HCV protease inhibitors and uses thereof

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 and R 1′ are independently hydrogen or optionally substituted C 1-6 aliphatic, or R 1 and R 1′ are taken together to form an optionally substituted 3-7 membered carbocyclic ring;

R 2a is —OH or —NHSO 2 R 2 ;

R 2 is —N(R) 2 or an optionally substituted group selected from C 3-7 cycloalkyl, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R is independently hydrogen, optionally substituted C 1-6 aliphatic, or:

two R on the same nitrogen atom are taken together with the nitrogen to form a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 3 is a warhead -L-Y, wherein:

L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—;

Y is hydrogen, C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R e groups; and

each R e is independently selected from -Q-Z, oxo, NO 2 , halogen, CN, a suitable leaving group selected from alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, diazonium, or C 1-6 aliphatic substituted with oxo, halogen, NO 2 , or CN, wherein:

Q is a bivalent C 1-6 unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO 2 —, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, or —SO 2 N(R)—; and

Z is hydrogen or C 1-6 aliphatic substituted with oxo, halogen, NO 2 , or CN;

or R 3 and R 1 are taken together with their intervening atoms to form an optionally substituted saturated or unsaturated 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen oxygen, or sulfur, wherein the ring formed thereby comprises a warhead group -L-Y; or

R 3 and a ring formed by R 1 and R 1 ′ are taken together with their intervening atoms to form an optionally substituted saturated or unsaturated 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen oxygen, or sulfur, wherein the ring formed thereby comprises a warhead group -L-Y;

R 4 is H, —NHC(O)R 5 , —NHC(O)OR 6 ,

or a natural or unnatural amino acid side-chain group;

each R 5 is independently —N(R) 2 or an optionally substituted group selected from C 1-6 aliphatic, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 6 is an optionally substituted group selected from C 1-6 aliphatic, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

R 7 is an optionally substituted group selected from C 1-6 aliphatic, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

R z is

 or R 4 and R z are taken together with their intervening atoms to form a saturated or unsaturated 16-22 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

wherein the 16-22 membered ring is optionally substituted with (R m ) p , wherein:

p is an integer from 1 to 6, inclusive;

each occurrence of R m is independently halogen, —OR o ; —CN; —N(R o ) 2 ; or an optionally substituted group selected from C 1-6 aliphatic or C 3-7 cycloalkyl; and

each R o is independently optionally substituted C 1-6 aliphatic;

each occurrence of R y is independently selected from halogen, —OR o , —CN, —NO 2 , —N(R o ) 2 , or optionally substituted C 1-4 aliphatic;

m is an integer from 0 to 4, inclusive;

s is an integer from 0 to 4, inclusive; and

t is an integer from 0 to 4, inclusive;

wherein the sum of s and t is non-zero.

2. The compound according to claim 1 , wherein:

L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one additional methylene unit of L is optionally replaced by —C(O)—; and

Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

3. The compound according to claim 1 , wherein L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, and one additional methylene unit of L is optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—.

4. The compound according to claim 2 , wherein L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —OC(O)—.

5. The compound according to claim 1 , wherein L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRC(O)CH═CHCH 2 O—, —NRSO 2 CH═CH—, —NRSO 2 CH═CHCH 2 —, —NRC(O)C(═CH 2 )CH 2 —, or —CH 2 NRC(O)CH═CH—; wherein R is H or optionally substituted C 1-6 aliphatic; and Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

6. The compound according to claim 5 , wherein L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHC(O)CH═CHCH 2 O—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, —NHC(O)C(═CH 2 )CH 2 —, or —CH 2 NHC(O)CH═CH—.

7. The compound according to claim 1 , wherein L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one additional methylene unit of L is optionally replaced by —C(O)—.

8. The compound according to claim 1 , wherein R 3 is selected from:

9. The compound according to claim 1 , wherein said compound is of formula II-a or II-b:

or a pharmaceutically acceptable salt thereof.

10. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

11. A composition comprising a compound according to claim 1 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

12. The composition according to claim 11 , in combination with an additional therapeutic agent.

13. The composition according to claim 12 , wherein the additional therapeutic agent is an antiviral agent.

14. The compound according to claim 1 , wherein R z is

15. The compound according to claim 1 , wherein R 4 and R z are taken together with their intervening atoms to form a saturated or unsaturated 16-22 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein the 16-22 membered ring is optionally substituted with (R m ) p , wherein:

p is an integer from 1 to 6, inclusive;

each occurrence of R m is independently halogen, —OR o ; —CN; —N(R o ) 2 ; or an optionally substituted group selected from C 1-6 aliphatic or C 3-7 cycloalkyl; and

each R o is independently optionally substituted C 1-6 aliphatic.

16. The compound according to claim 15 , wherein the compound is of formula I-e or I-f:

or a pharmaceutically acceptable salt thereof;

wherein: R o is an optionally substituted group selected from C 1-6 aliphatic.

17. The compound according to claim 1 , wherein R 1 and R 1′ are taken together to form an optionally substituted 3-7 membered carbocyclic ring.

18. The compound according to claim 17 , wherein R 1 and R 1′ are taken together to form:

wherein R o is an optionally substituted group selected from C 1-6 aliphatic.

19. The compound according to claim 18 , wherein R o is vinyl.

20. The compound according to claim 18 , wherein R o is ethyl.

21. A conjugate of the formula:

wherein:

R 1 and R 1′ are independently hydrogen or optionally substituted C 1-6 aliphatic, or R 1 and R 1′ are taken together to form an optionally substituted 3-7 membered carbocyclic ring;

R 2a is —OH or —NHSO 2 R 2 ;

R 4 is H, —NHC(O)R 5 , —NHC(O)OR 6 ,

or a natural or unnatural amino acid side-chain group;

each R 5 is independently —N(R) 2 or an optionally substituted group selected from C 1-6 aliphatic, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 6 is an optionally substituted group selected from C 1-6 aliphatic, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 7 is an optionally substituted group selected from C 1-6 aliphatic, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R z is

 or R 4 and R z are taken together with their intervening atoms to form a saturated or unsaturated 16-22 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

wherein the 16-22 membered ring is optionally substituted with (R m ) p , wherein:

p is an integer from 1 to 6, inclusive;

each occurrence of R m is independently halogen, —OR o ; —CN; —N(R o ) 2 ; or an optionally substituted group selected from C 1-6 aliphatic or C 3-7 cycloalkyl; and

each R o is independently optionally substituted C 1-6 aliphatic;

each occurrence of R y is independently selected from halogen, —OR o , —CN, —NO 2 , —N(R o ) 2 , or optionally substituted C 1-4 aliphatic;

m is an integer from 0 to 4, inclusive;

s is an integer from 0 to 4, inclusive;

t is an integer from 0 to 4, inclusive;

wherein the sum of s and t is non-zero;

Cys159 is Cys159 of HCV protease; and

the linker is a bivalent group corresponding to the reaction of an -L-Y warhead of a compound of claim 3 , or a pharmaceutically acceptable salt thereof, with Cys159 of HCV protease.

22. The conjugate of claim 21 , wherein the conjugate is of the formula:

wherein:

p is an integer from 1 to 6, inclusive;

each occurrence of R m is independently halogen, —OR o ; —CN; —N(R o ) 2 ; or an optionally substituted group selected from C 1-6 aliphatic or C 3-7 cycloalkyl; and

each R o is independently optionally substituted C 1-6 aliphatic.

23. A conjugate formed by reacting a compound of claim 1 with HCV protease.

24. The conjugate of claim 23 , wherein the conjugate is formed via a covalent bond between substituent R 3 and a cysteine sulfhydryl group of HCV protease, which cysteine is conserved at an equivalent position to Cys159 of HCV protease.

25. The conjugate of claim 23 , wherein the conjugate is formed via a covalent bond between substituent R 3 and a cysteine sulfhydryl group of HCV protease, which cysteine is Cys16 of HCV protease.

26. A conjugate formed by reacting a compound of claim 16 with HCV protease.