TYK2 inhibitors and uses thereof

1. A method of treating a TYK2-mediated disorder, disease, or condition in a patient comprising administering to said patient the 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;

wherein the TYK2-mediated disorder, disease, or condition is:

an autoimmune disorder selected from type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease;

an inflammatory disorder selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease;

a hematological cancer: or

Alzheimer's disease.

2. The method of claim 1 wherein the autoimmune disorder is selected from type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

3. The method of claim 1 wherein the inflammatory disorder is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

4. The method of claim 1 wherein the proliferative disorder is a hematological cancer.

5. The method of claim 1 wherein the hematological cancer is a leukemia.

6. The method of claim 5 wherein the leukemia is a T-cell leukemia.

7. The method of claim 6 wherein the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL).

8. The method of claim 1 wherein the TYK2-mediated disorder, disease, or condition is type 1 diabetes.

9. The method of claim 1 wherein the TYK2-mediated disorder, disease, or condition is ankylosing spondylitis.

10. The method of claim 1 wherein the TYK2-mediated disorder, disease, or condition is cutaneous lupus erythematosus.

11. The method of claim 1 wherein the TYK2-mediated disorder, disease, or condition is systemic lupus erythematosus.

12. The method of claim 1 wherein the TYK2-mediated disorder, disease, or condition is multiple sclerosis.

13. The method of claim 1 wherein the TYK2-mediated disorder, disease, or condition is systemic sclerosis.

14. The method of claim 1 wherein the TYK2-mediated disorder, disease, or condition is psoriasis.

15. The method of claim 1 wherein the TYK2-mediated disorder, disease, or condition is Crohn's disease.

16. The method of claim 1 wherein the TYK2-mediated disorder, disease, or condition is ulcerative colitis.

17. The method of claim 1 wherein the TYK2-mediated disorder, disease, or condition is inflammatory bowel disease.

18. The method of claim 1 wherein the TYK2-mediated disorder, disease, or condition is rheumatoid arthritis.

19. The method of claim 1 wherein the TYK2-mediated disorder, disease, or condition is asthma.

20. The method of claim 1 wherein the TYK2-mediated disorder, disease, or condition is chronic obstructive pulmonary disease.