Substituted thiophene- and furan-fused azolopyrimidine-5-(6H)-one compounds

The method of treating a cognitive impairment, comprising:

• (a) providing cognitive training to an animal in need of treatment of a cognitive impairment under conditions sufficient to produce an improvement in performance by said animal of a cognitive function whose deficit is associated with said cognitive impairment;
• (b) administering to said animal in conjunction with said cognitive training a chemical entity of Formula (I):
• wherein:
• X is —CH— or —N—;
• Y is —O— or —S—;
• M is 0-5;
• R1 is each independently selected from the group consisting of:
• H, halo, —CN, —C1-6alkyl, —C1-6haloalkyl, —C1-6thioalkyl, —C1-6haloalkoxy, —SO2C1-6alkyl, aryl, heteroaryl, and heterocycloalkyl;
• R3 and R4 are each independently selected from the group consisting of —H, halo, —C1-6alkyl, —C1-6haloalkyl, —CH2OH, —C1-6alkoxy, —C1-6haloalkoxy, aryl, optionally substituted 5 or 6 membered heteroaryl, —(C1-C6alkyl)aryl, —(C1-C6 alkyl)heteroaryl, and —(CR10R11)1-3NR12R13;
• or R3 and R4 taken together with the carbons to which they are attached form a saturated or unsaturated monocylic ring system, having the following structure:
• D is —O—, —N(R9)—, or a bond;
• m and n are each independently 0-4, with the proviso that the sum of m and n is 1-5 when D is —O—, —N(R9)—, or is 2-6 when D is a bond;
• and with the proviso that when D is a bond, R1 is not —Cl in the para position;
• R5, R6, R7, R8, are each independently selected from the group consisting of:
• —H, —F, —C1-6alkyl, —C1-6haloalkyl, —OH, —C1-6alkoxy, —C1-6haloalkoxy;
• R9 is selected from the group consisting of:
• —H, —C1-6alkyl, —C1-6thioalkyl, —C1-6haloalkyl, —CO2C1-6alkyl, —SO2(C1-6alkyl), —C1-6alkyl(aryl), —C1-6alkyl(C3-6cycloalkyl), —C1-6alkyl(heterocycloalkyl), —C1-6alkyl(heteroaryl), heteroaryl, —CO(aryl), —CO(heteroaryl), —CO(heterocycloalkyl), —CO(C3-6cycloalkyl), wherein each aryl, cycloalkyl, heterocycloalkyl, heteroaryl are optionally unsubstituted or substituted with a member each independently selected from the group consisting of —H, —Cl, —F, and —CH3;
• R10 and R11 are each independently selected from the group consisting of:
• —H, —F, —C1-6alkyl, —CF3 and —OH;
• and
• R12 and R13 are each independently selected from the group consisting of:
• —H, —C1-6alkyl, —C3-6cycloalkyl, —C1-6alkyl(aryl), —C1-6alkyl(heteroaryl), —C1-6alkyl(heterocycloalkyl), —CH2CON(C1-6alkyl)2;
• or R12 and R13 are taken together with the nitrogen to which they are attached form a heterocycloalkyl ring, optionally substituted with one or more R14, where each R14 is independently selected from the group consisting of:
• —H, —C1-6alkyl, —CH2OH, —OH, —COCH3, —SO2CH3, —O-pyridyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, —O-phenyl, —O-(2-fluorophenyl), -morpholino, 1,1-difluoro-cyclopropyl, or two R14 members are taken together to form a —C3-6heterocycloalkyl;
• wherein the chemical entity is selected from the group consisting of compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I), and pharmaceutically acceptable metabolites of compounds of Formula (I);
• (c) repeating said providing and administering steps one or more times;
• and
• (d) reducing the number of training sessions sufficient to produce the improvement in performance, relative to the improvement in performance produced by cognitive training alone.

A method of promoting neurogenesis, comprising administering to a subject in need of such treatment an effective amount of a chemical entity of Formula (I):

• wherein:
• X is —CH— or —N—;
• Y is —O— or —S—;
• M is 0-5;
• R1 is each independently selected from the group consisting of:
• H, halo, —CN, —C1-6alkyl, —C1-6haloalkyl, —C1-6thioalkyl, —C1-6alkoxy, —C1-6haloalkoxy, —SO2C1-6alkyl, aryl, heteroaryl, and heterocycloalkyl;
• R3 and R4 are each independently selected from the group consisting of —H, halo, —C1-6alkyl, —C1-6haloalkyl, —CH2OH, —C1-6alkoxy, —C1-6haloalkoxy, aryl, optionally substituted 5 or 6 membered heteroaryl, —(C1-C6alkyl)aryl, —(C1-C6alkyl)heteroaryl, and —(CR10R11)1-3NR12R13;
• or R3 and R4 taken together with the carbons to which they are attached form a saturated or unsaturated monocylic ring system, having the following structure:
• D is —O—, —N(R9)—, or a bond;
• m and n are each independently 0-4, with the proviso that the sum of m and n is 1-5 when D is —O—, —N(R9)—, or is 2-6 when D is a bond;
• and with the proviso that when D is a bond, R1 is not —Cl in the para position;
• R5, R6, R7, R8, are each independently selected from the group consisting of:
• —H, —F, —C1-6alkyl, —C1-6haloalkyl, —OH, —C1-6alkoxy, —C1-6haloalkoxy;
• R9 is selected from the group consisting of:
• —H, —C1-6alkyl, —C1-6thioalkyl, —C1-6haloalkyl, —CO2C1-6alkyl, —SO2(C1-6alkyl), —C1-6alkyl(aryl), —C1-6alkyl(C3-6cycloalkyl), —C1-6alkyl(heterocycloalkyl), —C1-6alkyl(heteroaryl), heteroaryl, —CO(aryl), —CO(heteroaryl), —CO(heterocycloalkyl), —CO(C3-6cycloalkyl), wherein each aryl, cycloalkyl, heterocycloalkyl, heteroaryl are optionally unsubstituted or substituted with a member each independently selected from the group consisting of —H, —Cl, —F, and —CH3;
• R10 and R11 are each independently selected from the group consisting of:
• —H, —F, —CF3 and —OH;
• and
• R12 and R13 are each independently selected from the group consisting of:
• —H, —C1-6 alkyl, —C3-6cycloalkyl, —C1-6alkyl(aryl), —C1-6alkyl(heteroaryl), —C1-6alkyl(heterocycloalkyl), —CH2CON(C1-6alkyl)2;
• or R12 and R13 are taken together with the nitrogen to which they are attached form a heterocycloalkyl ring, optionally substituted with one or more R14, where each R14 is independently selected from the group consisting of:
• —H, —C1-6alkyl, —CH2OH, —OH, —COCH3, —SO2CH3, —O-pyridyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, —O-phenyl, —O-(2-fluorophenyl), -morpholino, 1,1-difluoro-cyclopropyl, or two R14 members are taken together to form a —C3-6heterocycloalkyl;
• wherein the chemical entity is selected from the group consisting of compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I), and pharmaceutically acceptable metabolites of compounds of Formula (I).