Macrocyclic inhibitors of flaviviridae viruses

Patent metadata

Field	Value
Publication number	US-2017190734-A1
Application number	US-201715423469-A
Country	US
Kind code	A1
Filing date	Feb 2, 2017
Priority date	Jun 8, 2012
Publication date	Jul 6, 2017
Grant date	—

Abstract

Provided are compounds of Formula I:

and pharmaceutically acceptable salts and esters thereof. The compounds, compositions, and methods provided are useful for the treatment of virus infections, particularly hepatitis C infections.

First claim

1 .- 37 . (canceled)

38 . A compound of Formula I:

or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof, wherein:
A is CH 2 ;
A 1 is (C 2 -C 5 )alkenylene, wherein a sp 3 carbon atom of A 1 is optionally replaced by —O—, —S(O) n —, —NH— or —N((C 1 -C 4 )alkyl)-, and wherein a sp 3 or sp 2 carbon atom of A 1 is optionally substituted with one or more groups selected from the group consisting of halo, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl, heterocycloalkyl, cycloalkyl, aryl(C 1 -C 4 )alkyl, cycloalkyl(C 1 -C 4 )alkyl, heterocycloalkyl(C 1 -C 4 )alkyl, arylheterocycloalkyl(C 1 -C 4 )alkyl, —OR 9 , —SR 9 , —S(O)R 9 , —S(O) 2 R 9 and —N(R 9 ) 2 ;
A 2 is —CH(R 8 )-heteroarylene, wherein A 2 is optionally substituted with one or more substituents selected from the group consisting of —OR 9 , —SR 9 , —S(O)R 9 , —S(O) 2 R 9 , —N(R 9 ) 2 , halo, halo(C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, cyano and (C 1 -C 8 )alkyl;
L 1 is —O—C(O);
X 1 is —NH— or —N(CH 3 )—;
R 1 and R 2 , when taken together with the carbon to which they are both attached, form —C(═O)—;
R 3 is H or (C 1 -C 4 )alkyl optionally substituted with halo, cyano, hydroxyl or (C 1 -C 4 )alkoxy;
R 4a and R 4b are independently H or (C 1 -C 8 )alkyl, wherein each R 4a and R 4b is optionally substituted with one or more substituents selected from the group consisting of cyano, —COOH, halo, hydroxyl, amino, (C 1 -C 8 )alkoxy, mono(C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, aryl and heteroaryl;
R 5a and R 5b are independently H or (C 1 -C 5 )alkyl optionally substituted with one or more substituents selected from the group consisting of —N 3 , cyano, —COOH, halo, hydroxyl, amino, mono(C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, (C 1 -C 8 )alkoxy, aryl and heteroaryl, or
R 5a and R 5b together form a spirocycle having Formula (a):

wherein one or more carbon ring atoms of Formula (a) is optionally replaced by a nitrogen, oxygen or sulfur atom, and wherein a ring atom of Formula (a) optionally has one or more substituents selected from the group consisting of oxo, ═N(C 1 -C 4 )alkoxy, halo, hydroxyl, —NH 2 , (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, —OC(O)R 9 , —C(O) 2 R 9 , and —S(O) 2 R 9 ;
R 6a and R 6b together form a spirocycle having Formula (a);
R 8 is H, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl, wherein R 8 is optionally substituted with —OR, —N(R 9 ) 2 , —CON(R 9 ) 2 , or cyano;
each R 9 is independently H, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl or (C 2 -C 4 )alkynyl; and
m is 1, 2, 3, 4 or 5.

39 . The compound of claim 38 , wherein A 1 is

40 . The compound of claim 38 , wherein A 2 is —CH(R 8 )-quinolinylene.

41 . The compound of claim 38 , wherein R 8 is methyl.

42 . The compound of claim 38 , wherein R 3 is H or methyl; one of R 4a and R 4b is H and the other is methyl; and one of R 5a and R 5b is H and the other is isopropyl.

43 . The compound of claim 38 , wherein R 3 is H or methyl; one of R 4a and R 4b is H and the other is methyl; one of R 5a and R 5b is H and the other is isopropyl; A 2 is —CH(R 8 )— quinolinylene; and R 8 is methyl.

44 . The compound of claim 38 , wherein R 6a and R 6b together form

45 . The compound of claim 38 , wherein:
A 1 is

A 2 is

R 3 is H or methyl;
R 4a is methyl;
R 5 is iso-propyl; and
R 6a and R 6b together form

46 . A compound selected from:

47 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 38 or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof and a pharmaceutically acceptable excipient.

48 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 46 or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof and a pharmaceutically acceptable excipient.

49 . The pharmaceutical composition of claim 47 , further comprising at least one additional therapeutic agent selected from the group consisting of interferons, ribavirin, HCV NS3 protease inhibitors, HCV NS5a inhibitors, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, and TLR-7 agonists; or a mixture thereof.

50 . The pharmaceutical composition of claim 49 , wherein the at least one additional therapeutic agent is ribavirin, telaprevir, boceprevir or sofosbuvir.

51 . A method for treating a disease selected from the group consisting of dengue fever, yellow fever, hepatitis C virus, Japanese encephalitis, Kyasanur forest disease, Murray valley encephalitis, St. Louis encephalitis, tick-borne encephalitis or West Nile encephalitis, comprising administering to a human patient in need thereof a therapeutically effective amount of a compound of claim 38 or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof.

52 . The method of claim 51 , wherein the compound is selected from:

53 . The method of claim 51 , wherein the disease is Hepatitis C virus.

54 . A method for providing immunomodulation to a human patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound claim 38 or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof.

55 . The method of claim 54 , wherein the compound is selected from:

Assignees

• Selcia Ltd
• Gilead Sciences Inc

Inventors

• Aciro Caroline
• Chiva Jean Yves
• Dean David Kenneth
• Highton Adrian John
• Jansa Petr
• Keats Andrew John
• Lazarides Linos
• Mackman Richard
• Poullennec Karine G
• Schrier Adam James
• Siegel Dustin Scott
• Steadman Victoria Alexandra
• Watt Greg

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P31/18

  for HIV · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title