Patent Application

App. No. 18/146,242

Abstract

Claims (55)

1 . (canceled)

2 . (canceled)

3 . (canceled)

4 . A compound of formula IV:

or a pharmaceutically acceptable salt thereof, wherein:

each of X and Y is independently ═C(R 6 )—, ═N—, or ═N + (→O − )—, provided that X and Y are not simultaneously ═C(R 6 )—;

Ring A is phenyl; a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 4-6 membered saturated or partially unsaturated carbocyclic ring; wherein Ring A is substituted with m instances of R 7 ;

each R 2 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 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 3 is a group selected from C 1-6 alkyl, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, 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; wherein R 3 is substituted with n instances of R 8 ;

R 4 is hydrogen or optionally substituted C 1-6 aliphatic; or

R 4 and one instance of R 7 are taken together with their intervening atoms to form a 5-6 membered partially unsaturated or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

R 5 is a group selected from halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —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)S(O) 2 R, phenyl, a 3-14 membered saturated or partially unsaturated heterocyclic ring having 1-4 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; wherein R 5 is substituted with p instances of R 9 ;

R 6 is hydrogen, —R 2 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —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 , or —N(R)S(O) 2 R;

each instance of R 7 , R 8 , R 10 , and R 11 is independently oxo, —R 2 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —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 , or —N(R)S(O) 2 R;

each instance of R 9 is independently oxo, C 1-6 hydroxyaliphatic, —R 2 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —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 , or —N(R)S(O) 2 R;

L 1 is a covalent bond or a C 1-6 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 10 ) 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 —; or

L 1 and one instance of R 7 are taken together with their intervening atoms to form a 5-10 membered partially unsaturated or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur, and boron; wherein said ring is substituted by q instances of R 11 ; and R 5 is attached to any position of the ring formed by L 1 and R 7 ;

m is 0-4;

n is 0-4;

p is 0-6;

q is 0-4; and

each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic 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.

5 . The compound of claim 4 , wherein Ring A is phenyl, pyridin-2-yl, pyridine-3-yl, or pyrazol-4-yl.

6 . The compound of claim 4 , wherein Ring A is pyridin-2-yl.

7 . The compound of nm claim 4 , wherein X is ═C(R 6 )—; and Y is ═N—.

8 . The compound of nm claim 4 , wherein R 6 is hydrogen.

9 . The compound of nm claim 4 , wherein L 1 is —CH 2 C(O)—, —C(O)—, or a covalent bond.

10 . The compound of claim 9 , wherein L 1 is —C(O)—.

11 . The compound of claim 9 , wherein L 1 is a covalent bond.

12 . The compound of claim 4 , wherein R 3 is phenyl, pyrrolidinyl, or piperidinyl.

13 . The compound of nm claim 4 , wherein R 3 is phenyl.

14 . The compound of claim 4 , wherein n is 2, and at least one R 8 is fluoro.

15 . A compound of claim 4 selected from those depicted in Table 1 of the specification, or a pharmaceutically acceptable salt thereof.

16 . A pharmaceutical composition comprising a compound of claim 4 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

17 . A method of inhibiting TYK2 in a biological sample comprising contacting the sample with the compound of claim 4 , or a pharmaceutically acceptable salt thereof.

18 . A method of treating an TYK2-mediated disorder, disease, or condition in a patient comprising administering to said patient the pharmaceutical composition of claim 16 .

19 . The method of claim 18 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.

20 . The method of claim 19 wherein the disorder is an autoimmune disorder.

21 . The method of claim 20 wherein the autoimmune disorder is selected from type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

22 . The method of claim 19 wherein the disorder is an inflammatory disorder.

23 . The method of claim 22 wherein the inflammatory disorder is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

24 . The method of claim 19 wherein the disorder is a proliferative disorder.

25 . The method of claim 24 wherein the proliferative disorder is a hematological cancer.

26 . The method of claim 24 wherein the proliferative disorder is a leukemia.

27 . The method of claim 26 wherein the leukemia is a T-cell leukemia.

28 . The method of claim 27 wherein the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL).

29 . The method of claim 24 wherein the proliferative disorder is associated with one or more activating mutations in TYK2.

30 . The method of claim 19 wherein the disorder is associated with transplantation.

31 . The method of claim 30 wherein the disorder is transplant rejection or graft versus host disease.

32 . The method of claim 19 wherein the disorder is an endocrine disorder.

33 . The method of claim 32 wherein the endocrine disorder is polycystic ovary syndrome, Crouzon's syndrome, or type 1 diabetes.

34 . The method of claim 19 wherein the disorder is a neurological disorder.

35 . The method of claim 34 wherein the neurological disorder is Alzheimer's disease.

36 . The method of claim 18 wherein the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling.

Assignments (13)