Cannabinoid receptor ligands

1. A compound of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein:

R 1 is H, alkyl, haloC 1 -C 6 alkyl, cycloalkyl, cycloalkylNH—, arylalkyl, heterocycloalkyl, heteroaryl, N(R 2 ) 2 , or NR 2 aryl, unsubstituted aryl or aryl substituted with one to three X;

R 2 is the same or different in each occurrence and is independently selected from H or C 1 -C 6 alkyl;

R 3 is H, C 1 -C 6 alkyl, Cl, F, CF 3 , OCF 2 H, OCF 3 , OH or C 1 -C 6 alkoxy;

R 4 is heteroaryl, heterocycloalkyl, or heteroarylNH—, wherein said heteroaryl is optionally substituted with from one to three X;

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 form a carbonyl group;

L 1 is C 1 -C 6 alkylene, C 3 -C 6 alkenylene,

L 2 is a covalent bond, C 1 -C 6 alkylene,

X is the same or different, and is independently selected from 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 , NHR 2 , arylNH—, N(R 2 ) 2 , or NR 2 aryl;

Y is a covalent bond,

Z is a covalent bond,

Y, R 1 , Z and R 2 can be taken together with the nitrogen atom to form a heterocycloalkyl; with the proviso that if Y is a covalent bond, R 1 cannot form a N—N bond with the nitrogen atom; and

n is an integer of 0 to 4.

2. A compound according to claim 1 wherein

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 3 ) 2 , thiophenyl, morpholinyl, cyclopropanyl, 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 4 is furanyl, pyridyl, pyrimidyl, thiophenyl, quinolyl, dimethylpyrimdyl, or morpholinyiphenyl, all of the above optionally substituted with one to three substituents, which are the same or different and are independently selected from X;

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

X is H, Cl, CF 3 , OCH 3 , OCF 3 , OCF 2 H, CH 3 or C 1 -C 6 cycloalkyl;

Y is

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

L 1 is —SO 2 — or —CH 2 —;

L 2 is —SO 2 —;

R 1 is CH 3 or CF 3 ; and

R 4 is pyrimidyl or pyridyl, each of said pyrimidyl or pyridyl is optionally substituted with one to three substitutents which are the same or different, and are independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, OH, CF 3 and halogen.

4. The compound according to claim 1 of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug;

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

Example

X

R 4

P

OCH 3

T

Cl

U

OCH 3

AO

Cl

AV

Cl

FV

H

5. The compound according to claim 1 of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug;

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

Example

X

R 4

AW

Cl

GG

Cl

GH

CF 3

6. A pharmaceutical composition comprising an effective amount of a compound, a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug, according to claim 1 and a pharmaceutically acceptable carrier.

7. A pharmaceutical composition comprising an effective amount of a compound, a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug, according to claim 5 and a pharmaceutically acceptable carrier.

8. A method of treating inflammation or a respiratory disease selected from the group consisting of asthma, COPD, reversible airway obstruction, adult respiratory distress sydrome, and bronchitis, comprising administering to a mammal in need of such treatment an effective amount of a compound, a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug, according to claim 1 .

9. A method of treating rheumatoid arthritis, multiple sclerosis, seasonal allergic rhinitis or chronic obstructive pulmonary disease comprising administering to a mammal in need of such treatment an effective amount of a compound, a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug, according to claim 1 .

10. A pharmaceutical composition made by combining a compound, a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug, of claim 1 and a pharmaceutically acceptable carrier therefor.

11. A process for making a pharmaceutical composition comprising combining a compound, a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of a compound or of said prodrug, of claim 1 and a pharmaceutically acceptable carrier.

12. A method of treating rheumatoid arthritis which comprises co-administration of or use in combination with a COX-2 inhibitor, a COX-1 inhibitor, an immunosuppressive selected from the group consisting of cyclosporin, tacrolimus, rapamycin, muromonab-CD3, basiliximab, methotrexate, leflunimide, sulfasalazine, or glatiramer acetate, a steroid selected from glucocorticoids and secosteroids, or an anti-TNF-α compound and a compound, a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug, as defined in claim 1 .

13. A method of treating rheumatoid arthritis which comprises co-administration of a COX-2 inhibitor, a COX-1 inhibitor, an immunosuppressive selected from the group consisting of cyclosporin, tacrolimus, rapamycin, muromonab-CD3, basiliximab, methotrexate, leflunimide, sulfasalazine, or glatiramer acetate, a steroid selected from glucocorticoids and secosteroids, an anti-TNF-α compound, or a PDE IV inhibitor and a compound, a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug, as defined in claim 5 .

14. The method of claim 12 wherein the COX-2 inhibitor is celcoxib or rofexoxib, the COX-1 inhibitor is piroxicam, the immunosuppressive is methotrexate, leflunimide, sulfasalazine or cyclosporin, the steroid is β-methasone and the anti-TNF-α compound is etanercept or infliximab.

15. The method of claim 13 wherein the COX-2 inhibitor is celcoxib or rofexoxib, the COX-1 inhibitor is piroxicam, the immunosuppressive is methotrexate, leflunimide, sulfasalazine or cyclosporin, the steroid is β-methasone and the anti-TNF-α compound etanercept or infliximab.

16. A composition which comprises a COX-2 inhibitor, a COX-1 inhibitor, an immunosuppressive selected from the group consisting of cyclosporine, tacrolimus, rapamycin, muromonab-CD3, basiliximab, methotrexate, leflunimide, sulfasalazine, and glatiramer acetate, a steroid selected from a glucocorticoid and a secosteroid, or an anti-TNF-α compound and a compound, a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug, as defined in claim 1 .

17. A composition which comprises a COX-2 inhibitor, a COX-1 inhibitor, an immunosuppressive, selected from the group consisting of cyclosporine, tacrolimus, rapamycin, muromonab-CD3, basiliximab, methotrexate, leflunimide, sulfasalazine, and glatiramer acetate, a steroid selected from a glucocorticoid and a secosteroids, or an anti-TNF-α compound and a compound, a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug, as defined in claim 5 .

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

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

20. A method of treating multiple sclerosis which comprises co-administration of or use in combination with a compound selected from interferon beta-1, interferon beta 1b, and glatiramer acetate, and a compound a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug, as defined in claim 1 .

21. A method of treating multiple sclerosis which comprises co-administration of or use in combination with a compound selected from interferon beta-1, interferon beta 1b, and glatiramer acetate, and a compound a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug, as defined in claim 5 .

22. A composition which comprises a compound selected from interferon beta-1, interferon beta 1b, and glatiramer acetate and a compound, a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug, as defined in claim 1 .

23. A composition which comprises a compound selected from interferon beta-1, interferon beta 1b, and glatiramer acetate and a compound, a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug, as defined in claim 5 .

24. A method of treating psoriasis which comprises co-administration of or use in combination with an immunosuppressive selected from the group consisting of cyclosporine, tacrolimus, rapamycin, muromonab-CD3, basiliximab, methotrexate, leflunimide, sulfasalazine, and glatiramer acetate, a steroid selected from a glucocorticoid and a secosteroid, or an anti-TNF-α compound and a compound, a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug, as defined in claim 1 .

25. A method of treating psoriasis which comprises co-administration of or use in combination with an immunosuppressive selected from the group consisting of cyclosporine, tacrolimus, rapamycin, muromonab-CD3, basiliximab, methotrexate, leflunimide, sulfasalazine, and glatiramer acetate, a steroid selected from a glucocorticoid and a secosteroids, or an anti-TNF-α compound and a compound, a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug, as defined in claim 5 .

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

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

28. A composition which comprises a compound selected from an immunosuppressive selected from the group consisting of cyclosporine, tacrolimus, rapamycin, muromonab-CD3, basiliximab, methotrexate, leflunimide, sulfasalazine, and a glatiramer acetate, a steroid selected from a glucocorticoid and a secosteroid, and an anti-TNF-α compound and a compound, a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug, as defined in claim 1 .

29. A composition which comprises a compound selected from an immunosuppressive selected from the group consisting of cyclosporine, tacrolimus, rapamycin, muromonab-CD3, basiliximab, methotrexate, leflunimide, sulfasalazine, and glatiramer acetate, a steroid selected from a glucocorticoid and a secosteroid, or an anti-TNF-α compound and a compound, a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug, as defined in claim 5 .

30. The composition of claim 28 wherein the immunosuppressive is methotrexate, leflunimide, sulfasalazine or cyclosporin, the steroid is β-methasone and the anti-TNF-α compound is etanercept or infliximab.

31. The composition of claim 29 wherein the immunosuppressive is methotrexate, leflunimide, sulfasalazine or cyclosporin, the steroid is β-methasone and the anti-TNF-α compound is etanercept or infliximab.

32. A compound of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein:

R 1 is H, alkyl, haloC 1 -C 6 alkyl, cycloalkyl, cycloalkylNH—, arylalkyl, heterocycloalkyl, heteroaryl, N(R 2 ) 2 , or NR 2 aryl, unsubstituted aryl or aryl substituted with one to three X;

R 2 is the same or different in each occurrence and is independently selected from H or C 1 -C 6 alkyl;

R 3 is H, C 1 -C 6 alkyl, Cl, F, CF 3 , OCF 2 H, OCF 3 , OH or C 1 -C 6 alkoxy;

R 4 is heteroaryl, heterocycloalkyl, or heteroarylNH—, wherein said heteroaryl is optionally independently substituted with from one to three X;

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 form a carbonyl group;

L 1 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene,

L 2 is a covalent bond, C 1 -C 6 alkylene,

X is the same or different, and is independently selected from 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 , NHR 2 , arylNH—, N(R 2 ) 2 , or NR 2 aryl;

Y is a covalent bond,

Z is a covalent bond,

Y, R 1 , Z and R 2 can be taken together with the nitrogen atom to form a heterocycloalkyl; with the proviso that if Y is a covalent bond, R 1 cannot form a N—N bond with the nitrogen atom; and

n is an integer of 0to 4;

with the proviso that, when R 5 and R 6 are taken together with the carbon atom to form a carbonyl group, L 1 is C 1 -C 6 alkylene, C 3 -C 6 alkenylene,

33. A compound of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein:

R 1 is H, alkyl, haloC 1 -C 6 alkyl, cycloalkyl, cyclcalkylNH—, arylalkyl, heterocycloalkyl, heteroaryl, N(R 2 ) 2 , or NR 2 aryl, unsubstituted aryl or aryl substituted with one to three X;

R 2 is the same or different In each occurrence and is independently selected from H or C 1 -C 6 alkyl;

R 3 is H, C 1 -C 6 alkyl, Cl, F, CF 3 , OCF 2 H, OCF 3 , OH or C 1 -C 6 alkoxy;

R 4 is heteroaryl, heterocycloalkyl, or heteroarylNH—, wherein said is heteroaryl optionally independently substituted with from one to three X;

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 form a carbonyl group;

L 1 is C 1 -C 6 alkylene, C 2 -C 6 alkylene,

L 2 is a covalent bond, C 1 -C 6 alkylene,

X is the same or different, and is independently selected from 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 , NHR 2 , arylNH—, N(R 2 ) 2 , or NR 2 aryl;

Y is a covalent bond,

Z is a covalent bond,

Y, R 1 , Z and R 2 can be taken together with the nitrogen atom to form a heterocycloalkyl; with the proviso that if Y is a covalent bond, R 1 cannot form a N—N bond with the nitrogen atom; and

n is an integer of 0 to 4;

with the proviso that, when L 2 is

L 1 is C 1 -C 6 alkylene, C 3 -C 6 alkenylene,

34. A compound of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein:

R 1 is H, alkyl, haloC 1 -C 6 alkyl, cycloalkyl, cycloalkylNH—, arylalkyl, heterocycloalkyl, heteroaryl, N(R 2 ) 2 , or NR 2 aryl, unsubstituted aryl or aryl substituted with one to three X;

R 2 is the same or different in each occurrence and is independently selected from H or C 1 -C 6 alkyl;

R 3 is H, C 1 -C 6 alkyl, Cl, F, CF 3 , OCF 2 H, OCF 3 , OH or C 1 -C 6 alkoxy;

R 4 is heteroaryl, heterocycloalkyl, or heteroarylNH—, wherein said is heteroaryl optionally independently substituted with from one to three X;

R 5 is H or C 1 -C 6 alkyl;

R 6 is H or C 1 -C 6 alkyl; or

R 5 R 6 taken together with the carbon atom form a carbonyl group;

L 1 is C 1 -C 6 alkylene,

L 2 is a covalent bond, C 1 -C 6 alkylene,

X is the same or different, and is independently selected from 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 , NHR 2 , arylNH—, N(R 2 ) 2 , or NR 2 aryl;

Y is a covalent bond,

Z is a covalent bond,

Y, R 1 , Z and R 2 can be taken together with the nitrogen atom to form a heterocycloalkyl; with the proviso that if Y is a covalent bond, R 1 cannot form a N—N bond with the nitrogen atom; and

n is an integer of 0 to 4.