U.S. patent application number 14/000176 was filed with the patent office on 2014-06-05 for compounds and methods of treating diabetes.
This patent application is currently assigned to Medivation Technologies, Inc.. The applicant listed for this patent is Sarvajit Chakravarty, Andrew Asher Protter. Invention is credited to Sarvajit Chakravarty, Andrew Asher Protter.
Application Number | 20140155384 14/000176 |
Document ID | / |
Family ID | 46672975 |
Filed Date | 2014-06-05 |
United States Patent
Application |
20140155384 |
Kind Code |
A1 |
Protter; Andrew Asher ; et
al. |
June 5, 2014 |
COMPOUNDS AND METHODS OF TREATING DIABETES
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.sub.2A. The compounds
may also bind to and are an antagonist of the adrenergic receptor
.alpha..sub.2B; or the compounds are not antagonists of the
adrenergic receptor .alpha.2.beta. 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.
Inventors: |
Protter; Andrew Asher; (Palo
Alto, CA) ; Chakravarty; Sarvajit; (Mountain View,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Protter; Andrew Asher
Chakravarty; Sarvajit |
Palo Alto
Mountain View |
CA
CA |
US
US |
|
|
Assignee: |
Medivation Technologies,
Inc.
San Francisco
CA
|
Family ID: |
46672975 |
Appl. No.: |
14/000176 |
Filed: |
February 17, 2012 |
PCT Filed: |
February 17, 2012 |
PCT NO: |
PCT/US12/25751 |
371 Date: |
November 26, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61444622 |
Feb 18, 2011 |
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61444626 |
Feb 18, 2011 |
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61444547 |
Feb 18, 2011 |
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61561773 |
Nov 18, 2011 |
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61561761 |
Nov 18, 2011 |
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Current U.S.
Class: |
514/215 ;
514/250; 514/267; 514/275; 514/285; 514/286; 514/292; 514/293 |
Current CPC
Class: |
A61K 45/06 20130101;
C07D 471/18 20130101; A61K 31/519 20130101; C07D 471/08 20130101;
A61K 31/439 20130101; C07D 487/04 20130101; C07D 487/14 20130101;
C07D 471/04 20130101; A61K 31/4985 20130101; A61K 31/437 20130101;
C07D 487/18 20130101; A61K 31/506 20130101; C07D 487/08 20130101;
C07D 471/14 20130101; A61K 31/55 20130101 |
Class at
Publication: |
514/215 ;
514/292; 514/275; 514/286; 514/285; 514/250; 514/267; 514/293 |
International
Class: |
C07D 487/04 20060101
C07D487/04; C07D 471/04 20060101 C07D471/04; A61K 31/437 20060101
A61K031/437; A61K 31/506 20060101 A61K031/506; A61K 31/55 20060101
A61K031/55; A61K 31/439 20060101 A61K031/439; C07D 471/14 20060101
C07D471/14; A61K 31/4985 20060101 A61K031/4985; A61K 31/519
20060101 A61K031/519; C07D 487/14 20060101 C07D487/14; A61K 45/06
20060101 A61K045/06; C07D 471/18 20060101 C07D471/18 |
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: ##STR00313## or a salt, solvate or
N-oxide thereof, wherein: R.sup.1 is H, hydroxyl, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, perhaloalkyl, acyl, acyloxy,
carbonylalkoxy, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted aralkyl, C.sub.1-C.sub.8
perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or
unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or
carbonylalkylenealkoxy, or R.sup.1 and R.sup.2a are taken together
to form a propylene (--CH.sub.2CH.sub.2CH.sub.2--) moiety or a
butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1
and R.sup.3a are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1 and
R.sup.4a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety; each R.sup.2a and R.sup.2b
is independently H, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R.sup.2a and
R.sup.2b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.2a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and
R.sup.3a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and R.sup.4a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety; each R.sup.3a and R.sup.3b
is independently H, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R.sup.3a and
R.sup.3b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.3a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and
R.sup.2a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and R.sup.4a are
taken together to form a propylene (--CH.sub.2CH.sub.2CH.sub.2--)
moiety or a butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety;
each R.sup.4a and R.sup.4b is independently H, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, nitro,
substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy,
acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R.sup.4a
and R.sup.4b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.4a and R.sup.1 are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.2a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.3a
are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety; each X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is independently N, CH or CR.sup.6; Q
is a substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, or substituted of unsubstituted aralkyl,
wherein the aralkyl is a fused ring system where at least one
cycloalkyl moiety is fused with at least one aryl moiety and
wherein the aralkyl is attached to the parent structure via the
cycloalkyl moiety or the aryl moiety; and R.sup.6 is hydroxyl,
nitro, cyano, halo, C.sub.1-C.sub.8 perhaloalkyl, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, C.sub.1-C.sub.8
perhaloalkoxy, substituted or unsubstituted C.sub.1-C.sub.8 alkoxy,
substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,
thiol, substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aralkyl, thioalkyl, substituted or unsubstituted
amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,
alkylsulfonylamino or acyl, provided that: (1) at least one of
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CH or CR.sup.6; (2) when
each X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is independently CH or
CR.sup.6, none of R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b,
R.sup.4a and R.sup.4b are taken together to form a ring and Q is an
unsubstituted 6-membered aryl or an unsubstituted 6-membered
heteroaryl, then Q is other than unsubstituted phenyl,
unsubstituted pyridyl and unsubstituted pyrimidyl; (3) when each
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is independently CH or
CR.sup.6, none of R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b,
R.sup.4a and R.sup.4b are taken together to form a ring and Q is a
substituted phenyl, then Q is a phenyl substituted with a
substituent selected from the group consisting of substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclyl, and substituted or unsubstituted aralkyl; and (4)
when each X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is independently CH
or CR.sup.6, and R.sup.2a and R.sup.3a are taken together to form
an ethylene (--CH.sub.2CH.sub.2--) moiety, then Q is a substituted
aryl or substituted heteroaryl, where the substituted aryl or
substituted heteroaryl is substituted with at least one substituent
selected from the group consisting of substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted heterocyclyl, and
substituted or unsubstituted aralkyl; formula (IB) is: ##STR00314##
or a salt or solvate thereof, wherein: R.sup.1 is H, hydroxyl,
substituted or unsubstituted C.sub.1-C.sub.8 alkyl, substituted or
unsubstituted C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, perhaloalkyl, acyl, acyloxy,
carbonylalkoxy, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted aralkyl, C.sub.1-C.sub.8
perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or
unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or
carbonylalkylenealkoxy, or R.sup.1 and R.sup.2a are taken together
to form a propylene (--CH.sub.2CH.sub.2CH.sub.2--) moiety or a
butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1
and R.sup.3a are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1 and
R.sup.4a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety; each R.sup.2a and R.sup.2b
is independently H, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R.sup.2a and
R.sup.2b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.2a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and
R.sup.3a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and R.sup.4a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety; each R.sup.3a and R.sup.3b
is independently H, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R.sup.3a and
R.sup.3b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.3a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and
R.sup.2a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and R.sup.4a are
taken together to form a propylene (--CH.sub.2CH.sub.2CH.sub.2--)
moiety or a butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety;
each R.sup.4a and R.sup.4b is independently H, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, nitro,
substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy,
acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R.sup.4a
and R.sup.4b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.4a and R.sup.1 are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.2a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.3a
are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety; each X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is independently N, CH or CR.sup.6; Q
is a substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted aralkyl,
wherein the aralkyl is a fused ring system where at least one
cycloalkyl moiety is fused with at least one aryl moiety and
wherein the aralkyl is attached to the parent structure via the
cycloalkyl moiety or the aryl moiety; and R.sup.6 is hydroxyl,
nitro, cyano, halo, C.sub.1-C.sub.8 perhaloalkyl, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, C.sub.1-C.sub.8
perhaloalkoxy, substituted or unsubstituted C.sub.1-C.sub.8 alkoxy,
substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,
thiol, substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aralkyl, thioalkyl, substituted or unsubstituted
amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,
alkylsulfonylamino or acyl; provided that: (1) at least one of
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CR.sup.6; (2) when none of
X.sup.1, X.sup.2 and X.sup.3 is N, and none of R.sup.1, R.sup.2a,
R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b are taken
together to form a ring, then Q is other than an unsubstituted
phenyl; (3) when none of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is
N, and R.sup.2a and R.sup.2b are taken together with the carbon to
which they are attached to form a carbonyl moiety, then Q is other
than a 4-substituted phenyl group; and (4) when each X.sup.1,
X.sup.3 and X.sup.4 is CH, X.sup.2 is CR.sup.6 where R.sup.6 is
fluoro, and each R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a
and R.sup.4b is H, then Q is other than 4-fluorophenyl; formula
(J-1) is: ##STR00315## or a salt or solvate thereof, wherein:
R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl or carbonylalkylenealkoxy; each R.sup.2a, R.sup.2b
R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.10a and R.sup.10b is
independently H, hydroxyl, nitro, cyano, halo, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, perhaloalkyl, acyl, acyloxy,
carbonylalkoxy, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted aralkyl, C.sub.1-C.sub.8
perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl,
substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is
taken together with the carbon to which it is attached and a
geminal R.sup.2(a/b), R.sup.3(a/b), R.sup.4(a/b) or R.sup.10(a/b)
to form a carbonyl moiety or a cycloalkyl moiety; each X.sup.1,
X.sup.2 and X.sup.3 is independently N, CH or CR.sup.6; Q is a
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclyl, or substituted or unsubstituted aralkyl, wherein the
aralkyl is a fused ring system where at least one cycloalkyl moiety
is fused with at least one aryl moiety and wherein the aralkyl is
attached to the parent structure via the cycloalkyl moiety or the
aryl moiety; and R.sup.6 is hydroxyl, nitro, cyano, halo,
C.sub.1-C.sub.8 perhaloalkyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, C.sub.1-C.sub.8 perhaloalkoxy, substituted or
unsubstituted C.sub.1-C.sub.8 alkoxy, substituted or unsubstituted
aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,
thioalkyl, --S(O)-alkyl, --S(O)-aryl, --S(O)-aralkyl, substituted
or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,
carbonylalkylenealkoxy, alkylsulfonylamino or acyl; provided that
at least one of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CH or
CR.sup.6; and formula (K-1) is: ##STR00316## or a salt or solvate
thereof, wherein: R.sup.1 is H, hydroxyl, substituted or
unsubstituted C.sub.1-C.sub.8
alkyl, substituted or unsubstituted C.sub.2-C.sub.8 alkenyl,
substituted or unsubstituted C.sub.2-C.sub.8 alkynyl, perhaloalkyl,
acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted aralkyl,
C.sub.1-C.sub.8 perhaloalkoxy, alkoxy, aryloxy, substituted or
unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or
carbonylalkylenealkoxy; each R.sup.2a, R.sup.2b R.sup.3a, R.sup.3b,
R.sup.4a, R.sup.4b, R.sup.10a and R.sup.10b is independently H,
hydroxyl, nitro, cyano, halo, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted
amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or
carbonylalkylenealkoxy, or is taken together with the carbon to
which it is attached and a geminal R.sup.2(a/b), R.sup.3(a/b),
R.sup.4(a/b) or R.sup.10(a/b) to form a carbonyl moiety or a
cycloalkyl moiety; each X.sup.1, X.sup.2 and X.sup.3 is
independently N, CH or CR.sup.6; Q is a substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclyl, or substituted or unsubstituted aralkyl, wherein the
aralkyl is a fused ring system where at least one cycloalkyl moiety
is fused with at least one aryl moiety and wherein the aralkyl is
attached to the parent structure via the cycloalkyl moiety or the
aryl moiety; and R.sup.6 is hydroxyl, nitro, cyano, halo,
C.sub.1-C.sub.8 perhaloalkyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, C.sub.1-C.sub.8 perhaloalkoxy, substituted or
unsubstituted C.sub.1-C.sub.8 alkoxy, substituted or unsubstituted
aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,
thioalkyl, --S(O)-alkyl, --S(O)-aryl, --S(O)-aralkyl, substituted
or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,
carbonylalkylenealkoxy, alkylsulfonylamino or acyl; provided that
at least one of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CH or
CR.sup.6.
2. The method of claim 1, wherein the method reduces blood glucose
level in the individual.
3. The method of claim 2, wherein the method reduces blood glucose
level in the individual for a period of more than 0.5 hours
following administration.
4. The method of claim 1, wherein the method stabilizes of blood
glucose level in the individual.
5. A method of (i) increasing insulin secretion, and/or (ii)
promoting insulin release into the blood stream, in an individual
in need thereof comprising administering to the individual an
effective amount of a compound of the formula (IA), (IB), (J-1) or
(K-1), wherein formula (IA) is: ##STR00317## or a salt, solvate or
N-oxide thereof, wherein: R.sup.1 is H, hydroxyl, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, perhaloalkyl, acyl, acyloxy,
carbonylalkoxy, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted aralkyl, C.sub.1-C.sub.8
perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or
unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or
carbonylalkylenealkoxy, or R.sup.1 and R.sup.2a are taken together
to form a propylene (--CH.sub.2CH.sub.2CH.sub.2--) moiety or a
butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1
and R.sup.3a are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1 and
R.sup.4a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety; each R.sup.2a and R.sup.2b
is independently H, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R.sup.2a and
R.sup.2b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.2a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and
R.sup.3a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and R.sup.4a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety; each R.sup.3a and R.sup.3b
is independently H, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, halo, and cyano, hydroxyl, alkoxy, nitro or R.sup.3a an
R.sup.3b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.3a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and
R.sup.2a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and R.sup.4a are
taken together to form a propylene (--CH.sub.2CH.sub.2CH.sub.2--)
moiety or a butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety;
each R.sup.4a and R.sup.4b is independently H, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, nitro,
substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy,
acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R.sup.4a
and R.sup.4b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.4a and R.sup.1 are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.2a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.3a
are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety; each X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is independently N, CH or CR.sup.6; Q
is a substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, or substituted of unsubstituted aralkyl,
wherein the aralkyl is a fused ring system where at least one
cycloalkyl moiety is fused with at least one aryl moiety and
wherein the aralkyl is attached to the parent structure via the
cycloalkyl moiety or the aryl moiety; and R.sup.6 is hydroxyl,
nitro, cyano, halo, C.sub.1-C.sub.8 perhaloalkyl, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, C.sub.1-C.sub.8
perhaloalkoxy, substituted or unsubstituted C.sub.1-C.sub.8 alkoxy,
substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,
thiol, substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aralkyl, thioalkyl, substituted or unsubstituted
amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,
alkylsulfonylamino or acyl, provided that: (1) at least one of
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CH or CR.sup.6; (2) when
each X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is independently CH or
CR.sup.6, none of R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b,
R.sup.4a and R.sup.4b are taken together to form a ring and Q is an
unsubstituted 6-membered aryl or an unsubstituted 6-membered
heteroaryl, then Q is other than unsubstituted phenyl,
unsubstituted pyridyl and unsubstituted pyrimidyl; (3) when each
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is independently CH or
CR.sup.6, none of R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b,
R.sup.4a and R.sup.4b are taken together to form a ring and Q is a
substituted phenyl, then Q is a phenyl substituted with a
substituent selected from the group consisting of substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclyl, and substituted or unsubstituted aralkyl; and (4)
when each X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is independently CH
or CR.sup.6, and R.sup.2a and R.sup.3a are taken together to form
an ethylene (--CH.sub.2CH.sub.2--) moiety, then Q is a substituted
aryl or substituted heteroaryl, where the substituted aryl or
substituted heteroaryl is substituted with at least one substituent
selected from the group consisting of substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted heterocyclyl, and
substituted or unsubstituted aralkyl; formula (IB) is: ##STR00318##
or a salt or solvate thereof, wherein: R.sup.1 is H, hydroxyl,
substituted or unsubstituted C.sub.1-C.sub.8 alkyl, substituted or
unsubstituted C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, perhaloalkyl, acyl, acyloxy,
carbonylalkoxy, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted aralkyl, C.sub.1-C.sub.8
perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or
unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or
carbonylalkylenealkoxy, or R.sup.1 and R.sup.2a are taken together
to form a propylene (--CH.sub.2CH.sub.2CH.sub.2--) moiety or a
butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1
and R.sup.3a are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1 and
R.sup.4a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety; each R.sup.2a and R.sup.2b
is independently H, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R.sup.2a and
R.sup.2b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.2a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and
R.sup.3a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and R.sup.4a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety; each R.sup.3a and R.sup.3b
is independently H, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R.sup.3a and
R.sup.3b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.3a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and
R.sup.2a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and R.sup.4a are
taken together to form a propylene (--CH.sub.2CH.sub.2CH.sub.2--)
moiety or a butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety;
each R.sup.4a and R.sup.4b is independently H, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, nitro,
substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy,
acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R.sup.4a
and R.sup.4b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.4a and R.sup.1 are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.2a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.3a
are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety; each X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is independently N, CH or CR.sup.6; Q
is a substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted aralkyl,
wherein the aralkyl is a fused ring system where at least one
cycloalkyl moiety is fused with at least one aryl moiety and
wherein the aralkyl is attached to the parent structure via the
cycloalkyl moiety or the aryl moiety; and R.sup.6 is hydroxyl,
nitro, cyano, halo, C.sub.1-C.sub.8 perhaloalkyl, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, C.sub.1-C.sub.8
perhaloalkoxy, substituted or unsubstituted C.sub.1-C.sub.8 alkoxy,
substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,
thiol, substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aralkyl, thioalkyl, substituted or unsubstituted
amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,
alkylsulfonylamino or acyl; provided that: (1) at least one of
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CR.sup.6; (2) when none of
X.sup.1, X.sup.2 and X.sup.3 is N, and none of R.sup.1, R.sup.2a,
R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b are taken
together to form a ring, then Q is other than an unsubstituted
phenyl; (3) when none of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is
N, and R.sup.2a and R.sup.2b are taken together with the carbon to
which they are attached to form a carbonyl moiety, then Q is other
than a 4-substituted phenyl group; and (4) when each X.sup.1,
X.sup.3 and X.sup.4 is CH, X.sup.2 is CR.sup.6 where R.sup.6 is
fluoro, and each R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a
and R.sup.4b is H, then Q is other than 4-fluorophenyl; formula
(J-1) is: ##STR00319## or a salt or solvate thereof, wherein:
R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl or carbonylalkylenealkoxy; each R.sup.2a, R.sup.2b
R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.10a and R.sup.10b is
independently H, hydroxyl, nitro, cyano, halo, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, perhaloalkyl, acyl, acyloxy,
carbonylalkoxy, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted aralkyl, C.sub.1-C.sub.8
perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl,
substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is
taken together with the carbon to which it is attached and a
geminal R.sup.2(a/b), R.sup.3(a/b), R.sup.4(a/b) or R.sup.10(a/b)
to form a carbonyl moiety or a cycloalkyl moiety; each X.sup.1,
X.sup.2 and X.sup.3 is independently N, CH or CR.sup.6; Q is a
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclyl, or substituted or unsubstituted aralkyl, wherein the
aralkyl is a fused ring system where at least one cycloalkyl moiety
is fused with at least one aryl moiety and wherein the aralkyl is
attached to the parent structure via the cycloalkyl moiety or the
aryl moiety; and R.sup.6 is hydroxyl, nitro, cyano, halo,
C.sub.1-C.sub.8 perhaloalkyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, C.sub.1-C.sub.8 perhaloalkoxy, substituted or
unsubstituted C.sub.1-C.sub.8 alkoxy, substituted or unsubstituted
aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,
thioalkyl, --S(O)-alkyl, --S(O)-aryl, --S(O)-aralkyl, substituted
or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,
carbonylalkylenealkoxy, alkylsulfonylamino or acyl; provided that
at least one of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CH or
CR.sup.6; and formula (K-1) is: ##STR00320## or a salt or solvate
thereof, wherein:
R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl or carbonylalkylenealkoxy; each R.sup.2a, R.sup.2b
R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.10a and R.sup.10b is
independently H, hydroxyl, nitro, cyano, halo, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, perhaloalkyl, acyl, acyloxy,
carbonylalkoxy, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted aralkyl, C.sub.1-C.sub.8
perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl,
substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is
taken together with the carbon to which it is attached and a
geminal R.sup.2(a/b), R.sup.3(a/b), R.sup.4(a/b) or R.sup.10(a/b)
to form a carbonyl moiety or a cycloalkyl moiety; each X.sup.1,
X.sup.2 and X.sup.3 is independently N, CH or CR.sup.6; Q is a
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclyl, or substituted or unsubstituted aralkyl, wherein the
aralkyl is a fused ring system where at least one cycloalkyl moiety
is fused with at least one aryl moiety and wherein the aralkyl is
attached to the parent structure via the cycloalkyl moiety or the
aryl moiety; and R.sup.6 is hydroxyl, nitro, cyano, halo,
C.sub.1-C.sub.8 perhaloalkyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, C.sub.1-C.sub.8 perhaloalkoxy, substituted or
unsubstituted C.sub.1-C.sub.8 alkoxy, substituted or unsubstituted
aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,
thioalkyl, --S(O)-alkyl, --S(O)-aryl, --S(O)-aralkyl, substituted
or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,
carbonylalkylenealkoxy, alkylsulfonylamino or acyl; provided that
at least one of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CH or
CR.sup.6.
6. The method of claim 5, wherein the method increases insulin
secretion.
7. The method of claim 5, wherein the method promotes insulin
release into the blood stream.
8. The method of claim 1, wherein the individual has a disease or
condition that involves impaired insulin secretion.
9. The method of claim 1, wherein the individual has one or more
risk factors for developing a disease or condition that involves
impaired insulin secretion.
10. The method of claim 1, wherein the administration results in
decrease of blood pressure in the individual.
11. A method of treating a disease or condition that is responsive
to an increase in insulin secretion, comprising administering to an
individual in need thereof an effective amount of a compound of the
formula (IA), (IB), (J-1) or (K-1), wherein formula (IA) is:
##STR00321## or a salt, solvate or N-oxide thereof, wherein:
R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, thiol, thioalkyl, substituted or unsubstituted amino,
acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy,
or R.sup.1 and R.sup.2a are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1 and
R.sup.3a are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1 and
R.sup.4a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety; each R.sup.2a and R.sup.2b
is independently H, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R.sup.2a and
R.sup.2b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.2a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and
R.sup.3a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and R.sup.4a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety; each R.sup.3a and R.sup.3b
is independently H, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R.sup.3a and
R.sup.3b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.3a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and
R.sup.2a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and R.sup.4a are
taken together to form a propylene (--CH.sub.2CH.sub.2CH.sub.2--)
moiety or a butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety;
each R.sup.4a and R.sup.4b is independently H, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, nitro,
substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy,
acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R.sup.4a
and R.sup.4b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.4a and R.sup.1 are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.2a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.3a
are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety; each X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is independently N, CH or CR.sup.6; Q
is a substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, or substituted of unsubstituted aralkyl,
wherein the aralkyl is a fused ring system where at least one
cycloalkyl moiety is fused with at least one aryl moiety and
wherein the aralkyl is attached to the parent structure via the
cycloalkyl moiety or the aryl moiety; and R.sup.6 is hydroxyl,
nitro, cyano, halo, C.sub.1-C.sub.8 perhaloalkyl, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, C.sub.1-C.sub.8
perhaloalkoxy, substituted or unsubstituted C.sub.1-C.sub.8 alkoxy,
substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,
thiol, substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aralkyl, thioalkyl, substituted or unsubstituted
amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,
alkylsulfonylamino or acyl, provided that: (1) at least one of
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CH or CR.sup.6; (2) when
each X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is independently CH or
CR.sup.6, none of R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b,
R.sup.4a and R.sup.4b are taken together to form a ring and Q is an
unsubstituted 6-membered aryl or an unsubstituted 6-membered
heteroaryl, then Q is other than unsubstituted phenyl,
unsubstituted pyridyl and unsubstituted pyrimidyl; (3) when each
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is independently CH or
CR.sup.6, none of R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b,
R.sup.4a and R.sup.4b are taken together to form a ring and Q is a
substituted phenyl, then Q is a phenyl substituted with a
substituent selected from the group consisting of substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclyl, and substituted or unsubstituted aralkyl; and (4)
when each X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is independently CH
or CR.sup.6, and R.sup.2a and R.sup.3a are taken together to form
an ethylene (--CH.sub.2CH.sub.2--) moiety, then Q is a substituted
aryl or substituted heteroaryl, where the substituted aryl or
substituted heteroaryl is substituted with at least one substituent
selected from the group consisting of substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted heterocyclyl, and
substituted or unsubstituted aralkyl; formula (IB) is: ##STR00322##
or a salt or solvate thereof, wherein: R.sup.1 is H, hydroxyl,
substituted or unsubstituted C.sub.1-C.sub.8 alkyl, substituted or
unsubstituted C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, perhaloalkyl, acyl, acyloxy,
carbonylalkoxy, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted aralkyl, C.sub.1-C.sub.8
perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or
unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or
carbonylalkylenealkoxy, or R.sup.1 and R.sup.2a are taken together
to form a propylene (--CH.sub.2CH.sub.2CH.sub.2--) moiety or a
butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1
and R.sup.3a are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1 and
R.sup.4a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety; each R.sup.2a and R.sup.2b
is independently H, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R.sup.2a and
R.sup.2b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.2a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and
R.sup.3a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and R.sup.4a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety; each R.sup.3a and R.sup.3b
is independently H, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R.sup.3a and
R.sup.3b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.3a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and
R.sup.2a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and R.sup.4a are
taken together to form a propylene (--CH.sub.2CH.sub.2CH.sub.2--)
moiety or a butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety;
each R.sup.4a and R.sup.4b is independently H, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, nitro,
substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy,
acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R.sup.4a
and R.sup.4b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.4a and R.sup.1 are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.2a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.3a
are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety; each X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is independently N, CH or CR.sup.6; Q
is a substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted aralkyl,
wherein the aralkyl is a fused ring system where at least one
cycloalkyl moiety is fused with at least one aryl moiety and
wherein the aralkyl is attached to the parent structure via the
cycloalkyl moiety or the aryl moiety; and R.sup.6 is hydroxyl,
nitro, cyano, halo, C.sub.1-C.sub.8 perhaloalkyl, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, C.sub.1-C.sub.8
perhaloalkoxy, substituted or unsubstituted C.sub.1-C.sub.8 alkoxy,
substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,
thiol, substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aralkyl, thioalkyl, substituted or unsubstituted
amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,
alkylsulfonylamino or acyl; provided that: (1) at least one of
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CR.sup.6; (2) when none of
X.sup.1, X.sup.2 and X.sup.3 is N, and none of R.sup.1, R.sup.2a,
R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b are taken
together to form a ring, then Q is other than an unsubstituted
phenyl; (3) when none of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is
N, and R.sup.2a and R.sup.2b are taken together with the carbon to
which they are attached to form a carbonyl moiety, then Q is other
than a 4-substituted phenyl group; and (4) when each X.sup.1,
X.sup.3 and X.sup.4 is CH, X.sup.2 is CR.sup.6 where R.sup.6 is
fluoro, and each R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a
and R.sup.4b is H, then Q is other than 4-fluorophenyl; formula
(J-1) is: ##STR00323## or a salt or solvate thereof, wherein:
R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl or carbonylalkylenealkoxy; each R.sup.2a, R.sup.2b
R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.10a and R.sup.10b is
independently H, hydroxyl, nitro, cyano, halo, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, perhaloalkyl, acyl, acyloxy,
carbonylalkoxy, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted aralkyl, C.sub.1-C.sub.8
perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl,
substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is
taken together with the carbon to which it is attached and a
geminal R.sup.2(a/b), R.sup.3(a/b), R.sup.4(a/b) or R.sup.10(a/b)
to form a carbonyl moiety or a cycloalkyl moiety; each X.sup.1,
X.sup.2 and X.sup.3 is independently N, CH or CR.sup.6; Q is a
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclyl, or substituted or unsubstituted aralkyl, wherein the
aralkyl is a fused ring system where at least one cycloalkyl moiety
is fused with at least one aryl moiety and wherein the aralkyl is
attached to the parent structure via the cycloalkyl moiety or the
aryl moiety; and R.sup.6 is hydroxyl, nitro, cyano, halo,
C.sub.1-C.sub.8 perhaloalkyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, C.sub.1-C.sub.8 perhaloalkoxy, substituted or
unsubstituted C.sub.1-C.sub.8 alkoxy, substituted or unsubstituted
aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,
thioalkyl, --S(O)-alkyl, --S(O)-aryl, --S(O)-aralkyl, substituted
or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,
carbonylalkylenealkoxy, alkylsulfonylamino or acyl; provided that
at least one of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CH or
CR.sup.6; and formula (K-1) is: ##STR00324## or a salt or solvate
thereof, wherein: R.sup.1 is H, hydroxyl, substituted or
unsubstituted C
.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl or carbonylalkylenealkoxy; each R.sup.2a, R.sup.2b
R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.10a and R.sup.10b is
independently H, hydroxyl, nitro, cyano, halo, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, perhaloalkyl, acyl, acyloxy,
carbonylalkoxy, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted aralkyl, C.sub.1-C.sub.8
perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl,
substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is
taken together with the carbon to which it is attached and a
geminal R.sup.2(a/b), R.sup.3(a/b), R.sup.4(a/b) or R.sup.10(a/b)
to form a carbonyl moiety or a cycloalkyl moiety; each X.sup.1,
X.sup.2 and X.sup.3 is independently N, CH or CR.sup.6; Q is a
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclyl, or substituted or unsubstituted aralkyl, wherein the
aralkyl is a fused ring system where at least one cycloalkyl moiety
is fused with at least one aryl moiety and wherein the aralkyl is
attached to the parent structure via the cycloalkyl moiety or the
aryl moiety; and R.sup.6 is hydroxyl, nitro, cyano, halo,
C.sub.1-C.sub.8 perhaloalkyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, C.sub.1-C.sub.8 perhaloalkoxy, substituted or
unsubstituted C.sub.1-C.sub.8 alkoxy, substituted or unsubstituted
aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,
thioalkyl, --S(O)-alkyl, --S(O)-aryl, --S(O)-aralkyl, substituted
or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,
carbonylalkylenealkoxy, alkylsulfonylamino or acyl; provided that
at least one of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CH or
CR.sup.6.
12. A method of delaying the onset of a disease or condition that
is responsive to an increase in insulin secretion, comprising
administering to an individual in need thereof an effective amount
of a compound of the formula (IA), (IB), (J-1) or (K-1), wherein
formula (IA) is: ##STR00325## or a salt, solvate or N-oxide
thereof, wherein: R.sup.1 is H, hydroxyl, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, perhaloalkyl, acyl, acyloxy,
carbonylalkoxy, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted aralkyl, C.sub.1-C.sub.8
perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or
unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or
carbonylalkylenealkoxy, or R.sup.1 and R.sup.2a are taken together
to form a propylene (--CH.sub.2CH.sub.2CH.sub.2--) moiety or a
butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1
and R.sup.3a are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1 and
R.sup.4a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety; each R.sup.2a and R.sup.2b
is independently H, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R.sup.2a and
R.sup.2b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.2a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and
R.sup.3a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and R.sup.4a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety; each R.sup.3a and R.sup.3b
is independently H, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R.sup.3a and
R.sup.3b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.3a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and
R.sup.2a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and R.sup.4a are
taken together to form a propylene (--CH.sub.2CH.sub.2CH.sub.2--)
moiety or a butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety;
each R.sup.4a and R.sup.4b is independently H, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, nitro,
substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy,
acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R.sup.4a
and R.sup.4b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.4a and R.sup.1 are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.2a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.3a
are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety; each X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is independently N, CH or CR.sup.6; Q
is a substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, or substituted of unsubstituted aralkyl,
wherein the aralkyl is a fused ring system where at least one
cycloalkyl moiety is fused with at least one aryl moiety and
wherein the aralkyl is attached to the parent structure via the
cycloalkyl moiety or the aryl moiety; and R.sup.6 is hydroxyl,
nitro, cyano, halo, C.sub.1-C.sub.8 perhaloalkyl, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, C.sub.1-C.sub.8
perhaloalkoxy, substituted or unsubstituted C.sub.1-C.sub.8 alkoxy,
substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,
thiol, substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aralkyl, thioalkyl, substituted or unsubstituted
amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,
alkylsulfonylamino or acyl, provided that: (1) at least one of
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CH or CR.sup.6; (2) when
each X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is independently CH or
CR.sup.6, none of R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b,
R.sup.4a and R.sup.4b are taken together to form a ring and Q is an
unsubstituted 6-membered aryl or an unsubstituted 6-membered
heteroaryl, then Q is other than unsubstituted phenyl,
unsubstituted pyridyl and unsubstituted pyrimidyl; (3) when each
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is independently CH or
CR.sup.6, none of R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b,
R.sup.4a and R.sup.4b are taken together to form a ring and Q is a
substituted phenyl, then Q is a phenyl substituted with a
substituent selected from the group consisting of substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclyl, and substituted or unsubstituted aralkyl; and (4)
when each X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is independently CH
or CR.sup.6, and R.sup.2a and R.sup.3a are taken together to form
an ethylene (--CH.sub.2CH.sub.2--) moiety, then Q is a substituted
aryl or substituted heteroaryl, where the substituted aryl or
substituted heteroaryl is substituted with at least one substituent
selected from the group consisting of substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted heterocyclyl, and
substituted or unsubstituted aralkyl; formula (IB) is: ##STR00326##
or a salt or solvate thereof, wherein: R.sup.1 is H, hydroxyl,
substituted or unsubstituted C.sub.1-C.sub.8 alkyl, substituted or
unsubstituted C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, perhaloalkyl, acyl, acyloxy,
carbonylalkoxy, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted aralkyl, C.sub.1-C.sub.8
perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or
unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or
carbonylalkylenealkoxy, or R.sup.1 and R.sup.2a are taken together
to form a propylene (--CH.sub.2CH.sub.2CH.sub.2--) moiety or a
butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1
and R.sup.3a are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1 and
R.sup.4a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety; each R.sup.2a and R.sup.2b
is independently H, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R.sup.2a and
R.sup.2b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.2a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and
R.sup.3a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and R.sup.4a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety; each R.sup.3a and R.sup.3b
is independently H, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, halo, and cyano, hydroxyl, alkoxy, nitro or R.sup.3a an
R.sup.3b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.3a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and
R.sup.2a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and R.sup.4a are
taken together to form a propylene (--CH.sub.2CH.sub.2CH.sub.2--)
moiety or a butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety;
each R.sup.4a and R.sup.4b is independently H, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, nitro,
substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy,
acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R.sup.4a
and R.sup.4b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.4a and R.sup.1 are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.2a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.3a
are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety; each X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is independently N, CH or CR.sup.6; Q
is a substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted aralkyl,
wherein the aralkyl is a fused ring system where at least one
cycloalkyl moiety is fused with at least one aryl moiety and
wherein the aralkyl is attached to the parent structure via the
cycloalkyl moiety or the aryl moiety; and R.sup.6 is hydroxyl,
nitro, cyano, halo, C.sub.1-C.sub.8 perhaloalkyl, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, C.sub.1-C.sub.8
perhaloalkoxy, substituted or unsubstituted C.sub.1-C.sub.8 alkoxy,
substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,
thiol, substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aralkyl, thioalkyl, substituted or unsubstituted
amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,
alkylsulfonylamino or acyl; provided that: (1) at least one of
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CR.sup.6; (2) when none of
X.sup.1, X.sup.2 and X.sup.3 is N, and none of R.sup.1, R.sup.2a,
R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b are taken
together to form a ring, then Q is other than an unsubstituted
phenyl; (3) when none of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is
N, and R.sup.2a and R.sup.2b are taken together with the carbon to
which they are attached to form a carbonyl moiety, then Q is other
than a 4-substituted phenyl group; and (4) when each X.sup.1,
X.sup.3 and X.sup.4 is CH, X.sup.2 is CR.sup.6 where R.sup.6 is
fluoro, and each R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a
and R.sup.4b is H, then Q is other than 4-fluorophenyl;
##STR00327## formula (J-1) is: or a salt or solvate thereof,
wherein: R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl or carbonylalkylenealkoxy; each R.sup.2a, R.sup.2b
R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.10a and R.sup.10b is
independently H, hydroxyl, nitro, cyano, halo, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, perhaloalkyl, acyl, acyloxy,
carbonylalkoxy, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted aralkyl, C.sub.1-C.sub.8
perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl,
substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is
taken together with the carbon to which it is attached and a
geminal R.sup.2(a/b), R.sup.3(a/b), R.sup.4(a/b) or R.sup.10(a/b)
to form a carbonyl moiety or a cycloalkyl moiety; each X.sup.1,
X.sup.2 and X.sup.3 is independently N, CH or CR.sup.6; Q is a
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclyl, or substituted or unsubstituted aralkyl, wherein the
aralkyl is a fused ring system where at least one cycloalkyl moiety
is fused with at least one aryl moiety and wherein the aralkyl is
attached to the parent structure via the cycloalkyl moiety or the
aryl moiety; and R.sup.6 is hydroxyl, nitro, cyano, halo,
C.sub.1-C.sub.8 perhaloalkyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, C.sub.1-C.sub.8 perhaloalkoxy, substituted or
unsubstituted C.sub.1-C.sub.8 alkoxy, substituted or unsubstituted
aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,
thioalkyl, --S(O)-alkyl, --S(O)-aryl, --S(O)-aralkyl, substituted
or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,
carbonylalkylenealkoxy, alkylsulfonylamino or acyl; provided that
at least one of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CH or
CR.sup.6; and formula (K-1) is: ##STR00328## or a salt or solvate
thereof, wherein: R.sup.1 is H, hydroxyl, substituted or
unsubstituted C
.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl or carbonylalkylenealkoxy; each R.sup.2a, R.sup.2b
R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.10a and R.sup.10b is
independently H, hydroxyl, nitro, cyano, halo, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, perhaloalkyl, acyl, acyloxy,
carbonylalkoxy, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted aralkyl, C.sub.1-C.sub.8
perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl,
substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is
taken together with the carbon to which it is attached and a
geminal R.sup.2(a/b), R.sup.3(a/b), R.sup.4(a/b), or R.sup.10(a/b)
to form a carbonyl moiety or a cycloalkyl moiety; each X.sup.1,
X.sup.2 and X.sup.3 is independently N, CH or CR.sup.6; Q is a
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclyl, or substituted or unsubstituted aralkyl, wherein the
aralkyl is a fused ring system where at least one cycloalkyl moiety
is fused with at least one aryl moiety and wherein the aralkyl is
attached to the parent structure via the cycloalkyl moiety or the
aryl moiety; and R.sup.6 is hydroxyl, nitro, cyano, halo,
C.sub.1-C.sub.8 perhaloalkyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, C.sub.1-C.sub.8 perhaloalkoxy, substituted or
unsubstituted C.sub.1-C.sub.8 alkoxy, substituted or unsubstituted
aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,
thioalkyl, --S(O)-alkyl, --S(O)-aryl, --S(O)-aralkyl, substituted
or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,
carbonylalkylenealkoxy, alkylsulfonylamino or acyl; provided that
at least one of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CH or
CR.sup.6.
13. The method of claim 11, wherein the disease or condition is
type 2 diabetes.
14. The method of claim 13, wherein the individual is not
responsive to standard treatment of type 2 diabetes.
15. The method of claim 11, wherein the disease or condition is
glucose intolerance.
16. The method of claim 11, wherein the disease or condition is
metabolic syndrome.
17. The method of claim 11, further comprising administering to the
individual in need thereof one or more anti-diabetic agents.
18. The method of claim 17, wherein at least one of the
anti-diabetic agents is an insulin sensitizer.
19. The method of claim 1, wherein the compound binds to and is an
antagonist of the adrenergic receptor .alpha..sub.2A and, wherein
the compound either (a) also binds to and is an antagonist of the
adrenergic receptor .alpha..sub.2B or (b) the compound is not an
antagonist of the adrenergic receptor .alpha..sub.2B and the
compound is administered in conjunction with a second agent that
reduces blood pressure in the individual.
20. The method of claim 19, wherein the compound binds to and is an
antagonist of the adrenergic receptor .alpha..sub.2B.
21. The method of claim 19, wherein the compound binds to and is an
antagonist of the adrenergic receptor .alpha..sub.1B.
22. The method of claim 19, wherein the compound is not an
antagonist of the adrenergic receptor .alpha..sub.2B and the
compound is administered in conjunction with a diuretic, an
angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2
receptor antagonist, a beta blocker, a calcium channel blocker, or
any combination thereof.
23. A kit comprising (i) a compound of formula (IA), (IB), (J-1) or
(K-1), or a pharmaceutically acceptable salt thereof, and (ii)
instructions for use according to the method of claim 1.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] 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
[0002] 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.
[0003] 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
[0004] 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 .alpha..sub.2A
antagonists 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.
[0005] 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:
##STR00001##
or a salt, solvate or N-oxide thereof, wherein:
[0006] R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, thiol, thioalkyl, substituted or unsubstituted amino,
acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy,
or R.sup.1 and R.sup.2a are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1 and
R.sup.3a are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1 and
R.sup.4a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety;
[0007] each R.sup.2a and R.sup.2b is independently H, substituted
or unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, hydroxyl,
alkoxy, nitro or R.sup.2a and R.sup.2b are taken together with the
carbon to which they are attached to form a carbonyl moiety or a
cycloalkyl moiety, or R.sup.2a and R.sup.1 are taken together to
form a propylene (--CH.sub.2CH.sub.2CH.sub.2--) moiety or a
butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a
and R.sup.3a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and R.sup.4a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety;
[0008] each R.sup.3a and R.sup.3b is independently H, substituted
or unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, hydroxyl,
alkoxy, nitro or R.sup.3a and R.sup.3b are taken together with the
carbon to which they are attached to form a carbonyl moiety or a
cycloalkyl moiety, or R.sup.3a and R.sup.1 are taken together to
form a propylene (--CH.sub.2CH.sub.2CH.sub.2--) moiety or a
butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a
and R.sup.2a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and R.sup.4a are
taken together to form a propylene (--CH.sub.2CH.sub.2CH.sub.2--)
moiety or a butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--)
moiety;
[0009] each R and R.sup.4b independently H, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, halo cyano, nitro, substituted
or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl,
heteroaryl, cycloalkyl, heterocyclyl, or R.sup.4a and R.sup.4b are
taken together with the carbon to which they are attached to form a
carbonyl moiety or a cycloalkyl moiety, or R.sup.4a and R.sup.1 are
taken together to form an ethylene (--CH.sub.2CH.sub.2--) moiety or
a propylene (--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.4a and
R.sup.2a are taken together to form a methylene (--CH.sub.2--)
moiety or an ethylene (--CH.sub.2CH.sub.2--) moiety, or R.sup.4a
and R.sup.3a are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety;
[0010] each X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is independently
N, CH or CR.sup.6;
[0011] 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
[0012] R.sup.6 is hydroxyl, nitro, cyano, halo, C.sub.1-C.sub.8
perhaloalkyl, substituted or unsubstituted C.sub.1-C.sub.8 alkyl,
substituted or unsubstituted C.sub.2-C.sub.8 alkenyl, substituted
or unsubstituted C.sub.2-C.sub.8 alkynyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
C.sub.1-C.sub.8 perhaloalkoxy, substituted or unsubstituted
C.sub.1-C.sub.8 alkoxy, substituted or unsubstituted aryloxy,
carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,
substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl,
[0013] provided that: [0014] (1) at least one of X.sup.1, X.sup.2,
X.sup.3 and X.sup.4 is CH or CR.sup.6; [0015] (2) when each
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is independently CH or
CR.sup.6, none of R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b,
R.sup.4a and R.sup.4b are taken together to form a ring and Q is an
unsubstituted 6-membered aryl or an unsubstituted 6-membered
heteroaryl, then Q is other than unsubstituted phenyl,
unsubstituted pyridyl and unsubstituted pyrimidyl; [0016] (3) when
each X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is independently CH or
CR.sup.6, none of R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b,
R.sup.4a and R.sup.4b are taken together to form a ring and Q is a
substituted phenyl, then Q is a phenyl substituted with a
substituent selected from the group consisting of substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclyl, and substituted or unsubstituted aralkyl; and [0017]
(4) when each X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is
independently CH or CR.sup.6, and R.sup.2a and R.sup.3a are taken
together to form an ethylene (--CH.sub.2CH.sub.2--) moiety, then Q
is a substituted aryl or substituted heteroaryl, where the
substituted aryl or substituted heteroaryl is substituted with at
least one substituent selected from the group consisting of
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclyl, and substituted or unsubstituted aralkyl; formula
(IB) is:
##STR00002##
[0017] or a salt or solvate thereof, wherein:
[0018] R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, thiol, thioalkyl, substituted or unsubstituted amino,
acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy,
or R.sup.1 and R.sup.2a are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1 and
R.sup.3a are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1 and
R.sup.4a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety;
[0019] each R.sup.2a and R.sup.2b is independently H, substituted
or unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, hydroxyl,
alkoxy, nitro or R.sup.2a and R.sup.2b are taken together with the
carbon to which they are attached to form a carbonyl moiety or a
cycloalkyl moiety, or R.sup.2a and R.sup.1 are taken together to
form a propylene (--CH.sub.2CH.sub.2CH.sub.2--) moiety or a
butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a
and R.sup.3a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and R.sup.4a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety;
[0020] each R.sup.3a and R.sup.3b is independently H, substituted
or unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, hydroxyl,
alkoxy, nitro or R.sup.3a and R.sup.3b are taken together with the
carbon to which they are attached to form a carbonyl moiety or a
cycloalkyl moiety, or R.sup.3a and R.sup.1 are taken together to
form a propylene (--CH.sub.2CH.sub.2CH.sub.2--) moiety or a
butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a
and R are taken together to form an ethylene (--CH.sub.2CH.sub.2--)
moiety or a propylene (--CH.sub.2CH.sub.2CH.sub.2--) moiety, or
R.sup.3a and R.sup.4a are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety;
[0021] each R.sup.4a and R.sup.4b is independently H, substituted
or unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, nitro,
substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy,
acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R.sup.4a
and R.sup.4b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.4a and R.sup.1 are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.2a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.3a
are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety;
[0022] each X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is independently
N, CH or CR.sup.6;
[0023] 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
[0024] R.sup.6 is hydroxyl, nitro, cyano, halo, C.sub.1-C.sub.8
perhaloalkyl, substituted or unsubstituted C.sub.1-C.sub.8 alkyl,
substituted or unsubstituted C.sub.2-C.sub.8 alkenyl, substituted
or unsubstituted C.sub.2-C.sub.8 alkynyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
C.sub.1-C.sub.8 perhaloalkoxy, substituted or unsubstituted
C.sub.1-C.sub.8 alkoxy, substituted or unsubstituted aryloxy,
carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,
substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;
[0025] provided that:
[0026] (1) at least one of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is
CR.sup.6;
[0027] (2) when none of X.sup.1, X.sup.2 and X.sup.3 is N, and none
of R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and
R.sup.4b are taken together to form a ring, then Q is other than an
unsubstituted phenyl;
[0028] (3) when none of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is N,
and R.sup.2a and R.sup.2b are taken together with the carbon to
which they are attached to form a carbonyl moiety, then Q is other
than a 4-substituted phenyl group; and
[0029] (4) when each X.sup.1, X.sup.3 and X.sup.4 is CH, X.sup.2 is
CR.sup.6 where R.sup.6 is fluoro, and each R.sup.2a, R.sup.2b,
R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b is H, then Q is other
than 4-fluorophenyl;
formula (J-1) is:
##STR00003##
[0030] or a salt or solvate thereof, wherein:
[0031] R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl or carbonylalkylenealkoxy;
[0032] each R.sup.2a, R.sup.2b R.sup.3a, R.sup.3b, R.sup.4a,
R.sup.4b, R.sup.10a and R.sup.10b is independently H, hydroxyl,
nitro, cyano, halo, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, substituted or unsubstituted C.sub.2-C.sub.8 alkenyl,
substituted or unsubstituted C.sub.2-C.sub.8 alkynyl, perhaloalkyl,
acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted aralkyl,
C.sub.1-C.sub.8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,
thioalkyl, substituted or unsubstituted amino, acylamino,
aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl,
sulfonylamino, sulfonyl, alkylsulfonylamino, or
carbonylalkylenealkoxy, or is taken together with the carbon to
which it is attached and a geminal R.sup.2(a/b), R.sup.3(a/b),
R.sup.4(a/b), or R.sup.10(a/b) to form a carbonyl moiety or a
cycloalkyl moiety;
[0033] each X.sup.1, X.sup.2 and X.sup.3 is independently N, CH or
CR.sup.6;
[0034] 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
[0035] R.sup.6 is hydroxyl, nitro, cyano, halo, C.sub.1-C.sub.8
perhaloalkyl, substituted or unsubstituted C.sub.1-C.sub.8 alkyl,
substituted or unsubstituted C.sub.2-C.sub.8 alkenyl, substituted
or unsubstituted C.sub.2-C.sub.8 alkynyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
C.sub.1-C.sub.8 perhaloalkoxy, substituted or unsubstituted
C.sub.1-C.sub.8 alkoxy, substituted or unsubstituted aryloxy,
carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,
--S(O)-alkyl, --S(O)-aryl, --S(O)-aralkyl, substituted or
unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,
carbonylalkylenealkoxy, alkylsulfonylamino or acyl;
[0036] provided that at least one of X.sup.1, X.sup.2, X.sup.3 and
X.sup.4 is CH or CR.sup.6;
and formula (K-1) is:
##STR00004##
or a salt or solvate thereof, wherein:
[0037] R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl or carbonylalkylenealkoxy;
[0038] each R.sup.2a, R.sup.2b R.sup.3a, R.sup.3b, R.sup.4a,
R.sup.4b, R.sup.10a and R.sup.10b is independently H, hydroxyl,
nitro, cyano, halo, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, substituted or unsubstituted C.sub.2-C.sub.8 alkenyl,
substituted or unsubstituted C.sub.2-C.sub.8 alkynyl, perhaloalkyl,
acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted aralkyl,
C.sub.1-C.sub.8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,
thioalkyl, substituted or unsubstituted amino, acylamino,
aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl,
sulfonylamino, sulfonyl, alkylsulfonylamino, or
carbonylalkylenealkoxy, or is taken together with the carbon to
which it is attached and a geminal R.sup.2(a/b), R.sup.3(a/b),
R.sup.4(a/b) or R.sup.10(a/b) to form a carbonyl moiety or a
cycloalkyl moiety;
[0039] each X.sup.1, X.sup.2 and X.sup.3 is independently N, CH or
CR.sup.6;
[0040] 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
[0041] R.sup.6 is hydroxyl, nitro, cyano, halo, C.sub.1-C.sub.8
perhaloalkyl, substituted or unsubstituted C.sub.1-C.sub.8 alkyl,
substituted or unsubstituted C.sub.2-C.sub.8 alkenyl, substituted
or unsubstituted C.sub.2-C.sub.8 alkynyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
C.sub.1-C.sub.8 perhaloalkoxy, substituted or unsubstituted
C.sub.1-C.sub.8 alkoxy, substituted or unsubstituted aryloxy,
carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,
--S(O)-alkyl, --S(O)-aryl, --S(O)-aralkyl, substituted or
unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,
carbonylalkylenealkoxy, alkylsulfonylamino or acyl; provided that
at least one of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CH or
CR.sup.6.
[0042] 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.
[0043] 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.
[0044] 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.
[0045] 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.
[0046] 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.
[0047] 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.
[0048] 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 .alpha..sub.2A and,
wherein the compound either (a) also binds to and is an antagonist
of the adrenergic receptor .alpha..sub.2B or (b) the compound is
not an antagonist of the adrenergic receptor .alpha..sub.2B and 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
.alpha..sub.2B. In another variation, the compound binds to and is
an antagonist of the adrenergic receptor .alpha..sub.1B. In another
variation, the compound is not an antagonist of the adrenergic
receptor .alpha..sub.2B and the compound is administered in
conjunction with a diuretic, an angiotensin-converting enzyme (ACE)
inhibitor, an angiotensin-2 receptor antagonist, a beta blocker, a
calcium channel blocker, or any combination thereof.
[0049] 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.
[0050] 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.
[0051] 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
[0052] Not applicable.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0053] Unless clearly indicated otherwise, the terms "a," "an," and
the like, refer to one or more.
[0054] 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 .alpha..sub.2B antagonists) or pharmaceutically acceptable
salt or other form thereof as described herein.
[0055] 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".
[0056] 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.
[0057] 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).
[0058] As used herein, "treatment" or "treating" is an approach for
obtaining a beneficial or desired result, including clinical
results.
[0059] 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.
[0060] 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.
[0061] 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.
[0062] 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.
[0063] "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.
[0064] 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.
[0065] 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.
[0066] "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 "C.sub.1-C.sub.20 alkyl"). More particular alkyl groups
are those having 1 to 8 carbon atoms (a "C.sub.1-C.sub.8 alkyl").
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 "C.sub.3-C.sub.8 cycloalkyl").
Examples of cycloalkyl groups include adamantyl,
decahydronaphthalenyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and the like.
[0067] "Alkylene" refers to the same residues as alkyl, but having
bivalency. Examples of alkylene include methylene (--CH.sub.2--),
ethylene (--CH.sub.2CH.sub.2--), propylene
(--CH.sub.2CH.sub.2CH.sub.2--), butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) and the like.
[0068] "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.dbd.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
--CH.sub.2--CH.dbd.CH--CH.sub.3 and
--CH.sub.2--CH.sub.2-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 "C.sub.3-C.sub.8 cycloalkenyl"). Examples of cycloalkenyl
groups include cyclopropenyl, cyclobutenyl, cyclopentenyl,
cyclohexenyl and the like.
[0069] "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.
[0070] "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.
[0071] "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.
[0072] "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.
[0073] "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.
[0074] "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.
[0075] "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.
[0076] "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.
[0077] "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.
[0078] "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.
[0079] "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.
[0080] "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.
[0081] "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
"C.sub.1-C.sub.3 alkaryl").
[0082] "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.
[0083] "Unsubstituted amino" refers to the group --NH.sub.2.
[0084] "Substituted amino" refers to the group --NR.sub.aR.sub.b,
where either (a) each R.sub.a and R.sub.b group 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.sub.a and R.sub.b
groups are not H; or (b) R.sub.a and R.sub.b are joined together
with the nitrogen atom to form a heterocyclic or substituted
heterocyclic ring.
[0085] "Acylamino" refers to the group --C(O)NR.sub.aR.sub.b where
R.sub.a and R.sub.b are 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.sub.a and R.sub.b groups can be joined together
with the nitrogen atom to form a heterocyclic or substituted
heterocyclic ring.
[0086] "Aminoacyl" refers to the group --NR.sub.aC(O)R.sub.b where
each R.sub.a and R.sub.b group 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.sub.a is H or alkyl.
[0087] "Aminosulfonyl" refers to the groups --NRSO.sub.2-alkyl,
--NRSO.sub.2 substituted alkyl, --NRSO.sub.2-alkenyl,
--NRSO.sub.2-substituted alkenyl, --NRSO.sub.2-alkynyl,
--NRSO.sub.2-substituted alkynyl, --NRSO.sub.2-cycloalkyl,
--NRSO.sub.2-substituted cycloalkyl, --NRSO.sub.2-aryl,
--NRSO.sub.2-substituted aryl, --NRSO.sub.2-heteroaryl,
--NRSO.sub.2-substituted heteroaryl, --NRSO.sub.2-heterocyclic, and
--NRSO.sub.2-- 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.
[0088] "Sulfonylamino" refers to the groups --SO.sub.2NH.sub.2,
--SO.sub.2NR-alkyl, --SO.sub.2NR-substituted alkyl,
--SO.sub.2NR-alkenyl, --SO.sub.2NR-substituted alkenyl,
--SO.sub.2NR-alkynyl, --SO.sub.2NR-substituted alkynyl,
--SO.sub.2NR-aryl, --SO.sub.2NR-substituted aryl,
--SO.sub.2NR-heteroaryl, --SO.sub.2NR-substituted heteroaryl,
--SO.sub.2NR-heterocyclic, and --SO.sub.2NR-substituted
heterocyclic, where R is H or alkyl, or --SO.sub.2NR.sub.2, 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.
[0089] "Sulfonyl" refers to the groups --SO.sub.2-alkyl,
--SO.sub.2-substituted alkyl, --SO.sub.2-alkenyl,
--SO.sub.2-substituted alkenyl, --SO.sub.2-alkynyl,
--SO.sub.2-substituted alkynyl, --SO.sub.2-aryl,
--SO.sub.2-substituted aryl, --SO.sub.2-aralkyl,
--SO.sub.2-substituted aralkyl, --SO.sub.2-heteroaryl,
--SO.sub.2-substituted heteroaryl, --SO.sub.2-heterocyclic, and
--SO.sub.2-substituted heterocyclic.
[0090] "Aminocarbonylalkoxy" refers to the group
--NR.sub.aC(O)OR.sub.b where each R.sub.a and R.sub.b group 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.
[0091] "Carbonylalkylenealkoxy" refers to the group
--C(O)--(CH.sub.2).sub.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.
[0092] "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 (--CF.sub.3).
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 (--OCF.sub.3).
[0093] "Carbonyl" refers to the group C.dbd.O.
[0094] "Cyano" refers to the group --CN.
[0095] "Oxo" refers to the moiety .dbd.O.
[0096] "Nitro" refers to the group --NO.sub.2.
[0097] "Thioalkyl" refers to the groups --S-alkyl.
[0098] "Alkylsulfonylamino" refers to the groups
--R.sup.1SO.sub.2NR.sub.aR.sub.b where R.sub.a and R.sub.b are
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.sub.a and R.sub.b groups can be joined together with the
nitrogen atom to form a heterocyclic or substituted heterocyclic
ring and R.sup.1 is an alkyl group.
[0099] "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.
[0100] "Geminal" refers to the relationship between two moieties
that are attached to the same atom. For example, in the residue
--CH.sub.2--CHR.sup.1R.sup.2, R.sup.1 and R.sup.2 are geminal and
R.sup.1 may be referred to as a geminal R group to R.sup.2.
[0101] "Vicinal" refers to the relationship between two moieties
that are attached to adjacent atoms. For example, in the residue
--CHR.sup.1--CH.sub.2R.sup.2, R.sup.1 and R.sup.2 are vicinal and
R.sup.1 may be referred to as a vicinal R group to R.sup.2.
Receptor Binding Profile
[0102] In some embodiments, compounds provided herein bind to and
are antagonists of the adrenergic receptor .alpha..sub.2A. In one
variation, compounds provided herein bind to and are antagonists of
the adrenergic receptor .alpha..sub.2A and either (a) also bind to
and are antagonists of the adrenergic receptor .alpha..sub.2B or
(b) are not antagonists of the adrenergic receptor .alpha..sub.2B
but 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
.alpha..sub.2A and the adrenergic receptor .alpha..sub.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 .alpha..sub.2A Alternatively, compounds
provided herein that bind to and are antagonists of the adrenergic
receptor .alpha..sub.2A, but which do not bind to and are not
antagonists of the adrenergic receptor .alpha..sub.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 .alpha..sub.2A antagonist 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 .alpha..sub.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
.alpha..sub.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
.alpha..sub.2A. Compounds that exhibit the dual properties of
binding to and being an antagonist of both the adrenergic receptor
.alpha..sub.2A and the adrenergic receptor .alpha..sub.2B may also
be administered in conjunction with a second agent that reduces, or
is expected to reduce, blood pressure in an individual.
[0103] Compounds that antagonize the adrenergic receptor
.alpha..sub.2A and the adrenergic receptor .alpha..sub.2B may 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 .alpha..sub.2A and the
adrenergic receptor .alpha..sub.2B may also block the adrenergic
receptor .alpha..sub.1B and have utility in individuals with high
blood glucose and high blood pressure.
[0104] The compounds provided herein may in some embodiments also
bind to and be antagonists of the adrenergic receptor
.alpha..sub.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 .alpha..sub.2A antagonist.
Thus, in one variation, compounds that bind to and are antagonists
of the adrenergic receptor .alpha..sub.2A are provided, wherein the
compounds also bind to and are antagonists of the adrenergic
receptors .alpha..sub.2B and .alpha..sub.1B. In another variation,
compounds that bind to and are antagonists of the adrenergic
receptor .alpha..sub.2A are provided, wherein the compounds also
bind to and are antagonists of the adrenergic receptor
.alpha..sub.1B but which are not antagonists of the adrenergic
receptor .alpha..sub.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.
[0105] The compounds provided herein may in some embodiments also
bind to and be antagonists of the adrenergic receptor
.alpha..sub.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 .alpha..sub.2A antagonist.
Thus, in one variation, compounds that bind to and are antagonists
of the adrenergic receptor .alpha..sub.2A are provided, wherein the
compounds also bind to and are antagonists of the adrenergic
receptors .alpha..sub.1B, .alpha..sub.m and .alpha..sub.1B. In
another variation, compounds that bind to and are antagonists of
the adrenergic receptor .alpha..sub.2A are provided, wherein the
compounds also bind to and are antagonists of the adrenergic
receptor .alpha..sub.m and .alpha..sub.m but which are not
antagonists of the adrenergic receptor .alpha..sub.2B. In another
variation, compounds that bind to and are antagonists of the
adrenergic receptor .alpha..sub.2A are provided, wherein the
compounds also bind to and are antagonists of the adrenergic
receptor .alpha..sub.2B and .alpha..sub.m but which are not
antagonists of the adrenergic receptor .alpha..sub.1B. In another
variation, compounds that bind to and are antagonists of the
adrenergic receptor .alpha..sub.2A are provided, wherein the
compounds also bind to and are antagonists of the adrenergic
receptors .alpha..sub.1B, but which are not antagonists of the
adrenergic receptor .alpha..sub.2B or .alpha..sub.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.
[0106] 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 .alpha..sub.2B but which is not an antagonist of the
adrenergic receptor .alpha..sub.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.
[0107] In one variation, a compound provided herein exhibits equal
to or greater than about 50% inhibition of .alpha..sub.2A ligand
binding at 0.1 .mu.M and antagonist activity to adrenergic receptor
.alpha..sub.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
.alpha..sub.2A ligand binding at 0.1 .mu.M and antagonist activity
to adrenergic receptor .alpha..sub.2A. In one variation, a compound
provided herein exhibits equal to or greater than about 50%
inhibition of .alpha..sub.2A ligand binding at 0.03 .mu.M and
antagonist activity to adrenergic receptor .alpha..sub.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 .alpha..sub.2A ligand binding at
0.03 .mu.M and antagonist activity to adrenergic receptor
.alpha..sub.2A.
[0108] In another variation, a compound as provided herein (i)
binds to and is an antagonist of adrenergic receptor .alpha..sub.2A
and (ii) exhibits greater than or equal to about 50% inhibition of
.alpha..sub.2B ligand binding at 0.1 .mu.M and antagonist activity
to adrenergic receptor .alpha..sub.2B. In one such variation, a
compound as provided herein exhibits (i) greater than or equal to
about 50% inhibition of .alpha..sub.2A ligand binding at 0.1 .mu.M
and antagonist activity to adrenergic receptor .alpha..sub.2A and
(ii) greater than or equal to about 50% inhibition of
.alpha..sub.2B ligand binding at 0.1 .mu.M and antagonist activity
to adrenergic receptor .alpha..sub.2B When the compound exhibits
greater than or equal to about 50% inhibition of .alpha..sub.2B
ligand binding at 0.1 .mu.M and antagonist activity to adrenergic
receptor .alpha..sub.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 .alpha..sub.2B
ligand binding at 0.1 .mu.M and antagonist activity to adrenergic
receptor .alpha..sub.2B In another variation, a compound as
provided herein exhibits (i) greater than or equal to about 50%
inhibition of .alpha..sub.2A ligand binding at 0.03 .mu.M and
antagonist activity to adrenergic receptor .alpha..sub.2A and (ii)
greater than or equal to about 50% inhibition of .alpha..sub.2B
ligand binding at 0.03 .mu.M and antagonist activity to adrenergic
receptor .alpha..sub.2B In another variation, a compound as
provided herein exhibits (i) greater than or equal to about 50%
inhibition of .alpha..sub.2A ligand binding at 0.03 .mu.M and
antagonist activity to adrenergic receptor .alpha..sub.2A and (ii)
greater than or equal to about 50% inhibition of .alpha..sub.2B
ligand binding at 0.1 .mu.M and antagonist activity to adrenergic
receptor .alpha..sub.2B In another variation, a compound as
provided herein exhibits (i) greater than or equal to about 50%
inhibition of .alpha..sub.2A ligand binding at 0.1 .mu.M and
antagonist activity to adrenergic receptor .alpha..sub.2A and (ii)
greater than or equal to about 50% inhibition of .alpha..sub.2B
ligand binding at 0.03 .mu.M and antagonist activity to adrenergic
receptor .alpha..sub.2B When the compound exhibits greater than or
equal to about 50% inhibition of .alpha..sub.2B ligand binding at
0.03 .mu.M and antagonist activity to adrenergic receptor
.alpha..sub.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 .alpha..sub.2B ligand binding at
0.03 .mu.M and antagonist activity to adrenergic receptor
.alpha..sub.2B. It is understood and clearly conveyed herein that
an adrenergic receptor .alpha..sub.2A antagonist can exhibit any of
the adrenergic receptor .alpha..sub.2A binding profiles described
herein in combination with any of the adrenergic receptor
.alpha..sub.2B binding profiles described herein, as if each and
every combination were listed separately.
[0109] The adrenergic receptor .alpha..sub.2A antagonists may also
be used in conjunction with other agents that antagonize the
adrenergic receptor .alpha..sub.2B. Administration in conjunction
with another compound includes administration in the same or
different composition, either sequentially, simultaneously, or
continuously.
[0110] In one variation, compounds provided herein that bind to and
are antagonists of the adrenergic receptor .alpha..sub.2A will also
bind to and antagonize the adrenergic receptor .alpha..sub.1B. In
another variation, compounds provided herein that bind to and are
antagonists of the adrenergic receptor .alpha..sub.2A and either
(a) also bind to and are antagonists of the adrenergic receptor
.alpha..sub.2B or (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 .alpha..sub.1B. In some
embodiments, compounds provided herein may exhibit greater than or
equal to about 50% inhibition of .alpha..sub.m ligand binding at
0.1 .mu.M and antagonist activity to adrenergic receptor
.alpha..sub.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
.alpha..sub.m ligand binding at 0.1 .mu.M and antagonist activity
to adrenergic receptor .alpha..sub.1B. In some embodiments,
compounds provided herein may exhibit greater than or equal to
about 50% inhibition of .alpha..sub.m ligand binding at 0.03 .mu.M
and antagonist activity to adrenergic receptor .alpha..sub.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 .alpha..sub.m ligand
binding at 0.03 .mu.M and antagonist activity to adrenergic
receptor .alpha..sub.1B. For example, in one variation, a compound
provided herein exhibits equal to or greater than about 50%
inhibition of .alpha..sub.2A ligand binding at 0.1 .mu.M and
antagonist activity to adrenergic receptor .alpha..sub.2A and
greater than or equal to about 50% inhibition of .alpha..sub.1B
ligand binding at 0.1 .mu.M and antagonist activity to adrenergic
receptor .alpha..sub.1B. In another variation, a compound provided
herein exhibits equal to or greater than about 50% inhibition of
.alpha..sub.2A ligand binding at 0.1 .mu.M and antagonist activity
to adrenergic receptor .alpha..sub.2A, greater than or equal to
about 50% inhibition of .alpha..sub.2B ligand binding at 0.1 .mu.M
and antagonist activity to adrenergic receptor .alpha..sub.2B and
greater than or equal to about 50% inhibition of .alpha..sub.m
ligand binding at 0.1 .mu.M and antagonist activity to adrenergic
receptor .alpha..sub.1B. In one variation, a compound provided
herein exhibits equal to or greater than about 50% inhibition of
.alpha..sub.2A ligand binding at 0.1 .mu.M and antagonist activity
to adrenergic receptor .alpha..sub.2A, greater than or equal to
about 50% inhibition of .alpha..sub.2B ligand binding at 0.1 .mu.M
and antagonist activity to adrenergic receptor .alpha..sub.2B and
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 .alpha..sub.1B ligand binding at
0.1 .mu.M and antagonist activity to adrenergic receptor
.alpha..sub.1B. It is understood and clearly conveyed herein that
an adrenergic receptor .alpha..sub.2A antagonist can exhibit any of
the adrenergic receptor .alpha..sub.2A binding profiles described
herein in combination with any of the adrenergic receptor
.alpha..sub.2B binding profiles described herein, and/or any of the
adrenergic receptor .alpha..sub.1B binding profiles described
herein as if each and every combination were listed separately.
[0111] The adrenergic receptor .alpha..sub.2A antagonists may also
be used in conjunction with other agents that antagonize the
adrenergic receptor .alpha..sub.1B. Administration in conjunction
with another compound includes administration in the same or
different composition, either sequentially, simultaneously, or
continuously.
[0112] In one variation, compounds provided herein that bind to and
are antagonists of the adrenergic receptor .alpha..sub.2A will also
bind to and antagonize the adrenergic receptor .alpha..sub.1D. In
another variation, compounds provided herein that bind to and are
antagonists of the adrenergic receptor .alpha..sub.2A and either
(a) also bind to and are antagonists of the adrenergic receptor
.alpha..sub.2B or (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 .alpha..sub.1D. In
another variation, compounds provided herein that bind to and are
antagonists of the adrenergic receptor .alpha..sub.2A and either
(a) also bind to and are antagonists of the adrenergic receptor
.alpha..sub.2B or (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 .alpha..sub.1B will
also bind to and antagonize the adrenergic receptor .alpha..sub.1D.
In some embodiments, compounds provided herein may exhibit greater
than or equal to about 50% inhibition of .alpha..sub.1D ligand
binding at 0.1 .mu.M and antagonist activity to adrenergic receptor
.alpha..sub.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
.alpha..sub.1D ligand binding at 0.1 .mu.M and antagonist activity
to adrenergic receptor .alpha..sub.1D. In some embodiments,
compounds provided herein may exhibit greater than or equal to
about 50% inhibition of .alpha..sub.1D ligand binding at 0.03 .mu.M
and antagonist activity to adrenergic receptor .alpha..sub.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 .alpha..sub.1D
ligand binding at 0.03 .mu.M and antagonist activity to adrenergic
receptor .alpha..sub.1D. For example, in one variation, a compound
provided herein exhibits equal to or greater than about 50%
inhibition of .alpha..sub.2A ligand binding at 0.1 .mu.M and
antagonist activity to adrenergic receptor .alpha..sub.2A and
greater than or equal to about 50% inhibition of .alpha..sub.1D
ligand binding at 0.1 .mu.M and antagonist activity to adrenergic
receptor .alpha..sub.1D. In another variation, a compound provided
herein exhibits equal to or greater than about 50% inhibition of
.alpha..sub.2A ligand binding at 0.1 .mu.M and antagonist activity
to adrenergic receptor .alpha..sub.2A, greater than or equal to
about 50% inhibition of .alpha..sub.2B ligand binding at 0.1 .mu.M
and antagonist activity to adrenergic receptor .alpha..sub.2B and
greater than or equal to about 50% inhibition of .alpha..sub.1D
ligand binding at 0.1 .mu.M and antagonist activity to adrenergic
receptor .alpha..sub.1D. In another variation, a compound provided
herein exhibits equal to or greater than about 50% inhibition of
.alpha..sub.2A ligand binding at 0.1 .mu.M and antagonist activity
to adrenergic receptor .alpha..sub.2A, greater than or equal to
about 50% inhibition of .alpha..sub.2B ligand binding at 0.1 .mu.M
and antagonist activity to adrenergic receptor .alpha..sub.2B,
greater than or equal to about 50% inhibition of .alpha..sub.1B
ligand binding at 0.1 .mu.M and antagonist activity to adrenergic
receptor .alpha..sub.1B, and greater than or equal to about 50%
inhibition of .alpha..sub.1D ligand binding at 0.1 .mu.M and
antagonist activity to adrenergic receptor .alpha..sub.1B. In one
variation, a compound provided herein exhibits equal to or greater
than about 50% inhibition of .alpha..sub.2A ligand binding at 0.1
.mu.M and antagonist activity to adrenergic receptor
.alpha..sub.2A, greater than or equal to about 50% inhibition of
.alpha..sub.2B ligand binding at 0.1 .mu.M and antagonist activity
to adrenergic receptor .alpha..sub.2B, greater than or equal to
about 50% inhibition of .alpha..sub.1B ligand binding at 0.1 .mu.M
and antagonist activity to adrenergic receptor .alpha..sub.1B and
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 .alpha..sub.1D
ligand binding at 0.1 .mu.M and antagonist activity to adrenergic
receptor .alpha..sub.1D. It is understood and clearly conveyed
herein that an adrenergic receptor .alpha..sub.2A antagonist can
exhibit any of the adrenergic receptor .alpha..sub.2A binding
profiles described herein in combination with any of the adrenergic
receptor .alpha..sub.2B binding profiles described herein, and/or
any of the adrenergic receptor .alpha..sub.1B binding profiles
described herein and/or any of the adrenergic receptor
.alpha..sub.1D binding profiles described herein as if each and
every combination were listed separately.
[0113] The adrenergic receptor .alpha..sub.2A antagonists may also
be used in conjunction with other agents that antagonize the
adrenergic receptor .alpha..sub.1D. Administration in conjunction
with another compound includes administration in the same or
different composition, either sequentially, simultaneously, or
continuously.
[0114] 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
[0115] Antagonist activity to the adrenergic receptor
.alpha..sub.2A, .alpha..sub.2B, .alpha..sub.1B and .alpha..sub.1D
may be assessed by methods known in the art, such as standard
.alpha..sub.2A, .alpha..sub.2B, .alpha..sub.1B and .alpha..sub.1D
receptor 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 .alpha..sub.2A,
.alpha..sub.2B, .alpha..sub.1B or .alpha..sub.1D and the cell
membrane-based GTP.gamma.S binding assay may be used to assess
antagonist activity to the adrenergic receptor .alpha..sub.2B.
[0116] In one variation, adrenergic receptor .alpha..sub.2A
antagonists as provided herein exhibit an IC.sub.50 value 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
EC.sub.80 of UK14304 (for Aequorin assay) in an adrenergic receptor
.alpha..sub.2A antagonist assay.
[0117] In another variation, a compound provided herein binds to
and is an antagonist of the adrenergic receptor .alpha..sub.2A,
wherein the compound is also an antagonist of the adrenergic
receptor .alpha..sub.2B and exhibits an IC.sub.50 value 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
EC.sub.80 of oxymetazoline (for Aequorin assay) or guanfacine (for
GTP.gamma.S assay) in an adrenergic receptor .alpha..sub.2B
antagonist assay. In some embodiments, adrenergic receptor
.alpha..sub.2A antagonists as provided herein exhibit: (i) an
IC.sub.50 value in an .alpha..sub.2A antagonist 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
EC.sub.80 of UK14304 (for Aequorin assay), and (ii) an IC.sub.50
value in an .alpha..sub.2B antagonist 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
EC.sub.80 of oxymetazoline (for Aequorin assay) or guanfacine (for
GTP.gamma.S assay). In another variation, a compound provided
herein binds to and is an antagonist of the adrenergic receptor
.alpha..sub.2A, wherein the compound is also an antagonist of the
adrenergic receptor .alpha..sub.1B and exhibits an IC.sub.50 value
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 EC.sub.80 of cirazoline (for Aequorin assay) in an
adrenergic receptor .alpha..sub.1B antagonist assay. In some
embodiments, adrenergic receptor .alpha..sub.2A antagonists as
provided herein exhibit: (i) an IC.sub.50 value 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
EC.sub.80 of UK14304 (for Aequorin assay) in an adrenergic receptor
.alpha..sub.2A antagonist assay, and (ii) an IC.sub.50 value 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
EC.sub.80 of cirazoline) in an adrenergic receptor .alpha..sub.1B
antagonist assay. In yet another variation, a compound provided
herein binds to and is an antagonist of the adrenergic receptor
.alpha..sub.2A, wherein the compound is also an antagonist of the
adrenergic receptor .alpha..sub.1D and exhibits an IC.sub.50 value
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 EC.sub.80 of cirazoline (for Aequorin assay) in an adrenergic
receptor .alpha..sub.1D antagonist assay. In some embodiments,
adrenergic receptor .alpha..sub.2A antagonists as provided herein
exhibit: (i) an IC.sub.50 value 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 EC.sub.80 of UK14304 (for Aequorin
assay) in an adrenergic receptor .alpha..sub.2A antagonist assay,
and (ii) an IC.sub.50 value 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 EC.sub.80 of cirazoline) in an
adrenergic receptor .alpha..sub.1B antagonist assay.
[0118] In yet another embodiment, adrenergic receptor
.alpha..sub.2A antagonists as provided herein exhibit: (i) an
IC.sub.50 value in an .alpha..sub.2A antagonist 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
EC.sub.80 of UK14304 (for Aequorin assay); (ii) an IC.sub.50 value
in an .alpha..sub.2B antagonist 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 EC.sub.80 of
oxymetazoline (for Aequorin assay) or guanfacine (for GTP.gamma.S
assay); and (iii) an IC.sub.50 value 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 EC.sub.80 of cirazoline) in an
adrenergic receptor .alpha..sub.1B antagonist assay. In another
embodiment, adrenergic receptor .alpha..sub.2A antagonists as
provided herein exhibit: (i) an IC.sub.50 value in an
.alpha..sub.2A antagonist 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 EC.sub.80 of UK14304 (for Aequorin
assay); (ii) an IC.sub.50 value in an .alpha..sub.2B antagonist
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 EC.sub.80 of oxymetazoline (for Aequorin assay) or
guanfacine (for GTP.gamma.S assay); and (iii) an IC.sub.50 value
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
EC.sub.80 of cirazoline) in an adrenergic receptor .alpha..sub.1D
antagonist assay. In another embodiment, adrenergic receptor
.alpha..sub.2A antagonists as provided herein exhibit: (i) an
IC.sub.50 value in an .alpha..sub.2A antagonist 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
EC.sub.80 of UK14304 (for Aequorin assay); (ii) an IC.sub.50 value
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
EC.sub.80 of cirazoline) in an adrenergic receptor .alpha..sub.1B
antagonist assay; and (iii) an IC.sub.50 value 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 EC.sub.80 of
cirazoline) in an adrenergic receptor .alpha..sub.1D antagonist
assay.
[0119] In yet another embodiment, adrenergic receptor
.alpha..sub.2A antagonists as provided herein exhibit: (i) an
IC.sub.50 value in an .alpha..sub.2A antagonist 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
EC.sub.80 of UK14304 (for Aequorin assay); (ii) an IC.sub.50 value
in an .alpha..sub.2B antagonist 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 EC.sub.80 of
oxymetazoline (for Aequorin assay) or guanfacine (for GTP.gamma.S
assay); (iii) an IC.sub.50 value 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 EC.sub.80 of cirazoline) in an
adrenergic receptor .alpha..sub.1B antagonist assay; and (iv) an
IC.sub.50 value 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 EC.sub.80 of cirazoline) in an adrenergic receptor
.alpha..sub.1D antagonist assay.
[0120] In one variation, adrenergic receptor .alpha..sub.2A
antagonists as provided herein exhibit an IC.sub.50 value 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
EC.sub.80 of UK14304 (for Aequorin assay) in an adrenergic receptor
.alpha..sub.2A antagonist assay. In one variation, adrenergic
receptor .alpha..sub.2A antagonists as provided herein exhibit an
IC.sub.50 value equal to or less than about 10 nM at a given
concentration of agonist (e.g. concentration corresponding to
EC.sub.80 of UK14304 (for Aequorin assay) in an adrenergic receptor
.alpha..sub.2A antagonist assay. In one variation, adrenergic
receptor .alpha..sub.2A antagonists as provided herein exhibit an
IC.sub.50 value in an adrenergic receptor .alpha..sub.2A antagonist
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 EC.sub.80 concentration obtained by assay protocols described
herein. In one variation, adrenergic receptor .alpha..sub.2A
antagonists as provided herein exhibit an IC.sub.50 value 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 .alpha..sub.2A (Aequorin) antagonist assay. In
one variation, adrenergic receptor .alpha..sub.2A antagonists as
provided herein exhibit an IC.sub.50 value 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 .alpha..sub.2A (Aequorin)
antagonist assay.
[0121] In one variation adrenergic receptor .alpha..sub.2A
antagonists as provided herein exhibit an IC.sub.50 value 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
EC.sub.80 of oxymetazoline (for Aequorin assay) or guanfacine (for
GTP.gamma.S assay) in an .alpha..sub.2B antagonist assay. In some
embodiments, adrenergic receptor .alpha..sub.2A antagonists as
provided herein exhibit an IC.sub.50 value equal to or less than
about 10 nM at a given concentration of agonist (e.g. concentration
corresponding to EC.sub.80 of oxymetazoline (for Aequorin assay) or
guanfacine (for GTP.gamma.S assay) in an .alpha..sub.2B antagonist
assay. In some embodiments, a compound described herein exhibits an
IC.sub.50 value in an .alpha..sub.2B antagonist 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 EC.sub.80
concentration as obtained by assay protocols described herein. In
some embodiments, a compound described herein exhibits an IC.sub.50
value in an .alpha..sub.2B antagonist (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
IC.sub.50 value in an .alpha..sub.2B antagonist (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 IC.sub.50 value in an
.alpha..sub.2B antagonist (GTP.gamma.S) 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 IC.sub.50
value in an .alpha..sub.2B antagonist 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.
[0122] In one variation, a compound described herein exhibits an
IC.sub.50 value in an .alpha..sub.1B antagonist 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
EC.sub.80 of cirazoline) in an adrenergic receptor .alpha..sub.1B
antagonist assay. In some embodiments, a compound described herein
exhibits an IC.sub.50 value in an .alpha..sub.1B antagonist assay
equal to or less than about 10 nM at a given concentration of
agonist (e.g. concentration corresponding to EC.sub.80 of
cirazoline) in an adrenergic receptor .alpha..sub.1B antagonist
assay. In some embodiments, a compound described herein exhibits an
IC.sub.50 value in an .alpha..sub.1B antagonist 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 EC.sub.80
concentration as obtained by assay protocols described herein. In
some embodiments, a compound described herein exhibits an IC.sub.50
value in an .alpha..sub.1B antagonist (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
IC.sub.50 value in an .alpha..sub.1B antagonist (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.
[0123] In one variation, a compound described herein exhibits an
IC.sub.50 value in an .alpha..sub.1D antagonist 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
EC.sub.80 of cirazoline) in an adrenergic receptor .alpha..sub.1D
antagonist assay. In some embodiments, a compound described herein
exhibits an IC.sub.50 value in an .alpha..sub.1D antagonist assay
equal to or less than about 10 nM at a given concentration of
agonist (e.g. concentration corresponding to EC.sub.80 of
cirazoline) in an adrenergic receptor .alpha..sub.1D antagonist
assay. In some embodiments, a compound described herein exhibits an
IC.sub.50 value in an .alpha..sub.1D antagonist 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 EC.sub.80
concentration as obtained by assay protocols described herein. In
some embodiments, a compound described herein exhibits an IC.sub.50
value in an .alpha..sub.1D antagonist 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 IC.sub.50
value in an .alpha..sub.1D antagonist 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.
[0124] In some embodiments, compounds provided herein exhibit
inverse agonist activity for the adrenergic receptor
.alpha..sub.2A. In some embodiments, the compound binds to and is
an inverse agonist of the adrenergic receptor .alpha..sub.2A and
binds to and is antagonist of one or more of the adrenergic
receptors .alpha..sub.2B, .alpha..sub.1B and .alpha..sub.1D. In one
variation, the compound binds to and is an inverse agonist of the
adrenergic receptor .alpha..sub.2A and binds to and is antagonist
of any one of the adrenergic receptors .alpha..sub.2B,
.alpha..sub.1B and .alpha..sub.1D. In another variation, the
compound binds to and is an inverse agonist of the adrenergic
receptor .alpha..sub.2A and binds to and is antagonist of any two
of the adrenergic receptors .alpha..sub.2B, .alpha..sub.1B and
.alpha..sub.1D. In yet another variation, the compound binds to and
is an inverse agonist of the adrenergic receptor .alpha..sub.2A and
binds to and is antagonist of adrenergic receptors .alpha..sub.2B,
.alpha..sub.1B and .alpha..sub.1D. Inverse agonist activity to the
adrenergic receptor .alpha..sub.2A may be assessed by methods known
in the art, such as those described in Wade, S. M. et al., Mol.
Pharmacol. 59:532-542 (2001).
[0125] 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
.alpha..sub.2A ligand binding at 0.1 .mu.M to adrenergic receptor
.alpha..sub.2A and an IC.sub.50 value 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 EC.sub.80 of UK14304
(for Aequorin assay) in an adrenergic receptor .alpha..sub.2A
antagonist 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 .alpha..sub.2B
ligand binding at 0.1 .mu.M to adrenergic receptor .alpha..sub.2B
and IC.sub.50 value 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 EC.sub.80 of oxymetazoline (for
Aequorin assay) or guanfacine (for GTP.gamma.S assay) in an
.alpha..sub.2B antagonist assay.
Medical Use
[0126] Without being bound by theory, it is believed that compounds
that bind to and are antagonists of the adrenergic receptor
.alpha..sub.2A affect 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 .alpha..sub.2A antagonists as provided herein also bind to
and are antagonists of the adrenergic receptor .alpha..sub.2B
and/or the adrenergic receptor .alpha..sub.1B, and/or the
adrenergic receptor .alpha..sub.1D, it is believed that the
increases in an individual's blood pressure due to antagonizing the
adrenergic receptor .alpha..sub.2A may be reduced or eliminated. If
an adrenergic receptor .alpha..sub.2A antagonist as provided herein
is not also an antagonist of the adrenergic receptor .alpha..sub.2B
and/or the adrenergic receptor .alpha..sub.1B and/or the adrenergic
receptor .alpha..sub.1D, then the increase in an individual's blood
pressure as a result of the adrenergic receptor .alpha..sub.2A
antagonist 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.
[0127] Compounds provided herein, such as the adrenergic receptor
.alpha..sub.2A antagonists 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 .alpha..sub.2A antagonist
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.
[0128] Compounds that are inverse agonists of the adrenergic
receptor .alpha..sub.2A may stimulate islet cell release of insulin
even in the absence of sympathetic stimulation of the adrenergic
receptor .alpha..sub.2A with epinephrine and/or norepinephrine.
Inverse agonists of the adrenergic receptor .alpha..sub.2A provided
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 .alpha..sub.2A may 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.
[0129] 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-Barre 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-Barre syndrome, multiple
sclerosis, diabetic neuropathy, fibromyalgia, neuropathy associated
with spinal cord injury, schizophrenia, bipolar disorder,
psychosis, anxiety or depression.
[0130] The adrenergic receptor .alpha..sub.2A antagonists 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 .alpha..sub.2A antagonists 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
.alpha..sub.2A antagonist 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 .alpha..sub.2A antagonist 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
[0131] 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
.alpha..sub.2A antagonist, or pharmaceutically acceptable salt
thereof, to an individual in need thereof. In one aspect, the
adrenergic receptor .alpha..sub.2A antagonists of the methods also
bind to and are antagonists of one or more of the adrenergic
receptors .alpha..sub.2B, .alpha..sub.1B and .alpha..sub.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 .alpha..sub.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 .alpha..sub.2A, wherein the compound either (a) also binds
to and is an antagonist of the adrenergic receptor .alpha..sub.2B
or (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 .alpha..sub.2A are 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 .alpha..sub.2A are 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
.alpha..sub.2A antagonist 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 .alpha..sub.2A
antagonist 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.
[0132] 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.
[0133] Also provided herein are methods of using an adrenergic
receptor .alpha..sub.2A antagonist, 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.
[0134] Further provided herein are methods of using an adrenergic
receptor .alpha..sub.2A antagonist, 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 .alpha..sub.2A
antagonist also binds to and is an antagonist of one or more of the
adrenergic receptors .alpha..sub.2B, .alpha..sub.1B and
.alpha..sub.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
.alpha..sub.2A antagonist. 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
.alpha..sub.2A, wherein the compound either (a) also binds to and
is an antagonist of the adrenergic receptor .alpha..sub.2B or (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 .alpha..sub.2A
antagonist that also binds to and is an antagonist of one or more
of the adrenergic receptors .alpha..sub.2B, .alpha..sub.1B and
.alpha..sub.1D. In some embodiments, the method comprises
administering any of the compounds detailed herein in combination
with an insulin sensitizer.
[0135] 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 .alpha..sub.2A antagonist detailed herein. In one aspect,
the compound binds to and is an adrenergic receptor .alpha..sub.2A
antagonist. In some embodiments, the adrenergic receptor
.alpha..sub.2A antagonist also binds to and is an antagonist of one
or more of the adrenergic receptors .alpha..sub.2B, .alpha..sub.1B
and .alpha..sub.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 .alpha..sub.2A and wherein the compound either
(a) also binds to and is an antagonist of the adrenergic receptor
.alpha..sub.2B or (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 .alpha..sub.2A antagonist, 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 .alpha..sub.2A
antagonist, 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.
[0136] 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.
[0137] 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 .alpha..sub.2A antagonist,
or pharmaceutically acceptable salt thereof. In one aspect, the
adrenergic receptor .alpha..sub.2A antagonist also binds to and is
an antagonist of one or more of the adrenergic receptors
.alpha..sub.2B, .alpha..sub.1B and .alpha..sub.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 .alpha..sub.2A and wherein
the compound either (a) also binds to and is an antagonist of the
adrenergic receptor .alpha..sub.2B or (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 .alpha..sub.2A antagonist, 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 .alpha..sub.2A antagonist, or pharmaceutically acceptable
salt thereof, to the individual.
[0138] 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 .alpha..sub.2A antagonist. In some embodiments,
administration of an adrenergic receptor .alpha..sub.2A antagonist
reduces the blood glucose levels in an individual (e.g., a
hyperglycemic individual). In some embodiments, administration of
an adrenergic receptor .alpha..sub.2A antagonist 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
.alpha..sub.2A antagonist reduces and stabilizes the blood glucose
levels in an individual. In one aspect, the adrenergic receptor
.alpha..sub.2A antagonist also binds to and is an antagonist of one
or more of the adrenergic receptors .alpha..sub.2B, .alpha..sub.1B
and .alpha..sub.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 .alpha..sub.2A and wherein the compound
either (a) also binds to and is an antagonist of the adrenergic
receptor .alpha..sub.2B or (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 .alpha..sub.2A antagonist described herein may also be an
inverse agonist of the adrenergic receptor .alpha..sub.2A.
[0139] 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 .alpha..sub.2A antagonist, wherein the blood glucose level
is reduced to a desirable level. The adrenergic receptor
.alpha..sub.2A antagonist 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
.alpha..sub.2A antagonist. 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 .alpha..sub.2A
antagonist. 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 .alpha..sub.2A
antagonist. 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.
[0140] 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.about.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
.alpha..sub.2A antagonist, 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 .alpha..sub.2A antagonist also binds to and is
an antagonist of one or more of the adrenergic receptors
.alpha..sub.2B, .alpha..sub.1B and .alpha..sub.1D.
[0141] 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 .alpha..sub.2A antagonist detailed herein. In one aspect,
the compound binds to and is an adrenergic receptor .alpha..sub.2A
antagonist. In some embodiments, the adrenergic receptor
.alpha..sub.2A antagonist also binds to and is an antagonist of one
or more of the adrenergic receptors .alpha..sub.2B, .alpha..sub.1B
and .alpha..sub.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 .alpha..sub.2A, and wherein the compound
either (a) also binds to and is an antagonist of the adrenergic
receptor .alpha..sub.2B or (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 .alpha..sub.2A antagonist is administered to an
individual in conjunction with an insulin sensitizer.
[0142] 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.
[0143] 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 .alpha..sub.2A is also an
antagonist of the adrenergic receptor .alpha..sub.2B and/or
.alpha..sub.1B and/or .alpha..sub.1D to reduce blood pressure.
Alternatively, an adrenergic receptor .alpha..sub.2A antagonist
that does not also antagonize the adrenergic receptor
.alpha..sub.2B and/or .alpha..sub.1B may 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 .alpha..sub.2A antagonist. In one aspect, the adrenergic
receptor .alpha..sub.2A antagonist also binds to and is an
antagonist of one or more of the adrenergic receptors
.alpha..sub.2B, .alpha..sub.1B and .alpha..sub.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 .alpha..sub.2A, and wherein the compound
either (a) also binds to and is an antagonist of the adrenergic
receptor .alpha..sub.2B or (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
.alpha..sub.2A.
[0144] 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.
[0145] 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.
[0146] 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 .alpha..sub.2A antagonist, 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 .alpha..sub.2A antagonist, or pharmaceutically
acceptable salt thereof, and their insulin levels are then
assessed. In one embodiment of such methods, the adrenergic
receptor .alpha..sub.2A antagonist 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 .alpha..sub.2A antagonist, 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
.alpha..sub.2A antagonist, 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 .alpha..sub.2A antagonist, 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 .alpha..sub.2A antagonist) 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 .alpha..sub.2A antagonist, or pharmaceutically
acceptable salt thereof), is provided, the method comprising
administering an adrenergic receptor .alpha..sub.2A antagonist, 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.
[0147] 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 .alpha..sub.2A antagonist) 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 .alpha..sub.2A antagonist 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 .alpha..sub.2A antagonist), the method
comprising the steps of (i) administering an adrenergic receptor
.alpha..sub.2A antagonist 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 .alpha..sub.2A antagonist; (2) administering a glucose
tolerance test in which glucose is administered after the
administration of the adrenergic receptor .alpha..sub.2A
antagonist; and (3) correlating the results of the glucose
tolerance test administered in conjunction with the administration
of the adrenergic receptor .alpha..sub.2A antagonist 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 .alpha..sub.2A antagonist) with whether the
individual is more or less likely to be responsive to an adrenergic
receptor .alpha..sub.2A antagonist, 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
.alpha..sub.2A antagonist for adrenergic receptor .alpha..sub.2A
antagonist therapy). An individual so selected may then be
administered a compound that increases insulin secretion and/or
release (e.g., an adrenergic receptor .alpha..sub.2A antagonist for
adrenergic receptor .alpha..sub.2A antagonist 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 .alpha..sub.2A antagonist. 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 .alpha..sub.2A antagonist). 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 .alpha..sub.2A antagonist) 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 .alpha..sub.2A antagonist), either alone or in
conjunction with an insulin sensitizer. Methods of monitoring the
treatment of an individual for glucose intolerance are also
provided.
[0148] 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 .alpha..sub.2A antagonist and (ii)
administering a compound that increases insulin secretion and/or
release (e.g., an adrenergic receptor .alpha..sub.2A antagonist) 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
.alpha..sub.2A antagonist and the individual's insulin levels
increase in response to a glucose tolerance test which employed
administration of glucose and an adrenergic receptor .alpha..sub.2A
antagonist.
[0149] In any of the methods employing a glucose tolerance test in
conjunction with an adrenergic receptor .alpha..sub.2A antagonist,
in one variation, if the individual's insulin does not increase in
response to a glucose challenge in conjunction with an adrenergic
receptor .alpha..sub.2A antagonist, 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.
[0150] Some genetic polymorphisms of the adrenergic receptor
.alpha..sub.2A gene associate with high blood glucose and can be
used to screen for patients who respond to an adrenergic receptor
.alpha..sub.2A antagonist 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
.alpha..sub.2A associates with overexpression of the adrenergic
receptor .alpha..sub.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 .alpha..sub.2A antagonist. Other DNA
polymorphisms may also be used to identify individuals with
elevated blood sugar that would respond to an adrenergic receptor
.alpha..sub.2A antagonist; 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 .alpha..sub.2A
antagonist), the method comprising screening the individual for
polymorphisms of the adrenergic receptor .alpha..sub.2A gene
associate with high blood glucose, such as one or more of the DNA
polymorphisms Rs553668, Rs7911129, Rs1971596, Rs602618 and
Rs2203616.
[0151] 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 .alpha..sub.2A
gene associate with high blood glucose; and (ii) administering to
the individual carrying one or more genetic polymorphisms of the
adrenergic receptor .alpha..sub.2A gene associated with high blood
glucose an adrenergic receptor .alpha..sub.2A antagonist. 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 .alpha..sub.2A gene
associate with high blood glucose; and (ii) administering to the
individual carrying one or more genetic polymorphisms of the
adrenergic receptor .alpha..sub.2A gene associated with high blood
glucose an adrenergic receptor .alpha..sub.2A antagonist. 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 .alpha..sub.2A antagonist, wherein the individual carries
one or more genetic polymorphisms of the adrenergic receptor
.alpha..sub.2A gene 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 .alpha..sub.2A antagonist also binds to and is an
antagonist of one or more of the adrenergic receptors
.alpha..sub.2B, .alpha..sub.1B and .alpha..sub.1D. In some
embodiments, the adrenergic receptor .alpha..sub.2A antagonist also
binds to and is an antagonist of the adrenergic receptors
.alpha..sub.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.
[0152] Compounds described herein showing adrenergic receptors
.alpha..sub.2A and adrenergic receptor .alpha..sub.2B antagonist
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 .alpha..sub.2A gene.
Cell Viability and Mitochondrial Health
[0153] 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.
[0154] 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.
[0155] 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.
[0156] 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.
[0157] 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.
[0158] 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 .alpha..sub.2B antagonists are of the formula
(I) or any variations detailed herein.
Compounds of the Invention
[0159] 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.
[0160] In one aspect, compounds of the formula (IA) are
provided:
##STR00005##
or a salt or solvate thereof; wherein:
[0161] R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl or carbonylalkylenealkoxy, or R.sup.1 and R.sup.2a are
taken together to form a propylene (--CH.sub.2CH.sub.2CH.sub.2--)
moiety or a butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety,
or R.sup.1 and R.sup.3a are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1 and
R.sup.4a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety;
[0162] each R.sup.2a and R.sup.2b is independently H, substituted
or unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, hydroxyl,
alkoxy, nitro, substituted or unsubstituted amino, acyloxy,
acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R.sup.2a
and R.sup.2b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.2a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and
R.sup.3a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and R.sup.4a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety;
[0163] each R.sup.3a and R.sup.3b is independently H, substituted
or unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, hydroxyl,
alkoxy, nitro, substituted or unsubstituted amino, acyloxy,
acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R.sup.3a
and R.sup.3b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.3a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and
R.sup.2a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and R.sup.4a are
taken together to form a propylene (--CH.sub.2CH.sub.2CH.sub.2--)
moiety or a butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--)
moiety;
[0164] each R.sup.4a and R.sup.4b is independently H, substituted
or unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, nitro,
substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy,
acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R.sup.4a
and R.sup.4b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.4a and R.sup.1 are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.2a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.3a
are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety;
[0165] each X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is independently
N, CH or CR.sup.6;
[0166] 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
[0167] each R.sup.6 is independently hydroxyl, nitro, cyano, halo,
C.sub.1-C.sub.8 perhaloalkyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, C.sub.1-C.sub.8 perhaloalkoxy, substituted or
unsubstituted C.sub.1-C.sub.8 alkoxy, substituted or unsubstituted
aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,
thioalkyl, --S(O)-alkyl, --S(O)-aryl, --S(O)-aralkyl, substituted
or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,
carbonylalkylenealkoxy, alkylsulfonylamino or acyl.
[0168] In one variation, compounds of the formula (IA) are
provided:
##STR00006##
or a salt or solvate thereof; wherein:
[0169] R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, thiol, thioalkyl, substituted or unsubstituted amino,
acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy,
or R.sup.1 and R.sup.2a are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1 and
R.sup.3a are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1 and
R.sup.4a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety;
[0170] each R.sup.2a and R.sup.2b is independently H, substituted
or unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, hydroxyl,
alkoxy, nitro, substituted or unsubstituted amino, acyloxy,
acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R.sup.2a
and R.sup.2b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.2a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and
R.sup.3a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and R.sup.4a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety;
[0171] each R.sup.3a and R.sup.3b is independently H, substituted
or unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, hydroxyl,
alkoxy, nitro, substituted or unsubstituted amino, acyloxy,
acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R.sup.3a
and R.sup.3b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.3a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R and R are taken
together to form an ethylene (--CH.sub.2CH.sub.2--) moiety or a
propylene (--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and
R.sup.4a are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety;
[0172] each R.sup.4a and R.sup.4b is independently H, substituted
or unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, nitro,
substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy,
acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R.sup.4a
and R.sup.4b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.4a and R.sup.1 are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.2a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.3a
are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety;
[0173] each X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is independently
N, CH or CR.sup.6;
[0174] 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
[0175] each R.sup.6 is independently hydroxyl, nitro, cyano, halo,
C.sub.1-C.sub.8 perhaloalkyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, C.sub.1-C.sub.8 perhaloalkoxy, substituted or
unsubstituted C.sub.1-C.sub.8 alkoxy, substituted or unsubstituted
aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,
thioalkyl, substituted or unsubstituted amino, acylamino,
aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl,
sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino
or acyl.
[0176] In one variation, compounds of the formula (IA), and salts
and solvates thereof, are embraced, provided that at least one of
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CH or CR.sup.6. In another
variation, at least two of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is
CH or CR.sup.6.
[0177] 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: [0178] (i) when Q is an unsubstituted
aryl, the aryl group is other than phenyl; [0179] (ii) when Q is a
mono-substituted aryl wherein the aryl group is phenyl, the phenyl
group substituent is other than halo, nitro, methoxy, --NH.sub.2,
CF.sub.3 and methyl; [0180] (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; [0181] (iv) when none
of R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and
R.sub.4b are 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 X.sup.2 is
CR.sup.6, then R.sup.6 is other than an unsubstituted
C.sub.1-C.sub.8 alkyl; (c) R.sup.1 is other than an unsubstituted
C.sub.1-C.sub.8 alkyl; 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, --NO.sub.2 or --NHOH
moiety; [0182] (v) when none of R.sup.1, R.sup.2a, R.sup.2b,
R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b are 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.sup.2a and R.sup.2b are each H; (b) R.sup.1 is
other than an unsubstituted C.sub.1-C.sub.8 alkyl; and (c) at least
one of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is N or CR.sup.6;
[0183] (vi) when none of R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a,
R.sup.3b, R.sup.4a and R.sup.4b are 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 X.sup.1, X.sup.2,
X.sup.3 and X.sup.4 is N or CR.sup.6; (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; [0184] (vii)
when none of R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b,
R.sup.4a and R.sup.4b are 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, --NO.sub.2 and --OCH.sub.3; (c)
either each of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CH or at
least two of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are selected
from N and CR.sup.6; and (d) R.sup.1 is other than an unsubstituted
C.sub.1-C.sub.8 alkyl; [0185] (viii) when none of R.sup.1,
R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b are
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 X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is N or CR.sup.6; (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; [0186] (ix) when none of R.sup.1, R.sup.2a,
R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b are 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
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are N or CR.sup.6; (b)
X.sup.2 is 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
R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and
R.sup.4b is other than H; [0187] (x) when none of R.sup.1,
R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b are
taken together to form a ring and Q is an unsubstituted cycloalkyl
then at least one of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is N or
CR.sup.6; [0188] (xi) Q is other than a substituted or
unsubstituted C.sub.3-C.sub.8 cycloalkyl; a substituted or
unsubstituted heterocyclyl moiety; and a substituted or
unsubstituted C.sub.3-C.sub.8 cycloalkenyl moiety [0189] (xii) when
none of R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a
and R.sup.4b are 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 X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is N or
CR.sup.6; (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 [0190] (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 X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are N or CR.sup.6; (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.
[0191] In some variations, provided are compounds of the formula
(IA), where R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b,
R.sup.4a, R.sup.4b, X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are 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.
[0192] In some variations, provided are compounds of the formula
(IA), where R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b,
R.sup.4a, R.sup.4b, X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are 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:
[0193] (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
[0194] (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.
[0195] In some of these variations, one or more of provisions
(i)-(xiii) further apply.
[0196] In one variation, compounds of the formula (IA), and salts
and solvates thereof, are embraced, where R.sup.1, R.sup.2a,
R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, X.sup.1, X.sup.2,
X.sup.3, and X.sup.4 are 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:
[0197] (1) at least one of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is
CH or CR.sup.6;
[0198] (2) when each X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is
independently CH or CR.sup.6, none of R.sup.1, R.sup.2a, R.sup.2b,
R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b are taken together to
form a ring and Q is an unsubstituted 6-membered aryl or an
unsubstituted 6-membered heteroaryl, then Q is other than
unsubstituted phenyl, unsubstituted pyridyl and unsubstituted
pyrimidyl;
[0199] (3) when each X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is
independently CH or CR.sup.6, none of R.sup.1, R.sub.2a, R.sup.2b,
R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b are taken together to
form a ring and Q is a substituted phenyl, then Q is a phenyl
substituted with a substituent selected from the group consisting
of substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
heterocyclyl, and substituted or unsubstituted aralkyl; and
[0200] (4) when each X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is
independently CH or CR.sup.6, and R.sup.2a and R.sup.3a are 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.
[0201] 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.
[0202] In another aspect of the invention, compounds of the formula
(IB) are provided:
##STR00007##
or a salt or solvate thereof; wherein:
[0203] R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl or carbonylalkylenealkoxy, or R.sup.1 and R.sup.2a are
taken together to form a propylene (--CH.sub.2CH.sub.2CH.sub.2--)
moiety or a butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety,
or R.sup.1 and R.sup.3a are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1 and
R.sup.4a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety;
[0204] each R.sup.2a and R.sup.2b is independently H, substituted
or unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, hydroxyl,
alkoxy, nitro, substituted or unsubstituted amino, acyloxy,
acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R.sup.2a
and R.sup.2b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.2a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and
R.sup.3a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and R.sup.4a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety;
[0205] each R.sup.3a and R.sup.3b is independently H, substituted
or unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, hydroxyl,
alkoxy, nitro, substituted or unsubstituted amino, acyloxy,
acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R.sup.3a
and R.sup.3b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.3a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and
R.sup.2a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and R.sup.4a are
taken together to form a propylene (--CH.sub.2CH.sub.2CH.sub.2--)
moiety or a butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--)
moiety;
[0206] each R.sup.4a and R.sup.4b is independently H, substituted
or unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, nitro,
substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy,
acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R.sup.4a
and R.sup.4b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.4a and R.sup.1 are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.2a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.3a
are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety;
[0207] each X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is independently
N, CH or CR.sup.6;
[0208] 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
[0209] each R.sup.6 is independently hydroxyl, nitro, cyano, halo,
C.sub.1-C.sub.8 perhaloalkyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, C.sub.1-C.sub.8 perhaloalkoxy, substituted or
unsubstituted C.sub.1-C.sub.8 alkoxy, substituted or unsubstituted
aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,
thioalkyl, --S(O)-alkyl, --S(O)-aryl, --S(O)-aralkyl, substituted
or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,
carbonylalkylenealkoxy, alkylsulfonylamino or acyl.
[0210] In one variation, compounds of the formula (IB) are
provided:
##STR00008##
or a salt or solvate thereof; wherein:
[0211] R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, thiol, thioalkyl, substituted or unsubstituted amino,
acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy,
or R.sup.1 and R.sup.2a are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1 and
R.sup.3a are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.1 and
R.sup.4a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety;
[0212] each R.sup.2a and R.sup.2b is independently H, substituted
or unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, hydroxyl,
alkoxy, nitro, substituted or unsubstituted amino, acyloxy,
acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R.sup.2a
and R.sup.2b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.2a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and
R.sup.3a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.2a and R.sup.4a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety;
[0213] each R.sup.3a and R.sup.3b is independently H, substituted
or unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, hydroxyl,
alkoxy, nitro, substituted or unsubstituted amino, acyloxy,
acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R.sup.3a
and R.sup.3b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.3a and R.sup.1 are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and
R.sup.2a are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.3a and R.sup.4a are
taken together to form a propylene (--CH.sub.2CH.sub.2CH.sub.2--)
moiety or a butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--)
moiety;
[0214] each R.sup.4a and R.sup.4b is independently H, substituted
or unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, nitro,
substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy,
acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R.sup.4a
and R.sup.4b are taken together with the carbon to which they are
attached to form a carbonyl moiety or a cycloalkyl moiety, or
R.sup.4a and R.sup.1 are taken together to form an ethylene
(--CH.sub.2CH.sub.2--) moiety or a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.2a are
taken together to form a methylene (--CH.sub.2--) moiety or an
ethylene (--CH.sub.2CH.sub.2--) moiety, or R.sup.4a and R.sup.3a
are taken together to form a propylene
(--CH.sub.2CH.sub.2CH.sub.2--) moiety or a butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) moiety;
[0215] each X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is independently
N, CH or CR.sup.6;
[0216] 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
[0217] each R.sup.6 is independently hydroxyl, nitro, cyano, halo,
C.sub.1-C.sub.8 perhaloalkyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, C.sub.1-C.sub.8 perhaloalkoxy, substituted or
unsubstituted C.sub.1-C.sub.8 alkoxy, substituted or unsubstituted
aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,
thioalkyl, substituted or unsubstituted amino, acylamino,
aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl,
sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino
or acyl.
[0218] In one variation, compounds of the formula (IB), and salts
and solvates thereof, are embraced, provided that at least one of
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CH or CR.sup.6. In another
variation, at least two of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is
CH or CR.sup.6.
[0219] 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: [0220] (xxi) when Q is an
unsubstituted aryl, the aryl group is other than phenyl; [0221]
(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(.dbd.NH)NH.sub.2; [0222] (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 X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is N or
CR.sup.6; and (c) none of R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a,
R.sup.3b, R.sup.4a and R.sup.4b are taken together to form a ring;
[0223] (xxiv) when none of R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a,
R.sup.3b, R.sup.4a and R.sub.4b are 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 X.sup.1, X.sup.2,
X.sup.3 and X.sup.4 is N or CR.sup.6; and (b) the phenyl
substituent is other than --OCH.sub.3 and a substituted pyridyl;
[0224] (xxv) when none of R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a,
R.sup.3b, R.sup.4a and R.sup.4b are 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 X.sup.1, X.sup.2,
X.sup.3 and X.sup.4 is N or CR.sup.6; and (b) R.sup.1 is a
substituted or unsubstituted C.sub.1-C.sub.8 alkyl; [0225] (xxvi)
when Q is an unsubstituted cycloalkyl, then at least one of
provisions (a)-(c) applies: (a) at least one of X.sup.1, X.sup.2,
X.sup.3 and X.sup.4 is CR.sup.6; (b) none of R.sup.1, R.sup.2a,
R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b are taken
together to form a ring; and (c) the unsubstituted cycloalkyl has
greater than 3 annular carbon atoms; [0226] (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 X.sup.1, X.sup.2, X.sup.3 and X.sup.4
is CR.sup.6; (b) R.sup.1 is a substituted or unsubstituted
C.sub.1-C.sub.8 alkyl; (c) the substituted heterocyclyl group
contains an annular sulfur atom; and (d) the substituted
heterocyclyl group contains at least two annular heteroatoms;
[0227] (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 X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is CR.sup.6; (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; [0228] (xxix)
when none of R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b,
R.sup.4a and R.sup.4b are 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 X.sup.1, X.sup.2, X.sup.3 and
X.sup.4 are N or CR.sup.6; (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.
[0229] In some variations, provided are compounds of the formula
(IB), where R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b,
R.sup.4a, R.sup.4b, X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are 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.
[0230] In some variations, provided are compounds of the formula
(IB), where R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b,
R.sup.4a, R.sup.4b, X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are 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: [0231] (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 [0232] (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.
[0233] In some of these variations, one or more of provisions
(xxi)-(xxix) further apply.
[0234] In one variation, compounds of the formula (IB), and salts
and solvates thereof, are embraced, where R.sup.1, R.sup.2a,
R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, X.sup.1, X.sup.2,
X.sup.3 and X.sup.4 are 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:
[0235] (1) at least one of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is
CR.sup.6;
[0236] (2) when none of X.sup.1, X.sup.2 and X.sup.3 is N, and none
of R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and
R.sup.4b are taken together to form a ring, then Q is other than a
unsubstituted phenyl;
[0237] (3) when none of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is N,
and R.sup.2a and R.sup.4b are taken together with the carbon to
which they are attached to form a carbonyl moiety, then Q is other
than a 4-substituted phenyl group; and
[0238] (4) when each X.sup.1, X.sup.3 and X.sup.4 is CH, X.sup.2 is
CR.sup.6 where R.sup.6 is fluoro, and each R.sup.2a, R.sup.2b,
R.sup.3a, R.sup.3b, R and R is H, then Q is other than
4-fluorophenyl.
[0239] 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 C.sub.1-C.sub.8 unsubstituted alkyl
(e.g., methyl).
[0240] 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.
[0241] 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
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.1-C.sub.8
alkoxy, C.sub.1-C.sub.8 perhaloalkyl, C.sub.1-C.sub.8
perhaloalkoxy, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
substituted or unsubstituted aryl, substituted or unsubstituted
aryloxy, substituted or unsubstituted heteroaryl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aralkyl, substituted or
unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,
carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,
aminocarbonylalkoxy, aminosulfonyl, 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.
[0242] In one variation, the compound is of formula (IA) or (IB)
where at least one of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is N.
In another variation, one of X.sup.1, X.sup.2 and X.sup.3 is N. In
one variation, X.sup.1 is N and each X.sup.2, X.sup.3 and X.sup.4
is independently CH or CR.sup.6. In another variation, X.sup.2 is N
and each X.sup.1, X.sup.3 and X.sup.4 is independently CH or
CR.sup.6. In yet another variation, X.sup.3 is N and each X.sup.1,
X.sup.2 and X.sup.4 is independently CH or CR.sup.6. In yet another
variation, X.sup.4 is N and each X.sup.1, X.sup.2 and X.sup.3 is
independently CH or CR.sup.6. In another variation, two of X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is N. In one variation, each X.sup.1
and X.sup.3 is N, and X.sup.2 and X.sup.4 is independently CH or
CR.sup.6. In another variation, each X.sup.2 and X.sup.4 is N, and
X.sup.1 and X.sup.3 is independently CH or CR.sup.6. In another
variation, each X.sup.1 and X.sup.4 is N, and X.sup.2 and X.sup.3
is independently CH or CR.sup.6.
[0243] In one variation, the compound is of formula (IA) or (IB)
where at least one of X.sup.1-X.sup.4 is CR.sup.6 where R.sup.6 is
chloro. In such variation, X.sup.2 is CR.sup.6 where R.sup.6 is
chloro. In another variation, X.sup.2 is CR.sup.6 where R.sup.6 is
chloro, and X.sup.1 and X.sup.4 are each CH. In one aspect, the
compound is of formula (IA) or (IB) where at least one of
X.sup.1-X.sup.4 is CR.sup.6 where R.sup.6 is chloro (e.g., when
X.sup.2 is CR.sup.6 where R.sup.6 is 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, X.sup.2 is
CR.sup.6 where R.sup.6 is chloro, X.sup.1, X.sup.3 and X.sup.4 are
each CH, R.sup.1 is methyl or cyclopropyl and Q is an unsubstituted
aryl, a substituted aryl, an unsubstituted heteroaryl or a
substituted heteroaryl.
[0244] In specific variations, compounds of formula (IA) have the
structure:
##STR00009##
or a salt or solvate thereof; wherein R.sup.1, X.sup.1, X.sup.2,
X.sup.3, X.sup.4 and 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.
[0245] In one variation of formula (IA2), X.sup.2 is CH or CR.sup.6
where R.sup.6 is halo or substituted or unsubstituted
C.sub.1-C.sub.8 alkyl. In a particular variation of formula (IA2),
X.sup.2 is CR.sup.6 where R.sup.6 is halo (e.g., chloro). In
another particular variation of formula (IA2), X.sup.2 is CR.sup.6
where R.sup.6 is unsubstituted C.sub.1-C.sub.8 alkyl (e.g.,
methyl). In a particular variation of formula (IA2), X.sup.2 is 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), X.sup.2 is CH or CR.sup.6 where
R.sup.6 is halo or substituted or unsubstituted C.sub.1-C.sub.8
alkyl and Q is a substituted or unsubstituted heteroaryl. In one
aspect of formula (IA2), X.sup.2 is CR.sup.6 where R.sup.6 is a
C.sub.1-C.sub.8 alkyl (e.g., methyl) and Q is a substituted or
unsubstituted heteroaryl.
[0246] In another aspect of formula (IA2), X.sup.2 is CR.sup.6
where R.sup.6 is halo (e.g., chloro) and Q is a substituted or
unsubstituted heteroaryl. In another aspect of formula (IA2),
X.sup.2 is CH and Q is a substituted or unsubstituted heteroaryl.
In a further aspect of formula (IA2), X.sup.2 is CH or CR.sup.6
where R.sup.6 is methyl or chloro and Q is 4-pyridyl.
[0247] In one variation, compounds of the formula (IA3) are
provided, or a salt or solvate thereof, where R.sup.1 is a
substituted or unsubstituted C.sub.1-C.sub.8 alkyl; R.sup.6 is H,
halo, trifluoromethyl, a C.sub.1-C.sub.8 unsubstituted alkyl or a
substituted amino; and Q is substituted aryl or a substituted or
unsubstituted heteroaryl. In one variation of formula (IA3),
R.sup.1 is an unsubstituted C.sub.1-C.sub.8 alkyl or a
C.sub.1-C.sub.8 alkyl substituted with a halo or hydroxyl group. In
one such variation, R.sup.1 is methyl, 2-haloethyl (e.g.,
2-fluoroethyl), 2,2,2-trifluoroethyl, or a hydroxyl-substituted
pentyl group. In a particular variation of formula (IA3), R.sup.1
is --CH.sub.3, --CH.sub.2CH.sub.2F, --CH.sub.2CF.sub.3, or
--CH.sub.2CH.sub.2C(CH.sub.3).sub.2OH. In another variation of
formula (IA3), R.sup.6 is H, halo, methyl, trifluoromethyl, or a
substituted amino of the formula --N(H)(C.sub.1-C.sub.8
unsubstituted alkyl). When R.sup.6 is a halo (e.g., fluoro or
chloro), in one aspect R.sup.6 is chloro. In one variation of
formula (IA3), R.sup.6 is H, methyl or chloro. In one variation of
formula (IA3), R.sup.6 is methyl or chloro. When R.sup.6 is a
substituted amino of the formula --N(H)(C.sub.1-C.sub.8
unsubstituted alkyl), in one aspect C.sub.1-C.sub.8 unsubstituted
alkyl is a linear C.sub.1-C.sub.8 unsubstituted alkyl such as
methyl or ethyl. In a particular variation of formula (IA3),
R.sup.6 is --N(H)(CH.sub.3). It is understood that any R.sup.1 for
formula (IA3) may be combined with any R.sup.6 of 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 R.sup.1 is --CH.sub.3, --CH.sub.2CH.sub.2F,
--CH.sub.2CF.sub.3, or --CH.sub.2CH.sub.2C(CH.sub.3).sub.2OH and
R.sup.6 is H, chloro, fluoro, methyl, trifluoromethyl, or
--N(H)(CH.sub.3). Likewise, compounds of the formula (IA3) are
provided where R.sup.1 is methyl and R.sup.6 is H, halo, methyl or
a substituted amino of the formula --N(H)(C.sub.1-C.sub.8
unsubstituted alkyl). In one such aspect, compounds of the formula
(IA3) are provided where R.sup.1 is methyl and R.sup.6 is H, halo
or methyl. In one such aspect, compounds of the formula (IA3) are
provided where R.sup.1 is methyl and R.sup.6 is 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, C.sub.1-C.sub.8 alkoxy
(e.g., methoxy), an acylamino moiety of the formula
--C(O)NH(C.sub.1-C.sub.8 unsubstituted alkyl) or an acylamino
moiety of the formula --C(O)N(C.sub.1-C.sub.8 unsubstituted
alkyl).sub.2, such as 2-fluoro-phenyl, 4-fluoro-phenyl,
4-methoxy-phenyl, 4-(C(O)NH(CH.sub.3) and
4-(C(O)N(CH.sub.3).sub.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 C.sub.1-C.sub.8 alkoxy 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
C.sub.1-C.sub.8 alkoxy 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 R.sup.1
and/or R.sup.6 of 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 R.sup.1 is
--CH.sub.3, --CH.sub.2CH.sub.2F, --CH.sub.2CF.sub.3, or
--CH.sub.2CH.sub.2C(CH.sub.3).sub.2OH; R.sup.4 is H, chloro,
fluoro, methyl, trifluoromethyl, or --N(H)(CH.sub.3) 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 R.sup.1 is methyl; R.sup.6 is H, halo or
methyl and Q is an unsubstituted pyridyl.
[0248] 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.
[0249] 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 sp.sup.3 hybridized.
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.
[0250] 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.
[0251] In one variation, compounds of the formula (IA) are provided
where R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b
are each H; and the compounds are of the formula (IA4):
##STR00010##
or a salt or solvate thereof, wherein X.sup.1, X.sup.2, X.sup.3 and
X.sup.4 are as defined in formula (IA) and wherein:
[0252] R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, thiol, thioalkyl, substituted or unsubstituted amino,
acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl or
carbonylalkylenealkoxy;
[0253] either (i) one or more of X.sup.1, X.sup.2, X.sup.3 and
X.sup.4 is N or (ii) X.sup.1 and X.sup.3 are CH, X.sup.2 is
CR.sup.6 and X.sup.4 is N, CH or CR.sup.6; and
[0254] Q is an aromatic ring of the formula:
##STR00011##
where
[0255] Z is C, NH, N--CH.sub.3, O or S and the Z-containing
aromatic ring is attached to the parent structure at any available
ring position;
[0256] t is 0 or 1; and
[0257] 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,
[0258] provided that when X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are
each independently CH or CR.sup.6, then R.sup.1 is an unsubstituted
C.sub.1-C.sub.8 alkyl when W is a substituted amino, or (iii) H,
provided that when X, X.sup.2, X.sup.3 and X.sup.4 are each
independently CH or CR.sup.6, then W is H only when the
Z-containing ring is a 5-membered heteroaryl moiety.
[0259] In one variation, compounds of the formula (IA4) are
provided where at least one of X.sup.1, X.sup.2, X.sup.3 and
X.sup.4 is 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 X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is
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.
[0260] In another variation, compounds of the formula (IA4) are
provided wherein X.sup.1 and X.sup.3 are CH, X.sup.2 is CR.sup.6
and X.sup.4 is N, CH or CR.sup.6 and 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, X.sup.1, X.sup.3 and X.sup.4 are CH
and X.sup.2 is CR.sup.6. When X.sup.2 is CR.sup.6, in one
variation, R.sup.6 is selected from the group consisting of a
substituted or unsubstituted C.sub.1-C.sub.8alkyl, a substituted or
unsubstituted C.sub.3-C.sub.7cycloalkyl, halo, cyano and
trifluoromethyl. When X.sup.2 is CR.sup.6, in one variation R.sup.6
is an unsubstituted C.sub.1-C.sub.8 alkyl (such as methyl) or halo
(such as chloro). In some variations of formula (IA4), R.sup.1 is
selected from the group consisting of H, a substituted or
unsubstituted C.sub.1-C.sub.8alkyl, a substituted or unsubstituted
C.sub.3-C.sub.7cycloalkyl, 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 R.sup.1 alkaryl moiety is a
C.sub.4-C.sub.8alkyl. In some variations, R.sup.1 is an
unsubstituted C.sub.1-C.sub.8 alkyl (such as methyl). In a
particular variation, compounds of the formula (IA4) are provided
wherein X.sup.1, X.sup.3 and X.sup.4 are CH and X.sup.2 is
CR.sup.6, where R.sup.6 is selected from the group consisting of a
substituted or unsubstituted C.sub.1-C.sub.8alkyl, a substituted or
unsubstituted C.sub.3-C.sub.7cycloalkyl, halo, cyano and
trifluoromethyl, and R.sup.1 is selected from the group consisting
of H, a substituted or unsubstituted C.sub.1-C.sub.8alkyl, a
substituted or unsubstituted C.sub.3-C.sub.7cycloalkyl, 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 X.sup.1, X.sup.3 and X.sup.4 are
CH; X.sup.2 is CR.sup.6 where R.sup.6 is an unsubstituted
C.sub.1-C.sub.8 alkyl; 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.
[0261] In another variation, compounds of the formula (IA4) are
provided wherein X.sup.1 and X.sup.3 are CH; X.sup.2 is CR.sup.6;
X.sup.4 is N, CH or CR.sup.6; and W a substituted amino, provided
that when X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are each
independently CH or CR.sup.6, then R.sup.1 is an unsubstituted
C.sub.1-C.sub.8 alkyl. In one such variation, X.sup.1, X.sup.3 and
X.sup.4 are CH; X.sup.2 is CR.sup.6; R.sup.1 is an unsubstituted
C.sub.1-C.sub.8 alkyl and W is a substituted amino (e.g.,
dimethylamino). In another such variation, X.sup.1 and X.sup.3 are
CH, X.sup.2 is CR.sup.6; X.sup.4 is CH or CR.sup.6; R.sup.1 is an
unsubstituted C.sub.1-C.sub.8 alkyl and W is a substituted amino.
When X.sup.2 is CR.sup.6, in one variation R.sup.6 is an
unsubstituted C.sub.1-C.sub.8 alkyl (such as methyl) or a halo
(such as chloro). When R.sup.1 is an unsubstituted C.sub.1-C.sub.8
alkyl, in one variation R.sup.1 is 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 X.sup.1, X.sup.3 and X.sup.4 are CH; X.sup.2 is CR.sup.6
where R.sup.6 is an unsubstituted C.sub.1-C.sub.8 alkyl or halo;
and the Z-containing ring is a phenyl, thiophenyl or pyridyl ring
substituted with a substituted amino group (e.g.,
dimethylamino).
[0262] In another variation, compounds of the formula (IA4) are
provided wherein X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are each
independently CH or CR.sup.6; the Z-containing ring is a 5-membered
heteroaryl moiety (where Z is NH, N--CH.sub.3, O or S and t is 0)
and W is H. In one such variation, the Z-containing ring is
thiophene. In another variation, X.sup.1, X.sup.3 and X.sup.4 are
each CH and X.sup.2 is CR.sup.6. When X.sup.2 is CR.sup.6, in one
aspect R.sup.6 is selected from the group consisting of a
substituted or unsubstituted C.sub.1-C.sub.8alkyl, a substituted or
unsubstituted C.sub.3-C.sub.7cycloalkyl, halo, cyano and
trifluoromethyl, and in another aspect is an unsubstituted
C.sub.1-C.sub.8alkyl (such as methyl) or a halo (such as chloro).
In a further such variation, X.sup.1, X.sup.3 and X.sup.4 are each
CH; X.sup.2 is CR.sup.6 where R.sup.6 is an unsubstituted
C.sub.1-C.sub.8alkyl (such as methyl) or a halo (such as chloro);
R.sup.1 is an unsubstituted C.sub.1-C.sub.8alkyl (such as methyl);
the Z-containing ring is a 5-membered heteroaryl moiety and W is
H.
[0263] In one variation, compounds of the formula (IA4) are
provided where X.sup.1 and X.sup.3 are each CH, X.sup.2 is
CR.sup.6; and the compounds are of the formula (IA5):
##STR00012##
or a salt or solvate thereof, where R.sup.6 and X.sup.4 are as
defined in formula (IA) and wherein:
[0264] R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aryalkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, thiol, thioalkyl, substituted or unsubstituted amino,
acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl or
carbonylalkylenealkoxy;
[0265] Z is C, NH, N--CH.sub.3, O or S;
[0266] t is 0 or 1;
[0267] 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 R.sup.1 is a C.sub.1-C.sub.8 alkyl
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
[0268] wherein the Z-containing ring is aromatic and is attached to
the parent structure at any available ring position.
[0269] 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) X.sup.4 is CH; (ii) R.sup.1 is an
unsubstituted C.sub.1-C.sub.8 alkyl; (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) R.sup.6 is an
unsubstituted C.sub.1-C.sub.8 alkyl or halo.
[0270] 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.sup.A-Q.sup.B, wherein Q.sup.A
is substituted aryl or substituted heteroaryl and Q.sup.B is
substituted or unsubstituted aryl or substituted or unsubstituted
heteroaryl. In some embodiments, Q.sup.A is aryl (e.g., phenyl). In
some embodiments, Q.sup.A is a 6-membered heteroaryl containing one
annular heteroatom (e.g., pyridyl). In some embodiments, Q.sup.A is
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.sup.A is a 5-membered heteroaryl containing one annular
heteroatom (e.g., thiophenyl, furanyl and pyrrolyl). In some
embodiments, Q.sup.A is 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.sup.B is a substituted or unsubstituted aryl (e.g.,
phenyl, fluorophenyl and chlorophenyl). In some embodiments,
Q.sup.B is 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.sup.A moiety may be attached to
the parent structure at any viable annular atom of Q.sup.A. In some
embodiments, the bond between Q.sup.A and Q.sup.B is between any
viable annular atom of Q.sup.A and any viable annular atom of
Q.sup.B.
[0271] 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:
##STR00013## ##STR00014## ##STR00015## ##STR00016##
[0272] In one variation, compounds of the formula (IA) are
provided, where R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a
and R.sup.4b are each H; and the compounds have the structure
(IA6):
##STR00017##
or a salt or solvate thereof, where R.sup.6 and X.sup.1, X.sup.2,
X.sup.3 and X.sup.4 are as defined in formula (IA) and wherein:
[0273] R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, thiol, thioalkyl, substituted or unsubstituted amino,
acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl or
carbonylalkylenealkoxy;
[0274] either (1) one or more of X.sup.1, X.sup.2, X.sup.3 and
X.sup.4 is N or (ii) X.sup.1 and X.sup.3 are CH, X, is CRand
X.sup.4 is N, CH or CR.sup.6; and
[0275] 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 R.sup.1 is a
C.sub.1-C.sub.8 unsubstituted alkyl when W is a substituted
amino.
[0276] In one aspect of formula (IA6), one or more of X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is N. In one aspect, X.sup.1 is N and
X.sup.2, X.sup.3 and X.sup.4 are each CH. In another aspect,
X.sup.2 is N and X.sup.1, X.sup.3 and X.sup.4 are each CH. In
another aspect, X.sup.3 is N and X.sup.1, X.sup.2 and X.sup.4 are
each CH. In a further aspect, X.sup.4 is N and X.sup.1, X.sup.2 and
X.sup.3 are each CH. In one variation of formula (IA6), one of
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is N, one of X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is CR.sup.6 and two of X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 are CH. In one variation, X.sup.4 is
N, X.sup.1 and X.sup.3 are each CH and X.sup.2 is CR.sup.6.
[0277] In another aspect of formula (IA6), X.sup.1 and X.sup.3 are
CH, X.sup.2 is CR.sup.6 and X.sup.4 is N, CH or CR.sup.6. In one
such aspect, X.sup.2 is CR.sup.6 where R.sup.6 is selected from the
group consisting of a substituted or unsubstituted
C.sub.1-C.sub.8alkyl, a substituted or unsubstituted
C.sub.3-C.sub.7cycloalkyl, halo, cyano and trifluoromethyl. In
another variation, X.sup.1, X.sup.3 and X.sup.4 are each CH and
X.sup.2 is CR.sup.6. In another variation, X.sup.1, X.sup.3 and
X.sup.4 are each CH and X.sup.2 is CR.sup.6 where R.sup.6 is a
C.sub.1-C.sub.8 unsubstituted alkyl (e.g., methyl) or halo (e.g.,
chloro).
[0278] 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) X.sup.2 is
CR.sup.6 (where in one particular variation R.sup.6 is selected
from the group consisting of a substituted or unsubstituted
C.sub.1-C.sub.8alkyl, a substituted or unsubstituted
C.sub.3-C.sub.7cycloalkyl, halo, cyano and trifluoromethyl); (ii)
R.sup.1 is selected from the group consisting of H, a substituted
or unsubstituted C.sub.1-C.sub.8alkyl, a substituted or
unsubstituted C.sub.3-C.sub.7cycloalkyl, and an alkaryl, wherein
the alkaryl is bound to the parent structure via the alkyl portion
of the moiety; (iii) X.sup.1 and X.sup.3 are each CH;
[0279] (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), X.sup.1, X.sup.3 and X.sup.4 are each
CH; X.sup.2 is CR.sup.6 where R.sup.6 is a C.sub.1-C.sub.8
unsubstituted alkyl (e.g., methyl) or halo (e.g., chloro); R.sup.1
is selected from the group consisting of H, a substituted or
unsubstituted C.sub.1-C.sub.8alkyl, a substituted or unsubstituted
C.sub.3-C.sub.7cycloalkyl, 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.
[0280] In some instances, compounds of the formula (IA6) are
provided wherein X.sup.1 and X.sup.3 are each CH and the compound
is of the formula (A1) or (A2):
##STR00018##
or a salt or solvate thereof; wherein R.sup.6 and X.sup.4 are
defined as for formulae (IA) and, where applicable, any variation
thereof detailed herein, and wherein:
[0281] R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, thiol, thioalkyl, substituted or unsubstituted amino,
acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl or
carbonylalkylenealkoxy;
[0282] W is a substituted amino, substituted or unsubstituted aryl,
or substituted or unsubstituted heteroaryl. In one particular
aspect of this variation, X.sup.4 is N. In another particular
aspect of this variation, X.sup.4 is CH. In another aspect of this
variation, R.sup.1 and R.sup.6 are each a substituted or
unsubstituted C.sub.1-C.sub.8 alkyl. In one particular aspect of
this variation, R.sup.1 and R.sup.6 are 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.
[0283] 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.
[0284] In one variation, compounds of the formula (IA) are provided
wherein X.sup.1 and X.sup.3 are each CH, R.sup.2a, R.sup.2b,
R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b are each H and the
compounds are of the formula (IA7):
##STR00019##
or a salt or solvate thereof, where R.sup.6 and X.sup.1, X.sup.2,
X.sup.3 and X.sup.4 are as defined in formula (IA) and wherein:
[0285] R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, thiol, thioalkyl, substituted or unsubstituted amino,
acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl or
carbonylalkylenealkoxy;
[0286] either (i) one or more of X.sup.1, X.sup.2, X.sup.3 and
X.sup.4 is N or (ii) X.sup.1 and X.sup.3 are CH, X.sup.2 is
CR.sup.6 and X.sup.4 is N, CH or CR.sup.6;
[0287] W is H, hydroxyl, halo, nitro, cyano, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8 perhaloalkyl,
C.sub.1-C.sub.8 perhaloalkoxy, substituted or unsubstituted
C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted aryloxy, substituted or unsubstituted
heteroaryl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,
substituted or unsubstituted amino, aminoacyl, acyl, acylamino,
acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl,
aminocarbonylamino, aminocarbonylalkoxy, aminosulfonyl or
sulfonylamino; and
[0288] Z is NH, N--CH.sub.3, O or S.
[0289] In one aspect of formula (IA7), one or more of X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is N. In one aspect, X.sup.1 is N and
X.sup.2, X.sup.3 and X.sup.4 are each CH. In another aspect,
X.sup.2 is N and X.sup.1, X.sup.3 and X.sup.4 are each CH. In
another aspect, X.sup.3 is N and X.sup.1, X.sup.2 and X.sup.4 are
each CH. In a further aspect, X.sup.4 is N and
[0290] X.sup.1, X.sup.2 and X.sup.3 are each CH. In one variation
of formula (IA7), one of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is
N, one of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CR.sup.6 and two
of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are CH. In one variation,
X.sup.4 is N, X.sup.1 and X.sup.3 are each CH and X.sup.2 is
CR.sup.6.
[0291] In another aspect of formula (IA7), X.sup.1 and X.sup.3 are
CH, X.sup.2 is CR and X is N, CH or CR.sup.6. In one such aspect,
X.sup.2 is CR.sup.6 where R.sup.6 is selected from the group
consisting of a substituted or unsubstituted C.sub.1-C.sub.8alkyl,
a substituted or unsubstituted C.sub.3-C.sub.7cycloalkyl, halo,
cyano and trifluoromethyl. In another variation, X.sup.1, X.sup.3
and X.sup.4 are each CH and X.sup.2 is CR.sup.6. In another
variation, X.sup.1, X.sup.3 and X.sup.4 are each CH and X.sup.2 is
CR.sup.6 where R.sup.6 is a C.sub.1-C.sub.8 unsubstituted alkyl
(e.g., methyl) or halo (e.g., chloro).
[0292] 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) X.sup.2 is
CR.sup.6 (where in one particular variation R.sup.6 is selected
from the group consisting of a substituted or unsubstituted
C.sub.1-C.sub.8alkyl, a substituted or unsubstituted
C.sub.3-C.sub.7cycloalkyl, halo, cyano and trifluoromethyl); (ii)
R.sup.1 is selected from the group consisting of H, a substituted
or unsubstituted C.sub.1-C.sub.8alkyl, a substituted or
unsubstituted C.sub.3-C.sub.7cycloalkyl, and an alkaryl, wherein
the alkaryl is bound to the parent structure via the alkyl portion
of the moiety; (iii) X.sup.1 and X.sup.3 are each CH; (iv) X.sup.4
is 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) R.sup.1 and
R.sup.6 are each a substituted or unsubstituted C.sub.1-C.sub.8
alkyl; and (x) R.sup.1 is methyl and R.sup.6 is halo.
[0293] In particular variations of formula (IA7), compounds are
provided wherein X.sup.1 and X.sup.3 are each CH and the compounds
are of the formulae (B1)-(B6):
##STR00020##
or a salt or solvate thereof; wherein R.sup.6 and X.sup.4 are
defined as for formulae (IA) and, where applicable, any variation
thereof detailed herein, and wherein;
[0294] R is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, thiol, thioalkyl, substituted or unsubstituted amino,
acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl or
carbonylalkylenealkoxy;
[0295] Z is NH, N--CH.sub.3, O or S, and W is H, hydroxyl, halo,
nitro, cyano, substituted or unsubstituted C.sub.1-C.sub.8 alkyl,
substituted or unsubstituted C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 perhaloalkyl, C.sub.1-C.sub.8 perhaloalkoxy,
substituted or unsubstituted C.sub.2-C.sub.8 alkenyl, substituted
or unsubstituted C.sub.2-C.sub.8 alkynyl, substituted or
unsubstituted aryl, substituted or unsubstituted aryloxy,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aralkyl, substituted or
unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,
carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,
aminocarbonylalkoxy, aminosulfonyl 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, X.sup.4 is N. In another
particular aspect of this variation, X.sup.4 is CH. In another
aspect of this variation, R.sup.1 and R.sup.6 are each a
substituted or unsubstituted C.sub.1-C.sub.8 alkyl. In another
particular aspect of this variation, R.sup.1 and R.sup.6 are
methyl. In another particular aspect of this variation, R.sup.1 is
methyl and R.sup.6 is 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.
[0296] 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.
[0297] In another variation, compounds of the formula (IA) are
provided wherein X.sup.1 and X.sup.3 are each CH, R.sup.2a,
R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and R.sub.4b are each H and
the compound is of the formula (IA8):
##STR00021##
or a salt or solvate thereof, where R.sup.6 and X.sup.1, X.sup.2,
X.sup.3 and X.sup.4 are as defined in formula (IA) and wherein:
[0298] R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, thiol, thioalkyl, substituted or unsubstituted amino,
acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl or
carbonylalkylenealkoxy;
[0299] either (i) one or more of X.sup.1, X.sup.2, X.sup.3 and
X.sup.4 is N or (ii) X.sup.1 and X.sup.3 are CH, X.sup.2 is
CR.sup.6 and X.sup.4 is N, CH or CR.sup.6; and
[0300] W is H, hydroxyl, halo, nitro, cyano, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8 perhaloalkyl,
C.sub.1-C.sub.8 perhaloalkoxy, substituted or unsubstituted
C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted aryloxy, substituted or unsubstituted
heteroaryl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,
substituted or unsubstituted amino, aminoacyl, acyl, acylamino,
acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl,
aminocarbonylamino, aminocarbonylalkoxy, aminosulfonyl or
sulfonylamino,
[0301] provided that when X.sup.1, X.sup.3 and X.sup.4 are each H
and X.sup.2 is CR.sup.6 where R.sup.6 is H or fluoro, W is other
than H.
[0302] In one aspect of formula (IA8), one or more of X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is N. In one aspect, X.sup.1 is N and
X.sup.2, X.sup.3 and X.sup.4 are each CH. In another aspect,
X.sup.2 is N and X.sup.1, X.sup.3 and X.sup.4 are each CH. In
another aspect, X.sup.3 is N and X.sup.1, X.sup.2 and X.sup.4 are
each CH. In a further aspect, X.sup.4 is N and X.sup.1, X.sup.2 and
X.sup.3 are each CH. In one variation of formula (IA8), one of
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is N, one of X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is CR.sup.6 and two of X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 are CH. In one variation, X.sup.4 is
N, X.sup.1 and X.sup.3 are each CH and X.sup.2 is CR.sup.6.
[0303] In another aspect of formula (IA8), X.sup.1 and X.sup.3 are
CH, X.sup.2 is CR and X is N, CH or CR.sup.6. In one such aspect,
X.sup.2 is CR.sup.6 where R.sup.6 is selected from the group
consisting of a substituted or unsubstituted C.sub.1-C.sub.8alkyl,
a substituted or unsubstituted C.sub.3-C.sub.7cycloalkyl, halo,
cyano and trifluoromethyl. In another variation, X.sup.1, X.sup.3
and X.sup.4 are each CH and X.sup.2 is CR.sup.6. In another
variation, X.sup.1, X.sup.3 and X.sup.4 are each CH and X.sup.2 is
CR.sup.6 where R.sup.6 is a C.sub.1-C.sub.8 unsubstituted alkyl
(e.g., methyl) or halo (e.g., chloro).
[0304] 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) X.sup.2 is
CR.sup.6 (where in one particular variation R.sup.6 is selected
from the group consisting of a substituted or unsubstituted
C.sub.1-C.sub.8alkyl, a substituted or unsubstituted
C.sub.3-C.sub.7cycloalkyl, halo, cyano and trifluoromethyl); (ii)
R.sup.1 is selected from the group consisting of H, a substituted
or unsubstituted C.sub.1-C.sub.8alkyl, a substituted or
unsubstituted C.sub.3-C.sub.7cycloalkyl, and an alkaryl, wherein
the alkaryl is bound to the parent structure via the alkyl portion
of the moiety; (iii) X.sup.1 and X.sup.3 are each CH; (iv) X.sup.4
is CH; (v) W is H, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl; (vi) R.sup.1 and R.sup.6
are each a substituted or unsubstituted C.sub.1-C.sub.8 alkyl; and
(vii) R.sup.1 is methyl and R.sup.6 is halo.
[0305] In particular variations of formula (IA8), compounds are
provided wherein X.sup.1 and X.sup.3 are each CH, and the compounds
are of the formulae (C1)-(C3):
##STR00022##
or a salt or solvate thereof; wherein R.sup.6 and X.sup.4 are
defined as for formulae (IA) and, where applicable, any variation
thereof detailed herein, and wherein:
[0306] R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, thiol, thioalkyl, substituted or unsubstituted amino,
acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl or
carbonylalkylenealkoxy;
[0307] W is, H, hydroxyl, halo, nitro, cyano, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8 perhaloalkyl,
C.sub.1-C.sub.8 perhaloalkoxy, substituted or unsubstituted
C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted aryloxy, substituted or unsubstituted
heteroaryl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,
substituted or unsubstituted amino, aminoacyl, acyl, acylamino,
acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl,
aminocarbonylamino, aminocarbonylalkoxy, aminosulfonyl or
sulfonylamino,
[0308] provided that when X.sup.4 if CH and R.sup.6 is H or fluoro,
then W is other than H.
[0309] 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, X.sup.4
is N. In another particular aspect of this variation, X.sup.4 is
CH. In another aspect of this variation, R.sup.1 and R.sup.6 are
each a substituted or unsubstituted C.sub.1-C.sub.8 alkyl. In one
particular aspect of this variation, R.sup.1 and R.sup.6 are
methyl. In another particular aspect of this variation, R.sup.1 is
methyl and R.sup.6 is 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.
[0310] 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.
[0311] In one variation, compounds of the formula (IA) are provided
wherein R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and
R.sup.4b are each H and the compounds are of the formula (IA9):
##STR00023##
or a salt or solvate thereof, wherein R.sup.6 and X.sup.1, X.sup.2,
X.sup.3 and X.sup.4 are as defined in formula (IA) and wherein:
[0312] R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, thiol, thioalkyl, substituted or unsubstituted amino,
acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,
aminosulfonyl, sulfonylamino, sulfonyl or
carbonylalkylenealkoxy;
[0313] either (i) one or more of X.sup.1, X.sup.2, X.sup.3 and
X.sup.4 is N or (ii) X.sup.1 and X.sup.3 are CH, X.sup.2 is
CR.sup.6 and X.sup.4 is N, CH or CR.sup.6; and
[0314] W is H, hydroxyl, halo, nitro, cyano, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8 perhaloalkyl,
C.sub.1-C.sub.8 perhaloalkoxy, substituted or unsubstituted
C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted aryloxy, substituted or unsubstituted
heteroaryl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,
substituted or unsubstituted amino, aminoacyl, acyl, acylamino,
acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl,
aminocarbonylamino, aminocarbonylalkoxy, aminosulfonyl or
sulfonylamino.
[0315] In one aspect of formula (IA9), one or more of X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is N. In one aspect, X.sup.1 is N and
X.sup.2, X.sup.3 and X.sup.4 are each CH. In another aspect,
X.sup.2 is N and X.sup.1, X.sup.3 and X.sup.4 are each CH. In
another aspect, X.sup.3 is N and X.sup.1, X.sup.2 and X.sup.4 are
each CH. In a further aspect, X.sup.4 is N and X.sup.1, X.sup.2 and
X.sup.3 are each CH. In one variation of formula (IA9), one of
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is N, one of X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is CR.sup.6 and two of X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 are CH. In one variation, X.sup.4 is
N, X.sup.1 and X.sup.3 are each CH and X.sup.2 is CR.sup.6.
[0316] In another aspect of formula (IA9), X.sup.1 and X.sup.3 are
CH, X.sup.2 is CR.sup.6 and X.sup.4 is N, CH or CR.sup.6. In one
such aspect, X.sup.2 is CR.sup.6 where R.sup.6 is selected from the
group consisting of a substituted or unsubstituted
C.sub.1-C.sub.8alkyl, a substituted or unsubstituted
C.sub.3-C.sub.7cycloalkyl, halo, cyano and trifluoromethyl. In
another variation, X.sup.1, X.sup.3 and X.sup.4 are each CH and
X.sup.2 is CR.sup.6. In another variation, X.sup.1, X.sup.3 and
X.sup.4 are each CH and X.sup.2 is CR.sup.6 where R.sup.6 is a
C.sub.1-C.sub.8 unsubstituted alkyl (e.g., methyl) or halo (e.g.,
chloro).
[0317] 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) X.sup.2 is
CR.sup.6 (where in one particular variation R.sup.6 is selected
from the group consisting of a substituted or unsubstituted
C.sub.1-C.sub.8alkyl, a substituted or unsubstituted
C.sub.3-C.sub.7cycloalkyl, halo, cyano and trifluoromethyl); (ii)
R.sup.1 is selected from the group consisting of H, a substituted
or unsubstituted C.sub.1-C.sub.8alkyl, a substituted or
unsubstituted C.sub.3-C.sub.7cycloalkyl, and an alkaryl, wherein
the alkaryl is bound to the parent structure via the alkyl portion
of the moiety; (iii) X.sup.1 and X.sup.3 are each CH; (iv) X.sup.4
is 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) R.sup.1 and R.sup.6
are each a substituted or unsubstituted C.sub.1-C.sub.8 alkyl; and
(x) R.sup.1 is methyl and R.sup.6 is halo.
[0318] 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.
[0319] The invention also embraces compounds of formula (J-1):
##STR00024##
or a salt or solvate thereof, wherein:
[0320] R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl or carbonylalkylenealkoxy;
[0321] each R.sup.2a, R.sup.2b R.sup.3a, R.sup.3b, R.sup.4a,
R.sup.4b, R.sup.10a and R.sup.10b is independently H, hydroxyl,
nitro, cyano, halo, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, substituted or unsubstituted C.sub.2-C.sub.8 alkenyl,
substituted or unsubstituted C.sub.2-C.sub.8 alkynyl, perhaloalkyl,
acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted aralkyl,
C.sub.1-C.sub.8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,
thioalkyl, substituted or unsubstituted amino, acylamino,
aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl,
sulfonylamino, sulfonyl, alkylsulfonylamino, or
carbonylalkylenealkoxy, or is taken together with the carbon to
which it is attached and a geminal R.sup.2(a/b), R.sup.3(a/b),
R.sup.4(a/b) or R.sup.10(a/b) to form a carbonyl moiety or a
cycloalkyl moiety;
[0322] each X.sup.1, X.sup.2 and X.sup.3 is independently N, CH or
CR.sup.6;
[0323] 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
[0324] each R is independently hydroxyl, nitro, cyano, halo,
C.sub.1-C.sub.8 perhaloalkyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, C.sub.1-C.sub.8 perhaloalkoxy, substituted or
unsubstituted C.sub.1-C.sub.8 alkoxy, substituted or unsubstituted
aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,
thioalkyl, --S(O)-alkyl, --S(O)-aryl, --S(O)-aralkyl, substituted
or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,
carbonylalkylenealkoxy, alkylsulfonylamino or acyl.
[0325] In one variation, provided are compounds of the formula
(J-1), wherein at least one of X.sup.1, X.sup.2, X.sup.3 and
X.sup.4 is CH or CR.sup.6. In another variation, at least two of
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CH or CR.sup.6.
[0326] In a particular embodiment, compounds of formula (J-1) are
provided wherein the ring comprising X.sup.1, X.sup.2, X.sup.3 and
X.sup.4 is a phenyl, pyridyl, pyrimidinyl or pyrazinyl ring,
optionally substituted with 0-3 R.sup.6 groups (i.e.,
(R.sup.6).sub.n where n is 0, 1, 2 or 3). In some such embodiments,
n is 1, 2 or 3 and each R.sup.6 is independently halo, methyl or
CF.sub.3.
[0327] In a particular variation, compounds of formula (J-1) have
the structure:
##STR00025##
or a salt or solvate thereof; wherein R.sup.1, R.sup.6, X.sup.1,
X.sup.2, X.sup.3, X.sup.4 and 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.
[0328] In one variation, compounds of the formula (J-1) have the
structure:
##STR00026##
[0329] or a salt or solvate thereof; wherein R.sup.1, R.sup.6,
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are 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--CH.sub.3, O or S, and W
is H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.1-C.sub.8
alkoxy, C.sub.1-C.sub.8 perhaloalkyl, C.sub.1-C.sub.8
perhaloalkoxy, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
substituted or unsubstituted aryl, substituted or unsubstituted
aryloxy, substituted or unsubstituted heteroaryl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aralkyl, substituted or
unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,
carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,
aminocarbonylalkoxy, aminosulfonyl, 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 X.sup.1, X.sup.2,
X.sup.3 or X.sup.4 (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.
[0330] The invention also embraces compounds of formula (K-1):
##STR00027##
or a salt or solvate thereof, wherein:
[0331] R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl or carbonylalkylenealkoxy;
[0332] each R.sup.2a, R.sup.2b R.sup.3a, R.sup.3b, R.sup.4a,
R.sup.4b, R.sup.10a and R.sup.10b is independently H, hydroxyl,
nitro, cyano, halo, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, substituted or unsubstituted C.sub.2-C.sub.8 alkenyl,
substituted or unsubstituted C.sub.2-C.sub.8 alkynyl, perhaloalkyl,
acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted aralkyl,
C.sub.1-C.sub.8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,
thioalkyl, substituted or unsubstituted amino, acylamino,
aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl,
sulfonylamino, sulfonyl, alkylsulfonylamino, or
carbonylalkylenealkoxy, or is taken together with the carbon to
which it is attached and a geminal R.sup.2(a/b), R.sup.3(a/b),
R.sup.(a/b) or R.sup.10(a/b) to form a carbonyl moiety or a
cycloalkyl moiety;
[0333] each X.sup.1, X.sup.2 and X.sup.3 is independently N, CH or
CR.sup.6;
[0334] 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
[0335] each R.sup.6 is independently hydroxyl, nitro, cyano, halo,
C.sub.1-C.sub.8 perhaloalkyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, C.sub.1-C.sub.8 perhaloalkoxy, substituted or
unsubstituted C.sub.1-C.sub.8 alkoxy, substituted or unsubstituted
aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,
thioalkyl, --S(O)-alkyl, --S(O)-aryl, --S(O)-aralkyl, substituted
or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,
carbonylalkylenealkoxy, alkylsulfonylamino or acyl.
[0336] In one variation, provided are compounds of the formula
(K-1), wherein at least one of X.sup.1, X.sup.2, X.sup.3 and
X.sup.4 is CH or CR.sup.6. In another variation, at least two of
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CH or CR.sup.6.
[0337] In a particular variation, compounds of formula (K-1) have
the structure:
##STR00028##
or a salt or solvate thereof; wherein R.sup.1, X.sup.1, X.sup.2,
X.sup.3, X.sup.4 and 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.
[0338] In one variation, compounds of the formula (K-1) have the
structure:
##STR00029##
or a salt or solvate thereof; wherein R.sup.1, R.sup.6, X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 are 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--CH.sub.3, O or S, and W is H,
hydroxyl, halo, nitro, cyano, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.1-C.sub.8
alkoxy, C.sub.1-C.sub.8 perhaloalkyl, C.sub.1-C.sub.8
perhaloalkoxy, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
substituted or unsubstituted aryl, substituted or unsubstituted
aryloxy, substituted or unsubstituted heteroaryl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aralkyl, substituted or
unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,
carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,
aminocarbonylalkoxy aminosulfonyl, sulfonylamino. 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 X.sup.1, X.sup.2, X.sup.3 or X.sup.4 is 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.
[0339] 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.
[0340] 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 R.sup.1 is H, hydroxyl,
substituted or unsubstituted C.sub.1-C.sub.8 alkyl, substituted or
unsubstituted C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, perhaloalkyl, acyl, acyloxy,
carbonylalkoxy, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted aralkyl, C.sub.1-C.sub.8
perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or
unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,
aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or
carbonylalkylenealkoxy. In specific embodiments, R.sup.1 is a
substituted or unsubstituted C.sub.1-C.sub.8 alkyl, acyl, acyloxy,
carbonylalkoxy, substituted or unsubstituted heterocyclyl or
substituted or unsubstituted aryl. In more specific embodiments,
R.sup.1 is an unsubstituted C.sub.1-C.sub.8 alkyl such as methyl
and cyclopropyl.
[0341] In certain embodiments, compounds are provided wherein
R.sup.1 is H, hydroxyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aralkyl, C.sub.1-C.sub.8 perhaloalkoxy, alkoxy,
aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl,
aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,
sulfonyl or carbonylalkylenealkoxy. In more specific embodiments,
R.sup.1 is a sulfonyl such as --SO.sub.2-alkyl, --SO.sub.2-aryl and
--SO.sub.2-aralkyl.
[0342] In certain embodiments, compounds are provided where R.sup.1
is selected from the following moieties:
##STR00030##
[0343] In certain embodiments, compounds are provided where each
R.sup.2a and R.sup.2b is independently H, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, hydroxyl, alkoxy,
nitro or R.sup.2a and R.sup.2b are taken together to form a
carbonyl moiety. In specific embodiments, each R.sup.2a and
R.sup.2b is independently H, methyl, fluoro or R.sup.2a and
R.sup.2b are taken together to form a carbonyl moiety. In a
specific embodiment, R.sup.2a and R.sup.2b are both H.
[0344] In certain embodiments, compounds are provided where each
R.sup.3a and R.sup.3b is independently H, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, hydroxyl, alkoxy,
nitro or R.sup.3a and R.sup.3b are taken together to form a
carbonyl moiety. In specific embodiments, each R.sup.3a and
R.sup.3b is independently H or fluoro. In another specific
embodiment, R.sup.3a and R.sup.3b are both H. In a further specific
embodiment, R.sup.3a and R.sup.3b are both H and R.sup.4a and
R.sup.4b are both H.
[0345] In certain embodiments, compounds are provided where each
R.sup.4a and R.sup.4b is independently H, substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, hydroxyl, alkoxy,
nitro or R.sup.4a and R.sup.4b are taken together to form a
carbonyl moiety. In specific embodiments, each R.sup.4a and
R.sup.4b is independently H, halo, hydroxyl or methyl or R.sup.4a
and R.sup.4b are taken together to form a carbonyl moiety. In
another specific embodiment, R.sup.4a and R.sup.4b are both H. In a
further specific embodiment, R.sup.2a and R.sup.2b are both H and
R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b are each H.
[0346] In certain embodiments, compounds are provided where each
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is independently N, CH or
CR.sup.6. In certain embodiments, each X.sup.1, X.sup.2, X.sup.3
and X.sup.4 is CH or CR.sup.6, such that the ring comprising
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is an optionally substituted
phenyl ring. In specific embodiments, X.sup.2 is CR.sup.6 where
R.sup.6 is halo or alkyl and X.sup.1, X.sup.3 and X.sup.4 are each
CH. In other embodiments, one of X.sup.1, X.sup.2, X.sup.3 and
X.sup.4 is N, and the others are CH or CR.sup.6, such that the ring
is an optionally substituted pyridine ring. In further embodiments,
two of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are N, and the other
is CH or CR.sup.6, such that the ring is an optionally substituted
pyrimidine or pyrazine ring.
[0347] In certain embodiments, compounds are provided where each R
, where present, is independently hydroxyl, nitro, cyano, halo,
C.sub.1-C.sub.8 perhaloalkyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, C.sub.1-C.sub.8 perhaloalkoxy, substituted or
unsubstituted C.sub.1-C.sub.8 alkoxy, substituted or unsubstituted
aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,
thioalkyl, substituted or unsubstituted amino, acylamino,
aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl,
sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino
or acyl. In one variation, at least one of X.sup.1-X.sup.4 is
CR.sup.6 where R.sup.6 is halo. In a particular variation, one of
X.sup.1-X.sup.4 is CR.sup.6 where R.sup.6 is chloro and the others
are CH. In a specific variation, X.sup.1, X.sup.3 and X.sup.4 are
each CH and X.sup.2 is CR.sup.6 where R.sup.6 is chloro.
[0348] In certain embodiments, compounds are provided where each
R.sup.6, where present, is independently hydroxyl, halo,
C.sub.1-C.sub.8 perhaloalkyl, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, C.sub.1-C.sub.8 perhaloalkoxy, C.sub.1-C.sub.8 alkoxy,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aralkyl, thioalkyl, substituted or unsubstituted
amino, alkylsulfonylamino or acyl. In further embodiments, each
R.sup.6, where present, is independently hydroxyl, halo,
C.sub.1-C.sub.4 perhaloalkyl, substituted or unsubstituted
C.sub.1-C.sub.4 alkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, or C.sub.1-C.sub.4 alkoxy;
or in still a further variation, each R.sup.6, where present, is
independently halo, unsubstituted C.sub.1-C.sub.4 alkyl or
C.sub.1-C.sub.4 perhaloalkyl.
[0349] In specific embodiments, the ring comprising X.sup.1-X.sup.4
is a phenyl, pyridyl, pyrimidinyl or pyrazinyl ring, optionally
substituted with 0-2 R.sup.6 groups (i.e., (R.sup.6).sub.n) where n
is 0, 1 or 2. In some such embodiments, n is 1 or 2 and each
R.sup.6 is independently halo, methyl or CF.sub.3.
[0350] 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
C.sub.3-C.sub.8 cycloalkyl, substituted or unsubstituted
C.sub.3-C.sub.8 cycloalkenyl 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, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
perhaloalkyl, and C.sub.1-C.sub.4 alkoxy.
[0351] 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.
[0352] In certain embodiments, R.sup.1 is a substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, acyl, acyloxy, carbonylalkoxy,
substituted or unsubstituted heterocyclyl or substituted or
unsubstituted aryl; each R.sup.2a and R.sup.2b is independently H,
methyl, fluoro or R.sup.2a and R.sup.3b are taken together to form
a carbonyl moiety; each R.sup.3a and R.sup.3b is independently H or
fluoro; and each R.sup.4a and R.sup.4b is independently H, halo,
hydroxyl or methyl or R.sup.4a and R.sup.4b are taken together to
form a carbonyl moiety. In particular variations, R.sup.1 is an
unsubstituted C.sub.1-C.sub.8 alkyl and R.sup.2a, R.sup.2b,
R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b are each H. In still a
further variation, R.sup.1 is an unsubstituted C.sub.1-C.sub.8
alkyl, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and
R.sup.4b are 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, R.sup.1 is an unsubstituted C.sub.1-C.sub.8 alkyl,
R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b are
each H and X.sup.2 is CR.sup.6 where R.sup.6 is chloro. In yet a
further variation, R.sup.1 is an unsubstituted C.sub.1-C.sub.8
alkyl, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and
R.sup.4b are each H, X.sup.2 is CR.sup.6 where R.sup.6 is chloro
and Q is a substituted or unsubstituted aryl or a substituted or
substituted heteroaryl. In one such variation, Q is a substituted
phenyl.
[0353] In certain embodiments, compounds are provided where each
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is CH or CR.sup.6. In other
embodiments, at least one of X.sup.1, X.sup.2, X.sup.3 and X.sup.4
is N. Another variation provides a compound where at least two of
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are N. A further variation
provides a compound where two of X.sup.1, X.sup.2, X.sup.3 and
X.sup.4 are N and one of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is
CH or CR.sup.6. Compounds where one of X.sup.1, X.sup.2, X.sup.3
and X.sup.4 is N and two of X.sup.1, X.sup.2, X.sup.3 and X.sup.4
are CH or CR.sup.6 are also embraced by this invention.
[0354] In another variation, compounds are provided where wherein
the ring comprising X.sup.1-X.sup.4 is an aromatic moiety selected
from the following structures:
##STR00031##
where each R.sup.6 is as defined herein. In a particular variation,
each R.sup.6 is independently hydroxyl, halo, C.sub.1-C.sub.8
perhaloalkyl, substituted or unsubstituted C.sub.1-C.sub.8 alkyl,
substituted or unsubstituted C.sub.2-C.sub.8 alkenyl, substituted
or unsubstituted C.sub.2-C.sub.8 alkynyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
C.sub.1-C.sub.8 perhaloalkoxy, C.sub.1-C.sub.8 alkoxy, substituted
or unsubstituted heterocyclyl, substituted or unsubstituted
aralkyl, thioalkyl, substituted or amino, alkylsulfonylamino or
acyl. In a further variation, each R.sup.6 is independently halo,
unsubstituted C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 perhaloalkyl,
or C.sub.1-C.sub.4 alkoxy.
[0355] In still a further variation, compounds are provided wherein
the ring comprising X.sup.1-X.sup.4 is an aromatic moiety selected
from the following structures:
##STR00032##
wherein R.sup.6 is as defined herein; or in a particular variation,
where R.sup.6 is hydroxyl, halo, C.sub.1-C.sub.8 perhaloalkyl,
substituted or unsubstituted C.sub.1-C.sub.8 alkyl, substituted or
unsubstituted C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, C.sub.1-C.sub.8
perhaloalkoxy, C.sub.1-C.sub.8 alkoxy, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,
substituted or amino alkylsulfonylamino or acyl; or in still a
further variation, where each R.sup.6 is independently halo,
unsubstituted C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 perhaloalkyl,
or C.sub.1-C.sub.4 alkoxy.
[0356] In a further variation, compounds are provided wherein the
ring comprising X.sup.1-X.sup.4 is an aromatic moiety selected from
the following structures:
##STR00033## ##STR00034##
[0357] Any formula detailed herein, where applicable, may in one
variation have X.sup.1, X.sup.2, X.sup.3 and X.sup.4 taken together
to provide an aromatic moiety detailed herein above. It is
understood that by "where applicable" it is intended that in one
variation such X.sup.1, X.sup.2, X.sup.3 and X.sup.4 groups 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 X.sup.1, X.sup.2, X.sup.3 and
X.sup.4 groups 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 X.sup.1, X.sup.2, X.sup.3 and X.sup.4
groups are taken together provide a pyridyl moiety.
[0358] In another embodiment, compounds are provided wherein
X.sup.1-X.sup.4 are as defined herein or as detailed in any
variation herein, where R.sup.1 is H, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, 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 X.sup.1-X.sup.4 are as defined herein or as
detailed in any variation herein, where R.sup.1 is a substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, acyl, acyloxy, carbonylalkoxy,
substituted or unsubstituted heterocyclyl or substituted or
unsubstituted aryl. In a particular variation, compounds are
provided wherein X.sup.1-X.sup.4 are as defined herein or as
detailed in any variation herein, where R.sup.1 is 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.
[0359] In another variation, the compound of the invention is
provided where X.sup.1-X.sup.4 and R.sup.1 are as defined herein or
as detailed in any variation herein, where R.sup.2a and R.sup.2b
are independently H, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, halo, cyano, nitro or R.sup.2a and R.sup.3b are taken
together to form a carbonyl moiety and each R.sup.3a and R.sup.3b
is independently H, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, halo, cyano or nitro. In another variation, the compound of
the invention is provided where X.sup.1-X.sup.3 and R.sup.1 are as
defined herein or as detailed in any variation herein, where each
R.sup.2a and R.sup.2b is independently H, unsubstituted
C.sub.1-C.sub.8 alkyl, halo or R.sup.2a and R.sup.2b are taken
together to form a carbonyl moiety and each R.sup.3a and R.sup.3b
is independently H, unsubstituted C.sub.1-C.sub.8 alkyl, halo or
R.sup.3a and R.sup.3b are taken together to form a carbonyl moiety.
In still a further variation, the compound of the invention is
provided where X.sup.1-X.sup.4 and R.sup.1 are as defined herein or
as detailed in any variation herein, where each R.sup.2a and
R.sup.2b is independently H, unsubstituted C.sub.1-C.sub.8 alkyl,
halo or R.sup.2a and R.sup.2b are taken together to form a carbonyl
moiety; and each R.sup.3a and
[0360] R.sup.3b is independently H, unsubstituted C.sub.1-C.sub.8
alkyl, halo or R.sup.3a and R.sup.3b are taken together to form a
carbonyl moiety. The invention also embraces compounds of the
invention where X.sup.1-X.sup.4 and
[0361] R.sup.1 are as defined herein or as detailed in any
variation herein, where each R.sup.2a and R.sup.2b is independently
H, methyl, halo or R.sup.2a and R.sup.2b are taken together to form
a carbonyl moiety and each R.sup.3a and R.sup.3b is independently
H, methyl, halo or R.sup.3a and R.sup.3b are taken together to form
a carbonyl moiety.
[0362] The invention further embraces compounds of the invention
according to formula (IA) or (IB), where X.sup.1-X.sup.4 and
R.sup.1 are as defined herein or as detailed in any variation
herein, where each R.sup.2a, R.sup.2b, R.sup.3a and R.sup.3b is H.
In one variation, a compound of the invention is of the formula
(IA) or (IB) where X.sup.1-X.sup.4 and R.sup.1 are as defined
herein or as detailed in any variation herein, where at least one
of R.sup.2a, R.sup.2b, R.sup.3a and R.sup.3b is a substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano, nitro or is taken
together with a geminal R.sup.2 or R.sup.3 to form a carbonyl
moiety.
[0363] In another variation, a compound of the invention is of the
formula (IA) or (IB) where X.sup.1-X.sup.4 and R.sup.1 are as
defined herein or as detailed in any variation herein, where at
least two of R.sup.2a, R.sup.2b, R.sup.3a and R.sup.3b is a
substituted or unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano,
nitro or is taken together with a geminal R.sup.2 or R.sup.3 to
form a carbonyl moiety. In yet another variation, a compound of the
invention is of the formula (IA) or (IB) where X.sup.1-X.sup.4 and
R are as defined herein or as detailed in any variation herein,
where at least one of R.sup.2a, R.sup.2b, R.sup.3a and R.sup.3b is
fluoro or methyl or is taken together with a geminal R.sup.2 or
R.sup.3 to form a carbonyl moiety.
[0364] In still another variation, a compound of the invention is
of the formula (IA) or (IB) where X.sup.1-X.sup.4 and R.sup.1 are
as defined herein or as detailed in any variation herein, where
either R.sup.2a and R.sup.2b or R.sup.3a and R.sup.3b are each
methyl or fluoro (e.g., both R.sup.2a and R.sup.2b are methyl or
one is fluoro and one is methyl) or are taken together to form a
carbonyl moiety. In one variation, R.sup.2a and R.sup.2b are taken
together to form a carbonyl moiety. In another variation, at least
one of R.sup.2a and R.sup.2b is hydroxyl or alkoxy. In a particular
variation, each R.sup.2a and R.sup.2b is independently H,
substituted or unsubstituted C.sub.1-C.sub.8 alkyl, halo, cyano,
nitro or R.sup.2a and R.sup.2b are taken together to form a
carbonyl moiety. In another variation, each R.sup.2a and R.sup.2b
is independently H, substituted or unsubstituted C.sub.1-C.sub.8
alkyl, halo, cyano, nitro or R.sup.2a and R.sup.2b are taken
together to form a carbonyl moiety.
[0365] The invention also embraces compounds according to formula
(IA) or (IB), where X.sup.1-X.sup.4, R.sup.1, R.sup.2a, R.sup.2b,
R.sup.3a and R.sup.3b are as defined herein or as detailed in any
variation herein, where each R.sup.4a and R.sup.4b is independently
H, halo, an unsubstituted C.sub.1-C.sub.8 alkyl, hydroxyl or
R.sup.4a and R.sup.4b are taken together to form a carbonyl moiety.
Also embraced are compounds according to formula (IA) or (IB),
where X.sup.1-X.sup.4, R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a and
R.sup.3b are as defined herein or as detailed in any variation
herein, where each R.sup.4a and R.sup.4b is independently H, halo,
an unsubstituted C.sub.1-C.sub.4 alkyl, hydroxyl or R.sup.4a and
R.sup.4b are taken together to form a carbonyl moiety. In another
variation, a compound of the invention is of the formula (IA) or
(IB), where X.sup.1-X.sup.4, R.sup.1, R.sup.2, R.sup.2b, R.sup.3a
and R.sup.3b are as defined herein or as detailed in any variation
herein, where each R.sup.4a and R.sup.4b is independently H, bromo,
methyl, hydroxyl or R.sup.4a and R.sup.4b are taken together to
form a carbonyl moiety.
[0366] In yet another variation, a compound of the invention is of
the formula (IA) or (IB), where X.sup.1-X.sup.4, R.sup.1, R.sup.2a,
R.sup.2b, R.sup.3a and R.sup.3b are as defined herein or as
detailed in any variation herein, where at least one of R.sup.4a
and R.sup.4b is an unsubstituted C.sub.1-C.sub.8 alkyl, hydroxyl,
halo or R.sup.4a and R.sup.4b are 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 X.sup.1-X.sup.4, R.sup.1,
R.sup.2a, R.sup.2b, R.sup.3a and R.sup.3b are as defined herein or
as detailed in any variation herein, where at least one of R.sup.4a
and R.sup.4b is methyl, bromo, hydroxyl or R.sup.4a and R.sup.4b
are taken together to form a carbonyl moiety.
[0367] In another variation, a compound of the invention is of the
formula (IA) or (IB), where X.sup.1-X.sup.4, R.sup.1, R.sup.2a,
R.sup.2b, R.sup.3a and R.sup.3b are as defined herein or as
detailed in any variation herein, where both R.sup.4a and R.sup.4b
are methyl. In another variation, a compound of the invention is of
the formula (IA) or (IB), where X.sup.1-X.sup.4, R.sup.1, R.sup.2a,
R.sup.2b, R.sup.3a and R.sup.3b are as defined herein or as
detailed in any variation herein, where R.sup.4a and R.sup.4b are
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, R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a and R.sup.3b are as
defined herein or as detailed in any variation herein, where
R.sup.4a is H and R.sup.4b is methyl. In another variation, a
compound of the invention is of the formula (IA) or (IB), where
X.sup.1-X.sup.4, R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a and R.sup.3b
are as defined herein or as detailed in any variation herein, where
R.sup.4a is H and R.sup.4b is bromo. When the carbon of formula
(IA) or (IB) bearing R.sup.4a and R.sup.4b is 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.
[0368] In one variation, a compound of the invention is of the
formula (IA) or (IB) wherein the ring comprising N, R.sup.2a,
R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b is a moiety
selected from the following structures:
##STR00035##
wherein R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a
and R.sup.4b are as defined for formula (IA) or (IB), and p is 1 or
2.
[0369] In another variation, a compound of the invention is of the
formula (IA) or (IB) wherein the ring comprising N, R.sup.2a,
R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b is a moiety
selected from the following structures:
##STR00036##
wherein R.sup.1, R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a
and R.sup.4b are as defined for formula (Ia), and p is 1 or 2.
[0370] In another variation, a compound of the invention is of the
formula (IA) or (IB) wherein the ring comprising N, R.sup.2a,
R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b is a moiety
selected from the following structures:
##STR00037##
[0371] In another variation, a compound of the invention is of the
formula (IA) or (IB) wherein the ring comprising N, R.sup.2a,
R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b is a moiety
selected from the following structures:
##STR00038##
[0372] 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
##STR00039##
[0373] 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.
[0374] In some embodiments, the ring comprising N, R.sup.2a,
R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b is a moiety
selected from the following structures:
##STR00040##
where R.sup.1 in 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.sup.2a, R.sup.2b, R, R, Rand
R.sup.b is a moiety selected from the following structures:
##STR00041##
where R.sup.1 is 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.
[0375] 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 C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halo
or C.sub.1-C.sub.4 perhaloalkyl moiety.
[0376] 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
C.sub.3-C.sub.8 cycloalkyl or a substituted or unsubstituted
heterocyclyl. In another variation, Q is a substituted or
unsubstituted C.sub.3-C.sub.8 cycloalkyl 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,
CF.sub.3, methoxy or halo group.
[0377] 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
C.sub.3-C.sub.8 cycloalkyl 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.
[0378] In still another variation, a compound of the invention is
provided where Q is a moiety selected from the structures:
##STR00042##
wherein each R.sup.9 is independently a halo, cyano, nitro,
perhaloalkyl (C.sub.1-C.sub.8), perhaloalkoxy (C.sub.1-C.sub.8),
substituted or unsubstituted C.sub.1-C.sub.8 alkyl, substituted or
unsubstituted C.sub.2-C.sub.8 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.8 alkynyl, 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 R.sup.9 group. In another variation, Q is
substituted with only one R.sup.9 group. In one variation, Q is
substituted with two R.sup.9 groups. In another variation, Q is
substituted with two vicinal R.sup.9 groups 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
(R.sup.9).sub.0 such that each Q either contains no R.sup.9
functionality or a moiety of the formula N--R.sup.9.
[0379] In another variation, a compound of the invention is
provided where Q is a moiety selected from the structures:
##STR00043##
and wherein R.sup.9 is 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:
##STR00044##
and R.sup.9 is 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
##STR00045##
where each R.sup.9 is independently alkyl, perhaloalkyl or
halo.
[0380] In another variation, a compound of the invention is
provided where Q is a moiety selected from the structures:
##STR00046##
wherein each R.sup.9 is independently a halo, cyano, nitro,
perhaloalkyl, perhaloalkoxy, substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, substituted or unsubstituted C.sub.2-C.sub.8
alkenyl, substituted or unsubstituted C.sub.2-C.sub.8 alkynyl,
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 R.sup.9 group. In another variation, Q is
substituted with only one R.sup.9 group. In yet another variation,
Q is substituted with two R.sup.9 groups. In another variation, Q
is substituted with two vicinal R.sup.9 groups 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 (R.sup.9).sub.0 such that each Q either
contains no R.sup.9 functionality or a moiety of the formula
N--R.sup.9.
[0381] In any structure or variation detailed herein containing an
R.sup.9 group, in one variation, each R.sup.9 is independently a
substituted or unsubstituted C.sub.1-C.sub.4 alkyl, halo,
trifluoromethyl or hydroxyl. In another variation, each R.sup.9 is
independently methyl, --CH.sub.2OH, isopropyl, halo,
trifluoromethyl or hydroxyl.
[0382] In another variation, a compound of the invention is
provided where Q is an aromatic moiety selected from the
structures:
##STR00047## ##STR00048## ##STR00049##
[0383] In another variation, a compound of the invention is
provided where Q is a heteroaromatic moiety selected from the
structures:
##STR00050## ##STR00051## ##STR00052## ##STR00053##
##STR00054##
[0384] 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:
##STR00055## ##STR00056##
[0385] 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:
##STR00057##
[0386] In yet another variation, a compound of the invention is
provided where Q is selected from the structures:
##STR00058##
[0387] In a further variation, a compound of the invention is
provided where R.sup.1 is an unsubstituted alkyl, R.sup.2a,
R.sup.2b, R.sup.3a, R.sup.3b and R.sup.4 are each H, each X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is 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.
[0388] In yet a further variation, a compound of the invention is
provided where R is a substituted or unsubstituted C.sub.1-C.sub.8
alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl; each R.sup.2a and
R.sup.2b is independently H, unsubstituted C.sub.1-C.sub.8 alkyl or
halo; each R.sup.3a and R.sup.3b is independently H or halo; each
X.sup.1, X.sup.2 and X.sup.3 is CH or CR.sup.6, where R.sup.6 is as
defined or as detailed in a particular variation, R.sup.6 is halo,
pyridyl, methyl or trifluoromethyl; R.sup.4a and R.sup.4b are 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
C.sub.1-C.sub.8 alkyl, halo or perhaloalkyl moiety. In one
variation, a compound of the variation detailed herein is provided
wherein R.sup.1 is 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.
[0389] In still a further variation, a compound of the invention is
provided where R.sup.1 is a substituted or unsubstituted
C.sub.1-C.sub.8 alkyl; each R.sup.2a, R.sup.2b, R.sup.3a and
R.sup.3b is independently H or halo; each R.sup.6 is independently
halo, C.sub.1-C.sub.8 perhaloalkyl, substituted or a unsubstituted
C.sub.1-C.sub.8 alkyl; and Q is a substituted or unsubstituted
cyclohexyl, morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl
or pyrrolidinyl moiety. The invention also embraces a compound
where R.sup.1 is a methyl; at least one of X.sup.1 and X.sup.2 is
CR.sup.6, and each R.sup.6 is 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.
[0390] In a particular variation, a compound is provided where
R.sup.1 is a substituted or unsubstituted C.sub.1-C.sub.8 alkyl;
each R.sup.2a and R.sup.2b is independently H, a substituted or
unsubstituted C.sub.1-C.sub.8 alkyl or R.sup.2a and R.sup.2b are
taken together to form a carbonyl moiety; R.sup.3a and R.sup.3b are
both H; each R.sup.6 is independently halo or a substituted or
unsubstituted C.sub.1-C.sub.8 alkyl; each R.sup.4a and R.sup.4b is
independently H, halo, a substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, hydroxyl, alkoxy or R.sup.4a and R.sup.4b
are taken together to form a carbonyl moiety, provided that at
least one of R.sup.4a and R.sup.4b is 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, X.sup.1, X.sup.2
and X.sup.3 are CH or CR.sup.6 and each R.sup.6 is independently
halo or methyl.
[0391] 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.
[0392] 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).
[0393] In one embodiment, the invention relates to Compounds
described in Table 1, and uses thereof.
[0394] In another embodiment, the invention relates to Compounds
1-88, 100, 102-105 and 131-164, and uses thereof.
[0395] 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.
[0396] 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.
[0397] 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.
[0398] 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.
[0399] 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.
[0400] 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.
[0401] 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.
[0402] In one aspect, an adrenergic receptor .alpha..sub.2A
antagonist as provided herein exhibits the ability to cross the
blood-brain barrier. In another aspect, an adrenergic receptor
.alpha..sub.2A antagonist as provided herein is not able to cross
the blood-brain barrier. In one aspect, an adrenergic receptor
.alpha..sub.2A antagonist as provided herein exerts its therapeutic
effect in the brain only. In one aspect, an adrenergic receptor
.alpha..sub.2A antagonist as provided herein exerts its therapeutic
effect in the periphery only. In one aspect, an adrenergic receptor
.alpha..sub.2A antagonist as provided herein exerts its therapeutic
effect both in the brain and peripherally. In some embodiments, the
adrenergic receptor .alpha..sub.2A antagonist also exhibits
adrenergic receptor .alpha..sub.2A inverse agonist activity.
[0403] 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.
[0404] 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.
[0405] 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.
[0406] 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.
[0407] 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.
[0408] 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.sup.th ed. (2000), which is incorporated herein by
reference.
[0409] 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.
[0410] 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.
[0411] 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.
[0412] 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.
[0413] 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.
[0414] 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.
[0415] 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).
[0416] 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.
[0417] 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).
[0418] Representative compounds of the invention are shown in Table
1.
TABLE-US-00001 TABLE 1 Representative Compounds of the Invention
Compound No. Structure 1 ##STR00059## 2 ##STR00060## 3 ##STR00061##
4 ##STR00062## 5 ##STR00063## 6 ##STR00064## 7 ##STR00065## 8
##STR00066## 9 ##STR00067## 10 ##STR00068## 11 ##STR00069## 12
##STR00070## 13 ##STR00071## 14 ##STR00072## 15 ##STR00073## 16
##STR00074## 17 ##STR00075## 18 ##STR00076## 19 ##STR00077## 20
##STR00078## 21 ##STR00079## 22 ##STR00080## 23 ##STR00081## 24
##STR00082## 25 ##STR00083## 26 ##STR00084## 27 ##STR00085## 28
##STR00086## 29 ##STR00087## 30 ##STR00088## 31 ##STR00089## 32
##STR00090## 33 ##STR00091## 34 ##STR00092## 35 ##STR00093## 36
##STR00094## 37 ##STR00095## 38 ##STR00096## 39 ##STR00097## 40
##STR00098## 41 ##STR00099## 42 ##STR00100## 43 ##STR00101## 44
##STR00102## 45 ##STR00103## 46 ##STR00104## 47 ##STR00105## 48
##STR00106## 49 ##STR00107## 50 ##STR00108## 51 ##STR00109## 52
##STR00110## 53 ##STR00111## 54 ##STR00112## 55 ##STR00113## 56
##STR00114## 57 ##STR00115## 58 ##STR00116## 59 ##STR00117## 60
##STR00118## 61 ##STR00119## 62 ##STR00120## 63 ##STR00121## 64
##STR00122## 65 ##STR00123## 66 ##STR00124## 67 ##STR00125## 68
##STR00126## 69 ##STR00127## 70 ##STR00128## 71 ##STR00129## 72
##STR00130## 73 ##STR00131## 74 ##STR00132## 75 ##STR00133## 76
##STR00134## 77 ##STR00135## 78 ##STR00136## 79 ##STR00137## 80
##STR00138## 81 ##STR00139## 82 ##STR00140## 83 ##STR00141## 84
##STR00142## 85 ##STR00143## 86 ##STR00144## 87 ##STR00145## 88
##STR00146## 89 ##STR00147## 90 ##STR00148## 91 ##STR00149## 92
##STR00150## 93 ##STR00151## 94 ##STR00152## 95 ##STR00153## 96
##STR00154## 97 ##STR00155## 98 ##STR00156## 99 ##STR00157## 100
##STR00158## 101 ##STR00159## 102 ##STR00160## 103 ##STR00161## 104
##STR00162## 105 ##STR00163## 106 ##STR00164## 107 ##STR00165## 108
##STR00166## 109 ##STR00167## 110 ##STR00168## 111 ##STR00169## 112
##STR00170## 113 ##STR00171## 114 ##STR00172## 115 ##STR00173## 116
##STR00174## 117 ##STR00175## 118 ##STR00176## 119 ##STR00177## 120
##STR00178## 121 ##STR00179## 122 ##STR00180##
123 ##STR00181## 124 ##STR00182## 125 ##STR00183## 126 ##STR00184##
127 ##STR00185## 128 ##STR00186## 129 ##STR00187## 130 ##STR00188##
131 ##STR00189## 132 ##STR00190## 133 ##STR00191## 134 ##STR00192##
135 ##STR00193## 136 ##STR00194## 137 ##STR00195## 138 ##STR00196##
139 ##STR00197## 140 ##STR00198## 141 ##STR00199## 142 ##STR00200##
143 ##STR00201## 144 ##STR00202## 145 ##STR00203## 146 ##STR00204##
147 ##STR00205## 148 ##STR00206## 149 ##STR00207## 150 ##STR00208##
151 ##STR00209## 152 ##STR00210## 153 ##STR00211## 154 ##STR00212##
155 ##STR00213## 156 ##STR00214## 157 ##STR00215## 158 ##STR00216##
159 ##STR00217## 160 ##STR00218## 161 ##STR00219## 162 ##STR00220##
163 ##STR00221## 164 ##STR00222## 165 ##STR00223## 166 ##STR00224##
167 ##STR00225## 168 ##STR00226## 169 ##STR00227## 170 ##STR00228##
171 ##STR00229## 172 ##STR00230## 173 ##STR00231## 174 ##STR00232##
175 ##STR00233## 176 ##STR00234## 177 ##STR00235## 178 ##STR00236##
179 ##STR00237## 180 ##STR00238## 181 ##STR00239## 182 ##STR00240##
183 ##STR00241## 184 ##STR00242## 185 ##STR00243## 186 ##STR00244##
187 ##STR00245## 188 ##STR00246## 189 ##STR00247## 190 ##STR00248##
191 ##STR00249## 192 ##STR00250## 193 ##STR00251## 194 ##STR00252##
195 ##STR00253## 196 ##STR00254## 197 ##STR00255## 198 ##STR00256##
199 ##STR00257## 200 ##STR00258## 201 ##STR00259## 202 ##STR00260##
203 ##STR00261## 204 ##STR00262## 205 ##STR00263## 206 ##STR00264##
207 ##STR00265## 208 ##STR00266## 209 ##STR00267## 210 ##STR00268##
211 ##STR00269## 212 ##STR00270## 213 ##STR00271## 214 ##STR00272##
215 ##STR00273## 216 ##STR00274## 217 ##STR00275## 218 ##STR00276##
219 ##STR00277## 220 ##STR00278## 221 ##STR00279## 222 ##STR00280##
223 ##STR00281## 224 ##STR00282## 225 ##STR00283## 226 ##STR00284##
227 ##STR00285## 228 ##STR00286## 229 ##STR00287## 230 ##STR00288##
231 ##STR00289##
General Synthetic Methods
[0419] 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.
[0420] 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.
[0421] 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
[0422] For chiral separations, samples were dissolved in Methanol
and Ethanol according to the solubility of sample and filtered
through 0.22.mu. PTFE filters. The columns used were CHIRALPAK-AD;
20*250 mm, 10.mu. and CHIRALCEL-ODH; 20*250 mm, 5.mu.. 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.
[0423] The following abbreviations are used herein: thin layer
chromatography (TLC); hour (h); minute (min); second (sec); ethanol
(EtOH); dimethylsulfoxide (DMSO); N,N-dimethylformamide
[0424] (DMF); 1,2-dimethoxyethane (DME); trifluoroacetic acid
(TFA); tetrahydrofuran (THF); Normal (N); aqueous (aq.); methanol
(MeOH); dichloromethane (DCM); ethyl acetate (EtOAc); Retention
factor (R.sup.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).
[0425] Routes to synthesizing aryl-linked compounds of the
invention are shown below as General Methods 1 to 10. Although
identifiers such as R.sup.1 and R.sup.6 are 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 R.sup.1, R.sup.6 etc.).
##STR00290## ##STR00291##
General Method 1
[0426] 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.degree. 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
[0427] 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
K.sub.2CO.sub.3 (0.845 mmol) in DME (4 mL)-water (2 mL) was added
Pd(PPh.sub.3).sub.4 (0.013 mmol). The reaction mixture was purged
with N.sub.2 for 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
[0428] 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.degree. 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
[0429] 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
K.sub.2CO.sub.3 (0.845 mmol) in DME (4 mL)-water (2 mL) was purged
with nitrogen followed by addition of Pd(PPh.sub.3).sub.4 (0.013
mmol). The reaction mixture was stirred at 90.degree. 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
[0430] 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.degree. 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
[0431] 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
K.sub.2CO.sub.3 (0.845 mmol) in DME (4 mL)-water (2 mL) was purged
with nitrogen followed by addition of Pd(PPh.sub.3).sub.4 (0.013
mmol). The reaction mixture was stirred at 90.degree. 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
[0432] 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.degree. 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
[0433] 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
K.sub.2CO.sub.3 (0.87 mmol) in DME (4 mL)-water (2 mL) was purged
with nitrogen followed by addition of Pd(PPh.sub.3).sub.4 (0.0147
mmol). The reaction mixture was stirred at 90.degree. 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
##STR00292##
[0435] 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
##STR00293## ##STR00294##
[0437] 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.
[0438] 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.
[0439] The following Examples are provided to illustrate but not to
limit the invention.
[0440] All references disclosed herein are incorporated herein by
reference in their entireties.
EXAMPLES
Example No. 1
Preparation of Compound No. 1
[0441] 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), K.sub.3PO.sub.4 (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.degree. 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). .sup.1H NMR(HCl salt, CD.sub.3OD)
.delta. (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
[0442] A solution of
2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g,
.mu.mol), 4-bromopyridine (0.316 g, 2 mmol), K.sub.3PO.sub.4 (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.degree. 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). .sup.1H NMR(HCl salt, CD.sub.3OD)
.delta. (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
[0443] 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), K.sub.3PO.sub.4
(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.degree. 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). .sup.1H NMR(HCl salt, CD.sub.3OD)
.delta. (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
[0444] 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),
K.sub.3PO.sub.4 (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.degree. 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%
[0445] MeOH:DCM to yield
2,8-dimethyl-5-(6-trifluoromethyl-pyridin-3-yl)-2,3,4,5-tetrahydro-1H-pyr-
ido[4,3-b]indole as an off white solid (150 mg). .sup.1H NMR(HCl
salt, CD.sub.3OD) .delta. (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
[0446] 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 K.sub.3PO.sub.4 (270 mg, 1.27 mmol) in DMF-water (9:1 mL) was
added PdCl.sub.2(PPh.sub.3).sub.2 (18 mg, 5 mol %). The reaction
mixture was heated at 95.degree. 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). .sup.1H NMR (Freebase, CDCl.sub.3)
.delta. (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
[0447] 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),
K.sub.3PO.sub.4 (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.degree.
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]-dime-
thyl-amine (20 mg). .sup.1H NMR (TFA salt, CD.sub.3OD) .delta.
(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
[0448] 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),
K.sub.3PO.sub.4 (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.degree.
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]-dime-
thyl-amine as an off white solid (11 mg). .sup.1H NMR (Oxalate
salt, CD.sub.3OD) .delta. (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
[0449] 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
K.sub.3PO.sub.4 (149.7 mg, 0.706 mmol) in DMF-water (4:1 mL) was
added PdCl.sub.2(PPh.sub.3).sub.2 (10 mg, 5 mol %). The reaction
mixture was heated at 95.degree. 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). .sup.1H NMR (Freebase, CDCl.sub.3) .delta. (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
[0450] 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), K.sub.3PO.sub.4 (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.degree. 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). .sup.1H NMR (Oxalate salt,
CD.sub.3OD) .delta. (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
[0451] 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 K.sub.3PO.sub.4 (149 mg, 0.706 mmol) in DMF-water (4:1
mL) was added PdCl.sub.2(PPh.sub.3).sub.2 (10 mg, 5 mol %). The
reaction mixture was heated at 95.degree. 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). .sup.1H NMR (Oxalate salt,
CD.sub.3OD) .delta. (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
[0452] 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), K.sub.3PO.sub.4 (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.degree. 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). .sup.1H NMR(HCl salt, CD.sub.3OD)
.delta. (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
[0453] 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), K.sub.3PO.sub.4 (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.degree. 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). .sup.1H NMR(HCl salt, CD.sub.3OD)
.delta. (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
[0454] 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 K.sub.3PO.sub.4 (149 mg, 0.706 mmol) in DMF-water (4:1 mL) was
added PdCl.sub.2(PPh.sub.3).sub.2 (10 mg, 5 mol %). The reaction
mixture was heated at 95.degree. 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). .sup.1H NMR (Oxalate salt,
CD.sub.3OD) .delta. (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
[0455] 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), K.sub.3PO.sub.4 (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.degree. 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). .sup.1H NMR(HCl salt, CD.sub.3OD) .delta. (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
[0456] 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), K.sub.3PO.sub.4 (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.degree. 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). .sup.1H NMR (TFA salt, CD.sub.3OD) .delta. (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
[0457] 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), K.sub.3PO.sub.4 (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.degree. 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). .sup.1H NMR (TFA salt, CD.sub.3OD) .delta. (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
[0458] 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), K.sub.3PO.sub.4
(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.degree. 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). .sup.1H NMR (TFA salt, CD.sub.3OD) .delta. (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
[0459] 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),
K.sub.3PO.sub.4 (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.degree. 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). .sup.1H NMR(HCl salt, CD.sub.3OD) .delta.
(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
[0460] A solution of
2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g,
.mu.mol), 4-bromo-thiazole (0.246 g, 1.5 mmol), K.sub.3PO.sub.4
(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.degree. 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). .sup.1H NMR (TFA salt, CD.sub.3OD) .delta. (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
[0461] 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 K.sub.3PO.sub.4 (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.degree. 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-pyrid-
o[4,3-b]indole as an off white solid (90 mg). .sup.1H NMR (Oxalate
salt, CD.sub.3OD) .delta. (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
[0462] 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 K.sub.3PO.sub.4 (58.8 mg, 0.217 mmol) in DMF-water (4.5:0.5 mL)
was added PdCl.sub.2(PPh.sub.3).sub.2 (3.8 mg, 5 mol %). The
reaction mixture was heated at 95.degree. 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). .sup.1H NMR (TFA salt,
CD.sub.3OD) .delta. (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
[0463] 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 K.sub.3PO.sub.4 (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.degree. 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-pyrid-
o[4,3-b]indole (40 mg). .sup.1H NMR (Oxalate salt, CD.sub.3OD)
.delta. (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
[0464] 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 N.sub.2 for 20 min followed by addition of
dichlorobis(triphenylphosphine) palladium (II) (14.6 mg, 5 mol %).
The reaction mixture was then heated at 95.degree. 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. .sup.1H NMR (Oxalate salt, CD.sub.3OD) .delta. (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
[0465] 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), K.sub.3PO.sub.4 (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.degree. 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). .sup.1H NMR (Oxalate salt,
CD.sub.3OD) .delta. (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
[0466] 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.degree. 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. .sup.1H NMR (Freebase, CDCl.sub.3)
.delta. (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
[0467] 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.degree. 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. .sup.1H NMR (TFA salt, CD.sub.3OD)
.delta. (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
[0468] 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.degree. 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. .sup.1H NMR (TFA salt,
CD.sub.3OD) .delta. (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
[0469] 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.degree. 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. .sup.1H NMR (TFA salt,
CD.sub.3OD) .delta. (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
[0470] 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 K.sub.3PO.sub.4 (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.degree. 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]indo-
le (35 mg). .sup.1H NMR (TFA salt, CD.sub.3OD) .delta. (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
[0471] 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(PPh.sub.3).sub.4 (15 mg, 0.0128 mmol) and purged with N.sub.2.
1-Methylpyrazole-4-boronic acid pinacol ester (108 mg, 0.515 mmol),
K.sub.2CO.sub.3 (36 mg, 0.257 mmol) and water (2 mL) were added
followed by N.sub.2 purging and the reaction refluxed under N.sub.2
for 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.degree. 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.
.sup.1H NMR (freebase, CDCl.sub.3) .delta. (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
[0472] 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.degree. 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. .sup.1H NMR (TFA
salt, CD.sub.3OD) .delta. (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
[0473] 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.degree. 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. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta. (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
[0474] 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 K.sub.2CO.sub.3 (110 mg, 0.77 mmol) and purged solution with
N.sub.2. Pd(PPh.sub.3).sub.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 N.sub.2
for 45 min. The reaction mixture was cooled to RT and diluted with
EtOAc. The aqueous layer was extracted with EtOAc (3.times.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. .sup.1H NMR (TFA salt,
CD.sub.3OD) .delta. (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
[0475] 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 K.sub.2CO.sub.3 (110 mg, 0.77 mmol) and purged the solution
with N.sub.2. Pd(PPh.sub.3).sub.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 N.sub.2 for 45 min. The
reaction mixture was cooled to RT and diluted with EtOAc. Aqueous
layer was extracted with EtOAc (3.times.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. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta.
(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
[0476] 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 K.sub.2CO.sub.3 (110 mg, 0.77 mmol) and purged the solution
with N.sub.2. Pd(PPh.sub.3).sub.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 N.sub.2
for 45 min. The reaction mixture was cooled to RT and diluted with
EtOAc. The aqueous layer was extracted with EtOAc (3.times.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. .sup.1H NMR (TFA salt,
CD.sub.3OD) .delta. (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
[0477] 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.degree. 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. .sup.1H NMR (TFA salt, CD.sub.3OD)
.delta. (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
[0478] 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 K.sub.2CO.sub.3 (110 mg, 0.77 mmol) and purged the solution
with N.sub.2. Pd(PPh.sub.3).sub.4 (20 mg, 0.017 mmol) and
4-methoxyphenylboronic acid (70 mg) were added to the reaction
mixture which was refluxed under N.sub.2 for 45 min. The reaction
mixture was cooled to RT and diluted with EtOAc. The aqueous layer
was extracted with EtOAc (3.times.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. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta.
(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
[0479] 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.degree. C. Ice water was added
to the reaction mixture and extracted the organic part into EtOAc
(3.times.15 mL). The combined organic layer was washed with water
(2.times.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. .sup.1H
NMR(HCl salt, CD.sub.3OD) .delta. (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
[0480] 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 K.sub.2CO.sub.3 (110 mg, 0.77 mmol) and purged the solution
with N.sub.2. Pd(PPh.sub.3).sub.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
N.sub.2 for 45 min. The reaction mixture was cooled to RT and
diluted with EtOAc. Aqueous layer was extracted with EtOAc
(3.times.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. .sup.1H
NMR (TFA salt, CD.sub.3OD) .delta. (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
[0481] 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 K.sub.2CO.sub.3 (110 mg, 0.77 mmol) and purged solution with
N.sub.2. Pd(PPh.sub.3).sub.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 N.sub.2 for 45 min. The reaction mixture was cooled to RT and
diluted with EtOAc. Aqueous layer was extracted with EtOAc
(3.times.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. .sup.1H
NMR (TFA salt, CD.sub.3OD) .delta. (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
[0482] 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 K.sub.2CO.sub.3 (110 mg, 0.77 mmol) and purged the solution
with N.sub.2. Pd(PPh.sub.3).sub.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 N.sub.2 for 45 min. The
reaction mixture was cooled to RT and diluted with EtOAc. Aqueous
layer was extracted with EtOAc (3.times.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. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta.
(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
[0483] 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 K.sub.2CO.sub.3 (120 mg,
0.845 mmol) in DME (4 mL)-water (2 mL) was added
Pd(PPh.sub.3).sub.4 (16 mg, 0.013 mmol). The reaction mixture was
stirred at 90.degree. 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. .sup.1H NMR (TFA salt, CD.sub.3OD)
.delta. (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
[0484] 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 K.sub.2CO.sub.3 (120 mg, 0.845 mmol)
in DME (4 mL)-water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg,
0.013 mmol). The reaction mixture was stirred at 90.degree. 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-py-
rido[4,3-b]indole. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta.
(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
[0485] 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 K.sub.2CO.sub.3 (120 mg, 0.845 mmol) in
DME (4 mL)-water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.013
mmol). The reaction mixture was stirred at 90.degree. 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-pyr-
ido[4,3-b]indole. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta. (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
[0486] 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 K.sub.2CO.sub.3 (120 mg, 0.845 mmol)
in DME (4 mL)-water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg,
0.013 mmol). The reaction mixture was stirred at 90.degree. 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)p-
yridin-2-yl)acetamide. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta.
(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
[0487] 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 K.sub.2CO.sub.3 (120 mg, 0.845 mmol) in
DME (4 mL)-water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.013
mmol). The reaction mixture was stirred at 90.degree. 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. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta.
(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
[0488] 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.degree. C. Ice water
was added to the reaction mixture and extracted the organic part
into EtOAc (3.times.15 mL). The combined organic layer was washed
with water (2.times.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. .sup.1H NMR (TFA salt,
CD.sub.3OD) .delta. (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
[0489] 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.degree. 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.times.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. .sup.1H NMR (TFA salt,
CD.sub.3OD) .delta. (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
[0490] 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 K.sub.2CO.sub.3 (110 mg, 0.77 mmol) and purged the solution
with N.sub.2. Pd(PPh.sub.3).sub.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
N.sub.2 for 45 min. The reaction mixture was cooled to RT and
diluted with EtOAc. The aqueous layer was extracted with EtOAc
(3.times.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, CD.sub.3OD) .delta. (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
[0491] 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 K.sub.2CO.sub.3 (110 mg, 0.77 mmol) and purged the solution
with N.sub.2. Pd(PPh.sub.3).sub.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
N.sub.2 for 45 min. The reaction mixture was cooled to RT and
diluted with EtOAc. Aqueous layer was extracted with EtOAc
(3.times.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.
.sup.1H NMR (TFA salt, CD.sub.3OD) .delta. (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
[0492] 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 K.sub.2CO.sub.3 (116 mg, 0.845 mmol) in DME (4 mL)-water
(2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.013 mmol). The
reaction mixture was stirred at 90.degree. 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-py-
rido[4,3-b]indole. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta.
(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
[0493] 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 K.sub.2CO.sub.3 (116 mg, 0.845 mmol)
in DME (4 mL)-water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg,
0.013 mmol). The reaction mixture was stirred at 90.degree. 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)pyrid-
in-2-ol. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta. (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
[0494] 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 K.sub.2CO.sub.3 (116 mg, 0.845 mmol) in
DME (4 mL)-water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.013
mmol). The reaction mixture was stirred at 90.degree. 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-tetrahydr-
o-1H-pyrido[4,3-b]indole. .sup.1H NMR (TFA salt, CD.sub.3OD)
.delta. (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
[0495] 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 K.sub.2CO.sub.3 (116 mg, 0.845 mmol) in
DME (4 mL)-water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.013
mmol). The reaction mixture was stirred at 90.degree. 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-tetrahy-
dro-1H-pyrido[4,3-b]indole. .sup.1H NMR (TFA salt, CD.sub.3OD)
.delta. (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
[0496] 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 K.sub.2CO.sub.3 (116 mg, 0.845 mmol) in DME (4
mL)-water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.013 mmol).
The reaction mixture was stirred at 90.degree. 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. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta. (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
[0497] 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 K.sub.2CO.sub.3 (110 mg, 0.77 mmol) and purged the solution
with N.sub.2. Pd(PPh.sub.3).sub.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
N.sub.2 for 45 min. The reaction mixture was cooled to RT and
diluted with EtOAc. Aqueous layer was extracted with EtOAc
(3.times.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.
.sup.1H NMR (TFA salt, CD.sub.3OD) .delta. (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
[0498] To a de-aerated solution of
5-(3-bromophenyl)-2,6,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indo-
le (80 mg, 0.217 mmol), pyridine-4-boronic acid (53 mg, 0.431 mmol)
and K.sub.2CO.sub.3 (116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL)
was added Pd(PPh.sub.3).sub.4 (12 mg, 0.013 mmol). The reaction
mixture was heated at 90.degree. 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. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta. (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
[0499] 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.degree. 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]indo-
le. .sup.1H NMR (TFA salt, CD.sub.3OD) (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
[0500] 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 K.sub.2CO.sub.3 (233.48 mg, 0.845 mmol) in
DME-water (2:1) was added Pd(PPh.sub.3).sub.4 (32.58 mg, 0.028
mmol). The reaction mixture was stirred at 90.degree. 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. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta.
(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
[0501] 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 K.sub.2CO.sub.3 (116 mg, 0.845 mmol) in
DME-water (2:1) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.013 mmol).
The reaction mixture was stirred at 90.degree. 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. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta.
(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
[0502] 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
K.sub.2CO.sub.3 (116 mg, 0.845 mmol) in DME-water (2:1) was added
Pd(PPh.sub.3).sub.4 (16 mg, 0.013 mmol). The reaction mixture was
stirred at 90.degree. 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, CD.sub.3OD) .delta. (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
[0503] 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 K.sub.2CO.sub.3 (110 mg, 0.77 mmol) and purged the solution
with N.sub.2. Pd(PPh.sub.3).sub.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
N.sub.2 for 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. .sup.1H
NMR (TFA salt, CD.sub.3OD) .delta. (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
[0504] 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 K.sub.2CO.sub.3 (162 mg, 1.1 mmol)
in DME-water (2:1) was added Pd(PPh.sub.3).sub.4 (22 mg, 0.019
mmol). The reaction mixture was stirred at 90.degree. 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. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta.
(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
[0505] 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 K.sub.2CO.sub.3 (162 mg, 1.1 mmol)
in DME-water (2:1) was added Pd(PPh.sub.3).sub.4 (22 mg, 0.019
mmol). The reaction mixture was stirred at 90.degree. 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. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta.
(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
[0506] 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 K.sub.2CO.sub.3 (116 mg, 0.84 mmol)
in DME-water (2:1) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.014
mmol). The reaction mixture was stirred at 90.degree. 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)pheny-
l)-3,5-dimethylisoxazole. .sup.1H NMR (TFA salt, CD.sub.3OD)
.delta. (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
[0507] 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 K.sub.2CO.sub.3 (116 mg, 0.84 mmol)
in DME-water (2:1) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.014
mmol). The reaction mixture was stirred at 90.degree. 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-tetrahy-
dro-1H-pyrido[4,3-b]indole. .sup.1H NMR (TFA salt, CD.sub.3OD)
.delta. (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
[0508] 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 K.sub.2CO.sub.3 (116 mg, 0.84 mmol) in DME-water (2:1)
was added Pd(PPh.sub.3).sub.4 (16 mg, 0.014 mmol). The reaction
mixture was heated at 90.degree. 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, CD.sub.3OD) .delta. (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
[0509] 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
K.sub.2CO.sub.3 (110 mg, 0.77 mmol) and the solution purged with
N.sub.2. Pd(PPh.sub.3).sub.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 N.sub.2 for 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. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta. (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
[0510] 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 K.sub.2CO.sub.3 (116 mg, 0.84 mmol) in DME
(4 mL)-water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.014
mmol). The reaction mixture was stirred at 90.degree. 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. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta.
(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
[0511] 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 K.sub.2CO.sub.3 (116 mg, 0.84 mmol) in DME (4 mL)-water (2 mL)
was added Pd(PPh.sub.3).sub.4 (16 mg, 0.014 mmol). The reaction
mixture was stirred at 90.degree. 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. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta. (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
[0512] 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 K.sub.2CO.sub.3 (115 mg, 0.84 mmol) in
DME-water (2:1) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.014 mmol).
The reaction mixture was stirred at 90.degree. C. for 2 h,
additional Pd (PPh.sub.3).sub.4 (16 mg, 0.014 mmol) was added into
the reaction mixture and stirring continued at 90.degree. 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-m-
ethylpicolinamide as an off-white solid. .sup.1H NMR (TFA salt,
CD.sub.3OD) .delta. (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
[0513] 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 K.sub.3PO.sub.4 (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.degree. 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-methylbiph-
enyl-4-carboxamide. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta.
(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
[0514] 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
K.sub.2CO.sub.3 (110 mg, 0.77 mmol) and the solution purged with
N.sub.2. Pd(PPh.sub.3).sub.4 (20 mg, 0.017 mmol) and
N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbox-
amide (145 mg, 0.552 mmol) were added to the reaction mixture,
which was refluxed under N.sub.2 for 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. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta.
(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
[0515] 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),
K.sub.3PO.sub.4 (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.degree. 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]indo-
le as a yellow solid. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta.
(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
[0516] 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 K.sub.2CO.sub.3 (236 mg, 1.71 mmol) in
DME-water (2:1) was added Pd(PPh.sub.3).sub.4 (33 mg, 0.028 mmol).
The reaction mixture was stirred at 90.degree. 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-m-
ethylpicolinamide. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta.
(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
[0517] 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
K.sub.2CO.sub.3 (110 mg, 0.77 mmol) and the solution purged with
N.sub.2. Pd(PPh.sub.3).sub.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 N.sub.2 for
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, CD.sub.3OD) .delta. (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
[0518] 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-1-
H-isoquinoline-2-carbaldehyde (10 mg). .sup.1H NMR(HCl salt,
CD.sub.3OD) .delta. (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
[0519] To a solution of 3,4-dibromo-N-methylthiophene-2-carboxamide
(100 mg, 0.33 mmol) in DMF (2 mL) were added K.sub.3PO.sub.4 (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.degree. C. overnight. Ice water
was added into the reaction mixture and extracted the organic part
into EtOAc (3.times.25 mL). The combined organic layer was washed
with water (3.times.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. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta. (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
[0520] 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 K.sub.2CO.sub.3 (110 mg, 0.77 mmol) and purged the solution
with N.sub.2. Pd(PPh.sub.3).sub.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
N.sub.2 for 45 min. The reaction mixture was cooled to RT and
diluted with EtOAc. The aqueous layer was extracted with EtOAc
(3.times.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. .sup.1H
NMR (TFA salt, CD.sub.3OD) .delta. (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
[0521] 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 K.sub.2CO.sub.3 (120 mg, 0.845 mmol)
in DME (4 mL)-water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg,
0.013 mmol). The reaction mixture was stirred at 90.degree. 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)pyri-
din-2-ol. .sup.1H NMR (TFA salt, CD.sub.3OD) .delta. (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
[0522] 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 K.sub.2CO.sub.3 (116 mg, 0.845
mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh.sub.3).sub.4 (16
mg, 0.013 mmol). The reaction mixture was stirred at 90.degree. 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-py-
rido[4,3-b]indole as a TFA salt. .sup.1H NMR (TFA salt, CD.sub.3OD)
.delta. (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
[0523] 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 K.sub.2CO.sub.3 (116 mg, 0.845 mmol)
in DME (4 mL)-water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg,
0.013 mmol). The reaction mixture was stirred at 90.degree. 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, CD.sub.3OD) .delta. (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
[0524] 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 K.sub.2CO.sub.3 (116 mg, 0.845 mmol)
in DME (4 mL)-water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg,
0.013 mmol). The reaction mixture was stirred at 90.degree. 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)p-
yridin-2-yl)acetamide as a TFA salt. .sup.1H NMR (TFA salt,
CD.sub.3OD) .delta. (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
[0525] 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 K.sub.2CO.sub.3 (116 mg, 0.845 mmol) in
DME (4 mL)-water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.013
mmol). The reaction mixture was stirred at 90.degree. 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-pyr-
ido[4,3-b]indole as a TFA salt. .sup.1H NMR (TFA salt, CD.sub.3OD)
.delta. (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
[0526] 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 K.sub.2CO.sub.3 (116 mg, 0.845 mmol) in
DME (4 mL)-water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.013
mmol). The reaction mixture was stirred at 90.degree. 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-p-
yrido[4,3-b]indole as a TFA salt. .sup.1H NMR (TFA salt,
CD.sub.3OD) .delta. (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
[0527] 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 K.sub.2CO.sub.3 (116 mg, 0.845 mmol) in
DME (4 mL)-water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.013
mmol). The reaction mixture was stirred at 90.degree. 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. .sup.1H NMR (TFA salt,
CD.sub.3OD) .delta. (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
[0528] 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 K.sub.2CO.sub.3 (116 mg, 0.845 mmol) in DME (4 mL)-water
(2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.013 mmol). The
reaction mixture was stirred at 90.degree. 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. .sup.1H NMR (TFA salt, CD.sub.3OD)
.delta. (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
[0529] 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.degree. C. for 14 h. The reaction mixture was
diluted with water and extracted with EtOAc (.times.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). .sup.1H NMR (Freebase, CDCl.sub.3) .delta. (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
##STR00295##
[0531] 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), K.sub.3PO.sub.4
(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.degree. 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.times.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
##STR00296##
[0533] 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), K.sub.3PO.sub.4 (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.degree. 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.times.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]i-
ndole
##STR00297##
[0535] 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), K.sub.3PO.sub.4
(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.degree. 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.times.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]i-
ndole.
Example No. 92
Preparation of Compound No. 100
[0536] 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 K.sub.3PO.sub.4 (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.degree. 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. .sup.1H NMR (CD.sub.3OD, TFA
salt) .delta. (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
[0537] 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 K.sub.2CO.sub.3 (116 mg, 0.845 mmol)
in DME (4 mL) and water (2 mL) was added Pd(PPh.sub.3).sub.4 (16
mg, 0.013 mmol). The reaction mixture was stirred at 90.degree. 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-py-
rido[4,3-b]indole as the TFA salt. .sup.1H NMR (CD.sub.3OD, TFA
salt) .delta. (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
[0538] 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 K.sub.2CO.sub.3 (116 mg, 0.845 mmol) in DME (4 mL) and
water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.013 mmol). The
reaction mixture was stirred at 90.degree. 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-py-
rido[4,3-b]indole as the TFA salt. .sup.1H NMR (CD.sub.3OD, TFA
salt) .delta. (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
[0539] 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 K.sub.2CO.sub.3 (116 mg, 0.845 mmol) in DME (4 mL) and
water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.013 mmol). The
reaction mixture was stirred at 90.degree. 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. .sup.1H NMR (CD.sub.3OD, TFA salt)
.delta. (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
[0540] 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 K.sub.2CO.sub.3 (116 mg, 0.845 mmol) in DME (4
mL) and water (2 mL) was added Pd (PPh.sub.3).sub.4 (16 mg, 0.013
mmol). The reaction mixture was stirred at 90.degree. 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. .sup.1H NMR (CD.sub.3OD, TFA salt)
.delta. (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
[0541] 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 K.sub.2CO.sub.3 (116 mg, 0.845 mmol) in DME (4 mL)
and water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.013 mmol).
The reaction mixture was stirred at 90.degree. 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-p-
yrido[4,3-b]indole as the TFA salt. .sup.1H NMR (CD.sub.3OD, TFA
salt) .delta. (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
[0542] To a de-aerated solution of
5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]i-
ndole (90 mg, 0.253 mmol), pyridin-4-ylboronic acid (111 mg, 0.507
mmol) and K.sub.2CO.sub.3 (104.6 mg, 0.757 mmol) in DME (4 mL) and
water (2 mL) was added Pd(PPh.sub.3).sub.4 (14.6 mg, 0.0126 mmol).
The reaction mixture was stirred at 90.degree. 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]i-
ndole as the TFA salt. .sup.1H NMR (CD.sub.3OD, TFA salt) .delta.
(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
[0543] To a de-aerated solution of
5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]i-
ndole (100 mg, 0.280 mmol), pyridin-3-ylboronic acid (68 mg, 0.553
mmol) and K.sub.2CO.sub.3 (116 mg, 0.839 mmol) in DME (4 mL) and
water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.013 mmol). The
reaction mixture was stirred at 90.degree. 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]i-
ndole as the TFA salt. .sup.1H NMR (CD.sub.3OD, TFA salt) .delta.
(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
[0544] To a de-aerated solution of
5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]i-
ndole (100 mg, 0.280 mmol), 1-methylpyrazole-4-boronic acid pinacol
ester (116 mg, 0.557 mmol) and K.sub.2CO.sub.3 (116 mg, 0.839 mmol)
in DME (4 mL) and water (2 mL) was added Pd(PPh.sub.3).sub.4 (16
mg, 0.013 mmol). The reaction mixture was stirred at 90.degree. 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-tetrahy-
dro-1H-pyrido[4,3-b]indole as the TFA salt. .sup.1H NMR
(CD.sub.3OD, TFA salt) .delta. (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
[0545] To a de-aerated solution of
5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]i-
ndole (100 mg, 0.280 mmol), 4-isoquinolineboronic acid (96 mg,
0.554 mmol) and K.sub.2CO.sub.3 (116 mg, 0.839 mmol) in DME (4 mL)
and water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.013 mmol).
The reaction mixture was stirred at 90.degree. 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-p-
yrido[4,3-b]indole as the TFA salt. .sup.1H NMR (CD.sub.3OD, TFA
salt) .delta. (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
[0546] To a de-aerated solution of
5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]i-
ndole (100 mg, 0.280 mmol), 1-methylindole-5-boronic acid pinacol
ester (143 mg, 0.556 mmol) and K.sub.2CO.sub.3 (116 mg, 0.839 mmol)
in DME (4 mL) and water (2 mL) was added Pd(PPh.sub.3).sub.4 (16
mg, 0.013 mmol). The reaction mixture was stirred at 90.degree. 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-tetrahydr-
o-1H-pyrido[4,3-b]indole as the TFA salt. .sup.1H NMR (CD.sub.3OD,
TFA salt) .delta. (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
[0547] To a de-aerated solution of
5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]i-
ndole (100 mg, 0.280 mmol), 3,5-dimethylisoxazole-4-boronic acid
pinacol ester (124 mg, 0.556 mmol) and K.sub.2CO.sub.3 (116 mg,
0.839 mmol) in DME (4 mL) and water (2 mL) was added
Pd(PPh.sub.3).sub.4 (16 mg, 0.013 mmol). The reaction mixture was
stirred at 90.degree. 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)pyrid-
in-3-yl)-3,5-dimethylisoxazole as the TFA salt. .sup.1H NMR
(CD.sub.3OD, TFA salt) .delta. (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
[0548] To a de-aerated solution of
5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]i-
ndole (100 mg, 0.280 mmol), 2-(dimethylamino)pyrimidine-5-boronic
acid pinacol ester (139 mg, 0.557 mmol) and K.sub.2CO.sub.3 (116
mg, 0.839 mmol) in mixture of DME (4 mL) and water (2 mL) was added
Pd(PPh.sub.3).sub.4 (16 mg, 0.013 mmol). The reaction mixture was
stirred at 90.degree. 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-y-
l)-N,N-dimethylpyrimidin-2-amine as the TFA Salt. .sup.1H NMR
(CD.sub.3OD, TFA salt) .delta. (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
[0549] To a de-aerated solution of
5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]i-
ndole (100 mg, 0.280 mmol), 2-acetamidopyridine-5-boronic acid
pinacol ester (146 mg, 0.557 mmol) and K.sub.2CO.sub.3 (116 mg,
0.839 mmol) in DME (4 mL) and water (2 mL) was added
Pd(PPh.sub.3).sub.4 (16 mg, 0.013 mmol). The reaction mixture was
stirred at 90.degree. 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. .sup.1H NMR
(CD.sub.3OD, TFA salt) .delta. (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
[0550] To a de-aerated solution of
5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]i-
ndole (100 mg, 0.280 mmol), 4-fluorophenylboronic acid (146 mg,
0.557 mmol) and K.sub.2CO.sub.3 (116 mg, 0.839 mmol) in DME (4 mL)
and water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.013 mmol).
The reaction mixture was stirred at 90.degree. 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-pyr-
ido[4,3-b]indole as the TFA salt. .sup.1H NMR (CD.sub.3OD, TFA
salt) .delta. (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
[0551] To a de-aerated solution of
5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]i-
ndole (100 mg, 0.280 mmol), naphthalene-1-boronic acid (96 mg,
0.558 mmol) and K.sub.2CO.sub.3 (116 mg, 0.839 mmol) in DME (4 mL)
and water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.013 mmol).
The reaction mixture was stirred at 90.degree. 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-py-
rido[4,3-b]indole as the TFA salt. .sup.1H NMR (CD.sub.3OD, TFA
salt) .delta. (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
[0552] To a de-aerated solution of
5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]i-
ndole (100 mg, 0.280 mmol), 2-fluoropyridine-5-boronic acid pinacol
ester (124 mg, 0.556 mmol) and K.sub.2CO.sub.3 (116 mg, 0.839 mmol)
in DME (4 mL) and water (2 mL) was added Pd(PPh.sub.3).sub.4 (16
mg, 0.013 mmol). The reaction mixture was stirred at 90.degree. 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-1-
H-pyrido[4,3-b]indole as the TFA salt. .sup.1H NMR (CD.sub.3OD, TFA
salt) .delta. (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
[0553] To a de-aerated solution of
5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]i-
ndole (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 K.sub.2CO.sub.3 (116 mg, 0.839 mmol) in
DME (4 mL) and water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg,
0.013 mmol). The reaction mixture was stirred at 90.degree. 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)pyrid-
in-3-yl)-N-methylbenzamide as the TFA salt .sup.1H NMR (CD.sub.3OD,
TFA salt) .delta. (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
[0554] To a de-aerated solution of
5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]i-
ndole (100 mg, 0.280 mmol), 4-methylthiophene-2-boronic acid
pinacol ester (125 mg, 0.557 mmol) and K.sub.2CO.sub.3 (116 mg,
0.839 mmol) in DME (4 mL) and water (2 mL) was added
Pd(PPh.sub.3).sub.4 (16 mg, 0.013 mmol). The reaction mixture was
stirred at 90.degree. 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. .sup.1H NMR (CD.sub.3OD,
TFA salt) .delta. (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
[0555] To a de-aerated solution of
5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]i-
ndole (100 mg, 0.280 mmol),
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide
(158 mg, 0.558 mmol) and K.sub.2CO.sub.3 (116 mg, 0.839 mmol) in
DME (4 mL) and water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg,
0.013 mmol). The reaction mixture was stirred at 90.degree. 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-y-
l)benzenesulfonamide as the TFA salt. .sup.1H NMR (CD.sub.3OD, TFA
salt) .delta. (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
[0556] To a de-aerated solution of
5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]i-
ndole (100 mg, 0.280 mmol), 1-methyl-1H-pyrazole-5-boronic acid
pinacol ester (116 mg, 0.557 mmol) and K.sub.2CO.sub.3 (116 mg,
0.839 mmol) in DME (4 mL) and water (2 mL) was added
Pd(PPh.sub.3).sub.4 (16 mg, 0.013 mmol). The reaction mixture was
stirred at 90.degree. 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-tetrahy-
dro-1H-pyrido[4,3-b]indole as the TFA salt. .sup.1H NMR
(CD.sub.3OD, TFA salt) .delta. (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
[0557] To a de-aerated solution of
5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]i-
ndole (100 mg, 0.280 mmol), indazole-4-boronic acid hydrochloride
(111 mg, 0.559 mmol) and K.sub.2CO.sub.3 (116 mg, 0.839 mmol) in
DME (4 mL) and water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg,
0.013 mmol). The reaction mixture was stirred at 90.degree. 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-pyri-
do[4,3-b]indole as the TFA salt. .sup.1H NMR (CD.sub.3OD, TFA salt)
.delta. (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
[0558] To a de-aerated solution of
5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]i-
ndole (100 mg, 0.280 mmol), 3-methylthiophene-2-boronic acid
pinacol ester (125 mg, 0.557 mmol) and K.sub.2CO.sub.3 (116 mg,
0.839 mmol) in DME (4 mL) and water (2 mL) was added
Pd(PPh.sub.3).sub.4 (16 mg, 0.013 mmol). The reaction mixture was
stirred at 90.degree. 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. .sup.1H NMR (CD.sub.3OD,
TFA salt) .delta. (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
[0559] 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 K.sub.2CO.sub.3 (277 mg, 2.0 mmol) in DME-water
(2:1) was added Pd(PPh.sub.3).sub.4 (46 mg, 0.04 mmol). The
reaction mixture was stirred at 90.degree. 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. .sup.1H NMR (CD.sub.3OD, TFA salt)
.delta. (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
[0560] 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 K.sub.2CO.sub.3 (110 mg, 0.8
mmol) in DME-water (2:1) was added Pd(PPh.sub.3).sub.4 (20 mg,
0.016 mmol). The reaction mixture was stirred at 90.degree. 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. .sup.1H NMR
(CD.sub.3OD, TFA salt) .delta. (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
[0561] 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 K.sub.2CO.sub.3 (110 mg, 0.77 mmol) in
DME-water (2:1) was added Pd(PPh.sub.3).sub.4 (20 mg, 0.017 mmol).
The reaction mixture was stirred at 90.degree. 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. .sup.1H NMR (CD.sub.3OD, TFA salt)
.delta. (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
[0562] To a solution of 4-bromo-N,N-dimethylthiophene-3-carboxamide
(100 mg, 0.434 mmol) in DMF (1 mL) were added K.sub.3PO.sub.4 (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.degree. C. overnight. Ice
water was added into the reaction mixture and extracted with EtOAc
(2.times.25 mL). The organic layer was washed with water
(2.times.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.
.sup.1H NMR (CD.sub.3OD, TFA salt) .delta. (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
[0563] 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.degree. 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-p-
yrido[4,3-b]indole as the TFA salt (15 mg). .sup.1H NMR
(CD.sub.3OD, TFA salt) .delta. (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
[0564] To a degassed solution of
5-(4-bromothiophen-3-yl)-2,3,4,5-tetrahydro-dimethyl-1H-pyrido[4,3-b]indo-
le (50 mg, 0.138 mmol) and K.sub.2CO.sub.3 (8 mg, 0.07 mmol) in
DME-water (1:1) were added Pd(PPh.sub.3).sub.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.degree. C. for 1 h then diluted with EtOAc (20 mL). The organic
layer was washed with water (2.times.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. .sup.1H NMR
(CD.sub.3OD, HCl salt) .delta. (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
[0565] 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 K.sub.2CO.sub.3 (8 mg, 0.07 mmol) in
DME:water (2:1) were added Pd(PPh.sub.3).sub.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.degree. C. for 1 h, and diluted with EtOAc (20 mL). The organic
layer was washed with water (2.times.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. .sup.1H NMR
(CD.sub.3OD, HCl salt) .delta. (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
[0566] To a de-aerated solution of
5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]i-
ndole (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 K.sub.2CO.sub.3 (116 mg, 0.839 mmol) in
DME (4 mL) and water (2 mL) was added Pd(PPh.sub.3).sub.4 (16 mg,
0.013 mmol). The reaction mixture was stirred at 90.degree. 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-pyri-
do[4,3-b]indole as the TFA salt. .sup.1H NMR (CD.sub.3OD, TFA salt)
.delta. (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
[0567] 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.degree. C. for 16 h. The reaction mixture was
diluted with water and extracted with EtOAc (3.times.50 mL). The
organic layer was washed with water (5.times.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). .sup.1H NMR (CD.sub.3OD, di-HCl salt) .delta.
(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
[0568] 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 K.sub.2CO.sub.3 (350 mg, 2.532 mmol) in
DME (10 mL) and water (5 mL) was added Pd(PPh.sub.3).sub.4 (48 mg,
0.041 mmol). The reaction mixture was stirred at 90.degree. 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-su-
lfonamide as the TFA salt. .sup.1H NMR (CD.sub.3OD, TFA salt)
.delta. (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
[0569] 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 K.sub.2CO.sub.3 (116 mg, 0.843 mmol) in
DME (4 mL) and water (0.4 mL) was added Pd(PPh.sub.3).sub.4 (16 mg,
0.014 mmol). The reaction mixture was stirred at 90.degree. 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-pyr-
ido[4,3-b]indole as the TFA salt. .sup.1H NMR (CDCl.sub.3,
freebase) .delta. (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
[0570] 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 K.sub.3PO.sub.4 (297 mg, 1.40 mmol) in DMF (6 mL)
and water (0. mL) was added Pd(PPh.sub.3).sub.2Cl.sub.2 (20 mg,
0.028 mmol), and the reaction mixture heated at 90.degree. 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.times.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-p-
yrido[4,3-b]indole as the TFA salt. .sup.1H NMR (CD.sub.3OD, TFA
salt) .delta. (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
[0571] To a degassed solution of
5-(3-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3b]in-
dole (100 mg, 0.281 mmol), pyridin-4-ylboronic acid (69 mg, 0.563
mmol) and K.sub.2CO.sub.3 (116 mg, 0.843 mmol) in DME (0.9 mL) and
water (0.1 mL) was added Pd(PPh.sub.3).sub.4 (16 mg, 0.014 mmol).
The reaction mixture was irradiated in a microwave reactor at
90.degree. 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]i-
ndole as the TFA salt. .sup.1H NMR (CD.sub.3OD, TFA salt) .delta.
(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
[0572] 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 K.sub.2CO.sub.3 (233 mg, 1.689 mmol) in
DME (8 mL) and water (0.4 mL) was added Pd(PPh.sub.3).sub.4 (33 mg,
0.028 mmol). The reaction mixture was stirred at 90.degree. 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-methylbiph-
enyl-3-carboxamide as the TFA salt. .sup.1H NMR (CD.sub.3OD, TFA
salt) .delta. (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
[0573] 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 K.sub.2CO.sub.3 (350 mg, 2.53 mmol) in DME
(12 mL) and water (0.6 mL) was added Pd(PPh.sub.3).sub.4 (49 mg,
0.042 mmol). The reaction mixture was stirred overnight at
90.degree. 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-su-
lfonamide as the TFA salt. .sup.1H NMR (CD.sub.3OD, TFA salt)
.delta. (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
[0574] A solution of
2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (310 mg,
1.55 mmol), K.sub.3PO.sub.4 (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.degree. 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.times.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-pyr-
ido[4,3-b]indole as the TFA salt. .sup.1H NMR (CD.sub.3OD, TFA
salt) .delta. (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
##STR00298##
[0576] 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%).
##STR00299##
[0577] 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.degree. C. for 24 h. The reaction was cooled
and poured into water. The aqueous phase was extracted with EtOAc
(3.times.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.degree. C.
##STR00300##
[0578] 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.degree. 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.
##STR00301##
[0579] 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.degree. 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 NH.sub.4OH (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%).
##STR00302##
[0580] 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.degree. 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.
##STR00303##
[0581] 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.
##STR00304##
[0582] 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.
##STR00305##
[0583] 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.degree. 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.degree. 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). .sup.1H NMR
(DMSO) .delta. (ppm): 11.02 (s, 1H, D.sub.2O 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).
##STR00306##
[0584] 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.times.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
##STR00307##
[0586] To a solution of p-tolylhydrazine hydrochloride (7.5 g, 47.2
mmol) in 1,4-dioxane:conc. H.sub.2SO.sub.4 (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.degree. 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).
##STR00308##
[0587] 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.degree. 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.
##STR00309##
[0588] To a preheated (105.degree. 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).
##STR00310##
[0589] 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.degree. 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.
##STR00311##
[0590] 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.degree. 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).
##STR00312##
[0591] 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.degree.
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.degree. C. and then filtered. The filtrate was dried
over anhydrous sodium sulfate and evaporated to dryness to afford
the title compound (5.2 g). .sup.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 .alpha..sub.2A
[0592] To evaluate in radioligand binding assays the activity of
compounds, human recombinant adrenergic .alpha..sub.2A receptor
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 MgCl.sub.2, 2 mM EDTA) was used.
Compounds were incubated with 1 nM [.sup.3H]MK-912 for 60 min at
25.degree. C. MK912 is
(2S-trans)-1,3,4,5',6,6',7,12b-octahydro-1',3'-dimethyl-spiro[2H-benzofur-
o[2,3-a]quinolizine-2,4'(1'H)-pyrimidin]-2'(3'H)-one hydrochloride
Non-specific binding was estimated in the presence of 10 .mu.M
WB-4101 (2-(2,6-Dimethoxyphenoxyethyl)aminoethyl-1,4-benzodioxane
hydrochloride). Receptor proteins were filtered and washed, the
filters were then counted to determine [.sup.3H]MK-912 specifically
bound. Compounds were screened at 1 .mu.M 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 .alpha..sub.2B
[0593] To evaluate in radioligand binding assays the activity of
compounds, human recombinant adrenergic .alpha..sub.2B receptor
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 MgCl.sub.2, 1 mM EDTA, 0.2% BSA)
was used. Compounds were incubated with 2.5 nM [.sup.3H]Rauwolscine
for 60 min at 25.degree. C. Non-specific binding was estimated in
the presence of 10 .mu.M Prazosin. Receptor proteins were filtered
and washed, the filters were then counted to determine
[.sup.3H]Rauwolscine specifically bound. Compounds were screened at
1 .mu.M 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 .alpha..sub.1B
[0594] To evaluate in radioligand binding assays the activity of
compounds, rat adrenergic .alpha..sub.1B receptor 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
[.sup.3H]Prazosin for 60 min at 25.degree. M C. Non-specific
binding was estimated in the presence of 10 .mu.M phentolamine.
Receptor proteins were filtered and washed, the filters were then
counted to determine [.sup.3H]Prazosin specifically bound.
Compounds were screened at 1 .mu.M 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 .alpha..sub.1D
[0595] To evaluate in radioligand binding assays the activity of
compounds of the invention, human recombinant adrenergic
.alpha..sub.1D receptor 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.degree. C.
Non-specific binding was estimated in the presence of 10 .mu.M
phentolamine. Receptor proteins were filtered and washed, the
filters were then counted to determine [3H]Prazosin specifically
bound. Compounds were screened at 1 .mu.M or lower, using 1% DMSO
as vehicle. Biochemical assay results are presented as the percent
inhibition of specific binding in Table 2.
TABLE-US-00002 TABLE 2 Percentage inhibition of ligand binding to
adrenergic receptors by compounds of the invention Compound
Adrenergic (0.1 .mu.M)* Adrenergic (0.03 .mu.M)* No. .alpha..sub.1B
.alpha..sub.1D .alpha..sub.2A .alpha..sub.2B .alpha..sub.1B
.alpha..sub.2A .alpha..sub.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 .alpha..sub.1B,
Adrenergic .alpha..sub.2A Adrenergic .alpha..sub.2B and Adrenergic
.alpha..sub.1D Receptors Using Aequorin and GTP.gamma.S Functional
Assays
[0596] To study the functional activity of compounds of the
invention on the human recombinant adrenergic .alpha..sub.2B,
adrenergic .alpha..sub.2A, adrenergic .alpha..sub.1B or adrenergic
.alpha..sub.1D with Aequorin functional assays and on the human
recombinant adrenergic .alpha..sub.2B receptor with GTP.gamma.S
assay, CHO-K1 cell lines expressing adrenergic .alpha..sub.2B,
adrenergic .alpha..sub.2A, adrenergic .alpha..sub.1B or adrenergic
.alpha..sub.1D recombinant receptor, mitochondrial apoaequorin and
G.alpha.16 are used for the Aequorin assay. CHO-K1 cell line
expressing the recombinant .alpha..sub.2B receptor is amplified to
prepare membranes used for the GTP.gamma.S assay.
[0597] 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.
TABLE-US-00003 .alpha..sub.1B .alpha..sub.1D .alpha..sub.2A
.alpha..sub.2B .alpha..sub.2B Assay (aeq) (aeq) (aeq) (aeq) (GTPgS)
Agonist Cirazoline Cirazoline UK 14304 Oxymeta- Guanfacine ligand
zoline
[0598] Aequorin Assay Procedure: Aequorin adrenergic .alpha..sub.1B
(FAST-008A), adrenergic .alpha..sub.2A (FAST-006A) or adrenergic
.alpha..sub.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 .alpha..sub.1B reference agonist and antagonist
are cirazoline and qinazoline, respectively. The .alpha..sub.2A
reference agonist and antagonist are UK14,304 and rauwolscine,
respectively. The .alpha..sub.2B reference agonist and antagonist
are oxymetazoline and rauwolscine, respectively.
[0599] For agonist testing, 50 .mu.L of cell suspension are
injected on 50 .mu.L 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 .mu.L of reference agonist at a
concentration corresponding to its EC.sub.80 is injected on the 100
.mu.L 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 .mu.M
digitonin or a saturating concentration of ATP (20 .mu.M). Plates
also contained the reference agonist at a concentration equivalent
to the EC.sub.80 obtained during the test validation.
[0600] Agonist activity of test compound is expressed as a
percentage of the activity of the reference agonist at its
EC.sub.100 concentration. Antagonist activity of test compound is
expressed as a percentage of the inhibition of reference agonist
activity at its EC.sub.80 concentration.
[0601] Compounds are tested for agonist & antagonist activity
at the human adrenergic .alpha..sub.1B (FAST-008A), adrenergic
.alpha..sub.2A (FAST-006A) or adrenergic .alpha..sub.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.
[0602] GTP.gamma.S Assay Procedure: The procedure is carried out
with the following: assay buffer [20 mM HEPES pH 7.4; 100 mM NaCl,
10 .mu.g/mL saponin, 1 mM MgCl.sub.2]; membranes [Recombinant
CHO-K1-adrenergic .alpha..sub.2B membrane extracts thawed on ice
and diluted in assay buffer to give 10 .mu.g/well and kept on ice];
GDP [diluted in assay buffer to give 3 .mu.M final concentration];
beads [PVT-WGA (Amersham, RPNQ0001), diluted in assay buffer at 0.5
mg/well]; GTP.gamma..sup.35S [(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, GTP.gamma.[.sup.35S] is mixed
with the beads (volume:volume) just before starting the
reaction.
[0603] For agonist testing, the following reagents are successively
added in the wells of an Optiplate (Perkin Elmer): 50 .mu.L of test
or reference ligand, 20 .mu.L of the membranes:GDP mix, 10 .mu.L of
assay buffer and 20 .mu.L of the GTP.gamma.[.sup.35S]:beads mix.
For antagonist testing, the following reagents are successively
added in the wells of an Optiplate (Perkin Elmer): 50 .mu.L of test
or reference ligand, 20 .mu.L of the membranes:GDP mix, and then
after an incubation of 15 min. at RT, 10 .mu.L of reference ligand
at historical EC.sub.80 concentration and 20 .mu.L of the
GTP.gamma.[.sup.35S]:beads mix.
[0604] 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.
[0605] Compounds are tested for antagonist activity at the human
adrenergic .alpha..sub.2B receptor (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
[0606] SPA 35S-GTPgS and Radioligand Binding experiments are
conducted with Euroscreen membrane preparations. Compound is tested
for inverse agonist activity at the human Adrenergic .alpha..sub.2A
receptor using GTPg35S binding functional assay (FAST-006G) in
dose-reponse and in duplicates.
Example B3
Cell Culture and Cell Viability Assay
[0607] SH-SY5Y cells cultured in DMEM/F12 media supplemented with
10% FBS are seeded in 96-well microplates at 150,000
cells/cm.sup.2. 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.degree. 100107) in DMSO at 25 mM. Cells are then
treated with 4-Br-A23187 (2 .mu.M), hydrogen peroxide (300 .mu.M)
or the mitochondrial toxin rotenone (25 .mu.M) 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.RTM. 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-A2187 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 .mu.M 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
[0608] Cell Culture.
[0609] SH-SY5Y cells stably transfected with a doxycyline-inducible
wild-type .alpha.-synuclein (.alpha.-syn) gene along with control
SH-SY5Y cells over-expressing the .beta.-galactosidase (.beta.-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 .alpha.-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 .mu.g/mL G418 and 50 .mu.g/mL Hygromycin B. Expression of
.alpha.-syn is switched off in stock cultures with doxycycline (2
.mu.g/mL). For experimental procedures, cells are plated at
(4-8.times.10.sup.4 cells/cm.sup.2) and differentiated in absence
of doxycycline and in the presence of 20 .mu.M all-trans retinoic
acid (RA) (Sigma, St Louis, Mo., USA).
[0610] Viability Assay:
[0611] 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.RTM.
AQueous One Solution Cell Proliferation assay (Promega Corporation,
Madison, Wis., USA).
[0612] Immunoblotting of .alpha.-Synuclein and .alpha.-Synuclein
Aggregates:
[0613] Cells stably expressing .alpha.-synuclein are cultured in
6-well plates at a density of 4.times.10.sup.4 cells/cm.sup.2 cells
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, MgCl.sub.2, 1 mM PMSF
pH 7.4, and 1.times. 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.times.g for 30 min at 4.degree. 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.times. 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 .mu.M-pore
immobilon Biorad). Membranes are blocked in 1.times.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.degree. C. with the following
primary antibodies in blocking solution at the indicated dilutions:
monoclonal anti-.alpha.-synuclein .alpha.-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-.alpha.-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).
[0614] Isolation of RNA and RT-Quantitative PCR(RT-qPCR):
[0615] SH-SY5Y cells stably over-expressing .alpha.-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 .mu.g 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 .alpha.-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
[0616] Islet Isolation and In-Vitro Insulin Release from Rat
Islets:
[0617] 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.degree. C.
in a Krebs-Ringer bicarbonate buffer composed of 120 mM NaCl, 25 mM
NaHCO.sub.3, 5 mM KCl, 1 mM MgCl.sub.2, 2.5 mM CaCl.sub.2, 2.8 mM
glucose and 0.5% bovine serum albumin. The medium is gassed with
100% CO.sub.2 for 15 minutes to obtain constant pH. Next, groups of
15 islets are incubated in 1 mL for 60 minutes at 37.degree. 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
[0618] To demonstrate the insulin secretion ability and/or glucose
lowering effect of a test compound, several animal models are used,
including clonidine (an .alpha..sub.2A agonist) induced,
norepinephrine (a natural ligand of .alpha..sub.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:
[0619] 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:
[0620] 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:
[0621] 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:
[0622] 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:
[0623] 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.
[0624] 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:
[0625] 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
[0626] 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.times.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.
[0627] 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
[0628] 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.degree. 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).
[0629] 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 .mu.g 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
[0630] 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.
[0631] All references throughout, such as publications, patents,
patent applications and published patent applications, are
incorporated herein by reference in their entireties.
[0632] 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.
* * * * *