Adoptive cellular therapy using an agonist of retinoic acid receptor-related orphan receptor gamma and related therapeutic methods

1. A method of delivering to a patient a RORγ agonist treated lymphocyte cell, comprising administering to a patient in need thereof a pharmaceutical composition comprising said cell that has been exposed ex vivo to an agonist of RORγ.

2. The method of claim 1 , further comprising culturing a lymphocyte cell with an agonist of RORγ to provide the cell that has been exposed ex vivo to an agonist of RORγ.

3. The method of claim 2 , wherein the culturing comprises exposing the lymphocyte cell to a cytokine.

4. The method of claim 3 , wherein the cytokine is IL-1β, IL-2, IL-6, IL-7, IL-10, IL-12, IL-15, IL-18, IL-21, IL-23, or transforming growth factor beta.

5. The method of claim 4 , wherein the lymphocyte cell is a T cell.

6. The method of claim 4 , wherein the lymphocyte cell is a CD8 + T cell, CD4 + T cell, or T H 17 cell.

7. The method of claim 4 , wherein the lymphocyte cell is a Tc17 cell, natural killer T cell, or γδ T cell.

8. The method of claim 2 , wherein the culturing comprises exposing the lymphocyte cell to an antigen associated with a medical disorder.

9. The method of claim 8 , wherein the antigen comprises cancer tissue.

10. The method of claim 2 , further comprising obtaining a lymphocyte cell from said patient for use in the culturing step.

11. The method of claim 2 , further comprising obtaining a lymphocyte cell from a subject that produces cells allogenic to cells of the patient, for use in the culturing step.

12. The method of claim 1 , wherein the lymphocyte cell is obtained from blood, cancer tissue, bone marrow, the spleen, a lymph node, or the thymus.

13. The method of claim 1 , wherein the lymphocyte cell is obtained from a population of human peripheral blood mononuclear cells.

14. The method of claim 1 , wherein the lymphocyte cell is obtained from a lymph node in proximity to a tumor or site of infection.

15. The method of claim 1 , wherein the lymphocyte cell is obtained from cancer tissue.

16. The method of claim 1 , wherein the lymphocyte cell is a tumor-infiltrating-lymphocyte cell.

17. The method of claim 1 , wherein the cell expresses a receptor for an antigen specific for a medical disorder.

18. The method of claim 17 , wherein the medical disorder is a cancer, bacterial infection, fungal infection, or immune disorder.

19. The method of claim 1 , wherein the lymphocyte cell is a T cell.

20. The method of claim 1 , wherein the lymphocyte cell is a CD8 + T cell, CD4 + T cell, or T H 17 cell.

21. The method of claim 1 , wherein the lymphocyte cell is a natural killer cell.

22. The method of claim 1 , wherein the lymphocyte cell is a Tc17 cell, natural killer T cell, or γδ T cell.

23. The method of claim 1 , wherein the lymphocyte cell is a genetically altered cell.

24. The method of claim 1 , wherein the administering comprises injecting into the patient the pharmaceutical composition.

25. The method of claim 1 , further comprising administering to the patient one or more agents selected from the group consisting of a cytokine and an agonist of RORγ.

26. The method of claim 1 , wherein the patient is a human.

27. The method of claim 1 , wherein the agonist of RORγ is a small organic molecule.

28. The method of claim 1 , wherein the agonist of RORγ is a compound of 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 _6haloalkoxy, —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 —O—[C(R 6 )(R 7 )]—[C(R 6 ) 2 ] m -ψ, —O—C(R 6 ) 2 —C(R 6 )(R 7 )—C(R 6 ) 2 -ψ, —O—C(R 6 ) 2 —C(R 6 )(R 7 )-ψ, —C(R 6 ) 2 —[C(R 6 )(R 7 )]—[C(R 6 ) 2 ] m -ψ, —C(O)—[C(R 6 )(R 7 )]—[C(R 6 ) 2 ] m -ψ, —C(R 6 ) 2 —N(R 8 )—[C(R 6 )(R 7 )]—[C(R 6 ) 2 ]m-ψ, —C(R 6 )═N-ψ, —C(R 6 ) 2 C(R 6 )═N-ψ, —N═C(R 6 )-ψ, or —N═C(R 6 )C(R 6 ) 2 -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.

29. The method of claim 1 , wherein the agonist of RORγ is a compound of 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 2A is one of the following:

(i) hydrogen, C 1-6 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, —(C 1-6 alkylene)-(C 3-6 cycloalkyl), —O—(C 1-6 alkylene)-CO 2 R 4 , —O—(C 1-6 alkylene)-C(O)—(C 1-6 alkyl), —N(R 4 )—(C 1-6 alkylene)-CO 2 R 4 , or —N(R 4 )—(C 1-6 alkylene)-C(O)—(C 1-6 alkyl), wherein the C 1-6 alkyl, C 3-6 cycloalkyl, and C 1-6 alkylene are optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CO 2 R 4 , —C(O)N(R 4 )(R 5 ), —C(O)—N(R 4 )—(C 1-4 alkylene)-CO 2 R 4 , —N(R 4 )C(O)R 8 , —CN, halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, —N(R 4 )(R 5 ), —N(R 4 )C(O)N(R 4 )(R 5 ), —N(R 4 )CO 2 R 9 , —N(R 4 )S(O) 2 R 9 , and —N(R 4 )S(O) 2 N(R 4 )(R 5 ); or

(ii) —CO 2 R 4 , —N(R 4 )C(O)R 9 , —N(R 4 )CO 2 R 9 , —N(R 4 )C(O)N(R 4 )(R 5 ), —N(R 4 )C(O)N(R 4 )(heteroaryl), —N(R 4 )S(O) 2 R 9 , —N(R 4 )(R 5 ), or —OH;

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

R 3 represents independently for each occurrence hydrogen, C 1-6 haloalkyl, halogen, hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —N(R 4 )(R 8 ), —O—(C 1-6 hydroxyalkyl), or —O—(C 1-6 alkylene)-CO 2 R 4 ; or two vicinal occurrences of R 3 are taken together with intervening atoms to form a 4-6 membered ring;

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 6 and R 7 each represent independently for each occurrence hydrogen, fluoro, or C 1-6 alkyl, or R 6 and R 7 are taken together with the carbon atom to which they are attached to form a 3-6 membered carbocyclic ring; or R 6 and a vicinal occurrence of R 2B are taken together to form a bond;

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 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, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;

(ii) —S-aralkyl, —S-heteroaralkyl, —S-phenyl, —S-heteroaryl, —S-(partially unsaturated bicyclic carbocyclyl), —S—(C 1-6 alkylene)-(C 3-6 cycloalkyl), or —S—(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, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;

(iii) —(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), —(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), —(C 1-6 alkylene)-(C 3 -C 6 cycloalkyl), -(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, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;

(iv) —(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, —CO 2 R 4 , and —SO 2 R 9 , wherein A* is a 5-8 membered, partially saturated carbocyclic or heterocyclic ring; or

(v) —(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, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;

Y is —C(R 6 )(R 7 )—, —O—, —C(O)—, or —S(O) p —;

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

n is 1, 2, or 3.

30. The method of claim 29 , wherein A is phenylene or 5-6 membered heteroarylene.

31. The method of claim 30 , wherein R 1 represents independently for each occurrence halogen or C 1-6 alkyl.

32. The method of claim 30 , wherein 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 ), —C(O)—N(R 4 )—(C 1-4 alkylene)-CO 2 R 4 , —N(R 4 )C(O)R 8 , —CN, halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, —N(R 4 )(R 5 ), —N(R 4 )C(O)N(R 4 )(R 5 ), —N(R 4 )CO 2 R 9 , —N(R 4 )S(O) 2 R 9 , and —N(R 4 )S(O) 2 N(R 4 )(R 5 ).

33. A method of treating a medical disorder, comprising administering to a patient in need thereof a lymphocyte cell that has been exposed ex vivo to an agonist of RORγ to treat the medical disorder.

34. The method of claim 33 , wherein the lymphocyte cell is a T cell.

35. The method of claim 33 , wherein the lymphocyte cell is a CD8 + T cell, CD4 + T cell, or T H 17 cell.

36. The method of claim 33 , wherein the lymphocyte cell is a Tc17 cell, natural killer T cell, or γδ T cell.

37. The method of claim 33 , wherein the medical disorder is cancer.