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 selected from the group consisting of:

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 an optionally substituted, saturated or unsaturated 16-22 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

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

R ◯ is an optionally substituted group selected from C 1-6 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.

2. The compound according to claim 1 , wherein R 4 and R z are taken together with their intervening atoms to form an optionally substituted, saturated or unsaturated 16-22 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

3. The compound according to claim 2 , wherein the compound is of formula I-e or I-f:

or a pharmaceutically acceptable salt thereof;

wherein:

p is an integer from 1 to 6, inclusive; and

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

4. 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.

5. The compound according to claim 4 , wherein R 1 and R 1′ are taken together to form:

6. The compound according to claim 5 , wherein R ◯ is vinyl.

7. The compound according to claim 5 , wherein R ◯ is ethyl.

8. The compound according to claim 1 , wherein R 2a is —NHSO 2 R 2 and R 2 is cyclopropyl.

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

10. The compound according to claim 1 , wherein R 4 is —NHC(O)OR 6 and R 6 is C 1-6 aliphatic.

11. 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

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

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

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

R ◯ is an optionally substituted group selected from C 1-6 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; and

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

12. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

13. A composition comprising a compound according to claim 1 , 11 , or 12 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

14. The composition according to claim 13 , in combination with an additional therapeutic agent.

15. The composition according to claim 14 , wherein the additional therapeutic agent is an antiviral agent.