N-sulfonylated tetrahydroquinolines and related bicyclic compounds for inhibition of RORγ activity and the treatment of disease

1. A compound represented by Formula III:

or a pharmaceutically acceptable salt or solvate thereof; wherein:

A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —N(R 3 )(R 4 ), —CO 2 R 6 , —C 1-6 alkylene-N(R 3 )(R 4 ), —C 1-6 alkylene-C 1-6 alkoxy, —C 1-6 alkylene-CO 2 R 6 , —O-aryl, —O—C 1-6 alkylene-N(R 3 )(R 4 ), —N(R 6 )C(O)—C 1-6 alkylene-N(R 3 )(R 4 ), —CN, —S(O) p C 1-6 alkyl, —SO 2 N(R 3 )(R 4 ), —N(R 3 )SO 2 (C 1-6 alkyl), heterocyclyl, C(O)R 11 , —C(R 11 )(R 12 )OH, —C(O)N(R 3 )(R 4 ), and —N(R 3 )C(O)N(R 3 )(R 4 );

X is —O—[C(R 6 ) 2 ] m -ψ, —O—[C(R 6 )(R 9 )C(R 6 ) 2 ]-ψ, —O—[C(R 6 )(R 9 )]-ψ, —O—[C(R 6 ) 2 —C(hydroxyC 1-6 alkyl)(R 6 )]-ψ, —N(R 6 )—[C(R 6 ) 2 ] m -ψ, —N═C(R 6 )-ψ, —N═C(R 6 )C(R 6 ) 2 -ψ, —C(R 6 ) 2 C(O)C(R 6 ) 2 -ψ, —[C(R 6 ) 2 ] m —C(O)-ψ, —C(R 6 )═C(R 6 )C(O)-ψ, —C(O)C(R 6 )═C(R 6 )-ψ, or —N(R 6 )—C(O)-ψ; wherein ψ is a bond to the sulfonamide ring nitrogen atom in Formula III;

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

R 2 is —N(R 7 )C(O)R 8 , —(C 1-2 alkylene)-N(R 7 )C(O)R 8 , —N(R 7 )C(O)N(R 7 )(R 8 ), or heteroaryl, wherein said heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkyl, aryl, and heteroaryl;

R 3 and R 4 each represent independently hydrogen or C 1-6 alkyl; or R 3 and R 4 taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring;

R 5 represents independently for each occurrence hydrogen, halogen, or C 1-6 alkyl;

R 6 and R 7 each represent independently for each occurrence hydrogen or C 1-6 alkyl;

R 8 is aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocyclyl, —C(R 6 ) 2 -cycloalkyl, —C(R 6 ) 2 -cycloalkenyl, —C(R 6 ) 2 -heterocyclyl, or C 1-6 alkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, —N(R 3 )(R 4 ), —CN, —CO 2 —C 1-6 alkyl, —C(O)—C 1-6 alkyl, —C(O)N(R 3 )(R 4 ), —S(O) p C 1-6 alkyl, —SO 2 N(R 3 )(R 4 ), and —N(R 3 )SO 2 (C 1-6 alkyl);

R 9 is C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —C 1-6 alkylene-N(R 3 )(R 4 ), —C 1-6 alkylene-N(R 3 )C(O)—C 1-6 alkyl, —C 1-6 alkylene-CO 2 R 3 , —C 1-6 alkylene-CN, —C 1-6 alkylene-C 1-6 alkoxy, —C 1-6 alkylene-C(O)N(R 3 )(R 4 ), —C(O)N(R 3 )(R 4 ), —C 1-6 alkylene-N(R 3 )C(O)N(R 3 )(R 4 ), —C 1-6 alkylene-N(R 3 )C(O)—[C(OH)(R 3 )(R 4 )], —C 1-6 alkylene-O—C(O)N(R 3 )(R 4 ), —C 1-6 alkylene-SO 2 N(R 3 )(R 4 ), —C 1-6 alkylene-N(R 3 )SO 2 N(R 3 )(R 4 ), C 2-4 alkenyl, -arylene-CO 2 R 6 , or —CN;

R 11 is C 1-6 alkyl, C 1-6 haloalkyl, aryl, aralkyl, heteroaryl, or heterocycloalkyl; each of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —CO 2 R 3 , and, —N(R 3 )(R 4 );

R 12 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, aryl, aralkyl, heteroaryl, or heterocycloalkyl;

each of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —CO 2 R 3 , and, —N(R 3 )(R 4 );

m is 1 or 2;

p represents independently for each occurrence 0, 1, or 2;

y is 1 or 2; and

wherein the stereochemical configuration at a stereocenter in a compound represented by Formula III is R, S, or a mixture thereof.

2. The compound of claim 1 , wherein A is phenyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, —N(R 3 )(R 4 ), —CN, —CO 2 R 6 , —C(O)—C 1-6 alkyl, —C 1-6 alkylene-N(R 3 )(R 4 ), —C 1-6 alkylene-C 1-6 alkoxy, —C 1-6 alkylene-CO 2 R 6 , —O—C 1-6 alkylene-N(R 3 )(R 4 ), and —N(R 6 )C(O)—C 1-6 alkylene-N(R 3 )(R 4 ).

3. The compound of claim 1 , wherein A is phenyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, and —CN.

4. The compound of claim 1 , wherein X is —O—[C(R 6 ) 2 ] m -ψ or —O—[C(R 6 )(R 9 )C(R 6 ) 2 ]-ψ.

5. The compound of claim 1 , wherein R 2 is —N(R 7 )C(O)R 8 .

6. The compound of claim 1 , wherein R 8 is aryl or aralkyl, each of which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 haloalkyl.

7. The compound of claim 6 , wherein R 8 is phenyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 haloalkyl.

8. The compound of claim 1 , wherein said compound is represented by Formula III-C:

or a pharmaceutically acceptable salt or solvate thereof; wherein:

A is aryl or heteroaryl; each of which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, —CN, and —C(O)—C 1-6 alkyl;

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

R 2 is —N(R 7 )C(O)R 8 ;

R 3 and R 4 each represent independently hydrogen or C 1-6 alkyl; or R 3 and R 4 taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring;

R 6 and R 7 each represent independently for each occurrence hydrogen or C 1-6 alkyl;

R 8 is aryl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 haloalkyl;

R 9 is C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —C 1-6 alkylene-N(R 3 )(R 4 ), —C 1-6 alkylene-N(R 3 )C(O)—C 1-6 alkyl, —C 1-6 alkylene-CN, or —C 1-6 alkylene-C 1-6 alkoxy; and

wherein the stereochemical configuration at a stereocenter in a compound represented by Formula III-C is R, S, or a mixture thereof.

9. The compound of claim 8 , wherein A is phenyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, and —CN.

10. The compound of claim 8 , wherein R 8 is phenyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 haloalkyl.

11. The compound of claim 8 , wherein R 9 is C 1-6 haloalkyl, C 1 -6hydroxyalkyl, —C 1-6 alkylene-N(R 3 )C(O)—C 1-6 alkyl, or —C 1-6 alkylene-C 1-6 alkoxy.

12. The compound of claim 8 , wherein R 2 is attached to the 6-position of the benzoxazine ring.

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

14. A pharmaceutical composition comprising the compound of claim 4 and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising the compound of claim 8 and a pharmaceutically acceptable carrier.