Beta-carboline derivatives useful as inhibitors of phosphodiesterase

A compound of the formula (I):

• 33
• wherein
• R1 is independently selected from the group consisting of halogen, nitro, hydroxy, C1-C8alkyl, C1-C8alkoxy, —NH2, —NHRA, —N(RA)2, —O—RA, —C(O)NH2, —C(O)NHRA, —C(O)N(RA)2, —NC(O)—RA, —SO2NHRA, —SO2N(RA)2, phenyl (optionally substituted with 1 to 3 RB) and heteroaryl (optionally substituted with 1 to 3 RB);
• where each RA is independently is independently selected from the group consisting of C1-C8alkyl, aryl (optionally substituted with 1 to 3 RB), C1-C8aralkyl (optionally substituted with 1 to 3 RB) and heteroaryl (optionally substituted with 1 to 3 RB);
• where each RB is independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C1-C8alkyl, C1-C8alkoxy, C1-C8alkoxycarbonyl, carboxyC1-C8alkyl, C1-C8alkylsulfonyl, trifluoromethyl, trifluoromethoxy, amino, acetylamino, di(C1-C8alkyl)amino, di(C1-C8alkyl)aminoC1-C8alkoxy, di(C1-C8alkyl)aminoacetylC1-C8alkyl, di(C1-C8alkyl)aminoacetylamino, carboxyC1-C8alkylcarbonylamino, hydroxyC1-C8alkylamino, NHRA, N(RA)2 and heterocycloalkylC1-C8alkoxy;
• n is an integer from 0 to 4;
• X is selected from the group consisting of O, S and NRD;
• where RD is selected from the group consisting of hydrogen, hydroxy, —ORA, C1-C8alkyl (wherein the alkyl is optionally substituted with one to three substituent independently selected from halogen, carboxy, amino, C1-C8alkylamino, di(C1-C8alkyl)amino, C1-C8alkoxycarbonyl, heteroaryl or heterocycloalkyl), heteroaryl and heteroarylcarbonyl (wherein the heteroaryl may be optionally substituted with phenyl or substituted phenyl, where the phenyl substituents are one to three RB);
• R2 is selected from the group consisting of C5-C10alkyl (optionally substituted with 1 to 3 RC), aryl (optionally substituted with 1 to 3 RB), heteroaryl (optionally substituted with 1 to 3 RB) and heterocycloalkyl (optionally substituted with 1 to 3 RB);
• where each RC is independently selected from the group consisting of halogen, hydroxy, nitro, NH2, NHRA and N(RA)2;
• Z is selected from the group consisting of CH2, CHOH and C(O);
• provided that when Z is CHOH or C(O), then X is NH;
• R4 is selected from the group consisting of hydrogen, hydroxy, carboxy, C1-C6alkylcarbonyl, C1-C6alkoxylcarbonyl, di(C1-C8alkyl)aminoalkoxycarbonyl, di(C1-C8alkyl)aminoC1-C8alkylaminocarbonyl, and —CORF;
• where RF is selected from the group consisting of C1-C8alkyl, NH2, NHRA, NRA2, —C1-C8alkyl-NH2, —C1-C8alkyl-NHRA, —C1-C8alkyl-NRA2 and —NH—C1-C8alkyl-NRA2;
• a is an integer from 0 to 1;
• Y is selected from the group consisting of CH2, C(O), C(O)O, C(O)—NH and SO2;
• 34
• is selected from the group consisting of naphthyl, heteroaryl and heterocycloalkyl;
• m is an integer from 0 to 2;
• R3 is independently selected from the group consisting of halogen, nitro, C1-C8alkyl, C1-C8alkoxy, trifluoromethyl, trifluoromethoxy, phenyl (optionally substituted with 1 to 3 RB), phenylsulfonyl, naphthyl, C1-C8aralkyl, heteroaryl (optionally substituted with 1 to 3 RB), NH2, NHRA and N(RA)2;
• provided that when
• 35
• is 2-furyl or 2-thienyl, then m is an integer from 1 to 2;
• and pharmaceutically acceptable salts thereof.