US 2006/0223798 A1Published application

Tetrahydrothiopyrano pyrazole cannabinoid modulators

OwnerFina Liotta, Huajun Lu +2inventors

InventorsFina Liotta, Huajun Lu, Mingde Xia, Michael Wachter

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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.

Claims29

Dependent claims

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 X1R1 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 X2R2 is present;
the dashed line between position 7 and X4R4 in Formula (I) represents the location for a double bond;
X is sulfur, sulfoxo or sulfonyl;
X1 is absent or is lower alkylene;
X2 is absent or is lower alkylene;
wherein only one of X1X1 and X2R2 are present;
X3 is absent or is lower alkylene or lower alkylidene;
when the dashed line between position 7 and X4R4 is absent, then X4 is absent or is lower alkylene;
when the dashed line between position 7 and X4R4 is present, then X4 is absent;
R1 is hydrogen, aryl, C3-C12 cycloalkyl, or heterocyclyl, wherein each of aryl, C3-C12 cycloalkyl, or heterocyclyl is optionally substituted at one or more positions by halogen, lower alkyl, hydroxy or lower alkoxy;
R2 is hydrogen, aryl, C3-C12 cycloalkyl, or heterocyclyl, wherein each of aryl, C3-C12 cycloalkyl, or heterocyclyl is optionally substituted at one or more positions by halogen, lower alkyl, hydroxy or lower alkoxy;
R3 is —C(O)-heterocyclyl or -Z-N(R6)-Z1R7 (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 X4R4 is absent, then R4 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 C3-C12 cycloalkyl (optionally substituted on C3-C12 cycloalkyl at one or more positions by hydroxy, lower alkyl, lower alkoxy or halogen);
when the dashed line between position 7 and X4R4 is present, then R4 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);
R6 and R7 are each individually hydrogen, lower alkyl, —NR8R9, aryl (optionally substituted on aryl by one or more hydroxy, halogen, lower alkyl, carboxy, alkoxycarbonyl, lower alkoxy, hydroxy-alkylene-, aryloxy or arylalkoxy), C3-C12 cycloalkyl (optionally substituted on C3-C12 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);
R8 and R9 are each individually hydrogen, alkyl, heterocyclyl, C3-C12 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;
Z1 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.

19 more elements

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-5λ6-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-5λ6-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-5λ4-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ4-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-5λ4-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-5X4-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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-5λ6-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.

67 more elements

Dependencies are inferred from the claim text.

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