Tetrahydro-cyclopentyl pyrazole cannabinoid modulators

A compound of formula (I):

• or a salt, isomer, prodrug, metabolite or polymorph thereof wherein
• the dashed lines between positions 2-3 and positions 3a-6a in formula (I) represent locations for each of two double bonds present when X1R1 is present;
• the dashed lines between positions 3-3a and positions 6a-1 in formula (I) represent locations for each of two double bonds present when X2R2 is present;
• the dashed line between position 6 and X4R4 in formula (I) represents the location for a double bond;
• X1 is absent or lower alkylene;
• X2 is absent or lower alkylene;
• wherein only one of X1R1 and X2R2 are present;
• X3 is absent or lower alkylene, lower alkylidene or —NH—;
• when the dashed line between position 6 and X4R4 is absent, X4 is absent or lower alkylene;
• when the dashed line between position 6 and X4R4 is present, X4 is absent;
• R1 is selected from hydrogen, alkyl (optionally substituted at one or more positions with halogen, hydroxy or lower alkoxy), aryl, C3-C12 cycloalkyl or heterocyclyl, wherein aryl, C3-C12 cycloalkyl or heterocyclyl is each optionally substituted at one or more positions with halogen, alkyl (optionally substituted at one or more positions with halogen, hydroxy or lower alkoxy), hydroxy or alkoxy (optionally substituted at one or more positions with halogen or hydroxy);
• R2 is selected from hydrogen, alkyl (optionally substituted at one or more positions with halogen, hydroxy or lower alkoxy), aryl, C3-C12 cycloalkyl or heterocyclyl, wherein aryl, C3-C12 cycloalkyl or heterocyclyl is each optionally substituted at one or more positions with halogen, alkyl (optionally substituted at one or more positions with halogen, hydroxy or lower alkoxy), hydroxy or alkoxy (optionally substituted at one or more positions with halogen or hydroxy);
• R3 is —C(O)-Z1(R5), —SO2—NR6-Z2(R7) or —C(O)—NR8-Z3(R9);
• when the dashed line between position 6 and X4R4 is absent, X4 is absent or lower alkylene and R4 is hydroxy, lower alkoxy, halogen, aryl, C3-C12 cycloalkyl or heterocyclyl, wherein aryl, C3-C12 cycloalkyl or heterocyclyl is each optionally substituted at one or more positions with hydroxy, oxo, alkyl (optionally substituted at one or more positions with halogen, hydroxy or lower alkoxy), alkoxy (optionally substituted at one or more positions with halogen or hydroxy) or halogen;
• when the dashed line between position 6 and X4R4 is present, X4 is absent, and R4 is CH-aryl or CH-heterocyclyl, wherein aryl or heterocyclyl is each optionally substituted at one or more positions with hydroxy, alkyl (optionally substituted at one or more positions with halogen, hydroxy or lower alkoxy), alkoxy (optionally substituted at one or more positions with halogen or hydroxy) or halogen and R3 is not —C(O)-Z1(R5);
• R5 is aryl, C3-C12 cycloalkyl or heterocyclyl each optionally substituted with one or more hydroxy, oxo, halogen, amino, aminoalkyl, alkyl (optionally substituted at one or more positions with halogen, hydroxy or lower alkoxy), alkoxy (optionally substituted at one or more positions with halogen or hydroxy), carboxy, carbonylalkoxy, carbamoyl, carbamoylalkyl, aryl, aryloxy, arylalkoxy or heterocyclyl;
• R6 is hydrogen or lower alkyl;
• R7 is aryl, C3-C12 cycloalkyl or heterocyclyl each optionally substituted with one or more hydroxy, oxo, halogen, amino, aminoalkyl, alkyl (optionally substituted at one or more positions with halogen, hydroxy or lower alkoxy), alkoxy (optionally substituted at one or more positions with halogen or hydroxy), carboxy, carbonylalkoxy, carbamoyl, carbamoylalkyl, aryl, aryloxy, arylalkoxy or heterocyclyl;
• R8 is hydrogen or lower alkyl;
• R9 is aryl, C3-C12 cycloalkyl or heterocyclyl each optionally substituted with one or more hydroxy, oxo, halogen, amino, aminoalkyl, alkyl (optionally substituted at one or more positions with halogen, hydroxy or lower alkoxy), alkoxy (optionally substituted at one or more positions with halogen or hydroxy), carboxy, carbonylalkoxy, carbamoyl, carbamoylalkyl, aryl, aryloxy, arylalkoxy or heterocyclyl;
• Z1 and Z2 is each absent or alkyl;
• and,
• Z3 is absent, —NH—, —SO2— or alkyl (wherein alkyl is optionally further substituted at one or more positions with halogen, hydroxy, lower alkyl, lower alkoxy, carboxy or carbonylalkoxy).