Pyrido[4,3-b]indole and pyrido[3,4-b]indole derivatives and methods of use

摘要

This disclosure is directed to pyrido[4,3-b]indole and pyrido[3,4-b]indole derivatives. Pharmaceutical compositions comprising the compounds are also provided, as are methods of using the compounds in a variety of therapeutic applications, including the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder. The compounds may bind to and antagonize receptor α2B, α1B or α2A. The compounds may find use in therapy, e.g., to (i) reduce blood pressure and/or (ii) promote renal blood flow and/or (iii) decrease or inhibit sodium reabsorption, or to regulate blood glucose level, increase insulin secretion and treat diseases or conditions that are, or are expected to be, responsive to an increase in insulin production. The compounds may also be used to treat diseases or conditions that are expected to be responsive to a decrease in blood pressure. Use of the compounds to treat cardiovascular, renal disorders or type 2 diabetes is particularly described.

主权项

1. A compound of the formula (IA), (J-1), (J-2), (J-3), (J-4), (J-5), (K-1), (K-2), (K-3), (K-4) or (K-5):
wherein the formula (IA) is: or a salt or solvate thereof; wherein:
R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R1 and R2a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R4a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety;each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R4a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety;each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R4a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety;each R4a and R4b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R4a and R4b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R4a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4a and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety;each X1, X2, X3 and X4 is independently N, CH or CR6;each m, n, o and p is independently 0 or 1;each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;each R8a, R8b, R8c, R8d, R8e, R8f, R8g and R8h is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)aralkyl, —S(O)2-alkyl, —S(O)2-aryl, —S(O)2-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, or is taken together with a geminal R8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or is taken together with a vicinal R8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety, or is taken together with a vicinal R8(a-h) to form a bond provided when an R8(a-h) is taken together with a vicinal R8(a-h) to form a bond, the geminal R8(a-h) is other than hydroxyl and thiol; andQ is a group of the formula —CR9═CR10aR10b, wherein R9 is H or a substituted or unsubstituted C1-C8 alkyl and R10a and R10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety; the formula (J-1), (J-2), (J-3), (J-4) and (J-5) are: or a salt or solvate thereof, wherein:
R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;each R2a, R2b R3a, R3b, R4a, R4b, R10a and R10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2, R3, R4 or R10 to form a carbonyl moiety or a cycloalkyl moiety;each X1, X2, X3 and X4 is independently N, CH or CR6;each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;each R8a, R8b, R8c, R8d, R8e, R8f, R89g and R8h is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)2-alkyl, —S(O)2-aryl, —S(O)2-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, or is taken together with a geminal R8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or is taken together with a vicinal R8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety, or is taken together with a vicinal R8(a-h) to form a bond provided when an R8(a-h) is taken together with a vicinal R8(a-h) to form a bond, the geminal R8(a-h) is other than hydroxyl and thiol; andQ is a group of the formula —CR9═CR10aR10b or of the structure: wherein R9 is H or a substituted or unsubstituted C1-C8 alkyl and R10a and R10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety; the formula (K-1), (K-2), (K-3), (K-4) and (K-5) are: or a salt or solvate thereof, wherein:
R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;each R2a, R2b R3a, R3b, R4a, R4b, R10a and R10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2, R3, R4 or R10 to form a carbonyl moiety or a cycloalkyl moiety;each X1, X2, X3 and X4 is independently N, CH or CR6;each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;each R8a, R8b, R8c, R8d, R8e, R8f, R8g and R8h is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)2-alkyl, —S(O)2-aryl, —S(O)2-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, or is taken together with a geminal R8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or is taken together with a vicinal R8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety, or is taken together with a vicinal R8(a-h) to form a bond provided when an R8(a-h) is taken together with a vicinal R8(a-h) to form a bond, the geminal R8(a-h) is other than hydroxyl and thiol; andQ is a group of the formula —CR9═CR10aR10b or of the structure: wherein R9 is H or a substituted or unsubstituted C1-C8 alkyl and R10a and R10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety.