WO2023011629A1 - Dérivé de pyrrolidone et son utilisation en médecine - Google Patents

Dérivé de pyrrolidone et son utilisation en médecine Download PDF

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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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English (en)
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/zh
Publication of WO2023011629A1 publication Critical patent/WO2023011629A1/fr

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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.

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Abstract

L'invention concerne un dérivé de pyrrolidone ou un stéréoisomère de celui-ci, et son utilisation en médecine.
PCT/CN2022/110534 2021-08-06 2022-08-05 Dérivé de pyrrolidone et son utilisation en médecine WO2023011629A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101855221A (zh) * 2007-11-15 2010-10-06 P.安杰莱蒂分子生物学研究所 作为parp抑制剂的哒嗪酮衍生物
CN112424188A (zh) * 2018-04-30 2021-02-26 里邦医疗公司 作为parp7抑制剂的哒嗪酮
WO2021087025A1 (fr) * 2019-10-30 2021-05-06 Ribon Therapeutics, Inc. Pyridazinones utilisées en tant qu'inhibiteurs de parp7

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101855221A (zh) * 2007-11-15 2010-10-06 P.安杰莱蒂分子生物学研究所 作为parp抑制剂的哒嗪酮衍生物
CN112424188A (zh) * 2018-04-30 2021-02-26 里邦医疗公司 作为parp7抑制剂的哒嗪酮
WO2021087025A1 (fr) * 2019-10-30 2021-05-06 Ribon Therapeutics, Inc. Pyridazinones utilisées en tant qu'inhibiteurs de parp7

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Title
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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