Aldehyde Dehydrogenase Inhibitors and Their Therapeutic Use

A compound of the following formula:

• or a pharmaceutically acceptable salt or solvate thereof;
• wherein -J is:
• wherein:
• Ring A is:
• an aromatic monocyclic ring having 5 or 6 ring atoms;
• and is optionally substituted with one or more substituents —RA;
• wherein each —RA is independently —RAA, —RAAX, —OH, —ORAA, —ORAAX, —F, —Cl, —Br, —I, —NH2, —NHRAA, —NRAA2, —RAAN, —C(═O)RAA, —C(═O)OH, —C(═O)ORAA, —OC(═O)RAA, —NHC(═O)RAA, —C(═O)NH2, —C(═O)NHRAA, —C(═O)NRAA2, —C(═O)RAAN, —S(═O)2RAA, —S(═O)2NH2, —S(═O)2NHRAA, —S(═O)2NRAA2, —S(═O)2RAAN, —CN, or —NO2;
• wherein:
• each —RAA is independently saturated linear or branched C1-4alkyl or saturated C3-6cycloalkyl;
• each —RAAX is independently saturated linear or branched C1-4haloalkyl;
• and
• each —RAAN is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or 1,1-dioxo-thiomorpholino, and is optionally substituted with one or more substituents selected from —RAA, —OH, and —ORAA;
• either -M1 is:
• wherein:
• each of —RM1a and —RM1e is independently —H or —RM1-ortho;
• each of —RM1b and —RM1d is independently —H or —RM1-meta;
• —RM1c is independently —H or —RM1-para;
• with the proviso that —RM1a, —RM1b, —RM1c, —RM1d, and —RM1e are not all —H;
• wherein each —RM1-ortho, each —RM1-meta, —RM1-para is independently —RM11, —RM11X, —OH, —ORM11, —ORM11X, —F, —Cl, —Br, —I, —NH2, —NHRM11, —NRM112, —RM11N, —C(═O)RM11, —C(═O)OH, —C(═O)ORM11, —OC(═O)RM11, —NHC(═O)RM11, —C(═O)NH2, —C(═O)NHRM11, —C(═O)NRM112, —C(═O)RM11N, —S(═O)2RM11, —S(═O)2NH2, —S(═O)2NHRM11, —S(═O)2NRM112, —S(═O)2RM11N, —CN, or —NO2;
• and wherein -M1 is attached to Ring A by a bond between a ring carbon atom of -M1 and a ring carbon atom of Ring A;
• or -M1 is an aromatic monocyclic heterocyclic ring having 5 or 6 ring atoms, and is optionally substituted with one or more substituents —RM1;
• wherein each —RM1 is independently —RM11, —RM11X, —OH, —ORM11, —ORM11X, —F, —Cl, —Br, —I, —NH2, —NHRM11, —NRM112, —RM11N, —C(═O)RM11, —C(═O)OH, —C(═O)ORM11, —OC(═O)RM11, —NHC(═O)RM11, —C(═O)NH2, —C(═O)NHRM11, —C(═O)NRM112, —C(═O)RM11N, —S(═O)2RM11, —S(═O)2NH2, —S(═O)2NHRM11, —S(═O)2NRM112, —S(═O)2RM11N, —CN, or —NO2;
• wherein:
• each —RM11 is independently saturated linear or branched C1-4alkyl;
• each —RM11X is independently saturated linear or branched C1-4haloalkyl;
• and
• each —RM11N is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or 1,1-dioxo-thiomorpholino, and is optionally substituted with one or more substituents selected from —RM11, —OH, and —ORM11;
• and wherein -M1 is attached to Ring A by a bond between a ring carbon atom of -M1 and a ring carbon atom of Ring A;
• or wherein -J is:
• wherein:
• each —RJ1 is independently —H or —RJJ;
• each —RJ2 is independently —H or —RJJ;
• —RJ3 is independently —RJJ, -LJJ-OH, -LJJ-NH2, -LJJ-NHRJJ, or -LJJ-NRJJ2;
• —RJ4 is independently —H, —RJJ, -LJJ-OH, -LJJ-NH2, -LJJ-NHRJJ, or -LJJ-NRJJ2;
• —RJ5 is independently —H, —RJJ, -LJJ-OH, -LJJ-NH2, -LJJ-NHRJJ, or -LJJ-NRJJ2;
• or —RJ4 and —RJ5 taken together form ═O;
• wherein:
• each —RJJ is independently saturated linear or branched C1-4alkyl;
• each -LJJ- is independently saturated linear or branched C1-4alkylene;
• Ring B is independently Ring 1 or Ring B2;
• Ring B1 is a non-aromatic monocyclic heterocyclic ring having 4 to 7 ring atoms;
• and is optionally substituted with one or more substituents —RB1;
• and/or is optionally be substituted with ═O;
• wherein each —RB1 is independently —RBB, —RBBX, —OH, —ORBB, —ORBBX, —F, —Cl, —Br, —I, —NH2, —NHRBB, —NRBB2, —RBBN, —C(═O)RBB, —C(═O)OH, —C(═O)ORBB, —OC(═O)RBB, —NHC(═O)RBB, —C(═O)NH2, —C(═O)NHRBB, —C(═O)NRBB2, —C(═O)RBBN, —S(═O)2RBB, —S(═O)2NH2, —S(═O)2NHRBB, —S(═O)2NRBB2, —S(═O)2RBBN, —CN, or —NO2;
• Ring B2 is an heteroaromatic monocyclic ring having 5 or 6 ring atoms, and is optionally substituted with one or more substituents —RB2,
• wherein each —RB2 is independently —RBB, —RBBX, —OH, —ORBB, —ORBBX, —F, —Cl, —Br, —I, —NH2, —NHRBB, —NRBB2, —RBBN, —C(═O)RBB, —C(═O)OH, —C(═O)ORBB, —OC(═O)RBB, —NHC(═O)RBB, —C(═O)NH2, —C(═O)NHRBB, —C(═O)NRBB2, —C(═O)RBBN, —S(═O)2RBB, —S(═O)2NH2, —S(═O)2NHRBB, —S(═O)2NRBB2, —S(═O)2RBBN, —CN, or —NO2;
• wherein:
• each —RBB is independently saturated linear or branched C1-4alkyl or saturated C3-6cycloalkyl;
• each —RBBX is independently saturated linear or branched C1-4haloalkyl;
• and
• each —RBBN is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or 1,1-dioxo-thiomorpholino, and is optionally substituted with one or more substituents selected from —RBB, —OH, and —ORBB;
• -M2 is independently:
• phenyl,
• and is optionally substituted with one or more substituents —RM2;
• or
• an aromatic monocyclic heterocyclic ring having 5 or 6 ring atoms,
• and is optionally substituted with one or more substituents —RM2;
• wherein each —RM2 is independently —RM22, —RM22X, —OH, —ORM22, —ORM22X, —F, —Cl, —Br, —I, —NH2, —NHRM22, —NRM222, —RM22N, —C(═O)RM22, —C(═O)OH, —C(═O)ORM22, —OC(═O)RM22, —NHC(═O)RM22, —C(═O)NH2, —C(═O)NHRM22, —C(═O)NRM222, —C(═O)RM22N, —S(═O)2RM22, —S(═O)2NH2, —S(═O)2NHRM22, —S(═O)2NRM222, —S(═O)2RM22N, —CN, or —NO2;
• and wherein:
• each —RM22 is independently saturated linear or branched C1-4alkyl;
• each —RM22X is independently saturated linear or branched C1-4haloalkyl;
• and
• each —RM22N is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or 1,1-dioxo-thiomorpholino, and is optionally substituted with one or more substituents selected from —RM22, —OH, and —ORM22;
• and wherein -Q- is independently:
• —CH2—CRQ1RQ2—;
• —O—CRQ1RQ2—;
• —S—CRQ1RQ2—;
• —CH2—CH2—CRQ1RQ2—;
• or
• —CRQ3═CRQ4—;
• wherein:
• each —RQ1 is independently —H or —RQQ;
• each —RQ2 is independently —H or —RQQ;
• —RQ3 is independently —H or —RQQ;
• —RQ4 is independently —H or —RQQ;
• wherein:
• each —RQQ is independently saturated linear or branched C1-4alkyl;
• and wherein:
• —R1 is independently —H or —R11;
• —R3 is independently —H or —R33;
• —R4 is independently —H or —R44;
• each R11 is independently —R, —RX, —OH, —OR, —ORX, —F, —Cl, —Br, —I, —NH2, —NHR, —NR2, —RN, —CN, or —NO2;
• each R33 is independently —R, —RX, —OH, —OR, —ORX, —F, —Cl, —Br, —I, —NH2, —NHR, —NR2, —RN, —CN, or —NO2;
• each R44 is independently —R, —RX, —OH, —OR, —ORX, —F, —Cl, —Br, —I, —NH2, —NHR, —NR2, —RN, —CN, or —NO2;
• wherein:
• each —R is independently saturated linear or branched C1-4alkyl;
• each —RX is independently saturated linear or branched C1-4haloalkyl;
• and
• each —RN is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or 1,1-dioxo-thiomorpholino, and is optionally substituted with one or more substituents selected from —R, —OH, and —OR;
• with the proviso that the compound is not a compound of one of the following formulae, or a pharmaceutically acceptable salt or solvate thereof:
• and with the proviso that the compound is not a compound of one of the following formulae, or a pharmaceutically acceptable salt or solvate thereof:
• and with the proviso that the compound is not a compound of one of the following formulae, or a pharmaceutically acceptable salt or solvate thereof:
• and with the proviso that the compound is not a compound of one of the following formulae, or a pharmaceutically acceptable salt or solvate thereof:
• and with the proviso that the compound is not a compound of one of the following formulae, or a pharmaceutically acceptable salt or solvate thereof: