Tetrahydro[1,8]naphthyridine sulfonamide 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 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, C 1-6 alkoxy, C 1-6 haloalkoxy, —N(R 4 )(R 5 ), —CO 2 R 6 , —C(O)R 6 , —CN, —C 1-4 alkylene-C 1-4 alkoxy, —C 1-4 alkylene-N(R 4 )(R 5 ), —C 1-4 alkylene-CO 2 R 6 , —O—C 1-6 alkylene-N(R 4 )(R 5 ), —N(R 4 )C(O)—C 1-6 alkylene-N(R 4 )(R 5 ), —S(O) p C 1-6 alkyl, —SO 2 N(R 4 )(R 5 ), —N(R 4 )SO 2 (C 1-6 alkyl), —C(O)N(R 4 )(R 5 ), and —N(R 4 )C(O)N(R 4 )(R 5 );

X is —C(R 6 ) 2 —N(R 8 )—[C(R 6 )(R 7 )]—[C(R 6 ) 2 ] m -Ψ, wherein Ψ is a bond to the sulfonamide ring nitrogen atom in Formula I;

Y is —N(R 2 )(R 3 ) or —O-aralkyl, wherein said aralkyl 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 4 )(R 5 ), —CN, —CO 2 —C 1-6 alkyl, —C(O)—C 1-6 alkyl, —C(O)N(R 4 )(R 5 ), —S(O) p C 1-6 alkyl, —SO 2 N(R 4 )(R 5 ), and —N(R 4 )SO 2 (C 1-6 alkyl);

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

R 2 is —C(O)-aryl, —C(O)-aralkyl, —C(O)—[C(R 6 ) 2 ] m -cycloalkyl, —C(O)—[C(R 6 ) 2 ] m -heterocyclyl, —C(O)—C 1-8 alkyl, —C(O)—C 1-6 alkylene-C 1-6 alkoxyl, —C(O)—C 1-6 alkylene-cycloalkyl, or —C(O)—C 1-6 alkylene-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 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, —N(R 4 )(R 5 ), —CN, —CO 2 —C 1-6 alkyl, —C(O)—C 1-6 alkyl, —C(O)N(R 4 )(R 5 ), —S(O) p C 1-6 alkyl, —SO 2 N(R 4 )(R 5 ), and —N(R 4 )SO 2 (C 1-6 alkyl);

R 3 is hydrogen or C 1-6 alkyl;

R 4 and R 5 each represent independently for each occurrence hydrogen or C 1-6 alkyl; or R 4 and R 5 taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring;

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

R 7 is hydrogen, hydroxyl, C 1-6 hydroxyalkyl, C 1-6 alkyl, C 1-6 haloalkyl, —CO 2 R 6 , C 1-6 alkylene-CO 2 R 6 , C 1-4 hydroxyalkylene-CO 2 R 6 , —N(R 4 )(R 5 ), C 1-6 alkylene-N(R 4 )(R 5 ), C 1-6 hydroxyalkylene-N(R 4 )(R 5 ), —N(R 4 )C(O)R 9 , C 1-6 alkylene-N(R 4 )C(O)R 9 , C 1-6 alkylene-C(O)N(R 4 )(R 5 ), —N(R 4 )CO 2 —C 1-6 alkyl, or C 1-6 alkylene-N(R 4 )C(O)N(R 4 )(R 5 ); or R 7 is heterocycloalkyl or C 1-4 alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;

R 8 is hydrogen, C 1-6 alkyl, or —C(O)—C 1-6 alkyl;

R 9 is hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkylene-N(R 4 )(R 5 ), or C 1-6 alkylene-N(R 4 )C(O)—C 1-6 alkyl;

n is 1 or 2; and

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

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

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

4. The compound of claim 1 , wherein Y is —N(R 2 )(R 3 ).

5. The compound of claim 4 , wherein R 2 is —C(O)-aryl or —C(O)-aralkyl; 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, and C 1-6 haloalkyl.

6. The compound of claim 4 , wherein R 2 is —C(O)-phenyl or —C(O)-benzyl; each of which is optionally 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 1 , wherein Y is —O-aralkyl 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 4 )(R 5 ), —CN, —CO 2 —C 1-6 alkyl, and —C(O)—C 1-6 alkyl.

8. The compound of claim 1 , wherein Y is —O-benzyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 haloalkyl.

9. The compound of claim 5 , wherein R 7 is hydrogen.

10. The compound of claim 5 , wherein R 7 is C 1-3 hydroxyalkyl, methyl, ethyl, or C 1-3 alkylene-N(H)C(O)—C 1-4 alkyl.

11. A compound of claim 1 , wherein the compound is a compound in Table 2A or a pharmaceutically acceptable salt thereof:

TABLE 2A

No.

Y

Z

II-32

II-33

II-34

II-35

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

13. A method of treating a disorder selected from the group consisting of cancer, bacterial infection, and fungal infection, comprising administering a therapeutically effective amount of a compound of claim 1 to a subject in need thereof to treat the disorder, wherein the cancer is 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, or retinoblastoma.

14. The method of claim 13 , wherein the disorder is 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, or retinoblastoma.

15. A method of increasing the amount of IL-17 in a subject, comprising administering to a subject an effective amount of a compound of claim 1 to increase the amount of IL-17 in the subject.

16. The method of claim 13 , wherein the subject is a human.

17. 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.

18. The compound of claim 2 , wherein X is —C(R 6 ) 2 —N(R 8 )—[C(R 6 )(R 7 )]—[C(R 6 ) 2 ] m -Ψ; Y is —N(R 2 )(R 3 ); and R 2 is —C(O)-aryl or —C(O)-aralkyl, 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, and C 1-6 haloalkyl.

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