IP Library › Granted Patent US 11,053,219

Granted Patent B2

US 11,053,219 · App. 16/938,183 · Granted Jul 6, 2021

Substituted pyridines as TYK2 inhibitors

Inventors: Bohan Jin (San Diego, CA); Qing Dong (San Diego, CA); Gene Hung (San Diego, CA); Stephen W. Kaldor (San Diego, CA)

Assignee: Esker Therapeutics, Inc.

C07D401/14 C07D401/12 C07D403/12

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Quick Facts

Patent No.: US 11,053,219
App. No.: 16/938,183
Granted: Jul 6, 2021
Kind: B2

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Abstract

Described herein are pyridine compounds of Formula (XIII) that are useful in treating a TYK2-mediated disorder. In some embodiments, the TYK2-mediated disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation

Claims (92)

1. A compound of Formula (XIII):

or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein:

L is a bond;

Ring A is cycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl are each optionally substituted with one or more independently selected R A substituents;

Ring B is phenyl or pyridinyl;

R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 haloalkyl;

R 4 is hydrogen, deuterium, halogen, CN, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C(O)R a , C(O)NR c R d , C(O)OR b , NR c R d , NR b C(O)R a , NR b C(O)NR c R d , NR b C(O)OR b , NHS(O) 2 R a , OR b , OC(O)R a , OC(O)NR c R d , OC(O)OR b , P(O)R b R b , SR b , S(O)R a , S(O) 2 R a , or S(O) 2 NR c R d ;

R 5 is halogen, CN, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C(NCN)R 7 , C(NCN)NR 9 R 10 , C(NCN)OR 8 , C(O)R 7 , C(O)NR 9 R 10 , C(O)OR 8 , NR 9 R 10 , NR 8 C(NCN)R 7 , NR 8 C(NOH)R 7 , NR 8 C(NCN)NR 9 R 10 , NR 8 C(NCN)OR 8 , NR 8 C(O)R 7 , NR 8 C(O)NR 9 R 10 , NR 8 C(O)OR 8 , NR 8 S(O)R 7 , NR 8 S(NR 8 )(O)R 7 , NR 8 S(O) 2 R 7 , OR 8 , OC(NCN)R 7 , OC(NCN)NR 9 R 10 , OC(NCN)OR 8 , OC(O)R 7 , OC(O)NR 9 R 10 , OC(O)OR 8 , SR 8 , S(O)R 7 , S(O) 2 R 7 , S(O) 2 NR 9 R 10 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C(O)R a , C(O)NR c R d , C(O)OR b , NR c R d , OR b , oxo, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C(O)R a , C(O)NR c R d , C(O)OR b , NR c R d , OR b , and oxo;

R 7 is C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C(O)CH 3 , C(O)OH, C(O)OCH 3 , NH 2 , OH, OCH 3 , and oxo;

each R 8 is independently hydrogen, CN, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C(O)CH 3 , C(O)OH, C(O)OCH 3 , NH 2 , OH, OCH 3 , and oxo;

R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 hydroxydeuteroalkyl, C(O)CH 3 , C(O)OH, C(O)OCH 3 , NH 2 , OH, OCH 3 , OXO, cycloalkyl, and heterocycloalkyl;

R 10 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 hydroxydeuteroalkyl, C(O)CH 3 , C(O)OH, C(O)OCH 3 , NH 2 , OH, OCH 3 , oxo, cycloalkyl, and heterocycloalkyl; or

R 8 and R 9 , taken together with the atoms to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C(O)CH 3 , C(O)OH, C(O)OCH 3 , NH 2 , OH, OCH 3 , and oxo; or

R 9 and R 10 , taken together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C(O)CH 3 , C(O)OH, C(O)OCH 3 , NH 2 , OH, OCH 3 , and oxo;

R 11 is C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more independently selected R 11a substituents;

each R 11a is independently deuterium, halogen, CN, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C(O)R a , C(O)NR c R d , C(O)OR b , NR c R d , NR b C(O)R a , NR b C(O)NR c R d , NR b C(O)OR b , NHS(O) 2 R a , OR b , OC(O)R a , OC(O)NR c R d , OC(O)OR b , SR b , S(O)R a , S(O) 2 R a , or S(O) 2 NR c R d ;

each R A is independently deuterium, halogen, CN, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C(O)R a , C(O)NR c R d , C(O)OR b , NR c R d , NR b C(O)R a , NR b C(O)NR c R d , NR b C(O)OR b , NHS(O) 2 R a , OR b , OC(O)R a , OC(O)NR c R d , OC(O)OR b , SR b , S(O)R a , S(O) 2 R a , S(O) 2 NR c R d , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C(O)R a , C(O)NR c R d , C(O)OR b , NR c R d , OR b , and oxo; or

two R a , taken together with the carbon to which they are attached, form an oxo;

each R a is independently C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C(O)CH 3 , C(O)OH, C(O)OCH 3 , NH 2 , OH, OCH 3 , and oxo;

each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C(O)CH 3 , C(O)OH, C(O)OCH 3 , NH 2 , OH, OCH 3 , and oxo;

each R c is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C(O)CH 3 , C(O)OH, C(O)OCH 3 , NH 2 , OH, OCH 3 , and oxo;

each R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C(O)CH 3 , C(O)OH, C(O)OCH 3 , NH 2 , OH, OCH 3 , and oxo; or

R c and R d , taken together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C(O)CH 3 , C(O)OH, C(O)OCH 3 , NH 2 , OH, OCH 3 , and oxo; and

each R x is independently hydrogen, deuterium, halogen, CN, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C(O)R a , C(O)NR c R d , C(O)OR b , NR c R d , NR b C(O)R a , NR b C(O)NR c R d , NR b C(O)OR b , NHS(O) 2 R a , OR b , OC(O)R a , OC(O)NR c R d , OC(O)OR b , SR b , S(O)R a , S(O) 2 R a , or S(O) 2 NR c R d .

2. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

3. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is a 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted with one or more independently selected R A substituents.

4. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring Bis phenyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring B is pyridinyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is hydrogen.

7. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4 is OR b .

8. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 is NR 8 C(O)R 7 , NR 8 C(O)NR 9 R 10 , or heterocycloalkyl, wherein the heterocycloalkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), C 1- C 6 alkyl(heteroaryl), C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C(O)R a , C(O)NR c R d , C(O)OR b , NR c R d , OR b , oxo, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C(O)R a , C(O)NR c R d , C(O)OR b , NR c R d , OR b , and oxo.

9. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 is NR 8 C(O)R 7 .

10. The compound of claim 9 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 7 is cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C(O)CH 3 , C(O)OH, C(O)OCH 3 , NH 2 , OH, OCH 3 , and oxo.

11. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 is NR 8 C(O)NR 9 R 10 .

12. The compound of claim 11 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 9 and R 10 , taken together with the nitrogen atom to which they are attached, form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C(O)CH 3 , C(O)OH, C(O)OCH 3 , NH 2 , OH, OCH 3 , and oxo.

13. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 8 is independently hydrogen.

14. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 11 is C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, or cycloalkyl.

15. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 11 is C 1 -C 6 deuteroalkyl.

16. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 haloalkyl.

17. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt or stereoisomer thereof.

18. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.

19. A method for inhibiting tyrosine kinase 2 activity in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.

20. The method of claim 19 , wherein inhibiting tyrosine kinase 2 activity is associated with treating a disease or disorder selected from Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis.

21. The method of claim 20 , wherein the disease or disorder is rheumatoid arthritis.

22. The method of claim 20 , wherein the disease is psoriasis.

23. The method of claim 20 , wherein the disease or disorder is systemic lupus erythematosus.

24. The method of claim 20 , wherein the disease or disorder is ulcerative colitis.

25. The method of claim 20 , wherein the disease or disorder is psoriatic arthritis.

26. The method of claim 20 , wherein the disease or disorder is systemic sclerosis.

27. A compound having the structure: