Patent Application

App. No. 17/813,805

Abstract

Claims (44)

1 . A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X and Y are ═N—;

Ring A is phenyl; a 5-6 membered partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-12 membered partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered bicyclic heteroaryl ring having 2-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each of R 1 and R 1′ is independently 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; or

R 1 and R 1′ are taken together with their intervening atoms to form an optionally substituted 3-7 membered spiro-fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

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 C 2-6 aliphatic or Cy′; wherein R 3 is substituted with n instances of R 8 ;

R 5 is 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, and Cy 2 ; wherein R 5 is substituted with p instances of R 9 ; or

when Ring A is partially unsaturated, L 1 R 5 , taken together, may also be absent;

each of Cy 1 and Cy 2 is independently phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 6-12 membered bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each instance of R 7 and R 8 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 —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 —;

m is 0-2;

n is 0-4;

p is 0-3; 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.

2 . The compound of claim 1 of formula II:

or a pharmaceutically acceptable salt thereof

3 . (canceled)

4 . The compound of claim 1 of one of formulas VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, VI-j, VI-k, VI-l, VI-m, VI-n, VI-o, VI-p, VI-q, VI-r, VI-s, VI-t, VI-v, VI-x, VI-y, VI-z, or VI-aa:

or a pharmaceutically acceptable salt thereof.

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

6 . The compound of claim 1 wherein L 1 is —C(O)—.

7 . The compound of claim 1 , wherein R 3 is Cy 1 .

8 . The compound of claim 1 , wherein R 3 is one of the following:

9 . The compound of claim 1 wherein R 3 (R 8 ) n , taken together, is one of the following:

10 . The compound of claim 1 wherein R 5 is Cy 2 .

11 . The compound of claim 1 , wherein R 5 is one of the following:

12 . The compound of claim 1 wherein R 5 (R 9 ) p , taken together, is one of the following:

13 . The compound of claim 1 wherein at least one R 8 is halogen, —CN, or hydroxymethyl.

14 . The compound of claim 1 wherein Ring A is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

15 . The compound of claim 14 , wherein Ring A is pyrazolyl.

16 . The compound of claim 1 of formula VIII-c:

or a pharmaceutically acceptable salt thereof.

17 . The compound of claim 16 , wherein n is 2-3.

18 . (canceled)

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 . (canceled)

21 . A method of treating a TYK2-mediated disorder, disease, or condition in a patient comprising administering to the patient the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

22 . The method of claim 21 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.

23 - 41 . (canceled)

Assignments (18)