IP Library › Patent Application 14412331

Patent Application

App. No. 14/412,331

INHIBITORS OF HEPATITIS C VIRUS

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Patent No.: US None
App. No.: 14/412,331

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Abstract

Compounds of Formula I are disclosed, As well as pharmaceutically acceptable salts thereof. Methods of using said compounds and pharmaceutical compositions containing said compounds are also disclosed.

Claims (391)

1 . A compound of Formula (IV):

or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:

J is C 1 -C 4 alkyl or C 3 -C 6 carbocyclyl, wherein the C 1 -C 4 alkyl or C 3 -C 6 carbocyclyl is optionally substituted with 1-4 halogen, —OH, aryl or cyano;

is C 3 -C 5 carbocyclylene that is attached to L and to the remainder of the compound of Formula IV through two adjacent carbons, wherein said C 3 -C 5 carbocyclylene is optionally substituted with C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, halogen, —OH, or cyano, or is C 5 -C 8 bicyclic carbocyclylene that is attached to L and to the remainder of the compound of Formula IV through two adjacent carbons, or C 3 -C 6 carbocyclylene that is attached to L and to the remainder of the compound of Formula IV through two adjacent carbons, wherein said C 3 -C 6 carcbocyclene is optionally substituted with C 1 -C 4 alkyl or C 1 -C 3 haloalkyl;

L is C 3 -C 6 alkylene, C 3 -C 6 alkenylene or —(CH 2 ) 3 -cyclopropylene-, optionally substituted with 1-4 halogen, —OH, or cyano;

Q is C 2 -C 4 alkyl or C 3 -C 6 carbocyclyl optionally substituted with C 1 -C 3 alkyl, halogen, —OH, or cyano;

E is C 1 -C 3 alkyl or C 2 -C 3 alkenyl, optionally substituted with 1-3 halogen;

W is H, —OH, —O(C 1 -C 3 )alkyl, —O(C 1 -C 3 )haloalkyl, halogen or cyano; and

Z 2a is H or C 1 -C 3 alkyl.

2 . The compound of claim 1 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein J is C 1 -C 3 alkyl.

3 . The compound of claim 1 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein J is methyl or ethyl.

4 . The compound of any one of claims 1 to 3 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein is C 3 -C 6 carbocyclylene that is attached to L and to the remainder of the compound of Formula IV through two adjacent carbons, wherein said C 3 -C 6 carcbocyclene is optionally substituted with C 1 -C 4 alkyl or C 1 -C 3 haloalkyl.

5 . The compound of any one of claims 1 to 3 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein is C 3 -C 6 carbocyclylene that is attached to L and to the remainder of the compound of Formula IV through two adjacent carbons, wherein the C 3 -C 6 carcbocyclene is optionally substituted with methyl, ethyl or trifluoromethyl.

6 . The compound of any one of claims 1 to 3 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein is cyclopropylene.

7 . The compound of any one of claims 1 to 3 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein is C 6 -C 8 bridged bicyclic carbocyclylene or C 6 -C 8 fused bicyclic carbocyclylene that is attached to L and to the remainder of the compound of Formula IV through two adjacent carbons.

8 . The compound of any one of claims 1 to 7 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein L is C 3 -C 6 alkylene, substituted with 1-4 halogens.

9 . The compound of any one of claims 1 to 7 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein L is C 5 alkylene, substituted with two halogens.

10 . The compound of any one of claims 1 to 7 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein L is C 3 -C 6 alkylene.

11 . The compound of any one of claims 1 to 7 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein L is C 5 alkylene.

12 . The compound of claim 8 or claim 9 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein the halogens are each fluoro.

13 . The compound of any one of claims 1 to 12 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein Q is t-butyl or C 5 -C 6 carbocyclyl.

14 . The compound of any one of claims 1 to 12 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein Q is t-butyl.

15 . The compound of any one of claims 1 to 14 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein E is C 1 -C 3 alkyl optionally substituted with 1-3 halogen atoms.

16 . The compound of any one of claims 1 to 14 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein E is difluoromethyl.

17 . The compound of any one of claims 1 to 16 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein W is hydrogen, —O(C 1 -C 3 )alkyl, halogen or cyano.

18 . The compound of any one of claims 1 to 16 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein W is methoxy.

19 . The compound of any one of claims 1 to 18 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein Z 2a is hydrogen or methyl.

20 . The compound of any one of claims 1 to 18 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein Z 2a is methyl.

21 . A compound of Formula IVa:

or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

22 . A compound of Formula IVb:

or a pharmaceutically acceptable salt thereof.

23 . A compound of Formula IVc:

or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

24 . A compound of Formula IVd:

or a pharmaceutically acceptable salt thereof.

25 . A compound of Formula IVe:

or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

26 . A compound of Formula IVf:

or a pharmaceutically acceptable salt thereof.

27 . A compound of Formula IVg

or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

28 . A compound of Formula IVh:

or a pharmaceutically acceptable salt thereof.

29 . A compound of Formula (I):

or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:

J is J 1 , J 2 , J 3 , J 4 , J 5 , J 6 , J 7 , J 8 or J 9 ;

is T 1 , T 2 , T 3 , T 4 , T 5 , T 6 , T 7 , T 8 , T 9 , T 10 , T 11 , T 12 , T 13 or T 14 ;

L is L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 or L 10 ;

X is —O—, —CH 2 —, —OC(O)—, —C(O)O—, —O(O)—, —SO 2 —, —S(O)—, —N(R 16 )—, —S—, ═N—O— or a bond;

A is —C(O)—, —S(O) 2 —, a 6-10 membered arylene, 5-10 membered heteroarylene, or 4-10 membered heterocyclene, wherein any of said arylene, heterocyclene, or heteroarylene is optionally substituted with 1-4 Z 1 groups;

M is a bond, C 1 -C 6 alkylene, —O—, or —N(R 16 )—;

R 1 is H or F;

R 3 , R 4 , and R 5 are each independently selected from H or Z 1 ;

Q is Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 or Q 7 ;

E is E 1 , E 2 , E 3 , E 4 , E 5 , or E 6 ;

G is —CO 2 H, —CONHSO 2 Z 2 , tetrazolyl, —CONHP(O)(R 16 ) 2 , —P(O)(OH)(R 16 ), and —P(O)(R 16 ) 2 ;

is U 1 , U 2 , U 3 , U 4 , U 5 , U 6 or U 7 ;

J 1 is halogen;

J 2 is —OH and R 1 is H;

J 3 is —NR 17 R 18 and R 1 is H;

J 4 is C 1 -C 8 alkyl;

J 5 is C 1 -C 8 alkyl substituted with 1-4 Z 3 groups;

J 6 is C 3 -C 8 carbocyclyl optionally substituted with 1-4 Z 3 groups;

J 7 is C 6 -C 10 aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl optionally substituted with 1-4 Z 3 groups;

J 8 is C 1 -C 8 alkoxy optionally substituted with 1-4 Z 3 groups and R 1 is H;

J 9 is C 3 -C 8 carbocyclyloxy optionally substituted with 1-4 Z 3 groups and R 1 is H;

T 1 is C 3 -C 8 carbocyclylene that is attached to L and M through two adjacent carbons;

T 2 is C 3 -C 8 carcbocyclene that is attached to L and M through two adjacent carbons, wherein said carbocyclylene is substituted with 1-4 C 1 -C 8 alkyl groups;

T 3 is C 3 -C 8 carcbocyclene that is attached to L and M through two adjacent carbons, wherein said carbocyclylene is substituted with 1-4 halogen atoms and said carbocyclylene is optionally substituted with 1-4 C 1 -C 6 alkyl groups;

T 4 is C 3 -C 8 carbocyclene that is attached to L and M through two adjacent carbons, wherein said carbocyclylene is optionally substituted with a C 1 -C 8 alkyl group, wherein said alkyl group is optionally substituted with 1-4 Z 3 groups;

T 5 is 4-10 membered heterocyclene that is attached to L and M through two adjacent carbons;

T 6 is 4-10 membered heterocyclene that is attached to L through a carbon atom and attached to M through an N atom, wherein said heterocyclene is optionally substituted with 1-4 Z 1 groups;

T 7 is 4-10 membered heterocyclene that is attached to M through a carbon atom and attached to L through an N atom, wherein said heterocyclene is optionally substituted with 1-4 Z 1 groups;

T 8 is 4-10 membered heterocyclene that is attached to L and M through two adjacent carbons, wherein said heterocyclene is optionally substituted with 1-4 Z 1 groups;

T 9 is C 5 -C 12 spiro bicyclic carbocyclylene that is attached to L and M through two adjacent carbons, wherein said spiro bicyclic carbocyclylene is optionally substituted with 1-4 Z 1 groups;

T 10 is C 5 -C 12 fused bicyclic carbocyclylene that is attached to L and M through two adjacent carbons, wherein said fused bicyclic carbocyclylene is optionally substituted with 1-4 Z 1 groups;

T 11 is C 5 -C 12 bridged bicyclic carbocyclylene that is attached to L and M through two adjacent carbons, wherein said bridged bicyclic carbocyclylene is optionally substituted with 1-4 Z 1 groups;

T 12 is C 4 -C 8 carbocylene that is attached to L and M through two non-adjacent carbons, wherein said carcbocyclene is optionally substituted with 1-4 Z 1 groups;

T 13 is a 5-8 membered fused, bridged, or spiro bicyclic heterocyclene that is attached to L and M through two adjacent atoms, wherein said heterocyclene is optionally substituted with 1-4 Z 1 groups;

T 14 is C 3 -C 8 carbocyclylene that is attached to L and M through two adjacent carbons, wherein said carbocyclylene is optionally substituted with 1-4 Z 4 groups;

L 1 is C 1 -C 8 alkylene or C 2 -C 8 alkenylene;

L 2 is C 1 -C 8 alkylene or C 2 -C 8 alkenylene wherein said C 1 -C 8 alkylene is substituted with 1-4 halogens or said C 2 -C 8 alkenylene is substituted with 1-4 halogens;

L 3 is C 1 -C 8 alkylene or C 2 -C 8 alkenylene wherein said C 1 -C 8 alkylene is substituted with 1-4 Z 4 groups or said C 2 -C 8 alkenylene is substituted with 1-4 Z 4 groups and wherein each is optionally substituted with 1-4 halogens;

L 4 is C 1 -C 8 alkylene or C 2 -C 8 alkenylene substituted with two geminal C 1 -C 4 alkyl groups that come together to form a spiro C 3 -C 8 carbocyclyl group, wherein L 4 is optionally substituted with 1-4 Z 1 groups;

L 5 is 2-8 membered heteroalkylene or 4-8 membered heteroalkenylene that is connected to by an O, S or N atom and said heteroalkylene or heteroalkenylene is optionally substituted with 1-4 Z 3 groups;

L 6 is 2-8 membered heteroalkylene or 5-8 membered heteroalkenylene that is connected to by a carbon atom and said heteroalkylene or heteroalkenylene is substituted with 1-4 halogen atoms and is optionally substituted with 1-4 Z 4 groups;

L 7 is 2-8 membered heteroalkylene or 4-8 membered heteroalkenylene that is connected to by a carbon atom and said heteroalkylene or heteroalkenylene is optionally substituted with 1-4 Z 4 groups;

L 8 is L 8A -L 8B -L 8C wherein L 8A and L 8C are each independently selected from C 1 -C 6 alkylene, C 1 -C 6 heteroalkylene, C 2 -C 6 alkenylene or a bond and L 8B is a 3- to 6-membered saturated or unsaturated ring containing 0 to 3 heteroatoms selected from N, O, or S, wherein L 8A and L 8C connect to L 8B at two different ring atoms and L 8B is optionally substituted with 1-4 Z 1 groups;

L 9 is C 2 -C 8 alkynylene optionally substituted with 1-4 Z 1 groups;

L 10 is C 2 -C 8 alkylene or C 3 -C 8 alkenylene substituted with two geminal Z 1 groups that come together to form a spiro 4-8 membered heterocyclyl group, wherein L 10 is optionally substituted with 1-4 Z 1 groups;

U 1 is C 6 -C 14 membered arylene optionally substituted with 1-4 W groups;

U 2 is C 3 -C 8 membered carbocyclylene optionally substituted with 1-4 W groups;

U 3 is 4-14 membered heterocyclene optionally substituted with 1-4 W groups that are located on one or more ring atoms selected from C or N;

U 4 is 5 or 6 membered monocyclic heteroarylene containing 1, 2 or 3 heteroatoms independently selected from N, O, or S, wherein said heteroarylene is optionally substituted with 1-4 W groups that are located on one or more ring atoms selected from C or N;

U 5 is 8, 9 or 10 membered fused bicyclic heteroarylene containing 1, 2 or 3 heteroatom ring atoms independently selected from N, O, or S, wherein said heteroarylene is optionally substituted with 1-4 W groups that are located on one or more ring atoms selected from C or N;

U 6 is 11-14 membered fused tricyclic heteroarylene containing 1, 2, 3 or 4 heteroatom ring atoms independently selected from N, O, or S, wherein said heteroarylene is optionally substituted with 1-4 W groups that are located on one or more ring atoms selected from C or N;

U 7 is 8-10 membered fused bicyclic heteroarylene containing 4 heteroatom ring atoms independently selected from N, O, or S, wherein said heteroaryl is optionally substituted with 1-2 W groups that are located on one or more ring atoms selected from C or N;

W is independently W 1 , W 2 , W 3 , W 4 , W 5 , W 6 or W 7 ;

W 1 is oxo, halogen, —OR 6 , C 1 -C 6 alkyl, —CN, —CF 3 , —SR 6 , —C(O) 2 R 6 , —C(O)N(R 6 ) 2 , —C(O)R 6 , —N(R 6 )O(O)R 6 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), C 3 -C 8 carbocyclyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, —N(R 6 ) 2 , —NR 6 (C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), halo(C 1 -C 6 alkoxy), —NR 6 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCONHR 6 , C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl or —O(4-10 membered heterocyclyl), wherein said W 1 alkyl, carbocyclyl, cycloalkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1-4 Z 1c groups;

each R 6 is independently selected from H, C 6 -C 10 aryl or C 1 -C 6 alkyl, wherein said aryl or alkyl is optionally substituted with 1 to 4 substituents independently selected from halogen atoms, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 3 -C 8 carbocyclyl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, halo(C 1 -C 6 alkoxy), —OH, —O(C 1 -C 6 alkyl), —SH, —S(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —C(O)(C 1 -C 6 alkyl), —SO 2 N(C 1 -C 6 alkyl) 2 , —NHCOO(C 1 -C 6 alkyl), —NHCO(C 1 -C 6 alkyl), —NHCONH(C 1 -C 6 alkyl), —CO 2 (C 1 -C 6 alkyl), or —C(O)N(C 1 -C 6 alkyl) 2 ;

W 2 is C 1 -C 6 alkoxy substituted with a 5-14 membered heteroaryl or C 6 -C 10 aryl; wherein said heteroaryl or aryl is substituted with 1-4 Z 1 groups;

W 3 is C 2 -C 6 alkynyl substituted with an C 6 -C 10 aryl, C 3 -C 5 carbocyclyl, C 1 -C 5 alkyl, C 1 -C 6 haloalkyl, 4-10 membered heterocyclyl, or 5-14 membered heteroaryl; wherein said aryl, carbocyclyl, alkyl, haloalkyl, heterocyclyl, or heteroaryl is optionally substituted with 1-4 Z 1 groups;

W 4 is —SF 5 ;

W 5 is —O(C 2 -C 6 alkyl)OR 22 wherein R 22 is an C 6 -C 10 aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl, and wherein said aryl, heteroaryl or heterocyclyl is optionally substituted with 1-4 Z 1 groups;

W 6 is —O(C 2 -C 6 alkyl)NR 16 R 22 wherein R 22 is an C 6 -C 10 aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl, and wherein said aryl, heteroaryl or heterocyclyl is optionally substituted with 1-4 Z 1 groups;

W 7 is —O(5-14 membered heteroaryl); wherein said —O(5-14 membered heteroaryl) is optionally substituted with 1-4 Z 1 groups;

E 1 is C 2 -C 6 alkenyl;

E 2 is C 1 -C 6 alkyl;

E 3 is C 1 -C 6 haloalkyl;

E 4 is C 2 -C 6 haloalkenyl;

E 5 is C 3 -C 6 carbocyclyl;

E 6 is C 1 -C 6 alkyl substituted with —OCH 3 , —OCD 3 , —OCF 3 , or —OCF 2 H;

Q 1 is H, C 1 -C 8 alkyl, C 3 -C 8 carbocyclyl, C 6 -C 10 aryl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein when Q 1 is not H, said Q 1 is optionally substituted with 1-3 substituents independently selected from halogen, —OR 6 , —SR 6 , —N(R 6 ) 2 , C 6 -C 10 aryl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 6 SO 2 Z 2 , —SO 2 NR 17 R 18 , —NHCOOR 16 , —NHCOZ 2 , —NHCONHR 16 , —CO 2 R 6 , —C(O)R 6 , or —CON(R 6 ) 2 ;

Q 2 is C 5 -C 10 spiro bicyclic carbocyclyl optionally substituted with 1-4 Z 1 groups;

Q 3 is C 5 -C 10 fused bicyclic carbocyclyl optionally substituted with 1-4 Z 1 groups;

Q 4 is C 5 -C 10 bridged bicyclic carbocyclyl optionally substituted with 1-4 Z 1 groups;

Q 5 is 4-membered heterocyclyl having 1 heteroatom selected from N, O or S wherein Q 5 is optionally substituted with alkyl or 1-4 Z 3 groups;

Q 6 is C 1 -C 8 alkyl, C 3 -C 8 carbocyclyl, C 6 -C 10 aryl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein Q 6 is substituted with 1 oxo group and with 0 to 3 substituents independently selected from halogen, —OR 6 , —SR 6 , —N(R 6 ) 2 , C 6 -C 10 aryl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 6 SO 2 Z 2 , —SO 2 NR 17 R 18 , —NHCOOR 16 , —NHCOZ 2 , —NHCONHR 16 , —CO 2 R 6 , —C(O)R 6 , or —CON(R 6 ) 2 ;

Q 7 is C 3 -C 8 carbocyclyl, wherein Q 7 is substituted with 4-8 F atoms and each carbon of Q 7 is substituted with 0-2 F atoms;

each Z 1 is independently oxo, halogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 1 -C 8 haloalkyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, —CN, —C(O)R 16 , —C(O)OR 16 , —C(O)NR 17 R 18 , —NR 17 R 18 , —NR 16 C(O)R 16 , —NR 16 C(O)NR 17 R 18 , —NR 16 S(O) 2 R 16 , —NR 16 S(O) 2 NR 17 R 18 , —NR 16 S(O) 2 OR 16 , —OR 16 , —OC(O)R 16 , —OC(O)NR 17 R 18 , —SR 16 , —S(O)R 16 , —S(O) 2 R 16 or —S(O) 2 NR 17 R 18 wherein any alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl of Z 1 is optionally substituted with 1-4 Z 1a groups;

each Z 1a is independently oxo, halogen, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 1 -C 8 haloalkyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, —CN, —C(O)R 16 , —C(O)OR 16 , —C(O)NR 17 R 18 , —NR 17 R 18 , —NR 16 C(O)R 16 , —NR 16 C(O)OR 16 , —NR 16 C(O)NR 17 R 18 , —NR 16 S(O) 2 R 16 , —NR 16 S(O) 2 NR 17 R 18 , —NR 16 S(O) 2 OR 16 , —OR 16 , —OC(O)R 16 , —OC(O)NR 17 R 18 , —SR 16 , —S(O)R 16 , —S(O) 2 R 16 or —S(O) 2 NR 17 R 18 wherein any alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl of Z 1a is optionally substituted with 1-4 Z 1c groups;

each R 16 is independently H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 6 -C 10 aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl, wherein any alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl of R 16 is optionally substituted with 1-4 Z 1c groups;

each Z 1c is independently oxo, halogen, C 1 -C 8 alkyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 1 -C 8 haloalkyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, —CN, —C(O)(C 1 -C 8 alkyl), —C(O)O(C 1 -C 8 alkyl), —C(O)N(C 1 -C 8 alkyl) 2 , —NH 2 , —NH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl) 2 , —NHC(O)O(C 1 -C 8 alkyl), —NHC(O)(C 1 -C 8 alkyl), —NHC(O)NH(C 1 -C 8 alkyl), —OH, —O(C 1 -C 8 alkyl), C 3 -C 8 cycloalkoxy, C 5 -C 10 bicyclic carbocyclyloxy, —S(C 1 -C 8 alkyl) or —S(O) 2 N(C 1 -C 8 alkyl) 2 wherein any alkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl or cycloalkoxy portion of Z 1c is optionally substituted with 1-4 halogen atoms or C 1 -C 6 alkoxy groups;

R 17 and R 18 are each independently H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, —C(O)R 16 , —O(O)OR 16 , C 6 -C 10 aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl, wherein any alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl of R 17 or R 18 is optionally substituted with 1-4 Z 1c groups, or R 17 and R 18 together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl group, wherein said 4-7 membered heterocyclyl group is optionally substituted with 1-4 Z 1c groups;

each Z 2 is independently C 1 -C 8 alkyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, —NR 17 R 18 or —OR 16 wherein any alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl portion of Z 2 is optionally substituted with 1-4 Z 2a groups;

each Z 2a is independently oxo, halogen, C 1 -C 8 alkyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 1 -C 8 haloalkyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, —(C 2 -C 8 alkynyl)aryl, —(C 2 -C 8 alkynyl)heteroaryl, —CN, —C(O)(C 1 -C 6 alkyl), —C(O)O(C 1 -C 6 alkyl), —O(O)N(C 1 -C 6 alkyl) 2 , —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)O(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)NH(C 1 -C 6 alkyl), —OH, —O(C 1 -C 6 alkyl), halo(C 1 -C 6 alkoxy), C 3 -C 8 cycloalkoxy, —S(C 1 -C 6 alkyl), or —SO 2 N(C 1 -C 6 alkyl) 2 ; wherein any alkyl, alkynyl, carbocyclyl, cycloalkoxy, aryl, heteroaryl or heterocyclyl portions of Z 2a is optionally substituted with 1-4 halogen or C 1 -C 6 alkoxy groups;

each Z 3 is independently oxo, halogen, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 1 -C 8 haloalkyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, —CN, —O(O)OR 16 , —O(O)NR 17 R 18 , —NR 17 R 18 , —NR 16 C(O)NR 17 R 18 , —OR 16 , —SR 16 or —SO 2 R 16 ; wherein any alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl portions of Z 3 is optionally substituted with 1-4 halogen; and

each Z 4 is independently oxo, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 1 -C 8 haloalkyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, —CN, —C(O)OR 16 , —C(O)NR 17 R 18 , —NR 17 R 18 , —NR 16 C(O)NR 17 R 18 , —OR 16 , —SR 16 or —SO 2 R 16 , wherein any alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl portions of Z 4 is optionally substituted with 1-4 halogen.

30 . The compound of claim 29 , or a stereoisomer, or a mixture of stereoisomers, a pharmaceutically acceptable salt thereof, wherein A is —C(O)—, 6-10 membered arylene, or 5-6 membered heteroarylene, wherein said arylene or heteroarylene is optionally substituted with 1-4 halogens or haloalkyl groups.

31 . The compound of claim 29 or 30 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein M is —O— or a bond.

32 . The compound of any one of claims 29 - 31 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein G is —CO 2 H or —CONHSO 2 Z 2 .

33 . The compound of any one of claims 29 - 32 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein one of R 3 , R 4 , and R 5 is Z 1 and the other two are H.

34 . The compound of any one of claims 29 - 32 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 and R 5 are each H.

35 . The compound of any one of claims 29 - 34 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein X is —OC(O)—, —O—, or a direct bond.

36 . The compound of any one of claims 29 - 35 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein G is:

37 . A compound of Formula (II):

or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:

M is —O—;

J is J 1 , J 2 , J 3 , J 4 , J 5 , J 6 , J 7 , J 8 or J 9 ;

is T 1 , T 2 , T 3 , T 4 , T 5 , T 7 , T 8 , T 9 , T 10 , T 11 , T 12 , T 13 or T 14 ;

L is L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 or L 10 ;

R 1 is H or F;

Q is Q 1 ; Q 2 , Q 3 , Q 4 , Q 5 , Q 6 or Q 7 ;

E is E 1 , E 2 , E 3 , E 4 , E 5 , or E 6 ;

is U 1 , U 2 , U 3 , U 4 , U 5 , U 6 or U 7 ;

J 1 is halogen;

J 2 is —OH and R 1 is H;

J 3 is —NR 17 R 18 and R 1 is H;

J 4 is C 1 -C 8 alkyl;

J 5 is C 1 -C 8 alkyl optionally substituted with 1-4 Z 3 groups;

J 6 is C 3 -C 8 carbocyclyl optionally substituted with 1-4 Z 3 groups;

J 7 is C 6 -C 10 aryl, 5-14 membered heteroaryl, or 4-10 membered heterocyclyl, any of which are optionally substituted with 1-4 Z 3 groups;

J 8 is C 1 -C 8 alkoxy optionally substituted with 1-4 Z 3 groups and R 1 is H;

J 9 is C 3 -C 8 carbocyclyloxy optionally substituted with 1-4 Z 3 groups and R′ is H;

T 1 is C 3 -C 8 carbocyclylene that is attached to L and M through two adjacent carbons;

T 2 is C 3 -C 8 carbocyclylene that is attached to L and M through two adjacent carbons, wherein said carbocyclylene is optionally substituted with 1-4 C 1 -C 8 alkyl groups;

T 3 is C 3 -C 8 carbocyclylene that is attached to L and M through two adjacent carbons, wherein said carbocyclylene is optionally substituted with 1-4 halogen atoms and said carbocyclylene is optionally substituted with 1-4 C 1 -C 6 alkyl groups;

T 4 is C 3 -C 8 carbocyclylene that is attached to L and M through two adjacent carbons, wherein said carbocyclylene is optionally substituted with a C 1 -C 8 alkyl group, wherein said alkyl group is optionally substituted with 1-4 Z 3 groups;

T 5 is 4-10 membered heterocyclene that is attached to L and M through two adjacent carbons;

T 7 is 4-10 membered heterocyclene that is attached to M through a carbon atom and attached to L through a N atom, wherein said heterocyclene is optionally substituted with 1-4 Z 1 groups;

T 8 is 4-10 membered heterocyclene that is attached to L and M through two adjacent carbons, wherein said heterocyclene is optionally substituted with 1-4 Z 1 groups;

T 9 is C 5 -C 12 spiro bicyclic carbocyclylene that is attached to L and M through two adjacent carbons, wherein said spiro bicyclic carbocyclylene is optionally substituted with 1-4 Z 1 groups;

T 10 is C 5 -C 12 fused bicyclic carbocyclylene that is attached to L and M through two adjacent carbons, wherein said fused bicyclic carbocyclylene is optionally substituted with 1-4 Z 1 groups;

T 11 is C 5 -C 12 bridged bicyclic carbocyclylene that is attached to L and M through two adjacent carbons, wherein said bridged bicyclic carbocyclylene is optionally substituted with 1-4 Z 1 groups;

T 12 is C 4 -C 8 carbocyclylene that is attached to L and M through two non-adjacent carbons, wherein said carbocyclylene is optionally substituted with 1-4 Z 1 groups;

T 14 is C 3 -C 8 carbocyclylene that is attached to L and M through two adjacent carbons, wherein said carbocyclylene is optionally substituted with 1-4 Z 4 groups;

L 1 is C 1 -C 8 alkylene or C 2 -C 8 alkenylene;

L 2 is C 1 -C 8 alkylene or C 2 -C 8 alkenylene wherein said C 1 -C 8 alkylene is substituted with 1-4 halogens or said C 2 -C 8 alkenylene is substituted with 1-4 halogens;

L 7 is 2-8 membered heteroalkylene or 4-8 membered heteroalkenylene that is connected to by a carbon atom and said heteroalkylene or heteroalkenylene is optionally substituted with 1-4 Z 4 groups;

L 8 is L 8A -L 8B -L 8C wherein L 8A and L 8C are each independently selected from C 1 -C 6 alkylene, C 1 -C 6 heteroalkylene, C 2 -C 6 alkenylene or a bond and L 8B is a 3- to 6-membered saturated or unsaturated ring containing 0 to 3 heteroatoms selected from N, O, or S, wherein L 8A and L 8c connect to L 8B at two different ring atoms and L 8B is optionally substituted with 1-4 Z 1 groups;

L 9 is C 2 -C 8 alkynylene optionally substituted with 1-4 Z 1 groups;

L 10 is C 1 -C 8 alkylene or C 3 -C 8 alkenylene substituted with two geminal Z 1 groups that come together to form a spiro 4-8 membered heterocyclyl group, wherein L 10 is optionally substituted with 1-4 Z 1 groups;

U 1 is C 6 -C 14 membered arylene optionally substituted with 1-4 W groups;

each U 2 is C 3 -C 8 membered carbocyclylene optionally substituted 1-4 W groups;

each U 3 is 4-14 membered heterocyclene optionally substituted with 1-4 W groups that are located on one or more ring atoms selected from C or N;

each W is independently W 1 , W 2 , W 3 , W 4 , W 5 , W 6 or W 7 ;

each W 1 is oxo, halogen, —OR 6 , C 1 -C 6 alkyl, —CN, —CF 3 , —SR 6 , —C(O) 2 R 6 , —C(O)N(R 6 ) 2 , —C(O)R 6 , —N(R 6 )C(O)R 6 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), C 3 -C 8 carbocyclyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, —N(R 6 ) 2 , —NR 6 (C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), halo(C 1 -C 6 alkoxy), —NR 6 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCONHR 6 , C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl or —O(4-10 membered heterocyclyl), wherein said W 1 alkyl, carbocyclyl, cycloalkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1-4 Z 1c groups;

each W 2 is C 1 -C 6 alkoxy substituted with a 5-14 membered heteroaryl or C 6 -C 10 aryl; wherein said heteroaryl or aryl is substituted with 1-4 Z 1c groups;

each W 3 is C 2 -C 6 alkynyl substituted with an C 6 -C 10 aryl, C 3 -C 8 carbocyclyl, C 1 -C 8 alkyl, C 1 -C 6 haloalkyl, 4-10 membered heterocyclyl, or 5-14 membered heteroaryl; wherein said aryl, carbocyclyl, alkyl, haloalkyl, heterocyclyl, or heteroaryl is optionally substituted with 1-4 Z 1 groups;

each W 4 is —SF 5 ;

each W 5 is —O(C 2 -C 6 alkyl)OR 22 wherein R 22 is an C 6 -C 10 aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl optionally substituted with 1-4 Z 1 groups;

each W 6 is —O(C 2 -C 6 alkyl)NR 16 R 22 wherein R 22 is an C 6 -C 10 aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl optionally substituted with 1-4 Z 1 groups;

each W 7 is —O(5-14 membered heteroaryl); wherein said —O(5-14 membered heteroaryl) is optionally substituted with 1-4 Z 1 groups and 2 adjacent substituents of said —O(5-14 membered heteroaryl) may be taken together to form a 3- to 6-membered cyclic ring containing 0 to 3 heteroatoms independently selected from N, O, or S;

E 1 is C 2 -C 6 alkenyl;

E 2 is C 1 -C 6 alkyl;

E 3 is C 1 -C 6 haloalkyl;

E 4 is C 2 -C 6 haloalkenyl;

E 5 is C 3 -C 6 carbocyclyl;

E 6 is C 1 -C 6 alkyl optionally substituted with —OCH 3 , —OCD 3 , —OCF 3 , or —OCF 2 H;

Q 1 is selected from H, C 1 -C 8 alkyl, C 3 -C 8 carbocyclyl, C 6 -C 10 aryl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl groups, wherein when Q 1 is not H, said Q 1 is optionally substituted with 1-4 substituents independently selected from halogen, —OR 6 , —SR 6 , —N(R 6 ) 2 , C 6 -C 10 aryl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 6 SO 2 Z 2 , —SO 2 NR 17 R 18 , —NHCOOR 16 , —NHCOZ 2 , —NHCONHR 16 , —CO 2 R 6 , —C(O)R 6 , and —CON(R 6 ) 2 ;

Q 2 is C 5 -C 10 spiro bicyclic carbocyclyl optionally substituted with 1-4 Z 1 groups;

Q 3 is C 5 -C 10 fused bicyclic carbocyclyl optionally substituted with 1-4 Z 1 groups;

Q 4 is C 5 -C 10 bridged bicyclic carbocyclyl optionally substituted with 1-4 Z 1 groups;

Q 5 is 4-membered heterocyclyl having 1 heteroatom selected from N, O or S wherein Q 5 is optionally substituted with 1-4 Z 3 groups;

Q 7 is C 3 -C 8 carbocyclyl, wherein Q 7 is substituted with 4-8 F atoms and each carbon of Q 7 is substituted with 0-2 F atoms;

each Z 1a is independently oxo, halogen, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 1 -C 8 haloalkyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, —CN, —C(O)R 16 , —C(O)OR 16 , —C(O)NR 17 R 18 , —NR 17 R 18 , —NR 16 C(O)R 16 , —NR 16 C(O)OR 16 , —NR 16 C(O)NR 17 R 18 , —NR 16 S(O) 2 R 16 , —NR 16 S(O) 2 NR 17 R 18 , —NR 16 S(O) 2 OR 16 , —OR 16 , —OC(O)R 16 , —OC(O)NR17R 18 , —SR 16 , —S(O)R 16 , —S(O) 2 R 16 or —S(O) 2 NR 17 R 18 wherein any alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl of Z 1a is optionally substituted with 1-4 Z 1c groups;

each Z 3 is independently oxo, halogen, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 1 -C 8 haloalkyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, —CN, —O(O)OR 16 , —C(O)NR 17 R 18 , —NR 17 R 18 , —NR 16 C(O)NR 17 R 18 , —OR 16 , —SR 16 or —SO 2 R 16 ; wherein any alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl portions of Z 3 is optionally substituted with 1-4 halogen; and

each Z 4 is independently oxo, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 1 -C 8 haloalkyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, —CN, —C(O)OR 16 , —C(O)NR 17 R 18 , —NR 17 R 18 , NR 16 C(O)NR 17 R 18 , —OR 16 , —SR 16 or —SO 2 R 16 , wherein any alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl portions of Z 4 is optionally substituted with 1-4 halogen.

38 . The compound of claim 37 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein Z 2 is:

39 . The compound of claim 37 or 38 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein E is E 1 , E 2 , E 3 , or E 4 .

40 . The compound of any one of claims 37 to 39 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein is T 1 , T 2 , T 3 , T 4 , T 9 , T 10 , T 11 or T 14 .

41 . The compound of any one of claims 37 to 40 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein L is L 1 , L 2 , L 3 , L 4 , L 5 or L 6 .

42 . A compound of Formula (III):

or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:

M is —O—;

J is J 1 , J 2 , J 3 , J 4 , J 5 , J 6 , J 7 , J 8 or J 9 ;

is T 1 , T 2 , T 3 , T 4 , T 5 , T 7 , T 8 , T 9 , T 10 , T 11 , T 12 , T 13 or T 14 ;

L is L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 or L 10 ;

Q is Q 1 , Q 2 , Q 3 , Q 4 , Q 5 or Q 7 ;

E is E 1 , E 2 , E 3 , or E 4 ;

is selected from U 1 , U 3 , U 4 , U 5 , U 6 or U 7 ;

J 1 is halogen;

J 2 is —OH;

J 3 is —NR 17 R 18 ;

J 4 is C 1 -C 8 alkyl;

J 5 is C 1 -C 8 alkyl substituted with 1-4 Z 3 groups;

J 6 is C 3 -C 8 carbocyclyl optionally substituted with 1-4 Z 3 groups;

J 7 is C 6 -C 10 aryl, 5-14 membered heteroaryl, or 4-10 membered heterocyclyl any of which groups are optionally substituted with 1-4 Z 3 groups;

J 8 is C 1 -C 8 alkoxy optionally substituted with 1-4 Z 3 groups;

J 9 is C 3 -C 8 carbocyclyloxy optionally substituted with 1-4 Z 3 groups;

T 1 is C 3 -C 8 carbocyclylene attached to L and M through two adjacent carbons;

T 2 is C 3 -C 8 carbocyclylene attached to L and M through two adjacent carbons, wherein said carbocyclylene is substituted with 1-4 C 1 -C 8 alkyl groups;

T 3 is C 3 -C 8 carbocyclylene attached to L and M through two adjacent carbons, wherein said carbocyclylene is substituted with 1-4 halogen atoms and said carbocyclylene is optionally substituted with 1-4 C 1 -C 6 alkyl groups;

T 4 is C 3 -C 8 carbocyclylene that is attached to L and M through two adjacent carbons, wherein said carbocyclylene is substituted with a C 1 -C 8 alkyl group, wherein said alkyl group is substituted with 1-4 Z 3 groups;

T 5 is 4-10 membered heterocyclene that is attached to L and M through two adjacent carbons;

T 7 is 4-10 membered heterocyclene that is attached to M through a carbon atom and attached to L through a N atom, wherein said heterocyclene is optionally substituted with 1-4 Z 1 groups;

T 5 is 4-10 membered heterocyclene that is attached to L and M through two adjacent carbons, wherein said heterocyclene is substituted with 1-4 Z 1 groups;

T 9 is C 5 -C 12 spiro bicyclic carbocyclylene that is attached to L and M through two adjacent carbons, wherein said spiro bicyclic carbocyclylene is optionally substituted with 1-4 Z 1 groups;

T 10 is C 5 -C 12 fused bicyclic carbocyclylene that is attached to L and M through two adjacent carbons, wherein said fused bicyclic carbocyclylene is optionally substituted with 1-4 Z 1 groups;

T 11 is C 5 -C 12 bridged bicyclic carbocyclylene that is attached to L and M through two adjacent carbons, wherein said bridged bicyclic carbocyclylene is optionally substituted with 1-4 Z 1 groups;

T 12 is C 4 -C 8 carbocyclylene that is attached to L and M through two non-adjacent carbons, wherein said carbocyclylene is optionally substituted with 1-4 Z 1 groups;

T 14 is C 3 -C 8 carbocyclylene that is attached to L and M through two adjacent carbons, wherein said carbocyclylene is substituted with 1-4 Z 4 groups;

L 1 is C 1 -C 8 alkylene or C 2 -C 8 alkenylene;

L 2 is C 1 -C 8 alkylene or C 2 -C 8 alkenylene wherein said C 1 -C 8 alkylene or said C 2 -C 8 alkenylene is substituted with 1-4 halogens;

L 3 is C 1 -C 8 alkylene or C 2 -C 8 alkenylene wherein said C 1 -C 8 alkylene or said C 2 -C 8 alkenylene and wherein said C 1 -C 8 alkylene or said C 2 -C 8 alkenylene is optionally substituted with 1-4 halogens;

L 7 is 2-8 membered heteroalkylene or 4-8 membered heteroalkenylene that is connected to by a carbon atom and said heteroalkylene or heteroalkenylene is optionally substituted with 1-4 Z 4 groups;

L 8 is L 8A -L 8B -L 8C wherein L 8A and L 8C are each independently C 1 -C 6 alkylene, C 1 -C 6 heteroalkylene, C 2 -C 6 alkenylene or a bond and L 8B is a 3- to 6-membered saturated or unsaturated ring containing 0 to 3 heteroatoms selected from N, O, or S, wherein L 8A and L 8C connect to L 8B at two different ring atoms and L 8B is optionally substituted with 1-4 Z 1 groups;

L 9 is C 2 -C 8 alkynylene optionally substituted with 1-4 Z 1 groups;

U 1 is a C 6 -C 14 membered arylene optionally substituted with 1-4 W groups;

U 3 is a 4-14 membered heterocyclene optionally substituted with 1-4 W groups that are located on one or more ring atoms selected from C or N;

U 4 is a 5 or 6 membered monocyclic heteroarylene containing 1, 2 or 3 heteroatoms independently selected from N, O, or S, wherein said heteroarylene is optionally substituted with 1-4 W groups that are located on one or more ring atoms selected from C or N;

U 5 is a 8, 9 or 10 membered fused bicyclic heteroarylene containing 1, 2 or 3 heteroatom ring atoms independently selected from N, O, or S, wherein said heteroarylene is optionally substituted with 1-4 W groups that are located on one or more ring atoms selected from C or N;

U 6 is a 11-14 membered fused tricyclic heteroarylene containing 1, 2, 3 or 4 heteroatom ring atoms independently selected from N, O, or S, wherein said heteroarylene is optionally substituted with 1-4 W groups that are located on one or more ring atoms selected from C or N;

U 7 is a 8-10 membered fused bicyclic heteroarylene containing 4 heteroatom ring atoms independently selected from N, O, or S, wherein said heteroaryl is optionally substituted with 1-2 W groups that are located on one or more ring atoms selected from C or N;

each W is independently W 1 , W 2 , W 3 , W 4 , W 5 , W 6 or W 7 ;

each W 1 is independently oxo, halogen, —OR 6 , C 1 -C 6 alkyl, —CN, —CF 3 , —SR 6 , —C(O) 2 R 6 , —C(O)N(R 6 ) 2 , —C(O)R 6 , —N(R 6 )C(O)R 6 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), C 3 -C 8 carbocyclyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, —N(R 6 ) 2 , —NR 6 (C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), halo(C 1 -C 6 alkoxy), —NR 6 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCONHR 6 , C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl or —O(4-10 membered heterocyclyl), wherein said W 1 alkyl, carbocyclyl, cycloalkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1-4 Z 1c groups;

each R 6 is independently H, C 6 -C 10 aryl or C 1 -C 6 alkyl, wherein said aryl or alkyl is optionally substituted with 1 to 4 substituents independently selected from halogen atoms, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 3 -C 8 carbocyclyl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, halo(C 1 -C 6 alkoxy), —OH, —O(C 1 -C 6 alkyl), —SH, —S(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —C(O)(C 1 -C 6 alkyl), —SO 2 N(C 1 -C 6 alkyl) 2 , —NHCOO(C 1 -C 6 alkyl), —NHCO(C 1 -C 6 alkyl), —NHCONH(C 1 -C 6 alkyl), —CO 2 (C 1 -C 6 alkyl), or —C(O)N(C 1 -C 6 alkyl) 2 ;

each W 2 is C 1 -C 6 alkoxy substituted with a 5-14 membered heteroaryl or C 6 -C 10 aryl; wherein said heteroaryl or aryl is substituted with 1-4 Z 1 groups;

each W 3 is C 2 -C 6 alkynyl group substituted with a C 6 -C 10 aryl, C 3 -C 8 carbocyclyl, C 1 -C 8 alkyl, C 1 -C 6 haloalkyl, 4-10 membered heterocyclyl, or 5-14 membered heteroaryl group; wherein said aryl, carbocyclyl, alkyl, haloalkyl, heterocyclyl, or heteroaryl group is optionally substituted with 1-4 Z 1 groups;

each W 4 is —SF 5 ;

each W 5 is —O(C 2 -C 6 alkyl)OR 22 wherein R 22 is a C 6 -C 10 aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl group optionally substituted with 1-4 Z 1 groups;

each W 6 is —O(C 2 -C 6 alkyl)NR 16 R 22 wherein R 22 is an aryl, heteroaryl or heterocyclyl group optionally substituted with 1-4 Z 1 groups;

E 1 is

E 2 is

E 3 is

E 4 is

Q 1 is H, C 1 -C 8 alkyl, C 3 -C 8 carbocyclyl, C 6 -C 10 aryl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl groups, wherein when Q 1 is not H, said Q 1 is optionally substituted with 1-4 substituents independently selected from halogen, —OR 6 , —SR 6 , —N(R 6 ) 2 , C 6 -C 10 aryl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 6 SO 2 Z 2 , —SO 2 NR 17 R 18 , —NHCOOR 16 , —NHCOZ 2 , —NHCONHR 16 , —CO 2 R 6 , —C(O)R 6 or —CON(R 6 ) 2 ;

Q 2 is C 5 -C 10 spiro bicyclic carbocyclyl optionally substituted with 1-4 Z 1 groups;

Q 3 is C 5 -C 10 fused bicyclic carbocyclyl optionally substituted with 1-4 Z 1 groups;

Q 4 is C 5 -C 10 bridged bicyclic carbocyclyl optionally substituted with 1-4 Z 1 groups;

Q 5 is 4-membered heterocyclyl having 1 heteroatom selected from N, O or S wherein Q 5 is optionally substituted with 1-4 Z 3 groups;

Q 7 is C 3 -C 8 carbocyclyl substituted with 4-8 F atoms and each carbon of Q 7 is substituted with 0-2 F atoms;

—NR 16 C(O)R 16 , —NR 16 C(O)OR 16 , —NR 16 C(O)NR 17 R 18 , —NR 16 S(O) 2 R 16 , —NR 16 S(O) 2 NR 17 R 18 , —NR 16 S(O) 2 OR 16 , —OR 16 , —OC(O)R 16 , —OC(O)NR 17 R 18 , —SR 16 , —S(O)R 16 , —S(O) 2 R 16 or —S(O) 2 NR 17 R 18 wherein any alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl of Z 1a is optionally substituted with 1-4 Z 1c groups;

each Z 3 is independently oxo, halogen, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 1 -C 8 haloalkyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, —CN, —C(O)OR 16 , —C(O)NR 17 R 18 , —NR 17 R 18 , —NR 16 C(O)NR 17 R 18 , —OR 16 , —SR 16 or —SO 2 R 16 ; wherein any alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl portions of Z 3 is optionally substituted with 1-4 halogen; and

each Z 4 is independently oxo, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 1 -C 8 haloalkyl, C 8 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, —CN, —C(O)OR 16 , —C(O)NR 17 R 18 , NR 17 R 18 , NR 16 C(O)NR 17 R 18 , —OR 16 , —SR 16 or —SO 2 R 16 , wherein any alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl portions of Z 4 is optionally substituted with 1-4 halogen.

43 . The compound of claim 42 or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein J is J 1 , J 4 , J 5 or J 8 .

44 . The compound of claim 42 or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein J is J 4 .

45 . The compound of claim 42 or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein J is J 4 , and wherein J 4 is

46 . The compound of claim 42 or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein J is J 4 , and wherein J 4 is

47 . The compound of claim 42 or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein J is J 4 , and wherein J 4 is

48 . The compound of claim 42 or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein J is J 5 .

49 . The compound of claim 42 or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein J is J 5 , and wherein J 5 is

50 . The compound of any one of claims 42 - 49 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein

is T 1 , T 2 , T 3 , T 4 , T 5 , T 8 , T 9 , T 10 , T 11 , or T 12 ; and

T 1 is

T 2 is

T 3 is

T 4 is

T 5 is

T 9 is

T 10 is

T11 is

and

T12 is

51 . The compound of any one of claims 42 - 49 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein is

52 . The compound of any one of claims 42 to 49 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein is

53 . The compound of any one of claims 42 to 49 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein is

54 . The compound of any one of claims 42 to 49 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein is

55 . The compound of any one of claims 42 to 49 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein is

56 . The compound of any one of claims 42 to 55 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein: L is L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 or L 9 ; and wherein

L 1 is

L 2 is

L 3 is

L 4 is

L 5 is

L 6 is

L 7 is

L 8 is

L 9 is

57 . The compound of any one of claims 42 to 55 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein L is

58 . The compound of any one of claims 42 to 55 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein L is

59 . The compound of any one of claims 42 to 55 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein L is

60 . The compound of any one of claims 42 to 55 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein L is

61 . The compound of any one of claims 42 to 60 or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein Z 2a is

62 . The compound of any one of claims 42 to 60 or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein Z 2a is

63 . The compound of any one of claims 42 to 60 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein Z 2a is

64 . The compound of any one of claims 42 to 63 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein is U 1 , U 3 , U 4 , U 5 or U 6 , wherein each U 1 , U 3 , U 4 , U 5 or U 6 is optionally substituted with 1-3 W at any substitutable position, and each W is independently W 1 , W 2 , W 3 , W 4 , W 5 , W 6 or W 7 wherein

each W 1 is independently oxo, halogen, —OR 6 , C 1 -C 6 alkyl, —CN, —CF 3 , —SR 6 , —C(O) 2 R 6 , —C(O)N(R 6 ) 2 , —C(O)R 6 , —N(R 6 )O(O)R 6 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), C 3 -C 8 carbocyclyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, —N(R 6 ) 2 , —NR 6 (C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), halo(C 1 -C 6 alkoxy), —NR 6 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCONHR 6 , C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl or —O(4-10 membered heterocyclyl), wherein said W 1 alkyl, carbocyclyl, cycloalkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1-4 Z 1c groups;

each W 2 is C 1 -C 6 alkoxy substituted with a 5-14 membered heteroaryl or C 6 -C 10 aryl; wherein said heteroaryl or aryl is substituted with 1-4 Z 1c groups;

each W 3 is C 2 -C 8 alkynyl substituted with C 6 -C 10 aryl, C 3 -C 8 carbocyclyl, C 1 -C 8 alkyl, C 1 -C 6 haloalkyl, 4-10 membered heterocyclyl, or 5-14 membered heteroaryl; wherein said aryl, carbocyclyl, alkyl, haloalkyl, heterocyclyl, or heteroaryl is optionally substituted with 1-4 Z 1c groups;

each W 4 is —SF 5 ;

each W 5 is —O(C 2 -C 6 alkyl)OR 22 wherein R 22 is a C 6 -C 10 aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl group, and wherein R 22 is optionally substituted with 1-4 Z 1c groups;

U 1 is

wherein U 1 is optionally substituted with 1-2 Z 1 groups;

U 3 is

wherein U 3 is optionally substituted with 1-2 Z 1 groups;

U 4 is

wherein U 4 is optionally substituted with 1-2 Z 1 groups;

U 5 is

wherein U 5 is optionally substituted with 1-2 Z 1 groups;

U 6 is

wherein U 6 is optionally substituted with 1-2 Z 1 groups; and

U 7 is

wherein U 7 is optionally substituted with 1-2 Z 1 groups.

65 . The compound of any one of claims 42 to 63 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein is optionally substituted with one or two W at any substitutable position, and each W is independently W 1 , W 2 , W 3 , W 4 , W 5 , W 6 or W 7 wherein is

66 . The compound of any one of claims 42 to 63 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein is optionally substituted with one W at any substitutable position, and each W is independently W 1 , W 2 , W 3 , W 4 , W 5 , W 6 , or W 7 wherein is

67 . The compound of any one of claims 42 to 66 or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein each W is independently W 1 , W 2 , W 3 , W 4 , W 5 , W 6 , or W 7 , and wherein

W 1 is

W 2 is

W 3 is

W 5 is

W 6 is

and W 7 is

68 . The compound of any one of claims 40 to 66 , or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein W is

69 . The compound of any one of claims 42 to 68 , or a stereoisomer, or a mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein Q is Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , or Q 7 ; and wherein

Q 1 is

Q 2 is

Q 3 is

Q4 is

Q 5 is

and

Q 7 is

70 . The compound of any one of claims 42 to 68 , or a stereoisomer, or a mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein Q is

71 . The compound of any one of claims 42 to 68 , or a stereoisomer, or a mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein Q is

72 . The compound of any one of claims 42 to 71 , or a stereoisomer, or a mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein E is

73 . The compound of any one of claims 42 to 71 , or a stereoisomer, or a mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein E is

74 . The compound of any one of claims 42 to 71 , or a stereoisomer, or a mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein E is

75 . The compound of any one of claims 42 to 71 , or a stereoisomer, or a mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein E is

76 . A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

77 . A pharmaceutical composition comprising a compound of any one of claims 1 - 76 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

78 . A method of treating hepatitis C virus infection in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 76 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 77 or 78 .

79 . A compound of any one of claims 1 to 76 , or a pharmaceutically acceptable salt thereof for use in medical therapy.

80 . The pharmaceutical composition according to claim 77 for use in treating hepatitis C virus infection.

81 . A compound of any one of claims 1 to 76 or a pharmaceutically acceptable salt thereof, for the prophylactic or therapeutic treatment of a hepatitis C virus infection.

82 . The use of a compound as described in any one of claims 1 to 76 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a hepatitis C virus infection in a mammal.

83 . A pharmaceutical composition comprising a compound of any one of claims 1 - 76 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, further comprising at least one additional therapeutic agent.

84 . The pharmaceutical composition of claim 83 , wherein said additional therapeutic agent is an interferon, a ribavirin analog, an NS5a inhibitor, an NS4b inhibitor, an NS3 protease inhibitor, an NS5b inhibitor, an alpha-glucosidase 1 inhibitor, an hepatoprotectant, a non-nucleoside inhibitor of HCV, or other drug for treating hepatitis C virus infection.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 22, 2019

From: GILEAD SCIENCES, INC.

To: GILEAD PHARMASSET LLC

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