U.S. patent number RE45,173 [Application Number 13/929,901] was granted by the patent office on 2014-09-30 for inhibitors of cyp 17.
This patent grant is currently assigned to Novartis AG. The grantee listed for this patent is Novartis AG. Invention is credited to Mark Gary Bock, Christoph Gaul, Venkateshwar Rao Gunmadi, Saumitra Sengupta.
United States Patent |
RE45,173 |
Bock , et al. |
September 30, 2014 |
Inhibitors of CYP 17
Abstract
The present invention provides compounds of Formula (I) and
(II), or a pharmaceutically acceptable salts thereof, ##STR00001##
where R.sup.53, R.sup.54, p, q, and n are as defined herein. The
compounds of the present invention have been found to be useful as
17.alpha.-hydroxylase/C.sub.17,20-lyase inhibitors.
Inventors: |
Bock; Mark Gary (Boston,
MA), Gaul; Christoph (Aesch, CH), Gunmadi;
Venkateshwar Rao (Bangalore, IN), Sengupta; Saumitra
(Kolkata, IN) |
Applicant: |
Name |
City |
State |
Country |
Type |
Novartis AG |
Basel |
N/A |
CH |
|
|
Assignee: |
Novartis AG (Basel,
CH)
|
Family
ID: |
42357251 |
Appl.
No.: |
13/929,901 |
Filed: |
June 28, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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Reissue of: |
12824845 |
Jun 28, 2010 |
8263635 |
Sep 11, 2012 |
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Foreign Application Priority Data
|
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|
|
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Jun 26, 2009 [IN] |
|
|
01500/CHE/2009 |
Oct 21, 2009 [IN] |
|
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2181/DEL/2009 |
|
Current U.S.
Class: |
514/399;
548/316.4 |
Current CPC
Class: |
A61K
31/444 (20130101); A61P 43/00 (20180101); A61K
31/4439 (20130101); A61P 13/08 (20180101); C07D
413/14 (20130101); A61P 29/00 (20180101); C07D
487/04 (20130101); C07D 401/14 (20130101); C07D
495/04 (20130101); C07D 409/14 (20130101); C07D
471/04 (20130101); C07D 401/04 (20130101); A61K
45/06 (20130101); A61P 35/00 (20180101); C07D
405/14 (20130101); C07D 417/14 (20130101) |
Current International
Class: |
A61K
31/415 (20060101); C07D 233/00 (20060101) |
Field of
Search: |
;514/399 ;548/316.4 |
References Cited
[Referenced By]
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|
Primary Examiner: Zarek; Paul
Attorney, Agent or Firm: Johnson; Stephen
Claims
What is claimed is:
.[.1. A compound of Formula (Ib) ##STR00272## wherein R.sup.50,
R.sup.51 and R.sup.52 are each independently H, halo, -OH, -CN,
(C.sub.1-C.sub.4)alkyl, halo-substituted(C.sub.1-C.sub.4)alkyl,
hydroxy-substituted (C.sub.1-C.sub.4)alkyl, -(CH.sub.2).sub.r
-O(C.sub.1-C.sub.4)alkyl,
-(CH.sub.2).sub.r--CH(O(C.sub.1-C.sub.4)alkyl).sub.2, -NH.sub.2,
-NH(C.sub.1-C.sub.4)alkyl, -N((C.sub.1-C.sub.4)alkyl).sub.2,
-NHC(O)-(C.sub.1-C.sub.4)alkyl, --C(O)NH.sub.2,
-C(O)-NH(C.sub.1-C.sub.4)alkyl,
-C(O)-N((C.sub.1-C.sub.4)alkyl).sub.2, or
-C(O)-O(C.sub.1-C.sub.4)alkyl; wherein n is 1; R.sup.53 is (i)
phenyl optionally substituted with 1 to 3 substituents selected
from halo, -CN, -OH, (C.sub.1-C.sub.6)alkyl, halo-substituted
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, -NH.sub.2,
-NH(C.sub.1-C.sub.4)alkyl, -N((C.sub.1-C.sub.4)alkyl).sub.2,
-NHC(O)-(C.sub.1-C.sub.4)alkyl, -C(O)NH.sub.2,
-C(O)-NH(C.sub.1-C.sub.4)alkyl,
-C(O)-N((C.sub.1-C.sub.4)alkyl).sub.2, or a 5- to 6-membered
heterocycle, (ii) biphenyl optionally substituted with 1 to 3
substituents selected from (C.sub.1-C.sub.4)alkyl or halo, (iii)
phenyl fused to an additional phenyl, a 5- to 6-membered
heteroaryl, a 5- to 6-membered partially or fully saturated
cycloalkyl, or a 5- to 6-membered partially or fully saturated
heterocycle, where said fused phenyl is optionally substituted with
1 to 4 substituents each independently selected from halo, -CN,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
hydroxy-substituted (C.sub.1-C.sub.4)alkyl, halo-substituted
(C.sub.1-C.sub.4)alkyl, cyclopropyl, oxo, -NH.sub.2,
-NH(C.sub.1-C.sub.4)alkyl, -N((C.sub.1-C.sub.4)alkyl).sub.2,
-NHC(O)-(C.sub.1-C.sub.4)alkyl, or .dbd.N-OH, (iv) 5- to 6-membered
heteroaryl optionally substituted with 1 to 3 substituents selected
from halo, -CN, -OH, (C.sub.1-C.sub.6)akyl, halo-substituted
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, -NH.sub.2,
-NH(C.sub.1-C.sub.4)alkyl, -N((C.sub.1-C.sub.4)alkyl).sub.2,
-NHC(O)-(C.sub.1-C.sub.4)alkyl, -C(O)NH.sub.2,
-C(O)-NH(C.sub.1-C.sub.4)alkyl,
-C(O)-N((C.sub.1-C.sub.4)alkyl).sub.2, or a 5- to 6-membered
Heterocycle, (v) 5- to 6-membered heteroaryl fused to another 5- to
6-membered heteroaryl, phenyl, 5- to 6-membered partially or fully
saturated cycloalkyl, or a 5- to 6-membered partially or fully
saturated heterocycle, where said fused heteroaryl is optionally
substituted with 1 to 4 substituents each independently selected
from halo, -CN, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
hydroxy-substituted (C.sub.1-C.sub.4)alkyl, halo-substituted
(C.sub.1-C.sub.4)alkyl, cyclopropyl, oxo, -NH.sub.2,
-NH(C.sub.1-C.sub.4)alkyl, -N((C.sub.1-C.sub.4)alkyl).sub.2,
-NHC(O)-(C.sub.1-C.sub.4)alkyl, or .dbd.N-OH; R.sup.54 is
(C.sub.1-C.sub.4)alkyl, halo-substituted (C.sub.1-C.sub.4)alkyl, or
-CH.sub.2OH, or two R.sup.54 taken together with the carbon atom(s)
to which they are attached form a 3- to 6-membered fully or
partially saturated carbocyclic; p is 0, 1, 2, or 3; with the
proviso that when R.sup.50, R.sup.51, and R.sup.52 are H and
R.sup.53 is phenyl, R.sup.53 is not unsubstituted or substituted
with halogen or CF.sub.3, or a pharmaceutically acceptable salt
thereof..].
2. A compound of Formula (Ib) ##STR00273## wherein: n is 1;
R.sup.53 is .[.(i) phenyl optionally substituted with 1 to 3
substituents selected from halo, -CN, -OH, (C.sub.1-C.sub.6)alkyl,
halo-substituted (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
-NH.sub.2, -NH(C.sub.1-C.sub.4)alkyl,
-N((C.sub.1-C.sub.4)alkyl).sub.2, -NHC(O)-(C.sub.1-C.sub.4)alkyl,
-C(O)NH.sub.2, -C(O)-NH(C.sub.1-C.sub.4)alkyl,
-C(O)-N((C.sub.1-C.sub.4)alkyl).sub.2, or a 5- to 6-membered
heterocycle, (ii) biphenyl optionally substituted with 1 to 3
substituents selected from (C.sub.1-C.sub.4)alkyl or halo, (iii)
phenyl fused to an additional phenyl, a 5- to 6-membered
heteroaryl, a 5- to 6-membered partially or fully saturated
cycloalkyl, or a 5- to 6-membered partially or fully saturated
heterocycle, where said fused phenyl is optionally substituted with
1 to 4 substituents each independently selected from halo, -CN,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
hydroxy-substituted (C.sub.1-C.sub.4)alkyl, halo-substituted
(C.sub.1-C.sub.4)alkyl, cyclopropyl, oxo, -NH.sub.2,
-NH(C.sub.1-C.sub.4)alkyl, -N((C.sub.1-C.sub.4)alkyl).sub.2,
-NHC(O)-(C.sub.1-C.sub.4)alkyl, or .dbd.N-OH, (iv) 5- to 6-membered
heteroaryl optionally substituted with 1 to 3 substituents selected
from halo, -CN, -OH, (C.sub.1-C.sub.6)alkyl, halo-substituted
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, -NH.sub.2,
-NH(C.sub.1-C.sub.4)alkyl, -N((C.sub.1-C.sub.4)alkyl).sub.2,
-NHC(O)-(C.sub.1-C.sub.4)alkyl, -C(O)NH.sub.2,
-C(O)-NH(C.sub.1-C.sub.4)alkyl,
-C(O)-N((C.sub.1-C.sub.4)alkyl).sub.2, or a 5- to 6-membered
heterocycle, (v) 5- to 6-membered heteroaryl fused to another 5- to
6-membered heteroaryl, phenyl, 5- to 6-membered partially or fully
saturated cycloalkyl, or a 5- to 6-membered partially or fully
saturated heterocycle, where said fused heteroaryl is optionally
substituted with 1 to 4 substituents each independently selected
from halo, -CN, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
hydroxy-substituted (C.sub.1-C.sub.4)alkyl, halo-substituted
(C.sub.1-C.sub.4)alkyl, cyclopropyl, oxo, -NH.sub.2,
-NH(C.sub.1-C.sub.4)alkyl, -N((C.sub.1-C.sub.4)alkyl).sub.2,
-NHC(O)-(C.sub.1-C.sub.4)alkyl, or .dbd.N-OH;.]. .Iadd.(i) a phenyl
optionally substituted with 1 to 2 substituents each independently
selected from fluoro, chloro, methyl, methoxy, trifluoromethyl,
difluoromethyl, or cyano; (ii) a biphenyl; (iii) a fused phenyl
selected from naphthalen-2-yl, quinolin-6-yl,
3,4-dihydro-2-oxo-quinolin-6-yl, benzo[b]thiophen-5-yl,
benzo[d]isoxazol-5-yl, 1H-indazol-6-yl, 1H-indazol-5-yl,
benzothiazol-6-yl, 1,2-dihydro-3-oxo-indazol-6-yl, indan-5-yl,
1H-benzotriazol-5-yl, benzofuran-5-yl,
2,3-dihydro-benzo[1,4]dioxin-6-yl, 2,3-dihydro-benzofuran-5-yl, or
benzo[1,3]dioxol-5-yl where said fused phenyl is optionally
substituted with 1 to 2 substituents each independently selected
from chloro, fluoro, methyl, ethyl, difluoromethyl,
trifluoromethyl, cyclopropyl, cyano, or amino; (iv) a 5- to
6-membered heteroaryl selected from isothiazol-4-yl, thiophen-2-yl,
thiophen-3-yl, or pyridin-4-yl, where said isothiazol-4-yl, said
thiophen-2-yl, said thiophen-3-yl, and said pyridin-4-yl are
optionally substituted with fluoro, chloro, methyl,
trifluoromethyl, difluoromethyl, or methoxy; or (v) a fused
heteroaryl selected from thieno[3,2-c]pyridin-2-yl,
thieno[3,2-c]pyridin-3-yl, thieno[3,2-c]pyridin-2-yl,
imidazo[1,2-a]pyridin-7-yl, or benzo[b]thiophen-2-yl, where said
fused heteroaryl is optionally substituted with 1 to 2 substituents
each independently selected from fluoro, chloro, methyl,
difluoromethyl, trifluoromethyl, cyclopropyl, or amino; .Iaddend.
R.sup.54 is (C.sub.1-C.sub.4)alkyl, halo-substituted
(C.sub.1-C.sub.4)alkyl, or -CH.sub.2OH, or two R.sup.54 taken
together with the carbon atom(s) to which they are attached form a
3- to 6-membered fully or partially saturated carbocyclic ring; p
is 0, 1, 2, or 3; R.sup.50, R.sup.51 and R.sup.52 are each
independently H, halo, -OH, -CN, (C.sub.1-C.sub.4)alkyl,
halo-substituted (C.sub.1-C.sub.4)alkyl, hydroxy-substituted
(C.sub.1-C.sub.4)alkyl, -(CH.sub.2).sub.r-O(C.sub.1-C.sub.4)alkyl,
-(CH.sub.2).sub.r--CH(O(C.sub.1-C.sub.4)alkyl).sub.2, -NH.sub.2,
-NH(C.sub.1-C.sub.4)alkyl, -N((C.sub.1-C.sub.4)alkyl).sub.2,
-NHC(O)-(C.sub.1-C.sub.4)alkyl, -C(O)NH.sub.2,
-C(O)-NH(C.sub.1-C.sub.4)alkyl,
-C(O)-N((C.sub.1-C.sub.4)alkyl).sub.2, or
-C(O)-O(C.sub.1-C.sub.4)alkyl; r is 0, 1 or 2; with the proviso
that when R.sup.50, R.sup.51, and R.sup.52 are H and R.sup.53 is
phenyl, R.sup.53 is not unsubstituted or substituted with halogen
or CF.sub.3; or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2 wherein R.sup.54 is -CH.sub.3 or
CF.sub.3; or a pharmaceutically acceptable salt thereof.
4. The compound of claim 2 wherein R.sup.50 is H or methyl;
R.sup.51 is H, halo, methyl, trifluoromethyl, methoxy, or
-C(O)OCH.sub.3; and R.sup.52 is halo, -CN, methyl, ethyl, methoxy,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl,
difluoromethyl, trifluoromethyl, dimethoxymethyl, -NH.sub.2, or
-NHC(O)CH.sub.3; or a pharmaceutically acceptable salt thereof.
.[.5. The compound of claim 2 wherein R.sup.53 is (i) a phenyl
optionally substituted with 1 or 2 substituents each independently
selected form fluoro, chloro, cyano, methyl, difluoromethyl,
trifluoromethyl, methoxy, or --C(O)NHCH.sub.3; (ii) a biphenyl
optionally substituted with fluoro; (iii) a fused phenyl selected
from naphthalen-2-yl, naphthalen-1-yl, 1H-indol-5-yl,
1H-indol-6-yl, benzothiazol-5-yl, benzothiazol-6-yl,
1,2,3,4-tetrahydro-quinolin-6-yl, benzo[b]thiophen-5-yl,
quinolin-6-yl, quinolin-7-yl, indan-5-yl, 1,2-dihydroquinolin-6-yl,
1H-indazol-5-yl, 1H-indazol-6-yl, benzofuran-5-yl,
2,3-dihydrobenzo[1,4]dioxin-6-yl, 2,3-dihydro-benzofuran-5-yl,
benzo[1,3]dioxol-5-yl, 1,2,3,4-tetrahydro-quinolin-7-yl,
quinoxalin-6-yl, benzooxazol-5-yl, benzo[d]isoxazol-5-yl,
benzo[d]isoxazol-6-yl, 1H-benzoimidazol-5-yl,
2,3-dihydro-1H-indazol-5-yl, 2,3-dihydro-1H-indazol-6-yl,
indolin-5-yl, or 1 H-benzotriazol-5-yl, where said fused phenyl is
optionally substituted with 1 to 3 substituents each independently
selected from fluoro, chloro, methyl, ethyl, trifluoromethyl,
methoxy, oxo, -NH.sub.2, .dbd.N-OH or cyclopropyl; (iv) a 5- to
6-membered heteroaryl selected from thiophen-2-yl, thiophen-3-yl,
pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, 1H-pyrazol-4-yl,
thiazol-2-yl, or isothiazol-4-yl, where said 5- to 6-membered
heteroaryl is optionally substituted with 1 to 3 substituents each
independently selected from fluoro, chloro, methyl, ethyl,
isopropyl, hydroxy, difluoromethyl, trifluoromethyl, methoxy,
-NH.sub.2, -NHC(O)CH.sub.3, -C(O)NHCH.sub.3, or pyrrolidin-1-yl; or
(v) a fused heteroaryl selected from benzo[b]thiophen-2-yl,
benzo[b]thiophen-3-yl, quinolin-2-yl, quinolin-3-yl,
benzooxazol-2-yl, benzothiazol-2-yl,
4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl,
imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-6-yl,
imidazo[1,2-a]pyridin-7-yl, 3H-imidazo[4,5-b]pyridin-6-yl,
thieno[3,2-c]pyridin-2-yl, thieno[3,2-c]pyridin-3-yl, or
1H-indol-3-yl, where said fused heteroaryl is optionally
substituted with 1 to 4 substituents each independently selected
from fluoro, chloro, cyano, methyl, or methoxy; or a
pharmaceutically acceptable salt thereof..].
.[.6. The compound of claim 2 wherein R.sup.53 is (i) a phenyl
optionally substituted with 1 to 2 substituents each independently
selected from fluoro, chloro, methyl, methoxy, trifluoromethyl,
difluoromethyl, or cyano; (ii) a biphenyl; (iii) a fused phenyl
selected from naphthalen-2-yl, quinolin-6-yl,
3,4-dihydro-2-oxo-quinolin-6-yl, benzo[b]thiophen-5-yl,
benzo[d]isoxazol-5-yl, 1H-indazol-6-yl, 1H-indazol-5-yl,
benzothiazol-6-yl, 1,2-dihydro-3-oxo-indazol-6-yl, indan-5-yl,
1H-benzotriazol-5-yl, benzofuran-5-yl,
2,3-dihydro-benzo[1,4]dioxin-6-yl, 2,3-dihydro-benzofuran-5-yl, or
benzo[1,3]dioxol-5-yl where said fused phenyl is optionally
substituted with 1 to 2 substituents each independently selected
from chloro, fluoro, methyl, ethyl, difluoromethyl,
trifluoromethyl, cyclopropyl, cyano, or amino; (iv) a 5- to
6-membered heteroaryl selected from isothiazol-4-yl, thiophen-2-yl,
thiophen-3-yl, or pyridin-4-yl, where said isothiazol-4-yl, said
thiophen-2-yl, said thiophen-3-yl, and said pyridin-4-yl are
optionally substituted with fluoro, chloro, methyl,
trifluoromethyl, difluoromethyl, or methoxy; or (v) a fused
heteroaryl selected from thieno[3,2-c]pyridin-2-yl,
thieno[3,2-c]pyridin-3-yl, thieno[3,2-c]pyridin-2-yl,
imidazo[1,2-a]pyridin-7-yl, or benzo[b]thiophen-2-yl, where said
fused heteroaryl is optionally substituted with 1 to 2 substituents
each independently selected from fluoro, chloro, methyl,
difluoromethyl, trifluoromethyl, cyclopropyl, or amino; or a
pharmaceutically acceptable salt thereof..].
7. The compound of claim 2 wherein R.sup.53 is phenyl,
4-chloro-3-fluoro-phenyl, m-tolyl, 3-methoxy-phenyl,
3-chloro-4-fluoro-phenyl, 4-fluoro-3-methyl-phenyl,
3-trifluoromethyl-phenyl, 3-chloro-phenyl,
4-fluoro-3-trifluoromethyl-phenyl,
3-difluoromethyl-4-fluoro-phenyl, 3-cyano-4-fluorophenyl,
3-cyanophenyl, 3-chloro-4-cyanophenyl, 3,4-difluoro-phenyl,
4-trifluoromethyl-phenyl; or a pharmaceutically acceptable salt
thereof.
8. The compound of claim 2 wherein R.sup.53 is naphthalen-2-yl,
benzo[b]thiophen-5-yl, 3-methyl-benzo[d]isoxazol-5-yl,
1H-indazol-5-yl, 1-methyl-1H-indazol-5-yl, 3-amino-1H-indazol-5-yl,
1H-indazol-6-yl, 3-amino-1H-indazol-6-yl, 3-methyl-1H-indazol-6-yl,
3-trifluoromethyl-1H-indazol-6-yl, benzothiazol-6-yl,
1,2-dihydro-3-oxo-indazol-6-yl, indan-5-yl, 1H-benzotriazol-5-yl,
3-methyl-benzofuran-5-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yl,
2,3-dihydro-benzofuran-5-yl, or 2,2-difluoro-benzo[1,3]dioxol-5-yl;
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 8 wherein R.sup.53 is benzothiazol-6-yl,
3-methyl-benzofuran-5-yl, 1H-indazol-6-yl,
3-methyl-1H-indazol-6-yl, or 3-trifluoromethyl-1H-indazol-6-yl; or
a pharmaceutically acceptable salt thereof.
10. The compound of claim 2 wherein R.sup.53 is
5-methyl-thiophen-2-yl, 5-chloro-thiophen-2-yl,
5-trifluoromethyl-thiophen-2-yl, 5-difluoromethyl-thiophen-3-yl,
5-methyl-thiophen-3-yl, 2-methyl-pyridin-4-yl,
2-trifluoromethyl-pyridin-4-yl, 2-chloro-pyridin-4-yl, or
2-methoxy-pyridin-4-yl; or a pharmaceutically acceptable salt
thereof.
11. The compound of claim 2 wherein R.sup.53 is
4-chloro-thieno[3,2-c]pyridin-2-yl,
4-chloro-thieno[3,2-c]pyridin-3-yl, thieno[3,2-c]pyridin-2-yl,
3-chloro-imidazo[1,2-a]pyridin-7-yl, benzo[b]thiophen-2-yl, or
4-methylthieno[3,2-c]pyridin-2-yl; or a pharmaceutically acceptable
salt thereof.
12. A compound selected from the group consisting of
1-Benzothiazol-6-yl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one;
1-(2-Chloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one;
1-(4-Chloro-thieno[3,2-c]pyridin-2-yl)-3-(4-methyl-pyridin-3-yl)-imidazol-
idin-2-one;
1-(1H-Indazol-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one;
1-(3-Methyl-1H-indazol-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one-
; and
1-Benzothiazol-6-yl-4-methyl-3-(4-methyl-pyridin-3-yl)-imidazolidin--
2-one; Or a pharmaceutically acceptable salt thereof.
13. A compound selected from the group consisting of
1-Naphthalen-2-yl-3-pyridin-3-yl-imidazolidin-2-one; 1-Benzo
[b]thiophen-5-yl-3-pyridin-3-yl-imidazolidin-2-one;
1-(4-Methyl-pyridin-3-yl)-3-naphthalen-2-yl-imidazolidin-2-one;
1-(4-Methyl-pyridin-3-yl)-3-(5-methyl-thiophen-2-yl)-imidazolidin-2-one;
1-Benzothiazol-6-yl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one;
.[.1-Benzo[b]thiophen-2-yl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one;.-
].
1-Benzo[b]thiophen-5-yl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one;
1-(1H-Indazol-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one;
1-(3-Methyl-benzofuran-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one-
;
1-(5-Chloro-thiophen-2-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one;
1-(3,4-Difluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one;
1-(3-Chloro-4-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one-
;
1-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazol-
idin-2-one;
1-(2,3-Dihydro-benzofuran-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2--
one;
1-(4-Chloro-3-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-
-one; 1-(4-Methyl-pyridin-3-yl)-3-m-tolyl-imidazolidin-2-one;
1-(3-Methoxy-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one;
1-(2-Chloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one;
1-(4-Fluoro-3-methyl-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one-
;
1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazo-
lidin-2-one; 1-(4-Methyl-pyridin-3-yl)-3-phenyl-imidazolidin-2-one;
1-(4-Methyl-pyridin-3-yl)-3-(3-trifluoromethyl-phenyl)-imidazolidin-2-one-
;
1-(2-Methoxy-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one;
1-(5-Difluoromethyl-thiophen-3-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-
-2-one;
1-(3-Chloro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one;
1-(4-Fluoro-3-trifluoromethyl-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazoli-
din-2-one;
1-(3-Difluoromethyl-4-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)--
imidazolidin-2-one;
1-(4-Methyl-pyridin-3-yl)-3-(5-methyl-thiophen-3-yl)-imidazolidin-2-one;
1-(4-Chloro-thieno[3,2-c]pyridin-2-yl)-3-(4-methyl-pyridin-3-yl)-imidazol-
idin-2-one;
1-(4-Chloro-thieno[3,2-c]pyridin-3-yl)-3-(4-methyl-pyridin-3-yl)-imidazol-
idin-2-one;
1-(4-Methyl-pyridin-3-yl)-3-(2-methyl-pyridin-4-yl)-imidazolidin-2-one;
1-(3-Methyl-benzo[d]isoxazol-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-
-2-one;
1-(3-Methyl-1H-indazol-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidi-
n-2-one;
2-Fluoro-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-be-
nzonitrile;
3-[3-(4-Methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzonitrile;
2-Chloro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzonitri-
le;
1-(1-Methyl-1H-indazol-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2--
one;
1-(3-Amino-1H-indazol-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2--
one;
1-(4-Methyl-pyridin-3-yl)-3-thieno[3,2-c]pyridin-2-yl-imidazolidin-2--
one;
1-(1H-Indazol-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one;
1-(3-Amino-1H-indazol-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one;
1-Benzothiazol-6-yl-3-(4-methoxy-pyridin-3-yl)-imidazolidin-2-one;
1-Benzothiazol-6-yl-3-(4-difluoromethyl-pyridin-3-yl)-imidazolidin-2-one;
1-Benzothiazol-6-yl-3-(4-hydroxymethyl-pyridin-3-yl)-imidazolidin-2-one;
1-Benzothiazol-6-yl-3-(4-trifluoromethyl-pyridin-3-yl)-imidazolidin-2-one-
; 1-Indan-5-yl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one;
1-(1H-Benzotriazol-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one;
1-(3-Chloro-imidazo[1,2-a]pyridin-7-yl)-3-(4-methyl-pyridin-3-yl)-imidazo-
lidin-2-one;
1-(4-Methyl-pyridin-3-yl)-3-(2-trifluoromethyl-pyridin-4-yl)-imidazolidin-
-2-one;
1-Benzothiazol-6-yl-3-(4-dimethoxymethyl-pyridin-3-yl)-imidazolidi-
n-2-one;
1-Benzothiazol-6-yl-3-(5-chloro-4-methyl-pyridin-3-yl)-imidazolid-
in-2-one;
1-(4-Methylpyridin-3-yl)-3-(5-(trifluoromethyl)thiophen-2-yl)imi-
dazolidin-2-one;
1-(4-Methylpyridin-3-yl)-3-(4-methylthieno[3,2-c]pyridin-2-yl)imidazolidi-
n-2-one;
1-(Benzo[d]thiazol-6-yl)-3-(4-(1-hydroxyethyl)pyridin-3-yl)imidaz-
olidin-2-one;
1-(Benzo[d]thiazol-6-yl)-3-(4-ethylpyridin-3-yl)imidazolidin-2-one;
1-(4-Methylpyridin-3-yl)-3-(3-(trifluoromethyl)-1H-indazol-6-yl)imidazoli-
din-2-one;
1-Benzothiazol-6-yl-4-methyl-3-(4-methyl-pyridin-3-yl)-imidazol-
idin-2-one;
1-Benzothiazol-6-yl-3-pyridin-3-yl-4-trifluoromethyl-imidazolidin-2-one;
1-Benzothiazol-6-yl-4-methyl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one-
;
3-Benzothiazol-6-yl-1-pyridin-3-yl-4-trifluoromethyl-imidazolidin-2-one;
1-Benzothiazol-6-yl-3-(4-methyl-pyridin-3-yl)-4-trifluoromethyl-imidazoli-
din-2-one;
1-Benzothiazol-6-yl-4,5-dimethyl-3-(4-methyl-pyridin-3-yl)-imid-
azolidin-2-one;
.[.1-Benzothiazol-6-yl-3-(4-pyrrolidin-1-ylmethyl-pyridin-3-yl)-imidazoli-
din-2-one;.].
1-Benzothiazol-6-yl-3-(4-morpholin-4-ylmethyl-pyridin-3-yl)-imidazolidin--
2-one;
1-Benzothiazol-6-yl-3-(4-cyclopropylaminomethyl-pyridin-3-yl)-imida-
zolidin-2-one;
1-Benzothiazol-6-yl-3-(6-fluoro-4-methyl-pyridin-3-yl)-imidazolidin-2-one-
;
.[.1-Benzothiazol-6-yl-3-[4-(2-morpholin-4-yl-ethoxy)-pyridin-3-yl]-imid-
azolidin-2-one;
1-Benzothiazol-6-yl-3-[4-(1-methyl-pyrrolidin-2-yl-methoxy)-pyridin-3-yl]-
-imidazolidin-2-one;
1-Benzothiazol-6-yl-3-{4-[(5-methyl-1H-pyrazol-3-ylamino)-methyl]-pyridin-
-3-yl}-imidazolidin-2-one;
1-Benzothiazol-6-yl-3-[4-(1-methyl-piperidin-4-yl-methoxy)-pyridin-3-yl]--
imidazolidin-2-one;.].
3-(3-Benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-isonicotinamide;
1-Benzothiazol-6-yl-3-(4-methyl-5-trifluoromethyl-pyridin-3-yl)-imidazoli-
din-2-one;
1-Isothiazol-4-yl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one;
1-(4-Methyl-pyridin-3-yl)-3-(5-trifluoromethyl-thiophen-2-yl)-imidazolidi-
n-2-one;
1-Benzothiazol-6-yl-3-[4-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-
-imidazolidin-2-one;
1-(4-Methyl-pyridin-3-yl)-3-(4-methyl-thieno[3,2-c]pyridin-2-yl)-imidazol-
idin-2-one;
1-Benzothiazol-6-yl-3-[4-(1-hydroxy-ethyl)-pyridin-3-yl]-imidazolidin-2-o-
ne;
1-Benzothiazol-6-yl-3-(4-ethyl-pyridin-3-yl)-imidazolidin-2-one;
1-(4-Methyl-pyridin-3-yl)-3-(3-trifluoromethyl-1H-indazol-6-yl)-imidazoli-
din-2-one;
1-(3-Cyclopropyl-1H-indazol-6-yl)-3-(4-methyl-pyridin-3-yl)-imi-
dazolidin-2-one;
.[.1-(4-Methyl-pyridin-3-yl)-3-quinolin-7-yl-imidazolidin-2-one;.].
3-Benzothiazol-6-yl-4,4-dimethyl-1-(4-methyl-pyridin-3-yl)-imidazolidin-2-
-one:
1-Benzothiazol-6-yl-4,4-dimethyl-3-pyridin-3-yl-imidazolidin-2-one;
1-Benzothiazol-6-yl-4,4-dimethyl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-
-one;
3-Benzothiazol-6-yl-4-methyl-1-(4-methyl-pyridin-3-yl)-imidazolidin--
2-one;
1-Benzothiazol-6-yl-4-methyl-3-(4-methyl-pyridin-3-yl)-imidazolidin-
-2-one;
1-Benzothiazol-6-yl-4,5-dimethyl-3-(4-methyl-pyridin-3-yl)-imidazo-
lidin-2-one;
.[.1-Benzothiazol-6-yl-3-(4-pyrrolidin-1-ylmethyl-pyridin-3-yl)-imidazoli-
din-2-one;
1-Benzothiazol-6-yl-3-(4-morpholin-4-ylmethyl-pyridin-3-yl)-imi-
dazolidin-2-one;
1-Benzothiazol-6-yl-3-(4-cyclopropylaminomethyl-pyridin-3-yl)-imidazolidi-
n-2-one;
1-Benzothiazol-6-yl-3-{4-[(5-methyl-1H-pyrazol-3-ylamino)-methyl]-
-pyridin-3-yl}-imidazolidin-2-one;.].
1-Benzothiazol-6-yl-4,4-dimethyl-3-pyridin-3-yl-imidazolidin-2-one;
and
3-Benzothiazol-6-yl-4-methyl-1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one-
; or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound of claim 2
or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier or excipient.
15. The pharmaceutical composition of claim 14 further comprising
at least one additional pharmaceutical agent wherein said at least
one additional pharmaceutical agent is an anticancer agent,
chemotherapy agent, or antiproliferative compound.
16. A compound which is
1-(2-Chloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
having the structure: ##STR00274## or a pharmaceutically acceptable
salt thereof.
.Iadd.17. A pharmaceutical composition comprising a compound
according to claim 16, or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable carrier or excipient.
.Iaddend.
.Iadd.18. The pharmaceutical composition of claim 17 further
comprising at least one additional pharmaceutical agent wherein
said at least one additional pharmaceutical agent is an anticancer
agent, chemotherapy agent, or antiproliferative compound.
.Iaddend.
.Iadd.19. A compound which is
1-(2-Chloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
having the structure: .Iaddend. ##STR00275##
.Iadd.20. A pharmaceutical composition comprising a compound
according to claim 19 and a pharmaceutically acceptable carrier or
excipient. .Iaddend.
.Iadd.21. The pharmaceutical composition of claim 20 further
comprising at least one additional pharmaceutical agent wherein
said at least one additional pharmaceutical agent is an anticancer
agent, chemotherapy agent, or antiproliferative compound. .Iaddend.
Description
RELATED APPLICATIONS
This application claims priority to IN Application Serial No.
01500/CHE/2009 filed 26 Jun. 2009 and IN Application Serial No.
2181/DEL/2009 filed 21 Oct. 2009, the contents of which are
incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
The present invention relates to cyclic urea derivatives and their
use for the treatment of various disease conditions mediated by the
regulation of 17.alpha.-hydroxylase/C.sub.17,20-lyase.
BACKGROUND
The number of people diagnosed with cancer world wide has
significantly increased and continues to rise at an alarming rate.
Cancer is characterized by an increase in the number of abnormal
cells derived from a given normal tissue, invasion of adjacent
tissues by these abnormal cells, or lymphatic or blood-borne spread
of malignant cells to regional lymph nodes and to distant sites
(i.e., metastasis).
Of special interest are individuals diagnosed with
androgen-dependent disorders, such as prostate cancer, and
estrogen-dependent disorders, such as breast, uterine, and ovarian
cancer.
Prostate cancer is currently the most common non-skin cancer and
the second leading cause of cancer-related death in men after lung
cancer. The primary course of treatment for patients diagnosed with
organ-confined prostate cancer is usually prostatectomy or
radiotherapy. These treatments for prostate and breast cancer are
highly invasive and characterized by undesirable and serious side
effects. Furthermore, a large percent of individuals who receive
localized treatments such as surgery or radiotherapy may suffer
from recurring cancer and widespread metastases. As with surgery
and radiation therapies, there are several drawbacks to
chemotherapy, including the fact that almost all chemotherapeutic
agents are toxic, and chemotherapy causes significant, and often
dangerous, side effects, such as severe nausea, bone marrow
depression, and immunosuppression. Additionally, many tumor cells
are resistant or become resistant to chemotherapeutic agents
through multi-drug resistance.
Treatments such as hormone therapy are another option for
individuals diagnosed with hormone-dependent, hormone-responsive,
or hormone-sensitive cancers, such as prostate or breast cancer.
However, some individuals who have been administered current
hormone therapy treatments may not show a significant response to
such treatments and some may suffer from relapsing of cancer.
Currently chemo-refractory and hormone-refractory cancer patients
are left with very few treatment options and there remains an unmet
need for more effective was to treat cancer such as, but not
limited to, prostate cancer and breast cancer.
The demonstration by Huggins and Hodges C. V., (Cancer Res., 1941,
1, 293) and Huggins et al in Arch. Surg., 1941, 43, 209 lead to
androgen ablation being considered as a possible approach to
treatment. It has been demonstrated that testosterone levels are
reduced by orchidectomy or by administration of GnRH analogs
(gonadotropic releasing hormones). GnRH analogs can have side
effects such as cardiovascular degeneration and osteoporosis, which
are the two most potentially serious conditions induced by the
continuous presence of GnRH. Moreover these treatment options only
eliminate testosterone production from the testes and not that
produced by the adrenal.
In the adrenal glands, the biosynthetic cascade also leads to the
formation of gluco- and mineralcorticoids.
Since androgen and estrogen are hormones having various
physiological activities such as differentiation and proliferation
of cells and the like, it was thought that potent and specific
compounds that inhibit androgen synthesis in the testes, adrenals,
and other tissue may be more effective for the treatment of PCa
(Njar, V. C. O.; Brodie, A. M. H., "Inhibitors of
17.alpha.-hydroxylase-C.sub.17,20-lyase (CYP17): Potential agents
for the treatment of prostate cancer", Current Pharm. Design, 1999,
5: 163-180).
In order to avoid unwanted side effects, androgen biosnthesis
inhibitors have to be specific enough not to influence
corticosteroid biosynthesis. A promising novel strategy for the
treatment of prostrate cancer is the development of strong and
selective inhibitors of CYP 17 as this would result in complete and
exclusive elimination of androgen biosynthesis as suggested in
Current Medicinal Chemistry, 2005, 12, 1623-1629.
Steroid-type compounds and non-steroid-type compounds are already
known as steroid C.sub.17,20-lyase inhibitors. The steroid-type
compounds are disclosed in, for example, WO 92/15404, WO 93/20097,
EP-A 288053, EP-A 413270 and the like. As non-steroid-type
compounds, for example, in WO94/27989, WO96/14090 and WO97/00257
azole derivatives are described in WO95/09157 1H-benzimidazole
derivatives are described in U.S. Pat. No. 5,491,161,
dihydronaphthalene derivatives are described in WO99/18075, and
naphthalene derivatives are shown in WO99/54309.
A variety of potent steroidal and non-steroidal inhibitors of CYP17
have been reported and some have been shown to be potent inhibitors
of testosterone production in rodent models (Njar and Brodie,
above). Jarman and colleagues have described the hormonal impact of
their most potent CYP17 inhibitor, abiraterone in patients with
prostate cancer (O'Donnell et al., "Hormonal impact of the
17.alpha.-hydroxylase/C17,20-lyase inhibitors abiraterone acetate
(CB7630) in patients with prostate cancer", Br. J. Cancer, 2004,
90: 2317-2325). Abiraterone has been discussed in patents such as
WO 200900132, WO 2008024485, WO 2006021776, WO 09509178, WO
09320097
Non-steroidal small molecule inhibitors have been described for
example in BMC 2004,12, (4313), YM116,
2-(1H-imidazol-4-ylmethyl)-9H-carbazole, and their effects in
decreasing adrenal androgen synthesis by inhibiting C17-20 lyase
activity in NCI-H295 human adrenocortical carcinoma cells has been
described by Ideyama Y, Kudoh M, Tanimoto K, Susaki Y, Nanya T,
Nakahara T, Ishikawa H, Fujikura T, Akaza H, Shikama H in "Jpn. J.
Pharmacol., 1999, 79:No. 2(213-20)". Novel non-steroidal inhibitor
of cytochrome P450 (17 alpha-hydroxylase/C17-20 lyase), YM116, and
its role in decreased prostatic weights by reducing the serum
concentrations of testosterone and adrenal androgens in rats has
been reported by Ideyama Y, Kudoh M, Tanimoto K, Susaki Y, Nanya T,
Nakahara T, Ishikawa H, Yoden T, Okada M, Fujikura T, Shikama H
Proc. Am. Assoc. Cancer Res., 1998, 39:89 Meet. (384)
Synthesis and biological evaluation of novel non-steroidal
inhibitors of steroid 17,20 lyase has been described by-Yoden T,
Okada Ni, Kawaminami E, Kinoyama I, Ideyama Y, Isomura Y in Abstr.
Pap. Am. Chem. Soc., 1997, 213 Meet.:Pt. 2(MEDI206)
Further illustrative of the background of the invention are patent
applications such as US20080280864A1 or WO28154382A1.
SUMMARY
The compounds described herein have been shown to be inhibitors of
17.alpha.-hydroxylase/C.sub.17,20-lyase.
One embodiment of the present invention provides compounds of
Formula (I) or (II)
##STR00002## wherein
n is 1, 2, or 3;
R.sup.53 is
(i) phenyl optionally substituted with 1 to 3 substituents selected
from halo, -CN, -OH, (C.sub.1-C.sub.6)alkyl, halo-substituted
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, -NH.sub.2,
-NH(C.sub.1-C.sub.4)alkyl, -N((C.sub.1-C.sub.4)alkyl).sub.2,
-NHC(O)-(C.sub.1-C.sub.4)alkyl, -C(O)NH.sub.2,
-C(O)-NH(C.sub.1-C.sub.4)alkyl,
-C(O)--N((C.sub.1-C.sub.4)alkyl).sub.2, or a 5- to 6-membered
heterocycle,
(ii) biphenyl optionally substituted with 1 to 3 substituents
selected from (C.sub.1-C.sub.4)alkyl or halo,
(iii) phenyl fused to an additional phenyl, a 5- to 6-membered
heteroaryl, a 5- to 6-membered partially or fully saturated
cycloalkyl, or a 5- to 6-membered partially or fully saturated
heterocycle, where said fused phenyl is optionally substituted with
1 to 4 substituents each independently selected from halo, -CN,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
hydroxy-substituted (C.sub.1-C.sub.4)alkyl, halo-substituted
(C.sub.1-C.sub.4)alkyl, cyclopropyl, oxo, -NH.sub.2,
-NH(C.sub.1-C.sub.4)alkyl, -N((C.sub.1-C.sub.4)alkyl).sub.2,
-NHC(O)-(C.sub.1-C.sub.4)alkyl, or .dbd.N-OH,
(iv) 5- to 6-membered heteroaryl optionally substituted with 1 to 3
substituents selected from halo, -CN, -OH, (C.sub.1-C.sub.6)alkyl,
halo-substituted (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
-NH.sub.2, -NH(C.sub.1-C.sub.4)alkyl,
-N((C.sub.1-C.sub.4)alkyl).sub.2, -NHC(O)-(C.sub.1-C.sub.4)alkyl,
-C(O)NH.sub.2, -C(O)--NH(C.sub.1-C.sub.4)alkyl,
-C(O)-N((C.sub.1-C.sub.4)alkyl).sub.2, or a 5- to 6-membered
heterocycle,
(v) 5- to 6-membered heteroaryl fused to another 5- to 6-membered
heteroaryl, phenyl, 5- to 6-membered partially or fully saturated
cycloalkyl, or a 5- to 6-membered partially or fully saturated
heterocycle, where said fused heteroaryl is optionally substituted
with 1 to 4 substituents each independently selected from halo,
-CN, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
hydroxy-substituted (C.sub.1-C.sub.4)alkyl, halo-substituted
(C.sub.1-C.sub.4)alkyl, cyclopropyl, oxo, -NH.sub.2,
-NH(C.sub.1-C.sub.4)alkyl, -N((C.sub.1-C.sub.4)alkyl).sub.2,
-NHC(O)-(C.sub.1-C.sub.4)alkyl, or .dbd.N-OH;
R.sup.54 is (C.sub.1-C.sub.4)alkyl, halo-substituted
(C.sub.1-C.sub.4)alkyl, or -CH.sub.2OH, or two R.sup.54 taken
together with the carbon atom(s) to which they are attached form a
3- to 6-membered fully or partially saturated carbocyclic ring or
two R.sup.54 attached to adjacent carbons taken together with the
carbons to which they are attached form a fused phenyl;
p is 0, 1, 2, or 3;
q is 0, 1 or 2;
A is a 5- to 10-membered heteroaryl containing one or more nitrogen
atom(s), where said heteroaryl is optionally substituted with 1 to
3 substituents each independently selected from halo, -OH, -CN,
(C.sub.1-C.sub.4)alkyl, halo-substituted (C.sub.1-C.sub.4)alkyl,
hydroxy-substituted (C.sub.1-C.sub.4)alkyl, -(CH.sub.2).sub.rO
(C.sub.1-C.sub.4)alkyl,
-(CH.sub.2).sub.rCH(O(C.sub.1-C.sub.4)alkyl).sub.2,
-NH(C.sub.1-C.sub.4)alkyl,
-(CH.sub.2).sub.sNH(C.sub.1-C.sub.4)alkyl,
-(CH.sub.2).sub.rN((C.sub.1-C.sub.4)alkyl).sub.2,
-(CH.sub.2).sub.rNH(C.sub.3-C.sub.6)cycloalkyl), -NH.sub.2,
-NHC(O)-(C.sub.1-C.sub.4)alkyl, -C(O)NH.sub.2,
-C(O)-NH(C.sub.1-C.sub.4)alkyl,
-C(O)-N((C.sub.1-C.sub.4)alkyl).sub.2, or
-C(O)-O(C.sub.1-C.sub.4)alkyl, where said (C.sub.1-C.sub.4)alkyl,
said -(CH.sub.2).sub.rO(C.sub.1-C.sub.4)alkyl, and said
-(CH.sub.2).sub.sNH(C.sub.1-C.sub.4)alkyl are optionally
substituted with a 4- to 6-membered partially or fully saturated
heterocycle or heteroaryl containing 1 to 3 heteroatoms each
independently selected from O, S or N, where said heterocycle and
said heteroaryl are optionally substituted with 1 to 3
(C.sub.1-C.sub.4)alkyl groups;
r is 0, 1 or 2; and
s is 1 or 2; or a pharmaceutically acceptable salt thereof
with the proviso that (i) when A is an unsubstituted pyridine and
R.sup.53 is phenyl, R.sup.53 is not unsubstituted or
mono-substituted with halogen, CH.sub.3, NH.sub.2, -NHC(O)CH.sub.3,
or CF.sub.3; (ii) A and R.sup.53 are not both an unsubstituted
pyridin-2-yl; and (iii) said compound is not
1-(3,4-dichloro-phenyl)-3[-6-(2-piperidin-1-yl-ethoxy)-pyridin-3-yl]imida-
zolidine-2-one,
1-(3,5-dichloropyridin-2-yl)-3-phenyltetrahydropyrimidin-2(1H)-one,
1,3-bis(6-chloropyridin-2-yl)tetrahydropyrimidin-2(1H)-one,
1,3-bis(4-methylpyridin-2-yl)imidazolidin-2-one,
1-(5-chloro-1H-benzo[d]imidazol-2-yl)-3-phenylimidazolidin-2-one,
or
2-(2-oxo-3-phenylimidazolidin-1-yl)-1H-benzo[d]imidazole-5-carbonitrile.
In a particular embodiment, A is a 5-membered heteroaryl containing
1 to 2 nitrogen atom(s), where said heteroaryl is optionally
substituted with (C.sub.1-C.sub.4)alkyl or halo-substituted
(C.sub.1-C.sub.4)alkyl; or a pharmaceutically acceptable salt
thereof.
In another particular embodiment, A is a 6-membered heteroaryl
containing 1 to 2 nitrogen atom(s), where said heteroaryl is
optionally substituted with (C.sub.1-C.sub.4)alkyl or
halo-substituted (C.sub.1-C.sub.4)alkyl; or a pharmaceutically
acceptable salt thereof.
In another particular embodiment, A is a pyridine, where said
pyridine is optionally substituted with 1 to 3 substituents each
independently selected from halo, -CN, (C.sub.1-C.sub.4)alkyl,
halo-substituted (C.sub.1-C.sub.4)alkyl, hydroxy-substituted
(C.sub.1-C.sub.4)alkyl, -(CH.sub.2).sub.rO(C.sub.1-C.sub.4)alkyl,
-(CH.sub.2).sub.rCH(O(C.sub.1-C.sub.4)alkyl).sub.2,
-(CH.sub.2).sub.rNH(C.sub.1-C.sub.4)alkyl,
-(CH.sub.2).sub.rN((C.sub.1-C.sub.4)alkyl).sub.2,
-(CH.sub.2).sub.rNH(C.sub.3-C.sub.6)cycloalkyl), -NH.sub.2,
-NHC(O)-(C.sub.1-C.sub.4)alkyl, -C(O)NH.sub.2,
-C(O)-NH(C.sub.1-C.sub.4)alkyl,
-C(O)-N((C.sub.1-C.sub.4)alkyl).sub.2, or
-C(O)-O(C.sub.1-C.sub.4)alkyl, where said (C.sub.1-C.sub.4)alkyl,
said -(CH.sub.2).sub.rO(C.sub.1-C.sub.4)alkyl, and said
-(CH.sub.2).sub.rNH(C.sub.1-C.sub.4)alkyl are optionally
substituted with a 5- to 6-membered partially or fully saturated
heterocycle or heteroaryl containing 1 to 2 heteroatoms each
independently selected from O, S or N, where said heterocycle and
said heteroaryl are optionally substituted with 1 to 3
(C.sub.1-C.sub.4)alkyl groups; and r is 1 or 2; or a
pharmaceutically acceptable salt thereof. Preferably, A is an
optionally substituted pyridin-3-yl. In particular, a pyridin-3-yl
substituted with trifluoromethyl or a (C.sub.1-C.sub.4)alkyl
substituted with a 5- to 6-membered partially or fully saturated
heterocycle (preferably, the heterocycle is attached to the alkyl
group via a nitrogen ring atom, e.g. pyrrolidin-1-ylmethyl).
In yet another particular embodiment, the compound of Formula (I)
or (II) is a compound of Formula (Ia) or (Ib)
##STR00003## wherein n, R.sup.50, R.sup.51, R.sup.52, R.sup.53,
R.sup.54 and q are as defined above; or a pharmaceutically
acceptable salt thereof. In a particular embodiment of the compound
of Formula (Ib), R.sup.52 is CF.sub.3 or a (C.sub.1-C.sub.4)alkyl
substituted with a 5- to 6-membered partially or fully saturated
heterocycle (preferably, the heterocycle is attached to the alkyl
group via a nitrogen ring atom, e.g. pyrrolidin-1-ylmethyl). In
another particular embodiment of the compound of Formula (Ib), n is
1, and p is 0.
Another embodiment of the present invention provides compounds of
Formula (Ia) or (Ib).
##STR00004## wherein:
n is 1, 2, or 3;
R.sup.53 is
(i) phenyl optionally substituted with 1 to 3 substituents selected
from halo, -CN, -OH, (C.sub.1-C.sub.6)alkyl, halo-substituted
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, -NH.sub.2,
-NH(C.sub.1-C.sub.4)alkyl, -N((C.sub.1-C.sub.4)alkyl).sub.2,
-NHC(O)-(C.sub.1-C.sub.4)alkyl, -C(O)NH.sub.7,
-C(O)-NH(C.sub.1-C.sub.4)alkyl,
-C(O)-N((C.sub.1-C.sub.4)alkyl).sub.2, or a 5- to 6-membered
heterocycle,
(ii) biphenyl optionally substituted with 1 to 3 substituents
selected from (C.sub.1-C.sub.4)alkyl or halo,
(iii) phenyl fused to an additional phenyl, a 5- to 6-membered
heteroaryl, a 5- to 6-membered partially or fully saturated
cycloalkyl, or a 5- to 6-membered partially or fully saturated
heterocycle, where said fused phenyl is optionally substituted with
1 to 4 substituents each independently selected from halo, -CN,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
hydroxy-substituted (C.sub.1-C.sub.4)alkyl, halo-substituted
(C.sub.1-C.sub.4)alkyl, cyclopropyl, oxo, -NH.sub.2,
-NH(C.sub.1-C.sub.4)alkyl, -N((C.sub.1-C.sub.4)alkyl).sub.2,
-NHC(O)-(C.sub.1-C.sub.4)alkyl, or .dbd.N-OH,
(iv) 5- to 6-membered heteroaryl optionally substituted with 1 to 3
substituents selected from halo, -CN, -OH, (C.sub.1-C.sub.6)alkyl,
halo-substituted (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
-NH.sub.2, -NH(C.sub.1-C.sub.4)alkyl,
-N((C.sub.1-C.sub.4)alkyl).sub.2, -NHC(O)-(C.sub.1-C.sub.4)alkyl,
-C(O)NH.sub.2, -C(O)--NH(C.sub.1-C.sub.4)alkyl,
-C(O)-N((C.sub.1-C.sub.4)alkyl).sub.2, or a 5- to 6-membered
heterocycle.
(v) 5- to 6-membered heteroaryl fused to another 5- to 6-membered
heteroaryl, phenyl, 5- to 6-membered partially or fully saturated
cycloalkyl, or a 5- to 6-membered partially or fully saturated
heterocycle, where said fused heteroaryl is optionally substituted
with 1 to 4 substituents each independently selected from halo,
-CN, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
hydroxy-substituted (C.sub.1-C.sub.4)alkyl, halo-substituted
(C.sub.1-C.sub.4)alkyl, cyclopropyl, oxo, -NH.sub.2,
-NH(C.sub.1-C.sub.4)alkyl, -N((C.sub.1-C.sub.4)alkyl).sub.2,
-NHC(O)-(C.sub.1-C.sub.4)alkyl, or .dbd.N-OH;
R.sup.54 is (C.sub.1-C.sub.4)alkyl (e.g., -CH.sub.3),
halo-substituted (C.sub.1-C.sub.4)alkyl (e.g., -CF.sub.3), or
-CH.sub.2OH, or two R.sup.54 taken together with the carbon atom(s)
to which they are attached form a 3- to 6-membered fully or
partially saturated carbocyclic ring (e.g., for a compound of
Formula (Ia) when q is 2, the two R.sup.54 on adjacent carbons may
form a fused cycloalkenyl ring; and for compounds of Formula (Ib),
when p is 2 or 3, two R.sup.54 on adjacent carbons may form a fused
fully or partially saturated cycloalkyl ring or two R.sup.54 on the
same carbon atom may form a spiral ring);
p is 0, 1, 2, or 3;
q is 0, 1 or 2;
R.sup.50, R.sup.51 and R.sup.52 are each independently H, halo,
-OH, -CN, (C.sub.1-C.sub.4)alkyl, halo-substituted
(C.sub.1-C.sub.4)alkyl, hydroxy-substituted (C.sub.1-C.sub.4)alkyl,
-(CH.sub.2), -O(C.sub.1-C.sub.4)alkyl, --(CH.sub.2),
-CH(O(C.sub.1-C.sub.4)alkyl).sub.2, -NH.sub.2,
-NH(C.sub.1-C.sub.4)alkyl, -N((C.sub.1-C.sub.4)alkyl).sub.2,
-NHC(O)-(C.sub.1-C.sub.4)alkyl, -C(O)NH.sub.2,
-C(O)-NH(C.sub.1-C.sub.4)alkyl,
-C(O)-N((C.sub.1-C.sub.4)alkyl).sub.2, or
-C(O)-O(C.sub.1-C.sub.4)alkyl;
r is 0, 1 or 2;
with the proviso that when R.sup.50, R.sup.51, and R.sup.52 are H
and R.sup.53 is phenyl, R.sup.53 is not unsubstituted or
substituted with halogen or CF.sub.3, or a pharmaceutically
acceptable salt thereof.
In one embodiment, a compound of Formula (Ia) is provided having
the definitions above.
In another embodiment, a compound of Formula (Ib) is provided
having the definitions above.
In yet another embodiment, compounds of Formula (Ib) is provided
where n is 1.
Preferably, R.sup.50 is H or methyl (more preferably, R.sup.50 is
H); R.sup.51 is H, halo, methyl, trifluoromethyl, methoxy, or
-C(O)OCH.sub.3; and R.sup.52 is halo, -CN, methyl, ethyl, methoxy,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl,
difluoromethyl, trifluoromethyl, dimethoxymethyl, -NH.sub.2, or
-NHC(O)CH.sub.3.
Preferably (for compound of Formula (I), (II), (Ia) and (Ib)),
R.sup.53 is
(i) a phenyl optionally substituted with 1 of 2 substituents each
independently selected form fluoro, chloro, cyano, methyl,
difluoromethyl, trifluoromethyl, methoxy, or -C(O)NHCH.sub.3;
(ii) a biphenyl optionally substituted with fluoro;
(iii) a fused phenyl selected from naphthalen-2-yl,
naphthalen-1-yl, 1H-indol-5-yl, 1H-indol-6-yl, benzothiazol-5-yl,
benzothiazol-6-yl, 1,2,3,4-tetrahydro-quinolin-6-yl,
benzo[b]thiophen-5-yl, quinolin-6-yl, quinolin-7-yl indan-5-yl,
1,2-dihydroquinolin-6-yl, 1H-indazol-5-yl, 1H-indazol-6-yl,
benzofuran-5-yl, 2,3-dihydrobenzo[1,4]dioxin-6-yl,
2,3-dihydro-benzofuran-5-yl, benzo[1,3]dioxol-5-yl,
1,2,3,4-tetrahydro-quinolin-7-yl, quinoxalin-6-yl,
benzooxazol-5-yl, benzo[d]isoxazol-5-yl, benzo[d]isoxazol-6-yl,
1H-benzoimidazol-5-yl, 2,3-dihydro-1H-indazol-5-yl,
2,3-dihydro-1H-indazol-6-yl, indolin-5-yl, or 1H-benzotriazol-5-yl,
where said fused phenyl is optionally substituted with 1 to 3
substituents each independently selected from fluoro, chloro,
methyl, ethyl, trifluoromethyl, methoxy, oxo, -NH.sub.2, .dbd.N-OH
or cyclopropyl;
(iv) a 5- to 6-membered heteroaryl selected from thiophen-2-yl,
thiophen-3-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl,
1H-pyrazol-4-yl, thiazol-2-yl, or isothiazol-4-yl, where said 5- to
6-membered heteroaryl is optionally substituted with 1 to 3
substituents each independently selected from fluoro, chloro,
methyl, ethyl, isopropyl, hydroxy, difluoromethyl, trifluoromethyl,
methoxy, -NH.sub.2, -NHC(O)CH.sub.3, -C(O)NHCH.sub.3, or
pyrrolidin-1-yl; or
(v) a fused heteroaryl selected from benzo[b]thiophen-2-yl,
benzo[b]thiophen-3-yl, quinolin-2-yl, quinolin-3-yl,
benzooxazol-2-yl, benzothiazol-2-yl,
4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl,
imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-6-yl,
imidazo[1,2-a]pyridin-7-yl, 3H-imidazo[4,5-b]pyridin-6-yl,
thieno[3,2-c]pyridin-2-yl, thieno[3,2-c]pyridin-3-yl, or
1H-indol-3-yl, where said fused heteroaryl is optionally
substituted with 1 to 4 substituents each independently selected
from fluoro, chloro, cyano, methyl, or methoxy; or a
pharmaceutically acceptable salt thereof.
More preferably, R.sup.53 is
(i) a phenyl optionally substituted with 1 to 2 substituents each
independently selected from fluoro, chloro, methyl, methoxy,
trifluoromethyl, difluoromethyl, or cyano;
(ii) a biphenyl;
(iii) a fused phenyl selected from naphthalen-2-yl, quinolin-6-yl,
3,4-dihydro-2-oxo-quinolin-6-yl, benzo[b]thiophen-5-yl,
benzo[d]isoxazol-5-yl, 1H-indazol-6-yl, 1H-indazol-5-yl,
benzothiazol-6-yl, 1,2-dihydro-3-oxo-indazol-6-yl, indan-5-yl,
1H-benzotriazol-5-yl, benzofuran-5-yl,
2,3-dihydro-benzo[1,4]dioxin-6-yl, 2,3-dihydro-benzofuran-5-yl, or
benzo[1,3]dioxol-5-yl where said fused phenyl is optionally
substituted with 1 to 2 substituents each independently selected
from chloro, fluoro, methyl, ethyl, difluoromethyl,
trifluoromethyl, cyclopropyl, cyano, or amino;
(iv) a 5- to 6-membered heteroaryl selected from isothiazol-4-yl,
thiophen-2-yl, thiophen-3-yl, or pyridin-4-yl, where said
isothiazol-4-yl, said thiophen-2-yl, said thiophen-3-yl, and said
pyridin-4-yl are optionally substituted with fluoro, chloro,
methyl, trifluoromethyl, difluoromethyl, or methoxy; or
(v) a fused heteroaryl selected from thieno[3,2-c]pyridin-2-yl,
thieno[3,2-c]pyridin-3-yl, thieno[3,2-c]pyridin-2-yl,
imidazo[1,2-a]pyridin-7-yl, or benzo [b]thiophen-2-yl, where said
fused heteroaryl is optionally substituted with 1 to 2 substituents
each independently selected from fluoro, chloro, methyl,
difluoromethyl, trifluoromethyl, cyclopropyl, or amino; or a
pharmaceutically acceptable salt thereof.
In one preferred embodiment, R.sup.53 is phenyl,
4-chloro-3-fluoro-phenyl, m-tolyl, 3-methoxy-phenyl,
3-chloro-4-fluoro-phenyl, 4-fluoro-3-methyl-phenyl,
3-trifluoromethyl-phenyl, 3-chloro-phenyl,
4-fluoro-3-trifluoromethyl-phenyl,
3-difluoromethyl-4-fluoro-phenyl, 3-cyano-4-fluorophenyl,
3-cyanophenyl, 3-chloro-4-cyanophenyl, 3,4-difluoro-phenyl,
4-trifluoromethyl-phenyl; or a pharmaceutically acceptable salt
thereof.
In another preferred embodiment, R.sup.53 is naphthalen-2-yl,
benzo[b]thiophen-5-yl, 3-methyl-benzo[d]isoxazol-5-yl,
1H-indazol-5-yl, 1-methyl-1H-indazol-5-yl, 3-amino-1H-indazol-5-yl,
1H-indazol-6-yl, 3-amino-1H-indazol-6-yl, 3-methyl-1H-indazol-6-yl,
3-trifluoromethyl-1H-indazol-6-yl, benzothiazol-6-yl,
1,2-dihydro-3-oxo-indazol-6-yl, indan-5-yl, 1H-benzotriazol-5-yl,
3-methyl-benzofuran-5-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yl,
2,3-dihydro-benzofuran-5-yl, or 2,2-difluoro-benzo[1,3]dioxol-5-yl;
or a pharmaceutically acceptable salt thereof. More preferably,
R.sup.53 is benzothiazol-6-yl, 3-methyl-benzofuran-5-yl,
1H-indazol-6-yl, 3-methyl-1H-indazol-6-yl, or
3-trifluoromethyl-1H-indazol-6-yl; or a pharmaceutically acceptable
salt thereof.
In yet another preferred embodiment, R.sup.53 is
5-methyl-thiophen-2-yl, 5-chloro-thiophen-2-yl,
5-trifluoromethyl-thiophen-2-yl, 5-difluoromethyl-thiophen-3-yl,
5-methyl-thiophen-3-yl, 2-methyl-pyridin-4-yl,
2-trifluoromethyl-pyridin-4-yl, 2-chloro-pyridin-4-yl, or
2-methoxy-pyridin-4-yl; or a pharmaceutically acceptable salt
thereof.
In yet another preferred embodiment, R.sup.53 is
4-chloro-thieno[3,2-c]pyridin-2-yl,
4-chloro-thieno[3,2-c]pyridin-3-yl, thieno[3,2-c]pyridin-2-yl,
3-chloro-imidazo[1,2-a]pyridin-7-yl, benzo[b]thiophen-2-yl, or
4-methylthieno[3,2-c]pyridin-2-yl; or a pharmaceutically acceptable
salt thereof.
In another embodiment of the compounds of Formula (I), (II), (Ia)
or (Ib), R.sup.54 is -CH.sub.3 or CF.sub.3.
Particular compounds include:
1-Benzothiazol-6-yl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one;
1-(2-Chloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one;
1-(4-Chloro-thieno[3,2-c]pyridin-2-yl)-3-(4-methyl-pyridin-3-yl)-imidazol-
idin-2-one;
1-(1H-Indazol-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one;
1-(3-Difluoromethyl-4-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-1,3-dihydr-
o-imidazol-2-one;
1-(4-Methyl-pyridin-3-yl)-3-(5-methyl-thiophen-3-yl)-1,3-dihydro-imidazol-
-2-one;
1-(3-Methyl-1H-indazol-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidi-
n-2-one;
1-Benzothiazol-6-yl-4-methyl-3-(4-methyl-pyridin-3-yl)-imidazolid-
in-2-one;
1-Benzo[b]thiophen-5-yl-3-(4-methyl-pyridin-3-yl)-1,3-dihydro-im-
idazol-2-one; and
1-Benzothiazol-6-yl-3-(4-methyl-pyridin-3-yl)-1,3-dihydro-imidazol-2-one;
or a pharmaceutically acceptable salt thereof.
Other compounds include those described in the Example section
below, in particular, those compounds having an IC.sub.50 less than
1 .mu.M (or 1,000 nM), preferably, less than 500 nM, more
preferably, less than 100 nM.
In another aspect of the present invention a pharmaceutical
composition is provided which comprises a compound of Formula (I),
(II), (Ia) or (Ib) or a pharmaceutically acceptable salt thereof
and a pharmaceutically acceptable carrier or excipient. The
pharmaceutical composition optionally comprises at least one
additional pharmaceutical agent (suitable pharmaceutical agents are
described herein below).
In yet another aspect of the present invention, a method of
treating a disease, disorder, or syndrome mediated by Cyp17
inhibition is provided, where the method comprises administering a
compound according to Formula (I), (II), (Ia) or (Ib), or a
pharmaceutical composition comprising the compound of Formula (I),
(II), (Ia) or (Ib) and pharmaceutically acceptable excipients, to a
subject in need thereof.
Another aspect of the present invention includes a compound
according to Formula (I), (II), (Ia) or (Ib) for use in therapy
(e.g., the use of a compound of Formula (Ia) or (Ib) for the
treatment of a disease, disorder, or syndrome mediated by Cyp17
inhibition).
Yet another aspect of the present invention includes a method for
treating a disease, disorder or syndrome mediated by Cyp17
inhibition comprising the step of administering
(i) a first composition comprising a compound of claim 1 through
21, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier or excipient; and
(ii) a second composition comprising at least one additional
pharmaceutical agent and a pharmaceutically acceptable carrier or
excipient;
wherein said at least one additional pharmaceutical agent is all
anticancer agent, chemotherapy agent, or antiproliferative
compound. The first and second compositions may be administered
either simultaneously or sequentially in any order.
In one particular embodiment for each of the methods and uses
described above, the disease, disorder, or syndrome is selected
from the group consisting of cancer (in particular, prostate
cancer) and inflammation.
DEFINITIONS
As used herein, the terms "alkyl" refers to a hydrocarbon radical
of the general formula C.sub.nH.sub.2n+1. The alkane radical may be
straight or branched. For example, the term
"(C.sub.1-C.sub.6)alkyl" refers to a monovalent, straight, or
branched aliphatic group containing 1 to 6 carbon atoms (e.g.,
methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl,
n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl,
3,3-dimethylpropyl, hexyl, 2-methylpentyl, and the like).
Similarly, the alkyl portion (i.e., alkyl moiety) of an alkoxy,
acyl (e.g., alkanoyl), alkylamino, dialkylamino, and alkylthio
group have the same definition as above.
"Halo-substituted alkyl" refers to an alkyl group, as defined
above, substituted with at least one halogen atom. For example,
when the halogen atom is fluoro, common haloalkyl groups include
fluoromethyl, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 2,2,2,1,1-pentafluoroethyl, and the like.
Mixed halogen substitution are also included (e.g.,
chlorofluoromethyl).
The term "alkenyl" refers to a monovalent group derived from a
hydrocarbon having at least one carbon-carbon double bond. The term
"C.sub.2-C.sub.6-alkenyl" refers to a monovalent group derived from
a hydrocarbon having two to six carbon atoms and comprising at
least one carbon-carbon double bond. The alkenyl group can be
unbranched or branched. Representative examples of alkenyl include
vinyl, 1-propenyl, 2-propenyl, 1-methyl-1-propenyl,
1-methyl-2-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl,
1-butenyl, 2-butenyl, 3-butenyl, and so on.
The term "alkynyl" refers to a monovalent group derived from a
hydrocarbon having at least one carbon-carbon triple bond. The term
"C.sub.2-C.sub.6-alkynyl" refers to a monovalent group derived from
a hydrocarbon having two to six carbon atoms and comprising at
least one carbon-carbon triple bond. The alkynyl group can be
unbranched or branched. Representative examples include ethynyl,
propynyl, butyn-1-yl, butyn-2-yl, and so on.
The term "hydroxy-substituted alkyl" refers to an alkyl group, as
defined above, substituted with one or more hydroxyl (-OH) groups
(e.g., -CH.sub.2OH, -CH(OH).sub.2, -CH(OH)-CH(OH, -CH(OH)-CH.sub.3,
and so on). Preferably, the alkyl group is substituted with 1 to 2
hydroxyl groups, more preferably one hydroxyl group.
"Halogen" or "halo" may be fluorine, chlorine, bromine or iodine
(preferred halogens as substituents are fluorine and chlorine).
The term "oxo" or -C(O)- refers to a carbonyl group. For example, a
ketone, aldehyde, or part of an acid, ester, amide, lactone, or
lactam group.
The terms "partially or fully saturated carbocyclic ring" (also
referred to as "partially or fully saturated cycloalkyl") refers to
nonaromatic rings that are either partially or fully hydrogenated
and may exist as a single ring, bicyclic ring or a spiral ring.
Unless specified otherwise, the carbocyclic ring is generally a 3-
to 8-membered ring. For example, partially or fully saturated
carbocyclic rings (or cycloalkyl) include groups such as
cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl,
cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl,
cyclohexadienyl, norbornyl (bicyclo[2.2.1]heptyl), norbornenyl,
bicyclo[2.2.2]octyl, and the like.
The term "partially saturated or fully saturated heterocyclic ring"
(also referred to as "partially saturated or fully saturated
heterocycle") refers to nonaromatic rings that are either partially
or fully hydrogenated and may exist as a single ring, bicyclic ring
or a spiral ring. Unless specified otherwise, the heterocyclic ring
is generally a 3- to 6-membered ring containing 1 to 3 heteroatoms
(preferably 1 or 2 heteroatoms) each independently selected from
sulfur, oxygen and/or nitrogen. Partially saturated or fully
saturated heterocyclic rings include groups such as epoxy,
aziridinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl,
pyrolidinyl, N-methylpyrrolidinyl, imidazolidinyl, imidazolinyl,
piperidinyl, piperazinyl, pyrazolidinyl, 2H-pyranyl, 4H-pyranyl,
2H-chromenyl, oxazinyl, morpholino, thiomorpholino,
tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, and the like.
Unless specified otherwise, the heterocyclic ring may be attached
via any ring member.
The term "fused phenyl" refers to a phenyl group fused to another
ring, such as another phenyl (i.e., naphthalene (e.g.,
naphthalen-2-yl, naphthalen-1-yl), a partially or fully saturated
cycloalkyl (e.g., indan-5-yl, 2,3-dihydro-1H-indenyl, or
tetrahydronaphthalenyl, etc.), a heteroaryl (e.g., 1H-indol-5-yl,
1H-indol-6-yl, benzothiazol-5-yl, benzothiazol-6-yl,
benzo[b]thiophen-5-yl, quinolin-6-yl, quinolin-7-yl,
isoquinolin-5-yl, isoquinolin-6-yl isoquinolin-7-yl,
isoquinolin-8-yl, indazol-4-yl, indazol-5-yl, indazol-6-yl,
indazol-7-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl,
benzofuran-7-yl, benzimidazol-4-yl, or quinoxalin-6-yl,
benzooxazol-5-yl, benzo[d]isoxazol-5-yl, benzo[d]isoxazol-6-yl,
1H-benzoimidazol-4-yl, 1H-benzoimidazol-5-yl,
1H-benzoimidazol-6-yl, 1H-benzoimidazol-7-yl, 1H-benzotriazol-5-yl,
etc.) or a partially saturated or fully saturated heterocycle
(e.g., indolin-4-yl, indolin-5-yl, indolin-6-yl, indolin-7-yl,
1,2-dihydroquinolin-6-yl, 1,2,3,4-tetrahydro-quinolin-6-yl,
1,2,3,4-tetrahydro-quinolin-7-yl,
2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-dihydro-1H-indazolyl,
2,3-dihydrobenzo[d]oxazolyl, 2,3-dihydrobenzo[1,4]dioxin-6-yl,
2,3-dihydro-benzofuran-5-yl, benzo[1,3]dioxol-5-yl,
2,3-dihydro-1H-indazol-5-yl, 2,3-dihydro-1H-indazol-6-yl, etc.),
where the group is attached via one of the phenyl carbon atoms.
When substituted, the fused phenyl can be substituted on any of the
atoms within the fused system. For example, a benzofuranyl group
may be substituted on the phenyl or furanyl portion of the
benzofuranyl group.
The term "heteroaryl" or "heteroaromatic ring" refers to aromatic
moieties containing at least one heteratom (e.g., oxygen, sulfur,
nitrogen or combinations thereof) within a 5- to 6-membered
aromatic ring system (e.g., pyrrolyl, pyridyl, pyrazolyl, thienyl,
furanyl, oxazolyl, imidazolyl, tetrazolyl, triazinyl, pyrimidyl,
pyrazinyl, thiazolyl, isothiazolyl, etc.). A typical single
heteroaryl ring is generally a 5- to 6-membered ring containing one
to three heteroatoms each independently selected from oxygen,
sulfur and nitrogen.
The term "fused heteroaryl" refers to a heteroaryl group fused to
another ring, such as another heteroaryl (e.g. purinyl,
thieno[3,2-c]pyridinyl (e.g., thieno[3,2-c]pyridin-2-yl and
thieno[3,2-c]pyridin-3-yl), imidazo[1,2-a]pyridinyl (e.g.,
imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-6-yl,
imidazo[1,2-a]pyridin-7-yl and 3H-imidazo[4,5-b]pyridin-6-yl), or
benzo[b]thiophenyl, etc.), phenyl (e.g., benzo[b]thiophen-2-yl,
benzo[b]thiophen-3-yl, quinolin-2-yl, quinolin-3-yl,
benzooxazol-2-yl, benzothiazol-2-yl, 1H-indol-2-yl, 1H-indol-3-yl,
isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl,
benzofuran-2-yl, benzofuran-3-yl, indazol-3-yl, benzimidazol-2-yl,
etc.), a partially or fully saturated cycloalkyl (e.g.,
4,5,6,7-tetrahydrobenzo[d]oxazolyl, 4,5,6,7-tetrahydro-1H-indolyl,
5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl,
4,5,6,7-tetrahydrobenzo[b]thiophenyl,
4,5,6,7-tetrahydrobenzofuranyl, 4,5,6,7-tetrahydro-1H-indazolyl,
4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, or
4,5,6,7-tetrahydrobenzo[d]oxazolyl, etc.), or a partially saturated
or fully saturated heterocycle (e.g., 8,9-dihydro-7H-purinyl,
2,3-dihydrothieno[3,2-c]pyridinyl,
4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl,
4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl, or
5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl, etc.), where the
heteroaryl group is attached via one of the heteroaryl ring atoms.
When substituted, the fused heteroaryl can be substituted on any of
the atoms within the fused system. For example, an
imidazo[1,2-a]pyridinyl group may be substituted on the imidazole
or pyridine portion of the fused system.
The phrase "therapeutically effective amount" means an amount of a
compound of the present invention that (i) treats or prevents the
particular disease, condition, or disorder, (ii) attenuates,
ameliorates, or eliminates one or more symptoms of the particular
disease, condition, or disorder, or (iii) prevents or delays the
onset of one or more symptoms of the particular disease, condition,
or disorder described herein. The term "animal" refers to humans
(male or female), companion animals (e.g., dogs, cats and horses),
zoo animals, marine animals, birds and other similar animal
species.
The phrase "pharmaceutically acceptable" indicates that the
substance or composition must be compatible chemically and/or
toxicologically, with the other ingredients comprising a
formulation, and/or the mammal being treated therewith.
The terms "treating", "treat", or "treatment" embrace both
preventative, i.e., prophylactic, and palliative treatment.
The term "compounds of the present invention" (unless specifically
identified otherwise) refer to compounds of Formula (I), (II), (Ia)
and (Ib), prodrugs thereof, pharmaceutically acceptable salts of
the compounds, and/or prodrugs, and hydrates or solvates of the
compounds, salts, and/or prodrugs, as well as, all stereoisomers
(including diastereoisomers and enantiomers), tautomers and
isotopically labeled compounds.
DETAILED DESCRIPTION
The present invention provides compounds and pharmaceutical
formulations thereof that are useful in the treatment of diseases,
conditions and/or disorders modulated by the inhibition of
17.alpha.-hydroxylase/C.sub.17,20-lyase.
Compounds of the present invention may be synthesized by synthetic
routes that include processes analogous to those well-known in the
chemical arts, particularly in light of the description contained
herein. The starting materials are generally available from
commercial sources such as Aldrich Chemicals (Milwaukee, Wis.) or
are readily prepared using methods well known to those skilled in
the art (e.g., prepared by methods generally described in Louis F.
Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19,
Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der
organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including
supplements (also available via the Beilstein online
database)).
For illustrative purposes, the reaction schemes depicted below
provide potential routes for synthesizing the compounds of the
present invention as well as key intermediates. For a more detailed
description of the individual reaction steps, see the Examples
section below. Those skilled in the art will appreciate that other
synthetic routes may be used to synthesize the inventive compounds.
Although specific starting materials and reagents are depicted in
the schemes and discussed below, other starting materials and
reagents can be easily substituted to provide a variety of
derivatives and/or reaction conditions. In addition, many of the
compounds prepared by the methods described below can be further
modified in light of this disclosure using conventional chemistry
well known to those skilled in the art.
The schemes detailed below show general schemes for synthesizing
compounds of the present invention (e.g., compounds of Formula (I),
(II), (Ia) and (Ib)).
General Schemes
##STR00005## In Scheme I above, R is represented by -A or the
following group
##STR00006## Step-1 & 2:
The intermediate products of Steps 1 and 2 may be synthesized using
methods analogous to those described by Kak-Shan Shia, et al., in
J. Med. Chem., 2002, 45, 1644-1655 using the desired starting
materials which are available commercially or synthesized using
known procedures described in the art. For example, a variety of
2-chloroalkyl isocyanates can be prepared using the methods
described by C K Johnson in J Org Chem (1967), 32(5), 1508-10. The
reaction times in certain cases were prolonged to increase the %
yield as compared to reported yields in the above mentioned J Med
Chem reference.
Step-3:
The products of Step-2 obtained as described above may be converted
into the desired products by reacting with the appropriate alkyl or
aryl halides preferably chloro/bromo alkyl or an derivatives using
conditions well know to those of skill in the art, e.g., the
Buchwald-Hartwig C-N coupling conditions or NaH/DMF, and the like.
Preferred conditions are those known as the `Buchwald-Hartwig"
reaction, e.g., in the presence of (a) a catalyst, such as copper
iodide, (b) a base, such as potassium phosphate or cesium
carbonate; and (c) a ligand, such as trans-1,2-diamino cyclohexane,
in the presence of suitable solvents (e.g., 1,4-dioxane) at
temperatures ranging from about room temperature to the refluxing
temperature of the solvent. When p is zero, a compound of Formula
(Ia-1) may also form. When a protection group is used, then the
protecting group is removed using the conditions appropriate for
the particular protecting group used to produce compounds of the
present invention. For a more detailed description, see Examples 1
and 14 in the Example section below.
Alternatively, the substituents R.sup.53 and R may be introduced in
the reverse. For example, instead of starting with R-NH.sub.2,
R.sup.53-NH.sub.2 is used as the starting material. The R group is
then introduced in step 3 by using R-X instead of R.sup.53-X. See,
e.g., Example 79 in the Example section below for a more detailed
description.
Scheme 2 describes how one could make the starting material (SM-1)
above where R.sup.54 is other than hydrogen.
##STR00007##
The desired chloro carboxylic acid is first converted to its
corresponding acid chloride derivative using procedures well-known
to those of skill in the art. For example, the carboxylic acid
derivative may be treated with thionyl chloride in the presence of
dimethylformamide (DMF) and a solvent (e.g., dichloromethane
(DCM)). Other chlorinating agents may be used, e.g., phosphorous
trichloride or phosphorous pentachloride. The acid chloride can
then be converted to its corresponding azide by treatment with
sodium azide. The azide is then converted to the desired isocyanate
(SM-1) by the Curtius rearrangement, e.g., heating the azide at
elevated temperatures.
Scheme 3 describes a synthesis for compounds of the present
invention having an 1H-imidazol-2(3H)-one core (compounds of
Formula (I) or (Ia).
##STR00008## In Scheme 3 above, R is represented by -A or the
following moiety
##STR00009## Step 1:
In Step-1, certain aromatic or heteroaromatic amines (in
particular, 6-benzothiazolyl amine, 5-benzo[b]thiophenyl amine,
2-difluoromethyl-1-fluoro-phen-4-yl amine, 2-methyl-thiophene-4-yl
amine, and the like) can undergo coupling with
2,2-dimethoxy-ethylamine via an isocyanate intermediate using
reagents such as triphosgene, triethylamine (TEA) and suitable
solvents (e.g., THF) to provide the corresponding 1-substituted
3-(2,2-dimethoxy-ethyl)-urea intermediate compounds.
Step 2:
In Step 2,1-substituted-1H-imidazol-2(3H)-one intermediates can be
prepared by methods analagous to those known in art, such as the
procedures described by T. Hafner, et al., in Synthesis (2007) 9,
1403-1411.
Step 3:
The products of Step 2 obtained as described above may be converted
into the desired products by reacting with the desired aryl halides
preferably iodo or bromo aryl derivatives using conditions such as
the Buchwald-Hartwig C-N coupling conditions as described in Scheme
1 above. Alternatively, the product may be prepared via a
copper-catalyzed N-arylation of the
1-substituted-1H-imidazol-2(3H)-one intermediate with conventional
heating (e.g., R.sup.53-X, (CuOTf).sub.2-C.sub.6H.sub.6,
Cu:ligand:dibenzylideneacetone(dba)=1:5:1, in dioxane at about
150.degree. C.). See, Hafner, et al., Synthesis (2007) 9,
1403-1411. For a more detailed description, see Examples 142 in the
Example section below.
Scheme 4 provides an alternative synthesis for preparing compounds
of Formula (II) or (Ib).
##STR00010##
The desired R.sup.53 group may be attached to the desired amino
carboxylate compound via Buchwald-Hartwig C-N coupling conditions
or NaH/DMF, and the like.
The cyclic urea is then formed using methods analogous to those
described by Kak-Shan Shia, et al., in J. Med. Chem., 2002, 45,
1644-1655. The pyridine derivative may then be coupled to the
imidazoline via a Buchwald-Hartwig C-N coupling reaction described
previously.
Alternatively, the unsymmetrical
disubstituted-1H-imidazolin-2(31-1)-ones can be prepared by other
methods discussed by T. Hafner, et al., in Synthesis (2007) 9,
1403-1411 (e.g., Brazier, S. A, et al., J Chem. Soc. (1912), 101,
2352 and Schonherr, H. J., et al, Chem Ber (1970), 103, 1037).
Scheme 5 provides another alternative synthesis for preparing
compounds of Formula (II) or (Ib).
##STR00011##
In Scheme 5 above, R is represented by -A or the following
group
##STR00012##
Intermediate (I-5a) may be formed via a Michael addition of the
desired amine (R.sup.53-NH.sub.2) to the desired acrylic acid using
procedures well-known to those of skill in the art. For example,
the amine and acrylic acid in a suitable solvent (e.g., toluene)
are heated at an elevated temperature (e.g., about 70.degree. C. to
about 100.degree. C.) under an inert atmosphere. The amino acid
intermediate (I-5a) may then be cyclized to form the cyclic urea
intermediate (I-5b). For example, the cyclic urea intermediate
(I-5b) may be formed by treating the amino acid intermediate (I-5a)
with an activating agent (e.g., diphenyl phosphoryl azide (DPPA))
in the presence of an amine (e.g., triethylamine) and
appropropriate solvent (e.g., toluene) at elevated temperatures.
The desired A group may be coupled to the cyclic urea intermediate
(I-5b) using standard coupling conditions described above to form
the a compound of the Formula (II) or (Ib).
The Example section below provides a more detailed description of
the synthetic schemes as well as other alternative processes for
making compounds of the present invention which could be easily
modified (e.g., substituting different starting materials) by those
of skill in the art.
The compounds and intermediates described herein may be isolated
and used as the compound per se or its salt. Many of the compounds
represented by Formula (I), (II), (Ia), and (Ib) are capable of
forming acid addition salts, particularly pharmaceutically
acceptable acid addition salts. Pharmaceutically acceptable acid
addition salts of the compound of Formula (I), (II), (Ia) and (Ib)
include those of inorganic acids, for example, hydrohalic acids
such as hydrochloric acid, hydrobromic acid or hydroiodic acid,
nitric acid, sulfuric acid, phosphoric acid; and organic acids, for
example aliphatic monocarboxylic acids such as formic acid, acetic
acid, propionic acid and butyric acid, aliphatic hydroxy acids such
as lactic acid, citric acid, tartaric acid or malic acid,
dicarboxylic acids such as maleic acid or succinic acid, aromatic
carboxylic acids such as benzoic acid, p-chlorobenzoic acid,
diphenylacetic acid or triphenylacetic acid, aromatic hydroxy acids
such as o-hydroxybenzoic acid, p-hydroxybenzoic acid,
1-hydroxynaphthalene-2-carboxylic acid or
3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such as
methanesulfonic acid or benzenesulfonic acid. These salts may be
prepared from compounds of Formula (I), (II), (Ia) or (Ib) by known
salt-forming procedures.
Compounds of the present invention which contain acidic, e.g.
carboxyl, groups, are also capable of forming salts with bases, in
particular pharmaceutically acceptable bases such as those well
known in the art; suitable such salts include metal salts,
particularly alkali metal or alkaline earth metal salts such as
sodium, potassium, magnesium or calcium salts, or salts with
ammonia or pharmaceutically acceptable organic amines or
heterocyclic bases such as ethanolamines, benzylamines or pyridine.
These salts may be prepared from compounds of Formula (I), (II),
(Ia) and (Ib) by known salt-forming procedures.
In those compounds where there is an asymmetric carbon atom the
compounds exist in individual optically active isomeric forms or as
mixtures thereof, e.g. as racemic or diastereomeric mixtures. The
present invention embraces both individual optically active R and S
isomers as well as mixtures, e.g. racemic or diastereomeric
mixtures, thereof.
The present invention includes all pharmaceutically acceptable
isotopically-labeled compounds of the present invention wherein one
or more atoms are replaced by atoms having the same atomic number,
but an atomic mass or mass number different from the atomic mass or
mass number usually found in nature.
Examples of isotopes suitable for inclusion in the compounds of the
invention comprises isotopes of hydrogen, such as .sup.2H and
.sup.3H, carbon, such as .sup.11C, .sup.13C and .sup.14C, chlorine,
such as .sup.36Cl fluorine, such as .sup.18F, iodine, such as
.sup.123I and .sup.125I, nitrogen, such as .sup.13N and .sup.15N,
oxygen, such as .sup.15O, .sup.17O and .sup.18O, phosphorus, such
as .sup.32P, and sulphur, such as .sup.35S.
Substitution with heavier isotopes such as deuterium, i.e. .sup.2H,
may afford certain therapeutic advantages resulting from greater
metabolic stability, for example, increased in vivo half-life or
reduced dosage requirements, and hence may be preferred in some
circumstances.
Isotopically-labeled compounds of the present invention can
generally be prepared by conventional techniques known to those
skilled in the art or by processes analogous to those described in
the accompanying Examples and Preparations Sections using an
appropriate isotopically-labeled reagent in place of the
non-labeled reagent previously employed.
The compounds of the present invention may exist in unsolvated as
well as solvated forms with pharmaceutically acceptable solvents
such as water, ethanol, and the like, and it is intended that the
invention embrace both solvated and unsolvated forms. For purposes
of the present invention, solvates (including hydrates) are
considered pharmaceutical compositions, e.g., a compound of Formula
(I), (II), (Ia) or (Ib) (or pharmaceutically acceptable salt
thereof) in combination with all excipient, wherein the excipient
is a solvent.
Compounds of the present invention are useful for treating
diseases, conditions and disorders mediated by the regulation of
17.alpha.-hydroxylase/C.sub.17,20-lyase (e.g., cancer (in
particular, prostate cancer) or inflammation); consequently, the
compounds of the present invention (including the compositions and
processes used therein) may be used in the manufacture of a
medicament for the therapeutic applications described herein.
Hence, another embodiment of the present invention is a
pharmaceutical composition comprising a therapeutically effective
amount of a compound of the present invention and a
pharmaceutically acceptable excipient, diluent or carrier.
A typical formulation is prepared by mixing a compound of the
present invention and a carrier, diluent or excipient. Suitable
carriers, diluents and excipients are well known to those skilled
in the art and include materials such as carbohydrates, waxes,
water soluble and/or swellable polymers, hydrophilic or hydrophobic
materials, gelatin, oils, solvents, water, and the like. The
particular carrier, diluent or excipient used will depend upon the
means and purpose for which the compound of the present invention
is being applied. Solvents are generally selected based on solvents
recognized by persons skilled in the art as safe (GRAS) to be
administered to a mammal. In general, safe solvents are non-toxic
aqueous solvents such as water and other non-toxic solvents that
are soluble or miscible in water. Suitable aqueous solvents include
water, ethanol, propylene glycol, polyethylene glycols (e.g.,
PEG400, PEG300), etc. and mixtures thereof. The formulations may
also include one or more buffers, stabilizing agents, surfactants,
wetting agents, lubricating agents, emulsifiers, suspending agents,
preservatives, antioxidants, opaquing agents, glidants, processing
aids, colorants, sweeteners, perfuming agents, flavoring agents and
other known additives to provide an elegant presentation of the
drug (i.e., a compound of the present invention or pharmaceutical
composition thereof) or aid in the manufacturing of the
pharmaceutical product (i.e., medicament).
The formulations may be prepared using conventional dissolution and
mixing procedures. For example, the bulk drug substance (i.e.,
compound of the present invention or stabilized form of the
compound (e.g., complex with a cyclodextrin derivative or other
known complexation agent)) is dissolved in a suitable solvent in
the presence of one or more of the excipients. The compound of the
present invention is typically formulated into pharmaceutical
dosage forms to provide an easily controllable dosage of the drug
and to give the patient an elegant and easily handleable
product.
The pharmaceutical composition (or formulation) for application may
be packaged in a variety of ways depending upon the method used for
administering the drug. Generally, an article for distribution
includes a container having deposited therein the pharmaceutical
formulation in an appropriate form. Suitable containers are
well-known to those skilled in the art and include materials such
as bottles (plastic and glass), sachets, ampoules, plastic bags,
metal cylinders, and the like. The container may also include a
tamper-proof assemblage to prevent indiscreet access to the
contents of the package. In addition, the container has deposited
thereon a label that describes the contents of the container. The
label may also include appropriate warnings.
A Cyp17 inhibitor of the present invention may be usefully combined
with at least one additional pharmacologically active compound,
particularly in the treatment of cancer. For example, a compound of
the present invention, as defined above, may be administered
simultaneously, sequentially or separately in combination with one
or more agents selected from chemotherapy agents, e.g. mitotic
inhibitors such as a taxane (e.g., paclitaxel or docetaxel), a
vinca alkaloid (e.g., vincristine, vinblastine, vinorelbine or
vinflunine) or other anticancer agents, e.g. cisplatin,
5-fluorouracil or 5-fluoro-2-4(1H,3H)-pyrimidinedione (5FU),
flutamide or gemcitabine. Such combinations may offer significant
advantages, including synergistic activity, in therapy.
A compound of the present invention may also be used in combination
with other antiproliferative compounds. Such antiproliferative
compounds include, but are not limited to aromatase inhibitors;
antiestrogens; topoisomerase I inhibitors; topoisomerase II
inhibitors; microtubule active compounds; alkylating compounds;
compounds which induce cell differentiation processes;
cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors;
antineoplastic antimetabolites; platin compounds; compounds
targeting/decreasing a protein or lipid kinase activity and further
anti-angiogenic compounds; compounds which target, decrease or
inhibit the activity of a protein or lipid phosphatase; gonadorelin
agonists; anti-androgens; methionine aminopeptidase inhibitors;
bisphosphonates; biological response modifiers; antiproliferative
antibodies; heparanase inhibitors; inhibitors of Ras oncogenic
isoforms; telomerase inhibitors; proteasome inhibitors; compounds
used in the treatment of hematologic malignancies; compounds which
target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors
such as 17-AAG (17-allylamino-gelda-namycin, NSC330507), 17-DMAG
(17-dimethylaminoethylamino-17-demethoxy-geldana-mycin, NSC707545),
IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics;
temozolomide (TEMODAL); kinesin spindle protein inhibitors, such as
SB715992 or SB743921 from GlaxoSmithKline, or
pentamidine/chlorpromazine from CombinatoRx; PI3K inhibitors; RAF
inhibitors; EDG binders, antileukemia compounds, ribonucleotide
reductase inhibitors, S-adenosylmethionine decarboxylase
inhibitors, antiproliferative anti-bodies or other chemotherapeutic
compounds. Further, alternatively or in addition they may be used
in combination with other tumor treatment approaches, including
surgery, ionizing radiation, photodynamic therapy, implants, e.g.
with corticosteroids, hormones, or they may be used as
radiosensitizers. Also, in anti-inflammatory and/or
antiproliferative treatment, combination with anti-inflammatory
drugs is included. Combination is also possible with antihistamine
drug substances, bronchodilatatory drugs, NSAID or antagonists of
chemokine receptors.
The term "aromatase inhibitor" as used herein relates to a compound
which inhibits the estrogen production, i.e. the conversion of the
substrates androstenedione and testosterone to estrone and
estradiol, respectively. The term includes, but is not limited to
steroids, especially atame-stane, exemestane and formestane and, in
paricular, non-steroids, especially aminoglutethimide,
roglethimide, pyridoglutethimide, trilostane, testolactone,
ketokonazole, vorozole, fadrozole, anastrozole and letrozole.
Exemestane can be administered, e.g., in the form as it is
marketed, e.g. under the trademark AROMASIN. Formestane can be
administered, e.g., in the form as it is marketed, e.g. under the
trademark LENTARON. Fadrozole can be administered, e.g., in the
form as it is marketed, e.g. un-der the trademarkAFEMA. Anastrozole
can be administered, e.g., in the form as it is marketed, e.g.
under the trademark ARIMIDEX. Letrozole can be administered, e.g.,
in the form as it is marketed, e.g. under the trademark FEMARA or
FEMAR. Amino glutethimide can be administered, e.g., in the form as
it is marketed, e.g. under the trademark, ORIMETEN. A combination
of the invention comprising a chemo-therapeutic agent which is an
aromatase inhibitor is particularly useful for the treatment of
hormone receptor positive tumors, e.g., breast tumors.
The term "anti-estrogen" as used herein relates to a compound which
antagonizes the effect of estrogens at the estrogen receptor level.
The term includes, but is not limited to tamoxifen, fulvestrant,
raloxifene and raloxifene hydrochloride. Tamoxifen can be
administered, e.g., in the form as it is marketed, e.g. under the
trademark NOLVADEX. Raloxifene hydrochloride can be administered,
e.g., in the form as it is marketed, e.g. under the trademark
EVISTA. Fulvestrant can be formulated as disclosed in U.S. Pat. No.
4,659,516 or it can be administered, e.g., in the form as it is
marketed, e.g. under the trademark FASLODEX. A combination of the
invention comprising a chemotherapeutic agent which is an
anti-estrogen is particularly useful for the treatment of estrogen
receptor positive tumors, e.g. breast tumors.
The term "anti-androgen" as used herein relates to any substance
which is capable of inhibiting the biological effects of androgenic
hormones and includes, but is not limited to, bicalutamide
(CASODEX), which can be formulated, e.g. as disclosed in U.S. Pat.
No. 4,636,505.
The term "gonadorelin agonist" as used herein includes, but is not
limited to abarelix, goserelin and goserelin acetate. Goserelin is
disclosed in U.S. Pat. No. 4,100,274 and can be administered. e.g.,
in the form as it is marketed, e.g. under the trademark ZOLADEX.
Abarelix can be formulated, e.g. as disclosed in U.S. Pat. No.
5,843,901.
The term "topoisomerase I inhibitor" as used herein includes, but
is not limited to topotecan, gimatecan, irinotecan, camptothecin
and its analogues, 9-nitrocamptothecin and the macromolecular
camptothecin conjugate PNU-166148 (compound Al in WO99/17804).
Irinotecan can be administered, e.g. in the form as it is marketed,
e.g. under the trademark CAMPTOSAR. Topotecan can be administered,
e.g., in the form as it is marketed, e.g. under the trademark
HYCAMTIN.
The term "topoisomerase II inhibitor" as used herein includes, but
is not limited to the anthracyclines such as doxorubicin (including
liposomal formulation, e.g. CAELYX), daunorubicin, epirubicin,
idarubicin and nemorubicin, the anthraquinones mitoxantrone and
losoxantrone, and the podophillotoxines etoposide and teniposide.
Etoposide can be administered, e.g. in the form as it is marketed,
e.g. under the trademark ETOPOPHOS. Teniposide can be administered,
e.g. in the form as it is marketed, e.g. under the trademark VM
26-BRISTOL. Doxorubicin can be administered, e.g. in the form as it
is marketed, e.g. under the trademark ADRIBLASTIN or ADRIAMYCIN.
Epirubicin can be administered, e.g. in the form as it is marketed,
e.g. under the trademark FARMORUBICIN. Idarubicin can be
administered, e.g. in the form as it is marketed, e.g. under the
trademark ZAVEDOS. Mitoxantrone can be administered, e.g. in the
form as it is marketed, e.g. under the trademark NOVANTRON.
The term "microtubule active compound" relates to microtubule
stabilizing, microtubule destabilizing compounds and microtublin
polymerization inhibitors including, but not limited to taxanes,
e.g. paclitaxel and docetaxel, vinca alkaloids, e.g., vinblastine,
especially vinblastine sulfate, vincristine especially vincristine
sulfate, and vinorelbine, discodermolides, cochicine and
epothilones and derivatives thereof, e.g. epothilone B or D or
derivatives thereof. Paclitaxel may be administered e.g. in the
form as it is marketed, e.g. TAXOL. Docetaxel can be administered,
e.g., in the form as it is marketed, e.g. under the trademark
TAXOTERE. Vinblastine sulfate can be administered, e.g., in the
form as it is marketed, e.g. under the trademark VINBLASTIN R.P.
Vincristine sulfate can be administered, e.g., in the form as it is
marketed, e.g. under the trademark FARMISTIN. Discodermolide can be
obtained, e.g., as disclosed in U.S. Pat. No. 5,010,099. Also
included are Epothilone derivatives which are disclosed in WO
98/10121, U.S. Pat. No. 6,194,181, WO 98/25929, WO 98/08849, WO
99/43653, WO 98/22461 and WO 00/31247. Especially preferred are
Epothilone A and/or B.
The term "alkylating compound" as used herein includes, but is not
limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea
(BCNU or Gliadel). Cyclophosphamide can be administered, e.g., in
the form as it is marketed, e.g. under the trademark CYCLOSTIN.
Ifosfamide can be administered, e.g., in the form as it is
marketed, e.g., under the trademark HOLOXAN.
The term "antineoplastic antimetabolite" includes, but is not
limited to, 5-Fluorouracil or 5-FU, capecitabine, gemcitabine, DNA
demethylating compounds, such as 5-azacy-tidine and decitabine,
methotrexate and edatrexate, and folic acid antagonists such as
pemetrexed. Capecitabine can be administe-red, e.g., in the form as
it is marketed, e.g. under the trademark XELODA. Gemcitabine can be
administered, e.g., in the form as it is marketed, e.g. under the
trademark GEMZAR. The term "platin compound" as used herein
includes, but is not limited to, carboplatin, cis-platin,
cisplatinum and oxaliplatin. Carboplatin can be administered, e.g.,
in the form as it is marketed, e.g. under the trademark CARBOPLAT.
Oxaliplatin can be administered, e.g., in the form as it is
marketed, e.g. under the trademark ELOXATIN.
The term "compounds targeting/decreasing a protein or lipid kinase
activity"; or a "protein or lipid phosphatase activity"; or
"further anti-angiogenic compounds" as used herein includes, but is
not limited to, protein tyrosine kinase and/or serine and/or
threonine kinase inhibitors or lipid kinase inhibitors, e.g., a)
compounds targeting, decreasing or inhibiting the activity of the
platelet-derived growth factor-receptors (PDGFR), such as compounds
which target, decrease or inhibit the activity of PDGFR, especially
compounds which inhibit the PDGF receptor, e.g. a
N-phenyl-2-pyrimidine-amine derivative, e.g. imatinib, SU101,
SU6668 and GFB-111; b) compounds targeting, decreasing or
inhibiting the activity of the fibroblast growth factor-receptors
(FGFR); c) compounds targeting, decreasing or inhibiting the
activity of the insulin-like growth factor receptor I (IGF-IR),
such as compounds which target, decrease or inhibit the activity of
IGF-IR, especially compounds which inhibit the kinase activity of
IGF-I receptor, such as those compounds disclosed in WO 02/092599,
or antibodies that target the extracellular domain of IGF-I
receptor or its growth factors; d) compounds targeting, decreasing
or inhibiting the activity of the Trk receptor tyrosine kinase
family, or ephrin B4 inhibitors; e) compounds targeting, decreasing
or inhibiting the activity of the Axl receptor tyrosine kinase
family; f) compounds targeting, decreasing or inhibiting the
activity of the Ret receptor tyrosine kinase; g) compounds
targeting, decreasing or inhibiting the activity of the Kit/SCFR
receptor tyrosine kinase, i.e C-kit receptor tyrosine kinases-(part
of the PDGFR family), such as compounds which target, decrease or
inhibit the activity of the c-Kit receptor tyrosine kinase family,
especially compounds which inhibit the c-Kit receptor, e.g.
imatinib; h) compounds targeting, decreasing or inhibiting the
activity of members of the c-Abl family, their gene-fusion products
(e.g. BCR-Abl kinase) and mutants, such as com-pounds which target
decrease or inhibit the activity of c-AbI family members and their
gene fusion products, e.g. a N-phenyl-2-pyrimidine-amine
derivative, e.g. imatinib or nilotinib (AMN.sub.107); PD180970;
AG957; NSC 680410: PD173955 from ParkeDavis; or dasatinib
(BMS-354825); i) compounds targeting, decreasing or inhibiting the
activity of members of the protein kinase C (PKC) and Raf family of
serine/threonine kinases, members of the MEK, SRC, JAK, FAK, PDK1,
PKB/Akt, and Ras/MAPK family members, and/or members of the
cyclin-dependent kinase family (CDK) and are especially those
staurosporine derivatives disclosed in U.S. Pat. No. 5,093,330,
e.g. midostaurin; examples of further compounds include e.g.
UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine;
Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521;
LY333531/LY379196; isochinoline compounds such as those disclosed
in WO 00/09495; FTIs; BEZ235 (a PI3K inhibitor) or AT7519 (CDK
inhibitor); j) compounds targeting, decreasing or inhibiting the
activity of protein-tyrosine kinase inhibitors, such as compounds
which target, decrease or inhibit the activity of protein-tyrosine
kinase inhibitors include imatinib mesylate (GLEEVEC) or
tyrphostin. A tyrphostin is preferably a low molecular weight
(mw<1500) compound, or a pharmaceutically acceptable salt
thereof, especially a compound selected from the
benzylidenemalonitrile class or the S-arylbenzenemalonirile or
bisubstrate quinoline class of compounds, more especially any
compound selected from the group consisting of Tyrphostin
A23/RG-50810; AG 99; Tyrphostin AG 213: Tyrphostin AG 1748;
Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer;
Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin
(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl
ester; NSC 680410, adaphostin); k) compounds targeting, decreasing
or inhibiting the activity of the epidermal growth factor family of
receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- or
heterodimers) and their mutants, such as compounds which target,
decrease or inhibit the activity of the epidermal growth factor
receptor family are especially compounds, proteins or antibodies
which inhibit members of the EGF receptor tyrosine kinase family,
e.g. EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF
related ligands, and are in particular those compounds, proteins or
monoclonal antibodies generically and specifically disclosed in WO
97/02266, e.g. the compound of ex. 39, or in EP 0 564 409, WO
99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063,
U.S. Pat. No. 5,747,498, WO 98/10767, WO 97/30034, WO 97/49688, WO
97/38983 and, especially, WO 96/30347 (e.g. compound known as CP
358774), WO 96/33980 (e.g. compound ZD 1839) and WO 95/03283 (e.g.
compound ZM105180); e.g. trastuzumab (Herceptin), cetuximab
(Erbitux), Iressa, Tarceva, OSI-774, CI-1033, EKB-569, OW-2016,
E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and
7H-pyrrolo-[2,3-d]pyrimidine derivatives which are disclosed in WO
03/013541; and 1) compounds targeting, decreasing or inhibiting the
activity of the c-Met receptor, such as compounds which target,
decrease or inhibit the activity of c-Met, especially compounds
which inhibit the kinase activity of c-Met receptor, or antibodies
that target the extra-cellular domain of c-Met or bind to HGF.
Further anti-angiogenic compounds include compounds having another
mechanism for their activity, e.g. unrelated to protein or lipid
kinase inhibition e.g. thalidomide (THALOMID) and TNP-470.
Compounds which target, decrease or inhibit the activity of a
protein or lipid phosphatase are e.g., inhibitors of phosphatase 1,
phosphatase 2A, or CDC25, e.g. okadaic acid or a derivative
thereof.
Compounds which induce cell differentiation processes are e.g.
retinoic acid, or tocopherol or tocotrienol.
The term cyclooxygenase inhibitor as used herein includes, but is
not limited to, e.g. Cox-2 inhibitors, 5-alkyl substituted
2-arylaminophenylacetic acid and derivatives, such as celecoxib
(CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a
5-alkyl-2-arylaminophenylacetic acid, e.g.
5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid,
lumiracoxib.
The term "bisphosphonates" as used herein includes, but is not
limited to, etridonic, clodronic, tiludronic, pamidronic,
alendronic, ibandronic, risedronic and zoledronic acid. "Etridonic
acid" can be administered, e.g., in the form as it is marketed,
e.g. under the trademark DIDRONEL. "Clodronic acid" can be
administered, e.g., in the form as it is marketed, e.g. under the
trademark BONEFOS. "Tiludronic acid" can be administered, e.g., in
the form as it is marketed, e.g. under the trademark SKELID.
"Pamidronic acid" can be administered, e.g. in the form as it is
marketed, e.g. under the trademark AREDIA. "Alendronic acid" can be
administered, e.g., in the form as it is marketed, e.g. under the
trademark FOSAMAX. "Ibandronic acid" can be administered, e.g., in
the form as it is marketed, e.g. under the trademark BONDRANAT.
"Risedronic acid" can be administered, e.g., in the form as it is
marketed, e.g. under the trademark ACTONEL. "Zoledronic acid" can
be administered, e.g. in the form as it is marketed, e.g. under the
trademark ZOMETA.
The term "mTOR inhibitors" relates to compounds which inhibit the
mammalian target of rapamycin (mTOR) and which possess
antiproliferative activity such as sirolimus (Rapamune), everolimus
(CerticanO), CCI-779 and ABT578.
The term "heparanase inhibitor" as used herein refers to compounds
which target, decrease or inhibit heparin sulfate degradation. The
term includes, but is not limited to, PI-88.
The term "biological response modifier" as used herein refers to a
lymphokine or interferons, e.g. interferon.
The term "inhibitor of Ras oncogenic isoforms", e.g. H-Ras, K-Ras,
or N-Ras, as used herein refers to compounds which target, decrease
or inhibit the oncogenic activity of Ras e.g. a "farnesyl
transferase inhibitor" e.g. L-744832, DK8G557 or R115777
(Zarnestra).
The term "telomerase inhibitor" as used herein refers to compounds
which target, decrease or inhibit the activity of telomerase.
Compounds which target, decrease or inhibit the activity of
telomerase are especially compounds which inhibit the telomerase
receptor, e.g. telomestatin.
The term "methionine aminopeptidase inhibitor" as used herein
refers to compounds which target, decrease or inhibit the activity
of methionine aminopeptidase. Compounds which target, decrease or
inhibit the activity of methionine aminopeptidase are e.g.
bengamide or a derivative thereof.
The term "proteasome inhibitor" as used herein refers to compounds
which target, decrease or inhibit the activity of the proteasome.
Compounds which target, decrease or inhibit the activity of the
proteasome include e.g. Bortezomid (Velcade) and MLN 341. The term
"matrix metalloproteinase inhibitor" or ("MMP" inhibitor) as used
herein includes, but is not limited to, collagen peptidomimetic and
nonpeptidomimetic inhibitors, tetracycline derivatives, e.g.
hydroxamate peptidomimetic inhibitor batimastat and its orally
bioavailable analogue marimastat (BB-2516), prinomastat (AG3340),
metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or
AAJ996. The term "compounds used in the treatment of hematologic
malignancies" as used herein includes, but is not limited to,
FMS-like tyrosine kinase inhibitors e.g. compounds targeting,
decreasing or inhibiting the activity of FMS-like tyrosine kinase
receptors (Flt-3R); interferon, 1-b-D-arabinofuransylcytosine
(ara-c) and bisulfan; and ALK inhibitors e.g. compounds which
target, decrease or inhibit anaplastic lymphoma kinase. Compounds
which target, decrease or inhibit the activity of FMS-like tyrosine
kinase receptors (Flt-3R) are especially compounds, proteins or
antibodies which inhibit members of the Flt-3R receptor kinase
family, e.g. PKC412, TKI258, midostaurin, a staurosporine
derivative, SU11248 and MLN518.
The term "HSP90 inhibitors" as used herein includes, but is not
limited to, compounds targeting, decreasing or inhibiting the
intrinsic ATPase activity of HSP90; degrading, targeting,
decreasing or inhibiting the HSP90 client proteins via the
ubiquitin proteosome pathway. Compounds targeting, decreasing or
inhibiting the intrinsic ATPase activity of HSP90 are especially
compounds, proteins or antibodies which inhibit the ATPase activity
of HSP90 e.g., 17-allylamino,17-demethoxygeldanamycin (17AAG), a
geldanamycin derivative; other geldanamycin related compounds;
radicicol and HDAC inhibitors. An example HSP90 inhibitor is
AUY922.
The term "antiproliferative antibodies" as used herein includes,
but is not limited to, trastuzumab (Herceptin),
Trastuzumab-DM1,erbitux, bevacizumab (Avastin), rituximab
(Rituxan), PRO64553 (anti-CD40) and 2C4 Antibody. By antibodies is
meant e.g. intact monoclonal antibodies, polyclonal antibodies,
multispe-cific antibodies formed from at least 2 intact antibodies,
and antibodies fragments so long as they exhibit the desired
biological activity.
For the treatment of acute myeloid leukemia (AML), compounds of
formula (I) can be used in combination with standard leukemia
therapies, especially in combination with therapies used for the
treatment of AML. In particular, compounds of formula (I) can be
administered in combination with, e.g., farnesyl transferase
inhibitors and/or other drugs useful for the treatment of AML, such
as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide,
Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
The term "antileukemic compounds" includes, for example, Ara-C, a
pyrimidine analog, which is the 2-alpha-hydroxy ribose
(arabinoside) derivative of deoxycytidine. Also included is the
purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and
fludarabine phosphate.
Somatostatin receptor antagonists as used herein refers to
compounds which target, treat or inhibit the somatostatin receptor
such as octreotide, and SOM230 (pasireotide).
Tumor cell damaging approaches refer to approaches such as ionizing
radiation. The term "ionizing radiation" referred to above and
hereinafter means ionizing radiation that occurs as either
electromagnetic rays (such as X-rays and gamma rays) or particles
(such as alpha and beta particles). Ionizing radiation is provided
in, but not limited to, radiation therapy and is known in the art.
See Hellman, Principles of Radiation Therapy, Cancer, in Principles
and Practice of Oncology, Devita et al., Eds., 4.sup.th Edition,
Vol. 1, pp. 248-275 (1993).
The term "EDG binders" as used herein refers a class of
immunosuppressants that modulates lymphocyte recirculation, such as
FTY720.
The term "ribonucleotide reductase inhibitors" refers to pyrimidine
or purine nucleoside analogs including, but not limited to,
fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine,
5-fluorouracil, cladribine, 6-mercaptopurine (especially in
combination with ara-C against ALL) and/or pentostatin.
Ribonucleotide reductase inhibitors are especially hydroxyurea or
2-hydroxy-1H-isoindole-1,3-dione derivatives, such as PL-1, PL-2,
PL-3, PL-4, PL-5, PL-6, PL-7 or PL-8 mentioned in Nandy et al.,
Acta Oncologica, Vol. 33, No. 8, pp. 953-961 (1994).
The term "S-adenosylmethionine decarboxylase inhibitors" as used
herein includes, but is not limited to the compounds disclosed in
U.S. Pat. No. 5,461,076.
Also included are in particular those compounds, proteins or
monoclonal antibodies of VEGF disclosed in WO 98/35958, e.g.
1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a
pharmaceutically acceptable salt thereof, e.g. the succinate, or in
WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819 and
EP 0 769 947; those as described by Prewett et al, Cancer Res, Vol.
59, pp. 5209-5218 (1999); Yuan et al., Proc Natl Acad Sci USA, Vol.
93, pp. 14765-14770 (1996); Zhu et al., Cancer Res, Vol. 58, pp.
3209-3214 (1998); and Mordenti et al., Toxicol Pathol, Vol. 27, No.
1, pp. 14-21 (1999); in WO 00/37502 and WO 94/10202; ANGIOSTATIN,
described by O'Reilly et al., Cell, Vol. 79, pp. 315-328 (1994);
ENDOSTATIN, described by O'Reilly et al., Cell, Vol. 88, pp.
277-285 (1997); anthranilic acid amides; ZD4190; ZD6474; SU5416;
SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor
antibodies, e.g. rhuMAb and RHUFab, VEGF aptamer e.g. Macugon;
FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgG1 antibody,
Angiozyme (RPI 4610) and Bevacizumab (Avastin).
Photodynamic therapy as used herein refers to therapy which uses
certain chemicals known as photosensitizing compounds to treat or
prevent cancers. Examples of photodynamic therapy includes
treatment with compounds, such as e.g. VISUDYNE and porfimer
sodium.
Angiostatic steroids as used herein refers to compounds which block
or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone,
hydrocortisone, 11-epihydrocotisol, cortexolone,
17-hydroxyprogesterone, corticosterone, desoxycorticosterone,
testosterone, estrone and dexamethasone.
Implants containing corticosteroids refers to compounds, such as
e.g. fluocinolone, dexamethasone.
"Other chemotherapeutic compounds" include, but are not limited to,
plant alkaloids, hormonal compounds and antagonists; biological
response modifiers, preferably lymphokines or interferons:
antisense oligonucleotides or oligonucleotide derivatives; shRNA or
siRNA; or miscellaneous compounds or compounds with other or
unknown mechanism of action.
The structure of the active compounds identified by code nos.,
generic or trade names may be taken from the actual edition of the
standard compendium "The Merck Index" or from databases, e.g.
Patents International (e.g. IMS World Publications).
EXAMPLES
The following abbreviations used in the examples below have the
corresponding meanings:
TABLE-US-00001 DIPA: Diisopropylamine DPPA: Diphenylphosphoryl
Azide DCM: Dichloromethane DCE: Dichloroethane DMF:
N,N-Dimethylformamide DMSO: Dimethylsulfoxide TEA: Triethylamine
THF: Tetrahydrofuran NaBH(OAc).sub.3: Sodium triacetoxy borohydride
PTSA: Para toluene sulphonic acid TES: Triethyl silane LiHMDS:
Lithium bis(trimethylsilyl)amide TEA: Triethyl amine
Pd.sub.2(dba).sub.3: Tris(dibenzylideneacetone)dipalladium(0) TLC:
Thin Layer Chromatography NMR: Nuclear Magnetic Resonance LCMS:
Liquid chromatography Mass spectrometry HPLC: High Performance
Liquid Chromatography
Example 1
Preparation of 1-Naphthalen-2-yl-3-pyridin-3-yl-imidazolidin-2-one
(1A)
##STR00013##
Step 1: Preparation of Intermediate
1-(2-Chloro-ethyl)-3-pyridin-3-yl-urea (I-1a)
##STR00014##
1-Chloro-2-isocyanato-ethane (560 mg, 5.31 mmol) was added dropwise
to a stirred solution of pyridin-3-ylamine (500 mg, 5.31 mmol) in
toluene (10 mL) over a period of 30 minutes at 0.degree. C. The
reaction temperature was maintained at room temperature for 5
hours. The reaction was monitored by TLC (100% ethyl acetate). The
reaction mixture was filtered, washed with toluene and dried under
reduced pressure to afford 1.0 g (98% yield) of
1-(2-Chloro-ethyl)-3-pyridin-3-yl-urea.
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.9 (br s, 1H), 8.55
(br s, 1H), 8.1 (d, 1H), 7.9 (m, 1H), 7.3 (m, 1H), 6.5 (t, 1H),
3.65 (t, 2H), 3.45 (q, 2H)
LCMS purity: 99.75%, m/z=200.2(M+1)
Step 2: Preparation of Intermediate 1-Pyridin 3-yl-imidazolidin 2
one (I-1b)
##STR00015##
1-(2-Chloro-ethyl)-3-pyridin-3-yl-urea (I-1a: 1000 mg, 5.0 mmol) in
dry DMF (10 mL) was added to a stirred solution of sodium hydride
(216 mg, 9.0 mmol) in THF (10 mL) at 0.degree. C. The reaction
temperature was maintained at room temperature for 30 minutes. The
reaction was monitored by TLC (100% ethyl acetate). The reaction
mixture was quenched with MeOH (5 mL) at 0.degree. C. The reaction
mixture was concentrated under reduced pressure and partitioned
between ice water and chloroform. The organic layer was dried over
Na.sub.2SO.sub.4, and concentrated under reduced pressure to afford
800 mg (97% yield) of 1-pyridin-3-yl-imidazolidin-2-one.
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.75 (d, 1H), 8.2 (dd,
1H), 8.0 (m, 1H), 7.35 (m, 1H), 7.15 (br s, 1H), 3.9 (m, 2H), 3.45
(m, 2H)
LCMS purity: m/z=164.2(M+1)
Final Step: Preparation of
1-Naphthalen-2-yl-3-pyridin-3-yl-imidazolidin-2-one (1A)
Copper iodide (10.0 mg, 0.113 mmol), trans-1,2-diamino cyclohexane
(10.0 mg, 0.091 mmol) and potassium carbonate (169 mg, 1.22 mmol)
were added to a solution of 1,4-dioxane (5 mL) previously purged
with argon (10 minutes). The reaction mixture was purged with argon
for 10 minutes, followed by the addition of
1-pyridin-3-yl-imidazolidin-2-one (I-1b: 100 mg, 0.61 mmol) and
2-bromo naphthalene (126 mg, 0.61 mmol). The reaction mixture was
heated to reflux at 110.degree. C. for 15 hours. The reaction was
monitored by TLC (10% MeOH in chloroform). The reaction mixture was
filtered through a celite bed and the bed was washed with
chloroform. The organic layer was concentrated and purification by
column chromatography (using silica gel of mesh size of 60-120, 20%
ethyl acetate in hexane as eluent) afforded 48 mg (28% yield) of
1-naphthalen-2-yl-3-pyridin-3-yl-imidazolidin-2-one.
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.9 (d, 1H), 8.3 (d,
1H), 8.15-8.05 (m, 2H), 7.95-7.85 (m, 4H), 7.55-7.4 (m, 3H),
4.2-4.0 (m, 4H)
LCMS purity: 98.57%; m/z=290.0(M+1)
HPLC: 96.05%
Example 2
Preparation of
1-(1-Ethyl-1H-indol-5-yl)-3-pyridin-3-yl-imidazolidin-2-one
(2A)
##STR00016##
Using the same reaction conditions as in Example 1,
1-pyridin-3-yl-imidazolidin-2-one (I-1b: 200 mg, 1.226 mmol) was
reacted with 5-bromo-1-ethyl-1H-indole (274 mg, 1.226 mmol),
1,4-dioxane (10 mL), copper iodide (23.3 mg, 0.1226 mmol),
trans-1,2-diamino cyclohexane (20.99 mg, 1.839 mmol) and potassium
carbonate (338 mg, 2.452 mmol) to afford the crude product.
Purification by column chromatography on silica gel (30%
ethylacetate in hexane), afforded 185 mg of the product (49.33%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.85-8.8 (br s, 1H),
8.2 (d, 1H), 8.1-8.05 (m, 1H), 7.65 (s, 1H), 7.5 (s, 2H), 7.4-7.35
(m, 2H), 6.4 (d, 1H), 4.5 (q, 2H), 4.1-4.0 (m, 4H), 1.4 (t, 3H)
LCMS purity: 96.97%, m/z=307.0 (M+1)
HPLC: 98.74%
Example 3
Preparation of
1-(6-Methoxy-naphthalen-2-yl)-3-pyridin-3-O-imidazolidin-2-one
(3A)
##STR00017##
Using the same reaction conditions as in Example 1,
1-pyridin-3-yl-imidazolidin-2-one (I-1b: 68.7 mg, 0.4217 mmol) was
reacted with 2-bromo-6-methoxy-naphthalene (100 mg, 0.4217 mmol),
1,4-dioxane (5 mL), copper iodide (8.0 mg, 0.04217 mmol),
trans-1,2-diamino cyclohexane (7 mg, 0.0632 mmol) and potassium
carbonate (116 mg, 0.8432 mmol) to afford the crude product.
Purification by column chromatography on silica gel (50%
ethylacetate in hexane), afforded 72 mg of the product (55.22%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.9 (d, 1H), 8.3 (dd,
1H), 8.0-8.1 (m, 2H), 7.8 (m, 3H), 7.4 (m, 1H), 7.3 (d, 1H), 7.15
(dd, 1H), 4.2-4.0 (m, 4H), 3.85 (s, 3H)
LCMS purity: 96.72%, m/z=320.0 (M+1)
HPLC: 97.84%
Example 4
Preparation of
1-Benzothiazol-6-yl-3-pyridin-3-yl-imidazolidin-2-one (4A)
##STR00018##
Using the same reaction conditions as in Example 1,
1-pyridin-3-yl-imidazolidin-2-one (I-1b: 62 mg, 0.3831 mmol) was
reacted with 6-iodo-benzothiazole (100 mg, 0.3831 mmol),
1,4-dioxane (10 mL), copper iodide (7 mg, 0.03831 mmol),
trans-1,2-diamino cyclohexane (6 mg, 0.5747 mmol) and potassium
carbonate (105 mg, 0.7662 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1% MeOH in
chloroform), afforded 52 mg of the product (46.01% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.3 (s, 1H), 8.9 (d,
1H), 8.35-8.25 (m, 2H), 8.1-8.0 (m, 2H), 7.95 (dd, 1H), 7.45-7.4
(m, 1H), 4.2-4.0 (m, 4H)
LCMS purity: 93.45%, m/z=297.3 (M+1)
HPLC: 95.65%
Example 5
Preparation of
1-Ethyl-6-(2-oxo-3-pyridin-3-yl-imidazolidin-1-yl)-3,4-dihydro-1H-quinoli-
n-2-one (5A)
##STR00019##
Using the same reaction conditions as in Example 1,
1-pyridin-3-yl-imidazolidin-2-one (I-1b: 95 mg, 0.5882 mmol) was
reacted with 6-bromo-1-ethyl-3,4-dihydro-1H-quinolin-2-one (150 mg,
0.5882 mmol), 1,4-dioxane (5 mL), copper iodide (11 mg, 0.05882
mmol), trans-1,2-diamino cyclohexane (10 mg, 0.08823 mmol) and
potassium carbonate (162 mg, 1.1764 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1%
MeOH in chloroform), afforded 94 mg of the product (47.71%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.85 (d, 1H), 8.3 (dd,
1H), 8.1-8.0 (m, 1H), 7.55-7.45 (m, 2H), 7.45-7.35 (m, 1H), 7.15
(d, 1H), 4.0 (s, 4H), 3.9 (q, 2H), 2.85 (t, 2H), 2.55-2.5 (m, 2H),
1.1 (t, 3H)
LCMS purity: 99.16%, miz=337.3 (M+1)
HPLC: 95.77%
Example 6
Preparation of
1-(5-Fluoro-3-methyl-benzo[b]thiophen-2-yl)-3-pyridin-3-yl-imidazolidin-2-
-one (6A)
##STR00020##
Using the same reaction conditions as in Example 1,
1-pyridin-3-yl-imidazolidin-2-one (I-1b: 73 mg, 0.45 mmol) was
reacted with 2-bromo-5-fluoro-3-methyl-benzo[b]thiophene (110 mg,
0.45 mmol), 1,4-dioxane (5 mL), copper iodide (8 mg, 0.045 mmol),
trans-1,2-diamino cyclohexane (7 mg, 0.0675 mmol) and potassium
carbonate (124 mg, 0.9 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1% MeOH in
chloroform), afforded 90 mg of the product (61.64% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.9 (d, 1H), 8.3 (dd,
1H), 8.15-8.05 (m, 1H), 7.95-7.7 (m, 1H), 7.6 (dd, 1H), 7.45-7.4
(m, 1H), 7.3-7.2 (m, 1H), 4.15-4.0 (m, 4H), 2.3 (s, 3H)
LCMS purity: 98.04%, m/z=327.9 (M+1)
HPLC: 95.05%
Example 7
Preparation of
1-Benzo[b]thiophen-5-yl-3-pyridin-3-yl-imidazolidin-2-one (7A)
##STR00021##
Using the same reaction conditions as in Example 1,
1-pyridin-3-yl-imidazolidin-2-one (I-1b: 93.6 mg, 0.5747 mmol) was
reacted with 5-iodo-benzo[b]thiophene (150 mg, 0.5747 mmol),
1,4-dioxane (5 mL), copper iodide (10 mg, 0.05747 mmol),
trans-1,2-diamino cyclohexane (9 mg, 0.0862 mmol) and potassium
carbonate (158.9 mg, 1.149 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1% MeOH in
chloroform), afforded 70 mg of the product (41.42% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.9 (d, 1H), 8.3 (dd,
1H), 8.1-8.0 (m, 3H), 7.8-7.75 (m, 2H), 7.45-7.4 (m, 2H), 4.1-4.0
(m, 4H).
LCMS purity: 97.11%, m/z =296.3 (M+1)
HPLC: 97.46%
Example 8
Preparation of 1-Pyridin-3-yl-3-quinolin-6-yl-imidazolidin-2-one
(8A)
##STR00022##
Using the same reaction conditions as in Example 1,
1-pyridin-3-yl-imidazolidin-2-one (I-1b: 117 mg, 0.7215 mmol) was
reacted with 6-bromo-quinoline (150 mg, 0.7215 mmol), 1,4-dioxane
(5 mL), copper iodide (13 mg, 0.07215 mmol), trans-1,2-diamino
cyclohexane (24.78 mg, 0.21645 mmol) and potassium carbonate
(199.49 mg, 1.1443 mmol) to afford the crude product. Purification
by column chromatography on silica gel (1% MeOH in chloroform),
afforded 125 mg of the product (60.09% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.9 (d, 1H), 8.8 (dd,
1H), 8.4-8.25 (m, 3H), 8.15-8.0 (m, 2H), 7.9 (d, 1H), 7.55-7.4 (m,
2H), 4.2-4.0 (m, 4H)
LCMS purity: 98.99%, m/z =291.1 (M+1)
HPLC: 98.55%
Example 9
Preparation of
1-Benzothiazol-5-yl-3-pyridin-3-yl-imidazolidin-2-one (9A)
##STR00023##
Using the same reaction conditions as in Example 1,
1-pyridin-3-yl-imidazolidin-2-one (I-1b: 93.67 mg, 0.5747 mmol) was
reacted with 5-iodo-benzothiazole (150 mg, 0.5747 mmol),
1,4-dioxane (5 mL), copper iodide (10.9 mg, 0.05747 mmol),
trans-1,2-diamino cyclohexane (19.65 mg, 0.1724 mmol) and potassium
carbonate (159 mg, 1.1494 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1% MeOH in
chloroform) afforded 105 mg of the product (61.76% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.4 (s, 1H), 8.9 (d,
1H), 8.35-8.25 (m, 2H), 8.2-8.05 (m, 2H), 8.0-7.9 (dd, 1H),
7.45-7.4 (m, 1H), 4.2-4.0 (m, 4H)
LCMS purity: 98.09%, m/z =296.9 (M+1)
HPLC: 95.27%
Example 10
Preparation of
1-Naphthalen-2-yl-3-pyridin-3-yl-tetrahydro-pyrimidin-2-one
(10A)
##STR00024##
Step 1: Preparation of Intermediate
1-(3-Chloro-propyl)-3-pyridin-3-yl-urea (I-10a)
##STR00025##
1-Chloro-3-isocyanato-propane (1.897 g, 15.873 mmol) was added
dropwise to a stirred solution of pyridin-3-ylamine (1 g, 10.582
mmol) in toluene (15 mL) over a period of 30 minutes at 0.degree.
C. The reaction temperature was maintained at room temperature for
6 hours. The reaction was monitored by TLC (100% ethyl acetate).
The reaction mixture was filtered, washed with toluene and dried
under reduced pressure to afford 2.1 g (95.45% yield) of
1-(3-chloro-propyl)-3-pyridin-3-yl-urea.
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): 6; 8.65(brS, 1H), 8.5 (d, 1H),
8.15 (dd, 1H), 7.9 (m, 1H), 7.35 (m, 1H), 6.4 (t, 1H), 3.65 (t,
2H), 3.2 (q, 2H), 1.9 (m, 2H)
Step 2: 1-Pyridin-3-yl-tetrahydro-pyrimidin-2-one (I-10b)
##STR00026##
1-(3-Chloro-propyl)-3-pyridin-3-yl-urea (I-10a: 2.1 g, 9.859 mmol)
in dry DMF (10 mL) was added to a solution of sodium hydride (487
mg, 10.154 mmol) in THF (2 mL) at 0.degree. C. The reaction
temperature was maintained at room temperature for 30 minutes. The
reaction was monitored by TLC (100% ethyl acetate). The reaction
mixture was quenched with MeOH (5 mL) at 0.degree. C., concentrated
under reduced pressure and partitioned between ice cold water and
chloroform. The organic layer was dried over Na.sub.2SO.sub.4, and
concentrated under reduced pressure to afford 1.7 g (97.14% yield)
of 1-pyridin-3-yl-tetrahydro-pyrimidin-2-one.
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.59(d, 1H), 8.3 (dd,
1H), 7.7 (m, 1H), 7.35 (m, 1H), 6.75 (brS, 1H), 3.7 (t, 2H), 3.35
(m, 2H), 1.9 (m, 2H)
Final Step: Preparation of
1-Naphthalen-2-yl-3-pyridin-3-yl-tetrahydro-pyrimidin-2-one
(10A)
Using the same reaction conditions as in Example 1,
1-pyridin-3-yl-tetrahydro-pyrimidin-2-one (I-10b: 118 mg, 0.724
mmol) was reacted with 2-bromo-naphthalene (150 mg, 0.724 mmol),
1,4-dioxane (5 mL), copper iodide (13.79 mg, 0.0724 mmol),
trans-1,2-diamino cyclohexane (24.865 mg, 0.2172 mmol) and
potassium carbonate (200 mg, 1.448 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1%
MeOH in chloroform) afforded 75 mg of the product (35.71%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.65 (d, 1H), 8.35-8.3
(m, 1H), 7.95-7.75 (m, 5H), 7.6-7.4 (m, 4H), 3.95-3.8 (m, 4H),
2.3-2.2 (m, 2H)
LCMS purity: 98.98%, m/z =304.0 (M+1)
HPLC: 99.14%
Example 11
Preparation of
1-(2-Chloro-4-methyl-quinolin-6-yl)-3-pyridin-3-yl-imidazolidin-2-one
(11A)
##STR00027##
Using the same reaction conditions as in Example 1,
1-pyridin-3-yl-imidazolidin-2-one (I-1b: 95.8 mg, 0.5882 mmol) was
reacted with 6-bromo-2-chloro-4-methyl-quinoline (150 mg, 0.5882
mmol), 1,4-dioxane (5 mL), copper iodide (11.2 mg, 0.05882 mmol),
trans-1,2-diamino cyclohexane (20.20 mg, 0.1764 mmol) and potassium
carbonate (162.6 mg, 1.1764 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1% MeOH in
chloroform) afforded 70 mg of the product (35.17% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.85 (d, 1H), 8.4-8.3
(m, 2H), 8.15-7.95 (m, 3H), 7.5-7.4 (m, 2H), 4.3-4.0 (m, 4H), 2.6
(s, 3H)
LCMS purity: 89.47%, m/z=339.0 (M+1)
HPLC: 97.08%
Example 12
Preparation of
1-(I-1-Hydroxyimino-indan-5-O-3-pyridin-3-yl-imidazolidin-2-one
(12A)
##STR00028##
Using the same reaction conditions as in Example 1,
1-pyridin-3-yl-imidazolidin-2-one (I-1b: 270 mg, 1.6587 mmol) was
reacted with 5-bromo-indan-1-one (350 mg, 1.6587 mmol), 1,4-dioxane
(10 mL), copper iodide (31.59 mg, 0.165879 mmol), trans-1,2-diamino
cyclohexane (56.976 mg, 0.4976 mmol) and potassium carbonate
(458.63 mg, 3.3174 mmol) to afford the crude product. Purification
by column chromatography on silica gel (1% MeOH in chloroform)
afforded 300 mg of
1-(1-oxo-indan-5-yl)-3-pyridin-3-yl-imidazolidin-2-one (61.72%
yield). Hydroxylamine hydrochloride (141 mg, 2.044 mmol) and sodium
acetate (167.6 mg, 2.044 mmol) in 5 mL of water were added to a
solution of 1-(3-oxo-indan-5-yl)-3-pyridin-3-yl-imidazolidin-2-one
(200 mg, 0.6814 mmol) in ethanol (7 mL). The reaction mixture was
heated to 90.degree. C. and maintained for 6 hours. The reaction
mixture was then cooled to room temperature and the solvent was
distilled from the reaction mixture. The precipitate formed was
collected, washed with chloroform and dried under reduced pressure
to afford 200 mg of the product (90% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 10.5 (s, 1H), 8.9 (s,
1H), 8.35-8.25 (br s, 1H), 8.1 (d, 1H), 7.7-7.4 (m, 4H), 4.0 (s,
4H), 3.05-3.0 (m, 2H), 2.85-2.7 (m, 2H)
LCMS purity: 98.13%, m/z=309.2 (M+1)
HPLC: 83.39%
Example 13
Preparation of
1-Benzo[b]thiophen-5-yl-3-pyridin-3-yl-tetrahydro-pyrimidin-2-one
(13A)
##STR00029##
Using the same reaction conditions as in Example 1,
1-pyridin-3-yl-tetrahydro-pyrimidin-2-one (I-10b: 67.8 mg, 0.3831
mmol) was reacted with 5-iodo-benzo[b]thiophene (100 mg, 0.3831
mmol), 1,4-dioxane (5 mL), copper iodide (7.29 mg, 0.03831 mmol),
trans-1,2-diamino cyclohexane (13.15 mg, 0.1149 mmol) and potassium
carbonate (106.1 mg, 0.7662 mmol) to afford 15 mg of the product
(17.5% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.7-8.5 (br s, 1H),
8.4-8.3 (br s, 1H), 7.95 (d, 1H), 7.85-7.75 (m, 3H), 7.45-7.35 (m,
3H), 3.9 (q, 4H), 2.35-2.25 (m, 2H)
LCMS purity: 99.84%, m/z=309.9 (M+1)
HPLC: 94.28%
Example 14
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-naphthalen-2-yl-imidazolidin-2-one
(14A)
##STR00030##
Step 1: Preparation of Intermediate
1-(2-Chloro-ethyl)-3-(4-methyl-pyridin-3-yl)-urea (I-14a)
##STR00031##
1-Chloro-2-isocyanato-ethane (5.91 ml, 69.35 mmol) was added
dropwise to a stirred solution of 4-methyl-pyridin-3-ylamine (5 g,
46.23 mmol) in toluene (180 mL) at 0.degree. C. The reaction
temperature was maintained at room temperature for 5 hours. The
reaction was monitored by TLC (5% MeOH in chloroform). The reaction
mixture was filtered, washed with toluene and dried under reduced
pressure to afford 8.5 g (86% yield) of
1-(2-chloro-ethyl)-3-(4-methyl-pyridin-3-yl)-urea.
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.95 (s, 1H), 8.1 (m,
2H), 7.25 (d, 1H), 6.95 (t, 1H), 3.7 (t, 2H), 3.45 (q, 2H), 2.2 (s,
3H)
LCMS: m/z=214.1 (M+1)
Step 2: Preparation of Intermediate
1-(4-Methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b)
##STR00032##
1-(2-Chloro-ethyl)-3-(4-methyl-pyridin-3-yl)-urea (I-14a: 8.5 g,
39.96 mmol) in dry DMF (150 mL) was added to a stirred mixture of
sodium hydride (2.87 g, 59.94 mmol) in THF (150 mL) at 0.degree. C.
The reaction temperature was maintained at room temperature for 30
minutes. The reaction was monitored by TLC. The reaction mixture
was quenched with MeOH at 0.degree. C., concentrated under reduced
pressure and partitioned between ice water and chloroform. The
organic layer was dried over Na.sub.2SO.sub.4, and concentrated
under reduced pressure to afford 6.5 g (91% yield) of
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one.
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.4 (s, 1H), 8.3 (m,
1H), 7.3 (d, 1H), 6.85 (br s, 1H), 3.8 (t, 2H), 3.45 (t, 2H), 2.25
(s, 3H)
LCMS purity: 100%, m/z=178.3 (M+1)
Final Step: Preparation of
1-(4-Methyl-pyridin-3-yl)-3-naphthalen-2-yl-imidazolidin-2-one
(14A)
Copper iodide (21.5 mg, 0.113 mmol), trans-1,2-diamino cyclohexane
(0.041 mL, 0.339 mmol) and potassium carbonate (313 mg, 2.26 mmol)
were added to 1,4-Dioxane (15 mL) previously sparged with argon (10
minutes). The reaction mixture was sparged with argon for a further
10 minutes, followed by the addition of
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 200 mg, 1.13
mmol) and 2-bromo naphthalene (234 mg, 1.13 mmol). The resulting
mixture was heated to reflux at 110.degree. C. for 15 hours. The
reaction was monitored by TLC (10% MeOH in chloroform). The
reaction mixture was filtered through a celite and the bed was
washed with chloroform. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated. Purification by column
chromatography (using silica gel of mesh size of 60-120, 1% MeOH in
chloroform as eluent) afforded 250 mg (73% yield) of
1-(4-methyl-pyridin-3-yl)-3-naphthalen-2-yl-imidazolidin-2-one.
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.62 (s, 1H),
8.48-8.42 (m, 1H), 8.2 (dd, 1H), 8.0-7.85 (m, 4H), 7.55-7.4 (m,
3H), 4.4-4.25 (m, 2H), 3.95-4.1 (m, 2H), 2.35 (s, 3H)
LCMS purity: 98.31%, m/z=304.1 (M+1)
HPLC: 97.55%
Example 15
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-(5-methyl-thiophen-2-yl)-imidazolidin-2-one
(15A)
##STR00033##
Copper iodide (16 mg, 0.084 mmol), trans-1,2-diamino cyclohexane
(28.8 mg, 0.25 mmol) and potassium phosphate (445 mg, 2.1 mmol)
were added to 1,4-Dioxane (10 mL) previously degassed with argon
(10 minutes). The reaction mixture was purged with argon for a
further 10 minutes, followed by the addition of
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.84
mmol) and 2-bromo-5-methylthiophene (150 mg, 0.84 mmol). The
resulting mixture was heated to reflux at 110.degree. C. for 4
hours. The reaction was monitored by TLC (10% MeOH in chloroform).
The reaction mixture was filtered through celite and the celitebed
was washed with chloroform. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated. The concentrate was quenched
with ice, the precipitate formed was collected and dried to afford
170 mg (74% yield) of
1-(4-methyl-pyridin-3-yl)-3-(5-methyl-thiophen-2-yl)-imidazolidin-2-one.
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.5 (s, 1H), 8.4 (d,
1H), 7.35 (d, 1H), 6.55 (d, 1H), 6.25 (d, 1H), 4.0 (s, 4H), 2.35
(s, 3H), 2.25 (s, 3H)
LCMS purity: 98.84%, m/z=274.0 (M+1)
HPLC: 97.43%
Example 16
Preparation of
1-Benzothiazol-6-yl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(16A)
##STR00034##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847
mmol) was reacted with 6-iodo-benzothiazole (200.93 mg, 0.847
mmol), 1,4-dioxane (20 mL), copper iodide (16.135 mg, 0.0847 mmol),
trans-1,2-diamino cyclohexane (0.03 mL, 0.254 mmol) and potassium
carbonate (233.97 mg, 1.694 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1% MeOH in
chloroform) afforded 130 mg of the product (49.6% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.26 (s, 1H), 8.56 (s,
1H), 8.4 (d, 1H), 8.3 (d, 1H), 8.1-8.06 (m, 1H), 7.96 (dd, 1H),
7.38 (d, 1H), 4.2-4.1 (m, 2H), 4.0-3.92 (m, 2H), 2.3 (s, 3H)
LCMS purity: 97.79%, m/z =310.9 (M+1)
HPLC: 96.64%
Example 17
Preparation of
1-Ethyl-6-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-3,4-dihydro-
-1H-quinolin-2-one (17A)
##STR00035##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847
mmol) was reacted with
6-bromo-1-ethyl-3,4-dihydro-1H-quinolin-2-one (215.15 mg, 0.847
mmol), 1,4-dioxane (0.03 mL, 0.254 mmol), copper iodide (16.13 mg,
0.0847 mmol), trans-1,2-diamino cyclohexane (0.03 mL, 0.254 mmol)
and potassium carbonate (233.97 mg, 1.694 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1%
MeOH in chloroform) afforded 95 mg of the product (31.99%)
yield.
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.56-8.5 (br s, 1H),
8.42-8.38 (br s, 1H), 7.52-7.46 (m, 2H), 7.35 (d, 1H), 7.13 (d,
1H), 4.1-3.85 (m, 6H), 3.35-3.25 (m, 2H), 2.85 (t, 2H), 2.25 (s,
3H), 1.1 (t, 3H)
LCMS purity: 96.43%, m/z=351.0 (M+1)
HPLC: 96.26%
Example 18
Preparation of
1-(4-Fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(18A)
##STR00036##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465
mmol) was reacted with 1-bromo-4-fluoro-benzene (148.1 mg, 0.8465
mmol), 1,4-dioxane (25 mL), copper iodide (16 mg, 0.08465 mmol),
trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and potassium
carbonate (468 mg, 3.3860 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
chloroform) afforded 100 mg of the product (43% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.7-8.3 (m, 2H),
7.7-7.6 (m, 2H), 7.4-7.3 (br s, 1H), 7.2 (t, 2H), 4.1-3.9 (m, 4H),
2.3 (s, 3H)
LCMS purity: 99.85%, m/z =272.0 (M+1)
HPLC: 96.49%
Example 19
Preparation of
1-Biphenyl-4-O-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(19A)
##STR00037##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465
mmol) was reacted with 4-bromo-biphenyl (197.3 mg, 0.8465 mmol),
1,4-dioxane (25 mL), copper iodide (16 mg, 0.08465 mmol),
trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and potassium
carbonate (468 mg, 3.3860 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
chloroform) afforded 147 mg of the product (52% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.6 (s, 1H), 8.4 (d,
1H), 7.8-7.6 (m, 6H), 7.45 (t, 2H), 7.35 (t, 2H), 4.1 (t, 2H), 4.0
(t, 2H), 2.3 (s, 3H)
LCMS purity: 85.37%, m/z =330.1 (M+1)
HPLC: 96.0%
Example 20
Preparation of
1-Ethyl-4-methyl-6-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-1--
1H-quinolin-2-one (20A)
##STR00038##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 99 mg, 0.5597
mmol) was reacted with 6-bromo-1-ethyl-4-methyl-1H-quinolin-2-one
(150 mg, 0.5597 mmol), 1,4-dioxane (5 mL), copper iodide (10.66 mg,
0.05597 mmol), trans-1,2-diamino cyclohexane (19.22 mg, 0.1679
mmol) and potassium carbonate (77.37 mg, 1.1194 mmol) to afford the
crude product. Purification by column chromatography on silica gel
(1% MeOH in chloroform) afforded 56 mg of the product (28.1%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.55 (s, 1H), 8.4 (d,
1H), 8.0-7.85 (m, 2H), 7.6 (d, 1H), 7.35 (d, 1H), 6.55 (s, 1H),
4.25 (q, 2H), 4.2-4.1 (m, 2H), 4.0-3.9 (m, 2H), 2.4 (s, 3H), 2.3
(s, 3H), 1.15 (t, 3H)
LCMS purity: 99.36%, m/z =362.9 (M+1)
HPLC: 97.77%
Example 21
Preparation of
1-(2-Chloro-4-methyl-quinolin-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidi-
n-2-one (21A)
##STR00039##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 275.4 mg,
1.5564 mmol) was reacted with 6-bromo-2-chloro-4-methyl-quinoline
(400 mg, 1.5564 mmol), 1,4-dioxane (10 mL), copper iodide (29.649
mg, 0.15564 mmol), trans-1,2-diamino cyclohexane (53.448 mg, 0.4668
mmol) and potassium carbonate (430 mg, 3.112 mmol) to afford the
crude product. Purification by column chromatography on silica gel
(1% MeOH in chloroform) afforded 256 mg of the product (46.54%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.55 (s, 1H), 8.45-8.3
(m, 2H), 8.0-7.9 (m, 2H), 7.5-7.45 (br s, 1H), 7.35 (d, 1H),
4.25-4.15 (m, 2H), 4.05-3.95 (m, 2H), 2.65 (s, 3H), 2.3 (s, 3H)
LCMS purity: 96.22%, m/z=352.9 (M+1)
HPLC: 98.78%
Example 22
Preparation of
4-Methyl-6-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolodin-1yl]1H-quinolin--
2-one (22A)
##STR00040##
1N HCl (5 mL) was added to
1-(2-chloro-4-methyl-quinolin-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidi-
n-2-one (21A: 50 mg, 0.1418 mmol). The reaction mixture was stirred
at 120.degree. C. overnight. The reaction mass was cooled to
0.degree. C., aqueous NaHCO.sub.3 was added till a pH of about 8
was attained. The reaction mixture was extracted with chloroform.
The organic layer was dried over Na.sub.2SO.sub.4 and concentrated
to afford 38 mg of the product (80.85% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 11.5 (s, 1H), 8.55 (s,
1H), 8.4 (d, 1H), 7.85-7.8 (m, 2H), 7.4-7.3 (m, 2H), 6.5-6.4 (br s,
1H), 4.15-4.05 (m, 2H), 4.0-3.9 (m, 2H), 2.4 (s, 3H), 2.3 (s,
3H)
LCMS purity: 98.45%, m/z =334.9 (M+1)
HPLC: 93.73%
Example 23
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-quinolin-2-yl-imidazolidin-2-one
(23A)
##STR00041##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg,
0.84650 mmol) was reacted with 2-chloro-quinoline (138.4 mg,
0.84650 mmol), 1,4-dioxane (30 mL), copper iodide (16 mg, 0.08465
mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and
potassium carbonate (468 mg, 3.3860 mmol) to afford the crude
product. Purification by column chromatography on silica gel (2%
MeOH in DCM) afforded 105 mg of the product (40.8% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.6 (s, 1H), 8.5 (d,
1H), 8.4 (d, 1H), 8.3 (d, 1H), 7.9-7.8 (m, 2H), 7.75-7.65 (m, 1H),
7.5-7.45 (m, 1H), 7.4 (d, 1H), 4.3 (t, 2H), 4.0 (t, 2H), 2.3 (s,
3H)
LCMS purity: 97.22%, m/z =305.1 (M+1)
HPLC: 96.07%
Example 24
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-quinolin-3-yl-imidazolidin-2-one
(24A)
##STR00042##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847
mmol) was reacted with 3-bromo-quinoline (176.13 mg, 0.847 mmol),
1,4-dioxane (15 mL), copper iodide (16.13 mg, 0.0847 mmol),
trans-1,2-diamino cyclohexane (0.03 mL, 0.254 mmol) and potassium
carbonate (233.97 mg, 1.694 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1% MeOH in
chloroform) afforded 190 mg of the product (73.76% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.5 (d, 1H), 8.6 (s,
1H), 8.42 (d, 1H), 8.35 (d, 1H), 8.02-7.92 (m, 2H), 7.7-7.58 (m,
2H), 7.4 (d, 1H), 4.25-4.15 (m, 2H), 4.05-3.9 (m, 2H), 2.35 (s,
3H)
LCMS purity: 98.34%, m/z=305.2 (M+1)
HPLC: 95.64%
Example 25
Preparation of
1-(6-Methoxy-naphthalen-2-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-on-
e (25A)
##STR00043##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847
mmol) was reacted with 2-bromo-6-methoxy-naphthalene (200.74 mg,
0.847 mmol), 1,4-dioxane (15 mL), copper iodide (16.13 mg, 0.0847
mmol), trans-1,2-diamino cyclohexane (0.03 mL, 0.254 mmol) and
potassium carbonate (233.97 mg, 1.694 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1%
MeOH in chloroform) afforded 85 mg of the product (30.08%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.62-8.58 (br s, 1H),
8.44-8.4 (br s, 1H), 8.28 (dd, 1H), 7.86-7.76 (m, 3H), 7.4 (d, 1H),
7.28 (d, 1H), 7.16 (dd, 1H), 4.18-4.1 (m, 2H), 4.02-3.96 (m, 2H),
3.86 (s, 3H), 2.33 (s, 3H)
LCMS purity: 95.49%, m/z =334.1 (M+1)
HPLC: 93.56%
Example 26
Preparation of
1-Benzo[b]thiophen-2-yl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(26A)
##STR00044##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 109.25 mg,
0.6171 mmol) was reacted with 2-bromo-benzo[b]thiophene (150 mg,
0.6171 mmol), 1,4-dioxane (5 mL), copper iodide (11.75 mg, 0.06171
mmol), trans-1,2-diamino cyclohexane (21.19 mg, 0.1851 mmol) and
potassium carbonate (170.62 mg, 1.2342 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1%
MeOH in chloroform) afforded 75 mg of the product (62.5%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.5 (s, 1H), 8.4 (d,
1H), 7.8 (d, 1H), 7.75 (d, 1H), 7.4 (d, 1H), 7.35-7.25 (m, 1H), 7.2
(t, 1H), 6.75 (s, 1H), 4.25-4.1 (m, 2H), 4.1-4.0 (m, 2H), 2.3 (s,
3H)
LCMS purity: 97.09%, m/z =310.1 (M+1)
HPLC: 92.27%
Example 27
Preparation of
1-Benzo[b]thiophen-5-yl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(27A)
##STR00045##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847
mmol) was reacted with 5-bromo-benzo[b]thiophene (180.5 mg, 0.847
mmol), 1,4-dioxane (15 mL), copper iodide (16.13 mg, 0.0847 mmol),
trans-1,2-diamino cyclohexane (0.03 mL, 0.254 mmol) and potassium
carbonate (233.97 mg, 1.694 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1% MeOH in
chloroform) afforded 28 mg of the product in (10.69% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.75 (s, 1H), 8.55 (d,
1H), 8.04-7.98 (m, 2H), 7.84-7.76 (m, 2H), 7.63 (d, 1H), 7.45 (d,
1H), 4.2-4.1 (m, 2H), 4.05-3.95 (m, 2H), 2.4 (s, 3H)
LCMS purity: 91.88%, m/z =309.9 (M+1)
HPLC: 97.97%
Example 28
Preparation of
1-(1H-Indazol-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(28A)
##STR00046##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 0.095 g,
0.00058 mol) was reacted with
5-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (0.170 g,
0.00058 mmol), 1,4-dioxane (10 mL), copper iodide (0.011 g,
0.000051 mol), trans-1,2-diamino cyclohexane (0.018 g, 0.00016 mol)
and potassium carbonate (0.134 g, 0.00106 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1%
MeOH in chloroform) afforded 0.24 g of
1-(4-Methyl-pyridin-3-yl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indaz-
ol-5-yl]-imidazolidin-2-one (97.5% yield).
TFA (0.096 g, 0.00084 mol) was added to solution of
1-(4-methyl-pyridin-3-yl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indaz-
ol-5-yl]-imidazolidin-2-one (0.24 g, 0.00056 mol) in DCM (10 mL) at
0.degree. C. The reaction mixture was stirred at room temperature
overnight. The reaction was monitored by TLC (10% MeOH in
CHCl.sub.3). The reaction mixture was concentrated and the
concentrate was purified by preparative HPLC to afford 42 mg of the
product (19.47% yield).
.sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 8.52 (s, 1H), 8.35 (d,
1H), 8.06-8.0 (br s, 1H), 7.86-7.76 (m, 2H), 7.6-7.5 (m, 1H),
7.45-7.4 (m, 1H), 4.2-4.1 (m, 2H), 4.05-3.95 (m, 2H), 2.4 (s,
3H)
LCMS purity: m/z=294.1 (M+1)
HPLC: 98.89%
Example 29
Preparation of
1-(3-Methyl-benzofuran-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(29A)
##STR00047##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 105 mg, 0.8465
mol) was reacted with 5-bromo-3-methyl-benzofuran (197 mg, 0.9311
mmol), 1,4-dioxane (10 mL), copper iodide (20 mg),
trans-1,2-diamino cyclohexane (40 mg) and potassium carbonate (359
mg, 1.6930 mmol) to afford the crude product. Purification by
column chromatography on silica gel (2% MeOH in chloroform)
afforded 80 mg of the product (30.76% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.54 (s, 1H), 8.4 (d,
1H), 7.76-7.73 (m, 1H), 7.46-7.39 (m, 3H), 7.22 (d, 1H), 4.19-4.1
(m, 2H), 4.0-3.9 (m, 2H), 2.38 (s, 3H), 2.24 (s, 3H)
LCMS purity: 96.84%, m/z =307.9 (M+1)
HPLC: 96.37%
Example 30
Preparation of
1-(6-Fluoro-pyridin-3-O-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(30A)
##STR00048##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474
mmol) was reacted with 5-bromo-2-fluoro-pyridine (87.7 mL, 0.8474
mmol), 1,4-dioxane (10 mL), copper iodide (16.13 mg, 0.084 mmol),
trans-1,2-diamino cyclohexane (30.5 mL, 0.254 mmol) and potassium
carbonate (234 mg, 1.695 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
chloroform), followed by preparative HPLC afforded 165 mg of the
product (71.5% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.6-8.4 (m, 3H), 8.2 (s,
1H), 7.3-7.2 (m, 1H), 7.0-6.9 (m, 1H), 4.2-4.0 (m, 4H), 2.4 (s,
3H)
LCMS purity: 97.96%, m/z=273.1 (M+1)
HPLC: 95.26%
Example 31
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-thiophen-3-yl-imidazolidin-2-one
(31A)
##STR00049##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474
mmol) was reacted with 3-bromo-thiophene (79.4 mL, 0.8474 mmol),
1,4-dioxane (10 mL), copper iodide (16.13 mg, 0.084 mmol),
trans-1,2-diamino cyclohexane (30.5 mL, 0.254 mmol) and potassium
carbonate (234 mg, 1.695 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
chloroform), followed by preparative HPLC afforded 22 mg of the
product (10% yield).
.sup.1H NMR (DMSO-Dhd 6, 300 MHz): .delta. 8.5 (s, 1H), 8.4 (d,
1H), 7.6 (d, 2H), 7.4 (d, 1H), 7.1 (t, 1H), 4.1-3.9 (m, 4H), 2.3
(s, 3H)
LCMS purity: 97.96%, m/z =260.0 (M+1)
HPLC: 97.4%
Example 32
Preparation of
1-(5-Methoxy-pyridin-3-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(32A)
##STR00050##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847
mmol) was reacted with 3-bromo-5-methoxy-pyridine (159.24 mg, 0.847
mmol), 1,4-dioxane (15 mL), copper iodide (16.13 mg, 0.0847 mmol),
trans-1,2-diamino cyclohexane (0.03 mL, 0.254 mmol) and potassium
carbonate (233.97 mg, 1.694 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1% MeOH in
chloroform), followed by preparative HPLC afforded 23 mg of the
product (9.55% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.8 (s, 1H), 8.55 (d,
2H), 8.2 (s, 1H), 7.8 (s, 1H), 7.7 (d, 1H), 4.2-3.9 (m, 4H), 3.9
(s, 3H), 2.4 (s, 3H)
LCMS purity: 96.22%, m/z=285.0 (M+1)
HPLC: 99.27%
Example 33
Preparation of
1-(5-Fluoro-3-methyl-benzo[b]thiophen-2-yl)-3-(4-methyl-pyridin-3-yl)-imi-
dazolidin-2-one (33A)
##STR00051##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 79.79 mg,
0.4508 mmol) was reacted with
2-bromo-5-fluoro-3-methyl-benzo[b]thiophene (110 mg, 0.4508 mmol),
1,4-dioxane (5 mL), copper iodide (8.58 mg, 0.04508 mmol),
trans-1,2-diamino cyclohexane (15.48 mg, 0.1352 mmol) and potassium
carbonate (124.6 mg, 0.9016 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1% MeOH in
chloroform) afforded 84 mg of the product (60.45% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.55 (s, 1H), 8.4 (d,
1H), 7.95-7.85 (m, 1H), 7.62-7.55 (dd, 1H), 7.35 (d, 1H), 7.3-7.2
(m, 1H), 4.15-3.95 (m, 4H), 2.25 (d, 6H)
LCMS purity: 97.84%, m/z =342.0 (M+1)
HPLC: 97.83%
Example 34
Preparation of
1-(2-Chloro-pyrimidin-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(34A)
##STR00052##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465
mmol) was reacted with 5-bromo-2-chloro-pyrimidine (163.7 mg,
0.8465 mmol), 1,4-dioxane (30 mL), copper iodide (16 mg, 0.08465
mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and
potassium carbonate (468 mg, 3.3860 mmol) to afford the crude
product. Purification by column chromatography on silica gel (2%
MeOH in chloroform), followed by preparative HPLC afforded 65 mg of
the product (26.5% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.0 (s, 2H), 8.6 (s,
1H), 8.5 (s, 1H), 7.4 (s, 1H), 4.15-3.95 (m, 4H), 2.35 (s, 3H)
LCMS purity: 97.13%, m/z =290.0 (M+1)
HPLC: 96.83%
Example 35
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-(1H-pyrazol-4-yl)-imidazolidin-2-one
(35A)
##STR00053##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465
mmol) was reacted with 4-bromo-1-trityl-1H-pyrazole (369.3 mg,
0.8465 mmol), 1,4-dioxane (50 mL), copper iodide (16 mg, 0.08465
mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and
potassium carbonate (468 mg, 3.3860 mmol) to afford the crude
product. Purification by column chromatography on silica gel (2%
MeOH in chloroform) afforded 250 mg of
1-(4-Methyl-pyridin-3-yl)-3-(1-trityl-1H-pyrazol-4-yl)-imidazol-
idin-2-one (60% yield). Dioxane hydrochloride (10 mL) was added to
a stirred solution of
1-(4-methyl-pyridin-3-yl)-3-(1-trityl-1H-pyrazol-4-yl)-imidazolidin-2-one
(250 mg, 0.51484 mmol) in dioxane under nitrogen atmosphere at
0.degree. C. The reaction mixture was stirred at room temperature
for 2 hours with TLC monitoring (10% MeOH in DCM). The solvent was
distilled from the reaction mixture and washed with ether. The
precipitate was collected and dried under reduced pressure to
afford 80 mg of the product (55% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.95 (s, 1H), 8.7 (d,
1H), 8.0 (d, 1H), 7.8 (s, 2H), 4.1-4.0 (m, 2H), 4.0-3.95 (m, 2H),
2.5 (s, 3H)
LCMS purity: 98.04%, m/z =244.1 (M+1)
HPLC: 94.48%
Example 36
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-thiazol-2-yl-imidazolidin-2-one
(36A)
##STR00054##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465
mmol) was reacted with 2-bromo-thiazole (138.8 mg, 0.846 mmol),
1,4-dioxane (50 mL), copper iodide (16 mg, 0.08465 mmol),
trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and potassium
carbonate (468 mg, 3.3860 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
chloroform) afforded 125 mg of the product (56.8% yield). .sup.1H
NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.6 (s, 1H), 8.4 (s, 1H),
7.45-7.35 (m, 2H), 7.2 (d, 1H), 4.4 (t, 2H), 4.2 (t, 2H), 2.3 (s,
3H)
LCMS purity: 96.14%, m/z =261.0 (M+1)
HPLC: 97.87%
Example 37
Preparation of
1-(4-Methoxy-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(37A)
##STR00055##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474
mmol) was reacted with 1-bromo-4-methoxy-benzene (158 mg, 0.8474
mmol), 1,4-dioxane (5 mL), copper iodide (16.142 mg, 0.08474 mmol),
trans-1,2-diamino cyclohexane (29.108 mg, 0.2542 mmol) and
potassium carbonate (234.3 mg, 1.6948 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1%
MeOH in chloroform) afforded 172 mg of the product (72.26%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.5 (s, 1H), 8.4 (d,
1H), 7.55-7.45 (m, 2H), 7.39-7.3 (d, 1H), 7.0-6.9 (m, 2H), 4.1-4.0
(m, 2H), 3.95-3.85 (m, 2H), 3.75 (s, 3H), 2.25 (s, 3H)
LCMS purity: 95.51%, m/z=284.1 (M+1)
HPLC: 96.79%
Example 38
Preparation of
1-(4-Chloro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(38A)
##STR00056##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474
mmol) was reacted with 1-bromo-4-chloro-benzene (162 mg, 0.8474
mmol), 1,4-dioxane (5 mL), copper iodide (16.142 mg, 0.08474 mmol),
trans-1,2-diamino cyclohexane (29.108 mg, 0.2542 mmol) and
potassium carbonate (234.3 mg, 1.6948 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1%
MeOH in chloroform) afforded 155 mg of the product (63.78%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.55 (s, 1H), 8.4 (d,
1H), 7.7-7.6 (m, 2H), 7.5-7.3 (m, 3H), 4.05-3.9 (m, 2H), 3.9-3.8
(m, 2H), 2.25 (s, 3H)
LCMS purity: 98.81%, m/z=287.9 (M+1)
HPLC: 96.55%
Example 39
Preparation of
4-[3-(4-Methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzonitrile
(39A)
##STR00057##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465
mmol) was reacted with 4-bromo-benzonitrile (154 mg, 0.84650 mmol),
1,4-dioxane (50 mL), copper iodide (16 mg, 0.084650 mmol),
trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and potassium
carbonate (468 mg, 3.3860 mmol) to afford the crude product.
Purification by column chromatography on silica gel (5% MeOH in
DCM) afforded 151 mg of the product (64.2% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.55 (s, 1H), 8.4 (d,
1H), 7.8 (s, 4H), 7.3 (d, 1H), 4.2-4.15 (m, 2H), 4.0-3.95 (m, 2H),
2.3 (s, 3H)
LCMS purity: 100.00%, m/z=278.9 (M+1)
HPLC: 98.45%
Example 40
Preparation of
1-Benzooxazol-2-yl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(40A)
##STR00058##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg,
0.84650 mmol) was reacted with 2-chloro-benzooxazole (96 mL,
0.84650 mmol), 1,4-dioxane (50 mL), copper iodide (16 mg, 0.084650
mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and
potassium carbonate (468 mg, 3.3860 mmol) to afford the crude
product. Purification by column chromatography on silica gel (2%
MeOH in DCM) afforded 40 mg of the product (16% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.7-8.6 (br s, 1H),
8.5-8.45 (br s, 1H), 7.75-7.6 (m, 2H), 7.5 (d, 1H), 7.4-7.25 (m,
2H), 4.35-4.25 (m, 2H), 4.15-4.05 (m, 2H), 2.3 (s, 3H)
LCMS purity: 96.56%, m/z=295.1 (M+1)
HPLC: 95.79%
Example 41
Preparation of
1-(5-Chloro-thiophen-2-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(41A)
##STR00059##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 300 mg, 1.6949
mmol) was reacted with 2-bromo-5-chloro-thiophene (0.185 mL, 1.6949
mmol), 1,4-dioxane (10 mL), copper iodide (32 mg, 0.169 mmol),
trans-1,2-diamino cyclohexane (58 mg, 0.5084 mmol) and potassium
carbonate (467 mg, 3.3898 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1% MeOH in
DCM) afforded 240 mg of the product (48.4% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.59 (s, 1H), 8.45 (d,
1H), 7.4 (d, 1H), 6.97 (d, 1H), 6.38 (d, 1H), 4.05 (s, 4H), 2.3 (s,
3H)
LCMS purity: 93.37%, m/z =293.8 (M+1)
HPLC: 99.32%
Example 42
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-thiophen-2-yl-imidazolidin-2-one
(42A)
##STR00060##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847
mmol) was reacted with 2-bromo-thiophene (0.08 mL, 0.847 mmol),
1,4-dioxane (10 mL), copper iodide (16.13 mg, 0.0847 mmol),
trans-1,2-diamino cyclohexane (0.03 mL) and potassium carbonate
(233 mg, 1.694 mmol) to afford the crude product. Purification by
column chromatography on silica gel (1% MeOH in DCM) afforded 240
mg of the product (48.4% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.5 (s, 1H), 8.4 (d,
1H), 7.36 (d, 1H), 6.98 (dd, 1H), 6.92-6.86 (m, 1H), 6.5 (dd, 1H),
4.1-3.96 (m, 4H), 2.26 (s, 3H)
LCMS purity: 96.18%, m/z =260.0 (M+1)
HPLC: 98.53%
Example 43
Preparation of
1-(6-Hydroxy-pyridin-3-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(43A)
##STR00061##
1-(6-Fluoro-pyridin-3-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(30A: 0.1 g, 0.00036 mmol) in 5% HCl (10 mL) was added into the
reaction flask and the flask was heated to reflux at 100.degree. C.
overnight. The reaction was monitored by TLC (10% MeOH in
chloroform. The reaction mixture was basified with NaHCO.sub.3
solution and extracted with chloroform. The organic layer was
washed with water, brine solution, dried and concentrated to afford
72 mg of the product (98.96% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.5 (s, 1H), 8.35 (d,
1H), 7.75 (dd, 1H), 7.6-7.5 (m, 1H), 7.35 (d, 1H), 6.3 (d, 1H),
3.85 (s, 4H), 2.25 (s, 3H)
LCMS purity: 96.74%, m/z=270.9 (M+1)
HPLC: 98.42%
Example 44
Preparation of
N-Methyl-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzamide
(44A)
##STR00062##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg,
0.84650 mmol) was reacted with 4-bromo-benzoic acid methyl ester
(182 mg, 0.84650 mmol), 1,4-dioxane (50 mL), copper iodide (16 mg,
0.084650 mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol)
and potassium carbonate (468 mg, 3.3860 mmol) to afford the crude
product. Purification by column chromatography on silica gel (5%
MeOH in DCM) afforded 230 mg of
4-[3-(4-Methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzoic acid
methyl ester (91.6% yield).
LiOH (46.4 mg, 3.782 mmol) was added to a stirred solution of
4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzoic acid
methyl ester (230 mg, 0.7387 mmol) in (3:2:1) THF (10 mL, water (6
mL) and MeOH (3 mL). The reaction mixture was stirred at room
temperature for 4 hours. The reaction was monitored by TLC (10%
MeOH in DCM). The reaction mixture was concentrated under reduced
pressure, followed by the addition of ice water and neutralized
with 1N HCl till a pH of about 2 was attained. The precipitate was
collected and dried under reduced pressure to afford 210 mg of
4-[3-(4-Methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzoic acid
(95% yield).
EDCI (176.4 mg, 0.9205 mmol), HOBt (5.8 mg, 0.2525 mmol), DIPEA
(0.3 mL, 2.3006 mmol) and methylamine hydrochloride (62 mg, 0.9205
mmol) were added to a stirred solution of
4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzoic acid
(228 mg, 0.7668 mmol) in dry DMF (10 mL) at 0.degree. C. under
nitrogen atmosphere. The reaction mixture was stirred at room
temperature for 12 hours. The reaction mixture was partitioned
between water and ethylacetate. The organic layer was washed with
water, brine solution, dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure. Purification by column chromatography on
silica gel (5% MeOH in DCM) afforded 155 mg of the product (65.4%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.65-8.55 (br s, 1H),
8.45-8.4 (br s, 1H), 8.35 (d, 1H), 7.9 (d, 2H), 7.7 (d, 2H), 7.4
(d, 1H), 4.15-4.05 (m, 2H), 4.0-3.85 (m, 2H), 2.8 (d, 3H), 2.3 (s,
3H)
LCMS purity: 87.61%, m/z=311.1 (M+1)
HPLC: 98.28%
Example 45
Preparation of
1-(3,4-Difluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(45A)
##STR00063##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474
mmol) was reacted with 4-bromo-1,2-difluoro-benzene (163.5 mg,
0.8474 mmol), 1,4-dioxane (5 mL), copper iodide (16.14 mg, 0.08474
mmol), trans-1,2-diamino cyclohexane (29.10 mg, 0.253942 mmol) and
potassium carbonate (234.3 mg, 1.6948 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1%
MeOH in CHCl.sub.3) afforded 205 mg of the product (84.01%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.55 (s, 1H), 8.39 (d,
1H), 7.85-7.75 (m, 1H), 7.5-7.35 (m, 3H), 4.1-3.9 (m, 4H), 2.26 (s,
3H)
LCMS purity: 98.17%, m/z =290.0 (M+1)
HPLC: 98.83%
Example 46
Preparation of
1-(3-Chloro-4-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(46A)
##STR00064##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465
mmol) was reacted with 4-bromo-2-chloro-1-fluoro-benzene (102 mL,
0.8465 mmol), 1,4-dioxane (20 mL), copper iodide (16 mg, 0.08465
mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and
potassium carbonate (468 mg, 3.3860 mmol) to afford the crude
product. Purification by column chromatography on silica gel (5%
MeOH in DCM) afforded 220 mg of the product (84. 2% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.55 (s, 1H), 8.4 (d,
1H), 7.9 (dd, 1H), 7.6-7.55 (m, 1H), 7.45-7.35 (m, 2H), 4.15-4.0
(m, 2H), 4.0-3.9 (m, 2H), 2.3 (s, 3H)
LCMS purity: 96.91%, m/z =306.0 (M+1)
HPLC: 98.62%
Example 47
Preparation of
1-Benzothiazol-2-yl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(47A)
##STR00065##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.84
mmol) was reacted with 2-bromo-benzothiazole (179 mg, 0.847 mmol),
1,4-dioxane (10 mL), copper iodide (16 mg, 0.084 mmol),
trans-1,2-diamino cyclohexane (28.8 mg, 0.25 mmol) and potassium
carbonate (231 mg, 1.68 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1.5% MeOH in
CHCl.sub.3) afforded 95 mg of the product (36.5% yield).
.sup.1H NMR (DMSO-.sub.6, 300 MHz): .delta. 8.6 (s, 1H), 8.45 (d,
1H), 8.3 (s, 1H), 7.95 (d, 1H), 7.75 (d, 1H), 7.45-7.35 (m, 1H),
7.3-7.25 (m, 1H), 4.35 (t, 2H), 4.05 (t, 2H), 2.3 (s, 3H)
LCMS purity: 98.81%, m/z=310.9 (M+1)
HPLC: 97.25%
Example 48
Preparation of
1-(1H-Indol-5-O-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(48A)
##STR00066##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 250 mg, 1.412
mmol) was reacted with 5-bromo-indole-1-carboxylic acid tert-butyl
ester (0.499 g, 1.691 mmol), 1,4-dioxane (15 mL), copper iodide
(0.0080 g), trans-1,2-diamino cyclohexane (0.0241 g, 0.2110 mmol)
and potassium carbonate (0.389 g, 2.818 mmol) to afford the crude
product. Purification by column chromatography on silica gel (10%
MeOH in CHCl.sub.3) afforded 125 mg of
5-[3-(4-Methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-indole-1--
carboxylic acid tert-butyl ester (24% yield).
2N HCl (6 mL) was added to a solution of
5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-indole-1-carboxylic
acid tert-butyl ester (120 mg, 0.0306 mmol) in MeOH (3 mL) at
0.degree. C. The reaction mixture was stirred at room temperature
for 19 hours. The reaction was monitored by TLC (10% MeOH in
CHCl.sub.3). The resulting mixture was neutralized with
NaHCO.sub.3, filtered and dried to afford the crude product.
Purification by preparative HPLC afforded 17 mg of the product
(19.1% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 10.8 (s, 1H), 8.6 (s,
1H), 8.55 (s, 1H), 8.45-8.4 (m, 1H), 7.6 (s, 1H), 7.55-7.45 (m,
2H), 7.35-7.25 (m, 2H), 3.6-3.5 (m, 4H), 2.35 (s, 3H)
LCMS purity: 98.00%, m/z =293.0 (M+1)
HPLC: 92.87%
Example 49
Preparation of
1-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazoli-
din-2-one (49A)
##STR00067##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.84
mmol) was reacted with 6-bromo-2,3-dihydrobenzo[1,4]dioxine (180
mg, 0.84 mmol), 1,4-dioxane (10 mL), copper iodide (16 mg, 0.084
mmol), trans-1,2-diamino cyclohexane (28.8 mg, 0.25 mmol) and
potassium carbonate (231 mg, 1.68 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1%
MeOH in CHCl.sub.3) afforded 110 mg of the product (42.1%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.55 (s, 1H), 8.4 (d,
1H), 7.4 (d, 1H), 7.2 (d, 1H), 7.0 (dd, 1H), 6.85 (d, 1H), 4.3-4.2
(m, 4H), 4.0-3.9 (m, 4H), 2.3 (s, 3H)
LCMS purity: 99.67%, m/z =311.9 (M+1)
HPLC: 98.00%
Example 50
Preparation of
1-(4-Methyl-pyridin-3-O-3-(4-trifluoromethyl-phenyl)-imidazolidin-2-one
(50A)
##STR00068##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474
mmol) was reacted with 1-bromo-4-trifluoromethyl-benzene (92 mL,
1.0168 mmol), 1,4-dioxane (20 mL), copper iodide (16 mg, 0.08484
mmol), trans-1,2-diamino cyclohexane (20 mL, 0.254 mmol) and
potassium phosphate (355 mg, 212.27 mmol) to afford the crude
product. Purification by column chromatography on silica gel (2%
MeOH in CHCl.sub.3) afforded 180 mg of the product (66% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.6 (s, 1H), 8.4 (d,
1H), 7.9-7.5 (m, 4H), 7.4 (d, 1H), 4.15-4.05 (m, 2H), 4.0-3.9 (m,
2H), 2.3 (s, 3H)
LCMS purity: 99.63%, m/z =321.8 (M+1)
HPLC: 99.1%
Example 51
Preparation of
1-(2,3-Dihydro-benzofuran-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2--
one (51A)
##STR00069##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.84
mmol) was reacted with 5-bromo-2,3-dihydro-benzofuran (167 mg, 0.84
mmol), 1,4-dioxane (10 mL), copper iodide (16 mg, 0.084 mmol),
trans-1,2-diamino cyclohexane (28.8 mg, 0.25 mmol) and potassium
phosphate (445 mg, 2.1 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1% MeOH in
CHCl.sub.3) afforded 200 mg of the product (80.9% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.5 (s, 1H), 8.35 (d,
1H), 7.5 (s, 1H), 7.3 (d, 1H), 7.2 (d, 1H), 6.8 (d, 1H), 4.5 (t,
2H), 4.0-3.85 (m, 4H), 3.2 (t, 2H), 2.3 (s, 3H)
LCMS purity: 90.40%, m/z=296.1 (M+1)
HPLC: 98.45%
Example 52
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-quinolin-6-yl-imidazolidin-2-one
(52A)
##STR00070##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 200 mg, 1.13
mmol) was reacted with 6-bromo-quinoline (233.9 mg, 1.13 mmol),
1,4-dioxane (15 mL), copper iodide (16.53 mg, 0.113 mmol),
trans-1,2-diamino cyclohexane (0.04 mL, 0.339 mmol) and potassium
carbonate (312 mg, 2.26 mmol) to afford the crude product.
Purification by column chromatography on silica gel (0.5% MeOH in
CHCl.sub.3) afforded 150 mg of the product (43.668% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.8 (dd, 1H), 8.58 (s,
1H), 8.45-8.35 (m, 2H), 8.3 (d, 1H), 8.0 (d, 1H), 7.86 (d, 1H),
7.52-7.48 (m, 1H), 7.37 (d, 1H), 4.24-4.16 (m, 2H), 4.02-3.98 (m,
2H), 2.31 (s, 3H)
LCMS purity: 99.55%, m/z =305.2 (M+1)
HPLC: 95.53%
Example 53
Preparation of
1-(3-Fluoro-4-methoxy-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-on-
e (53A)
##STR00071##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474
mmol) was reacted with 4-bromo-2-fluoro-1-methoxy-benzene (191 mg,
0.932 mmol), 1,4-dioxane (20 mL), copper iodide (16 mg, 0.08474
mmol), trans-1,2-diamino cyclohexane (29.4 mg, 0.2542 mmol) and
potassium phosphate (449 mg, 2.11 mmol) to afford 220 mg of the
product (86% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.5 (s, 1H), 8.4 (d,
1H), 7.7-7.6 (dd, 1H), 7.35 (d, 1H), 7.3-7.1 (m, 2H), 4.0-3.8 (m,
7H), 2.3 (s, 3H)
LCMS purity: 99.59%, m/z=301.9 (M+1)
HPLC: 98.6%
Example 54
Preparation of
1-(4-Chloro-3-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(54A)
##STR00072##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474
mmol) was reacted with 4-bromo-1-chloro-2-fluoro-benzene (213 mg,
1.0168 mmol), 1,4-dioxane (20 mL), copper iodide (16 mg, 0.08474
mmol), trans-1,2-diamino cyclohexane (29.4 mg, 0.2542 mmol) and
potassium phosphate (449.7 mg, 2.1185 mmol) to afford 190 mg of the
product (73% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.5 (s, 1H), 8.4 (d,
1H), 7.6 (dd, 1H), 7.4-7.3 (m, 2H), 7.25-7.2 (m, 1H), 4.1-3.9 (m,
4H), 2.35 (s, 3H)
LCMS purity: 96.94%, m/z =306.1 (M+1)
HPLC: 96.4%
Example 55
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-m-tolyl-imidazolidin-2-one (55A)
##STR00073##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847
mmol) was reacted with 1-bromo-3-methyl-benzene (172.8 mg, 1.017
mmol), 1,4-dioxane (20 mL), copper iodide (16.13 mg, 0.0847 mmol),
trans-1,2-diamino cyclohexane (0.03 mL, 0.254 mmol) and potassium
phosphate (539.3 mg, 2.541 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1.2% MeOH in
CHCl.sub.3) afforded 153 mg of the product (67.69% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.54 (s, 1H), 8.38 (d,
1H), 7.48-7.38 (m, 2H), 7.35 (d, 1H), 7.23 (t, 1H), 6.86 (d, 1H),
4.08-3.98 (m, 2H), 3.96-3.88 (m, 2H), 2.28 (s, 3H), 2.32 (s,
3H)
LCMS purity: 93.74%, m/z =268.1 (M+1)
HPLC: 96.86%
Example 56
Preparation of
1-(3-Methoxy-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(56A)
##STR00074##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg,
0.84650 mmol) was reacted with 1-bromo-3-methoxy-benzene (107 mg,
0.84650 mmol), 1,4-dioxane (50 mL), copper iodide (16 mg, 0.08465
mmol), trans-1,2-diamino cyclohexane (0.03 mL, 0.2539 mmol) and
potassium phosphate (538 mg, 2.539 mmol) to afford the crude
product. Purification by column chromatography on silica gel (2%
MeOH in CHCl.sub.3) afforded 180 mg of the product (75% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.55 (s, 1H), 8.4 (d,
1H), 7.4 (d, 1H), 7.35-7.25 (m, 2H), 7.2 (d, 1H), 6.65 (dd, 1H),
4.15-4.0 (m, 2H), 4.0-3.95 (m, 2H), 3.75 (s, 3H), 2.3 (s, 3H)
LCMS purity: 95.82%, m/z =283.9 (M+1)
HPLC: 97.25%
Example 57
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-(4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl-
)-imidazolidin-2-one, hydrochloride (57A)
##STR00075##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 50 mg, 0.28216
mmol) was reacted with
2-bromo-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid
tert-butyl ester (90 mg, 0.28216 mmol), 1,4-dioxane (20 mL), copper
iodide (5.3 mg, 0.0282 mmol), trans-1,2-diamino cyclohexane (9.69
mg, 0.08464 mmol) and potassium phosphate (179.6 mg, 0.84650 mmol)
to afford the crude product. Purification by column chromatography
on silica gel (2% MeOH in DCM) afforded 70 mg of
2[3-(4-Methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-4,7-dihydro-5H-thien-
o[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (60%
yield).
6N HCl (5 mL) was added dropwise to stirred solution of
2-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-4,7-dihydro-5H-thie-
no[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (70 mg,
0.16887 mmol) in methanol (2 mL) at 0.degree. C. The reaction
mixture was stirred at room temperature for 12 hours. The reaction
was monitored by TLC (5% MeOH in DCM). The solvent was distilled
from the reaction mixture under reduced pressure, followed by the
addition of diethyl-ether. The precipitate was washed with ether
and dried under reduced pressure to afford 36 mg of the product
(61% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.55 (s, 2H), 8.8 (s,
1H), 8.7-8.5 (m, 2H), 7.8 (d, 1H), 6.35 (s, 1H), 4.2 (s, 2H), 4.0
(s, 4H), 3.4 (t, 2H), 2.8 (t, 2H), 2.4 (s, 3H)
LCMS purity: 90.09%, m/z=315.1 (M+1)
HPLC: 84.27%
Example 58
Preparation of
1-(2-Chloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(58A)
##STR00076##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 600 mg, 3.3898
mmol) was reacted with 2-chloro-4-iodo-pyridine (974 mg, 4.067
mmol), 1,4-dioxane (60 mL), copper iodide (65 mg, 0.3398 mmol),
trans-1,2-diamino cyclohexane (0.12 mL, 1.0169 mmol) and potassium
phosphate (2.15 g, 10.1694 mmol) to afford 810 mg of the product
(83% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.5-8.4 (m, 2H), 8.3 (d,
1H), 7.6-7.5 (m, 2H), 7.2 (s, 1H), 4.1-3.9 (m, 4H), 2.35 (s,
3H)
LCMS purity: 90.8%, m/z=289.1 (M+1)
HPLC: 97.14%
Example 59
Preparation of
1-(4-Fluoro-3-methyl-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(59A)
##STR00077##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 160 mg, 0.9039
mmol) was reacted with 4-bromo-1-fluoro-2-methyl-benzene (0.135 mL,
0.7142 mmol), 1,4-dioxane (15 mL), copper iodide (0.005 g, 0.0263
mmol), trans-1,2-diamino cyclohexane (0.015 g, 0.1315 mmol) and
potassium phosphate (0.575 g, 2.7094 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1%
MeOH in chloroform) afforded 26 mg of the product (30% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.6-8.4 (m, 2H), 7.5-7.4
(m, 1H), 7.35-7.25 (m, 2H), 7.0 (t, 1H), 4.1-3.9 (m, 4H), 2.4 (s,
3H), 2.3 (s, 3H)
LCMS purity: 95.40%, m/z=286.0 (M+1)
HPLC: 94.03%
Example 60
Preparation
1-(5-Chloro-2-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(60A)
##STR00078##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg,
0.84650 mmol) was reacted with 2-bromo-4-chloro-1-fluoro-benzene
(177 mg, 0.84650 mmol), 1,4-dioxane (10 mL), copper iodide (16 mg,
0.084650 mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol)
and potassium phosphate (538 mg, 2.539 mmol) to afford the crude
product. Purification by column chromatography on silica gel (2%
MeOH in DCM) afforded 180 mg of the product (69.7% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.6-8.5 (br s, 1H),
8.4 (d, 1H), 7.7 (d, 1H), 7.4-7.3 (m, 3H), 4.1-3.85 (m, 4H), 2.15
(s, 3H)
LCMS purity: 98.67%, m/z=305.8 (M+1)
HPLC: 92.0%
Example 61
Preparation of
1-(2,4-Difluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(61A)
##STR00079##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474
mmol) was reacted with 1-bromo-2,4-difluoro-benzene (0.114 mL,
1.0169 mmol), 1,4-dioxane (20 mL), copper iodide (16 mg, 0.08474
mmol), trans-1,2-diamino cyclohexane (29.4 mg, 0.254 mmol) and
potassium phosphate (449.7 mg, 2.118 mmol) to afford the crude
product. Purification by column chromatography on silica gel (2%
MeOH in CHCl.sub.3) afforded 150 mg of the product (61% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.52 (s, 1H), 8.39 (d,
1H), 7.65-7.55 (m, 1H), 7.45-7.30 (m, 2H), 7.2-7.1 (m, 1H), 3.9 (s,
4H), 2.3 (s, 3H)
LCMS purity: 99.49%, m/z=290.2 (M+1)
HPLC: 95.04%
Example 62
Preparation of
1-Benzothiazol-5-yl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(62A)
##STR00080##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg,
0.84650 mmol) was reacted with 5-iodo-benzothiazole (221 mg.
0.84650 mmol), 1,4-dioxane (25 mL), copper iodide (16 mg, 0.084650
mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and
potassium phosphate (538 mg, 2.539 mmol) to afford the crude
product. Purification by column chromatography on silica gel (2%
MeOH in DCM) afforded 185 mg of the product (70.6% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.4 (s, 1H), 8.59 (s,
1H), 8.4 (d, 1H), 8.24-8.22 (m, 1H), 8.15-8.1 (m, 1H), 8.0-7.9 (m,
1H), 7.39 (d, 1H), 4.2-4.1 (m, 2H), 4.0-3.9 (m, 2H), 2.3 (s,
3H)
LCMS purity: 93.36%, m/z =311 (M+1)
HPLC: 95.21%
Example 63
Preparation of
6-[3-(4-Methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-3,4-dihydro-1H-quin-
olin-2-one (63A)
##STR00081##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474
mmol) was reacted with
6-bromo-2-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl
ester (276 mg, 0.8474 mmol), 1,4-dioxane (5 mL), copper iodide
(16.14 mg, 0.08474 mmol), trans-1,2-diamino cyclohexane (29.1 mg,
0.2542 mmol) and potassium carbonate (234.3 mg, 1.6948 mmol) to
afford the crude product. Purification by preparative HPLC afforded
86 mg of the product (31.5% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 10.0 (s, 1H), 8.5 (s,
1H), 8.4 (d, 1H), 7.5-7.3 (m, 3H), 6.9-6.75 (d, 1H), 4.0-3.85 (m,
4H), 2.85 (t, 2H), 2.45-2.4 (m, 2H), 2.3 (s, 3H)
LCMS purity: 96.55%, m/z=322.9 (M+1)
HPLC: 97.13%
Example 64
Preparation of
1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazol-
idin-2-one (64A)
##STR00082##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg,
0.84650 mmol) was reacted with
5-bromo-2,2-difluoro-benzo[1,3]dioxole (200.6 mg, 0.84650 mmol),
1,4-dioxane (50 mL), copper iodide (16 mg, 0.084650 mmol),
trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and potassium
phosphate (538 mg, 2.539 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
DCM) afforded 260 mg of the product (92% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.6-8.4 (m, 2H),
7.7-7.69 (m, 1H), 7.25-7.2 (m, 1H), 7.06-6.9 (m, 2H), 4.1-3.9 (m,
4H), 2.35 (s, 3H)
LCMS purity: 95.12%, m/z=333.6 (M+1)
HPLC: 92.82%
Example 65
Preparation of
7-[3-(4-Methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-3,4-dihydro-1H-quin-
olin-2-one (65A)
##STR00083##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 0.15 g,
0.00084 mol) was reacted with
7-bromo-2-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl
ester (0.276 g 0.00084 mol), 1,4-dioxane (20 mL), copper iodide
(0.0158 g, 0.000084 mol), trans-1.2-diamino cyclohexane (0.28 g,
0.00025 mol) and potassium phosphate (0.356 g, 0.00168 mol) to
afford the crude product. Purification by column chromatography on
silica gel (5% MeOH in CHCl.sub.3) afforded 0.145 g of
7-[3-(4-Methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-2-oxo-3,4-dihydro-2-
H-quinoline-1-carboxylic acid tert-butyl ester (67.48% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.1-8.02 (br s, 1H),
7.15-7.0 (m, 2H), 6.99-6.92 (m, 1H), 2.95 (t, 2H), 2.65 (t, 2H),
2.1-2.0 (m, 2H), 1.8-1.7 (m, 1H), 1.45-1.40 (m, 5H), 1.25 (s,
11H)
Dioxane hydrochloride (3 mL) was added to
7-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-2-oxo-3,4-dihydro-2-
H-quinoline-1-carboxylic acid tert-butyl ester (0.145 g, 0.00034
mol) at 0.degree. C. The resulting reaction mixture was stirred at
room temperature for 2 hours. The reaction was monitored by TLC
(40% ethylacetate in hexane). Purification by preparative HPLC,
followed by column chromatography on silica gel (5% MeOH in
CHCl.sub.3) afforded 48 mg of the product (35.47% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 10.09 (s, 1H), 8.52
(s, 1H), 8.35 (d, 1H), 7.35 (d, 1H), 7.3-7.22 (m, 1H), 7.19-7.0 (m,
2H), 4.0-3.84 (m, 4H), 2.82 (t, 2H), 2.45-2.40 (m, 2H), 2.27 (s,
3H)
LCMS purity: 99.47%, m/z =322.8 (M+1)
Example 66
Preparation of
N-{3-[3-(4-Methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-phenyl}-acetamid-
e (66A)
##STR00084##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474
mmol) was reacted with N-(3-bromo-phenyl)-acetamide (217.6 mg,
1.0169 mmol), 1,4-dioxane (20 mL), copper iodide (16 mg, 0.08474
mmol), trans-1,2-diamino cyclohexane (449.7 mg, 0.2542 mmol) and
potassium phosphate (29.4 mg, 2.1185 mmol) to afford the crude
product. Purification by column chromatography on silica gel (5%
MeOH in CHCl.sub.3), followed by preparative HPLC afforded 60 mg of
the product (23% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.95 (s, 1H), 8.52 (s,
1H), 8.37 (d, 1H), 7.85 (s, 1H), 7.4-7.2 (m, 4H), 4.02-3.82 (m,
4H), 2.28 (s, 3H), 2.02 (s, 3H)
LCMS purity: 99.02%, m/z=310.9 (M+1) HPLC: 99.6%
Example 67
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-(3-methyl-thiophen-2-yl)-imidazolidin-2-one
(67A)
##STR00085##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.84
mmol) was reacted with 2-bromo-3-methyl-thiophene (150 mg, 0.84
mmol), 1,4-dioxane (10 mL), copper iodide (16 mg, 0.084 mmol),
trans-1,2-diamino cyclohexane (28.8 mg, 0.25 mmol) and potassium
phosphate (445 mg, 2.1 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
DCM) afforded 130 mg of the product (56.7% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.52 (s, 1H), 8.39 (d,
1H), 7.39-7.25 (dd, 2H), 6.85 (d, 1H), 4.0-3.82 (m, 4H), 2.29 (s,
3H), 2.12 (s, 3H)
LCMS purity: 98.05%, m/z=274.0 (M+1)
HPLC: 98.08%
Example 68
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-(2-methyl-quinolin-6-yl)-imidazolidin-2-one
(68A)
##STR00086##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 0.150 g, 0.847
mmol) was reacted with 6-bromo-2-methyl-quinoline (0.225 g, 1.016
mmol), 1,4-dioxane (20 mL), copper iodide (0.016 g, 0.084 mmol),
trans-1,2-diamino cyclohexane (0.029 g, 0.254 mmol) and potassium
phosphate (0.449 g, 2.1 mmol) to afford the crude product.
Purification by column chromatography on silica gel (5% MeOH in
CHCl.sub.3) afforded 115 mg of the product (43% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.55 (s, 1H), 8.45 (d,
1H), 8.12 (dd, 1H), 8.05-8.0 (m, 2H), 7.85 (d, 1H), 7.3-7.2 (m,
2H), 4.24-4.15 (m, 2H), 4.05-3.95 (m, 2H), 2.75 (s, 3H), 2.39 (s,
3H)
LCMS purity: 99.63%, m/z=318.9 (M+1) HPLC: 98.15%
Example 69
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-phenyl-imidazolidin-2-one (69A)
##STR00087##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 100 mg, 0.5643
mmol) was reacted with bromo-benzene (89 mg, 0.5643 mmol),
1,4-dioxane (20 mL), copper iodide (10 mg), trans-1,2-diamino
cyclohexane (20 mg) and potassium phosphate (359 mg, 1.693 mmol) to
afford the crude product. Purification by column chromatography on
silica gel (1.2-1.4% MeOH in CHCl.sub.3) afforded 132 mg of the
product (92.30% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.6-8.3 (m, 2H),
7.65-7.6 (m, 2H), 7.42-7.3 (m, 3H), 7.05 (t, 1H), 4.1-3.85 (m, 4H),
2.28 (s, 3H)
LCMS purity: 95.32%, m/z =254.1 (M+1)
HPLC: 95.86%
Example 70
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-(3-trifluoromethyl-phenyl)-imidazolidin-2-One
(70A)
##STR00088##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847
mmol) was reacted with 1-bromo-3-trifluoromethyl-benzene (0.14 mL,
1.016 mmol), 1,4-dioxane (10 mL), copper iodide (16.13 mg, 0.0847
mmol), trans-1,2-diamino cyclohexane (0.03 mL, 0.254 mmol) and
potassium phosphate (539 mg, 2.54 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1.2%
MeOH in CHCl.sub.3) afforded 190 mg of the product (70.11%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.55 (s, 1H), 8.4 (d,
1H), 8.18-8.12 (br s, 1H), 7.8-7.77 (d, 1H), 7.6 (t, 1H), 7.42-7.32
(m, 2H), 4.15-4.05 (m, 2H), 4.0-3.9 (m, 2H), 2.29 (s, 3H)
LCMS purity: 95.74%, m/z =322.1 (M+1)
HPLC: 97.15%
Example 71
Preparation of
1-(1-Isopropyl-1H-pyrazol-4-yl)-3-(4-methyl-pyridin-3-O-imidazolidin-2-on-
e (71A)
##STR00089##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg,
0.84650 mmol) was reacted with 4-iodo-1-isopropyl-1H-pyrazole
(199.8 mg, 0.84650 mmol), 1,4-dioxane (50 mL), copper iodide (16
mg, 0.084650 mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539
mmol) and potassium phosphate (538 mg, 2.539 mmol) to afford the
crude product. Purification by column chromatography on silica gel
(2% MeOH in DCM) afforded 175 mg of the product (72.6% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.55-8.25 (m, 2H),
7.82 (s, 1H), 7.54 (s, 1H), 7.36-7.3 (m, 1H), 4.45 (quin, 1H),
4.0-3.8 (m, 4H), 2.25 (s, 3H), 1.4 (d, 6H)
LCMS purity: 99.86%, m/z =286.1 (M+1)
HPLC: 96.85%
Example 72
Preparation of
1-(2-Methoxy-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(72A)
##STR00090##
Sodium methoxide (225 mg, 4.165 mmol) was added dropwise to a
stirred solution of
1-(2-chloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(58A: 100 mg, 0.374 mmol) in 1,4-dioxane (20 mL) over a period of
10 minutes. The resulting mixture was heated to 110.degree. C. and
maintained at the same temperature for 4 days. The reaction was
monitored by TLC (10% MeOH in CHCl.sub.3). The solvent was
distilled from the reaction mixture and the concentrate was
partitioned between water and ethylacetate. The organic layer was
dried over Na.sub.2SO.sub.4 to afford the crude product.
Purification by column preparative HPLC afforded 30 mg of the
product (30.61% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.5 (s, 1H), 8.45 (d,
1H), 8.08 (d, 1H), 7.44 (dd, 1H), 7.25-7.2 (d, 1H), 6.75 (d, 1H),
4.09-3.9 (m, 7H), 2.35 (s, 3H)
LCMS purity: 96.29%, m/z=285.1 (M+1)
HPLC: 98.13%
Example 73
Preparation of 1-imidazolidin-2-one (73A)
##STR00091##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474
mmol) was reacted with 7-bromo-imidazo[1,2-a]pyridine (166.94 mg,
0.8474 mmol), 1,4-dioxane (5 mL), copper iodide (16.1 mg, 0.08474
mmol), trans-1,2-diamino cyclohexane (29.1 mg, 0.2542 mmol) and
potassium phosphate (539.63 mg, 2.542 mmol) to afford the crude
product. Purification by column chromatography on silica gel (3%
MeOH in CHCl.sub.3) afforded 69 mg of the product (29.15%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): a 8.8-8.7 (br s, 1H), 8.6-8.5
(br s, 1H), 8.45-8.35 (br s, 1H), 8.1-7.9 (br s, 1H), 7.85-7.7 (m,
1H), 7.65-7.5 (br s, 2H), 7.4-7.3 (d, 1H), 4.1-3.9 (m, 4H), 2.3 (s,
3H)
LCMS purity: 98.45%, m/z=294.1 (M+1)
HPLC: 98.56%
Example 74
Preparation of
1-(4-Fluoro-3-methoxy-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-on-
e (74A)
##STR00092##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474
mmol) was reacted with 4-bromo-1-fluoro-2-methoxy-benzene (191 mg,
0.9315 mmol), 1,4-dioxane (20 mL), copper iodide (16 mg, 0.08474
mmol), trans-1,2-diamino cyclohexane (29.4 mg, 0.254 mmol) and
potassium phosphate (449.7 mg, 2.118 mmol) to afford the crude
product. Purification by column chromatography on silica gel (5%
MeOH in CHCl.sub.3) afforded 170 mg of the product (66.7%
yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.52 (s, 1H), 8.42 (d,
1H), 7.8 (dd, 1H), 7.22 (d, 1H), 7.1-7.0 (m, 1H), 6.7-6.6 (m, 1H),
4.1-3.85 (m, 7H), 2.35 (s, 3H)
LCMS purity: 98.3%, m/z =301.8 (M+1)
HPLC: 96.74%
Example 75
Preparation of
N-{5-[3-(4-Methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-pyridin-2-yl}-ac-
etamide (75A)
##STR00093##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465
mmol) was reacted with N-(5-bromo-pyridin-2-yl)-acetamide (217.4
mg, 1.016 mmol), 1,4-dioxane (20 mL), copper iodide (16 mg, 0.08474
mmol), trans-1,2-diamino cyclohexane (29.4 mg, 0.254 mmol) and
potassium phosphate (449.7 mg, 2.118 mmol) to afford the crude
product. Purification by column chromatography on silica gel (2%
MeOH in CHCl.sub.3) afforded 105 mg of the product (40% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.6-8.4 (m, 3H), 8.22
(d, 1H), 8.1-8.0 (br s, 1H), 8.0-7.9 (m, 1H), 7.25-7.2 (m, 1H),
4.15-3.95 (m, 4H), 2.35 (s, 3H), 2.2 (s, 3H)
LCMS purity: 97.86%, m/z =311.9 (M+1)
HPLC: 90.08%
Example 76
Preparation of
1-(2-Amino-pyridin-4-yl)-3-(4-methyl-pyridin-3-O-imidazolidin-2-one
(76A)
##STR00094##
6N HCl (4 mL) was added to a solution of
N-{3-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-phenyl}-acetamid-
e (75A: 100 mg, 0.3212 mmol) in ethanol (4 mL). The resulting
reaction mixture was heated to 65.degree. C. and maintained at
65.degree. C. for 3 hours. The reaction was monitored by TLC (5%
MeOH in CHCl.sub.3). The reaction mixture was concentrated,
followed by the addition of ice, NaHCO.sub.3 and extracted with
DCM. The organic layer was dried over Na.sub.2SO.sub.4 and
concentrated. The concentrate was dissolved in DCM, followed by the
addition of hexane to afford the precipitate which was collected
and dried under reduced pressure to afford 55 mg of the product
(63.5% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.52 (s, 1H), 8.39 (d,
1H), 7.78 (d, 1H), 7.35 (d, 1H), 6.88-6.8 (m, 1H), 6.63 (s, 1H),
5.8 (s, 2H), 4.0-3.8 (m, 4H), 2.25 (s, 3H)
LCMS purity: 99.73%, m/z =270.0 (M+1)
HPLC: 95.60%
Example 77
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-quinoxalin-6-yl-imidazolidin-2-one
(77A)
##STR00095##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg,
0.84650 mmol) was reacted with 6-bromo-quinoxaline (176.9 mg,
0.84650 mmol), 1,4-dioxane (20 mL), copper iodide (16 mg, 0.084650
mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and
potassium phosphate (538 mg, 2.539 mmol) to afford the crude
product. Purification by column chromatography on silica gel (2%
MeOH in DCM) afforded 175 mg of the product (67.8% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.9 (d, 1H), 8.8 (d,
1H), 8.55 (dd, 2H), 8.48-8.39 (brS, 1H), 8.1 (d, 1H), 7.95 (d, 1H),
7.42-7.36 (m, 1H), 4.3-4.2 (m, 2H), 4.05-3.95 (m, 2H), 2.3 (s,
3H)
LCMS purity: 91.95%, m/z =306.1 (M+1)
HPLC: 96.82%
Example 78
Preparation of
1-(5-Difluoromethyl-thiophen-3-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-
-2-one (78A)
##STR00096##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474
mmol) was reacted with 4-bromo-2-difluoromethyl-thiophene (179.6
mg, 0.8474 mmol), 1.4-dioxane (5 mL), copper iodide (16.14 mg,
0.08474 mmol), trans-1,2-diamino cyclohexane (29.1 mg, 0.2542 mmol)
and potassium phosphate (539.59 mg, 2.542 mmol) to afford the crude
product. Purification by column chromatography on silica gel (2%
MeOH in CHCl.sub.3) afforded 22 mg of the product (8.5% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.9 (s, 1H), 8.55 (d,
1H), 7.9-7.6 (m, 2H), 7.06 (s, 1H). 6.5-7.0 (m, 1H), 4.1 (s, 4H),
2.68-(s, 3H)
LCMS purity: 95.24%, m/z =309.8 (M+1)
HPLC: 96.51%
Example 79
Preparation of
1-Naphthalen-2-yl-3-(5-trifluoromethyl-pyridin-3-yl)-imidazolidin-2-one
(79A)
##STR00097##
Step 1: Preparation of Intermediate
1-(2-Chloroethyl)-3-naphthalen-2-yl-urea (I-79a)
##STR00098##
1-Chloro-2-isocyanato-ethane (0.81 mL, 9.42 mmol) was added
dropwise to a stirred solution of naphthalen-2-ylamine (900 mg,
6.28 mmol) in toluene (50 mL) over a period of 30 minutes at
0.degree. C. The reaction temperature was maintained at room
temperature for 5 hours. The reaction was monitored by TLC (5% MeOH
in chloroform). The reaction mixture was filtered, washed with
toluene and dried under reduced pressure to afford 1.3 g (83%
yield) of 1-(2-chloro-ethyl)-3-naphthalen-2-yl-urea.
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.85 (s, 1H), 8.05 (d,
1H), 7.75 (m, 3H), 7.4 (m, 3H), 6.5 (t, 1H), 3.7 (t, 2H), 3.5 (q,
2H)
LCMS purity: 91.47%, m/z=249.1(M+1)
Step 2: Preparation of Intermediate
1-Naphthalen-2-yl-imidazolidin-2-one (I-79b)
##STR00099##
1-(2-Chloro-ethyl)-3-naphthalen-2-yl-urea (I-79a: 750 mg, 3.01
mmol) in dry DMF (10 mL) was added to a stirred solution of sodium
hydride (150 mg, 3.1 mmol) in THF (10 mL) at 0.degree. C. The
reaction temperature was maintained at room temperature for 30
minutes. The reaction was monitored by TLC (5% MeOH in chloroform,
double run). The reaction mixture was quenched with MeOH at
0.degree. C., concentrated under reduced pressure and partitioned
between ice water and chloroform. The organic layer was dried over
Na.sub.2SO.sub.4, and concentrated under reduced pressure to afford
600 mg (94% yield) of 1-naphthalen-2-yl-imidazolidin-2-one.
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.15 (dd, 1H), 7.85
(m, 3H), 7.7 (d, 1H), 7.5-7.3 (m, 2H), 7.05 (br s, 1H), 3.95 (t,
2H), 3.45 (t, 2H)
LCMS purity: 100%, m/z=213.1 (M+1)
Step 3: Preparation of
1-Naphthalen-2-yl-3-(5-trifluoromethyl-pyridin-3-.beta.-imidazolidin-2-on-
e (79A)
Copper iodide (12.6 mg, 0.066 mmol), trans-1,2-diamino cyclohexane
(22.79 mg, 0.199 mmol) and potassium carbonate (183.5 mg, 1.32
mmol) were added to 1,4-dioxane (5 mL) and
3-bromo-5-trifluoromethyl-pyridine (150 mg, 0.66 mmol) previously
degassed with argon (10 minutes). The reaction was purged with
argon for a further 10 minutes, followed by the addition of
1-naphthalen-2-yl-imidazolidin-2-one (I-79b: 140 mg, 0.66 mmol) and
the resulting mixture was heated to reflux at 110.degree. C. for 15
hours. The reaction was monitored by TLC (50% ethyl acetate in
hexane). The reaction mixture was filtered through celite and the
bed was washed with chloroform. The organic layer was dried over
Na.sub.2O.sub.4 and concentrated. Purification by column
chromatography (using silica gel of mesh size of 60-120, 30% EtOAc
in hexane as eluant) afforded 120 mg (52% yield) of
1-naphthalen-2-yl-3-(5-trifluoromethyl-pyridin-3-yl)-imidazolid-
in-2-one.
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.2 (d, 1H), 8.6 (d,
2H), 8.1 (dd, 1H), 8-7.86 (m, 4H), 7.56-7.4 (m, 2H), 4.1 (s,
4H)
LCMS purity: 94.5%, m/z=357.9 (M+1)
HPLC: 97.34%
Example 80
Preparation of
1-(5-Chloro-pyridin-3-O-3-naphthalen-2-yl-imidazolidin-2-one
(80A)
##STR00100##
Using the same reaction conditions as in Example 79,
1-naphthalen-2-yl-imidazolidin-2-one (I-79b: 110 mg, 0.5196 mmol)
was reacted with 3-bromo-5-chloro-pyridine (100 mg, 0.5196 mmol),
1,4-dioxane (5 mL), copper iodide (9.89 mg, 0.05196 mmol),
trans-1,2-diamino cyclohexane (17.84 mg. 0.1558 mmol) and potassium
carbonate (143.5 mg, 1.039 mmol) to afford the crude product.
Purification by column chromatography on silica gel (30% EtOAc
inhexane) afforded 35 mg of the product (21.45% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.83 (d, 1H),
8.35-8.25 (m, 2H), 8.15-8.05 (m, 1H), 7.95-7.85 (m, 4H), 7.55-7.4
(m, 2H), 4.25-4.1 (m, 2H), 4.05-4.0 (m, 2H)
LCMS purity: 97.21%, m/z=323.9 (M+1)
HPLC: 96.37%
Example 81
Preparation of
1-(5-Fluoro-pyridin-3-yl)-3-naphthalen-2-yl-imidazolidin-2-one
(81A)
##STR00101##
Using the same reaction conditions as in Example 79,
1-naphthalen-2-yl-imidazolidin-2-one (I-79b: 120 mg, 0.5681 mmol)
was reacted with 3-bromo-5-fluoro-pyridine (100 mg, 0.5681 mmol),
1,4-dioxane (5 mL), copper iodide (10.82 mg, 0.05681 mmol),
trans-1,2-diamino cyclohexane (19.51 mg, 0.1704 mmol) and potassium
carbonate (157.07 mg, 1.1362 mmol) to afford the crude product.
Purification by column chromatography on silica gel (30% EtOAc
inhexane) afforded 100 mg of the product (57.15% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.76 (t, 1H), 8.3 (d,
1H), 8.2-8.15 (m, 2H), 8.0-7.8 (m, 4H), 7.55-7.4 (m, 2H), 4.25-4.1
(m, 2H), 4.05-4.0 (m, 2H)
LCMS purity: 97.34%, m/z=308.2 (M+1)
HPLC: 97.51%
Example 82
Preparation of
1-(5-Methoxy-pyridin-3-yl)-3-naphthalen-2-yl-imidazolidin-2-one
(82A)
##STR00102##
Using the same reaction conditions as in Example 79,
1-naphthalen-2-yl-imidazolidin-2-one (I-79b: 112.7 mg, 0.5319 mmol)
was reacted with 3-bromo-5-methoxy-pyridine (100 mg, 0.5319 mmol),
1,4-dioxane (5 mL), copper iodide (10.13 mg, 0.05319 mmol),
trans-1,2-diamino cyclohexane (18.27 mg, 0.1595 mmol) and potassium
carbonate (147.07 mg, 1.0638 mmol) to afford the crude product.
Purification by column chromatography on silica gel (30% EtOAc in
hexane) afforded 48 mg of the product (30.3% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.5-8.45 (br s, 1H),
8.2-8.1 (m, 1H), 8.1-8.0 (d, 1H), 8.0-7.8 (m, 5H), 7.55-7.4 (m,
2H), 4.2-4.0 (m, 4H), 3.9 (s, 3H)
LCMS purity: 95.38%, m/z=320.2 (M+1)
HPLC: 97.64%
Example 83
Preparation of
5-(3-Naphthalen-2-yl-2-oxo-imidazolidin-1-yl)-nicotinic Acid Methyl
Ester (83A)
##STR00103##
Using the same reaction conditions as in Example 79,
1-naphthalen-2-yl-imidazolidin-2-one (I-79b: 100 mg, 0.4711 mmol)
was reacted with 5-bromo-nicotinic acid methyl ester (112 mg,
0.5182 mmol), 1,4-dioxane (10 mL), copper iodide (11 mg),
trans-1,2-diamino cyclohexane (22 mg) and potassium phosphate (200
mg, 0.9422 mmol) to afford the crude product. Purification by
column chromatography on silica gel (80% EtOAc in hexane) afforded
44 mg of the product (26.99% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 9.1 (d, 1H), 8.99-8.92
(m, 1H), 8.58 (t, 1H), 8.05 (dd, 1H), 7.9-7.7 (m, 4H), 7.5-7.4 (m,
2H), 4.22-4.14 (m, 2H), 4.12-4.04 (m, 2H), 3.98 (s, 3H)
LCMS purity: 93.43%, m/z =348.0 (M+1)
HPLC: 92.04%
Example 84
Preparation of
1-benzothiazol-6-yl-3-(4-chloro-pyridin-3-O-imidazolidin-2-one
(84A)
##STR00104##
Step 1: Preparation of Intermediate
1-benzothiazol-6-yl-3-(2-chloro-ethyl)-urea (I-84a)
1-Chloro-2-isocyanato-ethane (2.1 g, 19.99 mmol) was added drop
wise to a stirred solution of benzothiazol-6-ylamine (2 g, 13.33
mmol) in toluene (80 mL) over a period of 15 minutes at 0.degree.
C. The reaction mixture was stirred at room temperature for 18
hours. The reaction was monitored by TLC (50% ethyl acetate in
hexane). The reaction mixture was filtered, washed with toluene and
dried under reduced pressure to afford 2.73 g (80.2% yield) of
1-benzothiazol-6-yl-3-(2-chloro-ethyl)-urea.
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.19 (s, 1H), 8.96 (s,
1H), 8.26 (d, 1H), 7.94 (d, 1H), 7.4 (dd, 1H), 6.55 (t, 1H),
3.72-3.64 (t, 2H), 3.5-3.42 (m, 2H)
LCMS purity: 85.64%, m/z=256.0 (M+1)
Step 2: Preparation of 1-benzothiazol-6-yl-imidazolidin-2-one
(I-84b)
1-Benzothiazol-6-yl-3-(2-chloro-ethyl)-urea (I-84a: 2.7 g, 10.58
mmol) in dry DMF (80 mL) was added dropwise to a stirred mixture of
sodium hydride (0.76 g, 31.74 mmol) in THF (100 mL) over a period
of 20 minutes at 0.degree. C. under nitrogen atmosphere. The
reaction mixture was stirred at room temperature for 2 hours. The
reaction was monitored by TLC (100% ethyl acetate). The reaction
mixture was quenched with MeOH (6 mL), concentrated under reduced
pressure, followed by the addition of ice. The precipitate was
collected and dried under reduced pressure to afford 2.3 g (85.18%
yield) of 1-benzothiazol-6-yl-imidazolidin-2-one as the required
product.
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.24-9.2 (m, 1H),
8.24-8.19 (m, 1H), 8.04-7.84 (m, 2H), 7.1 (s, 1H), 3.95 (t, 2H),
3.45 (t, 2H)
CMS purity: 92.37%, m/z=220.0 (M+1)
Final Step: Preparation of
1-Benzothiazol-6-yl-3-(4-chloro-pyridin-3-yl)-imidazolidin-2-one
(84A)
Using the same reaction conditions as in Example 14,
1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 0.150 g, 0.684 mmol)
was reacted with 3-bromo-4-chloro-pyridine (0.157 g, 0.820 mmol),
1,4-dioxane (20 mL), copper iodide (0.012 g, 0.0684 mmol),
trans-1,2-diamino cyclohexane (0.022 g. 0.20 mmol) and potassium
phosphate (0.362 g, 1.71 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
CHCl.sub.3) afforded 85 mg of the product (37.7% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.23 (s, 1H), 8.79 (s,
1H), 8.56 (d, 1H), 8.30 (d, 1H), 8.13 (d, 1H), 7.99 (d, 1H), 7.75
(d, 1H), 4.2-4.1 (m, 2H), 4.02-3.94 (m, 2H)
LCMS purity: 95.81%, m/z=331.0 (M+1)
HPLC: 95.36%
Example 85
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-(2-pyrrolidin-1-yl-pyridin-4-yl)-imidazolidin-
-2-one (85A)
##STR00105##
1-(2-Chloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(58A: 100 mg, 0.3463 mmol) and pyrrolidine (0.145 mL, 1.7317 mmol)
were added to toluene previously degassed for 10 minutes. The
resulting mixture was stirred for 5 minutes. This was followed by
the addition of Pd(OAc).sub.2 (4 mg, 0.01732 mmol),
diphenyl-phosphino-propane (14.3 mg, 0.03463 mmol) and potassium
tertiary butoxide (66 mg, 0.6926 mmol) and stirring was continued
for a further 10 minutes. The reaction mixture was heated to reflux
for 16 hours. The reaction was monitored by TLC (10% MeOH in
CHC1.sub.3). The reaction mixture was cooled to room temperature,
filtered and the filtrate was concentrated. Purification by column
chromatography on silica gel (8% MeOH in chloroform) afforded 45 mg
of the product (40% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.5 (s, 1H), 8.4 (d,
1H), 8.1 (d, 1H), 7.25-7.2 (m, 1H), 6.98-6.94 (br s, 1H), 6.6 (dd,
1H), 4.1-3.9 (m, 4H), 3.5 (t, 4H), 2.35 (s, 3H), 2.05-1.95 (m,
4H)
LCMS purity: 99.8%, m/z=324.2 (M+1)
HPLC: 84.5%
Example 86
Preparation of
1-(3-Chloro-2-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(86A)
##STR00106##
Using the same reaction conditions as described in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 0.15 g, 0.847
mmol) was reacted with 1-bromo-3-chloro-2-fluoro-benzene (0.211 g,
1.016 mmol), 1,4-dioxane (20 mL), copper iodide (0.015 g, 0.084
mmol), trans-1,2-diamino cyclohexane (0.028 g, 0.254 mmol) and
potassium phosphate (0.445 g, 2.1 mmol) to afford 8 mg of the
product (0.03% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.68 (s, 1H), 8.49 (d,
1H), 7.6-7.45 (m, 3H), 7.3-7.22 (m, 1H), 4.09-3.95 (m, 4H), 2.36
(s, 3H)
LCMS purity: 96.83%, m/z=306.0 (M+1)
HPLC: 98.93%
Example 87
Preparation of
1-(4'-Fluoro-biphenyl-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(87A)
##STR00107##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 100 mg, 0.5649
mmol) was reacted with 4'-fluoro-4-iodo-biphenyl (198 mg, 0.675
mmol), 1,4-dioxane (15 mL), copper iodide (0.0096 g, 0.0504 mmol),
trans-1,2-diamino cyclohexane (0.0032 g, 0.0280 mmol) and potassium
phosphate (0.359 g, 1.691 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1% MeOH in
CHCl.sub.3), followed by preparative HPLC afforded 12 mg of the
product (12.35% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.55 (s, 1H), 8.42 (d,
1H), 7.7-7.64 (m, 2H), 7.6-7.5 (m, 3H), 7.24-7.2 (m, 2H), 7.15-7.05
(m, 2H), 4.15-4.05 (m, 2H), 4.0-3.9 (m, 2H), 2.38 (s, 3H)
LCMS purity: 98.86%, m/z =348.1 (M+1)
HPLC: 96.84%
Example 88
Preparation of
1-(3-Chloro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(88A)
##STR00108##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 200 mg, 1.129
mmol) was reacted with 1-bromo-3-chloro-benzene (0.281 g, 1.471
mmol), 1,4-dioxane (20 mL), copper iodide (0.021 g, 0.110 mmol),
trans-1,2-diamino cyclohexane (0.038 g, 0.333 mmol) and potassium
phosphate (0.718 g, 3.386 mmol) to afford 192 mg of the product
(59.25% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.52 (s, 1H), 8.42 (d,
1H), 7.7-7.6 (m, 1H), 7.55-7.41 (m, 1H), 7.32-7.19 (m, 2H), 7.1-7.0
(m, 1H), 4.1-3.9 (m, 4H), 2.38 (s, 3H)
LCMS purity: 99.41%, m/z =288.1 (M+1)
HPLC: 91.65%
Example 89
Preparation of
1-(4-Chloro-2-methyl-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(89A)
##STR00109##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474
mmol) was reacted with 1-bromo-4-chloro-2-methyl-benzene (174 mg,
0.8474 mmol), 1,4-dioxane (5 mL), copper iodide (16.19 mg, 0.08474
mmol), trans-1,2-diamino cyclohexane (29.1 mg, 0.2542 mmol) and
potassium phosphate (539.63 g, 2.542 mmol) to afford 200 mg of the
product (78.43% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.52 (s, 1H), 8.36 (d,
1H), 7.42-7.3 (m, 4H), 3.99-3.85 (m, 4H), 2.29 (d, 6H)
LCMS purity: 99.27%, m/z=301.8 (M+1)
HPLC: 96.77%
Example 90
Preparation of
1-(4-Fluoro-3-trifluoromethyl-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazoli-
din-2-one (90A)
##STR00110##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847
mmol) was reacted with 4-bromo-1-fluoro-2-trifluoromethyl-benzene
(247 mg, 1.016 mmol), 1,4-dioxane (15 mL), copper iodide (16 mg,
0.0842 mmol), trans-1,2-diamino cyclohexane (0.0289 g, 0.2456 mmol)
and potassium phosphate (0.538 g, 2.537 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1%
MeOH in CHCl.sub.3) afforded 173 mg of the product (60.27%
yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.52 (s, 1H), 8.44 (d,
1H), 7.9-7.75 (m, 2H), 7.3-7.19 (m, 2H), 4.12-3.9 (m, 4H), 2.39 (s,
3H)
LCMS purity: 92.1%, m/z=340.1 (M+1)
HPLC: 94.55%
Example 91
Preparation of
1-(3-Difluoromethyl-4-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolid-
in-2-one (91A) and
1-(3-Difluoromethyl-4-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-1,3-dihydr-
o-imidazol-2-one (91B)
##STR00111##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847
mmol) was reacted with 4-bromo-2-difluoromethyl-1-fluoro-benzene
(228 mg, 1.016 mmol), 1,4-dioxane (10 mL), copper iodide (16.13 mg,
0.0847 mmol), trans-1,2-diamino cyclohexane (0.030 mL, 0.254 mmol)
and potassium phosphate (539 mg, 2.54 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1%
MeOH in CHCl.sub.3), followed by preparative HPLC afforded 23 mg of
compound 91A (8.45% yield) and 8 mg of compound 91B (2.94%
yield).
Compound (91A):
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.55 (s, 1H), 8.4 (d,
1H), 8.0-7.9 (m, 1H), 7.8-7.69 (m, 1H), 7.49-7.32 (m, 2H), 7.22 (s,
1H), 4.14-3.89 (m, 4H), 2.28 (s, 3H)
LCMS purity: 95.56%, m/z=322.1 (M+1)
HPLC: 99.42%
Compound (91B):
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.59-8.45 (br s, 2H),
8.15-7.9 (m, 2H), 7.59-7.36 (m, 3H), 7.3-7.22 (br s, 1H), 7.15-7.02
(br s, 1H), 2.3 (s, 3H)
LCMS purity: 98.54%, m/z=320.1 (M+1)
HPLC: 98.02%
Example 92
Preparation of
1-(4-Methylpyridin-3-yl)-3-(5-methylthiophen-3-yl)-1H-imidazol-2(3H)-one
(92A) and
1-(4-Methyl-pyridin-3-yl)-3-(5-methyl-thiophen-3-yl)-imidazolid-
in-2-one (92B)
##STR00112##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (1-14b: 0.150 g, 0.847
mmol) was reacted with 4-bromo-2-methyl-thiophene (0.179 g, 1.016
mmol), 1,4-dioxane (20 mL), copper iodide (0.015 g, 0.084 mmol),
trans-1,2-diamino cyclohexane (0.028 g, 0.254 mmol) and potassium
phosphate (0.445 g, 2.1 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1% MeOH in
CHCl.sub.3), followed by preparative HPLC afforded 10 mg of the
Compound 92A (4.3% yield) and 17 mg of Compound 92B (7.3% yield)
was obtained.
Compound (92A):
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.5 (m, 2H), 7.26 (s,
2H), 7.1 (s, 1H), 6.75 (d, 1H), 6.44 (d, 1H), 2.5 (s, 3H), 2.35 (s,
3H)
LCMS purity: 98.71%, m/z=271.9 (M+1)
HPLC: 99.56%
Compound (92B):
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.52 (s, 1H), 8.4 (d,
1H), 7.35-7.19 (m, 2H), 6.6 (s, 1H), 4.05-3.89 (m, 4H), 2.5 (s,
3H), 2.35 (s, 3H)
LCMS purity: 99.44%, m/z =273.8 (M+1)
HPLC: 98.76%
Example 93
Preparation of
1-(2-Methyl-benzooxazol-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-on-
e (93A)
##STR00113##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 0.1 g, 0.00057
mol) was reacted with 5-bromo-2-methyl-benzooxazole (0.119 g,
0.000597 mol), 1,4-dioxane (20 mL), copper iodide (0.01 g, 0.000057
mol), trans-1,2-diamino cyclohexane (0.019 g, 0.00017 mol) and
potassium phosphate (0.242 g, 0.00114 mol) to afford the crude
product. Purification by column chromatography on silica gel (2%
MeOH in CHCl.sub.3), followed by preparative HPLC afforded 29 mg of
the product (16% yield).
.sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 8.52 (s, 1H), 8.36 (d,
1H), 7.84 (d, 1H), 7.66-7.52 (m, 2H), 7.4 (d, 1H), 4.2-4.1 (m, 2H),
4.05-3.95 (m, 2H), 2.65 (s, 3H), 2.4 (s, 3H)
LCMS purity: 93.74%, m/z=309.1 (M+1)
HPLC: 99.08%
Example 94
Preparation of
1-Imidazo[1,2-a]pyridin-6-yl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(94A)
##STR00114##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847
mmol) was reacted with 6-bromo-imidazo[1,2-a]pyridine (249.5 mg,
1.27 mmol), 1,4-dioxane (10 mL), copper iodide (16.13 mg, 0.0847
mmol), trans-1,2-diamino cyclohexane (0.03 mL, 0.254 mmol) and
potassium phosphate (539 mg, 2.54 mmol) to afford the crude
product. Purification by column chromatography on silica gel (5%
MeOH in CHCl.sub.3) afforded 110 mg of the product (44.35%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.75-8.7 (m, 1H), 8.55
(s, 1H), 8.4 (d, 1H), 7.98 (s, 1H), 7.8 (dd, 1H), 7.65-7.55 (m,
2H), 7.36 (d, 1H), 4.12-3.9 (m, 4H), 2.3 (s, 3H)
LCMS purity: 94.08%, m/z=294.1 (M+1)
HPLC: 92.22%
Example 95
Preparation of
1-(3-Methyl-1H-indazol-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(95A)
##STR00115##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl-imidazolidin-2-one (I-14b: 500 mg, 2.8248
mmol) was reacted with 1-(5-bromo-2-fluoro-phenyl)-ethanone (610
mg, 2.8248 mmol), 1,4-dioxane (15 mL), copper iodide (53.81 mg,
0.28248 mmol), trans-1,2-diamino cyclohexane (97.03 mg, 0.8474
mmol) and potassium phosphate (1.798 g, 8.474 mmol) to afford the
crude product. Purification by column chromatography on silica gel
(2% MeOH in CHCl.sub.3) afforded 170 mg of
1-(3-acetyl-4-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazol-
idin-2-one (19.31% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.5 (d, 1H), 8.4-8.3 (m,
1H), 7.7-7.6 (m, 1H), 7.3-7.1 (m, 2H), 4.2-3.9 (m, 4H), 2.7 (d,
3H), 2.35 (s, 3H)
LCMS purity: 99.03%, m/z =314.0 (M+1)
1-(3-Acetyl-4-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(160 mg, 0.513 mmol) in hydrazine hydrate (5 mL) was taken in a
reaction flask and the flask was heated to reflux and maintained
for 21 hours. The reaction was monitored by TLC (10% MeOH in
CHCl.sub.3). The reaction mixture was partitioned between
ethylacetate and water. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated.
Purification by column chromatography on silica gel (3% MeOH in
CHCl.sub.3), followed by preparative HPLC afforded 22 mg of the
product (14% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.55 (s, 1H), 8.44-8.4
(d, 1H), 7.8 (d, 1H), 7.7 (s, 1H), 7.44-7.4 (d, 1H), 7.25-7.2 (m,
1H), 4.25-4.2 (m, 2H), 4.02-3.9 (m, 2H), 2.6 (s, 3H), 2.4 (s,
3H)
LCMS purity: 98.92%, m/z =308.0 (M+1)
HPLC: 93.18%
Example 96
Preparation of
N-{4-[3-(4-Methyl-pyridin-3-O-2-oxo-imidazolidin-1-yl]-pyridin-2-yl}-acet-
amide (96A)
##STR00116##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465
mmol) was reacted with N-(4-bromo-pyridin-2-yl)-acetamide (240 mg,
1.12 mmol), 1,4-dioxane (25 mL), copper iodide (16 mg, 0.084 mmol),
trans-1,2-diamino cyclohexane (29.4 mg, 0.254 mmol) and potassium
phosphate (449.7 mg, 2.118 mmol) to afford the crude product.
Purification by column chromatography on silica gel (5% MeOH in
CHCl.sub.3) afforded 120 mg of the product (45.5% yield).
.sup.1H (CDCl.sub.3, 300 MHz): .delta. 8.52 (s, 1H), 8.45 (d, 1H),
8.19-8.05 (m, 2H), 8.02-7.9 (m, 2H), 7.25-7.2 (m, 1H), 4.2-4.1 (m,
2H), 4.0-3.9 (m, 2H), 2.35 (s, 3H), 2.22 (s, 3H)
LCMS purity: 98.96%, m/z =312.2 (M+1)
HPLC: 86.35%
Example 97
Preparation of
1-(4-Methoxy-thieno[3,2-c]pyridin-2-yl)-3-(4-methyl-pyridin-3-yl)-imidazo-
lidin-2-one (97A)
##STR00117##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 62 mg, 0.3498
mmol) was reacted with 2-bromo-4-methoxy-thieno[3,2-c]pyridine
(85.4 mg, 0.3498 mmol), 1,4-dioxane (50 mL), copper iodide (6.6 mg,
0.03498 mmol), trans-1,2-diamino cyclohexane (12 mg, 0.1049 mmol)
and potassium phosphate (185.6 mg, 0.8747 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1%
MeOH in CHCl.sub.3) afforded 50 mg of the product (40% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.59 (s, 1H), 8.42 (d,
1H), 7.88 (d, 1H), 7.5 (d, 1H), 7.39 (d, 1H), 6.72 (s, 1H),
4.25-4.15 (m, 2H), 4.1-4.04 (m, 2H), 4.0 (s, 3H), 2.3 (s, 3H)
LCMS purity: 97.46%, m/z =341.1 (M+1)
HPLC: 93.75%
Example 98
Preparation of
1-(4-Chloro-thieno[3,2-c]pyridin-2-yl)-3-(4-methyl-pyridin-3-yl)-imidazol-
idin-2-one (98A)
##STR00118##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 100 mg, 0.5643
mmol) was reacted with 2-bromo-4-chloro-thieno[3,2-c]pyridine
(141.3 mg, 0.5643 mmol), 1,4-dioxane (20 mL), copper iodide (10.75
mg, 0.05643 mmol), trans-1,2-diamino cyclohexane (19.38 mg, 0.1693
mmol) and potassium phosphate (299 mg, 1.4108 mmol) to afford the
crude product. Purification by column chromatography on silica gel
(2% MeOH in CHCl.sub.3) afforded 43 mg of the product (22.16%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.7 (s, 1H), 8.55-8.49
(m, 1H), 8.1 (d, 1H), 7.98 (d, 1H), 7.56 (d, 1H), 6.75 (s, 1H),
4.3-4.2 (m, 4H), 2.38 (s, 3H)
LCMS purity: 91.81%, m/z=345.0 (M+1)
HPLC: 91.32%
Example 99
Preparation of
1-(4-Chloro-thieno[3,2-c]pyridin-3-yl)-3-(4-methyl-pyridin-3-yl)-imidazol-
idin-2-one (99A)
##STR00119##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (1-14b: 100 mg, 0.5643
mmol) was reacted with 3-bromo-4-chloro-thieno[3,2-c]pyridine
(141.3 mg, 0.5643 mmol), 1,4-dioxane (20 mL), copper iodide (10.75
mg, 0.05643 mmol), trans-1,2-diamino cyclohexane (19.38 mg, 0.1693
mmol) and potassium phosphate (299 mg, 1.4108 mmol) to afford the
crude product. Purification by preparative HPLC afforded 10 mg of
the product (10% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.68 (s, 1H), 8.5 (d,
1H), 8.1 (d, 1H), 7.98 (d, 1H), 7.54 (d, 1H), 6.75 (s, 1H), 4.3-4.2
(m, 2H), 4.12-4.05 (m, 2H), 2.36 (s, 3H)
LCMS purity: 98.12%, m/z =345.0 (M+1)
HPLC: 99.28%
Example 100
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-(2-methyl-pyridin-4-yl)-imidazolidin-2-one
(100A)
##STR00120##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 100 mg, 0.5649
mmol) was reacted with 4-bromo-2-methyl-pyridine (97 mg, 0.5649
mmol), 1,4-dioxane (5 mL), copper iodide (10.76 mg, 0.05649 mmol),
trans-1,2-diamino cyclohexane (19.4 mg, 0.1694 mmol) and potassium
phosphate (359.58 mg, 1.694 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
CHCl.sub.3) afforded 132 mg of the product (88.0% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.5-8.3 (m, 3H),
7.5-7.3 (m, 3H), 4.1-3.9 (m, 4H), 2.3 (s, 3H), 2.2 (s, 3H)
LCMS purity: 92.28%, m/z=269.0 (M+1)
HPLC: 97.29%
Example 101
Preparation of
1-(3-Methyl-benzo[d]isoxazol-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-
-2-one (101A)
##STR00121##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 0.500 g, 2.82
mmol) was reacted with 1-(5-bromo-2-fluoro-phenyl)-ethanone (0.612
g, 2.82 mmol), 1,4-dioxane (30 mL), copper iodide (53.81 mg, 0.282
mmol), trans-1,2-diamino cyclohexane (97.03 mg, 0.846 mmol) and
potassium phosphate (1.79 g, 8.46 mmol) to afford the crude
product. Purification by column chromatography on silica gel (2%
MeOH in CHCl.sub.3) afforded 220 mg of
1-(3-Acetyl-4-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazol-
idin-2-one (24.9% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.52 (s, 1H), 8.38 (d,
1H), 8.0-7.84 (m, 2H), 7.4-7.32 (m, 2H), 4.1-4.0 (m, 2H), 3.95-3.9
(m, 2H), 2.6 (d, 3H), 2.29 (s, 3H)
LCMS purity: 99.03%, m/z=314.0 (M+1) Hydroxylamine hydrochloride
(145 mg, 2.106 mmol) in pyridine (5 mL) was added to
1-(3-acetyl-4-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(220 mg, 0.702 mmol) under nitrogen atmosphere. The resulting
mixture was stirred at room temperature for 18 hours. The reaction
was monitored by TLC (10% MeOH in CHCl.sub.3). The reaction mixture
was partitioned between ethylacetate and water. The organic layer
was dried over Na.sub.2SO.sub.4 and concentrated to afford 220 mg
of
1-[4-Fluoro-3-(1-hydroxyimino-ethyl)-phenyl]-3-(4-methyl-pyridin-3-yl)-im-
idazolidin-2-one (90% yield).
LCMS purity: 98.93%, m/z=329.0 (M+1)
1-[4-Fluoro-3-(1-hydroxyimino-ethyl)-phenyl]-3-(4-methyl-pyridin-3-yl)-im-
idazolidin-2-one (220 mg, 0.670 mmol) in DMF (5 mL) was added to a
stirred mixture of NaH (19 mg, 0.804 mmol) in DMF (2 mL) under
nitrogen atmosphere at 0.degree. C. The resulting mixture was
stirred at room temperature for 21 hours. The reaction was
monitored by TLC (10% MeOH in CHCl.sub.3). The reaction mixture was
partitioned between ethylacetate and ice water. The organic layer
was washed with brine solution, dried over Na.sub.2SO.sub.4 and
concentrated. Purification by column chromatography on silica gel
(1% MeOH in CHCl.sub.3) afforded 28 mg of the product (14.5%
yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.6-8.5 (br s, 1H).
8.5-8.4 (br s, 1H), 7.9 (d, 1H), 7.78 (dd, 1H), 7.55 (d, 1H),
7.26-7.24 (m, 1H), 4.2-4.1 (m, 2H), 4.05-3.95 (m, 2H), 2.59 (s,
3H), 2.39 (s, 3H)
LCMS purity: 95.75%, m/z=309.0 (M+1)
HPLC: 88.61%
Example 102
Preparation of
1-(3-Methyl-1H-indazol-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(102A)
##STR00122##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 500 mg, 2.8216
mmol) was reacted with 1-(4-bromo-2-fluoro-phenyl)-ethanone (679.9
mg, 3.1038 mmol), 1,4-dioxane (50 mL), copper iodide (53.6 mg,
0.28216 mmol), trans-1,2-diamino cyclohexane (97.09 mg, 0.84650
mmol) and potassium phosphate (1.49 g, 7.0541 mmol) to afford the
crude product. Purification by column chromatography on silica gel
(2% MeOH in CHCl.sub.3) afforded 780 mg of
1-(4-acetyl-3-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazol-
idin-2-one (88.2% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.55 (s, 1H), 8.4 (d,
1H), 7.85 (t, 1H), 7.68 (dd, 1H), 7.52 (dd, 1H), 7.37 (d, 1H),
4.15-3.9 (m, 4H), 2.56 (s, 3H), 2.29 (s, 3H)
Hydrazine hydrate (10 mL) was added to
1-(4-acetyl-3-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(380 mg, 1.2128 mmol) under nitrogen atmosphere. The resulting
mixture was stirred at 120.degree. C. for 12 hours, cooled to room
temperature and continued stirring for the next 12 hours. The
reaction was monitored by TLC (10% MeOH in CHCl.sub.3). The
reaction mixture was partitioned between ethylacetate and ice
water. The organic layer was washed with brine solution, dried over
Na.sub.2SO.sub.4 and concentrated. Purification by column
chromatography on silica gel (4% MeOH in CHCl.sub.3) afforded 240
mg of the product (64.5% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.84 (s, 1H),
8.65-8.55 (m, 1H), 7.8-7.64 (m, 3H), 7.55-7.45 (d, 1H), 4.25-3.95
(m, 4H), 2.49 (d, 6H)
LCMS purity: 94.698%, m/z=308.2 (M+1)
HPLC: 96.12%
Example 103
Preparation of
2-Fluoro-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzonitri-
le (103A)
##STR00123##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 100 mg, 0.5643
mmol) was reacted with 5-bromo-2-fluoro-benzonitrile (124 mg,
0.6199 mmol), 1,4-dioxane (20 mL), copper iodide (10.7 mg, 0.056
mmol), trans-1,2-diamino cyclohexane (19.4 mg, 0.169 mmol) and
potassium phosphate (300 mg, 1.413 mmol) to afford the crude
product. Purification by column chromatography on silica gel (2%
MeOH in CHCl.sub.3) afforded 110 mg of the product (65.7%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.6-8.5 (br s, 1H),
8.4 (s, 1H), 8.1-8.0 (m, 2H), 7.6-7.5 (t, 1H), 7.4-7.3 (m, 1H),
4.1-3.9 (m, 4H), 2.3 (s, 3H)
LCMS purity: 98.73%, m/z=297.2 (M+1)
HPLC: 97.3%
Example 104
Preparation of
1-(2-Methyl-imidazo[1,2-a]pyridin-6-O-3-(4-methyl-pyridin-3-yl)-imidazoli-
din-2-one (104A)
##STR00124##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 118 mg, 0.6633
mmol) was reacted with 6-bromo-2-methyl-imidazo[1,2-a]pyridine (140
mg, 0.6633 mmol), 1,4-dioxane (10 mL), copper iodide (14 mg),
trans-1,2-diamino cyclohexane (28 mg) and potassium phosphate (422
mg, 1.9899 mmol) to afford the crude product. Purification by
column chromatography on silica gel (10% MeOH in DCM), followed by
preparative HPLC afforded 13 mg of the product (6.4% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.6 (d, 2H), 8.4 (d,
1H), 7.75-7.65 (m, 2H), 7.5 (d, 1H), 7.36 (d, 1H), 4.1-3.9 (m, 4H),
2.4-2.2 (d, 6H), LCMS purity: 99.71%, m/z=308.1 (M+1)
HPLC: 98.04%
Example 105
Preparation of
1-(2-Methyl-benzothiazol-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-o-
ne (105A)
##STR00125##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 100 mg, 0.5643
mmol) was reacted with 6-iodo-2-methyl-benzothiazole (154 mg,
0.5598 mmol), 1,4-dioxane (20 mL), copper iodide (10.7 mg, 0.056
mmol), trans-1,2-diamino cyclohexane (19.4 mg, 0.169 mmol) and
potassium phosphate (300 mg, 1.413 mmol) to afford the crude
product. Purification by column chromatography on silica gel (5%
MeOH in CHCl.sub.3) afforded 115 mg of the product (62.8%
yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.54 (s, 1H), 8.42 (d,
1H), 8.24 (s, 1H), 7.9 (d, 1H), 7.56 (d, 1H), 7.26-7.2 (m, 1H),
4.2-3.9 (m, 4H), 2.82 (s, 3H), 2.35 (s, 3H)
LCMS purity: 96.39%, m/z =324.8 (M+1)
HPLC: 96.16%
Example 106
Preparation of
3-[3-(4-Methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzonitrile
(106A)
##STR00126##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 100 mg, 0.5643
mmol) was reacted with 3-bromo-benzonitrile (115 mg, 0.6317 mmol),
1,4-dioxane (20 mL), copper iodide (10.7 mg, 0.0564 mmol),
trans-1,2-diamino cyclohexane (19.4 mg, 0.169 mmol) and potassium
phosphate (300 mg, 1.413 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
CHCl.sub.3), followed by preparative HPLC afforded 80 mg of the
product (49% yield).
.sup.1H NMR (DMSO-d.sub.6, 300 MHz): S 8.75 (s, 1H), 8.55 (s, 1H),
8.1-7.9 (m, 2H), 7.7-7.5 (m, 3H), 4.2-4.05 (m, 4H), 2.58 (s,
3H)
LCMS purity: 99.71%, m/z =279.0 (M+1)
HPLC: 95.64%
Example 107
Preparation of
1-(1H-Indol-3-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(107A)
##STR00127##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg,
0.00084 mol) was reacted with
3-bromo-1-(toluene-4-sulfonyl)-1H-indole (292 mg, 0.00084 mol),
1,4-dioxane (20 mL), copper iodide (0.015 g, 0.000084 mol),
trans-1,2-diamino cyclohexane (0.028 g, 0.00025 mol) and potassium
phosphate (356 mg, 0.00168 mol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
CHCl.sub.3), followed by preparative HPLC afforded 110 mg of
1-(4-Methyl-pyridin-3-yl)-3-[1-(toluene-4-sulfonyl)-1H-indol-3-yl]-imidaz-
olidin-2-one (33.66% yield).
LCMS purity: 92.68%, m/z=446.9 (M+1) 10% NaOH solution (10 mL) was
added to a solution of
1-(4-methyl-pyridin-3-yl)-3-[1-(toluene-4-sulfonyl)-1H-indol-3-yl]-imidaz-
olidin-2-one (110 mg, 0.0002 mol) in ethanol (10 mL) and the
resulting mixture was stirred at 90.degree. C. for 1 hour. The
reaction was monitored by TLC (10% MeOH in CHCl.sub.3). The
reaction mixture was partitioned between ethylacetate and ice
water. The organic layer was washed with brine solution, dried over
Na.sub.2SO.sub.4 and concentrated. Purification by column
chromatography on silica gel (2% MeOH in CHCl.sub.3) afforded 50 mg
of the product (86.2% yield).
.sup.1NMR (DMSO-D.sub.6, 300 MHz): .delta. 11.1 (s, 1H), 8.55 (s,
1H), 8.4-8.3 (m, 1H), 7.64 (d, 1H), 7.5-7.3 (m, 3H), 7.2-6.95 (m,
2H), 4.1-3.9 (m, 4H), 2.35 (s, 3H)
LCMS purity: 96.36%, m/z=292.8 (M+1)
HPLC: 88.07%
Example 108
Preparation of
1-(1H-Benzoimidazol-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(108A)
##STR00128##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474
mmol) was reacted with
5-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (332
mg, 1.0152 mmol), 1,4-dioxane (15 mL), copper iodide (16 mg, 0.0842
mmol), trans-1,2-diamino cyclohexane (28 mg, 0.2456 mmol) and
potassium phosphate (538 mg, 2.5377 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1%
MeOH in CHCl.sub.3) afforded 270 mg of
1-(4-Methyl-pyridin-3-yl)-3-[1-(2-trimethylsilanyl-ethoxymethyl-
)-1H-benzoimidazol-5-yl]-imidazolidin-2-one (75.41% yield).
LCMS purity: 98.46%, m/z =424.1 (M+1)
1-(4-Methyl-pyridin-3-yl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzo-
imidazol-5-yl]-imidazolidin-2-one (260 mg, 0.6138 mmol) in
1,4-dioxane hydrochloride (15 mL) was taken in a reaction flask and
the flask was stirred at room temperature for 12 hours. The
reaction was monitored by TLC (10% MeOH in CHCl.sub.3). The
reaction mixture was concentrated under reduced pressure and the
concentrate was washed with diethyl ether and hexane to afford 26
mg of the product (46.8% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.6-8.55 (br s, 1H),
8.45-8.35 (m, 1H), 8.25-8.15 (br s, 1H), 7.85-7.8 (br s, 1H),
7.65-7.5 (m, 2H), 7.4-7.35 (m, 1H), 4.2-3.9 (m, 4H), 2.3 (s,
3H)
LCMS purity: 99.71%, m/z =294.0 (M+1)
HPLC: 93.74%
Example 109
Preparation of
1-Benzo[b]thiophen-3-yl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(109A)
##STR00129##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465
mmol) was reacted with 3-bromo-benzo[b]thiophene (216.3 mg, 1.0158
mmol), 1,4-dioxane (50 mL), copper iodide (10.7 mg, 0.0865 mmol),
trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and potassium
phosphate (449.1 mg, 2.1162 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
CHCl.sub.3) afforded 95 mg of the product (36.3% yield).
.sup.1H NMR (DMSO-d.sub.6, 300 MHz): .delta. 8.65-8.55 s, 1H),
8.45-8.3 (br s, 1H), 8.05-7.8 (m, 2H), 7.69 (s, 1H), 7.5-7.3 (m,
3H), 4.15-3.9 (m, 4H), 2.35 (s, 3H)
LCMS purity: 93.71%, m/z =310.0 (M+1)
HPLC: 96.65%
Example 110
Preparation of
1-(4-Methoxy-thieno[3,2-c]pyridin-3-yl)-3-(4-methyl-pyridin-3-yl)-imidazo-
lidin-2-one (110A)
##STR00130##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 65 mg, 0.3668
mmol) was reacted with 3-bromo-4-methoxy-thieno[3,2-c]pyridine
(98.4 mg, 0.4034 mmol), 1,4-dioxane (20 mL), copper iodide (6.9 mg,
0.03668 mmol), trans-1,2-diamino cyclohexane (12.6 mg, 0.1100 mmol)
and potassium phosphate (194.6 mg, 0.91704 mmol) to afford the
crude product. Purification by column chromatography on silica gel
(2% MeOH in CHCl.sub.3) afforded 50 mg of the product (40.3%
yield).
.sup.1H NMR (DMSO-d.sub.5, 300 MHz): .delta. 8.65-8.3 (m, 2H), 8.05
(d, 1H), 7.8 (s, 1H), 7.65 (d, 1H), 7.45-7.4 (br s, 1H), 4.1-3.9
(m, 7H), 2.36 (s, 3H)
LCMS purity: 99.04%, m/z=340.9 (M+1)
HPLC: 95.61
Example 111
Preparation of
1-(3-Methyl-benzo[d]isoxazol-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-
-2-one (111A)
##STR00131##
Step 1: Preparation of Intermediate
1-(4-Acetyl-3-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(111A)
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 500 mg, 2.8216
mmol) was reacted with 1-(4-bromo-2-fluoro-phenyl)-ethanone (679.9
mg, 3.1038 mmol), 1,4-dioxane (50 mL), copper iodide (53.6 mg,
0.28216 mmol), trans-1,2-diamino cyclohexane (97.09 mg, 0.84650
mmol) and potassium phosphate (1.49 g, 7.0541 mmol) to afford the
crude product. Purification by column chromatography on silica gel
(2% MeOH in CHCl.sub.3) afforded 780 mg of
1-(4-acetyl-3-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazol-
idin-2-one (111a: 88.2% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.54 (s, 1H), 8.4 (d,
1H), 7.84 (t, 1H), 7.68 (dd, 1H), 7.5 (dd, 1H), 7.34 (d, 1H),
4.15-3.9 (m, 4H), 2.55 (s, 3H), 2.28 (s, 3H)
Step 2: Preparation of Intermediate
1-[3-Fluoro-4-(1-hydroxyimino-ethyl)-phenyl]-3-(4-methyl-pyridin-3-yl)-im-
idazolidin-2-one (111 h)
NaOH (72.7 mg, 1.8193 mmol) in water (5 mL) was added dropwise to a
stirred solution of
1-(4-acetyl-3-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(I-111a: 380 mg, 1.2128 mmol) and hydroxylamine hydrochloride in
ethanol (10 mL) over a period of 5 minutes. The resulting mixture
was stirred at room temperature for 4 hours. The reaction was
monitored by TLC (10% MeOH in CHCl.sub.3). Ice was added to the
reaction mixture to yield a precipitate which was collected and
dried under reduced pressure to afford 350 mg of
1-[3-Fluoro-4-(1-hydroxyimino-ethyl)-phenyl]-3-(4-methyl-pyridin-3-yl)-im-
idazolidin-2-one (I-111b: 87.9% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 11.3 (s, 1H), 8.52 (s,
1H), 8.4 (d, 1H), 7.6 (dd, 1H), 7.54-7.3 (m, 3H), 4.1-3.9 (m, 4H),
2.28 (s, 3H), 2.12 (s, 3H)
Final Step: Preparation of
1-(3-Methyl-benzo[d]isoxazol-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-
-2-one (111A)
NaH (32.8 mg, 1.3705 mmol) and DMF (4 mL) was added to
1-[3-fluoro-4-(1-hydroxyimino-ethyl)-phenyl]-3-(4-methyl-pyridin-3-yl)-im-
idazolidin-2-one (111b: 150 mg, 0.4568 mmol). The resulting mixture
was microwaved at 50.degree. C. for 1 hour. The reaction was
monitored by TLC (10% MeOH in DCM). The reaction mixture was
partitioned between ice water and ethylacetate. The organic layer
was washed with water, brine solution, dried over Na.sub.2SO.sub.4
and concentrated under reduced pressure. Purification by column
chromatography on silica gel (5% MeOH in CHCl.sub.3) afforded 15 mg
of the product (10.7% yield).
.sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 8.6-8.32 (m, 2H),
7.9-7.6 (m, 3H), 7.4 (s, 1H), 4.3-4.2 (m, 2H), 4.1-3.98 (m, 2H),
2.6 (s, 3H), 2.4 (s, 3H)
LCMS purity: 97.90%, m/z =309.0 (M+1)
HPLC: 83.77%
Example 112
Preparation of
2-Chloro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzonitri-
le (112A)
##STR00132##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465
mmol) was reacted with 2-chloro-4-iodo-benzonitrile (245.3 mg.
0.9311 mmol), 1,4-dioxane (20 mL), copper iodide (16.1 mg, 0.08465
mmol), trans-1,2-diamino cyclohexane (12.6 mg, 0.1100 mmol) and
potassium phosphate (30.6 mL, 0.254 mmol) to afford the crude
product which was purified by column chromatography on silica gel
(2% MeOH in CHCl.sub.3). The residue was washed with hexane and
dried to afford 85 mg of the product (32% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.52-8.4 (m, 2H), 7.85
(s, 1H), 7.62 (s, 2H), 7.3-7.2 (m, 1H), 4.12-3.9 (m, 4H), 2.32 (s,
3H)
LCMS purity: 99.54%, m/z =312.8 (M+1)
HPLC: 93.79%
Example 113
Preparation of
1-Benzo[d]isoxazol-5-yl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(113A)
##STR00133##
Step 1: Preparation of Intermediate
2-Fluoro-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehy-
de (I-113a)
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 200 mg, 1.12
mmol) was reacted with 5-bromo-2-fluoro-benzaldehyde (272 mg, 1.34
mmol), 1,4-dioxane (20 mL), copper iodide (18 mg, 0.098 mmol),
trans-1,2-diamino cyclohexane (0.05 mL, 0.294 mmol) and potassium
phosphate (520 mg, 2.54 mmol) to afford the crude product which was
purified by column chromatography on silica gel (2-3% MeOH in
CHCl.sub.3). The residue was washed with DCM and hexane in dry ice
and dried to afford 235 mg of
2-Fluoro-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehy-
de (70.35% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 10.38 (s, 1H), 8.6-8.3
(m, 3H), 7.6 (q, 1H), 7.3-7.25 (m, 2H), 4.12-3.9 (m, 4H), 2.32 (s,
3H)
LCMS purity: 98.49%, m/z=299.9 (M+1)
Step 2: Preparation of Intermediate
2-Fluoro-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehy-
de oxime (I-113b)
2-Fluoro-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehy-
de (I-113a: 230 mg, 0.769 mmol), hydroxylamine hydrochloride (160
mg, 2.307 mmol) and pyridine (5 mL) were taken in a reaction flask
and the flask was stirred at room temperature for 18 hours under
nitrogen atmosphere. The reaction was monitored by TLC (10% MeOH in
CHCl.sub.3). The reaction mixture was partitioned between ice water
and ethylacetate. The organic layer was dried over Na.sub.2SO.sub.4
and concentrated. The concentrate was washed with diethyl ether and
decanted to afford 170 mg of
2-Fluoro-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzald-
ehyde oxime (70.8% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.88-8.32 (m, 4H),
7.9-7.72 (m, 2H), 7.32-7.02 (m, 2H), 4.1-3.89 (m, 4H), 2.35 (s,
3H)
LCMS purity: 99.53%, m/z =314.9 (M+1)
Final Step: Preparation of
1-Benzo[d]isoxazol-5-yl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(113A)
2-Fluoro-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehy-
de oxime (I-113b:160 mg, 0.509 mmol) in dry DMF (2 mL) was added
dropwise to a stirred mixture of NaH (72 mg, 1.52 mmol) in DMF (1
mL) at 0.degree. C. The resulting mixture was stirred at room
temperature for 70 hours. The reaction was monitored by TLC (10%
MeOH in CHCl.sub.3). The reaction mixture was partitioned between
ice water and ethylacetate. The aqueous layer was distilled to
afford the solid residue which was dissolved 1:1 DCM:MeOH. The
crude product was purified by column chromatography on silica gel
(4-5% MeOH in CHCl.sub.3). The residue was washed with hexane and
dried to afford 105 mg of the product (70.4% yield).
.sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 8.58 (s, 1H), 8.38 (d,
1H), 7.76-7.68 (m, 2H), 7.42 (d, 1H), 7.0-6.92 (m, 1H), 4.1-3.9 (m,
4H), 2.41 (s, 3H)
LCMS purity: 97.14%, m/z=295.1 (M+1)
HPLC: 95.66%
Example 114
Preparation of
1-(1-Methyl-1H-indazol-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(114A)
##STR00134##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 100 mg, 0.5649
mmol) was reacted with 5-bromo-1-methyl-1H-indazole (142 mg, 0.6794
mmol), 1,4-dioxane (15 mL), copper iodide (10 mg, 0.0526 mmol),
trans-L2-diamino cyclohexane (19 mg, 0.1666 mmol) and potassium
phosphate (36 mg, 1.698 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
CHCl.sub.3) afforded 57 mg of the product (32.94% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.52 (s, 1H), 8.4 (d,
1H), 7.94 (m, 2H), 7.62 (s, 1H), 7.4 (d, 1H), 7.26-7.2 (d, 1H),
4.2-3.8 (m, 7H), 2.4 (s, 3H)
LCMS purity: 96.62%, m/z =308.1 (M+1)
HPLC: 97.44%
Example 115
Preparation of
1-(1-Methyl-1H-indol-3-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
Trifluoro-acetic acid (115A)
##STR00135##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg,
0.00084 mol) was reacted with 3-bromo-1-methyl-1H-indole (174 mg,
0.00084 mol), 1,4-dioxane (20 mL), copper iodide (15 mg, 0.000084
mol), trans-1,2-diamino cyclohexane (28 mg, 0.00025 mol) and
potassium phosphate (356 mg, 0.00168 mol) to afford the crude
product. Purification by column chromatography on silica gel (2-3%
MeOH in CHCl.sub.3), followed by preparative HPLC afforded 23 mg of
the product (9% yield).
.sup.1H NMR (CD.sub.3OD.sub.3, 300 MHz): .delta. 8.9-8.8 (br s,
1H), 8.6-8.5 (br s, 1H), 7.9-7.82 (m, 1H), 7.65 (d, 1H), 7.44-7.3
(m, 2H), 7.22 (t, 1H), 7.08 (t, 1H), 4.2-4.05 (m, 4H), 3.8 (s, 3H),
2.62 (s, 3H)
LCMS purity: 97.54%, m/z =307.0 (M+1)
HPLC: 97.65%
Example 116
Preparation of
1-(1-Methyl-1H-benzoimidazol-5-yl)-3-(4-methyl-pyridin-3-yl)-trifluoroace-
tic Acid (116A)
##STR00136##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847
mmol) was reacted with 5-bromo-1-methyl-1H-benzoimidazole (214 mg,
1.016 mmol), 1,4-dioxane (25 mL), copper iodide (14 mg, 0.071
mmol), trans-1,2-diamino cyclohexane (24 mg, 0.213 mmol) and
potassium phosphate (375 mg, 1.77 mmol) to afford the crude
product. Purification by column chromatography on silica gel (2%
MeOH in CHCl.sub.3), followed by preparative HPLC afforded 25 mg of
the product (9.6% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.9-8.8 (m, 2H),
8.52-8.35 (m, 2H), 7.82 (s, 1H), 7.61 (m, 2H), 4.25-4.12 (m, 2H),
4.15 (s, 5H), 2.5 (s, 3H)
LCMS purity: 89.78%, m/z=308.1 (M+1)
HPLC: 86.56%
Example 117
Preparation of
5-[3-(4-Methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-1,2-dihydro-indazol-
-3-one (174)
##STR00137##
Step 1: Preparation of Intermediate
2-Fluoro-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzoic
acid methyl ester (I-117a)
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 315 mg, 1.78
mmol) was reacted with 5-bromo-2-fluoro-benzoic acid methyl ester
(500 mg, 2.14 mmol), 1,4-dioxane (30 mL), copper iodide (34 mg,
0.178 mmol), trans-1,2-diamino cyclohexane (0.08 mL, 0.534 mmol)
and potassium phosphate (935 mg, 4.45 mmol) to afford 520 mg of
2-Fluoro-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzoic
acid methyl ester (88.8% yield).
NMR (CDCl.sub.3, 300 MHz): .delta. 8.55-8.4 (m, 2H), 8.1-7.82 (m,
2H), 7.3-7.1 (m, 2H), 4.1-3.9 (m, 7H), 2.35 (s, 3H)
Final Step: Preparation of
5-[3-(4-Methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-1,2-dihydro-indazol-
-3-one (117A)
2-Fluoro-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzoic
acid methyl ester (I-117a: 510 mg, 1.55 mmol) and hydrazine hydrate
were taken in a reaction flask and the flask was heated to
120.degree. C. for 18 hours with stirring. The reaction was
monitored by TLC (10% MeOH in CHCl.sub.3). The reaction mixture was
partitioned between ice water and ethylacetate. The aqueous layer
was concentrated to afford the solid residue which was dissolved in
1:1 DCM: MeOH and filtered. The filtrate was concentrated and
purified by column chromatography on silica gel (10-15% MeOH in
CHCl.sub.3). The residue was washed with DCM and dried to afford
180 mg of the product (37.6% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 11.2 (s, 1H), 8.55 (s,
1H), 8.46 (d, 1H), 7.86 (d, 1H), 7.6 (s, 1H), 7.39-7.28 (m, 2H),
4.1-3.89 (m, 4H), 2.3 (s, 3H)
LCMS purity: 86.23%, m/z =310.1 (M+1)
HPLC: 93.9%
Example 118
Preparation of
1-(3-Amino-1H-indazol-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(118A)
##STR00138##
Hydrazine hydrate (5 mL) was added to solution of
2-fluoro-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzonitri-
le (103A: 265 mg) in 2-methoxymethanol (5 mL). The resulting
mixture was heated to 170.degree. C. and maintained for 20 hours.
The reaction was monitored by TLC (20% MeOH in CHCl.sub.3). The
reaction mixture was partitioned between ice water and DCM. The
organic layer was dried over Na.sub.2SO.sub.4 and concentrated.
Purification by column chromatography on silica gel (10% MeOH in
CHCl.sub.3) afforded 125 mg of the product (45.3% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 11.28 (s, 1H), 8.55
(s, 1H), 8.4-8.32 (d, 1H), 7.75-7.62 (m, 2H), 7.4-7.2 (m, 2H),
5.5-5.2 (br s, 2H), 4.1-3.9 (m, 4H), 2.32 (s, 3H)
LCMS purity: 97.92%, m/z =308.8 (M+1) HPLC: 94.4%
Example 119
Preparation of
1-Imidazo[1,2-a]pyridin-3-yl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-One
(119A)
##STR00139##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 250 mg, 1.4108
mmol) was reacted with 3-iodo-imidazo[1,2-a]pyridine (344 mg,
1.4108 mmol), 1,4-dioxane (10 mL), copper iodide (34 mg),
trans-1,2-diamino cyclohexane (68 mg) and potassium phosphate (898
mg, 4.2325 mmol) to afford the crude product. Purification by
column chromatography on silica gel (10% MeOH in CHCl.sub.3)
afforded 82 mg of the product (19.81% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.62 (s, 1H), 8.42-8.3
(m, 2H), 7.66-7.58 (m, 2H), 7.4-7.26 (m, 2H), 7.02 (t, 1H), 4.05
(s, 4H), 2.38 (s, 3H)
LCMS purity: 98.51%, m/z=294.1 (M+1)
HPLC: 90.42%
Example 120
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-thieno[3,2-c]pyridin-2-yl-imidazolidin-2-one
(120A)
##STR00140##
10% Pd-C (10 mg) was added to a solution of
1-(4-chloro-thieno[3,2-c]pyridin-2-yl)-3-(4-methyl-pyridin-3-yl)-imidazol-
idin-2-one (98A: 80 mg, 0.232 mmol) in methanol (10 mL) under
nitrogen atmosphere. The resulting mixture was hydrogenated at 30
PSI (2.04 atm) for 12 hours at room temperature. The reaction was
monitored by TLC (10% MeOH in CHCl.sub.3). The reaction mixture was
filtered through celite bed, washed with methanol and the filtrate
was concentrated under reduced pressure to afford the crude
product. Purification by preparative TLC afforded 10 mg of the
product (14% yield).
.sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 8.85-8.75 (br s, 1H),
8.45 (s, 1H), 8.3 (d, 1H), 8.2-8.1 (m, 1H), 7.9 (d, 1H), 7.35 (d,
1H), 6.8 (s, 1H), 4.25-4.15 (m, 2H), 4.1-4.0 (m, 2H), 2.3 (s,
3H)
LCMS purity: 97.15%, m/z=311.0 (M+1)
HPLC: 93.24%
Example 121
Preparation of
1-(1H-Indazol-6-yl)-3-(4-methyl-pyridin-3-O-imidazolidin-2-one
(121A)
##STR00141##
Step 1: Preparation of Intermediate
2-Fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehy-
de (I-121a)
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 300 mg, 1.694
mmol) was reacted with 4-bromo-2-fluoro-benzaldehyde (403 mg, 2.118
mmol), 1,4-dioxane (25 mL), copper iodide (32.186 mg, 0.1694 mmol),
trans-1,2-diamino cyclohexane (72.16 mg, 0.5082 mmol) and potassium
phosphate (1.077 g, 5.082 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1.5% MeOH in
CHCl.sub.3) afforded 300 mg of
2-Fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]--
benzaldehyde (59.05% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 10.25 (s, 1H), 8.7-8.4
(m, 2H), 7.9 (t, 1H), 7.7 (d, 1H), 7.4-7.2 (m, 2H), 4.2-3.9 (m,
4H), 2.35 (s, 3H)
Step 2: Preparation of Intermediate
2-Fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehy-
de O-methyl-oxime (121b)
O-Methyl-hydroxylamine (84 mg, 1.003 mmol) and K.sub.2CO.sub.3 (207
mg, 1.5 mmol) were added to a solution of
2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehy-
de-(I-121a: 300 mg, 1.003 mmol) in dimethoxyethane (10 mL). The
resulting mixture was heated to 40.degree. C. for 2 hours. The
reaction was monitored by TLC (5% MeOH in CHCl.sub.3). The reaction
mixture was filtered, washed with CHCl.sub.3 and the filtrate was
concentrated under reduced pressure to afford 30 mg of crude
2-Fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehy-
de O-methyl-oxime, which was used in the next step without further
purification.
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.5 (s, 2H), 8.25 (s,
1H), 7.8 (t, 1H), 7.6-7.5 (m, 1H), 7.3-7.2 (m, 3H), 4.1-3.9 (m,
7H), 2.35 (s, 3H)
Final Step: Preparation of
1-(1H-Indazol-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(121A)
Hydrazine hydrate (5 mL) was added to solution of
2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehy-
de O-methyl-oxime (I-121b: 350 mg, 0.917 mmol) in 2-methoxy
methanol (10 mL). The resulting mixture was heated to 200.degree.
C. and maintained for 2 days. The reaction was monitored by TLC (5%
MeOH in CHCl.sub.3). The reaction mixture was cooled to room
temperature and concentrated. The crude product was purified by
column chromatography on silica gel (4% MeOH in CHCl.sub.3), washed
with ether and dried to afford 105 mg of the product (39.17%
yield).
.sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 8.45 (s, 1H), 8.29 (d,
1H), 7.9 (s, 1H), 7.7-7.6 (m, 2H), 7.45-7.3 (m, 2H), 4.2-4.1 (m,
2H), 4.0-3.9 (m, 2H), 2.32 (s, 3H)
LCMS purity: 99.18%, m/z =294.0 (M+1)
HPLC: 94.38%
Example 122
Preparation of
1-(3H-Imidazo[4,5-b]pyridin-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin--
2-one Trifluoroacetic Acid (122A)
##STR00142##
Step 1: Preparation of
Intermediate-(4-Methyl-pyridin-3-yl)-3-[1-(2-trimethylsilanyl-ethoxymethy-
l)-1H-pyrazolo[3,4-b]pyridin-5-yl]-imidazolidin-2-one (I-122a)
Using the same reaction conditions as in Example 18,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 0.108 g,
0.0006 mol) was reacted with
5-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine
(0.2 g, 0.0006 mol), 1,4-dioxane (20 mL), copper iodide (6.011 g,
0.00006 mol), trans-1,2-diamino cyclohexane (0.020 g, 0.00018 mol)
and potassium phosphate (0.254 g, 0.0012 mol) to afford the crude
product. Purification by column chromatography on silica gel (15%
MeOH in CHCl.sub.3) afforded 172 mg of
1-(4-Methyl-pyridin-3-yl)-3-[1-(2-trimethylsilanyl-ethoxymethyl-
)-1H-pyrazolo[3,4-b]pyridin-5-yl]-imidazolidin-2-one (67.71%
yield).
Final Step: Preparation of
1-(3H-Imidazo[4,5-b]pyridin-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin--
2-one trifluoroacetic acid (122A)
Dioxane HCl (5 mL) was added to
1-(4-methyl-pyridin-3-yl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyraz-
olo[3,4-b]pyridin-5-yl]-imidazolidin-2-one (I-122a: 172 mg) at
0.degree. C. The resulting mixture was stirred at room temperature
for 2 hours. The reaction was monitored by TLC (10% MeOH in
CHCl.sub.3). Purification by preparative HPLC afforded 38 mg of the
product (32% yield).
.sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 8.6 (s, 1H), 8.45 (s,
1H), 8.3-8.2 (m, 3H), 7.35 (d, 1H), 4.2-4.1 (m, 2H), 4.0-3.9 (m,
2H), 2.32 (s, 3H)
LCMS purity: 99.19%, m/z =295.0 (M+1)
HPLC: 95.78%
Example 123
Preparation of
1-(3-Amino-1H-indazol-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(123A)
##STR00143##
Step 1: Preparation of Intermediate
2-Fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzonitri-
le (I-123a)
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 300 mg, 1.693
mmol) was reacted with 4-bromo-2-fluoro-benzonitrile (372 mg, 1.86
mmol), 1,4-dioxane (50 mL), copper iodide (32.2 mg, 0.016 mmol),
trans-1,2-diamino cyclohexane (61 mL, 0.5079 mmol) and potassium
phosphate (900 mg, 4.23 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
CHCl.sub.3) afforded 163 mg of
2-Fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]--
benzonitrile (32.5% yield).
LCMS purity: 97.23%, m/z =297.0 (M+1)
Final Step: Preparation of
1-(3-Amino-1H-indazol-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(123A)
Hydrazine hydrate (5 mL) was added to solution of
2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzonitri-
le (I-123a: 163 mg) in 2-methoxymethanol (10 mL). The resulting
mixture was heated to 170.degree. C. and maintained for 22 hours.
The reaction was monitored by TLC (10% MeOH in CHCl.sub.3). The
reaction mixture was partitioned between ice water and
ethylacetate. The organic layer was washed with brine solution,
dried over Na.sub.2SO.sub.4 and concentrated. Purification by
preparative HPLC afforded 30 mg of the product (17.6% yield).
.sup.1H NMR (DMSO-d.sub.6, 300 MHz): .epsilon. 11.2 (s, 1H), 8.54
(s, 1H), 8.38 (d, 1H), 7.62 (d, 1H), 7.44 (s, 1H), 7.36 (d, 1H),
7.24 (d, 1H), 5.3 (s, 2H), 4.15-3.85 (m, 4H), 2.28 (s, 3H)
LCMS purity: 97.44%, m/z =308.9 (M+1)
HPLC: 95.39%
Example 124
Preparation of
1-Benzothiazol-6-yl-3-(4-methoxy-pyridin-3-yl)-imidazolidin-2-one
(124A)
##STR00144##
1-Benzothiazol-6-yl-3-(4-chloro-pyridin-3-yl)-imidazolidin-2-one
(84A: 50 mg, 0.1515 mmol) was added dropwise to a solution of
sodium methoxide (0.122 g, 2.259 mmol) in 1,4-dioxane (15 mL) over
a period of 5 minutes. The resulting mixture was refluxed for 10
hours. The reaction was monitored by TLC (10% MeOH in CHCl.sub.3).
The reaction mixture was partitioned between ice water and
ethylacetate. The organic layer was dried over Na.sub.2SO.sub.4 and
concentrated. Purification by preparative HPLC afforded 16 mg of
the product (31.66% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.9 (s, 1H), 8.58 (s,
1H), 8.46 (d, 1H), 8.39 (s, 1H), 8.1 (d, 1H), 7.7 (dd, 1H), 6.92
(d, 1H), 4.18-4.09 (m, 2H), 4.0-3.9 (m, 5H)
LCMS purity: 99.16%, m/z=326.9 (M+1)
HPLC: 91.89%
Example 125
Preparation of
1-Benzothiazol-6-yl-3-(4-difluoromethyl-pyridin-3-yl)-imidazolidin-2-one
(125A)
##STR00145##
Using the same reaction conditions as in Example 14,
1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 75 mg, 0.3173 mmol)
was reacted with 3-bromo-4-difluoromethyl-pyridine (60 mg, 0.2884
mmol), 1,4-dioxane (5 mL), copper iodide (7.5 mg),
trans-1,2-diamino cyclohexane (15 mg) and potassium phosphate (122
mg, 0.5769 mmol) to afford the crude product. Purification by
column chromatography on silica gel (2% MeOH in CHCl.sub.3),
followed by preparative HPLC afforded 2 mg of the product (2%
yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.92 (s, 1H), 8.68 (s,
2H), 8.36-8.32 (d, 1H), 8.16-8.12 (d, 1H), 7.72-7.58 (m, 2H),
7.24-6.8 (t, 1H), 4.24-4.04 (m, 4H)
LCMS purity: 95.49%, m/z=347 (M+1)
HPLC: 93.66%
Example 126
Preparation of
1-Benzothiazol-6-yl-3-(4-hydroxymethyl-pyridin-3-yl)-imidazolidin-2-one
(126A)
##STR00146##
Step 1: Preparation of Intermediate
3-(3-Benzothiazol-6-yl-2-oxo-imidazolidin-1-.beta.-pyridine-4-carbaldehyd-
e (I-126a)
Using the same reaction conditions as in Example 14,
1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 588.7 mg, 2.688
mmol) was reacted with 3-bromo-pyridine-4-carbaldehyde (500 mg,
2.688 mmol), 1,4-dioxane (10 mL), copper iodide (51.2 mg, 0.2688
mmol), trans-1,2-diamino cyclohexane (92.33 mg, 0.8064 mmol) and
potassium phosphate (1.711 g, 8.064 mmol) to afford the crude
product. Purification by column chromatography on silica gel (2%
MeOH in CHCl.sub.3) afforded 250 mg of
3-(3-Benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-pyridine-4-carb-
aldehyde (28.9% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.94 (s, 1H), 9.3 (s,
1H), 8.85 (s, 1H), 8.64 (d, 1H), 8.32 (d, 1H), 8.12-8.08 (d, 1H),
7.7 (dd, 1H), 7.66 (d, 1H), 4.32-4.16 (m, 4H)
Final Step: Preparation of
1-Benzothiazol-6-yl-3-(4-hydroxymethyl-pyridin-3-yl)-imidazolidin-2-one
(126A)
NaBH.sub.4 (82 mg, 2.1604 mmol) was added to a solution of
3-(3-benzothiazol-6-yl-2-oxo-imidazolidin-1-yl-pyridine-4-carbaldehyde
(I-126a: 140 mg, 0.4320 mmol) in MeOH (15 mL) and DCM (5 mL) at
0.degree. C. The resulting mixture was stirred for 10 minutes. The
reaction was monitored by TLC (10% MeOH in CHCl.sub.3). The
reaction mixture was partitioned between water and DCM. The organic
layer was washed with water and dried under reduced pressure to
afford 110 mg of the product (78.01% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.3 (s, 1H), 8.62 (s,
1H), 8.54 (d, 1H), 8.32 (s, 1H), 8.15-7.95 (m, 2H), 7.6 (d, 1H),
5.48 (t, 1H), 4.6 (d, 2H), 4.2-3.98 (m, 4H)
LCMS purity: 88.87%, m/z =327.1 (M+1)
HPLC: 94.07%
Example 127
Preparation of
1-Benzothiazol-6-yl-3-(6-methyl-pyridin-3-yl)-imidazolidin-2-one
(127A)
##STR00147##
Using the same reaction conditions as in Example 14,
1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 150 mg, 0.685 mmol)
was reacted with 5-bromo-2-methyl-pyridine (140.5 mg, 0.822 mmol),
1,4-dioxane (10 mL), copper iodide (12.92 mg, 0.068 mmol),
trans-1,2-diamino cyclohexane (23 mg, 0.205 mmol) and potassium
phosphate (435 mg, 2.055 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
CHCl.sub.3) afforded 110 mg of the product (51.80% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.3 (s, 1H), 8.7 (s,
1H), 8.3 (s, 1H), 8.1-7.9 (m, 3H), 7.3-7.2 (m, 1H), 4.1-4.0 (m,
4H), 2.5 (s, 3H)
LCMS purity: 91.9%, m/z=311.1 (M+1)
HPLC: 92.14%
Example 128
Preparation of
1-Benzothiazol-6-yl-3-(4-trifluoromethyl-pyridin-3-yl)-imidazolidin-2-one
(128A)
##STR00148##
Using the same reaction conditions as in Example 14,
1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 150 mg, 0.684 mmol)
was reacted with 3-bromo-4-trifluoromethyl-pyridine (185.75 mg,
0.822 mmol), 1,4-dioxane (10 mL), copper iodide (12.99 mg, 0.0684
mmol), trans-1,2-diamino cyclohexane (23.37 mg, 0.205 mmol) and
potassium phosphate (435 mg, 2.052 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1%
MeOH in CHCl.sub.3), followed by preparative HPLC afforded 7 mg of
the product (12.04% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.92 (s, 1H), 8.82-8.79
(m, 2H), 8.38 (s, 1H), 8.12 (d, 1H), 7.7-7.62 (m, 2H), 4.18 (t,
2H), 3.96 (t, 2H)
LCMS purity: 85.069%, m/z=365.1 (M+1)
HPLC: 92.93%
Example 129
Preparation of
3-(3-Benzothiazol-6-yl-2-oxo-imidazolidin-1-O-isonicotinonitrile
(129A)
##STR00149##
Using the same reaction conditions as in Example 14,
1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 120 mg, 0.5472 mmol)
was reacted with 3-bromo-isonicotinonitrile (100 mg, 0.5472 mmol),
1,4-dioxane (10 mL), copper iodide (12 mg), trans-1,2-diamino
cyclohexane (24 mg) and potassium phosphate (349 mg, 1.6418 mmol)
to afford the crude product. Purification by column chromatography
on silica gel (2% MeOH in CHCl.sub.3) afforded 47 mg of the product
(26.70% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.3 (s, 1H), 8.98 (s,
1H), 8.65 (d, 1H), 8.35 (s, 1H), 8.12-7.9 (m, 3H), 4.4-4.1 (m,
4H)
LCMS purity: 95.40%, m/z =322 (M+1)
HPLC: 98.74%
Example 130
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-naphthalen-2-yl-tetrahydro-pyrimidin-2-one
(130A)
##STR00150##
Step 1: Preparation of Intermediate
1-(3-chloro-propyl)-3-(4-methyl-pyridin-3-yl)-urea (I-130a)
1-Chloro-3-isocyanato-propane (1.6 g, 13.87 mmol) was added
dropwise to a stirred solution of 4-methyl-pyridin-3-ylamine (1 g,
9.25 mmol) in toluene (15 mL) at 0.degree. C. The reaction mixture
was stirred at room temperature for 18 hours. The reaction was
monitored by TLC (100% ethylacetate). The reaction mixture was
filtered, washed with toluene and dried under reduced pressure to
afford 2.12 g (99.5% yield) of
1-(3-chloro-propyl)-3-(4-methyl-pyridin-3-yl)-urea.
LCMS: 94.28%, m/z=228.1 (M+1)
Step 2: Preparation of Intermediate
1-(4-methyl-pyridin-3-yl)-tetrahydro-pyrimidin-2-one (I-130b)
1-(3-Chloro-propyl)-3-(4-methyl-pyridin-3-yl)-urea (I-130a: 2 g,
9.25 mmol) in dry DMF (15 mL) was added to a stirred mixture of
sodium hydride (330 mg, 13.87 mmol) in THF (30 mL) at 0.degree. C.
The reaction was stirred at room temperature for 1 hour. The
reaction was monitored by TLC (100% ethylacetate). The reaction
mixture was quenched with MeOH at 0.degree. C., concentrated under
reduced pressure and partitioned between ice water and chloroform.
The organic layer was washed with brine solution, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford
1.7 g (96.5% yield) of
1-(4-methyl-pyridin-3-yl)-tetrahydro-pyrimidin-2-one.
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.44-8.36 (m, 2H), 7.19
(d, 1H), 5.1-5.0 (br s, 1H), 3.72-3.64 (m, 1H), 3.52-3.4 (m, 3H),
2.29 (s, 3H), 2.2-2.1 (m, 2H)
Final Step: Preparation of
1-(4-Methyl-pyridin-3-yl)-3-naphthalen-2-yl-tetrahydro-pyrimidin-2-one
(130A)
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-tetrahydro-pyrimidin-2-one (I-130b: 150
mg, 0.785 mmol) was reacted with 2-bromo-naphthalene (195 mg, 0.942
mmol), 1,4-dioxane (20 mL), copper iodide (15 mg, 0.078 mmol),
trans-1,2-diamino cyclohexane (0.03 mL, 0.235 mmol) and potassium
phosphate (415 mg, 1.96 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1% MeOH in
CHCl.sub.3), followed by recrystallization using DCM and hexane
afforded 65 mg of the product (26.2% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.5 (s, 1H), 8.39 (d,
1H), 7.85-7.7 (m, 4H), 7.6-7.4 (m, 3H), 7.18 (d, 1H), 4.1-3.8 (m,
3H), 3.69-3.58 (m, 1H), 2.4-2.3 (m, 5H)
LCMS purity: 99.72%, m/z=318.1 (M+1)
HPLC: 98.65%
Example 131
Preparation of
1-m-Tolyl-3-(4-trifluoromethyl-pyridin-3-yl)-imidazolidin-2-one
(131A)
##STR00151##
Step 1: Preparation of Intermediate
1-(2-chloro-ethyl)-3-m-tolyl-urea (I-131a)
1-Chloro-2-isocyanato-ethane (2.36 g, 0.02239 mmol) was added
dropwise to a stirred solution of m-tolylamine (2 g, 0.01866 mmol)
in toluene (50 mL) over a period of 30 minutes at 0.degree. C. The
reaction mixture was stirred at room temperature for 12 hours. The
reaction was monitored by TLC (5% MeOH in DCM). The reaction
mixture was filtered, washed with toluene and dried under reduced
pressure to afford 3.8 g (97% yield) of
1-(2-chloro-ethyl)-3-m-tolyl-urea.
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.56 (s, 1H), 7.23 (s,
1H), 7.2-7.05 (m, 2H), 6.72 (d, 1H), 6.36 (t, 1H), 3.7-3.6 (m, 2H),
3.45-3.38 (m, 2H), 2.23 (s, 3H)
Step 2: Preparation of Intermediate 1-m tolyl imidazolidin 2 one
(I-131b)
1-(2-Chloro-ethyl)-3-m-tolyl-urea (I-131a: 4 g, 18.86 mmol) in dry
DMF (70 mL) was added to a stirred mixture of sodium hydride (1.358
g, 28.30 mmol) in THF (70 mL) at 0.degree. C. The reaction was
stirred at room temperature for 1 hour. The reaction was monitored
by TLC (100% ethylacetate). The reaction mixture was quenched with
MeOH at 0.degree. C., concentrated under reduced pressure and
partitioned between ice water and chloroform. The organic layer was
washed with brine solution, dried over Na.sub.2SO.sub.4, and
concentrated under reduced pressure to afford 2.7 g (81.34% yield)
of 1-m-tolyl-imidazolidin-2-one.
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 7.4-7.3 (m, 2H), 7.18
(t, 1H), 6.95-6.89 (br s, 1H), 6.8 (d, 1H), 3.85-3.78 (m, 2H),
3.44-3.36 (m, 2H), 2.26 (s, 3H)
LCMS purity: 96.44%, m/z=177.2 (M+1)
Final Step: Preparation of
1-m-Tolyl-3-(4-trifluoromethyl-pyridin-3-yl)-imidazolidin-2-one
(131A)
Using the same reaction conditions as in Example 14,
1-m-tolyl-imidazolidin-2-one (I-131b: 150 mg, 0.8522 mmol) was
reacted with 3-bromo-4-trifluoromethyl-pyridine (160 mg, 0.8522
mmol), 1,4-dioxane (5 mL), copper iodide (16.23 mg, 0.08522 mmol),
trans-1,2-diamino cyclohexane (29.27 mg, 0.2552 mmol) and potassium
phosphate (542.56 mg, 2.556 mmol) to afford the crude product.
Purification by preparative HPLC afforded 94 mg of the product
(34.43% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.82-8.75 (br s, 1H),
7.64 (d, 1H), 7.46 (s, 1H), 7.4-7.2 (m, 3H), 6.95 (d, 1H),
4.15-3.85 (m, 4H), 2.36 (s, 3H)
LCMS purity: 97.94%, m/z=321.7 (M+1)
HPLC: 97.47%
Example 132
Preparation of
1-(2-Methyl-2H-indazol-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(132A)
##STR00152##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 100 mg, 0.564
mmol) was reacted with 5-bromo-2-methyl-2H-indazole (120 mg, 0.5741
mmol), 1,4-dioxane (15 mL), copper iodide (10 mg, 0.056 mmol),
trans-1,2-diamino cyclohexane (19 mg, 0.166 mmol) and potassium
phosphate (360 mg, 1.698 mmol) to afford the crude product.
Purification by preparative HPLC afforded 3.6 mg of the product
(6.228% yield).
.sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 8.5-8.46 (br s, 1H),
8.43-8.32 (m, 1H), 8.15 (s, 1H), 7.82-7.54 (m, 3H), 7.4 (d, 1H),
4.3-4.1 (m, 5H), 4.05-3.92 (m, 2H), 2.4 (s, 3H)
LCMS purity: 96.38%, m/z=308.1 (M+1)
HPLC: 96.18%
Example 133
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-naphthalen-1-O-imidazolidin-2-one
(133A)
##STR00153##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465
mmol) was reacted with 1-bromo-naphthalene (118 mL, 0.8465 mmol),
1,4-dioxane (10 mL), copper iodide (18 mg), trans-1,2-diamino
cyclohexane (36 mg) and potassium phosphate (539 mg, 2.5395 mmol)
to afford the crude product. Purification by column chromatography
on silica gel (2% MeOH in DCM) afforded 162 mg of the product
(63.28% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.76-8.28 (m, 2H),
8.2-7.8 (m, 3H), 7.76-7.24 (m, 5H), 4.2-3.92 (br s, 4H), 2.35 (s,
3H)
LCMS purity: 98.99%, m/z=303.9 (M+1)
HPLC: 98.34%
Example 134
Preparation of
1-(1-Methyl-1H-indol-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(134A)
##STR00154##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847
mmol) was reacted with 5-bromo-1-methyl-1H-indole (215 mL, 1.016
mmol), 1,4-dioxane (20 mL), copper iodide (15 mg, 0.084 mmol),
trans-1,2-diamino cyclohexane (0.03 mL, 0.254 mmol) and potassium
carbonate (230 mg, 1.69 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
CHCl.sub.3), followed by recrystallization using DCM and hexane
afforded 55 mg of the product (27% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.53 (s, 1H), 8.38 (d,
1H), 7.7-7.55 (m, 2H), 7.4-7.15 (m, 2H), 7.1-7.01 (m, 1H), 6.5-6.45
(br s, 1H), 4.2-4.05 (m, 2H), 4.0-3.9 (m, 2H), 3.78 (s, 3H), 2.38
(s, 3H)
LCMS purity: 93.43%, m/z=307.1 (M+1)
HPLC: 87.91%
Example 135
Preparation of
6-[3-(4-Methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-1,2-dihydro-indazol-
-3-one (135A)
##STR00155##
Step 1: Preparation of Intermediate
2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzoic
acid methyl ester (I-135a)
Using the same reaction conditions as in Example 15,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 295 mg, 1.65
mmol) was reacted with 4-bromo-2-fluoro-benzoic acid methyl ester
(350 mg, 1.5 mmol), 1,4-dioxane (25 mL), copper iodide (32 mg,
0.165 mmol), trans-1,2-diamino cyclohexane (70 mg, 0.495 mmol) and
potassium phosphate (875 mg, 4.12 mmol). The resulting mixture was
refluxed for 18 hours. The reaction workup afforded 350 mg of
2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzoic
acid methyl ester (68.7% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.78-8.26 (m, 2H),
8.1-7.82 (m, 1H), 7.55 (d, 1H), 7.48-7.12 (m, 2H), 4.3-3.8 (m, 7H),
2.32 (s, 3H)
LCMS purity: 97.47%, m/z=330.1 (M+1)
Final Step: Preparation of
6-[3-(4-Methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-1,2-dihydro-indazol-
-3-one (135A)
Hydrazine hydrate (10 mL) was added to
2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzoic
acid methyl ester (I-135a: 350 mg, 1.06 mmol) and the resulting
mixture was heated to 120.degree. C. for 18 hours. The reaction was
monitored by TLC (10% MeOH in CHCl.sub.3). The reaction mixture was
partitioned between ice water and ethylacetate. The aqueous layer
was concentrated to afford the crude product. Purification by
column chromatography on silica gel (10% MeOH in CHCl.sub.3),
followed by preparative HPLC afforded 135 mg of the product (41.2%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 11.2-10.8 (br s, 1H),
10.7-10.4 (br s, 1H), 8.58-8.3 (m, 2H), 7.62-7.42 (m, 2H),
7.41-7.22 (m, 2H), 4.2-3.82 (m, 4H), 2.28 (s, 3H)
LCMS purity: 99.15%, m/z=310.0 (M+1)
HPLC: 97.14%
Example 136
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-thieno[3,2-c]pyridin-3-yl-imidazolidin-2-one
(136A)
##STR00156##
Step I. Preparation of Intermediate
1-(4-Chloro-thieno[3,2-c]pyridin-3-yl)-3-(4-methyl-pyridin-3-yl)-imidazol-
idin-2-one (I-136a)
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 321.4 mg,
1.8142 mmol) was reacted with
3-bromo-4-chloro-thieno[3,2-c]pyridine (500 mg, 1.9956 mmol),
1,4-dioxane (50 mL), copper iodide (34.4 mg, 0.1845 mmol),
trans-1,2-diamino cyclohexane (62.3 mg, 0.5434 mmol) and potassium
phosphate (961.3 mg, 4.528 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
CHCl.sub.3) afforded 220 mg of
1-(4-Chloro-thieno[3,2-c]pyridin-3-yl)-3-(4-methyl-pyridin-3-yl)-imidazol-
idin-2-one (35.2% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.55 (s, 1H), 8.46-8.2
(dd, 2H), 7.8-7.6 (m, 1H), 7.3-7.2 (m, 2H), 4.2-4.0 (m, 4H), 2.4
(s, 3H)
Final Step: Preparation of
1-(4-Methyl-pyridin-3-yl)-3-thieno[3,2-c]pyridin-3-yl-imidazolidin-2-one
(136A)
Activated Zinc (417 mg, 6.380 mmol) was added to a stirred solution
of
1-(4-chloro-thieno[3,2-c]pyridin-3-yl)-3-(4-methyl-pyridin-3-yl)-imidazol-
idin-2-one (I-136a: 220 mg, 0.6380 mmol) in acetic acid (10 mL).
The resulting mixture was stirred at room temperature for 2 days.
The reaction was monitored by TLC (10% MeOH in DCM). The reaction
mixture was filtered and the filtrate was concentrated under
reduced pressure. Aqueous NH.sub.3 solution was added to the
concentrate and extracted with DCM. The organic layer was dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure to
afford the crude product. Purification by column chromatography on
silica gel (5% MeOH in DCM) afforded 80 mg of the product (40.6%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.15 (s, 1H), 8.8-7.91
(m, 4H), 7.68 (s, 1H), 7.48-7.02 (m, 1H), 4.24-3.92 (m, 4H), 2.3
(s, 3H)
LCMS purity: 98.96%, m/z=310.9 (M+1)
HPLC: 95.37%
Example: 137
Preparation of
1-(5-Chloro-1-methyl-1H-indol-3-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidi-
n-2-one (137A)
##STR00157##
Step 1: Preparation of Intermediate
3-Bromo-5-chloro-1-methyl-1H-indole (I-137a)
K.sub.2CO.sub.3 (1.39 g, 10.08 mmol) was added to a stirred
solution of 3-bromo-5-chloro-1H-indole (775 mg, 3.36 mmol) in DMF
(7.5 mL) and the resulting mixture was stirred for 30 minutes. This
was followed by the addition of methyl iodide (572.5 mg, 4.03 mmol)
at 0-5.degree. C. and the stirring was continued for a further 2
hours at room temperature. The reaction was monitored by TLC (10%
ethylacetate in hexane). The reaction mixture was partitioned
between ice water and DCM. The organic layer was concentrated to
afford the crude product. Purification by column chromatography on
silica gel (5% ethylacetate in hexane) afforded 530 mg of
3-Bromo-5-chloro-1-methyl-1H-indole (65% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 7.94-7.2 (m, 4H), 3.8
(s, 3H)
Final Step: Preparation of
1-(5-Chloro-1-methyl-1H-indol-3-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidi-
n-2-one (137A)
Using the same reaction conditions as in Example 15,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-114b: 150 mg,
0.8465 mmol) was reacted with 3-bromo-5-chloro-1-methyl-1H-indole
(I-137a: 226.2 mg, 0.9311 mmol), 1,4-dioxane (20 mL), copper iodide
(16.1 mg, 0.8465 mmol), trans-1,2-diamino cyclohexane (30.6 mL,
0.255 mmol) and potassium phosphate (441 mg, 2.077 mmol). The
resulting mixture was heated to reflux for 16 hours. The reaction
workup afforded 170 mg of
1-(5-Chloro-1-methyl-1H-indol-3-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidi-
n-2-one (58.9% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.68-8.18 (m, 2H), 7.7
(s, 1H), 7.6-7.08 (m, 4H), 4.1-3.9 (br s, 4H), 3.78 (s, 3H), 2.3
(s, 3H)
LCMS purity: 100%, m/z=340.8 (M+1)
HPLC: 96.1%
Example 138
Preparation of
1-Indan-5-yl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(1384)
##STR00158##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847
mmol) was reacted with 5-bromo-indan (248 mg, 1.0163 mmol),
1,4-dioxane (10 mL), copper iodide (0.0161 g, 0.0842 mmol),
trans-1,2-diamino cyclohexane (0.028 g, 0.245 mmol) and potassium
phosphate (538 mg, 2.537 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1% MeOH in
CHCl.sub.3) afforded 45 mg of the product (20% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.8-8.2 (m, 2H), 7.7-7.0
(m, 4H), 4.15-3.8 (m, 4H), 3.15-2.65 (m, 4H), 2.34 (s, 3H), 2.2-1.8
(m, 2H)
LCMS purity: 85.44%, m/z=294.1 (M+1)
HPLC: 91.46%
Example 139
Preparation of
1-Benzo[b]thiophen-5-yl-3-(4-methyl-pyridin-3-yl)-1,3-dihydro-imidazol-2--
one (139A)
##STR00159##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 500 mg, 2.825
mmol) was reacted with 5-bromo-benzo[b]thiophene (661.86 mg, 3.12
mmol), 1,4-dioxane (20 mL), copper iodide (53.81 g, 0.2825 mmol),
trans-1,2-diamino cyclohexane (97.03 g, 0.8475 mmol) and potassium
phosphate (1.796 g, 8.475 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1.2% MeOH in
CHCl.sub.3), followed by preparative HPLC afforded mg of the
product (4.61% yield).
.sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 7.4-7.1 (m, 2H),
7.02-6.65 (m, 2H), 6.54-6.1 (m, 4H), 6.0-5.5 (m, 2H), 1.12 (s,
3H)
LCMS purity: 95.27%, m/z=308.0 (M+1)
HPLC: 97.39%
Example 140
Preparation of
2-Fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzonitri-
le (140A)
##STR00160##
The title compound was prepared in a manner analogous to the
procedures described for Example (I-123a).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.55 (s, 1H), 8.42 (d,
1H), 8.0-7.74 (m, 2H), 7.7-7.52 (m, 1H), 7.38 (d, 1H), 4.18-3.9 (m,
4H), 2.29 (s, 3H)
LCMS purity: 96.96%, m/z=297.1 (M+1)
HPLC: 97.49%
Example 141
Preparation of
1-(1H-Benzotriazol-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
Hydrochloride (141A)
##STR00161##
Step 1: Preparation of Intermediate
1-(4-Methyl-pyridin-3-yl)-3-yl)-(2-trimethylsilanyl-ethoxymethyl)-1H-benz-
otriazol-5-yl)-imidazolidin-2-one (I-141a)
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 175 mg, 0.9875
mmol) was reacted with
5-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzotriazole (353
mg, 1.08634 mmol), 1,4-dioxane (50 mL), copper iodide (80.76 mg,
0.09875 mmol), trans-1,2-diamino cyclohexane (33.9 mg, 0.2962 mmol)
and potassium phosphate (524 mg, 2.4689 mmol) to afford the crude
product. Purification by column chromatography on silica gel (2%
MeOH in CHCl.sub.3) afforded 350 mg of
1-(4-Methyl-pyridin-3-yl)-3-[1-(2-trimethylsilanyl-ethoxymethyl-
)-1H-benzotriazol-5-yl]-imidazolidin-2-one (79% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.66-8.25 (m, 2H),
8.2-7.6 (m, 2H), 7.2-7.4 (m, 2H), 6.15-5.8 (d, 2H), 4.35-3.9 (m,
4H), 3.7-3.4 (m, 2H), 2.4 (s, 3H), 1.05-0.7 (m, 2H), 0.2-0.2 (m,
9H)
Final Step: Preparation of
1-(1H-Benzotriazol-5-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
Hydrochloride (141A)
Dioxane HCl (10 ml) was added to
1-(4-methyl-pyridin-3-yl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzo-
triazol-5-yl]-imidazolidin-2-one (I-141a: 350 mg, 0.78125 mmol) and
the resulting mixture was stirred room temperature for 12 hours.
The reaction was monitored by TLC (10% MeOH in DCM). The reaction
mixture was concentrated and washed with ether. The solid formed
was collected and dried under reduced pressure to afford 230 mg of
the product (89.4% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.02 (s, 1H), 8.84-8.6
(m, 1H), 8.2-7.8 (m, 4H), 4.3-4.0 (m, 4H), 2.35 (s, 3H)
LCMS purity: 84.98%, m/z=295.1 (M+1)
HPLC: 95.17%
Example 142
Preparation of
1-Benzothiazol-6-yl-3-(4-methyl-pyridin-3-yl)-1,3-dihydro-imidazol-2-one
(142A)
##STR00162##
Step 1: Preparation of Intermediate
1-Benzothiazol-6-yl-3-(2,2-dimethoxy-ethyl)-urea (I-142a)
TEA (185 mL, 1.3315 mmol) and triphosgene (138 mg, 0.4660 mmol)
were added to a solution of benzothiazol-6-ylamine (200 mg, 1.3315
mmol) in THF (20 mL) at 0.degree. C. The resulting mixture was
stirred at room temperature for 3 hours. This was followed by the
addition of 2,2-dimethoxy-ethylamine (173 mL, 1.5978 mmol) in THF
and TEA (185 mL, 1.3315 mmol) and the stirring was continued for a
further 18 hours at room temperature. The reaction was monitored by
TLC (50% ethylacetate in hexane). The reaction mixture was
concentrated and the concentrate was partitioned between
ethylacetate and water. The organic layer was washed with water,
brine solution, dried over Na.sub.2SO.sub.4 and concentrated.
Purification by column chromatography on silica gel (100%
ethylacetate) afforded 300 mg of
1-Benzothiazol-6-yl-3-(2,2-dimethoxy-ethyl)-urea (80.21%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.2 (s, 1H), 8.85 (s,
1H), 8.3 (s, 1H), 7.95 (d, 1H), 7.4 (d, 1H), 6.3 (s, 1H), 4.6-4.2
(m, 1H), 3.4-3.1 (m, 8H)
LCMS purity: 98.37%, m/z=282.0 (M+1)
Step 2: Preparation of Intermediate
1-Benzothiazol-6-yl-1,3-dihydro-imidazol-2-one (I-142b)
1N H.sub.2SO.sub.4 (2 mL) was added to
1-benzothiazol-6-yl-3-(2,2-dimethoxy-ethyl)-urea (I-142a: 300 mg)
and the resulting mixture was stirred at 0.degree. C. for 30
minutes. The reaction mixture was heated to 50.degree. C. for 2
hours. The reaction was monitored by TLC (10% MeOH in CHCl.sub.3).
The reaction mixture was cooled to 0.degree. C. and basified with
10% KOH solution. The precipitate was collected, washed with water
and dried under reduced pressure to afford 170 mg of
1-Benzothiazol-6-yl-1,3-dihydro-imidazol-2-one (73.59% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 10.6-10.1 (br s, 1H),
9.35 (br s, 1H), 8.5 (s, 1H), 8.2-7.7 (m, 2H), 7.0 (s, 1H), 6.6 (s,
1H)
LCMS purity: 93.78%, m/z=217.9 (M+1)
HPLC: 94.03%
Final Step: Preparation of
1-Benzothiazol-6-yl-3-(4-methyl-pyridin-3-yl)-1,3-dihydro-imidazol-2-one
(142A)
Using the same reaction conditions as in Example 14,
1-benzothiazol-6-yl-1,3-dihydro-imidazol-2-one (I-142b: 170 mg,
0.7834 mmol) was reacted with 3-iodo-4-methyl-pyridine (172 mg,
0.7834 mmol), 1,4-dioxane (10 mL), copper iodide (17 mg),
trans-1,2-diamino cyclohexane (34 mg) and potassium phosphate (499
mg, 2.3502 mmol) to afford the crude product. Purification by
column chromatography on silica gel (2-3% MeOH in CHCl.sub.3),
followed by preparative HPLC afforded 16 mg of the product (6.63%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.42 (s, 1H),
8.67-8.45 (d, 2H), 8.25-8.14 (d, 1H), 8.05-7.94 (m, 1H), 7.55-7.32
(m, 2H), 7.18-7.05 (d, 1H), 2.34 (s, 3H)
LCMS purity: 97.90%, m/z=308.9 (M+1)
HPLC: 97.01%
Example 143
Preparation of
1-(3-Amino-1-methyl-1H-indazol-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolid-
in-2-one (143A)
##STR00163##
Methyl hydrazine (10 mL) was added to a stirred solution of
2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzonitri-
le (I-123a: 240 mg, 0.80998 mmol) in 2-methoxy ethanol (20 mL). The
resulting mixture was stirred at 170.degree. C. for 12 hours. The
reaction was monitored by TLC (10% MeOH in CHCl.sub.3). The
reaction mixture was cooled to room temperature and concentrated.
Ice was added to the concentrate and the precipitate formed was
collected and dried under reduced pressure to afford 180 mg of the
product (69.2% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.8-8.1 (d, 2H),
7.8-7.15 (m, 4H), 5.35 (s, 2H), 4.4-3.8 (m, 4H), 3.6 (s, 3H), 2.35
(s, 3H)
LCMS purity: 99.42%, m/z=323.1 (M+1)
HPLC: 95.08%
Example 144
Preparation of
1-(1H-Indol-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(144A)
##STR00164##
Step 1: Preparation of
Intermediate-(4-Methyl-pyridin-3-yl)-3-[1-(toluene-4-sulfonyl)-1H-indol-6-
-yl]-imidazolidin-2-one (I-144a)
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 130 mg,
0.00073 mol) was reacted with
6-bromo-1-(toluene-4-sulfonyl)-1H-indole (200 mg, 0.00073 mol),
1,4-dioxane (20 mL), copper iodide (13 mg, 0.000073 mol),
trans-1,2-diamino cyclohexane (26 mg, 0.00021 mol) and potassium
phosphate (309 mg, 0.00146 mol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
CHCl.sub.3) afforded 94 mg of
1-(4-Methyl-pyridin-3-yl)-3-[1-(toluene-4-sulfonyl)-1H-indol-6]--
imidazolidin-2-one (30.12% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.7-8.3 (m, 2H), 8.16
(s, 1H), 7.95-7.7 (m, 2H), 7.68-7.4 (m, 2H), 7.36-7.12 (m, 4H),
6.7-6.5 (s, 1H), 4.3-3.8 (m, 4H), 2.4 (s, 3H), 2.3 (s, 3H)
LCMS purity: 81.93%, m/z=447.1 (M+1)
Final Step: Preparation of
1-(1H-Indol-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(144A)
10% NaOH solution (10 mL) was added to a solution of
1-(4-methyl-pyridin-3-yl)-3-[1-(toluene-4-sulfonyl)-1H-indol-6-yl]-imidaz-
olidin-2-one (I-144a: 94 mg) in ethanol (10 mL). The resulting
mixture was heated to reflux at 90.degree. C. for 1 hour. The
reaction was monitored by TLC (10% MeOH in CHCl.sub.3). The
reaction mixture was concentrated and partitioned between
ethylacetate and water. The organic layer was washed with water,
brine solution, dried and concentrated. Purification by column
chromatography on silica gel (2% MeOH in DCM) afforded 29 mg of the
product (47.54% yield).
.sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 8.7-8.2 (m, 2H), 7.9-7.0
(m, 5H), 6.4 (s, 1H), 4.3-3.8 (m, 4H), 2.4 (s, 3H)
LCMS purity: 75.15%, m/z=293.0 (M+1)
HPLC: 85.90%
Example 145
Preparation of
1-(3-Chloro-imidazo[1,2-a]pyridin-7-yl)-3-(4-methyl-pyridin-3-yl)-imidazo-
lidin-2-one (145A)
##STR00165##
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 165 mg, 0.932
mmol) was reacted with 7-bromo-3-chloro-imidazo[1,2-a]pyridine (278
mg, 1.21 mmol). 1,4-dioxane (6 mL), copper iodide (17.71 mg, 0.093
mmol), trans-1,2-diamino cyclohexane (32.01 mg, 0.279 mmol) and
potassium phosphate (493.96 mg, 2.33 mmol) to afford the crude
product. Purification by column chromatography on silica gel (2%
MeOH in CHCl.sub.3), followed by preparative HPLC afforded 20 mg of
the product (6.57% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 9.1-8.9 (m, 2H), 8.6-8.3
(m, 2H), 8.0-7.6 (m, 3H), 4.4-4.1 (m, 4H), 2.6 (s, 3H)
LCMS purity: 83.31%, m/z=328.0 (M+1)
HPLC: 89.12%
Example 146
Preparation of
1-Methyl-3-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-1H-indole--
4-carbonitrile (146A)
##STR00166##
Step 1: Preparation of Intermediate
3-Bromo-1H-indole-4-carbonitrile (I-146a)
Bromine in DMF (0.796 g, 4.975 mmol) was added to a stirred
solution of 1H-indole-4-carbonitrile (700 mg, 4.9295 mmol) in DMF
(15 mL) at room temperature. The resulting mixture was stirred at
room temperature for 2 hours. The reaction was monitored by TLC
(10% ethylacetate in hexane). The reaction mixture was poured into
ice water containing 0.5% ammonia and 0.5% sodium metabisulphite.
The precipitate was collected, washed with cold water and dried to
afford 850 mg of 3-Bromo-1H-indole-4-carbonitrile (78.41%
yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 12.1 (s, 1H),
8.02-7.49 (m, 3H), 7.42-7.2 (m, 1H)
Step 2: Preparation of Intermediate
3-Bromo-1-methyl-1H-indole-4-carbonitrile (I-146b)
3-Bromo-1H-indole-4-carbonitrile (I-146a: 500 mg, 2.272 mmol) was
added dropwise to a stirred mixture of NaH (0.218 g, 9.0833 mmol)
in dry DMF (15 mL) at 0.degree. C. over a period of 10 minutes.
This was followed by the addition of methyl iodide and the
resulting mixture was stirred at 0.degree. C. for 2 hours. The
reaction was monitored by TLC (10% ethylacetate in hexane). The
reaction mixture was quenched with ice water; the precipitate
formed was collected and dried to afford 0.400 g of the crude
product.
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 7.8-7.0 (m, 4H), 3.82
(s, 3H)
Final Step: Preparation of Intermediate
1-Methyl-3-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-1H-indole--
4-carbonitrile (146A)
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 110 mg, 0.621
mmol) was reacted with 3-bromo-1-methyl-1H-indole-4-carbonitrile
(I-146b: 175 mg, 0.744 mmol), 1,4-dioxane (15 mL), copper iodide
(11 mg, 0.0573 mmol), trans-1,2-diamino cyclohexane (21 mg, 0.1843
mmol) and potassium carbonate (171 mg, 1.239 mmol) to afford the
crude product. Purification by column chromatography on silica gel
(3% MeOH in CHCl.sub.3) afforded 49 mg of
1-Methyl-3-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-1-
H-indole-4-carbonitrile (23.90% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.6 (s, 1H), 8.5-8.3 (m,
1H), 7.7-7.1 (m, 4H), 4.18-3.95 (m, 4H), 3.85 (s, 3H), 2.45 (s,
3H)
LCMS purity: 99.70%, m/z=331.9 (M+1)
HPLC: 95.81%
Example 147
Preparation of
1-Hydroxymethyl-3,3-dimethyl-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazoli-
din-1-yl]-1,3-dihydro-indol-2-one (147A)
##STR00167##
Step 1: Preparation of Intermediate
3,3-Dimethyl-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-1-(2-t-
rimethylsilanyl-ethoxymethyl)-1,3-dihydro-indol-2-one (147a)
Using the same reaction conditions as in Example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 0.123 g,
0.0007 mol) was reacted with
5-iodo-3,3-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indol-
-2-one (0.29 g, 0.0007 mol), 1,4-dioxane (20 mL), copper iodide
(0.013 g, 0.00007 mol), trans-1,2-diamino cyclohexane (0.028 g,
0.00025 mol) and potassium phosphate (356 mg, 0.00168 mol) to
afford the crude product. Purification by column chromatography on
silica gel (80% ethylacetate in hexane) afforded 170 mg of
3,3-Dimethyl-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-1-(2-t-
rimethylsilanyl-ethoxymethyl)-1,3-dihydro-indol-2-one (52.14%
yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.6-8.4 (m, 2H), 7.5-7.0
(m, 4H), 5.2 (s, 2H), 4.2-3.9 (m, 4H), 3.6-3.4 (m, 2H), 2.3 (s,
3H), 1.4 (s, 6H), 1.1-0.7 (m, 2H), 0.2-0.2 (s, 9H)
LCMS purity: 88.56%, m/z=467.2 (M+1)
Final Step: Preparation of
1-Hydroxymethyl-3,3-dimethyl-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazoli-
din-1-yl]-1,3-dihydro-indol-2-one (147A)
Dioxane HCl (4 mL) was added to
3,3-dimethyl-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-1-(2-t-
rimethylsilanyl-ethoxymethyl)-1,3-dihydro-indol-2-one (I-147a: 50
mg) and the resulting mixture was stirred room temperature for 1
hour. The reaction was monitored by TLC (10% MeOH in CHCl.sub.3).
The reaction mixture was basified with bicarbonate solution and
extracted with DCM. The organic layer was concentrated; the
concentrate was recrystallized with DCM and hexane and dried to
afford 37 mg of the product (94.87% yield).
.sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 8.7-8.3 (m, 2H), 7.7-7.1
(m, 4H), 5.2 (s, 2H), 4.3-3.9 (m, 4H), 2.4 (s, 3H), 1.4 (s, 6H)
LCMS purity: 79.51%, m/z=367.1 (M+1)
HPLC: 82.25%
Example 148
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-(2-trifluoromethyl-pyridin-4-yl)-imidazolidin-
-2-one (163A)
##STR00168##
Using the same reaction conditions as in Example 15,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847
mmol) was reacted with 4-bromo-2-trifluoromethyl-pyridine (229 mg,
1.017 mmol), 1,4-dioxane (10 mL), copper iodide (16.13 mg, 0.0847
mmol), trans-1,2-diamino cyclohexane (29.09 mg, 0.254 mmol) and
potassium phosphate (44.89 mg, 2.117 mmol). The resulting mixture
was heated to 120.degree. C. for 6 hours. The reaction workup
afforded 200 mg of the product (73.52% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.8-8.5 (m, 2H),
8.5-8.35 (m, 1H), 8.35-8.1 (br s, 1H), 7.8-7.6 (m, 1H), 7.5-7.25
(m, 1H), 4.3-3.8 (m, 4H), 2.3 (s, 3H)
LCMS purity: 98.05%, m/z=323.0 (M+1)
HPLC: 98.13%
Example 149
Preparation of
1-Benzothiazol-6-yl-3-(4-dimethoxymethyl-pyridin-3-yl)-imidazolidin-2-one
(149A)
##STR00169##
Step 1: Preparation of Intermediate
3-Bromo-4-dimethoxymethyl-pyridine (I-149a)
PTSA (834 mg, 4.384 mmol) was added to a solution of
3-bromo-pyridine-4-carbaldehyde (600 mg, 3.2256 mmol) in methanol
(20 mL). The resulting mixture was heated to reflux for 4 hours.
The reaction was monitored by TLC (20% ethylacetate in hexane). The
reaction mixture was concentrated and basified with NaHCO.sub.3
solution. The reaction mixture was partitioned between water and
DCM. The organic layer was washed with brine solution, dried over
Na.sub.7SO.sub.4, filtered and the filtrate was concentrated to
afford 700 mg of 3-Bromo-4-dimethoxymethyl-pyridine (93.5%
yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.8-8.4 (m, 2H), 7.5 (s,
1H), 5.5 (s, 1H), 3.4 (s, 6H)
Final Step Preparation of
1-Benzothiazol-6-yl-3-(4-dimethoxymethyl-pyridin-3-yl)-imidazolidin-2-one
(149A)
Using the same reaction conditions as in Example 14,
1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 590 mg, 2.7 mmol)
was reacted with 3-bromo-4-dimethoxymethyl-pyridine (I-149a: 690
mg, 2.97 mmol), 1,4-dioxane (50 mL), copper iodide (51.46 mg, 0.27
mmol), trans-1,2-diamino cyclohexane (93 mg, 0.81 mmol) and
potassium phosphate (1.72 g, 8.1 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1% MeOH in
CHCl.sub.3) afforded 510 mg of the product (51.2% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.28 (s, 1H), 8.8-8.5
(m, 2H), 8.3 (s, 1H), 8.18-7.82 (m, 2H), 7.68-7.42 (br s, 1H), 5.6
(s, 1H), 4.25-3.85 (m, 4H), 3.3 (s, 6H)
LCMS purity: 98.35%, m/z=371.2 (M+1)
HPLC: 96.82%
Example 150
Preparation of
N-[3-(3-Benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-pyridin-4-yl]-acetamid-
e (150A)
##STR00170##
Using the same reaction conditions as in Example 14,
1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 200 mg, 0.912 mmol)
was reacted with N-(3-iodo-pyridin-4-yl)-acetamide (262 mg, 1.003
mmol), 1,4-dioxane (10 mL), copper iodide (17.3 mg, 0.09 mmol),
trans-1,2-diamino cyclohexane (31.4 mg, 0.273 mmol) and potassium
phosphate (581 mg, 2.73 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
CHCl.sub.3) afforded 75 mg of the product (23.36% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.75 (s, 1H), 9.28 (s,
1H), 8.55 (s, 1H), 8.45-7.9 (m, 5H), 4.3-4.0 (m, 2H), 3.95-3.8 (m,
2H), 2.2 (s, 3H)
LCMS purity: 78.28%, m/z=354.0 (M+1)
HPLC: 90.16%
Example 151
Preparation of
1-Benzothiazol-6-yl-3-(5-chloro-4-methyl-pyridin-3-yl)-imidazolidin-2-one
(151A)
##STR00171##
Using the same reaction conditions as in Example 14,
1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 100 mg, 0.456 mmol)
was reacted with 3-bromo-5-chloro-4-methyl-pyridine (94 mg, 0.456
mmol), 1,4-dioxane (5 mL), copper iodide (8.68 mg, 0.0456 mmol),
trans-1,2-diamino cyclohexane (15.66 mg, 0.1368 mmol) and potassium
phosphate (290.38 mg, 1.368 mmol) to afford the crude product.
Purification by preparative HPLC afforded 52 mg of the product
(34.21% yield).
.sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 9.15 (s, 1H), 8.5 (s,
1H), 8.32 (s, 1H), 8.15-7.8 (m, 2H), 4.31-4.2 (m, 2H), 4.1-3.98 (m,
2H), 2.41 (s, 3H)
LCMS purity: 99.33%, m/z=344.9 (M+1)
HPLC: 97.28%
Example 152
Preparation of
1-(4-Amino-pyridin-3-yl)-3-benzothiazol-6-yl-imidazolidin-2-one
Hydrochloride Salt (152A)
##STR00172##
6N HCl (3 mL) was added to a solution of
N-[3-(3-benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-pyridin-4-yl]-acetamid-
e (150A: 70 mg, 0.198 mmol) in ethanol (3 mL) and the resulting
mixture was refluxed at 65.degree. C. overnight. The reaction was
monitored by TLC (10% MeOH in CHCl.sub.3). The reaction mixture was
concentrated and the concentrate was washed with diethyl ether and
dried to afford 20 mg of the product (29.02% yield).
.sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 9.6 (s, 1H), 8.6-8.3 (m,
2H), 8.1 (s, 3H), 7.1-6.9 (m, 1H), 4.4-4.2 (m, 2H), 4.05-3.85 (m,
2H)
LCMS purity: 98.71%, m/z=312.1 (M+1)
HPLC: 95.01%
Example 153
Preparation of
1-(benzo[d]thiazol-6-yl)-3-(4-methyl-5-(trifluoromethyl)pyridin-3-yl)imid-
azolidin-2-one, Trifluoroacetic Acid Salt (153A)
##STR00173##
Preparation of Starting Material
3-Bromo-4-methyl-5-trifluoromethyl-pyridine (SM-153a)
Butyl Lithium (1.9 mL, 3.044 mmol) was added to a solution of DIPA
(335.7 mg, 3.318 mmol) in THF (6 mL) at -78.degree. C. The reaction
mixture was stirred at -10.degree. C. for 10 minutes. This was
followed by the addition of 3-bromo-5-trifluoromethyl-pyridine (500
mg, 2.212 mmol) in THF (3 mL) at -100.degree. C. The reaction
mixture was stirred for a further 15 minutes at -90.degree. C. and
was followed by the addition of methyl iodide (557.0 mg, 3.924
mmol) in THF (2 mL) at -78.degree. C. with stirring over a period
of 30 minutes. The reaction was monitored by TLC (5% ethylacetate
in hexane). The reaction mixture was quenched with aqueous
NaHCO.sub.3 solution and extracted with ethylacetate (100 mL). The
organic layer was dried over Na.sub.2SO.sub.4 and concentrated.
Purification by column chromatography on silica gel (2%
ethylacetate in hexane) afforded 95 mg of the product (17.92%
yield).
LCMS: m/z=239.8 (M+1)
Final Step: Preparation of
14-benzo[d]thiazol-6-yl)-3-(4-methyl-5-(trifluoromethyl)pyridin-3-yl)imid-
azolidin-2-one, Trifluoroacetic Acid Salt (153A)
Using the same reaction conditions as described in example 14,
1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 80 mg, 0.365 mmol)
was reacted with 3-bromo-4-methyl-5-trifluoromethyl-pyridine
(SM-153a: 90 mg, 0.365 mmol), 1,4-dioxane (5 mL), copper iodide
(6.95 mg, 0.0365 mmol), trans-1,2-diamino cyclohexane (12.5 mg,
0.1095 mmol) and potassium phosphate (232.4 mg, 1.095 mmol) to
afford the crude product. Purification by preparative HPLC afforded
5 mg of the product (3.6% yield).
.sup.1HNMR (CDCl.sub.3, 300 MHz): .delta. 9.05-8.65 (m, 3H), 8.35
(s, 1H), 8.25-8.05 (m, 1H), 7.78-7.58 (m, 1H), 4.32-4.12 (m, 2H),
4.12-3.91 (m, 2H), 2.49 (s, 3H)
LCMS purity: 100%, m/z=378.9 (M+1)
HPLC: 93.5%
Example 154
Preparation of 1-(isothiazol-4-yl)-3-(4
ethylpyridin-3-yl)imidazolidin-2-one (154A)
##STR00174##
Using the same reaction conditions as described in example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847
mmol) was reacted with 4-bromo-isothiazole (166 mg, 1.016 mmol),
1,4-dioxane (15 mL), copper iodide (16.09 mg, 0.0847 mmol),
trans-1,2-diamino cyclohexane (29 mg, 0.254 mmol) and potassium
phosphate (540 mg, 2.541 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
CHCl.sub.3) afforded 120 mg of the product (54.54% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.82 (s, 1H), 8.65-8.25
(m, 3H), 7.4-7.1 (m, 1H), 4.20-3.95 (m, 4H), 2.19 (s, 3H)
LCMS purity: 97.95%, m/z=261.0 (M+1)
HPLC: 96.08%
Example 155
Preparation of
1-(4-Methylpyridin-3-yl)-3-(5-(trifluoromethyl)thiophen-2-yl)-imidazolidi-
n-2-one (155A)
##STR00175##
Using the same reaction conditions as described in example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 100 mg, 0.5643
mmol) was reacted with 2-bromo-5-trifluoromethyl-thiophene (136.9
mg, 0.5925 mmol), 1,4-dioxane (10 mL), copper iodide (10.75 mg,
0.0564 mmol), trans-1,2-diamino cyclohexane (20.4 mL, 0.1693 mmol)
and potassium phosphate (360 mg, 1.693 mmol) to afford the crude
product. Purification by column chromatography on silica gel (2%
MeOH in CHCl.sub.3) afforded 120 mg of the product (65% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.66-8.3 (m, 2H),
7.65-7.23 (m, 2H), 6.55 (d, 1H), 4.24-3.90 (m, 4H), 2.26 (s,
3H)
LCMS purity: 96.35%, m/z=327.9 (M+1)
HPLC: 95.04%
Example 156
Preparation of
1-(benzo[d]thiazol-6-yl)-3-(4-(2-hydroxypropan-2-yl)pyridin-3-yl)imidazol-
idin-2-one (156A)
##STR00176##
Preparation of Starting Material 2-(3-Bromo-pyridin-4-O-propan-2-ol
(SM-156a)
Butyl Lithium (10.28 mL, 16.455 mmol) was added to a solution of
DIPA (2.66 mL, 18.98 mmol) in THF (25 mL) at -78.degree. C. The
reaction mixture was stirred at -10.degree. C. for 10 minutes,
followed by the addition of 3-bromo-pyridine (500 mg, 2.212 mmol)
in THF (10 mL) at -100.degree. C. The reaction mixture was stirred
for a further 15 minutes at -90.degree. C. and was followed by the
addition of acetone (1.675 mL, 22.78 mmol) in THF (10 mL) at
-78.degree. C. with stirring over a period of 1 hour. The reaction
was monitored by TLC (5% ethylacetate in hexane). The reaction
mixture was quenched with aqueous NaHCO.sub.3 solution and
extracted with ethylacetate. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated. Purification by column
chromatography on silica gel (15% ethylacetate in hexane) afforded
200 mg of 2-(3-bromo-pyridin-4-yl)-propan-2-ol (11% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.7 (s, 1H), 8.5 (d,
1H), 7.65 (d, 1H), 1.7 (s, 6H)
LCMS purity: 89.57%, m/z=215.9 (M+1)
Final Step: Preparation of
1-(benzo[d]thiazol-6-yl)-3-(4-(2-hydroxypropan-2-yl)pyridin-3-yl)imidazol-
idin-2-one (156A)
Using the same reaction conditions as described in example 14,
1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 125 mg, 0.57 mmol)
was reacted with 2-(3-bromo-pyridin-4-yl)-propan-2-ol (SM-156a:
122.7 mg, 0.57 mmol), 1,4-dioxane (5 mL), copper iodide (10.85 mg,
0.057 mmol), trans-1,2-diamino cyclohexane (19.57 mg, 0.171 mmol)
and potassium phosphate (362.9 mg, 1.71 mmol) to afford the crude
product. Purification by preparative HPLC afforded 38 mg of the
product (19% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.68 (s, 1H), 8.50-8.32
(m, 2H), 7.86 (d, 1H), 7.18-7.02 (m, 2H), 6.82 (dd, 1H), 4.55-4.42
(m, 1H), 4.32 (t, 2H), 3.7-3.6 (m, 2H), 1.74-1.58 (m, 6H)
LCMS purity: 97.84%, m/z=354.9 (M+1)
HPLC: 95.61%
Example 157
Preparation of
1-(4-Methylpyridin-3-yl)-3-(4-methylthieno[3,2-e]pyridin-2-yl)imidazolidi-
n-2-one (157A)
##STR00177##
Tetrakis (triphenylphosphine) palladium (33 mg, 0.0288 mmol) was
added to potassium carbonate (120 mg, 0.8649 mmol) previously
purged with argon (30 minutes). The reaction mixture was purged
with argon for 15 minutes, followed by the addition of
1-(4-chloro-thieno[3,2-c]pyridin-2-yl)-3-(4-methyl-pyridin-3-yl)-imidazol-
idin-2-one (98A: 100 mg, 0.2883 mmol) and methyl boronic acid (21
mg, 0.3459 mmol). The reaction mixture was heated to reflux for 6
hours. The reaction was monitored by TLC (10% MeOH in CHCl.sub.3).
The reaction mixture was concentrated to afford the crude product.
Purification by column chromatography on silica gel (3-4% MeOH in
CHCl.sub.3), followed by preparative HPLC afforded 10 mg of the
product (16.39% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.7-8.35 (m, 2H),
8.35-8.2 (d, 1H), 7.5 (d, 1H), 6.58 (s, 1H), 4.4-3.9 (m, 4H), 2.79
(s, 3H), 2.36 (s, 3H)
LCMS purity: 96.01%, m/z=324.9 (M+1)
HPLC: 96.32%
Example 158
Preparation of
1-(benzo[d]thiazol-6-yl)-3-(4-(1-hydroxyethyl)pyridin-3-yl)imidazolidin-2-
-one (158A)
##STR00178##
Using the same reaction conditions as described in example 14,
1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 150 mg, 0.6849 mmol)
was reacted with 1-(3-bromo-pyridin-4-yl)-ethanol (137.6 mg, 0.6849
mmol), 1,4-dioxane (5 mL), copper iodide (13.04 mg, 0.06849 mmol),
trans-1,2-diamino cyclohexane (23.52 mg, 0.205 mmol) and potassium
phosphate (435.1 mg, 2.05 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
CHCl.sub.3), followed by preparative HPLC afforded 9 mg of the
product (3.9% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.92 (s, 1H), 8.65-8.54
(m, 2H), 8.32 (d, 1H), 8.15 (d, 1H), 7.70-7.62 (dd, 1H), 7.6 (d,
1H), 5.10-4.96 (m, 1H), 4.30-4.12 (m, 3H), 4.02-3.85 (m, 1H),
3.75-3.66 (br s, 1H), 1.60-1.45 (d, 3H)
LCMS purity: 98.20%, m/z=340.9 (M+1)
HPLC: 91.15%
Example 159
Preparation of
1-(benzo[d]thiazol-6-yl)-3-(4-ethylpyridin-3-yl)imidazolidin-2-one
(159A)
##STR00179##
Using the same reaction conditions as described in example 14,
1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 600 mg, 2.739 mmol)
was reacted with 3-bromo-4-ethyl-pyridine (512 mg, 2.739 mmol),
1,4-dioxane (10 mL), copper iodide (52 mg, 0.2739 mmol),
trans-1,2-diamino cyclohexane (94.08 mg, 0.82 mmol) and potassium
phosphate (1.74 mg, 8.2 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
CHCl.sub.3), followed by preparative HPLC afforded 30 mg of the
product (3.75% yield).
.sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 9.15 (s, 1H), 8.60-8.35
(m, 3H), 8.15-7.95 (m, 1H), 7.95-7.70 (m, 1H), 7.5 (d, 1H), 4.3-3.9
(m, 4H), 2.85-2.65 (q, 2H), 1.4-1.2 (t, 3H)
LCMS purity: 99.77%, m/z=325.1 (M+1)
HPLC: 95.03%
Example 160
Preparation of
1-(4-methylpyridin-3-yl)-3-(3-(trifluoromethyl)-1H-indazol-6-yl)imidazoli-
din-2-one (160A)
##STR00180##
Step 1: Preparation of Intermediate
1-[3-Fluoro-4-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-3-(4-methyl-pyrid-
in-3-yl)-imidazolidin-2-one (I-160a)
##STR00181##
A 0.5M solution of trimethyl-trifluoromethyl-silane in THF (6.68
mL, 3.344 mmol) and K.sub.2CO.sub.3 (250 mg, 10.82 mmol) was added
to
2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehy-
de (I-121a: 400 mg, 1.337 mmol) in dry DMF (5 mL) under nitrogen
atmosphere. The resulting mixture was stirred at room temperature
overnight. The reaction was monitored by thin layer chromatography
(5% MeOH in CHCl.sub.3). The reaction mixture was quenched with
brine solution and the THF layer was concentrated. The aqueous
layer was extracted with chloroform. The organic layer was dried
over Na.sub.2SO.sub.4 and concentrated to get the crude product.
Purification by column chromatography on silica gel (2.5% MeOH in
CHCl.sub.3), followed by hexane wash, afforded 325 mg of the
product (65.92% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.56-8.00 (m, 2H),
7.75-7.45 (m, 2H), 7.36-7.08 (m, 2H), 5.38 (q, 1H), 4.55-4.24 (br
s, 1H), 4.20-3.76 (m, 4H), 2.32 (s, 3H)
Step 2: Preparation of Intermediate
1-[3-Fluoro-4-(2,2,2-trifluoro-acetyl)-phenyl
methyl-pyridin-3-yl]-imidazolidin-2-one (I-160b)
##STR00182##
MnO.sub.2 (536 mg, 6.165 mmol) was added to
1-[3-fluoro-4-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-3-(4-methyl-pyrid-
in-3-yl)-imidazolidin-2-one (I-160a: 325 mg, 0.880 mmol) in DCM (20
mL) under nitrogen atmosphere. The resulting suspension was stirred
at 50.degree. C. overnight. The reaction was monitored by TLC (5%
MeOH in DCM). The reaction mixture was cooled to room temperature
and filtered through celite pad. The filtrate was washed with
CHCl.sub.3, dried over Na.sub.2SO.sub.4 and concentrated. The
concentrate was washed with hexane and dried to afford 240 mg of
the product (74.53% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.8-8.2 (m, 2H), 7.98
(t, 1H), 7.86-7.50 (m, 2H), 7.46-7.25 (m, 1H), 4.40-3.75 (m, 4H),
2.28 (s, 3H).
Final Step: Preparation of
1-(4-methylpyridin-3-yl)-3-(3-(trifluoromethyl)-1H-indazol-6-yl)imidazoli-
din-2-one (160A)
Acetic acid (0.1 mL, 1.36 mmol) and 1M hydrazine in THF (4 mL, 2.72
mmol) were added to
1-[3-fluoro-4-(2,2,2-trifluoro-acetyl)-phenyl]-3-(4-methyl-pyridin-3-yl)--
imidazolidin-2-one (I-160b: 100 mg, 0.272 mmol) in dry THF (2 mL).
The resulting mixture was stirred at 150.degree. C. overnight. The
reaction was monitored by TLC (5% MeOH in CHCl.sub.3). The reaction
mixture was partitioned between water and chloroform. The organic
layer was dried over Na.sub.2SO.sub.4 and concentrated.
Purification by column chromatography on silica gel (4% MeOH in
CHCl.sub.3), followed by preparative HPLC afforded 23 mg of the
product (23.46% yield).
.sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 8.57-8.48 (br s, 1H),
8.37 (d, 1H), 7.86-7.70 (m, 2H), 7.70-7.60 (m, 1H), 7.42 (d, 1H),
4.34-4.12 (m, 2H), 4.12-3.90 (m, 2H), 2.41 (s, 3H).
LCMS purity: 96.14%, m/z=362.0 (M+1)
HPLC: 94.33%
Example 161
Preparation of
1-(3-cyclopropyl-1-1H-indazol-6-yl)-3-(4-methylpyridin-3-yl)imidazolidin--
2-one (161A)
##STR00183##
Step 1: Preparation of Intermediate
1-[4-(Cyclopropyl-hydroxy-methyl)-3-fluoro-phenyl]-3-(4-methyl-pyridin-3--
yl)-imidazolidin-2-one (I-161a)
##STR00184##
A 0.5M solution of cyclopropyl magnesium bromide in THF (2.4 mL,
1.170 mmol) was added dropwise to
2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehy-
de (I-121a: 175 mg, 0.585 mmol) in dry THF (10 mL) at 0.degree. C.
under nitrogen atmosphere. The resulting mixture was stirred at
room temperature for 3 hours. The reaction was monitored by TLC (5%
MeOH in CHCl.sub.3). The reaction mixture was quenched with aqueous
NH.sub.4Cl solution and the THF layer was concentrated. The aqueous
layer was extracted with ethylacetate. The organic layer was dried
over Na.sub.2SO.sub.4 and concentrated to afford the crude product.
Purification by column chromatography on silica gel (3% MeOH in
CHCl.sub.3), followed by hexane wash, afforded 200 mg of the
product (99.41% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.72-8.28 (m, 2H),
7.70-7.48 (m, 2H), 7.42-7.25 (m, 2H), 5.30 (d, 1H), 4.48-4.20 (m,
1H), 4.18-3.82 (m, 4H), 2.32 (s, 3H), 1.2-1.0 (m, 1H), 0.7-0.1 (m,
4H)
LCMS purity: 97.58%, m/z=342.3 (M+1)
Step 2: Preparation of Intermediate
1-(4-Cyclopropanecarbonyl-3-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imid-
azolidin-2-one (I-161b)
##STR00185##
MnO.sub.2 (357 mg, 41.055 mmol) was added to
1-[4-(cyclopropyl-hydroxy-methyl)-3-fluoro-phenyl]-3-(4-methyl-pyridin-3--
yl)-imidazolidin-2-one (I-161a: 200 mg, 8.586 mmol) in DCM (20 mL)
under nitrogen atmosphere and worked up in a manner similar to what
has been described previously for example 160 (Step 2) to afford
175 mg of the product (60.13% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.56 (s, 1H), 8.41 (d,
1H), 7.82 (t, 1H), 7.76-7.65 (m, 1H), 7.60-7.47 (m, 1H), 7.37 (d,
1H), 4.22-3.82 (m, 4H), 2.80-2.60 (m, 1H), 2.29 (s, 3H), 1.18-0.93
(m, 4H)
LCMS purity: 98.34%, m/z=339.7 (M+1)
Final Step: Preparation of
1-(3-Cyclopropyl-1H-indazol-6-yl)-3-(4-methylpyridin-3-yl)imidazolidin-2--
one (161A)
1-(4-Cyclopropanecarbonyl-3-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imid-
azolidin-2-one (I-161b: 175 mg, 0.516 mmol) in hydrazine hydrate
solution (10 mL) was taken in a reaction flask. The flask was
refluxed at 120.degree. C. overnight. The reaction was monitored by
TLC (5% MeOH in CHCl.sub.3). The reaction mixture was cooled to
room temperature and partitioned between ice water and chloroform.
The organic layer was dried over Na.sub.2SO.sub.4 and concentrated.
Purification by column chromatography on silica gel (4% MeOH in
CHCl.sub.3), followed by hexane and ether wash, afforded 55 mg of
the product (31.97% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 12.42 (s, 1H), 8.55
(s, 1H), 8.39 (d, 1H), 7.85-7.28 (m, 4H), 4.28-3.80 (m, 4H),
2.6-2.1 (m, 4H), 1.04-0.80 (m, 4H)
LCMS purity: 100.00%, m/z=333.8 (M+1)
HPLC: 94.27%
Example 162
Preparation of
1-(4-methylpyridin-3-yl)-3-(quinolin-7-yl)imidazolidin-2-one
(162A)
##STR00186##
Using the same reaction conditions as described in example 14,
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 116 mg, 0.6554
mmol) was reacted with 7-bromo-quinoline (150 mg, 0.72098 mmol),
1,4-dioxane (50 mL), copper iodide (12.4 mg, 0.06554 mmol),
trans-1,2-diamino cyclohexane (22.5 mg, 0.19638 mmol) and potassium
phosphate (347.3 g, 1.6365 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
CHCl.sub.3) afforded 130 mg of the product (65.3% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.95-8.76 (m, 1H), 8.6
(s, 1H), 8.48-8.22 (m, 3H), 8.06-7.82 (m, 2H), 7.50-7.32 (m, 2H),
4.32-4.12 (m, 2H), 4.10-3.90 (m, 2H), 2.31 (s, 3H)
LCMS purity: 99.57%, m/z=305.0 (M+1)
HPLC: 93.16%
Example 163
Preparation of
3-Benzothiazol-6-yl-4,4-dimethyl-1-(4-methyl-pyridin-3-yl)-imidazolidin-2-
-one (163A)
##STR00187##
Preparation of Starting Material
1-Chloro-2-isocyanato-2-methyl-propane
SOCl.sub.2 (5.22 g, 44.23 mmol) was added dropwise to a stirred
solution of 3-chloro-2,2-dimethyl-propionic acid (5 g, 36.76 mmol)
in DCM (50 mL) at 0.degree. C. over a period of 5 mins. This was
followed by the addition of DMF (0.1 mL) and the resulting mixture
was heated to 60.degree. C. for 3 hours. The reaction was monitored
by TLC (5% MeOH in CHCl.sub.3). The reaction mixture was
concentrated and the crude product (6 g) was used in the next step
without further purification.
Sodium azide (4.64 g, 71.38 mmol) was added to a solution of
3-chloro-2,2-dimethyl-propionyl chloride (6 g, 35.71 mmol) in
1,4-dioxane (15 mL) and water (15 mL). The resulting mixture was
stirred at room temperature for 2 hours. The reaction was monitored
by TLC (5% ethylacetate in hexane). The reaction mixture was
extracted with diethyl ether and the organic layer was dried over
Na.sub.2SO.sub.4 to afford 3.5 g of the product (61.40% yield).
1-Chloro-2-isocyanato-2-methyl-propane (3.5 g, 20 mmol) in toluene
(35 mL) was taken a reaction flask and flask was heated to
85.degree. C. for 1.30 hour. The reaction was monitored by TLC (5%
ethylacetate in hexane). The crude product (3 g) was used in the
next step without further purification.
Preparation of Intermediate
1-(2-Chloro-1,1-dimethyl-ethyl)-3-(4-methyl-pyridin-3-yl)-urea
(I-163a)
##STR00188##
4-Methyl-pyridin-3-ylamine (1.98 g, 18.33 mmol) was added to
solution of 1-chloro-2-isocyanato-2-methyl-propane (3 g, 20.40
mmol) in toluene (30 mL). The resulting mixture was stirred at room
temperature for 3 days. The reaction was monitored by TLC (5% MeOH
in CHCl.sub.3). The reaction mixture was filtered and the residue
was dried to afford 4.3 g of the product (87.75% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.70 (s, 1H), 8.3 (s,
1H), 7.12 (s, 1H), 6.39 (s, 1H), 4.9 (s, 1H), 3.87 (s, 2H), 2.30
(s, 3H), 1.4 (s, 6H)
LCMS purity: 76.36%, m/z=242.0 (M+1)
Preparation of Intermediate
4,4-Dimethyl-1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(I-163b)
##STR00189##
1-(2-Chloro-1,1-dimethyl-ethyl)-3-(4-methyl-pyridin-3-yl)-urea
(I-163a: 1 g, 4.149 mmol) in dry THF (5 mL) was added dropwise to a
stirred mixture of NaH (298 mg, 6.208 mmol) in dry THF (10 mL)
under argon atmosphere over a period of 10 minutes at 0.degree. C.
The resulting reaction mixture was stirred for 2 hours. The
reaction was monitored by TLC (5% MeOH in CHCl.sub.3). The reaction
mixture was partitioned between water and ethylacetate. The organic
layer was dried over Na.sub.2SO.sub.4 and concentrated to afford
800 mg of the product (94.33% yield).
.sup.1H NMR (DMSO, 300 MHz): .delta. 8.4 (s, 1H), 8.3 (d, 1H), 7.30
(d, 1H), 7.0 (s, 1H), 3.53 (s, 2H), 2.22 (s, 3H), 1.3 (s, 6H) LCMS
purity: 100%, m/z=205.7 (M+1)
Final Step: Preparation of
3-Benzothiazol-6-yl-4,4-dimethyl-1-(4-methyl-pyridin-3-yl)-imidazolidin-2-
-one (163A)
Using the same reaction conditions as described in example 14,
4,4-dimethyl-1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-163b:
150 mg, 0.731 mmol) was reacted with 6-iodo-benzothiazole (248 mg,
0.950 mmol), 1,4-dioxane (10 mL), copper iodide (13 mg, 0.0682
mmol), trans-1,2-diamino cyclohexane (31 mg, 0.218 mmol) and
potassium phosphate (387 mg, 1.825 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1%
MeOH in CHCl.sub.3) afforded 30 mg of the product (12.14%
yield).
.sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 9.32 (s, 1H), 8.51 (s,
1H), 8.35 (d, 1H), 8.0-8.2 (m, 2H), 7.60 (d, 1H), 7.40 (d, 1H),
3.90 (s, 2H), 2.45 (s, 3H), 1.5 (s, 6H)
LCMS purity: 94.09%, m/z=339.1 (M+1)
HPLC: 89.11%
Example 164
Preparation of
1-Benzothiazol-6-yl-4,4-dimethyl-3-pyridin-3-yl-imidazolidin-2-one
(164A)
##STR00190##
Preparation of Intermediate
1-Benzothiazol-6-yl-3-(2-chloro-1,1-dimethyl-ethyl)-urea
(I-164a)
##STR00191##
Benzothiazol-6-ylamine (1.8 g, 12.00 mmol) was added portion wise
to solution of 1-chloro-2-isocyanato-2-methyl-propane (2 g, 13.60
mmol) in toluene (20 mL) over a period of 5 minutes. The resulting
mixture was stirred at room temperature for 21/2 days. The reaction
was monitored by TLC (5% MeOH in CHCl.sub.3). The reaction mixture
was concentrated and extracted with ethylacetate. The organic layer
was dried over Na.sub.2SO.sub.4 and concentrated. Purification by
column chromatography on silica gel (1% MeOH in CHCl.sub.3)
afforded 630 mg of the product (16.57% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.85 (s, 1H), 8.23 (d,
1H), 8.0 (d, 1H), 7.20-7.15 (dd, 1H), 7.03 (s, 1H), 5.10 (s, 1H),
3.89 (s, 2H), 1.49 (s, 6H)
LCMS purity: 98.84%, m/z=283.9 (M+1)
Preparation of Intermediate
1-Benzothiazol-6-yl-4,4-dimethyl-imidazolidin-2-one (I-64b)
##STR00192##
1-Benzothiazol-6-yl-3-(2-chloro-1,1-dimethyl-ethyl)-urea (I-164a:
620 mg, 2.18 mmol) in dry THF (5 mL) was added dropwise to a
stirred mixture of NaH (78 mg, 3.25 mmol) in dry THF (5 mL) under
argon atmosphere over a period of 10 mins at 0.degree. C. The
resulting reaction mixture was stirred at room temperature for 45
minutes. The reaction was monitored by TLC (5% MeOH in CHCl.sub.3).
The reaction mixture was partitioned between chilled water and
ethylacetate. The organic layer was dried over Na.sub.2SO.sub.4 and
concentrated to afford 410 mg of the product (77.35% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.90 (s, 1H), 8.31 (d,
1H), 8.09 (d, 1H), 7.69-7.58 (dd, 1H), 5.0 (br s, 1H), 3.73 (s,
2H), 1.49 (s, 6H)
LCMS purity: 99.16%, m/z=247.8 (M+1)
Final Step: Preparation of
1-Benzothiazol-6-yl-4,4-dimethyl-3-pyridin-3-yl-imidazolidin-2-one
(164A)
Using the same reaction conditions as described in example 14,
1-benzothiazol-6-yl-4,4-dimethyl-imidazolidin-2-one (I-164b: 100
mg, 0.4048 mmol) was reacted with 3-bromo-pyridine (83 mg, 0.525
mmol), 1,4-dioxane (10 mL), copper iodide (7 mg, 0.036 mmol),
trans-1,2-diamino cyclohexane (17 mg, 0.119 mmol) and potassium
phosphate (214 mg, 1.009 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1% MeOH in
CHCl.sub.3) afforded 15 mg of the product (11.45% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.90 (s, 1H), 8.7-8.5
(br s, 2H), 8.35 (d, 1H), 8.12 (d, 1H), 7.77-7.60 (m, 2H), 7.5-7.4
(m, 1H), 3.9 (s, 2H), 1.49 (s, 6H)
LCMS purity: 100%, m/z=325.1 (M+1)
HPLC: 95.40%
Example 165
Preparation of
1-Benzothiazol-6-yl-4,4-dimethyl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-
-one (165A)
##STR00193##
Using the same reaction conditions as described in example 14,
1-benzothiazol-6-yl-4,4-dimethyl-imidazolidin-2-one (I-164b: 100
mg, 0.4048 mmol) was reacted with 3-iodo-4-methyl-pyridine (115 mg,
0.525 mmol), 1,4-dioxane (10 mL), copper iodide (7 mg, 0.0368
mmol), trans-1,2-diamino cyclohexane (18 mg, 0.1197 mmol) and
potassium phosphate (214 mg, 1.0094 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1%
MeOH in CHCl.sub.3) afforded 6 mg of the product (4.8% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.30 (d, 1H), 8.15 (d,
1H), 7.7-7.6 (dd, 1H), 3.8 (s, 2H), 2.72 (s, 3H), 1.49 (s, 6H)
LCMS purity: 94.22%, m/z=339.1 (M+1)
HPLC: 86.98%
Example 166
Preparation of
3-Benzothiazol-6-yl-4-methyl-1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(166A)
##STR00194##
Preparation of Intermediate 3-(Benzothiazol-6-ylamino)-butyric acid
(I-166a)
##STR00195##
3-Amino-butyric acid ethyl ester (2 g, 15.27 mmol),
6-iodo-benzothiazole (3.98 g. 15.27 mmol) and potassium carbonate
(5.27 g, 38.18 mmol) were dissolved in DMF (50 mL) and the reaction
mixture was purged with argon for 10 minutes. This was followed by
the addition of copper iodide (290 mg, 1.527 mmol) and the
resulting mixture was heated to 110.degree. C. overnight. The
reaction was monitored by TLC (10% MeOH in CHCl.sub.3) which showed
the presence of starting material. The reaction mixture was heated
to 120.degree. C. for a further 24 hours. The reaction mixture was
concentrated and adjusted the pH to 5 using acetic acid. The
reaction mixture was partitioned between water and ethylacetate.
The organic layer was dried over Na.sub.2SO.sub.4 and concentrated.
Purification by column chromatography on silica gel (1% MeOH in
CHCl.sub.3) afforded 800 mg of the product (22.22% yield).
.sup.1H NMR (DMSO, 300 MHz): .delta. 12.2 (s, 1H), 8.9 (s, 1H),
7.75 (d, 1H), 7.15 (d, 1H), 6.85 (dd, 1H), 5.90-5.80 (m, 1H),
3.90-3.80 (m, 1H), 2.60-2.50 (m, 1H), 2.25-2.35 (m, 1H), 1.20 (d,
3H)
LCMS purity: 61.65%, m/z=237.0 (M+1)
Preparation of Intermediate
1-Benzothiazol-6-yl-5-methyl-imidazolidin-2-one (I-166b)
##STR00196##
Triethylamine (1.129 g, 11.18 mmol) was added to a mixture of
3-(benzothiazol-6-ylamino)-butyric acid (I-166a: 800 mg, 3.39 mmol)
in toluene (30 mL) and the reaction mixture was purged with argon
for 10 minutes. This was followed by the addition of DPPA (2.796 g,
10.17 mmol) and the resulting mixture was heated to 100.degree. C.
overnight. The reaction was monitored by TLC (10% MeOH in
CHCl.sub.3) which showed the presence of starting material. The
reaction mixture was heated to 120.degree. C. for the next 24
hours. The reaction mixture was partitioned between water and
ethylacetate. The organic layer was dried over Na.sub.2SO.sub.4 and
concentrated. Purification by column chromatography on silica gel
(2% MeOH in CHCl.sub.3) afforded 600 mg of the product (75.95%
yield).
.sup.1H NMR (DMSO, 300 MHz): .delta. 9.25 (s, 1H), 8.22 (d, 1H),
8.0 (d, 1H), 7.7 (dd, 1H), 7.0 (s, 1H), 4.6-4.5 (m, 1H), 3.6 (t,
1H), 3.0 (m, 1H), 1.2 (d, 3H)
LCMS purity: 81.90%, m/z=234.0 (M+1)
Final Step: Preparation of
3-Benzothiazol-6-yl-4-methyl-1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(166A)
Using the same reaction conditions as described in example 14,
1-benzothiazol-6-yl-5-methyl-imidazolidin-2-one (I-166b: 150 mg,
0.644 mmol) was reacted with 3-iodo-4-methyl-pyridine (140.99 mg,
0.644 mmol), 1,4-dioxane (10 mL), copper iodide (12.27 mg, 0.0644
mmol), trans-1,2-diamino cyclohexane (27.43 mg, 0.193 mmol) and
potassium phosphate (341 mg, 1.61 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1.5%
MeOH in DCM) afforded 50 mg of the product (24.15% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.95 (s, 1H), 8.55 (s,
1H), 8.43 (d, 1H), 8.26 (d, 1H), 8.15 (d, 1H), 7.55 (dd, 1H), 7.25
(d, 1H), 4.7-4.6 (m, 1H), 4.2-4.1 (m, 1H), 3.6-3.5 (m, 1H), 2.4 (s,
3H), 1.5 (d, 3H)
LCMS purity: 95.66%, m/z=325.0 (M+1)
HPLC: 96.32%
Example 167
Preparation of
1-Benzothiazol-6-yl-4-methyl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(167A)
##STR00197##
Step 1: Synthesis of Intermediate
3-(Benzothiazol-6-ylamino)-2-methyl-propionic Acid (I-167a)
##STR00198##
2-Methyl-acrylic acid (0.63 g, 0.00732 mol) and Benzene-1,4-diol
(0.029 g, 0.000266 mol) were added to a stirred solution of
Benzothiazol-6-ylamine (1 g, 0.00665 mol) in toluene (6 mL) under
nitrogen atmosphere. The resulting reaction mass was heated at
70.degree. C. for 72 hours and further at 100.degree. C. for 48
hours. The reaction was monitored by TLC (5% methanol in
chloroform). The reaction mixture was cooled to room temperature
and partitioned between water and ethyl acetate. The organic layer
was washed with brine solution, dried over Na.sub.2SO.sub.4 and
concentrated to afford the crude product. Purification by column
chromatography on silica gel (0.75% methanol in chloroform)
afforded 0.43 g of the product (26.87% yield).
.sup.1H NMR (300 MHz, DMSO): .delta. 12.25 (s, 1H), 8.9 (s, 1H),
7.75 (d, 1H), 7.15 (s, 1H), 6.85 (d, 1H), 6.20-6.05 (bs, 1H),
3.45-3.3 (m, 1H), 3.15-3.0 (m, 1H), 2.7 (q, 1H), 1.15 (d, 3H)
LCMS: 100%, m/z=237.3 (M+1)
Step 2: Synthesis of Intermediate
1-Benzothiazol-6-yl-4-methyl-imidazolidin-2-one (I-167b)
##STR00199##
3-(Benzothiazol-6-ylamino)-2-methyl-propionic acid (I-167a: 500 mg,
2.118 mmol) was refluxed with triethylamine (1 mL, 6.989 mmol),
DPPA (1.75 g, 6.35 mmol) and toluene (10 mL) at 120.degree. C. in a
sealed tube to afford the crude product. The reaction was monitored
by TLC (5% methanol in chloroform). Purification by column
chromatography on silica gel (2% methanol in chloroform) afforded
350 mg of the product (71.42% yield).
.sup.1H NMR (300 MHz, DMSO): .delta. 9.25(s, 1H), 8.25 (d, 1H), 8.0
(d, 1H), 7.9-7.8 (dd, 1H), 7.28 (s, 1H), 4.05 (t, 1H), 3.9-3.8 (m,
1H), 3.55-3.45 (m, 1H), 1.2 (d, 3H)
LCMS: 100%, m/z=233.8 (M+H)
Final Step: Synthesis of
1-Benzothiazol-6-yl-4-methyl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(167A)
Using the same reaction conditions and work up as described in
Example 1, step-3,1-benzothiazol-6-yl-4-methyl-imidazolidin-2-one
(I-167b: 150 mg, 0.643 mmol) was refluxed with
3-iodo-4-methyl-pyridine (155 mg, 0.708 mmol), copper iodide (12.21
mg, 0.0643 mmol), N,N'-dimethyl-cyclohexane-1,2-diamine (27.39 mg,
0.192 mmol), potassium phosphate (341.5 mg, 1.607 mmol) and
1,4-dioxane (5 mL) at 120.degree. C. for 12 hours to afford the
crude product. The reaction was monitored by TLC (10% MeOH in
chloroform). Purification by column chromatography on silica gel
(3% methanol in chloroform) followed by preparative HPLC afforded
34 mg of the product (16.66% yield).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.9 (s, 1H), 8.5-8.4
(bs, 2H), 8.35 (d, 1H), 8.1 (d, 1H), 7.65 (dd, 1H) 7.26 (s, 1H),
4.45-4.2 (m, 2H), 3.75 (t, 1H), 2.35 (s, 3H), 1.34 (d, 3H).
LCMS: 98.01%, m/z=325 (M+1)
HPLC: 96.28%
Example 168
Preparation of
1-Benzothiazol-6-yl-4-ethyl-3-(4-methyl-pyridin-3-yl)-1,3-dihydro-imidazo-
l-2-one (168A)
##STR00200##
Step 1: Synthesis of Intermediate
1-(Benzothiazol-6-ylamino)-butan-2-one (I-168a)
##STR00201##
Sodium acetate (300 mg, 3.66 mmol) and 1-bromo-butan-2-one (0.373
mL, 3.66 mmol) were added to a stirred solution of
benzothiazol-6-ylamine (500 mg, 3.328 mmol) in methanol (10 mL)
under nitrogen atmosphere. The resulting reaction mass was stirred
at room temperature for 24 hours. The reaction was monitored by TLC
(20% ethyl acetate in hexane). The reaction mixture was filtered
and the solid collected was dried under reduced pressure to afford
250 mg of the product (32% yield).
.sup.1H NMR (DMSO-d.sub.5, 300 MHz) .delta.: 8.9 (s, 1H), 7.8 (d,
1H), 7.1 (d, 1H), 6.9 (m, 1H), 6.3 (t, 1H), 4.1 (d, 2H), 2.5 (q,
2H), 1.0 (t, 3H)
LCMS: 50.40%, m/z=221.0 (M+1).
Step-2: Synthesis of Intermediate
1-Benzothiazol-6-yl-3-(4-methyl-pyridin-3-yl-(2-oxo-butyl)-urea
(I-168b)
##STR00202##
(4-Methyl-pyridin-3-yl)-carbamic acid phenyl ester (165 mg, 0.727
mmol) and 1-(benzothiazol-6-ylamino)-butan-2-one (I-168a: 160 mg,
0.727 mmol) in toluene (10 mL) were refluxed at 120.degree. C.
under nitrogen atmosphere for 48 hours. The reaction was monitored
by TLC (5% MeOH in chloroform). The reaction mixture was
concentrated under reduced pressure and partitioned between water
and chloroform. The organic layer was washed with brine solution,
dried over Na.sub.2SO.sub.4 and concentrated to afford the crude
product. Purification by column chromatography on silica gel (2%
methanol in chloroform) afforded 185 mg of the product (71.98%
yield).
LCMS: 99.81%, m/z=355.2 (M+1)
Final Step: Synthesis of
1-Benzothiazol-6-yl-4-ethyl-3-(4-methyl-pyridin-3-yl)-1,3-dihydro-imidazo-
l-2-one (168A)
1-Benzothiazol-6-yl-3-(4-methyl-pyridin-3-yl)-1-(2-oxo-butyl)-urea
(I-168b: 185 mg, 0.522 mmol) in toluene (15 mL) was refluxed at
120.degree. C. for 20 hours. The reaction was monitored by TLC (5%
MeOH in chloroform). The reaction mixture was concentrated under
reduced pressure and the crude residue was purified by column
chromatography on silica gel (2.5% methanol in chloroform) to
afford 50 mg of the product (28.57% yield).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 9.0 (s, 1H), 8.58-8.45
(m, 3H), 8.2 (d, 1H) 7.75 (dd, 1H), 7.34 (d, 1H), 6.6 (s, 1H),
2.4-2.1 (m, 5H), 1.1 (t, 3H).
LCMS: 100%, m/z=337 (M+1)
HPLC: 98.76%
Example 169
Preparation of
1-Benzothiazol-6-yl-4-ethyl-3-pyridin-3-yl-1,3-dihydro-imidazol-2-one
(169A)
##STR00203##
Triethylamine (0.2 mL, 1.219 mmol) and DPPA (0.3 mL, 1.219 mmol)
were added to a solution of nicotinic acid (150 mg, 1.219 mmol) in
toluene (12 mL) under nitrogen atmosphere and stirred at room
temperature for 1.5 hours. The reaction mixture was allowed to
reflux at 70.degree. C. for 1.5 hours. The reaction was monitored
by TLC (5% MeOH in DCM). This was followed by the addition of
1-(benzothiazol-6-ylamino)-butan-2-one (I-168a: 241 mg, 1.097 mmol)
at room temperature. The resulting reaction mass was heated at
100.degree. C. overnight. The reaction mixture was cooled to room
temperature, concentrated under reduced pressure and the crude
residue was partitioned between water and DCM. The organic layer
was washed with water, brine solution, dried over Na.sub.2S.sub.4
and concentrated to afford the crude product. Purification by
column chromatography on silica gel (1.5% methanol in chloroform)
followed by preparative HPLC afforded 5 mg of the product (1.5%
yield).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 9.0 (s, 1H), 8.7-8.6 (m,
2H), 8.44 (d, 1H), 8.2 (d, 1H), 7.85-7.68 (m, 2H), 7.5-7.44 (m,
1H), 6.55 (s, 1H), 2.46-2.35 (q, 2H), 1.15 (t, 3H).
LCMS: 90.98%, m/z=323.1 (M+1)
HPLC: 94.09%
Example 170
Preparation of
1-benzothiazol-6-yl-3-pyridin-3-yl-4-trifluoromethyl-imidazolidin-2-one
(170A)
##STR00204##
Step-1: Synthesis of Intermediate
2-(Benzothiazol-6-ylaminomethyl)-3,3,3-trifluoro-propionic Acid
##STR00205##
Benzothiazol-6-ylamine (1 g, 6.66 mmol) was reacted with
2-trifluoromethyl-acrylic acid (1.39 g, 9.99 mmol),
benzene-1,4-diol (51.3 mg, 0.46 mmol) and toluene (10 mL) to afford
the crude product. Purification by column chromatography on silica
gel (30% ethyl acetate in hexane) afforded 380 mg of the product
(19.67% yield).
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 13.8-13.0 (bs, 1H),
8.95 (s, 1H), 7.8 (d, 1H), 7.2 (d, 1H), 6.95-6.85 (dd, 1H),
3.75-3.50 (m, 3H)
LCMS: 100%, m/z=291.1 (M+1)
Step-2: Synthesis of Intermediate
1-Benzothiazol-6-yl-4-trifluoromethyl-imidazolidin-2-one
(I-170b)
##STR00206##
2-(Benzothiazol-6-ylaminomethyl)-3,3,3-trifluoro-propionic acid
(I-170a: 380 mg, 1.3 mmol) was refluxed with triethyl amine (433.29
mg, 4.29 mmol), DPPA (1.08 g, 3.9 mmol) and toluene (8 mL) at
110.degree. C. for 72 hours to afford the crude product.
Purification by column chromatography on silica gel (1.5% methanol
in chloroform) afforded 40 mg of the product (10.72% yield).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.93 (s, 1H), 8.3 (d,
1H), 8.1 (d, 1H), 7.61 (dd, 1H), 5.68-5.58 (bs, 1H), 4.42-4.22 (m,
2H), 4.12-4.04 (m, 1H)
Final Step: Synthesis of
1-Benzothiazol-6-yl-3-pyridin-3-yl-4-trifluoromethyl-imidazolidin-2-one
(170A)
Using the same reaction conditions and work up as described in
example 1,
step-3,1-Benzothiazol-6-yl-4-trifluoromethyl-imidazolidin-2-one
(I-170b: 50 mg, 0.174 mmol) was refluxed with 3-Bromo-pyridine (33
mg, 0.209 mmol), copper iodide (3.3 mg, 0.0174 mmol),
Cyclohexane-1,2-diamine (6 mg, 0.0522 mmol), potassium phosphate
(110 mg, 0.522 mmol) and 1,4-Dioxane (2 mL) at 120.degree. C. for
12 hours to afford the crude product. Purification by column
chromatography on silica gel (2% methanol in chloroform) followed
by n-pentane washing afforded 15 mg of the product (23.8%
yield).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.95(s, 1H), 8.92-8.4
(m, 2H), 8.35 (d, 1H), 8.15 (d, 1H), 7.95 (d, 1H), 7.7 (dd, 1H),
7.5-7.35 (bs, 1H), 5.1-4.9 (m, 1H), 4.4 (t, 1H), 4.25 (dd, 1H).
LCMS: 98.0%, m/z=364.7 (M+1)
HPLC: 90.04%
Example 171
Preparation of
1-Benzothiazol-6-yl-3-(4-methyl-pyridin-3-yl)-1,3-dihydro-benzoimidazol-2-
-one (171A)
##STR00207##
Step-1: Synthesis of Intermediate
(4-Methyl-pyridin-3-yl)-(2-nitro-phenyl)-amine (I-171a)
##STR00208##
1M LiHMDS solution (9.25 mL, 9.25 mmol) in THF was added drop wise
to a cooled solution of 4-Methyl-pyridin-3-ylamine (1 g, 9.25 mmol)
in THF (10 mL) at 0.degree. C. under nitrogen atmosphere. The
resulting mixture was added drop wise to a solution of
1-fluoro-2-nitro-benzene (0.98 mL, 9.25 mmol) in THF at 0.degree.
C. The resulting reaction mass was stirred at room temperature
overnight. The reaction was monitored by TLC (50% ethyl acetate in
hexane). The reaction mixture was diluted with ethyl acetate and
concentrated under reduced pressure. The crude residue was purified
by column chromatography on silica gel (50% ethyl acetate in
hexane) to afford 600 mg of the product (28.32% yield).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 9.3 (s, 1H), 8.55 (s,
1H), 8.45 (d, 1H), 8.25 (d, 1H), 7.40-7.25 (m, 2H), 6.85-6.75 (m,
2H), 2.3 (s, 3H)
Step-2: Synthesis of Intermediate
N-(4-Methyl-pyridin-3-yl)-benzene-1,2-diamine (I-171b)
##STR00209##
10% Pd/C (100 mg) was charged portion wise to a solution of
(4-methyl-pyridin-3-yl)-(2-nitro-phenyl)-amine (I-171a: 600 mg,
2.62 mmol) in methanol (15 mL) under nitrogen atmosphere. The
resulting mixture was stirred at room temperature under hydrogen
atmosphere for 2 hours. The reaction was monitored by TLC (80%
ethyl acetate in hexane). The reaction mixture was filtered and the
filtrate was concentrated under reduced pressure to afford 525 mg
of the product (98.91% yield).
.sup.1H NMR (300 MHz, DMSO): .delta. 7.82 (s, 1H), 7.6 (s, 1H),
7.08 (d, 1H), 6.9-6.7 (m, 3H), 6.65-6.50 (m, 2H), 5.0-4.7 (bs, 2H),
2.2 (s, 3H)
Step-3: Synthesis of Intermediate
1-(4-Methyl-pyridin-3-yl)-1,3-dihydro-benzoimidazol-2-one
(1471c)
##STR00210##
Triethylamine (0.76 mL, 5.276 mmol) was added to a solution of
N-(4-Methyl-pyridin-3-yl)-benzene-1,2-diamine (525 mg, 2.638 mmol)
in THF (10 mL) under nitrogen atmosphere. This was followed by the
drop wise addition of triphosgene (313 mg, 1.055 mmol) in THF (10
mL) at 0.degree. C. The resulting suspension was stirred at room
temperature for 1.5 hours. The reaction was monitored by TLC (50%
ethyl acetate in hexane). The reaction mixture was quenched with
ice and partitioned between water and ethyl acetate. The organic
layer was washed with water, brine solution, dried over
Na.sub.2SO.sub.4 and concentrated to afford the crude product.
Purification by column chromatography on silica gel (50% ethyl
acetate in hexane) afforded 270 mg of the product (46.37%
yield).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.9 (s, 1H), 8.15-8.05
(m, 2H), 7.80-7.65 (m, 3H), 6.7 (dd, 1H), 5.8 (dd, 1H), 1.9 (s,
3H)
Final Step: Synthesis of
1-Benzothiazol-6-yl-3-(4-methyl-pyridin-3-yl)-1,3-dihydro-benzoimidazol-2-
-one (171A)
Using the same reaction conditions and work up as described in
Example 1,
step-3,1-(4-methyl-pyridin-3-yl)-1,3-dihydro-benzoimidazol-2-one
(I-171c: 120 mg, 0.53 mmol) was refluxed with 6-Iodo-benzothiazole
(167 mg, 0.639 mmol), copper iodide (10.13 mg, 0.0533 mmol),
N,N'-Dimethyl-cyclohexane-1,2-diamine (22.7 mg, 0.159 mmol),
potassium phosphate (339 mg, 0.015 mmol) and 1,4-Dioxane (5 mL) at
120.degree. C. for 12 hours to afford the crude product.
Purification by column chromatography on silica gel (1% methanol in
chloroform) followed by hexane washing afforded 20 mg of the
product (10.5% yield).
.sup.1H NMR (300 MHz, DMSO): .delta. 9.55(s, 1H), 8.7-8.6 (m, 2H),
8.54 (s, 1H), 8.3 (d, 1H), 7.85 (dd, 1H), 7.6 (d, 1H), 7.3-7.1 (m,
3H), 6.9-6.8 (m, 1H), 2.2 (s, 3H).
LCMS: 97.32%, m/z=359.1(M+1)
HPLC: 95.78%
Example 172
Preparation of
1-Benzothiazol-6-yl-4-methyl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(172A)
##STR00211##
Step-1: Synthesis of Intermediate
3-(Benzothiazol-6-ylamino)-4,4,4-trifluoro-butyric acid
(I-172a)
##STR00212##
Benzothiazol-6-ylamine (1 g, 0.006 mol) was reacted with
4,4,4-trifluoro-but-2-enoic acid (1.39 g, 0.009 mol),
benzene-1,4-diol (0.05 g, 0.00046 mol) and toluene (50 mL) to
afford the crude product. Purification by column chromatography on
silica gel (15% ethyl acetate in hexane) afforded 1.02 g of the
product (53.68% yield).
.sup.1H NMR (300 MHz, DMSO-D.sub.6): .delta. 12.6 (bs, 1H), 9.0 (s,
1H), 7.9 (d, 1H), 7.5 (d, 1H), 7.0 (dd, 1H), 6.6 (d, 1H), 4.8-4.6
(m, 1H), 2.9 (dd, 1H), 2.7-2.55 (m, 1H)
Step-2: Synthesis of Intermediate
1-Benzothiazol-6-yl-5-trifluoromethyl-imidazolidin-2-one
(I-1726)
##STR00213##
3-(Benzothiazol-6-ylamino)-4,4,4-trifluoro-butyric acid (I-172a: 1
g, 0.003 mol) was refluxed with triethyl amine (0.4 g, 0.0041 mol),
DPPA (1.1 g, 0.004 mol) and toluene (510 mL) at 120.degree. C. to
afford the crude product. The reaction was monitored by TLC (80%
ethyl acetate in hexane). Purification by column chromatography on
silica gel (40% ethyl acetate in hexane) afforded 0.62 g of the
product (63.2% yield).
.sup.1H NMR (300 MHz, DMSO-D.sub.6): .delta. 9.4(s, 1H), 8.3 (d,
1H), 8.1 (d, 1H), 7.7 (dd, 1H), 7.5 (s, 1H), 5.65-5.5 (m, 1H), 3.85
(t, 1H), 3.5 (dd, 1H)
LCMS: 100.0%, (m/z)=288.2 (M+1)
Final Step: Synthesis of
1-Benzothiazol-6-yl-4-methyl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(172A)
Using the same reaction conditions and work up as described in
Example 1,
step-3,1-benzothiazol-6-yl-5-trifluoromethyl-imidazolidin-2-one
(I-172b: 0.15 g, 0.0005 mol) was refluxed with
3-Iodo-4-methyl-pyridine (0.168 g, 0.0007 mol), copper iodide (0.01
g, 0.00005 mol), N,N'-Dimethyl-cyclohexane-1,2-diamine (0.01 g,
0.000015 mol), potassium phosphate (0.3 g, 0.001 mol) and
1,4-dioxane (20 mL) at 120.degree. C. for 12 hours to afford the
crude product. The reaction was monitored by TLC (100% ethyl
acetate). Purification by column chromatography on silica gel (2%
methanol in DCM) afforded 75 mg of the product (39.47% yield).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 9.04 (s, 1H), 8.82-8.6
(bs, 1H), 8.5-8.3 (bs, 1H), 8.28-8.12 (m, 3H), 7.52 (dd, 1H),
7.4-7.28 (bs, 1H), 5.05-4.9 (m, 1H), 4.35 (t, 1H), 3.96 (dd, 1H),
2.4 (s, 3H).
LCMS: 98.43%, m/z=378.7 (M+1)
HPLC: 96.49%
Example 173
Preparation of
3-Benzothiazol-6-yl-1-pyridin-3-yl-4-trifluoromethyl-imidazolidin-2-one
(173A)
##STR00214##
Using the same reaction conditions and work up as described in
Example 1,
step-3,1-benzothiazol-6-yl-5-trifluoromethyl-imidazolidin-2-one
(I-172b: 0.1 g, 0.0004 mol) was refluxed with 3-bromo-pyridine
(0.085 g, 0.0005 mol), copper iodide (0.0076 g, 0.00004 mol),
N,N'-dimethyl-cyclohexane-1,2-diamine (0.017 g, 0.00012 mol),
potassium phosphate (0.22 g, 0.0012 mol) and 1,4-dioxane (20 mL) at
120.degree. C. for 12 hours to afford the crude product. The
reaction was monitored by TLC (100% ethyl acetate). Purification by
column chromatography on silica gel (2% methanol in DCM) afforded
54 mg of the product (45.2% yield).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 9.04 (s, 1H), 8.82-8.6
(bs, 1H), 8.5-8.36 (bs, 1H), 8.28-8.12 (m, 3H), 7.52 (dd, 1H),
7.4-7.28 (bs, 1H), 5.05-4.9 (m, 1H), 4.35 (t, 1H), 4.1 (dd,
1H).
LCMS: 99.42%, m/z=364.7 (M+1)
HPLC: 96.05%
Example 174
Preparation of
1-Benzothiazol-6-yl-3-(4-methyl-pyridin-3-yl)-4-trifluoromethyl-imidazoli-
din-2-one (174A)
##STR00215##
1-Benzothiazol-6-yl-4-trifluoromethyl-imidazolidin-2-one (I-170b:
100 mg, 0.348 mmol) was reacted with 3-iodo-4-methyl-pyridine (83.9
mg, 0.383 mmol), Pd.sub.2(dba).sub.3 (15.9 mg, 0.0174 mmol),
Xantphos (30.2 mg, 0.0528 mmol), cesium carbonate (170 mg, 0.152
mmol) and 1,4-dioxane (10 mL) to afford the crude product.
Purification by column chromatography on silica gel (2% methanol in
chloroform) followed by preparative HPLC afforded 10 mg of the
product (7.5% yield).
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 9.2-9.05 (bs, 1H),
8.74-8.58 (bs, 1H), 8.34 (d, 1H), 8.1-8.03 (m, 1H), 7.96-7.7 (m,
2H), 4.65-4.1 (m, 3H), 2.86 (s, 3H).
LCMS: 95.13%, m/z=379 (M+1)
HPLC: 76.33%
Example 175
Preparation of
1-Benzothiazol-6-yl-4,5-dimethyl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-
-one (175A)
##STR00216##
Step-1: Synthesis of Intermediate
3-(Benzothiazol-6-ylamino)-2-methyl-butyric acid (I-175a)
##STR00217##
Benzothiazol-6-ylamine (1 g, 6.667 mmol) was reacted with
2-methyl-but-2-enoic acid (1 g, 9.99 mmol), benzene-1,4-diol (51.38
mg, 0.467 mmol) and toluene (6 mL) to afford the crude product.
Purification by column chromatography on silica gel (50% ethyl
acetate in hexane) afforded 100 mg of the product (6.02%
yield).
LCMS: 59.05%, m/z=251 (M+1)
Step-2: Synthesis of Intermediate
1-Benzothiazol-6-yl-4,5-dimethyl-imidazolidin-2-one (I-175b)
##STR00218##
3-(Benzothiazol-6-ylamino)-2-methyl-butyric acid (I-175a: 100 mg,
0.4 mmol) was refluxed with triethyl amine (0.067 mL, 0.48 mmol),
DPPA (0.107 mLg, 6.35 mmol) and toluene (3 mL) at 120.degree. C. in
a sealed tube to afford the crude product. The reaction was
monitored by TLC (80% ethyl acetate in hexane). Purification by
column chromatography on silica gel (40% ethyl acetate in hexane)
afforded 50 mg of the product (50.6% yield).
LCMS: 79.64%, m/z=248 (M+1)
Final Step: Synthesis of
1-Benzothiazol-6-yl-4,5-dimethyl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-
-one (175A)
Using the same reaction conditions and work up as described in
Example 1,
step-3,1-benzothiazol-6-yl-4,5-dimethyl-imidazolidin-2-one (I-175b:
50 mg, 0.202 mmol) was refluxed with 3-iodo-4-methyl-pyridine
(44.33 mg, 0.202 mmol), copper iodide (3.85 mg, 0.0202 mmol),
N,N-dimethyl-cyclohexane-1,2-diamine (0.0095 mL, 0.061 mmol),
potassium phosphate (107.2 mg, 0.506 mmol) and 1,4-dioxane (5 mL)
at 120.degree. C. for 16 hours to afford the crude product. The
reaction was monitored by TLC (100% ethyl acetate). Purification by
column chromatography on silica gel (60% ethyl acetate in hexane)
followed by preparative HPLC afforded 6 mg of the product (8.76%
yield).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.95 (s, 1H), 8.5-8.4
(m, 2H), 8.16-8.1 (m, 2H), 7.59-7.5 (dd, 1H), 7.25 (s, 1H), 4.2-4.1
(m, 1H), 3.92-3.82 (m, 1H), 2.35 (s, 3H), 1.46 (d, 3H), 1.3 (d,
3H).
LCMS: 100.00%, m/z=339 (M+1)
HPLC: 95.46%
Example 176
Preparation of
1-Benzothiazol-6-yl-3-(4-pyrrolidin-1-ylmethyl-pyridin-3-yl)-imidazolidin-
-2-one (176A)
##STR00219##
Step I. Synthesis of Intermediate
3-Bromo-4-pyrrolidin-1-ylmethyl-pyridine (I-176a)
##STR00220##
Acetic acid (0.1 mL) was added to a stirred solution of
3-bromo-pyridine-4-carbaldehyde (220 mg, 1.18 mmol) and pyrrolidine
(0.11 mL, 1.34 mmol) in DCE (15 mL) under nitrogen atmosphere and
stirred at room temperature for 2 hours. This was followed by
addition of NaBH(OAc).sub.3 (342 mg, 1.612 mmol) at 0.degree. C.
over a period of 10 minutes. The resulting reaction mass was
stirred for 12 hours at room temperature. The reaction was
monitored by TLC (30% ethyl acetate in hexane). The reaction
mixture was washed with NaHCO.sub.3 solution and extracted using
ethyl acetate. The organic layer was dried over Na.sub.2SO.sub.4
and concentrated to afford 275 mg of the product (98.2% yield).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.63 (s, 1H), 8.46 (dd,
1H), 7.49 (d, 1H), 7.27 (d, 1H), 3.72 (s, 2H), 2.6 (m, 4H), 1.84
(m, 4H)
Final Step: Synthesis of
1-Benzothiazol-6-yl-3-(4-pyrrolidin-1-ylmethyl-pyridin-3-yl)-imidazolidin-
-2-one (176A)
Using the same reaction conditions and work up as described in
Example 1, step -3,3-bromo-4-pyrrolidin-1-ylmethyl-pyridine
(I-176a: 290 mg, 1.205 mmol) was refluxed with
1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 220 mg, 1.004 mmol),
copper iodide (19 mg, 0.1004 mmol),
N,N'-Dimethyl-cyclohexane-1,2-diamine (42.7 mg, 0.301 mmol),
potassium phosphate (640 mg, 3.012 mmol) and 1,4-dioxane (15 mL) at
120.degree. C. for 12 hours to afford the crude product. The
reaction was monitored by TLC (5% MeOH in DCM). Purification by
column chromatography on silica gel (5% MeOH in chloroform)
followed by preparative HPLC afforded 72 mg of the product (18.9%
yield).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.9 (s, 1H), 8.6-8.5 (m,
2H), 8.38 (d, 1H), 8.12 (d, 1H), 7.7 (dd, 1H) 7.54 (d, 1H),
4.2-3.95 (m, 4H), 3.7 (s, 2H), 2.5 (bs, 4H), 1.8 (m, 4H).
LCMS: 98.39%, m/z=380.1 (M+1)
HPLC: 99.11%
Example 177
Preparation of
1-benzothiazol-6-yl-3-(4-morpholin-4-ylmethyl-pyridin-3-yl)-imidazolidin--
2-one (177A)
##STR00221##
Step 1: Synthesis of Intermediate
1-Benzothiazol-6-yl-3-(4-dimethoxymethyl-pyridin-3-yl)-imidazolidin-2-one
(I-177a)
##STR00222##
Using the same reaction conditions and work up as described in
Example 1, step-3,1-benzothiazol-6-yl-imidazolidin-2-one (I-84b:
515 mg, 2.35 mmol) was refluxed with
3-bromo-4-dimethoxymethyl-pyridine (600 mg, 2.584 mmol), copper
iodide (44.7 mg, 0.2312 mmol),
N,N'-dimethyl-cyclohexane-1,2-diamine (80.8 mg, 0.7405 mmol),
potassium phosphate (1.4 g, 7.046 mmol) and 1,4-dioxane (20 mL) at
110.degree. C. for 12 hours to afford the crude product. The
reaction was monitored by TLC (10% MeOH in chloroform).
Purification by column chromatography on silica gel (2% methanol in
chloroform) afforded 460 mg of the product (52.9% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.9 (s, 1H), 8.6 (bs,
2H), 8.4 (d, 1H), 8.14-8.1 (d, 1H), 7.7 (dd, 1H), 7.64-7.6 (bs,
1H), 5.7 (s, 1H), 4.2-4.12 (m, 2H), 4.0-3.95 (m, 2H), 3.35 (s,
6H)
Step 2: Synthesis of
3-(3-Benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-pyridine-4-carbaldehyde
(I-177b)
##STR00223##
PTSA (2.2 g, 11.672 mmol) was added to a stirred solution of
1-benzothiazol-6-yl-3-(4-dimethoxymethyl-pyridin-3-yl)-imidazolidin-2-one
(I-177a: 460 mg, 1.2418 mmol) in acetone (20 mL) and water (20 mL).
The resulting reaction mass was stirred for 48 hours at room
temperature. The reaction was monitored by TLC (5% methanol in
chloroform). The reaction mixture was concentrated, the residue was
diluted with ice-water, basified with saturated NaHCO.sub.3
solution and extracted using ethyl acetate. The aqueous layer was
filtered and the solid collected was dried under reduced pressure.
The solid was dissolved in methanol and chloroform, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford
400 mg of the product (99.5% yield).
.sup.1H NMR (300 MHz, DMSO): .delta. 9.9 (s, 1H), 9.3 (s, 1H), 8.9
(s, 1H), 8.62 (d, 1H), 8.3 (d, 1H), 8.1 (d, 1H), 7.9 (dd, 1H), 7.65
(d, 1H), 4.3-4.15 (m, 4H)
Final Step: Synthesis of
1-Benzothiazol-6-yl-3-(4-morpholin-4-ylmethyl-pyridin-3-yl)-imidazolidin--
2-one (177A)
Morpholine (0.032 mL, 0.3699 mmol) was added to a stirred solution
of
3-(3-Benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-pyridine-4-carbaldehyde
(I-177b: 100 mg, 0.3082 mmol) in acetic acid (2 mL) and stirred at
room temperature for 4 hours. This was followed by the addition of
NaBH (OAc).sub.3 (98 mg, 0.4624 mmol). The resulting reaction mass
was stirred at room temperature for 24 hours. The reaction was
monitored by TLC (10% methanol in chloroform). The reaction mixture
was concentrated under reduced pressure, added ice, basified using
saturated NaHCO.sub.3 solution and extracted using ethyl acetate.
The organic layer was washed with water, brine solution, dried over
Na.sub.2SO.sub.4 and concentrated. Purification by column
chromatography on silica gel (2% methanol in chloroform) followed
by preparative HPLC afforded 25 mg of the product (20.6%
yield).
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.9 (s, 1H), 8.58-8.5
(m, 2H), 8.34 (d, 1H), 8.12 (d, 1H) 7.7 (dd, 1H), 7.54 (d, 1H),
4.2-4.14 (m, 2H), 4.04 (m, 2H), 3.7 (t, 4H), 3.6 (s, 2H), 2.44 (t,
4H).
LCMS: 99.10%, m/z=396.1 (M+1)
HPLC: 95.64%
Example 178
Preparation of
1-Benzothiazol-6-yl-3-(4-cyclopropylaminomethyl-pyridin-3-yl)-imidazolidi-
n-2-one (178A)
##STR00224##
3-(3-Benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-pyridine-4-carbaldehyde
(I-177b: 100 mg, 0.3083 mmol) was reacted with NaBH(OAc).sub.3 (98
mg, 0.4624 mmol), Cyclopropylamine (0.032 mL, 0.462 mmol) and
acetic acid (5 mL) at room temperature for 12 hours to afford the
crude product. The reaction was monitored by TLC (5% methanol in
chloroform). Purification by column chromatography on silica gel
(2% methanol in chloroform) followed by preparative HPLC afforded
13 mg of the product (11.6% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.9 (s, 1H), 8.6-8.5 (m,
2H), 8.35 (s, 1H), 8.1 (d, 1H), 7.7 (dd, 1H) 7.5 (d, 1H), 4.2 (m,
2H), 4.05 (m, 2H), 3.9 (s, 2H), 2.25-2.15 (m, 1H), 0.5-0.3 (m,
4H).
LCMS: 98.17%, m/z=366.1 (M+1)
HPLC: 93.36%
Example 179
Preparation of
1-Benzothiazol-6-yl-3-(6-fluoro-4-methyl-pyridin-3-yl)-imidazolidin-2-one
(179A)
##STR00225##
1-Benzothiazol-6-yl-imidazolidin-2-one (I-84b: 150 mg, 0.6849 mmol)
was reacted with 5-bromo-2-fluoro-4-methyl-pyridine (130 mg, 0.6849
mmol), 1,4-dioxane (5 mL), copper iodide (13 mg, 0.06849 mmol),
trans -N,N'-dimethyl-cyclohexane-1,2-diamine (32.3 mL, 0.2054 mmol)
and potassium phosphate (362.9 mg, 1.7122 mmol) to afford the crude
product. Purification by column chromatography on silica gel (60%
ethylacetate in hexane) afforded 65 mg of the product (28.9%
yield).
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.9 (s, 1H), 8.34 (d,
1H), 8.16-8.1 (m, 2H), 7.68 (dd, 1H), 6.9 (d, 1H), 4.16 (m, 2H),
3.95 (m, 2H), 2.4 (s, 3H).
LCMS: 98.93%, m/z=328.9 (M+1)
HPLC: 98.02%
Example 180
Preparation of
1-Benzothiazol-6-yl-3-[4-(2-morpholin-4-O-ethoxy)-pyridin-3-yl]imidazolid-
in-2-one (180A)
##STR00226##
Step 1: Preparation of Intermediate
1-Benzothiazol-6-yl-3-(4-chloro-pyridin-3-yl)-imidazolidin-2-one
(I-180a)
##STR00227##
Using the same reaction conditions and work up as described in
Example 1, step-3,1-benzothiazol-6-yl-imidazolidin-2-one (I-84b:
800 mg, 3.653 mmol) was refluxed with 3-bromo-4-chloro-pyridine
(879 mg, 4.566 mmol), copper iodide (70 mg, 0.365 mmol),
cyclohexane-1,2-diamine (125 mg, 1.0958 mmol), potassium phosphate
(2.32 g, 10.958 mmol) and 1,4-Dioxane (50 mL) at 110.degree. C. for
12 hours to afford the crude product. The reaction was monitored by
TLC (10% MeOH in chloroform). Purification by column chromatography
on silica gel (1.5% methanol in chloroform) afforded 715 mg of the
product (60% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.9 (s, 1H), 8.7 (s,
1H), 8.48 (d, 1H), 8.38 (d, 1H), 8.12 (d, 1H), 7.68 (dd, 1H), 7.46
(d, 1H), 4.22-4.14 (m, 2H), 4.06-4.0 (m, 2H).
LCMS: 96.70%, m/z=331 (M+1)
HPLC: 95.64%.
Final Step: Synthesis of
1-Benzothiazol-6-yl-3-[4-(2-morpholin-4-yl-ethoxy)-pyridin-3-yl]-imidazol-
idin-2-one (180A)
1-Benzothiazol-6-yl-3-(4-chloro-pyridin-3-yl)-imidazolidin-2-one
(I-180a: 100 mg, 0.3023 mmol) was refluxed with
2-morpholin-4-yl-ethanol (60 mg, 0.4534 mmol), potassium hydroxide
(68 mg, 1.2092 mmol), potassium carbonate (42 mg, 0.3023 mmol),
18-crown-ether (8 mg, 0.0302 mmol) and toluene (3 mL) at
120.degree. C. to afford the crude product. The reaction was
monitored by TLC (10% MeOH in chloroform). Purification by column
chromatography on silica gel (3.5% methanol in chloroform) followed
by hexane wash and ether wash afforded 8.5 mg of the product (6.6%
yield).
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.9 (s, 1H), 8.65 (s,
1H), 8.54 (d, 1H), 8.3 (s, 1H), 8.1 (d, 1H) 7.7 (d, 1H), 6.95 (d,
1H), 4.24 (t, 2H), 4.32-3.94 (m, 4H), 3.64 (t, 4H), 2.82 (t, 2H),
2.58-2.48 (m, 4H)
LCMS: 94.37%, m/z=426 (M+1)
HPLC: 91.83%
Example 181
Preparation of
1-Benzothiazol-6-yl-3-[4-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-3-yf]--
imidazolidin-2-one (181A)
##STR00228##
1-Benzothiazol-6-yl-3-(4-chloro-pyridin-3-yl)-imidazolidin-2-one
(I-180a: 100 mg, 0.3023 mmol) was added to a stirred mixture of KOH
(68 mg, 1.2092 mmol), K.sub.2CO.sub.3 (42 mg, 0.3023 mmol) and
toluene (3 mL) and the reaction mixture was stirred at RT for 5
mins. This was followed by the addition of
(1-methyl-pyrrolidin-2-yl)-methanol (52 mg, 0.4534 mmol) and 18
crown ether (8 mg, 0.0302 mmol) and the resulting mixture was
refluxed for 24 hrs. The reaction was monitored by TLC (10% MeOH in
CHCl.sub.3). The reaction mixture was concentrated and the
concentrate was partitioned between ethylacetate and water. The
organic layer was washed with water, brine, dried over
Na.sub.2SO.sub.4 and concentrated. Purification by preparative HPLC
afforded 6 mg of the
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.9 (s, 1H), 8.55 (s,
1H), 8.45 (d, 1H), 8.35 (d, 1H), 8.1 (d, 1H) 7.7 (dd, 1H), 6.9 (d,
1H), 4.2-3.9 (m, 7H), 3.1 (t, 1H), 2.7 (bs, 1H), 2.45 (s, 3H),
2.35-2.2 (m, 1H), 2.05-1.95 (m, 1H), 1.85-1.7 (m, 2H).
LCMS: 100%, m/z=410 (M+1)
HPLC: 96.12%
Example 182
Preparation of
1-Benzothiazol-6-yl-3-{4-[(5-methyl-1H-pyrazol-3-ylamino)-methyl]-pyridin-
-3-yl}-imidazolidin-2-one (182A)
##STR00229##
3-(3-benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-pyridine-4-carbaldehyde
(I-177b: 100 mg, 0.308 mmol) was reacted with NaBH(OAc).sub.3 (131
mg, 0.616 mmol), 5-methyl-1H-pyrazol-3-ylamine (40 mg, 0.370 mmol)
and acetic acid (10 mL) to afford the crude product. Purification
by column chromatography on silica gel (5% MeOH in CHCl.sub.3),
followed by preparative HPLC afforded 4 mg of the product (7.7%
yield).
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 9.18 (s, 1H), 8.64 (s,
1H), 8.5 (d, 1H), 8.32 (d, 1H), 8.06 (d, 1H), 7.9 (dd, 1H), 7.6 (d,
1H), 5.5 (s, 1H), 4.5 (s, 2H), 4.3-4.05 (m, 4H), 2.15 (s, 3H).
LCMS: 100%, m/z=405.9 (M+1)
HPLC: 80.60%
Example 183
Preparation of
1-Benzothiazol-6-yl-3-(3H-imidazo[4,5-b]pyridin-6-yl)-imidazolidin-2-one
(183A)
##STR00230##
Step 1: Synthesis of Intermediate
6-Bromo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridine
(I-183a)
##STR00231##
(2-Chloromethoxy-ethyl)-trimethyl-silane (508.6 mg, 3.0456 mmol),
catalytic amount of benzyl triethyl-ammonium chloride and NaOH
(203.04 mg, 5.076 mmol) were added to a solution of
6-bromo-3H-imidazo[4,5-b]pyridine (500 mg, 2.538 mmol) in DCM (10
mL) at 0.degree. C. The resulting mixture was stirred room
temperature for 6 hours. The reaction was monitored by TLC (80%
ethylacetate in hexane). The reaction mixture was partitioned
between DCM and water. The organic layer was washed with water,
brine, dried over Na.sub.2SO.sub.4 and concentrated. Purification
by column chromatography on silica gel (20% ethylacetate in hexane)
afforded 120 mg of the product (14.4% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3): 8.48 (d, 1H), 8.25 (d, 1H), 8.2
(s, 1H), 5.65 (s, 2H), 3.7-3.5 (t, 2H), 1.0-0.9 (t, 2H), -0.09-0.00
(m, 9H).
Step 2: Synthesis of Intermediate
1-Benzothiazol-6-yl-3-[3-(2-trimethylsilanyl-ethoxy)-3H-imidazo[4,5-b]pyr-
idin-6-yl]-imidazolidin-2-one (I-183b)
##STR00232##
1-Benzothiazol-6-yl-imidazolidin-2-one (I-84b: 80.3 mg, 0.3669
mmol) was reacted with
6-bromo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridine
(I-183a: 120 mg, 0.3669 mmol), 1,4-dioxane (5 mL), copper iodide
(6.9 mg, 0.03669 mmol), trans N,N'-dimethyl-cyclohexane-1,2-diamine
(17.3 mL, 0.1100 mmol) and potassium phosphate (194.4 mg, 0.9172
mmol) to afford the crude product. Purification by column
chromatography on silica gel (2% MeOH in DCM) afforded 100 mg of
the product (58.4% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.0-8.8 (m, 2H), 8.5-8.1
(m, 4H), 7.7 (d, 1H), 5.7 (bs, 2H), 4.2 (bs, 4H), 3.6 (t, 2H), 0.95
(t, 2H), -0.09-0.00 (m, 9H).
Final Step: Synthesis of
1-Benzothiazol-6-yl-3-(3H-imidazo[4,5-b]pyridin-6-yl)-imidazolidin-2-one
(183A)
1,4-Dioxane HCl (5 ml) was added to
1-benzothiazol-6-yl-3-[3-(2-trimethylsilanyl-ethoxy)-3H-imidazo[4,5-b]pyr-
idin-6-yl]-imidazolidin-2-one (I-183b: 100 mg, 0.2145 mmol) and the
resulting mixture was stirred room temperature for 6 hours. The
reaction was monitored by TLC (10% MeOH in DCM). The reaction
mixture was concentrated and washed with diethyl ether.
Purification by preparative HPLC afforded 20 mg of the product
(25.4% yield).
.sup.1H NMR (400 MHz, DMSO-D.sub.6): .delta. 13.2 (s, 0.5H), 12.6
(s, 0.5H), 9.3 (s, 1H), 8.7 (dd, 1H), 8.44 (s, 1H), 8.36 (s, 1H),
8.3 (dd, 1H), 8.1 (d, 1H), 8.0 (dd, 1H), 4.2 (s, 4H).
LCMS: 75.25%, m/z=337 (M+1)
HPLC: 95.02%
Example 184
Synthesis of
1-Benzothiazol-6-yl-3-[4-(1-methyl-piperidin-4-ylmethoxy)-pyridin-3-yl]-i-
midazolidin-2-one (184A)
##STR00233##
1-Benzothiazol-6-yl-3-(4-chloro-pyridin-3-yl)-imidazolidin-2-one
(I-180a: 150 mg, 0.4534 mmol) was reacted with
(1-methyl-piperidin-4-yl)-methanol (88 mg, 0.6801 mmol), KOH (101
mg, 1.8138 mmol), K.sub.2CO.sub.3 (63 mg, 0.4534 mmol) and toluene
(6 mL) to afford crude product. Purification by column
chromatography on silica gel (10% MeOH in CHCl.sub.3), followed by
preparative HPLC afforded 10 mg of the product (5% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.9 (s, 1H), 8.55 (s,
1H), 8.45 (d, 1H), 8.35 (d, 1H), 8.1 (d, 1H), 7.7 (dd, 1H), 6.9 (d,
1H), 4.15 (m, 2H), 4.0-3.9 (m, 4H), 2.9 (d, 2H), 2.3 (s, 3H),
2.0-1.75 (m, 5H), 1.5 (t, 2H).
LCMS: 100%, m/z=424.2 (M+1)
HPLC: 98.88%
Example 185
Preparation of
3-(3-Benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-isonicotinamide
(185A)
##STR00234##
Step 1: Synthesis of
3-(3-Benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-isonicotinic Acid
Ethyl Ester (I-185a)
##STR00235##
1-Benzothiazol-6-yl-imidazolidin-2-one (I-84b: 0.25 g, 1.1 mmol)
was reacted with 3-bromo-isonicotinic acid ethyl ester (0.28 g, 1.2
mmol), 1,4-dioxane (30 mL), copper iodide (0.065 g, 0.3 mmol),
trans N,N'-dimethyl-cyclohexane-1,2-diamine (0.048 g, 0.3 mmol) and
potassium phosphate (0.81 g, 2.8 mmol) to afford the crude product.
Purification by column chromatography on silica gel (100%
CHCl.sub.3) afforded 160 mg of the product (38.2% yield).
LC-MS (m/z), 61.53%, 369.0 (m+1)
Final Step: Synthesis of
3-(3-Benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-isonicotinamide
(185A)
3-(3-Benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-isonicotinic acid
ethyl ester (I-185a: 0.16 g, 0.4 mmol) in methanolic ammonia (20
mL) was taken in a reaction flask and the flask was heated to
40.degree. C. overnight. The reaction was monitored by TLC (10%
MeOH in CHCl.sub.3). The reaction mixture was cooled to room
temperature and concentrated. The concentrate was partitioned
between DCM and water. The organic layer was washed with water,
brine, dried over Na.sub.2SO.sub.4 and concentrated. Purification
by column chromatography on silica gel (10% MeOH in CHCl.sub.3)
afforded 40 mg of the product (28.57% yield).
.sup.1H NMR (400 MHz, DMSOd.sub.6): .delta. 9.3 (s, 1H), 8.7 (s,
1H), 8.55 (d, 1H), 8.3 (d, 1H), 8.1-7.9 (m, 3H) 7.6 (s, 1H), 7.5
(d, 1H), 4.1 (s, 4H).
LCMS: 100%, m/z=339.9 (M+1)
HPLC: 88.41%
Example 186
Preparation of
1-Benzothiazol-6-yl-3-imidazo[1,2-a]pyrazin-5-yl-imidazolidin-2-one
(186A)
##STR00236##
Synthesis of Intermediate 5-Chloro-imidazo[1,2-a]pyrazine
(I-186a)
##STR00237##
NaHCO.sub.3 (4.215 g, 50.1736 mmol) and IPA (40 mL) were added to a
mixture of 2-bromo-1,1-dimethoxy-ethane (6.37 mL, 10.8066 mmol),
40% HBr (475 mL, 2.3157 mmol) and 2 drops of water previously
refluxed for 1 hr. The reaction mixture was stirred for 5 mins and
filtered. To the filtrate was added 6-chloro-pyrazin-2-ylamine (1
g, 7.7190 mmol) and the resulting mixture was refluxed for
overnight. The reaction was monitored by TLC (50% ethylacetate in
hexane). The reaction mixture was neutralized with Na.sub.2CO.sub.3
and partitioned between ethylacetate and water. The organic layer
was washed with water, brine, dried over Na.sub.2SO.sub.4 and
concentrated. Purification by column chromatography on silica gel
(1-2% MeOH in CHCl.sub.3) afforded 300 mg of the product (25.31%
yield).
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.05 (s, 1H), 7.98 (s,
1H), 7.92-7.85 (m, 2H).
LCMS: 97.85%, m/z=154.0 (M+1)
Final Step: Synthesis of
1-Benzothiazol-6-yl-3-imidazo[1,2-a]pyrazin-5-yl-imidazolidin-2-one
(186A)
1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 240 mg, 1.0945 mmol)
was reacted with 5-chloro-imidazo[1,2-a]pyrazine (I-186a: 202 mg,
1.3135 mmol), 1,4-dioxane (3 mL), copper iodide (24 mg), trans
N,N'-dimethyl-cyclohexane-1,2-diamine (48 mg) and potassium
phosphate (581 mg, 2.7364 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
CHCl.sub.3), followed by preparative HPLC afforded 13 mg of the
product (3.53% yield).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.9 (s, 1H), 8.54 (d,
1H), 8.1 (d, 1H), 7.95 (d, 1H), 7.85 (d, 1H) 7.75-7.7 (m, 3H), 4.5
(t, 2H), 4.1 (t, 2H).
LCMS: 100%, m/z=337 (M+1)
HPLC: 91.78%
Example 187
Preparation of
1-Benzothiazol-6-yl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-imidazolidin-2-one
(187A)
##STR00238##
Step 1: Synthesis of
5-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine
(I-187a)
##STR00239##
5-bromo-1H-pyrrolo[2,3-b]pyridine (0.3 g, 1.6 mmol) was reacted
with (2-chloromethoxy-ethyl)-trimethyl-silane (0.35 g, 2.1 mmol),
catalytic amount of benzyl triethyl-ammonium chloride and NaOH (0.2
g, 5.2 mmol) and DCM (20 mL) to afford the crude product.
Purification by column chromatography on silica gel (20%
ethylacetate in hexane) afforded 0.32 g of the product (64.2%
yield).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 8.36 (d, 1H), 8.03 (d,
1H), 7.36 (d, 1H), 6.46 (d, 1H), 5.6 (s, 2H), 3.5 (t, 2H), 0.9 (t,
2H), -0.95 (m, 9H)
Step 2: Synthesis of Intermediate
1-(benzothiazol-6-yl)-3-(1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrrolo-
[2,3-b]pyridin-5-yl)imidazolidin-2-one (I-187b)
##STR00240##
1-Benzothiazol-6-yl-imidazolidin-2-one (I-84b: 0.2 g, 0.9 mmol) was
reacted with
5-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine
(I-187a: 0.32 g, 1.0 mmol), 1,4-dioxane (15 mL), copper iodide
(0.052 g, 0.2 mmol), trans N,N'-dimethyl-cyclohexane-1,2-diamine
(0.038 g, 0.27 mmol) and potassium phosphate (0.65 g, 2.2 mmol) to
afford the crude product. Purification by column chromatography on
silica gel (1.5% methanol in DCM) afforded 0.22 g of the product
(52.3% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 8.9 (s, 1H), 8.48 (d,
1H), 8.38 (d, 1H), 8.24 (d, 1H), 8.1 (d, 1H), 7.7 (dd, 1H), 7.37
(d, 1H), 6.5 (s, 1H), 5.7 (s, 2H), 4.1 (s, 4H), 3.55 (t, 2H), 0.9
(t,
Final Step: Synthesis of
1-Benzothiazol-6-yl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-imidazolidin-2-one
(187A)
1,4-Dioxane HCl (10 ml) was added to
1-(benzothiazol-6-yl)-3-(1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrrolo
[2,3-b]pyridin-5-yl)imidazolidin-2-one (I-187b: 0.07 g, 0.19 mmol)
and the resulting mixture was heated to 110.degree. C. for 2 days.
The reaction was monitored by TLC (20% MeOH in CHCl.sub.3). The
reaction mixture was basified with Na.sub.2CO.sub.3 solution
(pH.about.8), cooled to room temperature, concentrated and the
concentrate was washed with diethyl ether. Purification by
preparative HPLC afforded 1.7 mg of the product (25.6% yield).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.9 (s, 1H), 8.5 (s,
1H), 8.4 (d, 1H), 8.3 (s, 1H), 8.1 (d, 1H) 7.7 (dd, 1H), 7.35 (t,
1H), 6.55 (m, 1H), 4.2 (s, 4H).
LCMS: 97.14%, m/z=336 (M+1)
HPLC: 87.78%
Example 188
Synthesis of
3-Benzothiazol-6-yl-3'-methyl-4,5-dihydro-3H,3'H-[1,4]biimidazolyl-2-one
(179A)
##STR00241##
1-Benzothiazol-6-yl-imidazolidin-2-one (I-84b: 150 mg, 0.6849 mmol)
was reacted with 5-bromo-1-methyl-1H-imidazole (121.3 mg, 0.753
mmol), 1,4-dioxane (5 mL), copper iodide (12.99 mg, 0.0684 mmol),
trans N,N'-dimethyl-cyclohexane-1,2-diamine (29.176 mg, 0.205 mmol)
and potassium phosphate (435.01 mg, 2.05 mmol) to afford the crude
product. Purification by column chromatography on silica gel (2%
MeOH in CHCl.sub.3) afforded 85 mg of the product (41.64%
yield).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.9 (s, 1H), 8.35 (d,
1H), 8.1 (d, 1H), 7.7 (dd, 1H), 7.5-7.4 (brs, 1H), 7.0 (brs, 1H),
4.1 (t, 2H), 3.9 (t, 2H), 3.6 (s, 3H).
LCMS: 100%, m/z=299.8 (M+1)
HPLC: 98.52%
Example 189
Preparation of
1-Benzothiazol-6-yl-3-(4-methyl-5-trifluoromethyl-pyridin-3-yl)-imidazoli-
din-2-one Trifluoro-acetic Acid (189A)
##STR00242##
Step 1: Synthesis of 3-Bromo-4-methyl-5-trifluoromethyl-pyridine
(I-189a)
##STR00243##
n-Butyl Lithium (1.9 mL, 3.044 mmol) was added to a solution of
DIPA (335.7 mg, 3.318 mmol) in THF (6 mL) at -78.degree. C. The
reaction mixture was stirred at -10.degree. C. for 10 minutes. This
was followed by the addition of 3-bromo-5-trifluoromethyl-pyridine
(500 mg, 2.212 mmol) in THF (3 mL) at -100.degree. C. The reaction
mixture was stirred for a further 15 minutes at -90.degree. C. and
was followed by the addition of methyl iodide (557.0 mg, 3.924
mmol) in THF (2 mL) at -78.degree. C. with stirring over a period
of 30 minutes. The reaction was monitored by TLC (5% ethyl acetate
in hexane). The reaction mixture was quenched with aqueous
NaHCO.sub.3 solution and extracted with ethyl acetate (100 mL). The
organic layer was dried over Na.sub.2SO.sub.4 and concentrated.
Purification by column chromatography on silica gel (2%
ethylacetate in hexane) afforded 95 mg of the product (17.92%
yield). LCMS: m/z=239.8 (M+1)
Final Step: Synthesis of
1-Benzothiazol-6-yl-3-(4-methyl-5-trifluoromethyl-pyridin-3-yl)-imidazoli-
din-2-one Trifluoro-acetic Acid (189A)
1-Benzothiazol-6-yl-imidazolidin-2-one (I-84b: 80 mg, 0.365 mmol)
was reacted with 3-bromo-4-methyl-5-trifluoromethyl-pyridine
(I-189a: 90 mg, 0.365 mmol), 1,4-dioxane (5 mL), copper iodide
(6.95 mg, 0.0365 mmol), trans-1,2-diamino cyclohexane (12.5 mg,
0.1095 mmol) and potassium phosphate (232.4 mg, 1.095 mmol) to
afford the crude product. Purification by preparative HPLC afforded
Sing of the product (3.6% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 9.05-8.65 (m, 3H), 8.35
(s, 1H), 8.25-8.05 (m, 1H), 7.78-7.58 (m, 1H), 4.32-4.12 (m, 2H),
4.12-3.91 (m, 2H), 2.49 (s, 3H)
LCMS purity: 100%, m/z=378.9 (M+1)
HPLC: 93.5%
Example 190
Preparation of
1-Isothiazol-4-yl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(190A)
##STR00244##
1-(4-Methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847
mmol) was reacted with 4-bromo-isothiazole (166 mg, 1.016 mmol),
1,4-dioxane (15 mL), copper iodide (16.09 mg, 0.0847 mmol),
trans-1,2-diamino cyclohexane (29 mg, 0.254 mmol) and potassium
phosphate (540 mg, 2.541 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
CHl.sub.3) afforded 120 mg of the product (54.54% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.82 (s, 1H), 8.65-8.25
(m, 3H), 7.4-7.1 (m, 1H), 4.20-3.95 (m, 4H), 2.19 (s, 3H)
LCMS purity: 97.95%, m/z=261.0 (M+1)
HPLC: 96.08%
Example 191
Preparation of
1-Benzothiazol-6-yl-3-pyridin-2-yl-imidazolidin-2-one (191A)
##STR00245##
1-Benzothiazol-6-yl-imidazolidin-2-one (I-84b: 150 mg, 0.6904 mmol)
was reacted with 2-bromo-pyridine (99 mL, 1.0356 mmol), 1,4-dioxane
(10 mL), copper iodide (16 mg), trans-1,2-diamino cyclohexane (32
mg) and potassium phosphate (440 mg, 2.0713 mmol) to afford the
crude product. Purification by column chromatography on silica gel
(10% ethylacetate in hexane), followed by preparative HPLC afforded
37 mg of the product (18.13% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 9.3 (s, 1H), 8.5-8.3
(m, 2H), 8.25 (d, 1H), 8.18-8.02 (m, 1H), 8.02-7.9 (m, 1H),
7.88-7.70 (m, 1H), 7.18-7.00 (m, 1H), 4.2-4.0 (m, 4H)
LCMS purity: 97.44%, m/z=297.1 (M+1)
HPLC: 95.28%
Example 192
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-(5-trifluoromethyl-thiophen-2-yl)-imidazolidi-
n-2-one (192A)
##STR00246##
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 100 mg, 0.5643
mmol) was reacted with 2-bromo-5-trifluoromethyl-thiophene (136.9
mg, 0.5925 mmol), 1,4-dioxane (10 mL), copper iodide (10.75 mg,
0.0564 mmol), trans-1,2-diamino cyclohexane (20.4 mL, 0.1693 mmol)
and potassium phosphate (360 mg, 1.693 mmol) to afford the crude
product. Purification by column chromatography on silica gel (2%
MeOH in CHCl.sub.3) afforded 120 mg of the product (65% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.66-8.3 (m, 2H),
7.65-7.23 (m, 2H), 6.55 (d, 1H), 4.24-3.90 (m, 4H), 2.26 (s,
3H)
LCMS purity: 96.35%, m/z=327.9 (M+1)
HPLC: 95.04%
Example 193
Preparation of
1-Benzothiazol-6-yl-3-[4-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-imidazo-
lidin-2-one (193A)
##STR00247##
Step 1: Synthesis of Intermediate
2-(3-Bromo-pyridin-4-yl)-propan-2-ol (I-193a)
##STR00248##
n-Butyl Lithium (10.28 mL, 16.455 mmol) was added to a solution of
DIPA (2.66 mL, 18.98 mmol) in THF (25 mL) at -78.degree. C. The
reaction mixture was stirred at -10.degree. C. for 10 mins,
followed by the addition of 3-bromo-pyridine (500 mg, 2.212 mmol)
in THF (10 mL) at -100.degree. C. The reaction mixture was stirred
for a further 15 minutes at -90.degree. C. and was followed by the
addition of acetone (1.675 mL, 22.78 mmol) in THF (10 mL) at
-78.degree. C. with stirring over a period of 1 hr. The reaction
was monitored by TLC (5% ethylacetate in hexane). The reaction
mixture was quenched with aqueous NaHCO.sub.3 solution and
extracted with ethylacetate. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated. Purification by column
chromatography on silica gel (15% ethylacetate in hexane) afforded
200 mg of the product (11% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.7 (s, 1H), 8.5 (d,
1H), 7.65 (d, 1H), 1.7 (s, 6H)
LCMS purity: 89.57%, m/z=215.9 (M+1)
Final Step: Synthesis of
1-Benzothiazol-6-yl-3-[4-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-imidazo-
lidin-2-one (193A)
1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 125 mg, 0.57 mmol)
was reacted with 2-(3-bromo-pyridin-4-yl)-propan-2-ol (122.7 mg,
0.57 mmol), 1,4-dioxane (5 mL), copper iodide (10.85 mg, 0.057
mmol), trans-1,2-diamino cyclohexane (19.57 mg, 0.171 mmol) and
potassium phosphate (362.9 mg, 1.71 mmol) to afford the crude
product. Purification by preparative HPLC afforded 38 mg of the
product (19% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.68 (s, 1H), 8.50-8.32
(m, 2H), 7.86 (d, 1H), 7.18-7.02 (m, 2H), 6.82 (dd, 1H), 4.55-4.42
(m, 1H), 4.32 (t, 2H), 3.7-3.6 (m, 2H), 1.74-1.58 (m, 6H)
LCMS purity: 97.84%, m/z=354.9 (M+1)
HPLC: 95.61%
Example 194
Preparation of
1-(4-Methyl-pyridin-3-(4-methyl-thieno[3,2-c]pyridin-2-yl)-imidazolidin-2-
-one (194A)
##STR00249##
Tetrakis (triphenylphosphine) palladium (33 mg, 0.0288 mmol) was
added to potassium carbonate (120 mg, 0.8649 mmol) previously
purged with argon (30 minutes). The reaction mixture was purged
with argon for 15 minutes, followed by the addition of
1-(4-chloro-thieno[3,2-c]pyridin-2-yl)-3-(4-methyl-pyridin-3-yl)-imidazol-
idin-2-one (98A: 100 mg, 0.2883 mmol) and methyl boronic acid (21
mg, 0.3459 mmol). The reaction mixture was heated to reflux for 6
hours. The reaction was monitored by TLC (10% MeOH in CHCl.sub.3).
The reaction mixture was concentrated to afford the crude product.
Purification by column chromatography on silica gel (3-4% MeOH in
CHCl.sub.3), followed by preparative HPLC afforded 10 mg of the
product (16.39% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.7-8.35 (m, 2H),
8.35-8.2 (d, 1H), 7.5 (d, 1H), 6.58 (s, 1H), 4.4-3.9 (m, 4H), 2.79
(s, 3H), 2.36 (s, 3H)
LCMS purity: 96.01%, m/z=324.9 (M+1)
HPLC: 96.32%
Example 195
Preparation of
1-Benzothiazol-6-yl-3-[4-(1-hydroxyethyl)-pyridin-3-yl]-imidazolidin-2-on-
e (195A)
##STR00250##
1-Benzothiazol-6-yl-imidazolidin-2-one (I-84b: 150 mg, 0.6849 mmol)
was reacted with 1-(3-bromo-pyridin-4-yl)ethanol (137.6 mg, 0.6849
mmol), 1,4-dioxane (5 mL), copper iodide (13.04 mg, 0.06849 mmol),
trans-1,2-diamino cyclohexane (23.52 mg, 0.205 mmol) and potassium
phosphate (435.1 mg, 2.05 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
CHCl.sub.3), followed by preparative HPLC afforded 9 mg of the
product (3.9% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.92 (s, 1H), 8.65-8.54
(m, 2H), 8.32 (d, 1H), 8.15 (d, 1H), 7.70-7.62 (dd, 1H), 7.6 (d,
1H), 5.10-4.96 (m, 1H), 4.30-4.12 (m, 3H), 4.02-3.85 (m, 1H),
3.75-3.66 (br s, 1H), 1.60-1.45 (d, 3H)
LCMS purity: 98.20%, m/z=340.9 (M+1)
HPLC: 91.15%
Example 196
Synthesis of
1-Benzothiazol-6-yl-3-(4-ethyl-pyridin-3-yl)-imidazolidin-2-one
(196A)
##STR00251##
1-Benzothiazol-6-yl-imidazolidin-2-one (I-84b: 600 mg, 2.739 mmol)
was reacted with 3-bromo-4-ethyl-pyridine (512 mg, 2.739 mmol),
1,4-dioxane (10 mL), copper iodide (52 mg, 0.2739 mmol),
trans-1,2-diamino cyclohexane (94.08 mg, 0.82 mmol) and potassium
phosphate (1.74 mg, 8.2 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
CHCl.sub.3), followed by preparative HPLC afforded 30 mg of the
product (3.75% yield).
.sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 9.15 (s, 1H), 8.60-8.35
(m, 3H), 8.15-7.95 (m, 1H), 7.95-7.70 (m, 1H), 7.5 (d, 1H), 4.3-3.9
(m, 4H), 2.85-2.65 (q, 2H), 1.4-1.2 (t, 3H)
LCMS purity: 99.77%, m/z=325.1 (M+1)
HPLC: 95.03%
Example 197
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-(3-trifluoromethyl-1H-indazol-6-yl)-imidazoli-
din-2-one (197A)
##STR00252##
Step 1: Synthesis of
1-[3-Fluoro-4-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-3-(4-methyl-pyrid-
in-3-yl)-imidazolidin-2-one (I-197a)
##STR00253##
0.5M solution of trimethyl-trifluoromethyl-silane in THF (6.68 mL,
3.344 mmol) and K.sub.2CO.sub.3 (250 mg, 10.82 mmol) were added to
2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehy-
de (I-121a: 400 mg, 1.337 mmol) in dry DMF (5 mL) under nitrogen
atmosphere. The resulting mixture was stirred at room temperature
overnight. The reaction was monitored by TLC (5% MeOH in
CHCl.sub.3). The reaction mixture was quenched with brine solution
and the THF layer was concentrated. The aqueous layer was extracted
with chloroform. The organic layer was dried over Na.sub.2SO.sub.4
and concentrated to get the crude product. Purification by column
chromatography on silica gel (2.5% MeOH in CHCl.sub.3), followed by
hexane wash, afforded 325 mg of the product (65.92% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.56-8.00 (m, 2H),
7.75-7.45 (m, 2H), 7.36-7.08 (m, 2H), 5.38 (q, 1H), 4.55-4.24 (br
s, 1H), 4.20-3.76 (m, 4H), 2.32 (s, 3H)
Step 2: Synthesis of
1-[3-Fluoro-4-(2,2,2-trifluoroacetyl)-phenyl]-3-(4-methyl-pyridin-3-yl)-i-
midazolidin-2-one (I-197b)
##STR00254##
MnO.sub.2 (536 mg, 6.165 mmol) was added to
1-[3-fluoro-4-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-3-(4-methyl-pyrid-
in-3-yl)-imidazolidin-2-one (I-197a: 325 mg, 0.880 mmol) in DCM (20
mL) under nitrogen atmosphere. The resulting suspension was stirred
at 50.degree. C. overnight. The reaction was monitored by TLC (5%
MeOH in DCM). The reaction mixture was cooled to room temperature
and filtered through celite pad. The filtrate was washed with
CHCl.sub.3, dried over Na.sub.2SO.sub.4 and concentrated. The
concentrate was washed with hexane and dried to afford 240 mg of
the product (74.53% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.8-8.2 (m, 2H), 7.98
(t, 1H), 7.86-7.50 (m, 2H), 7.46-7.25 (m, 1H), 4.40-3.75 (m, 4H),
2.28 (s, 3H)
Final Step: Synthesis of
1-(4-Methyl-pyridin-3-yl)-3-(3-trifluoromethyl-1H-indazol-6-yl)-imidazoli-
din-2-one (197A)
Acetic acid (0.1 mL, 1.36 mmol) and 1M hydrazine in THF (4 mL, 2.72
mmol) were added to
1-[3-fluoro-4-(2,2,2-trifluoro-acetyl)-phenyl]-3-(4-methyl-pyridin-3-yl)--
imidazolidin-2-one (I-197b: 100 mg, 0.272 mmol) in dry THF (2 mL).
The resulting mixture was stirred at 150.degree. C. overnight. The
reaction was monitored by TLC (5% MeOH in CHCl.sub.3). The reaction
mixture was partitioned between water and chloroform. The organic
layer was dried over Na.sub.2SO.sub.4 and concentrated.
Purification by column chromatography on silica gel (4% MeOH in
CHCl.sub.3), followed by preparative HPLC afforded 23 mg of the
product (23.46% yield).
.sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 8.57-8.48 (br s, 1H),
8.37 (d, 1H), 7.86-7.70 (m, 2H), 7.70-7.60 (m, 1H), 7.42 (d, 1H),
4.34-4.12 (m, 2H), 4.12-3.90 (m, 2H), 2.41 (s, 3H)
LCMS purity: 96.14%, m/z=362.0 (M+1)
HPLC: 94.33%
Example 198
Preparation of
1-(3-Cyclopropyl-1H-indazol-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin--
2-one (198A)
##STR00255##
Step I. Synthesis of
1-[4-(Cyclopropyl-hydroxy-methyl)-3-fluoro-phenyl]-3-(4-methyl-pyridin-3--
yl)-imidazolidin-2-one (I-198a)
##STR00256##
0.5M solution of cyclopropyl magnesium bromide in THF (2.4 mL,
1.170 mmol) was added dropwise to
2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehy-
de (I-121a: 175 mg, 0.585 mmol) in dry THF (10 mL) at 0.degree. C.
under nitrogen atmosphere. The resulting mixture was stirred at
room temperature for 3 hours. The reaction was monitored by TLC (5%
MeOH in CHCl.sub.3). The reaction mixture was quenched with aqueous
NH.sub.4Cl solution and the THF layer was concentrated. The aqueous
layer was extracted with ethylacetate. The organic layer was dried
over N.sub.2SO.sub.4 and concentrated to afford the crude product.
Purification by column chromatography on silica gel (3% MeOH in
CHCl.sub.3), followed by hexane wash, afforded 200 mg of the
product (99.41% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.72-8.28 (m, 2H),
7.70-7.48 (m, 2H), 7.42-7.25 (m, 2H), 5.30 (d, 1H), 4.48-4.20 (m,
1H), 4.18-3.82 (m, 4H), 2.32 (s, 3H), 1.2-1.0 (m, 1H), 0.7-0.1 (m,
4H)
LCMS purity: 97.58%, m/z=342.3 (M+1)
Step 2: Synthesis of
1-(4-Cyclopropanecarbonyl-3-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imid-
azolidin-2-one (I-198b)
##STR00257##
MnO.sub.2 (357 mg, 41.055 mmol) was added to
1-[4-(cyclopropyl-hydroxy-methyl)-3-fluoro-phenyl]-3-(4-methyl-pyridin-3--
yl)-imidazolidin-2-one (I-198a: 200 mg, 8.586 mmol) in DCM (20 mL)
under nitrogen atmosphere and worked up in a manner similar to what
was described for Example 197 to afford 175 mg of the product
(60.13% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.56 (s, 1H), 8.41 (d,
1H), 7.82 (t, 1H), 7.76-7.65 (m, 1H), 7.60-7.47 (m, 1H), 7.37 (d,
1H), 4.22-3.82 (m, 4H), 2.80-2.60 (m, 1H), 2.29 (s, 3H), 1.18-0.93
(m, 4H)
LCMS purity: 98.34%, m/z=339.7 (M+1)
Final Step: Synthesis of
1-(3-Cyclopropyl-1H-indazol-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin--
2-one (198A)
1-(4-Cyclopropanecarbonyl-3-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imid-
azolidin-2-one (I-198b: 175 mg, 0.516 mmol) in hydrazine hydrate
solution (10 mL) was taken in a reaction flask. The flask was
refluxed at 120.degree. C. overnight. The reaction was monitored by
TLC (5% MeOH in CHCl.sub.3). The reaction mixture was cooled to
room temperature and partitioned between ice water and chloroform.
The organic layer was dried over Na.sub.2SO.sub.4 and concentrated.
Purification by column chromatography on silica gel (4% MeOH in
CHCl.sub.3), followed by hexane and ether wash, afforded 55 mg of
the product (31.97% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 12.42 (s, 1H), 8.55
(s, 1H), 8.39 (d, 1H), 7.85-7.28 (m, 4H), 4.28-3.80 (m, 4H),
2.6-2.1 (m, 4H), 1.04-0.80 (m, 4H)
LCMS purity: 100.00%, m/z=333.8 (M+1)
HPLC: 94.27%
Example 199
Preparation of
1-(4-Methyl-pyridin-3-yl)-3-quinolin-7-yl-imidazolidin-2-one
(199A)
##STR00258##
1-(4-Methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b:116 mg, 0.6554
mmol) was reacted with 7-bromo-quinoline (150 mg, 0.72098 mmol),
1,4-dioxane (50 mL), copper iodide (12.4 mg, 0.06554 mmol),
trans-1,2-diamino cyclohexane (22.5 mg, 0.19638 mmol) and potassium
phosphate (347.3 g, 1.6365 mmol) to afford the crude product.
Purification by column chromatography on silica gel (2% MeOH in
CHCl.sub.3) afforded 130 mg of the product (65.3% yield).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): .delta. 8.95-8.76 (m, 1H), 8.6
(s, 1H), 8.48-8.22 (m, 3H), 8.06-7.82 (m, 2H), 7.50-7.32 (m, 2H),
4.32-4.12 (m, 2H), 4.10-3.90 (m, 2H), 2.31 (s, 3H)
LCMS purity: 99.57%, m/z=305.0 (M+1)
HPLC: 93.16%
Example 200
Synthesis of
3-Benzothiazol-6-yl-4,4-dimethyl-1-(4-methyl-pyridin-3-yl)-imidazolidin-2-
-one (200A)
##STR00259##
Step 1: Synthesis of Intermediate 3-Chloro-2,2-dimethyl-propionyl
chloride (I-200a)
##STR00260##
SOCl.sub.2 (5.22 g, 44.23 mmol) was added dropwise to a stirred
solution of 3-chloro-2,2-dimethyl-propionic acid (5 g, 36.76 mmol)
in DCM (50 mL) at 0.degree. C. over a period of 5 mins. This was
followed by the addition of DMF (0.1 mL) and the resulting mixture
was heated to 60.degree. C. for 3 hours. The reaction was monitored
by TLC (5% MeOH in CHCl.sub.3). The reaction mixture was
concentrated and the crude product (6 g) was used in the next step
without further purification.
Step 2: Synthesis of Intermediate 3-Chloro-2,2-dimethyl-propionyl
azide (I-200b)
##STR00261##
Sodium azide (4.64 g, 71.38 mmol) was added to a solution of
3-chloro-2,2-dimethyl-propionyl chloride (I-200a: 6 g, 35.71 mmol)
in 1,4-dioxane (15 mL) and water (15 mL). The resulting mixture was
stirred at room temperature for 2 hours. The reaction was monitored
by TLC (5% ethylacetate in hexane). The reaction mixture was
extracted with diethyl ether and the organic layer was dried over
Na.sub.2SO.sub.4 to afford 3.5 g of the product (61.40% yield).
Step 3: Synthesis of 1-Chloro-2-isocyanato-2-methyl-propane
(I-200c)
##STR00262##
1-Chloro-2-isocyanato-2-methyl-propane (I-200b: 3.5 g, 20 mmol) in
toluene (35 mL) was taken a reaction flask and flask was heated to
85.degree. C. for 1.30 hr. The reaction was monitored by TLC (5%
ethylacetate in hexane). The crude product (3 .mu.m) was used in
the next step without further purification.
Step 4: Synthesis of
1-(2-Chloro-1,1-dimethyl-ethyl)-3-(4-methyl-pyridin-3-yl)-urea
(I-200d)
##STR00263##
4-Methyl-pyridin-3-ylamine (1.98 g, 18.33 mmol) was added to
solution of 1-chloro-2-isocyanato-2-methyl-propane (I-200c: 3 g,
20.40 mmol) in toluene (30 mL). The resulting mixture was stirred
at room temperature for 3 days. The reaction was monitored by TLC
(5% MeOH in CHCl.sub.3). The reaction mixture was filtered and the
residue was dried to afford 4.3 g of the product (87.75%
yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.70 (s, 1H), 8.3 (s,
1H), 7.12 (s, 1H), 6.39 (s, 1H), 4.9 (s, 1H), 3.87 (s, 2H), 2.30
(s, 3H), 1.4 (s, 6H)
LCMS purity: 76.36%, m/z=242.0 (M+1)
Step 5: Synthesis of intermediate
4,4-Dimethyl-1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(I-200e)
##STR00264##
1-(2-Chloro-1,1-dimethyl-ethyl)-3-(4-methyl-pyridin-3-yl)-urea
(I-200d: 1 g, 4.149 mmol) in dry THF (5 mL) was added dropwise to a
stirred mixture of NaH (298 mg, 6.208 mmol) in dry THF (10 mL)
under argon atmosphere over a period of 10 minutes at 0.degree. C.
The resulting reaction mixture was stirred for 2 hrs. The reaction
was monitored by TLC (5% MeOH in CHCl.sub.3). The reaction mixture
was partitioned between water and ethylacetate. The organic layer
was dried over Na.sub.2SO.sub.4 and concentrated to afford 800 mg
of the product (94.33% yield).
.sup.1H NMR (DMSO, 300 MHz): .delta. 8.4 (s, 1H), 8.3 (d, 1H), 7.30
(d, 1H), 7.0 (s, 1H), 3.53 (s, 2H), 2.22 (s, 3H), 1.3 (s, 6H)
LCMS purity: 100%, m/z=205.7 (M+1)
Final Step: Synthesis of
3-Benzothiazol-6-yl-4,4-dimethyl-1-(4-methyl-pyridin-3-yl)-imidazolidin-2-
-one (200A)
4,4-Dimethyl-1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-163b:
150 mg, 0.731 mmol) was reacted with 6-iodo-benzothiazole (I-200e:
248 mg, 0.950 mmol), 1,4-dioxane (10 mL), copper iodide (13 mg,
0.0682 mmol), trans-1,2-diamino cyclohexane (31 mg, 0.218 mmol) and
potassium phosphate (387 mg, 1.825 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1%
MeOH in CHCl.sub.3) afforded 30 mg of the product (12.14%
yield).
.sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 9.32 (s, 1H), 8.51 (s,
1H), 8.35 (d, 1H), 8.0-8.2 (m, 2H), 7.60 (d, 1H), 7.40 (d, 1H),
3.90 (s, 2H), 2.45 (s, 3H), 1.5 (s, 6H)
LCMS purity: 94.09%, m/z=339.1 (M+1)
HPLC: 89.11%
Example 201
Preparation of
1-Benzothiazol-6-yl-4,4-dimethyl-3-pyridin-3-yl-imidazolidin-2-one
(201A)
##STR00265##
Step 1: Synthesis of Intermediate
1-Benzothiazol-6-yl-3-(2-chloro-1,1-dimethyl-ethyl)-urea
(I-201a)
##STR00266##
Benzothiazol-6-ylamine (1.8 g, 12.00 mmol) was added portion wise
to solution of 1-chloro-2-isocyanato-2-methyl-propane (2 g, 13.60
mmol) in toluene (20 mL) over a period of 5 minutes. The resulting
mixture was stirred at room temperature for 21/2 days. The reaction
was monitored by TLC (5% MeOH in CHCl.sub.3). The reaction mixture
was concentrated and extracted with ethylacetate. The organic layer
was dried over Na.sub.2SO.sub.4 and concentrated. Purification by
column chromatography on silica gel (1% MeOH in CHCl.sub.3)
afforded 630 mg of the product (16.57% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.85 (s, 1H), 8.23 (d,
1H), 8.0 (d, 1H), 7.20-7.15 (dd, 1H), 7.03 (s, 1H), 5.10 (s, 1H),
3.89 (s, 2H), 1.49 (s, 6H)
LCMS purity: 98.84%, m/z=283.9 (M+1)
Step 2: Synthesis of intermediate
1-Benzothiazol-6-yl-4,4-dimethyl-imidazolidin-2-one (I-201 h)
##STR00267##
1-Benzothiazol-6-yl-3-(2-chloro-1,1-dimethyl-ethyl)-urea (I-201a:
620 mg, 2.18 mmol) in dry THF (5 mL) was added dropwise to a
stirred mixture of NaH (78 mg, 3.25 mmol) in dry THF (5 mL) under
argon atmosphere over a period of 10 minutes at 0.degree. C. The
resulting reaction mixture was stirred at room temperature for 45
minutes. The reaction was monitored by TLC (5% MeOH in CHCl.sub.3).
The reaction mixture was partitioned between chilled water and
ethylacetate. The organic layer was dried over Na.sub.2SO.sub.4 and
concentrated to afford 410 mg of the product (77.35% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.90 (s, 1H), 8.31 (d,
1H), 8.09 (d, 1H), 7.69-7.58 (dd, 1H), 5.0 (br s, 1H), 3.73 (s,
2H), 1.49 (s, 6H)
LCMS purity: 99.16%, m/z=247.8 (M+1)
Final Step: Synthesis of
1-Benzothiazol-6-yl-4,4-dimethyl-3-pyridin-3-yl-imidazolidin-2-one
(201A)
1-Benzothiazol-6-yl-4,4-dimethyl-imidazolidin-2-one (I-201b: 100
mg, 0.4048 mmol) was reacted with 3-bromo-pyridine (83 mg, 0.525
mmol), 1,4-dioxane (10 mL), copper iodide (7 mg, 0.036 mmol),
trans-1,2-diamino cyclohexane (17 mg, 0.119 mmol) and potassium
phosphate (214 mg, 1.009 mmol) to afford the crude product.
Purification by column chromatography on silica gel (1% MeOH in
CHCl.sub.3) afforded 15 mg of the product (11.45% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.90 (s, 1H), 8.7-8.5
(br s, 2H), 8.35 (d, 1H), 8.12 (d, 1H), 7.77-7.60 (m, 2H), 7.5-7.4
(m, 1H), 3.9 (s, 2H), 1.49 (s, 6H)
LCMS purity: 100%, m/z=325.1 (M+1)
HPLC: 95.40%
Example 202
Preparation of
1-Benzothiazol-6-yl-4,4-dimethyl-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-
-one (202A)
##STR00268##
1-Benzothiazol-6-yl-4,4-dimethyl-imidazolidin-2-one (I-201b: 100
mg, 0.4048 mmol) was reacted with 3-iodo-4-methyl-pyridine (115 mg,
0.525 mmol), 1,4-dioxane (10 mL), copper iodide (7 mg, 0.0368
mmol), trans-1,2-diamino cyclohexane (18 mg, 0.1197 mmol) and
potassium phosphate (214 mg, 1.0094 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1%
MeOH in CHCl.sub.3) afforded 6 mg of the product (4.8% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.30 (d, 1H), 8.15 (d,
1H), 7.7-7.6 (dd, 1H), 3.8 (s, 2H), 2.72 (s, 3H), 1.49 (s, 6H)
LCMS purity: 94.22%, m/z=339.1 (M+1)
HPLC: 86.98%
Example 203
Synthesis of
3-Benzothiazol-6-yl-4-methyl-1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(203A)
##STR00269##
Step 1: Synthesis of intermediate
3-(Benzothiazol-6-ylamino)-butyric Acid (I-203a)
##STR00270##
3-Amino-butyric acid ethyl ester (2 g, 15.27 mmol),
6-iodo-benzothiazole (3.98 g, 15.27 mmol) and potassium carbonate
(5.27 g, 38.18 mmol) were dissolved in DMF (50 mL) and the reaction
mixture was purged with argon for 10 minutes. This was followed by
the addition of copper iodide (290 mg, 1.527 mmol) and the
resulting mixture was heated to 110.degree. C. overnight. The
reaction was monitored by TLC (10% MeOH in CHCl.sub.3) which showed
the presence of starting material. The reaction mixture was heated
to 120.degree. C. for a further 24 hours. The reaction mixture was
concentrated and adjusted the pH to 5 using acetic acid. The
reaction mixture was partitioned between water and ethylacetate.
The organic layer was dried over Na.sub.2SO.sub.4 and concentrated.
Purification by column chromatography on silica gel (1% MeOH in
CHCl.sub.3) afforded 800 mg of the product (22.22% yield).
.sup.1H NMR (DMSO, 300 MHz): .delta. 12.2 (s, 1H), 8.9 (s, 1H),
7.75 (d, 1H), 7.15 (d, 1H), 6.85 (dd, 1H), 5.90-5.80 (m, 1H),
3.90-3.80 (m, 1H), 2.60-2.50 (m, 1H), 2.25-2.35 (m, 1H), 1.20 (d,
3H)
LCMS purity: 61.65%, m/z=237.0 (M+1)
Step 2: Synthesis of
1-Benzothiazol-6-yl-5-methyl-imidazolidin-2-one (I-203b)
##STR00271##
Triethylamine (1.129 g, 11.18 mmol) was added to a mixture of
3-(benzothiazol-6-ylamino)-butyric acid (I-203a: 800 mg, 3.39 mmol)
in toluene (30 mL) and the reaction mixture was purged with argon
for 10 minutes. This was followed by the addition of DPPA (2.796 g,
10.17 mmol) and the resulting mixture was heated to 100.degree. C.
overnight.
The reaction was monitored by TLC (10% MeOH in CHCl.sub.3) which
showed the presence of starting material. The reaction mixture was
heated to 120.degree. C. for the next 24 hours. The reaction
mixture was partitioned between water and ethylacetate. The organic
layer was dried over Na.sub.2SO.sub.4 and concentrated.
Purification by column chromatography on silica gel (2% MeOH in
CHCl.sub.3) afforded 600 mg of the product (75.95% yield).
.sup.1H NMR (DMSO, 300 MHz): .delta. 9.25 (s, 1H), 8.22 (d, 1H),
8.0 (d, 1H), 7.7 (dd, 1H), 7.0 (s, 1H), 4.6-4.5 (m, 1H), 3.6 (t,
1H), 3.0 (m, 1H), 1.2 (d, 3H)
LCMS purity: 81.90%, m/z=234.0 (M+1)
Final Step: Synthesis of
3-Benzothiazol-6-yl-4-methyl-1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
(203A)
1-Benzothiazol-6-yl-5-methyl-imidazolidin-2-one (I-203b: 150 mg,
0.644 mmol) was reacted with 3-iodo-4-methyl-pyridine (140.99 mg,
0.644 mmol), 1,4-dioxane (10 mL), copper iodide (12.27 mg, 0.0644
mmol), trans-1,2-diamino cyclohexane (27.43 mg, 0.193 mmol) and
potassium phosphate (341 mg, 1.61 mmol) to afford the crude
product. Purification by column chromatography on silica gel (1.5%
MeOH in DCM) afforded 50 mg of the product (24.15% yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 8.95 (s, 1H), 8.55 (s,
1H), 8.43 (d, 1H), 8.26 (d, 1H), 8.15 (d, 1H), 7.55 (dd, 1H), 7.25
(d, 1H), 4.7-4.6 (m, 1H), 4.2-4.1 (m, 1H), 3.6-3.5 (m, 1H), 2.4 (s,
3H), 1.5 (d, 3H)
LCMS purity: 95.66%, m/z=325.0 (M+1)
HPLC: 96.32%
Pharmacological Testing
The abbreviations listed below and used in the preparations below
have the corresponding meanings.
TABLE-US-00002 CYP Cytochrome P450 CPM Counts per minute Cyt b5
Cytochrome b5 DMSO Dimethyl sulfoxide DHEA Dehydroepiandrosterone
NADPH Nicotinamide adenine dinucleotide phosphate
Human and Rat-Cytochrome P450, 17-20 Lyase
1) Cytochrome P450, 17-20 lyase (CYP17-lyase) assay development
using recombinant human CYP17 enzyme and 17-.alpha.-hydroxy
pregnenolone [21-3H] as the substrate.
Cytochrome P450,17-.alpha.-Hydroxylase, 17-20 lyase (CYP17) is a
multi functional enzyme that plays a key role in the biosynthesis
of steroid hormones. It catalyses both conventional hydroxylation
and also the carbon-carbon bond cleavage reactions (Peter
Lee-Robichaud et al, Biochem. J, (1997) 321, 857-63). In the
hydroxylation reaction, it converts progesterone and pregnenolone
to the corresponding hydroxylated products 17-.alpha.-hydroxy
progesterone and 17-.alpha.-hydroxy pregnenolone. In the lyase
reaction, it catalyzes the conversion of these hydroxylated
substrates to Androstenedione and Dehydroepiandrosterone (DHEA)
respectively. In the Cyp17 lyase assay described here, the
conversion of 17-.alpha.-hydroxy pregnenolone to
Dehydroepiandrosterone and acetic acid is being monitored.
The hydroxylation and cleavage activities are catalyzed
sequentially at the common active site of Cyp17 and proceed through
transfer of two electrons from NADPH via its redox partner,
cytochrome P450 reductase (CPR). The reaction mechanism for each
activity is thought to involve formation of distinct iron-oxygen
complexes. Cytochromeb5 selectively stimulates the lyase activity
and has no significant effect on its hydroxylase activity. Lyase
activity is stimulated by cytochrome b5 up to 10-fold in
reconstituted assays with insignificant stimulation of the
hydroxylase activity (M K Akthar et al, Journal of Endocrinology
(2005) 187, 267-274 and Katagiri M et al, Biophysical Research
Communications (1982) 108, 379-384).
Assay method was adopted from a published protocol with some
modifications to suit our requirements (Dmitry N Grigoryev et al,
Analytical Biochemistry, (1999) 267, 319-330). The conversion of
17-.alpha.-hydroxy pregnenolone to Dehydroepiandrosterone is
accompanied by the release of acetic acid. In the Cyp17 lyase
assay, 17-.alpha.-hydroxy pregnenolone labeled with tritium (3H) at
position 21 is used as the substrate. Chloroform extraction removes
the radioactive steroids and acetic acid is taken into aqueous
layer. The tritiated acetic acid released in the assay thus
extracted is quantified to determine the enzyme activity.
Initial buffer conditions were, 50 mM Phosphate buffer, pH 7.5 was
used as the starting buffer for Cyp17 lyase activity based on the
data published in U.S. patent publication No. US2004/0198773 A1.
This buffer was found to be suitable for regular Cyp17 lyase assay.
Human Cyp 17 gene was cloned and expressed in Adenoviral expression
system in A549 cell lines. The purified cell membrane preparations
were used as the source for Human CYP17 enzyme. Total protein
concentration: 8 mg/mL. To identify the appropriate concentration
of the enzyme required for the assay, concentration dependent
enzyme activity was determined at a substrate
(17-.alpha.-hydroxypregnenolone [21-3H]) concentration of 0.5 .mu.M
(Vincent C. O, Nijar, et al., J Med Chem, (1998) 41, 902-912). The
protein activity was found to be in the linear range up to 20
.mu.g, the highest concentration tested. Based on the enzyme
concentration curve and stock concentration, 15 .mu.g was selected
for the assay. At this protein concentration, the S/N ratio was 30,
with a good signal window (CPM.sub.Pos.Ctrl-CPM.sub.Blank=1650)
K.sub.m (Michaelis Menton constant) is a measure of the binding
affinity of substrate to the enzyme. 17-.alpha.-hydroxy
pregnenolone [21-3H] is a substrate for 17, 20 lyase enzyme.
K.sub.m for this substrate was determined by monitoring the
tritiated acetic acid release as a function of substrate
concentration. Concentration of 17-.alpha.-hydroxy-pregnenolone
[21-3H] was varied from 0.03125 .mu.M to 1 .mu.M. For the K.sub.m
determination, the data was fit to a hyperbolic equation (Graphpad
Prism.RTM. software IV). The K.sub.m was estimated as 0.25 .mu.M,
close to the reported value. (Dmitry N. Grigoryev et al, Analytical
Biochemistry (1999) 267, 319-330)
For routine screening, the assay was set up with 16 .mu.g of enzyme
in 50 .mu.L reaction volume. 17.alpha.-hydroxy pregnenolone [21-3H]
was added to a final concentration of 0.25 .mu.M. NADPH is used at
a final concentration of 4.2 mM. Total reaction volume was made up
to 50 .mu.L with 50 mM Phosphate buffer pH 7.5. The reaction
mixture was incubated at room temperature for 90 minutes with
gentle shaking. The reaction was stopped by the addition of 100
.mu.L of buffer. 500 .mu.L of 5% freshly prepared activated
charcoal was added to the solution and mixed well by vortexing. The
samples were centrifuged at 17568.times.g for 5 minutes. (14000
rpm). The supernatant was carefully transferred to fresh tube and
1.3 mL of scintillation fluid was added, mixed by vortexing.
The radioactivity was measured in a 1450 MicroBeta TriLux.TM.
scintillation counter from Wallac-Perkin Elmer.RTM., USA. The
measurements were carried out in 2.0 mL Eppendorforf.TM. tubes.
Each tube was counted for 1 minute. The amount of tritiated acetic
acid released is proportional to the lyase activity. Percent lyase
activity in presence of inhibitor was calculated using the formula
given below.
.times..times. ##EQU00001## Sample: Enzyme reaction in presence of
inhibitor. Positive control: Enzyme reaction without inhibitor but
containing DMSO at 1% final concentration. Blank-Contains all
reagents except enzyme. % Inhibition=100%-% Lyase activity
For IC.sub.50 determination, the % inhibition was plotted as a
function of inhibitor concentration. The data was fitted to
sigmoidal equation using Graphpad Prism.RTM. software IV to
generate IC.sub.50 values.
Dose-response studies by standard compounds Abiraterone and
Ketoconazole were carried out as part of assay optimization.
For the rat CYP 17 Lyase Model:
The same procedure described above was used but using rat testes
microsomes as the source and with a substrate concentration of 0.5
.mu.M.
The results for the compounds tested from the Examples above using
the assay above are listed in Table 1 below.
TABLE-US-00003 TABLE 1 rCYP17 Lyase IC 50 Lyase Example nM % Inh @
No. Final compounds Human/Rat 100 nM 1A
1-Naphthalen-2-yl-3-pyridin-3- 34 nM/35 nM 84%
yl-imidazolidin-2-one 2A 1-(1-Ethyl-1H-indol-5-yl)-3- --/-- 23%
pyridin-3-yl-imidazolidin-2-one 3A 1-(6-Methoxy-naphthalen-2-yl)-
--/-- 31% 3-pyridin-3-yl-imidazolidin-2- one 4A
1-Benzothiazol-6-yl-3-pyridin-3- 77 nM/-- 59% yl-imidazolidin-2-one
5A 1-Ethyl-6-(2-oxo-3-pyridin-3-yl- --/-- 51%
imidazolidin-1-yl)-3,4-dihydro- 1H-quinolin-2-one 6A
1-(5-Fluoro-3-methyl- --/157 nM 51% benzo[b]thiophen-2-yl)-3-
pyridin-3-yl-imidazolidin-2-one 7A 1-Benzo[b]thiophen-5-yl-3- --/16
nM 87% pyridin-3-yl-imidazolidin-2-one 8A
1-Pyridin-3-yl-3-quinolin-6-yl- --/-- 48% imidazolidin-2-one 9A
1-Benzothiazol-5-yl-3-pyridin-3- --/-- 18% yl-imidazolidin-2-one
10A 1-Naphthalen-2-yl-3-pyridin-3- --/-- 11%
yl-tetrahydro-pyrimidin-2-one 11A 1-(2-Chloro-4-methyl-quinolin-
--/97 nM 59% 6-yl)-3-pyridin-3-yl- imidazolidin-2-one 12A
1-(1-Hydroxyimino-indan-5-yl)- --/-- 17%
3-pyridin-3-yl-imidazolidin-2- one 13A 1-Benzo[b]thiophen-5-yl-3-
--/-- 9% pyridin-3-yl-tetrahydro- pyrimidin-2-one 14A
1-(4-Methyl-pyridin-3-yl)-3- 17 nM/2 nM 102%
naphthalen-2-yl-imidazolidin-2- one 15A
1-(4-Methyl-pyridin-3-yl)-3-(5- 10 nM/-- -- methyl-thiophen-2-yl)-
imidazolidin-2-one 16A 1-Benzothiazol-6-yl-3-(4- 6 nM/5 nM 94%
methyl-pyridin-3-yl)- imidazolidin-2-one 17A
1-Ethyl-6-[3-(4-methyl-pyridin- --/21 nM 83%
3-yl)-2-oxo-imidazolidin-1-yl]- 3,4-dihydro-1H-quinolin-2-one 18A
1-(4-Fluoro-phenyl)-3-(4- 76 nM/12 nM 88% methyl-pyridin-3-yl)-
imidazolidin-2-one 19A 1-Biphenyl-4-yl-3-(4-methyl- --/11 nM 91%
pyridin-3-yl)-imidazolidin-2-one 20A 1-Ethyl-4-methyl-6-[3-(4-
--/56 nM 69% methyl-pyridin-3-yl)-2-oxo-
imidazolidin-1-yl]-1H-quinolin- 2-one 21A
1-(2-Chloro-4-methyl-quinolin- --/5 nM 98%
6-yl)-3-(4-methyl-pyridin-3-yl)- imidazolidin-2-one 22A
4-Methyl-6-[3-(4-methyl- --/24 nM 85% pyridin-3-yl)-2-oxo-
imidazolidin-1-yl]-1H-quinolin- 2-one 23A
1-(4-Methyl-pyridin-3-yl)-3- --/20 nM 85%
quinolin-2-yl-imidazolidin-2-one 24A 1-(4-Methyl-pyridin-3-yl)-3-
72 nM/-- 98% quinolin-3-yl-imidazolidin-2-one 25A
1-(6-Methoxy-naphthalen-2-yl)- --/-- 89% 3-(4-methyl-pyridin-3-yl)-
imidazolidin-2-one 26A 1-Benzo[b]thiophen-2-yl-3-(4- 15 nM/-- 100%
methyl-pyridin-3-yl)- imidazolidin-2-one 27A
1-Benzo[b]thiophen-5-yl-3-(4- 24 nM/-- 101% methyl-pyridin-3-yl)-
imidazolidin-2-one 28A 1-(1H-Indazol-5-yl)-3-(4- 4 nM/52 nM 61%
methyl-pyridin-3-yl)- imidazolidin-2-one 29A
1-(3-Methyl-benzofuran-5-yl)-3- 3 nM/-- 98%
(4-methyl-pyridin-3-yl)- imidazolidin-2-one 30A
1-(6-Fluoro-pyridin-3-yl)-3-(4- --/-- 76% methyl-pyridin-3-yl)-
imidazolidin-2-one 31A 1-(4-Methyl-pyridin-3-yl)-3- 108 nM/-- 74%
thiophen-3-yl-imidazolidin-2- one 32A 1-(5-Methoxy-pyridin-3-yl)-3-
--/-- 73% (4-methyl-pyridin-3-yl)- imidazolidin-2-one 33A
1-(5-Fluoro-3-methyl- --/-- -- benzo[b]thiophen-2-yl)-3-(4-
methyl-pyridin-3-yl)- imidazolidin-2-one 34A
1-(2-Chloro-pyrimidin-5-yl)-3- --/-- -- (4-methyl-pyridin-3-yl)-
imidazolidin-2-one 35A 1-(4-Methyl-pyridin-3-yl)-3- --/-- --
(1H-pyrazol-4-yl)-imidazolidin- 2-one 36A
1-(4-Methyl-pyridin-3-yl)-3- --/-- --
thiazol-2-yl-imidazolidin-2-one 37A 1-(4-Methoxy-phenyl)-3-(4-
--/-- -- methyl-pyridin-3-yl)- imidazolidin-2-one 38A
1-(4-Chloro-phenyl)-3-(4- 70 nM/-- -- methyl-pyridin-3-yl)-
imidazolidin-2-one 39A 4-[3-(4-Methyl-pyridin-3-yl)-2- --/-- --
oxo-imidazolidin-1-yl]- benzonitrile 40A 1-Benzooxazol-2-yl-3-(4-
--/-- -- methyl-pyridin-3-yl)- imidazolidin-2-one 41A
1-(5-Chloro-thiophen-2-yl)-3-(4- 10 nM/3 nM --
methyl-pyridin-3-yl)- imidazolidin-2-one 42A
1-(4-Methyl-pyridin-3-yl)-3- --/-- -- thiophen-2-yl-imidazolidin-2-
one 43A 1-(6-Hydroxy-pyridin-3-yl)-3-(4- --/-- --
methyl-pyridin-3-yl)- imidazolidin-2-one 44A
N-Methyl-4-[3-(4-methyl- --/-- -- pyridin-3-yl)-2-oxo-
imidazolidin-1-yl]-benzamide 45A 1-(3,4-Difluoro-phenyl)-3-(4- 27
nM/-- -- methyl-pyridin-3-yl)- imidazolidin-2-one 46A
1-(3-Chloro-4-fluoro-phenyl)-3- 10 nM/-- --
(4-methyl-pyridin-3-yl)- imidazolidin-2-one 47A
1-Benzothiazol-2-yl-3-(4- --/-- -- methyl-pyridin-3-yl)-
imidazolidin-2-one 48A 1-(1H-Indol-5-yl)-3-(4-methyl- --/-- --
pyridin-3-yl)-imidazolidin-2-one 49A 1-(2,3-Dihydro- 30 nM/-- --
benzo[1,4]dioxin-6-yl)-3-(4- methyl-pyridin-3-yl)-
imidazolidin-2-one 50A 1-(4-Methyl-pyridin-3-yl)-3-(4- 51 nM/-- --
trifluoromethyl-phenyl)- imidazolidin-2-one 51A
1-(2,3-Dihydro-benzofuran-5- 14 nM/-- --
yl)-3-(4-methyl-pyridin-3-yl)- imidazolidin-2-one 52A
1-(4-Methyl-pyridin-3-yl)-3- 96 nM/5 nM 97%
quinolin-6-yl-imidazolidin-2-one 53A 1-(3-Fluoro-4-methoxy-phenyl)-
136 nM/-- -- 3-(4-methyl-pyridin-3-yl)- imidazolidin-2-one 54A
1-(4-Chloro-3-fluoro-phenyl)-3- 15 nM/-- --
(4-methyl-pyridin-3-yl)- imidazolidin-2-one 55A
1-(4-Methyl-pyridin-3-yl)-3-m- 9 nM/7 nM --
tolyl-imidazolidin-2-one 56A 1-(3-Methoxy-phenyl)-3-(4- 25 nM/-- --
methyl-pyridin-3-yl)- imidazolidin-2-one 57A
1-(4-Methyl-pyridin-3-yl)-3- --/-- --
(4,5,6,7-tetrahydro-thieno[2,3- c]pyridin-2-yl)-imidazolidin-2- one
58A 1-(2-Chloro-pyridin-4-yl)-3-(4- 27 nM/-- --
methyl-pyridin-3-yl)- imidazolidin-2-one 59A
1-(4-Fluoro-3-methyl-phenyl)-3- 17 nM/-- --
(4-methyl-pyridin-3-yl)- imidazolidin-2-one 60A
1-(5-Chloro-2-fluoro-phenyl)-3- --/-- -- (4-methyl-pyridin-3-yl)-
imidazolidin-2-one 61A 1-(2,4-Difluoro-phenyl)-3-(4- --/-- --
methyl-pyridin-3-yl)- imidazolidin-2-one 62A
1-Benzothiazol-5-yl-3-(4- 426 nM/-- -- methyl-pyridin-3-yl)-
imidazolidin-2-one 63A 6-[3-(4-Methyl-pyridin-3-yl)-2- --/-- --
oxo-imidazolidin-1-yl]-3,4- dihydro-1H-quinolin-2-one 64A
1-(2,2-Difluoro- 35 nM/-- -- benzo[1,3]dioxol-5-yl)-3-(4-
methyl-pyridin-3-yl)- imidazolidin-2-one 65A
7-[3-(4-Methyl-pyridin-3-yl)-2- --/-- --
oxo-imidazolidin-1-yl]-3,4- dihydro-1H-quinolin-2-one 66A
N-{3-[3-(4-Methyl-pyridin-3- --/-- -- yl)-2-oxo-imidazolidin-1-yl]-
phenyl}-acetamide 67A 1-(4-Methyl-pyridin-3-yl)-3-(3- --/-- --
methyl-thiophen-2-yl)- imidazolidin-2-one 68A
1-(4-Methyl-pyridin-3-yl)-3-(2- --/-- -- methyl-quinolin-6-yl)-
imidazolidin-2-one 69A 1-(4-Methyl-pyridin-3-yl)-3- 34 nM/-- --
phenyl-imidazolidin-2-one 70A 1-(4-Methyl-pyridin-3-yl)-3-(3- 6.5
nM/2 nM -- trifluoromethyl-phenyl)- imidazolidin-2-one 71A
1-(1-Isopropyl-1H-pyrazol-4-yl)- --/-- --
3-(4-methyl-pyridin-3-yl)- imidazolidin-2-one 72A
1-(2-Methoxy-pyridin-4-yl)-3- 9.4 nM/10 nM --
(4-methyl-pyridin-3-yl)- imidazolidin-2-one 73A
1-Imidazo[1,2-a]pyridin-7-yl-3- 109 nM/-- --
(4-methyl-pyridin-3-yl)- imidazolidin-2-one 74A
1-(4-Fluoro-3-methoxy-phenyl)- 76 nM/-- --
3-(4-methyl-pyridin-3-yl)- imidazolidin-2-one 75A
N-{5-[3-(4-Methyl-pyridin-3- >10 .mu.M --
yl)-2-oxo-imidazolidin-1-yl]- pyridin-2-yl}-acetamide 76A
1-(2-Amino-pyridin-4-yl)-3-(4- 192 nM/-- -- methyl-pyridin-3-yl)-
imidazolidin-2-one 77A 1-(4-Methyl-pyridin-3-yl)-3- 195 nM/-- --
quinoxalin-6-yl-imidazolidin-2- one 78A
1-(5-Difluoromethyl-thiophen-3- 9.3 nM/-- --
yl)-3-(4-methyl-pyridin-3-yl)- imidazolidin-2-one, trifluoro-
acetic acid 79A 1-Naphthalen-2-yl-3-(5- --/-- 3.6%
trifluoromethyl-pyridin-3-yl)- imidazolidin-2-one 80A
1-(5-Chloro-pyridin-3-yl)-3- --/-- 57%
naphthalen-2-yl-imidazolidin-2- one 81A
1-(5-Fluoro-pyridin-3-yl)-3- --/-- 82%
naphthalen-2-yl-imidazolidin-2- one 82A
1-(5-Methoxy-pyridin-3-yl)-3- --/-- --
naphthalen-2-yl-imidazolidin-2- one 83A 5-(3-Naphthalen-2-yl-2-oxo-
--/-- -- imidazolidin-1-yl)-nicotinic acid methyl ester 84A
1-Benzothiazol-6-yl-3-(4-chloro- 85 nM/-- --
pyridin-3-yl)-imidazolidin-2-one
85A 1-(4-Methyl-pyridin-3-yl)-3-(2- 1,263 nM/-- --
pyrrolidin-1-yl-pyridin-4-yl)- imidazolidin-2-one 86A
1-(3-Chloro-2-fluoro-phenyl)-3- 1,200 nM/-- --
(4-methyl-pyridin-3-yl)- imidazolidin-2-one 87A
1-(4'-Fluoro-biphenyl-4-yl)-3-(4- 255 nM/-- --
methyl-pyridin-3-yl)- imidazolidin-2-one 88A
1-(3-Chloro-phenyl)-3-(4- 12 nM/-- -- methyl-pyridin-3-yl)-
imidazolidin-2-one 89A 1-(4-Chloro-2-methyl-phenyl)-3- 326 nM/-- --
(4-methyl-pyridin-3-yl)- imidazolidin-2-one 90A
1-(4-Fluoro-3-trifluoromethyl- 5 nM/-- --
phenyl)-3-(4-methyl-pyridin-3- yl)-imidazolidin-2-one 91A
1-(3-Difluoromethyl-4-fluoro- 4.3 nM/-- --
phenyl)-3-(4-methyl-pyridin-3- yl)-imidazolidin-2-one 91B
1-(3-Difluoromethyl-4-fluoro- 22 nM/-- --
phenyl)-3-(4-methyl-pyridin-3- yl)-1,3-dihydro-imidazol-2-one 92A
1-(4-Methyl-pyridin-3-yl)-3-(5- 21 nM/-- --
methyl-thiophen-3-yl)-1,3- dihydro-imidazol-2-one 92B
1-(4-Methyl-pyridin-3-yl)-3-(5- 12 nM/-- -- methyl-thiophen-3-yl)-
imidazolidin-2-one 93A 1-(2-Methyl-benzooxazol-5-yl)- >10
.mu.M/-- -- 3-(4-methyl-pyridin-3-yl)- imidazolidin-2-one 94A
1-Imidazo[1,2-a]pyridin-6-yl-3- 110 nM/-- --
(4-methyl-pyridin-3-yl)- imidazolidin-2-one 95A
1-(3-Methyl-1H-indazol-5-yl)-3- 119 nM/-- --
(4-methyl-pyridin-3-yl)- imidazolidin-2-one 96A
N-{4-[3-(4-Methyl-pyridin-3- >10 .mu.M/-- --
yl)-2-oxo-imidazolidin-1-yl]- pyridin-2-yl}-acetamide 97A
1-(4-Methoxy-thieno[3,2- 356 nM/-- -- c]pyridin-2-yl)-3-(4-methyl-
pyridin-3-yl)-imidazolidin-2-one 98A 1-(4-Chloro-thieno[3,2- 18
nM/-- -- c]pyridin-2-yl)-3-(4-methyl-
pyridin-3-yl)-imidazolidin-2-one 99A 1-(4-Chloro-thieno[3,2- 22
nM/-- -- c]pyridin-3-yl)-3-(4-methyl-
pyridin-3-yl)-imidazolidin-2-one 100A
1-(4-Methyl-pyridin-3-yl)-3-(2- 46 nM/-- -- methyl-pyridin-4-yl)-
imidazolidin-2-one 101A 1-(3-Methyl-benzo[d]isoxazol-5- 46 nM/-- --
yl)-3-(4-methyl-pyridin-3-yl)- imidazolidin-2-one 102A
1-(3-Methyl-1H-indazol-6-yl)-3- 7.5 nM/5 nM --
(4-methyl-pyridin-3-yl)- imidazolidin-2-one, trifluoroacetic acid
103A 2-Fluoro-5-[3-(4-methyl-pyridin- 19 nM/-- --
3-yl)-2-oxo-imidazolidin-1-yl]- benzonitrile 104A
1-(2-Methyl-imidazo[1,2- 1,991 nM/-- --
a]pyridin-6-yl)-3-(4-methyl- pyridin-3-yl)-imidazolidin-2-one 105A
1-(2-Methyl-benzothiazol-6-yl)- 1,469 nM/-- --
3-(4-methyl-pyridin-3-yl)- imidazolidin-2-one 106A
3-[3-(4-Methyl-pyridin-3-yl)-2- 35 nM/-- -- oxo-imidazolidin-1-yl]-
benzonitrile, trifluoroacetic acid 107A
1-(1H-Indol-3-yl)-3-(4-methyl- 334 nM/-- --
pyridin-3-yl)-imidazolidin-2-one 108A
1-(1H-Benzoimidazol-5-yl)-3-(4- 363 nM/-- -- methyl-pyridin-3-yl)-
imidazolidin-2-one 109A 1-Benzo[b]thiophen-3-yl-3-(4- 158 nM/-- --
methyl-pyridin-3-yl)- imidazolidin-2-one 110A
1-(4-Methoxy-thieno[3,2- >10 .mu.M/-- --
c]pyridin-3-yl)-3-(4-methyl- pyridin-3-yl)-imidazolidin-2-one 111A
1-(3-Methyl-benzo[d]isoxazol-6- 106 nM/-- --
yl)-3-(4-methyl-pyridin-3-yl)- imidazolidin-2-one 112A
2-Chloro-4-[3-(4-methyl- 28 nM/-- -- pyridin-3-yl)-2-oxo-
imidazolidin-1-yl]-benzonitrile 113A 1-Benzo[d]isoxazol-5-yl-3-(4-
230 nM/-- -- methyl-pyridin-3-yl)- imidazolidin-2-one 114A
1-(1-Methyl-1H-indazol-5-yl)-3- 24 nM/-- --
(4-methyl-pyridin-3-yl)- imidazolidin-2-one 115A
1-(1-Methyl-1H-indol-3-yl)-3- 173 nM/-- -- (4-methyl-pyridin-3-yl)-
imidazolidin-2-one, trifluoroacetic acid 116A
1-(1-Methyl-1H-benzoimidazol- >10 .mu.M/-- --
5-yl)-3-(4-methyl-pyridin-3-yl)- imidazolidin-2-one,
trifluoroacetic acid 117A 5-[3-(4-Methyl-pyridin-3-yl)-2- 94 nM/--
-- oxo-imidazolidin-1-yl]-1,2- dihydro-indazol-3-one 118A
1-(3-Amino-1H-indazol-5-yl)-3- 17 nM/-- -- (4-methyl-pyridin-3-yl)-
imidazolidin-2-one 119A 1-Imidazo[1,2-a]pyridin-3-yl-3- 3,198 nM/--
-- (4-methyl-pyridin-3-yl)- imidazolidin-2-one 120A
1-(4-Methyl-pyridin-3-yl)-3- 4 .mu.M/-- --
thieno[3,2-c]pyridin-2-yl- imidazolidin-2-one 121A
1-(1H-Indazol-6-yl)-3-(4- 2.5 nM/-- -- methyl-pyridin-3-yl)-
imidazolidin-2-one 122A 1-(3H-Imidazo[4,5-b]pyridin-6- 383 nM/-- --
yl)-3-(4-methyl-pyridin-3-yl)- imidazolidin-2-one, trifluoroacetic
acid 123A 1-(3-Amino-1H-indazol-6-yl)-3- 10 nM/-- --
(4-methyl-pyridin-3-yl)- imidazolidin-2-one 124A
1-Benzothiazol-6-yl-3-(4- 23 nM/12 nM -- methoxy-pyridin-3-yl)-
imidazolidin-2-one 125A 1-Benzothiazol-6-yl-3-(4- 17 nM/-- --
difluoromethyl-pyridin-3-yl)- imidazolidin-2-one 126A
1-Benzothiazol-6-yl-3-(4- 25 nM/-- -- hydroxymethyl-pyridin-3-yl)-
imidazolidin-2-one 127A 1-Benzothiazol-6-yl-3-(6- >10 .mu.M/--
-- methyl-pyridin-3-yl)- imidazolidin-2-one 128A
1-Benzothiazol-6-yl-3-(4- 44 nM/-- --
trifluoromethyl-pyridin-3-yl)- imidazolidin-2-one 129A
3-(3-Benzothiazol-6-yl-2-oxo- 202 nM/-- -- imidazolidin-1-yl)-
isonicotinonitrile 130A 1-(4-Methyl-pyridin-3-yl)-3- >10
.mu.M/-- -- naphthalen-2-yl-imidazolidin-2- one 131A
1-m-Tolyl-3-(4-trifluoromethyl- 103 nM/-- --
pyridin-3-yl)-imidazolidin-2-one 132A
1-(2-Methyl-2H-indazol-5-yl)-3- >10 .mu.M --
(4-methyl-pyridin-3-yl)- imidazolidin-2-one 133A
1-(4-Methyl-pyridin-3-yl)-3- 1,970 nM/-- --
naphthalen-1-yl-imidazolidin-2- one 134A
1-(1-Methyl-1H-indol-5-yl)-3- 950 nM/-- -- (4-methyl-pyridin-3-yl)-
imidazolidin-2-one 135A 6-[3-(4-Methyl-pyridin-3-yl)-2- 15.9 nM/--
-- oxo-imidazolidin-1-yl]-1,2- dihydro-indazol-3-one 136A
1-(4-Methyl-pyridin-3-yl)-3- 500 nM/-- --
thieno[3,2-c]pyridin-3-yl- imidazolidin-2-one 137A
1-(5-Chloro-1-methyl-1H-indol- 1,554 nM/-- --
3-yl)-3-(4-methyl-pyridin-3-yl)- imidazolidin-2-one 138A
1-Indan-5-yl-3-(4-methyl- 13 nM/-- --
pyridin-3-yl)-imidazolidin-2-one 139A 1-Benzo[b]thiophen-5-yl-3-(4-
83 nM/-- -- methyl-pyridin-3-yl)-1,3- dihydro-imidazol-2-one 140A
2-Fluoro-4-[3-(4-methyl-pyridin- 97 nM/-- --
3-yl)-2-oxo-imidazolidin-1-yl]- benzonitrile 141A
1-(1H-Benzotriazol-5-yl)-3-(4- 13 nM/-- -- methyl-pyridin-3-yl)-
imidazolidin-2-one, hydrochloride 142A 1-Benzothiazol-6-yl-3-(4- 21
nM/-- -- methyl-pyridin-3-yl)-1,3- dihydro-imidazol-2-one 143A
1-(3-Amino-1-methyl-1H- 116 nM/-- -- indazol-6-yl)-3-(4-methyl-
pyridin-3-yl)-imidazolidin-2-one 144A
1-(1H-Indol-6-yl)-3-(4-methyl- 174 nM/-- --
pyridin-3-yl)-imidazolidin-2-one 145A 1-(3-Chloro-imidazo[1,2- 31
nM/-- -- a]pyridin-7-yl)-3-(4-methyl-
pyridin-3-yl)-imidazolidin-2-one 146A 1-Methyl-3-[3-(4-methyl-
>10 .mu.M -- pyridin-3-yl)-2-oxo-
imidazolidin-1-yl]-1H-indole-4- carbonitrile 147A
1-Hydroxymethyl-3,3-dimethyl- 346 nM/-- --
5-[3-(4-methyl-pyridin-3-yl)-2- oxo-imidazolidin-1-yl]-1,3-
dihydro-indol-2-one 148A 1-(4-Methyl-pyridin-3-yl)-3-(2- 25 nM/--
-- trifluoromethyl-pyridin-4-yl)- imidazolidin-2-one 149A
1-Benzothiazol-6-yl-3-(4- 37 nM/-- --
dimethoxymethyl-pyridin-3-yl)- imidazolidin-2-one 150A
N-[3-(3-Benzothiazol-6-yl-2- 496 nM/-- --
oxo-imidazolidin-1-yl)-pyridin- 4-yl]-acetamide 151A
1-Benzothiazol-6-yl-3-(5-chloro- 13.3 nM/-- --
4-methyl-pyridin-3-yl)- imidazolidin-2-one 152A
1-(4-Amino-pyridin-3-yl)-3- 7 nM/-- --
benzothiazol-6-yl-imidazolidin- 2-one hydrochloride 153A
1-(benzo[d]thiazol-6-yl)-3-(4- 280 nM -- methyl-5-
(trifluoromethyl)pyridin-3- yl)imidazolidin-2-one, trifluoroacetic
acid salt 154A 1-(isothiazol-4-yl)-3-(4- 89 nM --
methylpyridin-3-yl)imidazolidin- 2-one 155A
1-(4-methylpyridin-3-yl)-3-(5- 2.7 nM --
(trifluoromethyl)thiophen-2- yl)imidazolidin-2-one 156A
1-(benzo[d]thiazol-6-yl)-3-(4-(2- >10 .mu.M --
hydroxypropan-2-yl)pyridin-3- yl)imidazolidin-2-one 157A
1-(4-methylpyridin-3-yl)-3-(4- 21 nM --
methylthieno[3,2-c]pyridin-2- yl)imidazolidin-2-one 158A
1-(benzo[d]thiazol-6-yl)-3-(4-(1- 38 nM -- hydroxyethyl)pyridin-3-
yl)imidazolidin-2-one 159A 1-(benzo[d]thiazol-6-yl)-3-(4- 3.4 nM --
ethylpyridin-3-yl)imidazolidin-2- one 160A
1-(4-methylpyridin-3-yl)-3-(3- 34 nM --
(trifluoromethyl)-1H-indazol-6- yl)imidazolidin-2-one 161A
1-(3-cyclopropyl-1H-indazol-6- 82 nM -- yl)-3-(4-methylpyridin-3-
yl)imidazolidin-2-one 162A 1-(4-methylpyridin-3-yl)-3- 317 nM --
(quinolin-7-yl)imidazolidin-2- one 163A 3-Benzothiazol-6-yl-4,4-
>10 .mu.M -- dimethyl-1-(4-methyl-pyridin-3-
yl)-imidazolidin-2-one 164A 1-Benzothiazol-6-yl-4,4- 70 nM/-- --
dimethyl-3-pyridin-3-yl- imidazolidin-2-one
165A 1-Benzothiazol-6-yl-4,4- 1,153 nM/-- --
dimethyl-3-(4-methyl-pyridin-3- yl)-imidazolidin-2-one 166A
3-Benzothiazol-6-yl-4-methyl-1- 32 nM/-- --
(4-methyl-pyridin-3-yl)- imidazolidin-2-one 167A
1-Benzothiazol-6-yl-4-methyl-3- 38 nM/-- --
(4-methyl-pyridin-3-yl)- imidazolidin-2-one 168A
1-Benzothiazol-6-yl-4-ethyl-3- 384 nM/-- --
(4-methyl-pyridin-3-yl)-1,3- dihydro-imidazol-2-one 169A
1-Benzothiazol-6-yl-4-ethyl-3- --/-- -- pyridin-3-yl-1,3-dihydro-
imidazol-2-one 170A 1-Benzothiazol-6-yl-3-pyridin-3- --/-- --
yl-4-trifluoromethyl- imidazolidin-2-one 171A
1-Benzothiazol-6-yl-3-(4- --/-- -- methyl-pyridin-3-yl)-1,3-
dihydro-benzoimidazol-2-one 172A 1-Benzothiazol-6-yl-4-methyl-3-
326 nM/-- -- (4-methyl-pyridin-3-yl)- imidazolidin-2-one 173A
3-Benzothiazol-6-yl-1-pyridin-3- --/-- -- yl-4-trifluoromethyl-
imidazolidin-2-one 174A 1-Benzothiazol-6-yl-3-(4- --/-- --
methyl-pyridin-3-yl)-4- trifluoromethyl-imidazolidin-2- one 175A
1-Benzothiazol-6-yl-4,5- 85 nM/-- --
dimethyl-3-(4-methyl-pyridin-3- yl)-imidazolidin-2-one 176A
1-Benzothiazol-6-yl-3-(4- 39 nM/-- --
pyrrolidin-1-ylmethyl-pyridin-3- yl)-imidazolidin-2-one 177A
1-Benzothiazol-6-yl-3-(4- 32 nM/-- --
morpholin-4-ylmethyl-pyridin-3- yl)-imidazolidin-2-one 178A
1-Benzothiazol-6-yl-3-(4- 19 nM/-- -- cyclopropylaminomethyl-
pyridin-3-yl)-imidazolidin-2-one 179A
1-Benzothiazol-6-yl-3-(6-fluoro- --/-- -- 4-methyl-pyridin-3-yl)-
imidazolidin-2-one 180A 1-Benzothiazol-6-yl-3-[4-(2- --/-- --
morpholin-4-yl-ethoxy)-pyridin- 3-yl]-imidazolidin-2-one 181A
1-Benzothiazol-6-yl-3-[4-(1- 3064 nM/-- --
methyl-pyrrolidin-2-ylmethoxy)- pyridin-3-yl]-imidazolidin-2-one
182A 1-Benzothiazol-6-yl-3-{4-[(5- 27 nM/-- --
methyl-1H-pyrazol-3-ylamino)- methyl]-pyridin-3-yl}-
imidazolidin-2-one 183A 1-Benzothiazol-6-yl-3-(3H- >10 .mu.M/--
-- imidazo[4,5-b]pyridin-6-yl)- imidazolidin-2-one 184A
1-Benzothiazol-6-yl-3-[4-(1- >10 .mu.M/-- --
methyl-piperidin-4-ylmethoxy)- pyridin-3-yl]-imidazolidin-2-one
185A 3-(3-Benzothiazol-6-yl-2-oxo- >10 .mu.M/-- --
imidazolidin-1-yl)- isonicotinamide 186A 1-Benzothiazol-6-yl-3-
>10 .mu.M/-- -- imidazo[1,2-a]pyrazin-5-yl- imidazolidin-2-one
187A 1-Benzothiazol-6-yl-3-(1H- >10 .mu.M/-- --
pyrrolo[2,3-b]pyridin-5-yl)- imidazolidin-2-one 188A
3-Benzothiazol-6-yl-3'-methyl- 195 nM/-- -- 4,5-dihydro-3H,3'H-
[1,4']biimidazolyl-2-one 189A 1-Benzothiazol-6-yl-3-(4- 280 nM/--
-- methyl-5-trifluoromethyl- pyridin-3-yl)-imidazolidin-2-one
trifluoro-acetic acid 190A 1-Isothiazol-4-yl-3-(4-methyl- 89 nM/--
-- pyridin-3-yl)-imidazolidin-2-one 191A
1-Benzothiazol-6-yl-3-pyridin-2- >10 .mu.M/-- --
yl-imidazolidin-2-one 192A 1-(4-Methyl-pyridin-3-yl)-3-(5- 2.7
nM/-- -- trifluoromethyl-thiophen-2-yl)- imidazolidin-2-one 193A
1-Benzothiazol-6-yl-3-[4-(1- >10 .mu.M/-- --
hydroxy-1-methyl-ethyl)- pyridin-3-yl]-imidazolidin-2-one 194A
1-(4-Methyl-pyridin-3-yl)-3-(4- 21 nM/-- --
methyl-thieno[3,2-c]pyridin-2- yl)-imidazolidin-2-one 195A
1-Benzothiazol-6-yl-3-[4-(1- 38 nM/-- 8%
hydroxy-ethyl)-pyridin-3-yl]- imidazolidin-2-one 196A
1-Benzothiazol-6-yl-3-(4-ethyl- 3.4 nM/-- --
pyridin-3-yl)-imidazolidin-2-one 197A
1-(4-Methyl-pyridin-3-yl)-3-(3- 34 nM/-- --
trifluoromethyl-1H-indazol-6- yl)-imidazolidin-2-one 198A
1-(3-Cyclopropyl-1H-indazol-6- 82 nM/-- --
yl)-3-(4-methyl-pyridin-3-yl)- imidazolidin-2-one 199A
1-(4-Methyl-pyridin-3-yl)-3- 317 nM/-- --
quinolin-7-yl-imidazolidin-2-one 200A 3-Benzothiazol-6-yl-4,4-
>10 .mu.M/-- -- dimethyl-1-(4-methyl-pyridin-3-
yl)-imidazolidin-2-one 201A 1-Benzothiazol-6-yl-4,4- 70 nM/-- --
dimethyl-3-pyridin-3-yl- imidazolidin-2-one 202A
1-Benzothiazol-6-yl-4,4- 1153 nM/-- --
dimethyl-3-(4-methyl-pyridin-3- yl)-imidazolidin-2-one 203A
3-Benzothiazol-6-yl-4-methyl-1- 32 nM/-- --
(4-methyl-pyridin-3-yl)- imidazolidin-2-one
The compounds of present invention in free form or in salt form,
exhibit valuable pharmacological properties, e.g. inhibition of
CYP17 lyase, e.g. as indicated in the in vitro tests provided above
and are therefore useful for therapy mediated by such inhibition.
For example, the compounds of the present invention are useful in
the treatment of inflammation and cancer (in particular, prostate
cancer) in a mammal (preferably, a human).
Thus, as a further embodiment, the present invention provides the
use of a compound of the present invention in therapy. In a further
embodiment, the therapy is selected from a disease mediated by the
regulation of 17.alpha.-hydroxylase/C.sub.17,20-lyase.
In another embodiment, the invention provides a method of treating
a disease which is treated by the regulation of
17.alpha.-hydroxylase/C.sub.17,20-lyase comprising administration
of a therapeutically acceptable amount of a compound of the present
invention. In a further embodiment, the disease is prostate
cancer.
Additional References:
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