Compounds as cannabinoid receptor ligands

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

wherein

R x is —C(═NOR f )R a , —(CR 1a R 1b ) q1 -A 1 , alkenyl, or alkynyl; wherein the alkenyl and the alkynyl are substituted with one or two A 2 groups;

each R y is independently G 1d , alkyl, alkenyl, alkynyl, halogen, haloalkyl, ═N—CN, ═N—OR f , NO 2 , —CN, oxo, —OR f , —OC(O)R f , —OC(O)N(R f ) 2 , —S(O) 2 R c , —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 , —(CR 1c R 1d ) q3 —OR f , —(CR 1c R 1d ) q3 —OC(O)R f , —(CR 1c R 1d ) q3 —OC(O)N(R f ) 2 , —(CR 1c R 1d ) q3 —S(O) 2 R e , —(CR 1c R 1d ) q3 —S(O) 2 N(R f ) 2 , —(CR 1c R 1d ) q3 —C(O)R f , —(CR 1c R 1d ) q3 —C(O)OR f , —(CR 1c R 1d ) q3 —C(O)N(R f ) 2 , —(CR 1c R 1d ) q3 —N(R f ) 2 , —(CR 1c R 1d ) q3 —N(R f )C(O)R f , —(CR 1c R 1d ) q3 —N(R 2 )S(O) 2 R e , —(CR 1c R 1d ) q3 —N(R f )C(O)O(R e ), —(CR 1c R 1d ) q3 —N(R f )C(O)N(R f ) 2 , or —(CR 1c R 1d ) q3 —CN;

A 1 is —OR a , —OC(O)R a , —OC(O)N(R b )(R c ), —N(R b )(R k ), —C(O)O(R a ), —C(O)R a , —S(O) 2 R d , —S(O)R d , —SR d , —C(O)N(R b )(R c ), —C(S)N(R b )(R c ), —S(O) 2 N(R b )(R c ), —C(═NOR f )R a , —CN, —N(R c )C(O)R a , —N(R c )C(O)OR d , —N(R c )S(O) 2 R d , —N(R c )C(O)N(R b )(R c ), —N(R c )S(O) 2 N(R b )(R c ), G 1a or G 1b ;

each occurrence of A 2 is independently —OR a , —OC(O)R a , —OC(O)N(R b )(R c ), —N(R b )(R k ), —C(O)O(R a ), —C(O)R a , —S(O) 2 R d , —S(O)R d , —SR d , —C(O)N(R b )(R c ), —C(S)N(R b )(R c , —S(O) 2 N(R b )(R c ), —C(═NOR f )R a , —CN, —N(R c )C(O)R a , —N(R c )C(O)OR d , —N(R c )S(O) 2 R d , —N(R c )C(O)N(R b )(R c ), —N(R c )S(O) 2 N(R b )(R c ), or G 1c ;

G 1a is a 4-, 5-, 6-, or 7-membered monocyclic heterocycle having zero double bond and one or two heteroatoms in the ring, wherein each ring is substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, alkyl, alkenyl, alkynyl, haloalkyl, —OH, alkoxy, —C(O)O(alkyl), and hydroxyalkyl;

G 1b is optionally substituted cycloalkyl or optionally substituted cycloalkenyl;

G 1c is cycloalkyl, cycloalkenyl, aryl, heterocycle, or heteroaryl;

each ring as represented by G 1b and G 1c 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(O)R a , —N(R c )S(O) 2 R d , —N(R c )C(O)O(R a ), —N(R)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 ) q3 -A 3 , G 1d , or —(CR 1a R 1b ) q3 -G 1d ;

R b , at each occurrence, is independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, monocyclic cycloalkyl, —(CR 1a R 1b ) q3 -(monocyclic cycloalkyl), or haloalkoxyalkyl;

R d , at each occurrence, is independently alkyl, haloalkyl, —(CR 1a R 1b ) q3 -A 3 , G 1d , or —(CR 1a R 1b ) q3 -G 1d ;

G 1d , at each occurrence, is independently a monocyclic heterocycle, a monocyclic heteroaryl, a phenyl, a monocyclic cycloalkyl, or a monocyclic cycloalkenyl; each of which is 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 h ) 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 c , at each occurrence, is independently C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, monocyclic cycloalkyl, monocyclic heterocycle, or —(CR 1c R 1d ) q3 -(monocyclic cycloalkyl);

R f , 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 ) q3 -(monocyclic cycloalkyl);

R k is haloalkyl, —(CR 1a R 1b ) q3 -A 3 , G 1d , or —(CR 1a R 1b ) q3 -G 1d ;

R k′ is hydrogen, alkyl, haloalkyl, —(CR 1a R 1b ) q3 -A 3 , G 1d , or —(CR 1a R 1b ) q3 -G 1d ;

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 ) q3 -(monocyclic cycloalkyl);

Ring A represents formula

R 22 is alkyl, alkenyl, alkynyl, haloalkyl, —(CR 2a R 2b ) q4 —OH, —(CR 2a R 2b ) q4 —O-alkyl, —(CR 2a R 2b ) q4 —O-haloalkyl, —(CR 2a R 2b ) q4 —O-G 2a , —(CR 2a R 2b ) q4 —O—(CR 2c R 2d ) q3 -G 2a , —(CR 2a R 2b ) q5 —C(O)—R a , —(CR 2a R 2b ) q5 —C(O)O(R a ), —(CR 2a R 2b ) q5 —C(═N—OR f )R a , —(CR 2a R 2b ) q5 —SO 2 —R d , —(CR 2a R 2b ) q5 -G 2b , —(CR 2a R 2b ) q5 —C(O)N(R b )(R c ), or —(CR 2a R 2b ) q5 —CN;

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

G 2b is a monocyclic cycloalkyl, monocyclic cycloalkenyl, thienyl, or phenyl; each of which is optionally fused with a benzo, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a 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 4 , and R 5 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 ) q6 —OR h , —(CR 3a R 3b ) q6 —N(R b ) 2 , —(CR 3a R 3b ) q6 —C(O)R h , or —(CR 3a R 3b ) q6 —C(O)O(R h );

G 3 , at each occurrence, is independently cycloalkyl, cycloalkenyl, aryl, heterocycle or heteroaryl, wherein each G 3 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 1 -C 4 alkynyl, halogen, C 1 -C 4 haloalkyl, ═N—CN, ═N—OR h , —CN, 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 c , —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 2 is N(R 10 ) wherein R 10 is alkyl, alkoxyalkyl, haloalkoxyalkyl, or haloalkyl;

q1 and q3, at each occurrence, are each independently 1, 2, 3, or 4;

q4, at each occurrence, is independently 2, 3, 4, or 5;

q5 and q6, at each occurrence, are each independently 1, 2, 3, 4, 5, or 6;

z is 0, 1, 2, 3, or 4; 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 R x is —(CR 1a R 1b ) q1 -A 1 , R 1a and R 1b are each independently hydrogen or alkyl, and A 1 is OR a wherein R a is G 1d , then G 1d is other than phenyl; and

with the further proviso that when R x is —(CR 1a R 1b ) q1 -A 1 , R 1a and R 1b are each independently hydrogen or alkyl, and A 1 is OC(O)R a , then R a is other than alkyl.

2. 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

R x is —(CR 1a R 1b ) q1 -A 1 or alkenyl substituted with one A 2 group; and

each R y , if present, is independently alkyl, —CN, haloalkyl, —OH, —O(C 1 -C 4 alkyl), or halogen.

3. 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 4 is alkyl or optionally substituted C 3 -C 6 cycloalkyl;

R 5 is hydrogen or halogen; and

R 10 is C 1 -C 4 alkyl.

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 22 is alkyl, —(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 .

5. The compound according to claim 4 or a pharmaceutically acceptable salt, solvate, salt of a solvate, prodrug, salt of a prodrug, or a combination thereof, wherein R x is —(CR 1a R 1b ) q1 -A 1 .

6. The compound according to claim 5 or a pharmaceutically acceptable salt, solvate, salt of a solvate, prodrug, salt of a prodrug, or a combination thereof, wherein A 1 is G 1a , and G 1a is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl, wherein each G 1a is substituted with a group selected from —OH, hydroxyalkyl, or —C(O)O(alkyl), and each G 1a is optionally further substituted with one or two substituents independently selected from the group consisting of alkyl and haloalkyl.

7. The compound according to claim 4 or a pharmaceutically acceptable salt, solvate, salt of a solvate, prodrug, salt of a prodrug, or a combination thereof, wherein R x is alkenyl substituted with one A 2 group.

8. The compound according to claim 5 or a pharmaceutically acceptable salt, solvate, salt of a solvate, prodrug, salt of a prodrug, or a combination thereof, wherein A 1 is —OR a .

9. The compound according to claim 5 or a pharmaceutically acceptable salt, solvate, salt of a solvate, prodrug, salt of a prodrug, or a combination thereof, wherein A 1 is —C(O)O(R a ).

10. 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

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

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

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

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

N-[(3E)-5-tert-butyl-1-methyl-2-propyl-1,2-dihydro-3H-pyrazol-3-ylidene]-2-[(1E)-3-hydroxy-3-methylbut-1-enyl]-5-(trifluoromethyl)benzamide;

N-[(3E)-5-tert-butyl-2-(cyclobutylmethyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-ylidene]-2-[(1E)-3-hydroxy-3-methylbut-1-enyl]-5-(trifluoromethyl)benzamide;

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

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

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

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

ethyl 3-[2-({[(3E)-2-butyl-5-tert-butyl-1-methyl-1,2-dihydro-3H-pyrazol-3-ylidene]amino}carbonyl)-4-(trifluoromethyl)phenyl]propanoate;

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

N-[(3E)-2-butyl-5-tert-butyl-1-methyl-1,2-dihydro-3H-pyrazol-3-ylidene]-2-{[(3R)-3-hydroxypyrrolidin-1-yl]methyl}-5-(trifluoromethyl)benzamide;

N-[(3E)-5-tert-butyl-2-(3-methoxypropyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-ylidene]-2-[(1E)-3-hydroxy-3-methylbut-1-enyl]-5-(trifluoromethyl)benzamide;

N-[(3E)-5-tert-butyl-2-(3-methoxypropyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-ylidene]-2-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)benzamide; and

tert-butyl[2-({[(3E)-2-butyl-5-tert-butyl-1-methyl-1,2-dihydro-3H-pyrazol-3-ylidene]amino}carbonyl)-4-(trifluoromethyl)phenyl]acetate;

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

N-[(3E)-2-butyl-5-tert-butyl-1-methyl-1,2-dihydro-3H-pyrazol-3-ylidene]-2-[(2-hydroxy-2-methylpropoxy)methyl]-5-(trifluoromethyl)benzamide.

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

12. 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-i) according to claim 1 , or a pharmaceutically acceptable salt, solvate, salt of a solvate, prodrug, salt of a prodrug, or a combination thereof.

13. 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-i) according to claim 1 , or a pharmaceutically acceptable salt, solvate, salt of a solvate, prodrug, salt of a prodrug, or a combination thereof.