )R b3 , C( =NR b6 )NR b4 R b5 , NR b4 C(=NR b6 )NR b4 R b5 , NR b4 S(=O)R b2 , NR b4 S(=O) 2 R b2 , NR b4 S(=O) 2 NR b4 R b5 , S(=O)R b2 , S(=O)NR b4 R b5 or S(=O) 2 NR b4 R b5 ; the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally selected from 1 to more of the following Substituent substitution: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 members Heteroaryl, 3- to 10-membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR b2 , SR b2 , C(=O)R b3 , C(=O)NR b4 R b5 , C(=O)OR b2 , OC(=O)R b3 , OC(=O)NR b4 R b5 , NR b4 R b5 , NR b4 C(=O)R b3 , NR b4 OC(=O )R b3 , NR b4 C(=O)NR b4 R b5 , C(=NR b6 )R b3 , C(=NR b6 )NR b4 R b5 , NR b4 C(=NR b6 )NR b4 R b5 , NR b4 S(=O)R b2 , NR b4 S(=O) 2 R b2 , NR b4 S(=O) 2 NR b4 R b5 , S(=O)R b2 , S(=O)NR b4 R b5 or S(=O) 2 NR b4 R b5 ; or R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 each independently form =O together with the carbon atom to which they are attached; or R 5 and R 7 , R 5 and R 9 , R 5 and R 11 , R 7 and R 9 , R 7 and R 11 , R 9 and R 11 are connected; the 5-12 membered heteroaryl, 3-10 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, S;
    B为3至10元的环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基，所述杂环、杂芳环包含至少1至3个选自N、O和S的杂原子；B is a cycloalkyl group with 3 to 10 members, a heterocycloalkyl group with 3 to 10 members, an aryl group with 6 to 12 members, and a heteroaryl group with 5 to 12 members, and the heterocycle and heteroaryl ring contain at least 1 to 3 a heteroatom selected from N, O and S;
    R 13为C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基、CN或CF 3，所述C 3-10环烷基、3至10元的杂环烷基、6至12元的芳基、5至12元杂芳基进一步被1或多个选自以下的取代基取代：H、D、卤素、CN、OH、NO 2、OR g2、SR g2、C(＝O)R g3、C(＝O)NR g4R g5、C(＝O)OR g2、OC(＝O)R g3、OC(＝O)NR g4R g5、NR g4R g5、NR g4C(＝O)R g3、NR g4OC(＝O)R g3、NR g4C(＝O)NR g4R g5、C(＝NR g6)R g3、C(＝NR g6)NR g4R g5、NR g4C(＝NR g6)NR g4R g5、NR g4S(＝O)R g2、NR g4S(＝O) 2R g2、NR g4S(＝O) 2 NR g4R g5、S(＝O)R g2、S(＝O)NR g4R g5或S(＝O) 2NR g4R g5；所述3至10元的杂环烷基、5至12元杂芳基包含1至3个选自N、O、S的杂原子； R 13 is C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, CN or CF 3 , the C 3-10 cycloalkane radical, 3 to 10 membered heterocycloalkyl, 6 to 12 membered aryl, 5 to 12 membered heteroaryl are further substituted by 1 or more substituents selected from the group consisting of: H, D, halogen, CN, OH , NO 2 , OR g2 , SR g2 , C(=O)R g3 , C(=O)NR g4 R g5 , C(=O)OR g2 , OC(=O)R g3 , OC(=O)NR g4 R g5 , NR g4 R g5 , NR g4 C(=O)R g3 , NR g4 OC(=O)R g3 , NR g4 C(=O)NR g4 R g5 , C(=NR g6 )R g3 , C(=NR g6 )NR g4 R g5 , NR g4 C(=NR g6 )NR g4 R g5 , NR g4 S(=O)R g2 , NR g4 S(=O) 2 R g2 , NR g4 S(= O) 2 NR g4 R g5 , S(=O)R g2 , S(=O)NR g4 R g5 or S(=O) 2 NR g4 R g5 ; the 3 to 10-membered heterocycloalkyl, 5 to 12 membered heteroaryls containing 1 to 3 heteroatoms selected from N, O, S;
    条件是：当R 13为CN或CF 3时，R 3和R 4为D； The condition is: when R 13 is CN or CF 3 , R 3 and R 4 are D;
    R a1、R a2、R a3、R a4、R a5、R a6、R b1、R b2、R b3、R b4、R b5、R b6、R c1、R c2、R c3、R c4、R c5、R c6、R d1、R d2、R d3、R d4、R d5、R d6、R x1、R x2、R x3、R x4、R x5或R x6、各自独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元杂芳基、3至10元杂环烷基或TBS，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR e2、SR e2、C(＝O)R e3、C(＝O)NR e4R e5、C(＝O)OR e2、OC(＝O)R e3、OC(＝O)NR e4R e5、NR e4R e5、NR e4C(＝O)R e3、NR e4OC(＝O)R e3、NR e4C(＝O)NR e4R e5、C(＝NR e6)R e3、C(＝NR e6)NR e4R e5、NR e4C(＝NR e6)NR e4R e5、NR e4S(＝O)R e2、NR e4S(＝O) 2R e2、NR e4S(＝O) 2NR e4Re 5、S(＝O)R e2、S(＝O)NR e4R e5或S(＝O) 2NR e4R e5；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R x1 , R x2 , R x3 , R x4 , R x5 or R x6 , each independently selected from H, C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl or TBS , the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 Membered heterocycloalkyl is optionally substituted by 1 to more substituents selected from the group consisting of H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR e2 , SR e2 , C(=O)R e3 , C(=O)NR e4 R e5 , C(=O)OR e2 , OC(=O)R e3 , OC(=O)NR e4 R e5 , NR e4 R e5 , NR e4 C(=O) R e3 , NR e4 OC(=O)R e3 , NR e4 C(=O)NR e4 R e5 , C(=NR e6 )R e3 , C(=NR e6 )NR e4 R e5 , NR e4 C(= NR e6 ) NR e4 R e5 , NR e4 S(=O)R e2 , NR e4 S(=O) 2 R e2 , NR e4 S(=O) 2 NR e4 Re 5 , S(=O)R e2 , S(=O)NR e4 R e5 or S(=O) 2 NR e4 R e5 ; the 5 to 12-membered heteroaryl, 3 to 10-membered heterocycloalkyl contains 1 to 3 members selected from N, O, S heteroatoms;
    R a4和R a5、R b4和R b5、R c4和R c5、R d4和R d5、R x4和R x5各自独立地连同其所连接的N原子形成4至7元杂环，所述杂环进一步被1或多个选自以下的取代基取代：卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、CN、OR f2、SR f2、C(＝O)R f3、C(＝O)NR f4R f5、C(＝O)OR f2、OC(＝O)R f3、OC(＝O)NR f4R f5、NR f4R f5、NR f4C(＝O)R f3、NR f4OC(＝O)R f3、NR f4C(＝O)NR f4R f5、C(＝NR f6)R f3、C(＝NR f6)NR f4R f5、NR f4C(＝NR f6)NR f4R f5、NR f4S(＝O)R f2、NR f4S(＝O) 2R f2、NR f4S(＝O) 2 NR f4R f5、S(＝O)R f2、S(＝O)NR f4R f5或S(＝O) 2NR f4R f5；所述4至7元杂环包含1至3个选自N、O、S的杂原子； R a4 and R a5 , R b4 and R b5 , R c4 and R c5 , R d4 and R d5 , R x4 and R x5 each independently form a 4- to 7-membered heterocycle together with the N atom to which they are attached, and the heterocycle The ring is further substituted by 1 or more substituents selected from the group consisting of halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, OR f2 , SR f2 , C(=O )R f3 , C(=O)NR f4 R f5 , C(=O)OR f2 , OC(=O)R f3 , OC(=O)NR f4 R f5 , NR f4 R f5 , NR f4 C(= O)R f3 , NR f4 OC(=O)R f3 , NR f4 C(=O)NR f4 R f5 , C(=NR f6 )R f3 , C(=NR f6 )NR f4 R f5 , NR f4 C (=NR f6 )NR f4 R f5 , NR f4 S(=O)R f2 , NR f4 S(=O) 2 R f2 , NR f4 S(=O) 2 NR f4 R f5 , S(=O)R f2 , S(=O)NR f4 R f5 or S(=O) 2 NR f4 R f5 ; the 4 to 7-membered heterocyclic ring contains 1 to 3 heteroatoms selected from N, O, S;
    R f1、R f2、R f3、R f4、R f5、R f6、R e1、R e2、R e3、R e4、R e5、R e6各自独立地选自C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1- 6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R f1 , R f2 , R f3 , R f4 , R f5 , R f6 , R e1 , R e2 , R e3 , R e4 , R e5 , R e6 are each independently selected from C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1-6 alkane C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl optionally Substituted by 1 to more substituents selected from : H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3- 10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH; the 5 to 12 membered heteroaryl, 3 to The 10-membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, S;
    m为0、1、2或者3；m is 0, 1, 2 or 3;
    n为0、1、2、3或者4；n is 0, 1, 2, 3 or 4;
    o为0或1；o is 0 or 1;
    p为1、2或者3。p is 1, 2 or 3.
  15. 根据权利要求14所述的中间体化合物或者其立体异构体、药学上可接受的盐或氘代物，其中所述化合物或者其立体异构体，药学上可接受的盐或氘代物选自以下结构：The intermediate compound or its stereoisomer, pharmaceutically acceptable salt or deuterated product according to claim 14, wherein said compound or its stereoisomer, pharmaceutically acceptable salt or deuterated product is selected from the following structure:
    Figure PCTCN2022110534-appb-100081
    Figure PCTCN2022110534-appb-100082
    或者
    Figure PCTCN2022110534-appb-100083
    Figure PCTCN2022110534-appb-100081
    Figure PCTCN2022110534-appb-100082
    or
    Figure PCTCN2022110534-appb-100083
  16. 用于制备通式(I)、(I-1)一种化合物或者其立体异构体，药学上可接受的盐或氘代物的中间体化合物或者其立体异构体，药学上可接受的盐或氘代物，其具有通式(IV)或(V)所示的化合物：For the preparation of a compound of general formula (I), (I-1) or its stereoisomer, a pharmaceutically acceptable salt or an intermediate compound of a deuterated product or its stereoisomer, a pharmaceutically acceptable salt Or deuterium, it has the compound shown in general formula (IV) or (V):
    Figure PCTCN2022110534-appb-100084
    Figure PCTCN2022110534-appb-100084
    其中：in:
    R 17为H、D或C 1-6烷基,所述C 1-6烷基任选地被1至3个卤素取代； R 17 is H, D or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
    X 3为CH 2或NH； X 3 is CH 2 or NH;
    R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、D、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、CN、NH 2、NO 2、N 3、COOH、OR b2、SR b2、C(＝O)R b3、C(＝O)NR b4R b5、C(＝O)OR b2、OC(＝O)R b3、OC(＝O)NR b4R b5、NR b4R b5、NR b4C(＝O)R b3、NR b4OC(＝O)R b3、NR b4C(＝O)NR b4R b5、C(＝NR b6)R b3、C(＝NR b6)NR b4R b5、NR b4C(＝NR b6)NR b4R b5、NR b4S(＝O)R b2、NR b4S(＝O) 2R b2、NR b4S(＝O) 2 NR b4R b5、S(＝O)R b2、S(＝O)NR b4R b5或S(＝O) 2NR b4R b5；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR b2、SR b2、C(＝O)R b3、C(＝O)NR b4R b5、C(＝O)OR b2、OC(＝O)R b3、OC(＝O)NR b4R b5、NR b4R b5、NR b4C(＝O)R b3、NR b4OC(＝O)R b3、NR b4C(＝O)NR b4R b5、C(＝NR b6)R b3、C(＝NR b6)NR b4R b5、NR b4C(＝NR b6)NR b4R b5、NR b4S(＝O)R b2、NR b4S(＝O) 2R b2、NR b4S(＝O) 2NR b4R b5、S(＝O)R b2、S(＝O)NR b4R b5或S(＝O) 2NR b4R b5；或R 5和R 6、R 7和R 8、R 9和R 10、R 11和R 12各自独立地连同其所连接的碳原子形成＝O；或R 5和R 7、R 5和R 9、R 5和R 11、R 7和R 9、R 7和R 11、R 9和R 11相连；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, D, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, CN, NH 2 , NO 2 , N 3 , COOH, OR b2 , SR b2 , C(=O)R b3 , C(=O)NR b4 R b5 , C(=O)OR b2 , OC(=O)R b3 , OC(=O)NR b4 R b5 , NR b4 R b5 , NR b4 C(=O)R b3 , NR b4 OC(=O)R b3 , NR b4 C(=O)NR b4 R b5 , C(=NR b6 )R b3 , C( =NR b6 )NR b4 R b5 , NR b4 C(=NR b6 )NR b4 R b5 , NR b4 S(=O)R b2 , NR b4 S(=O) 2 R b2 , NR b4 S(=O) 2 NR b4 R b5 , S(=O)R b2 , S(=O)NR b4 R b5 or S(=O) 2 NR b4 R b5 ; the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally selected from 1 to more of the following Substituent substitution: H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 members Heteroaryl, 3- to 10-membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH, OR b2 , SR b2 , C(=O)R b3 , C(=O)NR b4 R b5 , C(=O)OR b2 , OC(=O)R b3 , OC(=O)NR b4 R b5 , NR b4 R b5 , NR b4 C(=O)R b3 , NR b4 OC(=O )R b3 , NR b4 C(=O)NR b4 R b5 , C(=NR b6 )R b3 , C(=NR b6 )NR b4 R b5 , NR b4 C(=NR b6 )NR b4 R b5 , NR b4 S(=O)R b2 , NR b4 S(=O) 2 R b2 , NR b4 S(=O) 2 NR b4 R b5 , S(=O)R b2 , S(=O)NR b4 R b5 or S(=O) 2 NR b4 R b5 ; or R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 each independently form =O together with the carbon atom to which they are attached; or R 5 and R 7 , R 5 and R 9 , R 5 and R 11 , R 7 and R 9 , R 7 and R 11 , R 9 and R 11 are connected; the 5-12 membered heteroaryl, 3-10 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, S;
    R 20、R 21各自独立地选自H、卤素、CN、OH、C 1-6烷基、C 1-6烷氧基、C 6-10芳基、C 3-7环烷基、5至10元杂芳基或3至10元杂环烷基，所述C 1-6烷基、C 1-6烷氧基、C 6-10芳基、C 3-7环烷基、5至10元杂芳基、3至10元杂环烷基各自独立地被1至3个选自以下的取代基取代：H、卤素、CN、OH；所述杂芳基或杂环烷基包含1、2、3或4个独立地选自O、N和S的杂原子；C为5至10元碳环、5至10元杂环、6至10元芳环或者5至10元芳杂环。所述5至10元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R 20 and R 21 are each independently selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 3-7 cycloalkyl, 5 to 10-membered heteroaryl or 3 to 10-membered heterocycloalkyl, the C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 3-7 cycloalkyl, 5 to 10 Member heteroaryl, 3 to 10 member heterocycloalkyl are each independently substituted by 1 to 3 substituents selected from the following: H, halogen, CN, OH; the heteroaryl or heterocycloalkyl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, N and S; C is a 5- to 10-membered carbocyclic ring, a 5- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered aromatic heterocyclic ring. The 5- to 10-membered heteroaryl group and the 3- to 10-membered heterocycloalkyl group contain 1 to 3 heteroatoms selected from N, O, and S;
    R b1、R b2、R b3、R b4、R b5或R b6各自独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C6-12芳基、5至12元杂芳基、3至10元杂环烷基或TBS，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH、OR e2、SR e2、C(＝O)R e3、C(＝O)NR e4R e5、C(＝O)OR e2、OC(＝O)R e3、 OC(＝O)NR e4R e5、NR e4R e5、NR e4C(＝O)R e3、NR e4OC(＝O)R e3、NR e4C(＝O)NR e4R e5、C(＝NR e6)R e3、C(＝NR e6)NR e4R e5、NR e4C(＝NR e6)NR e4R e5、NR e4S(＝O)R e2、NR e4S(＝O) 2R e2、NR e4S(＝O) 2 NR e4Re 5、S(＝O)R e2、S(＝O)NR e4R e5或S(＝O) 2NR e4R e5；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R b1 , R b2 , R b3 , R b4 , R b5 or R b6 are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 ring Alkyl, C6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl or TBS, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl are optionally substituted by 1 to more substituents selected from the group consisting of: H, OH , halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, = O, CN, NH 2 , NO 2 , N 3 , COOH, OR e2 , SR e2 , C(=O)R e3 , C(=O)NR e4 R e5 , C(=O)OR e2 , OC(= O)R e3 , OC(=O)NR e4 R e5 , NR e4 R e5 , NR e4 C(=O)R e3 , NR e4 OC(=O)R e3 , NR e4 C(=O)NR e4 R e5 , C(=NR e6 )R e3 , C(=NR e6 )NR e4 R e5 , NR e4 C(=NR e6 )NR e4 R e5 , NR e4 S (=O)R e2 , NR e4 S(= O) 2 R e2 , NR e4 S(=O) 2 NR e4 Re 5 , S(=O)R e2 , S(=O)NR e4 R e5 or S(=O) 2 NR e4 R e5 ; the 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl contain 1 to 3 heteroatoms selected from N, O and S;
    R b4和R b5连同其所连接的N原子形成4至7元杂环，所述杂环进一步被1或多个选自以下的取代基取代：卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、CN、OR f2、SR f2、C(＝O)R f3、C(＝O)NR f4R f5、C(＝O)OR f2、OC(＝O)R f3、OC(＝O)NR f4R f5、NR f4R f5、NR f4C(＝O)R f3、NR f4OC(＝O)R f3、NR f4C(＝O)NR f4R f5、C(＝NR f6)R f3、C(＝NR f6)NR f4R f5、NR f4C(＝NR f6)NR f4R f5、NR f4S(＝O)R f2、NR f4S(＝O) 2R f2、NR f4S(＝O) 2 NR f4R f5、S(＝O)R f2、S(＝O)NR f4R f5或S(＝O) 2NR f4R f5；所述4至7元杂环包含1至3个选自N、O、S的杂原子； R b4 and R b5 form a 4 to 7-membered heterocyclic ring together with the N atom to which they are attached, and the heterocyclic ring is further substituted by 1 or more substituents selected from the group consisting of: halogen, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, CN, OR f2 , SR f2 , C(=O)R f3 , C(=O)NR f4 R f5 , C(=O)OR f2 , OC(=O) R f3 , OC(=O)NR f4 R f5 , NR f4 R f5 , NR f4 C(=O)R f3 , NR f4 OC(=O)R f3 , NR f4 C(=O)NR f4 R f5 , C(=NR f6 )R f3 , C(=NR f6 )NR f4 R f5 , NR f4 C(=NR f6 )NR f4 R f5 , NR f4 S(=O)R f2 , NR f4 S (=O) 2 R f2 , NR f4 S(=O) 2 NR f4 R f5 , S(=O)R f2 , S(=O)NR f4 R f5 or S(=O) 2 NR f4 R f5 ; the 4 to The 7-membered heterocycle contains 1 to 3 heteroatoms selected from N, O, S;
    R f1、R f2、R f3、R f4、R f5、R f6、R e1、R e2、R e3、R e4、R e5、R e6各自独立地选自C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-12芳基、5至12元杂芳基、3至10元杂环烷基任选地被1至多个选自以下的取代基取代：H、OH、卤素、C 1- 6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-10环烷基、5至12元杂芳基、3至10元杂环烷基、＝O、CN、NH 2、NO 2、N 3、COOH；所述5至12元杂芳基、3至10元杂环烷基包含1至3个选自N、O、S的杂原子； R f1 , R f2 , R f3 , R f4 , R f5 , R f6 , R e1 , R e2 , R e3 , R e4 , R e5 , R e6 are each independently selected from C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, the C 1-6 alkane C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-12 aryl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl optionally Substituted by 1 to more substituents selected from : H, OH, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3- 10 cycloalkyl, 5 to 12 membered heteroaryl, 3 to 10 membered heterocycloalkyl, =O, CN, NH 2 , NO 2 , N 3 , COOH; the 5 to 12 membered heteroaryl, 3 to The 10-membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, S;
    p为1、2或者3。p is 1, 2 or 3.
  17. 根据权利要求16所述的中间体化合物或者其立体异构体、药学上可接受的盐或或氘代物，其中所述化合物或者其立体异构体，药学上可接受的盐或氘代物选自以下结构：The intermediate compound or its stereoisomer, pharmaceutically acceptable salt or deuterated product according to claim 16, wherein said compound or its stereoisomer, pharmaceutically acceptable salt or deuterated product is selected from The following structure:
    Figure PCTCN2022110534-appb-100085
    或者
    Figure PCTCN2022110534-appb-100086
    Figure PCTCN2022110534-appb-100085
    or
    Figure PCTCN2022110534-appb-100086
  18. 一种药物组合物，所述药物组合物包括：A pharmaceutical composition comprising:
    (1)权利要求1至13所述的化合物或其立体异构体；(1) The compound or stereoisomer thereof according to claims 1 to 13;
    (2)任选的一种或者多种其他活性成分；以及(2) Optional one or more other active ingredients; and
    (3)药学上可接受的载体和/或赋形剂。(3) Pharmaceutically acceptable carriers and/or excipients.
  19. 权利要求18所述的药物组合物或者权利要求1至15所述的化合物或其立体异构体在制备抗肿瘤药物中的用途。Use of the pharmaceutical composition as claimed in claim 18 or the compound as claimed in claims 1 to 15 or its stereoisomers in the preparation of antitumor drugs.
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Citations (3)

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CN101855221A (en) * 2007-11-15 2010-10-06 P.安杰莱蒂分子生物学研究所 Pyridazinone derivatives as PARP inhibitors
CN112424188A (en) * 2018-04-30 2021-02-26 里邦医疗公司 Pyridazinones as PARP7 inhibitors
WO2021087025A1 (en) * 2019-10-30 2021-05-06 Ribon Therapeutics, Inc. Pyridazinones as parp7 inhibitors

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CN101855221A (en) * 2007-11-15 2010-10-06 P.安杰莱蒂分子生物学研究所 Pyridazinone derivatives as PARP inhibitors
CN112424188A (en) * 2018-04-30 2021-02-26 里邦医疗公司 Pyridazinones as PARP7 inhibitors
WO2021087025A1 (en) * 2019-10-30 2021-05-06 Ribon Therapeutics, Inc. Pyridazinones as parp7 inhibitors

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DATABASE REGISTRY ANONYMOUS : "3H-[1,2,3]Oxathiazolo[4,3-a]isoindole-8-acetonitrile, 3a,8-dihydro-4-methyl-, 1,1-dioxide, (3aR,8S)- (CA INDEX NAME)", XP093031782, retrieved from NCBI *

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