Benzenesulfonamido and related compounds for use as agonists of RORγ and the treatment of disease

1. A compound represented by Formula I:

or a pharmaceutically acceptable salt thereof; wherein:

A is phenylene, 5-6 membered heteroarylene, or C 3-6 heterocycloalkylene;

R 1 represents independently for each occurrence halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl;

R 2 is C 1-6 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, and C 1-6 alkoxy;

R 3 is C 1-6 haloalkyl;

R 4 represents independently for each occurrence hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl;

X is one of the following:

(i) —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)—(C 3-6 cycloalkyl), —O—(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )-phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), or —N(R 4 )—(C 1-6 alkylene)—(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, and cyano;

(ii) —(C 2-6 alkenylene)-phenyl, —(C 2-6 alkenylene)-heteroaryl, —(C 1-6 alkylene)-phenyl, —(C 1-6 alkylene)-heteroaryl, —(C 1-6 alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C 1-6 alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl), -(5-6 membered heterocycloalkylene)-phenyl, or —(C 3-6 cycloalkylene)-phenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, and cyano; or

(iii) —(C 1-6 alkylene)-Z 1 or —(C 2-6 alkenylene)-Z 1 , wherein Z 1 is —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)—(C 3-6 cycloalkyl), —O—(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )-phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), —N(R 4 )—(C 1-6 alkylene)—(C 3-6 cycloalkyl), or —N(R 4 )—(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, and cyano;

m is 0, 1, or 2; and

n is 1, 2, or 3.

2. The compound of claim 1 , wherein the compound is represented by Formula I-A:

or a pharmaceutically acceptable salt thereof; wherein:

A is phenylene or a 5-6 membered heteroarylene;

R 1 represents independently for each occurrence halogen, C 1-6 alkyl, or C 3-6 cycloalkyl;

R 2 is C 1-6 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, and C 1-6 alkoxy;

R 3 is C 1-6 haloalkyl;

R 4 represents independently for each occurrence hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl;

X is one of the following:

(i) —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)—(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )-phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), or —N(R 4 )—(C 1-6 alkylene)—(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;

(ii) —(C 2-6 alkenylene)-phenyl, —(C 2-6 alkenylene)-heteroaryl, —(C 1-6 alkylene)-phenyl, —(C 1-6 alkylene)-heteroaryl, —(C 1-6 alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C 1-6 alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl), or -(5-6 membered heterocycloalkylene)-phenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; or

(iii) —(C 1-6 alkylene)-Z 1 or —(C 2-6 alkenylene)-Z 1 , wherein Z 1 is —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)—(C 3-6 cycloalkyl), —O—(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )-phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), or —N(R 4 )—(C 1-6 alkylene)—(C3- 6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;

m is 0, 1, or 2; and

n is 1, 2, or 3.

3. The compound of claim 2 , wherein A is phenylene.

4. The compound of claim 2 , wherein A is a 5-6 membered heteroarylene.

5. The compound of claim 3 , wherein n is 1.

6. The compound of claim 5 , wherein R 3 is trifluoromethyl.

7. The compound of claim 5 , wherein R 2 is C 1-6 alkyl.

8. The compound of claim 5 , wherein R 2 is ethyl or propyl.

9. The compound of claim 2 , wherein Xis —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)—(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )-phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), or —N(R 4 )—(C 1-6 alkylene)—(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

10. The compound of claim 3 , wherein X is —O-aralkyl or —O-(partially unsaturated bicyclic carbocyclyl), each of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen and C 1-6 haloalkyl.

11. The compound of claim 8 , wherein X is —O-benzyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, bromo, and fluoro.

12. The compound of claim 8 , wherein X is —O—(C 1-6 alkylene)-phenyl or —N(R 4 )—(C 1-6 alkylene)-phenyl, each of which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy, where at least one substituent is present at the ortho position on the phenyl group in variable X.

13. The compound of claim 2 , wherein X is —(C 1-6 alkylene)-heteroaryl, —(C 1-6 alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C 1-6 alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl), or -(5-6 membered heterocycloalkylene)-phenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

14. The compound of claim 3 , wherein X is —(C 1-6 alkylene)-Z 1 , wherein Z 1 is —O-aralkyl, —N(R 4 )-aralkyl, or —N(R 4 )-phenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, and C 1-6 alkyl.

15. The compound of claim 3 , wherein X is attached at the meta or para position of the sulfonamido-phenyl group.

16. The compound of claim 15 , wherein m is 0.

17. A compound in Table 1-1 or 8-1 below, or a pharmaceutically acceptable salt thereof:

TABLE 1-1

(I-C)

(I-D)

(I-E)

(I-F)

(I-G)

(I-H)

(I-I)

(I-J)

No.

X

Z

I-49

I-50

TABLE 8-1

Compound Structure

18. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

19. A method of treating a disorder selected from the group consisting of colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, lung cancer, leukemia, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterus cancer, esophagus cancer, liver cancer, an acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, and retinoblastoma, comprising administering a therapeutically effective amount of a compound of claim 1 to a subject in need thereof to ameliorate a symptom of the disorder.

20. The method of claim 19 , wherein the disorder is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, lung cancer, leukemia, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterus cancer, or esophagus cancer.

21. The method of claim 19 , wherein the subject is a human.

22. A method of promoting the activity of RORγ, comprising exposing a RORγ to an effective amount of a compound of claim 1 to promote the activity of said RORγ.

23. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier.

24. A pharmaceutical composition comprising a compound of claim 10 and a pharmaceutically acceptable carrier.