IP Library › Patent Application 14000184

Patent Application

App. No. 14/000,184

COMPOUNDS AND METHODS OF TREATING HYPERTENSION

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Patent No.: US None
App. No.: 14/000,184

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Abstract

Hydrogenated pyrido[4,3-b]indoles, pyrido[3,4-b]indoles and azepino[4,5-b]indoles are described. The compounds may bind to and are adrenergic receptor α 2B antagonists. The compounds may also bind to and antagonize adrenergic receptor α 2B . 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. The compounds may also be used to treat diseases or conditions that are, or are expected to be, responsive to a decrease in blood pressure. Use of the compounds to treat cardiovascular and renal disorders is particularly described.

Claims (629)

1 : A method of lowering blood pressure in an individual in need thereof comprising administering to the individual an effective amount of a compound of the formulae (A1), (A2), (A3), (A4), (B1), (B2), (B3), (B4), (C1), (C2), (C3), (C4), (D1), (D2), (D3), or (D4); or a salt, solvate or N-oxide thereof:

wherein

wherein for formula (A1) or (A2):

R 1 is H, hydroxyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C 1 -C 8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R 1 and R 2a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 3a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 4a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety;

each R 2a and R 2b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R 2a and R 2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R 2a and R 1 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 2a and R 3a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 2a and R 4a are taken together to form a methylene (—CH 2 —) moiety or an ethylene (—CH 2 CH 2 —) moiety;

each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R 3a and R 3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R 3a and R 1 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 3a and R 2a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 3a and R 4a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety;

each R 4a and R 4b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R 4a and R 4b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R 4a and R 1 are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 4a and R 2a are taken together to form a methylene (—CH 2 —) moiety or an ethylene (—CH 2 CH 2 —) moiety, or R 4a and R 3a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety;

R 5 is H or unsubstituted C 1 -C 8 alkyl;

each X 1 , X 2 and X 3 is independently N, CH or CR 6 ;

each m, n, o and p is independently 0 or 1;

each R 6 is independently hydroxyl, nitro, cyano, halo, C 1 -C 8 perhaloalkyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 1 -C 8 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 R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 8g and R 8h , where present, 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 C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 2 -C 8 alkenyl, C 1 -C 8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety,

or is taken together with a vicinal R 8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety,

or is taken together with a vicinal R 8(a-h) to form a bond provided when an R 8(a-h) is taken together with a vicinal R 8(a-h) to form a bond, the geminal R 8(a-h) is other than hydroxyl and thiol and thiol; and

Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR 9 ═CR 10a R 10b , wherein R 9 is H or a substituted or unsubstituted C 1 -C 8 alkyl and R 10a and R 10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety;

wherein for formula (A3) or (A4):

each R 2a , R 2b R 3a , R 3b , R 4a , R 4b , R 10a and R 10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C 1 -C 8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, 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 R 2 , R 3 , R 4 or R 10 to form a carbonyl moiety or a cycloalkyl moiety;

R 5 is H or unsubstituted C 1 -C 8 alkyl;

each m, n, o and p is independently 0 or 1;

each X 1 , X 2 and X 3 is independently N, CH or CR 6 ;

each R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 8g and R 8h 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 C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 2 -C 8 alkenyl, C 1 -C 8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety,

wherein for formula (B1) or (B2):

each R 2a and R 2b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R 2a and R 2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R 2a and R 1 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 2a and R 3a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 2a and R 4a are taken together to form a methylene (—CH 2 —) moiety or an ethylene (—CH 2 CH 2 —) moiety;

each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R 3a and R 3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R 3a and R 1 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 3a and R 2a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 3a and R 4a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety;

each m, n, or o is independently 0 or 1;

each R 5a and R 5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R 5a and R 5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or

when m, n and o are each 0, then R 5a and R 7a are taken together to form a bond, or

when m is 1, and n and o are each 0, then R 5a and R 7c are taken together to form a bond, or

when m and n are each 1, and o is 0, then R 5a and R 7e are taken together to form a bond, or

when m, n and o are each 1, then R 5a and R 7g are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X 1 , X 2 and X 3 is independently N, CH or CR 6 ;

Y 1 is CR 7a R 7b , NR 8 , O, S, S(O) or SO 2 , provided that when Y 1 is NR 8 , O, S, S(O) or SO 2 , then Y 2 , where present, is CR 7c R 7d ;

Y 2 , where present, is CR 7c R 7d , NR 8 , O, S, S(O) or SO 2 , provided that when Y 2 is NR 8 , O, S, S(O) or SO 2 , then Y 1 is CR 7a R 7b and Y 3 , where present, is CR 7e R 7f ;

Y 3 , where present, is CR 7e R 7f , NR 8 , O, S, S(O) or SO 2 , provided that when Y 3 is NR 8 , O, S, S(O) or SO 2 , then Y 2 is CR 7c R 7d and Y 4 , where present, is CR 7g R 7h ;

Y 4 , where present, is CR 7g R 7h , NR 8 , O, S, S(O) or SO 2 , provided that when Y 4 is NR 8 , O, S, S(O) or SO 2 , then Y 3 is CR 7e R 7f ;

each R 7a and R 7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R 7a and R 7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R 7a and R 7c , where present, are taken together to form a bond;

each R 7c and R 7d , where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R 7c and R 7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R 7c and R 7a , where present, are taken together to form a bond, or R 7c and R 7e are taken together to form a bond;

each R 7e and R 7f , where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R 7e and R 7f are taken together with the carbon to which they are attached to form a carbonyl moiety, or R 7e and R 7c are taken together to form a bond, or R 7e and R 7g , where present, are taken together to form a bond;

each R 7g and R 7h , where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R 7g and R 7h are taken together with the carbon to which they are attached to form a carbonyl moiety, or R 7g and R 7e are taken together to form a bond, or R 7g and R 5a are taken together to form a bond; and

R 8 is H, hydroxyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C 1 -C 8 perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

wherein for formula (B3) or (B4):

each m, n and o is independently 0 or 1;

when m, n and o are each 0, then R 5a and R 7a are taken together to form a bond, or

when m is 1, and n and o are each 0, then R 5a and R 7c are taken together to form a bond, or

when m and n are each 1, and o is 0, then R 5a and R 7e are taken together to form a bond, or

when m, n and o are each 1, then R 5a and R 7g are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X 1 , X 2 and X 3 is independently N, CH or CR 6 ;

Y 1 is CR 7a R 7b , NR 8 , O, S, S(O) or SO 2 , provided that when Y 1 is NR 8 , O, S, S(O) or SO 2 , then Y 2 , where present, is CR 7c R 7d ;

Y 2 , where present, is CR 7c R 7d , NR 8 , O, S, S(O) or SO 2 , provided that when Y 2 is NR 8 , O, S, S(O) or SO 2 , then Y 1 is CR 7a R 7b and Y 3 , where present, is CR 7e R 7f ;

Y 3 , where present, is CR 7e R 7f , NR 8 , O, S, S(O) or SO 2 , provided that when Y 3 is NR 8 , O, S, S(O) or SO 2 , then Y 2 is CR 7c R 7d and Y 4 , where present, is CR 7g R 7h :

Y 4 , where present, is CR 7g R 7h , NR 8 , O, S, S(O) or SO 2 , provided that when Y 4 is NR 8 , O, S, S(O) or SO 2 , then Y 3 is CR 7e R 7f ;

each R 7c and R 7d , where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R 7c and R 7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R 7c and R 7a are taken together to form a bond, or R 7c and R 7e , where present, are taken together to form a bond;

each R 7e and R 7f , where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R 7e and R 7f , where present, are taken together with the carbon to which they are attached to form a carbonyl moiety, or R 7e and R 7c are taken together to form a bond, or R 7e and R 7g , where present, are taken together to form a bond;

wherein for formula (C1) or (C2):

R 1 is H, hydroxyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C 1 -C 8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R 1 and R 2 , where present, are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 2a , where present, are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 3a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 4 , where present, are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety or R 1 and R 4a , where present, are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety;

each R 2 , R 2a and R 2b , where present, is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R 2a and R 2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R 2 and R 1 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 2a and R 1 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 2 and R 3a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 2a and R 3a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 2 and R 4 are taken together to form a methylene (—CH 2 —) moiety or an ethylene (—CH 2 CH 2 —) moiety or R 2a and R 4 are taken together to form a methylene (—CH 2 —) moiety or an ethylene (—CH 2 CH 2 —) moiety, or R 2 and a vicinal R 8(a-h) are taken together to form a bond;

each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R 3a and R 3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R 3a and R 1 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 3a and R 2 are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 3a and R 2a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 3a and R 4 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety or R 3a and R 4a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety;

each R 4 or R 4a , where present, is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R 4 and R 1 are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 4a and R 1 are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 4 and R 2a are taken together to form a methylene (—CH 2 —) moiety or an ethylene (—CH 2 CH 2 —) moiety, or R 4a and R 2a are taken together to form a methylene (—CH 2 —) moiety or an ethylene (—CH 2 CH 2 —) moiety, or R 4 and R 3a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 4a and R 3a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 4 and a vicinal R 8(a-h) are taken together to form a bond;

R 5 is H or unsubstituted C 1 -C 8 alkyl;

each X 1 , X 2 , X 3 and X 4 is independently N, CH or CR 6 ;

each m, n, o and p is independently 0 or 1;

or is taken together with vicinal R 2 , where present, to form a bond,

or is taken together with vicinal R 4 , where present, to form a bond; and

wherein for formula (C3) or (C4):

each R 2a , R 2b , R 3a , R 3b , R 10a and R 10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C 1 -C 8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, 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 R 2 , R 3 or R 10 to form a carbonyl moiety or a cycloalkyl moiety;

R 4 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C 1 -C 8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or R 4 and a vicinal R 8a , where present, are taken together to form a bond;

R 5 is H or unsubstituted C 1 -C 8 alkyl;

each X 1 , X 2 , X 3 and X 4 is independently N, CH or CR 6 ;

each m, n, o and p is independently 0 or 1;

or is taken together with a geminal R 8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH 2 CH 2 O—, or is taken together with a geminal R 8(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 R 8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety,

or is taken together with vicinal R 4 to form a bond; and

wherein for formula (D1) or (D2):

R 1 is H, hydroxyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C 1 -C 8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R 1 and R 2 , where present, are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 2a , where present, are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 3a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 4 , where present, are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety or R 1 and R 4a , where present, are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety;

each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R 3a and R 3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R 3a and R 1 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 3a and R 2 are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 3a and R 2a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 3a and R 4 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety or R 3a and R 4a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety;

each m, n and o is independently 0 or 1; each R 5a and R 5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R 5a and R 5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or

when m-o are each 0, then R 5a and R 7a are taken together to form a bond, or

when m is 1, and n-o are each 0, then R 5a and R 7c are taken together to form a bond, or

when m-n are each 1, and o is 0, then R 5a and R 7e are taken together to form a bond, or

when m-o are each 1, then R 5a and R 7g are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X 1 , X 2 , X 3 and X 4 is independently N, CH or CR 6 ;

Y 1 is CR 7a R 7b , NR 8 , O, S, S(O) or SO 2 , provided that when Y 1 is NR 8 , O, S, S(O) or SO 2 , then Y 2 , where present, is CR 7c R 7d ;

Y 2 , where present, is CR 7c R 7d , NR 8 , O, S, S(O) or SO 2 , provided that when Y 2 is NR 8 , O, S, S(O) or SO 2 , then Y 1 is CR 7a R 7b and Y 3 , where present, is CR 7e R 7f ;

Y 3 , where present, is CR 7e R 7f , NR 8 , O, S, S(O) or SO 2 , provided that when Y 3 is NR 8 , O, S, S(O) or SO 2 , then Y 2 is CR 7c R 7d and Y 4 , where present, is CR 7g R 7h ;

Y 4 , where present, is CR 7g R 7h , NR 8 , O, S, S(O) or SO 2 , provided that when Y 4 is NR 8 , O, S, S(O) or SO 2 , then Y 3 is CR 7e R 7f ;

wherein for formula (D3) or (D4):

each m, n and o is independently 0 or 1;

when m-o are each 0, then R 5a and R 7a are taken together to form a bond, or

when m is 1, and n-o are each 0, then R 5a and R 7c are taken together to form a bond, or

when m-n are each 1, and o is 0, then R 5a and R 7e are taken together to form a bond, or

when m-o are each 1, then R 5a and R 7g are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X 1 , X 2 , X 3 and X 4 is independently N, CH or CR 6 ;

Y 1 is CR 7a R 7b , NR 8 , O, S, S(O) or SO 2 , provided that when Y 1 is NR 8 , O, S, S(O) or SO 2 , then Y 2 , where present, is CR 7c R 7d ;

Y 2 , where present, is CR 7c R 7d , NR 8 , O, S, S(O) or SO 2 , provided that when Y 2 is NR 8 , O, S, S(O) or SO 2 , then Y 1 is CR 7a R 7b and Y 3 , where present, is CR 7e R 7f ;

Y 3 , where present, is CR 7e R 7f , NR 8 , O, S, S(O) or SO 2 , provided that when Y 3 is NR 8 , O, S, S(O) or SO 2 , then Y 2 is CR 7c R 7d and Y 4 , where present, is CR 7g R 7h ;

Y 4 , where present, is CR 7g R 7h , NR 8 , O, S, S(O) or SO 2 , provided that when Y 4 is NR 8 , O, S, S(O) or SO 2 , then Y 3 is CR 7e R 7f ;

each R 7c and R 7d , where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R 7c and R 7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R 7c and R 7a where present, are taken together to form a bond, or R 7c and R 7e are taken together to form a bond;

2 : The method of claim 1 , wherein the individual has high blood pressure.

3 : The method of claim 2 , wherein the method reduces systolic blood pressure of the individual.

4 : The method of claim 2 , wherein the method reduces diastolic blood pressure of the individual.

5 : The method of claim 2 , wherein the method reduces (i) mean arterial blood pressure, or (ii) pulse pressure, of the individual.

6 : The method of claim 3 , wherein the method does not substantially increase heart rate of the individual.

7 : The method of claim 1 , wherein the individual has one or more risk factors for developing high blood pressure.

8 : A method of (i) increasing renal blood flow, and/or (ii) decreasing sodium reabsorption, in an individual in need thereof comprising administering to the individual an effective amount of a compound of the formulae (A1), (A2), (A3), (A4), (B1), (B2), (B3), (B4), (C1), (C2), (C3), (C4), (D1), (D2), (D3), or (D4); or a salt, solvate or N-oxide thereof:

wherein

wherein for formula (A1) or (A2):

R 5 is H or unsubstituted C 1 -C 8 alkyl;

each X 1 , X 2 and X 3 is independently N, CH or CR 6 ;

each m, n, o and p is independently 0 or 1;

wherein for formula (A3) or (A4):

R 5 is H or unsubstituted C 1 -C 8 alkyl;

each m, n, o and p is independently 0 or 1;

each X 1 , X 2 and X 3 is independently N, CH or CR 6 ;

wherein for formula (B1) or (B2):

each m, n, or o is independently 0 or 1;

when m, n and o are each 0, then R 5a and R 7a are taken together to form a bond, or

when m is 1, and n and o are each 0, then R 5a and R 7c are taken together to form a bond, or

when m and n are each 1, and o is 0, then R 5a and R 7e are taken together to form a bond, or

when m, n and o are each 1, then R 5a and R 79 are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X 1 , X 2 and X 3 is independently N, CH or CR 6 ;

Y 1 is CR 7a R 7b , NR 8 , O, S, S(O) or SO 2 , provided that when Y 1 is NR 8 , O, S, S(O) or SO 2 , then Y 2 , where present, is CR 7c R 7d ;

Y 2 , where present, is CR 7c R 7d , NR 8 , O, S, S(O) or SO 2 , provided that when Y 2 is NR 8 , O, S, S(O) or SO 2 , then Y 1 is CR 7a R 7b and Y 3 , where present, is CR 7e R 7f ;

Y 3 , where present, is CR 7e R 7f , NR 8 , O, S, S(O) or SO 2 , provided that when Y 3 is NR 8 , O, S, S(O) or SO 2 , then Y 2 is CR 7c R 7d and Y 4 , where present, is CR 7g R 7h ;

Y 4 , where present, is CR 7g R 7h , NR 8 , O, S, S(O) or SO 2 , provided that when Y 4 is NR 8 , O, S, S(O) or SO 2 , then Y 3 is CR 7e R 7f ;

wherein for formula (B3) or (B4):

each m, n and o is independently 0 or 1;

when m, n and o are each 0, then R 5a and R 7a are taken together to form a bond, or

when m is 1, and n and o are each 0, then R 5a and R 7c are taken together to form a bond, or

when m and n are each 1, and o is 0, then R 5a and R 7e are taken together to form a bond, or

when m, n and o are each 1, then R 5a and R 7g are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X 1 , X 2 and X 3 is independently N, CH or CR 6 ;

Y 1 is CR 7a R 7b , NR 8 , O, S, S(O) or SO 2 , provided that when Y 1 is NR 8 , O, S, S(O) or SO 2 , then Y 2 , where present, is CR 7c R 7d ;

Y 2 , where present, is CR 7c R 7d , NR 8 , O, S, S(O) or SO 2 , provided that when Y 2 is NR 8 , O, S, S(O) or SO 2 , then Y 1 is CR 7a R 7b and Y 3 , where present, is CR 7e R 7f ;

Y 3 , where present, is CR 7e R 7f , NR 8 , O, S, S(O) or SO 2 , provided that when Y 3 is NR 8 , O, S, S(O) or SO 2 , then Y 2 is CR 7c R 7d and Y 4 , where present, is CR 7g R 7h ;

Y 4 , where present, is CR 7g R 7h , NR 8 , O, S, S(O) or SO 2 , provided that when Y 4 is NR 8 , O, S, S(O) or SO 2 , then Y 3 is CR 7e R 7f ;

each R 7c and R 7d , where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R 7c and R 7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R 7c and R 7a are taken together to form a bond, or R 7c and R 7e , where present, are taken together to form a bond;

each R 7e and R 7f , where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R 7e and R 7f , where present, are taken together with the carbon to which they are attached to form a carbonyl moiety, or R 7e and R 7c are taken together to form a bond, or R 7e and R 7g , where present, are taken together to form a bond;

wherein for formula (C1) or (C2):

R 1 is H, hydroxyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C 1 -C 8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R 1 and R 2 , where present, are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 2a , where present, are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 3a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 4 , where present, are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety or R 1 and R 4a , where present, are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety;

each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R 3a and R 3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R 3a and R 1 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 3a and R 2 are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 3a and R 2a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 3a and R 4 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety or R 3a and R 4a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety;

R 5 is H or unsubstituted C 1 -C 8 alkyl;

each X 1 , X 2 , X 3 and X 4 is independently N, CH or CR 6 ;

each m, n, o and p is independently 0 or 1;

or is taken together with vicinal R 2 , where present, to form a bond,

or is taken together with vicinal R 4 , where present, to form a bond; and

wherein for formula (C3) or (C4):

R 5 is H or unsubstituted C 1 -C 8 alkyl;

each X 1 , X 2 , X 3 and X 4 is independently N, CH or CR 6 ;

each m, n, o and p is independently 0 or 1;

or is taken together with vicinal R 4 to form a bond; and

wherein for formula (D1) or (D2):

R 1 is H, hydroxyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C 1 -C 8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R 1 and R 2 , where present, are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 2a , where present, are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 3a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 4 , where present, are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety or R 1 and R 4a , where present, are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety;

each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R 3a and R 3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R 3a and R 1 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 3a and R 2 are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 3a and R 2a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 3a and R 4 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety or R 3a and R 4a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety;

when m-o are each 0, then R 5a and R 7a are taken together to form a bond, or

when m is 1, and n-o are each 0, then R 5a and R 7c are taken together to form a bond, or

when m-n are each 1, and o is 0, then R 5a and R 7e are taken together to form a bond, or

when m-o are each 1, then R 5a and R 7g are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X 1 , X 2 , X 3 and X 4 is independently N, CH or CR 6 ;

Y 1 is CR 7a R 7b , NR 8 , O, S, S(O) or SO 2 , provided that when Y 1 is NR 8 , O, S, S(O) or SO 2 , then Y 2 , where present, is CR 7c R 7d ;

Y 2 , where present, is CR 7c R 7d , NR 8 , O, S, S(O) or SO 2 , provided that when Y 2 is NR 8 , O, S, S(O) or SO 2 , then Y 1 is CR 7a R 7b and Y 3 , where present, is CR 7e R 7f ;

Y 3 , where present, is CR 7e R 7f , NR 8 , O, S, S(O) or SO 2 , provided that when Y 3 is NR 8 , O, S, S(O) or SO 2 , then Y 2 is CR 7c R 7d and Y 4 , where present, is CR 7g R 7h ;

Y 4 , where present, is CR 7g R 7h , NR 8 , O, S, S(O) or SO 2 , provided that when Y 4 is NR 8 , O, S, S(O) or SO 2 , then Y 3 is CR 7e R 7f ;

each R 7c and R 7d , where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R 7c and R 7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R 7c and R 7a where present, are taken together to form a bond, or R 7c and R 7e are taken together to form a bond;

wherein for formula (D3) or (D4):

each m, n and o is independently 0 or 1;

when m-o are each 0, then R 5a and R 7a are taken together to form a bond, or

when m is 1, and n-o are each 0, then R 5a and R 7c are taken together to form a bond, or

when m-n are each 1, and o is 0, then R 5a and R 7e are taken together to form a bond, or

when m-o are each 1, then R 5a and R 7g are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X 1 , X 2 , X 3 and X 4 is independently N, CH or CR 6 ;

Y 1 is CR 7a R 7b , NR 8 , O, S, S(O) or SO 2 , provided that when Y 1 is NR 8 , O, S, S(O) or SO 2 , then Y 2 , where present, is CR 7c R 7d ;

Y 2 , where present, is CR 7c R 7d , NR 8 , O, S, S(O) or SO 2 , provided that when Y 2 is NR 8 , O, S, S(O) or SO 2 , then Y 1 is CR 7a R 7b and Y 3 , where present, is CR 7e R 7f ;

Y 3 , where present, is CR 7e R 7f , NR 8 , O, S, S(O) or SO 2 , provided that when Y 3 is NR 8 , O, S, S(O) or SO 2 , then Y 2 is CR 7c R 7d and Y 4 , where present, is CR 7g R 7h ;

Y 4 , where present, is CR 7g R 7h , NR 8 , O, S, S(O) or SO 2 , provided that when Y 4 is NR 8 , O, S, S(O) or SO 2 , then Y 3 is CR 7e R 7f ;

9 : The method of claim 8 , wherein the method results in increase in renal blood flow.

10 : The method of claim 8 , wherein the method results in decrease in sodium reabsorption.

11 : The method of claim 9 , wherein the method results in increase in urine sodium content and/or increase in urine volume.

12 : The method of claim 9 , wherein the method results in any one or more of: (i) reducing edema, (ii) reducing elevated blood urea nitrogen to creatinine (BUN/Cr) ratio, and (iii) decreasing creatinine levels.

13 : The method of claim 1 , wherein the individual has or is at risk of developing acute or chronic congestive heart failure, acute decompensated congestive heart failure, acute or chronic renal failure, or acute or chronic renal failure due to renal insufficiency.

14 : A method of treating a disease or condition that is responsive to any one or more of: (i) a decrease in blood pressure; (ii) an increase in renal blood flow; and (iii) a decrease of sodium reabsorption, comprising administering to an individual in need thereof an effective amount of a compound of the formulae (A1), (A2), (A3), (A4), (B1), (B2), (B3), (B4), (C1), (C2), (C3), (C4), (D1), (D2), (D3), or (D4); or a salt, solvate or N-oxide thereof:

wherein

wherein for formula (A1) or (A2):

R 5 is H or unsubstituted C 1 -C 8 alkyl;

each X 1 , X 2 and X 3 is independently N, CH or CR 6 ;

each m, n, o and p is independently 0 or 1;

wherein for formula (A3) or (A4):

R 5 is H or unsubstituted C 1 -C 8 alkyl;

each m, n, o and p is independently 0 or 1;

each X 1 , X 2 and X 3 is independently N, CH or CR 6 ;

wherein for formula (B1) or (B2):

each m, n, or o is independently 0 or 1;

when m, n and o are each 0, then R 5a and R 7a are taken together to form a bond, or

when m is 1, and n and o are each 0, then R 5a and R 7c are taken together to form a bond, or

when m and n are each 1, and o is 0, then R 5a and R 7e are taken together to form a bond, or

when m, n and o are each 1, then R 5a and R 7g are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X 1 , X 2 and X 3 is independently N, CH or CR 6 ;

Y 1 is CR 7a R 7b , NR 8 , O, S, S(O) or SO 2 , provided that when Y 1 is NR 8 , O, S, S(O) or SO 2 , then Y 2 , where present, is CR 7c R 7d ;

Y 2 , where present, is CR 7c R 7d , NR 8 , O, S, S(O) or SO 2 , provided that when Y 2 is NR 8 , O, S, S(O) or SO 2 , then Y 1 is CR 7a R 7b and Y 3 , where present, is CR 7e R 7f ;

Y 3 , where present, is CR 7e R 7f , NR 8 , O, S, S(O) or SO 2 , provided that when Y 3 is NR 8 , O, S, S(O) or SO 2 , then Y 2 is CR 7c R 7d and Y 4 , where present, is CR 7g R 7h ;

Y 4 , where present, is CR 7g R 7h , NR 8 , O, S, S(O) or SO 2 , provided that when Y 4 is NR 8 , O, S, S(O) or SO 2 , then Y 3 is CR 7e R 7f ;

wherein for formula (B3) or (B4):

each m, n and o is independently 0 or 1;

when m, n and o are each 0, then R 5a and R 7a are taken together to form a bond, or

when m is 1, and n and o are each 0, then R 5a and R 7c are taken together to form a bond, or

when m and n are each 1, and o is 0, then R 5a and R 7e are taken together to form a bond, or

when m, n and o are each 1, then R 5a and R 7g are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X 1 , X 2 and X 3 is independently N, CH or CR 6 ;

Y 1 is CR 7a R 7b , NR 8 , O, S, S(O) or SO 2 , provided that when Y 1 is NR 8 , O, S, S(O) or SO 2 , then Y 2 , where present, is CR 7c R 7d ;

Y 2 , where present, is CR 7c R 7d , NR 8 , O, S, S(O) or SO 2 , provided that when Y 2 is NR 8 , O, S, S(O) or SO 2 , then Y 1 is CR 7a R 7b and Y 3 , where present, is CR 7e R 7f ;

Y 3 , where present, is CR 7e R 7f , NR 8 , O, S, S(O) or SO 2 , provided that when Y 3 is NR 8 , O, S, S(O) or SO 2 , then Y 2 is CR 7c R 7d and Y 4 , where present, is CR 7g R 7h ;

Y 4 , where present, is CR 7g R 7h , NR 8 , O, S, S(O) or SO 2 , provided that when Y 4 is NR 8 , O, S, S(O) or SO 2 , then Y 3 is CR 7e R 7f ;

each R 7c and R 7d , where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R 7c and R 7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R 7c and R 7a are taken together to form a bond, or R 7c and R 7e , where present, are taken together to form a bond;

each R 7e and R 7f , where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R 7e and R 7f , where present, are taken together with the carbon to which they are attached to form a carbonyl moiety, or R 7e and R 7c are taken together to form a bond, or R 7e and R 7g , where present, are taken together to form a bond;

wherein for formula (C1) or (C2):

R 1 is H, hydroxyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C 1 -C 8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R 1 and R 2 , where present, are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 2a , where present, are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 3a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 4 , where present, are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety or R 1 and R 4a , where present, are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety;

each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R 3a and R 3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R 3a and R 1 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 3a and R 2 are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 3a and R 2a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 3a and R 4 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety or R 3a and R 4a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety;

R 5 is H or unsubstituted C 1 -C 8 alkyl;

each X 1 , X 2 , X 3 and X 4 is independently N, CH or CR 6 ;

each m, n, o and p is independently 0 or 1;

or is taken together with vicinal R 2 , where present, to form a bond,

or is taken together with vicinal R 4 , where present, to form a bond; and

wherein for formula (C3) or (C4):

R 5 is H or unsubstituted C 1 -C 8 alkyl;

each X 1 , X 2 , X 3 and X 4 is independently N, CH or CR 6 ;

each m, n, o and p is independently 0 or 1;

or is taken together with vicinal R 4 to form a bond; and

wherein for formula (D1) or (D2):

R 1 is H, hydroxyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C 1 -C 8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R 1 and R 2 , where present, are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 2a , where present, are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 3a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 4 , where present, are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety or R 1 and R 4a , where present, are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety;

each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R 3a and R 3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R 3a and R 1 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 3a and R 2 are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 3a and R 2a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 3a and R 4 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety or R 3a and R 4a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety;

when m-o are each 0, then R 5a and R 7a are taken together to form a bond, or

when m is 1, and n-o are each 0, then R 5a and R 7c are taken together to form a bond, or

when m-n are each 1, and o is 0, then R 5a and R 7e are taken together to form a bond, or

when m-o are each 1, then R 5a and R 7g are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X 1 , X 2 , X 3 and X 4 is independently N, CH or CR 6 ;

Y 1 is CR 7a R 7b , NR 8 , O, S, S(O) or SO 2 , provided that when Y 1 is NR 8 , O, S, S(O) or SO 2 , then Y 2 , where present, is CR 7c R 7d ;

Y 2 , where present, is CR 7c R 7d , NR 8 , O, S, S(O) or SO 2 , provided that when Y 2 is NR 8 , O, S, S(O) or SO 2 , then Y 1 is CR 7a R 7b and Y 3 , where present, is CR 7e R 7f ;

Y 3 , where present, is CR 7e R 7f , NR 8 , O, S, S(O) or SO 2 , provided that when Y 3 is NR 8 , O, S, S(O) or SO 2 , then Y 2 is CR 7c R 7d and Y 4 , where present, is CR 7g R 7h ;

Y 4 , where present, is CR 7g R 7h , NR 8 , O, S, S(O) or SO 2 , provided that when Y 4 is NR 8 , O, S, S(O) or SO 2 , then Y 3 is CR 7e R 7f ;

each R 7c and R 7d , where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R 7c and R 7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R 7c and R 7a where present, are taken together to form a bond, or R 7c and R 7e are taken together to form a bond;

wherein for formula (D3) or (D4):

each m, n and o is independently 0 or 1;

when m-o are each 0, then R 5a and R 7a are taken together to form a bond, or

when m is 1, and n-o are each 0, then R 5a and R 7c are taken together to form a bond, or

when m-n are each 1, and o is 0, then R 5a and R 7e are taken together to form a bond, or

when m-o are each 1, then R 5a and R 7g are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X 1 , X 2 , X 3 and X 4 is independently N, CH or CR 6 ;

Y 1 is CR 7a R 7b , NR 8 , O, S, S(O) or SO 2 , provided that when Y 1 is NR 8 , O, S, S(O) or SO 2 , then Y 2 , where present, is CR 7c R 7d ;

Y 2 , where present, is CR 7c R 7d , NR 8 , O, S, S(O) or SO 2 , provided that when Y 2 is NR 8 , O, S, S(O) or SO 2 , then Y 1 is CR 7a R 7b and Y 3 , where present, is CR 7e R 7f ;

Y 3 , where present, is CR 7e R 7f , NR 8 , O, S, S(O) or SO 2 , provided that when Y 3 is NR 8 , O, S, S(O) or SO 2 , then Y 2 is CR 7c R 7d and Y 4 , where present, is CR 7g R 7h ;

Y 4 , where present, is CR 7g R 7h , NR 8 , O, S, S(O) or SO 2 , provided that when Y 4 is NR 8 , O, S, S(O) or SO 2 , then Y 3 is CR 7e R 7f ;

15 : The method of claim 14 , wherein the disease or condition is hypertension.

16 : The method of claim 15 , wherein the disease or condition is treatment-resistant hypertension.

17 : The method of claim 14 , wherein the disease or condition is hypertensive emergency.

18 : The method of claim 14 , wherein the disease or condition is a cardiac or renal disease or condition.

19 : The method of claim 1 , wherein the compound is an adrenergic receptor α 2B antagonist.

20 : The method of claim 19 , wherein the compound is also an adrenergic receptor α 1B antagonist.

21 : The method of claim 19 , wherein the compound is also an adrenergic receptor α 1D antagonist.

22 : A kit comprising (i) a compound of formulae (A1), (A2), (A3), (A4), (B1), (B2), (B3), (B4), (C1), (C2), (C3), (C4), (D1), (D2), (D3), or (D4); or a salt, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof, and (ii) instructions for use according to the method of claim 1 ; and wherein

wherein

wherein for formula (A1) or (A2):

R 5 is H or unsubstituted C 1 -C 8 alkyl;

each X 1 , X 2 and X 3 is independently N, CH or CR 6 ;

each m, n, o and p is independently 0 or 1;

wherein for formula (A3) or (A4):

R 5 is H or unsubstituted C 1 -C 8 alkyl;

each m, n, o and p is independently 0 or 1;

each X 1 , X 2 and X 3 is independently N, CH or CR 6 ;

wherein for formula (B1) or (B2):

each m, n, or o is independently 0 or 1;

when m, n and o are each 0, then R 5a and R 7a are taken together to form a bond, or

when m is 1, and n and o are each 0, then R 5a and R 7c are taken together to form a bond, or

when m and n are each 1, and o is 0, then R 5a and R 7e are taken together to form a bond, or

when m, n and o are each 1, then R 5a and R 7g are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X 1 , X 2 and X 3 is independently N, CH or CR 6 ;

Y 1 is CR 7a R 7b , NR 8 , O, S, S(O) or SO 2 , provided that when Y 1 is NR 8 , O, S, S(O) or SO 2 , then Y 2 , where present, is CR 7c R 7d ;

Y 2 , where present, is CR 7c R 7d , NR 8 , O, S, S(O) or SO 2 , provided that when Y 2 is NR 8 , O, S, S(O) or SO 2 , then Y 1 is CR 7a R 7b and Y 3 , where present, is CR 7e R 7f ;

Y 3 , where present, is CR 7e R 7f , NR 8 , O, S, S(O) or SO 2 , provided that when Y 3 is NR 8 , O, S, S(O) or SO 2 , then Y 2 is CR 7c R 7d and Y 4 , where present, is CR 7g R 7h ;

Y 4 , where present, is CR 7g R 7h , NR 8 , O, S, S(O) or SO 2 , provided that when Y 4 is NR 8 , O, S, S(O) or SO 2 , then Y 3 is CR 7e R 7f ;

wherein for formula (B3) or (B4):

each m, n and o is independently 0 or 1;

when m, n and o are each 0, then R 5a and R 7a are taken together to form a bond, or

when m is 1, and n and o are each 0, then R 5a and R 7c are taken together to form a bond, or

when m and n are each 1, and o is 0, then R 5a and R 7e are taken together to form a bond, or

when m, n and o are each 1, then R 5a and R 79 are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X 1 , X 2 and X 3 is independently N, CH or CR 6 ;

Y 1 is CR 7a R 7b , NR 8 , O, S, S(O) or SO 2 , provided that when Y 1 is NR 8 , O, S, S(O) or SO 2 , then Y 2 , where present, is CR 7c R 7d ;

Y 2 , where present, is CR 7c R 7d , NR 8 , O, S, S(O) or SO 2 , provided that when Y 2 is NR 8 , O, S, S(O) or SO 2 , then Y 1 is CR 7a R 7b and Y 3 , where present, is CR 7e R 7f ;

Y 3 , where present, is CR 7e R 7f , NR 8 , O, S, S(O) or SO 2 , provided that when Y 3 is NR 8 , O, S, S(O) or SO 2 , then Y 2 is CR 7c R 7d and Y 4 , where present, is CR 7g R 7h ;

Y 4 , where present, is CR 7g R 7h , NR 8 , O, S, S(O) or SO 2 , provided that when Y 4 is NR 8 , O, S, S(O) or SO 2 , then Y 3 is CR 7e R 7f ;

each R 7c and R 7d , where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R 7c and R 7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R 7c and R 7a are taken together to form a bond, or R 7c and R 7e , where present, are taken together to form a bond;

each R 7e and R 7f , where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R 7e and R 7f , where present, are taken together with the carbon to which they are attached to form a carbonyl moiety, or R 7e and R 7c are taken together to form a bond, or R 7e and R 7g , where present, are taken together to form a bond;

wherein for formula (C1) or (C2):

R 1 is H, hydroxyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C 1 -C 8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R 1 and R 2 , where present, are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 2a , where present, are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 3a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 4 , where present, are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety or R 1 and R 4a , where present, are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety;

each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R 3a and R 3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R 3a and R 1 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 3a and R 2 are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 3a and R 2a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 3a and R 4 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety or R 3a and R 4a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety;

R 5 is H or unsubstituted C 1 -C 8 alkyl;

each X 1 , X 2 , X 3 and X 4 is independently N, CH or CR 6 ;

each m, n, o and p is independently 0 or 1;

or is taken together with vicinal R 2 , where present, to form a bond,

or is taken together with vicinal R 4 , where present, to form a bond; and

wherein for formula (C3) or (C4):

R 5 is H or unsubstituted C 1 -C 8 alkyl;

each X 1 , X 2 , X 3 and X 4 is independently N, CH or CR 6 ;

each m, n, o and p is independently 0 or 1;

or is taken together with vicinal R 4 to form a bond; and

wherein for formula (D1) or (D2):

R 1 is H, hydroxyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C 1 -C 8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R 1 and R 2 , where present, are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 2a , where present, are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 3a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 4 , where present, are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety or R 1 and R 4a , where present, are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety;

each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R 3a and R 3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R 3a and R 1 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 3a and R 2 are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 3a and R 2a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 3a and R 4 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety or R 3a and R 4a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety;

when m-o are each 0, then R 5a and R 7a are taken together to form a bond, or

when m is 1, and n-o are each 0, then R 5a and R 7c are taken together to form a bond, or

when m-n are each 1, and o is 0, then R 5a and R 7e are taken together to form a bond, or

when m-o are each 1, then R 5a and R 7g are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X 1 , X 2 , X 3 and X 4 is independently N, CH or CR 6 ;

Y 1 is CR 7a R 7b , NR 8 , O, S, S(O) or SO 2 , provided that when Y 1 is NR 8 , O, S, S(O) or SO 2 , then Y 2 , where present, is CR 7c R 7d ;

Y 2 , where present, is CR 7c R 7d , NR 8 , O, S, S(O) or SO 2 , provided that when Y 2 is NR 8 , O, S, S(O) or SO 2 , then Y 1 is CR 7a R 7b and Y 3 , where present, is CR 7e R 7f ;

Y 3 , where present, is CR 7e R 7f , NR 8 , O, S, S(O) or SO 2 , provided that when Y 3 is NR 8 , O, S, S(O) or SO 2 , then Y 2 is CR 7c R 7d and Y 4 , where present, is CR 7g R 7h ;

Y 4 , where present, is CR 7g R 7h , NR 8 , O, S, S(O) or SO 2 , provided that when Y 4 is NR 8 , O, S, S(O) or SO 2 , then Y 3 is CR 7e R 7f ;

each R 7c and R 7d , where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R 7c and R 7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R 7c and R 7a where present, are taken together to form a bond, or R 7c and R 7e are taken together to form a bond;

wherein for formula (D3) or (D4):

each m, n and o is independently 0 or 1;

when m-o are each 0, then R 5a and R 7a are taken together to form a bond, or

when m is 1, and n-o are each 0, then R 5a and R 7c are taken together to form a bond, or

when m-n are each 1, and o is 0, then R 5a and R 7e are taken together to form a bond, or

when m-o are each 1, then R 5a and R 7g are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X 1 , X 2 , X 3 and X 4 is independently N, CH or CR 6 ;

Y 1 is CR 7a R 7b , NR 8 , O, S, S(O) or SO 2 , provided that when Y 1 is NR 8 , O, S, S(O) or SO 2 , then Y 2 , where present, is CR 7c R 7d ;

Y 2 , where present, is CR 7c R 7d , NR 8 , O, S, S(O) or SO 2 , provided that when Y 2 is NR 8 , O, S, S(O) or SO 2 , then Y 1 is CR 7a R 7b and Y 3 , where present, is CR 7e R 7f ;

Y 3 , where present, is CR 7e R 7f , NR 8 , O, S, S(O) or SO 2 , provided that when Y 3 is NR 8 , O, S, S(O) or SO 2 , then Y 2 is CR 7c R 7d and Y 4 , where present, is CR 7g R 7h ;

Y 4 , where present, is CR 7g R 7h , NR 8 , O, S, S(O) or SO 2 , provided that when Y 4 is NR 8 , O, S, S(O) or SO 2 , then Y 3 is CR 7e R 7f ;

Assignments (3)

RELEASE OF SECURITY INTEREST Recorded Sep 28, 2016

From: JPMORGAN CHASE BANK, N.A., AS ADMINISTRATIVE AGENT

To: MEDIVATION PROSTATE THERAPEUTICS, INC.; MEDIVATION TECHNOLOGIES, INC.

Reel/Frame 040181/0177 →

CONFIRMATORY GRANT OF SECURITY INTEREST IN UNITED STATES PATENTS Recorded Sep 4, 2015

From: MEDIVATION TECHNOLOGIES, INC.

To: JPMORGAN CHASE BANK, N.A., AS ADMINISTRATIVE AGENT

Reel/Frame 036553/0925 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 27, 2013

From: PROTTER, ANDREW ASHER; CHAKRAVARTY, SARVAJIT

To: MEDIVATION TECHNOLOGIES, INC.

Reel/Frame 031688/0864 →