US20140155384A1

US20140155384A1 - Compounds and methods of treating diabetes

Info

Publication number: US20140155384A1
Application number: US14/000,176
Authority: US
Inventors: Andrew Asher Protter; Sarvajit Chakravarty
Original assignee: Medivation Technologies LLC
Current assignee: Medivation Technologies LLC
Priority date: 2011-02-18
Filing date: 2012-02-17
Publication date: 2014-06-05
Also published as: US9199985B2; WO2012112963A1; WO2012112962A1; US20140296209A1

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.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application No. 61/444,626 filed Feb. 18, 2011, U.S. Provisional Patent Application No. 61/561,773 filed Nov. 18, 2011, U.S. Provisional Patent Application No. 61/444,622 filed Feb. 18, 2011, U.S. Provisional Patent Application No. 61/561,761 filed Nov. 18, 2011, and U.S. Provisional Patent Application No. 61/444,547 filed Feb. 18, 2011, the disclosures of each of which are incorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION

Type 2 diabetes is a serious and prevalent disease. This form of diabetes may involve insulin resistance and impaired insulin release. Approximately 25.8 million people in the United States alone suffer from diabetes, whereby type 2 diabetes accounts for about 90-95% of all diagnosed diabetes cases. From 1980 to 2008 the number of Americans with diabetes has more than tripled. Diabetes is also increasingly prevalent elsewhere, such as in certain Asian countries whose populations have experienced a dramatic increase in the disease. For example, in India and China, where rapid lifestyle and economic changes have led to a more sedentary lifestyle and poorer diet among the overall population, diabetes is becoming a major health concern. In addition, more than a third of adults at least 20 years old have pre-diabetes, which is a significant risk factor for developing type 2 diabetes. Other diseases and indications, such as glucose intolerance and metabolic syndrome may also be associated with impaired insulin release.
There remains a need for new and improved therapies that enhance insulin secretion and/or promote insulin release into the blood stream in individuals who have a reduced or impaired ability to secrete insulin and/or release insulin into the blood stream.

BRIEF SUMMARY OF THE INVENTION

Hydrogenated pyrido[4,3-b]indoles, pyrido[3,4-b]indoles and azepino[4,5-b]indoles are described. Compositions and kits comprising the compounds are also provided, as are methods of using and making the compounds. Compounds provided herein 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. In one aspect, compounds provided herein are α_2Aantagonists that may find use in therapy, e.g., to 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.
In one aspect, 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:
R¹is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹and R^2aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹and R^3aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹and R^4aare taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;
each R^2aand R^2bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R^2aand R^2bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^2aand R¹are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^2aand R^3aare taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^2aand R^4aare taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;
each R^3aand R^3bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R^3aand R^3bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^3aand R¹are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^3aand R^2aare taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^3aand R^4aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;
each R
and R^4bindependently H, substituted or unsubstituted C₁-C₈alkyl, halo cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^4aand R^4bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^4aand R¹are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^4aand R^2aare taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^4aand R^3aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;
each X¹, X², X³and X⁴is independently N, CH or CR⁶;
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
R⁶is hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, 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 X¹, X², X³and X⁴is CH or CR⁶;
- (2) when each X¹, X², X³and X⁴is independently CH or CR⁶, none of R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare 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 X¹, X², X³and X⁴is independently CH or CR⁶, none of R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare 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 X¹, X², X³and X⁴is independently CH or CR⁶, and R^2aand R^3aare taken together to form an ethylene (—CH₂CH₂—) 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:
R¹is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹and R^2aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹and R^3aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹and R^4aare taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;
each R^2aand R^2bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R^2aand R^2bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^2aand R¹are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^2aand R^3aare taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^2aand R^4aare taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;
each R^3aand R^3bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R^3aand R^3bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^3aand R¹are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^3aand R
are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^3aand R^4aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;
each R^4aand R^4bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^4aand R^4bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^4aand R¹are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^4aand R^2aare taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^4aand R^3aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;
each X¹, X², X³and X⁴is independently N, CH or CR⁶;
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
R⁶is hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, 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 X¹, X², X³and X⁴is CR⁶;
(2) when none of X¹, X²and X³is N, and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare taken together to form a ring, then Q is other than an unsubstituted phenyl;
(3) when none of X¹, X², X³and X⁴is N, and R^2aand R^2bare 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 X¹, X³and X⁴is CH, X²is CR⁶where R⁶is fluoro, and each R^2a, R^2b, R^3a, R^3b, R^4aand R^4bis H, then Q is other than 4-fluorophenyl;
formula (J-1) is:
or a salt or solvate thereof, wherein:
R¹is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;
each R^2a, R^2bR^3a, R^3b, R^4a, R^4b, R^10aand R^10bis independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, 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 X¹, X²and X³is independently N, CH or CR⁶;
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
R⁶is hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, 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 X¹, X², X³and X⁴is CH or CR⁶;
and formula (K-1) is:
or a salt or solvate thereof, wherein:
R¹is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;
each R^2a, R^2bR^3a, R^3b, R^4a, R^4b, R^10aand R^10bis independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, 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 X¹, X²and X³is independently N, CH or CR⁶;
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
R⁶is hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, 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 X¹, X², X³and X⁴is CH or CR⁶.
In one variation, the method reduces blood glucose level in the individual. In another variation, the method reduces blood glucose level in the individual for a period of more than 0.5 hours following administration. In another variation, the method stabilizes of blood glucose level in the individual.
In another aspect, a method is presented for (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), described above.
In one aspect a method is provided for one or more of the following: reducing blood glucose levels, increasing insulin secretion, and promoting insulin release in the blood stream.
In one variation, the method increases insulin secretion. In another variation, the method promotes insulin release into the blood stream. In another variation, the individual has a disease or condition that involves impaired insulin secretion. In another variation, the individual has one or more risk factors for developing a disease or condition that involves impaired insulin secretion. In another variation, the administration results in decrease of blood pressure in the individual.
In another aspect, a method is presented for 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), described above.
In another aspect, a method is presented for 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), described above.
In one variation, the disease or condition is type 2 diabetes. In another variation, the individual is not responsive to standard treatment of type 2 diabetes. In another variation, the disease or condition is glucose intolerance. In another variation, the disease or condition is metabolic syndrome. In another variation, the method further comprises administering to the individual in need thereof one or more anti-diabetic agents. In another variation, at least one of the anti-diabetic agents is an insulin sensitizer. In another variation, the compound binds to and is an antagonist of the adrenergic receptor α_2Aand, wherein the compound either (a) also binds to and is an antagonist of the adrenergic receptor α_2Bor (b) the compound is not an antagonist of the adrenergic receptor α_2Band the compound is administered in conjunction with a second agent that reduces blood pressure in the individual. In another variation, the compound binds to and is an antagonist of the adrenergic receptor α_2B. In another variation, the compound binds to and is an antagonist of the adrenergic receptor α_1B. In another variation, the compound is not an antagonist of the adrenergic receptor α_2Band 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.
In another aspect, a kit is presented comprising (i) a compound of formula (IA), (IB), (J-1) or (K-1) described above, or a pharmaceutically acceptable salt thereof, and (ii) instructions for use according to the methods described herein.
The invention also includes all salts of compounds referred to herein, such as pharmaceutically acceptable salts. The invention also includes N-oxides of the tertiary amines where one or more tertiary amine moieties are present in the compounds described. The invention also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms and geometric isomers of the compounds described, or mixtures thereof. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to embrace all possible stereoisomers, including geometric isomers, of a compound depicted. Unless olefin geometry is explicitly indicated, substituted olefinic bonds may be present as cis or trans or (Z) or (E) isomeric forms, or as mixtures thereof. In addition, where a specific stereochemical form is depicted, it is understood that other stereochemical forms are also embraced by the invention. For example, where only a Z form of a compound is specifically listed, it is understood that the E form of the compound is also embraced. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds. Compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, which in some embodiments is a specific stereochemical form, including a specific geometric isomer. Compositions comprising a mixture of compounds of the invention in any ratio are also embraced by the invention, including mixtures of two or more stereochemical forms of a compound of the invention in any ratio, such that racemic, non-racemic, enantio-enriched and scalemic mixtures of a compound are embraced, or mixtures thereof.
The invention is also directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient. Kits comprising a compound of the invention and instructions for use are also embraced by this invention. Compounds as detailed herein or a pharmaceutically acceptable salt thereof are also provided for the manufacture of a medicament for the treatment of a disease or condition provided herein.

BRIEF DESCRIPTION OF THE DRAWINGS

Not applicable.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless clearly indicated otherwise, the terms “a,” “an,” and the like, refer to one or more.
It is also understood and clearly conveyed by this disclosure that reference to “the compound” or “a compound” includes and refers to any compounds (e.g., selective adrenergic receptor α_2Bantagonists) or pharmaceutically acceptable salt or other form thereof as described herein.
Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.
Unless clearly indicated otherwise, “an individual” as used herein intends a mammal, including but not limited to a human. The invention may find use in both human medicine and in the veterinary context.
As used herein, an “at risk” individual is an individual who is at risk of developing a disease or condition. An individual “at risk” may or may not have a detectable disease or condition, and may or may not have displayed detectable disease prior to the treatment methods described herein. “At risk” denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of a disease or condition and are known in the art. An individual having one or more of these risk factors has a higher probability of developing the disease or condition than an individual without these risk factor(s).
As used herein, “treatment” or “treating” is an approach for obtaining a beneficial or desired result, including clinical results.
As used herein, “delaying” development of a disease or condition means to defer, hinder, slow, retard, stabilize and/or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition.
As used herein, the term “effective amount” intends such amount of a compound of the invention which should be effective in a given therapeutic form. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
As used herein, “unit dosage form” refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient, or compound which may be in a pharmaceutically acceptable carrier.
As used herein, by “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
“Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual. Such salts, for example, include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Further examples of pharmaceutically acceptable salts include those listed in Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 1977 January; 66(1):1-19. Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the invention in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification. It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
The term “excipient” as used herein includes an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound detailed herein, or a pharmaceutically acceptable salt thereof, as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression/encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (dc=“directly compressible”), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.
An inverse agonist is a compound that binds to a receptor and inhibits the activity of the receptor in the absence of an agonist. An inverse agonist requires that the receptor have some constitutive basal activity in the absence of an agonist. While an agonist increases activity of the receptor over basal level an inverse agonist reduces receptor activity below basal level.
“Alkyl” refers to and includes saturated linear, branched, or cyclic univalent hydrocarbon structures and combinations thereof. Particular alkyl groups are those having 1 to 20 carbon atoms (a “C₁-C₂₀alkyl”). More particular alkyl groups are those having 1 to 8 carbon atoms (a “C₁-C₈alkyl”). When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed and described; thus, for example, “butyl” is meant to include n-butyl, sec-butyl, iso-butyl, tert-butyl and cyclobutyl; “propyl” includes n-propyl, iso-propyl and cyclopropyl. This term is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl, cyclohexylmethyl, cyclopropyl and the like. Cycloalkyl is a subset of alkyl and can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. A preferred cycloalkyl is a saturated cyclic hydrocarbon having from 3 to 13 annular carbon atoms. A more preferred cycloalkyl is a saturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C₃-C₈cycloalkyl”). Examples of cycloalkyl groups include adamantyl, decahydronaphthalenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
“Alkylene” refers to the same residues as alkyl, but having bivalency. Examples of alkylene include methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—) and the like.
“Alkenyl” refers to an unsaturated hydrocarbon group having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C═C) and preferably having from 2 to 10 carbon atoms and more preferably 2 to 8 carbon atoms. Examples of alkenyl include but are not limited to —CH₂—CH═CH—CH₃and —CH₂—CH₂-cyclohexenyl, where the ethyl group of the latter example can be attached to the cyclohexenyl moiety at any available position on the ring. Cycloalkenyl is a subset of alkenyl and can consist of one ring, such as cyclohexyl, or multiple rings, such as norbornenyl. A more preferred cycloalkenyl is an unsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C₃-C₈cycloalkenyl”). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.
“Alkynyl” refers to an unsaturated hydrocarbon group having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula CC) and preferably having from 2 to 10 carbon atoms and more preferably 2 to 8 carbon atoms and the like.
“Substituted alkyl” refers to an alkyl group having from 1 to 5 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.
“Substituted alkenyl” refers to alkenyl group having from 1 to 5 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.
“Substituted alkynyl” refers to alkynyl groups having from 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.
“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substituted alkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—, alkynyl-C(O)—, substituted alkynyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O)—, heterocyclic-C(O)—, and substituted heterocyclic-C(O)—, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
“Acyloxy” refers to the groups H—C(O)O—, alkyl-C(O)O—, substituted alkyl-C(O)O—, alkenyl-C(O)O—, substituted alkenyl-C(O)O—, alkynyl-C(O)O—, substituted alkynyl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—, heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—, heterocyclic-C(O)O—, and substituted heterocyclic-C(O)O—, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
“Heterocycle”, “heterocyclic”, or “heterocyclyl” refers to a saturated or an unsaturated non-aromatic group having a single ring or multiple condensed rings, and having from 1 to 10 annular carbon atoms and from 1 to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like. A heterocycle comprising more than one ring may be fused, spiro or bridged, or any combination thereof. In fused ring systems, one or more of the rings can be aryl or heteroaryl. A heterocycle having more than one ring where at least one ring is aromatic may be connected to the parent structure at either a non-aromatic ring position or at an aromatic ring position. In one variation, a heterocycle having more than one ring where at least one ring is aromatic is connected to the parent structure at a non-aromatic ring position.
“Substituted heterocyclic” or “substituted heterocyclyl” refers to a heterocycle group which is substituted with from 1 to 3 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like. In one variation, a substituted heterocycle is a heterocycle substituted with an additional ring, wherein the additional ring may be aromatic or non-aromatic.
“Aryl” or “Ar” refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic. In one variation, the aryl group contains from 6 to 14 annular carbon atoms. An aryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, an aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.
“Heteroaryl” or “HetAr” refers to an unsaturated aromatic carbocyclic group having from 1 to 10 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur. A heteroaryl group may have a single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl) which condensed rings may or may not be aromatic. A heteroaryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, a heteroaryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.
“Substituted aryl” refers to an aryl group having 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.
“Substituted heteroaryl” refers to a heteroaryl group having 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.
“Aralkyl” refers to a residue in which an aryl moiety is attached to an alkyl residue and wherein the aralkyl group may be attached to the parent structure at either the aryl or the alkyl residue. Preferably, an aralkyl is connected to the parent structure via the alkyl moiety. In one variation, an aralkyl is a fused ring system where at least one cycloalkyl moiety is fused with at least one aryl moiety. A “substituted aralkyl” refers to a residue in which an aryl moiety is attached to a substituted alkyl residue and wherein the aralkyl group may be attached to the parent structure at either the aryl or the alkyl residue. When an aralkyl is connected to the parent structure via the alkyl moiety, it may also be referred to as an “alkaryl”. More particular alkaryl groups are those having 1 to 3 carbon atoms in the alkyl moiety (a “C₁-C₃alkaryl”).
“Alkoxy” refers to the group alkyl-O—, which includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like. Similarly, alkenyloxy refers to the group “alkenyl-O—” and alkynyloxy refers to the group “alkynyl-O—”. “Substituted alkoxy” refers to the group substituted alkyl-O.
“Unsubstituted amino” refers to the group —NH₂.
“Substituted amino” refers to the group —NR_aR_b, where either (a) each R_aand R_bgroup is independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, provided that both R_aand R_bgroups are not H; or (b) R_aand R_bare joined together with the nitrogen atom to form a heterocyclic or substituted heterocyclic ring.
“Acylamino” refers to the group —C(O)NR_aR_bwhere R_aand R_bare independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic or R_aand R_bgroups can be joined together with the nitrogen atom to form a heterocyclic or substituted heterocyclic ring.
“Aminoacyl” refers to the group —NR_aC(O)R_bwhere each R_aand R_bgroup is independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic. Preferably, R_ais H or alkyl.
“Aminosulfonyl” refers to the groups —NRSO₂-alkyl, —NRSO₂substituted alkyl, —NRSO₂-alkenyl, —NRSO₂-substituted alkenyl, —NRSO₂-alkynyl, —NRSO₂-substituted alkynyl, —NRSO₂-cycloalkyl, —NRSO₂-substituted cycloalkyl, —NRSO₂-aryl, —NRSO₂-substituted aryl, —NRSO₂-heteroaryl, —NRSO₂-substituted heteroaryl, —NRSO₂-heterocyclic, and —NRSO₂— substituted heterocyclic, where R is H or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
“Sulfonylamino” refers to the groups —SO₂NH₂, —SO₂NR-alkyl, —SO₂NR-substituted alkyl, —SO₂NR-alkenyl, —SO₂NR-substituted alkenyl, —SO₂NR-alkynyl, —SO₂NR-substituted alkynyl, —SO₂NR-aryl, —SO₂NR-substituted aryl, —SO₂NR-heteroaryl, —SO₂NR-substituted heteroaryl, —SO₂NR-heterocyclic, and —SO₂NR-substituted heterocyclic, where R is H or alkyl, or —SO₂NR₂, where the two R groups are taken together and with the nitrogen atom to which they are attached to form a heterocyclic or substituted heterocyclic ring.
“Sulfonyl” refers to the groups —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl, —SO₂-alkynyl, —SO₂-substituted alkynyl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂-aralkyl, —SO₂-substituted aralkyl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl, —SO₂-heterocyclic, and —SO₂-substituted heterocyclic.
“Aminocarbonylalkoxy” refers to the group —NR_aC(O)OR_bwhere each R_aand R_bgroup is independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclyl.
“Carbonylalkylenealkoxy” refers to the group —C(O)—(CH₂)_n—OR where R is a substituted or unsubstituted alkyl and n is an integer from 1 to 100, more preferably n is an integer from 1 to 10 or 1 to 5.
“Halo” or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85. Preferred halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each H is replaced with a halo group is referred to as a “perhaloalkyl.” A preferred perhaloalkyl group is trifluoroalkyl (—CF₃). Similarly, “perhaloalkoxy” refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (—OCF₃).
“Carbonyl” refers to the group C═O.
“Cyano” refers to the group —CN.
“Oxo” refers to the moiety ═O.
“Nitro” refers to the group —NO₂.
“Thioalkyl” refers to the groups —S-alkyl.
“Alkylsulfonylamino” refers to the groups —R¹SO₂NR_aR_bwhere R_aand R_bare independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, or the R_aand R_bgroups can be joined together with the nitrogen atom to form a heterocyclic or substituted heterocyclic ring and R¹is an alkyl group.
“Carbonylalkoxy” refers to as used herein refers to the groups —C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl, —C(O)O-substituted aryl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl, —C(O)O-alkynyl, —C(O)O-substituted alkynyl, —C(O)O-heteroaryl, —C(O)O-substituted heteroaryl, —C(O)O-heterocyclic or —C(O)O-substituted heterocyclic.
“Geminal” refers to the relationship between two moieties that are attached to the same atom. For example, in the residue —CH₂—CHR¹R², R¹and R²are geminal and R¹may be referred to as a geminal R group to R².
“Vicinal” refers to the relationship between two moieties that are attached to adjacent atoms. For example, in the residue —CHR¹—CH₂R², R¹and R²are vicinal and R¹may be referred to as a vicinal R group to R².

Receptor Binding Profile

In some embodiments, compounds provided herein bind to and are antagonists of the adrenergic receptor α_2A. In one variation, compounds provided herein bind to and are antagonists of the adrenergic receptor α_2Aand either (a) also bind to and are antagonists of the adrenergic receptor α_2Bor (b) are not antagonists of the adrenergic receptor α_2Bbut are administered in the methods detailed herein in conjunction with a second agent that reduces, or is expected to reduce, blood pressure in an individual. By exhibiting the dual properties of binding to and being an antagonist of both the adrenergic receptor α_2Aand the adrenergic receptor α_2B, compounds provided herein may exert the beneficial effect of increasing insulin secretion and/or promoting insulin release in an individual while reducing or eliminating the side effect of an increase in blood pressure that may be associated with antagonizing the adrenergic receptor α_2AAlternatively, compounds provided herein that bind to and are antagonists of the adrenergic receptor α_2A, but which do not bind to and are not antagonists of the adrenergic receptor α_2B, may be used in therapy in conjunction with a second agent that reduces, or is expected to reduce, blood pressure in an individual, thereby allowing the adrenergic receptor α_2Aantagonist to exert its therapeutic effects while reducing or eliminating the side effect of an increase in blood pressure that may be associated with antagonizing the adrenergic receptor α_2A. Thus, it is understood that a second compound that reduces, or is expected to reduce, blood pressure in an individual includes a second compound that reduces or prevents an increase in an individual's blood pressure associated with antagonizing the adrenergic receptor α_2A. It is further understood that any of the compounds provided herein may be administered in conjunction with a second agent that reduces, or is expected to reduce, blood pressure in an individual. For example, such a combination therapy may be utilized in an individual who has high blood pressure or has a propensity toward high blood pressure that is not associated with being administered a compound that antagonizes the adrenergic receptor α_2A. Compounds that exhibit the dual properties of binding to and being an antagonist of both the adrenergic receptor α_2Aand the adrenergic receptor α_2Bmay also be administered in conjunction with a second agent that reduces, or is expected to reduce, blood pressure in an individual.
Compounds that antagonize the adrenergic receptor α_2Aand the adrenergic receptor α_2Bmay lower blood glucose and reduce blood pressure and be of therapeutic utility in individuals with high glucose and high blood pressure, for example individuals who have metabolic syndrome. Compounds that antagonize the adrenergic receptor α_2Aand the adrenergic receptor α_2Bmay also block the adrenergic receptor α_1Band have utility in individuals with high blood glucose and high blood pressure.
The compounds provided herein may in some embodiments also bind to and be antagonists of the adrenergic receptor α_1B, which activity may also help reduce or eliminate an increase in blood pressure in an individual in response to a compound that is an adrenergic receptor α_2Aantagonist. Thus, in one variation, compounds that bind to and are antagonists of the adrenergic receptor α_2Aare provided, wherein the compounds also bind to and are antagonists of the adrenergic receptors α_2Band α_1B. In another variation, compounds that bind to and are antagonists of the adrenergic receptor α_2Aare provided, wherein the compounds also bind to and are antagonists of the adrenergic receptor α_1Bbut which are not antagonists of the adrenergic receptor α_2B. Such compounds, when are administered in the methods detailed herein, may be administered in conjunction with a second agent that reduces or is to expected to reduce, blood pressure in an individual.
The compounds provided herein may in some embodiments also bind to and be antagonists of the adrenergic receptor α_1B, which activity may also help reduce or eliminate an increase in blood pressure in an individual in response to a compound that is an adrenergic receptor α_2Aantagonist. Thus, in one variation, compounds that bind to and are antagonists of the adrenergic receptor α_2Aare provided, wherein the compounds also bind to and are antagonists of the adrenergic receptors α_1B, α_mand α_1B. In another variation, compounds that bind to and are antagonists of the adrenergic receptor α_2Aare provided, wherein the compounds also bind to and are antagonists of the adrenergic receptor α_mand α_mbut which are not antagonists of the adrenergic receptor α_2B. In another variation, compounds that bind to and are antagonists of the adrenergic receptor α_2Aare provided, wherein the compounds also bind to and are antagonists of the adrenergic receptor α_2Band α_mbut which are not antagonists of the adrenergic receptor α_1B. In another variation, compounds that bind to and are antagonists of the adrenergic receptor α_2Aare provided, wherein the compounds also bind to and are antagonists of the adrenergic receptors α_1B, but which are not antagonists of the adrenergic receptor α_2Bor α_1B. Such compounds, when administered in the methods detailed herein, may be administered in conjunction with a second agent that reduces, or is expected to reduce, blood pressure in an individual.
The second agent that reduces, or is expected to reduce, blood pressure in an individual may be a diuretic, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist, a beta blocker, a calcium channel blocker, or any combination thereof. In one variation, the second agent that reduces, or is expected to reduce, blood pressure in an individual is a compound that binds to and is an antagonist of the adrenergic receptor α_2Bbut which is not an antagonist of the adrenergic receptor α_2A. In one variation, the second agent is a single compound. However, it is understood that the second agent in one embodiment may be two or more compounds, such as a second agent that comprises a first compound that is a diuretic and a second compound that is an ACE-inhibitor.
In one variation, a compound provided herein exhibits equal to or greater than about 50% inhibition of α_2Aligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2A. In one variation, a compound provided herein exhibits greater than or equal to about any one of 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% or between about 50% and about 90% or between about 60% and about 90% or between about 70% and about 90% or between about 80% and about 100% inhibition of α_2Aligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2A. In one variation, a compound provided herein exhibits equal to or greater than about 50% inhibition of α_2Aligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2A. In one variation, a compound provided herein exhibits greater than or equal to about any one of 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% or between about 50% and about 90% or between about 60% and about 90% or between about 70% and about 90% or between about 80% and about 100% inhibition of α_2Aligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2A.
In another variation, a compound as provided herein (i) binds to and is an antagonist of adrenergic receptor α_2Aand (ii) exhibits greater than or equal to about 50% inhibition of α_2Bligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2B. In one such variation, a compound as provided herein exhibits (i) greater than or equal to about 50% inhibition of α_2Aligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2Aand (ii) greater than or equal to about 50% inhibition of α_2Bligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2BWhen the compound exhibits greater than or equal to about 50% inhibition of α_2Bligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2B, in some embodiments, it exhibits greater than or equal to about any one of 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% or between about 50% and about 90% or between about 60% and about 90% or between about 70% and about 90% or between about 80% and about 100% inhibition of α_2Bligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2BIn another variation, a compound as provided herein exhibits (i) greater than or equal to about 50% inhibition of α_2Aligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2Aand (ii) greater than or equal to about 50% inhibition of α_2Bligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2BIn another variation, a compound as provided herein exhibits (i) greater than or equal to about 50% inhibition of α_2Aligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2Aand (ii) greater than or equal to about 50% inhibition of α_2Bligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2BIn another variation, a compound as provided herein exhibits (i) greater than or equal to about 50% inhibition of α_2Aligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2Aand (ii) greater than or equal to about 50% inhibition of α_2Bligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2BWhen the compound exhibits greater than or equal to about 50% inhibition of α_2Bligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2B, in some embodiments, it exhibits greater than or equal to about any one of 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% or between about 50% and about 90% or between about 60% and about 90% or between about 70% and about 90% or between about 80% and about 100% inhibition of α_2Bligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2B. It is understood and clearly conveyed herein that an adrenergic receptor α_2Aantagonist can exhibit any of the adrenergic receptor α_2Abinding profiles described herein in combination with any of the adrenergic receptor α_2Bbinding profiles described herein, as if each and every combination were listed separately.
The adrenergic receptor α_2Aantagonists may also be used in conjunction with other agents that antagonize the adrenergic receptor α_2B. Administration in conjunction with another compound includes administration in the same or different composition, either sequentially, simultaneously, or continuously.
In one variation, compounds provided herein that bind to and are antagonists of the adrenergic receptor α_2Awill also bind to and antagonize the adrenergic receptor α_1B. In another variation, compounds provided herein that bind to and are antagonists of the adrenergic receptor α_2Aand either (a) also bind to and are antagonists of the adrenergic receptor α_2Bor (b) are administered in the methods detailed herein in conjunction with a second agent that reduces, or is expected to reduce, blood pressure in an individual, will also bind to and antagonize the adrenergic receptor α_1B. In some embodiments, compounds provided herein may exhibit greater than or equal to about 50% inhibition of α_mligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_1B. In some embodiments, compounds provided herein may exhibit greater than or equal to about any one of 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or between about 50% and about 90%, between about 60% and about 90%, between about 70% and about 90%, or between about 80% and about 100% inhibition of α_mligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_1B. In some embodiments, compounds provided herein may exhibit greater than or equal to about 50% inhibition of α_mligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_1B. In some embodiments, compounds provided herein may exhibit greater than or equal to about any one of 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or between about 50% and about 90%, between about 60% and about 90%, between about 70% and about 90%, or between about 80% and about 100% inhibition of α_mligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_1B. For example, in one variation, a compound provided herein exhibits equal to or greater than about 50% inhibition of α_2Aligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2Aand greater than or equal to about 50% inhibition of α_1Bligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_1B. In another variation, a compound provided herein exhibits equal to or greater than about 50% inhibition of α_2Aligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2A, greater than or equal to about 50% inhibition of α_2Bligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2Band greater than or equal to about 50% inhibition of α_mligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_1B. In one variation, a compound provided herein exhibits equal to or greater than about 50% inhibition of α_2Aligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2A, greater than or equal to about 50% inhibition of α_2Bligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2Band greater than or equal to about any one
, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or between about
and about 90%, between about 60% and about 90%, between about 70% and about 90%, or between about 80% and about 100% inhibition of α_1Bligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_1B. It is understood and clearly conveyed herein that an adrenergic receptor α_2Aantagonist can exhibit any of the adrenergic receptor α_2Abinding profiles described herein in combination with any of the adrenergic receptor α_2Bbinding profiles described herein, and/or any of the adrenergic receptor α_1Bbinding profiles described herein as if each and every combination were listed separately.
The adrenergic receptor α_2Aantagonists may also be used in conjunction with other agents that antagonize the adrenergic receptor α_1B. Administration in conjunction with another compound includes administration in the same or different composition, either sequentially, simultaneously, or continuously.
In one variation, compounds provided herein that bind to and are antagonists of the adrenergic receptor α_2Awill also bind to and antagonize the adrenergic receptor α_1D. In another variation, compounds provided herein that bind to and are antagonists of the adrenergic receptor α_2Aand either (a) also bind to and are antagonists of the adrenergic receptor α_2Bor (b) are administered in the methods detailed herein in conjunction with a second agent that reduces, or is expected to reduce, blood pressure in an individual, will also bind to and antagonize the adrenergic receptor α_1D. In another variation, compounds provided herein that bind to and are antagonists of the adrenergic receptor α_2Aand either (a) also bind to and are antagonists of the adrenergic receptor α_2Bor (b) are administered in the methods detailed herein in conjunction with a second agent that reduces, or is expected to reduce, blood pressure in an individual, and bind to and are antagonists of the adrenergic receptor α_1Bwill also bind to and antagonize the adrenergic receptor α_1D. In some embodiments, compounds provided herein may exhibit greater than or equal to about 50% inhibition of α_1Dligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_1D. In some embodiments, compounds provided herein may exhibit greater than or equal to about any one of 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or between about 50% and about 90%, between about 60% and about 90%, between about 70% and about 90%, or between about 80% and about 100% inhibition of α_1Dligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_1D. In some embodiments, compounds provided herein may exhibit greater than or equal to about 50% inhibition of α_1Dligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_1D. In some embodiments, compounds provided herein may exhibit greater than or equal to about any one of 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or between about 50% and about 90%, between about 60% and about 90%, between about 70% and about 90%, or between about 80% and about 100% inhibition of α_1Dligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_1D. For example, in one variation, a compound provided herein exhibits equal to or greater than about 50% inhibition of α_2Aligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2Aand greater than or equal to about 50% inhibition of α_1Dligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_1D. In another variation, a compound provided herein exhibits equal to or greater than about 50% inhibition of α_2Aligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2A, greater than or equal to about 50% inhibition of α_2Bligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2Band greater than or equal to about 50% inhibition of α_1Dligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_1D. In another variation, a compound provided herein exhibits equal to or greater than about 50% inhibition of α_2Aligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2A, greater than or equal to about 50% inhibition of α_2Bligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2B, greater than or equal to about 50% inhibition of α_1Bligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_1B, and greater than or equal to about 50% inhibition of α_1Dligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_1B. In one variation, a compound provided herein exhibits equal to or greater than about 50% inhibition of α_2Aligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2A, greater than or equal to about 50% inhibition of α_2Bligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2B, greater than or equal to about 50% inhibition of α_1Bligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_1Band greater than or equal to about any one of 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or between about 50% and about 90%, between about 60% and about 90%, between about 70% and about 90%, or between about 80% and about 100% inhibition of α_1Dligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_1D. It is understood and clearly conveyed herein that an adrenergic receptor α_2Aantagonist can exhibit any of the adrenergic receptor α_2Abinding profiles described herein in combination with any of the adrenergic receptor α_2Bbinding profiles described herein, and/or any of the adrenergic receptor α_1Bbinding profiles described herein and/or any of the adrenergic receptor α_1Dbinding profiles described herein as if each and every combination were listed separately.
The adrenergic receptor α_2Aantagonists may also be used in conjunction with other agents that antagonize the adrenergic receptor α_1D. Administration in conjunction with another compound includes administration in the same or different composition, either sequentially, simultaneously, or continuously.
The binding properties to adrenergic receptors of compounds disclosed herein may be assessed by methods known in the art, such as competitive binding assays. In one variation, compounds are assessed by the binding assays detailed herein. In one variation, inhibition of binding of a ligand to a receptor is measured by the assays described herein. In another variation, inhibition of binding of a ligand is measured in an assay known in the art.

Functional Assay Profile

Antagonist activity to the adrenergic receptor α_2A, α_2B, α_1Band α_1Dmay be assessed by methods known in the art, such as standard α_2A, α_2B, α_1Band α_1Dreceptor cell membrane-based or intact cell-based activity assays. For example, the Aequorin-based assay may be used to assess antagonist activity to the adrenergic receptor α_2A, α_2B, α_1Bor α_1Dand the cell membrane-based GTPγS binding assay may be used to assess antagonist activity to the adrenergic receptor α_2B.
In one variation, adrenergic receptor α_2Aantagonists as provided herein exhibit an IC₅₀value equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of UK14304 (for Aequorin assay) in an adrenergic receptor α_2Aantagonist assay.
In another variation, a compound provided herein binds to and is an antagonist of the adrenergic receptor α_2A, wherein the compound is also an antagonist of the adrenergic receptor α_2Band exhibits an IC₅₀value that is equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of oxymetazoline (for Aequorin assay) or guanfacine (for GTPγS assay) in an adrenergic receptor α_2Bantagonist assay. In some embodiments, adrenergic receptor α_2Aantagonists as provided herein exhibit: (i) an IC₅₀value in an α_2Aantagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of UK14304 (for Aequorin assay), and (ii) an IC₅₀value in an α_2Bantagonist assay that is equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of oxymetazoline (for Aequorin assay) or guanfacine (for GTPγS assay). In another variation, a compound provided herein binds to and is an antagonist of the adrenergic receptor α_2A, wherein the compound is also an antagonist of the adrenergic receptor α_1Band exhibits an IC₅₀value that is equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of cirazoline (for Aequorin assay) in an adrenergic receptor α_1Bantagonist assay. In some embodiments, adrenergic receptor α_2Aantagonists as provided herein exhibit: (i) an IC₅₀value equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of UK14304 (for Aequorin assay) in an adrenergic receptor α_2Aantagonist assay, and (ii) an IC₅₀value equal or less than about any one of 100 nM or 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of cirazoline) in an adrenergic receptor α_1Bantagonist assay. In yet another variation, a compound provided herein binds to and is an antagonist of the adrenergic receptor α_2A, wherein the compound is also an antagonist of the adrenergic receptor α_1Dand exhibits an IC₅₀value that is equal to or less than about any one of 100 nM,
or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of cirazoline (for Aequorin assay) in an adrenergic receptor α_1Dantagonist assay. In some embodiments, adrenergic receptor α_2Aantagonists as provided herein exhibit: (i) an IC₅₀value equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of UK14304 (for Aequorin assay) in an adrenergic receptor α_2Aantagonist assay, and (ii) an IC₅₀value equal or less than about any one of 100 nM or 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of cirazoline) in an adrenergic receptor α_1Bantagonist assay.
In yet another embodiment, adrenergic receptor α_2Aantagonists as provided herein exhibit: (i) an IC₅₀value in an α_2Aantagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of UK14304 (for Aequorin assay); (ii) an IC₅₀value in an α_2Bantagonist assay that is equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of oxymetazoline (for Aequorin assay) or guanfacine (for GTPγS assay); and (iii) an IC₅₀value equal or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of cirazoline) in an adrenergic receptor α_1Bantagonist assay. In another embodiment, adrenergic receptor α_2Aantagonists as provided herein exhibit: (i) an IC₅₀value in an α_2Aantagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of UK14304 (for Aequorin assay); (ii) an IC₅₀value in an α_2Bantagonist assay that is equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of oxymetazoline (for Aequorin assay) or guanfacine (for GTPγS assay); and (iii) an IC₅₀value equal or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of cirazoline) in an adrenergic receptor α_1Dantagonist assay. In another embodiment, adrenergic receptor α_2Aantagonists as provided herein exhibit: (i) an IC₅₀value in an α_2Aantagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of UK14304 (for Aequorin assay); (ii) an IC₅₀value equal or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of cirazoline) in an adrenergic receptor α_1Bantagonist assay; and (iii) an IC₅₀value equal or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of cirazoline) in an adrenergic receptor α_1Dantagonist assay.
In yet another embodiment, adrenergic receptor α_2Aantagonists as provided herein exhibit: (i) an IC₅₀value in an α_2Aantagonist assay equal to or less than about any one
100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of UK14304 (for Aequorin assay); (ii) an IC₅₀value in an α_2Bantagonist assay that is equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of oxymetazoline (for Aequorin assay) or guanfacine (for GTPγS assay); (iii) an IC₅₀value equal or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of cirazoline) in an adrenergic receptor α_1Bantagonist assay; and (iv) an IC₅₀value equal or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of cirazoline) in an adrenergic receptor α_1Dantagonist assay.
In one variation, adrenergic receptor α_2Aantagonists as provided herein exhibit an IC₅₀value equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of UK14304 (for Aequorin assay) in an adrenergic receptor α_2Aantagonist assay. In one variation, adrenergic receptor α_2Aantagonists as provided herein exhibit an IC₅₀value equal to or less than about 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of UK14304 (for Aequorin assay) in an adrenergic receptor α_2Aantagonist assay. In one variation, adrenergic receptor α_2Aantagonists as provided herein exhibit an IC₅₀value in an adrenergic receptor α_2Aantagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of UK14304 (for Aequorin assay) corresponding to its EC₈₀concentration obtained by assay protocols described herein. In one variation, adrenergic receptor α_2Aantagonists as provided herein exhibit an IC₅₀value equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of UK14304 between about 0.4 and about 40 nM in an adrenergic receptor α_2A(Aequorin) antagonist assay. In one variation, adrenergic receptor α_2Aantagonists as provided herein exhibit an IC₅₀value equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of about 4.57 nM UK14304 in an adrenergic receptor α_2A(Aequorin) antagonist assay.
In one variation adrenergic receptor α_2Aantagonists as provided herein exhibit an IC₅₀value equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of oxymetazoline (for Aequorin assay) or guanfacine (for GTPγS assay) in an α_2Bantagonist assay. In some embodiments, adrenergic receptor α_2Aantagonists as provided herein exhibit an IC₅₀value equal to or less than about 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of oxymetazoline (for Aequorin assay) or guanfacine (for GTPγS assay) in an α_2Bantagonist assay. In some embodiments, a compound described herein exhibits an IC₅₀value in an α_2Bantagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of oxymetazoline corresponding to its EC₈₀concentration as obtained by assay protocols described herein. In some embodiments, a compound described herein exhibits an IC₅₀value in an α_2Bantagonist (Aequorin) assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of oxymetazoline between about 50 nM to about 5000 nM. In some embodiments, a compound described herein exhibits an IC₅₀value in an α_2Bantagonist (Aequorin) assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of about 480 nM oxymetazoline. In some embodiments, a compound described herein exhibits an IC₅₀value in an α_2Bantagonist (GTPγS) assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of guanfacine between about 50 nM to about 5000 nM. In some embodiments, a compound described herein exhibits an IC₅₀value in an α_2Bantagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of about 500 nM guanfacine, which is a particular variation, is 504 nM guanfacine.
In one variation, a compound described herein exhibits an IC₅₀value in an α_1Bantagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of cirazoline) in an adrenergic receptor α_1Bantagonist assay. In some embodiments, a compound described herein exhibits an IC₅₀value in an α_1Bantagonist assay equal to or less than about 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of cirazoline) in an adrenergic receptor α_1Bantagonist assay. In some embodiments, a compound described herein exhibits an IC₅₀value in an α_1Bantagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of cirazoline corresponding to its EC₈₀concentration as obtained by assay protocols described herein. In some embodiments, a compound described herein exhibits an IC₅₀value in an α_1Bantagonist (Aequorin) assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of cirazoline between about 2.3 nM and about 230 nM. In some embodiments, a compound described herein exhibits an IC₅₀value in an α_1Bantagonist (Aequorin) assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of about 25 nM cirazoline, which in a particular variation is 23.56 nM cirazoline.
In one variation, a compound described herein exhibits an IC₅₀value in an α_1Dantagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of cirazoline) in an adrenergic receptor α_1Dantagonist assay. In some embodiments, a compound described herein exhibits an IC₅₀value in an α_1Dantagonist assay equal to or less than about 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of cirazoline) in an adrenergic receptor α_1Dantagonist assay. In some embodiments, a compound described herein exhibits an IC₅₀value in an α_1Dantagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of cirazoline corresponding to its EC₈₀concentration as obtained by assay protocols described herein. In some embodiments, a compound described herein exhibits an IC₅₀value in an α_1Dantagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of cirazoline between about 2.3 nM and about 230 nM. In some embodiments, a compound described herein exhibits an IC₅₀value in an α_1Dantagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of about 25 nM cirazoline, which in a particular variation is 23.56 nM cirazoline.
In some embodiments, compounds provided herein exhibit inverse agonist activity for the adrenergic receptor α_2A. In some embodiments, the compound binds to and is an inverse agonist of the adrenergic receptor α_2Aand binds to and is antagonist of one or more of the adrenergic receptors α_2B, α_1Band α_1D. In one variation, the compound binds to and is an inverse agonist of the adrenergic receptor α_2Aand binds to and is antagonist of any one of the adrenergic receptors α_2B, α_1Band α_1D. In another variation, the compound binds to and is an inverse agonist of the adrenergic receptor α_2Aand binds to and is antagonist of any two of the adrenergic receptors α_2B, α_1Band α_1D. In yet another variation, the compound binds to and is an inverse agonist of the adrenergic receptor α_2Aand binds to and is antagonist of adrenergic receptors α_2B, α_1Band α_1D. Inverse agonist activity to the adrenergic receptor α_2Amay be assessed by methods known in the art, such as those described in Wade, S. M. et al., Mol. Pharmacol. 59:532-542 (2001).
It is understood and clearly conveyed herein that any of the binding profiles detailed herein can be combined with any of the antagonist profiles detailed herein, as if each and every combination were listed separately. For example, in one variation, a compound provided herein exhibits (i) greater than or equal to about any one of 50%, 55%, 60%, 65%, 70%, 80%, 85%, 90%, 95%, or between about 50% and 90%, between about 60% and about 90%, between about 70% and about 90%, or about 80% and about 100% inhibition of α_2Aligand binding at 0.1 μM to adrenergic receptor α_2Aand an IC₅₀value equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of UK14304 (for Aequorin assay) in an adrenergic receptor α_2Aantagonist assay; and (ii) greater than or equal to about any one of 50%, 55%, 60%, 65%, 70%, 80%, 85%, 90%, 95%, or between about 50% and 90%, between about 60% and about 90%, between about 70% and about 90%, or about 80% and about 100% inhibition of α_2Bligand binding at 0.1 μM to adrenergic receptor α_2Band IC₅₀value equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g. concentration corresponding to EC₈₀of oxymetazoline (for Aequorin assay) or guanfacine (for GTPγS assay) in an α_2Bantagonist assay.

Medical Use

Without being bound by theory, it is believed that compounds that bind to and are antagonists of the adrenergic receptor α_2Aaffect an increase in insulin secretion and/or promote insulin release into the blood stream in an individual, which aids in glucose uptake. However, such compounds may also increase an individual's blood pressure. When the adrenergic receptor α_2Aantagonists as provided herein also bind to and are antagonists of the adrenergic receptor α_2Band/or the adrenergic receptor α_1B, and/or the adrenergic receptor α_1D, it is believed that the increases in an individual's blood pressure due to antagonizing the adrenergic receptor α_2Amay be reduced or eliminated. If an adrenergic receptor α_2Aantagonist as provided herein is not also an antagonist of the adrenergic receptor α_2Band/or the adrenergic receptor α_1Band/or the adrenergic receptor α_1D, then the increase in an individual's blood pressure as a result of the adrenergic receptor α_2Aantagonist may be reduced or eliminated by administering the compound in conjunction with a second agent that reduces, or is expected to reduce, blood pressure in an individual.
Compounds provided herein, such as the adrenergic receptor α_2Aantagonists provided herein, are expected to find use in therapy, particularly in indications in which an increase in an individual's insulin secretion and/or an increase in insulin release into the blood stream would be, or would be expected to be, beneficial. Thus, individuals who have a disease or condition that involves reduced or impaired insulin secretion and/or release may benefit from the compounds detailed herein, or pharmaceutically acceptable salts thereof. Such indications include, but are not limited to type 2 diabetes, glucose intolerance and metabolic syndrome. An individual who has a disease or condition that involves reduced or impaired insulin secretion and/or release may experience one or more beneficial or desirable results upon administration of an adrenergic receptor α_2Aantagonist provided herein, or pharmaceutically acceptable salt thereof. In one aspect, the beneficial or desirable result is a reduction in the individual's blood glucose level for a period of time (e.g., about any one of 6, 12, 24 or 48 hours or more) following administration of the compound or pharmaceutically acceptable salt thereof. In another aspect, the beneficial or desirable result is an increase in glucose metabolism for a period of time (e.g., about any one of 6, 12, 24 or 48 hours or more) following administration of the compound or pharmaceutically acceptable salt thereof.
Compounds that are inverse agonists of the adrenergic receptor α_2Amay stimulate islet cell release of insulin even in the absence of sympathetic stimulation of the adrenergic receptor α_2Awith epinephrine and/or norepinephrine. Inverse agonists of the adrenergic receptor α_2Aprovided herein are thus expected to find use in therapy, particularly in indications in which stimulation of islet cell release of insulin would be, or would be expected to be, beneficial. Individuals who have a disease or condition responsive to inhibition of the adrenergic receptor α_2Amay benefit from the compounds detailed herein, or pharmaceutically acceptable salts thereof. Such indications include, but are not limited to type 2 diabetes, metabolic syndrome, and glucose intolerence.
In one aspect, compounds are provided that do not bind appreciably any one or more of the histamine, dopamine and serotonin receptors. In any of the methods detailed herein, in one variation the individual does not have a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or neuronal disorder. As used herein, the term “cognitive disorders” refers to and intends diseases and conditions that are believed to involve or be associated with or do involve or are associated with progressive loss of structure and/or function of neurons, including death of neurons, and where a central feature of the disorder may be the impairment of cognition (e.g., memory, attention, perception and/or thinking). These disorders include pathogen-induced cognitive dysfunction, e.g., HIV associated cognitive dysfunction and Lyme disease associated cognitive dysfunction. Examples of cognitive disorders include Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, schizophrenia, amyotrophic lateral sclerosis (ALS), autism, mild cognitive impairment (MCI), stroke, traumatic brain injury (TBI) and age-associated memory impairment (AAMI). As used herein, the term “psychotic disorders” refers to and intends mental diseases or conditions that are believed to cause or do cause abnormal thinking and perceptions. Psychotic disorders are characterized by a loss of reality which may be accompanied by delusions, hallucinations (perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid, substantial, and located in external objective space), personality changes and/or disorganized thinking. Other common symptoms include unusual or bizarre behavior, as well as difficulty with social interaction and impairment in carrying out the activities of daily living. Exemplary psychotic disorders are schizophrenia, bipolar disorders, psychosis, anxiety and depression. As used herein, the term “neurotransmitter-mediated disorders” refers to and intends diseases or conditions that are believed to involve or be associated with or do involve or are associated with abnormal levels of neurotransmitters such as histamine, serotonin, dopamine, norepinephrine or impaired function of aminergic G protein-coupled receptors. Exemplary neurotransmitter-mediated disorders include spinal cord injury, diabetic neuropathy, allergic diseases and diseases involving geroprotective activity such as age-associated hair loss (alopecia), age-associated weight loss and age-associated vision disturbances (cataracts). Abnormal neurotransmitter levels are associated with a wide variety of diseases and conditions including, but not limited, to Alzheimer's disease, Parkinson's Disease, autism, Guillain-Barré syndrome, mild cognitive impairment, schizophrenia, anxiety, multiple sclerosis, stroke, traumatic brain injury, spinal cord injury, diabetic neuropathy, fibromyalgia, bipolar disorders, psychosis, depression and a variety of allergic diseases. As used herein, the term “neuronal disorders” refers to and intends diseases or conditions that are believed to involve, or be associated with, or do involve or are associated with neuronal cell death and/or impaired neuronal function or decreased neuronal function. Exemplary neuronal indications include neurodegenerative diseases and disorders such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, canine cognitive dysfunction syndrome (CCDS), Lewy body disease, Menkes disease, Wilson disease, Creutzfeldt-Jakob disease, Fahr disease, an acute or chronic disorder involving cerebral circulation, such as ischemic or hemorrhagic stroke or other cerebral hemorrhagic insult, age-associated memory impairment (AAMI), mild cognitive impairment (MCI), injury-related mild cognitive impairment (MCI), post-concussion syndrome, post-traumatic stress disorder, adjuvant chemotherapy, traumatic brain injury (TBI), neuronal death mediated ocular disorder, macular degeneration, age-related macular degeneration, autism, including autism spectrum disorder, Asperger syndrome, and Rett syndrome, an avulsion injury, a spinal cord injury, myasthenia gravis, Guillain-Barré syndrome, multiple sclerosis, diabetic neuropathy, fibromyalgia, neuropathy associated with spinal cord injury, schizophrenia, bipolar disorder, psychosis, anxiety or depression.
The adrenergic receptor α_2Aantagonists provided herein may also be administered in combination with an insulin sensitizer, and as such find use in therapy for treating indications in which increasing in an individual's insulin secretion and/or insulin release into the blood stream would be, or would be expected to be, beneficial, provided that the therapy also promotes insulin responsiveness to glucose. In one aspect, where the adrenergic receptor α_2Aantagonists provided herein may be administered in combination with another anti-diabetic drug, such as an insulin sensitizer, the beneficial or desirable result of which is a reduction in the individual's blood glucose levels for a period of time (e.g., about any one of 6, 12, 24 or 48 hours or more) following administration of the compound or pharmaceutically acceptable salt thereof. In a particular variation, such a therapy may include an adrenergic receptor α_2Aantagonist provided herein and a second agent that reduces, or is expected to reduce, blood pressure and an insulin sensitizer. In a further variation, such a therapy may include an adrenergic receptor α_2Aantagonist provided herein and a second agent that (i) is an agent that reduces, or is expected to reduce, blood pressure; (ii) is an agent that is an insulin sensitizer or (iii) is an agent that induces no or reduced (in number and/or severity) hypoglycemic episodes.

Methods

Methods of using the compounds detailed herein, or pharmaceutical salts thereof, to increase an individual's ability to secrete insulin and/or to release insulin into the blood stream are provided. In any of the methods detailed herein, the method may comprise the step of administering an adrenergic receptor α_2Aantagonist, or pharmaceutically acceptable salt thereof, to an individual in need thereof. In one aspect, the adrenergic receptor α_2Aantagonists of the methods also bind to and are antagonists of one or more of the adrenergic receptors α_2B, α_1Band α_1D. In one variation, a method of increasing insulin secretion and/or release into the blood stream in an individual in need thereof is provided, wherein the method comprises administering to an individual in need thereof a compound that binds to and is an antagonists of the adrenergic receptor α_2A. In another variation, a method of increasing insulin secretion and/or release into the blood stream in an individual in need thereof is provided, wherein the method comprises administering to an individual in need thereof a compound that binds to and is an antagonists of the adrenergic receptor α_2A, wherein the compound either (a) also binds to and is an antagonist of the adrenergic receptor α_2Bor (b) is administered in conjunction with a second agent that reduces, or is expected to reduce, blood pressure in the individual. In some variations, methods of using the compounds detailed herein to increase an individual's ability to secrete insulin and/or release insulin into the blood stream while reducing or eliminating an increase in the individual's blood pressure due to antagonizing the adrenergic receptor α_2Aare thus provided. Methods of using the compounds detailed herein to promote an individual's ability to metabolize glucose while reducing or eliminating an increase in the individual's blood pressure due to antagonizing the adrenergic receptor α_2Aare also provided. It is understood that in methods of promoting an individual's ability to metabolize glucose, the method in one variation may employ administration of both an adrenergic receptor α_2Aantagonist and an insulin sensitizer. The compounds or pharmaceutical salts thereof may also find use in treating a disease or condition that is, or is expected to be, responsive to an increase in an individual's ability to secrete insulin and/or release of insulin into the blood stream. Individuals to be treated in such methods in one variation have a reduced or impaired ability to secrete insulin and/or release insulin into the blood stream. The compounds as provided herein may also be used in a method of delaying the onset and/or development of a disease or condition associated with reduced or impaired ability to secrete insulin and/or release insulin into the blood stream, comprising administering a compound as provided herein, or a pharmaceutical salt thereof, to an individual who is at risk of developing a disease or condition associated with reduced or impaired ability to secrete insulin and/or release insulin into the blood stream. The compounds as provided herein may also be used in a method of delaying the onset and/or development of a disease or condition associated with reduced or impaired ability to metabolize glucose, comprising administering an adrenergic receptor α_2Aantagonist as provided herein, or a pharmaceutical salt thereof, to an individual who is at risk of developing a disease or condition associated with reduced or impaired ability to metabolize glucose. The individual may be an adult, child or teen who has or is at risk of developing type 2 diabetes, glucose intolerance or metabolic syndrome.
Non-limiting examples of a second agent that lowers blood pressure include diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-2 receptor antagonists, beta blockers, calcium channel blockers, or any combination thereof.
Also provided herein are methods of using an adrenergic receptor α_2Aantagonist, or a pharmaceutically acceptable salt thereof, in combination with one or more
other anti-diabetic agents, such as insulin sensitizers and secretagogue agents. Non-limiting examples of anti-diabetic agents include insulin therapies (e.g., insulin glargine and insulin lispro), secretagogue agents that increase insulin secretion and/or release (e.g., sulfonylureas such as glimepiride, glipizide and glyburide; meglitinides such as repaglinide and nateglinide), agents that increase insulin sensitivity (e.g., thiazolidinediones, such as pioglitazone and rosiglitazone), agents that decrease glucose absorption (e.g., alpha-glucosidase inhibitors such as miglitol and acarbose); and agents that reduce gluconeogenesis (biguanide such as metformin); amylinomimetics such as pramlintide, and agents that sequester bile acids.
Further provided herein are methods of using an adrenergic receptor α_2Aantagonist, or a pharmaceutically acceptable salt thereof, in combination with an insulin sensitizer to promote insulin responsiveness and increase an individual's ability to secrete insulin and/or to release insulin into the blood stream. In one aspect, the adrenergic receptor α_2Aantagonist also binds to and is an antagonist of one or more of the adrenergic receptors α_2B, α_1Band α_1D. In one variation, a method of promoting insulin responsiveness and increasing insulin secretion and/or release into the blood stream in an individual in need thereof is provided, wherein the method comprises administering to an individual in need thereof an insulin sensitizer and an adrenergic receptor α_2Aantagonist. In another variation, a method of promoting insulin responsiveness and increasing insulin secretion and/or release into the blood stream in an individual in need thereof is provided, wherein the method comprises administering to an individual in need thereof an insulin sensitizer and a compound that binds to and is an antagonists of the adrenergic receptor α_2A, wherein the compound either (a) also binds to and is an antagonist of the adrenergic receptor α_2Bor (b) is administered in conjunction with a second agent that reduces, or is expected to reduce, blood pressure in the individual. In a particular variation, a method of promoting insulin responsiveness and increasing insulin secretion and/or release into the blood stream in an individual in need thereof is provided, wherein the method comprises administering to an individual in need thereof an insulin sensitizer and an adrenergic receptor α_2Aantagonist that also binds to and is an antagonist of one or more of the adrenergic receptors α_2B, α_1Band α_1D. In some embodiments, the method comprises administering any of the compounds detailed herein in combination with an insulin sensitizer.
In one aspect, a method of treating type 2 diabetes is provided, where the method comprises administering to an individual in need thereof a compound detailed herein, such as an adrenergic receptor α_2Aantagonist detailed herein. In one aspect, the compound binds to and is an adrenergic receptor α_2Aantagonist. In some embodiments, the adrenergic receptor α_2Aantagonist also binds to and is an antagonist of one or more of the adrenergic receptors α_2B, α_1Band α_1D. In another aspect, a method of treating type 2 diabetes is provided, where the method comprises administering to an individual in need thereof a compound as provided herein, wherein the compound binds to and is an antagonist of the adrenergic receptor α_2Aand wherein the compound either (a) also binds to and is an antagonist of the adrenergic receptor α_2Bor (b) is administered in conjunction with a second agent that reduces, or is expected to reduce, blood pressure in an individual. Individuals to be treated in such methods in one variation have type 2 diabetes. The compounds as provided herein may also be used in a method of delaying the onset and/or development of type 2 diabetes, comprising administering an adrenergic receptor α_2Aantagonist, or pharmaceutically acceptable salt thereof, to an individual who has one or more risk factors associated with developing type 2 diabetes. In one variation, the compounds as provided herein are used in a method of delaying the onset and/or development of type 2 diabetes; and inducing extra-pancreatic effects such as reducing hepatic glucose production via glycogenolysis or gluconeogenesis or both, comprising administering an adrenergic receptor α_2Aantagonist, or pharmaceutically acceptable salt thereof, to an individual such as an individual who has one or more risk factors associated with developing type 2 diabetes. In one variation, compounds provided herein may (i) have an extra-pancreatic effect and/or (ii) prevent or lower hepatic glucose production.
Risk factors may include gender, race, ethnicity, age, family history, weight and/or lifestyle. For example, certain races and ethnicities (e.g., Blacks, Hispanics, Native Americans and Asians (which as used herein includes individuals of the continent of Asia, such as Indians and Chinese) and individuals of such descent) are more likely to develop type 2 diabetes. Being overweight (e.g., having a body mass index >25) is also a risk factor for type 2 diabetes, with higher amount of fatty tissue also correlating with higher resistance of cells to insulin. Inactivity, which can lead to weight gain, is also a risk factor for type 2 diabetes (physical activity helps not only to control an individual's weight, but also utilizes glucose as energy and makes cells more sensitive to insulin). Family history is often a risk factor for many diseases, including type 2 diabetes, where the risk of developing type 2 diabetes increases if a parent or sibling has type 2 diabetes. The risk of developing type 2 diabetes also increases with age, especially after age 45, which may also correlate with a tendency to exercise less, lose muscle mass and gain weight with age. However, as obesity rates rise in children and young adults, type 2 diabetes is increasing common in these individuals and children and young adults who are overweight and/or sedentary are also at risk of developing type 2 diabetes. Being pre-diabetic, in which an individual's blood sugar level is higher than normal, but not high enough to be classified as type 2 diabetes, if left untreated, often progresses to type 2 diabetes. Other risk factors associated with type 2 diabetes include: a woman who has had gestational diabetes, gave birth to a baby weighing more than 9 pounds or has a history of ploycystic ovary disease (PCOS); an individual who has metabolic syndrome; an individual who has a hypertension; an individual who has a high-density lipoprotein (HDL) value under 35 mg/dL (milligrams per deciliter) and/or a triglyceride level over 250 mg/dL; and an individual with a history of vascular disease, such as stroke. Individuals who have more than one risk factor are particularly susceptible to developing type 2 diabetes.
In one aspect, a method of treating glucose intolerance is provided, where the method comprises administering to an individual in need thereof an adrenergic receptor α_2Aantagonist, or pharmaceutically acceptable salt thereof. In one aspect, the adrenergic receptor α_2Aantagonist also binds to and is an antagonist of one or more of the adrenergic receptors α_2B, α_1Band α_1D. In another aspect, a method of treating glucose intolerance is provided, where the method comprises administering to an individual in need thereof a compound as provided herein, wherein the compound binds to and is an antagonist of the adrenergic receptor α_2Aand wherein the compound either (a) also binds to and is an antagonist of the adrenergic receptor α_2Bor (b) is administered in conjunction with a second agent that reduces, or is expected to reduce, blood pressure in the individual. The compounds as provided herein may also be used in a method of delaying the onset and/or development of glucose intolerance, comprising administering a compound as provided herein to an individual who has one or more risk factors associated with developing glucose intolerance. A method of reducing blood glucose levels in an individual in need thereof is also provided, the method comprising administering an adrenergic receptor α_2Aantagonist, or pharmaceutically acceptable salt thereof, to the individual. A method of enhancing glucose metabolism in an individual in need thereof is also provided, the method comprising administering an adrenergic receptor α_2Aantagonist, or pharmaceutically acceptable salt thereof, to the individual.
Further provided are methods of using the compounds detailed herein, or pharmaceutical salts thereof, to regulate blood glucose levels in an individual, for example, an individual experiencing hyperglycemia and/or undesirable fluctuation in blood glucose levels. In some embodiments, provided is a method of regulating blood glucose levels in an individual in need thereof, where the method comprises administering to an individual in need thereof an adrenergic receptor α_2Aantagonist. In some embodiments, administration of an adrenergic receptor α_2Aantagonist reduces the blood glucose levels in an individual (e.g., a hyperglycemic individual). In some embodiments, administration of an adrenergic receptor α_2Aantagonist stabilizes the blood glucose levels in an individual (e.g., an individual experiencing undesirable fluctuations in blood glucose levels). In some embodiments, administration of an adrenergic receptor α_2Aantagonist reduces and stabilizes the blood glucose levels in an individual. In one aspect, the adrenergic receptor α_2Aantagonist also binds to and is an antagonist of one or more of the adrenergic receptors α_2B, α_1Band α_1D. In another aspect, provided is a method of regulating (e.g., reducing and/or stabilizing) blood glucose levels in an individual in need thereof, where the method comprises administering to an individual in need thereof a compound as provided herein, wherein the compound binds to and is an antagonist of the adrenergic receptor α_2Aand wherein the compound either (a) also binds to and is an antagonist of the adrenergic receptor α_2Bor (b) is administered in conjunction with a second agent that reduces, or is expected to reduce, blood pressure in an individual. In some embodiments, the adrenergic receptor α_2Aantagonist described herein may also be an inverse agonist of the adrenergic receptor α_2A.
In some embodiments, provided is a method of reducing blood glucose level in an individual in need thereof, comprises administering to an individual in need thereof an adrenergic receptor α_2Aantagonist, wherein the blood glucose level is reduced to a desirable level. The adrenergic receptor α_2Aantagonist may be administered alone or in combination with other agents such as an agent that reduces blood pressure in the individual. In some embodiments, the blood glucose level is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, or about 70%, provided that the reduction in glucose level does not result in hypoglycemia. In some embodiments, the blood glucose level is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, or at least about 60%, provided that the reduction in glucose level does not result in hypoglycemia. In some embodiments, the blood glucose level is reduced by less than about 10%, between about 10% and about 30%, between about 30% and about 50%, between about 10% and about 50%, between about 50% and about 70%, between about 30% and about 70%, between about 20% and about 40%, between about 40% and about 60%, or between about 20% and about 60%, provided that the reduction in glucose level does not result in hypoglycemia. The reduction of blood glucose level occurs over a period of time after administration of the adrenergic receptor α_2Aantagonist. In some embodiments, the reduction of blood glucose occurs within about 15 minutes after administration of the compound or pharmaceutically acceptable salt thereof. In some embodiments, the reduction of blood glucose occurs within about 30 minutes, within about 1 hour, or within about 2 hours after administration of the adrenergic receptor α_2Aantagonist. In some embodiments, the reduction of blood glucose occurs at about 15 minutes or more, at about 30 minutes or more, at about 1 hour or more, or at about 2 hours or more after administration of the adrenergic receptor α_2Aantagonist. In some embodiments, the method results in a reduction in the individual's blood glucose level by any of the amount described herein for a period of time (e.g., about any one of 0.5, 1, 2, 3, 6, 12, 24 or 48 hours or more) following administration of the compound or pharmaceutically acceptable salt thereof. In some embodiments, the method results in a reduction in the individual's blood glucose level by any of the amount described herein for a period of about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, or about 24 hours or more following administration of the compound or pharmaceutically acceptable salt thereof.
The blood glucose levels in an individual can be measured by methods known in the art, such as by a calorimetric method or by using a device (e.g., a glucose meter). A blood glucose level in the range of about 80 to 120 mg/dL pre-meal and about 100 to 140 mg/dL post-meal is considered desirable in healthy human beings. A blood glucose level at above the desirable level is considered hyperglycemic, such as that in diabetic patients. The blood glucose level in a mildly diabetic human is about 100 to 200 mg/dL. The blood glucose level in a moderately diabetic human is about 200 to 350 mg/dL. The blood glucose level in a severely diabetic human is above 400 mg/dL. A blood glucose level at below the desirable level is considered hypoglycemic, e.g., at below 60 to 80 mg/dL. The blood glucose levels may be measured at a single time point. However, a more accurate measurement requires an average over multiple time points or an area under the curve (AUC) over a period of time (e.g., 2 to 3 hours). The blood glucose level over a past period of about 2˜3 months may be established by measuring the glycosylated hemoglobin (HbA1c) level in the blood. HbA1c is a useful way to monitor a patient's overall response to diabetes treatment over time. The HbA1c in a healthy human being is about 5%. It is desirable for a diabetic patient to keep the HbA1c level below about 7%. Provided is a method of reducing blood glucose level in an individual having an Hb1Ac level of above about 7%, comprises administering to the individual an adrenergic receptor α_2Aantagonist, wherein the Hb1Ac level is reduced to below about 7% following administration of the compound or pharmaceutically acceptable salt thereof. In some embodiments, the adrenergic receptor α_2Aantagonist also binds to and is an antagonist of one or more of the adrenergic receptors α_2B, α_1Band α_1D.
In one aspect, a method of treating metabolic syndrome is provided, where the method comprises administering to an individual in need thereof a compound detailed herein, such as an adrenergic receptor α_2Aantagonist detailed herein. In one aspect, the compound binds to and is an adrenergic receptor α_2Aantagonist. In some embodiments, the adrenergic receptor α_2Aantagonist also binds to and is an antagonist of one or more of the adrenergic receptors α_2B, α_1Band α_1D. In another aspect, a method of treating metabolic syndrome is provided, where the method comprises administering to an individual in need thereof a compound as provided herein, 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_2Bor (b) is administered in conjunction with a second agent that reduces, or is expected to reduce, blood pressure in an individual. The compounds as provided herein may also be used in a method of delaying the onset and/or development of metabolic syndrome, comprising administering a compound as provided herein to an individual who has one or more risk factors associated with developing metabolic syndrome. In a particular variation of the methods relating to metabolic syndrome, the adrenergic receptor α_2Aantagonist is administered to an individual in conjunction with an insulin sensitizer.
As is understood by those of skill in the art, metabolic syndrome is a cluster of conditions, which may include increased blood pressure, excess body fat around the waist, abnormal cholesterol levels and elevated insulin levels due to insulin resistance whereby cells have a diminished ability to respond to insulin and the pancreas compensates by secreting more insulin leading to high insulin levels in blood. According to the American Heart Association and the National Heart, Lung, and Blood Institute, metabolic syndrome is present if an individual has three or more of the following signs: blood pressure equal to or higher than 130/85 mm Hg; fasting blood sugar (glucose) equal to or higher than 100 mg/dL; large waist circumference, which for men is 40 inches or more and for women is 35 inches or more; low HDL cholesterol, which for men is under 40 mg/dL and for women is under 50 mg/dL; and triglycerides equal to or higher than 150 mg/dL.
Treatment of metabolic syndrome requires a careful and well-balanced approach to account for both treatment of elevated insulin levels and high blood pressure. Thus, it is desirable in the context of treating metabolic syndrome that a compound that is an antagonist of the adrenergic receptor α_2Ais also an antagonist of the adrenergic receptor α_2Band/or α_1Band/or α_1Dto reduce blood pressure. Alternatively, an adrenergic receptor α_2Aantagonist that does not also antagonize the adrenergic receptor α_2Band/or α_1Bmay be administered in conjunction with a second agent that reduces, or is expected to reduce blood pressure in an individual. In one aspect, provided is a method of regulating (e.g., reducing and/or stabilizing) blood glucose levels and reducing the blood pressure in an individual in need thereof (e.g., an individual experiencing metabolic syndrome, or an individual with hypertension who is also suffering from obesity and/or type 2 diabetes), where the method comprises administering to an individual in need thereof an adrenergic receptor α_2Aantagonist. In one aspect, the adrenergic receptor α_2Aantagonist also binds to and is an antagonist of one or more of the adrenergic receptors α_2B, α_1Band α_1D. In another aspect, provided a method of regulating (e.g., reducing and/or stabilizing) blood glucose levels and reducing the blood pressure in an individual in need thereof, where the method comprises administering to an individual in need thereof a compound as provided herein, 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_2Bor (b) is administered in conjunction with a second agent that reduces, or is expected to reduce, blood pressure in an individual. In some embodiments, the compound is an antagonist and an inverse agonist of the adrenergic receptor α_2A.
Risk factors associated with developing metabolic syndrome include: more than one parent or sibling who has type 2 diabetes, individuals with high blood pressure and/or cardiovascular disease; individuals who are obese or overweight (e.g., individual
s having a body mass index above 25); individuals who have more fat around their waist than around their hips (an apple shape); age greater than 40 years (although it is understood that children and young adults, particularly those who are overweight and/or sedentary, may also be at risk for developing metabolic syndrome); a woman who had gestational diabetes when pregnant or who has a history of polycystic ovary syndrome (PCOS); individuals who are pre-diabetic and individuals of Latino, Black, Asian or Native American ethnicity.
Further provided herein are methods of determining if an individual suffering from glucose intolerance (e.g., an individual testing negative in a glucose tolerance test) has (i) reduced or impaired insulin secretion or (ii) has reduced or impaired responsiveness to insulin, the method comprising administering a compound provided herein to the individual and testing the individual in a glucose tolerance test, wherein an increase in insulin levels after glucose challenge (the glucose tolerance test) indicates that the individual has reduced or impaired insulin secretion; or wherein insufficient increases in insulin levels indicates that the individual has reduced or impaired responsiveness to insulin.
Provided herein are methods of assessing whether an individual is likely to be responsive to a compound that promotes an increase in insulin secretion and/or release (e.g., an adrenergic receptor α_2Aantagonist, or pharmaceutically acceptable salt thereof), administered either alone or in conjunction with an insulin sensitizer. In one aspect of such a method, an individual who has failed a glucose tolerance test (e.g., an individual whose glucose levels do not return to normal levels following glucose challenge and/or whose insulin levels are not sufficiently elevated in response to administration of glucose, as measured by methods and as assessed by standards known in the art), is administered glucose following administration of an adrenergic receptor α_2Aantagonist, or pharmaceutically acceptable salt thereof, and their insulin levels are then assessed. In one embodiment of such methods, the adrenergic receptor α_2Aantagonist is administered to the individual about any one of 5, 10, 15, 30 and 60 minutes or more or between about 5 and about 15 or between about 5 and about 30 or between about 5 and about 60 or between about 15 and about 30 or between about 30 and about 60 minutes prior to administration of glucose. If such an individual, after administration of glucose and an adrenergic receptor α_2Aantagonist, or pharmaceutically acceptable salt thereof, exhibits an increase in insulin levels, the individual may be an individual who is responsive to a compound that promotes an increase in insulin secretion and/or release (e.g., an adrenergic receptor α_2Aantagonist, or pharmaceutically acceptable salt thereof). If such an individual exhibits an increase in insulin levels, but the individual's glucose levels do not decrease, then the individual may be an individual who is responsive to a compound that can increase insulin secretion and/or release (including but not limited to an adrenergic receptor α_2Aantagonist, or pharmaceutically acceptance salt thereof), used in conjunction with an insulin sensitizer. Sufficient levels
insulin increase and/or glucose decrease are known by those of skill in the art. Thus, a method of assessing whether an individual suffering from glucose intolerance (e.g., an individual who has failed (e.g., within the last 6 months, 3 months, 1 month, 2 weeks or 1 week) a glucose tolerance test administered in the absence of an adrenergic receptor α_2Aantagonist) is more likely to be responsive or less likely to be responsive to a therapy that can increase insulin secretion and/or release (including but not limited to an adrenergic receptor α_2Aantagonist, or pharmaceutically acceptable salt thereof), is provided, the method comprising administering an adrenergic receptor α_2Aantagonist, or pharmaceutically acceptable salt thereof, to the individual and testing the individual in a glucose tolerance test, wherein an increase in insulin levels after glucose challenge (the glucose tolerance test) indicates that the individual is more likely to be responsive to said therapy, and wherein a reduced or insignificant or no increase in insulin levels indicates that the individual is less likely to be responsive to said therapy.
Also provided herein are methods of selecting an individual suffering from glucose intolerance (e.g., an individual who has failed a glucose tolerance test) for a therapy comprising a compound which increases insulin secretion and/or release (e.g. an adrenergic receptor α_2Aantagonist) based on the levels of insulin and/or glucose of the individual following a glucose tolerance test in which the individual is administered an adrenergic receptor α_2Aantagonist prior to glucose challenge, wherein an increase in insulin levels after glucose challenge and/or failure of the individual's glucose levels to return to normal selects the individual for said therapy. Thus, a method of selecting an individual for therapy comprising a compound that increases insulin secretion and/or release is provided (e.g., an adrenergic receptor α_2Aantagonist), the method comprising the steps of (i) administering an adrenergic receptor α_2Aantagonist to an individual who has failed (e.g., within the last 6 months, 3 months, 1 month, 2 weeks or 1 week) a glucose tolerance test administered in the absence of an adrenergic receptor α_2Aantagonist; (2) administering a glucose tolerance test in which glucose is administered after the administration of the adrenergic receptor α_2Aantagonist; and (3) correlating the results of the glucose tolerance test administered in conjunction with the administration of the adrenergic receptor α_2Aantagonist to the individual (e.g., where glucose is administered about any one of 5, 15, 30, 60 or more minutes following administration of the adrenergic receptor α_2Aantagonist) with whether the individual is more or less likely to be responsive to an adrenergic receptor α_2Aantagonist, either alone, or in conjunction with an insulin sensitizer; and (4) selecting an individual who is more likely to be responsive to a compound that increases insulin secretion and/or release (e.g., an adrenergic receptor α_2Aantagonist for adrenergic receptor α_2Aantagonist therapy). An individual so selected may then be administered a compound that increases insulin secretion and/or release (e.g., an adrenergic receptor α_2Aantagonist for adrenergic receptor α_2Aantagonist therapy). In one aspect, the individual is selected for therapy if their insulin levels increase in response to the glucose tolerance test administered in conjunction with the administration of the adrenergic receptor α_2Aantagonist. If such an individual also exhibits a normal reduction in glucose levels, the individual may be selected for monotherapy with a compound that increases insulin secretion and/or release (e.g., an adrenergic receptor α_2Aantagonist). However, if such an individual does not exhibit a normal reduction in glucose levels, the individual may be selected for therapy with a compound that increases insulin secretion and/or release (e.g., an adrenergic receptor α_2Aantagonist) in conjunction with an insulin sensitizer. Individuals so selected may then be administered a compound that increases insulin secretion and/or release (e.g., an adrenergic receptor α_2Aantagonist), either alone or in conjunction with an insulin sensitizer. Methods of monitoring the treatment of an individual for glucose intolerance are also provided.
Also provided herein are methods of treating an individual suffering from a disease or condition which is, or is expected to be, responsive to an increase in insulin secretion and/or release, the method comprising (i) determining insulin levels of an individual in a glucose tolerance test after administration of an adrenergic receptor α_2Aantagonist and (ii) administering a compound that increases insulin secretion and/or release (e.g., an adrenergic receptor α_2Aantagonist) to an individual having an increase in insulin levels after the glucose tolerance test. In one aspect of such a method, the individual has failed (e.g., recently failed) a glucose tolerance test administered in the absence of an adrenergic receptor α_2Aantagonist and the individual's insulin levels increase in response to a glucose tolerance test which employed administration of glucose and an adrenergic receptor α_2Aantagonist.
In any of the methods employing a glucose tolerance test in conjunction with an adrenergic receptor α_2Aantagonist, in one variation, if the individual's insulin does not increase in response to a glucose challenge in conjunction with an adrenergic receptor α_2Aantagonist, the individual may have type 2 diabetes with a defect in insulin secretion. Therefore, also provided are methods of identifying individuals who may have type 2 diabetes with a defect in insulin secretion.
Some genetic polymorphisms of the adrenergic receptor α_2Agene associate with high blood glucose and can be used to screen for patients who respond to an adrenergic receptor α_2Aantagonist with an increase in insulin secretion and a decrease in blood glucose. For example the DNA polymorphism Rs553668 located in the 3′ UTR region of adrenergic receptor α_2Aassociates with overexpression of the adrenergic receptor α_2A, reduced insulin secretion, and increased type 2 diabetes risk (Rosengren et al., Science 327:217 (2010) and Talmud et al., Diabetologia 54:1710 (2011)). Human pancreatic islets from Rs553668 allele carriers exhibited reduced granule docking and secreted less insulin in response to glucose. Individuals with elevated blood glucose would be screened for the polymorphism. Individuals heterozygous or homozygous for this polymorphism would be anticipated to respond to treatment with an adrenergic receptor α_2Aantagonist. Other DNA polymorphisms may also be used to identify individuals with elevated blood sugar that would respond to an adrenergic receptor α_2Aantagonist; for example Rs7911129, Rs1971596, Rs602618, and Rs2203616. Thus provided herein is a method of selecting an individual for therapy comprising a compound that (i) increases insulin secretion and/or release, and/or (ii) regulates blood glucose (e.g., an adrenergic receptor α_2Aantagonist), the method comprising screening the individual for polymorphisms of the adrenergic receptor α_2Agene associate with high blood glucose, such as one or more of the DNA polymorphisms Rs553668, Rs7911129, Rs1971596, Rs602618 and Rs2203616.
Also provided is a method of regulating (e.g., reducing and/or stabilizing) blood glucose levels in an individual, the method comprises the steps of (i) screening the individual for genetic polymorphisms of the adrenergic receptor α_2Agene associate with high blood glucose; and (ii) administering to the individual carrying one or more genetic polymorphisms of the adrenergic receptor α_2Agene associated with high blood glucose an adrenergic receptor α_2Aantagonist. In one variation, provided is a method of increasing insulin seretion and/or release into the blood stream in an individual, the method comprises the steps of (i) screening the individual for genetic polymorphisms of the adrenergic receptor α_2Agene associate with high blood glucose; and (ii) administering to the individual carrying one or more genetic polymorphisms of the adrenergic receptor α_2Agene associated with high blood glucose an adrenergic receptor α_2Aantagonist. Further provided are methods of treating type 2 diabetes, glucose intolerance and/or metabolic syndrome, where the method comprises administering to an individual in need thereof an adrenergic receptor α_2Aantagonist, wherein the individual carries one or more genetic polymorphisms of the adrenergic receptor α_2Agene associated with high blood glucose, such as one or more of the DNA polymorphisms Rs553668, Rs7911129, Rs1971596, Rs602618 and Rs2203616. In some embodiments, the adrenergic receptor α_2Aantagonist also binds to and is an antagonist of one or more of the adrenergic receptors α_2B, α_1Band α_1D. In some embodiments, the adrenergic receptor α_2Aantagonist also binds to and is an antagonist of the adrenergic receptors α_2B. In some embodiments, the method of regulating blood glucose levels, increasing insulin seretion and/or release into the blood stream, or treating type 2 diabetes, glucose intolerance and/or metabolic syndrome, further comprises administering to the individual a second agent that reduces, or is expected to reduce, blood pressure in an individual.
Compounds described herein showing adrenergic receptors α_2Aand adrenergic receptor α_2Bantagonist activity may find particular use in patients with fatty liver or/and obesity or/and hypertension with type-2 diabetes associated with glucose intolerance; and super-added with polymorphisms in the adrenergic receptor α_2Agene.

Cell Viability and Mitochondrial Health

Methods of promoting cellular viability by promoting mitochondrial health are provided, the methods comprising contacting the cell with a compound detailed herein. The methods are applicable to various cells, such as neuronal and non-neuronal cells. In one variation, the cell is a non-neuronal cell, such as a renal or cardiac cell (e.g., myocardial muscle cell). In one aspect, methods of promoting cellular viability are provided wherein the cell is one whose viability would be, or would be expected to be, promoted by nutrient influx and/or oxygenation. Methods of promoting cellular viability in a cell experiencing, or exhibiting symptoms of, mitochondrial stress are also provided.
Methods of treating a disease or condition that is, or is expected to be, responsive to promoting mitochondrial health and cell viability are also described, the methods comprising administering to an individual in need thereof an effective amount of a compound provided herein. In one variation, the disease or condition is one which is associated with dysfunction of mitochondria in a non-neuronal cell. In a particular variation, the disease or condition is one which is associated with dysfunction of mitochondria in a renal or cardiac cell (e.g., myocardial muscle cell). In another variation, the disease or condition is one which would benefit from cellular (e.g., renal or cardiac) nutrient influx and/or oxygenation.
Thus, individuals who have a disease or condition that is associated with, or believed to be associated with, mitochondrial dysfunction may benefit from the compounds detailed herein, or pharmaceutically acceptable salts thereof. An individual who has a disease or condition that is associated with mitochondrial dysfunction should experience one or more beneficial or desirable results upon administration of an effective amount of a compound provided herein, or pharmaceutically acceptable salt thereof. In one aspect, the beneficial or desirable result is an increase in nutrient influx and/or oxygenation of a cell. In another aspect, the beneficial or desirable result is a reduction in the number and/or severity of symptoms associated with a disease or condition that is associated with mitochondrial dysfunction.
In one variation, a method of treating a renal or cardiac condition is provided, comprising administering to an individual in need thereof a compound as detailed herein. Such conditions include, but are not limited to, renal failure, such as acute renal failure and chronic renal failure, coronary (e.g., myocardial) ischemia, heart failure, such as acute and chronic congestive heart failure (including the muscle fatigue associated with these conditions), and coronary artery disease. Methods of treating other diseases and conditions are also described, such as methods of treating sleep apnea, acute respiratory distress syndrome (adult and infant) and peripheral vascular disease. The compounds as provided herein may also be used in a method of delaying the onset and/or development of a disease or condition associated with mitochondrial dysfunction, comprising administering a compound as provided herein, or a pharmaceutical salt thereof, to an individual who is at risk of developing a disease or condition associated with mitochondrial dysfunction.
Compounds that do not bind appreciably to neurotransmitter receptors but nevertheless enhance mitochondrial function, e.g., when administered to cells in the setting of mitochondrial stress (e.g., excess intracellular calcium), may be used in the methods herein to promote cell survival. In one aspect, the compounds exhibit the ability to enhance mitochondrial function by protecting against cell death mediated by mitochondrial dysfunction in an assay detailed herein. Thus, it is understood and clearly conveyed that enhancing mitochondrial function includes protecting a cell against cell death mediated by mitochondrial dysfunction. The compounds may also be assessed in assays known in the art.
It is understood and clearly conveyed that the binding and activity profiles detailed herein (e.g., in the disclosure above) in one variation apply to the formulae provided herein (e.g., the formulae for use in the methods). In one aspect, selective adrenergic receptor α_2Bantagonists are of the formula (I) or any variations detailed herein.

Compounds of the Invention

Compounds according to the invention are detailed herein, including in the Brief Summary of the Invention and elsewhere. The invention includes the use of all of the compounds described herein, including any and all stereoisomers, including geometric isomers (cis/trans or E/Z isomers), tautomers, salts and solvates of the compounds described herein, as well as methods of making such compounds.
In one aspect, compounds of the formula (IA) are provided:
or a salt or solvate thereof; wherein:
R¹is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹and R^2aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹and R^3aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹and R^4aare taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;
each R^2aand R^2bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^2aand R^2bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^2aand R¹are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^2aand R^3aare taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^2aand R^4aare taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;
each R^3aand R^3bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^3aand R^3bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^3aand R¹are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^3aand R^2aare taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^3aand R^4aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;
each R^4aand R^4bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^4aand R^4bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^4aand R¹are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^4aand R^2aare taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^4aand R^3aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;
each X¹, X², X³and X⁴is independently N, CH or CR⁶;
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; and
each R⁶is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, 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.
In one variation, compounds of the formula (IA) are provided:
or a salt or solvate thereof; wherein:
R¹is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹and R^2aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹and R^3aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹and R^4aare taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;
each R^2aand R^2bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^2aand R^2bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^2aand R¹are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^2aand R^3aare taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^2aand R^4aare taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;
each R^3aand R^3bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^3aand R^3bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^3aand R¹are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R
and R
are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^3aand R^4aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;
each R^4aand R^4bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^4aand R^4bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^4aand R¹are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^4aand R^2aare taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^4aand R^3aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;
each X¹, X², X³and X⁴is independently N, CH or CR⁶;
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; and
each R⁶is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, 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.
In one variation, compounds of the formula (IA), and salts and solvates thereof, are embraced, provided that at least one of X¹, X², X³and X⁴is CH or CR⁶. In another variation, at least two of X¹, X², X³and X⁴is CH or CR⁶.
In one variation, compounds of the formula (IA), and salts and solvates thereof, are embraced, provided that one or more of provisions (i)-(xiii) apply:

- (i) when Q is an unsubstituted aryl, the aryl group is other than phenyl;
- (ii) when Q is a mono-substituted aryl wherein the aryl group is phenyl, the phenyl group substituent is other than halo, nitro, methoxy, —NH₂, CF₃and methyl;
- (iii) when Q is a halo-substituted aryl wherein the aryl group is phenyl, the halo-substituted phenyl is not also substituted with a deuterium atom;
- (iv) when none of R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R_4bare taken together to form a ring and Q is a di-substituted phenyl wherein one of the phenyl substituents is bound to the ortho-position of the phenyl moiety via a nitrogen atom, then one or more
  provisions (a)-(d) apply: (a) the phenyl moiety is not substituted win a chloro group; (b) the phenyl group is unsubstituted at the para position; (c) when X²is CR⁶, then R⁶is other than an unsubstituted C₁-C₈alkyl; (c) R¹is other than an unsubstituted C₁-C₈alkyl; and (d) the substituent bound to the ortho-position of the phenyl moiety via a nitrogen atom is other than an unsubstituted or substituted amino, —NO₂or —NHOH moiety;
- (v) when none of R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare taken together to form a ring and Q is a di-substituted phenyl containing an ortho-chloro moiety and either a para-acylamino or a para-aminocarbonylamino moiety, then one or more of provisions (a)-(c) apply: (a) R^2aand R^2bare each H; (b) R¹is other than an unsubstituted C₁-C₈alkyl; and (c) at least one of X¹, X², X³and X⁴is N or CR⁶;
- (vi) when none of R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare taken together to form a ring and Q is a mono-substituted phenyl wherein the substituent is bound to the meta-position of the phenyl moiety, then one or more of provisions (a)-(c) apply: (a) at least one of X¹, X², X³and X⁴is N or CR⁶; (b) the substituent is bound to the phenyl moiety via an atom other than nitrogen; and (c) the substituent is other than a substituted amino moiety;
- (vii) when none of R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare taken together to form a ring and Q is a mono-substituted phenyl wherein the substituent is bound to the para-position of the phenyl moiety, then one or more of provisions (a)-(d) apply: (a) the substituent is bound to phenyl by an atom other than nitrogen or oxygen; (b) the substituent is other than an unsubstituted or substituted amino, —NO₂and —OCH₃; (c) either each of X¹, X², X³and X⁴is CH or at least two of X¹, X², X³and X⁴are selected from N and CR⁶; and (d) R¹is other than an unsubstituted C₁-C₈alkyl;
- (viii) when none of R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare taken together to form a ring and Q is an unsubstituted heteroaryl, then any one or more of provisions (a)-(e) apply: (a) at least one of X¹, X², X³and X⁴is N or CR⁶; (b) Q is other than 2-pyridyl; (c) the heteroaryl moiety contains at least two annular nitrogen atoms; (d) the heteroaryl moiety contains an annular sulfur atom; and (e) the heteroaryl moiety contains an annular oxygen atom;
- (ix) when none of R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare taken together to form a ring and Q is a substituted cycloalkyl, then any one or more of provisions (a)-(g) apply: (a) at least two of X¹, X², X³and X⁴are N or CR⁶; (b) X²is CH; (c) the substituted cycloalkyl moiety is not substituted with a hydroxyl group; (d) the substituted cycloalkyl group is substituted with more than one substituent, which may be the same or different; (e) the substituted cycloalkyl is a 3, 4 or 5-membered cycloalkyl moiety; (f) the substituted cycloalkyl is a 7, 8, 9 or 10-membered cycloalkyl moiety; and (g) at least one of R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bis other than H;
- (x) when none of R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare taken together to form a ring and Q is an unsubstituted cycloalkyl then at least one of X¹, X², X³and X⁴is N or CR⁶;
- (xi) Q is other than a substituted or unsubstituted C₃-C₈cycloalkyl; a substituted or unsubstituted heterocyclyl moiety; and a substituted or unsubstituted C₃-C₈cycloalkenyl moiety
- (xii) when none of R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare taken together to form a ring and Q is a substituted heterocyclyl wherein the heterocyclyl is a 6-membered heterocyclyl group, then one or more of provisions (a)-(d) apply: (a) at least one of X¹, X², X³and X⁴is N or CR⁶; (b) the 6-membered heterocyclyl group is a mono-substituted 6-membered heterocyclyl group; (c) the 6-membered heterocyclyl group contains at least one annular sulfur or oxygen atom; and (d) the 6-membered heterocyclyl group contains at least annular nitrogen atoms; and
- (xiii) when Q is a substituted heterocyclyl wherein the heterocyclyl is a 5-membered heterocyclyl group, then one or more of provisions (a)-(e) apply: (a) at least two of X¹, X², X³and X⁴are N or CR⁶; (b) the 5-membered heterocyclyl group is a mono-substituted heterocyclyl group; (c) the 5-membered heterocyclyl group contains at least one annular sulfur or oxygen atom; (d) the 5-membered heterocyclyl group contains at least two annular nitrogen atoms; and (e) the 5-membered heterocyclyl group is not substituted with a carboxy group.

In some variations, provided are compounds of the formula (IA), where R¹, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, X¹, X², X³and X⁴are as defined for formula (IA), and 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. In some of these variations, one or more of provisions (i)-(xiii) apply.
In some variations, provided are compounds of the formula (IA), where R¹, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, X¹, X², X³and X⁴are as defined for formula (IA), and Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, 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, provided that:
(xiv) when Q is substituted cycloalkenyl, any annular carbon atom of the cycloalkenyl which is adjacent to the carbon to which the parent structure is attached is not substituted with any substituent selected from the group consisting of substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted cycloalkenyl, unsubstituted cycloalkenyl, substituted heterocyclyl, unsubstituted heterocyclyl, alkoxy, acyloxy, substituted amino, unsubstituted amino, aminoacyl, aminocarbonylalkoxy, cyano, alkynyl, carboxy, carbonylalkoxy and acylamino; and
(xv) when Q is substituted heterocyclyl and the substituted heterocyclyl is attached to the parent structure at a annular carbon atom, then (a) Q is other than substituted or unsubstituted lactam; and (b) any annular carbon atom of the heterocyclyl which is adjacent to the carbon to which the parent structure is attached is not substituted with any substituent selected from the group consisting of substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted cycloalkenyl, unsubstituted cycloalkenyl, substituted heterocyclyl, unsubstituted heterocyclyl, alkoxy, acyloxy, substituted amino, unsubstituted amino, aminoacyl, aminocarbonylalkoxy, cyano, alkynyl, carboxy, carbonylalkoxy and acylamino.
In some of these variations, one or more of provisions (i)-(xiii) further apply.
In one variation, compounds of the formula (IA), and salts and solvates thereof, are embraced, where R¹, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, X¹, X², X³, and X⁴are as defined for formula (IA), and 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, provided that:
(1) at least one of X¹, X², X³and X⁴is CH or CR⁶;
(2) when each X¹, X², X³and X⁴is independently CH or CR⁶, none of R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare 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 X¹, X², X³and X⁴is independently CH or CR⁶, none of R¹, R_2a, R^2b, R^3a, R^3b, R^4aand R^4bare 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 X¹, X², X³and X⁴is independently CH or CR⁶, and R^2aand R^3aare taken together to form an ethylene (—CH2CH2-) 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.
In another variation, provided is a compound of the formula (IA), provided that each of provisions (i)-(xi) applies. In another variation, the compound is of the formula (IA), provided that each of provisions (i)-(x), (xii) and (xiii) applies. In yet another variation, the compound is of the formula (IA), provided that each of provisions (i)-(xiii) applies.
In another aspect of the invention, compounds of the formula (IB) are provided:
or a salt or solvate thereof; wherein:
R¹is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹and R^2aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹and R^3aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹and R^4aare taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;
each R^2aand R^2bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^2aand R^2bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^2aand R¹are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^2aand R^3aare taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^2aand R^4aare taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;
each R^3aand R^3bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^3aand R^3bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^3aand R¹are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^3aand R^2aare taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^3aand R^4aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;
each R^4aand R^4bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^4aand R^4bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^4aand R¹are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^4aand R^2aare taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^4aand R^3aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;
each X¹, X², X³and X⁴is independently N, CH or CR⁶;
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl; and
each R⁶is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, 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.
In one variation, compounds of the formula (IB) are provided:
or a salt or solvate thereof; wherein:
R¹is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹and R^2aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹and R^3aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹and R^4aare taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;
each R^2aand R^2bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^2aand R^2bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^2aand R¹are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^2aand R^3aare taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^2aand R^4aare taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;
each R^3aand R^3bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^3aand R^3bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^3aand R¹are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^3aand R^2aare taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^3aand R^4aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;
each R^4aand R^4bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^4aand R^4bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^4aand R¹are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^4aand R^2aare taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^4aand R^3aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;
each X¹, X², X³and X⁴is independently N, CH or CR⁶;
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl; and
each R⁶is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, 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.
In one variation, compounds of the formula (IB), and salts and solvates thereof, are embraced, provided that at least one of X¹, X², X³and X⁴is CH or CR⁶. In another variation, at least two of X¹, X², X³and X⁴is CH or CR⁶.
In one variation, compounds of the formula (IB), and salts and solvates thereof, are embraced, provided that on or more of provisions (xxi)-(xxix) apply:

- (xxi) when Q is an unsubstituted aryl, the aryl group is other than phenyl;
- (xxii) when Q is a mono-substituted aryl wherein the aryl group is phenyl, the phenyl group is substituted with a moiety other than halo and —C(═NH)NH₂;
- (xxiii) when Q is a substituted aryl wherein the aryl group is a phenyl substituted with two or more substituents which may be the same or different, then at least one of provisions (a)-(c) applies: (a) the phenyl group is substituted with at least one moiety other than methyl; (b) at least one of X¹, X², X³and X⁴is N or CR⁶; and (c) none of R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare taken together to form a ring;
- (xxiv) when none of R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R_4bare taken together to form a ring and Q is a mono-substituted phenyl wherein the substituent is bound to the para-position of the phenyl moiety, then one or both of provisions (a) and (b) apply: (a) least one of X¹, X², X³and X⁴is N or CR⁶; and (b) the phenyl substituent is other than —OCH₃and a substituted pyridyl;
- (xxv) when none of R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare taken together to form a ring and Q is a substituted aryl other than phenyl, then one or both of provisions (a) and (b) apply: (a) least one of X¹, X², X³and X⁴is N or CR⁶; and (b) R¹is a substituted or unsubstituted C₁-C₈alkyl;
- (xxvi) when Q is an unsubstituted cycloalkyl, then at least one of provisions (a)-(c) applies: (a) at least one of X¹, X², X³and X⁴is CR⁶; (b) none of R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare taken together to form a ring; and (c) the unsubstituted cycloalkyl has greater than 3 annular carbon atoms;
- (xxvii) when Q is a substituted heterocyclyl wherein the heterocyclyl group is a 6-membered heterocyclyl, then at least one of provisions (a)-(d) applies: (a) at least one of X¹, X², X³and X⁴is CR⁶; (b) R¹is a substituted or unsubstituted C₁-C₈alkyl; (c) the substituted heterocyclyl group contains an annular sulfur atom; and (d) the substituted heterocyclyl group contains at least two annular heteroatoms;
- (xxviii) when Q is a substituted heterocyclyl wherein the heterocyclyl group is a 5-membered heterocyclyl then at least one of provisions (a)-(c) applies: (a) at least one of X¹, X², X³and X⁴is CR⁶; (b) the substituted heterocyclyl group does not contain a carboxyl moiety; and (c) the substituted heterocyclyl group is substituted with more than one substituents, which may be the same or different;
- (xxix) when none of R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare taken together to form a ring and Q is an unsubstituted heterocyclyl then one or more of provisions (a)-(d) apply: (a) (a) at least two of X¹, X², X³and X⁴are N or CR⁶; (b) the heterocyclyl group contains an annular nitrogen or sulfur atom; (c) the heterocyclyl group is a 3, 4 or 5-membered heterocyclyl group; and (d) the heterocyclyl group is a 7 or 8 membered heterocyclic group.

In some variations, provided are compounds of the formula (IB), where R¹, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, X¹, X², X³and X⁴are as defined for formula (IB), and 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. In some of these variations, one or more of provisions (xxi)-(xxix) apply.
In some variations, provided are compounds of the formula (IB), where R¹, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, X¹, X², X³and X⁴are as defined for formula (IB), and Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, 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, provided that:

- (xxx) when Q is substituted cycloalkenyl, any annular carbon atom of the cycloalkenyl which is adjacent to the carbon to which the parent structure is attached is not substituted with any substituent selected from the group consisting of substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted cycloalkenyl, unsubstituted cycloalkenyl, substituted heterocyclyl, unsubstituted heterocyclyl, alkoxy, acyloxy, substituted amino, unsubstituted amino, aminoacyl, aminocarbonylalkoxy, cyano, alkynyl, carboxy, carbonylalkoxy and acylamino; and
- (xxxi) when Q is substituted heterocyclyl and the substituted heterocyclyl is attached to the parent structure at a annular carbon atom, then (a) Q is other than substituted or unsubstituted lactam; and (b) any annular carbon atom of the heterocyclyl which is adjacent to the carbon to which the parent structure is attached is not substituted with any substituent selected from the group consisting of substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted cycloalkenyl, unsubstituted cycloalkenyl, substituted heterocyclyl, unsubstituted heterocyclyl, alkoxy, acyloxy, substituted amino, unsubstituted amino, aminoacyl, aminocarbonylalkoxy, cyano, alkynyl, carboxy, carbonylalkoxy and acylamino.

In some of these variations, one or more of provisions (xxi)-(xxix) further apply.
In one variation, compounds of the formula (IB), and salts and solvates thereof, are embraced, where R¹, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, X¹, X², X³and X⁴are as defined for formula (IB), and 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, provided that:
(1) at least one of X¹, X², X³and X⁴is CR⁶;
(2) when none of X¹, X²and X³is N, and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare taken together to form a ring, then Q is other than a unsubstituted phenyl;
(3) when none of X¹, X², X³and X⁴is N, and R^2aand R^4bare 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 X¹, X³and X⁴is CH, X²is CR⁶where R⁶is fluoro, and each R^2a, R^2b, R^3a, R^3b, R
and R
is H, then Q is other than 4-fluorophenyl.
When Q is an unsubstituted or substituted heteroaryl, in one variation it is a heteroaryl containing an annular nitrogen atom. In one aspect, when Q is an unsubstituted or substituted heteroaryl the heteroaryl contains only nitrogen and carbon annular atoms. In a particular variation, Q is an unsubstituted pyridyl that may be bound to the parent structure at any available ring position. For example, in one variation of formula (IA) or (IB), Q is 4-pyridyl, 3-pyridyl or 2-pyridyl. When Q is a substituted heteroaryl in one aspect it is a substituted pyridyl. When Q is a substituted pyridyl, the pyridyl may be substituted with one or more than one substituent and the substituted pyridyl may be bound to the parent structure at any available ring position. For example, in one variation of formula (IA) or (IB), Q is a mono-substituted pyridyl where the substituent is a C₁-C₈unsubstituted alkyl (e.g., methyl).
In another variation, the compound is of formula (IA) or (IB) where Q is a di- or tri-substituted aryl, substituted heteroaryl, or substituted or unsubstituted heterocyclyl. In one aspect, the compound is of formula (IA) or (IB) where Q is a di- or tri-substituted aryl. When Q is a di- or tri-substituted aryl, the substituents may be the same or different and may be located at any available position on the aryl ring. In one aspect, Q is a di- or tri-substituted phenyl (e.g., 4-methoxy-3-fluorophenyl, 3,4-di-fluorophenyl, 4-chloro-3-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl and 2,4,6-trifluorophenyl). In another aspect, Q is a phenyl substituted with at least one chloro or methyl group (e.g., 4-chlorophenyl and 4-methylphenyl). In yet another aspect, the compound is of formula (IA) or (IB) where Q is a substituted heteroaryl (e.g., where Q is 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, 5-trifluoromethyl-3-pyridyl or pyrimidinyl). In one aspect, Q is a substituted pyridyl such as 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl and 5-trifluoromethyl-3-pyridyl.
In some variations, the compound is of formula (IA) or (IB) where Q is a di- or tri-substituted aryl, substituted heteroaryl, or substituted or unsubstituted heterocyclyl, wherein each substituent is independently selected from the group consisting of hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₁-C₈alkoxy, C₁-C₈perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, 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, and sulfonylamino. In some of these variations, at least one of the substituent is 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.
In one variation, the compound is of formula (IA) or (IB) where at least one of X¹, X², X³and X⁴is N. In another variation, one of X¹, X²and X³is N. In one variation, X¹is N and each X², X³and X⁴is independently CH or CR⁶. In another variation, X²is N and each X¹, X³and X⁴is independently CH or CR⁶. In yet another variation, X³is N and each X¹, X²and X⁴is independently CH or CR⁶. In yet another variation, X⁴is N and each X¹, X²and X³is independently CH or CR⁶. In another variation, two of X¹, X², X³and X⁴is N. In one variation, each X¹and X³is N, and X²and X⁴is independently CH or CR⁶. In another variation, each X²and X⁴is N, and X¹and X³is independently CH or CR⁶. In another variation, each X¹and X⁴is N, and X²and X³is independently CH or CR⁶.
In one variation, the compound is of formula (IA) or (IB) where at least one of X¹-X⁴is CR⁶where R⁶is chloro. In such variation, X²is CR⁶where R⁶is chloro. In another variation, X²is CR⁶where R⁶is chloro, and X¹and X⁴are each CH. In one aspect, the compound is of formula (IA) or (IB) where at least one of X¹-X⁴is CR⁶where R⁶is chloro (e.g., when X²is CR⁶where R⁶is chloro) and Q is an unsubstituted aryl (e.g., phenyl), a substituted aryl (e.g., 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3,4-difluorophenyl, 4-chloro-3-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2,4,5-trifluorophenyl and 2,4-dichlorophenyl), an unsubstituted heteroaryl (e.g., 3-pyridyl and 4-pyridyl) or a substituted heteroaryl (e.g., 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl and 5-trifluoromethyl-3-pyridyl). In a particular variation, X²is CR⁶where R⁶is chloro, X¹, X³and X⁴are each CH, R¹is methyl or cyclopropyl and Q is an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl or a substituted heteroaryl.
In specific variations, compounds of formula (IA) have the structure:
or a salt or solvate thereof; wherein R¹, X¹, X², X³, X⁴and Q are defined as for formula (IA) and, where applicable, any variation thereof detailed herein. That is, variations of formula (IA) detailed throughout, where applicable, apply equally to any of formulae (IA1)-(IA3), the same as if each and every variation were specifically and individually listed for formula (IA1)-(IA3). Pharmaceutically acceptable salts of compounds of formulae (IA1)-(IA3) are also provided.
In one variation of formula (IA2), X²is CH or CR⁶where R⁶is halo or substituted or unsubstituted C₁-C₈alkyl. In a particular variation of formula (IA2), X²is CR⁶where R⁶is halo (e.g., chloro). In another particular variation of formula (IA2), X²is CR⁶where R⁶is unsubstituted C₁-C₈alkyl (e.g., methyl). In a particular variation of formula (IA2), X²is CH. In further variations of formula (IA2), Q is a substituted or unsubstituted heteroaryl. In one variation, Q is an unsubstituted heteroaryl (e.g., 4-pyridyl or 4-pyrimidyl). In still further variations of formula (IA2), X²is CH or CR⁶where R⁶is halo or substituted or unsubstituted C₁-C₈alkyl and Q is a substituted or unsubstituted heteroaryl. In one aspect of formula (IA2), X²is CR⁶where R⁶is a C₁-C₈alkyl (e.g., methyl) and Q is a substituted or unsubstituted heteroaryl.
In another aspect of formula (IA2), X²is CR⁶where R⁶is halo (e.g., chloro) and Q is a substituted or unsubstituted heteroaryl. In another aspect of formula (IA2), X²is CH and Q is a substituted or unsubstituted heteroaryl. In a further aspect of formula (IA2), X²is CH or CR⁶where R⁶is methyl or chloro and Q is 4-pyridyl.
In one variation, compounds of the formula (IA3) are provided, or a salt or solvate thereof, where R¹is a substituted or unsubstituted C₁-C₈alkyl; R⁶is H, halo, trifluoromethyl, a C₁-C₈unsubstituted alkyl or a substituted amino; and Q is substituted aryl or a substituted or unsubstituted heteroaryl. In one variation of formula (IA3), R¹is an unsubstituted C₁-C₈alkyl or a C₁-C₈alkyl substituted with a halo or hydroxyl group. In one such variation, R¹is methyl, 2-haloethyl (e.g., 2-fluoroethyl), 2,2,2-trifluoroethyl, or a hydroxyl-substituted pentyl group. In a particular variation of formula (IA3), R¹is —CH₃, —CH₂CH₂F, —CH₂CF₃, or —CH₂CH₂C(CH₃)₂OH. In another variation of formula (IA3), R⁶is H, halo, methyl, trifluoromethyl, or a substituted amino of the formula —N(H)(C₁-C₈unsubstituted alkyl). When R⁶is a halo (e.g., fluoro or chloro), in one aspect R⁶is chloro. In one variation of formula (IA3), R⁶is H, methyl or chloro. In one variation of formula (IA3), R⁶is methyl or chloro. When R⁶is a substituted amino of the formula —N(H)(C₁-C₈unsubstituted alkyl), in one aspect C₁-C₈unsubstituted alkyl is a linear C₁-C₈unsubstituted alkyl such as methyl or ethyl. In a particular variation of formula (IA3), R⁶is —N(H)(CH₃). It is understood that any R¹for formula (IA3) may be combined with any R⁶of formula (IA3) the same as if each and every combination were specifically and individually listed. For example, compounds of the formula (IA3) are provided where R¹is —CH₃, —CH₂CH₂F, —CH₂CF₃, or —CH₂CH₂C(CH₃)₂OH and R⁶is H, chloro, fluoro, methyl, trifluoromethyl, or —N(H)(CH₃). Likewise, compounds of the formula (IA3) are provided where R¹is methyl and R⁶is H, halo, methyl or a substituted amino of the formula —N(H)(C₁-C₈unsubstituted alkyl). In one such aspect, compounds of the formula (IA3) are provided where R¹is methyl and R⁶is H, halo or methyl. In one such aspect, compounds of the formula (IA3) are provided where R¹is methyl and R⁶is halo (e.g., fluoro or chloro), trifluoromethyl, or methyl. When each Q of formula (IA3) is independently a substituted aryl, in one aspect Q is a substituted phenyl. In one aspect, Q is a mono-substituted phenyl. In a particular aspect, each Q of formula (IA3) is independently a halo-substituted phenyl, alkoxy-substituted phenyl or an acylamino-substituted phenyl. Thus, compounds of the formula (IA3) are provided where each Q in one variation is independently a phenyl mono-substituted with a fluoro, C₁-C₈alkoxy (e.g., methoxy), an acylamino moiety of the formula —C(O)NH(C₁-C₈unsubstituted alkyl) or an acylamino moiety of the formula —C(O)N(C₁-C₈unsubstituted alkyl)₂, such as 2-fluoro-phenyl, 4-fluoro-phenyl, 4-methoxy-phenyl, 4-(C(O)NH(CH₃) and 4-(C(O)N(CH₃)₂)-phenyl. In one aspect, Q is a di-substituted phenyl. In one aspect, each Q of formula (IA3) is independently a di-halo substituted phenyl group such as 3,4-difluoro-phenyl. In a particular aspect, each Q of formula (IA3) is independently a phenyl group substituted with one halo group and one C₁-C₈alkoxy group (e.g., methoxy). Thus, compounds of the formula (IA3) are provided where each Q in one variation is independently a phenyl substituted with a fluoro and a C₁-C₈alkoxy group, such as 3-fluoro-4-methoxy-phenyl. When each Q of formula (IA3) is independently a substituted or unsubstituted heteroaryl, in one variation the substituted or unsubstituted heteroaryl is a pyridyl or pyrimidyl moiety. Thus, in one aspect of formula (IA3), Q is an unsubstituted pyridyl or pyrimidyl, such as 3-pyridyl, 4-pyridyl and 4-pyrimidyl. In another aspect of formula (IA3), Q is a substituted pyridyl, such as 6-methyl-3-pyridyl. In another aspect of formula (IA3), Q is a substituted or unsubstituted aryl having multiple condensed rings, such as naphthyl, quinolinyl and isoquinolinyl. It is understood that any Q for formula (IA3) may be combined with any R¹and/or R⁶of formula (IA3) the same as if each and every combination were specifically and individually listed. For example, compounds of the formula (IA3) are provided where R¹is —CH₃, —CH₂CH₂F, —CH₂CF₃, or —CH₂CH₂C(CH₃)₂OH; R⁴is H, chloro, fluoro, methyl, trifluoromethyl, or —N(H)(CH₃) and Q is 4-pyridyl, 3-pyridyl, 6-methyl-3-pyridyl, 6-pyrimidyl, 4-fluoro-phenyl, 4-methoxy-phenyl, 3-fluoro-4-methoxy-phenyl or 4-dimethylcarbamoyl-phenyl. Likewise, compounds of the formula (IA3) are provided where R¹is methyl; R⁶is H, halo or methyl and Q is an unsubstituted pyridyl.
In one variation, compounds of formulae (IA) and (IA1)-(IA3) are provided wherein Q is a substituted or unsubstituted aromatic moiety such as, for example, phenyl, naphthyl, anthracenyl, and the like. In another variation, Q is a substituted or unsubstituted heteroaromatic moiety such as, for example, thiophenyl, pyridyl, pyrimidyl, imidazolyl, oxazolyl, and the like.
In another variation, Q is a substituted or unsubstituted cycloalkenyl, such as cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like, with the requirement that the carbon atom linking the cycloalkenyl group to the indole nitrogen atom of the pyrido[4,3-b]indole or pyrido[3,4-b]indole is sp³hybridized. Particular cycloalkenyl groups comprise, for example, cyclobut-2-enyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohexa-2,4-dienyl, and the like. In another variation, Q is a substituted or unsubstituted aralkyl such as, for example, a tetrahydronaphthyl moiety linked to the parent structure through the cyclohexyl or the phenyl portion.
All variations referring to the formulae herein, such as formulae (IA), (IA1), (IA2), (IA3), where applicable, may apply equally to formula (IB), the same as if each and every variation were specifically and individually listed.
In one variation, compounds of the formula (IA) are provided where R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare each H; and the compounds are of the formula (IA4):
or a salt or solvate thereof, wherein X¹, X², X³and X⁴are as defined in formula (IA) and wherein:
R¹is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;
either (i) one or more of X¹, X², X³and X⁴is N or (ii) X¹and X³are CH, X²is CR⁶and X⁴is N, CH or CR⁶; and
Q is an aromatic ring of the formula:
where
Z is C, NH, N—CH₃, O or S and the Z-containing aromatic ring is attached to the parent structure at any available ring position;
t is 0 or 1; and
W is: (i) a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl that is bound to the Z-containing ring via a single bond at any available ring position or is fused to the Z-containing ring at any available adjacent ring positions, (ii) a substituted amino,
provided that when X¹, X², X³and X⁴are each independently CH or CR⁶, then R¹is an unsubstituted C₁-C₈alkyl when W is a substituted amino, or (iii) H, provided that when X
, X², X³and X⁴are each independently CH or CR⁶, then W is H only when the Z-containing ring is a 5-membered heteroaryl moiety.
In one variation, compounds of the formula (IA4) are provided where at least one of X¹, X², X³and X⁴is N and W is (i) a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl that is bound to the Z-containing ring via a single bond at any available ring position or is fused to the Z-containing ring at any available adjacent ring positions, (ii) a substituted amino, or (iii) H. In one such variation, at least one of X¹, X², X³and X⁴is N and the Z-containing ring bearing W is selected from the group consisting of a substituted or unsubstituted phenyl, naphthalenyl, isoquinolinyl, thiophenyl and pyridyl.
In another variation, compounds of the formula (IA4) are provided wherein X¹and X³are CH, X²is CR⁶and X⁴is N, CH or CR⁶and W is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl that is bound to the Z-containing ring via a single bond at any available ring position or is fused to the Z-containing ring at any available adjacent ring positions. In one such variation, the Z-containing ring bearing W is a phenyl, naphthalenyl, isoquinolinyl, thiophenyl or pyridyl ring substituted with a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl. In some variations, X¹, X³and X⁴are CH and X²is CR⁶. When X²is CR⁶, in one variation, R⁶is selected from the group consisting of a substituted or unsubstituted C₁-C₈alkyl, a substituted or unsubstituted C₃-C₇cycloalkyl, halo, cyano and trifluoromethyl. When X²is CR⁶, in one variation R⁶is an unsubstituted C₁-C₈alkyl (such as methyl) or halo (such as chloro). In some variations of formula (IA4), R¹is selected from the group consisting of H, a substituted or unsubstituted C₁-C₈alkyl, a substituted or unsubstituted C₃-C₇cycloalkyl, and an alkaryl, wherein the alkaryl is bound to the parent structure via the alkyl portion of the moiety. In one aspect, the alkyl portion of the R¹alkaryl moiety is a C₄-C₈alkyl. In some variations, R¹is an unsubstituted C₁-C₈alkyl (such as methyl). In a particular variation, compounds of the formula (IA4) are provided wherein X¹, X³and X⁴are CH and X²is CR⁶, where R⁶is selected from the group consisting of a substituted or unsubstituted C₁-C₈alkyl, a substituted or unsubstituted C₃-C₇cycloalkyl, halo, cyano and trifluoromethyl, and R¹is selected from the group consisting of H, a substituted or unsubstituted C₁-C₈alkyl, a substituted or unsubstituted C₃-C₇cycloalkyl, and an alkaryl, wherein the alkaryl is bound to the parent structure via the alkyl portion of the moiety. In one aspect, compounds of the formula (IA4) are provided wherein X¹, X³and X⁴are CH; X²is CR⁶where R⁶is an unsubstituted C₁-C₈alkyl; and the Z-containing ring bearing W is a phenyl, naphthalenyl, isoquinolinyl, thiophenyl or pyridyl ring substituted with a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl. In one aspect, the Z-containing ring (such as phenyl, thiophenyl and pyridyl) is substituted with a W where W is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl that is bound to the Z-containing ring via a single bond at any available ring position. For example, in one aspect, the Z-containing ring (such as phenyl, thiophenyl and pyridyl) is substituted with a W where W is selected from the group consisting of a substituted or unsubstituted pyridyl, phenyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidinyl and isooxazolyl, where W is bound to the Z-containing ring via a single bond at any available ring position.
In another variation, compounds of the formula (IA4) are provided wherein X¹and X³are CH; X²is CR⁶; X⁴is N, CH or CR⁶; and W a substituted amino, provided that when X¹, X², X³and X⁴are each independently CH or CR⁶, then R¹is an unsubstituted C₁-C₈alkyl. In one such variation, X¹, X³and X⁴are CH; X²is CR⁶; R¹is an unsubstituted C₁-C₈alkyl and W is a substituted amino (e.g., dimethylamino). In another such variation, X¹and X³are CH, X²is CR⁶; X⁴is CH or CR⁶; R¹is an unsubstituted C₁-C₈alkyl and W is a substituted amino. When X²is CR⁶, in one variation R⁶is an unsubstituted C₁-C₈alkyl (such as methyl) or a halo (such as chloro). When R¹is an unsubstituted C₁-C₈alkyl, in one variation R¹is methyl. In another such variation, the Z-containing ring bearing W is a phenyl, thiophenyl or pyridyl substituted with W where W is a substituted amino group. Thus, in one aspect, compounds of the formula (IA4) are provided wherein X¹, X³and X⁴are CH; X²is CR⁶where R⁶is an unsubstituted C₁-C₈alkyl or halo; and the Z-containing ring is a phenyl, thiophenyl or pyridyl ring substituted with a substituted amino group (e.g., dimethylamino).
In another variation, compounds of the formula (IA4) are provided wherein X¹, X², X³and X⁴are each independently CH or CR⁶; the Z-containing ring is a 5-membered heteroaryl moiety (where Z is NH, N—CH₃, O or S and t is 0) and W is H. In one such variation, the Z-containing ring is thiophene. In another variation, X¹, X³and X⁴are each CH and X²is CR⁶. When X²is CR⁶, in one aspect R⁶is selected from the group consisting of a substituted or unsubstituted C₁-C₈alkyl, a substituted or unsubstituted C₃-C₇cycloalkyl, halo, cyano and trifluoromethyl, and in another aspect is an unsubstituted C₁-C₈alkyl (such as methyl) or a halo (such as chloro). In a further such variation, X¹, X³and X⁴are each CH; X²is CR⁶where R⁶is an unsubstituted C₁-C₈alkyl (such as methyl) or a halo (such as chloro); R¹is an unsubstituted C₁-C₈alkyl (such as methyl); the Z-containing ring is a 5-membered heteroaryl moiety and W is H.
In one variation, compounds of the formula (IA4) are provided where X¹and X³are each CH, X²is CR⁶; and the compounds are of the formula (IA5):
or a salt or solvate thereof, where R⁶and X⁴are as defined in formula (IA) and wherein:
R¹is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryalkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;
Z is C, NH, N—CH₃, O or S;
t is 0 or 1;
W is: (i) a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl that is bound to the Z-containing ring via a single bond at any available position or is fused to the Z-containing ring at two adjacent positions, (ii) a substituted amino, provided that R¹is a C₁-C₈alkyl when W is a substituted amino, or (iii) H, provided that W is only H when the Z-containing ring is a 5-membered heteroaryl moiety; and
wherein the Z-containing ring is aromatic and is attached to the parent structure at any available ring position.
Compound of the formula (IA5) may in certain variations have any one or more of the following structural features, provided that features (iii) and (iv) cannot be combined and features (vi) and (vii) cannot be combined: (i) X⁴is CH; (ii) R¹is an unsubstituted C₁-C₈alkyl; (iii) t is 0; (iv) t is 1; (iv) Z is C, S or N; (v) the Z-containing ring is selected from the group consisting of phenyl, thiophenyl and pyridyl; (vi) W is selected from the group consisting of a substituted or unsubstituted: pyridyl, phenyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidinyl and isooxazolyl, where W is bound to the Z-containing ring via a single bond at any available ring position; (vii) W is fused to the Z-containing ring at any available adjacent ring positions, thereby providing multiple condensed rings (e.g., naphthalenyl and isoquinolinyl); and (viii) R⁶is an unsubstituted C₁-C₈alkyl or halo.
In some embodiments, in compounds of the formulae (IA), (IB), (J-1) and (K-1), and any variations thereof detailed herein, Q is a group having the formula -Q^A-Q^B, wherein Q^Ais substituted aryl or substituted heteroaryl and Q^Bis substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In some embodiments, Q^Ais aryl (e.g., phenyl). In some embodiments, Q^Ais a 6-membered heteroaryl containing one annular heteroatom (e.g., pyridyl). In some embodiments, Q^Ais a 6-membered heteroaryl containing more than one annular heteroatoms, such as a 6-membered heteroaryl containing two annular heteroatoms (e.g., pyrimidyl and pyrazinyl). In some embodiments, Q^Ais a 5-membered heteroaryl containing one annular heteroatom (e.g., thiophenyl, furanyl and pyrrolyl). In some embodiments, Q^Ais a 5-membered heteroaryl containing more than one annular heteroatoms such as a 5-membered heteroaryl containing two annular heteroatoms (e.g., thiazolyl, oxazolyl, imidazolyl, isothiazoyl, isooxazolyl and pyrazolyl). In some embodiments, Q^Bis a substituted or unsubstituted aryl (e.g., phenyl, fluorophenyl and chlorophenyl). In some embodiments, Q^Bis a substituted or unsubstituted heteroaryl such as a substituted or unsubstituted pyridyl, pyrimidyl, pyrazinyl, thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazoyl, isooxazolyl, pyrazolyl, naphthyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, benzothiophenyl, and the like. In some embodiments, the Q^Amoiety may be attached to the parent structure at any viable annular atom of Q^A. In some embodiments, the bond between Q^Aand Q^Bis between any viable annular atom of Q^Aand any viable annular atom of Q^B.
Examples of Q moieties that are contemplated for the formulae herein, such as formulae (IA) and (IB) and any variations detailed herein (for example formula (IA4) and (IA5) where the Q group is also referred to as the Z-containing ring bearing a W moiety), include but are not limited to the following:
In one variation, compounds of the formula (IA) are provided, where R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare each H; and the compounds have the structure (IA6):
or a salt or solvate thereof, where R⁶and X¹, X², X³and X⁴are as defined in formula (IA) and wherein:
R¹is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;
either (1) one or more of X¹, X², X³and X⁴is N or (ii) X¹and X³are CH
, X
, is CR
and X⁴is N, CH or CR⁶; and
W is: (i) a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl that is bound to the parent structure via a single bond located at any available ring position or (ii) a substituted amino, provided that R¹is a C₁-C₈unsubstituted alkyl when W is a substituted amino.
In one aspect of formula (IA6), one or more of X¹, X², X³and X⁴is N. In one aspect, X¹is N and X², X³and X⁴are each CH. In another aspect, X²is N and X¹, X³and X⁴are each CH. In another aspect, X³is N and X¹, X²and X⁴are each CH. In a further aspect, X⁴is N and X¹, X²and X³are each CH. In one variation of formula (IA6), one of X¹, X², X³and X⁴is N, one of X¹, X², X³and X⁴is CR⁶and two of X¹, X², X³and X⁴are CH. In one variation, X⁴is N, X¹and X³are each CH and X²is CR⁶.
In another aspect of formula (IA6), X¹and X³are CH, X²is CR⁶and X⁴is N, CH or CR⁶. In one such aspect, X²is CR⁶where R⁶is selected from the group consisting of a substituted or unsubstituted C₁-C₈alkyl, a substituted or unsubstituted C₃-C₇cycloalkyl, halo, cyano and trifluoromethyl. In another variation, X¹, X³and X⁴are each CH and X²is CR⁶. In another variation, X¹, X³and X⁴are each CH and X²is CR⁶where R⁶is a C₁-C₈unsubstituted alkyl (e.g., methyl) or halo (e.g., chloro).
In any variation of formula (IA6), such as but not limited those provided herein above, the compound may further have any one or more of the following structural features: (i) X²is CR⁶(where in one particular variation R⁶is selected from the group consisting of a substituted or unsubstituted C₁-C₈alkyl, a substituted or unsubstituted C₃-C₇cycloalkyl, halo, cyano and trifluoromethyl); (ii) R¹is selected from the group consisting of H, a substituted or unsubstituted C₁-C₈alkyl, a substituted or unsubstituted C₃-C₇cycloalkyl, and an alkaryl, wherein the alkaryl is bound to the parent structure via the alkyl portion of the moiety; (iii) X¹and X³are each CH;
(iv) W is a substituted or unsubstituted pyridyl, phenyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidinyl and isooxazolyl; (v) W is bound at the ortho position of the phenyl ring; and (vi) W is bound to the meta position of the phenyl ring; (vii) W is bound to the para position of the phenyl ring. Thus, in one aspect of formula (IA6), X¹, X³and X⁴are each CH; X²is CR⁶where R⁶is a C₁-C₈unsubstituted alkyl (e.g., methyl) or halo (e.g., chloro); R¹is selected from the group consisting of H, a substituted or unsubstituted C₁-C₈alkyl, a substituted or unsubstituted C₃-C₇cycloalkyl, and an alkaryl, wherein the alkaryl is bound to the parent structure via the alkyl portion of the moiety; and W is bound at the ortho or meta position of the phenyl ring.
In some instances, compounds of the formula (IA6) are provided wherein X¹and X³are each CH and the compound is of the formula (A1) or (A2):
or a salt or solvate thereof; wherein R⁶and X⁴are defined as for formulae (IA) and, where applicable, any variation thereof detailed herein, and wherein:
R¹is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;
W is a substituted amino, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In one particular aspect of this variation, X⁴is N. In another particular aspect of this variation, X⁴is CH. In another aspect of this variation, R¹and R⁶are each a substituted or unsubstituted C₁-C₈alkyl. In one particular aspect of this variation, R¹and R⁶are methyl. Variations of formula (IA) detailed throughout, where applicable, apply to formulae (A1)-(A2) the same as if each and every variation were specifically and individually listed for formulae (A1)-(A2). Pharmaceutically acceptable salts of compounds of formulae (A1)-(A2) are also provided.
All variations referring to the formulae (IA), such as formulae (A1)-(A2), where applicable, may apply equally to formulae (IB), the same as if each and every variation were specifically and individually listed.
In one variation, compounds of the formula (IA) are provided wherein X¹and X³are each CH, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare each H and the compounds are of the formula (IA7):
or a salt or solvate thereof, where R⁶and X¹, X², X³and X⁴are as defined in formula (IA) and wherein:
R¹is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;
either (i) one or more of X¹, X², X³and X⁴is N or (ii) X¹and X³are CH, X²is CR⁶and X⁴is N, CH or CR⁶;
W is H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₁-C₈alkoxy, C₁-C₈perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, 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 or sulfonylamino; and
Z is NH, N—CH₃, O or S.
In one aspect of formula (IA7), one or more of X¹, X², X³and X⁴is N. In one aspect, X¹is N and X², X³and X⁴are each CH. In another aspect, X²is N and X¹, X³and X⁴are each CH. In another aspect, X³is N and X¹, X²and X⁴are each CH. In a further aspect, X⁴is N and
X¹, X²and X³are each CH. In one variation of formula (IA7), one of X¹, X², X³and X⁴is N, one of X¹, X², X³and X⁴is CR⁶and two of X¹, X², X³and X⁴are CH. In one variation, X⁴is N, X¹and X³are each CH and X²is CR⁶.
In another aspect of formula (IA7), X¹and X³are CH, X²is CR
and X
is N, CH or CR⁶. In one such aspect, X²is CR⁶where R⁶is selected from the group consisting of a substituted or unsubstituted C₁-C₈alkyl, a substituted or unsubstituted C₃-C₇cycloalkyl, halo, cyano and trifluoromethyl. In another variation, X¹, X³and X⁴are each CH and X²is CR⁶. In another variation, X¹, X³and X⁴are each CH and X²is CR⁶where R⁶is a C₁-C₈unsubstituted alkyl (e.g., methyl) or halo (e.g., chloro).
In any variation of formula (IA7), such as but not limited those provided herein above, the compound may further have any one or more of the following structural features: (i) X²is CR⁶(where in one particular variation R⁶is selected from the group consisting of a substituted or unsubstituted C₁-C₈alkyl, a substituted or unsubstituted C₃-C₇cycloalkyl, halo, cyano and trifluoromethyl); (ii) R¹is selected from the group consisting of H, a substituted or unsubstituted C₁-C₈alkyl, a substituted or unsubstituted C₃-C₇cycloalkyl, and an alkaryl, wherein the alkaryl is bound to the parent structure via the alkyl portion of the moiety; (iii) X¹and X³are each CH; (iv) X⁴is CH; (v) Z is S; (vi) W is bound to a position adjacent to Z; (vii) the Z-containing ring is bound to the parent structure at a carbon adjacent to Z; (viii) W is H, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; (ix) R¹and R⁶are each a substituted or unsubstituted C₁-C₈alkyl; and (x) R¹is methyl and R⁶is halo.
In particular variations of formula (IA7), compounds are provided wherein X¹and X³are each CH and the compounds are of the formulae (B1)-(B6):
or a salt or solvate thereof; wherein R⁶and X⁴are defined as for formulae (IA) and, where applicable, any variation thereof detailed herein, and wherein;
R
is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;
Z is NH, N—CH₃, O or S, and W is H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₁-C₈alkoxy, C₁-C₈perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, 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 or sulfonylamino. In one particular aspect of this variation, W is H, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In one particular aspect of this variation, Z is S. In another particular aspect of this variation, X⁴is N. In another particular aspect of this variation, X⁴is CH. In another aspect of this variation, R¹and R⁶are each a substituted or unsubstituted C₁-C₈alkyl. In another particular aspect of this variation, R¹and R⁶are methyl. In another particular aspect of this variation, R¹is methyl and R⁶is halo. Variations of formula (IA) detailed throughout, where applicable, apply to formulae (B1)-(B6) the same as if each and every variation were specifically and individually listed for formulae (B1)-(B6). Pharmaceutically acceptable salts of compounds of formulae (B1)-(B6) are also provided.
All variations referring to the formulae (IA), such as formulae (B1)-(B6), where applicable, may apply equally to formulae (IB), the same as if each and every variation were specifically and individually listed.
In another variation, compounds of the formula (IA) are provided wherein X¹and X³are each CH, R^2a, R^2b, R^3a, R^3b, R^4aand R_4bare each H and the compound is of the formula (IA8):
or a salt or solvate thereof, where R⁶and X¹, X², X³and X⁴are as defined in formula (IA) and wherein:
R¹is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;
either (i) one or more of X¹, X², X³and X⁴is N or (ii) X¹and X³are CH, X²is CR⁶and X⁴is N, CH or CR⁶; and
W is H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₁-C₈alkoxy, C₁-C₈perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, 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 or sulfonylamino,
provided that when X¹, X³and X⁴are each H and X²is CR⁶where R⁶is H or fluoro, W is other than H.
In one aspect of formula (IA8), one or more of X¹, X², X³and X⁴is N. In one aspect, X¹is N and X², X³and X⁴are each CH. In another aspect, X²is N and X¹, X³and X⁴are each CH. In another aspect, X³is N and X¹, X²and X⁴are each CH. In a further aspect, X⁴is N and X¹, X²and X³are each CH. In one variation of formula (IA8), one of X¹, X², X³and X⁴is N, one of X¹, X², X³and X⁴is CR⁶and two of X¹, X², X³and X⁴are CH. In one variation, X⁴is N, X¹and X³are each CH and X²is CR⁶.
In another aspect of formula (IA8), X¹and X³are CH, X²is CR
and X
is N, CH or CR⁶. In one such aspect, X²is CR⁶where R⁶is selected from the group consisting of a substituted or unsubstituted C₁-C₈alkyl, a substituted or unsubstituted C₃-C₇cycloalkyl, halo, cyano and trifluoromethyl. In another variation, X¹, X³and X⁴are each CH and X²is CR⁶. In another variation, X¹, X³and X⁴are each CH and X²is CR⁶where R⁶is a C₁-C₈unsubstituted alkyl (e.g., methyl) or halo (e.g., chloro).
In any variation of formula (IA8), such as but not limited those provided herein above, the compound may further have any one or more of the following structural features: (i) X²is CR⁶(where in one particular variation R⁶is selected from the group consisting of a substituted or unsubstituted C₁-C₈alkyl, a substituted or unsubstituted C₃-C₇cycloalkyl, halo, cyano and trifluoromethyl); (ii) R¹is selected from the group consisting of H, a substituted or unsubstituted C₁-C₈alkyl, a substituted or unsubstituted C₃-C₇cycloalkyl, and an alkaryl, wherein the alkaryl is bound to the parent structure via the alkyl portion of the moiety; (iii) X¹and X³are each CH; (iv) X⁴is CH; (v) W is H, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; (vi) R¹and R⁶are each a substituted or unsubstituted C₁-C₈alkyl; and (vii) R¹is methyl and R⁶is halo.
In particular variations of formula (IA8), compounds are provided wherein X¹and X³are each CH, and the compounds are of the formulae (C1)-(C3):
or a salt or solvate thereof; wherein R⁶and X⁴are defined as for formulae (IA) and, where applicable, any variation thereof detailed herein, and wherein:
R¹is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;
W is, H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₁-C₈alkoxy, C₁-C₈perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, 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 or sulfonylamino,
provided that when X⁴if CH and R⁶is H or fluoro, then W is other than H.
In one particular aspect of this variation, W is a substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In another particular aspect of this variation, X⁴is N. In another particular aspect of this variation, X⁴is CH. In another aspect of this variation, R¹and R⁶are each a substituted or unsubstituted C₁-C₈alkyl. In one particular aspect of this variation, R¹and R⁶are methyl. In another particular aspect of this variation, R¹is methyl and R⁶is halo. Variations of formula (IA) detailed throughout, where applicable, apply to formulae (C1)-(C3) the same as if each and every variation were specifically and individually listed for formulae (C1)-(C3). Pharmaceutically acceptable salts of compounds of formulae (C1)-(C3) are also provided.
All variations referring to the formulae (IA), such as formulae (C1)-(C3), where applicable, may apply equally to formulae (IB), the same as if each and every variation were specifically and individually listed.
In one variation, compounds of the formula (IA) are provided wherein R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare each H and the compounds are of the formula (IA9):
or a salt or solvate thereof, wherein R⁶and X¹, X², X³and X⁴are as defined in formula (IA) and wherein:
R¹is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;
either (i) one or more of X¹, X², X³and X⁴is N or (ii) X¹and X³are CH, X²is CR⁶and X⁴is N, CH or CR⁶; and
W is H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₁-C₈alkoxy, C₁-C₈perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, 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 or sulfonylamino.
In one aspect of formula (IA9), one or more of X¹, X², X³and X⁴is N. In one aspect, X¹is N and X², X³and X⁴are each CH. In another aspect, X²is N and X¹, X³and X⁴are each CH. In another aspect, X³is N and X¹, X²and X⁴are each CH. In a further aspect, X⁴is N and X¹, X²and X³are each CH. In one variation of formula (IA9), one of X¹, X², X³and X⁴is N, one of X¹, X², X³and X⁴is CR⁶and two of X¹, X², X³and X⁴are CH. In one variation, X⁴is N, X¹and X³are each CH and X²is CR⁶.
In another aspect of formula (IA9), X¹and X³are CH, X²is CR⁶and X⁴is N, CH or CR⁶. In one such aspect, X²is CR⁶where R⁶is selected from the group consisting of a substituted or unsubstituted C₁-C₈alkyl, a substituted or unsubstituted C₃-C₇cycloalkyl, halo, cyano and trifluoromethyl. In another variation, X¹, X³and X⁴are each CH and X²is CR⁶. In another variation, X¹, X³and X⁴are each CH and X²is CR⁶where R⁶is a C₁-C₈unsubstituted alkyl (e.g., methyl) or halo (e.g., chloro).
In any variation of formula (IA9), such as but not limited those provided herein above, the compound may further have any one or more of the following structural features: (i) X²is CR⁶(where in one particular variation R⁶is selected from the group consisting of a substituted or unsubstituted C₁-C₈alkyl, a substituted or unsubstituted C₃-C₇cycloalkyl, halo, cyano and trifluoromethyl); (ii) R¹is selected from the group consisting of H, a substituted or unsubstituted C₁-C₈alkyl, a substituted or unsubstituted C₃-C₇cycloalkyl, and an alkaryl, wherein the alkaryl is bound to the parent structure via the alkyl portion of the moiety; (iii) X¹and X³are each CH; (iv) X⁴is CH; (v) W is bound to the 4-position of the thiazole ring; (vii) the thiazole ring is bound to the parent structure at the 2-position; (viii) W is H, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; (ix) R¹and R⁶are each a substituted or unsubstituted C₁-C₈alkyl; and (x) R¹is methyl and R⁶is halo.
All variations referring to the formula (IA) detailed herein, such as formulae (IA9), where applicable, may apply equally to formula (IB), the same as if each and every variation were specifically and individually listed.
The invention also embraces compounds of formula (J-1):
or a salt or solvate thereof, wherein:
R¹is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;
each R^2a, R^2bR^3a, R^3b, R^4a, R^4b, R^10aand R^10bis independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, 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 X¹, X²and X³is independently N, CH or CR⁶;
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
each R
is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, 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.
In one variation, provided are compounds of the formula (J-1), wherein at least one of X¹, X², X³and X⁴is CH or CR⁶. In another variation, at least two of X¹, X², X³and X⁴is CH or CR⁶.
In a particular embodiment, compounds of formula (J-1) are provided wherein the ring comprising X¹, X², X³and X⁴is a phenyl, pyridyl, pyrimidinyl or pyrazinyl ring, optionally substituted with 0-3 R⁶groups (i.e., (R⁶)_nwhere n is 0, 1, 2 or 3). In some such embodiments, n is 1, 2 or 3 and each R⁶is independently halo, methyl or CF₃.
In a particular variation, compounds of formula (J-1) have the structure:
or a salt or solvate thereof; wherein R¹, R⁶, X¹, X², X³, X⁴and Q are defined as for formula (J-1) and, where applicable, any variation thereof detailed herein. That is, variations of formula (J-1) detailed throughout, where applicable, apply equally to any of formulae (J-1a)-(J-1c), the same as if each and every variation were specifically and individually listed for formula (J-1a)-(J-1c). Pharmaceutically acceptable salts of compounds of formulae (J-1a)-(J-1c) are also provided.
In one variation, compounds of the formula (J-1) have the structure:
or a salt or solvate thereof; wherein R¹, R⁶, X¹, X², X³and X⁴are defined as for formula (IA) and, where applicable, any variation thereof detailed herein, i is 0-5, j is 0-4, k is 0-3, Z is NH, N—CH₃, O or S, and W is H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₁-C₈alkoxy, C₁-C₈perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, 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, or sulfonylamino. In one particular aspect of this variation, W is H, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In one particular aspect of this variation, Z is S. In another particular aspect of this variation, one of X¹, X², X³or X⁴(where present) is N. Variations of formula (J-1) detailed throughout, where applicable, apply equally to any of formulae (J-2)-(J-4), the same as if each and every variation were specifically and individually listed for formula (J-2)-(J-4). Pharmaceutically acceptable salts of compounds of formulae (J-2)-(J-4) are also provided.
The invention also embraces compounds of formula (K-1):
or a salt or solvate thereof, wherein:
R¹is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;
each R^2a, R^2bR^3a, R^3b, R^4a, R^4b, R^10aand R^10bis independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, 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^(a/b)or R^10(a/b)to form a carbonyl moiety or a cycloalkyl moiety;
each X¹, X²and X³is independently N, CH or CR⁶;
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
each R⁶is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, 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.
In one variation, provided are compounds of the formula (K-1), wherein at least one of X¹, X², X³and X⁴is CH or CR⁶. In another variation, at least two of X¹, X², X³and X⁴is CH or CR⁶.
In a particular variation, compounds of formula (K-1) have the structure:
or a salt or solvate thereof; wherein R¹, X¹, X², X³, X⁴and Q are defined as for formula (K-1) and, where applicable, any variation thereof detailed herein. That is, variations of formula (K-1) detailed throughout, where applicable, apply equally to any of formulae (K-1a)-(K-1c), the same as if each and every variation were specifically and individually listed for formula (K-1a)-(K-1c). Pharmaceutically acceptable salts of compounds of formulae (K-1a)-(K-1c) are also provided.
In one variation, compounds of the formula (K-1) have the structure:
or a salt or solvate thereof; wherein R¹, R⁶, X¹, X², X³and X⁴are defined as for formula (IA) and, where applicable, any variation thereof detailed herein, n is 0-5, o is 0-4, p is 0-3, Z is NH, N—CH₃, O or S, and W is H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₁-C₈alkoxy, C₁-C₈perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, 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. In one particular aspect of this variation, W is H, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In one particular aspect of this variation, Z is S. In another particular aspect of this variation, one of X¹, X², X³or X⁴is N. Variations of formula (K-1) detailed throughout, where applicable, apply equally to any of formulae (K-2)-(K-4), the same as if each and every variation were specifically and individually
sted for formula (K-2)-(K-4). Pharmaceutically acceptable salts o
compounds of formulae (K-2)-(K-4) are also provided.
All variations referring to formula (J-1), such as formulae (J-1a)-(J-1c) and (J-2)-(J-4), where applicable, may apply equally to formula (K-1), the same as if each and every variation were specifically and individually listed.
In certain embodiments, compounds are provided, such as compounds of the formulae (IA), (IB), (J-1) and (K-1), and any variations thereof detailed herein, wherein R¹is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy. In specific embodiments, R¹is a substituted or unsubstituted C₁-C₈alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl. In more specific embodiments, R¹is an unsubstituted C₁-C₈alkyl such as methyl and cyclopropyl.
In certain embodiments, compounds are provided wherein R¹is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy. In more specific embodiments, R¹is a sulfonyl such as —SO₂-alkyl, —SO₂-aryl and —SO₂-aralkyl.
In certain embodiments, compounds are provided where R¹is selected from the following moieties:
In certain embodiments, compounds are provided where each R^2aand R^2bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R^2aand R^2bare taken together to form a carbonyl moiety. In specific embodiments, each R^2aand R^2bis independently H, methyl, fluoro or R^2aand R^2bare taken together to form a carbonyl moiety. In a specific embodiment, R^2aand R^2bare both H.
In certain embodiments, compounds are provided where each R^3aand R^3bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R^3aand R^3bare taken together to form a carbonyl moiety. In specific embodiments, each R^3aand R^3bis independently H or fluoro. In another specific embodiment, R^3aand R^3bare both H. In a further specific embodiment, R^3aand R^3bare both H and R^4aand R^4bare both H.
In certain embodiments, compounds are provided where each R^4aand R^4bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R^4aand R^4bare taken together to form a carbonyl moiety. In specific embodiments, each R^4aand R^4bis independently H, halo, hydroxyl or methyl or R^4aand R^4bare taken together to form a carbonyl moiety. In another specific embodiment, R^4aand R^4bare both H. In a further specific embodiment, R^2aand R^2bare both H and R^3a, R^3b, R^4aand R^4bare each H.
In certain embodiments, compounds are provided where each X¹, X², X³and X⁴is independently N, CH or CR⁶. In certain embodiments, each X¹, X², X³and X⁴is CH or CR⁶, such that the ring comprising X¹, X², X³and X⁴is an optionally substituted phenyl ring. In specific embodiments, X²is CR⁶where R⁶is halo or alkyl and X¹, X³and X⁴are each CH. In other embodiments, one of X¹, X², X³and X⁴is N, and the others are CH or CR⁶, such that the ring is an optionally substituted pyridine ring. In further embodiments, two of X¹, X², X³and X⁴are N, and the other is CH or CR⁶, such that the ring is an optionally substituted pyrimidine or pyrazine ring.
In certain embodiments, compounds are provided where each R
, where present, is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, 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. In one variation, at least one of X¹-X⁴is CR⁶where R⁶is halo. In a particular variation, one of X¹-X⁴is CR⁶where R⁶is chloro and the others are CH. In a specific variation, X¹, X³and X⁴are each CH and X²is CR⁶where R⁶is chloro.
In certain embodiments, compounds are provided where each R⁶, where present, is independently hydroxyl, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, alkylsulfonylamino or acyl. In further embodiments, each R⁶, where present, is independently hydroxyl, halo, C₁-C₄perhaloalkyl, substituted or unsubstituted C₁-C₄alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C₁-C₄alkoxy; or in still a further variation, each R⁶, where present, is independently halo, unsubstituted C₁-C₄alkyl or C₁-C₄perhaloalkyl.
In specific embodiments, the ring comprising X¹-X⁴is a phenyl, pyridyl, pyrimidinyl or pyrazinyl ring, optionally substituted with 0-2 R⁶groups (i.e., (R⁶)_n) where n is 0, 1 or 2. In some such embodiments, n is 1 or 2 and each R⁶is independently halo, methyl or CF₃.
In certain embodiments, compounds are provided where Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino. In one variation, compounds are of the formula (IA) or (IB) where Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl or substituted or a unsubstituted heterocyclyl. In certain embodiments, Q is a substituted or unsubstituted 5- or 6-membered aryl or heteroaryl. In some such embodiments, Q is a substituted or unsubstituted phenyl, pyridyl or pyrimidinyl ring. When Q is substituted, it is frequently substituted with from 1-3 substituents selected from group consisting of halo, C₁-C₄alkyl, C₁-C₄perhaloalkyl, and C₁-C₄alkoxy.
In a particular variation, Q is a substituted heteroaryl, a mono-substituted aryl group substituted with a chloro or alkyl group or a di- or tri-substituted aryl moiety. For instance, Q in one variation is selected from the group consisting of 4-methoxy-3-fluorophenyl, 3,4-di-fluorophenyl, 4-chloro-3-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,4,6-trifluorophenyl, 4-chlorophenyl, 4-methylphenyl, 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, 5-trifluoromethyl-3-pyridyl and pyrimidinyl. In one aspect, Q is a substituted pyridyl such as 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl and 5-trifluoromethyl-3-pyridyl.
In certain embodiments, R¹is a substituted or unsubstituted C₁-C₈alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl; each R^2aand R^2bis independently H, methyl, fluoro or R^2aand R^3bare taken together to form a carbonyl moiety; each R^3aand R^3bis independently H or fluoro; and each R^4aand R^4bis independently H, halo, hydroxyl or methyl or R^4aand R^4bare taken together to form a carbonyl moiety. In particular variations, R¹is an unsubstituted C₁-C₈alkyl and R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare each H. In still a further variation, R¹is an unsubstituted C₁-C₈alkyl, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare each H and Q is selected from the group consisting of 4-methoxy-3-fluorophenyl, 3,4-di-fluorophenyl, 4-chloro-3-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,4,6-trifluorophenyl, 4-chlorophenyl, 4-methylphenyl, 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, 5-trifluoromethyl-3-pyridyl and pyrimidinyl. In still a further variation, R¹is an unsubstituted C₁-C₈alkyl, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare each H and X²is CR⁶where R⁶is chloro. In yet a further variation, R¹is an unsubstituted C₁-C₈alkyl, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare each H, X²is CR⁶where R⁶is chloro and Q is a substituted or unsubstituted aryl or a substituted or substituted heteroaryl. In one such variation, Q is a substituted phenyl.
In certain embodiments, compounds are provided where each X¹, X², X³and X⁴is CH or CR⁶. In other embodiments, at least one of X¹, X², X³and X⁴is N. Another variation provides a compound where at least two of X¹, X², X³and X⁴are N. A further variation provides a compound where two of X¹, X², X³and X⁴are N and one of X¹, X², X³and X⁴is CH or CR⁶. Compounds where one of X¹, X², X³and X⁴is N and two of X¹, X², X³and X⁴are CH or CR⁶are also embraced by this invention.
In another variation, compounds are provided where wherein the ring comprising X¹-X⁴is an aromatic moiety selected from the following structures:
where each R⁶is as defined herein. In a particular variation, each R⁶is independently hydroxyl, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or amino, alkylsulfonylamino or acyl. In a further variation, each R⁶is independently halo, unsubstituted C₁-C₄alkyl, C₁-C₄perhaloalkyl, or C₁-C₄alkoxy.
In still a further variation, compounds are provided wherein the ring comprising X¹-X⁴is an aromatic moiety selected from the following structures:
wherein R⁶is as defined herein; or in a particular variation, where R⁶is hydroxyl, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or amino alkylsulfonylamino or acyl; or in still a further variation, where each R⁶is independently halo, unsubstituted C₁-C₄alkyl, C₁-C₄perhaloalkyl, or C₁-C₄alkoxy.
In a further variation, compounds are provided wherein the ring comprising X¹-X⁴is an aromatic moiety selected from the following structures:
Any formula detailed herein, where applicable, may in one variation have X¹, X², X³and X⁴taken together to provide an aromatic moiety detailed herein above. It is understood that by “where applicable” it is intended that in one variation such X¹, X², X³and X⁴groups are taken together to provide a moiety hereinabove if the formula encompasses such a structure. For example, if a given formula does not encompass structures wherein X¹, X², X³and X⁴groups are taken together provide a pyridyl moiety, then a pyridyl moiety as detailed hereinabove is not applicable to that particular formula, but remains applicable to formulae that do encompass structures where X¹, X², X³and X⁴groups are taken together provide a pyridyl moiety.
In another embodiment, compounds are provided wherein X¹-X⁴are as defined herein or as detailed in any variation herein, where R¹is H, substituted or unsubstituted C₁-C₈alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl. In a further embodiment, compounds are provided wherein X¹-X⁴are as defined herein or as detailed in any variation herein, where R¹is a substituted or unsubstituted C₁-C₈alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl. In a particular variation, compounds are provided wherein X¹-X⁴are as defined herein or as detailed in any variation herein, where R¹is methyl, ethyl, cyclopropyl, propylate, trifluoromethyl, isopropyl, tert-butyl, sec-butyl, 2-methylbutyl, propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted phenyl, piperidin-4-yl, hydroxycyclopent-3-yl, hydroxycyclopent-2-yl, hydroxycycloprop-2-yl, 1-hydroxy-1-methylcycloprop-2-yl, or 1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl.
In another variation, the compound of the invention is provided where X¹-X⁴and R¹are as defined herein or as detailed in any variation herein, where R^2aand R^2bare independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, nitro or R^2aand R^3bare taken together to form a carbonyl moiety and each R^3aand R^3bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano or nitro. In another variation, the compound of the invention is provided where X¹-X³and R¹are as defined herein or as detailed in any variation herein, where each R^2aand R^2bis independently H, unsubstituted C₁-C₈alkyl, halo or R^2aand R^2bare taken together to form a carbonyl moiety and each R^3aand R^3bis independently H, unsubstituted C₁-C₈alkyl, halo or R^3aand R^3bare taken together to form a carbonyl moiety. In still a further variation, the compound of the invention is provided where X¹-X⁴and R¹are as defined herein or as detailed in any variation herein, where each R^2aand R^2bis independently H, unsubstituted C₁-C₈alkyl, halo or R^2aand R^2bare taken together to form a carbonyl moiety; and each R^3aand
R^3bis independently H, unsubstituted C₁-C₈alkyl, halo or R^3aand R^3bare taken together to form a carbonyl moiety. The invention also embraces compounds of the invention where X¹-X⁴and
R¹are as defined herein or as detailed in any variation herein, where each R^2aand R^2bis independently H, methyl, halo or R^2aand R^2bare taken together to form a carbonyl moiety and each R^3aand R^3bis independently H, methyl, halo or R^3aand R^3bare taken together to form a carbonyl moiety.
The invention further embraces compounds of the invention according to formula (IA) or (IB), where X¹-X⁴and R¹are as defined herein or as detailed in any variation herein, where each R^2a, R^2b, R^3aand R^3bis H. In one variation, a compound of the invention is of the formula (IA) or (IB) where X¹-X⁴and R¹are as defined herein or as detailed in any variation herein, where at least one of R^2a, R^2b, R^3aand R^3bis a substituted or unsubstituted C₁-C₈alkyl, halo, cyano, nitro or is taken together with a geminal R²or R³to form a carbonyl moiety.
In another variation, a compound of the invention is of the formula (IA) or (IB) where X¹-X⁴and R¹are as defined herein or as detailed in any variation herein, where at least two of R^2a, R^2b, R^3aand R^3bis a substituted or unsubstituted C₁-C₈alkyl, halo, cyano, nitro or is taken together with a geminal R²or R³to form a carbonyl moiety. In yet another variation, a compound of the invention is of the formula (IA) or (IB) where X¹-X⁴and R
are as defined herein or as detailed in any variation herein, where at least one of R^2a, R^2b, R^3aand R^3bis fluoro or methyl or is taken together with a geminal R²or R³to form a carbonyl moiety.
In still another variation, a compound of the invention is of the formula (IA) or (IB) where X¹-X⁴and R¹are as defined herein or as detailed in any variation herein, where either R^2aand R^2bor R^3aand R^3bare each methyl or fluoro (e.g., both R^2aand R^2bare methyl or one is fluoro and one is methyl) or are taken together to form a carbonyl moiety. In one variation, R^2aand R^2bare taken together to form a carbonyl moiety. In another variation, at least one of R^2aand R^2bis hydroxyl or alkoxy. In a particular variation, each R^2aand R^2bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, nitro or R^2aand R^2bare taken together to form a carbonyl moiety. In another variation, each R^2aand R^2bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, nitro or R^2aand R^2bare taken together to form a carbonyl moiety.
The invention also embraces compounds according to formula (IA) or (IB), where X¹-X⁴, R¹, R^2a, R^2b, R^3aand R^3bare as defined herein or as detailed in any variation herein, where each R^4aand R^4bis independently H, halo, an unsubstituted C₁-C₈alkyl, hydroxyl or R^4aand R^4bare taken together to form a carbonyl moiety. Also embraced are compounds according to formula (IA) or (IB), where X¹-X⁴, R¹, R^2a, R^2b, R^3aand R^3bare as defined herein or as detailed in any variation herein, where each R^4aand R^4bis independently H, halo, an unsubstituted C₁-C₄alkyl, hydroxyl or R^4aand R^4bare taken together to form a carbonyl moiety. In another variation, a compound of the invention is of the formula (IA) or (IB), where X¹-X⁴, R¹, R², R^2b, R^3aand R^3bare as defined herein or as detailed in any variation herein, where each R^4aand R^4bis independently H, bromo, methyl, hydroxyl or R^4aand R^4bare taken together to form a carbonyl moiety.
In yet another variation, a compound of the invention is of the formula (IA) or (IB), where X¹-X⁴, R¹, R^2a, R^2b, R^3aand R^3bare as defined herein or as detailed in any variation herein, where at least one of R^4aand R^4bis an unsubstituted C₁-C₈alkyl, hydroxyl, halo or R^4aand R^4bare taken together to form a carbonyl moiety. In still a further variation, a compound of the invention is of the formula (IA) or (IB), where X¹-X⁴, R¹, R^2a, R^2b, R^3aand R^3bare as defined herein or as detailed in any variation herein, where at least one of R^4aand R^4bis methyl, bromo, hydroxyl or R^4aand R^4bare taken together to form a carbonyl moiety.
In another variation, a compound of the invention is of the formula (IA) or (IB), where X¹-X⁴, R¹, R^2a, R^2b, R^3aand R^3bare as defined herein or as detailed in any variation herein, where both R^4aand R^4bare methyl. In another variation, a compound of the invention is of the formula (IA) or (IB), where X¹-X⁴, R¹, R^2a, R^2b, R^3aand R^3bare as defined herein or as detailed in any variation herein, where R^4aand R^4bare taken together to form a carbonyl moiety. In another variation, a compound of the invention is of the formula (IA) or (IB), where X
-X
, R¹, R^2a, R^2b, R^3aand R^3bare as defined herein or as detailed in any variation herein, where R^4ais H and R^4bis methyl. In another variation, a compound of the invention is of the formula (IA) or (IB), where X¹-X⁴, R¹, R^2a, R^2b, R^3aand R^3bare as defined herein or as detailed in any variation herein, where R^4ais H and R^4bis bromo. When the carbon of formula (IA) or (IB) bearing R^4aand R^4bis optically active, it may be in the (R)- or (S)-configuration and compositions comprising substantially pure (R) or (S) compound or mixtures thereof in any amount are embraced by this invention.
In one variation, a compound of the invention is of the formula (IA) or (IB) wherein the ring comprising N, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bis a moiety selected from the following structures:
wherein R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare as defined for formula (IA) or (IB), and p is 1 or 2.
In another variation, a compound of the invention is of the formula (IA) or (IB) wherein the ring comprising N, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bis a moiety selected from the following structures:
wherein R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare as defined for formula (Ia), and p is 1 or 2.
In another variation, a compound of the invention is of the formula (IA) or (IB) wherein the ring comprising N, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bis a moiety selected from the following structures:
In another variation, a compound of the invention is of the formula (IA) or (IB) wherein the ring comprising N, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bis a moiety selected from the following structures:
In any one of the variations of compounds of the formulae described herein, all stereoisomers are intended. For example, the C-ring can be either
Where more than one stereocenter is present, it is understood that all such stereoisomers are intended. For example, a compound having two stereocenters may be present in the (S),(S); (S),(R); (R),(R); and (R),(S) forms. Compositions comprising a single stereoisomer or mixtures of more than one stereoisomer are also intended. Compositions comprising a mixture of stereoisomers in any ratio are embraced, including mixtures of two or more stereochemical forms of a compound of the invention in any ratio, such that racemic, non-racemic, enantioenriched and scalemic mixtures of a compound are embraced.
In some embodiments, the ring comprising N, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bis a moiety selected from the following structures:
where R¹in the structures above is as defined for formula (IA) or (IB) or any particular variation detailed herein. In some embodiments, the ring comprising N, R^2a, R^2b, R
, R
, R
and R
^bis a moiety selected from the following structures:
where R¹is as defined for formula (IA) or (IB) or any particular variation detailed herein. Any formula detailed herein, where applicable, may in one variation have a ring according to the structures above.
In compounds of formula (IA) or (IB), Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, which may be but is not limited to a substituted or unsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group. In one variation, a compound of the invention is of the formula (IA) or (IB) or any variation of the foregoing detailed herein, where Q is a substituted or unsubstituted phenyl or pyridyl group. In a particular variation, Q is a phenyl or pyridyl group substituted with at least one methyl, trifluoromethyl, methoxy or halo substituent. In another variation, a compound of the invention is of the formula (IA) or (IB) or any variation of the foregoing detailed herein, where Q is a pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group substituted with at least one substituted or unsubstituted C₁-C₄alkyl, C₁-C₄alkoxy, halo or C₁-C₄perhaloalkyl moiety.
In still another variation, a compound of the invention is of the formula (IA) or (IB) or any variation of the foregoing detailed herein, where Q is a substituted or unsubstituted C₃-C₈cycloalkyl or a substituted or unsubstituted heterocyclyl. In another variation, Q is a substituted or unsubstituted C₃-C₈cycloalkyl or a substituted or unsubstituted heterocyclyl. In yet another variation, a compound of the invention is of the formula (IA) or (IB) or any variation of the foregoing detailed herein, where Q is a substituted or unsubstituted pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group. In a particular variation, Q is a pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group substituted with at least one methyl, CF₃, methoxy or halo group.
In one variation, a compound of the invention is of the formula (IA) or (IB) or any variation of the foregoing detailed herein, where Q is an unsubstituted cycloalkyl or an unsubstituted heterocyclyl. In another variation, Q is an unsubstituted C₃-C₈cycloalkyl or an unsubstituted heterocyclyl. In another variation, a compound of the invention is of the formula (IA) or (IB) or any variation of the foregoing detailed herein, where Q is a substituted or unsubstituted cyclohexyl, morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinyl moiety. In yet another variation, a compound of the invention is of the formula (IA) or (IB) or any variation of the foregoing detailed herein, where Q is a substituted cyclohexyl, morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinyl moiety substituted with at least one carbonyl, hydroxymethyl, methyl or hydroxyl group. Q groups may be attached to the parent structure at any available position on the Q moiety. Thus, although specific attachment points for certain Q moieties are depicted herein, it is understood that such Q moieties, may also be connected to the parent structure at any available position. For example, if a mono-fluoro-phenyl is depicted herein, it is understood that each of the available mono-fluoro-phenyls are embraced, e.g., 2-fluoro-phenyl, 3-fluoro-phenyl and 4-fluoro-phenyl. It is also understood that any formula detailed herein, where applicable, may in one variation have a Q moiety as detailed herein and below.
In still another variation, a compound of the invention is provided where Q is a moiety selected from the structures:
wherein each R⁹is independently a halo, cyano, nitro, perhaloalkyl (C₁-C₈), perhaloalkoxy (C₁-C₈), substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstituted heterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino. In one variation, Q is substituted with no more than one R⁹group. In another variation, Q is substituted with only one R⁹group. In one variation, Q is substituted with two R⁹groups. In another variation, Q is substituted with two vicinal R⁹groups that are taken together with the annular atoms to which they are attached to form a second fused ring. In a further variation, Q is selected from the aromatic structures detailed where the residue has the moiety (R⁹)₀such that each Q either contains no R⁹functionality or a moiety of the formula N—R⁹.
In another variation, a compound of the invention is provided where Q is a moiety selected from the structures:
and wherein R⁹is connected to Q ortho or para to the position at which Q is connected to the indole nitrogen of the pyrido[4,3-b]indole or pyrido[3,4-b]indole. In a particular variation, Q is a structure of the formula:
and R⁹is connected to Q para to the position at which Q is connected to the indole nitrogen of the pyrido[4,3-b]indole or pyrido[3,4-b]indole. In another particular variation, Q is a structure of the formula
where each R⁹is independently alkyl, perhaloalkyl or halo.
In another variation, a compound of the invention is provided where Q is a moiety selected from the structures:
wherein each R⁹is independently a halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino. In one variation, Q is substituted with no more than one R⁹group. In another variation, Q is substituted with only one R⁹group. In yet another variation, Q is substituted with two R⁹groups. In another variation, Q is substituted with two vicinal R⁹groups which are taken together with the annular atoms to which they are attached to form a second fused ring. In a particular variation, Q is selected from the carbocyclic and heterocyclic structures detailed where the residue has the moiety (R⁹)₀such that each Q either contains no R⁹functionality or a moiety of the formula N—R⁹.
In any structure or variation detailed herein containing an R⁹group, in one variation, each R⁹is independently a substituted or unsubstituted C₁-C₄alkyl, halo, trifluoromethyl or hydroxyl. In another variation, each R⁹is independently methyl, —CH₂OH, isopropyl, halo, trifluoromethyl or hydroxyl.
In another variation, a compound of the invention is provided where Q is an aromatic moiety selected from the structures:
In another variation, a compound of the invention is provided where Q is a heteroaromatic moiety selected from the structures:
In yet another variation, a compound of the invention is provided where Q is a substituted or unsubstituted cycloalkyl or heterocyclyl selected from the structures:
In yet another variation, a compound of the invention is provided where Q is a substituted or unsubstituted cycloalkyl or heterocyclyl selected from the structures:
In yet another variation, a compound of the invention is provided where Q is selected from the structures:
In a further variation, a compound of the invention is provided where R¹is an unsubstituted alkyl, R^2a, R^2b, R^3a, R^3band R⁴are each H, each X¹, X², X³and X⁴is independently N or CH, and Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, including but not limited to a substituted or unsubstituted phenyl or pyridyl group. Where Q is a substituted phenyl or pyridyl group, in one variation it is substituted with at least one methyl or halo group.
In yet a further variation, a compound of the invention is provided where R
is a substituted or unsubstituted C₁-C₈alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl; each R^2aand R^2bis independently H, unsubstituted C₁-C₈alkyl or halo; each R^3aand R^3bis independently H or halo; each X¹, X²and X³is CH or CR⁶, where R⁶is as defined or as detailed in a particular variation, R⁶is halo, pyridyl, methyl or trifluoromethyl; R^4aand R^4bare both H, and Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, including but not limited to a substituted or unsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group. In a particular variation, Q is a pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group substituted with at least one substituted or unsubstituted C₁-C₈alkyl, halo or perhaloalkyl moiety. In one variation, a compound of the variation detailed herein is provided wherein R¹is propylate, methyl, ethyl, cyclopropyl, trifluoromethyl, isopropyl, tert-butyl, sec-butyl, 2-methylbutyl, propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted phenyl, piperidin-4-yl, hydroxycyclopent-3-yl, hydroxycyclopent-2-yl, hydroxycycloprop-2-yl, 1-hydroxy-1-methylcycloprop-2-yl, or 1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl.
In still a further variation, a compound of the invention is provided where R¹is a substituted or unsubstituted C₁-C₈alkyl; each R^2a, R^2b, R^3aand R^3bis independently H or halo; each R⁶is independently halo, C₁-C₈perhaloalkyl, substituted or a unsubstituted C₁-C₈alkyl; and Q is a substituted or unsubstituted cyclohexyl, morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinyl moiety. The invention also embraces a compound where R¹is a methyl; at least one of X¹and X²is CR⁶, and each R⁶is independently halo, methyl or trifluoromethyl. The invention embraces compounds where each Q in any variation detailed, where applicable, is independently substituted with at least one carbonyl, hydroxymethyl, methyl or hydroxyl group.
In a particular variation, a compound is provided where R¹is a substituted or unsubstituted C₁-C₈alkyl; each R^2aand R^2bis independently H, a substituted or unsubstituted C₁-C₈alkyl or R^2aand R^2bare taken together to form a carbonyl moiety; R^3aand R^3bare both H; each R⁶is independently halo or a substituted or unsubstituted C₁-C₈alkyl; each R^4aand R^4bis independently H, halo, a substituted or unsubstituted C₁-C₈alkyl, hydroxyl, alkoxy or R^4aand R^4bare taken together to form a carbonyl moiety, provided that at least one of R^4aand R^4bis other than H. In one aspect of this variation, each Q may independently be a substituted or unsubstituted pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group. In another aspect of this variation, Q is a pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group substituted with at least one methyl or halo group. In yet another aspect of this variation, X¹, X²and X³are CH or CR⁶and each R⁶is independently halo or methyl.
The embodiments and variations described herein are suitable for compounds of any formulae detailed herein, where applicable. For instance, all variations referring to the formula (IA) detailed herein, such as formulae (IA), (IA1), (IA2), (IA3), (IA4), (IA5), (IA6), (IA7), (IA8), (IA9), (A1), (A2), (B1), (B2), (B3), (B4), (B5), (B6), (C1), (C2) and (C3), where applicable, may apply to formulae (IB), (J-1), (J-1a), (J-1b), (J-1c), (J-2), (J-3), (J-4), (K-1), (K-la), (K-1b), (K-1c), (K-2), (K-3), (K-4) the same as if each and every variation were specifically and individually listed. In another instance, all variations referring to the formulae herein, such as formulae (IA), (IA1), (IA2) and (IA3), where applicable, may apply to formula (IA4), (IA5), (IA6), (IA7), (IA8), (IA9), (A1), (A2), (B1), (B2), (B3), (B4), (B5), (B6), (C1), (C2) or (C3), (IB), (J-1), (J-1a), (J-1b), (J-1c), (J-2), (J-3), (J-4), (K-1), (K-1a), (K-1b), (K-1c), (K-2), (K-3), (K-4) the same as if each and every variation were specifically and individually listed.
The embodiments and variations described herein for Formula (IA) are also suitable for compounds of formula (IA) or (IB). The embodiments and variations described herein for Formula (IB) are also suitable for compounds of formula (IA) or (IB).
In one embodiment, the invention relates to Compounds described in Table 1, and uses thereof.
In another embodiment, the invention relates to Compounds 1-88, 100, 102-105 and 131-164, and uses thereof.
Representative examples of compounds detailed herein, including intermediates and final compounds according to the invention are depicted in the tables below. It is understood that in one aspect, any of the compounds may be used in the methods detailed herein, including, where applicable, intermediate compounds that may be isolated and administered to an individual.
The compounds depicted herein may be present as salts even if salts are not depicted and it is understood that the invention embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan. In some embodiments, the salts of the compounds of the invention are pharmaceutically acceptable salts. Where one or more tertiary amine moiety is present in the compound, the N-oxides are also provided and described.
Pharmaceutical compositions of any of the compounds detailed herein are embraced by this invention. Thus, the invention includes pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form. In one aspect, “substantially pure” intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof. Taking compound 1 as an example, a composition of substantially pure compound 1 intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than compound 1 or a salt thereof. In one variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25% impurity. In another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 20% impurity. In still another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 10% impurity. In a further variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 5% impurity. In another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 3% impurity. In still another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 1% impurity. In a further variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 0.5% impurity. In yet other variations, a composition of “substantially pure” compound contains no more than 15% or preferably no more than 10% or more preferably no more than 5% or even more preferably no more than 3% and most preferably no more than 1% impurity, which impurity may be the compound in a different stereochemical form. For instance, a composition of substantially pure (S) compound means that the composition contains no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the (R) form of the compound.
In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, the invention embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
Kits comprising a compound of the invention, or a salt or solvate thereof, and suitable packaging are provided. In one embodiment, a kit further comprises instructions for use. In one aspect, a kit comprises a compound of the invention, or a salt or solvate thereof, and instructions for use of the compounds in the treatment of a disease or indication for which enhancing insulin secretion and/or promoting insulin release is expected to be or is beneficial.
Articles of manufacture comprising a compound of the invention, or a salt or solvate thereof, in a suitable container are provided. The container may be a vial, jar, ampoule, preloaded syringe, i.v. bag, and the like.
In one aspect, an adrenergic receptor α_2Aantagonist as provided herein exhibits the ability to cross the blood-brain barrier. In another aspect, an adrenergic receptor α_2Aantagonist as provided herein is not able to cross the blood-brain barrier. In one aspect, an adrenergic receptor α_2Aantagonist as provided herein exerts its therapeutic effect in the brain only. In one aspect, an adrenergic receptor α_2Aantagonist as provided herein exerts its therapeutic effect in the periphery only. In one aspect, an adrenergic receptor α_2Aantagonist as provided herein exerts its therapeutic effect both in the brain and peripherally. In some embodiments, the adrenergic receptor α_2Aantagonist also exhibits adrenergic receptor α_2Ainverse agonist activity.
Blood brain barrier permeability can be measured in rodents or dog by administering the compound orally or intravenously, recovering a blood and brain tissue sample at different time points and comparing how much compound is in each sample. Blood fraction is typically processed to plasma for determination of compound content. Brain exposure can be described from the ratio of brain to plasma levels of drug. In one variation, a compound that poorly crosses the blood brain barrier has a brain to plasma ratio of compound of about 0.1 or less. In another variation, the compound has a brain to plasma ratio of about 0.2 or less, about 0.3 or less, about 0.4 or less, about 0.5 or less, about 0.8 or less, or about 1.0 or less.
Preferably, the compounds provided herein are orally bioavailable. However, the compounds may also be formulated for parenteral (e.g., intravenous) administration. In some settings, parenteral administration may be desired.
One or several compounds described herein can be used in the preparation of a medicament by combining the compound or compounds as an active ingredient with a pharmaceutically acceptable carrier, which are known in the art. Depending on the therapeutic form of the medication, the carrier may be in various forms. In one variation, the manufacture of a medicament is for use in any of the methods disclosed herein, e.g., increasing insulin secretion of an individual or treating or delaying the onset and/or development of type 2 diabetes, glucose intolerance or metabolic syndrome.
Methods as provided as provided herein may comprise administering to an individual a pharmacological composition that contains an effective amount of a compound and a pharmaceutically acceptable carrier. The effective amount of the compound may in one aspect be a dose of between about 0.01 and about 100 mg.
The compound may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form. A compound may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.
One or several compounds described herein can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above. Depending on the therapeutic form of the system (e.g., transdermal patch vs. oral tablet), the carrier may be in various forms. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Formulations comprising the compound may also contain other substances which have valuable therapeutic properties. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 20^thed. (2000), which is incorporated herein by reference.
Compounds as described herein may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
Any of the compounds described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein or a pharmaceutically acceptable salt thereof can be formulated as a 10 mg tablet.
The compound may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual's life. In one variation, the compound is administered on a daily or intermittent schedule. The compound can be administered to an individual continuously (for example, at least once daily) over a period of time. The dosing frequency can also be less than once daily, e.g., about a once weekly dosing. The dosing frequency can be more than once daily, e.g., twice or three times daily. The dosing frequency can also be intermittent (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.
Compositions comprising a compound provided herein are also described. In one variation, the composition comprises a compound and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of substantially pure compound is provided.
The invention further provides kits for carrying out the methods of the invention, which comprises one or more compounds described herein or a pharmacological composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein or a pharmaceutically acceptable salt thereof. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for any one or more of the following uses: treating, preventing, and/or delaying the onset and/or development of diabetes type 2 and/or a disease or condition which is responsive, or expected to be responsive, to an increase in insulin secretion.
Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit.
The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or a second pharmaceutically active compound useful for a disease detailed herein (e.g., type 2 diabetes) to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).
The Kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present invention. The instructions included with the kit generally include information as to the components and their administration to an individual.
The invention also provides compositions (including pharmacological compositions) as described herein for the use in treating, preventing, and/or delaying the onset and/or development of diabetes type 2 and/or a disease or condition which is responsive, or expected to be responsive, to an increase in insulin secretion and other methods described herein. In certain embodiments, the composition comprises a pharmaceutical formulation which is present in a unit dosage form. As used herein, the term “unit dosage form” refers to a formulation that contains a predetermined dose of a compound as disclosed herein and optionally a second pharmaceutically active compound useful for treatment of a disease or condition detailed herein (e.g., type 2 diabetes).
Representative compounds of the invention are shown in Table 1.

TABLE 1

Representative Compounds of the Invention

Compound
No.	Structure

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

General Synthetic Methods

The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (IA) or (IB) or a variation thereof unless otherwise indicated.
Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.

General Protocol for Chiral Reverse Phase HPLC Separation of Racemic Compounds

For chiral separations, samples were dissolved in Methanol and Ethanol according to the solubility of sample and filtered through 0.22μ PTFE filters. The columns used were CHIRALPAK-AD; 20*250 mm, 10μ and CHIRALCEL-ODH; 20*250 mm, 5μ. A flow rate of 12 mL/min-17 mL/min was used according to the resolution. Alkanes such as n-Pentane, Hexane and Heptane (40%-95%) and alcohols such as Ethanol, Isopropyl alcohol and t-Butanol (5%-60%) were used as mobile phase. In some cases alcohol combinations i.e. (Ethanol+Methanol), (Ethanol+IPA), (IPA+Methanol), (t-Butanol+Methanol), (t-Butanol+Ethanol) were used instead of a single alcohol. Diethyl amine (up to 0.3%) was used as modifier in the mobile phase.
The following abbreviations are used herein: thin layer chromatography (TLC); hour (h); minute (min); second (sec); ethanol (EtOH); dimethylsulfoxide (DMSO); N,N-dimethylformamide
(DMF); 1,2-dimethoxyethane (DME); trifluoroacetic acid (TFA); tetrahydrofuran (THF); Normal (N); aqueous (aq.); methanol (MeOH); dichloromethane (DCM); ethyl acetate (EtOAc); Retention factor (R^f); room temperature (RT). General methods of preparing compounds according to the invention are depicted in exemplified methods below. Other compounds of the invention may be prepared by similar methods. Compounds detailed herein may be prepared by those of skill in the art by referral to General Methods and Examples described in published PCT applications WO2009/055828 (see e.g., General Methods 1-24 and Examples 1-325), WO2010/127177 (General Methods 1-3 and Examples 1-58), WO2009/120720 (General Methods 1-15C and Examples 1-134), WO2009/120717 (General Methods 1-17 and Examples 1-134), WO2010/051501 (General Methods 1-10 and Examples 1-450) and WO2010/051503 (General Methods 1-15 and Examples 1-111), WO2011/019417 (General Methods 1-9 and Examples 1-10), WO2011/038164 (General Methods 1-19), WO2011/038162 (General Methods 1-21 and Examples 1-6), WO2011/038163 (General Methods 1-19 and Examples 1-49) and WO2011/038161 (General Methods 1-15B and Examples 1-22). The PCT publications described above are incorporated herein by reference in their entireties. Particular methods of synthesizing compounds of the invention are described in the Examples below and in the PCT Publication No. WO2011/103430 (General Methods 1-10 and Examples 1-132).
Routes to synthesizing aryl-linked compounds of the invention are shown below as General Methods 1 to 10. Although identifiers such as R¹and R⁶are shown in the method below, it is understood that these moieties apply to the compounds detailed herein even if different identifiers or variations thereof are used elsewhere (e.g., it is understood that compounds may include more than one R¹, R⁶etc.).

General Method 1

A solution of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (9.09 mmol), 3,4-dihalo-thiophene (10.90 mmol), potassium phosphate (27.27 mmol), CuI (0.909 mmol) and L-Proline (1.81 mmol) in dry DMF (12 mL) was stirred at 150° C. for 24 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford the crude product, which was purified by column chromatography using neutral alumina and 3% EtOAc-Hexane as eluant to yield 0.3 g of 5-(4-halothiophen-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an oil.

General Method 2

To a de-aerated solution of 5-(4-halothiophen-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.217 mmol), aryl-boronic acid or aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.431 mmol) and K₂CO₃(0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh₃)₄(0.013 mmol). The reaction mixture was purged with N₂for 5 min and stirred at 90
C. for 4 min. The reaction mixture was concentrated under vacuum and the residue dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford the crude product, which was purified by reverse phase HPLC to yield 5-(4-arylthiophen-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

General Method 3

A solution of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (9.09 mmol), 1,2-dihalobenzene (13.65 mmol), potassium phosphate (27.27 mmol), CuI (0.909 mmol) and L-Proline (1.81 mmol) in dry DMF (12 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford the crude product, which was purified by column chromatography using neutral alumina and 3% EtOAc-Hexane as eluant to yield 5-(2-halophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an oil.

General Method 4

A solution of 5-(2-halophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.281 mmol), aryl-boronic acid or aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.557 mmol) and K₂CO₃(0.845 mmol) in DME (4 mL)-water (2 mL) was purged with nitrogen followed by addition of Pd(PPh₃)₄(0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under vacuum, the residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under vacuum to obtain the crude product, which was purified by reverse phase HPLC to yield 5-(2-(aryl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

General Method 5

A solution of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (9.09 mmol), 1,3-dihalobenzene (13.65 mmol), potassium phosphate (27.27 mmol), CuI (0.909 mmol) and L-Proline (1.81 mmol) in dry DMF (12 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford crude material, which was purified by column chromatography using neutral alumina and 3% EtOAc-Hexane as eluant to yield 5-(3-halophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an oil.

General Method 6

A solution of 5-(3-halophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.281 mmol), aryl-boronic acid or aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.557 mmol) and K₂CO₃(0.845 mmol) in DME (4 mL)-water (2 mL) was purged with nitrogen followed by addition of Pd(PPh₃)₄(0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture concentrated under vacuum, residue diluted with water (20 mL) and extracted with EtOAc (
mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under vacuum to obtain crude which was purified by reverse phase HPLC to yield 543-(aryl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

General Method 7

A solution of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (5 mmol), 1,2-dihalocycloalkene (6.4 mmol), potassium phosphate (10 mmol), CuI (0.5 mmol) and L-Proline (1 mmol) in dry DMF (7 mL) was stirred at 130° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford crude product, which was purified by column chromatography using neutral alumina and 3% EtOAc-Hexane as eluant to yield 5-(2-halocycloalk-1-en-1-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

General Method 8

A solution of 5-(2-halocycloalk-1-en-1-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.29 mmol), aryl-boronic acid or aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.579 mmol) and K₂CO₃(0.87 mmol) in DME (4 mL)-water (2 mL) was purged with nitrogen followed by addition of Pd(PPh₃)₄(0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under vacuum, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under vacuum to obtain crude, which was purified by reverse phase HPLC to yield 5-(2-arylcycloalk-1-en-1-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

General Method 9

Condensation of appropriately functionalized 4-hydrazino pyridine E-1 with functionalized azepan-4-ones in step 1 yields the 9-aza-hexahydroazepino[
,4-b]indole intermediate E-2. The indole nitrogen atom can be coupled in step 2 with appropriately functionalized aromatic or heteroaromatic reagents known to those skilled in the art to give E-3. When necessary, further conversion of substituents such as X, for example halo, with reagents such as aryl boronic acids under the Suzuki reaction, leads to derivative E-4. Although the Scheme depicts phenyl or pyridyl rings in the compounds, it is understood that a number of aromatic and heteroaromatic analogs are conceivable for such synthetic routes, including but not limited to pyrimidine, pyrazine, thiophene, furan, pyrrolo, imidazole, thiazole, and the like. Similarly, the point of attachment of groups such as R′ to the aromatic or heteroaromatic groups can be envisioned in a variety of chemically feasible locations. All possible attachment locations of functional groups on the aromatic ring(s) should be considered.

General Method 10

Condensation of appropriately functionalized aryl hydrazine G-1 with cyclohexane-1,3-dione in step 1 yields the dihydrocarbazolone intermediate G-2. The keto group is then converted in step 2 using standard conditions to give oxime G-3 that can undergo a Beckmann rearrangement in step 3 to yield the tetrahydroazepinoindolone G-4. Reduction of the amide in step 4 provides hexahydroazepinoindole G-5, the secondary amino group of which can be functionalized in step 5 to provide functionalized tertiary amine G-6. The indole nitrogen atom can be coupled in step 6 with appropriately functionalized aromatic or heteroaromatic reagents known to those skilled in the art to give G-7. When necessary, further conversion of substituents such as X
, for example halo, with reagents such as aryl boronic acids under the Suzuki reaction in step 7, leads to derivative G-8. Although the Scheme depicts phenyl or pyridyl rings in the compounds, it is understood that a number of aromatic and heteroaromatic analogs are conceivable for such synthetic routes, including but not limited to pyrimidine, pyrazine, thiophene, furan, pyrrolo, imidazole, thiazole, and the like. Similarly, the point of attachment of groups such as R′ to the aromatic or heteroaromatic groups can be envisioned in a variety of chemically feasible locations. All possible attachment locations of functional groups on the aromatic ring(s) should be considered.
The methods detailed above may be adapted as known by those of skill in the art to make compounds detailed herein. Particular examples of each of the General Methods are provided in the Examples below. One or more of the General Methods detailed above may be adapted or combined as required by those of skill in the art to make compounds detailed herein. Particular examples of each of the General Methods are provided in the Examples below. Compounds 1-88, 100-105 and 131-164 were prepared according to Example Nos. 1-88 and 92-130 respectively.
The following Examples are provided to illustrate but not to limit the invention.
All references disclosed herein are incorporated herein by reference in their entireties.

EXAMPLES

Example No. 1

Preparation of Compound No. 1

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 1 mmol), bromobenzene (0.314 g, 2 mmol), K₃PO₄(0.424 g, 2 mmol), CuI (19 mg, 0.1 mmol) and L-Proline (23 mg, 0.2 mmol) in dry DMF (3 mL) was stirred at 150° C. for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off white solid (83 mg). ¹H NMR(HCl salt, CD₃OD) δ (ppm): 7.60 (t, 2H), 7.5 (t, 1H), 7.4 (d, 2H), 7.35 (s, 1H), 7.1 (d, 1H), 7.05 (d, 1H), 4.8 (d, 1H), 4.4 (d, 1H), 3.85-3.8 (m, 1H), 3.6-3.59 (m, 1H), 3.2-3.19 (m, 1H), 3.18 (s, 3H), 3-2.95 (m, 1H), 2.4 (s, 3H).

Example No. 2

Preparation of Compound No. 2

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, μmol), 4-bromopyridine (0.316 g, 2 mmol), K₃PO₄(0.424 g, 2 mmol), CuI (19 mg, 0.1 mmol) and L-Proline (23 mg, 0.2 mmol) in dry DMF (3 mL) was stirred at 150° C. for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-pyridin-4-yl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off white solid (30 mg). ¹H NMR(HCl salt, CD₃OD) δ (ppm): 8.95 (d, 2H), 8.21 (d, 2H), 7.65 (d, 1H), 7.21 (s, 1H), 7.21 (d, 1H), 4.8 (d, 1H), 4.4 (d, 1H), 3.95-3.9 (m, 1H), 3.6-3.50 (m, 2H), 3.25 (m, 1H), 3.2 (s, 3H), 2.5 (s, 3H).

Example No. 3

Preparation of Compound No. 3

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 1 mmol), 5-bromo-2-methyl-pyridine (0.348 g, 2 mmol), K₃PO₄(0.424 g, 2 mmol), CuI (19 mg, 0.1 mmol) and L-Proline (23 mg, 0.2 mmol) in dry DMF (3 mL) was stirred at 150° C. for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(6-methyl-pyridin-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as semisolid (8.6 mg). ¹H NMR(HCl salt, CD₃OD) δ (ppm): 8.6 (s, 1H), 8.05 (d, 1H), 7.7 (d, 1H), 7.19 (s, 1H), 7.19-7.05 (dd, 2H), 4.8 (m, 1H), 4.4 (m, 1H), 3.90-3.8 (m, 1H), 3.6-3.50 (m, 1H), 3.25-3.20 (m, 1H), 3.2 (s, 3H), 3.05-3.0 (m, 1H), 2.75 (s, 3H), 2.45 (s, 3H).

Example No. 4

Preparation of Compound No. 4

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.4 g, 2 mmol), 5-bromo-2-trifluoromethyl-pyridine (1.356 g, 6 mmol), K₃PO₄(1.272 g, 6 mmol), CuI (38 mg, 0.2 mmol) and L-Proline (70 mg, 0.4 mmol) in dry DMF (5 mL) was stirred at 150° C. for 4 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by column chromatography using silica (100-200 mesh) and 3%
MeOH:DCM to yield 2,8-dimethyl-5-(6-trifluoromethyl-pyridin-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off white solid (150 mg). ¹H NMR(HCl salt, CD₃OD) δ (ppm): 8.85 (s, 1H), 8.2 (d, 1H), 8.1 (d, 1H), 7.4 (s, 1H), 7.2 (d, 1H), 7.1 (d, 1H), 4.8 (m, 1H), 4.4 (m, 1H), 3.9-3.85 (m, 1H), 3.6-3.59 (m, 1H), 3.25-3.2 (m, 1H), 3.2 (s, 3H), 3.1-3.0 (m, 1H), 2.41 (s, 3H).

Example No. 5

Preparation of Compound No. 5

To a de-aerated solution of 5-(2-bromo-phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (180 mg, 0.508 mmol), 4-pyridinylboronic acid (93.8 mg, 0.762 mmol) and K₃PO₄(270 mg, 1.27 mmol) in DMF-water (9:1 mL) was added PdCl₂(PPh₃)₂(18 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-pyridin-4-yl-phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as semisolid (14 mg). ¹H NMR (Freebase, CDCl₃) δ (ppm):
(d, 2H), 7.58 (m, 3H), 7.40 (d, 1H), 7.20 (s, 1H), 6.90 (m, 4H),
(m, 2H), 2.76 (m, 1H), 2.60 (m, 1H), 2.50 (m, 1H), 2.48 (s, 3H), 2.42 (s, 3H), 2.20 (m, 1H).

Example No. 6

Preparation of Compound No. 6

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 1 mmol), (2-bromo-phenyl)-dimethyl-amine (600 mg, 3 mmol), K₃PO₄(636 mg, 3 mmol), L-Proline (69 mg, 0.6 mmol) and CuI (57 mg, 0.3 mmol) in dry DMF (4 mL) was stirred at 150° C. for 16 h. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by column chromatography using neutral alumina and 10% EtOAc-Hexane followed by reverse phase HPLC purification to yield [2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-phenyl]-dimethyl-amine (20 mg). ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.50 (m, 1H), 7.38 (m, 2H), 7.18 (m, 2H), 7.0 (m, 2H), 4.75 (d, 1H), 4.40 (m, 1H), 3.80 (m, 1H), 3.58 (m, 1H), 3.15 (s, 3H), 3.0 (m, 1H), 2.70 (m, 1H), 2.56 (s, 6H), 2.42 (s, 3H).

Example No. 7

Preparation of Compound No. 7

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 1 mmol), (3-bromo-phenyl)-dimethyl-amine (600 mg, 3 mmol), K₃PO₄(636 mg, 3 mmol), L-Proline (69 mg, 0.6 mmol) and CuI (57 mg, 0.3 mmol) in dry DMF (4 mL) was stirred at 150° C. for 16 h. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by column chromatography using neutral alumina and 10% EtOAc-Hexane to yield [3-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-phenyl]-dimethyl-amine as an off white solid (11 mg). ¹H NMR (Oxalate salt, CD₃OD) δ (ppm): 7.40 (t, 1H), 7.30 (s, 1H), 7.10 (d, 1H), 7.86 (d, 1H), 6.64 (m, 2H), 4.58 (m, 2H), 3.64 (m, 2H), 3.16 (s, 3H), 3.08 (m, 2H), 2.96 (s, 6H), 2.42 (s, 3H).

Example No. 8

Preparation of Compound No. 8

To a de-aerated solution of 5-(2-bromo-phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.282 mmol), phenylboronic acid (51.7 mg, 0.423 mmol) and K₃PO₄(149.7 mg, 0.706 mmol) in DMF-water (4:1 mL) was added PdCl₂(PPh₃)₂(10 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-biphenyl-2-yl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (18 mg). ¹H NMR (Freebase, CDCl₃) δ (ppm): 7.58 (d, 1H), 7.44 (m, 2H), 7.30 (d, 1H), 7.18 (m, 4H), 6.98 (m, 3H), 6.82 (d, 1H), 3.70 (d, 1H), 3.60 (d, 1H), 3.64 (m, 1H), 2.50 (m, 1H), 2.44 (s, 3H), 2.40 (s, 3H), 2.18 (m, 2H).

Example No. 9

Preparation of Compound No. 9

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 1 mmol), 5-bromoisoquinoline (208 mg, 1 mmol), K₃PO₄(318 mg, 1.5 mmol), L-Proline (11.5 mg, 0.2 mmol) and CuI (9.5 mg, 0.05 mmol) in dry DMF (2 mL) was stirred at 150° C. for 24 h. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-isoquinolin-5-yl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off white solid (20 mg). ¹H NMR (Oxalate salt, CD₃OD) δ (ppm): 9.42 (s, 1H), 8.40 (m, 2H), 7.90 (m, 2H), 7.40 (s, 1H), 7.08 (d, 1H), 6.99 (d, 1H), 6.70 (d, 1H), 4.65 (m, 2H), 3.70 (m, 2H), 3.18 (s, 3H), 3.0 (m, 1H), 2.72 (m, 1H), 2.42 (s, 3H).

Example No. 10

Preparation of Compound No. 10

To a de-aerated solution of 5-(2-bromo-phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.282 mmol), 4-fluorophenylboronic acid (59 mg, 0.423 mmol) and K₃PO₄(149 mg, 0.706 mmol) in DMF-water (4:1 mL) was added PdCl₂(PPh₃)₂(10 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield crude, which was purified by reverse phase HPLC to yield 5-(4′-fluoro-biphenyl-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as semisolid (19.23 mg). ¹H NMR (Oxalate salt, CD₃OD) δ (ppm): 7.65-7.59 (m, 3H), 7.41 (d, 1H), 7.25 (s, 1H), 7.15 (m, 1H), 7.05-6.85 (m, 5H), 4.5-3.39 (m, 2H), 3.6-3.5 (m, 1H), 3.2-3.19 (m, 1H), 2.95 (s, 3H), 2.85-2.8 (m, 1H), 2.59-2.50 (m, 1H), 2.4 (s, 3H).

Example No. 11

Preparation of Compound No. 11

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.4 g, 4 mmol), 1-bromonaphthalene (0.828 g, 4 mmol), K₃PO₄(0.848 g, 4 mmol), CuI (38 mg, 0.2 mmol) and L-Proline (46 mg, 0.39 mmol) in dry DMF (6 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-naphthalen-2-yl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off white solid (20 mg). ¹H NMR(HCl salt, CD₃OD) δ (ppm): 8.15 (d, 1H), 8.05 (d, 1H), 7.7 (bs, 1H), 7.6-7.50 (m, 2H), 7.41-7.4 (m, 2H), 7.1 (t, 1H), 6.95 (d, 1H), 6.7-6.65 (dd, 1H), 4.9-4.8 (m, 1H), 4.5-4.4 (m, 1H), 3.8-3.79 (m, 1H), 3.6-3.59 (m, 1H), 3.2 (s, 3H), 2.85-2.8 (m, 1H), 2.6-2.59 (m, 1H), 2.45 (s, 3H).

Example No. 12

Preparation of Compound No. 12

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.4 g, 4 mmol), 2-Bromonaphthalene (0.828 g, 4 mmol), K₃PO₄(0.848 g, 4 mmol), CuI (38 mg, 0.2 mmol) and L-Proline (46 mg, 0.39 mmol) in dry DMF (6 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-naphthalen-2-yl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off white solid (50 mg). ¹H NMR(HCl salt, CD₃OD) δ (ppm): 8.15 (d, 1H), 8.05-7.95 (m, 2H), 7.9 (s, 1H), 7.6 (m, 2H), 7.5 (d, 2H), 7.35 (s, 1H), 7.19 (d, 1H), 7.05 (d, 1H), 4.8 (d, 1H), 4.45 (d, 1H), 3.8-3.79 (m, 1H), 3.6-3.59 (m, 1H), 3.3-3.25 (m, 1H), 3.19 (s, 3H), 3.05-3.0 (m, 1H), 2.45 (s, 3H).

Example No. 13

Preparation of Compound No. 13

To a de-aerated solution of 5-(2-bromo-phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.282 mmol), 3-pyridinylboronic acid (51 mg, 0.420 mmol) and K₃PO₄(149 mg, 0.706 mmol) in DMF-water (4:1 mL) was added PdCl₂(PPh₃)₂(10 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-pyridin-3-yl-phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as a semisolid (30 mg). ¹H NMR (Oxalate salt, CD₃OD) δ (ppm): 8.30 (s, 1H), 8.10 (s, 1H), 7.70 (m, 3H), 7.56 (d, 1H), 7.50 (d, 1H), 7.24 (m, 2H), 6.98 (d, 1H), 6.82 (d, 1H), 4.50 (m, 2H), 3.60 (m, 2H), 3.05 (s, 3H), 2.95 (m, 1H), 2.62 (m, 1H), 2.40 (s, 3H).

Example No. 14

Preparation of Compound No. 14

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.4 g, 2 mmol), 3-bromothiophene (0.347 mL, 4 mmol), K₃PO₄(0.848 g, 4 mmol), CuI (38 mg, 0.2 mmol) and L-Proline (46 mg, 0.39 mmol) in dry DMF (6 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-thiophen-3-yl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (25 mg). ¹H NMR(HCl salt, CD₃OD) δ (ppm): 7.65 (m, 1H), 7.50 (s, 1H), 7.30 (s, 1H), 7.21 (d, 1H), 7.19 (d, 1H), 7.02 (d, 1H), 4.76 (d, 1H), 4.40 (d, 1H), 3.82 (m, 1H), 3.60 (m, 1H), 3.2-3.0 (m, 5H), 2.42 (s, 3H).

Example No. 15

Preparation of Compound No. 15

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.4 g, 2 mmol), 3-bromofuran (0.35 mL, 4 mmol), K₃PO₄(0.848 g, 4 mmol), CuI (38 mg, 0.2 mmol) and L-Proline (46 mg, 0.39 mmol) in dry DMF (6 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-furan-3-yl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (3 mg). ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.90 (s, 1H), 7.70 (s, 1H), 7.30 (s, 1H), 7.21 (d, 1H), 7.05 (d, 1H), 6.68 (s, 1H), 4.70 (d, 1H), 4.40 (d, 1H), 3.82 (m, 1H), 3.58 (m, 1H), 3.20-3.0 (m, 5H), 2.42 (s, 3H).

Example No. 16

Preparation of Compound No. 16

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.4 g, 2 mmol), 2-bromothiophene (0.347 mL, 4 mmol), K₃PO₄(0.848 g, 4 mmol), CuI (38 mg, 0.2 mmol) and L-Proline (46 mg, 0.39 mmol) in dry DMF (6 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-thiophen-2-yl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (20 mg). ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.50 (d, 1H), 7.30 (s, 1H), 7.15 (m, 3H), 7.05 (d, 1H), 4.78 (m, 1H), 4.39 (m, 1H), 3.80 (m, 1H), 3.58 (m, 1H), 3.15 (s, 3H), 3.05 (m, 2H), 2.42 (s, 3H).

Example No. 17

Preparation of Compound No. 17

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.4 g, 2 mmol), 5-bromo-2-methoxypyridine (0.752 g, 4 mmol), K₃PO₄(0.848 g, 4 mmol), CuI (38 mg, 0.2 mmol) and L-Proline (46 mg, 0.39 mmol) in dry DMF (6 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified reverse phase HPLC to yield 5-(6-Methoxy-pyridin-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (35 mg). ¹H NMR (TFA salt, CD₃OD) δ (ppm): 8.20 (s, 1H), 7.74 (d, 1H), 7.32 (s, 1H), 7.0 (m, 3H), 4.78 (m, 1H), 4.40 (m, 1H), 4.0 (s, 3H), 3.82 (m, 1H), 3.60 (m, 1H), 3.16 (s, 3H), 3.10 (m, 1H), 2.98 (m, 1H), 2.42 (s, 3H).

Example No. 18

Preparation of Compound No. 18

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.4 g, 2 mmol), 5-bromo-1-methyl-1H-imidazole (0.644 g, 4 mmol), K₃PO₄(0.848 g, 4 mmol), CuI (38 mg, 0.2 mmol) and L-Proline (46 mg, 0.39 mmol) in dry DMF (6 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-methyl-3H-imidazol-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (15 mg). ¹H NMR(HCl salt, CD₃OD) δ (ppm): 9.20 (s, 1H), 8.0 (s, 1H), 7.40 (s, 1H), 7.20 (d, 1H), 7.10 (d, 1H), 4.76 (d, 1H), 4.40 (d, 1H),
.84 (m, 1H), 3.62 (m, 1H), 3.58 (d, 3H), 3.18 (s, 3H), 3.05 (m, 1H), (m, 1H), 2.90 (m, 1H), 2.44 (s, 3H).

Example No. 19

Preparation of Compound No. 19

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, μmol), 4-bromo-thiazole (0.246 g, 1.5 mmol), K₃PO₄(0.636 g, 3 mmol), CuI (19 mg, 0.1 mmol) and L-Proline (23 mg, 0.2 mmol) in dry DMF (5 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-thiazol-4-yl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (59 mg). ¹H NMR (TFA salt, CD₃OD) δ (ppm): 9.10 (s, 1H), 7.62 (s, 1H), 7.38 (d, 1H), 7.30 (s, 1H), 7.10 (d, 1H), 4.70 (d, 1H), 4.30 (d, 1H), 3.80 (m, 1H), 3.50 (m, 1H), 3.26 (m, 1H), 3.18 (s, 3H), 3.16 (m, 1H), 2.42 (s, 3H).

Example No. 20

Preparation of Compound No. 20

To a de-aerated solution of 5-(4-bromo-thiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (160 mg, 0.44 mmol), 4-pyridinylboronic acid (81.9 mg, 0.66 mmol) and K₃PO₄(235 mg, 1.11 mmol) in DMF-water (4.5:0.5 mL) was added dichlorobis(triphenylphosphine) palladium (II) (15.5 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(4-pyridin-4-yl-thiophen-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off white solid (90 mg). ¹H NMR (Oxalate salt, CD₃OD) δ (ppm): 8.4-8.3 (bs, 2H), 8.19 (s, 1H), 7.8 (s, 1H), 7.35 (s, 1H), 7.05-6.9 (m, 4H), 4.7-4.5 (m, 2H), 3.7-3.5 (m, 2H), 3.1 (s, 3H), 3.05-3.0 (m, 1H), 2.7-2.59 (m, 1H), 2.4 (s, 3H).

Example No. 21

Preparation of Compound No. 21

To a de-aerated solution of 5-(4-bromo-thiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (40 mg, 0.111 mmol), phenylboronic acid (20 mg, 0.166 mmol) and K₃PO₄(58.8 mg, 0.217 mmol) in DMF-water (4.5:0.5 mL) was added PdCl₂(PPh₃)₂(3.8 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(4-phenyl-thiophen-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off white solid (4 mg). ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.79-7.65 (m, 2H), 7.3 (s, 1H), 7.2-7.1 (m, 4H), 7.1-7.0 (m, 2H), 6.9 (d, 1H), 4.7 (d, 1H), 4.3 (d, 1H), 3.61-3.60 (m, 1H), 3.25-3.2 (m, 1H), 3.05-3.00 (m, 1H), 2.9 (s, 3H), 2.4 (s, 3H), 2.4-2.39 (m, 1H).

Example No. 22

Preparation of Compound No. 22

To a de-aerated solution of 5-(4-bromo-thiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (160 mg, 0.44 mmol), 3-pyridinylboronic acid (81.9 mg, 0.66 mmol) and K₃PO₄(235 mg, 1.11 mmol) in DMF-water (4.5:0.5 mL) was added dichlorobis(triphenylphosphine) palladium (II) (15.5 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(4-pyridin-3-yl-thiophen-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (40 mg). ¹H NMR (Oxalate salt, CD₃OD) δ (ppm): 8.35 (bs, 1H), 8.10 (bs, 1H), 7.95 (s, 1H), 7.8 (s, 1H), 7.45 (bs, 1H), 7.3-7.2 (m, 2H), 6.95 (d, 1H), 6.9 (d, 1H), 4.5 (bs, 2H), 3.6-3.45 (m, 2H), 3.15-3.05 (m, 1H), 3.0 (s, 3H), 2.65-2.59 (m, 1H), 2.4 (s, 3H).

Example No. 23

Preparation of Compound No. 23

A solution of 5-(4-bromo-thiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (150 mg, 0.416 mmol), 4-fluorophenylboronic acid (87.5 mg, 0.624 mmol), potassium phosphate (220 mg, 1.04 mmol) in DMF-water (9:1) was purged with N₂for 20 min followed by addition of dichlorobis(triphenylphosphine) palladium (II) (14.6 mg, 5 mol %). The reaction mixture was then heated at 95° C. for 30 min under nitrogen atmosphere. After completion of reaction, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer dried over anhydrous sodium sulfate and concentrated under vacuum to obtain crude product which was purified by reverse phase HPLC to yield 15 mg of the title compound. ¹H NMR (Oxalate salt, CD₃OD) δ (ppm): 7.74 (d, 1H), 7.65 (d, 1H), 7.23 (s, 1H), 6.82-7.0 (m, 6H), 4.5 (m, 2H), 3.6 (m, 2H), 2.9-3.0 (m, 5H), 2.4 (s, 3H).

Example No. 24

Preparation of Compound No. 24

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.5 mmol), 6-bromoquinoline (0.135 mL, 1 mmol), K₃PO₄(0.318 g, 1.5 mmol), CuI (9.5 mg, 0.05 mmol) and L-Proline (11.5 mg, 0.1 mmol) in dry DMF (5 mL) was stirred at 150° C. for 24 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-quinolin-6-yl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off white solid (8 mg). ¹H NMR (Oxalate salt, CD₃OD) δ (ppm): 8.92 (d, 1H), 8.43 (d, 1H), 8.2 (dd, 1H), 8.0 (d, 1H), 7.8 (d, 1H), 7.6 (dd, 1H), 7.38 (d, 1H), 7.18 (d, 1H), 7.0 (dd, 1H), 4.42 (s, 2H), 3.5 (m, 2H), 3.1 (m, 5H), 2.4 (s, 3H).

Example No. 25

Preparation of Compound No. 25

A solution of 5-(4-bromo-thiophen-3-yl)-8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.263 mmol), 4-fluoroboronic acid (55.16 mg, 0.394 mmol) and potassium phosphate (139.39 mg, 0.657 mmol) in DMF (2 mL)-water (0.2 mL) was purge with nitrogen followed by addition of dichlorobis(triphenylphosphine) palladium (II) (9.23 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain crude product which was purified by reverse phase HPLC to yield 20 mg of the title compound. ¹H NMR (Freebase, CDCl₃) δ (ppm): 7.42 (d, 1H), 7.18 (m, 2H), 7.0 (m, 2H), 6.8-6.92 (m, 4H), 3.61 (s, 2H), 2.38 (m, 2H), 2.42 (s, 3H), 2.2 (m, 2H).

Example No. 26

Preparation of Compound No. 26

A solution of 5-(4-bromo-thiophen-3-yl)-8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.263 mmol), phenylboronic acid (48.06 mg, 0.394 mmol) and potassium phosphate (139.39 mg, 0.657 mmol) in DMF (2 mL)-water (0.2 mL) was purged with nitrogen followed by addition of dichlorobis(triphenylphosphine) palladium (II) (9.23 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain crude product which was purified by reverse phase HPLC to yield 5 mg of the title compound. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.8-7.75 (m, 2H), 7.55 (s, 1H), 7.2-7.1 (m, 5H), 7.0-6.9 (m, 2H), 4.75-4.65 (m, 1H), 4.4-4.3 (m, 1H), 3.7-3.65 (m, 1H), 3.58-3.45 (m, 1H), 2.9 (s, 3H), 2.65-2.59 (m, 1H), 2.5-2.4 (m, 1H).

Example No. 27

Preparation of Compound No. 27

A solution of 5-(4-bromo-thiophen-3-yl)-8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.263 mmol), 3-pyridinylboronic acid (48.5 mg, 0.394 mmol) and potassium phosphate (139.39 mg, 0.657 mmol), in DMF (2 mL)-water (0.2 mL) was purged with nitrogen followed by addition of dichlorobis(triphenylphosphine) palladium (II) (9.23 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain crude product which was purified by reverse phase HPLC to yield 17 mg of the title compound. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 8.59 (bs, 1H), 8.15 (d, 2H), 7.95-7.8 (m, 2H), 7.63-7.59 (m, 2H), 7.1 (d, 1H), 6.95 (d, 1H), 4.8-4.5 (m, 1H), 4.42-4.39 (m, 1H), 3.85-3.75 (m, 1H), 3.61-3.45 (m, 1H), 3.2 (m, 1H), 3.15 (s, 3H), 2.9-2.75 (m, 1H).

Example No. 28

Preparation of Compound No. 28

A solution of 5-(4-bromo-thiophen-3-yl)-8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.263 mmol), 4-pyridinylboronic acid (48.5 mg, 0.394 mmol) and potassium phosphate (139.39 mg, 0.657 mmol) in DMF (2 mL)-water (0.2 mL) was purged with nitrogen followed by addition of dichlorobis(triphenylphosphine) palladium (II) mg, (9.2
mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain crude product which was purified by reverse phase HPLC to yield 11 mg of the title compound. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 8.6-8.59 (m, 3H), 8.00 (m, 1H), 7.6 (s, 1H), 7.41 (bs, 2H), 7.1 (d, 1H), 6.95 (bs, 1H), 4.8-4.79 (m, 1H), 4.41-4.39 (m, 1H), 3.81-3.79 (m, 1H), 3.6-3.5 (m, 1H), 3.15 (s, 3H), 3.15-3.00 (m, 1H), 2.85-2.79 (m, 1H).

Example No. 29

Preparation of Compound No. 29

To a de-aerated solution of 5-(4-bromo-thiophen-3-yl)-8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.263 mmol), 4-pyridinylboronic acid (48.5 mg, 0.394 mmol) and K₃PO₄(139.39 mg, 0.657 mmol) in DMF-water (2:0.2 mL) was added dichlorobis(triphenylphosphine) palladium (II) (9.23 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 8-chloro-2-methyl-5-thiophen-3-yl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (35 mg). ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.7 (dd, 1H), 7.58 (m, 2H), 7.2 (m, 3H), 4.76 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.2 (m, 4H), 3.0 (m, 1H).

Example No. 30

Preparation of Compound No. 30

To a solution of 5-(4-bromothiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.25 mmol) in DME (4 mL) was added Pd(PPh₃)₄(15 mg, 0.0128 mmol) and purged with N₂. 1-Methylpyrazole-4-boronic acid pinacol ester (108 mg, 0.515 mmol), K₂CO₃(36 mg, 0.257 mmol) and water (2 mL) were added followed by N₂purging and the reaction refluxed under N₂for 45 min. The reaction mixture was cooled to RT, and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc and heated at 50° C. along with stirring for 15 min followed by filtration. The filtrate was concentrated under reduced pressure and the product was isolated by reverse phase HPLC. ¹H NMR (freebase, CDCl₃) δ (ppm): 7.41 (d, 1H), 7.38 (m, 2H), 7.20 (d, 1H), 6.82 (m, 2H), 6.38 (s, 1H), 3.78 (s, 3H), 3.61 (s, 3H), 3.80 (s, 2H), 3.60 (d, 2H), 2.41 (s, 3H), 2.39 (d, 2H).

Example No. 31

Preparation of Compound No. 31

A solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.282 mmol), 2-(dimethylamino)pyrimidine-5-boronic acid pinacol ester (105.5 mg, 0.423 mmol) and potassium phosphate (149.7 mg, 0.706 mmol) in DMF (4 mL)-water (1 mL) was purged with nitrogen followed by addition of dichlorobis(triphenylphosphine) palladium (II) (9.91 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water, extracted with EtOAc, the organic layer dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude which was purified by reverse phase HPLC to yield 9 mg of the title compound. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 8.03 (s, 1H), 7.98 (s, 1H), 7.60-7.68 (m, 3H), 7.43 (d, 1H), 7.30 (s, 1H), 7.0 (d, 1H), 6.80 (m, 1H), 4.78 (m, 2H), 4.40 (d, 2H), 3.70 (m, 1H), 3.40-3.51 (m, 1H), 3.11 (m, 9H), 2.40 (s, 3H).

Example No. 32

Preparation of Compound No. 32

A solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.282 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (88 mg, 0.423 mmol) and potassium phosphate (149.7 mg, 0.706 mmol), in DMF (4 mL)-water (1 mL) was purged with nitrogen followed by addition of dichlorobis(triphenylphosphine) palladium (II) (9.91 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water, extracted with EtOAc, organic layer dried over anhydrous sodium sulfate and concentrated under vacuum to obtain crude which was purified by reverse phase HPLC to yield 3 mg of the title compound. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.78 (m, 3H), 7.55 (m, 1H), 7.23 (m, 2H), 7.0 (d, 1H), 6.83 (d, 1H), 5.80 (d, 1H), 4.70 (d, 1H), 4.38 (d, 1H), 3.70 (m, 4H), 3.40 (m, 2H), 2.97-3.14 (m, 4H), 2.40 (s, 3H).

Example No. 33

Preparation of Compound No. 33

To a solution of [5-(4-bromothiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole] (100 mg, 0.25 mmol) in DME (2 mL) were added water (1 mL) and K₂CO₃(110 mg, 0.77 mmol) and purged solution with N₂. Pd(PPh₃)₄(20 mg, 0.017 mmol) and 1-methylindole-5-boronic acid pinacol ester (140 mg, 0.546 mmol) were added to the reaction mixture which was refluxed under N₂for 45 min. The reaction mixture was cooled to RT and diluted with EtOAc. The aqueous layer was extracted with EtOAc (3×6 mL) and the combined organic layer dried over sodium sulfate. The solvent was removed under reduced pressure to afford crude product which was purified by reverse phase HPLC. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.62 (d, 2H), 7.31 (d, 1H), 7.10 (m, 4H), 6.77 (m, 2H), 6.20 (d, 1H), 4.60 (d, 1H), 4.23 (d, 1H), 3.65 (s, 3H), 3.51 (m, 2H), 3.37 (s, 3H), 3.02 (m, 1H), 2.80 (m, 1H), 2.44 (s, 3H).

Example No. 34

Preparation of Compound No. 34

To a solution of [5-(4-bromothiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole] (100 mg, 0.25 mmol) in DME (2 mL) were added water (1 mL) and K₂CO₃(110 mg, 0.77 mmol) and purged the solution with N₂. Pd(PPh₃)₄(20 mg, 0.017 mmol) and isoquinoline-4-boronic acid (70 mg, 0.404 mmol) were added to the reaction mixture which was refluxed under N₂for 45 min. The reaction mixture was cooled to RT and diluted with EtOAc. Aqueous layer was extracted with EtOAc (3×6 mL) and the combined organic layer dried over sodium sulfate. The solvent was removed under reduced pressure to afford crude product which was purified by reverse phase HPLC. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 9.
(s, 1H), 8.40 (m, 1H), 8.17 (m, 3H), 8.05 (s, 1H), 7.95 (m, 2H), 7.10 (d, 1H), 6.60-6.95 (m, 2H), 4.60 (dd, 1H), 4.20 (dd, 1H), 3.80 (m, 1H), 3.50 (m, 1H), 3.17 (m, 4H), 2.83 (m, 1H), 2.23 (s, 3H).

Example No. 35

Preparation of Compound No. 35

To a solution of [5-(4-bromothiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole] (100 mg, 0.25 mmol) in DME (2 mL) were added water (1 mL) and K₂CO₃(110 mg, 0.77 mmol) and purged the solution with N₂. Pd(PPh₃)₄(20 mg, 0.017 mmol) and 2-fluoropyridine-5-boronic acid pinacol ester (140 mg, 0.626 mmol) were added to the reaction mixture which was refluxed under N₂for 45 min. The reaction mixture was cooled to RT and diluted with EtOAc. The aqueous layer was extracted with EtOAc (3×6 mL) and the combined organic layer dried over sodium sulfate. The solvent was removed under reduced pressure to afford crude product which was purified by reverse phase HPLC. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.96 (s, 1H), 7.78 (d, 1H), 7.70 (d, 1H), 7.44 (dd, 1H), 7.31 (d, 1H), 6.98 (d, 1H), 6.82 (m, 2H), 4.71 (d, 1H), 4.40 (d, 1H), 3.78 (m, 1H), 3.57 (m, 1H), 3.15 (m, 5H), 2.40 (s, 3H).

Example No. 36

Preparation of Compound No. 36

A solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.282 mmol), 4-methylthiophene-2-boronic acid pinacol ester (94 mg, 0.419 mmol) and potassium phosphate (148 mg, 0.702 mmol) in DMF (4 mL)-water (1 mL) was purged with nitrogen followed by addition of dichlorobis(triphenylphosphine) palladium (II) (9.91 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water, extracted with EtOAc, organic layer dried over anhydrous sodium sulfate and concentrated under vacuum to obtain crude product which was purified by reverse phase HPLC to yield 8 mg of the title compound. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.84 (d, 1H), 7.60 (dd, 1H), 7.57 (dd, 1H), 7.37 (m, 2H), 7.0 (m, 1H), 6.80 (m, 2H), 6.57 (d, 1H), 4.40 (d, 2H), 3.63 (m, 1H), 4.43 (m, 1H), 3.38 (s, 3H), 2.7-2.9 (m, 2H), 2.41 (s, 3H), 2.04 (s, 3H).

Example No. 37

Preparation of Compound No. 37

To a solution of [5-(4-bromothiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole] (100 mg, 0.25 mmol) in DME (2 mL) were added water (1 mL) and K₂CO₃(110 mg, 0.77 mmol) and purged the solution with N₂. Pd(PPh₃)₄(20 mg, 0.017 mmol) and 4-methoxyphenylboronic acid (70 mg) were added to the reaction mixture which was refluxed under N₂for 45 min. The reaction mixture was cooled to RT and diluted with EtOAc. The aqueous layer was extracted with EtOAc (3×6 mL) and the combined organic layer dried over sodium sulfate. The solvent was removed under reduced pressure to afford crude product which was purified by reverse phase HPLC. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.61 (m, 2H), 7.30 (s, 1H),
(d, 2H), 6.91 (d, 1H), 6.80 (d, 1H), 6.71 (dd, 2H), 4.71 (d, 1H), 4.
8 (d, 1H), 8 (s, 3H), 3.62 (m, 1H), 3.23 (m, 1H), 2.87 (m, 5H), 2.40 (s, 3H).

Example 38

Preparation of Compound No. 38

To a solution of 6-bromoisoquinoline (124 mg, 0.6 mmol) in DMF (2 mL) were added potassium phosphate (212 mg, 1 mmol), CuI (9.5 mg, 0.05 mmol) and L-proline (11.5 mg, 0.1 mmol) and purged the solution with nitrogen. 2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (100 mg, 0.5 mmol) was added and again purged the reaction mixture with nitrogen followed by overnight heating at 140° C. Ice water was added to the reaction mixture and extracted the organic part into EtOAc (3×15 mL). The combined organic layer was washed with water (2×10 mL) and concentrated. The crude product was purified by column chromatography using silica (100-200 mesh) in 0-7% MeOH:DCM to yield 29 mg of the desired compound as free base. ¹H NMR(HCl salt, CD₃OD) δ (ppm): 9.82 (s, 1H), 8.78 (d, 1H), 8.62 (d, 1H), 8.57 (d, 1H), 8.4 (s, 1H), 8.2 (d, 1H), 7.41 (m, 2H), 7.18 (d, 1H), 4.78 (d, 1H), 4.43 (d, 1H), 3.82 (m, 1H), 3.6 (m, 1H), 3.58-3.5 (m, 1H), 3.1-3.2 (m, 4H), 2.42 (s, 3H).

Example No. 39

Preparation of Compound No. 39

To a solution of 5-(4-bromothiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.25 mmol) in DME (2 mL) were added water (1 mL) and K₂CO₃(110 mg, 0.77 mmol) and purged the solution with N₂. Pd(PPh₃)₄(20 mg, 0.017 mmol) and 3-methylthiophene-2-boronic acid pinacol ester (100 mg, 0.367 mmol) were added to the reaction mixture, which was refluxed under N₂for 45 min. The reaction mixture was cooled to RT and diluted with EtOAc. Aqueous layer was extracted with EtOAc (3×6 mL) and the combined organic layer dried over sodium sulfate. The solvent was removed under reduced pressure to afford crude material, which was purified by reverse phase HPLC. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.61-7.72 (m, 2H), 7.23 (s, 1H), 7.07 (d, 1H), 6.91 (m, 2H), 6.78 (d, 1H), 4.68 (d, 1H), 4.32 (d, 1H), 3.70 (m, 1H), 3.42 (m, 1H), 3.32 (s, 3H), 2.97 (m, 2H), 2.4 (s, 3H), 2.07 (s, 3H).

Example No. 40

Preparation of Compound No. 40

To a solution of 5-(4-bromothiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.25 mmol) in DME (2 mL) were added water (1 mL) and K₂CO₃(110 mg, 0.77 mmol) and purged solution with N₂. Pd(PPh₃)₄(20 mg, 0.017 mmol) and 2-(dimethylamino) pyrimidine-5-boronic acid pinacol ester (140 mg, 0.563 mmol) were added to the reaction mixture, which was refluxed under N₂for 45 min. The reaction mixture was cooled to RT and diluted with EtOAc. Aqueous layer was extracted with EtOAc (3×6 mL) and the combined organic layer dried over sodium sulfate. The solvent was removed under reduced pressure to afford crude material, which was purified by reverse phase HPLC. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 8.0 (m, 3H), 7.80 (dd, 1H), 7.38 (s, 1H), 7.0 (m, 1H), 6.82 (m, 1H), 4.77 (d, 1H), 4.40 (d, 1H), 3.80 (m, 1H), 3.58 (m, 1H), 3.20 (s, 6H), 3.18 (s, 3H),
(m, 1H), 2.76 (m, 1H), 2.40 (s, 3H).

Example No. 41

Preparation of Compound No. 41

To a solution of 5-(4-bromothiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.25 mmol) in DME (2 mL) were added water (1 mL) and K₂CO₃(110 mg, 0.77 mmol) and purged the solution with N₂. Pd(PPh₃)₄(20 mg, 0.017 mmol) and indazole-4-boronic acid. HCl (102 mg, 0.515 mmol) were added to the reaction mixture, which was refluxed under N₂for 45 min. The reaction mixture was cooled to RT and diluted with EtOAc. Aqueous layer was extracted with EtOAc (3×6 mL) and the combined organic layer dried over sodium sulfate. The solvent was removed under reduced pressure to afford crude product which was purified by reverse phase HPLC. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.83-7.98 (m, 2H), 7.77 (dd, 1H), 7.4 (d, 1H), 7.23 (s, 1H), 7.05-7.16 (m, 2H), 7.0 (d, 1H), 6.4 (dd, 1H), 4.61 (m, 1H), 4.24 (m, 1H), 3.58 (m, 1H), 3.38 (m, 4H), 3.10 (m, 1H), 2.8 (m, 1H), 2.4 (s, 3H).

Example No. 42

Preparation of Compound No. 42

To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 2-(dimethylamino)pyrimidine-5-boronic acid pinacol ester (140 mg, 0.561 mmol) and K₂CO₃(120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)-N,N-dimethylpyrimidin-2-amine. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 8.8 (s, 2H), 7.6-7.77 (m, 3H), 7.4 (d, 1H), 7.3 (s, 1H), 7.1 (d, 1H), 6.97 (d, 1H), 4.77 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.3 (s, 6H), 3.1 (m, 4H), 3.0 (m, 1H), 2.4 (s, 3H).

Example No. 43

Preparation of Compound No. 43

To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 3-methylthiophene-2-boronic acid pinacol ester (125 mg, 0.557 mmol) and K₂CO₃(120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(3-methylthiophen-2-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.52-7.71 (m, 2H), 7.42 (s, 1H), 7.4 (m, 2H), 7.35 (s, 1H), 7.18 (d, 1H), 7.04 (d, 1H), 6.97 (d, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.82 (m, 1H),
(m, 1H), 3.2 (m, 4H), 3.0 (m, 1H), 2.42 (s, 3H), 2.38 (s, 3H).

Example No. 44

Preparation of Compound No. 44

To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 2-fluoropyridine-5-boronic acid pinacol ester (125 mg, 0.560 mmol) and K₂CO₃(120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(3-(6-fluoropyridin-3-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 8.5 (s, 1H), 8.21 (dd, 1H), 7.72 (m, 2H), 7.62 (s, 1H), 7.5 (d, 1H), 7.3 (s, 1H), 7.17 (m, 2H), 7.06 (d, 1H), 4.8 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.56 (m, 1H), 3.21 (m, 1H), 3.18 (s, 3H), 3.1 (m, 1H), 2.4 (s, 3H).

Example No. 45

Preparation of Compound No. 45

To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 2-acetamidopyridine-5-boronic acid pinacol ester (147 mg, 0.560 mmol) and K₂CO₃(120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield N-(5-(3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)pyridin-2-yl)acetamide. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 8.6 (s, 1H), 8.18 (s, 2H), 7.8 (d, 1H), 7.62-7.77 (m, 2H), 7.42 (d, 1H), 7.3 (s, 1H), 7.17 (d, 1H), 7.03 (d, 1H), 4.7 (d, 1H), 4.42 (d, 1H), 3.8 (m, 1H), 3.58 (m, 1H), 3.0-3.2 (m, 5H), 2.41 (s, 3H), 2.2 (s, 3H).

Example No. 46

Preparation of Compound No. 46

To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (116 mg, 0.557 mmol) and K₂CO₃(120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 8.02 (s, 1H), 7.84 (s, 1H), 7.64 (d, 1H), 7.58 (m, 2H), 7.52 (s, 1H), 7.22 (d, 1H), 7.14 (d, 1H), 7.02 (d, 1H), 4.4 (m, 2H), 3.96 (s,
H), 3.8 (m, 1H), 3.58 (m, 1H), 3.0-3.2 (m, 5H), 2.41 (s, 3H).

Example No. 47

Preparation of Compound No. 47

To a solution of 5-bromoquinoline (100 mg, 0.469 mmol) in DMF (2 mL) were added potassium phosphate (198 mg, 0.938 mmol), CuI (8 mg, 0.046 mmol) and L-proline (10 mg, 0.938 mmol) and purged the solution with nitrogen. 2,3,4,5-Tetrahydro-2,6,8-trimethyl-1H-pyrido[4,3-b]indole (100 mg, 0.469 mmol) was added and again purged the reaction mixture with nitrogen followed by overnight heating at 140° C. Ice water was added to the reaction mixture and extracted the organic part into EtOAc (3×15 mL). The combined organic layer was washed with water (2×10 mL) and concentrated under reduced pressure. The crude obtained was purified by column chromatography using silica (100:200 mesh) in 0-7% MeOH-DCM. The compound was further purified through reverse phase HPLC to yield: 1.88 mg of the desired compound as the TFA salt. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 9.0 (d, 1H), 8.3 (d, 1H), 8.0 (dd, 1H), 7.42-7.81 (m, 3H), 7.31 (s, 1H), 6.9 (d, 1H), 4.4 (m, 2H), 3.7 (m, 1H), 3.5 (m, 1H), 3.17 (m, 5H), 2.4 (m, 6H).

Example No. 48

Preparation of Compound No. 48

To a solution of 6-bromoquinoline (0.059 mL, 0.431) in DMF (2 mL) were added potassium phosphate (152 mg, 1 mmol), CuI (6.8 mg, 0.0359 mmol), L-proline (8 mg, 0.0718 mmol) and 2,3,4,5-tetrahydro-2,6,8-trimethyl-1H-pyrido[4,3-b]indole (100 mg, 0.359 mmol). The reaction mixture was purged with nitrogen and stirred at 140° C. for overnight. Ice water (5 mL) was added into the reaction mixture and the solid obtained was filtered. The residue was dissolved in EtOAc and washed with water (2×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by column chromatography using silica (100:200) and 0-6% MeOH-DCM. The compound was further purified by reverse phase HPLC to yield 19 mg of the desired compound as the TFA salt. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 9.18 (d, 1H), 8.9 (d, 1H), 8.2-8.37 (m, 2H), 7.97 (m, 2H), 7.2 (s, 1H), 6.81 (s, 1H), 4.76 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.18 (s, 3H), 2.9 (m, 1H), 2.8 (m, 1H), 2.4 (s, 3H), 1.9 (s, 3H).

Example No. 49

Preparation of Compound No. 49

To a solution of [5-(4-bromothiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole] (100 mg, 0.25 mmol) in DME (2 mL) were added water (1 mL) and K₂CO₃(110 mg, 0.77 mmol) and purged the solution with N₂. Pd(PPh₃)₄(20 mg, 0.017 mmol) and 6-hydroxypyridine-3-boronic acid pinacol ester (114 mg, 0.515 mmol) were added to the reaction mixture, which was refluxed under N₂for 45 min. The reaction mixture was cooled to RT and diluted with EtOAc. The aqueous layer was extracted with EtOAc (3×6 mL) and the combined organic layer dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford crude material, which was purified by reverse phase HPLC.
H NMR (TFA salt, CD₃OD) δ (ppm): 7.78 (d, 1H), 7.72 (d, 1H), 7.38 (s, 1H), 7.2 (d, 1H), 7.02 (d, 1H), 6.92 (d, 1H), 6.82 (s, 1H), 6.3 (d, 1H), 4.5 (m, 2H), 3.6 (m, 2H), 3.0-3.17 (m, 4H), 2.7 (m, 1H), 2.41 (s, 3H).

Example No. 50

Preparation of Compound No. 50

To a solution of [5-(4-bromothiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole] (100 mg, 0.25 mmol) in DME (2 mL) were added water (1 mL) and K₂CO₃(110 mg, 0.77 mmol) and purged the solution with N₂. Pd(PPh₃)₄(20 mg, 0.017 mmol) and 4-methylthiophene-2-boronic acid pinacol ester (70 mg, 0.257 mmol) were added to the reaction mixture, which was refluxed under N₂for 45 min. The reaction mixture was cooled to RT and diluted with EtOAc. Aqueous layer was extracted with EtOAc (3×6 mL) and the combined organic layer dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford crude material, which was purified by reverse phase HPLC. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.8 (d, 1H), 7.62 (d, 1H), 7.3 (s, 1H), 7.0 (d, 1H), 6.9 (d, 1H), 6.78 (s, 1H), 6.43 (s, 1H), 4.61 (s, 2H), 3.5-3.7 (m, 2H), 3.02 (s, 3H), 2.9 (m, 1H), 2.6 (m, 1H), 2.4 (s, 3H), 2.0 (s, 3H).

Example No. 51

Preparation of Compound No. 51

To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), benzo[b]thien-2-ylboronic acid (100 mg, 0.557 mmol) and K₂CO₃(116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(3-(benzo[b]thiophen-2-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.8-7.91 (m, 3H), 7.78 (s, 2H), 7.61-7.7 (t, 1H), 7.3-7.4 (m, 4H), 7.18 (d, 1H), 7.02 (d, 1H), 4.8 (d, 1H), 4.4 (d, 1H), 3.81 (m, 1H), 3.5 (m, 1H), 3.2 (m, 1H), 3.18 (s, 3H), 3.01 (m, 1H), 2.41 (s, 3H).

Example No. 52

Preparation of Compound No. 52

To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 6-hydroxypyridine-3-boronic acid pinacol ester (124 mg, 0.557 mmol) and K₂CO₃(116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-
(2H)-yl)phenyl)pyridin-2-ol. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 8.0 (d, 1H), 7.8 (d, 1H), 7.68 (m, 2H), 7.6 (s, 1H), 7.4 (dd, 1H), 7.36 (s, 1H), 7.17 (d, 1H), 7.08 (d, 1H), 6.62 (d, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.56 (m, 1H), 3.18 (m, 4H), 3.02 (m, 1H), 2.4 (s, 3H).

Example No. 53

Preparation of Compound No. 53

To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1-methylindole-5-boronic acid pinacol ester (144 mg, 0.560 mmol) and K₂CO₃(116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(1-methyl-1H-indol-5-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.82 (s, 1H), 7.8 (d, 1H), 7.62 (dd, 2H), 7.46 (dd, 2H), 7.35 (m, 2H), 7.2 (m, 2H), 7.04 (d, 1H), 6.5 (d, 1H), 4.6 (m, 2H), 3.8 (s, 3H), 3.7 (m, 2H), 3.11 (m, 5H), 2.41 (s, 3H).

Example No. 54

Preparation of Compound No. 54

To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1H-benzimidazole-5-boronic acid pinacol ester (137 mg, 0.561 mmol) and K₂CO₃(116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(3-(1H-benzo[d]imidazol-5-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 9.08 (s, 1H), 8.02 (s, 1H), 7.86 (m, 3H), 7.72 (m, 2H), 7.48 (d, 1H), 7.37 (s, 1H), 7.18 (d, 1H), 7.0 (d, 1H), 4.4 (m, 2H), 3.8 (m, 1H), 3.6 (m, 1H), 3.02-3.2 (m, 5H), 2.41 (s, 3H).

Example No. 55

Preparation of Compound No. 55

To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), indazole-4-boronic acid hydrochloride (111 mg, 0.559 mmol) and K₂CO₃(116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(3-(1H-indazol-4-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 8.18 (s, 1H), 7.82 (d, 1H), 7.78 (t, 1H), 7.7 (s, 1H), 7.6 (d, 1H), 7.5 (m, 2H), 7.34 (m, 2H), 7.21 (d, 1H), 7.1 (d, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.04-3.18 (m, 5H), 2.4 (s, 3H).

Example No. 56

Preparation of Compound No. 56

To a solution of 5-(4-bromothiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.25 mmol) in DME (2 mL) were added water (1 mL) and K₂CO₃(110 mg, 0.77 mmol) and purged the solution with N₂. Pd(PPh₃)₄(20 mg, 0.017 mmol) and 2-acetamidopyridine-5-boronic acid pinacol ester (140 mg, 0.515 mmol) were added to the reaction mixture, which was refluxed under N₂for 45 min. The reaction mixture was cooled to RT and diluted with EtOAc. Aqueous layer was extracted with EtOAc (3×6 mL) and the combined organic layer dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford crude material, which was purified by reverse phase HPLC. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 8.0 (s, 1H), 7.8 (m, 2H), 7.68 (m, 1H), 7.51 (m, 1H), 7.33 (s, 1H), 6.82-7.0 (m, 2H), 4.77 (d, 1H), 4.4 (d, 1H), 3.78 (m, 1H), 3.5 (m, 1H), 3.1 (m, 4H), 2.7 (m, 1H), 2.4 (s, 3H), 2.2 (s, 3H).

Example No. 57

Preparation of Compound No. 57

To a de-aerated solution of 5-(3-bromophenyl)-2,6,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (80 mg, 0.217 mmol), pyridine-4-boronic acid (53 mg, 0.431 mmol) and K₂CO₃(116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh₃)₄(12 mg, 0.013 mmol). The reaction mixture was heated at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,6,8-trimethyl-5-(3-(pyridin-4-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 8.78 (d, 2H), 8.1 (m, 3H), 7.9 (m, 1H), 7.8 (t, 1H), 7.6 (m, 1H), 7.2 (s, 1H), 6.8 (s, 1H), 4.76 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.1 (s, 3H), 2.8-3.03 (m, 2H), 2.4 (s, 3H), 1.93 (s, 3H).

Example No. 58

Preparation of Compound No. 58

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.499 mmol), 8-bromoisoquinoline (0.155 g, 0.748 mmol), potassium phosphate (0.317 g, 1.495 mmol), CuI (9 mg, 0.047 mmol) and L-Proline (11 mg, 0.095 mmol) in dry DMF (3 mL) was heated at 150° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(isoquinolin-8-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. ¹H NMR (TFA salt, CD₃OD)
(ppm): 8.8 (d, 1H), 8.62 (d, 1H), 8.42 (bs, 1H), 8.4 (d, 1H), 8.
(t, 1H), 8.0 (d, 1H), 7.42 (s, 1H), 7.0 (d, 1H), 6.87 (bs, 1H), 4.7 (d, 1H), 4.3 (d, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.16 (m, 4H), 2.8 (m, 1H), 2.4 (s, 3H).

Example No. 59

Preparation of Compound No. 59

To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 0.564 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (247 mg, 1.12 mmol) and K₂CO₃(233.48 mg, 0.845 mmol) in DME-water (2:1) was added Pd(PPh₃)₄(32.58 mg, 0.028 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 8.18 (s, 1H), 7.74 (m, 4H), 7.38-7.58 (m, 2H), 7.28 (s, 1H), 6.93 (d, 1H), 6.78 (d, 1H), 4.4 (m, 2H), 3.7 (m, 2H), 3.1 (s, 3H), 2.8 (m, 2H), 2.57 (s, 3H), 2.38 (s, 3H).

Example No. 60

Preparation of Compound No. 60

To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (124 mg, 0.564 mmol) and K₂CO₃(116 mg, 0.845 mmol) in DME-water (2:1) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(6-methylpyridin-3-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 8.84 (s, 1H), 8.56 (d, 1H), 7.83 (d, 1H), 7.75-7.8 (m, 3H), 7.57 (d, 1H), 7.38 (s, 1H), 7.18 (d, 1H), 7.04 (d, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.0-3.22 (m, 5H), 2.77 (s, 3H), 2.4 (s, 3H).

Example No. 61

Preparation of Compound No. 61

To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 4-fluoroboronic acid (79 mg, 0.564 mmol) and K₂CO₃(116 mg, 0.845 mmol) in DME-water (2:1) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(4′-fluorophenyl-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.
H NMR (TFA salt, CD₃OD) δ (ppm): 7.63-7.38 (m, 4H), 7.61 (s, 1H), 7.4 (d, 1H), 7.36 (s, 1H), 7.1-7.23 (m, 3H), 7.04 (d, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.58 (m, 1H), 3.2 (m, 4H), 3.03 (m, 1H), 2.4 (s, 3H).

Example No. 62

Preparation of Compound No. 62

To a solution of 5-(4-bromothiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.25 mmol) in DME (2 mL) were added water (1 mL) and K₂CO₃(110 mg, 0.77 mmol) and purged the solution with N₂. Pd(PPh₃)₄(20 mg, 0.017 mmol) and 3,5-dimethylisoxazole-4-boronic acid pinacol ester (140 mg, 0.626 mmol) were added to the reaction mixture, which was refluxed under N₂for 45 min. The reaction mixture was cooled to RT and extracted with EtOAc. The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.7 (s, 2H), 7.22 (s, 1H), 6.8-7.0 (m, 2H), 4.65 (m, 1H), 4.38 (m, 1H), 3.8 (m, 1H), 3.4 (m, 1H), 2.95-3.2 (m, 4H), 2.63 (m, 1H), 2.41 (s, 3H), 2.0 (s, 3H), 1.8 (s, 3H).

Example No. 63

Preparation of Compound No. 63

To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 4-methylthiophene-2-boronic acid pinacol ester (175 mg, 0.784 mmol) and K₂CO₃(162 mg, 1.1 mmol) in DME-water (2:1) was added Pd(PPh₃)₄(22 mg, 0.019 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(4-methylthiophen-2-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.78 (d, 1H), 7.6 (m, 2H), 7.3-7.38 (m, 3H), 7.17 (d, 1H), 7.02 (d, 1H), 7.0 (s, 1H), 4.4 (m, 2H), 3.8 (m, 1H), 3.6 (m, 1H), 3.2 (s, 4H), 3.1 (m, 1H), 2.41 (s, 3H), 2.27 (s, 3H).

Example No. 64

Preparation of Compound No. 64

To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 5-methylthiophene-2-boronic acid pinacol ester (175 mg, 0.784 mmol) and K₂CO₃(162 mg, 1.1 mmol) in DME-water (2:1) was added Pd(PPh₃)₄(22 mg, 0.019 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(5-methylthiophen-2-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.7 (d, 1H), 7.6 (m, 2H),
(s, 1H), 7.23 (m, 2H), 7.19 (d, 1H), 7.03 (d, 1H), 6.8 (s, 1H), 4.6 (m, 2H), 3.7 (m, 2H), 3.3 (m, 1H), 3.1-3.2 (m, 4H), 2.5 (s, 3H), 2.42 (s, 3H).

Example No. 65

Preparation of Compound No. 65

To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 3,5-dimethylisoxazole-4-boronic acid pinacol ester (125 mg, 0.56 mmol) and K₂CO₃(116 mg, 0.84 mmol) in DME-water (2:1) was added Pd(PPh₃)₄(16 mg, 0.014 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 4-(3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)-3,5-dimethylisoxazole. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.7 (t, 1H), 7.41-7.5 (m, 2H), 7.4 (s, 1H), 7.37 (s, 1H), 7.18 (d, 1H), 7.03 (d, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.2 (m, 4H), 3.01 (m, 1H), 3.43 (m, 6H), 2.31 (s, 3H).

Example No. 66

Preparation of Compound No. 66

To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (116 mg, 0.56 mmol) and K₂CO₃(116 mg, 0.84 mmol) in DME-water (2:1) was added Pd(PPh₃)₄(16 mg, 0.014 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(1-methyl-1H-pyrazol-5-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.78 (t, 1H), 7.62 (d, 1H), 7.57 (m, 3H), 7.37 (d, 1H), 7.18 (d, 1H), 7.02 (d, 1H), 6.43 (d, 1H), 4.76 (d, 1H), 4.4 (d, 1H), 3.93 (s, 3H), 3.8 (m, 1H), 3.57 (m, 1H), 3.2 (m, 4H), 3.0 (m, 1H), 2.42 (s, 3H).

Example No. 67

Preparation of Compound No. 67

To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 4-isoquinolineboronic acid (96.8 mg, 0.56 mmol) and K₂CO₃(116 mg, 0.84 mmol) in DME-water (2:1) was added Pd(PPh₃)₄(16 mg, 0.014 mmol). The reaction mixture was heated at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(3-(isoquinolin-4-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.
H NMR (TFA salt, CD₃OD) δ (ppm): 9.5 (s, 1H), 8.57 (s, 1H), 8.4 (d, 1H), 8.09 (d, 1H), 8.0 (dd, 1H), 7.8-7.95 (m, 2H), 7.7 (d, 1H), 7.6 (m, 2H), 7.37 (s, 1H), 7.21 (d, 1H), 7.07 (d, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.81 (m, 1H), 3.61 (m, 1H), 3.1-3.3 (m, 5H), 2.4 (s, 3H).

Example No. 68

Preparation of Compound No. 68

To a solution of 5-(4-bromothiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.25 mmol) in DME-water (2:1) was added K₂CO₃(110 mg, 0.77 mmol) and the solution purged with N₂. Pd(PPh₃)₄(20 mg, 0.017 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (100 mg, 0.392 mmol) were added to the reaction mixture, which was refluxed under N₂for 45 min. The reaction mixture was cooled to RT and extracted with EtOAc. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 9.07 (s, 1H), 8.27 (d, 1H), 7.97 (d, 1H), 7.8 (d, 1H), 7.64 (d, 1H), 7.42 (d, 1H), 7.35 (s, 1H), 7.26 (d, 1H), 7.19 (s, 1H), 6.9 (d, 1H), 6.8 (d, 1H), 3.6 (m, 2H), 2.63 (m, 2H), 2.5 (m, 1H), 2.4 (m, 6H), 2.2 (m, 1H).

Example No. 69

Preparation of Compound No. 69

To a degassed solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1-methyl-2-pyrroleboronic acid pinacol ester (96.8 mg, 0.56 mmol) and K₂CO₃(116 mg, 0.84 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.014 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(1-methyl-1H-pyrrol-2-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.61 (dd, 1H), 7.57 (d, 1H), 7.4 (s, 1H), 7.37 (m, 2H), 7.17 (d, 1H), 7.07 (d, 1H), 6.8 (d, 1H), 6.21 (d, 1H), 6.1 (dd, 1H), 4.76 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.7 (m, 3H), 3.57 (m, 1H), 3.2 (m, 4H), 3.03 (m, 1H), 2.42 (s, 3H).

Example No. 70

Preparation of Compound No. 70

To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1H-pyrazole-4-boronic acid (62 mg, 0.56 mmol) and K₂CO₃(116 mg, 0.84 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.014 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure and residue and dissolved in EtOAc (30 mL). The organic layer was washed with water (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(3-(1H-pyrazol-4-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 8.03 (s, 2H), 7.7 (d, 1H), 7.58 (m, 2H),
(s, 1H) (s, 1H)
.22 (d, 1H), 7.1 (d, 1H), 7.0 (d, 1H), 4.8 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.57 (m, 1H), 3.2 (m, 1H), 3.17 (s, 3H), 3.0 (m, 1H), 2.42 (s, 3H).

Example No. 71

Preparation of Compound No. 71

To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.28 mmol), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (148 mg, 0.56 mmol) and K₂CO₃(115 mg, 0.84 mmol) in DME-water (2:1) was added Pd(PPh₃)₄(16 mg, 0.014 mmol). The reaction mixture was stirred at 90° C. for 2 h, additional Pd (PPh₃)₄(16 mg, 0.014 mmol) was added into the reaction mixture and stirring continued at 90° C. for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (30 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)-N-methylpicolinamide as an off-white solid. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 8.21 (d, 1H), 7.82 (d, 1H), 7.76 (m, 3H), 7.6 (d, 2H), 7.23 (s, 1H), 6.9 (d, 2H), 4.7 (m, 1H), 4.3 (m, 1H), 3.63 (m, 1H), 3.42 (m, 1H), 2.8-3.1 (m, 7H), 2.6 (m, 1H), 2.4 (s, 3H).

Example No. 72

Preparation of Compound No. 72

To a degassed solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (300 mg, 0.84 mmol), N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (328 mg, 1.27 mmol) and K₃PO₄(445 mg, 0.706 mmol), in DMF (6 mL)-water (0.6 mL) was added dichlorobis (triphenylphosphine) palladium (II) (30 mg, 0.042 mmol). The reaction mixture was heated at 90° C. for 95 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to yield 2′-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-N-methylbiphenyl-4-carboxamide. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.57-7.78 (m, 5H), 7.4 (dd, 1H), 7.25 (s, 1H), 6.92-7.2 (m, 4H), 4.6 (m, 1H), 4.2 (m, 1H), 3.6 (m, 1H), 3.4 (m, 1H), 3.1 (m, 1H), 2.83 (m, 6H), 2.5 (m, 1H), 2.4 (s, 3H).

Example No. 73

Preparation of Compound No. 73

To a solution of 5-(4-bromothiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.276 mmol) in DME-water (2:1) was added K₂CO₃(110 mg, 0.77 mmol) and the solution purged with N₂. Pd(PPh₃)₄(20 mg, 0.017 mmol) and N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (145 mg, 0.552 mmol) were added to the reaction mixture, which was refluxed under N₂for 45 min. The reaction mixture was cooled to RT and extracted with EtOAc. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 8.1-8.27 (m, 1H), 8.0 (s, 1H), 7.8 (m, 2H), 7.42 (m, 1H), 7.3 (s, 1H), 6.9-7.0 (m, 2H), 4.76 (d, 1H), 4.38 (d, 1H), 3.7 (m, 1H), 3.5 (m, 1H), 3.0 (m, 4H), 2.88 (s, 3H), 2.93 (m, 1H), 2.4 (s, 3H).

Example No. 74

Preparation of Compound No. 74

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.499 mmol), 7-bromoisoquinoline (155 mg, 0.748 mmol), K₃PO₄(317 mg, 1.495 mmol), CuI (9 mg, 0.047 mmol) and L-Proline (11 mg, 0.095 mmol) in dry DMF (2 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(isoquinolin-7-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as a yellow solid. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 9.57 (s, 1H), 8.6 (d, 1H), 8.37 (m, 2H), 8.2 (d, 1H), 8.0 (d, 1H), 7.4 (s, 1H), 7.21 (d, 1H), 7.1 (d, 1H), 4.76 (m, 1H), 4.42 (m, 1H), 3.82 (m, 1H), 3.61 (m, 1H), 3.21 (s, 3H), 3.1 (m, 2H), 2.42 (s, 3H).

Example No. 75

Preparation of Compound No. 75

To a degassed solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (101 mg, 0.286 mmol), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (150 mg, 0.57 mmol) and K₂CO₃(236 mg, 1.71 mmol) in DME-water (2:1) was added Pd(PPh₃)₄(33 mg, 0.028 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)-N-methylpicolinamide. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 8.97 (s, 1H), 8.23 (d, 1H), 8.12 (d, 1H), 7.85 (d, 1H), 7.78 (m, 2H), 7.5 (d, 1H), 7.37 (s, 1H), 7.21 (d, 1H), 7.04 (d, 1H), 4.76 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.08-3.21 (m, 5H), 3.0 (s, 3H), 2.4 (s, 3H).

Example No. 76

Preparation of Compound No. 76

To a solution of 5-(4-bromothiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.276 mmol) in DME-water (2:1) was added K₂CO₃(110 mg, 0.77 mmol) and the solution purged with N₂. Pd(PPh₃)₄(20 mg, 0.017 mmol) and 4-(methylsulfonyl)phenylboronic acid (110 mg, 0.552 mmol) were added to the reaction mixture, which was refluxed under N₂for 45 min. The reaction mixture was cooled to RT and extracted with EtOAc. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC.
H NMR (TFA salt, CD₃OD) δ (ppm): 7.98 (s, 1H), 7.7 (m,
H),
(s, 1H), 7.2 (m, 2H), 6.9 (m, 2H), 4.7 (d, 1H), 4.3 (d, 1H), 3.67 (m, 1H), 3.5 (m, 1H), 2.9-3.1 (m, 8H), 2.4 (s, 3H).

Example No. 77

Preparation of Compound No. 77

To a de-aerated solution of 5-isoquinolin-6-yl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (35 mg, 0.10 mmol) in MeOH (5 mL) were added 10% Pd—C (18 mg) and ammonium formate (68 mg, 1.07 mmol). The reaction mixture was refluxed for 15 h and filtered through Celite. The filtrate was concentrated under reduced pressure to afford crude material, which was purified by column chromatography using silica (100:200) and 3% MeOH-DCM to yield 6-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3,4-dihydro-1H-isoquinoline-2-carbaldehyde (10 mg). ¹H NMR(HCl salt, CD₃OD) δ (ppm): 8.2 (s, 1H), 7.41 (s, 1H), 7.3 (s, 1H), 7.25 (m, 2H), 7.1 (d, 1H), 7.03 (d, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 3.8 (m, 3H), 3.57 (m, 3H), 3.17 (s, 3H), 3.0 (m, 4H), 2.4 (s, 3H).

Example No. 78

Preparation of Compound No. 78

To a solution of 3,4-dibromo-N-methylthiophene-2-carboxamide (100 mg, 0.33 mmol) in DMF (2 mL) were added K₃PO₄(101 mg, 0.478 mmol), CuI (5 mg, 0.0239 mmol) and L-proline (6 mg, 0.0478 mmol). The solution was purged with nitrogen and 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (48 mg, 0.239 mmol) was added followed by nitrogen purging for 2 min. The reaction mixture was stirred at 140° C. overnight. Ice water was added into the reaction mixture and extracted the organic part into EtOAc (3×25 mL). The combined organic layer was washed with water (3×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by column chromatography using silica (100:200) and 0-5% MeOH-DCM. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.78 (d, 2H), 7.38 (s, 1H), 7.2 (d, 1H), 7.1 (d, 1H), 4.77 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.58 (m, 1H), 3.27 (m, 1H), 3.19 (m, 1H), 3.16 (s, 3H), 2.95 (s, 3H), 2.43 (s, 3H).

Example No. 79

Preparation of Compound No. 79

To a solution of [5-(4-bromothiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.25 mmol) in DME (2 mL) were added water (1 mL) and K₂CO₃(110 mg, 0.77 mmol) and purged the solution with N₂. Pd(PPh₃)₄(20 mg, 0.017 mmol) and 5-methylthiophene-2-boronic acid pinacol ester (0.15 mL, 0.628 mmol) were added to the reaction mixture which was refluxed under N₂for 45 min. The reaction mixture was cooled to RT and diluted with EtOAc. The aqueous layer was extracted with EtOAc (3×6 mL) and the combined organic layer dried over sodium sulfate. The solvent was removed under reduced pressure to afford crude material, which was purified by reverse phase HPLC. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.78 (d, 1H), 7.62 (d, 1H), 7.37 (s, 1H), 7.0 (d, 1H), 6.91 (d, 1H), 6.42 (d, 1H), 6.22 (d, 1H), 4.73 (m, 1H), 4.40 (m, 1H), 3.63 (m, 1H), 3.41 (m, 1H), 3.11 (s, 3H), 2.85 (m, 2H), 2.91 (s, 3H), 2.32 (s, 3H).

Example No. 80

Preparation of Compound No. 80

To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 6-hydroxypyridine-3-boronic acid pinacol ester (124 mg, 0.562 mmol) and K₂CO₃(120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure to dryness. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)pyridin-2-ol. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.59-7.68 (m, 3H), 7.4 (s, 1H), 7.3 (s, 1H), 6.98-7.18 (m, 3H), 6.82 (d, 1H), 6.23 (d, 1H), 4.7 (d, 1H), 4.37 (d, 1H), 3.7 (m, 1H), 3.4 (m, 1H), 3.0 (m, 4H), 2.8 (m, 1H), 2.4 (s, 3H).

Example No. 81

Preparation of Compound No. 81

To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 5-methylthiophene-2-boronic acid pinacol ester (0.13 ml, 0.562 mmol) and K₂CO₃(116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure to dryness. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(5-methylthiophen-2-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as a TFA salt. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.8 (d, 1H), 7.6 (t, 1H), 7.5 (t, 1H), 7.26-7.37 (m, 2H), 7.0 (d, 1H), 6.8 (d, 1H), 6.43-6.57 (m, 2H), 4.7 (m, 1H), 4.4 (m, 1H), 3.65 (m, 1H), 3.42 (m, 1H), 3.3 (m, 4H), 2.8 (m, 1H), 2.4 (s, 3H), 2.27 (s, 3H).

Example No. 82

Preparation of Compound No. 82

To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 3,5-dimethylisoxazole-4-boronic acid pinacol ester (125 mg, 0.562 mmol) and K₂CO₃(116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure to dryness. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 4-(2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3 -b]indol-5(2H)-yl)phenyl)-3,5-dimethylisoxazole as a TFA salt. H NMR (TFA salt, CD₃OD) δ (ppm): 7.62 (bs, 2H), 7.58 (t, 1H), 7.42 (bs, 1H), 7.22 (s, 1H), 6.9-7.1 (m, 2H), 4.65 (m, 1H), 4.27 (m, 1H), 3.7 (m, 1H), 3.4 (m, 1H), 3.08 (s, 3H), 2.8 (m, 1H), 2.6 (m, 1H), 2.4 (s, 3H), 2.0 (s, 3H), 1.8 (s, 3H).

Example No. 83

Preparation of Compound No. 83

To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 2-acetamidopyridine-5-boronic acid pinacol ester (147 mg, 0.562 mmol) and K₂CO₃(116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure to dryness. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield N-(5-(2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)pyridin-2-yl)acetamide as a TFA salt. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.8-8.0 (m, 2H), 7.6-7.78 (m, 3H), 7.35-7.48 (m, 2H), 7.27 (s, 1H), 7.0 (d, 1H), 6.9 (d, 1H), 4.63 (d, 1H), 4.3 (d, 1H), 3.64 (m, 1H), 3.42 (m, 1H), 2.92-3.1 (m, 4H), 2.8 (m, 1H), 2.4 (s, 3H), 2.1 (s, 3H).

Example No. 84

Preparation of Compound No. 84

To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 2-fluoropyridine-5-boronic acid pinacol ester (125 mg, 0.562 mmol) and K₂CO₃(116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure to dryness. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(2-(6-fluoropyridin-3-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as a TFA salt. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.79 (d, 1H), 7.7 (m, 3H), 7.57 (bs, 1H), 7.5 (d, 1H), 7.17 (s, 1H), 7.0 (d, 1H), 6.82 (d, 2H), 4.65 (m, 1H), 4.3 (m, 1H), 3.7 (m, 1H), 3.47 (m, 1H), 3.0 (m, 4H), 2.87 (m, 1H), 2.3 (s, 3H).

Example No. 85

Preparation of Compound No. 85

To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1-methylindole-5-boronic acid pinacol ester (144 mg, 0.562 mmol) and K₂CO₃(116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure to dryness. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(1-methyl-1H-indol-5-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as a TFA salt. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.7 (d, 1H), 7.62 (t, 1H), 7.38 (t, 1H), 7.4 (bs, 1H), 7.3 (s, 2H), 7.08-7.17 (m, 4H), 6.8 (bs, 1H), 6.21 (s, 1H), 4.5 (bs, 2H), 4.2 (bs, 2H), 3.7 (s, 3H), 3.4 (m, 1H), 2.68 (bs, 3H), 2.4 (m, 4H).

Example No. 86

Preparation of Compound No. 86

To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (116 mg, 0.562 mmol) and K₂CO₃(116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure to dryness. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as a TFA salt. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 7.8 (d, 1H), 7.6 (t, 1H), 7.42 (t, 1H), 7.27 (m, 2H), 7.1 (s, 1H), 7.0 (d, 1H), 6.62-6.83 (m, 2H), 4.4 (m, 2H), 3.43-3.8 (m, 5H), 2.8-3.1 (m, 5H), 2.4 (s, 3H).

Example No. 87

Preparation of Compound No. 87

To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 4-isoquinolineboronic acid (97 mg, 0.562 mmol) and K₂CO₃(116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure to dryness. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(2-(isoquinolin-4-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as a TFA salt. ¹H NMR (TFA salt, CD₃OD) δ (ppm): 9.08-9.2 (m, 1H), 7.85-8.21 (m, 3H), 7.8 (m, 5H), 7.5-7.62 (m, 1H), 6.97-7.2 (m, 2H), 6.41-6.63 (m, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 2.77-3.1 (m, 5H), 2.2 (s, 3H).

Example No. 88

Preparation of Compound No. 88

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (500 mg, 2.50 mmol), 3-bromoquinoline (1.040 g, 5.0 mmol), potassium phosphate tribasic (1.325 g, 6.25 mmol), L-proline (87 mg, 0.756 mmol) and copper iodide (143 mg, 0.752 mmol) in DMF (4 mL) was stirred at 150° C. for 14 h. The reaction mixture was diluted with water and extracted with EtOAc (
×
0 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was re-crystallized from MeOH-ether (1:99) to afford 2,8-dimethyl-5-quinolin-3-yl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (350 mg). ¹H NMR (Freebase, CDCl₃) δ (ppm): 9.0 (s, 1H), 8.2 (d, 1H), 8.17 (s, 1H), 7.82 (t, 1H), 7.68 (t, 1H), 7.61 (t, 1H), 7.25 (s, 1H), 7.18 (d, 1H), 7.0 (d, 1H), 3.7 (s, 2H), 2.8 (m, 4H), 2.58 (s, 3H), 2.4 (s, 3H).

Example No. 89

Preparation of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2 g, 9.986 mmol), 1,2-dibromobenzene (1.7 mL, 14.97 mmol), K₃PO₄(6.35 g, 29.95 mmol), CuI (189 mg, 0.99 mmol) and L-proline (229 mg, 1.99 mmol) in dry DMF (20 mL) was stirred at 150° C. for 24 h. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (250 mL). The organic layer was washed with water (10×100 mL), dried over anhydrous sodium sulfate and evaporated to afford crude material, which was purified by column chromatography using neutral alumina and 3% EtOAc-hexane, to yield 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

Example No. 90

Preparation of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 5 mmol), 1,3-dibromobenzene (1.7 g, 7.2 mmol), K₃PO₄(3.18 g, 15 mmol), CuI (95 mg, 0.5 mmol) and L-proline (115 mg, 1 mmol) in dry DMF (5 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (150 mL). The organic layer was washed with water (6×30 mL), dried over anhydrous sodium sulfate and evaporated to afford crude material, which was purified by column chromatography using neutral alumina and 5% EtOAc-hexane to yield 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

Example No. 91

Preparation of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 5 mmol), 2,5-dibromopyridine (1.78 g, 7.5 mmol), K₃PO₄(3.18 g, 15 mmol), CuI (95 mg, 0.5 mmol) and L-proline (115 mg, 1 mmol) in dry DMF (10 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (300 mL). The organic layer was washed with water (8×50 mL), dried over anhydrous sodium sulfate and evaporated to afford crude material, which was purified by column chromatography using neutral alumina and 5% EtOAc-hexane, to yield 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

Example No. 92

Preparation of Compound No. 100

To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole[4,3-b]indole (100 mg, 0.282 mmol), 1-methyl-2-pyrroleboronic acid pinacol ester (87.7 mg, 00.423 mmol) and K₃PO₄(149.5 mg, 0.705 mmol) in DMF (2 mL) and water (0.2 mL) was added dichloro bis-(triphenylphosphine) palladium (II) (9.89 mg, 0.014 mmol). The reaction mixture was stirred at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to yield 2,8-dimethyl-5-(2-(1-methyl-1H-pyrrol-2-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.6 (m, 3H), 7.4 (m, 1H), 7.26 (s, 1H), 7.0 (q, 2H), 6.6 (s, 1H), 5.83 (s, 1H), 5.4 (m, 1H), 4.65 (d, 1H), 4.3 (d, 1H), 3.6 (bs, 1H), 3.38 (m, 4H), 3.07 (bs, 1H), 2.9 (s, 3H), 2.8 (m, 1H), 2.4 (s, 3H).

Example No. 93

Preparation of Compound No. 102

To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 3-methylthiophene-2-boronic acid pinacol ester (125 mg, 0.562 mmol) and K₂CO₃(116 mg, 0.845 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to yield 2,8-dimethyl-5-(2-(3-methylthiophen-2-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.6 (m, 3H), 7.4 (m, 1H), 7.21 (s, 1H), 7.1 (m, 1H), 6.93 (d, 1H), 6.81 (t, 1H), 6.78 (d, 1H), 4.65 (d, 1H), 4.37 (d, 1H), 3.7 (m, 1H), 3.42 (m, 1H), 3.04 (s, 1H), 2.97 (s, 3H), 2.8 (m, 1H), 2.4 (s, 3H), 2.17 (s, 3H).

Example No. 94

Preparation of Compound No. 103

To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), benzo[b]thien-2-ylboronic acid (100 mg, 0.562 mmol) and K₂CO₃(116 mg, 0.845 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to yield 5-(2-(benzo[b]thiophen-2-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.0 (d, 1H), 7.65 (t, 2H), 7.6 (d, 2H), 7.35-7.42 (m, 2H), 7.22-7.3 (m, 2H), 7.0 (m, 2H), 6.9 (d, 1H), 4.72 (d, 1H), 4.4 (d, 1H), 3.62 (m, 1H), 3.4 (m, 1H), 3.0 (bs, 1H), 2.87 (s, 3H), 2.7 (m, 1H), 2.4 (s, 3H).

Example No. 95

Preparation of Compound No. 104

To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1H-pyrazole-4-boronic acid (62 mg, 0.554 mmol) and K₂CO₃(116 mg, 0.845 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to yield 5-(2-(1H-pyrazol-4-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.82 (d, 1H), 7.6 (t, 1H), 7.5 (t, 1H), 7.38 (bs, 2H), 7.0 (m, 3H), 6.83 (bs, 1H), 4.4 (bs, 2H), 3.63 (m, 1H), 3.42 (m, 1H), 3.0 (m, 4H), 2.8 (m, 1H), 2.42 (s, 3H).

Example No. 96

Preparation of Compound No. 105

To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), indazole-4-boronic acid hydrochloride (111 mg, 0.559 mmol) and K₂CO₃(116 mg, 0.845 mmol) in DME (4 mL) and water (2 mL) was added Pd (PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to yield 5-(2-(1H-indazol-4-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.8-7.97 (m, 2H), 7.7 (m, 2H), 7.42-7.57 (m, 1H), 7.4 (d, 1H), 7.2 (s, 1H), 6.96-7.16 (m, 3H), 6.5-6.7 (m, 1H), 4.57 (m, 1H), 4.2 (m, 1H), 3.5 (m, 1H), 3.0 (m, 2H), 2.8 (m, 1H), 2.7 (s, 3H), 2.4 (s, 3H).

Example No. 97

Preparation of Compound No. 131

To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 4-(methylsulfonyl)phenylboronic acid (111 mg, 0.563 mmol) and K₂CO₃(116 mg, 0.845 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc 50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to yield 2,8-dimethyl-5-(4′-(methylsulfonyl)biphenyl-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.03 (d, 2H), 7.97 (d, 2H), 7.85 (d, 1H), 7.78 (t, 2H), 7.5 (d, 1H), 7.38 (s, 1H), 7.2 (d, 1H), 7.08 (d, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.2 (m, 7H), 3.1 (m, 1H), 2.47 (s, 3H).

Example No. 98

Preparation of Compound No. 132

To a de-aerated solution of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (90 mg, 0.253 mmol), pyridin-4-ylboronic acid (111 mg, 0.507 mmol) and K₂CO₃(104.6 mg, 0.757 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh₃)₄(14.6 mg, 0.0126 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to yield 5-(3,4′-bipyridin-6-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 9.2 (s, 1H), 8.9 (bs, 2H), 8.6 (d, 1H), 8.43 (d, 2H), 7.9 (d, 1H), 7.62 (d, 1H), 7.38 (s, 1H), 7.18 (d, 1H), 4.73 (d, 1H), 4.4 (d, 1H), 3.85 (m, 1H), 3.6 (m, 2H), 3.4 (m, 1H), 3.18 (s, 3H), 2.43 (s, 3H).

Example No. 99

Preparation of Compound No. 133

To a de-aerated solution of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.280 mmol), pyridin-3-ylboronic acid (68 mg, 0.553 mmol) and K₂CO₃(116 mg, 0.839 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to yield 5-(3,3′-bipyridin-6-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 9.02 (s, 1H), 8.98 (s, 1H), 8.7 (s, 1H), 8.4 (d, 2H), 7.8 (d, 1H), 7.77 (m, 1H), 7.57 (d, 1H), 7.27 (s, 1H), 7.18 (d, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 3.8 (bs, 1H), 3.44-3.6 (m, 3H), 3.18 (s, 3H), 2.46 (s, 3H).

Example No. 100

Preparation of Compound No. 134

To a de-aerated solution of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.280 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (116 mg, 0.557 mmol) and K₂CO₃(116 mg, 0.839 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to 2,8-dimethyl-5-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.8 (s, 1H), 8.2 (d, 1H), 8.18 (s, 1H), 7.98 (s, 1H), 7.6 (d, 1H), 7.42 (d, 1H), 7.37 (s, 1H), 7.1 (d, 1H), 4.7 (m, 1H), 4.4 (d, 1H), 4.0 (s, 3H), 3.8 (bs, 1H), 3.6 (bs, 1H), 3.4 (m, 2H), 3.18 (s, 3H), 2.42 (s, 3H).

Example No. 101

Preparation of Compound No. 135

To a de-aerated solution of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.280 mmol), 4-isoquinolineboronic acid (96 mg, 0.554 mmol) and K₂CO₃(116 mg, 0.839 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 2 h. The reaction mixture concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to yield 5-(5-(isoquinolin-4-yl)pyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 9.6 (s, 1H), 8.8 (s, 1H), 8.6 (s, 1H), 8.46 (d, 1H), 8.3 (d, 1H), 8.1 (m, 2H), 7.82 (d, 1H), 7.9 (d, 1H), 7.62 (d, 1H), 7.4 (s, 1H), 7.2 (d, 1H), 4.7 (m, 1H), 4.4 (bs, 1H), 3.8 (bs, 1H), 3.4-3.66 (m, 3H), 3.18 (s, 3H), 2.46 (s, 3H).

Example No. 102

Preparation of Compound No. 136

To a de-aerated solution of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.280 mmol), 1-methylindole-5-boronic acid pinacol ester (143 mg, 0.556 mmol) and K₂CO₃(116 mg, 0.839 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 2 h. The reaction mixture concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to yield 2,8-dimethyl-5-(5-(1-methyl-1H-indol-5-yl)pyridin-2-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.88 (s, 1H), 8.3 (d, 1H), 7.94 (s, 1H), 7.64 (d, 1H), 7.57 (s, 2H), 7.51 (d, 1H), 7.38 (s, 1H), 7.24 (d, 1H), 7.16 (d, 1H), 6.58 (d, 1H), 4.7 (m, 1H), 4.4 (bs, 1H), 3.84 (s, 3H), 3.8 (m, 1H), 3.4-3.62 (m, 3H), 3.18 (s, 3H), 2.42 (s, 3H).

Example No. 103

Preparation of Compound No. 137

To a de-aerated solution of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.280 mmol), 3,5-dimethylisoxazole-4-boronic acid pinacol ester (124 mg, 0.556 mmol) and K₂CO₃(116 mg, 0.839 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to yield 4-(6-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)pyridin-3-yl)-3,5-dimethylisoxazole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.6 (s, 1H), 8.06 (d, 1H), 7.78 (d, 1H), 7.57 (d, 1H), 7.38 (s, 1H), 7.17 (d, 1H), 4.7 (m, 1H), 4.4 (d, 1H), 3.82 (bs, 1H), 3.46-3.62 (m, 2H), 3.2 (s, 3H), 3.17 (m, 1H), 2.51 (s, 3H), 2.47 (s, 3H), 2.36 (s, 3H).

Example No. 104

Preparation of Compound No. 138

To a de-aerated solution of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.280 mmol), 2-(dimethylamino)pyrimidine-5-boronic acid pinacol ester (139 mg, 0.557 mmol) and K₂CO₃(116 mg, 0.839 mmol) in mixture of DME (4 mL) and water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated to afford crude material, which was purified by reverse HPLC to yield 5-(6-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)pyridin-3-yl)-N,N-dimethylpyrimidin-2-amine as the TFA Salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.8 (s, 1H), 8.71 (s, 2H), 8.24 (d, 1H), 7.68 (d, 1H), 7.48 (d, 1H), 7.37 (s, 1H), 7.17 (d, 1H), 4.7 (d, 1H), 4.3 (d, 1H), 3.81 (bs, 1H), 3.4-3.6 (m, 3H), 3.3 (s, 6H), 3.18 (s, 3H), 2.42 (s, 3H).

Example No. 105

Preparation of Compound No. 139

To a de-aerated solution of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.280 mmol), 2-acetamidopyridine-5-boronic acid pinacol ester (146 mg, 0.557 mmol) and K₂CO₃(116 mg, 0.839 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to yield N-(6′-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3,3′-bipyridin-6-yl)acetamide as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.9 (s, 1H), 8.63 (s, 1H), 8.3 (d, 1H), 8.22 (d, 1H), 8.18 (d, 1H), 7.76 (d, 1H), 7.5 (d, 1H), 7.38 (s, 1H), 7.13 (d, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 3.82 (bs, 1H), 3.42-3.6 (m, 3H), 3.18 (s, 3H), 2.42 (s, 3H), 2.2 (s, 3H).

Example No. 106

Preparation of Compound No. 140

To a de-aerated solution of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.280 mmol), 4-fluorophenylboronic acid (146 mg, 0.557 mmol) and K₂CO₃(116 mg, 0.839 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to yield 5-(5-(4-fluorophenyl)pyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.82 (s, 1H), 8.3 (d, 1H), 7.79 (t, 2H), 7.7 (d, 1H), 7.5 (d, 1H), 7.37 (s, 1H), 7.3 (t, 2H), 7.17 (d, 1H), 4.7 (m, 1H), 4.4 (bs, 1H), 3.8 (bs, 1H), 3.4-3.6 (m, 3H), 3.18 (s, 3H), 2.42 (s, 3H).

Example No. 107

Preparation of Compound No. 141

To a de-aerated solution of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.280 mmol), naphthalene-1-boronic acid (96 mg, 0.558 mmol) and K₂CO₃(116 mg, 0.839 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to yield 2,8-dimethyl-5-(5-(naphthalen-1-yl)pyridin-2-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.7 (s, 1H), 8.2 (d, 1H), 8.0 (d, 2H), 7.88 (d, 1H), 7.8 (d, 1H), 7.5-7.62 (m, 5H), 7.38 (s, 1H), 7.18 (d, 1H), 4.7 (m, 1H), 4.4 (s, 1H), 3.9 (bs, 1H), 3.3 (m, 3H), 3.18 (s, 3H), 2.47 (s, 3H).

Example No. 108

Preparation of Compound No. 142

To a de-aerated solution of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.280 mmol), 2-fluoropyridine-5-boronic acid pinacol ester (124 mg, 0.556 mmol) and K₂CO₃(116 mg, 0.839 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude material which, was purified by reverse HPLC to yield 5-(6′-fluoro-3,3′-bipyridin-6-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.9 (s, 1H), 8.6 (s, 1H), 8.3 (m, 2H), 7.77 (d, 1H), 7.56 (d, 1H), 7.28 (s, 1H), 7.25 (d, 1H), 7.17 (d, 1H), 4.7 (m, 1H), 4.4 (bs, 1H), 3.82 (bs, 1H), 3.46-3.62 (m, 3H), 3.18 (s, 3H), 2.44 (s, 3H).

Example No. 109

Preparation of Compound No. 143

To a de-aerated solution of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.280 mmol), N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (146 mg, 0.559 mmol) and K₂CO₃(116 mg, 0.839 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to yield 3-(6-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)pyridin-3-yl)-N-methylbenzamide as the TFA salt ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.96 (s, 1H), 8.37 (d, 1H), 8.2 (s, 1H), 7.9 (m, 2H), 7.76 (d, 1H), 7.64 (t, 1H), 7.56 (d, 1H), 7.38 (s, 1H), 7.18 (d, 1H), 4.7 (bs, 1H), 4.4 (bs, 1H), 3.82 (bs, 1H), 3.45-3.62 (m, 3H), 3.2 (s, 3H), 3.0 (s, 3H), 2.45 (s, 3H).

Example No. 110

Preparation of Compound No. 144

To a de-aerated solution of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.280 mmol), 4-methylthiophene-2-boronic acid pinacol ester (125 mg, 0.557 mmol) and K₂CO₃(116 mg, 0.839 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(5-(4-methylthiophen-2-yl)pyridin-2-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.82 (s, 1H), 8.21 (d, 1H), 7.61 (d, 1H), 7.48 (d, 1H), 7.4 (s, 1H), 7.38 (s, 1H), 7.13 (m, 2H), 4.
(bs, 1H), 4.4 (bs, 1H), 3.8 (bs, 1H), 3.56 (bs, 1H), 4.4 (m, 2H), 3.18 (s,
H), 2.42 (s, 3H), 2.3 (s, 3H).

Example No. 111

Preparation of Compound No. 145

To a de-aerated solution of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.280 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (158 mg, 0.558 mmol) and K₂CO₃(116 mg, 0.839 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL), The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 4-(6-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)pyridin-3-yl)benzenesulfonamide as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.96 (s, 1H), 8.38 (d, 1H), 8.08 (d, 2H), 7.95 (d, 2H), 7.77 (d, 1H), 7.57 (d, 1H), 7.37 (s, 1H), 7.18 (d, 1H), 4.7 (bs, 1H), 4.4 (bs, 1H), 3.8 (bs, 1H), 3.5 (m, 3H), 3.2 (s, 3H), 2.42 (s, 3H).

Example No. 112

Preparation of Compound No. 146

To a de-aerated solution of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.280 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (116 mg, 0.557 mmol) and K₂CO₃(116 mg, 0.839 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.77 (s, 1H), 8.18 (d, 1H), 7.8 (d, 1H), 7.6 (d, 1H), 7.58 (s, 1H), 7.36 (s, 1H), 7.16 (d, 1H), 6.58 (s, 1H), 4.7 (bs, 1H), 4.4 (bs, 1H), 3.98 (s, 3H), 3.8 (bs, 1H), 3.5 (m, 3H), 3.2 (s, 3H), 2.45 (s, 3H).

Example No. 113

Preparation of Compound No. 147

To a de-aerated solution of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.280 mmol), indazole-4-boronic acid hydrochloride (111 mg, 0.559 mmol) and K₂CO₃(116 mg, 0.839 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(5-(1H-indazol-4-yl)pyridin-2-yl)-2,8-dimethyl-2,
,4,
-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.97 (s, 1H), 8.4 (d, 1H), 8.2 (s, 1H), 7.8 (d, 1H), 7.62 (d, 1H), 7.5 (m, 2H), 7.4 (s, 1H), 7.38 (d, 1H), 7.17 (d, 1H), 3.6-4.0 (m, 4H), 3.2 (s, 3H), 3.18 (m, 2H), 2.41 (s, 3H).

Example No. 114

Preparation of Compound No. 148

To a de-aerated solution of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.280 mmol), 3-methylthiophene-2-boronic acid pinacol ester (125 mg, 0.557 mmol) and K₂CO₃(116 mg, 0.839 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(5-(3-methylthiophen-2-yl)pyridin-2-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.7 (s, 1H), 8.14 (d, 1H), 7.7 (d, 1H), 7.5 (d, 1H), 7.42 (d, 1H), 7.37 (s, 1H), 7.1 (d, 1H), 7.03 (d, 1H), 4.7 (bs, 1H), 4.4 (bs, 1H), 3.8 (bs, 1H), 3.5 (m, 3H), 3.18 (s, 3H), 2.42 (s, 3H), 2.38 (s, 3H).

Example No. 115

Preparation of Compound No. 149

To a de-aerated solution of 5-(4-bromothiophen-3-yl)-2,6,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (250 mg, 0.668 mmol), pyridine-4-boronic acid (165 mg, 1.33 mmol) and K₂CO₃(277 mg, 2.0 mmol) in DME-water (2:1) was added Pd(PPh₃)₄(46 mg, 0.04 mmol). The reaction mixture was stirred at 90° C. for 45 min and concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated and the residue purified by reverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.8 (d, 2H), 8.6 (s, 1H), 8.38 (d, 2H), 8.1 (s, 1H), 6.8 (s, 1H), 6.2 (s, 1H), 3.82 (bs, 1H), 3.7 (m, 1H), 3.4 (m, 3H), 3.07 (s, 3H), 2.43 (s, 3H), 2.22 (m, 1H), 2.2 (s, 3H).

Example No. 116

Preparation of Compound No. 150

To a de-aerated solution of 5-(4-bromothiophen-3-yl)-2,6,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.276 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (86 mg, 0.413 mmol) and K₂CO₃(110 mg, 0.8 mmol) in DME-water (2:1) was added Pd(PPh₃)₄(20 mg, 0.016 mmol). The reaction mixture was stirred at 90° C. for 45 min and concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated and residue purified by reverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.96 (s, 1H),
9 (d, 1H), 7.08 (s, 1H), 7.01 (s, 1H), 7.0 (m, 2H), 5.6 (m, 1H), 4.7 (d, 1H), 4.
(m, 1H), 3.7 (m, 4H), 3.5 (m, 1H), 3.05 (m, 5H), 2.4 (s, 3H).

Example No. 117

Preparation of Compound No. 151

To a de-aerated solution of 5-(4-bromothiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.25 mmol), benzo[b]thiophen-2-ylboronic acid (100 mg, 0.367 mmol) and K₂CO₃(110 mg, 0.77 mmol) in DME-water (2:1) was added Pd(PPh₃)₄(20 mg, 0.017 mmol). The reaction mixture was stirred at 90° C. for 45 min and concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated and residue purified by reverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.99 (s, 1H), 7.65 (s, 1H), 7.6 (d, 1H), 7.5 (d, 1H), 7.37 (s, 1H), 7.2 (m, 2H), 7.0 (d, 1H), 6.95 (d, 1H), 6.76 (d, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.68 (bs, 1H), 3.42 (bs, 1H), 3.0 (m, 5H), 2.4 (s, 3H).

Example No. 118

Preparation of Compound No. 152

To a solution of 4-bromo-N,N-dimethylthiophene-3-carboxamide (100 mg, 0.434 mmol) in DMF (1 mL) were added K₃PO₄(5.31 mg, 2 mmol), CuI (5.9 mg, 0.031 mmol), L-proline (7.13 mg, 0.062 mmol) and 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (62 mg, 0.31 mmol) and stirred at 140° C. overnight. Ice water was added into the reaction mixture and extracted with EtOAc (2×25 mL). The organic layer was washed with water (2×10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue purified by silica column chromatography (0-3% MeOH-DCM) followed by reverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.83 (d, 1H), 7.68 (d, 1H), 7.3 (s, 1H), 7.0 (d, 1H), 6.98 (d, 1H), 4.7 (d, 1H), 4.38 (d, 1H), 3.8 (m, 1H), 3.57 (m, 1H), 3.02-3.17 (m, 5H), 2.85 (d, 3H), 2.7 (d, 3H), 2.4 (s, 3H).

Example No. 119

Preparation of Compound No. 153

To a de-aerated solution of 2,8-dimethyl-5-quinolin-3-yl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (50 mg, 0.152 mmol) in methanol (5 mL) were added palladium hydroxide (50 mg, 100% w/w) and ammonium formate (48 mg, 0.761 mmol). The reaction mixture was stirred at 100° C. for 2 h then cooled to RT. The mixture was filtered through Celite and washed with MeOH (5 mL). The filtrate was concentrated under reduced pressure and the residue purified by reverse phase HPLC to yield 2,8-dimethyl-5-(1,2,3,4-tetrahydro-quinolin-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt (15 mg). ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.62 (s, 1H), 8.19 (s, 1H), 7.38 (s, 1H), 7.2 (d, 1H), 7.1 (d, 1H), 4.76 (m, 1H), 4.4 (bs, 1H), 3.8 (bs, 1H), 3.56 (bs, 1H), 3.28 (m, 6H), 3.01 (t, 3H), 2.43 (s, 3H), 2.01 (t, 2H), 1.95 (t, 2H).

Example No. 120

Preparation of Compound No. 154

To a degassed solution of 5-(4-bromothiophen-3-yl)-2,3,4,5-tetrahydro-dimethyl-1H-pyrido[4,3-b]indole (50 mg, 0.138 mmol) and K₂CO₃(8 mg, 0.07 mmol) in DME-water (1:1) were added Pd(PPh₃)₄(19 mg, 0.138 mmol) and N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (109 mg, 0.417 mmol). The reaction mixture was stirred at 85° C. for 1 h then diluted with EtOAc (20 mL). The organic layer was washed with water (2×5 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0-1.5% MeOH-DCM) followed by reverse phase HPLC purification. ¹H NMR (CD₃OD, HCl salt) δ (ppm): 7.82 (dd, 1H), 7.77 (dd, 1H), 7.58 (d, 1H), 7.4 (d, 1H), 7.28 (d, 1H), 7.2 (m, 1H), 7.18 (d, 1H), 7.0 (m, 2H), 4.7 (d, 1H), 4.37 (d, 1H), 3.7 (m, 1H), 3.5 (m, 1H), 3.1 (s, 2H), 2.94 (s, 3H), 2.82 (s, 3H), 2.41 (d, 3H).

Example No. 121

Preparation of Compound No. 155

To a degassed solution of 5-(4-bromothiophen-3-yl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (50 mg, 0.138 mmol) and K₂CO₃(8 mg, 0.07 mmol) in DME:water (2:1) were added Pd(PPh₃)₄(19 mg, 0.138 mmol) and N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (109 mg, 0.417 mmol). The reaction mixture was stirred at 85° C. for 1 h, and diluted with EtOAc (20 mL). The organic layer was washed with water (2×5 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0-2% MeOH-DCM) followed by reverse phase HPLC purification. ¹H NMR (CD₃OD, HCl salt) δ (ppm): 7.83 (dd, 1H), 7.7 (dd, 1H), 7.58 (d, 2H), 7.3 (d, 1H), 7.07 (d, 1H), 7.0 (d, 3H), 4.7 (d, 1H), 4.38 (d, 1H), 3.62 (m, 1H), 3.52 (m, 1H), 3.03 (s, 2H), 2.9 (s, 3H), 2.83 (s, 3H), 2.4 (s, 3H).

Example No. 122

Preparation of Compound No. 156

To a de-aerated solution of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.280 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (122 mg, 0.557 mmol) and K₂CO₃(116 mg, 0.839 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh₃)₄(16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 2 h and concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue purified by reverse phase HPLC to yield 2,8-dimethyl-5-(6′-methyl-3,3′-bipyridin-6-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.9 (s, 1H), 8.82 (s, 1H), 8.37 (d, 1H), 8.22 (d, 1H), 7.78 (d, 1H), 7.58 (d, 1H), 7.5 (d, 1H), 7.38 (s, 1H), 7.17 (d, 1H), 4.5 (bs, 2H), 3.7 (bs, 2H), 3.4 (bs, 2H), 3.17 (s, 3H), 2.68 (s, 3H), 2.42 (s, 3H).

Example No. 123

Preparation of Compound No. 157

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (300 mg, 1.50 mmol), 6-bromo-2-methyl-quinoline (600 mg, 2.7 mmol), potassium phosphate tribasic (954 mg, 4.50 mmol), L-proline (87 mg, 0.75 mmol) and copper iodide (143 mg, 0.
mmol) in DMF (3 mL) was stirred at 100° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3×50 mL). The organic layer was washed with water (5×50 mL), dried over anhydrous sodium sulfate, concentrated and the residue obtained was purified by flash chromatography using silica gel (100-200 mesh) and 4% MeOH-DCM to yield of 2,8-dimethyl-5-(2-methyl-quinolin-6-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (130 mg). ¹H NMR (CD₃OD, di-HCl salt) δ (ppm): 9.1 (d, 1H), 8.4 (m, 2H), 8.23 (d, 1H), 8.03 (d, 1H), 7.4 (s, 1H), 7.26 (d, 1H), 7.1 (d, 1H), 4.7 (d, 1H), 4.42 (d, 1H), 3.82 (m, 1H), 3.6 (m, 1H), 3.37 (m, 1H), 3.2 (s, 3H), 3.1 (m, 1H), 3.08 (s, 3H), 2.45 (s, 3H).

Example No. 124

Preparation of Compound No. 158

To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (300 mg, 0.845 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide (478 mg, 1.689 mmol) and K₂CO₃(350 mg, 2.532 mmol) in DME (10 mL) and water (5 mL) was added Pd(PPh₃)₄(48 mg, 0.041 mmol). The reaction mixture was stirred at 90° C. for 2 h and concentrated under reduced pressure. The residue was diluted with water (60 mL) and extracted with EtOAc (100 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and residue was purified by reverse phase HPLC to yield 3′-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)biphenyl-4-sulfonamide as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.0 (d, 2H), 7.84 (m, 3H), 7.7 (m, 2H), 7.46 (d, 1H), 7.27 (s, 1H), 7.18 (d, 1H), 7.04 (d, 1H), 4.7 (bs, 1H), 4.4 (bs, 1H), 3.8 (bs, 1H), 3.6 (bs, 1H), 3.2 (m, 1H), 3.17 (s, 3H), 3.07 (m, 1H), 2.42 (s, 3H).

Example No. 125

Preparation of Compound No. 159

To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (124 mg, 0.563 mmol) and K₂CO₃(116 mg, 0.843 mmol) in DME (4 mL) and water (0.4 mL) was added Pd(PPh₃)₄(16 mg, 0.014 mmol). The reaction mixture was stirred at 90° C. for 2 h and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (40 mL). The organic layer was dried over anhydrous sodium sulfate, evaporated and the residue obtained was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(4-methylpyridin-3-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CDCl₃, freebase) δ (ppm): 8.2 (d, 2H), 7.5 (m, 2H), 7.4 (t, 1H), 7.38 (t, 1H), 7.1 (s, 1H), 6.9 (s, 1H), 6.8 (s, 2H), 3.6 (q, 2H), 2.7 (t, 2H), 2.6 (t, 2H), 2.5 (s, 3H), 2.38 (s, 3H), 2.0 (bs, 3H).

Example No. 126

Preparation of Compound No. 160

To a degassed solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 0.563 mmol), 4-(methylsulfonyl)phenylboronic acid (169 mg, 0.84
mmol) and K₃PO₄(297 mg, 1.40 mmol) in DMF (6 mL) and water (0.
mL) was added Pd(PPh₃)₂Cl₂(20 mg, 0.028 mmol), and the reaction mixture heated at 90° C. for 16 h. Water (40 mL) was added to the reaction mixture, which was then extracted with EtOAc. The organic layer was washed with water (10×30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by silica gel flash chromatography, followed by reverse phase HPLC to yield 2,8-dimethyl-5-(4′-(methylsulfonyl)biphenyl-2-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.7 (m, 4H), 7.5 (bs, 1H), 7.3 (m, 4H), 7.0 (d, 1H), 6.9 (d, 1H), 4.63 (bs, 1H), 4.3 (bs, 1H), 3.63 (bs, 1H), 3.5 (bs, 1H), 3.0 (m, 5H), 2.9 (s, 3H), 2.4 (s, 3H).

Example No. 127

Preparation of Compound No. 161

To a degassed solution of 5-(3-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3b]indole (100 mg, 0.281 mmol), pyridin-4-ylboronic acid (69 mg, 0.563 mmol) and K₂CO₃(116 mg, 0.843 mmol) in DME (0.9 mL) and water (0.1 mL) was added Pd(PPh₃)₄(16 mg, 0.014 mmol). The reaction mixture was irradiated in a microwave reactor at 90° C. for 45 min and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to afford crude material, which was purified by reverse phase HPLC to yield 5-(3,4′-bipyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.8 (d, 1H), 8.4 (d, 2H), 8.3 (d, 1H), 7.8 (t, 1H), 7.3 (m, 3H), 6.87 (bs, 1H), 6.76 (bs, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.8 (bs, 1H), 3.6 (bs, 1H), 3.17 (s, 3H), 2.8 (m, 2H), 2.38 (s, 3H).

Example No. 128

Preparation of Compound No. 162

To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 0.563 mmol), N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (294 mg, 1.126 mmol) and K₂CO₃(233 mg, 1.689 mmol) in DME (8 mL) and water (0.4 mL) was added Pd(PPh₃)₄(33 mg, 0.028 mmol). The reaction mixture was stirred at 90° C. for 45 min and concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (60 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated to afford crude material, which was purified by reverse phase HPLC to yield 3′-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-N-methylbiphenyl-3-carboxamide as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.1 (s, 1H), 7.8 (m, 3H), 7.7 (m, 2H), 7.58 (t, 1H), 7.4 (d, 1H), 7.36 (s, 1H), 7.18 (d, 1H), 7.02 (d, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 3.8 (bs, 1H), 3.58 (bs, 1H), 3.2 (m, 1H), 3.1 (s, 3H), 3.0 (m, 1H), 2.9 (s, 3H), 2.4 (s, 3H).

Example No. 129

Preparation of Compound No. 163

To a degassed solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,
-tetrahydro-1H pyrido[4,3-b]indole (300 mg, 0.845 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (478 mg, 1.69 mmol) and K₂CO₃(350 mg, 2.53 mmol) in DME (12 mL) and water (0.6 mL) was added Pd(PPh₃)₄(49 mg, 0.042 mmol). The reaction mixture was stirred overnight at 90° C. and concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (60 mL). The organic extract was dried over anhydrous sodium sulfate, and concentrated to afford crude material, which was triturated with diethyl ether and the solid was purified by reverse phase HPLC to yield 2′-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)biphenyl-4-sulfonamide as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.62 (m, 5H), 7.38-7.5 (m, 1H), 7.28 (s, 2H), 7.17 (d, 1H), 6.9-7.08 (m, 2H), 4.6 (d, 1H), 4.2 (d, 1H), 3.6 (bs, 1H), 3.52 (bs, 1H), 3.2 (bs, 1H), 2.9 (bs, 1H), 2.8 (s, 3H), 2.4 (s, 3H).

Example No. 130

Preparation of Compound No. 164

A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (310 mg, 1.55 mmol), K₃PO₄(0.985 g, 4.65 mmol), CuI (29.4 mg, 0.15 mmol), L-proline (35.6 mg, 0.31 mmol) and 4-bromo-1-methylisoquinoline (0.520 g, 2.35 mmol) in dry DMF (3 mL) was stirred at RT for 10 min and then at 150° C. for 16 h. Water (50 mL) was added to the reaction mixture and then extracted with EtOAc (150 mL). The organic layer was washed with water (6×30 mL), dried over anhydrous sodium sulfate and evaporated to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(1-methylisoquinolin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.6-8.74 (m, 2H), 8.0 (m, 2H), 7.41 (s, 1H), 7.38 (bs, 1H), 7.0 (d, 1H), 6.8 (bs, 1H), 4.8 (bs, 1H), 4.5 (bs, 1H), 3.8 (bs, 1H), 3.6 (bs, 1H), 3.3 (s, 3H), 3.18 (s, 3H), 3.0 (bs, 1H), 2.82 (bs, 1H), 2.41 (s, 3H).

Example No. 131

Preparation of N-Methyl and N-Ethyl 9-Chloro-1,2,3,4,5,6-hexhydroazepino[4,3-b]indole

A mixture of 4-chloro-2-iodoaniline (0.5 g, 1.97 mmol), 1,3-cyclohexanedione (0.22 g, 1.96 mmol) and p-toluenesulfonic acid monohydrate (catalytic) in toluene (6 mL) were heated to reflux for 2 h. The reaction was cooled and EtOAc (50 mL) was added and the organic phase was washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered and evaporated to give a brown solid, which was purified by column chromatography [Silica, eluent:EtOAc:hexane to give 3-(4-chloro-2-iodophenylamino)cyclohex-2-enone as a yellow solid (0.55 g, 80%).
A mixture of 3-(4-chloro-2-iodo-phenylamino)-cyclohex-2-enone (0.5 g, 1.44 mmol), cuprous iodide (27.4 mg, 0.14 mmol), L-proline (33.12 mg, 0.29 mmol) and potassium hydroxide (0.32 g, 5.70 mmol) in DMSO (6 mL) were heated to 90° C. for 24 h. The reaction was cooled and poured into water. The aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phase was washed with brine (25 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give a dark brown solid. This was recrystallized using acetonitrile water to give a brown solid (0.17 g, 54%). mp 281-282° C.
A solution of 6-chloro-2,3-dihydro-1H-carbazol-4(9H)-one (500 mg, 2.27 mmol), hydroxylamine hydrochloride (238 mg, 3.41 mmol) and NaOAc (280 mg, 3.41 mmol) in EtOH:water (4.5:2 mL) was heated to reflux (125° C.) for 5 h. The reaction mixture was concentrated to dryness. Water was added to the residue and the solid filtered, dried under vacuum to yield the title compound.
6-Chloro-2,3-dihydro-1H-carbazol-4(9H)-one oxime (4.39 g, 18.71 mMol) and polyphosphoric acid (119 g) was heated together at 120° C. for 20 min. After cooling to RT, ice-water mixture was added to hydrolyze the mixture and stirred for 2 h. The mixture was filtered and washed with NH₄OH (40 ml) followed by water. The resultant solid was dissolved in MeOH and filtered. The methanolic solution was concentrated to yield 4.7 g of crude as a brown solid. The crude product was purified by flash column chromatography over silica-gel (230-400 mesh) using EtOAc/Hexane followed by MeOH/EtOAc, the product eluting at 2-10% MeOH/EA. Yield: 2.1 g (47.8%).
To an ice-cooled stirred suspension of lithium aluminum hydride (48
mg, 12.8 mmol) in dry THF (29 mL) was added dropwise a solution of 9-chloro-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (380 mg, 1.62 mmol) in dry THF (20 mL), and the reaction mixture heated to reflux for 15 h (89° C.). The reaction mixture was cooled to RT, quenched with water (3 mL), and 15% NaOH solution (6 mL) and water (9 mL), and then diluted with THF. The reaction mixture was filtered through Celite and the filtrate concentrated under reduced pressure to yield the title compound.
A solution of 9-chloro-1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (360 mg, 1.6 mmol) in THF (1 mL) was added dropwise to ethyl formate (1 mL). The reaction mixture was stirred at RT for 30 min, followed by heating to reflux for 14 h. The solvent was removed under reduced pressure to yield the title compound.
A solution of 9-chloro-1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (360 mg, 1.6 mmol) was stirred in acetic anhydride for 12 h. The solvent was removed under reduced pressure to yield the title compound.
A solution of 9-chloro-1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (12.3 g, 55.9 mmol) in ethyl formate (369 mL) was stirred at 55° C. for 2 h. The progress of reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure and the crude product (13.5 g) was used for the next step without purification. To a stirred suspension of lithium aluminum hydride (4.13 g, 108.8 mmol) in dry THF (405 mL) was added portionwise 9-chloro-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carbaldehyde (13.5 g) and the mixture heated to reflux for 2 h. The progress of reaction was monitored by TLC. The reaction was quenched with saturated aqueous sodium sulfate solution at 0° C., and the mixture filtered. The filtrate was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was washed with diethyl ether to yield the title compound (9.7 g). ¹H NMR (DMSO) δ (ppm): 11.02 (s, 1H, D₂O exchangeable), 7.45 (s, 1H), 7.25-7.22 (d, 1H), 6.98-6.95 (d, 1H), 3.72 (s, 2H), 2.90-2.80 (m, 4H), 2.30 (s, 3H), 1.82-1.77 (m, 2H).
To an ice-cooled stirred suspension of lithium aluminum hydride (390 mg, 10.09 mmol) in 1,4-dioxane (15 mL) was added portionwise 1-(9-chloro-4,5-dihydroazepino[4,3-b]indol-2(1H,3H,6H)-yl)ethanone (300 mg, 1.14 mmol), and the reaction mixture heated to reflux for 6 h. The reaction mixture was quenched with water (1 mL), 15% aq. NaOH solution (3 mL) and water (3 mL), and extracted with warm EtOAc (3×50 mL). The combined organic extract was concentrated and the residue purified by silica gel (230-400 mesh) flash column chromatography (100% EtOAc) to yield the title compound (115 mg).

Example No. 132

Preparation of 2,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indole

To a solution of p-tolylhydrazine hydrochloride (7.5 g, 47.2 mmol) in 1,4-dioxane:conc. H₂SO₄(225:16.5 mL) was added cyclohexane-1,3-dione (4.42 g, 39.4 mmol), and the mixture heated to reflux for 16 h (85-90° C.). The reaction mixture was cooled to RT, basified with 15% aqueous KOH (pH 10) and extracted with EtOAc. The organic layer was washed twice with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the title compound (7.7 g, crude).
A solution of 2,3-dihydro-6-methyl-1H-carbazol-4(9H)-one (5.8 g, 19.1 mmol), hydroxylamine hydrochloride (3.0 g, 43.6 mmol) and NaOAc (3.58 g, 43.6 mmol) in EtOH:water (58:25.3 mL) was heated to reflux (125° C.) for 5 h. The reaction mixture was concentrated to dryness. Water was added to the residue and the solid filtered, dried under vacuum to yield title compound.
To a preheated (105° C.) solution of polyphosphoric acid (225 g) was added powdered 6-methyl-2,3-dihydro-1H-carbazol-4(9H)-one oxime (10 g) under nitrogen and heating continued for 15 min. The reaction mixture was cooled and to it was added crushed ice water. The crystallized solid obtained was collected by filtration. The solid was washed with water and then by dilute ammonium hydroxide, then dried under vacuum to obtain the desired product (8 g, crude product).
Lithium aluminum hydride (3 g, 78.95 mmol) was placed in 1,4-dioxane (100 mL) under inert atmosphere and 9-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (3 g, 14.018 mmol) was added, and the mixture heated to reflux for 15 h. The reaction was monitored by TLC. The reaction was quenched with saturated aqueous sodium sulfate at 0° C., and the reaction mixture filtered. The filtrate was dried over anhydrous sodium sulfate and evaporated to dryness to afford solid, which was washed with water followed by EtOAc, and dried to afford 1.25 g of the title compound.
9-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (0.25 g, 1.25 mmol) was taken in ethyl formate (18 mL, 227 mmol) and stirred at 55° C. for 3 h. The reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure and used for the next step without purification (0.2 g).
To a stirred suspension of lithium aluminum hydride (2 g, 52.63 mmol) in dry THF (150 mL) was added portionwise 9-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carbaldehyde (5.9 g, 25.87 mmol) and the reaction mixture stirred at 55° C. for 2 h. The progress of reaction was monitored by TLC. The reaction mixture was quenched with saturated sodium aqueous sulfate solution at 0° C. and then filtered. The filtrate was dried over anhydrous sodium sulfate and evaporated to dryness to afford the title compound (5.2 g). ¹H NMR (DMSO)
(ppm): 7.12-7.05 (m, 2H), 6.80-6.6.76 (d, 1H), 3.65 (s, 2H), 2.90-2.80 (m, 4H), 2.34 (s, 3H), 2.26 (s, 3H), 1.80-1.72 (m, 2H).

Example B 1

Determination of the Ability of Compounds of the Invention to Bind an Adrenergic Receptor

Adrenergic α_2A

To evaluate in radioligand binding assays the activity of compounds, human recombinant adrenergic α_2Areceptor expressed in insect Sf9 cells (Uhlen, S. et al, J. Pharmacol. Exp. Ther. 271:1558, 1994) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mM MgCl₂, 2 mM EDTA) was used. Compounds were incubated with 1 nM [³H]MK-912 for 60 min at 25° C. MK912 is (2S-trans)-1,3,4,5′,6,6′,7,12b-octahydro-1′,3′-dimethyl-spiro[2H-benzofuro[2,3-a]quinolizine-2,4′(1′H)-pyrimidin]-2′(3′H)-one hydrochloride Non-specific binding was estimated in the presence of 10 μM WB-4101 (2-(2,6-Dimethoxyphenoxyethyl)aminoethyl-1,4-benzodioxane hydrochloride). Receptor proteins were filtered and washed, the filters were then counted to determine [³H]MK-912 specifically bound. Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds were tested in this biochemical assay and percent inhibition of specific binding was determined. Biochemical assay results are presented as the percent inhibition of specific binding in Table 2.

Adrenergic α_2B

To evaluate in radioligand binding assays the activity of compounds, human recombinant adrenergic α_2Breceptor expressed in Chinese hamster ovary (CHO) K1 cells (Uhlen, S. et al, Eur. J. Pharmacol. 343(1):93, 1998) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mM MgCl₂, 1 mM EDTA, 0.2% BSA) was used. Compounds were incubated with 2.5 nM [³H]Rauwolscine for 60 min at 25° C. Non-specific binding was estimated in the presence of 10 μM Prazosin. Receptor proteins were filtered and washed, the filters were then counted to determine [³H]Rauwolscine specifically bound. Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds were tested in this biochemical assay and percent inhibition of specific binding was determined. Biochemical assay results are presented as the percent inhibition of specific binding in Table 2.

Adrenergic α_1B

To evaluate in radioligand binding assays the activity of compounds, rat adrenergic α_1Breceptor obtained from Wistar Rat liver (Garcia-S' ainz, J. et al, Biochem. Biophys. Res. Commun. 186:760, 1992; Michel, A. et al, Br. J. Pharmacol. 98:883, 1989) in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mM EDTA) was used. Compounds were incubated with 0.25 nM [³H]Prazosin for 60 min at 25° M C. Non-specific binding was estimated in the presence of 10 μM phentolamine. Receptor proteins were filtered and washed, the filters were then counted to determine [³H]Prazosin specifically bound. Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds were tested in this biochemical assay and percent inhibition of specific binding was determined. Biochemical assay results are presented as the percent inhibition of specific binding in Table 2.

Adrenergic α_1D

To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant adrenergic α_1Dreceptor expressed in human embryonic kidney (HEK-293) cells (Kenny, B. et al, Br. J. Pharmacol. 115(6):981, 1995) in a 50 mM Tris-HCl buffer, pH 7.4, was used. Compounds were incubated with 0.6 nM [3H]Prazosin for 60 min at 25° C. Non-specific binding was estimated in the presence of 10 μM phentolamine. Receptor proteins were filtered and washed, the filters were then counted to determine [3H]Prazosin specifically bound. Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 2.

TABLE 2

Percentage inhibition of ligand binding to adrenergic
receptors by compounds of the invention

Compound

Adrenergic (0.1 μM)*

Adrenergic (0.03 μM)*

No.	α_1B	α_1D	α_2A	α_2B	α_1B	α_2A	α_2B

5	52	45	26	78	—	—	—
10	61	63	88	85	—	—	—
14	38	20	23	51	—	—	—
15	35	19	10	30	—	—	—
16	8	16	−1	16	—	—	—
30	32	17	42	86	—	—	—
31	36	80	74	67	—	—	—
32	73	65	72	80	—	—	—
33	52, 73	69	92, 96, 100	95, 105, 106	46	87, 96	100, 102
34	16	18	28	1	—	—	—
35	67	68	84	95	—	—	—
36	13	26	90	79	—	—	—
37	77	79	88, 94	96, 104	—	81	104
38	31	32	32	57	—	—	—
39	67	62	98	70	—	—	—
40	43	79	91	89	—	—	—
41	77	76	87	70	—	—	—
42	10	−3	17	7	—	—	—
43	9	3	31	6	—	—	—
44	0	2	29	12	—	—	—
45	1	1	12	6	—	—	—
46	−7	8	48	21	—	—	—
47	5	3	62	6	—	—	—
48	1	−5	19	16	—	—	—
49	12	14	−3	31	—	—	—
50	42	51	88, 93	103	—	82	97
51	10	12	27	7	—	—	—
52	6	−3	43	36	—	—	—
53	8	0	24	15	—	—	—
54	8	−3	23	3	—	—	—
55	10	9	19	26	—	—	—
56	36	65	4	90	—	—	—
57	6	−1	7	11	—	—	—
58	22	24	22	39	—	—	—
59	47	65	77	91	—	—	—
60	4	9	62	14	—	—	—
61	11	5	23	7	—	—	—
62	32	18	67	19	—	—	—
63	2	5	30	11	—	—	—
64	10	−1	25	1	—	—	—
65	14	1	33	46	—	—	—
66	13	11	39	18	—	—	—
67	2	−1	39	13	—	—	—
68	61	68	86, 90	86, 93	—	76	71
69	11	9	39	3	—	—	—
70	18	9	34	19	—	—	—
71	66	87	11	89	—	—	—
72	28	56	3	17	—	—	—
73	64	83	16	94	—	—	—
74	41	18	38	70	—	—	—
75	20	15	21	16	—	—	—
76	68	73	68, 90	94, 100	—	44	89
77	15	6	15	45	—	—	—
78	8	21	63	86	—	—	—
79	51	53	90, 92	104, 106	—	82	102
80	9	23	12	27	—	—	—
81	37	36	88	95	—	—	—
82	14	14	30	21	—	—	—
83	18	64	20	71	—	—	—
84	54	58	68	89	—	—	—
85	36	62	89, 94	98, 102	—	80	89
86	26	22	33	67	—	—	—
87	13	16	30	18	—	—	—
88	36	20	15	80	—	—	—
100	79	64	84, 95	99, 109	—	74	103
102	57	50	85	90	—	—	—
103	41	62	98	97	—	—	—
104	6, 15	22	10, 19	87	—	—	61
105	71	65	79	84	—	—	—
131	0	3	75	28	—	—	—
132	33	28	17	69	—	—	—
133	63	53	31	77	—	—	—
134	43	30	38	73	—	—	—
135	59	64	56	99	—	—	—
136	70	59	59	105	—	—	—
137	72	74	57	92	—	—	—
138	73	73	40	82	—	—	—
139	55	45	18	59	—	—	—
140	69	56	70	96	—	—	—
141	62	50	69	82	—	—	—
142	83	78	59	91	—	—	—
143	83	72	44	77	—	—	—
144	68	52	72	95	—	—	—
145	86	73	71	83	—	—	—
146	70	79	26	54	—	—	—
147	72	61	46	43	—	—	—
148	63	68	50	90	—	—	—
149	16	8	−6	14	—	—	—
150	72	73	55	77	—	—	—
151	59	67	96	99	—	—	—
152	10	16	9	51	—	—	—
153	8	9	1	58	—	—	—
154	46	70	20	42	—	—	—
155	43	63	9	74	—	—	—
156	78	69	40	78	—	—	—
157	22	13	8	60	—	—	—
158	7	14	73	60	—	—	—
159	—	—	—	56	—	—	—
160	—	—	—	74	—	—	—
161	—	—	—	26	—	—	—
162	—	—	—	40	—	—	—
163	—	—	—	69	—	—	—
164	—	—	—	3	—	—	—

*Where shown, some compounds were tested in repeat assays, each datapoint is shown.

Example B2

Functional Activity on Recombinant Adrenergic α_1B, Adrenergic α_2AAdrenergic α_2Band Adrenergic α_1DReceptors Using Aequorin and GTPγS Functional Assays

To study the functional activity of compounds of the invention on the human recombinant adrenergic α_2B, adrenergic α_2A, adrenergic α_1Bor adrenergic α_1Dwith Aequorin functional assays and on the human recombinant adrenergic α_2Breceptor with GTPγS assay, CHO-K1 cell lines expressing adrenergic α_2B, adrenergic α_2A, adrenergic α_1Bor adrenergic α_1Drecombinant receptor, mitochondrial apoaequorin and Gα16 are used for the Aequorin assay. CHO-K1 cell line expressing the recombinant α_2Breceptor is amplified to prepare membranes used for the GTPγS assay.
The following reference agonists are used as both the reference ligand in agonist mode and as the agonist that needs to be inhibited in antagonist mode.


	α_1B	α_1D	α_2A	α_2B	α_2B
Assay	(aeq)	(aeq)	(aeq)	(aeq)	(GTPgS)

Agonist	Cirazoline	Cirazoline	UK 14304	Oxymeta-	Guanfacine
ligand				zoline

Aequorin Assay Procedure: Aequorin adrenergic α_1B(FAST-008A), adrenergic α_2A(FAST-006A) or adrenergic α_2B(FAST-007A) cells are grown 18 h prior to the test in media without antibiotics. They are then detached by gentle flushing with PBS-EDTA (5 mM EDTA), recovered by centrifugation and re-suspended in “assay buffer” (DMEM/HAM's F12 with HEPES+0.1% BSA protease free). Cells are incubated at RT for at least 4 h with Coelenterazine h (Molecular Probes). Dose response curves with reference compounds are performed before testing the compounds of the invention. The α_1Breference agonist and antagonist are cirazoline and qinazoline, respectively. The α_2Areference agonist and antagonist are UK14,304 and rauwolscine, respectively. The α_2Breference agonist and antagonist are oxymetazoline and rauwolscine, respectively.
For agonist testing, 50 μL of cell suspension are injected on 50 μL of test compound or reference agonist plated in a 96-well plate. The resulting emission of light is recorded using the Hamamatsu Functional Drug Screening System 6000 (FDSS 6000). For antagonist testing, following an incubation of 15 min. after the first injection, 100 μL of reference agonist at a concentration corresponding to its EC₈₀is injected on the 100 μL of the mixture of cell suspension and test compound. The resulting emission of light is recorded using the same luminometer as for agonist testing. To standardize the emission of recorded light (determination of the “100% signal”) across plates and across different experiments, some of the wells contained 100 μM digitonin or a saturating concentration of ATP (20 μM). Plates also contained the reference agonist at a concentration equivalent to the EC₈₀obtained during the test validation.
Agonist activity of test compound is expressed as a percentage of the activity of the reference agonist at its EC₁₀₀concentration. Antagonist activity of test compound is expressed as a percentage of the inhibition of reference agonist activity at its EC₈₀concentration.
Compounds are tested for agonist & antagonist activity at the human adrenergic α_1B(FAST-008A), adrenergic α_2A(FAST-006A) or adrenergic α_2B(FAST-007A) at the following nanomolar concentrations, in duplicate: Agonist (nM): 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000, 10000; Antagonist (nM): 0.15, 0.5, 1.5, 5, 15, 50, 150, 500, 1500, 5000.
GTPγS Assay Procedure: The procedure is carried out with the following: assay buffer [20 mM HEPES pH 7.4; 100 mM NaCl, 10 μg/mL saponin, 1 mM MgCl₂]; membranes [Recombinant CHO-K1-adrenergic α_2Bmembrane extracts thawed on ice and diluted in assay buffer to give 10 μg/well and kept on ice]; GDP [diluted in assay buffer to give 3 μM final concentration]; beads [PVT-WGA (Amersham, RPNQ0001), diluted in assay buffer at 0.5 mg/well]; GTPγ³⁵S [(PerkinElmer NEG030X), diluted in assay buffer to give 0.1 nM final concentration]; ligand [Guanfacine (Tocris, 1030) as reference agonist and Rauwolscine (Tocris, 891) as reference antagonist, diluted in assay buffer]. Membranes are mixed with GDP (volume:volume) and incubated for at least 15 min. on ice. In parallel, GTPγ[³⁵S] is mixed with the beads (volume:volume) just before starting the reaction.
For agonist testing, the following reagents are successively added in the wells of an Optiplate (Perkin Elmer): 50 μL of test or reference ligand, 20 μL of the membranes:GDP mix, 10 μL of assay buffer and 20 μL of the GTPγ[³⁵S]:beads mix. For antagonist testing, the following reagents are successively added in the wells of an Optiplate (Perkin Elmer): 50 μL of test or reference ligand, 20 μL of the membranes:GDP mix, and then after an incubation of 15 min. at RT, 10 μL of reference ligand at historical EC₈₀concentration and 20 μL of the GTPγ[³⁵S]:beads mix.
The plates are covered with a top seal, mixed on an orbital shaker for 2 min, and then incubated for 1 h at RT. Then the plates are centrifuged for 10 min. at 2000 rpm, incubated at RT 4 h and counted for 1 min/well with a Perkin Elmer TopCount reader.
Compounds are tested for antagonist activity at the human adrenergic α_2Breceptor (FAST-007G) at the following nanomolar concentrations, in duplicate: Agonist and antagonist (nM): 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000, 10000.

Inverse Agonist Activity

SPA 35S-GTPgS and Radioligand Binding experiments are conducted with Euroscreen membrane preparations. Compound is tested for inverse agonist activity at the human Adrenergic α_2Areceptor using GTPg35S binding functional assay (FAST-006G) in dose-reponse and in duplicates.

Example B3

Cell Culture and Cell Viability Assay

SH-SY5Y cells cultured in DMEM/F12 media supplemented with 10% FBS are seeded in 96-well microplates at 150,000 cells/cm². After 24 h, cells are depleted from FBS and kept in culture for 24 h before the experiment. A stock solution is prepared by dissolving the calcium ionophore 4-Br-A23187 (Calbiochem Cat. N° 100107) in DMSO at 25 mM. Cells are then treated with 4-Br-A23187 (2 μM), hydrogen peroxide (300 μM) or the mitochondrial toxin rotenone (25 μM) in the presence of vehicle or Compound of the Invention for 24 h. Cell death is determined by measurements of LDH release according to the Cytotoxicity Detection KitPlus (Roche, Mannheim, Germany). Cell viability is determined by measuring the capacity of cells to metabolize MTS tetrazolium (MTS) according to the Cytotoxicity Detection KitPlus (Roche, Mannheim, Germany) and MTS reduction is assessed by the CellTiter 96® AQueous One Solution Cell Proliferation assay (Promega Corporation, Madison, Wis., USA). Compounds are screened at 10 nM using DMSO as vehicle. Assay results for the experiments with Br-A2
187 m are presented as the MTS reduction capacity (cell viability) of untreated cells (control), 4-Br-A23187-treated cells (vehicle), and co-incubation of Br-A23187 with Compounds of the Invention treated cells and using p-trifluoromethoxyphenylhydrazone (FCCP) at 10 μM for 30 min as a control. This assay assesses the ability of the test compounds to protect against cell death that is mediated by mitochondrial dysfunction. In the assay, the calcium ionophore 4-Br-A23187 is used to challenge the cells, causing calcium levels to rise in mitochondria, which leads to depolarization and cell death. Test compounds are assessed for their ability to prevent cell death in response to challenge with 4-Br-A23187.

Example B4

Cell Culture and Cell Viability Assay

Cell Culture.
SH-SY5Y cells stably transfected with a doxycyline-inducible wild-type α-synuclein (α-syn) gene along with control SH-SY5Y cells over-expressing the β-galactosidase (β-gal) gene (a gift from L. Stefanis, Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens, Greece) are cultured as described by Vekrellis et al. (Vekrellis K, Xilouri M, Emmanouilidou E, Stefanis L. (2009). Inducible over-expression of α-syn in human neuronal cells leads to caspase-dependent non-apoptotic death. J. Neurochem. 109, 1348-1362). In accordance with this method, cells are cultured and maintained in RPMI 1640, 10% fetal bovine serum supplemented with 250 μg/mL G418 and 50 μg/mL Hygromycin B. Expression of α-syn is switched off in stock cultures with doxycycline (2 μg/mL). For experimental procedures, cells are plated at (4−8×10⁴cells/cm²) and differentiated in absence of doxycycline and in the presence of 20 μM all-trans retinoic acid (RA) (Sigma, St Louis, Mo., USA).
Viability Assay:
Cells are cultured in 96-well plates. After 24 h, cells are treated with RA and Compounds of Invention at 0.1 and 10 nM in the absence of doxycyline. Culture medium with RA and drugs is fully replaced after 7 days. Cell viability is measured by the release of lactate dehydrogenase (LDH) from necrotic cells into the culture medium and by measuring the capacity of cells to metabolize MTS tetrazolium (MTS) after 14 days in culture. LDH leakage is assessed according to the Cytotoxicity Detection KitPlus (Roche, Mannheim, Germany) and MTS reduction is assessed by the CellTiter 96® AQueous One Solution Cell Proliferation assay (Promega Corporation, Madison, Wis., USA).
Immunoblotting of α-Synuclein and α-Synuclein Aggregates:
Cells stably expressing α-synuclein are cultured in 6-well plates at a density of 4×10⁴cells/cm²cells per well. Cells are differentiated and treated with Compound of the Invention at 10 nM in absence of dox after 24 h of plating. Drug treatments are repeated after 7 days in freshly prepared medium containing RA. After 14 days, cells are washed twice with cold PBS and lysed in lysis buffer containing 1% Triton X-100, 20 mM HEPES, 150 mM NaCl, 10% glycerol, 1 mM EGTA, 1.
mM, MgCl₂, 1 mM PMSF pH 7.4, and 1× protease inhibitor mixture (Roche, Mannheim, Germany). Lysates are homogenized and subjected to four successive freeze-thaw cycles to disrupt membranes. Triton soluble fractions and triton insoluble pellets are obtained by ultracentrifugation at 100,000×g for 30 min at 4° C. The concentration of protein in each fraction is determined by BCA assay (Thermo Scientific). Samples from total, soluble and triton insoluble fractions, are boiled in 1× sample buffer (20 mM Tris, 1% glycerol, 180 mM (3-mercaptoethanol, 0.003% bromophenol blue, and 2% SDS, pH 6.8), loaded on 12% SDS-PAGE gels, and transferred to polyvinylidene difluoride (PVDF) membranes (0.2 μM-pore immobilon Biorad). Membranes are blocked in 1×TBS-Tween (20 mM Tris, pH 7.4, 150 mM NaCl, and 0.2% Tween 20) containing 5% milk for 1 h and incubated overnight at 4° C. with the following primary antibodies in blocking solution at the indicated dilutions: monoclonal anti-α-synuclein α-syn-1 (1:1000; BD Transduction Laboratories). (Perrin, R. J., Payton, J. E., Barnett, D. H., Wraight, C. L., Woods, W. S., Ye, L., and George, J. M. (2003). Epitope mapping and specificity of the anti-α-synuclein monoclonal antibody Syn-1 in mouse brain and cultured cell lines. Neurosci. Lett. 349, 133-135), and monoclonal vimentin (1:1000; BD PharMingen). Primary antibodies are detected with secondary anti-mouse antibodies conjugated to HRP (1:5000).
Isolation of RNA and RT-Quantitative PCR(RT-qPCR):
SH-SY5Y cells stably over-expressing α-syn are treated with Compound of the Invention (10 nM). Total RNA from these cells as well as control cells not treated with test compound is extracted using the E.Z.N.A RNA extraction Kit (OMEGAbiotek, Norcross, Ga.). 1 μg of RNA is reverse transcribed to cDNA using the M-Mulv reverse transcriptase enzyme (Promega Corporation, Madison, Wis., USA). RT-qPCR of cDNA templates is carried out using TAQMAN probes for human α-synuclein (Hs00240906_M1) and TAQMAN masterMix (Applied Biosystems) and a Mx3005P real-time PCR system (Agilent Technologies Inc., Santa Clara, Calif.). Levels of alpha-tubulin mRNA are used to normalize the amounts of total RNA between samples. Fold changes are calculated as described by (Pfaffl, M. W. (2001). A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29, e45).

Example B5

Insulin Secretion Ability—In Vitro

Islet Isolation and In-Vitro Insulin Release from Rat Islets:
Rat isolated pancreatic islets are prepared from rat pancreas by collagenase digestion. After digestion, islets are hand-picked and incubated in a humidified atmosphere with RPMI 1640 tissue culture medium supplemented with 10% (vol/vol) fetal bovine serum and penicillin/streptomycin [Carter J D, Dula S B, Corbin K L, Wu R, Nunemaker C S. (2009) “A practical guide to rodent islet isolation and assesment.” Biol. Proced. Online 11(1): 3-31]. In-vitro insulin secretion is measured in static incubations. Prior to experiments, islets are preincubated for 1 hour at 37° C. in a Krebs-Ringer bicarbonate buffer composed of 120 mM NaCl, 25 mM NaHCO₃, 5 mM KCl, 1 mM MgCl₂, 2.5 mM CaCl₂, 2.8 mM glucose and 0.5% bovine serum albumin. The medium is gassed with 100% CO₂for 15 minutes to obtain constant pH. Next, groups of 15 islets are incubated in 1 mL for 60 minutes at 37° C. in Krebs-Ringer buffered solution supplemented with glucose (2.8 mM as low glucose or 20 mM as high glucose), test compound, clonidine, yohimbine or norepinephrine as indicated. Immediately after incubation, an aliquot of the medium is removed for analysis of insulin content by ELISA (Mercodia). This assay demonstrates the effect of the test compound on insulin release, in competition with either norepinephrine or clonidine.

Example B6

Insulin Secretion Ability—In Vitro

To demonstrate the insulin secretion ability and/or glucose lowering effect of a test compound, several animal models are used, including clonidine (an α_2Aagonist) induced, norepinephrine (a natural ligand of α_2A) induced, glucose induced, and spontaneous (no agonist) rat (normal Wistar rats or spontaneously hypertensive rats with obesity (SHR.OB)) models of hyperglycemia and norepinephrine induced and spontaneous (no agonist) obese mouse (ob/ob) models of hyperglycemia. These models and their pathophysiology are reported in e.g., Kuhn C. M. et al., Pharmacol. Biochem. Behav. 26:491-495 (1987); Velliquette R. A. and Ernsberger P, J. Pharmacol. Exp. Ther. 306:646-657 (2003); Rosengren A. H., et al., Science, 327:217-220 (2010); Chen B., et al., Exp. Biol. Med., 236:309-414 (2011); and Saperstein R., et al., Metabolism, 39:445-451 (1990). To rule out the possible hypoglycemic effects, normoglycemic rats are used. Male or female 16 week old spontaneously hypertensive obese rats (SHR.OB), 10 week old male Wistar rats and 10 week old male ob/ob mice are utilized in these studies. Free access to standard lab chow and reverse osmosis (RO) water is supplied to all rats. All aspects of this work, including housing and feeding, experimentation and disposal of animals are performed in general accordance with the Guide for the Care and Use of Laboratory Animals (National Academy Press, Washington, D.C., 1996).

Effect of Test Compound on Blood Glucose Levels in Clonidine Induced Rat Models of Hyperglycemia:

In separate studies, six hour fasted SHR.OB or Wistar rats are randomized according to their baseline blood glucose levels and divided into several groups with an “n” of 4 for group depending on the experimental design. All the experimental agents are dissolved in sterile saline or appropriate solvents and administered sub-cutaneously (SC), oral (PO) or intra-peritoneal (IP) as indicated. The vehicle group received saline alone via SC route. Test compound at doses of 0 (vehicle), 6 mg/kg and 18 mg/kg in SHR.OB rats; and 0 (vehicle), 5 mg/kg and 15 mg/kg to Wistar rats are administered via SC route at −30 minutes. Hyperglycemia is induced in both SHR.OB and wistar rats with clonidine at a dose of 0.05 mg/kg via PO route at 0 min. At all the study points, blood glucose levels are measured by one touch glucose meter (Lifescan, Milpitas, Calif.). The tip of the tail is snipped by sharp scissors and gently squeezed for a drop of blood. The glucose strip is inserted in the slot of the hand-held glucose meter and a drop of blood is added to the strip. Within 20 seconds, the device determined the blood glucose levels. Blood glucose levels are recorded at −30, 0, 15, 30, 60 and 120 minutes. Effect of test compound on blood glucose and serum insulin levels in norepinephrine induced rat models of hyperglycemia:
All experimental conditions and experimental procedures are identical to that of clonidine induced rat models of hyperglycemia in SHR.OB and Wistar rats except norepinephrine is given in the place of clonidine at a dose of 1 mg/kg via IP route; and test compound is tested at a single dose, 15 or 18 mg/kg via SC route. In further studies, both blood glucose and serum insulin levels are measured in the same study at 10 or 30 mg/kg SC doses of test compound.
Effect of Test Compound on Blood Glucose and Serum Insulin Levels in Norepinephrine Induced ob/ob Mouse Model Hyperglycemia:
Studies with ob/ob mice, all experimental procedures are identical to that of norepinephrine induced rat models of hyperglycemia and test compound is tested via SC route at a dose of 30 mg/kg. Number of mice used per group per time point are 3.
Effect of Test Compound on Blood Glucose and Serum Insulin Levels in Ob/Ob Mouse Model Spontaneous Hyperglycemia with No Norephinephrine:
All experimental procedures are identical to that of studies conducted in ob/ob mice where norepinephrine is not given at 0 minutes; and test compound at a dose of 30 mg/kg via SC route is dosed at −30 minutes. Number of mice used per group and each time point are 3. Effect of test compound on blood glucose and serum insulin levels in glucose induced (oral glucose tolerance test—OGTT) rat SHR.OB model of hyperglycemia:
All experimental procedures are identical to that of norepinephrine induced hyperglycemia in SHR.OB rats except glucose is given in the place of norepinephrine at 0 minutes at a dose of 6 g/kg via oral route as reported by Chen et al, Exp. Biol. Med., 236:309-414 (2011). Number of rats used per group are 8.
This assay demonstrates the effect of the test compound on insulin secretion ability in norepinephrine or clonidine induced hyperglycemia ob/ob mice.

Effect of Test Compound on Blood Glucose Levels in Normoglycemic Rats:

In addition to the studies with rat models of hyperglycemia, the effect of test compound at high dose (18 mg/kg, SC) on blood glucose levels is also tested in normoglycemic SHR.OB rats, which is an animal model of metabolic syndrome. This is to rule out possible hypoglycemic effects in normoglycemic rats. The experimental protocol in this study is identical to that of the other studies except that the rats are normoglycemic and are not administered clonidine or norepinephrine at 0 minutes.

Example B7

Blood Pressure Lowering Ability—In Vivo

To demonstrate the blood pressure lowering effect of a test compound, male spontaneously hypertensive rats (SHR) are used. SHR rats are anaesthetized with sodium pentobarbital (50 mg/kg IP). The left carotid artery cannulated with a polyethylene catheter (38 cm in length; PE60, Portex, Ltd.) connected with a polyurethane tubing (12 cm in length; PU-40, Cat. # BB520-40, Scientific Commodities, Inc.), which is tunneled under the skin and exited through the nape of the neck. The arterial cannula is connected to a pressure transducer through a swivel system, allowing free roaming during continuous recording of mean arterial pressure and heart rate. The animals are housed individually with food and water freely available during recovery. On the following day, the arterial cannula is connected via a Statham (P 23×L) pressure transducer to a NEC/San-Ei amplifier and data acquisition and analysis system (Power Lab 8/SP) for direct mean arterial pressure and heart rate measurements. To determine the effect of test compound on systolic blood pressure, oral or i.v. bolus or i.v. escalating doses of compound administration in every 30 minutes is performed and systolic blood pressure is monitored at various time points, baseline data is collected during 0 to 120 minutes time points; test compound is dosed at 120 minutes; and compound effect is monitored from 120 minutes to 255 minutes.
This assay demonstrates the effect of the test compound on lowering blood pressure while potentially also lowering blood glucose levels when test compound is administered orally (10 mg/kg) or i.v., bolus (1 mg/kg) or i.v., escalating doses (1, 3, 10 and 30 mg/kg/iv for every 30 minutes).

Example B8

Synergistic Studies with Other Secretagogue Drugs

Similar to the methods mentioned in the earlier section (Insulin Secreation Ability—in vitro), male Sprague Dawley rats are anesthetized with a mixture of ketamine and xilazine (1:1) and their abdominal walls are cut open. Ten milliliter Hank's buffer saline containing collagenase (2 mg/ml) is injected into the common bile duct of the rat. The pancreas swollen with the digestion solution is quickly excised and immersed into a plastic culture bottle with solution for 12 minutes-14 minutes incubation at 37° C. The digested suspension obtained is washed with Hank's buffer complement with 0.2% bovine serum albumin. Islets are obtained from a rat by gradient centrifugation (Histopaque-1077). After, islets are cultured for 24 hours in RPMI medium and collected for tests. Different scretagogue drugs like sulfonylureas (nateglitinide, a meglitinide class) or sulfonylureas (glibenclamide, a second generation sulfonylureas or glimepiride, a third generation sulfonylurea) are tested with Test compound and found synergism (FIG. 8, FIG. 23 and FIG. 24).
Test compound Blocks pERK1/2: For Western blotting, whole-cell extracts, cells are washed with ice-cold PBS and lysate with lysis buffer and collected by scraping. The protein concentration is determined using a BCA Protein Assay Reagent Kit. Cell lysates containing 30 μg proteins are electrophoresed on 10% SDS-PAGE and then transferred onto a PVDF membrane. The membranes are rinsed with TBST, followed by incubation with p-ERK (mouse, 1/1000, SCBT) or ERK (rabbit, 1/1000, SCBT) for 2 or 1 hour, respectively, at room temperature. After being washed with TBST, the membranes are incubated with the anti-mouse or anti-rabbit, respectively, HRP antibody (1:5000; Rockland) for 1 hour. Immunoreactive bands are visualized by ECL Western blotting detection (PIERCE). As shown in the FIG. 25 (Westernblot), Test compound blocked pERK1/2 norepinephrine mediated effects in rat pancreatic islets.

Example B9

Human Clinical Studies

The compound is studied in a clinical trial of adult-onset type 2 diabetic patients whose blood glucose levels remain suboptimally controlled despite use of metformin. The study compares the active compound against a matched placebo with the primary objective of comparing mean hemoglobin A1c changes from baseline to the end of the study between the active compound and placebo.
All references throughout, such as publications, patents, patent applications and published patent applications, are incorporated herein by reference in their entireties.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

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:

R¹is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹and R^2aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹and R^3aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹and R^4aare taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;

each R^2aand R^2bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R^2aand R^2bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^2aand R¹are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^2aand R^3aare taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^2aand R^4aare taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

each R^3aand R^3bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R^3aand R^3bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^3aand R¹are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^3aand R^2aare taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^3aand R^4aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;

each R^4aand R^4bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^4aand R^4bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^4aand R¹are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^4aand R^2aare taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^4aand R^3aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;

each X¹, X², X³and X⁴is independently N, CH or CR⁶;

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

R⁶is hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, 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 X¹, X², X³and X⁴is CH or CR⁶;

(2) when each X¹, X², X³and X⁴is independently CH or CR⁶, none of R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare 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 X¹, X², X³and X⁴is independently CH or CR⁶, none of R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare 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 X¹, X², X³and X⁴is independently CH or CR⁶, and R^2aand R^3aare taken together to form an ethylene (—CH₂CH₂—) 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 X¹, X², X³and X⁴is independently N, CH or CR⁶;

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

R⁶is hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, 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 X¹, X², X³and X⁴is CR⁶;

(2) when none of X¹, X²and X³is N, and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4aand R^4bare taken together to form a ring, then Q is other than an unsubstituted phenyl;

(3) when none of X¹, X², X³and X⁴is N, and R^2aand R^2bare 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 X¹, X³and X⁴is CH, X²is CR⁶where R⁶is fluoro, and each R^2a, R^2b, R^3a, R^3b, R^4aand R^4bis H, then Q is other than 4-fluorophenyl;

formula (J-1) is:

or a salt or solvate thereof, wherein:

R¹is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^2a, R^2bR^3a, R^3b, R^4a, R^4b, R^10aand R^10bis independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, 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 X¹, X²and X³is independently N, CH or CR⁶;

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

R⁶is hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, 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 X¹, X², X³and X⁴is CH or CR⁶;

and formula (K-1) is:

or a salt or solvate thereof, wherein:

each X¹, X²and X³is independently N, CH or CR⁶;

provided that at least one of X¹, X², X³and X⁴is CH or CR⁶.

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^3aand R^3bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, and cyano, hydroxyl, alkoxy, nitro or R^3aan R^3bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^3aand R¹are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^3aand R^2aare taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^3aand R^4aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;

each X¹, X², X³and X⁴is independently N, CH or CR⁶;

provided that:

(1) at least one of X¹, X², X³and X⁴is CH or CR⁶;

formula (IB) is:

or a salt or solvate thereof, wherein:

each X¹, X², X³and X⁴is independently N, CH or CR⁶;

provided that:

(1) at least one of X¹, X², X³and X⁴is CR⁶;

formula (J-1) is:

or a salt or solvate thereof, wherein:

each X¹, X²and X³is independently N, CH or CR⁶;

provided that at least one of X¹, X², X³and X⁴is CH or CR⁶;

and formula (K-1) is:

or a salt or solvate thereof, wherein:

each X¹, X²and X³is independently N, CH or CR⁶;

provided that at least one of X¹, X², X³and X⁴is CH or CR⁶.

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 X¹, X², X³and X⁴is independently N, CH or CR⁶;

provided that:

(1) at least one of X¹, X², X³and X⁴is CH or CR⁶;

formula (IB) is:

or a salt or solvate thereof, wherein:

each R^3aand R^3bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R^3aand R^3bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^3aand R¹are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^3aand R^2aare taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or

R^3aand R^4aare taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;

each X¹, X², X³and X⁴is independently N, CH or CR⁶;

provided that:

(1) at least one of X¹, X², X³and X⁴is CR⁶;

formula (J-1) is:

or a salt or solvate thereof, wherein:

each X¹, X²and X³is independently N, CH or CR⁶;

provided that at least one of X¹, X², X³and X⁴is CH or CR⁶;

and formula (K-1) is:

or a salt or solvate thereof, wherein:

each X¹, X²and X³is independently N, CH or CR⁶;

provided that at least one of X¹, X², X³and X⁴is CH or CR⁶.

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 X¹, X², X³and X⁴is independently N, CH or CR⁶;

provided that:

(1) at least one of X¹, X², X³and X⁴is CH or CR⁶;

formula (IB) is:

or a salt or solvate thereof, wherein:

each R^3aand R^3bis independently H, substituted or unsubstituted C₁-C₈alkyl, halo, and cyano, hydroxyl, alkoxy, nitro or R^3aan R^3bare taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^3aand R¹are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^3aand R^2aare taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or

each X¹, X², X³and X⁴is independently N, CH or CR⁶;

provided that:

(1) at least one of X¹, X², X³and X⁴is CR⁶;

formula (J-1) is:

or a salt or solvate thereof, wherein:

each X¹, X²and X³is independently N, CH or CR⁶;

provided that at least one of X¹, X², X³and X⁴is CH or CR⁶;

and formula (K-1) is:

or a salt or solvate thereof, wherein:

each R^2a, R^2bR^3a, R^3b, R^4a, R^4b, R^10aand R^10bis independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, 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 X¹, X²and X³is independently N, CH or CR⁶;

provided that at least one of X¹, X², X³and X⁴is CH or CR⁶.

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_2Aand, wherein the compound either (a) also binds to and is an antagonist of the adrenergic receptor α_2Bor (b) the compound is not an antagonist of the adrenergic receptor α_2Band 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_2Band 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.