Cannabinoid receptor ligands

1. A compound of the formula

or a pharmaceutically acceptable salt or solvate thereof; wherein:

R 1 is selected from the group consisting of H, alkyl, haloC 1 –C 6 alkyl, cycloalkyl, cycloalkylNH—, arylalkyl, heterocycloalkyl, heteroaryl, —N(R 2 ) 2 , —N(R 2 )aryl, unsubstituted aryl and aryl substituted with one to three X, wherein each R 2 can be the same or different and is independently selected when there are more than one R 2 present;

R 2 is selected from the group consisting of H and C 1 –C 6 alkyl;

R 3 is 1–3 substituents selected from the group consisting of H, C 1 –C 6 alkyl, Cl, F, CF 3 , OCF 2 H, OCF 3 , OH and C 1 –C 6 alkoxy, wherein R 3 can be the same or different and is independently selected when there are more than one R 3 present;

R 4 is pyridine-N-oxide or pyridyl optionally substituted with one to three X, wherein X can be the same or different and is independently selected when there are more than one X present;

R 5 is H or C 1 –C 6 alkyl;

R 6 is H or C 1 –C 6 alkyl; or

R 5 and R 6 taken together with the carbon atom to which they are attached form a carbonyl group;

L 1 is —SO 2 —, —SO—, or —S—;

L 2 is —SO 2 —, —SO—, or —S—;

X is selected from the group consisting of H, halogen, CF 3 , CN, OCF 2 H, OCF 2 CF 3 , OCF 3 , OR 2 , C 1 –C 6 alkyl, cycloalkyl, cycloalkoxy, C 1 –C 6 alkoxy, alkoxyC 1 –C 6 alkoxy, O-cycloalkyl, cycloalkylamino, cycloalkylalkoxy, heteroalkyl, —OSO 2 R 2 ,

—COOR 2 , —CON(R 2 ) 2 , N(R 2 ) 2 , and NR 2 aryl, wherein X can be the same or different, and is independently selected when there are more than one X present;

Y is a covalent bond, —CH 2 —, —SO 2 —, or —C(O)—;

Z is a covalent bond, —CH 2 —, —SO 2 — or —C(O)—; or

Y, R 1 , Z and R 2 can be taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl; with the following provisos:

L 2 and R 4 , when taken together, cannot have two heteroatoms covalently bonded together;

when R 2 is H, Z cannot be —S(O)—, —SO 2 —, or —C(O)—; and

when Y is a covalent bond, R 1 cannot form a N—N bond with the nitrogen atom.

2. A compound according to claim 1 wherein

L 1 is —SO 2 —, —S— or —S(O)—;

L 2 is —SO 2 —;

R 1 is H, —CH 3 NH 2 , —CH 2 CF 3 , —NHC 3 H 7 , —NHC 2 H 6 , —NHC 4 H 9 , C 1 –C 6 alkyl, —CF 3 , —CH(CH 2 ) 2 , thiophenyl, morpholinyl, cyclopropyl, benzyl, naphthyl, —C(CH 3 ) 3 , NHphenyl, 3,5-difluorophenyl, phenyl, N-cyclopentyl or N(CH 3 ) 2 ;

R 2 is H or CH 3 ;

R 3 is OH;

R 4 is pyridyl optionally substituted with one to three X, wherein X can be the same or different and are independently selected when the are more than one X present;

R 5 and R 6 are independently H or CH 3 ;

Y is a covalent bond, —SO 2 — or —C(O)—;

Z is a covalent bond; or

R 1 , Y, R 2 and Z taken together with the nitrogen atom form a morpholinyl group.

3. The compound according to claim 2 wherein

X is halogen, OH, or cyclopropyl;

R 3 is OH;

R 5 and R 6 are independently H or CH 3 ;

X is H, halogen, CF 3 , OCH 3 , OH, OCF 3 , OCF 2 H, CH 3 or C 1 –C 6 cycloalkyl;

Y is a covalent bond;

Z is —SO 2 — or —C(O)—;

L 1 is —SO 2 —;

L 2 is —SO 2 —;

R 1 is CH 3 or CF 3 ; and

R 4 is pyridyl, and said pyridyl group is optionally substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl, C 1 –C 6 alkoxy, OH, CF 3 and halogen, wherein said substituents can be the same or different and are independently selected when there is more than one substituent.

4. The compound according to claim 1 of the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein X and R 4 are as shown in the table below:

Example

X

R 4

T

Cl

AO

Cl

5. The compound according to claim 1 of the formula

or a pharmaceutically acceptable salt or solvate thereof,

wherein X and R 4 are as shown in the table below:

Example

X

R 4

GG

Cl

GH

CF 3

6. The compound according to claim 1 of the formula

or a pharmaceutically acceptable salt or solvate thereof;

wherein X, R 1 and R 4 are as shown in the table below:

Example

X

R 1

R 4

GG

Cl

CF 3

GH

CF 3

CF 3

XXIX

CF 3

XXXI

CF 3

XXXV

Cl

CF 3

XXXVI

Cl

CF 3

XXXVII

CF 3

XXXVIII

CN

CF 3

XXXXXV

OCH 3

CF 3

XXXXXVI

CH 3

7. The compound according to claim 1 of the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein X is cyclopropyl and R 1 is CF 3 .

8. The compound according to claim 1 of the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein X is Cl and R 1 is CF 3 .

9. The compound according to claim 1 of the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein X is CF 3 and R 1 is CF 3 .

10. The compound according to claim 1 of the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein X is cyclopropyl and R 1 is CF 3 .

11. The compound according to claim 1 of the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein X is Cl and R 1 is CF 3 .

12. The compound according to claim 1 of the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein X is cyclopropyl and R 1 is CH 3 .

13. A pharmaceutical composition comprising one or more compounds according to claim 1 and one or more pharmaceutically acceptable carriers.

14. A pharmaceutical composition comprising one or more compounds according to claim 5 and one or more pharmaceutically acceptable carriers.

15. A pharmaceutical composition made by combining one or more compounds of claim 1 and one or more pharmaceutically acceptable carriers.

16. A composition which comprises one or more compounds selected from the group consisting of a COX-2 inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, and an anti-TNF-α compound, and one or more compounds of claim 1 .

17. A composition which comprises one or more compounds selected from the group consisting of a COX-2 inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, and an anti-TNF-α compound, and one or more compounds of claim 5 .

18. The composition of claim 16 wherein the COX-2 inhibitor is celecoxib or rofecoxib, the COX-1 inhibitor is piroxicam, the immunosuppressive is methotrexate, leflunomide, sulfasalazine or cyclosporin, the steroid is β-methasone and the anti-TNF-α compound is etanercept or infliximab.

19. The composition of claim 17 wherein the COX-2 inhibitor is celecoxib or rofecoxib, the COX-1 inhibitor is piroxicam, the immunosuppressive is methotrexate, leflunomide, sulfasalazine or cyclosporin, the steroid is β-methasone and the anti-TNF-α compound is etanercept or infliximab.

20. A composition which comprises one or more compounds selected from the group consisting of interferon beta-1a, interferon beta-1b, and glatiramer acetate, and one or more compounds of claim 1 .

21. A composition which comprises one or more compounds selected from the group consisting of interferon beta-1a, interferon beta-1b, and glatiramer acetate, and one or more compounds of claim 5 .

22. A composition which comprises one or more compounds selected from the group consisting of an immunosuppressive, a steroid, and an anti-TNF-α compound, and one or more compounds of claim 1 .

23. A composition which comprises one or more compounds selected from the group consisting of an immunosuppressive, a steroid, and an anti-TNF-α compound, and one or more compounds of claim 5 .

24. The composition of claim 22 wherein the immunosuppressive is methotrexate, leflunomide, sulfasalazine or cyclosporin, the steroid is β-methasone and the anti-TNF-α compound is etanercept or infliximab.

25. The composition of claim 23 wherein the immunosuppressive is methotrexate, leflunomide, sulfasalazine or cyclosporin, the steroid is β-methasone and the anti-TNF-α compound is etanercept or infliximab.

26. The compound according to claim 1 of the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein X is cyclopropyl and R 1 is CF 3 .

27. The compound according to claim 1 of the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein X is Cl and R 1 is CF 3 .

28. The compound according to claim 1 of the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein X is CF 3 and R 1 is CF 3 .

29. The compound according to claim 1 of the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein X is cyclopropyl and R 1 is CF 3 .

30. The compound according to claim 1 of the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein X is Cl and R 1 is CF 3 .

31. compound according to claim 1 of the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein X is cyclopropyl and R 1 is CH 3 .