Substituted imidazo[1,5-a]pyrazines and [1,2,4]triazolo[4,3-a]pyrazines for the modulation of AhR
Provided herein are compounds, compositions and methods of using the compounds and compositions for the treatment of diseases modulated, as least in part, by AhR. The compounds are represented by formula: wherein the letters and symbols a, b, c, d, e, f, A, R 1 , X 1 , Ar 1 and Ar 2 have the meanings provided in the specification.
1. A compound having formula Ib or formula Id:
or a pharmaceutically acceptable salt thereof,
wherein:
X 1 is C 1-6 alkylene;
Ar 1 is a 5- to 9-membered heteroaryl, wherein the 5- to 9-membered heteroaryl contains at least one N heteroatom, and further wherein the 5- to 9-membered heteroaryl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of deuterium, halogen, CN, C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 haloalkyl, C(O)R a , C(O)NR a R b , C(O)OR a , NR a R b , NR b C(O)R a , NR a C(O)NR a R b , NR b C(O)OR c , OR a , OC(O)R a , OC(O)NR a R b , S(O) 0-2 R a , and S(O) 2 NR a R b ;
Ar 2 is phenyl or a 5- to 9-membered heteroaryl, wherein the phenyl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of deuterium, halogen, CN, C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 haloalkyl, C(O)R c , C(O)NR a R b , C(O)OR a , NR a R b , NR b C(O)R a , NR a C(O)NR a R b , NR b C(O)OR c , OR a , OC(O)R a , OC(O)NR a R b , S(O) 0-2 R a , and S(O) 2 NR a R b , and further wherein the 5- to 9-membered heteroaryl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of deuterium, halogen, CN, C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 haloalkyl, C(O)R c , C(O)NR a R b , C(O)OR a , NR a R b , NR b C(O)R a , NR a C(O)NR a R b , NR b C(O)OR c , OR a , OC(O)R a , OC(O)NR a R b , S(O) 0-2 R a , and S(O) 2 NR a R b ;
R 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-7 cycloalkyl, or C 3-7 heterocycloalkyl;
each R a is independently H, C 1-4 alkyl, or C 1-4 haloalkyl;
each R b is independently H, C 1-4 alkyl, or C 1-4 haloalkyl; or
each R a and R b , together with the N heteroatom to which they are attached, independently forms a 4- to 6-membered ring, wherein each 4- to 6-membered ring independently contains 0, 1, or 2 additional ring heteroatoms or ring heteroatomic groups independently selected from the group consisting of N, O, S, S(O), and S(O) 2 ; and
each R c is independently C 1-4 alkyl or C 1-4 haloalkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is —CH 2 —.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is —CH 2 CH 2 —.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is —CH(CH 3 )CH 2 —.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 1 is pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, wherein the pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of deuterium, halogen, CN, C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 haloalkyl, C(O)R a , C(O)NR a R b , C(O)OR a , NR a R b , NR b C(O)R a , NR a C(O)NR a R b , NR b C(O)OR c , OR a , OC(O)R a , OC(O)NR a R b , S(O) 0-2 R a , and S(O) 2 NR a R b .
6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein Ar 1 is:
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is phenyl, wherein the phenyl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of deuterium, halogen, CN, C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 haloalkyl, C(O)R c , C(O)NR a R b , C(O)OR a , NR a R b , NR b C(O)R a , NR a C(O)NR a R b , NR b C(O)OR c , OR a , OC(O)R a , OC(O)NR a R b , S(O) 0-2 R a , and S(O) 2 NR a R b .
8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein the phenyl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C(O)NR a R b , C(O)OR a , NR a R b , NR b C(O)R a , NR b C(O)OR c , OR a , OC(O)R a , and OC(O)NR a R b .
9. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein the phenyl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of C(O)NH 2 and OH.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is a 5- to 9-membered heteroaryl, wherein the 5- to 9-membered heteroaryl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of deuterium, halogen, CN, C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 haloalkyl, C(O)R c , C(O)NR a R b , C(O)OR a , NR a R b , NR b C(O)R a , NR a C(O)NR a R b , NR b C(O)OR c , OR a , OC(O)R a , OC(O)NR a R b , S(O) 0-2 R a , and S(O) 2 NR a R b .
11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is pyrrolyl, indolyl, benzopyrazolyl, benzimidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, or 1H-pyrrolo[3,2-b]pyridinyl, wherein the pyrrolyl, indolyl, benzopyrazolyl, benzimidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, or 1H-pyrrolo[3,2-b]pyridinyl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of deuterium, halogen, CN, C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 haloalkyl, C(O)R c , C(O)NR a R b , C(O)OR a , NR a R b , NR b C(O)R a , NR a C(O)NR a R b , NR b C(O)OR c , OR a , OC(O)R a , OC(O)NR a R b , S(O) 0-2 R a , and S(O) 2 NR a R b .
12. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is:
wherein each is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C(O)R c , C(O)NR a R b , C(O)OR a , OR a , and OC(O)NR a R b .
13. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is pyrrolyl, wherein the pyrrolyl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C(O)R c , C(O)NR a R b , C(O)OR a , OR a , and OC(O)NR a R b .
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is CH(CH 3 ) 2 or CH 3 CHCH 2 OH.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is CH(CH 3 ) 2 .
16. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
19. A method for modulating aryl hydrocarbon receptor activity in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
20. The method of claim 19 , wherein the subject has cancer.
21. The method of claim 20 , wherein the compound of claim 1 , or a pharmaceutically acceptable salt thereof, is administered in combination with at least one additional anticancer therapy.