U.S. patent application number 15/489971 was filed with the patent office on 2017-08-03 for bicyclo[3.2.1]octyl amide derivatives and uses of same.
This patent application is currently assigned to H. Lundbeck A/S. The applicant listed for this patent is H. Lundbeck A/S. Invention is credited to James Ford Burns, Dario Doller, Guiying Li, Jesse Weiss, Hao Zhou.
Application Number | 20170217950 15/489971 |
Document ID | / |
Family ID | 46314466 |
Filed Date | 2017-08-03 |
United States Patent
Application |
20170217950 |
Kind Code |
A1 |
Li; Guiying ; et
al. |
August 3, 2017 |
Bicyclo[3.2.1]Octyl Amide Derivatives and Uses of Same
Abstract
The present invention provides bicyclo[3.2.1]octyl amide
derivatives of formula (I): ##STR00001## wherein L, R.sup.1 and
R.sup.2 are as defined herein, or a pharmaceutically acceptable
salt thereof; and pharmaceutical compositions and methods using the
same.
Inventors: |
Li; Guiying; (River Edge,
NJ) ; Zhou; Hao; (Paramus, NJ) ; Weiss;
Jesse; (Woodbridge, NJ) ; Doller; Dario;
(Sparta, NJ) ; Burns; James Ford; (Glen Ridge,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
H. Lundbeck A/S |
Valby |
|
DK |
|
|
Assignee: |
H. Lundbeck A/S
Valby
DK
|
Family ID: |
46314466 |
Appl. No.: |
15/489971 |
Filed: |
April 18, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14532114 |
Nov 4, 2014 |
9656975 |
|
|
15489971 |
|
|
|
|
13334129 |
Dec 22, 2011 |
8921370 |
|
|
14532114 |
|
|
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|
61426379 |
Dec 22, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 241/20 20130101;
C07D 277/56 20130101; C07D 239/28 20130101; A61P 43/00 20180101;
A61P 25/22 20180101; A61P 25/06 20180101; A61P 25/18 20180101; C07D
213/81 20130101; A61P 25/04 20180101; A61P 25/00 20180101; C07D
401/12 20130101; C07D 239/42 20130101; C07D 403/12 20130101; C07D
213/82 20130101; C07D 241/24 20130101; A61P 25/24 20180101; A61P
29/00 20180101; A61P 25/28 20180101; C07D 417/12 20130101; C07D
213/75 20130101 |
International
Class: |
C07D 417/12 20060101
C07D417/12; C07D 401/12 20060101 C07D401/12; C07D 213/82 20060101
C07D213/82; C07D 403/12 20060101 C07D403/12; C07D 239/28 20060101
C07D239/28; C07D 277/56 20060101 C07D277/56; C07D 213/81 20060101
C07D213/81; C07D 241/24 20060101 C07D241/24 |
Claims
1. A compound having the formula (I): ##STR00261## or a
pharmaceutically acceptable salt thereof; wherein: L is --NHCO-- or
--CONH--; and R.sup.1 and R.sup.2 are both heteroaryl, wherein at
least one of R.sup.1 and R.sup.2 is unsubstituted and one of
R.sup.1 and R.sup.2 is optionally mono-, di-, or tri-substituted
independently with alkyl, alkoxy, halogen, cyano, nitro,
trifluoroalkyl, amino, alkylamino, dialkylamino, acyl, aryl,
heteroaryl, heterocyclyl, heterocyclyl-R.sup.3, --N(alkyl)R.sup.3,
--C(O)NHR.sup.3, --C(O)N(alkyl)R.sup.3, --NHC(O)R.sup.3,
--N(alkyl)C(O)R.sup.3, --OH or --OR.sup.3, wherein: R.sup.3 is
C.sub.1-C.sub.6alkyl or C.sub.1-C.sub.6cycloalkyl, which is
optionally substituted with halogen, --CN, --NH.sub.2,
--NH(C.sub.1-C.sub.3alkyl), --N(C.sub.1-C.sub.3alkyl).sub.2,
C.sub.1-C.sub.3alkylheterocyclyl, C.sub.1-C.sub.3alkylcarbamate,
--C(O)NH(C.sub.1-C.sub.3alkyl),
--C(O)N(C.sub.1-C.sub.3alkyl).sub.2,
--NHC(O)--C.sub.1-C.sub.3alkyl,
--N(C.sub.1-C.sub.3alkyl)-C(O)--C.sub.1-C.sub.3alkyl, OH, or
--O--C.sub.1-C.sub.6alkyl.
2. The compound or pharmaceutically acceptable salt thereof of
claim 1 wherein one of R.sup.1 and R.sup.2 is optionally mono-,
di-, or tri-substituted independently with alkyl, alkoxy, halogen,
cyano, nitro, trifluoroalkyl, amino, alkylamino, dialkylamino,
acyl, --OH or --OR.sup.3; and wherein R.sup.3 is
C.sub.1-C.sub.6alkyl.
3. The compound or pharmaceutically acceptable salt thereof of
claim 1 wherein R.sup.1 and R.sup.2 are each independently selected
from the group consisting of pyridinyl, pyridazinyl, triazinyl,
pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (1,2,4)-triazolyl,
pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl,
thiazolyl, oxazolyl, 2-quinolinyl, 2-quinazolinyl and
3-phenyl-2-quinolinyl.
4. The compound or pharmaceutically acceptable salt thereof of
claim 3, wherein R.sup.1 and R.sup.2 are both pyridinyl.
5. The compound or pharmaceutically acceptable salt thereof of
claim 1 wherein L is --NHCO--.
6. The compound or pharmaceutically acceptable salt thereof
according to claim 1, wherein said compound is selected from the
group consisting of: 1:
N,N'-(bicyclo[3.2.1]octane-1,5-diyl)dipicolinamide; 4:
6-methyl-pyrazine-2-carboxylic acid
{5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide; 56:
N-(5-{[(5-methylpyrazin-2-yl)carbonyl]amino}bicyclo[3.2.1]oct-1-yl)pyrimi-
dine-4-carboxamide; 57:
N-(5-(5-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octan-1-yl)thiazole-2--
carboxamide; 68:
6-methyl-N-(5-(nicotinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxami-
de; 71:
N-(5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octan-1-yl)pyri-
midine-4-carboxamide; 72:
N-(5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octan-1-yl)thiazole-2--
carboxamide; 78:
6-methyl-N-(5-(pyrazine-2-carboxamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-
-carboxamide; 79:
N-(5-(6-methyl-N-(6-(methylpyrazine-2-carboxamido)bicyclo[3.2.1]octan-1-y-
l)pyrimidine-2-carboxamide; 83:
N-(5-(6-methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamid-
e; 84:
N-(5-(6-methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-2-ca-
rboxamide; 85:
N-(5-(6-methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-4-carboxam-
ide; 86:
N-(5-(6-methylpicolinamido)bicyclo[3.2.1]octan-1-yl)thiazole-2-ca-
rboxamide; 94:
N-(5-(3-fluoro-6-methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-c-
arboxamide; 97: pyrazine-2-carboxylic acid
{5-[(3-fluoro-pyridine-2-carbonyl)-amino]bicyclo[3.2.1]oct-1-yl}-amide;
100:
2-methyl-N-(5-(pyrazine-2-carboxamido)bicyclo[3.2.1]octan-1-yl)pyrim-
idine-4-carboxamide; 101:
4-methyl-N-(5-(pyrazine-2-carboxamido)bicyclo[3.2.1]octan-1-yl)thiazole-2-
-carboxamide; 102:
N-(5-(5-fluoropicolinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamid-
e; 103:
N-(5-(4-methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-car-
boxamide; 104:
2-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-4-carboxa-
mide; 105:
6-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)picolinami-
de; 106:
5-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-c-
arboxamide; 107:
4-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-2-carboxa-
mide; 108:
4-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)thiazole-2-
-carboxamide; 109:
2-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl(thiazole-5-carboxami-
de; 110:
5-fluoro-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide-
; 111:
5-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide;
112:
4-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide;
113:
N-(5-(5-methylnicotinamido)bicyclo[3.2.1]octan-1-yl)picolinamide;
119: 6-methyl-pyridine-2-carboxylic acid
{(1R,5S)-5-[(pyridine-2-carbonyl)-amino]bicyclo[3.2.1]oct-1-yl}-amide;
121: pyrimidine-4-carboxylic acid
{(1S,5R)-5-[(6-methyl-pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-
amide; 126: 6-methyl-pyridine-2-carboxylic acid
{(1S,5R)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide;
127: pyrimidine-4-carboxylic acid
{(1R,5S)-5-[(6-methyl-pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-
-amide; 129: 6-methyl-pyridine-2-carboxylic acid
{(1S,5R)-5-[(thiazole-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide;
143: pyridine-2-carboxylic acid
{(1S,5R)-5-[(4-methyl-thiazole-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-
-amide; 144: 2-methyl-pyrimidine-4-carboxylic acid
{(1R,5S)-5-[(pyridine-2-carbonyl)-amino]bicyclo[3.2.1]oct-1-yl}-amide;
145: 5-fluoro-pyridine-2-carboxylic acid
{(1R,5S)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}amide;
146: 6-fluoro-pyridine-2-carboxylic acid
{(1R,5S)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}amide;
147: 3-fluoro-6-methyl-pyridine-2-carboxylic acid
{(1R,5S)-5-[pyridine-2-carbonyl)-amino]bicyclo[3.2.1]oct-1-yl}-amide;
158: 6-methyl-pyrazine-2-carboxylic acid
{(1R,5S)-5-pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide;
and 159: 6-methyl-pyrazine-2-carboxylic acid
{(1S,5R)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide.
7. The compound or pharmaceutically acceptable salt thereof
according to claim 1, wherein said compound is: 110:
5-fluoro-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide.
8. The compound or pharmaceutically acceptable salt thereof
according to claim 1, wherein said compound is: 111:
5-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide.
9. The compound or pharmaceutically acceptable salt thereof
according to claim 1, wherein said compound is: 119:
6-methyl-pyridine-2-carboxylic acid
{(1R,5S)-5-[(pyridine-2-carbonyl)-amino]bicyclo[3.2.1]oct-1-yl}-amid-
e.
10. The compound or pharmaceutically acceptable salt thereof
according to claim 1, wherein said compound is: 146:
6-fluoro-pyridine-2-carboxylic acid
{(1R,5S)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}amid-
e.
11. A pharmaceutical composition comprising the compound or
pharmaceutically acceptable salt thereof of claim 1 and a
pharmaceutically acceptable carrier.
12. A pharmaceutical composition comprising the compound or
pharmaceutically acceptable salt thereof of claim 6 and a
pharmaceutically acceptable carrier.
13. The pharmaceutical composition comprising the compound or
pharmaceutically acceptable salt thereof of claim 12, wherein said
compound is: 110:
5-fluoro-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide;
111:
5-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide;
119: 6-methyl-pyridine-2-carboxylic acid
{(1R,5S)-5-[(pyridine-2-carbonyl)-amino]bicyclo[3.2.1]oct-1-yl}-amide,
or 146: 6-fluoro-pyridine-2-carboxylic acid
{(1R,5S)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}amide.
14. A method of treating a central nervous system disease or
disorder, which comprises administering a therapeutically effective
amount of the pharmaceutical composition of claim 11 to a subject
in need thereof.
15. A method of treating a central nervous system disease or
disorder, which comprises administering a therapeutically effective
amount of the pharmaceutical composition of claim 12 to a subject
in need thereof.
16. A method of treating a central nervous system disease or
disorder, which comprises administering a therapeutically effective
amount of the pharmaceutical composition of claim 13 to a subject
in need thereof.
17. The method of claim 14, wherein the central nervous system
disease or disorder is a cognitive, neurodegenerative, psychiatric
or neurological disease or disorder.
18. The method of claim 14, wherein the central nervous system
disease or disorder is one or more of the anxiety diseases or
disorders selected from the group consisting of: generalized
anxiety disorder, panic anxiety, obsessive compulsive disorder,
social phobia, performance anxiety, post-traumatic stress disorder,
acute stress reaction, an adjustment disorder, a hypochondriacal
disorder, separation anxiety disorder, agoraphobia, a specific
phobia, anxiety disorder due to general medical condition,
substance-induced anxiety disorder, and alcohol withdrawal-induced
anxiety.
19. The method of claim 14, wherein the central nervous system
disease or disorder is one or more of the depressive disorders
selected from the group consisting of: atypical depression, bipolar
depression, unipolar depression, major depression, endogenous
depression, involutional depression, reactive depression,
postpartum depression, primary depression, psychotic depression and
secondary depression.
20. The method of claim 14, wherein the central nervous system
disease or disorder is one or more of the pain diseases or
disorders selected from the group consisting of: inflammatory pain,
neuropathic pain, migraine pain and a migraine pain disease or
disorder selected from the group consisting of allodynia,
hyperalgesic pain, phantom pain, neuropathic pain related to
diabetic neuropathy, and neuropathic pain related to migraine.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a Continuation of U.S.
application Ser. No. 14/532,114, filed Nov. 4, 2014 (pending),
which is a Continuation of U.S. application Ser. No. 13/334,129,
filed Dec. 22, 2011, which issued as U.S. Pat. No. 8,921,370 on
Dec. 30, 2014, and which claims the benefit of priority to U.S.
Provisional Application No. 61/426,379, filed Dec. 22, 2010 (now
expired). Each of these applications is hereby incorporated by
reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention provides bicyclo[3.2.1]octyl amide
derivatives, as well as pharmaceutical compositions and methods of
treatment using same.
BACKGROUND OF THE INVENTION
[0003] This invention concerns bicyclo[3.2.1]octyl amide
derivatives, which act as allosteric modulators of the metabotropic
glutamate receptor 5 (mGluS receptors or mGluR5), as well as
pharmaceutical compositions and methods of treatment utilizing
these compounds.
[0004] Glutamate is the major excitatory neurotransmitter in the
mammalian central nervous system. One means of modulating glutamate
neurotransmission is through metabotropic glutamate receptors
(mGluRs); another means being ionotropic receptors. Presently,
eight mGluRs have been cloned and classified into three groups
based on sequence homology, preferred signal transduction pathway
and pharmacology. Group 1 of mGluRs includes mGluR 1 and mGluR5,
while Group II comprises mGluR2 and mGluR3 and Group III comprises
mGlu4, 6, 7 and 8 receptors.
[0005] mGlu receptors have an essential role in normal brain
functions, as well as in neurological, psychiatric, and
neuromuscular disorders. mGlu5 receptors are located primarily
postsynaptically and highly expressed in the limbic brain regions.
mGlu5 receptors also are expressed in the thalamus, spinal cord,
and vagal nerve systems, as well as peripherally in the skin on
nerve endings and C fibers.
[0006] Ligands to the mGluS receptors have been shown to have
promise for peripheral and central nervous system disorders. See
e.g., G. Jaeschke el al., "mGlu5 receptor antagonists and their
therapeutic potential," Expert Opin. Ther. Patents, 2008, 18, 2:
123-142. Yet some proffer that glutamate analogs targeting the
orthosteric binding site may be limited by low brain penetration
and insufficient selectivity with respect to the different mGluRs
subtypes. Synthetic agonists may lead to continuous stimulation of
the receptor since they are often designed to be metabolically
stable. This continuous stimulation is not necessarily desirable,
due to potential receptor desensitization issues. Also, with
respect to receptor occupancy, synthetic antagonists may lead to
prolonged blockade of receptor function, which may not be
compatible with the kinetics of the pathology of a central nervous
system disorder.
[0007] However, a more selective and controlled "fine-tuning"
action on the mGlu5 receptor is feasible through allosteric
modulation. See e.g., P. Bach el al., "Metabotropic glutamate
receptor 5 modulators and their potential therapeutic
applications," Expert Opin. Ther. Patents, 2007, 17, 4: 371-381.
Allosteric modulation refers to binding by a modulator ligand to a
site on a receptor that is different from the orthosteric primary
substrate or ligand binding site. This ligand binding process
results in conformational changes, which may profoundly influence
the function of the protein (e.g., G protein-coupled receptors such
as mGluRs, including mGluR5). Novel mGluR5 ligands that
allosterically modulate the mGlu5 receptor may improve the
therapeutic window of traditional central nervous system agents
and/or the treatment of central nervous system disorders. The
present invention is directed these, and other important, ends.
SUMMARY OF THE INVENTION
[0008] The present invention provides a compound of formula
(I):
##STR00002##
[0009] wherein: [0010] L is --NHCO-- or --CONH--; and [0011]
R.sup.1 and R.sup.2 are each independently alkyl, cycloalkyl,
ketocycloalkyl, heterocyclyl, aryl or heteroaryl, which is
optionally mono-, di-, or tri-substituted independently with alkyl,
alkoxy, halogen, cyano, nitro, trifluoroalkyl, amino, alkylamino,
dialkylamino, acyl, aryl, heteroaryl, heterocyclyl,
heterocyclyl-R.sup.3, --NHR.sup.3, --N(alkyl)R.sup.3,
--C(O)NHR.sup.3, --C(O)N(alkyl)R.sup.3, --NHC(O)R.sup.3,
--N(alkyl)C(O)R.sup.3, --OH or --OR.sup.3, wherein: [0012] R.sup.3
is C.sub.1-C.sub.6alkyl or C.sub.1-C.sub.6cycloalkyl, which is
optionally substituted with halogen, --CN, --NH.sub.2,
--NH(C.sub.1-C.sub.3alkyl), --N(C.sub.1-C.sub.3alkyl).sub.2,
C.sub.1-C.sub.3alkylheterocyclyl, C.sub.1-C.sub.3alkylcarbamate,
--C(O)NH(C.sub.1-C.sub.3alkyl),
--C(O)N(C.sub.1-C.sub.3alkyl).sub.2,
--NHC(O)--C.sub.1-C.sub.3alkyl,
--N(C.sub.1-C.sub.3alkyl)-C(O)--C.sub.1-C.sub.3alkyl, OH, or
--O--C.sub.1-C.sub.6alkyl; or
[0013] a pharmaceutically acceptable salt thereof.
[0014] The present invention also provides a pharmaceutical
composition comprising at least one compound of the invention or a
pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable carrier.
[0015] The present invention also provides a method of treating a
disease or disorder, the method comprises administering a
therapeutically effective amount of at least one compound of the
present invention or a pharmaceutically acceptable salt thereof to
a mammal in need thereof, wherein the disease or disorder is a
central nervous system disease or disorder. In some embodiments of
the method, a symptom of the disease or disorder is treated.
DETAILED DESCRIPTION OF THE INVENTION
[0016] In one aspect, the present invention provides
bicyclo[3.2.1]octyl amide derivatives. The present invention
comprises a compound of formula (I-A) or (I-B):
##STR00003##
[0017] wherein: [0018] R.sup.1 and R.sup.2 are each independently
alkyl, cycloalkyl, ketocycloalkyl, heterocyclyl, aryl or
heteroaryl, which is optionally mono-, di-, or tri-substituted
independently with alkyl, alkoxy, halogen, cyano, nitro,
trifluoroalkyl, amino, alkylamino, dialkylamino, acyl, aryl,
heteroaryl, heterocyclyl, heterocyclyl-R.sup.3, --NHR.sup.3,
--N(alkyl)R.sup.3, --C(O)NHR.sup.3, --C(O)N(alkyl)R.sup.3,
--NHC(O)R.sup.3, --N(alkyl)C(O)R.sup.3, --OH or --OR.sup.3,
wherein: [0019] R.sup.3 is C.sub.1-C.sub.6alkyl or
C.sub.1-C.sub.6cycloalkyl, which is optionally substituted with
halogen, --CN, --NH.sub.2, --NH(C.sub.1-C.sub.3alkyl),
--N(C.sub.1-C.sub.3alkyl).sub.2, C.sub.1-C.sub.3alkylheterocyclyl,
C.sub.1-C.sub.3alkylcarbamate, --C(O)NH(C.sub.1-C.sub.3alkyl),
--C(O)N(C.sub.1-C.sub.3alkyl).sub.2,
--NHC(O)--C.sub.1-C.sub.3alkyl,
--N(C.sub.1-C.sub.3alkyl)-C(O)--C.sub.1-C.sub.3alkyl, OH, or
--O--C.sub.1-C.sub.6alkyl; or a pharmaceutically acceptable salt
thereof.
[0020] The term "alkyl", employed alone or as part of a group, is
defined herein, unless otherwise stated, as either a straight-chain
or branched saturated hydrocarbon of 1 to 8 carbon atoms. In some
embodiments, the alkyl moiety contains 8, 7, 6, 5, 4, 3, 2 or 1
carbon atoms. Where the term "alkyl" appears herein without a
carbon atom range it means a range of C.sub.1-C.sub.8. Examples of
saturated hydrocarbon alkyl moieties include, but are not limited
to, chemical groups such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, tert-butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl, and
the like.
[0021] The term "alkoxy", employed alone or in combination with
other terms, is defined herein, unless otherwise stated, as
--O-alkyl, where "alkyl" is as previously defined herein. Examples
of alkoxy moieties include, but are not limited to, chemical groups
such as methoxy, ethoxy, iso-propoxy, sec-butoxy, tert-butoxy, and
homologs, isomers, and the like. Alkoxy also refers to --O-alkyl
moieties where the alkyl group is substituted by hydroxy, cyano,
alkoxy, alkylamino, dialkylamino, alkylamide, dialkylamide, and the
like, including without limitation, --OC.sub.1-C.sub.4alkyl-OH,
--OC.sub.1-C.sub.4alkyl-OCH.sub.3,
--OC.sub.1-C.sub.4alkyl-NHCH.sub.3,
--OC.sub.1-C.sub.4alkyl-N(CH.sub.3).sub.2,
--OC.sub.1-C.sub.4alkyl-CONHCH.sub.3,
--OC.sub.1-C.sub.4alkyl-CON(CH.sub.3).sub.2,
--OC.sub.1-C.sub.4alkyl-NHCOCH.sub.3, and
--OC.sub.1-C.sub.4alkyl-N(CH.sub.3)COCH.sub.3.
[0022] As used herein, the term "cycloalkyl", employed alone or in
combination with other terms, is defined herein, unless otherwise
stated, as a cyclized alkyl group having from 3 to 8 ring carbon
atoms, where "alkyl" is as defined herein. Examples of cycloalkyl
moieties include, but are not limited to, chemical groups such as
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
[0023] As used herein, the term "ketocycloalkyl", employed alone or
in combination with other terms, is defined herein, unless
otherwise stated, as a cycloalkyl having a keto radical attached
thereto, where "cycloalkyl" is as defined herein. Examples include
cyclopentanone or cyclohexanone.
[0024] The terms "halo" or "halogen", employed alone or in
combination with other tennis, is defined herein, unless otherwise
stated, as fluoro, chloro, bromo, or iodo.
[0025] The term "aryl", employed alone or in combination with other
terms, is defined herein, unless otherwise stated, as an aromatic
hydrocarbon of up to 14 carbon atoms, which can be a single ring
(monocyclic) or multiple rings (e.g., bicyclic, tricyclic,
polycyclic) fused together or linked covalently. Any suitable ring
position of the aryl moiety can be covalently linked to the defined
chemical structure. Examples of aryl moieties include, but are not
limited to, chemical groups such as phenyl, benzyl, 1-naphthyl,
2-naphthyl, and the like. An aryl group can be unsubstituted or
substituted as described herein.
[0026] The term "heteroaryl" employed alone or in combination with
other terms, is defined herein, unless otherwise stated, as a
monocyclic or polycyclic (fused together or linked covalently)
aromatic hydrocarbon ring comprising one or more heteroatoms
independently selected from nitrogen, oxygen, and sulfur. A
heteroaryl group comprises up to 14 carbon atoms and 1 to 6
heteroatoms. Examples of heteroaryl groups include, but are not
limited to, pyridinyl, pyridazinyl, triazinyl, pyrrolyl, pyrazolyl,
imidazolyl, (1,2,3,)- and (1,2,4)-triazolyl, pyrazinyl,
pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,
oxazolyl, 2-quinolinyl, 2-quinazolinyl, 3-phenyl-2-quinolinyl and
the like. A heteroaryl group can be unsubstituted or substituted as
described herein.
[0027] The term "heterocyclyl" employed alone or in combination
with other terms, is defined herein, unless otherwise stated, as a
univalent group formed by removing a hydrogen atom from any ring
atom of a heterocycle.
[0028] The term "acyl" employed alone or in combination with other
terms, is defined herein, unless otherwise stated, as groups of
formula --C(O)-alkyl, where alkyl is a previously described herein;
i.e., an alkylcarbonyl, such as formyl, acetyl and the like.
[0029] The term "aminoalkyl" employed alone or in combination with
other terms, is defined herein, unless otherwise stated, as
alkyl-amino, where the term "alkyl" is as previously defined herein
and the term "amino" is --NH.sub.2, --NH--, or --N<.
Non-limiting examples include --CH.sub.3NH-- and
CH.sub.3CH.sub.2NH--.
[0030] The term "alkylamino" employed alone or in combination with
other terms, is defined herein, unless otherwise stated, as
amino-alkyl, where the term "alkyl" is as previously defined herein
and the term "amino" is --NH.sub.2, --NH--, or --N<.
Non-limiting examples include --NHCH.sub.3 and
--NHCH.sub.2CH.sub.3.
[0031] In some embodiments of the invention, R.sup.1 and R.sup.2
are both aryl. In some embodiments, R.sup.1 and R.sup.2 are both
heteroaryl. In some embodiments, R.sup.1 is aryl and R.sup.2 is
heteroaryl. In some embodiments, either R.sup.1 or R.sup.2 is
heteroaryl. In some embodiments, either R.sup.1 or R.sup.2 is
aryl.
[0032] In some embodiments of the invention, at least one aryl is
phenyl. In some embodiments, at least one heteroaryl is
benzofuranyl, benzo[c]isoxazolyl, benzooxazolyl, benzothiazolyl,
dihydrothieno[3,4-b][1,4]dioxinyl, furanyl,
imidazo[1,2-a]pyridinyl, indazolyl, indolinyl, indolyl,
isoquinolinyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl,
pyrrolo[3,2-c]pyridine, quinolinyl, quinoxalinyl, thiazolyl, or
thiophenyl.
[0033] In some embodiments, both aryls are phenyl. In some
embodiments, both heteroaryls are selected from a group consisting
of at least one heteroaryl is benzofuranyl, benzo[c]isoxazolyl,
benzoxazolyl, benzothiazolyl, dihydrothieno[3,4-b][1,4]dioxinyl,
furanyl, imidazo[1,2-a]pyridinyl, indazolyl, indolinyl, indolyl,
isoquinolinyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl,
pyrrolo[3,2-c]pyridinyl, quinolinyl, quinoxalinyl, thiazolyl, or
thiophenyl.
[0034] In some embodiments, the heteroaryl is pyridinyl, and the
pyridinyl is mono-, di-, or tri-substituted as previously defined.
In some such embodiments, the mono-, di-, or tri-substitutions are
independently heteroaryl, heterocyclyl, heterocyclyl-R.sup.3,
--NHR.sup.3, --N(alkyl)R.sup.3, wherein R.sup.3 is as previously
defined.
[0035] In some embodiments of the invention, R.sup.1 is aryl or
heteroaryl and R.sup.2 is cycloalkyl, ketocycloalkyl or
heterocyclyl. In some embodiments, either R.sup.1 or R.sup.2 is
cycloalkyl. In some embodiments, at least one cycloalkyl is
cyclobutyl, cyclohexyl, cyclopentyl, or cyclopropyl. In some
embodiments, the cycloalkyl is further substituted beyond the
tri-substitution previously defined, i.e., the cycloalkyl is
substituted more than three times as previously described; for
example, the cycloalkyl is tetra-substituted with fluorine.
[0036] In some embodiments of the invention, at least one
cycloalkyl, ketocycloalkyl, heterocyclyl, aryl, or heteroaryl is
substituted as previously described. In some such embodiments, the
1, 2, or 3 substituents are independently selected from the group
consisting of methyl, methoxy, dimethylamino-ethoxy, amino,
methylamino, dimethylamino, cyano, chloro, fluoro, (uranyl and
thiophenyl.
[0037] In some embodiments, the mono-, di-, or tri-substituents are
independently selected from the group consisting of amino, chloro,
cyano, dimethylamino, dimethylamino-ethoxy, methyl, methylamino,
methoxy, fluoro, --C(O)NHCH.sub.3, furanyl, pyrrolidinyl,
thiophenyl and trifluoromethyl.
[0038] In some embodiments, the compound of the present invention
is a compound disclosed in the Experimental Section below. In some
embodiments, the compound is one from Table 1 or Table 2,
below.
[0039] Another aspect of the present invention is a composition
that comprises a pharmaceutically effective amount of a compound
according to the present invention, and a pharmaceutically
acceptable carrier or excipient.
[0040] A composition of the present invention may be adapted to any
mode of administration, such as orally (including sublingually),
via implants, parentally (including intravenous, intraperitoneal,
intraarticularly and subcutaneous injections), rectally,
intranasally, topically, ocularly (via eye drops), vaginally, and
transdermally.
[0041] A compound of the present invention can be used either as a
free base or in the form of a salt derived from pharmaceutically
acceptable acids or bases. The salt includes without limitation the
following: salts with inorganic acids, e.g., hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid,
and organic acids e.g., acetic acid, oxalic acid, citric acid,
tartaric acid, succinic acid, maleic acid, benzoic acid, benzene
sulfonic acid, fumaric acid, malic acid, methane sulfonic acid,
pamoic acid, and para-toluene sulfonic acid. Other salts include
salts with alkali metals or alkaline earth metals, e.g., sodium,
potassium, calcium and magnesium, or with organic bases, including
quaternary ammonium salts. Further non-limiting examples of
pharmaceutically acceptable inorganic and organic acid addition
salts include those listed in [S. M. Berge et al., J. Pharm. Sci.
1977, 66, 1: 2, and G. S. Paulekuhn, et al., J. Med. Chem. 2007,
50, 26: 6665-6672].
[0042] A compound of the present invention can also be used in the
form of an ester, carbamate and other conventional prodrug form,
which generally will be a functional derivative of the compound
that is readily converted to the active moiety in viva. Also
included are metabolites of a compound of the present invention
defined as active species produced upon introduction of the
compound into a biological system.
[0043] When a compound of the present invention is employed as
described above, it may be combined with one or more
pharmaceutically acceptable excipients or carriers, e.g., solvents,
diluents and the like. Such pharmaceutical preparations may be
administered orally in such forms as tablets, capsules (including,
e.g., time release and sustained release formulations), pills,
lozenges, aerosols, dispersible powders, granules, solutions,
suspensions (containing, e.g., a suspending agent, at, e.g., from
about 0.05 to about 5% of suspending agent), syrups (containing,
e.g., sugar or a sugar substitute such as aspartame, at, e.g.,
about 10 to about 50% sugar or sugar substitute), elixirs and the
like, or parenterally in the form of sterile injectable solutions,
suspensions or emulsions containing, e.g., from about 0.05 to about
5% suspending agent in an isotonic medium. Such preparations may
contain, e.g., from about 25 to about 90% of the active ingredient
in combination with the carrier, more customarily from about 5% and
about 60% by weight. The effective dosage of an active ingredient
(e.g., a compound or salt of the present invention and a prodrug or
metabolite thereof) employed may vary depending on the particular
compound, salt, prodrug or metabolite used, the mode of
administration, age, weight, sex and medical condition of the
patient, and the severity of the disease, disorder, condition,
and/or system being treated. The selection of the appropriate
administration and dosage form for an individual mammal will be
apparent to those skilled in the art. Such determinations are
routine to a physician, veterinarian or clinician of ordinary skill
in the art (see e.g., Harrison's Principles of Internal Medicine,
Anthony Fauci et al. (eds.) 14.sup.th ed. New York: McGraw Hill
(1998)). Further, the dosage regimen may be adjusted to provide the
optimal therapeutic response. For example, several divided doses
may be administered daily or the dose may be proportionally reduced
as indicated by the needs of the therapeutic situation.
[0044] Solid carriers, e.g., starch, lactose, dicalcium phosphate,
microcrystalline cellulose, sucrose and kaolin, liquid carriers,
e.g., sterile water, polyethylene glycols, glycerol, non-ionic
surfactants and edible oils such as corn, peanut and sesame oils,
may be employed as are appropriate to the nature of the active
ingredient and the particular form of administration desired.
Adjuvants customarily employed in the preparation of pharmaceutical
compositions may be advantageously included. Non-limiting examples
of adjuvants include flavoring agents, coloring agents, preserving
agents, and antioxidants, such as vitamin E, ascorbic acid, BHT and
BHA.
[0045] An active compound also may be administered parenterally or
intraperitoneally. Solutions or suspensions of the active compound
as a free base, neutral compound or pharmacologically acceptable
salt can be prepared in water suitably mixed with a surfactant such
as hydroxypropylcellulose. Dispersions also can be prepared in
glycerol, liquid polyethylene glycols and mixtures thereof in oils.
These preparations may contain a preservative to prevent the growth
of microorganisms under ordinary conditions of storage and use.
[0046] The pharmaceutical forms suitable for injectable or infusing
use include sterile aqueous solutions, suspensions or dispersions,
and sterile powders for the extemporaneous preparation of sterile
injectable or infusing solutions, suspension or dispersions. In all
cases, the form must be sterile and must be fluid to the extent
that easy injectability and infusing exists. It must be stable
under conditions of manufacture and storage and must be preserved
against the contaminating action of microorganisms. The carrier can
be a solvent or dispersion medium containing, for example, water,
ethanol, and polyol (e.g., glycerol, propylene glycol, and liquid
polyethylene glycol), suitable mixtures thereof, and vegetable
oil.
[0047] Furthermore, active compounds of the present invention can
be administered intranasally or transdermally using vehicles
suitable for intranasal or transdermal delivery known to those
ordinarily skilled in the art. Transdermal administration includes
all administrations across the surface of the body and the inner
linings of bodily passages including epithelial and mucosal
tissues, using carrier systems such as lotions, creams, foams,
pastes, patches, suspensions, solutions, and suppositories (rectal
and vaginal). Creams and ointments may be viscous liquid or
semisolid emulsions of either the oil-in-water or water-in-oil
type. Pastes comprised of absorptive powders dispersed in petroleum
or hydrophilic petroleum containing the active ingredient also may
be suitable. A variety of occlusive devices may be used to release
the active ingredient into the blood stream such as a
semi-permeable membrane Covering a reservoir containing the active
ingredient with or without a carrier, or a matrix containing the
active ingredient. Other occlusive devices are known in the
literature. When using a transdermal delivery system, the dosage
administration will be continuous rather than a single or divided
daily dose.
[0048] A compound of the present invention can also be administered
in the form of a liposome delivery system where the liposomal lipid
bilayer is formed from a variety of phospholipids. A compound of
the present invention also may be delivered by the use of a carrier
such as monoclonal antibodies to which the compound is coupled.
Other carriers to which a compound of the present invention also
may be coupled are a soluble polymer or a biodegradable polymer
useful in achieving controlled release of an active ingredient.
[0049] It is understood by those practicing the art that some of
the compounds of the present invention may contain one or more
asymmetric centers, and thus may give rise to enantiomers and
diastereomers. The present invention includes all stereoisomers
including individual diastereomers and resolved, enantiomerically
pure stereoisomers, as well as racemates, and all other variations
of stereoisomers, and mixtures and pharmaceutically acceptable
salts thereof, which possess the indicated activity. Optical
isomers may be obtained in pure form by customary procedures known
to those skilled in the art, and include, but are not limited to,
chiral chromatographic separations, diastereomeric salt formation,
kinetic resolution, and asymmetric synthesis. It is also understood
that this invention encompasses all possible regioisomers, endo-exo
isomers, and mixtures thereof that possess the indicated activity.
Such isomers can be obtained in pure form by customary procedures
known to those skilled in the art, and include, but are not limited
to, column chromatography, thin-layer chromatography, and
high-performance liquid chromatography. It is understood by those
practicing the art that some of the compounds of the present
invention may be chiral due to hindered rotation, and give rise to
atropisomers, which can be resolved and obtained in pure form by
customary procedures known to those skilled in the art. It is
further understood by those practicing the art that some of the
compounds of the present invention include structural isomers,
including tautomers.
[0050] Included also in this invention are all polymorphs and
hydrates of the compounds of the present invention.
[0051] Another aspect of the present invention is a use or a method
for using the compounds of the invention. The invention is to be
understood as embracing all simultaneous, sequential or separate
use of any combination of the compounds of the invention with any
pharmaceutical composition useful in the methods described
herein.
[0052] In some embodiments, the use or method includes
administering an effective amount of a combination of two or more
of the compounds described herein, or salts thereof. It is
specifically intended that the phrases "combination of two or more
of the compounds described herein, or salts thereof," or "at least
one compound as described herein, or a pharmaceutically acceptable
salt thereof," or similar language describing specific compounds,
includes the administration of such compounds in any proportion and
combination of salt, neutral or free base forms; i.e., includes the
administration of such compounds each in the base form, each in the
neutral form or each in the salt form, or one or more in the base
form and one or more in the neutral form, or one or more in the
base form and one or more in the salt form, or one or more in the
neutral form and one or more in the salt form, in any proportion of
the neutral and/or basic compounds and/or salts.
[0053] As used herein, the phrase "effective amount" when applied
to a compound of the invention, is intended to denote an amount
sufficient to cause an intended biological effect. The phrase
"therapeutically effective amount" when applied to a compound of
the invention is intended to denote an amount of the compound that
is sufficient to ameliorate, palliate, stabilize, reverse, slow or
delay the progression of a disorder or disease state, or of a
symptom of the disorder or disease. In some embodiments, the method
of the present invention provides for administration of
combinations of compounds. In such instances, the "effective
amount" is the amount of the combination sufficient to cause the
intended biological effect.
[0054] The term "treatment" or "treating" as used herein means
curing, ameliorating or reversing the progress of a disease or
disorder, or ameliorating or reversing one or more symptoms or side
effects of such disease or disorder. "Treatment" or "treating", as
used herein, also means to inhibit or block, as in retard, arrest,
restrain, impede or obstruct, the progress of a system, condition
or state of a disease or disorder. For purposes of this invention,
"treatment" or "treating" further means an approach for obtaining
beneficial or desired clinical results, where "beneficial or
desired clinical results" include, without limitation, alleviation
of a symptom, diminishment of the extent of a disorder or disease,
stabilized (i.e., not worsening) disease or disorder state, delay
or slowing of a disease or disorder state, amelioration or
palliation of a disease or disorder state, and remission of a
disease or disorder, whether partial or total, detectable or
undetectable.
[0055] The term "prevent" or "preventing" as used herein means to
keep from happening or existing. The term "administering" as used
herein refers to either directly administering a compound of the
present invention, or administering a prodrug, derivative, or
analog of same, that will form an effective amount of the compound
within a mammal.
[0056] The present invention also provides a method of treating a
disease or disorder, the method comprises administering a
therapeutically effective amount of at least one compound of the
present invention or a pharmaceutically acceptable salt thereof to
a mammal in need thereof, wherein the disease or disorder is a
central nervous system disease or disorder.
[0057] The present invention also provides a use of a compound of
formula (I), including a pharmaceutically acceptable salt thereof,
in the preparation of a medicament for the treatment of a central
nervous system disease or disorder. The present invention further
provides a compound of formula (I) for use in treating a disease or
disorder.
[0058] A compound of formula (I) can allosterically modulate the
mGlu5 receptor. An allosteric modulator that enhances or
potentiates the affinity of an orthosteric ligand for the mGluR5
receptor and/or enhances or potentiates an orthosteric agonist's
efficacy is an allosteric enhancer (or potentiator) or positive
allosteric modulator (PAM). See e.g., May, L. T. Annu. Rev.
Pharmacol. Toxicol. 2007, 47, 1-51. An allosteric modulator that
reduces or diminishes the affinity of an orthosteric ligand for the
mGluR5 receptor and/or reduces or diminishes an orthosteric
agonist's efficacy is an allosteric antagonist (or inhibitor) or
negative allosteric modulator (NAM). Id.
[0059] In some embodiments, the mammal of the method of the
invention is a human.
[0060] In some embodiments of the method or use of the invention,
the central nervous system disease or disorder is a cognitive or
neurodegenerative disease or disorder. In some such embodiments,
the cognitive or neurodegenerative disease or disorder is selected
from a group consisting of a mood disorder, an anxiety, a
schizophrenia (including schizoaffective disorders), Alzheimer's
disease, Parkinson's disease, multiple sclerosis, Huntington's
chorea, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, a
trauma-induced neurodegeneration, AIDS-induced encephalopathy,
another infection-related encephalopathy (i.e., a non-AIDS-induced
encephalopathy), Fragile X syndrome, an autism spectrum disorder,
and a combination thereof.
[0061] As used herein, the phrase "mood disorder" refers to any of
several psychological disorders characterized by abnormalities of
emotional state, such as, without limitation, bipolar disorders,
depressive disorders, cyclothymic disorders, dysthymic disorders,
mood disorders due to a general medical condition, mood disorders
not otherwise specified and substance-induced mood disorders; and
as characterized by the Diagnostic and Statistical Manual ref
Mental Disorders, Fourth Edition (DSM-IV) (American Psychiatric
Association: Arlington, Va., 1994).
[0062] As used herein, the phrase "autism spectrum disorder" (ASD)
refers to a disorder that causes severe and pervasive impairment in
thinking, feeling, language, and the ability to relate to others,
which is often first diagnosed in early childhood and range from a
severe form, called autistic disorder ("classic" autism), through
pervasive development disorder not otherwise specified (PDD-NOS),
to a much milder form, Asperger syndrome. The phrase, as used
herein, also includes Rett syndrome and childhood disintegrative
disorder, and as used herein, is synonymous with the phrase,
"pervasive developmental disorders" (PDDs).
[0063] In some such embodiments, the mood disorder is a depression
(i.e., a depressive disorder). In some such embodiments, the
depression is selected from the group consisting of atypical
depression, bipolar depression, unipolar depression, major
depression, endogenous depression (i.e., acute depression with no
obvious cause), involutional depression (i.e., depression that
occurs in mid-life or the elderly), reactive depression (i.e.,
depression caused by an obvious traumatic life episode), postpartum
depression, primary depression (i.e., depression that has no
obvious physical or psychological cause such as a medical illness
or disorder), psychotic depression, and secondary depression (i.e.,
depression that seems to be caused by some other underlying
condition such another medical illness or disorder).
[0064] In some such embodiments, the anxiety disease or disorder is
selected from a group comprising generalized anxiety disorder,
panic anxiety, obsessive compulsive disorder, social phobia,
performance anxiety, post-traumatic stress disorder, acute stress
reaction, an adjustment disorder, a hypochondriacal disorder,
separation anxiety disorder, agoraphobia, a specific phobia,
anxiety disorder due to general medical condition,
substance-induced anxiety disorder, alcohol withdrawal-induced
anxiety, and a combination thereof.
[0065] In some embodiments, the central nervous system disease or
disorder of the method or use comprising a compound of the
invention is a seizure disease or disorder. In some embodiments,
the seizure disease or disorder is selected from the group
consisting of a convulsion, epilepsy, status epilepticus, and a
combination thereof.
[0066] In some embodiments, the central nervous system disease or
disorder of the method or use comprising a compound of the
invention is a pain disease or disorder selected from the group
consisting of inflammatory pain, neuropathic pain and migraine
pain. In some embodiments, the neuropathic pain or migraine pain
disease or disorder is selected from the group consisting of
allodynia, hyperalgesic pain, phantom pain, neuropathic pain
related to diabetic neuropathy, neuropathic pain related to
migraine, and a combination thereof.
[0067] In some embodiments, the central nervous system disease or
disorder of the method or use comprising a compound of the
invention is a neuronal hyperexcitation state disease or disorder.
In some embodiments, the neuronal hyperexcitation state disease or
disorder is a neuronal hyperexcitation state in medicament
withdrawal, a neuronal hyperexcitation state in intoxication, or a
combination thereof.
[0068] In some embodiments of the method or use comprising a
compound of the invention, at least one symptom of the cognitive
neurodegenerative, psychiatric or neurological disease or disorder
is treated.
[0069] In some embodiments, the cognitive, neurodegenerative,
psychiatric or neurological disease or disorder is a depression. In
some such embodiments, the at least one symptom of the depression
is depressed feeling, depressed mood, loss of interest or pleasure
in some or all activities, changes in appetite, changes in weight,
changes in sleep patterns, lack of energy, fatigue, low self
esteem, diminished capacity for thinking, concentration, or
decisiveness, feelings of hopelessness or worthlessness,
psychomotor agitation or retardation, self-reproach, inappropriate
guilt, frequent thoughts of death or suicide, plans or attempts to
commit suicide, or a combination thereof.
[0070] In some embodiments, the cognitive, neurodegenerative,
psychiatric or neurological disease or disorder is an anxiety. In
some such embodiments, the at least one symptom of anxiety is
apprehension, fear, trembling, muscle aches, insomnia, abdominal
upsets, dizziness, irritability, persistent, recurring thoughts,
compulsions, heart palpitations, chest pain, chest discomfort,
sweating, tingling sensations, feeling of choking, fear of losing
control, flashbacks, nightmares, intrusive thoughts, intrusive
recollections, avoidance behaviors, emotional numbing, an inability
to sleep, anxious feelings, overactive startle response,
hypervigilance, outbursts of anger, faintness, blushing, profuse
sweating, or a combination thereof.
[0071] In some embodiments, the cognitive, neurodegenerative,
psychiatric or neurological disease or disorder is schizophrenia.
In some such embodiments, the at least one symptom of schizophrenia
is a positive symptom selected from the group consisting of
hallucination, delusion, paranoia, and a combination thereof. In
some such embodiments, the symptom of schizophrenia is a negative
symptom selected from the group consisting of social withdrawal,
flat affect, anhedonia, decreased motivation, and a combination
thereof. In some such embodiments, the symptom of schizophrenia is
a cognitive symptom selected from the group consisting of severe
deficit in attention, severe deficit in object naming, severe
deficit in working memory, severe deficit in long-term memory
storage, severe deficit in executive functioning, a slowing of
information processing, a slowing of neural activity, long term
depression, and a combination thereof.
[0072] In some embodiments of the method or use comprising a
compound of the invention, the cognitive, neurodegenerative,
psychiatric or neurological disease or disorder is Parkinson's
disease. In some such embodiments, the at least one symptom of
Parkinson's disease is levodopa-induced dyskinesia, poor balance,
Parkinsonian gait, bradykinesia, rigidity, tremor, change in
speech, loss of facial expression, micrographia, difficulty
swallowing, drooling, pain, dementia, confusion, a sleep
disturbance, constipation, a skin problem, depression, fear,
anxiety, difficulty with memory, slowed thinking, sexual
dysfunction, an urinary problem, fatigue, aching, loss of energy,
or a combination thereof.
[0073] In some embodiments, the cognitive, neurodegenerative,
psychiatric or neurological disease or disorder is Alzheimer's
disease. In some such embodiments, the at least one symptom of
Alzheimer's disease is impairment in memory, impairment in
attention, impairment in judgment, impairment in decision-making,
impairment in orientation to physical surroundings, language
impairment, impairment in speed-dependent activities, impairment in
abstract reasoning, impairment in visuospatial abilities,
impairment in executive functioning, impairment in behavioral
disturbances, disinterest and passivity, apathy, inappropriate
dressing, poor self care, agitation, violent outburst, aggression,
depression, anxiety, hallucination, delusion, change in
personality, change in mood, dementia, or a combination
thereof.
[0074] In some embodiments, the cognitive, neurodegenerative,
psychiatric or neurological disease or disorder is multiple
sclerosis. In some such embodiments, the at least one symptom of
multiple sclerosis is optic neuritis blurred vision, eye pain, loss
of color vision, blindness, diplopia double vision, nystagmus jerky
eye movements, ocular dysmetria, constant under- or overshooting
eye movements, internuclear ophthalmoplegia, nystagmus, diplopia,
movement and sound phosphenes, diplopia, afferent pupillary defect,
motor paresis, monoparesis, paraparesis, hemiparesis, quadraparesis
plegia, paraplegia, hemiplegia, tetraplegia, quadriplegia,
spasticity, dysarthria, muscle atrophy, spasms, cramps, hypotonia,
dorms, myoclonus, myokymia, restless leg syndrome, footdrop
dysfunctional reflexes (MRSs, Babinski's, Hoffman's, Chaddock's),
paraesthesia, anaesthesia, neuralgia, neuropathic pain, neurogenic
pain, l'hermitte's, proprioceptive dysfunction, trigeminal
neuralgia, ataxia, intention tremor, dysmetria, vestibular ataxia,
vertigo, speech ataxia, dystonia, dysdiadochokinesia, frequent
micturation, bladder spasticity, flaccid bladder,
detrusor-sphincter dyssynergia, erectile dysfunction, anorgasmy,
retrograde ejaculation, frigidity, constipation, fecal urgency,
depression, cognitive dysfunction, dementia, mood swings, emotional
lability, euphoria, bipolar syndrome, anxiety, aphasia, dysphasia,
fatigue, uhthoffs symptom, gastroesophageal reflux, a sleeping
disorder, or a combination thereof.
[0075] The present invention further provides a method of treating
gastroesophageal reflux, the method comprises administering a
therapeutically effective amount of at least one compound of claim
1 or a pharmaceutically acceptable salt thereof to a mammal in need
thereof. The present invention further provides a use of a compound
of the invention in the preparation of a medicament for the
treatment of gastroesophageal reflux. The present invention further
provides a compound of the invention for use in treating
gastroesophageal reflux.
[0076] The present invention further provides a method of treating
alcohol dependence, the method comprises administering a
therapeutically effective amount of at least one compound of claim
1 or a pharmaceutically acceptable salt thereof to a mammal in need
thereof. The present invention further provides a use of a compound
of the invention in the preparation of a medicament for the
treatment of alcohol dependence. The present invention further
provides a compound of the invention for use in treating alcohol
dependence.
[0077] In some embodiments, the compound of the present invention
is used in the preparation of a medicament for treatment of a
central nervous system disease or disorder. In some embodiments,
the central nervous disease or disorder is as previously disclosed
herein.
[0078] Another aspect of the present invention is a process for
producing the compounds of the present invention.
Preparation of the Compounds of the Present Invention
[0079] The compounds of the present invention may be prepared,
without limitation, according to one of the general methods
outlined below. For example, Schemes 1-9 that follow are intended
as an illustration of some embodiments of the invention and no
limitation of the present invention is implied because of them.
[0080] The following defines acronyms as used herein unless
specified otherwise in a particular instance.
[0081] BINAP=2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, CAS No.
98327-87-8;
BOP=benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium
hexafluorophosphate, CAS No. 56602-33-6; DCM=dichloromethane or
methylene chloride; DIEA=DIPEA=N,N-diisopropylethylamine, CAS No.
7087-68-5; DMA=N,N-dimethylacetamide, CAS No. 127-19-5;
DMC=dimethylimidazolinium chloride; DMF=N,N-dimethylformamide, CAS
No. 68-12-2; DPPA=Diphenylphosphoryl azide, CAS No. 26386-88-9;
EDCI=N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride,
CAS No. 93128-40-6;
HATU=2-(7-Azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate, CAS No. 873798-09-5;
HBTU=2-(1H-Benzotriazole-1-yl)-1,1,3,3-Tetramethyluronium
hexafluorophosphate, CAS No. 94790-37-1; NMP=N-Methyl-Pyrrolidone,
CAS No. 872-50-4;
PyBOP=benzotriazol-1-yl-oxytripyrrolidinophosphonium
hexafluorophosphate, CAS No. 128625-52-5; RT or rt=room
temperature; TEA=triethanolamine, CAS No. 102-71-6;
THF=tetrahydrofuran, CAS No. 109-99-9; and TMSOK=potassium
trimethylsilanolate, CAS No. 10519-96-7
[0082] Symmetrical amides of the formula (I-A) (R.sup.1=R.sup.2)
can be prepared via the process outlined in Scheme 1 using
customary amidation procedures from intermediate A, where R.sup.1
is equal to R.sup.2, and R.sup.1 and R.sup.2 are as previously
defined herein.
##STR00004##
[0083] Unsymmetrical amides of formula (I-A)
(R.sup.1.noteq.R.sup.2) can be prepared via the process outlined in
Scheme 2. Amidation of intermediate A with a mixture of R.sup.1COCl
and R.sup.2COCl, or a mixture of R.sup.1CO.sub.2H and
R.sup.2CO.sub.2H using customary amidation procedures affords
unsymmetrical amides of formula (I-A), where R.sup.1 and R.sup.2
are as previously defined herein.
##STR00005##
[0084] Compounds of formula (I-A) can also be made via the process
outlined in Scheme 3. Amidation of intermediate B with R.sup.2COCl
or R.sup.2CO.sub.2H using customary amidation procedures affords
unsymmetrical amides of formula (I-A).
##STR00006##
[0085] Compounds of formula (I-B) can be made via the process
outlined in Scheme 4 or 5 using customary amidation procedures from
intermediate C or D, respectively
##STR00007##
##STR00008##
[0086] Intermediate A can be made via the process outlined in
Scheme 6. Esterification of commercially available
cyclohexane-1,3-dicarboxylic acid 1 under conditions such as in
methanol in the presence of chlorotrimethylsilane affords ester 2.
Alkylation of compound 2 with 1-bromo-2-chloroethane in the
presence of base produces bicyclic compound 3. Saponification of 3
under standard conditions gives carboxylic acid 4, which is
converted to diamine intermediate A via a standard Curtius
rearrangement, followed by the treatment with aqueous (aq.)
HCl.
##STR00009##
[0087] Intermediate B can be made via the process outlined in
Scheme 7. Mono-hydrolysis of di-ester 2 by treatment with base such
as 0.5 eq Ba(OH).sub.2 in methanol affords carboxylic acid 5, which
was converted to benzyl carbamate 6 via standard Curtius
rearrangement, followed by the treatment with benzyl alcohol.
Saponification of compound 6 under standard conditions produces
carboxylic acid 7, which was converted to compound 8 via standard
Curtius rearrangement, followed by the treatment with tert-butyl
alcohol. Removal of benzyl group under standard conditions such as
hydrogenation gives amine 9. Customary amidation of amine 9 with
R.sup.1CO.sub.2H followed by removal of BOC (butoxycarbonyl)
protecting group under standard conditions affords intermediate
B.
##STR00010##
[0088] Intermediate B and C can be made via the process outlined in
Scheme 8. Removal of benzyl protecting group of compound 6 under
standard conditions such as hydrogenation gives amine 10. Customary
amidation of 10 with R.sup.1CO.sub.2H or R.sup.1COCl yields amide
11. Saponification of compound 11 under standard conditions
produces intermediate C, which upon Curtius rearrangement followed
by the treatment with aq. HCl, affords intermediate B.
##STR00011##
[0089] Intermediate D can be made via the process outlined in
Scheme 9. Amidation of compound 5 and R.sup.2NH.sub.2 using
customary conditions affords compound 12. Saponification of ester
12 under standard conditions yields carboxylic acid 13, which upon
standard Curtius rearrangement followed by the treatment of aq.
HCl, yields intermediate D.
##STR00012##
Experimental Section
[0090] 1. General Methods
[0091] Unless specifically stated otherwise, the experimental
procedures were performed under the following conditions. All
operations were carried out at room temperature (about 18.degree.
C. to about 25.degree. C.) under nitrogen atmosphere. Evaporation
of solvent was carried out using a rotary evaporator under reduced
pressure or in a high performance solvent evaporation system HT-4X.
(Genevac Inc., Gardiner, N.Y., USA). The course of the reaction was
followed by thin layer chromatography (TLC) or liquid
chromatography-mass spectrometry (LC-MS), and reaction times are
given for illustration only. Silica gel chromatography was carried
out on a CombiFlash.RTM. system (Teledyne Isco, Inc., Lincoln,
Nebr., USA) with pre-packed silica gel cartridge or performed on
Merck silica gel 60 (230-400 mesh). The structure and purity of all
final products was assured by at least one of the following
analytical methods: nuclear magnetic resonance (NMR) and LC-MS. NMR
spectra was recorded on a Bruker Avance.TM. 300 spectrometer
(Bruker BioSpin Corp., Billerica, Mass., USA) or a Varian UNITY
INOVA.RTM. 400 (Varian, Inc., Palo Alto, Calif., USA) or Bruker
AVANCE III 500 MHz UltraShield-Plus.TM. Digital NMR Spectrometer
using the indicated solvent. Chemical shift (.delta.) is given in
parts per million (ppm) relative to tetramethylsilane (TMS) as an
internal standard. Coupling constants (J) are expressed in hertz
(Hz), and conventional abbreviations used for signal shape are:
s=singlet; d=doublet; t=triplet; m=multiplet; br=broad; etc. Unless
stated otherwise, mass spectra were obtained using electrospray
ionization (ESMS) via a Micromass.RTM. Platform II system or a
Quattro Micro.TM. system (both from Waters Corp., Milford, Mass.,
USA) or 1200RRLC/6140 SQ system (Agilent Technologies, Santa Clara,
Calif., USA), and (M+H).sup.+ is reported.
Preparation of Intermediates of the Invention
[0092] Unless specified otherwise, all starting materials and
reagents were obtained from commercial suppliers, such as
Sigma-Aldrich (St. Louis, Mo., USA) and its subsidiaries, and used
without further purification.
Intermediate 1: Bicyclo[3.2.1]octane-1,5-diamine
dihydrochloride
##STR00013##
[0094] Intermediate 1 was prepared via the process of Scheme 6,
supra, as follows:
Step 1: Cyclohexane-1,3-dicarboxylic acid dimethyl ester
##STR00014##
[0096] 1,3-Cyclohexanedicarboxylic acid (45.0 g, 261.4 mmol) was
dissolved in methanol (250 mL). Chlorotrimethylsilane (10.00 mL,
78.79 mmol) was added and the reaction was stirred at room
temperature for 4 days. The reaction was checked by LC-MS with the
product mass [M+H].sup.+ 201 seen. The mixture was concentrated
under reduced pressure. The resulting residue was diluted with
dichloromethane (200 mL). The organic layer was then washed with
saturated. NaHCO.sub.3, dried over sodium sulfate, filtered and
concentrated under reduced pressure to give a slightly viscous,
clear and colorless oil. The oil was redissolved in anhydrous THF
and concentrated to yield 49.5 g (95%) of
cyclohexane-1,3-dicarboxylic acid dimethyl ester, which was used in
the next step without further purification.
Step 2: Bicyclo[3.2.1]octane-1,5-dicarboxylic acid dimethyl
ester
##STR00015##
[0098] A solution of N,N-diisopropylamine (4.5 mL, 32 mmol) in
tetrahydrofuran (25 mL) was cooled at -78.degree. C. and treated
with 1.6 M of n-butyllithium in hexane (19 mL). The reaction was
warmed to 0.degree. C., stirred for 5 minutes, then cooled back to
-78.degree. C. 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(15 mL, 120 mmol) was added dropwise over 20 minutes, then a
solution of cyclohexane-1,3-dicarboxylic acid dimethyl ester (5.0
g, 25 mmol) in tetrahydrofuran (10 mL) was added dropwise and the
mixture stirred for 1 hour at the same temperature. Then a solution
of 1-bromo-2-chloroethane (2.9 mL, 35 mmol) in tetrahydrofuran (8
mL) was added dropwise. The reaction was allowed to return slowly
to room temperature and stirred overnight. The reaction mixture was
cooled to 0.degree. C. and quenched with saturated ammonium
chloride solution. The reaction mixture was concentrated under
reduced pressure and the resulting residue was diluted with a small
amount of water and extracted with dichloromethane (4.times.50 mL).
The organic layers were combined, dried over anhydrous sodium
sulfate, filtered, and concentrated under reduced pressure. The
resulting residue was purified with chromatography to give the
intermediate 1-(2-chloro-ethyl)-cyclohexane-1,3-dicarboxylic acid
dimethyl ester (1.22 g). A solution of N,N-diisopropylamine (0.91
mL, 6.50 mmol) in tetrahydrofuran (10 mL) was cooled at -78.degree.
C. and treated with 1.6 M of n-butyllithium in hexane (4.06 mL).
The reaction was warmed to 0.degree. C., stirred for 5 minutes, and
then cooled back to -78.degree. C.
1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.24 mL, 18.6
mmol) was added dropwise over 20 minutes, then a solution of
1-(2-chloro-ethyl)-cyclohexane-1,3-dicarboxylic acid dimethyl ester
(1.22 g, 4.64 mmol) in tetrahydrofuran (10 mL) was added dropwise
and the mixture was stirred for 1 hour at the same temperature. The
reaction was allowed to return slowly at room temperature and
stirred overnight. The reaction was quenched with saturated
ammonium chloride solution and concentrated under reduced pressure.
The resulting residue was diluted with a small amount of water and
extracted with dichloromethane (4.times.50 mL). The organic layers
were combined, dried over anhydrous sodium sulfate, filtered, and
evaporated to give crude product (3.05 g) containing DMPU. The
product was used in the next step without further purification.
Step 3: Bicyclo[3.2.1]octane-1,5-dicarboxylic acid
##STR00016##
[0100] A solution of bicyclo[3.2.1]octane-1,5-dicarboxylic acid
dimethyl ester (crude 3.01 g from step 2) in tetrahydrofuran (100
mL) was treated with 1 M of lithium hydroxide in water (75 mL) and
warmed at 70.degree. C. for 6 hours. The reaction was concentrated
under reduced pressure and the resulting residue was partitioned
between water and ethyl acetate. The aqueous layer was collected
and washed again with ethyl acetate. The aqueous layer was
acidified with 1N HCl to pH 2, and then extracted with ethyl
acetate. The organic layer was collected, dried over anhydrous
sodium sulfate, filtered, and evaporated to afford 725 mg of white
solid, which was used in the next step without further
purification.
Step 4; Bicyclo[3.2.1]octane-1,5-diamine dihydrochloride
##STR00017##
[0102] A mixture of bicyclo[3.2.1]octane-1,5-dicarboxylic acid (725
mg, 3.66 mmol) in toluene (60 mL) was treated with triethylamine
(1.53 mL, 11.0 mmol) followed by diphenylphosphonic azide (1.97 mL,
9.14 mmol). The reaction was heated at 90.degree. C. for 3 hours,
then cooled down to rt and concentrated under reduced pressure. The
resulting residue was cooled in an ice bath and treated with 6 M of
hydrogen chloride in water (60 mL). The ice bath was removed and
the reaction was stirred overnight. Most of the water was removed
in vacuo and the resulting residue was stirred with acetonitrile in
an ice bath until a colorless precipitate deposited. The
precipitate was collected by filtration and dried under vacuum to
give product as a colorless solid (250 mg, 32%), which was used in
the next step without further purification.
Intermediate 2: 6-Methyl-pyrazine-2-carboxylic acid
(5-amino-bicyclo[3.2.1]oct-1-yl)-amide HCl salt
##STR00018##
[0104] Intermediate 2 was prepared via the processes of Schemes 7
and 8, supra, as follows:
Step 1: Bicyclo[3.2.1]octane-1,5-dicarboxylic acid diethyl
ester
##STR00019##
[0106] Using the similar experimental procedure described in the
synthesis of intermediate 1 (step 2),
bicyclo[3.2.1]octane-1,5-dicarboxylic acid diethyl ester was
prepared from cyclohexane-1,3-dicarboxylic acid diethyl ester at
0.18 mol reaction scale. ESI-MS m/z: 277 (M+H).sup.+
Step 2: Bicyclo[3.2.1]octane-1,5-dicarboxylic acid monoethyl
ester
##STR00020##
[0108] Partial hydrolysis of the cyclized diethyl ester 4 (1.3 g)
was done by using barium hydroxide (0.5 equiv) in ethanol (13 mL)
and water (3 mL) at ambient temperature for 18 hours. The reaction
was concentrated under reduced pressure and the resulting residue
was partitioned between water and ethyl acetate. The aqueous layer
was collected and washed again with ethyl acetate. The aqueous
layer was acidified with 1N HCl to pH 2, and then extracted with
ethyl acetate. The organic layer was collected, dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by column chromatography to
afford 500 mg (47%) of the desired product. ESI-MS m/z: 227
(M+H).sup.+
Step 3: 5-Benzyloxycarbonylamino-bicyclo[3.2.1]octane-1-carboxylic
acid ethyl ester
##STR00021##
[0110] Using the similar experimental procedure described in the
synthesis of intermediate 1 (step 4),
5-benzyloxycarbonylamino-bicyclo[3.2.1]octane-1-carboxylic acid
ethyl ester was made from bicyclo[3.2.1]octane-1,5-dicarboxylic
acid monoethyl ester via Curtius rearrangement with DPPA and TEA in
toluene, and quenched with BnOH at 1.1-10.3 mmol reaction scales.
ESI-MS m/z: 332 (M+H).sup.+
Step 4: 5-Amino-bicyclo[3.2.1]octane-1-carboxylic acid ethyl
ester
##STR00022##
[0112] 5-Benzyloxycarbonylamino-bicyclo[3.2.1]octane-1-carboxylic
acid ethyl ester (2.0 g, 6.05 mmol) was dissolved in ethanol (50.0
mL). Pd/C (10%) (0.32 g, 0.30 mmol) was added. The mixture was
hydrogenated under 50 psi H.sub.2 at rt for 6 hrs. The catalyst was
removed by filtration through a layer of Celite.RTM.. The filtrate
was concentrated under reduced pressure to afford 1.0 g (84%) of
the desired product. ESI-MS m/z: 198 (M+H).sup.+.
Step 5:
5-[(6-Methyl-pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]octane-1-ca-
rboxylic acid ethyl ester
##STR00023##
[0114] 5-Amino-bicyclo[3.2.1]octane-1-carboxylic acid ethyl ester
(0.5 g, 2.53 mmol) was dissolved in methylene chloride (10.0 mL,
156 mmol). 6-Methylpyrazine-2-carboxylic acid (0.35 g, 2.53 mmol),
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (1.12 g, 2.53 mmol) and triethylamine (0.71 mL,
5.07 mmol) in methylene chloride (10.0 mL, 156 mmol) were added.
The mixture was stirred at rt for 2 hours. The mixture was
concentrated under reduced pressure. The resulting residue was
purified on the CombiFlash.RTM. system (hexane/ethyl acetate: 100/0
to 30/70 in 8 min, then hexane/ethyl acetate: 30/70) to afford 0.60
g (75%) of the desired product. ESI-MS m/z: 318 (M+H).sup.+
Step 6:
5-[(6-Methyl-pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]octane-1-ca-
rboxylic acid
##STR00024##
[0116]
5-[(6-Methyl-pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]octane-1-car-
boxylic acid ethyl ester (0.60 g, 1.89 mmol) was dissolved in
tetrahydrofuran (10.0 mL, 123 mmol). Lithium hydroxide monohydrate
(0.40 g, 9.45 mmol) in water (6.0 mL, 333 mmol) was added. The
mixture was stirred at rt overnight. The mixture was concentrated
under reduced pressure. The resulting residue was participated in
ethyl acetate (20 mL) and water (20 mL). The aqueous layer was
collected, acidified with 1N HCl to pH 2, and extracted with ethyl
acetate (60 mL). The organic layer was washed with brine, dried
over Na.sub.2SO.sub.4 and concentrated to afford 340 mg (62%) of
the desired product as white solid. It was used in the next step
without further purification. ESI-MS m/z: 290 (M+H).sup.+
Step 7: 6-Methyl-pyrazine-2-carboxylic acid
(5-amino-bicyclo[3.2.1]oct-1-yl)-amide HCl salt
##STR00025##
[0118]
5-[(6-Methyl-pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]octane-1-car-
boxylic acid (0.340 g, 1.18 mmol) was suspended in toluene (10.0
mL, 93.9 mmol). Triethylamine (0.20 mL, 1.41 mmol) was added,
followed by the addition of diphenylphosphonic azide (0.25 mL, 1.18
mmol). The mixture was stirred at rt for 2 hours. Then the mixture
was heated at 90.degree. C. for 1 hour. The mixture was cooled down
and poured into ice-cold 6M aqueous HCl and stirred overnight. The
aqueous layer was collected, cooled down at 0.degree. C., basified
with solid K.sub.2CO.sub.3 to pH 11, and extracted with
CH.sub.2Cl.sub.2 (4.times.25 mL). The combined organic layer was
dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The resulting residue was dissolved in CH.sub.2Cl.sub.2,
4 M HCl/dioxane (1.0 mL). The mixture was concentrated under
reduced pressure to afford 345 mg (99%) of
6-methyl-pyrazine-2-carboxylic acid
(5-amino-bicyclo[3.2.1]oct-1-yl)-amide HCl salt as a white solid.
It was used in the next step without further purification. ESI-MS
m/z: 261 (M+H).sup.+.
Intermediate 3:
N-(5-Aminobicyclo[3.2.1]octan-1-yl)-3-fluorobenzamide
##STR00026##
[0119] Step 1: Dimethyl cyclohexane-1,3-dicarboxylate
##STR00027##
[0121] To a solution of 1,3-cyclohexanedicarboxylic acid (25 g,
0.145 mol) in methanol (250 mL) was added concentrated
H.sub.2SO.sub.4 (10 mL) and the reaction solution was refluxed
overnight. After cooled to room temperature, methanol was removed
under reduced pressure. The residue was diluted with ethyl acetate
(500 mL), washed with Sat. Na.sub.2CO.sub.3 (2.times.300 mL) and
brine (100 mL), dried over MgSO.sub.4 and concentrated under
reduced pressure to give 27.4 g (94%) of dimethyl
cyclohexane-1,3-dicarboxylate as a light yellow oil. ESI-MS m/z:
201 (M+H).sup.+.
Step 2: Dimethyl
1-(3-chloropropyl)cyclohexane-1,3-dicarboxylate
##STR00028##
[0123] To a pre-cooled (-78.degree. C.) solution of lithium
diisopropylamide (36 mL, 78 mmol) in THF (250 mL) was added DMPU
(30.5 g, 238 mmol) dropwise (not allowing the temperature to exceed
-65.degree. C.), followed by an addition of a solution of dimethyl
cyclohexane-1,3-dicarboxylate (11.9 g, 59.5 mmol) in THF (50 mL) at
-78.degree. C. over 20 min. After stirring at -78.degree. C. for
one hour, 1-bromo-2-chloroethane (11.1 g, 77.4 mmol) was added and
the reaction mixture was slowly warmed up to room temperature
overnight. After quenched with Sat. NH.sub.4Cl (100 mL), the
mixture was concentrated under reduced pressure. The resulting
residue was diluted with water (200 mL) and extracted with
dichloromethane (4.times.100 mL). The combined organic layer was
washed with water (100 mL) and brine (100 mL), dried over MgSO4 and
concentrated under reduced pressure. The resulting residue was
purified by column chromatography (silica gel, petroleum
ether/ethyl acetate: 20/1) to afford 11.7 g (75%) of dimethyl
1-(3-chloropropyl)cyclohexane-1,3-dicarboxylate as a yellow oil.
ESI-MS m/z: 263 (M+H).sup.+.
Step 3: Dimethyl bicyclo[3.3.1]nonane-1,5-dicarboxylate
##STR00029##
[0125] To a pre-cooled (-78.degree. C.) solution of lithium
diisopropylamide (27 mL, 54 mmol) in THF (80 mL) was added DMPU
(30.2 g, 236 mol) dropwise, followed by an addition of dimethyl
1-(3-chloropropyl)cyclohexane-1,3-dicarboxylate (11.7 g, 44.7 mmol)
in THF (50 mL) within 20 min. The reaction mixture was stirred for
30 min at -78.degree. C. and then allowed to warm up to room
temperature over a period of 1.5 h. After quenched with saturated
ammonium chloride (100 mL), the mixture was concentrated under
reduced pressure. The residue was diluted with water (300 mL) and
extracted with dichloromethane (4.times.100 mL). The combined
organic layer was washed with water (100 mL) and brine (100 mL),
dried over MgSO4 and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel,
petroleum ether/ethyl acetate: 20/1) to afford 8.32 g (82%) of
dimethyl bicyclo[3.3.1]nonane-1,5-dicarboxylate as a light yellow
oil. ESI-MS m/z: 227 (M+H).sup.+.
Step 4: 5-(methoxycarbonyl)bicyclo[3.3.1]nonane-1-carboxylic
acid
##STR00030##
[0127] A solution of dimethyl
bicyclo[3.3.1]nonane-1,5-dicarboxylate (8.32 g, 36.8 mmol) and
Ba(OH).sub.2.8H.sub.2O (5.80 g, 18.4 mmol) in ethanol (40 mL) and
H.sub.2O (10 mL) was refluxed overnight. After cooled to room
temperature, the mixture was concentrated under reduced pressure.
The resulting residue was added diluted with water (100 mL) and
extracted with diethyl ether (3.times.200 mL). The combined organic
layer was washed with brine (100 mL), dried over sodium sulfate and
concentrated under reducer pressure to recover starting material as
an orange oil. The aqueous phase was adjusted to pH 1.about.2 with
2N aq. HCl, and extracted with dichloromethane (3.times.100 mL).
The combined organic layer was washed with brine (100 mL), dried
over sodium sulfate and concentrated under reduced pressure to
afford 1.8 g (67%) of
5-(methoxycarbonyl)bicyclo[3.3.1]nonane-1-carboxylic acid as a
white solid. ESI-MS m/z: 213 (M+H).sup.+.
Step 5: Methyl
5-(benzyloxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylate
##STR00031##
[0129] A mixture of
5-(methoxycarbonyl)bicyclo[3.3.1]nonane-1-carboxylic acid (5.23 g,
24.7 mmol), diphenylphosphonic azide (8.0 mL, 36.9 mmol) and
triethylamine (1.0 mL, 136 mmol) in toluene (150 mL) was stirred at
room temperature for one hour, and then refluxed for three hours.
Benzyl alcohol (4.0 mL, 38.7 mmol) was added, and the mixture was
continued to reflux overnight. After cooled to room temperature,
the reaction mixture was diluted with ethyl acetate (100 mL),
washed with Sat. NaHCO.sub.3 and brine, dried over sodium sulfate,
and concentrated under reduced pressure. The resulting residue was
purified by column chromatography (silica gel, petroleum
ether/ethyl acetate: 20/1) to afford 10 g of methyl
5-(benzyloxycarbonylamino)bicyclo-[3.2.1]octane-1-carboxylate
(containing BnOH) as a brown oil. ESI-MS m/z: 318 (M+H).sup.+. It
was used in the next step without purification.
Step 6: 5-(benzyloxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylic
acid
##STR00032##
[0131] To a solution of methyl
5-(benzyloxycarbonylamino)bicyclo-[3.2.1]octane-1-carboxylate (25
g, crude product) in methanol (200 mL) was added NaOH (5N, 50 mL)
and the reaction mixture was refluxed for two hours. After cooled
to room temperature, the mixture was concentrated under reduced
pressure. The residue was diluted with water (100 mL) and extracted
with diethyl ether (3.times.100 mL) to remove the organic
impurities. The aqueous phase was adjusted to pH 1.about.2 with 2N
aq. HCl, and extracted with dichloromethane (3.times.100 mL). The
combined organic layer was washed with brine, dried over sodium
sulfate and concentrated under reduced pressure to afford 8.5 g
(49%, steps 5 and 6) of
5-(benzyloxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylic acid as
a yellow oil. ESI-MS m/z: 304 (M+H).sup.+.
Step 7: Benzyl 5-aminobicyclo[3.2.1]octan-1-ylcarbamate
##STR00033##
[0133] A mixture of
5-(benzyloxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylic acid
(8.5 g, 28.0 mmol), diphenylphosphonic azide (9.3 g, 33.8 mmol) and
triethylamine (5 mL, 68 mmol) in toluene (150 mL) was stirred at
room temperature for one hour, and then refluxed for three hours.
After cooled to 0.degree. C., a solution of TMSOK (10.7 g, 83.6
mmol) in THF (85 mL) was added. The reaction mixture was warmed to
room temperature and stirred for 1 h, and then quenched with 5%
citric acid (20 mL) and concentrated under reduced pressure. The
residue was treated with aq. HCl (2 N, 200 mL) at 0.degree. C. The
resulting mixture was extracted with ethyl acetate (3.times.100
mL). The aqueous phase was adjusted to pH 9.about.10 with
Na.sub.2CO.sub.3 and extracted with dichloromethane/methanol (10/1,
3.times.150 mL). The combined organic layer was washed with water
and brine, dried over sodium sulfate and concentrated under reduced
pressure to afford 5.13 g (42%) of benzyl
5-aminobicyclo[3.2.1]octan-1-ylcarbamate as a yellow solid. ESI-MS
m/z: 275 (M.sup.++1).
Step 8: Benzyl
(5-(3-fluorobenzamido)bicyclo[3.2.1]octan-1-yl)carbamate
##STR00034##
[0135] To a solution of benzyl
5-aminobicyclo[3.2.1]octan-1-ylcarbamate (402 mg, 1.47 mmol) and
3-fluorobenzoic acid (309 mg, 2.21 mmol) in DMF (20 mL) was added
HATU (1.12 g, 2.95 mmol) and DIPEA (1 mL). After stirring at room
temperature for 1 hour, water (100 mL) was added and the mixture
was extracted with ethyl acetate (3.times.50 mL). The combined
organic layer was washed with brine, dried over Na.sub.2SO.sub.4,
and concentrated under reduced pressure. The resulting residue was
purified by column chromatography (silica gel, petroleum
ether/ethyl acetate: 2/1) to give 513 mg (88%) of benzyl
(5-(3-fluorobenzamido)bicyclo[3.2.1]octan-1-yl) carbamate as a
white solid. ESI-MS m/z: 397 (M+H).sup.+.
Step 9: N-(5-aminobicyclo[3.2.1]octan-1-yl)-3-fluorobenzamide
##STR00035##
[0137] To a solution of
N-(5-aminobicyclo[3.2.1]octan-1-yl)-3-fluorobenzamide (513 mg, 1.30
mmol) in methanol (50 mL) was added Pd/C (10%, 100 mg) and the
reaction mixture was hydrogenated (1 atm) at room temperature
overnight. The reaction mixture was then filtered through a Celite
pad, and the filtrate was concentrated under reduced pressure to
afford N-(5-aminobicyclo[3.2.1]octan-1-yl)-3-fluorobenzamide (329
mg, 97%) as a white solid. ESI-MS m/z: 263 (M+H).sup.+.
Intermediate 4: 6-Methyl-pyrazine-2-carboxylic
acid(5-amino-bicyclo[3.2.1]oct-1-yl)-amide
##STR00036##
[0139] Intermediate 4 (6.2 g) was prepared analogously to
intermediate 3. .sup.1H NMR (500 MHz, CD.sub.3OD): .delta. 8.87 (s,
1H), 8.56 (s, 1H), 2.51 (s, 3H), 2.11-2.01 (m, 3H), 1.89-1.88 (m,
1H), 1.71-1.40 (m, 8H). ESI-MS m/z: 261 (M+H).sup.+.
Intermediate 5:
N-(5-aminobicyclo[3.2.1]oct-1-yl)-3-chlorobenzamide
##STR00037##
[0141] Intermediate 5 (2.3 g) was prepared analogously to
intermediate 3. .sup.1H NMR (500 MHz, CDCl3): .delta. 7.71 (s, 1H),
7.61 (d, J=2.5 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.37-7.34 (m, 1H),
6.13 (s, 1H), 2.21-1.98 (m, 4H), 1.79-1.52 (m, 10H). ESI-MS m/z:
279 (M+H).sup.+.
Intermediate 6:
N-(5-aminobicyclo[3.2.1]oct-1-yl)-3-methylbenzamide
##STR00038##
[0143] Intermediate 6 (2.2 g) was prepared analogously to
intermediate 3. .sup.1H NMR (500 MHz, CDCl3): b 7.54-7.50 (m, 2H),
7.22 (d, J=6.0 Hz, 2H), 6.78 (s, 1H), 2.32 (s, 3H), 2.12-1.96 (m,
4H), 1.69-1.41 (m, 10H). ESI-MS m/z: 259 (M+H).sup.+.
Intermediate 7:
N-(5-aminobicyclo[3.2.1]oct-1-yl)-5-fluoropyridine-2-carboxamide
##STR00039##
[0145] Intermediate 7 (50 mg) was prepared analogously to
intermediate 3. ESI-MS m/z: 264 (M+H).sup.+.
Intermediate 8:
N-(5-aminobicyclo[3.2.1]oct-1-yl)-5-methylpyrazine-2-carboxamide
##STR00040##
[0147] Intermediate 8 (500 mg) was prepared analogously to
intermediate 3. ESI-MS m/z: 261 (M+H).sup.+.
Intermediate 9:
N-(5-aminobicyclo[3.2.1]oct-1-yl)pyrazine-2-carboxamide
##STR00041##
[0149] Intermediate 9 (800 mg) was prepared analogously to
intermediate 3. .sup.1H NMR (500 MHz, CDCl3): .delta. 9.39 (d,
J=1.0 Hz, 1H), 8.74 (d, J=2.0 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H), 7.88
(s, 1H), 2.27-1.97 (m, 4H), 1.82-1.70 (m, 6H), 1.60-1.54 (m, 4H).
ESI-MS m/z: 247 (M+H).sup.+.
Intermediate 10:
N-(5-aminobicyclo[3.2.1]oct-1-yl)pyridine-2-carboxamide
##STR00042##
[0151] Intermediate 10 (2.8 g) was prepared analogously to
intermediate 3. .sup.1H NMR (500 MHz, CDCl3): .delta. 8.53-8.52 (m,
1H), 8.18-8.15 (m, 2H), 7.86-7.82 (m, 1H), 7.42-7.40 (m, 1H),
2.28-1.97 (m, 4H), 1.80-1.55 (m, 10H). ESI-MS m/z: 246
(M+H).sup.+.
Intermediate 11: 6-Methyl-pyridine-2-carboxylic acid
(5-amino-bicyclo[3.2.1]oct-1-yl)-amide
##STR00043##
[0153] Intermediate 11 (3.2 g) was prepared analogously to
intermediate 3. .sup.1H NMR (500 MHz, CDCl.sub.3): .delta. 8.20 (s,
1H), 7.96 (d, J=9.5 Hz, 1H), 7.69 (t, J=9.5 Hz, 1H), 7.26 (d, J=9.5
Hz, 1H), 2.56 (s, 3H), 2.28-1.96 (m, 4H), 1.80-1.55 (m, 10H);
ESI-MS m/z: 260 (M+H).sup.+.
Intermediates 12 and 13:
{(1S,5R)-5-[(6-Methyl-pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-
-carbamic acid tert-butyl ester and
{(1R,5S)-5-[(6-methyl-pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-
-carbamic acid tert-butyl ester
##STR00044##
[0155] To a solution of 6-methyl-pyrazine-2-carboxylic acid
(5-amino-bicyclo[3.2.1]oct-1-yl)-amide (intermediate 4, 1.15 g,
4.42 mmol) in DCM (20.0 mL) was added triethylamine (1.23 mL, 8.83
mmol), followed by di-tert-butyldicarbonate (1.01 g, 4.64 mmol).
After stirring at rt overnight, the reaction mixture was
concentrated under reduced pressure. The residue was purified on
the CombiFlash.RTM. system (hexane/ethyl acetate: 100/0 to 40/60 in
8 mins, then hexane/ethyl acetate: 40/60) to afford 1.0 g (63%) of
{5-[(6-methyl-pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-carbami-
c acid tert-butyl ester (ESI-MS m/z: 361 (M+H).sup.+), which was
then resolved on a Supercritical Fluid Chromatography (SFC)
preparative separation system (Column: 30.times.150 mm OJ-H (Chiral
Technologies Inc). Solvent: isopropyl alcohol/CO.sub.2: 5/95.
Detector: UV at 250 nm. Flow rate: 100 mL/min). The front peak was
arbitrarily assigned as
{(1S,5R)-5-[(Pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-carbamic
acid tert-butyl ester (intermediate 12, 0.32 g, ESI-MS m/z: 361
(M+H).sup.+) and the back peak was arbitrarily assigned as
{(1R,5S)-5-[(pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-carbamic
acid tert-butyl ester (intermediate 13, 0.33 g, ESI-MS m/z: 361
(M+H).sup.+).
Intermediates 14 and 15:
{(1S,5R)-5-[(Pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-carbamic
acid tert-butyl ester and
{(1R,5S)-5-[(pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-carbamic
acid tert-butyl ester
##STR00045##
[0157] In an analogous manner to intermediates 12 and 13,
intermediates 14 (ESI-MS m/z: 347 (M+H).sup.+) and 15 (ESI-MS m/z:
347 (M+H).sup.+) were made from 0.95 g of intermediate 9. The
absolute stereochemistry of 14 and 15 were arbitrarily
assigned.
Intermediates 16 and 17:
{(1S,5R)-5-[(6-Methyl-pyridine-2-carbonyl)-amino]bicyclo[3.2.1]oct-1-yl}--
carbamic acid tert-butyl ester and
{(1R,5S)-5-[(6-methyl-pyridine-2-carbonyl)-amino]
bicyclo[3.2.1]oct-1-yl}-carbamic acid tert-butyl ester
##STR00046##
[0159] In an analogous manner to intermediates 12 and 13,
intermediates 16 (2.2 g, ESI-MS m/z: 360 (M+H).sup.+) and 17 (2.2
g, ESI-MS m/z: 360 (M+H).sup.+) were made from 5.2 g of
intermediate 11. The absolute stereochemistry of 16 and 17 were
arbitrarily assigned.
Intermediates 18 and 19: {(1S,5R)-5-[(Pyridine-2-carbonyl)-amino]
bicyclo[3.2.1]oct-1-yl}-carbamic acid tert-butyl ester and
{(1R,5S)-5-[(pyridine-2-carbonyl)-amino]bicyclo[3.2.1]oct-1-yl}-carbamic
acid tert-butyl ester
##STR00047##
[0161] In an analogous manner to intermediates 12 and 13,
intermediates 18 (1.2 g, ESI-MS m/z: 346 (M+H).sup.+) and 19 (1.25
g, ESI-MS m/z: 346 (M+H).sup.+) were made from 2.0 g of
intermediate 10. The absolute stereochemistry of 16 and 17 were
arbitrarily assigned.
Intermediate 20: Pyrazine-2-carboxylic acid
((1S,5R)-5-amino-bicyclo[3.2.1]oct-1-yl)-amide HCl salt
##STR00048##
[0163] To a solution of
{(1R,5S)-5-[(pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-carbamic
acid tert-butyl ester (intermediate 15, 0.9 g, 2.6 mmol) in
methylene chloride (5.0 mL) was added 4 M of hydrogen chloride in
1,4-dioxane (6.5 mL). After stirring at room temperature overnight,
the reaction mixture was concentrated under reduced pressure to
afford 0.7 g of pyrazine-2-carboxylic acid
((1S,5R)-5-amino-bicyclo[3.2.1]oct-1-yl)-amide HCl salt, which was
used in the next step without further purification. ESI-MS m/z: 247
(M+H).sup.+.
Intermediate 21: 6-Methyl-pyridine-2-carboxylic acid
((1S,5R)-5-amino-bicyclo[3.2.1]oct-1-yl)-amide
##STR00049##
[0165] In an analogous manner to intermediate 20, intermediate 21
(2.0 g, ESI-MS m/z: 260 (M+H).sup.+) was prepared from intermediate
17 (2.5 g).
Intermediate 22: 6-Methyl-pyridine-2-carboxylic acid
((1R,5S)-5-amino-bicyclo[3.2.1]oct-1-yl)-amide
##STR00050##
[0167] In an analogous manner to intermediate 20, intermediate 22
(1.36 g, ESI-MS m/z: 260 (M+H).sup.+) was prepared from
intermediate 16 (2.2 g).
Intermediate 23: Pyridine-2-carboxylic acid
((1S,5R)-5-amino-bicyclo[3.2.1]oct-1-yl)-amide
##STR00051##
[0169] In an analogous manner to intermediate 20, intermediate 23
(1.1 g, ESI-MS m/z: 246 (M+H).sup.+) was prepared from intermediate
19 (1.25 g).
Intermediate 24: Pyridine-2-carboxylic acid
((1R,5S)-5-amino-bicyclo[3.2.1]oct-1-yl)-amide
##STR00052##
[0171] In an analogous manner to intermediate 20, intermediate 24
(1.05 g, ESI-MS m/z: 246 (M+H).sup.+) was prepared from
intermediate 18 (1.2 g).
Intermediate 25: 6-Methyl-pyrazine-2-carboxylic acid
((1S,5R)-5-amino-bicyclo[3.2.1]oct-1-yl)-amide HCl salt
##STR00053##
[0173] In an analogous manner to intermediate 20, intermediate 25
(1.2 g, ESI-MS m/z: 261 (M+H).sup.+) was prepared from intermediate
13 (1.5 g).
Intermediate 26:
5-(6-Methylpyrazine-2-carboxamido)bicyclo[3.2.1]octane-1-carboxylic
acid
##STR00054##
[0175] Intermediate 26 was prepared via the processes of Scheme 8,
supra, as follows:
Step 1: Methyl 5-aminobicyclo[3.2.1]octane-1-carboxylate
##STR00055##
[0177] To a solution of methyl
5-(benzyloxycarbonylamino)bicyclo-[3.2.1]octane-1-carboxylate (10
g) in methanol (150 mL) was added 10% Pd/C (1 g) and the reaction
mixture was stirred under H.sub.2 (1 atm) at room temperature
overnight. The reaction mixture was filtered through a Celite pad,
and the filtrate was concentrated. The residue was treated with
aqueous HCl (2N, 200 mL) at 0.degree. C. and then extracted with
ethyl acetate (3.times.100 mL) to remove organic impurities. The
aqueous phase was adjusted to pH 9.about.10 with Sat.
Na.sub.2CO.sub.3 and extracted with dichloromethane/methanol (10/1,
3.times.100 mL). The combined organic layer was washed with water
(100 mL) and brine (100 mL), dried over sodium sulfate and
concentrated under reduced pressure to afford 2.98 g of methyl
5-aminobicyclo[3.2.1]octane-1-carboxylate as a yellow oil. ESI-MS
m/z: 184 (M+H).sup.+.
Step 2: methyl
5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octane-1-carboxylate
##STR00056##
[0179] To a solution of methyl
5-aminobicyclo[3.2.1]octane-1-carboxylate (0.98 g, 5.36 mmol) and
6-methylpyrazine-2-carboxylic acid (0.89 g, 6.45 mmol) in DCM (30
mL) and TEA (2 mL) was added PyBOP (3.35 g, 6.44 mmol). After
stirring at room temperature overnight, water (30 mL) was added and
the mixture was extracted with DCM (3.times.50 mL). The combined
organic layer was washed with Sat. NaHCO.sub.3 (50 mL) and brine
(50 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The residue was purified by column chromatography (silica
gel, petroleum ether/ethyl acetate: 1/1) to afford 1.28 g (79%) of
methyl
5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octane-1-carboxylate
as an off-white solid. ESI-MS m/z: 304 (M+H).sup.+.
Step 3:
5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octane-1-carboxyli-
c acid
##STR00057##
[0181] A solution of methyl
5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octane-1-carboxylate
(1.28 g, 4.21 mmol) and LiOH (0.15 g, 6.25 mmol) in methanol (30
mL) and H.sub.2O (3 mL) was refluxed for two hours. After cooled to
room temperature, methanol was removed under reduced pressure. The
residue was partitioned between water (50 mL) and diethyl ether (50
mL) to remove organic impurities. The aqueous phase was adjusted to
pH 1.about.2 with 2N aq. HCl and then extracted with
dichloromethane (3.times.50 mL). The combined organic layer was
washed with water (50 mL) and brine (50 mL), dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford
1.11 g (91%) of
5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octane-1-carboxylic
acid as a white solid. ESI-MS m/z: 290 (M+H).sup.+.
Intermediate 27:
5-amino-N-(2-methylpyrimidin-4-yl)bicyclo[3.2.1]octane-1-carboxamide
##STR00058##
[0183] Intermediate 27 was prepared via the processes of Scheme 9,
supra, as follows:
Step 1: 5-(benzyloxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylic
acid
##STR00059##
[0185] To a solution of
5-(benzyloxycarbonylamino)bicyclo-[3.2.1]octane-1-carboxylate (10
g, 31.5 mmol) in MeOH (150 mL) was added NaOH (2N, 50 mL) and the
reaction solution was stirred at room temperature overnight. The
organic solvent was removed under reduced pressure and the
remaining aqueous solution was extracted with ethyl acetate (20 mL)
to remove the organic impurities, and then adjusted to pH 3 with 2N
aq. HCl. The acidic aqueous solution was extracted with ethyl
acetate (3.times.20 mL) and the combined organic layer was washed
with brine, dried over Na.sub.2SO.sub.4 and concentrated to give 9
g (95%) 5-(benzyloxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylic
acid as a colorless oil, which was solidified after standing at
room temperature overnight. ESI-MS m/z: 304 (M+H).sup.+.
Step 2: Benzyl 5-carbamoylbicyclo[3.2.1]octan-1-ylcarbamate
##STR00060##
[0187] To a solution of
5-(benzyloxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylic acid
(1.0 g, 3.3 mmol) in DCM (30 mL) was added dropwise oxalyl chloride
(5 mL), followed by two or three drops of DMF. After stirring at
room temperature for an hour, the reaction mixture was concentrated
under reduced pressure. The resulting residue was dissolved in THF
(30 mL) and the solution was bubbled with NH.sub.3 (gas). A white
solid crashed out and the reaction mixture was continued to stir
for half an hour. After quenched with brine (20 mL), the mixture
was extracted with ethyl acetate (3.times.20 mL). The combined
organic layer was washed with brine, dried over Na.sub.2SO.sub.4
and concentrated under reduced pressure to afford 1 g (100%) of
benzyl 5-carbamoylbicyclo[3.2.1]octan-1-ylcarbamate as a colorless
oil, which was used in the next step without purification. ESI-MS
m/z: 303 (M+H).sup.+.
Step 3: Benzyl 5-(2-methylpyrimidin-4-ylcarbamoyl)bicyclo[3.2.1]
octan-1-ylcarbamate
##STR00061##
[0189] To a mixture of benzyl
5-carbamoylbicyclo[3.2.1]octan-1-ylcarbamate (1 g, 3.3 mmol) and
Cs.sub.2CO.sub.3 (1.6 g, 4.9 mmol) and BINAP (200 mg, 0.3 mmol) in
toluene (60 mL), was added 4-chloro-2-methylpyrimidine (430 mg, 3.3
mmol), followed by Pd.sub.2(dba).sub.3 (300 mg, 0.32 mmol). The
mixture was stirred at 100.degree. C. under N.sub.2 overnight.
After cooled to room temperature, the reaction mixture was
concentrated under reduced pressure and the resulting residue was
purified by column chromatography (silica gel, petroleum
ether/ethyl acetate: 4/1) to give 1 g (77%) of benzyl
5-(2-methylpyrimidin-4-ylcarbamoyl)bicyclo[3.2.1]
octan-1-ylcarbamate as a light yellow oil. ESI-MS m/z: 395
(M+H).sup.+.
Step 4:
5-amino-N-(2-methylpyrimidin-4-yl)bicyclo[3.2.1]octane-1-carboxami-
de
##STR00062##
[0191] A solution of benzyl
5-(2-methylpyrimidin-4-ylcarbamoyl)bicyclo[3.2.1]octan-1-ylcarbamate
(1 g, 2.5 mmol) in HBr/HOAc (33% solution, 8 mL) was stirred at
room temperature for an hour and then concentrated under reduced
pressure. The resulting residue was dissolved in aq. HCl (6N, 10
mL) and extracted with ethyl acetate (10 mL) to remove the organic
impurities. The aqueous phase was basified with aq. NaOH (6N, 4
mL), and then extracted with DCM (4.times.20 mL). The combined
organic layer was washed with brine, dried over Na.sub.2SO.sub.4
and concentrated under reduced pressure to afford 350 mg (66%) of
5-amino-N-(2-methylpyrimidin-4-yl)bicyclo[3.2.1]octane-1-carboxamide
as a white solid ESI-MS m/z: 261 (M+H).sup.+.
Intermediate 28:
5-amino-N-(6-methylpyrazin-2-yl)bicyclo[3.2.1]octane-1-carboxamide
##STR00063##
[0193] In an analogous manner to intermediate 27, 520 mg of
intermediate 28 was made. ESI-MS m/z: 261 (M+H).sup.+.
Intermediate 29:
5-amino-N-pyridin-3-ylbicyclo[3.2.1]octane-1-carboxamide
##STR00064##
[0195] In an analogous manner to intermediate 27, 175 mg of
intermediate 29 was made. ESI-MS m/z: 246 (M+H).sup.+.
Intermediate 30:
5-amino-N-pyrazin-2-ylbicyclo[3.2.1]octane-1-carboxamide
##STR00065##
[0197] In an analogous manner to intermediate 27, 110 mg of
intermediate 30 was made. ESI-MS m/z: 247 (M+H).sup.+.
Intermediate 31:
5-amino-N-(6-methylpyridin-2-yl)bicyclo[3.2.1]octane-1-carboxamide
##STR00066##
[0199] In an analogous manner to intermediate 27, 530 mg of
intermediate 31 was made. ESI-MS m/z: 260 (M+H).sup.+.
[0200] 3. Preparation of Compounds of the Invention
[0201] Unless specified otherwise, all starting materials and
reagents were obtained from commercial suppliers, such as
Sigma-Aldrich Corp. (St. Louis, Mo., USA) and its subsidiaries, and
used without further purification.
Example 1: N,N'-(bicyclo[3.2.1]octane-1,5-diyl)dipicolinamide
##STR00067##
[0203] Example 1 of Table was prepared from intermediate 1 via the
process of Scheme 1, supra, as follows:
[0204] A mixture of bicyclo[3.2.1]octane-1,5-diamine
dihydrochloride (20 mg, 0.094 mmol) and picolinic acid (34.6 mg,
0.28 mmol) in methylene chloride (6 mL) was treated with
triethylamine (0.13 mL, 0.94 mmol). The mixture was stirred at rt
for a few minutes. N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (72.0 mg, 0.38 mmol) and 4-dimethylaminopyridine (2.3
mg, 0.02 mmol) were added. The reaction was stirred at rt
overnight. The reaction was diluted with a small amount of
dichloromethane and washed with water. The organic layer was
collected, dried over anhydrous sodium sulfate, filtered, and
concentrated under reduced pressure. The resulting residue was
purified with chromatography to give 5.4 mg (16%) of the desired
product. Analytical data were listed in Table 3.
Example 2 and 3:
N-(5-(3-chlorobenzamido)bicyclo[3.2.1]octan-1-yl)-6-methylpicolinamide
and
N,N'-(bicyclo[3.2.1]octane-1,5-diyl)bis(6-methylpicolinamide)
##STR00068##
[0206] Example 2 and 3 of Table 1 were prepared from intermediate 1
via the process of Scheme 2, supra, as follows:
[0207] A mixture of bicyclo[3.2.1]octane-1,5-diamine
dihydrochloride (100 mg, 0.469 mmol), 6-methylpicolinic acid (64.3
mg, 0.47 mmol) and 3-chloro-benzoic acid (73.4 mg, 0.47 mmol) in
methylene chloride (10 mL, 200 mmol) was treated with triethylamine
(0.66 mL, 4.69 mmol). The mixture was stirred for a few minutes.
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (360
mg, 1.88 mmol) and 4-dimethylaminopyridine (11.5 mg, 0.0938 mmol)
were added. The reaction mixture was stirred at rt overnight. The
reaction was diluted with a small amount of dichloromethane and
washed with water. The organic layer was dried over anhydrous
sodium sulfate, filtered, and concentrated under reduced pressure.
The crude material was purified on a reversed phase liquid
chromatography/mass spectrometry (RP-HPLC/MS) purification system
(Gradient: acetonitrile in water, 25-95% in 3.6 minutes with a
cycle time of 5 min. A shallow gradient of 30-58% of acetonitrile
was used between 0.75-3.6 min to separate close-eluting impurities.
Flow rate: 100 mL/min. Mobile phase additive: 48 mM of ammonium
formate. Column: Inertsil.RTM. C18, 30.times.50 mm, 5 um particle
size) to afford 3.0 mg (2%) of 6-methyl-pyridine-2-carboxylic acid
[5-(3-chloro-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide (Example
2) and 7.0 mg (4%) of
N,N'-(bicyclo[3.2.1]octane-1,5-diyl)bis(6-methylpicolinamide)
(Example 3). Analytical data were listed in Table 3.
Example 4: 6-Methyl-pyrazine-2-carboxylic acid
{5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide
##STR00069##
[0209] Example 4 of Table 1 was prepared from intermediate 2 via
the process of Scheme 3, supra, as follows:
[0210] A mixture of 6-methyl-pyrazine-2-carboxylic acid
(5-amino-bicyclo[3.2.1]oct-1-yl)-amide.ClH (15 mg, 0.05 mmol),
picolinic acid (6.2 mg, 0.05 mmol),
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (22.4 mg, 0.05 mmol) and triethylamine (0.02
mL, 0.15 mmol) in methylene chloride (2.0 mL) was stirred at rt for
2 hours. The mixture was concentrated under reduced pressure, and
the resulting residue was purified on a reversed phase liquid
chromatography/mass spectrometry (RP-HPLC/MS) purification system
(Gradient: acetonitrile in water, 19-95% in 3.5 minutes with a
cycle time of 5 min. A shallow gradient between 25-48% of
acetonitrile was used between 0.65-3.2 min to separate
close-eluting impurities. Flow rate: 100 mL/min. Mobile phase
additive: 48 mM of ammonium formate. Column: Inertsil.RTM. C18,
30.times.50 mm, 5 um particle size (GL Sciences)) to afford 8 mg
(40%) of the desired product. Analytical data were listed in Table
3.
[0211] In an analogous manner to Examples 4, Examples 5-8 of Table
1 were made from commercially available
6-methyl-pyrazine-2-carboxylic acid, 3-fluoro-benzoic acid,
4-fluoro-benzoic acid and 2-methyl-pyrimidine-4-carboxylic acid at
0.05-2 mmol reaction scales. Analytical data were listed in Table
3.
Example 98:
N-(5-(3-methylbenzamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide
##STR00070##
[0213] Example 98 of Table 1 was prepared from intermediate 9 via
the process of Scheme 3, supra, as follows:
[0214] To a solution of intermediate 9 (25 mg, 0.11 mmol) and
3-methylbenzoic acid (23 mg, 0.15 mmol) in DMF (5 mL) was added
DIPEA (78 mg, 0.66 mmol) and HATU (54 mg, 0.15 mmol). After
stirring at room temperature for one hour, water (20 mL) was added
and the solution was extracted with ethyl acetate (3.times.20 mL).
The combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, and concentrated under reduced pressure. The
resulting residue was purified on a reversed phase liquid
chromatography/mass spectrometry (RP-HPLC/MS) purification system
(Mobile phase: A) 10 mM NH.sub.4HCO.sub.3 in water; B)
acetonitrile. Gradient: 32-37% B in 17 min, 37-95% B in 0.2 min,
then hold at 95% B for 4 min, back to 10% B in 0.2 min, stop at 24
min. Flow rate: 30 mL/min. Column: Shimadzu prc-ods 20.times.250
mm, 15 .mu.m, two connected in series) to afford 10 mg (27%) of
N-(5-(3-methylbenzamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide
as a white solid. Analytical data were listed in Table 3.
[0215] In an analogous manner to example 98, examples 9-19, 20-34,
35-48, 49-51, 52-64, 65-79, 80-93, 94-103 and 104-115 of Table 1
were made at 0.1-2 mmol reaction scales from commercially available
carboxylic acids and amine intermediates 5, 3, 4, 6, 7, 8, 4, 11, 9
and 10 with yield ranging from 20-80%, respectively. Analytical
data were listed in Table 3.
[0216] In an analogous manner to example 4, examples 116-121,
122-131, 141-150 and 151-155 of Table 1 were made at 0.1-1 mmol
from commercially available carboxylic acids and chiral amine
intermediates 22, 21, 23 and 25 with yield ranging from 40-70%,
respectively. The absolute stereochemistry of these compounds was
arbitrarily assigned. Analytical data were listed in Table 3.
Example 133. 6-Methyl-pyrazine-2-carboxylic acid
{(1S,5R)-5-[(4-methyl-thiazole-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-
-amide
##STR00071##
[0218] To a solution of
{(1R,5S)-5-[(6-methyl-pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-
-carbamic acid tert-butyl ester (intermediate 13, 0.050 g, 0.14
mmol) in 1 mL of methylene chloride, 4 M of hydrogen chloride in
1,4-dioxane (0.5 mL) was added. After stirring at rt overnight, the
reaction mixture was concentrated under reduced pressure to
dryness. The resulting residue was dissolved in methylene chloride
(1.0 mL), 4-methyl-1,3-thiazole-2-carboxylic acid (19.8 mg, 0.14
mmol), triethylamine (7.73 .mu.L, 0.56 mmol) and
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (61.4 mg, 0.14 mmol) were added. After stirring
at rt for 1 hour, the reaction mixture was concentrated under
reduced pressure. The resulting residue was purified on the
CombiFlash.RTM. system (hexane/ethyl acetate: 100/0 to 10/90 in 10
mins, then hexane/ethyl acetate: 10/90) to afford 31 mg (58%) of
6-methyl-pyrazine-2-carboxylic acid
{(1S,5R)-5-[(4-methyl-thiazole-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-
-amide. Analytical data are listed in Table 3.
[0219] In an analogous manner to example 133, examples 132, 134 and
135 of Table 1 were made at .about.0.15 mmol reaction scale from
intermediate 13 and commercially available carboxylic acids with
yield .about.60%; examples 136-140 of Table 1 were made at
.about.0.15 mmol reaction scale from intermediate 12 and
commercially available carboxylic acids with yield .about.60%.
Analytical data were listed in Table 3.
Examples 158 and 159: 6-Methyl-pyrazine-2-carboxylic acid
{(1R,5S)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide
and 6-methyl-pyrazine-2-carboxylic acid
{(1S,5R)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide
##STR00072##
[0221] Example 8 (0.37 g, 1.0 mmol) was resolved on a chiral HPLC
system (column: 30.times.150 mm OJ (Chiral Technologies Inc).
Solvent: EtOH/hexane: 10/90. Detector: UV at 290 nm. Flow rate: 14
mL/min). The front peak was arbitrarily assigned as
6-methyl-pyrazine-2-carboxylic acid
{(1R,5S)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-ami-
de (example 158, 56 mg) and the back peak was arbitrarily assigned
as 6-methyl-pyrazine-2-carboxylic acid
{(1S,5R)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide
(example 159, 81 mg).
[0222] Similarly, examples 156 (31 mg) and 157 (33 mg) of Table 1
were obtained by resolution of example 8, examples 160 (90 mg) and
161 (90 mg) of Table 1 were obtained by resolution of example 6,
and examples 162 (50 mg) and 163 (66 mg) of Table 1 were obtained
by resolution of example 99, respectively. Analytical data were
listed in Table 3.
Example 164:
6-methyl-N-{5-[(pyridin-2-ylamino)carbonyl]bicyclo[3.2.1]oct-1-yl}pyrazin-
e-2-carboxamide
##STR00073##
[0224] Example 164 of Table 2 was prepared from intermediate 26 via
the process of Scheme 4, supra, as follows:
[0225] To a solution of
5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octane-1-carboxylic
acid (intermediate 26, 100 mg, 0.35 mmol) and pyridin-2-amine (39
mg, 0.41 mmol) in DMF (5 mL) was added HATU (158 mg, 0.41 mmol) and
DIPEA (0.5 mL). After stirring at room temperature for one hour,
water (20 mL) was added, and the solution was extracted with ethyl
acetate (3.times.20 mL). The combined organic layer was washed with
brine, dried over Na.sub.2SO.sub.4, and concentrated under reduced
pressure. The resulting residue was purified by column
chromatography (silica gel, petroleum ether/ethyl acetate: 2/1) to
yield 35 mg (27%) of
6-methyl-N-{5-[(pyridin-2-ylamino)carbonyl]bicyclo[3.2.1]oct-1-yl}pyrazin-
e-2-carboxamide as a white solid. Analytical data were listed in
Table 3.
[0226] In an analogous manner to example 164, 165-168 of Table 2
was made from intermediate 26 and commercially available heteroaryl
amines at .about.0.3-0.6 mmol reaction scales. Analytical data were
listed in Table 3.
[0227] Using the procedure described in the preparation of example
98, examples 169-177, 178-182, 183-185, 186 and 187 of Table 2 were
synthesized from commercially available carboxylic acids and amine
intermediates 31, 27, 28, 29 and 30, respectively. Analytical data
were listed in Table 3.
TABLE-US-00001 TABLE 1 Compounds of formula (I-A) Example No.
Structure Chemical Name 1 ##STR00074##
N,N-bicyclo[3.2.1]octane-1,5-diyl)dipicolinamide 2 ##STR00075##
6-Methyl-pyridine-2-carboxylic acid [5-(3-chloro-
benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 3 ##STR00076##
N,N-bicyclo[3.2.1]octane-1,5-diyl)bis(6- methylpicolinamide) 4
##STR00077## 6-Methyl-pyrazine-2-carboxylic acid {5-[(pyridine-2-
carbonyl)amino]-bicyclo[3.2.1]oct-1-yl}-amide 5 ##STR00078##
N,N-(bicyclo[3.2.1]octane-1,5-diyl)bis(6-methylpyrazine-2
carboxamide) 6 ##STR00079## 6-Methyl-pyrazine-2-carboxylic acid
[5-(3-fluoro- benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 7
##STR00080## 6-Methyl-pyrazine-2-carboxylic acid [5-(4-fluoro-
benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 8 ##STR00081##
2-Methyl-pyrimidine-4-carboxylic acid {5-[(6-methyl-
pyrazine-2-carbonyl)amino]-bicyclo[3.2.1]oct-1-yl}-amide 9
##STR00082## N-(5-(3-chlorobenzamido)bicyclo[3.2.1]octan-1-yl)-4-
methylpyrimidine-2-carboxamide 10 ##STR00083##
N-(5-(3-chlorobenzamido)bicyclo[3.2.1]octan-1-
yl)pyrimidine-2-carboxamide 11 ##STR00084##
N-(5-(3-chlorobenzamido)bicyclo[3.2.1]octan-1-
yl)pyrimidine-4-carboxamide 12 ##STR00085##
N-(5-(3-chlorobenzamido)bicyclo[3.2.1]octan-1-yl)thiazole
2-carboxamide 13 ##STR00086##
N-(5-(3-chlorobenzamido)bicyclo[3.2.1]octan-1-yl)-2-
methylpyrimidine-4-carboxamide 14 ##STR00087##
N-(5-(3-chlorobenzamido)bicyclo[3.2.1]octan-1-yl)-4-
methylthiazole-2-carboxamide 15 ##STR00088##
N-(5-(3-chlorobenzamido)bicyclo[3.2.1]octan-1-yl)-2-
methylthiazole-5-carboxamide 16 ##STR00089##
N-(5-(3-chlorobenzamido)bicyclo[3.2.1]octan-1-yl)-5-
fluoropicolinamide 17 ##STR00090##
N-(5-(3-chlorobenzamido)bicyclo[3.2.1]octan-1-yl)-5-
methylpicolinamide 18 ##STR00091##
N-(5-(3-chlorobenzamido)bicyclo[3.2.1]octan-1-yl)-4-
methylpicolinamide 19 ##STR00092##
N-(5-(3-chlorobenzamido)bicyclo[3.2.1]octan-1-yl)-5-
methylnicotinamide 20 ##STR00093##
N-(5-(3-fluorobenzamido)bicyclo[3.2.1]octan-1-
yl)pyrazine-2-carboxamide 21 ##STR00094##
N-(5-(3-fluorobenzamido)bicyclo[3.2.1]octan-1- yl)picolinamide 22
##STR00095## N-(5-(3-fluorobenzamido)bicyclo[3.2.1]octan-1-
yl)isonicotinamide 23 ##STR00096##
N-(5-(3-fluorobenzamido)bicyclo[3.2.1]octan-1-yl)-5-
methylpicolinamide 24 ##STR00097##
N-(5-(3-fluorobenzamido)bicyclo[3.2.1]octan-1-yl)-6-
methylpicolinamide 25 ##STR00098##
N-(5-(3-fluorobenzamido)bicyclo[3.2.1]octan-1-yl)-2-
methylpyrimidine-4-carboxamide 26 ##STR00099##
N-(5-(3-fluorobenzamido)bicyclo[3.2.1]octan-1- yl)nicotinamide 27
##STR00100## N-(5-[(3-fluorobenzoyl)amino]bicyclo[3.2.1]oct-1-
yl)pyrimidine-2-carboxamide 28 ##STR00101##
N-(5-(3-fluorobenzamido)bicyclo[3.2.1]octan-1-yl)-4-
methylpyrimidine-2-carboxamide 29 ##STR00102##
N-(5-(3-fluorobenzamido)bicyclo[3.2.1]octan-1-yl)-4-
methylthiazole-2-carboxamide 30 ##STR00103##
N-(5-(3-fluorobenzamido)bicyclo[3.2.1]octan-1-yl)-2-
methylthiazole-5-carboxamide 31 ##STR00104##
N-(5-(3-fluorobenzamido)bicyclo[3.2.1]octan-1-yl)-4-
methylpicolinamide 32 ##STR00105##
N-(5-(3-fluorobenzamido)bicyclo[3.2.1]octan-1-yl)-5-
methylnicotinamide 33 ##STR00106##
N-(5-(3-fluorobenzamido)bicyclo[3.2.1]octan-1-
yl)pyrimidine-4-carboxamide 34 ##STR00107##
N-(5-(3-fluorobenzamido)bicyclo[3.2.1]octan-1-yl)thiazole-
2-carboxamide 35 ##STR00108##
N-(5-(3-methylbenzamido)bicyclo[3.2.1]octan-1- yl)nicotinamide 36
##STR00109## N-(5-(3-methylbenzamido)bicyclo[3.2.1]octan-1-
yl)isonicotinamide 37 ##STR00110##
6-methyl-N-(5-(3-methylbenzamido)bicyclo[3.2.1]octan-1-
yl)pyrazine-2-carboxamide 38 ##STR00111##
4-methyl-N-(5-(3-methylbenzamido)bicyclo[3.2.1]octan-1-
yl)pyrimidine-2-carboxamide 39 ##STR00112##
5-methyl-N-(5-(3-methylbenzamido)bicyclo[3.2.1]octan-1-
yl)nicotinamide 40 ##STR00113##
N-(5-(3-methylbenzamido)bicyclo[3.2.1]octan-1-
yl)pyrimidine-2-carboxamide 41 ##STR00114##
N-(5-(3-methylbenzamido)bicyclo[3.2.1]octan-1-
yl)pyrimidine-4-carboxamide 42 ##STR00115##
N-(5-(3-methylbenzamido)bicyclo[3.2.1]octan-1-
yl)thiazole-2-carboxamide 43 ##STR00116##
2-methyl-N-(5-(3-methylbenzamido)bicyclo[3.2.1]octan-1-
yl)pyrimidine-4-carboxamide 44 ##STR00117##
4-methyl-N-(5-(3-methylbenzamido)bicyclo[3.2.1]octan-1-
yl)thiazole-2-carboxamide 45 ##STR00118##
2-methyl-N-(5-(3-methylbenzamido)bicyclo[3.2.1]octan-1-
yl)thiazole-5-carboxamide 46 ##STR00119##
5-fluoro-N-(5-(3-methylbenzamido)bicyclo[3.2.1]octan-1-
yl)picolinamide 47 ##STR00120##
5-methyl-N-(5-(3-methylbenzamido)bicyclo[3.2.1]octan-1-
yl)picolinamide 48 ##STR00121##
4-methyl-N-(5-(3-methylbenzamido)bicyclo[3.2.1]octan-1-
yl)picolinamide 49 ##STR00122##
N-(5-(5-fluoropicolinamido)bicyclo[3.2.1]octan-1-yl)-2-
methylpyrimidine-4-carboxamide 50 ##STR00123##
5-fluoro-N-(5-(6-methylpicolinamido)bicyclo[3.2.1]octan-1
yl)picolinamide 51 ##STR00124##
N-(5-(5-fluoropicalinamido)bicyclo[3.2.1]octan-1-yl)-6-
methylpyrazine-2-carboxamide 52 ##STR00125##
5-methyl-N-(5-(6-methylpyrazine-2-
carboxamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2- carboxamide 53
##STR00126##
5-methyl-N-(5-(3-methylbenzamido)bicyclo[3.2.1]octan-1-
yl)pyrazine-2-carboxamide 54 ##STR00127##
N-(5-(3-fluorobenzamido)bicyclo[3.2.1]octan-1-yl)-5-
methylpyrazine-2-carboxamide 55 ##STR00128##
N-(5-(3-chlorobenzamido)bicyclo[3.2.1]octan-1-yl)-5-
methylpyrazine-2-carboxamide 56 ##STR00129##
N-(5-{[(5-methylpyrazin-2-
yl)carbonyl]amino}bicyclo[3.2.1]oct-1-yl)pyrimidine-4- carboxamide
57 ##STR00130## N-(5-(5-methylpyrazine-2-
carboxamido)bicyclo[3.2.1]octan-1-yl)thiazole-2- carboxamide 58
##STR00131## N-(5-benzamidobicyclo[3.2.1]octan-1-yl)-5-
methylpyrazine-2-carboxamide 59 ##STR00132##
4-methyl-N-(5-(5-methylpyrazine-2-
carboxamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-2- carboxamide 60
##STR00133## 2-methyl-N-(5-(5-methylpyrazine-2-
carboxamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-4- carboxamide 61
##STR00134## 5-methyl-N-(5-{[(4-methyl-1,3-thiazol-2-
yl)carbonyl]amino}bicyclo[3.2.1]oct-1-yl)pyrazine-2- carboxamide 62
##STR00135## N-(5-{[(5-fluoropyridin-2-
yl)carbonyl]amino}bicyclo[3.2.1]oct-1-yl)-5-methylpyrazine
2-carboxamide 63 ##STR00136##
5-methyl-N-(5-(5-methylpicolinamido)bicyclo[3.2.1]octan-
1-yl)pyrazine-2-carboxamide 64 ##STR00137##
5-methyl-N-(5-(4-methylpicolinamido)bicyclo[3.2.1]octan-
1-yl)pyrazine-2-carboxamide 65 ##STR00138##
N-(5-(3-fluoro-6-methylpicolinamido)bicyclo[3.2.1]octan-1
yl)-6-methylpyrazine-2-carboxamide 66 ##STR00139##
N-(5-(2-fluorobenzamido)bicyclo[3.2.1]octan-1-yl)-6-
methylpyrazine-2-carboxamide 67 ##STR00140##
N-(5-(3,5-difluorobenzamido)bicyclo[3.2.1]octan-1-yl)-6-
methylpyrazine-2-carboxamide 68 ##STR00141##
6-methyl-N-(5-(nicotinamido)bicyclo[3.2.1]octan-1-
yl)pyrazine-2-carboxamide 69 ##STR00142##
N-(5-(3-chlorobenzamido)bicyclo[3.2.1]octan-1-yl)-6-
methylpyrazine-2-carboxamide 70 ##STR00143##
4-methyl-N-(5-(6-methylpyrazine-2-
carboxamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-2- carboxamide 71
##STR00144## N-(5-(6-methylpyrazine-2-
carboxamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-4- carboxamide 72
##STR00145## N-(5-(6-methylpyrazine-2-
carboxamido)bicyclo[3.2.1]octan-1-yl)thiazole-2- carboxamide 73
##STR00146## N-(5-benzamidobicyclo[3.2.1]octan-1-yl)-6-
methylpyrazine-2-carboxamide 74 ##STR00147##
4-methyl-N-(5-(6-methylpyrazine-2-
carboxamido)bicyclo[3.2.1]octan-1-yl)thiazole-2- carboxamide 75
##STR00148##
6-methyl-N-(5-(5-methylpicolinamido)bicyclo[3.2.1]octan-
1-yl)pyrazine-2-carboxamide 76 ##STR00149##
6-methyl-N-(5-(4-methylpicolinamido)bicyclo[3.2.1]octan-
1-yl)pyrazine-2-carboxamide 77 ##STR00150##
6-methyl-N-(5-(5-methylnicotinamido)bicyclo[3.2.1]octan-
1-yl)pyrazine-2-carboxamide 78 ##STR00151##
6-methyl-N-(5-(pyrazine-2-
carboxamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2- carboxamide 79
##STR00152## N-(5-(6-methylpyrazine-2-
carboxamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-2- carboxamide 80
##STR00153##
6-methyl-N-(5-(6-methylpicolinamido)bicyclo[3.2.1]octan-
1-yl)pyrazine-2-carboxamide 81 ##STR00154##
6-methyl-N-(5-(5-methylnicotinamido)bicyclo[3.2.1]octan-
1-yl)picolinamide
82 ##STR00155##
6-methyl-N-(5-(3-methylbenzamido)bicyclo[3.2.1]octan-1-
yl)picolinamide 83 ##STR00156##
N-(5-(6-methylpicolinamido)bicyclo[3.2.1]octan-1-
yl)pyrazine-2-carboxamide 84 ##STR00157##
N-(5-(6-methylpicolinamido)bicyclo[3.2.1]octan-1-
yl)pyrimidine-2-carboxamide 85 ##STR00158##
N-(5-(6-methylpicolinamido)bicyclo[3.2.1]octan-1-
yl)pyrimidine-4-carboxamide 86 ##STR00159##
N-(5-(6-methylpicolinamido)bicyclo[3.2.1]octan-1-
yl)thiazole-2-carboxamide 87 ##STR00160##
N-(5-benzamidobicyclo[3.2.1]octan-1-yl)-6- methylpicolinamide 88
##STR00161##
5-methyl-N-(5-(6-methylpicolinamido)bicyclo[3.2.1]octan-
1-yl)pyrazine-2-carboxamide 89 ##STR00162##
4-methyl-N-(5-(6-methylpicolinamido)bicyclo[3.2.1]octan-
1-yl)pyrimidine-2-carboxamide 90 ##STR00163##
2-methyl-N-(5-(6-methylpicolinamido)bicyclo[3.2.1]octan-
1-yl)pyrimidine-4-carboxamide 91 ##STR00164##
2-methyl-N-(5-(6-methylpicolinamido)bicyclo[3.2.1]octan-
1-yl)thiazole-5-carboxamide 92 ##STR00165##
6-methyl-N-(5-(5-methylpicolinamido)bicyclo[3.2.1]octan-
1-yl)picolinamide 93 ##STR00166##
6-methyl-N-(5-(4-methylpicolinamido)bicyclo[3.2.1]octan-
1-yl)picolinamide 94 ##STR00167##
N-(5-(3-fluoro-6-methylpicolinamido)bicyclo[3.2.1]octan-1
yl)pyrazine-2-carboxamide 95 ##STR00168## Pyrazine-2-carboxylic
acid [5-(3-trifluoromethyl-
benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 96 ##STR00169##
Pyrazine-2-carboxylic acid [5-(3-cyano-benzoylamino)-
bicyclo[3.2.1]oct-1-yl]-amide 97 ##STR00170## Pyrazine-2-carboxylic
acid {5-[(3-fluoro-pyridine-2-
carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide 98 ##STR00171##
N-(5-(3-methylbenzamido)bicyclo[3.2.1]octan-1-
yl)pyrazine-2-carboxamide 99 ##STR00172##
N-(5-(3-chlorobenzamido)bicyclo[3.2.1]octan-1-
yl)pyrazine-2-carboxamide 100 ##STR00173##
2-methyl-N-(5-(pyrazine-2-
carboxamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-4- carboxamide 101
##STR00174## 4-methyl-N-(5-(pyrazine-2-
carboxamido)bicyclo[3.2.1]octan-1-yl)thiazole-2- carboxamide 102
##STR00175## N-(5-(5-fluoropicolinamido)bicyclo[3.2.1]octan-1-
yl)pyrazine-2-carboxamide 103 ##STR00176##
N-(5-(4-methylpicolinamido)bicyclo[3.2.1]octan-1-
yl)pyrazine-2-carboxamide 104 ##STR00177##
2-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-
yl)pyrimidine-4-carboxamide 105 ##STR00178##
6-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1- yl)picolinamide
106 ##STR00179## 5-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-
yl)pyrazine-2-carboxamide 107 ##STR00180##
4-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-
yl)pyrimidine-2-carboxamide 108 ##STR00181##
4-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-
yl)thiazole-2-carboxamide 109 ##STR00182##
2-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-
yl)thiazole-5-carboxamide 110 ##STR00183##
5-fluoro-N-(5-(picolinamido)bicyclo[3.2.1]octan-1- yl)picolinamide
111 ##STR00184## 5-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-
yl)picolinamide 112 ##STR00185##
4-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1- yl)picolinamide
113 ##STR00186## N-(5-(5-methylnicotinamido)bicyclo[3.2.1]octan-1-
yl)picolinamide 114 ##STR00187##
N-(5-(3-methylbenzamido)bicyclo[3.2.1]octan-1- yl)picolinamide 115
##STR00188## N-(5-(3-chlorobenzamido)bicyclo[3.2.1]octan-1-
yl)picolinamide 116 ##STR00189##
3-Fluoro-6-methyl-pyridine-2-carboxylic acid {(1S,5R)-5-
[(6-methyl-pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-
yl}-amide 117 ##STR00190## 6-Methyl-pyridine-2-carboxylic acid
[(1R,5S)-5-(3-fluoro- benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide
118 ##STR00191## 6-Methyl-pyridine-2-carboxylic acid
[(1R,5S)-5-(3-methyl- benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide
119 ##STR00192## 6-Methyl-pyridine-2-carboxylic acid
{[(1R,5S)-5-[(pyridine-
2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide 120 ##STR00193##
2-Methyl-pyrimidine-4-carboxylic acid {(1S,5R)-5-[(6-
methyl-pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}- amide
121 ##STR00194## Pyrimidine-4-carboxylic acid
{(1S,5R)-5-[(6-methyl-
pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide 122
##STR00195## 6-Methyl-pyridine-2-carboxylic acid ((1S,5R)-5-
benzolamino-bicyclo[3.2.1]oct-1-yl)-amide 123 ##STR00196##
3-Fluoro-6-methyl-pyridine-2-carboxylic acid ((1R,5S)-5-
[(6-methyl-pyridine-2-carbonyl)aminol-bicyclo[3.2.1]oct-1-
yl)-amide 124 ##STR00197## 2-Methyl-pyrimidine-4-carboxylic acid
{(1R,5S)-5-[(6-
methyl-pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}- amide
125 ##STR00198## 6-Methyl-pyridine-2-carboxylic acid
[(1S,5R)-5-(3-fluoro- benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide
126 ##STR00199## 6-Methyl-pyridine-2-carboxylic acid
{(1S,5R)-5-[(pyridine-
2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide 127 ##STR00200##
Pyrimidine-4-carboxylic acid {(1R,5S)-5-[(6-methyl-
pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide 128
##STR00201## 5-fluoro-N-((1R,5S)-5-(6-
methylpicolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide 129
##STR00202## 6-Methyl-pyridine-2-carboxylic acid
{(1S,5R)-5-[(thiazole-2
carbonyl)aminoybicyclo[3.2.1]oct-1-yl}-amide 130 ##STR00203##
6-methyl-N-((1R,5S)-5-(4-
methylpicolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide 131
##STR00204## 5-methoxy-N-((1R,5S)-5-(6-
methylpicolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide 132
##STR00205## 6-Methyl-pyrazine-2-carboxylic acid
{(1S,5R)-5-[(6-methyl,
pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide 133
##STR00206## 6-Methyl-pyrazine-2-carboxylic acid
{(1S,5R)-5-[(4-methyl-
thiazole-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide 134
##STR00207## 6-Methyl-pyrazine-2-carboxylic acid
[(1S,5R)-5-(3-methyl- benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide
135 ##STR00208## 6-Methyl-pyrazine-2-carboxylic acid
{(1S,5R)-5-[(3-fluoro-
pyridine-2-carbonyl)amino]-bicyclo[3.2.1]oct-1-yl}-amide 136
##STR00209## 6-Methyl-pyrazine-2-carboxylic acid [(1R,5S)-5-(3,5-
difluoro-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 137
##STR00210## 6-Methyl-pyrazine-2-carboxylic acid
{(1R,5S)-5-[(6-methyl-
pyridine-2-carbonyl)amino]-bicyclo[3.2.1]oct-1-yl)-amide 138
##STR00211## 6-Methyl-pyrazine-2-carboxylic acid
{(1R,58)-5-[(4-methyl.
thiazole-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide 139
##STR00212## 6-Methyl-pyrazine-2-carboxylic acid
[(1R,5S)-5-(3-methyl- benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide
140 ##STR00213## 6-Methyl-pyrazine-2-carboxylic acid
{(1R,5S)-5-[(3-fluoro-
pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl)-amide 141
##STR00214## Pyridine-2-carboxylic acid [(1S,5R)-5-(3-methyl-
benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 142 ##STR00215##
Pyridine-2-carboxylic acid [(1S,5R)-5-(3-fluoro-
benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 143 ##STR00216##
Pyridine-2-carboxylic acid {(1S,5R)-5-[(4-methyl-thiazole-
2-carbonyl)amino]-bicyclo[3.2.1]oct-1-yl}-amide 144 ##STR00217##
2-Methyl-pyrimidine-4-carboxylic acid {(1R,5S)-5-
[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide 145
##STR00218## 5-Fluoro-pyridine-2-carboxylic acid
{(1R,5S)-5-[(pyridine-2
carbonyl)amino]-bicyclo[3.2.1]oct-1-yl}-amide 146 ##STR00219##
6-Fluoro-pyridine-2-carboxylic acid {(1R,5S)-5-[(pyridine-2
carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide 147 ##STR00220##
3-Fluoro-6-methyl-pyridine-2-carboxylic acid ((1R,5S)-5-
[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl)-amide 148
##STR00221## Pyridine-2-carboxylic acid
[(1S,5R)-5-(3-trifluoromethyl-
benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 149 ##STR00222##
Pyridine-2-carboxylic acid [(1S,5R)-5-(3-cyano-
benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 150 ##STR00223##
Pyridine-2-carboxylic acid [(1S,5R)-5-(3-cyano-5-fluoro-
benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 151 ##STR00224##
6-Methyl-pyrazine-2-carboxylic acid [(1S,5R)-5-(2,5-
difluoro-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 152
##STR00225## 6-Methyl-pyrazine-2-carboxylic acid
{(1S,5R)-5-[(6-fluoro-
pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide 153
##STR00226## 6-Methyl-pyrazine-2-carboxylic acid
[(1S,5R)-5-(3-cyano-
5-fluoro-benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide 154
##STR00227## 6-Methyl-pyrazine-2-carboxylic acid
{(1S,5R)-5-[(5-fluoro-
pyridine-2-carbonyl)-amino]bicyclo[3.2.1]oct-1-yl}-amide 155
##STR00228## 6-Methyl-pyrazine-2-carboxylic acid {(1S,5R)-5-[(3,5-
difluoro-pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}- amide
156 ##STR00229## 2-Methyl-pyrimidine-4-carboxylic acid
{(1S,5R)-5-[(6-
methyl-pyrazine-2-carbonyl)-aminol-bicyclo[3.2.1]oct-1-yl}- amide
157 ##STR00230## 2-Methyl-pyrimidine-4-carboxylic acid
{(1R,5S)-5-[(6-
methyl-pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}- amide
158 ##STR00231## 6-Methyl-pyrazine-2-carboxylic acid
{(1R,5S)-5-[(pyridine-
2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide 159 ##STR00232##
6-Methyl-pyrazine-2-carboxylic acid {(1S,5R)-5-[(pyridine-
2-carbonyl)-amino]bicyclo[3.2.1]oct-1-yl}-amide 160 ##STR00233##
6-Methyl-pyrazine-2-carboxylic acid {(1R,5S)-5-(3-fluoro-
benzoylamino)-bicyclo[3.2.1]oct-1-yl}-amide
161 ##STR00234## 6-Methyl-pyrazine-2-carboxylic acid
[(1S,5R)-5-(3-fluoro- benzoylamino)-bicyclo[3.2.1]oct-1-yl]-amide
162 ##STR00235## Pyrazine-2-carboxylic acid [(1S,5R)-5-(3-chloro-
benzoylamino)-bicyclo[3.2.1]oct-1-yl]amide 163 ##STR00236##
Pyrazine-2-carboxylic acid [(1R,5S)-5-(3-chloro-
benzoylamino)-bicyclo[3.2.1]oct-1-yl)-amide
TABLE-US-00002 TABLE 2 Compounds of formula (I-B) Example No.
Structure Chemical Name 164 ##STR00237##
6-methyl-N-(5-(pyridin-2-ylcarbamoyl)bicyclo[3.2.1]octan-
1-yl)pyrazine-2-carboxamide 165 ##STR00238##
6-methyl-N-(5-(6-methylpyrazin-2-
ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2- carboxamide 166
##STR00239## 6-methyl-N-(5-(2-methylpyrimidin-4-
ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2- carboxamide 167
##STR00240## 6-methyl-N-(5-(4-methylthiazol-2-
ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2- carboxamide 168
##STR00241##
6-methyl-N-(5-(thiazol-2-ylcarbamoyl)bicyclo[3.2.1]octan-
1-yl)pyrazine-2-carboxamide 169 ##STR00242##
6-methyl-N-(5-(6-methylpyridin-2-
ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)picolinamide 170 ##STR00243##
2-methyl-N-(5-(6-methylpyridin-2-
ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)pyrimidine-4- carboxamide 171
##STR00244## 4-methyl-N-(5-(6-methylpyridin-2-
ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)thiazole-2- carboxamide 172
##STR00245##
N-(5-(6-methylpyridin-2-ylcarbamoyl)bicyclo[3.2.1]octan-1
yl)thiazole-2-carboxamide 173 ##STR00246##
5-methyl-N-(5-(6-methylpyridin-2-
ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2- carboxamide 174
##STR00247##
N-(5-(6-methylpyridin-2-ylcarbamoyl)bicyclo[3.2.1]octan-1
yl)pyrazine-2-carboxamide 175 ##STR00248##
5-(3-methylbenzamido)-N-(6-methylpyridin-2-
yl)bicyclo[3.2.1]octane-1-carboxamide 176 ##STR00249##
5-(3-chlorobenzamido)-N-(6-methylpyridin-2-
yl)bicyclo[3.2.1]octane-1-carboxamide 177 ##STR00250##
N-(5-(6-methylpyridin-2-ylcarbamoyl)bicyclo[3.2.1]octan-1
yl)picolinamide 178 ##STR00251##
6-methyl-N-(5-(2-methylpyrimidin-4-
ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)picolinamide 179 ##STR00252##
2-methyl-N-(5-(2-methylpyrimidin-4-
ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)pyrimidine-4- carboxamide 180
##STR00253## 4-methyl-N-(5-(2-methytpyrimidin-4-
ylcarbamoyl)bicyclo[3.2.1]octan-1-yl)thiazole-2- carboxamide 181
##STR00254## 5-(3-methylbenzamido)-N-(2-methylpyrimidin-4-
yl)bicyclo[3.2.1]octane-1-carboxamide 182 ##STR00255##
5-(3-chlorobenzamido)-N-(2-methylpyrimidin-4-
yl)bicyclo[3.2.1]octane-1-carboxamide 183 ##STR00256##
6-methyl-N-(5-(6-methylpyrazin-2- yl
carbamoyl)bicyclo[3.2.1]octan-1-yl)picolinamide 184 ##STR00257##
4-methyl-N-(5-(6-methylpyrazin-2-
ylcarbamoyl)bicyclo[3.2.1)octan-1-yl)thiazole-2- carboxamide 185
##STR00258## 5-(3-chlorobenzamido)-N-(6-methylpyrazin-2-
yl)bicyclo[3.2.1]octane-1-carboxamide 186 ##STR00259##
5-(3-chlorobenzamido)-N-(pyridin-3-
yl)bicyclo[3.2.1]octane-1-carboxamide 187 ##STR00260##
5-(3-chlorobenzamido)-N-(pyrazin-2-
yl)bicyclo[3.2.1]octane-1-carboxamide
TABLE-US-00003 TABLE 3 Analytical data of compounds of formula I
ESI-MS Example m/z No. .sup.1H NMR (400 or 500 MHz, CDCl.sub.3),
.delta. (PPM) (M + H).sup.+) 1 8.23 (s, 2H), 8.15-8.19 (m, 2H),
7.81-7.86 (m, 2H), 7.38-7.43 (m, 4H), 351 2.75-2.80 (m, 1H),
2.05-2.30 (m, 7H), 1.77-1.92 (m, 4H) 2 8.29 (s, 1H), 7.96 (d, J =
8.0 Hz, 2H), 7.69-7.74 (m, 2H), 7.57-7.61 (m, 1H), 398 7.44-7.48
(m, 1H), 7.36 (t, J = 7.8 Hz, 2H), 7.24-7.28 (m, 1H), 6.17 (s, 1H),
2.72-2.77 (m, 1H), 2.57 (s, 6H), 2.02-2.30 (m, 7H), 1.77-1.90 (m,
4H) 3 8.31 (s, 2H), 7.97 (d, J = 7.4 Hz, 2H), 7.71 (t, J = 7.7 Hz,
2H), 7.25 (d, J = 7.9 Hz, 379 2H), 2.75-2.80 (m, 1H), 2.56 (s, 6H),
2.17-2.27 (m, 5H), 2.09-2.15 (m, 2H), 1.77-1.91 (m, 4H) 4 9.17 (s,
1H), 8.57 (s, 1H), 8.51-8.54 (m, 1H), 8.23 (s, 1H), 8.15-8.19 (m,
366 1H), 8.01 (s, 1H), 7.82-7.87 (m, 1H), 7.39-7.44 (m, 1H),
2.77-2.82 (m, 1H), 2.60 (s, 3H), 2.01-2.35 (m, 7H), 1.76-1.95 (m,
4H) 5 9.18 (s, 2H), 8.60 (s, 2H), 8.00 (s, 2H), 2.77-2.83 (m, 1H),
2.60 (s, 6H), 381 2.16-2.30 (m, 5H), 2.06-2.12 (m, 2H), 1.77-1.93
(m, 4H) 6 9.17 (s, 1H), 8.60 (s, 1H), 7.99 (s, 1H), 7.36-7.49 (m,
3H), 7.15-7.22 (m, 383 1H), 6.18 (s, 1H), 2.73-2.78 (m, 1H), 2.60
(s, 3H), 2.01-2.30 (m, 7H), 1.75-1.92 (m, 4H) 7 9.16 (s, 1H), 8.60
(s, 1H), 7.98 (s, 1H), 7.71-7.76 (m, 2H), 7.06-7.13 (m, 383 2H),
6.18 (s, 1H), 2.73-2.78 (m, 1H), 2.60 (s, 3H), 2.11-2.29 (m, 5H),
2.01-2.09 (m, 2H), 1.75-1.92 (m, 4H) 8 9.18 (s, 1H), 8.85 (d, J =
5.1 Hz, 1H), 8.60 (s, 1H), 8.19 (s, 1H), 8.00 (s, 1H), 381 7.88 (d,
J = 5.0 Hz, 1H), 2.77-2.83 (m, 1H), 2.77 (s, 3H), 2.60 (s, 3H),
2.05-2.29 (m, 7H), 1.75-1.92 (m, 4H) 9 8.67 (d, J = 5.0 Hz, 1H),
8.19 (s, 1H), 7.72 (s, 1H), 7.61 (d, J = 7.0 Hz, 1H), 399 7.45 (d,
J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.26-7.25 (m, 1H), 6.26
(s, 1H), 2.72 (m, 1H), 2.61 (s, 3H), 2.21-1.80 (m, 11H) 10 8.86 (d,
J = 6.0 Hz, 2H), 8.16 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.62-7.60
(m, 385 1H), 7.44-7.41 (m, 2H), 7.35-7.31 (m, 1H), 6.41 (s, 1H),
2.72 (m, 1H), 2.23-1.79 (m, 11H) 11 9.21 (s, 1H), 8.96 (d, J = 5.0
Hz, 1H), 8.13 (s, 1H), 8.08 (dd, J = 5.0 Hz, 1.5 Hz, 385 1H), 7.70
(s, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.47-7.45 (m, 1H), 7.36 (t, J =
8.0 Hz, 1H), 6.15 (s, 1H), 2.75 (d, J = 12.5 Hz, 1H), 2.27-1.81 (m,
11H) 12 7.82 (s, 1H), 7.71 (s, 1H), 7.59 (dd, J = 7.5 Hz, 1.5 Hz,
1H), 7.55 (d, J = 3.0 Hz, 390 1H), 7.44-7.32 (m, 3H), 6.34 (s, 1H),
2.71 (m, 1H), 2.19-2.17 (m, 11H) 13 8.84 (d, J = 6.0 Hz, 1H), 8.17
(s, 1H), 7.87 (d, J = 6.5 Hz, 1H), 7.70 (t, J = 2.0 Hz, 399 1H),
7.60-7.58 (m, 1H), 7.45-7.27 (m, 2H), 6.27 (s, 1H), 2.77-2.73 (m,
4H), 2.24-1.81 (m, 11H) 14 7.71 (d, J = 2.0 Hz, 1H), 7.60 (d, J =
8.0 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 404 7.35-7.32 (m, 2H), 7.09
(s, 1H), 6.38 (s, 1H), 2.70 (d, J = 10.5 Hz, 1H), 2.45 (s, 3H),
2.24-1.78 (m, 11H) 15 7.92 (s, 1H), 7.69 (s, 1H), 7.58-7.33 (m,
3H), 6.26 (s, 1H), 6.16 (s, 1H), 404 2.71-2.66 (m, 4H), 2.19-1.74
(m, 11H) 16 8.36 (d, J = 2.5 Hz, 1H), 8.35-8.17 (m, 1H), 8.03 (s,
1H), 7.70 (s, 1H), 402 7.59 (d, J = 8.0 Hz, 1H), 7.54-7.50 (m, 1H),
7.44 (d, J = 8.0 Hz, 1H), 7.36-7.33 (m, 1H), 6.28 (s, 1H), 2.73 (d,
J = 10.0 Hz, 1H), 2.26-1.75 (m, 11H) 17 8.33 (s, 1H), 8.14 (s, 1H),
8.04 (d J = 8.0 Hz, 1H), 7.71 (t, J = 2.0 Hz, 1H), 398 7.63-7.58
(m, 2H), 7.45-7.43 (m, 1H), 7.36-7.33 (m, 1H), 6.25 (s, 1H), 2.73
(d, J = 10.0 Hz, 1H), 2.39 (s, 3H), 2.19-1.77 (m, 11H) 18 8.37 (d,
J = 6.0 Hz, 1H), 8.20 (s, 1H), 7.96 (s, 1H), 7.71 (d, J = 2.5 Hz,
1H), 398 7.60-7.58 (m, 1H), 7.47-7.20 (m, 3H), 6.33 (s, 1H),
2.73-2.69 (m, 1H), 2.40 (s, 3H), 2.28-1.80 (m, 11H) 19 8.71 (s,
1H), 8.49 (s, 1H), 7.84 (s, 1H), 7.60 (t, J = 2.0 Hz, 1H), 7.58 (t,
J = 2.0 Hz, 398 1H), 7.44-7.30 (m, 2H), 6.49 (s, 1H), 6.39 (s, 1H),
2.70 (m, 1H), 2.35 (s, 3H), 2.21-1.80 (m, 11H) 20 9.38 (s, 1H),
8.74 (d, J = 2.5 Hz, 1H), 8.50 (t, J = 2.0 Hz, 1H), 7.94 (s, 1H),
369 7.47-7.37 (m, 3H), 7.20-7.18 (m, 1H), 6.17 (s, 1H), 2.76-2.73
(m, 1H), 2.25-2.13 (m, 5H), 2.06-2.01 (m, 2H), 1.89-1.81 (m, 4H) 21
8.53 (d, J = 4.5 Hz, 1H), 8.21 (s, 1H), 8.16 (d, J = 8.0 Hz, 1H),
7.84 (t, J = 8.0 Hz, 368 1H), 7.47-7.37 (m, 4H), 7.18 (t, J = 1.5
Hz, 1H), 6.19 (s, 1H), 2.76-2.74 (m, 1H), 2.30-1.80 (m, 11H) 22
8.75 (s, 2H), 7.61 (s, 2H), 7.47-7.38 (m, 3H), 7.21-7.19 (m, 1H),
6.26 (s, 368 1H), 6.13 (s, 1H), 2.75-2.73 (m, 1H), 2.25-1.83 (m,
11H) 23 8.34 (s, 1H), 8.16 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.63
(m, 1H), 382 7.49-7.45 (m, 2H), 7.41-7.38 (m, 1H), 7.18 (m, 1H),
6.25 (s, 1H), 2.74 (m, 1H), 2.40 (s, 3H), 2.34-2.25 (m, 1H),
2.21-1.78 (m, 10H) 24 8.36 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.72
(t, J = 7.5 Hz, 1 H), 7.48-7.39 (m, 382 3H), 7.28-7.26 (m, 1H),
7.19 (t, J = 1.0 Hz, 1H), 6.19 (s, 1H), 2.76-2.74 (m, 1H), 2.58 (s,
3H), 2.32-2.18 (m, 5H), 2.09-2.06 (m, 2H), 1.86-1.82 (m, 4H) 25
8.77 (d, J = 5.0 Hz, 1H), 8.10 (s, 1H), 7.80 (d, J = 5.0 Hz, 1H),
7.40-7.29 (m, 383 3H), 7.12-7.09 (m, 1H), 6.15 (s, 1H), 2.70-2.66
(m, 4H), 2.17-1.72 (m, 11H) 26 8.94 (s, 1H), 8.72 (d, J = 3.5 Hz,
1H), 8.08-8.06 (m, 1H), 7.47-7.37 (m, 4H), 368 7.20-7.18 (m, 1H),
6.23 (s, 1H), 6.16 (s, 1H), 2.74-2.71 (m, 1H), 2.24-2.13 (m, 5H),
2.05-2.00 (m, 2H), 1.87-1.79 (m, 4H) 27 8.87 (d, J = 4.5 Hz, 2H),
8.18 (s, 1H), 7.50-7.38 (m, 4H), 7.21-7.18 (m, 1H), 369 6.24 (s,
1H), 2.74-2.71 (m, 1H), 2.27-2.15 (m, 5H), 2.09-2.04 (m, 2H),
1.92-1.67 (m, 4H) 28 8.67 (d, J = 5.0 Hz, 1H), 8.19 (s, 1H),
7.50-7.47 (m, 2H), 7.39-7.35 (m, 1H), 383 7.27-7.25 (m, 1H),
7.18-7.14 (m, 1H), 6.38 (s, 1H), 2.71 (d, J = 10.0 Hz, 1H), 2.61
(s, 3H), 2.25-1.79 (m, 11H) 29 7.47-7.37 (m, 2H), 7.41-7.36 (m,
1H), 7.34 (s, 1H), 7.18 (t, J = 8.5 Hz, 1H), 388 7.09 (s, 1H), 6.18
(s, 1H), 2.71 (d, J = 10.0 Hz, 1H), 2.40 (s, 3H), 2.25-1.80 (m,
11H) 30 7.91 (s, 1H), 7.46-7.42 (m, 2H), 7.38 (d, J = 5.0 Hz, 1H),
7.17 (t, J = 8.0 Hz, 388 1H), 6.19 (s, 1H), 6.06 (s, 1H), 2.71-2.67
(m, 4H), 2.20-1.79 (m, 11H) 31 8.37 (d, J = 5.0 Hz, 1H), 8.20 (s,
1H), 7.97 (s, 1H), 7.47-7.44 (m, 2H), 382 7.40-7.36 (m, 1H),
7.22-7.17 (m, 2H), 6.23 (s, 1H), 2.73-2.70 (m, 1H), 2.41 (s, 3H),
2.28-1.78 (m, 11H) 32 8.74 (s, 1H), 8.54 (s, 1H), 7.89 (s, 1H),
7.47-7.39 (m, 3H), 7.18 (s, 1H), 382 6.25 (s, 1H), 6.17 (s, 1H),
2.72 (m, 1H), 2.40 (s, 3H), 2.23-1.81 (m, 11H) 33 9.21 (s, 1H),
8.97 (d, J = 5.5 Hz, 1H), 8.14 (s, 1H), 8.09 (d, J = 5.0 Hz, 1H),
369 7.47-7.37 (m, 3H), 7.20-7.17 (m, 1H), 6.16 (s, 1H), 2.75 (d, J
= 10.0 Hz, 1H), 2.27-1.79 (m, 11H) 34 7.83 (d, J = 3.5 Hz, 1H),
7.55 (d, J = 3.0 Hz, 1H), 7.47-7.44 (m, 2H), 374 7.39-7.38 (m, 2H),
7.18 (s, 1H), 6.18 (s, 1H), 2.72 (d, J = 10.0 Hz, 1H), 2.26-1.78
(m, 11H) 35 8.94 (s, 1H), 8.72 (s, 1H), 8.07 (d, J = 7.5 Hz, 1H),
7.54 (s, 1H), 7.49 (d, J = 4.5 Hz, 364 1H), 7.38 (s, 1H), 7.30-7.26
(m, 2H), 6.29 (s, 1H), 6.19 (s, 1H), 2.73-2.71 (m, 1H), 2.39 (s,
3H), 2.26-1.67 (m, 11H) 36 8.74 (d, J = 5.5 Hz, 2H), 7.60-7.49 (m,
4H), 7.31-7.30 (m, 2H), 6.30 (s, 1H), 364 6.15 (s, 1H), 2.74-2.72
(m, 1H), 2.39 (s, 3H), 2.28-1.78 (m, 11H) 37 9.16 (s, 1H), 8.59 (s,
1H), 8.00 (s, 1H), 7.54 (s, 1H), 7.51-7.49 (m, 1H), 379 7.29-7.27
(m, 2H), 6.27 (s, 1H), 2.75-2.73 (m, 1H), 2.59 (s, 3H), 2.38 (s,
3H), 2.24-1.78 (m, 11H) 38 8.67 (d, J = 6.5 Hz, 1H), 8.20 (s, 1H),
7.55 (s, 1H), 7.51-7.49 (m, 1H), 379 7.31-7.25 (m, 3H), 6.19 (s,
1H), 2.71-2.69 (m, 1H), 2.62 (s, 3H), 2.39 (s, 3H), 2.23-1.80 (m,
11H) 39 8.73 (s, 1H), 8.56 (s, 1H), 7.88 (s, 1H), 7.55 (s, 1H),
7.51 (d, J = 6.0 Hz, 1H), 378 7.32 (d, J = 6.0 Hz, 2H), 6.20 (s,
1H), 6.18 (s, 1H), 2.71 (m, 1H), 2.41 (s, 6H), 2.26-1.84 (m, 11H)
40 8.86 (d, J = 5.0 Hz, 2H), 8.18 (s, 1H), 7.55 (s, 1H), 7.51 (d, J
= 6.0 Hz, 1H), 365 7.43 (m, 1H), 7.32-7.30 (m, 2H), 6.22 (s, 1H),
2.71 (m, 1H), 2.41 (s, 3H), 2.27-1.83 (m, 11H) 41 9.21 (s, 1H),
8.97 (d, J = 5.0 Hz, 1H), 8.15 (s, 1H), 8.10 (d, J = 5.0 Hz, 1H),
365 7.54 (s, 1H), 7.50 (d, J = 5.5 Hz, 1H), 7.32-7.26 (m, 2H), 6.17
(s, 1H), 2.74 (m, 1H), 2.39 (s, 3H), 2.28-1.80 (m, 11H) 42 7.82 (s,
1H), 7.54-7.49 (m, 3H), 7.41 (s, 1H), 7.30-7.27 (m, 2H), 6.31 (s,
370 1H), 2.70-2.68 (m, 1H), 2.37 (s, 3H), 2.25-1.79 (m, 11H) 43
8.85 (d, J = 5.0 Hz, 1H), 8.19 (s, 1H), 7.88 (d, J = 5.0 Hz, 1H),
7.54 (s, 1H), 379 7.50 (d, J = 6.0 Hz, 1H), 7.32-7.26 (m, 2H), 6.19
(s, 1H), 2.77-2.73 (m, 4H), 2.39 (s, 3H), 2.24-1.80 (m, 11H) 44
7.54 (s, 1H), 7.50-7.48 (m, 1H), 7.41 (s, 1H), 7.32-7.26 (m, 2H),
7.10 (s, 384 1H), 6.17 (s, 1H), 2.71-2.69 (m, 1H), 2.47 (s, 3H),
2.39 (s, 3H), 2.26-1.77 (m, 11H) 45 7.91 (s, 1H), 7.53 (s, 1H),
7.49 (m, 1H), 7.30-7.26 (m, 2H), 6.14 (s, 1H), 384 5.96 (s, 1H),
2.72-2.67 (m, 4H), 2.39 (s, 3H), 2.23-1.78 (m, 11H) 46 8.36 (d, J =
2.5 Hz, 1H), 8.21-8.18 (m, 1H), 8.03 (s, 1H), 7.54-7.48 (m, 3H),
382 7.30-7.26 (m, 2H), 6.18 (s, 1H), 2.73-2.70 (m, 1H), 2.39 (s,
3H), 2.26-1.81 (m, 11H) 47 8.33 (s, 1H), 8.18 (s, 1H), 8.06 (d, J =
8.0 Hz, 1H), 7.64 (d, J = 7.0 Hz, 1H), 378 7.54 (s, 1H), 7.50 (d, J
= 6.0 Hz, 1H), 7.30-7.26 (m, 2H), 6.20 (s, 1H), 2.72-2.70 (m, 1H),
2.40 (s, 6H), 2.30-1.79 (m, 11H) 48 8.37 (d, J = 5.0 Hz, 1H), 8.22
(s, 1H), 7.98 (s, 1H), 7.54 (s, 1H), 7.50 (d, J = 6.5 Hz, 378 1H),
7.32-7.22 (m, 3H), 6.20 (s, 1H), 2.72-2.70 (m, 1H), 2.42 (s, 3H),
2.39 (s, 3H), 2.27-1.80 (m, 11H) 49 8.86 (d, J = 4.5 Hz, 1H), 8.37
(d, J = 3.0 Hz, 1H), 8.22-8.20 (m, 2H), 384 8.05 (s, 1H), 7.89 (d,
J = 4.5 Hz, 1H), 7.56-7.52 (m, 1H), 2.80-2.78 (m, 4H), 2.28-1.60
(m, 11H) 50 8.37 (d, J = 3.0 Hz, 1H), 8.31 (s, 1H), 8.22-8.20 (m,
1H), 8.06 (s, 1H), 383 7.98 (d, J = 7.5 Hz, 1H), 7.72 (t, J = 8.0
Hz, 1H), 7.55-7.51 (m, 1H), 7.27-7.26 (m, 1H), 2.79-2.76 (m, 1H),
2.57 (s, 3H), 2.26-2.05 (m, 7H), 1.88-1.84 (m, 4H) 51 9.17 (s, 1H),
8.59 (s, 1H), 8.36 (d, J = 3.0 Hz, 1H), 8.21-8.18 (m, 1H), 384 8.04
(s, 1H), 8.00 (s, 1H), 7.54-7.50 (m, 1H), 2.79-2.76 (m, 1H), 2.59
(s, 3H), 2.28-1.80 (m, 11H) 52 9.25 (s, 1H), 9.18 (s, 1H), 8.61 (s,
1H), 8.36 (s, 1H), 8.01 (s, 1H), 7.91 (s, 381 1H), 2.80 (m, 1H),
2.66 (s, 3H), 2.58 (s, 3H), 2.27-1.84 (m, 11H) 53 9.25 (s, 1H),
8.36 (s, 1H), 7.90 (s, 1H), 7.55-7.50 (m, 2H), 7.32-7.30 (m, 379
2H), 6.19 (s, 1H), 2.74 (d, J = 9.5 Hz, 1H), 2.66 (s, 3H), 2.40 (s,
3H), 2.28-1.83 (m, 11H) 54 9.25 (s, 1H), 8.36 (s, 1H), 7.90 (s,
1H), 7.48-7.40 (m, 3H), 7.27-7.19 (m, 383 1H), 6.17 (s, 1H), 2.75
(m, 1H), 2.66 (s, 3H), 2.28-1.83 (m, 11H) 55 9.25 (s, 1H), 8.96 (s,
1H), 7.90 (s, 1H), 7.71 (s, 1H), 7.66-7.36 (m, 3H), 399 6.17 (s,
1H), 2.76-2.74 (m, 1H), 2.66 (s, 3H), 2.25-1.82 (m, 11H) 56
9.25-9.22 (m, 2H), 8.98 (d, J = 5.0 Hz, 1H), 8.36 (s, 1H),
8.11-8.09 (m, 2H), 367 7.90 (s, 1H), 2.79 (d, J = 10.0 Hz, 1H),
2.66 (s, 3H), 2.28-1.86 (m, 11H) 57 9.25 (s, 1H), 8.36 (d, J = 4.5
Hz, 1H), 7.90-7.84 (m, 2H), 7.56 (d, J = 3.0 Hz, 372 1H), 7.40 (s,
1H), 2.76 (d, J = 10.0 Hz, 1H), 2.65 (s, 3H), 2.27-1.81 (m, 11H) 58
9.25 (s, 1H), 8.36 (s, 1H), 7.91 (s, 1H), 7.74-7.72 (m, 2H),
7.50-7.42 (m, 3H), 365
6.22 (s, 1H), 2.75 (m, 1H), 2.65 (s, 3H), 2.26-1.82 (m, 11H) 59
9.25 (s, 1H), 8.69 (d, J = 5.0 Hz, 1H); 8.36 (s, 2H), 7.90 (s, 1H),
7.27 (s, 381 1H), 2.76-2.74 (m, 1H), 2.65 (s, 3H), 2.63 (s, 3H),
2.27-1.82 (m, 11H) 60 9.25 (s, 1H), 8.86 (d, J = 5.0 Hz, 1H), 8.36
(s, 1H), 8.20 (s, 1H), 381 7.91-7.88 (m, 2H), 2.80-2.78 (m, 4H),
2.66 (s, 3H), 2.28-1.85 (m, 11H) 61 9.24 (s, 1H), 8.35 (s, 1H),
7.90 (s, 1H), 7.37 (s, 1H), 7.10 (s, 1H), 2.75 (m, 386 1H), 2.65
(s, 3H), 2.47 (s, 3H), 2.26-1.82 (m, 11H) 62 9.25 (s, 1H),
8.37-8.19 (m, 3H), 8.05 (s, 1H), 7.91 (s, 1H), 7.55-7.51 (m, 384
1H), 2.77 (m, 1H), 2.65 (s, 3H), 2.27-1.84 (m, 11H) 63 9.25 (s,
1H), 8.35-8.34 (m, 2H), 8.17 (s, 1H), 8.05 (d, J = 10.5 Hz, 1H),
380 7.91 (s, 1H), 7.64-7.62 (m, 1H), 2.77 (m, 1H), 2.65 (s, 3H),
2.40 (s, 3H), 2.29-1.83 (m, 11H) 64 9.25 (s, 1H), 8.38-8.35 (m,
2H), 8.22 (s, 1H), 7.99 (s, 1H), 7.91 (s, 1H), 380 7.23-7.22 (m,
1H), 2.76 (m, 1H), 2.65 (s, 3H), 2.43 (s, 3H), 2.29-1.81 (m, 11H)
65 398 66 9.17 (s, 1H), 8.59 (s, 1H), 8.06-8.00 (m, 2H), 7.47-7.43
(m, 1H), 383 7.26-7.24 (m, 1H), 7.12-7.08 (m, 1H), 6.87-6.85 (m,
1H), 2.74-2.72 (m, 1H), 2.60 (s, 3H), 2.24-1.79 (m, 11H) 67 9.17
(s, 1H), 8.60 (s, 1H), 7.98 (s, 1H), 7.26-7.23 (m, 2H), 6.93 (t, J
= 3.5 Hz, 401 1H), 6.12 (s, 1H), 2.76-2.74 (m, 1H), 2.60 (s, 3H),
2.26-2.14 (m, 5H), 2.07-2.01 (m, 2H), 1.87-1.80 (m, 4H) 68 9.10 (s,
1H), 8.86 (s, 1H), 8.65 (d, J = 3.5 Hz, 1H), 8.53 (s, 1H), 366
8.01-7.99 (m, 1H), 7.92 (s, 1H), 7.32-7.30 (m, 1H), 6.16 (s, 1H),
2.72-2.71 (m, 1H), 2.53 (s, 3H), 2.20-1.74 (m, 11H) 69 9.09 (s,
1H), 8.52 (s, 1H), 7.91 (s, 1H), 7.63 (s, 1H), 7.52 (d, J = 8.0 Hz,
399 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 6.12
(s, 1H), 2.69-2.67 (m, 1H), 2.53 (s, 3H), 2.21-1.75 (m, 11H) 70
9.19 (s, 1H), 8.69 (d, J = 5.5 Hz, 1H), 8.61 (s, 1H), 8.22 (s, 1H),
8.01 (s, 381 1H), 7.27 (s, 1H), 2.78 (m, 1H), 2.63 (s, 3H), 2.61
(s, 3H), 2.28-1.62 (m, 11H) 71 9.23 (s, 1H), 9.19 (s, 1H), 8.98 (d,
J = 5.0 Hz, 1H), 8.61 (s, 1H), 8.16 (s, 367 1H), 8.11 (m, 1H), 8.01
(s, 1H), 2.82 (m, 1H), 2.61 (s, 3H), 2.29-1.86 (m, 11H) 72 9.19 (s,
1H), 8.61 (s, 1H), 8.00 (s, 1H), 7.85 (d, J = 3.0 Hz, 1H), 7.57 (d,
J = 3.0 Hz, 372 1H), 7.41 (s, 1H), 2.79 (m, 1H), 2.61 (s, 3H),
2.27-1.83 (m, 11H) 73 9.17 (s, 1H), 8.60 (s, 1H), 7.99 (s, 1H),
7.73 (d, J = 8.0 Hz, 2H), 365 7.50-7.41 (m, 3H), 7.18 (s, 1H), 2.77
(m, 1H), 2.60 (s, 3H), 2.25-1.83 (m, 11H) 74 9.19 (s, 1H), 8.61 (s,
1H), 8.03 (s, 1H), 7.36 (s, 1H), 7.11 (s, 1H), 2.79 (m, 386 1H),
2.61 (s, 3H), 2.48 (s, 3H), 2.26-1.82 (m, 11H) 75 9.17 (s, 1H),
8.59 (s, 1H), 8.33 (s, 1H), 8.16 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H),
380 8.00 (s, 1H), 7.63 (d, J = 7.5 Hz, 1H), 2.79 (m, 1H), 2.59 (s,
3H), 2.40 (s, 3H), 2.30-1.83 (m, 11H) 76 9.18 (s, 1H), 8.60 (s,
1H), 8.39 (d, J = 5.0 Hz, 1H), 8.23 (s, 1H), 8.02 (d, J = 10.0 Hz,
380 2H), 7.24 (d, J = 5.0 Hz, 1H), 2.80 (m, 1H), 2.61 (s, 3H), 2.43
(s, 3H), 2.25-1.83 (m, 11H) 77 9.17 (s, 1H), 8.72 (s, 1H), 8.60 (s,
1H), 8.54 (s, 1H), 7.98 (s, 1H), 7.87 (s, 380 1H), 6.18 (s, 1H),
2.77 (d, J = 10.0 Hz, 1H), 2.60 (s, 3H), 2.39 (s, 3H), 2.27-1.84
(m, 11H) 78 9.40 (s, 1H), 9.19 (s, 1H), 8.76 (d, J = 3.0 Hz, 1H),
8.61 (s, 1H), 8.52 (t, J = 2.0 Hz, 367 1H), 8.01 (s, 1H), 7.96 (s,
1H), 2.82 (d, J = 10.0 Hz, 1H), 2.61 (s, 3H), 2.29-1.86 (m, 11H) 79
9.18 (s, 1H), 8.88 (d, J = 2.0 Hz, 2H), 8.61 (s, 1H), 8.20 (t, J =
2.0 Hz, 1H), 367 8.01 (s, 1H), 7.44 (s, 1H), 2.79 (d, J = 10.0 Hz,
1H), 2.62 (s, 3H), 2.29-1.82 (m, 11H) 80 9.19 (s, 1H), 8.61 (s,
1H), 8.35 (s, 1H), 8.03-7.98 (m, 2H), 7.75-7.72 (t, J = 8.0 Hz, 380
1H), 7.29 (s, 1H), 2.81-2.79 (m, 1H), 2.61 (s, 3H), 2.59 (s, 3H),
2.25-1.85 (m, 11H) 81 8.74 (s, 1H), 8.55 (s, 1H), 8.30 (s, 1H),
8.24 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 379 7.90 (s, 1H), 7.73 (t,
J = 8.0 Hz, 1H), 7.27 (s, 1H), 6.24 (s, 1H), 2.77-2.75 (m 1H), 2.57
(s, 3H), 2.40 (s, 3H), 2.26-1.82 (m, 11H) 82 8.30 (s, 1H), 7.98 (d,
J = 7.5 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.56-7.50 (m, 378 2H),
7.32-7.27 (m, 3H), 6.21 (s, 1H), 2.74 (m, 1H), 2.57 (s, 3H), 2.51
(s, 3H), 2.21-1.81 (m, 11H) 83 9.40 (s, 1H), 8.75 (d, J = 3.0 Hz,
1H), 8.52 (d, J = 4.0 Hz, 1H), 8.31 (s, 1H), 366 7.98-7.97 (m, 1H),
7.73 (t, J = 8.0 Hz, 1H), 7.27 (s, 1H), 2.79 (m, 1H), 2.57 (s, 3H),
2.28-1.82 (m, 11H) 84 8.87-8.86 (m, 2H), 8.32 (s, 1H), 8.20 (s,
1H), 7.98 (d, J = 7.0 Hz, 1H), 366 7.73 (t, J = 8.0 Hz, 1H), 7.43
(t, J = 5.0 Hz, 1H), 7.28 (s, 1H), 2.78-2.76 (m, 1H), 2.58 (s, 3H),
2.28-1.82 (m, 11H) 85 9.23 (d, J = 2.0 Hz, 1H), 8.98 (d, J = 5.0
Hz, 1H), 8.31 (s, 1H), 366 8.17-8.10 (m, 2H), 7.98 (d, J = 8.0 Hz,
1H), 7.73 (t, J = 8.0 Hz, 1H), 7.28 (s, 1H), 2.79 (m, 1H), 2.57 (s,
3H), 2.28-1.82 (m, 11H) 86 8.30 (s 1H), 7.97 (d, J = 8.0 Hz, 1H),
7.85 (d, J = 3.5 Hz, 1H), 7.72 (t, J = 7.5 Hz, 371 1H), 7.56 (d, J
= 3.0 Hz, 1H), 7.41 (s, 1H), 7.27 (s, 1H), 2.76 (m, 1H), 2.57 (s,
3H), 2.28-1.82 (m, 11H) 87 8.31 (s 1H), 7.98 (d, J = 7.5 Hz, 1H),
7.74-7.71 (m, 3H), 7.50-7.42 (m, 3H), 364 7.27 (s, 1H), 6.22 (s,
1H), 2.75 (m, 1H), 2.57 (s, 3H), 2.28-1.82 (m, 11H) 88 9.26 (d, J =
1.0 Hz, 1H), 8.36-8.32 (m, 2H), 7.99-7.92 (m, 2H), 7.73 (t, J = 8.0
Hz, 380 1H), 7.27 (s, 1H), 2.78 (m, 1H), 2.66 (s, 3H), 2.57 (s,
3H), 2.27-1.84 (m, 11H) 89 8.68 (d, J = 5.0 Hz, 1H), 8.30 (s, 1H),
8.22 (s, 1H), 7.98 (d, J = 7.5 Hz, 1H), 380 7.71 (t, J = 8.0 Hz,
1H), 7.27-7.25 (m, 2H), 2.77 (m, 1H), 2.62 (s, 3H), 2.57 (s, 3H),
2.27-1.82 (m, 11H) 90 8.86 (d, J = 5.0 Hz, 1H), 8.31 (s, 1H), 8.21
(s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 380 7.90 (d, J = 5.5 Hz, 1H),
7.73 (t, J = 8.0 Hz, 1H), 7.28 (s, 1H), 2.81-2.78 (m, 4H), 2.57 (s,
3H), 2.30-1.84 (m, 11H) 91 8.28 (s, 1H), 7.97 (d, J = 7.5 Hz, 1H),
7.92 (s, 1H), 7.73 (t, J = 8.0 Hz, 1H), 385 7.27 (s, 1H), 5.99 (s,
1H), 2.74-2.72 (m, 4H), 2.57 (s, 3H), 2.26-1.82 (m, 11H) 92 8.34
(m, 2H), 8.20 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.0
Hz, 1H), 379 7.73 (t, J = 8.0 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H),
7.27 (s, 1H), 2.77 (m, 1H), 2.57 (s, 3H), 2.41 (s, 3H), 2.26-1.82
(m, 11H) 93 8.38 (d, J = 5.5 Hz, 1H), 8.32 (s, 1H), 8.24 (s, 1H),
8.00-7.97 (m, 2H), 379 7.72 (t, J = 8.0 Hz, 1H), 7.27-7.22 (m, 2H),
2.78-2.76 (m, 1H), 2.57 (s, 3H), 2.43 (s, 3H), 2.26-1.82 (m, 11H)
94 384 95 9.38 (s, 1H), 8.75 (s, 1H), 8.51 (m, 1H), 7.99 (s, 1H),
7.89-7.97 (m, 2H), 419 7.74 (m, 1H), 7.58 (m, 1H), 6.21 (s, 1H),
2.79 (m, 1H), 1.78-2.35 (m, 11H) 96 9.38 (s, 1H), 8.75 (m, 1H),
8.51 (m, 1H), 8.02 (s, 1H), 7.89-7.99 (m, 2H), 376 7.78 (m, 1H),
7.57 (m, 1H), 6.20 (s, 1H), 2.78 (m, 1H), 1.78-2.32 (m, 11H) 97
9.40 (s, 1H), 8.73 (m, 1H), 8.50 (m, 1H), 8.07 (m, 1H), 7.90-7.99
(m, 2H), 370 7.85 (m, 1H), 7.07 (m, 1H), 2.78 (m, 1H), 1.78-2.32
(m, 11H) 98 9.38 (d, J = 2.5 Hz, 1H), 8.74 (d, J = 2.5 Hz, 1H),
8.51-8.50 (m, 1H), 365 7.95 (s, 1H), 7.54 (s, 1H), 7.50-7.49 (d, J
= 6.0 Hz, 1H), 7.31-7.30 (d, J = 5.5 Hz, 2H), 6.18 (s, 1H),
2.75-2.73 (m, 1H), 2.39 (s, 3H), 2.25-1.82 (m, 11H) 99 9.39 (d, J =
2.0 Hz, 1H), 8.75 (d, J = 2.5 Hz, 1H), 8.52-8.51 (t, J = 2.0 Hz,
385 1H), 7.95 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.61-7.60 (d, J =
7.0 Hz, 1H), 7.48-7.46 (m, 1H), 7.39-7.36 (m, 1H), 6.18 (s, 1H),
2.77-2.75 (m, 1H), 2.27-1.82 (m, 11H) 100 9.39 (d, J = 1.0 Hz, 1H),
8.85 (d, J = 5.0 Hz, 1H), 8.75 (d, J = 2.0 Hz, 1H), 367 8.50 (s,
1H), 8.19 (s, 1H), 7.95 (s, 1H), 7.88 (d, J = 5.0 Hz, 1H), 2.81 (m,
1H), 2.77 (s, 3H), 2.28-1.84 (m, 11H) 101 9.39 (d, J = 1.0 Hz, 1H),
8.75 (d, J = 2.0 Hz, 1H), 8.52 (t, J = 2.0 Hz, 1H), 372 7.96 (s,
1H), 7.37 (s, 1H), 7.11 (s, 1H), 2.78 (m, 1H), 2.47 (s, 3H),
2.27-1.84 (m, 11H) 102 9.38 (d, J = 1.0 Hz, 1H), 8.74 (d, J = 2.5
Hz, 1H), 8.50 (d, J = 2.0 Hz, 1H), 370 8.36 (d, J = 2.0 Hz, 1H),
8.21 (m, 1H), 8.04 (s, 1H), 7.95 (s, 1H), 7.54-7.51 (m, 1H), 2.79
(m, 1H), 2.27-1.84 (m, 11H) 103 9.40 (d, J = 1.5 Hz, 1H), 8.75 (d,
J = 2.5 Hz, 1H), 8.52 (t, J = 2.0 Hz, 1H), 366 8.39 ((d, J = 4.5
Hz, 1H), 8.23 (s, 1H), 8.00 (s, 1H), 7.97 (s, 1H), 7.24 (d, J = 5.0
Hz, 1H), 2.77-2.75 (m, 1H), 2.43 (s, 3H), 2.22-1.84 (m, 11H) 104
8.85 (d, J = 5.0 Hz, 1H), 8.54-8.53 (m, 1H), 8.23-8.17 (m, 3H),
7.89-7.84 (m, 366 2H), 7.44-7.41 (m, 1H), 2.80-2.78 (m, 4H),
2.23-1.82 (m, 11H) 105 8.54 (d, J = 5.0 Hz, 1H), 8.32 (s, 1H), 8.25
(s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 365 7.98 (d, J = 7.5 Hz, 1H),
7.87-7.83 (m, 1H), 7.73-7.70 (m, 1H), 7.43-7.41 (m, 1H), 7.27-7.26
(m, 1H), 2.79-2.77 (m, 1H), 2.57 (s, 3H), 2.27-1.82 (m, 11H) 106
9.25 (s, 1H), 8.84 (d, J = 4.0 Hz, 1H), 8.36 (s, 1H), 8.24 (s, 1H),
8.18 (d, J = 6.0 Hz, 366 1H), 7.92-7.84 (m, 2H), 7.43 (dd, J = 12.0
Hz, 5.0 Hz, 1H), 2.79-2.77 (m, 1H), 2.65 (s, 3H), 2.25-1.57 (m,
11H) 107 8.69 (d, J = 5.0 Hz, 1H), 8.54 (d, J = 5.0 Hz, 1H),
8.23-8.17 (m, 3H), 366 7.86-7.83 (m, 1H), 7.43-7.41 (m, 1H),
7.27-7.25 (m, 1H), 2.77-2.74 (m, 1H), 2.63 (s, 3H), 2.26-1.82 (m,
11H) 108 8.54 (d, J = 5.0 Hz, 1H), 8.22-8.17 (m, 2H), 7.85 (m, 1H),
7.43-7.39 (m, 2H), 371 7.10 (s, 1H), 2.77-2.75 (m, 1H), 2.47 (s,
3H), 2.27-1.84 (m, 11H) 109 8.53 (d, J = 4.5 Hz, 1H), 8.21-8.16 (m,
2H), 7.92 (s, 1H), 7.86-7.83 (m, 1H), 371 7.43-7.41 (m, 1H), 6.04
(s, 1H), 2.74-2.72 (m, 4H), 2.29-1.78 (m, 11H) 110 8.54 (d, J = 4.0
Hz, 1H), 8.37 (d, J = 3.0 Hz, 1H), 8.27-8.18 (m, 3H), 369 8.06 (s,
1H), 7.86 (t, J = 8.0 Hz, 1H), 7.53-7.42 (m, 2H), 2.78-2.76 (m,
1H), 2.27-1.84 (m, 11H) 111 8.52 (d, J = 4.5 Hz, 1H), 8.33 (s, 1H),
8.23 (s, 1H), 8.19 (s, 1H), 8.17 (d, J = 7.5 Hz, 365 1H), 8.06 (d,
J = 8.0 Hz, 1H), 7.85-7.82 (m, 1H), 7.64 (dd, J = 8.0 Hz, 1.5 Hz,
1H), 7.42-7.39 (m, 1H), 2.77-2.75 (m, 1H), 2.39 (s, 3H), 2.27-1.80
(m, 11H) 112 8.54 (d, J = 5.0 Hz, 1H), 8.38 (d, J = 5.0 Hz, 1H),
8.25 (m, 2H), 8.18 (d, J = 8.0 Hz, 365 1H), 8.00 (s, 1H), 7.85 (t,
J = 8.0 Hz, 1H), 7.42-7.39 (m, 1H), 7.22 (d, J = 5.0 Hz, 1H),
2.77-2.75 (m, 1H), 2.43 (s, 3H), 2.27-1.84 (m, 11H) 113 8.73 (s,
1H), 8.54 (d, J = 5.0 Hz, 2H), 8.23-8.16 (m, 2H), 7.89-7.84 (m,
2H), 365 7.44-7.42 (m, 1H), 6.24 (s, 1H), 2.77-2.75 (m, 1H), 2.40
(s, 3H), 2.32-1.81 (m, 11H) 114 8.54 (d, J = 4.0 Hz, 1H), 8.23 (s,
1H), 8.18 (d, J = 8.0 Hz, 1H), 7.85 (t, J = 7.5 Hz, 364 1H), 7.55
(s, 1H), 7.51 (d, J = 6.5 Hz, 1H), 7.44-7.27 (m, 3H), 6.22 (s, 1H),
2.75-2.73 (m, 1H), 2.42 (s, 3H), 2.40-1.80 (m, 11H) 115 8.54 (d, J
= 5.0 Hz, 1H), 8.22 (s, 1H), 8.18 (d, J = 7.5 Hz, 1H), 7.85 (t, J =
8.0 Hz, 384 1H), 7.72 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.47-7.27
(m, 3H), 6.20 (s, 1H), 2.76-2.73 (m, 1H), 2.30-1.80 (m, 11H) 116
8.35 (s, 1H), 8.10 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.75 (t, J =
7.5 Hz, 1H), 397 7.24-7.43 (m, 3H), 2.80 (m, 1H), 2.60 (s, 3H),
2.57 (s, 3H), 1.78-2.30 (m, 11H) 117 8.28 (s, 1H), 7.97 (d, J = 8.0
Hz, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.36-7.50 (m, 382 3H), 7.25-7.29
(m, 1H), 7.19 (t, J = 1.0 Hz, 1H), 6.20 (s, 1H), 2.74-2.76 (m, 1H),
2.58 (s, 3H), 1.78-2.32 (m, 11H) 118 8.30 (s, 1H), 7.98 (d, J = 7.5
Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.48-7.60 (m, 378 2H), 7.22-7.32
(m, 3H), 6.20 (s, 1H), 2.72-2.78 (m, 1H), 2.58 (s, 3H), 2.41 (s,
3H), 1.78-2.32 (m, 11H)
119 8.54 (d, J = 5.0 Hz, 1H), 8.32 (s, 1H), 8.25 (s, 1H), 8.18 (d,
J = 8.0 Hz, 1H), 365 7.98 (d, J = 7.5 Hz, 1H), 7.87-7.83 (m, 1H),
7.73-7.70 (m, 1H), 7.43-7.41 (m, 1H), 7.27-7.26 (m, 1H), 2.79-2.77
(m, 1H), 2.57 (s, 3H), 1.78-2.32 (m, 11H) 120 8.86 (d, J = 5.0 Hz,
1H), 8.31 (s, 1H), 8.21 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 380 7.90
(d, J = 5.5 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.22-7.30 (m, 1H),
2.75-2.83 (m, 4H), 2.58 (s, 3H), 1.78-2.32 (m, 11H) 121 9.22 (d, J
= 2.0 Hz, 1H), 8.98 (d, J = 5.0 Hz, 1H), 8.31 (s, 1H), 8.18 (s,
1H), 366 8.09-8.12 (m, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.72 (t, J =
8.0 Hz, 1H), 7.22-7.30 (m, 1H), 2.75-2.82 (m, 1H), 2.57 (s, 3H),
1.78-2.32 (m, 11H) 122 8.40 (s, 1H), 8.00 (d, J = 7.5 Hz, 1H),
7.74-7.79 (m, 3H), 7.41-7.54 (m, 3H), 364 7.27 (s, 1H), 6.24 (s,
1H), 2.75 (m, 1H), 2.60 (s, 3H), 1.76-2.32 (m, 1H) 123 8.35 (s,
1H), 8.10 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.75 (t, J = 7.5 Hz,
1H), 397 7.24-7.43 (m, 3H), 2.80 (m, 1H), 2.60 (s, 3H), 2.57 (s,
3H), 1.78-2.30 (m, 11H) 124 8.86 (d, J = 5.0 Hz, 1H), 8.31 (s, 1H),
8.21 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 380 7.90 (d, J = 5.5 Hz,
1H), 7.73 (t, J = 8.0 Hz, 1H), 7.22-7.30 (m, 1H), 2.75-2.83 (m,
4H), 2.58 (s, 3H), 1.78-2.32 (m, 11H) 125 8.28 (s, 1H), 7.97 (d, J
= 8.0 Hz, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.36-7.50 (m, 382 3H),
7.25-7.29 (m, 1H), 7.19 (t, J = 1.0 Hz, 1H), 6.18 (s, 1H),
2.72-2.78 (m, 1H), 2.56 (s, 3H), 1.78-2.32 (m, 11H) 126 8.54 (d, J
= 5.0 Hz, 1H), 8.32 (s, 1H), 8.25 (s, 1H), 8.18 (d, J = 8.0 Hz,
1H), 365 7.98 (d, J = 7.5 Hz, 1H), 7.87-7.83 (m, 1H), 7.73-7.70 (m,
1H), 7.43-7.41 (m, 1H), 727-7.26 (m, 1H), 2.77-2.79 (m, 1H), 2.57
(s, 3H), 1.78-2.32 (m, 11H) 127 9.22 (d, J = 2.0 Hz, 1H), 8.98 (d,
J = 5.0 Hz, 1H), 8.31 (s, 1H), 8.18 (s, 1H), 366 8.09-8.12 (m, 1H),
7.97 (d, J = 8.0 Hz, 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.22-7.30 (m,
1H), 2.75-2.82 (m, 1H), 2.57 (s, 3H), 1.78-2.32 (m, 11H) 128 8.37
(d, J = 3.0 Hz, 1H), 8.31 (s, 1H), 8.17-8.22 (m, 1H), 8.05 (s, 1H),
383 7.98 (d, J = 7.5 Hz, 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.48-7.55
(m, 1H), 7.25-7.30 (m, 1H), 2.73-2.80 (m, 1H), 2.57 (s, 3H),
1.78-2.30 (m, 11H) 129 8.35 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.85
(d, J = 3.5 Hz, 1H), 7.74 (t, J = 7.5 Hz, 371 1H), 7.56 (d, J = 3.0
Hz, 1H), 7.45 (s, 1H), 7.24-7.32 (m, 1H), 2.78 (m, 1H), 2.60 (s,
3H), 1.78-2.32 (m, 11H) 130 8.40 (d, J = 5.5 Hz, 1H), 8.35 (s, 1H),
8.29 (s, 1H), 7.89-8.02 (m, 2H), 379 7.72 (t, J = 8.0 Hz, 1H),
7.15-7.33 (m, 2H), 2.76 (m, 1H), 2.58 (s, 3H), 2.42 (s, 3H),
1.75-2.28 (m, 11H) 131 8.32 (s, 1H), 8.20 (m, 1H), 8.12 (m, 1H),
8.05 (s, 1H), 7.97 (m, 1H), 7.70 (t, J = 8.0 Hz), 395 7.23-7.29 (m,
2H), 3.91 (s, 3H), 2.78 (m, 1H), 2.57 (s, 3H), 1.78-2.30 (m, 11H)
132 9.19 (s, 1H), 8.61 (s, 1H), 8.35 (s, 1H), 7.98-8.03 (m, 2H),
7.72-7.75 (t, J = 8.0 Hz, 380 1H), 7.29 (s, 1H), 2.82 (m, 1H), 2.61
(s, 3H), 2.59 (s, 3H), 1.82-2.32 (m, 11H) 133 9.19 (s, 1H), 8.61
(s, 1H), 8.03 (s, 1H), 7.36 (s, 1H), 7.11 (s, 1H), 2.79 (m, 386
1H), 2.61 (s, 3H), 2.48 (s, 3H), 1.80-2.32 (m, 11H) 134 9.17 (s,
1H), 8.60 (s, 1H), 7.99 (s, 1H), 7.57 (s, 1H), 7.50-7.60 (m, 1H),
379 7.28-7.40 (m, 2H), 6.20 (s, 1H), 2.78 (m, 1H), 2.61 (s, 3H),
2.40 (s, 3H), 1.78-2.32 (m, 11H) 135 9.19 (s, 1H), 8.61 (s, 1H),
7.82-8.09 (m, 4H), 7.06-7.12 (m, 1H), 2.80 (m, 384 1H), 2.61 (s,
3H), 1.78-2.32 (m, 11H) 136 9.16 (s, 1H), 8.60 (s, 1H), 7.99 (s,
1H), 7.20-7.30 (m, 2H), 6.89-6.97 (m, 1H), 401 6.27 (s, 1H), 2.75
(m, 1H), 2.60 (s, 3H), 1.78-2.31 (m, 11H) 137 9.19 (s, 1H), 8.61
(s, 1H), 8.35 (s, 1H), 7.98-8.03 (m, 2H), 7.72-7.75 (t, J = 8.0 Hz,
380 1H), 7.29 (s, 1H), 2.82 (m, 1H), 2.61 (s, 3H), 2.59 (s, 3H),
1.82-2.32 (m, 11H) 138 9.19 (s, 1H), 8.61 (s, 1H), 8.03 (s, 1H),
7.36 (s, 1H), 7.11 (s, 1H), 2.79 (m, 386 1H), 2.61 (s, 3H), 2.48
(s, 3H), 1.80-2.32 (m, 11H) 139 9.17 (s, 1H), 8.60 (s, 1H), 7.99
(s, 1H), 7.57 (s, 1H), 7.50-7.60 (m, 1H), 379 7.28-7.40 (m, 2H),
6.20 (s, 1H), 2.78 (m, 1H), 2.61 (s, 3H), 2.40 (s, 3H), 1.78-2.32
(m, 11H) 140 9.19 (s, 1H), 8.61 (s, 1H), 7.82-8.09 (m, 4H),
7.06-7.12 (m, 1H), 2.80 (m, 384 1H), 2.61 (s, 3H), 1.78-2.32 (m,
11H) 141 8.54 (d, J = 4.0 Hz, 1H), 8.23 (s, 1H), 8.18 (d, J = 8.0
Hz, 1H), 7.88 (t, J = 7.5 Hz, 364 1H), 7.55 (s, 1H), 7.53 (d, J =
6.5 Hz, 1H), 7.27-7.50 (m, 3H), 6.20 (s, 1H), 2.75 (m, 1H), 2.44
(s, 3H), 1.78-2.32 (m, 11H) 142 8.54 (d, J = 5.0 Hz, 1H), 8.30 (s,
1H), 8.20 (d, J = 7.5 Hz, 1H), 7.88 (t, J = 8.0 Hz, 368 1H),
7.36-7.50 (m, 4H), 7.16-7.22 (m, 1H), 6.20 (s, 1H), 2.75 (m, 1H),
1.78-2.32 (m, 11H) 143 8.54 (d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.20
(d, J = 7.5 Hz, 1H), 7.88 (t, J = 8.0 Hz, 371 1H), 7.35-7.48 (m,
2H), 7.10 (s, 1H), 2.76 (m, 1H), 2.47 (s, 3H), 1.78-2.32 (m, 11H)
144 8.86 (d, J = 5.0 Hz, 1H), 8.52-8.58 (m, 1H), 8.18-8.32 (m, 3H),
7.83-7.92 (m, 366 2H), 7.40-7.50 (m, 1H), 2.81 (m, 1H), 2.80 (s,
3H), 1.78-2.32 (m, 11H) 145 8.54 (d, J = 4.0 Hz, 1H), 8.20-8.45 (m,
4H), 8.06 (s, 1H), 7.95 (t, J = 8.0 Hz, 369 1H), 7.44-7.60 (m, 2H),
2.76-2.81 (m, 1H), 1.78-2.32 (m, 11H) 146 8.54 (d, J = 4.0 Hz, 1H),
8.28 (s, 1H), 7.80-8.20 (m, 5H), 7.42-7.50 (m, 1H), 369 7.06-7.12
(m, 1H), 2.75 (m, 1H), 1.78-2.32 (m, 11H) 147 8.54 (d, J = 4.0 Hz,
1H), 8.25 (s, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.10 (s, 1H), 383 7.85
(t, J = 8.0 Hz, 1H), 7.20-7.47 (m, 3H), 2.75-2.82 (m, 1H), 2.56 (s,
3H), 1.78-2.32 (m, 11H) 148 8.54 (d, J = 4.0 Hz, 1H), 8.25 (s, 1H),
8.20 (d, J = 8.0 Hz, 1H), 8.0 (s, 1H), 418 7.40-7.98 (m, 5H), 6.25
(s, 1H), 2.80 (m, 1H), 1.78-2.40 (m, 11H) 149 8.54 (d, J = 4.0 Hz,
1H), 8.24 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.40-8.05 (m, 375 6H),
6.25 (s, 1H), 2.75-2.80 (m, 1H), 1.78-2.40 (m, 11H) 150 8.54 (d, J
= 4.0 Hz, 1H), 8.25 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.89 (t, J =
7.8 Hz, 393 1H), 7.80 (s, 1H), 7.42-7.78 (m, 3H), 6.20 (s, 1H),
2.80 (m, 1H), 1.78-2.40 (m, 11H) 151 9.18 (s, 1H), 8.61 (s, 1H),
8.00 (s, 1H), 7.75-7.80 (m, 1H), 7.07-7.20 (m, 401 2H), 6.81-6.90
(m, 1H), 2.75 (m, 1H), 2.63 (s, 3H), 1.78-2.32 (m, 11H) 152 9.20
(s, 1H), 8.72 (s, 1H), 7.95-8.11 (m, 3H), 7.76 (s, 1H), 7.08-7.12
(m, 384 1H), 2.80 (m, 1H), 2.63 (s, 3H), 1.78-2.32 (m, 11H) 153
9.20 (s, 1H), 8.73 (s, 1H), 8.00 (s, 1H), 7.82 (s, 1H), 7.70-7.75
(m, 1H), 408 7.48-7.54 (m, 1H), 6.20 (s, 1H), 2.80 (m, 1H), 2.63
(s, 3H), 1.78-2.40 (m, 11H) 154 9.17 (s, 1H), 8.59 (s, 1H), 8.36
(d, J = 3.0 Hz, 1H), 8.18-8.21 (m, 1H), 384 8.04 (s, 1H), 8.00 (s,
1H), 7.50-7.54 (m, 1H), 2.76-2.79 (m, 1H), 2.59 (s, 3H), 1.78-2.32
(m, 11H) 155 9.16 (s, 1H), 8.60 (s, 1H), 8.25-8.30 (m, 1H), 8.00
(s, 1H), 7.80 (s, 1H), 402 7.26-7.35 (m, 1H), 2.80 (m, 1H), 2.60
(s, 3H), 1.78-2.32 (m, 11H) 156 9.18 (s, 1H), 8.85 (d, J = 5.1 Hz,
1H), 8.60 (s, 1H), 8.19 (s, 1H), 8.00 (s, 1H), 381 7.88 (d, J = 5.0
Hz, 1H), 2.77-2.83 (m, 1H), 2.77 (s, 3H), 2.60 (s, 3H), 1.78-2.32
(m, 11H). 157 9.18 (s, 1H), 8.85 (d, J = 5.1 Hz, 1H), 8.60 (s, 1H),
8.19 (s, 1H), 8.00 (s, 1H), 381 7.88 (d, J = 5.0 Hz, 1H), 2.77-2.83
(m, 1H), 2.77 (s, 3H), 2.60 (s, 3H), 1.78-2.32 (m, 11H). 158 9.17
(s, 1H), 8.57 (s, 1H), 8.51-8.54 (m, 1H), 8.23 (s, 1H), 8.15-8.19
(m, 366 1H), 8.01 (s, 1H), 7.82-7.87 (m, 1H), 7.39-7.44 (m, 1H),
2.77-2.82 (m, 1H), 2.60 (s, 3H), 1.78-2.32 (m, 11H). 159 9.17 (s,
1H), 8.57 (s, 1H), 8.51-8.54 (m, 1H), 8.23 (s, 1H), 8.15-8.19 (m,
366 1H), 8.01 (s, 1H), 7.82-7.87 (m, 1H), 7.39-7.44 (m, 1H),
2.77-2.82 (m, 1H), 2.60 (s, 3H), 1.78-2.32 (m, 11H). 160 9.17 (s,
1H), 8.60 (s, 1H), 7.99 (s, 1H), 7.36-7.49 (m, 3H), 7.15-7.22 (m,
383 1H), 6.18 (s, 1H), 2.73-2.78 (m, 1H), 2.60 (s, 3H), 1.78-2.32
(m, 11H). 161 9.17 (s, 1H), 8.60 (s, 1H), 7.99 (s, 1H), 7.36-7.49
(m, 3H), 7.15-7.22 (m, 383 1H), 6.18 (s, 1H), 2.73-2.78 (m, 1H),
2.60 (s, 3H), 1.78-2.32 (m, 11H). 162 9.39 (d, J = 2.0 Hz, 1H),
8.75 (d, J = 2.5 Hz, 1H), 8.47-8.51 (m, 1H), 7.95 (s, 385 1H), 7.72
(t, J = 2.0 Hz, 1H), 7.58-7.63 (m, 1H), 7.42-7.50 (m, 1H),
7.32-7.40 (m, 1H), 6.20 (s, 1H), 2.75 (m, 1H), 1.78-2.32 (m, 11H)
163 9.39 (d, J = 2.0 Hz, 1H), 8.75 (d, J = 2.5 Hz, 1H), 8.47-8.51
(m, 1H), 7.95 (s, 385 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.58-7.63 (m,
1H), 7.42-7.50 (m, 1H), 7.32-7.40 (m, 1H), 6.20 (s, 1H), 2.75 (m,
1H), 1.78-2.32 (m, 11H) 164 9.18 (s, 1H), 8.61 (s, 1H), 8.24 (m,
2H), 8.02 (s, 1H), 7.95 (s, 1H), 366 7.72-7.69 (m, 1H), 7.04 (s,
1H), 2.61 (s, 3H), 2.58-2.56 (m, 1H), 2.30-2.05 (m, 5H), 1.91-1.73
(m, 6H) 165 9.34 (s, 1H), 9.17 (s, 1H), 8.61 (s, 1H), 8.21 (s, 1H)
8.01 (s, 1H), 7.83 (s, 381 1H), 2.60-2.54 (m, 4H), 2.45 (s, 3H),
2.30-2.20 (m, 3H), 2.11-2.07 (m, 2H), 1.96-1.73 (m, 6H) 166 9.10
(s, 1H), 8.54 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 7.93-7.90 (m, 2H),
381 7.84 (s, 1H), 2.53-2.50 (m, 7H), 2.18-1.65 (m, 11H) 167 9.17
(s, 1H), 8.79 (m, 1H), 8.61 (s, 1H), 7.97 (s, 1H), 6.52 (d, J = 1.0
Hz, 386 1H), 2.60-2.57 (m, 4H), 2.34 (s, 3H), 2.28-2.21 (m, 3H),
2.11-2.01 (m, 2H), 1.93-1.75 (m, 5H), 1.73-1.70 (m, 1H) 168 9.26
(m, 1H), 9.17 (s, 1H), 8.61 (s, 1H), 7.98 (s, 1H), 7.46 (d, J = 3.5
Hz, 372 1H), 6.98 (d, J = 3.5 Hz, 1H), 2.61-2.57 (m, 4H), 2.31-2.20
(m, 3H), 2.11-2.04 (m, 2H), 1.92-1.71 (m, 6H) 169 8.33 (s, 1H),
8.00-7.79 (m, 3H), 7.74-7.71 (m, 1H), 7.60-7.57 (m, 1H), 379
7.28-7.27 (m, 1H), 6.90 (d, J = 7.5 Hz, 1H), 2.58 (m, 4H), 2.43 (s,
3H), 2.24-2.00 (m, 5H), 1.91-1.84 (m, 6H) 170 8.86 (d, J = 7.5 Hz,
1H), 8.21 (s, 1H), 8.02 (d, J = 10.0 Hz, 1H), 380 7.92-7.88 (m,
2H), 7.58 (m, 1H), 6.89 (d, J = 7.5 Hz, 1H), 2.78 (s, 3H),
2.58-2.55 (m, 1H), 2.43 (s, 3H), 2.24-2.05 (m, 6H), 1.91-1.84 (m,
5H) 171 8.02 (d, J = 7.5 Hz, 1H), 7.86 (s, 1H), 7.58-7.56 (m, 1H),
7.36 (s, 1H), 385 7.09 (s, 1H), 6.89 (d, J = 7.5 Hz, 1H), 2.56-2.54
(m, 1H), 2.46 (s, 3H), 2.44 (s, 3H), 2.27-2.05 (m, 5H), 1.92-1.84
(m, 6H) 172 8.02 (d, J = 7.5 Hz, 1H), 7.88-7.86 (m, 2H), 7.57-7.64
(m, 2H), 7.42 (s, 1H), 371 6.89 (d, J = 7.5 Hz, 1H), 2.58-2.57 (m,
1H), 2.43 (s, 3H), 2.24-2.05 (m, 5H), 1.91-1.84 (m, 6H) 173 9.25
(d, J = 7.5 Hz, 1H), 8.36 (s, 1H), 8.03-7.88 (m, 3H), 7.60-7.56 (m,
1H), 380 6.89 (d, J = 7.5 Hz, 1H), 2.65 (s, 3H), 2.58-2.57 (m, 1H),
2.43 (s, 3H), 2.24-2.05 (m, 5H), 1.91-1.77 (m, 6H) 174 9.40 (d, J =
7.5 Hz, 1H), 8.75 (s, 1H), 8.52 (s, 1H), 8.03-7.86 (m, 3H), 366
7.60-7.56 (m, 1H), 6.89 (d, J = 7.5 Hz, 1H), 2.58 (m, 1H), 2.43 (s,
3H), 2.24-2.05 (m, 5H), 1.91-1.77 (m, 6H) 175 8.04-8.03 (m, 2H),
7.61-7.50 (m, 3H), 7.32-7.27 (m, 2H), 6.90 (d, J = 7.5 Hz, 378 1H),
6.22 (s, 1H), 2.53 (m, 1H), 2.46 (s, 3H), 2.42 (s, 3H), 2.14-1.88
(m, 5H), 1.86-1.72 (m, 6H) 176 8.01 (d, J = 7.5 Hz, 1H), 7.90 (s,
1H), 7.71-7.70 (m, 1H), 7.60-7.57 (m, 2H), 398 7.46-7.45 (m, 1H),
7.37-7.34 (m, 1H), 6.89 (d, J = 7.0 Hz, 1H), 6.25 (s, 1H),
2.51-2.49 (m, 1H), 2.44 (s, 3H), 2.24-2.00 (m, 5H), 1.89-1.82 (m,
6H) 177 8.53 (d, J = 7.5 Hz, 1H), 8.25 (s, 1H), 8.17-8.16 (m, 1H),
8.03-8.01 (m, 1H), 365 7.92 (s, 1H), 7.84-7.82 (m, 1H), 7.58-7.55
(m, 1H), 7.42-7.40 (m, 1H), 6.88-6.87 (m, 1H), 2.60 (m, 1H), 2.43
(s, 3H), 2.24-2.00 (m, 5H), 1.89-1.76 (m, 6H) 178 8.53 (d, J = 6.0
Hz, 1H), 8.31 (s, 1H), 8.05-7.74 (m, 3H), 7.73 (t, J = 8.0 Hz, 380
1H), 7.29-7.27 (m, 1H), 2.64-2.57 (m, 7H), 2.27-1.72 (m, 11H) 179
8.87 (d, J = 5.0 Hz, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.20 (s, 1H),
7.99 (d, J = 5.5 Hz, 381 1H), 7.89 (d, J = 5.0 Hz, 1H), 2.79 (s,
3H), 2.61 (d, J = 5.0 Hz, 3H), 2.58 (s, 1H), 2.23 (d, J = 6.0 Hz,
3H), 2.08-2.06 (m, 2H), 1.93-1.81 (m,
7H) 180 8.54 (d, J = 6.0 Hz, 1H), 7.98 (d, J = 6.0 Hz, 1H), 7.89
(s, 1H), 7.37 (s, 1H), 386 7.12 (d, J = 1.5 Hz, 1H), 2.62-2.48 (m,
7H), 2.25-1.73 (m, 11H) 181 8.53 (d, J = 7.5 Hz, 1H), 8.00-7.95 (m,
2H), 7.56-7.53 (m, 2H), 7.32-7.30 (m, 379 2H), 6.21 (s, 1H), 2.60
(s, 3H), 2.58 (m, 1H), 2.55 (s, 3H), 2.24-2.05 (m, 5H), 1.91-1.71
(m, 6H) 182 8.53 (d, J = 7.5 Hz, 1H), 7.98-7.95 (m, 2H), 7.71-7.63
(m, 2H), 7.48-7.36 (m, 399 2H), 6.21 (s, 1H), 2.60 (s, 3H), 2.58
(m, 1H), 2.24-2.05 (m, 5H), 1.91-1.71 (m, 6H) 183 9.31 (s, 1H),
8.32 (s, 1H), 8.22 (s, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.88 (s, 1H),
380 7.74-7.71 (m, 1H), 7.28-7.27 (m, 1H), 2.64-2.62 (m, 1H), 2.61
(s, 3H), 2.46 (s, 3H), 2.27-1.75 (m, 11H) 184 9.35 (s, 1H), 8.22
(s, 1H), 7.72 (s, 1H), 7.38 (s, 1H), 7.12 (s, 1H), 386 2.61-2.58
(m, 1H), 2.48 (s, 3H), 2.47 (s, 3H), 2.25-1.88 (m, 11H) 185 9.35
(s, 1H), 8.23 (s, 1H), 7.79 (s, 1H), 7.72 (s, 1H), 7.61 (d, J = 6.5
Hz, 1H), 399 7.48 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H),
6.18 (s, 1H), 2.57-2.54 (m, 1H), 2.47 (s, 3H), 2.29-1.75 (m, 11H)
186 9.49 (s, 1H), 8.82 (s, 1H), 8.45 (s, 1H), 8.25 (s, 1H), 8.07
(d, J = 8.0 Hz, 384 1H), 7.89 (s, 1H), 7.80 (d, J = 3.0 Hz, 1H),
7.58 (d, J = 8.0 Hz, 1H), 7.49-7.46 (m, 1H), 7.33-7.32 (m, 1H),
2.26-1.65 (m, 12H) 187 9.57 (s, 1H), 8.35 (s, 1H), 8.24 (s, 1H),
7.89 (s, 1H), 7.55 (s, 1H), 385 7.51-7.49 (m, 1H), 7.33-7.30 (m,
2H), 6.20 (s, 1H), 2.57-2.55 (m, 1H), 2.39 (s, 3H), 2.31-1.71 (m,
11H)
[0228] 4. Pharmacological Evaluation of Compounds of the
Invention
[0229] Compounds of the present invention have been tested in vitro
and in vivo, and can be tested in vitro and in vivo, in the assays
as described below.
[0230] In Vitro Assays
[0231] Radioligand Binding Assays
[0232] Binding assays were performed as described in [J. A. O'Brien
et al. Mol Pharmacol., 2003, 64, 731-740] with slight
modifications, including that a radioligand that binds to the
methyl-5-(2-pyridinylethynyl)pyridine (MPEP) binding site was used
in place of [.sup.3H]-MPEP. Briefly, after thawing, the membrane
homogenates were resuspended in 50 mM Tris-HCl and 0.9% NaCl
binding buffer at pH 7.4 to a final assay concentration of 20 .mu.g
protein/well for radioligand filtration binding. Incubations
included 5 nM radioligand, membranes and either buffer or varying
concentrations of compound. Samples were incubated for 60 min at
room temperature with shaking. Non-specific binding was defined
with 10 .mu.M cold MPEP when using the radioligand. After
incubation, samples were filtered over a GF/C filter (presoaked in
0.25% polyethyleneimine (PEI)) and then washed 4 times using a
Tomtec.RTM. Harvester 96.RTM. Mach III cell harvester (Tomtec,
Hamden, Conn.) with 0.5 mL ice-cold 50 mM Tris-HCl (pH 7.4).
IC.sub.50 values were derived from the inhibition curve and Ki
values were calculated according to the Cheng and Prusoff equation
of Ki=IC.sub.50/(1+[L]/Kd) described in [Y. Cheng and W. H. Prusoff
Biochem. Pharmacol. 1973, 22, 3099-3108] where [L] is the
concentration of radioligand and Kd is its dissociation constant at
the receptor, derived from the saturation isotherm. The Ki values
of compounds of the invention were <10 .mu.M. The Ki values of
representative compounds were listed in Table 4.
[0233] Calcium Mobilization Assay to Test for Negative or Positive
Allosteric Activity
[0234] The cDNA for rat metabotropic glutamate receptor 5 (rmGluR5)
and the cDNA for human metabotropic glutamate receptor 5 (hmGluR5)
were generous gifts from S. Nakanishi (Kyoto University, Kyoto,
Japan). The rmGluR5 or hmGluR5 was stably expressed in a HEK 293
cell line and grown in Dulbecco's Modified Eagle Medium (DMEM)
(Invitrogen, Carlsbad, Calif.) with supplements (10% bovine calf
serum, 4 mM glutamine, 100 units/mL penicillin, 100 .mu.g/mL
streptomycin and 0.75 mM G1418) at 37.degree. C., 5% CO.sub.2.
Twenty-four hours prior to assay, cells were seeded into 384-well
black wall microtiter plates coated with poly-D-lysine. Just prior
to assay, media was aspirated and cells dye-loaded (25 .mu.L/well)
with 3 .mu.M Fluo-4/0.01% pluronic acid in assay buffer (Hank's
Balanced Saline Solution (HBSS)): 150 mM NaCl, 5 mM KCl, 1 mM
CaCl.sub.2, 1 mM MgCl.sub.2, plus 20 mM
N-2-Hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), pH
7.4, 0.1% bovine serum albumin (BSA) and 2.5 mM probenicid) for 1
hour in 5% CO.sub.2 at 37.degree. C. After excess dye was
discarded, cells were washed in assay buffer and layered with a
final volume equal to 30 .mu.L/well. Basal fluorescence is
monitored in a fluorometric imaging plate reader (FLIPR) (Molecular
Devices, Sunnyvale, Calif.) with an excitation wavelength of 488 nm
and an emission range of 500 to 560 nm. Laser excitation energy was
adjusted so that basal fluorescence readings were approximately
10,000 relative fluorescent units. Cells were stimulated with an
EC.sub.20 or an EC.sub.80 concentration of glutamate in the
presence of a compound to be tested, both diluted in assay buffer,
and relative fluorescent units were measured at defined intervals
(exposure=0.6 sec) over a 3 min period at room temperature. Basal
readings derived from negative controls were subtracted from all
samples. Maximum change in fluorescence was calculated for each
well. Concentration-response curves derived from the maximum change
in fluorescence were analyzed by nonlinear regression (Hill
equation). A negative modulator can be identified from these
concentration-response curves if a compound produces a
concentration dependent inhibition of the EC.sub.80 glutamate
response. Representative Examples were tested in the above assay
using hmGluR5, and FLIPR maximum inhibition ranged from about 70%
to about 100%, while FLIPR IC.sub.50 ranged from about 0.32 nM to
about 1 .mu.M. The IC.sub.50 values of representative compounds
were listed in Table 4.
[0235] A positive modulator (PAM) can be identified from these
concentration-response curves if a compound produces a
concentration dependent increase in the EC.sub.20 glutamate
response.
[0236] A silent allosteric modulator (SAM) can be identified based
on results from both the radioligand assay and the calcium
mobilization assay. If a compound actively binds to an allosteric
site of the receptor based on the radioligand assay, but has no
measurable intrinsic efficacy in the calcium mobilization assay,
the compound is a SAM.
TABLE-US-00004 TABLE 4 In vitro activity of representative
compounds Example hmGluR5 hmGluR5 hmGlu5 FLIPR % No. Ki (nM) FLIPR
IC.sub.50 (nM) inhibition 2 27 3.7 89 6 78 9 92 15 340 26 88 36 280
35 87 126 39 0.32 86 160 35 3.9 89 161 1200 134 90 171 65 4.7 94
176 500 33 91 178 370 38 90
[0237] In Vivo Assays
[0238] Compounds of formula (I) can be tested for in vivo
anxiolytic effect in a mouse marble burying (mMB) assay similar to
that described in [K. Njung'e, K. and S. L. Handley, Pharmacology,
Biochemistry and Behavior, 1991, 38, 63-67].
[0239] Anxiolytic effect in vivo can also be tested via a modified
Geller-Seifter conflict test described in [N. A. Moore et al.
Behavioural Pharmacology. 1994, 5, 196-202].
[0240] The "Vogel Conflict Test" as described by Vogel et al.
[Psychopharmacologia, 1971, 21, 1-7] also can be used to detect
anxiolytic activity of a compound of formula (I) because
anxiolytics increase punished drinking.
[0241] Compounds of the invention also can be evaluated in vivo for
anxiolytic effects using a light-enhanced startle (LES) reflex
method as that described in [Walker and Davis. Biol. Psychiatry,
1997, 42, 461-471].
[0242] Anxiolytic-like properties also can be evaluated using these
additional tests: (1) social interaction described in [S. E. File
and P. Seth European Journal of Pharmacology, 2003. 463, 35-53],
and (2) elevated plus-maze described in [S. M. Korte and S. F. De
Boer European Journal of Pharmacology, 2003, 463, 163-175].
[0243] Compounds of formula (I) can be evaluated in vivo for
antidepressive effects. An assessment of depression-like actions
can be measured using a forced swim test similar to that described
in [J. F. Cryan, et al. Neuroscience and Biobehavioral Reviews
2005, 29, 547-569.]
[0244] Antidepressive effect also can be evaluated using the
Flinders Sensitive Line (FSL) rat in the FST and social interaction
test as described in [D. H. Overstreet and G. Griebel Pharmacol
Biochem Behav., 2005, 82, 1: 223-227].
[0245] Anxiolytic and antidepressive effects also can be evaluated
using a paradigm for decreased HPA axis feedback (David et al.,
2007, SFN meeting in San Diego). This model based on the chronic
delivery of corticosterone in the drinking water, causes anxiety-
and depression-like behaviors in mice.
[0246] Parkinson's disease (PD) can be assessed by measuring the
neurotoxicity of MPTP in rats as described in [E. H. Lee et al.
Chin. J. Physiol., 1992, 35, 4: 317-36]. Also, experimentally
induced striatal DA depletion in animals is a valid model of
Parkinsonism, as described in [W. Schultz Prog. Neurobiol., 1982,
18, 2-3: 121-66]. The capacity of certain substances to damage
catecholaminergic neurons has been used extensively to produce DA
deficiency in animals, as described in [L. E. Annett et al. Exp.
Neurol., 1994, 125, 2: 228-46]. PD can also be assessed by
measuring the neurotoxicity induced by 6-hydroxydopamine (6-OHDA)
as described in [N. Breysse et al. J. Neurosci., 2002, 22, 13:
5669-5678; D. Rylander et al. J. Pharmacol. Exp. Ther., 2009, 330,
1: 227-235; and L. Chen et al., "Chronic, systemic treatment with a
metabotropic glutamate receptor 5 antagonist in 6-hydroxydopamine
partially lesioned rats reverses abnormal firing of dopaminergic
neurons," Brain Res., 2009, 1286, 192-200].
[0247] Fragile X Syndrome can be assessed using the fmr1.sup.tm1Cgr
mouse model as described in [Q. J. Yan et al. Neuropharmacol.,
2005, 49, 1053-1066], as well as the Fmr1 knockout mice with a
selective reduction in mGluR5 expression as described in [G. Dolen
et al. Neuron, 2007, 56, 955-962].
[0248] Preclinically, animals also can be evaluated for
blockade/attenuation of symptoms associated with schizophrenia.
Positive symptoms in animal models of schizophrenia can be
evaluated by measuring changes in the overall level of activity of
dopamine (DA) activity with concomitant parallel changes in
locomotor activity as described in [R. Depoortere et al.
Neuropsychopharmacology, 2003, 28, 11: 1889-902], D-amphetamine
(AMPH) and phencyclidine (PCP) via induction of model psychosis or
locomotor hyperactivity as described in [W. J. Freed et al.
Neuropharmacology, 1984, 23, 2A: 175-81; F. Sams-Dodd
Neuropsychopharmacology, 1998 19, 1: 18-25]. For example,
Depoortere et al., 2003, have described tests for evaluating
locomotor activity, catalepsy, climbing and stereotypy, which
relate to positive symptomology and side effect profile, by
characterizing compounds with typical and atypical antipsychotic
efficacy. Attenuation in apomorphine-induced climbing, stereotypy
and catalepsy (AIC) can be evaluated as described in [Y. K. Fung et
al. Pharmacol. Biochem. Behav., 1986, 24, 1: 139-41 and Y. K. Fung
et al. Steroids, 1987, 49, 4-5: 287-94]. Additionally, negative
symptoms of schizophrenia can be evaluated by measuring social
interaction under the influence of NMDA antagonists such as PCP, as
described in F. Sams-Dodd, 1998, supra.
[0249] Cognitive symptoms of memory, including those from
Alzheimer's disease, can be evaluated by such models as the Fear
Conditioning Paradigm described in [T. J. Gould et al. Behav.
Pharmacol., 2002, 13, 4: 287-94, and A. O. Hamm et al. Brain, 2003,
126, Pt 2: 267-75] and the Radial Arm Test described in [J. P.
Aggleton et al. Behav. Brain Res., 1996, 19, 2: 133-46], while
spatial reference memory and learning can be evaluated in the
Morris watermaze test as described in [Morris. Learn. Motiv., 1981,
12, 239-260; B. Bontempi et al. Eur. J. Neurosci. 1996, 8, 11:
2348-60].
[0250] Additionally, with respect to cognition, memory and
hippocampal hypo-functioning can be assessed by measuring the
restoration of synaptic plasticity in ovariectomized (OVX) female
rats as described in [M. Day and M. Good Neurobiol. Learn. Mem.,
2005, 83, 1: 13-21]. Further, changes in attention function because
of schizophrenia can be examined by the Five (5) Choice Serial
Reaction Time Test (5CSRT) described in [J. L. Muir et al.
Psychopharmacology (Berl), 1995, 118, 1: 82-92 and Robbins et al.
Ann. N. Y. Acad. Sci., 1998, 846, 222-37].
[0251] Human patients can be evaluated for cognitive diseases or
disorders by any of the tests within the skill of those in the
art.
[0252] Analgesic activity can be evaluated by neuropathic pain
model (the "Chung model") as described in [Kim and Chung, Pain,
1992, 50, 355-363]. Analgesic/anti-inflammatory activity can be
evaluated in vivo using the Formalin Paw Test in the mouse such as
that described by [Wheeler-Aceto et al, Psychopharmacology, 1991,
104, 35-44).
[0253] Multiple sclerosis can be evaluated by the experimental
autoimmune encephalomyelitis (EAE) model described in [H. Y. Liu et
al. J. Neurosci. Res., 2002, 70, 2: 238-48].
[0254] Those skilled in the art will recognize that various changes
and/or modifications may be made to aspects or embodiments of this
invention and that such Changes and/or modifications may be made
without departing from the spirit of this invention. Therefore, it
is intended that the appended claims cover all such equivalent
variations as will fall within the spirit and scope of this
invention.
[0255] Each reference cited in the present application, including
literature references, books, patents and patent applications, is
incorporated herein by reference in its entirety.
* * * * *