TYK2 inhibitors and uses thereof

1. A compound of formula I′:

or a pharmaceutically acceptable salt thereof, wherein:

X is N or CH;

L 1 is a covalent bond or a C 1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —C(R 4 ) 2 —, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O) 2 —;

R 4 is independently R A or R B ;

each instance of R A is independently halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O)(NR)R, —S(O) 2 NR 2 , —S(O)R, —S(O)NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)S(O) 2 NR 2 , —N(R)S(O) 2 R, or —P(O)R 2 ; or two instances of R A are optionally taken together to form an oxo;

each instance of R B is independently C 1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by q instances of R C ;

each instance of R C is independently oxo, halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)NR 2 , —N(R)S(O) 2 NR 2 , —N(R)S(O) 2 R, —N═S(O)R 2 , —S(NR)(O)R, —N(R)S(O)R, —N(R)CN, —P(O)(R)NR 2 , —P(O)(R)OR or —P(O)R 2 or an optionally substituted group selected from C 1-6 aliphatic; phenyl; naphthalenyl; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or for each instance of R B , optionally:

two R C groups on the same atom are taken together with the atom to form an optionally substituted 4-7 membered saturated, spirocyclic heterocyclic ring having 1-2 heteroatoms, independently selected from nitrogen, oxygen, and sulfur;

two R C groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered saturated or partially unsaturated, fused ring having 0-2 heteroatoms, independently selected from nitrogen, oxygen, and sulfur; or

two R C groups are taken together with their intervening atoms to form an optionally substituted 5-6 membered fused aryl ring having 0-3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur;

each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic; phenyl; naphthalenyl; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or:

two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

R 1 is Cy 1 ;

Cy 1 is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 1 is substituted with p instances of R 1A ;

each instance of R 1A , is independently R A or R B ;

R 2 is C 1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by q instances of R C ;

R 3 is —C(O)NH 2 , —C(O)NHCH 3 , or —C(O)NHCD 3 ;

each of p and q is independently 0, 1, 2, 3, or 4; and

r is 0 or 1.

2. The compound of claim 1 , wherein the compound is of formula II:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound is of formula III:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein the compound is of formula IV:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein the compound is of formula VI:

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein the compound is one of formulae VII, VIII, or IX

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein the compound is of formula X:

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein the compound is one of formulae XI, XII, or XIII:

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , wherein Cy 1 is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 1 is substituted with p instances of R.

10. The compound of claim 1 , wherein Cy 1 is phenyl or a 6 membered monocyclic heteroaryl ring having 1-2 nitrogen atoms; wherein Cy 1 is substituted with p instances of R.

11. The compound of claim 10 , wherein X is CH.

12. The compound of claim 11 , wherein R 2 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted by q instances of R C .

13. The compound of claim 1 , wherein R 2 is cyclopropyl or pyrazolyl.

14. The compound of claim 13 , wherein at least one instance of R 1A is R B .

15. The compound of claim 14 , wherein R B is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of R C .

16. The compound of claim 15 , wherein p is 1, 2, or 3.

17. The compound of claim 16 , wherein q is 0, 1, or 2.

18. The compound of claim 1 , wherein the compound is selected from

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or a pharmaceutically acceptable salt thereof.

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

20. A method of inhibiting TYK2 in a biological sample comprising contacting the sample with the compound of claim 1 , or a pharmaceutically acceptable salt thereof.