MK2 inhibitors and uses thereof

1. A compound of formula I′:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 nitrogens, or a 8-14 membered bridged or fused bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

T is a bivalent moiety selected from by —N(R)—, —O—, —S—, —S(O)—, —SO 2 —, —C(S)—, —Si(R 4 ) 2 —, —P(R 5 )—, —P(O) 2 —, or a bivalent saturated straight or branched 1-3 membered hydrocarbon chain, wherein the hydrocarbon chain is optionally substituted with oxo or —OR;

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

two R groups on the same nitrogen are taken together with the nitrogen to form a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur;

R a is hydrogen or an optionally substituted C 1-6 aliphatic;

R 1 is R or -(CH 2 ) p R x ;

p is 0, 1, 2, or 3;

R x is —CN, —NO 2 , halogen, —OR, —SR, —N(R) 2 , —C(O)N(R) 2 , —C(O)OR, —C(O)R, —N(R)C(O)R, —SO 2 N(R) 2 , or —N(R)SO 2 ;

R 2 is halogen, —CN, —SR y , —S(O)R y , —SO 2 R y , —OSO 2 R y , —OC(O)R y , or —OP(O) 2 OR y ;

each R y is independently selected from optionally substituted C 1-6 aliphatic or optionally substituted phenyl;

R 3 is hydrogen, optionally substituted C 1-6 aliphatic, —CN, —NO 2 , halogen, —OR, —N(R) 2 , —C(O)N(R) 2 , —C(O)OR, —Cy, —C(O)N(R)—Cy, —C(O)—Cy, —O—Cy, —O—(CH 2 ), r Cy, —(CH 2 ) n —O—Cy, —(CH 2 ) m N(R) 2 , —(CH 2 ) m OR, —N(R)—Cy, —N(R)—(CH 2 ) n —Cy, —(CH 2 ) n —N(R)—Cy, or —(CH 2 ) m —Cy;

each R 4 is independently hydrogen, —OR, C 1-6 aliphatic, phenyl, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R 5 is independently —OR, C 1-6 aliphatic, phenyl, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each of m and n is independently 0-4; and

each Cy is independently an optionally substituted ring selected from a 3-9 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 3-9 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated fused or bridged bicyclic carbocyclic ring, or a 6-12 membered saturated or partially unsaturated fused or bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

wherein said compound is other than:

2. The compound according to claim 1 , wherein T is —N(R)—, —O—, or —S—.

3. The compound according to claim 2 , wherein T is —NH—or —O—.

4. The compound according to claim 3 , wherein T is —NH—.

5. The compound according to claim 1 , wherein R 1 is R, —CH 2 OR, or —CH 2 N(R) 2 .

6. The compound according to claim 1 , wherein le is methyl, —CH 2 OCH 3 , or —CH 2 NH 2 .

7. The compound according to claim 6 , wherein R 1 is methyl.

8. The compound according to claim 1 , of formula I,

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is phenyl or a 5-6 membered heteroaryl ring having 1-3 nitrogens;

T is a bivalent moiety selected from by —N(R)—, —O—, —S—, —S(O)—, —SO 2 —, —C(S)—, —Si(R 4 ) 2 —, —P(R 5 )—, —P(O) 2 —, or a bivalent saturated straight or branched 1-3 membered hydrocarbon chain, wherein the hydrocarbon chain is optionally substituted with oxo or —OR;

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

two R groups on the same nitrogen are taken together with the nitrogen to form a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur;

R a is hydrogen or an optionally substituted C 1-6 aliphatic;

R 1 is R or —(CH 2 ) p R x ;

p is 0, 1, 2, or 3;

R x is —CN, —NO 2 , halogen, —OR, —SR, —N(R) 2 , —C(O)N(R) 2 , —C(O)OR, —C(O)R, —N(R)C(O)R, —SO 2 N(R) 2 , or —N(R)SO 2 ;

R 2 is halogen, —CN, —SR y , —S(O)R y , —SO 2 R y , —OSO 2 R y , —OC(O)R y , or —OP(O) 2 OR y ;

each R y is independently selected from optionally substituted C 1-6 aliphatic or optionally substituted phenyl;

R 3 is hydrogen, optionally substituted C 1-6 aliphatic, —CN, —NO 2 , halogen, —OR, —N(R) 2 , —C(O)N(R) 2 , —C(O)OR, —Cy, —C(O)N(R)—Cy, —C(O)—Cy, —O—Cy, —O—(CH 2 ) n —Cy, —(CH 2 ) n —O—Cy, —N(R)—Cy, —N(R)—(CH 2 ) n —Cy, —(CH 2 ) n —N(R)—Cy, or -(CH 2 ) m —Cy;

each R 4 is independently hydrogen, —OR, C 1-6 aliphatic, phenyl, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R 5 is independently —OR, C 1-6 aliphatic, phenyl, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each of m and n is independently 0-4; and

each Cy is independently an optionally substituted ring selected from a 3-9 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 3-9 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated fused or bridged bicyclic carbocyclic ring, or a 7-12 membered saturated or partially unsaturated fused or bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

9. The compound according to claim 1 , wherein Ring A is phenyl and R 3 is selected from —CN, —NO 2 , halogen, —C(O)N(R) 2 , —C(O)OR, —Cy, —C(O)N(R)—Cy, or —C(O)—Cy.

10. The compound according to claim 9 , wherein Ring A is phenyl and R 3 is selected from —CN, —NO 2 , or halogen.

11. The compound according to claim 10 , wherein Ring A is phenyl and R 3 is selected from —CN or halogen.

12. The compound according to claim 1 , wherein Ring A is a 6-membered heteroaryl ring having 1-3 nitrogens.

13. The compound according to claim 12 , wherein Ring A is pyridyl, pyrimidinyl, pyridazinyl, or triazinyl.

14. The compound according to claim 13 , wherein said compound is any one of formula II, III, IV, V, or VI:

or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1 , wherein R 2 is halogen.

16. The compound according to claim 15 , wherein R 2 is fluoro or chloro.

17. The compound according to claim 1 , wherein R 2 is —SR y or —SO 2 R y .

18. The compound according to claim 15 , wherein R 2 is —SCH 3 or —SO 2 CH 3 .

19. The compound according to claim 12 , wherein R 3 is hydrogen.

20. The compound according to claim 12 , wherein R 3 is optionally substituted C 1-6 aliphatic.

21. The compound according to claim 20 , wherein R 3 is selected from —CH 2 OH, —CH 2 OCH 3 and —CH 3 .

22. The compound according to claim 12 , wherein R 3 is —OR.

23. The compound according to claim 22 , wherein R 3 is selected from —O(CH 2 ) 2 OCH 3 , —O(CH 2 ) 2 N(CH 3 ) 2 , and —OCH 3 .

24. The compound according to claim 1 , wherein R 3 is halogen, —CN, NO 2 ,—C(O)N(R) 2 , or —C(O)OR.

25. The compound according to claim 24 , wherein R 3 is halogen, —CN, or NO 2 .

26. The compound according to claim 24 , wherein R 3 is —C(O)N(R) 2 , or —C(O)OR.

27. The compound according to claim 26 , wherein R 3 is selected from —C(O)NH 2 , —C(O)OCH 2 CH 3 , and —C(O)OCH 3 .

28. The compound according to claim 12 , wherein R 3 is —Cy, —(CH 2 ) m —Cy, —C(O)N(R)—Cy, —C(O)—Cy, —OR, —O—Cy, —N(R)—Cy, —N(R)—(CH 2 ) n —Cy, -(CH 2 ) n —N(R)—Cy, or —O—(CH 2 ),—Cy.

29. The compound according to claim 28 , wherein each —Cy is independently an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring.

30. The compound according to claim 28 , wherein each —Cy is independently an optionally substituted ring selected from a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

31. The compound according to claim 30 , wherein each —Cy is independently an optionally substituted ring selected from oxetanyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, piperazinyl, and morpholinyl.

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