Compounds as cannabinoid receptor ligands

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof,

wherein

X is N;

R 1 is phenyl or quinolin-8-yl wherein said phenyl is substituted with one group represented by R 10 and optionally further substituted with 1, 2, or 3 groups represented by R 11a ; and wherein said quinolin-8-Y1 is optionally substituted with 1 or 2 groups represented by R 11b ;

R 2 is —NR 23a SO 2 R 105a , —NR 23b COR 105b , —NR 23b CO(O)R 105b , —NR 23c CONR 101a R 102a , —NR 23d SO 2 NR 101b R 102b , —NR 23e R 24 , —SO 2 NR 101c R 102c , —OC(O)NR 101a R 102a , A 1 , A 2 , or A 3 ;

A 1 is a monocyclic heterocycle containing 1 or 2 nitrogen atoms and 0 or 1 sulfur atoms, wherein each A 1 is independently unsubstituted or substituted with 1, 2, or 3 substituents represented by R 21a ;

A 2 is a bicyclic spiroheterocycle containing 1 or 2 nitrogen atoms and 0 or 1 sulfur atoms, wherein each A 2 is independently unsubstituted or substituted with 1, 2, or 3 substituents represented by R 21b ;

A 3 is imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, isothiazolyl, triazolyl, or pyridinyl, wherein each A 3 is independently unsubstituted or substituted with 1, 2, or 3 substituents represented by R 22a ;

R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, halo, cyano, or cyanoalkyl;

R 4 is alkyl, alkenyl, alkynyl, cycloalkyl, hydrogen, or haloalkyl;

R 10 is alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkenyl, alkynyl, alkylcarbonyl, cycloalkylalkyl, cyano, cyanoalkyl, formyl, halo, haloalkoxy, haloalkoxyalkoxy, haloalkyl, —CR 106a (═N—OR 106b ), —O—NR 23f R 23g , —O—(CR 25b R 26b ) u -A 4 , —O—(CR 25b R 26b ) u —C(═O)NR 101d R 102d , —O—(CR 25b R 26b ) u —C(═S)NR 101d R 102d , —O—(CR 25b R 26b ) u —SO 2 NR 101d R 102d , —O—(CR 25b R 26b ) q —NR 103 R 104 , —NR 23f R 23g , —NR 23f (CR 25b R 26b ) u -A 4 , —NR 23f —(CR 25b R 26b ) u —C(═O)NR 101d R 102d , —NR 23f —(CR 25b R 26b ) u —C(═S)NR 101d R 102d , —NR 23f —(CR 25b R 26b ) u —SO 2 NR 101d R 102d , —NR 23f —(CR 25b R 26b ) q —NR 103 R 104 , or A 4 ;

R 11a and R 11b at each occurrence, are each independently alkoxy, alkyl, alkenyl, alkynyl, alkylcarbonyl, cycloalkyl, cycloalkyloxy, cyano, cyanoalkyl, formyl, halo, haloalkoxy, haloalkoxyalkoxy, haloalkyl, —CR 106a (═N—OR 106b ), furanyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, pyrazolyl, thiazolyl, oxetanyl, tetrahydrofuranyl, or pyranyl;

R 21a , R 21b , R 21c , and R 21d , at each occurrence, are each independently alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, halo, haloalkyl, haloalkoxy, haloalkoxyalkyl, oxo, ═S, hydroxy, cyano, cyanoalkyl, ═N—CN, ═N—OR 106b , —CR 106a (═N—OR 106b ), —CONR 101d R 102d , —SO 2 NR 101d R 102d , —COR 105d , —C(O)OR 105c , or —SO 2 R 105c ;

R 22a and R 22b , at each occurrence, are each independently alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, halo, haloalkyl, haloalkoxy, haloalkoxyalkyl, hydroxy, cyano, cyanoalkyl, —CR 106a (═N—OR 106b ), —CONR 101d R 102d , —SO 2 NR 101d R 102d , —COR 105d , —C(O)OR 105c , or —SO 2 R 105c ;

R 23a , R 23b , R 23c , R 23d , R 23e , R 23f , and R 23g are each independently hydrogen, alkyl, cycloalkyl, haloalkyl, alkoxyalkyl, or haloalkoxyalkyl;

R 24 is alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, or A 5 ;

A 4 and A 5 , at each occurrence, are each independently a cycloalkyl, a monocyclic heterocycle that is optionally substituted with 1, 2, or 3 substituents represented by R 21c ; a bicyclic spiroheterocycle that is optionally substituted with 1, 2, or 3 substituents represented by R 21d ; or a monocyclic heteroaryl that is optionally substituted with 1, 2, or 3 substituents represented by R 22b ;

R 25a and R 26a , at each occurrence, are each independently hydrogen, alkyl, cyclopropyl, cyclobutyl, cyclopentyl, halo, haloalkyl, or alkoxy; R 25a and R 26a taken together with the carbon atom to which they are attached optionally form a monocyclic ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; wherein each of the cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl is independently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, oxo, hydroxy, cyano, and haloalkoxy;

R 25b and R 26b , at each occurrence, are each independently hydrogen, alkyl, cyclopropyl, cyclobutyl, cyclopentyl, halo, haloalkyl, or alkoxy;

R 101a , R 101b , R 101c , R 102a , R 102b , and R 102c , at each occurrence, are each independently hydrogen, alkyl, alkoxyalkyl, cycloalkyl, haloalkyl or haloalkoxyalkyl; R 101a and R 102a , or R 101b and R 102b , or R 101c and R 102c , together with the respective nitrogen atom to which they are attached optionally form a 4-7 membered monocyclic heterocycle; wherein said monocyclic heterocycle contains 0 or 1 additional heteroatom, 0 or 1 double bond, and is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, halo, hydroxy, and oxo;

R 101d and R 102d , at each occurrence, are each independently hydrogen, alkyl, alkoxyalkyl, cycloalkyl, haloalkyl or haloalkoxyalkyl; R 101d and R 102d , together with the nitrogen atom to which they are attached, optionally form a 4-7 membered monocyclic heterocycle; wherein said monocyclic heterocycle contains 0 or 1 additional heteroatom, 0 or 1 double bond, and is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, halo, hydroxy, and oxo;

R 103 is hydrogen, alkyl, haloalkyl, or alkoxyalkyl;

R 104 is hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, alkoxyalkyl, cycloalkyl, haloalkyl, or haloalkoxyalkyl;

R 105a , R 105b , and R 105c , at each occurrence, are each independently alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkyl, or cyanoalkyl;

R 105d , at each occurrence, is independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkyl, or cyanoalkyl;

R 106a and R 106b , at each occurrence, are each independently hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, or cyclobutyl;

n is 1, 2, 3, or 4;

u is 0, 1, 2, 3, or 4;

q is 2, 3, or 4, and

each occurrence of the cycloalkyl, the cycloalkyl moiety of the cycloalkylalkyl and the cycloalkyloxy, the cyclopropyl, the cyclobutyl, and the cyclopentyl, as represented by R 3 , R 4 , R 10 , R 11a , R 11b , R 23a , R 23b , R 23c , R 23d , R 23e , R 23f , R 23g , A 4 , A 5 , R 25a , R 26a , R 25b , R 26b , R 101a , R 101b , R 101c , R 101d , R 102a , R 102b , R 102c , R 102d , R 104 , R 105a , R 105b , R 105c , R 105d , R 106a , and R 106b , are each independently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, oxo, hydroxy, cyano, and haloalkoxy.

2. The compound of claim 1 having formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 is —NR 23a SO 2 R 105a , —NR 23b C(O)OR 105b , —NR 23e R 24 , —SO 2 NR 101c R 102c , or —OC(O)NR 101a R 102a .

3. The compound of claim 1 having formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 is A 1 , A 2 or A 3 .

4. The compound of claim 1 having formula (I-A), or a pharmaceutically acceptable salt thereof

wherein y is 0, 1, 2, or 3.

5. The compound of claim 4 having formula (I-A), or a pharmaceutically acceptable salt thereof wherein R 2 is —NR 23a SO 2 R 105a , —NR 23b (O)OR 105b , NR 23c R 24 , —SO 2 NR 101c R 102c , or —OC(O)NR 101a R 102a .

6. The compound of claim 4 having formula (I-A), or a pharmaceutically acceptable salt thereof wherein R 2 is —NR 23a SO 2 R 105a , —NR 23b C(O)OR 105b , —NR 23e R 24 , —SO 2 NR 101c R 102c , or —OC(O)NR 101a R 102a ; and R 3 is C 1-6 alkyl, optionally substituted cycloalkyl, halo, haloalkyl, or hydroxyalkyl.

7. The compound of claim 4 having formula (I-A), or a pharmaceutically acceptable salt thereof wherein R 2 is A 1 , A 2 , or A 3 .

8. The compound of claim 4 having formula (I-A), or a pharmaceutically acceptable salt thereof wherein R 2 is A 1 , and R 3 is C 1-6 alkyl, optionally substituted cycloalkyl, halo, haloalkyl, or hydroxyalkyl.

9. The compound of claim 4 having formula (I-A), or a pharmaceutically acceptable salt thereof wherein R 2 is A 3 , and R 3 is C 1-6 alkyl, optionally substituted cycloalkyl, halo, haloalkyl, or hydroxyalkyl.

10. The compound of claim 1 having formula (I-D), or a pharmaceutically acceptable salt thereof

wherein z is 0, 1, or 2.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of

N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;

N-[(2Z)-5-tert-butyl-3-{[(2R)-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;

N-[(2Z)-5-tert-butyl-3-{[(2S)-1-methyl-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;

N-[(2Z)-5-tert-butyl-3-(1,3-thiazol-4-ylmethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;

2-[(tert-butylamino)oxy]-N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

N-[(2Z)-5-tert-butyl-3-{[(2R)-5-thioxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;

N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-2-methoxy-5-(trifluoromethyl)benz amide;

N-[(2Z)-5-tert-butyl-3-{[(2R)-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-2-methoxy-5-(trifluoromethyl)benz amide; and

N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-2-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-5-(trifluoromethyl)benzamide.

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carrier.

13. A method for treating pain in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof.