MODULATORS OF CANNABINOID RECEPTOR

摘要

Compounds of formula (I) suppress the normal signalling activity CB1 receptors, and are thus useful in the treatment of diseases or conditions which are mediated by CB1 receptor signalling activity, such as treatment of obesity and overweight, prevention of weigh gain, treatment of diseases and conditions directly or indirectly associated with obesity and overweight: Wherein A<SUB>1</SUB> is hydrogen, -COOH, or tetrazolyl, and A<SUB>2</SUB> is hydrogen, -COOH, or tetrazolyl, provided that one of A<SUB>1</SUB> and A<SUB>2</SUB> is either -COOH or tetrazolyl; p is O or 1; A<SUB>3</SUB> is phenyl or cycloalkyl, either of which is optionally substituted with R<SUB>4</SUB> and/or R<SUB>5</SUB>; q is O or 1; R<SUB>3</SUB> is hydrogen, C<SUB>1</SUB>C<SUB>4</SUB> alkyl, cycloalkyl, -CF<SUB>3</SUB>, or -OR<SUB>9</SUB>; R<SUB>4</SUB> and R<SUB>5</SUB> independently -R<SUB>9</SUB>, -CN, -F, -Cl, -Br, -OR<SUB>9</SUB>, -NR<SUB>7</SUB>R<SUB>8</SUB>, -NR<SUB>7</SUB>COR<SUB>6</SUB>, -NR<SUB>7</SUB>SO<SUB>2</SUB>R<SUB>6</SUB>, -COR<SUB>6</SUB>, -SR<SUB>9</SUB>, -SOR<SUB>9</SUB>, Or -SO2R<SUB>6</SUB>, R<SUB>6</SUB> is C<SUB>1</SUB>-C4 alkyl, cycloalkyl, -CF<SUB>3</SUB> Or -NR<SUB>7</SUB>R<SUB>8</SUB>; R<SUB>7</SUB> and R<SUB>8</SUB> are independently hydrogen, C<SUB>1</SUB>-C<SUB>4</SUB> alkyl or cycloalkyl; R<SUB>9</SUB> is hydrogen, C<SUB>1</SUB>-C<SUB>4</SUB> alkyl, cycloalkyl, fully or partially fluorinated C<SUB>1</SUB>-C<SUB>4</SUB> alkyl; R<SUB>1</SUB> is a divalent radical selected from -C(R<SUB>10</SUB>)(R<SUB>11</SUB>)-*, -C(R<SUB>10</SUB>)(R<SUB>11</SUB>)-O-*, -C(R<SUB>10</SUB>)(R<SUB>11</SUB>)CH<SUB>2</SUB>-*, -C(R<SUB>10</SUB>)(R<SUB>11</SUB>)CH<SUB>2</SUB>-O-*, -CH<SUB>2</SUB>C(R<SUB>10</SUB>)(R<SUB>11</SUB>)-*, -CH<SUB>2</SUB>C(R<SUB>10</SUB>)(R<SUB>11</SUB>)-O-*, -CH<SUB>2</SUB>-O-C(R<SUB>10</SUB>)(R<SUB>11</SUB>)-* and -C(R<SUB>10</SUB>)(R<SUB>11</SUB>)-O-CH<SUB>2</SUB>-*, wherein the bond indicated by an asterisk is attached to the pyrazole ring, and R<SUB>10</SUB> is hydrogen and R<SUB>11</SUB> is (C<SUB>1</SUB>-C<SUB>3</SUB>)alkyl or -OH; or R<SUB>10</SUB> and R<SUB>11</SUB> are both (C<SUB>1</SUB>-C<SUB>3</SUB>)alkyl; or R<SUB>10</SUB> and R<SUB>11</SUB> taken together with the carbon atom to which they are attached form a (C<SUB>3</SUB>- C<SUB>5</SUB>)cycloalkyl ring; and R<SUB>2</SUB> is a bond, -(CH<SUB>2</SUB>)<SUB>a</SUB>B<SUB>1</SUB>(CH<SUB>2</SUB>)<SUB>b</SUB>- or -[(CH<SUB>2</SUB>)<SUB>a</SUB>B<SUB>1</SUB>(CH<SUB>2</SUB>)b]<SUB>n</SUB>-A<SUB>4</SUB>- [(CH<SUB>2</SUB>)<SUB>c</SUB>B<SUB>2</SUB>(CH<SUB>2</SUB>)<SUB>d</SUB>]<SUB>m</SUB>- wherein a and b are independently 0, 1, 2 or 3 provided that a+b is not greater than 4, and B<SUB>1</SUB> and B<SUB>2</SUB> are independently is -CO-, -0-, -S-, -SO-, -SO<SUB>2</SUB>-, -CH<SUB>2</SUB>-, - CHOH- or -NR<SUB>7</SUB>-; c and d are independently 0,1, 2 or 3; with the proviso that a+b+c+d is not greater than 6, n and m are independently 0 or 1 and A<SUB>4</SUB> is (i) a monocyclic carbocyclic ring, having 3 to 8 ring atoms, optionally substituted with one or more of -F, -Cl, -Br, -CN, -CF<SUB>3</SUB>, C<SUB>1</SUB>-C<SUB>4</SUB> alkyl, cycloalkyl, -OR<SUB>9</SUB>, oxo or -NR<SUB>7</SUB>R<SUB>8</SUB>; or (ii) a monocyclic heterocyclic ring, having 4 to 8 ring atoms, optionally substituted with one or more of -F, -Cl, -Br, -CN, -CF<SUB>3</SUB>, C<SUB>1</SUB>-C<SUB>4</SUB> alkyl, cycloalkyl, -OR<SUB>9</SUB>, oxo or -NR<SUB>7</SUB>R<SUB>8</SUB>.