Tetrahydrothiopyrano pyrazole cannabinoid modulators

Abstract

The invention relates to a CB modulator compound of Formula (I) or a pharmaceutically acceptable form thereof and a method for use in treating, ameliorating or preventing a CB receptor mediated syndrome, disorder or disease.

1 . A compound of Formula (I)  
     
       
         
         
             
             
         
       
       wherein  
       the dashed lines between positions 2-3 and positions 3a-7a in Formula (I) each represent the location for a double bond when X 1 R 1  is present;  
       the dashed lines between positions 3-3a and positions 7a-1 in Formula (I) each represent the location for a double bond when X 2 R 2  is present;  
       the dashed line between position 7 and X 4 R 4  in Formula (I) represents the location for a double bond;  
       X is sulfur, sulfoxo or sulfonyl;  
       X 1  is absent or is lower alkylene;  
       X 2  is absent or is lower alkylene;  
       wherein only one of X 1 X 1  and X 2 R 2  are present;  
       X 3  is absent or is lower alkylene or lower alkylidene;  
       when the dashed line between position 7 and X 4 R 4  is absent, then X 4  is absent or is lower alkylene;  
       when the dashed line between position 7 and X 4 R 4  is present, then X 4  is absent;  
       R 1  is hydrogen, aryl, C 3 -C 12  cycloalkyl, or heterocyclyl, wherein each of aryl, C 3 -C 12  cycloalkyl, or heterocyclyl is optionally substituted at one or more positions by halogen, lower alkyl, hydroxy or lower alkoxy;  
       R 2  is hydrogen, aryl, C 3 -C 12  cycloalkyl, or heterocyclyl, wherein each of aryl, C 3 -C 12  cycloalkyl, or heterocyclyl is optionally substituted at one or more positions by halogen, lower alkyl, hydroxy or lower alkoxy;  
       R 3  is —C(O)-heterocyclyl or -Z-N(R 6 )-Z 1 R 7  (optionally substituted on heterocyclyl by one or more hydroxy, halogen, amino, lower alkyl, carboxy, alkoxycarbonyl, lower alkoxy, lower alkoxy-lower alkylene-, hydroxy-alkylene-, aryloxy or arylalkoxy);  
       when the dashed line between position 7 and X 4 R 4  is absent, then R 4  is hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, aryl (optionally substituted on aryl at one or more positions by hydroxy, lower alkyl, lower alkoxy or halogeno, heterocyclyl (optionally substituted on heterocyclyl at one or more positions by hydroxy, lower alkyl, lower alkoxy or halogen) or C 3 -C 12  cycloalkyl (optionally substituted on C 3 -C 12  cycloalkyl at one or more positions by hydroxy, lower alkyl, lower alkoxy or halogen);  
       when the dashed line between position 7 and X 4 R 4  is present, then R 4  is CH-aryl (optionally substituted on aryl at one or more positions by hydroxy, lower alkyl, lower alkoxy or halogen) or CH-heterocyclyl (optionally substituted on heterocyclyl at one or more positions by hydroxy, lower alkyl, lower alkoxy or halogen);  
       R 6  and R 7  are each individually hydrogen, lower alkyl, —NR 8 R 9 , aryl (optionally substituted on aryl by one or more hydroxy, halogen, lower alkyl, carboxy, alkoxycarbonyl, lower alkoxy, hydroxy-alkylene-, aryloxy or arylalkoxy), C 3 -C 12  cycloalkyl (optionally substituted on C 3 -C 12  cycloalkyl by one or more hydroxy, halogen, amino, lower alkyl, carboxy, alkoxycarbonyl, lower alkoxy, hydroxy-alkylene-, aryloxy, arylalkoxy or lower alkylene) or heterocyclyl (optionally substituted on heterocyclyl by one or more hydroxy, halogen, amino, lower alkyl, carboxy, alkoxycarbonyl, lower alkoxy, lower alkoxy-lower alkylene-, hydroxy-alkylene-, aryloxy or arylalkoxy);  
       R 8  and R 9  are each individually hydrogen, alkyl, heterocyclyl, C 3 -C 12  cycloalkyl, or aryl (optionally substituted on aryl by one or more lower alkyl, hydroxy, alkoxy, halogen, heterocyclyl or aryl-lower alkylene-);  
       Z is carbonyl or sulfonyl;  
       Z 1  is absent; or is lower alkylene optionally substituted at one or more positions by halogen, hydroxy, lower alkoxy, carboxy or lower alkoxycarbonyl;  
       or a pharmaceutically acceptable salt, isomer, prodrug, metabolite or polymorph thereof.  
     
   
   
       2 . The compound of  claim 1 , wherein X 1  is absent or is lower alkylene and R 1  is hydrogen, C 3 -C 12  cycloalkyl or aryl (optionally substituted on aryl at one or more positions by lower alkyl, lower alkoxy or halogen).  
   
   
       3 . The compound of  claim 1 , wherein when the dashed line between position 7 and X 4 R 4  is absent, then X 4  is absent or is lower alkylene and R 4  is hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, aryl (optionally substituted on aryl at one or more positions by lower alkoxy or halogen), heterocyclyl (optionally substituted on heterocyclyl at one or more positions by halogen) or C 3 -C 8  cycloalkyl.  
   
   
       4 . The compound of  claim 1 , wherein when the dashed line between positions 7 and X 4 R 4  is absent then X 4  is absent and R 4  is hydrogen.  
   
   
       5 . The compound of  claim 1 , wherein X 3  is absent or is lower alkylidene; R 3  is —C(O)-heterocyclyl or -Z-N(R 6 )-Z 1 R 7  (optionally substituted on heterocyclyl by one or more hydroxy, halogen, amino, lower alkyl, carboxy, alkoxycarbonyl, lower alkoxy, lower alkoxy-lower alkylene-, hydroxy-alkylene-, aryloxy or arylalkoxy); Z is carbonyl or sulfonyl; Z 1  is absent or is lower alkylene; and R 6  and R 7  are each individually hydrogen, lower alkyl, —NR 8 R 9 , aryl (optionally substituted on aryl by one or more hydroxy, halogen, lower alkyl, carboxy, alkoxycarbonyl, lower alkoxy, hydroxy-alkylene-, aryloxy or arylalkoxy), C 3 -C 12  cycloalkyl (optionally substituted on C 3 -C 12  cycloalkyl by one or more hydroxy, halogen, amino, lower alkyl, carboxy, alkoxycarbonyl, lower alkoxy, hydroxy-alkylene-, aryloxy, arylalkoxy or lower alkylene) or heterocyclyl (optionally substituted on heterocyclyl by one or more hydroxy, halogen, amino, lower alkyl, carboxy, alkoxycarbonyl, lower alkoxy, lower alkoxy-lower alkylene-, hydroxy-alkylene-, aryloxy or arylalkoxy), wherein R 8  and R 9  are each individually hydrogen, alkyl, heterocyclyl, C 3 -C 12  cycloalkyl or aryl (optionally substituted on aryl by one or more lower alkyl, hydroxy, alkoxy, halogen, heterocyclyl or aryl-lower alkylene-).  
   
   
       6 . The compound of  claim 1 , wherein X 3  is absent or is lower alkylidene; R 3  is —C(O)-heterocyclyl or -Z-N(R 6 )-Z 1 R 7 ; Z is carbonyl or sulfonyl; Z 1  is absent or is lower alkylene; and R 6  and R 7  are each individually hydrogen, lower alkyl, —NR 8 R 9 , aryl (optionally substituted on aryl by one or more hydroxy, halogen, lower alkyl, lower alkoxy or hydroxy-alkylene-); C 3 -C 12  cycloalkyl (optionally substituted on C 3 -C 12  cycloalkyl by one or more hydroxy, halogen, amino, lower alkyl, carboxy, alkoxycarbonyl, lower alkoxy or hydroxy-alkylene-) or heterocyclyl (optionally substituted on heterocyclyl by one or more hydroxy, halogen, amino, lower alkyl, carboxy, alkoxycarbonyl, lower alkoxy, lower alkoxy-lower alkylene- or hydroxy-alkylene-), wherein R 8  and R 9  are each individually hydrogen, alkyl, heterocyclyl, C 3 -C 12  cycloalkyl or aryl (optionally substituted on aryl by one or more lower alkyl, hydroxy, alkoxy or halogen).  
   
   
       7 . The compound of  claim 1 , wherein X 3  is absent or is lower alkylidene; R 3  is —C(O)-heterocyclyl or -Z-N(R 6 )-Z 1 R 7 ; Z is carbonyl or sulfonyl; Z 1  is absent or is lower alkylene; and R 6  and R 7  are each individually hydrogen, lower alkyl, —NR 8 R , aryl, C 3 -C 12  cycloalkyl (optionally substituted on C 3 -C 12  cycloalkyl by one or more hydroxy, lower alkyl or alkoxycarbonyl) or heterocyclyl (optionally substituted on heterocyclyl by one or more lower alkyl, alkoxycarbonyl, lower alkoxy-lower alkylene- or hydroxy-alkylene-), wherein R 8  and R 9  are each individually hydrogen, alkyl, C 3 -C 12  cycloalkyl or aryl (optionally substituted on aryl by one or more halogen).  
   
   
       8 . The compound of  claim 1 , wherein X 2  is absent or is lower alkylene; and, R 2  is C 3 -C 12  cycloalkyl or aryl (optionally substituted on aryl at one or more positions by lower alkyl, lower alkoxy or halogen).  
   
   
       9 . The compound of  claim 1 , wherein when the dashed line between position 7 and X 4 R is present, then X 4  is absent and R 4  is CH-aryl (optionally substituted on aryl at one or more positions by hydroxy, lower alkyl, lower alkoxy or halogen) or CH-heterocyclyl (optionally substituted on heterocyclyl at one or more positions by hydroxy, lower alkyl, lower alkoxy or halogen).  
   
   
       10 . The compound of  claim 1 , wherein when the dashed line between position 7 and X 4 R 4  is present, then X 4  is absent and R 4  is CH-aryl (optionally substituted on aryl at one or more positions by lower alkyl, lower alkoxy or halogen) or CH-heterocyclyl (optionally substituted on heterocyclyl at one or more positions by lower alkyl, lower alkoxy or halogen).  
   
   
       11 . The compound of  claim 1 , wherein when the dashed line between position 7 and X 4 R 4  is present, then X 4  is absent and R 4  is CH-phenyl, CH-thienyl or CH-furyl (optionally substituted on phenyl, thienyl or furyl at one or more positions by lower alkyl, lower alkoxy or halogen).  
   
   
       12 . The compound of  claim 1 , wherein X is sulfur, sulfoxo or sulfonyl; X 1  is absent or is lower alkylene; R 1  is hydrogen, C 3 -C 12  cycloalkyl or aryl (optionally substituted on aryl at one or more positions by lower alkyl, lower alkoxy or halogen); when the dashed line between positions 7 and X 4 R 4  is absent, then X 4  is absent and R 4  is hydrogen; X 3  is absent or is lower alkylidene; R 3  is —C(O)-heterocyclyl or -Z-N(R 6 )-Z 1 R 7 ; Z is carbonyl or sulfonyl; Z 1  is absent or is lower alkylene; R 6  and R 7  are each individually hydrogen, lower alkyl, —NR 8 R 9 , aryl, C 3 -C 12  cycloalkyl (optionally substituted on C 3 -C 12  cycloalkyl by one or more hydroxy, lower alkyl or alkoxycarbonyl) or heterocyclyl (optionally substituted on heterocyclyl by one or more lower alkyl, alkoxycarbonyl, lower alkoxy-lower alkylene- or hydroxy-alkylene-), wherein R 8  and R 9  are each individually hydrogen, alkyl, C 3 -C 12  cycloalkyl or aryl (optionally substituted on aryl by one or more halogen); X 2  is absent or is lower alkylene; R 2  is C 3 -C 12  cycloalkyl or aryl (optionally substituted on aryl at one or more positions by lower alkyl, lower alkoxy or halogen); and, when the dashed line between position 7 and X 4 R 4  is present, then X 4  is absent and R 4  is CH-phenyl, CH-thienyl or CH-furyl (optionally substituted on phenyl, thienyl or furyl at one or more positions by lower alkyl, lower alkoxy or halogen).  
   
   
       13 . A compound of the formula:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       14 . A compound selected from the group consisting of: 
 1-benzyl-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R)-1-phenyl-ethyl]-amide,    (E)-2-(1-benzyl-1,4,6,7-tetrahydro-thiopyrano[4-3-c]pyrazol-3-yl)-ethenesulfonic acid [(1S)-1-phenyl-ethyl]-amide,    1-benzyl-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R)-1-phenyl-ethyl]-amide,    1-benzyl-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid (1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide,    1-benzyl-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid (1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide,    1-benzyl-5-oxo-4,5,6,7-tetrahydro-1H-5λ 4 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid (1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide,    (E)-2-[1-(2,4-difluoro-phenyl)-7-(3-fluoro-benzyl)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl]-ethenesulfonic acid [(1R)-1-cyclohexyl-ethyl]-amide,    (2R,3S)-3-{[1-(2,4-difluoro-phenyl)-(7S)-(3-fluoro-benzyl)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carbonyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid N′-(2,4-dichloro-phenyl)-hydrazide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid N′-(2,4-dichloro-phenyl)-hydrazide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid piperidin-1-ylamide,    (7Z)-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl]-piperidin-1-yl-methanone,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid pyrrolidin-1-ylamide,    (7Z)-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl]-pyrrolidin-1-yl-methanone,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R,2S)-2-hydroxy-indan-1-yl]-amide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1S,2R)-2-hydroxy-indan-1-yl]-amide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R,2R)-2-hydroxy-cyclopentyl]-amide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R,2R)-2-hydroxy-cyclohexyl]-amide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1S)-1-phenyl-ethyl]-amide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R)-1-phenyl-ethyl]-amide,    4-{[(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carbonyl]-amino}-piperazine-1-carboxylic acid tert-butyl ester,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1S)-1-phenyl-ethyl]-amide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R)-1-phenyl-ethyl]-amide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1 H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1S,2S)-2-hydroxy-cyclohexyl]-amide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R,2S)-2-hydroxy-indan-1-yl]-amide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1 H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1S,2R)-2-hydroxy-indan-1-yl]-amide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid (pyridin-2-ylmethyl)-amide,    (7Z)-1-(2,4-dihloro-phenyl)-7-(4-fluoro-benzylidene)-5-oxo-4,5,6,7-tetrahydro-1H-5λ 4 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R)-1-phenyl-ethyl]-amide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5-oxo-4,5,6,7-tetrahydro-1H-5λ 4 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid N′-(2,4-dichloro-phenyl)-hydrazide,    (7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R)-1-phenyl-ethyl]-amide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5-oxo-4,5,6,7-tetrahydro-1H-5X 4 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid piperidin-1-ylamide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-14,5,6,7-tetrahydro-1H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid piperidin-1-ylamide,    (7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-2H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R)-1-phenyl-ethyl]-amide,    (7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-2H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid piperidin-1-ylamide,    (7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-2H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R)-cyclohexyl-ethyl]-amide,    (7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-2H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1S)-1-cyclohexyl-ethyl]-amide,    (7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-2H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1S)-1-phenyl-ethyl]-amide,    (7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-2H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide,    (7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R)-1-cyclohexyl-ethyl]-amide,    (7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid piperidin-1-ylamide,    (7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R)-1-phenyl-ethyl]-amide,    (7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R)-1-phenyl-ethyl]-amide,    (7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-14,5,6,7-tetrahydro 1H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide,    (7Z)-[1 (4-chloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-14,5,6,7-tetrahydro-1H-5λ 6 -thiopyrano[4,3-c]pyrazol-3-yl]-piperidin-1-yl-methanone,    (7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid piperidin-1-ylamide,    (7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid N′-methyl-N′-phenyl-hydrazide,    (7Z)-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ 6 -thiopyrano[4,3-c]pyrazol-3-yl]-piperidin-1-yl-methanone,    (7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid pyrrolidin-1-ylamide,    (7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1 H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide,    (7Z)-1-(2,4-difluoro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1 H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid azepan-1-ylamide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1 H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid (2,6-dimethyl-piperidin-1-yl)-amide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid (2,6-dimethyl-piperidin-1-yl)-amide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid azepan-1-ylamide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid N′-cyclohexyl-hydrazide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide,    (7Z)-7-(5-chloro-furan-2-ylmethylene)-1-(2,4-dichloro-phenyl)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R)-1-phenyl-ethyl]-amide,    (7Z)-7-(5-chloro-furan-2-ylmethylene)-1-(2,4-dichloro-phenyl)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R)-1-cyclohexyl-ethyl]-amide,    (7Z)-7-(5-chloro-furan-2-ylmethylene)-1-(2,4-dichloro-phenyl)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid piperidin-1-ylamide,    (7Z)-7-(5-chloro-furan-2-ylmethylene)-1-(2,4-dichloro-phenyl)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid azepan-1-ylamide,    (7Z)-7-(5-chloro-furan-2-ylmethylene)-1-(2,4-dichloro-phenyl)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(2R)-2-(methoxymethyl)-pyrrolidin-1-yl]-amide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(2S)-2-(methoxymethyl)-pyrrolidin-1-yl]-amide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R)-1-(pyridin-2-yl)-ethyl]-amide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1 H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(2S)-2-(methoxymethyl)-pyrrolidin-1-yl]-amide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-14,5,6,7-tetrahydro-1H-5λ 6 -thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(2R)-2-(methoxymethyl)-pyrrolidin-1-yl]-amide,    (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R)-1-(pyridin-2-yl)-ethyl]-amide,    (7Z)-(4-Bromo-benzylidene)-1-(2,4-dichloro-phenyl)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R)-1-phenyl-ethyl]-amide, and    (7Z)-(4-Bromo-benzylidene)-1-(2,4-dichloro-phenyl)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid piperidin-1-ylamide.    
   
   
       15 . Use of the compound of  claim 1  for the manufacture of a medicament for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease.  
   
   
       16 . Use of the compound of  claim 14  for the manufacture of a medicament for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease.  
   
   
       17 . A method for treating, ameliorating or preventing a cannabinoid receptor mediated syndrome, disorder or disease in a subject in need thereof comprising the step of administering to the subject an effective amount of a compound of  claim 1 .  
   
   
       18 . The method of  claim 17  wherein the cannabinoid receptor is a CB1 or CB2 receptor; and, the compound of  claim 1  is an agonist, antagonist or inverse-agonist of the receptor.  
   
   
       19 . The method of  claim 17  wherein the syndrome, disorder or disease is related to appetite, metabolism, diabetes, glaucoma-associated intraocular pressure; social and mood disorders, seizures, substance abuse, learning, cognition or memory, organ contraction or muscle spasm, bowel disorders, respiratory disorders, locomotor activity or movement disorders, immune and inflammation disorders, unregulated cell growth, pain management or neuroprotection.  
   
   
       20 . The method of  claim 17  wherein the effective amount of the compound of  claim 1  is from about 0.001 mg/kg/day to about 300 mg/kg/day.  
   
   
       21 . The method of  claim 20 , wherein the compound is a compound of  claim 14 .  
   
   
       22 . The method of  claim 21 , wherein the effective amount is from about 0.001 mg/kg/day to about 300 mg/kg/day.  
   
   
       23 . The method of  claim 17  further comprising treating, ameliorating or preventing a CB1 receptor inverse-agonist mediated appetite related, obesity related or metabolism related syndrome, disorder or disease in a subject in need thereof comprising the step of administering to the subject an effective amount of a CB1 inverse-agonist compound of  claim 1 .  
   
   
       24 . The method of  claim 23  wherein the effective amount of the compound of  claim 1  is from about 0.001 mg/kg/day to about 300 mg/kg/day.  
   
   
       25 . The method of  claim 17  further comprising the step of administering to the subject a combination product and/or therapy comprising an effective amount of a compound of  claim 1  and a therapeutic agent.  
   
   
       26 . The method of  claim 25  wherein the therapeutic agent is an anticonvulsant or a contraceptive agent.  
   
   
       27 . The method of  claim 26  wherein the anticonvulsant is topiramate, analogs of topiramate, carbamazepine, valproic acid, lamotrigine, gabapentin, phenytoin and the like and mixtures or pharmaceutically acceptable salts thereof.  
   
   
       28 . The method of  claim 26  wherein the contraceptive agent is a progestin-only contraceptive, a contraceptive having a progestin component and an estrogen component, or an oral contraceptive optionally having a folic acid component.  
   
   
       29 . A method of contraception in a subject comprising the step of administering to the subject a composition, wherein the composition comprises a contraceptive and a CB1 receptor inverse-agonist or antagonist compound of  claim 1 , wherein the composition reduces the urge to smoke in the subject and/or assists the subject in losing weight.