IP Library › Patent Application 14000176

Patent Application

App. No. 14/000,176

COMPOUNDS AND METHODS OF TREATING DIABETES

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App. No.: 14/000,176

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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 antagonists of the adrenergic receptor a 2A . The compounds may also bind to and are an antagonist of the adrenergic receptor α 2B ; or the compounds are not antagonists of the adrenergic receptor α2β and the compounds are administered in conjunction with a second agent that reduces, or is expected to reduce, blood pressure in an individual. The compounds may find use in therapy, e.g., 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. Use of the compounds to treat type 2 diabetes is particularly described.

Claims (197)

1 . A method of regulating blood glucose levels in an individual in need thereof comprising administering to the individual an effective amount of a compound of formulae (IA), (IB), (J-1) or (K-1), wherein formula (IA) is:

or a salt, solvate or N-oxide thereof, wherein:

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, 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 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 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;

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

Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted of unsubstituted aralkyl, wherein the aralkyl is a fused ring system where at least one cycloalkyl moiety is fused with at least one aryl moiety and wherein the aralkyl is attached to the parent structure via the cycloalkyl moiety or the aryl moiety; and

R 6 is 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, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl,

provided that:

(1) at least one of X 1 , X 2 , X 3 and X 4 is CH or CR 6 ;

(2) when each X 1 , X 2 , X 3 and X 4 is independently CH or CR 6 , none of R 1 , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b are taken together to form a ring and Q is an unsubstituted 6-membered aryl or an unsubstituted 6-membered heteroaryl, then Q is other than unsubstituted phenyl, unsubstituted pyridyl and unsubstituted pyrimidyl;

(3) when each X 1 , X 2 , X 3 and X 4 is independently CH or CR 6 , none of R 1 , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b are taken together to form a ring and Q is a substituted phenyl, then Q is a phenyl substituted with a substituent selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aralkyl; and

(4) when each X 1 , X 2 , X 3 and X 4 is independently CH or CR 6 , and R 2a and R 3a are taken together to form an ethylene (—CH 2 CH 2 —) moiety, then Q is a substituted aryl or substituted heteroaryl, where the substituted aryl or substituted heteroaryl is substituted with at least one substituent selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aralkyl;

formula (IB) is:

or a salt or solvate thereof, wherein:

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

Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aralkyl, wherein the aralkyl is a fused ring system where at least one cycloalkyl moiety is fused with at least one aryl moiety and wherein the aralkyl is attached to the parent structure via the cycloalkyl moiety or the aryl moiety; and

provided that:

(1) at least one of X 1 , X 2 , X 3 and X 4 is CR 6 ;

(2) when none of X 1 , X 2 and X 3 is N, and none of R 1 , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b are taken together to form a ring, then Q is other than an unsubstituted phenyl;

(3) when none of X 1 , X 2 , X 3 and X 4 is N, and R 2a and R 2b are taken together with the carbon to which they are attached to form a carbonyl moiety, then Q is other than a 4-substituted phenyl group; and

(4) when each X 1 , X 3 and X 4 is CH, X 2 is CR 6 where R 6 is fluoro, and each R 2a , R 2b , R 3a , R 3b , R 4a and R 4b is H, then Q is other than 4-fluorophenyl;

formula (J-1) is:

or a salt or solvate thereof, wherein:

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, 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(a/b) , R 3(a/b) , R 4(a/b) or R 10(a/b) to form a carbonyl moiety or a cycloalkyl moiety;

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

Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted aralkyl, wherein the aralkyl is a fused ring system where at least one cycloalkyl moiety is fused with at least one aryl moiety and wherein the aralkyl is attached to the parent structure via the cycloalkyl moiety or the aryl moiety; and

R 6 is 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;

provided that at least one of X 1 , X 2 , X 3 and X 4 is CH or CR 6 ;

and formula (K-1) is:

or a salt or solvate thereof, wherein:

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

R 6 is 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;

provided that at least one of X 1 , X 2 , X 3 and X 4 is CH or CR 6 .

2 . The method of claim 1 , wherein the method reduces blood glucose level in the individual.

3 . The method of claim 2 , wherein the method reduces blood glucose level in the individual for a period of more than 0.5 hours following administration.

4 . The method of claim 1 , wherein the method stabilizes of blood glucose level in the individual.

5 . A method of (i) increasing insulin secretion, and/or (ii) promoting insulin release into the blood stream, in an individual in need thereof comprising administering to the individual an effective amount of a compound of the formula (IA), (IB), (J-1) or (K-1), wherein formula (IA) is:

or a salt, solvate or N-oxide thereof, wherein:

each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, and cyano, hydroxyl, alkoxy, nitro or R 3a an 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 X 1 , X 2 , X 3 and X 4 is independently N, CH or CR 6 ;

provided that:

(1) at least one of X 1 , X 2 , X 3 and X 4 is CH or CR 6 ;

formula (IB) is:

or a salt or solvate thereof, wherein:

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

provided that:

(1) at least one of X 1 , X 2 , X 3 and X 4 is CR 6 ;

(2) when none of X 1 , X 2 and X 3 is N, and none of R 1 , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b are taken together to form a ring, then Q is other than an unsubstituted phenyl;

(4) when each X 1 , X 3 and X 4 is CH, X 2 is CR 6 where R 6 is fluoro, and each R 2a , R 2b , R 3a , R 3b , R 4a and R 4b is H, then Q is other than 4-fluorophenyl;

formula (J-1) is:

or a salt or solvate thereof, wherein:

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

R 6 is 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;

provided that at least one of X 1 , X 2 , X 3 and X 4 is CH or CR 6 ;

and formula (K-1) is:

or a salt or solvate thereof, wherein:

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

R 6 is 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;

provided that at least one of X 1 , X 2 , X 3 and X 4 is CH or CR 6 .

6 . The method of claim 5 , wherein the method increases insulin secretion.

7 . The method of claim 5 , wherein the method promotes insulin release into the blood stream.

8 . The method of claim 1 , wherein the individual has a disease or condition that involves impaired insulin secretion.

9 . The method of claim 1 , wherein the individual has one or more risk factors for developing a disease or condition that involves impaired insulin secretion.

10 . The method of claim 1 , wherein the administration results in decrease of blood pressure in the individual.

11 . A method of treating a disease or condition that is responsive to an increase in insulin secretion, comprising administering to an individual in need thereof an effective amount of a compound of the formula (IA), (IB), (J-1) or (K-1), wherein formula (IA) is:

or a salt, solvate or N-oxide thereof, wherein:

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

provided that:

(1) at least one of X 1 , X 2 , X 3 and X 4 is CH or CR 6 ;

formula (IB) is:

or a salt or solvate thereof, wherein:

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

provided that:

(1) at least one of X 1 , X 2 , X 3 and X 4 is CR 6 ;

(2) when none of X 1 , X 2 and X 3 is N, and none of R 1 , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b are taken together to form a ring, then Q is other than an unsubstituted phenyl;

(4) when each X 1 , X 3 and X 4 is CH, X 2 is CR 6 where R 6 is fluoro, and each R 2a , R 2b , R 3a , R 3b , R 4a and R 4b is H, then Q is other than 4-fluorophenyl;

formula (J-1) is:

or a salt or solvate thereof, wherein:

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

R 6 is 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;

provided that at least one of X 1 , X 2 , X 3 and X 4 is CH or CR 6 ;

and formula (K-1) is:

or a salt or solvate thereof, wherein:

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

R 6 is 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;

provided that at least one of X 1 , X 2 , X 3 and X 4 is CH or CR 6 .

12 . A method of delaying the onset of a disease or condition that is responsive to an increase in insulin secretion, comprising administering to an individual in need thereof an effective amount of a compound of the formula (IA), (IB), (J-1) or (K-1), wherein formula (IA) is:

or a salt, solvate or N-oxide thereof, wherein:

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

provided that:

(1) at least one of X 1 , X 2 , X 3 and X 4 is CH or CR 6 ;

formula (IB) is:

or a salt or solvate thereof, wherein:

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

provided that:

(1) at least one of X 1 , X 2 , X 3 and X 4 is CR 6 ;

(2) when none of X 1 , X 2 and X 3 is N, and none of R 1 , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b are taken together to form a ring, then Q is other than an unsubstituted phenyl;

(4) when each X 1 , X 3 and X 4 is CH, X 2 is CR 6 where R 6 is fluoro, and each R 2a , R 2b , R 3a , R 3b , R 4a and R 4b is H, then Q is other than 4-fluorophenyl;

formula (J-1) is:

or a salt or solvate thereof, wherein:

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

R 6 is 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;

provided that at least one of X 1 , X 2 , X 3 and X 4 is CH or CR 6 ;

and formula (K-1) is:

or a salt or solvate thereof, wherein:

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, 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(a/b) , R 3(a/b) , R 4(a/b) , or R 10(a/b) to form a carbonyl moiety or a cycloalkyl moiety;

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

R 6 is 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;

provided that at least one of X 1 , X 2 , X 3 and X 4 is CH or CR 6 .

13 . The method of claim 11 , wherein the disease or condition is type 2 diabetes.

14 . The method of claim 13 , wherein the individual is not responsive to standard treatment of type 2 diabetes.

15 . The method of claim 11 , wherein the disease or condition is glucose intolerance.

16 . The method of claim 11 , wherein the disease or condition is metabolic syndrome.

17 . The method of claim 11 , further comprising administering to the individual in need thereof one or more anti-diabetic agents.

18 . The method of claim 17 , wherein at least one of the anti-diabetic agents is an insulin sensitizer.

19 . The method of claim 1 , wherein the compound binds to and is an antagonist of the adrenergic receptor α 2A and, wherein the compound either (a) also binds to and is an antagonist of the adrenergic receptor α 2B or (b) the compound is not an antagonist of the adrenergic receptor α 2B and the compound is administered in conjunction with a second agent that reduces blood pressure in the individual.

20 . The method of claim 19 , wherein the compound binds to and is an antagonist of the adrenergic receptor α 2B .

21 . The method of claim 19 , wherein the compound binds to and is an antagonist of the adrenergic receptor α 1B .

22 . The method of claim 19 , wherein the compound is not an antagonist of the adrenergic receptor α 2B and the compound is administered in conjunction with a diuretic, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist, a beta blocker, a calcium channel blocker, or any combination thereof.

23 . A kit comprising (i) a compound of formula (IA), (IB), (J-1) or (K-1), or a pharmaceutically acceptable salt thereof, and (ii) instructions for use according to the method of claim 1 .

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.

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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

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ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 26, 2013

From: ANDREW ASHER PROTTER; CHAKRAVARTY, SARVAJIT

To: MEDIVATION TECHNOLOGIES, INC.

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