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CN-122010903-A - Quinoxaline derivatives as anticancer agents

CN122010903ACN 122010903 ACN122010903 ACN 122010903ACN-122010903-A

Abstract

The present invention relates to quinoxaline derivatives as anticancer agents. In particular, it relates to azaquinolone compounds having formula (I), and their use in medicine.

Inventors

  • PARKER MARAN J.
  • S. L. Degos
  • J. W. Johannes
  • S. M. hand
  • A. Gosh
  • ZHENG XIAOLAN

Assignees

  • 阿斯利康(瑞典)有限公司

Dates

Publication Date
20260512
Application Date
20210624
Priority Date
20200625

Claims (10)

  1. 1. A compound having the formula I or a pharmaceutically acceptable salt thereof, Wherein: R 1 is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl or C 1-4 alkyloxy; R 2 is independently selected from H, halogen, C 1-4 alkyl or C 1-4 fluoroalkyl, and R 3 is H or C 1-4 alkyl; r 4 is halogen or C 1-4 alkyl.
  2. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from any one of methyl, ethyl, isopropyl, cyclopropyl, and methoxy.
  3. 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from any one of H, chloro, fluoro, methyl and difluoromethyl.
  4. 4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from any one of chloro, fluoro and methyl.
  5. 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is independently selected from C 1-4 alkyl or C 1-4 alkyloxy.
  6. 6. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from: 5- [4- [ (2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -6-fluoro-N-methyl-pyridine-2-carboxamide, 5- [4- [ (2, 5-Dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 6-Chloro-5- [4- [ (2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 5- [4- [ (2, 5-Dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N, 6-dimethyl-pyridine-2-carboxamide, 5- [4- [ (2, 5-Dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -6-fluoro-pyridine-2-carboxamide, 5- [4- [ (5-Fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -6-methyl-pyridine-2-carboxamide, 5- [4- [ (2, 5-Dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -6-methyl-pyridine-2-carboxamide, 6-Chloro-5- [4- [ (5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 5- [4- [ (5-Chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -6-fluoro-N-methyl-pyridine-2-carboxamide, 5- [4- [ (5-Chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 5- [4- [ (5-Chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N, 6-dimethyl-pyridine-2-carboxamide, 6-Fluoro-5- [4- [ [ 5-fluoro-2- [ (1S and 1R) -1-fluoroethyl ] -3-oxo-4H-quinoxalin-6-yl ] methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 5- [4- [ [ 5-Fluoro-2- [ (1S and 1R) -1-fluoroethyl ] -3-oxo-4H-quinoxalin-6-yl ] methyl ] piperazin-1-yl ] -N, 6-dimethyl-pyridine-2-carboxamide, 5- [4- [ (5-Chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 5- [4- [ (5-Chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -6-fluoro-N-methyl-pyridine-2-carboxamide, 5- [4- [ (5-Chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N, 6-dimethyl-pyridine-2-carboxamide, 5- [4- [ [2- (1, 1-Difluoroethyl) -5-fluoro-3-oxo-4H-quinoxalin-6-yl ] methyl ] piperazin-1-yl ] -N, 6-dimethyl-pyridine-2-carboxamide, 6-Fluoro-5- [4- [ (5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 6- (Difluoromethyl) -5- [4- [ (5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 6-Fluoro-5- [4- [ (5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] pyridine-2-carboxamide, 5- [4- [ (2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N, 6-dimethyl-pyridine-2-carboxamide, 6- (Difluoromethyl) -5- [4- [ (2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 5- [4- [ (2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] pyridine-2-carboxamide, 5- [4- [ (2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -6-methyl-pyridine-2-carboxamide, 5- [4- [ (2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -6-fluoro-N-methyl-pyridine-2-carboxamide, 6-Chloro-5- [4- [ (2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 5- [4- [ (2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 6-Chloro-5- [4- [ (5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 5- [4- [ (5-Fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N, 6-dimethyl-pyridine-2-carboxamide, 5- [4- [ (5-Fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 5- [4- [ (5-Fluoro-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 6-Chloro-5- [4- [ (5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 5- [4- [ (5-Fluoro-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N, 6-dimethyl-pyridine-2-carboxamide, 6-Fluoro-5- [4- [ (5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 5- [4- [ [2- (Difluoromethyl) -5-fluoro-3-oxo-4H-quinoxalin-6-yl ] methyl ] piperazin-1-yl ] -N, 6-dimethyl-pyridine-2-carboxamide, 5- [4- [ (5-Fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 6-Fluoro-5- [4- [ (5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 5- [4- [ (5-Fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N, 6-dimethyl-pyridine-2-carboxamide, 6-Chloro-5- [4- [ (5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 5- [4- [ (2-Ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N, 6-dimethyl-pyridine-2-carboxamide, 5- [4- [ (2-Ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -6-fluoro-N-methyl-pyridine-2-carboxamide, 5- [4- [ (2-Ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, N-ethyl-6-fluoro-5- [4- [ (5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] pyridine-2-carboxamide, N-ethyl-5- [4- [ (5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -6-methyl-pyridine-2-carboxamide, 5- [4- [ [ 5-Fluoro-3-oxo-2- (trifluoromethyl) -4H-quinoxalin-6-yl ] methyl ] piperazin-1-yl ] -N, 6-dimethyl-pyridine-2-carboxamide, 6-Fluoro-5- [4- [ [ 5-fluoro-3-oxo-2- (trifluoromethyl) -4H-quinoxalin-6-yl ] methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 6-Chloro-5- [4- [ [ 5-fluoro-3-oxo-2- (trifluoromethyl) -4H-quinoxalin-6-yl ] methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 5- [4- [ [ 5-Fluoro-3-oxo-2- (trifluoromethyl) -4H-quinoxalin-6-yl ] methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 6-Fluoro-5- [4- [ (5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 5- [4- [ (5-Fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N, 6-dimethyl-pyridine-2-carboxamide, 5- [4- [ (5-Fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 5- [4- [ (2-Cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -6-fluoro-N-methyl-pyridine-2-carboxamide, 5- [4- [ (2-Cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N, 6-dimethyl-pyridine-2-carboxamide, 5- [4- [ (2-Cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 5- [4- [ (2-Methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N, 6-dimethyl-pyridine-2-carboxamide, 6-Fluoro-5- [4- [ (2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, 6- (Difluoromethyl) -5- [4- [ (2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide, or 6- (Difluoromethyl) -5- [4- [ (2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide.
  7. 7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is: 6-fluoro-5- [4- [ (5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl ] piperazin-1-yl ] -N-methyl-pyridine-2-carboxamide.
  8. 8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient or inert carrier.
  9. 9. The pharmaceutical composition of claim 8, wherein the excipient comprises at least one pharmaceutically acceptable diluent.
  10. 10. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a disease or disorder in which inhibition of PARP1 is beneficial, wherein the disease or disorder is cancer, wherein the cancer is selected from any one of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, gastrointestinal cancer, lung cancer, and brain cancer.

Description

Quinoxaline derivatives as anticancer agents The present application is a divisional application of an application patent application of which the application date is 2021, 6, 24, application number is 202180043057.8 and the name is quinoxaline derivative as an anticancer drug. Technical Field The present disclosure relates to substituted azaquinolone compounds and pharmaceutically acceptable salts thereof that inhibit the poly (ADP-ribose) polymerase (PARP) family of enzymes. The disclosure also relates to the use of these compounds, and pharmaceutically acceptable salts thereof, in medicine, for example in the treatment of diseases in which inhibition of PARP1 or PARP1 function is of therapeutic interest. The disclosure also relates to methods of treatment and methods of manufacturing medicaments using compounds according to the disclosure. Background The PARP family of enzymes plays an important role in many cellular processes (e.g., replication, recombination, chromatin remodeling, and DNA damage repair) (O' Connor MJ, mol Cell [ molecular cells ] (2015) 60 (4): 547-60). Examples of PARP inhibitors and their mechanism of action are taught, for example, in WO 2004/080976. PARP1 and PARP2 are widely studied PARPs because of their role in DNA damage repair. PARP1 is activated by DNA damage fragmentation and serves to catalyze the addition of poly (ADP-ribose) (PAR) chains to target proteins. This post-translational modification, known as PAR glycosylation (PARylation), mediates the recruitment of additional DNA repair factors into DNA damage. Upon completion of this recruitment task, PARP auto-PAR-glycosylation triggers release of bound PARP from DNA, allowing the use of other DNA repair proteins to complete repair. Thus, the binding of PARP to the site of damage, its catalytic activity and ultimately its release from DNA are important steps in cancer cells to cope with chemotherapy and radiotherapy-induced DNA damage (Bai P. Biology of poly (ADP-ribose) polymers: the factotums of CELL MAINTENANCE [ biological: cell-sustained manifold ]. Mol Cell [ molecular cytology ]2015; 58:947-58.). Inhibition of PARP family enzymes has been used as a strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Many preclinical and clinical studies have shown that tumor cells harboring deleterious alterations of BRCA1 or BRCA2, a key tumor suppressor protein involved in repair of double-stranded DNA breaks (DSBs) by Homologous Recombination (HR), are selectively sensitive to small molecule inhibitors of the PARP family of DNA repair enzymes. The Homologous Recombination Repair (HRR) pathway of such tumors is defective and its survival depends on the function of the PARP enzyme. Although PARP inhibitor therapy targets primarily BRCA mutated cancers, PARP inhibitors have been tested clinically in non-BRCA mutated tumors that exhibit Homologous Recombination Defects (HRD) (Turner N, tutt a, ashworth a. HALLMARKS OF 'BRCAness' in sporadic cancers [ sign of 'BRCAness' in sporadic cancers ]. NAT REV CANCER [ natural reviews of cancer ] 2004; 4:814-9). PARP inhibitors with increased selectivity for PARP1 are believed to result in increased efficacy and reduced toxicity compared to other clinical PARP1/2 inhibitors. It is also believed that a strong selective inhibition of PARP1 will result in the capture of PARP1 on DNA, which leads to DNA Double Strand Breaks (DSBs) by collapsing the replication fork in S phase. PARP1-DNA capture is also believed to be an effective mechanism for selectively killing tumor cells with HRDs. Thus, there is an unmet medical need for effective and safe PARP inhibitors. In particular PARP inhibitors selective for PARP 1. Disclosure of Invention Applicants have found that the azaquinolones described herein surprisingly have PARP inhibitory activity and are therefore useful in the treatment of diseases and conditions in which PARP function is pharmacologically significant. Furthermore, the azaquinolones described herein are unexpectedly more selective for PARP1 than other PARP family members (such as PARP2, PARP3, PARP5a, and PARP 6). Applicants have also found that the azaquinolone compounds described herein are surprisingly capable of penetrating the Blood Brain Barrier (BBB). Thus, the azaquinolones described herein may be used to treat diseases and conditions that occur in central nervous system tissues (e.g., brain and spinal cord). In one aspect, applicants provide a class of compounds having formula (I): Wherein: R 1 is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 fluoroalkyl, and C 1-4 alkyloxy; R 2 is independently selected from H, halogen, C 1-4 alkyl, and C 1-4 fluoroalkyl, and R 3 is H or C 1-4 alkyl; R 4 is halogen or C 1-4 alkyl, Or a pharmaceutically acceptable salt thereof. In another aspect, applicants provide a class of compounds having formula (I): Wherein: R 1 is independently selected from H, C 1-4 alkyl, C 1-4 fluoroalkyl, a