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CN-122010912-A - Antiviral 1, 3-dioxoindene compounds

CN122010912ACN 122010912 ACN122010912 ACN 122010912ACN-122010912-A

Abstract

The present invention provides compounds of formula (I) as described herein, as well as pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods of using these compounds, salts, and compositions for treating viral infections.

Inventors

  • J. Neuters
  • SHEN ZHENZHU
  • JIN HAIZHU
  • LI ZHONGJIAO
  • D. Pune
  • PFISTER KEITH B.
  • ZHENG YONGZHI
  • HAN SHUIFENG
  • Y.R. Marpani
  • P. Chaklasari
  • B.K. Bisgas
  • JIN TIANSHENG

Assignees

  • 诺华股份有限公司
  • 鲁汶天主教大学
  • 韩国化学研究院

Dates

Publication Date
20260512
Application Date
20210420
Priority Date
20200420

Claims (20)

  1. 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: Wherein, the G 1 is selected from the group consisting of linear or branched C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, or linear or branched C 1 -C 4 alkoxy, wherein the C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, and C 1 -C 4 alkoxy can be substituted with one, two, or three substituents independently selected from cyclopropyl and linear or branched C 1 -C 3 alkyl; L is a bond or CH 2 ; E is A) -CH (CHOHCH 3 )(NMe 2 ), or B) A monocyclic 4-6 membered heterocyclyl containing one or two nitrogen atoms or a 5-6 membered heteroaryl containing one nitrogen atom, wherein said 4-6 membered heterocyclyl and said 5-6 membered heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of linear or branched C 1 -C 3 alkyl, -OH, =o, -SO 2 R, wherein each R is independently selected from the group consisting of linear or branched C 1 -C 3 alkyl, a monocyclic 5-6 membered heterocyclyl containing one or two nitrogen atoms, and NR 1 R 2 , wherein said monocyclic 5-6 membered heterocyclyl is optionally substituted with C 1 -C 3 alkyl or NR 3 R 4 ; Each R 1 and R 2 is independently selected from H and C 1 -C 3 alkyl, wherein the C 1 -C 3 alkyl is optionally substituted with NR 3 R 4 , and Each R 3 and R 4 is independently selected from H or methyl.
  2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula (II): 。
  3. 3. the compound of any one of claims 1, or a pharmaceutically acceptable salt thereof, having formula (III): 。
  4. 4. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L is a bond.
  5. 5. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein E is-CH (CHOHCH 3 )(NMe 2 ).
  6. 6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein E is a monocyclic 5-6 membered heteroaryl containing one nitrogen atom, wherein the 5-6 membered heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of linear or branched C 1 -C 3 alkyl, -OH, -SO 2 R.
  7. 7. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein G 1 is linear or branched C 1 -C 4 alkyl optionally substituted with one, two, or three substituents independently selected from cyclopropyl and linear or branched C 1 -C 3 alkyl.
  8. 8. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein G 1 is C 3 -C 4 cycloalkyl optionally substituted with one, two or three substituents independently selected from linear or branched C 1 -C 3 alkyl.
  9. 9. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein G 1 is linear or branched C 1 -C 4 alkoxy optionally substituted with one, two or three substituents independently selected from cyclopropyl and linear or branched C 1 -C 3 alkyl.
  10. 10. The compound according to any one of claims 1 and 7 to 9, or a pharmaceutically acceptable salt thereof, having formula (Ia): Wherein A 1 is selected from the group consisting of H, straight or branched C 1 -C 3 alkyl, and SO 2 R, and A 2 is selected from the group consisting of H and SO 2 R.
  11. 11. The compound of claim 10, wherein a 1 is methyl or SO 2 CH 3 .
  12. 12. The compound of claim 10 or claim 11, wherein A 2 is SO 2 R, and R is selected from the group consisting of CH 3 , a monocyclic 5-6 membered heterocyclyl containing one or two nitrogen atoms and substituted with CH 3 or N (CH 3 ) 2 ), and NR 1 R 2 .
  13. 13. A compound according to any one of claims 1, 4 to 6 and 10 to 12, or a pharmaceutically acceptable salt thereof, having formula (Ib): wherein Y is H or CH 3 .
  14. 14. The compound according to any one of claims 1, 4 to 6 and 10 to 12, or a pharmaceutically acceptable salt thereof, having formula (Ic): Wherein X is selected from the group consisting of methyl, ethyl and cyclopropyl.
  15. 15. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 。
  16. 16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 。
  17. 17. A compound according to any one of claims 1 to 15, a pharmaceutically acceptable salt thereof or an optical isomer thereof for use in the prevention or treatment of a viral disease.
  18. 18. A pharmaceutical composition for preventing or treating a viral disease, comprising a compound according to any one of claims 1 to 15, a pharmaceutically acceptable salt thereof or an optical isomer thereof, and a pharmaceutically acceptable diluent or excipient.
  19. 19. A combination comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9, and one or more therapeutically active agents.
  20. 20. A method of treating a viral disease, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, or a combination according to claim 19.

Description

Antiviral 1, 3-dioxoindene compounds The application is a divisional application of Chinese patent application with the application number of 202180029147.1 and the name of 'antiviral 1, 3-dioxoindene compound' of 2021, 04 and 20. Technical Field The present invention relates to novel 1, 3-dioxoindene compounds which are inhibitors of picornaviruses (including coxsackievirus, enterovirus, epochs virus, polioviruses and rhinoviruses) and are therefore useful in the treatment of viral infections including poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis a, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, cold, herpetic angina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis or otitis media. The present invention provides novel tetracyclic pyridone compounds as disclosed herein, pharmaceutical compositions containing such compounds, and methods of using these compounds and compositions to treat and prevent viral diseases. Background Picornaviruses are non-enveloped positive single stranded RNA viruses with RNA genomes 7.2Kb-8.5Kb long. These viruses are very small and spherical in shape, about 22nm ~ nm in size, and were first identified long ago. Viruses belonging to the family picornaviridae are enteroviruses, including rhinoviruses, polioviruses, coxsackieviruses a, coxsackieviruses B, and the epothilones and hepatitis a viruses. Diseases caused by picornaviruses are diverse, from respiratory diseases to digestive diseases, to circulatory diseases and to skin diseases, examples of which include poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis a, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, cold, herpetic angina, and foot-and-mouth disease. However, there are no therapeutic agents for curing these diseases. Most of the drugs being developed are uncoated inhibitors. Viruses belonging to the picornaviridae family cause a variety of diseases, including the aforementioned respiratory diseases, which cause health, social and economic problems. Picornaviruses are the primary causative agent of water borne diseases. RNA viruses are constantly causing related diseases because they are very stable and difficult to disinfect. Human rhinovirus (hRV) has recently been associated with most asthma exacerbations and is known to exist even in the bronchial tissues of many stable asthmatic patients. Comparison of corresponding bronchial mucosa biopsy samples taken from asthmatic and non-asthmatic patients shows that the frequency of human rhinovirus detection in the lower respiratory tract of asthmatic patients is significantly higher compared to non-asthmatic patients. There is also reported a correlation between the presence of human rhinovirus and the clinical severity of asthma. In addition, rhinoviruses cause chronic obstructive pulmonary disease, pneumonia, sinusitis and otitis media, and asthma. Rhinoviruses are the primary cause of the common cold, whereas enterovirus-induced diseases include meningitis, respiratory tract infections, and the like. Extensive efforts to provide vaccination against polioviruses have significantly reduced the onset of polioviruses worldwide, but there are still cases reported for this disease in nival, nigeria, egypt, india, pakistan and afghrelin. Hepatitis a is now likely to be controlled to some extent due to vaccines against hepatitis a virus. However, no vaccine against coxsackievirus, epox virus or rhinovirus has been developed so far. In particular, coxsackievirus B is a major cause of myocarditis, and in severe cases, it can develop into idiopathic dilated cardiomyopathy requiring heart transplantation. The enrolment oxime (Enviroxime) derivatives are considered to be the most promising candidates with broad anti-enterovirus and anti-rhinovirus activity. Enrobed oxime interferes with the synthesis of positive strand RNA by binding to viral protein 3A required for the formation of RNA intermediates during viral replication (Heinz B A and Vance L M: J Virol, 1995, 69 (7), 4189-97). However, in clinical studies, the compounds were observed to have insignificant or little therapeutic effect, with adverse pharmacokinetics and undesired side effects detected (Miller F D et al Antimicrob Agents Chemother, 1985, 27 (1), 102-6). The protease inhibitor AG 7088 has been developed based on knowledge about the fine structure and function of viral protease 2C. In cell culture in the nanomolar range AG 7088 has effects on 48 rhinovirus types and Coxsackie viruses A21, B3, enterovirus 70 and Epstein-Barr virus 11 (PATTICK A K et al: antimicrobila Agents Chemother, 1999, 43 (10), 2444-50). Due to the clarification of the molecular structure of the viral capsid, a precondition for the purposeful design of the capsid bloc