Hepatitis C virus inhibitors

Patent metadata

Field	Value
Publication number	US-9676802-B2
Application number	US-201414254265-A
Country	US
Kind code	B2
Filing date	Apr 16, 2014
Priority date	Oct 17, 2011
Publication date	Jun 13, 2017
Grant date	Jun 13, 2017

Abstract

The present invention discloses compounds of Formula (I), and pharmaceutically acceptable salts, esters, or prodrugs thereof:

Q-G-A-L-B—Z—W  (I),

which inhibit RNA-containing virus, particularly the hepatitis C virus (HCV). Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

First claim

What is claimed:

1. A compound represented by Formula (I):
Q-G-A-L-B—Z—W  (I),

or a pharmaceutically acceptable salt thereof, wherein:
A and B are each independently absent or a monocyclic or polycyclic group independently selected from the group consisting of aryl, heteroaryl, heterocyclic, C 3 -C 8 cycloalkyl and C 3 -C 8 cycloalkenyl, each optionally substituted;
L is absent or an aliphatic group;
wherein at least one of A, B and L is present;
Z is —C(O)NH—, an optionally substituted 5-membered heteroaryl containing one or more nitrogen atoms, or an optionally substituted 5-membered heteroaryl fused to a mono- or bicyclic ring, wherein the mono- or bicyclic ring is aromatic or non-aromatic, wherein the mono- or bicyclic ring is attached to one of groups A, L and B and wherein the 5-membered heteroaryl contains one or more nitrogen atoms;
G is absent, —C(O)NH—, an optionally substituted 5-membered heteroaryl containing one or more nitrogen atoms, or an optionally substituted 5-membered heteroaryl fused to a mono- or bicyclic ring, wherein the mono- or bicyclic ring is aromatic or non-aromatic, wherein the mono- or bicyclic ring is attached to one of groups A, L and B and wherein the 5-membered heteroaryl contains one or more nitrogen atoms;
W is

Q is hydrogen,

Y at each occurrence is independently C(O) or S(O) 2 ;
R 1 and R 1a at each occurrence are independently hydrogen, hydroxy, O(C 1 -C 4 alkyl) or optionally substituted C 1 -C 4 alkyl;
R 3 , R 3a , R 4 and R 4a are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, and optionally substituted C 3 -C 8 cycloalkyl; alternatively, R 3 and R 4 or R 3a and R 4a can be taken together with the carbon atom to which they are attached to form optionally substituted C 3 -C 8 cycloalkyl or optionally substituted heterocyclic;
R 5 and R 5a are each independently hydrogen, optionally substituted C 1 -C 8 alkyl, or optionally substituted C 3 -C 8 cycloalkyl;
wherein one of R 3 , R 4 and R 5 is connected to group Z via a linker of -L 1 -L 2 -L 3 -; or alternatively one of R 3 , R 4 and R 5 is connected to group B via a linker of -L 1 -L 2 -L 3 -; wherein group B is present; alternatively, wherein one of R 3a , R 4a and R 5a is connected to group G via a linker of -L 1 -L 2 -L 3 - wherein group G is present; or alternatively, one of R 3a , R 4a and R 5a is connected to group A via a linker of -L 1 -L 2 -L 3 - wherein group A is present; yet alternatively, wherein one of R 3 , R 4 and R 5 is connected to group Z or group B via a linker of -L 1 -L 2 -L 3 - and one of R 3a , R 4a and R 5a is connected to group G or group A via a linker of -L 1 -L 2 -L 3 ;
L 1 and L 3 at each occurrence are each independently an aliphatic group, or one of L 1 and L 3 is absent and the other of L 1 and L 3 is an aliphatic group;
L 2 at each occurrence is independently absent, or selected from the group consisting of aryl, heteroaryl, heterocyclic, C 3 -C 8 cycloalkyl, and C 3 -C 8 cycloalkenyl, each optionally substituted;
wherein -L 1 -L 2 -L 3 - together form a linker;
R 6 at each occurrence is independently selected from the group consisting of O(C 1 -C 8 alkyl), amino, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted;
U and U a are each independently absent or each independently selected from O, S, S(O), SO 2 , NC(O)—(C 1 -C 4 alkyl), C(O), protected carbonyl, OCH 2 , OCH 2 CH 2 , SCH 2 , SCH 2 CH 2 , C(R 7 ) 2 , Si(R 7 ) 2 , C(R 7 ) 2 C(R 7 ) 2 , and C═C(R 2 ) 2 ;
R 2 at each occurrence is independently hydrogen, halogen, optionally substituted C 1 -C 4 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R 7 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, optionally substituted O(C 1 -C 4 alkyl), S(C 1 -C 4 alkyl), amino optionally substituted with one or two C 1 -C 4 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 1 -C 4 alkyl, and optionally substituted C 3 -C 8 cycloalkyl;
alternatively two geminal R 7 groups are taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3- to 7-membered cyclic group selected from the group consisting of C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl or 3- to 7-membered heterocyclic;
R 7a , R 7aa , R 7b , and R 7ba at each occurrence are independently selected from the group consisting of hydrogen, optionally substituted aryl, optionally substituted C 1 -C 4 alkyl, and optionally substituted C 3 -C 8 cycloalkyl;
alternatively, CHR 7a —U, CHR 7b —U, CHR 7aa —U a or CHR 7ba —U a are taken together to form a group selected from CH═CH, fused and optionally substituted C 3 -C 8 cycloalkyl, fused and optionally substituted aryl, or fused and optionally substituted heterocyclic; and
yet alternatively, U, R 7a , and R 7b are taken together with the carbon atoms to which they are attached to form a bridged, optionally substituted 4- to 7-membered cyclic group selected from the group consisting of C 4 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and 4- to 7- membered heterocyclic; and
wherein one of R 7a , R 7b and U is connected to group Z via a linker of -L 1 -L 2 -L 3 -; or alternatively one of R 7a , R 7b and U is connected to group B via a linker of -L 1 -L 2 -L 3 -; wherein group B is present; alternatively, wherein one of R 7aa , R 7ba , and U a is connected to group G via a linker of -L 1 -L 2 -L 3 - wherein group G is present; or alternatively, one of R 7aa ; R 7ba , and U a is connected to group A via a linker of -L 1 -L 2 -L 3 - wherein group A is present; yet alternatively, wherein one of R 7a , R 7b and U is connected to group Z or group B via a linker of -L 1 -L 2 -L 3 - and one of R 7aa , R 7ba , and U a is connected to group G or group A via a linker of -L 1 -L 2 -L 3 -; alternatively, U is connected to group R 6 via a linker of -L 1 -L 2 -L 3 -; or

alternatively, U a is connected to group R 6 via a linker of -L 1 -L 2 -L 3 .

2. The compound of claim 1 , represented by Formula (Ia), (Ib), (Ic), (Id) or (Ie):

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , represented by Formula (IIa), (IIb), (IIc) or (IId):

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein:
R 1 and R 1a are hydrogen;
Y is C(O);
L is absent or selected from the group consisting of O, —C(O)NH—, —(C 1 -C 4 alkyl)-NH—(C 1 -C 4 alkyl)-, heterocyclic, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl, each optionally substituted;
A and B are each independently absent, optionally substituted aryl, or optionally substituted heteroaryl; or alternatively A, L and B are taken together to form a linker selected from one of the groups illustrated below:

Assignees

• Enanta Pharm Inc

Inventors

• Qiu Yao-Ling
• Cao Hui
• Peng Xiaowen
• Chen Zhigang
• Or Yat Sun

Classifications

• A61K31/5377

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

• A61P31/14

  for RNA viruses · CPC title

• A61K31/7056

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

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title