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

1. A method of promoting the activity of RORγ, comprising exposing a RORγ to an effective amount of a compound of Formula I or IV, or a pharmaceutically acceptable salt thereof, to promote the activity of said RORγ; wherein Formula I is represented by:

wherein:

A is phenylene or 5-6 membered heteroarylene;

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

R 2A is C 1-6 alkyl substituted with 1 or 2 substituents independently selected from the group consisting of —CO 2 R 4 , —N(R 4 )C(O)(C 1-6 alkyl), —CN, halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and —N(R 4 )(R 5 );

R 2B is C 1-6 alkyl, C 1-3 haloalkyl, or fluoro;

R 3 represents independently for each occurrence C 1-6 haloalkyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, or —O—(C 1-6 alkylene)-OH;

R 4 and R 5 each represent independently for each occurrence hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl; or an occurrence of R 4 and R 5 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-8 membered heterocyclic ring;

R 9 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, —(C 1-6 alkylene)-(C 3-6 cycloalkyl), C 1-6 haloalkyl, or C 1-6 hydroxyalkyl;

X is one of the following:

—(C 2-6 alkenylene)-phenyl, —(C 2-6 alkenylene)-heteroaryl, —(C 2-6 alkenylene)-(partially unsaturated 8-10 membered bicyclic ring containing 0-3 heteroatoms), 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, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ; or

—(C 2-6 alkenylene)-(C 1-6 alkyl), —(C 2-6 alkenylene)-(C 3-6 cycloalkyl), or

 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, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 , wherein A* is a 5-8 membered, partially saturated carbocyclic or heterocyclic ring;

Y is —O—;

m and p each represent independently for each occurrence 0, 1, or 2; and

n is 1, 2, or 3; and

Formula IV is represented by:

wherein:

A is phenylene or 5-6 membered heteroarylene;

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

R 2A is C 1-6 alkyl substituted with 1 or 2 substituents independently selected from the group consisting of —CO 2 R 4 , —C(O)N(R 4 )(R 5 ), —N(R 4 )C(O)R 8 , —CN, halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and —N(R 4 )(R 5 ); or

R 2B is C 1-6 alkyl, C 1-3 haloalkyl, or fluoro;

R 3 represents independently for each occurrence C 1-6 haloalkyl, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, or —O—(C 1-6 hydroxyalkyl);

R 4 and R 5 each represent independently for each occurrence hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl; or an occurrence of R 4 and R 5 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-8 membered heterocyclic ring;

R 8 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, —(C 1-6 alkylene)-(C 3-6 cycloalkyl), or aryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, or —CO 2 R 4 ; or R 8 is —CO 2 R 4 ;

R 9 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, —(C 1-6 alkylene)-(C 3-6 cycloalkyl), C 1-6 haloalkyl, or C 1-6 hydroxyalkyl;

X is C 4-7 cycloalkenyl 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, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;

Y is —O—;

m and p each represent independently for each occurrence 0, 1, or 2; and

n is 1, 2, or 3.

2. The method of claim 1 , wherein the compound is a compound of Formula I or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 , wherein the compound is a compound of Formula IV or a pharmaceutically acceptable salt thereof.

4. A method of promoting the activity of RORγ, comprising exposing a RORγ to an effective amount of a compound of Formula I-C to promote the activity of said RORγ; wherein Formula I-C is represented by:

or a pharmaceutically acceptable salt thereof; wherein:

A is phenylene or pyridinylene;

R 1 represents independently for each occurrence halogen, methyl, ethyl, or cyclopropyl;

R 2A is C 1-6 alkyl substituted with 1 or 2 substituents independently selected from the group consisting of —CO 2 R 4 , —C(O)N(R 4 )(R 5 ), —N(R 4 )C(O)R 8 , halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and —N(R 4 )(R 5 );

R 2B is methyl or ethyl;

R 3 represents independently for each occurrence C 1-3 haloalkyl, halogen, C 1-3 alkyl, or —O—(C 1-6 hydroxyalkyl);

R 4 and R 5 each represent independently for each occurrence hydrogen or methyl; or an occurrence of R 4 and R 5 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring;

R 8 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, or —(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, hydroxyl, and —CO 2 R 4 ;

X is —(C 2-6 alkenylene)-phenyl 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 and p are independently 0 or 1; and

n is 1 or 2.

5. The method of claim 4 , wherein A is phenylene.

6. The method of claim 5 , wherein R 2A is C 1-6 alkyl substituted with —CO 2 R 4 .

7. The method of claim 6 , wherein R 3 represents independently for each occurrence trifluoromethyl, m and p are 0, and n is 1.

8. The method of claim 4 , wherein X is —(C 2-4 alkenylene)-phenyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 1-6 haloalkyl.

9. The method of claim 5 , wherein X is —(C 2-4 alkenylene)-phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl, and said substituents are located at the ortho positions of the phenyl group.

10. A method of promoting the activity of RORγ, comprising exposing a RORγ to an effective amount of a compound selected from the following or a pharmaceutically acceptable salt thereof, to promote the activity of said RORγ:

11. The method of claim 10 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

12. The method of claim 10 , wherein the compound is

13. The method of claim 10 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

14. The method of claim 10 , wherein the compound is

15. The method of claim 10 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

16. The method of claim 10 , wherein the compound is

17. The method of claim 10 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

18. The method of claim 10 , wherein the compound is

19. The method of claim 10 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

20. The method of claim 10 , wherein the compound is