Compounds as cannabinoid receptor ligands

1. A compound of formula (I),

or a pharmaceutically acceptable salt thereof, wherein

A is formula (v)

wherein formula (v) is independently unsubstituted or further substituted with 1 or 2 substituents independently selected from the group consisting of alkyl or halogen;

R 1 is hydrogen, alkyl, or haloalkyl;

R 2 is alkyl, alkenyl, alkynyl, G 1 , —N(R b )(R f ), —(CR d R e ) m —CN, —(CR d R e ) n —OR f , —(CR d R e ) n —S(R c ), —(CR d R e ) m —S(O) 2 R c , —(CR d R e ) n —N(R b )(R f ), —(CR d R e ) m —C(O)R b , —(CR d R e ) m —C(O)O(R b ), —(CR d R e ) m -G 1 , or haloalkyl; or

R 1 and R 2 , together with the nitrogen atom to which they are attached, form a 4- to 6-membered monocyclic heterocycle containing zero or one additional heteroatom selected from the group consisting of O, or S, and two non-adjacent atoms of said monocyclic heterocycle are optionally linked by an alkylene bridge of 1-4 carbon atoms, said monocyclic heterocycle is optionally substituted with 1, or 2 substituents independently selected from the group consisting of alkyl, halogen, oxo, —OR a , haloalkyl;

G 1 , at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; wherein each G 1 is independently unsubstituted or further substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, oxo, —CN, —NO 2 , OR a , —S(R c ), —S(O)(R c ), —S(O) 2 R c , —S(O) 2 N(R b ) 2 , C(O)R b , —C(O)O(R b ), —C(O)N(R b ) 2 , —N(R b ) 2 , —N(R b )C(O)R b , —N(R b )C(O)O(R b ), —N(R b )S(O) 2 R c , haloalkyl, —(CR d R e ) m —OR a , —(CR d R e ) m —S(R c ), and —(CR d R e ) m —S(O)(R c );

R a , at each occurrence, is independently hydrogen, alkyl, haloalkyl, or —(CR d R e ) m —O(alkyl),

R b , at each occurrence, is independently hydrogen, alkyl, or haloalkyl;

R c , at each occurrence, is independently alkyl or haloalkyl;

R f , at each occurrence, is independently hydrogen, alkyl, G 1 , —(CR d R e ) m -G 1 , or haloalkyl;

R d and R e , at each occurrence, are each independently hydrogen, halogen, alkyl, or haloalkyl;

m, at each occurrence, is independently 1, 2, 3, 4, 5, or 6;

n, at each occurrence, is independently 2, 3, 4, 5, or 6;

R 3 is formula (a) or (b),

wherein formula (a) and (b) are each independently unsubstituted or further substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, halogen, oxo, —CN, —O(alkyl), and haloalkyl.

2. The compound according to claim 1 having formula (II), or a pharmaceutically acceptable salt thereof

wherein R x is an optional substituent, and each R x is independently alkyl or halogen; and

t is 0, 1, or 2.

3. The compound according to claim 2 , wherein R 3 is formula (a)

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 8-membered monocyclic heterocycle.

5. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen and R 2 is alkyl, alkynyl, or haloalkyl.

6. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen and R 2 is —(CR d R e ) n —OR f , —(CR d R e ) m —CN, —(CR d R e ) n —S(R c ), —(CR d R e ) m —S(O) 2 R c , or —N(R b )(R f ).

7. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, R 2 is —(CR d R e ) m -G 1 , and G 1 is aryl, heteroaryl, heterocycle, or cycloalkyl.

8. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, R 2 is G 1 , and G 1 is aryl, cycloalkyl, or heterocycle.

9. The compound according to claim 2 or a pharmaceutically acceptable salt thereof wherein R 3 is formula (b)

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen and R 2 is alkyl.

11. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 , together with the nitrogen atom to which they are attached form a 4- to 6-membered monocyclic heterocycle.

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

N-{3-[(2,5-dimethylmorpholin-4-yl)carbonyl]-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl}hexahydro-2,5-methanopentalene-3a(1H)-carboxamide;

N-{3-[(4-hydroxypiperidin-1-yl)carbonyl]-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl}hexahydro-2,5-methanopentalene-3a(1H)-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-propyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

N-[3-(morpholin-4-ylcarbonyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl]hexahydro-2,5-methanopentalene-3a(1H)-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(2-methoxyethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(tetrahydro-2H-pyran-4-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(3-hydroxypropyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

N-ethyl-2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(2-phenylethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(2-thien-2-ylethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

N-[2-(2-fluorophenyl)ethyl]-2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-[2-(2-methoxyphenyl)ethyl]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(2-pyridin-2-ylethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

N-(2-cyanoethyl)-2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

N-{3-[(propylamino)carbonyl]-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl}-2-oxatricyclo[3.3.1.1 3,7 ]decane-1-carboxamide;

N-(2-ethoxyethyl)-2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(3-hydroxybutyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-[(1R)-1-(hydroxymethyl)-2-methylpropyl]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(1-methyl-3-phenylpropyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-isobutyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(2-methoxy-1-methylethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-[(2R)-tetrahydrofuran-2-ylmethyl]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(2-hydroxypropyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(2-hydroxybutyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-[2-(methylthio)ethyl]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-prop-2-ynyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

N-(cyanomethyl)-2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

Trans-2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(2-hydroxycyclopentyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

N-hexahydro-2,5-methanopentalen-3a(1H)-yl-2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(3-hydroxy-2,2-dimethylpropyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

N-{3-[(2-phenylhydrazino)carbonyl]-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl}hexahydro-2,5-methanopentalene-3 all H)-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-[2-(methylsulfonyl)ethyl]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

Trans-2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(2-hydroxycyclohexyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

Cis-2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(2-hydroxycyclohexyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(3,3,3-trifluoropropyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

Trans-2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(2-(hydroxymethyl)cyclohexyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

N-cyclobutyl-2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

N-cyclopentyl-2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

Cis-2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(2-methylcyclohexyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

Trans-2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(2-methylcyclohexyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(4-methylcyclohexyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-[(1S,2R,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

N-{[3-(dimethylamino)tetrahydrothien-3-yl]methyl}-2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

N-benzyl-2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-[3-(methylthio)propyl]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

N-{3-[(3,3-difluoroazetidin-1-yl)carbonyl]-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl}hexahydro-2,5-methanopentalene-3a(1H)-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

exo-N-[bicyclo[2.2.1]hept-2-yl]-2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(2,2,2-trifluoroethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

N-{3-[2-azabicyclo[2.2.1]hept-2-ylcarbonyl]-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl}hexahydro-2,5-methanopentalene-3a(1H)-carboxamide;

N-{3-[(3-hydroxyazetidin-1-yl)carbonyl]-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl}hexahydro-2,5-methanopentalene-3a(1H)-carboxamide;

N-{3-[(3-methoxyazetidin-1-yl)carbonyl]-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl}hexahydro-2,5-methanopentalene-3a(1H)-carboxamide;

N-[3-(azetidin-1-ylcarbonyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl]hexahydro-2,5-methanopentalene-3a(1H)-carboxamide;

N-{3-[(3,3-difluoropyrrolidin-1-yl)carbonyl]-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl}hexahydro-2,5-methanopentalene-3a(1H)-carboxamide;

2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-[(3R)-tetrahydrofuran-3-yl]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide;

N-{3-[(3,3-difluoroazetidin-1-yl)carbonyl]-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl}-2-oxatricyclo[3.3.1.1 3,7 ]decane-1-carboxamide; and

N-cyclopropyl-2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide.

13. 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 a pharmaceutically acceptable carrier.