Benzimidazole derivatives and methods of use thereof

A method for treating a condition in a patient, comprising administering to the patient an effective amount of one or more compounds having the formula:

• or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:
• the dotted line represents an optional and additional bond;
• M1 is C(R3);
• X is a bond or C1-C6 alkylene;
• Y is —C(O)—, —C(S)—, —(CH2)q—, —C(O)NR4—, —C(O)CH2—, —SO2—, or —C(═N—CN)—NH—, such that when M1 is N, Y is not —C(O)NR4— or —C(═N—CN)—NH—.
• Z is a bond, C1-C6 alkylene, C1-C6 alkenylene, —C(O)—, —CH(CN)—, or —CH2C(O)NR4—;
• R1 is
• Q is —N(R8)—, —S— or —O—;
• R is H, OH, C1-C6 alkyl, halo(C1-C6)alkyl-, C1-C6 alkoxy, (C1-C6)alkoxy-(C1-C6)alkyl-, (C1-C6)-alkoxy-(C1-C6)alkoxy, (C1-C6)alkoxy-(C1-C6)alkyl-SO0-2, R32-aryl(C1-C6)alkoxy-, R32-aryl(C1-C6)alkyl-, R32-aryl, R32-aryloxy, R32-heteroaryl, (C3-C6)cycloalkyl, (C3-C6)cyclo-alkyl-(C1-C6)alkyl, (C3-C6)cycloalkyl-(C1-C6)alkoxy, (C3-C6)cycloalkyl-oxy-, R37-hetero-cycloalkyl, N(R30)(R31)—(C1-C6)alkyl-, —N(R30)(R31), —NH—(C1-C6)alkyl-O—(C1-C6)alkyl, —NHC(O)NH(R29);
• R29—S(O)0-2—, halo(C1-C6)alkyl-S(O)0-2—, N(R30)(R31)—(C1-C6)alkyl-S(O)0-2— or benzoyl;
• R2 is a six-membered heteroaryl ring having 1 or 2 heteroatoms independently selected from N or N—O, with the remaining ring atoms being carbon;
• a five-membered heteroaryl ring having 1, 2 or 3 heteroatoms independently selected from N, O or S, with the remaining ring atoms being carbon;
• R32-quinolyl;
• R32-aryl;
• heterocycloalkyl;
• wherein said six-membered heteroaryl ring or said five-membered heteroaryl ring is optionally substituted by R6;
• R3 is H, halo, C1-C6 alkyl, —OH or (C1-C6)alkoxy;
• R4 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, R33-aryl, R33-aryl(C1-C6)alkyl, and R32-heteroaryl;
• R5 is hydrogen, C1-C6 alkyl, —C(O)R20, —C(O)2R20, —C(O)N(R20)2, (C1-C6)alkyl-SO2—, or (C1-C6)alkyl-SO2—NH—;
• R6 is 1 to 3 substituents independently selected from the group consisting of —OH, halo, C1-C6 alkyl-, C1-C6 alkoxy, C1-C6 alkylthio, —CF3, —NR4R5, phenyl, R33-phenyl, NO2, —CO2R4, —CON(R4)2,
• R7 is —N(R29)—, —O— or —SO0-2—;
• R8 is H, C1-C6 alkyl, halo(C1-C6)alkyl-, (C1-C6)alkoxy-(C1-C6)alkyl-, R32-aryl(C1-C6)alkyl-, R32-aryl, R32-heteroaryl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, R37-heterocycloalkyl, N(R30)(R31)—(C1-C6)alkyl-, R29—S(O)2—,halo(C1-C6)alkyl-S(O)2—, R29—S(O)0-1—(C2-C6)alkyl-, halo(C1-C6)alkyl-S(O)0-1—(C2-C6)alkyl-;
• R12 is independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, or fluoro, provided that when R12 is hydroxy or fluoro, then R12 is not bound to a carbon adjacent to a nitrogen;
• or R12 forms a C1 to C2 alkyl bridge from one ring carbon to another ring carbon;
• R13 is independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, or fluoro, provided that when R13 is hydroxy or fluoro then R13 is not bound to a carbon adjacent to a nitrogen;
• or forms a C1 to C2 alkyl bridge from one ring carbon to another ring carbon;
• or R13 is ═O;
• R20 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, or aryl, wherein said aryl group is optionally substituted with from 1 to 3 groups independently selected from halo, —CF3, —OCF3, hydroxyl, or methoxy;
• or when two R20 groups are present, said two R20 groups taken together with the nitrogen to which they are bound form a five or six membered heterocyclic ring;
• R22 is C1-C6 alkyl, R34-aryl or heterocycloalkyl;
• R24 is H, C1-C6 alkyl, —SO2R22 or R34-aryl;
• R25 is independently selected from the group consisting of C1-C6 alkyl, halo, —CF3, —OH, C1-C6 alkoxy, (C1-C6)alkyl-C(O)—, aryl-C(O)—, N(R4)(R5)—C(O)—, N(R4)(R5)—S(O)1-2—, halo-(C1-C6)alkyl- or halo-(C1-C6)alkoxy-(C1-C6)alkyl-;
• R29 is H, C1-C6 alkyl, C3-C6 cycloalkyl, R35-aryl or R35-aryl(C1-C6)alkyl-;
• R30 is H, C1-C6 alkyl-, R35-aryl or R35-aryl(C1-C6)alkyl-;
• R31 is H, C1-C6 alkyl-, R35-aryl, R35-aryl(C1-C6)alkyl-, R35-heteroaryl, (C1-C6)alkyl-C(O)—, R35-aryl-C(O)—, N(R4)(R5)—C(O)—, (C1-C6)alkyl-S(O)2— or R35-aryl-S(O)2—;
• or R30 and R31 together are —(CH2)4-5—, —(CH2)2—O—(CH2)2— or —(CH2)2—N(R38)—(CH2)2— and form a ring with the nitrogen to which they are attached;
• R32 is 1 to 3 substituents independently selected from the group consisting of H, —OH, halo, C1-C6 alkyl, C1-C6 alkoxy, R35-aryl-O—, —SR22, —CF3, —OCF3, —OCHF2, —NR4R5, phenyl, R33-phenyl, NO2, —CO2R4, —CON(R4)2, —S(O)2R22, —S(O)2N(R20)2, —N(R24)S(O)2R22, —CN, hydroxy-(C1-C6)alkyl-, —OCH2CH2OR22, and R35-aryl(C1-C6)alkyl-O—, or two R32 groups on adjacent carbon atoms together form a —OCH2O— or —O(CH2)2O— group;
• R33 is 1 to 3 substituents independently selected from the group consisting of C1-C6 alkyl, halo, —CN, —NO2, —CF3, —OCF3, —OCHF2 and —O—(C1-C6)alkyl;
• R34 is 1 to 3 substituents independently selected from the group consisting of H, halo, —CF3, —OCF3, —OH and —OCH3.
• R35 is 1 to 3 substituents independently selected from hydrogen, halo, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, phenoxy, —CF3, —N(R36)2, —COOR20 and —NO2;
• R36 is independently selected form the group consisting of H and C1-C6 alkyl;
• R37 is 1 to 3 substituents independently selected from hydrogen, halo, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, phenoxy, —CF3, —N(R36)2, —COOR20, —C(O)N(R29)2 and —NO2, or R37 is one or two ═O groups;
• R38 is H, C1-C6 alkyl, R35-aryl, R35-aryl(C1-C6)alkyl-, (C1-C6)alkyl-SO2 or halo(C1-C6)alkyl-SO2—;
• a is 0, 1 or 2;
• b is 0, 1 or 2;
• k is 0, 1, 2, 3 or 4;
• k1 is 0, 1, 2 or 3;
• k2 is 0, 1 or 2;
• n is 2;
• p is 1, 2 or 3;
• q is an integer ranging from 1 to 5;
• and
• r is an integer ranging from 0 to 3,
• such that:
• (i) when M2 is N, p is not 1;
• (ii) when r is 0, M2 is C;
• and (iii) the sum of p and r is 3,
• wherein the condition is diabetes, a diabetic complication, impaired glucose tolerance or impaired fasting glucose.