Substituted pyridines, pyridazines, and pyrimidines as TYK2 inhibitors
Described herein are compounds of Formula (XIII) that are TYK2 inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of TYK2 activity.
1. A compound of Formula (XIII):
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
Z is —NR 10 —, —O—, —S—, —S(═O)—, or —SO 2 —;
X 1 is CR 11 or N;
X 2 is CR 11 or N;
X 3 is CR 11 or N;
B 1 is CR 12a and B 2 is CR 12b ;
or B 1 is N and B 2 is CR 12b ;
or B 1 is CR 12a and B 2 is N;
R 2 is a Ring B that is an unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 ;
or R 2 is —C(═O)R 14 , —C(═O)NR 14 R 15 , or —C(═O)OR 14 ;
R 4 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl;
R 6 is hydrogen, deuterium, halogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl;
R 7 is hydrogen, deuterium, halogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl; or
or one R 6 and one R 7 attached to the same carbon atom are taken together with the carbon atom to which they are attached to form —(C═O)— or C 3 -C 4 cycloalkylidenyl;
R 8 is hydrogen, halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 deuteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, —CN, —OH, —OR 17 , —C(═O)R 16 , —CO 2 R 16 , —C(═O)N(R 16 ) 2 , —N(R 16 ) 2 , —NR 16 C(═O)R 17 , —SR 16 ;
wherein the substituted C 1 -C 6 alkyl or substituted C 1 -C 6 deuteroalkyl is substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —NH 2 , —OH, —NH(CH 3 ), —N(CH 3 ) 2 , —OCH 3 , —OCHF 2 , and —OCF 3 ; and
wherein the substituted carbocyclyl or substituted heterocyclyl is substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —NH 2 , —OH, —NH(CH 3 ), —N(CH 3 ) 2 , —CH 3 , —CH 2 CH 3 , —CHF 2 , —CF 3 , —OCH 3 , —OCHF 2 , and —OCF 3 ;
R 10 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, or monocyclic heterocyclyl;
each R 11 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, —CN, —OH, —OR 17 , or —N(R 16 ) 2 ;
R 12a is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or —CN;
R 12b is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or —CN;
each R 13 is independently halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, —CN, —OH, —OR 17 , —C(═O)R 16 , —CO 2 R 16 , —C(═O)N(R 16 ) 2 , —N(R 16 ) 2 , —NR 16 C(═O)R 17 , —SO 2 R 17 , or —SO 2 N(R 16 ) 2 ;
wherein each substituted C 1 -C 6 alkyl is independently substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —NH 2 , —OH, —NH(CH 3 ), —N(CH 3 ) 2 , —OCH 3 , —OCHF 2 , and —OCF 3 ; and
wherein each substituted carbocyclyl and substituted heterocyclyl is independently substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —NH 2 , —OH, —NH(CH 3 ), —N(CH 3 ) 2 , —CH 3 , —CH 2 CH 3 , —CHF 2 , —CF 3 , —OCH 3 , —OCHF 2 , and —OCF 3 ;
R 14 is hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl;
wherein the substituted C 1 -C 6 alkyl is substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —NH 2 , —OH, —NH(CH 3 ), —N(CH 3 ) 2 , —OCH 3 , —OCHF 2 , and —OCF 3 ; and
wherein the substituted carbocyclyl or substituted heterocyclyl is substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —NH 2 , —OH, —NH(CH 3 ), —N(CH 3 ) 2 , —CH 3 , —CH 2 CH 3 , —CHF 2 , —CF 3 , —OCH 3 , —OCHF 2 , and —OCF 3 ;
R 15 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl;
each R 16 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl;
or any two R 16 on the same nitrogen atom are taken together with the nitrogen atom to which they are attached to independently form a 4- to 6-membered heterocycloalkyl;
each R 17 is independently C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl;
n is 1; and
q is 1 or 2.
2. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
(i) X 1 is CR 11 ;
X 2 is CR 11 ;
X 3 is CR 11 ; and
each R 11 is independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or —CN; or
(ii) X 1 is CR 11 ;
X 2 is CR 11 ;
X 3 is N; and
each R 11 is independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or —CN; or
(iii) X 1 is CR 11 ;
X 2 is N;
X 3 is CR 11 ; and
each R 11 is independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or —CN; or
(iv) X 1 is N;
X 2 is CR 11 ;
X 3 is CR 11 ; and
each R 11 is independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or —CN; and
B 1 is CH or CF, and B 2 is CH or CF; or
or B 1 is N, and B 2 is CH or CF.
3. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
(i) X 1 is CR 11 ;
X 2 is CR 11 ;
X 3 is CR 11 ; and
each R 11 is hydrogen; or
(ii) X 1 is CR 11 ;
X 2 is CR 11 ;
X 3 is N; and
each R 11 is hydrogen; and
B 1 is CH, and B 2 is CH;
or B 1 is N, and B 2 is CH.
4. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 4 is C 1 -C 4 alkyl or C 1 -C 4 deuteroalkyl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 4 is C 1 -C 4 deuteroalkyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 8 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocycloalkyl, —CN, —OH, —OR 17 , —C(═O)R 16 , —CO 2 R 16 , or —C(═O)N(R 16 ) 2 .
7. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 8 is hydrogen, —Cl, —F, methyl, ethyl, isopropyl, —CD 3 , —CH 2 OH, —CF 3 , cyclopropyl, oxetanyl, azetidinyl, —CN, —OH, —CO 2 H, or —CO 2 CH 3 .
8. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
Z is —NR 10 —; and
R 10 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or cyclopropyl.
9. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
Z is —NR 10 —;
R 6 is hydrogen, deuterium, —F, or methyl;
R 7 is hydrogen, deuterium, —F, or methyl; and
R 10 is —CH 3 or —CD 3 .
10. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
R 2 is a Ring B that is an unsubstituted or substituted pyridinyl or unsubstituted or substituted pyrimidinyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
11. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
R 2 is —C(═O)R 14 ; and
R 14 is unsubstituted or substituted C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, unsubstituted or substituted monocyclic or bicyclic C 3 -C 6 cycloalkyl, or unsubstituted or substituted 4- to 6-membered monocyclic or bicyclic heterocycloalkyl;
wherein the substituted C 1 -C 6 alkyl is substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —NH 2 , —OH, —NH(CH 3 ), —N(CH 3 ) 2 , —OCH 3 , —OCHF 2 , and —OCF 3 ; and
wherein the substituted C 3 -C 6 cycloalkyl or substituted 4- to 6-membered heterocycloalkyl is independently substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —NH 2 , —OH, —NH(CH 3 ), —N(CH 3 ) 2 , —CH 3 , —CH 2 CH 3 , —CHF 2 , —CF 3 , —OCH 3 , —OCHF 2 , and —OCF 3 .
12. The compound of claim 11 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
R 2 is —C(═O)R 14 ; and
R 14 is unsubstituted or substituted C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, unsubstituted or substituted monocyclic C 3 -C 4 cycloalkyl, or unsubstituted or substituted 4-membered monocyclic heterocycloalkyl;
wherein the substituted C 1 -C 6 alkyl is substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —NH 2 , —OH, —NH(CH 3 ), —N(CH 3 ) 2 , —OCH 3 , —OCHF 2 , and —OCF 3 ; and
wherein the substituted C 3 -C 4 cycloalkyl or substituted 4-membered heterocycloalkyl is independently substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —NH 2 , —OH, —NH(CH 3 ), —N(CH 3 ) 2 , —CH 3 , —CH 2 CH 3 , —CHF 2 , —CF 3 , —OCH 3 , —OCHF 2 , and —OCF 3 .
13. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
Z is —NR 10 — or —O—;
R 2 is a Ring B that is an unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 ;
or R 2 is —C(═O)R 14 ;
R 8 is hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 deuteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, —C(═O)R 16 , —CO 2 R 16 , or —C(═O)N(R 16 ) 2 ;
wherein the substituted C 1 -C 6 alkyl or substituted C 1 -C 6 deuteroalkyl is substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —NH 2 , —OH, —NH(CH 3 ), —N(CH 3 ) 2 , —OCH 3 , —OCHF 2 , and —OCF 3 ; and
wherein the substituted carbocyclyl or substituted heterocyclyl is substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —NH 2 , —OH, —NH(CH 3 ), —N(CH 3 ) 2 , —CH 3 , —CH 2 CH 3 , —CHF 2 , —CF 3 , —OCH 3 , —OCHF 2 , and —OCF 3 ;
R 10 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or cyclopropyl; and
R 14 is unsubstituted or substituted C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, unsubstituted or substituted monocyclic C 3 -C 4 cycloalkyl, or unsubstituted or substituted 4-membered monocyclic heterocycloalkyl;
wherein the substituted C 1 -C 6 alkyl is substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —NH 2 , —OH, —NH(CH 3 ), —N(CH 3 ) 2 , —OCH 3 , —OCHF 2 , and —OCF 3 ; and
wherein the substituted C 3 -C 4 cycloalkyl or substituted 4-membered heterocycloalkyl is independently substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —NH 2 , —OH, —NH(CH 3 ), —N(CH 3 ) 2 , —CH 3 , —CH 2 CH 3 , —CHF 2 , —CF 3 , —OCH 3 , —OCHF 2 , and —OCF 3 .
14. The compound of claim 13 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
Z is —NR 10 —;
(i) X 1 is CR 11 ;
X 2 is CR 11 ; and
X 3 is CR 11 ; or
(ii) X 1 is CR 11 ;
X 2 is CR 11 ; and
X 3 is N; and
B 1 is CH, and B 2 is CH;
or B 1 is N, and B 2 is CH;
R 4 is C 1 -C 4 alkyl or C 1 -C 4 deuteroalkyl;
R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocycloalkyl, —CN, —OH, —OR 17 , —C(═O)R 16 , —CO 2 R 16 , or —C(═O)N(R 16 ) 2 ;
R 10 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or cyclopropyl; and
each R 11 is hydrogen.
15. The compound of claim 13 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
Z is —NR 10 —
(i) X 1 is CR 11 ;
X 2 is CR 11 ; and
X 3 is CR 11 ; or
(ii) X 1 is CR 11 ,
X 2 is CR 11 , and
X 3 is N; and
B 1 is CH, and B 2 is CH;
or B 1 is N, and B 2 is CH;
R 4 is C 1 -C 4 deuteroalkyl;
R 6 is hydrogen, deuterium, —F, or methyl;
R 7 is hydrogen, deuterium, —F, or methyl;
R 8 is hydrogen, methyl, ethyl, isopropyl, —CD 3 , —CH 2 OH, —CF 3 , cyclopropyl, oxetanyl, azetidinyl, —CN, —OH, —CO 2 H, or —CO 2 CH 3 ;
R 10 is CH 3 or CD 3 ; and
each R 11 is hydrogen.
16. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
17. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
18. A method for inhibiting tyrosine-protein kinase 2 (TYK2) activity, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
19. The method of claim 18 , wherein the patient has a TYK2-mediated disease or condition selected from the group consisting of: rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, Sjögren's syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, intestinal bowel disease, Crohn's disease, ulcerative colitis, celiac disease, Bechet's disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis.
20. The method of claim 18 , wherein a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, is orally administered to the patient in need thereof.
21. The method of claim 20 , wherein a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, is provided in a tablet, a pill, or a capsule.