A method for treating a subject suffering from or susceptible to diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, chemotherapeutic-induced neuropathy, neuropathy associated with an ischemic event, ocular diseases and/or disorders, cardiovascular disease, blood clotting disorders, inflammation, and/or flushing, comprising administering to the subject in need thereof of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of formula (I):
- wherein:
- one of D and E is N and the other is C;
- and
- when D is N, one of A and B is N and the other is CR;
- and
- when E is N, B is N and A is N or CR;
- or
- a salt thereof, wherein:
- each R is independently selected from hydrogen, halo, OH, C≡N, C1-C4 alkyl, halo-substituted C2-C4 alkyl, C1-C4 alkoxy-substituted C1-C4 alkyl, hydroxy-substituted C1-C8 alkyl, OR3, O—(C1-C4 alkyl)-OR3, S—(C1-C2 alkyl), S-(halo-substituted C1-C4 alkyl), N(hydroxy-substituted C1-C4 alkyl)2, N(methoxy-substituted C1-C4 alkyl)2, N(C1-C4 alkyl)(hydroxy-substituted C1-C4 alkyl), N(C1-C4 alkyl)(methoxy-substituted C1-C4 alkyl), N(hydroxy-substituted C1-C4 alkyl)(methoxy-substituted C1-C4 alkyl), C5-C7 cycloalkyl, and 4- to 8-membered non-aromatic heterocycle, and when one or both of E and A is N, then R can additionally be selected from halo-substituted methyl and C3-C4 cycloalkyl;
- R1 is an aromatic heterocycle or a fused carbocycle, wherein R1 is optionally substituted with one or more substituents independently selected from halo, C≡N, C1-C4 alkyl, halo-substituted C1-C4 alkyl, C1-C4 alkoxy-substituted C1-C4 alkyl, hydroxy-substituted C1-C8 alkyl, O—R3, O—(C1-C4 alkyl)-OR3, ═O, C3-C7 cycloalkyl, SO2R3, S—R3, (C1-C4 alkyl)-N(R3)(R3), N(R3)(R3), O—(C1-C4 alkyl)-N(R3)(R3), O—(C0-C4 alkyl)-CR3R3(C0-C4 alkyl), (C1-C4 alkyl)-O—(C1-C4 alkyl)-N(R3)(R3), C(═O)—N(R3)(R3), (C1-C4 alkyl)-C(═O)—N(R3)(R3), O—(C0-C4 alkyl)-CRxRx—(C0-C4 alkyl), CRxRx, phenyl, O-phenyl, second heterocycle, O-(second heterocycle), 3,4-methylenedioxy, halo-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, and halo substituted 3,4-ethylenedioxy, wherein any phenyl, saturated heterocycle, or second heterocycle substituent of R1 is optionally substituted with one or more substituents independently selected from halo, C≡N, C1-C4 alkyl, halo-substituted C1-C4 lkyl, O-(halo-substituted C1-C4 alkyl), O—(C1-C4 alkyl), S—(C1-C4 alkyl), and S-(halo-substituted C1-C4 alkyl);
- R2 is a carbocycle or a heterocycle, wherein R2 is optionally substituted with one or more substituents independently selected from halo, C≡N, C1-C4 alkyl, halo-substituted C1-C4 alkyl, C1-C4 alkoxy-substituted C1-C4 alkyl, hydroxy-substituted C1-C8 alkyl, O—R3, —O—(C1-C4 alkyl)-OR3, ═O, C3-C7 cycloalkyl, SO2R3, S—R3, (C1-C4 alkyl)-N(R3)(R3), N(R3)(R3), O—(C1-C4 alkyl)-N(R3)(R3), O—(C0-C4 alkyl)-CR3R3(C0-C4 alkyl), (C1-C4 alkyl)-O—(C1-C4 alkyl)-N(R3)(R3), C(═O)—N(R3)(R3), (C1-C4 alkyl)-C(═O)—N(R3)(R3), O-phenyl, O-(second heterocycle), 3,4-methylenedioxy, halo-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, and halo-substituted 3,4-ethylenedioxy, and when E is N, substituents on R2 can additionally be selected from a second heterocycle, and when both D and A are N, substituents on R2 can additionally be selected from phenyl and a second heterocycle, wherein any phenyl, saturated heterocycle or second heterocycle substituent of R2 is optionally substituted with one or more substituents independently selected from halo, C≡N, C1-C4 alkyl, halo-substituted C1-C4 alkyl, O-(halo-substituted C1-C4 alkyl), O—(C1-C4 alkyl), S—(C1-C4 alkyl), and S-(halo-substituted C1-C4 alkyl);
- each R3 is independently selected from hydrogen and C1-C4 alkyl optionally substituted with one or more of OH, O—(C1-C4 alkyl), halo, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(methoxy-substituted C1-C4 alkyl), NH(hydroxy-substituted C1-C4 alkyl), N(hydroxy-substituted C1-C4 alkyl)2 and N(methoxy-substituted C1-C4 alkyl)2;
- or
- two R3 are taken together with the nitrogen or carbon atom to which they are bound to form a 4- to 8-membered saturated heterocycle optionally comprising one additional heteroatom independently selected from N, S, S(═O), S(═O)2, and O, wherein the heterocycle formed by two R3 is optionally substituted at any carbon atom with one or more of OH, halo, C1-C4 alkyl, halo-substituted C1-C4 alkyl, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, —O(C1-C4 alkyl), NH(hydroxy-substituted C1-C4 alkyl), N(hydroxy-substituted C1-C4 alkyl)2NH(methoxy-substituted C1-C4 alkyl), or N(methoxy-substituted C1-C4 alkyl)2, and optionally substituted at any substitutable nitrogen atom with C1-C4 alkyl or halo-substituted C1-C4 alkyl;
- two Rx taken together with the carbon atom to which they are bound form a 4- to 8-membered carbocycle or heterocycle optionally comprising one or two heteroatoms independently selected from N, S, S(═O), S(═O)2, and O, wherein the carbocycle or heterocycle is optionally substituted at any carbon atom with one or more of OH, halo, C1-C4 alkyl, halo-substituted C1-C4 alkyl, NH2, and N(R3)(R3) and optionally substituted at any substitutable nitrogen atom with C1-C4 alkyl or halo-substituted C1-C4 alkyl;
- and
- when D is N, A is CR and B is N, then X is selected from C(═O)—NH-†, NH—C(═O)-†, S(═O)—NH-†, S(═O)2—NH-†, and NH—C(═O)—O—CR4R5-†;
- and
- when E is N, B is N and A is N or CR then X is selected from C(═O)—NH-†, NH—C(═O)-†, S(═O)—NH-†, S(═O)2—NH-†, NH—C(═S)-†, C(═S)—NH-†, NH—S(═O)-†, NH—S(═O)2-†, NH—S(═O)2—NR4-†, NR4—S(═O)2—NH-†, NH—C(═O)—O-†, O—C(═O)—NH-†, NH—C(═O)—NH-†, NH—C(═O)—NR4-†, NR4—C(═O)—NH-†, CH2—NH—C(═O)-†, NH—C(═S)—CR4R5-†, CR4R5—C(═S)—NH-†, NH—S(═O)—CR4R5-†, CR4R5—S(═O)—NH-†, NH—S(═O)2—CR4R5-†, CR4R5—S(═O)2—NH-†, CR4R5—O—C(═O)—NH-†, NH—C(═O)—CR4R5-†, NH—C(═O)—CR4R5—NH-†, CR4R5—NH—C(═O)—O—† and NH—C(═O)—O—CR4R5—;
- and
- when D is N, A is N and B is CR then X is selected from C(═O)—NH-†, NH—C(═O)†, NH—CR4R5-†, C(═O)—NH—CR4R5-†, S(═O)—NH-†, S(═O)2—NH-†, CR4R5—NH-†, —NH—C(═O)O—CR4R5-†, NH-†, NH—C(═S)-†, C(═S)—NH-†, NH—S(═O)-†, NH—S(═O)2-†, NH—S(═O)2—NR4-†, NR4—S(O)2—NH-†, NH—C(═O)—O-†, O—C(═O)—NH-†, NH—C(═O)—NH-†, NH—C(═O)—NR4-†, NR4—C(═O)—NH-†, CR4R5—NH—C(O)-†, NH—C(═S)—CR4R5-†, CR4R5—C(═S)—NH-†, NH—S(═O)—CR4R5-†, CR4R5—S(═O)—NH-†, NH—S(═O)2—CR4R5-†, CR4R5—S(═O)2—NH—, CR4R5—O—C(═O)—NH-†, NH—C(═O)—CR4R5-†, NH—C(═O)—CR4R5—NH† and CR4R5—NH—C(═O)—O-†;
- wherein:
- † represents where X is bound to R1;
- and
- each R4 and R5 is independently selected from hydrogen, C1-C4 alkyl, CF3 and (C1-C3 alkyl)-CF3.