Benzazole Potentiators of Metabotropic Glutatmate Receptors

A compound of the formula I:

• wherein:
• A is phenyl or pyridyl;
• W is selected from the group consisting of:
• (1) -tetrazolyl,
• (2) —CO2H,
• (3) —NHSO2C1-6alkyl,
• (4) —NHSO2-phenyl, wherein the phenyl is unsubstituted or substituted with C1-6alkyl, and
• (5) —CONHCO—C1-6alkyl,
• (6) hydrogen;
• X is selected from the group consisting of:
• (1) —O—,
• (2) —O—C1-6alkyl-,
• (3) —O—C2-6alkenyl-,
• (4) a bond,
• (5) —O—C3-7cycloalkyl-
• (6) -pyrrolidine-,
• (7) -piperidine-,
• (8) —S—,
• (9) —O-phenyl-, wherein the phenyl is unsubstituted or substituted with C1-6alkyl, or halogen,
• (10) —S-phenyl-, wherein the phenyl is unsubstituted or substituted with C1-6alkyl, or halogen, and
• (11) -phenyl-, wherein the phenyl is unsubstituted or substituted with C1-6alkyl, or halogen;
• Y is selected from the group consisting of:
• (1) —O—,
• (2) —NH(CO)—, and
• (3) a bond;
• Z1, Z2 and Z3 are selected from C, N and O such that together with the fused phenyl ring they form an indolyl, indolinyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, or benzotriazolyl ring;
• R1a, R1b and R1c may be absent if the valency at Z1, Z2 or Z3 does not permit such substitution and are independently selected from the group consisting of:
• (1) hydrogen,
• (2) C1-6alkyl, which is unsubstituted or substituted with a substituent selected from:
• (a) halogen,
• (b) hydroxyl,
• (c) phenyl, wherein the phenyl is unsubstituted or substituted with 1-5 substituents independently selected from halogen, cyano, CF3, hydroxyl, C1-6alkyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, and OC1-6alkyl,
• (d) C3-7cycloalkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,
• (e) pyridyl, which is unsubstituted or substituted with halogen, C1-6alkyl or phenyl,
• (f) naphthyl, which is unsubstituted or substituted with halogen, C1-6alkyl or phenyl,
• (g) tetrahydropyranyl, which is unsubstituted or substituted with halogen, C1-6alkyl or phenyl, and
• (h) isoxazolyl, which is unsubstituted or substituted with halogen, C1-6alkyl or phenyl,
• (i) —CO—C1-6alkyl, and
• (j) —COO—C1-6alkyl,
• (3) C3-7cycloalkyl, which is unsubstituted or substituted with halogen, C1-6alkyl, hydroxyl or phenyl,
• (4) phenyl, wherein the phenyl is unsubstituted or substituted with 1-5 substituents independently selected from halogen, hydroxyl, cyano, CF3, C1-6alkyl, and OC1-6alkyl, wherein the C1-6alkyl and OC1-6alkyl are linear or branched and optionally substituted with 1-5 halogen,
• (5) —CO—C1-6alkyl, and
• (6) —COO—C1-6alkyl;
• R2 is selected from the group consisting of:
• (1) hydrogen,
• (2) halogen,
• (3) hydroxyl,
• (4) OC1-6alkyl,
• (5) C2-6alkenyl, and
• (6) C1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl;
• R3a and R3b are selected from the group consisting of:
• (1) hydrogen,
• (2) halogen,
• (3) C1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, and
• (4) OC1-6alkyl;
• R4 may include multiple substituents and is independently selected from the group consisting of:
• (1) hydrogen,
• (2) halogen,
• (3) C1-6alkyl, and
• (4) —O—C1-6alkyl;
• m is an integer selected from 0, 1, 2 and 3;
• n is an integer selected from 0, 1, 2, 3, 4, 5 and 6;
• or a pharmaceutically acceptable salt thereof.

A compound which is selected from the group consisting of:

• 1-(2,2-dimethylpropyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole;
• 2,2-dimethyl-1-(7-propyl-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indol-3-yl)propan-1-one;
• 1-(2,2-dimethylpropyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indazole;
• 2-(2,2-dimethylpropyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-2H-indazole;
• 1-(2,2-dimethylpropyl)-4-propyl-5-[4-(pyridin-3-yloxy)butoxy]-1H-indole;
• 1-(2,2-dimethylpropyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole;
• 1-(2,2-dimethylpropyl)-7-propyl-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole;
• 1-(2,2-dimethylpropyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-benzimidazole;
• 1-(2,2-dimethylpropyl)-7-propyl-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-benzimidazole;
• 1-(2,2-dimethylpropyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}indoline;
• 4-bromo-1-(2,2-dimethylpropyl)-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole;
• 1-(2,2-dimethylpropyl)-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole;
• 1-(2,2-dimethylpropyl)-4-propyl-5-{[4-(1H-tetrazol-5-yl)benzyl]oxy}-1H-indole;
• 1-(2,2-dimethylpropyl)-4-propyl-5-{[3-(1H-tetrazol-5-yl)benzyl]oxy}-1H-indole;
• 1-(2,2-dimethylpropyl)-4-methyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole;
• 1-(2,2-dimethylpropyl)-2-methyl-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole;
• ethyl 1-(2,2-dimethylpropyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole-2-carboxylate;
• 1-(2,2-dimethylpropyl)-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole;
• 1-(2,2-dimethylpropyl)-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole;
• 1-(2,2-dimethylpropyl)-4-propyl-5-{[3′-(1H-tetrazol-5-yl)biphenyl-3-yl]methoxy}-1H-indole;
• 1-(2,2-dimethylpropyl)-4-propyl-5-{[4′-(2H-tetrazol-5-yl)biphenyl-3-yl]methoxy}-1H-indole;
• 4-bromo-1-(2,2-dimethylpropyl)-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole;
• 7-bromo-1-(2,2-dimethylpropyl)-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-1,2,3-benzotriazole;
• 1-(2,2-dimethylpropyl)-4-propyl-5-{2-[4-(1H-tetrazol-5-yl)phenoxy]ethoxy}-1H-indole;
• 1-(2,2-dimethylpropyl)-4-propyl-5-{3-[4-(1H-tetrazol-5-yl)phenoxy]propoxy}-1H-indole;
• 1-(2,2-dimethylpropyl)-4-propyl-5-({5-[4-(1H-tetrazol-5-yl)phenoxy]pentyl}oxy)-1H-indole;
• 3′-({[1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-yl]oxy}methyl)biphenyl-3-carboxylic acid;
• 3′-({[1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-yl]oxy}methyl)biphenyl-4-carboxylic acid;
• 1-(2,2-dimethylpropyl)-4-propyl-5-({1-[4-(2H-tetrazol-5-yl)phenyl]pyrrolidin-3-yl}methoxy)-1H-indole;
• 1-(2,2-dimethylpropyl)-4-propyl-5-({1-[4-(2H-tetrazol-5-yl)phenyl]piperidin-3-yl}methoxy)-1H-indole;
• 1-(2,2-dimethylpropyl)-4-propyl-5-({4-[4-(2H-tetrazol-5-yl)phenoxy]benzyl}oxy)-1H-indole;
• 4-allyl-1-(2,2-dimethylpropyl)-5-({3-[4-(1H-tetrazol-5-yl)phenoxy]benzyl}oxy)-1H-indole;
• 1-(2,2-dimethylpropyl)-4-propyl-5-({3-[4-(1H-tetrazol-5-yl)phenoxy]benzyl}oxy)-1H-indole;
• 5-({2-chloro-5-[4-(1H-tetrazol-5-yl)phenoxy]benzyl}oxy)-1-(2,2-dimethylpropyl)-4-propyl-1H-indole;
• 1-(2,2-dimethylpropyl)-5-({2-ethyl-5-[4-(1H-tetrazol-5-yl)phenoxy]benzyl}oxy)-4-propyl-1H-indole;
• 1-(2,2-dimethylpropyl)-5-({2-fluoro-5-[4-(1H-tetrazol-5-yl)phenoxy]benzyl}oxy)-4-propyl-1H-indole;
• 4-[3-({[1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-yl]oxy}methyl)pyrrolidin-1-yl]benzoic acid;
• 6-[3-({[1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-yl]oxy}methyl)phenyl]pyridine-2-carboxylic acid;
• 5-[3-({[1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-yl]oxy}methyl)phenyl]nicotinic acid;
• 5-[3-({[1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-yl]oxy}methyl)phenyl]pyridine-2-carboxylic acid;
• 1-(2,2-dimethylpropyl)-4-propyl-5-({3-[5-(1H-tetrazol-5-yl)pyridin-3-yl]benzyl}oxy)-1H-indole;
• 1-(2,2-dimethylpropyl)-4-propyl-5-({3-[6-(2H-tetrazol-5-yl)pyridin-3-yl]benzyl}oxy)-1H-indole;
• 1-Cyclohexylmethyl-4-propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole;
• (4-Propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-indol-1-yl)-acetic acid tert-butyl ester;
• 4-Propyl-1-(tetrahydro-pyran-2-ylmethyl)-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole;
• 1-Naphthalen-2-ylmethyl-4-propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole;
• 4-Propyl-1-(4-pyrrol-1-yl-benzyl)-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole;
• (4-Propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-indol-1-yl)-acetic acid ethyl ester;
• 1-Cyclopropylmethyl-4-propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole;
• 1,4-Dipropyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole;
• 1-(5-Methyl-isoxazol-3-ylmethyl)-4-propyl-5-{4-[4-(5H-[1,2,4]triazol-3-yl)-phenoxy]-butoxy}-1H-indol;
• 1-Isopropyl-4-propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole;
• 1-(3-Methyl-butyl)-4-propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole;
• 1-Isobutyl-4-propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole;
• 1-Butyl-4-propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole;
• 1-Pentyl-4-propyl-5-{4-[4-(2H-tetrazol-5-yl)-phenoxy]-butoxy}-1H-indole;
• 1-(2,2-Dimethyl-propyl)-4-propyl-5-{(E)-4-[4-(2H-tetrazol-5-yl)-phenoxy]-but-2-enyloxy}-1H-indole;
• 1-(2,2-Dimethyl-propyl)-4-propyl-5-{3-[4-(2H-tetrazol-5-yl)-phenoxy]-cyclopentyloxy}-1H-indole;
• 4-[1-(2,2-Dimethyl-propyl)-4-propyl-1H-indol-5-yloxymethyl]-benzoic acid;
• 4-{4-[1-(2,2-Dimethyl-propyl)-4-propyl-2H-benzotriazol-5-yloxy]-butoxy}-benzoic acid;
• 4-{4-[3-(2,2-Dimethyl-propyl)-4-propyl-3H-benzotriazol-5-yloxy]-butoxy}-benzoic acid;
• 4-{4-[2-(2,2-Dimethyl-propyl)-4-propyl-1H-benzotriazol-5-yloxy]-butoxy}-benzoic acid;
• 4-{4-[1-(2,2-Dimethyl-propyl)-4-propyl-1H-indol-5-yloxy]-butoxy}-benzoic acid;
• 3-ethyl-7-propyl-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1,2-benzisoxazole;
• 3-(2,2-dimethylpropyl)-7-propyl-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1,2-benzisoxazole;
• 3-cyclohexyl-7-propyl-6-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1,2-benzisoxazole;
• 1-benzyl-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole;
• 1-(2,2-dimethylpropanoyl)-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole;
• 1-(4-methylbenzyl-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole;
• 1-(3-methylbenzyl-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole;
• 1-(2-methylbenzyl-4-propyl-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole;
• 4-propyl-1-(pyridin-2-ylmethyl)-5-{4-[4-(1H-tetrazol-5-yl)phenoxy]butoxy}-1H-indole;
• or a pharmaceutically acceptable salt thereof.