Macrocyclic hepatitis C serine protease inhibitors

Patent metadata

Field	Value
Publication number	US-9493506-B2
Application number	US-201414299095-A
Country	US
Kind code	B2
Filing date	Jun 9, 2014
Priority date	Jun 7, 2010
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

The present invention relates to novel macrocyclic compounds and methods of treating a hepatitis C infection in a subject in need of such therapy with said macrocyclic compounds. The present invention further relates to pharmaceutical compositions comprising the compounds of the present invention, or pharmaceutically acceptable salts, esters, or prodrugs thereof, in combination with a pharmaceutically acceptable carrier or excipient.

First claim

What is claimed is:

1. A compound of Formula I:

wherein
A is H, —(C═O)—O—R 1 , —(C═O)—R 1 , —(C═O)—N(R 1 R 2 ), —S(O) 2 —R 1 , or —S(O) 2 —N(R 1 R 2 ),
each R 1 is independently selected from the group consisting of:
(i) H, aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(ii) heterocycloalkyl or substituted heterocycloalkyl; and
(iii) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl or —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S, and N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl or substituted —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S and N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;

each R 2 is independently selected from the group consisting of:
(i) hydrogen;
(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl; and
(iv) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl or —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S, and N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl or substituted —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S and N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;

G is —NHS(O) 2 —R 3 , —O—R 4 , or —NH(SO 2 )NR 4 R 5 ;
each R 3 is independently selected from:
(i) C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl, aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(ii) heterocycloalkyl or substituted heterocycloalkyl; and
(iii) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl or —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S, and N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl or substituted —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S and N; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl; and

each R 4 and R 5 is independently selected from:
(i) hydrogen;
(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl; and
(iv) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl or —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S, and N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl or substituted —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S and N; —C 3 -C 12 cycloalkyl, or substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;

L is a C 2 —O 5 saturated or unsaturated chain, optionally containing one to three heteroatoms independently selected from O, N and S(O) n , wherein L is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl, wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl, group is optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl and cyano;
Z is
(i) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl or —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S, and N and optionally substituted with one or more halo; or
(ii) heteroaryl or substituted heteroaryl;
j=0, 1, 2, 3, or 4;
k=0, 1, 2, or 3;
m=0, 1, or 2;
n is 0, 1, or 2;
denotes a carbon-carbon single or double bond (i.e.,

means

R 6 is H or halo;
R 7 is H or halo;
R 8 is H or halo;
R 9 is H or halo;
wherein if each of R 6 , R 7 , R 8 and R 9 is H, then Z is —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl or —C 2 -C 8 alkynyl, each substituted with one or more halo and each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S, and N; and

salts, solvates and hydrates thereof.

2. The compound of claim 1 , wherein R 3 is independently cyclopropyl optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, —C(O)OH, —C(O)NH 2 , or —C(O)O—C 1 -C 6 alkyl.

3. The compound of claim 1 , wherein A is —(C═O)—O—R 1 .

4. The compound of claim 1 , wherein A is —(C═O)—R 1 .

5. The compound of claim 4 , wherein R 1 is optionally substituted aryl.

6. The compound of claim 4 , wherein R 1 is optionally substituted heteroaryl.

7. The compound of claim 5 , wherein Z is —C 1 -C 8 alkyl containing 0, 1, 2, or 3 heteroatoms selected from 0, S, or NR 1 and substituted with one or more halo.

8. The compound of claim 7 wherein each of R 6 , R 7 , R 8 and R 9 is H.

9. The compound of claim 7 wherein one of R 6 , R 7 , R 8 and R 9 is halo.

10. The compound of claim 7 wherein two of R 6 , R 7 , R 8 and R 9 are halo.

11. The compound of claim 7 wherein one of R 7 or R 8 is halo.

12. The compound of claim 7 wherein R 7 is fluoro.

13. The compound of claim 7 wherein R 8 is fluoro.

14. The compound of claim 7 wherein R 9 is fluoro.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient.

16. A method of producing a compound of Formula I, or a pharmaceutically acceptable salt thereof, comprising the step of reacting a compound of Formula (II) with a compound of Formula (III) to provide a compound of Formula (I):

wherein for Formulae (I), (II) and (III):
A is —(C═O)—R 1 ,
each R 1 is independently selected from the group consisting of:
(i) H, aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(ii) heterocycloalkyl or substituted heterocycloalkyl; and
(iii) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl or —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S, and N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl or substituted —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S and N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;

G is —NHS(O) 2 —R 3 , —O—R 4 , or —NH(SO 2 )NR 4 R 5 ;
each R 3 is independently selected from:
(i) C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl, aryl; substituted aryl;

heteroaryl; substituted heteroaryl;
(ii) heterocycloalkyl or substituted heterocycloalkyl; and
(iii) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl or —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S, and N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl or substituted —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently sel

Assignees

• Enanta Pharm Inc
• Abbvie Inc
• Abbvie Inc
• Enata Pharmacueticals Inc

Inventors

• Chen Hui-Ju
• Mcdaniel Keith F
• Green Brian E
• Shanley Jason P
• Kruger Albert W
• Gandarilla Jorge
• Welch Dennie S
• Cink Russell D
• Cullen Steven C
• Gai Yonghua
• Wang Guoqiang
• Or Yat Sun

Classifications

• A61P31/14

  for RNA viruses · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P43/00

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

• C07K5/081 Primary

  the side chain containing O or S as heteroatoms, e.g. Cys, Ser · CPC title

• A61P1/16

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