N-heterocyclic derivatives as NOS inhibitors

A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (II):

• wherein:
• A is —R1, —OR1, —C(O)N(R1)R2, —P(O)[N(R1)R2]2, —N(R1)C(O)R2, —N(R16)C(O)OR2, —N(R1)R21, —N(R16)C(O)N(R1)R16, —S(O)tR1, —SO2NHC(O)R1, —N(R1)SO2R22, —SO2N(R1)H, —C(O)NHSO2R22, or —CH═NOR1, provided that when A is hydrogen, n can not be zero;
• U is C(R5);
• each X, Y and Z is C(R19);
• each W is N or CH;
• n is zero or an integer from 1 to 3;
• t is zero, one or two;
• is an optionally substituted non-aromatic partially or fully saturated N-heterocyclyl;
• each R1 and R2 are independently chosen from the group consisting of hydrogen, optionally substituted C1-C20 alkyl, optionally substituted cycloalkyl, —[C0-C8 alkyl]-R9, —[C2-C8 alkenyl]-R9, —C2-C8 alkynyl]-R9, —[C2-C8 alkyl]-R10 (optionally substituted by hydroxy), —[C1-C8]-R11 (optionally substituted by hydroxy), optionally substituted heterocyclyl;
• or R1 and R2 together with the nitrogen atom to which they are attached is an optionally substituted N-heterocyclyl;
• R5 is chosen from the group consisting of hydrogen, halo, alkyl, haloalkyl, optionally substituted aralkyl, optionally substituted aryl, —OR16, —S(O)t—R16, —N(R16)R21, —N(R16)C(O)N(R1)R16, —N(R16)C(O)OR16, —N(R16)C(O)R16, —[C0-C8 alkyl]-C(O)OR16, —[C0-C8 alkyl]-C(H)[C(O)OR16]2, and —[C0-C8 alkyl]-C(O)N(R1)R16;
• each R9 independently chosen from the group consisting of haloalkyl, cycloalkyl (optionally substituted with halo, cyano, alkyl or alkoxy), carbocyclyl (optionally substituted with one or more substituents selected from the group consisting of halo, alkyl and alkoxy), and heterocyclyl (optionally substituted with alkyl, aralkyl or alkoxy);
• each R10 is independently chosen from the group consisting of halo, alkoxy, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted —S(O)t—R22, acylamino, amino, monoalkylamino, dialkylamino, (triphenylmethyl)amino, hydroxy, mercapto, alkylsulfonamido;
• each R11 is independently chosen from the group consisting of cyano, di(alkoxy)alkyl, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl and dialkylaminocarbonyl;
• each R14 and R20 are independently hydrogen or alkyl;
• each R16 is independently hydrogen, alkyl, optionally substituted aryl, optionally substituted aralkyl or cycloalkyl;
• each R19 is independently hydrogen, alkyl (optionally substituted with hydroxy), cyclopropyl, halo or haloalkyl;
• each R21 is independently hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, —C(O)R22 or —SO22;
• or R21 taken together with R1 and the nitrogen to which they are attached is an optionally substituted N-heterocyclyl;
• or R21 taken together with R16 and the nitrogen to which they are attached is an optionally substituted N-heterocyclyl;
• and
• each R22 is independently alkyl, cycloalkyl, optionally substituted aryl or optionally substituted aralkyl;
• as a single stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof.

A method of treating a condition resulting from an abnormality in nitric oxide production which comprises administering to a mammal having a condition resulting from an abnormality in nitric oxide production a therapeutically effective amount of a compound of formula (II):

• wherein:
• A is —R1, —OR1, —C(O)N(R1)R2, —P(O)[N(R1)R2]2, —N(R1)C(O)R2, —N(R16)C(O)OR2, —N(R1)R21, —N(R16)C(O)N(R1)R16, —S(O)tR1, —SO2NHC(O)R1, —N(R1)SO2R22, —SO2N(R1)H, —C(O)NHSO2R22, or —CH═NOR1, provided that when A is hydrogen, n can not be zero;
• U is C(R5);
• each X, Y and Z is C(R19);
• each W is N or CH;
• n is zero or an integer from 1 to 3;
• t is zero, one or two;
• is an optionally substituted non-aromatic partially or fully saturated N-heterocyclyl;
• each R1 and R2 are independently chosen from the group consisting of hydrogen, optionally substituted C1-C20 alkyl, optionally substituted cycloalkyl, —[C0-C8 alkyl]-R9, —[C2-C8 alkenyl]-R9, —[C2-C8 alkynyl]-R9, —[C2-C8 alkyl]-R10 (optionally substituted by hydroxy), —[C1-C8]-R11 (optionally substituted by hydroxy), optionally substituted heterocyclyl;
• or R1 and R2 together with the nitrogen atom to which they are attached is an optionally substituted N-heterocyclyl;
• R5 is chosen from the group consisting of hydrogen, halo, alkyl, haloalkyl, optionally substituted aralkyl, optionally substituted aryl, —OR16, —S(O)t—R16, —N(R16)R21, —N(R16)C(O)N(R1)R16, —N(R16)C(O)OR16, N(R16)C(O)R16, —[C0-C8 alkyl]-C(O)OR16, —[C0-C8 alkyl]-C(H)[C(O)OR162, and —[C0-C8 alkyl]-C(O)N(R1)R16;
• each R9 is independently chosen from the group consisting of haloalkyl, cycloalkyl (optionally substituted with halo, cyano, alkyl or alkoxy), carbocyclyl (optionally substituted with one or more substituents selected from the group consisting of halo, alkyl and alkoxy), and heterocyclyl (optionally substituted with alkyl, aralkyl or alkoxy);
• each R10 is independently chosen from the group consisting of halo, alkoxy, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted —S(O)t—R22, acylamino, amino, monoalkylamino, dialkylamino, (triphenylmetyl)amino, hydroxy, mercapto, alkylsulfonamido;
• each R11 is independently chosen from the group consisting of cyano, di(alkoxy)alkyl, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl and dialkylaminocarbonyl;
• each R14 and R20 are independently hydrogen or alkyl;
• each R16 is independently hydrogen, alkyl, optionally substituted aryl, optionally substituted aralkyl or cycloalkyl;
• each R19 is independently hydrogen, alkyl (optionally substituted with hydroxy), cyclopropyl, halo or haloalkyl;
• each R21 is independently hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, —C(O)R22 or —SO2R22;
• or R21 taken together with R1 and the nitrogen to which they are attached is an optionally substituted N-heterocyclyl;
• or R21 taken together with R16 and the nitrogen to which they are attached is an optionally substituted N-heterocyclyl;
• and
• each R22 is independently alkyl, cycloalkyl, optionally substituted aryl or optionally substituted aralkyl;
• as a single stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof.