Indole AHR inhibitors and uses thereof
The present invention provides compounds useful as inhibitors of AHR, compositions thereof, and methods of using the same.
1. A compound of formula VIII-b:
or a pharmaceutically acceptable salt thereof, wherein:
X is N or CH;
p is 0, 1, or 2;
each R is independently hydrogen, deuterium, or an optionally substituted group selected from C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or aromatic ring having 1-2 heteroatoms in addition to the nitrogen independently selected from oxygen, nitrogen, or sulfur;
each of R x , R y , and R z is independently selected from R, halogen, cyano, nitro, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —C(O)N(R)OR, —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO 2 R;
m is 1, 2, 3, or 4;
n is 1, 2, 3, 4, or 5;
L 1 is a covalent bond or an optionally substituted C 1-6 membered straight or branched bivalent hydrocarbon chain wherein a methylene unit of L 1 is optionally replaced with —Cy—, —O—, —S—, —NR—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R)—, —N(R)C(O)—, —SO 2 —, —N(R)SO 2 —, or —SO 2 N(R)—S —SO 2 N(R)—; and
-Cy- is a 3-8 membered bivalent saturated, partially unsaturated, or aromatic monocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bivalent saturated, partially unsaturated, or aromatic bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
2. The compound of claim 1 , wherein the compound is of formula IX-b:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein the compound is selected from any of formulae X-b, X-e, and X-h:
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein the compound is selected from any one of formulae XI-b, XI-e, and XI-h:
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , wherein the compound is of formula XII-b:
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R x is halogen.
7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R x is F.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R z is optionally substituted C 1-6 aliphatic.
9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R z is optionally substituted C 1-6 alkyl.
10. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R z is optionally substituted C 1-6 alkenyl.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R y is hydrogen, and n is 1.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein p is 1.
14. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R x is halogen.
15. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R x is F.
16. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R z is optionally substituted C 1-6 aliphatic.
17. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein R z is optionally substituted C 1-6 alkyl.
18. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein R z is optionally substituted C 1-6 alkenyl.
19. A composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
20. A method for treating an AHR-mediated disorder in a patient in need thereof, comprising administering to said patient the compound of claim 1 , or a pharmaceutically acceptable salt thereof.