Hepatitis C inhibitor compounds

Patent metadata

Field	Value
Publication number	US-9340539-B2
Application number	US-201214240641-A
Country	US
Kind code	B2
Filing date	Aug 22, 2012
Priority date	Aug 24, 2011
Publication date	May 17, 2016
Grant date	May 17, 2016

Abstract

A compound of formula (I) useful for the treatment or prevention of hepatitis C viral infection, (Formula (I)) wherein: X 1 and X 2 are each independently CR B or N; R B is H, (C 1-6 )alkyl, (C 1-6 )haloalkyl, halo. —O—(C 1-6 )alkyl, NH 2 , NH(C 1-6 )alkyl or N((C 1-6 )alkyl) 2 ; R 1 and R 2 are each independently (C 1-6 )alkyl optionally mono- or di-substituted with —O—(C 1-6 )alkyl, NH 2 , NH(C 1-6 )alkyl or N((C 1-6 )alkyl) 2 ; or R 1 and R 2 , together with the carbon to which they are attached, are linked to form a (C 3-7 )cycloalkyl group or a 3- to 7-membered heterocyclyl, said cycloalkyl and heterocyclyl being optionally mono- or di-substituted with —(C 1-6 )alkyl; R A is —C(═O)N(R 3 )(R 4 ), —C(═O)O(R 4 ), heterocyclyl or heteroaryl, wherein each said heterocyclyl and heteroaryl is optionally substituted 1 to 3 times with R 41 ; R 5 and R 6 are each independently H or (C 1-6 )alkyl optionally mono- or di-substituted with —O—(C 1-6 )alkyl, NH 2 , NH(C 1-6 )alkyl or N((C 1-6 )alkyl) 2 ; or R 5 and R 6 , together with the carbon to which they are attached, are linked to form a (C 3-7 )cycloalkyl group or a 3- to 7-membered heterocyclyl, said cycloalkyl and heterocyclyl being optionally mono- or di-substituted with —(C 1-6 )alkyl; and n is 0, 1 or 2.

First claim

The invention claimed is:

1. A compound of Formula (I) or salt thereof:

wherein:
X 1 and X 2 are each CR B ;
R B is H, (C 1-6 )alkyl, (C 1-6 )haloalkyl, halo, —O—(C 1-6 )alkyl, NH 2 , NH(C 1-6 )alkyl or N((C 1-6 )alkyl) 2 ;
R 1 and R 2 are each independently (C 1-6 )alkyl optionally mono- or di-substituted with —O—(C 1-6 )alkyl, NH 2 , NH(C 1-6 )alkyl or N((C 1-6 )alkyl) 2 ; or
R 1 and R 2 , together with the carbon to which they are attached, are linked to form a (C 3-7 )cycloalkyl group or a 3- to 7-membered heterocyclyl, said cycloalkyl and heterocyclyl being optionally mono- or di-substituted with —(C 1-6 )alkyl;
R A is —C(═O)N(R 3 )(R 4 ), —C(═O)O(R 4 ), heterocyclyl or heteroaryl, wherein each said heterocyclyl and heteroaryl is optionally substituted 1 to 3 times with R 41 ;
R 3 is H or (C 1-6 )alkyl optionally mono- or di-substituted with —O—(C 1-6 )alkyl, NH 2 , NH(C 1-6 )alkyl, N((C 1-6 )alkyl) 2 , —C(═O)—(C 1-6 )alkyl, —SO 2 NH 2 , —SO 2 —NH(C 1-6 )alkyl, —SO 2 —N((C 1-6 )alkyl) 2 , —SO 2 (C 1-6 )alkyl, —C(═O)—NH 2 , —C(═O)—NH(C 1-6 )alkyl or —C(═O)—N((C 1-6 )alkyl) 2 ;
R 4 is H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, —(C 1-6 )alkyl-aryl, —(C 1-6 )alkyl-heterocyclyl,—(C 1-6 )alkyl-heteroaryl, aryl, heterocyclyl or heteroaryl, wherein each said alkyl, cycloalkyl, aryl or heterocyclyl, either alone or in combination with another radical, is optionally substituted 1 to 3 times with R 41 , and each heteroaryl is mono-substituted with —C(═O)—R 42 ; or
R 3 and R 4 , together with the N atom to which they are attached, are linked to form a heterocyclyl or heteroaryl, wherein said heterocyclyl and heteroaryl are optionally substituted 1 to 3 times with R 41 ;
R 41 is each independently selected from the group consisting of halo, oxo, cyano, nitro, R 42 , —C(═O)—R 42 , —C(═O)OR 42 , —OR 42 , —SR 42 , —SOR 42 , —SO 2 R 42 , —N(R 43 )R 42 , —C(═O)—N(R 43 )R 42 , —N(R 43 )—C(═O)R 42 , —O—C(═O)—N(R 3 )R 42 and —SO 2 —N(R 43 )R 42 ;
R 42 is each independently selected from the group consisting of H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, —(C 1-6 )alkyl-aryl, —(C 1-6 )alkyl-heterocyclyl, —(C 1-6 )alkyl-heteroaryl, aryl, heterocyclyl and heteroaryl, wherein each said alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, either alone or in combination with another radical, is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of:
halo, cyano, OH, —COOH, —O—(C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )haloalkyl, —C(═O)—(C 1-6 )alkyl, —SO 2 NH 2 , —SO 2 —NH(C 1-6 )alkyl, —SO 2 —N((C 1-6 )alkyl) 2 , —SO 2 (C 1-6 )alkyl, —C(═O)—NH 2 , —C(═O)—NH(C 1-6 )alkyl, —C(═O)—N((C 1-6 )alkyl) 2 , —NH 2 , —NH(C 1-6 )alkyl, —N((C 1-6 )alkyl) 2 , —NH—C(═O)(C 1-6 )alkyl and (C 1-6 )alkyl optionally mono- or di-substituted with OH or —O—(C 1-6 )alkyl;
R 43 is H or (C 1-6 )alkyl;
R 5 and R 6 are each independently H or (C 1-6 )alkyl optionally mono- or di-substituted with —O—(C 1-6 )alkyl, NH 2 , NH(C 1-6 )alkyl or N((C 1-6 )alkyl) 2 ; or
R 5 and R 6 , together with the carbon to which they are attached, are linked to form a (C 3-7 )cycloalkyl group or a 3- to 7-membered heterocyclyl, said cycloalkyl and heterocyclyl being optionally mono- or di-substituted with —(C 1-6 )alkyl; and
n is 1.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
X 1 and X 2 are each CR B ;
R B is H, (C 1-6 )alkyl, (C 1-6 )haloalkyl, halo, —O—(C 1-6 )alkyl, NH 2 , NH(C 1-6 )alkyl or N((C 1-6 )alkyl) 2 ;
R 1 and R 2 are each independently (C 1-6 )alkyl optionally mono- or di-substituted with —O—(C 1-6 )alkyl, NH 2 , NH(C 1-6 )alkyl or N((C 1-6 )alkyl) 2 ; or
R 1 and R 2 , together with the carbon to which they are attached, are linked to form a (C 3-7 )cycloalkyl group or a 3- to 7-membered heterocyclyl, said cycloalkyl and heterocyclyl being optionally mono- or di-substituted with —(C 1-6 )alkyl;
R A is —C(═O)N(R 3 )(R 4 );
R 3 is H or (C 1-6 )alkyl optionally mono- or di-substituted with —O—(C 1-6 )alkyl, NH 2 , NH(C 1-6 )alkyl, N((C 1-6 )alkyl) 2 , —C(═O)—(C 1-6 )alkyl, —SO 2 NH 2 , —SO 2 —NH(C 1-6 )alkyl, —SO 2 —N((C 1-6 )alkyl) 2 , —SO 2 (C 1-6 )alkyl, —C(═O)—NH 2 , —C(═O)—NH(C 1-6 )alkyl or —C(═O)—N((C 1-6 )alkyl) 2 ;
R 4 is (C 3-7 )cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein each said cycloalkyl, aryl, heterocyclyl and heteroaryl, either alone or in combination with another radical, is mono-substituted with —C(═O)—R 42 ;
R 42 is each independently selected from the group consisting of (C 1-6 )alkyl, (C 3-7 )cycloalkyl, —(C 1-6 )alkyl-aryl, —(C 1-6 )alkyl-heterocyclyl, —(C 1-6 )alkyl-heteroaryl, aryl and heteroaryl, wherein each said alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, either alone or in combination with another radical, is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of:
halo, cyano, OH, —COOH, —O—(C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )haloalkyl, —C(═O)—(C 1-6 )alkyl, —SO 2 NH 2 , —SO 2 —NH(C 1-6 )alkyl, —SO 2 —N((C 1-6 )alkyl) 2 , —SO 2 (C 1-6 )alkyl, —C(═O)—NH 2 , —C(═O)—NH(C 1-6 )alkyl, —C(═O)—N((C 1-6 )alkyl) 2 , —NH 2 , —NH(C 1-6 )alkyl, —N((C 1-6 )alkyl) 2 , —NH—C(═O)(C 1-6 )alkyl and (C 1-6 )alkyl optionally mono- or di-substituted with OH or —O—(C 1-6 )alkyl;
R 5 and R 6 are each independently H or (C 1-6 )alkyl optionally mono- or di-substituted with —O—(C 1-6 )alkyl, NH 2 , NH(C 1-6 )alkyl or N((C 1-6 )alkyl) 2 ; or
R 5 and R 6 , together with the carbon to which they are attached, are linked to form a (C 3-7 )cycloalkyl group or a 3- to 7-membered heterocyclyl, said cycloalkyl and heterocyclyl being optionally mono- or di-substituted with —(C 1-6 )alkyl; and
n is 1.

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 are CH.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently (C 1-3 )alkyl optionally mono-substituted with —O—(C 1-3 )alkyl, NH 2 , NH(C 1-3 )alkyl or N((C 1-3 )alkyl) 2 ; or
R 1 and R 2 and the carbon to which they are attached are linked to form a (C 3-7 )cycloalkyl group.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently (C 1-3 )alkyl optionally mono-substituted with —O—(C 1-3 )alkyl; or
R 1 and R 2 and the carbon to which they are attached are linked to form a (C 3-4 )cycloalkyl group.

6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A is —C(═O)N(R 3 )(R 4 ).

7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is H.

8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is heterocyclyl mono-substituted with —C(═O)—R 42 ;
R 42 is each independently selected from the group consisting of (C 5-7 )cycloalkyl, —(C 1-4 )alkyl-heterocyclyl, —(C 1-4 )alkyl-heteroaryl and heteroaryl, wherein each said alkyl, cycloalkyl, heterocyclyl and heteroaryl, either alone or in combination with another radical, is optionally mono- or di-substituted with substitutents each independently selected from the group consisting of:
halo, OH, —O—(C 1-6 )alkyl, —SO 2 NH 2 , —SO 2 —NH(C 1-6 )alkyl, —SO 2 —N((C 1-6 )alkyl) 2 , —SO 2 (C 1-6 )alkyl, —NH 2 , —NH(C 1-6 )alkyl, —N((C 1-6 )alkyl) 2 , —NH—C(═O)(C 1-6 )alkyl and (C 1-6 )alkyl.

9. The compound according to claim 8 ,

Assignees

• Brochu Christian
• Grand-Maitre Chantal
• Fader Lee
• Kuhn Cyrille
• Bertrand-Laperle Megan
• Pesant Marc
• Boehringer Ingelheim Int

Inventors

• Brochu Christian
• Grand-Maitre Chantal
• Fader Lee
• Kuhn Cyrille
• Bertrand-Laperle Megan
• Pesant Marc

Classifications

• A61P31/14

  for RNA viruses · CPC title

• A61K31/4178

  not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title