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Msg  4167 of 4338  at  9/17/2020 1:30:03 AM  by

JBWIN


Building IP: BMY Patent Application re "BENZOFURAN DERIVATIVES FOR THE TREATMENT OF HEPATITIS C"

 
United States Patent Application20200291002
Kind CodeA1
Yeung; Kap-Sun ; et al.September 17, 2020

BENZOFURAN DERIVATIVES FOR THE TREATMENT OF HEPATITIS C

Abstract

The disclosure provides compounds of formula (I), including their salts, as well as compositions and methods of using the compounds. The compounds have activity against hepatitis C virus (HCV) and may be useful in treating those infected with HCV. ##STR00001##


Inventors:Yeung; Kap-Sun; (Madison, CT) ; Kadow; John F.; (Wallingford, CT) ; Bora; Rajesh Onkardas; (Bangalore, IN) ; Anjanappa; Prakash; (Bangalore, IN) ; Selvakumar; Kumaravel; (Bangalore, IN) ; Gupta; Samayamunthula Venkata Satya Arun; (Bangalore, IN)
Applicant:
NameCityStateCountryType

BRISTOL-MYERS SQUIBB COMPANY

Princeton

NJ

US
Family ID:1000004869688
Appl. No.:16/083972
Filed:March 17, 2017
PCT Filed:March 17, 2017
PCT NO:PCT/US17/23045
371 Date:September 11, 2018

Related U.S. Patent Documents

Application NumberFiling DatePatent Number
62311026Mar 21, 2016

Current U.S. Class:1/1
Current CPC Class:C07D 413/12 20130101; C07D 307/84 20130101; C07D 405/12 20130101
International Class:C07D 405/12 20060101 C07D405/12; C07D 307/84 20060101 C07D307/84; C07D 413/12 20060101 C07D413/12

Claims



1. A compound of formula I ##STR00225## where: R.sup.1 is phenyl or pyridinyl and is substituted with 0-3 substituents selected from the group consisting of halo, alkyl, cycloalkyl, haloalkyl, alkoxy, or haloalkoxy, and wherein the phenyl or pyridinyl is also substituted with 1 CON(R.sup.9)(R.sup.10) substituent; R.sup.2 is hydrogen, halo, alkyl, or alkoxy; R.sup.3 is CON(R.sup.7)(R.sup.8); R.sup.4 is phenyl that is independently substituted with 0-2 halo, alkyl, or alkoxy or is para substituted with X--Ar.sup.1; R.sup.5 is hydrogen, nitro, halo, alkyl, or alkoxy; R.sup.6 is hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, or N(R.sup.14)(R.sup.15); R.sup.7 is alkyl; R.sup.8 is hydrogen; R.sup.9 is ##STR00226## R.sup.10 is hydrogen; R.sup.11 is alkyl; R.sup.12 and R.sup.13 are independently hydrogen, halo, hydroxy, alkoxy, or haloalkoxy, or taken together are carbonyl; R.sup.14 is hydrogen, alkyl, or haloalkyl; R.sup.15 is hydrogen, alkyl, haloalkyl, or alkylsulfonyl; Ar.sup.1 is phenyl or para-halophenyl; Ar.sup.2 is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, or tetrazolyl; and X is --O-- or --NH--; or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 where R.sup.1 is phenyl substituted with 0-3 substituents selected from the group consisting of halo, alkyl, cycloalkyl, haloalkyl, alkoxy, and haloalkoxy, and wherein the phenyl is also substituted with 1 CON(R.sup.9)(R.sup.10) substituent; R.sup.2 is hydrogen or halo; R.sup.3 is CON(R.sup.7)(R.sup.8); R.sup.4 is phenyl that is independently substituted with 0-1 halo; R.sup.5 is hydrogen; R.sup.6 is hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, or N(R.sup.14)(R.sup.15); R.sup.7 is alkyl; R.sup.8 is hydrogen; R.sup.9 is ##STR00227## R.sup.10 is hydrogen; R.sup.11 is alkyl; R.sup.12 and R.sup.13 are independently hydrogen, halo, hydroxy, alkoxy, or haloalkoxy, or taken together are carbonyl; R.sup.14 is alkyl, or haloalkyl; R.sup.15 is hydrogen or alkylsulfonyl; and Ar.sup.2 is pyrimidinyl or oxadiazolyl; or a pharmaceutically acceptable salt thereof.

3. A compound of claim 2 where R.sup.1 is phenyl substituted with 0-3 substituents selected from the group consisting of halo, alkyl, and alkoxy, and wherein the phenyl is also substituted with 1 CON(R.sup.9)(R.sup.10) substituent; R.sup.2 is hydrogen or fluoro; R.sup.3 is CON(R.sup.7)(R.sup.8); R.sup.4 is phenyl that is independently substituted with 0-1 fluoro; R.sup.5 is hydrogen; R.sup.6 is hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, or N(R.sup.7)(R.sup.8); R.sup.7 is alkyl; R.sup.8 is hydrogen; R.sup.9 is ##STR00228## R.sup.10 is hydrogen; R.sup.11 is alkyl; R.sup.12 and R.sup.13 are independently hydrogen, halo, hydroxy, alkoxy, or haloalkoxy, or taken together are carbonyl; R.sup.14 is alkyl, or haloalkyl; R.sup.15 is hydrogen or alkylsulfonyl; and Ar.sup.2 is pyrimidinyl or oxadiazolyl; or a pharmaceutically acceptable salt thereof.

4. A compound of claim 1 where R.sup.1 is phenyl substituted with 0-3 substituents selected from the group consisting of halo, alkyl, and alkoxy, and wherein the phenyl is also substituted with 1 CON(R.sup.9)(R.sup.10) substituent.

5. A compound of claim 1 where R.sup.2 is hydrogen or halo.

6. A compound of claim 1 where R.sup.3 is CON(R.sup.7)(R.sup.8); R.sup.7 is methyl, and R.sup.8 is hydrogen.

7. A compound of claim 1 where R.sup.9 is ##STR00229## and R.sup.11 is alkyl.

8. A compound of claim 1 where R.sup.9 is ##STR00230##

9. A compound of claim 1 where R.sup.14 is haloalkyl and R.sup.15 is hydrogen or where R.sup.14 is alkyl and R.sup.15 is alkylsulfonyl.

10. A compound of claim 1 where Ar.sup.2 is pyrimidinyl or oxadiazolyl

11. A compound of claim 1 selected from the group consisting of ##STR00231## ##STR00232## ##STR00233## ##STR00234## ##STR00235## ##STR00236## ##STR00237## ##STR00238## ##STR00239## ##STR00240## ##STR00241## ##STR00242## ##STR00243## or a pharmaceutically acceptable salt thereof.

12. A composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

13. A method of treating hepatitis C infection comprising administering a therapeutically effective amount of a compound of claim 1 to a patient.
Description



CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Patent Application Ser. No. 62/311,026, filed Mar. 21, 2016, which is incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] The disclosure generally relates to the novel compounds of formula I, including their salts, which have activity against hepatitis C virus (HCV) and are useful in treating those infected with HCV. The disclosure also relates to compositions and methods of using these compounds.

[0003] Hepatitis C virus (HCV) is a major human pathogen, infecting an estimated 170 million persons worldwide--roughly five times the number infected by human immunodeficiency virus type 1. A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma (Lauer, G. M.; Walker, B. D. N. Engl. J. Med. 2001, 345, 41-52).

[0004] HCV is a positive-stranded RNA virus. Based on a comparison of the deduced amino acid sequence and the extensive similarity in the 5'-untranslated region, HCV has been classified as a separate genus in the Flaviviridae family. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame.

[0005] Considerable heterogeneity is found within the nucleotide and encoded amino acid sequence throughout the HCV genome. At least six major genotypes have been characterized, and more than 50 subtypes have been described. The major genotypes of HCV differ in their distribution worldwide, and the clinical significance of the genetic heterogeneity of HCV remains elusive despite numerous studies of the possible effect of genotypes on pathogenesis and therapy.

[0006] The single strand HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins. In the case of HCV, the generation of mature non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. The first one is believed to be a metalloprotease and cleaves at the NS2-NS3 junction; the second one is a serine protease contained within the N-terminal region of NS3 (also referred to as NS3 protease) and mediates all the subsequent cleavages downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components. The complex formation of the NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficiency at all of the sites. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B (also referred to as HCV polymerase) is a RNA-dependent RNA polymerase that is involved in the replication of HCV. The HCV NS5B protein is described in "Structural Analysis of the Hepatitis C Virus RNA Polymerase in Complex with Ribonucleotides (Bressanelli; S. et al., Journal of Virology 2002, 3482-3492; and Defrancesco and Rice, Clinics in Liver Disease 2003, 7, 211-242.

[0007] Currently, the most effective HCV therapy employs a combination of alpha-interferon and ribavirin, leading to sustained efficacy in 40% of patients (Poynard, T. et al. Lancet 1998, 352, 1426-1432). Recent clinical results demonstrate that pegylated alpha-interferon is superior to unmodified alpha-interferon as monotherapy (Zeuzem, S. et al. N. Engl. J. Med. 2000, 343, 1666-1672). However, even with experimental therapeutic regimens involving combinations of pegylated alpha-interferon and ribavirin, a substantial fraction of patients do not have a sustained reduction in viral load. Thus, there is a clear and important need to develop effective therapeutics for treatment of HCV infection.

[0008] HCV-796, an HCV NS5B inhibitor, showed an ability to reduce HCV RNA levels in patients. The viral RNA levels decreased transiently and then rebounded during dosing when treatment was with the compound as a single agent but levels dropped more robustly when combined with the standard of care which is a form of interferon and ribavirin. The development of this compound was suspended due to hepatic toxicity observed during extended dosing of the combination regimens.

[0009] The invention provides technical advantages, for example, the compounds are novel and are effective against hepatitis C. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.


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