U.S. patent application number 12/697135 was filed with the patent office on 2010-09-16 for factor xa inhibitors.
This patent application is currently assigned to Millennium Pharmaceuticals, Inc.. Invention is credited to Shawn M. Bauer, Zhaozhong J. Jia, Gary D. Probst, Robert M. Scarborough, Yonghong Song, Yanchen Zhang, Bing-Yan Zhu.
Application Number | 20100234352 12/697135 |
Document ID | / |
Family ID | 39512540 |
Filed Date | 2010-09-16 |
United States Patent
Application |
20100234352 |
Kind Code |
A1 |
Zhu; Bing-Yan ; et
al. |
September 16, 2010 |
FACTOR XA INHIBITORS
Abstract
The present invention is directed to compounds represented by
Formula (I) or a pharmaceutically acceptable salt, ester, or
prodrug thereof which are inhibitors of Factor Xa. The present
invention is also directed to and intermediates used in making such
compounds, pharmaceutical compositions containing such compounds,
methods to prevent or treat a number of conditions characterized by
undesired thrombosis and methods of inhibiting the coagulation of a
blood sample.
Inventors: |
Zhu; Bing-Yan; (Palo Alto,
CA) ; Bauer; Shawn M.; (Pacifica, CA) ; Jia;
Zhaozhong J.; (San Mateo, CA) ; Song; Yonghong;
(Foster City, CA) ; Probst; Gary D.; (San
Francisco, CA) ; Zhang; Yanchen; (Union City, CA)
; Scarborough; Robert M.; (Half Moon Bay, CA) |
Correspondence
Address: |
Swiss Tanner, P.C.;P.O. Box 1749
Four Main Street, Suite 100
Los Altos
CA
94022
US
|
Assignee: |
Millennium Pharmaceuticals,
Inc.
|
Family ID: |
39512540 |
Appl. No.: |
12/697135 |
Filed: |
January 29, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11620615 |
Jan 5, 2007 |
7696352 |
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12697135 |
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11158274 |
Jun 20, 2005 |
7521470 |
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11620615 |
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60580899 |
Jun 18, 2004 |
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Current U.S.
Class: |
514/217.04 ;
514/218; 514/230.5; 514/236.2; 514/252.05; 514/253.09; 514/254.07;
514/274; 514/313; 514/318; 514/326; 514/333; 514/340; 514/359;
514/397 |
Current CPC
Class: |
C07D 417/12 20130101;
C07D 409/12 20130101; C07D 409/14 20130101; C07D 413/12 20130101;
A61P 7/02 20180101; C07D 413/14 20130101; A61P 9/10 20180101; C07D
333/38 20130101; A61P 43/00 20180101; C07D 417/14 20130101; A61P
9/00 20180101 |
Class at
Publication: |
514/217.04 ;
514/253.09; 514/274; 514/252.05; 514/218; 514/359; 514/340;
514/333; 514/397; 514/254.07; 514/326; 514/318; 514/236.2;
514/230.5; 514/313 |
International
Class: |
A61K 31/55 20060101
A61K031/55; A61K 31/497 20060101 A61K031/497; A61K 31/513 20060101
A61K031/513; A61K 31/501 20060101 A61K031/501; A61K 31/551 20060101
A61K031/551; A61K 31/4192 20060101 A61K031/4192; A61K 31/4439
20060101 A61K031/4439; A61K 31/444 20060101 A61K031/444; A61K
31/4178 20060101 A61K031/4178; A61K 31/454 20060101 A61K031/454;
A61K 31/4545 20060101 A61K031/4545; A61K 31/5377 20060101
A61K031/5377; A61K 31/538 20060101 A61K031/538; A61K 31/4709
20060101 A61K031/4709; A61P 7/02 20060101 A61P007/02; A61P 9/00
20060101 A61P009/00 |
Claims
1-19. (canceled)
20. A method for preventing or treating thrombosis in a mammal
comprising administering to said mammal a therapeutically effective
amount of a compound of Formula (I) or a pharmaceutically
acceptable salt, ester, prodrug or composition thereof ##STR00269##
wherein: R.sup.1 is selected from the group consisting of halogen,
C.sub.1-8 alkyl, C.sub.2-8 alkenyl, and C.sub.2-8 alkynyl; R.sup.2
is hydrogen or C.sub.1-4 alkyl; A is selected from the group
consisting of: ##STR00270## ##STR00271## wherein the wavy line
indicates the point of attachment to ring B and the dashed line
indicates the point of attachment to the rest of the molecule;
R.sup.3 is independently hydrogen or R.sup.3a; R.sup.3a is
independently selected from the group consisting of halogen,
C.sub.1-8 alkyl, C.sub.2-8 alkenyl, and C.sub.2-8alkynyl; m is 0,
1, 2, or 3; X is C--R.sup.4 or N or X and Y are C and are fused to
a 6-membered aryl, heteroaryl, or heterocyclic ring; Y is
C--R.sup.5 or N provided that X and Y are not both N; R.sup.4 is
selected from the group consisting of hydrogen, halogen, and
##STR00272## R.sup.4a is hydrogen or C.sub.1-8 alkyl; R.sup.5 is
selected from the group consisting of hydrogen, halogen, and
C.sub.1-8alkoxy; or R.sup.5 and R.sup.6 together join to form a
6-membered aryl, heteroaryl, or heterocyclic ring fused to ring B;
R.sup.6 is selected from the group consisting of --R.sup.6a,
--NR.sup.7aR.sup.7b, --NR.sup.7aC(O)R.sup.7c,
--NR.sup.7aC(O)OR.sup.7c, --CONR.sup.8aR.sup.8b, --OR.sup.7c,
--SR.sup.7c, --C(.dbd.NR.sup.7a)NR.sup.8aR.sup.8b,
--S(O).sub.2NR.sup.8aR.sup.8b, and --S(O).sub.2R.sup.7c; R.sup.6a
is selected from the group consisting of ##STR00273## ##STR00274##
wherein R.sup.8 can be at any position suitable for a substituent,
and if R.sup.8 is attached to a nitrogen atom, then it replaces the
hydrogen atom attached thereto; R.sup.7a and R.sup.7b are
independently selected from the group consisting of hydrogen,
C.sub.1-8 alkyl, and C.sub.1-8 alkyl substituted with one to three
R.sup.9; R.sup.7c is selected from the group consisting of aryl,
heteroaryl, C.sub.1-8 alkyl, and C.sub.1-8 alkyl substituted with
one to three R.sup.9; R.sup.8 is independently selected from the
group consisting of nitro, hydroxyl, --CO.sub.2H, --C(O)R.sup.8c,
--C(O)NR.sup.8aR.sup.8b, --NR.sup.8aR.sup.8b,
--SO.sub.2NR.sup.8aR.sup.8b, halogen, C.sub.1-8 alkyl, and
C.sub.1-8 alkoxy wherein said C.sub.1-8 alkyl and C.sub.1-8 alkoxy
are optionally substituted with one to three R.sup.9; R.sup.8a and
R.sup.8b are independently selected from the group consisting of
hydrogen, C.sub.1-8 alkyl, and C.sub.1-8 alkyl substituted with one
to three R.sup.9, or R.sup.8a and R.sup.8b together form a 5 to 7
membered heterocyclic ring optionally substituted with one to three
R.sup.9 and optionally having one additional ring heteroatom
selected from N, O, or S; R.sup.8c is selected from the group
consisting of C.sub.1-8 alkyl and C.sub.1-8 alkyl substituted with
one to three R.sup.9; R.sup.9 is independently selected from the
group consisting of halogen, heterocyclic, heteroaryl, --OH,
--R.sup.10, --OR.sup.10, --SR.sup.10, --S(O)R.sup.10,
--S(O).sub.2R.sup.10, --SO.sub.2NH.sub.2, --C(O)NH.sub.2,
--C(O)R.sup.10, --C(NH)R.sup.10, --NHC(O)R.sup.10,
--NHC(NH)R.sup.10, --NHC(O)NH.sub.2, --CO.sub.2H, --NH.sub.2,
--NHR.sup.10, --N(R.sup.10).sub.2 and --N(R.sup.10).sub.3.sup.+;
each R.sup.10 is independently C.sub.1-6 alkyl; and n is 0, 1, 2,
or 3; provided that when X is C--R.sup.4, Y is C--R.sup.5, R.sup.6
is R.sup.6a, and A is ##STR00275## then R.sup.6a is bound to ring B
through a carbon atom.
21. The method of claim 20 wherein R.sup.1 is 2-chloro.
22. The method of claim 20 wherein R.sup.2 is hydrogen.
23. The method of claim 20 wherein X and Y are CH.
24. The method of claim 20 wherein A is selected from the group
consisting of: ##STR00276##
25. The method of claim 20 wherein R.sup.6 is R.sup.6a.
26. The method of claim 25 wherein R.sup.6a is selected from the
group consisting of: ##STR00277##
27. The method of claim 20 wherein R.sup.6 is selected from the
group consisting of: ##STR00278## ##STR00279##
28. The method of claim 20 wherein R.sup.6 is selected from the
group consisting of: ##STR00280##
29. The method of claim 20 wherein R.sup.6 is selected from the
group consisting of: ##STR00281##
30. The method of claim 20 wherein R.sup.6 is selected from the
group consisting of: ##STR00282##
31. The method of claim 20 wherein R.sup.6 is selected from the
group consisting of: ##STR00283##
32. The method of claim 20 wherein R.sup.6 is ##STR00284## and
R.sup.8 is as previously defined.
33. The method of claim 32, wherein R.sup.8 is selected from the
group consisting of: hydrogen, ##STR00285##
34. The method of claim 20 wherein the compound is selected from
the group consisting of:
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(piperazin-1-yl)phenyl)-1H-1,-
2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(2-(4-ethylpiperazin-1-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl-
)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(2-(4-isopropylpiperazin-1-yl)-4-(2-oxopyridin-1(2H)-yl)ph-
enyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(2-oxopyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)-
methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-1H-1,-
2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(2,4-dimethoxypyrimidin-5-yl)phenyl)-1H-1,2,3-triazol-4-
-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-2-fluoroph-
enyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-1,2,3-triazol-4-y-
l)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1H-1,2,3-triazol-4--
yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(2-oxoimidazolidin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)m-
ethyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(2'-methoxybiphenyl-4-yl)-1H-1,2,3-triazol-4-yl)methyl)thi-
ophene-2-carboxamide,
5-Chloro-N-((1-(T-hydroxybiphenyl-4-yl)-1H-1,2,3-triazol-4-yl)methyl)thio-
phene-2-carboxamide,
5-Chloro-N-((1-(2'-(trifluoromethoxy)biphenyl-4-yl)-1H-1,2,3-triazol-4-yl-
)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(6-chloropyridin-3-yl)phenyl)-1H-1,2,3-triazol-4-yl)met-
hyl)thiophene-2-carboxamide,
N-((1-(4-(1H-Indol-2-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-chlorothi-
ophene-2-carboxamide,
5-Chloro-N-((1-(4-(methylsulfonyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)th-
iophene-2-carboxamide,
5-Chloro-N-((1-(3-fluoro-2'-sulfamoylbiphenyl-4-yl)-1H-1,2,3-triazol-4-yl-
)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(pyrrolidine-1-carbonyl)phenyl)-1H-1,2,3-triazol-4-yl)m-
ethyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(2,5-dihydro-1H-pyrrole-1-carbonyl)phenyl)-1H-1,2,3-tri-
azol-4-yl)methyl)thiophene-2-carboxamide,
N-((1-(4-Carbamoylphenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-
-2-carboxamide,
N-((1-(4-(2-Amino-N-methylacetamido)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-
-5-chlorothiophene-2-carboxamide,
5-Chloro-N-((1-(4-(methyl(2-(methylamino)ethyl)amino)phenyl)-1H-1,2,3-tri-
azol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(methylamino)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiop-
hene-2-carboxamide,
5-Chloro-N-((1-(4-(N-methylpropionamido)phenyl)-1H-1,2,3-triazol-4-yl)met-
hyl)thiophene-2-carboxamide, Ethyl
4-(44(5-chlorothiophene-2-carboxamido)methyl)-1H-1,2,3-triazol-1-yl)pheny-
l(methyl)carbamate,
5-Chloro-N-((1-(4-(2-methoxy-N-methylacetamido)phenyl)-1H-1,2,3-triazol-4-
-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(2-(dimethylamino)-N-methylacetamido)phenyl)-1H-1,2,3-t-
riazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(N-methylacetamido)phenyl)-1H-1,2,3-triazol-4-yl)methyl-
)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(2-hydroxyethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methyl)t-
hiophene-2-carboxamide,
5-Chloro-N-((1-(4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-1H-1,2,3-triaz-
ol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((3-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-5-methyl-4,5-di-
hydroisoxazol-5-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-4,5-dihydro-1H-pyr-
azol-3-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((2-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1,2-dihydropyridin-
-3-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((6-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1,6-dihydropyridin-
-3-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-methyl-2-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide,
5-Chloro-N-((1-(4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)--
1H-imidazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(2-methoxypyridin-3-yl)phenyl)-1H-imidazol-4-yl)methyl)-
thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(2-oxo-1,2-dihydropyridin-3-yl)phenyl)-1H-imidazol-4-yl-
)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)-1H-imid-
azol-4-yl)methyl)thiophene-2-carboxamide,
N-((1-(4-Aminophenyl)-1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carbox-
amide,
5-Chloro-N-((1-(4-(2,5-dihydro-1H-pyrrole-1-carbonyl)phenyl)-1H-imi-
dazol-4-yl)methyl)thiophene-2-carboxamide,
4-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-
benzamide,
N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl-
)acetamide,
5-Chloro-N-((1-(5-(2-oxopyridin-1(2'-1)-yl)pyridin-2-yl)-1H-imidazol-4-yl-
)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(6-(2-oxopyridin-1(2H)-yl)pyri
din-3-yl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((2,5-dibromo-1-(4-(N,N-dimethylcarbamimidoyl)phenyl)-1H-imida-
zol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((2,5-dibromo-1-(4-(imino(pyrrolidin-1-yl)methyl)phenyl)-1H-im-
idazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((2,5-dibromo-1-(4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phen-
yl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(9-methyl-2,6-dioxo-1H-purin-3
(2H,6H,9H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamid-
e,
5-Chloro-N-((1-(4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-1H--
imidazol-5-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((4-methyl-1-(4-(2-oxopyridin-1(211)-yl)phenyl)-1H-imidazol-5--
yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(2-oxopyrazin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)me-
thyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(2-fluoro-4-(2-oxopyrazin-1(2H)-yl)phenyl)-1H-1,2,3-triazo-
l-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(2-fluoro-4-(2-oxopyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-tria-
zol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(2-oxotetrahydropyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-tri-
azol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(2-fluoro-4-(2-oxo-tetrahydropyrimidin-1(2H)-yl)phenyl)-1H-
-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(2-fluoro-4-(3-methyl-2-oxo-tetrahydropyrimidin-1(2H)-yl)p-
henyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(2-fluoro-4-(2-oxopiperidin-1-yl)phenyl)-1H-1,2,3-triazol--
4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(3-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazo-
l-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(3-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triaz-
ol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(3-(2-hydroxyethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1-
,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(3-(2-methoxyethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1-
,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(3-(2-(dimethylamino)ethoxy)-2-oxopyridin-1(2H)-yl)phen-
yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(3-(2-(dimethyl(dimethylamino)amino)ethoxy)-2-oxopyridi-
n-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(2-oxo-3-(2-(piperidin-1-yl)ethoxy)pyridin-1(2H)-yl)phe-
nyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(2-oxo-3-(3-(piperidin-1-yl)propoxy)pyridin-1(2H)-yl)ph-
enyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(3-(2-(methylthio)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-
-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(3-(2-(methylsulfinyl)ethoxy)-2-oxopyridin-1(2H)-yl)phe-
nyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(3-(2-(methylsulfonyl)ethoxy)-2-oxopyridin-1(2H)-yl)phe-
nyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(3-(2-morpholinoethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1-
H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
N-((1-(4-(3-(2-(1H-Imidazol-1-yl)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-
-1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide,
5-N-Chloro-N-((1-(4-(3-((1-methyl-1H-imidazol-2-yl)methoxy)-2-oxopyridin--
1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(5-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triaz-
ol-4-yl)methyl)thiophene-2-carboxamide,
5-N-Chloro-N-((1-(4-(5-(2-(dimethylamino)ethoxy)-2-oxopyridin-1(2H)-yl)ph-
enyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(2-oxo-5-(2-(piperidin-1-yl)ethoxy)pyridin-1(2H)-yl)phe-
nyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(5-(2-morpholinoethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1-
H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(5-nitro-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-
-4-yl)methyl)thiophene-2-carboxamide,
N-((1-(4-(4-Amino-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)m-
ethyl)-5-chlorothiophene-2-carboxamide,
5-Chloro-N-((1-(4-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)-1H-1,2-
,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
N-((1-(4-(4-Amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triaz-
ol-4-yl)methyl)-5-chlorothiophene-2-carboxamide,
5-Chloro-N-((1-(4-(3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pheny-
l)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(2-oxopiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)meth-
yl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(4-methyl-2-oxopiperazin-1-yl)phenyl)-1H-1,2,3-triazol--
4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(4-isopropyl-2-oxopiperazin-1-yl)phenyl)-1H-1,2,3-triaz-
ol-4-yl)methyl)thiophene-2-carboxamide,
4-(4-(4((5-Chlorothiophene-2-carboxamido)methyl)-1H-1,2,3-triazol-1-yl)ph-
enyl)-3-oxopiperazine-1-carboxamide,
5-Chloro-N-((1-(4-(3-hydroxy-2-oxopyrazin-1(2H)-yl)phenyl)-1H-1,2,3-triaz-
ol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(4-(2-(dimethylamino)ethyl)-2,3-dioxo-3,4-dihydropyrazi-
n-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(3-hydroxy-6-oxopyridazin-1(6H)-yl)phenyl)-1H-1,2,3-tri-
azol-4-yl)methyl)thiophene-2-carboxamide,
2-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methylcarba-
moyl)benzoic acid,
N-((1-(2-(3-oxopiperazin-1-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3--
triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl)-1H-1,2,3-
-triazol-5-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(N,N-dimethylcarbamimidoyl)phenyl)-1H-1,2,3-triazol-5-y-
l)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(imino(pyrrolidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol--
5-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(imino(piperidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-5-
-yl)methyl)thiophene-2-carboxamide,
N-((1-(4-Carbamoylphenyl)-1H-1,2,3-triazol-5-yl)methyl)-5-chlorothiophene-
-2-carboxamide,
5-Chloro-N-((1-(4-(methylsulfonyl)phenyl)-1H-1,2,3-triazol-5-yl)methyl)th-
iophene-2-carboxamide,
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-5-yl)me-
thyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(pyridin-2-ylthio)phenyl)-1H-1,2,3-triazol-5-yl)methyl)-
thiophene-2-carboxamide,
5-Chloro-N-((1-(6-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-4-yl)me-
thyl)thiophene-2-carboxamide,
1-(5-(4-((5-Chlorothiophene-2-carboxamido)methyl)-1H-1,2,3-triazol-1-yl)p-
yridin-2-yl)piperidine-4-carboxylic acid,
N-((1-(6-(Azepan-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-4-yl)methyl)-5-chlor-
othiophene-2-carboxamide,
5-Chloro-N-((1-(6-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl)-1H-1,2,3-tria-
zol-5-yl)methyl)thiophene-2-carboxamide,
N-((1-(6-(1,4-Diazepan-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-5-yl)methyl)-5-
-chlorothiophene-2-carboxamide,
5-Chloro-N-((1-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol--
5-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(6-(piperazin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-5-yl)met-
hyl)thiophene-2-carboxamide,
5-Chloro-N-(4-(4((5-chlorothiophene-2-carboxamido)methyl)-1H-imidazol-1-y-
l)benzyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-pyrrol-3-yl)methyl)th-
iophene-2-carboxamide,
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-pyrazol-4-yl)methyl)t-
hiophene-2-carboxamide,
5-Chloro-N-((1-(4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1H-pyrazol-4-yl)met-
hyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-(2-oxopyrazin-1(2H)-yl)phenyl)-1H-pyrazol-4-yl)methyl)t-
hiophene-2-carboxamide,
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-pyrazol-3-yl)methyl)t-
hiophene-2-carboxamide,
5-Chloro-N-((1-(3-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)me-
thyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[.beta.][1,4]oxazin-7--
yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,
5-Chloro-N-((1-(3-methoxy-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triaz-
ol-4-yl)methyl)thiophene-2-carboxamide, and
5-Chloro-N-((1-(5-(2-oxopyridin-1(2H)-yl)quinolin-8-yl)-1H-1,2,3-triazol--
4-yl)methyl)thiophene-2-carboxamide, or a pharmaceutically
acceptable salt, ester, or prodrug thereof.
35. The method of claim 20, wherein the thrombosis is associated
with a condition selected from the group consisting of acute
coronary syndrome, myocardial infarction, unstable angina,
refractory angina, occlusive coronary thrombus occurring
post-thrombolytic therapy or post-coronary angioplasty, a
thrombotically mediated cerebrovascular syndrome, embolic stroke,
thrombotic stroke, transient ischemic attacks, venous thrombosis,
deep venous thrombosis, pulmonary embolus, coagulopathy,
disseminated intravascular coagulation, thrombotic thrombocytopenic
purpura, thromboangiitis obliterans, thrombotic disease associated
with heparin-induced thrombocytopenia, thrombotic complications
associated with extracorporeal circulation, thrombotic
complications associated with instrumentation such as cardiac or
other intravascular catheterization, intra-aortic balloon pump,
coronary stent or cardiac valve, and conditions requiring the
fitting of prosthetic devices.
36. The method of claim 35, wherein the condition is selected from
the group consisting of embolic stroke, thrombotic stroke, venous
thrombosis, deep venous thrombosis, acute coronary syndrome, and
myocardial infarction.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part application of
U.S. patent application Ser. No. 11/158,274, filed Jun. 20, 2005,
which claims the benefit of U.S. Provisional Application No.
60/580,899, filed Jun. 18, 2004, which applications are
incorporated herein by reference in their entireties.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention is directed to novel compounds which act as
inhibitors of Factor Xa. This invention is also directed to
pharmaceutical compositions containing the compounds and methods of
using the compounds or compositions to treat a condition
characterized by undesired thrombosis. The invention is also
directed to methods of making the compounds described herein.
[0004] 2. State of the Art
[0005] Hemostasis, the control of bleeding, occurs by surgical
means, or by the physiological properties of vasoconstriction and
coagulation. This invention is particularly concerned with blood
coagulation and ways in which it assists in maintaining the
integrity of mammalian circulation after injury, inflammation,
disease, congenital defect, dysfunction or other disruption.
Although platelets and blood coagulation are both involved in
restoring hemostasis and in thrombotic diseases, certain components
of the coagulation cascade are primarily responsible for the
amplification and acceleration of the processes involved in
platelet aggregation and fibrin deposition which are major events
in thrombosis and hemostasis.
[0006] Clot formation involves the conversion of fibrinogen to
fibrin which polymerizes into a network to restore hemostasis after
injury. A similar process results in occluded blood vessels in
thrombotic diseases. The conversion of fibrinogen to fibrin is
catalyzed by thrombin, the end product of a series of reactions in
the blood coagulation cascade. Thrombin is also a key player in
activating platelets, thereby contributing to thrombosis under
conditions of both arterial and venous blood flow. For these
reasons, it has been postulated that efficient regulation of
thrombin can lead to efficient regulation of thrombosis. Several
classes of currently used anticoagulants directly or indirectly
affect thrombin (i.e. unfractionated heparins, low-molecular weight
heparins, heparin-like compounds, pentasaccharide and warfarin).
Direct or indirect inhibition of thrombin activity has also been
the focus of a variety of anticoagulants in clinical development
(reviewed by Eriksson and Quinlan, Drugs 11: 1411-1429, 2006).
[0007] Prothrombin, the precursor for thrombin, is converted to the
active enzyme by factor Xa. Localized activation of tissue
factor/factor VIIa mediated factor Xa generation is amplified by
the factor IXa/factor VIIIa complex and leads to prothrombinase
assembly on activated platelets. Factor Xa, as a part of the
prothrombinase complex, is the sole enzyme responsible for
sustained thrombin formation in the vasculature. Factor Xa is a
serine protease, the activated form of its precursor Factor X, and
a member of the calcium ion binding, gamma carboxyglutamic acid
(GLA)-containing, vitamin K dependent, blood coagulation factors.
Unlike thrombin, which acts on a variety of protein substrates
including fibrinogen and the PAR receptors (Protease activated
receptors, Coughlin, J Thrombosis Haemostasis 3: 1800-1814, 2005),
factor Xa appears to have a single physiologic substrate, namely
prothrombin. Since one molecule of factor Xa may be able to
generate greater than 1000 molecules of thrombin (Mann, et al., J.
Thrombosis. Haemostasis 1: 1504-1514, 2003), direct inhibition of
factor Xa as a way of indirectly inhibiting the formation of
thrombin is considered an efficient anticoagulant strategy. This
assertion is based on the key role of prothrombinase in thrombin
synthesis and on the fact that inhibition of prothrombinase will
have a pronounced effect on the overall platelet aggregation and
clotting pathways. Activated proteases such as factor VIIa, factor
IXa or factor Xa have poor proteolytic activity on their own.
However, their assembly into cofactor-dependent, membrane-bound
complexes significantly enhances their catalytic efficiencies. This
effect is most dramatic for factor Xa, where the efficiency is
increased by a factor of 10.sup.5 (Mann, et al., Blood 76(1):1-16,
1990). Due to the higher concentration of the zymogens present in
blood (1.4 micromolar prothrombin versus 150 nanomolar factor X)
and the kinetics of activation, a smaller amount of factor Xa than
thrombin needs to be inhibited to achieve an anticoagulant effect.
Indirect proof of the hypothesis of superiority of factor Xa as a
therapeutic target compared to thrombin can also be found in
clinical trials for the prevention of deep vein thrombosis.
Fondaparinux, an antithrombin III dependent factor Xa inhibitor,
was proven to be superior to enoxaparin (a low molecular weight
heparin that inhibits both thrombin and factor Xa) in four trials
of orthopedic surgery (Turpie, et al., Archives Internal Medicine
162(16): 1833-1840, 2002). Therefore, it has been suggested that
compounds which selectively inhibit factor Xa may be useful as in
vitro diagnostic agents, or for therapeutic administration in
certain thrombotic disorders, see e.g., WO 94/13693.
[0008] Several Factor Xa inhibitors have been reported as
polypeptides derived from hematophagous organisms, as well as
compounds which are not large polypeptide-type inhibitors.
Additional Factor Xa inhibitors include small molecule organic
compounds, such as nitrogen containing heterocyclic compounds which
have amidino substituent groups, wherein two functional groups of
the compounds can bind to Factor Xa at two of its active sites. For
example, WO 98/28269 describes pyrazole compounds having a terminal
C(.dbd.NH)--NH.sub.2 group; WO 97/21437 describes benzimidazole
compounds substituted by a basic radical which are connected to a
naphthyl group via a straight or branched chain alkylene,
--C(.dbd.O) or --S(.dbd.O).sub.2 bridging group; WO 99/10316
describes compounds having a 4-phenyl-N-alkylamidino-piperidine and
4-phenoxy-N-alkylamidino-piperidine group connected to a
3-amidinophenyl group via a carboxamidealkyleneamino bridge; and EP
798295 describes compounds having a
4-phenoxy-N-alkylamidino-piperidine group connected to an
amidinonaphthyl group via a substituted or unsubstituted
sulfonamide or carboxamide bridging group. Additional reported
Factor Xa inhibitors include those having a structure comprising a
phenyl-amidino, phenyl and halo-phenyl connected via amide linkages
(U.S. Pat. No. 6,844,367 B1). Other Factor Xa inhibitors by the
same group have replaced the halo-phenyl with a halo-pyridyl (see
U.S. Pat. Nos. 6,376,515 B2 and 6,835,739 B2).
[0009] There exists a need for effective therapeutic agents for the
regulation of hemostasis, and for the prevention and treatment of
thrombus formation and other pathological processes in the
vasculature induced by thrombin such as restenosis and
inflammation. In particular, there continues to be a need for
compounds which selectively inhibit factor Xa or its precursors.
Compounds that have different combinations of bridging groups and
functional groups than compounds previously discovered are needed,
particularly compounds which selectively or preferentially bind to
Factor Xa. Compounds with a higher degree of binding to Factor Xa
than to thrombin are desired, especially those compounds having
good bioavailability and/or solubility.
BRIEF SUMMARY OF THE INVENTION
[0010] The present invention provides in one aspect, compounds
having the formula:
##STR00001##
[0011] In formula (I), the symbol R.sup.1 is halogen, C.sub.1-8
alkyl, C.sub.2-8 alkenyl, and C.sub.2-8 alkynyl.
[0012] The symbol R.sup.2 is hydrogen or C.sub.1-4 alkyl.
[0013] The symbol A is selected from the group consisting of:
##STR00002## ##STR00003##
wherein the wavy line indicates the point of attachment to ring B
and the dashed line indicates the point of attachment to the rest
of the molecule;
[0014] The symbol R.sup.3 is independently hydrogen or R.sup.3a,
wherein R.sup.3a is independently selected from the group
consisting of halogen, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, and
C.sub.2-8 alkynyl.
[0015] The subscript m is 0, 1, 2, or 3.
[0016] The symbol X is C--R.sup.4 or N.
[0017] The symbol Y is C--R.sup.5 or N provided that X and Y are
not both N.
[0018] In some embodiments, X and Y are C and are fused to form a
6-membered aryl, heteroaryl, or heterocyclic ring.
[0019] The symbol R.sup.4 is selected from the group consisting of
hydrogen, halogen, and
##STR00004##
wherein R.sup.4a is hydrogen or C.sub.1-8 alkyl.
[0020] The symbol R.sup.5 is selected from the group consisting of
hydrogen, halogen, and C.sub.hs alkoxy.
[0021] The symbol R.sup.6 is selected from the group consisting of
--R.sup.6a, --NR.sup.7aR.sup.7b, --NR.sup.7aC(O)R.sup.7c,
--NR.sup.7aC(O)OR.sup.7c, --CONR.sup.8aR.sup.8b, --OR.sup.7c,
--SR.sup.7c, --C(.dbd.NR.sup.7a)NR.sup.8aR.sup.8b,
--S(O).sub.2NR.sup.8aR.sup.8b, and --S(O).sub.2R.sup.7c.
[0022] In some embodiments, R.sup.5 and R.sup.6 join together with
the atoms bound thereto to form a 6-membered aryl, heteroaryl, or
heterocyclic ring fused to ring B.
[0023] The symbol R.sup.6a is selected from the group consisting
of
##STR00005## ##STR00006##
wherein R.sup.8 can be at any position suitable for a substituent,
and if R.sup.8 is attached to a nitrogen atom, then it replaces the
hydrogen atom attached thereto.
[0024] The symbol R.sup.7a and R.sup.7b are independently selected
from the group consisting of hydrogen, C.sub.1-8 alkyl, and
C.sub.1-8 alkyl substituted with one to three R.sup.9.
[0025] The symbol R.sup.7c is selected from the group consisting of
aryl, heteroaryl, C.sub.1-8 alkyl, and C.sub.1-8 alkyl substituted
with one to three R.sup.9.
[0026] The symbol R.sup.8 is independently selected from the group
consisting of nitro, hydroxy, --CO.sub.2H, --C(O)R.sup.8c,
--C(O)NR.sup.8aR.sup.8b, --NR.sup.8aR.sup.8b,
--SO.sub.2NR.sup.8aR.sup.8b, halogen, C.sub.1-8 alkyl, and
C.sub.1-8 alkoxy wherein said C.sub.1-8 alkyl and C.sub.1-8 alkoxy
are optionally substituted with one to three R.sup.9.
[0027] The symbol R.sup.8a and R.sup.8b are independently selected
from the group consisting of hydrogen, C.sub.1-8 alkyl, and
C.sub.1-8 alkyl substituted with one to three R.sup.9, or R.sup.8a
and R.sup.8b join together along with the atom bound thereto to
form a 5 to 7 membered heterocyclic ring optionally substituted
with one to three R.sup.9 and optionally having one additional ring
heteroatom selected from N, O, or S.
[0028] The symbol R.sup.8C is selected from the group consisting of
C.sub.1-8 alkyl and C.sub.1-8 alkyl substituted with one to three
R.sup.9.
[0029] The symbol R.sup.9 is independently selected from the group
consisting of halogen, heterocyclic, heteroaryl, --OH, --R.sup.10,
--OR.sup.10, --SR.sup.10, --S(O)R.sup.10, --S(O).sub.2R.sup.10,
--SO.sub.2NH.sub.2, --C(O)NH.sub.2, --C(O)R.sup.10,
--C(NH)R.sup.10, --NHC(O)R.sup.10, --NHC(NH)R.sup.10,
--NHC(O)NH.sub.2, --CO.sub.2H, --NH.sub.2, --NHR.sup.10,
--N(R.sup.10).sub.2, and --N(R.sup.10).sub.3.
[0030] The symbol R.sup.10 is independently C.sub.1-6 alkyl.
[0031] The subscript n is 0, 1, 2, or 3.
[0032] Formula (I) is with the proviso that when X is C--R.sup.4, Y
is C--R.sup.5, R.sup.6 is R.sup.6a, and A is
##STR00007##
then R.sup.6a is bound to ring B through a carbon atom.
[0033] The present invention also contemplates pharmaceutically
acceptable salts, esters, and prodrugs of formula (I).
[0034] The present invention further provides chemical
intermediates, pharmaceutical compositions and methods for
preventing or treating a condition in a mammal characterized by
undesired thrombosis comprising the step of administering to said
mammal a therapeutically effective amount of a compound of the
present invention. Such conditions include but are not limited to
acute coronary syndrome, myocardial infarction, unstable angina,
refractory angina, occlusive coronary thrombus occurring
post-thrombolytic therapy or post-coronary angioplasty, a
thrombotically mediated cerebrovascular syndrome, embolic stroke,
thrombotic stroke, transient ischemic attacks, venous thrombosis,
deep venous thrombosis, pulmonary embolus, coagulopathy,
disseminated intravascular coagulation, thrombotic thrombocytopenic
purpura, thromboangiitis obliterans, thrombotic disease associated
with heparin-induced thrombocytopenia, thrombotic complications
associated with extracorporeal circulation, thrombotic
complications associated with instrumentation such as cardiac or
other intravascular catheterization, intra-aortic balloon pump,
coronary stent or cardiac valve, conditions requiring the fitting
of prosthetic devices, and the like.
[0035] The present invention further provides methods for
inhibiting the coagulation of a blood sample comprising contacting
said sample with a compound of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Abbreviations and Definitions
[0036] The term "alkyl", by itself or as part of another
substituent, means, unless otherwise stated, a straight or branched
chain hydrocarbon radical, having the number of carbon atoms
designated (i.e. C.sub.1-8 means one to eight carbons). Examples of
alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,
t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,
and the like. The term "alkenyl" refers to an unsaturated alkyl
group is one having one or more, preferably 1 to 3, double bonds.
Similarly, the term "alkynyl" refers to an unsaturated alkyl group
having one or more, preferably 1 to 3, triple bonds. Examples of
such unsaturated alkyl groups include vinyl, 2-propenyl, crotyl,
2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,
3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the
higher homologs and isomers.
[0037] The term "cycloalkyl" refers to hydrocarbon rings having the
indicated number of ring atoms (e.g., C.sub.3-6 cycloalkyl) and
being fully saturated between ring vertices. The term
"cycloalkenyl" refers to a cycloalkyl group that has at least one
point of alkenyl unsaturation between the ring vertices. The term
"cycloalkynyl" refers to a cycloalkyl group that has at least one
point of alkynyl unsaturation between the ring vertices. When
"cycloalkyl" is used in combination with "alkyl", as in C.sub.3-5
cycloalkyl-alkyl, the cycloalkyl portion is meant to have the
stated number of carbon atoms (e.g., from three to five carbon
atoms), while the alkyl portion is an alkylene moiety having from
one to three carbon atoms (e.g., --CH.sub.2--, --CH.sub.2CH.sub.2--
or --CH.sub.2CH.sub.2CH.sub.2--).
[0038] The term "alkylene" by itself or as part of another
substituent means a divalent radical derived from an alkane, as
exemplified by --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--. Typically, an
alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with
those groups having 10 or fewer carbon atoms being preferred in the
present invention. A "lower alkyl" or "lower alkylene" is a shorter
chain alkyl or alkylene group, generally having four or fewer
carbon atoms.
[0039] The terms "alkoxy," "alkylamino," and "alkylthio" (or
thioalkoxy) are used in their conventional sense, and refer to
those alkyl groups attached to the remainder of the molecule via an
oxygen atom (--O-alkyl), an amino group, or a sulfur atom
(--S-alkyl), respectively. Additionally, for dialkylamino groups
(typically provided as --NR.sup.aR.sup.b or a variant thereof,
where R.sup.a and R.sup.b are independently alkyl or substituted
alkyl), the alkyl portions can be the same or different and can
also be combined to form a 3-7 membered ring with the nitrogen atom
to which each is attached. Accordingly, a group represented as
--NR.sup.aR.sup.b is meant to include piperidinyl, pyrrolidinyl,
morpholinyl, azetidinyl and the like.
[0040] The terms "halo" or "halogen," by themselves or as part of
another substituent, mean, unless otherwise stated, a fluorine,
chlorine, bromine, or iodine atom. Additionally, terms such as
"haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl
up to the maximum number of halogens permitted. For example, the
term "C.sub.1-4 haloalkyl" is mean to include trifluoromethyl,
2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the
like.
[0041] The term "hydroxy" or "hydroxyl" refers to the group
--OH.
[0042] The term "aryl" means, unless otherwise stated, a
polyunsaturated, aromatic, hydrocarbon group containing from 6 to
14 carbon atoms, which can be a single ring or multiple rings (up
to three rings) which are fused together or linked covalently. The
term "heteroaryl" refers to aryl groups (or rings) that contain
from one to five heteroatoms selected from N, O, and S, wherein the
nitrogen and sulfur atoms are optionally oxidized, and the nitrogen
atom(s) are optionally quaternized. A heteroaryl group can be
attached to the remainder of the molecule through a heteroatom or
through a carbon atom and can contain 5 to 10 carbon atoms.
Non-limiting examples of aryl groups include phenyl, naphthyl and
biphenyl, while non-limiting examples of heteroaryl groups include
1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl,
2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,
5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,
4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,
5-benzothiazolyl, purinyl, 2-benzimidazolyl, benzopyrazolyl,
5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl,
5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. If not specifically
stated, substituents for each of the above noted aryl and
heteroaryl ring systems are selected from the group of acceptable
substituents described below.
[0043] For brevity, the term "aryl" when used in combination with
other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both
aryl and heteroaryl rings as defined above. Thus, the term
"arylalkyl" is meant to include those radicals in which an aryl or
heteroaryl group is attached to an alkyl group (e.g., benzyl,
phenethyl, pyridylmethyl and the like).
[0044] The term "heterocycle" or "heterocyclyl" or "heterocyclic"
refers to a saturated or unsaturated non-aromatic cyclic group
containing at least one sulfur, nitrogen or oxygen heteroatom. Each
heterocycle can be attached at any available ring carbon or
heteroatom. Each heterocycle may have one or more rings. When
multiple rings are present, they can be fused together or linked
covalently. Each heterocycle must contain at least one heteroatom
(typically 1 to 5 heteroatoms) selected from nitrogen, oxygen or
sulfur. Preferably, these groups contain 1-10 carbon atoms, 0-5
nitrogen atoms, 0-2 sulfur atoms and 0-2 oxygen atoms, wherein the
nitrogen and sulfur atoms are optionally oxidized, and the nitrogen
atom(s) are optionally quaternized. More preferably, these groups
contain 0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygen
atoms.
[0045] Non-limiting examples of heterocycle and heteroaryl groups
include pyridine, pyridimidine, pyrazine, morpholin-3-one,
piperazine-2-one, pyridine-2-one, piperidine, morpholine,
piperazine, isoxazole, isothiazole, pyrazole, imidazole, oxazole,
thiazole, isoxazoline, pyrazoline, imidazoline, 1,2,3-triazole,
1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole,
1,2,4-oxadiazole, 1,2,4-thiadiazole, pyrazol-5-one,
pyrrolidine-2,5-dione, imidazolidine-2,4-dione, pyrrolidine,
pyrrole, furan, thiophene, and the like.
[0046] The term "heterocycloalkyl" refers to the group
alkylene-heterocycle, wherein both heterocycle and alkylene are as
defined above.
[0047] The above terms (e.g., "aryl" and "heteroaryl"), in some
embodiments, will include both substituted and unsubstituted forms
of the indicated radical. Preferred substituents for each type of
radical are provided below. For brevity, the terms aryl and
heteroaryl will refer to substituted or unsubstituted versions as
provided below.
[0048] Substituents for the aryl and heteroaryl groups are varied
and are generally selected from: -halogen, --OR', --OC(O)R',
--NR'R'', --SR', --R', --CN, --NO.sub.2, --CO.sub.2R', --CONR'R'',
--C(O)R', --OC(O)NR'R'', --NR''C(O)R', --NR''C(O).sub.2R',
--NR'--C(O)NR''R''', --NH--C(NH.sub.2).dbd.NH,
--NR'C(NH.sub.2).dbd.NH, --NH--C(NH.sub.2).dbd.NR', --S(O)R',
--S(O).sub.2R', --S(O).sub.2NR'R'', --NR'S(O).sub.2R'', --N.sub.3,
perfluoro(C.sub.1-C.sub.4)alkoxy, and
perfluoro(C.sub.1-C.sub.4)alkyl, in a number ranging from zero to
the total number of open valences on the aromatic ring system; and
where R', R'' and R''' are independently selected from hydrogen,
C.sub.1-8alkyl, C.sub.3-6cycloalkyl, C.sub.2-8alkenyl,
C.sub.2-8alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted
aryl)-C.sub.1-4alkyl, and unsubstituted aryloxy-C.sub.1-4alkyl.
Other suitable substituents include each of the above aryl
substituents attached to a ring atom by an alkylene tether of from
1-4 carbon atoms.
[0049] Two of the substituents on adjacent atoms of the aryl or
heteroaryl ring may optionally be replaced with a substituent of
the formula -T-C(O)--(CH.sub.2).sub.q-U-, wherein T and U are
independently --NH--, --O--, --CH.sub.2-- or a single bond, and q
is an integer of from 0 to 2.
[0050] Alternatively, two of the substituents on adjacent atoms of
the aryl or heteroaryl ring may optionally be replaced with a
substituent of the formula -A-(CH.sub.2).sub.r-B-, wherein A and B
are independently --CH.sub.2--, --O--, --NH--, --S--, --S(O)--,
--S(O).sub.2--, --S(O).sub.2NR'-- or a single bond, and r is an
integer of from 1 to 3. One of the single bonds of the new ring so
formed may optionally be replaced with a double bond.
Alternatively, two of the substituents on adjacent atoms of the
aryl or heteroaryl ring may optionally be replaced with a
substituent of the formula --(CH.sub.2).sub.s--X--(CH.sub.2).sub.t,
where s and t are independently integers of from 0 to 3, and X is
--O--, --NR'--, --S--, --S(O)--, --S(O).sub.2--, or
--S(O).sub.2NR'--. The substituent R' in --NR'- and
--S(O).sub.2NR'-- is selected from hydrogen or unsubstituted
C.sub.1-6alkyl.
[0051] As used herein, the term "heteroatom" is meant to include
oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
[0052] The term "pharmaceutically acceptable salts" is meant to
include salts of the active compounds which are prepared with
relatively nontoxic acids or bases, depending on the particular
substituents found on the compounds described herein. When
compounds of the present invention contain relatively acidic
functionalities, base addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired base, either neat or in a suitable inert solvent. Examples
of salts derived from pharmaceutically-acceptable inorganic bases
include aluminum, ammonium, calcium, copper, ferric, ferrous,
lithium, magnesium, manganic, manganous, potassium, sodium, zinc
and the like. Salts derived from pharmaceutically-acceptable
organic bases include salts of primary, secondary and tertiary
amines, including substituted amines, cyclic amines,
naturally-occurring amines and the like, such as arginine, betaine,
caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine,
2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine
resins, procaine, purines, theobromine, triethylamine,
trimethylamine, tripropylamine, tromethamine and the like. When
compounds of the present invention contain relatively basic
functionalities, acid addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired acid, either neat or in a suitable inert solvent. Examples
of pharmaceutically acceptable acid addition salts include those
derived from inorganic acids like hydrochloric, hydrobromic,
nitric, carbonic, monohydrogencarbonic, phosphoric,
monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,
monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
as well as the salts derived from relatively nontoxic organic acids
like acetic, propionic, isobutyric, malonic, benzoic, succinic,
suberic, fumaric, mandelic, phthalic, benzenesulfonic,
p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
Also included are salts of amino acids such as arginate and the
like, and salts of organic acids like glucuronic or galactunoric
acids and the like (see, e.g., Berge, S. M., et al, "Pharmaceutical
Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain
specific compounds of the present invention contain both basic and
acidic functionalities that allow the compounds to be converted
into either base or acid addition salts.
[0053] The neutral forms of the compounds may be regenerated by
contacting the salt with a base or acid and isolating the parent
compound in the conventional manner. The parent form of the
compound differs from the various salt forms in certain physical
properties, such as solubility in polar solvents, but otherwise the
salts are equivalent to the parent form of the compound for the
purposes of the present invention.
[0054] In addition to salt forms, the present invention provides
compounds which are in a prodrug form. Prodrugs of the compounds
described herein are those compounds that readily undergo chemical
changes under physiological conditions to provide the compounds of
the present invention. Additionally, prodrugs can be converted to
the compounds of the present invention by chemical or biochemical
methods in an ex vivo environment. For example, prodrugs can be
slowly converted to the compounds of the present invention when
placed in a transdermal patch reservoir with a suitable enzyme or
chemical reagent.
[0055] Certain compounds of the present invention can exist in
unsolvated forms as well as solvated forms, including hydrated
forms. In general, the solvated forms are equivalent to unsolvated
forms and are intended to be encompassed within the scope of the
present invention. Certain compounds of the present invention may
exist in multiple crystalline or amorphous forms. In general, all
physical forms are equivalent for the uses contemplated by the
present invention and are intended to be within the scope of the
present invention.
[0056] Certain compounds of the present invention possess
asymmetric carbon atoms (optical centers) or double bonds; the
racemates, diastereomers, geometric isomers, regioisomers and
individual isomers (e.g., separate enantiomers) are all intended to
be encompassed within the scope of the present invention. The
compounds of the present invention may also contain unnatural
proportions of atomic isotopes at one or more of the atoms that
constitute such compounds. For example, the compounds may be
radiolabeled with radioactive isotopes, such as for example tritium
(.sup.3H), iodine-125 (.sup.125I) or carbon-14 (.sup.14C). All
isotopic variations of the compounds of the present invention,
whether radioactive or not, are intended to be encompassed within
the scope of the present invention.
[0057] Accordingly, in one embodiment provided is a compound having
Formula (I) or a pharmaceutically acceptable salt, ester, or
prodrug thereof:
##STR00008##
[0058] In Formula (I), the symbol R.sup.1 is halogen, C.sub.1-8
alkyl, C.sub.2-8 alkenyl, and C.sub.2-8 alkynyl.
[0059] The symbol R.sup.2 is hydrogen or C.sub.1-4 alkyl.
[0060] The symbol A is selected from the group consisting of:
##STR00009## ##STR00010##
wherein the wavy line indicates the point of attachment to ring B
and the dashed line indicates the point of attachment to the rest
of the molecule.
[0061] The symbol R.sup.3 is independently hydrogen or R.sup.3a,
wherein R.sup.3a is independently selected from the group
consisting of halogen, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, and
C.sub.2-8 alkynyl.
[0062] The subscript m is 0, 1, 2, or 3.
[0063] The symbol X is C--R.sup.4 or N.
[0064] The symbol Y is C--R.sup.5 or N provided that X and Y are
not both N. In some embodiments, X and Y are C and are fused to
form a 6-membered aryl, heteroaryl, or heterocyclic ring.
[0065] The symbol R.sup.4 is selected from the group consisting of
hydrogen, halogen, and
##STR00011##
wherein R.sup.4a is hydrogen or C.sub.1-8 alkyl.
[0066] The symbol R.sup.5 is selected from the group consisting of
hydrogen, halogen, and C.sub.1-8 alkoxy; or R.sup.5 and R.sup.6
join together along with the atom bound thereto to form a
6-membered aryl, heteroaryl, or heterocyclic ring fused to ring
B.
[0067] The symbol R.sup.6 is selected from the group consisting of
--R.sup.6a, --NR.sup.7aR.sup.7b, --NR.sup.7aC(O)R.sup.7c,
--NR.sup.7aC(O)OR.sup.7c, --CONR.sup.8aR.sup.8b, --OR.sup.7c,
--SR.sup.7c, --C(.dbd.NR.sup.7a)NR.sup.8aR.sup.8b,
--S(O).sub.2NR.sup.8aR.sup.8b, and --S(O).sub.2R.sup.7c.
[0068] The symbol R.sup.6a is selected from the group consisting
of
##STR00012## ##STR00013##
wherein R.sup.8 an be at any position suitable for a substituent,
and if R.sup.8 is attached to a nitrogen atom, then it replaces the
hydrogen atom attached thereto.
[0069] The symbol R.sup.7a and R.sup.7b are independently selected
from the group consisting of hydrogen, C.sub.1-8 alkyl, and
C.sub.1-8 alkyl substituted with one to three R.sup.9.
[0070] The symbol R.sup.7c is selected from the group consisting of
aryl, heteroaryl, C.sub.1-8 alkyl, and C.sub.1-8 alkyl substituted
with one to three R.sup.9.
[0071] The symbol R.sup.8 is independently selected from the group
consisting of nitro, hydroxy, --CO.sub.2H, --C(O)R.sup.8c,
--C(O)NR.sup.8aR.sup.8b, --NR.sup.8aR.sup.8b,
--SO.sub.2NR.sup.8aR.sup.8b, halogen, C.sub.1-8 alkyl, and
C.sub.1-8 alkoxy wherein said C.sub.1-8 alkyl and C.sub.1-8 alkoxy
are optionally substituted with one to three R.sup.9.
[0072] The symbol R.sup.8a and R.sup.8b are independently selected
from the group consisting of hydrogen, C.sub.1-8 alkyl, and
C.sub.1-8 alkyl substituted with one to three R.sup.9, or R.sup.8a
and R.sup.8b together form a 5 to 7 membered heterocyclic ring
optionally substituted with one to three R.sup.9 and optionally
having one additional ring heteroatom selected from N, O, or S.
[0073] The symbol R.sup.8c is selected from the group consisting of
C.sub.1-8 alkyl and C.sub.1-8 alkyl substituted with one to three
R.sup.9.
[0074] The symbol R.sup.9 is independently selected from the group
consisting of halogen, heterocyclic, heteroaryl, --OH, --R.sup.10,
--OR.sup.10, --S(O)R.sup.10, --S(O).sub.2R.sup.10,
--SO.sub.2NH.sub.2, --C(O)NH.sub.2, --C(O)R.sup.10,
--C(NH)R.sup.10, --NHC(O)R.sup.10, --NHC(NH)R.sup.10,
--NHC(O)NH.sub.2, --CO.sub.2H, --NH.sub.2, --NHR.sup.10,
--N(R.sup.10).sub.2, and --N(R.sup.10).sub.3.sup.+.
[0075] The symbol R.sup.10 is independently C.sub.1-6 alkyl.
[0076] The subscript n is 0, 1, 2, or 3.
[0077] Formula (I) is with the proviso that when X is C--R.sup.4, Y
is C--R.sup.5, R.sup.6 is R.sup.6a, and A is
##STR00014##
then R.sup.6a is bound to ring B through a carbon atom.
[0078] With respect to the above formula, there are a number of
specific embodiments of the invention. In one group of embodiments,
R.sup.1 is 2-chloro.
[0079] In another group of embodiments, R.sup.2 is hydrogen.
[0080] In another group of embodiments, X and Y are both CH.
[0081] In another group of embodiments, A is selected from the
group consisting of:
##STR00015##
[0082] In another group of embodiments, R.sup.6 is R.sup.6a.
[0083] In another group of embodiments, R.sup.6a is selected from
the group consisting of:
##STR00016##
[0084] In another group of embodiments, R.sup.6 is selected from
the group consisting of:
##STR00017## ##STR00018##
[0085] In another group of embodiments, R.sup.6 is selected from
the group consisting of:
##STR00019##
[0086] In another group of embodiments, R.sup.6 is selected from
the group consisting of:
##STR00020##
[0087] In another group of embodiments, R.sup.6 is selected from
the group consisting of:
##STR00021##
[0088] In another group of embodiments, R.sup.6 is selected from
the group consisting of:
##STR00022##
[0089] In another group of embodiments, R.sup.6 is
##STR00023##
and R.sup.8 is as previously defined. In still another group of
embodiments, R.sup.8 is selected from the group consisting of
hydrogen,
##STR00024##
[0090] In another embodiment, ring B is
##STR00025##
[0091] In another embodiment, the compound is a compound selected
from Table 1 or a pharmaceutically acceptable salt, ester, or
prodrug thereof.
TABLE-US-00001 TABLE 1 Compound Structure Name 1 ##STR00026##
5-Chloro-N-((1-(4-(2-oxopyridin-
1(2H)-yl)-2-(piperazin-1-yl)phenyl)- 1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide 2 ##STR00027##
5-Chloro-N-((1-(2-(4-ethylpiperazin- 1-yl)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 3
##STR00028## 5-Chloro-N-((1-(2-(4- isopropylpiperazin-1-yl)-4-(2-
oxopyridin-1(2H)-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 4 ##STR00029##
5-Chloro-N-((1-(4-(2-oxopyrimidin-
1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide 5 ##STR00030##
5-Chloro-N-((1-(4-(1-methyl-6-oxo-
1,6-dihydropyridazin-3-yl)phenyl)- 1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide 6 ##STR00031##
5-Chloro-N-((1-(4-(2,4- dimethoxypyrimidin-5-yl)phenyl)-
1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 7
##STR00032## 5-Chloro-N-((1-(4-(2- ((dimethylamino)methyl)-1H-
imidazol-1-yl)-2-fluorophenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 8 ##STR00033##
5-Chloro-N-((1-(4-(2-methyl-1H- imidazol-1-yl)phenyl)-1H-1,2,3-
triazol-4-yl)methyl)thiophene-2- carboxamide 9 ##STR00034##
5-Chloro-N-((1-(4-(4-methyl-1,4- diazepan-1-yl)phenyl)-1H-1,2,3-
triazol-4-yl)methyl)thiophene-2- carboxamide 10 ##STR00035##
5-Chloro-N-((1-(4-(2- oxoimidazolidin-1-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 11 ##STR00036##
5-Chloro-N-((1-(2'-methoxybiphenyl- 4-yl)-1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide 12 ##STR00037##
5-Chloro-N-((1-(2'-hydroxybiphenyl- 4-yl)-1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide 13 ##STR00038##
5-Chloro-N-((1-(2'- (trifluoromethoxy)biphenyl-4-yl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 14 ##STR00039##
5-Chloro-N-((1-(4-(6-chloropyridin-
3-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide
15 ##STR00040## N-((1-(4-(1H-Indol-2-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)-5- chlorothiophene-2-carboxamide 16
##STR00041## 5-Chloro-N-((1-(4- (methylsulfonyl)phenyl)-1H-1,2,3-
triazol-4-yl)methyl)thiophene-2- carboxamide 17 ##STR00042##
5-Chloro-N-((1-(3-fluoro-2'- sulfamoylbiphenyl-4-yl)-1H-1,2,3-
triazol-4-yl)methyl)thiophene-2- carboxamide 18 ##STR00043##
5-Chloro-N-((1-(4-(pyrrolidine-1-
carbonyl)phenyl)-1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide 19 ##STR00044##
5-Chloro-N-((1-(4-(2,5-dihydro-1H-
pyrrole-1-carbonyl)phenyl)-1H-1,2,3-
triazol-4-yl)methyl)thiophene-2- carboxamide 20 ##STR00045##
N-((1-(4-Carbamoylphenyl)- 1,2,3-triazol-4-yl)methyl)-5-
chlorothiophene-2-carboxamide 21 ##STR00046## N-((1-(4-(2-Amino-N-
methylacetamido)phenyl)-1H-1,2,3- triazol-4-yl)methyl)-5-
chlorothiophene-2-carboxamide 22 ##STR00047##
5-Chloro-N-((1-(4-(methyl(2- (methylamino)ethyl)amino)phenyl)-
1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 23
##STR00048## 5-Chloro-N-((1-(4- (methylamino)phenyl)-1H-1,2,3-
triazol-4-yl)methyl)thiophene-2- carboxamide 24 ##STR00049##
5-Chloro-N-((1-(4-(N- methylpropionamido)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 25 ##STR00050##
Ethyl 4-(4-((5-chlorothiophene-2- carboxamido)methyl)-1H-1,2,3-
triazol-1-yl)phenyl(methyl)carbamate 26 ##STR00051##
5-Chloro-N-((1-(4-(2-methoxy-N- methylacetamido)phenyl)-1H-1,2,3-
triazol-4-yl)methyl)thiophene-2- carboxamide 27 ##STR00052##
5-Chloro-N-((1-(4-(2- (dimethylamino)-N-
methylacetamido)phenyl)-1H-1,2,3- triazol-4-yl)methyl)thiophene-2-
carboxamide 28 ##STR00053## 5-Chloro-N-((1-(4-(N-
methylacetamido)phenyl)-1H-1,2,3- triazol-4-yl)methyl)thiophene-2-
carboxamide 29 ##STR00054## 5-Chloro-N-((1-(4-(2-
hydroxyethoxy)phenyl)-1H-1,2,3- triazol-4-yl)methyl)thiophene-2-
carboxamide 30 ##STR00055## 5-Chloro-N-((1-(4-(6-oxo-1,6-
dihydropyridazin-3-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 31 ##STR00056##
5-Chloro-N-((3-(2-fluoro-4-(2- oxopyridin-1(2H)-yl)phenyl)-5-
methyl-4,5-dihydroisoxazol-5- yl)methyl)thiophene-2-carboxamide 32
##STR00057## 5-Chloro-N-((5-oxo-1-(4-(2-
oxopyridin-1(2H)-yl)phenyl)-4,5- dihydro-1H-pyrazol-3-
yl)methyl)thiophene-2-carboxamide 33 ##STR00058##
5-Chloro-N-((2-oxo-1-(4-(2- oxopyridin-1(2H)-yl)phenyl)-1,2-
dihydropyridin-3- yl)methyl)thiophene-2-carboxamide 34 ##STR00059##
5-Chloro-N-((6-oxo-1-(4-(2- oxopyridin-1(2H)-yl)phenyl)-1,6-
dihydropyridin-3- yl)methyl)thiophene-2-carboxamide 35 ##STR00060##
5-Chloro-N-((1-methyl-2-(4-(2- oxopyridin-1(2H)-yl)phenyl)-1H-
imidazol-4-yl)methyl)thiophene-2- carboxamide 36 ##STR00061##
5-Chloro-N-((1-(4-iodophenyl)-1H- imidazol-4-yl)methyl)thiophene-2-
carboxamide 37 ##STR00062## 5-Chloro-N-((1-(4-(1-methyl-6-oxo-
1,6-dihydropyridazin-3-yl)phenyl)-
1H-imidazol-4-yl)methyl)thiophene- 2-carboxamide 38 ##STR00063##
5-Chloro-N-((1-(4-(2- methoxypyridin-3-yl)phenyl)-1H-
imidazol-4-yl)methyl)thiophene-2- carboxamide 39 ##STR00064##
5-Chloro-N-((1-(4-(2-oxo-1,2- dihydropyridin-3-yl)phenyl)-1H-
imidazol-4-yl)methyl)thiophene-2- carboxamide 40 ##STR00065##
5-Chloro-N-((1-(4-(1-methyl-2-oxo-
1,2-dihydropyridin-3-yl)phenyl)-1H-
imidazol-4-yl)methyl)thiophene-2- carboxamide 41 ##STR00066##
N-((1-(4-Aminophenyl)-1H-imidazol-
4-yl)methyl)-5-chlorothiophene-2- carboxamide 42 ##STR00067##
5-Chloro-N-((1-(4-(2,5-dihydro-1H- pyrrole-1-carbonyl)phenyl)-1H-
imidazol-4-yl)methyl)thiophene-2- carboxamide 43 ##STR00068##
4-Chloro-N-((1-(4-(2-oxopyridin- 1(2H)-yl)phenyl)-1H-imidazol-4-
yl)methyl)benzamide 44 ##STR00069## N-((1-(4-(2-Oxopyridin-1(2H)-
yl)phenyl)-1H-imidazol-4- yl)methyl)acetamide 45 ##STR00070##
5-Chloro-N-((1-(5-(2-oxopyridin-
1(2H)-yl)pyridin-2-yl)-1H-imidazol-
4-yl)methyl)thiophene-2-carboxamide 46 ##STR00071##
5-Chloro-N-((1-(6-(2-oxopyridin-
1(2H)-yl)pyridin-3-yl)-1H-imidazol-
4-yl)methyl)thiophene-2-carboxamide 47 ##STR00072##
5-Ch1oro-N-((2,5-dibromo-1-(4-(N,N-
dimethylcarbamimidoyl)phenyl)-1H- imidazol-4-yl)methyl)thiophene-2-
carboxamide 48 ##STR00073## 5-Chloro-N-((2,5-dibromo-1-(4-
(imino(pyrrolidin-1- yl)methyl)phenyl)-1H-imidazol-4-
yl)methyl)thiophene-2-carboxamide 49 ##STR00074##
5-Chloro-N-((2,5-dibromo-1-(4-(1- methyl-4,5-dihydro-1H-imidazol-2-
yl)phenyl)-1H-imidazol-4- yl)methyl)thiophene-2-carboxamide 50
##STR00075## 5-Chloro-N-((1-(4-(9-methyl-2,6-
dioxo-1H-purin-3(2H,6H,9H)- yl)phenyl)-1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide 51 ##STR00076##
5-Chloro-N-((1-(4-(1-methyl-6-oxo-
1,6-dihydropyridazin-3-yl)phenyl)-
1H-imidazol-5-yl)methyl)thiophene- 2-carboxamide 52 ##STR00077##
5-Chloro-N-((4-methyl-1-(4-(2- oxopyridin-1(2H)-yl)phenyl)-1H-
imidazol-5-yl)methyl)thiophene-2- carboxamide 53 ##STR00078##
5-Chloro-N-((1-(4-(2-oxopyrazin-
1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide 54 ##STR00079##
5-Chloro-N-((1-(2-fluoro-4-(2- oxopyrazin-1(2H)-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 55 ##STR00080##
5-Chloro-N-((1-(2-fluoro-4-(2- oxopyrimidin-1(2H)-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 56 ##STR00081##
5-Chloro-N-((1-(4-(2- oxotetrahydropyrimidin-1(2H)-
yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 57
##STR00082## 5-Chloro-N-((1-(2-fluoro-4-(2-oxo-
tetrahydropyrimidin-1(2H)- yl)phenyl)-1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide 58 ##STR00083##
5-Chloro-N-((1-(2-fluoro-4-(3- methyl-2-oxo-tetrahydropyrimidin-
1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide 59 ##STR00084##
5-Chloro-N-((1-(2-fluoro-4-(2- oxopiperidin-1-yl)phenyl)-1H-1,2,3-
triazol-4-yl)methyl)thiophene-2- carboxamide 60 ##STR00085##
5-Chloro-N-((1-(3-fluoro-4-(2- oxopyridin-1(2H)-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 61 ##STR00086##
5-Chloro-N-((1-(4-(3-hydroxy-2- oxopyridin-1(2H)-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 62 ##STR00087##
5-Chloro-N-((1-(4-(3-(2- hydroxyethoxy)-2-oxopyridin-1(2H)-
yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 63
##STR00088## 5-Chloro-N-((1-(4-(3-(2-
methoxyethoxy)-2-oxopyridin-1(2H)- yl)phenyl)-1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide 64 ##STR00089##
5-Chloro-N-((1-(4-(3-(2- (dimethylamino)ethoxy)-2-
oxopyridin-1(2H)-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 65 ##STR00090##
5-Chloro-N-((1-(4-(3-(2- (dimethyl(dimethylamino)
amino)ethoxy)-2-oxopyridin-1(2H)- yl)phenyl)-1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide 66 ##STR00091##
5-Chloro-N-((1-(4-(2-oxo-3-(2-
(piperidin-1-yl)ethoxy)pyridin-1(2H)-
yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 67
##STR00092## 5-Chloro-N-((1-(4-(2-oxo-3-(3-
(piperidin-1-yl)propoxy)pyridin-
1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide 68 ##STR00093##
5-Chloro-N-((1-(4-(3-(2- (methylthio)ethoxy)-2-oxopyridin-
1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide
69 ##STR00094## 5-Chloro-N-((1-(4-(3-(2- (methylsulfinyl)ethoxy)-2-
oxopyridin-1(2H)-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 70 ##STR00095##
5-Chloro-N-((1-(4-(3-(2- (methylsulfonyl)ethoxy)-2-
oxopyridin-1(2H)-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 71 ##STR00096##
5-Chloro-N-((1-(4-(3-(2- morpholinoethoxy)-2-oxopyridin-
1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide 72 ##STR00097##
N-((1-(4-(3-(2-(1H-Imidazol-1- yl)ethoxy)-2-oxopyridin-1(2H)-
yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)-5-chlorothiophene-2-
carboxamide 73 ##STR00098## 5-Chloro-N-((1-(4-(3-((1-methyl-1H-
imidazol-2-yl)methoxy)-2- oxopyridin-1(2H)-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 74 ##STR00099##
5-Chloro-N-((1-(4-(5-hydroxy-2- oxopyridin-1(2H)-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 75 ##STR00100##
5-Chloro-N-((1-(4-(5-(2- (dimethylamino)ethoxy)-2-
oxopyridin-1(2H)-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 76 ##STR00101##
5-Chloro-N-((1-(4-(2-oxo-5-(2-
(piperidin-1-yl)ethoxy)pyridin-1(2H)-
yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 77
##STR00102## 5-Chloro-N-((1-(4-(5-(2-
morpholinoethoxy)-2-oxopyridin-
1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide 78 ##STR00103##
5-Chloro-N-((1-(4-(5-nitro-2- oxopyridin-1(2H)-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 79 ##STR00104##
N-((1-(4-(4-Amino-2-oxopyrimidin-
1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-
yl)methyl)-5-chlorothiophene-2- carboxamide 80 ##STR00105##
5-Chloro-N-((1-(4-(2,4-dioxo-3,4-
dihydropyrimidin-1(2H)-yl)phenyl)- 1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide 81 ##STR00106##
N-((1-(4-(4-Amino-5-fluoro-2- oxopyrimidin-1(2H)-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)-5- chlorothiophene-2-carboxamide 82
##STR00107## 5-Chloro-N-((1-(4-(3-methyl-2,4-
dioxo-3,4-dihydropyrimidin-1(2H)- yl)phenyl)-1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide 83 ##STR00108##
5-Chloro-N-((1-(4-(2-oxopiperazin-1- yl)phenyl)-1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide 84 ##STR00109##
5-Chloro-N-((1-(4-(4-methyl-2- oxopiperazin-1-yl)phenyl)-1H-1,2,3-
triazol-4-yl)methyl)thiophene-2- carboxamide 85 ##STR00110##
5-Chloro-N-((1-(4-(4-isopropyl-2-
oxopiperazin-1-yl)phenyl)-1H-1,2,3-
triazol-4-yl)methyl)thiophene-2- carboxamide 86 ##STR00111##
4-(4-(4-((5-Chlorothiophene-2- carboxamido)methyl)-1H-1,2,3-
triazol-1-yl)phenyl)-3-oxopiperazine- 1-carboxamide 87 ##STR00112##
5-Chloro-N-((1-(4-(3-hydroxy-2- oxopyrazin-1(2H)-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 88 ##STR00113##
5-Chloro-N-((1-(4-(4-(2- (dimethylamino)ethyl)-2,3-dioxo-3,4-
dihydropyrazin-1(2H)-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 89 ##STR00114##
5-Chloro-N-((1-(4-(3-hydroxy-6- oxopyridazin-1(6H)-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 90 ##STR00115##
1-(4-(2-Oxopyridin-1(2H)- yl)phenyl)-1H-1,2,3-triazol-4-
yl)methylcarbamoyl)benzoic acid 91 ##STR00116##
N-((1-(2-(3-Oxopiperazin-1-yl)-4-(2-
oxopyridin-1(2H)-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 92 ##STR00117##
5-Chloro-N-((1-(4-(1-methyl-4,5- dihydro-1H-imidazol-2-yl)phenyl)-
1H-1,2,3-triazol-5- yl)methyl)thiophene-2-carboxamide 93
##STR00118## 5-Chloro-N-((1-(4-(N,N-
dimethylcarbamimidoyl)phenyl)-1H-
1,2,3-triazol-5-yl)methyl)thiophene- 2-carboxamide 94 ##STR00119##
5-Chloro-N-((1-(4-(imino(pyrrolidin-
1-yl)methyl)phenyl)-1H-1,2,3-triazol-
5-yl)methyl)thiophene-2-carboxamide 95 ##STR00120##
5-Chloro-N-((1-(4-(imino(piperidin-
1-yl)methyl)phenyl)-1H-1,2,3-triazol-
5-yl)methyl)thiophene-2-carboxamide 96 ##STR00121##
N-((1-(4-Carbamoylphenyl)-1H- 1,2,3-triazol-5-yl)methyl)-5-
chlorothiophene-2-carboxamide 97 ##STR00122## 5-Chloro-N-((1-(4-
(methylsulfonyl)phenyl)-1H-1,2,3- triazol-5-yl)methyl)thiophene-2-
carboxamide 98 ##STR00123## 5-Chloro-N-((1-(4-(2-oxopyridin-
1(2H)-yl)phenyl)-1H-1,2,3-triazol-5-
yl)methyl)thiophene-2-carboxamide 99 ##STR00124##
5-Chloro-N-((1-(4-(pyridin-2- ylthio)phenyl)-1H-1,2,3-triazol-5-
yl)methyl)thiophene-2-carboxamide 100 ##STR00125##
5-Chloro-N-((1-(6-(pyrrolidin-1-
yl)pyridin-3-yl)-1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide 101 ##STR00126##
1-(5-(4-((5-Chlorothiophene-2- carboxamido)methyl)-1H-1,2,3-
triazol-1-yl)pyridin-2-yl)piperidine-4- carboxylic acid 102
##STR00127## N-((1-(6-(Azepan-1-yl)pyridin-3-yl)-
1H-1,2,3-triazol-4-yl)methyl)-5- chlorothiophene-2-carboxamide 103
##STR00128## 5-Chloro-N-((1-(6-(4-methyl-1,4-
diazepan-1-yl)pyridin-3-yl)-1H-1,2,3-
triazol-5-yl)methyl)thiophene-2- carboxamide 104 ##STR00129##
N-((1-(6-(1,4-Diazepan-1-yl)pyridin-
3-yl)-1H-1,2,3-triazol-5-yl)methyl)-5-
chlorothiophene-2-carboxamide 105 ##STR00130##
5-Chloro-N-((1-(6-(4- methylpiperazin-1-yl)pyridin-3-yl)-
1H-1,2,3-triazol-5- yl)methyl)thiophene-2-carboxamide 106
##STR00131## 5-Chloro-N-((1-(6-(piperazin-1-
yl)pyridin-3-yl)-1H-1,2,3-triazol-5-
yl)methyl)thiophene-2-carboxamide 107 ##STR00132##
5-Chloro-N-(4-(4-((5- chlorothiophene-2-
carboxamido)methyl)-1H-imidazol-1-
yl)benzyl)thiophene-2-carboxamide 108 ##STR00133##
5-Chloro-N-((1-(4-(2-oxopyridin- 1(2H)-yl)phenyl)-1H-pyrrol-3-
yl)methyl)thiophene-2-carboxamide 109 ##STR00134##
5-Chloro-N-((1-(4-(2-oxopyridin- 1(2H)-yl)phenyl)-1H-pyrazol-4-
yl)methyl)thiophene-2-carboxamide 110 ##STR00135##
5-Chloro-N-((1-(4-(4-methyl-1,4-
diazepan-1-yl)phenyl)-1H-pyrazol-4-
yl)methyl)thiophene-2-carboxamide 111 ##STR00136##
5-Chloro-N-((1-(4-(2-oxopyrazin- 1(2H)-yl)phenyl)-1H-pyrazol-4-
yl)methyl)thiophene-2-carboxamide 112 ##STR00137##
5-Chloro-N-((1-(4-(2-oxopyridin- 1(2H)-yl)phenyl)-1H-pyrazol-3-
yl)methyl)thiophene-2-carboxamide 113 ##STR00138##
5-Chloro-N-((1-(3-(2-oxopyridin-
1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide 114 ##STR00139##
5-Chloro-N-((1-(4-methyl-3-oxo-3,4-
dihydro-2H-benzo[.beta.][1,4]oxazin-7- yl)-1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide 115 ##STR00140##
5-Chloro-N-((1-(3-methoxy-4-(2- oxopyridin-1(2H)-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 116 ##STR00141##
5-Chloro-N-((1-(5-(2-oxopyridin- 1(2H)-yl)quinolin-8-yl)-1H-1,2,3-
triazol-4-yl)methyl)thiophene-2- carboxamide
[0092] All the preferred, more preferred, and most preferred
compounds listed above are selective inhibitors of Factor Xa.
Compositions
[0093] The present invention further provides compositions
comprising one or more compounds of Formula (I) or a
pharmaceutically acceptable salt, ester, or prodrug thereof and a
pharmaceutically acceptable excipient or carrier. It will be
appreciated that the compounds of Formula (I) in this invention may
be derivatized at functional groups to provide prodrug derivatives
which are capable of conversion back to the parent compounds in
vivo. Examples of such prodrugs include the physiologically
acceptable and metabolically labile ester derivatives, such as
methoxymethyl esters, methylthiomethyl esters, or pivaloyloxymethyl
esters derived from a hydroxyl group of the compound or a carbamoyl
moiety derived from an amino group of the compound. Additionally,
any physiologically acceptable equivalents of the compounds of
Formula (I), similar to metabolically labile esters or carbamates,
which are capable of producing the parent compounds of Formula (I)
in vivo, are within the scope of this invention.
[0094] If pharmaceutically acceptable salts of the compounds of
this invention are utilized in these compositions, those salts are
preferably derived from inorganic or organic acids and bases.
Included among such acid salts are the following: acetate, adipate,
alginate, aspartate, benzoate, benzene sulfonate, bisulfate,
butyrate, citrate, camphorate, camphor sulfonate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate,
pamoate, pectinate, persulfate, 3-phenyl-propionate, picrate,
pivalate, propionate, succinate, tartrate, thiocyanate, tosylate
and undecanoate. Base salts include ammonium salts, alkali metal
salts, such as sodium and potassium salts, alkaline earth metal
salts, such as calcium and magnesium salts, salts with organic
bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and
salts with amino acids such as arginine, lysine, and so forth.
[0095] Furthermore, the basic nitrogen-containing groups may be
quaternized with agents like lower alkyl halides, such as methyl,
ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl
sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates,
long chain halides, such as decyl, lauryl, myristyl and stearyl
chlorides, bromides and iodides; aralkyl halides, such as benzyl
and phenethyl bromides and others. Water or oil-soluble or
dispersible products are thereby obtained.
[0096] The compounds utilized in the compositions and methods of
this invention may also be modified by appending appropriate
functionalities to enhance selective biological properties. Such
modifications are known in the art and include those which increase
biological penetration into a given biological system (e.g., blood,
lymphatic system, central nervous system, etc.), increase oral
availability, increase solubility to allow administration by
injection, alter metabolism and alter rate of excretion.
[0097] The pharmaceutical compositions of the invention can be
manufactured by methods well known in the art such as conventional
granulating, mixing, dissolving, encapsulating, lyophilizing, or
emulsifying processes, among others. Compositions may be produced
in various forms, including granules, precipitates, or
particulates, powders, including freeze dried, rotary dried or
spray dried powders, amorphous powders, tablets, capsules, syrup,
suppositories, injections, emulsions, elixirs, suspensions or
solutions. Formulations may optionally contain stabilizers, pH
modifiers, surfactants, bioavailability modifiers and combinations
of these.
[0098] Pharmaceutical formulations may be prepared as liquid
suspensions or solutions using a sterile liquid, such as oil,
water, alcohol, and combinations thereof. Pharmaceutically suitable
surfactants, suspending agents or emulsifying agents, may be added
for oral or parenteral administration. Suspensions may include
oils, such as peanut oil, sesame oil, cottonseed oil, corn oil and
olive oil. Suspension preparation may also contain esters of fatty
acids, such as ethyl oleate, isopropyl myristate, fatty acid
glycerides and acetylated fatty acid glycerides. Suspension
formulations may include alcohols, such as ethanol, isopropyl
alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers,
such as poly(ethyleneglycol), petroleum hydrocarbons, such as
mineral oil and petrolatum, and water may also be used in
suspension formulations.
[0099] Pharmaceutically acceptable excipients or carriers that may
be used in these compositions include ion exchangers, alumina,
aluminum stearate, lecithin, serum proteins, such as human serum
albumin, buffer substances, such as phosphates, glycine, sorbic
acid, potassium sorbate, partial glyceride mixtures of saturated
vegetable fatty acids, water, salts or electrolytes, such as
protamine sulfate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based substances,
polyethylene glycol, sodium carboxymethylcellulose, polyacrylates,
waxes, polyethylene-polyoxypropyl en e-block polymers, polyethylene
glycol and wool fat.
[0100] According to a preferred embodiment, the compositions of
this invention are formulated for pharmaceutical administration to
a mammal, preferably a human being. Such pharmaceutical
compositions of the invention may be administered orally,
parenterally, by inhalation spray, topically, rectally, nasally,
buccally, vaginally or via an implanted reservoir. The term
"parenteral" as used herein includes subcutaneous, intravenous,
intramuscular, intra-articular, intra-synovial, intrasternal,
intrathecal, intrahepatic, intralesional and intracranial injection
or infusion techniques. Preferably, the compositions are
administered orally or intravenously. The formulations of the
invention may be designed as short-acting, fast-releasing, or
long-acting. Still further, compounds can be administered in a
local rather than systemic means, such as administration (e.g.,
injection) as a sustained release formulation.
[0101] Sterile injectable forms of the compositions of this
invention may be aqueous or oleaginous suspension. These
suspensions may be formulated according to techniques known in the
art using suitable dispersing or wetting agents and suspending
agents. The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, for example as a solution in
1,3-butanediol.
[0102] Among the acceptable vehicles and solvents that may be
employed are water, Ringer's solution and isotonic sodium chloride
solution. In addition, sterile, fixed oils are conventionally
employed as a solvent or suspending medium. For this purpose, any
bland fixed oil may be employed including synthetic mono- or
di-glycerides. Fatty acids, such as oleic acid and its glyceride
derivatives are useful in the preparation of injectables, as are
natural pharmaceutically-acceptable oils, such as olive oil or
castor oil, especially in their polyoxyethylated versions. These
oil solutions or suspensions may also contain a long-chain alcohol
diluent or dispersant, such as carboxymethyl cellulose or similar
dispersing agents which are commonly used in the formulation of
pharmaceutically acceptable dosage forms including emulsions and
suspensions. Other commonly used surfactants, such as Tweens, Spans
and other emulsifying agents or bioavailability enhancers which are
commonly used in the manufacture of pharmaceutically acceptable
solid, liquid, or other dosage forms may also be used for the
purposes of formulation. Compounds may be formulated for parenteral
administration by injection such as by bolus injection or
continuous infusion. A unit dosage form for injection may be in
ampoules or in multi-dose containers.
[0103] The pharmaceutical compositions of this invention may be in
any orally acceptable dosage form, including capsules, tablets,
aqueous suspensions or solutions. In the case of tablets for oral
use, excipients or carriers that are commonly used include lactose
and corn starch. Lubricating agents, such as magnesium stearate,
are also typically added. For a capsule form, useful diluents
include lactose and dried cornstarch. When aqueous suspensions are
required for oral use, the active ingredient is combined with
emulsifying and suspending agents. If desired, certain sweetening,
flavoring or coloring agents may also be added.
[0104] Alternatively, the pharmaceutical compositions of this
invention may be in the form of suppositories for rectal
administration. These may be prepared by mixing the agent with a
suitable non-irritating excipient which is solid at room
temperature but liquid at rectal temperature and therefore will
melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax and polyethylene glycols.
[0105] The pharmaceutical compositions of this invention may also
be in a topical form, especially when the target of treatment
includes areas or organs readily accessible by topical application,
including diseases of the eye, the skin, or the lower intestinal
tract. Suitable topical formulations are readily prepared for each
of these areas or organs.
[0106] Topical application for the lower intestinal tract may be
effected in a rectal suppository formulation (see above) or in a
suitable enema formulation. Topically-transdermal patches may also
be used. For topical applications, the pharmaceutical compositions
may be formulated in a suitable ointment containing the active
component suspended or dissolved in one or more carriers. Carriers
for topical administration of the compounds of this invention
include, but are not limited to, mineral oil, liquid petrolatum,
white petrolatum, propylene glycol, polyoxyethylene,
polyoxypropylene compound, emulsifying wax and water.
Alternatively, the pharmaceutical compositions may be formulated in
a suitable lotion or cream containing the active components
suspended or dissolved in one or more pharmaceutically acceptable
carriers. Suitable carriers include mineral oil, sorbitan
monostearate, polysorbate 60, cetyl esters, wax, cetyl alcohol,
2-octyldodecanol, benzyl alcohol and water.
[0107] For ophthalmic use, the pharmaceutical compositions may be
formulated as micronized suspensions in isotonic, pH adjusted
sterile saline, or, preferably, as solutions in isotonic, pH
adjusted sterile saline, either with our without a preservative,
such as benzylalkonium chloride. Alternatively, for ophthalmic
uses, the pharmaceutical compositions may be formulated in an
ointment, such as petrolatum.
[0108] The pharmaceutical compositions of this invention may also
be administered by nasal aerosol or inhalation. Such compositions
are prepared according to techniques known in the art of
pharmaceutical formulation and may be prepared as solutions in
saline, employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, fluorocarbons
and/or other conventional solubilizing or dispersing agents.
[0109] Any of the above dosage forms containing effective amounts
are within the bounds of routine experimentation and within the
scope of the invention. A therapeutically effective dose may vary
depending upon the route of administration and dosage form. The
preferred compound or compounds of the invention is a formulation
that exhibits a high therapeutic index. The therapeutic index is
the dose ratio between toxic and therapeutic effects which can be
expressed as the ratio between LD.sub.50 and ED.sub.50. The
LD.sub.50 is the dose lethal to 50% of the population and the
ED.sub.50 is the dose therapeutically effective in 50% of the
population. The LD.sub.50 and ED.sub.50 are determined by standard
pharmaceutical procedures in animal cell cultures or experimental
animals.
[0110] Besides those representative dosage forms described above,
pharmaceutically acceptable excipients and carriers and dosage
forms are generally known to those skilled in the art and are
included in the invention. It should be understood that a specific
dosage and treatment regimen for any particular patient will depend
upon a variety of factors, including the activity of the specific
compound employed, the age, body weight, general health, sex and
diet of the patient, and the time of administration, rate of
excretion, drug combination, judgment of the treating physician and
severity of the particular disease being treated. The amount of
active ingredient(s) will also depend upon the particular compound
and other therapeutic agent, if present, in the composition.
Methods of Use
[0111] The invention provides methods of inhibiting or decreasing
Factor Xa activity as well as treating or ameliorating a Factor Xa
associated state, symptom, disorder or disease in a patient in need
thereof (e.g., human or non-human). "Treating" within the context
of the invention means an alleviation of symptoms associated with a
disorder or disease, or halt of further progression or worsening of
those symptoms, or prevention or prophylaxis of the disease or
disorder.
[0112] The term "mammal" includes organisms which express Factor
Xa. Examples of mammals include mice, rats, cows, sheep, pigs,
goats, horses, bears, monkeys, dogs, cats and, preferably, humans.
Transgenic organisms which express Factor Xa are also included in
this definition.
[0113] The inventive methods comprise administering an effective
amount of a compound or composition described herein to a mammal or
non-human animal. As used herein, "effective amount" of a compound
or composition of the invention includes those amounts that
antagonize or inhibit Factor Xa. An amount which antagonizes or
inhibits Factor Xa is detectable, for example, by any assay capable
of determining Factor Xa activity, including the one described
below as an illustrative testing method. Effective amounts may also
include those amounts which alleviate symptoms of a Factor Xa
associated disorder treatable by inhibiting Factor Xa. Accordingly,
"antagonists of Factor Xa" include compounds which interact with
the Factor Xa and modulate, e.g., inhibit or decrease, the ability
of a second compound, e.g., another Factor Xa ligand, to interact
with the Factor Xa. The Factor Xa binding compounds are preferably
antagonists of Factor Xa. The language "Factor Xa binding compound"
(e.g., exhibits binding affinity to the receptor) includes those
compounds which interact with Factor Xa resulting in modulation of
the activity of Factor Xa. Factor Xa binding compounds may be
identified using an in vitro (e.g., cell and non-cell based) or in
vivo method. A description of an in vitro method is provided
below.
[0114] The amount of compound present in the methods and
compositions described herein should be sufficient to cause a
detectable decrease in the severity of the disorder, as measured by
any of the assays described in the examples. The amount of Factor
Xa modulator needed will depend on the effectiveness of the
modulator for the given cell type and the length of time required
to treat the disorder. In certain embodiments, the compositions of
this invention may further comprise another therapeutic agent. When
a second agent is used, the second agent may be administered either
as a separate dosage form or as part of a single dosage form with
the compounds or compositions of this invention. While one or more
of the inventive compounds can be used in an application of
monotherapy to treat a disorder, disease or symptom, they also may
be used in combination therapy, in which the use of an inventive
compound or composition (therapeutic agent) is combined with the
use of one or more other therapeutic agents for treating the same
and/or other types of disorders, symptoms and diseases. Combination
therapy includes administration of the two or more therapeutic
agents concurrently or sequentially. The agents may be administered
in any order. Alternatively, the multiple therapeutic agents can be
combined into a single composition that can be administered to the
patient. For instance, a single pharmaceutical composition could
comprise the compound or pharmaceutically acceptable salt or
solvate according to the formula I, another therapeutic agent
(e.g., methotrexate) or a pharmaceutically acceptable salt or
solvate thereof, and a pharmaceutically acceptable excipient or
carrier.
[0115] The invention comprises a compound having the formula I, a
method for making an inventive compound, a method for making a
pharmaceutical composition from at least one inventive compound and
at least one pharmaceutically acceptable carrier or excipient, and
a method of using one or more inventive compounds to treat a
variety of disorders, symptoms and diseases (e.g., inflammatory,
autoimmune, neurological, neurodegenerative, oncology and
cardiovascular), such as RA, osteoarthritis, irritable bowel
disease IBD, asthma, chronic obstructive pulmonary disease COPD and
MS. The inventive compounds and their pharmaceutically acceptable
salts and/or neutral compositions may be formulated together with a
pharmaceutically acceptable excipient or carrier and the resulting
composition may be administered in vivo to mammals, such as men,
women and animals, to treat a variety of disorders, symptoms and
diseases. Furthermore, the inventive compounds can be used to
prepare a medicament that is useful for treating a variety of
disorders, symptoms and diseases.
[0116] Kits
[0117] Still another aspect of this invention is to provide a kit
comprising separate containers in a single package, wherein the
inventive pharmaceutical compounds, compositions and/or salts
thereof are used in combination with pharmaceutically acceptable
carriers to treat states, disorders, symptoms and diseases where
Factor Xa plays a role.
General Methods
[0118] The starting materials and reagents used in preparing these
compounds generally are either available from commercial suppliers,
such as Aldrich Chemical Co., or are prepared by methods known to
those skilled in the art following procedures set forth in
references such as Fieser and Fieser's Reagents for Organic
Synthesis; Wiley & Sons: New York, 1967-2004, Volumes 1-22;
Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers,
1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley
& Sons: New York, 2005, Volumes 1-65. The following synthetic
reaction schemes are merely illustrative of some methods by which
the compounds of the present invention can be synthesized, and
various modifications to these synthetic reaction schemes can be
made and will be suggested to one skilled in the art having
referred to the disclosure contained in this application.
[0119] The starting materials and the intermediates of the
synthetic reaction schemes can be isolated and purified if desired
using conventional techniques, including but not limited to,
filtration, distillation, crystallization, chromatography, and the
like. Such materials can be characterized using conventional means,
including physical constants and spectral data.
[0120] Unless specified to the contrary, the reactions described
herein preferably are conducted under an inert atmosphere at
atmospheric pressure at a reaction temperature range of from about
-78.degree. C. to about 150.degree. C., more preferably from about
0.degree. C. to about 125.degree. C., and most preferably and
conveniently at about room (or ambient) temperature, e.g., about
20.degree. C. to about 75.degree. C.
[0121] Referring to the examples that follow, compounds of the
present invention were synthesized using the methods described
herein, or other methods, which are well known in the art.
[0122] The compounds and/or intermediates may be characterized by
high performance liquid chromatography (HPLC) using a Waters
Alliance chromatography system with a 2695 Separation Module
(Milford, Mass.). The analytical columns may be C-18 SpeedROD
RP-18E Columns from Merck KGaA (Darmstadt, Germany). Alternately,
characterization may be performed using a Waters Unity (HPLC)
system with Waters Acquity HPLC BEH C-18 2.1 mm.times.15 mm
columns. A gradient elution may be used, typically starting with 5%
acetonitrile/95% water and progressing to 95% acetonitrile over a
period of 5 minutes for the Alliance system and 1 minute for the
Acquity system. All solvents may contain 0.1% trifluoroacetic acid
(TFA). Compounds may be detected by ultraviolet light (UV)
absorption at either 220 or 254 nm. HPLC solvents may be from EMD
Chemicals, Inc. (Gibbstown, N.J.). In some instances, purity may be
assessed by thin layer chromatography (TLC) using glass backed
silica gel plates, such as, for example, EMD Silica Gel 60 2.5
cm.times.7.5 cm plates. TLC results may be readily detected
visually under ultraviolet light, or by employing well known iodine
vapor and other various staining techniques.
[0123] Mass spectrometric analysis may be performed on one of two
Agilent 1100 series LCMS instruments with acetonitrile/water as the
mobile phase. One system using TFA as the modifier and measures in
positive ion mode (reported as MH+, (M+1) or (M+H)+) and the other
may use either formic acid or ammonium acetate and measures in both
positive (reported as MH.sup.+, (M+1) or (M+H).sup.+) and negative
(reported as M-, (M-1) or (M-H).sup.-) ion modes.
[0124] Nuclear magnetic resonance (NMR) analysis may be performed
on some of the compounds with a Varian 400 MHz NMR (Palo Alto,
Calif.). The spectral reference may be either TMS or the known
chemical shift of the solvent.
[0125] The purity of some of compounds of the invention may be
assessed by elemental analysis (Robertson Microlit, Madison
N.J.).
[0126] Melting points may be determined on a Laboratory Devices
MeI-Temp apparatus (Holliston, Mass.).
[0127] Preparative separations may be carried out using either an
Sq16x or an Sg100c chromatography system and prepackaged silica gel
columns all purchased from Teledyne Isco, (Lincoln, Nebr.).
Alternately, compounds and intermediates may be purified by flash
column chromatography using silica gel (230-400 mesh) packing
material, or by HPLC using a C-18 reversed phase column. Typical
solvents employed for the Isco systems and flash column
chromatography may be dichloromethane, methanol, ethyl acetate,
hexane, acetone, aqueous hydroxyamine and triethyl amine. Typical
solvents employed for the reverse phase HPLC may be varying
concentrations of acetonitrile and water with 0.1% trifluoroacetic
acid.
EXAMPLES
[0128] The following abbreviations are used throughout the
Examples: [0129] .mu.L=microliter [0130] .mu.M=micromolar [0131]
AIBN=azobisisobutyronitrile [0132] aq.=aqueous [0133]
Boc=tert-butoxycarbonyl [0134]
BOP=benzotriazol-1-yloxytris(dimethylamino)-phosphonium
hexafluorophosphate [0135] conc.=concentrated [0136]
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene [0137] DCM=dichloromethane
[0138] DIEA=diisopropylethyl amine [0139] DMF=dimethyl formamide
[0140] DMSO=dimethyl sulfoxide [0141] eq.=equivalent [0142]
EtOAc=ethyl acetate [0143] g=gram [0144] h or hr(s)=hour(s) [0145]
HATU=2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium
hexafluorophosphate [0146] HOBt=N-hydroxybenzotriazole [0147]
HPLC=high pressure liquid chromatography [0148] IC.sub.50=the
concentration of an inhibitor that is required for 50% inhibition
of an enzyme in vitro [0149] kg=kilogram [0150] M=molar [0151]
m/z=mass to charge ratio [0152] MeOH=methanol [0153] mg=milligram
[0154] MHz=mega Hertz [0155] min=minute [0156] mL=milliliter [0157]
mM=millimolar [0158] mm=millimeter [0159] mmol=millimole [0160]
mOD/min=millioptical density units per minute [0161] MS=Mass Spec
[0162] N=Normal [0163] NaSMc=sodium methylthiolate [0164]
NBS=N-bromosuccinamide [0165] nBuOH=n-butanol [0166] ng=nanogram
[0167] nM=nanomolar [0168] nm=nanometer [0169]
Pd(PPh.sub.3).sub.4=tetrakis-(triphenylphosphine)-palladium [0170]
PEG=polyethylene glycol [0171] pM=picomolar [0172] PPh.sub.3 or
Ph.sub.3P=triphenyl phosphine [0173]
PyBOP=(benzotriazol-1-yloxy)tripyrrolidinophosphonium
hexafluorophosphate [0174] prep=preparative [0175] Ra--Ni=Rainey
Nickel [0176] RT=room temperature [0177] TEA=triethylamine [0178]
TFA=trifluoroacetic acid [0179] TMSCl=trimethylsilyl chloride
[0180] TLC=thin layer chromatography
Example 1
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(piperazin-1-yl)phenyl)-1H-1,2-
,3-triazol-4-yl)methyl)thiophene-2-carboxamide (1)
##STR00142##
##STR00143##
[0182] Step 1:
[0183] 2-Fluoro-4-iodoaniline (1.1, 6.50 g, 27.4 mmol) was
dissolved in 25 mL TFA and stirred in ice bath. Solid NaNO.sub.2
(2.07 g, 30.1 mmol) was added in small portions. The resulting
mixture was stirred for 30 min in ice bath. Sodium azide (1.87 g,
28.8 mmol) was dissolved in 10 mL water and chilled in ice bath.
This cold solution was then added to the TFA solution in three
portions. The mixture was stirred in ice bath for 1 hr and
concentrated in vacuo to remove TFA. The residue was taken into 600
mL DCM and washed with water three times. The organic phase was
dried using MgSO.sub.4 and concentrated in vacuo to afford
1-azido-2-fluoro-4-iodobenzene 1.2 as a brownish waxy solid in
>99% yield. In the mean time, 5-chlorothiophene-2-carboxylic
acid (1.3, 9.13 g, 56 mmol) was dissolved in 200 mL dry DCM along
with 0.5 mL dry DMF. To the vigorously stirred solution was
carefully added oxalyl chlororide (14.7 mL, 169 mmol) dropwise. The
resulting solution was stirred for 3 hrs at RT and concentrated in
vacuo. The residue was pumped to dryness and then dissolved in 300
mL dry DCM. To this solution was added propargylamine (5.8 mL, 84
mmol) dropwise. The mixture was stirred at RT overnight during
which time solid precipitated out. 600 mL hexane was added and the
mixture was vigorously stirred for a few hours. The solid was
collected by filtration and washed with hexane to give
5-chloro-N-(prop-2-ynyl)thiophene-2-carboxamide 1.4 (9.47 g, 85%)
which was used directly without further purification. MS found for
C.sub.8H.sub.6ClNOS as (M+H)+ 200.0, 202.0 (chlorine pattern).
[0184] Step 2:
[0185] To a solution of the aryl azide 1.2 (27 mmol) and alkyne 1.4
(5.37 g, 27 mmol) in 500 mL dry methanol, were added DBU (4.00 mL,
54 mmol) and CuI (5.13 g, 27 mmol). The mixture was stirred at RT
overnight. The mixture was diluted with 1.0 liter acetonitrile and
stirred vigorously for 1 hr. It was filtered through celite and the
filtrate was concentrated and purified using flash column to give
compound 1.5 (8.30 g, 67%). MS found for 1.5
C.sub.14H.sub.9ClFIN.sub.4OS as (M+H)+ 463.0, 465.0 (Cl
pattern).
[0186] Step 3:
[0187] To a solution of aryl iodide 1.5 (100 mg, 0.22 mmol) and
2-hydroxypyridine (42 mg, 0.44 mmol) in 5 mL dry DMSO in a sealed
tube, were added 8-hydroxyquinoline (10 mg, 0.007 mmol), CuI (13
mg, 0.07 mmol) and Cs.sub.2CO.sub.3 (145 mg, 0.44 mmol). The
mixture was stirred in 120.degree. C. bath for overnight. It was
then filtered and the filtrate was directly subjected to reverse
phase preparative HPLC to isolate the compound 1.6 (66 mg) as a
white powder in 68% yield after lyophilization. MS found for
C.sub.19H.sub.13ClFN.sub.5O.sub.2S as (M+H)+ 430.0, 432.0 (Cl
pattern).
[0188] Step 4:
[0189] To a solution of compound 1.6 (100 mg, 0.23 mmol) in 1 mL
anhydrous DMSO in a sealed tube was added 500 mg piperazine. The
mixture was stirred in 140.degree. C. bath overnight. It was cooled
to RT, and directly subjected to reverse phase HPLC to isolate the
title compound as a white powder after lyophilization. MS found for
C.sub.23H.sub.22ClN.sub.7O.sub.2S (M+H)+ 496.1, 498.1 (Cl
pattern).
Example 2
5-Chloro-N-((1-(2-(4-ethylpiperazin-1-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-
-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (2)
##STR00144##
[0191] The title compound was prepared using conditions similar to
those described in Example 1. MS found for
C.sub.25H.sub.26ClN.sub.7O.sub.2S (M+H)+ 524.1, 526.1 (Cl
pattern).
Example 3
5-Chloro-N-((1-(2-(4-isopropylpiperazin-1-yl)-4-(2-oxopyridin-1(2H)-yl)phe-
nyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (3)
##STR00145##
[0193] The title compound was prepared using conditions similar to
those described in Example 1. MS found for
C.sub.26H.sub.28ClN.sub.7O.sub.2S (M+H)+ 538.1, 540.1 (Cl
pattern).
Example 4
5-Chloro-N-((1-(4-(2-oxopyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)m-
ethyl)thiophene-2-carboxamide (4)
##STR00146##
##STR00147##
[0195] Step 1:
[0196] 2-Hydroxypyrimidine hydrogenchloride (2.1, 1.50 g, 11.3
mmol) was stirred in 20 mL dry NMP at RT. To it was added sodium
hydride (60% in mineral oil, 0.95 g, 23.5 mmol) in small portions
carefully. The mixture was stirred for 30 min before
4-fluoro-1-nitrobenzene (1.0 mL, 9.4 mmol) was added. The mixture
was sent to 80.degree. C. bath and stirred overnight. It was
concentrated in vacuo and taken into acetonitrile. After vigorously
stirring, the insoluble solid was collected, which was a mixture of
leftover 2-hydroxypyrimidine and
1-(4-nitrophenyl)pyrimidin-2(1H)-one 2.2. MS found for
C.sub.10H.sub.7N.sub.101 (M+H).sup.+ 218.0. This solid (1.27 g, 5.8
mmol) was dissolved in 100 mL ethanol and 30 mL water. To it was
added ammonium chloride (3.1 g, 58 mmol) and indium powder (2.6 g,
23 mmol). The mixture was refluxed for 6 hrs. It was concentrated
in vacuo, filtered through celite. The solid cake was rinsed with
water. The filtrate was concentrated and subjected to reverse phase
prep HPLC to isolate 1-(4-aminophenyl)pyrimidin-2(1H)-one 2.3. MS
found for C.sub.10H.sub.9N.sub.3O (M+H)+ 188.1.
[0197] Step 2:
[0198] 1-(4-Aminophenyl)pyrimidin-2(1H)-one (2.3, 250 mg, 1.3 mmol)
was dissolved in 10 mL TFA and stirred in ice bath. To it was added
sodium nitrite (95 mg, 1.3 mmol) in small portions. The mixture was
stirred in ice bath for 30 min. Sodium azide (260 mg, 4.0 mmol) was
dissolved in 2 mL water and chilled in ice bath and added to the
reaction mixture. The mixture was stirred for 2 hrs and directly
subjected to reverse phase prep HPLC to isolate
1-(4-azidophenyl)pyrimidin-2(1H)-one 2.4. MS found for
C.sub.10H.sub.7N.sub.5O (M+H)+ 214.1.
[0199] Step 3:
[0200] 1-(4-Azidophenyl)pyrimidin-2(1H)-one (2.4, 20 mg, 0.09 mmol)
was dissolved in 5 mL methanol. To it were added
5-chloro-N-(prop-2-ynyl)thiophene-2-carboxamide (compound 1.4, 18
mg, 0.09 mmol), DBU (26 .mu.L, 0.18 mmol) and CuI (17 mg, 0.09
mmol). The mixture was stirred for 2 hrs at RT, diluted with 30 mL
acetonitrile, filtered through celite, concentrated in vacuo and
subjected to prep HPLC to isolate the title compound. MS found for
C.sub.18H.sub.13ClN.sub.6O.sub.2S (M+H)+ 413.0, 415.0 (Cl
pattern).
Example 5
5-Chloro-N-((1-(4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-1H-1,2-
,3-triazol-4-yl)methyl)thiophene-2-carboxamide (5)
##STR00148##
##STR00149##
[0202] Step 1:
[0203] The mixture of 4-iodoacetophenone (3.1, 1.00 g, 4.06 mmol)
and glyoxalic acid monohydrate (0.45 g, 4.9 mmol) in 20 mL acetic
acid was refluxed for 18 hrs and concentrated in vacuo. The dry
residue was then stirred in 15 mL water to get a slurry material.
To it was added carefully ammonium hydroxide (30%) until pH=9 as
indicated by pH paper. The pH was critical for this reaction.
Methylhydrazine (0.43 mL) was added, and the mixture was sent to
100.degree. C. bath for 3 hrs. Reaction mixture was diluted with
ethyl acetate. The organic phase was washed with brine, dried,
concentrated in vacuo, and purified by flash column using 5%
methanol in DCM isocratically to yield compound 3.2 (680 mg, 54%).
MS found for C.sub.11H.sub.9IN.sub.2O (M+H)+ 313.0.
[0204] Step 2:
[0205] Compound 3.2 (51 mg, 0.16 mmol),
5-chloro-N-(prop-2-ynyl)thiophene-2-carboxamide (compound 1.4, 36
mg, 0.18 mmol), L-proline (8 mg, 0.06 mmol), sodium carbonate (7
mg, 0.06 mmol), sodium azide (17 mg, 0.24 mmol) and sodium
ascorbate (6 mg, 0.03 mmol) were mixed in 2 mL DMSO and 0.2 mL
water in a sealed tube at RT. To it was added CuSO.sub.4.5H.sub.2O
(8 mg, 0.03 mmol). The mixture was stirred in 70.degree. C. bath
overnight. Reaction was about 70% complete. The title compound was
isolated through direct reverse phase prep HPLC. MS found for
C.sub.19H.sub.15ClN.sub.6O.sub.2S (M+H)+ 427.1, 429.1 (Cl
pattern).
Example 6
5-Chloro-N-((1-(4-(2,4-dimethoxypyrimidin-5-yl)phenyl)-1H-1,2,3-triazol-4--
yl)methyl)thiophene-2-carboxamide (6)
##STR00150##
##STR00151##
[0207] The mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-ca-
rboxamide (4.1, 48 mg, 0.11 mmol, synthesized by procedures similar
to those that were used to make compound 1.5 described in SCHEME
1), 2,4-dimethoxypyrimidin-5-ylboronic acid (4.2, 24 mg, 0.13
mmol), PdCl.sub.2(PPH.sub.3).sub.2 (38 mg, 0.05 mmol),
K.sub.2CO.sub.3 (23 mg, 0.16 mmol) in 1 mL acetonitrile and 1 mL
water was degassed using argon stream and heated in microwave
reactor at 125.degree. C. for 15 min. The mixture was filtered and
directly subjected to reverse phase prep HPLC to isolate the title
compound. MS found for C.sub.20H.sub.17ClN.sub.6O.sub.1S (M+H)+
457.1, 459.1 (Cl pattern).
Example 7
5-Chloro-N-((1-(4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1H-1,2,3-triazol-4-y-
l)methyl)thiophene-2-carboxamide (9)
##STR00152##
[0209] The mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-ca-
rboxamide (4.1, 100 mg, 0.22 mmol), N-methylhomopiperazine (140
.mu.L, 1.1 mmol), CuI (42 mg, 0.22 mmol), ethylene glycol (25
.mu.L, 0.44 mmol), potassium phosphate (93 mg, 0.44 mmol) in 2 mL
isopropanol in a sealed tube was stirred for 16 hrs at 120.degree.
C. The title compound was isolated directly from the reaction
mixture using reverse phase prep HPLC. MS found for
C.sub.20H.sub.23ClN.sub.6OS (M+H)+ 431.1, 433.1 (Cl pattern).
Example 8
5-Chloro-N-((1-(2'-methoxybiphenyl-4-yl)-1H-1,2,3-triazol-4-yl)methyl)thio-
phene-2-carboxamide (11)
##STR00153##
[0211] The title compound was prepared according to a procedure
similar to that described in Example 6. MS found for
C.sub.21H.sub.17ClN.sub.4O.sub.2S (M+H)+ 425.1, 427.1 (Cl
pattern).
Example 9
5-Chloro-N-((1-(2'-hydroxybiphenyl-4-yl)-1H-1,2,3-triazol-4-yl)methyl)thio-
phene-2-carboxamide (12)
##STR00154##
[0213] The title compound was prepared according to a procedure
similar to that described in Example 6. MS found for
C.sub.20H.sub.15ClN.sub.4O.sub.2S (M+H)+ 411.1, 413.1 (Cl
pattern).
Example 10
5-Chloro-N-((1-(2'-(trifluoromethoxy)biphenyl-4-yl)-1H-1,2,3-triazol-4-yl)-
methyl)thiophene-2-carboxamide (13)
##STR00155##
[0215] The title compound was prepared according to a procedure
similar to that described in Example 6. MS found for
C.sub.21H.sub.14ClF.sub.3N.sub.4O.sub.2S (M+H)+ 479.0, 481.0 (Cl
pattern).
Example 11
5-Chloro-N-((1-(4-(6-chloropyridin-3-yl)phenyl)-1H-1,2,3-triazol-4-yl)meth-
yl)thiophene-2-carboxamide (14)
##STR00156##
[0217] The title compound was prepared according to a procedure
similar to that described in Example 6. MS found for
C.sub.19H.sub.13Cl.sub.2N.sub.5OS (M+H)+ 430.0, 432.0 (Cl
pattern).
Example 12
5-Chloro-N-((1-(4-(pyrrolidine-1-carbonyl)phenyl)-1H-1,2,3-triazol-4-yl)me-
thyl)thiophene-2-carboxamide (18)
##STR00157##
[0219] The title compound was prepared according to a procedure
similar to that described in Example 1 using the corresponding
substituted aniline. MS found for C.sub.19H.sub.18ClN.sub.5O.sub.2S
(M+H)+ 416.0, 418.0 (Cl pattern).
Example 13
5-Chloro-N-((1-(4-(2,5-dihydro-1H-pyrrole-1-carbonyl)phenyl)-1H-1,2,3-tria-
zol-4-yl)methyl)thiophene-2-carboxamide (19)
##STR00158##
[0221] The title compound was prepared according to a procedure
similar to that described in Example 1 using the corresponding
substituted aniline. MS found for C.sub.19K.sub.6ClN.sub.5O.sub.2S
(M+H)+ 414.0, 416.0 (Cl pattern).
Example 14
N-((1-(4-(2-Amino-N-methylacetamido)phenyl)-1H-1,2,3-triazol-4-yl)methyl)--
5-chlorothiophene-2-carboxamide (21)
##STR00159##
[0223] The mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-ca-
rboxamide (100 mg, 0.22 mmol), H-Gly-NHMe.HCl (110 mg, 0.88 mmol),
CuI (42 mg, 0.22 mmol), N,N'-dimethylethylenediamine (24 .mu.L,
0.22 mmol), cesium carbonate (440 mg, 1.4 mmol) in 5 mL dioxane in
a sealed tube was stirred for 15 hrs at 120.degree. C. The title
compound was isolated directly from the reaction mixture using
reverse phase prep HPLC. MS found for
C.sub.17H.sub.17ClN.sub.6O.sub.2S (M+H)+ 405.1, 407.1 (Cl
pattern).
Example 15
5-Chloro-N-((1-(4-(N-methylpropionamido)phenyl)-1H-1,2,3-triazol-4-yl)meth-
yl)thiophene-2-carboxamide (24)
##STR00160##
[0225] The mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-ca-
rboxamide (100 mg, 0.22 mmol), C.sub.2H.sub.5CONHCH.sub.3 (77
.mu.L, 0.88 mmol), CuI (42 mg, 0.22 mmol),
N,N'-dimethylethylenediamine (24 .mu.L, 0.22 mmol), cesium
carbonate (290 mg, 0.88 mmol) in 5 mL dioxane in a sealed tube was
stirred for 15 hrs at 120.degree. C. The title compound was
isolated directly from the reaction mixture using reverse phase
prep HPLC. MS found for C.sub.18H.sub.18ClN.sub.5O.sub.2S (M+H)+
404.1, 406.1 (Cl pattern).
Example 16
[0226] Ethyl
4-(4-((5-chlorothiophene-2-carboxamido)methyl)-1H-1,2,3-triazol-1-yl)phen-
yl(methyl)carbamate (25)
##STR00161##
[0227] The title compound was prepared using a similar procedure as
described in Example 16. MS found for
C.sub.18H.sub.18ClN.sub.5O.sub.3S (M+H)+ 420.1, 422.1 (Cl
pattern).
Example 17
5-Chloro-N-((1-(4-(2-methoxy-N-methylacetamido)phenyl)-1H-1,2,3-triazol-4--
yl)methyl)thiophene-2-carboxamide (26)
##STR00162##
[0229] Compound 25 (60 mg, 0.14 mmol) was treated with 2 mL 2N NaOH
and 2 mL methanol at 80.degree. C. for 2 hrs and acidified with 2N
HCl. The major product in this reaction,
5-chloro-N-((1-(4-(methylamino)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiop-
hene-2-carboxamide, was isolated with prep HPLC. MS found for
C.sub.15H.sub.14ClN.sub.5OS (M+H)+ 348.1, 350.1. This compound (10
mg, 0.023 mmol) was dissolved in 1 mL DMSO. To it were added 20
.mu.L DIEA and CH.sub.3OCH.sub.2COCl (25 .mu.L, 0.23 mmol). The
mixture was stirred for 30 min and directly subjected to prep HPLC
to isolate the title compound. MS found for
C.sub.18H.sub.18ClN.sub.5O.sub.1S (M+H)+ 420.1, 422.1 (Cl
pattern).
Example 18
5-Chloro-N-((1-(4-(2-(dimethylamino)-N-methylacetamido)phenyl)-1H-1,2,3-tr-
iazol-4-yl)methyl)thiophene-2-carboxamide (27)
##STR00163##
[0231]
5-Chloro-N-((1-(4-(methylamino)phenyl)-1H-1,2,3-triazol-4-yl)methyl-
)thiophene-2-carboxamide (34 mg, 0.1 mmol), prepared as shown in
Example 17, was dissolved in 10 mL methanol and treated with
MP-carbonate for 1 hr. The mixture was filtered and the filtrate
was concentrated in vacuo. The residue was dissolved in 3 mL
pyridine and N,N-dimethylglycine (16 mg, 0.1 mmol) was added. The
mixture was then stirred in ice bath. POCl.sub.3 (28 .mu.L, 0.3
mmol) was added. The reaction was stirred for 20 min and quenched
with methanol. The mixture was concentrated and directly subjected
to prep HPLC to isolate the title compound. MS found for
C.sub.19H.sub.21ClN.sub.6O.sub.2S (M+H)+ 433.1, 435.1 (Cl
pattern).
Example 19
5-Chloro-N-((1-(4-(N-methylacetamido)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-
thiophene-2-carboxamide (28)
##STR00164##
[0233] The title compound was prepared using a similar procedure as
described in Example 15. MS found for
C.sub.17H.sub.16ClN.sub.5O.sub.2S (M+H)+ 390.1, 392.1 (Cl
pattern).
Example 20
5-Chloro-N-((1-(4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-1H-1,2,3-triazo-
l-4-yl)methyl)thiophene-2-carboxamide (30)
##STR00165##
[0235] The title compound was prepared according to a procedure
similar to that describe in Example 5. MS found for
C.sub.18H.sub.13ClN.sub.6O.sub.2S (M+H)+ 413.1, 415.1 (Cl
pattern).
Example 21
5-Chloro-N-((3-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-5-methyl-4,5-dih-
ydroisoxazol-5-yl)methyl)thiophene-2-carboxamide (31)
##STR00166##
##STR00167##
[0237] Step 1:
[0238] 4-Bromo-2-fluorobenzaldehyde (5.1, 6.64 g, 32.7 mmol) was
stirred in 100 mL ethanol and 100 mL pyridine. To it was added
hydroxylamine hydrochloride (2.27 g, 32.7 mmol). The mixture was
stirred at RT for 2 hrs. It was concentrated in vacuo to dryness.
The residue was then dissolved in 100 mL DMF. To it was added NCS
(5.24 g, 39.2 mmol), and the mixture was stirred for 1 day. It was
concentrated in vacuo, taken into ethyl acetate, washed with brine
twice, dried and concentrated in vacuo to afford compound 5.2 in
quantitative yield. MS found for C.sub.7H.sub.4BrClFNO (M+H)+
252.0, 254.0.
[0239] Step 2:
[0240] 5-Chloro-2-thiophenecarboxylic acid (5.3, 200 mg, 1.23 mmol)
was dissolved in 10 mL anhydrous DCM. To it were added 1 drop of
DMF and 0.32 mL oxalyl chloride (3.7 mmol). The mixture was stirred
at RT for 3 hrs and concentrated in vacuo to dryness. The residue
was dissolved in 20 mL anhydrous DCM and 2-methylallylamine (0.3
mL, 3.2 mmol) was added. The mixture was stirred for 30 min at RT,
concentrated in vacuo, taken into ethyl acetate, washed with brine
three times, dried and concentrated in vacuo to give compound 5.4
(218 mg, 82%). MS found for C.sub.9H.sub.10ClNOS (M+H)+ 216.0,
218.0 (Cl pattern).
[0241] Step 3:
[0242] The mixture of compound 5.2 (250 mg, 1.0 mmol), compound 5.4
(218 mg, 1.0 mmol), and DBU (180 .mu.L, 1.2 mmol) in 10 mL toluene
was heated at 125.degree. C. in a sealed tube for 1 week. The
reaction was still incomplete. It was concentrated in vacuo and
subjected to flash column to isolate compound 5.5 (58 mg, 13%)
using 3% methanol in DCM. MS found for
C.sub.16H.sub.13BrClFN.sub.2O.sub.2S (M+H)+ 431.0, 433.0.
[0243] Step 4:
[0244] Compound 5.5 (58 mg, 0.13 mmol) was dissolved in 6 mL
dioxane and 2 mL DMSO in a sealed tube. To it were added
2-hydroxypyridine (29 mg, 0.30 mmol), N,N'-dimethylethylenediamine
(9 .mu.L, 0.08 mmol), K.sub.3PO.sub.4 (58 mg, 0.27 mmol) and CuI
(13 mg, 0.07 mmol). The mixture was stirred for 3 days at
130.degree. C. It was concentrated and directly subjected to
reverse phase preparative HPLC to isolate the title compound. MS
found for C.sub.21H.sub.17ClFN.sub.3O.sub.3S (M+H)+ 446.1, 448.1
(Cl pattern).
Example 22
5-Chloro-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-4,5-dihydro-1H-pyra-
zol-3-yl)methyl)thiophene-2-carboxamide (32)
##STR00168##
##STR00169##
[0246] Step 1:
[0247] Compound 6.1 hydrochloride (1.77 g, 7.9 mmol) and compound
6.2 (1.30 g, 7.9 mmol) in 50 mL dioxane were stirred in 60.degree.
C. bath overnight. The mixture was concentrated, taken into 300 mL
ethyl acetate, washed with brine three times, dried, and
concentrated in vacuo. The residue was dissolved in 20 mL DMSO and
treated with sodium azide (1.04 g, 16 mmol) for 4 hrs. The mixture
was diluted with ethyl acetate, washed with brine three times,
dried, concentrated and purified using flash column to isolate
compound 6.3 (0.79 g, 34%). MS found for C.sub.10H.sub.8BrN.sub.5O
(M+H).sup.+ 294.0, 296.0 (Br pattern).
[0248] Step 2:
[0249] Compound 6.3 (0.79 g, 2.7 mmol) was dissolved in 20 mL
ethanol and 20 mL acetic acid, and was treated with iron powder
(0.70 g, 13.5 mmol) at 100.degree. C. for 30 min. The mixture was
diluted with acetonitrile, filtered through a celite bed,
concentrated and subjected to reverse phase preparative HPLC to
isolate compound 6.4 (40%). MS found for C.sub.10H.sub.10BrN.sub.3O
(M+H)+ 268.0, 270.0 (Br pattern).
[0250] Step 3:
[0251] Compound 6.4 (120 mg, 0.44 mol) and
5-chloro-2-thiophenecarboxylic acid (110 mg, 0.66 mmol) were
dissolved in 15 mL anhydrous DMF. To it were added DIEA (310 .mu.L,
1.76 mmol) and PyBOP (460 mg, 0.88 mmol). The mixture was stirred
at RT overnight. It was diluted with ethyl acetate, washed with
brine three times, dried, concentrated in vacuo and purified using
reverse phase preparative HPLC to isolate compound 6.5 (50%). MS
found for C.sub.15H.sub.11BrClN.sub.3O.sub.2S (M+H)+ 412.0,
414.0.
[0252] Step 4:
[0253] The title compound was prepared from compound 6.5 using a
similar procedure shown in Step 4 in Example 21. MS found for
C.sub.20H.sub.15ClN.sub.4O.sub.3S (M+H)+ 427.1, 429.1 (Cl
pattern).
Example 23
5-Chloro-N-((2-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1,2-dihydropyridin--
3-yl)methyl)thiophene-2-carboxamide (33)
##STR00170##
##STR00171##
[0255] Step 1:
[0256] The mixture of 1,4-diiodobenzene (7.1, 1.00 g, 3.0 mmol),
2-hydroxy-3-methylpyridine (0.50 g, 4.5 mmol), 8-hydroxyquinoline
(132 mg, 0.9 mmol), K.sub.2CO.sub.3 (0.84 g, 6.0 mmol) and CuI (173
mg, 0.9 mmol) in 12 mL DMSO was stirred at 120.degree. C. for 16
hrs in a sealed tube. It was diluted with 300 mL ethyl acetate,
washed with brine three times, dried, concentrated and purified
using flash column to give compound 7.2 (393 mg, 42%). MS found for
C.sub.12H.sub.10INO (M+H)+ 312.0.
[0257] Step 2:
[0258] The mixture of compound 7.2 (393 mg, 1.26 mmol), NBS (247
mg, 1.39 mmol) and AIBN (82 mg, 0.50 mmol) in 20 mL carbon
tetrachloride was refluxed overnight. It was concentrated, taken
into ethyl acetate, washed with brine three times, dried, and
concentrated in vacuo to dryness. The residue was dissolved in 5 mL
DMSO and treated with sodium azide (200 mg) overnight. It was
diluted with ethyl acetate, washed with brine three times, dried
and concentrated in vacuo. The residue was then dissolved in 10 mL
ethanol and 10 mL acetic acid and treated with iron powder (300 mg)
at 100.degree. C. for 30 min. The mixture was diluted with
acetonitrile, filtered through a celite bed, concentrated and
subjected to reverse phase preparative HPLC to isolate compound 7.3
(20%). MS found for C.sub.12H.sub.111N.sub.2O (M+H)+ 327.0.
[0259] Step 3:
[0260] Compound 7.3 (80 mg, 0.24 mmol) was dissolved in 10 mL DMF.
To it were added 5-chloro-2-thiophenecarboxylic acid (60 mg, 0.36
mmol), DIEA (210 .mu.L, 1.2 mmol) and PyBOP (250 mg, 0.48 mmol).
The mixture was stirred overnight. It was then diluted with ethyl
acetate, washed with brine three times, dried, concentrated and
purified by flash column to give compound 7.4 (90%). MS found for
C.sub.17H.sub.12Cl.sub.1N.sub.2O.sub.2S (M+H)+ 471.0, 473.0.
[0261] Step 4:
[0262] Compound 7.4 (0.24 mmol) was dissolved in 3 mL DMSO. To it
were added 2-hydroxypyridine (68 mg, 0.72 mmol), 8-hydroxyquinoline
(10 mg, 0.07 mmol), cesium carbonate (156 mg, 0.48 mmol) and CuI
(14 mg, 0.07 mmol). The mixture was stirred at 120.degree. C. for
16 hrs. It was directly subjected to reverse phase preparative HPLC
to isolate the title compound. MS found for
C.sub.22H.sub.16ClN.sub.3O.sub.3S (M+H)+ 438.1, 440.1 (Cl
pattern).
Example 24
5-Chloro-N-((6-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1,6-dihydropyridin--
3-yl)methyl)thiophene-2-carboxamide (34)
##STR00172##
[0264] The title compound was prepared according to a procedure
similar to that described in Example 23. MS found for
C.sub.22H.sub.16ClN.sub.3O.sub.3S (M+H)+ 438.1, 440.1 (Cl
pattern).
Example 25
5-Chloro-N-((1-methyl-2-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl-
)methyl)thiophene-2-carboxamide (35)
##STR00173##
##STR00174## ##STR00175##
[0266] To a solution of potassium acetate (0.860 g, 8.78 mmol) in
H.sub.2O (3 mL), 3,3-dibromo-1,1,1-trifluoroacetone (1.10 g, 4.07
mmol) was added. The solution was heated at 100.degree. C. for 30
min. After being cooled to room temperature, a solution of
4-iodobenzaldehyde (0.860 g, 3.71 mmol) in MeOH (4 mL) and THF (4
mL) was added, followed by conc. NH.sub.4OH (8 mL). The mixture was
stirred at room temperature overnight. Water and EtOAc were added.
The organic layer was separated, dried over Na.sub.2SO.sub.4,
concentrated in vacuo to give
2-(4-iodophenyl)-4-(trifluoromethyl)-1H-imidazole as a solid (1.34
g).
[0267] The mixture of
2-(4-iodophenyl)-4-(trifluoromethyl)-1H-imidazole prepared above
(1.34 g) in 5N aq. NaOH (12 mL) was heated at 90.degree. C. for 2
h. It was filtered. The filtrate was neutralized with 6 N HCl
carefully to pH 6-7. The product was extracted with nBuOH. The
nBuOH solution was then concentrated in vacuo to give
2-(4-iodophenyl)-1H-imidazole-4-carboxylic acid as a solid (0.512
g).
[0268] To a mixture of 2-(4-iodophenyl)-1H-imidazole-4-carboxylic
acid prepared above (257 mg, 0.818 mmol) and NaH (60% suspension,
washed with hexane, 82 mg, 2.1 mmol) in DMF (8 mL) was added
iodomethane (0.130 mL, 2.1 mmol). The mixture was heated at
50.degree. C. for 2 h. More iodomethane (0.100 mL) was added to the
reaction mixture. After being stirred at 50.degree. C. for an
additional 2 h, water and EtOAc were added. The organic layer was
separated, dried over Na.sub.2SO.sub.4, concentrated in vacuo to
give methyl 2-(4-iodophenyl)-1-methyl-1H-imidazole-4-carboxylate
(152 mg). MS 342.8 (M+H).
[0269] To a suspension of methyl
2-(4-iodophenyl)-1-methyl-1H-imidazole-4-carboxylate prepared above
(72 mg, 0.21 mmol) in toluene (4 mL), LiAlH.sub.4 (61 mg, 1.6 mmol)
was added.
[0270] The mixture was heated at 110.degree. C. overnight. After
being cooled to room temperature, EtOAc (15 mL) and 1N aq. NaOH (15
mL) were added. The mixture was filtered through celite.
[0271] The organic layer was separated, dried over
Na.sub.2SO.sub.4, concentrated in vacuo to give
(2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methanol (46 mg). MS
315.0 (M+H).
[0272] A solution of
(2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methanol prepared above
(46 mg, 0.15 mmol) in SOCl.sub.2 (2 mL) was stirred at room
temperature for 15 min. It was concentrated in vacuo to give a
residue, which was then partitioned between EtOAc and 5% aq.
NaHCO.sub.3. The organic phase was separated, dried over
Na.sub.2SO.sub.4, concentrated in vacuo.
[0273] The residue was dissolved in DMF (2 mL). To the solution,
NaN.sub.3 (70 mg, 1.1 mmol) was added. After the mixture was
stirred at room temperature for 2 days, water and EtOAc were added.
The organic layer was separated, dried over Na.sub.2SO.sub.4,
concentrated in vacuo to give
(2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methyl azide (46 mg).
MS 340.0 (M+H).
[0274] A mixture of
(2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methyl azide prepared
above (46 mg, 0.14 mmol) and Ra--Ni (50% slurry in H.sub.2O, 100
mg) in MeOH (5 mL) was hydrogenated under balloon H.sub.2 for 1 h.
It was filtered. The filtrate was concentrated in vacuo to give
(2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methyl amine (42 mg).
MS 314.0 (M+H).
[0275] To a solution of 5-chloro-thiophene-2-carboxylic acid (23
mg, 0.14 mmol), (2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methyl
amine prepared above (21 mg, 0.067 mmol) and TEA (0.050 mL, 0.36
mmol) in DMF (2 mL) was added BOP (70 mg, 0.16 mmol). The mixture
was stirred at room temperature overnight. It was then purified by
HPLC to give
5-chloro-N-((2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methyl)thiophene--
2-carboxamide (14 mg). MS 457.9 and 459.9 (M+H).
[0276] A mixture of
5-chloro-N4(2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methyl)thiophene-2-
-carboxamide prepared above (14 mg, 0.031 mmol), 2-hydroxypyridine
(14 mg, 0.15 mmol), 8-hydroxyquinoline (14 mg, 0.097 mmol) and
K.sub.2CO.sub.3 (30 mg, 0.22 mmol) in DMSO (0.5 mL) was degassed
with Argon before being charged with CuI (9 mg, 0.047 mmol). The
mixture in a sealed tube was heated at 130.degree. C. overnight. It
was then purified by HPLC to give the titled compound (2 mg). MS
425.1 and 427.1 (M+H, Cl pattern).
Example 26
5-Chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxam-
ide (36)
##STR00176##
##STR00177##
[0278] A mixture of 1,4-diiodobenzene 9.1 (4.00 g, 12.1 mmol),
4-(hydroxymethyl)imidazole 9.2 (1.20 g, 12.2 mmol),
8-hydroxyquinoline (0.176 g, 1.21 mmol) and K.sub.2CO.sub.3 (1.69
g, 12.2 mmol) in DMSO (12 mL) was degassed before being charged
with CuI (0.230 g, 1.21 mmol). The mixture in a sealed tube was
heated at 130.degree. C. overnight. Water and EtOAc were added. The
mixture was filtered. The organic layer was separated, then applied
to a silica gel column, which was eluted with 0-5% MeOH in
CH.sub.2Cl.sub.2 to give
(1-(4-iodophenyl)-1H-imidazol-4-yl)methanol 9.3 (0.810 g) and its
isomer (1-(4-iodophenyl)-1H-imidazol-5-yl)methanol 9.4. MS 301.2
(M+H).
Step 2:
[0279] The compound 4-hydroxymethyl 1-(4-iodophenyl)imidazole 9.3
(0.810 g, 2.70 mmol) was dissolved in SOCl.sub.2 (6 mL). The
solution was stirred at room temperature for 15 min. It was then
concentrated in vacuo. The residue was partitioned between EtOAc
and 5% aq. NaHCO.sub.3. The organic layer was separated, dried over
Na.sub.2SO.sub.4, concentrated in vacuo to give
4-(chloromethyl)-1-(4-iodophenyl)-1H-imidazole 9.5 as a solid
(0.780 g). MS 318.9 and 320.9 (M+H, Cl pattern)
Step 3:
[0280] The compound 4-(chloromethyl)-1-(4-iodophenyl)-1H-imidazole
9.5 (0.780 g, 2.45 mmol) was dissolved in DMF (10 mL). To the
solution, NaN.sub.3 (0.520 g, 8.00 mmol) was added. After being
stirred at room temperature overnight, water and EtOAc were added.
The organic layer was separated, dried over Na.sub.2SO.sub.4,
concentrated in vacuo to give
4-(azidomethyl)-1-(4-iodophenyl)-1H-imidazole 9.6 as a solid (0.725
g). MS 326.0 (M+H).
Step 4:
[0281] A solution of 4-(azidomethyl)-1-(4-iodophenyl)-1H-imidazole
9.6 (0.725 g, 2.23 mmol) over Ra--Ni (50% aq. slurry, 300 mg) in
MeOH (12 mL) was hydrogenated under balloon H.sub.2 for 3 h. The
mixture was filtrated through CELITE. The filtrate was concentrated
in vacuo to give (1-(4-iodophenyl)-1H-imidazol-4-yl)methanamine 9.7
as a solid (0.603 g). MS 300.0 (M+H).
Step 5:
[0282] To a mixture of 5-chlorothiophene-2-carboxylic acid (0.346
g, 2.13 mmol), (1-(4-iodophenyl)-1H-imidazol-4-yl)methanamine 9.7
(0.578 g, 1.93 mmol) and TEA (0.670 mL, 4.82 mmol) in DMF (10 mL),
BOP (1.03 g, 2.33 mmol) was added. The mixture was then stirred at
room temperature overnight. Water and EtOAc were added. The organic
layer was separated, washed with 5% NaHCO.sub.3, dried over
Na.sub.2SO.sub.4, concentrated in vacuo to give the title compound
as a solid (0.832 g). MS found for C.sub.15H.sub.11ClIN.sub.3OS:
443.9 and 445.9 ((M+H)+, Cl pattern).
Example 27
5-Chloro-N-((1-(4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-1H-imi-
dazol-4-yl)methyl)thiophene-2-carboxamide (37)
##STR00178##
[0284] Step 1:
[0285] The mixture of 4-iodoacetophenone (1.00 g, 4.06 mmol) and
glyoxalic acid monohydrate (0.45 g, 4.9 mmol) in 20 mL acetic acid
was refluxed for 18 hrs before concentrated in vacuo. The dry
residue was then stirred in 15 mL water to form a slurry material.
To it was added carefully with ammonium hydroxide (30%) until pH 9
as indicated by pH paper. The pH was critical for this reaction.
Methylhydrazine (0.43 mL) was added, and the reaction was sent to
100.degree. C. bath for 3 hrs before the mixture was diluted with
ethyl acetate. The organic phase was washed with brine, dried,
concentrated in vacuo, and purified by flash column using 5%
methanol in DCM isocratically to yield
6-(4-iodophenyl)-2-methylpyridazin-3(2H)-one (680 mg, 54%). MS
found for C.sub.11H.sub.9IN.sub.2O (M+H)+ 313.0.
[0286] Step 2:
[0287] The above-prepared compound (145 mg, 0.49 mmol) was
dissolved in 10 mL DMSO in a sealed tube. To it were added
(1H-imidazol-4-yl)methanol hydrochloride (134 mg, 1.0 mmol), cesium
carbonate (815 mg, 2.5 mmol), CuI (48 mg, 0.25 mmol) and
8-hydroxyquinoline (37 mg, 0.25 mmol). The mixture was stirred at
130.degree. C. for 17 hrs. It was filtered and subjected to prep
HPLC to isolate
6-(4-(4-(hydroxymethyl)-1H-imidazol-1-yl)phenyl)-2-methylpyridazin-3(2H)--
one (95 mg, 69%). MS found for C.sub.15H.sub.14N.sub.4O.sub.2
(M+H)+ 283.1.
[0288] Step 3:
[0289] The above-prepared compound (95 mg, 0.34 mmol) was stirred
in 4 mL acetonitrile at RT. To it was added 4 mL thionyl chloride
and the mixture was stirred for 30 min. It was concentrated in
vacuo. The residue was then dissolved in 5 mL DMSO and 5 mL ammonia
hydroxide was added. The mixture was stirred at 75.degree. C. in a
sealed tube for 30 min. It was concentrated in vacuo and subjected
to prep HPLC to isolate
6-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)-2-methylpyridazin-3(2H)-on-
e. MS found for C.sub.15H.sub.15N.sub.5O (M+H)+ 282.1.
[0290] Step 4:
[0291] The above-prepared compound was dissolved in 40 mL methanol
and treated with MP-carbonate (10 eq.). The mixture was gently
stirred for 1 hr and filtered. The filtrate was concentrated in
vacuo to give the corresponding free amine (47 mg, 0.17 mmol). It
was dissolved in 2 mL DMF. To it was added DIEA (36 .mu.L, 0.20
mmol) and the mixture was stirred at RT. In the meantime,
5-chlorothiophene-2-carboxylic acid (32 mg, 0.20 mmol) was
dissolved in 2 mL dry DMF. To it were added DIEA (36 .mu.L, 0.20
mmol) and HATU (76 mg, 0.20 mmol). The mixture was stirred for 10
min. It was added to the stirred solution of the free amine in DMF.
The mixture was stirred for 2 hrs and subjected to preparative HPLC
to isolate the title compound. MS found for
C.sub.20H.sub.16ClNO.sub.2S (M+H)+ 426.1, 428.1 (Cl pattern).
Example 28
5-Chloro-N-((1-(4-(2-methoxypyridin-3-yl)phenyl)-1H-imidazol-4-yl)methyl)t-
hiophene-2-carboxamide (38)
##STR00179##
[0293] To a solution of diisopropylamine (1.42 mL, 10 mmol) in THF
(10 mL) at 0.degree. C. was added nBuLi (2.5 M, 4.25 mL, 10.6 mmol)
dropwise. After stirring at 0.degree. C. for 45 min, a solution of
2-methoxypyridine (0.96 mL, 9.2 mmol) in THF (5 mL) was added, and
the mixture was stirred for an additional 1 h before B(OiPr).sub.3
(2.54 mL, 11 mmol) was added. 30 min later, H.sub.2O was added to
quench the reaction, the THF was removed in vacuo and the aqueous
layer was extracted with ether. The aqueous layer was separated,
acidified with 48% HBr to pH=4, the resulting precipitates were
collected by filtration to yield 2-methoxypyridine-3-ylboronic acid
(0.46 g, 40%).
[0294] A mixture of
5-chloro-N-((1-(4-iodophenyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxam-
ide (0.044 g, 0.1 mmol), 2-methoxypyridine-3-ylboronic acid (0.016
g, 0.11 mmol) and Pd(PPh.sub.3).sub.2Cl.sub.2 (0.007 g, 0.01 mmol)
in p-dioxane (0.7 mL) was purged with Argon for 5 min. A degassed
aqueous solution of Na.sub.2CO.sub.3 (1M, 0.3 mL) was added. After
being heated at 100.degree. C. for 2 h, the mixture was cooled to
room temperature, and purified by preparative HPLC to yield
5-chloro-N-((1-(4-(2-methoxypyridin-3-yl)phenyl-1H-imidazol-4-yl)methyl)t-
hiophene-2-carboxamide (MS 425.0, 427.0 (M+H), Cl pattern).
Example 29
5-chloro-N-((1-(4-(2-oxo-1,2-dihydropyridin-3-yl)phenyl)-1H-imidazol-4-yl)-
methyl)thiophene-2-carboxamide (39)
##STR00180##
[0296] To a solution of
5-chloro-N-((1-(4-(2-methoxypyridin-3-yl)phenyl-1H-imidazol-4-yl)methyl)t-
hiophene-2-carboxamide (0.01 g, 0.024 mmol) in AcCN (1 mL) was
added NaI (0.011 g, 0.072 mmol) and TMSCl (0.045 mL, 0.36 mmol).
After heating at 80.degree. C. for 90 min, the reaction mixture was
cooled to room temperature, and purified by preparative HPLC to
yield
5-chloro-N-((1-(4-(2-oxo-1,2-dihydropyridin-3-yl)phenyl-1H-imidazol-4-yl)-
methyl)thiophene-2-carboxamide (MS 411.0, 413.0 (M+H) Cl
pattern).
Example 30
5-Chloro-N-((1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)-1H-imida-
zol-4-yl)methyl)thiophene-2-carboxamide (40)
##STR00181##
[0298] To a solution of
5-chloro-N-((1-(4-(2-oxo-1,2-dihydropyridin-3-yl)phenyl-1H-imidazol-4-yl)-
methyl)thiophene-2-carboxamide (0.02 g, 0.05 mmol) in DMF (0.5 mL)
was added Cs.sub.2CO.sub.3 (0.049 g, 0.15 mmol) and MeI (0.01 mL,
0.15 mmol). After stirring for 30 min at ambient temperature, the
mixture was purified by preparative HPLC to give
5-chloro-N-((1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl-1H-imida-
zol-4-yl)methyl)thiophene-2-carboxamide (MS 425.1, 427.1 (M+H) Cl
pattern).
Example 31
4-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)b-
enzamide (43)
##STR00182##
[0300] To a solution of 4-chlorobenzoic acid (40 mg, 0.26 mmol) and
triethylamine (0.150 mL, 1.08 mmol) in DMF (2 mL), BOP (135 mg,
0.30 mmol) was added. After 5 min of stirring,
1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one
hydrochloride (53 mg, 0.18 mmol) was added. The mixture was stirred
at room temperature for 2 h. It was then purified by HPLC to give
the titled compound (25 mg). MS 405.1 and 407.1 (M+H, Cl
pattern).
Example 32
5-Chloro-N-((1-(5-(2-oxopyridin-1(2H)-yl)pyridin-2-yl)-1H-imidazol-4-yl)me-
thyl)thiophene-2-carboxamide (45)
##STR00183##
[0302] Step 1:
[0303] A mixture of 5-bromo-2-fluoropyridine (630 mg, 3.58 mmol),
4-imidazolecarboxaldehyde (355 mg, 3.70 mmol) and K.sub.2CO.sub.3
(1.00 g, 7.25 mmol) in DMF (10 mL) was stirred at 70.degree. C.
overnight. After being cooled down, H.sub.2O was added to induce
precipitation. The precipitate was collected and dried on vacuum to
give 1-(5-bromopyridin-2-yl)-1H-imidazole-4-carbaldehyde (738
mg).
[0304] Step 2:
[0305] To a suspension of
1-(5-bromopyridin-2-yl)-1H-imidazole-4-carbaldehyde (730 mg, 2.90
mmol) in MeOH (10 mL) at room temperature was added NaBH.sub.4 (134
mg, 3.53 mmol). The mixture was stirred for 30 min, during which
time the suspension became clear. The solvent was removed in vacuo.
The residue was partitioned between H.sub.2O and EtOAc. The organic
phase was separated, washed with 5% NaHCO.sub.3, dried over
Na.sub.2SO.sub.4, concentrated in vacuo to give
(1-(5-bromopyridin-2-yl)-1H-imidazol-4-yl)methanol as a solid (520
mg).
[0306] Step 3:
[0307] To a suspension of
(1-(5-bromopyridin-2-yl)-1H-imidazol-4-yl)methanol (520 mg, 2.05
mmol) in CH.sub.3CN (5 mL) at room temperature was added SOCl.sub.2
(2.5 mL). With the addition, the suspension became clear. After 10
min of stirring, the mixture was concentrated in vacuo. The residue
was dissolved in DMF (12 mL), and NaN.sub.3 (565 mg, 8.69 mmol) was
added. The mixture was stirred at room temperature overnight.
H.sub.2O and EtOAc were added. The organic phase was separated,
washed with 5% NaHCO.sub.3, dried over Na.sub.2SO.sub.4,
concentrated in vacuo to give
2-(4-(azidomethyl)-1H-imidazol-1-yl)-5-bromopyridine (500 mg).
[0308] Step 4:
[0309] A mixture of
2-(4-(azidomethyl)-1H-imidazol-1-yl)-5-bromopyridine (500 mg, 1.79
mmol) and iron powder (767 mg, 13.7 mmol) in EtOH (8 mL) and HOAc
(6 mL) was heated at reflux for 2 h. It was filtered through
celite. The filtrate was concentrated in vacuo. The residue was
partitioned between 5% NaHCO.sub.1 and EtOAc. The biphasic solution
was filtered. The EtOAc phase was separated, dried over
Na.sub.2SO.sub.4, and concentrated in vacuo to give
(1-(5-bromopyridin-2-yl)-1H-imidazol-4-yl)methanamine (253 mg).
[0310] Step 5:
[0311] To a solution of 5-chloro-2-thiophenecarboxylic acid (195
mg, 1.20 mmol) and triethylamine (0.400 mL, 2.87 mmol) in DMF (5
mL), BOP (550 mg, 1.24 mmol) was added.
[0312] After 5 min of stirring, a solution of
(1-(5-bromopyridin-2-yl)-1H-imidazol-4-yl)methanamine (253 mg, 1.00
mmol) in DMF (5 mL) was added. The mixture was stirred at room
temperature overnight. H.sub.2O and EtOAc were added. The organic
phase was separated, washed with 5% NaHCO.sub.3, dried over
Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was
purified by HPLC to give
N-((1-(5-bromopyridin-2-yl)-1H-imidazol-4-yl)methyl)-5-chlorothiophene-2--
carboxamide (85 mg).
[0313] Step 6:
[0314] A mixture of
N-((1-(5-bromopyridin-2-yl)-1H-imidazol-4-yl)methyl)-5-chlorothiophene-2--
carboxamide (42 mg, 0.11 mmol), 2-hydroxypyridine (40 mg, 0.42
mmol), N,N'-dimethylethylenediamine (0.035 mL, 0.32 mmol) and
K.sub.2CO.sub.3 (52 mg, 0.38 mmol) in DMSO (1 mL) and dioxane (1
mL) was degassed with Argon before being charged with CuI (23 mg,
0.12 mmol). The mixture was heated at 110.degree. C. overnight in a
sealed tube. It was then purified by HPLC to give the title
compound (3 mg). MS found for C.sub.19H.sub.14ClN.sub.5O.sub.2S:
412.2 and 414.2 (M+H, Cl pattern).
Example 33
5-Chloro-N-((1-(6-(2-oxopyridin-1(2H)-yl)pyridin-3-yl)-1H-imidazol-4-yl)me-
thyl)thiophene-2-carboxamide (46)
##STR00184##
[0316] A mixture of 3-amino-6-bromopyridine (865 mg, 5.00 mmol),
2-hydroxypyridine (475 mg, 5.00 mmol), N,N'-dimethylethylenediamine
(0.215 mL, 2.00 mmol) and K.sub.2CO.sub.3 (1.38 g, 10.0 mmol) in
dioxane (8 mL) was degassed with Argon before being charged with
CuI (190 mg, 1.00 mmol). The mixture in a sealed tube was heated at
110.degree. C. overnight. After being cooled down, H.sub.2O and
nBuOH were added. The organic phase was separated, and concentrated
in vacuo to give 1-(5-aminopyridin-2-yl)pyridin-2(1H)-one (316
mg).
[0317] To a solution of 1-(5-aminopyridin-2-yl)pyridin-2(1H)-one
(316 mg, 1.69 mmol) in concentrated HCl (8 mL) cooled in an ice
bath, a solution of NaNO.sub.2 (117 mg, 1.69 mmol) in H.sub.2O (3
mL) was added dropwise. After 30 min of stirring, NaI (1.03 g, 6.87
mmol) in H.sub.2O (4 mL) was added. The mixture was stirred at
0.degree. C. for 1 h. It was then allowed to warm up to room
temperature and stirred at room temperature overnight. The mixture
was extracted with EtOAc. The EtOAc solution was washed with 5%
NaHCO.sub.3, then with Na.sub.2S.sub.2O.sub.3, dried over
Na.sub.2SO.sub.4, and concentrated in vacuo to give
1-(5-iodopyridin-2-yl)pyridin-2(1H)-one (189 mg).
[0318] A mixture of 1-(5-iodopyridin-2-yl)pyridin-2(1H)-one (75 mg,
0.25 mmol),
N-((1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide (60
mg, 0.17 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and
K.sub.2CO.sub.3 (100 mg, 0.72 mmol) in DMSO (1 mL) was degassed
with Argon before being charged with CuI (19 mg, 0.10 mmol). The
mixture in a sealed tube was heated at 130.degree. C. overnight. It
was then purified by HPLC to give the title compound (11 mg). MS
found for C.sub.19H.sub.14ClN.sub.5O.sub.2S: 412.0 and 414.0 (M+H,
Cl pattern).
Example 34
5-Chloro-N-((1-(4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-1H-imi-
dazol-5-yl)methyl)thiophene-2-carboxamide (51)
##STR00185##
##STR00186##
[0320] The compound 10.1 was prepared from
(1-(4-iodophenyl)-1H-imidazol-5-yl)methanol (Compound 9.4, prepared
as shown in Example 26) using a similar procedure as described in
Example 26. The title compound was prepared from compound 10.1
under conditions similar to that described in step 4 of Example 1.
MS found for C.sub.20H.sub.16ClN.sub.5O.sub.2S (M+H)+ 426.1 (Cl
pattern).
Example 35
5-Chloro-N-((1-(2-fluoro-4-(2-oxopyrazin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-
-4-yl)methyl)thiophene-2-carboxamide (54)
##STR00187##
[0322] The title compound was prepared using a similar procedure as
described in EXAMPLE 4. MS found for
C.sub.18H.sub.12ClFN.sub.6O.sub.2S (M+H)+ 431.0, 433.0 (Cl
pattern).
Example 36
5-Chloro-N-((1-(2-fluoro-4-(2-oxopyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triaz-
ol-4-yl)methyl)thiophene-2-carboxamide (55)
##STR00188##
[0324] The title compound was prepared using a similar procedure as
described in Example 4. MS found for
C.sub.18H.sub.12ClFN.sub.6O.sub.2S (M+H)+ 431.0, 433.0 (Cl
pattern).
Example 37
5-Chloro-N-((1-(2-fluoro-4-(2-oxo-tetrahydropyrimidin-1(2H)-yl)phenyl)-1H--
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (57)
##STR00189##
[0326] The title compound was prepared using a similar procedure as
described in Example 4. MS found for
C.sub.18H.sub.16ClFN.sub.6O.sub.2S (M+H)+ 435.0, 437.0 (Cl
pattern).
Example 38
5-Chloro-N-((1-(2-fluoro-4-(3-methyl-2-oxo-tetrahydropyrimidin-1(2H)-yl)ph-
enyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (58)
##STR00190##
[0328] The title compound was prepared using a similar procedure as
described in Example 4. MS found for
C.sub.19H.sub.18ClFN.sub.6O.sub.2S (M+H)+ 449.0, 451.0 (Cl
pattern).
Example 39
5-Chloro-N-((1-(2-fluoro-4-(2-oxopiperidin-1-yl)phenyl)-1H-1,2,3-triazol-4-
-yl)methyl)thiophene-2-carboxamide (59)
##STR00191##
[0330] The title compound was prepared using a similar procedure as
described in Example 4. MS found for
C.sub.19H.sub.17ClFN.sub.5O.sub.2S (M+H)+ 434.1, 436.1 (Cl
pattern).
Example 40
5-Chloro-N-((1-(3-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-
-4-yl)methyl)thiophene-2-carboxamide (60)
##STR00192##
[0332] The title compound was prepared using a similar procedure as
described in Example 4. MS found for
C.sub.19H.sub.13ClFN.sub.5O.sub.2S (M+H)+ 430.0, 432.0 (Cl
pattern).
Example 41
5-Chloro-N-((1-(4-(3-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazo-
l-4-yl)methyl)thiophene-2-carboxamide (61)
##STR00193##
[0334]
5-Chloro-N-((1-(4-(3-methoxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-
-triazol-4-yl)methyl)thiophene-2-carboxamide (306 mg, 0.69 mmol,
prepared using a similar procedure as described in Example 4) was
stirred in 40 mL DCM as a slurry. BBr.sub.3 (200 .mu.L, 2.1 mmol)
was added. The mixture was stirred for 2 hrs and concentrated in
vacuo. The residue was dissolved in 1 mL and 5 mL DMSO and
subjected to prep HPLC to isolate the title compound as a white
powder. MS found for C.sub.19H.sub.14ClN.sub.5O.sub.3S (M+H)+
428.1, 430.1 (Cl pattern).
Example 42
5-Chloro-N-((1-(4-(3-(2-hydroxyethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,-
2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (62)
##STR00194##
[0336]
5-Chloro-N-((1-(4-(3-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-
-triazol-4-yl)methyl)thiophene-2-carboxamide (30 mg, 0.07 mmol,
prepared as shown in EXAMPLE 61) was dissolved in 2 mL DMSO. To it
were added cesium carbonate (69 mg, 0.21 mmol) and 2-bromoethanol
(10 .mu.L, 0.14 mmol). The mixture was stirred in a sealed tube at
70.degree. C. for 30 min, and was directly subjected to reverse
phase prep HPLC to isolate the title compound. MS found for
C.sub.21H.sub.18ClN.sub.5O.sub.4S (M+H)+ 472.1, 474.1 (Cl
pattern).
Example 43
5-Chloro-N-((1-(4-(3-(2-methoxyethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,-
2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (63)
##STR00195##
[0338] The title compound was prepared using a similar procedure as
described in Example 42. MS found for
C.sub.22H.sub.20ClN.sub.5O.sub.4S (M+H)+ 486.1, 488.1 (Cl
pattern).
Example 44
5-Chloro-N-((1-(4-(3-(2-(dimethylamino)ethoxy)-2-oxopyridin-1(2H)-yl)pheny-
l)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (64)
##STR00196##
[0340] The title compound was prepared using a similar procedure as
described in Example 42. MS found for
C.sub.23H.sub.23ClN.sub.6O.sub.3S (M+H)+ 499.1, 501.1 (Cl
pattern).
Example 45
5-Chloro-N-((1-(4-(3-(2-(dimethyl(dimethylamino)amino)ethoxy)-2-oxopyridin-
-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide
(65)
##STR00197##
[0342] The title compound was prepared using a similar procedure as
described in Example 42. MS found for
C.sub.27H.sub.33ClN.sub.7O.sub.3S (M+H)+ 570.1, 572.1 (Cl
pattern).
Example 46
5-Chloro-N-((1-(4-(2-oxo-3-(2-(piperidin-1-yl)ethoxy)pyridin-1(2H)-yl)phen-
yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (66)
##STR00198##
[0344] The title compound was prepared using a similar procedure as
described in Example 42. MS found for
C.sub.26H.sub.27ClN.sub.6O.sub.1S (M+H)+ 539.1, 541.1 (Cl
pattern).
Example 47
5-Chloro-N-((1-(4-(2-oxo-3-(3-(piperidin-1-yl)propoxy)pyridin-1(2H)-yl)phe-
nyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (67)
##STR00199##
[0346] The title compound was prepared using a similar procedure as
described in Example 42. MS found for
C.sub.27H.sub.29ClN.sub.6O.sub.3S (M+H)+ 553.1, 555.1 (Cl
pattern).
Example 48
5-Chloro-N-((1-(4-(3-(2-(methylthio)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)--
1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (68)
##STR00200##
[0348] The title compound was prepared using a similar procedure as
described in Example 42. MS found for
C.sub.22H.sub.20ClN.sub.5O.sub.3S.sub.2 (M+H)+ 502.1, 504.1 (Cl
pattern).
Example 49
5-Chloro-N-((1-(4-(3-(2-(methylsulfinyl)ethoxy)-2-oxopyridin-1(2H)-yl)phen-
yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (69)
##STR00201##
[0350] To a solution of Example 48 in a 2:1 mixture of methanol and
water was added 1.0 equivalent of oxone. The mixture was stirred at
room temperature for 10 min and directly subjected to reverse phase
HPLC to isolate the title compound as a white powder after
lyophilization. MS found for
C.sub.22H.sub.20ClN.sub.5O.sub.4S.sub.2 (M+H)+ 518.1, 520.1 (Cl
pattern).
Example 50
5-Chloro-N-((1-(4-(3-(2-(methylsulfonyl)ethoxy)-2-oxopyridin-1(2H)-yl)phen-
yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (70)
##STR00202##
[0352] To a solution of Example 48 in a 2:1 mixture of methanol and
water was added 3 equivalent of oxone. The mixture was stirred at
room temperature for 1 hr and directly subjected to reverse phase
HPLC to isolate the title compound as a white powder after
lyophilization. MS found for
C.sub.22H.sub.20ClN.sub.5O.sub.5S.sub.2 (M+H)+ 534.1, 536.1 (Cl
pattern).
Example 51
5-Chloro-N-((1-(4-(3-(2-morpholinoethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-
-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (71)
##STR00203##
[0354] The title compound was prepared using a similar procedure as
described in Example 42. MS found for
C.sub.25H.sub.25ClN.sub.6O.sub.4S (M+H)+ 541.1, 543.1 (Cl
pattern).
Example 52
N-((1-(4-(3-(2-(1H-Imidazol-1-yl)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H--
1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide (72)
##STR00204##
[0356] The title compound was prepared using a similar procedure as
described in Example 42. MS found for
C.sub.24H.sub.20ClN.sub.7O.sub.1S (M+H)+ 522.1, 524.1 (Cl
pattern).
Example 53
5-Chloro-N-((1-(4-(3-((1-methyl-1H-imidazol-2-yl)methoxy)-2-oxopyridin-1(2-
H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide
(73)
##STR00205##
[0358] The title compound was prepared using a similar procedure as
described in Example 42. MS found for
C.sub.24H.sub.20ClN.sub.7O.sub.3S (M+H)+ 522.1, 524.1 (Cl
pattern).
Example 54
5-Chloro-N-((1-(4-(5-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazo-
l-4-yl)methyl)thiophene-2-carboxamide (74)
##STR00206##
[0360] The title compound was prepared using a similar procedure as
described in Example 41 from
5-chloro-N-((1-(4-(5-methoxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triaz-
ol-4-yl)methyl)thiophene-2-carboxamide (prepared using a similar
procedure as described in Example 4). MS found for
C.sub.19H.sub.14ClN.sub.5O.sub.3S (M+H)+ 428.1, 430.1 (Cl
pattern).
Example 55
5-Chloro-N-((1-(4-(5-(2-(dimethylamino)ethoxy)-2-oxopyridin-1(2H)-yl)pheny-
l)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (75)
##STR00207##
[0362] The title compound was prepared using the same procedure
described in Example 42 from
5-Chloro-N-((1-(4-(5-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triaz-
ol-4-yl)methyl)thiophene-2-carboxamide (prepared as shown in
EXAMPLE 74). MS found for C.sub.23H.sub.23ClN.sub.6O.sub.3S (M+H)+
499.1, 501.1 (Cl pattern).
Example 56
N-((1-(4-(4-Amino-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)me-
thyl)-5-chlorothiophene-2-carboxamide (79)
##STR00208##
[0364] The mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-ca-
rboxamide (100 mg, 0.23 mmol), cytosine (100 mg, 0.90 mmol), CuI
(23 mg, 0.12 mmol), 8-hydroxyquinoline (18 mg, 0.12 mmol),
potassium carbonate (96 mg, 0.69 mmol) in 2 mL DMSO in a sealed
tube was stirred for 15 hrs at 120.degree. C. The title compound
was isolated directly from the reaction mixture using reverse phase
prep HPLC. MS found for C.sub.18H.sub.14ClN.sub.7O.sub.2S (M+H)+
428.1, 430.1 (Cl pattern).
Example 57
5-Chloro-N-((1-(4-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)-1H-1,2,-
3-triazol-4-yl)methyl)thiophene-2-carboxamide (80)
##STR00209##
[0366] The mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-ca-
rboxamide (100 mg, 0.23 mmol), uracil (100 mg, 0.90 mmol), CuI (23
mg, 0.12 mmol), 8-hydroxyquinoline (18 mg, 0.12 mmol), potassium
carbonate (96 mg, 0.69 mmol) in 2 mL DMSO in a sealed tube was
stirred for 15 hrs at 120.degree. C. The title compound was
isolated directly from the reaction mixture using reverse phase
prep HPLC. MS found for C.sub.18H.sub.13ClN.sub.6O.sub.3S (M+H)+
429.1, 431.1 (Cl pattern).
Example 58
N-((1-(4-(4-Amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazo-
l-4-yl)methyl)-5-chlorothiophene-2-carboxamide (81)
##STR00210##
[0368] The title compound was prepared using a similar procedure as
described in Example 57. MS found for
C.sub.18H.sub.13ClFN.sub.7O.sub.2S (M+H)+ 446.1, 448.1 (Cl
pattern).
Example 59
5-Chloro-N-((1-(4-(3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl-
)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (82)
##STR00211##
[0370] The title compound was prepared using a similar procedure as
described in Example 57. MS found for
C.sub.19H.sub.15ClN.sub.6O.sub.3S (M+H)+ 443.1, 445.1 (Cl
pattern).
Example 60
5-Chloro-N-((1-(4-(2-oxopiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methy-
l)thiophene-2-carboxamide (83)
##STR00212##
[0372] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-ca-
rboxamide (100 mg, 0.22 mmol), 4-N-Boc-2-oxo-piperazine (88 mg,
0.44 mmol), CuI (13 mg, 0.066 mmol), N,N'-dimethylethylenediamine
(8 .mu.L, 0.066 mmol), potassium carbonate (61 mg, 0.44 mmol) in 5
mL dioxane in a sealed tube was stirred for 2 days at 120.degree.
C. The mixture was diluted with ethyl acetate (200 mL). It was
washed with brine, dried, and concentrated in vacuo. The residue
was treated with neat TFA for 15 min and directly subjected to prep
HPLC to isolate the title compound. MS found for
C.sub.18H.sub.17ClN.sub.6O.sub.2S (M+H)+ 417.1, 419.1 (Cl
pattern).
Example 61
5-Chloro-N-((1-(4-(4-methyl-2-oxopiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-
-yl)methyl)thiophene-2-carboxamide (84)
##STR00213##
[0374]
5-Chloro-N-((1-(4-(2-oxopiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-y-
l)methyl)thiophene-2-carboxamide (24 mg, 0.06 mmol, prepared as
shown in Example 60) was stirred in 2 mL acetic acid at RT. To it
was added formaldehyde (37% in water, 22 .mu.L, 0.3 mmol). The
mixture was stirred for 10 min. NaBH.sub.3CN (30 mg, 0.48 mmol) was
added. The reaction was allowed for 10 min, and directly subjected
to reverse phase prep HPLC to isolate the title compound. MS found
for C.sub.19H.sub.19ClN.sub.6O.sub.2S (M+H)+ 431.1, 433.1 (Cl
pattern).
Example 62
5-Chloro-N-((1-(4-(4-isopropyl-2-oxopiperazin-1-yl)phenyl)-1H-1,2,3-triazo-
l-4-yl)methyl)thiophene-2-carboxamide (85)
##STR00214##
[0376] The title compound was prepared using a similar procedure as
described in Example 61. MS found for
C.sub.21H.sub.23ClN.sub.6O.sub.2S (M+H)+ 459.1, 461.1 (Cl
pattern).
Example 63
4-(4-(4-((5-Chlorothiophene-2-carboxamido)methyl)-1H-1,2,3-triazol-1-yl)ph-
enyl)-3-oxopiperazine-1-carboxamide (86)
##STR00215##
[0378]
5-Chloro-N-((1-(4-(2-oxopiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-y-
l)methyl)thiophene-2-carboxamide (23 mg, 0.055 mmol, prepared as
shown in Example 60) was dissolved in 2 mL water and 0.5 mL DMSO.
To it was added KOCN (23 mg, 0.28 mmol). The mixture was stirred at
RT over the weekend. The title compound was the major product in
this reaction and was isolated using direct reverse phase prep
HPLC. MS found for C.sub.19H.sub.18ClN.sub.7O.sub.3S (M+H)+ 460.1,
462.1 (Cl pattern).
Example 64
5-Chloro-N-((1-(4-(3-hydroxy-2-oxopyrazin-1(2H)-yl)phenyl)-1H-1,2,3-triazo-
l-4-yl)methyl)thiophene-2-carboxamide (87)
##STR00216##
[0380] The mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-ca-
rboxamide (100 mg, 0.22 mmol), 2,3-pyrazinediol (74 mg, 0.66 mmol),
CuI (21 mg, 0.11 mmol), 8-hydroxyquinoline (16 mg, 0.11 mmol),
potassium carbonate (152 mg, 1.1 mmol) in 2 mL DMSO in a sealed
tube was stirred for 15 hrs at 130.degree. C. The title compound
was isolated directly from the reaction mixture using reverse phase
prep HPLC. MS found for C.sub.18H.sub.13ClN.sub.6O.sub.3S (M+H)+
429.1, 431.1 (Cl pattern).
Example 65
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-pyrrol-3-yl)methyl)thi-
ophene-2-carboxamide (108)
##STR00217##
[0382] A solution of 4-iodoaniline (0.684 g, 3.12 mmol) and
2,5-dimethoxy-3-tetrahydrofurancarboxaldehyde (90%, 0.492 mL, 3.12
mmol) in HOAc (10 mL) was stirred at 90.degree. C. for 1 h. The
solvent was removed in vacuo. The residue was partitioned between
EtOAc and H.sub.2O. The organic phase was separated, washed with 5%
NaHCO.sub.3, dried over Na.sub.2SO.sub.4, and concentrated in vacuo
to give 1-(4-iodophenyl)-1H-pyrrole-3-carbaldehyde (0.927 g).
[0383] To a suspension of
1-(4-iodophenyl)-1H-pyrrole-3-carbaldehyde (927 mg, 3.12 mmol) in
MeOH (15 mL) at room temperature was added NaBH.sub.4 (142 mg, 3.74
mmol). The mixture was stirred at room temperature for 10 min,
during which time the suspension became clear. The solvent was
removed in vacuo. The residue was partitioned between H.sub.2O and
EtOAc. The organic phase was separated, washed with 1N HCl, 1N NaOH
and brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo
to give the alcohol (877 mg).
[0384] To a solution of the alcohol (220 mg, 0.736 mmol) and
diphenyl phosphoryl azide (0.174 mL, 0.808 mmol) in THF (5 mL) was
added DBU (0.110 mL, 0.737 mmol). The mixture was stirred at room
temperature overnight. It was concentrated in vacuo. The residue
was purified by HPLC to give the azide (124 mg).
[0385] A mixture of the azide (124 mg, 0.38 mmol) and Ra--Ni (50%
aq. slurry, .about.100 mg) in MeOH (8 mL) was hydrogenated under
balloon H.sub.2 for 3 h. It was then filtered through celite, and
filtrate was concentrated in vacuo to give
(1-(4-iodophenyl)-1H-pyrrol-3-yl)methanamine (91 mg).
[0386] To a solution of 5-chloro-thiophene-2-carboxylic acid (60
mg, 0.37 mmol) and TEA (0.102 mL, 0.73 mmol) in DMF (4 mL) was
added BOP (196 mg, 0.44 mmol). After 10 min of stirring, the
solution was added to a sample of
(1-(4-iodophenyl)-1H-pyrrol-3-yl)methanamine (91 mg, 0.31 mmol) in
a flask. The mixture was stirred at room temperature overnight.
H.sub.2O was added to induce precipitation. The resulting
precipitate was collected and dried on vacuum to give
5-chloro-N-((1-(4-iodophenyl)-1H-pyrrol-3-yl)methyl)thiophene-2-carboxami-
de (118 mg).
[0387] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-pyrrol-3-yl)methyl)thiophene-2-carboxami-
de (118 mg, 0.27 mmol), 2-hydroxypyridine (50 mg, 0.53 mmol),
8-hydroxyquinoline (14 mg, 0.097 mmol) and K.sub.2CO.sub.3 (120 mg,
0.87 mmol) in DMSO (2 mL) was degassed with Argon before being
charged with CuI (19 mg, 0.10 mmol). The mixture in a sealed tube
was heated at 130.degree. C. for 4 h. It was then purified by HPLC
to give the titled compound (20 mg). MS 410.0 and 412.0 (M+H, Cl
pattern).
Example 66
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-pyrazol-4-yl)methyl)th-
iophene-2-carboxamide (109)
##STR00218##
[0389] A mixture of 1,4-diiodobenzene (4.00 g, 12.1 mmol),
4-methylpyrazole (0.972 g, 12.1 mmol), 8-hydroxyquinoline (0.176 g,
1.21 mmol) and K.sub.2CO.sub.3 (1.69 g, 12.2 mmol) in DMSO (12 mL)
was degassed before being charged with CuI (0.310 g, 1.63 mmol).
The mixture in a sealed tube was heated at 130.degree. C.
overnight. Water and EtOAc were added. The mixture was filtered.
The organic layer was separated, then applied to a silica gel
column, which was eluted with hexane, then with 5% EtOAc in hexane
to give 1-(4-iodophenyl)-4-methyl-1H-pyrazole (1.70 g).
[0390] A mixture of 1-(4-iodophenyl)-4-methyl-1H-pyrazole (1.70 g,
5.99 mmol), NBS (1.38 g, 7.75 mmol) and AIBN (0.30 g, 1.83 mmol) in
CCl.sub.4 (25 mL) was heated at reflux for 1 hr. After being cooled
to room temperature, the upper clear solution was decanted out and
concentrated in vacuo. The residue was dissolved in DMF (10 mL),
NaN.sub.3 (0.934 g, 14.3 mmol) was added. The mixture was stirred
at room temperature overnight. H.sub.2O and EtOAc were added. The
organic phase was separated, dried over Na.sub.2SO.sub.4,
concentrated in vacuo. The residue was purified by a silica gel
column, eluted with hexane, then with 5% EtOAc in hexane to give
4-(azidomethyl)-1-(4-iodophenyl)-1H-pyrazole (0.70 g).
[0391] A mixture of 4-(azidomethyl)-1-(4-iodophenyl)-1H-pyrazole
(530 mg, 1.63 mmol) and Ra--Ni (50% aq. slurry, 200 mg) in MeOH (3
mL) was hydrogenated under balloon H.sub.2 for 1 hr. It was
filtered through celite. The filtrate was concentrated in vacuo to
give (144-iodophenyl)-1H-pyrazol-4-yl)methanamine (396 mg).
[0392] To a solution of 5-chloro-thiophene-2-carboxylic acid (237
mg, 1.46 mmol), (1-(4-iodophenyl)-1H-pyrazol-4-yl)methanamine (396
mg, 1.32 mmol) and TEA (0.500 mL, 3.59 mmol) in DMF (10 mL), BOP
(828 mg, 1.87 mmol) were added. The mixture was stirred at room
temperature overnight. H.sub.2O and EtOAc were added. The organic
phase was separated, washed with 5% NaHCO.sub.3, dried over
Na.sub.2SO.sub.4, concentrated in vacuo to give
5-chloro-N-((1-(4-iodophenyl)-1H-pyrazol-4-yl)methyl)thiophene-2--
carboxamide (462 mg).
[0393] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-pyrazol-4-yl)methyl)thiophene-2-carboxam-
ide (200 mg, 0.451 mmol), 2-hydroxypyridine (85 mg, 0.90 mmol),
8-hydroxyquinoline (30 mg, 0.21 mmol) and K.sub.2CO.sub.3 (247 mg,
1.79 mmol) in DMSO (2 mL) was degassed with Argon before being
charged with CuI (43 mg, 0.22 mmol). The mixture in a sealed tube
was heated at 130.degree. C. overnight. It was then purified by
HPLC to give the title compound (60 mg). MS 411.0 and 413.0 (M+H,
Cl pattern).
Example 67
5-Chloro-N-((1-(4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1H-pyrazol-4-yl)meth-
yl)thiophene-2-carboxamide (110)
##STR00219##
[0395] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-pyrazol-4-yl)methyl)thiophene-2-carboxam-
ide (100 mg, 0.225 mmol), 1-methylhomopiperazine (0.100 mL, 0.81
mmol), ethylene glycol (0.025 mL, 0.45 mmol) and K.sub.3PO.sub.4
(100 mg, 0.47 mmol) in isopropanol (1 mL) was degassed with Argon
before being charged with CuI (20 mg, 0.11 mmol). The mixture in a
sealed tube was heated at 85.degree. C. overnight. It was then
purified by HPLC to give the title compound (5 mg). MS 430.0 and
432.0 (M+H, Cl pattern).
Example 68
5-Chloro-N-((1-(4-(2-oxopyrazin-1(2H)-yl)phenyl)-1H-pyrazol-4-yl)methyl)th-
iophene-2-carboxamide (111)
##STR00220##
[0397] To a solution of glycinamide hydrochloride (1.10 g, 10.0
mmol) in 5 N NaOH (6 mL) at room temperature, glyoxal (40% in
H.sub.2O, 1.5 mL, 13.1 mmol) was added. The solution was stirred at
room temperature overnight. The product was extracted from the
aqueous solution with nBuOH, and nBuOH extract was concentrated in
vacuo to give 2-hydroxypyrazine as a white solid (0.20 g).
[0398] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-pyrazol-4-yl)methyl)thiophene-2-carboxam-
ide (75 mg, 0.17 mmol), 2-hydroxypyrazine (43 mg, 0.45 mmol),
8-hydroxyquinoline (15 mg, 0.10 mmol) and K.sub.2CO.sub.3 (100 mg,
0.72 mmol) in DMSO (1 mL) was degassed with Argon before being
charged with CuI (19 mg, 0.10 mmol). The mixture in a sealed tube
was heated at 130.degree. C. overnight. It was then purified by
HPLC to give the title compound (10 mg). MS 412.0 and 414.0 (M+H,
Cl pattern).
Example 69
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-pyrazol-3-yl)methyl)th-
iophene-2-carboxamide (112)
##STR00221##
[0400] A mixture of 1,4-diiodobenzene (4.00 g, 12.1 mmol),
3-methylpyrazole (0.972 g, 12.1 mmol), 8-hydroxyquinoline (0.176 g,
1.21 mmol) and K.sub.2CO.sub.3 (1.69 g, 12.2 mmol) in DMSO (12 mL)
was degassed before being charged with CuI (0.230 g, 1.21 mmol).
The mixture in a sealed tube was heated at 130.degree. C.
overnight. Water and EtOAc were added. The mixture was filtered.
The organic layer was separated, then purified by silica gel column
chromatography with hexane followed by 4-6% EtOAc in hexane to give
1-(4-iodophenyl)-3-methyl-1H-pyrazole (0.98 g).
[0401] A mixture of 1-(4-iodophenyl)-3-methyl-1H-pyrazole (0.98 g,
3.45 mmol), NBS (0.80 g, 4.49 mmol) and AIBN (0.17 g, 1.03 mmol) in
CCl.sub.4 (15 mL) was heated at reflux for 5 hrs. After being
cooled to room temperature, it was filtered. The filtrate was
concentrated in vacuo. The residue was dissolved in DMF (8 mL),
NaN.sub.3 (0.400 g, 6.15 mmol) was added. The mixture was stirred
at room temperature overnight. H.sub.2O and EtOAc were added. The
organic phase was separated, dried over Na.sub.2SO.sub.4,
concentrated in vacuo. The residue was purified by a silica gel
column, eluted with hexane, then with 4-6% EtOAc in hexane to give
3-(azidomethyl)-1-(4-iodophenyl)-1H-pyrazole (0.10 g).
[0402] A mixture of 3-(azidomethyl)-1-(4-iodophenyl)-1H-pyrazole
(100 mg, 0.31 mmol) and Ra--Ni (50% aq. slurry, 150 mg) in MeOH (8
mL) was hydrogenated under balloon H.sub.2 for 3 hrs. It was
filtered through celite. The filtrate was concentrated in vacuo to
give (1-(4-iodophenyl)-1H-pyrazol-3-yl)methanamine (78 mg).
[0403] To a solution of 5-chloro-thiophene-2-carboxylic acid (51
mg, 0.31 mmol), (1-(4-iodophenyl)-1H-pyrazol-3-yl)methanamine (78
mg, 0.26 mmol) and TEA (0.100 mL, 0.72 mmol) in DMF (3 mL), BOP
(170 mg, 0.38 mmol) was added. The mixture was stirred at room
temperature overnight. H.sub.2O and EtOAc were added. The organic
phase was separated, washed with 5% NaHCO.sub.3, dried over
Na.sub.2SO.sub.4, concentrated in vacuo. The residue was purified
by a preparative TLC plate (developed in EtOAc/hexane (35/65)) to
give
5-chloro-N-((1-(4-iodophenyl)-1H-pyrazol-3-yl)methyl)thiophene-2-carboxam-
ide (60 mg).
[0404] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-pyrazol-3-yl)methyl)thiophene-2-carboxam-
ide (60 mg, 0.14 mmol), 2-hydroxypyridine (30 mg, 0.32 mmol),
8-hydroxyquinoline (10 mg, 0.070 mmol) and K.sub.2CO.sub.3 (50 mg,
0.36 mmol) in DMSO (1 mL) was degassed with Argon before being
charged with CuI (15 mg, 0.080 mmol). The mixture in a sealed tube
was heated at 130.degree. C. overnight. It was then purified by
HPLC to give the titled compound (15 mg). MS 411.0 and 413.0 (M+H,
Cl pattern).
Example 70
5-Chloro-N-((1-(3-methoxy-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazo-
l-4-yl)methyl)thiophene-2-carboxamide (115)
##STR00222##
[0406] The title compound was prepared using a similar procedure as
described in Example 1 for preparing compound 1.6. MS found for
C.sub.20H.sub.16ClN.sub.5O.sub.3S (M+H)+ 442.1, 444.1.
[0407] The compounds in the following Table 2 were prepared using
methods similar to those above or using methods similar to those
disclosed in U.S. patent application Ser. No. 11/158,274, filed
Jun. 20, 2005, which claims the benefit of U.S. Provisional
Application No. 60/580,899, filed Jun. 18, 2004, which applications
are incorporated herein by reference in their entireties.
TABLE-US-00002 TABLE 2 Compound Structure Name MS 7 ##STR00223##
5-Chloro-N-((1-(4-(2- ((dimethylamino)meth- yl)-1H-imidazol-1-
yl)-2-fluorophenyl)- 1H-1,2,3-triazol-4- yl)methyl)thiophene-
2-carboxamide 460.1 8 ##STR00224## 5-Chloro-N-((1-(4-(2-
methyl-1H-imidazol- 1-yl)phenyl)-1H- 1,2,3-triazol-4-
yl)methyl)thiophene- 2-carboxamide 399.1 10 ##STR00225##
5-Chloro-N-((1-(4-(2- oxoimidazolidin-1- yl)phenyl)-1H-1,2,3-
triazol-4- yl)methyl)thiophene- 2-carboxamide 403.1 15 ##STR00226##
N-((1-(4-(1H-Indol-2- yl)phenyl)-1H-1,2,3- triazol-4-yl)methyl)-
5-chlorothiophene-2- carboxamide 434 16 ##STR00227##
5-Chloro-N-((1-(4- (methylsulfonyl)phen- yl)-1H-1,2,3-triazol-4-
yl)methyl)thiophene- 2-carboxamide 397.0 17 ##STR00228##
5-Chloro-N-((1-(3- fluoro-2'- sulfamoylbiphenyl-4-
yl)-1H-1,2,3-triazol-4- yl)methyl)thiophene- 2-carboxamide 492.0 20
##STR00229## N-((1-(4- Carbamoylphenyl)- 1H-1,2,3-triazol-4-
yl)methyl)-5- chlorothiophene-2- carboxamide 362.0 22 ##STR00230##
5-Chloro-N-((1-(4- (methyl(2- (methylamino)ethyl) amino)phenyl)-1H-
1,2,3-triazol-4- yl)methyl)thiophene- 2-carboxamide 405.1 23
##STR00231## 5-Chloro-N-((1-(4- (methylamino)phenyl)-
1H-1,2,3-triazol-4- yl)methyl)thiophene- 2-carboxamide 348.1 29
##STR00232## 5-Chloro-N-((1-(4-(2- hydroxyethoxy)phen-
yl)-1H-1,2,3-triazol-4- yl)methyl)thiophene- 2-carboxamide 379.1 41
##STR00233## N-((1-(4- Aminophenyl)-1H- imidazol-4- yl)methyl)-5-
chlorothiophene-2- carboxamide 333.0 42 ##STR00234##
5-Chloro-N-((1-(4- (2,5-dihydro-1H- pyrrole-1- carbonyl)phenyl)-1H-
imidazol-4- yl)methyl)thiophene- 2-carboxamide 413.1 44
##STR00235## N-((1-(4-(2- Oxopyridin-1(2H)- yl)phenyl)-1H-
imidazol-4- yl)methyl)acetamide 309.1 47 ##STR00236##
5-Chloro-N-((2,5- dibromo-1-(4-(N,N- dimethylcarbamimido
yl)phenyl)-1H- imidazol-4- yl)methyl)thiophene- 2-carboxamide
544.0, 546.0, 548.0 48 ##STR00237## 5-Chloro-N-((2,5- dibromo-1-(4-
(imino(pyrrolidin-1- yl)methyl)phenyl)- 1H-imidazol-4-
yl)methyl)thiophene- 2-carboxamide 570.0, 572.0, 574.0 49
##STR00238## 5-Chloro-N-((2,5- dibromo-1-(4-(1- methyl-4,5-dihydro-
1H-imidazol-2- yl)phenyl)-1H- imidazol-4- yl)methyl)thiophene-
2-carboxamide 556.0, 558.0, 560.0 50 ##STR00239##
5-Chloro-N-((1-(4-(9- methyl-2,6-dioxo-1H- purin-3(2H,6H,9H)-
yl)phenyl)-1H-1,2,3- triazol-4- yl)methyl)thiophene- 2-carboxamide
483.1 52 ##STR00240## 5-Chloro-N-((4- methyl-1-(4-(2-
oxopyridin-1(2H)- yl)phenyl)-1H- imidazol-5- yl)methyl)thiophene-
2-carboxamide 425.1 53 ##STR00241## 5-Chloro-N-((1-(4-(2-
oxopyrazin-1(2H)- yl)phenyl)-1H-1,2,3- triazol-4-
yl)methyl)thiophene- 2-carboxamide 413.1 56 ##STR00242##
5-Chloro-N-((1-(4-(2- oxotetrahydropyrimidin- 1(2H)-yl)phenyl)-
1H-1,2,3-triazol-4- yl)methyl)thiophene- 2-carboxamide 417.1 76
##STR00243## 5-Chloro-N-((1-(4-(2- oxo-5-(2-(piperidin-1-
yl)ethoxy)pyridin- 1(2H)-yl)phenyl)-1H- 1,2,3-triazol-4-
yl)methyl)thiophene- 2-carboxamide 539.1 77 ##STR00244##
5-Chloro-N-((1-(4-(5- (2- morpholinoethoxy)-2- oxopyridin-1(2H)-
yl)phenyl)-1H-1,2,3- triazol-4- yl)methyl)thiophene- 2-carboxamide
541.1 78 ##STR00245## 5-Chloro-N-((1-(4-(5- nitro-2-oxopyridin-
1(2H)-yl)phenyl)-1H- 1,2,3-triazol-4- yl)methyl)thiophene-
2-carboxamide 457 88 ##STR00246## 5-Chloro-N-((1-(4-(4- (2-
(dimethylamino)ethyl)- 2,3-dioxo-3,4- dihydropyrazin-
1(2H)-yl)phenyl)-1H- 1,2,3-triazol-4- yl)methyl)thiophene-
2-carboxamide 500.1 89 ##STR00247## 5-Chloro-N-((1-(4-(3-
hydroxy-6- oxopyridazin-1(6H)- yl)phenyl)-1H-1,2,3- triazol-4-
yl)methyl)thiophene- 2-carboxamide 429.1 90 ##STR00248##
2-((1-(4-(2- Oxopyridin-1(2H)- yl)phenyl)-1H-1,2,3- triazol-4-
yl)methylcarbamoyl) benzoic acid 414.1 91 ##STR00249## N-((1-(2-(3-
Oxopiperazin-1-yl)-4- (2-oxopyridin-1(2H)- yl)phenyl)-1H-1,2,3-
triazol-4- yl)methyl)thiophene- 2-carboxamide 476.1 92 ##STR00250##
5-Chloro-N-((1-(4-(1- methyl-4,5-dihydro- 1H-imidazol-2-
yl)phenyl)-1H-1,2,3- triazol-5- yl)methyl)thiophene- 2-carboxamide
401.1 93 ##STR00251## 5-Chloro-N-((1-(4- (N,N- dimethylcarbamimido
yl)phenyl)-1H-1,2,3- triazol-5- yl)methyl)thiophene- 2-carboxamide
389.1 94 ##STR00252## 5-Chloro-N-((1-(4- (imino(pyrrolidin-1-
yl)methyl)phenyl)- 1H-1,2,3-triazol-5- yl)methyl)thiophene-
2-carboxamide 415.1 95 ##STR00253## 5-Chloro-N-((1-(4-
(imino(piperidin-1- yl)methyl)phenyl)- 1H-1,2,3-triazol-5-
yl)methyl)thiophene- 2-carboxamide 429.1 96 ##STR00254## N-((1-(4-
Carbamoylphenyl)- 1H-1,2,3-triazol-5- yl)methyl)-5-
chlorothiophene-2- carboxamide 362.0 97 ##STR00255##
5-Chloro-N-((1-(4- (methylsulfonyl)phen- yl)-1H-1,2,3-triazol-5-
yl)methyl)thiophene- 2-carboxamide 397.0 98 ##STR00256##
5-Chloro-N-((1-(4-(2- oxopyridin-1(2H)- yl)phenyl)-1H-1,2,3-
triazol-5- yl)methyl)thiophene- 2-carboxamide 412.1 99 ##STR00257##
5-Chloro-N-((1-(4- (pyridin-2- ylthio)phenyl)-1H- 1,2,3-triazol-5-
yl)methyl)thiophene- 2-carboxamide 428.0 100 ##STR00258##
5-Chloro-N-((1-(6- (pyrrolidin-1- yl)pyridin-3-yl)-1H-
1,2,3-triazol-4- yl)methyl)thiophene- 2-carboxamide 389.1 101
##STR00259## 1-(5-(4-((5- Chlorothiophene-2- carboxamido)methyl)-
1H-1,2,3-triazol-1- yl)pyridin-2- yl)piperidine-4- carboxylic acid
447.1 102 ##STR00260## N-((1-(6-(Azepan-1- yl)pyridin-3-yl)-1H-
1,2,3-triazol-4- yl)methyl)-5- chlorothiophene-2- carboxamide 417.1
103 ##STR00261## 5-Chloro-N-((1-(6-(4- methyl-1,4-diazepan-
1-yl)pyridin-3-yl)-1H- 1,2,3-triazol-5- yl)methyl)thiophene-
2-carboxamide 432.1 104 ##STR00262## N-((1-(6-(1,4- Diazepan-1-
yl)pyridin-3-yl)-1H- 1,2,3-triazol-5- yl)methyl)-5-
chlorothiophene-2- carboxamide 418.1 105 ##STR00263##
5-Chloro-N-((1-(6-(4- methylpiperazin-1- yl)pyridin-3-yl)-1H-
1,2,3-triazol-5- yl)methyl)thiophene- 2-carboxamide 418.1 106
##STR00264## 5-Chloro-N-((1-(6- (piperazin-1- yl)pyridin-3-yl)-1H-
1,2,3-triazol-5- yl)methyl)thiophene- 2-carboxamide 404.1 107
##STR00265## 5-Chloro-N-(4-(4-((5- chlorothiophene-2-
carboxamido)methyl)- 1H-imidazol-1- yl)benzyl)thiophene-
2-carboxamide 491.0, 493.0 113 ##STR00266## 5-Chloro-N-((1-(3-(2-
oxopyridin-1(2H)- yl)phenyl)-1H-1,2,3- triazol-4-
yl)methyl)thiophene- 2-carboxamide 412.1 114 ##STR00267##
5-Chloro-N-((1-(4- methyl-3-oxo-3,4- dihydro-2H-
benzo[.beta.][1,4]oxazin- 7-yl)-1H-1,2,3-triazol- 4-
yl)methyl)thiophene- 2-carboxamide 404 116 ##STR00268##
5-Chloro-N-((1-(5-(2- oxopyridin-1(2H)- yl)quinolin-8-yl)-1H-
1,2,3-triazol-4- yl)methyl)thiophene- 2-carboxamide 463
Example 71
[0408] This example illustrates methods for evaluating the
compounds of the invention, along with results obtained for such
assays. The in vitro and in vivo human Factor Xa activities of the
inventive compounds can be determined by various procedures known
in the art, such as a test for their ability to inhibit the
activity of human plasma Factor Xa. The potent affinities for human
Factor Xa inhibition exhibited by the inventive compounds can be
measured by an IC.sub.50 value (in nM). The IC.sub.50 value is the
concentration (in nM) of the compound required to provide 50%
inhibition of human Factor Xa proteolytic activity. The smaller the
IC.sub.50 value, the more active (potent) is a compound for
inhibiting Factor Xa activity.
[0409] An in vitro assay for detecting and measuring inhibition
activity against Factor Xa is as follows:
IC.sub.50 and Ki Determinations:
Substrate:
[0410] The substrate S-2765 (Z-D-Arg-Gly-Arg-pNA.HCl) was obtained
from Diapharma (West Chester, Ohio).
Enzyme:
[0411] The human plasma protein factor Xa was purchased from
Haematologic Technologies (Essex Junction, Vt.).
Methods
[0412] IC.sub.50 Determinations
[0413] All assays, which are performed in 96-well microliter
plates, measure proteolytic activity of the enzyme (factor Xa) by
following cleavage of a paranitroanilide peptide substrate. The
assay buffer used for proteolytic assays was Tris buffered saline
(20 mM Tris, 150 mM NaCl, 5 mM CaCl.sub.2, 0.1% Bovine serum
albumin (BSA), 5% Dimethyl Sulfoxide (DMSO) pH 7.4). In a 96-well
microtiter plate, inhibitor was serially diluted to give a range of
final concentrations from 0.01 nM to 10 .mu.M. Duplicate sets of
wells were assayed and control wells without inhibitor were
included. Enzyme was added to each well, (factor Xa concentration=1
nM), the plate was shaken for 5 seconds and then incubated for 5
minutes at room temperature. S-2765 was added (100 .mu.M final) and
the plate was shaken for 5 seconds (final volume in each well was
200 .mu.l). The degree of substrate hydrolysis was measured at 405
nm on a Thermomax plate reader (Molecular Devices, Sunnyvale,
Calif.) for 2 minutes. The initial velocities of substrate cleavage
(mOD/min), for each range of inhibitor concentrations, were fitted
to a four parameter equation using Softmax data analysis software.
The parameter C, derived from the resulting curve-fit, corresponded
to the concentration for half maximal inhibition (IC.sub.50).
[0414] K.sub.i Determination
[0415] The assay buffer for this series of assays was Hepes
buffered saline (20 mM Hepes, 150 mM NaCl, 5 mM CaCl.sub.2, 0.1%
PEG-8000, pH 7.4). In a 96-well microtiter plate, inhibitor was
serially diluted in a duplicate set of wells to give a range of
final concentrations from 5 .mu.M to 3 .mu.M. Controls without
inhibitor (8 wells) were included. The enzyme, factor Xa (final
concentration=1 nM) was added to the wells. The substrate S-2765
(final concentration=200 .mu.M) was added and the degree of
substrate hydrolysis was measured at 405 nm on a Thermomax plate
reader for 5 minutes, using Softmax software. Initial velocities
(mOD/min) were analyzed by non-linear least squares regression in
the Plate K, software (BioKin Ltd, Pullman, Wash.) (Kusmic, et al.,
Analytical Biochemistry 281: 62-67, 2000). The model used for
fitting the inhibitor dose-response curves was the Morrison
equation. An apparent K.sub.i (Ki*) was determined. The overall K
was calculated using the following equation:
Ki = Ki * 1 + [ S ] Km ##EQU00001##
[0416] where [S] is substrate concentration (200 .mu.M) and K.sub.m
is the Michaelis constant for S-2765.
[0417] The following compounds exhibited Factor Xa IC.sub.50 values
less than or equal to 100 nM: 1, 3, 4, 7-9, 18, 19, 21, 22, 27, 28,
39, 40, 42, 45, 47-49, 53, 56, 59, 60, 62-74, 79-83, 86, 87, 98,
115.
[0418] The following compounds exhibited Factor Xa IC.sub.50 values
greater than 100 nM and less than 500 nM: 5, 6, 10, 20, 24-26, 37,
46, 61, 78, 100, 102.
[0419] The following compounds exhibited Factor Xa IC.sub.50 values
greater than or equal to 500 nM: 11-17, 23, 29, 38, 41, 43, 44,
50-52, 75-77, 84, 85, 88-97, 99, 101, 103-106, 113, 114, 116.
* * * * *