TYK2 inhibitors and uses thereof
The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of TYK2, and the treatment of TYK2-mediated disorders.
1. A method of inhibiting TYK2 in a biological sample comprising contacting the sample with a compound of formula I′:
or a pharmaceutically acceptable salt thereof, wherein:
X is N or C(R 3 );
R 1 is R D , —NR 2 , —NRR D , —N(R D ) 2 , —CH 2 F, —CHF 2 , —OR D , or an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R 2 is R C , —N(R)C(O)Cy 2 , —N(R)S(O) 2 Cy 2 , —N(R)Cy 2 , —OCy 2 , —SCy 2 , or Cy 2 ;
R 3 is H, halogen, or C 1-6 aliphatic; or
R 2 and R 3 are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with m instances of R 4 ;
each of Cy 1 and Cy 2 is independently 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 heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 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′ is substituted with n instances of R 5 ; and; wherein Cy 2 is substituted with p instances of R 6 ;
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 7 ) 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 —;
each instance of R 4 , R 5 , R 6 , and R 7 is independently R A or R B , and is substituted by q instances of R C ;
each instance of R A is independently oxo, halogen, —CN, —NO 2 , —OR, —OR D , —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, —N(R D ) S(O) 2 R, —N(R) S(O) 2 R D , —N(R D ) S(O) 2 R D , or —P(O)R 2 ;
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 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 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)S(O) 2 NR 2 , or —N(R)S(O) 2 R or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R D is a C1-4 aliphatic group wherein one or more hydrogens are replaced by deuterium;
each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered 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 their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and
each of m, n, p, and q is independently 0, 1, 2, 3, or 4.
2. A method of treating a TYK2-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound of formula I′, or a pharmaceutical composition thereof:
or a pharmaceutically acceptable salt thereof, wherein:
X is N or C(R 3 );
R 1 is R D , —NR 2 , —NRR D , —N(R D ) 2 , —CH 2 F, —CHF 2 , —OR D or an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R 2 is R C , —N(R)C(O)Cy 2 , —N(R)S(O) 2 Cy 2 , —N(R)Cy 2 , —OCy 2 , —SCy 2 , or Cy t ;
R 3 is H, halogen, or C 1-6 aliphatic; or
R 2 and R 3 are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with m instances of R 4 ;
each of Cy′ and Cy 2 is independently 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 heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 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′ is substituted with n instances of R 5 ; and; wherein Cy 2 is substituted with p instances of R 6 ;
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 7 ) 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 —;
each instance of R 4 , R 5 , R 6 , and R 7 is independently R A or R B , and is substituted by q instances of R C ;
each instance of R A is independently oxo, halogen, —CN, —NO 2 , —OR, —OR D , —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, —N(R D )S(O) 2 R, —N(R)S(O) 2 R D , —N(R D )S(O) 2 R D , or —P(O)R 2 ;
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 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 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)S(O) 2 NR 2 , or —N(R)S(O) 2 R or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R D is a C1-4 aliphatic group wherein one or more hydrogens are replaced by deuterium;
each R is independently hydrogen, or an optionally substituted group selected from C1.6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered 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 their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and
each of m, n, p, and q is independently 0, 1, 2, 3, or 4.
3. The method of claim 2 wherein the disorder is selected from an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.
4. The method of claim 3 wherein the disorder is an autoimmune disorder.
5. The method of claim 4 wherein the autoimmune disorder is selected from type 1 diabetes, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.
6. The method of claim 3 wherein the disorder is an inflammatory disorder.
7. The method of claim 6 wherein the inflammatory disorder is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.
8. The method of claim 3 wherein the disorder is a proliferative disorder.
9. The method of claim 8 wherein the proliferative disorder is a hematological cancer.
10. The method of claim 8 wherein the proliferative disorder is a leukemia.
11. The method of claim 10 wherein the leukemia is a T-cell leukemia.
12. The method of claim 11 wherein the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL).
13. The method of claim 8 wherein the proliferative disorder is associated with one or more activating mutations in TYK2.
14. The method of claim 3 wherein the disorder is associated with transplantation.
15. The method of claim 14 wherein the disorder is transplant rejection or graft versus host disease.
16. The method of claim 3 wherein the disorder is an endocrine disorder.
17. The method of claim 16 wherein the endocrine disorder is polycystic ovary syndrome, Crouzon's syndrome, or type 1 diabetes.
18. The method of claim 3 wherein the disorder is a neurological disorder.
19. The method of claim 18 wherein the neurological disorder is Alzheimer's disease.
20. The method of claim 2 wherein the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling.