U.S. patent application number 14/492736 was filed with the patent office on 2015-01-08 for compounds and compositions for the treatment of parasitic diseases.
This patent application is currently assigned to IRM LLC. The applicant listed for this patent is Venkatataiah Bollu, Arnab Kumar Chatterjee, Ravinder Reddy Kondreddi, Seh Yong Leong, Pranab Kumar Mishra, Robert Joseph Moreau, Advait Suresh Nagle, Prasuna Paraselli, Jason Thomas Roland, Wei Lin Sandra Sim, Oliver Simon, Liying Jocelyn Tan, Bryan KS Yeung, Bin Zou. Invention is credited to Venkatataiah Bollu, Arnab Kumar Chatterjee, Ravinder Reddy Kondreddi, Seh Yong Leong, Pranab Kumar Mishra, Robert Joseph Moreau, Advait Suresh Nagle, Prasuna Paraselli, Jason Thomas Roland, Wei Lin Sandra Sim, Oliver Simon, Liying Jocelyn Tan, Bryan KS Yeung, Bin Zou.
Application Number | 20150011522 14/492736 |
Document ID | / |
Family ID | 50826032 |
Filed Date | 2015-01-08 |
United States Patent
Application |
20150011522 |
Kind Code |
A1 |
Chatterjee; Arnab Kumar ; et
al. |
January 8, 2015 |
COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF PARASITIC
DISEASES
Abstract
The present invention provides compounds of formula I:
##STR00001## or a pharmaceutically acceptable salt, tautomer, or
stereoisomer, thereof, wherein the variables are as defined herein.
The present invention further provides pharmaceutical compositions
comprising such compounds and methods of using such compounds for
treating, preventing, inhibiting, ameliorating, or eradicating the
pathology and/or symptomology of a disease caused by a Plasmodium
parasite, such as malaria.
Inventors: |
Chatterjee; Arnab Kumar;
(San Diego, CA) ; Nagle; Advait Suresh; (San
Diego, CA) ; Paraselli; Prasuna; (San Diego, CA)
; Kondreddi; Ravinder Reddy; (Singapore, SG) ;
Leong; Seh Yong; (Singapore, SG) ; Mishra; Pranab
Kumar; (West Bengal, IN) ; Moreau; Robert Joseph;
(Emeryville, CA) ; Roland; Jason Thomas; (San
Diego, CA) ; Sim; Wei Lin Sandra; (Singapore, SG)
; Simon; Oliver; (Singapore, SG) ; Tan; Liying
Jocelyn; (Singapore, SG) ; Yeung; Bryan KS;
(Singapore, SG) ; Zou; Bin; (Singapore, SG)
; Bollu; Venkatataiah; (San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Chatterjee; Arnab Kumar
Nagle; Advait Suresh
Paraselli; Prasuna
Kondreddi; Ravinder Reddy
Leong; Seh Yong
Mishra; Pranab Kumar
Moreau; Robert Joseph
Roland; Jason Thomas
Sim; Wei Lin Sandra
Simon; Oliver
Tan; Liying Jocelyn
Yeung; Bryan KS
Zou; Bin
Bollu; Venkatataiah |
San Diego
San Diego
San Diego
Singapore
Singapore
West Bengal
Emeryville
San Diego
Singapore
Singapore
Singapore
Singapore
Singapore
San Diego |
CA
CA
CA
CA
CA
CA |
US
US
US
SG
SG
IN
US
US
SG
SG
SG
SG
SG
US |
|
|
Assignee: |
IRM LLC
Hamilton
BM
Novartis AG
Basel
CH
|
Family ID: |
50826032 |
Appl. No.: |
14/492736 |
Filed: |
September 22, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14083203 |
Nov 18, 2013 |
8871754 |
|
|
14492736 |
|
|
|
|
61728018 |
Nov 19, 2012 |
|
|
|
Current U.S.
Class: |
514/187 ;
514/230.5; 514/252.11; 514/275; 514/292; 514/297; 514/300; 544/105;
546/121 |
Current CPC
Class: |
Y02A 50/30 20180101;
Y02A 50/411 20180101; A61K 31/437 20130101; C07D 519/00 20130101;
C07D 471/04 20130101; A61K 45/06 20130101; A61K 31/538 20130101;
A61K 31/444 20130101; A61K 31/437 20130101; A61K 2300/00 20130101;
A61K 31/538 20130101; A61K 2300/00 20130101; A61K 31/444 20130101;
A61K 2300/00 20130101 |
Class at
Publication: |
514/187 ;
546/121; 514/300; 544/105; 514/230.5; 514/275; 514/252.11; 514/292;
514/297 |
International
Class: |
A61K 31/437 20060101
A61K031/437; A61K 31/538 20060101 A61K031/538; A61K 45/06 20060101
A61K045/06; C07D 471/04 20060101 C07D471/04 |
Claims
1. A compound of Formula I, ##STR00203## or a pharmaceutical
acceptable salt, tautomer or stereoisomer thereof, wherein n is 0,
1, 2 or 3; p is 0, 1, 2 or 3; L is selected from the group
consisting of *--(CHR.sub.3).sub.1-3--, *--CHR.sub.3N(R.sub.2)--,
*--CHR.sub.3O--, *--CHR.sub.3S--, *--CHR.sub.3S(O)--,
*--CHR.sub.3N(R.sub.2)CHR.sub.3--, *--C(O)--, *--C(O)N(R.sub.2)--,
*--C(O)N(R.sub.2)CHR.sub.3--, *--N(R.sub.2)--,
*--N(R.sub.2)CHR.sub.3--, *--N(R.sub.2)C(O)--,
*--N(R.sub.2)C(O)N(R.sub.2)--, *--N(R.sub.2)S(O).sub.2--, wherein *
represents the point of attachment of L to the
pyrazolo[1,5-a]pyridine fused ring depicted in Formula I; each
R.sub.2 is independently selected from the group consisting of
hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, R--C.sub.0-4alkylene,
and R--C.sub.0-4alkylene-C(O)--, wherein R is selected from the
group consisting of hydroxyl, C.sub.1-4alkoxy, amino,
C.sub.1-4alkylamino, C.sub.3-6cycloalkyl,
C.sub.4-6heterocycloalkyl, and C.sub.5-6heteroaryl, wherein the
C.sub.3-6cycloalkyl, C.sub.4-6heterocycloalkyl, and
C.sub.5-6heteroaryl of R are each unsubstituted or substituted with
1-2 substituents independently selected from the group consisting
of halo, amino, hydroxyl, C.sub.1-4alkyl, C.sub.1-4alkoxy, oxo, and
C.sub.5-6heteroaryl; and each R.sub.3 is independently selected
from the group consisting of hydrogen and C.sub.1-4alkyl; Ring A is
selected from the group consisting of C.sub.6-10aryl and
C.sub.3-10heteroaryl; Ring C is selected from the group consisting
of C.sub.6-10aryl, C.sub.5-10heteroaryl, C.sub.3-7cycloalkyl,
C.sub.5-7heterocycloalkyl, and fused bicyclyl comprising a
C.sub.5-6heterocycloalkyl fused to a phenyl; each R.sub.1 is
independently selected from the group consisting of halo, cyano,
amino, C.sub.1-4alkyl, C.sub.1-4alkoxyl, halo-C.sub.1-4alkyl,
--C(O)NR.sub.7R.sub.8, --NHC(O)R.sub.11, phenyl, and
C.sub.5-6heteroaryl; wherein the phenyl and C.sub.5-6heteroaryl of
R.sub.1 are each unsubstituted or substituted with 1-2 substituents
independently selected from the group consisting of C.sub.1-4alkyl,
amino, halo, and C.sub.1-4alkylamino; R.sub.7 and R.sub.8 are each
independently selected from hydrogen, C.sub.1-4alkyl and
haloC.sub.1-4alkyl; R.sub.11 is C.sub.1-6alkyl, unsubstituted or
substituted with 1-2 substituents independently selected from the
group consisting of amino, C.sub.3-6cycloalkyl and
C.sub.4-6heterocycloalkyl; R.sub.17 is selected from the group
consisting of cyano, halo, C.sub.1-4alkyl, halo-C.sub.1-4alkyl,
oxo, C.sub.3-6cycloalkyl, and --SO.sub.2--C.sub.1-4alkyl.
2. The compound of claim 1, wherein L is selected from the group
consisting of *--C(O)N(R.sub.2)-- and *--N(R.sub.2)C(O)--, wherein
each R.sub.2 is independently selected from hydrogen,
C.sub.1-4alkyl, and R--C.sub.0-4alkylene, and wherein R is selected
from the group consisting of C.sub.4-6heterocycloalkyl and
C.sub.5-6heteroaryl, each of which is unsubstituted or substituted
with 1-2 substituents independently selected from the group
consisting of halo, amino, hydroxyl, C.sub.1-4alkyl,
C.sub.1-4alkoxy, oxo, and C.sub.5-6heteroaryl.
3. The compound of claim 1, wherein L is selected from the group
consisting of *--CH(CH.sub.3)--, *--CH.sub.2CH.sub.2--,
*--CH.sub.2N(CH.sub.3)--,
*--CH.sub.2N(C(O)(CH.sub.2).sub.1-2NH(CH.sub.3))--,
*--CH.sub.2N(C(O)--(CH.sub.2).sub.1-2NH.sub.2)--,
*--CH.sub.2N((C(O)--(CH.sub.2).sub.1-2N(CH.sub.3).sub.2)--,
*--CH.sub.2N(C(O)(CH.sub.2).sub.1-2OH)--,
*--CH(CH.sub.3)N(CH.sub.3)--, *--CH.sub.2O--, *--CH.sub.2S--,
*--CH.sub.2S(O)--, *--C(O)--, *--C(O)N(CH.sub.3)--,
*--C(O)N(CH.sub.2CH.sub.3)--, *--C(O)N(CH(CH.sub.3).sub.2)--,
*--C(O)N(C(CH.sub.3).sub.3)--,
*--C(O)N(CH.sub.2CH(CH.sub.3).sub.2)--,
*--C(O)N(CH(CH.sub.3)CH.sub.2CH.sub.3)--,
*--C(O)N(CH.sub.2CH.sub.2OCH.sub.3)--,
*--C(O)N(CH.sub.2CH.sub.2N(CH.sub.3).sub.2)--,
*--C(O)N(CH.sub.3)CH.sub.2--, *--NHCH.sub.2--,
*--N(CH.sub.3)CH.sub.2--,
*--N(CH.sub.2-tetrahydropyran-4-yl)-C(O)--, *--N(CH.sub.3)C(O)--,
*--N(CH.sub.3)C(O)NH--, *--N(CH.sub.3)S(O).sub.2--,
*--C(O)N((CH.sub.2).sub.0-1-cyclopropyl)-,
*--C(O)N((CH.sub.2).sub.0-1-cyclobutyl)-,
*--C(O)N((CH.sub.2).sub.0-1-cyclopentyl)-,
*--C(O)N((CH.sub.2).sub.0-1-cyclohexyl)-,
*--C(O)N(CH.sub.2-tetrahydropyran-4-yl)-,
*--C(O)N((CH.sub.2)-2-(1,1-dioxidothiomorpholino-4-yl))-,
*--C(O)N(CH.sub.2-1,1-dioxidothiomorpholino-4-yl)-,
*--C(O)N((CH.sub.2)-2-tetrahydropyran-4-yl)),
*--C(O)N((CH.sub.2).sub.1-2-morpholin-4-yl)-,
*--C(O)N(oxetan-3-yl)-, *--C(O)N(CH.sub.2-oxetan-3-yl)-,
*--C(O)N(CH(CH.sub.3)--CH.sub.2-1-H-pyrazoly-1-yl)-,
*--CH.sub.2N(C(O)--(CH.sub.2).sub.1-2-morpholinyl))-,
*--CH.sub.2N(C(O)--(CH.sub.2).sub.1-2-4-methylpiperizin-1-yl)),
*--CH.sub.2N(C(O)--(CH.sub.2).sub.1-2-tetrahydropyran-4-yl)-, and
*--CH.sub.2N(C(O)(CH.sub.2).sub.1-2-oxetan-3-yl)-.
4. The compound according to claim 1, wherein Ring A is selected
from the group consisting of phenyl, pyridinyl, pyrimidinyl,
pyrazinyl, pyridazinyl, pyrrolopyridinyl, and indazolyl, each of
which is unsubstituted or substituted by (R.sub.1).sub.n.
5. The compound according to claim 1, wherein Ring C is selected
from the group consisting of ##STR00204## each of which is
unsubstituted or substituted by (R.sub.17).sub.p.
6. The compound according to claim 1, wherein Ring C is selected
from the group consisting of phenyl and pyridinyl, each of which is
unsubstituted or substituted by (R.sub.17).sub.p.
7. The compound according to claim 1, wherein each R.sub.1 is
independently selected from the group consisting of
trifluoromethyl, cyano, --NH.sub.2--, --C(O)NH.sub.2,
--C(O)NHCH.sub.3, --C(O)N(CH.sub.3).sub.2, and
--NHC(O)CH(NH.sub.2)(CH.sub.3).
8. The compound according to claim 1, wherein each R.sub.17 is
independently selected from the group consisting of cyano, halo,
C.sub.1-4alkyl, haloC.sub.1-4alkyl, --SO.sub.2--C.sub.1-4alkyl, and
C.sub.3-6cycloalkyl.
9. The compound of claim 1, wherein the compound is of Formula Ia:
##STR00205## or a pharmaceutical acceptable salt, tautomer or
stereoisomer thereof, wherein n is 1 or 2; p is 1 or 2; Ring A is
phenyl, pyridinyl, or pyrimidinyl; Ring C is phenyl or pyridinyl; L
is *--C(O)NR.sub.2-- or *--NR.sub.2C(O)--, wherein R.sub.2 is
selected from hydrogen, C.sub.1-4alkyl,
C.sub.3-6cycloalkyl-(C.sub.0-4)alkylene,
C.sub.4-6heterocycloalkyl-(C.sub.0-4)alkylene, wherein the
C.sub.4-6heterocycloalkyl is selected from the group consisting of
piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, and
oxetanyl, and wherein the C.sub.3-6cycloalkyl is selected from
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; each R.sub.1
is independently *--C(O)NR.sub.7R.sub.8 or --NH.sub.2--, wherein
R.sub.7 and R.sub.8 are each independently hydrogen or
C.sub.1-4alkyl; and R.sub.17 is selected from the group consisting
of cyano, halo, --NH.sub.2--, --C(O)NH.sub.2, --C(O)NH(CH.sub.3),
and --C(O)N(CH.sub.3).sub.2.
10. The compound of claim 1, wherein the compound, or a
pharmaceutical acceptable salt, tautomer or stereoisomer thereof,
is selected from the group consisting of:
N-(4-cyanophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]py-
ridine-5-carboxamide;
4-fluoro-N-methyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-
-5-yl)methyl)aniline;
N-(4-chlorophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]p-
yridine-5-carboxamide;
N-(4-fluorophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]p-
yridine-5-carboxamide;
N-methyl-N-(5-methylpyridin-2-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1-
,5-a]pyridine-5-carboxamide;
4-chloro-N-methyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-
-5-yl)methyl)aniline;
N,5-dimethyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl-
)methyl)pyridine-2-amine;
5-((4-fluorophenoxy)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]p-
yridine;
N-(4-cyanophenyl)-N-(2-methoxyethyl)-3-(4-(trifluoromethyl)phenyl-
)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(4-cyanophenyl)-N-(2-(dimethylamino)ethyl)-3-(4-(trifluoromethyl)phenyl-
)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(4-cyanophenyl)-N-((tetrahydro-2H-pyran-4-ylmethyl)-3-(4-(trifluorometh-
yl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(4-(methylsulfonyl)phenyl)-N-((tetrahydro-2H-pyran-4-ylmethyl)-3-(4-(tr-
ifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,-
5-a]pyridine-5-carboxamide;
N-methyl-N-(5-methylpyridin-3-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1-
,5-a]pyridine-5-carboxamide;
5-(((5-methylpyridin-2-yl)oxy)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazo-
lo[1,5-a]pyridine;
5-(4-fluorophenethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-
e;
N-(4-cyanophenyl)-N-methyl-3-(1-methyl-1H-indazol-5-yl)pyrazolo[1,5-a]p-
yridine-5-carboxamide;
3-(6-acetamidopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyri-
dine-5-carboxamide;
3-(4-carbamoylphenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-
-carboxamide;
3-(4-carbamoylphenyl)-N-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine--
5-carboxamide;
5-(((4-fluorophenyl)thio)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,-
5-a]pyridine;
5-(((4-fluorophenyl)sulfinylmethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo-
[1,5-a]pyridine;
3-(4-(1H-pyrazol-5-yl)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]py-
ridine-5-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-(5-(trifluoromethyl)pyridine-2-yl)pyrazolo[1-
,5-a]pyridine-5-carboxamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-(5-(trifluoromethyl)pyridine-2-yl)pyra-
zolo[1,5-a]pyridine-5-carboxamide;
(S)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1-
,5-a]pyridine-5-carboxamide;
3-(5-carbamoylpyridin-2-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyri-
dine-5-carboxamide;
4-cyano-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-
-yl)benzamide;
4-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine--
5-yl)benzamide;
4-cyano-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine--
5-yl)benzenesulfonamide;
4-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-
-5-yl)benzenesulfonamide;
3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyri-
dine-5-carboxamide;
N-methyl-3-(4-(trifluoromethyl)phenyl)-N-(5-(trifluoromethyl)yridine-2-yl-
)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-methyl-N-(5-(methylsulfonyl)pyridine-2-yl)-3-(4-(trifluoromethyl)phenyl-
)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(4-fluorobenzyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5--
amine
N-(4-fluorobenzyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridi-
ne-5-amine;
N-methyl-6-(trifluoromethyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-
-a]yridine-5-yl)nicotinamide;
N-methyl-5-(trifluoromethyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-
-a]yridine-5-yl)picolinamide;
4-cyano-N-((tetrahydro-2H-pyran-4-ylmethyl)-N-(3-(4-(trifluoromethyl)phen-
yl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;
N-(4-cyanophenyl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5--
a]pyridine-5-carboxamide;
3-(6-aminopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-
-5-carboxamide;
3-(4-aminophenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-car-
boxamide;
3-(4-(2-aminoacetamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazol-
o[1,5-a]pyridine-5-carboxamide;
(R)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1-
,5-a]pyridine-5-carboxamide;
(S)-3-(4-(2-amino-3-methylbutanamido)phenyl)-N-(4-cyanophenyl)-N-methylpy-
razolo[1,5-a]pyridine-5-carboxamide;
(S)-3-(4-(2-amino-2-cyclohexylacetamido)phenyl)-N-(4-cyanophenyl)-N-methy-
lpyrazolo[1,5-a]pyridine-5-carboxamide;
3-(4-fluorophenyl)-1-methyl-1-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5--
a]pyridin-5-yl)urea;
6-(1,1-difluoroethyl)-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1-
,5-a]pyridin-5-yl)nicotinamide;
6-cyclopropyl-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyr-
idin-5-yl)nicotinamide;
4-cyclopropyl-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyr-
idin-5-yl)benzamide;
5-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin--
5-yl)picolinamide;
N-methyl-4-(methylsulfonyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5--
a]pyridin-5-yl)benzamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-
o[1,5-a]pyridine-5-carboxamide;
3-(6-aminopyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]py-
ridine-5-carboxamide;
4-chloro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin--
5-yl)benzamide;
N-(3-(4-carbamoylphenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-fluoro-N-methylben-
zamide
4-fluoro-N-methyl-N-(3-(4-(5-(methylamino)-1,3,4-thiadiazol-2-yl)ph-
enyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;
N-methyl-N-(5-(methylsulfonyl)pyridin-2-yl)-3-(1H-pyrrolo[2,3-b]pyridin-5-
-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-(5-methylpyridin-2-yl)pyrazolo[1,5-a]p-
yridine-5-carboxamide;
N-(5-cyanopyridin-2-yl)-3-(5-methoxypyridin-2-yl)-N-methylpyrazolo[1,5-a]-
pyridine-5-carboxamide;
3-(5-carbamoylpyridin-2-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5--
a]pyridine-5-carboxamide;
3-(4-carbamoylphenyl)-N-methyl-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazol-
o[1,5-a]pyridine-5-carboxamide;
3-(4-carbamoylphenyl)-N-methyl-N-(5-methylpyridin-2-yl)pyrazolo[1,5-a]pyr-
idine-5-carboxamide;
N-(4-fluorophenyl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]p-
yridine-5-carboxamide;
4-(5-(1-(methyl(5-methylpyridin-2-yl)amino)ethyl)pyrazolo[1,5-a]pyridin-3-
-yl)benzamide;
4-(5-(1-(7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl)pyrazolo[1,-
5-a]pyridin-3-yl)benzamide;
N-(4-cyanophenyl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]py-
ridine-5-carboxamide;
N-(4-(5-(1-(methyl(5-methylpyridin-2-yl)amino)ethyl)pyrazolo[1,5-a]pyridi-
n-3-yl)phenyl)acetamide;
3-(4-acetamidophenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyri-
dine-5-carboxamide;
4-(5-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,-
5-a]pyridin-3-yl)benzamide;
4-(5-(7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)py-
razolo[1,5-a]pyridin-3-yl)benzamide;
4-(5-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,-
5-a]pyridin-3-yl)-N-methylbenzamide;
4-(5-(7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)py-
razolo[1,5-a]pyridin-3-yl)-N-methylbenzamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,-
5-a]pyridine-5-carboxamide;
N-(5-cyanopyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)-N-(oxetan-3-yl)pyra-
zolo[1,5-a]pyridine-5-carboxamide;
N-(1-(1H-pyrazol-1-yl)propan-2-yl)-3-(4-carbamoylphenyl)-N-(5-cyanopyridi-
n-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;
3-(6-amino-5-fluoropyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a-
]pyridine-5-carboxamide;
3-(4-amino-3,5-dimethylphenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]p-
yridine-5-carboxamide;
3-(6-amino-5-methylpyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a-
]pyridine-5-carboxamide;
3-(4-carbamoylphenyl)-N-(4-cyanocyclohexyl)-N-methylpyrazolo[1,5-a]pyridi-
ne-5-carboxamide;
3-(2-aminopyrimidin-5-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridi-
ne-5-carboxamide;
3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-met-
hylpyrazolo[1,5-a]pyridine-5-carboxamide;
3-(6-amino-5-cyanopyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[-
1,5-a]pyridine-5-carboxamide;
3-(6-amino-5-chloropyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo-
[1,5-a]pyridine-5-carboxamide;
3-(6-amino-5-(dimethylcarbamoyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-m-
ethylpyrazolo[1,5-a]pyridine-5-carboxamide;
3-(6-amino-5-methoxypyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazol-
o[1,5-a]pyridine-5-carboxamide; and
3-(4-carbamoylphenyl)-N-(4-chloro-2-formylphenyl)-N-methylpyrazolo[1,5-a]-
pyridine-5-carboxamide.
11. A pharmaceutical composition comprising at least one compound
according to claim 1, or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable carrier, diluent or
excipient.
12. The pharmaceutical composition according to claim 11, further
comprising a second agent, wherein the second agent is an
antimalarial drug selected from artemisinin, artemether,
artesunate, arteflene, dihydroartemisinin, chlorproguanil,
trimethoprim, chloroquine, quinine, mefloquine, amodiaquine,
atovaquone, proguanil, lumefantrine, piperaquine, pyronaridine,
halofantrine, pyrimethamine-sulfadoxine, quinacrine,
pyrimethamine-dapsone, quinidine, amopyroquine, sulphonamides,
primaquine, ferroquine, tafenoquine, arterolane, and
pyronaridine.
13. A method for treating, preventing, inhibiting, ameliorating, or
eradicating the pathology and/or symptomology of a disease caused
by a Plasmodium parasite, comprising administering to a subject a
therapeutically effective amount of a compound according to claim 1
or a composition according to claim 11, wherein the administering
may be in combination with a second agent.
14. The method according to claim 13, wherein the disease is
malaria.
15. The method according to claim 13, wherein the Plasmodium
parasite is at the blood stages.
16. The method according to claim 13, wherein the Plasmodium
parasite is at the hepatic stages.
17. The method of claim 14, wherein the Plasmodium parasite is
selected from group consisting of Plasmodium falciparum, Plasmodium
vivax, Plasmodium ovale, and Plasmodium malaria.
18. The method according to claim 13, wherein the second agent is
selected from a kinase inhibitor, an anti-malarial drug and an
anti-inflammatory agent.
19. The method according to claim 18, wherein the anti-malarial
drug is selected from artemisinin, artemether, artesunate,
arteflene, dihydroartemisinin, chlorproguanil, trimethoprim,
chloroquine, quinine, mefloquine, amodiaquine, atovaquone,
proguanil, lumefantrine, piperaquine, pyronaridine, halofantrine,
pyrimethamine-sulfadoxine, quinacrine, pyrimethamine-dapsone,
quinidine, amopyroquine, sulphonamides, primaquine, ferroquine,
tafenoquine, arterolane, and pyronaridine.
20. The method according to claim 18, wherein the compound is
administered prior to, simultaneously with, or after the second
agent.
Description
CROSS-REFERENCED TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to U.S.
Provisional Patent Application No. 61/728,018, filed 19 Nov. 2012;
the disclosure of which is incorporated by reference herein in its
entirety and for all purposes.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention provides a class of compounds, pharmaceutical
compositions comprising such compounds and methods of using such
compounds to treat or prevent malaria.
[0004] 2. Background
[0005] Malaria is an infectious disease caused by four protozoan
parasites: Plasmodium falciparum; Plasmodium vivax; Plasmodium
ovale; and Plasmodium malaria. These four parasites are typically
transmitted by the bite of an infected female Anopheles mosquito.
Malaria is a problem in many parts of the world and over the last
few decades the malaria burden has steadily increased. An estimated
1-3 million people die every year from malaria--mostly children
under the age of 5. This increase in malaria mortality is due in
part to the fact that Plasmodium falciparum, the deadliest malaria
parasite, has acquired resistance against nearly all available
antimalarial drugs, with the exception of the artemisinin
derivatives. Further for true causal prophylaxis and interrupt
transmission of the disease, prevention of liver stage development
is crucial, because development of the proceeding infectious blood
stage gametocytes would be block. A single drug effective against
hepatichypnozoites, primaquine, is available, but its deployment is
curtailed by its potential side effects.
[0006] Leishmaniasis is caused by one or more than 20 varieties of
parasitic protozoa that belong to the genus Leishmania, and is
transmitted by the bite of female sand flies. Leishmaniasis is
endemic in about 88 countries, including many tropical and
sub-tropical areas.
[0007] There are four main forms of Leishmaniasis. Visceral
leishmaniasis, also called kala-azar, is the most serious form and
is caused by the parasite Leishmania donovani. Patients who develop
visceral leishmaniasis can die within months unless they receive
treatment. The two main therapies for visceral leishmaniasis are
the antimony derivatives sodium stibogluconate (Pentostam.RTM.) and
meglumine antimoniate (Glucantim.RTM.). Sodium stibogluconate has
been used for about 70 years and resistance to this drug is a
growing problem. In addition, the treatment is relatively long and
painful, and can cause undesirable side effects.
[0008] Human African Trypanosomiasis, also known as sleeping
sickness, is a vector-borne parasitic disease. The parasites
concerned are protozoa belonging to the Trypanosoma Genus. They are
transmitted to humans by tsetse fly (Glossina Genus) bites which
have acquired their infection from human beings or from animals
harboring the human pathogenic parasites.
[0009] Chagas disease (also called American Trypanosomiasis) is
another human parasitic disease that is endemic amongst poor
populations on the American continent. The disease is caused by the
protozoan parasite Trypanosoma cruzi, which is transmitted to
humans by blood-sucking insects. The human disease occurs in two
stages: the acute stage, which occurs shortly after infection and
the chronic stage, which can develop over many years. Chronic
infections result in various neurological disorders, including
dementia, damage to the heart muscle and sometimes dilation of the
digestive tract, as well as weight loss. Untreated, the chronic
disease is often fatal.
[0010] The drugs currently available for treating Chagas disease
are Nifurtimox and benzindazole. However, problems with these
current therapies include their diverse side effects, the length of
treatment, and the requirement for medical supervision during
treatment. Furthermore, treatment is really only effective when
given during the acute stage of the disease. Resistance to the two
frontline drugs has already occurred. The antifungal agent
Amphotericin b has been proposed as a second-line drug, but this
drug is costly and relatively toxic.
[0011] In view of the foregoing, it is desirable to develop novel
compounds as antiparasitic agents.
SUMMARY OF THE INVENTION
[0012] The invention therefore provides a compound of the formula
(I):
##STR00002##
[0013] or a pharmaceutical acceptable salt, tautomer or
stereoisomer thereof, wherein [0014] n is 0, 1, 2 or 3; [0015] p is
0, 1, 2 or 3; [0016] L is selected from the group consisting of
*--(CHR.sub.3).sub.1-3--, *--CHR.sub.3N(R.sub.2)--,
*--CHR.sub.3O--, *--CHR.sub.3S--, *--CHR.sub.3S(O)--,
*--CHR.sub.3N(R.sub.2)CHR.sub.3--, *--C(O)--, *--C(O)N(R.sub.2)--,
*--C(O)N(R.sub.2)CHR.sub.3--, *--N(R.sub.2)--,
*--N(R.sub.2)CHR.sub.3--, *--N(R.sub.2)C(O)--,
*--N(R.sub.2)C(O)N(R.sub.2)--, *--N(R.sub.2)S(O).sub.2--, wherein
[0017] * represents the point of attachment of L to the
pyrazolo[1,5-a]pyridine fused ring depicted in Formula I; [0018]
each R.sub.2 is independently selected from the group consisting of
hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, R--C.sub.0-4alkylene,
and R--C.sub.0-4alkylene-C(O)--, wherein R is selected from the
group consisting of hydroxyl, C.sub.1-4alkoxy, amino,
C.sub.1-4alkylamino, C.sub.3-6cycloalkyl,
C.sub.4-6heterocycloalkyl, and C.sub.5-6heteroaryl, wherein the
C.sub.3-6cycloalkyl, C.sub.4-6heterocycloalkyl, and
C.sub.5-6heteroaryl of R are each unsubstituted or substituted with
1-2 substituents independently selected from the group consisting
of halo, amino, hydroxyl, C.sub.1-4alkyl, C.sub.1-4alkoxy, oxo, and
C.sub.5-6heteroaryl; and [0019] each R.sub.3 is independently
selected from the group consisting of hydrogen and C.sub.1-4alkyl;
[0020] Ring A is selected from the group consisting of
C.sub.6-10aryl and C.sub.3-10heteroaryl; [0021] Ring C is selected
from the group consisting of C.sub.6-10aryl, C.sub.5-10heteroaryl,
C.sub.5-7cycloalkyl, C.sub.5-7heterocycloalkyl, and a fused
bicyclyl comprising a C.sub.5-6heterocycloalkyl fused to a phenyl;
[0022] each R.sub.1 is independently selected from the group
consisting of halo, cyano, amino, C.sub.1-4alkyl, C.sub.1-4alkoxyl,
halo-C.sub.1-4alkyl, --C(O)NR.sub.7R.sub.8, --NHC(O)R.sub.11,
phenyl, and C.sub.5-6heteroaryl; wherein [0023] the phenyl and
C.sub.5-6heteroaryl of R.sub.1 are each unsubstituted or
substituted with 1-2 substituents independently selected from the
group consisting of C.sub.1-4alkyl, amino, halo, and
C.sub.1-4alkylamino; [0024] R.sub.7 and R.sub.8 are each
independently selected from the group consisting of hydrogen,
C.sub.1-4alkyl or haloC.sub.1-4alkyl; [0025] R.sub.11 is
C.sub.1-6alkyl unsubstituted or substituted with 1-2 substituents
independently selected from the group consisting of amino,
C.sub.3-6cycloalkyl and C.sub.4-6heterocycloalkyl; [0026] R.sub.17
is selected from the group consisting of cyano, halo,
C.sub.1-4alkyl, halo-C.sub.1-4-alkyl, oxo, C.sub.3-6cycloalkyl, and
--SO.sub.2--C.sub.1-4alkyl.
[0027] In a second aspect, the present invention provides a
pharmaceutical composition which contains a compound selected from
Formula I, IA, or a N-oxide derivative, individual isomers and
mixture of isomers thereof; or a pharmaceutically acceptable salt
thereof, in admixture with one or more suitable excipients.
[0028] In a third aspect, the present invention provides a method
of treating a disease in an animal in which a compound of the
invention can prevent, inhibit, ameliorate, or eradicate the
pathology and/or symptomology of disease caused by a parasite (such
as, for example, Plasmodium falciparum, Plasmodium vivax,
Plasmodium ovale, Plasmodium malaria, Trypanosoma cruzi or a
parasite of the Leishmania genus such as, for example, Leishmania
donovani) which method comprises administering to the animal a
therapeutically effective amount of a compound selected from
Formula I, IA, or a N-oxide derivative, individual isomers and
mixture of isomers thereof, or a pharmaceutically acceptable salt
thereof.
[0029] In a fourth aspect, the present invention provides a
compound for treating, preventing, inhibiting, ameliorating, or
eradicating the pathology and/or symptomology of a disease caused
by a parasite (such as, for example, Plasmodium falciparum,
Plasmodium vivax, Plasmodium ovale, Plasmodium malaria, Trypanosoma
cruzi or a parasite of the Leishmania genus such as, for example,
Leishmania donovani). Particularly, the parasite is a Plasmodium
which can be at the blood stages or at the hepatic stages, and the
disease is malaria.
[0030] In a fifth aspect, the present invention provides the use of
a compound selected from Formula I or Formula 1a in the manufacture
of a medicament for treating a disease caused by a parasite in an
animal. The disease may be malaria, leishmaniasis and/or Chagas
disease.
[0031] In a sixth aspect, the present invention provides a process
for preparing compounds selected from Formula I, Formula 1a and the
N-oxide derivatives, prodrug derivatives, individual isomers and
mixture of isomers thereof, and the pharmaceutically acceptable
salts thereof.
[0032] Unless specified otherwise, the term "compounds of the
present invention" refers to compounds of Formula (I) and
subformulae thereof, salts of the compound, hydrates or solvates of
the compounds, salts, as well as all stereoisomers (including
diastereoisomers and enantiomers), tautomers and isotopically
labeled compounds (including deuterium substitutions). Compounds of
the present invention further comprise polymorphs of compounds of
formula I (or subformulae thereof) and salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0033] For purposes of interpreting this specification, the
following definitions will apply and whenever appropriate, terms
used in the singular will also include the plural and vice
versa.
[0034] "Acyl" as used herein refers to the radical
--C(.dbd.O)R.sub.a, where R.sub.a is hydrogen or a non-hydrogen
substituent on the carbonyl carbon, forming different
carbonyl-containing groups including, but are not limited to,
acids, acid halides, aldehydes, amides, esters, and ketones.
[0035] "Alkoxy" as used herein refers the radical --O-alkyl,
wherein the alkyl is as defined herein. C.sub.Xalkoxy and
C.sub.X-Yalkoxy as used herein describe alkoxy groups where X and Y
indicate the number of carbon atoms in the alkyl chain.
Representative examples of C.sub.1-10alkoxy include, but are not
limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,
tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and decyloxy.
The alkyl portion of the alkoxy may be optionally substituted, and
the substituents include those described for the alkyl group
below.
[0036] "Alkyl" as used herein refers to a fully saturated branched
or unbranched hydrocarbon chain having up to 10 carbon atoms.
C.sub.X alkyl and C.sub.X-Y alkyl as used herein describe alkyl
groups where X and Y indicate the number of carbon atoms in the
alkyl chain. For example, C.sub.1-10 alkyl refers to an alkyl
radical as defined above containing one to ten carbon atoms.
C.sub.1-10 alkyl includes, but are not limited to, methyl, ethyl,
n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,
n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,
2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,
n-decyl and the like. Alkyl represented along with another radical
like arylalkyl, heteroarylalkyl, alkoxyalkyl, alkoxyalkyl,
alkylamino, where the alkyl portion shall have the same meaning as
described for alkyl and is bonded to the other radical. For
example, (C.sub.6-10)aryl(C.sub.1-3)alkyl includes, benzyl,
phenylethyl, 1-phenylethyl, 3-phenylpropyl, 2-thienylmethyl,
2-pyridinylmethyl and the like.
[0037] Unless stated otherwise specifically in the specification,
an alkyl group may be unsubstituted or substituted by one or more
substituents to the extent that such substitution makes sense
chemically. Typical substituents include, but are not limited to
halo, hydroxyl, alkoxy, cyano, amino, acyl, aryl, arylalkyl, and
cycloalkyl, or an heteroforms of one of these groups, and each of
which can be substituted by the substituents that are appropriate
for the particular group.
[0038] "Alkenyl" as used herein refers to a straight or branched,
hydrocarbon chain having up to 10 carbon atoms and at least one
carbon-carbon double bond. C.sub.Xalkenyl and C.sub.X-Yalkenyl as
used herein describe alkenyl groups where X and Y indicate the
number of carbon atoms in the alkenyl chain. Examples of
C.sub.2-7alkenyl include vinyl, allyl, isopropenyl, pentenyl,
hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and
the like. The alkenyl may be optionally substituted, and the
substituents include those described for the alkyl group descried
herein.
[0039] "Alkynyl" as used herein refers to a straight or branched,
hydrocarbon chain having up to 10 carbon atoms and at least one
carbon-carbon triple bond. C.sub.Xalkenyl and C.sub.X-Yalkenyl as
used herein describe alkynyl groups, where X and Y indicate the
number of carbon atoms in the alkynyl chain. For example,
C.sub.2-7alkenyl include, but are not limited to, ethynyl,
propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. An alkynyl
may be optionally substituted, and the substituents include those
described for the alkyl group described herein.
[0040] "Alkylene" as used herein refers to a divalent alkyl group
defined herein. Examples of C.sub.1-10alkylene includes, but are
not limited to, methylene, ethylene, n-propylene, iso-propylene,
n-butylene, sec-butylene, iso-butylene, tert-butylene, n-pentylene,
isopentylene, neopentylene, n-hexylene, 3-methylhexylene,
2,2-dimethylpentylene, 2,3-dimethylpentylene, n-heptylene,
n-octylene, n-nonylene and n-decylene. An alkylene group may be
optionally substituted, and the substituents include those
described for the alkyl group described herein.
[0041] "Alkenylene" as used herein refers to a divalent alkenyl
group defined herein. Examples of C.sub.1-3alkenylene include, but
are not limited to, ethene-1,2-diyl, propene-1,3-diyl, and
methylene-1,1-diyl. An alkenylene may be optionally substituted,
and the substituents include those described for the alkyl group
described herein.
[0042] "Alkynylene" as used herein refers to a divalent alkynyl
group defined herein. Examples of alkynylene include
ethyne-1,2-diylene, propyne-1,3-diylene, and the like. An
alkynylene may be optionally substituted, and the substituents
include those described for the alkyl group described herein.
[0043] "Amino" as used herein refers to the radical --NH.sub.2.
When an amino is described as "substituted" or "optionally
substituted", the term includes NR'R'' wherein each R' and R'' is
independently H, or is an alkyl, alkenyl, alkynyl, acyl, aryl,
aryl, cycloalkyl, arylalkyl cycloalkylalkyl group or a heteroform
of one of these groups, and each of the alkyl, alkenyl, alkynyl,
acyl, aryl, arylalkyl or groups or heteroforms of one of these
groups, each of which is optionally substituted with the
substituents described herein as suitable for the corresponding
group.
[0044] The term "amino" also includes forms wherein R' and R'' are
linked together to form a 3-8 membered ring which may be saturated,
unsaturated or aromatic and which contains 1-3 heteroatoms
independently selected from N, O and S as ring members, and which
is optionally substituted with the substituents described as
suitable for alkyl groups or, if NR'R'' is an aromatic group, it is
optionally substituted with the substituents described as typical
for heteroaryl groups.
[0045] Unless indicated otherwise, the compounds of the invention
containing amino moieties may include protected derivatives
thereof. Suitable protecting groups for amino moieties include
acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.
[0046] "Alkylamino" as used herein refers to the radical
--NR.sub.aR.sub.b, where at least one of, or both, R.sub.a and
R.sub.b are an alkyl group as described herein. An
C.sub.1-4alkylamino group includes --NHC.sub.1-4alkyl and
--N(C.sub.1-4alkyl).sub.2; e.g., --NHCH.sub.3, --N(CH.sub.3).sub.2,
--NH(CH.sub.2CH.sub.3), --N(CH.sub.2CH.sub.3).sub.2, and the
like.
[0047] "Aromatic" as used herein refers to a moiety wherein the
constituent atoms make up an unsaturated ring system, where all
atoms in the ring system are sp.sup.2 hybridized and the total
number of pi electrons is equal to 4n+2. An aromatic ring may be
such that the ring atoms are only carbon atoms or may include
carbon and non-carbon atoms (see Heteroaryl).
[0048] "Aryl" as used herein refers to a 6-14 membered monocyclic
or polycyclic aromatic ring assembly where all the ring atoms are
carbon atoms. Typically, the aryl is a 6 membered monocyclic, a
10-12 membered bicyclic or a 14-membered fused tricyclic aromatic
ring system. C.sub.Xaryl and C.sub.X-Yaryl as used herein describe
an aryl group where X and Y indicate the number of carbon atoms in
the ring system. C.sub.6-14aryls include, but are not limited to,
phenyl, biphenyl, naphthyl, azulenyl, and anthracenyl.
[0049] An aryl may be unsubstituted or substituted by 1-5 (such as
one, or two, or three) substituents independently selected from the
group consisting of hydroxy, thiol, cyano, nitro, C.sub.1-4alkyl,
C.sub.1-4alkenyl, C.sub.1-4alkynyl, C.sub.1-4alkoxy,
thioC.sub.1-4alkyl, C.sub.1-4alkenyloxy, C.sub.1-4alkynyloxy,
halogen, C.sub.1-4alkylcarbonyl, carboxy, C.sub.1-4alkoxycarbonyl,
amino, C.sub.1-4alkylamino, di-C.sub.1-4alkylamino,
C.sub.1-4alkylaminocarbonyl, di-C.sub.1-4alkylaminocarbonyl,
C.sub.1-4alkylcarbonylamino,
C.sub.1-4alkylcarbonyl(C.sub.1-4alkyl)amino, sulfonyl, sulfamoyl,
alkylsulfamoyl, C.sub.1-4alkylaminosulfonyl, aryl, heteroaryl,
cycloalkyl and heterocycloalkyl, wherein each of the
afore-mentioned substitutents may be further substituted by one or
more substituents independently selected from halogen, alkyl,
hydroxyl or C.sub.1-4alkoxy groups.
[0050] When an "aryl" is represented along with another radical
like "arylalkyl", "aryloxyalkyl", "aryloxycarbonyl",
"aryloxy-carbonylalkyl", the aryl portion shall have the same
meaning as described in the above-mentioned definition of
"aryl".
[0051] "Aryloxy" as used herein, refers to the radical --O-aryl,
wherein aryl is as defined herein.
[0052] "Bicyclic" or "bicyclyl" as used here in refers to a ring
assembly of two rings where the two rings are fused together,
linked by a single bond or linked by two bridging atoms. The rings
may be a carbocyclyl, a heterocyclyl, or a mixture thereof.
[0053] "Bridging ring" as used herein refers to a polycyclic ring
system where two ring atoms that are common to two rings are not
directly bound to each other. One or more rings of the ring system
may also comprise heteroatoms as ring atoms. Non-exclusive examples
of bridging rings include norbornanyl, 7-oxabicyclo[2.2.1]heptanyl,
adamantanyl, and the like.
[0054] "Carbamoyl" as used herein refers to the radical
--C(O)NR.sub.a-- where R.sub.a is H, or is an alkyl, alkenyl,
alkynyl, acyl, aryl, or arylalkyl group or a heteroform of one of
these groups, and each of the alkyl, alkenyl, alkynyl, acyl, aryl,
arylalkyl or heteroforms of one of these groups is optionally
substituted with the substituents described herein as suitable for
the corresponding group.
[0055] "Cycloalkyl", as used herein, means a radical comprising a
non-aromatic, saturated or partially unsaturated, monocyclic,
bicyclic, tricyclic, fused, bridged or spiro polycyclic hydrocarbon
ring system of 3-20 carbon atoms. C.sub.Xcycloalkyl and
C.sub.X-Ycycloalkyl are typically used where X and Y indicate the
number of carbon atoms in the ring assembly. For example,
C.sub.3-6cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl.
[0056] Exemplary monocyclic cycloalkyl include, but are not limited
to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl
and cyclohexenyl and the like. Exemplary bicyclic cycloalkyls
include bornyl, norbornanyl, indyl, hexahydroindyl,
tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl,
bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,
6,6-dimethylbicyclo[3.1.1]heptyl,
2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl. Exemplary
tricyclic cycloalkyl groups include, for example, adamantyl.
[0057] A cycloalkyl may be unsubstituted or substituted by one, or
two, or three, or more substituents independently selected from the
group consisting of hydroxyl, thiol, cyano, nitro, oxo, alkylimino,
C.sub.1-4alkyl, C.sub.1-4alkenyl, C.sub.1-4alkynyl,
C.sub.1-4alkoxy, C.sub.1-4thioalkyl, C.sub.1-4alkenyloxy,
C.sub.1-4alkynyloxy, halogen, C.sub.1-4alkylcarbonyl, carboxy,
C.sub.1-4alkoxycarbonyl, amino, C.sub.1-4alkylamino,
di-C.sub.1-4alkylamino, C.sub.1-4alkylaminocarbonyl,
di-C.sub.1-4alkylaminocarbonyl, C.sub.1-4alkylcarbonylamino,
C.sub.1-4alkylcarbonyl(C.sub.1-4alkyl)amino, sulfonyl, sulfamoyl,
alkylsulfamoyl, C.sub.1-4alkylaminosulfonyl where each of the
afore-mentioned hydrocarbon groups (e.g., alkyl, alkenyl, alkynyl,
alkoxy residues) may be further substituted by one or more residues
independently selected at each occurrence from halogen, hydroxyl or
C.sub.1-4alkoxy groups.
[0058] "Cycloalkylene", as used herein, refers to a divalent
radical comprising a cycloalkyl ring assembly as defined
herein.
[0059] "Cycloalkoxy", as used herein, refers to --O-cycloalkyl,
wherein the cycloalkyl is defined herein. Representative examples
of C.sub.3-12cycloalklyoxy include, but are not limited to,
monocyclic groups such as cyclopropoxy, cyclobutoxy,
cyclopentyloxy, cyclopentenyloxy, cyclohexyloxy and cyclohexenyloxy
and the like. Exemplary bicyclic hydrocarbon groups include
bornyloxy, indyloxy, hexahydroindyloxy, tetrahydronaphthyloxy,
decahydronaphthyloxy, bicyclo[2.1.1]hexyloxy,
bicyclo[2.2.1]heptyloxy, bicyclo[2.2.1]heptenyloxy,
6,6-dimethylbicyclo[3.1.1]heptyloxy,
2,6,6-trimethylbicyclo[3.1.1]heptyloxy, bicyclo[2.2.2]octyloxy and
the like. Exemplary tricyclic hydrocarbon groups include, for
example, adamantyloxy.
[0060] "Cyano", as used herein, refers to the radical --CN.
[0061] "EC.sub.50", refers to the molar concentration of an
inhibitor or modulator that produces 50% efficacy.
[0062] "Fused ring", as used herein, refers to a multi-ring
assembly wherein the rings comprising the ring assembly are so
linked that the ring atoms that are common to two rings are
directly bound to each other. The fused ring assemblies may be
saturated, partially saturated, aromatics, carbocyclics,
heterocyclics, and the like. Non-exclusive examples of common fused
rings include decalin, naphthalene, anthracene, phenanthrene,
indole, benzofuran, purine, quinoline, and the like.
[0063] "Halo" or "halogen" as used herein refers to fluoro, chloro,
bromo, and iodo.
[0064] "Haloalkyl", or halo-substituted-alkyl" as used herein,
refers to an alkyl as defined herein, which is substituted by one
or more halo atoms defined herein. The haloalkyl can be
mono-haloalkyl, dihaloalkyl or polyhaloalkyl including
perhaloalkyl. A monohaloalkyl can have one iodo, bromo, chloro or
fluoro within the alkyl group. Dihaloalky and polyhaloalkyl groups
can have two or more of the same halo atoms or a combination of
different halo groups within the alkyl. C.sub.Xhaloalkyl and
C.sub.X-Yhaloalkyl are typically used where X and Y indicate the
number of carbon atoms in the alkyl chain. Non-limiting examples of
C.sub.1-4haloalkyl include fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,
dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl
and dichloropropyl. A C.sub.1-4perhaloalkyl group refers to a
C.sub.1-4alkyl group having all hydrogen atoms replaced with halo
atoms.
[0065] "Heteroaryl", as used herein, refers to a 5-14 membered ring
assembly (e.g., a 5-7 membered monocycle, an 8-10 membered bicycle,
or a 13-14 membered tricyclic ring system) having 1 to 8
heteroatoms selected from N, O and S as ring atoms and the
remaining ring atoms are carbon atoms. The nitrogen atoms of such
heteroaryl rings can be optionally quaternerized and the sulfur
atoms of such heteroaryl rings can be optionally oxidized.
C.sub.Xheteroaryl and C.sub.X-Yheteroaryl as used herein describe
heteroaryls where X and Y indicate the number of ring atoms in the
heteroaryl ring. Typical C.sub.5-7heteroaryl groups include
thienyl, furanyl, imidazolyl, pyrazolyl, pyrrolyl, pyrrolinyl,
thiazolyl, 1,3,4-thiadiazolyl, isothiazolyl, oxazolyl, oxadiazole
isoxazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrazinyl,
pyrazinyl, pyrimidinyl, and the like. Bicyclic or tricyclic
C.sub.8-14heteroaryls include, but are not limited to, those
derived from benzo[b]furan, benzo[b]thiophene, benzimidazole,
imidazo[4,5-c]pyridine, quinazoline, thieno[2,3-c]pyridine,
thieno[3,2-b]pyridine, thieno[2,3-b]pyridine, quinazolinyle,
pteridinyl, indolizine, imidazo[1,2a]pyridine, quinoline,
quinolinyl, isoquinoline, phthalazine, quinoxaline, naphthyridine,
naphthyridinyl, quinolizine, indolyl, indole, isoindole, indazole,
indoline, benzoxazole, benzopyrazole, benzothiazole,
imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine,
imidazo[1,2-a]pyrimidine, imidazo[1,2-c]pyrimidine,
imidazo[1,5-a]pyrimidine, imidazo[1,5-c]pyrimidine,
pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine,
pyrrolo[3,2-c]pyridine, pyrrolo[3,2-b]pyridine,
pyrrolo[2,3-d]pyrimidine, pyrrolo[3,2-d]pyrimidine,
pyrrolo[2,3-b]pyrazine, pyrazolo[1,5-a]pyridine,
pyrrolo[1,2-b]pyridazine, pyrrolo[1,2-c]pyrimidine,
pyrrolo[1,2-a]pyrimidine, pyrrolo[1,2-a]pyrazine,
triazo[1,5-a]pyridine, pteridine, purine, purinyl, carbazole,
acridine, phenazine, phenothiazene, phenoxazine,
1,2-dihydropyrrolo[3,2,1-hi]indole, indolizine, pyrido[1,2-a]indole
and 2(1H)-pyridinone.
[0066] A heteroaryl may be unsubstituted or substituted with one or
more substituents independently selected from hydroxyl, thiol,
cyano, nitro, C.sub.1-4alkyl, C.sub.1-4alkenyl, C.sub.1-4alkynyl,
C.sub.1-4alkoxy, thioC.sub.1-4alkyl, C.sub.1-4alkenyloxy,
C.sub.1-4alkynyloxy, halogen, C.sub.1-4alkylcarbonyl, carboxy,
C.sub.1-4alkoxycarbonyl, amino, C.sub.1-4alkylamino,
di-C.sub.1-4alkylamino, C.sub.1-4alkylaminocarbonyl,
di-C.sub.1-4alkylaminocarbonyl, C.sub.1-4alkylcarbonylamino,
C.sub.1-4alkylcarbonyl(C.sub.1-4alkyl)amino, sulfonyl, sulfamoyl,
alkylsulfamoyl, C.sub.1-4alkylaminosulfonyl where each of the
afore-mentioned hydrocarbon groups (e.g., alkyl, alkenyl, alkynyl,
alkoxy residues) may be further substituted by one or more residues
independently selected at each occurrence from halogen, hydroxyl or
C.sub.1-4alkoxy groups.
[0067] When a heteroaryl is represented along with another radical
like "heteroaryloxy", "heteroaryloxyalkyl",
"heteroaryloxycarbonyl", the heteroaryl portion shall have the same
meaning as described in the above-mentioned definition of
"heteroaryl".
[0068] "Heteroaryloxy", as used herein, refers to an --O-heteroaryl
group, wherein the heteroaryl is as defined in this application.
"Heteroatom", as used herein, refers to an atom that is not a
carbon atom. Particular examples of heteroatoms include, but are
not limited to nitrogen, oxygen, and sulfur.
[0069] "Heterocycloalkyl", as used herein, refers to a 4-20
membered, non-aromatic, saturated or partially unsaturated,
monocyclic or polycyclic ring system, comprising 1-8 heteroatoms as
ring atoms and that the remaining ring atoms are carbon atoms. The
heteroatoms are selected from N, O, and S, preferably O and N. The
nitrogen atoms of the heterocycloalkyl can be optionally
quaternerized and the sulfur atoms of the heterocycloalkyl can be
optionally oxidized. The heterocycloalkyl can include fused or
bridged rings as well as spirocyclic rings. C.sub.Xheterocycloalkyl
and C.sub.X-Yheterocycloalkyl are typically used where X and Y
indicate the number of ring atoms in the ring. Typically, the
heterocycloalkyl is 4-8-membered monocyclic ring containing 1 to 3
heteroatoms, a 7 to 12-membered bicyclic ring system containing 1-5
heteroatoms, or a 10-15-membered tricyclic ring system containing 1
to 7 heteroatoms. Examples of C.sub.4-6heterocycloalkyl include
azetidinyl, tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane,
morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane,
imidazolidine, imidazoline, pyrazolidinyl, pyrroline, pyrrolidine,
tetrahydropyran, dihydropyran, oxathiolane, dithiolane,
1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, and the
like
[0070] A heterocycloalkyl may be unsubstituted or substituted with
1-5 substituents (such as one, or two, or three) each independently
selected from hydroxyl, thiol, cyano, nitro, oxo, alkylimino,
C.sub.1-4alkyl, C.sub.1-4alkenyl, C.sub.1-4alkynyl,
C.sub.1-4alkoxy, C.sub.1-4thioalkyl, C.sub.1-4alkenyloxy,
C.sub.1-4alkynyloxy, halogen, C.sub.1-4alkylcarbonyl, carboxy,
C.sub.1-4alkoxycarbonyl, amino, C.sub.1-4alkylamino,
di-C.sub.1-4alkylamino, C.sub.1-4alkylaminocarbonyl,
di-C.sub.1-4alkylaminocarbonyl, C.sub.1-4alkylcarbonylamino,
C.sub.1-4alkylcarbonyl(C.sub.1-4alkyl)amino, sulfonyl, sulfamoyl,
alkylsulfamoyl, C.sub.1-4alkylaminosulfonyl where each of the
afore-mentioned hydrocarbon groups (e.g., alkyl, alkenyl, alkynyl,
alkoxy residues) may be further substituted by one or more residues
independently selected at each occurrence from halogen, hydroxyl or
C.sub.1-4alkoxy groups. When a heterocycloalkyl forms part of other
groups like "heterocycloalkyl-alkyl", "heterocycloalkoxy",
"heterocycloalkyl-aryl", the heteroaryl portion shall have the same
meaning as described in the above-mentioned definition of
"heteroaryl"
[0071] "Heterocycloalkylene", as used herein, refers to a
cycloalkylene, as defined in this application, provided that one or
more of the ring member carbon atoms is replaced by a
heteroatom.
[0072] "Heterocycloalkyl fused to a phenyl" as used herein, refers
to a bicyclic fused ring system that one of the ring is
heterocycloalkyl as defined above and the other ring is a phenyl. A
heterocycloalkyl fused to a phenyl includes but are not limited to
benzo[b][1,4]oxazinyl, oxo-benzo[b][1,4]oxazinyl,
tetrahydroquinoxalinyl, tetrahydroquinolinyl, indolinyl,
benzo[d]imidazolyl, and the like.
[0073] "Heterocyclyl", "heterocycle" or "heterocyclo", as used
herein, refers to a 3-20 membered, monocyclic or polycyclic ring
system containing at least one heteroatom moiety selected from the
group consisting of N, O, SO, SO.sub.2, (C.dbd.O), and S, and
preferably N, O, S, optionally containing one to four additional
heteroatoms in each ring. C.sub.Xheterocyclyl and
C.sub.X-Yheterocyclyl are typically used where X and Y indicate the
number of ring atoms in the ring system. Unless otherwise
specified, a heterocyclyl may be saturated, partially unsaturated,
aromatic or partially aromatic.
[0074] Hydroxy, as used herein, refers to the radical --OH.
[0075] "Hydroxyalkyl" or "hydroxyl-substituted alkyl" as used
herein, refers to an alkyl as defined herein, having one or more of
the available hydrogen of the alkyl replaced by a hydroxyl group.
For example, a hydroxyC.sub.1-4alkyl includes, but are not limited
to, --CH.sub.2CH.sub.2OH, --CH(OH)CH.sub.2CH.sub.2OH,
--CH(OH)CH.sub.2CH(OH)CH.sub.3.
[0076] "Nitro", as used herein, refers to the radical
--NO.sub.2.
[0077] "Oxo", as used herein, refers to the divalent radical
.dbd.O
[0078] "Protected derivatives" means derivatives of inhibitors in
which a reactive site or sites are blocked with protecting groups.
Protected derivatives are useful in the preparation of inhibitors
or in themselves may be active as inhibitors. Examples of protected
group includes, but are not limited to, acetyl, tetrahydropyran,
methoxymethyl ether, .beta.-methoxyethoxym ethyl ether,
.rho.-methoxybenzyl, methylthiomethyl ether, pivaloyl, silyl ether,
carbobenzyloxy, benzyl, tert-butoxycarbonyl, .rho.-methoxyphenyl,
9-fluorenylmethyloxycarbonyl, acetals, ketals, acylals, dithianes,
methylesters, benzyl esters, tert-butyl esters, and silyl esters. A
comprehensive list of suitable protecting groups can be found in T.
W. Greene, Protecting Groups in Organic Synthesis, 3rd edition,
John Wiley & Sons, Inc. 1999.
[0079] "Unsubstituted or substituted" or "optionally substituted"
as used herein indicate the substituent bound on the available
valance of a named group or radical. "Unsubstituted" as used herein
indicates that the named group or radical will have no further
non-hydrogen substituents. "Substituted" or "optionally
substituted" as used herein indicates that at least one of the
available hydrogen atoms of named group or radical has been (or may
be) replaced by a non-hydrogen substituent.
[0080] "Substituted terminally" as used herein referred to a
substituent replacing a hydrogen at a terminal position of the
parent molecule. For example C.sub.1-4alkyl substituted terminally
by an amino means --C.sub.1-4alkylene-amino, which includes
--(CH.sub.2)--NH.sub.2, --(CH.sub.2).sub.2--NH.sub.2,
--(CH.sub.2).sub.3--NH.sub.2,
--(CH.sub.2)CH.sub.2(CH.sub.2--NH.sub.2),
--(CH.sub.2).sub.4--NH.sub.2,
--C(CH.sub.2)(CH.sub.2CH.sub.2--NH.sub.2)--C(CH.sub.3).sub.2(CH.sub.2--NH-
.sub.2), and the like.
[0081] Unless otherwise specified, examples of substituents may
include, but are not limited to, halo, nitro, cyano, thio, oxy,
hydroxy, carbonyloxy, C.sub.1-6alkoxy, C.sub.6-10aryloxy,
heteroC.sub.5-10aryloxy, carbonyl, oxycarbonyl, aminocarbonyl,
amino, C.sub.1-6alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, hydroxyC.sub.1-6alkyl,
carbonylC.sub.1-6alkyl, thiocarbonylC.sub.1-10alkyl,
sulfonylC.sub.1-6alkyl, sulfinylC.sub.1-6alkyl, C.sub.1-10azaalkyl,
iminoC.sub.1-6alkyl, C.sub.3-12cycloalkylC.sub.1-6alkyl,
C.sub.4-15heterocycloalkylC.sub.1-6alkyl,
C.sub.6-10arylC.sub.1-6alkyl, C.sub.5-10heteroarylC.sub.1-6alkyl,
C.sub.10-12bicycloarylC.sub.1-6alkyl,
C.sub.9-12heterobicycloarylC.sub.1-6alkyl, C.sub.3-12cycloalkyl,
C.sub.4-12heterocycloalkyl, C.sub.9-12bicycloalkyl,
C.sub.3-12heterobicycloalkyl, C.sub.4-12aryl, heteroC.sub.1-10aryl,
C.sub.3-12bicycloaryl and C.sub.4-12heterobicycloaryl.
[0082] "Sulfamoyl" as used herein refers to the radical
--S(O).sub.2NR.sub.aR.sub.b where R.sub.a and R.sub.b are
independently H, or is an alkyl, alkenyl, alkynyl, acyl, aryl,
aryl, cycloalkyl, arylalkyl cycloalkylalkyl group or a heteroform
of one of these groups, and each of the alkyl, alkenyl, alkynyl,
acyl, aryl, arylalkyl groups or heteroforms of one of these groups,
is optionally substituted with the substituents described herein as
suitable for the corresponding group.
[0083] "Sulfanyl" as used herein, means the radical --S--.
[0084] "Sulfinyl", as used herein, means the radical --S(O)--. It
is noted that the term "sulfinyl" when referring to a monovalent
substituent can alternatively refer to a substituted sulfinyl
group, --S(.dbd.O)R, where R is hydrogen or a non-hydrogen
substituent on the sulfur atom forming different sulfinyl groups
including sulfinic acids, sulfinamides, sulfinyl esters, and
sulfoxides.
[0085] "Sulfonyl", as used herein, means the radical
--S(O).sub.2--. It is noted that the term "sulfonyl" when referring
to a monovalent substituent can alternatively refer to a
substituted sulfonyl group, --S(.dbd.O).sub.2R, where R is hydrogen
or a non-hydrogen substituent on the sulfur atom forming different
sulfonyl groups including sulfonic acids, sulfonamides, sulfonate
esters, and sulfones.
[0086] "Thiocarbonyl", as used herein, refers to the radical
--C(.dbd.S)--. It is noted that the term thiocarbonyl when
referring to a monovalent substituent can alternatively refer to a
substituted thiocarbonyl group, --C(.dbd.S)R, where R is hydrogen
or a non-hydrogen substituent on the carbon atom forming different
thiocarbonyl groups including thioacids, thioamides, thioesters,
and thioketones.
##STR00003##
are symbols denoting the point of attachment of X, to other part of
the molecule.
[0087] Any definition herein may be used in combination with any
other definition to describe a composite structural group. By
convention, the trailing element of any such definition is that
which attaches to the parent moiety. For example, the composite
group alkoxyalkyl would represent an alkoxy group attached to the
parent molecule through an alkyl group.
[0088] It is noted in regard to all of the definitions provided
herein that the definitions should be interpreted as being open
ended in the sense that further substituents beyond those specified
may be included. Hence, a C.sub.1alkyl indicates that there is one
carbon atom but does not indicate what are the substituents on the
carbon atom. Hence, a C.sub.1alkyl comprises methyl (i.e.,
--CH.sub.3) as well as --CR.sub.aR.sub.bR.sub.c where R.sub.a,
R.sub.b, and R.sub.c may each independently be hydrogen or any
other substituent where the atom attached to the carbon is not a
hydrogen atom. Hence, --CF.sub.3, --CH.sub.2OH and --CH.sub.2CN,
for example, are all C.sub.1alkyls.
Description of the Preferred Embodiments
[0089] The invention provides a novel class of compounds,
pharmaceutical compositions comprising such compounds and methods
of using such compounds to treat or prevent diseases or disorders
associated with a parasite. In particular, the compounds can be
used to treat malaria, leishmaniasis and/or Chagas disease. The
compounds of the invention are effective in inhibiting,
ameliorating, or eradicating the pathology and/or symptomology of
the parasite at both the blood stage and hepatic stage.
[0090] In one embodiment, the compounds of the invention are of
Formula I:
##STR00004##
or a pharmaceutical acceptable salt, enantiomer or tautomer or
stereoisomer thereof, wherein [0091] n is 0, 1, 2 or 3; [0092] p is
0, 1, 2 or 3; [0093] L is selected from the group consisting of
*--(CHR.sub.3).sub.1-3--, *--CHR.sub.3N(R.sub.2)--,
*--CHR.sub.3O--, *--CHR.sub.3S--, *--CHR.sub.3S(O)--,
*--CHR.sub.3N(R.sub.2)CHR.sub.3--, *--C(O)--, *--C(O)N(R.sub.2)--,
*--C(O)N(R.sub.2)CHR.sub.3--, *--N(R.sub.2)--,
*--N(R.sub.2)CHR.sub.3--, *--N(R.sub.2)C(O)--,
*--N(R.sub.2)C(O)N(R.sub.2)--, *--N(R.sub.2)S(O).sub.2--, wherein
[0094] * represents the point of attachment of L to the
pyrazolo[1,5-a]pyridine fused ring depicted in Formula I; [0095]
each R.sub.2 is independently selected from the group consisting of
hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, R--C.sub.0-4alkylene,
and R--C.sub.0-4alkylene-C(O)--, wherein R is selected from the
group consisting of hydroxyl, C.sub.1-4alkoxy, amino,
C.sub.1-4alkylamino, C.sub.3-6cycloalkyl,
C.sub.4-6heterocycloalkyl, and C.sub.5-6heteroaryl, wherein the
C.sub.3-6cycloalkyl, C.sub.4-6heterocycloalkyl, and
C.sub.5-6heteroaryl of R are each unsubstituted or substituted with
1-2 substituents independently selected from the group consisting
of halo, amino, hydroxyl, C.sub.1-4alkyl, C.sub.1-4alkoxy, oxo, and
C.sub.5-6heteroaryl; and. [0096] each R.sub.3 is independently
selected from the group consisting of hydrogen and C.sub.1-4alkyl,
[0097] Ring A is selected from the group consisting of
C.sub.6-10aryl and C.sub.6-10heteroaryl; [0098] Ring C is selected
from the group consisting of C.sub.6-10aryl, C.sub.5-10heteroaryl,
C.sub.5-7cycloalkyl, C.sub.5-7heterocycloalkyl, and a fused
bicyclyl comprising a C.sub.5-6heterocycloalkyl fused to a phenyl;
[0099] each R.sub.1 is independently selected from the group
consisting of halo, cyano, amino, C.sub.1-4alkyl, C.sub.1-4alkoxyl,
halo-C.sub.1-4alkyl, --C(O)NR.sub.7R.sub.8, --NHC(O)R.sub.11,
phenyl, and C.sub.5-6heteroaryl; wherein [0100] the phenyl and
C.sub.5-6heteroaryl of R.sub.1 are each unsubstituted or
substituted with 1-2 substituents independently selected from the
group consisting of C.sub.1-4alkyl, amino, halo, and
C.sub.1-4alkylamino; [0101] R.sub.7 and R.sub.8 are each
independently selected from the group consisting of hydrogen,
C.sub.1-4alkyl and haloC.sub.1-4alkyl; [0102] R.sub.11 is
C.sub.1-6alkyl unsubstituted or substituted with 1-2 substituents
independently selected from the group consisting of amino,
C.sub.3-6cycloalkyl and C.sub.4-6heterocycloalkyl; [0103] R.sub.17
is selected from the group consisting of cyano, halo,
C.sub.1-4alkyl, halo-C.sub.1-4alkyl, oxo, C.sub.3-6cycloalkyl, and
--SO.sub.2--C.sub.1-4alkyl.
[0104] In one embodiment of the compounds of the invention, with
reference to Formula I, L is selected from the group consisting of
*--(CHR.sub.3).sub.1-3--, *--CHR.sub.3N(R.sub.2)--,
*--CHR.sub.3O--, *--CHR.sub.3S--, *--CHR.sub.3S(O)--, *--C(O)--,
*--C(O)N(R.sub.2)--, *--N(R.sub.2)--, *--N(R.sub.2)CHR.sub.3--,
*--N(R.sub.2)C(O)--, *--N(R.sub.2)C(O)N(R.sub.2)--,
*--N(R.sub.2)S(O).sub.2--, wherein each R.sub.2 is independently
selected from the group consisting of hydrogen, C.sub.1-6alkyl,
haloC.sub.1-6alkyl, R--C.sub.0-4alkylene, and
R--C.sub.0-4alkylene-C(O)--, wherein each R is independently
selected from the group consisting of hydroxyl, C.sub.1-4alkoxy,
amino, C.sub.1-4alkylamino, di-C.sub.1-4alkylamino,
C.sub.3-6cycloalkyl, C.sub.4-6heterocycloalkyl, and
C.sub.5-6heteroaryl, wherein said C.sub.3-6cycloalkyl,
C.sub.4-6heterocycloalkyl and C.sub.5-6heteroaryl are each
unsubstituted or substituted with 1-2 substituents independently
selected from the group consisting of C.sub.1-4alkyl, halo, amino,
hydroxyl, C.sub.1-4alkoxy, oxo, and C.sub.5-6heteroaryl.
[0105] In another variation, L is selected from the group
consisting of *--(CHR.sub.3).sub.1-3--, *--CHR.sub.3N(R.sub.2)--,
*--CHR.sub.3O--, *--CHR.sub.3S--, *--CHR.sub.3S(O)--, *--C(O)--,
*--C(O)N(R.sub.2)--, *--N(R.sub.2)--, *--N(R.sub.2)CHR.sub.3--,
*--N(R.sub.2)C(O)--, *--N(R.sub.2)C(O)N(R.sub.2)--,
*--N(R.sub.2)S(O).sub.2--, wherein each R.sub.2 is independently
selected from the group consisting of hydrogen, C.sub.1-6alkyl,
R--C.sub.0-4alkylene, wherein R is selected from the group
consisting of C.sub.1-4alkoxy, C.sub.1-4alkylamino,
di-C.sub.1-4alkylamino, C.sub.3-6cycloalkyl,
C.sub.4-6heterocycloalkyl and C.sub.5-6heteroaryl, wherein the
C.sub.3-6cycloalkyl, C.sub.4-6heterocycloalkyl and
C.sub.5-6heteroaryl of R are each unsubstituted or substituted with
1-2 substituents independently selected from the group consisting
of halo, amino, hydroxyl, C.sub.1-4alkyl, C.sub.1-4alkoxy, oxo, and
C.sub.5-6heteroaryl.
[0106] In another variation, L is selected from the group
consisting of *--C(O)N(R.sub.2)--, and *--N(R.sub.2)C(O)--, wherein
each R.sub.2 is independently selected from hydrogen,
C.sub.1-6alkyl, and R--C.sub.0-4alkylene, and wherein R is selected
from the group consisting of C.sub.3-6cycloalkyl,
C.sub.4-6heterocycloalkyl and C.sub.5-6heteroaryl, each of which is
unsubstituted or substituted with 1-2 substituents independently
selected from the group consisting of halo, amino, hydroxyl,
C.sub.1-4alkyl, C.sub.1-4alkoxy, oxo, and C.sub.5-6heteroaryl
[0107] In still another variation, L is selected from the group
consisting of *--CH(CH.sub.3)--, *--CH.sub.2CH.sub.2--,
*--CH.sub.2N(CH.sub.3)--,
*--CH.sub.2N(C(O)(CH.sub.2).sub.1-2NH(CH.sub.3))--,
*--CH.sub.2N(C(O)--(CH.sub.2).sub.1-2NH.sub.2)--,
*--CH.sub.2N((C(O)--(CH.sub.2).sub.1-2N(CH.sub.3).sub.2)--,
*--CH.sub.2N(C(O)(CH.sub.2).sub.1-2OH)--,
*--CH(CH.sub.3)N(CH.sub.3)--, *--CH.sub.2O--, *--CH.sub.2S--,
*--CH.sub.2S(O)--, *--C(O)--, *--C(O)N(CH.sub.3)--,
*--C(O)N(CH.sub.2CH.sub.3)--, *--C(O)N(CH(CH.sub.3).sub.2)--,
*--C(O)N(C(CH.sub.3).sub.3)--,
*--C(O)N(CH.sub.2CH(CH.sub.3).sub.2)--,
*--C(O)N(CH(CH.sub.3)CH.sub.2CH.sub.3)--,
*--C(O)N(CH.sub.2CH.sub.2OCH.sub.3)--,
*--C(O)N(CH.sub.2CH.sub.2N(CH.sub.3).sub.2)--,
*--C(O)N(CH.sub.3)CH.sub.2--, *--NHCH.sub.2--,
*--N(CH.sub.3)CH.sub.2--,
*--N(CH.sub.2-tetrahydropyran-4-yl)-C(O)--, *--N(CH.sub.3)C(O)--,
*--N(CH.sub.3)C(O)NH--, *--N(CH.sub.3)S(O).sub.2--,
*--C(O)N((CH.sub.2).sub.0-1-cyclopropyl)-,
*--C(O)N((CH.sub.2).sub.0-1-cyclobutyl)-,
*--C(O)N((CH.sub.2).sub.0-1-cyclopentyl)-,
*--C(O)N((CH.sub.2).sub.0-1-cyclohexyl)-,
*--C(O)N(CH.sub.2-tetrahydropyran-4-yl)-,
*--C(O)N((CH.sub.2)-2-(1,1-dioxidothiomorpholino-4-yl))-,
*--C(O)N(CH.sub.2-1,1-dioxidothiomorpholino-4-yl)-,
*--C(O)N((CH.sub.2)-2-tetrahydropyran-4-yl))-,
*--C(O)N((CH.sub.2).sub.1-2-morpholin-4-yl)-,
*--C(O)N(oxetan-3-yl)-, *--C(O)N(CH.sub.2-oxetan-3-yl)-,
*--C(O)N(CH(CH.sub.3)--CH.sub.2-1-H-pyrazoly-1-yl)-,
*--CH.sub.2N(C(O)--(CH.sub.2).sub.1-2-morpholinyl))-,
*--CH.sub.2N(C(O)--(CH.sub.2).sub.1-2-4-methylpiperizin-1-yl)),
*--CH.sub.2N(C(O)--(CH.sub.2).sub.1-2-tetrahydropyran-4-yl)-, and
*--CH.sub.2N(C(O)(CH.sub.2).sub.1-2-oxetan-3-yl)-.
[0108] In still another variation, L is selected from the group
consisting of *--CH(CH.sub.3)--, *--CH.sub.2CH.sub.2--,
*--CH.sub.2N(CH.sub.3)--, *--CH(CH.sub.3)N(CH.sub.3)--,
*--CH.sub.2O--, *--CH.sub.2S--, *--CH.sub.2S(O)--, *--C(O)--,
*--C(O)N(CH.sub.3)--, *--C(O)N(CH.sub.3)CH.sub.2--,
*--C(O)N(CH.sub.2CH.sub.2OCH.sub.3)--,
*--C(O)N(CH.sub.2CH.sub.2N(CH.sub.3).sub.2)--, *--NHCH.sub.2--,
*--N(CH.sub.3)CH.sub.2--,
*--N(CH.sub.2-tetrahydropyran-4-yl)-C(O)--, *--N(CH.sub.3)C(O)--,
*--N(CH.sub.3)C(O)NH--, *--N(CH.sub.3)S(O).sub.2--,
*--C(O)N((CH.sub.2).sub.0-1-cyclopropyl)-,
*--C(O)N(CH.sub.2-tetrahydropyran-4-yl)-, *--C(O)N(oxetan-3-yl)-,
and *--C(O)N(CH(CH.sub.3)CH.sub.2-(1-H-pyrazoly-1yl))-.
[0109] In a further variation, L is selected from the group
consisting of *--C(O)N(CH.sub.3)--, *--C(O)N(CH.sub.2CH.sub.3)--,
*--C(O)N(CH(CH.sub.3).sub.2)--, *--C(O)N(C(CH.sub.3).sub.3)--,
*--C(O)N(CH.sub.2CH(CH.sub.3).sub.2)--,
*--C(O)N(CH(CH.sub.3)CH.sub.2CH.sub.3)--,
*--C(O)N((CH.sub.2).sub.0-1-cyclopropyl)-,
*--C(O)N((CH.sub.2).sub.0-1-cyclobutyl)-,
*--C(O)N((CH.sub.2).sub.0-1-cyclopentyl)-, and
*--C(O)N((CH.sub.2).sub.0-1-cyclohexyl)-.
[0110] In a particular variation, L is *--C(O)N(CH.sub.3)-- or
*--N(CH.sub.3)C(O)--. In a particular variation, L is
*--C(O)N(CH.sub.3)--. In another particular variation, L is
*--N(CH.sub.3)C(O)--. In another particular variation, L is
*--N((CH.sub.2).sub.0-2)-tetrahydropyran-4-yl)-C(O)--. In still
another particular variation, L is *--C(O)--. In still another
particular variation, L is --CH(CH.sub.3)--. In yet still another
particular variation, L is *--C(O)N(CH.sub.2-cyclopropyl)-. In yet
still another particular variation, L is
*--C(O)N(CH.sub.2-cyclopropyl)-.
[0111] In still another embodiment of the compounds of the
invention, with reference to any one of the above embodiments and
variations, Ring A is selected from the group consisting of phenyl,
pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolopyridinyl,
indazolyl, each of which is unsubstituted or substituted by
(R.sub.1).sub.n.
[0112] In one variation, Ring A is selected from the group
consisting of
##STR00005##
each of which is unsubstituted or substituted by (R.sub.1).sub.n.
In another particular variation, Ring A is selected from the group
consisting of
##STR00006##
each unsubstituted or substituted by 1 to 2 R.sub.1 groups.
[0113] In a particular variation, Ring A is of the formula
##STR00007##
In another particular variation, Ring A is of the formula
##STR00008##
In yet another particular variation, Ring A is of the formula
##STR00009##
In yet still another particular variation, Ring A is of the
formula
##STR00010##
[0114] In another embodiment of the compounds of the invention,
with reference to any one of the above embodiments and variations,
Ring C is selected from the group consisting of
##STR00011##
each of which
[0115] is unsubstituted or substituted by (R.sub.17).sub.p.
[0116] In one variation, Ring C is selected from the group
consisting of phenyl and pyridinyl, each unsubstituted or
substituted by (R.sub.17).sub.p.
[0117] In another variation, Ring C is of the formula
##STR00012##
In still another variation, Ring C is of the formula
##STR00013##
[0118] In yet another variation, Ring C is of the formula
##STR00014##
each of which is unsubstituted or substituted by 1 to 3
(R.sub.17).
[0119] In still another embodiment of the compounds of the
invention, with reference to any one of the above embodiments and
variations, each R.sub.1 is independently selected from the group
consisting of fluoro, chloro, cyano, methyl, trifluoromethyl,
methoxy, --NH.sub.2, --C(O)NH.sub.2, --C(O)NH(CH.sub.3),
--C(O)N(CH.sub.3).sub.2, --NHC(O)CH.sub.3,
--NHC(O)CH.sub.2NH.sub.2, --NHC(O)CH(NH.sub.2)(CH.sub.3),
--NHC(O)CH(NH.sub.2)(cyclohexyl),
--NHC(O)CH(NH.sub.2)CH(CH.sub.3).sub.2,
--NHC(O)CH(CH.sub.3).sub.2,
##STR00015##
[0120] In one variation, each R.sub.1 is independently selected
from the group consisting of trifluoromethyl, cyano, --NH.sub.2--,
--C(O)NH.sub.2, --C(O)NHCH.sub.3, --C(O)N(CH.sub.3).sub.2, and
--NHC(O)CH(NH.sub.2)(CH.sub.3). In another variation, R.sub.1 is
trifluoromethyl. In another variation, is --NH.sub.2. In still
another variation, R.sub.1 is --C(O)NH.sub.2. In yet another
variation, R.sub.1 is --C(O)NHCH.sub.3. In yet another variation,
R.sub.1 is --C(O)N(CH.sub.3).sub.2. In still yet another variation
R.sub.1 is NH.sub.2.
[0121] In another embodiment of the compound of the invention, with
reference to any one of the above embodiments and variations, each
R.sub.17 is independently selected from the group consisting of
cyano, halo, C.sub.1-4alkyl, haloC.sub.1-4alkyl,
--SO.sub.2--C.sub.1-4alkyl, and C.sub.3-6cycloalkyl.
[0122] In one variation, each R.sub.17 is independently selected
from the group consisting of cyano, fluoro, chloro, methyl,
trifluoromethyl, 1,1-difluoroethyl, methylsulfonyl, and
cyclopropyl.
[0123] In another variation, each R.sub.17 is independently
selected from the group consisting of cyano, chloro, fluoro,
methylsulfonyl, and trifluoromethyl.
[0124] In one particular variation, at least one of R.sub.17 is
cyano. In another particular variation, at least one of R.sub.17 is
trifluoromethyl. In another particular variation, R.sub.17 is
chloro or fluoro. In still another variation, R.sub.17 is
methylsulfonyl. In still another variation, R.sub.17 is methyl or
fluoro. In yet still another variation, R.sub.17 is cyano.
[0125] In another embodiment of the compound of the invention
according to any one of the above embodiments and variations, n is
1 or 2. In another variation, n is 1. In another variation, n is
2.
[0126] In another embodiment of the compounds of the present
invention, with reference to any one of the above embodiments and
variations, p is 1, 2 or 3. In another variation, p is 1. In still
another variation, p is 1. In yet still another variation, p is
3.
[0127] In a particular embodiment of the compounds of the
invention, or a pharmaceutical acceptable salt, tautomer or
stereoisomer thereof, the compound is of Formula Ia
##STR00016## [0128] wherein [0129] n is 1 or 2; [0130] Ring A is
phenyl, pyridinyl, or pyrimidinyl; [0131] Ring C is phenyl or
pyridinyl; [0132] L is *--C(O)NR.sub.2-- or *--NR.sub.2C(O)--,
wherein R.sub.2 is selected from hydrogen, C.sub.1-4alkyl,
C.sub.3-6cycloalkyl-(C.sub.0-4)alkylene,
C.sub.4-6heterocycloalkyl-(C.sub.0-4)alkylene, wherein the
C.sub.4-6heterocycloalkyl is selected from the group consisting of
piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, and
oxetanyl, and wherein the C.sub.3-6cycloalkyl is selected from
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; [0133] each
R.sub.1 is independently *--C(O)NR.sub.7R.sub.8 or --NH.sub.2--,
wherein R.sub.7 and R.sub.8 are each independently hydrogen or
C.sub.1-4alkyl; and [0134] R.sub.17 is selected from the group
consisting of cyano, halo, --NH.sub.2--, --C(O)NH.sub.2,
--C(O)NH(CH.sub.3), and --C(O)N(CH.sub.3).sub.2.
[0135] In one variation of the compounds of the present invention,
with reference to the particular embodiment above, Ring A is of the
formula
##STR00017##
In another variation, Ring A is of the formula
##STR00018##
[0136] In another variation of the compounds of the present
invention, with reference to the particular embodiment and any one
of the variations above, Ring C is of the formula
##STR00019##
In another variation, Ring C is of the formula
##STR00020##
[0137] In still another variation of the compounds of the present
invention, with reference to the particular embodiment or any one
of the variations above, L is *--C(O)N(CH.sub.3)--
or*--N(CH.sub.3)C(O)--. In another variation, L is
*--C(O)N(CH.sub.3)--. In another variation, L
is*--N(CH.sub.3)C(O)--. In still another variation, L is
*--C(O)N(CH.sub.2-cyclopropyl)-. In still another variation, L is
*--C(O)N(cyclopropyl)-.
[0138] In still another variation of the compounds of the present
invention, with reference to the particular embodiment or any one
of the variations above, R.sub.1 is --NH.sub.2--. In another
variation, R.sub.1 is *--C(O)NH.sub.2. In another variation,
R.sub.1 is --C(O)NH.sub.2. In still another variation, R.sub.1 is
--C(O)NCH.sub.3.
[0139] In still another variation of the compounds of the present
invention, with reference to the particular embodiment or any one
of the variations above, R.sub.17 is cyano. In another variation
R.sub.17 is halo.
[0140] Particular examples of compounds or a pharmaceutically
acceptable salt, tautomer or stereoisomer thereof, according to the
present invention include, but are not limited to:
N-(4-cyanophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]py-
ridine-5-carboxamide;
4-fluoro-N-methyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-
-5-yl)methyl)aniline;
N-(4-chlorophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]p-
yridine-5-carboxamide;
N-(4-fluorophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]p-
yridine-5-carboxamide;
N-methyl-N-(5-methylpyridin-2-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1-
,5-a]pyridine-5-carboxamide;
4-chloro-N-methyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-
-5-yl)methyl)aniline;
N,5-dimethyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl-
)methyl)yridine-2-amine;
5-((4-fluorophenoxy)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]p-
yridine;
N-(4-cyanophenyl)-N-(2-methoxyethyl)-3-(4-(trifluoromethyl)phenyl-
)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(4-cyanophenyl)-N-(2-(dimethylamino)ethyl)-3-(4-(trifluoromethyl)phenyl-
)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(4-cyanophenyl)-N-((tetrahydro-2H-pyran-4-ylmethyl)-3-(4-(trifluorometh-
yl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(4-(methylsulfonyl)phenyl)-N-((tetrahydro-2H-pyran-4-ylmethyl)-3-(4-(tr-
ifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,-
5-a]pyridine-5-carboxamide;
N-methyl-N-(5-methylpyridin-3-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1-
,5-a]pyridine-5-carboxamide;
5-(((5-methylpyridin-2-yl)oxy)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazo-
lo[1,5-a]pyridine;
5-(4-fluorophenethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-
e;
N-(4-cyanophenyl)-N-methyl-3-(1-methyl-1H-indazol-5-yl)pyrazolo[1,5-a]p-
yridine-5-carboxamide;
3-(6-acetamidopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyri-
dine-5-carboxamide;
3-(4-carbamoylphenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-
-carboxamide;
3-(4-carbamoylphenyl)-N-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine--
5-carboxamide;
5-(((4-fluorophenyl)thio)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,-
5-a]pyridine;
5-(((4-fluorophenyl)sulfinylmethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo-
[1,5-a]pyridine;
3-(4-(1H-pyrazol-5-yl)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]py-
ridine-5-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-(5-(trifluoromethyl)pyridine-2-yl)pyrazolo[1-
,5-a]pyridine-5-carboxamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-(5-(trifluoromethyl)pyridine-2-yl)pyra-
zolo[1,5-a]pyridine-5-carboxamide;
(S)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1-
,5-a]pyridine-5-carboxamide;
3-(5-carbamoylpyridin-2-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyri-
dine-5-carboxamide;
4-cyano-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-
-yl)benzamide;
4-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine--
5-yl)benzamide;
4-cyano-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine--
5-yl)benzenesulfonamide;
4-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-
-5-yl)benzenesulfonamide;
3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyri-
dine-5-carboxamide;
N-methyl-3-(4-(trifluoromethyl)phenyl)-N-(5-(trifluoromethyl)yridine-2-yl-
)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-methyl-N-(5-(methylsulfonyl)pyridine-2-yl)-3-(4-(trifluoromethyl)phenyl-
)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(4-fluorobenzyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5--
amine;
N-(4-fluorobenzyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yrid-
ine-5-amine;
N-methyl-6-(trifluoromethyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-
-a]yridine-5-yl)nicotinamide;
N-methyl-5-(trifluoromethyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-
-a]yridine-5-yl)picolinamide;
4-cyano-N-((tetrahydro-2H-pyran-4-ylmethyl)-N-(3-(4-(trifluoromethyl)phen-
yl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;
N-(4-cyanophenyl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5--
a]pyridine-5-carboxamide;
3-(6-aminopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-
-5-carboxamide;
3-(4-aminophenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-car-
boxamide;
3-(4-(2-aminoacetamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazol-
o[1,5-a]pyridine-5-carboxamide;
(R)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1-
,5-a]pyridine-5-carboxamide;
(S)-3-(4-(2-amino-3-methylbutanamido)phenyl)-N-(4-cyanophenyl)-N-methylpy-
razolo[1,5-a]pyridine-5-carboxamide;
(S)-3-(4-(2-amino-2-cyclohexylacetamido)phenyl)-N-(4-cyanophenyl)-N-methy-
lpyrazolo[1,5-a]pyridine-5-carboxamide;
3-(4-fluorophenyl)-1-methyl-1-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5--
a]pyridin-5-yl)urea;
6-(1,1-difluoroethyl)-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1-
,5-a]pyridin-5-yl)nicotinamide;
6-cyclopropyl-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyr-
idin-5-yl)nicotinamide;
4-cyclopropyl-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyr-
idin-5-yl)benzamide;
5-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin--
5-yl)picolinamide;
N-methyl-4-(methylsulfonyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5--
a]pyridin-5-yl)benzamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-
o[1,5-a]pyridine-5-carboxamide;
3-(6-aminopyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]py-
ridine-5-carboxamide;
4-chloro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin--
5-yl)benzamide;
N-(3-(4-carbamoylphenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-fluoro-N-methylben-
zamide;
4-fluoro-N-methyl-N-(3-(4-(5-(methylamino)-1,3,4-thiadiazol-2-yl)p-
henyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;
N-methyl-N-(5-(methylsulfonyl)pyridin-2-yl)-3-(1H-pyrrolo[2,3-b]pyridin-5-
-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-(5-methylpyridin-2-yl)pyrazolo[1,5-a]p-
yridine-5-carboxamide;
N-(5-cyanopyridin-2-yl)-3-(5-methoxypyridin-2-yl)-N-methylpyrazolo[1,5-a]-
pyridine-5-carboxamide;
3-(5-carbamoylpyridin-2-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5--
a]pyridine-5-carboxamide;
3-(4-carbamoylphenyl)-N-methyl-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazol-
o[1,5-a]pyridine-5-carboxamide;
3-(4-carbamoylphenyl)-N-methyl-N-(5-methylpyridin-2-yl)pyrazolo[1,5-a]pyr-
idine-5-carboxamide;
N-(4-fluorophenyl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]p-
yridine-5-carboxamide;
4-(5-(1-(methyl(5-methylpyridin-2-yl)amino)ethyl)pyrazolo[1,5-a]pyridin-3-
-yl)benzamide;
4-(5-(1-(7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl)pyrazolo[1,-
5-a]pyridin-3-yl)benzamide;
N-(4-cyanophenyl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]py-
ridine-5-carboxamide;
N-(4-(5-(1-(methyl(5-methylpyridin-2-yl)amino)ethyl)pyrazolo[1,5-a]pyridi-
n-3-yl)phenyl)acetamide;
3-(4-acetamidophenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyri-
dine-5-carboxamide;
4-(5-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,-
5-a]pyridin-3-yl)benzamide;
4-(5-(7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)py-
razolo[1,5-a]pyridin-3-yl)benzamide;
4-(5-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,-
5-a]pyridin-3-yl)-N-methylbenzamide;
4-(5-(7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)py-
razolo[1,5-a]pyridin-3-yl)-N-methylbenzamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,-
5-a]pyridine-5-carboxamide;
N-(5-cyanopyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)-N-(oxetan-3-yl)pyra-
zolo[1,5-a]pyridine-5-carboxamide;
3-(6-amino-5-fluoropyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a-
]pyridine-5-carboxamide;
3-(4-amino-3,5-dimethylphenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]p-
yridine-5-carboxamide;
3-(6-amino-5-methylpyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a-
]pyridine-5-carboxamide;
3-(4-carbamoylphenyl)-N-(4-cyanocyclohexyl)-N-methylpyrazolo[1,5-a]pyridi-
ne-5-carboxamide;
3-(2-aminopyrimidin-5-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridi-
ne-5-carboxamide;
3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-met-
hylpyrazolo[1,5-a]pyridine-5-carboxamide;
3-(6-amino-5-cyanopyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[-
1,5-a]pyridine-5-carboxamide;
3-(6-amino-5-chloropyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo-
[1,5-a]pyridine-5-carboxamide;
3-(6-amino-5-(dimethylcarbamoyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-m-
ethylpyrazolo[1,5-a]pyridine-5-carboxamide;
3-(6-amino-5-methoxypyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazol-
o[1,5-a]pyridine-5-carboxamide; and
3-(4-carbamoylphenyl)-N-(4-chloro-2-formylphenyl)-N-methylpyrazolo[1,5-a]-
pyridine-5-carboxamide.
[0141] Particular examples of the compounds or a pharmaceutically
acceptable salt, tautomer or stereoisomer thereof, according to the
present invention include, but are not limited to:
3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyri-
dine-5-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5--
a]pyridine-5-carboxamide;
3-(6-aminopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-
-5-carboxamide;
(R)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1-
,5-a]pyridine-5-carboxamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-
o[1,5-a]pyridine-5-carboxamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,-
5-a]pyridine-5-carboxamide;
3-(2-aminopyrimidin-5-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridi-
ne-5-carboxamide; and
3-(6-amino-5-(dimethylcarbamoyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-m-
ethylpyrazolo[1,5-a]pyridine-5-carboxamide.
[0142] It is noted that the compounds of the present invention may
be in the form of a pharmaceutically acceptable salt. It is further
note that the compounds of the present invention may be a mixture
of stereoisomers, or the compound may comprise a single
stereoisomer.
[0143] Further compounds of the invention are detailed in the
Examples, infra.
[0144] In another aspect, the present invention is directed to a
pharmaceutical composition which includes as an active ingredient a
compound according to any one of the above embodiments and
variations in combination with a pharmaceutically acceptable
carrier, diluent or excipient.
[0145] In one embodiment, the pharmaceutical composition further
includes a second agent which can be a kinase inhibitor, an
anti-malarial drug or an anti-inflammatory agent.
[0146] In another embodiment, the pharmaceutical composition
includes an antimalarial drug as a second agent. The selections for
the antimalarial drug may includes, but are not limited to,
artemisinin, artemether, artesunate, arteflene, dihydroartemisinin,
chlorproguanil, trimethoprim, chloroquine, quinine, mefloquine,
amodiaquine, atovaquone, proguanil, lumefantrine, piperaquine,
pyronaridine, halofantrine, pyrimethamine-sulfadoxine, quinacrine,
pyrimethamine-dapsone, quinidine, amopyroquine, sulphonamides,
primaquine, ferroquine, tafenoquine, arterolane, and
pyronaridine.
[0147] In another embodiment, the pharmaceutical composition is a
solid formulation adapted for oral administration. In another
embodiment, the composition is a liquid formulation adapted for
oral administration. In yet another embodiment, the composition is
a tablet. In still another embodiment, the composition is a liquid
formulation adapted for parenteral administration.
[0148] In yet another embodiment, the pharmaceutical composition is
adapted for administration by a route selected from the group
consisting of orally, parenterally, intraperitoneally,
intravenously, intraarterially, transdermally, sublingually,
intramuscularly, rectally, transbuccally, intranasally,
liposomally, via inhalation, vaginally, intraoccularly, via local
delivery (for example by catheter or stent), subcutaneously,
intraadiposally, intraarticularly, and intrathecally.
[0149] In another aspect, the present application is directed to a
compound or a pharmaceutical composition according to any one of
the above embodiments and variations for use in a therapeutic
application.
[0150] In another aspect, the present application is directed to a
compound or a pharmaceutical composition according to any one of
the above embodiments and variations for use as a medicament.
[0151] In yet another aspect, the present invention is directed to
a method for treating, preventing, inhibiting, ameliorating, or
eradicating the pathology and/or symptomology of a disease caused
by a Plasmodium parasite. The method involves administering to a
subject a therapeutically effective amount of a compound or a
pharmaceutical composition according to the above embodiments and
variations. In addition, the administering may be in combination
with a second agent.
[0152] In one embodiment of the method of the invention, the method
is directed to treatment of malaria; particularly malaria caued by
the parasites Plasmodium falciparum, Plasmodium vivax, Plasmodium
ovale, and Plasmodium malaria; more particularly, the parasite
Plasmodium falciparum. Further, the Plasmodium parasite can be at
the blood stages or at the hepatic stages.
[0153] In the treatment method of the invention, the compounds or
pharmaceutical compositions may be administered with prior to,
simultaneously with, or after a second agent. The second agent can
be a kinase inhibitor, an anti-malarial drug or an
anti-inflammatory agent. In one particular variation of the method,
the second agent is an anti-malarial drug. The selection of the
antimalarial drug, includes, but is not limited to, artemisinin,
artemether, artesunate, arteflene, dihydroartemisinin,
chlorproguanil, trimethoprim, chloroquine, quinine, mefloquine,
amodiaquine, atovaquone, proguanil, lumefantrine, piperaquine,
pyronaridine, halofantrine, pyrimethamine-sulfadoxine, quinacrine,
pyrimethamine-dapsone, quinidine, amopyroquine, sulphonamides,
primaquine, ferroquine, tafenoquine, arterolane, and
pyronaridine.
[0154] In another aspect, the invention is directed to a compound,
salt, steroisomer, or pharmaceutical composition thereof, according
to any one of the above embodiments or variation, for treating,
preventing, inhibiting, ameliorating, or eradicating the pathology
and/or symptomology of a disease caused by a Plasmodium parasite.
In one embodiment, the disease is malaria caused by the Plasmodium
parasite Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale,
or Plasmodium malaria; particularly, the parasite Plasmodium
falciparum. Further, the Plasmodium parasite can be at the blood
stages, or the Plasmodium parasite can be at the hepatic
stages.
[0155] In still another aspect, the present invention is directed
to the use of the compound, or a salt, a stereoisomer, or a
pharmaceutical composition thereof, according to the any one of the
above embodiments or variations in the manufacture of a medicament
for treating, preventing, inhibiting, ameliorating, or eradicating
the pathology and/or symptomology of a disease caused by a
Plasmodium parasite. In one embodiment, the medicament is for
treating malaria causes by the parasite Plasmodium falciparum,
Plasmodium vivax, Plasmodium ovale, or Plasmodium malaria; in
particular, the parasite Plasmodium falciparum. Further, the
Plasmodium parasite can be at the blood stages or at the hepatic
stages.
[0156] The medicament, in addition to the compound of the
invention, may further include a second agent. The second agent may
be a kinase inhibitor, an anti-malarial drug or an
anti-inflammatory agent. In one particular embodiment, the second
agent is an anti-malarial drug selected from artemisinin,
artemether, artesunate, arteflene, dihydroartemisinin,
chlorproguanil, trimethoprim, chloroquine, quinine, mefloquine,
amodiaquine, atovaquone, proguanil, lumefantrine, piperaquine,
pyronaridine, halofantrine, pyrimethamine-sulfadoxine, quinacrine,
pyrimethamine-dapsone, quinidine, amopyroquine, sulphonamides,
primaquine, ferroquine, tafenoquine, arterolane, and
pyronaridine.
[0157] In another aspect, the invention is related to a kit which
comprises a compound of any one of the above embodiments and
variations, and optionally a second therapeutic agent. In one
particular variation, the kit comprises the compound in a multiple
dose form.
Enumerated Embodiments
[0158] Various enumerated embodiments of the invention are
described herein. It will be recognized that features specified in
each embodiment may be combined with other specified features to
provide further embodiments of the present invention.
[0159] In a first embodiment, the invention provides a compound of
the formula (I), or a pharmaceutical acceptable salt, tautomer or
stereoisomer thereof,
##STR00021## [0160] wherein: [0161] n is 0, 1, 2 or 3; [0162] p is
0, 1, 2 or 3; [0163] L is selected from the group consisting of
*--(CHR.sub.3).sub.1-3--, *--CHR.sub.3N(R.sub.2)--,
*--CHR.sub.3O--, *--CHR.sub.3S--, *--CHR.sub.3S(O)--,
*--CHR.sub.3N(R.sub.2)CHR.sub.3--, *--C(O)--, *--C(O)N(R.sub.2)--,
*--C(O)N(R.sub.2)CHR.sub.3--, *--N(R.sub.2)--,
*--N(R.sub.2)CHR.sub.3--, *--N(R.sub.2)C(O)--,
*--N(R.sub.2)C(O)N(R.sub.2)--, and *--N(R.sub.2)S(O).sub.2--,
wherein [0164] * represents the point of attachment of L to the
pyrazolo[1,5-a]pyridine fused ring depicted in Formula I; [0165]
each R.sub.2 is independently selected from the group consisting of
hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, R--C.sub.0-4alkylene,
and R--C.sub.0-4alkylene-C(O)--, wherein R is selected from the
group consisting of hydroxyl, C.sub.1-4alkoxy, amino,
C.sub.1-4alkylamino, C.sub.3-6cycloalkyl,
C.sub.4-6heterocycloalkyl, and C.sub.5-6heteroaryl, wherein the
C.sub.3-6cycloalkyl, C.sub.4-6heterocycloalkyl, and
C.sub.5-6heteroaryl of R are each unsubstituted or substituted with
1-2 substituents independently selected from the group consisting
of halo, amino, hydroxyl, C.sub.1-4alkyl, C.sub.1-4alkoxy, oxo, and
C.sub.5-6heteroaryl; and [0166] each R.sub.3 is independently
selected from the group consisting of hydrogen and C.sub.1-4alkyl,
[0167] Ring A is selected from the group consisting of
C.sub.6-10aryl and C.sub.5-10heteroaryl; [0168] Ring C is selected
from the group consisting of C.sub.6-10aryl, C.sub.5-10heteroaryl,
C.sub.5-7cycloalkyl, C.sub.5-7heterocycloalkyl, and a fused
bicyclyl comprising a C.sub.5-6heterocycloalkyl fused to a phenyl;
[0169] each R.sub.1 is independently selected from the group
consisting of halo, cyano, amino, C.sub.1-4alkyl, C.sub.1-4alkoxyl,
halo-C.sub.1-4alkyl, --C(O)NR.sub.7R.sub.8, --NHC(O)R.sub.11,
phenyl, and C.sub.5-6heteroaryl; wherein [0170] the phenyl and
C.sub.5-6heteroaryl are each unsubstituted or substituted with 1-2
substituents independently selected from the group consisting of
C.sub.1-4alkyl, amino, halo, and C.sub.1-4alkylamino; [0171]
R.sub.7 and R.sub.8 are each independently selected from hydrogen,
C.sub.1-4alkyl and haloC.sub.1-4alkyl; [0172] R.sub.11 is
C.sub.1-6alkyl unsubstituted or substituted with 1-2 substituents
independently selected from the group consisting of amino,
C.sub.3-6cycloalkyl and C.sub.4-6heterocycloalkyl; [0173] R.sub.17
is selected from the group consisting of cyano, halo,
C.sub.1-4alkyl, halo-C.sub.1-4alkyl, oxo, C.sub.3-6cycloalkyl, and
--SO.sub.2--C.sub.1-4alkyl.
Embodiment 2
[0174] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to embodiment 1, wherein L is
selected from the group consisting of*--(CHR.sub.3).sub.1-3--,
*--CHR.sub.3N(R.sub.2)--, *--CHR.sub.3O--, *--CHR.sub.3S--,
*--CHR.sub.3S(O)--, *--C(O)--, *--C(O)N(R.sub.2)--,
*--N(R.sub.2)--, *--N(R.sub.2)CHR.sub.3--, *--N(R.sub.2)C(O)--,
*--N(R.sub.2)C(O)N(R.sub.2)--, *--N(R.sub.2)S(O).sub.2--, wherein
[0175] each R.sub.2 is independently selected from the group
consisting of hydrogen, C.sub.1-6alkyl, R--C.sub.0-4alkylene,
wherein R is selected from the group consisting of C.sub.1-4alkoxy,
C.sub.1-4alkylamino, di-C.sub.1-4alkylamino, C.sub.3-6cycloalkyl,
C.sub.4-6heterocycloalkyl and C.sub.5-6heteroaryl, wherein the
C.sub.3-6cycloalkyl, C.sub.4-6heterocycloalkyl and
C.sub.5-6heteroaryl of R are each unsubstituted or substituted with
1-2 substituents independently selected from the group consisting
of halo, amino, hydroxyl, C.sub.1-4alkyl, C.sub.1-4alkoxy, oxo, and
C.sub.5-6heteroaryl.
Embodiment 3
[0176] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to embodiment 1, wherein L is
selected from the group consisting of *--C(O)N(R.sub.2)--, and
*--N(R.sub.2)C(O)--, wherein each R.sub.2 is independently selected
from hydrogen, C.sub.1-4alkyl, and R--C.sub.0-4alkylene, wherein R
is selected from the group consisting of C.sub.4-6heterocycloalkyl
and C.sub.5-6heteroaryl, each unsubstituted or substituted with 1-2
substituents independently selected from the group consisting of
halo, amino, hydroxyl, C.sub.1-4alkyl, C.sub.1-4alkoxy, oxo, and
C.sub.5-6heteroaryl.
Embodiment 4
[0177] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to embodiment 1, wherein L is
selected from the group consisting of *--CH(CH.sub.3)--,
*--CH.sub.2CH.sub.2--, *--CH.sub.2N(CH.sub.3)--,
*--CH.sub.2N(C(O)(CH.sub.2).sub.1-2NH(CH.sub.3))--,
*--CH.sub.2N(C(O)--(CH.sub.2).sub.1-2NH.sub.2)--,
*--CH.sub.2N((C(O)--(CH.sub.2).sub.1-2N(CH.sub.3).sub.2)--,
*--CH.sub.2N(C(O)(CH.sub.2).sub.1-2OH)--,
*--CH(CH.sub.3)N(CH.sub.3)--, *--CH.sub.2O--, *--CH.sub.2S--,
*--CH.sub.2S(O)--, *--C(O)--, *--C(O)N(CH.sub.3)--,
*--C(O)N(CH.sub.2CH.sub.3)--, *--C(O)N(CH(CH.sub.3).sub.2)--,
*--C(O)N(C(CH.sub.3).sub.3)--,
*--C(O)N(CH.sub.2CH(CH.sub.3).sub.2)--,
*--C(O)N(CH(CH.sub.3)CH.sub.2CH.sub.3)--,
*--C(O)N(CH.sub.2CH.sub.2OCH.sub.3)--,
*--C(O)N(CH.sub.2CH.sub.2N(CH.sub.3).sub.2)--,
*--C(O)N(CH.sub.3)CH.sub.2--, *--NHCH.sub.2--,
*--N(CH.sub.3)CH.sub.2--,
*--N(CH.sub.2-tetrahydropyran-4-yl)-C(O)--, *--N(CH.sub.3)C(O)--,
*--N(CH.sub.3)C(O)NH--, *--N(CH.sub.3)S(O).sub.2--,
*--C(O)N((CH.sub.2).sub.0-1-cyclopropyl)-,
*--C(O)N((CH.sub.2).sub.0-1-cyclobutyl)-,
*--C(O)N((CH.sub.2).sub.0-1-cyclopentyl)-,
*--C(O)N((CH.sub.2).sub.0-1-cyclohexyl)-,
*--C(O)N(CH.sub.2-tetrahydropyran-4-yl)-,
*--C(O)N((CH.sub.2)-2-(1,1-dioxidothiomorpholino-4-yl)-,
*--C(O)N(CH.sub.2-1,1-dioxidothiomorpholino-4-yl)-,
*--C(O)N((CH.sub.2)-2-tetrahydropyran-4-yl))-,
*--C(O)N((CH.sub.2).sub.1-2-morpholin-4-yl)-,
*--C(O)N(oxetan-3-yl)-, *--C(O)N(CH.sub.2-oxetan-3-yl)-,
*--C(O)N(CH(CH.sub.3)--CH.sub.2-1-H-pyrazoly-1-yl)-,
*--CH.sub.2N(C(O)--(CH.sub.2).sub.1-2-morpholinyl)-,
*--CH.sub.2N(C(O)--(CH.sub.2).sub.1-2-4-methylpiperizin-1-yl)),
*--CH.sub.2N(C(O)--(CH.sub.2).sub.1-2-tetrahydropyran-4-yl)-, and
*--CH.sub.2N(C(O)(CH.sub.2).sub.1-2-oxetan-3-yl)-.
Embodiment 5
[0178] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to embodiment 1, wherein L is
selected from the group consisting of *--CH(CH.sub.3)--,
*--CH.sub.2CH.sub.2--, *--CH.sub.2N(CH.sub.3)--,
*--CH(CH.sub.3)N(CH.sub.3)--, *--CH.sub.2O--, *--CH.sub.2S--,
*--CH.sub.2S(O)--, *--C(O)--, *--C(O)N(CH.sub.3)--,
*--C(O)N(CH.sub.3)CH.sub.2--,
*--C(O)N(CH.sub.2CH.sub.2OCH.sub.3)--,
*--C(O)N(CH.sub.2CH.sub.2N(CH.sub.3).sub.2)--, *--NHCH.sub.2--,
*--N(CH.sub.3)CH.sub.2--,
*--N(CH.sub.2-tetrahydropyran-4-yl)-C(O)--, *--N(CH.sub.3)C(O)--,
*--N(CH.sub.3)C(O)NH--, *--N(CH.sub.3)S(O).sub.2--,
*--C(O)N((CH.sub.2).sub.0-1-cyclopropyl)-,
*--C(O)N(CH.sub.2-tetrahydropyran-4-yl)-, *--C(O)N(oxetan-3-yl)-,
and *--C(O)N(CH(CH.sub.3)CH.sub.2-(1-H-pyrazoly-1-yl))-.
Embodiment 6
[0179] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to embodiment 1, wherein L is
*--C(O)N(CH.sub.3)-- or *--N(CH.sub.3)C(O)--.
Embodiment 7
[0180] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to embodiment 1, wherein L is
*--C(O)N(cyclopropyl)-.
Embodiment 8
[0181] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to embodiment 1, wherein L is
*--C(O)-- or --CH(CH.sub.3)--.
Embodiment 9
[0182] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to embodiments 1 to 8, wherein Ring
A is selected from the group consisting of phenyl, pyridinyl,
pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolopyridinyl, and
indazolyl, each of which is unsubstituted or substituted by
(R.sub.1).sub.n.
Embodiment 10
[0183] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1 to 8,
wherein Ring A is selected from the group consisting of
##STR00022##
each of which is unsubstituted or substituted by
(R.sub.1).sub.n.
Embodiment 11
[0184] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1 to 8,
wherein Ring A is of the formula
##STR00023##
Embodiment 12
[0185] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1 to 8,
wherein Ring A is of the formula
##STR00024##
Embodiment 13
[0186] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1 to 8,
wherein Ring A is of the formula
##STR00025##
Embodiment 14
[0187] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1 to 8,
wherein Ring A is of the formula
##STR00026##
Embodiment 15
[0188] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1 to 14,
wherein Rind C is selected from the group consisting of
##STR00027##
each of which is unsubstituted or substituted by
(R.sub.17).sub.p.
Embodiment 16
[0189] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1 to 7
and 9-14, wherein Ring C is selected from the group consisting of
phenyl and pyridinyl, each of which is unsubstituted or substituted
by (R.sub.17).sub.p.
Embodiment 17
[0190] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1 to 7
and 9-14, wherein Ring C is of the formula
##STR00028##
Embodiment 18
[0191] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1 to 7
and 9-14, wherein Ring C is of the formula
##STR00029##
Embodiment 19
[0192] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1-2, 4-5
and 8-14, wherein Ring C is of the formula
##STR00030##
each of which is unsubstituted or substituted by 1 to 3
(R.sub.17).
Embodiment 20
[0193] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1 to 19,
wherein each R.sub.1 is independently selected from the group
consisting of fluoro, chloro, cyano, methyl, trifluoromethyl,
methoxy, --NH.sub.2, --C(O)NH.sub.2, --C(O)NH(CH.sub.3),
--C(O)N(CH.sub.3).sub.2, --NHC(O)CH.sub.3,
--NHC(O)CH.sub.2NH.sub.2, --NHC(O)CH(NH.sub.2)(CH.sub.3),
--NHC(O)CH(NH.sub.2)(cyclohexyl),
--NHC(O)CH(NH.sub.2)CH(CH.sub.3).sub.2,
--NHC(O)CH(CH.sub.3).sub.2,
##STR00031##
Embodiment 21
[0194] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1 to 19,
wherein each R.sub.1 is independently selected from the group
consisting of trifluoromethyl, cyano, --NH.sub.2--, --C(O)NH.sub.2,
--C(O)NHCH.sub.3, and --C(O)N(CH.sub.3).sub.2,
Embodiment 22
[0195] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1 to 19,
wherein R.sub.1 is trifluoromethyl.
Embodiment 23
[0196] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1 to 19,
wherein R.sub.1 is --NH.sub.2.
Embodiment 24
[0197] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1 to 19,
wherein R.sub.1 is --C(O)NH.sub.2.
Embodiment 25
[0198] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1 to 19,
wherein R.sub.1 is --C(O)NHCH.sub.3.
Embodiment 26
[0199] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1 to 19,
wherein R.sub.1 is --NHC(O)CH(NH.sub.2)(CH.sub.3).
Embodiment 27
[0200] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1 to 26,
wherein each R.sub.17 is independently selected from the group
consisting of cyano, halo, C.sub.1-4alkyl,
--SO.sub.2--C.sub.1-4alkyl, and C.sub.3-6cycloalkyl.
Embodiment 28
[0201] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1 to 26,
wherein each R.sub.17 is independently selected from the group
consisting of cyano, fluoro, chloro, methyl, trifluoromethyl,
1,1-difluoroethyl, methylsulfonyl, and cyclopropyl.
Embodiment 29
[0202] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1-7, 9-18
and 20-26, R.sub.17 is cyano.
Embodiment 30
[0203] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1-7, 9-18
and 20-26, R.sub.17 is trifluoromethyl
Embodiment 31
[0204] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1-7, 9-18
and 20-26, wherein R.sub.17 is fluoro or chloro.
Embodiment 32
[0205] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1-7, 9-18
and 20-26, wherein R.sub.17 is methylsulfonyl.
Embodiment 33
[0206] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to any one of embodiments 1-2, 4-5,
8-15 and 19, where each R.sub.17 is methyl.
Embodiment 34
[0207] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to embodiment 1, wherein the
compound is of Formula Ia
##STR00032## [0208] wherein [0209] n is 1 or 2; [0210] Ring A is
phenyl, pyridinyl, or pyrimidinyl; [0211] Ring C is phenyl or
pyridinyl; [0212] L is *--C(O)NR.sub.2-- or *--NR.sub.2C(O)--,
wherein R.sub.2 is selected from hydrogen, C.sub.1-4alkyl,
C.sub.3-6cycloalkyl-(C.sub.0-4)alkylene,
C.sub.4-6heterocycloalkyl-(C.sub.0-4)alkylene, wherein the
C.sub.4-6heterocycloalkyl is selected from the group consisting of
piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, and
oxetanyl, and wherein the C.sub.3-6cycloalkyl is selected from
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; [0213] each
R.sub.1 is independently *--C(O)NR.sub.7R.sub.8 or --NH.sub.2--,
wherein R.sub.7 and R.sub.8 are each independently hydrogen or
C.sub.1-4alkyl; and [0214] R.sub.17 is selected from the group
consisting of cyano, halo, --NH.sub.2--, --C(O)NH.sub.2,
--C(O)NH(CH.sub.3), and --C(O)N(CH.sub.3).sub.2.
Embodiment 35
[0215] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to embodiment 34, wherein Ring A is
of the formula
##STR00033##
Embodiment 36
[0216] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to embodiment 34, wherein Ring A is
of the formula
##STR00034##
Embodiment 37
[0217] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to embodiments 34-36, wherein Ring
C is of the formula
##STR00035##
Embodiment 38
[0218] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to embodiments 34-36, wherein Ring
C is of the formula
##STR00036##
Embodiment 39
[0219] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to embodiments 36-38, wherein L is
*--C(O)NH(CH.sub.3)-- or *--NH(CH.sub.3)C(O)--.
Embodiment 40
[0220] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to embodiments 36-38, wherein L is
*--C(O)N(cyclopropyl)-
Embodiment 41
[0221] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to embodiments 36-40, wherein
R.sub.1 is --NH.sub.2--.
Embodiment 42
[0222] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to embodiments 36-40, wherein
R.sub.1 is --C(O)NH.sub.2 or --C(O)NCH.sub.3.
Embodiment 43
[0223] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to embodiments 36-42, wherein
R.sub.17 is cyano.
Embodiment 44
[0224] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to embodiments 36-42, wherein
R.sub.17 is halo.
Embodiment 45
[0225] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to embodiment 1, wherein the
compound is selected from the group consisting of:
N-(4-cyanophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]py-
ridine-5-carboxamide;
4-fluoro-N-methyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-
-5-yl)methyl)aniline;
N-(4-chlorophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]p-
yridine-5-carboxamide;
N-(4-fluorophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]p-
yridine-5-carboxamide;
N-methyl-N-(5-methylpyridin-2-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1-
,5-a]pyridine-5-carboxamide;
4-chloro-N-methyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-
-5-yl)methyl)aniline;
N,5-dimethyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl-
)methyl)pyridine-2-amine;
5-((4-fluorophenoxy)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]p-
yridine;
N-(4-cyanophenyl)-N-(2-methoxyethyl)-3-(4-(trifluoromethyl)phenyl-
)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(4-cyanophenyl)-N-(2-(dimethylamino)ethyl)-3-(4-(trifluoromethyl)phenyl-
)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(4-cyanophenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(4-(trifluoromet-
hyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(4-(methylsulfonyl)phenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(4-(t-
rifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,-
5-a]pyridine-5-carboxamide;
N-methyl-N-(5-methylpyridin-3-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1-
,5-a]pyridine-5-carboxamide;
5-(((5-methylpyridin-2-yl)oxy)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazo-
lo[1,5-a]pyridine;
5-(4-fluorophenethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-
e;
N-(4-cyanophenyl)-N-methyl-3-(1-methyl-1H-indazol-5-yl)pyrazolo[1,5-a]p-
yridine-5-carboxamide;
3-(6-acetamidopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyri-
dine-5-carboxamide;
3-(4-carbamoylphenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-
-carboxamide;
3-(4-carbamoylphenyl)-N-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine--
5-carboxamide;
5-(((4-fluorophenyl)thio)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,-
5-a]pyridine;
5-(((4-fluorophenyl)sulfinyl)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazol-
o[1,5-a]pyridine;
3-(4-(1H-pyrazol-5-yl)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]py-
ridine-5-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-(5-(trifluoromethyl)pyridine-2-yl)pyrazolo[1-
,5-a]pyridine-5-carboxamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-(5-(trifluoromethyl)pyridine-2-yl)pyra-
zolo[1,5-a]pyridine-5-carboxamide;
(S)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1-
,5-a]pyridine-5-carboxamide;
3-(5-carbamoylpyridin-2-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyri-
dine-5-carboxamide;
4-cyano-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-
-yl)benzamide;
4-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine--
5-yl)benzamide;
4-cyano-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine--
5-yl)benzenesulfonamide;
4-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-
-5-yl)benzenesulfonamide;
3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyri-
dine-5-carboxamide;
N-methyl-3-(4-(trifluoromethyl)phenyl)-N-(5-(trifluoromethyl)yridine-2-yl-
)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-methyl-N-(5-(methylsulfonyl)pyridine-2-yl)-3-(4-(trifluoromethyl)phenyl-
)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(4-fluorobenzyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5--
amine;
N-(4-fluorobenzyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yrid-
ine-5-amine;
N-methyl-6-(trifluoromethyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-
-a]yridine-5-yl)nicotinamide;
N-methyl-5-(trifluoromethyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-
-a]yridine-5-yl)picolinamide;
4-cyano-N-((tetrahydro-2H-pyran-4-ylmethyl)-N-(3-(4-(trifluoromethyl)phen-
yl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;
N-(4-cyanophenyl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5--
a]pyridine-5-carboxamide;
3-(6-aminopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-
-5-carboxamide;
3-(4-aminophenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-car-
boxamide;
3-(4-(2-aminoacetamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazol-
o[1,5-a]pyridine-5-carboxamide;
(R)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1-
,5-a]pyridine-5-carboxamide;
(S)-3-(4-(2-amino-3-methylbutanamido)phenyl)-N-(4-cyanophenyl)-N-methylpy-
razolo[1,5-a]pyridine-5-carboxamide;
(S)-3-(4-(2-amino-2-cyclohexylacetamido)phenyl)-N-(4-cyanophenyl)-N-methy-
lpyrazolo[1,5-a]pyridine-5-carboxamide;
3-(4-fluorophenyl)-1-methyl-1-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5--
a]pyridin-5-yl)urea;
6-(1,1-difluoroethyl)-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1-
,5-a]pyridin-5-yl)nicotinamide;
6-cyclopropyl-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyr-
idin-5-yl)nicotinamide;
4-cyclopropyl-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyr-
idin-5-yl)benzamide;
5-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin--
5-yl)picolinamide;
N-methyl-4-(methylsulfonyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5--
a]pyridin-5-yl)benzamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-
o[1,5-a]pyridine-5-carboxamide;
3-(6-aminopyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]py-
ridine-5-carboxamide;
4-chloro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin--
5-yl)benzamide;
N-(3-(4-carbamoylphenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-fluoro-N-methylben-
zamide;
4-fluoro-N-methyl-N-(3-(4-(5-(methylamino)-1,3,4-thiadiazol-2-yl)p-
henyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;
N-methyl-N-(5-(methylsulfonyl)pyridin-2-yl)-3-(1H-pyrrolo[2,3-b]pyridin-5-
-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-(5-methylpyridin-2-yl)pyrazolo[1,5-a]p-
yridine-5-carboxamide;
N-(5-cyanopyridin-2-yl)-3-(5-methoxypyridin-2-yl)-N-methylpyrazolo[1,5-a]-
pyridine-5-carboxamide;
3-(5-carbamoylpyridin-2-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5--
a]pyridine-5-carboxamide;
3-(4-carbamoylphenyl)-N-methyl-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazol-
o[1,5-a]pyridine-5-carboxamide;
3-(4-carbamoylphenyl)-N-methyl-N-(5-methylpyridin-2-yl)pyrazolo[1,5-a]pyr-
idine-5-carboxamide;
N-(4-fluorophenyl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]p-
yridine-5-carboxamide;
4-(5-(1-(methyl(5-methylpyridin-2-yl)amino)ethyl)pyrazolo[1,5-a]pyridin-3-
-yl)benzamide;
4-(5-(1-(7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-ylethyl)pyrazolo[1,5-
-a]pyridin-3-yl)benzamide;
N-(4-cyanophenyl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]py-
ridine-5-carboxamide;
N-(4-(5-(1-(methyl(5-methylpyridin-2-yl)amino)ethyl)pyrazolo[1,5-a]pyridi-
n-3-yl)phenyl)acetamide;
3-(4-acetamidophenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyri-
dine-5-carboxamide;
4-(5-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,-
5-a]pyridin-3-yl)benzamide;
4-(5-(7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)py-
razolo[1,5-a]pyridin-3-yl)benzamide;
4-(5-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,-
5-a]pyridin-3-yl)-N-methylbenzamide;
4-(5-(7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)py-
razolo[1,5-a]pyridin-3-yl)-N-methylbenzamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,-
5-a]pyridine-5-carboxamide;
N-(5-cyanopyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)-N-(oxetan-3-yl)pyra-
zolo[1,5-a]pyridine-5-carboxamide;
3-(6-amino-5-fluoropyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a-
]pyridine-5-carboxamide;
3-(4-amino-3,5-dimethylphenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]p-
yridine-5-carboxamide;
3-(6-amino-5-methylpyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a-
]pyridine-5-carboxamide;
3-(4-carbamoylphenyl)-N-(4-cyanocyclohexyl)-N-methylpyrazolo[1,5-a]pyridi-
ne-5-carboxamide;
3-(2-aminopyrimidin-5-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridi-
ne-5-carboxamide;
3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-met-
hylpyrazolo[1,5-a]pyridine-5-carboxamide;
3-(6-amino-5-cyanopyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[-
1,5-a]pyridine-5-carboxamide;
3-(6-amino-5-chloropyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo-
[1,5-a]pyridine-5-carboxamide;
3-(6-amino-5-(dimethylcarbamoyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-m-
ethylpyrazolo[1,5-a]pyridine-5-carboxamide;
3-(6-amino-5-methoxypyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazol-
o[1,5-a]pyridine-5-carboxamide; and
3-(4-carbamoylphenyl)-N-(4-chloro-2-formylphenyl)-N-methylpyrazolo[1,5-a]-
pyridine-5-carboxamide.
Embodiment 46
[0226] A compound of the formula (I), or a salt, tautomer or
stereoisomer thereof, according to embodiment 1, wherein the
compound is selected from the group consisting of:
3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyri-
dine-5-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5--
a]pyridine-5-carboxamide;
3-(6-aminopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-
-5-carboxamide;
(R)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1-
,5-a]pyridine-5-carboxamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-
o[1,5-a]pyridine-5-carboxamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,-
5-a]pyridine-5-carboxamide;
3-(2-aminopyrimidin-5-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridi-
ne-5-carboxamide;
3-(6-amino-5-(dimethylcarbamoyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-m-
ethylpyrazolo[1,5-a]pyridine-5-carboxamide.
Embodiment 47
[0227] A pharmaceutical composition comprising at least one
compound of any one of embodiments 1 to 46 or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable carrier,
diluent or excipient.
Embodiment 48
[0228] A pharmaceutical composition according to embodiment 47
further comprising a second agent.
Embodiment 49
[0229] A pharmaceutical composition according to embodiment 48,
wherein the second agent is an antimalarial drug selected from the
group consisting of artemisinin, artemether, artesunate, arteflene,
dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine,
quinine, mefloquine, amodiaquine, atovaquone, proguanil,
lumefantrine, piperaquine, pyronaridine, halofantrine,
pyrimethamine-sulfadoxine, quinacrine, pyrimethamine-dapsone,
quinidine, amopyroquine, sulphonamides, primaquine, ferroquine,
tafenoquine, arterolane, and pyronaridine.
Embodiment 50
[0230] A compound according to any one of embodiments 1 to 46 or a
pharmaceutical composition according to any one of embodiments
47-49 for use as a medicament.
Embodiment 51
[0231] A method for treating, preventing, inhibiting, ameliorating,
or eradicating the pathology and/or symptomology of a disease
caused by a Plasmodium parasite, comprising administering to a
subject a therapeutically effective amount of a compound according
to any one of claims 1-46 or a composition according to any one of
claims 47 to 49, wherein the administering may be in combination
with a second agent.
Embodiment 52
[0232] A method for treating, preventing, inhibiting, ameliorating,
or eradicating the pathology and/or symptomology of a disease
caused by a Plasmodium parasite, according to embodiment 51,
wherein the disease is malaria.
Embodiment 53
[0233] A method for treating, preventing, inhibiting, ameliorating,
or eradicating the pathology and/or symptomology of a disease
caused by a Plasmodium parasite according to embodiments 51-52,
wherein the Plasmodium parasite is at the blood stages.
Embodiment 54
[0234] A method for treating, preventing, inhibiting, ameliorating,
or eradicating the pathology and/or symptomology of a Plasmodium
related disease caused by a Plasmodium parasite according to
embodiments 51-52, wherein the Plasmodium parasite is at the
hepatic stages.
Embodiment 55
[0235] A method for treating, preventing, inhibiting, ameliorating,
or eradicating the pathology and/or symptomology of a Plasmodium
related disease caused by a Plasmodium parasite according to
embodiments 51-54, wherein the Plasmodium parasite is selected from
group consisting of Plasmodium falciparum, Plasmodium vivax,
Plasmodium ovale, and Plasmodium malaria.
Embodiment 56
[0236] A method for treating, preventing, inhibiting, ameliorating,
or eradicating the pathology and/or symptomology of a Plasmodium
related disease caused by a Plasmodium parasite according to
embodiments 51-54, wherein the Plasmodium parasite is Plasmodium
falciparum.
Embodiment 57
[0237] A method for treating, preventing, inhibiting, ameliorating,
or eradicating the pathology and/or symptomology of a Plasmodium
related disease caused by a Plasmodium parasite according to
embodiments 51-56, wherein the second agent is selected from a
kinase inhibitor, an anti-malarial drug and an anti-inflammatory
agent.
Embodiment 58
[0238] A method for treating, preventing, inhibiting, ameliorating,
or eradicating the pathology and/or symptomology of a disease
caused by Plasmodium parasite according to embodiment 57, wherein
the anti-malarial drug is selected from the group consisting of
artemisinin, artemether, artesunate, arteflene, dihydroartemisinin,
chlorproguanil, trimethoprim, chloroquine, quinine, mefloquine,
amodiaquine, atovaquone, proguanil, lumefantrine, piperaquine,
pyronaridine, halofantrine, pyrimethamine-sulfadoxine, quinacrine,
pyrimethamine-dapsone, quinidine, amopyroquine, sulphonamides,
primaquine, ferroquine, tafenoquine, arterolane, and
pyronaridine.
Embodiment 59
[0239] A method for treating, preventing, inhibiting, ameliorating,
or eradicating the pathology and/or symptomology of a disease
caused by Plasmodium parasite according to embodiments 51-58,
wherein the compound is administered prior to, simultaneously with,
or after the second agent.
Embodiment 60
[0240] A compound according to any one of claims 1-46 or a
composition according to any one of claims 47 to 49 for treating,
preventing, inhibiting, ameliorating, or eradicating the pathology
and/or symptomology of a disease caused by a Plasmodium
parasite.
Embodiment 61
[0241] Use of a compound according to any one of embodiments 1-46
or a pharmaceutical composition according to embodiments 47-49 in
the manufacture of a medicament for treating, preventing,
inhibiting, or ameliorating the pathology and/or symptomology of a
disease caused by a Plasmodium parasite, wherein the medicament may
further include a second agent.
[0242] As used herein, the term "an optical isomer" or "a
stereoisomer" refers to any of the various stereo isomeric
configurations which may exist for a given compound of the present
invention and includes geometric isomers. It is understood that a
substituent may be attached at a chiral center of a carbon atom.
The term "chiral" refers to molecules which have the property of
non-superimposability on their mirror image partner, while the term
"achiral" refers to molecules which are superimposable on their
mirror image partner. Therefore, the invention includes
enantiomers, diastereomers or racemates of the compound.
"Enantiomers" are a pair of stereoisomers that are
non-superimposable mirror images of each other. A 1:1 mixture of a
pair of enantiomers is a "racemic" mixture. The term is used to
designate a racemic mixture where appropriate. "Diastereoisomers"
are stereoisomers that have at least two asymmetric atoms, but
which are not mirror-images of each other. The absolute
stereochemistry is specified according to the Cahn-Ingold-Prelog
R-S system. When a compound is a pure enantiomer the
stereochemistry at each chiral carbon may be specified by either R
or S. Resolved compounds whose absolute configuration is unknown
can be designated (+) or (-) depending on the direction (dextro- or
levorotatory) which they rotate plane polarized light at the
wavelength of the sodium D line. Certain compounds described herein
contain one or more asymmetric centers or axes and may thus give
rise to enantiomers, diastereomers, and other stereoisomeric forms
that may be defined, in terms of absolute stereochemistry, as (R)-
or (S)-.
[0243] Depending on the choice of the starting materials and
procedures, the compounds can be present in the form of one of the
possible isomers or as mixtures thereof, for example as pure
optical isomers, or as isomer mixtures, such as racemates and
diastereoisomer mixtures, depending on the number of asymmetric
carbon atoms. The present invention is meant to include all such
possible isomers, including racemic mixtures, diasteriomeric
mixtures and optically pure forms. Optically active (R)- and
(S)-isomers may be prepared using chiral synthons or chiral
reagents, or resolved using conventional techniques. If the
compound contains a double bond, the substituent may be E or Z
configuration. If the compound contains a disubstituted cycloalkyl,
the cycloalkyl substituent may have a cis- or trans-configuration.
All tautomeric forms are also intended to be included.
[0244] As used herein, the terms "salt" or "salts" refers to an
acid addition or base addition salt of a compound of the invention.
"Salts" include in particular "pharmaceutical acceptable salts".
The term "pharmaceutically acceptable salts" refers to salts that
retain the biological effectiveness and properties of the compounds
of this invention and, which typically are not biologically or
otherwise undesirable. In many cases, the compounds of the present
invention are capable of forming acid and/or base salts by virtue
of the presence of amino and/or carboxyl groups or groups similar
thereto.
[0245] Pharmaceutically acceptable acid addition salts can be
formed with inorganic acids and organic acids, e.g., acetate,
aspartate, benzoate, besylate, bromide/hydrobromide,
bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate,
chloride/hydrochloride, chlortheophyllonate, citrate,
ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate,
hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate,
laurylsulfate, malate, maleate, malonate, mandelate, mesylate,
methylsulphate, naphthoate, napsylate, nicotinate, nitrate,
octadecanoate, oleate, oxalate, palmitate, pamoate,
phosphate/hydrogen phosphate/dihydrogen phosphate,
polygalacturonate, propionate, stearate, succinate,
sulfosalicylate, tartrate, tosylate and trifluoroacetate salts.
[0246] Inorganic acids from which salts can be derived include, for
example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, and the like. Organic acids from which salts
can be derived include, for example, acetic acid, propionic acid,
glycolic acid, oxalic acid, maleic acid, malonic acid, succinic
acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
mandelic acid, methanesulfonic acid, ethanesulfonic acid,
toluenesulfonic acid, sulfosalicylic acid, and the like.
Pharmaceutically acceptable base addition salts can be formed with
inorganic and organic bases.
[0247] Inorganic bases from which salts can be derived include, for
example, ammonium salts and metals from columns I to XII of the
periodic table. In certain embodiments, the salts are derived from
sodium, potassium, ammonium, calcium, magnesium, iron, silver,
zinc, and copper; particularly suitable salts include ammonium,
potassium, sodium, calcium and magnesium salts.
[0248] Organic bases from which salts can be derived include, for
example, primary, secondary, and tertiary amines, substituted
amines including naturally occurring substituted amines, cyclic
amines, basic ion exchange resins, and the like. Certain organic
amines include isopropylamine, benzathine, cholinate,
diethanolamine, diethylamine, lysine, meglumine, piperazine and
tromethamine.
[0249] The pharmaceutically acceptable salts of the present
invention can be synthesized from a basic or acidic moiety, by
conventional chemical methods. Generally, such salts can be
prepared by reacting free acid forms of these compounds with a
stoichiometric amount of the appropriate base (such as Na, Ca, Mg,
or K hydroxide, carbonate, bicarbonate or the like), or by reacting
free base forms of these compounds with a stoichiometric amount of
the appropriate acid. Such reactions are typically carried out in
water or in an organic solvent, or in a mixture of the two.
Generally, use of non-aqueous media like ether, ethyl acetate,
ethanol, isopropanol, or acetonitrile is desirable, where
practicable. Lists of additional suitable salts can be found, e.g.,
in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing
Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical
Salts Properties, Selection, and Use" by Stahl and Wermuth
(Wiley-VCH, Weinheim, Germany, 2002).
[0250] Any formula given herein is also intended to represent
unlabeled forms as well as isotopically labeled forms of the
compounds. Isotopically labeled compounds have structures depicted
by the formulas given herein except that one or more atoms are
replaced by an atom having a selected atomic mass or mass number.
Examples of isotopes that can be incorporated into compounds of the
invention include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorous, fluorine, and chlorine, such as .sup.2H, .sup.3H,
.sup.11C, .sup.13C, .sup.14C, .sup.15N, .sup.18F .sup.31F,
.sup.32F, .sup.35S, .sup.36Cl, .sup.125I respectively. The
invention includes various isotopically labeled compounds as
defined herein, for example those into which radioactive isotopes,
such as .sup.3H and .sup.14C, or those into which non-radioactive
isotopes, such as .sup.2H and .sup.13C are present. Such
isotopically labelled compounds are useful in metabolic studies
(with .sup.14C), reaction kinetic studies (with, for example
.sup.2H or .sup.3H), detection or imaging techniques, such as
positron emission tomography (PET) or single-photon emission
computed tomography (SPECT) including drug or substrate tissue
distribution assays, or in radioactive treatment of patients. In
particular, an .sup.18F or labeled compound may be particularly
desirable for PET or SPECT studies. Isotopically-labeled compounds
of formula (I) can generally be prepared by conventional techniques
known to those skilled in the art or by processes analogous to
those described in the accompanying Examples and Preparations using
an appropriate isotopically-labeled reagents in place of the
non-labeled reagent previously employed.
[0251] Further, substitution with heavier isotopes, particularly
deuterium (i.e., .sup.2H or D) may afford certain therapeutic
advantages resulting from greater metabolic stability, for example
increased in vivo half-life or reduced dosage requirements or an
improvement in therapeutic index. It is understood that deuterium
in this context is regarded as a substituent of a compound of the
formula (I). The concentration of such a heavier isotope,
specifically deuterium, may be defined by the isotopic enrichment
factor. The term "isotopic enrichment factor" as used herein means
the ratio between the isotopic abundance and the natural abundance
of a specified isotope. If a substituent in a compound of this
invention is denoted deuterium, such compound has an isotopic
enrichment factor for each designated deuterium atom of at least
3500 (52.5% deuterium incorporation at each designated deuterium
atom), at least 4000 (60% deuterium incorporation), at least 4500
(67.5% deuterium incorporation), at least 5000 (75% deuterium
incorporation), at least 5500 (82.5% deuterium incorporation), at
least 6000 (90% deuterium incorporation), at least 6333.3 (95%
deuterium incorporation), at least 6466.7 (97% deuterium
incorporation), at least 6600 (99% deuterium incorporation), or at
least 6633.3 (99.5% deuterium incorporation).
[0252] Pharmaceutically acceptable solvates in accordance with the
invention include those wherein the solvent of crystallization may
be isotopically substituted, e.g. D.sub.2O, d.sub.6-acetone,
d.sub.6-DMSO.
[0253] Compounds of the invention, i.e. compounds of formula (I)
that contain groups capable of acting as donors and/or acceptors
for hydrogen bonds may be capable of forming co-crystals with
suitable co-crystal formers. These co-crystals may be prepared from
compounds of formula (I) by known co-crystal forming procedures.
Such procedures include grinding, heating, co-subliming,
co-melting, or contacting in solution compounds of formula (I) with
the co-crystal former under crystallization conditions and
isolating co-crystals thereby formed. Suitable co-crystal formers
include those described in WO 2004/078163. Hence the invention
further provides co-crystals comprising a compound of formula
(I).
[0254] As used herein, the term "pharmaceutically acceptable
carrier" includes any and all solvents, dispersion media, coatings,
surfactants, antioxidants, preservatives (e.g., antibacterial
agents, antifungal agents), isotonic agents, absorption delaying
agents, salts, preservatives, drug stabilizers, binders,
excipients, disintegration agents, lubricants, sweetening agents,
flavoring agents, dyes, and the like and combinations thereof, as
would be known to those skilled in the art (see, for example,
Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing
Company, 1990, pp. 1289-1329). Except insofar as any conventional
carrier is incompatible with the active ingredient, its use in the
therapeutic or pharmaceutical compositions is contemplated.
[0255] The term "a therapeutically effective amount" of a compound
of the present invention refers to an amount of the compound of the
present invention that will elicit the biological or medical
response of a subject, for example, reduction or inhibition of an
enzyme or a protein activity, or ameliorate symptoms, alleviate
conditions, slow or delay disease progression, or prevent a
disease, etc. In one non-limiting embodiment, the term "a
therapeutically effective amount" refers to the amount of the
compound of the present invention that, when administered to a
subject, is effective to (1) at least partially alleviate, inhibit,
prevent and/or ameliorate a condition, or a disorder or a disease
(i) mediated by Plasdmodium or (ii) associated with Plasdmodium
activity, or (iii) characterized by activity (normal or abnormal)
of Plasdmodium or (2) reduce or inhibit the activity of
Plasdmodium; or (3) reduce or inhibit the growth of Plasdmodium. In
another non-limiting embodiment, the term "a therapeutically
effective amount" refers to the amount of the compound of the
present invention that, when administered to a cell, or a tissue,
or a non-cellular biological material, or a medium, is effective to
at least partially reducing or inhibiting the activity of
Plasdmodium; or at least partially reducing or inhibiting the
growth of Plasdmodium.
[0256] As used herein, the term "subject" refers to an animal.
Typically the animal is a mammal. A subject also refers to for
example, primates (e.g., humans, male or female), cows, sheep,
goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the
like. In certain embodiments, the subject is a primate. In yet
other embodiments, the subject is a human.
[0257] As used herein, the term "inhibit", "inhibition" or
"inhibiting" refers to the reduction or suppression of a given
condition, symptom, or disorder, or disease, or a significant
decrease in the baseline activity of a biological activity or
process.
[0258] As used herein, the term "treat", "treating" or "treatment"
of any disease or disorder refers in one embodiment, to
ameliorating the disease or disorder (i.e., slowing or arresting or
reducing the development of the disease or at least one of the
clinical symptoms thereof). In another embodiment "treat",
"treating" or "treatment" refers to alleviating or ameliorating at
least one physical parameter including those which may not be
discernible by the patient. In yet another embodiment, "treat",
"treating" or "treatment" refers to modulating the disease or
disorder, either physically, (e.g., stabilization of a discernible
symptom), physiologically, (e.g., stabilization of a physical
parameter), or both. In yet another embodiment, "treat", "treating"
or "treatment" refers to preventing or delaying the onset or
development or progression of the disease or disorder.
[0259] As used herein, a subject is "in need of" a treatment if
such subject would benefit biologically, medically or in quality of
life from such treatment.
[0260] As used herein, the term "a," "an," "the" and similar terms
used in the context of the present invention (especially in the
context of the claims) are to be construed to cover both the
singular and plural unless otherwise indicated herein or clearly
contradicted by the context.
[0261] All methods described herein can be performed in any
suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g. "such as") provided herein is intended
merely to better illuminate the invention and does not pose a
limitation on the scope of the invention otherwise claimed.
[0262] Any asymmetric atom (e.g., carbon or the like) of the
compound(s) of the present invention can be present in racemic or
enantiomerically enriched, for example the (R)-, (S)- or
(R,S)-configuration. In certain embodiments, each asymmetric atom
has at least 50% enantiomeric excess, at least 60% enantiomeric
excess, at least 70% enantiomeric excess, at least 80% enantiomeric
excess, at least 90% enantiomeric excess, at least 95% enantiomeric
excess, or at least 99% enantiomeric excess in the (R)- or
(S)-configuration. Substituents at atoms with unsaturated double
bonds may, if possible, be present in cis-(Z)- or
trans-(E)-form.
[0263] Accordingly, as used herein a compound of the present
invention can be in the form of one of the possible isomers,
rotamers, atropisomers, tautomers or mixtures thereof, for example,
as substantially pure geometric (cis or trans) isomers,
diastereomers, optical isomers (antipodes), racemates or mixtures
thereof.
[0264] Any resulting mixtures of isomers can be separated on the
basis of the physicochemical differences of the constituents, into
the pure or substantially pure geometric or optical isomers,
diastereomers, racemates, for example, by chromatography and/or
fractional crystallization.
[0265] Any resulting racemates of final products or intermediates
can be resolved into the optical antipodes by known methods, e.g.,
by separation of the diastereomeric salts thereof, obtained with an
optically active acid or base, and liberating the optically active
acidic or basic compound. In particular, a basic moiety may thus be
employed to resolve the compounds of the present invention into
their optical antipodes, e.g., by fractional crystallization of a
salt formed with an optically active acid, e.g., tartaric acid,
dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluoyl
tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic
acid. Racemic products can also be resolved by chiral
chromatography, e.g., high pressure liquid chromatography (HPLC)
using a chiral adsorbent.
[0266] Furthermore, the compounds of the present invention,
including their salts, can also be obtained in the form of their
hydrates, or include other solvents used for their crystallization.
The compounds of the present invention may inherently or by design
form solvates with pharmaceutically acceptable solvents (including
water); therefore, it is intended that the invention embrace both
solvated and unsolvated forms. The term "solvate" refers to a
molecular complex of a compound of the present invention (including
pharmaceutically acceptable salts thereof) with one or more solvent
molecules. Such solvent molecules are those commonly used in the
pharmaceutical art, which are known to be innocuous to the
recipient, e.g., water, ethanol, and the like. The term "hydrate"
refers to the complex where the solvent molecule is water.
[0267] The compounds of the present invention, including salts,
hydrates and solvates thereof, may inherently or by design form
polymorphs.
[0268] The present invention also includes processes for the
preparation of compounds of the invention. In the reactions
described, it can be necessary to protect reactive functional
groups, for example hydroxy, amino, imino, thio or carboxy groups,
where these are desired in the final product, to avoid their
unwanted participation in the reactions. Conventional protecting
groups can be used in accordance with standard practice, for
example, see T. W. Greene and P. G. M. Wuts in "Protective Groups
in Organic Synthesis", John Wiley and Sons, 1991.
[0269] Typically, the compounds of formula (I) can be prepared
according to synthetic routes 1-6 provided infra., where Ring A,
Ring C, R.sub.1, R.sub.2, R.sub.17, n and p are as defined in the
Summary of the Invention. The following reaction schemes are given
to be illustrative, not limiting, descriptions of the synthesis of
compounds of the invention. Detailed descriptions of the synthesis
of compounds of the invention are given in the Examples, infra.
General Synthetic Route I
##STR00037## ##STR00038##
[0270] Reaction Conditions:
[0271] a. mild heating in a polar, aprotic solvent such as DMF,
NMP, DMA or DMSO; [0272] b. base such as K.sub.2CO.sub.3 or
Na.sub.2CO.sub.3 in a polar organic solvent such as DMF, NMP or
DMSO; [0273] c. esters can be hydrolyzed under conventional acidic
or basic conditions; decarboxylation occurs when the di-acid is
heated at 50-100.degree. C.; [0274] d. esterification can be done
in alcohol (MeOH, EtOH) using acid catalysis (AcCl or TMSCl to
generate HCl, or catalytic H.sub.2SO.sub.4 or toluene sulfonic
acid, for example); [0275] e. N-bromosuccinimide (NBS) or similar
brominating agent in CH.sub.2Cl.sub.2, CHCl.sub.3 or CCl.sub.4 at
-78.degree. C. to room temperature; [0276] f. conventional
base-catalyzed hydrolysis in aqueous alcohol solvent; [0277] g. the
carboxylic acid can be activated by various known methods, e.g.,
forming an acid chloride using oxalyl chloride or thionyl chloride
and DMF followed by acylation of an amine of formula
[0277] ##STR00039## in a non-reactive solvent using an amine bse
such as Et.sub.3N, DIEA (Hunig's base) or DMAP
(dimethylaminopyridine). Various amide coupling reagents such as
dicyclohexyl carbodiimide can also be used; and [0278] h.
Pd-catalyzed Suzuki coupling.
General Synthetic Route 2
##STR00040##
[0279] Reaction Conditions:
[0280] a. mild heating in a polar, aprotic solvent such as DMF,
NMP, DMA or DMSO; [0281] b. base such as K.sub.2CO.sub.3 or
Na.sub.2CO.sub.3 in a polar organic solvent such as DMF, NMP or
DMSO; [0282] c. conventional base-catalyzed hydrolysis in aqueous
alcohol solvent.
[0283] Ring C can then be added using known methods, such as amide
formation to link the carboxylic acid with an amine of formula
##STR00041##
General Synthetic Route 3
##STR00042##
[0284] Reaction Conditions:
[0285] a. Curtius rearrangement of carboxylic acid using diphenyl
phosphoryl azide, t-butyl alcohol and an appropriate base. [0286]
b. optionally exchanged hydrogen on the carbamate with an R.sub.2
group by reacting with and R.sub.2X group where X is a leaving
group (such as Cl), in basic DMF at room temperature or lightly
elevated temperature for a few hours; [0287] c. Acidic cleavage of
t-butyl carbamate [0288] d. acylation with acid chlorides in
dichloromethane/triethylamine at room temperature.
General Synthetic Route 4
##STR00043##
[0290] Ring A may be added by known methods such as the Suzuki
coupling illustrated in Synthetic Route 1.
General Synthetic Route 5
##STR00044##
[0292] The amine intermediate (Step c of Synthetic Route 3) may be
alkylated with the Ring C moiety (where X is a leaving group, such
as Cl, Br or I, or a sulfonate ester such as MeSO.sub.3-- TsO--,
and the like) in an organic solvent, with a catalytic amount of
DMAP and a non-nucleophilic base, at 0.degree. C. to mild heating.
Typical organic solvent includes halogenated solvents like DCM or
CHCl.sub.3; ether solvents such as THF, dioxane, MTBE, diethyl
ether. Typical non-nucleophilic base includes triethylamine,
diisopropyl ethylamine, potassium t-butoxide, potassium carbonate,
and the like.
General Synthetic Route 6
##STR00045##
[0294] Ring A may be then added by known methods such as the Suzuki
coupling illustrated in Synthetic Route I.
General Procedures for Boronic Ester Synthesis
##STR00046##
[0295] Boronic Ester Synthesis Procedure A:
PdCl.sub.2(dppf).CH.sub.2Cl.sub.2;
[0296] A mixture of bromo compound (1.0 eq.) and
bis(pinacolato)diboron (1.1 eq.) and potassium acetate (2.0 eq.)
dissolved in 1,4-dioxane (10 vol) was degassed with argon gas for
15 min. Subsequently, PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (0.05 eq.)
was added and the reaction mixture was stirred at 85-100.degree. C.
for 16 h. The reaction mixture (generally black color) was filtered
and concentrated under reduced pressure. The resulting black
mixture was used further without any purification.
Boronic Ester Synthesis Procedure B: Pd(PPh.sub.3).sub.4;
[0297] A mixture of bromo compound (1.0 eq.) and
bis(pinacolato)diboron (1.1 eq.), and potassium acetate (2.0 eq.)
dissolved in 1,4-dioxane (10 vol) was degassed with argon gas for
15 min. Subsequently, Pd.sub.2(dba).sub.3 (0.05 eq.) and
tricyclohexyl phosphine (0.05 eq.) were added and the reaction
mixture was stirred at 90-110.degree. C. for 16 h. The reaction
mixture (generally black color) was filtered and concentrated under
reduced pressure. The crude product was used further without any
purification.
General Procedures for Suzuki Couplings
##STR00047##
[0298] Suzuki Procedure A: SiliaCat.RTM. DPP-Pd and
K.sub.2CO.sub.3:
[0299] A mixture of bromo compound (51 mg, 0.2 mmol, 1.0 equiv.),
boronic acid (0.22 mmol, 1.1 equiv.), and SiliaCat.RTM. DPP-Pd
(0.25 mmol/g loading, 34 mg, 0.01 mmol, 0.05 equiv.) was treated
with 660 .mu.L dioxane and 220 .mu.L 1 M aq. K.sub.2CO.sub.3 and
the resulting mixture was allowed to heat overnight at 100 cc in a
capped vial. The resulting black mixture was dry-loaded onto silica
gel and was purified by silica gel chromatography, eluting with
hexanes/EtOAc to give the desired product.
Suzuki Procedure B: Pd(dppf)Cl.sub.2 and K.sub.2CO.sub.3 in the
Microwave:
[0300] A mixture of aryl bromide (1.0 equiv.), aryl boronic acid
(1.5 equiv.), K.sub.2CO.sub.3 (2.5 equiv.), and Pd(dppf)Cl.sub.2
(0.05-0.15 equiv.) in THF/water was allowed to heat at 140.degree.
C. in a microwave reactor for 40 minutes. Purified by
mass-triggered HPLC or silica gel chromatography to provide the
desired product.
Suzuki Procedure C: SiliaCat.RTM. DPP-Pd/Pd(dppf)Cl.sub.2 and
K.sub.2HPO.sub.4 in the Microwave:
[0301] A mixture of aryl bromide (1.0 equiv.), aryl boronic acid
(1.5 equiv.), KH.sub.2PO.sub.4 (3.5 equiv.), and SiliaCat.RTM.
DPP-Pd or Pd(dppf)Cl.sub.2 (0.05-0.15 equiv.) in THF/water was
allowed to heat at 150.degree. C. in a microwave reactor for 40-60
minutes. Purified by mass-triggered HPLC or silica gel
chromatography to provide the desired product.
Suzuki Procedure D: Pd(dppf)Cl.sub.2, K.sub.2CO.sub.3,
DME-WATER:
[0302] A mixture of aryl bromide (1.0 equiv.), aryl boronic acid
(1.5 equiv.), K.sub.2CO.sub.3 (3.0 equiv.), and Pd(dppf)Cl.sub.2
(0.05-0.15 equiv.) in DME/water was allowed to heat at 110.degree.
C. for two hours. Following extraction of the reaction mixture with
CH.sub.2Cl.sub.2, the combined organic extracts were concentrated
and the residue was purified by silica gel chromatography, eluting
with hexanes/EtOAc to give the desired product.
##STR00048##
Suzuki Procedure E: Pd.sub.2(dba).sub.3, P(O-tolyl).sub.3, 2M KF
Solution in Toluene/Ethanol:
[0303] A mixture of aryl bromide (1.0 equiv.), aryl boronic acid
(1.2-2.0 equiv.), 2 M aq KF (3 equiv.), and Pd.sub.2(dba).sub.3
(0.1 equiv.), P(o-tolyl).sub.3 (0.1 equiv.) in toluene:ethanol
(7:3) was degassed and heated to 100.degree. C. for 1-5 h. The
crude products were purified by preparative TLC or silica gel
chromatography to provide the desired product.
Suzuki Procedure F: Pd(PPh.sub.3).sub.4, 1N Na.sub.2CO.sub.3,
dioxane:
[0304] A mixture of aryl bromide (1.0 equiv.), aryl boronic acid
(1.2-2.0 equiv.), 1 N Na.sub.2CO.sub.3 (2.0 equiv.), and
Pd(PPh.sub.3).sub.4 (0.2 equiv.) in 1,4-dioxane was degassed and
heated in a sealed tube to 100.degree. C. (microwave or convential
heating) for 2-6 h. The crude products were purified by preparative
TLC or silica gel chromatography to provide the desired
product.
[0305] The invention further includes any variant of the present
processes, in which an intermediate product obtainable at any stage
thereof is used as starting material and the remaining steps are
carried out, or in which the starting materials are formed in situ
under the reaction conditions, or in which the reaction components
are used in the form of their salts or optically pure material.
[0306] Compounds of the invention and intermediates can also be
converted into each other according to methods generally known to
those skilled in the art.
[0307] Compounds of the invention are useful in the treatment
and/or prevention of infections such as those caused by Plasmodium
falciparum; Plasmodium vivax; Plasmodium ovale; and Plasmodium
malaria, Trypanosoma cruzi and parasites of the Leishmania genus,
such as, for example, Leishmania donovani.
[0308] Plasmodia spp. which causes malaria belong to the phylum,
Apicomplexa, which is a large and diverse group of protists that
are human or animal parasites. These parasites are unicellular,
spore-forming, and possess motile structures such as flagella or
pseudopods at certain gamete stages. Most of these parasites
possess a unique organelle called apicoplast and an apical comples
structure involved in penetrating a host's cell. The pathogenesis
associated the diseases caused by these parasites is due to
repeated cycles of host-cell invasion, intracellular replication
and host-cell lysis. Therefore, understanding parasite
proliferation is essential for development of novel drugs and
vaccines, for example, to treat malaria.
[0309] In vertebrate hosts, the parasite undergoes two main phases
of development, the hepathocytic and erythrocytic phases, but it is
the erythrocytic phase of its life cycle that causes severe
pathology. During the erythrocytic phase, the parasite goes through
a complex but well synchronized series of stages, suggesting the
existence of tightly regulated signaling pathways.
[0310] Calcium serves as an intracellular messenger to control
synchronization and development in the erythrocytic life phase. The
Plasmodium spp. genomes reveal many sequence identities with
calcium binding/sensing protein motifs that include Pf39,
calmodulin, and calcium dependent protein kinases (CDPKs).
Plasmodium CDPKs, Plasmodium CDPK3 and 4, have been shown to be
involved in mosquito infection. CDPK4 has been demonstrated to be
essential for the sexual reproduction in the midgut of mosquito by
translating the calcium signal into a cellular response and
regulating cell cycle progression in the male gametocyte. CDPK3
regulates ookinete gliding motility and penetration of the layer
covering the midgut epithelium. P. falciparum CDPK1 (PfCDPK1) is
expressed during late schizogony of blood stage and in the
infectious sporozoite stage and is secreted to the parasitophorous
vacuole by an acylation-dependent mechanism. It can be
myristoylated and is abundantly found in detergent-resistant
membrane fractions isolated from schizogony-phase parasites.
Ontology based pattern identification analysis reveals that PfCDPK1
is clustered with genes associated with either parasite egress or
erythrocyte invasion. Direct inhibition of PfCDPK1 can arrest the
parasite erythrocytic life cycle progression in the late schizogony
phase.
[0311] Therefore, kinase activity is distributed in all the stages
of P. falciparum parasite maturation and kinase inhibitors of the
present invention can be used for treating Plasmodium related
diseases.
[0312] The in vitro cellular assay, infra, can be used to assess
the activity of compounds of the invention against a variety of
malarial parasite strains.
[0313] In accordance with the foregoing, the present invention
further provides a method for preventing or treating malaria in a
subject in need of such treatment, which method comprises
administering to the subject a therapeutically effective amount of
a compound selected from Formula I and Ia or a pharmaceutically
acceptable salt, tautomer or stereoisomer, thereof. The required
dosage will vary depending on the mode of administration, the
particular condition to be treated and the effect desired.
[0314] In general, compounds of the invention will be administered
in therapeutically effective amounts via any of the usual and
acceptable modes known in the art, either singly or in combination
with one or more therapeutic agents. A therapeutically effective
amount may vary widely depending on the severity of the disease,
the age and relative health of the subject, the potency of the
compound used and other factors. In general, satisfactory results
are indicated to be obtained systemically at daily dosages of from
about 0.03 to 2.5 mg/kg per body weight. An indicated daily dosage
in the larger mammal, e.g. humans, is in the range from about 0.5
mg to about 100 mg, conveniently administered, e.g. in divided
doses up to four times a day or in retard form. Suitable unit
dosage forms for oral administration comprise from ca. 1 to 50 mg
active ingredient.
[0315] Compounds of the invention can be administered as
pharmaceutical compositions by any conventional route, in
particular enterally, e.g., orally, e.g., in the form of tablets or
capsules, or parenterally, e.g., in the form of injectable
solutions or suspensions, topically, e.g., in the form of lotions,
gels, ointments or creams, or in a nasal or suppository form.
Pharmaceutical compositions comprising a compound of the present
invention in free form or in a pharmaceutically acceptable salt
form in association with at least one pharmaceutically acceptable
carrier or diluent can be manufactured in a conventional manner by
mixing, granulating or coating methods. For example, oral
compositions can be tablets or gelatin capsules comprising the
active ingredient together with a) diluents, e.g., lactose,
dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b)
lubricants, e.g., silica, talcum, stearic acid, its magnesium or
calcium salt and/or polyethyleneglycol; for tablets also c)
binders, e.g., magnesium aluminum silicate, starch paste, gelatin,
tragacanth, methylcellulose, sodium carboxymethylcellulose and or
polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches,
agar, alginic acid or its sodium salt, or effervescent mixtures;
and/or e) absorbents, colorants, flavors and sweeteners. Injectable
compositions can be aqueous isotonic solutions or suspensions, and
suppositories can be prepared from fatty emulsions or suspensions.
The compositions may be sterilized and/or contain adjuvants, such
as preserving, stabilizing, wetting or emulsifying agents, solution
promoters, salts for regulating the osmotic pressure and/or
buffers. In addition, they may also contain other therapeutically
valuable substances. Suitable formulations for transdermal
applications include an effective amount of a compound of the
present invention with a carrier. A carrier can include absorbable
pharmacologically acceptable solvents to assist passage through the
skin of the host. For example, transdermal devices are in the form
of a bandage comprising a backing member, a reservoir containing
the compound optionally with carriers, optionally a rate
controlling barrier to deliver the compound to the skin of the host
at a controlled and predetermined rate over a prolonged period of
time, and means to secure the device to the skin. Matrix
transdermal formulations may also be used. Suitable formulations
for topical application, e.g., to the skin and eyes, are preferably
aqueous solutions, ointments, creams or gels well-known in the art.
Such may contain solubilizers, stabilizers, tonicity enhancing
agents, buffers and preservatives.
[0316] Compounds of the invention can be administered in
therapeutically effective amounts in combination with one or more
therapeutic agents (pharmaceutical combinations). Non-limiting
examples of compounds which can be used in combination with
compounds of the invention are known anti-malarial drugs, for
example, artemisinin, artemether, artesunate, arteflene,
dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine,
quinine, mefloquine, amodiaquine, atovaquone, proguanil,
lumefantrine, piperaquine, pyronaridine, halofantrine,
pyrimethamine-sulfadoxine, quinacrine, pyrimethamine-dapsone,
quinidine, amopyroquine, sulphonamides, primaquine, ferroquine,
tafenoquine, arterolane, and pyronaridine, etc.
[0317] Where the compounds of the invention are administered in
conjunction with other therapies, dosages of the co-administered
compounds will of course vary depending on the type of co-drug
employed, on the specific drug employed, on the condition being
treated and so forth.
[0318] The invention also provides for a pharmaceutical
combinations, e.g. a kit, comprising a) a first agent which is a
compound of the invention as disclosed herein, in free form or in
pharmaceutically acceptable salt form, and b) at least one
co-agent. The kit can comprise instructions for its
administration.
[0319] The terms "co-administration" or "combined administration"
or the like as utilized herein are meant to encompass
administration of the selected therapeutic agents to a single
patient, and are intended to include treatment regimens in which
the agents are not necessarily administered by the same route of
administration or at the same time.
[0320] The term "pharmaceutical combination" as used herein means a
product that results from the mixing or combining of more than one
active ingredient and includes both fixed and non-fixed
combinations of the active ingredients. The term "fixed
combination" means that the active ingredients, e.g. a compound of
Formula I and a co-agent, are both administered to a patient
simultaneously in the form of a single entity or dosage. The term
"non-fixed combination" means that the active ingredients, e.g. a
compound of Formula I and a co-agent, are both administered to a
patient as separate entities either simultaneously, concurrently or
sequentially with no specific time limits, wherein such
administration provides therapeutically effective levels of the 2
compounds in the body of the patient. The latter also applies to
cocktail therapy, e.g. the administration of 3 or more active
ingredients.
Biological Assays
[0321] The activity of a compound according to the present
invention for inhibition of parasitemai in infected blood cells and
liver cells can be assessed by the following assays. It is
understood that the assays illustrate the invention without in any
way limiting the scope of the invention.
Assay for P. falciparum Proliferation in Infected Human Blood
Cells
[0322] Compounds of the invention can be assayed to measure their
capacity to inhibit proliferation of P. falciparum parasitemia in
infected red blood cells. This parasite proliferation assay
measures the increase in parasite DNA content using a DNA
intercalating dye, SYBR Green.RTM. (INVITROGEN.RTM.) which has a
high affinity for double stranded DNA.
[0323] NF54 or 3D7 P. falciparum strain is grown in complete
culturing media until parasitemia reaches 3% to 8% with O+ human
erythrocytes. The selection of either strain is of convenience (3D7
is a clone of NF54) and does not make a difference to the assay. 20
.mu.l of screening media is dispensed into 384 well assay plates.
50 nl of compounds of the invention (in DMSO), including
antimalarial controls (mefloquine, pyrimethamine and artemisinin),
are then transferred into the assay plates, as well as DMSO alone
to serve as a negative control for inhibition. Then 30 .mu.l of a
suspension of a NF54 or 3D7 P. falciparum infected erythrocytes in
screening media is dispensed into the assay plates such that the
final hematocrit is 2.5% with a final parasitemia of 0.3%. The
plates are placed in a 37.degree. C. incubator for 72 hours in a
low oxygen environment containing 93% N.sub.2, 4% CO.sub.2, and 3%
O.sub.2 gas mixture. 10 .mu.l of lysis buffer (saponin, triton-X,
EDTA) containing a 10.times. solution of SYBR Green I.RTM. in RPMI
media is dispensed into the plates. The plates are lidded and kept
at room temperature overnight for the lysis of the infected red
blood cells. The fluorescence intensity is measured (excitation 425
nm, emission 530 nm) using the Envision.TM. system (Perkin Elmer).
The percentage inhibition of 50%, EC.sub.50, is calculated for each
compound.
[0324] Using the P. falciparum Proliferation Assay above, compounds
of the invention exhibit inhibitory efficacy (EC.sub.50) of
typically 10 .mu.M or less, more typically less than 1 .mu.M, most
typically less than 200 nM. Compounds of the invention can
significantly delay the increase in P. falciparum parasitemia. For
example,
3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyri-
dine-5-carboxamide (Example 32),
N-(4-cyanophenyl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5--
a]pyridine-5-carboxamide (Example 40),
3-(6-aminopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-
-5-carboxamide (Example 41),
(R)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1-
,5-a]pyridine-5-carboxamide (Example 44),
N-(5-cyanopyridin-2-yl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-
o[1,5-a]pyridine-5-carboxamide (Example 53),
N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,-
5-a]pyridine-5-carboxamide (Example 75), and
3-(2-aminopyrimidin-5-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridi-
ne-5-carboxamide (Example 83) all have EC.sub.50 values of less
than 5 nM.
[0325] The inhibitory efficacy of the compounds of the invention in
delaying the increase in P. falciparum parasitemia in infected
human blood cells is provided in Table 1.
TABLE-US-00001 TABLE 1 Inhibitory Efficacy of Compounds of the
Invention in delaying P. falciparum Proliferation in Infected Human
Blood Cells Example EC50 No. (nM) 1 8 2 342 3 94 4 46 5 88 6 284 7
975 8 532 9 6 10 7 11 6 12 9 13 8 14 134 15 2318 16 477 17 3 18 3
19 1 20 9 21 472 22 25 23 2 24 10 25 7 26 22 27 10 28 7 29 150 30
62 31 143 32 1 33 59 34 22 35 2044 36 390 37 121 38 179 39 831 40 1
41 2 42 18 43 9 44 1 45 16 46 18 47 >9000 48 288 49 2290 50 3850
51 60 52 13 53 1 54 9 55 32 56 8 57 4 58 30 59 228 60 683 61 20 62
ND 63 6 64 20 65 504 66 49 67 5 68 6750 69 13 71 3 72 5 73
>10,000 74 52 75 4 76 82 77 146 79 7 80 824 81 36 82 1160 83 4
84 6 85 16 86 10 87 41 88 83 89 6
Assay for Profiferation of Parasite in Infected Liver Cells
[0326] Compounds of the invention can be assayed to measure their
capacity to inhibit proliferation of parasites in liver cells. The
proliferation is quantified by determine the number of infected
cells by immunofluorescence.
Parasites
[0327] Due to the difficulty of successfully infecting immortalized
human liver cell lines with the human malaria sporozoites
(liver-stage parasite), rodent malaria sporozoites from Plasmodium
yoelii (17XNL) and P. berghei (ANKA) are the preferred surrogate.
Sporozoites are obtained from Anopheles stephensi mosquitoes
supplied by the New York University Insectary, which ships the
malaria-infected mosquitoes 10-13 days following the ingestion of
an infective blood meal.
Cell Line
[0328] A transgenic HepG2 cell line expressing the tetraspanin CD81
receptor (HepG2-A16-CD81.sup.EGFP) is used to increase the
infectivity rate of rodent-malaria sporozoites into human cells.
HepG2-A16-CD81.sup.EGFP cells are stably transformed to express a
GFP-CD81 fusion protein. A continuous in vitro culture of this line
was maintained at 37.degree. C. in 4% CO.sub.2 in complete media
(CM) which contains: DMEM (Invitrogen, Carlsbad, USA) supplemented
with 10% FCS, 0.29 mg/ml glutamine, 100 units penicillin and 100
.mu.g/ml streptomycin (SigmaAldrich, USA).
P. yoelii Sporozoite Invasion Assay
[0329] Twenty to twenty-six hours prior to sporozoite infection,
7.5.times.10.sup.3 HepG2-A16-CD81.sup.EGFP cells are seeded into
384-well plates (Aurora 384 IQ-EB black plates with clear bottoms;
50 .mu.l of 1.5.times.10.sup.5 cells/ml in CM). These plates are
incubated at 37.degree. C. with 4% CO.sub.2 overnight. Two hours
prior to infection, 50 nl of compound dissolved in DMSO (0.1% final
DMSO concentration per well) were transferred with a PinTool (GNF
Systems) into the assay plates (10 .mu.M final concentration). A
1:3 serial dilution of atovaquone (10 .mu.M at the highest final
concentration) and wells treated only with DMSO were used as
positive and negative controls, respectively.
[0330] Freshly dissected salivary glands from infected mosquitoes
were homogenized in a glass tissue grinder, filtered twice through
Nylon cell strainers (40 .mu.m pore size, BD Falcon) and counted
using a hemocytometer. The assay plate with HepG2-A16-CD81.sup.EGFP
cells and compound were then infected with 8.times.10.sup.3
sporozoitesper well and the plates are subjected to a centrifugal
force of 650.times.g to pellet the sporozoites onto the liver cell
monolayer. The assay plate is incubated at 37.degree. C. for 2
hours to permit sporozoite invasion, then the media is aspirated
from the media plate, and replaced with 50 .mu.l CM (containing a
5.times. concentration of penicillin/streptomycin; 500 units
penicillin and 0.5 mg streptomycin per ml) per well. 50 nl of
compound is re-introduced by PinTool and the assay plate incubated
for 48 hours at 37.degree. C. before quantification of infected
cells by immunofluorescence. The increased antibiotic concentration
does not interfere with the parasite or HepG2-A16-CD81.sup.EGFP
growth.
[0331] Atovaquone and uninfected wells were used as controls on
each plate. Two replicate plates are tested for each assay.
Immunofluorescence Quantification of Exo-Erythrocytic Forms
(EEFs)
[0332] After fixing the cells by addition of 12.5 .mu.l of 20%
solution of paraformaldehyde (EMS, Hatfield, USA) to each assay
well (4% final formaldehyde concentration), membranes were
permeabilized with 0.5% Triton-X-100 (Thermo Fisher Scientific) and
EEFs were stained using a mouse polyclonal serum raised against the
Plasmodium yoelii heat shock protein 70 (PyHSP70), a DyLight 649
goat anti-mouse IgG, Fc(gamma) fragment specific secondary antibody
(Jackson Immuno Research, Cat#115-495-071) and the Hoechst 33342
nucleic acid dye (Invitrogen, Carlsbad, USA). Stained EEFs were
then quantified using the Opera Confocal High Content Screening
System (Perkin Elmer, Waltham, USA). Images were collected using a
20.times. objective lens (20.times./0.45 NA, LWD Plan Fluor,
Olympus) at a binning of 2, using a 365 nm Xeon arc lamp
illumination to detect the Hoechst-labeled nuclei and 635 nm laser
line to excite DyLight649-labeled parasites. The image resolution
yielded was approximately 0.66 .mu.m/pixel (.about.0.43 .mu.m
2/pixel). All images were analyzed using a custom Acapella.TM.
(PerkinElmer) script parametrized for this assay. In brief, images
from fields inside the well were first discarded as out-of focus
when the intensity in the nuclear channel was too low. Then,
HepG2-A16-CD81.sup.EGFP cells were counted by detecting the nuclei
labeled with Hoechst using the nuclei detection libraries available
with Acapella.TM.. Parasites were later segmented using the
.alpha.PyHSP70 immuno-labeling signal, using a custom script
library. Once the objects were segmented from the picture,
morphological-based (e.g. size, roundness, etc) and intensity-based
features were measured for each object detected in the image (i.e.
nuclei and parasites). Infection ratio was set as the ratio between
parasite number and number of nuclei counted in images considered
as "in-focus". EC.sub.50 values were obtained using parasite area
and a custom curve fitting model, and a standard logistic
regression model was applied for curve fitting.
[0333] Using the P. yoelii Sporozoite Invasion Assay, compounds of
the invention exhibit inhibitory efficacy (EC.sub.50) of typically
500 nM or less, more typically less than 200 nM, most typically
less than 10 nM. Compounds of the invention show significantly
delay of the proliferation of P. yoelii in liver cells. For example
N-(4-cyanophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]py-
ridine-5-carboxamide (Example 1),
3-(4-carbamoylphenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-
-carboxamide (Example 19),
3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyri-
dine-5-carboxamide (Example 32),
3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyri-
dine-5-carboxamide (Example 67), and
N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,-
5-a]pyridine-5-carboxamide (Example 75) all have EC.sub.50 of less
than 10 nM.
[0334] Inhibitory efficacy of selected compounds in delaying the
proliferation of P. yoelii Sporozoite in liver cells is listed in
Table 2.
TABLE-US-00002 TABLE 2 Inhibitory Efficacy of Compounds of the
Invention by the P. yoelii Sporozoite Invasion Assay Example
EC.sub.50 Example EC50 Example EC.sub.50 No. (nM) No. (nM) No. (nM)
1 7.3 27 201 41 14.3 13 17.9 28 23.2 54 79 19 4.3 32 8.0 67 4.6 20
13.5 34 53.2 75 2.25 25 229 40 63.1
EXAMPLES
[0335] The present invention is further exemplified, but not to be
limited, by the following examples and intermediates that
illustrate the preparation of compounds of the invention. It is
understood that if there appears to be a discrepancy between the
name and structure of a particular compound, the structure is to be
considered correct as the compound names were generated from the
structures.
[0336] Temperatures are given in degrees Celsius. If not mentioned
otherwise, all evaporations are performed under reduced pressure,
typically between about 15 mm Hg and 100 mm Hg (=20-133 mbar). The
structure of final products, intermediates and starting materials
is confirmed by standard analytical methods, e.g., microanalysis
and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations
used are those conventional in the art.
[0337] All starting materials, building blocks, reagents, acids,
bases, dehydrating agents, solvents, and catalysts utilized to
synthesis the compounds of the present invention are either
commercially available or can be produced by organic synthesis
methods known to one of ordinary skill in the art (Houben-Weyl 4th
Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21).
Further, the compounds of the present invention can be produced by
organic synthesis methods known to one of ordinary skill in the art
as shown in the following examples.
LC-MS Methods
Method 1:
[0338] Waters Acquity Binary Gradient Pump; Waters Acquity PDA
Detector. Waters Auto sampler; Waters Quattro micro API Mass
Spectrometer with ESI and APCI ion source; UPLC Column: Waters
Acquity; BEH; C18 1.7 um 50.times.2.1 mm; Mobile Phase: (A)
H.sub.2O+0.025% TFA and (B) Acetonitrile+0.025% TFA. Gradient: 0.4
mL/minute, initial 15% B ramp to 95% B over 3.0 minutes, then hold
until 4.0 minutes, return to 15% B at 4.1 minutes until end of run,
then equilibrated the column for 2.0 minutes; MS Scan: 100 to 1000
amu in 0.5 seconds per channel; Diode Array Detector: 200 nm and
400 nm.
Method 2:
[0339] Waters Acquity Binary Gradient Pump; Waters Acquity PDA
Detector. Waters Auto sampler; Waters Quattro micro API Mass
Spectrometer with ESI and APCI ion source; UPLC Column: Waters
Acquity; BEH; C18 1.7 um 50.times.2.1 mm; Mobile Phase: (A)
H.sub.2O+0.025% TFA and (B) Acetonitrile+0.025% TFA. Gradient: 0.4
mL/minute, initial 20% B ramp to 90% B over 2.0 minutes, then hold
until 4.0 minutes, return to 20% B at 4.1 minutes until end of run,
then equilibrated the column for 2.0 minutes; MS Scan: 100 to 1000
amu in 0.5 seconds per channel; Diode Array Detector: 200 nm and
400 nm.
Method 3:
[0340] Waters Acquity Binary Gradient Pump; Waters Acquity PDA
Detector. Waters Auto sampler; Waters Acquity Evaporative Light
Scattering Detector; Waters Quattro micro API Mass Spectrometer
with ESI and APCI ion source; UPLC Column: Waters Acquity; BEH; C18
1.7 um 100.times.2.1 mm; Mobile Phase: (A) H.sub.2O+0.025% TFA and
(B) Acetonitrile+0.025% TFA. Gradient: 0.3 mL/minute, initial 10% B
ramp to 80% B over 4.0 minutes, then hold until 6.0 minutes, return
to 10% B at 6.1 minutes until end of run, then equilibrated the
column for 2.5 minutes; MS Scan: 100 to 1000 amu in 0.5 seconds per
channel; Diode Array Detector: 200 nm and 400 nm; Drift tube
temperature: 50.degree. C. and N2 gas flow: 40 Psi for ELSD
Detector.
Method 4:
[0341] Waters Acquity Binary Gradient Pump; Waters Acquity PDA
Detector. Waters Auto sampler; Waters Quattro micro API Mass
Spectrometer with ESI and APCI ion source; UPLC Column: Waters
Acquity; BEH; C18 1.7 um 50.times.2.1 mm; Mobile Phase: (A)
H2O+0.025% TFA and (B) Acetonitrile+0.025% TFA. Gradient: 0.4
mL/minute, initial 20% B ramp to 80% B over 2.0 minutes, then hold
until 4.0 minutes, return to 20% B at 4.1 minutes until end of run,
then equilibrated the column for 2.0 minutes; MS Scan: 100 to 1000
amu in 0.5 seconds per channel; Diode Array Detector: 200 nm and
400 nm
Method 5:
[0342] Waters Acquity Binary Gradient Pump; Waters Acquity PDA
Detector. Waters Auto sampler; Waters Quattro micro API Mass
Spectrometer with ESI and APCI ion source; UPLC Column: Waters
Acquity; BEH; C18 1.7 um 50.times.2.1 mm; Mobile Phase: (A)
H2O+0.025% TFA and (B) Acetonitrile+0.025% TFA. Gradient: 0.4
mL/minute, initial 10% B ramp to 80% B over 3.0 minutes, then hold
until 4.0 minutes, return to 20% B at 4.1 minutes until end of run,
then equilibrated the column for 2.0 minutes; MS Scan: 100 to 1000
amu in 0.5 seconds per channel; Diode Array Detector: 200 nm and
400 nm
Method 6:
[0343] Agilent G1379A Degasser; Agilent G1312A Binary Pump; Agilent
G1315C Diode Array Detector; Agilent G1367A Auto sampler; Agilent
Ion Trap Mass Spectrometer with ESI source; HPLC Column: Waters
X-Terra; MS; C18; 2.5 um 50.times.4.6 mm; Mobile Phase: (A) 0.01M
Ammonium Bicarbonate in Water and (B) Acetonitrile; Gradient: 1
mL/minute, initial 50% B, ramp to 80% B over 4.0 minutes, and hold
until 6.0 minutes, return to 50% B at 6.1 minutes until end of run.
The column is re-equilibrated for 3 minutes. MS Scan: 100 to 1200
amu; Diode Array Detector: 200 nm-400 nm.
Method 7:
[0344] Agilent G1379A Degasser; Agilent G1312A Binary Pump; Agilent
G1315C Diode Array Detector; Agilent G1367A Auto sampler; Agilent
Ion Trap Mass Spectrometer with ESI source; HPLC Column: Waters
X-Bridge; C18; 3.5 um 150.times.4.6 mm; Mobile Phase: (A) 0.01M
Ammonium Bicarbonate in Water and (B) Acetonitrile; Gradient: 1
mL/minute, initial 20% B, ramp to 80% B over 4.0 minutes, and hold
until 8.0 minutes, return to 20% B at 8.1 minutes until end of run.
The column is re-equilibrated for 3 minutes. MS Scan: 100 to 1200
amu; Diode Array Detector: 200 nm-400 nm.
Method 8:
[0345] Agilent G1379A Degasser; Agilent G1312A Binary Pump; Agilent
G1315C Diode Array Detector; Agilent G1367A Auto sampler; Agilent
Ion Trap Mass Spectrometer with ESI source; HPLC Column: Waters
Symmetry; C18; 3.5 um 75.times.4.6 mm; Mobile Phase: (A)
H.sub.2O+0.1% Formic acid and (B) Acetonitrile+0.1% Formic acid;
Gradient: 1 mL/minute, initial 20% B, ramp to 80% B over 4.0
minutes, and hold until 7.0 minutes, return to 20% B at 7.1 minutes
until end of run. The column is re-equilibrated for 3 minutes. MS
Scan: 100 to 1200 amu; Diode Array Detector: 200 nm-400 nm.
Intermediate 1-1: Methyl
3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxylate
##STR00049##
[0347] To a solution of methyl isonicotinate (500 .mu.L, 4.23 mmol,
1.0 equiv.) in 2 mL DMF was added
O-(2,4-dinitrophenyl)hydroxylamine (1 g, 5.02 mmol, 1.2 equiv.) and
the resulting solution was allowed to stir overnight at 40.degree.
C., during which time the reaction became heterogeneous. The
mixture was allowed to cool to rt before being diluted with 10 mL
DMF, then treated with
4-ethynyl-.alpha.,.alpha.,.alpha.-trifluorotoluene (863 .mu.L, 5.29
mmol, 1.25 equiv.) and potassium carbonate (877 mg, 6.35 mmol, 1.5
equiv.). The mixture was allowed to stir overnight at 100.degree.
C. The resulting mixture was allowed to cool to rt, and then the
solvent was removed under reduced pressure. The residue was diluted
with water and the aqueous layer was extracted with EtOAc five
times. The combined EtOAc extracts were washed once with water,
once with brine, and then dried with MgSO.sub.4, filtered, and the
solvent removed under reduced pressure. The material was purified
by silica gel chromatography, eluting with hexanes/EtOAc (Rf=0.26
in 5:1 hexanes/EtOAc) to give 335 mg (25% yield) I-1. .sup.1H NMR
(400 MHz, CDCl.sub.3, .delta.): 8.52 (m, 2H), 8.23 (s, 1H), 7.72
(s, 4H), 7.40 (dd, J=1.59, 7.50 Hz, 1H), 3.96 (s, 3H).
Intermediate 1-2:
3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxylic
acid
##STR00050##
[0349] A solution of ester (320 mg, 1 mmol, 1.0 equiv.) in 3 mL 1:1
MeOH-dioxane was treated with 1 N aq. NaOH (1.5 mL, 1.5 mmol, 1.5
equiv.) dropwise over a few minutes, during which time the reaction
became heterogeneous. The thick mixture was allowed to stir well at
room temperature until complete (approximately three hours). As the
reaction progressed, it became homogeneous. The resulting solution
was diluted with 6 mL water, then was treated with 1 N aq. HCl (1.5
mL, 1.5 mmol, 1.5 equiv.) dropwise over a few minutes and allowed
to stir well several minutes more to break up any clumps. The
mixture was filtered and the filter cake was rinsed with water,
followed by hexanes. The solid was dried under high vacuum
overnight to provide I-2 (quant.).
Intermediate 1-3: 3-ethyl
5-methylpyrazolo[1,5-a]pyridine-3,5-dicarboxylate
##STR00051##
[0351] To a solution of methyl isonicotinate (500 .mu.L, 4.23 mmol,
1.0 equiv.) in 2 mL DMF was added
O-(2,4-dinitrophenyl)hydroxylamine (1 g, 5.02 mmol, 1.2 equiv.) and
the solution was allowed to stir overnight at 40.degree. C., during
which time the reaction became heterogeneous. The mixture was
allowed to cool to room temperature before being diluted with 10 mL
DMF, then treated with ethyl propiolate (536 .mu.L, 5.29 mmol, 1.25
equiv.) and potassium carbonate (877 mg, 6.35 mmol, 1.5 equiv.).
The mixture was allowed to stir overnight at rt. After the solvent
was removed under reduced pressure, the residue was diluted with
water and the aqueous layer was extracted with EtOAc five times.
The combined EtOAc extracts were washed once with water and once
with brine, then dried with MgSO.sub.4, filtered, and the solvent
was removed under reduced pressure. The material was purified by
silica gel chromatography, eluting with hexanes/EtOAc to give 778
mg (74% yield) of I-3. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.86 (dd, J=0.9, 1.8, 1H), 8.55 (dd, J=0.9, 7.2, 1H), 8.47 (s, 1H),
7.52 (dd, J=1.8, 7.2, 1H), 4.42 (q, J=7.1, 2H), 3.99 (s, 3H), 1.44
(t, J=7.1, 3H).
Intermediate 1-4: Pyrazolo[1,5-a]pyridine-5-carboxylic acid
##STR00052##
[0353] A suspension of diester (8.5 g, 34.2 mmol, 1.0 equiv.) in
150 mL 40% H.sub.2SO.sub.4 was allowed to heat at 100.degree. C.
overnight in a septum-capped vial fitted with a needle outlet to an
empty balloon to accommodate the gas evolution. The resulting
solution was allowed to cool to rt, then placed in a cold water
bath before bringing to approx. pH=2 with NaOH. During this pH
adjustment, the acid precipitated and was isolated by filtration.
The solid was washed with water, and then dried under high vacuum
overnight to provide acid I-4. .sup.1H NMR (400 MHz, DMSO) .delta.
12.5 (br s, 1H), 8.74 (d, J=7.3, 1H), 8.34 (m, 1H), 8.11 (d, J=2.3,
1H), 7.25 (dd, J=1.9, 7.3, 1H), 6.89 (dd, J=0.8, 2.3, 1H).
Intermediate 1-5: Methyl pyrazolo[1,5-a]pyridine-5-carboxylate
##STR00053##
[0355] A solution of acid (200 mg, 1.23 mmol, 1.0 equiv.) in 3.7 mL
MeOH was allowed to cool to 0.degree. C., then AcCl (370 .mu.L) was
added dropwise with efficient stirring. The resulting solution was
allowed to warm to rt, then allowed to heat at 65.degree. C.
overnight in a sealed vial. The resulting solution was allowed to
cool to rt before the solvent was evaporated. The residue was
diluted with EtOAc, and then washed with saturated aq. NaHCO.sub.3
and brine, dried with MgSO.sub.4, filtered, and the solvent was
removed under reduced pressure to give 110 mg of the desired ester
I-5, which was taken on without further purification.
Intermediate 1-6: Methyl
3-bromopyrazolo[1,5-a]pyridine-5-carboxylate
##STR00054##
[0357] A solution ester (110 mg, 0.62 mmol, 1.0 equiv.) in 6.3 mL
CH.sub.2Cl.sub.2 was allowed to cool to -78.degree. C., then NBS
(110 mg, 0.62 mmol, 1.0 equiv.) was added in one portion. The
resulting mixture was allowed to warm to rt and then stir at that
temperature for one hour. The solvent was removed under reduced
pressure and the resulting material was purified by silica gel
chromatography, eluting with hexanes/EtOAc to give I-6. .sup.1H NMR
(400 MHz, CDCl.sub.3, .delta.): 8.43 (dd, J=0.80, 7.28, 1H), 8.27
(m, 1H), 7.99 (s, 1H), 7.36 (dd, J=1.83, 7.30 Hz, 1H), 3.96 (s,
3H).
Intermediate 1-7: 3-bromopyrazolo[1,5-a]pyridine-5-carboxylic
acid
##STR00055##
[0359] A solution of ester (195 mg, 0.764 mmol, 1.0 equiv.) in 4 mL
MeOH was treated with 1 N aq. NaOH (2 mL, 2.0 mmol, 2.6 equiv.) at
rt, and then allowed to stir at rt for one hour. Concentrated under
reduced pressure, then diluted with water and acidified with 4 N
aq. HCl. Extracted 3.times.10 mL EtOAc, dried the combined organic
extracts with Na.sub.2SO.sub.4, filtered and the solvent removed
under reduced pressure to give the desired acid I-7, which was
taken on without further purification.
Intermediate 1-8:
3-bromo-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide
##STR00056##
[0361] A solution of acid (1.0 equiv.) in CH.sub.2Cl.sub.2
(.about.0.05-0.1 M) was treated with oxalyl chloride (2.0-3.0
equiv.) and a catalytic amount of DMF. The resulting solution was
allowed to stir at rt for between five minutes and one hour, then
was concentrated and dried briefly under high vacuum. The resulting
acid chloride was diluted with CH.sub.2Cl.sub.2 (.about.0.05-0.1
M), and to this solution was added 4-cyano-N-methylaniline (1.1-3.0
equiv.) and either DIEA or Et3N (3.0 equiv.). The resulting mixture
was allowed to stir at room temperature until complete conversion
(generally less than three hours). The solvent was removed under
reduced pressure, and the residue was purified by silica gel
chromatography.
Intermediate 1-9:
3-bromo-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxa-
mide
##STR00057##
[0363] Intermediate I-9 was prepared according to the procedure
described for the synthesis of intermediate I-8 by replacing
4-(methylamino)benzonitrile with
6-(methylamino)nicotinonitrile.
Intermediate 1-10:
3-bromo-N-methyl-N-(5-(methylsulfonyl)pyridin-2-yl)pyrazolo[1,5-a]pyridin-
e-5-carboxamide
##STR00058##
[0365] Intermediate I-10 was prepared according to the procedure
described for the synthesis of intermediate I-8 by replacing
4-(methylamino)benzonitrile with
N-methyl-5-(methylsulfonyl)pyridin-2-amine.
Intermediate 1-11:
3-bromo-N-methyl-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridi-
ne-5-carboxamide
##STR00059##
[0367] Intermediate I-11 was prepared according to the procedure
described for the synthesis of intermediate I-8 by replacing
4-(methylamino)benzonitrile with
N-methyl-5-(trifluoromethyl)pyridin-2-amine.
Intermediate 1-12:
3-bromo-N-methyl-N-(5-methylpyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carbox-
amide
##STR00060##
[0369] Intermediate I-12 was prepared according to the procedure
described for the synthesis of intermediate I-8 by replacing
4-(methylamino)benzonitrile with N,5-dimethylpyridin-2-amine.
Intermediate 1-13:
3-bromo-N-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide
(Example 64)
##STR00061##
[0371] Intermediate I-13 was prepared according to the procedure
described for the synthesis of intermediate I-8 by replacing
4-(methylamino)benzonitrile with 4-fluoro-N-methylaniline. .sup.1H
NMR (400 MHz, METHANOL-d.sub.4) .delta. 3.49 (s, 3H) 6.80 (d,
J=7.53 Hz, 1H) 7.00-7.14 (m, 2H) 7.24-7.37 (m, 2H) 7.50 (s, 1H)
7.97 (s, 1H) 8.38 (d, J=7.28 Hz, 1H); ESI-LC/MS (m/z): [M-H].sup.+
349.
Intermediate 1-14:
3-bromo-N-(4-chloro-2-formylphenyl)-N-methylimidazo[1,2-a]pyrazine-6-carb-
oxamide
##STR00062##
[0373] Intermediate I-14 was prepared according to the procedure
described for the synthesis of intermediate I-8 by replacing
4-(methylamino)benzonitrile with
5-chloro-2-(methylamino)benz-aldehyde. .sup.1H NMR (400 MHz,
CDCL.sub.3) .delta. 10.21 (s, 1H), 8.77 (s, 1H), 8.45-8.48 (m, 1H),
7.77-7.84 (m, 2H), 7.44-7.46 (m, 2H), 7.09-7.11 (m, 1H), 3.52 (s,
3H); ESI-LC/MS (Method 1) (m/z): [M+H].sup.+ 392.89 [M+2H].sup.+
394.90 & [M+4H].sup.+ 396.92.
Intermediate 1-15:
3-bromo-N-(4-chloro-2-formylphenyl)-N-methylpyrazolo[1,5-a]pyridine-5-car-
boxamide
##STR00063##
[0375] Intermediate I-15 was prepared according to the procedure
described for the synthesis of intermediate I-8 by replacing
4-(methylamino)benzonitrile with
5-chloro-2-(methylamino)benz-aldehyde. .sup.1H NMR (400 MHz,
CDCL.sub.3) .delta. 10.04 (s, 1H), 8.18-8.28 (m, 1H) 7.90-7.95 (m,
1H) 7.77 (s, 1H) 7.57-7.61 (m, 1H) 7.40 (s, 1H) 6.61 (br. s, 1H)
3.49 (s, 3H); ESI-LC/MS (Method 1) (m/z): [M+H].sup.+ 391.94 &
[M+2H].sup.+ 393.89 & [M+4H].sup.+ 395.91.
Intermediate 1-16:
3-(4-aminophenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-car-
boxamide
##STR00064##
[0377] A mixture of aryl bromide (1.0 equiv.), aryl boronic acid
(1.5 equiv.), K.sub.2CO.sub.3 (2.5 equiv.), and Pd(dppf)Cl.sub.2
(0.05-0.15 equiv.) in THF/water was allowed to heat at 140.degree.
C. in a microwave reactor for 40 minutes. The resulting mixture was
concentrated under reduced pressure and purified by silica gel
chromatography to give 1-16.
Intermediate 1-17: 3-bromo-5-ethylpyrazolo[1,5-a]pyridine
##STR00065##
[0379] To a stirred solution of 5-ethylpyrazolo[1,5-a]pyridine (1.1
g, 0.008 mmol) in dichloromethane (10 mL) at 0.degree. C. was added
NBS (1.75 g, 0.009 mmol) and reaction mixture was stirred at room
temperature for 5 min. Subsequently, water was added and the
reaction mixture was extracted with dichloromethane (2.times.10
mL). The organic layer was washed with water (1.times.30 mL), sat.
NaHCO.sub.3 solution (1.times.10 mL), brine (1.times.10 mL), dried
over Na.sub.2SO.sub.4 and concentrated to afford 2.1 g (84%) of
3-bromo-5-ethylpyrazolo[1,5-a]pyridine (1-17) as a brownish highly
viscous liquid. The crude was progressed to next step without any
further purification. ESI-LC/MS (m/z): [M+H].sup.+ 225.0,
[(M+2)+H].sup.+ 227.0, RT 2.50 min.
Intermediate 1-18:
3-bromo-5-(1-bromoethyl)pyrazolo[1,5-a]pyridine
##STR00066##
[0381] To a stirred solution of
3-bromo-5-ethylpyrazolo[1,5-a]pyridine (I-17, 2.1 g, 0.0094 mmol)
in CCl.sub.4 (20 mL) at rt was added NBS (2 g, 0.01 mmol) followed
by benzoyl peroxide (1.1 g, 0.004 mmol). The resulting reaction
mixture was heated to 77.degree. C. After 2 h, the reaction mixture
was allowed to cool to rt and subsequently water (20 mL) was added
followed by extraction with dichloromethane (2.times.20 mL). The
combined organic layers were washed with water (1.times.20 mL), sat
NaHCO.sub.3 solution (1.times.10 mL), brine (1.times.10 mL), dried
over Na.sub.2SO.sub.4 and the solvent was removed under reduced
pressure. The resulting crude product was purified by column
chromatography over silica gel (petroleum ether/EtOAc, 0-5% EtOAc)
to afford 820 mg (29%) of
3-bromo-5-(1-bromoethyl)pyrazolo[1,5-a]pyridine (I-18) as a brown
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.45 (d, J=7.91
Hz, 1H), 7.93 (s, 1H), 7.46 (d, J=1.32 Hz, 1H), 6.90-6.92 (dd,
J=1.76, 5.71 Hz, 1H), 5.19-5.24 (m, 2H), 2.08 (d, J=7.04 Hz, 3H);
ESI-LC/MS (m/z): [M+H].sup.+ 302.9, [(M+2)+H].sup.+ 304.9,
[(M+4)+H].sup.+ 306.9, RT 2.65 min
Intermediate 1-19:
N-(1-(3-bromopyrazolo[1,5-a]pyridin-5-yl)ethyl)-N,5-dimethylpyridin-2-ami-
ne
##STR00067##
[0383] A suspension of
3-bromo-5-(1-bromoethyl)pyrazolo[1,5-a]pyridine (I-18, 400 mg, 1.32
mmol), N,5-dimethylpyridin-2-amine (230 mg, 1.98 mmol) and
K.sub.2CO.sub.3 (546 mg, 3.96 mmol) in acetonitrile was heated to
90.degree. C. in a sealed tube for overnight. The reaction mixture
was cooled to room temperature and water (10 mL) was added. The
aqueous phase was extracted with ethyl acetate (2.times.10 mL). The
combined organic layers were dried over Na.sub.2SO.sub.4 and
solvents were removed under reduced pressure. The resulting crude
product was purified by column chromatography over silica gel
(petroleum ether/EtOAc, 0-4% EtOAc) to afford 210 mg (46%) of
N-(1-(3-bromopyrazolo[1,5-a]pyridin-5-yl)ethyl)-N,5-dimethylpyridin-2-ami-
ne (I-19) as a yellow solid. ESI-LC/MS (m/z): [M+H].sup.+ 345.2,
[(M+2)+H].sup.+ 347, RT 3.31 min.
Intermediate 1-20:
(3-bromopyrazolo[1,5-a]pyridin-5-yl)(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H-
)-yl)methanone
##STR00068##
[0385] To a solution of 3-bromopyrazolo[1,5-a]pyridine-5-carboxylic
acid (I-7, 250 mg, 1.040 mmol) in dichloromethane (10 mL) was added
oxalyl chloride (0.25 mL), followed by catalytic amount DMF (0.1 M)
at rt and the mixture was stirred for 30 min. The resultant
volatiles were removed under reduced pressure to afford a residue
of acid chloride. To this residue was added
7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (191 mg, 1.25 mmol) in
dichloromethane (10.0 mL), followed by DIPEA (0.5 mL) and the
mixture was stirred at rt for 30 min. The reaction mixture was
diluted with dichloromethane (50 mL). The reaction mixture was
washed with 1N HCl, sat. NaHCO.sub.3 solution, water, brine, dried
over Na.sub.2SO.sub.4, and the solvent was removed under reduced
pressure to afford 300 mg (77%) of
(3-bromopyrazolo[1,5-a]pyridin-5-yl)(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H-
)-yl)methanone (I-20) as a brown solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.87 (d, J=7.68 Hz, 1H), 8.27 (s, 1H), 7.80
(s, 1H), 7.06 (d, J=6.7 Hz, 1H), 6.84 (d, J=10.3 Hz, 1H), 6.65-6.68
(m, 1H), 6.50-6.52 (m, 1H), 4.36 (m, 2H), 3.92 (m, 2H); ESI-LC/MS
(m/z): [M+H].sup.+ 376.0, [(M+2)+H].sup.+ 378.0, RT 2.37 min.
Intermediate 1-21:
2-chloro-N-(4-fluoro-2-hydroxyphenyl)acetamide
##STR00069##
[0387] To a solution of 2-amino-5-fluorophenol (1.0 g, 7.87 mmol)
in dichloromethane (50 mL) at 0.degree. C. was added 2-Chloroacetyl
chloride (978 mg, 8.66 mmol). The reaction mixture was stirred at
rt for 2 h, followed by addition of aqueous saturated NaOH
solution. The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4 and solvent was removed under reduced pressure to
afford 550 mg (35%) of
2-chloro-N-(4-fluoro-2-hydroxyphenyl)acetamide (I-21) as a brown
solid. ESI-LC/MS (m/z): (M-H).sup.- 201.6, RT 2.65 min.
Intermediate 1-22:
7-fluoro-4a,5-dihydro-2H-benzo[b][1,4]oxazin-3(4H)-one
##STR00070##
[0389] To a solution of
2-chloro-N-(4-fluoro-2-hydroxyphenyl)acetamide (5.5 g, 27 mmol) in
acetonitrile (40 mL) was added DIPEA (7 g, 54 mmol) and the
reaction solution was stirred at 80.degree. C. for 2 h. The solvent
was removed under reduced pressure and the residue was partitioned
between dichloromethane (50 mL) and water (50 mL). The organic
layer was washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to afford 3.5 g (78%) of
7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one as a brown solid. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.35 (br. s, 1H) 6.67-6.77 (m,
3H) 4.62 (s, 2H).
Intermediate 1-23:
7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine
##STR00071##
[0391] To a stirred solution of
7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (I-22, 1 g, 5.98 mmol) in
THF (25 mL) at 0.degree. C. was added 3M CH.sub.3MgBr (8 mL, 24
mmol). After addition, the cooling bath was removed and the mixture
was heated to 65.degree. C. for 4 h. The reaction mixture was
quenched with acetic acid (10 mL) at 0.degree. C. and NaBH.sub.4
(568 mg, 15 mmol) was added to the solution. The resulting solution
was stirred at rt for overnight. Subsequently, 3N aqueous NaOH
solution was cautiously added until pH value of the mixture was
adjusted to 10.0. The basic solution was extracted with ethyl
acetate (2.times.30 mL). The combined organic layers were washed
with water, brine, dried over Na.sub.2SO.sub.4 and the solvent was
removed under reduced pressure. The resulting crude product was
purified by column chromatography over neutral alumina (petroleum
ether/EtOAc, 0-15% EtOAc) to afford 135 mg (14%) of
7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (I-23) as a
brown oil. .sup.1H NMR (400 MHz, DMSO) .delta. 6.45-6.55 (m, 3H),
4.16-4.19 (m, 1H), 3.73-3.77 (m, 1H), 3.44-3.51 (m, 2H), 1.17 (d,
J=6.34 Hz, 3H).
Intermediate 1-24:
(3-bromopyrazolo[1,5-a]pyridin-5-yl)(7-fluoro-3-methyl-2H-benzo[b][1,4]ox-
azin-4(3H)-yl)methanone
##STR00072##
[0393] Intermediate I-24 was prepared according to the procedure
described for the synthesis of intermediate I-8 by replacing
4-(methylamino)benzonitrile with
7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (I-23, 350
mg, 2.1 mmol). The resulting crude product was purified by column
chromatography over silica gel (chloroform/EtOAc, 0-30% EtOAc) to
afford 150 mg (20%) of
(3-bromopyrazolo[1,5-a]pyridin-5-yl)(7-fluoro-3-methyl-2H-benzo[b][1,4]ox-
azin-4(3H)-yl)-methanone (I-24) as an off-white solid. .sup.1H NMR
(400 MHz, DMSO) .delta. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.36 (d, J=7.0 Hz, 1H), 7.99 (s, 1H), 7.81 (s, 1H), 6.88 (br. s,
1H), 6.67-6.78 (m, 3H), 6.42-6.46 (m, 1H), 4.82 (br. s, 1H),
4.28-4.35 (m, 2H), 1.33 (d, J=7.0 Hz, 3H).
Intermediate 1-25: 6-(oxetan-3-ylamino)nicotinonitrile
##STR00073##
[0395] In a microwave vial, oxetan-3-amine (125 mg, 1.736 mmol),
triethylamine (526 mg, 5.21 mmol) were added to a solution of
2-bromo-5-cyanopyridine (317 mg, 1.736 mmol) in isopropanol (3 mL).
The vial was capped and irradiated in a microwave oven at
120.degree. C. for 5 h. The reaction mixture was partitioned
between ethyl acetate (10 mL) and water (10 mL). The organic layer
was washed with brine, dried over Na.sub.2SO.sub.4 and the solvent
was removed under reduced pressure. The resulting crude product was
purified by column chromatography over silica gel (chloroform/MeOH,
0-5% EtOAc) to afford 75 mg (25%) of
6-(oxetan-3-ylamino)nicotinonitrile (I-25) as an off-white solid.
.sup.1H NMR (400 MHz, DMSO) .delta. 8.36 (s, 1H), 7.58-7.61 (dd,
J=1.9, 6.9 Hz, 1H), 6.39 (d, J=8.7 Hz, 2H), 5.37 (br. s, 1H),
4.91-5.06 (m, 3H), 4.54-4.57 (m, 2H); ESI-LC/MS (m/z): [M+H].sup.+
176.2, RT 1.65 min.
Intermediate 1-26:
3-bromo-N-(5-cyanopyridin-2-yl)-N-(oxetan-3-yl)pyrazolo[1,5-a]pyridine-5--
carboxamide
##STR00074##
[0397] To a solution of 3-bromopyrazolo[1,5-a]pyridine-5-carboxylic
acid (I-7, 240 mg, 1 mmol) in dichloromethane (10 mL) was added
oxalyl chloride (0.25 mL) and catalytic amounts of anhydrous
dimethylformamide at rt. The reaction mixture was stirred for 30
minutes and subsequently the solvent was removed under reduced
pressure. To the residual acid chloride was added a solution of
6-(oxetan-3-ylamino)nicotinonitrile (I-25, 175 mg, 1 mmol) in
dichloromethane (10 mL). The resulting reaction mixture was quickly
transferred to a microwave vial and NaH (60% in mineral oil) (191
mg, 5 mmol) was added. The vial was heatedin a microwave oven at
80.degree. C. for 3 h. The reaction mixture was diluted with
dichloromethane (15 mL) and subsequently washed with water, sat.
NaHCO.sub.3 solution and brine. The organic layer was dried over
Na.sub.2SO.sub.4 and the solvent was removed under reduced
pressure. The resulting crude product was purified by column
chromatography over silica gel (chloroform/MeOH, 0-10% EtOAc) to
afford 75 mg (20%) of
3-bromo-N-(5-cyanopyridin-2-yl)-N-(oxetan-3-yl)pyrazolo[1,5-a]pyridine-5--
carboxamide (I-26) as a brown solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.45 (d, J=7.0 Hz, 1H), 8.16 (s, 1H), 8.02 (t,
J=7.90 Hz, 1H), 7.53 (d, J=0.8 Hz, 1H), 7.33-7.31 (m, 1H),
6.90-6.87 (m, 1H), 6.43 (d, J=10.1 Hz, 1H), 4.67-4.62 (m, 1H),
4.52-4.43 (m, 2H), 4.25-4.19 (m, 1H), 4.03-3.98 (m, 1H); ESI-LC/MS
(m/z): [M+H].sup.+ 398.13, [(M+2)+H].sup.+ 400.08, RT 1.25 min.
Intermediate 1-27:
N-(1-(1H-pyrazol-1-yl)propan-2-yl)-3-bromo-N-(5-cyanopyridin-2-yl)pyrazol-
o[1,5-a]pyridine-5-carboxamide
##STR00075##
[0399] Intermediate I-27 was prepared according to the procedure
described for the synthesis of intermediate I-7 by replacing
6-(oxetan-3-ylamino)nicotinonitrile with
6-(1-(1H-pyrazol-1-yl)propan-2-ylamino)nicotinonitrile (283 mg,
1.25 mmol). Microwave irradiation at 85.degree. C. for 5 h. The
resulting crude product was purified by preparative TLC to afford
180 mg (32%) of
N-(1-(1H-pyrazol-1-yl)propan-2-yl)-3-bromo-N-(5-cyanopyridin-2-yl)pyrazol-
o[1,5-a]pyridine-5-carboxamide (I-27) as a pale brown highly
viscious oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.84 (d,
J=2.2 Hz, 1H), 8.60 (d, J=7.1 Hz, 1H), 8.19 (s, 1H), 8.13 (d, J=2.2
Hz, 1H), 7.75 (d, J=1.8 Hz, 1H), 7.38 (d, J=1.3 Hz, 1H), 7.27 (s,
1H), 7.12 (d, J=8.3 Hz, 1H), 6.62 (d, J=1.7 Hz, 1H), 6.19 (t, J=1.7
Hz, 1H), 5.06-5.10 (m, 1H), 4.82-4.87 (m, 1H), 4.43-4.47 (m, 1H),
1.36 (d, J=7.0 Hz, 3H); ESI-LC/MS (m/z): [M+H].sup.+ 450.2, RT 3.73
min.
Intermediate 1-28: (5-cyanopyridin-2-yl)(methyl)carbamic
chloride
##STR00076##
[0401] To a solution of bis(trichloromethyl) carbonate (50 mg, 0.17
mmol) in tetrahydrofuran (2.0 mL) was added pyridine (0.04 mL,
0.510 mmol) dropwise under ice-cooling. After stirring under
ice-cooling for 30 min, 6-(methylamino)nicotinonitrile (68 mg,
0.510 mmol) was added and the mixture was stirred at room
temperature for 2.5 hours. The precipitated solid was filtered off.
The filtrate containing (5-cyanopyridin-2-yl)(methyl)carbamic
chloride (I-28) was directly used for next step.
Intermediate 1-29:
3-bromo-N-(5-cyanopyridin-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)--
carboxamide
##STR00077##
[0403] To a solution of (5-cyanopyridin-2-yl)(methyl)carbamic
chloride (I-28) in THF (2.0 mL) were added
3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (137 mg, 0.680
mmol), triethylamine (0.14 mL, 1.021 mmol) and
4-dimethylaminopyridine (2.0 mg, 0.017 mmol). The mixture was
stirred at 60.degree. C. for 1 h. Subsequently, water (25 mL) was
added and the mixture was extracted with ethyl acetate. The organic
layer was washed with brine, dried over Na.sub.2SO.sub.4 and the
solvent was removed under reduced pressure. The resulting crude
product was purified by preparative TLC to afford 60 mg (44%) of
3-bromo-N-(5-cyanopyridin-2-yl)-N-methyl-6,7-dihydropyrazolo-[1,-
5-a]pyrazine-5(4H)-carboxamide (I-29) as a off white solid. .sup.1H
NMR (400 MHz, DMSO) .delta. 8.64 (s, 1H), 8.07 (d, J=8.8 Hz, 1H),
7.60 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 4.53 (s, 2H), 4.16 (t, J=4.9
Hz, 2H), 3.84 (t, J=4.9 Hz, 2H), 3.26 (s, 3H); ESI-LC/MS (m/z):
[M+H].sup.+ 360.91, [(M+2)+H].sup.+ 362.93, RT 1.63 min.
Intermediate 1-30: 4-(chloromethyl)-N-methylbenzamide
##STR00078##
[0405] To a solution 4-(chloromethyl)benzoyl chloride (1.0 g, 5.29
mmol) and methylamine.HCl (1.0 g, 5.80 mmol) in dichloromethane (40
mL) was added DIPEA (2.01 g, 15.6 mmol) at 0.degree. C. and stirred
for 1 h. The reaction mixture was extracted with water (1.times.50
mL). The organic layer was extracted with brine (1.times.50 mL),
dried over Na.sub.2SO.sub.4 and the solvent was removed under
reduced pressure to afford 1.0 g (quantitative) of
4-(chloromethyl)-N-methylbenzamide (I-30) as an off white solid.
.sup.1H NMR (400 MHz, DMSO) .delta. 8.46 (d, J=3.5 Hz, 1H), 7.82
(d, J=8.4 Hz, 2H), 7.51 (d, J=8.3 Hz, 2H), 4.80 (s, 2H), 2.78 (d,
J=4.4 Hz, 3H); ESI-LC/MS (m/z): [M+H].sup.+ 184.2, RT 2.46 min.
Intermediate 1-31:
N-methyl-4-((trimethylstannyl)methyl)benzamide
##STR00079##
[0407] A solution of 4-(chloromethyl)-N-methylbenzamide (I-30, 200
mg, 1.092 mmol) and hexamethylditin (0.26 mL, 1.20 mmol) in toluene
(5 mL) was degassed with argon gas for 15 min, followed by addition
of Pd(PPh.sub.3).sub.4 (63.05 mg, 0.054 mmol). The mixture was
heated to reflux for 8 h. The reaction mixture was filtered and the
solvent was removed under reduced pressure to afford 200 mg (58%)
of N-methyl-4-((trimethylstannyl)methyl)benzamide (I-31) as a a
brown semi-solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.58
(d, J=8.0 Hz, 2H), 7.00 (d, J=7.9 Hz, 2H), 2.99 (d, J=5.8 Hz, 2H),
2.35 (s, 2H), 0.04 (s, 9H); MS (m/z): [M+H].sup.+ 314.0.
Intermediate 1-32: 4-(methylamino)cyclohexanecarbonitrile
##STR00080##
[0409] To a solution of 4-cyanocyclohexanone (200 mg, 1.626 mmol)
and CH.sub.3NH.sub.2 (2M in THF) (0.8 mL, 1.626 mmol) in
THF:CH.sub.2Cl.sub.2 (1:1) (4.0 mL) at 0.degree. C. was added
NaBH(OAc).sub.3 (689 mg, 3.252 mmol) and the resulting mixture was
stirred at rt for 48 h. Subsequently, the solvent was removed under
reduced pressure and the residue was dissolved in ethyl acetate,
washed with water, brine, dried over Na.sub.2SO.sub.4 and
concentrated to afford 200 mg (89%) of
4-(methylamino)cyclohexanecarbonitrile as a white solid. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) 2.91 & 2.61 (two signals, 1H)
2.23-2.24 (m, 3H) 1.02-1.99 (m, 9H); ELSD/MS (Method 3) (m/z):
[M+H].sup.+ 139.06.
Intermediate 1-33:
3-bromo-N-(4-cyanocyclohexyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxami-
de (Example 84)
##STR00081##
[0411] Intermediate I-33 was prepared according to the procedure
described for the synthesis of intermediate I-8 by replacing
4-(methylamino)benzonitrile with
4-(methylamino)cyclohexane-carbonitrile. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) 8.77-8.79 (m, 1H) 8.23 (s, 1H) 7.58 (br.s, 1H)
6.95-6.97 (m, 1H) 4.30 & 3.50 (two signals, 1H) 2.76-3.19 (m,
4H) 1.48-1.98 (m, 8H); ESI-LC/MS (Method 1) (m/z): [M+H].sup.+ 361
& [M+2H].sup.+ 363.
Intermediate 1-34: 2-amino-5-bromonicotinonitrile
##STR00082##
[0413] To a solution of 2-aminonicotinonitrile (1.5 g, 12.5 mmol,
1.0 eq.) in AcOH (30 mL) was added Na.sub.2CO.sub.3 (1.3 g, 12.5
mmol). Bromine (0.7 ml, 13.8 mmol) was added drop wise to the
resulting suspension and reaction mixture was stirred at rt for 1
h. The orange precipitate formed was collected by filtration,
washed with water and dried to afford 2.0 g (80%) of I-34 as a
yellow solid. .sup.1H NMR (400 MHz, DMSO) .delta. 8.27 (s, 1H),
8.15 (s, 1H), 7.12 (brs, 2H).
Intermediate 1-35: 2-amino-5-bromonicotinonitrile
##STR00083##
[0415] To a solution of 2-amino-5-bromopyridine (3 g, 17.3 mmol,
1.0 eq.) dissolved in DMF (10 ml) was added NCS (2.54 g, 19.07
mmol, 1.1 eq.) and the resulting mixture was stirred at rt for 2 h.
Subsequently, 5N NaOH was used to adjust the pH of the reaction
mixture to 7-8 followed by extraction with ethyl acetate
(2.times.40 mL). The combined organic layers were washed with
water, brine, dried over anhydrous Na.sub.2SO.sub.4 solution and
concentrated under reduced pressure to afford 2.0 g (55%) of I-35
as a yellow solid. .sup.1H NMR (400 MHz, DMSO) .delta. 7.98 (s,
1H), 7.84 (s, 1H), 6.52 (brs, 2H); ESI-LC/MS (m/z): [M+H].sup.+
206.96, [(M+2)+H].sup.+ 208.91, RT 1.59 min.
Intermediate 1-36: 2-amino-5-bromo-N,N-dimethylnicotinamide
##STR00084##
[0417] To a stirred solution of 2-amino-5-bromo-3-carboxypyridine
(1.0 g, 4.60 mmol, 1.0 eq.), dimethylamine (0.227 g, 5.06 mmol, 1.1
eq.) and TEA (1.2 ml, 9.20 mmol, 2.0 eq.) dissolved in THF (20 mL)
was added diethyl cyanophosphate (0.8 ml, 5.06 mmol, 1.1 eq.) drop
wise. Stirring at rt was continued for 4 h. The reaction mixture
was partitioned between water and ethyl acetate (2.times.30 mL).
The combined organic layers were washed with water, brine, dried
over anhydrous Na.sub.2SO.sub.4 solution and concentrated under
reduced pressure. The crude compound was purified by column
chromatography over silica gel (100-200 mesh) using a solvent
gradient of 4% MeOH in DCM as eluant to afford 500 mg (44%) of I-36
as a off-white solid. .sup.1H NMR (400 MHz, DMSO) .delta. 8.05 (s,
1H), 7.54 (s, 1H), 6.20 (brs, 2H), 2.90 (brs, 6H); ESI-LC/MS (m/z):
[M+H].sup.+ 244.01, [(M+2)+H].sup.+ 246.01, RT 0.84 min.
Intermediate 1-37:
3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
##STR00085##
[0419] Intermediate I-37 was prepared according to the general
boronic ester synthesis procedure A by utilizing
5-bromo-3-fluoropyridin-2-amine (reaction time: 16 h, temperature:
85.degree. C.). ESI-LC/MS (m/z): [M+H].sup.+ 239.1, RT 5.60
min.
Intermediate 1-38:
2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
##STR00086##
[0421] Intermediate I-38 was prepared according to the general
boronic ester synthesis procedure A by utilizing
4-bromo-2,6-dimethylaniline (reaction time: 16 h, temperature:
85.degree. C.). ESI-LC/MS (m/z): [M+H].sup.+ 248.1, RT 6.67
min.
Intermediate 1-39:
3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
##STR00087##
[0423] Intermediate I-39 was prepared according to the general
boronic ester synthesis procedure B by utilizing
2-amino-3-methyl-5-bromopyridine (reaction time: 16 h, temperature:
90.degree. C.). ESI-LC/MS (m/z): [M+H].sup.+ 235.1, RT 1.26
min.
Intermediate 1-40:
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine
##STR00088##
[0425] Intermediate I-40 was prepared according to the general
boronic ester synthesis procedure A by utilizing
5-bromopyrimidin-2-amine (reaction time: 5 h, temperature:
100.degree. C.). .sup.1H NMR (400 MHz, DMSO) .delta. 8.59 (s, 2H),
5.43 (brs, 2H), 1.32 (s, 12H);
Intermediate 1-41:
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridi-
n-2-amine
##STR00089##
[0427] Intermediate I-41 was prepared according to the general
boronic ester synthesis procedure A by utilizing
5-bromo-3-(trifluoromethyl)pyridin-2-amine (reaction time: 5 h,
temperature: 100.degree. C.). .sup.1H NMR (400 MHz, DMSO) .delta.
8.37 (s, 1H), 7.80 (s, 1H), 6.89 (s, 2H), 1.27 (s, 12H); ESI-LC/MS
(m/z): [M+H].sup.+ 289.1, RT 4.83 min.
Intermediate 1-42:
2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile
##STR00090##
[0429] Intermediate I-42 was prepared according to the general
boronic ester synthesis procedure A by utilizing
2-amino-5-bromonicotinonitrile (I-34) (reaction time: 5 h,
temperature: 100.degree. C.). .sup.1H NMR (400 MHz, DMSO) .delta.
8.57 (s, 1H), 8.08 (s, 1H), 5.42 (s, 2H), 1.27 (s, 12H); ESI-LC/MS
(m/z): [M+H].sup.+ 246.1, RT 5.05 min.
Intermediate 1-43:
3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
##STR00091##
[0431] Intermediate I-43 was prepared according to the general
boronic ester synthesis procedure A by utilizing
5-bromo-3-chloropyridin-2-amine (I-35) (reaction time: 16 h,
temperature: 100.degree. C.). .sup.1H NMR (400 MHz, DMSO) .delta.
8.32 (s, 1H), 7.84 (s, 1H), 5.12 (s, 2H), 1.37 (s, 12H); ESI-LC/MS
(m/z): [M+H].sup.+ 256.5, RT 1.67 min.
Intermediate 1-44:
2-amino-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicot-
inamide
##STR00092##
[0433] Intermediate I-44 was prepared according to the general
boronic ester synthesis procedure A by utilizing
2-amino-5-bromo-N,N-dimethylnicotinamide (I-36) (reaction time: 16
h, temperature: 100.degree. C.). ESI-LC/MS (m/z):
[M-boronicacid].sup.+ 210.1, RT 0.42 min.
Intermediate 1-45:
3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
##STR00093##
[0435] Intermediate I-45 was prepared according to the general
boronic ester synthesis procedure A by utilizing
2-amino-3-methoxy-5-bromopyridine (reaction time: 5 h, temperature:
100.degree. C.). .sup.1H NMR (400 MHz, DMSO) .delta. 8.03 (s, 1H),
7.19 (s, 1H), 5.17 (s, 2H), 3.84 (s, 3H), 1.27 (s, 12H).
Intermediate 1-46: Methyl
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-5--
carboxylate
##STR00094##
[0437] A solution of pyrazolopyridine (100 mg, 0.568 mmol, 1.0
equiv.) and bis(pinacolato)diboron (158.75 mg, 0.625 mmol, 1.1
equiv.) in 1 mL THF was treated with 2,2'-bipyridine (0.6 mg,
0.00224 mmol, 0.04 equiv.) and
(1,5-cyclooctadiene)(methoxy)iridium(I) dimer (0.75 mg, 0.00113
mmol, 0.02 equiv.) at rt. The flask was charged with nitrogen gas,
and the resulting mixture was allowed to stir at 50.degree. C. for
three hours. The reaction was concentrated and the residue was
purified by silica gel chromatography, eluting with
CH.sub.2Cl.sub.2/EtOAc to give I-46. .sup.1H NMR (400 MHz, MeOD)
.delta. 8.68 (dd, J=0.6, 7.2, 1H), 8.60-8.57 (m, 1H), 8.24 (s, 1H),
7.46 (dd, J=1.9, 7.3, 1H), 3.98 (s, 3H), 1.39 (s, 12H).
##STR00095##
[0438] Alternatively, a solution of pyrazolopyridine (750 mg, 4.26
mmol, 1.0 equiv.) and bis(pinacolato)diboron (1.19 g, 4.69 mmol,
1.1 equiv.) in 10 mL 1:1 THF/hexanes was treated with
(1,5-cyclooctadiene)(methoxy)iridium(I) dimer (84 mg, 0.128 mmol,
0.03 equiv.) and 4,4'-di-tert-butyl-2,2'-bipyridine (68 mg, 0.256
mmol, 0.06 equiv.) at rt. The flask was charged with nitrogen gas,
and the resulting mixture was allowed to stir at rt overnight. The
reaction was concentrated and the residue was purified by silica
gel chromatography, eluting with hexanes/EtOAc to give intermediate
I-46.
Intermediate 1-47:
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-5--
carboxylic acid
##STR00096##
[0440] A solution of ester (400 mg, 1.32 mmol, 1.0 equiv.) in 3 mL
MeOH was treated with 1 N aq. NaOH (3 mL, 3.0 mmol, 2.26 equiv.) at
rt, and then allowed to stir at rt for 30 minutes. The reaction
mixture was then neutralized with 3 mL 1 N aq. HCl, and the
resulting white solid was isolated by filtration. The filtrate was
extracted with EtOAc and the organic extracts were concentrated.
The solid products were combined, and then diluted with 22 mL 10:1
CH.sub.2Cl.sub.2/THF before pinacol (157 mg, 1.32 mmol, 1.0 equiv.)
and 1 g MgSO4 were added. The resulting mixture was allowed to stir
at rt for 20 minutes, filtered, and concentrated under reduced
pressure. The resulting white solid was triturated with hexanes to
give the acid I-47, which was taken on without further
purification.
Intermediate 1-48: Methyl
3-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxylate
##STR00097##
[0442] A mixture of 2-chloro-5-(trifluoromethyl)pyridine (1.5
equiv.), aryl boronic ester (1.0 equiv.), K2HPO4 (3.5 equiv.), and
SiliaCat.RTM. DPP-Pd or Pd(dppf)Cl2 (0.05-0.15 equiv.) in THF/water
was allowed to heat at 150.degree. C. in a microwave reactor for
40-60 minutes. After cooling to room temperature, the solvent was
removed under reduced pressure. The crude residue was purified by
mass-triggered HPLC or silica gel chromatography to provide
intermediate I-48.
Intermediate 1-49:
3-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxylic
acid
##STR00098##
[0444] Intermediate I-49 was prepared according to the procedure
described for the synthesis of intermediate I-7.
Intermediate 1-50:
N-(4-cyanophenyl)-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)pyrazolo[1,5-a]pyridine-5-carboxamide
##STR00099##
[0446] Intermediate I-50 was prepared according to the procedure
described for the synthesis of intermediate I-8.
Intermediate 1-51 & 1-52:
(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)methanol
##STR00100##
[0448] A solution of acid (450 mg, 1.47 mmol, 1.0 equiv.) in 8 mL
MeOH was treated with SOCl.sub.2 (300 .mu.L, 4.14 mmol, 2.8 equiv.)
dropwise and the resulting solution was allowed to heat at
50.degree. C. overnight. The solution was diluted with 10 mL
CH.sub.2Cl.sub.2, then washed with saturated aq. NaHCO.sub.3, dried
with Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure to give the desired ester (I-1), which was taken on
without further purification. .sup.1H NMR (400 MHz, CDCl.sub.3,):
8.52 (m, 2H), 8.23 (s, 1H), 7.72 (s, 4H), 7.40 (dd, J=1.59, 7.50
Hz, 1H), 3.96 (s, 3H).
[0449] A solution of the ester (100 mg, 0.31 mmol, 1.0 equiv.) in 3
mL CH.sub.2Cl.sub.2 was allowed to cool to -78.degree. C., and then
a solution of DIBAL-H (1.0 M in toluene, 1.24 mL, 1.24 mmol, 4.0
equiv.) was added dropwise. The resulting solution was allowed to
stir at -78.degree. C. for 90-120 minutes and then was quenched
with Na.sub.2SO.sub.4.10H.sub.2O. The resulting mixture was allowed
to stir at rt for 30 minutes, then was filtered and concentrated.
The residue was purified by silica gel chromatography, eluting with
hexanes/EtOAc to give the desired alcohol (I-51), as well as a
small amount of the corresponding aldehyde (I-52).
Intermediate 1-53:
5-(bromomethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine
##STR00101##
[0451] A solution of alcohol (160 mg, 0.546 mmol, 1.0 equiv.) in 3
mL CH.sub.2Cl.sub.2 was treated with PBr.sub.3 (27 .mu.L, 0.273
mmol, 0.5 equiv.) dropwise at rt, then was allowed to stir at rt
for two hours. The solution was diluted with 20 mL
CH.sub.2Cl.sub.2, then washed with saturated aq. NaHCO.sub.3, dried
with Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure to give the desired bromide (I-53), which was taken on
without further purification.
Intermediate 1-54:
3-bromo-N-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide
##STR00102##
[0453] Intermediate I-54 was prepared according to the procedure
described for the synthesis of intermediate I-8 by replacing
4-(methylamino)benzonitrile with 4-fluoro-N-methylaniline.
Intermediate 1-55:
N-(5-cyanopyridin-2-yl)-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborola-
n-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide
##STR00103##
[0455] Intermediate I-55 was prepared according to the procedure
described for the synthesis of intermediate I-8 by replacing
4-(methylamino)benzonitrile with
6-(methylamino)nicotinonitrile.
Intermediate 1-56: tert-butyl
(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)carbamate
##STR00104##
[0457] A mixture of pyrazolopyridine (153 mg, 0.50 mmol), DPPA
(0.129 mL, 0.60 mmol), t-BuOH (0.5 mL) and toluene (2.0 mL) was
heated to 80.degree. C. overnight. After cooling to room
temperature, water was added to the reaction mixture and extracted
with dichloromethane. The combined organic layers were washed with
brine and dried over anhydrous Na.sub.2SO.sub.4. The solvent was
removed and the product was purified by silica gel chromatography,
eluting with ethyl acetate and hexanes. .sup.1H NMR (400 MHz, DMSO)
.delta. 9.88 (s, 1H), 8.67 (d, J=7.6, 1H), 8.40 (d, J=7.8, 1H),
8.30-8.07 (m, 1H), 7.91-7.64 (m, 4H), 7.00 (dd, J=2.1, 7.5, 1H),
1.59-1.41 (m, 9H).
Intermediate 1-57: tert-butyl
methyl(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)carbamate
##STR00105##
[0459] NaH (7 mg, 0.15 mmol) was added to a solution of
pyrazolopyridine in DMF (2.0 mL). The reaction stirred at room
temperature for 15 minutes. Methyl iodide was added (0.018 mL, 0.12
mmol) and the reaction stirred for 4 hours at room temperature. The
reaction was quenched with water and extracted with ethyl acetate.
The combined organic layers were washed with brine and dried over
anhydrous Na.sub.2SO.sub.4. The solvent was removed and the
material was purified by silica gel chromatography, eluting with
ethyl acetate and hexanes. .sup.1H NMR (400 MHz, MeOD) .delta. 8.44
(d, J=7.5, 1H), 8.20 (s, 1H), 7.77-7.59 (m, 5H), 6.94 (d, J=5.3,
1H), 3.26 (s, 3H), 1.41 (s, 9H).
Intermediate 1-58:
N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-amine
##STR00106##
[0461] To a solution of pyrazolopyridine (30 mg, 0.80 mmol) in
dioxane (1.0 mL) was added 4N HCl in dioxane and the reaction
stirred at room temperature for 2 hours. The resultant HCl salt was
filtered and dried to give the desired product. No further
purification was necessary.
Intermediate 1-59: tert-butyl
4-fluorobenzyl(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)c-
arbamate
##STR00107##
[0463] Intermediate I-59 was prepared according to the procedure
described for the synthesis of intermediate I-57 by replacing
methyl iodide with 4-fluorobenzyl bromide.
Intermediate 1-60: tert-butyl
((tetrahydro-2H-pyran-4-yl)methyl)(3-(4-(trifluoromethyl)phenyl)pyrazolo[-
1,5-a]pyridin-5-yl)carbamate
##STR00108##
[0465] Intermediate I-60 was prepared according to the procedure
described for the synthesis of intermediate I-25 by replacing
methyl iodide with 4-(bromomethyl)tetrahydro-2H-pyran.
Intermediate 1-61:
N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazol-
o[1,5-a]pyridin-5-amine
##STR00109##
[0467] Intermediate I-29 was prepared according to the procedure
described for the synthesis of intermediate I-57.
Intermediate 1-62: tert-butyl
(3-bromopyrazolo[1,5-a]pyridin-5-yl)carbamate
##STR00110##
[0469] To a mixture of pyrazolopyridine (240 mg, 1.00 mmol),
diisopropylethylamine (0.160 mL, 1.00 mmol), t-BuOH (1.00 mL) and
toluene (4.00 mL) was added dry 4 angstrom molecular sieves. The
reaction stirred at room temperature for 30 minutes. DPPA (0.260
mL, 1.20 mmol) was added and the reaction was heated to 80.degree.
C. overnight. After cooling to room temperature, the material was
purified by silica gel chromatography, eluting with ethyl acetate
and hexanes.
Intermediate 1-63: tert-butyl
(3-bromopyrazolo[1,5-a]pyridin-5-yl)(methyl)carbamate
##STR00111##
[0471] Intermediate I-63 was prepared according to the procedure
described for the synthesis of intermediate I-57.
Intermediate 1-63:
3-bromo-N-methylpyrazolo[1,5-a]pyridin-5-amine
##STR00112##
[0473] Intermediate I-64 was prepared according to the procedure
described for the synthesis of intermediate I-58.
Intermediate 1-65:
N-(3-bromopyrazolo[1,5-a]pyridin-5-yl)-4-fluoro-N-methylbenzamide
##STR00113##
[0475] To a solution of pyrazolopyridine (22.6 mg, 0.10 mmol) in
dichloromethane (2.0 mL) was added triethylamine (0.042 mL, 0.30
mmol) and a catalytic amount of DMAP. The reaction was cooled to
0.degree. C. and 4-fluorobenzoyl chloride was added. The reaction
warmed to room temperature and stirred for 2 hours. The reaction
was diluted with water and extracted with dichloromethane. The
organic extracts were washed with brine and dried over anhydrous
Na.sub.2SO.sub.4. The solvent was removed and the material was
purified by silica gel chromatography, eluting with ethyl acetate
and hexanes.
Intermediate 1-66:
3-bromo-N-methyl-N-(5-(methylsulfonyl)pyridin-2-yl)pyrazolo[1,5-a]pyridin-
e-5-carboxamide
##STR00114##
[0477] Intermediate I-66 was prepared according to the procedure
described for the synthesis of intermediate I-8 by replacing
4-(methylamino)benzonitrile with
N-methyl-5-(methylsulfonyl)pyridin-2-amine.
Intermediate 1-67:
4-(1-(3-Bromopyrazolo[1,5-a]pyridin-5-yl)ethyl)-7-fluoro-2H-benzo[b][1,4]-
oxazin-3(4H)-one
##STR00115##
[0479] Potassium tert-butoxide (75 mg, 0.666 mmol) was added to a
stirred solution of 7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one
(I-22, 100 mg, 0.606 mmol) in dry THF at rt. After 5 min, a
solution of 3-bromo-5-(1-bromoethyl)pyrazolo[1,5-a]pyridine (I-18,
202 mg, 0.666 mmol) in dry THF was added drop wise to reaction
mixture at rt. The resulting reaction mixture was heated to reflux
for overnight and subsequently cooled to room temperature. The
reaction mixture was diluted with water (10 mL) and extracted with
ethyl acetate (2.times.10 mL). The combined organic layers were
dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The crude compound was purified by column chromatography
over silica gel (chloroform/EtOAc, 0-4% EtOAc) to afford 110 mg
(42%) of
4-(1-(3-bromopyrazolo[1,5-a]pyridin-5-yl)ethyl)-7-fluoro-2H-benzo[b][1,4]-
oxazin-3(4H)-one I-67 as a yellow solid. ESI-LC/MS (Method 1)
(m/z): [M+H].sup.+ 389.9, [(M+2)+H].sup.+ 391.9.
Example 1
N-(4-cyanophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyr-
idine-5-carboxamide
##STR00116##
[0481] A solution of acid (1.0 equiv.) in CH.sub.2Cl.sub.2
(.about.0.05-0.1 M) was treated with oxalyl chloride (2.0-3.0
equiv.) and a catalytic amount of DMF. The resulting solution was
allowed to stir at rt for between five minutes and one hour, then
was concentrated and dried briefly under high vacuum. The resulting
acid chloride was diluted with CH.sub.2Cl.sub.2 (.about.0.05-0.1
M), and to this solution was added 4-(methylamino)benzonitrile
(1.1-3.0 equiv.) and either DIEA or Et3N (3.0 equiv.). The
resulting mixture was allowed to stir at rt until complete
conversion (generally less than three hours). The solvent was
removed under reduced pressure, and the residue was purified by
silica gel chromatography, eluting with hexanes/ethyl acetate to
provide 1. .sup.1H NMR (400 MHz, CDCl3) .delta. 8.30 (dd, J=0.7,
7.3, 1H), 8.16 (s, 1H), 7.82 (m, 1H), 7.66 (d, J=8.2, 2H), 7.60 (d,
J=8.6, 2H), 7.47 (d, J=8.1, 2H), 7.23 (obscured by CDCl.sub.3 peak,
2H), 6.64 (dd, J=1.8, 7.3, 1H), 3.54 (s, 3H). ESI-MS (m/z):
[M+H].sup.+ 421.1, RT 1.8703 min. ESI-LC/MS m/z 421.1 (M+H)+;
r.t.=1.871.
Example 2
4-fluoro-N-methyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-
-5-yl)methyl)aniline
##STR00117##
[0483] A solution of N-methyl aniline (18.8 mg, 0.15 mmol, 1.5
equiv.) in 0.5 mL THF was allowed to cool to 0.degree. C., then a
solution of NaHMDS (1.0 M in THF, 150 .mu.L, 0.15 mmol, 1.5 equiv.)
was added dropwise. After allowing the resulting solution to stir
at 0.degree. C. for 10 minutes, a solution of bromide (35.4 mg,
0.10 mmol, 1.0 equiv.) in 0.5 mL THF was added dropwise. The
reaction mixture was allowed to stir at 0.degree. C. for another
10-20 minutes, and then the reaction was quenched with water and
concentrated under reduced pressure. The residue was diluted with
MeOH-DMSO and the resulting solution was purified by mass-triggered
HPLC to provide 2 as the TFA salt. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.44 (d, J=7.2, 1H), 8.14 (s, 1H), 7.65 (d,
J=8.3, 2H), 7.59 (m, 3H), 6.94 (m, 2H), 6.72 (m, 3H), 4.48 (s, 2H),
2.99 (s, 3H). ESI-MS (m/z): [M+H].sup.+ 400.2, RT 2.409 min.
Example 3
N-(4-chlorophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]py-
ridine-5-carboxamide
##STR00118##
[0485] Example 3 was prepared according to the procedure described
for the synthesis of Example 1 by replacing
4-(methylamino)benzonitrile with 4-chloro-N-methylaniline.
ESI-LC/MS m/z 430.1 (M+H)+; r.t.=2.275.
Example 4
N-(4-fluorophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]py-
ridine-5-carboxamide
##STR00119##
[0487] Example 4 was prepared according to the procedure described
for the synthesis of Example 1 by replacing
4-(methylamino)benzonitrile with 4-fluoro-N-methylaniline.
ESI-LC/MS m/z 414.1 (M+H)+; r.t.=2.165.
Example 5
N-methyl-N-(5-methylpyridin-2-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,-
5-a]pyridine-5-carboxamide
##STR00120##
[0489] Example 5 was prepared according to the procedure described
for the synthesis of Example 1 by replacing
4-(methylamino)benzonitrile with N,5-dimethylpyridin-2-amine.
ESI-LC/MS m/z 411.2 (M+H)+; r.t.=2.005.
Example 6
4-chloro-N-methyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-
-5-yl)methyl)aniline
##STR00121##
[0491] Example 6 was prepared according to the procedure described
for the synthesis of Example 2 by replacing
4-fluoro-N-methylaniline with 4-chloro-N-methylaniline. .sup.1H NMR
(400 MHz, CDCl3) .delta. 8.48 (d, J=7.2, 1H), 8.15 (s, 1H), 7.66
(d, J=8.3, 2H), 7.62-7.55 (m, 3H), 7.18 (d, J=9.1, 2H), 6.74-6.65
(m, 3H), 4.53 (s, 2H), 3.03 (s, 3H). .sup.1H NMR (400 MHz, CDCl3)
.delta. 8.48 (d, J=7.2, 1H), 8.15 (s, 1H), 7.66 (d, J=8.3, 2H),
7.61-7.55 (m, 3H), 7.18 (d, J=9.1, 2H), 6.75-6.65 (m, 3H), 4.53 (s,
2H), 3.03 (s, 3H). ESI-MS (m/z): [M+H].sup.+ 416.1, RT 2.5357
min.
Example 7
N,5-dimethyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]101yridine-5--
yl)methyl)pyridine-2-amine
##STR00122##
[0493] Example 7 was prepared according to the procedure described
for the synthesis of Example 2 by replacing
4-fluoro-N-methylaniline with N,5-dimethylpyridin-2-amine (2.0
equiv) and using 2.0 equiv of NaHMDS. .sup.1H NMR (400 MHz, CDCl3)
.delta. 8.50 (d, J=7.2, 1H), 8.18 (s, 1H), 8.03 (s, 1H), 7.73-7.65
(m, 3H), 7.62 (d, J=8.2, 3H), 6.82 (d, J=9.2, 1H), 6.66 (dd, J=1.8,
7.2, 1H), 4.88 (s, 2H), 3.37 (s, 3H), 2.27 (s, 3H). .sup.1H NMR
(400 MHz, CDCl3) .delta. 8.50 (d, J=7.2, 1H), 8.18 (s, 1H), 8.03
(s, 1H), 7.72-7.66 (m, 3H), 7.62 (d, J=8.2, 3H), 6.82 (d, J=9.2,
1H), 6.66 (dd, J=1.8, 7.2, 1H), 4.88 (s, 2H), 3.37 (s, 3H), 2.27
(s, 3H). ESI-MS (m/z): [M+H].sup.+ 397.2, RT 1.5837 min.
Example 8
5-((4-fluorophenoxy)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]py-
ridine
##STR00123##
[0495] A mixture of pyrazolopyridine alkyl bromide (I-53) (17.7 mg,
0.05 mmol, 1.0 equiv.), 4-fluorophenol (11.2 mg, 0.1 mmol, 2.0
equiv.), and Cs.sub.2CO.sub.3 (48 mg, 0.15 mmol, 3.0 equiv.) in
acetone was allowed to stir at rt for one hour. The mixture was
filtered and purified by mass-triggered HPLC to provide 8. .sup.1H
NMR (400 MHz, CDCl3) .delta. 8.51 (d, J=7.2, 1H), 8.17 (s, 1H),
7.83 (s, 1H), 7.68 (d, J=1.6, 4H), 7.05-6.82 (m, 5H), 5.07 (s, 2H).
ESI-MS (m/z): [M+H].sup.+ 387.1, RT 2.5104 min.
Example 9
N-(4-cyanophenyl)-N-(2-methoxyethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo-
[1,5-a]pyridine-5-carboxamide
##STR00124##
[0497] Example 9 was prepared according to the procedure described
for the synthesis of Example 1 by replacing
4-(methylamino)benzonitrile with
4-((2-methoxyethyl)amino)benzonitrile. ESI-LC/MS m/z 465.2 (M+H)+;
r.t.=2.098.
Example 10
N-(4-cyanophenyl)-N-(2-(dimethylamino)ethyl)-3-(4-(trifluoromethyl)phenyl)-
pyrazolo[1,5-a]pyridine-5-carboxamide
##STR00125##
[0499] Example 10 was prepared according to the procedure described
for the synthesis of Example 1 by replacing
4-(methylamino)benzonitrile with
4-((2-(dimethylamino)ethyl)amino)benzonitrile. ESI-LC/MS m/z 478.2
(M+H)+; r.t.=1.550.
Example 11
N-(4-cyanophenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(4-(trifluorometh-
yl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide
##STR00126##
[0501] Example 11 was prepared according to the procedure described
for the synthesis of Example 1 by replacing
4-(methylamino)benzonitrile with
4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzonitrile. ESI-LC/MS
m/z 505.2 (M+H)+; r.t.=1.997.
Example 12
N-(4-(methylsulfonyl)phenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(4-(tr-
ifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide
##STR00127##
[0503] Example 12 was prepared according to the procedure described
for the synthesis of Example 1 by replacing
4-(methylamino)benzonitrile with
4-(methylsulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)aniline.
ESI-LC/MS m/z 558.2 (M+H)+; r.t.=1.828.
Example 13
N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-
-a]pyridine-5-carboxamide
##STR00128##
[0505] Example 13 was prepared according to the procedure described
for the synthesis of Example 1 by replacing
4-(methylamino)benzonitrile with 6-(methylamino)nicotinonitrile.
Purification by silica gel chromatography, eluting with
hexane/ethyl acetate provided the desired product (13). .sup.1H NMR
(400 MHz, CDCl3) .delta. 8.67 (dd, J=0.8, 2.3, 1H), 8.41 (dd,
J=0.7, 7.2, 1H), 8.21 (s, 1H), 7.98 (m, 1H), 7.80 (dd, J=2.3, 8.6,
1H), 7.69 (d, J=8.2, 2H), 7.59 (d, J=8.1, 2H), 7.35 (dd, J=0.8,
8.7, 1H), 6.73 (dd, J=1.9, 7.2, 1H), 3.62 (s, 3H). ESI-MS (m/z):
[M+H].sup.+ 422.1, RT 1.9712 min. Anal. Calcd for
C.sub.22H.sub.14F.sub.3N.sub.5O+0.2H.sub.2O: C, 62.18; H, 3.42; N,
16.48. Found: C, 62.26, 62.26; H, 3.39, 3.38; N, 16.40, 16.38.
Example 14
N-methyl-N-(5-methylpyridin-3-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,-
5-a]pyridine-5-carboxamide
##STR00129##
[0507] Example 14 was prepared according to the procedure described
for the synthesis of Example 1 by replacing
4-(methylamino)benzonitrile with N,5-dimethylpyridin-3-amine. The
reaction was purified by mass-triggered HPLC to provide the desired
product, 14. ESI-MS (m/z): [M+H].sup.+ 411.2, RT 1.5164 min.
Example 15
5-(((5-methylpyridin-2-yl)oxy)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazol-
o[1,5-a]pyridine
##STR00130##
[0509] Example 15 was prepared according to the procedure described
for the synthesis of Example 8 by replacing 4-fluorophenol with 1.5
equiv. of 5-methylpyridin-2-ol and using 2.0 equiv.
Cs.sub.2CO.sub.3 in acetonitrile (to replace acetone). The reaction
was purified by mass-triggered HPLC to provide the desired product.
.sup.1H NMR (400 MHz, MeOD) .delta. 8.57 (d, J=7.2, 1H), 8.32 (s,
1H), 7.91 (s, 1H), 7.84 (d, J=8.2, 2H), 7.74 (d, J=8.3, 2H), 7.61
(s, 1H), 7.47 (dd, J=2.5, 9.2, 1H), 6.94 (dd, J=1.8, 7.2, 1H), 6.57
(d, J=9.2, 1H), 5.26 (s, 2H), 2.12 (s, 3H). ESI-MS (m/z):
[M+H].sup.+ 384.1, RT 1.8029 min.
Example 16
5-(4-fluorophenethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine
##STR00131##
[0511] A mixture of pyrazolopyridine aldehyde (I-52) (48 mg, 0.165
mmol, 1.0 equiv.) and Wittig salt (74 mg, 0.18 mmol, 1.1 equiv.) in
acetonitrile was treated with DBU (28 mg, 0.18 mmol, 1.1 equiv.).
The resulting mixture was allowed to stir at 50.degree. C. for two
hours, and then the reaction mixture was concentrated. The residue
was purified by silica gel chromatography, eluting with
hexanes/EtOAc to give the desired olefin. A solution of olefin (22
mg, 0.0575 mmol, 1.0 equiv.) in 5 mL EtOH was purged with nitrogen
gas, then 10% Pd/C (5 mg) was added. The resulting mixture was
purged with hydrogen gas and allowed to stir at room temperature
overnight under an atmosphere of hydrogen gas. The mixture was then
filtered through Celite.RTM. and purified by mass-triggered HPLC to
provide the desired product. .sup.1H NMR (400 MHz, CDCl3) .delta.
8.40 (d, J=7.6, 1H), 8.12 (s, 1H), 7.66 (d, J=8.3, 2H), 7.59 (d,
J=8.2, 2H), 7.42 (s, 1H), 7.10 (dd, J=5.4, 8.6, 2H), 6.96 (t,
J=8.7, 2H), 6.63 (dd, J=1.8, 7.1, 1H), 2.95 (s, 4H). ESI-MS (m/z):
[M+H].sup.+ 385.2, RT 2.5863 min.
Example 17
N-(4-cyanophenyl)-N-methyl-3-(1-methyl-1H-indazol-5-yl)pyrazolo[1,5-a]pyri-
dine-5-carboxamide
##STR00132##
[0513] A mixture of aryl bromide (I-8) (1.0 equiv.),
(1-methyl-1H-indazol-5-yl)boronic acid (1.5 equiv.),
KH.sub.2PO.sub.4 (3.5 equiv.), and SiliaCat.RTM. DPP-Pd or
Pd(dppf)Cl.sub.2 (0.05-0.15 equiv.) in THF/water was allowed to
heat at 150.degree. C. in a microwave reactor for 40-60 minutes.
The solvent was removed under reduced pressure and the crude
material was purified by silica gel chromatography eluting with
ethyl acetate and hexanes. .sup.1H NMR (400 MHz, CDCl3) .delta.
8.28 (dd, J=0.8, 7.4, 1H), 8.12 (s, 1H), 8.01 (d, J=0.8, 1H), 7.80
(m, 1H), 7.65 (s, 1H), 7.60 (d, J=8.6, 2H), 7.44 (d, J=8.6, 1H),
7.36 (dd, J=1.5, 8.6, 1H), 7.22 (obscured by CDCl.sub.3 peak, 2H),
6.62 (dd, J=1.9, 7.3, 1H), 4.11 (s, 3H), 3.53 (s, 3H). ESI-MS
(m/z): [M+H].sup.+ 407.1, RT 1.6596 min. Anal. Calcd for
C.sub.24H.sub.18N.sub.6O+0.1H.sub.2O: C, 70.61; H, 4.49; N, 20.59.
Found: C, 70.59, 70.57; H, 4.43, 4.43; N, 20.57, 20.57.
Example 18
3-(6-acetamidopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyrid-
ine-5-carboxamide
##STR00133##
[0515] A mixture of aryl bromide (I-8) (1.0 equiv.),
(6-acetamidopyridin-3-yl)boronic acid (1.5 equiv.), K.sub.2CO.sub.3
(3.0 equiv.), and Pd(dppf)Cl.sub.2 (0.05-0.15 equiv.) in DME/water
was allowed to heat at 110.degree. C. for two hours. Following
extraction of the reaction mixture with CH.sub.2Cl.sub.2, the
combined organic extracts were concentrated and the residue was
purified by silica gel chromatography, eluting with hexanes/EtOAc
to give the desired product. .sup.1H NMR (400 MHz, MeOD) .delta.
8.48 (dd, J=0.8, 7.0, 1H), 8.35 (d, J=2.4, 1H), 8.26 (s, 1H), 8.18
(d, J=8.4, 1H), 7.81 (dd, J=2.4, 8.6, 1H), 7.78 (s, 1H), 7.71 (d,
J=8.6, 2H), 7.48 (d, J=8.6, 2H), 6.87 (dd, J=1.8, 7.3, 1H), 3.55
(s, 3H), 2.21 (s, 3H). ESI-MS (m/z): [M+H].sup.+ 411.2, RT 1.2806
min.
Example 19
3-(4-carbamoylphenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5--
carboxamide
##STR00134##
[0517] Example 19 was prepared according to the procedure described
for the synthesis of Example 17 by replacing
(1-methyl-1H-indazol-5-yl)boronic acid with
(4-carbamoylphenyl)boronic acid. The reaction was purified by
silica gel chromatography, eluting with hexanes/EtOAc to give 19 as
the desired product. .sup.1H NMR (400 MHz, MeOD) .delta. 8.49 (dd,
J=0.8, 7.2, 1H), 8.31 (s, 1H), 7.97 (d, J=8.4, 2H), 7.84 (s, 1H),
7.74 (d, J=8.6, 2H), 7.53-7.46 (2d, J=8.6, 4H), 6.91 (dd, J=1.6,
7.2, 1H), 3.56 (s, 3H). ESI-MS (m/z): [M+H].sup.+ 397.2, RT 1.3648
min. Anal. Calcd for C.sub.23H.sub.17N.sub.5O.sub.2+0.5H.sub.2O: C,
68.31; H, 4.49; N, 17.32. Found: C, 68.61, 68.54; H, 4.46, 4.40; N,
17.07, 16.99.
Example 20
3-(4-carbamoylphenyl)-N-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-
-carboxamide
##STR00135##
[0519] A mixture of aryl bromide (I-54) (1.0 equiv.),
(4-carbamoylphenyl)boronic acid (1.5 equiv.), KH.sub.2PO.sub.4 (3.5
equiv.), and SiliaCat.RTM. DPP-Pd or Pd(dppf)Cl2 (0.05-0.15 equiv.)
in THF/water was allowed to heat at 150.degree. C. in a microwave
reactor for 40-60 minutes. The solvent was removed under reduced
pressure and the crude material was purified by silica gel
chromatography, eluting with hexanes/EtOAc to give 20 as the
desired product. .sup.1H NMR (400 MHz, CDCl3) .delta. 8.28 (dd,
J=0.8, 7.2, 1H), 8.14 (s, 1H), 7.84 (dt, J=2.0, 8.4, 2H), 7.74 (s,
1H), 7.42 (d, J=8.4, 2H), 7.14-7.08 (m, 2H), 7.06-6.99 (m, 2H),
6.75 (dd, J=1.8, 7.4, 1H), 6.07 (br s, 1H), 5.56 (br s, 1H), 3.49
(s, 3H). ESI-MS (m/z): [M+H].sup.+ 389.1, RT 1.4322 min. Anal.
Calcd for C.sub.22H.sub.17FN.sub.4O.sub.2+0.4H.sub.2O: C, 66.79; H,
4.54; N, 14.16. Found: C, 66.97, 66.74; H, 4.49, 4.43; N, 14.20,
14.16.
Example 21
5-(((4-fluorophenyl)thio)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-
-a]pyridine
##STR00136##
[0521] A solution of pyrazolopyridine alkyl bromide (I-53) (45 mg,
0.127 mmol, 1.0 equiv.) and 4-fluorobenzenethiol (24 mg, 0.19 mmol,
1.5 equiv.) in CH.sub.2Cl.sub.2 was treated with DIEA (33 mg, 0.254
mmol, 2.0 equiv.) and the resulting solution was allowed to stir at
rt for 20 minutes. The reaction was concentrated and the residue
was purified by silica gel chromatography, eluting with
hexanes/EtOAc to give 21 as the desired product. .sup.1H NMR (400
MHz, CDCl3) .delta. 8.41 (d, J=7.2, 1H), 8.11 (s, 1H), 7.64 (d,
J=8.1, 2H), 7.50 (d, J=8.1, 2H), 7.36-7.27 (m, 3H), 6.96 (t, J=8.7,
2H), 6.78 (dd, J=1.9, 7.2, 1H), 4.00 (s, 2H). ESI-MS (m/z):
[M+H].sup.+ 403.1, RT 2.5275 min.
Example 22
5-(((4-fluorophenyl)sulfinyl)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo-
[1,5-a]pyridine
##STR00137##
[0523] A solution of sulfide (21) (30 mg, 0.75 mmol, 1.0 equiv.) in
1 mL of CH.sub.2Cl.sub.2 was treated with m-CPBA (77% purity, 16.6
mg, 0.75 mmol, 1.0 equiv.) and the resulting mixture was allowed to
stir at rt for 20 minutes. The reaction was concentrated and the
residue was purified by silica gel chromatography, eluting with
hexanes/EtOAc to give 22 as the desired product. .sup.1H NMR (400
MHz, CDCl3) .delta. 8.38 (d, J=7.2, 1H), 8.15 (s, 1H), 7.66 (d,
J=8.2, 2H), 7.53 (d, J=8.0, 2H), 7.49-7.43 (m, 2H), 7.32 (d, J=0.7,
1H), 7.20-7.13 (m, 2H), 6.46 (dd, J=1.8, 7.1, 1H), 4.12 (d, J=12.9,
1H), 3.95 (d, J=12.9, 1H). ESI-MS (m/z): [M+H].sup.+ 419.1, RT
2.0051 min.
Example 23
3-(4-(1H-pyrazol-5-yl)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyr-
idine-5-carboxamide
##STR00138##
[0525] Example 23 was prepared according to the procedure described
for the synthesis of Example 17 by replacing
(1-methyl-1H-indazol-5-yl)boronic acid with
((4-(1H-pyrazol-5-yl)phenyl)boronic acid. The reaction was purified
by mass-triggered HPLC to provide 23 as the desired product.
.sup.1H NMR (400 MHz, CDCl3) .delta. 8.30 (dd, J=0.9, 7.3, 1H),
8.15 (s, 1H), 7.83-7.78 (m, 3H), 7.65 (d, J=2.3, 1H), 7.64-7.59 (m,
2H), 7.41-7.34 (m, 2H), 7.25-7.21 (m, 2H), 6.70-6.65 (m, 2H), 3.54
(s, 3H). ESI-MS (m/z): [M+H].sup.+ 419.2, RT 1.5585 min.
Example 24
N-(4-cyanophenyl)-N-methyl-3-(5-(trifluoromethyl)109yridine-2-yl)pyrazolo[-
1,5-a]pyridine-5-carboxamide
##STR00139##
[0527] A mixture of 2-chloro-5-(trifluoromethyl)pyridine (1.0
equiv.), I-50 (1.5 equiv.), KH.sub.2PO.sub.4 (3.5 equiv.), and
SiliaCat.RTM. DPP-Pd or Pd(dppf)Cl2 (0.05-0.15 equiv.) in THF/water
was allowed to heat at 150.degree. C. in a microwave reactor for
40-60 minutes. The solvent was removed under reduced pressure and
the crude material was purified by silica gel chromatography
eluting with ethyl acetate and hexanes. .sup.1H NMR (400 MHz,
CDCl3) .delta. 8.77 (s, 1H), 8.63 (dd, J=0.8, 2.0, 1H), 8.40 (s,
1H), 8.33 (dd, J=0.8, 7.2, 1H), 7.88 (dd, J=2.4, 8.4, 1H), 7.66 (d,
J=8.4, 1H), 7.56 (dt, J=2.1, 8.7, 2H), 7.25 (app dt, obscured by
CDCl3 peak, 2H), 6.79 (dd, J=1.9, 7.2, 1H), 3.56 (s, 3H). ESI-MS
(m/z): [M+H].sup.+ 422.1, RT 1.8535 min.
Example 25
N-(5-cyanopyridin-2-yl)-N-methyl-3-(5-(trifluoromethyl)109yridine-2-yl)pyr-
azolo[1,5-a]pyridine-5-carboxamide
##STR00140##
[0529] A mixture of 2-chloro-5-(trifluoromethyl)pyridine (1.0
equiv.), I-50 (1.5 equiv.), KH.sub.2PO.sub.4 (3.5 equiv.), and
SiliaCat.RTM. DPP-Pd or Pd(dppf)Cl2 (0.05-0.15 equiv.) in THF/water
was allowed to heat at 150.degree. C. in a microwave reactor for
40-60 minutes. The solvent was removed under reduced pressure and
the crude material was purified by silica gel chromatography
eluting with ethyl acetate and hexanes. .sup.1H NMR (400 MHz, MeOD)
.delta. 8.88-8.84 (m, 1H), 8.73 (dd, J=0.8, 2.4, 1H), 8.69 (s, 1H),
8.65 (dd, J=1.2, 2.4, 1H), 8.61 (dd, J=0.8, 7.2, 1H), 8.09-8.02 (m,
2H), 7.99 (d, J=8.5, 1H), 7.53 (dd, J=0.8, 8.5, 1 H), 7.02 (dd,
J=2.0, 7.2, 1H), 3.65 (s, 3H). ESI-MS (m/z): [M+H].sup.+ 423.0, RT
1.8535 min.
Example 26
(S)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,-
5-a]pyridine-5-carboxamide
##STR00141##
[0531] A solution of the aniline (30 mg, 0.082 mmol, 1.0 equiv.) in
CH.sub.2Cl.sub.2 was treated with N-Boc-L-Ala-OH (18.5 mg, 0.098
mmol, 1.2 equiv.), followed by HATU (34.3 mg, 0.0902 mmol, 1.1
equiv.) and DIEA (21 mg, 0.16 mmol, 2.0 equiv.). The resulting
mixture was allowed to stir at rt for two hours, and then was
purified by silica gel chromatography, eluting with
CH.sub.2Cl.sub.2/EtOAc to give the desired N-Boc coupled product.
The N-Boc alanine amide (35 mg) was dissolved in 1 mL
CH.sub.2Cl.sub.2 and 1 mL TFA was added. The resulting solution was
allowed to stir at rt for 30 minutes, and the solvents were removed
under reduced pressure. The residue was taken up in 2 mL EtOAc and
3 mL hexanes was added to precipitate the product TFA salt, which
was isolated by filtration and dried under high vacuum. A solution
of the TFA salt (16 mg) in 20% MeOH/CH.sub.2Cl.sub.2 was run
through a 100 mg cartridge of Varian Stratospheres.TM. PL-HCO3 MP
resin. The solvents were removed under reduced pressure, and the
residue was dissolved in 10% MeOH/CH.sub.2Cl.sub.2 and run through
a 200 mg cartridge of Varian Stratospheres.TM. PL-HCO3 MP resin.
The solvents were removed under reduced pressure to provide 26 as
the free base. .sup.1H NMR (400 MHz, MeOD) .delta. 8.45 (dd, J=0.8,
7.2, 1H), 8.18 (s, 1H), 7.75-7.71 (m, 3H), 7.68 (d, J=8.6, 2H),
7.47 (d, J=8.6, 2H), 7.32 (d, J=8.6, 2H), 6.87 (dd, J=1.8, 7.3,
1H), 3.61 (q, J=6.9, 1H), 3.55 (s, 3H), 1.40 (d, J=6.9, 3H). ESI-MS
(m/z): [M+H].sup.+ 439.1, RT 1.1711 min.
Example 27
3-(5-carbamoylpyridin-2-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyrid-
ine-5-carboxamide
##STR00142##
[0533] Example 27 was prepared according to the procedure described
for the synthesis of Example 25 by replacing
2-chloro-5-(trifluoromethyl)pyridine with 6-chloronicotinamide.
Purification by silica gel chromatography, eluting with
hexanes/EtOAc, then 5% MeOH/CH.sub.2Cl.sub.2 gave the desired
product. .sup.1H NMR (400 MHz, DMSO) .delta. 9.04 (dd, J=0.8, 2.3,
1H), 8.81 (s, 1H), 8.68 (dd, J=0.8, 7.2, 1H), 8.56 (s, 1H), 8.22
(dd, J=2.3, 8.4, 1H), 8.14 (s, 1H), 7.94 (d, J=8.3, 1H), 7.81 (d,
J=8.7, 2H), 7.58 (s, 1H), 7.54 (d, J=8.6, 2H), 6.85 (dd, J=1.9,
7.2, 1H), 3.47 (s, 3H). ESI-MS (m/z): [M+H].sup.+ 397.1, RT 1.2047
min.
Example 28
4-cyano-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-
-yl)benzamide
##STR00143##
[0535] To a solution of pyrazolopyridine (15 mg, 0.05 mmol) in
CH.sub.2Cl.sub.2 containing triethylamine (0.020 mL, 3.00 mmol) at
0.degree. C. was added 4-cyanobenzoyl chloride (14 mg, 1.50 mmol).
The reaction was allowed to warm to room temperature and stir for 1
hour. The reaction was diluted with water and extracted with
dichloromethane. The organic extracts were washed with brine and
dried over anhydrous Na.sub.2SO.sub.4. The solvent was removed and
the residue was purified by mass-trigger HPLC. .sup.1H NMR (400
MHz, MeOD) .delta. 8.54 (d, J=7.4, 1H), 8.29 (s, 1H), 7.66 (ddd,
J=8.1, 12.9, 29.8, 9H), 6.92 (dd, J=2.2, 7.4, 1H), 3.56 (s, 3H); MS
m/z 421.0 (M+H).sup.+.
Example 29
4-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine--
5-yl)benzamide
##STR00144##
[0537] Example 29 was prepared according to the procedure described
for the synthesis of Example 28 by replacing 4-cyanobenzoyl
chloride with 4-fluorobenzoyl chloride. .sup.1H NMR (400 MHz, MeOD)
.delta. 8.43 (d, J=7.4, 1H), 8.18 (s, 1H), 8.06-7.84 (m, 1H), 7.60
(d, J=8.3, 2H), 7.50 (d, J=8.5, 3H), 7.40 (dd, J=5.3, 8.8, 2H),
7.08 (t, J=8.8, 1H), 6.96 (t, J=8.8, 2H), 6.78 (d, J=7.4, 1H), 3.45
(s, 3H); MS m/z 414.1 (M+H).sup.+.
Example 30
4-cyano-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-
-yl)benzenesulfonamide
##STR00145##
[0539] To a solution of pyrazolopyridine (15 mg, 0.05 mmol) and a
catalytic amount of DMAP in pyridine (1.0 mL) at 0.degree. C. was
added 4-cyanobenzene-1-sulfonyl chloride (18 mg, 0.08 mmol). The
reaction was allowed to warm to room temperature and stir
overnight. The reaction was diluted with water and extracted with
dichloromethane. The organic extracts were washed with saturated
CuSO.sub.4 solution and brine, dried over anhydrous
Na.sub.2SO.sub.4. The solvent was removed and the crude material
was purified by mass-triggered HPLC. .sup.1H NMR (400 MHz, MeOD)
.delta. 8.57 (d, J=7.6, 1H), 8.34 (s, 1H), 7.95 (d, J=8.3, 2H),
7.83 (d, J=8.4, 2H), 7.73 (s, 4H), 7.61 (s, 1H), 6.85 (d, J=7.5,
1H), 3.32 (s, 3H, obscured by MeOD peak); MS m/z 457.0
(M+H).sup.+.
Example 31
4-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine--
5-yl)benzenesulfonamide
##STR00146##
[0541] Example 31 was prepared according to the procedure described
for the synthesis of Example 30 by replacing
4-cyanobenzene-1-sulfonyl chloride with 4-fluorobenzene-1-sulfonyl
chloride. ESI-LC/MS m/z 450.0 (M+H)+; r.t.=1.954.
Example 32
3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyrid-
ine-5-carboxamide
##STR00147##
[0543] Example 32 was prepared from intermediate I-9 according to
the procedure described for the synthesis of Example 17 by
replacing (1-methyl-1H-indazol-5-yl)boronic acid with
(4-carbamoylphenyl)boronic acid. The reaction was purified by
silica gel chromatography, eluting with dichloromethane/ethyl
acetate then 5% methanol/dichloromethane to give 32 as the desired
product. .sup.1H NMR (400 MHz, DMSO) .delta. 8.87 (dd, J=0.6, 2.2,
1H), 8.72 (dd, J=0.7, 7.2, 1H), 8.53 (s, 1H), 8.26 (dd, J=2.3, 8.6,
1H), 8.03 (s, 1H), 8.00-7.91 (m, 3H), 7.67-7.57 (m, 3H), 7.40 (s,
1H), 6.85 (dd, J=1.8, 7.2, 1H), 3.53 (s, 3H). ESI-MS (m/z):
[M+H].sup.+ 398.1, RT 1.2637 min.
Example 33
N-methyl-3-(4-(trifluoromethyl)phenyl)-N-(5-(trifluoromethyl)pyridine-2-yl-
)pyrazolo[1,5-a]pyridine-5-carboxamide
##STR00148##
[0545] Example 33 was prepared according to the procedure described
for the synthesis of Example 1 by replacing
4-(methylamino)benzonitrile with
N-methyl-5-(trifluoromethyl)pyridine-2-amine. The reaction was
purified by mass-triggered HPLC to provide 33 as the desired
product. ESI-MS (m/z): [M+H].sup.+ 465.1, RT 2.0724 min.
Example 34
N-methyl-N-(5-(methylsulfonyl)114yridine-2-yl)-3-(4-(trifluoromethyl)pheny-
l)pyrazolo[1,5-a]pyridine-5-carboxamide
##STR00149##
[0547] Example 33 was prepared according to the procedure described
for the synthesis of Example 1 by replacing
4-(methylamino)benzonitrile with
N-methyl-5-(methylsulfonyl)pyridine-2-amine. The reaction was
purified by silica gel chromatography, eluting with hexanes/EtOAc,
followed by purification by mass-triggered HPLC to provide 34 as
the desired product. .sup.1H NMR (400 MHz, MeOD) .delta. 8.89 (d,
J=2.4, 1H), 8.56 (d, J=7.2, 1H), 8.35 (s, 1H), 8.23 (dd, J=2.5,
8.6, 1H), 7.91 (s, 1H), 7.75 (d, J=8.3, 2H), 7.66 (d, J=8.2, 2H),
7.56 (d, J=8.6, 1H), 6.94 (dd, J=1.8, 7.3, 1H), 3.65 (s, 3H), 3.12
(s, 3H). ESI-MS (m/z): [M+H].sup.+ 475.1, RT 1.7860 min.
Example 35
N-(4-fluorobenzyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5--
amine
##STR00150##
[0549] To a stirred solution of pyrazolopyridine (25 mg, 0.05 mmol)
in dioxane (1.0 mL) was added 4N HCl in dioxane (1.0 mL). The
reaction was monitored by LCMS and when the reaction was complete,
the resultant HCl salt was filtered and dried to give 35. ESI-LC/MS
m/z 386.1 (M+H)+; r.t.=2.167.
Example 36
N-(4-fluorobenzyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]py-
ridine-5-amine
##STR00151##
[0551] NaH (5 mg, 0.08 mmol) was added to a solution of
pyrazolopyridine (19 mg, 0.05 mmol) and DMF (1.0 mL). MeI (0.020
mL, 0.06 mmol) was added and the reaction was stirred for 4 h at
room temperature. The reaction was quenched by addition of
H.sub.2O. The solution was extracted with ethyl acetate. The
combined extracts were washed with brine, dried over anhydrous
Na.sub.2SO.sub.4 and concentrated. The crude material was purified
by silica gel chromatography, eluting with ethyl acetate and
hexanes. .sup.1H NMR (400 MHz, MeOD) .delta. 8.21 (d, J=8.7, 1H),
8.02 (s, 1H), 7.57 (q, J=8.7, 4H), 7.19 (dd, J=5.4, 8.5, 2H), 6.98
(t, J=8.8, 2H), 6.78-6.63 (m, 2H), 4.60 (s, 2H), 3.09 (s, 3H); MS
m/z 400.2 (M+H).sup.+.
Example 37
N-methyl-6-(trifluoromethyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5--
a]pyridine-5-yl)nicotinamide
##STR00152##
[0553] Example 37 was prepared according to the procedure described
for the synthesis of Example 28 by replacing 4-cyanobenzoyl
chloride with 6-(trifluoromethyl)nicotinoyl chloride. .sup.1H NMR
(400 MHz, MeOD) .delta. 8.69 (s, 1H), 8.48 (d, J=7.5, 1H), 8.20 (s,
1H), 7.97 (d, J=8.1, 1H), 7.63 (dd, J=8.2, 24.5, 5H), 7.48 (d,
J=8.1, 2H), 6.86 (dd, J=2.2, 7.4, 1H), 3.48 (s, 3H). ESI-LC/MS m/z
465.1 (M+H)+; r.t.=1.696.
Example 38
N-methyl-5-(trifluoromethyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5--
a]pyridine-5-yl)picolinamide
##STR00153##
[0555] Example 38 was prepared according to the procedure described
for the synthesis of Example 28 by replacing 4-cyanobenzoyl
chloride with 5-(trifluoromethyl)picolinoyl chloride. .sup.1H NMR
(400 MHz, CDCl3) .delta. 8.56 (s, 1H), 8.35 (d, J=7.4, 1H), 8.08
(s, 1H), 7.94 (d, J=6.9, 1H), 7.81 (d, J=8.2, 1H), 7.59 (d, J=8.2,
2H), 7.40 (d, J=7.8, 2H), 7.32 (s, 1H), 6.63 (s, 1H), 3.51 (s, 3H).
ESI-LC/MS m/z 465.1 (M+H)+; r.t.=1.740.
Example 39
4-cyano-N-((tetrahydro-2H-pyran-4-yl)methyl)-N-(3-(4-(trifluoromethyl)phen-
yl)pyrazolo[1,5-a]pyridin-5-yl)benzamide
##STR00154##
[0557] Example 39 was prepared according to the procedure described
for the synthesis of Example 28. .sup.1H NMR (400 MHz, CDCl3)
.delta. 8.35 (d, J=7.4, 1H), 8.09 (s, 1H), 7.61 (d, J=8.1, 2H),
7.52 (d, J=8.4, 2H), 7.43 (d, J=8.5, 2H), 7.29 (d, J=8.1, 2H), 7.17
(s, 1H), 6.50 (dd, J=2.3, 7.4, 1H), 3.97-3.81 (m, 4H), 3.25 (dd,
J=9.8, 11.7, 2H), 1.96 (d, J=13.1, 1H), 1.55 (d, J=18.6, 2H),
1.45-1.29 (m, 2H). ESI-LC/MS m/z 505.1 (M+H)+; r.t.=1.689.
Example 40
N-(4-cyanophenyl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a-
]pyridine-5-carboxamide
##STR00155##
[0559] A mixture of aryl bromide (I-8) (1.0 equiv.),
(1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (1.5 equiv.),
K.sub.2HPO.sub.4 (2.5 equiv.), and Pd(dppf)Cl2 (0.05-0.15 equiv.)
in THF/water was allowed to heat at 80.degree. C. overnight. The
solvent was removed and the crude residue was purified by silica
gel chromatography, eluting with hexanes/EtOAc, then 5%
MeOH/CH.sub.2Cl.sub.2 gave the desired product. .sup.1H NMR (400
MHz, DMSO) .delta. 11.76 (s, 1H), 8.64 (dd, J=0.7, 7.2, 1H), 8.39
(s, 1H), 8.33 (d, J=2.1, 1H), 7.88 (d, J=2.0, 1H), 7.84 (d, J=8.6,
2H), 7.79 (s, 1H), 7.59-7.50 (m, 3H), 6.79 (dd, J=1.8, 7.2, 1H),
6.53 (dd, J=1.8, 3.4, 1H), 3.46 (s, 3H). ESI-MS (m/z): [M+H].sup.+
393.1, RT 1.1533 min.
Example 41
3-(6-aminopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine--
5-carboxamide
##STR00156##
[0561] Example 41 was prepared according to the procedure described
for the synthesis of Example 40 by replacing
(1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid with
(6-aminopyridin-3-yl)boronic acid. The reaction was purified by
silica gel chromatography, eluting with hexanes/EtOAc, then 5%
MeOH/CH.sub.2Cl.sub.2, followed by purification by mass-triggered
HPLC and a NaHCO.sub.3/EtOAc workup gave the desired product.
.sup.1H NMR (400 MHz, MeOD) .delta. 8.43 (dd, J=0.7, 7.3, 1H), 8.12
(s, 1H), 7.93 (d, J=1.6, 1H), 7.72 (d, J=8.6, 2H), 7.68 (s, 1H),
7.50 (dd, J=2.4, 8.6, 1H), 7.46 (d, J=8.6, 2H), 6.83 (dd, J=1.8,
7.3, 1H), 6.69 (d, J=8.6, 1H), 3.54 (s, 3H). ESI-MS (m/z):
[M+H].sup.+ 369.1, RT 0.8592 min.
Example 42
3-(4-aminophenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carb-
oxamide
##STR00157##
[0563] A mixture of aryl bromide (I-8) (1.0 equiv.),
(4-aminophenyl)boronic acid (1.5 equiv.), K.sub.2HPO.sub.4 (2.5
equiv.), and Pd(dppf)Cl2 (0.05-0.15 equiv.) in THF/water was
allowed to heat at 110.degree. C. overnight. The solvent was
removed and the crude residue was by silica gel chromatography,
eluting with hexanes/EtOAc gave the desired product. ESI-MS (m/z):
[M+H].sup.+ 368.1, RT 1.0446 min.
Example 43
3-(4-(2-aminoacetamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]py-
ridine-5-carboxamide
##STR00158##
[0565] A solution of Example 42 (1.0 equiv.) in CH.sub.2Cl.sub.2
(.about.0.1M) was treated with 2-((tert-butoxycarbonyl)amino)acetic
acid (1.2 equiv.), followed by HATU (1.1 equiv (2.5 equiv.). The
resulting mixture was allowed to stir at rt for two hours, and then
was filtered and treated with one volume of TFA. The resulting
solution was allowed to stir at rt for 30 minutes, and the solvents
were removed under reduced pressure. The residue was purified by
mass-triggered HPLC to provide the desired product. ESI-MS (m/z):
[M+H].sup.+ 425.1, RT 1.1033 min.
Example 44
(R)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,-
5-a]pyridine-5-carboxamide
##STR00159##
[0567] Example 44 was prepared according to the procedure described
for the synthesis of Example 43 by replacing
2-((tert-butoxycarbonyl)amino)acetic acid with
(R)-2-((tert-butoxycarbonyl)amino)propanoic acid. ESI-MS (m/z):
[M+H].sup.+ 439.2, RT 1.0950 min.
Example 45
(S)-3-(4-(2-amino-3-methylbutanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyr-
azolo[1,5-a]pyridine-5-carboxamide
##STR00160##
[0569] Example 45 was prepared according to the procedure described
for the synthesis of Example 43 by replacing
2-((tert-butoxycarbonyl)amino)acetic acid with
(S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid. ESI-LC/MS
m/z 467.2 (M+H).sup.+; RT=1.230.
Example 46
(S)-3-(4-(2-amino-2-cyclohexylacetamido)phenyl)-N-(4-cyanophenyl)-N-methyl-
pyrazolo[1,5-a]pyridine-5-carboxamide
##STR00161##
[0571] Example 46 was prepared according to the procedure described
for the synthesis of Example 43 by replacing
2-((tert-butoxycarbonyl)amino)acetic acid with
(S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid. ESI-MS
(m/z): [M+H].sup.+ 507.2, RT 1.4154 min.
Example 47
3-(4-fluorophenyl)-1-methyl-1-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a-
]pyridin-5-yl)urea
##STR00162##
[0573] NaH (8 mg, 0.15 mmol) was added to a solution of
pyrazolopyridine (30 mg, 0.10 mmol) and DMF (2.0 mL). The reaction
was stirred at room temperature for 15 minutes. The isocyanate was
added and the reaction stirred at room temperature for an
additional 4 hours. The reaction ws quenched with water and
extracted with ethyl acetate. The combined organic extracts were
washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The
solvent was removed and the material was purified by silica gel
chromatography eluting with ethyl acetate and hexanes. .sup.1H NMR
(400 MHz, CDCl3) .delta. 8.49 (d, J=7.3, 1H), 8.16 (s, 1H), 7.61
(dd, J=8.5, 25.1, 5H), 7.19 (s, 3H), 6.89 (t, J=7.5, 2H), 6.76 (d,
J=7.3, 1H), 6.31 (s, 1H), 3.33 (s, 3H).
Example 48
6-(1,1-difluoroethyl)-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,-
5-a]pyridin-5-yl)nicotinamide
##STR00163##
[0575] To a solution of 6-(1,1-difluoroethyl)nicotinic acid (28 mg,
0.15 mmol) in dichloromethane (1.00 mL) was added triethyl amine
(0.042 mL, 0.30 mmml) and a catalytic amount of DMF. The reaction
was cooled to 0.degree. C. Oxallyl chloride was added dropwise and
the reaction mixture was stirred for 30 minutes. The solvent was
removed and the solid was dried under vacuum for 15 minutes. To the
crude acid chloride was added dichloromethane (1.00 mL) and
triethylamine (0.042 mL, 0.30 mmol) followed by the amine (29 mg,
0.10 mmol) at 0.degree. C. The reaction was allowed to warm to room
temperature and stir for two hours. The reaction was quenched with
water, extracted with dichloromethane, washed with brine, dried
over Na.sub.2SO.sub.4 and concentrated. The reaction was purified
by silica gel chromatography, eluting with ethyl acetate and
hexanes. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.67 (s, 1H),
8.46 (d, J=7.4, 1H), 8.17 (s, 1H), 7.92 (d, J=8.1, 1H), 7.69 (d,
J=8.1, 2H), 7.63 (d, J=8.1, 1H), 7.41 (d, J=7.9, 2H), 7.35 (s, 1H),
6.64 (d, J=7.3, 1H), 3.60 (s, 3H). ESI-LC/MS m/z 461.1 (M+H)+;
r.t.=1.993.
Example 49
6-cyclopropyl-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyri-
din-5-yl)nicotinamide
##STR00164##
[0577] Example 49 was prepared according to the procedure described
for the synthesis of Example 48 by replacing
6-(1,1-difluoroethyl)nicotinic acid with 6-cyclopropylnicotinic
acid. ESI-LC/MS m/z 437.1 (M+H)+; RT=1.640.
Example 50
4-cyclopropyl-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyri-
din-5-yl)benzamide
##STR00165##
[0579] Example 50 was prepared according to the procedure described
for the synthesis of Example 48 by replacing
6-(1,1-difluoroethyl)nicotinic acid with 4-cyclopropylbenzoic acid.
ESI-LC/MS m/z 436.0 (M+H)+; RT=2.408.
Example 51
5-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-
-yl)picolinamide
##STR00166##
[0581] Example 51 was prepared according to the procedure described
for the synthesis of Example 48 by replacing
6-(1,1-difluoroethyl)nicotinic acid with 5-fluoropicolinic acid.
.sup.1H NMR (400 MHz, CDCl3) .delta. 7.71 (d, J=7.4, 1H), 7.48 (s,
1H), 7.46 (s, 1H), 7.00 (s, 1H), 6.95-6.78 (m, 6H), 6.08 (d, J=7.4,
1H), 2.80 (d, J=38.0, 3H). ESI-LC/MS m/z 415.0 (M+H)+;
r.t.=2.158.
Example 52
N-methyl-4-(methylsulfonyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a-
]pyridin-5-yl)benzamide
##STR00167##
[0583] Example 52 was prepared according to the procedure described
for the synthesis of Example 48 by replacing
6-(1,1-difluoroethyl)nicotinic acid with 4-(methylsulfonyl)benzoic
acid. ESI-LC/MS m/z 474.1 (M+H)+; RT=2.071
Example 53
N-(5-cyanopyridin-2-yl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo-
[1,5-a]pyridine-5-carboxamide
##STR00168##
[0585] Example 53 was prepared from intermediate I-9 according to
the procedure described for the synthesis of Example 32 by
replacing (4-carbamoylphenyl)boronic acid with
(1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid. Purification by silica
gel chromatography, eluting with hexanes/EtOAc, and then 5%
EtOH/EtOAc gave the desired product. .sup.1H NMR (400 MHz, DMSO)
.delta. 11.76 (s, 1H), 8.88 (dd, J=0.6, 2.3, 1H), 8.70 (dd, J=0.8,
7.2, 1H), 8.44 (s, 1H), 8.38 (d, J=2.1, 1H), 8.26 (dd, J=2.3, 8.6,
1H), 7.99 (d, J=2.0, 1H), 7.91 (s, 1H), 7.60 (dd, J=0.5, 8.6, 1H),
7.57-7.50 (m, 1H), 6.82 (dd, J=1.8, 7.2, 1H), 6.51 (dd, J=1.8, 3.4,
1H), 3.53 (s, 3H). ESI-MS (m/z): [M+H].sup.+ 394.0, RT 1.4237
min.
Example 54
3-(6-aminopyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyr-
idine-5-carboxamide
##STR00169##
[0587] Example 54 was prepared from intermediate I-9 according to
the procedure described for the synthesis of Example 32 by
replacing (4-carbamoylphenyl)boronic acid with
(6-aminopyridin-3-yl)boronic acid. Purification by silica gel
chromatography, eluting with hexanes/EtOAc, and then 10% EtOH/EtOAc
gave the desired product. .sup.1H NMR (400 MHz, DMSO) .delta. 8.84
(d, J=2.3, 1H), 8.63 (dd, J=0.7, 7.3, 1H), 8.29 (s, 1H), 8.23 (dd,
J=2.3, 8.6, 1H), 8.09 (d, J=2.2, 1H), 7.86-7.80 (m, 1H), 7.58 (d,
J=8.6, 1H), 7.54 (dd, J=2.5, 8.5, 1H), 6.75 (dd, J=1.8, 7.2, 1H),
6.54 (d, J=8.6, 1H), 6.05 (s, 2H), 3.52 (s, 3H). ESI-MS (m/z):
[M+H].sup.+ 370.0, RT 1.2469 min.
Example 55
4-chloro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-
-yl)benzamide
##STR00170##
[0589] Example 25 was prepared according to the procedure described
for the synthesis of Example 28 by replacing 4-cyanobenzoyl
chloride with 4-fluorobenzoyl chloride. .sup.1H NMR (400 MHz,
CDCl3) .delta. 8.33 (d, J=7.5, 1H), 8.07 (s, 1H), 7.58 (d, J=8.2,
2H), 7.42-7.26 (m, 4H), 7.26-7.12 (m, 3H), 6.53 (dd, J=2.3, 7.4,
1H), 3.47 (s, 3H). ESI-LC/MS m/z 430.0 (M+H)+; r.t.=2.376.
Example 56
N-(3-(4-carbamoylphenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-fluoro-N-methylbenz-
amide
##STR00171##
[0591] Example 56 was prepared from intermediate I-54 according to
the procedure described for the synthesis of Example 17 by
replacing (1-methyl-1H-indazol-5-yl)boronic acid with
(4-carbamoylphenyl)boronic acid. ESI-LC/MS m/z 389.1 (M+H)+;
r.t.=1.603.
Example 57
4-fluoro-N-methyl-N-(3-(4-(5-(methylamino)-1,3,4-thiadiazol-2-yl)phenyl)py-
razolo[1,5-a]pyridin-5-yl)benzamide
##STR00172##
[0593] Example 57 was prepared from intermediate I-54 according to
the procedure described for the synthesis of Example 17 by
replacing (1-methyl-1H-indazol-5-yl)boronic acid with
(4-(5-(methylamino)-1,3,4-thiadiazol-2-yl)phenyl)boronic acid.
.sup.1H NMR (400 MHz, MeOD) .delta. 8.53 (d, J=7.4, 1H), 8.29 (s,
1H), 7.85 (d, J=8.4, 2H), 7.66-7.45 (m, 5H), 7.07 (t, J=8.8, 2H),
6.90 (dd, J=2.3, 7.5, 1H), 3.56 (s, 3H), 3.12 (s, 3H). ESI-LC/MS
m/z 459.0 (M+H)+; r.t.=1.708.
Example 58
N-methyl-N-(5-(methylsulfonyl)pyridin-2-yl)-3-(1H-pyrrolo[2,3-b]pyridin-5--
yl)pyrazolo[1,5-a]pyridine-5-carboxamide
##STR00173##
[0595] Example 58 was prepared from intermediate I-66 according to
the procedure described for the synthesis of Example 17 by
replacing (1-methyl-1H-indazol-5-yl)boronic acid with
(1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid. ESI-MS (m/z):
[M+H].sup.+ 447.0, RT 1.3983 min. ESI-LC/MS m/z 447.0 (M+H)+;
r.t.=1.398.
Example 59
N-(5-cyanopyridin-2-yl)-N-methyl-3-(5-methylpyridin-2-yl)pyrazolo[1,5-a]py-
ridine-5-carboxamide
##STR00174##
[0597] Example 29 was prepared according to the procedure described
for the synthesis of Example 25 by replacing
2-chloro-5-(trifluoromethyl)pyridine with
2-chloro-5-methylpyridine. The reaction was purified by
mass-triggered HPLC to provide the desired product. ESI-MS (m/z):
[M+H].sup.+ 369.1, RT 1.3394 min.
Example 60
N-(5-cyanopyridin-2-yl)-3-(5-methoxypyridin-2-yl)-N-methylpyrazolo[1,5-a]p-
yridine-5-carboxamide
##STR00175##
[0599] Example 60 was prepared according to the procedure described
for the synthesis of Example 25 by replacing
2-chloro-5-(trifluoromethyl)pyridine with
2-chloro-5-methoxypyridine. The reaction was purified by
mass-triggered HPLC to provide the desired product. ESI-MS (m/z):
[M+H].sup.+ 385.1, RT 1.5073 min.
Example 61
3-(5-carbamoylpyridin-2-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a-
]pyridine-5-carboxamide
##STR00176##
[0601] Example 61 was prepared according to the procedure described
for the synthesis of Example 25 by replacing
2-chloro-5-(trifluoromethyl)pyridine with 6-chloronicotinamide. The
reaction was purified by mass-triggered HPLC to provide the desired
product. ESI-MS (m/z): [M+H].sup.+ 398.1, RT 1.4232 min.
Example 62
3-(4-carbamoylphenyl)-N-methyl-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo-
[1,5-a]pyridine-5-carboxamide
##STR00177##
[0603] Example 62 was prepared according to the procedure described
for the synthesis of Example 32. The reaction was purified by
mass-triggered HPLC to provide the desired product. ESI-MS (m/z):
[M+H].sup.+ 440.0, RT 1.7179 min.
Example 63
3-(4-carbamoylphenyl)-N-methyl-N-(5-methylpyridin-2-yl)pyrazolo[1,5-a]pyri-
dine-5-carboxamide
##STR00178##
[0605] Example 63 was prepared according to the procedure described
for the synthesis of Example 32. The reaction was purified by
mass-triggered HPLC to provide the desired product. ESI-MS (m/z):
[M+H].sup.+ 386.1, RT 1.4742 min.
Example 64
N-(4-fluorophenyl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]py-
ridine-5-carboxamide
##STR00179##
[0607] A mixture of aryl bromide (I-54, 1.0 equiv.),
(4-(methylcarbamoyl)phenyl)boronic acid (2.0 equiv.), KF (2.0
equiv.), and Pd(PPh).sub.3 (0.05 equiv.) in 1,4-dioxane/DME/water
was allowed to heat at 100.degree. C. in a microwave reactor for 5
minutes. Following extraction of the reaction mixture with ethyl
acetate, the solvent was removed under reduced pressure and the
residue was purified by silica gel chromatography, eluting with
ethyl acetate and hexanes to give 64 as the desired product.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta..delta. ppm 8.46 (d,
J=8.00 Hz, 1H) 8.26 (s, 1H), 7.89 (d, J=8.00 Hz, 2H) 7.76 (s, 1H),
7.49 (d, J=8.00 Hz, 2H) 7.32-7.35 (m, 2H) 7.12 (t, J=8.00 Hz, 2H)
6.91 (d, J=8.00 Hz, 1H) 3.50 (s, 3H) 2.96 (s, 3H); ESI-MS (m/z):
[M+H].sup.+ 403.
Example 65
4-(5-(1-(methyl(5-methylpyridin-2-yl)amino)ethyl)pyrazolo[1,5-a]pyridin-3--
yl)benzamide
##STR00180##
[0609] Example 65 was prepared from intermediate I-19 according to
general Suzuki procedure E. A mixture of aryl bromide (I-19, 1.0
equiv.), (4-carbamoylphenyl)boronic acid (1.5 equiv.), 2 M aq KF (3
equiv.), and Pd.sub.2(dba).sub.3 (0.1 equiv.), P(o-tolyl).sub.3(0.1
equiv.) in toluene:ethanol (7:3) was degassed and heated to
90.degree. C. for 4 h. The crude product was purified by silica gel
chromatography, eluting with ethyl acetate and hexanes to give 65
as the desired product. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.65 (d, J=7.50 Hz, 1H), 8.43 (s, 1H), 7.97 (d, J=8.3 Hz,
4H), 7.75 (d, J=7.9 Hz, 3H), 7.42-7.40 (m, 1H), 7.38 (d, J=5.0 Hz,
1H), 6.75 (d, J=7.10 Hz, 1H), 6.60 (d, J=8.8 Hz, 1H), 6.14-6.11 (m,
1H), 2.70 (s, 3H), 2.15 (s, 3H), 1.57 (d, J=7.9 Hz, 3H); ESI-MS
(m/z): [M+H].sup.+ 386.1.
Example 66
4-(5-(1-(7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl)pyrazolo[1,5-
-a]pyridin-3-yl)benzamide
##STR00181##
[0611] Example 66 was prepared from intermediate I-67 according to
general Suzuki procedure E. A mixture of aryl bromide (I-67, 1.0
equiv.), (4-carbamoylphenyl)boronic acid (1.5 equiv.), 2 M aq KF (3
equiv.), and Pd.sub.2(dba).sub.3 (0.1 equiv.), P(o-tolyl).sub.3
(0.1 equiv.) in toluene:ethanol (7:3) was degassed and heated to
90.degree. C. for 7 h. The crude compound was purified by silica
gel chromatography, eluting with 2% MeOH/DCM to give
4-(5-(1-(7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl)pyrazolo[1,-
5-a]pyridin-3-yl)benzamide 66 as the desired product (37%). .sup.1H
NMR (400 MHz, DMSO-d.sub.6). .delta. 8.69 (d, J=7.50 Hz, 1H), 8.47
(s, 1H), 8.01 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.90 (s, 1H), 7.80
(d, J=8.4 Hz, 2H), 7.37 (br. s, 1H), 7.02 (dd, J=3.1, 9.4 Hz, 1H),
6.96-6.92 (m, 1H), 6.82 (dd, J=1.8, 7.3 Hz, 1H), 6.73 (dt, J=3.0,
8.6, Hz, 1H), 6.16-6.21 (m, 1H), 4.80 (m, 2H), 1.85 (d, J=7.0 Hz,
3H); ESI-LC/MS (Method 1) (m/z): [M+H].sup.+ 431.
Example 67
N-(4-cyanophenyl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyr-
idine-5-carboxamide
##STR00182##
[0613] Example 67 was prepared from intermediate I-8 according to
general Suzuki procedure F. A mixture of aryl bromide (I-8) (1.0
equiv.), (4-(methylcarbamoyl)phenyl)boronic acid (1.2 equiv.),
Na.sub.2CO.sub.3 (2.0 equiv.), and Pd(PPh.sub.3).sub.4 (0.1 equiv.)
in dioxane was allowed to heat at 100.degree. C. in microwave
reactor for 40 minutes. The reaction was filtered over celite and
the filtrate was concentrated under reduced pressure. The residue
was purified by silica gel chromatography, eluting with
hexanes/EtOAc to give 67 as the desired product. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 8.66 (d, J=7.28 Hz, 1H) 8.48 (s, 2H)
7.91 (d, J=8.03 Hz, 2H) 7.81-7.88 (m, 3H) 7.54 (t, J=7.78 Hz, 4H)
6.83 (d, J=7.53 Hz, 1H) 3.46 (s, 3H) 2.82 (d, J=4.02 Hz, 3H).
ESI-MS (m/z): [M+H].sup.+ 410.
Example 68
N-(4-(5-(1-(methyl(5-methylpyridin-2-yl)amino)ethyl)pyrazolo[1,5-a]pyridin-
-3-yl)phenyl)acetamide
##STR00183##
[0615] Example 68 was prepared from intermediate I-19 according to
the procedure described for the synthesis of Example 65 (general
Suzuki procedure E) by replacing (4-carbamoylphenyl)boronic acid
with (4-acetamidophenyl)boronic acid. The crude product was
purified by silica gel chromatography, eluting with ethyl acetate
and hexanes to give 68 as the desired product. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.01 (s, 1H), 8.60 (d, J=7.5 Hz, 1H),
8.27 (s, 1H), 7.97 (s, 1H), 7.66-7.68 (m, 3H), 7.58 (d, J=8.6 Hz,
2H), 7.40 (d, J=7.0 Hz, 1H), 6.68 (d, J=7.5 Hz, 1H), 6.63 (d, J=8.6
Hz, 1H), 6.11 (d, J=6.5 Hz, 1H), 2.7 (s, 3H), 2.1 (s, 3H), 2.0 (s,
3H), 1.55 (d, J=7.0 Hz, 3H); ESI-LC/MS (Method 2) (m/z):
[M+H].sup.+ 400.
Example 69
3-(4-acetamidophenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyrid-
ine-5-carboxamide
##STR00184##
[0617] Example 69 was prepared from intermediate I-9 according to
the procedure described for the synthesis of Example 65 (general
Suzuki procedure E) by replacing (4-carbamoylphenyl)boronic acid
with (4-acetamidophenyl)boronic acid. The crude product was
purified by column chromatography over silica gel
(MeOH/CH.sub.2Cl.sub.2, 0-2% MeOH) to give 68 as the desired
product. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.0 (s, 1H),
8.85 (m, 1H), 8.66 (d, J=7.3 Hz, 1H), 8.38 (s, 1H), 8.24 (dd,
J=2.1, 8.5 Hz, 1H), 7.93 (s, 1H), 7.66 (d, J=8.6 Hz), 7.61 (d,
J=8.6 Hz, 3H), 7.47 (d, J=8.6 Hz, 2H), 6.78 (dd, J=1.6, 7.3 Hz,
1H), 3.5 (s, 3H), 2.06 (s, 3H); ESI-MS (method 2) (m/z):
[M+H].sup.+ 411.21.
Example 71
4-(5-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,5-
-a]pyridin-3-yl)benzamide
##STR00185##
[0619] Example 71 was prepared from intermediate I-20 according to
the procedure described for the synthesis of Example 65 (general
Suzuki procedure E). The crude product was purified by column
chromatography over silica gel (MeOH/Chloroform, 0-5% MeOH). to
give 71 as the desired product. .sup.1H NMR (400 MHz, DMSO-d.sub.6
at 80.degree. C.): .delta. 9.75 (s, 1H), 8.76 (d, J=7.0 Hz, 1H),
8.40 (s, 1H), 8.11 (s, 1H), 7.57-7.68 (m, 4H), 7.28-7.32 (m, 1H),
6.97-6.99 (m, 1H), 6.84-6.87 (m, 1H), 6.68-6.72 (m, 1H), 4.6 (bs,
1H), 4.22-4.4 (m, 2H), 2.06 (s, 3H), 1.195 (d, J=6.6 Hz, 3H);
ESI-MS (method 2) (m/z): [M+H].sup.+ 445.
Example 72
4-(5-(7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyr-
azolo[1,5-a]pyridin-3-yl)benzamide
##STR00186##
[0621] Example 72 was prepared from intermediate I-24 according to
the procedure described for the synthesis of Example 65 (general
Suzuki procedure E). The crude product was purified by silica gel
chromatography (MeOH/Chloroform, 0-5% MeOH) to give 72 as the
desired product. .sup.1H NMR (400 MHz, DMSO-d6 at 80.degree. C.):
.delta. 8.73 (d, J=7.0 Hz, 1H), 8.47 (s, 1H), 8.10 (s, 1H), 7.94
(d, J=8.4 Hz, 2H), 7.69 (d, J=8.3 Hz, 2H), 7.35-7.31 (m, 3H),
6.99-7.02 (m, 1H), 6.78-6.82 (m, 1H), 6.59-6.65 (m, 1H), 4.63 (d,
J=6.2 Hz, 1H), 4.36-4.39 (m, 1H), 4.21-4.24 (m, 1H), 1.22 (d, J=7.0
Hz, 3H); ESI-MS (method 2) (m/z): [M+H].sup.+ 431.
Example 73
4-(5-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,5-
-a]pyridin-3-yl)-N-methylbenzamide
##STR00187##
[0623] Example 73 was prepared from intermediate I-20 according to
the procedure described for the synthesis of Example 65 (general
Suzuki procedure E) by replacing (4-carbamoylphenyl)boronic acid
with (4-(methylcarbamoyl)phenyl)boronic acid. The residue was
purified column chromatography over silica gel (MeOH/Chloroform,
0-2% MeOH) to give 73 as the desired product. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 9.99 (s, 1H), 8.77 (d, J=7.03 Hz, 1H), 8.40
(d, J=1.31 Hz, 1H), 8.10 (s, 1H), 7.57-7.67 (m, 5H), 6.99-7.01 (m,
1H), 6.83-6.85 (m, 1H), 6.69 (m, 1H), 4.36 (m, 2H), 3.94 (m, 2H),
2.05 (s, 3H); ESI-MS (method 1) (m/z): [M+H].sup.+ 431.15.
Example 74
4-(5-(7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyr-
azolo[1,5-a]pyridin-3-yl)-N-methylbenzamide
##STR00188##
[0625] Example 74 was prepared from intermediate I-24 according to
the procedure described for the synthesis of Example 65 (general
Suzuki procedure E) by replacing (4-carbamoylphenyl)boronic acid
with (4-(methylcarbamoyl)phenyl)boronic acid. The crude product was
purified by column chromatography over silica gel (MeOH/Chloroform,
0-5% MeOH) to give 74 as the desired product. .sup.1H NMR (400 MHz,
DMSO-d6 at 80.degree. C.): .delta. 9.75 (s, 1H), 8.76 (d, J=7.0 Hz,
1H), 8.40 (s, 1H), 8.11 (s, 1H), 7.57-7.68 (m, 4H), 7.28-7.32 (m,
1H), 6.97-6.99 (m, 1H), 6.84-6.87 (m, 1H), 6.68-6.72 (m, 1H), 4.6
(bs, 1H), 4.22-4.4 (m, 2H), 2.06 (s, 3H), 1.195 (d, J=6.6 Hz, 3H);
ESI-MS (m/z): [M+H].sup.+ 445.
Example 75
N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-
-a]pyridine-5-carboxamide
##STR00189##
[0627] Example 75 was prepared from intermediate I-9 according to
the procedure described for the synthesis of Example 65 (general
Suzuki procedure E) by replacing (4-carbamoylphenyl)boronic acid
with (4-(methylcarbamoyl)phenyl)boronic acid. The crude product was
purified by column chromatography over silica gel (MeOH/Chloroform,
0-2% MeOH) to give 74 as the desired product. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.86 (d, J=1.6 Hz, 1H), 8.71 (dd, J=0.7, 7.3
Hz, 1H), [8.53 (s), 8.49 (d, J=4.6 Hz) 2H], 8.26 (dd, J=2.3, 8.7
Hz, 1H), [7.99 (d, J=0.7 Hz), 7.92 (d, J=8.5 Hz) 3H], 7.65 (m, 3H),
6.84 (dd, J=1.9, 7.3 Hz, 1H), 3.53 (s, 3H), 2.81 (d, J=4.6 Hz, 3H)
ESI-MS (Method 2) (m/z): [M+H].sup.+ 411.2.
[0628] The difference with Method 2 used here is Gradient: 0.4
mL/minute, initial 20% B ramp to 80% B over 2.0 minutes, (instead
of ramp to 90% over 2.0 minutes in Method 2), then hold until 4.0
minutes, return to 20% B at 4.1 minutes until end of run.
Example 76
N-(5-cyanopyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)-N-(oxetan-3-yl)pyraz-
olo[1,5-a]pyridine-5-carboxamide
##STR00190##
[0630] Example 76 was prepared from intermediate I-26 according to
the procedure described for the synthesis of Example 64 by
replacing (4-carbamoylphenyl)boronic acid with
(4-(methylcarbamoyl)phenyl)boronic acid. The residue was purified
by silica gel chromatography, eluting with ethyl acetate and
hexanes to give 76 as the desired product. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) 8.66 (d, J=7.28 Hz, 1H) 8.52 (s, 1H) 8.38 (s, 1H)
7.93-8.00 (m, 3H) 7.75 (d, J=8.78 Hz, 2H) 7.40 (dd, J=7.28, 1.76
Hz, 1H) 7.00 (dd, J=9.91, 1.88 Hz, 1H) 6.38 (d, J=10.29 Hz, 1H)
4.52-4.62 (m, 1H) 4.46 (d, J=1.00 Hz, 2H) 4.32 (t, J=11.42 Hz, 1H)
4.14 (dd, J=11.92, 7.15 Hz, 1H) 2.96 (s, 3H); ESI-MS (m/z):
[M+H].sup.+ 443.
Example 77
N-(1-(1H-pyrazol-1-yl)propan-2-yl)-3-(4-carbamoylphenyl)-N-(5-cyanopyridin-
-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide
##STR00191##
[0632] Example 77 was prepared from intermediate I-27 according to
the procedure described for the synthesis of Example 65 (general
Suzuki procedure E). The residue was purified by preparative TLC
(silica gel GF 254) using 3% methanol in chloroform as eluant to
give 77 as the desired product. .sup.1H NMR (400 MHz, DMSO) .delta.
8.90 (s, 1H), 8.63 (d, J=7.5 Hz, 1H), 8.47 (s, 1H), 8.15 (d, J=8.3
Hz, 1H), 8.03 (s, 1H), 7.99 (d, J=8.3 Hz, 2H), 7.75 (s, 1H), 7.61
(s, 1H), 7.51 (d, J=7.9 Hz, 2H), 7.39 (s, 1H), 7.34 (s, 1H), 7.17
(d, J=8.3 Hz, 1H), 6.68 (d, J=7.0 Hz, 1H), 6.14 (s, 1H), 5.75 (m,
1H), 4.85-4.86 (m, 1H), 4.47-4.48 (m, 1H), 1.35 (d, J=7.0 Hz, 3H);
ESI-LC/MS (Method 2) (m/z): [M+H].sup.+ 491.3, RT 1.32 min. The
difference with Method-2 used here is Gradient: 0.4 mL/minute,
initial 20% B ramp to 80% B over 2.0 minutes, (instead of ramp to
90% over 2.0 minutes in Method 2) then hold until 4.0 minutes,
return to 20% B at 4.1 minutes until end of run.
Example 79
3-(6-amino-5-fluoropyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]-
pyridine-5-carboxamide
##STR00192##
[0634] A mixture of
3-bromo-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide
(I-8; 400 mg, 1.10 mmol 1.0 eq),
3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
(I-37, 550 mg, 2.20 mmol 2.0 eq) and 1N Na.sub.2CO.sub.3 solution
(4.0 mL) in 1,4-dioxane (10 mL) was degassed with argon gas for 10
min. Subsequently, tetrakis(triphenyl phosphine)-palladium(0) (250
mg, 0.22 mmol 0.2 eq) was added and the reaction mixture was
stirred in a sealed tube at 100.degree. C. for 2.5 h (cf. general
Suzuki Procedure F). The solvent was removed under reduced
pressure. Purification by silica gel chromatography, eluting with
5% MeOH/CH.sub.2Cl.sub.2 provided 79 as the desired product (37%).
.sup.1H NMR (400 MHz, DMSO) .delta. 8.58 (d, J=7.0 Hz, 1H), 8.31
(s, 1H), 7.91 (s, 1H), 7.78 (d, J=8.8 Hz, 3H), 7.53 (d, J=8.30 Hz,
2H), 7.46 (d, J=12.3 Hz, 1H), 6.74 (d, J=7.0 Hz, 1H), 6.30 (s, 2H),
3.45 (s, 3H); ESI-LC/MS (m/z): [M+H].sup.+ 387.10, RT 1.71 min.
Example 80
3-(4-amino-3,5-dimethylphenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]py-
ridine-5-carboxamide
##STR00193##
[0636] Example 80 was prepared from intermediate I-8 according to
the procedure described for the synthesis of Example 79 by
replacing
3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
(I-37) with
2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(I-38). Purification by silica gel chromatography, eluting with 5%
MeOH/CH.sub.2Cl.sub.2 provided 80 as the desired product (34%)
.sup.1H NMR (400 MHz, DMSO) .delta. 8.54 (d, J=7.10 Hz, 1H), 8.15
(s, 1H) I-37, 7.81 (d, J=8.40 Hz, 2H), 7.65 (s, 1H), 7.52 (d, J=8.3
Hz, 2H), 6.87 (s, 2H), 6.72 (d, J=7.40 Hz, 1H), 4.65 (s, 2H), 3.45
(s, 3H), 2.14 (s, 6H); ESI-LC/MS (m/z): [M+H].sup.+ 396.16, RT 1.51
min.
Example 81
3-(6-amino-5-methylpyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]-
pyridine-5-carboxamide
##STR00194##
[0638] Example 81 was prepared from intermediate I-8 according to
the procedure described for the synthesis of Example 79 by
replacing
3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
(I-37) with
3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
(I-39). Purification by silica gel chromatography, eluting with 5%
MeOH/CH.sub.2Cl.sub.2 provided 81 as the desired product (44%).
.sup.1H NMR (400 MHz, DMSO) .delta. 8.56 (d, J=7.50 Hz, 1H), 8.23
(s, 1H), 7.91 (s, 1H), 7.79 (d, J=8.30 Hz, 1H), 7.71 (s, 1H), 7.52
(d, J=8.30 Hz, 1H), 7.31 (s, 1H), 6.72 (d, J=7.50 Hz, 1H), 5.80 (s,
2H), 3.44 (s, 3H), 2.11 (s, 3H); ESI-LC/MS (m/z): [M+H].sup.+
383.07, RT 1.66 min.
Example 82
3-(4-carbamoylphenyl)-N-(4-cyanocyclohexyl)-N-methylpyrazolo[1,5-a]pyridin-
e-5-carboxamide
##STR00195##
[0640] Example 82 was prepared from intermediate I-33 according to
the procedure described for the synthesis of Example 65 (general
Suzuki procedure E). The residue was purified by silica gel
chromatography, eluting with 3% MeOH/CHCl.sub.3 to give 82 as the
desired product (30%). .sup.1H NMR (400 MHz, DMSO) .delta. 8.68 (d,
J=6.6 Hz, 1H), 8.38 (s, 1H), 7.97-8.01 (m, 3H), 7.76-7.78 (m, 2H),
6.97 (m, 1H), 4.42 & 3.62 (two broad signals, 1H), 3.30 (m,
3H), 1.50-2.59 (m, 8H); ESI-LC/MS (m/z): [M+H].sup.+ 402.14, RT
1.02 min.
Example 83
3-(2-aminopyrimidin-5-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridin-
e-5-carboxamide
##STR00196##
[0642] Example 83 was prepared from intermediate I-8 according to
the procedure described for the synthesis of Example 79 by
replacing
3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
(I-37) with
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine
(I-40). Purification by silica gel chromatography, eluting with 5%
MeOH/CH.sub.2Cl.sub.2 provided 83 as the desired product (27%).
.sup.1H NMR (400 MHz, DMSO) .delta. 8.59 (d, J=7.50 Hz, 1H), 8.37
(s, 1H), 8.31 (s, 1H), 7.77 (s, 3H), 7.52 (d, J=7.90 Hz, 2H), 6.73
(s, 3H), 3.30 (s, 3H); ESI-LC/MS (m/z): [M+H].sup.+ 370.10, RT 0.93
min.
Example 84
3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-meth-
ylpyrazolo[1,5-a]pyridine-5-carboxamide
##STR00197##
[0644] Example 84 was prepared from intermediate I-9 according to
the procedure described for the synthesis of Example 79 by
replacing
3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
(I-37) with
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoro-methyl)pyrid-
in-2-amine (I-41). Purification by silica gel chromatography,
eluting with 1% MeOH/CHCl.sub.3 gave the desired product (41%).
.sup.1H NMR (400 MHz, DMSO) .delta. 8.82 (d, J=1.2 Hz, 1H), 8.64
(d, J=7.1 Hz, 1H), 8.39-8.41 (m, 2H), 8.21 (dd, J=2.2, 6.1 Hz, 1H),
7.80-7.86 (m, 2H), 7.58 (d, J=8.7 Hz, 1H), 6.78-6.81 (m, 1H),
6.52-6.56 (m, 2H), 3.52 (s, 1H); ESI-LC/MS (m/z): [M+H].sup.+
438.08, RT 1.37 min.
Example 85
3-(6-amino-5-cyanopyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1-
,5-a]pyridine-5-carboxamide
##STR00198##
[0646] Example 85 was prepared from intermediate I-9 according to
the procedure described for the synthesis of Example 79 by
replacing
3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
(I-37) with
2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotino-nitrile
(I-42). Purification by silica gel chromatography, eluting with 5%
MeOH/CH.sub.2Cl.sub.2 provided 85 the desired product (23%).
.sup.1H NMR (400 MHz, DMSO) .delta. 8.83 (d, J=1.70 Hz, 1H), 8.66
(d, J=7.10 Hz, 1H), 8.45 (d, J=2.60 Hz, 1H), 8.40 (s, 1H), 8.21
(dd, J=2.2, 6.6 Hz, 1H), 8.06 (d, J=2.10 Hz, 1H), 7.98 (s, 1H),
7.60 (d, J=8.70 Hz, 1H), 7.00 (s, 2H), 6.78 (d, J=8.8 Hz, 1H), 3.52
(s, 3H); ESI-LC/MS (m/z): [M+H].sup.+ 395.09, RT 1.45 min.
Example 86
3-(6-amino-5-chloropyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[-
1,5-a]pyridine-5-carboxamide
##STR00199##
[0648] Example 86 was prepared from intermediate I-9 according to
the procedure described for the synthesis of Example 79 by
replacing
3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
(I-37) with
3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
(I-43). Purification by preparative TLC provided 86 the desired
product (41%). .sup.1H NMR (400 MHz, DMSO) .delta. 8.85 (s, 1H),
8.65 (d, J=7.50 Hz, 1H), 8.36 (s, 1H), 8.22 (d, J=8.8 Hz, 1H), 8.11
(s, 1H), 7.79 (s, 1H), 7.65 (s, 1H), 7.58 (d, J=8.8 Hz, 1H), 6.79
(d, J=7.0 Hz, 1H), 6.40 (s, 2H), 3.52 (s, 3H); ESI-LC/MS (m/z):
[M+H].sup.+ 404.09, RT 1.27 min.
Example 87
3-(6-amino-5-(dimethylcarbamoyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-me-
thylpyrazolo[1,5-a]pyridine-5-carboxamide
##STR00200##
[0650] Example 87 was prepared from intermediate I-9 according to
the procedure described for the synthesis of Example 79 by
replacing
3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
(I-37) with
2-amino-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicot-
inamide (I-44). Purification by preparative TLC provided 87 as the
desired product (10%). .sup.1H NMR (400 MHz, DMSO) .delta. 8.81 (d,
J=2.2 Hz, 1H), 8.64 (d, J=7.0 Hz, 1H), 8.35 (s, 1H), 8.20 (d, J=2.2
Hz, 2H), 8.17 (d, J=2.20 Hz, 1H), 7.80 (s, 1H), 7.55 (d, J=8.8 Hz,
1H), 7.48 (d, J=2.2 Hz, 1H), 6.76 (dd, J=1.7, 7.0 Hz, 1H), 3.52 (s,
3H), 2.97 (s, 6H); ESI-LC/MS (m/z): [M+H].sup.+ 441.11, RT 1.54
min.
Example 88
3-(6-amino-5-methoxypyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo-
[1,5-a]pyridine-5-carboxamide
##STR00201##
[0652] Example 88 was prepared from intermediate I-9 according to
the procedure described for the synthesis of Example 79 by
replacing
3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
(I-37) with
3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-amine
(I-45). Purification by silica gel chromatography, eluting with 5%
MeOH/CH.sub.2Cl.sub.2 provided 88 as the desired product (36%).
.sup.1H NMR (400 MHz, DMSO) .delta. 8.78 (s, 1H), 8.62 (d, J=7.40
Hz, 1H), 8.33 (s, 1H), 8.28-8.20 (dd, J=2.2, 6.60 Hz, 1H), 7.86 (s,
1H), 7.66 (s, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.16 (s, 1H), 6.77 (d,
J=5.70 Hz, 1H), 5.79 (s, 2H), 3.84 (s, 3H), 3.52 (s, 3H); ESI-LC/MS
(m/z): [M+H].sup.+ 400.06, RT 1.11 min.
Example 89
3-(4-carbamoylphenyl)-N-(4-chloro-2-formylphenyl)-N-methylpyrazolo[1,5-a]p-
yridine-5-carboxamide
##STR00202##
[0654] Example 89 was prepared from intermediate I-15 according to
the procedure described for the synthesis of Example 65 (general
Suzuki procedure E). The crude product was purified by preparative
TLC to give 89 as the desired product. .sup.1H NMR (400 MHz, DMSO)
.delta. 10.02 (s, 1H), 8.62 (d, J=7.0 Hz, 1H), 8.44 (s, 1H),
8.02-7.86 (m, 3H), 7.86 (s, 2H), 7.74 (d, J=5.2 Hz, 1H), 7.63 (s,
1H), 7.43-7.35 (m, 3H), 6.81 (d, J=7.0 Hz, 1H), 3.80 (s, 3H);
ESI-LC/MS (m/z): [M+H].sup.+ 433.2, RT 4.75 min.
[0655] It is understood that the examples and embodiments described
herein are for illustrative purposes only and that various
modifications or changes in light thereof will be suggested to
persons skilled in the art and are to be included within the spirit
and purview of this application and scope of the appended claims.
All publications, patents, and patent applications cited herein are
hereby incorporated by reference for all purposes.
* * * * *