Compounds as cannabinoid receptor ligands

1. A compound according to formula (I), or a pharmaceutically acceptable salt, solvate, salt of a solvate, prodrug, salt of a prodrug, or a combination thereof

wherein

R 1 is aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; each of which is substituted by one R x group and each is optionally further substituted with 1, 2, 3, or 4 R y group(s);

R x is —O—(CR 1a R 1b ) q1 —N(R 1m ) 2 or —O-G 1 ;

each R y is independently G 1d , alkyl, alkenyl, alkynyl, halogen, haloalkyl, ═N—CN, NO 2 , ═N—OR f , —CN, oxo, —OR f , —OC(O)R f , —OC(O)N(R f ) 2 , —S(O) 2 R e , —S(O) 2 N(R f ) 2 , —C(O)R f , —C(O)OR f , —C(O)N(R f ) 2 , —N(R f ) 2 , —N(R f )C(O)R f , —N(R f )S(O) 2 R e , —N(R f )C(O)O(R e ), —N(R f )C(O)N(R f ) 2 , —N(R f )S(O) 2 N(R f ) 2 , —(CR 1c R 1d ) q2 —OR f , —(CR 1c R 1d ) q2 —OC(O)R f , —(CR 1c R 1d ) q2 —OC(O)N(R f ) 2 , —(CR 1c R 1d ) q2 —S(O) 2 R e , —(CR 1c R 1d ) q2 —S(O) 2 N(R f ) 2 , —(CR 1c R 1d ) q2 —C(O)R f , —(CR 1c R 1d ) q2 —C(O)OR f , —(CR 1c R 1d ) q2 —C(O)N(R f ) 2 , —(CR 1c R 1d ) q2 —N(R f ) 2 , —(CR 1c R 1d ) q2 —N(R f )C(O)R f , —(CR 1c R 1d ) q2 —N(R f )S(O) 2 R e , —(CR 1c R 1d ) q2 —N(R f )C(O)O(R e ), —(CR 1c R 1d ) q2 —N(R f )C(O)N(R f ) 2 , —(CR 1c R 1d ) q2 —N(R f )S(O) 2 N(R f ) 2 , or —(CR 1c R 1d ) q2 —CN;

R 1m , at each occurrence, is independently, hydrogen or C 1 -C 4 alkyl;

R 1a , at each occurrence, is independently hydrogen or C 1 -C 4 alkyl;

R 1b , at each occurrence, is independently hydrogen or C 1 -C 4 alkyl;

G 1 is cycloalkyl, cycloalkenyl, aryl, heterocycle, or heteroaryl; each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of oxo, alkyl, alkenyl, alkynyl, halogen, haloalkyl, ═N—CN, —C(═NOR f )R a , ═N—OR f , —CN, NO 2 , oxo, —OR a , —OC(O)R a , —OC(O)N(R b )(R c ), —S(O)R d , —S(O) 2 R d , —S(O) 2 N(R b )(R c ), —C(O)R a , —C(O)OR a , —C(O)N(R b )(R c ), —N(R b )(R c ), —N(R c )C(O)R a , —N(R c )S(O) 2 R d , —N(R c )C(O)O(R a ), —N(R c )S(O) 2 N(R b )(R c ), —N(R c )C(O)N(R b )(R c ), —(CR 1c R 1d ) q3 —OR a , —(CR 1c R 1d ) q3 —OC(O)R a , —(CR 1c R 1d ) q3 —OC(O)N(R b )(R c ), —(CR 1c R 1d ) q3 —S(O)R d , —(CR 1c R 1d ) q3 —S(O) 2 R d , —(CR 1c R 1d ) q3 —S(O) 2 N(R b )(R c ), —(CR 1c R 1d ) q3 —C(O)R a , —(CR 1c R 1d ) q3 —C(O)OR a , —(CR 1c R 1d ) q3 —C(O)N(R b )(R c ), —(CR 1c R 1d ) q3 —N(R b )(R c ), —(CR 1c R 1d ) q3 —N(R c )C(O)R a , —(CR 1c R 1d ) q3 —N(R c )S(O) 2 R d , —(CR 1c R 1d ) q3 —N(R c )C(O)O(R a ), —(CR 1c R 1d ) q3 —N(R c )S(O) 2 N(R b )(R c ), —(CR 1c R 1d ) q3 —N(R c )C(O)N(R b )(R c ), and —(CR 1c R 1d ) q3 —CN;

R a and R c , at each occurrence, are each independently hydrogen, alkyl, haloalkyl, —(CR 1a′ R 1b′ ) q4 -A 3 , G 1d , or —(CR 1a′ R 1b′ ) q4 -G 1d ;

R b , at each occurrence, is independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, monocyclic cycloalkyl, —(CR 1c R 1d ) q4 -(monocyclic cycloalkyl), or haloalkoxyalkyl;

R d , at each occurrence, is independently alkyl, haloalkyl, —(CR 1a′ R 1b′ ) q4 -A 3 , G 1d , or —(CR 1a′ R 1b′ ) q4 -G 1d ;

G 1d , at each occurrence, is independently a monocyclic heterocycle, a monocyclic heteroaryl, a phenyl, a monocyclic cycloalkyl, or a monocyclic cycloalkenyl; optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of —N(R h ) 2 , —CN, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, and —OH;

each occurrence of A 3 is independently —C(O)R h , —S(O) 2 R e , —C(O)N(R h ) 2 , —C(S)N(R 11 ) 2 , —S(O) 2 N(R h ) 2 , —C(═NOR h )R h , —N(R h )C(O)R h , —N(R h )C(O)OR e , —N(R h )S(O) 2 R e , —N(R h )C(O)N(R h ) 2 , —N(R h )S(O) 2 N(R h ) 2 , —CN, —OR h , or —N(R h ) 2 ;

R e , at each occurrence, is independently C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, monocyclic cycloalkyl, monocyclic heterocycle, or —(CR 1c R 1d ) q4 -(monocyclic cycloalkyl);

R f , at each occurrence, is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —(CR 1c R 1d ) q4 —OR h , monocyclic heterocycle, monocyclic cycloalkyl, or —(CR 1c R 1d ) q4 -(monocyclic cycloalkyl);

R h , at each occurrence, is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, monocyclic heterocycle, monocyclic cycloalkyl, or —(CR 1c R 1d ) q4 -(monocyclic cycloalkyl);

Ring A represents formula (a), (b), (c), or (d)

R 21 , R 22 , R 23 , and R 24 are each independently alkyl, alkenyl, alkynyl, haloalkyl, —(CR 2a R 2b ) q5 —OH, —(CR 2a R 2b ) q5 —O-alkyl, —(CR 2a R 2b ) q5 —O-haloalkyl, —(CR 2a R 2b ) q5 —O-G 2 a, —(CR 2a R 2b ) q5 —O—(CR 2c R 2d ) q6 -G 2a , —(CR 2a R 2b ) q6 —C(O)—R a , —(CR 2a R 2b ) q6 —C(O)O(R a ), —(CR 2a R 2b ) q6 —C(═N—OR f )R a , —(CR 2a R 2b ) q6 —SO 2 —R d , —(CR 2a R 2b ) q6 -G 2b , —(CR 2a R 2b ) q6 —C(O)N(R b )(R c ), or —(CR 2a R 2b ) q6 —CN;

each occurrence of G 2a is independently cycloalkyl, heterocycle, aryl, or heteroaryl;

G 2b is monocyclic cycloalkyl, monocyclic cycloalkenyl, thienyl, or phenyl; each of which is optionally fused with benzo, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic heteroaryl;

G 2a and G 2b , at each occurrence, are each independently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of oxo, alkyl, halogen, —OH, alkoxy, haloalkoxy, and haloalkyl;

R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 11 , and R 12 are each independently G 3 , hydrogen, alkyl, alkenyl, alkynyl, —NO 2 , —CN, halogen, —OR h , —N(R h ) 2 , —C(O)R h , —C(O)O(R h ), haloalkyl, —(CR 3a R 3b ) q7 —OR h , —(CR 3a R 3b ) q7 —N(R h ) 2 , —(CR 3a R 3b ) q7 —C(O)R h , or —(CR 3a R 3b ) q7 —C(O)O(R h );

G 3 , at each occurrence, is independently cycloalkyl, cycloalkenyl, aryl, heterocycle or heteroaryl, each of which is independently unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, halogen, C 1 -C 4 haloalkyl, ═N—CN, ═N—OR h , oxo, —OR h , —OC(O)R h , —OC(O)N(R h ) 2 , —S(O) 2 R e , —S(O) 2 N(R h ) 2 , —C(O)R h , —C(O)OR h , —C(O)N(R h ) 2 , —N(R h ) 2 , —N(R h )C(O)R h , —N(R h )S(O) 2 R e , —N(R h )C(O)O(R e ), and —N(R h )C(O)N(R h ) 2 ;

R 1a′ , at each occurrence, is independently hydrogen, halogen, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl;

R 1b′ , at each occurrence, is independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —OR h , —N(R h ) 2 , —N(R h )C(O)R h , —N(R h )C(O)OR e , or —N(R h )S(O) 2 R e ;

R 1c , R 1d , R 2a , R 2b , R 2c , R 2d , R 3a , and R 3b , at each occurrence, are each independently hydrogen, halogen, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl;

X 1 and X 2 are each independently O, S, or N(R 10 ) wherein R 10 is alkyl, alkoxyalkyl, haloalkoxyalkyl, or haloalkyl;

q1 and q5, at each occurrence, are each independently 2, 3, or 4;

q2, q3, q4, q6, and q7, at each occurrence, are each independently 1, 2, 3, 4, 5, or 6; and

the monocyclic cycloalkyl and the monocyclic heterocycle, as a substituent or as part of a substituent, of R b , R e , R f , and R h , are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of oxo, C 1 -C 4 alkyl, halogen, —OH, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and C 1 -C 4 haloalkyl;

with the proviso that when G 1 is aryl, then R 21 , R 22 , R 23 , and R 24 are each independently —(CR 2a R 2b ) q5 —O-G 2a , —(CR 2a R 2b ) q5 —O—(CR 2c R 2d ) q6 -G 2a , —(CR 2a R 2b ) q6 —C(O)—R a , —(CR 2a R 2b ) q6 —C(═N—OR f )R a , or —(CR 2a R 2b ) q6 —SO 2 —R d .

2. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, salt of a solvate, prodrug, salt of a prodrug, or a combination thereof wherein R 1 is heteroaryl.

3. The compound according to claim 1 having formula (I-i) or a pharmaceutically acceptable salt, solvate, salt of a solvate, prodrug, salt of a prodrug, or a combination thereof

wherein z is 0, 1, 2, 3, or 4, Ring A, R x , and R y are as set forth in claim 1 .

4. The compound according to claim 3 or a pharmaceutically acceptable salt, solvate, salt of a solvate, prodrug, salt of a prodrug, or a combination thereof, wherein R x is —O—(CR 1a R 1b ) q1 —N(R 1m ) 2 .

5. The compound according to claim 3 or a pharmaceutically acceptable salt, solvate, salt of a solvate, prodrug, salt of a prodrug, or a combination thereof, wherein

R x is —O—(CR 1a R 1b ) q1 —N(R 1m ) 2 , and

Ring A is formula (a).

6. The compound according to claim 3 or a pharmaceutically acceptable salt, solvate, salt of a solvate, prodrug, salt of a prodrug, or a combination thereof, wherein

R x is —O—(CR 1a R 1b ) q1 —N(R 1m ) 2 ), and

Ring A is formula (b).

7. The compound according to claim 3 or a pharmaceutically acceptable salt, solvate, salt of a solvate, prodrug, salt of a prodrug, or a combination thereof, wherein

R x is —O—(CR 1a R 1b ) q1 —N(R 1m ) 2 ,

Ring A is formula (b), and

X 2 is N(R 10 ).

8. The compound according to claim 3 or a pharmaceutically acceptable salt, solvate, salt of a solvate, prodrug, salt of a prodrug, or a combination thereof, wherein

R x is —O—(CR 1a R 1b ) q1 —N(R 1m ) 2 ,

Ring A is formula (b),

X 2 is N(R 10 ), and

R 22 is alkyl, haloalkyl, —(CR 2a R 2b ) q4 —OH, —(CR 2a R 2b ) q4 —O-alkyl, —(CR 2a R 2b ) q4 —O-haloalkyl, or —(CR 2a R 2b ) q5 -G 2b .

9. The compound according to claim 3 or a pharmaceutically acceptable salt, solvate, salt of a solvate, prodrug, salt of a prodrug, or a combination thereof, wherein R x is —O-G 1 .

10. The compound according to claim 3 or a pharmaceutically acceptable salt, solvate, salt of a solvate, prodrug, salt of a prodrug, or a combination thereof, wherein

R x is —O-G 1 , and

Ring A is formula (a).

11. The compound according to claim 3 or a pharmaceutically acceptable salt, solvate, salt of a solvate, prodrug, salt of a prodrug, or a combination thereof, wherein

R x is —O-G 1 , and

Ring A is formula (b).

12. The compound according to claim 3 or a pharmaceutically acceptable salt, solvate, salt of a solvate, prodrug, salt of a prodrug, or a combination thereof, wherein

R x is —O-G 1 ,

Ring A is formula (b), and

X 2 is N(R 10 ).

13. The compound according to claim 3 or a pharmaceutically acceptable salt, solvate, salt of a solvate, prodrug, salt of a prodrug, or a combination thereof, wherein

R x is —O-G 1 ,

Ring A is formula (b),

X 2 is N(R 10 ), and

R 22 is alkyl, haloalkyl, —(CR 2a R 2b ) q4 —OH, —(CR 2a R 2b ) q4 —O-alkyl, —(CR 2a R 2b ) q4 —O-haloalkyl, or —(CR 2a R 2b ) q5 -G 2b .

14. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, salt of a solvate, prodrug, salt of a prodrug, or a combination thereof, wherein Ring A is formula (c), R 6 and R 9 are hydrogen, R 7 and R 8 are each independently hydrogen or C 1 -C 4 alkyl, and R 23 is alkyl, haloalkyl, —(CR 2a R 2b ) q4 —OH, —(CR 2a R 2b ) q4 —O-alkyl, —(CR 2a R 2b ) q4 —O -haloalkyl, or —(CR 2a R 2b ) q5 -G 2b .

15. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, salt of a solvate, prodrug, salt of a prodrug, or a combination thereof, wherein Ring A is formula (d), R 11 and R 12 are each independently hydrogen, halogen, or alkyl, and R 24 is alkyl, haloalkyl, —(CR 2a R 2b ) q4 —OH, —(CR 2a R 2b ) q4 —O-alkyl, —(CR 2a R 2b ) q4 —O-haloalkyl, or —(CR 2a R 2b ) q5 -G 2b .

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

2-[2-(tert-butylamino)ethoxy]-N-[(3E)-5-tert-butyl-2-(cyclopropylmethyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-ylidene]-5-(trifluoromethyl)benzamide;

2-[(1-tert-butylazetidin-3-yl)oxy]-N-[(3E)-5-tert-butyl-2-(cyclopropylmethyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-ylidene]-5-(trifluoromethyl)benzamide;

2-[(1-tert-butylazetidin-3-yl)oxy]-N-[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;

2-[2-(tert-butylamino)ethoxy]-N-[(3E)-2-butyl-5-tert-butyl-1-methyl-1,2-dihydro-3H-pyrazol-3-ylidene]-5-(trifluoromethyl)benzamide;

2-[2-(tert-butylamino)ethoxy]-N-[(3E)-5-tert-butyl-2-(cyclobutylmethyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-ylidene]-5-(trifluoromethyl)benzamide; and

N-[(3E)-5-tert-butyl-2-(cyclobutylmethyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-ylidene]-2-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-5-(trifluoromethyl)benzamide.

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

18. 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, solvate, or salt of a solvate thereof.

19. A method of treating, neuropathic pain, nociceptive pain, inflammatory pain, cancer pain, or osteoarthritis pain in a mammal in need thereof, said method comprises administering to the mammal a therapeutically effective amount of a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt, solvate, or salt of a solvate thereof.

20. A method for providing neuroprotection 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, solvate, or salt of a solvate thereof.