Novel Compounds for Preventing SARS-CoV-2 Viral Replication and Treating COVID-19

Abstract

the outbreak of COVID-19 evolved into a global pandemic. The causative agent for COVID-19 has been identified as a novel coronavirus, which has been named Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2). On the basis of a recent analysis of 103 sequenced genomes of SARS-CoV-2, it has been proposed that SARS-CoV-2 can be divided into two major types (L and S types), with the S type being ancestral and the L type having evolved from the S type. Recent evidence clearly shows that the newly emerged coronavirus SARS-CoV-2, the causative agent of COVID-19, has acquired the ability to transmit from human to human, leading to community spread of the virus. The sequence of the SARS-CoV-2 receptor binding domain (RBD), including its receptor binding motif (RBM) that directly contacts the angiotensin 2 receptor, ACE 2, is like the RBD and the RBM of SARS-CoV-2, strongly suggesting that SARS-CoV-2 uses ACE2 as its receptor. The coronavirus replication and transcription function is encoded by the so-called "replicase" gene, which consists of two overlapping polyproteins that are extensively processed by viral proteases. The present application describes a series of novel compounds as SARS-CoV-2-related 3C-like protease inhibitors for preventing SARS-CoV-2 viral replication and that could be useful in the treatment of COVID-19. Furthermore, the application discloses compounds and their preparation, use, pharmaceutical composition, and treatment. Definitions. R 1 = H, −C(O)C 1 −C 6 alkyl, −C(O)OC 1 −C 6 alkyl, and −C 1 −C 6 alkyl OC(O)OC 1 −C 6 alkyl; and when R 1 is H, then R 2 is selected from the group consisting of ethyl, isopropyl, 2-methylpropyl, C 1 −C 6 alkyl substituted with one to three R 3 , cyclopropyl substituted with one to three R 4 , C 5 −C 12 bicycloalkyl unsubstituted or substituted with one to three R 4 , four-to seven-membered heterocycloalkyl comprising one to three heteroatoms selected from N, O, and S and that is unsubstituted or substituted with one to three R 4 , 2-methylphenyl, 2-methoxyphenyl, 2-chlorophenyl, 2-methoxy-methylphenyl, 2-(dimethylamino)methylphenyl, 2-(dimethylamino)methyl-6-methylphenyl, 2-methoxymethyl-6-methyl-phenyl, 4-cyano-2,6-dimethylphenyl, 2-methoxy-6-methyl-phenyl, 2-chloro-6-methylphenyl, 4-chloro-6-methyl-phenyl, 2,6-dimethyl-4-methoxyphenyl, 2,6-dimethyl-4-fluoroy-phenyl, and 2,6-dimethyl-3-fluoroyphenyl.