HCV NS3 protease inhibitors

Patent metadata

Field	Value
Publication number	US-9328138-B2
Application number	US-201214358050-A
Country	US
Kind code	B2
Filing date	Nov 9, 2012
Priority date	Nov 15, 2011
Publication date	May 3, 2016
Grant date	May 3, 2016

Abstract

The present invention relates to macrocyclic compounds of formula (I) that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use for treating or preventing HCV infections.

First claim

What is claimed is:

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein:
Y is CH or N;
R 1 is:
—OC 1-6 alkyl,
—OC 1-6 alkyl-het 1 ,
—OC 1-6 alkyl-OH,
—OC 1-6 alkyl-NR a R b ,
—O-het 1 ,
—OC 1-6 alkylCO 2 H,
—OC 1-6 alkylC(═O)-het 1 ,
—O(CH 2 ) 1-6 OC(═O)CH 2 NR a R b ,
—OC 1-6 alkyl-C 1-6 alkoxy,
—OC 1-6 alkyl-C 1-6 alkoxy-C 1-6 alkoxy,
—OC(O)NR a R b ,
—OC 1-6 alkyl-S-het 1 ,
—OC 1-6 alkyl-phosphate,
a phosphate group,
—(CH 2 ) 1-6 -het 1 ,
pyridinyl, or
thiazolyl;
wherein
said alkyl is optionally substituted with 1 or 2 fluoro substituents,
said phosphate group is optionally substituted with 1, 2 or 3 C 1-6 alkyl;
said het 1 is:
a) naphthyl optionally substituted with 1 or 2 substituents selected from —OH, C 1-6 alkyl, or halo;
b) heteroaryl selected from 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein said heteroaryl is attached through a ring atom selected from C or N and optionally substituted with 1 or 2 substituents independently selected from C 1-6 alkyl and —OH; or
c) heterocycle selected from 4-7 membered monocyclic or 6-10 membered polycyclic bridged, linearly fused or spirocyclic saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, wherein said heterocycle is attached through a ring atom selected from C or N and optionally substituted with 1 or 2 substituents independently selected from C 1-6 alkyl, oxo, —(CH 2 ) m F, Boc, —(CH 2 ) m CF 3 , —(CH 2 ) m OCF 3 , —OH, —NR a R b , —C 1-6 alkoxy, —(CH 2 ) m SO 2 CH 3 , aryl, —C 1-6 alkoxy-C 1-6 alkyl, —C 1-6 alkyl-C 1-6 alkoxy optionally substituted with CF 3 , cyano, C(═O)NH 2 , C 3-6 cycloalkyl,
—C 1-6 alkyl-C 3-6 cycloalkyl, —COOC 1-6 alkyl,
C 1-6 alkyl-SO 2 C 1-6 alkyl, and benzimidazolyl wherein the benzimidazolyl is optionally substituted with F;

R a and R b are independently selected from H; C 1-6 alkyl; t-Boc; aryl; C 3-6 cycloalkyl optionally substituted with 1 or 2 fluoro; C 1-6 alkoxy-C 1-6 alkyl; tetrahydropyranyl; C 1-6 alkyl-OH; C 1-6 alkyl-arylA; C 1-6 alkyl-C(H)(OH)-arylA; C 1-6 alkyl-imidazolyl optionally substituted with methyl, C 1-6 alkyl-benzimidazolyl optionally substituted with methyl; C 1-6 alkyl-pyrazolyl; C 1-6 alkyl-dihydrotriazole optionally substituted with oxo; or C 1-6 alkyl-pyrrolidinyl optionally substituted with oxo;
wherein
m is 0 or 1 to 4;
said arylA is phenyl, naphthalenyl, tetrahydronaphthalenyl, or 7-10 membered fused bicyclic ring structure wherein at least one of the rings is aromatic and is optionally substituted with 2 —OH;
said tetrahydropyranyl is optionally substituted with 1 oxo;

R 2 is C 1-6 alkyl, C 2-6 alkenyl, C 3 -C 6 cycloalkyl or NR c R d ;
wherein
the C 3-6 cycloalkyl is optionally substituted with C 1-6 alkyl optionally substituted with —OH, morpholinyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkoxy,
C 1-6 alkoxy-phenyl, or C 2-6 alkenyl;
R c and R d are independently H or C 1-6 alkyl, or may be taken together, with the N to which they are attached, to form a 4-7-membered monocyclic ring;

R 3 is C 1-6 alkyl, C 2-6 alkenyl, C 3 -C 6 cycloalkyl, CHF 2 or CF 3 ;
R 4 is C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkyl-C 3-8 cycloalkyl, adamantyl, dihydroindenyl, or a 4-8 membered heterocycloalkyl having 1 or 2 heteroatoms selected from N, O, or S, wherein R 4 is optionally substituted with one or two substituents independently selected from (C 1 -C 6 )alkyl, halo, and —O(C 1 -C 6 )alkyl; or
R 3 and R 4 together form heptene;
Z is C or N;
R 5 is H or C 1-6 alkyl; or R 5 is absent when Z is N;
W is a bond, O or NR;
R is H or C 1-6 alkyl;
X is absent or is halo, CF 3 , —OCHF 2 , —OCH 2 F, —OCD 2 F, —OCDF 2 , C 1 -C 6 alkyl, C 1-6 alkoxy, aryl, heteroaryl, or —O(CH 2 ) 1-6 NR a R b ;
A is absent, O or N;
B is (CH 2 ) m ; and
n is 1-4.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, having a formula of

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, having a formula of

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, having a formula of

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H or CH 3 .

6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is ethyl, ethylene, or cyclopropyl.

7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is propyl, t-butyl, cyclopentyl, cyclohexyl optionally substituted with 1 or 2 F, cyclohexylmethyl, methylcyclohexyl, methylcyclopentyl, dihydroindenyl, or tetrahydro-2H-pyranyl.

8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1 to 3.

9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is cyclopropyl, N(CH 3 ) 2 , or azetidinyl, wherein the cyclopropyl is optionally substituted with methyl, CH(CH 3 ) 2 , C(CH 3 )═CH 2 , C(CH 3 ) 2 OH, CH 2 CH 2 -morpholinyl, CH 2 OCH 3 , CH 2 OCH 2 CH 2 OCH 3 , or CH 2 OCH 2 -phenyl.

10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —O—C 1-6 alkyl;
—OC 1-6 alkyl-het 1 ; —OC 1-6 alkyl-C 1-6 alkoxy;
—OC 1-6 alkyl-C 1-6 alkoxy-C 1-6 alkoxy; —OCH 2 C(═O)-het 1 ; —O(CH 2 ) 1-6 OC(═O)CH 2 NR a R b ;
—OC(O)NR a R b ; —OC 1-6 alkyl-phosphate; —OC 1-6 alkyl-S-het 1 ; —O-het 1 ; —O—C 1-6 alkyl-OH optionally substituted with 1 or 2 fluoro substituents; or —OC 1-6 alkyl-NR a R b
wherein R a and R b are independently
H,
C 1-6 alkyl,
t-Boc,
C 3-6 cycloalkyl optionally substituted with 1 or 2 fluoro substituents,
C 1-6 alkyl-C 1-6 alkoxy,
C 1-6 alkyl-OH, phenyl,
C 1-6 alkyl-phenyl,
tetrahydropyranyl,
C 1-6 alkyl-C(H)(OH)-phenyl,
naphthalenyl,
C 1-6 alkyl-naphthalenyl,
C 1-6 alkyl-oxopyrrolidinyl,
C 1-6 alkyl-benzimidazolyl optionally substituted with methyl,
C 1-6 alkyl-pyrazolyl,
C 1-6 alkyl-dihydrotriazole optionally substituted with oxo, or
C 1-6 alkyl-imidazolyl optionally substituted with methyl.

11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the het 1 is: oxazepanyl; oxooxazolidinyl; pyridinyl; pyrazolyl; pyrrolyl; tetrahydropyranyl; triazolyl optionally substituted with C 1-6 alkyl; dioxolanyl; oxoimidazolidinyl; morpholinyl optionally substituted with dimethyl or ethyl; pyrrolidinyl optionally substituted with 1 or 2 substituents independently selected from oxo, Boc, C 1-6 alkyl, OH, C(O)NH 2 , dimethylamino, and methylsulfonyl; piperidinyl optionally substituted with 1 or 2 substituents independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl optionally substituted with CF 3 , cyclopropyl-C 1-6 alkyl, cyclopropyl, —(CH 2 ) m F, OH, —C 1-6 alkyl-SO 2 C 1-6 alkyl, —(CH 2 ) m CF 3 , —COOC 1-6 alkyl, Boc, and benzimidazolyl; imidizolyl; thiazolyl optionally substituted with methyl; azabicycloheptyl; azaspiroheptyl; azaspirononyl; oxaazabicycloheptyl; oxaazaspiroheptyl optionally subst

Assignees

• Merck Sharp & Dohme
• Msd Italia Srl
• Merck Canada Inc

Inventors

• Rudd Michael T
• Mccauley John
• Liverton Nigel
• Grisé-Bard Christiane
• Brochu Marie-Christine
• Charron Sylvie
• Aulakh Virender
• Bachand Benoit
• Beaulieu Patrick
• Zaghdane Helmi
• Han Yongxin
• Ferrara Marco
• Harper Steven
• Summa Vincenzo
• Chackalamannil Samuel
• Venkatraman Srikanth
• Shah Unmesh
• Velazquez Francisco

Classifications

• A61P31/14

  for RNA viruses · CPC title

• A61P31/12

  Antivirals · CPC title

• A61K31/7056

  containing five-membered rings with nitrogen as a ring hetero atom · CPC title

• C07K5/0804

  and aliphatic · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title