Indole AHR inhibitors and uses thereof

1. A method for treating an AHR-mediated disorder in a patient in need thereof, comprising administering to said patient a compound selected from any one of formulae IX-a, IX-b and IX-c:

or a pharmaceutically acceptable salt thereof, wherein X is N or CH;

each or 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 RN(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —C(O)OR, —S(O)R, or —SO 2 R, or:

two R x on the same carbon are taken together to form ═O or ═S; or:

two R y on the same carbon are taken together to form ═O or ═S;

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 p is independently 0, 1, or 2, as valency will allow; and

each of m and n is independently 1, 2, 3, 4, or 5.

2. The method according to claim 1 , wherein the AHR-mediated disorder is a cancer.

3. The method according to claim 1 , wherein the AHR-mediated disorder is an inflammatory disorder.

4. A method for treating an AHR-mediated disorder in a patient in need thereof, comprising administering to said patient a compound selected from any one of formulae X-a, X-b, X-c, X-d, X-e, X-f, X-g, X-h and X-i:

or a pharmaceutically acceptable salt thereof, wherein X is N or CH;

each or 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 RN(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —C(O)OR, —S(O)R, or —SO 2 R, or:

two R x on the same carbon are taken together to form ═O or ═S; or:

two R y on the same carbon are taken together to form ═O or ═S;

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 p is independently 0, 1, or 2, as valency will allow; and

each of m and n is independently 1, 2, 3, 4, or 5.

5. The method according to claim 4 , wherein the compound is selected from any one of formulae XI-a, XI-b, XI-c, XI-d, XI-e, XI-f, XI-g, XI-h and XI-i:

or a pharmaceutically acceptable salt thereof.

6. The method according to claim 4 , wherein the compound is selected from any one of formulae XII-a, XII-b and XI-c:

or a pharmaceutically acceptable salt thereof.

7. The method according to claim 4 , wherein the compound is selected from:

I-2

I-16

I-24

I-25

I-29

I-33

I-34

I-35

I-38

I-39

I-40

I-41

I-43

I-46

I-47

I-55

I-56

I-57

I-58

I-61

I-65

I-66

I-68

I-70

I-73

I-75a

I-75b

I-75c

I-78

I-81

I-83

I-84

I-85

I-86

I-87

I-89

I-90

I-91

I-92

I-96

I-99

I-103

I-107

I-112

I-115

I-117

I-118

I-123

I-129

I-130

I-131

I-132

I-133

I-137a

I-137b

I-137c

I-139a

I-139b

I-139c

I-141

I-142

I-143

I-149

I-154

I-157

I-164

I-165

I-168

I-169

I-172

I-177

I-179

I-183

I-197

I-198a

I-198b

I-198c

I-200

I-202

I-203

I-212

I-214

I-215

I-216a

I-216b

I-221

I-222a

I-222b

I-222c

I-224

I-225

I-226

I-230

I-231

I-235

I-236

I-237

I-243a

I-243b

I-245

I-247a

I-247b

I-249a

I-249b

I-249c

I-251

I-253

I-255

I-259a

I-259b

I-259c

I-262

I-265

I-267

I-273

I-274

I-275

I-276

I-277

I-278

I-279

I-280

I-281

I-282

I-283

I-285

I-286

I-287

I-288

or a pharmaceutically acceptable salt thereof.

8. The method according to claim 4 , wherein the compound is selected from

or a pharmaceutically acceptable salt thereof.

9. The method according to claim 4 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

10. The method according to claim 4 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

11. The method according to claim 4 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

12. The method according to claim 4 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

13. The method according to claim 4 , wherein the AHR-mediated disorder is a cancer.

14. The method according to claim 4 , wherein the AHR-mediated disorder is an inflammatory disorder.

15. The method according to claim 13 , wherein the cancer is selected from bladder cancer, melanoma, ovarian cancer, head and neck squamous cell carcinoma (HNSCC), lung cancer, kidney cancer, stomach cancer, esophageal cancer, and acute myeloid leukemia (AML).

16. A method for treating a cancer in a patient in need thereof, comprising administering to said patient a compound selected from:

I-2

I-16

I-24

I-25

I-29

I-33

I-34

I-35

I-38

I-39

I-40

I-41

I-43

I-46

I-47

I-55

I-56

I-57

I-58

I-61

I-65

I-66

I-68

I-70

I-73

I-75a

I-75b

I-75c

I-78

I-81

I-83

I-84

I-85

I-86

I-87

I-89

I-90

I-91

I-92

I-96

I-99

I-103

I-107

I-112

I-115

I-117

I-118

I-123

I-129

I-130

I-131

I-132

I-133

I-137a

I-137b

I-137c

I-139a

I-139b

I-139c

I-141

I-142

I-143

I-149

I-154

I-157

I-164

I-165

I-168

I-169

I-172

I-177

I-179

I-183

I-197

I-198a

I-198b

I-198c

I-200

I-202

I-203

I-212

I-214

I-215

I-216a

I-216b

I-221

I-222a

I-222b

I-222c

I-224

I-225

I-226

I-230

I-231

I-235

I-236

I-237

I-243a

I-243b

I-245

I-247a

I-247b

I-249a

I-249b

I-249c

I-251

I-253

I-255

I-259a

I-259b

I-259c

I-262

I-265

I-267

I-273

I-274

I-275

I-276

I-277

I-278

I-279

I-280

I-281

I-282

I-283

I-285

I-286

I-287

I-288

or a pharmaceutically acceptable salt thereof.

17. The method according to claim 16 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

18. The method according to claim 16 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

19. The method according to claim 16 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

20. The method according to claim 16 , wherein the compound is

or a pharmaceutically acceptable salt thereof.