Liver X receptor (LXR) modulators for the treatment of dermal diseases, disorders and conditions

1. A compound of Formula (E):

wherein:

A and B are each nitrogen, wherein A and B are bonded together to form a five-membered heteroaryl ring;

L 1 is a bond, C 1 -C 6 alkyl, or C 1 -C 6 heteroalkyl;

L 2 is C 1 -C 6 alkyl or C 1 -C 6 heteroalkyl;

R 1 is hydrogen, halogen, —CF 3 , —OR 8 , —N(R 8 ) 2 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)N(R 8 ) 2 , —C(═N—OH)R 8 , —C(═S)N(R 8 ) 2 , —C(═CH 2 )CH 3 , or —C(═O)OCH 2 SCH 3 ;

R 2 is —C(═O)OR 9 , —C(═O)N(R 9 ) 2 , —NR 10 C(═O)R 9 , —C(═N—OH)R 9 , —C(═S)N(R 9 ) 2 , or —C(═O)OCH 2 SCH 3 ;

R 3 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R 4 is aryl or heteroaryl; wherein aryl or heteroaryl is substituted with at least one R 11 ;

each R 8 , each R 9 , and each R 10 are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, —C 1 -C 6 alkyl-aryl, aryl, or heteroaryl;

each R 11 is independently halogen, nitro, —OR 10 , —N(R 10 ) 2 , —CN, —C(═O)R 10 , —C(═O)OR 10 , —C(═O)N(R 10 ) 2 , —NR 10 C(═O)R 10 , NR 10 SO 2 R 10 , —SOR 10 , —SO 2 R 10 , —SO 2 N(R 10 ) 2 , —C(═O)OCH 2 SCH 3 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, —C 1 -C 6 alkyl-aryl, optionally substituted aryl, or optionally substituted heteroaryl;

or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

2. The compound of claim 1 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein R 4 is aryl.

3. The compound of claim 2 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein R 2 is —C(═O)OR 9 ; and R 9 is C 1 -C 6 alkyl or C 1 -C 6 heteroalkyl.

4. The compound of claim 3 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein L 2 is C 1 -C 6 alkyl.

5. The compound of claim 4 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein L 2 is —CH 2 —.

6. The compound of claim 5 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein L 1 is a bond.

7. The compound of claim 6 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein R 1 is —CF 3 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)N(R 8 ) 2 , or —C(═CH 2 )CH 3 .

8. The compound of claim 7 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein R 4 is phenyl; wherein phenyl is substituted with one R 11 .

9. The compound of claim 8 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein R 11 is —SO 2 R 10 and R 10 is C 1 -C 6 alkyl.

10. A compound of Formula (F):

wherein:

X is —S—;

A and B are each nitrogen, wherein A and B are bonded together to form a five-membered heteroaryl ring;

L 1 is a bond, C 1 -C 6 alkyl, or C 1 -C 6 heteroalkyl;

L 2 is C 1 -C 6 alkyl or C 1 -C 6 heteroalkyl;

R 1 is hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —CF 3 , —OR 8 , —N(R 8 ) 2 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)N(R 8 ) 2 , —C(═N—OH)R 8 , —C(═S)N(R 8 ) 2 , —C(═CH 2 )CH 3 , or —C(═O)OCH 2 SCH 3 ;

R 2 is —C(═O)OR 13 , —NR 10 C(═O)R 9 , —C(═N—OH)R 9 , —C(═S)N(R 9 ) 2 , or —C(═O)OCH 2 SR 15 ;

R 3 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R 4 is aryl or heteroaryl; wherein aryl or heteroaryl is substituted with at least one R 11 ;

each R 8 , each R 9 , and each R 10 are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, —C 1 -C 6 alkyl-aryl, aryl, or heteroaryl;

each R 11 is independently halogen, nitro, —OR 10 , —N(R 10 ) 2 , —CN, —C(═O)R 10 , —C(═O)OR 10 , —C(═O)N(R 10 ) 2 , —NR 10 C(═O)R 10 , NR 10 SO 2 R 10 , —SOR 10 , —SO 2 R 14 , —SO 2 N(R 10 ) 2 , —C(═O)OCH 2 SCH 3 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted —C 1 -C 6 alkyl-aryl, optionally substituted aryl, or optionally substituted heteroaryl;

R 13 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, —C 1 -C 6 alkyl-aryl, aryl, or heteroaryl;

R 14 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, —C 1 -C 6 alkyl-aryl, aryl, or heteroaryl;

R 15 is C 1 -C 6 alkyl;

or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.

11. The compound of claim 10 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein:

R 2 is —C(═O)OR 13 and R 13 is C 2 -C 6 alkyl, C 1 -C 6 heteroalkyl, —C 1 -C 6 alkyl-aryl, aryl, or heteroaryl;

R 13 is C 2 -C 6 alkyl or C 1 -C 6 heteroalkyl;

R 4 is phenyl, wherein R 4 is substituted with at least two R 11 ; and

each R 11 is independently halogen, —SO 2 R 14 , —NR 10 SO 2 R 10 , or —SO 2 N(R 10 ) 2 .

12. The compound of claim 10 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein:

R 2 is —C(═O)OR 13 and R 13 is C 2 -C 6 alkyl, C 1 -C 6 heteroalkyl, —C 1 -C 6 alkyl-aryl, aryl, or heteroaryl;

R 13 is C 2 -C 6 alkyl or C 1 -C 6 heteroalkyl;

R 4 is phenyl, wherein R 4 is substituted with one R 11 and R 11 is —SO 2 R 14 ; and R 14 is C 2 -C 6 alkyl;

R 14 is C 2 -C 6 alkyl;

L 2 is —CH 2 —;

L 1 is a bond; and

R 1 is hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —OR 8 , —N(R 8 ) 2 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)N(R 8 ), —C(═N—OH)R 8 , —C(═S)N(R 8 ) 2 , —C(═CH 2 )CH 3 , or —C(═O)OCH 2 SCH 3 .

13. The compound of claim 1 , selected from:

or a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate thereof.

14. The compound of claim 10 , selected from:

or a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate thereof.

15. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.

16. A method of modulating LXR activity, comprising contacting LXR, or portion thereof, with a compound according to claim 1 , or a pharmaceutically acceptable salt or pharmaceutically acceptable thereof.

17. A method of treating a dermal disease, disorder or condition selected from skin aging, scarring, psoriasis, dermatitis, eczema, urticaria, rosacea, burns, and acne in a mammal, comprising administering to the mammal a compound according to claim 1 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

18. A pharmaceutical composition comprising a compound according to claim 10 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.

19. A method of modulating LXR activity, comprising contacting LXR, or portion thereof, with a compound according to claim 10 , or a pharmaceutically acceptable salt or pharmaceutically acceptable thereof.

20. A method of treating a dermal disease, disorder or condition selected from skin aging, scarring, psoriasis, dermatitis, eczema, urticaria, rosacea, burns, and acne in a mammal, comprising administering to the mammal a compound according to claim 10 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

21. A compound, which is:

or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.

22. A pharmaceutical composition comprising a compound according to claim 21 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.

23. A method of modulating LXR activity, comprising contacting LXR, or portion thereof, with a compound according to claim 21 , or a pharmaceutically acceptable salt or pharmaceutically acceptable thereof.

24. A method of treating a dermal disease, disorder or condition selected from skin aging, scarring, psoriasis, dermatitis, eczema, urticaria, rosacea, burns, and acne in a mammal, comprising administering to the mammal a compound according to claim 21 , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

25. The compound of claim 15 , which is:

26. A pharmaceutical composition comprising a compound according to claim 25 and a pharmaceutically acceptable carrier.

27. A method of modulating LXR activity, comprising contacting LXR, or portion thereof, with a compound according to claim 25 .

28. A method of treating a dermal disease, disorder or condition selected from skin aging, scarring, psoriasis, dermatitis, eczema, urticaria, rosacea, burns, and acne in a mammal, comprising administering to the mammal a compound according to claim 25 .