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CN-116710433-B - Selective PARP1 inhibitor and application thereof

CN116710433BCN 116710433 BCN116710433 BCN 116710433BCN-116710433-B

Abstract

Selective PARP1 inhibitor and application thereof

Inventors

  • ZHANG JING
  • WEI YONGGANG
  • ZHOU XIBING
  • YANG KE
  • SUN YI

Assignees

  • 成都百裕制药股份有限公司

Dates

Publication Date
20260505
Application Date
20220420
Priority Date
20210423

Claims (4)

  1. 1. A compound or a stereoisomer thereof, said compound being selected from the group consisting of compounds of general formula (IV): ra 3 is C 1-6 alkyl; R e is selected from C 1-6 alkyl, C 1-6 alkoxy or C 3-8 heterocycloalkyl, optionally further substituted with 1 or more substituents selected from hydroxy.
  2. 2. A compound or a stereoisomer thereof, said compound selected from the group consisting of:
  3. 3. A pharmaceutical composition, the pharmaceutical composition comprising: (1) A compound of claim 1 or 2 or a stereoisomer thereof; (2) Optionally one or more further active ingredients, and (3) Pharmaceutically acceptable carriers and/or excipients.
  4. 4. Use of a pharmaceutical composition according to claim 3 or a compound according to claim 1 or 2 or a stereoisomer thereof in the preparation of an antitumor drug.

Description

Selective PARP1 inhibitor and application thereof Technical Field The invention relates to a selective PARP1 inhibitor or a stereoisomer thereof and application thereof in medicine. Background PARPs (ploy (ADP-ribose) polymerase is a type of Poly ADP-ribose polymerase that catalyzes the ribosylation of multiple proteins, poly-ADP-ribosylation, which plays an important role in many cellular processes such as DNA damage repair, transcriptional regulation, chromatin recombination and remodeling. At present, although a plurality of PARP1/2 inhibitors are successfully marketed, no matter the PARP1/2 inhibitors are used singly or in combination, side effects such as blood, gastrointestinal tract and the like still commonly exist clinically, so that the clinical application is limited. Therefore, the development of safer and more effective PARP inhibitors remains a problem to be solved clinically. A series of researches show that compared with the PARP1/2 inhibitor, the high-selectivity PARP1 inhibitor has better curative effect and lower toxicity, is hopeful to reduce the potential risk of the PARP medicament in clinic at present, widens the clinical application range and improves the life quality of patients. Disclosure of Invention The invention aims to provide a selective PARP1 inhibitor or a stereoisomer thereof, a pharmaceutical composition thereof and a medical application thereof. The invention provides a compound shown in a general formula (I) or a stereoisomer thereof: Wherein: A is R a0 is selected from halogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl, said C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl optionally further substituted with 1 or more substituents selected from halogen or C 1-6 alkyl; R a1 is selected from H, halogen, or C 1-6 alkyl, said C 1-6 alkyl optionally further substituted with 1 or more substituents selected from halogen or C 1-6 alkyl; Each L a1、La2、La3 is independently N or CR L; R L is selected from H, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, or C 3-8 cycloalkyl; l is selected from-NH-, -CO-or- (CR 1R2)n -; R 1、R2 is each independently selected from H or C 1-6 alkyl, said C 1-6 alkyl optionally further substituted with 1 or more substituents selected from halogen, hydroxy or cyano; B is a4 to 12 membered heterocycle selected from a4 to 12 membered monocyclic ring, a5 to 12 membered spiro ring, a4 to 12 membered fused ring or a4 to 12 membered bridged ring, said 4 to 12 membered heterocycle may contain 1 to 4 heteroatoms selected from N, O or S and may optionally be further substituted with 1 or more R b; R b is selected from H, hydroxy, cyano, or C 1-6 alkyl, said C 1-6 alkyl optionally being further substituted with 1 or more substituents selected from hydroxy, halogen, or cyano; Or any two R b may form a 3 to 8 membered ring; C is X 1、X2、X3 are each independently selected from CH or N, where X 1 or X 2 is CH, optionally further substituted with halogen, and where X 3 is selected from N, X 1 and X 2 cannot both be CH; each R 3、R4 is independently selected from H, halogen, cyano, or C 1-6 alkyl; r c is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl optionally being further substituted with 1 or more substituents selected from D, halogen, hydroxy, cyano, NR c1Rc2、C1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; Each R c1、Rc2 is independently selected from H or C 1-6 alkyl; n is 1 or 2; The conditions are as follows: the compound of formula (I) is not The compounds of formula (I) are optionally further substituted with 1 or more deuterium. The invention provides a compound or a stereoisomer thereof, wherein the compound is selected from compounds shown in a general formula (II): Wherein: R a0 is selected from halogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl, said C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl optionally further substituted with 1 or more substituents selected from halogen or C 1-6 alkyl; R a1 is selected from H, halogen, or C 1-6 alkyl, said C 1-6 alkyl optionally further substituted with 1 or more substituents selected from halogen or C 1-6 alkyl; Each Z 1、Z2 is independently N or CR L; R L is selected from H, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, or C 3-8 cycloalkyl; l is selected from-NH-, -CO-or- (CR 1R2)n -; R 1、R2 is each independently selected from H or C 1-6 alkyl, said C 1-6 alkyl optionally further substituted with 1 or more substituents selected from halogen, hydroxy or cyano; B is a4 to 12 membered heterocycle selected from a4 to 12 membered monocyclic ring, a5 to 12 membered spiro ring, a4 to 12 membered fused ring or a4 to 12 membered bridged ring, said 4 to 12 membered heterocycle may contain 1 to 4 heteroatoms selecte