Thienopyrimidinone nmda receptor modulators and uses thereof

A method of treating Alzheimer's disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound selected from the group consisting of:

• 5-[6-chloro-5-(trifluoromethyl)pyridin-3-yl]-3-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(3,4-dichlorophenyl)-3-{2-[(3 S)-3-fluoropyrrolidin-1-yl]-2-oxoethyl}-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(3,4-dichlorophenyl)-3-{2-[(3R)-3-fluoropyrrolidin-1-yl]-2-oxoethyl}-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(3,4-dichlorophenyl)-3-{2-[(3R,4S)-3,4-difluoropyrrolidin-1-yl]-2-oxoethyl}-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-[4-chloro-3-(trifluoromethyl)phenyl]-3-{2-[(3R,4S)-3,4-difluoropyrrolidin-1-yl]-2-oxoethyl}-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-[4-chloro-3-(trifluoromethyl)phenyl]-3-{2-[(3S)-3-fluoropyrrolidin-1-yl]-2-oxoethyl}-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-[4-chloro-3-(trifluoromethyl)phenyl]-3-{2-[(3R)-3-fluoropyrrolidin-1-yl]-2-oxoethyl}-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(5,6-dichloropyridin-3-yl)-3-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-[3-chloro-4-(trifluoromethyl)phenyl]-3-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-[4-fluoro-3-(trifluoromethyl)phenyl]-3-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(3,4-dichlorophenyl)-3-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-chloro-3-fluorophenyl)-3-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(3-chloro-4-fluorophenyl)-4-oxo-3H,4H-thieno[2,3-d]pyrimidin-3-yl 3-fluoropyrrolidine-1-carboxylate;
• 5-[4-chloro-3-(trifluoromethyl)phenyl]-3-[(E)-(pyrrolidin-1-ylmethylidene)amino]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• N-{5-[4-chloro-3-(trifluoromethyl)phenyl]-4-oxo-3H,4H-thieno[2,3-d]pyrimidin-3-yl}cyclopentanecarboxamide;
• 5-(4-chloro-3-fluorophenyl)-4-oxo-3H,4H-thieno[2,3-d]pyrimidin-3-yl pyrrolidine-1-carboxylate;
• 5-[4-chloro-3-(trifluoromethyl)phenyl]-3-{3-oxo-3-[2-(trifluoromethyl)pyrrolidin-1-yl]propyl}-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• N-[5-(3-chloro-4-fluorophenyl)-4-oxo-3H,4H-thieno[2,3-d]pyrimidin-3-yl]cyclopentanecarboxamide;
• 5-(3-chloro-4-fluorophenyl)-3-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• (E)-N′-{5-[4-chloro-3-(trifluoromethyl)phenyl]-4-oxo-3H,4H-thieno[2,3-d]pyrimidin-3-yl}-N,N-dimethylmethanimidamide;
• 5-(3-chloro-4-fluorophenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-[4-chloro-3-(trifluoromethyl)phenyl]-3-[3-(3-fluoropyrrolidin-1-yl)-3-oxopropyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-[4-chloro-3-(trifluoromethyl)phenyl]-3-[3-oxo-3-(pyrrolidin-1-yl)propyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• N-[5-(3-chloro-4-fluorophenyl)-4-oxo-3H,4H-thieno[2,3-d]pyrimidin-3-yl]pyrrolidine-1-carboxamide;
• 5-(3-chloro-4-fluorophenyl)-3-[1-oxo-1-(pyrrolidin-1-yl)propan-2-yl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(3-chloro-4-fluorophenyl)-4-oxo-3H,4H-thieno[2,3-d]pyrimidin-3-yl pyrrolidine-1-carboxylate;
• 5-[4-chloro-3-(trifluoromethyl)phenyl]-3-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-[4-chloro-3-(trifluoromethyl)phenyl]-4-oxo-3H,4H-thieno[2,3-d]pyrimidin-3-yl pyrrolidine-1-carboxylate;
• 5-[4-chloro-3-(trifluoromethyl)phenyl]-3-{[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino}-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• N-{5-[4-chloro-3-(trifluoromethyl)phenyl]-4-oxo-3H,4H-thieno[2,3-d]pyrimidin-3-yl}pyrrolidine-1-carboxamide;
• 5-[4-chloro-3-(trifluoromethyl)phenyl]-3-[1-oxo-1-(pyrrolidin-1-yl)propan-2-yl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-[4-chloro-3-(trifluoromethyl)phenyl]-3-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-5-[3-(trifluoromethyl)phenyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(2-chloro-4-fluorophenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(3,4-dichlorophenyl)-6-methyl-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(3-chloro-4-fluorophenyl)-6-methyl-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(2-chlorophenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-5-[3-(trifluoromethoxy)phenyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-[2-methyl-4-(trifluoromethyl)phenyl]-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-[4-(dimethylamino)phenyl]-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-[4-fluoro-3-(trifluoromethyl)phenyl]-6-methyl-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-[4-fluoro-3-(trifluoromethyl)phenyl]-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-5-[2-(trifluoromethyl)pyridin-4-yl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(2,3-dichlorophenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-[2-methoxy-5-(trifluoromethyl)phenyl]-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• ethyl 2-[5-(4-chlorophenyl)-2-methyl-4-oxo-3H,4H-thieno[2,3-d]pyrimidin-3-yl]acetate;
• 5-(4-chlorophenyl)-2-methyl-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-chlorophenyl)-2-methyl-3-{2-oxo-2-[2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-[2-chloro-4-(trifluoromethyl)phenyl]-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-chlorophenyl)-3-{2-oxo-2-[2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-2-(trifluoromethyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(3,4-difluorophenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-methoxyphenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-5-(pyrimidin-5-yl)-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-chlorophenyl)-6-methyl-3-{2-oxo-2-[2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-chlorophenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-2-(trifluoromethyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(5-fluoropyridin-3-yl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(3,4-dichlorophenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(6-methoxypyridin-3-yl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-chlorophenyl)-6-methyl-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-[4-chloro-3-(trifluoromethyl)phenyl]-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-tert-butylphenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-5-[4-(trifluoromethoxy)phenyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(1-methyl-1H-pyrazol-5-yl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 4-{4-oxo-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-5-yl}benzonitrile;
• 5-(3-fluorophenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(3-chloro-4-fluorophenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-5-(pyridin-4-yl)-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-chloro-3-fluorophenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-methylphenyl)-3-{2-oxo-2-[2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-fluorophenyl)-3-{2-oxo-2-[2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 3-{2-oxo-2-[2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-5-[4-(trifluoromethyl)phenyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 3-[2-oxo-2-(piperidin-1-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-methylphenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-fluorophenyl)-3-[2-oxo-2-(piperidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-fluorophenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 6-(4-chlorophenyl)-3-[2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 6-(4-chlorophenyl)-3-[2-(morpholin-4-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-methylphenyl)-3-[2-oxo-2-(piperidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 2-[6-(4-chlorophenyl)-4-oxo-3H,4H-thieno[2,3-d]pyrimidin-3-yl]-N-cyclopropylacetamide;
• 6-(4-chlorophenyl)-3-[2-oxo-2-(piperidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-chlorophenyl)-3-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 6-(4-chlorophenyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-chlorophenyl)-3-[2-(4-hydroxy-4-phenylpiperidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-chlorophenyl)-3-[2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 2-[5-(4-chlorophenyl)-4-oxo-3H,4H-thieno[2,3-d]pyrimidin-3-yl]-N,N-diethylacetamide;
• 5-(4-chlorophenyl)-3-[2-(2,6-dimethylpiperidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-chlorophenyl)-3-{2-oxo-2-[2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-chlorophenyl)-3-{2-[(2S)-2-methylpyrrolidin-1-yl]-2-oxoethyl}-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 2-[5-(4-chlorophenyl)-4-oxo-3H,4H-thieno[2,3-d]pyrimidin-3-yl]-N-cyclobutylacetamide;
• 5-(4-chlorophenyl)-3-[2-oxo-2-(piperidin-1-yl)ethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 2-[5-(4-chlorophenyl)-4-oxo-3H,4H-thieno[2,3-d]pyrimidin-3-yl]-N-(1-methylpyrrolidin-3-yl)acetamide;
• 5-(4-chlorophenyl)-3-[2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 2-[5-(4-chlorophenyl)-4-oxo-3H,4H-thieno[2,3-d]pyrimidin-3-yl]-N-cyclopropylacetamide;
• 5-(4-chlorophenyl)-3-[2-(morpholin-4-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-chlorophenyl)-3-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-chlorophenyl)-3-[2-(4-fluoropiperidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(4-chlorophenyl)-3-[2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(5-chloro-6-fluoropyridin-3-yl)-3-[2-(3,4-difluoropyrrolidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-(5,6-dichloropyridin-3-yl)-3-[2-(3,4-difluoropyrrolidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• 5-[6-chloro-5-(trifluoromethyl)pyridin-3-yl]-3-[2-(3,4-difluoropyrrolidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;
• or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

A method of treating Alzheimer's disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound represented by Formula II:

• or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein:
• L1 is selected from the group consisting of —(CR11R22)n—, —O—, —NRa—, —(CR11R22)nNRa—, —(CR11R22)nO—, and —H(C═N)—;
• R11 and R22 are each independently selected for each occurrence from the group consisting of hydrogen and C1-4 alkyl;
• n is 1 or 2;
• R1 and R2, together with the nitrogen to which they are attached, form a 4-6 membered heterocyclic ring substituted on a carbon not adjacent to the nitrogen by one, two or more substituents each independently selected from the group consisting of halogen, cyano, oxo, hydroxyl and C1-6 alkyl (optionally substituted by one, two or three halogens);
• R3 is selected from the group consisting of phenyl, naphthyl, heteroaryl, heterocyclyl and C3-6cycloalkyl, wherein R3 is optionally substituted with one, two or three substituents each independently selected from C1-4 alkyl, halogen, hydroxyl, cyano, C1-4 alkoxy, C2-6 alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6 alkyl-S(O)2—, C1-6 alkylcarbonyl, RaRbN—SO2—, NRaRb, C(O)OH, C1-4alkoxycarbonyl, and NRaRbcarbonyl, wherein C1-4alkyl, C1-4alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6 alkyl-S(O)2—, and C1-6 alkylcarbonyl may be optionally substituted by one or more substituents each independently selected from halogen, hydroxyl, cyano, and NRaRb;
• R66 and R67 are each independently selected from the group consisting of hydrogen, halogen, C1-4 alkyl (optionally substituted by one, two, three substituents selected from halogen, hydroxyl, cyano and NRaRb), and phenyl (optionally substituted by one, two or three halogens);
• and
• Ra and Rb are independently selected, for each occurrence, from the group consisting of:
• hydrogen, hydroxyl, and C1-3 alkyl;
• or Ra and Rb, together with the nitrogen to which they are attached, form a 4-6 membered heterocyclic ring which may have an additional heteroatom selected from O, S, or N.