U.S. patent application number 16/150484 was filed with the patent office on 2019-01-31 for benzimidazole derivatives useful as cb-1 inverse agonists.
This patent application is currently assigned to Janssen Pharmaceutica NV. The applicant listed for this patent is Janssen Pharmaceutica NV. Invention is credited to Bart L. DeCorte, Michael N. Greco, Donald W. Ludovici, Mark J. Macielag, Michael H. Parker, Daniel J. Parks, Rui Zhang, Yue-Mei Zhang, Bin Zhu.
Application Number | 20190031618 16/150484 |
Document ID | / |
Family ID | 58097587 |
Filed Date | 2019-01-31 |
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United States Patent
Application |
20190031618 |
Kind Code |
A1 |
Macielag; Mark J. ; et
al. |
January 31, 2019 |
BENZIMIDAZOLE DERIVATIVES USEFUL AS CB-1 INVERSE AGONISTS
Abstract
The present invention is directed to benzimidazole derivatives,
pharmaceutical compositions containing them and their use in the
treatment of disorders and conditions mediated by the CB-1
receptor, more particularly, use in the treatment of disorders and
conditions responsive to inverse agonism of the CB-1 receptor. More
particularly, the compounds of the present invention are useful in
the treatment of metabolic disorders.
Inventors: |
Macielag; Mark J.; (Gwynedd
Valley, PA) ; Zhang; Rui; (Belle Mead, NJ) ;
Zhang; Yue-Mei; (Wellesley, MA) ; Zhu; Bin;
(Newtown, PA) ; Parker; Michael H.; (Chalfont,
PA) ; Ludovici; Donald W.; (Quakertown, PA) ;
Parks; Daniel J.; (Downington, PA) ; DeCorte; Bart
L.; (Southampton, PA) ; Greco; Michael N.;
(Lansdale, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Janssen Pharmaceutica NV |
Beerse |
|
BE |
|
|
Assignee: |
Janssen Pharmaceutica NV
Beerse
BE
|
Family ID: |
58097587 |
Appl. No.: |
16/150484 |
Filed: |
October 3, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15244372 |
Aug 23, 2016 |
10118900 |
|
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16150484 |
|
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62209381 |
Aug 25, 2015 |
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62233655 |
Sep 28, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 405/04 20130101;
C07D 417/06 20130101; C07D 417/14 20130101; C07D 401/14 20130101;
C07D 405/14 20130101; C07D 409/10 20130101; C07D 401/06 20130101;
C07D 471/08 20130101; C07C 53/18 20130101; C07D 235/18 20130101;
C07D 409/14 20130101; C07D 403/04 20130101; C07D 401/04 20130101;
C07D 405/06 20130101 |
International
Class: |
C07D 235/18 20060101
C07D235/18; C07D 401/14 20060101 C07D401/14; C07D 405/04 20060101
C07D405/04; C07D 409/14 20060101 C07D409/14; C07D 401/06 20060101
C07D401/06; C07D 401/04 20060101 C07D401/04; C07C 53/18 20060101
C07C053/18; C07D 417/14 20060101 C07D417/14; C07D 409/10 20060101
C07D409/10; C07D 403/04 20060101 C07D403/04; C07D 405/06 20060101
C07D405/06; C07D 471/08 20060101 C07D471/08; C07D 417/06 20060101
C07D417/06; C07D 405/14 20060101 C07D405/14 |
Claims
1. A compound of formula (I) ##STR00484## wherein R.sup.0 is
selected from the group consisting of hydrogen, --OH, --C(O)OH,
--C(O)O--(C.sub.1-4alkyl), --CH.sub.2--OH,
--CH.sub.2--O--(C.sub.1-2alkyl) and
--CH.sub.2--O--(C.sub.1-2alkyl)-CO.sub.2H; ##STR00485## is selected
from the group consisting of cylopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, phenyl, furyl, thienyl, thiazolyl, benzothiazolyl and
benzo[d][1,3]dioxolyl; wherein the phenyl, furyl, thienyl,
thiazolyl or benzothiazolyl is optionally substituted with one or
more substituents independently selected from the group consisting
of halogen, hydroxy, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl,
C.sub.1-4alkoxy, fluorinated C.sub.1-2alkoxy, cyano, --C(O)OH,
--C(O)O--(C.sub.1-4alkyl), --C(O)NR.sup.AR.sup.B and
NR.sup.AR.sup.B; wherein R.sup.A and R.sup.B are each independently
selected from the group consisting of hydrogen, alkyl and hydroxy
substituted C.sub.1-2alkyl; provided that each substituent is bound
to a carbon atom; ##STR00486## is selected from the group
consisting of cylopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
phenyl, furyl, thienyl, thiazolyl, benzothiazolyl and
benzo[d][1,3]dioxolyl; wherein the phenyl, furyl, thienyl,
thiazolyl or benzothiazolyl is optionally substituted with one or
more substituents independently selected from the group consisting
of halogen, hydroxy, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl,
C.sub.1-4alkoxy, fluorinated C.sub.1-2alkoxy, cyano, --C(O)OH,
--C(O)O--(C.sub.1-4alkyl), --C(O)NR.sup.CR.sup.D and
NR.sup.CR.sup.D; wherein R.sup.C and R.sup.D are each independently
selected from the group consisting of hydrogen, alkyl and hydroxy
substituted C.sub.1-2alkyl; provided that each substituent is bound
to a carbon atom; R.sup.1 is selected from the group consisting of
hydrogen, hydroxy and C.sub.1-4alkoxy; R.sup.2 is selected from the
group consisting of hydrogen, halogen, C.sub.1-4alkyl, fluorinated
C.sub.1-2alkyl, --(C.sub.1-2alkyl)-OH, --(C.sub.1-2alkyl)-C(O)OH,
--(C.sub.1-2alkyl)-NR.sup.ER.sup.F, --(C.sub.2-4alkenyl)-OH,
--C(O)OH, --C(O)O--(C.sub.1-2alkyl), --NR.sup.ER.sup.F,
C.sub.3-6cycloalkyl, phenyl, furyl, thienyl, pyridyl,
azetidin-3-yl, oxetan-3-yl, tetrahydrofuran-2-yl and
tetrahydropyran-4-yl; wherein the phenyl is optionally substituted
with one to two halogen; wherein the azetidin-3-yl is optionally
substituted with --C(O)O--(C.sub.1-4alkyl); and wherein R.sup.E and
R.sup.F are each independently selected from the group consisting
of hydrogen and C.sub.1-4alkyl; provided that when R.sup.2 is
selected from the group consisting of pyridyl, furyl and thienyl,
then the R.sup.2 is bound to the benzimidazole core through a
carbon atom; R.sup.3 is selected from the group consisting of (a)
through (k); wherein (a) is ##STR00487## wherein R.sup.4 is
selected from the group consisting of hydrogen, --C(O)OH,
--C(O)O--(C.sub.1-2alkyl), --C(O)NR.sup.GR.sup.H, --NH-(phenyl),
and --NH--SO.sub.2-(phenyl); wherein the phenyl is optionally
substituted with one or more substituents independently selected
from the group consisting of halogen, hydroxy and carboxy; and
wherein R.sup.G and R.sup.H are each independently selected from
the group consisting of hydrogen and C.sub.1-4alkyl; (b) is
##STR00488## (c) is ##STR00489## (d) is ##STR00490## (e) is
##STR00491## (f) is ##STR00492## wherein a is an integer from 0 to
1; wherein L.sup.1 is selected from the group consisting of
--CH.sub.2--, --CH.sub.2--CH.sub.2, --CH.sub.2CH.sub.2CH.sub.2--,
--CH(CH.sub.3)CH.sub.2-- and --CH.sub.2--CH(CH.sub.3)--; wherein
R.sup.5 is selected from the group consisting of hydrogen,
C.sub.1-2alkyl, fluorinated C.sub.1-2alkyl, C.sub.2-4alkenyl,
--(C.sub.1-2alkyl)-C(O)OH,
--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--(C.sub.2-3alkyl)-O-(phenyl), --C(O)--(C.sub.1-2alkyl)-OH,
--C(O)--(C.sub.1-2alkyl)-C(O)OH,
--C(O)--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--C(O)--(C.sub.1-2alkyl)-C(O)--NH.sub.2, --C(O)OH,
--C(O)O--(C.sub.1-4alkyl), --C(O)O--(C.sub.3-5cycloalkyl),
--C(O)--NR.sup.JR.sup.K, --C(O)NH--(C.sub.3-5cycloalkyl),
--C(O)NH-(phenyl), --C(O)NH--(C.sub.1-2alkyl)-(phenyl),
--SO.sub.2--(C.sub.1-2alkyl), --SO.sub.2-(fluorinated
C.sub.1-2alkyl), --SO.sub.2--(C.sub.1-2alkyl)-C(O)OH,
--SO.sub.2--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--SO.sub.2--NR.sup.JR.sup.K,
--SO.sub.2--(C.sub.1-2alkyl)-C(O)NR.sup.JR.sup.K, phenyl,
--(C.sub.1-3alkyl)-phenyl, --C(O)-(phenyl), --C(O)O-(phenyl),
--C(O)O--(C.sub.1-2alkyl)-(phenyl), --SO.sub.2-(phenyl),
pyrimidin-2-yl, pyridyl, --(C.sub.1-2alkyl)-pyridyl,
--C(O)-(pyridyl), --SO.sub.2-(pyridyl), furyl,
--(C.sub.1-2alkyl)-furyl, --C(O)-- furyl, --SO.sub.2-(furyl),
thienyl, --(C.sub.1-2alkyl)-thienyl, --C(O)-thienyl,
--SO.sub.2-(thienyl), --C(O)-(1,2,3-triazol-4-yl),
--C(O)-(1,2,4,-triazol-3-yl) and
--SO.sub.2--(C.sub.1-2alkyl)-(piperazin-1-yl); wherein the phenyl,
pyrimidin-2-yl, pyridyl, furyl, thienyl or pyridyl, is optionally
substituted with one or more substituents independently selected
from the group consisting of halogen, hydroxy, C.sub.1-4alkyl,
fluorinated C.sub.1-2alkyl, --(C.sub.1-2alkyl)-OH,
--(C.sub.1-2alkyl)-C(O)OH,
--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--C(.sub.1-2alkyl)-C(O)OH,
--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--(C.sub.1-2alkyl)-C(O)--NR.sup.LR.sup.M, --O--(C.sub.1-4alkyl),
--O-(fluorinated C.sub.1-2alkyl), --O--(C.sub.2-6alkenyl),
--O--(C.sub.1-2alkyl)-C(O)OH,
--O--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--O--(C.sub.1-2alkyl)-C(O)NR.sup.LR.sup.M,
--O--(C.sub.1-2alkyl)-C(O)--NR.sup.LR.sup.M, --C(O)OH,
--C(O)O--(C.sub.1-4alkyl), --C(O)--NR.sup.LR.sup.M,
--C(O)--NH--(C.sub.1-3alkyl)-OH,
--C(O)--NH--(C.sub.1-2alkyl)-C(O)OH,
--C(O)--NH--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--NR.sup.LR.sup.M and --SO.sub.2--NR.sup.LR.sup.M; wherein R.sup.J
and R.sup.K are each independently selected from the group
consisting of hydrogen and C.sub.1-4alkyl; and wherein R.sup.L and
R.sup.M are each independently selected from the group consisting
of hydrogen and C.sub.1-4alkyl; (g) is ##STR00493## wherein b is an
integer from 0 to 1; wherein L.sup.2 is selected from the group
consisting of --CH.sub.2--, --CH.sub.2CH.sub.2--, --CH(CH.sub.3)--,
--CH(CH.sub.3)--CH.sub.2--, --CH.sub.2--CH(CH.sub.3)--,
--CH.sub.2CH.sub.2--O--, --CH.sub.2--CH(OH)--,
--CH(CH.sub.3)--CH(OH) and
--CH.sub.2CH.sub.2CH.sub.2--NH--SO.sub.2--; wherein R.sup.6 is
selected from the group consisting of hydrogen, halogen, hydroxy,
C.sub.1-2alkyl, fluorinated C.sub.1-2alkyl, C.sub.1-2alkoxy,
fluorinated C.sub.1-2alkoxy, --C(O)OH, --C(O)O--(C.sub.1-2alkyl),
--O--(C.sub.1-2alkyl)-O--(C.sub.1-2alkyl),
--O--(C.sub.1-2alkyl)-C(O)OH,
--O--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--C(O)--NR.sup.NR.sup.P,
--O--(C.sub.1-2alkyl)-C(O)--NR.sup.NR.sup.P, phenyl, furyl and
thienyl; wherein the phenyl, furyl or thienyl is optionally
substituted with a substituent selected from the group consisting
of halogen, C.sub.1-4alkyl and carboxy; and wherein R.sup.N and
R.sup.P are each independently selected from the group consisting
of hydrogen and C.sub.1-4alkyl; wherein R.sup.7 is selected from
the group consisting of hydrogen, halogen, hydroxy, C.sub.1-4alkyl,
fluorinated C.sub.1-2alkyl, C.sub.1-4alkoxy, fluorinated
C.sub.1-2alkoxy, --C(O)OH and --C(O)O--(C.sub.1-4alkyl); (h) is
##STR00494## wherein L.sup.3 is selected from the group consisting
of --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH(CH.sub.3)CH.sub.2--,
--CH.sub.2CH(CH.sub.3)-- and --CH.sub.2CH.sub.2--O--; wherein
R.sup.8 is selected from the group consisting of hydrogen, halogen,
C.sub.1-4alkyl, C.sub.1-4alkoxy, --C(O)OH and
--C(O)O--(C.sub.1-4alkyl); (i) is ##STR00495## wherein c is an
integer from 0 to 1; and wherein L.sup.4 is selected from the group
consisting of --CH.sub.2-- and --CH.sub.2--CH.sub.2--; (j) is
##STR00496## and (k) is ##STR00497## or a stereoisomer, tautomer or
pharmaceutically acceptable salt thereof.
2. A compound as in claim 1, wherein R.sup.0 is selected from the
group consisting of hydrogen, --OH, --C(O)OH,
--C(O)O--(C.sub.1-2alkyl), --CH.sub.2--OH,
--CH.sub.2--O--(C.sub.1-2alkyl) and
--CH.sub.2--O--(C.sub.1-2alkyl)-CO.sub.2H; ##STR00498## is selected
from the group consisting of phenyl, thiazolyl, and
benzo[d][1,3]dioxolyl; wherein the phenyl or thiazolyl is
optionally substituted with one to two substituents independently
selected from the group consisting of halogen C.sub.1-4alkyl,
fluorinated C.sub.1-2alkyl, C.sub.1-2alkoxy, fluorinated
C.sub.1-2alkoxy, --C(O)OH and --C(O)O--(C.sub.1-4alkyl);
##STR00499## is selected from the group consisting of phenyl,
thiazolyl and benzo[d][1,3]dioxolyl; wherein the phenyl or
thiazolyl is optionally substituted with one to two substituents
independently selected from the group consisting of halogen
C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl, C.sub.1-2alkoxy,
fluorinated C.sub.1-2alkoxy, --C(O)OH and
--C(O)O--(C.sub.1-4alkyl); R.sup.1 is selected from the group
consisting of hydrogen, hydroxy and C.sub.1-2alkoxy; R.sup.2 is
selected from the group consisting of hydrogen, halogen,
C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl, --(C.sub.1-2alkyl)-OH,
--(C.sub.1-2alkyl)-C(O)OH, --(C.sub.1-2alkyl)-NH.sub.2,
--(C.sub.2-4alkenyl)-OH, --C(O)O--(C.sub.1-2alkyl),
--NR.sup.ER.sup.F, C.sub.3-6cycloalkyl, phenyl, furyl, thienyl,
pyridyl, oxetan-3-yl, azetidin-3-yl, tetrahydrofuran-2-yl and
tetrahydropyran-4-yl; wherein the phenyl is optionally substituted
with one to two halogen; wherein the azetidin-3-yl is optionally
substituted with --C(O)O--(C.sub.1-4alkyl); and wherein R.sup.E and
R.sup.F are each independently selected from the group consisting
of hydrogen and C.sub.1-4alkyl; provided that when R.sup.2 is
selected from the group consisting of pyridyl, furyl and thienyl,
then the R.sup.2 is bound to the benzimidazole core through a
carbon atom; R.sup.3 is selected from the group consisting of (a)
through (k); wherein (a) is ##STR00500## wherein R.sup.4 is
selected from the group consisting of hydrogen, --C(O)OH,
--C(O)O--(C.sub.1-2alkyl), --C(O)NR.sup.GR.sup.H, --NH-(phenyl),
and --NH--SO.sub.2-(phenyl); wherein the phenyl is optionally
substituted with hydroxy or carboxy; and wherein R.sup.G and
R.sup.H are each independently selected from the group consisting
of hydrogen and methyl; (b) is ##STR00501## (c) is ##STR00502## (d)
is ##STR00503## (e) is ##STR00504## (f) is ##STR00505## wherein a
is an integer from 0 to 1; wherein L.sup.1 is selected from the
group consisting of --CH.sub.2--, --CH.sub.2--CH.sub.2,
--CH(CH.sub.3)CH.sub.2-- and --CH.sub.2--CH(CH.sub.3)--; wherein
R.sup.5 is selected from the group consisting of hydrogen,
C.sub.1-2alkyl, fluorinated C.sub.1-2alkyl, C.sub.2-4alkenyl,
--(C.sub.1-2alkyl)-C(O)OH,
--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--(C.sub.2alkyl)-O-(phenyl), --C(O)--(C.sub.1-2alkyl)-OH,
--C(O)--(C.sub.1-2alkyl)-C(O)OH,
--C(O)--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--C(O)--(C.sub.1-2alkyl)-C(O)--NH.sub.2, --C(O)O--(C.sub.1-4alkyl),
--C(O)O--(C.sub.3-5cycloalkyl), --C(O)O-(phenyl),
--C(O)O--CH.sub.2-(phenyl), --C(O)--NH.sub.2,
--C(O)NH--(C.sub.1-2alkyl), --C(O)NH--(C.sub.3-5cycloalkyl),
--C(O)NH-(phenyl), --C(O)NH--(C.sub.1-2alkyl)-(phenyl),
--SO.sub.2--(C.sub.1-2alkyl), --SO.sub.2-(fluorinated
C.sub.1-2alkyl), --SO.sub.2--(C.sub.1-2alkyl)-C(O)OH,
--SO.sub.2--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--(C.sub.1-2alkyl),
--SO.sub.2--(C.sub.1-2alkyl)-C(O)NH.sub.2, phenyl,
--(C.sub.1-3alkyl)-phenyl, --C(O)-(phenyl), --C(O)O-(phenyl),
--C(O)O--(C.sub.1-2alkyl)-(phenyl), --SO.sub.2-(phenyl),
pyrimidin-2-yl, pyrid-2-yl, pyrid-3-yl,
--(C.sub.1-2alkyl)-pyrid-2-yl, --(C.sub.1-2alkyl)-pyrid-3-yl,
--(C.sub.1-2alkyl)-fur-2-yl, --(C.sub.1-2alkyl)-thien-2-yl,
--C(O)-fur-2-yl, --C(O)-thien-2-yl, --C(O)-(pyrid-3-yl),
--C(O)-(1,2,3-triazol-4-yl), --C(O)-(1,2,4,-triazol-3-yl),
--SO.sub.2--(C.sub.1-2alkyl)-(piperazin-1-yl),
--SO.sub.2-(fury-2-yl), --SO.sub.2-(thien-2-yl) and
--SO.sub.2-(pyrid-3-yl); wherein the phenyl, pyrimidin-2-yl,
pyridyl, furyl, thienyl or pyridyl, is optionally substituted with
one to three substituents independently selected from the group
consisting of halogen, hydroxy, C.sub.1-2alkyl, fluorinated
C.sub.1-2alkyl, --(C.sub.1-2alkyl)-OH, --C(.sub.1-2alkyl)-C(O)OH,
--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl), --O--(C.sub.1-2alkyl),
--O-(fluorinated C.sub.1-2alkyl), --O--(C.sub.2-6alkenyl),
--O--(C.sub.1-2alkyl)-C(O)OH, --O--(C.sub.1-2alkyl)-C(O)NH.sub.2,
--C(O)OH, --C(O)O--(C.sub.1-4alkyl), --C(O)--NH.sub.2,
--C(O)--NH--(C.sub.1-2alkyl), --C(O)--NH--(C.sub.1-3alkyl)-OH,
--C(O)--NH--(C.sub.1-2alkyl)-C(O)OH,
--C(O)--NH--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--(C.sub.1-2alkyl)-C(O)--NH.sub.2,
--O--(C.sub.1-2alkyl)-C(O)--NH.sub.2, --O--(C.sub.1-2alkyl)-C(O)OH,
--NH.sub.2, --NH(C.sub.1-2alkyl), --SO.sub.2--NH.sub.2 and
--SO.sub.2--NH(C.sub.1-2alkyl); (g) is ##STR00506## wherein b is an
integer from 0 to 1; wherein L.sup.2 is selected from the group
consisting of --CH.sub.2--, --CH.sub.2CH.sub.2--, --CH(CH.sub.3)--,
--CH(CH.sub.3)--CH.sub.2--, --CH.sub.2--CH(CH.sub.3)--,
--CH.sub.2CH.sub.2--O--, --CH.sub.2--CH(OH)--,
--CH(CH.sub.3)--CH(OH) and
--CH.sub.2CH.sub.2CH.sub.2--NH--SO.sub.2--; wherein R.sup.6 is
selected from the group consisting of hydrogen, halogen, hydroxy,
C.sub.1-2alkyl, fluorinated C.sub.1-2alkyl, C.sub.1-2alkoxy,
fluorinated C.sub.1-2alkoxy, --C(O)OH, --C(O)O--(C.sub.1-2alkyl),
--O--(C.sub.1-2alkyl)-C(O)OH,
--O--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl), --C(O)--NH.sub.2,
--O--(C.sub.1-2alkyl)-C(O)--NH.sub.2, phenyl, furyl and thienyl;
wherein the phenyl, furyl or thienyl is optionally substituted with
carboxy; and wherein R.sup.7 is selected from the group consisting
of hydrogen, hydroxy, C.sub.1-2alkyl, fluorinated C.sub.1-2alkyl,
C.sub.1-2alkoxy, fluorinated C.sub.1-2alkoxy, --C(O)OH and
--C(O)O--(C.sub.1-4alkyl); (h) is ##STR00507## wherein L.sup.3 is
selected from the group consisting of --CH.sub.2--,
--CH.sub.2CH.sub.2-- and --CH.sub.2CH.sub.2--O--; and wherein
R.sup.8 is selected from the group consisting of hydrogen,
-halogen, C.sub.1-2alkyl, C.sub.1-2alkoxy, --C(O)OH and
--C(O)O--(C.sub.1-4alkyl); (i) is ##STR00508## wherein c is an
integer from 0 to 1; and wherein L.sup.4 is selected from the group
consisting of --CH.sub.2-- and --CH.sub.2--CH.sub.2--; (j) is
##STR00509## and (k) is ##STR00510## or a stereoisomer, tautomer or
pharmaceutically acceptable salt thereof.
3. A compound as in claim 2, wherein R.sup.0 is selected from the
group consisting of hydrogen, --OH, --C(O)OH,
--C(O)O--(C.sub.1-2alkyl), --CH.sub.2--OH,
--CH.sub.2--O--(C.sub.1-2alkyl) and
--CH.sub.2--O--(C.sub.1-2alkyl)-CO.sub.2H; ##STR00511## is phenyl;
wherein the phenyl is optionally substituted a substituent selected
from the group consisting of halogen and C.sub.1-2alkoxy;
##STR00512## is selected from the group consisting of phenyl,
thiazol-2-yl and benzo[d][1,3]dioxol-5-yl; wherein the phenyl or
thiazol-2-yl is optionally substituted with a substituent selected
from the group consisting of halogen, C.sub.1-4alkyl, fluorinated
C.sub.1-2alkyl, C.sub.1-2alkoxy and --C(O)OH; R.sup.1 is selected
from the group consisting of hydrogen, hydroxy and C.sub.1-2alkoxy;
R.sup.2 is selected from the group consisting of hydrogen, halogen,
C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl, --(C.sub.1-2alkyl)-OH,
--(C.sub.1-2alkyl)-C(O)OH, --(C.sub.1-2alkyl)-NH.sub.2,
--(C.sub.2-4alkenyl)-OH, --C(O)O--(C.sub.1-2alkyl),
--NR.sup.ER.sup.F, C.sub.3-6cycloalkyl, phenyl, fur-2-yl, fur-3-yl,
thien-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, oxetan-3-yl,
azetidin-3-yl, tetrahydrofuran-2-yl and tetrahydro-pyran-4-yl;
wherein the phenyl is optionally substituted with one to two
halogen; wherein the azetidin-3-yl is optionally substituted with
--C(O)O--(C.sub.1-4alkyl); and wherein R.sup.E and R.sup.F are each
independently selected from the group consisting of hydrogen,
methyl and ethyl; R.sup.3 is selected from the group consisting of
(a) through (k); wherein (a) is ##STR00513## wherein R.sup.4 is
selected from the group consisting of hydrogen, --C(O)OH,
--C(O)NR.sup.GR.sup.H, --NH-(phenyl) and --NH--SO.sub.2-(phenyl);
wherein the phenyl is optionally substituted with hydroxy or
carboxy; wherein R.sup.G and R.sup.H are each independently
selected from the group consisting of hydrogen and methyl; (b) is
##STR00514## (c) is ##STR00515## (d) is ##STR00516## (e) is
##STR00517## (f) is ##STR00518## wherein a is an integer from 0 to
1; and wherein L.sup.1 is selected from the group consisting of
--CH.sub.2-- and --CH.sub.2--CH(CH.sub.3)--; wherein R.sup.5 is
selected from the group consisting of hydrogen, C.sub.2-4alkenyl,
--(C.sub.1-2alkyl)-C(O)OH,
--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--(C.sub.2alkyl)-O-(phenyl), --C(O)--(C.sub.1-2alkyl)-OH,
--C(O)--(C.sub.1-2alkyl)-C(O)OH,
--C(O)--(C.sub.1-2alkyl)-C(O)--NH.sub.2, --C(O)O--(C.sub.1-4alkyl),
--C(O)O-(hydroxy substituted C.sub.1-4alkyl),
--C(O)O--(C.sub.3-5cycloalkyl), --C(O)NH--(C.sub.1-2alkyl),
--C(O)NH--(C.sub.3-5cycloalkyl), --C(O)NH-(phenyl),
--C(O)NH--(C.sub.1-2alkyl)-(phenyl), --SO.sub.2--(C.sub.1-2alkyl),
--SO.sub.2-(fluorinated C.sub.1-2alkyl),
--SO.sub.2--(C.sub.1-2alkyl)-C(O)OH, --SO.sub.2--NH.sub.2,
--SO.sub.2--NH--(C.sub.1-2alkyl),
--SO.sub.2--(C.sub.1-2alkyl)-C(O)NH.sub.2, phenyl,
--(C.sub.1-3alkyl)-phenyl, --C(O)-(phenyl), --C(O)O-(phenyl),
--C(O)O--(C.sub.1-2alkyl)-(phenyl), --SO.sub.2-(phenyl),
pyrimidin-2-yl, --(C.sub.1-2alkyl)-pyrid-2-yl,
--(C.sub.1-2alkyl)-pyrid-3-yl, --(C.sub.1-2alkyl)-fur-2-yl,
--(C.sub.1-2alkyl)-thien-2-yl, --C(O)-(pyrid-3-yl),
--C(O)-(1,2,3-triazol-4-yl), --C(O)-(1,2,4,-triazol-3-yl),
--SO.sub.2--(C.sub.1-2alkyl)-(piperazin-1-yl),
--SO.sub.2-(fury-2-yl), --SO.sub.2-(thien-2-yl) and
--SO.sub.2-(pyrid-3-yl); wherein the phenyl is optionally
substituted with one to three substituents independently selected
from the group consisting of halogen, hydroxy, C.sub.1-2alkyl,
fluorinated C.sub.1-2alkyl, --O--(C.sub.1-2alkyl), --O-(fluorinated
C.sub.1-2alkyl), --O--(C.sub.2-6alkenyl),
--O--(C.sub.1-2alkyl)-C(O)OH, --O--(C.sub.1-2alkyl)-C(O)NH.sub.2,
--C(O)OH, --C(O)O--(C.sub.1-2alkyl), --C(.sub.1-2alkyl)-C(O)OH,
--C(O)--NH.sub.2, --C(O)--NH--(C.sub.1-2alkyl),
--C(O)--NH--(C.sub.1-3alkyl)-OH,
--C(O)--NH--(C.sub.1-2alkyl)-C(O)OH,
--C(O)--NH--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--(C.sub.1-2alkyl)-C(O)--NH.sub.2,
--O--(C.sub.1-2alkyl)-C(O)--NH.sub.2, --O--(C.sub.1-2alkyl)-C(O)OH,
--NH.sub.2 and --SO.sub.2--NH.sub.2; and wherein the
pyrimidin-2-yl, pyrid-2-yl, pyrid-3-yl, fur-2-yl or thien-2-yl is
optionally substituted with one to two substituents independently
selected from the group consisting of C.sub.1-2alkyl,
--(C.sub.1-2alkyl)-OH, --C(O)OH, --C(O)O--(C.sub.1-2alkyl),
--C(O)--NH.sub.2, --C(O)NH--(C.sub.1-2alkyl)-OH,
--C(O)NH--(C.sub.1-2alkyl)-C(O)OH and
--C(O)NH--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl); (g) is
##STR00519## wherein b is an integer from 0 to 1; and wherein
L.sup.2 is selected from the group consisting of --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH(CH.sub.3)--, --CH(CH.sub.3)--CH.sub.2--,
--CH.sub.2--CH(CH.sub.3)--, --CH.sub.2CH.sub.2--O--,
--CH.sub.2--CH(OH)--, --CH(CH.sub.3)--CH(OH) and
--CH.sub.2CH.sub.2CH.sub.2--NH--SO.sub.2--; wherein R.sup.6 is
selected from the group consisting of hydrogen, halogen, hydroxy,
C.sub.1-2alkoxy, fluorinated C.sub.1-2alkyl, --C(O)OH,
--C(O)O--(C.sub.1-2alkyl), --O--(C.sub.1-2alkyl)-C(O)OH,
--O--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl), --C(O)--NH.sub.2,
--O--(C.sub.1-2alkyl)-C(O)--NH.sub.2, phenyl and thienyl; wherein
the phenyl or thienyl is optionally substituted with carboxy; and
wherein R.sup.7 is selected from the group consisting of hydrogen
and fluorinated C.sub.1-2alkyl; (h) is ##STR00520## wherein L.sup.3
is selected from the group consisting of --CH.sub.2-- and
--CH.sub.2CH.sub.2--O--; and wherein R.sup.8 is selected from the
group consisting of hydrogen, --C(O)OH and
--C(O)O--(C.sub.1-2alkyl); (i) is ##STR00521## wherein c is an
integer from 0 to 1; wherein L.sup.4 is --CH.sub.2--; (j) is
##STR00522## and (k) is ##STR00523## or a stereoisomer, tautomer or
pharmaceutically acceptable salt thereof.
4. A compound as in claim 3, wherein R.sup.0 is selected from the
group consisting of hydrogen, --OH, --C(O)OH, --C(O)OCH.sub.3,
--CH.sub.2--OH, --CH.sub.2--OCH.sub.3 and
--CH.sub.2--OCH.sub.2--CO.sub.2H; ##STR00524## is selected from the
group consisting of phenyl, 2-chlorophenyl, 4-chlorophenyl and
4-methoxyphenyl; ##STR00525## is selected from the group consisting
of phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methylphenyl,
4-trifluoromethyl-phenyl, 4-carboxyphenyl, 4-methoxyphenyl,
thiazol-2-yl, 4-ethyl-thiazol-2-yl, 5-ethyl-thiazol-2-yl,
4-t-butyl-thiazol-2-yl, 4-trifluoromethyl-thiazol-2-yl and
benzo[d][1,3]dioxol-5-yl, R.sup.1 is selected from the group
consisting of hydrogen, hydroxy and methoxy; R.sup.2 is selected
from the group consisting of hydrogen, chloro, methyl, ethyl,
n-propyl, isopropyl, isobutyl, t-butyl, --CHF.sub.2, --CF.sub.3,
--CH.sub.2--CF.sub.3, --CH.sub.2OH, --CH.sub.2CH.sub.2--C(O)OH,
--CH.sub.2CH.sub.2--NH.sub.2, --C(.dbd.CH.sub.2)--CH.sub.2OH,
--C(O)OCH.sub.3, --C(O)OCH.sub.2CH.sub.3, --NH.sub.2,
--N(CH.sub.3).sub.2, cyclopropyl, cyclobutyl, cyclopentyl,
oxetan-3-yl, azetidin-3-yl, 1-(t-butoxycarbonyl)-azetidin-3-yl,
tetrahydrofuran-2-yl, tetrahydro-pyran-4-yl, 4-chlorophenyl,
2,4-dichlorophenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fur-2-yl,
fur-3-yl and thien-3-yl; R.sup.3 is selected from the group
consisting of (a) through (k); wherein (a) is ##STR00526## wherein
R.sup.4 is selected from the group consisting of hydrogen,
--C(O)OH, --C(O)NH.sub.2, --NH--SO.sub.2-(3-carboxyphenyl),
--NH-(3-hydroxyphenyl), --NH-(3-carboxyphenyl),
--NH-(4-carboxyphenyl) and --NH--SO.sub.2-(4-carboxyphenyl); and
wherein the cyclohexyl is bound to the benzimidazole core in a
cis-, trans- or racemic stereo-orientation; (b) is ##STR00527##
wherein a 0; and wherein R.sup.5 is selected from the group
consisting of 3-carboxybenzyl-, 4-carboxyphenyl-sulfonyl- and
5-carboxyfur-2-yl-sulfonyl-; (c) is ##STR00528## wherein a is 0;
and wherein R.sup.5 is selected from the group consisting of
3-carboxybenzyl-, 4-carboxyphenyl-sulfonyl- and
5-carboxy-fur-2-yl-sulfonyl-; (d) is ##STR00529## wherein a is an
integer from 0 to 1; wherein L.sup.1 is selected from the group
consisting of --CH.sub.2-- and --CH.sub.2--CH(R*--CH.sub.3)--;
wherein R.sup.5 is selected from the group consisting of hydrogen,
propyn-3-yl, carboxy-methyl-, methoxy-carbonyl-methyl-,
3-carboxyphenyl-oxy-ethyl-, 2-hydroxyethyl-carbonyl-,
hydroxymethyl-carbonyl-, 2-carboxy-ethyl-carbonyl-,
aminocarbonyl-methyl-carbonyl-, 2-(aminocarbonyl)-ethyl-carbonyl-,
ethoxycarbonyl-, t-butoxycarbonyl-, cyclopentyloxy-carbonyl-,
2,3,4-trihydroxy-n-butyloxy-carbonyl-, 3-carboxyphenyl,
4-carboxyphenyl, 3-(carboxy-methyl)-phenyl,
4-(carboxy-methyl)-phenyl, 3-(methoxycarbonyl)-phenyl,
3-(aminocarbonyl)-phenyl, 4-(aminocarbonyl)-phenyl,
3-(aminocarbonyl-methyl)-phenyl, 4-(aminocarbonyl-methyl)-phenyl,
3-(aminocarbonyl-methoxy)-phenyl, 4-(aminocarbonyl-methoxy)-phenyl,
3-(carboxy-methoxy)-phenyl, 4-(carboxy-methoxy)-phenyl,
3-hydroxy-benzyl, 3-(hex-2-en-1-yloxy)-benzyl,
2-trifluoromethyl-benzyl, 3-carboxy-benzyl, 4-carboxy-benzyl,
3-(methoxycarbonyl)-benzyl, 3-(aminocarbonyl)-benzyl,
4-(aminocarbonyl)-benzyl, 3-(2-hydroxyethyl-aminocarbonyl)-benzyl,
2-hydroxy-3-carboxy-benzyl, 2-hydroxy-5-carboxy-benzyl,
2-fluoro-3-carboxy-benzyl, 2-fluoro-5-carboxy-benzyl,
2-chloro-3-carboxy-benzyl, 2-chloro-5-carboxy-benzyl,
2-trifluoromethyl-5-carboxy-benzyl, 3-fluoro-5-carboxy-benzyl,
3-carboxy-4-fluoro-benzyl, 3-carboxy-4-hydroxy-benzyl,
3-trifluoromethyl-5-carboxy-benzyl, 1-(3-hydroxyphenyl)-ethyl-,
1-(3-carboxyphenyl)-ethyl-, 1R*-(3-carboxyphenyl)-ethyl-,
1-(3-carboxyphenyl)-n-propyl-, 4-carboxy-pyrimidin-2-yl,
5-carboxy-pyrimidin-2-yl, 5-methoxycarbonyl-pyrimidin-2-yl,
2-carboxy-pyrid-4-yl-methyl-, 4-carboxy-pyrid-2-yl-methyl-,
5-carboxy-pyrid-2-yl-methyl-, 6-carboxy-pyrid-2-yl-methyl-,
5-carboxy-pyrid-3-yl-methyl-, 6-carboxy-pyrid-3-yl-methyl-,
5-aminocarbonyl-pyrid-2-yl-methyl-,
6-aminocarbonyl-pyrid-2-yl-methyl-,
5-aminocarbonyl-pyrid-3-yl-methyl-,
6-aminocarbonyl-pyrid-3-yl-methyl-,
1-(4-carboxy-pyrid-2-yl)-ethyl-, 5-carboxy-fur-2-yl-methyl-,
5-aminocarbonyl-fur-2-yl-methyl-, 1-(5-carboxy-fur-2-yl)-ethyl-,
4-carboxy-thien-2-yl-methyl-, 5-carboxy-thien-2-yl-methyl-,
5-aminocarbonyl-thien-2-yl-methyl-,
4-aminocarbonyl-thien-2-yl-methyl-, phenoxy-carbonyl-,
benzyloxy-carbonyl-, ethylamino-carbonyl-,
cyclopentyl-amino-carbonyl-, phenyl-aminocarbonyl-,
benzyl-amino-carbonyl-, 4-carboxy-phenyl-carbonyl-,
4-aminoarbonyl-phenyl-carbonyl-, 3-aminosulfonyl-phenyl-carbonyl-,
4-aminosulfonyl-phenyl-carbonyl-, 6-carboxy-pyrid-3-yl-carbonyl-,
6-aminocarbonyl-pyrid-3-yl-carbonyl-, 1,2,3-triazol-4-yl-carbonyl-,
1,2,4-triazol-3-yl-carbonyl-, methyl-sulfonyl-,
trifluoromethyl-sulfonyl-, carboxymethyl-sulfonyl-,
carboxyethyl-sulfonyl-, amino-sulfonyl-, amino-ethyl-sulfonyl-,
aminocarbonyl-methyl-sulfonyl-, phenyl-sulfonyl-,
4-fluorophenyl-sulfonyl-, 4-chlorophenyl-sulfonyl,
2-hydroxyphenyl-sulfonyl-, 3-hydroxyphenyl-sulfonyl-,
4-hydroxyphenyl-sulfonyl-, 2-methoxy-phenyl-sulfonyl-,
3-methoxy-phenyl-sulfonyl-, 4-methoxy-phenyl-sulfonyl-,
2-trifluoromethyl-phenyl-sulfonyl-,
3-trifluoromethyl-phenyl-sulfonyl-,
4-trifluoromethyl-phenyl-sulfonyl-,
4-trifluoromethoxy-phenyl-sulfonyl-, 2-carboxyphenyl-sulfonyl-,
3-carboxyphenyl-sulfonyl-, 4-carboxyphenyl-sulfonyl-,
4-carboxy-methoxy-phenyl-sulfonyl-, 3-aminophenyl-sulfonyl-,
4-aminophenyl-sulfonyl-, 2-aminocarbonyl-phenyl-sulfonyl-,
3-aminocarbonyl-phenyl-sulfonyl-, 4-aminocarbonyl-phenyl-sulfonyl-,
4-aminocarbonyl-methoxy-phenyl-sulfonyl-,
3-(methylamino-carbonyl)-phenyl-sulfonyl-,
3-(carboxy-ethyl-amino-carbonyl)-phenyl-sulfonyl-,
3-(3-hydroxy-n-propyl-amino-carbonyl)-phenyl-sulfonyl-,
3-(2-(methoxycarbonyl)-ethyl-amino-carbonyl)-phenyl-sulfonyl-,
3-(2-hydroxyethyl-amino-carbonyl)-phenyl-sulfonyl-,
3-fluoro-4-hydroxy-phenyl-sulfonyl-,
3-fluoro-4-methoxy-phenyl-sulfonyl-,
3-fluoro-4-aminocabonyl-phenyl-sulfonyl-,
3-fluoro-4-carboxy-phenyl-sulfonyl-,
3-chloro-4-aminocarbonyl-phenyl-sulfonyl-,
3-chloro-4-carboxy-phenyl-sulfonyl-,
3-methyl-4-aminocarbonyl-phenyl-sulfonyl-,
3-methyl-4-carboxy-phenyl-sulfonyl-,
3-trifluoromethyl-4-carboxy-phenyl-sulfonyl-,
3-trifluoromethyl-4-aminocarbonyl-phenyl-sulfonyl,
3-methoxy-4-carboxy-phenyl-sulfonyl,
3-methoxy-4-aminocarbonyl-phenyl-sulfonyl-,
3-carboxy-4-chloro-phenyl-sulfonyl-,
3-carboxy-4-fluoro-phenyl-sulfonyl-,
3-carboxy-4-methyl-phenyl-sulfonyl-,
3-carboxy-4-methoxy-phenyl-sulfonyl-,
3-aminocarbonyl-4-fluoro-phenyl-sulfonyl-,
3-aminocarbonyl-4-methyl-phenyl-sulfonyl-,
3-aminocarbonyl-4-methoxy-phenyl-sulfonyl-,
3,5-dichloro-4-hydroxy-phenyl-sulfonyl-,
piperazin-1-yl-ethyl-sulfonyl-,
5-(hydroxymethyl)-fur-2-yl-sulfonyl-, 5-carboxy-fur-2-yl-sulfonyl-,
5-(aminocarbonyl)-fur-2-yl-sulfonyl-,
4-carboxy-thien-2-yl-sulfonyl-,
4-(aminocarbonyl)-thien-2-yl-sulfonyl-,
3-methyl-5-carboxy-thien-2-yl-sulfonyl-,
3-methyl-5-(aminocarbonyl)-thien-2-yl-sulfonyl-,
6-carboxy-pyrid-3-yl-sulfonyl-,
6-aminocarbonyl-pyrid-3-yl-sulfonyl-,
6-(2-hydroxyethyl-amino-carbonyl)-pyrid-3-yl-sulfonyl-,
6-(carboxyethyl-amino-carbonyl)-pyrid-3-yl-sulfonyl- and
6-(methoxycarbonyl-ethyl-amino-carbonyl)-pyrid-3-yl-sulfonyl-; (e)
is ##STR00530## wherein a is 0; and wherein R.sup.5 is selected
from the group consisting of ethoxycarbonyl- and
trifluoromethyl-sulfonyl-; (f) is ##STR00531## wherein R.sup.5 is
trifluoromethyl-sulfonyl-; (g) is ##STR00532## wherein b is an
integer from 0 to 1; wherein L.sup.2 is selected from the group
consisting of --CH.sub.2--, --CH.sub.2CH.sub.2--, --CH(CH.sub.3)--,
--CH(CH.sub.3)--CH.sub.2--, --CH.sub.2--CH(CH.sub.3)--,
--CH.sub.2--CH(R*--CH.sub.3)--, --CH.sub.2--CH(S*--CH.sub.3)--,
--CH.sub.2CH.sub.2--O--, --CH.sub.2--CH(OH)--,
--CH.sub.2--CH(R*--OH), --CH(CH.sub.3)--CH(OH) and
--CH.sub.2CH.sub.2CH.sub.2--NH--SO.sub.2--; wherein R.sup.8 is
selected from the group consisting of hydrogen, 3-bromo, 3-chloro,
4-chloro, 3-hydroxy, 4-hydroxy, 3-methoxy, 4-methoxy,
4-trifluoromethyl, 3-carboxy, 4-carboxy, 3-carboxy-methoxy-,
4-carboxy-methoxy-, 3-methoxycarbonyl-,4-methoxycarbonyl-,
3-ethoxy-carbonyl-methoxy-, 4-ethoxy-carbonyl-methoxy-,
4-aminocarbonyl-, 3-amino-carbonyl-methoxy-,
4-amino-carbonyl-methoxy-, 3-(3-carboxyphenyl),
3-(4-carboxy-phenyl), 4-(3-carboxyphenyl), 4-(4-carboxyphenyl) and
3-(5-carboxy-thien-2-yl); and wherein R.sup.7 is selected from the
group consisting of hydrogen and 5-trifluoromethyl; (h) is
##STR00533## wherein L.sup.3 is selected from the group consisting
of --CH.sub.2-- and --CH.sub.2CH.sub.2--O--; and wherein R.sup.8 is
selected from the group consisting of hydrogen, carboxy and
methoxycarbonyl-; (i) is ##STR00534## wherein c is an integer from
0 to 1; and wherein L.sup.4 is --CH.sub.2--; (j) is ##STR00535##
and (k) is ##STR00536## or a stereoisomer, tautomer or
pharmaceutically acceptable salt thereof.
5. A compound as in claim 4, wherein R.sup.0 is selected from the
group consisting of hydrogen, --OH, --CO.sub.2H, --C(O)OCH.sub.3
and --CH.sub.2OCH.sub.3; ##STR00537## is selected from the group
consisting of 4-chlorophenyl, 4-fluorophenyl, 4-methylphenyl and
4-methoxyphenyl; ##STR00538## is selected from the group consisting
of phenyl, 4-chlorophenyl, 4-fluorphenyl, 4-methylphenyl,
4-trifluoromethyl-phenyl, 4-methoxyphenyl, 4-carboxyphenyl,
thiazol-2-yl and benzo[d][1,3]dioxol-5-yl; R.sup.1 is selected from
the group consisting of hydrogen, --OH and --OCH.sub.3; R.sup.2 is
selected from the group consisting of hydrogen, methyl, ethyl,
cyclopropyl, cyclobutyl, amino-ethyl-,
--C.dbd.(CH.sub.2)--CH.sub.2OH, oxetan-3-yl, tetrahydrofur-2-yl and
pyrid-3-yl; R.sup.3 is selected from the group consisting of (a),
(b), (d), (f), (g), (h) and (i); wherein (a) is ##STR00539##
wherein the cyclohexyl group is bound in a cis-, trans- or racemic
orientation; and wherein R.sup.4 is selected from the group
consisting of hydrogen, aminocarbonyl-, 3-hydroxyphenyl-amino-,
3-carboxyphenyl-amino-, 4-carboxyphenyl-amino-,
3-carboxyphenyl-sulfonyl-amino- and
4-carboxyphenyl-sulfonyl-amino-; (b) is ##STR00540## wherein a 0;
and wherein R.sup.5 is selected from the group consisting of
3-carboxybenzyl- and 4-carboxyphenyl-sulfonyl-; (d) is ##STR00541##
wherein a is an integer from 0 to 1; wherein L.sup.1 is
--CH.sub.2--; and wherein R.sup.5 is selected from the group
consisting of propyn-3-yl, methoxy-carbonyl-methyl-,
3-carboxyphenyl-oxy-ethyl-, 2-hydroxyethyl-carbonyl-,
hydroxymethyl-carbonyl-, aminocarbonyl-methyl-carbonyl-,
aminocarbonyl-ethyl-carbonyl-, ethoxycarbonyl-, t-butoxycarbonyl-,
cyclopentyloxy-carbonyl-, 2,3,4-trihydroxy-n-butyloxy-carbonyl-,
3-carboxyphenyl, 4-carboxyphenyl, 3-(aminocarbonyl)-phenyl,
4-(aminocarbonyl)-phenyl, 3-(aminocarbonyl-methyl)-phenyl,
4-(aminocarbonyl-methyl)-phenyl, 3-(aminocarbonyl-methoxy)-phenyl,
4-(aminocarbonyl-methoxy)-phenyl, 3-hydroxy-benzyl,
2-trifluoromethyl-benzyl, 3-carboxy-benzyl, 4-carboxy-benzyl,
3-(aminocarbonyl)-benzyl, 4-(aminocarbonyl)-benzyl,
3-(2-hydroxyethyl-aminocarbonyl)-benzyl,
2-hydroxy-3-carboxy-benzyl, 2-fluoro-5-carboxy-benzyl,
3-fluoro-5-carboxy-benzyl, 2-chloro-3-carboxy-benzyl,
2-chloro-5-carboxy-benzyl, 2-trifluoromethyl-5-carboxy-benzyl,
3-carboxy-4-fluoro-benzyl, 3-carboxy-4-hydroxy-benzyl,
1-(3-hydroxyphenyl)-ethyl-, 1-(3-carboxyphenyl)-ethyl-,
1R*-(3-carboxyphenyl)-ethyl-, 1-(3-carboxyphenyl)-n-propyl-,
5-carboxy-pyrimidin-2-yl, 5-methoxycarbonyl-pyrimidin-2-yl,
2-carboxy-pyrid-4-yl-methyl-, 4-carboxy-pyrid-2-yl-methyl-,
5-carboxy-pyrid-2-yl-methyl-, 6-carboxy-pyrid-2-yl-methyl-,
5-carboxy-pyrid-3-yl-methyl-, 6-carboxy-pyrid-3-yl-methyl-,
5-aminocarbonyl-pyrid-2-yl-methyl-,
6-aminocarbonyl-pyrid-2-yl-methyl-,
5-aminocarbonyl-pyrid-3-yl-methyl-,
6-aminocarbonyl-pyrid-3-yl-methyl-,
1-(4-carboxy-pyrid-2-yl)-ethyl-, 5-carboxy-fur-2-yl-methyl-,
1-(5-carboxy-fur-2-yl)-ethyl-, 5-aminocarbonyl-fur-2-yl-methyl-,
4-carboxy-thien-2-yl-methyl-, 5-carboxy-thien-2-yl-methyl-,
5-aminocarbonyl-thien-2-yl-methyl-,
4-aminocarbonyl-thien-2-yl-methyl-, phenoxy-carbonyl-,
benzyloxy-carbonyl-, ethylamino-carbonyl-,
cyclopentyl-amino-carbonyl-, phenyl-aminocarbonyl-,
benzyl-amino-carbonyl-, 4-aminocarbonyl-phenyl-carbonyl-,
3-aminosulfonyl-phenyl-carbonyl-, 4-aminosulfonyl-phenyl-carbonyl-,
6-aminocarbonyl-pyrid-3-yl-carbonyl-, 1,2,4-triazol-3-yl-carbonyl-,
methylsulfonyl-, trifluoromethyl-sulfonyl-, phenyl-sulfonyl-,
4-fluorophenyl-sulfonyl-, 4-chlorophenyl-sulfonyl,
2-hydroxyphenyl-sulfonyl-, 3-hydroxyphenyl-sulfonyl-,
4-hydroxyphenyl-sulfonyl-, 2-methoxy-phenyl-sulfonyl-,
3-methoxy-phenyl-sulfonyl-, 4-methoxy-phenyl-sulfonyl-,
2-trifluoromethyl-phenyl-sulfonyl-,
3-trifluoromethyl-phenyl-sulfonyl-,
4-trifluoromethyl-phenyl-sulfonyl-,
4-trifluoromethoxy-phenyl-sulfonyl-,3-carboxyphenyl-sulfonyl-,
4-carboxyphenyl-sulfonyl-, 3-aminophenyl-sulfonyl-,
4-aminophenyl-sulfonyl-, 2-aminocarbonyl-phenyl-sulfonyl-,
3-aminocarbonyl-phenyl-sulfonyl-, 4-aminocarbonyl-phenyl-sulfonyl-,
4-aminocarbonyl-methoxy-phenyl-sulfonyl-,
3-(methylamino-carbonyl)-phenyl-sulfonyl-,
3-(3-hydroxy-n-propyl-amino-carbonyl)-phenyl-sulfonyl-,
3-(2-(methoxycarbonyl)-ethyl-amino-carbonyl)-phenyl-sulfonyl-,
3-(2-hydroxyethyl-amino-carbonyl)-phenyl-sulfonyl-,
3-fluoro-4-methoxy-phenyl-sulfonyl-,
3-fluoro-4-aminocabonyl-phenyl-sulfonyl-,
3-fluoro-4-carboxy-phenyl-sulfonyl-,
3-chloro-4-aminocarbonyl-phenyl-sulfonyl-,
3-chloro-4-carboxy-phenyl-sulfonyl,
3-methyl-4-carboxy-phenyl-sulfonyl-,
3-trifluoromethyl-4-carboxy-phenyl-sulfonyl-,
3-trifluoromethyl-4-aminocarbonyl-phenyl-sulfonyl,
3-methoxy-4-aminocarbonyl-phenyl-sulfonyl-,
3-methoxy-4-carboxy-phenyl-sulfonyl-,
3-carboxy-4-chloro-phenyl-sulfonyl-,
3-carboxy-4-fluoro-phenyl-sulfonyl-,
3-aminocarbonyl-4-fluoro-phenyl-sulfonyl-,
3-aminocarbonyl-4-methyl-phenyl-sulfonyl-,
3-aminocarbonyl-4-methoxy-phenyl-sulfonyl-,
3,5-dichloro-4-hydroxy-phenyl-sulfonyl-,
5-(hydroxymethyl)-fur-2-yl-sulfonyl-, 5-carboxy-fur-2-yl-sulfonyl-,
5-(aminocarbonyl)-fur-2-yl-sulfonyl-,
4-carboxy-thien-2-yl-sulfonyl-,
4-(aminocarbonyl)-thien-2-yl-sulfonyl-,
3-methyl-5-carboxy-thien-2-yl-sulfonyl-,
3-methyl-5-(aminocarbonyl)-thien-2-yl-sulfonyl-,
6-carboxy-pyrid-3-yl-sulfonyl-,
6-aminocarbonyl-pyrid-3-yl-sulfonyl-,
6-(2-hydroxyethyl-amino-carbonyl)-pyrid-3-yl-sulfonyl-,
6-(carboxyethyl-amino-carbonyl)-pyrid-3-yl-sulfonyl- and
6-(methoxycarbonyl-ethyl-amino-carbonyl)-pyrid-3-yl-sulfonyl-; (f)
is ##STR00542## wherein R.sup.5 is trifluoromethyl-sulfonyl-; (g)
is ##STR00543## wherein b is an integer from 0 to 1; L.sup.2 is
selected from the group consisting of --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH(CH.sub.3)--CH.sub.2--,
--CH.sub.2--CH(R*--CH.sub.3)--, --CH.sub.2--CH(S*--CH.sub.3)--,
--CH.sub.2CH.sub.2--O--, --CH.sub.2--CH(OH)-- and
--CH.sub.2CH.sub.2CH.sub.2--NH--SO.sub.2--; and wherein R.sup.6 is
selected from the group consisting of hydrogen, 3-chloro-,
4-chloro-, 3-bromo-, 4-bromo-, 3-hydroxy, 4-hydroxy-,
4-trifluoromethyl, 3-methoxy-, 4-methoxy-, 4-methoxycarbonyl-,
3-(ethoxy-carbonyl-methoxy)-, 4-(ethoxy-carbonyl-methoxy)-,
3-(aminocarbonyl-methoxy)-, 4-(aminocarbonyl-methoxy)-,
3-(3-carboxyphenyl), 3-(4-carboxyphenyl) and
3-(5-carboxy-thein-2-yl); and R.sup.7 is selected from the group
consisting of hydrogen and 5-trifluoromethyl; (h) is ##STR00544##
wherein L.sup.3 is --CH.sub.2CH.sub.2-- and wherein R.sup.8 is
5-methoxycarbonyl-; and (i) is ##STR00545## wherein c is an integer
from 0 to 1; and wherein L.sup.4 is --CH.sub.2--; or a
stereoisomer, tautomer or pharmaceutically acceptable salt
thereof.
6. A compound as in claim 4, wherein R.sup.0 is selected from the
group consisting of hydrogen, --OH, --CO.sub.2H and
--C(O)OCH.sub.3; ##STR00546## is selected from the group consisting
of 4-chlorophenyl, 4-fluorophenyl and 4-methylphenyl; ##STR00547##
is selected from the group consisting of phenyl, 4-chlorophenyl,
4-fluorphenyl, 4-methylphenyl, 4-trifluoromethyl-phenyl,
thiazol-2-yl and benzo[d][1,3]dioxol-5-yl; R.sup.1 is selected from
the group consisting of hydrogen, --OH and --OCH.sub.3; R.sup.2 is
selected from the group consisting of hydrogen, methyl, ethyl,
cyclopropyl, cyclobutyl, oxetan-3-yl and tetrahydrofur-2-yl;
R.sup.3 is selected from the group consisting of (a), (b), (d),
(f), (g) and (i); wherein (a) is ##STR00548## wherein the
cyclohexyl group is bound in trans-orientation; and wherein R.sup.4
is 3-hydroxyphenyl-amino-; (b) is ##STR00549## wherein a 0; and
wherein R.sup.5 is 3-carboxybenzyl-; (d) is ##STR00550## wherein a
is an integer from 0 to 1; wherein L.sup.1 is --CH.sub.2--; and
wherein R.sup.5 is selected from the group consisting of
propyn-3-yl, methoxy-carbonyl-methyl-, 3-carboxyphenyl-oxy-ethyl-,
2-hydroxyethyl-carbonyl-, hydroxymethyl-carbonyl-,
ethoxycarbonyl-cyclopentyloxy-carbonyl-, 4-carboxyphenyl,
3-(aminocarbonyl)-phenyl, 4-(aminocarbonyl)-phenyl,
3-(aminocarbonyl-methyl)-phenyl, 4-(aminocarbonyl-methyl)-phenyl,
3-(aminocarbonyl-methoxy)-phenyl, 4-(aminocarbonyl-methoxy)-phenyl,
3-hydroxy-benzyl, 3-carboxy-benzyl, 4-carboxy-benzyl,
3-(aminocarbonyl)-benzyl, 4-(aminocarbonyl)-benzyl,
3-(2-hydroxyethyl-aminocarbonyl)-benzyl, 2-fluoro-5-carboxy-benzyl,
3-fluoro-5-carboxy-benzyl, 2-chloro-5-carboxy-benzyl,
3-carboxy-4-fluoro-benzyl, 3-carboxy-4-hydroxy-benzyl,
1-(3-hydroxyphenyl)-ethyl-, 1-(3-carboxyphenyl)-ethyl-,
1R*-(3-carboxyphenyl)-ethyl-, 1-(3-carboxyphenyl)-n-propyl-,
5-carboxy-pyrimidin-2-yl, 5-carboxy-pyrid-3-yl-methyl-,
6-carboxy-pyrid-3-yl-methyl-, 5-aminocarbonyl-pyrid-2-yl-methyl-,
6-aminocarbonyl-pyrid-2-yl-methyl-,
5-aminocarbonyl-pyrid-3-yl-methyl-,
6-aminocarbonyl-pyrid-3-yl-methyl-,
1-(4-carboxy-pyrid-2-yl)-ethyl-, 5-carboxy-fur-2-yl-methyl-,
5-aminocarbonyl-fur-2-yl-methyl-, 1-(5-carboxy-fur-2-yl)-ethyl-,
4-carboxy-thien-2-yl-methyl-, 5-carboxy-thien-2-yl-methyl-,
5-aminocarbonyl-thien-2-yl-methyl-,
4-aminocarbonyl-thien-2-yl-methyl-, phenoxy-carbonyl-,
benzyloxy-carbonyl-, ethylamino-carbonyl-,
3-aminosulfonyl-phenyl-carbonyl-,
6-aminocarbonyl-pyrid-3-yl-carbonyl-, methylsulfonyl-,
trifluoromethyl-sulfonyl-, phenyl-sulfonyl-,
4-fluorophenyl-sulfonyl-, 4-chlorophenyl-sulfonyl,
2-hydroxyphenyl-sulfonyl-, 3-hydroxyphenyl-sulfonyl-,
4-hydroxyphenyl-sulfonyl-, 2-methoxy-phenyl-sulfonyl-,
3-methoxy-phenyl-sulfonyl-, 4-methoxy-phenyl-sulfonyl-,
2-trifluoromethyl-phenyl-sulfonyl-,
3-trifluoromethyl-phenyl-sulfonyl-,
4-trifluoromethyl-phenyl-sulfonyl-, 3-carboxyphenyl-sulfonyl-,
4-carboxyphenyl-sulfonyl-, 3-aminophenyl-sulfonyl-,
3-aminocarbonyl-phenyl-sulfonyl-, 4-aminocarbonyl-phenyl-sulfonyl-,
4-aminocarbonyl-methoxy-phenyl-sulfonyl-,
3-(methylamino-carbonyl)-phenyl-sulfonyl-,
3-(3-hydroxy-n-propyl-amino-carbonyl)-phenyl-sulfonyl-,
3-fluoro-4-aminocabonyl-phenyl-sulfonyl-,
3-fluoro-4-carboxy-phenyl-sulfonyl-,
3-chloro-4-aminocarbonyl-phenyl-sulfonyl-,
3-chloro-4-carboxy-phenyl-sulfonyl,
3-methyl-4-carboxy-phenyl-sulfonyl-,
3-trifluoromethyl-4-carboxy-phenyl-sulfonyl-,
3-methoxy-4-aminocarbonyl-phenyl-sulfonyl-,
3-methoxy-4-carboxy-phenyl-sulfonyl-,
3-carboxy-4-chloro-phenyl-sulfonyl-,
3-carboxy-4-fluoro-phenyl-sulfonyl-,
3-aminocarbonyl-4-fluoro-phenyl-sulfonyl-,
3,5-dichloro-4-hydroxy-phenyl-sulfonyl-,
5-(hydroxymethyl)-fur-2-yl-sulfonyl-, 5-carboxy-fur-2-yl-sulfonyl-,
5-(aminocarbonyl)-fur-2-yl-sulfonyl-,
4-carboxy-thien-2-yl-sulfonyl-,
4-(aminocarbonyl)-thien-2-yl-sulfonyl-,
3-methyl-5-carboxy-thien-2-yl-sulfonyl-,
3-methyl-5-(aminocarbonyl)-thien-2-yl-sulfonyl-,
6-carboxy-pyrid-3-yl-sulfonyl-,
6-aminocarbonyl-pyrid-3-yl-sulfonyl- and
6-(methoxycarbonyl-ethyl-amino-carbonyl)-pyrid-3-yl-sulfonyl-; (f)
is ##STR00551## wherein R.sup.5 is trifluoromethyl-sulfonyl-; (g)
is ##STR00552## wherein b is an integer from 0 to 1; L.sup.2 is
selected from the group consisting of --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2--CH(R*--CH.sub.3)--,
--CH.sub.2CH.sub.2--O--, --CH.sub.2--CH(OH)-- and
--CH.sub.2CH.sub.2CH.sub.2--NH--SO.sub.2--; and wherein R.sup.6 is
selected from the group consisting of hydrogen, 3-chloro-,
3-bromo-, 4-bromo-, 3-hydroxy, 4-trifluoromethyl, 3-methoxy-,
4-methoxy-, 3-(ethoxy-carbonyl-methoxy)-,
4-(ethoxy-carbonyl-methoxy)-, and 3-(5-carboxy-thein-2-yl); and
R.sup.7 is hydrogen; and (i) is ##STR00553## wherein c is 1; and
wherein L.sup.4 is --CH.sub.2--; or a stereoisomer, tautomer or
pharmaceutically acceptable salt thereof.
7. A compound as in claim 4, wherein R.sup.0 is selected from the
group consisting of hydrogen, --OH and --CO.sub.2H; ##STR00554## is
4-chlorophenyl; ##STR00555## is selected from the group consisting
of 4-chlorophenyl, thiazol-2-yl and benzo[d][1,3]dioxol-5-yl;
R.sup.1 is selected from the group consisting of hydrogen and
--OCH.sub.3; R.sup.2 is selected from the group consisting of
ethyl, cyclopropyl, cyclobutyl, oxetan-3-yl and tetrahydrofur-2-yl;
R.sup.3 is selected from the group consisting of (d), (f) and (g);
wherein (d) is ##STR00556## wherein a is an integer from 0 to 1;
wherein L.sup.1 is --CH.sub.2--; and wherein R.sup.5 is selected
from the group consisting of propyn-3-yl, methoxy-carbonyl-methyl-,
3-(aminocarbonyl)-phenyl, 4-(aminocarbonyl)-phenyl,
3-(aminocarbonyl-methyl)-phenyl, 3-(aminocarbonyl-methoxy)-phenyl,
3-carboxy-benzyl, 3-(aminocarbonyl)-benzyl,
3-(2-hydroxyethyl-aminocarbonyl)-benzyl, 3-fluoro-5-carboxy-benzyl,
1-(3-carboxyphenyl)-ethyl-, 1R*-(3-carboxyphenyl)-ethyl-,
1-(3-carboxyphenyl)-n-propyl-, 5-carboxy-pyrimidin-2-yl,
5-aminocarbonyl-pyrid-2-yl-methyl-,
5-aminocarbonyl-pyrid-3-yl-methyl-,
6-aminocarbonyl-pyrid-3-yl-methyl-,
1-(4-carboxy-pyrid-2-yl)-ethyl-, 5-aminocarbonyl-fur-2-yl-methyl-,
5-carboxy-thien-2-yl-methyl-, 5-aminocarbonyl-thien-2-yl-methyl-,
4-aminocarbonyl-thien-2-yl-methyl-, benzyloxy-carbonyl-,
methylsulfonyl-, trifluoromethyl-sulfonyl-, phenyl-sulfonyl-,
4-fluorophenyl-sulfonyl-, 4-chlorophenyl-sulfonyl,
3-hydroxyphenyl-sulfonyl-, 4-hydroxyphenyl-sulfonyl-,
2-methoxy-phenyl-sulfonyl-, 3-trifluoromethyl-phenyl-sulfonyl-,
4-carboxyphenyl-sulfonyl-, 3-aminophenyl-sulfonyl-,
3-aminocarbonyl-phenyl-sulfonyl-,
4-aminocarbonyl-methoxy-phenyl-sulfonyl-,
3-chloro-4-carboxy-phenyl-sulfonyl,
3-methyl-4-carboxy-phenyl-sulfonyl-,
3-trifluoromethyl-4-carboxy-phenyl-sulfonyl-,
3-methoxy-4-aminocarbonyl-phenyl-sulfonyl-,
3-methoxy-4-carboxy-phenyl-sulfonyl-,
5-(aminocarbonyl)-fur-2-yl-sulfonyl-,
4-carboxy-thien-2-yl-sulfonyl-,
4-(aminocarbonyl)-thien-2-yl-sulfonyl-,
3-methyl-5-carboxy-thien-2-yl-sulfonyl-,
3-methyl-5-(aminocarbonyl)-thien-2-yl-sulfonyl- and
6-aminocarbonyl-pyrid-3-yl-sulfonyl-; (f) is ##STR00557## wherein
R.sup.5 is trifluoromethyl-sulfonyl-; and (g) is ##STR00558##
wherein b is an integer from 0 to 1; L.sup.2 is
--CH.sub.2CH.sub.2--; and wherein R.sup.6 is selected from the
group consisting of 3-chloro-, 4-trifluoromethyl, 4-methoxy- and
4-(ethoxy-carbonyl-methoxy)-; and R.sup.7 is hydrogen; or a
stereoisomer, tautomer or pharmaceutically acceptable salt
thereof.
8. A compound as in claim 4, wherein R.sup.0 is selected from the
group consisting of hydrogen and --OH; ##STR00559## is
4-chlorophenyl; ##STR00560## is 4-chlorophenyl; R.sup.1 is selected
from the group consisting of hydrogen and --OCH.sub.3; R.sup.2 is
selected from the group consisting of cyclopropyl, cyclobutyl and
tetrahydrofur-2-yl; R.sup.3 is selected from the group consisting
of (d), (f) and (g); wherein (d) is ##STR00561## wherein a is an
integer from 0 to 1; wherein L.sup.1 is --CH.sub.2--; and wherein
R.sup.5 is selected from the group consisting of
methoxy-carbonyl-methyl-, 3-(aminocarbonyl)-benzyl,
1R*-(3-carboxyphenyl)-ethyl-, 5-aminocarbonyl-pyrid-2-yl-methyl-,
1-(4-carboxy-pyrid-2-yl)-ethyl 5-aminocarbonyl-thien-2-yl-methyl-,
4-aminocarbonyl-thien-2-yl-methyl-, trifluoromethyl-sulfonyl-,
phenyl-sulfonyl-, 4-chlorophenyl-sulfonyl,
3-hydroxyphenyl-sulfonyl-, 2-methoxy-phenyl-sulfonyl-,
3-aminocarbonyl-phenyl-sulfonyl-,
4-aminocarbonyl-methoxy-phenyl-sulfonyl-,
3-chloro-4-carboxy-phenyl-sulfonyl,
3-trifluoromethyl-4-carboxy-phenyl-sulfonyl3-methyl-5-(aminocarbonyl)-thi-
en-2-yl-sulfonyl- and 6-aminocarbonyl-pyrid-3-yl-sulfonyl-; (f) is
##STR00562## wherein R.sup.5 is trifluoromethyl-sulfonyl-; and (g)
is ##STR00563## wherein b is an integer from 0 to 1; L.sup.2 is
--CH.sub.2CH.sub.2--; and wherein R.sup.6 is selected from the
group consisting of 4-trifluoromethyl, 4-methoxy- and
4-(ethoxy-carbonyl-methoxy)-; and R.sup.7 is hydrogen; or a
stereoisomer, tautomer or pharmaceutically acceptable salt
thereof.
9. A compound as in claim 4, wherein R.sup.0 is hydrogen;
##STR00564## is selected from the group consisting of
4-chlorophenyl and 4-methoxyphenyl; ##STR00565## is selected from
the group consisting of 4-chlorophenyl, 4-methoxyphenyl and
thiazol-2-yl; R.sup.1 is hydrogen; R.sup.2 is selected from the
group consisting of ethyl, cyclopropyl and cyclobutyl; R.sup.3 is
selected from the group consisting of
1-(3-fluoro-5-carboxy-benzyl)-piperidin-4-yl,
1-(2-fluoro-5-carboxy-benzyl)-piperidin-4-yl,
1-(5-carboxy-pyrid-2-yl-methyl)-piperidin-4-yl,
1-(6-carboxy-pyrid-2-yl-methyl)-piperidin-4-yl,
1-(5-carboxy-thien-2-yl-methyl)-piperidin-4-yl,
1-(4-carboxy-thien-2-yl-sulfonyl)-piperidin-4-yl,
1-(5-carboxy-fur-2-yl-sulfonyl)-piperidin-4-yl,
1-(3-carboxy-benzyl)-piperidin-4-yl,
1-(3-carboxy-phenyl-sulfonyl)-piperidin-4-yl,
1-(3-hydroxy-phenyl-sulfonyl)-piperidin-4-yl,
1-(4-carboxy-phenyl-sulfonyl)-piperidin-4-yl,
1-trifluoromethyl-sulfonyl-piperidin-4-yl-methyl- and
1-trifluoromethyl-sulfonyl-piperidin-4-yl; or a stereoisomer,
tautomer or pharmaceutically acceptable salt thereof.
10. A compound as in claim 4, wherein R.sup.0 is hydrogen,
##STR00566## is selected from the group consisting of
4-chlorophenyl and 4-methoxyphenyl; ##STR00567## is selected from
the group consisting of 4-chlorophenyl and 4-methoxyphenyl; R.sup.1
is hydrogen; R.sup.2 is selected from the group consisting of
ethyl, cyclopropyl and cyclobutyl; R.sup.3 is selected from the
group consisting of 1-(3-fluoro-5-carboxy-benzyl)-piperidin-4-yl,
1-(2-fluoro-5-carboxy-benzyl)-piperidin-4-yl,
1-(5-carboxy-pyrid-2-yl-methyl)-piperidin-4-yl,
1-(6-carboxy-pyrid-2-yl-methyl)-piperidin-4-yl,
1-(5-carboxy-thien-2-yl-methyl)-piperidin-4-yl,
1-(3-carboxy-benzyl)-piperidin-4-yl,
1-(3-carboxy-phenyl-sulfonyl)-piperidin-4-yl,
1-(3-hydroxy-phenyl-sulfonyl)-piperidin-4-yl,
1-trifluoromethyl-sulfonyl-piperidin-4-yl-methyl-,
1-trifluoromethyl-sulfonyl-piperidin-4-yl, or a stereoisomer,
tautomer or pharmaceutically acceptable salt thereof.
11. A compound of formula (II) ##STR00568## or a stereoisomer,
tautomer or pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a compound of claim 1 or claim 11.
13. A pharmaceutical composition made by mixing a compound of claim
1 or claim 11 and a pharmaceutically acceptable carrier.
14. A process for making a pharmaceutical composition comprising
mixing a compound of claim 1 or claim 11 and a pharmaceutically
acceptable carrier.
15. A method of treating a disorder mediated by the CB-1 receptor,
comprising administering to a subject in need thereof a
therapeutically effective amount of the compound of claim 1 or
claim 11.
16. The method of claim 15, wherein the disorder mediated by the
CB-1 receptor is selected from the group consisting of obesity,
Type I diabetes, Type II diabetes, gestational diabetes, latent
autoimmune diabetes of adults (LADA), pre-diabetes, insulin
resistance, inadequate glucose tolerance, dyslipidemias (including,
but not limited to elevated triglycerides and LDL, and low HDL),
nonalcoholic steatohepatitis (NASH), cirrhosis, fatty liver
disease, atherosclerosis, hypertension, inflammatory bowel disease,
Alzheimer's disease, osteoporosis, multiple sclerosis, traumatic
brain injury, arthritis, and neuropathic pain.
17. A method of treating a disorder selected from the group
consisting of obesity, Type I diabetes, Type II diabetes,
gestational diabetes, latent autoimmune diabetes of adults (LADA),
pre-diabetes, insulin resistance, inadequate glucose tolerance,
dyslipidemias (including, but not limited to elevated triglycerides
and LDL, and low HDL), nonalcoholic steatohepatitis (NASH),
cirrhosis, fatty liver disease, atherosclerosis, hypertension,
inflammatory bowel disease, Alzheimer's disease, osteoporosis,
multiple sclerosis, traumatic brain injury, arthritis, and
neuropathic pain, comprising administering to a subject in need
thereof a therapeutically effective amount of the composition of
claim 12.
18. The use of a compound as in claim 1 or claim 11 for the
preparation of a medicament for treating: (a) obesity, (b) Type I
diabetes, (c) Type II diabetes, (d) gestational diabetes, (e)
latent autoimmune diabetes of adults (LADA), (f) pre-diabetes, (g)
insulin resistance, (h) inadequate glucose tolerance, (i)
dyslipidemia (including, but not limited to elevated triglycerides
and LDL, and low HDL), (j) nonalcoholic steatohepatitis (NASH), (k)
cirrhosis, (I) fatty liver disease, (m) atherosclerosis, (n)
hypertension, (o) inflammatory bowel disease, (p) Alzheimer's
disease, (q) osteoporosis, (r) multiple sclerosis, (s) traumatic
brain injury, (t) arthritis, or (u) neuropathic pain, in a subject
in need thereof.
19. The use of a compound as in claim 1 or claim 11, for use in a
method for treating a disorder selected from the group consisting
of obesity, Type I diabetes, Type II diabetes, gestational
diabetes, latent autoimmune diabetes of adults (LADA),
pre-diabetes, insulin resistance, inadequate glucose tolerance,
dyslipidemias (including, but not limited to elevated triglycerides
and LDL, and low HDL), nonalcoholic steatohepatitis (NASH),
cirrhosis, fatty liver disease, atherosclerosis, hypertension,
inflammatory bowel disease, Alzheimer's disease, osteoporosis,
multiple sclerosis, traumatic brain injury, arthritis, and
neuropathic pain, in a subject in need thereof.
20. A compound as in claim 1 or claim 11 for use as a
medicament.
21. A compound as in claim 1 or claim 11 for use in the treatment
of a disorder mediated by the CB-1 receptor.
22. A compound as in claim 1 or claim 11, for us in the treatment
of a disorder mediated by the CB-1 receptor, selected from the
group consisting of obesity, Type I diabetes, Type II diabetes,
gestational diabetes, latent autoimmune diabetes of adults (LADA),
pre-diabetes, insulin resistance, inadequate glucose tolerance,
dyslipidemias (including, but not limited to elevated triglycerides
and LDL, and low HDL), nonalcoholic steatohepatitis (NASH),
cirrhosis, fatty liver disease, atherosclerosis, hypertension,
inflammatory bowel disease, Alzheimer's disease, osteoporosis,
multiple sclerosis, traumatic brain injury, arthritis, and
neuropathic pain.
23. A composition comprising a compound as in claim 1 or claim 11,
for use in the treatment of a disorder mediated by the CB-1
receptor.
24. A composition comprising a compound as in claim 1 or claim 11,
for use in the treatment of a disorder mediated by CB-1 receptor
selected from the group consisting of obesity, Type I diabetes,
Type II diabetes, gestational diabetes, latent autoimmune diabetes
of adults (LADA), pre-diabetes, insulin resistance, inadequate
glucose tolerance, dyslipidemias (including, but not limited to
elevated triglycerides and LDL, and low HDL), nonalcoholic
steatohepatitis (NASH), cirrhosis, fatty liver disease,
atherosclerosis, hypertension, inflammatory bowel disease,
Alzheimer's disease, osteoporosis, multiple sclerosis, traumatic
brain injury, arthritis, and neuropathic pain.
25. A compound, composition or method of treatment as described
herein.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 15/244,372, filed on Aug. 23, 2016, which claims priority from
U.S. Provisional Application 62/209,381, filed on Aug. 25, 2015,
and U.S. Provisional Application 62/233,655, filed on Sep. 28, 2015
which is incorporated by reference herein in its entirety.
FIELD OF THE INVENTION
[0002] The present invention is directed to benzimidazole
derivatives, pharmaceutical compositions containing them and their
use in the treatment of disorders and conditions mediated by the
CB-1 receptor, more particularly, use in the treatment of disorders
and conditions responsive to inverse agonism of the CB-1 receptor.
More particularly, the compounds of the present invention are
useful in the treatment of metabolic disorders.
BACKGROUND OF THE INVENTION
[0003] Centrally penetrant cannabanoid-1 receptor (CB1) inverse
agonist compounds are efficacious for weight loss, glycemic control
and treatment of cardiovascular risk factors associated with
obesity and/or Type II diabetes mellitus. However such compounds
are also associated with serious adverse effects such as anxiety,
depression, suicidal ideation, and others, which adverse effects
preclude their use. Peripherally restricted cannabanoid-1 receptor
(CB1R) inverse agonists aim to selectively inhibit the CB1R in
organs/tissues outside the blood-brain barrier, for example in the
liver, adipose tissue and/or skeletal muscle, to avoid these
adverse effects.
[0004] Thus, there is a need for peripherally restricted
cannabanoid-1 receptor (CB1R) inverse agonists for the treatment
of, for example metabolic disorders, such as obesity, Type II
diabetes mellitus, metabolic syndrome, Syndrome X, and the
like.
SUMMARY OF THE INVENTION
[0005] The present invention is directed to compounds of formula
(I)
##STR00001##
[0006] wherein
[0007] R.sup.0 is selected from the group consisting of hydrogen,
--OH, --C(O)OH, --C(O)O--(C.sub.1-4alkyl), --CH.sub.2--OH,
--CH.sub.2--O--(C.sub.1-2alkyl) and
--CH.sub.2--O--(C.sub.1-2alkyl)-CO.sub.2H;
##STR00002##
is selected from the group consisting of cylopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, phenyl, furyl, thienyl, thiazolyl,
benzothiazolyl and benzo[d][1,3]dioxolyl;
[0008] wherein the phenyl, furyl, thienyl, thiazolyl or
benzothiazolyl is optionally substituted with one or more
substituents independently selected from the group consisting of
halogen, hydroxy, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl,
C.sub.1-4alkoxy, fluorinated C.sub.1-2alkoxy, cyano, --C(O)OH,
--C(O)O--(C.sub.1-4alkyl), --C(O)NR.sup.AR.sup.B and
NR.sup.AR.sup.B; wherein R.sup.A and R.sup.B are each independently
selected from the group consisting of hydrogen, alkyl and hydroxy
substituted C.sub.1-2alkyl; provided that each substituent is bound
to a carbon atom;
##STR00003##
is selected from the group consisting of cylopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, phenyl, furyl, thienyl, thiazolyl,
benzothiazolyl and benzo[d][1,3]dioxolyl;
[0009] wherein the phenyl, furyl, thienyl, thiazolyl or
benzothiazolyl is optionally substituted with one or more
substituents independently selected from the group consisting of
halogen, hydroxy, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl,
C.sub.1-4alkoxy, fluorinated C.sub.1-2alkoxy, cyano, --C(O)OH,
--C(O)O--(C.sub.1-4alkyl), --C(O)NR.sup.CR.sup.D and
NR.sup.CR.sup.D; wherein R.sup.C and R.sup.D are each independently
selected from the group consisting of hydrogen, alkyl and hydroxy
substituted C.sub.1-2alkyl; provided that each substituent is bound
to a carbon atom;
[0010] R.sup.1 is selected from the group consisting of hydrogen,
hydroxy and C.sub.1-4alkoxy;
[0011] R.sup.2 is selected from the group consisting of hydrogen,
halogen, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl,
--(C.sub.1-2alkyl)-OH, --(C.sub.1-2alkyl)-C(O)OH,
--(C.sub.1-2alkyl)-NR.sup.ER.sup.F, --(C.sub.2-4alkenyl)-OH,
--C(O)OH, --C(O)O--(C.sub.1-2alkyl), --NR.sup.ER.sup.F,
C.sub.3-6cycloalkyl, phenyl, furyl, thienyl, pyridyl,
azetidin-3-yl, oxetan-3-yl, tetrahydrofuran-2-yl and
tetrahydropyran-4-yl;
[0012] wherein the phenyl is optionally substituted with one to two
halogen; wherein the azetidin-3-yl is optionally substituted with
--C(O)O--(C.sub.1-4alkyl); and wherein R.sup.E and R.sup.F are each
independently selected from the group consisting of hydrogen and
C.sub.1-4alkyl;
[0013] provided that when R.sup.2 is selected from the group
consisting of pyridyl, furyl and thienyl, then the R.sup.2 is bound
to the benzimidazole core through a carbon atom;
[0014] R.sup.3 is selected from the group consisting of (a) through
(k); wherein
[0015] (a) is
##STR00004##
[0016] wherein R.sup.4 is selected from the group consisting of
hydrogen, --C(O)OH, --C(O)O--(C.sub.1-2alkyl),
--C(O)NR.sup.GR.sup.H, --NH-(phenyl), and --NH--SO.sub.2-(phenyl);
wherein the phenyl is optionally substituted with one or more
substituents independently selected from the group consisting of
halogen, hydroxy and carboxy; and wherein R.sup.G and R.sup.H are
each independently selected from the group consisting of hydrogen
and C.sub.1-4alkyl;
(b) is
##STR00005##
(c) is
##STR00006##
(d) is
##STR00007##
(e) is
##STR00008##
(f) is
##STR00009##
[0017] wherein a is an integer from 0 to 1;
[0018] wherein L.sup.1 is selected from the group consisting of
--CH.sub.2--, --CH.sub.2--CH.sub.2, --CH.sub.2CH.sub.2CH.sub.2--,
--CH(CH.sub.3)CH.sub.2-- and --CH.sub.2--CH(CH.sub.3)--;
[0019] wherein R.sup.5 is selected from the group consisting of
hydrogen, C.sub.1-2alkyl, fluorinated C.sub.1-2alkyl,
C.sub.2-4alkenyl, --(C.sub.1-2alkyl)-C(O)OH,
--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--(C.sub.2-3alkyl)-O-(phenyl), --C(O)--(C.sub.1-2alkyl)-OH,
--C(O)--(C.sub.1-2alkyl)-C(O)OH,
--C(O)--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--C(O)--(C.sub.1-2alkyl)-C(O)--NH.sub.2, --C(O)OH,
--C(O)O--(C.sub.1-4alkyl), --C(O)O--(C.sub.3-5cycloalkyl),
--C(O)--NR.sup.JR.sup.K, --C(O)NH--(C.sub.3-5cycloalkyl),
--C(O)NH-(phenyl), --C(O)NH--(C.sub.1-2alkyl)-(phenyl),
--SO.sub.2--(C.sub.1-2alkyl), --SO.sub.2-(fluorinated
C.sub.1-2alkyl), --SO.sub.2--(C.sub.1-2alkyl)-C(O)OH,
--SO.sub.2--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--SO.sub.2--NR.sup.JR.sup.K,
--SO.sub.2--(C.sub.1-2alkyl)-C(O)NR.sup.JR.sup.K, phenyl,
--(C.sub.1-3alkyl)-phenyl, --C(O)-(phenyl), --C(O)O-(phenyl),
--C(O)O--(C.sub.1-2alkyl)-(phenyl), --SO.sub.2-(phenyl),
pyrimidin-2-yl, pyridyl, --(C.sub.1-2alkyl)-pyridyl,
--C(O)-(pyridyl), --SO.sub.2-(pyridyl), furyl,
--(C.sub.1-2alkyl)-furyl, --C(O)-- furyl, --SO.sub.2-(furyl),
thienyl, --(C.sub.1-2alkyl)-thienyl, --C(O)-thienyl,
--SO.sub.2-(thienyl), --C(O)-(1,2,3-triazol-4-yl),
--C(O)-(1,2,4,-triazol-3-yl) and
--SO.sub.2--(C.sub.1-2alkyl)-(piperazin-1-yl);
[0020] wherein the phenyl, pyrimidin-2-yl, pyridyl, furyl, thienyl
or pyridyl, is optionally substituted with one or more substituents
independently selected from the group consisting of halogen,
hydroxy, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl,
--(C.sub.1-2alkyl)-OH, --(C.sub.1-2alkyl)-C(O)OH,
--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--C(.sub.1-2alkyl)-C(O)OH,
--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--(C.sub.1-2alkyl)-C(O)--NR.sup.LR.sup.M, --O--(C.sub.1-4alkyl),
--O-(fluorinated C.sub.1-2alkyl), --O--(C.sub.2-6alkenyl),
--O--(C.sub.1-2alkyl)-C(O)OH,
--O--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--O--(C.sub.1-2alkyl)-C(O)NR.sup.LR.sup.M,
--O--(C.sub.1-2alkyl)-C(O)--NR.sup.LR.sup.M, --C(O)OH,
--C(O)O--(C.sub.1-4alkyl), --C(O)--NR.sup.LR.sup.M,
--C(O)--NH--(C.sub.1-3alkyl)-OH,
--C(O)--NH--(C.sub.1-2alkyl)-C(O)OH,
--C(O)--NH--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--NR.sup.LR.sup.M and --SO.sub.2--NR.sup.LR.sup.M;
[0021] wherein R.sup.J and R.sup.K are each independently selected
from the group consisting of hydrogen and C.sub.1-4alkyl; and
wherein R.sup.L and R.sup.M are each independently selected from
the group consisting of hydrogen and C.sub.1-4alkyl;
[0022] (g) is
##STR00010##
[0023] wherein b is an integer from 0 to 1;
[0024] wherein L.sup.2 is selected from the group consisting of
--CH.sub.2--, --CH.sub.2CH.sub.2--, --CH(CH.sub.3)--,
--CH(CH.sub.3)--CH.sub.2--, --CH.sub.2--CH(CH.sub.3)--,
--CH.sub.2CH.sub.2--O--, --CH.sub.2--CH(OH)--,
--CH(CH.sub.3)--CH(OH) and
--CH.sub.2CH.sub.2CH.sub.2--NH--SO.sub.2--;
[0025] wherein R.sup.6 is selected from the group consisting of
hydrogen, halogen, hydroxy, C.sub.1-2alkyl, fluorinated
C.sub.1-2alkyl, C.sub.1-2alkoxy, fluorinated C.sub.1-2alkoxy,
--C(O)OH, --C(O)O--(C.sub.1-2alkyl),
--O--(C.sub.1-2alkyl)-O--(C.sub.1-2alkyl),
--O--(C.sub.1-2alkyl)-C(O)OH,
--O--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--C(O)--NR.sup.NR.sup.P,
--O--(C.sub.1-2alkyl)-C(O)--NR.sup.NR.sup.P, phenyl, furyl and
thienyl; wherein the phenyl, furyl or thienyl is optionally
substituted with a substituent selected from the group consisting
of halogen, C.sub.1-4alkyl and carboxy; and wherein R.sup.N and
R.sup.P are each independently selected from the group consisting
of hydrogen and C.sub.1-4alkyl;
[0026] wherein R.sup.7 is selected from the group consisting of
hydrogen, halogen, hydroxy, C.sub.1-4alkyl, fluorinated
C.sub.1-2alkyl, C.sub.1-4alkoxy, fluorinated C.sub.1-2alkoxy,
--C(O)OH and --C(O)O--(C.sub.1-4alkyl);
[0027] (h) is
##STR00011##
[0028] wherein L.sup.3 is selected from the group consisting of
--CH.sub.2--, --CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
--CH(CH.sub.3)CH.sub.2--, --CH.sub.2CH(CH.sub.3)-- and
--CH.sub.2CH.sub.2--O--;
[0029] wherein R.sup.8 is selected from the group consisting of
hydrogen, halogen, C.sub.1-4alkyl, C.sub.1-4alkoxy, --C(O)OH and
--C(O)O--(C.sub.1-4alkyl);
[0030] (i) is
##STR00012##
[0031] wherein c is an integer from 0 to 1;
[0032] and wherein L.sup.4 is selected from the group consisting of
--CH.sub.2-- and --CH.sub.2--CH.sub.2--;
[0033] (j) is
##STR00013##
[0034] and (k) is
##STR00014##
[0035] and stereoisomers, tautomers and pharmaceutically acceptable
salts thereof.
[0036] The present invention is further directed to a compound of
formula (II)
##STR00015##
[0037] and stereoisomers, tautomers and pharmaceutically acceptable
salts thereof.
[0038] The present invention is further directed to processes for
the preparation of the compounds of formula (I) and the compound of
formula (II). The present invention is further directed to a
product prepared according to any of the process(es) described
herein.
[0039] The present invention is further directed to intermediate
compounds useful in the synthesis of the compounds of formula (I)
and the compound of formula (II), as described and defined in the
synthesis schemes and examples which follow herein.
[0040] Illustrative of the invention is a pharmaceutical
composition comprising a pharmaceutically acceptable carrier and
the product prepared according to the process described herein. An
illustration of the invention is a pharmaceutical composition made
by mixing the product prepared according to the process described
herein and a pharmaceutically acceptable carrier. Illustrating the
invention is a process for making a pharmaceutical composition
comprising mixing the product prepared according to the process
described herein and a pharmaceutically acceptable carrier.
[0041] Exemplifying the invention are methods of treating a
disorder mediated by the CB-1 receptor (selected from the group
consisting of obesity, Type I diabetes, Type II diabetes,
gestational diabetes, latent autoimmune diabetes of adults (LADA),
pre-diabetes, insulin resistance, inadequate glucose tolerance,
dyslipidemias (including, but not limited to elevated triglycerides
and LDL, and low HDL), nonalcoholic steatohepatitis (NASH),
cirrhosis, fatty liver disease, atherosclerosis, hypertension,
inflammatory bowel disease, Alzheimer's disease, osteoporosis,
multiple sclerosis, traumatic brain injury, arthritis, and
neuropathic pain) comprising administering to a subject in need
thereof a therapeutically effective amount of any of the compounds
or pharmaceutical compositions described above.
[0042] In an embodiment, the present invention is directed to a
compound of formula (I) for use as a medicament. In another
embodiment, the present invention is directed to a compound of
formula (I) or compound of formula (II) for use in the treatment of
a disorder mediated by the CB-1 receptor (selected from the group
consisting of obesity, Type I diabetes, Type II diabetes,
gestational diabetes, latent autoimmune diabetes of adults (LADA),
pre-diabetes, insulin resistance, inadequate glucose tolerance,
dyslipidemias (including, but not limited to elevated triglycerides
and LDL, and low HDL), nonalcoholic steatohepatitis (NASH),
cirrhosis, fatty liver disease, atherosclerosis, hypertension,
inflammatory bowel disease, Alzheimer's disease, osteoporosis,
multiple sclerosis, traumatic brain injury, arthritis, and
neuropathic pain). In another embodiment, the present invention is
directed to a composition comprising a compound of formula (I) or
compound of formula (II) for the treatment of a disorder mediated
by the CB-1 receptor (selected from the group consisting of
obesity, Type I diabetes, Type II diabetes, gestational diabetes,
latent autoimmune diabetes of adults (LADA), pre-diabetes, insulin
resistance, inadequate glucose tolerance, dyslipidemias (including,
but not limited to elevated triglycerides and LDL, and low HDL),
nonalcoholic steatohepatitis (NASH), cirrhosis, fatty liver
disease, atherosclerosis, hypertension, inflammatory bowel disease,
Alzheimer's disease, osteoporosis, multiple sclerosis, traumatic
brain injury, arthritis, and neuropathic pain).
[0043] Another example of the invention is the use of any of the
compounds described herein in the preparation of a medicament for
treating: (a) obesity, (b) Type I diabetes, (c) Type II diabetes,
(d) gestational diabetes, (e) latent autoimmune diabetes of adults
(LADA), (f) pre-diabetes, (g) insulin resistance, (h) inadequate
glucose tolerance, (i) dyslipidemia (including, but not limited to
elevated triglycerides and LDL, and low HDL), (j) nonalcoholic
steatohepatitis (NASH), (k) cirrhosis, (I) fatty liver disease, (m)
atherosclerosis, (n) hypertension, (o) inflammatory bowel disease,
(p) Alzheimer's disease, (q) osteoporosis, (r) multiple sclerosis,
(s) traumatic brain injury, (t) arthritis, or (u) neuropathic pain,
in a subject in need thereof. In another example, the present
invention is directed to a compound as described herein for use in
method for treating a disorder selected from the group consisting
of obesity, Type I diabetes, Type II diabetes, gestational
diabetes, latent autoimmune diabetes of adults (LADA),
pre-diabetes, insulin resistance, inadequate glucose tolerance,
dyslipidemias (including, but not limited to elevated triglycerides
and LDL, and low HDL), nonalcoholic steatohepatitis (NASH),
cirrhosis, fatty liver disease, atherosclerosis, hypertension,
inflammatory bowel disease, Alzheimer's disease, osteoporosis,
multiple sclerosis, traumatic brain injury, arthritis, and
neuropathic pain, in a subject in need thereof.
[0044] In additional embodiments the present invention is as
described herein.
DETAILED DESCRIPTION OF THE INVENTION
[0045] The present invention is directed to compounds of formula
(I)
##STR00016##
[0046] wherein
##STR00017##
R.sup.0, R.sup.1, R.sup.2 and R.sup.3 are as herein defined; and
stereoisomers, tautomers and pharmaceutically acceptable salts
thereof. The present invention is further directed to a compound of
formula (II)
##STR00018##
[0047] (also known as
N-(2-(2-(benzyloxy)ethoxy)ethyl)-3-((4-(6-(bis(4-chlorophenyl)methyl)-2-c-
yclopropyl-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)sulfonyl)aniline)
and stereoisomers, tautomers and pharmaceutically acceptable salts
thereof.
[0048] The compounds of formula (I) and the compound of formula
(II) of the present invention are CB-1 receptor inverse agonists,
useful in the treatment of metabolic disorders, including but not
limited to obesity, Type I diabetes, Type II diabetes, gestational
diabetes, latent autoimmune diabetes of adults (LADA),
pre-diabetes, insulin resistance, inadequate glucose tolerance,
dyslipidemias (including, but not limited to elevated triglycerides
and LDL, and low HDL), nonalcoholic steatohepatitis (NASH),
cirrhosis, fatty liver disease, atherosclerosis, hypertension,
inflammatory bowel disease, Alzheimer's disease, osteoporosis,
multiple sclerosis, traumatic brain injury, arthritis, and
neuropathic pain.
[0049] In an embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.0 is selected from the group
consisting of hydrogen, --OH, --C(O)OH, --C(O)O--(C.sub.1-2alkyl),
--CH.sub.2--OH, --CH.sub.2--O--(C.sub.1-2alkyl) and
--CH.sub.2--O--(C.sub.1-2alkyl)-CO.sub.2H. In another embodiment,
the present invention is directed to compounds of formula (I)
wherein R.sup.0 is selected from the group consisting of hydrogen,
--OH, --C(O)OH, --C(O)O--(C.sub.1-2alkyl), --CH.sub.2--OH,
--CH.sub.2--O--(C.sub.1-2alkyl) and
--CH.sub.2--O--(C.sub.1-2alkyl)-CO.sub.2H. In another embodiment,
the present invention is directed to compounds of formula (I)
wherein R.sup.0 is selected from the group consisting of hydrogen,
--OH, --C(O)OH, --C(O)OCH.sub.3, --CH.sub.2--OH,
--CH.sub.2--OCH.sub.3 and --CH.sub.2--OCH.sub.2--CO.sub.2H. In
another embodiment, the present invention is directed to compound
of formula (I) wherein R.sup.0 is selected from the group
consisting of hydrogen and --OH. In another embodiment, the present
invention is directed to compound of formula (I) wherein R.sup.0 is
selected from the group consisting of hydrogen, --C(O)OH and
--C(O)OCH.sub.3. In another embodiment, the present invention is
directed to compound of formula (I) wherein R.sup.0 is selected
from the group consisting of hydrogen, --OH, --CH.sub.2OH and
--CH.sub.2--OCH.sub.3. In another embodiment, the present invention
is directed to compound of formula (I) wherein R.sup.0 is
hydrogen.
[0050] In an embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.0 is selected from the group
consisting of hydrogen, --OH, --CO.sub.2H, --C(O)OCH.sub.3 and
--CH.sub.2OCH.sub.3. In another embodiment, the present invention
is directed to compounds of formula (I) wherein R.sup.0 is selected
from the group consisting of hydrogen, --OH, --CO.sub.2H and
--C(O)OCH.sub.3. In another embodiment, the present invention is
directed to compounds of formula (I) wherein R.sup.0 is selected
from the group consisting of hydrogen, --OH and --CO.sub.2H. In
another embodiment, the present invention is directed to compounds
of formula (I) wherein R.sup.0 is selected from the group
consisting of hydrogen and --OH.
[0051] In an embodiment, the present invention is directed to
compounds of formula (I) wherein
##STR00019##
is selected from the group consisting of phenyl, thiazolyl and
benzo[d][1,3]dioxolyl; wherein the phenyl or thiazolyl is
optionally substituted with one to two substituents independently
selected from the group consisting of halogen C.sub.1-4alkyl,
fluorinated C.sub.1-2alkyl, C.sub.1-2alkoxy, fluorinated
C.sub.1-2alkoxy, --C(O)OH and --C(O)O--(C.sub.1-4alkyl). In another
embodiment, the present invention is directed to compounds of
formula (I) wherein
##STR00020##
is phenyl; wherein the phenyl is optionally substituted a
substituent independently selected from the group consisting of
halogen and C.sub.1-2alkoxy.
[0052] In another embodiment, the present invention is directed to
compounds of formula (I) wherein
##STR00021##
is selected from the group consisting of phenyl, 2-chlorophenyl,
4-chlorophenyl and 4-methoxyphenyl. In another embodiment, the
present invention is directed to compounds of formula (I)
wherein
##STR00022##
is selected from the group consisting of 4-chlorophenyl and
4-methoxyphenyl.
[0053] In an embodiment, the present invention is directed to
compounds of formula (I) wherein
##STR00023##
is selected from the group consisting of 4-chlorophenyl,
4-fluorophenyl, 4-methylphenyl and 4-methoxyphenyl. In another
embodiment, the present invention is directed to compounds of
formula (I) wherein
##STR00024##
is selected from the group consisting of 4-chlorophenyl,
4-fluorophenyl and 4-methylphenyl. In another embodiment, the
present invention is directed to compounds of formula (I)
wherein
##STR00025##
is 4-chlorophenyl.
[0054] In an embodiment, the present invention is directed to
compounds of formula (I) wherein
##STR00026##
is selected from the group consisting of phenyl, thiazolyl and
benzo[d][1,3]dioxolyl; wherein the phenyl or thiazolyl is
optionally substituted with one to two substituents independently
selected from the group consisting of halogen C.sub.1-4alkyl,
fluorinated C.sub.1-2alkyl, C.sub.1-2alkoxy, fluorinated
C.sub.1-2alkoxy, --C(O)OH and --C(O)O--(C.sub.1-4alkyl). In another
embodiment, the present invention is directed to compounds of
formula (I) wherein
##STR00027##
is selected from the group consisting of phenyl, thiazol-2-yl and
benzo[d][1,3]dioxol-5-yl; wherein the phenyl or thiazol-2-yl is
optionally substituted with a substituent selected from the group
consisting of halogen, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl,
C.sub.1-2alkoxy and --C(O)OH.
[0055] In another embodiment, the present invention is directed to
compounds of formula (I) wherein
##STR00028##
is selected from the group consisting of phenyl, 4-chlorophenyl,
4-fluorophenyl, 4-methylphenyl, 4-trifluoromethyl-phenyl,
4-carboxyphenyl, 4-methoxyphenyl, thiazol-2-yl,
4-ethyl-thiazol-2-yl, 5-ethyl-thiazol-2-yl, 4-t-butyl-thiazol-2-yl,
4-trifluoromethyl-thiazol-2-yl and benzo[d][1,3]dioxol-5-yl. In
another embodiment, the present invention is directed to compounds
of formula (I) wherein
##STR00029##
is selected from the group consisting of 4-chlorophenyl,
4-methoxyphenyl and thiazol-2-yl.
[0056] In an embodiment, the present invention is directed to
compounds of formula (I) wherein
##STR00030##
is selected from the group consisting of phenyl, 4-chlorophenyl,
4-fluorphenyl, 4-methylphenyl, 4-trifluoromethyl-phenyl,
4-methoxyphenyl, 4-carboxyphenyl, thiazol-2-yl and
benzo[d][1,3]dioxol-5-yl. In another embodiment, the present
invention is directed to compounds of formula (I) wherein
##STR00031##
is selected from the group consisting of phenyl, 4-chlorophenyl,
4-fluorphenyl, 4-methylphenyl, 4-trifluoromethyl-phenyl,
thiazol-2-yl and benzo[d][1,3]dioxol-5-yl. In another embodiment,
the present invention is directed to compounds of formula (I)
wherein
##STR00032##
is selected from the group consisting of 4-chlorophenyl,
thiazol-2-yl and benzo[d][1,3]dioxol-5-yl. In another embodiment,
the present invention is directed to compounds of formula (I)
wherein
##STR00033##
is 4-chlorophenyl.
[0057] In an embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.1 is selected from the group
consisting of hydrogen, hydroxy and C.sub.1-2alkoxy. In another
embodiment, the present invention is directed to compounds of
formula (I) wherein R.sup.1 is selected from the group consisting
of hydrogen, hydroxy and methoxy. In another embodiment, the
present invention is directed to compounds of formula (I) wherein
R.sup.1 is selected from the group consisting of hydroxy and
methoxy. In another embodiment, the present invention is directed
to compounds of formula (I) wherein R.sup.1 is selected from the
group consisting of hydrogen and methoxy. In another embodiment,
the present invention is directed to compounds of formula (I)
wherein R.sup.1 is hydrogen.
[0058] In an embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.2 is selected from the group
consisting of hydrogen, halogen, C.sub.1-4alkyl, fluorinated
C.sub.1-2alkyl, --(C.sub.1-2alkyl)-OH, --(C.sub.1-2alkyl)-C(O)OH,
--(C.sub.1-2alkyl)-NH.sub.2, --(C.sub.2-4alkenyl)-OH,
--C(O)O--(C.sub.1-2alkyl), --NR.sup.ER.sup.F, C.sub.3-5cycloalkyl,
phenyl, furyl, thienyl, pyridyl, oxetan-3-yl, azetidin-3-yl,
tetrahydrofuran-2-yl and tetrahydropyran-4-yl; wherein the phenyl
is optionally substituted with one to two halogen; wherein the
azetidin-3-yl is optionally substituted with
--C(O)O--(C.sub.1-4alkyl); and wherein R.sup.E and R.sup.F are each
independently selected from the group consisting of hydrogen and
C.sub.1-4alkyl; provided that when R.sup.2 is selected from the
group consisting of pyridyl, furyl and thienyl, then the R.sup.2 is
bound to the benzimidazole core through a carbon atom. In another
embodiment, the present invention is directed to compounds of
formula (I) wherein R.sup.2 is selected from the group consisting
of hydrogen, halogen, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl,
--(C.sub.1-2alkyl)-OH, --(C.sub.1-2alkyl)-C(O)OH,
--(C.sub.1-2alkyl)-NH.sub.2, --(C.sub.2-4alkenyl)-OH,
--C(O)O--(C.sub.1-2alkyl), --NR.sup.ER.sup.F, C.sub.3-6cycloalkyl,
phenyl, fur-2-yl, fur-3-yl, thien-3-yl, pyrid-2-yl, pyrid-3-yl,
pyrid-4-yl, oxetan-3-yl, azetidin-3-yl, tetrahydrofuran-2-yl and
tetrahydro-pyran-4-yl; wherein the phenyl is optionally substituted
with one to two halogen; wherein the azetidin-3-yl is optionally
substituted with --C(O)O--(C.sub.1-4alkyl); and wherein R.sup.E and
R.sup.F are each independently selected from the group consisting
of hydrogen, methyl and ethyl.
[0059] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.2 is selected from the group
consisting of hydrogen, chloro, methyl, ethyl, n-propyl, isopropyl,
isobutyl, t-butyl, --CHF.sub.2, --CF.sub.3, --CH.sub.2--CF.sub.3,
--CH.sub.2OH, --CH.sub.2CH.sub.2--C(O)OH,
--CH.sub.2CH.sub.2--NH.sub.2, --C(.dbd.CH.sub.2)--CH.sub.2OH,
--C(O)OCH.sub.3, --C(O)OCH.sub.2CH.sub.3, --NH.sub.2,
--N(CH.sub.3).sub.2, cyclopropyl, cyclobutyl, cyclopentyl,
oxetan-3-yl, azetidin-3-yl, 1-(t-butoxycarbonyl)-azetidin-3-yl,
tetrahydrofuran-2-yl, tetrahydro-pyran-4-yl, 4-chlorophenyl,
2,4-dichlorophenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fur-2-yl,
fur-3-yl and thien-3-yl. In another embodiment, the present
invention is directed to compounds of formula (I) wherein R.sup.2
is selected from the group consisting of ethyl, cyclopropyl and
cyclobutyl. In another embodiment, the present invention is
directed to compounds of formula (I) wherein R.sup.2 is selected
from the group consisting of ethyl and cyclopropyl. In another
embodiment, the present invention is directed to compounds of
formula (I) wherein R.sup.2 is cyclopropyl.
[0060] In an embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.2 is selected from the group
consisting of hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl,
amino-ethyl-, --C.dbd.(CH.sub.2)--CH.sub.2OH, oxetan-3-yl,
tetrahydrofur-2-yl and pyrid-3-yl. In another embodiment, the
present invention is directed to compounds of formula (I) wherein
R.sup.2 is selected from the group consisting of hydrogen, methyl,
ethyl, cyclopropyl, cyclobutyl, oxetan-3-yl and tetrahydrofur-2-yl.
In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.2 is selected from the group
consisting of ethyl, cyclopropyl, cyclobutyl, oxetan-3-yl and
tetrahydrofur-2-yl. In another embodiment, the present invention is
directed to compounds of formula (I) wherein R.sup.2 is selected
from the group consisting of cyclopropyl, cyclobutyl and
tetrahydrofur-2-yl.
[0061] In an embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is selected from the group
consisting of (a) through (k); wherein
[0062] (a) is
##STR00034##
wherein R.sup.4 is selected from the group consisting of hydrogen,
--C(O)OH, --C(O)O--(C.sub.1-2alkyl), --C(O)NR.sup.GR.sup.H,
--NH-(phenyl), and --NH--SO.sub.2-(phenyl); wherein the phenyl is
optionally substituted with hydroxy or carboxy; and wherein R.sup.G
and R.sup.H are each independently selected from the group
consisting of hydrogen and methyl; (b) is
##STR00035##
(c) is
##STR00036##
(d) is
##STR00037##
(e) is
##STR00038##
(f) is
##STR00039##
[0063] wherein a is an integer from 0 to 1; wherein L.sup.1 is
selected from the group consisting of --CH.sub.2--,
--CH.sub.2--CH.sub.2, --CH(CH.sub.3)CH.sub.2-- and
--CH.sub.2--CH(CH.sub.3)--; wherein R.sup.5 is selected from the
group consisting of hydrogen, C.sub.1-2alkyl, fluorinated
C.sub.1-2alkyl, C.sub.2-4alkenyl, --(C.sub.1-2alkyl)-C(O)OH,
--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--(C.sub.2alkyl)-O-(phenyl), --C(O)--(C.sub.1-2alkyl)-OH,
--C(O)--(C.sub.1-2alkyl)-C(O)OH,
--C(O)--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--C(O)--(C.sub.1-2alkyl)-C(O)--NH.sub.2, --C(O)O--(C.sub.1-4alkyl),
--C(O)O--(C.sub.3-5cycloalkyl), --C(O)O-(phenyl),
--C(O)O--CH.sub.2-(phenyl), --C(O)--NH.sub.2,
--C(O)NH--(C.sub.1-2alkyl), --C(O)NH--(C.sub.3-5cycloalkyl),
--C(O)NH-(phenyl), --C(O)NH--(C.sub.1-2alkyl)-(phenyl),
--SO.sub.2--(C.sub.1-2alkyl), --SO.sub.2-(fluorinated
C.sub.1-2alkyl), --SO.sub.2--(C.sub.1-2alkyl)-C(O)OH,
--SO.sub.2--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--(C.sub.1-2alkyl),
--SO.sub.2--(C.sub.1-2alkyl)-C(O)NH.sub.2, phenyl,
--(C.sub.1-3alkyl)-phenyl, --C(O)-(phenyl), --C(O)O-(phenyl),
--C(O)O--(C.sub.1-2alkyl)-(phenyl), --SO.sub.2-(phenyl),
pyrimidin-2-yl, pyrid-2-yl, pyrid-3-yl,
--(C.sub.1-2alkyl)-pyrid-2-yl, --(C.sub.1-2alkyl)-pyrid-3-yl,
--(C.sub.1-2alkyl)-fur-2-yl, --(C.sub.1-2alkyl)-thien-2-yl,
--C(O)-fur-2-yl, --C(O)-thien-2-yl, --C(O)-(pyrid-3-yl),
--C(O)-(1,2,3-triazol-4-yl), --C(O)-(1,2,4,-triazol-3-yl),
--SO.sub.2--(C.sub.1-2alkyl)-(piperazin-1-yl),
--SO.sub.2-(fury-2-yl), --SO.sub.2-(thien-2-yl) and
--SO.sub.2-(pyrid-3-yl); wherein the phenyl, pyrimidin-2-yl,
pyridyl, furyl, thienyl or pyridyl, is optionally substituted with
one to three substituents independently selected from the group
consisting of halogen, hydroxy, C.sub.1-2alkyl, fluorinated
C.sub.1-2alkyl, --(C.sub.1-2alkyl)-OH, --C(.sub.1-2alkyl)-C(O)OH,
--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl), --O--(C.sub.1-2alkyl),
--O-(fluorinated C.sub.1-2alkyl), --O--(C.sub.2-6alkenyl),
--O--(C.sub.1-2alkyl)-C(O)OH, --O--(C.sub.1-2alkyl)-C(O)NH.sub.2,
--C(O)OH, --C(O)O--(C.sub.1-4alkyl), --C(O)--NH.sub.2,
--C(O)--NH--(C.sub.1-2alkyl), --C(O)--NH--(C.sub.1-3alkyl)-OH,
--C(O)--NH--(C.sub.1-2alkyl)-C(O)OH,
--C(O)--NH--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--(C.sub.1-2alkyl)-C(O)--NH.sub.2,
--O--(C.sub.1-2alkyl)-C(O)--NH.sub.2, --O--(C.sub.1-2alkyl)-C(O)OH,
--NH.sub.2, --NH(C.sub.1-2alkyl), --SO.sub.2--NH.sub.2 and
--SO.sub.2--NH(C.sub.1-2alkyl);
[0064] (g) is
##STR00040##
wherein b is an integer from 0 to 1; wherein L.sup.2 is selected
from the group consisting of --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH(CH.sub.3)--, --CH(CH.sub.3)--CH.sub.2--,
--CH.sub.2--CH(CH.sub.3)--, --CH.sub.2CH.sub.2--O--,
--CH.sub.2--CH(OH)--, --CH(CH.sub.3)--CH(OH) and
--CH.sub.2CH.sub.2CH.sub.2--NH--SO.sub.2--; wherein R.sup.6 is
selected from the group consisting of hydrogen, halogen, hydroxy,
C.sub.1-2alkyl, fluorinated C.sub.1-2alkyl, C.sub.1-2alkoxy,
fluorinated C.sub.1-2alkoxy, --C(O)OH, --C(O)O--(C.sub.1-2alkyl),
--O--(C.sub.1-2alkyl)-C(O)OH,
--O--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl), --C(O)--NH.sub.2,
--O--(C.sub.1-2alkyl)-C(O)--NH.sub.2, phenyl, furyl and thienyl;
wherein the phenyl, furyl or thienyl is optionally substituted with
carboxy; and wherein R.sup.7 is selected from the group consisting
of hydrogen, hydroxy, C.sub.1-2alkyl, fluorinated C.sub.1-2alkyl,
C.sub.1-2alkoxy, fluorinated C.sub.1-2alkoxy, --C(O)OH and
--C(O)O--(C.sub.1-4alkyl);
[0065] (h) is
##STR00041##
wherein L.sup.3 is selected from the group consisting of
--CH.sub.2--, --CH.sub.2CH.sub.2-- and --CH.sub.2CH.sub.2--O--; and
wherein R.sup.8 is selected from the group consisting of hydrogen,
-halogen, C.sub.1-2alkyl, C.sub.1-2alkoxy, --C(O)OH and
--C(O)O--(C.sub.1-4alkyl);
[0066] (i) is
##STR00042##
wherein c is an integer from 0 to 1; and wherein L.sup.4 is
selected from the group consisting of --CH.sub.2-- and
--CH.sub.2--CH.sub.2--;
[0067] (j) is
##STR00043##
and (k) is
##STR00044##
[0068] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is selected from the group
consisting of (a) through (k); wherein
[0069] (a) is
##STR00045##
wherein R.sup.4 is selected from the group consisting of hydrogen,
--C(O)OH, --C(O)NR.sup.GR.sup.H, --NH-(phenyl) and
--NH--SO.sub.2-(phenyl); wherein the phenyl is optionally
substituted with hydroxy or carboxy; wherein R.sup.G and R.sup.H
are each independently selected from the group consisting of
hydrogen and methyl; (b) is
##STR00046##
(c) is
##STR00047##
(d) is
##STR00048##
(e) is
##STR00049##
(f) is
##STR00050##
[0070] wherein a is an integer from 0 to 1; and wherein L.sup.1 is
selected from the group consisting of --CH.sub.2-- and
--CH.sub.2--CH(CH.sub.3)--; wherein R.sup.5 is selected from the
group consisting of hydrogen, C.sub.2-4alkenyl,
--(C.sub.1-2alkyl)-C(O)OH,
--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--(C.sub.2alkyl)-O-(phenyl), --C(O)--(C.sub.1-2alkyl)-OH,
--C(O)--(C.sub.1-2alkyl)-C(O)OH,
--C(O)--(C.sub.1-2alkyl)-C(O)--NH.sub.2, --C(O)O--(C.sub.1-4alkyl),
--C(O)O-(hydroxy substituted C.sub.1-4alkyl),
--C(O)O--(C.sub.3-5cycloalkyl), --C(O)NH--(C.sub.1-2alkyl),
--C(O)NH--(C.sub.3-5cycloalkyl), --C(O)NH-(phenyl),
--C(O)NH--(C.sub.1-2alkyl)-(phenyl), --SO.sub.2--(C.sub.1-2alkyl),
--SO.sub.2-(fluorinated C.sub.1-2alkyl),
--SO.sub.2--(C.sub.1-2alkyl)-C(O)OH, --SO.sub.2--NH.sub.2,
--SO.sub.2--NH--(C.sub.1-2alkyl),
--SO.sub.2--(C.sub.1-2alkyl)-C(O)NH.sub.2, phenyl,
--(C.sub.1-3alkyl)-phenyl, --C(O)-(phenyl), --C(O)O-(phenyl),
--C(O)O--(C.sub.1-2alkyl)-(phenyl), --SO.sub.2-(phenyl),
pyrimidin-2-yl, --(C.sub.1-2alkyl)-pyrid-2-yl,
--(C.sub.1-2alkyl)-pyrid-3-yl, --(C.sub.1-2alkyl)-fur-2-yl,
--(C.sub.1-2alkyl)-thien-2-yl, --C(O)-(pyrid-3-yl),
--C(O)-(1,2,3-triazol-4-yl), --C(O)-(1,2,4,-triazol-3-yl),
--SO.sub.2--(C.sub.1-2alkyl)-(piperazin-1-yl),
--SO.sub.2-(fury-2-yl), --SO.sub.2-(thien-2-yl) and
--SO.sub.2-(pyrid-3-yl); wherein the phenyl is optionally
substituted with one to three substituents independently selected
from the group consisting of halogen, hydroxy, C.sub.1-2alkyl,
fluorinated C.sub.1-2alkyl, --O--(C.sub.1-2alkyl), --O-(fluorinated
C.sub.1-2alkyl), --O--(C.sub.2-6alkenyl),
--O--(C.sub.1-2alkyl)-C(O)OH, --O--(C.sub.1-2alkyl)-C(O)NH.sub.2,
--C(O)OH, --C(O)O--(C.sub.1-2alkyl), --C(.sub.1-2alkyl)-C(O)OH,
--C(O)--NH.sub.2, --C(O)--NH--(C.sub.1-2alkyl),
--C(O)--NH--(C.sub.1-3alkyl)-OH,
--C(O)--NH--(C.sub.1-2alkyl)-C(O)OH,
--C(O)--NH--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--(C.sub.1-2alkyl)-C(O)--NH.sub.2,
--O--(C.sub.1-2alkyl)-C(O)--NH.sub.2, --O--(C.sub.1-2alkyl)-C(O)OH,
--NH.sub.2 and --SO.sub.2--NH.sub.2; and wherein the
pyrimidin-2-yl, pyrid-2-yl, pyrid-3-yl, fur-2-yl or thien-2-yl is
optionally substituted with one to two substituents independently
selected from the group consisting of C.sub.1-2alkyl,
--(C.sub.1-2alkyl)-OH, --C(O)OH, --C(O)O--(C.sub.1-2alkyl),
--C(O)--NH.sub.2, --C(O)NH--(C.sub.1-2alkyl)-OH,
--C(O)NH--(C.sub.1-2alkyl)-C(O)OH and
--C(O)NH--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl);
[0071] (g) is
##STR00051##
wherein b is an integer from 0 to 1; and wherein L.sup.2 is
selected from the group consisting of --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH(CH.sub.3)--, --CH(CH.sub.3)--CH.sub.2--,
--CH.sub.2--CH(CH.sub.3)--, --CH.sub.2CH.sub.2--O--,
--CH.sub.2--CH(OH)--, --CH(CH.sub.3)--CH(OH) and
--CH.sub.2CH.sub.2CH.sub.2--NH--SO.sub.2--; wherein R.sup.6 is
selected from the group consisting of hydrogen, halogen, hydroxy,
C.sub.1-2alkoxy, fluorinated C.sub.1-2alkyl, --C(O)OH,
--C(O)O--(C.sub.1-2alkyl), --O--(C.sub.1-2alkyl)-C(O)OH,
--O--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl), --C(O)--NH.sub.2,
--O--(C.sub.1-2alkyl)-C(O)--NH.sub.2, phenyl and thienyl; wherein
the phenyl or thienyl is optionally substituted with carboxy; and
wherein R.sup.7 is selected from the group consisting of hydrogen
and fluorinated C.sub.1-2alkyl;
[0072] (h) is
##STR00052##
wherein L.sup.3 is selected from the group consisting of
--CH.sub.2-- and --CH.sub.2CH.sub.2--O--; and wherein R.sup.8 is
selected from the group consisting of hydrogen, --C(O)OH and
--C(O)O--(C.sub.1-2alkyl);
[0073] (i) is
##STR00053##
wherein c is an integer from 0 to 1; wherein L.sup.4 is
--CH.sub.2--;
[0074] (j) is
##STR00054##
and (k) is
##STR00055##
[0075] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is selected from the group
consisting of (a) through (k); wherein
[0076] (a) is
##STR00056##
wherein R.sup.4 is selected from the group consisting of hydrogen,
--C(O)OH, --C(O)NH.sub.2, --NH--SO.sub.2-(3-carboxyphenyl),
--NH-(3-hydroxyphenyl), --NH-(3-carboxyphenyl),
--NH-(4-carboxyphenyl) and --NH--SO.sub.2-(4-carboxyphenyl); and
wherein the cyclohexyl is bound to the benzimidazole core in a
cis-, trans- or racemic stereo-orientation;
[0077] (b) is
##STR00057##
wherein a 0; and wherein R.sup.5 is selected from the group
consisting of 3-carboxybenzyl-, 4-carboxyphenyl-sulfonyl- and
5-carboxyfur-2-yl-sulfonyl-;
[0078] (c) is
##STR00058##
wherein a is 0; and wherein R.sup.5 is selected from the group
consisting of 3-carboxybenzyl-, 4-carboxyphenyl-sulfonyl- and
5-carboxy-fur-2-yl-sulfonyl-;
[0079] (d) is
##STR00059##
wherein a is an integer from 0 to 1; L.sup.1 is selected from the
group consisting of --CH.sub.2-- and
--CH.sub.2--CH(R*--CH.sub.3)--; and wherein R.sup.5 is selected
from the group consisting of hydrogen, propyn-3-yl,
carboxy-methyl-, methoxy-carbonyl-methyl-,
3-carboxyphenyl-oxy-ethyl-, 2-hydroxyethyl-carbonyl-,
hydroxymethyl-carbonyl-, 2-carboxy-ethyl-carbonyl-,
aminocarbonyl-methyl-carbonyl-, 2-(aminocarbonyl)-ethyl-carbonyl-,
ethoxycarbonyl-, t-butoxycarbonyl-, cyclopentyloxy-carbonyl-,
2,3,4-trihydroxy-n-butyloxy-carbonyl-, 3-carboxyphenyl,
4-carboxyphenyl, 3-(carboxy-methyl)-phenyl,
4-(carboxy-methyl)-phenyl, 3-(methoxycarbonyl)-phenyl,
3-(aminocarbonyl)-phenyl, 4-(aminocarbonyl)-phenyl,
3-(aminocarbonyl-methyl)-phenyl, 4-(aminocarbonyl-methyl)-phenyl,
3-(aminocarbonyl-methoxy)-phenyl, 4-(aminocarbonyl-methoxy)-phenyl,
3-(carboxy-methoxy)-phenyl, 4-(carboxy-methoxy)-phenyl,
3-hydroxy-benzyl, 3-(hex-2-en-1-yloxy)-benzyl,
2-trifluoromethyl-benzyl, 3-carboxy-benzyl, 4-carboxy-benzyl,
3-(methoxycarbonyl)-benzyl, 3-(aminocarbonyl)-benzyl,
4-(aminocarbonyl)-benzyl, 3-(2-hydroxyethyl-aminocarbonyl)-benzyl,
2-hydroxy-3-carboxy-benzyl, 2-hydroxy-5-carboxy-benzyl,
2-fluoro-3-carboxy-benzyl, 2-fluoro-5-carboxy-benzyl,
2-chloro-3-carboxy-benzyl, 2-chloro-5-carboxy-benzyl,
2-trifluoromethyl-5-carboxy-benzyl, 3-fluoro-5-carboxy-benzyl,
3-carboxy-4-fluoro-benzyl, 3-carboxy-4-hydroxy-benzyl,
3-trifluoromethyl-5-carboxy-benzyl, 1-(3-hydroxyphenyl)-ethyl-,
1-(3-carboxyphenyl)-ethyl-, 1R*-(3-carboxyphenyl)-ethyl-,
1-(3-carboxyphenyl)-n-propyl-, 4-carboxy-pyrimidin-2-yl,
5-carboxy-pyrimidin-2-yl, 5-methoxycarbonyl-pyrimidin-2-yl,
2-carboxy-pyrid-4-yl-methyl-,
4-carboxy-pyrid-2-yl-methyl-,5-carboxy-pyrid-2-yl-methyl-,
6-carboxy-pyrid-2-yl-methyl-, 5-carboxy-pyrid-3-yl-methyl-,
6-carboxy-pyrid-3-yl-methyl-, 5-aminocarbonyl-pyrid-2-yl-methyl-,
6-aminocarbonyl-pyrid-2-yl-methyl-,
5-aminocarbonyl-pyrid-3-yl-methyl-,
6-aminocarbonyl-pyrid-3-yl-methyl-,
1-(4-carboxy-pyrid-2-yl)-ethyl-, 5-carboxy-fur-2-yl-methyl-,
5-aminocarbonyl-fur-2-yl-methyl-, 1-(5-carboxy-fur-2-yl)-ethyl-,
4-carboxy-thien-2-yl-methyl-, 5-carboxy-thien-2-yl-methyl-,
5-aminocarbonyl-thien-2-yl-methyl-,
4-aminocarbonyl-thien-2-yl-methyl-, phenoxy-carbonyl-,
benzyloxy-carbonyl-, ethylamino-carbonyl-,
cyclopentyl-amino-carbonyl-, phenyl-aminocarbonyl-,
benzyl-amino-carbonyl-, 4-carboxy-phenyl-carbonyl-,
4-aminoarbonyl-phenyl-carbonyl-, 3-aminosulfonyl-phenyl-carbonyl-,
4-aminosulfonyl-phenyl-carbonyl-, 6-carboxy-pyrid-3-yl-carbonyl-,
6-aminocarbonyl-pyrid-3-yl-carbonyl-, 1,2,3-triazol-4-yl-carbonyl-,
1,2,4-triazol-3-yl-carbonyl-, methyl-sulfonyl-,
trifluoromethyl-sulfonyl-, carboxymethyl-sulfonyl-,
carboxyethyl-sulfonyl-, amino-sulfonyl-, amino-ethyl-sulfonyl-,
aminocarbonyl-methyl-sulfonyl-, phenyl-sulfonyl-,
4-fluorophenyl-sulfonyl-, 4-chlorophenyl-sulfonyl,
2-hydroxyphenyl-sulfonyl-, 3-hydroxyphenyl-sulfonyl-,
4-hydroxyphenyl-sulfonyl-, 2-methoxy-phenyl-sulfonyl-,
3-methoxy-phenyl-sulfonyl-, 4-methoxy-phenyl-sulfonyl-,
2-trifluoromethyl-phenyl-sulfonyl-,
3-trifluoromethyl-phenyl-sulfonyl-,
4-trifluoromethyl-phenyl-sulfonyl-,
4-trifluoromethoxy-phenyl-sulfonyl-, 2-carboxyphenyl-sulfonyl-,
3-carboxyphenyl-sulfonyl-, 4-carboxyphenyl-sulfonyl-,
4-carboxy-methoxy-phenyl-sulfonyl-, 3-aminophenyl-sulfonyl-,
4-aminophenyl-sulfonyl-, 2-aminocarbonyl-phenyl-sulfonyl-,
3-aminocarbonyl-phenyl-sulfonyl-, 4-aminocarbonyl-phenyl-sulfonyl-,
4-aminocarbonyl-methoxy-phenyl-sulfonyl-,
3-(methylamino-carbonyl)-phenyl-sulfonyl-,
3-(carboxy-ethyl-amino-carbonyl)-phenyl-sulfonyl-,
3-(3-hydroxy-n-propyl-amino-carbonyl)-phenyl-sulfonyl-,
3-(2-(methoxycarbonyl)-ethyl-amino-carbonyl)-phenyl-sulfonyl-,
3-(2-hydroxyethyl-amino-carbonyl)-phenyl-sulfonyl-,
3-fluoro-4-hydroxy-phenyl-sulfonyl-,
3-fluoro-4-methoxy-phenyl-sulfonyl-,
3-fluoro-4-aminocabonyl-phenyl-sulfonyl-,
3-fluoro-4-carboxy-phenyl-sulfonyl-,
3-chloro-4-aminocarbonyl-phenyl-sulfonyl-,
3-chloro-4-carboxy-phenyl-sulfonyl-,
3-methyl-4-aminocarbonyl-phenyl-sulfonyl-,
3-methyl-4-carboxy-phenyl-sulfonyl-,
3-trifluoromethyl-4-carboxy-phenyl-sulfonyl-,
3-trifluoromethyl-4-aminocarbonyl-phenyl-sulfonyl,
3-methoxy-4-carboxy-phenyl-sulfonyl,
3-methoxy-4-aminocarbonyl-phenyl-sulfonyl-,
3-carboxy-4-chloro-phenyl-sulfonyl-,
3-carboxy-4-fluoro-phenyl-sulfonyl-,
3-carboxy-4-methyl-phenyl-sulfonyl-,
3-carboxy-4-methoxy-phenyl-sulfonyl-,
3-aminocarbonyl-4-fluoro-phenyl-sulfonyl-,
3-aminocarbonyl-4-methyl-phenyl-sulfonyl-,
3-aminocarbonyl-4-methoxy-phenyl-sulfonyl-,
3,5-dichloro-4-hydroxy-phenyl-sulfonyl-,
piperazin-1-yl-ethyl-sulfonyl-,
5-(hydroxymethyl)-fur-2-yl-sulfonyl-, 5-carboxy-fur-2-yl-sulfonyl-,
5-(aminocarbonyl)-fur-2-yl-sulfonyl-,
4-carboxy-thien-2-yl-sulfonyl-,
4-(aminocarbonyl)-thien-2-yl-sulfonyl-,
3-methyl-5-carboxy-thien-2-yl-sulfonyl-,
3-methyl-5-(aminocarbonyl)-thien-2-yl-sulfonyl-,
6-carboxy-pyrid-3-yl-sulfonyl-,
6-aminocarbonyl-pyrid-3-yl-sulfonyl-,
6-(2-hydroxyethyl-amino-carbonyl)-pyrid-3-yl-sulfonyl-,
6-(carboxyethyl-amino-carbonyl)-pyrid-3-yl-sulfonyl- and
6-(methoxycarbonyl-ethyl-amino-carbonyl)-pyrid-3-yl-sulfonyl-;
[0080] (e) is
##STR00060##
wherein a is 0; and wherein R.sup.5 is selected from the group
consisting of ethoxycarbonyl- and trifluoromethyl-sulfonyl-;
[0081] (f) is
##STR00061##
wherein R.sup.5 is trifluoromethyl-sulfonyl-;
[0082] (g) is
##STR00062##
wherein b is an integer from 0 to 1; wherein L.sup.2 is selected
from the group consisting of --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH(CH.sub.3)--, --CH(CH.sub.3)--CH.sub.2--,
--CH.sub.2--CH(CH.sub.3)--, --CH.sub.2--CH(R*--CH.sub.3)--,
--CH.sub.2--CH(S*--CH.sub.3)--, --CH.sub.2CH.sub.2--O--,
--CH.sub.2--CH(OH)--, --CH.sub.2--CH(R*--OH),
--CH(CH.sub.3)--CH(OH) and
--CH.sub.2CH.sub.2CH.sub.2--NH--SO.sub.2--; wherein R.sup.6 is
selected from the group consisting of hydrogen, 3-bromo, 3-chloro,
4-chloro, 3-hydroxy, 4-hydroxy, 3-methoxy, 4-methoxy,
4-trifluoromethyl, 3-carboxy, 4-carboxy, 3-carboxy-methoxy-,
4-carboxy-methoxy-, 3-methoxycarbonyl-,4-methoxycarbonyl-,
3-ethoxy-carbonyl-methoxy-, 4-ethoxy-carbonyl-methoxy-,
4-aminocarbonyl-, 3-amino-carbonyl-methoxy-,
4-amino-carbonyl-methoxy-, 3-(3-carboxyphenyl),
3-(4-carboxy-phenyl), 4-(3-carboxyphenyl), 4-(4-carboxyphenyl) and
3-(5-carboxy-thien-2-yl); and wherein R.sup.7 is selected from the
group consisting of hydrogen and 5-trifluoromethyl;
[0083] (h) is
##STR00063##
wherein L.sup.3 is selected from the group consisting of
--CH.sub.2-- and --CH.sub.2CH.sub.2--O--; and wherein R.sup.8 is
selected from the group consisting of hydrogen, carboxy and
methoxycarbonyl-;
[0084] (i) is
##STR00064##
wherein c is an integer from 0 to 1; wherein L.sup.4 is
--CH.sub.2--;
[0085] (j) is
##STR00065##
and (k) is
##STR00066##
[0086] In an embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is selected from the group
consisting of (a), (b), (d), (f), (g), (h) and (i); wherein
[0087] (a) is
##STR00067##
wherein the cyclohexyl group is bound in a cis-, trans- or racemic
orientation; and wherein R.sup.4 is selected from the group
consisting of hydrogen, aminocarbonyl-, 3-hydroxyphenyl-amino-,
3-carboxyphenyl-amino-, 4-carboxyphenyl-amino-,
3-carboxyphenyl-sulfonyl-amino- and
4-carboxyphenyl-sulfonyl-amino-;
[0088] (b) is
##STR00068##
wherein a 0; and wherein R.sup.5 is selected from the group
consisting of 3-carboxybenzyl- and 4-carboxyphenyl-sulfonyl-;
[0089] (d) is
##STR00069##
wherein a is an integer from 0 to 1; wherein L.sup.1 is
--CH.sub.2--; and wherein R.sup.5 is selected from the group
consisting of propyn-3-yl, methoxy-carbonyl-methyl-,
3-carboxyphenyl-oxy-ethyl-, 2-hydroxyethyl-carbonyl-,
hydroxymethyl-carbonyl-, aminocarbonyl-methyl-carbonyl-,
aminocarbonyl-ethyl-carbonyl-, ethoxycarbonyl-, t-butoxycarbonyl-,
cyclopentyloxy-carbonyl-, 2,3,4-trihydroxy-n-butyloxy-carbonyl-,
3-carboxyphenyl, 4-carboxyphenyl, 3-(aminocarbonyl)-phenyl,
4-(aminocarbonyl)-phenyl, 3-(aminocarbonyl-methyl)-phenyl,
4-(aminocarbonyl-methyl)-phenyl, 3-(aminocarbonyl-methoxy)-phenyl,
4-(aminocarbonyl-methoxy)-phenyl, 3-hydroxy-benzyl,
2-trifluoromethyl-benzyl, 3-carboxy-benzyl, 4-carboxy-benzyl,
3-(aminocarbonyl)-benzyl, 4-(aminocarbonyl)-benzyl,
3-(2-hydroxyethyl-aminocarbonyl)-benzyl,
2-hydroxy-3-carboxy-benzyl, 2-fluoro-5-carboxy-benzyl,
3-fluoro-5-carboxy-benzyl, 2-chloro-3-carboxy-benzyl,
2-chloro-5-carboxy-benzyl, 2-trifluoromethyl-5-carboxy-benzyl,
3-carboxy-4-fluoro-benzyl, 3-carboxy-4-hydroxy-benzyl,
1-(3-hydroxyphenyl)-ethyl-, 1-(3-carboxyphenyl)-ethyl-,
1R*-(3-carboxyphenyl)-ethyl-, 1-(3-carboxyphenyl)-n-propyl-,
5-carboxy-pyrimidin-2-yl, 5-methoxycarbonyl-pyrimidin-2-yl,
2-carboxy-pyrid-4-yl-methyl-, 4-carboxy-pyrid-2-yl-methyl-,
5-carboxy-pyrid-2-yl-methyl-, 6-carboxy-pyrid-2-yl-methyl-,
5-carboxy-pyrid-3-yl-methyl-, 6-carboxy-pyrid-3-yl-methyl-,
5-aminocarbonyl-pyrid-2-yl-methyl-,
6-aminocarbonyl-pyrid-2-yl-methyl-,
5-aminocarbonyl-pyrid-3-yl-methyl-,
6-aminocarbonyl-pyrid-3-yl-methyl-,
1-(4-carboxy-pyrid-2-yl)-ethyl-, 5-carboxy-fur-2-yl-methyl-,
1-(5-carboxy-fur-2-yl)-ethyl-, 5-aminocarbonyl-fur-2-yl-methyl-,
4-carboxy-thien-2-yl-methyl-, 5-carboxy-thien-2-yl-methyl-,
5-aminocarbonyl-thien-2-yl-methyl-,
4-aminocarbonyl-thien-2-yl-methyl-, phenoxy-carbonyl-,
benzyloxy-carbonyl-, ethylamino-carbonyl-,
cyclopentyl-amino-carbonyl-, phenyl-aminocarbonyl-,
benzyl-amino-carbonyl-, 4-aminocarbonyl-phenyl-carbonyl-,
3-aminosulfonyl-phenyl-carbonyl-, 4-aminosulfonyl-phenyl-carbonyl-,
6-aminocarbonyl-pyrid-3-yl-carbonyl-, 1,2,4-triazol-3-yl-carbonyl-,
methylsulfonyl-, trifluoromethyl-sulfonyl-, phenyl-sulfonyl-,
4-fluorophenyl-sulfonyl-, 4-chlorophenyl-sulfonyl,
2-hydroxyphenyl-sulfonyl-, 3-hydroxyphenyl-sulfonyl-,
4-hydroxyphenyl-sulfonyl-, 2-methoxy-phenyl-sulfonyl-,
3-methoxy-phenyl-sulfonyl-, 4-methoxy-phenyl-sulfonyl-,
2-trifluoromethyl-phenyl-sulfonyl-,
3-trifluoromethyl-phenyl-sulfonyl-,
4-trifluoromethyl-phenyl-sulfonyl-,
4-trifluoromethoxy-phenyl-sulfonyl-,3-carboxyphenyl-sulfonyl-,
4-carboxyphenyl-sulfonyl-, 3-aminophenyl-sulfonyl-,
4-aminophenyl-sulfonyl-, 2-aminocarbonyl-phenyl-sulfonyl-,
3-aminocarbonyl-phenyl-sulfonyl-, 4-aminocarbonyl-phenyl-sulfonyl-,
4-aminocarbonyl-methoxy-phenyl-sulfonyl-,
3-(methylamino-carbonyl)-phenyl-sulfonyl-,
3-(3-hydroxy-n-propyl-amino-carbonyl)-phenyl-sulfonyl-,
3-(2-(methoxycarbonyl)-ethyl-amino-carbonyl)-phenyl-sulfonyl-,
3-(2-hydroxyethyl-amino-carbonyl)-phenyl-sulfonyl-,
3-fluoro-4-methoxy-phenyl-sulfonyl-,
3-fluoro-4-aminocabonyl-phenyl-sulfonyl-,
3-fluoro-4-carboxy-phenyl-sulfonyl-,
3-chloro-4-aminocarbonyl-phenyl-sulfonyl-,
3-chloro-4-carboxy-phenyl-sulfonyl,
3-methyl-4-carboxy-phenyl-sulfonyl-,
3-trifluoromethyl-4-carboxy-phenyl-sulfonyl-,
3-trifluoromethyl-4-aminocarbonyl-phenyl-sulfonyl,
3-methoxy-4-aminocarbonyl-phenyl-sulfonyl-,
3-methoxy-4-carboxy-phenyl-sulfonyl-,
3-carboxy-4-chloro-phenyl-sulfonyl-,
3-carboxy-4-fluoro-phenyl-sulfonyl-,
3-aminocarbonyl-4-fluoro-phenyl-sulfonyl-,
3-aminocarbonyl-4-methyl-phenyl-sulfonyl-,
3-aminocarbonyl-4-methoxy-phenyl-sulfonyl-,
3,5-dichloro-4-hydroxy-phenyl-sulfonyl-,
5-(hydroxymethyl)-fur-2-yl-sulfonyl-, 5-carboxy-fur-2-yl-sulfonyl-,
5-(aminocarbonyl)-fur-2-yl-sulfonyl-,
4-carboxy-thien-2-yl-sulfonyl-,
4-(aminocarbonyl)-thien-2-yl-sulfonyl-,
3-methyl-5-carboxy-thien-2-yl-sulfonyl-,
3-methyl-5-(aminocarbonyl)-thien-2-yl-sulfonyl-,
6-carboxy-pyrid-3-yl-sulfonyl-,
6-aminocarbonyl-pyrid-3-yl-sulfonyl-,
6-(2-hydroxyethyl-amino-carbonyl)-pyrid-3-yl-sulfonyl-,
6-(carboxyethyl-amino-carbonyl)-pyrid-3-yl-sulfonyl- and
6-(methoxycarbonyl-ethyl-amino-carbonyl)-pyrid-3-yl-sulfonyl-;
[0090] (f) is
##STR00070##
wherein R.sup.5 is trifluoromethyl-sulfonyl-;
[0091] (g) is
##STR00071##
wherein b is an integer from 0 to 1; L.sup.2 is selected from the
group consisting of --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH(CH.sub.3)--CH.sub.2--, --CH.sub.2--CH(R*--CH.sub.3)--,
--CH.sub.2--CH(S*--CH.sub.3)--, --CH.sub.2CH.sub.2--O--,
--CH.sub.2--CH(OH)-- and
--CH.sub.2CH.sub.2CH.sub.2--NH--SO.sub.2--; and wherein R.sup.6 is
selected from the group consisting of hydrogen, 3-chloro-,
4-chloro-, 3-bromo-, 4-bromo-, 3-hydroxy, 4-hydroxy-,
4-trifluoromethyl, 3-methoxy-, 4-methoxy-, 4-methoxycarbonyl-,
3-(ethoxy-carbonyl-methoxy)-, 4-(ethoxy-carbonyl-methoxy)-,
3-(aminocarbonyl-methoxy)-, 4-(aminocarbonyl-methoxy)-,
3-(3-carboxyphenyl), 3-(4-carboxyphenyl) and
3-(5-carboxy-thein-2-yl); and R.sup.7 is selected from the group
consisting of hydrogen and 5-trifluoromethyl;
[0092] (h) is
##STR00072##
wherein L.sup.3 is --CH.sub.2CH.sub.2-- and wherein R.sup.8 is
5-methoxycarbonyl-;
[0093] and (i) is
##STR00073##
wherein c is an integer from 0 to 1; and wherein L.sup.4 is
--CH.sub.2--.
[0094] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is selected from the group
consisting of (a), (b), (d), (f), (g) and (i); wherein
[0095] (a) is
##STR00074##
wherein the cyclohexyl group is bound in trans-orientation; and
wherein R.sup.4 is 3-hydroxyphenyl-amino-;
[0096] (b) is
##STR00075##
wherein a 0; and wherein R.sup.5 is 3-carboxybenzyl-;
[0097] (d) is
##STR00076##
wherein a is an integer from 0 to 1; wherein L.sup.1 is
--CH.sub.2--; and wherein R.sup.5 is selected from the group
consisting of propyn-3-yl, methoxy-carbonyl-methyl-,
3-carboxyphenyl-oxy-ethyl-, 2-hydroxyethyl-carbonyl-,
hydroxymethyl-carbonyl-, ethoxycarbonyl-cyclopentyloxy-carbonyl-,
4-carboxyphenyl, 3-(aminocarbonyl)-phenyl,
4-(aminocarbonyl)-phenyl, 3-(aminocarbonyl-methyl)-phenyl,
4-(aminocarbonyl-methyl)-phenyl, 3-(aminocarbonyl-methoxy)-phenyl,
4-(aminocarbonyl-methoxy)-phenyl, 3-hydroxy-benzyl,
3-carboxy-benzyl, 4-carboxy-benzyl, 3-(aminocarbonyl)-benzyl,
4-(aminocarbonyl)-benzyl, 3-(2-hydroxyethyl-aminocarbonyl)-benzyl,
2-fluoro-5-carboxy-benzyl, 3-fluoro-5-carboxy-benzyl,
2-chloro-5-carboxy-benzyl, 3-carboxy-4-fluoro-benzyl,
3-carboxy-4-hydroxy-benzyl, 1-(3-hydroxyphenyl)-ethyl-,
1-(3-carboxyphenyl)-ethyl-, 1R*-(3-carboxyphenyl)-ethyl-,
1-(3-carboxyphenyl)-n-propyl-, 5-carboxy-pyrimidin-2-yl,
5-carboxy-pyrid-3-yl-methyl-, 6-carboxy-pyrid-3-yl-methyl-,
5-aminocarbonyl-pyrid-2-yl-methyl-,
6-aminocarbonyl-pyrid-2-yl-methyl-,
5-aminocarbonyl-pyrid-3-yl-methyl-,
6-aminocarbonyl-pyrid-3-yl-methyl-,
1-(4-carboxy-pyrid-2-yl)-ethyl-, 5-carboxy-fur-2-yl-methyl-,
5-aminocarbonyl-fur-2-yl-methyl-, 1-(5-carboxy-fur-2-yl)-ethyl-,
4-carboxy-thien-2-yl-methyl-, 5-carboxy-thien-2-yl-methyl-,
5-aminocarbonyl-thien-2-yl-methyl-,
4-aminocarbonyl-thien-2-yl-methyl-, phenoxy-carbonyl-,
benzyloxy-carbonyl-, ethylamino-carbonyl-,
3-aminosulfonyl-phenyl-carbonyl-,
6-aminocarbonyl-pyrid-3-yl-carbonyl-, methylsulfonyl-,
trifluoromethyl-sulfonyl-, phenyl-sulfonyl-,
4-fluorophenyl-sulfonyl-, 4-chlorophenyl-sulfonyl,
2-hydroxyphenyl-sulfonyl-, 3-hydroxyphenyl-sulfonyl-,
4-hydroxyphenyl-sulfonyl-, 2-methoxy-phenyl-sulfonyl-,
3-methoxy-phenyl-sulfonyl-, 4-methoxy-phenyl-sulfonyl-,
2-trifluoromethyl-phenyl-sulfonyl-,
3-trifluoromethyl-phenyl-sulfonyl-,
4-trifluoromethyl-phenyl-sulfonyl-, 3-carboxyphenyl-sulfonyl-,
4-carboxyphenyl-sulfonyl-, 3-aminophenyl-sulfonyl-,
3-aminocarbonyl-phenyl-sulfonyl-, 4-aminocarbonyl-phenyl-sulfonyl-,
4-aminocarbonyl-methoxy-phenyl-sulfonyl-,
3-(methylamino-carbonyl)-phenyl-sulfonyl-,
3-(3-hydroxy-n-propyl-amino-carbonyl)-phenyl-sulfonyl-,
3-fluoro-4-aminocabonyl-phenyl-sulfonyl-,
3-fluoro-4-carboxy-phenyl-sulfonyl-,
3-chloro-4-aminocarbonyl-phenyl-sulfonyl-,
3-chloro-4-carboxy-phenyl-sulfonyl,
3-methyl-4-carboxy-phenyl-sulfonyl-,
3-trifluoromethyl-4-carboxy-phenyl-sulfonyl-,
3-methoxy-4-aminocarbonyl-phenyl-sulfonyl-,
3-methoxy-4-carboxy-phenyl-sulfonyl-,
3-carboxy-4-chloro-phenyl-sulfonyl-,
3-carboxy-4-fluoro-phenyl-sulfonyl-,
3-aminocarbonyl-4-fluoro-phenyl-sulfonyl-,
3,5-dichloro-4-hydroxy-phenyl-sulfonyl-,
5-(hydroxymethyl)-fur-2-yl-sulfonyl-, 5-carboxy-fur-2-yl-sulfonyl-,
5-(aminocarbonyl)-fur-2-yl-sulfonyl-,
4-carboxy-thien-2-yl-sulfonyl-,
4-(aminocarbonyl)-thien-2-yl-sulfonyl-,
3-methyl-5-carboxy-thien-2-yl-sulfonyl-,
3-methyl-5-(aminocarbonyl)-thien-2-yl-sulfonyl-,
6-carboxy-pyrid-3-yl-sulfonyl-,
6-aminocarbonyl-pyrid-3-yl-sulfonyl- and
6-(methoxycarbonyl-ethyl-amino-carbonyl)-pyrid-3-yl-sulfonyl-;
[0098] (f) is
##STR00077##
wherein R.sup.5 is trifluoromethyl-sulfonyl-;
[0099] (g) is
##STR00078##
wherein b is an integer from 0 to 1; L.sup.2 is selected from the
group consisting of --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2--CH(R*--CH.sub.3)--, --CH.sub.2CH.sub.2--O--,
--CH.sub.2--CH(OH)-- and
--CH.sub.2CH.sub.2CH.sub.2--NH--SO.sub.2--; and wherein R.sup.6 is
selected from the group consisting of hydrogen, 3-chloro-,
3-bromo-, 4-bromo-, 3-hydroxy, 4-trifluoromethyl, 3-methoxy-,
4-methoxy-, 3-(ethoxy-carbonyl-methoxy)-,
4-(ethoxy-carbonyl-methoxy)-, and 3-(5-carboxy-thein-2-yl); and
R.sup.7 is hydrogen;
[0100] and (i) is
##STR00079##
wherein c is 1; and wherein L.sup.4 is --CH.sub.2--.
[0101] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is selected from the group
consisting of (d), (f) and (g); wherein
[0102] (d) is
##STR00080##
wherein a is an integer from 0 to 1; wherein L.sup.1 is
--CH.sub.2--; and wherein R.sup.5 is selected from the group
consisting of propyn-3-yl, methoxy-carbonyl-methyl-,
3-(aminocarbonyl)-phenyl, 4-(aminocarbonyl)-phenyl,
3-(aminocarbonyl-methyl)-phenyl, 3-(aminocarbonyl-methoxy)-phenyl,
3-carboxy-benzyl, 3-(aminocarbonyl)-benzyl,
3-(2-hydroxyethyl-aminocarbonyl)-benzyl, 3-fluoro-5-carboxy-benzyl,
1-(3-carboxyphenyl)-ethyl-, 1R*-(3-carboxyphenyl)-ethyl-,
1-(3-carboxyphenyl)-n-propyl-, 5-carboxy-pyrimidin-2-yl,
5-aminocarbonyl-pyrid-2-yl-methyl-,
5-aminocarbonyl-pyrid-3-yl-methyl-,
6-aminocarbonyl-pyrid-3-yl-methyl-,
1-(4-carboxy-pyrid-2-yl)-ethyl-, 5-aminocarbonyl-fur-2-yl-methyl-,
5-carboxy-thien-2-yl-methyl-, 5-aminocarbonyl-thien-2-yl-methyl-,
4-aminocarbonyl-thien-2-yl-methyl-, benzyloxy-carbonyl-,
methylsulfonyl-, trifluoromethyl-sulfonyl-, phenyl-sulfonyl-,
4-fluorophenyl-sulfonyl-, 4-chlorophenyl-sulfonyl,
3-hydroxyphenyl-sulfonyl-, 4-hydroxyphenyl-sulfonyl-,
2-methoxy-phenyl-sulfonyl-, 3-trifluoromethyl-phenyl-sulfonyl-,
4-carboxyphenyl-sulfonyl-, 3-aminophenyl-sulfonyl-,
3-aminocarbonyl-phenyl-sulfonyl-,
4-aminocarbonyl-methoxy-phenyl-sulfonyl-,
3-chloro-4-carboxy-phenyl-sulfonyl,
3-methyl-4-carboxy-phenyl-sulfonyl-,
3-trifluoromethyl-4-carboxy-phenyl-sulfonyl-,
3-methoxy-4-aminocarbonyl-phenyl-sulfonyl-,
3-methoxy-4-carboxy-phenyl-sulfonyl-,
5-(aminocarbonyl)-fur-2-yl-sulfonyl-,
4-carboxy-thien-2-yl-sulfonyl-,
4-(aminocarbonyl)-thien-2-yl-sulfonyl-,
3-methyl-5-carboxy-thien-2-yl-sulfonyl-,
3-methyl-5-(aminocarbonyl)-thien-2-yl-sulfonyl- and
6-aminocarbonyl-pyrid-3-yl-sulfonyl-;
[0103] (f) is
##STR00081##
wherein R.sup.5 is trifluoromethyl-sulfonyl-;
[0104] and (g) is
##STR00082##
wherein b is an integer from 0 to 1; L.sup.2 is
--CH.sub.2CH.sub.2--; and wherein R.sup.6 is selected from the
group consisting of 3-chloro-, 4-trifluoromethyl, 4-methoxy- and
4-(ethoxy-carbonyl-methoxy)-; and R.sup.7 is hydrogen.
[0105] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is selected from the group
consisting of (d), (f) and (g); wherein
[0106] (d) is
##STR00083##
wherein a is an integer from 0 to 1; wherein L.sup.1 is
--CH.sub.2--; and wherein R.sup.5 is selected from the group
consisting of methoxy-carbonyl-methyl-, 3-(aminocarbonyl)-benzyl,
1R*-(3-carboxyphenyl)-ethyl-, 5-aminocarbonyl-pyrid-2-yl-methyl-,
1-(4-carboxy-pyrid-2-yl)-ethyl 5-aminocarbonyl-thien-2-yl-methyl-,
4-aminocarbonyl-thien-2-yl-methyl-, trifluoromethyl-sulfonyl-,
phenyl-sulfonyl-, 4-chlorophenyl-sulfonyl,
3-hydroxyphenyl-sulfonyl-, 2-methoxy-phenyl-sulfonyl-,
3-aminocarbonyl-phenyl-sulfonyl-,
4-aminocarbonyl-methoxy-phenyl-sulfonyl-,
3-chloro-4-carboxy-phenyl-sulfonyl,
3-trifluoromethyl-4-carboxy-phenyl-sulfonyl3-methyl-5-(aminocarbonyl)-thi-
en-2-yl-sulfonyl- and 6-aminocarbonyl-pyrid-3-yl-sulfonyl-;
[0107] (f) is
##STR00084##
wherein R.sup.5 is trifluoromethyl-sulfonyl-;
[0108] and (g) is
##STR00085##
wherein b is an integer from 0 to 1; L.sup.2 is
--CH.sub.2CH.sub.2--; and wherein R.sup.6 is selected from the
group consisting of 4-trifluoromethyl, 4-methoxy- and
4-(ethoxy-carbonyl-methoxy)-; and R.sup.7 is hydrogen.
[0109] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (a)
##STR00086##
In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (b)
##STR00087##
In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (c)
##STR00088##
In another embodiment, the present invention is directed to
compounds of formula (I) wherein
[0110] R.sup.3 is (d)
##STR00089##
In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (e)
##STR00090##
In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (f)
##STR00091##
[0111] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (g)
##STR00092##
In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (h)
##STR00093##
In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (i)
##STR00094##
In another embodiment, the present invention is directed to
compounds of formula (I) wherein
[0112] R.sup.3 is (j)
##STR00095##
In another embodiment the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (k)
##STR00096##
[0113] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (a); wherein (a) is
##STR00097##
wherein R.sup.4 is selected from the group consisting of hydrogen,
--C(O)OH, --C(O)O--(C.sub.1-2alkyl), --C(O)NR.sup.GR.sup.H,
--NH-(phenyl), and --NH--SO.sub.2-(phenyl); wherein the phenyl is
optionally substituted with hydroxy or carboxy; and wherein R.sup.G
and R.sup.H are each independently selected from the group
consisting of hydrogen and methyl.
[0114] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (a); wherein (a) is
##STR00098##
wherein R.sup.4 is selected from the group consisting of hydrogen,
--C(O)OH, --C(O)NR.sup.GR.sup.H, --NH-(phenyl) and
--NH--SO.sub.2-(phenyl); wherein the phenyl is optionally
substituted with hydroxy or carboxy; wherein R.sup.G and R.sup.H
are each independently selected from the group consisting of
hydrogen and methyl.
[0115] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (a); wherein (a) is
##STR00099##
wherein R.sup.4 is selected from the group consisting of hydrogen,
--C(O)OH, --C(O)NH.sub.2, --NH--SO.sub.2-(3-carboxyphenyl),
--NH-(3-hydroxyphenyl), --NH-(3-carboxyphenyl),
--NH-(4-carboxyphenyl) and --NH--SO.sub.2-(4-carboxyphenyl); and
wherein the cyclohexyl is bound to the benzimidazole core in a
cis-, trans- or racemic stereo-orientation.
[0116] In an embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (a) is
##STR00100##
wherein the cyclohexyl group is bound in a cis-, trans- or racemic
orientation; and wherein R.sup.4 is selected from the group
consisting of hydrogen, aminocarbonyl-, 3-hydroxyphenyl-amino-,
3-carboxyphenyl-amino-, 4-carboxyphenyl-amino-,
3-carboxyphenyl-sulfonyl-amino- and
4-carboxyphenyl-sulfonyl-amino-. In another embodiment, the present
invention is directed to compounds of formula (I) wherein R.sup.3
is (a) is
##STR00101##
wherein the cyclohexyl group is bound in trans-orientation; and
wherein R.sup.4 is 3-hydroxyphenyl-amino-.
[0117] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is selected from the group
consisting of (b) through (f);
wherein (b) is
##STR00102##
(c) is
##STR00103##
(d) is
##STR00104##
(e) is
##STR00105##
(f) is
##STR00106##
wherein a is an integer from 0 to 1; wherein L.sup.1 is selected
from the group consisting of --CH.sub.2--, --CH.sub.2--CH.sub.2,
--CH(CH.sub.3)CH.sub.2-- and --CH.sub.2--CH(CH.sub.3)--; wherein
R.sup.5 is selected from the group consisting of hydrogen,
C.sub.1-2alkyl, fluorinated C.sub.1-2alkyl, C.sub.2-4alkenyl,
--(C.sub.1-2alkyl)-C(O)OH,
--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--(C.sub.2alkyl)-O-(phenyl), --C(O)--(C.sub.1-2alkyl)-OH,
--C(O)--(C.sub.1-2alkyl)-C(O)OH,
--C(O)--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--C(O)--(C.sub.1-2alkyl)-C(O)--NH.sub.2, --C(O)O--(C.sub.1-4alkyl),
--C(O)O--(C.sub.3-5cycloalkyl), --C(O)O-(phenyl),
--C(O)O--CH.sub.2-(phenyl), --C(O)--NH.sub.2,
--C(O)NH--(C.sub.1-2alkyl), --C(O)NH--(C.sub.3-5cycloalkyl),
--C(O)NH-(phenyl), --C(O)NH--(C.sub.1-2alkyl)-(phenyl),
--SO.sub.2--(C.sub.1-2alkyl), --SO.sub.2-(fluorinated
C.sub.1-2alkyl), --SO.sub.2--(C.sub.1-2alkyl)-C(O)OH,
--SO.sub.2--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--(C.sub.1-2alkyl),
--SO.sub.2--(C.sub.1-2alkyl)-C(O)NH.sub.2, phenyl,
--(C.sub.1-3alkyl)-phenyl, --C(O)-(phenyl), --C(O)O-(phenyl),
--C(O)O--(C.sub.1-2alkyl)-(phenyl), --SO.sub.2-(phenyl),
pyrimidin-2-yl, pyrid-2-yl, pyrid-3-yl,
--(C.sub.1-2alkyl)-pyrid-2-yl, --(C.sub.1-2alkyl)-pyrid-3-yl,
--(C.sub.1-2alkyl)-fur-2-yl, --(C.sub.1-2alkyl)-thien-2-yl,
--C(O)-fur-2-yl, --C(O)-thien-2-yl, --C(O)-(pyrid-3-yl),
--C(O)-(1,2,3-triazol-4-yl), --C(O)-(1,2,4,-triazol-3-yl),
--SO.sub.2--(C.sub.1-2alkyl)-(piperazin-1-yl),
--SO.sub.2-(fury-2-yl), --SO.sub.2-(thien-2-yl) and
--SO.sub.2-(pyrid-3-yl); wherein the phenyl, pyrimidin-2-yl,
pyridyl, furyl, thienyl or pyridyl, is optionally substituted with
one to three substituents independently selected from the group
consisting of halogen, hydroxy, C.sub.1-2alkyl, fluorinated
C.sub.1-2alkyl, --(C.sub.1-2alkyl)-OH, --C(.sub.1-2alkyl)-C(O)OH,
--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl), --O--(C.sub.1-2alkyl),
--O-(fluorinated C.sub.1-2alkyl), --O--(C.sub.2-6alkenyl),
--O--(C.sub.1-2alkyl)-C(O)OH, --O--(C.sub.1-2alkyl)-C(O)NH.sub.2,
--C(O)OH, --C(O)O--(C.sub.1-4alkyl), --C(O)--NH.sub.2,
--C(O)--NH--(C.sub.1-2alkyl), --C(O)--NH--(C.sub.1-3alkyl)-OH,
--C(O)--NH--(C.sub.1-2alkyl)-C(O)OH,
--C(O)--NH--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--(C.sub.1-2alkyl)-C(O)--NH.sub.2,
--O--(C.sub.1-2alkyl)-C(O)--NH.sub.2, --O--(C.sub.1-2alkyl)-C(O)OH,
--NH.sub.2, --NH(C.sub.1-2alkyl), --SO.sub.2--NH.sub.2 and
--SO.sub.2--NH(C.sub.1-2alkyl).
[0118] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is selected from the group
consisting of (b) through (f);
wherein (b) is
##STR00107##
(c) is
##STR00108##
(d) is
##STR00109##
(e) is
##STR00110##
(f) is
##STR00111##
wherein a is an integer from 0 to 1; and wherein L.sup.1 is
selected from the group consisting of --CH.sub.2-- and
--CH.sub.2--CH(CH.sub.3)--; wherein R.sup.5 is selected from the
group consisting of hydrogen, C.sub.2-4alkenyl,
--(C.sub.1-2alkyl)-C(O)OH,
--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--(C.sub.2alkyl)-O-(phenyl), --C(O)--(C.sub.1-2alkyl)-OH,
--C(O)--(C.sub.1-2alkyl)-C(O)OH,
--C(O)--(C.sub.1-2alkyl)-C(O)--NH.sub.2, --C(O)O--(C.sub.1-4alkyl),
--C(O)O-(hydroxy substituted C.sub.1-4alkyl),
--C(O)O--(C.sub.3-5cycloalkyl), --C(O)NH--(C.sub.1-2alkyl),
--C(O)NH--(C.sub.3-5cycloalkyl), --C(O)NH-(phenyl),
--C(O)NH--(C.sub.1-2alkyl)-(phenyl), --SO.sub.2--(C.sub.1-2alkyl),
--SO.sub.2-(fluorinated C.sub.1-2alkyl),
--SO.sub.2--(C.sub.1-2alkyl)-C(O)OH, --SO.sub.2--NH.sub.2,
--SO.sub.2--NH--(C.sub.1-2alkyl),
--SO.sub.2--(C.sub.1-2alkyl)-C(O)NH.sub.2, phenyl,
--(C.sub.1-3alkyl)-phenyl, --C(O)-(phenyl), --C(O)O-(phenyl),
--C(O)O--(C.sub.1-2alkyl)-(phenyl), --SO.sub.2-(phenyl),
pyrimidin-2-yl, --(C.sub.1-2alkyl)-pyrid-2-yl,
--(C.sub.1-2alkyl)-pyrid-3-yl, --(C.sub.1-2alkyl)-fur-2-yl,
--(C.sub.1-2alkyl)-thien-2-yl, --C(O)-(pyrid-3-yl),
--C(O)-(1,2,3-triazol-4-yl), --C(O)-(1,2,4,-triazol-3-yl),
--SO.sub.2--(C.sub.1-2alkyl)-(piperazin-1-yl),
--SO.sub.2-(fury-2-yl), --SO.sub.2-(thien-2-yl) and
--SO.sub.2-(pyrid-3-yl); wherein the phenyl is optionally
substituted with one to three substituents independently selected
from the group consisting of halogen, hydroxy, C.sub.1-2alkyl,
fluorinated C.sub.1-2alkyl, --O--(C.sub.1-2alkyl), --O-(fluorinated
C.sub.1-2alkyl), --O--(C.sub.2-6alkenyl),
--O--(C.sub.1-2alkyl)-C(O)OH, --O--(C.sub.1-2alkyl)-C(O)NH.sub.2,
--C(O)OH, --C(O)O--(C.sub.1-2alkyl), --C(.sub.1-2alkyl)-C(O)OH,
--C(O)--NH.sub.2, --C(O)--NH--(C.sub.1-2alkyl),
--C(O)--NH--(C.sub.1-3alkyl)-OH,
--C(O)--NH--(C.sub.1-2alkyl)-C(O)OH,
--C(O)--NH--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl),
--(C.sub.1-2alkyl)-C(O)--NH.sub.2,
--O--(C.sub.1-2alkyl)-C(O)--NH.sub.2, --O--(C.sub.1-2alkyl)-C(O)OH,
--NH.sub.2 and --SO.sub.2--NH.sub.2; and wherein the
pyrimidin-2-yl, pyrid-2-yl, pyrid-3-yl, fur-2-yl or thien-2-yl is
optionally substituted with one to two substituents independently
selected from the group consisting of C.sub.1-2alkyl,
--(C.sub.1-2alkyl)-OH, --C(O)OH, --C(O)O--(C.sub.1-2alkyl),
--C(O)--NH.sub.2, --C(O)NH--(C.sub.1-2alkyl)-OH,
--C(O)NH--(C.sub.1-2alkyl)-C(O)OH and
--C(O)NH--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl).
[0119] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (b); wherein (b) is
##STR00112##
wherein a 0; and wherein R.sup.5 is selected from the group
consisting of 3-carboxybenzyl-, 4-carboxyphenyl-sulfonyl- and
5-carboxyfur-2-yl-sulfonyl-.
[0120] In an embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (b) is
##STR00113##
wherein a 0; and wherein R.sup.5 is selected from the group
consisting of 3-carboxybenzyl- and 4-carboxyphenyl-sulfonyl-. In
another embodiment, the present invention is directed to compounds
of formula (I) wherein R.sup.3 is (b) is
##STR00114##
wherein a 0; and wherein R.sup.5 is 3-carboxybenzyl-.
[0121] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (c); wherein (c) is
##STR00115##
wherein a is 0; and wherein
[0122] R.sup.5 is selected from the group consisting of
3-carboxybenzyl-, 4-carboxyphenyl-sulfonyl- and
5-carboxy-fur-2-yl-sulfonyl-.
[0123] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (d); wherein (d) is
##STR00116##
wherein a is an integer from 0 to 1; L.sup.1 is selected from the
group consisting of --CH.sub.2-- and
--CH.sub.2--CH(R*--CH.sub.3)--; and wherein R.sup.5 is selected
from the group consisting of hydrogen, propyn-3-yl,
carboxy-methyl-, methoxy-carbonyl-methyl-,
3-carboxyphenyl-oxy-ethyl-, 2-hydroxyethyl-carbonyl-,
hydroxymethyl-carbonyl-, 2-carboxy-ethyl-carbonyl-,
aminocarbonyl-methyl-carbonyl-, 2-(aminocarbonyl)-ethyl-carbonyl-,
ethoxycarbonyl-, t-butoxycarbonyl-, cyclopentyloxy-carbonyl-,
2,3,4-trihydroxy-n-butyloxy-carbonyl-, 3-carboxyphenyl,
4-carboxyphenyl, 3-(carboxy-methyl)-phenyl,
4-(carboxy-methyl)-phenyl, 3-(methoxycarbonyl)-phenyl,
3-(aminocarbonyl)-phenyl, 4-(aminocarbonyl)-phenyl,
3-(aminocarbonyl-methyl)-phenyl, 4-(aminocarbonyl-methyl)-phenyl,
3-(aminocarbonyl-methoxy)-phenyl, 4-(aminocarbonyl-methoxy)-phenyl,
3-(carboxy-methoxy)-phenyl, 4-(carboxy-methoxy)-phenyl,
3-hydroxy-benzyl, 3-(hex-2-en-1-yloxy)-benzyl,
2-trifluoromethyl-benzyl, 3-carboxy-benzyl, 4-carboxy-benzyl,
3-(methoxycarbonyl)-benzyl, 3-(aminocarbonyl)-benzyl,
4-(aminocarbonyl)-benzyl, 3-(2-hydroxyethyl-aminocarbonyl)-benzyl,
2-hydroxy-3-carboxy-benzyl, 2-hydroxy-5-carboxy-benzyl,
2-fluoro-3-carboxy-benzyl, 2-fluoro-5-carboxy-benzyl,
2-chloro-3-carboxy-benzyl, 2-chloro-5-carboxy-benzyl,
2-trifluoromethyl-5-carboxy-benzyl, 3-fluoro-5-carboxy-benzyl,
3-carboxy-4-fluoro-benzyl, 3-carboxy-4-hydroxy-benzyl,
3-trifluoromethyl-5-carboxy-benzyl, 1-(3-hydroxyphenyl)-ethyl-,
1-(3-carboxyphenyl)-ethyl-, 1R*-(3-carboxyphenyl)-ethyl-,
1-(3-carboxyphenyl)-n-propyl-, 4-carboxy-pyrimidin-2-yl,
5-carboxy-pyrimidin-2-yl, 5-methoxycarbonyl-pyrimidin-2-yl,
2-carboxy-pyrid-4-yl-methyl-, 4-carboxy-pyrid-2-yl-methyl-,
5-carboxy-pyrid-2-yl-methyl-, 6-carboxy-pyrid-2-yl-methyl-,
5-carboxy-pyrid-3-yl-methyl-,
6-carboxy-pyrid-3-yl-methyl-,5-aminocarbonyl-pyrid-2-yl-methyl-,
6-aminocarbonyl-pyrid-2-yl-methyl-,
5-aminocarbonyl-pyrid-3-yl-methyl-,
6-aminocarbonyl-pyrid-3-yl-methyl-,
1-(4-carboxy-pyrid-2-yl)-ethyl-, 5-carboxy-fur-2-yl-methyl-,
5-aminocarbonyl-fur-2-yl-methyl-, 1-(5-carboxy-fur-2-yl)-ethyl-,
4-carboxy-thien-2-yl-methyl-, 5-carboxy-thien-2-yl-methyl-,
5-aminocarbonyl-thien-2-yl-methyl-,
4-aminocarbonyl-thien-2-yl-methyl-, phenoxy-carbonyl-,
benzyloxy-carbonyl-, ethylamino-carbonyl-,
cyclopentyl-amino-carbonyl-, phenyl-aminocarbonyl-,
benzyl-amino-carbonyl-, 4-carboxy-phenyl-carbonyl-,
4-aminoarbonyl-phenyl-carbonyl-, 3-aminosulfonyl-phenyl-carbonyl-,
4-aminosulfonyl-phenyl-carbonyl-,
6-carboxy-pyrid-3-yl-carbonyl-,6-aminocarbonyl-pyrid-3-yl-carbonyl-,
1,2,3-triazol-4-yl-carbonyl-, 1,2,4-triazol-3-yl-carbonyl-,
methyl-sulfonyl-, trifluoromethyl-sulfonyl-,
carboxymethyl-sulfonyl-, carboxyethyl-sulfonyl-, amino-sulfonyl-,
amino-ethyl-sulfonyl-, aminocarbonyl-methyl-sulfonyl-,
phenyl-sulfonyl-, 4-fluorophenyl-sulfonyl-,
4-chlorophenyl-sulfonyl, 2-hydroxyphenyl-sulfonyl-,
3-hydroxyphenyl-sulfonyl-, 4-hydroxyphenyl-sulfonyl-,
2-methoxy-phenyl-sulfonyl-, 3-methoxy-phenyl-sulfonyl-,
4-methoxy-phenyl-sulfonyl-, 2-trifluoromethyl-phenyl-sulfonyl-,
3-trifluoromethyl-phenyl-sulfonyl-,
4-trifluoromethyl-phenyl-sulfonyl-,
4-trifluoromethoxy-phenyl-sulfonyl-, 2-carboxyphenyl-sulfonyl-,
3-carboxyphenyl-sulfonyl-, 4-carboxyphenyl-sulfonyl-,
4-carboxy-methoxy-phenyl-sulfonyl-, 3-aminophenyl-sulfonyl-,
4-aminophenyl-sulfonyl-, 2-aminocarbonyl-phenyl-sulfonyl-,
3-aminocarbonyl-phenyl-sulfonyl-, 4-aminocarbonyl-phenyl-sulfonyl-,
4-aminocarbonyl-methoxy-phenyl-sulfonyl-,
3-(methylamino-carbonyl)-phenyl-sulfonyl-,
3-(carboxy-ethyl-amino-carbonyl)-phenyl-sulfonyl-,
3-(3-hydroxy-n-propyl-amino-carbonyl)-phenyl-sulfonyl-,
3-(2-(methoxycarbonyl)-ethyl-amino-carbonyl)-phenyl-sulfonyl-,
3-(2-hydroxyethyl-amino-carbonyl)-phenyl-sulfonyl-,
3-fluoro-4-hydroxy-phenyl-sulfonyl-,
3-fluoro-4-methoxy-phenyl-sulfonyl-,
3-fluoro-4-aminocabonyl-phenyl-sulfonyl-,
3-fluoro-4-carboxy-phenyl-sulfonyl-,
3-chloro-4-aminocarbonyl-phenyl-sulfonyl-,
3-chloro-4-carboxy-phenyl-sulfonyl-,
3-methyl-4-aminocarbonyl-phenyl-sulfonyl-,
3-methyl-4-carboxy-phenyl-sulfonyl-,
3-trifluoromethyl-4-carboxy-phenyl-sulfonyl-,
3-trifluoromethyl-4-aminocarbonyl-phenyl-sulfonyl,
3-methoxy-4-carboxy-phenyl-sulfonyl,
3-methoxy-4-aminocarbonyl-phenyl-sulfonyl-,
3-carboxy-4-chloro-phenyl-sulfonyl-,
3-carboxy-4-fluoro-phenyl-sulfonyl-,
3-carboxy-4-methyl-phenyl-sulfonyl-,
3-carboxy-4-methoxy-phenyl-sulfonyl-,
3-aminocarbonyl-4-fluoro-phenyl-sulfonyl-,
3-aminocarbonyl-4-methyl-phenyl-sulfonyl-,
3-aminocarbonyl-4-methoxy-phenyl-sulfonyl-,
3,5-dichloro-4-hydroxy-phenyl-sulfonyl-,
piperazin-1-yl-ethyl-sulfonyl-,
5-(hydroxymethyl)-fur-2-yl-sulfonyl-, 5-carboxy-fur-2-yl-sulfonyl-,
5-(aminocarbonyl)-fur-2-yl-sulfonyl-,
4-carboxy-thien-2-yl-sulfonyl-,
4-(aminocarbonyl)-thien-2-yl-sulfonyl-,
3-methyl-5-carboxy-thien-2-yl-sulfonyl-,
3-methyl-5-(aminocarbonyl)-thien-2-yl-sulfonyl-,
6-carboxy-pyrid-3-yl-sulfonyl-,
6-aminocarbonyl-pyrid-3-yl-sulfonyl-,
6-(2-hydroxyethyl-amino-carbonyl)-pyrid-3-yl-sulfonyl-,
6-(carboxyethyl-amino-carbonyl)-pyrid-3-yl-sulfonyl- and
6-(methoxycarbonyl-ethyl-amino-carbonyl)-pyrid-3-yl-sulfonyl-.
[0124] In an embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (d) is
##STR00117##
wherein a is an integer from 0 to 1; wherein L.sup.1 is
--CH.sub.2--; and wherein R.sup.5 is selected from the group
consisting of propyn-3-yl, methoxy-carbonyl-methyl-,
3-carboxyphenyl-oxy-ethyl-, 2-hydroxyethyl-carbonyl-,
hydroxymethyl-carbonyl-, aminocarbonyl-methyl-carbonyl-,
aminocarbonyl-ethyl-carbonyl-, ethoxycarbonyl-, t-butoxycarbonyl-,
cyclopentyloxy-carbonyl-, 2,3,4-trihydroxy-n-butyloxy-carbonyl-,
3-carboxyphenyl, 4-carboxyphenyl, 3-(aminocarbonyl)-phenyl,
4-(aminocarbonyl)-phenyl, 3-(aminocarbonyl-methyl)-phenyl,
4-(aminocarbonyl-methyl)-phenyl, 3-(aminocarbonyl-methoxy)-phenyl,
4-(aminocarbonyl-methoxy)-phenyl, 3-hydroxy-benzyl,
2-trifluoromethyl-benzyl, 3-carboxy-benzyl, 4-carboxy-benzyl,
3-(aminocarbonyl)-benzyl, 4-(aminocarbonyl)-benzyl,
3-(2-hydroxyethyl-aminocarbonyl)-benzyl,
2-hydroxy-3-carboxy-benzyl, 2-fluoro-5-carboxy-benzyl,
3-fluoro-5-carboxy-benzyl, 2-chloro-3-carboxy-benzyl,
2-chloro-5-carboxy-benzyl, 2-trifluoromethyl-5-carboxy-benzyl,
3-carboxy-4-fluoro-benzyl, 3-carboxy-4-hydroxy-benzyl,
1-(3-hydroxyphenyl)-ethyl-, 1-(3-carboxyphenyl)-ethyl-,
1R*-(3-carboxyphenyl)-ethyl-, 1-(3-carboxyphenyl)-n-propyl-,
5-carboxy-pyrimidin-2-yl, 5-methoxycarbonyl-pyrimidin-2-yl,
2-carboxy-pyrid-4-yl-methyl-, 4-carboxy-pyrid-2-yl-methyl-,
5-carboxy-pyrid-2-yl-methyl-, 6-carboxy-pyrid-2-yl-methyl-,
5-carboxy-pyrid-3-yl-methyl-, 6-carboxy-pyrid-3-yl-methyl-,
5-aminocarbonyl-pyrid-2-yl-methyl-,
6-aminocarbonyl-pyrid-2-yl-methyl-,
5-aminocarbonyl-pyrid-3-yl-methyl-,
6-aminocarbonyl-pyrid-3-yl-methyl-,
1-(4-carboxy-pyrid-2-yl)-ethyl-, 5-carboxy-fur-2-yl-methyl-,
1-(5-carboxy-fur-2-yl)-ethyl-, 5-aminocarbonyl-fur-2-yl-methyl-,
4-carboxy-thien-2-yl-methyl-, 5-carboxy-thien-2-yl-methyl-,
5-aminocarbonyl-thien-2-yl-methyl-,
4-aminocarbonyl-thien-2-yl-methyl-, phenoxy-carbonyl-,
benzyloxy-carbonyl-, ethylamino-carbonyl-,
cyclopentyl-amino-carbonyl-, phenyl-aminocarbonyl-,
benzyl-amino-carbonyl-, 4-aminocarbonyl-phenyl-carbonyl-,
3-aminosulfonyl-phenyl-carbonyl-, 4-aminosulfonyl-phenyl-carbonyl-,
6-aminocarbonyl-pyrid-3-yl-carbonyl-, 1,2,4-triazol-3-yl-carbonyl-,
methylsulfonyl-, trifluoromethyl-sulfonyl-, phenyl-sulfonyl-,
4-fluorophenyl-sulfonyl-, 4-chlorophenyl-sulfonyl,
2-hydroxyphenyl-sulfonyl-, 3-hydroxyphenyl-sulfonyl-,
4-hydroxyphenyl-sulfonyl-, 2-methoxy-phenyl-sulfonyl-,
3-methoxy-phenyl-sulfonyl-, 4-methoxy-phenyl-sulfonyl-,
2-trifluoromethyl-phenyl-sulfonyl-,
3-trifluoromethyl-phenyl-sulfonyl-,
4-trifluoromethyl-phenyl-sulfonyl-,
4-trifluoromethoxy-phenyl-sulfonyl-,3-carboxyphenyl-sulfonyl-,
4-carboxyphenyl-sulfonyl-, 3-aminophenyl-sulfonyl-,
4-aminophenyl-sulfonyl-, 2-aminocarbonyl-phenyl-sulfonyl-,
3-aminocarbonyl-phenyl-sulfonyl-, 4-aminocarbonyl-phenyl-sulfonyl-,
4-aminocarbonyl-methoxy-phenyl-sulfonyl-,
3-(methylamino-carbonyl)-phenyl-sulfonyl-,
3-(3-hydroxy-n-propyl-amino-carbonyl)-phenyl-sulfonyl-,
3-(2-(methoxycarbonyl)-ethyl-amino-carbonyl)-phenyl-sulfonyl-,
3-(2-hydroxyethyl-amino-carbonyl)-phenyl-sulfonyl-,
3-fluoro-4-methoxy-phenyl-sulfonyl-,
3-fluoro-4-aminocabonyl-phenyl-sulfonyl-,
3-fluoro-4-carboxy-phenyl-sulfonyl-,
3-chloro-4-aminocarbonyl-phenyl-sulfonyl-,
3-chloro-4-carboxy-phenyl-sulfonyl,
3-methyl-4-carboxy-phenyl-sulfonyl-,
3-trifluoromethyl-4-carboxy-phenyl-sulfonyl-,
3-trifluoromethyl-4-aminocarbonyl-phenyl-sulfonyl,
3-methoxy-4-aminocarbonyl-phenyl-sulfonyl-,
3-methoxy-4-carboxy-phenyl-sulfonyl-,
3-carboxy-4-chloro-phenyl-sulfonyl-,
3-carboxy-4-fluoro-phenyl-sulfonyl-,
3-aminocarbonyl-4-fluoro-phenyl-sulfonyl-,
3-aminocarbonyl-4-methyl-phenyl-sulfonyl-,
3-aminocarbonyl-4-methoxy-phenyl-sulfonyl-,
3,5-dichloro-4-hydroxy-phenyl-sulfonyl-,
5-(hydroxymethyl)-fur-2-yl-sulfonyl-, 5-carboxy-fur-2-yl-sulfonyl-,
5-(aminocarbonyl)-fur-2-yl-sulfonyl-,
4-carboxy-thien-2-yl-sulfonyl-,
4-(aminocarbonyl)-thien-2-yl-sulfonyl-,
3-methyl-5-carboxy-thien-2-yl-sulfonyl-,
3-methyl-5-(aminocarbonyl)-thien-2-yl-sulfonyl-,
6-carboxy-pyrid-3-yl-sulfonyl-,
6-aminocarbonyl-pyrid-3-yl-sulfonyl-,
6-(2-hydroxyethyl-amino-carbonyl)-pyrid-3-yl-sulfonyl-,
6-(carboxyethyl-amino-carbonyl)-pyrid-3-yl-sulfonyl- and
6-(methoxycarbonyl-ethyl-amino-carbonyl)-pyrid-3-yl-sulfonyl-.
[0125] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (d) is
##STR00118##
wherein a is an integer from 0 to 1; wherein L.sup.1 is
--CH.sub.2--; and wherein R.sup.5 is selected from the group
consisting of propyn-3-yl, methoxy-carbonyl-methyl-,
3-carboxyphenyl-oxy-ethyl-, 2-hydroxyethyl-carbonyl-,
hydroxymethyl-carbonyl-, ethoxycarbonyl-cyclopentyloxy-carbonyl-,
4-carboxyphenyl, 3-(aminocarbonyl)-phenyl,
4-(aminocarbonyl)-phenyl, 3-(aminocarbonyl-methyl)-phenyl,
4-(aminocarbonyl-methyl)-phenyl, 3-(aminocarbonyl-methoxy)-phenyl,
4-(aminocarbonyl-methoxy)-phenyl, 3-hydroxy-benzyl,
3-carboxy-benzyl, 4-carboxy-benzyl, 3-(aminocarbonyl)-benzyl,
4-(aminocarbonyl)-benzyl, 3-(2-hydroxyethyl-aminocarbonyl)-benzyl,
2-fluoro-5-carboxy-benzyl, 3-fluoro-5-carboxy-benzyl,
2-chloro-5-carboxy-benzyl, 3-carboxy-4-fluoro-benzyl,
3-carboxy-4-hydroxy-benzyl, 1-(3-hydroxyphenyl)-ethyl-,
1-(3-carboxyphenyl)-ethyl-, 1R*-(3-carboxyphenyl)-ethyl-,
1-(3-carboxyphenyl)-n-propyl-, 5-carboxy-pyrimidin-2-yl,
5-carboxy-pyrid-3-yl-methyl-, 6-carboxy-pyrid-3-yl-methyl-,
5-aminocarbonyl-pyrid-2-yl-methyl-,
6-aminocarbonyl-pyrid-2-yl-methyl-,5-aminocarbonyl-pyrid-3-yl-methyl-,
6-aminocarbonyl-pyrid-3-yl-methyl-,
1-(4-carboxy-pyrid-2-yl)-ethyl-, 5-carboxy-fur-2-yl-methyl-,
5-aminocarbonyl-fur-2-yl-methyl-, 1-(5-carboxy-fur-2-yl)-ethyl-,
4-carboxy-thien-2-yl-methyl-, 5-carboxy-thien-2-yl-methyl-,
5-aminocarbonyl-thien-2-yl-methyl-,
4-aminocarbonyl-thien-2-yl-methyl-, phenoxy-carbonyl-,
benzyloxy-carbonyl-, ethylamino-carbonyl-,
3-aminosulfonyl-phenyl-carbonyl-,
6-aminocarbonyl-pyrid-3-yl-carbonyl-, methylsulfonyl-,
trifluoromethyl-sulfonyl-, phenyl-sulfonyl-,
4-fluorophenyl-sulfonyl-, 4-chlorophenyl-sulfonyl,
2-hydroxyphenyl-sulfonyl-, 3-hydroxyphenyl-sulfonyl-,
4-hydroxyphenyl-sulfonyl-, 2-methoxy-phenyl-sulfonyl-,
3-methoxy-phenyl-sulfonyl-, 4-methoxy-phenyl-sulfonyl-,
2-trifluoromethyl-phenyl-sulfonyl-,
3-trifluoromethyl-phenyl-sulfonyl-,
4-trifluoromethyl-phenyl-sulfonyl-, 3-carboxyphenyl-sulfonyl-,
4-carboxyphenyl-sulfonyl-, 3-aminophenyl-sulfonyl-,
3-aminocarbonyl-phenyl-sulfonyl-, 4-aminocarbonyl-phenyl-sulfonyl-,
4-aminocarbonyl-methoxy-phenyl-sulfonyl-,
3-(methylamino-carbonyl)-phenyl-sulfonyl-,
3-(3-hydroxy-n-propyl-amino-carbonyl)-phenyl-sulfonyl-,
3-fluoro-4-aminocabonyl-phenyl-sulfonyl-,
3-fluoro-4-carboxy-phenyl-sulfonyl-,
3-chloro-4-aminocarbonyl-phenyl-sulfonyl-,
3-chloro-4-carboxy-phenyl-sulfonyl,
3-methyl-4-carboxy-phenyl-sulfonyl-,
3-trifluoromethyl-4-carboxy-phenyl-sulfonyl-,
3-methoxy-4-aminocarbonyl-phenyl-sulfonyl-,
3-methoxy-4-carboxy-phenyl-sulfonyl-,
3-carboxy-4-chloro-phenyl-sulfonyl-,
3-carboxy-4-fluoro-phenyl-sulfonyl-,
3-aminocarbonyl-4-fluoro-phenyl-sulfonyl-,
3,5-dichloro-4-hydroxy-phenyl-sulfonyl-,
5-(hydroxymethyl)-fur-2-yl-sulfonyl-, 5-carboxy-fur-2-yl-sulfonyl-,
5-(aminocarbonyl)-fur-2-yl-sulfonyl-,
4-carboxy-thien-2-yl-sulfonyl-,
4-(aminocarbonyl)-thien-2-yl-sulfonyl-,
3-methyl-5-carboxy-thien-2-yl-sulfonyl-,
3-methyl-5-(aminocarbonyl)-thien-2-yl-sulfonyl-,
6-carboxy-pyrid-3-yl-sulfonyl-,
6-aminocarbonyl-pyrid-3-yl-sulfonyl- and
6-(methoxycarbonyl-ethyl-amino-carbonyl)-pyrid-3-yl-sulfonyl-.
[0126] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (d) is
##STR00119##
wherein a is an integer from 0 to 1; wherein L.sup.1 is
--CH.sub.2--; and wherein R.sup.5 is selected from the group
consisting of propyn-3-yl, methoxy-carbonyl-methyl-,
3-(aminocarbonyl)-phenyl, 4-(aminocarbonyl)-phenyl,
3-(aminocarbonyl-methyl)-phenyl, 3-(aminocarbonyl-methoxy)-phenyl,
3-carboxy-benzyl, 3-(aminocarbonyl)-benzyl,
3-(2-hydroxyethyl-aminocarbonyl)-benzyl, 3-fluoro-5-carboxy-benzyl,
1-(3-carboxyphenyl)-ethyl-, 1R'-(3-carboxyphenyl)-ethyl-,
1-(3-carboxyphenyl)-n-propyl-, 5-carboxy-pyrimidin-2-yl,
5-aminocarbonyl-pyrid-2-yl-methyl-,
5-aminocarbonyl-pyrid-3-yl-methyl-,
6-aminocarbonyl-pyrid-3-yl-methyl-,
1-(4-carboxy-pyrid-2-yl)-ethyl-, 5-aminocarbonyl-fur-2-yl-methyl-,
5-carboxy-thien-2-yl-methyl-, 5-aminocarbonyl-thien-2-yl-methyl-,
4-aminocarbonyl-thien-2-yl-methyl-, benzyloxy-carbonyl-,
methylsulfonyl-, trifluoromethyl-sulfonyl-, phenyl-sulfonyl-,
4-fluorophenyl-sulfonyl-, 4-chlorophenyl-sulfonyl,
3-hydroxyphenyl-sulfonyl-, 4-hydroxyphenyl-sulfonyl-,
2-methoxy-phenyl-sulfonyl-, 3-trifluoromethyl-phenyl-sulfonyl-,
4-carboxyphenyl-sulfonyl-, 3-aminophenyl-sulfonyl-,
3-aminocarbonyl-phenyl-sulfonyl-,
4-aminocarbonyl-methoxy-phenyl-sulfonyl-,
3-chloro-4-carboxy-phenyl-sulfonyl,
3-methyl-4-carboxy-phenyl-sulfonyl-,
3-trifluoromethyl-4-carboxy-phenyl-sulfonyl-,
3-methoxy-4-aminocarbonyl-phenyl-sulfonyl-,
3-methoxy-4-carboxy-phenyl-sulfonyl-,
5-(aminocarbonyl)-fur-2-yl-sulfonyl-,
4-carboxy-thien-2-yl-sulfonyl-,
4-(aminocarbonyl)-thien-2-yl-sulfonyl-,
3-methyl-5-carboxy-thien-2-yl-sulfonyl-,
3-methyl-5-(aminocarbonyl)-thien-2-yl-sulfonyl- and
6-aminocarbonyl-pyrid-3-yl-sulfonyl-.
[0127] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (d) is
##STR00120##
wherein a is an integer from 0 to 1; wherein L.sup.1 is
--CH.sub.2--; and wherein R.sup.5 is selected from the group
consisting of methoxy-carbonyl-methyl-, 3-(aminocarbonyl)-benzyl,
1R*-(3-carboxyphenyl)-ethyl-, 5-aminocarbonyl-pyrid-2-yl-methyl-,
1-(4-carboxy-pyrid-2-yl)-ethyl 5-aminocarbonyl-thien-2-yl-methyl-,
4-aminocarbonyl-thien-2-yl-methyl-, trifluoromethyl-sulfonyl-,
phenyl-sulfonyl-, 4-chlorophenyl-sulfonyl,
3-hydroxyphenyl-sulfonyl-, 2-methoxy-phenyl-sulfonyl-,
3-aminocarbonyl-phenyl-sulfonyl-,
4-aminocarbonyl-methoxy-phenyl-sulfonyl-,
3-chloro-4-carboxy-phenyl-sulfonyl,
3-trifluoromethyl-4-carboxy-phenyl-sulfonyl3-methyl-5-(aminocarbonyl)-thi-
en-2-yl-sulfonyl- and 6-aminocarbonyl-pyrid-3-yl-sulfonyl-.
[0128] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (e); wherein (e) is
##STR00121##
wherein a is 0; and wherein R.sup.5 is selected from the group
consisting of ethoxycarbonyl- and trifluoromethyl-sulfonyl-.
[0129] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (f); wherein (f) is
##STR00122##
wherein R.sup.5 is trifluoromethyl-sulfonyl-.
[0130] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (g); wherein (g) is
##STR00123##
wherein b is an integer from 0 to 1; wherein L.sup.2 is selected
from the group consisting of --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH(CH.sub.3)--, --CH(CH.sub.3)--CH.sub.2--,
--CH.sub.2--CH(CH.sub.3)--, --CH.sub.2CH.sub.2--O--,
--CH.sub.2--CH(OH)--, --CH(CH.sub.3)--CH(OH) and
CH.sub.2CH.sub.2CH.sub.2--NH--SO.sub.2--; wherein R.sup.6 is
selected from the group consisting of hydrogen, halogen, hydroxy,
C.sub.1-2alkyl, fluorinated C.sub.1-2alkyl, C.sub.1-2alkoxy,
fluorinated C.sub.1-2alkoxy, --C(O)OH, --C(O)O--(C.sub.1-2alkyl),
--O--(C.sub.1-2alkyl)-C(O)OH,
--O--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl), --C(O)--NH.sub.2,
--O--(C.sub.1-2alkyl)-C(O)--NH.sub.2, phenyl, furyl and thienyl;
wherein the phenyl, furyl or thienyl is optionally substituted with
carboxy; and wherein R.sup.7 is selected from the group consisting
of hydrogen, hydroxy, C.sub.1-2alkyl, fluorinated C.sub.1-2alkyl,
C.sub.1-2alkoxy, fluorinated C.sub.1-2alkoxy, --C(O)OH and
--C(O)O--(C.sub.1-4alkyl).
[0131] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (g); wherein (g) is
##STR00124##
wherein b is an integer from 0 to 1; and wherein L.sup.2 is
selected from the group consisting of --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH(CH.sub.3)--, --CH(CH.sub.3)--CH.sub.2--,
--CH.sub.2--CH(CH.sub.3)--, --CH.sub.2CH.sub.2--O--,
--CH.sub.2--CH(OH)--, --CH(CH.sub.3)--CH(OH) and
CH.sub.2CH.sub.2CH.sub.2--NH--SO.sub.2--; wherein R.sup.6 is
selected from the group consisting of hydrogen, halogen, hydroxy,
C.sub.1-2alkoxy, fluorinated C.sub.1-2alkyl, --C(O)OH,
--C(O)O--(C.sub.1-2alkyl), --O--(C.sub.1-2alkyl)-C(O)OH,
--O--(C.sub.1-2alkyl)-C(O)O--(C.sub.1-2alkyl), --C(O)--NH.sub.2,
--O--(C.sub.1-2alkyl)-C(O)--NH.sub.2, phenyl and thienyl; wherein
the phenyl or thienyl is optionally substituted with carboxy; and
wherein R.sup.7 is selected from the group consisting of hydrogen
and fluorinated C.sub.1-2alkyl.
[0132] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (g); wherein (g) is
##STR00125##
wherein b is an integer from 0 to 1; wherein L.sup.2 is selected
from the group consisting of --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH(CH.sub.3)--, --CH(CH.sub.3)--CH.sub.2--,
--CH.sub.2--CH(CH.sub.3)--, --CH.sub.2--CH(R*--CH.sub.3)--,
--CH.sub.2--CH(S*--CH.sub.3)--, --CH.sub.2CH.sub.2--O--,
--CH.sub.2--CH(OH)--, --CH.sub.2--CH(R*--OH),
--CH(CH.sub.3)--CH(OH) and
CH.sub.2CH.sub.2CH.sub.2--NH--SO.sub.2--; wherein R.sup.6 is
selected from the group consisting of hydrogen, 3-bromo, 3-chloro,
4-chloro, 3-hydroxy, 4-hydroxy, 3-methoxy, 4-methoxy,
4-trifluoromethyl, 3-carboxy, 4-carboxy, 3-carboxy-methoxy-,
4-carboxy-methoxy-, 3-methoxycarbonyl-, 4-methoxycarbonyl-,
3-ethoxy-carbonyl-methoxy-, 4-ethoxy-carbonyl-methoxy-,
4-aminocarbonyl-, 3-amino-carbonyl-methoxy-,
4-amino-carbonyl-methoxy-, 3-(3-carboxyphenyl),
3-(4-carboxy-phenyl), 4-(3-carboxyphenyl), 4-(4-carboxyphenyl) and
3-(5-carboxy-thien-2-yl); and wherein R.sup.7 is selected from the
group consisting of hydrogen and 5-trifluoromethyl.
[0133] In an embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (g) is
##STR00126##
wherein b is an integer from 0 to 1; L.sup.2 is selected from the
group consisting of --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH(CH.sub.3)--CH.sub.2--, --CH.sub.2--CH(R*--CH.sub.3)--,
--CH.sub.2--CH(S*--CH.sub.3)--, --CH.sub.2CH.sub.2--O--,
--CH.sub.2--CH(OH)-- and
--CH.sub.2CH.sub.2CH.sub.2--NH--SO.sub.2--; and wherein R.sup.8 is
selected from the group consisting of hydrogen, 3-chloro-,
4-chloro-, 3-bromo-, 4-bromo-, 3-hydroxy, 4-hydroxy-,
4-trifluoromethyl, 3-methoxy-, 4-methoxy-, 4-methoxycarbonyl-,
3-(ethoxy-carbonyl-methoxy)-, 4-(ethoxy-carbonyl-methoxy)-,
3-(aminocarbonyl-methoxy)-, 4-(aminocarbonyl-methoxy)-,
3-(3-carboxyphenyl), 3-(4-carboxyphenyl) and
3-(5-carboxy-thein-2-yl); and R.sup.7 is selected from the group
consisting of hydrogen and 5-trifluoromethyl.
[0134] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (g) is
##STR00127##
wherein b is an integer from 0 to 1; L.sup.2 is selected from the
group consisting of --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2--CH(R*--CH.sub.3)--, --CH.sub.2CH.sub.2--O--,
--CH.sub.2--CH(OH)-- and
--CH.sub.2CH.sub.2CH.sub.2--NH--SO.sub.2--; and wherein R.sup.5 is
selected from the group consisting of hydrogen, 3-chloro-,
3-bromo-, 4-bromo-, 3-hydroxy, 4-trifluoromethyl, 3-methoxy-,
4-methoxy-, 3-(ethoxy-carbonyl-methoxy)-,
4-(ethoxy-carbonyl-methoxy)-, and 3-(5-carboxy-thein-2-yl); and
R.sup.7 is hydrogen.
[0135] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (g) is
##STR00128##
wherein b is an integer from 0 to 1; L.sup.2 is
--CH.sub.2CH.sub.2--; and wherein R.sup.6 is selected from the
group consisting of 3-chloro-, 4-trifluoromethyl, 4-methoxy- and
4-(ethoxy-carbonyl-methoxy)-; and R.sup.7 is hydrogen.
[0136] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (g) is
##STR00129##
wherein b is an integer from 0 to 1; L.sup.2 is
--CH.sub.2CH.sub.2--; and wherein R.sup.6 is selected from the
group consisting of 4-trifluoromethyl, 4-methoxy- and
4-(ethoxy-carbonyl-methoxy)-; and R.sup.7 is hydrogen.
[0137] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (h); wherein (h) is
##STR00130##
wherein L.sup.3 is selected from the group consisting of
--CH.sub.2--, --CH.sub.2CH.sub.2-- and --CH.sub.2CH.sub.2--O--; and
wherein R.sup.8 is selected from the group consisting of hydrogen,
-halogen, C.sub.1-2alkyl, C.sub.1-2alkoxy, --C(O)OH and
--C(O)O--(C.sub.1-4alkyl).
[0138] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (h); wherein (h) is
##STR00131##
wherein L.sup.3 is selected from the group consisting of
--CH.sub.2-- and --CH.sub.2CH.sub.2--O--; and wherein R.sup.8 is
selected from the group consisting of hydrogen, --C(O)OH and
--C(O)O--(C.sub.1-2alkyl).
[0139] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (h); wherein (h) is
##STR00132##
wherein L.sup.3 is selected from the group consisting of
--CH.sub.2-- and --CH.sub.2CH.sub.2--O--; and wherein R.sup.8 is
selected from the group consisting of hydrogen, carboxy and
methoxycarbonyl-. In an embodiment, the present invention is
directed to compounds of formula (I) wherein
[0140] R.sup.3 is (h) is
##STR00133##
wherein L.sup.3 is --CH.sub.2CH.sub.2-- and wherein R.sup.8 is
5-methoxycarbonyl-.
[0141] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (i); wherein (i) is
##STR00134##
wherein c is an integer from 0 to 1; and wherein L.sup.4 is
selected from the group consisting of --CH.sub.2-- and
--CH.sub.2--CH.sub.2--.
[0142] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is (i); wherein (i) is
##STR00135##
wherein c is an integer from 0 to 1; wherein L.sup.4 is
--CH.sub.2--. In another embodiment, the present invention is
directed to compounds of formula (I) wherein R.sup.3 is (i) is
##STR00136##
wherein c is 1; and wherein L.sup.4 is --CH.sub.2--.
[0143] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is selected from the group
consisting of 1-(3-fluoro-5-carboxy-benzyl)-piperidin-4-yl,
1-(2-fluoro-5-carboxy-benzyl)-piperidin-4-yl,
1-(5-carboxy-pyrid-2-yl-methyl)-piperidin-4-yl,
1-(6-carboxy-pyrid-2-yl-methyl)-piperidin-4-yl,
1-(5-carboxy-thien-2-yl-methyl)-piperidin-4-yl,
1-(4-carboxy-thien-2-yl-sulfonyl)-piperidin-4-yl,
1-(5-carboxy-fur-2-yl-sulfonyl)-piperidin-4-yl,
1-(3-carboxy-benzyl)-piperidin-4-yl,
1-(3-carboxy-phenyl-sulfonyl)-piperidin-4-yl,
1-(3-hydroxy-phenyl-sulfonyl)-piperidin-4-yl,
1-(4-carboxy-phenyl-sulfonyl)-piperidin-4-yl,
1-trifluoromethyl-sulfonyl-piperidin-4-yl-methyl- and
1-trifluoromethyl-sulfonyl-piperidin-4-yl.
[0144] In another embodiment, the present invention is directed to
compounds of formula (I) wherein R.sup.3 is selected from the group
consisting of 1-(3-fluoro-5-carboxy-benzyl)-piperidin-4-yl,
1-(2-fluoro-5-carboxy-benzyl)-piperidin-4-yl,
1-(5-carboxy-pyrid-2-yl-methyl)-piperidin-4-yl,
1-(6-carboxy-pyrid-2-yl-methyl)-piperidin-4-yl,
1-(5-carboxy-thien-2-yl-methyl)-piperidin-4-yl,
1-(3-carboxy-benzyl)-piperidin-4-yl,
1-(3-carboxy-phenyl-sulfonyl)-piperidin-4-yl,
1-(3-hydroxy-phenyl-sulfonyl)-piperidin-4-yl,
1-trifluoromethyl-sulfonyl-piperidin-4-yl-methyl-,
1-trifluoromethyl-sulfonyl-piperidin-4-yl.
[0145] In additional embodiments, the present invention is directed
to compounds of formula (I) wherein the substituents selected for
the variables defined herein (e.g.
##STR00137##
R.sup.0, R.sup.1, R.sup.2 and R.sup.3, etc.) are independently
selected to be any individual substituent or any subset of
substituents selected from the substituents found on compounds
listed in Table BIO-1 as exhibiting CB-1 binding EC.sub.50 (as
measured according to the procedure described in Biological Example
1) of less than about 0.1 .mu.M, preferably exhibiting CB-1 binding
EC.sub.50 of less than about 0.01 .mu.M, more preferably,
exhibiting CB-1 binding EC.sub.50 less than about 0.05 .mu.M, more
preferably, exhibiting CB-1 binding EC.sub.50 less than about 0.025
.mu.M.
[0146] Additional embodiments, the present invention is directed to
compound of formula (I), wherein the substituents selected for one
or more of the variables defined herein (e.g.
##STR00138##
R.sup.0, R.sup.1, R.sup.2 and R.sup.3, etc.) are independently
selected to be any individual substituent or any subset of
substituents selected from the complete list as defined herein.
[0147] Additional embodiments of the present invention, include
those wherein the substituents selected for one or more of the
variables defined herein (e.g.
##STR00139##
R.sup.0, R.sup.1, R.sup.2 and R.sup.3, etc.) are independently
selected to be any individual substituent or subset of substituents
selected from those exemplified in the Tables which follow
herein.
[0148] In additional embodiments, the present invention is directed
to any single compound or subset of compounds selected from the
representative compounds listed in Tables 1-5 below.
[0149] Representative compounds of the present invention are as
listed in Tables 1-5, below. Unless otherwise noted, wherein a
stereogenic center is present in the listed compound, the compound
was prepared as a mixture of stereo-configurations. Where a
stereogenic center is present, the S*-- and R* designations are
intended to indicate that the exact stereo-configuration of the
center has not been determined.
TABLE-US-00001 TABLE 1 Representative Compounds of Formula (I)
##STR00140## ID No. ##STR00141## ##STR00142## R.sup.2 Stereo*
R.sup.4 21 4-chloro- 4-chloro- cyclo- trans- 4-carboxy-phenyl-
phenyl phenyl propyl cyclohexyl sulfonyl-amino- 22 4-chloro-
4-chloro- cyclo- trans- 3-carboxy-phenyl- phenyl phenyl propyl
cyclohexyl sulfonyl-amino- 28 4-chloro- 4-chloro- cyclo- trans-
3-hydroxy-phenyl- phenyl phenyl propyl cyclohexyl amino- 29
4-chloro- 4-chloro- cyclo- cis- 3-hydroxy-phenyl- phenyl phenyl
propyl cyclohexyl amino- 30 4-chloro- 4-chloro- cyclo- trans-
4-carboxy-phenyl- phenyl phenyl propyl cyclohexyl amino- 31
4-chloro- 4-chloro- cyclo- trans- 3-carboxy-phenyl- phenyl phenyl
propyl cyclohexyl amino- 32 4-chloro- 4-chloro- cyclo- cis-
4-carboxy-phenyl- phenyl phenyl propyl cyclohexyl amino- 40
4-chloro- 4-chloro- cyclo- cis- 3-carboxy-phenyl- phenyl phenyl
propyl cyclohexyl amino- 42 4-chloro- 4-chloro- cyclo- cis-
4-carboxy-phenyl- phenyl phenyl propyl cyclohexyl sulfonyl-amino-
43 4-chloro- 4-chloro- cyclo- cis- 3-carboxy-phenyl- phenyl phenyl
propyl cyclohexyl sulfonyl-amino- 134 4-chloro- 4-chloro- cyclo-
trans- carboxy phenyl phenyl propyl cyclohexyl 135 4-chloro-
4-chloro- cyclo- trans- amino-carbonyl- phenyl phenyl propyl
cyclohexyl 136 4-chloro- 4-chloro- cyclo- cis- amino-carbonyl-
phenyl phenyl propyl cyclohexyl 137 4-chloro- 4-chloro- cyclo- cis-
carboxy phenyl phenyl propyl cyclohexyl 442 4-chloro- thiazol-2- 4-
cyclohexyl H phenyl yl chloro- phenyl 444 4-chloro- thiazol-2- 2,4-
cyclohexyl H phenyl yl dichloro- phenyl 446 4-chloro- thiazol-2-
methyl cyclohexyl H phenyl yl 465 4-chloro- thiazol-2- H cyclohexyl
H phenyl yl *The column headed "Stereo" indicates the
stereo-orientation of the bonds at the 1- and 4-positions of the
cyclohexyl ring. Where neither "cis-" nor "trans-" is indicated,
the compound was prepared as a racemate.
TABLE-US-00002 TABLE 2 Representative Compounds of Formula (I)
##STR00143## ID No. R.sup.0 ##STR00144## ##STR00145## R.sup.2
(L.sup.2).sub.b R.sup.6 and R.sup.7* 6 H 4-chloro- 4-chloro- cyclo-
--CH.sub.2CH.sub.2-- 3-(5-carboxy- phenyl phenyl propyl thien-2-yl)
7 H 4-chloro- 4-chloro- cyclo- --CH.sub.2CH.sub.2O-- 3-bromo phenyl
phenyl propyl 8 H 4-chloro- 4-chloro- cyclo-
--CH.sub.2CH.sub.2--CH.sub.2--NH--SO.sub.2-- 3-(4-carboxy- phenyl
phenyl propyl phenyl) 9 H 4-chloro- 4-chloro- cyclo-
--CH.sub.2CH.sub.2--CH.sub.2--NH--SO.sub.2-- 3-bromo phenyl phenyl
propyl 11 H 4-chloro- 4-chloro- cyclo- --CH.sub.2CH.sub.2--
3-(3-carboxy- phenyl phenyl propyl phenyl) 16 H 4-chloro- 4-chloro-
cyclo- --CH.sub.2CH.sub.2O-- 3-carboxy-5- phenyl phenyl propyl
trifluoro- methyl 17 H 4-chloro- 4-chloro- cyclo-
--CH.sub.2CH.sub.2-- 3-(4-carboxy- phenyl phenyl propyl phenyl) 18
H 4-chloro- 4-chloro- cyclo- --CH.sub.2CH.sub.2O-- 3-methoxy-
phenyl phenyl propyl carbonyl-5- trifluoro- methyl- 19 H 4-chloro-
4-chloro- cyclo- --CH.sub.2CH.sub.2-- 3-bromo phenyl phenyl propyl
20 H 4-chloro- 4-chloro- cyclo- --CH.sub.2CH.sub.2-- 3-bromo phenyl
phenyl propyl 23 H 4-chloro- 4-chloro- cyclo- --CH.sub.2CH.sub.2O--
3-carboxy phenyl phenyl propyl 24 H 4-chloro- 4-chloro- cyclo-
--CH.sub.2CH.sub.2-- 4-(3-carboxy- phenyl phenyl propyl phenyl) 25
H 4-chloro- 4-chloro- cyclo- --CH.sub.2CH.sub.2-- 4-(4-carboxy-
phenyl phenyl propyl phenyl) 26 H 4-chloro- 4-chloro- cyclo-
--CH.sub.2CH.sub.2O-- 3-methoxy- phenyl phenyl propyl carbonyl- 27
H 4-chloro- 4-chloro- cyclo- --CH.sub.2CH.sub.2-- 4-bromo phenyl
phenyl propyl 35 H 4-chloro- 4-chloro- cyclo- --CH.sub.2CH.sub.2O--
4-carboxy phenyl phenyl propyl 36 H 4-chloro- 4-chloro- cyclo-
--CH.sub.2CH.sub.2O-- 4-methoxy- phenyl phenyl propyl carbonyl- 37
H 4-chloro- 4-chloro- cyclo- --CH.sub.2CH.sub.2-- 4-hydroxy phenyl
phenyl propyl 38 H 4-chloro- 4-chloro- cyclo- --CH.sub.2CH.sub.2--
4-carboxy phenyl phenyl propyl 132 H 4-chloro- 4-chloro- cyclo-
--CH.sub.2-- 4-carboxy phenyl phenyl propyl 133 H 4-chloro-
4-chloro- cyclo- --CH.sub.2-- 4-amino- phenyl phenyl propyl
carbonyl 144 H 4-chloro- 4-chloro- cyclo- --CH.sub.2-- 3-(ethoxy-
phenyl phenyl propyl carbonyl- methoxy-) 145 H 4-chloro- 4-chloro-
cyclo- --CH.sub.2-- 3-hydroxy phenyl phenyl propyl 146 H 4-chloro-
4-chloro- cyclo- --CH.sub.2-- 3-methoxy phenyl phenyl propyl 165 H
4-chloro- 4-chloro- cyclo- b = 0 4-carboxy- phenyl phenyl propyl
methoxy- 169 H 4-chloro- 4-chloro- cyclo- b = 0 4-amino- phenyl
phenyl propyl carbonyl- methoxy- 170 H 4-chloro- 4-chloro- cyclo- b
= 0 4-ethoxy- phenyl phenyl propyl carbonyl- methoxy- 171 H
4-chloro- 4-chloro- cyclo- b = 0 4-hydroxy phenyl phenyl propyl 172
H 4-chloro- 4-chloro- cyclo- b = 0 3-amino- phenyl phenyl propyl
carbonyl- methoxy- 173 H 4-chloro- 4-chloro- cyclo- b = 0 3-ethoxy-
phenyl phenyl propyl carbonyl- methoxy- 174 H 4-chloro- 4-chloro-
cyclo- b = 0 3-carbonyl- phenyl phenyl propyl methoxy- 175 H
4-chloro- 4-chloro- cyclo- --CH.sub.2-- 4-ethoxy- phenyl phenyl
propyl carbonyl- methoxy- 176 H 4-chloro- 4-chloro- cyclo-
--CH.sub.2-- 4-carboxy- phenyl phenyl propyl methoxy- 177 H
4-chloro- 4-chloro- cyclo- --CH.sub.2-- 4-methoxy phenyl phenyl
propyl 179 H 4-chloro- 4-chloro- cyclo- b = 0 4-methoxy phenyl
phenyl propyl 180 H 4-chloro- 4-chloro- cyclo- b = 0 3-hydroxy
phenyl phenyl propyl 181 H 4-chloro- 4-chloro- cyclo- b = 0
3-methoxy phenyl phenyl propyl 182 H 4-chloro- 4-chloro- cyclo-
--CH.sub.2-- 4-amino- phenyl phenyl propyl carbonyl- methoxy- 183 H
4-chloro- 4-chloro- cyclo- --CH.sub.2-- 4-hydroxy phenyl phenyl
propyl 268 OH 4-chloro- 4-chloro- cyclo- --CH.sub.2--CH(OH)-- --
phenyl phenyl propyl 286 H 4-chloro- 4-chloro- ethyl
--CH(CH.sub.3)--CH.sub.2-- 4-chloro phenyl phenyl 289 H 4-chloro-
4-chloro- cyclo- --CH.sub.2--CH(R*--OH) -- phenyl phenyl propyl 299
H 4-chloro- 4-chloro- cyclo- --CH(CH.sub.3)--CH(OH)-- -- phenyl
phenyl propyl 301 H 4-chloro- 4-chloro- cyclo- --CH.sub.2--CH(OH)--
-- phenyl phenyl propyl 305 H phenyl phenyl cyclo-
--CH.sub.2--CH(S*--CH.sub.3) -- propyl 306 H phenyl 4-chloro-
cyclo- --CH.sub.2--CH(S*--CH.sub.3) -- phenyl propyl 309 H
4-chloro- 4-chloro- cyclo- --CH.sub.2CH.sub.2-- 4-trifluoro- phenyl
phenyl propyl methyl- 311 H 4-chloro- 4-chloro- ethyl
--CH.sub.2CH.sub.2-- 3-chloro phenyl phenyl 312 H 4-chloro-
4-chloro- ethyl --CH.sub.2--CH(S*--CH.sub.3) -- phenyl phenyl 313 H
4-chloro- 4-chloro- methyl --CH.sub.2--CH(S*--CH.sub.3) -- phenyl
phenyl 314 H 4-chloro- 4-chloro- ethyl --CH.sub.2CH.sub.2
4-trifluoro- phenyl phenyl methyl- 317 H 4-chloro- 4-chloro- ethyl
--CH.sub.2--CH(R*--CH.sub.3)-- -- phenyl phenyl 329 H 4-chloro-
thiazol-2- --CHF.sub.2 --CH(CH.sub.3)--CH.sub.2-- 4-chloro phenyl
yl 330 H 4-chloro- thiazol-2- ethyl --CH(CH.sub.3)--CH.sub.2--
4-chloro phenyl yl 331 H 4-chloro- thiazol-2- cyclo-
--CH(CH.sub.3)--CH.sub.2-- 4-chloro phenyl yl propyl 333 H
4-chloro- thiazol-2- cyclo- --CH.sub.2--CH(OH)-- 4-chloro phenyl yl
propyl 334 H 4-chloro- thiazol-2- ethyl --CH.sub.2--CH(OH)--
4-chloro phenyl yl 336 H 4-chloro- thiazol-2- cyclo-
--CH.sub.2--CH(CH.sub.3)-- 4-chloro phenyl yl propyl 337 H
4-chloro- thiazol-2- 2,2,2- --CH.sub.2--CH(CH.sub.3)-- 4-chloro
phenyl yl trifluoro- ethyl 338 H 4-chloro- thiazol-2- cyclo-
--CH.sub.2CH.sub.2-- 4-chloro phenyl yl propyl 339 OH 4-chloro-
thiazol-2- 2,2,2- --CH.sub.2CH.sub.2-- 3-chloro phenyl yl
trifluoro- ethyl 340 H 4-chloro- thiazol-2- 2,2,2-
--CH.sub.2CH.sub.2-- 3-chloro phenyl yl trifluoro- ethyl 374 H
4-chloro- thiazol-2- --CH.sub.2--OH b = 0 3-chloro phenyl yl 375 H
4-chloro- thiazol-2- thien-3-yl b = 0 3-chloro phenyl yl 376 H
4-chloro- thiazol-2- fur-3-yl b = 0 3-chloro phenyl yl 377 H
4-chloro- thiazol-2- fur-2-yl b = 0 3-chloro phenyl yl 401 H
4-chloro- thiazol-2- cyclo- --CH(CH.sub.3)-- 4-chloro phenyl yl
propyl 402 H 4-chloro- thiazol-2- iso-propyl b = 0 3-chloro phenyl
yl 404 H 4-chloro- thiazol-2- azetidin- --CH.sub.2CH.sub.2--
3-chloro phenyl yl 3-yl 405 OH 4-chloro- thiazol-2- H
--CH.sub.2CH.sub.2-- 3-chloro phenyl yl 406 H 4-chloro- thiazol-2-
1-t- --CH.sub.2CH.sub.2-- 3-chloro phenyl yl butoxy- carbonyl-
azetidin- 3-yl 409 H 4-chloro- thiazol-2- ethyl
--CH.sub.2CH.sub.2-- 3-chloro phenyl yl 410 H 4-chloro- thiazol-2-
n-propyl --CH.sub.2CH.sub.2-- 3-chloro phenyl yl 423 H 4-chloro-
thiazol-2- cyclo- --CH.sub.2CH.sub.2-- 3-chloro phenyl yl propyl
424 H 4-chloro- thiazol-2- --CF.sub.3 --CH.sub.2CH.sub.2-- 3-chloro
phenyl yl 429 H 4-chloro- thiazol-2- --C(O)O-- b = 0 3-chloro
phenyl yl CH.sub.2CH.sub.3 431 H 4-chloro- thiazol-2- n-propyl b =
0 3-chloro phenyl yl 432 H 4-chloro- thiazol-2- cyclo- b = 0
3-chloro phenyl yl propyl 433 H 4-chloro- thiazol-2- isobutyl b = 0
3-chloro phenyl yl 434 H 4-chloro- thiazol-2- ethyl b = 0 3-chloro
phenyl yl 435 H 4-chloro- thiazol-2- H b = 0 3-chloro phenyl yl 436
H 4-chloro- thiazol-2- methyl b = 0 3-chloro phenyl yl 437 H
4-chloro- thiazol-2- methyl --CH.sub.2CH.sub.2-- 3-chloro phenyl yl
438 H 4-chloro- thiazol-2- H --CH.sub.2CH.sub.2-- 3-chloro phenyl
yl 449 H 4-chloro- 4-t-butyl- H --CH.sub.2-- 4-chloro phenyl
thiazol-2- yl 451 H 4-chloro- 5-ethyl- methyl --CH.sub.2-- 4-chloro
phenyl thiazol-2- yl 452 H 4-chloro- 4-ethyl- methyl --CH.sub.2--
4-chloro phenyl thiazol-2- yl 455 H 4-chloro- 4- methyl
--CH.sub.2-- 4-chloro phenyl trifluoro- methyl- thiazol-2- yl 456 H
4-chloro- 4-ethyl- 4-chloro- --CH.sub.2-- 4-chloro phenyl
thiazol-2- phenyl yl 460 H 4-chloro- 4-ethyl- H --CH.sub.2--
4-chloro phenyl thiazol-2- yl 462 H 4-chloro- 4- H --CH.sub.2--
4-chloro phenyl trifluoro- methyl- thiazol-2- yl 463 H 4-chloro-
thiazol-2- methyl --CH.sub.2-- 4-chloro phenyl yl 464 H 4-chloro-
thiazol-2- 4-chloro- --CH.sub.2-- 4-chloro phenyl yl phenyl 466 H
4-chloro- thiazol-2- H --CH.sub.2-- 4-chloro phenyl yl 474 H
2-chloro- thiazol-2- H --CH.sub.2-- -- phenyl yl *In the column
titled "R.sup.6 and R.sup.7", if no substituent group(s) are
listed, then both R.sup.6 and R.sup.7 are hydrogen; if only one
substituent group is listed, then one of R.sup.6 or R.sup.7 is
hydrogen.
TABLE-US-00003 TABLE 3 Representative Compounds of Formula (I)
##STR00146## ID No. R.sup.0 ##STR00147## ##STR00148## R.sup.2
R.sup.3 33 H 4-chloro- 4-chloro- cyclo- 5-carboxy-pyrid- phenyl
phenyl propyl 2-yl-O--CH.sub.2CH.sub.2-- 34 H 4-chloro- 4-chloro-
cyclo- 5-(methoxy-carbonyl)- phenyl phenyl propyl
pyrid-2-yl-O--CH.sub.2CH.sub.2-- 119 H 4-chloro- 4-chloro- cyclo-
tetrahydro-pyran-4-yl phenyl phenyl propyl 120 H 4-chloro-
4-chloro- cyclo- tetrahydro-pyran-4-yl- phenyl phenyl propyl
CH.sub.2-- 297 H 4-chloro- 4-chloro- ethyl 2,3-dihydro-1H-inden-2-
phenyl phenyl yl 298 H 4-chloro- 4-chloro- H
2,3-dihydro-1H-inden-2- phenyl phenyl yl 300 H 4-chloro- 4-chloro-
cyclo- 2,3-dihydro-1H-inden-2- phenyl phenyl propyl yl 341 OH
4-chloro- thiazol-2-yl cyclo- 1,2,3,4-tetrahydro- phenyl propyl
naphth-2-yl 342 H 4-chloro- thiazol-2-yl cyclo- 1,2,3,4-tetrahydro-
phenyl propyl naphth-2-yl 361 H 4-chloro- thiazol-2-yl methyl
2,3-dihydro-1H-inden-2- phenyl yl 362 H 4-chloro- thiazol-2-yl
cyclo- 2,3-dihydro-1H-inden-2- phenyl propyl yl 403 H 4-chloro-
thiazol-2-yl cyclo- pyrid-2-yl-CH.sub.2-- phenyl propyl
TABLE-US-00004 TABLE 4 Representative Compounds of Formula (I)
##STR00149## ID No. R.sup.0 ##STR00150## ##STR00151## R.sup.1
R.sup.2 (L.sup.1).sub.a R.sup.5 1 H 4-chloro- 4-chloro- H cyclo-
--CH.sub.2-- 4-carboxy- phenyl phenyl propyl phenyl 2 H 4-chloro-
4-chloro- H cyclo- --CH.sub.2-- 4-carboxy- phenyl phenyl propyl
pyrimidin-2- yl 3 H 4-chloro- 4-chloro- H cyclo- a = 0 3-(hex-2-en-
phenyl phenyl propyl 1-yloxy)- benzyl 4 H 4-chloro- 4-chloro- H
cyclo- --CH.sub.2-- 5-carboxy- phenyl phenyl propyl pyrimidin-2- yl
5 H 4-chloro- 4-chloro- H cyclo- --CH.sub.2-- 5-methoxy- phenyl
phenyl propyl carbonyl- pyrimidin-2- yl 10 H 4-chloro- 4-chloro- H
cyclo- --CH.sub.2-- 3-carboxy- phenyl phenyl propyl benzyl 12
--CO.sub.2H 4-chloro- 4-chloro- H cyclo- --CH.sub.2-- trifluoro-
phenyl phenyl propyl methyl- sulfonyl 13 H 4-chloro- 4-chloro- H
cyclo- --CH.sub.2-- 3-methoxy- phenyl phenyl propyl carbonyl-
phenyl 14 --C(O)--OCH.sub.3 4-chloro- 4-chloro- H cyclo-
--CH.sub.2-- trifluoro- phenyl phenyl propyl methyl- sulfonyl 15 H
4-chloro- 4-chloro- H cyclo- --CH.sub.2-- 4-carboxy- phenyl phenyl
propyl phenyl- sulfonyl 41 --OH 4-chloro- 4-chloro- H cyclo- a = 0
t-butoxy- phenyl phenyl propyl carbonyl- 44 H 4-chloro- 4-chloro- H
cyclo- a = 0 3-carboxy- phenyl phenyl propyl phenyl-ox- ethyl- 45 H
4-chloro- 4-chloro- H cyclo- a = 0 piperazin- phenyl phenyl propyl
1yl-ethyl- sulfonyl- 46 H 4-chloro- 4-chloro- H cyclo- a = 0
amino-ethyl- phenyl phenyl propyl sulfonyl- 47 H 4-chloro-
4-chloro- H cyclo- a = 0 1R*-(3- phenyl phenyl propyl carboxy-
phenyl)- ethyl- 48 H 4-chloro- 4-chloro- H cyclo- a = 0 1R*-(3-
phenyl phenyl propyl carboxy- phenyl)- ethyl- 49 H 4-chloro-
4-chloro- H cyclo- a = 0 1-(3- phenyl phenyl propyl carboxy-
phenyl)-n- propyl 50 H 4-chloro- 4-chloro- H cyclo- a = 0 phenyl-
phenyl phenyl propyl amino- carbonyl- 52 H 4-chloro- 4-chloro- H
cyclo- a = 0 3-amino- phenyl phenyl propyl phenyl- sulfonyl- 55 H
4-chloro- 4-chloro- H cyclo- a = 0 5-(hydroxy- phenyl phenyl propyl
methyl)-fur- 2-yl-sulfonyl- 56 H 4-chloro- 4-chloro- H cyclo- a = 0
1-(3- phenyl phenyl propyl hydroxy- phenyl)- ethyl- 59 H 4-chloro-
4-chloro- H cyclo- a = 0 1-(4- phenyl phenyl propyl carboxy-
pyrid-2-yl)- ethyl- 61 H 4-chloro- 4-chloro- H cyclo- a = 0
phenoxy- phenyl phenyl propyl carbonyl- 63 H 4-chloro- 4-chloro- H
cyclo- a = 0 carboxy- phenyl phenyl propyl methyl- 64 H 4-chloro-
4-chloro- H cyclo- a = 0 methoxy- phenyl phenyl propyl carbonyl-
methyl- 69 H 4-chloro- 4-chloro- H cyclo- a = 0 benzyloxy- phenyl
phenyl propyl carbonyl- 70 H 4-chloro- 4-chloro- H cyclo- a = 0
3-(2- phenyl phenyl propyl hydroxy- ethyl-amino- carbonyl)- benzyl
71 H 4-chloro- 4-chloro- H cyclo- a = 0 cyclopentyl- phenyl phenyl
propyl oxy- carbonyl- 72 H 4-chloro- 4-chloro- H 2- a = 0
3-methoxy- phenyl phenyl carboxy- carbonyl- ethyl- benzyl 73 H
4-chloro- 4-chloro- H cyclo- a = 0 ethyl-amino- phenyl phenyl
propyl carbonyl- 74 H 4-chloro- 4-chloro- H cyclo- a = 0
cyclopentyl- phenyl phenyl propyl amino- carbonyl- 75 H 4-chloro-
4-chloro- H cyclo- a = 0 benzyl- phenyl phenyl propyl amino-
carbonyl- 76 H 4-chloro- 4-chloro- H cyclo- a = 0 propyn-3-yl
phenyl phenyl propyl 77 H 4-chloro- 4-chloro- H amino- a = 0
3-carboxy- phenyl phenyl ethyl- benzyl 78 H 4-chloro- 4-chloro- H
2- a = 0 trifluoro- phenyl phenyl carboxy- methyl- ethyl- sulfonyl
79 H 4-chloro- 4-chloro- H cyclo- a = 0 2-hydroxy-3- phenyl phenyl
propyl carboxy- benzyl 80 H 4-chloro- 4-chloro- H cyclo- a = 0
2-trifluoro- phenyl phenyl propyl methyl-5- carboxy- benzyl 81 H
4-chloro- 4-chloro- H cyclo- a = 0 3-carboxy-4- phenyl phenyl
propyl hydroxy- benzyl 82 H 4-chloro- 4-chloro- H cyclo- a = 0
2-hydroxy-5- phenyl phenyl propyl carboxy- benzyl 83 H 4-chloro-
4-chloro- H cyclo- a = 0 2-carboxy- phenyl phenyl propyl
pyrid-4-yl- methyl- 84 H 4-chloro- 4-chloro- H cyclo- a = 0
2-trifluoro- phenyl phenyl propyl methyl- benzyl 85 H 4-chloro-
4-chloro- H cyclo- a = 0 2-fluoro-3- phenyl phenyl propyl carboxy-
benzyl 86 H 4-chloro- 4-chloro- H cyclo- a = 0 1-(5- phenyl phenyl
propyl carboxy-fur- 2-yl)-ethyl 87 H 4-chloro- 4-chloro- H cyclo- a
= 0 1-(3- phenyl phenyl propyl carboxy- phenyl)-ethyl 88 H
4-chloro- 4-chloro- H cyclo- a = 0 4-carboxy- phenyl phenyl propyl
pyrid-2-yl- methyl- 89 H 4-chloro- 4-chloro- H cyclo- a = 0
3-fluoro-5- phenyl phenyl propyl carboxy- benzyl 90 H 4-chloro-
4-chloro- H cyclo- a = 0 3-hydroxy- phenyl phenyl propyl benzyl 91
H 4-chloro- 4-chloro- H cyclo- a = 0 2-chloro-3- phenyl phenyl
propyl carboxy- benzyl 92 H 4-chloro- 4-chloro- H cyclo- a = 0
2-fluoro-5- phenyl phenyl propyl carboxy- benzyl 93 H 4-chloro-
4-chloro- H cyclo- a = 0 3-trifluoro- phenyl phenyl propyl
methyl-5- carboxy- benzyl 94 H 4-chloro- 4-chloro- H cyclo- a = 0
2-chloro-5- phenyl phenyl propyl carboxy- benzyl 95 H 4-chloro-
4-chloro- H cyclo- a = 0 3-carboxy-4- phenyl phenyl propyl
fluoro-benzyl 96 H 4-methyl- 4-methyl- H cyclo- a = 0 3-carboxy-
phenyl phenyl propyl benzyl 97 H 4-fluoro- 4-fluoro- H cyclo- a = 0
3-carboxy- phenyl phenyl propyl benzyl 98 H 4-chloro- 4-fluoro- H
cyclo- a = 0 3-carboxy- phenyl phenyl propyl benzyl 99 H 4-chloro-
4- H cyclo- a = 0 3-carboxy- phenyl trifluoro- propyl benzyl
methyl- phenyl 100 H 4-chloro- 4-methyl- H cyclo- a = 0 3-carboxy-
phenyl phenyl propyl benzyl 101 H 4-chloro- phenyl H cyclo- a = 0
3-carboxy- phenyl propyl benzyl 102 H 4-chloro- 4-chloro- H cyclo-
a = 0 2,3,4- phenyl phenyl propyl trihydroxy-n- butyl-oxy- carbonyl
104 H 4-chloro- 4-chloro- H cyclo- a = 0 6-amino- phenyl phenyl
propyl carbonyl- pyrid-2-yl- methyl- 105 H 4-chloro- 4-chloro- H
cyclo- a = 0 6-amino- phenyl phenyl propyl carbonyl- pyrid-3-yl-
methyl- 106 H 4-chloro- 4-chloro- H cyclo- a = 0 6-carboxy- phenyl
phenyl propyl pyrid-3-yl- methyl- 118 H 4-chloro- 4-chloro- H
--C(.dbd.CH.sub.2)--CH.sub.2OH a = 0 trifluoro- phenyl phenyl
methyl- sulfonyl 121 H 4-chloro- 4-chloro- H cyclo- a = 0 5-amino-
phenyl phenyl propyl carbonyl- pyrid-3-yl- methyl- 122 H 4-chloro-
4-chloro- H cyclo- a = 0 5-amino- phenyl phenyl propyl carbonyl-
pyrid-2-yl- methyl- 123 H 4-chloro- 4-chloro- H cyclo- a = 0
5-carboxy- phenyl phenyl propyl pyrid-3-yl- methyl- 124 H 4-chloro-
4-chloro- H cyclo- a = 0 5-carboxy- phenyl phenyl propyl
pyrid-2-yl- methyl- 125 H 4-chloro- 4-chloro- H cyclo- a = 0
6-carboxy- phenyl phenyl propyl pyrid-2-yl- methyl- 126 H 4-chloro-
4-chloro- H cyclo- a = 0 5-amino- phenyl phenyl propyl carbonyl-
thien-2-yl- methyl- 127 H 4-chloro- 4-chloro- H cyclo- a = 0
4-amino- phenyl phenyl propyl carbonyl- thien-2-yl- methyl- 128 H
4-chloro- 4-chloro- H cyclo- a = 0 5-carboxy- phenyl phenyl propyl
thien-2-yl- methyl- 129 H 4-chloro- 4-chloro- H cyclo- a = 0
5-carboxy- phenyl phenyl propyl fur-2-yl- methyl- 130 H 4-chloro-
4-chloro- H cyclo- a = 0 4-carboxy- phenyl phenyl propyl
thien-2-yl- methyl- 131 H 4-chloro- 4-chloro- H cyclo- a = 0
5-amino- phenyl phenyl propyl carbonyl-fur- 2-yl-methyl- 138 H
4-chloro- 4-chloro- H cyclo- a = 0 4-amino- phenyl phenyl propyl
carbonyl- benzyl 140 H 4-chloro- 4- H cyclo- a = 0 trifluoro-
phenyl phenyl propyl methyl- sulfonyl 141 H 4-chloro- 4-chloro- H
cyclo- a = 0 3-amino- phenyl phenyl propyl carbonyl- benzyl 142 H
4-chloro- 4-chloro- H cyclo- a = 0 4-(amino- phenyl phenyl propyl
carbonyl- methoxy)- phenyl 143 --CH.sub.2--O--CH.sub.2--CO.sub.2H
4-chloro- 4-chloro- H cyclo- a = 0 trifluoro- phenyl phenyl propyl
methyl- sulfonyl 147 H 4-chloro- 4-chloro- H cyclo- a = 0
4-carboxy-
phenyl phenyl propyl benzyl 148 H 4-chloro- 4-chloro- H cyclo- a =
0 3-carboxy- phenyl phenyl propyl benzyl 150 --OH 4-chloro- 4- H
cyclo- a = 0 trifluoro- phenyl carboxy- propyl methyl- phenyl
sulfonyl 151 H 4-chloro- 4-chloro- H cyclo- a = 0 4-amino- phenyl
phenyl propyl phenyl- sulfonyl- 152 H 4-chloro- 4-chloro- H cyclo-
a = 0 4-(carboxy- phenyl phenyl propyl methoxy)- phenyl 153 H
4-chloro- 4-chloro- H cyclo- a = 0 3-(amino- phenyl phenyl propyl
carobnyl- methoxy)- phenyl 154 H 4-chloro- 4-chloro- H cyclo- a = 0
3-(carboxy- phenyl phenyl propyl methoxy)- phenyl 155 H 4-chloro-
4-chloro- H cyclo- a = 0 3-amino- phenyl phenyl propyl carbonyl-
methyl- phenyl 157 H 4-chloro- 4-chloro- H cyclo- a = 0 4-carboxy-
phenyl phenyl propyl methyl- phenyl 158 H 4-chloro- 4-chloro- H
cyclo- a = 0 3-carboxy- phenyl phenyl propyl methyl- phenyl 159 H
4-chloro- 4-chloro- H cyclo- a = 0 4-carboxy- phenyl phenyl propyl
phenyl) 160 H 4-chloro- 4-chloro- H cyclo- a = 0 4-amino- phenyl
phenyl propyl carbonyl- methyl- phenyl 161 H 4-chloro- 4-chloro- H
cyclo- a = 0 4-amino- phenyl phenyl propyl carbonyl- phenyl 162 H
4-chloro- 4-chloro- H cyclo- a = 0 3-amino- phenyl phenyl propyl
carbonyl- phenyl 163 H 4-chloro- 4-chloro- H cyclo- a = 0
3-carboxy- phenyl phenyl propyl phenyl 164 H 4-chloro- 4-chloro- H
cyclo- a = 0 6-(methoxy- phenyl phenyl propyl carbonyl-
ethyl-amino- carbonyl)- pyrid-3-yl- sulfonyl- 166 H 4-chloro-
4-chloro- H cyclo- a = 0 3-trifluoro- phenyl phenyl propyl
methyl-4- carboxy- phenyl- sulfonyl- 167 H 4-chloro- 4-chloro- H
cyclo- a = 0 6-(carboxy- phenyl phenyl propyl ethyl-amino-
carbonyl)- pyrid-3-yl- sulfonyl 168 H 4-chloro- 4-chloro- H cyclo-
a = 0 3-amino- phenyl phenyl propyl carbonyl-4- methyl- phenyl-
sulfonyl- 178 --CH.sub.2--OCH.sub.3 4-chloro- 4-chloro- H cyclo- a
= 0 3-chloro-4- phenyl phenyl propyl carboxy- phenyl- sulfonyl- 184
H 4-chloro- 4-chloro- H cyclo- a = 0 3-trifluoro- phenyl phenyl
propyl methyl-4- amino- carbonyl- phenyl- sulfonyl 185 H 4-chloro-
4-chloro- H cyclo- a = 0 3-(carboxy- phenyl phenyl propyl
ethyl-amino- carbonyl)- phenyl- sulfonyl 186 H 4-chloro- 4-chloro-
H cyclo- a = 0 3- phenyl phenyl propyl methylamino- carbonyl-
phenyl- sulfonyl- 187 H 4-chloro- 4-chloro- H cyclo- a = 0 3-amino-
phenyl phenyl propyl carbonyl-4- methoxy- phenyl- sulfonyl- 188 H
4-chloro- 4-chloro- H cyclo- a = 0 3-carboxy-4- phenyl phenyl
propyl methyl- phenyl- sulfonyl- 189 H 4-chloro- 4-chloro- H cyclo-
a = 0 3-fluoro-4- phenyl phenyl propyl amino- carbonyl- phenyl-
sulfonyl- 190 H 4-chloro- 4-chloro- H cyclo- a = 0 3-fluoro-4-
phenyl phenyl propyl carboxy- phenyl- sulfonyl- 191 H 4-chloro-
4-chloro- H cyclo- a = 0 3-(3- phenyl phenyl propyl hydroxy-n-
propyl- amino- carbonyl)- phenyl- sulfonyl- 192 --CH.sub.2--OH
4-chloro- 4-chloro- H cyclo- a = 0 3-methoxy- phenyl phenyl propyl
4-amino- carbonyl- phenyl- sulfonyl- 193 --CH.sub.2--OH 4-chloro-
4-chloro- H cyclo- a = 0 3-methoxy- phenyl phenyl propyl 4-carboxy-
phenyl- sulfonyl- 198 H phenyl phenyl H cyclo- a = 0 1,2,3-triazol-
propyl 4-yl- carbonyl- 199 H 4-chloro- 4-chloro- H cyclo- a = 0
1,2,3-triazol- phenyl phenyl propyl 4-yl- carbonyl- 200 H phenyl
phenyl H cyclo- a = 0 1,2,4-triazol- propyl 3-yl- carbonyl- 201 H
4-chloro- 4-chloro- H cyclo- a = 0 1,2,4-triazol- phenyl phenyl
propyl 3-yl- carbonyl- 202 H 4-chloro- 4-chloro- --OH cyclo- a = 0
trifluoro- phenyl phenyl propyl methyl- sulfonyl 203 H 4-chloro-
4-chloro- H cyclo- a = 0 3-(2- phenyl phenyl propyl (methoxy-
carbonyl)- ethyl-amino- carbonyl)- phenyl- sulfonyl- 204 H
4-chloro- 4-chloro- H cyclo- a = 0 6-(2- phenyl phenyl propyl
hydroxy- ethyl-amino- carbonyl)- pyrid-3-yl- sulfonyl- 205 H
4-chloro- 4-chloro- H cyclo- a = 0 3-(2- phenyl phenyl propyl
hydroxy- ethyl-amino- carbonyl)- phenyl- sulfonyl- 206 H 4-chloro-
4-chloro- H cyclo- a = 0 3-methyl-4- phenyl phenyl propyl amino-
carbonyl- phenyl- sulfonyl- 207 H 4-chloro- 4-chloro- H cyclo- a =
0 3-methyl-4- phenyl phenyl propyl carboxy- phenyl- sulfonyl- 211 H
4-chloro- 4-chloro- H cyclo- a = 0 3-carboxy-4- phenyl phenyl
propyl methoxy- phenyl- sulfonyl- 212 --CH.sub.2--OH 4-chloro-
4-chloro- H cyclo- a = 0 3-chloro-4- phenyl phenyl propyl amino-
carbonyl- phenyl- sulfonyl- 213 --CH.sub.2--OH 4-chloro- 4-chloro-
H cyclo- a = 0 3-chloro-4- phenyl phenyl propyl carboxy- phenyl-
sulfonyl- 214 H 4-chloro- 4-chloro- H cyclo- a = 0 3-carboxy-4-
phenyl phenyl propyl chloro- phenyl- sulfonyl- 215 H 4-chloro-
4-chloro- H cyclo- a = 0 3-methyl-5- phenyl phenyl propyl amino-
carbonyl- thien-2-yl- sulfonyl- 216 H 4-chloro- 4-chloro- H cyclo-
a = 0 4-amino- phenyl phenyl propyl carbonyl- thien-2-yl- sulfonyl-
217 H 4-chloro- 4-chloro- H cyclo- a = 0 3-amino- phenyl phenyl
propyl carbonyl-4- fluoro- phenyl- sulfonyl- 218 H 4-chloro-
4-chloro- H cyclo- a = 0 3-methyl-5- phenyl phenyl propyl carboxy-
thien-2-yl- sulfonyl- 220 H 4-chloro- 4-chloro- H cyclo- a = 0
3-fluoro-4- phenyl phenyl propyl hydroxy- phenyl- sulfonyl- 221 H
4-chloro- 4-chloro- H cyclo- a = 0 4-carboxy- phenyl phenyl propyl
thien-2-yl- sulfonyl- 222 H 4-chloro- 4-chloro- H cyclo- a = 0
3,5-dichloro- phenyl phenyl propyl 4-hydroxy- phenyl- sulfonyl- 223
H 4-chloro- 4-chloro- H cyclo- a = 0 6-amino- phenyl phenyl propyl
carbonyl- pyrid-3-yl- carbonyl- 224 H 4-chloro- 4-chloro- H cyclo-
a = 0 5-amino- phenyl phenyl propyl carbonyl-fur- 2-yl-sulfonyl-
225 H 4-chloro- 4-chloro- H cyclo- a = 0 3-fluoro-4- phenyl phenyl
propyl methoxy- phenyl- sulfonyl- 226 H 4-chloro- 4-chloro- H
cyclo- a = 0 3-carboxy-4- phenyl phenyl propyl fluoro- phenyl-
sulfonyl- 227 --CH.sub.2--OH 4-chloro- 4-chloro- H cyclo- a = 0
4-amino- phenyl phenyl propyl carbonyl- phenyl- sulfonyl- 228
--CH.sub.2--OH 4-chloro- 4-chloro- H cyclo- a = 0 4-carboxy- phenyl
phenyl propyl phenyl- sulfonyl- 229 H 4-chloro- 4-chloro- H cyclo-
a = 0 3-amino- phenyl phenyl propyl sulfonyl- phenyl- carbonyl- 230
H 4-chloro- 4-chloro- H cyclo- a = 0 4-amino- phenyl phenyl propyl
sulfonyl- phenyl- carbonyl- 231 H 4-chloro- 4-chloro- H cyclo- a =
0 6-carboxy- phenyl phenyl propyl pyrid-3-yl- carbonyl- 232 H
4-chloro- 4-chloro- H cyclo- a = 0 5-carboxy- phenyl phenyl propyl
fur-2-yl- sulfonyl- 234 H 4-chloro- 4-chloro- H cyclo- a = 0
2-hydroxy- phenyl phenyl propyl ethyl- carbonyl- 235 H 4-chloro-
4-chloro- H cyclo- a = 0 carboxy- phenyl phenyl propyl ethyl-
sulfonyl- 238 H 4-chloro- 4-chloro- H cyclo- a = 0 6-amino- phenyl
phenyl propyl carbonyl-
pyrid-3-yl- sulfonyl- 239 H 4-chloro- 4-chloro- H cyclo- a = 0
6-carboxy- phenyl phenyl propyl sulfonyl- 240 H 4-chloro- 4-chloro-
H cyclo- a = 0 hydroxy- phenyl phenyl propyl methyl- carbonyl- 241
H 4-chloro- 4-chloro- H cyclo- a = 0 2-carboxy- phenyl phenyl
propyl phenyl- sulfonyl- 242 H 4-chloro- 4-chloro- H cyclo- a = 0
3-carboxy- phenyl phenyl propyl phenyl- sulfonyl- 243 H 4-chloro-
4-chloro- H cyclo- a = 0 2-amino- phenyl phenyl propyl carbonyl-
phenyl- sulfonyl- 244 --CH.sub.2--OH 4-chloro- 4-chloro- H ethyl a
= 0 trifluoro- phenyl phenyl methyl- sulfonyl 245 --CH.sub.2--OH
4-chloro- 4-chloro- H cyclo- a = 0 trifluoro- phenyl phenyl propyl
methyl- sulfonyl 246 H 4-chloro- 4-chloro- H cyclo- a = 0
4-carboxy- phenyl phenyl propyl phenyl- carbonyl- 247 H 4-chloro-
4-chloro- H cyclo- a = 0 amino- phenyl phenyl propyl carbonyl-
methyl- sulfonyl- 248 H 4-chloro- 4-chloro- H cyclo- a = 0 carboxy-
phenyl phenyl propyl methyl- sulfonyl- 249 H 4-chloro- 4-chloro- H
cyclo- a = 0 4-amino- phenyl phenyl propyl carbonyl- methoxy-
phenyl- sulfonyl- 250 H 4-chloro- 4-chloro- H cyclo- a = 0
3-methoxy- phenyl phenyl propyl 4-amino- carbonyl- phenyl-
sulfonyl- 251 H 4-chloro- 4-chloro- H cyclo- a = 0 3-methoxy-
phenyl phenyl propyl 4-carboxy- phenyl- sulfonyl- 252 H 4-chloro-
4-chloro- H cyclo- a = 0 3-chloro-4- phenyl phenyl propyl amino-
carbonyl- phenyl- sulfonyl- 253 H 4-chloro- 4-chloro- H cyclo- a =
0 3-chloro-4- phenyl phenyl propyl carboxy- phenyl- sulfonyl- 254 H
4-chloro- 4-chloro- H cyclo- a = 0 4-amino- phenyl phenyl propyl
carbonyl- phenyl- carbonyl- 255 OH 4-chloro- 4-chloro- H oxetan-3-
a = 0 trifluroo- phenyl phenyl yl methyl- sulfonyl 256 H 4-chloro-
4-chloro- H cyclo- a = 0 4-carboxy- phenyl phenyl propyl methoxy-
phenyl- sulfonyl- 257 H 4-chloro- 4-chloro- H cyclo- a = 0
4-hydroxy- phenyl phenyl propyl phenyl- sulfonyl- 258 H 4-chloro-
4-chloro- H cyclo- a = 0 2-hydroxy- phenyl phenyl propyl phenyl-
sulfonyl- 259 H 4-chloro- 4-chloro- H cyclo- a = 0 3-hydroxy-
phenyl phenyl propyl phenyl- sulfonyl- 260 H 4-chloro- 4-chloro- H
cyclo- a = 0 3-amino- phenyl phenyl propyl carbonyl)- phenyl-
sulfonyl- 261 H 4-chloro- 4-chloro- H cyclo- a = 0 3-methoxy-
phenyl phenyl propyl phenyl- sulfonyl- 262 H 4-chloro- 4-chloro- H
cyclo- a = 0 4-amino- phenyl phenyl propyl carbonyl- phenyl-
sulfonyl- 266 --CO.sub.2H 4-chloro- 4-chloro- H ethyl a = 0
trifluoro- phenyl phenyl methyl- sulfonyl 267 --CO.sub.2H 4-chloro-
4-chloro- H cyclo- a = 0 trifluoro- phenyl phenyl propyl methyl-
sulfonyl 269 H 4-chloro- 4-chloro- H cyclo- a = 0 2-carboxy- phenyl
phenyl propyl ethyl- carbonyl- 270 H 4-chloro- 4-chloro- H cyclo- a
= 0 methyl- phenyl phenyl propyl sulfonyl- 271 H 4-chloro-
4-chloro- H tetra- a = 0 trifluoro- phenyl phenyl hydro- methyl-
fur-2-yl sulfonyl 272 H 4-chloro- 4-chloro- H cyclo- a = 0
2-trifluoro- phenyl phenyl propyl methyl- phenyl- sulfonyl- 273 H
4-chloro- 4-chloro- H cyclo- a = 0 2-amino- phenyl phenyl propyl
carbonyl- ethyl- carbonyl- 274 H 4-chloro- 4-chloro- H cyclo- a = 0
amino- phenyl phenyl propyl sulfonyl- 275 H 4-chloro- 4-chloro- H
cyclo- a = 0 2-methoxy- phenyl phenyl propyl phenyl- sulfonyl- 276
H 4-chloro- 4-chloro- H cyclo- a = 0 4-carboxy- phenyl phenyl
propyl phenyl- sulfonyl- 277 H 4-chloro- 4-chloro- H cyclo- a = 0
4-chloro- phenyl phenyl propyl sulfonyl- 278 H 4-chloro- 4-chloro-
H cyclo- a = 0 amino- phenyl phenyl propyl carbonyl- methyl-
carbonyl- 279 H 4-chloro- 4-chloro- H cyclo- a = 0 4-trifluoro-
phenyl phenyl propyl methoxy- phenyl- sulfonyl- 280 H 4-chloro-
4-chloro- H cyclo- a = 0 4-trifluoro- phenyl phenyl propyl methyl-
phenyl- sulfonyl- 281 H 4-chloro- 4-chloro- H cyclo- a = 0
4-methoxy- phenyl phenyl propyl phenyl- sulfonyl- 282 H 4-chloro-
4-chloro- H cyclo- a = 0 4-fluoro- phenyl phenyl propyl phenyl-
sulfonyl- 283 H 4-chloro- 4-chloro- H cyclo- a = 0 phenyl- phenyl
phenyl propyl sulfonyl- 284 H 4-chloro- 4-chloro- H cyclo- a = 0
3-trifluoro- phenyl phenyl propyl methyl- phenyl- sulfonyl- 285 OH
4-chloro- 4-chloro- H tetrahydro- a = 0 trifluoro- phenyl phenyl
fur-2-yl methyl- sulfonyl 287 H 4-chloro- 4-chloro- --O--CH.sub.3
cyclo- a = 0 trifluoro- phenyl phenyl propyl methyl- sulfonyl 288 H
4-chloro- 4-chloro- H cyclo- --CH.sub.2-- trifluoro- phenyl phenyl
butyl methyl- sulfonyl 291 H 4-chloro- 4-chloro- H t-butyl a = 0
trifluoro- phenyl phenyl methyl- sulfonyl 292 OH 4-chloro-
4-chloro- H t-butyl a = 0 trifluoro- phenyl phenyl methyl- sulfonyl
293 OH 4-chloro- 4-chloro- H --CH.sub.2OH a = 0 trifluoro- phenyl
phenyl methyl- sulfonyl 294 OH 4-chloro- 4-chloro- H cyclo-
--CH.sub.2-- trifluoro- phenyl phenyl propyl methyl- sulfonyl 303
OH 4-chloro- 4-chloro- H cyclo- a = 0 trifluoro- phenyl phenyl
propyl methyl- sulfonyl 308 OH 4-chloro- 4-chloro- H ethyl a = 0
trifluoro- phenyl phenyl methyl- sulfonyl 315 H 4-chloro- 4-chloro-
H ethyl --CH.sub.2-- trifluoro- phenyl phenyl methyl- sulfonyl 316
H 4-chloro- 4-chloro- H cyclo- --CH.sub.2-- trifluoro- phenyl
phenyl propyl methyl- sulfonyl 318 H 4-chloro- 4-chloro- H cyclo- a
= 0 trifluoro- phenyl phenyl butyl methyl- sulfonyl 319 OH
4-chloro- 4-chloro- H cyclo- a = 0 trifluoro- phenyl phenyl butyl
methyl- sulfonyl 320 H 4- 4- H cyclo- a = 0 trifluoro- methoxy-
methoxy- butyl methyl- phenyl phenyl sulfonyl 321 H 4-chloro-
benzo[d][1,3]- H cyclo- a = 0 trifluoro- phenyl dioxol-5- propyl
methyl- yl sulfonyl 322 H 4-chloro- thiazol-2- H H --CH.sub.2--
trifluoro- phenyl yl methyl- sulfonyl 323 H 4-chloro- thiazol-2- H
ethyl --CH.sub.2-- trifluoro- phenyl yl methyl- sulfonyl 324 H
4-chloro- thiazol-2- H cyclo- --CH.sub.2-- trifluoro- phenyl yl
propyl methyl- sulfonyl 328 H 4-chloro- 4-chloro- H ethyl a = 0
trifluoro- phenyl phenyl methyl- sulfonyl 332 H 4-chloro- 4-chloro-
H ethyl a = 0 ethoxy- phenyl phenyl carbonyl- 335 H 4-chloro-
4-chloro- H cyclo- a = 0 trifluoro- phenyl phenyl propyl methyl-
sulfonyl 384 H 4-chloro- thiazol-2- H cyclo- a = 0 trifluoro-
phenyl yl propyl methyl- sulfonyl 385 H 4-chloro- thiazol-2- H
pyrid-2-yl a = 0 trifluoro- phenyl yl methyl- sulfonyl 386 H
4-chloro- thiazol-2- H methyl a = 0 trifluoro- phenyl yl methyl-
sulfonyl 387 H 4-chloro- thiazol-2- H --C(O)O--CH.sub.2--CH.sub.3 a
= 0 trifluoro- phenyl yl methyl- sulfonyl 390 H 4-chloro-
thiazol-2- H pyrid-4-yl a = 0 trifluoro- phenyl yl methyl- sulfonyl
391 H 4-chloro- thiazol-2- H cyclo- a = 0 trifluoro- phenyl yl
butyl methyl- sulfonyl 393 H 4-chloro- thiazol-2- H pyrid-3-yl a =
0 trifluoro- phenyl yl methyl- sulfonyl 394 H 4-chloro- thiazol-2-
H 4-chloro- a = 0 trifluoro- phenyl yl phenyl methyl- sulfonyl 395
H 4-chloro- thiazol-2- H cyclo- a = 0 trifluoro- phenyl yl pentyl
methyl- sulfonyl 396 H 4-chloro- thiazol-2- H isobutyl a = 0
trifluoro- phenyl yl methyl- sulfonyl 397 H 4-chloro- thiazol-2- H
isopropyl a = 0 trifluoro- phenyl yl methyl- sulfonyl 398 H
4-chloro- thiazol-2- H H a = 0 trifluoro- phenyl yl methyl-
sulfonyl 399 H 4-chloro- thiazol-2- H n-propyl a = 0 trifluoro-
phenyl yl methyl- sulfonyl 400 H 4-chloro- thiazol-2- H ethyl a = 0
trifluoro- phenyl yl methyl- sulfonyl 408 H 4-chloro- thiazol-2- H
t-butyl a = 0 ethoxy- phenyl yl carbonyl- 411 H 4-chloro-
thiazol-2- H tetra- a = 0 ethoxy- phenyl yl hydro- carbonyl-
fur-2-yl 412 H 4-chloro- thiazol-2- H tetra- a = 0 ethoxy- phenyl
yl hydro- carbonyl- pyran-4- yl 413 H 4-chloro- thiazol-2- H
--C(O)O--CH.sub.2CH.sub.3 a = 0 ethoxy- phenyl yl carbonyl- 414 H
4-chloro- thiazol-2- H azetidin- a = 0 ethoxy- phenyl yl 3-yl
carbonyl- 415 H 4-chloro- thiazol-2- H --CF.sub.3 a = 0 ethoxy-
phenyl yl carbonyl- 416 H 4-chloro- thiazol-2- H n-propyl a = 0
ethoxy- phenyl yl carbonyl- 417 H 4-chloro- thiazol-2- H 1-t- a = 0
ethoxy- phenyl yl butoxy- carbonyl- carbonyl- azetidin- 3-yl 418 H
4-chloro- thiazol-2- H 4-chloro- a = 0 ethoxy- phenyl yl phenyl
carbonyl- 419 H 4-chloro- thiazol-2- H thiazol-2- a = 0 ethoxy-
phenyl yl yl carbonyl- 420 H 4-chloro- thiazol-2- H isobutyl a = 0
ethoxy- phenyl yl carbonyl- 421 H 4-chloro- thiazol-2- H cyclo- a =
0 ethoxy- phenyl yl propyl carbonyl- 422 H 4-chloro- thiazol-2- H
chloro a = 0 ethoxy- phenyl yl carbonyl- 439 H 4-chloro- thiazol-2-
H dimethyl- a = 0 ethoxy- phenyl yl amino carbonyl- 440 H 4-chloro-
thiazol-2- H amino a = 0 ethoxy- phenyl yl carbonyl- 441 H
4-chloro- thiazol-2- H 4-chloro- a = 0 ethoxy- phenyl yl phenyl
carbonyl- 443 H 4-chloro- thiazol-2- H 2,4- a = 0 ethoxy- phenyl yl
dichloro- carbonyl- phenyl 445 H 4-chloro- thiazol-2- H methyl a =
0 ethoxy- phenyl yl carbonyl- 448 H 4-chloro- thiazol-2- H H a = 0
ethoxy- phenyl yl carbonyl-
TABLE-US-00005 TABLE 5 Representative Compounds of Formula (I)
##STR00152## ID. No. ##STR00153## ##STR00154## R.sup.2 R.sup.3 53
4-chloro- 4-chloro- cyclo- 3-(carboxy-benzyl)-azetidin- phenyl
phenyl propyl 3-yl 54 4-chloro- 4-chloro- cyclo-
5-(carboxy-fur-2-yl-sulfonyl)- phenyl phenyl propyl azetidin-3-yl
57 4-chloro- 4-chloro- cyclo- 4-(carboxy-phenyl-sulfonyl)- phenyl
phenyl propyl azetidin-3-yl 65 4-chloro- 4-chloro- cyclo-
4-(carboxy-phenyl-sulfonyl)- phenyl phenyl propyl pyrrolidin-3-yl
67 4-chloro- 4-chloro- cyclo- 3-(carboxy-benzyl)-pyrrolidin- phenyl
phenyl propyl 3-yl 68 4-chloro- 4-chloro- cyclo-
5-(carboxy-fur-2-yl-sulfonyl)- phenyl phenyl propyl pyrrolidin-3-yl
295 4-chloro- 4-chloro- cyclo- 1-(trifluoro-methyl-sulfonyl)-
phenyl phenyl propyl 4-hydroxy-piperidin-4-yl-CH.sub.2-- 343
4-chloro- thiazol-2-yl --C(O)O--CH.sub.3
1-(trifluoro-methyl-sulfonyl)- phenyl 8-azabicyclo[3.2.1]octan-3-yl
344 4-chloro- thiazol-2-yl cyclo- 1-(trifluoro-methyl-sulfonyl)-
phenyl butyl 8-azabicyclo[3.2.1]octan-3-yl 345 4-chloro-
thiazol-2-yl --C(O)O--CH.sub.2CH.sub.3 1-(ethoxy-carbonyl)-8-
phenyl azabicyclo[3.2.1]octan-3-yl 347 4-chloro- thiazol-2-yl
pyrid-3-yl 1-(trifluoro-methyl-sulfonyl)- phenyl
8-azabicyclo[3.2.1]octan-3-yl 348 4-chloro- thiazol-2-yl ethyl
1-(trifluoro-methyl-sulfonyl)- phenyl 8-azabicyclo[3.2.1]octan-3-yl
349 4-chloro- thiazol-2-yl pyrid-4-yl
1-(trifluoro-methyl-sulfonyl)- phenyl 8-azabicyclo[3.2.1]octan-3-yl
350 4-chloro- thiazol-2-yl H 1-(trifluoro-methyl-sulfonyl)- phenyl
8-azabicyclo[3.2.1]octan-3-yl 351 4-chloro- thiazol-2-yl 4-chloro-
1-(trifluoro-methyl-sulfonyl)- phenyl phenyl
8-azabicyclo[3.2.1]octan-3-yl 352 4-chloro- thiazol-2-yl cyclo-
1-(trifluoro-methyl-sulfonyl)- phenyl pentyl
8-azabicyclo[3.2.1]octan-3-yl 353 4-chloro- thiazol-2-yl n-propyl
1-(trifluoro-methyl-sulfonyl)- phenyl 8-azabicyclo[3.2.1]octan-3-yl
356 4-chloro- thiazol-2-yl isopropyl 1-(trifluoro-methyl-sulfonyl)-
phenyl 8-azabicyclo[3.2.1]octan-3-yl 357 4-chloro- thiazol-2-yl
methyl 1-(trifluoro-methyl-sulfonyl)- phenyl
8-azabicyclo[3.2.1]octan-3-yl 358 4-chloro- thiazol-2-yl pyrid-2-yl
1-(trifluoro-methyl-sulfonyl)- phenyl 8-azabicyclo[3.2.1]octan-3-yl
359 4-chloro- thiazol-2-yl isobutyl 1-(trifluoro-methyl-sulfonyl)-
phenyl 8-azabicyclo[3.2.1]octan-3-yl 360 4-chloro- thiazol-2-yl
cyclo- 1-(trifluoro-methyl-sulfonyl)- phenyl propyl
8-azabicyclo[3.2.1]octan-3-yl 363 4-chloro- thiazol-2-yl cyclo-
1-(ethoxy-carbonyl)-8- phenyl propyl azabicyclo[3.2.1]octan-3-yl
366 4-chloro- thiazol-2-yl pyrid-4-yl 1-(ethoxy-carbonyl)-8- phenyl
azabicyclo[3.2.1]octan-3-yl 367 4-chloro- thiazol-2-yl pyrid-3-yl
1-(ethoxy-carbonyl)-8- phenyl azabicyclo[3.2.1]octan-3-yl 368
4-chloro- thiazol-2-yl cyclo- 1-(ethoxy-carbonyl)-8- phenyl propyl
azabicyclo[3.2.1]octan-3-yl 369 4-chloro- thiazol-2-yl isobutyl
1-(ethoxy-carbonyl)-8- phenyl azabicyclo[3.2.1]octan-3-yl 378
4-chloro- thiazol-2-yl pyrid-2-yl 1-(ethoxy-carbonyl)-8- phenyl
azabicyclo[3.2.1]octan-3-yl 379 4-chloro- thiazol-2-yl methyl
1-(ethoxy-carbonyl)-8- phenyl azabicyclo[3.2.1]octan-3-yl 380
4-chloro- thiazol-2-yl H 1-(ethoxy-carbonyl)-8- phenyl
azabicyclo[3.2.1]octan-3-yl 381 4-chloro- thiazol-2-yl isopropyl
1-(ethoxy-carbonyl)-8- phenyl azabicyclo[3.2.1]octan-3-yl 382
4-chloro- thiazol-2-yl n-propyl 1-(ethoxy-carbonyl)-8- phenyl
azabicyclo[3.2.1]octan-3-yl 383 4-chloro- thiazol-2-yl ethyl
1-(ethoxy-carbonyl)-8- phenyl azabicyclo[3.2.1]octan-3-yl 388
4-chloro- thiazol-2-yl 4-chloro- 1-(ethoxy-carbonyl)-8- phenyl
phenyl azabicyclo[3.2.1]octan-3-yl 389 4-chloro- thiazol-2-yl
cyclo- 1-(ethoxy-carbonyl)-8- phenyl pentyl
azabicyclo[3.2.1]octan-3-yl
Definitions
[0150] As used herein, unless otherwise noted, "halogen" shall mean
chlorine, bromine, fluorine and iodine.
[0151] As used herein, unless otherwise noted, the term "carboxy"
shall mean --C(O)OH.
[0152] As used herein, unless otherwise noted, the term "alkyl"
whether used alone or as part of a substituent group, include
straight and branched chains. For example, alkyl radicals include
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
t-butyl, pentyl and the like. Unless otherwise noted,
"C.sub.X-Yalkyl" wherein X and Y are integers, shall mean a carbon
chain composition of between X and Y carbon atoms. For example,
"C.sub.1-4alkyl" shall mean any straight or branched chain
composition of between 1 and 4 carbon atoms (including methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl).
[0153] One skilled in the art will recognize that the term
"--(C.sub.X-Yalkyl)-" shall denote any C.sub.X-Yalkyl straight or
branched chain composition as defined above, wherein said
C.sub.X-Yalkyl straight or branched chain composition is divalent
and is therefore bound through two points of attachment, preferably
through two terminal carbon atoms.
[0154] As used herein, unless otherwise noted, the term
"halogenated C.sub.1-4alkyl" shall mean any C.sub.X-Yalkyl group as
defined above substituted with at least one halogen atom,
preferably substituted with a least one fluoro atom. Suitable
examples include but are not limited to --CH.sub.2F, --CH.sub.2I,
--CH.sub.2Br, --CH.sub.2Cl, --CF.sub.3, --CCl.sub.3,
--CH.sub.2--CF.sub.3, CH.sub.2--CCl.sub.3,
--CF.sub.2--CF.sub.2--CF.sub.2--CF.sub.3, and the like. Similarly,
the term "fluorinated C.sub.1-4alkyl" shall mean any C.sub.X-Yalkyl
group as defined above substituted with at least one fluoro atom,
preferably one to three fluoro atoms. Suitable examples include,
but are not limited, to --CF.sub.3, --CH.sub.2--CF.sub.3,
--CF.sub.2--CF.sub.2--CF.sub.2--CF.sub.3, and the like.
[0155] As used herein, unless otherwise noted, the term "hydroxy
substituted C.sub.X-Yalkyl" shall mean any C.sub.X-Yalkyl group as
defined above, substituted with at least one hydroxy group,
preferably one to two hydroxy groups, more preferably one hydroxy
group; provided that when the "hydroxy substituted C.sub.X-Yalkyl"
is bound to a N or O atom of a substituent group as defined herein,
then the hydroxy group(s) on the "hydroxy substituted
C.sub.X-Yalkyl" are not bound to C-1 carbon atom of the
C.sub.X-Yalkyl portion of the "hydroxy substituted C.sub.X-Yalkyl"
(i.e. the hydroxy group(s) are not bound to the carbon atom which
is directly bound to the N or O atom of said substituent group).
Suitable examples include but are not limited to --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, --CH(OH)CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2OH, --CH.sub.2CH(OH)CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH,
--C(CH.sub.2CH.sub.2OH).sub.2--CH.sub.2CH.sub.2OH, and the like. In
an embodiment, the C.sub.X-Yalkyl is substituted with the hydroxy
group(s) at terminal carbon atom(s).
[0156] As used herein, unless otherwise noted, the term "C.sub.X-Y
alkenyl" wherein X and Y are integers, shall mean a carbon chain
composition of between X and Y carbon atoms wherein the carbon
chain contains at least one, preferably one, double bond. For
example, "C.sub.3-4alkenyl" shall mean a 3 to 4 carbon chain
composition containing at least one, preferably one, double bond.
Suitable example include, but are not limited to
--CH.sub.2--CH.dbd.CH.sub.2, --CH.dbd.CH--CH.sub.2 and the
like.
[0157] One skilled in the art will recognize that the term
"--(C.sub.X-Y alkenyl)-" shall denote any C.sub.X-Y alkenyl carbon
chain composition as defined above, wherein said C.sub.X-Y alkenyl
is divalent and is therefore bound through two points of
attachment, preferably through two terminal carbon atoms. For
example, the term "--(C.sub.2-4alkenyl)-" shall mean any 2 to 4
carbon atom chain containing at least one, preferably one double
bond. Suitable examples include, but are not limited to
--CH.dbd.CH--, --CH.sub.2--CH.dbd.CH--, --CH.dbd.CH--CH.sub.2--,
--CH.dbd.CH--CH(CH.sub.3)-- and the like.
[0158] As used herein, unless otherwise noted, "alkoxy" shall
denote an oxygen ether radical of the above described straight or
branched chain alkyl groups. For example, methoxy, ethoxy,
n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like. Unless
otherwise noted, "C.sub.X-Yalkoxy" wherein X and Y are integers,
shall mean an oxygen ether radical of the above described straight
or branched chain carbon chain composition of between X and Y
carbon atoms. For example, "C.sub.1-4alkoxy" shall mean any oxygen
ether radical of the above described straight or branched chain
composition of between 1 and 4 carbon atoms.
[0159] As used herein, unless otherwise noted, the term
"halogenated C.sub.1-4alkoxy" shall mean any C.sub.1-4alkoxy group
as defined above substituted with at least one halogen atom,
preferably substituted with a least one fluoro atom. Suitable
examples include but are not limited to --OCH.sub.2F, --OCH.sub.2I,
--OCH.sub.2Br, --OCH.sub.2Cl, --OCF.sub.3, --OCCl.sub.3,
--OCH.sub.2--CF.sub.3, --OCH.sub.2--CCl.sub.3,
--OCF.sub.2--CF.sub.2--CF.sub.2--CF.sub.3, and the like. Similarly,
the term "fluorinated C.sub.1-4alkoxy" shall mean any
C.sub.1-4alkoxy group as defined above substituted with at least
one fluoro atom, preferably one to three fluoro atoms. Suitable
examples include but are not limited to --OCF.sub.3,
--OCH.sub.2--CF.sub.3, --OCF.sub.2--CF.sub.2--CF.sub.2--CF.sub.3,
and the like.
[0160] As used herein, unless otherwise noted, the term
"cycloalkyl" shall mean any stable 3-8 membered monocyclic,
saturated ring system, for example cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Unless
otherwise noted, "C.sub.X-ycycloalkyl" wherein X and Y are
integers, shall mean a cycloalkyl ring structure as herein defined
wherein the ring structure contains between X and Y carbon atoms.
For example, C.sub.3-6cycloalkyl shall include cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl.
[0161] When a particular group is "substituted" (e.g., alkyl,
cycloalkyl, aryl, heteroaryl, heterocycloalkyl, etc.), that group
may have one or more substituents, preferably from one to five
substituents, more preferably from one to three substituents, most
preferably from one to two substituents, independently selected
from the list of substituents.
[0162] With reference to substituents, the term "Independently"
means that when more than one of such substituents is possible,
such substituents may be the same or different from each other.
[0163] As used herein, the notation "*" shall denote the presence
of a stereogenic center.
[0164] Where the compounds according to this invention have at
least one chiral center, they may accordingly exist as enantiomers.
Where the compounds possess two or more chiral centers, they may
additionally exist as diastereomers. It is to be understood that
all such isomers and mixtures thereof are encompassed within the
scope of the present invention. Preferably, wherein the compound is
present as an enantiomer, the enantiomer is present at an
enantiomeric excess of greater than or equal to about 80%, more
preferably, at an enantiomeric excess of greater than or equal to
about 90%, more preferably still, at an enantiomeric excess of
greater than or equal to about 95%, more preferably still, at an
enantiomeric excess of greater than or equal to about 98%, most
preferably, at an enantiomeric excess of greater than or equal to
about 99%. Similarly, wherein the compound is present as a
diastereomer, the diastereomer is present at an diastereomeric
excess of greater than or equal to about 80%, more preferably, at
an diastereomeric excess of greater than or equal to about 90%,
more preferably still, at an diastereomeric excess of greater than
or equal to about 95%, more preferably still, at an diastereomeric
excess of greater than or equal to about 98%, most preferably, at
an diastereomeric excess of greater than or equal to about 99%.
[0165] Furthermore, some of the crystalline forms for the compounds
of the present invention may exist as polymorphs and as such are
intended to be included in the present invention. In addition, some
of the compounds of the present invention may form solvates with
water (i.e., hydrates) or common organic solvents, and such
solvates are also intended to be encompassed within the scope of
this invention.
[0166] Furthermore, it is intended that within the scope of the
present invention, any element, in particular when mentioned in
relation to a compound of formula (I), shall comprise all isotopes
and isotopic mixtures of said element, either naturally occurring
or synthetically produced, either with natural abundance or in an
isotopically enriched form. For example, a reference to hydrogen
includes within its scope .sup.1H, .sup.2H (D), and .sup.3H (T).
Similarly, references to carbon and oxygen include within their
scope respectively .sup.12C, .sup.13C and .sup.14C and .sup.16O and
.sup.18O. The isotopes may be radioactive or non-radioactive.
Radiolabelled compounds of formula (I) may comprise a radioactive
isotope selected from the group of .sup.3H, .sup.11C, .sup.18F,
.sup.122I, .sup.123I, .sup.125I, .sup.131I, .sup.75Br, .sup.76Br,
.sup.77Br and .sup.82Br. Preferably, the radioactive isotope is
selected from the group of .sup.3H, .sup.11C and .sup.18F.
[0167] Under standard nomenclature used throughout this disclosure,
the terminal portion of the designated side chain is described
first, followed by the adjacent functionality toward the point of
attachment. Thus, for example, a
"phenylC.sub.1-C.sub.6alkylaminocarbonylC.sub.1-C.sub.6alkyl"
substituent refers to a group of the formula
##STR00155##
[0168] Abbreviations used in the specification, particularly the
Schemes and Examples, are as follows: [0169] AcOH or HOAc=Acetic
acid [0170] Alloc=Allyloxycarbonyl [0171] aq. or aq=Aqueous [0172]
Boc or BOC=tert-butoxycarbonyl [0173] Boc.sub.2O=Boc anhydride
(i.e. di-tert-butyl dicarbonate) [0174] BSA=Bovine Serum Albumin
[0175] cAMP=Cyclic Adenosine Monophosphate [0176] CB1 or CB1R or
CB1R=Cannabinoid 1 Receptor [0177] CB2 or CB2R or CB2R=Cannabinoid
2 Receptor [0178] CDI=Carbonyldiimidazole [0179] conc.=Concentrated
[0180] DBU=1,8-Diazabicyclo[5.4.0]undec-7-ene [0181]
DCE=1,1-Dichloroethane [0182] DCM=Dichloromethane [0183]
DIAD=Diisopropylazodicarboxylate [0184]
DIC=N,N'-diisopropylcarbodiimide [0185] DIO=Diet-Induced Obesity
(Mouse Model) [0186] DIPEA or DIEA or Hunig's
Base=Diisopropylethylamine [0187] DME=Dimethoxyethane [0188]
DMEM=Dulbecco's Modified Eagle Medium [0189]
DMF=N,N-Dimethylformamide [0190] DMP=Dess-Martin Periodinane
(1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one) [0191]
DMSO=Dimethylsulfoxide [0192] DPPA=Diphenylphosphoryl azide [0193]
dppf=1,1'-Bis(diphenylphosphino)ferrocene [0194]
EDCl=1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide [0195] EtOAc or
EA=Ethyl acetate [0196] EtOH=Ethanol [0197] Et.sub.2O=Diethyl ether
[0198] Et.sub.3SiH=Triethylsilane [0199] FBS=Fetal Bovine Serum
[0200] GCMS or GC-MS=Gas Chromatography-Mass Spectroscopy [0201]
GPCR=G-coupled Receptor [0202]
HATU=O-(7-Azabenzotriazol-1-yl)-N,N,N'',N''-Tetramethyl Uronium
Hexafluorophosphate [0203] HBSS=Hank's Balanced Salt Solution
[0204] HBTU=N N,N,N',N'-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium
hexafluorophosphate [0205] HDL=High Density Lipoprotein [0206]
HEPES=4-(2-Hydroxyethyl)-1-Piperazine Ethane Sulfonic Acid [0207]
HPLC=High Performance Liquid Chromatography [0208] IPA or
i-PrOH=Isopropyl alcohol [0209] KOt-Bu or t-BuOK=Potassium
t-butoxide [0210] LADA=Latent Autoimmune Diabetes of Adults [0211]
LAH=Lithium Aluminum Hydride [0212] LCMS or LC-MS=Liquid
Chromatography-Mass Spectrometry [0213] LDL=Low Density Lipoprotein
[0214] LiHMDS or LiN(SiMe.sub.3).sub.2=Lithium
bis(trimethylsilyl)amide [0215] MeOH=Methanol [0216]
Mesyl=Methylsulfonyl [0217] MOMBr=Bromomethyl methyl ether [0218]
MTBE=Methyl t-butyl ether [0219] n-BuLi=n-Butyl Lithium [0220]
NaBH(OAc).sub.3=Sodium triacetoxyborohydride [0221] NaHMDS or
NaN(SiMe.sub.3).sub.2=Sodium bis(trimethylsilyl)amide [0222]
NaOt-Bu or t-BuONa=Sodium terf-butoxide [0223] NASH=NonAlcoholic
Steatohepatitis [0224] NMR=Nuclear magnetic Resonance [0225]
NSB=Non-Specific Binding [0226] PBS=Phosphate Buffered Saline
[0227] Pd/C=Palladium on Carbon (catalyst) [0228]
Pd.sub.2(Oac).sub.2=Palladium(II)acetate [0229]
Pd.sub.2(dba).sub.3=Tris(dibenzylidene acetone)dipalladium (0)
[0230] Pd(dppf)Cl.sub.2=[1,1'-Bis(diphenylphosphino)
ferrocene]dichloro palladium(II) [0231] PE=Petroleum Ether [0232]
PPh.sub.3=Triphenyl Phosphine [0233] Raney nickel or Raney Ni or
RaNi W.R. Grace and Co. Trademarked Nickel Catalyst [0234]
sat.=Saturated [0235] t-BuLi=tert-Butyl lithium [0236]
t-BuOH=tert-Butanol [0237] TEA or Et.sub.3N=Triethylamine [0238]
TFA=Trifluoroacetic Acid [0239] THF=Tetrahydrofuran [0240]
Ti(OiPr).sub.4=Titanium isopropoxide [0241] TLC=Thin Layer
Chromatography [0242] Tosyl=p-Toluenesulfonyl [0243] Tris HCl or
Tris-Cl=Tris[hydroxymethyl]aminomethyl hydrochloride [0244]
XantPhos=4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene [0245]
XPhos=2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
[0246] The compounds of the present invention are CB-1 inverse
agonists useful for the treatment and/or prevention of metabolic
disorders, including obesity, Type I diabetes, Type II diabetes,
gestational diabetes, latent autoimmune diabetes of adults (LADA),
pre-diabetes, insulin resistance, inadequate glucose tolerance,
dyslipidemias (including, but not limited to elevated triglycerides
and LDL, and low HDL), nonalcoholic steatohepatitis (NASH),
cirrhosis, fatty liver disease, atherosclerosis, hypertension,
inflammatory bowel disease, Alzheimer's disease, osteoporosis,
multiple sclerosis, traumatic brain injury, arthritis, and
neuropathic pain. Preferably, the metabolic disorder is selected
from the group consisting of obesity, Type II diabetes, and
dyslipidemias. More preferably, the metabolic disorder is obesity
or Type II diabetes.
[0247] As used herein, unless otherwise noted, the terms
"treating", "treatment" and the like, shall include the management
and care of a subject or patient (preferably mammal, more
preferably human) for the purpose of combating a disease,
condition, or disorder and includes the administration of a
compound of the present invention to prevent the onset of the
symptoms or complications, alleviate the symptoms or complications,
or eliminate the disease, condition, or disorder.
[0248] As used herein, unless otherwise noted, the term
"prevention" shall include (a) reduction in the frequency of one or
more symptoms; (b) reduction in the severity of one or more
symptoms; (c) the delay or avoidance of the development of one or
more additional symptoms; and/or (d) delay or avoidance of the
development or progression of the disorder or condition.
[0249] One skilled in the art will recognize that wherein the
present invention is directed to methods of prevention, a subject
in need of thereof (i.e. a subject in need of prevention) shall
include any subject or patient (preferably a mammal, more
preferably a human) who has experienced or exhibited at least one
symptom of the disorder, disease or condition to be prevented.
Further, a subject in need thereof may additionally be a subject
(preferably a mammal, more preferably a human) who has not
exhibited any symptoms of the disorder, disease or condition to be
prevented, but who has been deemed by a physician, clinician or
other medical profession to be at risk of developing said disorder,
disease or condition. For example, the subject may be deemed at
risk of developing a disorder, disease or condition (and therefore
in need of prevention or preventive treatment) as a consequence of
the subject's medical history, including, but not limited to,
family history, pre-disposition, co-existing (comorbid) disorders
or conditions, genetic testing, and the like.
[0250] The term "subject" as used herein, refers to an animal,
preferably a mammal, most preferably a human, who has been the
object of treatment, observation or experiment. Preferably, the
subject has experienced and/or exhibited at least one symptom of
the disease or disorder to be treated and/or prevented.
[0251] The term "therapeutically effective amount" as used herein,
means that amount of active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue system,
animal or human that is being sought by a researcher, veterinarian,
medical doctor or other clinician, which includes alleviation of
the symptoms of the disease or disorder being treated.
[0252] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combinations of the specified ingredients in
the specified amounts.
[0253] To provide a more concise description, some of the
quantitative expressions given herein are not qualified with the
term "about". It is understood that whether the term "about" is
used explicitly or not, every quantity given herein is meant to
refer to the actual given value, and it is also meant to refer to
the approximation to such given value that would reasonably be
inferred based on the ordinary skill in the art, including
approximations due to the experimental and/or measurement
conditions for such given value.
[0254] To provide a more concise description, some of the
quantitative expressions herein are recited as a range from about
amount X to about amount Y. It is understood that wherein a range
is recited, the range is not limited to the recited upper and lower
bounds, but rather includes the full range from about amount X
through about amount Y, or any amount or range therein.
[0255] As more extensively provided in this written description,
terms such as "reacting" and "reacted" are used herein in reference
to a chemical entity that is any one of: (a) the actually recited
form of such chemical entity, and (b) any of the forms of such
chemical entity in the medium in which the compound is being
considered when named. One skilled in the art will recognize that,
where not otherwise specified, the reaction step(s) is performed
under suitable conditions, according to known methods, to provide
the desired product. One skilled in the art will further recognize
that, in the specification and claims as presented herein, wherein
a reagent or reagent class/type (e.g. base, solvent, etc.) is
recited in more than one step of a process, the individual reagents
are independently selected for each reaction step and may be the
same or different from each other. For example wherein two steps of
a process recite an organic or inorganic base as a reagent, the
organic or inorganic base selected for the first step may be the
same or different than the organic or inorganic base of the second
step. Further, one skilled in the art will recognize that wherein a
reaction step of the present invention may be carried out in a
variety of solvents or solvent systems, said reaction step may also
be carried out in a mixture of the suitable solvents or solvent
systems. Examples of suitable solvents, bases, reaction
temperatures, and other reaction parameters and components are
provided in the detailed descriptions which follow herein. One
skilled in the art will recognize that the listing of said examples
is not intended, and should not be construed, as limiting in any
way the invention set forth in the claims which follow
thereafter.
[0256] As used herein, unless otherwise noted, the term "aprotic
solvent" shall mean any solvent that does not yield a proton.
Suitable examples include, but are not limited to DMF, 1,4-dioxane,
THF, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE,
toluene, acetone, and the like.
[0257] As used herein, unless otherwise noted, the term "leaving
group" shall mean a charged or uncharged atom or group which
departs during a substitution or displacement reaction. Suitable
examples include, but are not limited to, Br, Cl, I, mesylate,
tosylate, and the like.
[0258] One skilled in the art will recognize that during any of the
processes for preparation of the compounds of the present
invention, as herein described in more detail, it may be necessary
and/or desirable to protect sensitive or reactive groups on any of
the molecules concerned. This may be achieved by means of
conventional protecting groups, such as those described in
Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum
Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective
Groups in Organic Synthesis, John Wiley & Sons, 1991. The
protecting groups may be removed at a convenient subsequent stage
using methods known from the art.
[0259] As used herein, unless otherwise noted, the term "nitrogen
protecting group" shall mean a group which may be attached to a
nitrogen atom to protect said nitrogen atom from participating in a
reaction and which may be readily removed following the reaction.
Suitable nitrogen protecting groups include, but are not limited to
carbamates--groups of the formula --C(O)O--R wherein R is for
example methyl, ethyl, t-butyl, benzyl, phenylethyl,
CH.sub.2.dbd.CH--CH.sub.2--, and the like; amides--groups of the
formula --C(O)--R' wherein R' is for example methyl, phenyl,
trifluoromethyl, and the like; N-sulfonyl derivatives--groups of
the formula --SO.sub.2--R'' wherein R'' is for example tolyl,
phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-,
2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable
nitrogen protecting groups may be found in texts such as T. W.
Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,
John Wiley & Sons, 1991.
[0260] Where the processes for the preparation of the compounds
according to the invention give rise to mixture of stereoisomers,
these isomers may be separated by conventional techniques such as
preparative chromatography. The compounds may be prepared in
racemic form, or individual enantiomers may be prepared either by
enantiospecific synthesis or by resolution. The compounds may, for
example, be resolved into their component enantiomers by standard
techniques, such as the formation of diastereomeric pairs by salt
formation with an optically active acid, such as
(-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric
acid followed by fractional crystallization and regeneration of the
free base. The compounds may also be resolved by formation of
diastereomeric esters or amides, followed by chromatographic
separation and removal of the chiral auxiliary. Alternatively, the
compounds may be resolved using a chiral HPLC column.
[0261] Additionally, chiral HPLC against a standard may be used to
determine percent enantiomeric excess (% ee). The enantiomeric
excess may be calculated as follows
[(Rmoles-Smoles)/(Rmoles+Smoles)].times.100%
where Rmoles and Smoles are the R and S mole fractions in the
mixture such that Rmoles+Smoles=1. The enantiomeric excess may
alternatively be calculated from the specific rotations of the
desired enantiomer and the prepared mixture as follows:
ee=([.alpha.-obs]/[.alpha.-max]).times.100.
[0262] The present invention includes within its scope prodrugs of
the compounds of this invention. In general, such prodrugs will be
functional derivatives of the compounds which are readily
convertible in vivo into the required compound. Thus, in the
methods of treatment of the present invention, the term
"administering" shall encompass the treatment of the various
disorders described with the compound specifically disclosed or
with a compound which may not be specifically disclosed, but which
converts to the specified compound in vivo after administration to
the patient. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for
example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier,
1985.
[0263] For use in medicine, the salts of the compounds of this
invention refer to non-toxic "pharmaceutically acceptable salts."
Other salts may, however, be useful in the preparation of compounds
according to this invention or of their pharmaceutically acceptable
salts. Suitable pharmaceutically acceptable salts of the compounds
include acid addition salts which may, for example, be formed by
mixing a solution of the compound with a solution of a
pharmaceutically acceptable acid such as hydrochloric acid,
sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic
acid, benzoic acid, citric acid, tartaric acid, carbonic acid or
phosphoric acid. Furthermore, where the compounds of the invention
carry an acidic moiety, suitable pharmaceutically acceptable salts
thereof may include alkali metal salts, e.g., sodium or potassium
salts; alkaline earth metal salts, e.g., calcium or magnesium
salts; and salts formed with suitable organic ligands, e.g.,
quaternary ammonium salts. Thus, representative pharmaceutically
acceptable salts include, but are not limited to, the following:
acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,
bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,
chloride, clavulanate, citrate, dihydrochloride, edetate,
edisylate, estolate, esylate, fumarate, gluceptate, gluconate,
glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,
hydrobromide, hydrochloride, hydroxynaphthoate, iodide,
isothionate, lactate, lactobionate, laurate, malate, maleate,
mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,
mucate, napsylate, nitrate, N-methylglucamine ammonium salt,
oleate, pamoate (embonate), palmitate, pantothenate,
phosphate/diphosphate, polygalacturonate, salicylate, stearate,
sulfate, subacetate, succinate, tannate, tartrate, teoclate,
tosylate, triethiodide and valerate.
[0264] Representative acids which may be used in the preparation of
pharmaceutically acceptable salts include, but are not limited to,
the following: acids including acetic acid, 2,2-dichloroacetic
acid, acylated amino acids, adipic acid, alginic acid, ascorbic
acid, L-aspartic acid, benzenesulfonic acid, benzoic acid,
4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid,
(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid,
caprylic acid, cinnamic acid, citric acid, cyclamic acid,
dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic
acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,
galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic
acid, D-glucuronic acid, L-glutamic acid, .alpha.-oxo-glutaric
acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric
acid, (+)-L-lactic acid, (.+-.)-DL-lactic acid, lactobionic acid,
maleic acid, (-)-L-malic acid, malonic acid, (.+-.)-DL-mandelic
acid, methanesulfonic acid, naphthalene-2-sulfonic acid,
naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid,
nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid,
palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid,
salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid,
succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid,
thiocyanic acid, p-toluenesulfonic acid and undecylenic acid.
[0265] Representative bases which may be used in the preparation of
pharmaceutically acceptable salts include, but are not limited to,
the following: ammonia, L-arginine, benethamine, benzathine,
calcium hydroxide, choline, deanol, diethanolamine, diethylamine,
2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,
N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium
hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium
hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide,
triethanolamine, tromethamine and zinc hydroxide.
Synthesis Schemes
[0266] Compounds of formula (I) (preferably compounds of formula
(I) wherein
##STR00156##
are both aromatic, and more preferably,
##STR00157##
are each optionally substituted phenyl), may be prepared according
to the process outlined in Schemes 1-2, below.
##STR00158##
[0267] Accordingly, a suitably substituted compound of formula (X),
a known compound or compound prepared by known methods, is reacted
with a suitably selected alcohol of the formula A.sup.1OH, wherein
A.sup.1 is C.sub.1-4alkyl, in the presence of a suitably selected
acid such as H.sub.2SO.sub.4, p-toluenesuffonic acid, HCl, and the
like; in a suitably selected solvent such as methanol, ethanol, and
the like; to yield the corresponding compound of formula (XI).
[0268] The compound of formula (XI) is reacted with
2,4-difluoro-1-nitrobenzene, a known compound, in the presence of a
suitably selected base such as KOt-Bu, LiHMDS, NaHMDS, NaOt-Bu, and
the like; in a suitably selected solvent such as THF, DME, and the
like; to yield the corresponding compound of formula (XII).
[0269] The compound of formula (XII) is reacted with a suitably
substituted compound of formula (XIII), wherein Q.sup.1 is selected
from the group consisting of --R.sup.3,
##STR00159##
wherein PG.sup.1 is a suitably selected nitrogen protecting group
such as Boc, alloc, and the like; a known compound or compound
prepared by known methods, in the presence of a suitably selected
base such as DIPEA, TEA, pyridine, and the like; in a suitably
selected solvent such as acetonitrile, DMSO, DMF, and the like; at
a temperature in the range of from about 60.degree. C. to about
100.degree. C., for example at about 85.degree. C.; to yield the
corresponding compound of formula (XIV).
[0270] The compound of formula (XIV) is hydrogenated according to
known methods, for example, by reacting with H.sub.2 gas, in the
presence of Raney nickel catalyst or Pd/C catalyst, in a suitably
selected solvent or mixture of solvents such as methanol/THF or
ethanol/THF; to yield the corresponding compound of formula
(XV).
[0271] The compound of formula (XV) is reacted with a suitably
substituted compound of formula (XVI), a known compound or compound
prepared by known methods; in the presence of a suitably selected
base such as TEA, DIPEA, pyridine, and the like; in a suitably
selected solvent such as DCM, DCE, and the like; to yield the
corresponding compound of formula (XVII).
[0272] The compound of formula (XVII) is reacted with a suitably
selected acid such as acetic acid, and the like; neat or in a
suitably selected solvent; at a temperature in the range of from
about 80.degree. C. to about reflux temperature, for example at
about 120.degree. C., to yield the corresponding compound of
formula (XVIII).
[0273] Alternatively, the compound of formula (XV) is reacted with
a suitably substituted compound of formula (XXXIX), a known
compound or compound prepared by known methods; in the presence of
air; in a suitably selected solvent such as DMSO, and the like; at
a temperature in the range of from about room temperature to about
75.degree. C., for example at about 50.degree. C., to yield the
corresponding compound of formula (XVIII).
[0274] The compound of formula (XVIII) is reacted with a suitably
selected base such as NaOH, LiOH, and the like; in a suitably
selected solvent or mixture of solvents such as methanol/THF,
ethanol/THF, and the like; to yield the corresponding compound of
formula (XIX).
[0275] The compound of formula (XIX) is reacted with DBU; in a
suitably selected solvent such as toluene, and the like; at a
temperature in the range of from about 75.degree. C. to about
reflux temperature, for example, at about 90.degree. C.; to yield
the corresponding compound of formula (XX).
[0276] One skilled in the art will recognize that wherein the
compound of formula (XVIII), formula (XIX) and/or formula (XX),
Q.sup.1 is R.sup.3, then said compounds of formula (XVIII), formula
(XIX) and/or formula (XX) correspond to compounds of formula (I)
wherein R.sup.0 is --C(O)O--(C.sub.1-4alkyl), --C(O)OH and
hydrogen, respectively.
[0277] Wherein the compounds of formula (XVIII), formula (XIX)
and/or formula (XX) Q.sup.1 is selected from the group consisting
of
##STR00160##
then the desired compound of formula (I) may be prepared by further
reacting the corresponding compound of formula (XVIII), as
described in Scheme 2 below.
##STR00161##
[0278] Accordingly, a suitably substituted compound of formula
(XVIIIa), a compound of formula (XVIII) wherein Q.sup.2 is selected
from the group consisting of
##STR00162##
and wherein PG.sup.1 is a suitably selected nitrogen protecting
group such as Boc, alloc and the like; is de-protected according to
known methods, (for example, wherein PG.sup.1 is Boc, the compound
of formula (XVIII) is reacted with a suitably selected acid such as
TFA, HCl, and the like, in a suitably selected solvent such as
1,4-dioxane, DCM, DCE, and the like; to yield the corresponding
compound of formula (XXI).
[0279] The compound of formula (XXI) is reacted with a suitably
substituted compound of formula (XXII), wherein LG.sup.1 is a
suitably selected leaving group such as, Cl (for example, wherein
the compound of formula (XXII) is an acyl chloride or a sulfonyl
chloride), Br, and the like, a known compound or compound prepared
by known methods; according to known methods; to yield the
corresponding compound of formula (XXIII). For example, when the
compound of formula (XXII) is an acyl chloride or a sulfonyl
chloride, the compound of formula (XXI) is reacted with the
compound of formula (XXII) in the presence of a base such as TEA,
DIPEA, pyridine, and the like; in a suitably selected solvent such
as DCM, DCE, THF, and the like. Alternatively, wherein the compound
of formula (XXII) is for example an optionally substituted phenyl
bromide, and the like; the compound of formula (XXI) is reacted
with the compound of formula (XXII); in the presence of a suitably
selected catalyst such as Pd.sub.2(dba).sub.3, Pd(OAc).sub.2, and
the like; in the presence of a suitably selected ligand such as
dppf, XantPhos, XPhos, and the like; in the presence of a suitably
selected base such as Cs.sub.2CO.sub.3, K.sub.2CO.sub.3,
K.sub.3PO.sub.4, and the like; in a suitably selected organic
solvent such as 1,4-dioxane, toluene, THF, DME, and the like; at an
elevated temperature in the range of from about 75.degree. C. to
about 150.degree. C.
[0280] The compound of formula (XXIII) is reacted with a suitably
selected base such as NaOH, LiOH, and the like; in a suitably
selected solvent or mixture of solvents such as methanol/THF,
ethanol/THF, and the like; to yield the corresponding compound of
formula (XXIV).
[0281] The compound of formula (XXIV) is reacted with DBU, and the
like; in a suitably selected solvent such as toluene, and the like;
at a temperature in the range of from about 75.degree. C. to about
reflux temperature; to yield the corresponding compound of formula
(XXV).
[0282] One skilled in the art will recognize that the compound of
formula (XXII), formula (XXIII) and/or formula (XXIV), correspond
to compounds of formula (I) wherein R.sup.0 is
--C(O)O--(C.sub.1-4alkyl), --C(O)OH and hydrogen, respectively.
[0283] Alternatively, the compound of formula (XVIIIa) is reacted
with a suitably substituted base such as NaOH, LiOH, and the like;
in a suitably selected solvent such as a mixture of methanol/THF,
ethanol/THF, and the like; to yield the corresponding compound
wherein the R.sup.0--C(O)OA.sup.1 ester group is converted to acid
(--C(O)OH). This intermediate is then reacted with DBU; in a
suitably selected solvent such as toluene, and the like; at a
temperature in the range of from about 75.degree. C. to about
reflux temperature, for example, at about 90.degree. C.; to yield
the corresponding compound wherein the R.sup.0 acid group
(--C(O)OH) is removed, such that R.sup.0 is hydrogen, a compound of
formula (XVIII-ALT).
##STR00163##
[0284] The compound of formula (XVIII-ALT) is then substituted for
the compound of formula (XVIIIa) in the Scheme 2 and reacted as
described therein, (to remove the PG.sup.1 protecting group, and
further to attach the desired R.sup.5 group), to yield the desired
compound of formula (I).
[0285] Compounds of formula (I) wherein R.sup.0 is --CH.sub.2OH may
be prepared from the corresponding compound of formula (XVIII),
wherein R.sup.0 is CO.sub.2A.sup.1 by reduction. In an example, a
suitably substituted compound of formula (XVIIIa) is reacted with a
suitably selected reducing agent such as LAH, and the like; in a
suitably selected solvent such as THF, DME, and the like; to yield
the corresponding compound wherein the --CO.sub.2A.sup.1 ester at
the R.sup.0 position is converted to --CH.sub.2OH. The resulting
compound is then substituted for the compound of formula (XVIIIa)
in Scheme 2 and reacted as described therein, to yield the desired
compound of formula (I).
[0286] Compounds of formula (I) wherein R.sup.0 is
--CH.sub.2--O--(C.sub.1-2alkyl) may be prepared by reacting a
suitably substituted compound of formula (I) wherein R.sup.0 is
--CH.sub.2OH with a suitably selected alkylating agent such as
CH.sub.31 (for the corresponding methyl ether) or CH.sub.3CH.sub.2I
(for the corresponding ethyl ether), in the presence of a suitably
selected base such as NaH, KOt-Bu, NaOt-Bu, and the like; in a
suitably selected solvent such as DMF, THF, and the like.
[0287] Compound of formula (I) wherein R.sup.0 is
--CH.sub.2--O--(C.sub.1-2alkyl)-CO.sub.2H may be prepared by
reacting a suitably substituted compound of formula (I) wherein
R.sup.0 is --CH.sub.2OH with a suitably selected
C.sub.3-4alken-1-yl bromide, a known compound or compound prepared
by known methods; in the presence of a suitably selected base such
as KOt-Bu, NaOt-Bu, and the like; in a suitably selected solvent
such as DMSO, THF, DMF, and the like; to yield the corresponding
intermediate compound, wherein the --CH.sub.2--OH at the R.sup.0
position is converted to the corresponding
--CH.sub.2--O--(CH.sub.2).sub.1-2--CH--CH.sub.2 group. This
intermediate is then reacted with a suitably selected oxidizing
agent such as a mixture of NaIO.sub.4 and RuCl.sub.3, and the like;
in a suitably selected solvent or mixture of solvent such as a
mixture of acetonitrile, DCM and water to yield the corresponding
compound of formula (I) wherein R.sup.0 is
--CH.sub.2--O--(C.sub.1-2alkyl)-CO.sub.2H.
[0288] Compounds of formula (I) wherein R.sup.3 is
##STR00164##
may be similarly prepared according to the procedure as described
in Scheme 1. More particularly, a suitably substituted compound of
formula (CXXV)
##STR00165##
[0289] wherein Q.sup.3 is selected from the group consisting of
R.sup.4, --C(O)OA.sup.2 and --NH-PG.sup.2, wherein A.sup.2 is
selected from the group consisting of C.sub.1-4alkyl, and wherein
PG.sup.2 is a suitably selected nitrogen protecting group, is
substituted for the compound of formula (XIII) and reacted as
described in Scheme 1 to yield the corresponding compound of
formula (XVIII), formula (XIX) and formula (XX), wherein the
Q.sup.1 group is replaced with corresponding
##STR00166##
group.
[0290] One skilled in the art will recognize that the compound of
formula (XVIII), formula (XIX) or formula (XX) wherein the Q.sup.1
group is replaced with
##STR00167##
and wherein Q.sup.3 is --NH-PG.sup.2 may be de-protected according
to known methods (to remove the PG.sup.2 protecting group) to yield
the corresponding compound of formula (I) wherein R.sup.3
4-amino-cyclohex-1-yl. This intermediate is then further reacted
with a compound of formula LG.sup.2-Q.sup.4, wherein LG.sup.2 is a
suitably selected leaving group such as Cl, Br, and the like; and
wherein Q.sup.4 is selected from the group consisting of -phenyl
and --SO.sub.2-phenyl, and wherein the phenyl is optionally
substituted as defined above for the R.sup.4 substituent group; to
yield the corresponding compound of formula (I) wherein R.sup.3
is
##STR00168##
and wherein R.sup.4 is selected from the group consisting of
--NH-(optionally substituted phenyl) and --NH--SO.sub.2-(optionally
substituted phenyl).
[0291] One skilled in the art will recognize that the compounds of
formula (XVIII), formula (XIX) and formula (XX) wherein Q.sup.1 is
replaced with
##STR00169##
and Q.sup.3 is --C(O)OA.sup.2, represent the corresponding
compounds of formula (I) wherein R.sup.3 is
##STR00170##
[0292] One skilled in the art will recognize that the compound of
formula (XVIII), formula (XIX) or formula (XX) wherein the Q.sup.1
group is replaced with
##STR00171##
and wherein Q.sup.3 is --C(O)OA.sup.2 may be reacted to convert the
alkyl ester (i.e. --C(O)OA.sup.2) to the corresponding acid group
(i.e. --C(O)OH), by for example reacting with a suitably selected
base such as NaOH, LiOH, and the like; in a suitably selected
solvent or mixture of solvents such as methanol/THF, ethanol/THF,
and the like. The acid group (i.e. --C(O)OH) may be further,
optionally reacted with NH.sub.4Cl or a suitably substituted amine
(e.g. a compound of the formula NHR.sup.GR.sup.H, a known compound
or compound prepared by known methods), in the presence of a
suitably selected coupling agent such as HATU, DIC, EDCl, and the
like; in the presence of a suitably selected base such as DIPEA,
TEA, pyridine, and the like; in a suitably selected solvent such as
DMF, DCM, THF and the like; to yield the corresponding compound,
wherein the R.sup.4 substituent group is the corresponding amide
(i.e. --C(O)--NH.sub.2 or --C(O)--NR.sup.GR.sup.H).
[0293] One skilled in the art will recognize that the above
described transformations and variations thereof will result in the
preparation of the corresponding compounds of formula (I) wherein
R.sup.3 is
##STR00172##
[0294] Compounds of formula (I) wherein R.sup.3 is selected from
the group consisting
##STR00173##
wherein b is 1 and L.sup.2 is --CH.sub.2CH.sub.2--O-- and
##STR00174##
wherein L.sup.3 is --CH.sub.2CH.sub.2--O-- may be similarly
prepared as described in Scheme 1 above, by reacting a suitably
substituted compound of formula (XII) with 2-hydroxyethylamine, a
known compound, to yield the corresponding compound of formula
(XIV), wherein the --NH-Q.sup.1 group is replaced with
--NH--CH.sub.2CH.sub.2--OH. This intermediate is then reacted as
described in Scheme 1 to yield the corresponding compound of
formula (XX), wherein the Q.sup.1 group is replaced with
--CH.sub.2CH.sub.2--OH, a compound of formula (CXX)
##STR00175##
[0295] The compound of formula (CXX) is then reacted with a
suitably substituted phenol or hydroxy-pyridyl; under Mitsunobu
conditions (for example, in the presence of DIAD, PPH.sub.3 and in
a solvent such as THF); to yield the corresponding compound of
formula (I) wherein R.sup.3 is selected from the group
consisting
##STR00176##
wherein b is 1 and L.sup.2 is --CH.sub.2CH.sub.2--O-- and
##STR00177##
wherein L.sup.3 is --CH.sub.2CH.sub.2--O--, respectively.
[0296] Compounds of formula (I) wherein R.sup.3 is selected from
the group consisting
##STR00178##
wherein b is 1 and L.sup.2 is
--CH.sub.2CH.sub.2CH.sub.2--NH--SO.sub.2-- may be similarly
prepared as described in Scheme 1 and 2, by preparing the
corresponding compounds wherein the -Q.sup.2-PG.sup.1 substituent
group is replaced with --CH.sub.2CH.sub.2CH.sub.2--NH--PG.sup.5 (by
reacting with a suitably substituted and suitably protected amine
of the formula NH.sub.2--CH.sub.2CH.sub.2CH.sub.2--NH-PG.sup.5
wherein PG.sup.5 is a suitably selected nitrogen protecting group
such as Boc, alloc, and the like); and then reacting as described
above to remove the PG.sup.5 protecting group and further
functionalizing to the desired product by reacting with a suitably
substituted sulfonyl chloride, according to known methods.
[0297] Compounds of formula (I) wherein R.sup.3 is selected from
the group consisting of
##STR00179##
may be prepared as described in Scheme 1 above.
[0298] Compounds of formula (I) wherein
##STR00180##
is an optionally substituted phenyl and wherein
##STR00181##
is thiazol-2-yl may alternatively be prepared as described in
Scheme 3, below.
##STR00182## ##STR00183##
[0299] Accordingly, a suitably substituted compound of formula
(XXX), wherein each HAL.sup.1 is independently selected from F or
Cl, a known compound or compound prepared by known methods, is
reacted with a suitably substituted compound of formula (XXXI), a
known compound or compound prepared by known methods; in the
presence of a suitably selected base such as DIPEA, TEA, pyridine,
and the like; in a suitably selected solvent such as DMSO,
acetonitrile, and the like; to yield the corresponding compound of
formula (XXXII).
[0300] The compound of formula (XXXII) is reacted with a suitably
substituted compound of formula (XXXIII), a known compound or
compound prepared by known methods; in the presence of a suitably
selected base such as KOt-Bu, NaOt-Bu, and the like; in a suitably
selected solvent such as THF, i-PrOH, and the like; to yield the
corresponding compound of formula (XXXIV).
[0301] The compound of formula (XXXIV) is reacted with
P.sub.2S.sub.5, a known compound; in a suitably selected solvent
such as ethanol, methanol, and the like; to yield the corresponding
compound of formula (XXXV). Alternatively, the compound of formula
(XXIV) is reacted with H.sub.2S; in the presence of a base such as
TEA; in a suitably selected solvent such as pyridine, and the like;
to yield the corresponding compound of formula (XXXV).
[0302] The compound of formula (XXXV) is reacted with
2-bromo-1,1-diethoxyethane, a known compound; in the presence of a
suitably selected acid such as acetic acid, and the like; in water;
to yield the corresponding compound of formula (XXXVI) wherein
##STR00184##
is thiazol-2-yl and R.sup.1 is hydrogen.
[0303] Alternatively, the compound of formula (XXXV) is reacted
with a suitably substituted compound of formula (XXXVII), wherein
R.sup.10 is a substituent on the
##STR00185##
thiazolyl ring, as defined herein, a known compound or compound
prepared by known methods; in the presence of a suitably selected
acid such as acetic acid, and the like; at a temperature in the
range of from about 50.degree. C. to about 120.degree. C., for
example at about 100.degree. C.; to yield the corresponding
compound of formula (XXXVI) wherein
##STR00186##
is the corresponding 4-(R.sup.11 substituted)-thiazol-2-yl.
[0304] The compound of formula (XXXVI) is reacted with hydrogen
(preferably hydrogen gas); in the presence of a suitably selected
catalyst, such as Raney nickel or Pd/C; in a suitably selected
solvent or mixture of solvents such as ethanol, THF, and the like;
to yield the corresponding compound of formula (XXXVIII).
[0305] The compound of formula (XXXVIII) is reacted with a suitably
substituted compound of formula (XXXIX), a known compound or
compound prepared by known methods; in a suitably selected solvent
such as DMSO, and the like; in air; at a temperature in the range
of from about 20.degree. C. to about 50.degree. C.; to yield the
corresponding compound of formula (Ib).
[0306] Wherein the desired compound of formula (Ib) R.sup.2 is
hydrogen, the compound of formula (XXXVIII) is reacted with
triethylorthoformate, a known compound; in the presence of an acid
such as conc HCl, and the like; neat; at a temperature in the range
of from about 75.degree. C. to about 150.degree. C., for example,
at about 125.degree. C.
[0307] Wherein the desired compound of formula (Ib) R.sup.2 is
methyl, the compound of formula (XXXVIII) is reacted with
trimethylorthoacetate, a known compound; in the presence of an acid
such as conc HCl, and the like; neat; at a temperature in the range
of from about 75.degree. C. to about reflux temperature.
[0308] Compounds of formula (I) wherein R.sup.1 is hydrogen may
alternatively be prepared as described in Scheme 4, below.
##STR00187##
[0309] Accordingly, a suitably substituted compound of formula
(XL), wherein HAL.sup.1 is selected from F or Cl, a known compound
or compound prepared by known methods, is reacted with a suitably
substituted compound of formula (XXXIII), a known compound or
compound prepared by known methods; in the presence of a suitably
selected base such as KOt-Bu, NaOt-Bu, and the like; in a suitably
selected solvent such as THF, i-PrOH, and the like; to yield the
corresponding compound of formula (XLI).
[0310] The compound of formula (XLI) is reacted with t-BuONO,
NaNO.sub.2, and the like, a known compound; in the presence of a
suitably selected source of chlorine such as CuCl.sub.2, CuCl, and
the like; in a suitably selected solvent such as acetonitrile,
water, and the like; to yield the corresponding compound of formula
(XLII). One skilled in the art will recognize that the reaction of
the compound of formula (XLI) may alternative be carried out in the
presence of a source of bromide such as CuBr.sub.2, and the like;
to yield the corresponding compound of formula (XLII) wherein the
Cl is replaced with a Br.
[0311] The compound of formula (XLII) is reacted with a suitably
substituted compound of formula (XLIII), wherein M.sup.3 is H or
Br, a known compound or compound prepared by known methods; in the
presence of a suitably selected lithiating agent such as n-BuLi,
t-BuLi, and the like; in a suitably selected solvent or mixture of
solvents such as hexanes, THF, DME, and the like; to yield the
corresponding compound of formula (XLIV).
[0312] Alternatively, the compound of formula (XLII) is reacted
with a suitably substituted compound of formula (XLIII), wherein
M.sup.3 is MgBr or MgCl, a known compound or compound prepared by
known methods; under Grignard conditions, to yield the
corresponding compound of formula (XLIV).
[0313] The compound of formula (XLIV) is reacted with a suitably
substituted compound of formula (XXXI), a known compound or
compound prepared by known methods; in the presence of a suitably
selected base such as KF, K.sub.2CO.sub.3, DIPEA, and the like; in
a suitably selected solvent such as DMSO, DMF, and the like; to
yield the corresponding compound of formula (XLV).
[0314] The compound of formula (XLV) is reacted with a suitably
selected reducing agent such as SnCl.sub.2, and the like; in the
presence of a suitably selected acid such as acetic acid, conc.
HCl, and the like; in water; at a temperature in the range of from
about 20.degree. C. to about 60.degree. C., for example, at about
50.degree. C.; to yield the corresponding compound of formula
(XLVI).
[0315] The compound of formula (XLVI) is reacted with a suitably
substituted compound of formula (XXXIX), a known compound or
compound prepared by known methods; in air; in a suitably selected
solvent such as DMSO, and the like; to yield the corresponding
compound of formula (Ic).
[0316] Compounds of formula (I) (for example, compounds of formula
(I) wherein
##STR00188##
are each an optionally substituted phenyl) may alternatively be
prepared as described in Scheme 5, below.
##STR00189##
[0317] Accordingly, a suitably substituted compound of formula
(XLVII), wherein Q.sup.1 is selected from the group consisting of
--R.sup.3,
##STR00190##
a known compound or compound prepared as described herein, is
reacted with N,O-dimethylhydroxylamine, a known compound; in the
presence of a suitably selected base such as LiHMDS, NaHMDS, and
the like; in a suitably selected solvent such as THF, DME, and the
like; to yield the corresponding compound of formula (XLVIII).
[0318] The compound of formula (XLVIII) is reacted with a suitably
substituted compound of formula (XLIX), wherein M.sup.1 is MgBr or
MgCl, a known compound or compound prepared by known methods; under
Grignard conditions; to yield the corresponding compound of formula
(L).
[0319] The compound of formula (L) is reacted with a suitably
substituted compound of formula (LI), where M.sup.2 is I, a known
compound or compound prepared by known methods; in the presence of
magnesium; in the presence of 12, in a suitably selected solvent
such as THF; to yield the corresponding compound of formula (LII).
Alternatively, the compound of formula (L) is reacted with a
suitably substituted compound of formula (LI) wherein M.sup.2 is
MgBr or MgCl; under Grignard conditions; to yield the corresponding
compound of formula (LII). Alternatively, the compound of formula
(L) is reacted with a suitably substituted compound of formula (LI)
wherein M.sup.2 is Li; according to known methods; to yield the
corresponding compound of formula (LII).
[0320] The compound of formula (LII) is reacted with Et.sub.3SiH in
combination with TFA or SnCl.sub.2 in combination with HCl or
TiCl.sub.4; in a suitably selected organic solvent such as DCM,
DCE, and the like; to yield the corresponding compound of formula
(LIII), wherein Q.sup.2 is selected from the group consisting of
--R.sup.3,
##STR00191##
One skilled in the art will recognize that in the reaction of the
compound of formula (LII) to yield the corresponding compound of
formula (LIII), wherein Q.sup.1 is R.sup.3, the R.sup.3 group does
not participate in the reaction, whereas when Q.sup.1 is selected
from the group consisting of
##STR00192##
the PG.sup.1 group is simultaneously removed.
[0321] One skilled in the art will further recognize that for the
compound of formula (LIII) when Q.sup.2 is R.sup.3, then the
compound of formula (LIII) corresponds to the compound of formula
(I). Wherein the compound of formula (LIII), Q.sup.2 is selected
from the group consisting of
##STR00193##
the desired compounds of formula (I) may be prepared by further
reacting the compound of formula (LIII), as described in more
detail hereinafter (for example by reacting with a suitably
substituted alkylating reagent, with a suitably selected acid
chloride, a suitably selected sulfonyl chloride, and the like).
[0322] Compounds of formula (LVII) may be prepared as described in
Scheme 6, below.
##STR00194##
[0323] Accordingly, a suitably substituted compound of formula
(CLIII), a known compound or compound prepared by known methods, is
reacted with a suitably substituted compound of formula (XIII),
wherein Q.sup.1 is selected from the group consisting of
--R.sup.3--,
##STR00195##
a known compound or compound prepared by known methods; in the
presence of s suitably selected base such as DIPEA, TEA, pyridine,
and the like; in a suitably selected solvent such as acetonitrile,
DMF, and the like; at a temperature in the range of from about
20.degree. C. to about reflux, for example at about 85.degree. C.;
to yield the corresponding compound of formula (LIV).
[0324] The compound of formula (LIV) is hydrogenated by reacting
with, for example hydrogen gas, in the presence of a suitably
selected catalyst such as Raney nickel, Pd/C, and the like; in a
suitably selected solvent or mixture of solvents such as
methanol/THF, ethanol/THF, and the like; to yield the corresponding
compound of formula (LV).
[0325] The compound of formula (LV) is reacted with a suitably
substituted compound of formula (XVI), a known compound or compound
prepared by known methods; in the presence of a suitably selected
base such as TEA, DIPEA, pyridine, and the like; in a suitably
selected solvent such as DCM, THF, and the like; to yield the
corresponding compound of formula (LVI).
[0326] The compound of formula (LVI) is reacted with a suitably
selected acid such as acetic acid; neat; at a temperature in the
range of from about 60.degree. C. to about 150.degree. C., for
example at about 120.degree. C.; to yield the corresponding
compound of formula (LVII), wherein Q.sup.2 is selected from the
group consisting of --R.sup.3,
##STR00196##
[0327] Alternatively, the compound of formula (LV) is reacted with
a suitably substituted compound of formula (XXXIX), a known
compound or compound prepared by known methods; in air; in a
suitably selected solvent such as DMSO, and the like; to yield the
corresponding compound of formula (LVII).
[0328] One skilled in the art will recognize that wherein the
compound of formula (LVII) Q.sup.2 is R.sup.3, then the compound of
formula (LVII) corresponds to the compound of formula (XLVII).
[0329] One skilled in the art will further recognize that wherein
the compound of formula (LVI) Q.sup.1 is selected from the group
consisting of
##STR00197##
the reaction of the compound of formula (LVI) with acetic acid will
result in not only the cyclization of the benzimidazole ring
structure, but also the removal of the PG.sup.1 group, to yield the
corresponding compound of formula (LVII) wherein Q.sup.2 is
selected from the group consisting of
##STR00198##
The compound of formula (LVII) is then further reacted, according
to known methods, to protect the nitrogen atom of the Q.sup.1
group, as needed or desired. For example, the compound of formula
(LVII) may be reacted with BOC anhydride, in the presence of a base
such as NaHCO.sub.3, and the like, in a solvent such as DCM, and
the like; to yield the corresponding compound of formula (XLVII),
wherein PG.sup.1 is BOC.
[0330] Compounds of formula (I) wherein R.sup.1 is C.sub.1-4alkoxy
may be prepared from a suitably substituted intermediate compound
of formula (LIX), which may prepared as described in Scheme 7
below.
##STR00199##
[0331] Accordingly, a suitably substituted compound of formula (XI)
is reacted with a suitably substituted compound of formula (LVIII),
a known compound or compound prepared by known methods; in the
presence of a base such as LiHMDS, NaHMDS, and the like; in a
suitably selected solvent such as 1,4-dioxane, THF, and the like;
to yield the corresponding compound of formula (LIX).
[0332] The compound of formula (LIX) is reacted with a suitably
selected sodium alkoxide (NaOA.sup.3) or potassium alkoxide
(KOA.sup.3), wherein A.sup.3 is a C.sub.1-4alkyl and wherein
--OA.sup.3 corresponds to the desired R.sup.1 alkoxy group; in a
suitably selected solvent such as DMF, THF, and the like; to yield
the corresponding compound of formula (LX). One skilled in the art
will recognize that wherein the sodium alkoxide is sodium
methoxide, said reagent is preferably added as a mixture with
methanol.
[0333] The compound of formula (LX) is then substituted for the
compound of formula (XII) in Scheme 1, and reacted as described in
the Schemes herein; to yield the desired compound of formula (I)
wherein R.sup.1 is C.sub.1-4alkoxy.
[0334] One skilled in the art will recognize that the R.sup.2 group
may be incorporated into the compound of formula (I) as a single
substituent group (as described in the Schemes above and the
examples which follow hereinafter) or may alternatively, be
incorporated into the compound of formula (I) via two or more
reaction steps.
[0335] More particularly, the R.sup.2 group may be incorporated
into the desired compound of formula (I) as described in Scheme 8,
below.
##STR00200##
[0336] Accordingly, a suitably substituted compound of formula
(LXI), prepared according to the processes as herein described is
reacted with a suitably substituted R.sup.2 containing reagent, a
compound of formula (LXII); to yield the corresponding compound of
formula (LXIII) (a compound of formula (I) wherein R.sup.1 and
R.sup.0 are each hydrogen).
[0337] In an example, the compound of formula (LXII) corresponds to
a suitably substituted aldehyde (wherein X is --CHO); and the
compound of formula (LXI) is reacted with the compound of formula
(LXII) in air; in a suitably selected solvent such as DMSO, and the
like; to yield the corresponding compound of formula (LXIII).
[0338] In another example, the compound of formula (LXII)
corresponds to a suitably substituted acid (wherein X is --C(O)OH);
and the compound of formula (LXI) is reacted with the compound of
formula (LXII), in the presence of a suitably selected acid such as
TFA, and the like; neat in a suitably selected solvent; to yield
the corresponding compound of formula (LXIII).
[0339] In another example, the compound of formula (LXII)
corresponds to R.sup.2--C(OCH.sub.3).sub.3, wherein R.sup.2 is
C.sub.1-4alkyl, and the compound of formula (LXI) is reacted with
the compound of formula (LXII) in the presence of a suitably
selected acid such as HCl; neat or in a suitably selected solvent;
to yield the corresponding compound of formula (LXIII). One skilled
in the art will recognize that compounds of formula (I) wherein
R.sup.2 is hydrogen, may be similarly prepared from the compound of
formula (LXI) with a compound of the formula H--C(OCH.sub.3).sub.3,
as described above.
[0340] Compounds of formula (I) wherein R.sup.2 is NH.sub.2 may be
similarly prepared by reacting a suitably substituted compound of
formula (LXI) with cyanogen bromide, a known compound; in a
suitably selected solvent such as ethanol, methanol, and the like;
to yield the corresponding compound of formula (LXIII) wherein
R.sup.2 is NH.sub.2.
[0341] Compounds of formula (I) wherein R.sup.2 is NR.sup.ER.sup.F
(and wherein one or both of R.sup.E and R.sup.F are selected
C.sub.1-4alkyl) may be similarly prepared by reacting a suitably
substituted compound of formula (LXI) with
1,1,-carbonyldiimidazole, a known compound; in a suitably selected
solvent such as THF, DCM, and the like; to yield the corresponding
compound of formula (LXIII) wherein R.sup.2 group is replaced with
a .dbd.O group; which compound is then reacted with a suitably
selected source of chlorine such as POCl.sub.3, and the like; neat
or in a suitably selected solvent; at a temperature in the range of
from about 50.degree. C. to about 120.degree. C., for example at
about 90.degree. C.; to yield the corresponding compound of formula
(LXIII) wherein R.sup.2 is chloro; and which compound is further
reacted with a suitably substituted amine of the formula
NHR.sup.ER.sup.F, a known compound or compound prepared by known
methods; in a suitably selected solvent such as THF, DCM,
1,4-dioxane, and the like; to yield the corresponding compound of
formula (LXIII) wherein R.sup.2 is NR.sup.ER.sup.F.
[0342] One skilled in the art will further recognize that the
R.sup.2 group may be incorporated into the desired compound of
formula (I) as a complete substituent group, or may alternatively
be incorporated via two or more reaction steps. For example,
wherein R.sup.2 is --CH.sub.2CH.sub.2--NH.sub.2, a compound of
formula (LXIII) wherein R.sup.2 is
--CH.sub.2CH.sub.2--C(O)O--CH.sub.2CH.sub.3 may be prepared as
described herein and then reacted with a suitably selected base
such as NaOH, and the like, according to known methods; to yield
the corresponding compound wherein the ester is converted to the
corresponding acid (i.e. R.sup.2 is --CH.sub.2CH.sub.2--C(O)OH).
This compound may then be further reacted in a mixture of DPPA,
TEA, benzene, according to known methods, to yield the
corresponding compound wherein R.sup.2 is
--CH.sub.2CH.sub.2--NH.sub.2. Additional transformations would be
readily known to those skilled in the art, and are further
described in specific examples which follow hereinafter.
[0343] Compounds of formula (I) wherein R.sup.3 is selected from
the group consisting of
##STR00201##
may alternatively be prepared according to the process as outlined
in Scheme 9, below.
##STR00202##
[0344] Accordingly, a suitably substituted compound of formula
(LXIV), wherein Q.sup.3 is
##STR00203##
a compound prepared for example as described in the Schemes 1-2
above, is reacted with a suitably substituted compound of formula
(LXV), wherein LG.sup.3 is a suitably selected leaving group, a
known compound or compound prepared by known methods; to yield the
corresponding compound of formula (Ie).
[0345] In an example, the compound of formula (LXIV) is reacted
with a compound of formula (LXV), a suitably substituted sulfonyl
chloride, wherein LG.sup.3 is chloro; in the presence of a suitably
selected base such as K.sub.2CO.sub.3, Na.sub.2CO.sub.3, TEA,
DIPEA, pyridine, and the like; to yield the corresponding compound
of formula (Ie) wherein R.sup.5 is a substituent group bound
through a sulfonyl (i.e. --SO.sub.2--) group.
[0346] In another example, the compound of formula (LXIV) is
reacted with a compound of formula (LXV), a suitably substituted
phenyl bromide, and the like, wherein LG.sup.3 is bromo; in the
presence of a suitably selected catalyst such as
Pd.sub.2(dba).sub.3, Pd(OAc).sub.2, and the like; in the presence
of a suitably selected ligand such as dppf, XantPhos, XPhos, and
the like; in the presence of a suitably selected base such as
Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3P.sub.04, and the like;
in a suitably selected organic solvent such as 1,4-dioxane,
toluene, THF, DME, and the like; at an elevated temperature in the
range of from about 75.degree. C. to about 150.degree. C.; to yield
the corresponding compound of formula (Ie) wherein R.sup.5 is the
corresponding optionally substituted phenyl, and the like.
[0347] In another example, the compound of formula (LXIV) is
reacted with a compound of formula (LXV), a suitably substituted
C.sub.1-4alkyl bromide, and the like, wherein LG.sup.3 is bromo; in
the presence of a suitably selected base such as Hunig's base,
K.sub.2CO.sub.3, and the like; in a suitably selected solvent such
as acetonitrile, and the like; to yield the corresponding compound
of formula (Ia) wherein R.sup.5 is the corresponding optionally
substituted C.sub.1-4alkyl, and the like.
[0348] In another example, the compound of formula (LXIV) is
reacted with a compound of formula (LXV), a suitably substituted
aldehyde, wherein LG.sup.3 is .dbd.O; in the presence of a suitably
selected reducing agent such as NaBH(OAc).sub.3, and the like; in a
suitably selected solvent such as DCE, methanol, ethanol, and the
like; to yield the corresponding compound of formula (Ia). One
skilled in the art will recognize that the carbon atom of the
aldehyde of formula (LXV) is incorporated into the R.sup.5
substituent group as a --CH.sub.2-- (for example wherein the
compound of formula (LXV) is an optionally substituted phenyl
aldehyde, then the resulting R.sup.5 substituent group is the
corresponding, optionally substituted benzyl group.) Alternatively,
the compound of formula (LXIV) is reacted with a suitably
substituted isocyanate, in the presence of a suitably selected base
such as TEA, DIPEA, pyridine, and the like; in a suitably selected
solvent such as DCM, THF, DMF, and the like; to yield the
corresponding compound wherein the R.sup.5 group is bound through a
--C(O)--NH-- group.
[0349] Alternatively, the compound of formula (LXIV) is reacted
with a suitably substituted chloroformate, in the presence of a
suitably selected base such as TEA, DIPEA, pyridine, and the like;
in a suitably selected solvent such as THF, and the like; to yield
the corresponding compound wherein the R.sup.5 group is bound
through a --C(O)--O-- group.
[0350] Alternatively, the compound of formula (LXIV) is reacted
with CDI, a known compound; in the presence of a suitably selected
base such as TEA, DIPEA, pyridine, and the like; in a suitably
selected solvent such as DCM, THF, and the like; to yield the
corresponding compound wherein the R.sup.5 group replaced with
--C(O)-imidazol-1-yl; which compound is further reacted with a
suitably substituted alcohol or amine; in the presence of a
suitably selected base such as Cs.sub.2CO.sub.3, K.sub.2CO.sub.3,
TEA, DIPEA, and the like; in a suitably selected solvent such as
DMF, acetonitrile, and the like; to yield the corresponding
compound wherein the R.sup.5 group is bound through --C(O)--O-- or
a --C(O)--NH-- group, respectively.
[0351] Compounds of formula (I), wherein R.sup.0 is hydroxy may
alternatively be prepared as described in Scheme 10, below.
##STR00204##
[0352] Accordingly, a suitably substituted compound of formula
(CLXV), wherein Q.sup.1 is as defined above, a known compound or
compound prepared as described herein, is reacted with a suitably
substituted compound of formula (LXVI), a known compound or
compound prepared by known methods; in the presence of a suitably
selected lithiating reagent such as n-BuLi, t-BuLi, and the like;
in a suitably selected solvent such as THF, DME, and the like; to
yield the corresponding compound of formula (LXXI).
[0353] Alternatively, a suitably substituted compound of formula
(CLXV), a known compound or compound prepared by known methods, is
reacted with a suitably substituted compound of formula (LXVII), a
known compound or compound prepared by known methods; in the
presence of a suitably selected lithiating reagent such as n-BuLi,
t-BuLi, and the like; in a suitably selected solvent such as THF,
DME, and the like; to yield the corresponding compound of formula
(LXVIII).
[0354] The compound or formula (LXVIII) is reacted with a suitably
selected oxidizing agent such as DMP, and the like; in a suitably
selected solvent such as DCM, and the like; to yield the
corresponding compound of formula (LXIX).
[0355] The compound of formula (LXIX) is reacted with a suitably
substituted compound of formula (LXX), wherein M.sup.1 is MgBr or
MgCl, a known compound or compound prepared by known methods; under
Grignard conditions; to yield the corresponding compound of formula
(LXXI). One skilled in the art will recognize that the compound of
formula (LXIX) may alternatively be reacted with a compound of
formula (LXX) wherein M.sup.1 is replaced with lithium, according
to known methods, to yield the corresponding compound of formula
(LXXI).
[0356] One skilled in the art will recognize that wherein Q.sup.1
is R.sup.3, then the compound of formula (LXXI) is the
corresponding compound of formula (I). One skilled in the art will
further recognize that when in the compound of formula (LXXI),
Q.sup.1 is other than R.sup.3, then the compound of formula (LXXI)
may be further reacted, as described herein, to yield the desired
compound of formula (I). For example, the compound of formula
(LXXI) may be substituted for the compound of formula (XVIIIa) in
Scheme 2 and reacted as described therein to yield the desired
R.sup.3 substituent group.
[0357] One skilled in the art will further recognize that the
compound of formula (LXXI) may be further optionally reacted, as
described herein to convert the hydroxy group at the R.sup.0
position to hydrogen.
[0358] One skilled in the art will further recognize that the
compounds of formula (LXV) may be prepared according to known
methods, and/or by adapting the procedures as described in the
Example which follow hereinafter.
[0359] Compounds of formula (LXV) wherein R.sup.1 is hydrogen may
alternative be prepared as described in Scheme 11 below.
##STR00205##
[0360] Accordingly, a suitably substituted compound of formula
(LXXI), wherein Q.sup.1 is as defined above, a known compound or
compound prepared by known methods, is reacted with
4-bromo-2-fluoro-1-nitrobenzene, a known compound; in the presence
of a suitably selected base such as DIPEA, TEA, pyridine and the
like; in a suitably selected solvent such as acetonitrile, DCM, and
the like; to yield the corresponding compound of formula
(LXXII).
[0361] The compound of formula (LXXII) is reacted Fe in the
presence of NH.sub.4Cl; in a suitably selected solvent such as
methanol, ethanol, and the like; in the presence of water; at a
temperature in the range of from about 50.degree. C. to about
100.degree. C., for example at about 80.degree. C.; to yield the
corresponding compound of formula (LXXIII). One skilled in the art
will recognize that alternate reduction conditions, for example
reacting the compound of formula (LXXII) with H.sub.2 gas in the
presence of Raney nickel in a mixture of methanol/THF may also be
used to yield the corresponding compound of formula (LXXIII).
[0362] The compound of formula (LXXIII) is reacted with a suitably
substituted compound of formula (XXXIX), a known compound or
compound prepared by known methods; in the presence of air; in a
suitably selected solvent such as DMSO, and the like; at a
temperature in the range of from about room temperature to about
75.degree. C., for example at about 50.degree. C., to yield the
corresponding compound of formula (LXVa).
[0363] Compounds of formula (LXV) wherein R.sup.1 is
--OC.sub.1-4alkyl may alternatively be prepared as described in
Scheme 12 below.
##STR00206##
[0364] Accordingly, 2-amino-3-nitrophenol, a known compound, is
reacted with a suitably selected source of bromine such as
Br.sub.2, and the like; in the presence of a suitably selected acid
such as acetic acid, and the like; neat or in a suitably selected
solvent and the like; to yield 2-amino-5-bromo-3-nitrophenol.
[0365] The 2-amino-5-bromo-3-nitrophenol is reacted with a suitably
selected alkylating agent, according to known methods, to yield the
corresponding compound of formula (LXXIV), wherein A.sup.1 is the
corresponding C.sub.1-4alkyl. For example, wherein the compound of
formula (LXXIV) A.sup.1 is --CH.sub.3, the
2-amino-5-bromo-3-nitrophenol may be reacted with CH.sub.31, in the
presence of a base such as K.sub.2CO.sub.3, and the like; in a
solvent such as DMF, and the like.
[0366] The compound of formula (LXXIV) is reacted with a suitably
substituted compound of formula (XVI), a known compound or compound
prepared by known methods; in the presence of a suitably selected
base such as TEA, DIPEA, pyridine, and the like; in a suitably
selected solvent such as DCM, DCE, and the like; to yield the
corresponding compound of formula (LXXV).
[0367] The compound of formula (LXXV) is reacted Fe in the presence
of NH.sub.4Cl; in a suitably selected solvent such as methanol,
ethanol, and the like; in the presence of water; at a temperature
in the range of from about 50.degree. C. to about 100.degree. C.,
for example at about 80.degree. C.; to yield the corresponding
compound of formula (LXXVI).
[0368] The compound of formula (LXXVI) is reacted with a suitably
substituted aldehyde or carbonyl compound, according to known
methods or methods as described in the Schemes and Examples herein;
to yield the corresponding compound of formula (LXXVII), wherein
Q.sup.1 is as defined herein. For example, the compound of formula
(LXXVI) may be reacted with
1-((trifluoromethyl)sulfonyl)piperidin-4-one, in the presence of
NaBH(OAc).sub.3, in the presence of acetic acid, in DCE, to yield
the corresponding compound of formula (LXXVII) wherein Q.sup.1 is
1-trifluoromethyl-sulfonyl-piperidin-4-yl.
[0369] The compound of formula (LXXVII) is reacted with a suitably
selected acid such as acetic acid, and the like; neat or in a
suitably selected solvent; to yield the corresponding compound of
formula (LXVb).
[0370] One skilled in the art will recognize that the
2-amino-5-bromo-3-nitrophenol may alternatively be reacted with
(CH.sub.3).sub.3Si--CH.sub.2CH.sub.2--O--CH.sub.2Cl, a known
compound, in the presence of a suitably selected base such as
K.sub.2CO.sub.3, Na.sub.2CO.sub.3, and the like; in a suitably
selected solvent such as DMF, acetonitrile, and the like; to yield
the corresponding compound of formula (LXXIV) wherein the
--OA.sup.1 group is replaced with
--O--CH.sub.2--O--CH.sub.2CH.sub.2--Si(CH.sub.3).sub.3. Said
intermediate is then reacted as described in Scheme 12 above to
yield the corresponding compound of formula (CLXV)
##STR00207##
[0371] The compound of formula (CLXV) may then be reacted according
to the procedures as described in the Schemes and Examples herein
to yield the corresponding compound of formula (I) wherein the
R.sup.1 group is replaced with
--O--CH.sub.2--O--CH.sub.2CH.sub.2--Si(CH.sub.3).sub.3, which
compound is then de-protected according to known methods, to yield
the desired compound of formula (I) wherein R.sup.1 is hydroxy.
[0372] One skilled in the art will further recognize that the
R.sup.5 substituent group may alternatively be incorporated into
the desired compound of formula (I) via multiple reaction steps,
according to known methods, and as exemplified for representative
compounds in the Synthesis Examples which follow hereinafter.
[0373] One skilled in the art will further recognize that
additional substituent groups as defined herein may be similarly
incorporated into the desired compound of formula (I) via one or
more coupling reactions and/or substituent transformations (e.g.
removal of an alkyl group, conversion of a --CO.sub.2H group to
corresponding --C(O)NH.sub.2 group, hydrogenation, reductive
amination, nucleophilic substitution, Suzuki coupling, Mitsunobu
coupling, etc.), according to the methods known in the art, and/or
according to procedures as described in the general synthesis
schemes and examples herein. One skilled in the art will further
recognize that the reaction steps and processes described herein
(in the synthesis schemes and examples) may be adapted and/or
applied to the synthesis of any of the compounds of the present
invention.
[0374] One skilled in the art will further recognize that in any of
the processes described herein, the
##STR00208##
rings (as substituent groups or in reagents containing said
substituent groups) may be interchanged, and the synthesis
completed as described, to yield the corresponding desired
compound.
[0375] One skilled in the art will further recognize that in the
synthesis of the compounds of formula (I) of the present invention,
the various substituent groups may be incorporated in the order
specifically described in the Scheme and Examples herein, or may
alternatively be incorporated in a different order, adapting and/or
adjusting the individual reaction step conditions to yield the
desired intermediate or product compound.
Pharmaceutical Compositions and Methods of Treatment
[0376] The present invention further comprises pharmaceutical
compositions containing one or more compounds of formula (I) with a
pharmaceutically acceptable carrier. Pharmaceutical compositions
containing one or more of the compounds of the invention described
herein as the active ingredient can be prepared by intimately
mixing the compound or compounds with a pharmaceutical carrier
according to conventional pharmaceutical compounding techniques.
The carrier may take a wide variety of forms depending upon the
desired route of administration (e.g., oral, parenteral). Thus for
liquid oral preparations such as suspensions, elixirs and
solutions, suitable carriers and additives include water, glycols,
oils, alcohols, flavoring agents, preservatives, stabilizers,
coloring agents and the like; for solid oral preparations, such as
powders, capsules and tablets, suitable carriers and additives
include starches, sugars, diluents, granulating agents, lubricants,
binders, disintegrating agents and the like. Solid oral
preparations may also be coated with substances such as sugars or
be enteric-coated so as to modulate major site of absorption. For
parenteral administration, the carrier will usually consist of
sterile water and other ingredients may be added to increase
solubility or preservation. Injectable suspensions or solutions may
also be prepared utilizing aqueous carriers along with appropriate
additives.
[0377] To prepare the pharmaceutical compositions of this
invention, one or more compounds of the present invention as the
active ingredient is intimately admixed with a pharmaceutical
carrier according to conventional pharmaceutical compounding
techniques, which carrier may take a wide variety of forms
depending of the form of preparation desired for administration,
e.g., oral or parenteral such as intramuscular. In preparing the
compositions in oral dosage form, any of the usual pharmaceutical
media may be employed. Thus, for liquid oral preparations, such as
for example, suspensions, elixirs and solutions, suitable carriers
and additives include water, glycols, oils, alcohols, flavoring
agents, preservatives, coloring agents and the like; for solid oral
preparations such as, for example, powders, capsules, caplets,
gelcaps and tablets, suitable carriers and additives include
starches, sugars, diluents, granulating agents, lubricants,
binders, disintegrating agents and the like. Because of their ease
in administration, tablets and capsules represent the most
advantageous oral dosage unit form, in which case solid
pharmaceutical carriers are obviously employed. If desired, tablets
may be sugar coated or enteric coated by standard techniques. For
parenterals, the carrier will usually comprise sterile water,
through other ingredients, for example, for purposes such as aiding
solubility or for preservation, may be included. Injectable
suspensions may also be prepared, in which case appropriate liquid
carriers, suspending agents and the like may be employed. The
pharmaceutical compositions herein will contain, per dosage unit,
e.g., tablet, capsule, powder, injection, teaspoonful and the like,
an amount of the active ingredient necessary to deliver an
effective dose as described above. The pharmaceutical compositions
herein will contain, per unit dosage unit, e.g., tablet, capsule,
powder, injection, suppository, teaspoonful and the like, of from
about 0.01 mg to about 1000 mg or any amount or range therein, and
may be given at a dosage of from about 0.01 mg/kg/day to about 300
mg/kg/day, or any amount or range therein, preferably from about
0.1 mg/kg/day to about 50 mg/kg/day, or any amount or range
therein, preferably from about 0.5 mg/kg/day to about 15 mg/kg/day,
or any amount or range therein. The dosages, however, may be varied
depending upon the requirement of the patients, the severity of the
condition being treated and the compound being employed. The use of
either daily administration or post-periodic dosing may be
employed.
[0378] Preferably these compositions are in unit dosage forms such
as tablets, pills, capsules, powders, granules, sterile parenteral
solutions or suspensions, metered aerosol or liquid sprays, drops,
ampoules, autoinjector devices or suppositories; for oral
parenteral, intranasal, sublingual or rectal administration, or for
administration by inhalation or insufflation. Alternatively, the
composition may be presented in a form suitable for once-weekly or
once-monthly administration; for example, an insoluble salt of the
active compound, such as the decanoate salt, may be adapted to
provide a depot preparation for intramuscular injection. For
preparing solid compositions such as tablets, the principal active
ingredient is mixed with a pharmaceutical carrier, e.g.
conventional tableting ingredients such as corn starch, lactose,
sucrose, sorbitol, talc, stearic acid, magnesium stearate,
dicalcium phosphate or gums, and other pharmaceutical diluents,
e.g. water, to form a solid preformulation composition containing a
homogeneous mixture of a compound of the present invention, or a
pharmaceutically acceptable salt thereof. When referring to these
preformulation compositions as homogeneous, it is meant that the
active ingredient is dispersed evenly throughout the composition so
that the composition may be readily subdivided into equally
effective dosage forms such as tablets, pills and capsules. This
solid preformulation composition is then subdivided into unit
dosage forms of the type described above containing from about 0.01
mg to about 1,000 mg, or any amount or range therein, of the active
ingredient of the present invention. The tablets or pills of the
novel composition can be coated or otherwise compounded to provide
a dosage form affording the advantage of prolonged action. For
example, the tablet or pill can comprise an inner dosage and an
outer dosage component, the latter being in the form of an envelope
over the former. The two components can be separated by an enteric
layer which serves to resist disintegration in the stomach and
permits the inner component to pass intact into the duodenum or to
be delayed in release. A variety of material can be used for such
enteric layers or coatings, such materials including a number of
polymeric acids with such materials as shellac, cetyl alcohol and
cellulose acetate.
[0379] The liquid forms in which the novel compositions of the
present invention may be incorporated for administration orally or
by injection include, aqueous solutions, suitably flavoured syrups,
aqueous or oil suspensions, and flavoured emulsions with edible
oils such as cottonseed oil, sesame oil, coconut oil or peanut oil,
as well as elixirs and similar pharmaceutical vehicles. Suitable
dispersing or suspending agents for aqueous suspensions, include
synthetic and natural gums such as tragacanth, acacia, alginate,
dextran, sodium carboxymethylcellulose, methylcellulose,
polyvinyl-pyrrolidone or gelatin.
[0380] The method of treating disorders described herein may also
be carried out using a pharmaceutical composition comprising any of
the compounds as defined herein and a pharmaceutically acceptable
carrier. The pharmaceutical composition may contain between about
0.01 mg and about 1000 mg of the compound, or any amount or range
therein; preferably from about 1.0 mg to about 500 mg of the
compound, or any amount or range therein, and may be constituted
into any form suitable for the mode of administration selected.
Carriers include necessary and inert pharmaceutical excipients,
including, but not limited to, binders, suspending agents,
lubricants, flavorants, sweeteners, preservatives, dyes, and
coatings. Compositions suitable for oral administration include
solid forms, such as pills, tablets, caplets, capsules (each
including immediate release, timed release and sustained release
formulations), granules, and powders, and liquid forms, such as
solutions, syrups, elixirs, emulsions, and suspensions. Forms
useful for parenteral administration include sterile solutions,
emulsions and suspensions.
[0381] Advantageously, compounds of the present invention may be
administered in a single daily dose, or the total daily dosage may
be administered in divided doses of two, three or four times daily.
Furthermore, compounds for the present invention can be
administered in intranasal form via topical use of suitable
intranasal vehicles, or via transdermal skin patches well known to
those of ordinary skill in that art. To be administered in the form
of a transdermal delivery system, the dosage administration will,
of course, be continuous rather than intermittent throughout the
dosage regimen.
[0382] For instance, for oral administration in the form of a
tablet or capsule, the active drug component can be combined with
an oral, non-toxic pharmaceutically acceptable inert carrier such
as ethanol, glycerol, water and the like. Moreover, when desired or
necessary, suitable binders; lubricants, disintegrating agents and
coloring agents can also be incorporated into the mixture. Suitable
binders include, without limitation, starch, gelatin, natural
sugars such as glucose or beta-lactose, corn sweeteners, natural
and synthetic gums such as acacia, tragacanth or sodium oleate,
sodium stearate, magnesium stearate, sodium benzoate, sodium
acetate, sodium chloride and the like. Disintegrators include,
without limitation, starch, methyl cellulose, agar, bentonite,
xanthan gum and the like.
[0383] The liquid forms may contain suitably flavored suspending or
dispersing agents such as the synthetic and natural gums, for
example, tragacanth, acacia, methyl-cellulose and the like. For
parenteral administration, sterile suspensions and solutions are
desired. Isotonic preparations which generally contain suitable
preservatives are employed when intravenous administration is
desired.
[0384] To prepare a pharmaceutical composition of the present
invention, a compound of formula (I) as the active ingredient is
intimately admixed with a pharmaceutical carrier according to
conventional pharmaceutical compounding techniques, which carrier
may take a wide variety of forms depending of the form of
preparation desired for administration (e.g. oral or parenteral).
Suitable pharmaceutically acceptable carriers are well known in the
art. Descriptions of some of these pharmaceutically acceptable
carriers may be found in The Handbook of Pharmaceutical Excipients,
published by the American Pharmaceutical Association and the
Pharmaceutical Society of Great Britain.
[0385] Methods of formulating pharmaceutical compositions have been
described in numerous publications such as Pharmaceutical Dosage
Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3,
edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral
Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical
Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et
al; published by Marcel Dekker, Inc.
[0386] Compounds of the present invention may be administered in
any of the foregoing compositions and according to dosage regimens
established in the art whenever treatment of metabolic disorders is
required.
[0387] The daily dosage of the products may be varied over a wide
range from about 0.01 mg to about 1,000 mg per adult human per day,
or any amount or range therein. For oral administration, the
compositions are preferably provided in the form of tablets
containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0,
50.0, 100, 150, 200, 250 and 500 milligrams of the active
ingredient for the symptomatic adjustment of the dosage to the
patient to be treated. An effective amount of the drug is
ordinarily supplied at a dosage level of from about 0.01 mg/kg to
about 300 mg/kg of body weight per day, or any amount or range
therein. Preferably, the range is from about 0.01 to about 50.0
mg/kg of body weight per day, or any amount or range therein. More
preferably, from about 0.05 to about 15.0 mg/kg of body weight per
day, or any amount or range therein. More preferably, from about
0.07 to about 7.5 mg/kg of body weight per day, or any amount or
range therein. The compounds may be administered on a regimen of 1
to 4 times per day.
[0388] Optimal dosages to be administered may be readily determined
by those skilled in the art, and will vary with the particular
compound used, the mode of administration, the strength of the
preparation, the mode of administration, and the advancement of the
disease condition. In addition, factors associated with the
particular patient being treated, including patient age, weight,
diet and time of administration, will result in the need to adjust
dosages.
[0389] One skilled in the art will recognize that, both in vivo and
in vitro trials using suitable, known and generally accepted cell
and/or animal models are predictive of the ability of a test
compound to treat or prevent a given disorder.
[0390] One skilled in the art will further recognize that human
clinical trials including first-in-human, dose ranging and efficacy
trials, in healthy patients and/or those suffering from a given
disorder, may be completed according to methods well known in the
clinical and medical arts.
EXAMPLES
[0391] The following Examples are set forth to aid in the
understanding of the invention, and are not intended and should not
be construed to limit in any way the invention set forth in the
claims which follow thereafter.
[0392] In the Synthesis Examples which follow, some synthesis
products are listed as having been isolated as a residue. It will
be understood by one of ordinary skill in the art that the term
"residue" does not limit the physical state in which the product
was isolated and may include, for example, a solid, an oil, a foam,
a gum, a syrup, and the like.
Example PH-1
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]-
piperidine-1-sulfonyl)benzoic acid
##STR00209##
[0393] Step 1: Synthesis of methyl
2,2-bis(4-chlorophenyl)acetate
[0394] Into a 1000-mL round-bottom flask, was placed a solution of
2,2-bis(4-chlorophenyl)acetic acid (150 g, 533.55 mmol, 1.00 equiv)
in methanol (600 mL) and sulfuric acid (50 mL). The resulting
solution was stirred overnight at 80.degree. C. The mixture was
concentrated under vacuum. The reaction was then quenched by the
addition of water (500 mL). The pH value of the solution was
adjusted to pH 7 with sodium hydroxide. The resulting solution was
extracted with ethyl acetate (3.times.500 mL) and the organic
layers combined and dried over anhydrous sodium sulfate to yield
methyl 2,2-bis(4-chlorophenyl)acetate as yellow oil. LC/MS (ES,
m/z): 295 [M+H]+.
Step 2: Synthesis of methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate
[0395] Into a 1000-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of nitrogen, was placed a
solution of methyl 2,2-bis(4-chlorophenyl)acetate (54 g, 182.95
mmol, 1.00 equiv) in tetrahydrofuran (250 mL). To the mixture was
then added t-BuOK (201 mL, 1.10 equiv) dropwise with stirring at
0.degree. C. in 20 min. To the resulting mixture was added a
solution of 2,4-difluoro-1-nitrobenzene (37.5 g, 235.72 mmol, 1.05
equiv) in tetrahydrofuran (250 mL) dropwise with stirring. The
resulting solution was stirred overnight at room temperature. The
residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:20) to yield methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate as yellow
oil. LC/MS (ES, m/z): 434 [M+H].sup.+.
Step 3: Synthesis of tert-butyl
4-([5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-nitrophenyl]amino)-
piperidine-1-carboxylate
[0396] Into a 1000-mL round-bottom flask, was placed a solution of
methyl 2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate
(35 g, 80.60 mmol, 1.00 equiv) in CH.sub.3CN (200 mL), tert-butyl
4-aminopiperidine-1-carboxylate (19 g, 94.87 mmol, 1.20 equiv) and
DIEA (26 g, 201.18 mmol, 2.50 equiv). The resulting solution was
stirred overnight at 85.degree. C. The resulting mixture was
concentrated under vacuum. The solids were collected by filtration
to yield tert-butyl
4-([5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-nitrophenyl]amino)-
piperidine-1-carboxylate as a yellow solid. LC/MS (ES, m/z): 614
[M+H]+.
Step 4: Synthesis of tert-butyl
4-([2-amino-5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]phenyl]amino)-
piperidine-1-carboxylate
[0397] Into a 500-mL round-bottom flask, was placed a solution of
tert-butyl
4-([5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-nitrophenyl]amino)-
piperidine-1-carboxylate (31 g, 25.22 mmol, 1.00 equiv, 50%) in
methanol/THF (200/100 mL) and Raney Ni (20 g). The resulting
solution was stirred overnight at room temperature. The resulting
mixture was concentrated under vacuum to yield tert-butyl
4-([2-amino-5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]phenyl]amino)-
piperidine-1-carboxylate as a red solid. LC/MS (ES, m/z): 584
[M+H]+.
Step 5: Synthesis of tert-butyl
4-([5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-cyclopropaneamidop-
henyl]amino)piperidine-1-carboxylate
[0398] Into a 25-mL round-bottom flask, was placed a solution of
tert-butyl
4-([2-amino-5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]phenyl]amino)-
piperidine-1-carboxylate (24 g, 41.06 mmol, 1.00 equiv) in
dichloromethane (400 ml), cyclopropanecarbonyl chloride (4.2 g,
40.18 mmol, 1.00 equiv) and triethylamine (15 g, 148.24 mmol, 3.00
equiv). The resulting solution was stirred overnight at room
temperature. The resulting mixture was concentrated under vacuum to
yield tert-butyl
4-([5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-cyclopropaneamidop-
henyl]amino)piperidine-1-carboxylate as red oil. LC/MS (ES, m/z):
652 [M+H]+.
Step 6: Synthesis of tert-butyl
4-[6-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-cyclopropyl-1H-1,3--
benzodiazol-1-yl]piperidine-1-carboxylate
[0399] Into a 500-mL round-bottom flask, was placed a solution of
tert-butyl
4-([5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-cyclopropaneamidop-
henyl]amino)piperidine-1-carboxylate (25 g, 38.31 mmol, 1.00 equiv)
in acetic acid (300 mL). The resulting solution was stirred for 3 h
at 120.degree. C. The resulting mixture was concentrated under
vacuum to yield tert-butyl
4-[6-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-cyclopropyl-1H-1,3--
benzodiazol-1-yl]piperidine-1-carboxylate as red oil. LC/MS (ES,
m/z): 634 [M+H]+.
Step 7: Synthesis of
2-(1-[1-[(tert-butoxy)carbonyl]piperidin-4-yl]-2-cyclopropyl-1H-1,3-benzo-
diazol-6-yl)-2,2-bis(4-chlorophenyl)acetic acid
[0400] Into a 1000-mL round-bottom flask, was placed a solution of
tert-butyl
4-[6-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-cyclopropyl-1H-1,3--
benzodiazol-1-yl]piperidine-1-carboxylate (26 g, 40.97 mmol, 1.00
equiv) in tetrahydrofuran/MeOH (150/150 mL) and sodium hydroxide
(3N) (300 mL). The resulting solution was stirred for 4 h at
50.degree. C. The pH value of the solution was adjusted to pH 6
with hydrogen chloride (12 mol/L). The resulting solution was
extracted with ethyl acetate (3.times.500 mL) and the organic
layers combined to yield
2-(1-[1-[(tert-butoxy)carbonyl]piperidin-4-yl]-2-cyclopropyl-1H-1,3-benzo-
diazol-6-yl)-2,2-bis(4-chlorophenyl)acetic acid as red oil. LC/MS
(ES, m/z): 620 [M+H]+.
Step 8: Synthesis of tert-butyl
4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]pi-
peridine-1-carboxylate
[0401] Into a 500-mL round-bottom flask, was placed a solution of
2-(1-[1-[(tert-butoxy)carbonyl]piperidin-4-yl]-2-cyclopropyl-1H-1,3-benzo-
diazol-6-yl)-2,2-bis(4-chlorophenyl)acetic acid (23 g, 37.06 mmol,
1.00 equiv) in toluene (200 mL) and DBU (36 g, 236.47 mmol, 6.00
equiv). The resulting solution was stirred for 3 h at 90.degree. C.
The resulting mixture was concentrated under vacuum. The residue
was applied onto a silica gel column with DCM:MeOH (1:10) to yield
tert-butyl
4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]pi-
peridine-1-carboxylate as a light-yellow solid. LC/MS (ES, m/z):
576 [M+H]+.
Step 9: Synthesis of
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-(piperidin-4-yl)-1H-1,3-ben-
zodiazole
[0402] Into a 500-mL round-bottom flask, was placed a solution of
tert-butyl
4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]pi-
peridine-1-carboxylate (24 g, 41.63 mmol, 1.00 equiv) in
dichloromethane (100 mL) and CF.sub.3COOH (20 g, 175.41 mmol, 4.21
equiv). The resulting solution was stirred overnight at room
temperature. The resulting mixture was concentrated under vacuum.
The reaction was then quenched by the addition of water (100 mL).
The pH value of the solution was adjusted to pH 8 with sodium
carbonate (100%). The resulting solution was extracted with DCM
(3.times.100 mL) and the organic layers combined and dried over
anhydrous sodium sulfate, then concentrated under vacuum to yield
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-(piperidin-4-yl)-1H-1,3-ben-
zodiazole as a red solid. LC/MS (ES, m/z): 476 [M+H]+.
Step 10: Synthesis of
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)benzoic acid
[0403] Into a 8-mL vial, was placed a solution of
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-(piperidin-4-yl)-1H-1,3-ben-
zodiazole (200 mg, 0.42 mmol, 1.00 equiv) in tetrahydrofuran (4
mL), triethylamine (85 mg, 0.84 mmol, 2.00 equiv) and
4-(chlorosulfonyl)benzoic acid (93 mg, 0.42 mmol, 1.00 equiv). The
resulting solution was stirred overnight at room temperature. The
resulting mixture was concentrated under vacuum. The product
residue was purified by Prep-HPLC with the following conditions
(Waters-2767-1): Column, Column, Column, Sunfire prep C18.5 um,
19*100 mm; mobile phase, water in 0.05% TFA and CH.sub.3CN (45%
CH.sub.3CN up to 65% in 8 min, up to 100% in 9 min, down to 45% in
10 min; Detector, UV 254 nm to yield
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)benzoic acid as a white solid.
[0404] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.: 8.29 (d, J=8.1
Hz, 2H), 7.98 (d, J=8.1 Hz, 2H), 7.78 (s, 1H), 7.65 (d, J=8.4 Hz,
1H), 7.34-7.37 (m, 5H), 7.13-7.15 (m, 4H), 5.88 (s, 1H), 4.07 (d,
J=10.8 Hz, 2H), 2.47-2.74 (m, 5H), 2.13-2.16 (m, 2H), 1.26-1.42 (m,
4H). LC/MS (ES, m/z): 660 [M+H]+.
Example PH-2
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-(methylsulfonyl)piperidin-
-4-yl)-1H-benzo[d]imidazole
##STR00210##
[0406] The title compound was prepared according to the procedure
as described in Example PH-1 substituting methanesulfonyl chloride
for 4-(chlorosulfonyl)benzoic acid in Step 10.
[0407] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 7.61 (d, J=8.4
Hz, 1H), 7.25-7.28 (m, 4H), 7.18 (s, 1H), 7.02-7.04 (m, 4H), 6.92
(d, J=8.4 Hz, 1H), 5.62 (s, 1H), 4.52-4.60 (m, 1H), 4.05 (d, J=12.6
Hz, 2H), 2.86-2.93 (m, 5H), 2.49-2.62 (m, 2H), 1.89-2.03 (m, 3H),
1.20-1.24 (m, 2H), 1.12-1.17 (m, 2H). LC/MS (ES, m/z): 554
[M+H]+.
Example PH-3
4-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)piperidin-1-yl)-4-oxobutanamide
##STR00211##
[0408] Step 1: Synthesis of ethyl
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidin-1-yl)-4-oxobutanoate
[0409] Into a 100-mL round-bottom flask, was placed a solution of
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-(piperidin-4-yl)-1H-1,3-ben-
zodiazole (100 mg, 0.21 mmol, 1.00 equiv) in CH.sub.3CN (10 mL),
potassium carbonate (87 mg, 0.63 mmol, 3.00 equiv) and ethyl
4-chloro-4-oxobutanoate (41.25 mg, 0.25 mmol, 1.20 equiv). The
resulting solution was stirred overnight at room temperature. The
reaction was then quenched by the addition of water (10 mL). The
resulting solution was extracted with DCM (3.times.10 mL) and the
organic layers combined, then dried over anhydrous sodium sulfate
and concentrated under vacuum to yield ethyl
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidin-1-yl)-4-oxobutanoate as a white solid.
Step 2: Synthesis of
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidin-1-yl)-4-oxobutanamide
[0410] Into a 30-mL sealed tube, was placed a solution of ethyl
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidin-1-yl)-4-oxobutanoate (100 mg, 0.17 mmol, 1.00 equiv) in
methanol/NH.sub.3 (10 mL). The resulting solution was stirred for 1
min at 70.degree. C. The resulting mixture was concentrated under
vacuum. The product residue was purified by Prep-HPLC with the
following conditions (Waters-2767-1): Column, Sunfire prep C18.5
um, 19*100 mm; mobile phase, water in 0.05% NH.sub.4HCO.sub.3 and
CH.sub.3CN (30% CH.sub.3CN up to 80% in 7 min, up to 100% in 9 min,
down to 65% in 11 min); Detector, UV 254 nm to yield
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidin-1-yl)-4-oxobutanamide as a white solid.
[0411] .sup.1H NMR (300 MHz, CD3OD) .delta.: 7.48 (d, J=9.3 Hz,
1H), 7.30-7.33 (m, 5H), 7.09-7.12 (m, 4H), 6.97 (d, J=8.4 Hz, 1H),
5.77 (s, 1H), 4.87-4.95 (m, 1H), 4.73 (d, J=12.0 Hz, 1H), 4.21 (d,
J=15.3 Hz, 1H), 3.30-3.35 (m, 1H), 2.59-2.83 (m, 5H), 2.22-2.40 (m,
3H), 1.90-2.10 (m, 2H), 1.12-1.17 (m, 4H). LC/MS (ES, m/z): 575
[M+H]+.
Example PH-4
1-[1-(benzenesulfonyl)piperidin-4-yl]-6-[bis(4-chlorophenyl)methyl]-2-cycl-
opropyl-1H-1,3-benzodiazole
##STR00212##
[0413] The title compound was prepared according to the procedure
as described in Example PH-1 substituting benzenesulfonyl chloride
for 4-(chlorosulfonyl)benzoic acid in Step 10.
[0414] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 7.82 (d, J=6.9
Hz, 1H), 7.56-7.68 (m, 4H), 7.22-7.32 (m, 5H), 7.01-7.04 (m, 4H),
6.90 (d, J=8.1 Hz, 1H), 5.61 (s, 1H), 4.34-4.42 (m, 1H), 4.08 (d,
J=11.1 Hz, 2H), 2.43-2.64 (m, 4H), 1.80-1.99 (m, 3H), 1.20-1.30 (m,
2H), 1.02-1.12 (m, 2H). LC/MS (ES, m/z): 616 [M+H]+.
Example PH-5
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-(4-fluorophenylsulfonyl)p-
iperidin-4-yl)-1H-benzo[d]imidazole
##STR00213##
[0416] The title compound was prepared according to the procedure
as described in Example PH-1 substituting
4-fluorobenzene-1-sulfonyl chloride for 4-(chlorosulfonyl)benzoic
acid in Step 10.
[0417] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 7.84-7.89 (m,
2H), 7.64 (d, J=8.4 Hz, 1H), 7.24-7.32 (m, 7H), 7.04-7.07 (m, 4H),
6.94 (d, J=8.1 Hz, 1H), 5.64 (s, 1H), 4.39-4.46 (m, 1H), 4.09 (d,
J=11.4 Hz, 2H), 2.46-2.68 (m, 4H), 1.90-2.03 (m, 3H), 1.23-1.33 (m,
2H), 1.06-1.12 (m, 2H). LC/MS (ES, m/z): 634 [M+H]+.
Example PH-6
6-(bis(4-chlorophenyl)methyl)-1-(1-(4-chlorophenylsulfonyl)piperidin-4-yl)-
-2-cyclopropyl-1H-benzo[d]imidazole
##STR00214##
[0419] The title compound was prepared according to the procedure
as described in Example PH-1 substituting
4-chlorobenzene-1-sulfonyl chloride for 4-(chlorosulfonyl)benzoic
acid in Step 10.
[0420] .sup.1H NMR (300 MHz, DMSO-d6) .delta.: 7.84 (dd, J1=2.1 Hz,
J2=6.6 Hz, 2H), 7.77 (dd, J1=2.1 Hz, J2=6.6 Hz, 2H), 7.52 (s, 1H),
7.35-7.43 (m, 5H), 7.12-7.14 (m, 4H), 6.81 (d, J=8.7 Hz, 1H), 5.82
(s, 1H), 4.64-4.74 (m, 1H), 3.84 (d, J=11.1 Hz, 2H), 2.51-2.61 (m,
2H), 2.35-2.42 (m, 2H), 2.14-2.20 (m, 1H), 1.85-1.95 (m, 2H),
0.96-0.98 (m, 4H). LC/MS (ES, m/z): 651 [M+H]+.
Example PH-7
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-(4-methoxyphenylsulfonyl)-
piperidin-4-yl)-1H-benzo[d]imidazole
##STR00215##
[0422] The title compound was prepared according to the procedure
as described in Example PH-1 substituting
4-methoxybenzene-1-sulfonyl chloride for 4-(chlorosulfonyl)benzoic
acid in Step 10.
[0423] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 7.78 (d, J=9.0
Hz, 2H), 7.66 (d, J=8.4 Hz, 1H), 7.28-7.31 (m, 5H), 7.04-7.08 (m,
6H), 6.94 (d, J=8.4 Hz, 1H), 5.64 (s, 1H), 4.36-4.46 (m, 1H), 4.07
(d, J=11.1 Hz, 2H), 3.93 (s, 3H), 2.44-2.64 (m, 4H), 1.90-2.01 (m,
3H), 1.15-1.35 (m, 3H), 1.11-1.18 (m, 2H). LC/MS (ES, m/z): 646
[M+H]+.
Example PH-8
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-(4
(trifluoromethyl)phenylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole
##STR00216##
[0425] The title compound was prepared according to the procedure
as described in Example PH-1 substituting
4-(trifluoromethyl)benzene-1-sulfonyl chloride
4-(chlorosulfonyl)benzoic acid in Step 10.
[0426] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 7.90-8.01 (m,
2H), 7.84-7.87 (m, 2H), 7.62 (d, J=8.4 Hz, 1H), 7.22-7.26 (m, 5H),
7.01-7.08 (m, 4H), 6.92 (d, J=9.0 Hz, 1H), 5.62 (s, 1H), 4.40-4.50
(m, 1H), 4.09 (d, J=10.8 Hz, 2H), 2.45-2.66 (m, 4H), 1.98-2.02 (m,
2H), 1.85-1.95 (m, 1H), 1.20-1.35 (m, 2H), 1.07-1.15 (m, 2H). LC/MS
(ES, m/z): 684 [M+H]+.
Example PH-9
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-(4-(trifluoromethoxy)phen-
ylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole
##STR00217##
[0428] The title compound was prepared according to the procedure
as described in Example PH-1 substituting
4-(trifluoromethoxy)benzene-1-sulfonyl chloride for
4-(chlorosulfonyl)benzoic acid in Step 10.
[0429] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 7.87 (d, J=8.7
Hz, 2H), 7.61-7.66 (m, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.24-7.28 (m,
5H), 7.01-7.04 (m, 4H), 6.93 (d, J=7.8 Hz, 2H), 5.62 (s, 1H),
4.39-4.47 (m, 1H), 4.08 (d, J=11.4 Hz, 2H), 2.45-2.67 (m, 4H),
1.92-2.02 (m, 3H), 1.25-1.35 (m, 2H), 1.10-1.15 (m, 2H). LC/MS (ES,
m/z): 700 [M+H]+.
Example PH-10
4-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)piperidin-1-ylsulfonyl)benzamide 2,2,2-trifluoroacetate
##STR00218##
[0431] Into a 8-mL vial, was placed solution of
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)benzoic acid (45 mg, 0.07 mmol, 1.00 equiv)
in N,N-dimethylformamide (4 mL), HATU (31 mg, 0.08 mmol, 5.00
equiv), NH.sub.4Cl (18 mg, 0.34 mmol, 1.20 equiv) and DIEA (26 mg,
0.20 mmol, 3.00 equiv). The resulting solution was stirred
overnight at room temperature. The resulting mixture was
concentrated under vacuum. The product residue was purified by
Prep-HPLC with the following conditions (Waters-2767-1): Column,
Sunfire prep C18.5 um, 19*100 mm; mobile phase, water in 0.05% TFA
and CH.sub.3CN (50% CH.sub.3CN up to 70% in 5 min, up to 100% in 7
min, down to 50% in 9 min); Detector, UV 254 nm to yield
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)benzamide trifluoroacetic acid as a white
solid.
[0432] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 8.13 (d, J=8.4
Hz, 2H), 7.96 (d, J=8.4 Hz, 2H), 7.78 (s, 1H), 7.64 (d, J=8.8 Hz,
1H), 7.34-7.37 (m, 5H), 7.14-7.16 (m, 4H), 5.88 (s, 1H), 4.88-4.93
(m, 1H), 4.07 (d, J=10.8 Hz, 2H), 2.66-2.72 (m, 2H), 2.44-2.60 (m,
3H), 2.13-2.16 (m, 2H), 1.40-1.42 (m, 2H), 1.26-1.29 (m, 2H). LC/MS
(ES, m/z): 659 [M+H]+.
Example PH-11
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-(3-(trifluoromethyl)pheny-
lsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole
##STR00219##
[0434] The title compound was prepared according to the procedure
as described in Example PH-1 substituting
3-(trifluoromethyl)benzene-1-sulfonyl chloride for
4-(chlorosulfonyl)benzoic acid in Step 10.
[0435] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 8.07 (s, 1H),
8.02 (d, J=7.8 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.75 (t, J=8.1 Hz,
1H), 7.60-7.64 (m, 1H), 7.23-7.29 (m, 5H), 7.01-7.08 (m, 4H), 6.94
(d, J=8.7 Hz, 1H), 5.62 (s, 1H), 4.38-4.48 (m, 1H), 4.10 (d, J=11.7
Hz, 2H), 2.46-2.67 (m, 4H), 1.96-2.04 (m, 2H), 1.89-1.93 (m, 1H),
1.25-1.36 (m, 2H), 1.12-1.18 (m, 2H). LC/MS (ES, m/z): 684
[M+H]+.
Example PH-12
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-(3-methoxyphenylsulfonyl)-
piperidin-4-yl)-1H-benzo[d]imidazole 2,2,2-trifluoroacetate
##STR00220##
[0437] The title compound was prepared according to the procedure
as described in Example PH-1 substituting
3-methoxybenzene-1-sulfonyl chloride for 4-(chlorosulfonyl)benzoic
acid in Step 10.
[0438] .sup.1H NMR (400 MHz, CD3OD) .delta.: 7.76 (s, 1H), 7.64 (d,
J=8.8 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H),
7.27-7.36 (m, 7H), 7.13-7.15 (m, 4H), 5.87 (s, 1H), 4.87-4.94 (m,
1H), 4.04 (d, J=12.4 Hz, 2H), 3.90 (s, 3H), 2.52-2.68 (m, 2H),
2.43-2.47 (m, 3H), 2.11-2.14 (m, 2H), 1.30-1.41 (m, 2H), 1.27-1.29
(m, 2H). LC/MS (ES, m/z): 646 [M+H]+.
Example PH-13
3-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)piperidin-1-yl)sulfonyl)benzamide 2,2,2-trifluoroacetate
##STR00221##
[0439] Step 1: Synthesis of 3-(4-[6-(bis (4-chlorophenyl)
methyl]-2-cyclopropyl-1H-1, 3-benzodiazol-1-yl
piperidine-1-sulfonyl) benzoic acid
[0440] Into a 8-mL vial, was placed a solution of
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-(piperidin-4-yl)-1H-1,3-ben-
zodiazole (150 mg, 0.31 mmol, 1.00 equiv) in tetrahydrofuran (4
mL), triethylamine (65 mg, 0.64 mmol, 2.00 equiv) and
3-(chlorosulfonyl)benzoic acid (70 mg, 0.32 mmol, 1.00 equiv). The
resulting solution was stirred overnight at room temperature. The
resulting mixture was concentrated under vacuum to yield
3-(4-[6-[bis (4-chlorophenyl) methyl]-2-cyclopropyl-1H-1,
3-benzodiazol-1-yl] piperidine-1-sulfonyl) benzoic acid as a white
solid. LC/MS (ES, m/z): 661 [M+H]+.
Step 2: Synthesis of 3-(4-[6-[bis (4-chlorophenyl)
methyl]-2-cyclopropyl-1H-1, 3-benzodiazol-1-yl]
piperidine-1-sulfonyl) benzamide trifluoroacetic acid
[0441] Into a 8-mL vial, was placed a solution of
3-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)benzoic acid (200 mg, 0.30 mmol, 1.00 equiv)
in N,N-dimethylformamide (4 mL), NH.sub.4Cl (80 mg, 1.50 mmol, 5.00
equiv), HATU (138 mg, 0.36 mmol, 1.20 equiv) and DIEA (117 mg, 0.91
mmol, 3.00 equiv). The resulting solution was stirred overnight at
room temperature. The resulting mixture was concentrated under
vacuum. The product residue was purified by Prep-HPLC with the
following conditions (Waters-2767-1): Column, Sunfire prep C18.5
um, 19*100 mm; mobile phase, water in 0.05% TFA and CH.sub.3CN (40%
CH.sub.3CN up to 60% in 6 min, up to 100% in 8 min, down to 55% in
10 min); Detector, UV 254 nm to yield 3-(4-[6-[bis (4-chlorophenyl)
methyl]-2-cyclopropyl-1H-1, 3-benzodiazol-1-yl]
piperidine-1-sulfonyl) benzamide trifluoroacetic acid as a white
solid.
[0442] .sup.1H NMR (300 MHz, CD3OD) .delta.: 8.36 (s, 1H), 8.21 (d,
J=7.8 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.74-7.79 (m, 2H), 7.63 (d,
J=8.4 Hz, 1H), 7.29-7.36 (m, 5H), 7.12-7.15 (m, 4H), 5.87 (s, 1H),
4.87-4.94 (m, 1H), 4.07 (d, J=11.4 Hz, 2H), 2.39-2.73 (m, 5H),
2.11-2.14 (m, 2H), 1.30-1.42 (m, 2H), 1.25-1.29 (m, 2H). LC/MS (ES,
m/z): 649 [M+H]+.
Example PH-14
3-(4-(6-(bis (4-chlorophenyl)
methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)
piperidin-1-ylsulfonyl) phenol 2, 2, 2-trifluoroacetate
##STR00222##
[0443] Step 1: Synthesis of 6-[bis (4-chlorophenyl)
methyl]-2-cyclopropyl-1-[1-[(3-methoxybenzene) sulfonyl]
piperidin-4-yl]-1H-1, 3-benzodiazole
[0444] Into a 25-mL round-bottom flask, was placed
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-(piperidin-4-yl)-1H-1,3-ben-
zodiazole (400 mg, 0.84 mmol, 1.00 equiv),
3-methoxybenzene-1-sulfonyl chloride (190 mg, 0.92 mmol, 1.10
equiv) and a solution of triethylamine (254 mg, 2.51 mmol, 2.99
equiv) in dichloromethane (10 mL). The resulting solution was
stirred for 2 h at room temperature. The resulting mixture was
concentrated under vacuum to yield 6-[bis (4-chlorophenyl)
methyl]-2-cyclopropyl-1-[1-[(3-methoxybenzene)
sulfonyl]piperidin-4-yl]-1H-1, 3-benzodiazole as yellow oil. LC/MS
(ES, m/z): 647 [M+H]+.
Step 2: Synthesis of
3-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)phenol trifluoroacetic acid
[0445] Into a 50-mL round-bottom flask, was placed a solution of
6-[bis (4-chlorophenyl)
methyl]-2-cyclopropyl-1-[1-[(3-methoxybenzene) sulfonyl]
piperidin-4-yl]-1H-1, 3-benzodiazole (200 mg, 0.31 mmol, 1.00
equiv) in dichloromethane (5 ml) and BBr.sub.3 (0.29 mL, 10.00
equiv). The resulting solution was stirred for 4 h at room
temperature. The pH value of the solution was adjusted to pH 7 with
sodium bicarbonate (100%). The resulting solution was extracted
with DCM (3.times.5 mL) and the organic layers combined and
concentrated under vacuum. The product residue was purified by
Prep-HPLC with the following conditions (Waters-2767-1): Column,
Sunfire prep C18.5 um, 19*100 mm; mobile phase, water in 0.05% TFA
and CH.sub.3CN (50% CH.sub.3CN up to 65% in 6 min, up to 100% in 2
min, down to 50% in 2 min); Detector, UV 254 nm to yield
3-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)phenol trifluoroacetic acid as a white
solid.
[0446] .sup.1H NMR (300 MHz, CD3OD) .delta.: 7.79 (s, 1H), 7.65 (d,
J=8.4 Hz, 1H), 7.46 (t, J=8.1 Hz, 1H), 7.29-7.37 (m, 6H), 7.24 (t,
J=2.1 Hz, 1H), 7.09-7.16 (m, 5H), 5.89 (s, 1H), 4.87-4.93 (m, 1H),
4.02 (d, J=12.3 Hz, 2H), 2.66-2.74 (m, 2H), 2.45-2.60 (m, 3H),
2.12-2.16 (m, 2H), 1.40-1.47 (m, 2H), 1.33-1.36 (m, 2H). LC/MS (ES,
m/z): 632 [M+H]+.
Example PH-15
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-(2-(trifluoromethyl)pheny-
lsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole
##STR00223##
[0448] The title compound was prepared according to the procedure
as described in Example PH-1 substituting 2-(trifluoromethyl)
benzene-1-sulfonyl chloride for 4-(chlorosulfonyl) benzoic acid in
Step 10.
[0449] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 8.22-8.26 (m,
1H), 7.91-7.94 (m, 1H), 7.73-7.76 (m, 2H), 7.62 (d, J=7.5 Hz, 1H),
7.23-7.28 (m, 5H), 7.03-7.06 (m, 4H), 6.94 (d, J=8.7 Hz, 1H), 5.59
(s, 1H), 4.51-4.61 (m, 1H), 4.02 (d, J=13.2 Hz, 2H), 2.89-2.97 (m,
2H), 2.53-2.58 (m, 2H), 1.93-1.97 (m, 3H), 1.20-1.30 (m, 2H),
1.11-1.18 (m, 2H). LC/MS (ES, m/z): 684 [M+H]+.
Example PH-16
6-(bis(4-chlorophenyl
methyl)-2-cyclopropyl-1-(1-(2-methoxyphenylsulfonyl)piperidin-4-yl)-1H-be-
nzo[d]imidazole
##STR00224##
[0451] The title compound was prepared according to the procedure
as described in Example PH-1 substituting
2-methoxybenzene-1-sulfonyl chloride for 4-(chlorosulfonyl)benzoic
acid in Step 10.
[0452] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 7.94 (d, J=7.8
Hz, 1H), 7.54-7.66 (m, 2H), 7.23-7.28 (m, 5H), 7.01-7.11 (m, 6H),
6.92 (d, J=8.1 Hz, 1H), 5.60 (s, 1H), 4.45-4.55 (m, 1H), 4.15 (d,
J=11.1 Hz, 2H), 3.92 (s, 3H), 2.79-2.86 (m, 2H), 2.47-2.58 (m, 2H),
1.93-1.97 (m, 3H), 1.25-1.35 (m, 2H), 1.14-1.19 (m, 2H). LC/MS (ES,
m/z): 646 [M+H]+.
Example PH-17
2-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)piperidin-1-ylsulfonyl)phenol 2,2,2-trifluoroacetate
##STR00225##
[0454] The title compound was prepared according to the procedure
as described in Example PH-14 substituting
2-methoxybenzene-1-sulfonyl chloride for
3-methoxybenzene-1-sulfonyl chloride in Step 1.
[0455] .sup.1H NMR (400 MHz, CD3OD) .delta.: 7.76-7.80 (m, 2H),
7.64 (d, J=8.4 Hz, 1H), 7.49-7.52 (m, 1H), 7.32-7.37 (m, 5H),
7.13-7.15 (m, 4H), 7.01-7.04 (m, 2H), 5.86 (s, 1H), 4.90-4.99 (m,
1H), 4.11 (d, J=11.2 Hz, 2H), 2.94-3.01 (m, 2H), 2.50-2.56 (m, 3H),
2.10-2.12 (m, 2H), 1.41-1.43 (m, 2H), 1.29-1.30 (m, 2H). LC/MS (ES,
m/z): 632 [M+H]+.
Example PH-18
2-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)piperidin-1-ylsulfonyl)benzamide 2,2,2-trifluoroacetate
##STR00226##
[0456] Step 1: Synthesis of methyl
2-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)benzoate
[0457] Into a 8-mL vial, was placed a solution of
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-(piperidin-4-yl)-1H-1,3-ben-
zodiazole (150 mg, 0.31 mmol, 1.00 equiv) in CH.sub.3CN (5 ml),
potassium carbonate (131 mg, 0.95 mmol, 3.00 equiv) and methyl
2-(chlorosulfonyl)benzoate (89 mg, 0.38 mmol, 1.20 equiv). The
resulting solution was stirred overnight at room temperature. The
reaction was then quenched by the addition of water (5 mL). The
resulting solution was extracted with DCM (3.times.5 mL) and the
organic layers combined and dried over anhydrous sodium sulfate,
then concentrated under vacuum to yield methyl
2-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)benzoate as a white solid. LC/MS (ES, m/z):
674 [M+H]+.
Step 2: Synthesis of
2-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)benzoic acid
[0458] Into a 50-mL round-bottom flask, was placed a solution of
methyl
2-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)benzoate (150 mg, 0.22 mmol, 1.00 equiv) in
methanol/THF (5/1 mL), sodiumol (5 mL, 3N). The resulting solution
was stirred overnight at room temperature. The pH value of the
solution was adjusted to pH 6 with hydrogen chloride (3 mol/L). The
resulting solution was extracted with DCM (3.times.10 mL) and the
organic layers combined, then dried over anhydrous sodium sulfate
to yield
2-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)benzoic acid as colorless oil.
Step 3: Synthesis of
2-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)benzamide trifluoroacetic acid
[0459] Into a 8-mL vial, was placed a solution of
2-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)benzoic acid (150 mg, 0.23 mmol, 1.00 equiv)
in N,N-dimethylformamide (4 ml), NH.sub.4Cl (60 mg, 1.12 mmol, 5.00
equiv), HATU (104 mg, 0.27 mmol, 1.20 equiv) and DIEA (88 mg, 0.68
mmol, 3.00 equiv). The resulting solution was stirred overnight at
room temperature. The product residue was purified by Prep-HPLC
with the following conditions (Waters-2767-1): Column, Sunfire prep
C18.5 um, 19*100 mm; mobile phase, water in 0.05% TFA and
CH.sub.3CN (40% CH.sub.3CN up to 50% in 6 min, up to 100% in 7 min,
down to 40% in 8 min); Detector, UV254 nm to yield
2-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodi-
azol-1-yl]piperidine-1-sulfonyl)benzamide trifluoroacetic acid as a
white solid.
[0460] .sup.1H NMR (300 MHz, CD3OD) .delta.: 8.04 (d, J=7.8 Hz,
1H), 7.95 (s, 1H), 7.60-7.76 (m, 4H), 7.33-7.37 (m, 5H), 7.14-7.17
(m, 4H), 5.87 (s, 1H), 5.00-5.08 (m, 1H), 4.04 (d, J=13.5 Hz, 2H),
2.99-3.07 (m, 2H), 2.51-2.63 (m, 3H), 2.06-2.11 (m, 2H), 1.42-1.49
(m, 2H), 1.28-1.33 (m, 2H). LC/MS (ES, m/z): 659 [M+H]+.
Example PH-19
4-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)piperidin-1-ylsulfonyl)phenol hydrochloride
##STR00227##
[0462] The title compound was prepared according to the procedure
as described in Example PH-1 substituting
4-hydroxybenzene-1-sulfonyl chloride for 4-(chlorosulfonyl)benzoic
acid in Step 10.
[0463] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.81 (s, 1H),
7.65-7.72 (m, 3H), 7.34-7.36 (m, 5H), 7.14-7.16 (m, 4H), 7.00 (d,
J=8.8 Hz, 2H), 5.87 (s, 1H), 4.87-4.95 (m, 1H), 4.00 (d, J=12.0 Hz,
2H), 2.47-2.68 (m, 5H), 2.11-2.14 (m, 2H), 1.42-1.47 (m, 2H),
1.30-1.34 (m, 2H). LC/MS (ES, m/z): 632 [M+H]+.
Example PH-20
2-(4-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-3aH-benzo[d]imidazol--
1(7aH)-yl)piperidin-1-ylsulfonyl)phenoxy)acetamide
2,2,2-trifluoroacetate
##STR00228##
[0464] Step 1: Synthesis of ethyl
2-[4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-
-yl]piperidin-1-yl)phenoxy]acetate
[0465] Into a 50-mL round-bottom flask, was placed a solution of
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)phenol (266 mg, 0.42 mmol, 1.00 equiv) in
N,N-dimethylformamide (10 mL), ethyl 2-bromoacetate (105 mg, 0.63
mmol, 1.50 equiv) and potassium carbonate (174 mg, 1.26 mmol, 3.00
equiv). The resulting solution was stirred overnight at room
temperature. The reaction was then quenched by the addition of
water (10 mL). The resulting solution was extracted with DCM
(3.times.10 mL) and the organic layers combined, then dried over
anhydrous sodium sulfate and concentrated under vacuum to yield
ethyl
2-[4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-
-yl]piperidin-1-yl)phenoxy]acetate as a white solid.
Step 2: Synthesis of
2-[4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-
-yl]piperidine-1-sulfonyl)phenoxy]acetamide; trifluoroacetic
acid
[0466] Into a 30-mL sealed tube, was placed a solution of ethyl
2-[4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-
-yl]piperidine-1-sulfonyl)phenoxy]acetate (100 mg, 0.14 mmol, 1.00
equiv) in methanol/NH.sub.3 (20 mL). The resulting solution was
stirred for 1 overnight at room temperature. The resulting mixture
was concentrated under vacuum. The product residue was purified by
Prep-HPLC with the following conditions (Waters-2767-1): Column,
Column, Sunfire prep C18.5 um, 19*100 mm; mobile phase, water in
0.05% TFA and CH.sub.3CN (30% CH.sub.3CN up to 55% in 10 min, up to
100% in 12 min, down to 50% in 14 min; Detector, UV 254 nm to yield
2-[4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-
-yl]piperidine-1-sulfonyl)phenoxy]acetamide; trifluoroacetic acid
as an off-white solid.
[0467] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.: 7.81-7.84 (m,
3H), 7.65 (d, J=8.7 Hz, 1H), 7.34-7.37 (m, 5H), 7.23-7.26 (m, 2H),
7.13-7.16 (m, 4H), 5.88 (s, 1H), 4.81-4.91 (m, 1H), 3.99-4.12 (m,
2H), 2.50-2.68 (m, 5H), 2.11-2.16 (m, 2H), 1.41-1.47 (m, 2H),
1.30-1.38 (m, 2H). LC/MS (ES, m/z): 689 [M+H]+.
Example PH-21
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-3-(1-(trifluoromethylsulfonyl)pip-
eridin-4-yl)-3H-benzo[d]imidazol-5-yl)acetic acid hydrochloride
##STR00229##
[0469] The title compound was prepared according to the procedure
as described in Example PH-23 substituting cyclopropanecarbonyl
chloride for propanoyl chloride in Step 4.
[0470] .sup.1H NMR (400 MHz, DMSO-d6) .delta.: 7.46 (d, J=8.4 Hz,
1H), 7.38-7.40 (m, 4H), 7.30 (s, 1H), 7.16-7.19 (m, 4H), 6.88 (d,
J=8.4 Hz, 1H), 4.93-5.03 (m, 1H), 3.93 (d, J=12.8 Hz, 2H),
3.45-3.52 (m, 2H), 2.31-2.34 (m, 1H), 2.01-2.12 (m, 4H), 1.01-1.07
(m, 4H). LC/MS (ES, m/z): 652 [M+H]+.
Example PH-22
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-(trifluoromethylsulfonyl)-
piperidin-4-yl)-1H-benzo[d]imidazole hydrochloride
##STR00230##
[0472] The title compound was prepared according to the procedure
as described in Example PH-1 substituting trifluoromethanesulfonic
anhydride for 4-(chlorosulfonyl)benzoic acid in Step 10.
[0473] .sup.1H NMR (300 MHz, DMSO-d6) .delta.: 7.69-7.80 (m, 2H),
7.39-7.42 (m, 4H), 7.24 (d, J=8.7 Hz, 1H), 7.12-7.15 (m, 4H), 5.96
(s, 1H), 5.14-5.22 (m, 1H), 4.01 (d, J=12.6 Hz, 2H), 3.70-3.77 (m,
2H), 2.57-2.66 (m, 1H), 2.18-2.40 (m, 4H), 1.34-1.42 (m, 4H). LC/MS
(ES, m/z): 608 [M+H]+.
Example PH-23
6-(bis(4-chlorophenyl)methyl)-2-ethyl-1-(1-(trifluoromethylsulfonyl)piperi-
din-4-yl)-1H-benzo[d]imidazole hydrochloride
##STR00231##
[0474] Step 1: Synthesis of methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate
[0475] Into a 1000-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of nitrogen, was placed a
solution of methyl 2,2-bis(4-chlorophenyl)acetate (50 g, 169.40
mmol, 1.00 equiv) in tetrahydrofuran (150 mL). To the mixture was
then added t-BuOK (190 mL, 1M, 1.10 equiv) dropwise with stirring
at 0.degree. C. in 20 min. The resulting solution was stirred for
30 min at 0.degree. C. To the resulting mixture was added a
solution of 2,4-difluoro-1-nitrobenzene (28 g, 176.00 mmol, 1.05
equiv) in tetrahydrofuran (150 mL) dropwise with stirring. The
resulting solution was stirred overnight at room temperature. The
mixture was concentrated under vacuum. The residue was applied onto
a silica gel column with ethyl acetate/petroleum ether (1:10) to
yield methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate as yellow
oil.
Step 2: Synthesis of methyl
2,2-bis(4-chlorophenyl)-2-(4-nitro-3-[[1-(trifluoromethane)sulfonylpiperi-
din-4-yl]amino]phenyl)acetate
[0476] Into a 1000-mL round-bottom flask, was placed a solution of
methyl 2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate
(70 g, 161.20 mmol, 1.00 equiv) in CH.sub.3CN (300 mL), DIEA (104
g, 804.70 mmol, 3.00 equiv) and
1-(trifluoromethane)sulfonylpiperidin-4-amine hydrochloride (52 g,
193.54 mmol, 1.20 equiv). The resulting solution was stirred
overnight at 85.degree. C. The reaction was then quenched by the
addition of water (200 mL). The resulting solution was extracted
with ethyl acetate (3.times.200 mL) and the organic layers
combined, then dried over anhydrous sodium sulfate to yield methyl
2,2-bis(4-chlorophenyl)-2-(4-nitro-3-[[1-(trifluoromethane)sulfonylpiperi-
din-4-yl]amino]phenyl)acetate as yellow oil.
Step 3: Synthesis of methyl
2-(4-amino-3-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]phenyl)-2-
,2-bis(4-chlorophenyl)acetate
[0477] Into a 500-mL round-bottom flask, was placed a solution of
methyl
2,2-bis(4-chlorophenyl)-2-(4-nitro-3-[[1-(trifluoromethane)sulfonylpiperi-
din-4-yl]amino]phenyl)acetate (50 g, 77.34 mmol, 1.00 equiv) in
methanol/THF (100/100 ml) and Raney Ni (2 g). To the mixture was
then introduced hydrogen. The resulting solution was stirred
overnight at room temperature to yield methyl
2-(4-amino-3-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]phenyl)-2-
,2-bis(4-chlorophenyl)acetate as a red solid.
Step 4: Synthesis of methyl
2,2-bis(4-chlorophenyl)-2-(4-propanamido-3-[[1-(trifluoromethane)sulfonyl-
piperidin-4-yl]amino]phenyl)acetate
[0478] Into a 500-mL round-bottom flask, was placed a solution of
methyl
2-(4-amino-3-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]phenyl)-2-
,2-bis(4-chlorophenyl)acetate (50 g, 81.11 mmol, 1.00 equiv) in
dichloromethane (250 mL), triethylamine (24.6 g, 243.11 mmol, 3.00
equiv) and propanoyl chloride (7.5 g, 81.06 mmol, 1.00 equiv). The
resulting solution was stirred overnight at room temperature. The
resulting mixture was concentrated under vacuum to yield methyl
2,2-bis(4-chlorophenyl)-2-(4-propanamido-3-[[1-(trifluoromethane)sulfonyl-
piperidin-4-yl]amino]phenyl)acetate as brown oil. LC/MS (ES, m/z):
672 [M+H]+.
Step 5: Synthesis of methyl
2,2-bis(4-chlorophenyl)-2-[2-ethyl-1-[1-(trifluoromethane)sulfonylpiperid-
in-4-yl]-1H-1,3-benzodiazol-6-yl]acetate
[0479] Into a 500-mL round-bottom flask, was placed a solution of
methyl
2,2-bis(4-chlorophenyl)-2-(4-propanamido-3-[[1-(trifluoromethane)sulfonyl-
piperidin-4-yl]amino]phenyl)acetate (54 g, 40.15 mmol, 1.00 equiv,
50%) in acetic acid (200 mL). The resulting solution was stirred
for 24 hrs at reflux. The resulting mixture was concentrated under
vacuum to yield methyl
2,2-bis(4-chlorophenyl)-2-[2-ethyl-1-[1-(trifluoromethane)sulfonyl-
piperidin-4-yl]-1H-1,3-benzodiazol-6-yl]acetate as brown oil. LC/MS
(ES, m/z): 654 [M+H]+.
Step 6: Synthesis of
2,2-bis(4-chlorophenyl)-2-[2-ethyl-1-[1-(trifluoromethane)sulfonylpiperid-
in-4-yl]-1H-1,3-benzodiazol-6-yl]acetic acid
[0480] Into a 1000-mL round-bottom flask, was placed a solution of
methyl
2,2-bis(4-chlorophenyl)-2-[2-ethyl-1-[1-(trifluoromethane)sulfonylpiperid-
in-4-yl]-1H-1,3-benzodiazol-6-yl]acetate (32 g, 24.45 mmol, 1.00
equiv, 50%) in tetrahydrofuran/MeOH (150/100 mL) and sodium
hydroxide (250 mL). The resulting solution was stirred overnight at
50.degree. C. The resulting solution was extracted with ethyl
acetate (3.times.250 mL) and the organic layers combined. The pH
value of the aqueous layers was adjusted to pH 2 with hydrogen
chloride (3 mol/L). The resulting solution was extracted with ethyl
acetate (100 mL) acetate and the organic layers combined to yield
2,2-bis(4-chlorophenyl)-2-[2-ethyl-1-[1-(trifluoromethane)sulfonylpiperid-
in-4-yl]-1H-1,3-benzodiazol-6-yl]acetic acid as a white solid.
LC/MS (ES, m/z): 640 [M+H]+.
Step 7: Synthesis of
6-[bis(4-chlorophenyl)methyl]-2-ethyl-1-[1-(trifluoromethane)sulfonylpipe-
ridin-4-yl]-1H-1,3-benzodiazole hydrochloride
[0481] Into a 500-mL round-bottom flask, was placed
2,2-bis(4-chlorophenyl)-2-[2-ethyl-1-[1-(trifluoromethane)sulfonylpiperid-
in-4-yl]-1H-1,3-benzodiazol-6-yl]acetic acid (30 g, 46.84 mmol,
1.00 equiv), toluene (300 mL) and DBU (42.8 g, 281.14 mmol, 6.00
equiv). The resulting solution was stirred for 3 h at 90.degree. C.
The resulting mixture was concentrated under vacuum. The resulting
solution was extracted with ethyl acetate (3.times.300 mL) and the
organic layers combined, then dried over anhydrous sodium sulfate
and concentrated under vacuum. The residue was applied onto a
silica gel column with EA:PE (1:1). The residue was dissolved in
diethyl ether/MeOH (100 mL) and reacted with hydrochloric acid to
yield the corresponding hydrochloride salt, which precipitated from
the mixture. The solids were collected by filtration. The product
was re-crystallized from ethyl ether/ethanol in the ratio of 1:10
to yield
6-[bis(4-chlorophenyl)methyl]-2-ethyl-1-[1-(trifluoromethane)sulfonylpipe-
ridin-4-yl]-1H-1,3-benzodiazole hydrochloride as an off-white
solid.
[0482] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.: 7.76 (d, J=8.7
Hz, 1H), 7.64 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.34-7.37 (m, 4H),
7.13-7.16 (m, 4H), 5.91 (s, 1H), 4.94-4.99 (m, 1H), 4.12 (d, J=13.2
Hz, 2H), 3.36-3.52 (m, 3H), 2.33-2.45 (m, 2H), 2.18-2.22 (m, 2H),
1.54 (t, J=7.5 Hz, 3H). LC/MS (ES, m/z): 596 [M+H]+.
Example PH-24
2,2-bis(4-chlorophenyl)-2-(2-ethyl-3-(1-(trifluoromethylsulfonyl)piperidin-
-4-yl)-3H-benzo[d]imidazol-5-yl)acetic acid
##STR00232##
[0484] The title compound was prepared according to the procedure
as describe din Example PH-23, Step 6.
[0485] .sup.1H NMR (300 MHz, DMSO-d6) .delta.: 7.52 (d, J=8.7 Hz,
1H), 7.37-7.48 (m, 4H), 7.31 (d, J=9.0 Hz, 1H), 7.11-7.18 (m, 4H),
6.91 (d, J=8.4 Hz, 1H), 4.61-4.71 (m, 1H), 3.90 (d, J=12.3 Hz, 2H),
3.43-3.47 (m, 2H), 2.91-2.98 (m, 2H), 1.95-2.10 (m, 4H), 1.31 (t,
J=7.5 Hz, 3H). LC/MS (ES, m/z): 640 [M+H]+.
Example PH-25
4-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)piperidine-1-carbonyl)benzamide
##STR00233##
[0487] The title compound was prepared according to the procedure
as described in Example PH-18 substituting methyl
4-(chlorocarbonyl)benzoate for methyl 2-(chlorosulfonyl)benzoate in
Step 1.
[0488] .sup.1H NMR (300 MHz, DMSO-d6) .delta.: 8.04-8.07 (m, 1H),
7.95 (d, J=8.1 Hz, 2H), 7.72-7.80 (m, 1H), 7.61-7.64 (m, 1H),
7.40-7.49 (m, 7H), 7.14-7.24 (m, 5H), 5.95 (s, 1H), 4.73-4.76 (m,
1H), 4.62-4.70 (m, 1H), 3.40-3.60 (m, 8H), 1.20-1.30 (m, 4H). LC/MS
(ES, m/z): 623 [M+H]+.
Example PH-26
1-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)piperidin-1-yl)-2-hydroxyethanone 2,2,2-trifluoroacetate
##STR00234##
[0489] Step 1: Synthesis of
2-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)-2-oxoethyl acetate
[0490] Into a 25-mL round-bottom flask, was placed
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(piperidin-4-yl)-1H-benzo[d-
]imidazole (100 mg, 0.21 mmol, 1.00 equiv), 2-chloro-2-oxoethyl
acetate (34.5 mg, 0.23 mmol, 1.09 equiv) and a solution of
triethylamine (63 mg, 0.62 mmol, 2.97 equiv) in dichloromethane (5
mL). The resulting solution was stirred for 3 h at room
temperature. The resulting mixture was concentrated under vacuum to
yield
2-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)-2-oxoethyl acetate as yellow oil. LC/MS (ES,
m/z): 576.5 [M+H]+.
Step 2: Synthesis of
1-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)-2-hydroxyethanone
[0491] Into a 25-mL round-bottom flask, was placed
2-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidin-1-yl)-2-oxoethyl acetate (110 mg, 0.19 mmol, 1.00
equiv), a solution of LiOH*H.sub.2O (48 mg, 1.14 mmol, 6.00 equiv)
in tetrahydrofuran/H.sub.2O (5/3 mL). The resulting solution was
stirred for 3 h at room temperature. The resulting solution was
extracted with ethyl acetate (3.times.10 mL) and the organic layers
combined, then dried over anhydrous sodium sulfate and concentrated
under vacuum. The product residue was purified by Prep-HPLC with
the following conditions (Waters-2767-1): Column, Sunfire prep C18,
5 um, 19*100 mm; mobile phase, 0.05% TFA in water and CH.sub.3CN
(20% CH.sub.3CN up to 65% in 8 min); Detector, 254 nm to yield
1-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)-2-hydroxyethanone as trifluoroacetic acid salt as
an off-white solid.
[0492] 1H NMR (300 MHz, DMSO-d6) .delta.: 7.78 (s, 1H), 7.62 (d,
J=8.4 Hz, 1H), 7.37-7.40 (m, 4H), 7.09-7.15 (m, 5H), 5.90 (m, 1H),
5.01-5.06 (m, 1H), 4.57-4.61 (m, 1H), 4.16 (d, J=6.3 Hz, 2H),
3.87-3.99 (m, 2H), 3.16-3.20 (m, 1H), 2.79-2.87 (m, 1H), 1.95-2.30
(m, 5H), 1.20-1.35 (m, 4H). LC/MS (ES, m/z): 534 [M+H]+.
Example PH-27
1-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)piperidin-1-yl)-3-hydroxypropan-1-one 2,2,2-trifluoroacetate
##STR00235##
[0493] Step 1: Synthesis of methyl
3-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidin-1-yl)-3-oxopropanoate
[0494] Into a 8-mL vial, was placed a solution of
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-(piperidin-4-yl)-1H-1,3-ben-
zodiazole (150 mg, 0.31 mmol, 1.00 equiv) in dichloromethane (4
mL), triethylamine (96 mg, 0.95 mmol, 3.00 equiv) and methyl
3-chloro-3-oxopropanoate (52 mg, 0.38 mmol, 1.20 equiv). The
resulting solution was stirred overnight at room temperature. The
reaction was then quenched by the addition of water (4 mL). The
resulting solution was extracted with DCM (3.times.4 mL) and the
organic layers combined, then dried over anhydrous sodium sulfate
and concentrated under vacuum to yield methyl
3-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidin-1-yl)-3-oxopropanoate as colorless oil. LC/MS (ES, m/z):
576.5 [M+H]+.
Step 2: Synthesis of
1-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidin-1-yl)-3-hydroxypropan-1-one trifluoroacetic acid
[0495] Into a 25-mL round-bottom flask, was placed a solution of
methyl
3-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidin-1-yl)-3-oxopropanoate (200 mg, 0.35 mmol, 1.00 equiv) in
tetrahydrofuran (4 ml), LiBH.sub.4 (38 mg, 5.00 equiv) and water
(0.04 mL). The resulting solution was stirred for 2 h at room
temperature. The resulting mixture was concentrated under vacuum.
The reaction was then quenched by the addition of water (10 mL).
The resulting solution was extracted with DCM (3.times.10 mL) and
the organic layers combined, then concentrated under vacuum to
yield
1-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidin-1-yl)-3-hydroxypropan-1-one trifluoroacetic acid as a
light yellow semi-solid.
[0496] .sup.1H NMR (400 MHz, CD3OD) .delta.: 7.71 (s, 1H), 7.66 (d,
J=6.3 Hz, 1H), 7.33-7.36 (m, 5H), 7.12-7.14 (m, 4H), 5.87 (s, 1H),
5.15-5.25 (m, 1H), 4.82-4.87 (m, 1H), 4.27-4.30 (m, 1H), 3.92 (t,
J=6.0 Hz, 2H), 3.33-3.41 (m, 1H), 2.83-2.93 (m, 1H), 2.59-2.73 (m,
3H), 2.12-2.44 (m, 4H), 1.47-1.52 (m, 2H), 1.32-1.36 (m, 2H).
[0497] LC/MS (ES, m/z): 548 [M+H]+.
Example PH-28
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]-
piperidine-1-sulfonyl)-2-chlorobenzoic acid; trifluoroacetic
acid
##STR00236##
[0498] Step 1: Synthesis of methyl
2-chloro-4-(chlorosulfonyl)benzoate
[0499] Into a 100-mL round-bottom flask, was placed a solution of
methyl 4-amino-2-chlorobenzoate (1.86 g, 10.02 mmol, 1.00 equiv) in
hydrogen chloride(aq) (20 mL). To the mixture was then added a
solution of NaNO.sub.2 (759 mg, 11.00 mmol, 1.10 equiv) in water (3
mL) dropwise with stirring at 0.degree. C. To the resulting mixture
was added a solution of CuCl.sub.2 (1.47 g, 10.97 mmol, 1.09 equiv)
in SO.sub.02/HOAc (8.3 mL) dropwise with stirring at 0.degree. C.
The resulting solution was stirred for 30 min at 0.degree. C. The
resulting solution was allowed to react, with stirring, for an
additional 3 h at room temperature. The resulting solution was
diluted with ethyl acetate (100 mL). The resulting mixture was
washed with sodium chloride (aq) (3.times.10 mL). The mixture was
dried over anhydrous sodium sulfate and concentrated under vacuum
to yield methyl 2-chloro-4-(chlorosulfonyl)benzoate as yellow oil.
LC/MS (ES, m/z): 269 [M+H]+.
Step 2: Synthesis of methyl
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)-2-chlorobenzoate
[0500] Into a 50-mL round-bottom flask, was placed methyl
2-chloro-4-(chlorosulfonyl)benzoate (248 mg, 0.92 mmol, 1.10
equiv),
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-(piperidin-4-yl)-1H-1,3-ben-
zodiazole (400 mg, 0.84 mmol, 1.00 equiv) and a solution of
triethylamine (254 mg, 2.51 mmol, 2.99 equiv) in dichloromethane
(10 mL). The resulting solution was stirred for 2 h at room
temperature. The resulting mixture was concentrated under vacuum to
yield methyl
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)-2-chlorobenzoate as yellow oil. LC/MS (ES,
m/z): 709 [M+H]+.
Step 3: Synthesis of
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)-2-chlorobenzoic acid in a mixture with the
corresponding trifluoroacetic acid
[0501] Into a 25-mL round-bottom flask, was placed methyl
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)-2-chlorobenzoate (230 mg, 0.32 mmol, 1.00
equiv) and a solution of LiOH*H.sub.2O (82 mg, 1.95 mmol, 6.02
equiv) in tetrahydrofuran/H.sub.2O (5/3 mL). The resulting solution
was stirred for 6 h at room temperature. The pH value of the
solution was adjusted to pH 3 with hydrogen chloride (1 mol/L). The
resulting solution was extracted with ethyl acetate (3.times.10 mL)
and the organic layers combined, then dried over anhydrous sodium
sulfate and concentrated under vacuum. The product residue was
purified by Prep-HPLC with the following conditions: Column,
Sunfire prep C18, 5 um, 19*100 mm; mobile phase, 0.05% TFA in water
and CH.sub.3CN (20% CH.sub.3CN up to 65% in 10 min); Detector, 254
nm to yield
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)-2-chlorobenzoic acid trifluoroacetic acid
as a white solid. LC/MS (ES, m/z): 695 [M+H]+.
Alternate Step 2: Synthesis of
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)-2-chlorobenzoic acid hydrochloride
[0502] Into a 50-mL round-bottom flask, was placed methyl
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)-2-chlorobenzoate (400 mg, 0.56 mmol, 1.00
equiv) and a solution of LiOH*H.sub.2O (118 mg, 2.81 mmol, 4.99
equiv) in tetrahydrofuran/H.sub.2O (5/5 mL). The resulting solution
was stirred for 5 h at room temperature. The resulting mixture was
concentrated under vacuum. The pH value of the solution was
adjusted to pH 3 with hydrogen chloride (1 mol/L). The resulting
solution was extracted with ethyl acetate (3.times.50 mL) and the
organic layers combined, then dried over anhydrous sodium sulfate
and concentrated under vacuum. The product residue was purified by
Prep-HPLC with the following conditions (Waters-2767-1): Column,
Sunfire prep C18, 5 um, 19*100 mm; mobile phase, 0.05% TFA in water
and CH.sub.3CN (22% CH.sub.3CN up to 55% in 8 min); Detector, UV
254 nm. 50 mL product was obtained. The CH.sub.3CN was evaporated
and HCl (conc., 1 mL) was added. The resulting mixture was
lyophilized to yield
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidine-1-sulfonyl)-2-chlorobenzoic acid hydrochloride as an
off-white solid.
[0503] .sup.1H NMR (300 MHz, DMSO-d6) .delta.: 8.03 (d, J=8.1 Hz,
1H), 7.92 (d, J=1.5 Hz, 1H), 7.85 (dd, J1=1.5 Hz, J2=8.1 Hz, 1H),
7.72 (s, 1H), 7.51 (d, J=8.1 Hz, 1H), 7.36-7.39 (m, 4H), 7.11-7.14
(m, 4H), 6.97 (d, J=8.1 Hz, 1H), 5.88 (m, 1H), 4.74-4.84 (m, 1H),
3.89 (d, J=10.5 Hz, 2H), 2.50-2.65 (m, 2H), 2.26-2.43 (m, 3H),
1.98-2.07 (m, 2H), 1.05-1.15 (m, 4H). LC/MS (ES, m/z): 694
[M+H]+.
Example PH-29
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]-
piperidine-1-sulfonyl)-2-methoxybenzamide; trifluoroacetic acid
##STR00237##
[0505] The title compound was prepared according to the procedure
as described in Example PH-10 substituting
4-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)sulfonyl)-2-chlorobenzoic acid for
4-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)sulfonyl)benzoic acid.
[0506] .sup.1H NMR (300 MHz, DMSO-d6) .delta.: 8.07 (s, 1H),
7.72-7.87 (m, 5H), 7.57 (d, J=8.4 Hz, 1H), 7.37-7.40 (m, 4H),
7.12-7.14 (m, 4H), 7.05-7.08 (m, 1H), 5.93 (s, 1H), 4.80-4.84 (m,
1H), 3.89-4.04 (m, 2H), 2.55-2.72 (m, 2H), 2.38-2.49 (m, 3H),
2.03-2.07 (m, 2H), 1.15-1.23 (m, 4H). LC/MS (ES, m/z): 693
[M+H]+.
Example PH-30
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]-
piperidine-1-sulfonyl)-2-methoxybenzoic acid; trifluoroacetic
acid
##STR00238##
[0508] The title compound was prepared according to the procedure
as described in Example PH-28 substituting
4-amino-2-methoxybenzoate for methyl 4-amino-2-chlorobenzoate in
Step 1.
[0509] .sup.1H NMR (300 MHz, DMSO-d6) .delta.: 7.80-7.86 (m, 2H),
7.55 (d, J=8.4 Hz, 1H), 7.37-7.44 (m, 6H), 7.11-7.14 (m, 4H),
7.01-7.04 (m, 1H), 5.92 (s, 1H), 4.77-4.81 (m, 1H), 3.93 (s, 3H),
3.78-3.88 (m, 2H), 2.55-2.72 (m, 2H), 2.36-2.49 (m, 3H), 2.00-2.07
(m, 2H), 1.12-1.20 (m, 4H). LC/MS (ES, m/z): 690 [M+H]+.
Example PH-31
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]-
piperidine-1-sulfonyl)-2-methoxybenzamide; trifluoroacetic acid
##STR00239##
[0511] The title compound was prepared according to the procedure
as described in Example PH-10 substituting
4-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)sulfonyl)-2-methoxybenzoic acid for
4-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)sulfonyl)benzoic acid.
[0512] .sup.1H NMR (300 MHz, DMSO-d6) .delta.: 7.90-7.95 (m, 2H),
7.75 (d, J=5.7 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.37-7.46 (m, 6H),
7.11-7.14 (m, 4H), 5.95 (s, 1H), 4.79-4.89 (m, 1H), 3.98 (s, 3H),
3.89-3.93 (m, 2H), 2.54-2.72 (m, 2H), 2.42-2.49 (m, 3H), 2.03-2.07
(m, 2H), 1.18-1.25 (m, 4H). LC/MS (ES, m/z): 689 [M+H]+.
Example PH-32
5-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]-
piperidine-1-sulfonyl)pyridine-2-carboxylic acid; trifluoroacetic
acid
##STR00240##
[0514] The title compound was prepared according to the procedure
as described in Example PH-28 substituting methyl
5-(chlorosulfonyl)pyridine-2-carboxylate for methyl
4-amino-2-chlorobenzoate in Step 2.
[0515] .sup.1H NMR (300 MHz, DMSO-d6) .delta.: 9.09 (s, 1H), 8.41
(d, J=9.3 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.86 (s, 1H), 7.59 (d,
J=8.4 Hz, 1H), 7.38-7.41 (m, 4H), 7.08-7.15 (m, 5H), 5.94 (s, 1H),
4.80-4.84 (m, 1H), 3.91-4.05 (m, 3H), 2.61-2.73 (m, 2H), 2.39-2.50
(m, 2H), 2.04-2.08 (m, 2H), 1.13-1.23 (m, 4H). LC/MS (ES, m/z): 661
[M+H]+.
Example PH-33
5-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]-
piperidine-1-sulfonyl)pyridine-2-carboxamide trifluoroacetic
acid
##STR00241##
[0517] The title compound was prepared according to the procedure
as described in Example PH-10 substituting
5-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)sulfonyl)picolinic acid for
4-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)sulfonyl)benzoic acid.
[0518] .sup.1H NMR (300 MHz, DMSO-d6) .delta.: 8.99 (s, 1H),
8.30-8.43 (m, 3H), 7.89-7.95 (m, 2H), 7.60 (d, J=9.0 Hz, 1H),
7.38-7.41 (m, 4H), 7.12-7.15 (m, 5H), 5.95 (s, 1H), 4.80-4.90 (m,
1H), 3.91-3.95 (m, 3H), 2.59-2.73 (m, 2H), 2.40-2.44 (m, 2H),
2.05-2.08 (m, 2H), 1.15-1.25 (m, 4H). LC/MS (ES, m/z): 660
[M+H]+
Example PH-34
3-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]-
piperidine-1-sulfonyl)benzoic acid; trifluoroacetic acid
##STR00242##
[0520] The title compound was prepared according to the procedure
as described in Example PH-1 substituting 3-(chlorosulfonyl)benzoic
acid for 4-(chlorosulfonyl)benzoic acid in Step 10.
[0521] .sup.1H NMR (300 MHz, CD3OD) .delta.: 8.32 (d, J=1.5 Hz,
1H), 8.23 (d, J=7.8 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.65-7.70 (m,
2H), 7.53 (d, J=8.4 Hz, 1H), 7.21-7.25 (m, 5H), 6.98-7.04 (m, 4H),
5.76 (s, 1H), 4.76-4.84 (m, 1H), 3.95 (d, J=11.4 Hz, 2H), 2.31-2.61
(m, 5H), 2.00-2.04 (m, 2H), 1.14-1.33 (m, 4H). LC/MS (ES, m/z): 660
[M+H]+.
Example PH-35
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]-
piperidine-1-sulfonyl)-2-fluorobenzoic acid hydrochloride
##STR00243##
[0523] The title compound was prepared according to the procedure
as described in Example PH-28 substituting methyl
4-(chlorosulfonyl)-2-fluorobenzoate for methyl
4-amino-2-chlorobenzoate in Step 2.
[0524] .sup.1H NMR (300 MHz, CD3OD) .delta.: 8.12-8.18 (m, 1H),
7.60-7.74 (m, 4H), 7.29-7.33 (m, 5H), 7.08-7.11 (m, 4H), 5.84 (s,
1H), 4.82-4.91 (m, 1H), 4.22 (d, J=12.0 Hz, 2H), 2.65-2.73 (m, 2H),
2.46-2.56 (m, 3H), 2.10-2.14 (m, 2H), 1.26-1.43 (m, 4H). LC/MS (ES,
m/z): 678 [M+H]+.
Example PH-36
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]-
piperidine-1-sulfonyl)-2-fluorobenzamide hydrochloride
##STR00244##
[0526] The title compound was prepared according to the procedure
as described in Example PH-10 substituting
4-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)sulfonyl)-2-fluorobenzoic acid for
4-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)sulfonyl)benzoic acid.
[0527] .sup.1H NMR (300 MHz, CD3OD) .delta.: 7.96-8.01 (m, 1H),
7.67-7.73 (m, 3H), 7.58 (d, J=8.4 Hz, 1H), 7.24-7.32 (m, 5H),
7.08-7.11 (m, 4H), 5.82 (s, 1H), 4.82-4.90 (m, 1H), 4.01 (d, J=12.3
Hz, 2H), 2.36-2.71 (m, 5H), 2.00-2.11 (m, 2H), 1.31-1.36 (m, 2H),
1.21-1.25 (m, 2H). LC/MS (ES, m/z): 677 [M+H]+.
Example PH-37
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]-
piperidine-1-sulfonyl)-2-methylbenzoic acid; trifluoroacetic
acid
##STR00245##
[0529] The title compound was prepared according to the procedure
as described in Example PH-1 substituting
4-(chlorosulfonyl)-2-methylbenzoic acid for
4-(chlorosulfonyl)benzoic acid in Step 10.
[0530] 1H NMR (300 MHz, CD3OD) .delta.: 8.11 (d, J=7.5 Hz, 1H),
7.73-7.76 (m, 3H), 7.63 (d, J=8.4 Hz, 1H), 7.33-7.36 (m, 5H),
7.12-7.15 (m, 4H), 5.87 (s, 1H), 4.05 (d, J=10.8 Hz, 2H), 2.43-2.71
(m, 9H), 2.11-2.14 (m, 2H), 1.32-1.41 (m, 2H), 1.26-1.28 (m, 2H).
LC/MS (ES, m/z): 674 [M+H]+.
Example PH-38
3-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]-
piperidine-1-sulfonyl)-N-methylbenzamide hydrochloride
##STR00246##
[0532] The title compound was prepared according to the procedure
as described in Example PH-10 substituting CH.sub.3NH.sub.2*HCl for
ammonium chloride in Step 1.
[0533] 1H NMR (300 MHz, CD.sub.3OD) .delta.: 8.25 (t, J=1.8 Hz,
1H), 8.10 (t, J=1.5 Hz, 1H), 7.96-8.08 (m, 1H), 7.72-7.74 (m, 2H),
7.58-7.69 (m, 1H), 7.29-7.32 (m, 5H), 7.08-7.11 (m, 4H), 5.83 (s,
1H), 4.82-4.87 (m, 1H), 4.02 (d, J=12.6 Hz, 2H), 2.92 (s, 3H),
2.42-2.69 (m, 5H), 2.08-2.11 (m, 2H), 1.34-1.39 (m, 2H), 1.23-1.27
(m, 2H). LC/MS (ES, m/z): 673 [M+H]+.
Example PH-39
3-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-)p-
iperidin-1-ylsulfonyl)-N-(2-hydroxyethyl)benzamide; trifluoroacetic
acid
##STR00247##
[0535] The title compound was prepared according to the procedure
as described in Example PH-10 substituting 2-aminoethan-1-ol for
ammonium chloride in Step 1.
[0536] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.: 8.33 (s, 1H),
8.18 (d, J=6.0 Hz, 1H), 8.03 (d, J=5.7 Hz, 1H), 7.75-7.79 (m, 2H),
7.64 (d, J=6.0 Hz, 1H), 7.34-7.37 (m, 5H), 7.13-7.16 (m, 4H), 5.88
(s, 1H), 4.86-4.91 (m, 1H), 4.08 (d, J=9.0 Hz, 2H), 3.75 (t, J=4.2
Hz, 2H), 3.56 (t, J=4.2 Hz, 2H), 2.67-2.73 (m, 2H), 2.45-2.65 (m,
3H), 2.13-2.16 (m, 2H), 1.28-1.42 (m, 5H). LC/MS (ES, m/z): 703
[M+H]+.
Example PH-40
3-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]-
piperidine-1-sulfonyl)-N-(3-hydroxypropyl)benzamide
hydrochloride
##STR00248##
[0538] The title compound was prepared according to the procedure
as described in Example PH-10 substituting 3-aminoethan-1-ol for
ammonium chloride in Step 1.
[0539] .sup.1H NMR (400 MHz, CD3OD) .delta.: 8.30 (s, 1H), 8.15 (d,
J=7.2 Hz, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.75-7.80 (m, 2H), 7.66 (d,
J=8.4 Hz, 1H), 7.34-7.36 (m, 5H), 7.13-7.16 (m, 4H), 5.89 (s, 1H),
4.82-4.92 (m, 1H), 4.07 (d, J=11.6 Hz, 2H), 3.68 (t, J=6.0 Hz, 2H),
3.53 (t, J=6.0 Hz, 2H), 2.68-2.74 (m, 2H), 2.52-2.57 (m, 3H),
2.14--2.17 (m, 2H), 1.87 (t, J=6.4 Hz, 2H), 1.42-1.44 (m, 2H),
1.31-1.40 (m, 2H).
[0540] LC/MS (ES, m/z): 717 [M+H]+.
Example PH-41
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]-
piperidine-1-sulfonyl-2-(trifluoromethyl)benzoic acid
hydrochloride
##STR00249##
[0542] The title compound was prepared according to the procedure
as described in Example PH-28 substituting
4-amino-2-(trifluoromethyl)benzoic acid for
4-amino-2-chlorobenzoate in Step 1.
[0543] .sup.1H NMR (300 MHz, DMSO-d6) .delta.: 8.48-8.49 (br.m,
1H), 8.17 (d, J=8.7 Hz, 1H), 8.04-8.09 (m, 2H), 7.77 (br.s, 1H),
7.52 (d, J=8.7 Hz, 1H), 7.33-7.36 (m, 4H), 6.99-7.18 (m, 5H), 5.89
(s, 1H), 4.76-4.80 (m, 1H), 3.89 (d, J=10.5 Hz, 2H), 2.56-2.69 (m,
2H), 2.34-2.45 (m, 3H), 1.99-2.03 (m, 2H), 1.09-1.23 (m, 4H). LC/MS
(ES, m/z): 728 [M+H]+.
Example PH-42
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]-
piperidine-1-sulfonyl)-2-(trifluoromethyl)benzamide
hydrochloride
##STR00250##
[0545] The title compound was prepared according to the procedure
as described in Example PH-10 substituting
4-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)sulfonyl)-2-(trifluoromethyl)benzoic acid for
4-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)sulfonyl)benzoic acid.
[0546] .sup.1H NMR (300 MHz, CD3OD) .delta.: 8.10-8.13 (m, 2H),
7.82 (d, J=8.1 Hz, 1H), 7.74 (s, 1H), 7.60 (d, J=8.4 Hz, 1H),
7.28-7.33 (m, 5H), 7.08-7.11 (m, 4H), 5.84 (s, 1H), 4.82-4.89 (m,
1H), 4.03 (d, J=11.4 Hz, 2H), 2.41-2.70 (m, 5H), 2.09-2.14 (m, 2H),
1.26-1.40 (m, 4H). LC/MS (ES, m/z): 727 [M+H]+.
Example PH-43
methyl
3-[[3-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzod-
iazol-1-yl]piperidine-1-sulfonyl)phenyl]formamido]propanoate:
trifluoroacetic acid
##STR00251##
[0548] The title compound was prepared according to the procedure
as described in Example PH-13 substituting methyl 3-aminopropanoate
hydrochloride for ammonium chloride in Step 2.
[0549] .sup.1H NMR (300 MHz, CD3OD) .delta.: 8.29 (s, 1H),
8.11-8.15 (m, 1H), 8.01-8.04 (m, 1H), 7.73-7.79 (m, 2H), 7.64 (d,
J=8.7 Hz, 1H), 7.31-7.37 (m, 5H), 7.12-7.16 (m, 4H), 5.87 (s, 1H),
4.85-4.91 (m, 1H), 4.07 (d, J=11.7 Hz, 2H), 3.66-3.71 (m, 5H),
2.66-2.72 (m, 4H), 2.46-2.56 (m, 3H), 2.12-2.15 (m, 2H), 1.38-1.42
(m, 2H), 1.26-1.30 (m, 2H). LC/MS (ES, m/z): 745 [M+H]+.
Example PH-44
Methyl
3-[[5-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzod-
iazol-1-yl]piperidine-1-sulfonyl)pyridin-2-yl]formamido]propanoate:
trifluoroacetic acid
##STR00252##
[0551] The title compound was prepared according to the procedure
as described in Example PH-18 substituting methyl
5-(chlorosulfonyl)pyridine-2-carboxylate for methyl
2-(chlorosulfonyl)benzoate in Step 1, and substituting methyl
3-aminopropanoate hydrochloride for ammonium chloride in Step
3.
[0552] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.: 9.01 (d, J=1.5
Hz, 1H), 8.28-8.39 (m, 2H), 7.68 (s, 1H), 7.58 (d, J=8.7 Hz, 1H),
7.26-7.32 (m, 5H), 7.08-7.11 (m, 4H), 5.82 (s, 1H), 4.83-4.90 (m,
1H), 4.04 (d, J=11.4 Hz, 2H), 3.66-3.72 (m, 5H), 2.63-2.73 (m, 4H),
2.36-2.56 (m, 3H), 2.08-2.12 (m, 2H), 1.31-1.35 (m, 2H), 1.23-1.35
(m, 2H). LC/MS: (m/z) 746 [M+H]+.
Example PH-45
5-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]-
piperidine-1-sulfonyl)furan-2-carboxylic acid trifluoroacetic
acid
##STR00253##
[0554] The title compound was prepared according to the procedure
as described in Example PH-13 substituting
5-(chlorosulfonyl)furan-2-carboxylic acid for
3-(chlorosulfonyl)benzoic acid in Step 1.
[0555] .sup.1H NMR (300 MHz, CD3OD) .delta.: 7.76 (s, 1H), 7.65 (d,
J=8.7 Hz, 1H), 7.33-7.36 (m, 6H), 7.25 (d, J=3.6 Hz, 1H), 7.12-7.15
(m, 4H), 5.88 (s, 1H), 4.97-5.07 (m, 1H), 4.11 (d, J=12.6 Hz, 2H),
2.98-3.06 (m, 2H), 2.49-2.56 (m, 3H), 2.17-2.21 (m, 2H), 1.41-1.45
(m, 2H), 1.30-1.34 (m, 2H). LC/MS (ES, m/z): 650 [M+H]+.
Example PH-46
5-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]-
piperidine-1-sulfonyl)furan-2-carboxamide; trifluoroacetic acid
##STR00254##
[0557] The title compound was prepared according to the procedure
as described in Example PH-10 substituting
5-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)sulfonyl)furan-2-carboxylic acid for
4-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)sulfonyl)benzoic acid. 1H NMR (300 MHz, CD3OD)
.delta.: 7.76 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.21-7.40 (m, 7H),
7.12-7.20 (m, 4H), 5.88 (s, 1H), 4.95-5.05 (m, 1H), 4.12 (d, J=11.4
Hz, 2H), 2.94-3.04 (m, 2H), 2.42-2.58 (m, 3H), 2.16-2.19 (m, 2H),
1.21-1.49 (m, 4H). LC/MS (ES, m/z): 649 [M+H]+.
Example PH-47
3-(4-(6-(bis(4-chlorophenyl
methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)benzamide
2,2,2-trifluoroacetate
##STR00255##
[0558] Step 1: Synthesis of methyl
3-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidin-1-yl)benzoate
[0559] Into a 100-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of nitrogen, was placed a
solution of
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-(piperidin-4-yl)-1H-1,3-ben-
zodiazole (300 mg, 0.63 mmol, 1.00 equiv) in toluene (10 mL),
methyl 3-bromobenzoate (162 mg, 0.75 mmol, 1.20 equiv),
Pd.sub.2(dba).sub.3 (90 mg, 0.10 mmol, 0.30 equiv), XPhos (58 mg,
0.10 equiv) and Cs.sub.2CO.sub.3 (411 mg, 1.26 mmol, 2.00 equiv).
The resulting solution was stirred overnight at 95.degree. C. The
residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:1) to yield methyl
3-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiaz-
ol-1-yl]piperidin-1-yl)benzoate as yellow oil. LC/MS (ES, m/z): 610
[M+H]+.
Step 2: Synthesis of
3-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidin-1-yl)benzoic acid; trifluoroacetic acid
[0560] Into a 50-mL round-bottom flask, was placed a solution of
methyl
3-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidin-1-yl)benzoate (240 mg, 0.39 mmol, 1.00 equiv) in
tetrahydrofuran/MeOH (10/2 mL) and LiOH (10 mL). The resulting
solution was stirred overnight at room temperature. The reaction
was then quenched by the addition of water (10 mL).
[0561] The pH value of the solution was adjusted to pH 6 with
hydrogen chloride (1 mol/L). The solids were collected by
filtration. The product residue was purified by Prep-HPLC with the
following conditions (Waters 2767-1): Column, SunFire Prep C18, 5
um, 19*100 mm; mobile phase, 0.05% TFA in water and CH.sub.3CN (25%
CH.sub.3CN up to 55% in 9 min); Detector, UV 254 nm to yield
3-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidin-1-yl)benzoic acid; trifluoroacetic acid as a white
solid. LC/MS (ES, m/z): 596 [M+H]+.
Step 3: Synthesis of
3-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidin-1-yl)benzamide; trifluoroacetic acid
[0562] Into a 50-mL round-bottom flask, was placed a solution of
3-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidin-1-yl)benzoic acid (100 mg, 0.17 mmol, 1.00 equiv) in
N,N-dimethylformamide (5 mL), NH.sub.4Cl (45 mg, 0.84 mmol, 5.00
equiv), HATU (77 mg, 0.20 mmol, 1.20 equiv) and DIEA (43 mg, 0.33
mmol, 2.00 equiv). The resulting solution was stirred overnight at
room temperature. The reaction was then quenched by the addition of
water. The solids were collected by filtration. The product residue
(100 mg) was purified by Prep-HPLC with the following conditions
(Waters 2767-1): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile
phase, 0.05% TFA in water and CH.sub.3CN (25% CH.sub.3CN up to 45%
in 9 min); Detector, UV 254 nm to yield
3-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazo-
l-1-yl]piperidin-1-yl)benzamide; trifluoroacetic acid as a white
solid.
[0563] .sup.1H NMR (300 MHz, CD3OD) .delta.: 7.56-7.63 (m, 3H),
7.19-7.38 (m, 8H), 7.01-7.06 (m, 4H), 5.68 (s, 1H), 5.08-5.16 (m,
1H), 4.00 (d, J=12.9 Hz, 2H), 3.06-3.14 (m, 2H), 2.49-2.62 (m, 3H),
2.08-2.12 (m, 2H), 1.42-1.49 (m, 2H), 1.28-1.33 (m, 2H). LC/MS (ES,
m/z): 595 [M+H]+.
Example PH-48
4-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)piperidin-1-yl)benzamide 2,2,2-trifluoroacetate
##STR00256##
[0565] The title compound was prepared according to the procedure
as described in Example PH-47 substituting methyl 4-bromobenzoate
for methyl 3-bromobenzoate in Step 1.
[0566] .sup.1H NMR (300 MHz, CD3OD) .delta.: 7.81 (d, J=8.7 Hz,
2H), 7.60 (d, J=8.4 Hz, 1H), 7.39 (s, 2H), 7.23-7.30 (m, 4H),
6.96-7.04 (m, 6H), 5.59 (s, 1H), 5.13-5.21 (m, 1H), 4.13 (d, J=14.1
Hz, 2H), 3.12-3.29 (m, 2H), 2.41-2.61 (m, 3H), 2.05-2.09 (m, 2H),
1.41-1.47 (m, 2H), 1.26-1.36 (m, 2H). LC/MS (ES, m/z): 595
[M+H]+.
Example PH-49
2-(3-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-
-yl)piperidin-1-yl)phenyl)acetamide 2,2,2-trifluoroacetate
##STR00257##
[0568] The title compound was prepared according to the procedure
as described in Example PH-47 substituting methyl
2-(3-bromophenyl)acetate for methyl 3-bromobenzoate in Step 1.
[0569] .sup.1H NMR (400 MHz, CD3OD) .delta.: 7.75-7.76 (m, 1H),
7.67 (d, J=8.8 Hz, 1H), 7.27-7.39 (m, 6H), 6.92-7.17 (m, 7H), 5.79
(s, 1H), 5.11-5.15 (m, 1H), 3.96 (d, J=12.0 Hz, 2H), 3.51 (s, 2H),
3.15-3.24 (m, 2H), 2.62-2.75 (m, 3H), 2.15-2.17 (m, 2H), 1.48-1.53
(m, 2H), 1.20-1.37 (m, 2H). LC/MS (ES, m/z): 609 [M+H]+.
Example PH-50
2-(4-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-
-yl)piperidin-1-yl)phenyl)acetamide 2,2,2-trifluoroacetate
##STR00258##
[0571] The title compound was prepared according to the procedure
as described in Example PH-47 substituting methyl
2-(4-bromophenyl)acetate for methyl 3-bromobenzoate in Step 1.
[0572] .sup.1H NMR (300 MHz, CD3OD) .delta.: 7.70-7.72 (m, 1H),
7.62 (d, J=8.4 Hz, 1H), 7.20-7.33 (m, 7H), 7.03-7.15 (m, 6H), 5.74
(s, 1H), 5.04-5.14 (m, 1H), 3.87 (d, J=11.1 Hz, 2H), 3.42-3.44 (m,
2H), 3.06-3.15 (m, 2H), 2.54-2.61 (m, 3H), 2.08-2.18 (m, 2H),
1.42-1.49 (m, 2H), 1.25-1.31 (m, 2H). LC/MS (ES, m/z): 609
[M+H]+.
Example PH-51
2-(3-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-
-yl)piperidin-1-yl)phenoxy)acetamide 2,2,2-trifluoroacetate
##STR00259##
[0574] The title compound was prepared according to the procedure
as described in Example PH-47 substituting ethyl
2-(3-bromophenoxy)acetate for methyl 3-bromobenzoate in Step 1.
[0575] .sup.1H NMR (400 MHz, CD3OD) .delta.: 7.63-7.68 (m, 2H),
7.31-7.38 (m, 5H), 7.22 (t, J=8.4 Hz, 1H), 7.06-7.09 (m, 4H),
6.73-6.74 (m, 2H), 6.56 (d, J=8.4 Hz, 1H), 5.72 (s, 1H), 5.13-5.19
(m, 1H), 4.50 (s, 2H), 4.00 (d, J=13.6 Hz, 2H), 3.12-3.20 (m, 2H),
2.55-2.67 (m, 3H), 2.05-2.13 (m, 2H), 1.48-1.53 (m, 2H), 1.33-1.37
(m, 2H). LC/MS (ES, m/z): 625 [M+H]+.
Example PH-52
2-(4-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-
-yl)piperidin-1-yl)phenoxy)acetamide 2,2,2-trifluoroacetate
##STR00260##
[0577] The title compound was prepared according to the procedure
as described in Example PH-47 substituting ethyl
2-(4-bromophenoxy)acetate for methyl 3-bromobenzoate in Step 1.
[0578] .sup.1H NMR (400 MHz, CD3OD) .delta.: 7.83 (s, 1H), 7.68 (d,
J=8.8 Hz, 1H), 7.33-7.38 (m, 5H), 7.02-7.20 (m, 8H), 5.82 (s, 1H),
5.10-5.20 (m, 1H), 4.49 (s, 2H), 3.80 (d, J=12.0 Hz, 2H), 3.12-3.22
(m, 2H), 2.62-2.72 (m, 3H), 2.16-2.26 (m, 2H), 1.48-1.51 (m, 2H),
1.35-1.38 (m, 2H). LC/MS (ES, m/z): 625 [M+H]+.
Example PH-53
2,2,2-trifluoroacetic acid compound with
3-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)methyl)benzoic acid (1:1)
##STR00261##
[0579] Step 1: Synthesis of yield methyl
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]benzoate
[0580] Into a 100-mL round-bottom flask, was placed a solution of
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-(piperidin-4-yl)-1H-1,3-ben-
zodiazole (2 g, 4.20 mmol, 1.00 equiv) in dichloromethane (30 mL),
methyl 3-formylbenzoate (690 mg, 4.20 mmol, 1.00 equiv) and
triethylamine (a catalytic amount). The resulting solution was
stirred for overnight at room temperature. To the mixture was added
NaBH(OAc).sub.3 (1.96 g, 9.25 mmol, 2.20 equiv). The resulting
solution was stirred for 4 h at room temperature. The resulting
mixture was concentrated under vacuum. The residue was applied onto
a silica gel column with ethyl acetate/petroleum ether (1:1) to
yield methyl
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]benzoate as a red solid. LC/MS (ES, m/z):
624 [M+H]+.
Step 2: Synthesis of
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]benzoic acid trifluoroacetic acid
[0581] Into a 100-mL round-bottom flask, was placed a solution of
methyl
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]benzoate (780 mg, 1.25 mmol, 1.00 equiv) in
tetrahydrofuran/MeOH (30/5 mL) and LiOH (30 mL, 3M). The resulting
solution was stirred overnight at room temperature. The resulting
mixture was concentrated under vacuum. The pH value of the solution
was adjusted to pH 7 with hydrogen chloride (12 mol/L). The solids
were collected by filtration. The product residue (600 mg) was
purified by Flash-Prep-HPLC with the following conditions
(CombiFlash-1): Column, C18 silica gel; mobile phase, 0.05% TFA in
water and CH.sub.3CN (CH.sub.3CN 10% up to 80% in 10 min);
Detector, UV 254 nm to yield
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]benzoic acid trifluoroacetic acid as a
white solid.
[0582] .sup.1H NMR (300 MHz, CD3OD) .delta.: 8.25 (s, 1H), 8.19 (d,
J=7.8 Hz, 1H), 7.79-7.82 (m, 2H), 7.64-7.69 (m, 2H), 7.31-7.34 (m,
5H), 7.09-7.12 (m, 4H), 5.81 (s, 1H), 5.26 (brs, 1H), 4.50 (s, 2H),
3.75-3.79 (m, 2H), 3.34-3.42 (m, 2H), 2.87-2.91 (m, 2H), 2.51-2.58
(m, 1H), 2.34-2.39 (m, 2H), 1.31-1.50 (m, 2H). LC/MS (ES, m/z): 610
[M+H]+.
Example PH-54
3-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)methyl)benzamide 2,2,2-trifluoroacetate
##STR00262##
[0584] Into a 50-mL round-bottom flask, was placed a solution of
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]benzoic acid (70 mg, 0.11 mmol, 1.00 equiv)
in N,N-dimethylformamide (5 mL), NH.sub.4Cl (30.5 mg, 0.57 mmol,
5.00 equiv), HATU (52.4 mg, 0.14 mmol, 1.20 equiv) and DIEA (29.7
mg, 0.23 mmol, 2.00 equiv). The resulting solution was stirred
overnight at room temperature. The reaction was then quenched by
the addition of water (10 mL). The resulting solution was extracted
with ethyl acetate (3.times.10 mL) and the organic layers combined,
then dried over anhydrous sodium sulfate and concentrated under
vacuum. The product residue was purified by Prep-HPLC with the
following conditions (Waters 2767-1): Column, SunFire Prep C18, 5
um, 19*100 mm; mobile phase, 0.05% TFA in water and CH.sub.3CN (25%
CH.sub.3CN up to 55% in 10 min); Detector, UV 254 nm to yield
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiaz-
ol-1-yl]piperidin-1-yl)methyl]benzamide trifluoroacetic acid as a
white solid.
[0585] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.: 8.00-8.07 (m,
2H), 7.91 (s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.61-7.66 (m, 2H),
7.24-7.33 (m, 5H), 7.09 (d, J=8.4 Hz, 4H), 5.81 (s, 1H), 5.22-5.30
(m, 1H), 4.48 (s, 2H), 3.75-3.79 (m, 2H), 3.38-3.42 (m, 2H),
2.82-2.94 (m, 2H), 2.50-2.59 (m, 1H), 2.34-2.38 (m, 2H), 1.32-1.49
(m, 4H).
[0586] LC/MS (ES, m/z): 609 [M+H]+.
Example PH-55
2,2,2-trifluoroacetic acid compound with
4-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)methyl)benzoic acid (1:1)
##STR00263##
[0588] The title compound was prepared according to the procedure
as described in Example PH-53 substituting methyl 4-formylbenzoate
for methyl 3-formylbenzoate in Step 1.
[0589] .sup.1H NMR (300 MHz, CD3OD) .delta.: 8.17 (d, J=8.1 Hz,
2H), 7.89-7.95 (m, 1H), 7.70-7.64 (m, 3H), 7.34-7.26 (m, 5H), 7.10
(d, J=8.4 Hz, 4H), 5.81 (s, 1H), 5.26 (m, 1H), 4.48 (s, 1H),
3.78-3.74 (m, 2H), 3.33-3.32 (m, 2H), 2.82-2.91 (m, 2H), 2.54 (brs,
1H), 2.30-2.40 (m, 2H), 1.32-1.54 (m, 4H). LC/MS (ES, m/z): 610
[M+H]+.
Example PH-56
4-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)methyl)benzamide 2,2,2-trifluoroacetate
##STR00264##
[0591] The title compound was prepared according to the procedure
as described in Example PH-554 substituting
4-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)methyl)benzoic acid for
3-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)methyl)benzoic acid.
[0592] .sup.1H NMR (300 MHz, CD3OD) .delta.: 8.01-8.08 (m, 2H),
7.96 (s, 1H), 7.65-7.69 (m, 3H), 7.18-7.34 (m, 5H), 7.09-7.12 (m,
4H), 5.83 (s, 1H), 5.23-5.27 (m, 1H), 4.49 (s, 2H), 3.56-3.82 (m,
2H), 3.34-3.42 (m, 2H), 2.86-2.98 (m, 2H), 2.53-2.62 (m, 1H),
2.35-2.39 (m, 2H), 1.43-1.52 (m, 2H), 1.29-1.43 (m, 2H). LC/MS:
(m/z) 609 [M+H]+.
Example PH-57
5-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)methyl)furan-2-carboxylic acid hydrochloride
##STR00265##
[0594] The title compound was prepared according to the procedure
as described in Example PH-53 substituting
5-formylfuran-2-carboxylic acid for methyl 3-formylbenzoate in Step
1.
[0595] .sup.1H NMR (300 MHz, CD3OD) .delta.: 8.28 (s, 1H), 7.66 (d,
J=8.7 Hz, 1H), 7.29-7.33 (m, 6H), 7.13-7.16 (m, 4H), 6.98 (d, J=3.3
Hz, 1H), 5.91 (s, 1H), 5.28-5.36 (m, 1H), 4.57 (s, 2H), 3.76-3.80
(m, 2H), 3.39-3.55 (m, 2H), 2.97-3.09 (m, 2H), 2.58-2.67 (m, 1H),
2.35-2.39 (m, 2H), 1.35-1.53 (m, 4H). LC/MS (ES, m/z): 600
[M+H]+.
Example PH-58
5-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)piperidin-1-yl)methyl)furan-2-carboxamide hydrochloride
##STR00266##
[0597] The title compound was prepared according to the procedure
as described in Example PH-54 substituting
5-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)methyl)furan-2-carboxylic acid for
3-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)methyl)benzoic acid.
[0598] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.: 8.49 (s, 1H),
7.68 (d, J=8.7 Hz, 1H), 7.30-7.42 (m, 5H), 7.15-7.21 (m, 5H), 6.95
(d, J=3.6 Hz, 1H), 5.95 (s, 1H), 5.32-5.40 (m, 1H), 4.59 (s, 1H),
3.41-3.82 (m, 2H), 3.10-3.22 (m, 2H), 2.62-2.70 (m, 1H), 2.35-2.39
(m, 2H), 1.32-1.55 (m, 4H). LC/MS (ES, m/z): 599 [M+H]+.
Example PH-59
5-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)piperidin-1-yl)methyl)thiophene-2-carboxylic acid
hydrochloride
##STR00267##
[0600] The title compound was prepared according to the procedure
as described in Example PH-53 substituting
5-formylthiophene-2-carboxylic acid for methyl 3-formylbenzoate in
Step 1.
[0601] .sup.1H NMR (400 MHz, CD3OD) .delta.: 8.41 (s, 1H), 7.81 (s,
1H), 7.67 (d, J=8.8 Hz, 1H), 7.53 (d, J=3.6 Hz, 1H), 7.32-7.35 (m,
4H), 7.17 (d, J=8.4 Hz, 3H), 5.94 (s, 1H), 5.30-5.37 (m, 1H), 4.71
(s, 2H), 3.80 (d, J=12.0 Hz, 2H), 3.33-3.50 (m, 2H), 3.07-3.15 (m,
2H), 2.62-2.69 (m, 1H), 2.37 (d, J=12.0 Hz, 2H), 1.49-1.54 (m, 2H),
1.31-1.41 (m, 2H). LC/MS (ES, m/z): 616 [M+H]+.
Example PH-60
5-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)methyl)thiophene-2-carboxamide hydrochloride
##STR00268##
[0603] The title compound was prepared according to the procedure
as described in Example PH-54 substituting
5-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)methyl)thiophene-2-carboxylic acid for
3-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)methyl)benzoic acid.
[0604] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 8.43 (s, 1H),
7.75 (d, J=4.0 Hz, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.53 (d, J=3.6 Hz,
1H), 7.32-7.37 (m, 5H), 7.17 (d, J=8.4 Hz, 4H), 5.94 (s, 1H),
5.30-5.40 (t, 1H), 4.70 (s, 2H), 3.80 (d, J=12.4 Hz, 2H), 3.33-3.50
(m, 2H), 3.10-3.15 (m, 2H), 2.64-2.68 (m, 1H), 2.38 (d, J=12.4 Hz,
2H), 1.49-1.54 (m, 2H), 1.31-1.38 (m, 2H). LC/MS (ES, m/z): 615
[M+H]+.
Example PH-61
5-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)methyl)thiophene-3-carboxylic acid
hydrochloride
##STR00269##
[0606] The title compound was prepared according to the procedure
as described in Example PH-53 substituting methyl
5-formylthiophene-3-carboxylate for methyl 3-formylbenzoate in Step
1.
[0607] .sup.1H NMR (400 MHz, CD3OD) .delta.: 8.46 (s, 1H), 8.40 (s,
1H), 7.86 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.36 (s, 1H), 7.32 (d,
J=8.4 Hz, 4H), 7.17 (d, J=8.4 Hz, 4H), 5.95 (s, 1H), 5.37 (t,
J=12.4 Hz, 1H), 4.71 (s, 2H), 3.81 (d, J=12.0 Hz, 2H), 3.41-3.50
(m, 2H), 3.12-3.18 (m, 2H), 2.64-2.71 (m, 1H), 2.38 (d, J=13.2 Hz,
2H), 1.50-1.55 (m, 2H), 1.35-1.38 (m, 2H). LC/MS (ES, m/z): 616
[M+H]+.
Example PH-62
5-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)methyl)thiophene-3-carboxamide hydrochloride
##STR00270##
[0609] The title compound was prepared according to the procedure
as described in Example PH-54 substituting
5-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)methyl)thiophene-3-carboxylic acid for
3-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)methyl)benzoic acid.
[0610] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 8.50 (s, 1H),
8.29 (s, 1H), 7.83 (s, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.31-7.36 (m,
4H), 7.17 (d, J=8.4 Hz, 4H), 5.95 (s, 1H), 5.38 (t, J=11.6 Hz, 1H),
4.71 (s, 2H), 3.82 (d, J=11.6 Hz, 2H), 3.45 (t, J=12.4 Hz, 2H),
3.17 (t, J=11.6 Hz, 3H), 2.65-2.72 (m, 1H), 2.39 (d, J=12.4 Hz,
2H), 1.51-1.56 (m, 2H), 1.35-1.41 (m, 2H). LC/MS (ES, m/z): 615
[M+H]+.
Example PH-63
6-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)methyl)picolinic acid
##STR00271##
[0612] The title compound was prepared according to the procedure
as described in Example PH-53 substituting methyl
6-formylpyridine-2-carboxylate in Step 1 was used instead of methyl
3-formylbenzoate in Step 1.
[0613] .sup.1H NMR (300 MHz, DMSO) .delta.: 7.88-7.97 (m, 2H),
7.48-7.50 (d, J=6.0 Hz, 1H), 7.22-7.43 (m, 6H), 7.13-7.16 (m, 4H),
6.80 (d, J=12.0 Hz, 1H), 5.83 (s, 1H), 4.56 (brs, 1H), 3.62 (s,
2H), 2.90-3.06 (m, 2H), 2.19-2.33 (m, 4H), 1.90 (s, 1H), 1.75-1.79
(m, 2H), 1.00-1.25 (m, 4H). LC/MS (ES, m/z): 611 [M+H]+.
Example PH-64
6-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)methyl)picolinamide 2,2,2-trifluoroacetate
##STR00272##
[0615] The title compound was prepared according to the procedure
as described in Example PH-54 substituting
6-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)methyl)picolinic acid for
3-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)methyl)benzoic acid.
[0616] .sup.1H NMR (300 MHz, DMSO) .delta.: 8.20 (d, J=7.8 Hz, 1H),
8.13 (d, J=7.8 Hz, 1H), 8.06-8.10 (m, J=11.7 Hz, 1H), 7.74 (d,
J=7.2 Hz, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.29-7.35 (m, 5H), 7.07-7.14
(m, 4H), 5.86 (s, 1H), 5.30 (m, 1H), 4.64 (s, 2H), 3.85-3.89 (m,
2H), 3.45-3.46 (m, 2H), 2.97-3.08 (m, 2H), 2.60-2.75 (m, 1H),
2.30-2.39 (m, 2H), 1.35-1.50 (m, 2H), 1.21-1.35 (m, 2H). LC/MS (ES,
m/z): 610 [M+H]+.
Example PH-65
6-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)piperidin-1-yl)methyl)nicotinic acid
##STR00273##
[0618] The title compound was prepared according to the procedure
as described in Example PH-53 substituting methyl
6-formylpyridine-3-carboxylate for methyl 3-formylbenzoate in Step
1.
[0619] .sup.1H NMR (300 MHz, DMSO) .delta.: 8.92 (s, 1H), 8.22 (d,
J=8.4 Hz, 1H), 7.38-7.43 (m, 7H), 7.15 (d, J=8.1 Hz, 1H), 6.82 (d,
J=8.1 Hz, 1H), 5.84 (s, 1H), 4.50-4.60 (m, 1H), 3.75 (s, 2H),
2.96-3.03 (m, 2H), 2.26-2.50 (m, 4H), 1.90 (s, 1H), 1.79-1.81 (m,
2H), 0.91-1.03 (m, 4H). LC/MS (ES, m/z): 611 [M+H]+.
Example PH-66
6-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)methyl)nicotinamide 2,2,2-trifluoroacetate
##STR00274##
[0621] The title compound was prepared according to the procedure
as described in Example PH-54 substituting
6-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)methyl)nicotinic acid for
3-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)methyl)benzoic acid.
[0622] .sup.1H NMR (300 MHz, CD3COCD3) .delta.: 9.11 (s, 1H),
8.31-8.35 (m, 2H), 7.69-7.84 (m, 3H), 7.29-7.33 (m, 4H), 7.15-7.24
(m, 5H), 5.89 (s, 1H), 5.40-5.50 (m, 1H), 4.59 (s, 2H), 3.88-3.92
(m, 2H), 3.53-3.56 (m, 2H), 3.19-3.23 (m, 2H), 2.55-2.57 (m, 1H),
2.41-2.44 (m, 2H), 1.44-1.49 (m, 2H), 1.24-1.29 (m, 2H). LC/MS (ES,
m/z): 610 [M+H]+.
Example PH-67
5-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)methyl)nicotinic acid
##STR00275##
[0624] The title compound was prepared according to the procedure
as described in Example PH-53 substituting methyl
5-formylpyridine-3-carboxylate methyl 3-formylbenzoate, in Step
1.
[0625] .sup.1H NMR (300 MHz, DMSO) .delta.: 8.89 (s, 1H), 8.45 (s,
1H), 8.09 (s, 1H), 7.38-7.44 (m, 6H), 7.13 (d, J=8.4 Hz, 4H), 6.80
(d, J=8.8 Hz, 1H), 5.85 (s, 1H), 4.52-4.58 (m, 1H), 3.59 (s, 2H),
2.95-2.97 (m, 2H), 2.18-2.36 (m, 5H), 1.79-1.82 (m, 2H), 0.96-1.04
(m, 4H). LC/MS (ES, m/z): 611 [M+H]+.
Example PH-68
5-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)methyl)nicotinamide 2,2,2-trifluoroacetate
##STR00276##
[0627] The title compound was prepared according to the procedure
as described in Example PH-54 substituting
5-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)methyl)nicotinic acid for
3-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)methyl)benzoic acid.
[0628] .sup.1H NMR (300 MHz, CD3OD) .delta.: 9.12 (s, 1H), 8.85 (s,
1H), 8.45 (s, 1H), 7.86 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.23-7.29
(m, 5H), 7.06 (d, J=8.4 Hz, 4H), 5.79 (s, 1H), 5.20-5.35 (m, 1H),
4.52 (s, 2H), 3.74-3.78 (m, 2H), 3.32-3.50 (m, 2H), 2.76-2.80 (m,
2H), 2.50-2.56 (m, 1H), 2.37-2.41 (m, 2H), 1.45-1.51 (m, 2H),
1.28-1.35 (m, 2H). LC/MS (ES, m/z): 610 [M+H]+.
Example PH-69
5-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)methyl)picolinamide 2,2,2-trifluoroacetate
##STR00277##
[0630] The title compound was prepared according to the procedure
as described in Example PH-53 and PH-54, substituting methyl
5-formylpyridine-2-carboxylate for methyl 3-formylbenzoate in Step
1.
[0631] .sup.1H NMR (300 MHz, DMSO) .delta.: 8.82 (s, 1H), 8.16-8.25
(m, 2H), 7.95 (s, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.27-7.34 (m, 5H),
7.10 (d, J=8.4 Hz, 4H), 5.83 (s, 1H), 5.19-5.30 (m, 1H), 4.51 (s,
2H), 3.73-3.83 (m, 2H), 3.34-3.56 (m, 2H), 2.88-3.09 (m, 2H),
2.50-2.60 (m, 1H), 2.34-2.38 (m, 2H), 1.26-1.49 (m, 4H). LC/MS (ES,
m/z): 610 [M+H]+.
Example PH-70
3-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)methyl)-2-fluorobenzoic acid
##STR00278##
[0632] Step 1: Synthesis of methyl
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]-2-fluorobenzoate
[0633] Into a 100-mL round-bottom flask, was placed a solution of
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-(piperidin-4-yl)-1H-1,3-ben-
zodiazole (250 mg, 0.52 mmol, 1.00 equiv) in CH.sub.3CN (15 mL),
methyl 3-(bromomethyl)-2-fluorobenzoate (155 mg, 0.63 mmol, 1.20
equiv) and potassium carbonate (219 mg, 1.58 mmol, 3.00 equiv). The
resulting solution was stirred overnight at room temperature. The
resulting mixture was concentrated under vacuum. The resulting
solution was diluted with water (20 mL). The resulting solution was
extracted with ethyl acetate (3.times.30 mL) and the organic layers
combined, then dried over anhydrous sodium sulfate. The resulting
mixture was concentrated under vacuum. The residue was applied onto
a silica gel column with ethyl acetate/petroleum ether (35%) to
yield methyl
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]-2-fluorobenzoate as colorless oil.
Step 2: Synthesis of
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]-2-fluorobenzoic acid
[0634] Into a 100-mL round-bottom flask, was placed a solution of
methyl
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]-2-fluorobenzoate (290 mg, 0.45 mmol, 1.00
equiv) in methanol/THF/H.sub.2O (4 ml/12 ml/4 mL), and
LiOH*H.sub.2O (927 mg, 22.09 mmol, 50.00 equiv). The resulting
solution was stirred overnight at room temperature. The resulting
mixture was concentrated under vacuum. The pH value of the solution
was adjusted to pH 4-5 with hydrogen chloride (1%). The solids were
collected by filtration. The residue was applied onto a C18 silica
gel column with CH.sub.3CN/H.sub.2O (TFA) (30%) to yield
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzod-
iazol-1-yl]piperidin-1-yl)methyl]-2-fluorobenzoic acid as a white
solid.
[0635] 1H NMR (300 MHz, CD3OD) .delta.: 7.92 (t, J=6.0 Hz, 1H),
7.61-7.67 (m, 2H), 7.48 (d, J=8.4 Hz, 1H), 7.28-7.35 (m, 5H), 7.09
(d, J=8.7 Hz, 4H), 6.94 (d, J=1.2 Hz, 1H), 5.70 (s, 1H), 4.08 (s,
2H), 3.43 (d, J=12.3 Hz, 2H), 2.87 (t, J=11.4 Hz, 2H), 2.60-2.73
(m, 2H), 2.23-2.30 (m, 1H), 2.05 (d, J=10.2 Hz, 2H), 1.09-1.21 (m,
4H). LC/MS (ES, m/z): 628 [M+H]+.
Example PH-71
3-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)piperidin-1-yl)methyl)-4-fluorobenzoic acid
##STR00279##
[0637] The title compound was prepared according to the procedure
as described in Example PH-70 substituting methyl
3-(bromomethyl)-4-fluorobenzoate for methyl
3-(bromomethyl)-2-fluorobenzoate in Step 1.
[0638] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 8.35 (d, J=7.2
Hz, 1H), 8.24-8.28 (m, 1H), 7.91 (s, 1H), 7.66 (s, 1H), 7.44 (t,
J=9.2 Hz, 1H), 7.27-7.34 (m, 5H), 7.11 (d, J=8.4 Hz, 4H), 5.82 (s,
1H), 5.27 (s, 1H), 4.54 (s, 2H), 3.81 (d, J=12.4 Hz, 2H), 3.40-3.46
(m, 2H), 2.90 (t, J=11.6 Hz, 2H), 2.53-2.57 (m, 1H), 2.38 (d,
J=12.8 Hz, 2H), 1.45-1.50 (m, 2H), 1.32-1.36 (m, 2H). LC/MS (ES,
m/z): 628 [M+H]+.
Example PH-72
3-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)methyl)-5-fluorobenzoicacid
##STR00280##
[0640] The title compound was prepared according to the procedure
as described in Example PH-70 substituting methyl
3-(bromomethyl)-5-fluorobenzoate for methyl
3-(bromomethyl)-2-fluorobenzoate in Step 1.
[0641] .sup.1H NMR (400 MHz, CD3OD) .delta.: 8.08 (s, 1H), 7.92 (s,
1H), 7.88 (d, J=7.6 Hz, 1H), 7.61-7.67 (m, 2H), 7.32-7.34 (m, 4H),
7.27 (d, J=8.8 Hz, 1H), 7.11 (d, J=8.4 Hz, 4H), 5.83 (s, 1H),
5.19-5.30 (m, 1H), 4.47 (s, 2H), 3.75 (d, J=12.0 Hz, 2H), 3.32-3.37
(m, 1H), 2.84-2.93 (m, 2H), 2.52-2.59 (m, 1H), 2.36 (d, J=13.2 Hz,
2H), 1.44-1.49 (m, 2H), 1.31-1.35 (m, 2H). LC/MS (ES, m/z): 628
[M+H]+.
Example PH-73
2,2,2-trifluoroacetic acid compound with
5-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)methyl)-2-fluorobenzoic acid (1:1)
##STR00281##
[0643] The title compound was prepared according to the procedure
as described in Example PH-70 substituting methyl
5-(bromomethyl)-2-fluorobenzoate for methyl
3-(bromomethyl)-2-fluorobenzoate in Step 1.
[0644] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.: 8.17 (d, J=1.8
Hz, 1H), 7.78-7.88 (m, 2H), 7.64 (d, J=8.4 Hz, 1H), 7.19-7.42 (m,
6H), 7.08 (d, J=8.4 Hz, 4H), 5.81 (s, 1H), 5.22 (brs, 1H), 4.43 (s,
2H), 3.72-3.75 (m, 2H), 3.31-3.32 (m, 2H), 2.82-2.96 (m, 2H),
2.41-2.55 (m, 1H), 2.03-2.37 (m, 2H), 1.31-1.45 (m, 4H). LC/MS (ES,
m/z): 628 [M+H]+.
Example PH-74
3-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)piperidin-1-yl)methyl)-2-chlorobenzoic acid
##STR00282##
[0645] Step 1: Synthesis of
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]-2-chlorobenzonitrile
[0646] Into a 50-mL round-bottom flask, was placed a solution of
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-(piperidin-4-yl)-1H-1,3-ben-
zodiazole (200 mg, 0.42 mmol, 1.00 equiv) in dichloromethane (8
mL), 2-chloro-3-formylbenzonitrile (77 mg, 0.47 mmol, 1.10 equiv)
and TEA (0.5 mL). The resulting solution was stirred overnight at
room temperature. To the mixture was then added NaBH(OAc).sub.3
(233 mg, 1.10 mmol, 2.50 equiv). The resulting solution was stirred
for 3 h at room temperature. The resulting mixture was concentrated
under vacuum. The residue was applied onto a silica gel column with
ethyl acetate/petroleum ether (45%) to yield
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzod-
iazol-1-yl]piperidin-1-yl)methyl]-2-chlorobenzonitrile as a pink
solid. LC/MS (ES, m/z): 626 [M+H]+.
Step 2: Synthesis of
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]-2-chlorobenzoic acid
[0647] Into a 100-mL round-bottom flask, was placed a solution of
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]-2-chlorobenzonitrile (200 mg, 0.32 mmol,
1.00 equiv) in ethanol (10 mL) and a solution of sodium hydroxide
(128 mg, 3.20 mmol, 10.00 equiv) in water (10 mL). The resulting
solution was stirred overnight at 80.degree. C. in an oil bath. The
resulting mixture was concentrated under vacuum. The pH value of
the solution was adjusted to pH 4-5 with hydrogen chloride (1%).
The solids were collected by filtration. The residue was applied
onto a C18 reversed column with CH.sub.3CN/H.sub.2O (TFA) (55%) to
yield
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]-2-chlorobenzoic acid as a white solid.
[0648] .sup.1H NMR (400 MHz, CD3OD) .delta.: 7.84-7.96 (m, 3H),
7.65 (d, J=8.4 Hz, 1H), 7.58 (t, J=7.6 Hz, 1H), 7.33 (d, J=8.4 Hz,
4H), 7.25 (d, J=8.4 Hz, 1H), 7.11 (d, J=8.4 Hz, 4H), 5.82 (s, 1H),
5.26-5.32 (m, 1H), 4.61 (s, 2H), 3.79 (d, J=10.8 Hz, 2H), 3.46-3.54
(m, 2H), 2.79-2.98 (m, 2H), 2.53-2.53 (m, 1H), 2.35 (d, J=13.2 Hz,
2H), 1.46 (d, J=8.4 Hz, 2H), 1.28-1.34 (m, 2H). LC/MS (ES, m/z):
644 [M+H]+.
Example PH-75
2,2,2-trifluoroacetic acid compound with
3-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)methyl)-4-chlorobenzoic acid (1:1)
##STR00283##
[0650] The title compound was prepared according to the procedure
as described in Example PH-70 substituting methyl
3-(bromomethyl)-4-chlorobenzoate for methyl
3-(bromomethyl)-2-fluorobenzoate in Step 1.
[0651] .sup.1H NMR (300 MHz, CD3OD) .delta.: 8.37 (s, 1H), 8.14 (d,
J=6.3 Hz, 1H), 7.86 (brs, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.65 (d,
J=8.7 Hz, 1H), 7.25-7.33 (m, 5H), 7.09 (d, J=8.7 Hz, 4H), 5.81 (s,
1H), 5.26 (brs, 1H), 4.60-4.66 (m, 2H), 3.73-3.76 (m, 2H),
3.46-3.55 (m, 2H), 2.79-2.89 (m, 2H), 2.53-2.56 (m, 1H), 2.33-2.37
(m, 2H), 1.45-1.47 (m, 2H), 1.34 (brs, 2H). LC/MS (ES, m/z): 644
[M+H]+.
Example PH-76
3-(1-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-
-yl)piperidin-1-yl)ethyl)benzoic acid
##STR00284##
[0653] The title compound was prepared according to the procedure
as described in Example PH-70 substituting methyl
3-(1-bromoethyl)benzoate for methyl
3-(bromomethyl)-2-fluorobenzoate in Step 1.
[0654] .sup.1H NMR (300 MHz, DMSO) .delta.: 12.88 (brs, 1H),
7.84-7.90 (m, 2H), 7.47-7.59 (m, 2H), 7.31-7.42 (m, 6H), 7.14 (d,
J=8.1 Hz, 4H), 6.83 (d, J=9.0 Hz, 1H), 5.83 (s, 1H), 4.43-4.48 (m,
1H), 3.63-3.68 (m, 1H), 3.04-3.07 (m, 1H), 2.90-2.94 (m, 1H),
2.00-2.27 (m, 5H), 1.73-1.81 (m, 2H), 1.35-1.37 (m, 3H), 0.83-1.00
(m, 4H).
[0655] LC/MS (ES, m/z): 624 [M+H]+.
Example PH-77
2,2,2-trifluoroacetic acid compound with
4-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)methyl)picolinic acid (1:1)
##STR00285##
[0657] The title compound was prepared according to the procedure
as described in Example PH-70 substituting methyl
4-(bromomethyl)pyridine-2-carboxylate for methyl
3-(bromomethyl)-2-fluorobenzoate in Step 1.
[0658] .sup.1H NMR (400 MHz, CD3OD) .delta.: 8.80 (d, J=4.4 Hz,
1H), 8.37 (s, 1H), 7.92 (s, 1H), 7.82-7.86 (m, 1H), 7.67 (d, J=8.4
Hz, 1H), 7.20-7.44 (m, 5H), 7.13 (d, J=8.4 Hz, 4H), 5.86 (s, 1H),
5.19 (m, 1H), 4.44 (s, 2H), 3.50-3.62 (m, 2H), 3.11-3.34 (m, 2H),
2.82-2.88 (m, 2H), 2.55-2.64 (m, 1H), 2.28-2.31 (m, 2H), 1.42-1.49
(m, 2H), 1.28-1.35 (m, 2H). LC/MS (ES, m/z): 611 [M+H]+.
Example PH-78
2-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)methyl)isonicotinic acid
##STR00286##
[0660] The title compound was prepared according to the procedure
as described in Example PH-70 substituting methyl
2-(bromomethyl)pyridine-4-carboxylate in step 1 was used instead of
methyl 3-(bromomethyl)-2-fluorobenzoate in Step 1.
[0661] .sup.1H NMR (400 MHz, CD3OD) .delta.: 8.90 (d, J=5.2 Hz,
1H), 8.10 (s, 1H), 8.00 (s, 2H), 7.67 (d, J=8.4 Hz, 1H), 7.34 (t,
J=8.0 Hz, 4H), 7.28 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.8 Hz, 4H), 5.85
(s, 1H), 5.28-5.35 (m, 1H), 4.66 (s, 2H), 3.88 (d, J=12.4 Hz, 2H),
3.50 (t, J=11.2 Hz, 2H), 2.92-3.01 (m, 2H), 2.55-2.62 (m, 1H), 2.39
(d, J=13.2 Hz, 2H), 1.45-1.50 (m, 2H), 1.33-1.37 (m, 2H). LC/MS
(ES, m/z): 611 [M+H]+.
Example PH-79
2-[1-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1--
yl]piperidin-1-yl)ethyl]pyridine-4-carboxylic acid
##STR00287##
[0663] The title compound was prepared according to the procedure
as described in Example PH-70 substituting methyl
2-(1-bromoethyl)pyridine-4-carboxylate for methyl
3-(bromomethyl)-2-fluorobenzoate in Step 1.
[0664] .sup.1H NMR (300 MHz, DMSO) .delta.: 8.72 (d, J=5.1 Hz, 1H),
7.88 (s, 1H), 7.70 (d, J=5.1 Hz, 1H), 7.36-7.41 (m, 6H), 7.13 (d,
J=7.5 Hz, 4H), 6.82 (d, J=7.2 Hz, 1H), 5.82 (s, 1H), 4.32-4.52 (m,
1H), 3.90-3.92 (m, 1H), 3.01-3.11 (m, 1H), 2.92-2.99 (m, 1H),
2.22-2.27 (m, 5H), 1.72-1.83 (m, 2H), 1.41 (d, J=6.9 Hz, 3H),
0.95-0.99 (m, 4H). LC/MS (ES, m/z): 625 [M+H]+.
Example PH-80
5-(1-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-
-yl)piperidin-1-yl)ethyl)furan-2-carboxylic acid
##STR00288##
[0666] The title compound was prepared according to the procedure
as described in Example PH-70 substituting methyl
5-(1-bromoethyl)furan-2-carboxylate for methyl
3-(bromomethyl)-2-fluorobenzoate in Step 1.
[0667] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.: 7.64 (s, 1H),
7.47 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 4H), 7.05-7.11 (m, 5H),
6.93 (d, J=9.6 Hz, 1H), 6.59 (d, J=3.3 Hz, 1H), 5.71 (s, 1H),
4.77-5.00 (m, 1H), 4.34-4.41 (m, 1H), 3.41 (s, 2H), 2.93 (t, J=10.8
Hz, 1H), 2.58-2.75 (m, 3H), 2.18-2.27 (m, 1H), 2.05 (d, J=11.7 Hz,
2H), 1.66 (d, J=6.9 Hz, 3H), 1.06-1.17 (m, 4H). LC/MS (ES, m/z):
614 [M+H]+.
Example PH-81
3-[1-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1--
yl]piperidin-1-yl)propyl]benzoic acid; trifluoroacetic acid
##STR00289##
[0669] The title compound was prepared according to the procedure
as described in Example PH-70 substituting methyl
3-(1-bromopropyl)benzoate for methyl
3-(bromomethyl)-2-fluorobenzoate, in Step 1.
[0670] .sup.1H NMR (300 MHz, DMSO-d6) .delta.: 9.90 (brs, 1H), 8.15
(s, 1H), 8.08 (d, J=7.5 Hz, 1H), 7.72 (d, J=9.6 Hz, 1H), 7.66-7.69
(m, 2H), 7.54 (d, J=8.4 Hz, 1H), 7.38 (d, J=8.4 Hz, 4H), 7.10 (d,
J=2.4 Hz, 4H), 6.93 (d, J=8.1 Hz, 1H), 5.72 (s, 1H), 4.90-5.08 (m,
1H), 4.58-4.61 (m, 1H), 3.79 (m, 1H), 3.65 (m, 1H), 2.94-2.97 (m,
2H), 2.68-2.72 (m, 2H), 2.34-2.36 (m, 2H), 2.14-2.17 (m, 3H), 1.14
(s, 4H), 0.71 (t, J=6.9 Hz, 3H). LC/MS (ES, m/z): 638 [M+H]+.
Example PH-82
2,2,2-trifluoroacetic acid compound with
3-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)methyl)-2-hydroxybenzoic acid (1:1)
##STR00290##
[0671] Step 1: Synthesis of
2-cyclopropyl-1H-1,3-benzodiazol-1-yl]piperidin-1-yl)methyl]-6-bromopheno-
l
[0672] Into a 100-mL round-bottom flask, was placed a solution of
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-(piperidin-4-yl)-1H-1,3-ben-
zodiazole (300 mg, 0.63 mmol, 1.00 equiv) in dichloromethane (30
mL), 3-bromo-2-hydroxybenzaldehyde (127 mg, 0.63 mmol, 1.00 equiv)
and acetic acid (a catalytic amount). The resulting solution was
stirred for 4 h at room temperature NaBH(OAc).sub.3 (335 mg, 2.50
equiv). The resulting solution was stirred for overnight at room
temperature. The residue was applied onto a silica gel column with
ethyl acetate/petroleum ether (1:1) to yield
2-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzod-
iazol-1-yl]piperidin-1-yl)methyl]-6-bromophenol as a white solid.
LC/MS (ES, m/z): 661 [M+H]+
Step 2: Synthesis of
6-[bis(4-chlorophenyl)methyl]-1-(1-[[3-bromo-2-(methoxymethoxy)
phenyl]methyl]piperidin-4-yl)-2-cyclopropyl-1H-1,3-benzodiazole
[0673] Into a 50-mL round-bottom flask, was placed a solution of
2-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]-6-bromophenol (170 mg, 0.26 mmol, 1.00
equiv) in tetrahydrofuran (10 mL), sodium hydride (15.5 mg, 0.39
mmol, 1.50 equiv) and MOMBr (42 mg, 1.30 equiv). The resulting
solution was stirred for 2 h at room temperature. The reaction was
then quenched by the addition of water (2 mL). The resulting
solution was extracted with ethyl acetate (3.times.5 mL) and the
organic layers combined, then dried over anhydrous sodium sulfate
and concentrated under vacuum to yield
6-[bis(4-chlorophenyl)methyl]-1-(1-[[3-bromo-2-(methoxymethoxy)
phenyl]methyl]piperidin-4-yl)-2-cyclopropyl-1H-1,3-benzodiazole as
a yellow solid. LC/MS (ES, m/z): 705.5 [M+H]+
Step 3: Synthesis of methyl
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]-2-(methoxymethoxy)benzoate
[0674] Into a 30-mL pressure tank reactor (3.5 atm), was placed a
solution of
6-[bis(4-chlorophenyl)methyl]-1-(1-[[3-bromo-2-(methoxymethoxy)phenyl]-
methyl]piperidin-4-yl)-2-cyclopropyl-1H-1,3-benzodiazole (100 mg,
0.14 mmol, 1.00 equiv) in DMF/MeOH (1/1 mL), Pd(OAc).sub.2 (3.0 mg,
0.01 mmol, 0.10 equiv), dppf (7.4 mg, 0.01 mmol, 0.10 equiv) and
triethylamine (1.3 mg, 0.01 mmol, 0.10 equiv). To the resulting
mixture was then introduced CO(g). The resulting solution was
stirred overnight at 130.degree. C. The resulting mixture was
concentrated under vacuum to yield methyl
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]-2-(methoxymethoxy)benzoate as brown oil.
LC/MS (ES, m/z): 685 [M+H]+
Step 4: Synthesis of methyl
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]-2-hydroxybenzoate
[0675] Into a 50-mL round-bottom flask, was placed a solution of
methyl
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]-2-(methoxymethoxy)benzoate (170 mg, 0.25
mmol, 1.00 equiv) in dichloromethane (20 mL) and CF.sub.3COOH (10
mL). The resulting solution was stirred overnight at room
temperature. The resulting mixture was concentrated under vacuum to
yield methyl
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]-2-hydroxybenzoate as brown oil.
[0676] LC/MS (ES, m/z): 641 [M+H]+
Step 5: Synthesis of
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]-2-hydroxybenzoic acid trifluoroacetic
acid
[0677] Into a 50-mL round-bottom flask, was placed a solution of
methyl
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]-2-hydroxybenzoate (100 mg, 0.16 mmol, 1.00
equiv) in tetrahydrofuran/MeOH (20/5 mL) and LiOH (20 mL). The
resulting solution was stirred overnight at room temperature. The
resulting mixture was concentrated under vacuum. The pH value of
the solution was adjusted to pH 6 with hydrogen chloride (12
mol/L). The solids were collected by filtration. The product
residue (50 mg) was purified by Prep-HPLC with the following
conditions (Waters 2767-1)): Column, Sunfire Prep C18.5 um, 19*100
mm; mobile phase, trifluoroacetic acid in water and CH.sub.3CN (25%
CH.sub.3CN up to 50% in 10 min); Detector, UV 254 nm to yield
3-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]piperidin-1-yl)methyl]-2-hydroxybenzoic acid trifluoroacetic acid
as a pink solid.
[0678] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.: 8.07 (d, J=7.5
Hz, 1H), 7.97 (s, 1H), 7.64-7.73 (m, 2H), 7.26-7.42 (m, 5H),
7.08-7.11 (m, 5H), 5.81 (s, 1H), 5.29 (s, 1H), 4.31-4.59 (m, 2H),
3.63-3.96 (m, 2H), 3.38-3.55 (m, 2H), 2.71-3.11 (m, 2H), 2.45-2.68
(m, 1H), 2.22-2.37 (m, 2H), 1.45-1.94 (m, 2H), 1.23-1.34 (m, 2H).
LC/MS (ES, m/z): 626 [M+H]+.
Example PH-83
2,2,2-trifluoroacetic acid compound with
5-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)methyl)-2-hydroxybenzoic acid (1:1)
##STR00291##
[0680] The title compound was prepared according to the procedure
as described in Example PH-53 substituting methyl
5-formyl-2-hydroxybenzoate for methyl 3-formylbenzoate in Step
1.
[0681] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.13 (s, 1H), 7.99
(s, 1H), 7.66-7.77 (m, 2H), 7.31-7.77 (m, 4H), 7.25-7.27 (d, J=8.4
Hz, 1H), 7.01-7.17 (m, 5H), 5.81 (s, 1H), 5.27 (s, 1H), 4.31-4.39
(m, 2H), 3.76-3.79 (m, 2H), 3.51-3.53 (m, 2H), 2.77-2.92 (m, 2H),
2.48-2.55 (m, 1H), 2.35-2.39 (m, 2H), 1.25-1.47 (m, 4H). LC/MS (ES,
m/z): 626 [M+H]+.
Example PH-84
4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]-N--
phenylpiperidine-1-carboxamide; trifluoroacetic acid
##STR00292##
[0683] Into a 50-mL round-bottom flask, was placed a solution of
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-(piperidin-4-yl)-1H-1,3-ben-
zodiazole (150 mg, 0.31 mmol, 1.00 equiv) in dichloromethane (10
mL), isocyanatobenzene (45 mg, 0.38 mmol, 1.20 equiv) and
triethylamine (96 mg, 0.95 mmol, 3.00 equiv). The resulting
solution was stirred overnight at room temperature. The resulting
mixture was concentrated under vacuum. The product residue was
purified by Prep-HPLC with the following conditions (Waters2767-1):
Column, Sunfire Prep C18, 5 um, 19*100 mm; mobile phase, 0.03%
ammonia in water and CH.sub.3CN (55% CH.sub.3CN up to 95% in 10
min); Detector, UV 254 nm to yield
4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]-N-
-phenyl]piperidine-1-carboxamide as a white solid.
[0684] .sup.1H NMR (400 MHz, DMSO-d6) .delta.: 8.62 (s, 1H), 7.49
(d, J=7.6 Hz, 2H), 7.44 (d, J=4.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 4H),
7.24 (t, J=7.6 Hz, 2H), 7.09 (d, J=8.4 Hz, 4H), 6.95 (t, J=7.6 Hz,
1H), 6.84 (d, J=8.8 Hz, 1H), 5.77 (s, 1H), 4.84-4.90 (m, 1H), 4.33
(d, J=13.2 Hz, 2H), 3.02 (t, J=12.4 Hz, 2H), 2.21-2.34 (m, 3H),
1.91 (d, J=10.8 Hz, 2H), 1.00-1.08 (m, 4H). LC/MS (ES, m/z): 595
[M+H]+.
Example PH-85
N-benzyl-4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-
-1-yl]piperidine-1-carboxamide
##STR00293##
[0686] The title compound was prepared according to the procedure
as described in Example PH-84 substituting
(isocyanatomethyl)benzene for isocyanatobenzene in Step 1.
[0687] .sup.1H NMR (300 MHz, DMSO-d6) .delta.: 7.29-7.44 (m, 6H),
7.26-7.27 (m, 4H), 7.16-7.22 (m, 2H), 7.09-7.12 (m, 4H), 6.82 (d,
J=6.2 Hz, 1H), 5.75 (s, 1H), 4.80 (br s, 1H), 4.26 (d, J=5.7 Hz,
2H), 4.16-4.20 (m, 2H), 2.87-2.95 (m, 2H), 2.15-2.27 (m, 3H),
1.81-1.85 (m, 2H), 1.00-1.02 (m, 4H). LC/MS (ES, m/z): 609
[M+H]+.
Example PH-86
4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)-N-
-ethylpiperidine-1-carboxamide
##STR00294##
[0689] The title compound was prepared according to the procedure
as described in Example PH-84 substituting
(isocyanatomethyl)benzene for isocyanatoethane in Step 1.
[0690] .sup.1H NMR (400 MHz, DMSO-d6) .delta.: 7.43 (d, J=8.4 Hz,
1H), 7.35-7.38 (m, 5H), 7.10-7.12 (m, 4H), 6.76-6.85 (m, 1H), 6.56
(s, 1H), 5.77 (s, 1H), 4.76-4.89 (m, 1H), 4.11-4.15 (m, 2H),
3.05-3.08 (m, 2H), 2.85-2.96 (m, 2H), 2.29-2.31 (m, 1H), 2.10-2.20
(m, 2H), 1.75-1.87 (m, 2H), 1.00-1.03 (m, 7H). LC/MS (ES, m/z) 547
[M+H]+.
Example PH-87
Phenyl
4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol--
1-yl)piperidine-1-carboxylate 2,2,2-trifluoroacetate
##STR00295##
[0692] Into a 100-mL round-bottom flask, was placed a solution of
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-(piperidin-4-yl)-1H-1,3-ben-
zodiazole (100 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (30
mL), phenyl chloroformate (40 mg, 0.26 mmol, 1.20 equiv) and
triethylamine (64 mg, 0.63 mmol, 3.00 equiv).
[0693] The resulting solution was stirred overnight at room
temperature. The resulting mixture was concentrated under vacuum.
The product residue was purified by Prep-HPLC with the following
conditions (Waters2767-1): Column, Sunfire Prep C18.5 um, 19*100
mm; mobile phase, 0.05% trifluoroacetic acid in water and
CH.sup.3CN (CH.sub.3CN 10% up to 60% in 9 min); Detector, 254 nm to
yield phenyl
4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]pi-
peridine-1-carboxylate; trifluoroacetic acid as a white solid.
[0694] .sup.1H NMR (300 MHz, DMSO-d6) .delta.: 7.84 (s, 1H), 7.62
(d, J=8.4 Hz, 1H), 7.37-7.44 (m, 6H), 7.21-7.28 (m, 1H), 7.12-7.15
(m, 7H), 5.94 (m, 1H), 5.01-5.94 (m, 1H), 4.11-4.36 (m, 2H),
3.15-3.28 (m, 2H), 2.55-2.64 (m, 1H), 2.41-2.29 (m, 2H), 2.04-2.08
(m, 2H), 1.25-1.27 (m, 4H). LC/MS (ES, m/z) 596 [M+H]+.
Example PH-88
benzyl
4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol--
1-yl)piperidine-1-carboxylate
##STR00296##
[0696] The title compound was prepared according to the procedure
as described in Example PH-87 substituting benzyl carbonochloridate
for phenyl chloroformate in Step 1.
[0697] .sup.1H NMR (400 MHz, DMSO-d6) .delta.: 7.30-7.44 (m, 11H),
7.11 (m, 4H), 6.82 (d, J=8.4 Hz, 1H), 5.79 (s, 1H), 5.14 (brs, 2H),
4.80-4.86 (m, 2H), 3.02 (brs, 2H), 2.08-2.34 (m, 3H), 1.86-1.89 (m,
2H), 1.01-1.06 (m, 4H). LC/MS (ES, m/z): 610 [M+H]+.
Example PH-89
cyclopentyl4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imida-
zol-1-yl)piperidine-1-carboxylate
##STR00297##
[0699] The title compound was prepared according to the procedure
as described in Example PH-87 substituting cyclopentyl
carbonochloridate for phenyl chloroformate in Step 1.
[0700] .sup.1H NMR (400 MHz, DMSO-d6) .delta.: 7.30-7.44 (m, 6H),
7.11 (d, J=8.4 Hz, 4H), 6.82 (d, J=8.7 Hz, 1H), 5.79 (s, 1H), 5.14
(brs, 2H), 4.80-4.86 (m, 2H), 2.90-3.06 (m, 2H), 2.08-2.34 (m, 3H),
1.70-1.89 (m, 4H), 1.51-1.69 (m, 6H), 1.01-1.06 (m, 4H). LC/MS (ES,
m/z): 588 [M+H]+.
Example PH-90
ethyl
4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-
-yl)piperidine-1-carboxylate
##STR00298##
[0702] The title compound was prepared according to the procedure
as described in Example PH-87 substituting ethyl carbonochloridate
for phenyl chloroformate in Step 1.
[0703] .sup.1H NMR (300 MHz, DMSO-d6) .delta.: 7.34-7.35 (m, 6H),
7.10-7.13 (m, 4H), 6.82 (d, J=8.4 Hz, 1H), 5.80 (s, 1H), 4.77-4.85
(m, 1H), 4.04-4.17 (m, 4H), 2.90-3.10 (brs, 2H), 2.12-2.33 (m, 3H),
1.83-1.86 (m, 2H), 1.18-1.23 (m, 3H), 1.01-1.04 (m, 4H). LC/MS (ES,
m/z): 548 [M+H]+.
Example PH-91
2,2,2-trifluoroacetic acid compound with
3-((3-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)azetidin-1-yl)methyl)benzoic acid (1:1)
##STR00299##
[0704] Step 1: Synthesis of methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate
[0705] Into a 1000-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of nitrogen, was placed a
solution of methyl 2,2-bis(4-chlorophenyl) acetate (54 g, 182.95
mmol, 1.00 equiv) in tetrahydrofuran (250 mL). To the mixture was
then added t-BuOK (201 mL, 1.10 equiv) dropwise with stirring at
0.degree. C. in 20 min. To the resulting mixture was added a
solution of 2,4-difluoro-1-nitrobenzene (37.5 g, 235.72 mmol, 1.05
equiv) in tetrahydrofuran (250 mL) dropwise with stirring. The
resulting solution was stirred overnight at room temperature. The
residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:20) to yield methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate as yellow
oil.
Step 2: Synthesis of yield
tert-butyl3-([5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-nitrophe-
nyl] amino)azetidine-1-carboxylate
[0706] Into a 250-mL round-bottom flask, was placed tert-butyl
3-aminoazetidine-1-carboxylate (2.38 g, 13.82 mmol, 1.20 equiv),
DIEA (4.45 g, 34.43 mmol, 3.00 equiv), CH.sub.3CN (100 mL) and
methyl 2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate
(5.0 g, 11.51 mmol, 1.00 equiv). The resulting solution was heated
to reflux for 72 h in an oil bath. The resulting mixture was
concentrated under vacuum. The residue was applied onto a silica
gel column with ethyl acetate/petroleum ether (1:5) to yield
tert-butyl3-([5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-nitrophe-
nyl] amino)azetidine-1-carboxylate as yellow oil.
[0707] LC/MS (ES, m/z): 586 [M+H]+.
Step 3: Synthesis of tert-butyl
3-([2-amino-5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]phenyl]amino)-
azetidine-1-carboxylate
[0708] Into a 250-mL round-bottom flask, was placed a solution of
tert-butyl
3-([5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-nitrophenyl]amino)-
azetidine-1-carboxylate (4.4 g, 7.50 mmol, 1.00 equiv) in
tetrahydrofuran/MeOH (60/30 mL) and Raney Ni (8 g). Hydrogen was
then introduced into the resulting mixture. The resulting solution
was stirred overnight at room temperature. The solids were filtered
out. The resulting mixture was concentrated under vacuum to yield
tert-butyl
3-([2-amino-5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]phenyl]amino)-
azetidine-1-carboxylate as yellow oil. LC/MS (ES, m/z): 556
[M+H]+.
Step 4: Synthesis of tert-butyl
3-([5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-cyclopropaneamidop-
henyl]amino)azetidine-1-carboxylate
[0709] Into a 250-mL round-bottom flask, was placed a solution of
tert-butyl
3-([2-amino-5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]phenyl]amino)-
azetidine-1-carboxylate (3.87 g, 6.12 mmol, 1.00 equiv, 88%) in
dichloromethane (100 mL), triethylamine (2.112 g, 20.87 mmol, 3.00
equiv) and cyclopropanecarbonyl chloride (729 mg, 6.97 mmol, 1.00
equiv). The resulting solution was stirred overnight at room
temperature. The resulting mixture was concentrated under vacuum.
The resulting mixture was washed with water (1.times.100 mL). The
resulting solution was extracted with DCM (2.times.100 mL) and the
organic layers combined, then concentrated under vacuum to yield
tert-butyl
3-([5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-cyclopropaneamidop-
henyl]amino)azetidine-1-carboxylate as light yellow oil. LC/MS (ES,
m/z): 625 [M+H]+.
Step 5: Synthesis of tert-butyl
3-[6-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-cyclopropyl-1H-1,3--
benzodiazol-1-yl]azetidine-1-carboxylate
[0710] Into a 250-mL round-bottom flask, was placed tert-butyl
3-([5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-cyclopropaneamidop-
henyl]amino)azetidine-1-carboxylate (4.38 g, 7.01 mmol, 1.00 equiv)
and acetic acid (150 mL). The resulting solution was stirred for 3
h at 120.degree. C. The resulting mixture was concentrated under
vacuum. The residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:5) to yield tert-butyl
3-[6-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-cyclopropyl-1H-1,3--
benzodiazol-1-yl]azetidine-1-carboxylate as light yellow oil.
Step 6: Synthesis of
2-(1-[1-[(tert-butoxy)carbonyl]azetidin-3-yl]-2-cyclopropyl-1H-1,3-benzod-
iazol-6-yl)-2,2-bis(4-chlorophenyl)acetic acid
[0711] Into a 250-mL round-bottom flask, was placed tert-butyl
3-[6-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-cyclopropyl-1H-1,3--
benzodiazol-1-yl]azetidine-1-carboxylate (1.6 g, 2.64 mmol, 1.00
equiv), sodium hydroxide (6.0 g, 150.00 mmol, 57.00 equiv),
methanol (50 mL), water (50 mL) and tetrahydrofuran (20 mL). The
resulting solution was stirred overnight at room temperature. The
resulting mixture was concentrated under vacuum. The pH value of
the solution was adjusted to pH 7.0 with hydrogen chloride (3
mol/L). The solids were collected by filtration to yield
2-(1-[1-[(tert-butoxy)carbonyl]azetidin-3-yl]-2-cyclopropyl-1H-1,3-benzod-
iazol-6-yl)-2,2-bis(4-chlorophenyl)acetic acid as a white
solid.
Step 7: Synthesis of tert-butyl
3-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]az-
etidine-1-carboxylate
[0712] Into a 100-mL round-bottom flask, was placed
2-(1-[1-[(tert-butoxy)carbonyl]azetidin-3-yl]-2-cyclopropyl-1H-1,3-benzod-
iazol-6-yl)-2,2-bis(4-chlorophenyl)acetic acid (1.0 g, 1.69 mmol,
1.00 equiv), toluene (30 mL) and DBU (1.27 g, 8.34 mmol, 6.00
equiv). The resulting solution was stirred for 3 h at 90.degree. C.
in an oil bath. The resulting mixture was washed with water (100
mL). The resulting solution was extracted with ethyl acetate
(3.times.100 mL) and the organic layers combined, then dried over
anhydrous sodium sulfate. The residue was applied onto a silica gel
column with ethyl acetate/petroleum ether (1:1) to yield tert-butyl
3-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]az-
etidine-1-carboxylate as light yellow oil.
Step 8: Synthesis of
1-(azetidin-3-yl)-6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benz-
odiazole
[0713] Into a 50-mL round-bottom flask, was placed tert-butyl
3-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]az-
etidine-1-carboxylate (800 mg, 1.46 mmol, 1.00 equiv),
dichloromethane (15 mL) and trifluoroacetic acid (5 mL). The
resulting solution was stirred for 3 h at room temperature. The
resulting mixture was concentrated under vacuum. The residue was
applied onto a silica gel column with ethyl acetate/petroleum ether
(3:1) to yield
1-(azetidin-3-yl)-6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benz-
odiazole as a white solid.
Step 9: Synthesis of methyl
3-[(3-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]azetidin-1-yl)methyl]benzoate
[0714] Into a 50-mL round-bottom flask, was placed a solution of
1-(azetidin-3-yl)-6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benz-
odiazole (200 mg, 0.45 mmol, 1.00 equiv) in dichloromethane (30
mL), methyl 3-formylbenzoate (88 mg, 0.54 mmol, 1.20 equiv), acetic
acid (0.1 mL), NaBH(OAc).sub.3 (285 mg, 1.34 mmol, 3.00 equiv). The
resulting solution was stirred overnight at room temperature. The
resulting mixture was concentrated under vacuum. The residue was
applied onto a silica gel column with ethyl acetate/petroleum ether
(1:1) to yield methyl
3-[(3-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]azetidin-1-yl)methyl]benzoate as a white solid. LC/MS (ES, m/z):
597 [M+H]+.
Step 10: Synthesis of
3-[(3-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l] azetidin-1-yl)methyl]benzoic acid trifluoroacetic acid
[0715] Into a 50-mL round-bottom flask, was placed a solution of
methyl
3-[(3-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]azetidin-1-yl)methyl]benzoate (160 mg, 0.27 mmol, 1.00 equiv) in
tetrahydrofuran/MeOH (20/2 mL) and LiOH (20 mL). The resulting
solution was stirred overnight at room temperature e. The resulting
mixture was concentrated under vacuum. The pH value of the solution
was adjusted to pH 7 with hydrogen chloride (12 mol/L). The solids
were collected by filtration. The product residue (100 mg) was
purified by Prep-HPLC with the following conditions (Waters2767-1):
Column, Sunfire Prep C18.5 um, 19*100 mm; mobile phase, 0.05%
trifluoroacetic acid in water and CH.sub.3CN (25% CH.sub.3CN up to
50% in 10 min); Detector, 254 nm to yield
3-[(3-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiaz-
ol-1-yl] azetidin-1-yl)methyl]benzoic acid trifluoroacetic acid as
a white solid.
[0716] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.: 8.10-8.12 (m,
2H), 7.77 (s, 1H), 7.55-7.66 (m, 3H), 7.33 (d, J=1.8 Hz, 5H), 7.18
(d, J=8.4 Hz, 4H), 5.86 (s, 2H), 4.52-4.62 (brs, 1H), 4.41-4.48 (m,
2H), 4.31 (s, 1H), 2.29-2.38 (m, 1H), 1.29-1.44 (m, 4H).
[0717] LC/MS (ES, m/z): 582 [M+H]+.
Example PH-92
2,2,2-trifluoroacetic acid compound with
3-(1-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol--
1-yl)piperidin-1-yl)propyl)benzoic acid (1:1)
##STR00300##
[0719] The title compound was prepared according to the procedure
as described in Example PH-70 substituting methyl
3-(1-bromopropyl)benzoate for methyl
3-(bromomethyl)-2-fluorobenzoate in Step 1.
[0720] .sup.1H NMR (300 MHz, DMSO-d6) .delta.: 9.98 (brs, 1H), 8.15
(s, 1H), 8.08 (d, J=7.5 Hz, 1H), 7.84-7.86 (m, 1H), 7.66-7.74 (m,
2H), 7.53-7.55 (m, 1H), 7.37-7.40 (m, 4H), 7.07-7.10 (m, 4H),
6.92-6.95 (m, 1H), 5.72 (s, 1H), 4.99-5.02 (m, 1H), 4.58-4.61 (m,
1H), 3.60-3.85 (m, 2H), 2.90-3.10 (m, 2H), 2.68-2.72 (m, 2H),
2.34-2.36 (m, 2H), 2.14-2.17 (m, 3H), 1.14 (s, 4H), 0.69-0.74 (m,
3H). LC/MS (ES, m/z): 638 [M+H]+.
Example PH-93
3-((4-(6-((4-chlorophenyl)(phenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazo-
l-1-yl)piperidin-1-yl)methyl)benzoic acid
##STR00301##
[0721] Step 1: Synthesis of methyl 3-fluoro-4-nitrobenzoate
[0722] Into a 500-mL round-bottom flask, was placed a solution of
3-fluoro-4-nitrobenzoic acid (20 g, 108.04 mmol, 1.00 equiv) in
methanol (300 mL), sulfuric acid (20 mL). The resulting solution
was stirred overnight at 70.degree. C. The resulting mixture was
concentrated under vacuum. The reaction was then quenched by the
addition of water (100 mL). The pH value of the solution was
adjusted to pH 7 with NaOH. The resulting solution was extracted
with ethyl acetate (3.times.100 mL) and the organic layers
combined, then and dried over anhydrous sodium sulfate and
concentrated under vacuum to yield methyl 3-fluoro-4-nitrobenzoate
as a light yellow solid. LC/MS (ES, m/z): 200 [M+H]+
Step 2: Synthesis of tert-butyl
4-[[5-(methoxycarbonyl)-2-nitrophenyl]amino]piperidine-1-carboxylate
[0723] Into a 500-mL round-bottom flask, was placed a solution of
methyl 3-fluoro-4-nitrobenzoate (21 g, 105.46 mmol, 1.00 equiv) in
CH.sub.3CN (300 mL), tert-butyl 4-aminopiperidine-1-carboxylate (25
g, 124.83 mmol, 1.20 equiv) and DIEA (34 g, 263.08 mmol, 2.50
equiv). The resulting solution was stirred overnight at 85.degree.
C.
[0724] The resulting mixture was concentrated under vacuum. The
residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:1) to yield tert-butyl
4-[[5-(methoxycarbonyl)-2-nitrophenyl]amino]piperidine-1-carboxylate
as a yellow solid. LC/MS (ES, m/z): 380 [M+H]+.
Step 3: Synthesis of tert-butyl
4-[[2-amino-5-(methoxycarbonyl)phenyl]amino]piperidine-1-carboxylate
[0725] Into a 500-mL round-bottom flask, was placed a solution of
tert-butyl
4-[[5-(methoxycarbonyl)-2-nitrophenyl]amino]piperidine-1-carboxylate
(18 g, 47.44 mmol, 1.00 equiv) in methanol (200 mL) and Pd/C (2 g).
To the resulting mixture was then introduced H.sub.2(g). The
resulting solution was stirred overnight at room temperature. The
solids were filtered out. The resulting mixture was concentrated
under vacuum to yield tert-butyl
4-[[2-amino-5-(methoxycarbonyl)phenyl]amino]piperidine-1l-carboxylate
as a gray solid. LC/MS (ES, m/z): 350 [M+H]+
Step 4: Synthesis of tert-butyl
4-[[2-cyclopropaneamido-5-(methoxycarbonyl)phenyl]amino]piperidine-1-carb-
oxylate
[0726] Into a 500-mL round-bottom flask, was placed a solution of
tert-butyl
4-[[2-amino-5-(methoxycarbonyl)phenyl]amino]piperidine-1-carboxylate
(15 g, 42.93 mmol, 1.00 equiv) in dichloromethane (300 mL) and
triethylamine (13 g, 128.47 mmol, 3.00 equiv). To the mixture was
then added cyclopropanecarbonyl chloride (4.47 g, 42.76 mmol, 1.00
equiv) dropwise with stirring at 0.degree. C. The resulting
solution was stirred overnight at room temperature. The resulting
mixture was concentrated under vacuum to yield tert-butyl
4-[[2-cyclopropaneamido-5-(methoxycarbonyl)phenyl]amino]piperidine-1-carb-
oxylate as a gray solid. LC/MS (ES, m/z): 418 [M+H]+
Step 5: Synthesis of methyl
2-cyclopropyl-1-(piperidin-4-yl)-1H-1,3-benzodiazole-6-carboxylate
[0727] Into a 500-mL round-bottom flask, was placed a solution of
tert-butyl
4-[[2-cyclopropaneamido-5-(methoxycarbonyl)phenyl]amino]piperidine-1-carb-
oxylate (20 g, 47.90 mmol, 1.00 equiv) in acetic acid (300 mL). The
resulting solution was stirred overnight at room temperature. The
resulting mixture was concentrated under vacuum to yield methyl
2-cyclopropyl-1-(piperidin-4-yl)-1H-1,3-benzodiazole-6-carboxylate
as brown oil. LC/MS (ES, m/z): 300 [M+H]+
Step 6: Synthesis of methyl
1-[1-[(tert-butoxy)carbonyl]piperidin-4-yl]-2-cyclopropyl-1H-1,3-benzodia-
zole-6-carboxylate
[0728] Into a 1000-mL round-bottom flask, was placed a solution of
methyl
2-cyclopropyl-1-(piperidin-4-yl)-1H-1,3-benzodiazole-6-carboxylate
(17 g, 56.79 mmol, 1.00 equiv) in dichloromethane (300 mL) and a
solution of sodium bicarbonate in Water (300 mL). To the mixture
was then added di-tert-butyl dicarbonate (15 g, 68.73 mmol, 1.20
equiv) at 0.degree. C. The resulting solution was stirred overnight
at room temperature. The resulting solution was extracted with DCM
(3.times.300 mL) and the organic layers combined, then concentrated
under vacuum. The residue was applied onto a silica gel column with
ethyl acetate/petroleum ether (1:1) to yield methyl
1-[1-[(tert-butoxy)carbonyl]piperidin-4-yl]-2-cyclopropyl-1H-1,3-benzodia-
zole-6-carboxylate as an off-white solid.
[0729] LC/MS (ES, m/z): 400 [M+H]+.
Step 7: Synthesis of 4 tert-butyl
4-[2-cyclopropyl-6-[methoxy(methyl)carbamoyl]-1H-1,3-benzodiazol-1-yl]pip-
eridine-1-carboxylate
[0730] Into a 250-mL round-bottom flask, was placed a solution of
methyl
1-[1-[(tert-butoxy)carbonyl]piperidin-4-yl]-2-cyclopropyl-1H-1,3-benzodia-
zole-6-carboxylate (4.5 g, 11.26 mmol, 1.00 equiv) in
tetrahydrofuran (50 mL) and methoxy(methyl)amine hydrochloride
(1.31 g, 13.43 mmol, 1.20 equiv). To the mixture was then added
LiHMDS (13.5 mL, 1.20 equiv) dropwise with stirring at 0.degree. C.
The resulting solution was stirred overnight at room temperature.
The mixture was concentrated under vacuum. The residue was applied
onto a silica gel column with ethyl acetate/petroleum ether (1:0)
to yield 4 tert-butyl
4-[2-cyclopropyl-6-[methoxy(methyl)carbamoyl]-1H-1,3-benzodiazol-1-yl]pip-
eridine-1-carboxylate as yellow oil. LC/MS (ES, m/z): 429
[M+H]+
Step 8: Synthesis of tert-butyl
4-[6-[(4-chlorophenyl)carbonyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]pip-
eridine-1-carboxylate
[0731] Into a 100-mL round-bottom flask, was placed a solution of
tert-butyl
4-[2-cyclopropyl-6-[methoxy(methyl)carbamoyl]-1H-1,3-benzodiazol-1-yl]pip-
eridine-1-carboxylate (4.2 g, 9.80 mmol, 1.00 equiv) in
tetrahydrofuran (30 mL) and a solution of
bromo(4-chlorophenyl)magnesium (14.7 mL, 1.50 equiv, 1M) in
toluene. The resulting solution was stirred overnight at room
temperature. The mixture was concentrated under vacuum. The residue
was applied onto a silica gel column with ethyl acetate/petroleum
ether (9:1) to yield tert-butyl
4-[6-[(4-chlorophenyl)carbonyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]pip-
eridine-1-carboxylate as an off-white solid. LC/MS (ES, m/z): 480
[M+H]+
Step 9: Synthesis of tert-butyl
4-[6-[(4-chlorophenyl)(hydroxy)benzyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-
-yl]piperidine-1-carboxylate
[0732] Into a 50-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of nitrogen, was placed Mg (150
mg, 6.00 equiv), a solution of iodobenzene (1.024 g, 5.02 mmol,
5.00 equiv) in tetrahydrofuran (5 mL) and 12 (a catalytic amount).
The mixture was stirred for 3 hour at 60.degree. C. To the mixture
was then added a solution of tert-butyl
4-6-[(4-chlorophenyl)carbonyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]pipe-
ridine-1-carboxylate (500 mg, 1.04 mmol, 1.00 equiv) in
tetrahydrofuran (25 mL) dropwise with stirring. The mixture was
stirred for overnight at 25.degree. C. The resulting mixture was
concentrated under vacuum. The residue was applied onto a silica
gel column with dichloromethane/methanol (1:10) to yield tert-butyl
4-[6-[(4-chlorophenyl)(hydroxy)benzyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-
-yl]piperidine-1-carboxylate as an off-white solid. LC/MS (ES,
m/z): 558 [M+H]+
Step 10: Synthesis of
6-[(4-chlorophenyl)(phenyl)methyl]-2-cyclopropyl-1-(piperidin-4-yl)-1H-1,-
3-benzodiazole
[0733] Into a 50-mL round-bottom flask, was placed a solution of
tert-butyl
4-[6-[(4-chlorophenyl)(hydroxy)benzyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-
-yl]piperidine-1-carboxylate (350 mg, 0.63 mmol, 1.00 equiv) in
dichloromethane (30 mL), CF.sub.3COOH (6 mL) and Et.sub.3SiH (3
mL). The resulting solution was stirred overnight at room
temperature. The resulting mixture was concentrated under vacuum.
The reaction was then quenched by the addition of water (50 mL).
The resulting solution was extracted with DCM (3.times.50 mL) and
the organic layers combined, then dried over anhydrous sodium
sulfate and concentrated under vacuum. The residue was applied onto
a silica gel column with dichloromethane/methanol (1:10) to yield
6-[(4-chlorophenyl)(phenyl)methyl]-2-cyclopropyl-1-(piperidin-4-yl)-1H-1,-
3-benzodiazole as a light yellow solid. LC/MS (ES, m/z): 442
[M+H]+
Step 11: Synthesis of methyl
3-[(4-[6-[(4-chlorophenyl)(phenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazo-
l-1-yl]piperidin-1-yl)methyl]benzoate
[0734] Into a 100-mL round-bottom flask, was placed a solution of
6-[(4-chlorophenyl)(phenyl)methyl]-2-cyclopropyl-1-(piperidin-4-yl)-1H-1,-
3-benzodiazole (300 mg, 0.68 mmol, 1.00 equiv) in dichloromethane
(20 mL), methyl 3-formylbenzoate (112 mg, 0.68 mmol, 1.00 equiv)
and triethylamine (catalytic amount). The resulting solution was
stirred overnight at room temperature. To the mixture was added
NaBH(OAc).sub.3 (361 mg, 1.70 mmol, 2.50 equiv). The resulting
solution was allowed to react, with stirring for an additional 4 h
at room temperature. The resulting mixture was concentrated under
vacuum. The residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:1) to yield methyl
3-[(4-[6-[(4-chlorophenyl)(phenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazo-
l-1-yl]piperidin-1-yl)methyl]benzoate as colorless oil. LC/MS (ES,
m/z): 590 [M+H]+
Step 12: Synthesis of yield
3-[(4-[6-[(4-chlorophenyl)(phenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazo-
l-1-yl]piperidin-1-yl)methyl]benzoic acid
[0735] Into a 100-mL round-bottom flask, was placed a solution of
methyl
3-[(4-[6-[(4-chlorophenyl)(phenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazo-
l-1-yl]piperidin-1-yl)methyl]benzoate (280 mg, 0.47 mmol, 1.00
equiv) in tetrahydrofuran/MeOH (30/5 mL) and LiOH (30 mL). The
resulting solution was stirred overnight at room temperature. The
resulting mixture was concentrated under vacuum. The pH value of
the solution was adjusted to pH 7 with hydrogen chloride (12
mol/L). The solids were collected by filtration. The product
residue (100 mg) was purified by Prep-HPLC with the following
conditions (Waters 2767-1): Column, SunFire Prep C18, 5 um, 19*100
mm; mobile phase, 0.03% NH.sub.3*H.sub.2O in water and CH.sub.3CN
(50% CH.sub.3CN up to 65% in 8 min); Detector, UV 254 nm to yield
3-[(4-[6-[(4-chlorophenyl)(phenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazo-
l-1-yl]piperidin-1-yl)methyl]benzoic acid as a white solid.
[0736] .sup.1H NMR (300 MHz, DMSO-d6) 5:12.97 (brs, 1H), 7.85-7.91
(m, 2H), 7.49-7.59 (m, 2H), 7.31-7.42 (m, 6H), 7.21-7.26 (m, 1H),
7.14 (d, J=8.4 Hz, 4H), 6.85 (d, J=9.3 Hz, 1H), 5.80 (s, 1H), 4.56
(brs, 1H), 3.60 (m, 2H), 2.93 (brs, 2H), 2.17-2.43 (m, 5H), 1.775
(s, 2H), 0.95-1.24 (m, 4H). LC/MS (ES, m/z): 576 [M+H]+.
Example PH-94
2,2,2-trifluoroacetic acid compound with
3-((4-(6-((4-chlorophenyl)(4-fluorophenyl)methyl)-2-cyclopropyl-1H-benzo[-
d]imidazol-1-yl)piperidin-1-yl)methyl)benzoic acid (1:1)
##STR00302##
[0738] The title compound was prepared according to the procedure
as described in Example PH-93 substituting
(4-fluorophenyl)magnesium bromide for phenylmagnesium bromide in
Step 9.
[0739] .sup.1H NMR (300 MHz, CD3OD) .delta.: 8.24 (s, 1H), 8.19 (d,
J=7.8 Hz, 1H), 7.88 (s, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.63-7.68 (m,
2H), 7.24-7.33 (m, 3H), 7.01-7.15 (m, 6H), 5.81 (s, 1H), 5.20-5.29
(m, 1H), 4.49 (s, 2H), 3.74-3.78 (m, 2H), 3.37-3.41 (m, 2H),
2.79-2.91 (m, 2H), 2.49-2.56 (m, 1H), 2.34-2.38 (m, 2H), 1.40-1.49
(m, 2H), 1.30-1.35 (m, 2H). LC/MS: (m/z) 594 [M+H]+
Example PH-95
3-((4-(6-((4-chlorophenyl)(p-tolyl)methyl)-2-cyclopropyl-1H-benzo[d]imidaz-
ol-1-yl)piperidin-1-yl)methyl)benzoic acid
##STR00303##
[0741] The title compound was prepared according to the procedure
as described in Example PH-93 substituting p-tolylmagnesium bromide
for phenylmagnesium bromide in Step 9.
[0742] .sup.1H NMR (300 MHz, DMSO-d6) .delta.: 7.85-7.91 (m, 2H),
7.50-7.59 (m, 2H), 7.35-7.41 (m, 4H), 7.11-7.20 (m, 4H), 6.99-7.02
(m, 2H), 6.81 (d, J=8.4 Hz, 1H), 5.74 (s, 1H), 4.50-4.60 (m, 1H),
3.61 (s, 2H), 2.85-3.00 (m, 2H), 2.17-2.29 (m, 8H), 1.77-1.81 (m,
2H), 0.98-1.05 (m, 4H). LC/MS (ES, m/z): 590 [M+H]+.
Example PH-96
2,2,2-trifluoroacetic acid compound with
3-((4-(6-((4-chlorophenyl)(4-(trifluoromethyl)phenyl)methyl)-2-cyclopropy-
l-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)methyl)benzoic acid
(1:1)
##STR00304##
[0744] The title compound was prepared according to the procedure
as described in Example PH-93 substituting
(4-(trifluoromethyl)phenyl)magnesium bromide for phenylmagnesium
bromide in Step 9.
[0745] 1H NMR (300 MHz, CD.sub.3OD) .delta. 9.96 (s, 1H), 8.17-8.25
(m, 1H), 7.92-7.96 (m, 1H), 7.79-7.82 (d, J=7.5 Hz), 7.61-7.68 (m,
4H), 7.24-7.35 (m, 5H), 7.10-7.13 (m, 2H), 5.91 (s, 1H), 5.08-5.31
(m, 1H), 4.50 (s, 1H), 3.69-3.79 (m, 2H), 3.38-3.42 (m, 2H),
2.87-2.99 (m, 2H), 2.52-2.60 (m, 1H), 2.26-2.39 (m, 2H), 1.40-1.47
(m, 2H), 1.33 (m, 2H). LC/MS (ES, m/z): 644 [M+H]+.
Example PH-97
2,2,2-trifluoroacetic acid compound with
3-((4-(6-(bis(4-fluorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)methyl)benzoic acid
##STR00305##
[0747] The title compound was prepared according to the procedure
as described in Example PH-93 substituting
(4-fluorophenyl)magnesium bromide for (4-chlorophenyl)magnesium
bromide in Step 8, and substituting (4-fluorophenyl)magnesium
bromide for phenylmagnesium bromide in Step 9.
[0748] .sup.1H NMR (300 MHz, CD3OD) .delta. 8.25 (s, 1H), 8.19 (d,
J=8.7 Hz, 1H), 7.89 (s, 1H), 7.79-7.81 (m, 1H), 7.63-7.68 (m, 2H),
7.24-7.73 (m, 1H), 7.01-7.14 (m, 8H), 5.82 (s, 1H), 5.21-5.25 (m,
1H), 4.49 (s, 2H), 3.74-3.78 (m, 2H), 3.32-3.42 (m, 2H), 2.80-2.91
(m, 2H), 2.49-2.54 (m, 1H), 2.34-2.38 (m, 2H), 1.38-1.46 (m, 2H),
1.29-1.34 (m, 2H). LC/MS (ES, m/z): 578 [M+H]+.
Example PH-98
2,2,2-trifluoroacetic acid compound with
3-((4-(2-cyclopropyl-6-(dip-tolylmethyl)-1H-benzo[d]imidazol-1-yl)piperid-
in-1-yl)methyl)benzoic acid (1:1)
##STR00306##
[0750] The title compound was prepared according to the procedure
as described in Example PH-93 substituting p-tolylmagnesium bromide
for (4-chlorophenyl)magnesium bromide in Step 8.
[0751] .sup.1H NMR (300 MHz, CD3OD) .delta.: 8.18-8.23 (m, 2H),
7.87 (s, 1H), 7.78-7.80 (m, 1H), 7.60-7.68 (m, 2H), 7.28 (d, J=8.7
Hz, 1H), 7.08-7.11 (m, 4H), 6.95-6.98 (m, 4H), 5.72 (s, 1H),
5.23-5.27 (m, 1H), 4.48 (s, 2H), 3.740-3.78 (m, 2H), 3.32-3.43 (m,
2H), 2.79-2.87 (m, 2H), 2.50-2.58 (m, 1H), 2.35-2.39 (m, 2H), 2.29
(s, 6H), 1.42-1.48 (m, 2H), 1.35-1.39 (m, 2H). LC/MS (ES, m/z): 570
[M+H]+.
Example PH-99
2,2,2-trifluoroacetic acid compound with
3-((4-(2-(2-aminoethyl)-6-(bis(4-chlorophenyl)methyl)-1H-benzo[d]imidazol-
-1-yl)piperidin-1-yl)methyl)benzoic acid (1:1)
##STR00307##
[0752] Step 1: Synthesis of ethyl
3-([4-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-[(piperidin-4-yl)a-
mino]phenyl]carbamoyl)propanoate
[0753] Into a 250-mL round-bottom flask, was placed a solution of
tert-butyl
4-([2-amino-5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]phenyl]amino)-
piperidine-1-carboxylate (3.7 g, 6.33 mmol, 1.00 equiv) in
dichloromethane (30 mL), ethyl 4-chloro-4-oxobutanoate (1.25 g,
7.59 mmol, 1.20 equiv) and triethylamine (1.9 g, 18.78 mmol, 3.00
equiv). The resulting solution was stirred overnight at room
temperature. The resulting mixture was concentrated under vacuum to
yield ethyl
3-([4-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-[(piperdin-4-yl)am-
ino]phenyl]carbamoyl)propanoate as brown oil. LC/MS (ES, m/z): 613
[M+H]+.
Step 2: Synthesis of tert-butyl
4-[6-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-(3-ethoxy-3-oxoprop-
yl) H-1H-1,3-benzodiazol-1-yl]piperidine-1-carboxylate
[0754] Into a 250-mL round-bottom flask, was placed a solution of
ethyl
3-([4-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-[(piperidin-4-yl)a-
mino]phenyl]carbamoyl)propanoate (5 g, 8.16 mmol, 1.00 equiv) in
dichloromethane (50 mL), di-tert-butyl dicarbonate (2.14 g, 9.81
mmol, 1.20 equiv) and a saturated solution of sodium
bicarbonate/H.sub.2O (50 mL). The resulting solution was stirred
for 6 h at room temperature. The resulting mixture was concentrated
under vacuum. The resulting solution was extracted with ethyl
acetate (3.times.100 mL) and the organic layers combined, then
dried over anhydrous sodium sulfate and concentrated under vacuum
to yield tert-butyl
4-[6-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-(3-ethoxy-3-oxoprop-
yl)-1H-1,3-benzodiazol-1-yl]piperidine-1-carboxylate as brown oil.
LC/MS (ES, m/z): 695 [M+H]+.
Step 3: Synthesis of
3-[6-[bis(4-chlorophenyl)(carboxy)methyl]-1-[1-[(tert-butoxy)carbonyl]pip-
eridin-4-yl]-1H-1,3-benzodiazol-2-yl]propanoic acid
[0755] Into a 250-mL round-bottom flask, was placed a solution of
tert-butyl
4-[6-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-(3-ethoxy-3-oxoprop-
yl)-1H-1,3-benzodiazol-1-yl]piperidine-1-carboxylate (5 g, 7.20
mmol, 1.00 equiv) in tetrahydrofuran/MeOH (50/20 mL) and sodium
hydroxide (20 mL). The resulting solution was stirred overnight at
50.degree. C. The resulting mixture was concentrated under vacuum.
The pH value of the solution was adjusted to pH 6 with hydrogen
chloride (12 mol/L). The solids were collected by filtration to
yield
3-[6-[bis(4-chlorophenyl)(carboxy)methyl]-1-[1-[(tert-butoxy)carbonyl]pip-
eridin-4-yl]-1H-1,3-benzodiazol-2-yl]propanoic acid as a brown
solid. LC/MS (ES, m/z): 653 [M+H]+.
Step 4: Synthesis of
3-[6-[bis(4-chlorophenyl)methyl]-1-[1-[(tert-butoxy)carbonyl]piperidin-4--
yl]-1H-1,3-benzodiazol-2-yl]propanoic acid
[0756] Into a 250-mL round-bottom flask, was placed a solution of
3-[6-[bis(4-chlorophenyl)(carboxy)methyl]-1-[1-[(tert-butoxy)carbonyl]pip-
eridin-4-yl]-1H-1,3-benzodiazol-2-yl]propanoic acid (4 g, 6.13
mmol, 1.00 equiv) in toluene (50 ml) and DBU (5.6 g, 22.23 mmol,
6.00 equiv). The resulting solution was stirred for 3 h at
90.degree. C. The resulting mixture was concentrated under vacuum.
The residue was applied onto a silica gel column with DCM:MeOH
(10:1) to yield
3-[6-[bis(4-chlorophenyl)methyl]-1-[1-[(tert-butoxy)carbonyl]piperidin-4--
yl]-1H-1,3-benzodiazol-2-yl]propanoic acid as a solid. LC/MS (ES,
m/z): 609 [M+H]+.
Step 5: Synthesis of
3-[6-[bis(4-chlorophenyl)methyl]-1-(piperidin-4-yl)-1H-1,3-benzodiazol-2--
yl]propanoic acid
[0757] Into a 250-mL round-bottom flask, was placed a solution of
3-[6-[bis(4-chlorophenyl)methyl]-1-[1-[(tert-butoxy)carbonyl]piperidin-4--
yl]-1H-1,3-benzodiazol-2-yl]propanoic acid (1.2 g, 1.97 mmol, 1.00
equiv) in dichloromethane (30 ml) and trifluoroacetic acid (5 mL),
(30 L). The resulting solution was stirred overnight at room
temperature. The resulting mixture was concentrated under vacuum.
The product residue (1.2 g) was purified by Flash-Prep-HPLC with
the following conditions (CombiFlash-1): Column, C18 silica gel;
mobile phase, water and CH.sub.3CN (CH.sub.3CN 10% up to 60% in 6
min; Detector, UV 254 nm. 700 mg product was obtained to yield
3-[6-[bis(4-chlorophenyl)methyl]-1-(piperidin-4-yl)-1H-1,3-benzodiazol-2--
yl]propanoic acid as a yellow solid. LC/MS (ES, m/z): 508
[M+H]+.
Step 6: Synthesis of
3-[6-[bis(4-chlorophenyl)methyl]-1-(1-[[3-(methoxycarbonyl)phenyl]methyl]-
piperidin-4-yl)-1H-1,3-benzodiazol-2-yl]propanoic acid
[0758] Into a 50-mL round-bottom flask, was placed a solution of
3-[6-[bis(4-chlorophenyl)methyl]-1-(piperidin-4-yl)-1H-1,3-benzodiazol-2--
yl]propanoic acid (350 mg, 0.69 mmol, 1.00 equiv) in methanol (10
ml), methyl 3-formylbenzoate (136 mg, 0.83 mmol, 1.20 equiv),
acetic acid (a catalytic amount) and NaBH.sub.3(CN) (130 mg, 3.00
equiv). The resulting solution was stirred overnight at room
temperature. The resulting mixture was concentrated under vacuum.
The residue was applied onto a silica gel column with DCM:MeOH
(10:1) to yield
3-[6-[bis(4-chlorophenyl)methyl]-1-(1-[[3-(methoxycarbonyl)phenyl]methyl]-
piperdin-4-yl)-1H-1,3-benzodiazol-2-yl]propanoic acid as a white
solid. LC/MS (ES, m/z): 656.6 [M+H]+.
Step 7: Synthesis of 254 nm
3-([4-[2-(2-aminoethyl)-6-[bis(4-chlorophenyl)methyl]-1H-1,3-benzodiazol--
1-yl]piperidin-1-yl]methyl)benzoic acid; trifluoroacetic acid
[0759] Into a 50-mL round-bottom flask, was placed a solution of
3-[6-[bis(4-chlorophenyl)methyl]-1-(1-[[3-(methoxycarbonyl)phenyl]methyl]-
piperidin-4-yl)-1H-1,3-benzodiazol-2-yl]propanoic acid (140 mg,
0.21 mmol, 1.00 equiv) in benzene (20 mL), DPPA (65 mg, 0.24 mmol,
1.10 equiv) and triethylamine (26 mg, 0.26 mmol, 1.20 equiv). The
resulting solution was stirring for 2 h at reflux. The resulting
solution was diluted with ethyl acetate (20 mL). The resulting
mixture was washed with water (1.times.20 mL) and then brine
(1.times.20 mL). The resulting mixture was concentrated under
vacuum. To the resulting mixture was then added LiOH (10 mL, 1M)
and tetrahydrofuran (20 mL). The resulting solution was stirred
overnight at room temperature. The resulting solution was extracted
with ethyl acetate (2.times.20 mL) and the organic layers combined.
The resulting solution was extracted with DCM (2.times.20 mL) and
the organic layers combined and concentrated under vacuum. The
product residue was purified by Prep-HPLC with the following
conditions (Waters 2767-1): Column, SunFire Prep C18, 5 um, 19*100
mm; mobile phase, 0.05% TFA in water and CH.sub.3CN (45% CH.sub.3CN
up to 75% in 9 min); Detector, UV 254 nm
3-([4-[2-(2-aminoethyl)-6-[bis(4-chlorophenyl)methyl]-1H-1,3-benzodiazol--
1-yl]piperidin-1-yl]methyl)benzoic acid; trifluoroacetic acid as a
white solid.
[0760] .sup.1H NMR (300 MHz, CD3OD) .delta.: 8.25 (s, 1H),
8.19-8.17 (d, J=7.5 Hz, 1H), 7.86-7.80 (m, 2H), 7.62-7.68 (m, 2H),
7.28-7.33 (m, 4H), 7.02-7.11 (m, 4H), 6.94 (d, J=3.6 Hz, 1H), 5.77
(s, 1H), 4.50 (s, 2H), 3.59-3.82 (m, 2H), 3.31-3.53 (m, 6H),
2.78-2.98 (m, 2H), 1.30-1.36 (m, 2H). LC/MS (ES, m/z):
613[M+H]+.
Example PH-100
4-(1s,4s)-4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidaz-
ol-1-yl)cyclohexylamino)benzoic acid
##STR00308##
[0761] Step 1: Synthesis of methyl
2,2-bis(4-chlorophenyl)-2-(4-nitro-3-[[(1s,4s)-4-[[(tert-butoxy)carbonyl]-
amino]cyclohexyl]amino]phenyl)acetate
[0762] Into a 500-mL round-bottom flask, was placed a solution of
methyl 2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate
(10 g, 23.03 mmol, 1.00 equiv) in CH.sub.3CN (300 mL), tert-butyl
N-[(1s,4s)-4-aminocyclohexyl]carbamate (5.44 g, 25.38 mmol, 1.10
equiv) and DIEA (14.8 g, 114.52 mmol, 4.97 equiv). The resulting
solution was stirred overnight at 85.degree. C. The resulting
mixture was concentrated under vacuum. The residue was applied onto
a silica gel column with ethyl acetate/petroleum ether
(0:100-100:0) to yield methyl
2,2-bis(4-chlorophenyl)-2-(4-nitro-3-[[(1s,4s)-4-[[(tert-butoxy)carbonyl]-
amino]cyclohexyl]amino]phenyl)acetate as yellow oil. LC/MS (ES,
m/z): 629 [M+H]+.
Step 2: Synthesis of yield methyl
2-(4-amino-3-[[(1s,4s)-4-[[(tert-butoxy)carbonyl]amino]cyclohexyl]amino]p-
henyl)-2,2-bis(4-chlorophenyl)acetate
[0763] Into a 1000-mL round-bottom flask, was placed a solution of
methyl 2,2-bis(4-chlorophenyl)-2-(4-nitro-3-[[(1
s,4s)-4-[[(tert-butoxy)carbonyl]amino]cyclohexyl]amino]phenyl)acetate
(9 g, 14.32 mmol, 1.00 equiv) in methanol/THF (400/50 mL) and Raney
Ni (832 mg, 14.34 mmol, 1.00 equiv). To the reaction mixture was
then introduced hydrogen. The resulting solution was stirred
overnight at room temperature. The solids were filtered out. The
resulting mixture was concentrated under vacuum to yield methyl
2-(4-amino-3-[[(1
s,4s)-4-[[(tert-butoxy)carbonyl]amino]cyclohexyl]amino]phenyl)-2,2-bis(4--
chlorophenyl)acetate as light yellow oil. LC/MS (ES, m/z): 598.5
[M+H]+.
Step 3: Synthesis of methyl
2,2-bis(4-chlorophenyl)-2-(4-cyclopropaneamido-3-[[(1s,4s)-4-[[(tert-buto-
xy)carbonyl]amino]cyclohexyl]amino]phenyl)acetate
[0764] Into a 500-mL round-bottom flask, was placed a solution of
methyl
2-(4-amino-3-[[(1s,4s)-4-[[(tert-butoxy)carbonyl]amino]cyclohexyl]amino]p-
henyl)-2,2-bis(4-chlorophenyl)acetate (7.9 g, 13.20 mmol, 1.00
equiv) in dichloromethane (300 mL), triethylamine (4 g, 39.53 mmol,
3.00 equiv) and cyclopropanecarbonyl chloride (1.65 g, 15.78 mmol,
1.20 equiv). The resulting solution was stirred overnight at room
temperature. The resulting mixture was concentrated under vacuum to
yield methyl
2,2-bis(4-chlorophenyl)-2-(4-cyclopropaneamido-3-[[(1s,4s)-4-[[(tert-buto-
xy)carbonyl]amino]cyclohexyl]amino]phenyl)acetate as light yellow
oil. LC/MS (ES, m/z): 667 [M+H]+.
Step 4: Synthesis of methyl
2,2-bis(4-chlorophenyl)-2-[2-cyclopropyl-1-[(1s,4s)-4-[[(tert-butoxy)carb-
onyl]amino]cyclohexyl]-1H-1,3-benzodiazol-6-yl]acetate
[0765] Into a 500-mL round-bottom flask, was placed methyl
2,2-bis(4-chlorophenyl)-2-(4-cyclopropaneamido-3-[[(1
s,4s)-4-[[(tert-butoxy)carbonyl]amino]cyclohexyl]amino]phenyl)acetate
(8 g, 12.00 m mol, 1.00 equiv) and acetic acid (350 mL). The
resulting solution was stirred for 3 h at 120.degree. C. The
resulting mixture was concentrated under vacuum. The residue was
applied onto a silica gel column with ethyl acetate/petroleum ether
(0:100-100:0) to yield methyl
2,2-bis(4-chlorophenyl)-2-[2-cyclopropyl-1-[(1
s,4s)-4-[[(tert-butoxy)carbonyl]amino]cyclohexyl]-1H-1,3-benzodiazol-6-yl-
]acetate as colorless oil.
Step 5: Synthesis of yield
2,2-bis(4-chlorophenyl)-2-[2-cyclopropyl-1-[(1s,4s)-4-[[(tert-butoxy)carb-
onyl]amino]cyclohexyl]-1H-1,3-benzodiazol-6-yl]acetic acid
[0766] Into a 1000-mL round-bottom flask, was placed a solution of
methyl 2,2-bis(4-chlorophenyl)-2-[2-cyclopropyl-1-[(1
s,4s)-4-[[(tert-butoxy)carbonyl]amino]cyclohexyl]-1H-1,3-benzodiazol-6-yl-
]acetate (7.2 g, 11.10 mmol, 1.00 equiv) in tetrahydrofuran/MeOH
(300/50 mL) and sodium hydroxide (55.5 mL). The resulting solution
was stirred overnight at 50.degree. C. The resulting mixture was
concentrated under vacuum. The residue was dissolved in ethyl
acetate (300 mL). The resulting mixture was washed with water
(3.times.300 mL). The organic phase was dried over anhydrous sodium
sulfate and concentrated under vacuum to yield
2,2-bis(4-chlorophenyl)-2-[2-cyclopropyl-1-[(1
s,4s)-1-[[(tert-butoxy)carbonyl]amino]cyclohexyl]-1H-1,3-benzodiazol-6-yl-
]acetic acid as a white solid. LC/MS (ES, m/z): 635 [M+H]+.
Step 6: Synthesis of tert-butyl
N-[(1s,4s)-4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodia-
zol-1-yl]cyclohexyl]carbamate
[0767] Into a 500-mL round-bottom flask, was placed a solution of
2,2-bis(4-chlorophenyl)-2-[2-cyclopropyl-1-[(1
s,4s)-4-[[(tert-butoxy)carbonyl]amino]cyclohexyl]-1H-1,3-benzodiazol-6-yl-
]acetic acid (6.5 g, 10.24 mmol, 1.00 equiv) in toluene (200 mL)
and DBU (9.36 g, 61.48 mmol, 6.00 equiv). The resulting solution
was stirred for 3 h at 90.degree. C. The resulting mixture was
concentrated under vacuum. The residue was dissolved in ethyl
acetate (300 mL). The resulting mixture was washed with water
(3.times.300 mL). The organic phase was dried over anhydrous sodium
sulfate and concentrated under vacuum to yield tert-butyl N-[(1
s,4s)-4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-
-yl]cyclohexyl]carbamate as colorless oil. LC/MS (ES, m/z): 591
[M+H]+.
Step 7: Synthesis of
(1s,4s)-4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-
-1-yl]cyclohexan-1-amine
[0768] Into a 100-mL round-bottom flask, was placed a solution of
tert-butyl N-[(1
s,4s)-4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-
-yl]cyclohexyl]carbamate (5.7 g, 9.65 mmol, 1.00 equiv) in
dichloromethane (50 mL) and trifluoroacetic acid (10 mL). The
resulting solution was stirred overnight at room temperature. The
resulting mixture was concentrated under vacuum. The residue was
dissolved in DCM (100 mL). The resulting mixture was washed with
sat. sodium bicarbonate (3.times.50 mL). The organic phase was
dried over anhydrous sodium sulfate and concentrated under vacuum.
The product residue was purified by re-crystallization from DCM to
yield
(1s,4s)-4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-
-1-yl]cyclohexan-1-amine as a white solid. LC/MS (ES, m/z): 490
[M+H]+.
Step 8: Synthesis of methyl
4-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]cyclohexyl)amino]benzoate
[0769] Into a 100-mL round-bottom flask, was placed
4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]cy-
clohexan-1-amine (400 mg, 0.82 mmol, 1.00 equiv), methyl
4-bromobenzoate (352 mg, 1.64 mmol, 2.00 equiv),
Pd.sub.2(dba).sub.3*CHCl.sub.3 (126 mg, 0.12 mmol, 0.15 equiv),
X-phos (58 mg, 0.12 mmol, 0.15 equiv), Cs.sub.2CO.sub.3 (1.064 g,
3.27 mmol, 4.00 equiv) and toluene (20 mL). The resulting solution
was stirred overnight at 90.degree. C. in an oil bath. The reaction
progress was monitored by LC-MS. The solids were filtered out. The
resulting solution was extracted with ethyl acetate (3.times.30 mL)
and the organic layers combined, then dried over anhydrous sodium
sulfate and concentrated under vacuum. The residue was applied onto
a silica gel column with ethyl acetate/petroleum ether (1/2) to
yield methyl
4-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]cyclohexyl)amino]benzoate as light yellow oil. LC/MS (ES, m/z):
625 [M+H]+.
Step 9: Synthesis of
4-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]cyclohexyl)amino]benzoic acid
[0770] Into a 100-mL round-bottom flask, was placed methyl
4-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]cyclohexyl)amino]benzoate (270 mg, 0.43 mmol, 1.00 equiv),
tetrahydrofuran (15 mL), water (15 mL), methanol (3 mL) and
LiOH*H.sub.2O (909 mg, 21.66 mmol, 50.00 equiv). The resulting
solution was stirred overnight at room temperature. The reaction
progress was monitored by LC-MS. The pH value of the solution was
adjusted to pH 7.0 with hydrogen chloride solution (1 mol/L). The
resulting solution was extracted with ethyl acetate (3.times.30 mL)
and the organic layers combined and concentrated under vacuum. The
residue was applied onto a silica gel column with
dichloromethane/methanol (13/1). The product residue was purified
by Prep-HPLC with the following conditions (Waters (2767-1)):
Column, Sunfire Prep C18.5 um, 19*100 mm; mobile phase, 0.05%
NH.sub.4HCO.sub.3 in Water and CH.sub.3CN (10% CH.sub.3CN up to 55%
in 13 min); Detector, UV 254 nm to yield
4-[(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-y-
l]cyclohexyl)amino]benzoic acid as a white solid.
[0771] .sup.1H NMR (300 MHz, DMSO-d6): 11.96 (s, 1H), 7.69 (d,
J=8.7 Hz, 2H), 7.61 (s, 1H), 7.33-7.42 (m, 5H), 7.13-7.15 (d, J=8.4
Hz, 4H), 6.59-6.80 (m, 4H), 5.74 (s, 1H), 4.65-4.65 (m, 1H), 3.73
(s, 1H), 2.29-2.33 (m, 1H), 2.01-2.07 (m, 2H), 1.77-1.85 (m, 2H),
1.65-1.69 (m, 2H), 0.99-1.04 (m, 4H). LC/MS (ES, m/z): 610
[M+H]+.
Example PH-101
2,2,2-trifluoroacetic acid compound with
4-((1r,4r)-4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-1H-benzo[d]im-
idazol-1-yl)cyclohexylamino)benzoic acid
##STR00309##
[0773] The title compound was prepared according to the procedure
as described in Example PH-100 substituting tert-butyl
N-[(1r,4r)-4-aminocyclohexyl]carbamate for tert-butyl
N-[(1s,4s)-4-aminocyclohexyl]carbamate in Step 1.
[0774] .sup.1H NMR (400 MHz, DMSO) .delta.: 7.94 (s, 1H), 7.64-7.72
(m, 3H), 7.43 (d, J=8.4 Hz, 4H), 7.15-7.20 (m, 5H), 6.64 (d, J=8.8
Hz, 2H), 6.43 (brs, 1H), 5.95 (s, 1H), 4.82-4.84 (m, 1H), 3.48-3.51
(m, 1H), 2.66 (brs, 1H), 2.31-2.40 (m, 2H), 2.12-2.15 (m, 2H),
2.03-2.05 (m, 2H), 1.45-1.54 (m, 2H), 1.15-1.30 (m, 4H). LC/MS (ES,
m/z): 610 [M+H]+.
Example PH-102
3-((1r,4r)-4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imida-
zol-1-yl)cyclohexylamino)phenol 2,2,2-trifluoroacetate
##STR00310##
[0775] Step 1: Synthesis of
3-methoxy-N-[(1r,4r)-4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,-
3-benzodiazol-1-yl]cyclohexyl]aniline
[0776] Into a 100-mL round-bottom flask purged and maintained with
an inert atmosphere of nitrogen, was placed a solution of
(1r,4r)-4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-
-1-yl]cyclohexan-1-amine (400 mg, 0.82 mmol, 1.00 equiv) in Toluene
(50 mL), 1-bromo-3-methoxybenzene (228.2 mg, 1.22 mmol, 1.50
equiv), Pd.sub.2(dba).sub.3*CHCl.sub.3 (127 mg, 0.12 mmol, 0.15
equiv), X-Phos (175 mg, 0.37 mmol, 0.45 equiv) and Cs.sub.2CO.sub.3
(2 g, 6.14 mmol, 7.53 equiv). The resulting solution was stirred
overnight at 90.degree. C. The resulting solution was diluted with
ethyl acetate (50 mL). The resulting mixture was washed with water
(3.times.50 mL). The organic phase was dried over anhydrous sodium
sulfate and concentrated under vacuum. The residue was applied onto
a silica gel column with ethyl acetate/petroleum ether (0:100-1:1)
to yield
3-methoxy-N-[(1r,4r)-4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,-
3-benzodiazol-1-yl]cyclohexyl]aniline as yellow oil. LC/MS (ES,
m/z): 597 [M+H]+.
Step 2: Synthesis of
3-[[(1r,4r)-4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodi-
azol-1-yl]cyclohexyl]amino]phenol; trifluoroacetic acid
[0777] Into a 100-mL round-bottom flask, was placed a solution of
3-methoxy-N-[(1r,4r)-4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,-
3-benzodiazol-1-yl]cyclohexyl]aniline (250 mg, 0.42 mmol, 1.00
equiv) in dichloromethane (50 mL). To the mixture was then added
BBr.sub.3 (1.26 mL) dropwise with stirring at -78.degree. C. The
resulting solution was stirred overnight at room temperature. The
resulting mixture was concentrated under vacuum. The residue was
dissolved in DCM (100 mL). The resulting mixture was washed with
sat. NH.sub.4Cl (3.times.50 mL). The organic phase was dried over
anhydrous sodium sulfate and concentrated under vacuum. The product
residue was purified by Prep-HPLC with the following conditions
(Waters 2767-1): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile
phase, 0.05% trifluoroacetic acid in Water and CH.sub.3CN (18%
CH.sub.3CN up to 50% in 8 min); Detector, UV 254 nm to yield
3-[[(1r,4r)-4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-b-
enzodiazol-1-yl]cyclohexyl]amino]phenol; trifluoroacetic acid as a
white solid.
[0778] .sup.1H NMR (300 MHz, DMSO-d6) .delta.: 9.10 (brs, 1H), 7.99
(s, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.41-7.43 (m, 4H), 7.11-7.22 (m,
5H), 6.94-6.95 (m, 1H), 6.04-6.21 (m, 3H), 5.95 (s, 1H), 4.79-4.82
(m, 1H), 3.41-3.43 (m, 1H), 2.63-2.69 (m, 1H), 2.27-2.39 (m, 2H),
2.03-2.15 (m, 4H), 1.46-1.53 (m, 2H), 1.29-1.30 (m, 4H).
[0779] LC/MS (ES, m/z): 582 [M+H]+.
Example PH-103
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-[(3-methoxyphenyl)methyl]-1H-
-1,3-benzodiazole trifluoroacetic acid
##STR00311##
[0780] Step 1: Synthesis of methyl
2,2-bis(4-chlorophenyl)-2-(3-[[(3-hydroxyphenyl)methyl]amino]-4-nitrophen-
yl)acetate
[0781] Into a 250-mL round-bottom flask, was placed methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate (4 g,
9.21 mmol, 1.00 equiv), (3-methylphenyl)methanamine (1.25 g, 10.32
mmol, 1.12 equiv) and a solution of DIEA (3 g, 23.21 mmol, 2.52
equiv) in CH.sub.3CN (100 mL). The resulting solution was stirred
overnight at 75.degree. C. The resulting mixture was concentrated
under vacuum. The residue was applied onto a silica gel column with
ethyl acetate/petroleum ether (1:5) to yield methyl
2,2-bis(4-chlorophenyl)-2-(3-[[(3-hydroxyphenyl)methyl]amino]-4-nitrophen-
yl)acetate as an orange solid. LC/MS (ES, m/z): 537 [M+H]+.
Step 2: Synthesis of methyl
2-(4-amino-3-[[(4-hydroxyphenyl)methyl]amino]phenyl)-2,2-bis(4-chlorophen-
yl)acetate
[0782] Into a 250-mL round-bottom flask, was placed methyl
2,2-bis(4-chlorophenyl)-2-(3-[[(4-hydroxyphenyl)methyl]amino]-4-nitrophen-
yl)acetate (3 g, 5.58 mmol, 1.00 equiv) and a solution of Raney Ni
(3 g, 1.00 equiv) in methanol (80 mL). To the resulting mixture was
then introduced H.sub.2(g). The resulting solution was stirred
overnight at room temperature. The solids were filtered out. The
resulting mixture was concentrated under vacuum to yield methyl
2-(4-amino-3-[[(4-hydroxyphenyl)methyl]amino]phenyl)-2,2-bis(4-chlorophen-
yl)acetate as a brown solid. LC/MS (ES, m/z): 507 [M+H]+.
Step 3: Synthesis of methyl
2,2-bis(4-chlorophenyl)-2-[2-cyclopropyl-1-[(3-hydroxyphenyl)methyl]-1H-1-
,3-benzodiazol-6-yl]acetate
[0783] Into a 50-mL round-bottom flask, was placed methyl
2-(4-amino-3-[[(3-hydroxyphenyl)methyl]amino]phenyl)-2,2-bis(4-chlorophen-
yl)acetate (1 g, 1.97 mmol, 1.00 equiv) and a solution of
cyclopropanecarbaldehyde (828 mg, 11.81 mmol, 5.99 equiv) in DMSO
(10 mL). The resulting solution was stirred overnight at 50.degree.
C. The resulting solution was diluted with ethyl acetate (150 mL).
The resulting mixture was washed with aq. sodium chloride
(3.times.50 mL). The organic phase was dried over anhydrous sodium
sulfate and concentrated under vacuum. The residue was applied onto
a silica gel column with ethyl acetate/petroleum ether (1:1) to
yield methyl
2,2-bis(4-chlorophenyl)-2-[2-cyclopropyl-1-[(3-hydroxyphenyl)methyl]-1H-1-
,3-benzodiazol-6-yl]acetate as a brown solid. LC/MS (ES, m/z):
557.5 [M+H]+.
Step 4: Synthesis of
2,2-bis(4-chlorophenyl)-2-[2-cyclopropyl-1-[(3-hydroxyphenyl)methyl]-1H-1-
,3-benzodiazol-6-yl]acetic acid
[0784] Into a 100-mL round-bottom flask, was placed a solution of
methyl
2,2-bis(4-chlorophenyl)-2-[2-cyclopropyl-1-[(3-hydroxyphenyl)methyl]-1H-1-
,3-benzodiazol-6-yl]acetate (700 mg, 1.26 mmol, 1.00 equiv) in
tetrahydrofuran (20 mL) and a solution of LiOH*H.sub.2O (527 mg,
12.56 mmol, 10.00 equiv) in water (20 mL). The resulting solution
was stirred overnight at 50.degree. C. The resulting mixture was
concentrated under vacuum. The resulting solution was diluted with
water (20 mL). The resulting solution was extracted with ethyl
acetate (2.times.20 mL) and the organic layers combined, then dried
in an oven under reduced pressure. and concentrated under vacuum to
yield
2,2-bis(4-chlorophenyl)-2-[2-cyclopropyl-1-[(3-hydroxyphenyl)methyl]-1H-1-
,3-benzodiazol-6-yl]acetic acid as yellow oil. LC/MS (ES, m/z): 543
[M+H]+.
Step 5: Synthesis of
3-([6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]m-
ethyl)phenol
[0785] Into a 100-mL round-bottom flask, was placed
2,2-bis(4-chlorophenyl)-2-[2-cyclopropyl-1-[(3-hydroxyphenyl)methyl]-1H-1-
,3-benzodiazol-6-yl]acetic acid (600 mg, 1.10 mmol, 1.00 equiv) and
a solution of DBU (1 g, 6.57 mmol, 6.00 equiv) in toluene (30 mL).
The resulting solution was stirred for 2 h at 100.degree. C. The
resulting mixture was concentrated under vacuum. The residue was
applied onto a silica gel column with ethyl acetate/petroleum ether
(1:1) to yield
3-([6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]m-
ethyl)phenol as a yellow solid.
Step 6: Synthesis of
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-[(3-methoxyphenyl)methyl]-1-
H-1,3-benzodiazole trifluoroacetic acid
[0786] Into a 50-mL round-bottom flask, was placed a solution of
3-([6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]m-
ethyl)phenol (100 mg, 0.20 mmol, 1.00 equiv) in
N,N-dimethylformamide (20 mL), potassium carbonate (83 mg, 0.60
mmol, 3.00 equiv) and iodomethane (32 mg, 0.23 mmol, 1.10 equiv).
The resulting solution was stirred overnight at room temperature.
The reaction was then quenched by the addition of water (20 mL).
The resulting solution was extracted with ethyl acetate (3.times.20
mL) and the organic layers combined, then dried over anhydrous
sodium sulfate and concentrated under vacuum. The product residue
was purified by Prep-HPLC with the following conditions (Waters
2767-1): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile phase,
water in 0.05% TFA and CH.sub.3CN (20% CH.sub.3CN up to 45% in 12
min); Detector, UV 254 nm to yield
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-[(3-methoxyphenyl)methyl]-1-
H-1,3-benzodiazole trifluoroacetic acid as a white solid.
[0787] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 7.90 (d, J=8.4
Hz, 1H), 7.21-7.30 (m, 6H), 6.89-6.94 (m, 6H), 6.60-6.62 (m, 2H),
5.60 (s, 1H), 5.42 (s, 2H), 3.78 (s, 3H), 2.07-2.11 (m, 1H),
1.67-1.69 (m, 2H), 1.38-1.43 (m, 2H). LC/MS (ES, m/z): 513
[M+H]+.
Example PH-104
Ethyl
2-[3-([6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazo-
l-1-yl]methyl)phenoxy]acetate trifluoroacetic acid
##STR00312##
[0789] The title compound was prepared according to the procedure
as described in Example PH-103 substituting ethyl 2-bromoacetate
for (3-methylphenyl)methanamine in Step 6.
[0790] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 7.90 (d, J=8.7
Hz, 1H), 7.28-7.31 (m, 1H), 7.20-7.25 (m, 5H), 6.84-6.96 (m, 6H),
6.65-6.67 (m, 2H), 5.60 (s, 1H), 5.42 (s, 2H), 4.60 (s, 2H), 4.25
(dd, J1=6.9 Hz, J2=14.1 Hz, 2H), 2.05-2.10 (m, 1H), 1.66-1.67 (m,
2H), 1.37-1.39 (m, 2H), 1.31 (t, J=6.9 Hz, 3H). LC/MS (ES, m/z):
585 [M+H]+.
Example PH-105
4-([6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]me-
thyl)phenol hydrochloride
##STR00313##
[0792] The title compound was prepared according to the procedure
as described in Example PH-103 substituting 4-(aminomethyl)phenol
for (3-methylphenyl)methanamine in Step 1.
[0793] .sup.1H NMR (400 MHz, CD3OD) .delta.: 7.56 (d, J=8.4 Hz,
1H), 7.31 (d, J=8.4 Hz, 4H), 7.23 (d, J=8.4 Hz, 1H), 7.14 (s, 1H),
7.00-7.04 (m, 6H), 6.75 (d, J=8.4 Hz, 2H), 5.73 (s, 1H), 5.51 (s,
1H), 2.47-2.50 (m, 1H), 1.28-1.39 (m, 4H). LC/MS (ES, m/z): 499
[M+H]+.
Example PH-106
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-(3-methoxyphenyl)-1H-1,3-ben-
zodiazole hydrochloride
##STR00314##
[0795] The title compound was prepared according to the procedure
as described in Example PH-103 substituting 3-methoxyaniline for
(3-methylphenyl)methanamine in Step 1.
[0796] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.: 7.56-7.65 (m,
2H), 7.20-7.36 (m, 6H), 7.06-7.15 (m, 6H), 7.00 (s, 1H), 5.76 (s,
1H), 3.85 (s, 1H), 2.11-2.12 (m, 1H), 1.25-1.31 (m, 4H). LC/MS (ES,
m/z): 499 [M+H]+.
Example PH-107
3-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]phe-
nol hydrochloride
##STR00315##
[0798] Into a 50-mL round-bottom flask, was placed a solution of
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-(3-methoxyphenyl)-1H-1,3-be-
nzodiazole (100 mg, 0.20 mmol, 1.00 equiv) in dichloromethane (10
mL). To the mixture was then added BBr.sub.3 (500 mg, 1.99 mmol,
9.95 equiv) dropwise with stirring at 0.degree. C. The resulting
solution was stirred for 2 h at room temperature. The resulting
mixture was concentrated under vacuum. The pH value of the solution
was adjusted to pH 8 with sodium bicarbonate. The resulting
solution was extracted with ethyl acetate (3.times.20 mL) and the
organic layers combined, then concentrated under vacuum. The
product residue was purified by Prep-HPLC with the following
conditions (Waters-2767-1): Column, Sunfire prep C18.5 um, 19*100
mm; mobile phase, 0.05% TFA in water and CH.sub.3CN (20% CH.sub.3CN
up to 65% in 8 min); Detector, UV 254 nm to yield a residue. The
CH.sub.3CN was evaporated and conc. HCl (1 mL) was added. The
mixture was lyophilized to yield
3-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-
-yl]phenol hydrochloride as an off-white solid.
[0799] .sup.1H NMR (400 MHz, CD3OD) .delta.: 7.68 (d, J=8.4 Hz,
1H), 7.51 (t, J=11.6 Hz, 1H), 7.30-7.42 (m, 5H), 7.00-7.17 (m, 8H),
5.81 (s, 1H), 2.20-2.23 (m, 1H), 1.35-1.48 (m, 4H). LC/MS (ES,
m/z): 485 [M+H]+.
Example PH-108
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-(4-methoxyphenyl)-1H-1,3-ben-
zodiazole hydrochloride
##STR00316##
[0801] The title compound was prepared according to the procedure
as described in Example PH-103 substituting 4-methoxyaniline for
(3-methylphenyl)methanamine in Step 1.
[0802] 1H NMR (400 MHz, CD3OD) .delta.: 7.56-7.68 (m, 3H), 7.35 (d,
J=8.4 Hz, 4H), 7.06-7.21 (m, 8H), 5.84 (s, 1H), 3.84 (s, 3H), 1.94
(m, 1H), 1.15-1.28 (m, 4H).
[0803] LC/MS (ES, m/z): 499 [M+H]+.
Example PH-109
ethyl
2-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-
-1-yl]phenoxy)acetate hydrochloride
##STR00317##
[0804] Step 1: Synthesis of
4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]ph-
enol hydrochloride
[0805] Into a 25-mL round-bottom flask, was placed a solution of
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-(4-methoxyphenyl)-1H-1,3-be-
nzodiazole (100 mg, 0.20 mmol, 1.00 equiv) in dichloromethane (10
mL). To the mixture was then added BBr.sub.3 (500 mg, 1.99 mmol,
9.95 equiv) dropwise with stirring at 0.degree. C. The resulting
solution was stirred for 2 h at room temperature. The resulting
mixture was concentrated under vacuum. The pH value of the solution
was adjusted to pH 8 with sodium bicarbonate. The resulting
solution was extracted with ethyl acetate (3.times.20 mL) and the
organic layers combined, then concentrated under vacuum. The
product residue was purified by Prep-HPLC with the following
conditions (Waters-2767-1): Column, Sunfire prep C18, 5 um, 19*100
mm; mobile phase, 0.05% TFA in water and CH.sub.3CN (22% CH.sub.3CN
up to 58% in 8 min); Detector, UV 254 nm to yield a residue. The
CH.sub.3CN was evaporated and conc. HCl (1 mL) was added. The
mixture was lyophilized to yield
4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-
-yl]phenol hydrochloride as an off-white solid. LC/MS (ES, m/z):
521.8 [M+H]+.
Step 2: Synthesis of ethyl
2-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]phenoxy)acetate hydrochloride
[0806] Into a 25-mL round-bottom flask, was placed
4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]ph-
enol (97 mg, 0.20 mmol, 1.00 equiv), potassium carbonate (83 mg,
0.60 mmol, 3.01 equiv) and a solution of
BrCH.sub.2CO.sub.2CH.sub.2CH.sub.3 (50.1 mg, 0.30 mmol, 1.50 equiv)
in N,N-dimethylformamide (5 mL). The resulting solution was stirred
for 3 h at room temperature. The resulting solution was diluted
with ethyl acetate (50 mL). The resulting mixture was washed with
aq. sodium chloride (3.times.10 mL). The resulting mixture was
concentrated under vacuum. The product residue was purified by
Prep-HPLC with the following conditions (Waters-2767-1): Column,
Sunfire prep C18, 5 um, 19*100 mm; mobile phase, 0.05% TFA in water
and CH.sub.3CN (25% CH.sub.3CN up to 60% in 8 min); Detector, UV
254 nm to yield a residue. The CH.sub.3CN was evaporated and conc.
HCl (1 mL) was added. The mixture was lyophilized to yield ethyl
2-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]phenoxy)acetate hydrochloride as an off-white solid.
[0807] .sup.1H NMR (400 MHz, CD3OD) .delta.: 7.70 (d, J=4.0 Hz,
1H), 7.58 (d, J=8.0 Hz, 2H), 7.39-7.51 (m, 1H), 7.31-7.37 (m, 4H),
7.28 (d, J=4.0 Hz, 2H), 7.06-7.09 (m, 5H), 5.79 (s, 1H), 4.95-5.00
(m, 1H), 4.86-4.91 (m, 1H), 4.22-4.32 (m, 2H), 2.14-2.21 (m, 1H),
1.40-1.42 (m, 4H), 1.26-1.34 (m, 3H). LC/MS (ES, m/z): 571
[M+H]+.
Example PH-110
2-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]-
phenoxy)acetamide hydrochloride
##STR00318##
[0809] The title compound was prepared according to the procedure
as described in Example PH-3 substituting ethyl
2-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)phenoxy)acetate for
4-(4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl-
]piperidin-1-yl)-4-oxobutanoate.
[0810] .sup.1H NMR (400 MHz, CD3OD) .delta.: 7.72 (d, J=8.4 Hz,
1H), 7.59 (d, J=9.6 Hz, 2H), 7.41 (d, J=8.4 Hz, 1H), 7.25-7.33 (m,
6H), 7.06-7.12 (m, 5H), 5.79 (s, 1H), 4.66 (s, 2H), 2.16-2.23 (m,
1H), 1.39-1.44 (m, 4H). LC/MS (ES, m/z): 542 [M+H]+.
Example PH-111
4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]cyc-
lohexane-1-carboxamide; trifluoroacetic acid
##STR00319##
[0811] Step 1: Synthesis of methyl
4-([5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-nitrophenyl]amino)-
cyclohexane-1-carboxylate
[0812] Into a 250-mL round-bottom flask, was placed methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate (3 g,
6.91 mmol, 1.00 equiv), methyl 4-aminocyclohexane-1-carboxylate
hydrochloride (1.6 g, 8.26 mmol, 1.20 equiv) and a solution of DIEA
(4.47 g, 34.59 mmol, 5.01 equiv) in CH.sub.3CN (100 mL). The
resulting solution was heated to reflux overnight. The resulting
mixture was concentrated under vacuum. The product residue was
purified by Flash-Prep-HPLC with the following conditions
(IntelFlash-1): Column, silica gel; mobile phase, EA:PE=5:100
increasing to EA:PE=20:100 within 50 min; Detector, UV 254 nm to
yield methyl
4-([5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-nitrophenyl]amino)-
cyclohexane-1-carboxylate as a yellow solid. LC/MS (ES, m/z): 571
[M+H]+.
Step 2: Synthesis of methyl
4-([2-amino-5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]phenyl]amino)-
cyclohexane-1-carboxylate
[0813] Into a 250-mL round-bottom flask, was placed methyl
4-([5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-nitrophenyl]amino)-
cyclohexane-1-carboxylate (2 g, 3.50 mmol, 1.00 equiv) and a
solution of Raney Ni (3 g, 1.00 equiv) in methanol (80 mL).
H.sub.2(g) was then introduced into the resulting mixture. The
resulting solution was stirred overnight at room temperature. The
solids were filtered out. The resulting mixture was concentrated
under vacuum to yield methyl
4-([2-amino-5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]phenyl]amino)-
cyclohexane-1-carboxylate as a white solid. LC/MS (ES, m/z): 541.5
[M+H]+.
Step 3: Synthesis of methyl
4-[6-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-cyclopropyl-1H-1,3--
benzodiazol-1-yl]cyclohexane-1-carboxylate
[0814] Into a 50-mL round-bottom flask, was placed methyl
4-([2-amino-5-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]phenyl]amino)-
cyclohexane-1-carboxylate (1.08 g, 1.99 mmol, 1.00 equiv) and a
solution of cyclopropanecarbaldehyde (840 mg, 11.98 mmol, 6.01
equiv) in DMSO (10 mL). The resulting solution was stirred
overnight at 50.degree. C. The resulting solution was diluted with
ethyl acetate (100 mL). The resulting mixture was washed with aq.
sodium chloride (3.times.20 mL). The organic phase was dried over
anhydrous sodium sulfate, then concentrated under vacuum. The
residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:2) to yield methyl
4-[6-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-cyclopropyl-1H-1,3--
benzodiazol-1-yl]cyclohexane-1-carboxylate as yellow oil. LC/MS
(ES, m/z): 592 [M+H]+.
Step 4: Synthesis of
4-[6-[bis(4-chlorophenyl)(carboxy)methyl]-2-cyclopropyl-1H-1,3-benzodiazo-
l-1-yl]cyclohexane-1-carboxylic
[0815] Into a 50-mL round-bottom flask, was placed a solution of
methyl
4-[6-[1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl]-2-cyclopropyl-1H-1,3--
benzodiazol-1-yl]cyclohexane-1-carboxylate (900 mg, 1.52 mmol, 1.00
equiv) in tetrahydrofuran (10 mL) and a solution of LiOH*H.sub.2O
(640 mg, 15.25 mmol, 10.02 equiv) in water (10 mL). The resulting
solution was stirred overnight at 50.degree. C. The resulting
mixture was concentrated under vacuum. The pH value of the solution
was adjusted to pH 3 with hydrogen chloride (1 mol/L). The
resulting solution was extracted with ethyl acetate (3.times.50 mL)
and the organic layers combined, then dried over anhydrous sodium
sulfate and concentrated under vacuum to yield
4-[6-[bis(4-chlorophenyl)(carboxy)methyl]-2-cyclopropyl-1H-1,3-benzodiazo-
l-1-yl]cyclohexane-1-carboxylic acid as a yellow solid.
Step 5: Synthesis of
4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]cy-
clohexane-1-carboxylic acid trifluoroacetic acid
[0816] Into a 100-mL round-bottom flask, was placed a solution of
4-[6-[bis(4-chlorophenyl)(carboxy)methyl]-2-cyclopropyl-1H-1,3-benzodiazo-
l-1-yl]cyclohexane-1-carboxylic acid (300 mg, 0.53 mmol, 1.00
equiv) in toluene (10 ml) and DBU (487 mg, 3.20 mmol, 6.00 equiv).
The resulting solution was stirred for 3 h at 90.degree. C. The
resulting mixture was concentrated under vacuum. The reaction was
then quenched by the addition of water (10 mL). The resulting
solution was extracted with ethyl acetate (3.times.10 mL) and the
organic layers combined, then dried over anhydrous sodium sulfate
and concentrated under vacuum. The product residue was purified by
Prep-HPLC with the following conditions (Waters 2767-1): Column,
SunFire Prep C18, 5 um, 19*100 mm; mobile phase, 0.05% TFA in water
and CH.sub.3CN (25% CH.sub.3CN up to 45% in 9 min); Detector, UV
254 nm to yield
4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]cy-
clohexane-1-carboxylic acid trifluoroacetic acid as a white
solid.
Step 6: Synthesis of
4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]cy-
clohexane-1-carboxamide; trifluoroacetic acid
[0817] Into a 25-mL round-bottom flask, was placed a solution of
4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]cy-
clohexane-1-carboxylic acid (110 mg, 0.21 mmol, 1.00 equiv) in
N,N-dimethylformamide (10 mL), NH.sub.4Cl (56 mg, 1.05 mmol, 5.00
equiv), HATU (97 mg, 0.26 mmol, 1.20 equiv) and DIEA (55 mg, 0.43
mmol, 2.00 equiv). The resulting solution was stirred overnight at
room temperature. The reaction was then quenched by the addition of
water (10 mL). The resulting solution was extracted with ethyl
acetate (3.times.10 mL) and the organic layers combined, then dried
over anhydrous sodium sulfate and concentrated under vacuum. The
product residue was purified by Prep-HPLC with the following
conditions (Waters 2767-1): Column, SunFire Prep C18, 5 um, 19*100
mm; mobile phase, 0.05% TFA in water and CH.sub.3CN (25% CH.sub.3CN
up to 55% in 10 min); Detector, UV 254 nm to yield
4-[6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1H-1,3-benzodiazol-1-yl]cy-
clohexane-1-carboxamide; trifluoroacetic acid as a white solid.
[0818] 1H NMR (300 MHz, CD3OD) .delta.: 7.75 (s, 1H), 7.63-7.66 (m,
1H), 7.33-7.38 (m, 5H), 7.12-7.18 (m, 4H), 5.90 (s, 1H), 2.55-2.65
(m, 1H), 2.42-2.55 (m, 1H), 2.13-2.42 (m, 6H), 1.73-1.83 (m, 2H),
1.43-1.52 (m, 2H), 1.31-1.40 (m, 2H).
[0819] LC/MS (ES, m/z): 518 [M+H]+.
Example PH-112
2-((4-chlorophenyl)(3-(1-(trifluoromethylsulfonyl)piperidin-4-yl)-3H-benzo-
[d]imidazol-5-yl)methyl)thiazole
##STR00320##
[0820] Step 1: Synthesis of
N-(5-fluoro-2-nitrophenyl)-1-(trifluoromethylsulfonyl)piperidin-4-amine
[0821] Into a 250-mL round-bottom flask, was placed a solution of
2,4-difluoro-1-nitrobenzene (2.7 g, 16.98 mmol, 1.00 equiv) in
CH.sub.3CN (60 mL), triethylamine (5.2 g, 51.49 mmol, 3.03 equiv)
and 1-(trifluoromethylsulfonyl) piperidin-4-amine hydrochloride
(5.5 g, 20.52 mmol, 1.21 equiv). The resulting solution was stirred
overnight at 90.degree. C. in an oil bath. The reaction progress
was monitored by LCMS. The reaction was then quenched by the
addition of water (100 mL). The solids were collected by
filtration. The solid was dried in an oven under reduced pressure
to yield
N-(5-fluoro-2-nitrophenyl)-1-(trifluoromethylsulfonyl)piperidin-4-amine
as a yellow solid. LC/MS (ES, m/z): 371 [M+H]+.
Step 2: Synthesis of
2-(4-chlorophenyl)-2-(4-nitro-3-(1-(trifluoromethylsulfonyl)piperidin-4-y-
lamino)phenyl)acetonitrile
[0822] Into a 500-mL round-bottom flask, was placed a solution of
2-(4-chlorophenyl) acetonitrile (5.4 g, 35.76 mmol, 1.11 equiv) in
THF/i-PrOH (200/50 mL) and potassium 2-methylpropan-2-olate (9 g,
80.36 mmol, 2.48 equiv), and the resulting mixture stirred for 10
min at room temperature. To the reaction mixture was then added
N-(5-fluoro-2-nitrophenyl)-1-(trifluoromethylsulfonyl)piperidin-4-amine
(12 g, 32.35 mmol, 1.00 equiv). The resulting solution was stirred
for 1 h at room temperature. The resulting mixture was washed with
aq. sodium chloride (1.times.200 mL). The resulting solution was
extracted with ethyl acetate (2.times.200 mL) and the organic
layers combined, then dried over anhydrous sodium sulfate. The
residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:15) to yield
2-(4-chlorophenyl)-2-(4-nitro-3-(1-(trifluoromethylsulfonyl)piperidin-4-y-
lamino)phenyl)acetonitrile as a reddish-brown solid. LC/MS (ES,
m/z): 502 [M+H]+.
Step 3: Synthesis of
2-(4-chlorophenyl)-2-(4-nitro-3-(1-(trifluoromethylsulfonyl)piperidin-4-y-
lamino)phenyl)ethanethioamide
[0823] Into a 150-mL sealed tube, was placed a solution of
2-(4-chlorophenyl)-2-(4-nitro-3-(1-(trifluoromethylsulfonyl)piperidin-4-y-
lamino)phenyl)acetonitrile (8.5 g, 16.93 mmol, 1.00 equiv) in
ethanol (100 mL) and P.sub.2S.sub.5 (7.5 g, 33.78 mmol, 2.00
equiv). The resulting solution was stirred overnight at 70.degree.
C. in an oil bath. The reaction progress was monitored by LCMS. The
reaction mixture was cooled to room temperature with a water/ice
bath. The reaction was then quenched by the addition of water/ice
(300 mL). The resulting solution was extracted with ethyl acetate
(2.times.200 mL) and the organic layers combined, then dried over
anhydrous sodium sulfate. The residue was applied onto a silica gel
column with ethyl acetate/petroleum ether (1:5) to yield
2-(4-chlorophenyl)-2-(4-nitro-3-(1-(trifluoromethylsulfonyl)pipe-
ridin-4-ylamino)phenyl)ethanethioamide as an orange solid. LC/MS
(ES, m/z): 536 [M+H]+.
Step 4: Synthesis of
N-(5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nitrophenyl)-1-(trifluorome-
thylsulfonyl)piperidin-4-amine
[0824] Into a 250-mL round-bottom flask, was placed a solution of
2-(4-chlorophenyl)-2-(4-nitro-3-(1-(trifluoromethylsulfonyl)
piperidin-4-ylamino) phenyl) ethanethioamide (10 g, 18.66 mmol,
1.00 equiv) in acetic acid (100 mL), 2-bromo-1,1-diethoxyethane (15
g, 76.53 mmol, 4.10 equiv) and water (4 mL). The resulting solution
was stirred for 30 min at 100.degree. C. in an oil bath. The
reaction progress was monitored by LCMS. The resulting mixture was
concentrated under vacuum. The resulting mixture was washed with
aq. sodium bicarbonate (1.times.200 mL). The resulting solution was
extracted with ethyl acetate (3.times.200 mL) and the organic
layers combined. The resulting mixture was washed with aq. sodium
bicarbonate (1.times.300 mL). The mixture was dried over anhydrous
sodium sulfate. The residue was applied onto a silica gel column
with ethyl acetate/petroleum ether (1:15) to
N-(5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nitrophenyl)-1-(trifluorome-
thylsulfonyl)piperidin-4-amine as an orange solid. LC/MS (ES, m/z):
560 [M+H]+.
Step 5: Synthesis of
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-N1-(1-(trifluoromethylsulfonyl)p-
iperidin-4-yl)benzene-1,2-diamine
[0825] Into a 250-mL round-bottom flask purged and maintained with
an inert atmosphere of nitrogen, was placed a solution of
N-(5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nitrophenyl)-1-(trifluorome-
thylsulfonyl)piperidin-4-amine (5 g, 8.93 mmol, 1.00 equiv) in
tetrahydrofuran/MeOH (30/30 mL) and Raney Ni (2.5 g). To the
resulting mixture was then introduced hydrogen. The resulting
solution was stirred overnight at room temperature. The solids were
collected by filtration. The resulting mixture was concentrated
under vacuum to yield
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-N1-(1-(trifluoromethylsulfonyl)p-
iperidin-4-yl)benzene-1,2-diamine as a green solid. LC/MS (ES,
m/z): 530 [M+H]+.
Step 6: Synthesis of
2-((4-chlorophenyl)(3-(1-(trifluoromethylsulfonyl)piperidin-4-yl)-3H-benz-
o[d]imidazol-5-yl) methyl)thiazole
[0826] Into a 50-mL round-bottom flask, was placed
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-N1-(1-(trifluoromethylsulfonyl)p-
iperidin-4-yl)benzene-1,2-diamine (200 mg, 0.38 mmol, 1.00 equiv),
triethoxymethane (3 mL) and hydrogen chloride (0.1 mL, con.). The
resulting solution was stirred for 4 h at 125.degree. C. in an oil
bath. The reaction progress was monitored by LCMS. The resulting
mixture was diluted with aq. sodium chloride (20 mL). The resulting
solution was extracted with ethyl acetate (3.times.20 mL) and the
organic layers combined, then dried over anhydrous sodium sulfate.
The residue was applied onto a silica gel column with
dichloromethane/methanol (60:1) to yield
2-((4-chlorophenyl)(3-(1-(trifluoromethylsulfonyl)piperidin-4-yl)-3-
H-benzo[d]imidazol-5-yl) methyl)thiazole as a light yellow
solid.
[0827] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 8.02 (s, 1H),
7.79-7.84 (m, 2H), 7.21-7.34 (m, 7H), 5.98 (s, 1H), 4.33-4.41 (m,
1H), 4.18-4.23 (m, 2H), 3.25-3.33 (m, 2H), 2.13-2.32 (m, 4H). LC/MS
(ES, m/z): 541[M+H]+.
Example PH-113
2-((4-chlorophenyl)(2-methyl-3-(1-(trifluoromethylsulfonyl)piperidin-4-yl)-
-3H-benzo[d]imidazol-5-yl)methyl)thiazole
##STR00321##
[0829] The title compound was prepared according to the procedure
as described in Example PH-112 substituting acetaldehyde for
triethoxymethane in Step 6.
[0830] .sup.1H NMR (300 MHz, DMSO) .delta.: 7.81 (d, J=3.3 Hz, 1H),
7.67 (m, 1H), 7.56 (s, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.37-7.40 (m,
2H), 7.31 (d, J=8.4 Hz, 2H), 7.08-7.12 (m, 1H), 6.16 (s, 1H),
4.61-4.69 (m, 1H), 3.97 (d, J=13.2 Hz, 2H), 3.44-3.52 (m, 2H), 2.58
(s, 3H), 2.25-2.28 (m, 2H), 1.99-2.03 (m, 2H). LC/MS (ES, m/z): 555
[M+H]+.
Example PH-114
2-((4-chlorophenyl)(2-ethyl-3-(1-(trifluoromethylsulfonyl)piperidin-4-yl)--
3H-benzo[d]imidazol-5-yl)methyl)thiazole
##STR00322##
[0832] The title compound was prepared according to the procedure
as described in Example PH-112 substituting propionaldehyde for
triethoxymethane in Step 6.
[0833] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 7.85 (s, 1H),
7.74 (d, J=8.1 Hz, 1H), 7.18-7.34 (m, 7H), 5.96 (s, 1H), 4.34-4.42
(m, 1H), 4.189-4.23 (m, 2H), 3.21-3.29 (m, 2H), 2.95-3.03 (m, 2H),
2.43-2.58 (m, 2H), 2.00-2.11 (m, 2H), 1.47 (t, J=7.2 Hz, 3H). LC/MS
(ES, m/z): 569 [M+H]+.
Example PH-115
2-((4-chlorophenyl)(2-cyclopropyl-3-(1-trifluoromethylsulfonyl)piperidin-4-
-yl)-3H-benzo[d]imidazol-5-yl)methyl)thiazole
##STR00323##
[0835] The title compound was prepared according to the procedure
as described in Example PH-112 substituting
cyclopropanecarbaldehyde for triethoxymethane in Step 6.
[0836] .sup.1H NMR (300 MHz, DMSO-d6) .delta.: 7.80 (d, J=3.3 Hz,
1H), 7.66 (d, J=3.3 Hz, 1H), 7.57 (s, 1H), 7.45-7.51 (m, 1H), 7.39
(d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.4 Hz, 1H),
6.14 (s, 1H), 4.95-5.03 (m, 1H), 3.99 (d, J=13.2 Hz, 2H), 1.05 (d,
J=7.8 Hz, 4H). LC/MS (ES, m/z): 581 [M+H]+.
Example PH-116
2-(4-chlorophenyl)(2-(pyridin-3-yl)-3-(1-trifluoromethylsulfonyl)piperidin-
-4-yl)-3H-benzo[d]imidazol-5-yl)methyl)thiazole
##STR00324##
[0838] The title compound was prepared according to the procedure
as described in Example PH-112 substituting nicotinaldehyde for
triethoxymethane in Step 6.
[0839] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 8.83 (s, 2H),
8.02 (d, J=8.1 Hz, 1H), 7.80-7.88 (m, 2H), 7.52-7.56 (m, 1H), 7.47
(s, 1H), 7.26-7.36 (m, 4H), 6.01 (s, 1H), 4.43-4.51 (m, 1H), 4.14
(d, J=13.2 Hz, 2H), 3.07-3.16 (m, 2H), 2.52-2.64 (m, 2H), 2.02-2.09
(m, 2H). LC/MS (ES, m/z): 618 [M+H]+.
Example PH-117
2-((4-chlorophenyl)(3-(8-(trifluoromethylsulfonyl)-8-aza-bicyclo[3.2.1]oct-
an-3-yl)-3H-benzo[d]imidazol-5-yl)methyl)thiazole
##STR00325##
[0841] The title compound was prepared according to the procedure
as described in Example PH-112 substituting
8-(trifluoromethylsulfonyl)-8-aza-bicyclo [3.2.1]octan-3-amine for
1-(trifluoromethylsulfonyl) piperidin-4-amine hydrochloride in Step
1.
[0842] .sup.1HNMR (300 MHz, DMSO-d6) .delta.: 8.47 (s, 1H), 7.83
(s, 1H), 7.62-7.82 (m, 2H), 7.34-7.42 (m, 5H), 7.19 (d, J=1.2 Hz,
1H), 6.22 (s, 1H), 4.46-4.58 (m, 3H), 2.60-2.70 (m, 2H), 2.07-2.14
(m, 4H), 1.90 (d, J=10.8 Hz, 2H). LC/MS (ES, m/z): 567 [M+H]+
Example YM-1
2-((4-chlorophenyl)(3-(1-(trifluoromethylsulfonyl)piperidin-4-yl)-3H-benzo-
[d]imidazol-5-yl)methyl)thiazole
##STR00326##
[0843] Step 1:
N-(5-fluoro-2-nitrophenyl)-1-((trifluoromethyl)sulfonyl)piperidin-4-amine
[0844] Into a 250-mL round-bottom flask, was placed a solution of
2,4-difluoro-1-nitrobenzene (2.7 g, 16.98 mmol, 1.00 equiv) in
CH.sub.3CN (60 mL), triethylamine (5.2 g, 51.49 mmol, 3.03 equiv),
1-(trifluoromethylsulfonyl) piperidin-4-amine hydrochloride (5.5 g,
20.52 mmol, 1.21 equiv). The resulting solution was stirred
overnight at 90.degree. C. in an oil bath. The reaction progress
was monitored by LCMS. The reaction was then quenched by the
addition of water (100 mL). The solids were collected by
filtration. The solid was dried in an oven under reduced pressure
to yield
N-(5-fluoro-2-nitrophenyl)-1-(trifluoromethylsulfonyl)piperidin-4-amine
as a yellow solid.
[0845] LC/MS (ES, m/z): 413 [M+CH.sub.3CN+H].sup.+
Step 2:
2-(4-chlorophenyl)-2-(4-nitro-3-((1-((trifluoromethyl)sulfonyl)pip-
eridin-4-yl)amino)phenyl)acetonitrile
[0846] Into a 500-mL round-bottom flask, was placed a solution of
2-(4-chlorophenyl) acetonitrile (5.4 g, 35.76 mmol, 1.11 equiv) in
tetrahydrofuran/iPrOH (200/50 mL), potassium 2-methylpropan-2-olate
(9 g, 80.36 mmol, 2.48 equiv). The resulting mixture was stirred
for 10 min at room temperature, and then
N-(5-fluoro-2-nitrophenyl)-1-(trifluoromethylsulfonyl)piperidin-4-amine
(12 g, 32.35 mmol, 1.00 equiv) was added. The resulting solution
was stirred for 1 h at room temperature. The resulting mixture was
washed with aq. sodium chloride (1.times.200 mL). The resulting
solution was extracted with ethyl acetate (2.times.200 mL) and the
organic layers combined and dried over anhydrous sodium sulfate.
The residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:15) to yield
2-(4-chlorophenyl)-2-(4-nitro-3-(1-(trifluoromethylsulfonyl)piperid-
in-4-ylamino)phenyl)acetonitrile as a reddish-brown solid.
[0847] LC/MS (ES, m/z): 503 [M+H].sup.+
Step 3
2-(4-chlorophenyl)-2-(4-nitro-3-((1-((trifluoromethyl)sulfonyl)pipe-
ridin-4-yl)amino)phenyl)ethanethioamide
[0848] Into a 150-mL sealed tube, was placed a solution of
2-(4-chlorophenyl)-2-(4-nitro-3-(1-(trifluoromethylsulfonyl)piperidin-1-y-
lamino)phenyl)acetonitrile (8.5 g, 16.93 mmol, 1.00 equiv) in
ethanol (100 mL), P.sub.2S.sub.5 (7.5 g, 33.78 mmol, 2.00 equiv).
The resulting solution was stirred overnight at 70.degree. C. in an
oil bath. The reaction progress was monitored by LCMS. The reaction
mixture was cooled to room temperature with a water/ice bath. The
reaction was then quenched by the addition of water/ice (300 mL).
The resulting solution was extracted with ethyl acetate
(2.times.200 mL) and the organic layers combined and dried over
anhydrous sodium sulfate. The residue was applied onto a silica gel
column with ethyl acetate/petroleum ether (1:5) to yield
2-(4-chlorophenyl)-2-(4-nitro-3-(1-(trifluoromethylsulfonyl)piperid-
in-4-ylamino)phenyl)ethanethioamide as an orange solid.
[0849] LC/MS (ES, m/z): 537 [M+H].sup.+
Step 4
N-(5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nitrophenyl)-1-((trif-
luoromethyl)sulfonyl)piperidin-4-amine
[0850] Into a 250-mL round-bottom flask, was placed a solution of
2-(4-chlorophenyl)-2-(4-nitro-3-(1-(trifluoromethylsulfonyl)
piperidin-4-ylamino) phenyl) ethanethioamide (10 g, 18.66 mmol,
1.00 equiv) in acetic acid (100 mL), 2-bromo-1,1-diethoxyethane (15
g, 76.53 mmol, 4.10 equiv), water (4 mL). The resulting solution
was stirred for 30 min at 100.degree. C. in an oil bath. The
reaction progress was monitored by LCMS. The resulting mixture was
concentrated under vacuum. The resulting mixture was washed with
aq. sodium bicarbonate (1.times.200 mL). The resulting solution was
extracted with ethyl acetate (3.times.200 mL) and the organic
layers combined. The resulting mixture was washed with aq. sodium
bicarbonate (1.times.300 mL). The mixture was dried over anhydrous
sodium sulfate. The residue was applied onto a silica gel column
with ethyl acetate/petroleum ether (1:15) to yield
N-(5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nitrophenyl)-1-(trifluorome-
thylsulfonyl)piperidin-4-amine as an orange solid.
[0851] LC/MS (ES, m/z): 561 [M+H].sup.+
Step 5
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-N1-(1-((trifluoromethyl)su-
lfonyl)piperidin-4-yl)benzene-1,2-diamine
[0852] Into a 250-mL round-bottom flask purged and maintained with
an inert atmosphere of nitrogen, was placed a solution of
N-(5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nitrophenyl)-1-(trifluorome-
thylsulfonyl)piperidin-4-amine (5 g, 8.93 mmol, 1.00 equiv) in
tetrahydrofuran/MeOH (30/30 mL), Raney Ni (2.5 g). To the above was
introduced hydrogen. The resulting solution was stirred overnight
at room temperature. The solids were collected by filtration. The
resulting mixture was concentrated under vacuum to yield
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-N1-(1-(trifluoromethylsulfonyl)p-
iperidin-4-yl)benzene-1,2-diamine as a green solid.
[0853] LC/MS (ES, m/z): 531 [M+H].sup.+
Step 6
2-((4-chlorophenyl)(1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-
-1H-benzo[d]imidazol-6-yl)methyl)thiazole
[0854] Into a 50-mL round-bottom flask, was placed
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-N1-(1-(trifluoromethylsulfonyl)p-
iperidin-4-yl)benzene-1,2-diamine (200 mg, 0.38 mmol, 1.00 equiv),
triethoxymethane (3 mL), hydrogen chloride (0.1 mL, con.). The
resulting solution was stirred for 4 h at 125.degree. C. in an oil
bath. The reaction progress was monitored by LCMS. The resulting
mixture was diluted with aq. sodium chloride (20 mL). The resulting
solution was extracted with ethyl acetate (3.times.20 mL) and the
organic layers combined and dried over anhydrous sodium sulfate.
The residue was applied onto a silica gel column with
dichloromethane/methanol (60:1) to yield
2-((4-chlorophenyl)(3-(1-(trifluoromethylsulfonyl)piperidin-4-yl)-3H-benz-
o[d]imidazol-5-yl) methyl)thiazole as a light yellow solid.
[0855] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 8.02 (s, 1H),
7.79-7.84 (m, 2H), 7.21-7.34 (m, 7H), 5.98 (s, 1H), 4.33-4.41 (m,
1H), 4.18-4.23 (d, J=13.5 Hz, 2H), 3.25-3.33 (m, 2H), 2.13-2.32 (m,
4H). LC/MS (ES, m/z): 541 [M+H].sup.+
[0856] The following compounds were prepared in according to the
procedure as described in Example YM-1 above, selecting and
substituting suitable reactants and reagents, as would be readily
recognized by those skilled in the art.
Example YM-2
2-((4-chlorophenyl)(2-methyl-3-(1-(trifluoromethylsulfonyl)piperidin-4-yl)-
-3H-benzo[d]imidazol-5-yl)methyl)thiazole
##STR00327##
[0858] .sup.1H NMR (300 MHz, DMSO) .delta.: 7.81 (d, J=3.3 Hz, 1H),
7.69 (s, 1H), 7.56 (s, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.37-7.40 (m,
2H), 7.31 (d, J=8.4 Hz, 2H), 7.09-7.12 (m, 1H), 6.16 (s, 1H),
4.61-4.69 (m, 1H), 3.97 (d, J=13.2 Hz, 2H), 3.44-3.52 (m, 2H), 2.58
(s, 3H), 2.25-2.28 (m, 2H), 2.00-2.03 (m, 2H). LC/MS (ES, m/z): 555
[M+H]+.
Example YM-3
2-((4-chlorophenyl)(2-ethyl-3-(1-(trifluoromethylsulfonyl)piperidin-4-yl)--
3H-benzo[d]imidazol-5-yl)methylthiazole
##STR00328##
[0860] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 7.84 (s, 1H),
7.74 (d, J=8.4 Hz, 1H), 7.18-7.34 (m, 7H), 5.96 (s, 1H), 4.34-4.42
(m, 1H), 4.19-4.23 (m, 2H), 3.21-3.30 (m, 2H), 2.95-3.03 (m, 2H),
2.44-2.58 (m, 2H), 2.00-2.11 (m, 2H), 1.47 (t, J=7.2 Hz, 3H). LC/MS
(ES, m/z): 569 [M+H]+.
Example YM-4
2-((4-chlorophenyl)(2-propyl-3-(1-(trifluoromethylsulfonyl)piperidin-4-yl)-
-3H-benzo[d]imidazol-5-yl)methyl)thiazole
##STR00329##
[0862] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 7.85 (s, 1H),
7.72 (d, J=8.4 Hz, 1H), 7.17-7.34 (m, 7H), 5.96 (s, 1H), 4.25-4.45
(m, 1H), 4.19-4.22 (m, 2H), 3.21-3.30 (m, 2H), 2.92 (brm, 2H),
2.49-2.52 (m, 2H), 1.88-2.03 (m, 4H), 1.10 (t, J=7.2 Hz, 3H).
[0863] LC/MS (ES, m/z): 583 [M+H].sup.+.
Example YM-5
2-(4-chlorophenyl)(2-isobutyl-3-(1-(trifluoromethylsulfonyl)piperidin-4-yl-
)-3H-benzo[d]imidazol-5-yl)methyl)thiazole
##STR00330##
[0865] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 7.85 (d, J=3.3
Hz, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.17-7.34 (m, 7H), 5.96 (s, 1H),
4.35-4.41 (m, 1H), 4.20 (d, J=12.6 Hz, 2H), 3.20-3.29 (m, 2H), 2.81
(d, J=7.5 Hz, 2H), 2.46-2.58 (m, 2H), 2.18-2.23 (m, 1H), 1.97-2.01
(m, 2H), 1.07 (d, J=3.6 Hz, 6H). LC/MS (ES, m/z): 597
[M+H].sup.+.
Example YM-6
2-((4-chlorophenyl)(2-cyclopropyl-3-(1-(trifluoromethylsulfonyl)piperidin--
4-yl)-3H-benzo[d]imidazol-5-yl)methyl)thiazole
##STR00331##
[0867] .sup.1H NMR (300 MHz, DMSO) .delta.: 7.81 (d, J=3.3 Hz, 1H),
7.66 (d, J=3.3 Hz, 1H), 7.57 (brs, 1H), 7.49 (d, J=9.6 Hz, 1H),
7.38 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz,
1H), 6.14 (s, 1H), 4.95-5.03 (m, 1H), 4.00 (d, J=13.2 Hz, 2H),
3.47-3.55 (m, 2H), 2.28-2.35 (m, 3H), 2.01-2.05 (m, 2H), 1.03-1.06
(m, 4H). LC/MS (ES, m/z) 581 [M+H].sup.+.
Example YM-7
2-((4-chlorophenyl)(2-cyclobutyl-3-(1-(trifluoromethylsulfonyl)piperidin-4-
-yl)-3H-benzo[d]imidazol-5-yl)methyl)thiazole
##STR00332##
[0869] .sup.1H NMR (300 MHz, DMSO) .delta.: 7.81 (d, J=3.3 Hz, 1H),
7.66 (d, J=3.3 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.30-7.40 (m, 4H),
7.11 (d, J=8.4 Hz, 1H), 6.17 (s, 1H), 4.52-4.55 (m, 1H), 3.88-3.97
(m, 3H), 3.49-3.54 (m, 2H), 2.37-2.50 (m, 4H), 2.28-2.27 (m, 2H),
2.05-2.08 (m, 1H), 1.90-1.94 (m, 3H). LC/MS (ES, nm/z): 595
[M+H].sup.+.
Example YM-8
2-((4-chlorophenyl)(2-cyclopentyl-3-(1-(trinfluoromethylsulfonyl)piperidin-
-4-yl)-3H-benzo[d]imidazol-5-yl)methyl)thiazole
##STR00333##
[0871] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 7.88 (m, 1H),
7.73 (d, J=8.4 Hz, 1H), 7.14-7.40 (m, 7H), 5.95 (s, 1H), 4.41-4.49
(m, 1H), 4.20 (d, J=13.2 Hz, 2H), 3.20-3.28 (m, 3H), 2.46-2.57 (m,
2H), 2.07-2.12 (m, 4H), 1.91-2.01 (m, 4H), 1.62-1.81 (m, 2H). LC/MS
(ES, nm/z): 609 [M+H].sup.+.
Example YM-9
2-((4-chlorophenyl)(2-(4-chlorophenyl)-3-(1-(trifluoromethylsulfonyl)piper-
idin-4-yl)-3H-benzo[d]imidazol-5-ylmethyl)thiazole
##STR00334##
[0873] LC/MS (ES, m/z): 651 [M+H].sup.+.
Example YM-10
2-((4-chlorophenyl)(2-(pyridin-2-yl)-3-(1-(trifluoromethylsulfonyl)piperid-
in-4-yl)-3H-benzo[d]imidazol-5-yl)methyl)thiazole
##STR00335##
[0875] .sup.1H NMR (300 MHz, DMSO) .delta.: 8.75 (d, J=4.2 Hz, 1H),
8.15-8.17 (m, 1H), 8.03-8.05 (m, 1H), 7.84 (s, 1H), 7.68-7.75 (m,
3H), 7.54-7.58 (m, 1H), 7.34-7.43 (m, 4H), 7.24-7.26 (d, J=8.4 Hz,
1H), 6.26 (s, 1H), 5.58-5.66 (m, 1H), 3.97 (d, J=13.2 Hz, 2H),
3.40-3.44 (m, 2H), 2.40-2.50 (m, 2H), 2.10-2.13 (m, 2H). LC/MS (ES,
m/z): 618 [M+H]+.
Example YM-11
2-(4-chlorophenyl)(2-pyridin-3-yl)-3-(1-(trifluoromethylsulfonyl)piperidin-
-4-yl)-3H-benzo[d]imidazol-5-yl)methyl)thiazole
##STR00336##
[0877] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 8.83 (s, 2H),
8.02 (d, J=8.1 Hz, 1H), 7.80-7.88 (m, 2H), 7.52-7.56 (m, 1H), 7.47
(s, 1H), 7.26-7.36 (m, 6H), 6.01 (s, 1H), 4.43-4.51 (m, 1H), 4.14
(d, J=13.2 Hz, 2H), 3.07-3.16 (m, 2H), 2.52-2.64 (m, 2H), 2.02-2.09
(m, 2H). LC/MS (ES, m/z): 618 [M+H]+.
Example YM-12
2-((4-chlorophenyl)(2-pyridin-4-yl)-3-(1-trifluoromethylsulfonyl)piperdin--
4-yl)-3H-benzo[d]imidazol-5-yl)methyl)thiazole
##STR00337##
[0879] LC/MS (ES, m/z): 618 [M+H].sup.+.
Example YM-13
Ethyl
6-((4-chlorophenyl)(thiazol-2-yl)methyl)-1-(1-(trifluoromethylsulfon-
yl)piperidin-4-yl)-1H-benzo[d]imidazole-2-carboxylate
##STR00338##
[0881] LC/MS (ES, m/z): 613 [M+H].sup.+.
Example YM-14
2-((4-chlorophenyl)(3-(8-trifluoromethylsulfonyl)-8-aza-bicyclo[3.2.1]octa-
n-3-yl)-3H-benzo[d]imidazol-5-yl)methyl)thiazole
##STR00339##
[0882] Step 1
N-(5-fluoro-2-nitrophenyl)-8-((trifluoromethyl)sulfonyl)-8-azabicyclo[3.2-
.1]octan-3-amine
[0883] Into a 500-mL round-bottom flask, was placed a solution of
2,4-difluoro-1-nitrobenzene (8.4 g, 52.83 mmol, 1.00 equiv) in
CH.sub.3CN (250 mL),
8-(trifluoromethylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-amine (15
g, 58.14 mmol, 1.10 equiv), triethylamine (16 g, 158.42 mmol, 3.00
equiv). The resulting solution was stirred overnight at 90.degree.
C. in an oil bath. The reaction progress was monitored by LCMS. The
reaction was then quenched by the addition of brine (200 mL). The
resulting solution was extracted with ethyl acetate (2.times.200
mL) and the organic layers combined and dried over anhydrous sodium
sulfate. The residue was applied onto a silica gel column with
dichloromethane/methanol to yield
N-(5-fluoro-2-nitrophenyl)-8-(trifluoromethylsulfonyl)-8-aza-bicyclo[3.2.-
1]octan-3-amine as a yellow solid.
[0884] LC/MS (ES, m/z): 398 [M+H].sup.+
Step 2
2-(4-chlorophenyl)-2-(4-nitro-3-(8-(trifluoromethylsulfonyl)-8-aza--
bicyclo[3.2.1]octan-3-ylamino)phenyl)acetonitrile
[0885] Into a 500-mL round-bottom flask, was placed a solution of
2-(4-chlorophenyl)acetonitrile (3.6 g, 23.84 mmol, 1.11 equiv) in
tetrahydrofuran/iPrOH (200/40 mL), potassium 2-methylpropan-2-olate
(6 g, 53.57 mmol, 2.50 equiv), stirred for 10 min. To the mixture
was then added
N-(5-fluoro-2-nitrophenyl)-8-(trifluoromethylsulfonyl)-8-aza-bicycl-
o[3.2.]octan-3-amine (8.5 g, 21.41 mmol, 1.00 equiv). The resulting
solution was stirred for 30 min at room temperature. The resulting
mixture was poured into water (200 mL), and the pH of the mixture
adjusted to pH 7 with 2 M HCl. The resulting solution was extracted
with ethyl acetate (2.times.200 mL) and the organic layers combined
and dried over anhydrous sodium sulfate. The residue was applied
onto a silica gel column with ethyl acetate/petroleum ether (1:15)
to yield
2-(4-chlorophenyl)-2-(4-nitro-3-(8-(trifluoromethylsulfonyl)-8-aza-bicycl-
o[3.2.1]octan-3-ylamino)phenyl)acetonitrile as a yellow solid
[0886] LC/MS (ES, m/z): 529 [M+H].sup.+
Step 3
2-(4-chlorophenyl)-2-(4-nitro-3-(8-(trifluoromethylsulfonyl)-8-aza--
bicyclo[3.2.1]octan-3-ylamino)phenyl)ethanethioamide
[0887] Into a 150-mL sealed tube, was placed a solution of
2-(4-chlorophenyl)-2-(4-nitro-3-(8-(trifluoromethylsulfonyl)-8-aza-bicycl-
o[3.2.1]octan-3-ylamino)phenyl)acetonitrile (9 g, 17.05 mmol, 1.00
equiv) in ethanol (100 mL), P.sub.2S.sub.5 (11.3 g, 50.90 mmol,
2.99 equiv). The resulting solution was stirred overnight at
70.degree. C. in an oil bath. The reaction progress was monitored
by LCMS. The reaction mixture was cooled to room temperature with a
water/ice bath. The reaction was then quenched by the addition of
water/ice (200 mL). The resulting solution was extracted with ethyl
acetate (2.times.200 mL) and the organic layers combined and dried
over anhydrous sodium sulfate. The residue was applied onto a
silica gel column with DCM/MeOH (60:1) to yield
2-(4-chlorophenyl)-2-(4-nitro-3-(8-(trifluoromethylsulfonyl)-8-aza-bicycl-
o[3.2.1]octan-3-ylamino)phenyl)ethanethioamide as a yellow
solid.
[0888] LC/MS (ES, m/z): 563 [M+H].sup.+
Step 4
N-(5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nitrophenyl)-8-(trifl-
uoromethylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-amine
[0889] Into a 250-mL round-bottom flask, was placed a solution of
2-(4-chlorophenyl)-2-(4-nitro-3-(8-(trifluoromethylsulfonyl)-8-aza-bicycl-
o[3.2.1]octan-3-ylamino)phenyl)ethanethioamide (9 g, 16.01 mmol,
1.00 equiv) in acetic acid (100 mL), 2-bromo-1,1-diethoxyethane
(12.5 g, 63.78 mmol, 3.98 equiv), water (4 mL). The resulting
solution was stirred for 30 min at 100.degree. C. in an oil bath.
The reaction progress was monitored by LCMS. The resulting mixture
was concentrated under vacuum. The reaction was then quenched by
the addition of aq. sodium chloride (200 mL). The resulting
solution was extracted with ethyl acetate (3.times.200 mL) and the
organic layers combined. The resulting mixture was washed with aq.
sodium bicarbonate (1.times.300 mL). The mixture was dried over
anhydrous sodium sulfate. The residue was applied onto a silica gel
column with ethyl acetate/petroleum ether (1:15) to yield
N-(5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nitrophenyl)-8-(trifluorome-
thylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-amine as an orange
solid.
[0890] LC/MS (ES, m/z): 587 [M+H].sup.+
Step 5
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-N1-(8-(trifluoromethylsulf-
onyl)-8-aza-bicyclo[3.2.1]octan-3-yl)benzene-1,2-diamine
[0891] Into a 250-mL round-bottom flask purged and maintained with
an inert atmosphere of nitrogen, was placed a solution of
N-(5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nitrophenyl)-8-(trifluorome-
thylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-amine (5.3 g, 9.04 mmol,
1.00 equiv) in tetrahydrofuran/MeOH (30/30 mL), Raney Ni (2.5 g).
To the resulting mixture was introduced hydrogen. The resulting
solution was stirred overnight at room temperature. The reaction
progress was monitored by LCMS. The solids were filtered out. The
resulting mixture was concentrated under vacuum to yield
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-N1-(8-(trifluoromethylsulfonyl)--
8-aza-bicyclo[3.2.]octan-3-yl)benzene-1,2-diamine as a green
solid.
[0892] LC/MS (ES, m/z): 557 [M+H].sup.+
Step 6
2-((4-chlorophenyl)(3-(8-(trifluoromethylsulfonyl)-8-aza-bicyclo[3.-
2.1]octan-3-yl)-3H-benzo[d]imidazol-5-yl)methyl)thiazole
[0893] Into a 50-mL round-bottom flask, was placed
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-N1-(8-(trifluoromethylsulfonyl)--
8-aza-bicyclo[3.2.1]octan-3-yl)benzene-1,2-diamine (200 mg, 0.36
mmol, 1.00 equiv), triethoxymethane (4 mL), hydrogen chloride (0.5
mL). The resulting solution was stirred for 4 h at 120.degree. C.
in an oil bath. The reaction progress was monitored by LCMS. The
reaction was then quenched by the addition of brine (20 mL). The
resulting solution was extracted with ethyl acetate and the organic
layers combined and dried over anhydrous sodium sulfate. The
residue was purified by TLC method with dichloromethane/methanol
(100:1) to yield
2-((4-chlorophenyl)(3-(8-(trifluoromethylsulfonyl)-8-aza-bicyclo[3.2.1]oc-
tan-3-yl)-3H-benzo[d]imidazol-5-yl)methyl)thiazole as a yellow
solid.
[0894] .sup.1H NMR (300 MHz, DMSO) .delta.: 8.47 (s, 1H), 7.83 (s,
1H), 7.62-7.82 (m, 2H), 7.33-7.42 (m, 5H), 7.17-7.20 (m, 1H), 6.22
(s, 1H), 4.47-4.58 (m, 3H), 2.60-2.70 (m, 2H), 2.07-2.14 (m, 4H),
1.88-1.92 (m, 2H). LC/MS (ES, m/z): 567 [M+H].sup.+.
[0895] The following compounds were prepared according to the
procedure as described in Example YM-14 above, selecting and
substituting suitable reactants and reagents, as would be readily
recognized by those skilled in the art.
Example YM-15
2-((4-chlorophenyl)(2-ethyl-3-(8-trifluoromethylsulfonyl)-8-aza-bicyclo[3.-
2.1]octan-3-yl)-3H-benzo[d]imidazol-5-yl)methyl)thiazole
##STR00340##
[0897] LC/MS (ES, m/z): 595 [M+H]+.
Example YM-16
2-((4-chlorophenyl)(2-(pyridin-3-yl)-3-(8-(trifluoromethylsulfonyl)-8-aza--
bicyclo[3.2.1]octan-3-yl)-3H-benzo[d]imidazol-5-yl)methyl)thiazole
##STR00341##
[0899] LC/MS (ES, m/z): 644 [M+H]+.
Example YM-17
2-((4-chlorophenyl)(2-(pyridin-4-yl)-3-(8-(trifluoromethylsulfonyl)-8-aza--
bicyclo[3.2.1]octan-3-yl)-3H-benzo[d]imidazo-5-yl)methyl)thiazole
##STR00342##
[0901] LC/M (E, m/z): 644 [M+H]+.
Example YM-18
methyl6-((4-chlorophenyl)(thiazol-2-yl)methyl)-1-(8-(trifluoromethylsulfon-
yl)-8-aza-bicyclo[3.2.1]octan-3-yl)-1H-benzo[d]imidazole-2-carboxylate
##STR00343##
[0903] .sup.1H NMR (300 MHz, DMSO) .delta.: 7.87 (d, J=3.3 Hz, 1H),
7.72-7.79 (m, 2H), 7.37-7.45 (m, 5H), 7.31 (d, J=9.0 Hz, 1H), 6.35
(s, 1H), 5.60 (brm, 1H), 4.48-4.52 (m, 2H), 3.92 (s, 3H), 2.65-2.73
(m, 2H), 2.19 (brm, 2H), 1.76-1.98 (m, 4H).
[0904] LC/MS (ES, m/z): 625 [M+H]+.
Example YM-19
ethyl 3-(6-((4-chlorophenyl
W)(thiazol-2-yl)methyl)-1H-benzo[d]imidazol-1-yl)-8-azabicyclo[3.2.1]octa-
ne-8-carboxylate
##STR00344##
[0905] Step 1 ethyl
3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate
[0906] Into a 1000-mL round-bottom flask, was placed a solution of
Sm (19.7 mg, 100.00 mmol, 1.00 equiv) in ethanol/NH.sub.3 (500 mL),
Ti(OiPr).sub.4 (60 mL, 200 mmol, 2.00 equiv), stirred for overnight
at room temperature. Then added NaBH.sub.4 (6 g, 150.00 mmol, 1.50
equiv). The resulting solution was allowed to react, with stirring,
for an additional 4 h at room temperature. The resulting solution
was diluted with of 2 M NH.sub.3/H.sub.2O (500 mL). The solids were
filtered out, washed with ethyl acetate (500 mL). The aqueous
solution was extracted with ethyl acetate (3.times.500 mL) and the
organic layers combined. The pH value of the solution was adjusted
to 3-4 with hydrogen chloride (1 M). The aqueous phase was
collected, and potassium hydroxide (2 M) was employed to adjust the
pH to 10. The resulting solution was extracted with ethyl acetate
(3.times.500 mL) of ethyl acetate and the organic layers combined
and dried over anhydrous sodium sulfate and concentrated under
vacuum to yield ethyl
3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate as a white
solid.
[0907] LC/MS (ES, m/z) 199 [M+H].sup.+.
Step 2 ethyl
3-((5-fluoro-2-nitrophenyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate
[0908] Into a 500-mL round-bottom flask, was placed a solution of
2,4-difluoro-1-nitrobenzene (13.29 g, 83.58 mmol, 1.00 equiv) in
CH.sub.3CN (350 mL), ethyl
3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (18.2 g, 91.92
mmol, 1.10 equiv), triethylamine (18.6 g, 184.16 mmol, 2.20 equiv).
The resulting solution was stirred overnight at 90.degree. C. The
resulting mixture was concentrated under vacuum. The residue was
dissolved in dichloromethane (500 mL). The resulting mixture was
washed with sodium bicarbonate (1.times.100 mL) and brine
(1.times.100 mL). The mixture was dried over anhydrous sodium
sulfate and concentrated. The residue was applied onto a silica gel
column with ethyl acetate/petroleum ether (1:50-1:10) to yield
ethyl
3-((5-fluoro-2-nitrophenyl)amino)-8-azabicyclo[3.2.]octane-8-carbox-
ylate as a yellow solid.
[0909] LC/MS (ES, m/z) 338 [M+H].sup.+.
Step 3
2-(3-((8-butyryl-8-azabicyclo[3.2.1]octan-3-yl)amino)-4-nitrophenyl-
)-2-(4-chlorophenyl)acetonitrile
[0910] Into a 1000-mL round-bottom flask, was placed a solution of
ethyl
3-((5-fluoro-2-nitrophenyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate
(25.9 g, 76.85 mmol, 1.00 equiv) in tetrahydrofuran/i-PrOH (760/190
mL), 2-(4-chlorophenyl)acetonitrile (12.8 g, 84.53 mmol, 1.10
equiv), t-BuOK (21.52 g, 192.14 mmol, 2.50 equiv). The resulting
solution was stirred for 30 min at room temperature. The resulting
solution was diluted with water (400 mL). The resulting solution
was extracted with dichloromethane (3.times.600 mL) and the organic
layers combined. The resulting mixture was washed with water
(2.times.100 mL) and brine (1.times.100 mL). The mixture was dried
over anhydrous sodium sulfate and concentrated. The residue was
applied onto a silica gel column with ethyl acetate/petroleum ether
(1:20-1:5) to yield of
2-(3-((8-butyryl-8-azabicyclo[3.2.1]octan-3-yl)amino)-4-nitrophenyl)-2-(4-
-chlorophenyl)acetonitrile as a yellow solid.
[0911] LC/MS (ES, m/z) 467 [M+H].sup.+.
Step 4 ethyl
3-((5-(2-amino-1-(4-chlorophenyl)-2-thioxoethyl)-2-nitrophenyl)amino)-8-a-
zabicyclo[3.2.1]octane-8-carboxylate
[0912] Into a 250-mL sealed tube, was placed a solution of
2-(3-((8-butyryl-8-azabicyclo[3.2.1]octan-3-yl)amino)-4-nitrophenyl)-2-(4-
-chlorophenyl)acetonitrile (14.5 g, 30.98 mmol, 1.00 equiv) in
ethanol (150 mL), P.sub.2S.sub.5 (9 g, 40.49 mmol, 2.00 equiv). The
resulting solution was stirred overnight at 70.degree. C. The
resulting solution was diluted with water (100 mL). The resulting
solution was extracted with ethyl acetate (3.times.250 mL) and the
organic layers combined. The resulting mixture was washed with
water (2.times.50 mL) and brine (50 mL). The mixture was dried over
anhydrous sodium sulfate. The residue was applied onto a silica gel
column with ethyl acetate/petroleum ether (1:20-1:5) to yield ethyl
3-((5-(2-amino-1-(4-chlorophenyl)-2-thioxoethyl)-2-nitrophenyl)amino)-8-a-
zabicyclo[3.2.1]octane-8-carboxylate as a yellow solid.
[0913] LC/MS (ES, m/z) 503 [M+H].sup.+.
Step 5 ethyl
3-((5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nitrophenyl)amino)-8-azabi-
cyclo[3.2.1]octane-8-carboxylate
[0914] Into a 500-mL round-bottom flask, was placed a solution of
ethyl
3-((5-(2-amino-1-(4-chlorophenyl)-2-thioxoethyl)-2-nitrophenyl)amino)-8-a-
zabicyclo[3.2.1]octane-8-carboxylate (13.5 g, 26.89 mmol, 1.00
equiv) in H.sub.2O/HOAc (50/150 mL), 2-bromo-1,1-diethoxyethane (21
g, 106.60 mmol, 4.00 equiv). The resulting solution was stirred for
30 min at 100.degree. C. The resulting solution was diluted with
water (250 mL). The resulting solution was extracted with ethyl
acetate (3.times.300 mL) and the organic layers combined. The
resulting mixture was washed with sodium bicarbonate (3.times.100
mL) and brine (1.times.100 mL). The mixture was dried over
anhydrous sodium sulfate. The residue was applied onto a silica gel
column with ethyl acetate/petroleum ether (1:20-1:5) to yield ethyl
3-((5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nitrophenyl)amino)-8-
-azabicyclo[3.2.1]octane-8-carboxylate as a yellow solid.
[0915] LC/MS (ES, m/z) 527 [M+H].sup.+.
Step 6 ethyl
3-((2-amino-5-((4-chlorophenyl)(thiazol-2-yl)methyl)phenyl)amino)-8-azabi-
cyclo[3.2.1]octane-8-carboxylate
[0916] Into a 250-mL round-bottom flask, was placed a solution of
ethyl
3-((5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nitrophenyl)amino)-8-azabi-
cyclo[3.2.1]octane-8-carboxylate (9 g, 17.11 mmol, 1.00 equiv) in
tetrahydrofuran/MeOH (80/80 mL), RaNi (3 g, 3.00 equiv). To the
above hydrogen gas was bubbled in. The resulting solution was
stirred overnight at room temperature. The solids were filtered
out. The resulting mixture was concentrated under vacuum to yield
ethyl
3-((2-amino-5-((4-chlorophenyl)(thiazol-2-yl)methyl)phenyl)amino)-8-azabi-
cyclo[3.2.1]octane-8-carboxylate as a yellow solid.
[0917] LC/MS (ES, m/z) 497 [M+H].sup.+.
Step 7 ethyl
3-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)-1H-benzo[d]imidazol-1-yl)-8-a-
zabicyclo[3.2.1]octane-8-carboxylate
[0918] Into a 10-mL round-bottom flask, was placed ethyl
3-((2-amino-5-((4-chlorophenyl)(thiazol-2-yl)methyl)phenyl)amino)-8-azabi-
cyclo[3.2.]octane-8-carboxylate (250 mg, 0.50 mmol, 1.00 equiv),
trimethoxymethane (3 ml, 4.00 equiv), hydrogen chloride (0.02 ml).
The resulting solution was heated to reflux for 6 hr. The resulting
solution was diluted with water (20 mL). The resulting solution was
extracted with ethyl acetate (3.times.50 mL) and the organic layers
combined. The resulting mixture was washed with water (3.times.30
mL) and brine (30 mL). The mixture was dried over anhydrous sodium
sulfate and concentrated. The residue was purified by TLC method
with DCM:MeOH=50:1 to yield ethyl
3-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)-1H-benzo[d]imidazol-1-yl)-8-a-
zabicyclo[3.2.1]octane-8-carboxylate as a white solid.
[0919] .sup.1H NMR (400 MHz, DMSO) .delta.: 8.42 (s, 1H), 7.82 (d,
J=2.4 Hz, 1H), 7.67 (d, J=2.7 Hz, 1H), 7.62 (d, J=6.3 Hz, 1H),
7.34-7.41 (m, 5H), 7.16-7.18 (d, J=6.3 Hz, 1H), 6.19 (s, 1H),
4.35-4.39 (m, 1H), 4.30 (brm, 2H), 4.06-4.12 (m, 2H), 2.50-2.55 (m,
2H), 1.89-1.96 (m, 4H), 1.66-1.70 (m, 2H), 1.21 (t, J=7.2 Hz,
3H).
[0920] LC/MS (ES, m/z): 507 [M+H].sup.+.
[0921] The following compounds were prepared according to the
procedure as described in Example YM-19 above, selecting and
substituting suitable reactants and reagents, as would be readily
recognized by those skilled in the art.
Example YM-20
ethyl
3-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-ethyl-1H-benzo[d]imida-
zol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate
##STR00345##
[0923] LC/MS (ES, m/z): 535 [M+H].sup.+.
Example YM-21
ethyl
3-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-propyl-1H-benzo[d]imid-
azol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate
##STR00346##
[0925] LC/MS (ES, m/z): 549 [M+H].sup.+.
Example YM-22
ethyl 3-(6-f
(4-chlorophenyl)(thiazol-2-yl)methyl)-2-isopropyl-1H-benzo[d]imidazol-1-y-
l)-8-azabicyclo[3.2.1]octane-8-carboxylate
##STR00347##
[0927] LC/MS (ES, m/z): 549 [M+H].sup.+.
Example YM-23
ethyl
3-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-cyclopropyl-1H-benzo[d-
]imidazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate
##STR00348##
[0929] LC/MS (ES, m/z): 547 [M+H].sup.+.
Example YM-24
ethyl
3-(2-(4-chlorophenyl)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)-1H-be-
nzo[d]imidazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate
##STR00349##
[0931] LC/MS (ES, m/z): 617 [M+H].sup.+.
Example YM-25
ethyl
3-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-(pyridin-3-yl)-1H-benz-
o[d]imidazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate
##STR00350##
[0933] LC/MS (ES, m/z): 584 [M+H].sup.+.
Example YM-26
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-(trifluoromethylsulfonyl)-
piperidin-4-yl)-1H-benzo[d]imidazole, Compound #
##STR00351##
[0934] Step 1 1-(trifluoromethane)sulfonylpiperidin-4-amine
hydrochloride
[0935] Into a 1-L round-bottom flask, was placed tert-butyl
N-[1-(trifluoromethane)sulfonylpiperidin-4-yl]carbamate (70 g,
210.63 mmol, 1.00 equiv), 1,4-dioxane (200 mL), hydrogen chloride
(100 mL, 3.00 equiv, 6M). The resulting solution was stirred
overnight at 60.degree. C. in an oil bath. The resulting mixture
was concentrated under vacuum. The resulting residue was purified
by re-crystallization from DCM to yield
1-(trifluoromethane)sulfonylpiperidin-4-amine hydrochloride as a
light brown solid.
[0936] LC/MS (ES, m/z) 233 [M-HCl+H].sup.+
Step 2
N-(5-bromo-2-nitrophenyl)-1-(trifluoromethane)sulfonylpiperidin-4-a-
mine
[0937] Into a 500-mL round-bottom flask, was placed a solution of
1-(trifluoromethane)sulfonylpiperidin-4-amine hydrochloride (13.3
g, 49.50 mmol, 1.00 equiv) in CH.sub.3CN (mL),
4-bromo-2-fluoro-1-nitrobenzene (10 g, 45.46 mmol, 1.00 equiv),
triethylamine (14.5 g, 143.29 mmol, 3.20 equiv). The resulting
solution was stirred for 1 overnight at 90.degree. C. The solids
were collected by filtration to yield
N-(5-bromo-2-nitrophenyl)-1-(trifluoromethane)sulfonylpiperidin-4-amine
as a yellow solid.
[0938] LC/MS (ES, m/z) 434 [M+H].sup.+.
Step 3
5-bromo-1-N-[1-(trifluoromethane)sulfonylpiperidin-4-yl]benzene-1,2-
-diamine
[0939] Into a 500-mL round-bottom flask, was placed
N-(5-bromo-2-nitrophenyl)-1-(trifluoromethane)sulfonylpiperidin-4-amine
(18 g, 41.65 mmol, 1.00 equiv), methanol (100 mL), tetrahydrofuran
(200 mL), Ni (9 g). To the resulting mixture was introduced
hydrogen. The resulting solution was stirred for 1 overnight at
room temperature. The solids were filtered out. The resulting
mixture was concentrated under vacuum to yield
5-bromo-1-N-[1-(trifluoromethane)sulfonylpiperidin-4-yl]benzene-1,2-diami-
ne as brown oil.
[0940] LC/MS (ES, m/z) 402 [M+H].sup.+.
Step 4
N-(4-bromo-2-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]phe-
nyl)cyclopropanecarboxamide
[0941] Into a 250-mL round-bottom flask, was placed
5-bromo-1-N-[1-(trifluoromethane)sulfonylpiperidin-4-yl]benzene-1,2-diami-
ne (7 g, 17.40 mmol, 1.00 equiv), N,N-dimethylformamide (100 mL),
HATU (8.581 g, 22.57 mmol, 1.30 equiv), DIEA (4.481 g, 34.67 mmol,
1.99 equiv), cyclopropanecarboxylic acid (1.643 g, 19.08 mmol, 1.10
equiv). The resulting solution was stirred overnight at room
temperature. The reaction progress was monitored by LCMS. The
reaction was then quenched by the addition of water (500 mL). The
resulting solution was extracted with ethyl acetate (3.times.300
mL) and the organic layers combined and dried over anhydrous sodium
sulfate. The solids were filtered out. The resulting mixture was
concentrated under vacuum to yield of
N-(4-bromo-2-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]phenyl)cy-
clopropanecarboxamide as a brown solid.
[0942] LC/MS (ES, m/z) 470 [M+H].sup.+.
Step 5
6-bromo-2-cyclopropyl-1-[1-(trifluoromethane)sulfonylpiperidin-4-yl-
]-1H-1,3-benzodiazole
[0943] Into a 250-mL round-bottom flask, was placed
N-(4-bromo-2-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]phenyl)cy-
clopropanecarboxamide (7.9 g, 16.80 mmol, 1.00 equiv), CF.sub.3COOH
(100 mL). The resulting solution was stirred overnight at
120.degree. C. The resulting mixture was concentrated under vacuum.
The resulting solution was diluted with ethyl acetate (200 mL). The
resulting mixture was washed with 30% NaHCO.sub.3 (3.times.100 mL).
The resulting mixture was washed with sodium chloride (100 mL). The
mixture was dried over anhydrous sodium sulfate. The solids were
filtered out. The resulting mixture was concentrated under vacuum.
The resulting residue was re-crystallized from ethyl acetate in the
ratio of 1:10 to yield
6-bromo-2-cyclopropyl-1-[1-(trifluoromethane)sulfonylpiperidin-4-yl]-1H-1-
,3-benzodiazole as a pink solid.
[0944] LC/MS (ES, m/z) 452 [M+H].sup.+.
Step 6
bis(4-chlorophenyl)(2-cyclopropyl-1-[1-(trifluoromethane)sulfonylpi-
peridin-4-yl]-1H-1,3-benzodiazol-6-yl)methanol
[0945] Into a 250-mL 3-necked-round-bottom flask purged and
maintained with an inert atmosphere of nitrogen, was placed
6-bromo-2-cyclopropyl-1-[1-(trifluoromethane)sulfonylpiperidin-4-yl]-1H-1-
,3-benzodiazole (6 g, 13.27 mmol, 1.00 equiv), tetrahydrofuran (100
mL), n-BuLi (8 mL, 1.50 equiv, 2.5M) dropwise with stirring at
-78.degree. C. The resulting solution was stirred for 0.5 h at
-78.degree. C. Then bis(4-chlorophenyl)methanone (3.973 g, 15.82
mmol, 1.19 equiv) was added dropwise with stirring at -78.degree.
C. The resulting solution was stirred for 0.5 h at -78.degree. C.,
then with stirring, overnight at room temperature. The reaction was
then quenched by the addition of water (300 mL). The resulting
solution was extracted with ethyl acetate (3.times.300 mL) and the
organic layers combined and dried over anhydrous sodium sulfate.
The solids were filtered out. The resulting mixture was
concentrated under vacuum. The residue was applied onto a silica
gel column with ethyl acetate/petroleum ether (1:3) to yield
bis(4-chlorophenyl)([2-cyclopropyl-1-[1-(trifluoromethane)sulfonylpiperid-
in-4-yl]-1H-1,3-benzodiazol-6-yl])methanol as a white solid.
[0946] LC/MS (ES, m/z) 624 [M+H].sup.+.
Step 7
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-[1-(trifluoromethane)su-
lfonylpiperidin-4-yl]-1H-1,3-benzodiazole
[0947] Into a 250-mL round-bottom flask, was placed
bis(4-chlorophenyl)([2-cyclopropyl-1-[1-(trifluoromethane)sulfonylpiperid-
in-4-yl]-1H-1,3-benzodiazol-6-yl])methanol (5 g, 8.01 mmol, 1.00
equiv), dichloromethane (100 mL), Et.sub.3SiH (3.723 g, 32.02 mmol,
4.00 equiv). This was followed by the addition of CF.sub.3COOH
(22.87 g, 200.58 mmol, 25.06 equiv) dropwise with stirring. The
resulting solution was stirred for 2 h at room temperature. The
reaction progress was monitored by LCMS. The reaction was then
quenched by the addition of water (500 mL). The resulting solution
was extracted with ethyl acetate (3.times.300 mL) and the organic
layers combined and dried over anhydrous sodium sulfate and
concentrated under vacuum. The residue was applied onto a silica
gel column with ethyl acetate/petroleum ether (1:5) to yield
6-[bis(4-chlorophenyl)methyl]-2-cyclopropyl-1-[1-(trifluoromethane)sulfon-
ylpiperidin-4-yl]-1H-1,3-benzodiazole as a white solid.
[0948] .sup.1H NMR (300 MHz, DMSO) .delta.: 7.46 (d, J=8.4 Hz, 1H),
7.38 (d, J=8.4 Hz, 4H), 7.31 (brs, 1H), 7.14 (d, J=8.4 Hz, 4H),
6.88 (d, J=8.4 Hz, 1H), 5.82 (s, 1H), 4.94-4.98 (m, 1H), 3.95-3.99
(m, 2H), 3.46-3.55 (m, 2H), 2.27-2.33 (m, 3H), 2.00-2.04 (m, 2H),
1.04-1.07 (m, 4H). LC/MS (ES, m/z): 608 [M+H].sup.+. The following
compound was prepared according to the procedure as described in
Example YM-26 above, selecting and substituting suitable reactants
and reagents, as would be readily recognized by those skilled in
the art.
Example YM-27
6-(bis(4-chlorophenyl)methyl)-2-ethyl-1-(1-(trifluoromethylsulfonyl)piperi-
din-4-yl)-1H-benzo[d]imidazole hydrochloride
##STR00352##
[0950] .sup.1H NMR (300 MHz, DMSO) .delta.: 7.79 (d, J=8.4 Hz, 2H),
7.43 (d, J=8.4 Hz, 4H), 7.28 (d, J=8.4 Hz, 1H), 7.16 (d, J=8.4 Hz,
4H), 6.00 (s, 1H), 4.95 (brm, 1H), 3.99-4.06 (m, 2H), 3.49-3.52 (m,
2H), 3.21-3.28 (m, 2H), 2.29 (brm, 2H), 2.15-2.19 (m, 2H), 1.14 (t,
J=7.5 Hz, 3H). LC/MS (ES, m/z): 596 [M-HCl+H].sup.+.
Example BZ-1
((4R,5R)-5-(hydroxymethyl)-2,2-dimethyl-1, 3-dioxolan-4-yl)methyl
4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)p-
iperidine-1-carboxylate; Compound #102
##STR00353##
[0951] STEP A:
(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)-
piperidin-1-yl)(1H-imidazol-1-yl)methanone
[0952] A solution of
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(piperidin-4-yl)-1H-benzo[d-
]imidazole (106 mg, 0.18 mmol), 1,1'-carbonyldiimidazole (44 mg,
0.27 mmol) and Et.sub.3N (0.075 mL, 0.54 mmol) in THF (3 mL) was
stirred at room temperature overnight. The resulting mixture was
then diluted with EtOAc and washed with aq. NaHCO.sub.3 and aqueous
NaCl. The organic layer was dried over Na.sub.2SO.sub.4 and
concentrated to yield
(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)-
piperidin-1-yl)(1H-imidazol-1-yl)methanone.
STEP B:
((4R,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl
4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)p-
iperidine-1-carboxylate
[0953] A mixture of
(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)-
piperidin-1-yl)(1H-imidazol-1-yl)methanone (60 mg, 0.105 mmol),
(-)-2,3-O-isopropylidene-D-threitol (34 mg, 0.21 mmol) and
Cs.sub.2CO.sub.3 (34 mg, 0.105 mmol) in DMF (2 mL) was stirred at
room temperature overnight. The reaction mixture was diluted with
H.sub.2O and filtered. The solid was collected and purified by
chromatography (silica gel column, 2% MeOH/CH.sub.2Cl.sub.2) to
yield
((4R,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl
4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)p-
iperidine-1-carboxylate.
STEP C:
((4R,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl
4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)p-
iperidine-1-carboxylate
[0954] A solution of
((4R,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl
4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)p-
iperidine-1-carboxylate (30 mg, 0.045 mmol) in TFA (1 mL) and
H.sub.2O (1 mL) was stirred at room temperature for 3 hours. The
mixture was concentrated. The resulting residue was diluted with
EtOAc and washed with aq NaHCO.sub.3 and aq NaCl. The organic
solution was dried over Na.sub.2SO.sub.4 and concentrated. The
resulting residue was purified by chromatography (silica gel
column, 6% MeOH/CH.sub.2Cl.sub.2) to yield
((4R,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl
4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)p-
iperidine-1-carboxylate.
[0955] .sup.1H NMR (CHLOROFORM-d) Shift: 7.58 (d, J=8.6 Hz, 1H),
7.19-7.36 (m, 4H), 6.95-7.18 (m, 5H), 6.88 (dd, J=8.3, 1.3 Hz, 1H),
5.61 (s, 1H), 4.50-4.70 (m, 1H), 4.31 (br d, J=10.6 Hz, 4H),
3.88-4.00 (m, 1H), 3.63-3.74 (m, 1H), 2.95 (br s, 2H), 2.32 (br s,
2H), 1.85-2.03 (m, 3H), 1.75 (br s, 2H), 1.06-1.24 (m, 4H). MS:
624.2 (M+H.sup.+).
Example BZ-2
3-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)methyl)phenol: Compound #90
##STR00354##
[0957] To a solution of
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(piperidin-4-yl)-1H-benzo[d-
]imidazole (100 mg, 0.17 mmol) and 3-hydroxy-benzaldehyde (31 mg,
0.25 mmol) in 1,2-dichloroethane (3 mL) at room temperature was
added acetic acid (0.15 mL) followed by sodium
triacetoxyborohydride (72 mg, 0.34 mmol). The reaction was stirred
at room temperature for 6 hours. To the mixture was then added
additional 3-hydroxy-benzaldehyde (31 mg, 0.25 mmol), acetic acid
(0.15 mL), and sodium triacetoxyborohydride (72 mg, 0.34 mmol). The
reaction was stirred at room temperature overnight before it was
then quenched with aq NaHCO.sub.3. The resulting mixture was
extracted with EtOAc, and the organic layer was washed with aq
NaCl, dried over Na.sub.2SO.sub.4 and concentrated. The resulting
residue was purified by chromatography (silica gel column, 3%
MeOH/CH.sub.2Cl.sub.2) to yield
3-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]im-
idazol-1-yl)piperidin-1-yl)methyl)phenol.
[0958] .sup.1H NMR (CHLOROFORM-d) Shift: 7.54 (d, J=8.1 Hz, 1H),
7.17-7.31 (m, 6H), 7.00 (d, J=8.6 Hz, 4H), 6.82-6.91 (m, 2H), 6.76
(dd, J=8.1, 2.5 Hz, 2H), 5.54 (s, 1H), 4.65-4.65 (m, 1H), 4.40-4.49
(m, 1H), 3.53 (s, 2H), 3.10 (br d, J=11.6 Hz, 2H), 2.42-2.56 (m,
2H), 2.18 (br t, J=11.1 Hz, 2H), 1.90-2.08 (m, 1H), 1.84 (br d,
J=10.1 Hz, 2H), 1.11-1.19 (m, 2H), 1.00-1.11 (m, 2H). MS: 581.8
(M+H.sup.+).
Example BZ-3
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-(prop-2-yn-1-yl)piperidin-
-4-yl)-1H-benzo[d]imidazole; Compound #76
##STR00355##
[0960] A mixture of
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(piperidin-4-yl)-1H-benzo[d-
]imidazole (200 mg, 0.34 mmol), propargyl bromide (80% in toluene,
0.057 mL, 0.51 mmol) and K.sub.2CO.sub.3 (94 mg, 0.68 mmol) in
CH.sub.3CN (4 mL) was stirred at room temperature for 6 h. The
mixture was diluted with EtOAc, washed with H.sub.2O and aqueous
NaCl. The organic layer was dried over Na.sub.2SO.sub.4 and
concentrated. The resulting residue was purified by chromatography
(silica gel column, 3% MeOH/CH.sub.2Cl.sub.2) to yield
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-(prop-2-yn-1-yl-
)piperidin-4-yl)-1H-benzo[d]imidazole.
[0961] .sup.1H NMR (CHLOROFORM-d) .delta.: 7.57 (d, J=8.6 Hz, 1H),
7.33 (s, 1H), 7.22-7.28 (m, 4H), 6.99-7.06 (m, 4H), 6.84 (dd,
J=8.6, 1.5 Hz, 1H), 5.59 (s, 1H), 4.39-4.49 (m, 1H), 3.41 (d, J=2.5
Hz, 2H), 3.08 (br d, J=11.1 Hz, 2H), 2.41-2.60 (m, 4H), 2.31 (t,
J=2.3 Hz, 1H), 1.86-2.05 (m, 3H), 1.05-1.28 (m, 4H). MS: 514.2
(M+H.sup.+).
Example BZ-4
Methyl
2-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidaz-
ol-1-yl)piperidin-1-yl)acetate; Compound #64
##STR00356##
[0963] Methyl
2-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)acetate was prepared according to the procedure as
described in Example BZ-3 above, substituting methyl bromoacetate
for propargyl bromide.
[0964] .sup.1H NMR (CHLOROFORM-d) .delta.: 7.57 (d, J=8.6 Hz, 1H),
7.36 (s, 1H), 7.22-7.28 (m, 5H), 7.00-7.05 (m, 4H), 6.84 (dd,
J=8.6, 1.5 Hz, 1H), 5.60 (s, 1H), 4.40-4.50 (m, 1H), 3.76 (s, 3H),
3.34 (s, 2H), 3.13 (br d, J=10.6 Hz, 2H), 2.45-2.63 (m, 4H),
1.97-2.05 (m, 1H), 1.84-1.93 (m, 2H), 1.06-1.28 (m, 4H). MS: 548.3
(M+H.sup.+).
Example BZ-5
2-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)piperidin-1-yl)acetic acid; Compound #63
##STR00357##
[0966] A mixture of methyl
2-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)acetate (70 mg, 0.13 mmol) and LiOH*H.sub.2O (16
mg, 0.38 mmol) in THF (2 mL) and H.sub.2O (1 mL) was stirred at
room temperature for 2 h. To the reaction mixture was added 1N HCl
(0.38 mL) and H.sub.2O. The organic solvent was removed and the
mixture was filtered. The resulting solid was collected and
dissolved in MeOH/CH.sub.2Cl.sub.2, and filtered. The solution was
concentrated to yield
2-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)acetic acid. MS: 534.2 (M+H.sup.+).
Example BZ-6
3-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)sulfonyl)aniline; Compound #52
##STR00358##
[0967] STEP A:
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-((3-nitrophenyl)sulfonyl-
)piperidin-4-yl)-1H-benzo[d]imidazole
[0968] To a solution of
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(piperidin-4-yl)-1H-benzo[d-
]imidazole (400 mg, 0.68 mmol) and Et.sub.3N (0.33 mL, 2.37 mmol)
in CH.sub.2Cl.sub.2 (8 mL) at 0.degree. C. was added
3-nitrobenzenesulfonyl chloride (195 mg, 0.88 mmol). The reaction
was stirred at 0.degree. C. for 30 min then warmed up to room
temperature and stirred for 2 h. The reaction was quenched with aq
NaHCO.sub.3 and extracted with diethyl ether. The organic layer was
washed with aq NaCl, dried over Na.sub.2SO.sub.4 and concentrated.
The resulting residue was purified by chromatography (silica gel
column, 70% EtOAc/heptane) to yield
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-((3-nitrophenyl)sulfonyl-
)piperidin-4-yl)-1H-benzo[d]imidazole.
STEP B:
3-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imid-
azol-1-yl)piperidin-1-yl)sulfonyl)aniline
[0969] To a solution of
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-((3-nitrophenyl)sulfonyl-
)piperidin-4-yl)-1H-benzo[d]imidazole (250 mg, 0.38 mmol) and
NiCl.sub.2 (71 mg, 0.76 mmol) in MeOH (15 mL) at 0.degree. C. was
added NaBH.sub.4 (114 mg, 3.03 mmol). The reaction was stirred at
0.degree. C. for 1 h before H.sub.2O was added. The mixture was
then concentrated to remove most of the organic solvent, and then
filtered. The resulting solid was washed with 20%
MeOH/CH.sub.2Cl.sub.2 for 3 times. The solution was combined and
concentrated to yield compound
3-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)sulfonyl)aniline.
[0970] .sup.1H NMR (DMSO-d6) .delta.: 7.51 (s, 1H), 7.24-7.43 (m,
6H), 7.13 (d, J=8.1 Hz, 4H), 6.99 (t, J=1.8 Hz, 1H), 6.78-6.89 (m,
3H), 5.81 (s, 1H), 5.69 (s, 2H), 4.67 (br t, J=11.9 Hz, 1H), 3.80
(br d, J=11.6 Hz, 2H), 2.61 (br t, J=11.4 Hz, 2H), 2.27-2.47 (m,
2H), 2.10-2.19 (m, 1H), 1.89 (br d, J=10.1 Hz, 2H), 0.89-1.03 (m,
4H). MS: 631.2 (M+H.sup.+).
Example BZ-7
N-(2-(2-(benzyloxy)ethoxy)ethyl)-3-((4-(6-(bis(4-chlorophenyl)methyl)-2-cy-
clopropyl-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)sulfonyl)aniline:
Compound of Formula (II)
##STR00359##
[0972] To a solution of
3-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)sulfonyl)aniline (50 mg, 0.079 mmol) and 7a (50
mg, 0.26 mmol) in acetic acid (0.3 mL) and 1,2-dichloroethane (3
mL) at room temperature was added NaBH(OAc).sub.3 (50 mg, 0.24
mmol). The reaction mixture was stirred at room temperature over
night before it was quenched with aq NaHCO.sub.3. The resulting
mixture was extracted with EtOAc, and the organic layer was washed
with aq NaCl, dried over Na.sub.2SO.sub.4 and concentrated. The
resulting residue was purified by chromatography (silica gel
column, 60% EtOAc/heptane) to yield
N-(2-(2-(benzyloxy)ethoxy)ethyl)-3-((4-(6-(bis(4-chlorophenyl)methyl)-2-c-
yclopropyl-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)sulfonyl)aniline.
[0973] .sup.1H NMR (CHLOROFORM-d) .delta.: 7.56 (d, J=8.4 Hz, 1H),
7.22-7.47 (m, 11H), 7.01-7.16 (m, 5H), 6.70-6.98 (m, 3H), 5.61 (s,
1H), 4.58 (s, 2H), 4.53 (m, 1H), 4.25-4.44 (m, 1H), 4.01 (br d,
J=11.1 Hz, 2H), 3.59-3.86 (m, 6H), 3.33 (br d, J=4.0 Hz, 2H),
2.42-2.62 (m, 4H), 1.76-1.97 (m, 3H), 0.97-1.20 (m, 4H). MS: 809.2
(M+H.sup.+).
Example BZ-8
2-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)sulfonyl)ethanamine; Compound #46
##STR00360##
[0974] STEP A:
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-(vinylsulfonyl)piperidin-
-4-yl)-1H-benzo[d]imidazole
[0975] To a solution of
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(piperidin-4-yl)-1H-benzo[d-
]imidazole (200 mg, 0.34 mmol) and Et.sub.3N (0.19 mL, 1.36 mmol)
in CH.sub.2Cl.sub.2 (4 mL) at 0.degree. C. was added
2-chloroethanesulfonyl chloride (0.043 mL, 0.41 mmol). The reaction
was stirred at 0.degree. C. for 30 min before it was warmed up to
room temperature and stirred for another 1 h. The reaction was
quenched with aq NaHCO.sub.3 and the resulting mixture was
extracted with EtOAc. The organic layer was washed with aq NaCl,
dried over Na.sub.2SO.sub.4 and concentrated. The resulting residue
was purified by chromatography (silica gel column, 80%
EtOAc/heptane) to yield
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-(vinylsulfonyl)piperidin-
-4-yl)-1H-benzo[d] imidazole.
STEP B:
2-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imid-
azol-1-yl)piperidin-1-yl)sulfonyl)ethanamine
[0976] A mixture of
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-(vinylsulfonyl)piperidin-
-4-yl)-1H-benzo[d]imidazole (34 mg, 0.06 mmol) and Cs.sub.2CO.sub.3
(20 mg, 0.06 mmol) in 28% NH.sub.4OH aqueous solution (0.5 mL) and
CH.sub.3CN (2 mL) was stirred at room temperature for 2 days. The
mixture was concentrated and the residue was diluted with
CH.sub.2Cl.sub.2 and washed with aq NaCl. The organic layer was
dried over Na.sub.2SO.sub.4 and concentrated. The resulting residue
was purified by chromatography (silica gel column, 6%
MeOH/CH.sub.2Cl.sub.2) to yield
2-((4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)piperidin-1-yl)sulfonyl)ethanamine.
[0977] MS: 583.2 (M+H.sup.+).
Example BZ-9
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-((2-(piperazin-1-yl)ethyl-
)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole: Compound #45
##STR00361##
[0979]
6-(Bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-(vinylsulfonyl)pip-
eridin-4-yl)-1H-benzo[d]imidazole was prepared according to the
procedure as described in Example BZ-8 above, reacting N-Boc
piperazine instead of 28% NH.sub.4OH aqueous solution.
[0980] A solution of
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-(vinylsulfonyl)piperidin-
-4-yl)-1H-benzo[d]imidazole (34 mg, 0.045 mmol) in TFA (0.5 mL) and
CH.sub.2Cl.sub.2 (2.5 mL) was stirred at room temperature for 2 h.
The reaction mixture was concentrated and the residue was dissolved
in CH.sub.2Cl.sub.2 and washed with aq NaHCO.sub.3. The aqueous
layer was extracted again with CH.sub.2Cl.sub.2. The organic layers
were combined, dried over Na.sub.2SO.sub.4 and concentrated to
yield
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-((2-(piperazin-1-yl)ethy-
l)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole.
[0981] MS: 652.2 (M+H.sup.+).
Example BZ-10
3-(2-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-
-yl)piperidin-1-yl)ethoxy)benzoic acid: Compound #44
##STR00362##
[0982] STEP A:
2-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)ethanol
[0983] To a solution of methyl
2-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)acetate (81 mg, 0.15 mmol) in THF (4 mL) at room
temperature was added LiBH.sub.4 (2M solution in THF, 0.3 mL, 0.6
mmol). The reaction was stirred overnight, then quenched with
H.sub.2O and extracted with EtOAc. The organic layer was washed
with aq NaCl, dried over Na.sub.2SO.sub.4 and concentrated. The
resulting residue was dissolved in MeOH (2 mL)/1N NaOH (1 mL) and
heated at 100.degree. C. by microwave for 1 h. The reaction mixture
was concentrated to remove MeOH and the remaining aqueous solution
was extracted with CH.sub.2Cl.sub.2. The organic layer was dried
over Na.sub.2SO.sub.4 and concentrated. The resulting residue was
purified by chromatography (silica gel column, 3%
MeOH/CH.sub.2Cl.sub.2) to yield
2-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)ethanol.
STEP B: methyl
3-(2-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol--
1-yl)piperidin-1-yl)ethoxy)benzoate
[0984] To a solution of
2-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)piperidin-1-yl)ethanol (35 mg, 0.067 mmol), methyl
3-hydroxybenzoate (30.7 mg, 0.20 mmol) and PPh.sub.3 (53 mg, 0.20
mmol) in THF (2 mL) at room temperature was added DIAD (0.039 mL,
0.20 mmol). The reaction was stirred overnight. The resulting
mixture was then concentrated and the resulting residue purified by
chromatography (silica gel column, 80% EtOAc/heptane) to yield
methyl
3-(2-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol--
1-yl)piperidin-1-yl)ethoxy)benzoate.
STEP C:
3-(2-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]im-
idazol-1-yl)piperidin-1-yl)ethoxy)benzoic acid
[0985] A solution of methyl
3-(2-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol--
1-yl)piperidin-1-yl)ethoxy)benzoate (31 mg, 0.047 mmol) and LiOH
(10 mg, 0.24 mmol) in H.sub.2O (1 mL) and THF (2 mL) was stirred at
room temperature for overnight. 1N HCl solution was added to the
reaction mixture to adjust the pH to .about.3. The mixture was
extracted with CH.sub.2Cl.sub.2 for 3 times. The organic layers
were combined, dried over Na.sub.2SO.sub.4 and concentrated. The
resulting residue was purified by chromatography (silica gel
column, 8% MeOH/CH.sub.2Cl.sub.2) to yield
3-(2-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]-
imidazol-1-yl)piperidin-1-yl)ethoxy)benzoic acid.
[0986] .sup.1H NMR (CHLOROFORM-d) .delta.: 7.58-7.70 (m, 2H),
7.46-7.54 (m, 2H), 7.33-7.40 (m, 1H), 7.23 (d, J=8.1 Hz, 4H), 7.13
(dd, J=8.1, 2.0 Hz, 1H), 7.01 (d, J=8.6 Hz, 4H), 6.88 (dd, J=8.3,
1.3 Hz, 1H), 5.58 (s, 1H), 4.50-4.60 (m, 1H), 4.22 (t, J=5.3 Hz,
2H), 3.27-3.40 (m, 2H), 2.97 (br t, J=5.3 Hz, 2H), 2.55-2.73 (m,
2H), 2.41-2.53 (m, 2H), 2.00-2.09 (m, 1H), 1.92 (br d, J=10.6 Hz,
2H), 1.09-1.17 (m, 4H). MS: 640.2 (M+H.sup.+).
Example BZ-11
2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)et-
hanol
##STR00363##
[0987] STEP A: methyl 2,2-bis(4-chlorophenyl)acetate methyl
2,2-bis(4-chlorophenyl)acetate
[0988] A solution of 2,2-bis(4-chlorophenyl)acetic acid (5 g, 17.8
mmol) and H.sub.2SO.sub.4 (0.47 mL, 8.9 mmol) in MeOH (100 mL) was
heated at 65.degree. C. for 6 h, and was then stirred at room
temperature overnight. The solution was concentrated and the
residue was dissolved in diethyl ether and washed with aq
NaHCO.sub.3 and aq NaCl. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated yield methyl
2,2-bis(4-chlorophenyl)acetate.
STEP B: methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate
[0989] To a solution of methyl 2,2-bis(4-chlorophenyl)acetate (1.0
g, 3.39 mmol) and 2,4-difluoro-1-nitrobenzene (0.39 mL, 3.56 mmol)
in THF (15 mL) at -78.degree. C. was slowly added LiHMDS (1M in
THF, 3.7 mL, 3.7 mmol). The reaction was stirred at -78.degree. C.
for 20 min before it was warmed up to room temperature and stirred
overnight. To the reaction was added aq NH.sub.4Cl and the mixture
was extracted with ethyl ether. The organic layer was washed with
aq NaCl, dried over Na.sub.2SO.sub.4 and concentrated. The
resulting residue was purified by chromatography (silica gel
column, 30% CH.sub.2Cl.sub.2/heptane) to yield methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate.
STEP C: methyl
2,2-bis(4-chlorophenyl)-2-(3-((2-hydroxyethyl)amino)-4-nitrophenyl)acetat-
e
[0990] To a solution of methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate (275 mg)
in CH.sub.3CN (5 mL) at room temperature was added ethanolamine
(0.076 mL, 1.27 mmol) followed by Hunig's base (0.22 mL, 1.27
mmol). The reaction was heated at 55.degree. C. for 2 h, and was
then cooled to room temperature and stirred overnight. The reaction
mixture was concentrated and the resulting residue was dissolved in
EtOAc and washed with aq NaHCO.sub.3 and aq NaCl. The organic
solution was dried over Na.sub.2SO.sub.4 and concentrated. The
resulting residue was purified by chromatography (silica gel
column, 40% EtOAc/heptane) to yield methyl
2,2-bis(4-chlorophenyl)-2-(3-((2-hydroxyethyl)amino)-4-nitrophenyl)acetat-
e.
STEP D: methyl
2-(4-amino-3-((2-hydroxyethyl)amino)phenyl)-2,2-bis(4-chlorophenyl)acetat-
e
[0991] To a solution of methyl
2,2-bis(4-chlorophenyl)-2-(3-((2-hydroxyethyl)amino)-4-nitrophenyl)acetat-
e (140 mg, 0.30 mmol) in EtOH (4 mL) and H.sub.2O (1 mL) was added
NH.sub.4Cl (158 mg, 2.95 mmol) followed by Zn dust (96 mg, 1.47
mmol). The reaction was then heated at 70.degree. C. for 1 h. The
reaction mixture was cooled to room temperature and diluted with
EtOAc. The solution was washed with aq NaHCO.sub.3 and aq NaCl,
dried Na.sub.2SO.sub.4 and concentrated to yield methyl
2-(4-amino-3-((2-hydroxyethyl)amino)phenyl)-2,2-bis(4-chlorophenyl)acetat-
e.
STEP E: methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-(2-hydroxyethyl)-1H-benzo[d]im-
idazol-6-yl)acetate
[0992] A solution of methyl
2-(4-amino-3-((2-hydroxyethyl)amino)phenyl)-2,2-bis(4-chlorophenyl)acetat-
e (120 mg, 0.27 mmol) and cyclopropanecarboxaldehyde (0.04 mL, 0.54
mmol) in DMSO (1 mL) was stirred at room temperature under air for
2 days. The solution was diluted with CH.sub.2Cl.sub.2 and washed
with H.sub.2O and aq NaCl, dried over Na.sub.2SO.sub.4 and
concentrated. The resulting residue was purified by chromatography
(silica gel column, 40% EtOAc/heptane) to yield methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-(2-hydroxyethyl)-1H-benzo[d]im-
idazol-6-yl)acetate.
STEP F:
2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-
-1-yl)ethanol
[0993] A solution of methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-(2-hydroxyethyl)-1H-benzo[d]im-
idazol-6-yl)acetate (85 mg, 0.17 mmol) in 3N NaOH aqueous solution
(1 mL, 3 mmol) and 1,4-dioxane (4 mL) was heated at 100.degree. C.
for 16 h. The reaction was cooled to room temperature and 1N HCl
aqueous solution was added to adjust pH to .about.7. The mixture
was extracted with EtOAc and the organic solution was washed with
aq NaCl, dried over Na.sub.2SO.sub.4, and concentrated. The
resulting residue was purified by chromatography (silica gel
column, 70% EtOAc/heptane) to yield
2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)e-
thanol.
[0994] MS: 437.1 (M+H.sup.+).
Example BZ-12
4-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)ethyl)benzoic acid; Compound #38
##STR00364##
[0996]
4-(2-(6-(Bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidaz-
ol-1-yl)ethyl)benzoic acid was prepared according to the procedure
as described in Example BZ-11, substituting methyl
4-(2-aminoethyl)benzoate for ethanolamine.
[0997] MS: 541.0 (M+H.sup.+).
Example BZ-13
4-(2-(6-(Bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)ethyl)phenol; Compound #37
##STR00365##
[0999]
4-(2-(6-(Bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidaz-
ol-1-yl)ethyl)phenol was prepared according to the procedures
described in Example BZ-11, substituting 4-(2-aminoethyl)phenol for
ethanolamine.
[1000] MS: 513.2 (M+H.sup.+).
Examples BZ-14
methyl
4-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidaz-
ol-1-yl)ethoxy)benzoate; Compound #36
##STR00366##
[1002] To a solution of
2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)e-
thanol (50 mg, 0.11 mmol), methyl 4-hydroxybenzoate (52 mg, 0.34
mmol) and PPh.sub.3 (90 mg, 0.34 mmol) in THF (2 mL) was added DIAD
(0.067 mL, 0.34 mmol). The reaction was stirred at room temperature
overnight. The resulting mixture was then concentrated and purified
by chromatography (silica gel column, 60% CH.sub.2Cl.sub.2/heptane)
to yield methyl
4-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)ethoxy)benzoate.
[1003] MS: 571.2 (M+H.sup.+).
Example BZ-15
4-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)ethoxy)benzoic acid: Compound #35
##STR00367##
[1005] A solution of methyl
4-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)ethoxy)benzoate (38 mg, 0.067 mmol) and LiOH (10 mg, 0.42 mmol)
in H.sub.2O (1 mL) and THF (2 mL) was stirred at room temperature
for 2 days. The reaction mixture was acidified with 1N HCl aq
solution and extracted with EtOAc. The organic layer was washed
with aq NaCl, dried over Na.sub.2SO.sub.4 and concentrated. The
resulting residue was purified by chromatography (silica gel
column, 3% MeOH/CH.sub.2Cl.sub.2) to yield
4-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imi-
dazol-1-yl)ethoxy)benzoic acid. MS: 557.1 (M+H.sup.+).
Example BZ-16
methyl
6-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidaz-
ol-1-yl)ethoxy)nicotinate; Compound #33
##STR00368##
[1007] Methyl
6-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)ethoxy)nicotinate was prepared according to the procedure as
described in Example BZ-14, substituting methyl 6-hydroxynicotinate
for methyl 4-hydroxybenzoate.
[1008] .sup.1H NMR (CHLOROFORM-d) Shift: 8.72 (d, J=2.0 Hz, 1H),
8.08 (dd, J=8.6, 2.5 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.23-7.28 (m,
4H), 6.99-7.05 (m, 4H), 6.92 (dd, J=8.3, 1.8 Hz, 1H), 6.42 (d,
J=8.6 Hz, 1H), 5.61 (s, 1H), 4.68 (t, J=5.3 Hz, 2H), 4.58 (t, J=5.3
Hz, 2H), 3.92 (s, 3H), 2.00-2.08 (m, 1H), 1.16-1.34 (m, 2H),
1.06-1.14 (m, 2H). MS: 572.1 (M+H.sup.+).
Example BZ-17
6-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)ethoxy)nicotinic acid; Compound #35
##STR00369##
[1010]
6-(2-(6-(Bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidaz-
ol-1-yl)ethoxy)nicotinic acid was prepared according to the
procedure as described in Example BZ-15.
[1011] MS: 558.2 (M+H.sup.+).
Example BZ-18
methyl
3-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidaz-
ol-1-yl)ethoxy)benzoate; Compound #26
##STR00370##
[1013] Methyl
3-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)ethoxy)benzoate was prepared according to the procedure as
described in Example BZ-14, substituting methyl 3-hydroxybenzoate
for methyl 4-hydroxybenzoate.
[1014] MS: 571.1 (M+H.sup.+).
Example BZ-19
3-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)ethoxy)benzoic acid; Compound #23
##STR00371##
[1016]
3-(2-(6-(Bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidaz-
ol-1-yl)ethoxy)benzoic acid was prepared according to the procedure
as described in Example BZ-15 substituting NaOH for LiOH.
[1017] MS: 557.1 (M+H.sup.+).
Example BZ-20
6-(bis(4-chlorophenyl)methyl)-1-(4-bromophenethyl)-2-cyclopropyl-1H-benzo[-
d]imidazole; Compound #27
##STR00372##
[1019]
6-(Bis(4-chlorophenyl)methyl)-1-(4-bromophenethyl)-2-cyclopropyl-1H-
-benzo[d]imidazole was prepared according to the procedure as
described in Example BZ-11, substituting
2-(4-bromophenyl)ethanamine for ethanolamine.
[1020] .sup.1H NMR (CHLOROFORM-d) .delta.: 7.54 (d, J=8.1 Hz, 1H),
7.24-7.34 (m, 6H), 6.99 (d, J=8.1 Hz, 4H), 6.90 (dd, J=8.1, 1.5 Hz,
1H), 6.78 (d, J=8.1 Hz, 2H), 6.64 (s, 1H), 5.57 (s, 1H), 4.32 (t,
J=6.8 Hz, 2H), 2.98 (t, J=6.8 Hz, 2H), 1.66-1.73 (m, 1H), 1.10-1.17
(m, 2H), 0.96-1.06 (m, 2H). MS: 577.0 (M+H.sup.+).
Example BZ-21
4'-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
lethyl)-[1,1'-biphenyl]-4-carboxylic acid: Compound #25
##STR00373##
[1022] A mixture of
6-(bis(4-chlorophenyl)methyl)-1-(4-bromophenethyl)-2-cyclopropyl-1H-benzo-
[d]imidazole (75 mg, 0.13 mmol), (4-methoxycarbonyl)phenyl) boronic
acid (47 mg, 0.26 mmol), K.sub.2CO.sub.3 (36 mg, 0.26 mmol) and
Pd(dppf)C12 (5.3 mg, 0.0065 mmol) in EtOH (1 mL) and H.sub.2O (0.2
mL) was heated at 130.degree. C. by microwave for 30 min. The
reaction mixture was cooled to room temperature and to it was added
H.sub.2O (1 mL), THF (2 mL) and LiOH*H.sub.2O (42 mg, 1.0 mmol).
The reaction was stirred at room temperature overnight before 1N
HCl aq solution was added to adjust pH to .about.3. The resulting
mixture was extracted with EtOAc for 2 times. The organic layers
were combined, washed with aq NaCl, dried over Na.sub.2SO.sub.4 and
concentrated. The resulting residue was purified by chromatography
(silica gel column, 3% MeOH/CH.sub.2Cl.sub.2) to yield
4'-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)ethyl)-[1,1'-biphenyl]-4-carboxylic acid.
[1023] MS: 617.3 (M+H.sup.+).
Example BZ-22
4'-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)ethyl)-[1,1'-biphenyl]-3-carboxylic acid: Compound #24
##STR00374##
[1025]
4'-(2-(6-(Bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imida-
zol-1-yl)ethyl)-[1,1'-biphenyl]-3-carboxylic acid was prepared
according to the procedure described in Example BZ-21 substituting
(3-methoxycarbonyl)phenyl) boronic acid for
(4-methoxycarbonyl)phenyl) boronic acid.
[1026] MS: 617.1 (M+H.sup.+).
Example BZ-23
6-(bis(4-chlorophenyl)methyl)-1-(3-bromophenethyl)-2-cyclopropyl-1H-benzo[-
d]imidazole; Compound #20
##STR00375##
[1028]
6-(Bis(4-chlorophenyl)methyl)-1-(3-bromophenethyl)-2-cyclopropyl-1H-
-benzo[d]imidazole was prepared according to the procedure
described in Example BZ-11 substituting 2-(3-bromophenyl)ethanamine
for ethanolamine.
[1029] .sup.1H NMR (CHLOROFORM-d) Shift: 7.55 (d, J=8.1 Hz, 1H),
7.25-7.32 (m, 5H), 7.18 (s, 1H), 6.96-7.08 (m, 5H), 6.90 (dd,
J=8.1, 1.5 Hz, 1H), 6.79 (d, J=7.6 Hz, 1H), 6.69 (s, 1H), 5.57 (s,
1H), 4.34 (t, J=6.8 Hz, 2H), 3.00 (t, J=6.8 Hz, 2H), 1.71-1.79 (m,
1H), 1.11-1.18 (m, 2H), 0.88-1.09 (m, 2H). MS: 577.0
(M+H.sup.+).
Example BZ-24
2-(1-(3-bromophenethyl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)-2,2-bis(4--
chlorophenyl)acetic acid; Compound #19
##STR00376##
[1031] Methyl
2-(1-(3-bromophenethyl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)-2,2-bis(4-
-chlorophenyl)acetate was prepared according to the procedure
described in Example BZ-11 (Step E) substituting
2-(3-bromophenyl)ethanamine for ethanolamine.
[1032] A solution of methyl
2-(1-(3-bromophenethyl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)-2,2-bis(4-
-chlorophenyl)acetate (66 mg, 0.01 mmol) and 3N NaOH aq solution
(0.5 mL, 1.5 mmol) in THF (2 mL) and MeOH (1 mL) was stirred at
room temperature for 4 days. 1N HCl aq solution was added to adjust
the pH to .about.3. The mixture was extracted with EtOAc. The
organic layer was washed with aq NaCl, dried over Na.sub.2SO.sub.4
and concentrated to yield
2-(1-(3-bromophenethyl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)-2,2-bis(4-
-chlorophenyl)acetic acid.
[1033] MS: 621.0 (M+H.sup.+).
Example BZ-25
methyl
3-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidaz-
ol-1-yl)ethoxy)-5-(trifluoromethyl)benzoate Compound #18
##STR00377##
[1035] Methyl
3-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)ethoxy)-5-(trifluoromethyl)benzoate was prepared according to the
procedure described in Example BZ-14 substituting methyl
3-hydroxy-5-(trifluoromethyl)benzoate for methyl
4-hydroxybenzoate.
[1036] MS: 639.2 (M+H.sup.+).
Example BZ-26
3-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)ethoxy)-5-trifluoromethyl)benzoic acid; Compound #16
##STR00378##
[1038]
3-(2-(6-(Bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidaz-
ol-1-yl)ethoxy)-5-(trifluoromethyl)benzoic acid was prepared
according to the procedure described in Example BZ-15.
[1039] MS: 625.2 (M+H.sup.+).
Example BZ-27
3'-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)ethyl)-[1,1'-biphenyl]-4-carboxylic acid; Compound #17
##STR00379##
[1041]
3'-(2-(6-(Bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imida-
zol-1-yl)ethyl)-[1,1'-biphenyl]-4-carboxylic acid was prepared
according to the procedure described in Example BZ-21 substituting
6-(Bis(4-chlorophenyl)methyl)-1-(3-bromophenethyl)-2-cyclopropyl-1H-benzo-
[d]imidazole for
6-(bis(4-chlorophenyl)methyl)-1-(4-bromophenethyl)-2-cyclopropyl-1H-benzo-
[d]imidazole.
[1042] MS: 617.1 (M+H.sup.+).
Example BZ-28
3'-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
lethyl)-[1,1'-biphenyl]-3-carboxylic acid: Compound #11
##STR00380##
[1044]
3'-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imida-
zol-1-yl)ethyl)-[1,1'-biphenyl]-3-carboxylic acid was prepared
according to the procedure described in Example BZ-22 substituting
6-(Bis(4-chlorophenyl)methyl)-1-(3-bromophenethyl)-2-cyclopropyl-1H-benzo-
[d]imidazole for
6-(bis(4-chlorophenyl)methyl)-1-(4-bromophenethyl)-2-cyclopropyl-1H-benzo-
[d]imidazole.
[1045] .sup.1H NMR (CHLOROFORM-d) Shift: 8.01-8.14 (m, 2H), 7.67
(br d, J=8.1 Hz, 1H), 7.46-7.58 (m, 2H), 7.40 (br d, J=7.6 Hz, 1H),
7.22-7.35 (m, 1H), 7.17 (br d, J=8.6 Hz, 4H), 7.06 (br s, 1H), 6.99
(br d, J=7.1 Hz, 1H), 6.87-6.95 (m, 5H), 6.65 (br s, 1H), 5.50 (s,
1H), 4.43 (br s, 2H), 3.13 (br s, 2H), 1.80 (br s, 1H), 1.26 (br s,
2H), 1.04 (br d, J=5.6 Hz, 2H). MS: 617.3 (M+H.sup.+).
Example BZ-29
5-(3-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-
-yl)ethyl)phenyl)thiophene-2-carboxylic acid: Compound #6
##STR00381##
[1047]
5-(3-(2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imi-
dazol-1-yl)ethyl)phenyl)thiophene-2-carboxylic acid was prepared
according to the procedure described in Example BZ-27 substituting
(5-(methoxycarbonyl)thiophen-2-yl)boronic acid for
(4-methoxycarbonyl)phenyl) boronic acid.
[1048] .sup.1H NMR (CHLOROFORM-d) Shift: 7.58-7.87 (m, 2H), 7.42
(br d, J=8.1 Hz, 1H), 7.14-7.36 (m, 5H), 6.99-7.11 (m, 1H),
6.84-6.99 (m, 7H), 6.70 (s, 1H), 5.53 (s, 1H), 4.29-4.48 (m, 2H),
3.08 (br t, J=6.3 Hz, 2H), 1.71 (br s, 1H), 1.14-1.39 (m, 2H), 1.01
(br d, J=6.1 Hz, 2H). MS: 623.1 (M+H.sup.+).
Example BZ-30
6-(bis(4-chlorophenyl)methyl)-1-(2-(3-bromophenoxy)ethyl)-2-cyclopropyl-1H-
-benzo[d]imidazole; Compound #7
##STR00382##
[1050]
6-(Bis(4-chlorophenyl)methyl)-1-(2-(3-bromophenoxy)ethyl)-2-cyclopr-
opyl-1H-benzo[d]imidazole was prepared according to the procedure
described in Example BZ-14 substituting 3-bromophenol for methyl
4-hydroxybenzoate.
[1051] .sup.1H NMR (CHLOROFORM-d) Shift: 7.57 (d, J=8.6 Hz, 1H),
7.23-7.36 (m, 5H), 6.89-7.10 (m, 8H), 6.54-6.59 (m, 1H), 5.64 (s,
1H), 4.56 (t, J=5.3 Hz, 2H), 4.23 (t, J=5.1 Hz, 2H), 2.02-2.12 (m,
1H), 1.07-1.31 (m, 4H). MS: 593.1 (M+H.sup.+).
Example BZ-31
methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((1-((trifluoromethyl)su-
lfonyl)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetate;
Compound #14
##STR00383##
[1053] tert-Butyl
4-((6-(1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl)-2-cyclopropyl-1H-ben-
zo[d]imidazol-1-yl)methyl)piperidine-1-carboxylate was prepared
according to the procedure as described in Example BZ-11 (Step E)
substituting tert-butyl 4-(aminomethyl)piperidine-1-carboxylate for
ethanolamine.
[1054] A solution of tert-butyl
4-((6-(1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl)-2-cyclopropyl-1H-ben-
zo[d]imidazol-1-yl)methyl)piperidine-1-carboxylate (75 mg, 0.12
mmol) in TFA (0.5 mL) and CH.sub.2Cl.sub.2 (2.5 mL) was stirred at
room temperature for 1.5 h before It was concentrated. The
resulting residue was dissolved in CH.sub.2Cl.sub.2 and washed with
aq NaHCO.sub.3 solution and aq NaCl solution. The organic layer was
dried over Na.sub.2SO.sub.4 and concentrated to yield a residue. To
a solution of the residue in CH.sub.2Cl.sub.2 (3 mL) at 0.degree.
C. was added Et.sub.3N (0.08 mL, 0.58 mmol) followed by
trifluoromethanesulfonic anhydride (Tf.sub.2O, 0.039 mL, 0.23
mmol). The reaction was stirred at 0.degree. C. for 1 h then warmed
up to room temperature and stirred for another 1 h. To the reaction
was added aq NaHCO.sub.3 solution and the mixture was extracted
with EtOAc. The organic layer was washed with aq NaCl solution,
dried over Na.sub.2SO.sub.4 and concentrated. The resulting residue
was purified by chromatography (silica gel column, 60%
EtOAc/heptane) to yield methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((1-((trifluoromethyl)sulfonyl-
)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetate. 1H NMR
(CHLOROFORM-d) Shift: 7.56 (d, J=8.6 Hz, 1H), 7.20-7.33 (m, 4H),
7.05-7.17 (m, 4H), 6.93-7.06 (m, 1H), 6.90 (d, J=1.5 Hz, 1H),
3.89-4.08 (m, 4H), 3.81 (s, 3H), 2.78-3.02 (m, 2H), 1.79-1.98 (m,
2H), 1.60-1.74 (m, 2H), 1.00-1.48 (m, 6H). MS: 680.1
(M+H.sup.+).
Example BZ-32
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((1-((trifluoromethyl)sulfonyl)-
piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetic acid;
Compound #12
##STR00384##
[1056]
2,2-Bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((1-((trifluoromethyl)su-
lfonyl)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetic acid
was prepared from methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((1-((trifluoromethyl)sulfonyl-
)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetate according
to the procedure as described in Example BZ-24.
[1057] MS: 666.2 (M+H.sup.+).
Example BZ-33
4-((4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)methyl)piperidin-1-yl)sulfonyl)benzoic acid; Compound #15
##STR00385##
[1058] STEP A:
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(piperidin-4-ylmethyl)-1H-b-
enzo[d]imidazole
[1059] tert-Butyl
4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)-
methyl)piperidine-1-carboxylate was prepared according to the
procedure described in Example BZ-11 substituting tert-butyl
4-(aminomethyl)piperidine-1-carboxylate for ethanolamine.
[1060] A solution of tert-butyl
4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)-
methyl)piperidine-1-carboxylate (125 mg, 0.21 mmol) in TFA (1 mL)
and CH.sub.2Cl.sub.2 (5 mL) was stirred at room temperature for 1.5
h. The resulting mixture was then concentrated and the residue
dissolved in CH.sub.2Cl.sub.2. The resulting solution was washed
with aq NaHCO.sub.3 solution and aq NaCl solution, dried over
Na.sub.2SO.sub.4 and concentrated to yield
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(piperidin-4-ylmethyl)-1H-b-
enzo[d]imidazole.
STEP B:
4-((4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imi-
dazol-1-yl)methyl)piperidin-1-yl)sulfonyl)benzoic acid
[1061] To a solution of
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(piperidin-4-ylmethyl)-1H-b-
enzo[d]imidazole (38 mg, 0.078 mmol) in CH.sub.2Cl.sub.2 (2 mL) at
room temperature was added Et.sub.3N (0.043 mL, 0.31 mmol) followed
by methyl 4-(chlorosulfonyl)benzoate (27 mg, 0.12 mmol). The
reaction was stirred overnight. The reaction mixture was
concentrated and to the resulting residue was added THF (2 mL) and
1N NaOH aq solution (1 mL). The reaction was stirred at room
temperature for 2 h before 1N HCl aq solution was added to adjust
pH to .about.3. The mixture was extracted with EtOAc. The organic
layer was washed with aq NaCl solution, dried over Na.sub.2SO.sub.4
and concentrated. The resulting residue was purified by
chromatography (silica gel column, 4% MeOH/CH.sub.2Cl.sub.2) to
yield
4-((4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-
-yl)methyl)piperidin-1-yl)sulfonyl)benzoic acid.
[1062] MS: 674.2 (M+H.sup.+)
Examples BZ-34
methyl
3-((4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imid-
azol-1-yl)methyl)piperidin-1-yl)methyl)benzoate: Compound #13
##STR00386##
[1064] A mixture of
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(piperidin-4-ylmethyl)-1H-b-
enzo[d]imidazole (28 mg, 0.057 mmol), methyl
3-(bromomethyl)benzoate (13 mg, 0.057 mmol) and K.sub.2CO.sub.3 (16
mg, 0.11 mmol) in CH.sub.3CN (2 mL) was stirred at room temperature
for 2 h. The reaction mixture was diluted with EtOAc and washed
with H.sub.2O and aq NaCl aq solution. The organic layer was dried
over Na.sub.2SO.sub.4 and concentrated. The resulting residue was
purified by chromatography (silica gel column, 90% EtOAc/heptane)
to yield methyl
3-((4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-
-yl)methyl)piperidin-1-yl)methyl)benzoate.
[1065] MS: 638.3 (M+H.sup.+).
Example BZ-35
3-((4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)methyl)piperidin-1-yl)methyl)benzoic acid; Compound #10
##STR00387##
[1067] A solution of methyl
3-((4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-
-yl)methyl)piperidin-1-yl)methyl)benzoate (25 mg, 0.039 mmol) and
LiOH*H.sub.2O (12 mg, 0.29 mmol) in H.sub.2O (1 mL) and THF (2 mL)
was stirred at room temperature overnight. To the reaction mixture
was added 1N HCl aq solution to adjust pH to .about.4. The
resulting mixture was extracted with EtOAc. The organic layer was
washed with aq NaCl solution, dried over Na.sub.2SO.sub.4 and
concentrated to yield
3-((4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-
-yl)methyl)piperidin-1-yl)methyl)benzoic acid.
[1068] MS: 624.3 (M+H.sup.+).
Example BZ-36
N-(3-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-1--
yl)propyl)-3-bromobenzenesulfonamide; Compound #9
##STR00388##
[1070] tert-Butyl
(3-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)-
propyl)carbamate was prepared according to the procedure as
described in Example BZ-11 substituting tert-butyl
(3-aminopropyl)carbamate for ethanolamine.
[1071]
3-(6-(Bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol--
1-yl)propan-1-amine was prepared according to the procedure as
described in Example BZ-33 (Step A).
[1072] To a solution of
3-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)p-
ropan-1-amine (0.19 mmol) in CH.sub.2Cl.sub.2 (3 mL) at 0.degree.
C. was added Et.sub.3N (0.11 mL, 0.76 mmol) followed by
3-bromobenzene-1-sulfonyl chloride (0.041 mL, 0.29 mmol). The
reaction was warmed up to room temperature and stirred overnight.
To the reaction was added aq NaHCO.sub.3 solution and the resulting
mixture was extracted with EtOAc. The organic layer was washed with
aq NaCl solution, dried over Na.sub.2SO.sub.4 and concentrated. The
resulting residue was purified by chromatography (silica gel
column, 60% EtOAc/heptane) to yield
N-(3-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidaz-
ol-1-yl)propyl)-3-bromobenzenesulfonamide.
[1073] .sup.1H NMR (CHLOROFORM-d) Shift: 7.95 (t, J=1.8 Hz, 1H),
7.69 (ddd, J=8.1, 3.3, 1.8 Hz, 2H), 7.53 (d, J=8.6 Hz, 1H), 7.35
(t, J=7.9 Hz, 1H), 7.21-7.28 (m, 4H), 6.90-7.05 (m, 6H), 5.60 (s,
1H), 5.10 (t, J=6.3 Hz, 1H), 4.24 (t, J=6.8 Hz, 2H), 2.96 (q, J=6.2
Hz, 2H), 1.97-2.06 (m, 2H), 1.84-1.93 (m, 1H), 1.01-1.20 (m, 4H).
MS: 670.0 (M+H.sup.+).
Example BZ-37
3'-(N-(3-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol--
1-yl)propyl)sulfamoyl)-[1,1'-biphenyl]-4-carboxylic acid; Compound
#8
##STR00389##
[1075]
3'-(N-(3-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]im-
idazol-1-yl)propyl)sulfamoyl)-[1,1'-biphenyl]-4-carboxylic acid was
prepared according to the procedure as described in Example BZ-21,
substituting
N-(3-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)propyl)-3-bromobenzenesulfonamide for
6-(bis(4-chlorophenyl)methyl)-1-(4-bromophenethyl)-2-cyclopropyl-1H-benzo-
[d]imidazole.
[1076] .sup.1H NMR (CHLOROFORM-d) Shift: 8.01-8.17 (m, 3H),
7.73-7.88 (m, 2H), 7.52-7.68 (m, 4H), 7.20-7.29 (m, 4H), 6.97-7.09
(m, 5H), 6.92 (dd, J=8.3, 1.3 Hz, 1H), 5.60 (s, 1H), 4.27 (brt,
J=7.1 Hz, 2H), 2.96 (t, J=6.3 Hz, 2H), 1.84-2.05 (m, 3H), 0.98-1.30
(m, 4H). MS: 710.3 (M+H.sup.+).
Examples BZ-38
Methyl
2-(4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imida-
zol-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxylate: Compound
#5
##STR00390##
[1078] A solution of
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(piperidin-4-ylmethyl)-1H-b-
enzo[d]imidazole (27 mg, 0.055 mmol), methyl
2-bromopyrimidine-5-carboxylate (16 mg, 0.072 mmol) and Hunig's
base (0.03 mL, 0.17 mmol) in CH.sub.3CN (2 mL) was stirred at room
temperature overnight. The reaction mixture was concentrated and
the residue was dissolved in EtOAc. The resulting solution was
washed with aq NaHCO.sub.3 solution and aq NaCl solution, dried
over Na.sub.2SO.sub.4 and concentrated. The resulting residue was
purified by chromatography (silica gel column, 60% EtOAc/heptane)
to yield methyl
2-(4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)methyl)piperidin-1-yl)pyrimidine-5-carboxylate.
[1079] .sup.1H NMR (CHLOROFORM-d) Shift: 8.77-8.93 (m, 2H), 7.57
(d, J=8.6 Hz, 1H), 7.17-7.34 (m, 5H), 6.81-7.11 (m, 5H), 5.54-5.72
(m, 1H), 4.94 (br d, J=13.6 Hz, 2H), 3.98-4.14 (m, 2H), 3.88 (s,
3H), 2.84 (br t, J=11.9 Hz, 2H), 2.05-2.26 (m, 1H), 1.83-2.02 (m,
1H), 1.60-1.81 (m, 2H), 1.18-1.39 (m, 4H), 1.03-1.15 (m, 2H).
[1080] MS: 626.2 (M+H.sup.+).
Example BZ-39
2-(4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)methyl)piperidin-1-yl)pyrimidine-5-carboxylic acid: Compound
#4
##STR00391##
[1082] A solution of methyl
2-(4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)methyl)piperidin-1-yl)pyrimidine-5-carboxylate (25 mg, 0.04
mmol) and LiOH.H.sub.2O (6.7 mg, 0.16 mmol) in H.sub.2O (1 mL) and
THF (2 mL) was stirred at room temperature overnight. To the
reaction solution was added 1N HCl aq solution to adjust pH to
.about.3. The resulting mixture was extracted with EtOAc. The
organic layer was washed with aq NaCl solution, dried over
Na.sub.2SO.sub.4 and concentrated yield
2-(4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)methyl)piperidin-1-yl)pyrimidine-5-carboxylic acid.
[1083] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.90 (s, 2H), 7.78 (br
d, J=6.1 Hz, 1H), 7.21-7.34 (m, 4H), 6.97-7.09 (m, 5H), 6.94 (br s,
1H), 5.64 (s, 1H), 4.98 (br d, J=12.6 Hz, 2H), 3.99-4.16 (m, 2H),
2.87 (br t, J=12.4 Hz, 2H), 2.09-2.20 (m, 1H), 1.87-2.07 (m, 3H),
1.72 (brd, J=11.6 Hz, 2H), 1.17-1.38 (m, 4H). MS: 612.2
(M+H.sup.+).
Example BZ-40
2-(4-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl-
)methyl)piperidin-1-yl)pyrimidine-4-carboxylic acid: Compound
#2
##STR00392##
[1085]
2-(4-((6-(Bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imida-
zol-1-yl)methyl)piperidin-1-yl)pyrimidine-4-carboxylic acid was
prepared according to the procedure as described in Example BZ-39,
substituting methyl 2-bromopyrimidine-4-carboxylate for methyl
2-bromopyrimidine-5-carboxylate.
[1086] MS: 612.0 (M+H.sup.+).
Example BZ-41
4-(4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)methyl)piperidin-1-yl)benzoic acid; Compound #1
##STR00393##
[1087] STEP A: methyl
4-(4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)methyl)piperidin-1-yl)benzoate
[1088] A mixture of
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(piperidin-4-ylmethyl)-1H-b-
enzo[d]imidazole (30 mg, 0.06 mmol), methyl 4-bromobenzoate (26 mg,
0.12 mmol), Cs.sub.2CO.sub.3 (40 mg, 0.12 mmol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(8.7 mg, 0.018 mmol) and Pd(OAc).sub.2 (2.1 mg, 0.009 mmol) in
1,4-dioxane (1.5 mL) was heated at 140.degree. C. by microwave for
3 h. The reaction mixture was cooled to room temperature, diluted
with EtOAc, and filtered. The solution was concentrated and
purified by chromatography (silica gel column, 60% EtOAc/heptane)
to yield methyl
4-(4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)methyl)piperidin-1-yl)benzoate.
STEP B:
4-(4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imid-
azol-1-yl)methyl)piperidin-1-yl)benzoic acid
[1089] To a solution of methyl
4-(4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)methyl)piperidin-1-yl)benzoate (30 mg, 0.05 mmol) in H.sub.2O (1
mL) and THF (2 mL) at room temperature was added 1N NaOH aq
solution (0.38 mL, 0.38 mmol). The reaction was stirred for 5 days
before 1N HCl aq solution was added to adjust pH to .about.3. The
resulting mixture was extracted with EtOAc. The organic layer was
washed with aq NaCl solution, dried over Na.sub.2SO.sub.4 and
concentrated. The resulting residue was purified by chromatography
(silica gel column, 5% MeOH/CH.sub.2Cl.sub.2) to yield
4-(4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]im-
idazol-1-yl)methyl)piperidin-1-yl)benzoic acid.
[1090] .sup.1H NMR (CHLOROFORM-d) .delta.: 7.99 (br d, J=8.6 Hz,
2H), 7.61 (d, J=8.6 Hz, 1H), 7.21-7.31 (m, 4H), 7.03 (d, J=8.1 Hz,
4H), 6.83-6.97 (m, 4H), 5.62 (s, 1H), 3.97-4.15 (m, 2H), 3.71-3.96
(m, 2H), 2.78 (br t, J=11.9 Hz, 2H), 2.05 (m, 1H), 1.87-2.01 (m,
1H), 1.69 (br d, J=11.6 Hz, 2H), 1.33-1.46 (m, 2H), 1.23-1.33 (m,
2H), 1.04-1.16 (m, 2H). MS: 610.3 (M+H.sup.+).
Example MP-1
bis(4-chlorophenyl)(2-(tetrahydrofuran-2-yl)-1-(1-((trifluoromethyl)sulfon-
yl)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)methanol
##STR00394##
[1091] and
6-(bis(4-chlorophenyl)methyl)-2-(tetrahydrofuran-2-yl)-1-(1-((t-
rifluoromethyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole
##STR00395##
[1092] Step 1:
6-bromo-2-(tetrahydrofuran-2-yl)-1-(1-((trifluoromethyl)sulfonyl)piperidi-
n-4-yl)-1H-benzo[d]imidazole
[1093] A solution of
5-bromo-N1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)benzene-1,2-diami-
ne (484 mg, 1.20 mmol, prepared as described in Example YM-4) and
2-tetrahydrofuroic acid (279 mg, 2.41 mmol) in THF (2 mL) was
heated at reflux temperature overnight. The solution was diluted
with saturated aqueous NaHCO.sub.3 and the mixture was extracted
with ethyl acetate. The organic layer was concentrated and the
residue purified by chromatography on silica gel eluting with a
0-40% ethyl acetate in dichloromethane gradient to yield
6-bromo-2-(tetrahydrofuran-2-yl)-1-(1-((trifluoromethyl)sulfonyl)piperidi-
n-4-yl)-1H-benzo[d]imidazole as an off-white solid.
Step 2:
bis(4-chlorophenyl)(2-(tetrahydrofuran-2-yl)-1-(1-((trifluoromethy-
l)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)methanol
[1094] A solution of
6-bromo-2-(tetrahydrofuran-2-yl)-1-(1-((trifluoromethyl)sulfonyl)piperidi-
n-4-yl)-1H-benzo[d]imidazole (205 mg, 0.43 mmol) and
4,4'-dichlorobenzophenone (107 mg, 0.43 mmol) in THF (3 mL) was
cooled to -78.degree. C. tert-Butyllithium (1.7M in pentane, 0.625
mL, 1.06 mmol) was added slowly by syringe. The reaction was
stirred at -78.degree. C. for 15 minutes, and then the cooling bath
was removed. The reaction mixture was stirred overnight at room
temperature. The reaction was quenched by addition of saturated
aqueous NaHCO.sub.3 and extracted with ethyl acetate. The organic
layer was concentrated and the residue purified by chromatography
on silica gel eluting with a 0-40% ethyl acetate in dichloromethane
gradient to yield
bis(4-chlorophenyl)(2-(tetrahydrofuran-2-yl)-1-(1-((trifluoromethyl)sulfo-
nyl)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)methanol as a white
solid. MS: 654.2 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.67 (d, J=8.6 Hz, 1H), 7.53 (s, 1H), 7.33-7.29 (m, 3H),
7.27-7.21 (m, 5H), 7.05 (br d, J=8.6 Hz, 1H), 5.15 (t, J=6.6 Hz,
1H), 4.86-4.74 (m, 1H), 4.13 (br d, J=13.0 Hz, 1H), 3.95-3.87 (m,
1H), 3.87-3.78 (m, 1H), 3.23 (q, J=12.3 Hz, 2H), 2.94 (td, J=6.6,
13.4 Hz, 1H), 2.88 (br s, 1H), 2.54-2.40 (m, 1H), 2.40-2.29 (m,
2H), 2.18 (td, J=6.4, 13.1 Hz, 1H), 2.12-2.01 (m, 3H), 1.98 (br d,
J=13.2 Hz, 1H).
Step 3:
6-(bis(4-chlorophenyl)methyl)-2-(tetrahydrofuran-2-yl)-1-(1-((trif-
luoromethyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole
[1095] A solution of
bis(4-chlorophenyl)(2-(tetrahydrofuran-2-yl)-1-(1-((trifluoromethyl)sulfo-
nyl)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)methanol (138 mg, 0.21
mmol), boron trifluoride diethyl etherate (0.029 mL, 0.23 mmol),
and triethylsilane (123 mg, 1.05 mmol) in dichloromethane (2 mL)
was stirred at room temperature for 3 days. The solution was
diluted with saturated aqueous NaHCO.sub.3 and the mixture was
extracted with dichloromethane. The organic layer was concentrated
and the residue purified by chromatography on silica gel eluting
with a 0-40% ethyl acetate in dichloromethane gradient to yield
6-(bis(4-chlorophenyl)methyl)-2-(tetrahydrofuran-2-yl)-1-(1-((trifluorome-
thyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole as a white
solid. MS: 638.1 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.69 (d, J=8.6 Hz, 1H), 7.30-7.24 (m, 4H), 7.18 (s, 1H),
7.04 (d, J=8.6 Hz, 4H), 6.98 (dd, J=1.3, 8.3 Hz, 1H), 5.63 (s, 1H),
5.15 (dd, J=6.1, 7.1 Hz, 1H), 4.80 (ddd, J=4.0, 8.1, 12.1 Hz, 1H),
4.23-4.08 (m, 2H), 3.91 (dt, J=5.8, 7.7 Hz, 1H), 3.87-3.79 (m, 1H),
3.23 (q, J=12.5 Hz, 2H), 3.00-2.91 (m, 1H), 2.52-2.40 (m, 1H),
2.40-2.29 (m, 2H), 2.22-2.12 (m, 1H), 2.12-1.95 (m, 3H).
Example MP-2
6-(benzo[d][1,3]dioxol-5-yl(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-((tr-
ifluoromethyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole
##STR00396##
[1096] Step 1:
benzo[d][1,3]dioxol-5-yl(4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluorome-
thyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)methanol
[1097] A solution of
6-bromo-2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H--
benzo[d]imidazole (106 mg, 0.23 mmol, prepared as described in
Example YM-4) and 1,3-benzodioxol-5-yl(4-chlorophenyl)methanone
(61.1 mg, 0.23 mmol) in THF (1 mL) was cooled to -78.degree. C.
tert-Butyllithium (1.7M in pentane, 0.345 mL, 0.59 mmol) was added
and the reaction was stirred at -78.degree. C. for 15 minutes. The
cooling bath was removed and the reaction mixture was warm to room
temperature over 1 hour. The reaction was quenched by addition of
saturated aqueous NaHCO.sub.3 and extracted with ethyl acetate. The
organic layer was concentrated and the residue purified by
chromatography on silica gel eluting with a 0-50% ethyl acetate in
heptane gradient to yield
benzo[d][1,3]dioxol-5-yl(4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluorome-
thyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)methanol as
a white solid.
Step 2:
6-(benzo[d][1,3]dioxol-5-yl(4-chlorophenyl)methyl)-2-cyclopropyl-1-
-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole
[1098] To a solution of
benzo[d][1,3]dioxol-5-yl(4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluorome-
thyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)methanol (50
mg, 0.079 mmol) and triethylsilane (45.8 mg, 0.39 mmol) in
dichloromethane (4 mL) was added trifluoroacetic acid (1 mL). The
reaction mixture turned deep red upon addition of trifluoroacetic
acid but faded within minutes leaving a clear, colorless solution.
After 1 hour, the reaction mixture was diluted with saturated
aqueous NaHCO.sub.3 and the mixture was extracted with
dichloromethane. The organic layer was concentrated to yield
6-(benzo[d][1,3]dioxol-5-yl(4-chlorophenyl)methyl)-2-cyclopropyl-1--
(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole.
MS: 617.8 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
7.58 (d, J=8.3 Hz, 1H), 7.28-7.22 (m, 2H), 7.11-7.00 (m, 3H), 6.96
(dd, J=1.3, 8.4 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H), 6.58 (d, J=1.7 Hz,
1H), 6.57-6.51 (m, 1H), 5.94 (q, J=1.3 Hz, 2H), 5.56 (s, 1H),
4.70-4.57 (m, 1H), 4.22-4.14 (m, 2H), 3.24 (br t, J=12.5 Hz, 2H),
2.57-2.38 (m, 2H), 2.10-1.98 (m, 2H), 1.94 (tt, J=5.0, 8.2 Hz, 1H),
1.23-1.17 (m, 2H), 1.13-1.06 (m, 2H).
Example MP-3
bis(4-chlorophenyl)(2-cyclobutyl-1-(1-((trifluoromethyl)sulfonyl)piperidin-
-4-yl)-1H-benzo[d]imidazol-6-yl)methanol
##STR00397##
[1099] and
6-(bis(4-chlorophenyl)methyl)-2-cyclobutyl-1-(1-((trifluorometh-
yl)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazoleas
##STR00398##
[1100] Step 1:
6-bromo-2-cyclobutyl-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-b-
enzo[d]imidazole
[1101] A solution of
5-bromo-N1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)benzene-1,2-diami-
ne (724 mg, 1.8 mmol, prepared as described in Example YM-4) and
cyclobutanecarboxaldehyde (167 mg, 1.98 mmol) in DMSO (10 mL) was
stirred at room temperature overnight open to air. The solution was
diluted with brine and the mixture was extracted with ethyl
acetate. The organic layer was concentrated and the residue
purified by chromatography on silica gel eluting with a 0-40% ethyl
acetate in dichloromethane gradient to yield
6-bromo-2-cyclobutyl-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-b-
enzo[d]imidazole as a white solid.
Step 2:
bis(4-chlorophenyl)(2-cyclobutyl-1-(1-((trifluoromethyl)sulfonyl)p-
iperidin-4-yl)-1H-benzo[d]imidazol-6-yl)methanol
[1102] A solution of
6-bromo-2-cyclobutyl-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-b-
enzo[d]imidazole (95 mg, 0.20 mmol) and 4,4'-dichlorobenzophenone
(51.2 mg, 0.20 mmol) in THF (2 mL) was cooled to -78.degree. C.
tert-Butyllithium (1.7M in pentane, 0.3 mL, 0.51 mmol) was added
slowly by syringe. The reaction was stirred at -78.degree. C. for
15 minutes and then allowed to warm to room temperature. The
reaction mixture was stirred for 4 hours, quenched by addition of
saturated aqueous NaHCO.sub.3, and extracted with ethyl acetate.
The organic layer was concentrated and the residue purified by
chromatography on silica gel eluting with a 25-40% ethyl acetate in
dichloromethane gradient to yield
bis(4-chlorophenyl)(2-cyclobutyl-1-(1-((trifluoromethyl)sulfonyl)piperidi-
n-4-yl)-1H-benzo[d]imidazol-6-yl)methanol as a white solid. MS:
638.1 (M+H.sup.+).
Step 3:
6-(bis(4-chlorophenyl)methyl)-2-cyclobutyl-1-(1-((trifluoromethyl)-
sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole
[1103] A solution of
bis(4-chlorophenyl)(2-cyclobutyl-1-(1-((trifluoromethyl)sulfonyl)piperidi-
n-4-yl)-1H-benzo[d]imidazol-6-yl)methanol (66 mg, 0.103 mmol) and
triethylsilane (60.1 mg, 0.517 mmol) were combined in dry
dichloromethane and the solution cooled to 0.degree. C. Boron
trifluoride diethyl etherate (0.014 mL, 0.114 mmol) was added and
the reaction mixture was stirred at room temperature overnight. The
reaction was quenched with saturated aqueous NaHCO.sub.3 and the
mixture was extracted with dichloromethane. The organic layer was
concentrated and the residue purified by chromatography on silica
gel eluting with a 25-40% ethyl acetate in dichloromethane gradient
to yield
6-(bis(4-chlorophenyl)methyl)-2-cyclobutyl-1-(1-((trifluoromethyl)sulfony-
l)piperidin-4-yl)-1H-benzo[d]imidazole as a colorless oil. MS:
622.1 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.69
(d, J=8.1 Hz, 1H), 7.30-7.23 (m, 4H), 7.1-7.07 (m, 1H), 7.07-7.00
(m, 4H), 6.96 (dd, J=1.3, 8.3 Hz, 1H), 5.62 (s, 1H), 4.25-4.15 (m,
2H), 3.74-3.65 (m, 1H), 3.18 (br t, J=12.6 Hz, 2H), 2.66-2.53 (m,
2H), 2.48-2.33 (m, 4H), 2.23-2.10 (m, 1H), 2.08-2.00 (m, 2H), 1.92
(br d, J=11.1 Hz, 2H).
Example MP-4
ethyl
4-(6-(bis(4-chlorophenyl)methyl)-2-ethyl-1H-benzo[d]imidazol-1-yl)pi-
peridine-1-carboxylate
##STR00399##
[1104] Step 1: 3-fluoro-N-methoxy-N-methyl-4-nitrobenzamide
[1105] 3-Fluoro-4-nitrobenzoic acid (15.2 g, was suspended in
dichloromethane (300 mL) and the mixture was cooled to 0.degree. C.
and stirred vigorously. Oxalyl chloride (45.16 mL, 90.32 mmol, 2M
in dichloromethane) was added slowly by addition funnel,
maintaining the temperature below 10.degree. C. After the addition
of oxalyl chloride was complete, the ice bath was removed and the
reaction, still a suspension, was allowed to warm to room
temperature. Gas evolution was evident. After 2 hours, the solution
was homogeneous and gas evolution had ceased. The flask was
returned to an ice bath and cooled to 0.degree. C. A mixture of
N,O-dimethylhydroxylamine hydrochloride (9.61 g, 98.54 mmol) and
triethylamine (57.07 mL, 410.56 mmol) in dichloromethane (100 mL)
was added slowly by addition funnel, maintaining a temperature less
than 25.degree. C. Once this mixture was added, the ice bath was
removed and the orange reaction mixture was stirred at room
temperature for 1 hour. The reaction mixture was diluted with
saturated aqueous NaHCO.sub.3 and water and then extracted with
dichloromethane. The organic layer was concentrated to yield
3-fluoro-N-methoxy-N-methyl-4-nitrobenzamide as a dark red-orange
solid, which was used without further purification in the next
step.
Step 2: ethyl
4-((5-(methoxy(methyl)carbamoyl)-2-nitrophenyl)amino)piperidine-1-carboxy-
late
[1106] A solution of 3-fluoro-N-methoxy-N-methyl-4-nitrobenzamide
(17.5 g, 76.69 mmol), ethyl 4-amino-1-piperidinecarboxylate (13.81
mL, 80.53 mmol), and diisopropylethylamine (19.83 mL, 115.04 mmol)
in acetonitrile (300 mL) was heated at reflux temperature for 18
hours and then stirred at room temperature for an additional 48
hours. The reaction mixture was concentrated to -50 mL and then
diluted with EtOAc (500 mL). The organic mixture was washed with
saturated aqueous NaHCO.sub.3 and then brine. The organic layer was
concentrated to a dark oil and then purified by silica gel
chromatography using a gradient of 50:50 EtOAc:heptane to 100%
EtOAc as the eluent to yield ethyl
4-((5-(methoxy(methyl)carbamoyl)-2-nitrophenyl)amino)piperidine-1-carboxy-
late as an orange oil.
Step 3: ethyl
4-((5-(4-chlorobenzoyl)-2-nitrophenyl)amino)piperidine-1-carboxylate
[1107] To a solution of ethyl
4-((5-(methoxy(methyl)carbamoyl)-2-nitrophenyl)amino)piperidine-1-carboxy-
late (8.50 g, 22.33 mmol) in THF (250 mL) cooled to 0.degree. C.
was added 4-chlorophenylmagnesium bromide (24.57 mL, 24.57 mmol, 1M
in diethyl ether) slowly by addition funnel. The cooling bath was
removed and the reaction mixture was stirred at room temperature of
2 hours. The reaction was quenched with saturated aqueous
NaHCO.sub.3 and the mixture extracted with ethyl acetate. The
organic layer was concentrated and the residue purified by
chromatography on silica gel using heptane/ethyl acetate as the
eluent to yield ethyl
4-((5-(4-chlorobenzoyl)-2-nitrophenyl)amino)piperidine-1-carboxylate
as a yellow solid.
Step 4: ethyl
4-((5-(bis(4-chlorophenyl)(hydroxy)methyl)-2-nitrophenyl)amino)piperidine-
-1-carboxylate
[1108] To a solution of ethyl
4-((5-(4-chlorobenzoyl)-2-nitrophenyl)amino)piperidine-1-carboxylate
(7.45 g, 17.25 mmol) in THF (200 mL) cooled to 0.degree. C. was
added 4-chlorophenylmagnesium bromide (37.95 mL, 27.95 mmol, 1M in
diethyl ether) slowly by syringe. After 1 hour at 0.degree. C., the
reaction was quenched with saturated aqueous NaHCO.sub.3 and
extracted with ethyl acetate. The organic layer was concentrated
and the residue purified by chromatography on silica gel eluting
with a 10-40% ethyl acetate in heptane gradient to yield ethyl
4-((5-(bis(4-chlorophenyl)(hydroxy)methyl)-2-nitrophenyl)amino)piperidine-
-1-carboxylate.
Step 5: ethyl
4-((5-(bis(4-chlorophenyl)methyl)-2-nitrophenyl)amino)piperidine-1-carbox-
ylate
[1109] To a solution of ethyl
4-((5-(bis(4-chlorophenyl)(hydroxy)methyl)-2-nitrophenyl)amino)piperidine-
-1-carboxylate (6.38 g, 1171 mmol) and triethylsilane (5.45 g,
46.84 mmol) in dichloromethane (589 mL) was added trifluoroacetic
acid (39.3 mL). The reaction mixture was stirred overnight at room
temperature and then neutralized with saturated aqueous
NaHCO.sub.3. The reaction mixture was extracted with
dichloromethane. The organic layer was concentrated and the residue
purified by chromatography on silica gel to yield ethyl
4-((5-(bis(4-chlorophenyl)methyl)-2-nitrophenyl)amino)piperidine-1-carbox-
ylate.
Step 6: ethyl
4-((2-amino-5-(bis(4-chlorophenyl)methyl)phenyl)amino)piperidine-1-carbox-
ylate
[1110] Ethyl
4-((5-(bis(4-chlorophenyl)methyl)-2-nitrophenyl)amino)piperidine-1-carbox-
ylate (3.32 g, 6.28 mmol) was dissolved in ethyl acetate (250 mL)
and nitrogen was bubbled through the solution for a few minutes.
Raney nickel (300 mg, 5.11 mmol) was added and the reaction mixture
was placed on a Parr shaker under 45 psi H.sub.2 for 5 hours. The
catalyst was filtered through CELITE and the filtrate was
evaporated in vacuo. The residue was purified by chromatography on
silica gel to yield ethyl
4-((2-amino-5-(bis(4-chlorophenyl)methyl)phenyl)amino)piperidine-1-carbox-
ylate as a brown solid.
Step 7: ethyl
4-(6-(bis(4-chlorophenyl)methyl)-2-ethyl-1H-benzo[d]imidazol-1-yl)piperid-
ine-1-carboxylate
[1111] A solution of ethyl
4-((2-amino-5-(bis(4-chlorophenyl)methyl)phenyl)amino)piperidine-1-carbox-
ylate (209 mg, 0.42 mmol) and propionaldehyde (48.7 mg, 0.84 mmol)
in DMSO (3 mL) was stirred at room temperature open to air for 72
hours. The solution was diluted with brine and the mixture was
extracted with ethyl acetate. The organic layer was concentrated
and the residue purified by chromatography on silica gel to yield
ethyl
4-(6-(bis(4-chlorophenyl)methyl)-2-ethyl-1H-benzo[d]imidazol-1-yl)piperid-
ine-1-carboxylate.
[1112] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.63 (d, J=8.6
Hz, 1H), 7.30-7.20 (m, 4H), 7.17 (s, 1H), 7.03 (d, J=8.6 Hz, 4H),
6.90 (dd, J=1.5, 8.3 Hz, 1H), 5.61 (s, 1H), 4.53-4.34 (m, 2H), 4.29
(tdd, J=4.1, 8.3, 12.3 Hz, 1H), 4.19 (q, J=7.1 Hz, 2H), 2.98-2.82
(m, 4H), 2.40-2.15 (m, 2H), 1.85 (br d, J=11.7 Hz, 2H), 1.44 (t,
J=7.5 Hz, 3H), 1.30 (t, J=7.1 Hz, 3H)
Example MP-5
ethyl
4-(6-(bis(4-chlorophenyl)methyl)-2-(pyridin-3-yl)-1H-benzo[d]imidazo-
l-1-yl)piperidine-1-carboxylate
##STR00400##
[1114] Ethyl
4-(6-(bis(4-chlorophenyl)methyl)-2-(pyridin-3-yl)-1H-benzo[d]imidazol-1-y-
l)piperidine-1-carboxylate was prepared according to the procedure
as described in Example MP-4 above, modifying the procedure used in
Step 7 as follows:
[1115] A solution of ethyl
4-((2-amino-5-(bis(4-chlorophenyl)methyl)phenyl)amino)piperidine-1-carbox-
ylate (147 mg, 0.30 mmol) and pyridine-3-carboxaldehyde (31.6 mg,
0.30 mmol) in DMSO (1 mL) was stirred at room temperature open to
air overnight. The solution was diluted with brine and the mixture
was extracted with ethyl acetate. The organic layer was
concentrated and the resulting brown oil purified by chromatography
on silica gel using a gradient of 10-50% ethyl acetate in heptane
followed by 5% methanol in dichloromethane as eluent to yield ethyl
4-(6-(bis(4-chlorophenyl)methyl)-2-(pyridin-3-yl)-1H-benzo[d]imidazol-1-y-
l)piperidine-1-carboxylate as an orange oil.
[1116] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 8.84 (d, J=1.5
Hz, 1H), 8.78 (dd, J=1.7, 4.9 Hz, 1H), 8.00 (td, J=1.9, 7.9 Hz,
1H), 7.75 (d, J=8.6 Hz, 1H), 7.50 (ddd, J=0.7, 4.9, 7.8 Hz, 1H),
7.32 (s, 1H), 7.30-7.24 (m, 4H), 7.10-7.04 (m, 4H), 7.02 (dd,
J=1.5, 8.6 Hz, 1H), 5.66 (s, 1H), 4.46-4.27 (m, 3H), 4.18 (q, J=7.1
Hz, 2H), 2.76 (br t, J=12.5 Hz, 2H), 2.35 (br d, J=8.8 Hz, 2H),
1.90 (br d, J=11.2 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H).
Example MP-6
bis(4-chlorophenyl)(2-ethyl-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl-
)-1H-benzo[d]imidazol-6-yl)methanol
##STR00401##
[1118] A solution of
6-bromo-2-ethyl-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-benzo[-
d]imidazole (700 mg, 1.59 mmol, prepared according to the
procedures as described in YM-4, Steps 4 and 5) and
4,4'-dichlorobenzophenone (399.2 mg, 1.59 mmol) in THF (2 mL) was
cooled to -78.degree. C. tert-Butyllithium (1.7M in pentane, 2.34
mL, 3.98 mmol) was added slowly by syringe. The reaction was
stirred at -78.degree. C. for 15 minutes and then allowed to warm
to room temperature. The reaction mixture was stirred for 3 hours,
quenched by addition of saturated aqueous NaHCO.sub.3, and
extracted with ethyl acetate. The organic layer was concentrated
and the residue purified by chromatography on silica gel eluting
with a 0-40% ethyl acetate in dichloromethane gradient to yield
bis(4-chlorophenyl)(2-ethyl-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-y-
l)-1H-benzo[d]imidazol-6-yl)methanol as a white solid. MS: 611.8
(M+H.sup.+).
Example MP-7
6-(bis(4-methoxyphenyl)methyl)-2-cyclobutyl-1-(1-((trifluoromethyl)sulfony-
l)piperidin-4-yl)-1H-benzo[d]imidazole
##STR00402##
[1119] Step 1:
(2-cyclobutyl-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]-
imidazol-6-yl)bis(4-methoxyphenyl)methanol
[1120] A solution of
6-bromo-2-cyclobutyl-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-b-
enzo[d]imidazole (131 mg, 0.28 mmol, prepared as described in
Example MP-3) and 4,4'-dimethoxybenzophenone (68.1 mg, 0.28 mmol)
in THF (2 mL) was cooled to -78.degree. C. tert-Butyllithium (1.7M
in pentane, 0.41 mL, 0.70 mmol) was added slowly by syringe. The
reaction was stirred at -78.degree. C. for 15 minutes and then
allowed to warm to room temperature. The reaction mixture was
stirred for 1 hour, quenched by addition of saturated aqueous
NaHCO.sub.3, and extracted with ethyl acetate. The organic layer
was concentrated and the residue purified by chromatography on
silica gel eluting with a 10-40% ethyl acetate in heptane gradient
to yield
(2-cyclobutyl-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]-
imidazol-6-yl)bis(4-methoxyphenyl)methanol as a white solid.
Step 2:
6-(bis(4-methoxyphenyl)methyl)-2-cyclobutyl-1-(1-((trifluoromethyl-
)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole
[1121] To a solution of
(2-cyclobutyl-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]-
imidazol-6-yl)bis(4-methoxyphenyl)methanol (114 mg, 0.181 mmol) and
triethylsilane (46.2 mg, 0.40 mmol) in dichloromethane (2 mL) was
added trifluoroacetic acid (0.25 mL) and the reaction mixture was
stirred at room temperature overnight. An additional amount of
triethylsilane (100 .mu.L) and trifluoroacetic acid (259 .mu.L)
were added and stirring was continued at room temperature
overnight. The reaction mixture was neutralized with saturated
aqueous NaHCO.sub.3 extracted with dichloromethane, and the solvent
removed in vacuo. The residue was purified by chromatography on
silica gel eluting with a 10-50% ethyl acetate in heptane gradient
to yield
6-(bis(4-methoxyphenyl)methyl)-2-cyclobutyl-1-(1-((trifluoromethyl)sulfon-
yl)piperidin-4-yl)-1H-benzo[d]imidazole as a white solid. MS: 614.0
(M+H.sup.+).
Example MP-8
ethyl
4-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-cyclopropyl-1H-benzo[d-
]imidazol-1-yl)piperidine-1-carboxylate
##STR00403##
[1122] Step 1: ethyl
4-((5-chloro-2-nitrophenyl)amino)piperidine-1-carboxylate
[1123] A solution of 2,4-dichloronitrobenzene (19.2 g, 100 mmol),
ethyl 4-amino-1-piperidine-carboxylate (18.95 g, 110 mmol), and
triethylamine (16.619 mL, 120 mmol) in acetonitrile (75 mL) was
heated at reflux temperature for 13 days. The solvent was
evaporated, the residue was dissolved in dichloromethane (5400 mL),
and the resulting solution was washed with a 1N HCl solution (250
mL). The organic layer was further washed with brine (100 mL),
dried over MgSO.sub.4, filtered, and evaporated. The residue was
purified by chromatography on silica gel using a 0-10% methanol in
dichloromethane gradient as eluent to yield ethyl
4-((5-chloro-2-nitrophenyl)amino)piperidine-1-carboxylate as an
orange solid.
Step 2: ethyl
4-((5-((4-chlorophenyl)(cyano)methyl)-2-nitrophenyl)amino)piperidine-1-ca-
rboxylate
[1124] To a solution of 4-chlorophenylacetonitrile (4.78 g, 31.5
mmol) in THF (50 mL) and isopropyl alcohol (10 mL) was added t-BuOK
(8.42 g, 75 mmol) and the mixture was stirred at room temperature
for 15 minutes. Compound 8a (9.83 g, 30 mmol) was added and the
reaction was stirred at room temperature overnight. Water (200 mL)
was added and the mixture extracted with ethyl acetate (500 mL).
The organic layer was washed with brine (50 mL), dried over
MgSO.sub.4, and evaporated in vacuo. The residue was purified by
silica gel chromatography using a 20-60% ethyl acetate in heptane
gradient as eluent to yield ethyl
4-((5-((4-chlorophenyl)(cyano)methyl)-2-nitrophenyl)amino)piperidine-1-ca-
rboxylate as a bright yellow-orange solid.
Step 3: ethyl
4-((5-(2-amino-1-(4-chlorophenyl)-2-thioxoethyl)-2-nitrophenyl)amino)pipe-
ridine-1-carboxylate
[1125] To a solution of ethyl
4-((5-((4-chlorophenyl)(cyano)methyl)-2-nitrophenyl)amino)piperidine-1-ca-
rboxylate (6.18 g, 13.95 mmol) in EtOH (50 mL) was added phosphorus
pentasulfide (6.82 g, 15.35 mmol) and the reaction mixture was
heated to 70.degree. C. overnight. The reaction mixture was cooled
in an ice-water bath, water (150 mL) was added dropwise and a
bright orange oil separated. The mixture was filtered over a bed of
CELITE (the orange oil stayed on top) and the oily residue on the
filter was washed with water (200 mL). The residue on the filter
was dissolved in dichloromethane (200 mL) and the resulting
solution was dried over MgSO.sub.4, filtered, and evaporated to
give 11.3 g of a bright orange oil. The material was purified by
silica gel chromatography using a 40-80% ethyl acetate in heptane
gradient as eluent, to yield ethyl
4-((5-(2-amino-1-(4-chlorophenyl)-2-thioxoethyl)-2-nitrophenyl)amino)pipe-
ridine-1-carboxylate as a bright orange solid.
Step 4: ethyl
4-((5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nitrophenyl)amino)piperidi-
ne-1-carboxylate
[1126] To a solution of ethyl
4-((5-(2-amino-1-(4-chlorophenyl)-2-thioxoethyl)-2-nitrophenyl)amino)pipe-
ridine-1-carboxylate (6.15 g, 12.89 mmol) and bromoacetaldehyde
diethylacetal (7.76 mL, 51.57 mmol) in acetic acid (75 mL) was
added water (3 mL). The reaction mixture was heated to 100.degree.
C. for 30 minutes, cooled to room temperature, and water (150 mL)
was added. The mixture was extracted with ethyl acetate
(2.times.250 mL) and the combined organic layers were washed with
brine (50 mL). The organic layer was dried over MgSO.sub.4,
filtered, and evaporated. The residue was purified by silica gel
chromatography using a 30-70% ethyl acetate in heptane gradient to
yield ethyl
4-((5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nitrophenyl)amino)piperidi-
ne-1-carboxylateas an orange solid.
Step 5: ethyl
4-((2-amino-5-((4-chlorophenyl)(thiazol-2-yl)methyl)phenyl)amino)piperidi-
ne-1-carboxylate
[1127] A solution of ethyl
4-((5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nitrophenyl)amino)piperidi-
ne-1l-carboxylate (5.9 g, 11.78 mmol) in THF (25 mL) and methanol
(25 mL) in a 200 mL Parr flask was purged with nitrogen and Raney
nickel (0.5 g, 8.52 mmol) was added. The mixture was hydrogenated
at room temperature overnight on a Parr apparatus under 30 psi
hydrogen pressure. The catalyst was removed by filtration over
CELITE and the solvent was evaporated. The residue was stored under
vacuum for 3 days, to yield ethyl
4-((2-amino-5-((4-chlorophenyl)(thiazol-2-yl)methyl)phenyl)amino)pi-
peridine-1-carboxylate as a purple solid.
Step 6: ethyl
4-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-cyclopropyl-1H-benzo[d]imid-
azol-1-yl)piperidine-1-carboxylate
[1128] A stirred solution of ethyl
4-((2-amino-5-((4-chlorophenyl)(thiazol-2-yl)methyl)phenyl)amino)piperidi-
ne-1-carboxylate (147 mg, 0.30 mmol) and cyclopropanecarboxaldehyde
(31.59 mg, 0.30 mmol) in DMSO (1 mL) was kept at room temperature
in the presence of air overnight. The reaction mixture was diluted
with brine and extracted with ethyl acetate. The organic layer was
concentrated to a brown oil and purified by chromatography on
silica gel using a 10-50% ethyl acetate in heptane gradient
followed by 5% methanol in dichloromethane as eluent to yield ethyl
4-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-cyclopropyl-1H-benzo[d]imid-
azol-1-yl)piperidine-1-carboxylateas an orange oil. The ethyl
4-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-cyclopropyl-1H-benzo[d]imid-
azol-1-yl)piperidine-1-carboxylate solid was converted to the
corresponding HCl salt with 1N HCl in diethyl ether. MS: 585.2
(M+H.sup.+).
Example MP-9
ethyl
4-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-isobutyl-1H-benzo[d]im-
idazol-1-yl)piperidine-1-carboxylate
##STR00404##
[1130] Ethyl
4-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-isobutyl-1H-benzo[d]imidazo-
l-1-yl)piperidine-1-carboxylate was prepared according to the
procedure as described in Example MP-8 above, substituting
isovaleraldehyde for cyclopropanecarboxaldehyde in Step 6. MS:
537.0 (M+H.sup.+).
Example MP-10
ethyl
6-((4-chlorophenyl)(thiazol-2-yl)methyl)-1-(1-(ethoxycarbonyl)piperi-
din-4-yl)-1H-benzo[d]imidazole-2-carboxylate
##STR00405##
[1132] Ethyl
6-((4-chlorophenyl)(thiazol-2-yl)methyl)-1-(1-(ethoxycarbonyl)piperidin-4-
-yl)-1H-benzo[d]imidazole-2-carboxylate was prepared according to
the procedure as in Example MP-8 above, substituting ethyl
glyoxalate for cyclopropanecarboxaldehyde in Step 6. MS: 553.2
(M+H.sup.+).
Example MP-11
ethyl
4-(6-((4-chlorophenyl)thiazol-2-yl)methyl)-2-(tetrahydrofuran-2-yl)--
1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate
##STR00406##
[1134] Ethyl
4-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-(tetrahydrofuran-2-yl)-1H-b-
enzo[d]imidazol-1-yl)piperidine-1-carboxylate was prepared
according to the procedure as described in Example MP-8 above,
substituting tetrahydrofuran-3-carboxaldehyde for
cyclopropanecarboxaldehyde in Step 6. MS: 551.2 (M+H.sup.+).
Example MP-12
ethyl
4-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-propyl-1H-benzo[d]imid-
azol-1-yl)piperidine-1-carboxylate
##STR00407##
[1136] Ethyl
4-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-propyl-1H-benzo[d]imidazol--
1-yl)piperidine-1-carboxylate was prepared according to the
procedure as described Example MP-8 above, substituting
butyraldehyde for cyclopropanecarboxaldehyde in Step 6. MS: 523.2
(M+H.sup.+).
Example MP-13
ethyl
4-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-tetrahydro-2H-pyran-4--
yl)-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate
##STR00408##
[1138] Ethyl
4-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-(tetrahydro-2H-pyran-4-yl)--
1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate was prepared
according to the procedure as described in Example MP-8 above,
substituting tetrahydropyran-4-carboxaldehyde for
cyclopropanecarboxaldehyde in Step 6. MS: 565.2 (M+H.sup.+).
Example MP-14
ethyl
4-(2-(4-chlorophenyl)-6-((4-chlorophenyl)thiazol-2-yl)methyl)-1H-ben-
zo[d]imidazol-1-yl)piperidine-1-carboxylate
##STR00409##
[1140] Ethyl
4-(2-(4-chlorophenyl)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)-1H-benzo[d-
]imidazol-1-yl)piperidine-1-carboxylate was prepared according to
the procedure as described in Example MP-8 above, substituting
4-chlorobenzaldehyde for cyclopropanecarboxaldehyde in Step 6. MS:
591.1 (M+H.sup.+).
Example MP-15
ethyl
4-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-thiazol-2-yl)-1H-benzo-
[d]imidazol-1-yl)piperidine-1-carboxylate
##STR00410##
[1142] Ethyl
4-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-(thiazol-2-yl)-1H-benzo[d]i-
midazol-1-yl)piperidine-1-carboxylate was prepared according to the
procedure as described in Example MP-8 above, substituting
2-thiazolecarboxaldehyde for cyclopropanecarboxaldehyde in Step 6.
MS: 564.0 (M+H.sup.+).
Example MP-16
ethyl
4-(2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-6-((4-chlorophenyl)(thia-
zol-2-yl)methyl)-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate
##STR00411##
[1143] and ethyl
4-(2-(azetidin-3-yl)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)-1H-benzo[d]-
imidazol-1-yl)piperidine-1-carboxylate
##STR00412##
[1144] Step 1: ethyl
4-(2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-6-((4-chlorophenyl)(thiazol-2-
-yl)methyl)-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate
[1145] Ethyl
4-(2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-6-((4-chlorophenyl)(thiazol-2-
-yl)methyl)-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate was
prepared according to the procedure as described in Example MP-8
above, substituting 1-t-butoxycarbonyl-3-azetidinecarboxaldehyde
for cyclopropanecarboxaldehyde in Step 6. MS: 636.0
(M+H.sup.+).
Step 2: ethyl
4-(2-(azetidin-3-yl)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)-1H-benzo[d]-
imidazol-1-yl)piperidine-1-carboxylate
[1146] Ethyl
4-(2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-6-((4-chlorophenyl)(thiazol-2-
-yl)methyl)-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (20
mg, 0.030 mmol) was dissolved in 1,4-dioxane (1 mL) and 4N
HCl/1,4-dioxane (1 mL, 4 mmol) was added. The resulting solution
was stirred for 4 hours at room temperature. The solvent was
evaporated to yield ethyl
4-(2-(azetidin-3-yl)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)-1H-benzo[d]-
imidazol-1-yl)piperidine-1-carboxylate as its corresponding HCl
salt. MS: 536.2 (M+H.sup.+).
Example MP-17
(2-(tert-butyl)-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-benzo[d-
]imidazol-6-yl)bis(4-chlorophenyl)methanol
##STR00413##
[1147] and 6-(bis(4-chlorophenyl
methyl)-2-(tert-butyl)-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-
-benzo[d]imidazole
##STR00414##
[1148] Step 1:
N-(4-bromo-2-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)phenyl)p-
ivalamide
[1149] A solution of
5-bromo-N1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)benzene-1,2-diami-
ne (362 mg, 0.9 mmol, prepared as described in Example YM-26),
pivaloyl chloride (119 mg, 0.99 mmol), and 4-dimethylaminopyridine
(121 mg, 0.99 mmol) in dichloromethane (5 mL) was stirred at room
temperature overnight. The solution was diluted with saturated
aqueous NaHCO.sub.3 and the mixture was extracted with
dichloromethane. The organic layer was concentrated to yield
N-(4-bromo-2-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)phenyl)p-
ivalamide as an off-white solid, which was sufficiently pure to use
in the next step.
Step 2:
6-bromo-2-(tert-butyl)-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-
-yl)-1H-benzo[d]imidazole
[1150] A solution of
N-(4-bromo-2-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)phenyl)p-
ivalamide (426 mg, 0.876 mmol) in acetic acid (2 mL) was heated to
reflux temperature for 20 hours and then stirred at room
temperature for 40 hours. Water (1 mL) was added and the mixture
heated to reflux temperature overnight. The solvent was evaporated
and the resulting dark oil was quenched with saturated aqueous
NaHCO.sub.3. The aqueous mixture was extracted with dichloromethane
and the organic layer was evaporated. The residue was purified by
chromatography on silica gel eluting with a 0-40% ethyl acetate in
dichloromethane gradient to yield
6-bromo-2-(tert-butyl)-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-
-benzo[d]imidazole.
Step 3:
(2-(tert-butyl)-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-
-benzo[d]imidazol-6-yl)bis(4-chlorophenyl)methanol
[1151] A solution of
6-bromo-2-(tert-butyl)-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-
-benzo[d]imidazole (128 mg, 0.27 mmol) and
4,4'-dichlorobenzophenone (68.6 mg, 0.27 mmol) in THF (5 mL) was
cooled to -78.degree. C. tert-Butyllithium (1.7M in pentane, 0.40
mL, 0.68 mmol) was added slowly by syringe. The reaction was
stirred at -78.degree. C. for 15 minutes and then allowed to warm
to room temperature. The reaction mixture was stirred for 2 hours,
quenched by addition of saturated aqueous NaHCO.sub.3, and
extracted with ethyl acetate. The organic layer was concentrated
and the residue purified by chromatography on silica gel eluting
with a 0-40% ethyl acetate in dichloromethane gradient to yield
(2-(tert-butyl)-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-benzo[-
d]imidazol-6-yl)bis(4-chlorophenyl)methanol as a white solid. MS:
640.1 (M+H.sup.+).
Step 4:
6-(bis(4-chlorophenyl)methyl)-2-(tert-butyl)-1-(1-((trifluoromethy-
l)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole
[1152] A solution of
(2-(tert-butyl)-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-benzo[-
d]imidazol-6-yl)bis(4-chlorophenyl)methanol (26 mg, 0.041 mmol),
boron trifluoride diethyl etherate (0.006 mL, 0.048 mmol), and
triethylsilane (23.6 mg, 0.203 mmol) in dichloromethane (1 mL) was
stirred at room temperature for 2 hours. The solution was diluted
with saturated aqueous NaHCO.sub.3 and the mixture was extracted
with dichloromethane. The organic layer was concentrated and the
residue purified by chromatography on silica gel eluting with a
0-40% ethyl acetate in dichloromethane gradient to yield
6-(bis(4-chlorophenyl)methyl)-2-(tert-butyl)-1-(1-((trifluoromethyl)sulfo-
nyl)piperidin-4-yl)-1H-benzo[d]imidazole as a colorless oil. MS:
624.2 (M+H.sup.+). The oil was converted to the corresponding HCl
salt by reacting with 1N HCl in diethyl ether to yield the HCl salt
as a white powder.
Example MP-18
ethyl
4-(2-(tert-butyl)-6-((4-chlorophenyl)thiazol-2-yl)methyl)-1H-benzo[d-
]imidazol-1-yl)piperidine-1-carboxylate
##STR00415##
[1154] Ethyl
4-(2-(tert-butyl)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)-1H-benzo[d]imi-
dazol-1-yl)piperidine-1-carboxylate was prepared according to the
procedure as described in Example MP-8 above, substituting
pivaldehyde for cyclopropanecarboxaldehyde in Step 6. MS: 537.2
(M+H.sup.+).
Example MP-19
bis(4-chlorophenyl)(2-(hydroxymethyl)-1-(1-((trifluoromethyl)sulfonyl)pipe-
ridin-4-yl)-1H-benzo[d]imidazol-6-yl)methanol
##STR00416##
[1155] Step 1:
6-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-(1-((trifluoromethyl)s-
ulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole
[1156] A solution of
5-bromo-N1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)benzene-1,2-diami-
ne (484 mg, 1.20 mmol, prepared as described in Example YM-26) and
tert-butyldimethylsilyloxyacetaldehyde (0.255 mL, 1.20 mmol) in
DMSO (3 mL) was stirred at room temperature overnight open to air.
The solution was diluted with brine and the mixture was extracted
with ethyl acetate. The organic layer was concentrated and the
residue purified by chromatography on silica gel eluting with a
0-25% ethyl acetate in dichloromethane gradient to yield
6-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-(1-((trifluoromethyl)s-
ulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole as an off-white
solid.
Step 2:
(2-(((tert-butyldimethylsiyl)oxy)methyl)-1-(1-((trifluoromethyl)su-
lfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)bis(4-chlorophenyl)methano-
l
[1157] A solution of
6-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-(1-((trifluoromethyl)s-
ulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole (195 mg, 0.35 mmol)
and 4,4'-dichlorobenzophenone (88.0 mg, 0.35 mmol) in THF (3 mL)
was cooled to -78.degree. C. tert-Butyllithium (1.7M in pentane,
0.53 mL, 0.88 mmol) was added slowly by syringe. The reaction was
stirred at -78.degree. C. for 15 minutes and then allowed to warm
to room temperature. The reaction mixture was stirred for 2 hours,
quenched by addition of saturated aqueous NaHCO.sub.3, and
extracted with ethyl acetate. The organic layer was concentrated
and the residue purified by chromatography on silica gel eluting
with a 0-40% ethyl acetate in dichloromethane gradient to yield
(2-(((tert-butyldimethylsilyl)oxy)methyl)-1-(1-((trifluoromethyl)sulfonyl-
)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)bis(4-chlorophenyl)methanol
as a yellow oil.
Step 3:
bis(4-chlorophenyl)(2-(hydroxymethyl)-1-(1-((trifluoromethyl)sulfo-
nyl)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)methanol
[1158] A solution of
(2-(((tert-butyldimethylsilyl)oxy)methyl)-1-(1-((trifluoromethyl)sulfonyl-
)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)bis(4-chlorophenyl)methanol
(50 mg, 0.069 mmol), triethylsilane (39.9 mg, 0.343 mmol), and
boron trifluoride diethyl etherate (0.017 mL, 0.137 mmol) in
dichloromethane (2 mL) was stirred at room temperature overnight.
The reaction was quenched with saturated aqueous NaHCO.sub.3 and
the mixture was extracted with dichloromethane. The organic layer
was concentrated and the residue purified by chromatography on
silica gel eluting with a 0-40% ethyl acetate in dichloromethane
gradient to yield
bis(4-chlorophenyl)(2-(hydroxymethyl)-1-(1-((trifluoromethyl)sulfonyl)pip-
eridin-4-yl)-1H-benzo[d]imidazol-6-yl)methanol as a white solid.
MS: 614.1 (M+H.sup.+).
Example DL-1
6-(bis(4-chlorophenyl)methyl)-2-cyclobutyl-1-((1-((trifluoromethyl)sulfony-
l)piperidin-4-yl)methyl)-1H-benzo[d]imidazole
##STR00417##
[1159] Step 1: methyl 2,2-bis(4-chlorophenyl)acetate
[1160] A solution of 2,2-bis(4-chlorophenyl)acetic acid (4 g, 13.9
mmol) and H.sub.2SO.sub.4 (0.37 mL, 7.0 mmol) in MeOH (20 mL) was
heated at reflux temperature overnight. The solution was
concentrated, water added to the residue, and the mixture extracted
with ethyl ether. The organic layer was dried over Na.sub.2SO.sub.4
and concentrated in vacuo to yield methyl
2,2-bis(4-chlorophenyl)acetate as a clear oil. The residue was
purified by chromatography on silica gel eluting with a 0-70%
dichloromethane:heptane gradient to yield methyl
2,2-bis(4-chlorophenyl)acetate as a clear oil, which overtime
became a white solid.
Step 2: methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate
[1161] To a solution of methyl 2,2-bis(4-chlorophenyl)acetate (1.92
g, 6.51 mmol) and 2,4-difluoro-1-nitrobenzene (0.76 mL, 6.83 mmol)
in THF (40 mL) at -37.degree. C. to -32.degree. C. was added t-BuOK
(1M in THF, 7.2 mL, 7.2 mmol) over 10 minutes. The reaction was
allowed to warm slowly to room temperature and then stirred
overnight. To the reaction was added ethyl acetate and the
resulting organic mixture was washed with aq NH.sub.4Cl and brine.
The organic layer was dried over MgSO.sub.4 and concentrated in
vacuo to yield a red oil. The residue was purified by silica gel
chromatography with a 0-70% dichloromethane:heptane gradient as
eluent to yield methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate as a pale
yellow oil.
Step 3: methyl
2,2-bis(4-chlorophenyl)-2-(4-nitro-3-(((1-((trifluoromethyl)sulfonyl)pipe-
ridin-4-yl)methyl)amino)phenyl)acetate
[1162] To a solution of methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate (0.45 g,
1.036 mmol) and diisopropylethylamine (0.446 mL, 2.591 mmol) in
CH.sub.3CN (2.25 mL) at room temperature was added
4-aminomethyl-1-trifluoromethylsulfonyl]piperidine hydrochloride
(396.9 mg, 1.24 mmol). The resulting reaction mixture was heated to
reflux temperature for 4 hours and the solvent was removed in
vacuo. The residue was purified by silica gel chromatography using
a 50-100% dichloromethane:heptane gradient as eluent to yield
methyl
2,2-bis(4-chlorophenyl)-2-(4-nitro-3-(((1-((trifluoromethyl)sulfonyl)pipe-
ridin-4-yl)methyl)amino)phenyl)acetate as a yellow solid.
Step 4: methyl
2-(4-amino-3-(((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methyl)amino)-
phenyl)-2,2-bis(4-chlorophenyl)acetate
[1163] To a solution of methyl
2,2-bis(4-chlorophenyl)-2-(4-nitro-3-(((1-((trifluoromethyl)sulfonyl)pipe-
ridin-4-yl)methyl)amino)phenyl)acetate (0.62 g, 0.94 mmol) in MeOH
(200 mL) was added Raney nickel catalyst (200 mg, 3.41 mmol) and
the mixture was placed under 40 psi hydrogen and left overnight.
The reaction mixture was filtered through CELITE and the solvent
evaporated in vacuo to yield methyl
2-(4-amino-3-(((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methyl-
)amino)phenyl)-2,2-bis(4-chlorophenyl)acetate as an off-white
solid.
Step 5: methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclobutyl-1-((1-((trifluoromethyl)sulfonyl)-
piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetate
[1164] A rapidly stirred solution of methyl
2-(4-amino-3-(((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methyl)amino)-
phenyl)-2,2-bis(4-chlorophenyl)acetate (0.19 g, 0.30 mmol) and
cyclobutanecarboxaldehyde (0.052 g, 0.60 mmol) in DMSO (1 mL) was
kept at room temperature in the presence of air for 4 days. The
reaction mixture was purified by silica gel chromatography using a
0-2% methanol:dichloromethane gradient as eluent to yield methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclobutyl-1-((1-((trifluoromethyl)sulfonyl)-
piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetate.
Step 6:
2,2-bis(4-chlorophenyl)-2-(2-cyclobutyl-1-((1-((trifluoromethyl)su-
lfonyl)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetic
acid
[1165] A solution of methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclobutyl-1-((1-((trifluoromethyl)sulfonyl)-
piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetate (180 mg,
0.26 mmol) in 3N NaOH aqueous solution (2 mL, 6 mmol) and methanol
(8 mL) was heated at 50.degree. C. The reaction was cooled to room
temperature and 1N HCl aqueous solution was added (8 mL). The
mixture was extracted with EtOAc and the organic solution was
washed with brine and evaporated in vacuo to yield
2,2-bis(4-chlorophenyl)-2-(2-cyclobutyl-1-((1-((trifluoromethyl)sulfonyl)-
piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetic acid as a
pale green oil.
Step 7:
6-(bis(4-chlorophenyl)methyl)-2-cyclobutyl-1-((1-((trifluoromethyl-
)sulfonyl)piperidin-4-yl)methyl)-1H-benzo[d]imidazole
[1166] A solution of
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((1-((trifluoromethyl)sulfonyl-
)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetic acid (360
mg, 0.53 mmol) and DBU (0.2 mL, 1.34 mmol) in toluene (10 mL) was
heated at 90.degree. C. overnight. After evaporation of the
solvent, the residue was purified by reverse phase HPLC and the
fractions containing the product were lyophilized to yield
6-(bis(4-chlorophenyl)methyl)-2-cyclobutyl-1-((1-((trifluoromethyl)sulfon-
yl)piperidin-4-yl)methyl)-1H-benzo[d]imidazole trifluoroacetate
salt as a white solid. MS: 636.2 (M+H.sup.+); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 7.89 (d, J=8.6 Hz, 1H), 7.33-7.28 (m, 5H),
6.98 (br d, J=8.3 Hz, 4H), 6.96 (br s, 1H), 5.68 (s, 1H), 4.19-3.95
(m, 4H), 3.81 (td, J=8.7, 17.7 Hz, 1H), 2.92 (brt, J=12.7, 2H),
2.86-2.74 (m, 2H), 2.52 (d, J=8.6 Hz, 2H), 2.29-2.19 (m, 1H),
2.19-2.10 (m, 1H), 1.95-1.83 (m, 1H), 1.66 (br d, J=12.5 Hz, 2H),
1.44-1.28 (m, 2H).
Example DL-2
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(4-(trifluoromethyl)phenethy-
l)-1H-benzo[d]imidazole
##STR00418##
[1167] Step 1: methyl
2-(3-chloro-4-nitrophenyl)-2,2-bis(4-chlorophenyl)acetate
[1168] To a solution of compound methyl
2,2-bis(4-chlorophenyl)acetate (5.06 g, 17.14 mmol), prepared as
described in Example DL-1, and 2-chloro-4-fluoro-1-nitrobenzene
(3.16 g, 18.00 mmol) in THF (100 mL) at -45.degree. C. to
-40.degree. C. was added t-BuOK (1M in THF, 18.86 mL, 18.86 mmol)
over 5 minutes. The reaction was allowed to warm slowly to room
temperature and then stirred overnight. To the reaction was added
ethyl acetate and the resulting organic mixture was washed with aq
NH.sub.4Cl and brine. The organic layer was dried over MgSO.sub.4
and concentrated in vacuo to yield a red oil. The residue was
purified by silica gel chromatography using a 25-60%
dichloromethane:heptane gradient as eluent to yield methyl
2-(3-chloro-4-nitrophenyl)-2,2-bis(4-chlorophenyl)acetate as a
clear viscous oil.
Step 2:
5-(bis(4-chlorophenyl)methyl)-2-nitro-N-(4-(trifluoromethyl)phenet-
hyl)aniline
[1169] To a solution of methyl
2-(3-chloro-4-nitrophenyl)-2,2-bis(4-chlorophenyl)acetate (600 mg,
1.33 mmol) and 4-trifluoromethylphenethylamine (626 mg, 2.66 mmol)
in 1,4-dioxane (3 mL) was added diisopropylethylamine (0.574 mL,
3.33 mmol) and DBU (0.497 mL, 3.33 mmol). The resulting reaction
mixture was heated under argon at 95.degree. C. for 4 days. After
evaporation of the solvent, ethyl acetate was added to the residue
and the organic mixture was washed with water, aqueous NaHCO.sub.3,
and brine. The organic layer was evaporated in vacuo to yield a
yellow oil. The residue was purified by silica gel chromatography
to yield
5-(bis(4-chlorophenyl)methyl)-2-nitro-N-(4-(trifluoromethyl)phenethyl)ani-
line as a yellow oil.
Step 3:
5-(bis(4-chlorophenyl)methyl)-N1-(4-(trifluoromethyl)phenethyl)ben-
zene-1,2-diamine
[1170] To a solution of
5-(bis(4-chlorophenyl)methyl)-2-nitro-N-(4-(trifluoromethyl)phenethyl)ani-
line (530 mg, 0.97 mmol) in MeOH (200 mL) was added 5% Pd/C sulfide
(100 mg) and the mixture was placed under 60 psi hydrogen at room
temperature for 24 hours. The reaction mixture was filtered through
CELITE and the solvent evaporated in vacuo to yield
5-(bis(4-chlorophenyl)methyl)-N1-(4-(trifluoromethyl)phenethyl)benzene-1,-
2-diamine as a dark solid.
Step 4:
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(4-(trifluoromethyl)-
phenethyl)-1H-benzo[d]imidazole
[1171] A rapidly stirred solution of
5-(bis(4-chlorophenyl)methyl)-N1-(4-(trifluoromethyl)phenethyl)benzene-1,-
2-diamine (440 mg, 0.85 mmol) and cyclopropanecarboxaldehyde (0.13
mL, 1.71 mmol) in DMSO (2 mL) was kept at room temperature in the
presence of air for 3 days. The reaction mixture was purified by
reverse phase HPLC and the fractions containing the product were
lyophilized to yield 0.24 g of compound 2 trifluoroacetate salt as
an off-white solid. The free base of
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(4-(trifluoromethyl)phen-
ethyl)-1H-benzo[d]imidazole was prepared by partitioning the solid
between ethyl acetate and aqueous NaHCO.sub.3, separating the
organic layer, and removing the solvent in vacuo. The free base was
purified by silica gel chromatography to yield
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(4-(trifluoromethyl)pheneth-
yl)-1H-benzo[d]imidazole as a clear oil. Addition of 0.30 mL 1N HCl
in Et.sub.2O and evaporation under vacuum yielded
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(4-(trifluoromethyl)pheneth-
yl)-1H-benzo[d]imidazole as its corresponding HCl salt. MS: 565.2
(M+H.sup.+); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 7.66-7.56
(m, 3H), 7.51 (s, 1H), 7.42 (d, J=8.6 Hz, 4H), 7.36 (br d, J=7.6
Hz, 2H), 7.23 (br d, J=8.6 Hz, 1H), 7.11 (d, J=8.6 Hz, 4H), 5.83
(s, 1H), 4.77 (br t, J=6.6 Hz, 2H), 3.20 (br t, J=6.6 Hz, 2H),
2.48-2.41 (m, 1H), 1.36-1.22 (m, 4H).
Example DL-3
6-(bis(4-chlorophenyl)methyl)-2-ethyl-1-((1-((trifluoromethyl)sulfonyl)pip-
eridin-4-yl)methyl)-1H-benzo[d]imidazole
##STR00419##
[1173]
6-(Bis(4-chlorophenyl)methyl)-2-ethyl-1-((1-((trifluoromethyl)sulfo-
nyl)piperidin-4-yl)methyl)-1H-benzo[d]imidazole was prepared
according to the procedure as described in Example DL-1 above
substituting propionaldehyde for cyclobutanecarboxaldehyde in Step
5. MS: 609.9 (M+H.sup.+); .sup.1H NMR (400 MHz, DMSO-d6) .delta.:
7.79 (s, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.43-7.38 (m, 4H), 7.31 (d,
J=8.1 Hz, 1H), 7.17 (d, J=8.6 Hz, 4H), 5.88 (s, 1H), 4.34 (brd,
J=7.3 Hz, 2H), 3.79 (br d, J=13.2 Hz, 2H), 3.18 (q, J=7.5 Hz, 2H),
3.06 (br t, J=12.6, 2H), 2.12-1.99 (m, 1H), 1.64 (brd, J=11.5 Hz,
2H), 1.42 (t, J=7.5 Hz, 3H), 1.35 (br d, J=11.2 Hz, 2H).
Example DL-4
2-((1-(3-chlorohenethyl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)(4-chlorop-
henyl)methyl)thiazole
##STR00420##
[1174] Step 1: 5-chloro-N-(3-chlorophenethyl)-2-nitroaniline
[1175] To a solution of 2,4-dichloronitrobenzene (6.43 g, 32.49
mmol) and m-chlorophenethylamine (5.73 g, 35.73 mmol) in
acetonitrile (15 mL) was added a solution of triethylamine (5.418
mL, 38.98 mmol) in acetonitrile (15 mL). The reaction mixture was
stirred at room temperature overnight, heated to 50.degree. C. for
24 hours, and then heated at reflux temperature for 48 hours. The
solvent was evaporated, triethylamine (5 mL) in acetonitrile (10
mL) was added to the residue, and the reaction mixture heated at
reflux temperature for another 2 hours. Water was added (20 mL),
the resulting mixture stirred for 30 minutes, and
5-chloro-N-(3-chlorophenethyl)-2-nitroaniline was isolated by
filtrations an orange solid.
Step 2:
2-(3-((3-chlorophenethyl)amino)-4-nitrophenyl)-2-(4-chlorophenyl)a-
cetonitrile
[1176] To a stirred solution of 4-chlorophenylacetonitrile (4.34 g,
27.50 mmol) in THF (40 mL) cooled to 0.degree. C. was added t-BuOK
(1M in t-BuOH, 37.50 mL, 37.50 mmol). After 10 minutes
5-chloro-N-(3-chlorophenethyl)-2-nitroaniline (7.78 g, 25.00 mmol)
was added to the reaction mixture. The reaction mixture was allowed
to warm to room temperature and then stirred overnight. To the
thick dark solution was added THF (20 mL),
4-chlorophenylacetonitrile (0.90 g), and isopropyl alcohol (5 mL).
2N HCl (25 mL) was added and the mixture extracted with ethyl
acetate. The organic layer was washed with brine, dried over
MgSO.sub.4, and evaporated in vacuo to yield a reddish oil. The
residue was purified by silica gel chromatography using a 0-80%
dichloromethane:heptane gradient as eluent to yield
2-(3-((3-chlorophenethyl)amino)-4-nitrophenyl)-2-(4-chlorophenyl)acetonit-
rile.
Step 3:
2-(3-((3-chlorophenethyl)amino)-4-nitrophenyl)-2-(4-chlorophenyl)e-
thanethioamide
[1177] To a solution of
2-(3-((3-chlorophenethyl)amino)-4-nitrophenyl)-2-(4-chlorophenyl)acetonit-
rile (3.54 g, 8.30 mmol) in EtOH (90 mL) was added phosphorus
pentasulfide (7.38 g, 16.61 mmol) and the reaction mixture was
heated to reflux temperature for 24 hours. An additional 2.9 g of
phosphorus pentasulfide was added and the resulting mixture was
heated to reflux temperature overnight. The reaction mixture was
poured into ice water and extracted with ethyl acetate. The organic
layer was washed with water, brine, and dried over MgSO.sub.4. The
solvent was removed in vacuo and the residue was purified by silica
gel chromatography using a 50-100% dichloromethane:heptane gradient
as eluent to yield
2-(3-((3-chlorophenethyl)amino)-4-nitrophenyl)-2-(4-chlorophenyl)ethaneth-
ioamide as a red amorphous solid.
Step 4:
N-(3-chlorophenethyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-n-
itroaniline
[1178] To a solution of
2-(3-((3-chlorophenethyl)amino)-4-nitrophenyl)-2-(4-chlorophenyl)ethaneth-
ioamide (3.45 g, 7.49 mmol) in acetic acid (40 mL) was added water
(1.5 mL) and bromoacetaldehyde diethylacetal (4.65 mL, 29.98 mmol).
The reaction mixture was heated to 100.degree. C. for 30 minutes
and then poured into water (200 mL) and the resulting mixture was
extracted with ethyl ether. The organic layer was washed with water
(4.times.), saturated NaHCO.sub.3, and brine and then dried over
MgSO.sub.4. Removal of the solvent in vacuo a residue, which was
purified by silica gel chromatography using a 50-100%
dichloromethane:heptane gradient to yield
N-(3-chlorophenethyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nitroani-
lineas a red oil.
Step 5:
N1-(3-chlorophenethyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)ben-
zene-1,2-diamine
[1179] To a 10 mL graduated cylinder was added 8 mL of Raney nickel
(50% slurry in water). The catalyst was washed twice with EtOH and
the solvent decanted. The catalyst was washed into a hydrogenation
flask with ethyl alcohol (60 mL) under an argon atmosphere and
additional ethyl alcohol (48 mL) was added.
N-(3-chlorophenethyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nitroani-
line (2.61 g, 5.39 mmol) dissolved in THF (24 mL) was added to
flask and the reaction mixture was placed under a hydrogen
atmosphere for 72 hours. The catalyst was filtered off and the
filtrate was evaporated in vacuo to yield a residue. Purification
by silica gel chromatography using a 0-2% 1:1 MeOH:DCM/DCM gradient
yielded
NI-(3-chlorophenethyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)benzene-1,-
2-diamine as a light red oil.
Step 6:
2-((1-(3-chlorophenethyl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)(-
4-chlorophenyl)methyl)thiazole
[1180] A rapidly stirred solution of
N1-(3-chlorophenethyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)benzene-1,-
2-diamine (100 mg, 0.22 mmol) and cyclopropanecarboxaldehyde (0.034
mL, 0.44 mmol) in DMSO (1 mL) was kept at room temperature in the
presence of air for 24 hours. The reaction mixture was purified by
reverse phase HPLC and the fractions containing the product were
lyophilized to yield
2-((1-(3-chlorophenethyl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)(4-chlor-
ophenyl)methyl)thiazoletrifluoroacetate salt as a white solid. MS:
504.0 (M+H.sup.+); .sup.1H NMR (400 MHz, DMSO-d6) .delta.:
7.95-7.81 (m, 1H), 7.79-7.71 (m, 2H), 7.65 (br d, J=8.6 Hz, 1H),
7.49-7.38 (m, 3H), 7.36-7.29 (m, 3H), 7.25 (br d, J=3.9 Hz, 2H),
7.13-7.06 (m, 1H), 6.18 (s, 1H), 4.74 (br t, J=6.7 Hz, 2H), 3.13
(br t, J=6.8 Hz, 2H), 2.48-2.41 (m, 1H), 1.35-1.18 (m, 4H).
Example DL-5
6-(bis(4-chlorophenyl)methyl)-1-(3-chlorophenethyl)-2-ethyl-1H-benzo[d]imi-
dazole
##STR00421##
[1181] Step 1: methyl
2-(3-((3-chlorophenethyl)amino)-4-nitrophenyl)-2,2-bis(4-chlorophenyl)ace-
tate
[1182] To a solution of methyl
2-(3-chloro-4-nitrophenyl)-2,2-bis(4-chlorophenyl)acetate (400 mg,
0.89 mmol), prepared as described in Example DL-2 above, and
potassium fluoride (258 mg, 4.44 mmol) in acetonitrile (4 mL) was
added m-chlorophenethylamine (0.19 mL, 1.33 mmol) and
diisopropylethylamine (0.31 mL, 1.78 mmol) and the resulting
mixture placed under an argon atmosphere. The reaction mixture was
heated to reflux temperature for 72 hours. An additional 0.191 mL
of m-chlorophenethylamine was added and the reaction mixture was
heated to reflux temperature for an additional 48 hours. The
solvent was evaporated in vacuo, water was added to the residue,
and the mixture was extracted with ethyl acetate. The organic layer
was washed with water and brine and then dried over
Na.sub.2SO.sub.4. Evaporation of the solvent in vacuo yielded a
residue as a reddish oil, which was purified by silica gel
chromatography using a 30-70% dichloromethane: heptane gradient to
yield methyl
2-(3-((3-chlorophenethyl)amino)-4-nitrophenyl)-2,2-bis(4-chlorophenyl)ace-
tate as a yellow solid.
Step 2: methyl
2-(4-amino-3-((3-chlorophenethyl)amino)phenyl)-2,2-bis(4-chlorophenyl)ace-
tate
[1183] To a solution of methyl
2-(3-((3-chlorophenethyl)amino)-4-nitrophenyl)-2,2-bis(4-chlorophenyl)ace-
tate (200 mg, 0.35 mmol) in MeOH (100 mL) was added Raney nickel
catalyst (100 mg, 1.70 mmol) and the mixture was placed under 35
psi hydrogen and left overnight. The reaction mixture was filtered
through CELITE and the solvent evaporated in vacuo to yield methyl
2-(4-amino-3-((3-chlorophenethyl)amino)phenyl)-2,2-bis(4-chlorophenyl)ace-
tate.
Step 3: methyl
2-(1-(3-chlorophenethyl)-2-ethyl-1H-benzo[d]imidazol-6-yl)-2,2-bis(4-chlo-
rophenyl)acetate
[1184] A solution of methyl
2-(4-amino-3-((3-chlorophenethyl)amino)phenyl)-2,2-bis(4-chlorophenyl)ace-
tate (200 mg, 0.37 mmol) and propionaldehyde (0.055 mL, 0.74 mmol)
in DMSO (2 mL) was stirred at room temperature in the presence of
air for 3 days. The reaction mixture was purified by reverse phase
HPLC and lyophilized to yield methyl
2-(1-(3-chlorophenethyl)-2-ethyl-1H-benzo[d]imidazol-6-yl)-2,2-bis(4-chlo-
rophenyl)acetate as a white solid.
Step 4:
2-(1-(3-chlorophenethyl)-2-ethyl-1H-benzo[d]imidazol-6-yl)-2,2-bis-
(4-chlorophenyl)acetic acid
[1185] A solution of methyl
2-(1-(3-chlorophenethyl)-2-ethyl-1H-benzo[d]imidazol-6-yl)-2,2-bis(4-chlo-
rophenyl)acetate (120 mg, 0.21 mmol) in 3N NaOH aqueous solution
(2.04 mL, 6.13 mmol) and methanol (8 mL) was heated at 45.degree.
C. overnight. The solvent was removed in vacuo and then water and 6
mL 1N HCl was added. The mixture was extracted with ethyl acetate
and the organic layer was dried over MgSO.sub.4 and evaporated in
vacuo to yield
2-(1-(3-chlorophenethyl)-2-ethyl-1H-benzo[d]imidazol-6-yl)-2,2-bis(4-chlo-
rophenyl)acetic acid as a yellow oil.
Step 5:
6-(bis(4-chlorophenyl)methyl)-1-(3-chlorophenethyl)-2-ethyl-1H-ben-
zo[d]imidazole
[1186] A solution of
2-(1-(3-chlorophenethyl)-2-ethyl-1H-benzo[d]imidazol-6-yl)-2,2-bis(4-chlo-
rophenyl)acetic acid (100 mg, 0.18 mmol) and DBU (0.11 mL, 0.71
mmol) in toluene (10 mL) was heated at 90.degree. C. overnight
under argon. An additional 0.104 mL of DBU was added and the
reaction mixture was heated at 90.degree. C. for another 3 hours.
After evaporation of the solvent, the residue was purified by
reverse phase HPLC and the fractions containing the product were
lyophilized to yield
6-(bis(4-chlorophenyl)methyl)-1-(3-chlorophenethyl)-2-ethyl-1H-benzo[d]im-
idazoletrifluoroacetate salt as a white solid. MS: 520.8
(M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.81 (d,
J=8.6 Hz, 1H), 7.37-7.29 (m, 5H), 7.25-7.20 (m, 1H), 7.20-7.15 (m,
1H), 7.01 (t, J=1.8 Hz, 1H), 6.99-6.93 (m, 4H), 6.89 (s, 1H), 6.67
(d, J=7.6 Hz, 1H), 5.63 (s, 1H), 4.39 (t, J=6.8 Hz, 2H), 3.04 (t,
J=6.6 Hz, 2H), 2.93 (q, J=7.6, 2H), 1.41 (t, J=7.3 Hz, 3H).
Example DL-6
bis(4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)piperidi-
n-4-yl)-1H-benzo[d]imidazol-6-yl)methanol
##STR00422##
[1188] To a solution of
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-((trifluoromethyl)sulfon-
yl)piperidin-4-yl)-1H-benzo[d]imidazole hydrochloride salt (130 mg,
0.202 mmol) in DMSO (6 mL) was added 3N NaOH (0.4 mL) and the
reaction mixture was stirred in air for 72 hours. Water was added
and the mixture was extracted with ethyl acetate. The organic layer
was evaporated in vacuo, the residue purified by reverse phase
HPLC, and fractions containing the product were lyophilized to
yield
bis(4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)piperid-
in-4-yl)-1H-benzo[d]imidazol-6-yl)methanol as a white solid. MS:
624.1 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.84
(s, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.32-7.28 (m, 4H), 7.26-7.22 (m,
1H), 7.19-7.14 (m, 4H), 4.88 (ddd, J=4.0, 8.6, 12.6 Hz, 1H), 4.24
(br d, J=13.6 Hz, 2H), 3.31 (br t, J=12.1 Hz, 2H), 2.55 (dq, J=4.8,
12.7 Hz, 2H), 2.21-2.10 (m, 3H), 1.57-1.49 (m, 2H), 1.49-1.37 (m,
2H).
Example DL-7
6-(bis(4-chlorophenyl)methyl)-2-ethyl-1-(4-(trifluoromethyl)phenethyl)-1H--
benzo[d]imidazole
##STR00423##
[1189] Step 1: methyl
2,2-bis(4-chlorophenyl)-2-(4-nitro-3-((4-(trifluoromethyl)phenethyl)amino-
)phenyl)acetate
[1190] A solution of compound methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate (100 mg,
0.23 mmol), prepared as described in Example DL-2 above,
p-trifluoromethylphenethylamine hydrochloride (90.5 mg, 0.35 mmol),
and potassium carbonate (95.5 mg, 0.69 mmol) in DMSO (1 mL) was
degassed with nitrogen and heated at 80.degree. C. overnight. Ethyl
ether was added and the mixture was washed with water and brine.
The solvent was removed in vacuo to yield a yellow semi-solid,
which was purified by reverse phase HPLC and fractions containing
the product were lyophilized to yield methyl
2,2-bis(4-chlorophenyl)-2-(4-nitro-3-((4-(trifluoromethyl)phenethy-
l)amino)phenyl)acetate as a yellow oil.
Step 2: methyl
2-(4-amino-3-((4-(trifluoromethyl)phenethyl)amino)phenyl)-2,2-bis(4-chlor-
ophenyl)acetate
[1191] To a solution of methyl
2,2-bis(4-chlorophenyl)-2-(4-nitro-3-((4-(trifluoromethyl)phenethyl)amino-
)phenyl)acetate (100 mg, 0.17 mmol) in MeOH (100 mL) was added
Raney nickel catalyst (200 mg, 3.41 mmol) and the mixture was
placed under 30 psi hydrogen at room temperature for 4 hours. The
reaction mixture was filtered through CELITE and the solvent
evaporated in vacuo to yield methyl
2-(4-amino-3-((4-(trifluoromethyl)phenethyl)amino)phenyl)-2,2-bis(-
4-chlorophenyl)acetate as a white solid.
Step 3: methyl
2,2-bis(4-chlorophenyl)-2-(2-ethyl-1-(4-(trifluoromethyl)phenethyl)-1H-be-
nzo[d]imidazol-6-yl)acetate
[1192] A solution of methyl
2-(4-amino-3-((4-(trifluoromethyl)phenethyl)amino)phenyl)-2,2-bis(4-chlor-
ophenyl)acetate (40 mg, 0.07 mmol) and propionaldehyde (0.01 mL,
0.14 mmol) in DMSO (0.5 mL) was rapidly stirred at room temperature
in the presence of air overnight. An additional 0.015 mL of
propionaldehyde was added and the reaction mixture rapidly stirred
overnight. The reaction mixture was purified by reverse phase HPLC
and the fractions containing product were lyophilized to yield
methyl
2,2-bis(4-chlorophenyl)-2-(2-ethyl-1-(4-(trifluoromethyl)phenethyl)-1H-be-
nzo[d]imidazol-6-yl)acetate.
Step 4:
2,2-bis(4-chlorophenyl)-2-(2-ethyl-1-(4-(trifluoromethyl)phenethyl-
)-1H-benzo[d]imidazol-6-yl)acetic acid
[1193] A solution of methyl
2,2-bis(4-chlorophenyl)-2-(2-ethyl-1-(4-(trifluoromethyl)phenethyl)-1H-be-
nzo[d]imidazol-6-yl)acetate (50 mg, 0.08 mmol) in 3N NaOH aqueous
solution (1 mL, 3 mmol) and methanol (4 mL) was heated at
45.degree. C. overnight. 2N HCl (1.5 mL) was added and the mixture
was extracted with ethyl acetate. The organic layer was evaporated
in vacuo to yield a first batch of
2,2-bis(4-chlorophenyl)-2-(2-ethyl-1-(4-(trifluoromethyl)phenethyl)-1H-
-benzo[d]imidazol-6-yl)acetic acid. The aqueous layer was also
evaporated in vacuo. The residue was washed with acetonitrile, the
solvent was decanted, and then evaporated to yield additional
2,2-bis(4-chlorophenyl)-2-(2-ethyl-1-(4-(trifluoromethyl)phenethyl)-1H-be-
nzo[d]imidazol-6-yl)acetic acid.
Step 5:
6-(bis(4-chlorophenyl)methyl)-2-ethyl-1-(4-(trifluoromethyl)phenet-
hyl)-1H-benzo[d]imidazole
[1194] A solution of
2,2-bis(4-chlorophenyl)-2-(2-ethyl-1-(4-(trifluoromethyl)phenethyl)-1H-be-
nzo[d]imidazol-6-yl)acetic acid (30 mg, 0.05 mmol) and DBU (0.017
mL, 0.12 mmol) in toluene (2 mL) was heated at 90.degree. C. for 3
hours under argon. An additional 34.6 .mu.L of DBU was added and
the reaction mixture was heated at reflux temperature overnight.
After evaporation of the solvent, the residue was purified by
reverse phase HPLC and the fractions containing the product were
lyophilized to yield
6-(bis(4-chlorophenyl)methyl)-2-ethyl-1-(4-(trifluoromethyl)phenethyl)-1H-
-benzo[d]imidazole trifluoroacetate salt as a clear oil. MS: 552.9
(M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.89 (d,
J=8.6 Hz, 1H), 7.56 (d, J=8.1 Hz, 2H), 7.33-7.28 (m, 5H), 7.03 (d,
J=7.8 Hz, 2H), 6.97 (d, J=8.6 Hz, 4H), 6.88 (s, 1H), 5.64 (s, 1H),
4.38 (t, J=7.2 Hz, 2H), 3.10 (br t, J=7.1 Hz, 2H), 2.94 (q, J=7.7
Hz, 2H), 1.41 (t, J=7.6 Hz, 3H).
Example DL-8
2-((4-chlorophenyl
1-(3-chlorophenyl)-2-ethyl-1H-benzo[d]imidazol-6-yl)methyl)thiazole
##STR00424##
[1195] Step 1: 5-chloro-N-(3-chlorophenyl)-2-nitroaniline
[1196] To a solution of 2,4-dichloronitrobenzene (7 g, 35.36 mmol)
and m-chloroaniline (4.13 mL, 38.90 mmol) in DMSO (2 mL) was added
diisopropylethylamine (7.31 mL, 42.44 mmol). The reaction mixture
was heated at 120.degree. C. for 10 days. Water was added and the
resulting mixture was extracted with ethyl ether. The organic layer
was washed with brine and dried over Na.sub.2SO.sub.4. The solvent
was removed in vacuo to yield a red oil. The oil was heated with
heptane and the solvent decanted (3.times.). Dichloromethane was
added to make it homogenous and the resulting orange solution was
purified by silica gel chromatography using a 0-40%
dichloromethane:heptane gradient to yield
5-chloro-N-(3-chlorophenyl)-2-nitroaniline as an orange solid.
Step 2:
2-(4-chlorophenyl)-2-(3-((3-chlorophenyl)amino)-4-nitrophenyl)acet-
onitrile
[1197] To a stirred solution of 4-chlorophenylacetonitrile (2.20 g,
13.90 mmol) in THF (75 mL) and isopropyl alcohol (25 mL) cooled to
0.degree. C. was added t-BuOK (1M in t-BuOH, 23.17 mL, 23.17 mmol).
After 10 minutes 5-chloro-N-(3-chlorophenyl)-2-nitroaniline (3.28
g, 11.59 mmol) was added to the reaction mixture. The reaction
mixture was allowed to warm to room temperature, stirred for 1.5
hours at room temperature, and then heated at 50.degree. C.
overnight. 1M HCl in ethyl ether (30 mL) was added and the solvent
evaporated in vacuo. The residue was dissolved in ethyl acetate and
the organic mixture washed with NaHCO.sub.3 and brine, and then
dried over Na.sub.2SO.sub.4. The solvent was evaporated in vacuo
and the residue purified by silica gel chromatography using a
25-75% dichloromethane:heptane gradient to yield
2-(4-chlorophenyl)-2-(3-((3-chlorophenyl)amino)-4-nitrophenyl)acetonitril-
e as a red oil.
Step 3:
2-(4-chlorophenyl)-2-(3-((3-chlorophenyl)amino)-4-nitrophenyl)etha-
nethioamide
[1198] To a solution of
2-(4-chlorophenyl)-2-(3-((3-chlorophenyl)amino)-4-nitrophenyl)acetonitril-
e (3.4 g, 8.53 mmol) in EtOH (85 mL) under argon was added
phosphorus pentasulfide (7.59 g, 17.08 mmol) and the reaction
mixture was heated to reflux temperature for 24 hours. The reaction
mixture was poured into ice water and extracted with ethyl acetate
(2.times.). The organic layer was dried over Na.sub.2SO.sub.4. The
solvent was removed in vacuo and the residue was purified by silica
gel chromatography using a 50-100% dichloromethane:heptane gradient
as eluent to yield
2-(4-chlorophenyl)-2-(3-((3-chlorophenyl)amino)-4-nitrophenyl)ethanethioa-
mide as a red amorphous solid.
Step 4:
N-(3-chlorophenyl)-5-((4-chlorophenyl)(thiazol-2-yl)(methyl)-2-nit-
roaniline
[1199] To a solution of
2-(4-chlorophenyl)-2-(3-((3-chlorophenyl)amino)-4-nitrophenyl)ethanethioa-
mide (4.55 g, 10.52 mmol) in acetic acid (50 mL) was added water (2
mL) and bromoacetaldehyde diethylacetal (6.53 mL, 42.10 mmol). The
reaction mixture was heated at 100.degree. C. for 30 minutes and
then poured into water (200 mL) and the resulting mixture was
extracted with ethyl acetate. The organic layer was washed with
water, saturated NaHCO.sub.3, and brine and then dried over
MgSO.sub.4. Removal of the solvent in vacuo yielded
N-(3-chlorophenyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nit-
roaniline as a red oil.
Step 5:
N1-(3-chlorophenyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)benzen-
e-1,2-diamine
[1200] To a 10 mL graduated cylinder was added 6 mL of Raney nickel
(50% slurry in water). The catalyst was washed with EtOH and the
solvent decanted. The catalyst was washed into a hydrogenation
flask with ethyl alcohol (30 mL).
N-(3-chlorophenyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nitroanilin-
e (4.37 g, 9.58 mmol) dissolved in EtOH (120 mL) and THF (24 mL)
was added to flask and the reaction mixture was placed under a
hydrogen atmosphere for 2 hours. The catalyst was filtered off and
the filtrate was evaporated in vacuo to yield
N1-(3-chlorophenyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)benzene-1,2-d-
iamine as a tan foam.
Step 6:
2-((4-chlorophenyl)(1-(3-chlorophenyl)-2-ethyl-1H-benzo[d]imidazol-
-6-yl)methyl)thiazole
[1201] A solution of
N1-(3-chlorophenyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)benzene-1,2-d-
iamine (100 mg, 0.24 mmol) and propionaldehyde (0.035 mL, 0.47
mmol) in DMSO (1 mL) was rapidly stirred at room temperature in the
presence of air for 72 hours. Acetonitrile (0.5 mL) was added and
the reaction mixture was purified by reverse phase HPLC. The
fractions containing the product were lyophilized to yield
2-((4-chlorophenyl)(1-(3-chlorophenyl)-2-ethyl-1H-benzo[d]imidazol-6-yl)m-
ethyl)thiazole trifluoroacetate salt as a gummy gray solid. MS:
464.1 (M+H.sup.+); .sup.1H NMR (400 MHz, DMSO-d6) .delta.:
7.85-7.83 (m, 1H), 7.83-7.78 (m, 2H), 7.78-7.71 (m, 2H), 7.67 (d,
J=3.4 Hz, 1H), 7.66-7.63 (m, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.42-7.34
(m, 3H), 7.34-7.27 (m, 2H), 6.23 (s, 1H), 2.87 (q, J=7.3 Hz, 2H),
1.27 (t, J=7.6 Hz, 3H).
Example DL-9
(R)-2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)-1-phenylethanol
##STR00425##
[1202] Step 1: methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate
[1203] To a solution of methyl 2,2-bis(4-chlorophenyl)acetate (1.92
g, 6.51 mmol), prepared as described in Example DL-1 above, and
2,4-difluoro-1-nitrobenzene (0.76 mL, 6.83 mmol) in THF (40 mL) at
-60.degree. C. to -50.degree. C. was added LHMDS (1M in THF, 7.2
mL, 7.2 mmol) over 10 minutes. The reaction was allowed to warm
slowly to room temperature and then stirred overnight. To the
reaction was added ethyl ether and the resulting organic mixture
was washed with water, aq NH.sub.4Cl, and brine. The organic layer
was dried over MgSO.sub.4 and concentrated in vacuo to yield a
yellow oil. The residue was purified by silica gel chromatography
with a 0-70% dichloromethane:heptane gradient as eluent to yield
methyl 2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate as
a pale yellow oil.
Step 2: (R)-methyl
2,2-bis(4-chlorophenyl)-2-(3-((2-hydroxy-2-phenylethyl)amino)-4-nitrophen-
yl)acetate
[1204] A solution of methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate (300 mg,
0.69 mmol), (R)-2-amino-1-phenylethanol (126.4 mg, 0.83 mmol), and
DIPEA (0.238 mL, 1.38 mmol) in acetonitrile (3 mL) was heated at
reflux temperature for 48 hours. The solvent was removed in vacuo
and the residue was purified by silica gel chromatography with 0-2%
methanol:dichloromethane gradient as eluent to yield (R)-methyl
2,2-bis(4-chlorophenyl)-2-(3-((2-hydroxy-2-phenylethyl)amino)-4-nitrophen-
yl)acetate as a yellow oil.
Step 3: (R)-methyl
2-(4-amino-3-((2-hydroxy-2-phenylethyl)amino)phenyl)-2,2-bis(4-chlorophen-
yl)acetate
[1205] To a solution of (R)-methyl
2,2-bis(4-chlorophenyl)-2-(3-((2-hydroxy-2-phenylethyl)amino)-4-nitrophen-
yl)acetate (260 mg, 0.47 mmol) in MeOH (100 mL) was added 5% Pd/C
sulfide (100 mg) and the mixture was placed under 45 psi hydrogen
at room temperature for 3 hours. The reaction mixture was filtered
through CELITE and the solvent evaporated in vacuo to yield
(R)-methyl
2-(4-amino-3-((2-hydroxy-2-phenylethyl)amino)phenyl)-2,2-bis(4-chlorophen-
yl)acetate as a yellowish oil.
Step 4: (R)-methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-(2-hydroxy-2-phenylethyl)-1H-b-
enzo[d]imidazol-6-yl)acetate
[1206] A solution of (R)-methyl
2-(4-amino-3-((2-hydroxy-2-phenylethyl)amino)phenyl)-2,2-bis(4-chlorophen-
yl)acetate (220 mg, 0.42 mmol) and cyclopropanecarboxaldehyde
(59.14 mg, 0.84 mmol) in DMSO (2 mL) was rapidly stirred at room
temperature in the presence of air overnight. An additional 0.015
mL of propionaldehyde was added and the reaction mixture rapidly
stirred overnight. Ethyl acetate was added and the organic mixture
was washed with water and brine. The organic layer was dried over
MgSO.sub.4 and evaporated in vacuo to yield a residue as a dirty
yellow oil. The reaction mixture was purified by silica gel
chromatography to yield (R)-methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-(2-hydroxy-2-phenylethyl)-1H-b-
enzo[d]imidazol-6-yl)acetate.
Step 5:
(R)-2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-(2-hydroxy-2-phenyl-
ethyl)-1H-benzo[d]imidazol-6-yl)acetic acid
[1207] A solution of (R)-methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-(2-hydroxy-2-phenylethyl)-1H-b-
enzo[d]imidazol-6-yl)acetate (160 mg, 0.28 mmol) in 3N NaOH aqueous
solution (1 mL, 3 mmol) and methanol (4 mL) was stirred under argon
for 5 days at 65.degree. C. The methanol was evaporated and then
water, 1N HCl, and 0.5 mL DBU were added. The mixture was extracted
with dichloromethane, the organic layer separated, and the solvent
evaporated to yield
(R)-2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-(2-hydroxy-2-phen-
ylethyl)-1H-benzo[d]imidazol-6-yl)acetic acid.
Step 6:
(R)-2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imid-
azol-1-yl)-1-phenylethanol
[1208] A solution of
(R)-2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-(2-hydroxy-2-phenylethyl)--
1H-benzo[d]imidazol-6-yl)acetic acid (155 mg, 0.28 mmol) and DBU
(0.5 mL, 3.35 mmol) in toluene (10 mL) was heated at 90.degree. C.
overnight under argon. After evaporation of the solvent, the
residue was purified by silica gel chromatography with a 0-2%
methanol:dichloromethane gradient as eluent to yield 0.07 g of a
white solid. The solid was heated in acetonitrile, cooled, and
filtered to yield
(R)-2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)-1-phenylethanol as a white solid. MS: 513.2 (M+H.sup.+);
.sup.1H NMR (400 MHz, DMSO-de) .delta.: 7.43-7.34 (m, 5H),
7.34-7.22 (m, 5H), 7.16-7.07 (m, 4H), 7.01 (s, 1H), 6.84 (br d,
J=8.3 Hz, 1H), 5.76-5.69 (m, 2H), 4.88-4.81 (m, 1H), 4.34 (br dd,
J=7.7, 14.5 Hz, 1H), 4.24 (br dd, J=4.0, 14.5 Hz, 1H), 2.26-2.18
(m, 1H), 1.10-1.03 (m, 1H), 0.99 (q, J=8.2 Hz, 2H), 0.91-0.81 (m,
1H).
Example DL-10
(R)-6-(bis(4-chlorophenyl)methyl)-2-ethyl-1-(2-phenylpropyl)-1H-benzo[d]im-
idazole
##STR00426##
[1210]
(R)-6-(bis(4-chlorophenyl)methyl)-2-ethyl-1-(2-phenylpropyl)-1H-ben-
zo[d]imidazole was prepared according to the procedure as described
in Example DL-7 above substituting (R)-2-phenyl-1-propylamine for
p-trifluoromethylphenethylamine hydrochloride in step 1. MS: 499.0
(M+H.sup.+); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 7.67 (d,
J=8.6 Hz, 1H), 7.45 (br s, 1H), 7.43 (dd, J=1.2, 8.6 Hz, 4H),
7.24-7.14 (m, 4H), 7.14-7.08 (m, 6H), 5.83 (s, 1H), 4.56 (dd,
J=6.6, 14.7 Hz, 1H), 4.45 (dd, J=8.6, 14.4 Hz, 1H), 3.25-3.15 (m,
1H), 3.12-3.01 (m, 1H), 2.96-2.85 (m, 1H), 1.35-1.25 (m, 6H).
Example DL-11
6-(bis(4-chlorophenyl)methyl)-2-ethyl-1-(1-phenylpropan-2-yl)-1H-benzo[d]i-
midazole
##STR00427##
[1212]
6-(Bis(4-chlorophenyl)methyl)-2-ethyl-1-(1-phenylpropan-2-yl)-1H-be-
nzo[d]imidazole was prepared according to the procedure as
described in Example DL-9 above substituting 1-phenylpropan-2-amine
for (R)-2-amino-1-phenylethanol in step 2 and propionaldehyde for
cyclopropanecarboxaldehyde in step 4. MS: 533.1 (M+H.sup.+).
Example DL-13
(S)-2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-y-
l)-1-phenylethanol
##STR00428##
[1213] Step 1: (S)-methyl
2,2-bis(4-chlorophenyl)-2-(3-((2-hydroxy-2-phenylethyl)amino)-4-nitrophen-
yl)acetate
[1214] A solution of methyl
2-(3-chloro-4-nitrophenyl)-2,2-bis(4-chlorophenyl)acetate (200 mg,
0.44 mmol), prepared as described in Example DL-2 above,
(S)-2-amino-1-phenylethanol (126 mg, 0.89 mmol), and DIPEA (0.229
mL, 1.33 mmol) in 1,4-dioxane (2 mL) was heated under argon at
95.degree. C. for 4 days. Ethyl acetate was added and the organic
mixture was washed with water and brine and then dried over
Na.sub.2SO.sub.4. The solvent was evaporated in vacuo and the
yellow oily residue was purified by silica gel chromatography to
yield (S)-methyl
2,2-bis(4-chlorophenyl)-2-(3-((2-hydroxy-2-phenylethyl)amino)-4-nitrophen-
yl)acetateas a yellow oil.
Step 2: (S)-methyl
2-(4-amino-3-((2-hydroxy-2-phenylethyl)amino)phenyl)-2,2-bis(4-chlorophen-
yl)acetate
[1215] To a solution of (S)-methyl
2,2-bis(4-chlorophenyl)-2-(3-((2-hydroxy-2-phenylethyl)amino)-4-nitrophen-
yl)acetate (100 mg, 0.18 mmol) in MeOH (200 mL) was added 5% Pd/C
sulfide (65 mg) and the mixture was placed under 50 psi hydrogen at
room temperature for 4.5 hours. The reaction mixture was filtered
through CELITE and the solvent evaporated in vacuo to yield
(S)-methyl
2-(4-amino-3-((2-hydroxy-2-phenylethyl)amino)phenyl)-2,2-bis(4-chlorophen-
yl)acetate as a white oil.
Step 3: (S)-methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-(2-hydroxy-2-phenylethyl)-1H-b-
enzo[d]imidazol-6-yl)acetate
[1216] A solution of (S)-methyl
2-(4-amino-3-((2-hydroxy-2-phenylethyl)amino)phenyl)-2,2-bis(4-chlorophen-
yl)acetate (100 mg, 0.19 mmol) and cyclopropanecarboxaldehyde
(0.029 mL, 0.38 mmol) in DMSO (1 mL) was rapidly stirred at room
temperature in the presence of air for 2 days. The reaction mixture
was purified by reverse phase HPLC. Fractions containing the
desired product were combined and lyophilized to yield (S)-methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-(2-hydroxy-2-phenylethyl)-1H-b-
enzo[d]imidazol-6-yl)acetate as a white solid.
Step 4:
(S)-2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-(2-hydroxy-2-phenyl-
ethyl)-1H-benzo[d]imidazol-6-yl)acetic acid
[1217] A solution of (S)-methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-(2-hydroxy-2-phenylethyl)-1H-b-
enzo[d]imidazol-6-yl)acetate (75 mg, 0.11 mmol) in 3N NaOH aqueous
solution (2 mL, 6 mmol) and methanol (8 mL) was stirred under argon
overnight at 40.degree. C. The temperature of the reaction mixture
was increased to 50.degree. C. and the reaction was stirred for
another day. 1N HCl was added and the methanol was evaporated in
vacuo. Water and 0.5 mL DBU were added and the mixture was
extracted with dichloromethane. The organic layer was separated and
the solvent evaporated to yield
(S)-2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-(2-hydroxy-2-phenylethyl)--
1H-benzo[d]imidazol-6-yl)acetic acid as a clear oil.
Step 5:
(S)-2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imid-
azol-1-yl)-1-phenylethanol
[1218] A solution of
(S)-2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-(2-hydroxy-2-phenylethyl)--
1H-benzo[d]imidazol-6-yl)acetic acid (60.77 mg, 0.11 mmol) and DBU
(0.08 mL, 0.55 mmol) in toluene (10 mL) was heated at 90.degree. C.
overnight under argon. After evaporation of the solvent, the
residue was purified by reverse phase HPLC to yield
(S)-2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)-1-phenylethanol as a white solid. MS: 513.2 (M+H.sup.+);
.sup.1H NMR (400 MHz, DMSO-d6) .delta.: 7.63 (d, J=8.6 Hz, 1H),
7.48 (s, 1H), 7.43 (dd, J=6.3, 8.3 Hz, 4H), 7.35 (d, J=4.0 Hz, 4H),
7.32-7.26 (m, 1H), 7.24 (br d, J=8.6 Hz, 1H), 7.14 (dd, J=3.8, 8.3
Hz, 4H), 5.87 (s, 1H), 4.95 (dd, J=3.8, 7.8 Hz, 1H), 4.67-4.51 (m,
2H), 2.64-2.55 (m, 1H), 1.34 (br d, J=6.1 Hz, 3H), 1.25 (br s,
1H).
Example DL-14
2-((1-(3-chlorophenethyl)-2-ethyl-1H-benzo[d]imidazol-6-yl)(4-chlorophenyl-
)methyl)thiazole
##STR00429##
[1220]
2-((1-(3-Chlorophenethyl)-2-ethyl-1H-benzo[d]imidazol-6-yl)(4-chlor-
ophenyl)methyl)thiazole was prepared according to the procedure as
described in Example DL-4 above substituting propionaldehyde for
cyclopropanecarboxaldehyde in Step 6. MS: 492.0 (M+H.sup.+);
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 7.86 (d, J=3.4 Hz,
1H), 7.81-7.72 (m, 3H), 7.48 (d, J=8.6 Hz, 1H), 7.44 (d, J=8.6 Hz,
2H), 7.36-7.29 (m, 3H), 7.29-7.23 (m, 2H), 7.16-7.09 (m, 1H), 6.19
(s, 1H), 4.70-4.58 (m, 2H), 3.15-3.03 (m, 4H), 1.32 (t, J=7.5 Hz,
3H).
Example DL-15
(S)-6-(bis(4-chlorophenyl)methyl)-2-ethyl-1-(2-phenylpropyl)-1H-benzo[d]im-
idazole
##STR00430##
[1222]
(S)-6-(Bis(4-chlorophenyl)methyl)-2-ethyl-1-(2-phenylpropyl)-1H-ben-
zo[d]imidazole was prepared according to the procedure as described
in Example DL-7 above substituting (S)-2-phenyl-1-propylamine for
p-trifluoromethylphenethylamine hydrochloride in Step 1. MS: 498.9
(M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.80 (d,
J=8.6 Hz, 1H), 7.34-7.28 (m, 4H), 7.28-7.21 (m, 4H), 6.96 (d, J=8.1
Hz, 4H), 6.92-6.81 (m, 3H), 5.63 (s, 1H), 4.30 (dd, J=5.6, 14.7 Hz,
1H), 4.15 (dd, J=8.8, 14.4 Hz, 1H), 3.20-3.10 (m, 1H), 2.79 (td,
J=7.6, 15.5 Hz, 1H), 2.74-2.63 (m, 1H), 1.42 (d, J=7.1 Hz, 3H),
1.33 (t, J=7.6 Hz, 3H).
Example DL-16
2-((1-(4-chlorophenethyl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)(4-chloro-
phenyl)methyl)thiazole
##STR00431##
[1223] Step 1:
2-(3-amino-4-nitrophenyl)-2-(4-chlorophenyl)acetonitrile
[1224] To a stirred solution of 4-chlorophenylacetonitrile (6.46 g,
40.89 mmol) in THF (100 mL) cooled to 0.degree. C. was added t-BuOK
(1M in THF, 74.97 mL, 23.17 mmol). After 10 minutes
5-fluoro-2-nitroaniline (3.28 g, 11.59 mmol) was added to the
reaction mixture. The reaction mixture was allowed to warm to room
temperature and stirred overnight at room temperature. THF (25 mL)
was added and saturated NH.sub.4Cl was added until the deep purple
color disappeared. The mixture was extracted with ethyl ether and
the organic layer was washed with brine and dried over MgSO.sub.4.
The solvent was removed in vacuo to yield
2-(3-amino-4-nitrophenyl)-2-(4-chlorophenyl)acetonitrile as a red
oil. The oil was dissolved in 40 mL of 3:2 dichloromethane:heptane
and the resulting yellow precipitate was collected by filtration
(7.63 g). The filtrate was evaporated and the residue was purified
by silica gel chromatography eluting with a 75%
dichloromethane:heptane to 100% dichloromethane gradient to yield
additional
2-(3-amino-4-nitrophenyl)-2-(4-chlorophenyl)acetonitrile.
Step 2: (3-chloro-4-nitrophenyl)(4-chlorophenyl)methanone
[1225] To a solution of CuCl.sub.2 (5.18 g, 38.54 mmol) and
t-butylnitrite (6.55 mL, 49.56 mmol) in CH.sub.3CN (160 mL) heated
to 65.degree. C. was added
2-(3-amino-4-nitrophenyl)-2-(4-chlorophenyl)acetonitrile (7.92 g,
27.53 mmol). The reaction mixture was heated at 65.degree. C. for 2
hours with the argon atmosphere maintained over the reaction by
bubbling the gas through a mixture of 3N NaOH/bleach. An additional
amount of t-butylnitrite was added (1.45 mL) and the reaction
mixture was heated overnight. The reaction was cooled in ice and
300 mL of 2N HCl was added. The mixture was extracted with ethyl
ether and the organic layer was washed with water, brine, and then
dried over MgSO.sub.4. The solvent was evaporated to yield a
residue as a yellow solid. The solid was recrystallized with
isopropanol to yield
(3-chloro-4-nitrophenyl)(4-chlorophenyl)methanone as an orange
solid. The filtrate was concentrated and the residue was purified
by silica gel chromatography using a 25-50% dichloromethane:heptane
gradient as eluent to yield additional
(3-chloro-4-nitrophenyl)(4-chlorophenyl)methanone as a white
solid.
Step 3:
(3-chloro-4-nitrophenyl)(4-chlorophenyl)(thiazol-2-yl)methanol
[1226] A solution of thiazole (2.28 mL, 31.75 mmol) in THF (100 mL)
was cooled to -78.degree. C. and treated dropwise with n-BuLi (10M
in hexanes, 3.49 mL, 34.92 mmol). After 30 minutes a solution of
(3-chloro-4-nitrophenyl)(4-chlorophenyl)methanone (4.7 g, 15.87
mmol) in THF (100 mL) was added dropwise and the reaction mixture
was allowed to warm to room temperature and stirred overnight.
Water was added and the mixture was extracted with ethyl ether. The
organic layer was washed with brine and dried over MgSO.sub.4. The
solvent was evaporated to yield a dark oil. The oil was purified by
silica gel chromatography eluting with a gradient of 1:1
dichloromethane:hexane to dichloromethane to yield
(3-chloro-4-nitrophenyl)(4-chlorophenyl)(thiazol-2-yl)methanol as a
yellow-orange gum.
Step 4:
(3-((4-chlorophenethyl)amino)-4-nitrophenyl)(4-chlorophenyl)(thiaz-
ol-2-yl)methanol
[1227] A solution of
(3-chloro-4-nitrophenyl)(4-chlorophenyl)(thiazol-2-yl)methanol (250
mg, 0.66 mmol), p-chlorophenethylamine (0.28 mL, 1.97 mmol), and
potassium fluoride (190 mg, 3.28 mmol) in DMSO (1 mL) was heated
under argon at 100.degree. C. for 72 hours. Water was added and the
mixture was extracted with ethyl ether. The organic layer was
washed with water (2.times.) and brine (IX) and then dried over
MgSO.sub.4. Evaporation of the solvent in vacuo to yield residue,
which was purified by silica gel chromatography using a 50%
dichloromethane:heptane to 100% dichloromethane gradient to yield
(3-((4-chlorophenethyl)amino)-4-nitrophenyl)(4-chlorophenyl)(thiazol-2-yl-
)methanol as an orange solid.
Step 5: Mixture of
N1-(4-chlorophenethyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)benzene-1,-
2-diamine and
N-(2-((4-chlorophenethyl)amino)-4-((4-chlorophenyl)(thiazol-2-yl)methyl)p-
henyl)acetamide
[1228] To a solution of
(3-((4-chlorophenethyl)amino)-4-nitrophenyl)(4-chlorophenyl)(thiazol-2-yl-
)methanol (130 mg, 0.26 mmol) in acetic acid (3.75 mL) was added
tin chloride dihydrate (293 mg, 1.30 mmol) and water (0.25 mL). The
reaction mixture was heated at 50.degree. C. and the solvent was
evaporated in vacuo. Water and 3N NaOH were added to the residue
and the mixture was extracted with dichloromethane (3.times.). The
organic layer was dried over Na.sub.2SO.sub.4, filtered, and the
solvent evaporated in vacuo to yield a mixture of
N1-(4-chlorophenethyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)benzene-1,-
2-diamine and
N-(2-((4-chlorophenethyl)amino)-4-((4-chlorophenyl)(thiazol-2-yl)methyl)p-
henyl)acetamide as a brown oil.
Step 6:
2-((1-(4-chlorophenethyl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)(-
4-chlorophenyl)methyl)thiazole
[1229] A solution of
N1-(4-chlorophenethyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)benzene-1,-
2-diamine and
N-(2-((4-chlorophenethyl)amino)-4-((4-chlorophenyl)(thiazol-2-yl)methyl)p-
henyl)acetamide (140 mg, 0.31 mmol) and cyclopropanecarboxaldehyde
(0.047 mL, 0.62 mmol) in DMSO (1 mL) was rapidly stirred at room
temperature in the presence of air. The reaction mixture was
purified by reverse phase HPLC. The fractions containing the
product were lyophilized to yield
2-((1-(4-chlorophenethyl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)(4-chlor-
ophenyl)methyl)thiazole trifluoroacetate salt. MS: 504.0
(M+H.sup.+).
Example DL-17
2-((4-chlorophenyl)(1-(3-chlorophenyl)-2-cyclopropyl-1H-benzo[d]imidazol-6-
-yl)methyl)thiazole
##STR00432##
[1231]
2-((4-Chlorophenyl)(1-(3-chlorophenyl)-2-cyclopropyl-1H-benzo[d]imi-
dazol-6-yl)methyl)thiazole was prepared according to the procedure
as described in Example DL-8 above substituting
cyclopropanecarboxaldehyde for propionaldehyde in Step 6. MS: 476.0
(M+H.sup.+).
Example DL-18
2-((4-chlorophenyl)(1-(3-chlorophenyl)-2-propyl-1H-benzo[d]imidazol-6-yl)m-
ethyl)thiazole
##STR00433##
[1233]
2-((4-Chlorophenyl)(1-(3-chlorophenyl)-2-propyl-1H-benzo[d]imidazol-
-6-yl)methyl)thiazole was prepared according to the procedure as
described in Example DL-8 above substituting 1-butyraldehyde for
propionaldehyde in Step 6.
[1234] MS: 478.0 (M+H.sup.+).
Example DL-19
2-((4-chlorophenyl)(1-(1-(4-chlorophenyl)propan-2-yl)-2-ethyl-1H-benzo[d]i-
midazol-6-yl)methyl)thiazole
##STR00434##
[1235] Step 1:
(4-chlorophenyl)(3-((1-(4-chlorophenyl)propan-2-yl)amino)-4-nitrophenyl)(-
thiazol-2-yl)methanol
[1236] A solution of
(3-chloro-4-nitrophenyl)(4-chlorophenyl)(thiazol-2-yl)methanol (500
mg, 1.31 mmol), prepared as described in Example DL-16 above,
2-(4-chlorophenyl)-1-methylethylamine hydrochloride (828 mg, 3.94
mmol), potassium fluoride (381 mg, 6.56 mmol), and K.sub.2CO.sub.3
(544 mg, 3.94 mmol) in DMSO (2 mL) was heated under argon at
100.degree. C. for 72 hours. Water was added and the mixture was
extracted with ethyl ether. The organic layer was washed with water
(2.times.) and brine (1.times.) and then dried over MgSO.sub.4.
Evaporation of the solvent in vacuo yielded an orange solid, which
was purified by silica gel chromatography using a 50%
dichloromethane:heptane to 100% dichloromethane gradient to yield
(4-chlorophenyl)(3-((1-(4-chlorophenyl)propan-2-yl)amino)-4-nitroph-
enyl)(thiazol-2-yl)methanolas an orange solid.
Step 2:
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-N1-(1-(4-chlorophenyl)pro-
pan-2-yl)benzene-1,2-diamine
[1237] To a solution of
(4-chlorophenyl)(3-((1-(4-chlorophenyl)propan-2-yl)amino)-4-nitrophenyl)(-
thiazol-2-yl)methanol (420 mg, 0.82 mmol) in acetic acid (15 mL)
under an argon atmosphere was added tin chloride dihydrate (921 mg,
4.08 mmol) and conc. HCl (1 mL). The reaction mixture was heated at
50.degree. C. for 5 days and then another 0.95 g of tin chloride
dihydrate was added and the reaction mixture stirred at 50.degree.
C. for 16 hours. Ice and 3N NaOH (90 mL) were added to the residue
and the mixture was extracted with ethyl acetate. The organic layer
was washed with water and brine and then dried over
Na.sub.2SO.sub.4. Evaporation of the solvent in vacuo yielded a
green oil. The oil was purified by silica gel chromatography using
a 0-2% methanol:dichloromethane gradient to yield
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-N1-(1-(4-chlorophenyl)propan-2-y-
l)benzene-1,2-diamine as a green oil.
Step 3:
2-((4-chlorophenyl)(1-(1-(4-chlorophenyl)propan-2-yl)-2-ethyl-1H-b-
enzo[d]imidazol-6-yl)methyl)thiazole
[1238] A solution of
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-N1-(1-(4-chlorophenyl)propan-2-y-
l)benzene-1,2-diamine (550 mg, 1.17 mmol) and propionaldehyde
(0.175 mL, 2.35 mmol) in DMSO (1 mL) was rapidly stirred at room
temperature in the presence of air for 72 hours. The reaction
mixture was purified by reverse phase HPLC. The fractions
containing the product were lyophilized to yield
2-((4-chlorophenyl)(1-(1-(4-chlorophenyl)propan-2-yl)-2-ethyl-1H-
-benzo[d]imidazol-6-yl)methyl)thiazole trifluoroacetate salt. MS:
506.2 (M+H.sup.4).
Example DL-20
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(2,3-dihydro-1H-inden-2-yl)--
1H-benzo[d]imidazole
##STR00435##
[1239] Step 1: methyl
2,2-bis(4-chlorophenyl)-2-(3-((2,3-dihydro-1H-inden-2-yl)amino)-4-nitroph-
enyl)acetate and
N-(5-(bis(4-chlorophenyl)methyl)-2-nitrophenyl)-2,3-dihydro-1H-inden-2-am-
ine
[1240] A solution of methyl
2-(3-chloro-4-nitrophenyl)-2,2-bis(4-chlorophenyl)acetate (670 mg,
1.49 mmol), prepared as described in Example DL-2 above,
(S)-2-indanamine (0.38 mL, 2.97 mmol), and DIPEA (0.538 mL, 3.12
mmol) in 1,4-dioxane (2 mL) was heated under argon at 95.degree. C.
for 18 hours. The solvent was evaporated to the point that the
mixture became thick, another 0.38 g of 2-indanamine was added, and
the reaction was heated at 110.degree. C. for 72 hours. The
remaining solvent was evaporated in vacuo and the residue was
purified by reverse phase HPLC. The fractions containing the
product were lyophilized to yield methyl
2,2-bis(4-chlorophenyl)-2-(3-((2,3-dihydro-1H-inden-2-yl)amino)-4-nitroph-
enyl)acetate and
N-(5-(bis(4-chlorophenyl)methyl)-2-nitrophenyl)-2,3-dihydro-1H-inden-2-am-
ine trifluoroacetate salts as green solids. MS: 489
(M+H.sup.+).
Step 2:
5-(bis(4-chlorophenyl)methyl)-N1-(2,3-dihydro-1H-inden-2-yl)benzen-
e-1,2-diamine
[1241] To a solution of
N-(5-(bis(4-chlorophenyl)methyl)-2-nitrophenyl)-2,3-dihydro-1H-inden-2-am-
ine (140 mg, 0.29 mmol) in MeOH (100 mL) was added 5% Pd/C sulfide
(130 mg) and the mixture was placed under 40 psi hydrogen at room
temperature for 5.5 hours. The reaction mixture was filtered
through CELITE and the solvent evaporated in vacuo. The residue was
purified by silica gel chromatography using a 50%
dichloromethane:heptane to 100% dichloromethane gradient to yield
5-(bis(4-chlorophenyl)methyl)-N1-(2,3-dihydro-1H-inden-2-yl)benzene-1,2-d-
iamine as a white solid.
Step 3:
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(2,3-dihydro-1H-inde-
n-2-yl)-1H-benzo[d]imidazole
[1242] A solution of
5-(bis(4-chlorophenyl)methyl)-N1-(2,3-dihydro-1H-inden-2-yl)benzene-1,2-d-
iamine (70 mg, 0.12 mmol) and cyclopropanecarboxaldehyde (0.019 mL,
0.24 mmol) in DMSO (0.7 mL) was rapidly stirred at room temperature
in the presence of air for 18 hours. The reaction mixture was
purified by reverse phase HPLC. Fractions containing the desired
product were combined and lyophilized to yield
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(2,3-dihydro-1H-inden-2-yl)-
-1H-benzo[d]imidazole as a white solid.
Example DL-21
2-((4-chlorophenyl)(2-cyclopropyl-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-
-benzo[d]imidazol-6-yl)methyl)thiazole
##STR00436##
[1243] and
(4-chlorophenyl)(2-cyclopropyl-1-(1,2,3,4-tetrahydronaphthalen--
2-yl)-1H-benzo[d]imidazol-6-yl)(thiazol-2-yl)methanol
##STR00437##
[1244] Step 1:
(4-chlorophenyl)(4-nitro-3-((1,2,3,4-tetrahydronaphthalen-2-yl)amino)phen-
yl)(thiazol-2-yl)methanol
[1245] A solution of
(3-chloro-4-nitrophenyl)(4-chlorophenyl)(thiazol-2-yl)methanol (200
mg, 0.53 mmol), prepared as described in Example DL-16 above,
2-aminotetralin (89.4 mg, 0.58 mmol), potassium fluoride (152 mg,
2.62 mmol), and diisopropylethylamine (0.181 mL, 1.05 mmol) in DMSO
(1 mL) was heated under argon at 100.degree. C. for 18 hours. An
additional 2 equivalents of diisopropylethylamine were added and
the reaction was heated at 100.degree. C. for 3 hours. An
additional 90 mg of 2-aminotetralin were added and the reaction
heated at 100.degree. C. for 72 hours. Saturated NaHCO.sub.3 was
added and the reaction mixture was extracted with a mixture of
ethyl ether and ethyl acetate. The organic layer was washed with
water and brine and then dried over MgSO.sub.4. Evaporation of the
solvent in vacuo yielded a brown oil, which was purified by silica
gel chromatography using a 50% dichloromethane:heptane to 100%
dichloromethane gradient to yield
(4-chlorophenyl)(4-nitro-3-((1,2,3,4-tetrahydronaphthalen-2-yl)amino)phen-
yl)(thiazol-2-yl)methanol.
Step 2:
(4-chlorophenyl)(4-nitro-3-((1,2,3,4-tetrahydronaphthalen-2-yl)ami-
no)phenyl)(thiazol-2-yl)methanol and
N-(4-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-((1,2,3,4-tetrahydronaphtha-
len-2-yl)amino)phenyl)acetamide
[1246] To a solution of
(4-chlorophenyl)(4-nitro-3-((1,2,3,4-tetrahydronaphthalen-2-yl)amino)phen-
yl)(thiazol-2-yl)methanol (160 mg, 0.33 mmol) in acetic acid (3.75
mL) under an argon atmosphere was added tin chloride dihydrate (367
mg, 1.63 mmol) and conc. HCl (0.25 mL). The reaction mixture was
heated at 50.degree. C. for 1.5 hours. Water and 3N NaOH were added
and the mixture was extracted with dichloromethane (3.times.). The
organic layer was dried over Na.sub.2SO.sub.4 and the solvent was
evaporated in vacuo to yield 0.15 g of a mixture of
(4-chlorophenyl)(4-nitro-3-((1,2,3,4-tetrahydronaphthalen-2-yl)amino)phen-
yl)(thiazol-2-yl)methanol and
N-(4-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-((1,2,3,4-tetrahydronaphtha-
len-2-yl)amino)phenyl)acetamide as a brown foam.
Step 3:
2-((4-chlorophenyl)(2-cyclopropyl-1-(1,2,3,4-tetrahydronaphthalen--
2-yl)-1H-benzo[d]imidazol-6-yl)methyl)thiazole and
(4-chlorophenyl)(2-cyclopropyl-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-b-
enzo[d]imidazol-6-yl)(thiazol-2-yl)methanol trifluoroacetate
salt
[1247] A solution of
(4-chlorophenyl)(4-nitro-3-((1,2,3,4-tetrahydronaphthalen-2-yl)amino)phen-
yl)(thiazol-2-yl)methanol (75 mg, 0.17 mmol) and
cyclopropanecarboxaldehyde (0.026 mL, 0.34 mmol) in DMSO (1 mL) was
rapidly stirred at room temperature in the presence of air. The
reaction mixture was purified by reverse phase HPLC. The fractions
containing the products were lyophilized to yield
2-((4-chlorophenyl)(2-cyclopropyl-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1-
H-benzo[d]imidazol-6-yl)methyl)thiazole trifluoroacetate salt [MS:
496.0 (M+H.sup.+)] and
(4-chlorophenyl)(2-cyclopropyl-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-b-
enzo[d]imidazol-6-yl)(thiazol-2-yl)methanol trifluoroacetate salt
[MS: 512.1 (M+H.sup.+)].
Example DL-22
2-((4-chlorophenyl)(1-(3-chlorophenyl)-2-isopropyl-1H-benzo[d]imidazol-6-y-
l)methyl)thiazole
##STR00438##
[1249]
2-((4-Chlorophenyl)(1-(3-chlorophenyl)-2-isopropyl-1H-benzo[d]imida-
zol-6-yl)methyl)thiazole was prepared according to the procedure as
described in Example DL-8 above substituting isobutyraldehyde for
propionaldehyde in Step 6.
[1250] MS: 478.0 (M+H.sup.+).
Example DL-23
2-((1-(3-chlorophenethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)(4-chloropheny-
l)methyl)thiazole
##STR00439##
[1251] Step 1:
2-(3-((3-chlorophenethyl)amino)-4-nitrophenyl)-2-(4-chlorophenyl)ethaneth-
ioamide
[1252] To a solution of
2-(3-((3-chlorophenethyl)amino)-4-nitrophenyl)-2-(4-chlorophenyl)acetonit-
rile (1.04 g, 2.44 mmol), prepared as described in Example 20 DL-4
above, and triethylamine (0.679 mL, 4.88 mmol) in pyridine (12 mL)
was bubbled hydrogen sulfide gas (0.831 g, 24.40 mmol) for 2 hours.
The reaction mixture was stirred at room temperature overnight.
Acetonitrile was added to the reaction mixture and the solvent was
evaporated to yield an orange solid which was dissolved in ethyl
ether. The organic solution was washed with saturated NaHCO.sub.3
and brine, and then dried over K.sub.2CO.sub.3. The solvent was
evaporated in vacuo to yield
2-(3-((3-chlorophenethyl)amino)-4-nitrophenyl)-2-(4-chlorophenyl)ethaneth-
ioamide as an orange solid (1.51 g).
Steps 2 and 3:
N-(3-chlorophenethyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nitroani-
line and
N1-(3-chlorophenethyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)be-
nzene-1,2-diamine
[1253]
N-(3-chlorophenethyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-ni-
troaniline and
N1-(3-chlorophenethyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)benzene-1,-
2-diamine were prepared as described in Example DL-4 above.
Step 4:
2-((1-(3-chlorophenethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)(4-chl-
orophenyl)methyl)thiazole
[1254] To a solution of
N1-(3-chlorophenethyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)benzene-1,-
2-diamine (100 mg, 0.22 mmol) in trimethylorthoacetate (3 mL, 23.34
mmol) was added concentrated HCl (0.02 mL) and the solution was
heated at reflux temperature for 18 hours. The reaction mixture was
purified by reverse phase HPLC and the fractions containing the
product were lyophilized to yield
2-((1-(3-chlorophenethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)(4-chlorophen-
yl)methyl)thiazole trifluoroacetate salt as a light brown oil. MS:
478.0 (M+H.sup.+).
Example DL-24
2-((4-chlorophenyl)(1-(2,3-dihydro-1H-inden-2-yl)-2-methyl-1H-benzo[d]imid-
azol-6-yl)methyl)thiazole
##STR00440##
[1255] and
2-((4-chlorophenyl)(2-cyclopropyl-1-(2,3-dihydro-1H-inden-2-yl)-
-1H-benzo[d]imidazol-6-yl)methyl)thiazole
##STR00441##
[1256] Step 1:
(4-chlorophenyl)(3-((2,3-dihydro-1H-inden-2-yl)amino)-4-nitrophenyl)(thia-
zol-2-yl)methanol
[1257] A solution of
(3-chloro-4-nitrophenyl)(4-chlorophenyl)(thiazol-2-yl)methanol (220
mg, 0.58 mmol), prepared as described in Example DL-16 above and
2-indanamine (0.39 g, 2.89 mmol) in n-butanol (1 mL) was heated in
a microwave at 160.degree. C. for 1 hour. Ethyl acetate was added
and the resulting mixture was washed with water (4.times.) and
brine (IX). The organic layer was evaporated and the residue
purified by silica gel chromatography using a 50%
dichloromethane:heptane to 100% dichloromethane gradient to yield
(4-chlorophenyl)(3-((2,3-dihydro-1H-inden-2-yl)amino)-4-nitrophenyl)(thia-
zol-2-yl)methanol as a yellow oil.
Step 2: A mixture of
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-N1-(2,3-dihydro-1H-inden-2-yl)be-
nzene-1,2-diamine,
N-(4-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-((2,3-dihydro-1H-inden-2-yl-
)amino)phenyl)acetamide and
2-((4-chlorophenyl)(1-(2,3-dihydro-1H-inden-2-yl)-2-methyl-1H-benzo[d]imi-
dazol-6-yl)methyl)thiazole
[1258] To a solution of
(4-chlorophenyl)(3-((2,3-dihydro-1H-inden-2-yl)amino)-4-nitrophenyl)(thia-
zol-2-yl)methanol (0.08 g, 0.33 mmol) in acetic acid (3 mL) under
an argon atmosphere was added tin chloride dihydrate (0.19 g, 0.84
mmol) and conc. HCl (0.2 mL). The reaction mixture was heated at
50.degree. C. for 18 hours. The solvent was evaporated, ethyl ether
and dichloromethane were added, and the mixture was washed with 1N
NaOH. The organic layer was separated and the solvent was
evaporated in vacuo to yield a mixture of
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-N1-(2,3-dihydro-1H-inden-2-yl)be-
nzene-1,2-diamine,
N-(4-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-((2,3-dihydro-1H-inden-2-yl-
)amino)phenyl)acetamide and
2-((4-chlorophenyl)(1-(2,3-dihydro-1H-inden-2-yl)-2-methyl-1H-benzo[d]imi-
dazol-6-yl)methyl)thiazole.
Step 3:
2-((4-chlorophenyl)(2-cyclopropyl-1-(2,3-dihydro-1H-inden-2-yl)-1H-
-benzo[d]imidazol-6-yl)methyl)thiazole and
2-((4-chlorophenyl)(1-(2,3-dihydro-1H-inden-2-yl)-2-methyl-1H-benzo[d]imi-
dazol-6-yl)methyl)thiazole
[1259] A solution of the mixture of
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-N1-(2,3-dihydro-1H-inden-2-yl)be-
nzene-1,2-diamine,
N-(4-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-((2,3-dihydro-1H-inden-2-yl-
)amino)phenyl)acetamide and
2-((4-chlorophenyl)(1-(2,3-dihydro-1H-inden-2-yl)-2-methyl-1H-benzo[d]imi-
dazol-6-yl)methyl)thiazole from Step 2 above (70 mg, 0.152 mmol)
and cyclopropanecarboxaldehyde (0.025 mL, 0.32 mmol) in DMSO (1 mL)
was rapidly stirred at room temperature in the presence of air. The
reaction mixture was purified by reverse phase HPLC. The fractions
containing the desired products were lyophilized to yield
2-((4-chlorophenyl)(2-cyclopropyl-1-(2,3-dihydro-1H-inden-2-yl)-1H-benzo[-
d]imidazol-6-yl)methyl)thiazole trifluoroacetate salt [MS: 482.1
(M+H.sup.+)] and
2-((4-chlorophenyl)(1-(2,3-dihydro-1H-inden-2-yl)-2-methyl-1H-benzo[d]imi-
dazol-6-yl)methyl)thiazole trifluoroacetate salt [MS: 456
(M+H.sup.+)].
Example DL-25
2-((4-chlorophenyl)(1-(1-(4-chlorophenyl)propan-2-yl)-2-cyclopropyl-1H-ben-
zo[d]imidazol-6-yl)methyl)thiazole
##STR00442##
[1261]
2-((4-Chlorophenyl)(1-(1-(4-chlorophenyl)propan-2-yl)-2-cyclopropyl-
-1H-benzo[d]imidazol-6-yl)methyl)thiazole was prepared according to
the procedure as described in Example DL-19 above substituting
cyclopropanecarboxaldehyde for propionaldehyde in Step 3. MS: 518.2
(M+H.sup.+).
Example DL-26
2-(4-chlorophenyl).sub.1-(2-(4-chlorophenyl)propyl)-2-cyclopropyl-1H-benzo-
[d]imidazol-6-yl)methyl)thiazole
##STR00443##
[1263]
2-((4-Chlorophenyl)(1-(2-(4-chlorophenyl)propyl)-2-cyclopropyl-1H-b-
enzo[d]imidazol-6-yl)methyl)thiazole was prepared according to the
procedure as described in Example DL-25 above substituting
2-methyl-2-(4-chlorophenyl)ethylamine hydrochloride for
1-methyl-2-(4-chlorophenyl)ethylamine hydrochloride in Step 1. MS:
518.0 (M+H.sup.+).
Example DL-27
2-((1-(3-chlorophenethyl)-2-propyl-1H-benzo[d]imidazol-6-yl)(4-chloropheny-
l)methyl)thiazole
##STR00444##
[1265]
2-((1-(3-Chlorophenethyl)-2-propyl-1H-benzo[d]imidazol-6-yl)(4-chlo-
rophenyl)methyl)thiazole was prepared according to the procedure as
described in Example DL-4 above substituting butyraldehyde for
cyclopropanecarboxaldehyde in Step 6. MS: 506.1 (M+H.sup.+).
Example DL-28
2-((1-(3-chlorophenethyl)-1H-benzo[d]imidazol-6-yl)(4-chlorophenyl)methyl)-
thiazole
##STR00445##
[1267]
2-((1-(3-Chlorophenethyl)-1H-benzo[d]imidazol-6-yl)(4-chlorophenyl)-
methyl)thiazole was prepared according to the procedure as
described in Example DL-23 above substituting trimethylorthoformate
for trimethylorthoacetate in Step 4. MS: 464.0 (M+H.sup.+).
Example DL-29
1-(4-chlorophenyl)-2-(6-((4-chlorophenyl)thiazol-2-yl)methyl)-2-ethyl-1H-b-
enzo[d]imidazol-1-yl)ethanol
##STR00446##
[1269]
1-(4-Chlorophenyl)-2-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-et-
hyl-1H-benzo[d]imidazol-1-yl)ethanol was prepared according to the
procedure as described in Example DL-19 above substituting
2-(4-chlorophenyl)-2-hydroxyethylamine hydrochloride for
2-(4-chlorophenyl)-1-methylethylamine hydrochloride in Step 1. MS:
508.0 (M+H.sup.+).
Example DL-30
2-(4-chlorophenyl).sub.1-(1-(4-chlorophenyl)propan-2-yl)-2-(difluoromethyl-
)-1H-benzo[d]imidazol-6-yl)methyl)thiazole
##STR00447##
[1271] A solution of
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-N1-(1-(4-chlorophenyl)propan-2-y-
l)benzene-1,2-diamine (550 mg, 1.17 mmol), prepared as described in
Example DL-19 above, and difluoroacetic acid (1 mL) was heated at
50.degree. C. under an argon atmosphere for 72 hours. The solvent
was evaporated in vacuo and the residue was purified by reverse
phase HPLC. The fractions containing the product were lyophilized
to yield
2-((4-chlorophenyl)(1-(1-(4-chlorophenyl)propan-2-yl)-2-(difluoromethyl)--
1H-benzo[d]imidazol-6-yl)methyl)thiazole trifluoroacetate salt [MS:
528.1 (M+H.sup.+)].
Example DL-31
6-((4-chlorophenyl)(phenyl)methyl)-2-cyclopropyl-1-((S)-2-phenylpropyl)-1H-
-benzo[d]imidazole
##STR00448##
[1272] and
(S)-6-benzhydryl-2-cyclopropyl-1-(2-phenylpropyl)-1H-benzo[d]im-
idazole
##STR00449##
[1273] Step 1: Mixture of
(S)-bis(4-chlorophenyl)(4-nitro-3-((2-phenylpropyl)amino)phenyl)methanol.
(S)-methyl
2,2-bis(4-chlorophenyl)-2-(4-nitro-3-((2-phenylpropyl)amino)phenyl)acetat-
e and
(S)-5-(bis(4-chlorophenyl)methyl)-2-nitro-N-(2-phenylpropyl)aniline
[1274] A solution of methyl
2-(3-chloro-4-nitrophenyl)-2,2-bis(4-chlorophenyl)acetate (400 mg,
0.89 mmol), prepared as described in Example DL-2 above,
(S)-2-phenylpropylamine (180 mg, 1.33 mmol), potassium carbonate
(368 mg, 2.66 mmol), and potassium fluoride (258 mg, 4.44 mmol) in
DMSO (2 mL) was heated under argon at 100.degree. C. for 18 hours.
Ethyl acetate was added and the organic mixture was washed with
water and brine and then evaporated in vacuo to yield a yellow
semi-solid. The residue was purified by reverse phase HPLC and
fractions containing the products were lyophilized to yield
(S)-bis(4-chlorophenyl)(4-nitro-3-((2-phenylpropyl)amino)phenyl)methanol
as an orange solid as well as a mixture of (S)-methyl
2,2-bis(4-chlorophenyl)-2-(4-nitro-3-((2-phenylpropyl)amino)phenyl)acetat-
e and
(S)-5-(bis(4-chlorophenyl)methyl)-2-nitro-N-(2-phenylpropyl)aniline
as an orange oil.
Step 2: A mixture of
(S)-5-(bis(4-chlorophenyl)methyl)-N1-(2-phenylpropyl)benzene-1,2-diamine,
5-((4-chlorophenyl)(phenyl)methyl)-N1-((S)-2-phenylpropyl)benzene-1,2-dia-
mine and
(S)-5-benzhydryl-N1-(2-phenylpropyl)benzene-1,2-diamine
[1275] To a solution of
(S)-bis(4-chlorophenyl)(4-nitro-3-((2-phenylpropyl)amino)phenyl)methanol
(80 mg, 0.158 mmol) in MeOH (80 mL) and ethyl acetate (80 mL) was
added 5% Pd/C sulfide (420 mg) and the mixture was placed under 50
psi hydrogen at room temperature for 2.5 hours. The reaction
mixture was filtered through CELITE elite and the solvent
evaporated in vacuo to yield a mixture of
(S)-5-(bis(4-chlorophenyl)methyl)-N1-(2-phenylpropyl)benzene-1,2-diamine,
5-((4-chlorophenyl)(phenyl)methyl)-N1-((S)-2-phenylpropyl)benzene-1,2-dia-
mine and
(S)-5-benzhydryl-N1-(2-phenylpropyl)benzene-1,2-diamine.
Step 3:
6-((4-chlorophenyl)(phenyl)methyl)-2-cyclopropyl-1-((S)-2-phenylpr-
opyl)-1H-benzo[d]imidazole and
(S)-6-benzhydryl-2-cyclopropyl-1-(2-phenylpropyl)-1H-benzo[d]imidazole
[1276] A solution of the mixture of
(S)-5-(bis(4-chlorophenyl)methyl)-N1-(2-phenylpropyl)benzene-1,2-diamine,
5-((4-chlorophenyl)(phenyl)methyl)-N1-((S)-2-phenylpropyl)benzene-1,2-dia-
mine and (S)-5-benzhydryl-N1-(2-phenylpropyl)benzene-1,2-diamine
(120 mg, 0.26 mmol) and cyclopropanecarboxaldehyde (0.040 mL, 0.52
mmol) in DMSO (2 mL) was rapidly stirred at room temperature in the
presence of air for 4 days. The reaction mixture was purified by
reverse phase HPLC. Fractions containing the desired products were
combined and lyophilized to yield
6-((4-chlorophenyl)(phenyl)methyl)-2-cyclopropyl-1-((S)-2-phenyl-
propyl)-1H-benzo[d]imidazole (12.7 mg) as a white foam and
(S)-6-benzhydryl-2-cyclopropyl-1-(2-phenylpropyl)-1H-benzo[d]imidazole
as a white foam.
Example DL-32
(S)-6-(bis(4-chlorophenyl)methyl)-2-methyl-1-(2-phenylpropyl)-1H-benzo[d]i-
midazole
##STR00450##
[1277] Step 1: (S)-methyl
2,2-bis(4-chlorophenyl)-2-(2-methyl-1-(2-phenylpropyl)-1H-benzo[d]imidazo-
l-6-yl)acetate
[1278] To a solution of (S)-methyl
2-(4-amino-3-((2-phenylpropyl)amino)phenyl)-2,2-bis(4-chlorophenyl)acetat-
e (114 mg, 0.22 mmol), prepared as described in Example DL-15
above, in trimethylorthoacetate (3 mL, 23.34 mmol) is added
concentrated HCl (0.02 mL) and the solution is heated at reflux
temperature for 18 hours. The reaction mixture is purified by
reverse phase HPLC and the fractions containing the product are
lyophilized to yield (S)-methyl
2,2-bis(4-chlorophenyl)-2-(2-methyl-1-(2-phenylpropyl)-1H-benzo[d]imidazo-
l-6-yl)acetate trifluoroacetate salt.
Step 2:
(S)-2,2-bis(4-chlorophenyl)-2-(2-methyl-1-(2-phenylpropyl)-1H-benz-
o[d]imidazol-6-yl)acetic acid
[1279] To a solution of (S)-methyl
2,2-bis(4-chlorophenyl)-2-(2-methyl-1-(2-phenylpropyl)-1H-benzo[d]imidazo-
l-6-yl)acetate (117 mg, 0.215 mmol) in MeOH (4 mL) is added 3N NaOH
(1 mL, 3 mmol) and the solution is heated at 45.degree. C.
overnight. The solvent is removed in vacuo and then water and 3 mL
1N HCl is added. The mixture is extracted with ethyl acetate and
the organic layer is dried over MgSO.sub.4 and evaporated in vacuo
to yield
(S)-2,2-bis(4-chlorophenyl)-2-(2-methyl-1-(2-phenylpropyl)-1H-benzo[d]imi-
dazol-6-yl)acetic acid.
Step 3:
(S)-6-(bis(4-chlorophenyl)methyl)-2-methyl-1-(2-phenylpropyl)-1H-b-
enzo[d]imidazole
[1280] A solution of
(S)-2,2-bis(4-chlorophenyl)-2-(2-methyl-1-(2-phenylpropyl)-1H-benzo[d]imi-
dazol-6-yl)acetic acid (117 mg, 0.221 mmol) and DBU (0.099 mL, 0.66
mmol) in toluene (10 mL) is heated at 90.degree. C. overnight under
argon. After evaporation of the solvent, the residue is purified by
reverse phase HPLC and the fractions containing the product are
lyophilized to yield
(S)-6-(bis(4-chlorophenyl)methyl)-2-methyl-1-(2-phenylpropyl)-1H-be-
nzo[d]imidazole trifluoroacetate salt. MS: 485.0 (M+H.sup.+).
Example DL-33
1-(4-chlorophenyl)-2-(6-((4-chlorophenyl)(thiazol-2-yl)meth
yl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)ethanol
##STR00451##
[1282]
1-(4-Chlorophenyl)-2-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-cy-
clopropyl-1H-benzo[d]imidazol-1-yl)ethanol was prepared according
to the procedure as described in Example DL-29 above substituting
cyclopropanecarboxaldehyde for propionaldehyde in the final step.
MS: 520.0 (M+H.sup.+).
Example DL-34
ethyl 1-(3-chlorophenyl)-6-((4-chlorophenyl
thiazol-2-yl)methyl)-1H-benzo[d]imidazole-2-carboxylate
##STR00452##
[1284] Ethyl
1-(3-chlorophenyl)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)-1H-benzo[d]im-
idazole-2-carboxylate was prepared according to the procedure as
described in Example DL-8 above substituting ethyl glyoxalate (50%
in toluene) for propionaldehyde in Step 6. MS: 508.0
(M+H.sup.+).
Example DL-35
2-((4-chlorophenyl)(1-(3-chlorophenyl)-2-(furan-3-yl)-1H-benzo[d]imidazol--
6-yl)methyl)thiazole
##STR00453##
[1286]
2-((4-Chlorophenyl)(1-(3-chlorophenyl)-2-(furan-3-yl)-1H-benzo[d]im-
idazol-6-yl)methyl)thiazole was prepared according to the procedure
as described in Example DL-8 above substituting
3-furancarboxaldehyde for propionaldehyde in Step 6. MS: 502.0
(M+H.sup.+).
Example DL-36
2-((4-chlorophenyl)(1-(3-chlorophenyl)-2-methyl-1H-benzo[d]imidazol-6-yl)m-
ethyl)thiazole
##STR00454##
[1288] To a solution of
N1-(3-chlorophenyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)benzene-1,2-d-
iamine (200 mg, 0.47 mmol), prepared as described in Example DL-8
above, in trimethylorthoacetate (3 mL, 23.34 mmol) was added
concentrated HCl (0.02 mL) and the solution was heated at reflux
temperature for 18 hours. The reaction mixture was purified by
reverse phase HPLC and the fractions containing the product were
lyophilized to yield
2-((4-chlorophenyl)(1-(3-chlorophenyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-
methyl)thiazole trifluoroacetate salt as a white solid. MS: 450.1
(M+H.sup.+).
Example DL-37
2-((4-chlorophenyl)(2-cyclopropyl-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidaz-
ol-6-yl)methyl)thiazole
##STR00455##
[1289] Step 1: 5-fluoro-2-nitro-N-(pyridin-2-ylmethyl)anline
[1290] To a solution of 2,4-difluoronitrobenzene (10 mL, 90.29
mmol) and 2-aminomethylpyridine (10.14 mL, 99.32 mmol) in
acetonitrile (60 mL) was added triethylamine (15.061 mL, 108.35
mmol). The reaction mixture was stirred at room temperature
overnight. Water (50 mL) was added, the mixture stirred for 30
minutes, and the resulting yellow precipitate was filtered off to
yield 5-fluoro-2-nitro-N-(pyridin-2-ylmethyl)aniline. Excess water
was added to the filtrate to yield additional
5-fluoro-2-nitro-N-(pyridin-2-ylmethyl)aniline as a yellow
solid.
Step 2:
2-(4-chlorophenyl)-2-(4-nitro-3-((pyridin-2-ylmethyl)amino)phenyl)-
acetonitrile
[1291] To a stirred solution of 4-chlorophenylacetonitrile (7.32
mL, 55.1 mmol) in THF (80 mL) and isopropyl alcohol (8 mL) was
added t-BuOK (14.73 g, 131 mmol) and the mixture was stirred at
room temperature for 5 minutes. The temperature of the reaction was
lowered to 0.degree. C. and
5-fluoro-2-nitro-N-(pyridin-2-ylmethyl)aniline (12.98 g, 52.50
mmol) in THF (40 mL) was added and the reaction mixture was stirred
overnight at room temperature. Water was added and the mixture was
extracted with ethyl acetate. The yellow precipitate that formed
was filtered off and discarded. The organic layer was washed with
aqueous NaHCO.sub.3, dried over Na.sub.2SO.sub.4, and the solvent
was evaporated in vacuo to yield a black oil.
[1292] The residue was subjected to silica gel chromatography using
a methanol/dichloromethane solvent gradient to yield
2-(4-chlorophenyl)-2-(4-nitro-3-((pyridin-2-ylmethyl)amino)phenyl)acetoni-
trile as a residue. Final purification by silica gel chromatography
using dichloromethane as eluent yielded
2-(4-chlorophenyl)-2-(4-nitro-3-((pyridin-2-ylmethyl)amino)phenyl)acetoni-
trile.
Step 3:
2-(4-chlorophenyl)-2-(4-nitro-3-((pyridin-2-ylmethyl)amino)phenyl)-
ethanethioamide
[1293] To a solution of
2-(4-chlorophenyl)-2-(4-nitro-3-((pyridin-2-ylmethyl)amino)phenyl)acetoni-
trile (2.9 g, 4.29 mmol) in EtOH (75 mL) under an argon atmosphere
was added phosphorus pentasulfide (3.81 g, 8.57 mmol) and the
reaction mixture was heated to reflux temperature for 24 hours. The
solvent was evaporated and the residue was subjected to silica gel
chromatography reaction mixture was poured into ice water and
extracted with ethyl acetate. The organic layer was washed with
water, brine, and dried over MgSO.sub.4. The solvent was removed in
vacuo and the residue was purified by silica gel chromatography
using a dichloromethane to 5% methanol:dichloromethane gradient as
eluent to yield
2-(4-chlorophenyl)-2-(4-nitro-3-((pyridin-2-ylmethyl)amino)phenyl)ethanet-
hioamide.
Step 4:
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nitro-N-(pyridin-2-ylme-
thyl)aniline
[1294] To a solution of
2-(4-chlorophenyl)-2-(4-nitro-3-((pyridin-2-ylmethyl)amino)phenyl)ethanet-
hioamide (0.94 g, 1.37 mmol) in acetic acid (15 mL) was added water
(0.5 mL) and bromoacetaldehyde diethylacetal (0.847 mL, 5.46 mmol).
The reaction mixture was heated to 100.degree. C. for 30 minutes
and then aqueous NaHCO.sub.3. The resulting mixture was extracted
with ethyl ether and the organic layer was washed with brine and
evaporated in vacuo to yield 0.75 g a dark oil. The residue was
purified by silica gel chromatography using a dichloromethane to 4%
methanol:dichloromethane gradient to yield
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nitro-N-(pyridin-2-ylmethyl)an-
iline as a yellow oil.
Step 5:
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-N1-(pyridin-2-ylmethyl)be-
nzene-1,2-diamine
[1295] A solution of
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-nitro-N-(pyridin-2-ylmethyl)an-
iline (0.63 g, 1.44 mmol) in ethyl alcohol (150 mL) was placed
under a hydrogen atmosphere in the presence of 3 mL of Raney nickel
(50% slurry in water) overnight. The catalyst was filtered off and
the filtrate was evaporated in vacuo to yield
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-NI-(pyridin-2-ylmethyl)benzene-1-
,2-diamine as a dark gum.
Step 6:
2-((4-chlorophenyl)(2-cyclopropyl-1-(pyridin-2-ylmethyl)-1H-benzo[-
d]imidazol-6-yl)methyl)thiazole
[1296] A rapidly stirred solution of
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-N1-(pyridin-2-ylmethyl)benzene-1-
,2-diamine (140 mg, 0.34 mmol) and cyclopropanecarboxaldehyde
(0.053 mL, 0.69 mmol) in DMSO (1.4 mL) was kept at room temperature
in the presence of air for 4 days. The reaction mixture was
purified by reverse phase HPLC and the fractions containing the
product were lyophilized to yield 35.8 mg of
2-((4-chlorophenyl)(2-cyclopropyl-1-(pyridin-2-ylmethyl)-1H-benzo[d]imida-
zol-6-yl)methyl)thiazole bistrifluoroacetate salt as a white solid.
MS: 457.0 (M+H.sup.+).
Example DL-38
(1S,2R)-2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-
-1-yl)-1-phenyl propan-1-ol
##STR00456##
[1298] (1
S,2R)-2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]-
imidazol-1-yl)-1-phenylpropan-1-ol was prepared according to the
procedure as described in Example DL-13 above substituting
(+)-(1S,2R)-norephedrine for (S)-2-amino-1-phenylethanol in Step 1.
MS: 527.2 (M+H.sup.+).
Example DL-39
6-(bis(4-chlorophenyl)methyl)-1-(2,3-dihydro-1H-inden-2-yl)-2-ethyl-1H-ben-
zo[d]imidazole
##STR00457##
[1299] Step 1: methyl
2,2-bis(4-chlorophenyl)-2-(3-((2,3-dihydro-1H-inden-2-yl)amino)-4-nitroph-
enyl)acetate and
N-(5-(bis(4-chlorophenyl)methyl)-2-nitrophenyl)-2,3-dihydro-1H-inden-2-am-
ine
[1300] A solution of methyl
2-(3-chloro-4-nitrophenyl)-2,2-bis(4-chlorophenyl)acetate (670 mg,
1.49 mmol), prepared as described in Example DL-2 above,
2-indanamine (0.381 mL, 2.97 mmol), and DIPEA (0.538 mL, 3.12 mmol)
in 1,4-dioxane (2 mL) was heated under argon at 95.degree. C.
overnight. Sufficient 1,4-dioxane was evaporated to produce a thick
reaction mixture, another 0.38 g of 2-indanamine was added, and
then the reaction mixture was heated at 110.degree. C. for 72
hours. The solvent was evaporated and the residue was purified by
reverse phase HPLC. Fractions containing the products of the
reaction were combined and lyophilized to yield methyl
2,2-bis(4-chlorophenyl)-2-(3-((2,3-dihydro-1H-inden-2-yl)amino)-4-nitroph-
enyl)acetate trifluoroacetate salt and
N-(5-(bis(4-chlorophenyl)methyl)-2-nitrophenyl)-2,3-dihydro-1H-inden-2-am-
ine trifluoroacetate salt (140 mg) as green solids.
Step 2:
5-(bis(4-chlorophenyl)methyl)-N1-(2,3-dihydro-1H-inden-2-yl)benzen-
e-1,2-diamine
[1301] To a solution of
N-(5-(bis(4-chlorophenyl)methyl)-2-nitrophenyl)-2,3-dihydro-1H-inden-2-am-
ine trifluoroacetate salt (60 mg, 0.099 mmol) in MeOH (100 mL) was
added 5% Pt/C sulfide (110 mg) and the mixture was placed under 45
psi hydrogen at room temperature for 4 hours. The reaction mixture
was filtered through CELITE and the solvent evaporated in vacuo to
yield
5-(bis(4-chlorophenyl)methyl)-N1-(2,3-dihydro-1H-inden-2-yl)benzene-1,2-d-
iamine.
Step 3:
6-(bis(4-chlorophenyl)methyl)-1-(2,3-dihydro-1H-inden-2-yl)-2-ethy-
l-1H-benzo[d]imidazole
[1302] A solution of
5-(bis(4-chlorophenyl)methyl)-N1-(2,3-dihydro-1H-inden-2-yl)benzene-1,2-d-
iamine (56.5 mg, 0.12 mmol) and propionaldehyde (0.018 mL, 0.25
mmol) in DMSO (1 mL) was rapidly stirred at room temperature in the
presence of air for 18 hours. The reaction mixture was purified by
reverse phase HPLC. Fractions containing the desired product were
combined and lyophilized to yield
6-(bis(4-chlorophenyl)methyl)-1-(2,3-dihydro-1H-inden-2-yl)-2-ethyl-1H-be-
nzo[d]imidazole trifluoroacetate salt as a clear oil. MS: 497.2
(M+H.sup.+).
Example DL-40
6-(bis(4-chlorophenyl)methyl)-1-(2,3-dihydro-1H-inden-2-yl)-1H-benzo[d]imi-
dazole
##STR00458##
[1304] To a solution of
5-(bis(4-chlorophenyl)methyl)-N1-(2,3-dihydro-1H-inden-2-yl)benzene-1,2-d-
iamine (100 mg, 0.22 mmol), prepared as described in Example DL-39
above, in trimethylorthoacetate (3 mL, 23.34 mmol) is added
concentrated HCl (0.02 mL) and the solution is heated at reflux
temperature for 18 hours. The reaction mixture is purified by
reverse phase HPLC and the fractions containing the product are
lyophilized to yield
6-(bis(4-chlorophenyl)methyl)-1-(2,3-dihydro-1H-inden-2-yl)-1H-benzo[d]im-
idazole trifluoroacetate salt. MS: 469.1 (M+H.sup.+).
Example DL-41
2-(4-chlorophenyl)(1-(3-chlorophenyl)-2-(thiophen-3-yl)-1H-benzo[d]imidazo-
l-6-yl)methyl)thiazole
##STR00459##
[1306]
2-((4-Chlorophenyl)(1-(3-chlorophenyl)-2-(thiophen-3-yl)-1H-benzo[d-
]imidazol-6-yl)methyl)thiazole was prepared according to the
procedure as described in Example DL-8 above substituting
3-thiophenecarboxaldehyde for propionaldehyde in Step 6. MS: 518.0
(M+H.sup.+).
Example DL-42
tert-butyl
3-(1-(3-chlorophenyl)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)--
1H-benzo[d]imidazol-2-yl)azetidine-1-carboxylate
##STR00460##
[1308] A solution of
NI-(3-chlorophenyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)benzene-1,2-d-
iamine (100 mg, 0.24 mmol), prepared as described in Example DL-8
above, and 1-t-butyloxycarbonylazetidine-3-carboxaldehyde (88.7 mg,
0.47 mmol) in DMSO (1 mL) was rapidly stirred at room temperature
in the presence of air for 4 days. The reaction mixture was heated
at 50.degree. C. for another 4 days. The reaction mixture was
purified by reverse phase HPLC. Fractions containing the desired
product were combined and lyophilized to yield tert-butyl
3-(1-(3-chlorophenyl)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)-1H-benzo[d-
]imidazol-2-yl)azetidine-1-carboxylate trifluoroacetate salt (64.4
mg). MS: 591.0 (M+H.sup.+).
Example DL-43
(R)-2-(6-(bis(4-chlorophenyl)(hydroxy)methyl)-2-cyclopropyl-1H-benzo[d]imi-
dazol-1-yl)-1-phenylethanol
##STR00461##
[1310]
(R)-2-(6-(bis(4-chlorophenyl)(hydroxy)methyl)-2-cyclopropyl-1H-benz-
o[d]imidazol-1-yl)-1-phenylethanol was prepared according to the
procedure as described in Example DL-6 above substituting
(R)-2-(6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1--
yl)-1-phenylethanol in the reaction. MS: 529.1 (M+H.sup.+).
Example DL-44
(1-(3-chlorophenyl)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)-1H-benzo[d]im-
idazol-2-yl)methanol
##STR00462##
[1312]
(1-(3-Chlorophenyl)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)-1H-ben-
zo[d]imidazol-2-yl)methanol was prepared according to the procedure
as described in Example DL-8 above substituting glycolaldehyde for
propionaldehyde in Step 6. MS: 466.0 (M+H.sup.+).
Example DL-45
2-(4-chlorophenyl(1-(2-(4-chlorophenyl)propyl)-2-(2,2,2-trifluoroethyl)-1H-
-benzo[d]imidazol-6-yl)methyl)thiazole
##STR00463##
[1314]
2-((4-Chlorophenyl)(1-(2-(4-chlorophenyl)propyl)-2-(2,2,2-trifluoro-
ethyl)-1H-benzo[d]imidazol-6-yl)methyl)thiazole was prepared
according to the procedure as described in Example DL-19 above
substituting 2-methyl-2-(4-chlorophenyl)ethylamine hydrochloride
for 1-methyl-2-(4-chlorophenyl)ethylamine hydrochloride in Step 1
and 3,3,3-trifluoropropionaldehyde for propionaldehyde in Step 3.
MS: 560.0 (M+H.sup.+).
Example DL-46
2-((1-(3-chlorophenethyl)-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-y-
l)(4-chlorophenyl)methyl)thiazole
##STR00464##
[1315] and
(1-(3-chlorophenethyl)-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imid-
azol-6-yl)(4-chlorophenyl(thiazol-2-yl)methanol
##STR00465##
[1317] A rapidly stirred solution of
N1-(3-chlorophenethyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)benzene-1,-
2-diamine (210 mg, 0.46 mmol), prepared as described in Example
DL-4 above, and 3,3,3-trifluoropropionaldehyde (103.6 mg, 0.92
mmol) in DMSO (1 mL) was kept at room temperature in the presence
of air for 48 hours. The reaction mixture was purified by reverse
phase HPLC and the fractions containing the products were
lyophilized to yield
2-((1-(3-chlorophenethyl)-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6--
yl)(4-chlorophenyl)methyl)thiazole trifluoroacetate salt [MS: 546.0
(M+H.sup.+)] and
(1-(3-chlorophenethyl)-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)-
(4-chlorophenyl)(thiazol-2-yl)methanol trifluoroacetate salt [MS:
546.0 (M+H.sup.+)] as white solids.
Example DL-47
tert-butyl
3-(1-(3-chlorophenethyl)-6-((4-chlorophenyl)(thiazol-2-yl)methy-
l)-1H-benzo[d]imidazol-2-yl)azetidine-1-carboxylate
##STR00466##
[1319] tert-Butyl
3-(1-(3-chlorophenethyl)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)-1H-benz-
o[d]imidazol-2-yl)azetidine-1-carboxylate was prepared according to
the procedure as described in Example DL-4 above substituting
1-t-butyloxycarbonylazetidine-3-carboxaldehyde for
cyclopropanecarboxaldehyde in Step 6. MS: 619.0 (M+H.sup.+).
Example DL-48
2-((1-(3-chlorophenethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)(4--
chlorophenyl)methyl)thiazole
##STR00467##
[1321] A solution of
NI-(3-chlorophenethyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)benzene-1,-
2-diamine (100 mg, 0.22 mmol), prepared as described in Example
DL-4 above, and trifluoroacetic acid (2 mL) was stirred at room
temperature under an argon atmosphere for 18 hours. The solvent was
evaporated in vacuo and the residue was purified by reverse phase
HPLC. The fractions containing the product were lyophilized to
yield
2-((1-(3-chlorophenethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)(4-
-chlorophenyl)methyl)thiazole trifluoroacetate salt. MS: 532.0
(M+H.sup.+).
Example DL-49
(1-(3-chlorophenethyl)-1H-benzo[d]imidazol-6-yl)(4-chlorophenyl)(thiazol-2-
-yl)methanol
##STR00468##
[1322] Step 1:
2-((1-(3-chlorophenethyl)-1H-benzo[d]imidazol-6-yl)(4-chlorophenyl)methyl-
)thiazole
[1323] A rapidly stirred solution of
N1-(3-chlorophenethyl)-5-((4-chlorophenyl)(thiazol-2-yl)methyl)benzene-1,-
2-diamine (350 mg, 0.77 mmol), prepared as described in Example
DL-4 above, and ethyl glyoxalate (0.305 mL, 1.54 mmol) in DMSO (3.5
mL) was kept at room temperature in the presence of air for 7 days.
The reaction mixture was purified by reverse phase HPLC and the
fractions containing the product were lyophilized to yield
2-((1-(3-chlorophenethyl)-1H-benzo[d]imidazol-6-yl)(4-chlorophenyl)methyl-
)thiazole trifluoroacetate salt.
[1324] MS: 464 (M+H.sup.+).
Step 2:
(1-(3-chlorophenethyl)-1H-benzo[d]imidazol-6-yl)(4-chlorophenyl)(t-
hiazol-2-yl)methanol
[1325] To a solution of
2-((1-(3-chlorophenethyl)-1H-benzo[d]imidazol-6-yl)(4-chlorophenyl)methyl-
)thiazole trifluoroacetate salt (63.5 mg, 0.11 mmol) in DMSO (1.5
mL) was added saturated KOH (20 .mu.L) and the reaction mixture was
stirred rapidly at room temperature under a stream of air. t-Butyl
alcohol (0.5 mL) and DMSO (5 mL) were added and the solution was
stirred for 4 hours. The solution was then heated to 50.degree. C.
for 96 hours. The reaction mixture was purified by reverse phase
HPLC, and fractions containing the product were lyophilized to
yield
(1-(3-chlorophenethyl)-1H-benzo[d]imidazol-6-yl)(4-chlorophenyl)(thiazol--
2-yl)methanol as the trifluoroacetate salt. The purified compound
was dissolved in dichloromethane and the organic solution was
washed with saturated NaHCO.sub.3. The organic layer was dried over
Na.sub.2SO.sub.4 and the solvent evaporated in vacuo to yield
(1-(3-chlorophenethyl)-1H-benzo[d]imidazol-6-yl)(4-chlorophenyl)(thiazol--
2-yl)methanol. MS: 480 (M+H.sup.+).
Example DL-50
2-((4-chlorophenyl)(1-(1-(4-chlorophenyl)ethyl)-2-cyclopropyl-1H-benzo[d]i-
midazol-6-yl)methyl)thiazole
##STR00469##
[1326] Step 1: 3-fluoro-4-nitrobenzoyl chloride
[1327] A solution of 3-fluoro-4-nitrobenzoic acid (2 g, 10.80 mmol)
in thionyl chloride (10 mL) and DMF (0.05 mL) was heated to reflux
temperature for 4 hours and then stirred at room temperature
overnight. The thionyl chloride was evaporated in vacuo and heptane
was added and evaporated (2.times.) to yield
3-fluoro-4-nitrobenzoyl chloride as a yellow oil, which was used as
such in the next step.
Step 2: (4-chlorophenyl)(3-fluoro-4-nitrophenyl)methanone
[1328] To 3-fluoro-4-nitrobenzoyl chloride (2.2 g, 10.81 mmol) in
chloroform (12 mL) under an argon atmosphere was added aluminum
chloride (1.67 g, 12.54 mmol) and chlorobenzene (2.20 mL, 21.62
mmol). The reaction mixture was stirred overnight at room
temperature and then heated to reflux temperature for 1 hour. The
reaction mixture was poured on ice, concentrated HCl (3.2 mL) was
added, and the resulting mixture stirred for 1 hour. The mixture
was extracted with dichloromethane and the organic layer was washed
with brine and dried over Na.sub.2SO.sub.4. The solvent was
evaporated in vacuo to yield a red solid. The residue was subjected
to silica gel chromatography using a gradient of 40-75%
dichloromethane:heptane as the eluent to yield a clear oil. The oil
was slurried in acetonitrile (100 mL) at 40.degree. C. for 30
minutes, the mixture was cooled in ice, and the orange precipitate
filtered off. Evaporation of the filtrate yielded
(4-chlorophenyl)(3-fluoro-4-nitrophenyl)methanone as an amber
oil.
Step 3:
(4-chlorophenyl)(3-((1-(4-chlorophenyl)ethyl)amino)-4-nitrophenyl)-
methanone
[1329] To (4-chlorophenyl)(3-fluoro-4-nitrophenyl)methanone (0.82
g, 2.93 mmol) and p-chloro-a-methylbenzylamine (0.51 g, 2.93 mmol)
in acetonitrile (10 mL) was added triethylamine (0.448 mL, 3.23
mmol). The reaction mixture was heated at 50.degree. C. for 16
hours, heated at 80.degree. C. for the next 6 hours, and then
heated at 82.degree. C. for 18 hours. The solvent was evaporated to
yield 1.37 g of an orange semi-solid. The residue was purified by
silica gel chromatography using a 25-75% dichloromethane:heptane
gradient as the eluent to yield
(4-chlorophenyl)(3-((1-(4-chlorophenyl)ethyl)amino)-4-nitrophenyl)methano-
ne as a yellow solid.
Step 4:
(4-chlorophenyl)(3-((1-(4-chlorophenyl)ethyl)amino)-4-nitrophenyl)-
(thiazol-2-yl)methanol
[1330] A solution of thiazole (0.156 mL, 2.17 mmol) in THF (10 mL)
was cooled to -78.degree. C. and treated dropwise with n-BuLi (10M
in hexane, 0.221 mL, 2.21 mmol). After 30 minutes a solution of
(4-chlorophenyl)(3-((1-(4-chlorophenyl)ethyl)amino)-4-nitrophenyl)methano-
ne (0.45 g, 1.08 mmol) in THF (10 mL) was added dropwise and the
reaction mixture was allowed to warm to room temperature and
stirred overnight. Water was added and the mixture was extracted
with ethyl acetate. The organic layer was washed with brine and
dried over Na.sub.2SO.sub.4. The solvent was evaporated and the
residue was purified by silica gel chromatography eluting with
dichloromethane to yield
(4-chlorophenyl)(3-((1-(4-chlorophenyl)ethyl)amino)-4-nitrophenyl)(thiazo-
l-2-yl)methanol as a yellow oil.
Step 5:
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-N1-(1-(4-chlorophenyl)eth-
yl)benzene-1,2-diamine
[1331] To a solution of
(4-chlorophenyl)(3-((1-(4-chlorophenyl)ethyl)amino)-4-nitrophenyl)(thiazo-
l-2-yl)methanol (0.32 g, 0.64 mmol) in acetic acid (7.5 mL) was
added tin chloride dihydrate (721 mg, 3.20 mmol) and concentrated
HCl (0.5 mL). The reaction mixture was heated at 50.degree. C.
overnight and the solvent was evaporated in vacuo. Ethyl acetate
was added to the residue, the organic layer was washed with water
and brine and then dried over Na.sub.2SO.sub.4. Evaporation of the
solvent yielded the residue, which was purified by silica gel
chromatography using dichloromethane as the eluent to yield
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-N1-(1-(4-chlorophenyl)ethyl)benz-
ene-1,2-diamine as a brown foam.
Step 6:
2-((4-chlorophenyl)(1-(1-(4-chlorophenyl)ethyl)-2-cyclopropyl-1H-b-
enzo[d]imidazol-6-yl)methyl)thiazole
[1332] A solution of
5-((4-chlorophenyl)(thiazol-2-yl)methyl)-N1-(1-(4-chlorophenyl)ethyl)benz-
ene-1,2-diamine (80 mg, 0.31 mmol) and cyclopropanecarboxaldehyde
(0.027 mL, 0.35 mmol) in DMSO (1 mL) was rapidly stirred at room
temperature in the presence of air. The reaction mixture was
purified by reverse phase HPLC. The fractions containing the
product were lyophilized to yield
2-((4-chlorophenyl)(1-(1-(4-chlorophenyl)ethyl)-2-cyclopropyl-1H-benzo[d]-
imidazol-6-yl)methyl)thiazole trifluoroacetate salt as a white
solid. MS: 504.0 (M+H.sup.+).
Example DL-51
2-(2-(azetidin-3-yl)-1-(3-chlorophenethyl)-1H-benzo[d]imidazol-6-yl)(4-chl-
orophenyl)methyl)thiazole
##STR00470##
[1334] A solution of tert-butyl
3-(1-(3-chlorophenethyl)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)-1H-benz-
o[d]imidazol-2-yl)azetidine-1-carboxylate (100 mg, 0.16 mmol),
prepared as described in Example DL-47 above, in dichloromethane
(10 mL) was cooled in ice and trifluoroacetic acid (1 mL) was
added. The reaction mixture was stirred overnight at room
temperature and then washed with 13.8 mL of 1N NaOH. The organic
layer was dried over Na.sub.2SO.sub.4 and evaporated to yield a
white foam. The residue was purified by reverse phase HPLC and the
fractions containing the product were lyophilized to yield
2-((2-(azetidin-3-yl)-1-(3-chlorophenethyl)-1H-benzo[d]imidazol-6-yl)(4-c-
hlorophenyl)methyl)thiazole trifluoroacetate salt. MS: 519.0
(M+H.sup.+).
Example DP-1
1-((trifluoromethyl)sulfonyl)piperidin-4-one
##STR00471##
[1336] 4-Piperidone HCl salt monohydrate (2 g, 12.89 mmol) was
placed in a 40 mL vial equipped with a stir bar then
dichloromethane (25 mL) was added. 3M NaOH (4.30 mL, 12.89 mmol)
was added and the mixture was stirred until the solid dissolved
(.about.30 min). The organic phase was separated then the aqueous
layer was extracted with dichloromethane (3.times.20 mL). The
combined organic extracts were dried over MgSO.sub.4 and filtered
into a 200 mL round bottom flask equipped with a stir bar.
Diisopropylethylamine (3.33 mL, 19.34 mmol) was added then triflic
anhydride (1M solution in dichloromethane, 1.289 mL, 12.89 mmol)
was placed in a dropping funnel and the solution was added dropwise
over 30 min. After completion of addition, the reaction was stirred
at room temperature for 2 hours then the solvent was removed under
reduced pressure. The residue was purified by chromatography on
silica gel eluting with 0-80% ethyl acetate/heptane gradient to
yield 1-((trifluoromethyl)sulfonyl)piperidin-4-one.
Example DP-2
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-4-methoxy-1-(1-((trifluorometh-
yl)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole
##STR00472##
[1337] Step 1: 2-amino-5-bromo-3-nitrophenol
[1338] 2-Amino-3-nitrophenol (3 g, 19.465 mmol) was placed in a 200
mL round bottom flask equipped with a stir bar then AcOH (45 mL)
was added. Bromine (3.111 g, 19.465 mmol) in acetic acid (25 mL)
was placed in a dropping funnel and the solution was added dropwise
over 1 hour. The mixture was stirred at room temperature for 18
hours then ethanol (100 mL) and ethyl acetate (300 mL) were added.
The solution was neutralized with 2 N NaOH to pH 5 then the organic
phase was separated, washed with brine (100 mL), and dried over
Na.sub.2SO.sub.4 and filtered. The solvent was removed under
reduced pressure yielding 2-amino-5-bromo-3-nitrophenol as a red
solid, which was used in the next step without further
purification.
Step 2: 4-bromo-2-methoxy-6-nitroaniline
[1339] 2-Amino-5-bromo-3-nitrophenol (0.74 g, 3.176 mmol) was
placed in a 20 mL vial equipped with a stir bar then
K.sub.2CO.sub.3 (570.6 mg, 4.128 mmol) and DMF (10 mL) were added.
CH.sub.31 (0.217 mL, 3.493 mmol) was added dropwise then the
reaction was stirred at room temperature for 3 hours. The reaction
was poured into H.sub.2O (50 mL) and the precipitate was isolated
by filtration. The solid was washed with H.sub.2O (3.times.30 mL)
then dissolved in ethyl acetate (100 mL). The solution was dried
over MgSO.sub.4 and filtered. The solvent was removed under reduced
pressure to yield 4-bromo-2-methoxy-6-nitroaniline, which was in
the next step without further purification.
Step 3:
N-(4-bromo-2-methoxy-6-nitrophenyl)cyclopropanecarboxamide
[1340] 4-Bromo-2-methoxy-6-nitroaniline (743.1 mg, 3.008 mmol) was
placed in a 100 mL round bottom flask equipped with a stir bar then
the vial was evacuated and filled with argon. Dry tetrahydrofuran
(30 mL) was added via syringe then the solution was cooled to
0.degree. C. Sodium hydride (360.9 mg, 9.024 mmol, 60% dispersion
in mineral oil) was added as a solid and the reaction turned
blood-red immediately. The mixture was stirred at 0.degree. C. for
5 minutes then cyclopropanecarbonyl chloride (0.303 mL, 3.309 mmol)
was added. The reaction was stirred at 0.degree. C. for 1.5 hours
then additional cyclopropanecarbonyl chloride (0.15 mL) was added.
The reaction was warmed to room temperature and stirred for 1 hour
then additional sodium hydride (100 mg) was added. The reaction was
stirred at room temperature for 18 hours. An additional amount of
cyclopropanecarbonyl chloride (0.15 mL) was added and the reaction
was stirred for 3 days.
[1341] The reaction mixture was diluted with H.sub.2O (20 mL) and
stirred at room temperature for 1 hour. The reaction was warmed to
60.degree. C. and stirred for 2 hours. 3M NaOH (2 mL) was added and
the reaction mixture was stirred at 60.degree. C. for 6 hours. The
reaction was cooled to room temperature then diluted with ethyl
acetate (50 mL) and the organic phase was separated. The aqueous
phase was extracted with ethyl acetate (3.times.30 mL) then the
organic extracts were combined, washed with brine (30 mL), dried
over MgSO.sub.4 and filtered. The solvent was removed under reduced
pressure. The residue was purified by chromatography on silica gel
eluting with 0-60% ethyl acetate/heptane gradient to yield
N-(4-bromo-2-methoxy-6-nitrophenyl)cyclopropanecarboxamide.
Step 4:
N-(2-amino-4-bromo-6-methoxyphenyl)cyclopropanecarboxamide
[1342] N-(4-bromo-2-methoxy-6-nitrophenyl)cyclopropanecarboxamide
(851.3 mg, 2.701 mmol) was placed in a 40 mL vial equipped with a
stir bar then iron powder (754.3 mg, 13.507 mmol) and ammonium
chloride (1.445 g, 27.015 mmol) were added. Anhydrous ethanol (25
mL) and water (10 mL) were added and the reaction was stirred at
50.degree. C. for 2 hours. The reaction mixture was cooled to room
temperature, diluted with ethyl acetate (10 mL), then filtered
through a CELITE cartridge. The filter cake was washed with ethyl
acetate (3.times.20 mL) and water (2.times.10 mL) then the organic
layer was separated and washed with brine (20 mL). The combined
aqueous extracts were extracted with ethyl acetate (2.times.20 mL).
The organic extracts were combined, dried over Na.sub.2SO.sub.4,
and filtered. The solvent was removed under reduced pressure to
yield N-(2-amino-4-bromo-6-methoxyphenyl)cyclopropanecarboxamide,
which was used in the next step without further purification.
Step 5:
N-(4-bromo-2-methoxy-6-((1-((trifluoromethyl)sulfonyl)piperidin-4--
yl)amino)phenyl)cyclopropanecarboxamide
[1343] N-(2-amino-4-bromo-6-methoxyphenyl)cyclopropanecarboxamide
(785.8 mg, 2.756 mmol) and
1-((trifluoromethyl)sulfonyl)piperidin-4-one (637.1 mg, 2.756 mmol)
were placed in an 8 mL vial equipped with a stir bar then
dichloroethane (50 mL) and acetic acid (0.316 mL, 5.512 mmol) were
added. The mixture was stirred at room temperature for 30 minutes
then sodium triacetoxyborohydride (564 mg, 2.756 mmol) was added as
a solid. The reaction mixture was stirred at room temperature for 4
hours then additional sodium triacetoxyborohydride (564 mg, 2.756
mmol) was added. The reaction mixture was stirred at room
temperature for 4 hours then additional sodium
triacetoxyborohydride (564 mg, 2.756 mmol) was added. The reaction
was stirred at room temperature for 18 h then additional sodium
triacetoxyborohydride (1564 mg, 2.756 mmol) was added. The reaction
was stirred at room temperature for 3 days then additional
1-((trifluoromethyl)sulfonyl)piperidin-4-one (637.1 mg, 2.756 mmol)
was added and stirred for 18 hours. The reaction mixture was
diluted with water (20 mL) and stirred for 30 minutes then the
mixture was poured into saturated sodium bicarbonate solution (20
mL) and extracted with dichloromethane (3.times.20 mL). The organic
extracts were combined, dried over Na.sub.2SO.sub.4, and filtered.
The solvent was removed under reduced pressure. The residue was
purified by chromatography on silica gel eluting with a 0-100%
ethyl acetate/heptane gradient to yield a mixture of
N-(4-bromo-2-methoxy-6-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amin-
o)phenyl)cyclopropanecarboxamide and the corresponding compound in
which the trifluorosulfonylpiperidin-4-yl moiety is replaced with
an ethyl group (882.5 mg).
Step 6:
6-bromo-2-cyclopropyl-4-methoxy-1-(1-((trifluoromethyl)sulfonyl)pi-
peridin-4-yl)-1H-benzo[d]imidazole
[1344] The mixture of compounds prepared in (882.5 mg, 1.764 mmol)
was placed in a 40 mL vial equipped with a stir bar then glacial
acetic acid (10 mL) was added. The reaction was stirred at
80.degree. C. for 3 days then cooled to room temperature, poured
into water (100 mL) and extracted with ethyl acetate (3.times.30
mL). The organic extracts were combined, washed with 3 M NaOH (30
mL), dried over MgSO.sub.4, and filtered. The solvent was removed
under reduced pressure. The residue was purified by chromatography
on silica gel eluting with a 0-100% ethyl acetate/heptane gradient
to yield
6-bromo-2-cyclopropyl-4-methoxy-1-(1-((trifluoromethyl)sulfonyl)piperidin-
-4-yl)-1H-benzo[d]imidazole and the corresponding compound in which
the trifluorosulfonylpiperidin-4-yl moiety is replaced with an
ethyl group.
Step 7:
bis(4-chlorophenyl)(2-cyclopropyl-4-methoxy-1-(1-((trifluoromethyl-
)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)methanol
[1345]
6-Bromo-2-cyclopropyl-4-methoxy-1-(1-((trifluoromethyl)sulfonyl)pip-
eridin-4-yl)-1H-benzo[d]imidazole (496 mg, 1.028 mmol) and
4,4'-dichlorobenzophenone (284.1 mg, 1.131 mmol) were placed in a
40 mL vial equipped with a stir bar then the vial was evacuated and
filled with argon. Dry tetrahydrofuran (4.66 mL) was added then the
solution was cooled to -78.degree. C. t-BuLi (1.209 mL, 2.057 mmol,
1.7 M in pentane) was added dropwise and the reaction mixture was
stirred at -78.degree. C. for 2 hours then the dry ice bath was
allowed to reach room temperature overnight (18 hours). The
reaction mixture was quenched with saturated ammonium chloride
solution (20 mL) and extracted with ethyl acetate (3.times.15 mL).
The combined organic extracts were dried over MgSO.sub.4, filtered,
and the solvent removed under reduced pressure. The resulting
reaction mixture was purified by chromatography on silica gel
eluting with a 0-80% ethyl acetate/heptane gradient yield
bis(4-chlorophenyl)(2-cyclopropyl-4-methoxy-1-(1-((trifluoromethyl)sulfon-
yl)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)methanol, which was
isolated as a 1:1 mixture with
2-cyclopropyl-4-methoxy-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1-
H-benzo[d]imidazole (515.5 mg).
Step 8:
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-4-methoxy-1-(1-((trifl-
uoromethyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole
[1346]
Bis(4-chlorophenyl)(2-cyclopropyl-4-methoxy-1-(1-((trifluoromethyl)-
sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)methanol (515.5
mg, 0.788 mmol, used as a 1:1 mixture as described above) was
placed in a 40 mL vial equipped with a stir bar then dry
dichloromethane (10 mL) and triethylsilane (0.629 mL, 3.938 mmol)
were added. Trifluoroacetic acid (0.303 mL, 3.938 mmol) was added
and the reaction was stirred at room temperature for 18 hours then
the reaction mixture was washed with saturated sodium bicarbonate
solution (50 mL), dried over MgSO.sub.4, and filtered. The solvent
was removed under reduced pressure. The resulting residue was
purified by preparative thin layer chromatography on 4.times.2000
micron silica gel plates developed with 15% acetonitrile containing
0.1% trifluoroacetic acid/dichloromethane yield
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-4-methoxy-1-(1-((trifluoromet-
hyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole.
[1347] MS: 638.0 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.27 (d, J=8.1 Hz, 4H), 7.04 (d, J=8.6 Hz, 4H), 6.66 (s,
1H), 6.38 (s, 1H), 5.58 (s, 1H), 4.61 (tt, J=12.4, 4.0 Hz, 1H),
4.16 (d, J=13.6 Hz, 2H), 3.85 (s, 3H), 3.23 (t, J=12.9 Hz, 2H),
2.43 (qd, J=12.6, 4.0 Hz, 2H), 2.00 (d, J=10.6 Hz, 2H), 1.86-1.95
(m, 1H), 1.21-1.28 (m, 2H), 1.03-1.10 (m, 2H).
Example DP-3
bis(4-chlorophenyl)(2-(oxetan-3-yl)-1-(1-(trifluoromethyl)sulfonyl)piperid-
in-4-yl)-1H-benzo[d]imidazol-6-yl)methanol
##STR00473##
[1348] Step 1:
N-(4-bromo-2-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)phenyl)o-
xetane-3-carboxamide
[1349] Oxetane-3-carboxylic acid (52.5 mg, 0.514 mmol) was placed
in an 8 mL vial equipped with a stir bar then dry dichloromethane
(5 mL) was added followed by diisopropylethylamine (0.114 mL, 0.637
mmol).
5-Bromo-N1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)benzene-1,2-diami-
ne (197 mg, 0.49 mmol, prepared as described in Example YM-26) was
added followed by HATU (242.09 mg, 0.637 mmol). The reaction
mixture was stirred at room temperature for 18 hours. The reaction
mixture was diluted with water (30 mL) then extracted with
dichloromethane (3.times.10 mL). The organic extracts were
combined, dried over Na.sub.2SO.sub.4, and filtered. The solvent
was removed under reduced pressure to yield
N-(4-bromo-2-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)phenyl)o-
xetane-3-carboxamide, which was used in the next step without
further purification.
Step 2:
6-bromo-2-(oxetan-3-yl)-1-(1-((trifluoromethyl)sulfonyl)piperidin--
4-yl)-1H-benzo[d]imidazole
[1350]
N-(4-bromo-2-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)ph-
enyl)oxetane-3-carboxamide (81.6 mg, 0.168 mmol) was placed in an 8
mL vial equipped with a stir bar then acetic acid (1 mL) was added.
The mixture was stirred at 80.degree. C. for 36 hours then cooled
to room temperature. The reaction mixture was diluted with water (6
mL) then poured into saturated sodium bicarbonate solution (30 mL)
and extracted with dichloromethane (3.times.20 mL). The organic
extracts were combined, washed with brine (20 mL), dried over
Na.sub.2SO.sub.4, and filtered. The solvent was removed under
reduced pressure. The resulting residue was purified by preparative
TLC using 2.times.2000 micron silica gel plates developed with 30%
ethyl acetate/dichloromethane to yield
6-bromo-2-(oxetan-3-yl)-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1-
H-benzo[d]imidazole.
Step 3:
bis(4-chlorophenyl)(2-(oxetan-3-yl)-1-(1-((trifluoromethyl)sulfony-
l)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)methanol
[1351]
6-Bromo-2-(oxetan-3-yl)-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-
-yl)-1H-benzo[d]imidazole (56.1 mg, 0.12 mmol) and
4,4'-dichlorobenzophenone (33.09 mg, 0.132 mmol) were placed in a 8
mL vial equipped with a stir bar then the vial was evacuated and
filled with argon. Dry tetrahydrofuran (1 mL) was added and the
solution was cooled to -78.degree. C. t-BuLi (176.17 .mu.L, 0.299
mmol, 1.7M in pentane) was added dropwise then the reaction was
stirred at -78.degree. C. for 30 minutes. The reaction mixture was
quenched with saturated ammonium chloride solution at -78.degree.
C. then warmed to room temperature, poured into saturated ammonium
chloride solution (20 mL), and extracted with ethyl acetate
(3.times.15 mL). The combined organic extracts were dried over
Na.sub.2SO.sub.4, filtered, and the solvent removed under reduced
pressure. The resulting residue was purified by preparative TLC on
a 2000 micron silica gel plate developed with 30% ethyl
acetate/dichloromethane. The isolated product was further purified
by preparative reverse-phase HPLC yielding
bis(4-chlorophenyl)(2-(oxetan-3-yl)-1-(1-((trifluoromethyl)sulfonyl)piper-
idin-4-yl)-1H-benzo[d]imidazol-6-yl)methanol as its TFA salt
containing 1 eq of TFA as determined by NMR.
[1352] MS: 617.8 (M+H.sup.+); .sup.1H NMR (400 MHz,
CDCl.sub.3+CD.sub.3OD) .delta.: 7.67 (d, J=8.6 Hz, 1H), 7.65 (s,
1H), 7.29 (d, J=9.1 Hz, 4H), 7.22 (d, J=8.6 Hz, 4H), 7.15 (d, J=8.6
Hz, 1H), 5.12 (d, J=8.1 Hz, 4H), 4.74 (quin, J=7.7 Hz, 1H), 4.25
(tt, J=12.2, 4.0 Hz, 1H), 4.12-4.18 (m, 2H), 3.27 (t, J=12.9 Hz,
2H), 2.43 (qd, J=12.7, 4.3 Hz, 2H), 1.97 (d, J=10.6 Hz, 2H).
Example DP-4
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-((tetrahydro-2H-pyran-4-yl)m-
ethyl)-1H-benzo[d]imidazole
##STR00474##
[1353] Step 1: methyl
2,2-bis(4-chlorophenyl)-2-(4-nitro-3-(((tetrahydro-2H-pyran-4-yl)methyl)a-
mino)phenyl)acetate
[1354] Methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate (1.033 g,
2.379 mmol, prepared as described in Example DL-1),
4-aminomethyltetrahydropyran (301.4 mg, 2.617 mmol), and potassium
carbonate (493.1 mg, 3.568 mmol) were placed in a 20 mL vial
equipped with a stir bar then dry DMSO (10 mL) was added. The
mixture was stirred at 80.degree. C. for 18 hours then the reaction
was cooled to room temperature and poured into water (30 mL) and
saturated ammonium chloride solution (30 mL). The solid was
isolated by filtration and washed with water (2.times.10 mL). The
precipitate was dissolved in ethyl acetate (50 mL), dried over
MgSO.sub.4, and filtered. The solvent was removed under reduced
pressure to yield methyl
2,2-bis(4-chlorophenyl)-2-(4-nitro-3-(((tetrahydro-2H-pyran-4-yl)methyl)a-
mino)phenyl)acetate, which was used in the next step without
further purification.
Step 2: methyl
2-(4-amino-3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)-2,2-bis(4-c-
hlorophenyl)acetate
[1355] Methyl
2,2-bis(4-chlorophenyl)-2-(4-nitro-3-(((tetrahydro-2H-pyran-4-yl)methyl)a-
mino)phenyl)acetate (529 mg, 0.999 mmol) was placed in a 40 mL vial
equipped with a stir bar then iron powder (279 mg, 4.996 mmol) and
ammonium chloride (534 mg, 9.992 mmol) were added. Anhydrous
ethanol (16 mL) and water (4 mL) were added then the reaction was
stirred at 80.degree. C. for 4 hours. The reaction was cooled to
room temperature and diluted with dichloromethane (20 mL) then the
suspension was filtered through CELITE. The filter was washed with
dichloromethane (3.times.10 mL) then the solvent was removed under
reduced pressure. The residue was dissolved in dichloromethane (30
mL), dried over MgSO.sub.4, and filtered. The solvent was removed
under reduced pressure to yield methyl
2-(4-amino-3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)-2,2-bis(4-c-
hlorophenyl)acetate, which was used directly in the next step
without further purification.
Step 3: methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((tetrahydro-2H-pyran-4-yl)met-
hyl)-1H-benzo[d]imidazol-6-yl)acetate
[1356] Methyl
2-(4-amino-3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)-2,2-bis(4-c-
hlorophenyl)acetate (498.9 mg, 0.999 mmol) was placed in a 20 mL
vial equipped with a stir bar then DMSO (1.91 mL) was added.
[1357] Cyclopropanecarboxaldehyde (149.3 .mu.L, 1.998 mmol) was
added via syringe then the reaction was stirred at room temperature
for 5 days. The reaction was diluted with water (10 mL) then the
mixture was extracted with ethyl acetate (3.times.15 mL). The
organic extracts were combined, washed with brine (20 mL), dried
over MgSO.sub.4, and filtered. The solvent was removed under
reduced pressure. The residue was purified by chromatography on
silica gel eluting with a 0-60% ethyl acetate/heptane gradient to
yield methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((tetrahydro-2H-pyran-4-yl)met-
hyl)-1H-benzo[d]imidazol-6-yl)acetate.
Step 4:
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((tetrahydro-2H-pyran-4-
-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetic acid
[1358] Methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((tetrahydro-2H-pyran-4-yl)met-
hyl)-1H-benzo[d]imidazol-6-yl)acetate (399.4 mg, 0.727 mmol) was
placed in a 20 mL vial equipped with a stir bar then MeOH (4 mL),
1,4-dioxane (4 mL), and 3 M NaOH (2.737 mL, 8.21 mmol) were added.
The reaction mixture was stirred at 60.degree. C. for 18 hours then
the solvent was removed under reduced pressure. The residue was
treated with dichloromethane (30 mL) and 10% citric acid (30 mL)
then the organic layer was separated. The aqueous phase was
extracted with dichloromethane (2.times.30 mL) then the organic
extracts were combined, dried over Na.sub.2SO.sub.4, and filtered.
The solvent was removed under reduced pressure to yield
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((tetrahydro-2H-pyran-4-yl)met-
hyl)-1H-benzo[d]imidazol-6-yl)acetic acid, which was used in the
next step without further purification.
Step 5:
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-((tetrahydro-2H-pyra-
n-4-yl)methyl)-1H-benzo[d]imidazole
[1359]
2,2-Bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((tetrahydro-2H-pyran-4--
yl)methyl)-1H-benzo[d]imidazol-6-yl)acetic acid (371.1 mg, 0.693
mmol) was placed in a 40 mL vial equipped with a stir bar then dry
toluene (20 mL) was added. DBU (10.354 .mu.L, 0.0693 mmol) was
added via micro-syringe and the solution was heated to 90.degree.
C. and stirred for 2 hours. The reaction was cooled to room
temperature then the solvent was removed under reduced pressure.
The resulting residue was purified by chromatography on silica gel
eluting with a 0-80% ethyl acetate/heptane gradient to yield
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-((tetrahydro-2H-pyran-4-yl)-
methyl)-1H-benzo[d]imidazole.
[1360] MS: 491.2 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.56 (d, J=8.1 Hz, 1H), 7.25 (d, J=8.1 Hz, 4H), 7.03 (d,
J=8.6 Hz, 4H), 6.92 (dd, J=8.1, 1.5 Hz, 1H), 6.89 (s, 1H), 5.62 (s,
1H), 4.01 (d, J=7.6 Hz, 2H), 3.95 (dd, J=11.4, 3.3 Hz, 2H),
3.23-3.36 (m, 2H), 1.98-2.11 (m, 1H), 1.89-1.98 (m, 1H), 1.45-1.54
(m, 2H), 1.33-1.45 (m, 2H), 1.23-1.28 (m, 2H), 1.07-1.14 (m,
2H).
Example DP-5
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-((trifluoromethyl)sulfony-
l)piperidin-4-yl)-1H-benzo[d]imidazol-4-ol
##STR00475##
[1361] Step 1:
4-bromo-2-nitro-6-((2-(trimethylsilyl)ethoxy)methoxy)aniline
[1362] 2-Amino-5-bromo-3-nitrophenol (1 g, 4.291 mmol, prepared as
described in Example DP-2 above) was placed in a 20 mL vial
equipped with a stir bar then potassium carbonate (771 mg, 5.579
mmol) and DMF (16 mL) were added. SEM chloride (0.835 mL, 4.721
mmol) was added dropwise then the reaction was stirred at room
temperature for 24 hours. The reaction mixture was quenched with
water (50 mL) and extracted with ethyl acetate (3.times.50 mL). The
organic extracts were combined, washed with brine (30 mL), dried
over Na.sub.2SO.sub.4, and filtered. The solvent was removed under
reduced pressure. The residue was purified by chromatography on
silica gel eluting with a 0-100% ethyl acetate/heptane gradient to
yield
4-bromo-2-nitro-6-((2-(trimethylsilyl)ethoxy)methoxy)aniline.
Step 2:
5-bromo-3-((2-(trimethylsilyl)ethoxy)methoxy)benzene-1,2-diamine
[1363] 4-Bromo-2-nitro-6-((2-(trimethylsilyl)ethoxy)methoxy)aniline
(363 mg, 1 mmol) was placed in a 20 mL vial equipped with a stir
bar then iron powder (279 mg, 5 mmol) and ammonium chloride (534
mg, 10 mmol) were added. Anhydrous ethanol (9 mL) and water (3 mL)
were added then the reaction was stirred at 80.degree. C. for 1
hour. The reaction was cooled to room temperature and diluted with
dichloromethane (10 mL) then the suspension was filtered through a
CELITE cartridge. The filter cake was washed with dichloromethane
(3.times.10 mL) and water (2.times.10 mL) then the organic layer
was separated and washed with brine (20 mL). The combined aqueous
extracts were extracted with dichloromethane (2.times.20 mL). The
organic extracts were combined, dried over Na.sub.2SO.sub.4, and
filtered. The solvent was removed under reduced pressure to yield
5-bromo-3-((2-(trimethylsilyl)ethoxy)methoxy)benzene-1,2-diamine,
which was used in the next step without further purification.
Step 3:
5-bromo-N1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-3-((2-(tr-
imethylsilyl)ethoxy)methoxy)benzene-1,2-diamine
[1364]
5-Bromo-3-((2-(trimethylsilyl)ethoxy)methoxy)benzene-1,2-diamine
(332.5 mg, 0.998 mmol) and
1-((trifluoromethyl)sulfonyl)piperidin-4-one (231 mg, 0.998 mmol)
were placed in a 20 mL vial equipped with a stir bar then
dichloroethane (5 mL) and acetic acid (114 .mu.L, 1.995 mmol) were
added. The mixture was stirred at room temperature for 30 minutes
then sodium triacetoxyborohydride (634 mg, 2.993 mmol) was added as
a solid. The reaction was stirred at room temperature for 36 hours.
The reaction was diluted with water (3 mL) and stirred for 30
minutes then the mixture was poured into saturated sodium
bicarbonate solution (20 mL) and extracted with dichloromethane
(3.times.20 mL). The organic extracts were combined, dried over
Na.sub.2SO.sub.4, and filtered. The solvent was removed under
reduced pressure. The residue was purified by chromatography on
silica gel eluting with a 0-100% ethyl acetate/heptane gradient to
yield
5-bromo-N1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-3-((2-(trimethyl-
silyl)ethoxy)methoxy)benzene-1,2-diamine, in a mixture with other
aromatic amine impurities.
Step 4:
6-bromo-2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)piperidin-4--
yl)-4-((2-(trimethylsilyl)ethoxy)methoxy)-1H-benzo[d]imidazole
[1365]
5-Bromo-N1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-3-((2-(tri-
methylsilyl)ethoxy)methoxy)benzene-1,2-diamine (372 mg, 0.677 mmol,
used as the mixture described above) was placed in a 20 mL vial
equipped with a stir bar then DMSO (1.295 mL) was added.
Cyclopropanecarboxaldehyde (101.25 .mu.L, 1.355 mmol) was added via
syringe then the reaction mixture was stirred at room temperature
for 3 days. The reaction mixture was diluted with ethyl acetate (10
mL) then poured into a mixture of water (40 mL) and saturated
sodium chloride solution (20 mL). The organic phase was separated
then the aqueous layer was extracted with ethyl acetate (3.times.30
mL). The combined organic extracts were washed with brine (30 mL)
then dried over MgSO.sub.4 and filtered. The solvent was removed
under reduced pressure. The resulting residue was purified by
chromatography on silica gel eluting with a 0-80% ethyl
acetate/heptane gradient. The isolated product was further purified
by chromatography on silica gel eluting with a 40% ethyl
acetate/heptane isocratic to yield
6-bromo-2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-4-(-
(2-(trimethylsilyl)ethoxy)methoxy)-1H-benzo[d]imidazole.
Step 5:
bis(4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)-
piperidin-4-yl)-4-((2-(trimethylsilyl)ethoxy)methoxy)-1H-benzo[d]imidazol--
6-yl)methanol
[1366]
6-Bromo-2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-y-
l)-4-((2-(trimethylsilyl)ethoxy)methoxy)-1H-benzo[d]imidazole
(112.8 mg, 0.188 mmol) and 4,4'-dichlorobenzophenone (52 mg, 0.207
mmol) were placed in an 8 mL vial equipped with a stir bar then the
vial was evacuated and filled with argon. Dry tetrahydrofuran
(0.854 mL) was added then the solution was cooled to -78.degree. C.
t-BuLi (221.7 .mu.L, 0.377 mmol, 1.7 M in pentane) was added
dropwise and the reaction was stirred at -78.degree. C. for 2 hour
then the dry ice bath was allowed to reach room temperature
overnight (18 hours). The reaction mixture was quenched with water
(0.6 mL) then the mixture was poured into saturated ammonium
chloride solution (20 mL) and extracted with ethyl acetate
(3.times.15 mL). The combined organic extracts were dried over
Na.sub.2SO.sub.4, filtered, and the solvent removed under reduced
pressure. The resulting reaction mixture was purified by
chromatography on silica gel eluting with a 0-80% ethyl
acetate/heptane gradient to yield
bis(4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)piperid-
in-4-yl)-4-((2-(trimethylsilyl)ethoxy)methoxy)-1H-benzo[d]imidazol-6-yl)me-
thanol.
Step 6:
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-((trifluoromethyl-
)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-4-ol
[1367]
Bis(4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)p-
iperidin-4-yl)-4-((2-(trimethylsilyl)ethoxy)methoxy)-1H-benzo[d]
imidazol-6-yl)methanol (112.8 mg, 0.188 mmol) was placed in an 8 mL
vial equipped with a stir bar then dry dichloromethane (1 mL) was
added. Trifluoroacetic acid (0.2 mL) was added then the reaction
mixture was stirred at room temperature for 1 hour. The solvent was
removed under reduced pressure then the residue was dissolved in
dichloromethane (1 mL) and triethylsilane (36.3 .mu.L, 0.227 mmol)
was added. TFA (17.4 .mu.L, 0.227 mmol) was added then the reaction
was stirred at room temperature for 24 hours. The reaction mixture
was diluted with dichloromethane (20 mL) and washed with saturated
sodium bicarbonate solution (20 mL) then the organic layer was
separated. The aqueous phase was extracted with dichloromethane
(3.times.10 mL) then the organic extracts were combined, dried over
MgSO.sub.4, and filtered. The solvent was removed under reduced
pressure and the resulting residue was purified by chromatography
on silica gel eluting with a 0-100% ethyl acetate/heptane gradient
to yield
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(1-((trifluoromethyl)-
sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-4-ol.
[1368] MS: 491.2 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 8.71 (br. s., 1H), 7.25 (d, J=8.1 Hz, 4H), 7.04 (d, J=8.6
Hz, 4H), 6.65 (s, 1H), 6.48 (s, 1H), 5.54 (s, 1H), 4.61 (tt,
J=12.4, 4.0 Hz, 1H), 4.14-4.24 (m, 2H), 3.23 (t, J=12.6 Hz, 2H),
2.47 (qd, J=12.6, 4.0 Hz, 2H), 2.00 (d, J=11.1 Hz, 2H), 1.85-1.94
(m, 1H), 1.00-1.14 (m, 4H).
Example DP-6
4-((4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)piperidi-
n-4-yl)-1H-benzo[d]imidazol-6-yl)hydroxy)methyl)benzoic acid
##STR00476##
[1369] and
4-((4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfon-
yl)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)methyl)benzoic acid
##STR00477##
[1370] Step 1:
(4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)piperidin--
4-yl)-1H-benzo[d]imidazol-6-yl)methanol and
(4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)piperidin--
4-yl)-1H-benzo[d]imidazol-6-yl)methanone
[1371]
6-Bromo-2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)piperidin-4-y-
l)-1H-benzo[d]imidazole (209.3 mg, 0.463 mmol, prepared as
described in Example YM-26) was placed in an 8 mL vial equipped
with a stir bar then the vial was evacuated and filled with argon.
Dry tetrahydrofuran (1 mL) was added then the solution was cooled
to -78.degree. C. n-BuLi (318.1 .mu.L, 0.509 mmol, 1.6 M in hexane)
was added dropwise then the reaction was stirred at -78.degree. C.
for 5 minutes.
[1372] 4-Chlorobenzaldehyde (130 mg, 0.926 mmol) was placed in an 8
mL vial equipped with a stir bar then the vial was evacuated and
filled with argon. Dry tetrahydrofuran (1 mL) was added then the
solution was added dropwise to the stirred aryllithium solution at
-78.degree. C. The reaction mixture was allowed to warm to room
temperature, stirred for 18 hours, then poured into saturated
ammonium chloride solution (20 mL) and extracted with ethyl acetate
(3.times.5 mL). The combined organic extracts were dried over
Na.sub.2SO.sub.4, filtered, and the solvent was removed under
reduced pressure. The resulting reaction mixture was purified by
chromatography on silica gel eluting with a 0-100% ethyl
acetate/heptane gradient to yield
(4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)piperidin--
4-yl)-1H-benzo[d]imidazol-6-yl)methanol and a smaller amount
(4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)piperidin--
4-yl)-1H-benzo[d]imidazol-6-yl)methanone.
Step 2:
(4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)pip-
eridin-4-yl)-1H-benzo[d]imidazol-6-yl)methanone
[1373]
(4-Chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)pipe-
ridin-4-yl)-1H-benzo[d]imidazol-6-yl)methanol (141.7 mg, 0.276
mmol) was placed in an 8 mL vial equipped with a stir bar then
dichloromethane (2 mL) was added. Dess-Martin periodinane (128.6
mg, 0.303 mmol) was added as a solid then the reaction mixture was
stirred at room temperature for 18 hours. The reaction mixture was
diluted with dichloromethane (100 mL) and washed with 10%
Na.sub.2S.sub.2O.sub.3 (50 mL) and 2 M Na.sub.2CO.sub.3 solution
(50 mL), then dried over MgSO.sub.4 and filtered. The solvent was
removed under reduced pressure. The residue was combined with the
small amount of product prepared in the previous step and purified
by chromatography on silica gel eluting with a 0-100% ethyl
acetate/heptane gradient to yield
(4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)piperidin--
4-yl)-1H-benzo[d]imidazol-6-yl)methanone.
Step 3:
(4-(1,3-dioxolan-2-yl)phenyl)(4-chlorophenyl)(2-cyclopropyl-1-(1-(-
(trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)methano-
l
[1374]
(4-Chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)pipe-
ridin-4-yl)-1H-benzo[d]imidazol-6-yl)methanone (50 mg, 0.098 mmol)
was placed in an 8 mL vial equipped with a stir bar then the vial
was evacuated and filled with argon. Dry tetrahydrofuran (1 mL) was
added then (4-(1,3-dioxolan-2-yl)phenyl)magnesium bromide (0.391
mL, 0.195 mmol, 0.5 M in tetrahydrofuran) was added at room
temperature. The mixture was stirred at room temperature for 18
hours then quenched with saturated ammonium chloride solution (2
mL). The mixture was extracted with ethyl acetate (3.times.5 mL)
then the organic extracts were combined, dried over MgSO.sub.4, and
filtered. The solvent was removed under reduced pressure. The
resulting residue was purified by preparative TLC on a 2000 micron
silica gel plate developed with 30% ethyl acetate/dichloromethane.
The isolated product fraction was further purified by preparative
TLC on a 2000 micron silica gel plate developed with 30% ethyl
acetate/dichloromethane to yield
(4-(1,3-dioxolan-2-yl)phenyl)(4-chlorophenyl)(2-cyclopropyl-1-(1-((triflu-
oromethyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)methanol.
Step 4:
4-((4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)-
piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)(hydroxy)methyl)benzaldehyde
[1375]
(4-(1,3-Dioxolan-2-yl)phenyl)(4-chlorophenyl)(2-cyclopropyl-1-(1-((-
trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)methanol
(72.3 mg, 0.109 mmol) was placed in an 8 mL vial equipped with a
stir bar then acetone (3 mL) and water (1 mL) were added.
AMBERLYST.TM. 15 resin (70 mg) was added then the mixture was
stirred at 60.degree. C. for 2 h. The reaction mixture was cooled
to room temperature then the resin was filtered off and rinsed with
acetone. The solvent was removed under reduced pressure. The
residue was dissolved in dichloromethane (20 mL) then dried over
MgSO.sub.4 and filtered. The solvent was removed under reduced
pressure. The resulting residue was purified by preparative TLC on
a 2000 micron silica gel plate developed with 30% ethyl
acetate/dichloromethane to yield
4-((4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)piperid-
in-4-yl)-1H-benzo[d]imidazol-6-yl)(hydroxy)methyl)benzaldehyde.
Step 5:
4-((4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)-
piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)(hydroxy)methyl)benzoic
acid
[1376]
4-((4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)p-
iperidin-4-yl)-1H-benzo[d]imidazol-6-yl)(hydroxy)methyl)benzaldehyde
(43.5 mg, 0.07 mmol) was dissolved in 1,4-dioxane (4 mL) then
sulfamic acid (15.03 mg, 0.155 mmol) was added as a solid. A
solution of sodium chlorite (17.50 mg, 0.155 mmol) in water (2 mL)
was added dropwise with stirring and then the reaction mixture was
stirred at room temperature for 15 hours. The reaction mixture was
diluted with ethyl acetate (20 mL) and washed with brine (10 mL)
then the organic layer was dried over MgSO.sub.4 and filtered. The
solvent was removed under reduced pressure. The residue was
purified by preparative TLC on a 2000 micron silica gel plate
developed with 10% methanol/dichloromethane to yield
4-((4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)piperid-
in-4-yl)-1H-benzo[d]imidazol-6-yl)(hydroxy)methyl)benzoic acid.
[1377] MS: 634.2 (M+H.sup.+); .sup.1H NMR (400 MHz,
CDCl.sub.3+CD.sub.3OD) .delta.: 7.94 (d, J=8.1 Hz, 2H), 7.57 (s,
1H), 7.48 (d, J=8.6 Hz, 1H), 7.32 (d, J=8.1 Hz, 2H), 7.28 (d, J=8.6
Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 7.01 (d, J=8.1 Hz, 1H), 4.75 (tt,
J=12.3, 3.9 Hz, 1H), 4.16 (d, J=12.6 Hz, 2H), 3.31 (t, J=13.1 Hz,
2H), 2.52 (q, J=12.3 Hz, 2H), 2.00-2.11 (m, 3H), 1.16 (d, J=7.1 Hz,
4H).
Step 6:
4-((4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)-
piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)methyl)benzoic acid
[1378]
4-((4-Chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)p-
iperidin-4-yl)-1H-benzo[d]imidazol-6-yl)(hydroxy)methyl)benzoic
acid (24.9 mg, 0.039 mmol) was placed in an 8 mL vial equipped with
a stir bar then dry dichloromethane (1 mL) and triethylsilane
(31.36 .mu.L, 0.196 mmol) were added. Trifluoroacetic acid (15.13
.mu.L, 0.196 mmol) was added then the reaction mixture was stirred
at room temperature for 4 days at which time additional
trifluoroacetic acid (15.13 .mu.L, 0.196 mmol) and triethylsilane
(31.36 .mu.L, 0.196 mmol) were added. The reaction mixture was
stirred at room temperature for 24 hours. An additional amount of
trifluoroacetic acid (15.13 .mu.L, 0.196 mmol) and triethylsilane
(31.36 .mu.L, 0.196 mmol) were added. The reaction mixture was
stirred for an additional 5 days then the solvent was removed under
reduced pressure. The residue was triturated with diethyl ether (3
mL) then the supernatant was decanted. This was repeated once more
then the residual solvent was removed under reduced pressure to
yield
4-((4-chlorophenyl)(2-cyclopropyl-1-(1-((trifluoromethyl)sulfonyl)piperid-
in-4-yl)-1H-benzo[d]imidazol-6-yl)methyl)benzoic acid
trifluoroacetate salt as a white powder.
[1379] MS: 618.1 (M+H.sup.+); .sup.1H NMR (400 MHz, DMSO-d6)
.delta.: 7.90 (d, J=8.6 Hz, 2H), 7.55 (d, J=8.6 Hz, 1H), 7.50 (br.
s., 1H), 7.36-7.43 (m, J=8.6 Hz, 2H), 7.20-7.28 (m, J=8.1 Hz, 2H),
7.15 (d, J=8.6 Hz, 2H), 7.04 (d, J=8.1 Hz, 1H), 5.94 (s, 1H), 5.05
(t, J=11.9 Hz, 1H), 3.98 (d, J=12.1 Hz, 2H), 3.52 (br. s., 2H),
2.38-2.45 (m, 1H), 2.17-2.36 (m, 2H), 2.08 (d, J=11.1 Hz, 2H),
1.09-1.24 (m, 4H).
Example DP-8
6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1-
H-benzo[d]imidazole
##STR00478##
[1381]
6-(Bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-(tetrahydro-2H-pyran--
4-yl)-1H-benzo[d]imidazole was prepared by according to the
procedure as described in Example DP-4 above, substituting
4-aminotetrahydropyran for 4-aminomethyltetrahydropyran in Step
1.
[1382] MS: 515.2 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 8.09 (d, J=9.1 Hz, 1H), 8.00 (d, J=6.6 Hz, 1H), 7.30 (d,
J=8.6 Hz, 4H), 7.10 (d, J=8.6 Hz, 4H), 6.52 (dd, J=9.1, 2.0 Hz,
1H), 6.42 (d, J=2.0 Hz, 1H), 3.91-3.99 (m, 2H), 3.83 (s, 3H),
3.32-3.41 (m, 2H), 3.22-3.32 (m, 1H), 1.80 (d, J=12.6 Hz, 2H),
1.49-1.62 (m, 2H).
Example DP-9
2-(6-(bis(4-chlorophenyl)methyl)-1-(1-((trifluoromethyl)sulfonyl)piperidin-
-4-v)-1H-benzo[d]imidazol-2-yl)prop-2-en-1-ol
##STR00479##
[1383] Step 1: methyl
2,2-bis(4-chlorophenyl)-2-(4-nitro-3-((1-((trifluoromethyl)sulfonyl)piper-
idin-4-yl)amino)phenyl)acetate
[1384] Methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate (589.2
mg, 1.357 mmol, prepared as described in Example DL-1),
4-aminopiperidine-1-trifluoromethylsulfonyl hydrochloride (401 mg,
1.49 mmol) and K.sub.2CO.sub.3 (563 mg, 4.07 mmol) were placed in
an 8 mL vial equipped with a stir bar then dry DMSO (5 mL) was
added. The reaction mixture was stirred at 80.degree. C. for 3
days, cooled to room temperature, and poured into water (30 mL).
The solid was isolated by filtration and washed with water
(2.times.10 mL). The precipitate was dissolved in ethyl acetate (50
mL), dried over MgSO.sub.4, and filtered. The solvent was removed
under reduced pressure. The resulting residue was purified by
chromatography on silica gel eluting with a 0-40% ethyl
acetate/heptane gradient to yield methyl
2,2-bis(4-chlorophenyl)-2-(4-nitro-3-((1-((trifluoromethyl)sulfonyl)piper-
idin-4-yl)amino)phenyl)acetate.
Step 2: methyl
2-(4-amino-3-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)phenyl)--
2,2-bis(4-chlorophenyl)acetate
[1385] Methyl
2,2-bis(4-chlorophenyl)-2-(4-nitro-3-((1-((trifluoromethyl)sulfonyl)piper-
idin-4-yl)amino)phenyl)acetate (612.2 mg, 0.947 mmol) was placed in
a 40 mL vial equipped with a stir bar then iron powder (264.4 mg,
4.735 mmol) and ammonium chloride (506.6 mg, 9.47 mmol) were added.
Anhydrous ethanol (16 mL) and water (4 mL) were added then the
reaction was stirred at 80.degree. C. for 4 hours. The reaction
mixture was cooled to room temperature and diluted with
dichloromethane (20 mL) then the suspension was filtered through
CELITE. The filter was washed with dichloromethane (3.times.10 mL)
then the solvent was removed under reduced pressure. The residue
was dissolved in dichloromethane (30 mL), dried over MgSO.sub.4,
and filtered. The solvent was removed under reduced pressure to
yield methyl
2-(4-amino-3-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)p-
henyl)-2,2-bis(4-chlorophenyl)acetate, which was used directly in
the next step without further purification.
Step 3: methyl
2,2-bis(4-chlorophenyl)-2-(4-(oxetane-3-carboxamido)-3-((1-((trifluoromet-
hyl)sulfonyl)piperidin-4-yl)amino)phenyl)acetate
[1386] Oxetane-3-carboxylic acid (43.5 mg, 0.426 mmol) was placed
in an 8 mL vial equipped with a stir bar then dry dichloromethane
(5 mL) was added followed by diisopropylethylamine (0.094 mL, 0.527
mmol). Methyl
2-(4-amino-3-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)phenyl)--
2,2-bis(4-chlorophenyl)acetate (250 mg, 0.406 mmol) was added
followed by HBTU (199.9 mg, 0.527 mmol). The reaction was stirred
at room temperature for 18 hours. The reaction mixture was diluted
with water (30 mL) then extracted with dichloromethane (3.times.10
mL). The organic extracts were combined, dried over MgSO.sub.4, and
filtered. The solvent was removed under reduced pressure. The
resulting residue was purified by chromatography on silica gel
eluting with a 0-100% ethyl acetate/heptane gradient to yield
methyl
2,2-bis(4-chlorophenyl)-2-(4-(oxetane-3-carboxamido)-3-((1-((trifluoromet-
hyl)sulfonyl)piperidin-4-yl)amino)phenyl)acetate.
Step 4: methyl
2,2-bis(4-chlorophenyl)-2-(2-(3-hydroxyprop-1-en-2-yl)-1-(1-((trifluorome-
thyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)acetate
[1387] Methyl
2,2-bis(4-chlorophenyl)-2-(4-(oxetane-3-carboxamido)-3-((1-((trifluoromet-
hyl)sulfonyl)piperidin-4-yl)amino)phenyl)acetate (126.4 mg, 0.18
mmol) was placed in an 8 mL vial equipped with a stir bar then
acetic acid (1 mL) was added. The reaction mixture was stirred at
80.degree. C. for 36 hours then cooled to room temperature. The
reaction was diluted with water (6 mL) then poured into saturated
sodium bicarbonate solution (30 mL) and extracted with
dichloromethane (3.times.20 mL). The organic extracts were
combined, washed with brine (20 mL), dried over Na.sub.2SO.sub.4,
and filtered. The solvent was removed under reduced pressure. The
resulting residue was purified by preparative TLC using
2.times.2000 micron silica gel plates developed with 30% ethyl
acetate/dichloromethane to yield methyl
2,2-bis(4-chlorophenyl)-2-(2-(3-hydroxyprop-1-en-2-yl)-1-(1-((trif-
luoromethyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)acetate.
Step 5:
2,2-bis(4-chlorophenyl)-2-(2-(3-hydroxyprop-1-en-2-yl)-1-(1-((trif-
luoromethyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)acetic
acid
[1388] Methyl
2,2-bis(4-chlorophenyl)-2-(2-(3-hydroxyprop-1-en-2-yl)-1-(1-((trifluorome-
thyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)acetate
(16.1 mg, 0.024 mmol) was placed in an 8 mL vial equipped with a
stir bar then methanol (1 mL) and 3 M sodium hydroxide (88.8 .mu.L,
0.266 mmol) were added. The reaction mixture was stirred at
60.degree. C. for 36 hours, then 10% citric acid solution (3 mL)
and dichloromethane (3 mL) were added. The organic layer was
separated then the aqueous phase was extracted with dichloromethane
(3.times.3 mL). The organic extracts were combined, dried over
MgSO.sub.4, and filtered. The solvent was removed under reduced
pressure to yield
2,2-bis(4-chlorophenyl)-2-(2-(3-hydroxyprop-1-en-2-yl)-1-(1-((trifluorome-
thyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)acetic acid,
which was used directly in the next step without further
purification.
Step 6:
2-(6-(bis(4-chlorophenyl)methyl)-1-(1-((trifluoromethyl)sulfonyl)p-
iperidin-4-yl)-1H-benzo[d]imidazol-2-yl)prop-2-en-1-ol
[1389]
2,2-bis(4-chlorophenyl)-2-(2-(3-hydroxyprop-1-en-2-yl)-1-(1-((trifl-
uoromethyl)sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-6-yl)acetic
acid (9.2 mg, 0.0138 mmol) was placed in an 8 mL vial equipped with
a stir bar then dry toluene (1 mL) was added. DBU (0.206 .mu.L,
0.0014 mmol) was added via microsyringe and the solution was heated
to 90.degree. C. and stirred for 2 hours. The reaction mixture was
cooled to room temperature, diluted with dichloromethane (1 mL)
then applied to a 2000 micron silica gel preparative TLC plate. The
plate was developed with 50% ethyl acetate/heptane to yield
2-(6-(bis(4-chlorophenyl)methyl)-1-(1-((trifluoromethyl)sulfonyl)piperidi-
n-4-yl)-1H-benzo[d]imidazol-2-yl)prop-2-en-1-ol.
[1390] MS: 624.1 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.68 (d, J=8.6 Hz, 1H), 7.29 (d, J=8.6 Hz, 4H), 7.22 (s,
1H), 7.00-7.07 (m, 5H), 5.88 (s, 1H), 5.65 (s, 1H), 5.36 (s, 1H),
4.71 (tt, J=12.5, 3.9 Hz, 1H), 4.55 (s, 2H), 4.13 (d, J=13.6 Hz,
2H), 3.17 (t, J=12.9 Hz, 2H), 2.47 (qd, J=12.9, 4.3 Hz, 2H),
1.93-2.03 (m, 2H).
Example BD-1
bis(4-chlorophenyl)(2-cyclopropyl-1-((1-((trifluoromethyl)sulfonyl)piperid-
in-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)methanol
##STR00480##
[1391] Step 1: methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate
[1392] To a solution of methyl 2,2-bis(4-chlorophenyl)acetate
(4.427 g; 15 mmol) in tetrahydrofuran (80 mL) under Argon was added
potassium a 1M solution of tert-butoxide in THF (15 mL; 1M in THF;
15 mmol). The mixture was stirred for 15 min at 0.degree. C. and a
solution of 2,4-difluoronitrobenzene (2.531 g; 15.75 mmol) in
tetrahydrofuran (20 mL) was added dropwise. The mixture was allowed
to stir at room temperature overnight. The reaction mixture was
quenched with a sat NH.sub.4Cl solution (20 mL). The organic phase
was separated and dried over MgSO.sub.4, filtered, and evaporated.
The residue was purified via flash column chromatography (eluent
gradient: 0 to 70% CH.sub.2Cl.sub.2 in heptane). The desired
fractions were combined and evaporated to yield methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate as a
yellow oil.
[1393] Rf (CH.sub.2Cl.sub.2:heptane; 1:1)=0.31; No clear molecular
ion observed; Purity: 78% pure @ 214 nm and 92% @ 254 nm
Step 2: tert-butyl
4-(((5-(1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl)-2-nitrophenyl)amino-
)methyl)piperidine-1-carboxylate
[1394] Methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate (2.171 g;
5 mmol), tert-butyl
4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (1.286 g; 6
mmol), and diisopropylethylamine (2.154 mL; 12.5 mmol) were
dissolved in acetonitrile (10.856 mL) in a sealable tube and the
mixture was heated at 75.degree. C. for 1 hour. HPLC/MS analysis of
an aliquot revealed mostly desired material. The reaction mixture
was purified via flash column chromatography to tert-butyl
4-(((5-(1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl)-2-nitrophenyl)amino-
)methyl)piperidine-1-carboxylate. The material was used in the next
reaction without further purification.
[1395] (M-Boc)+=528.2/530.1
Step 3: tert-butyl
4-(((2-amino-5-(1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl)phenyl)amino-
)methyl)piperidine-1-carboxylate
[1396] A solution of tert-butyl
4-(((5-(1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl)-2-nitrophenyl)amino-
)methyl)piperidine-1-carboxylate (1.6 g; 2.546 mmol) in THF (90 mL)
and methanol (10 mL) in a 200 mL Parr flask was purged with
nitrogen, and Raney-Ni (0.5 g) was added. The mixture was
hydrogenated at room temperature overnight on a Parr apparatus
under 15 psi hydrogen pressure. The catalyst was removed via
filtration over CELITE and the filtrate was evaporated, yielding
tert-butyl
4-(((2-amino-5-(1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl)phenyl)amino-
)methyl)piperidine-1-carboxylate, which was used in the next
reaction without further purification.
[1397] Purity: 77% pure @ 214 nm and 90% @ 254 nm;
M+Na=620.2/622.2
Step 4: tert-butyl
4-((6-(1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl)-2-cyclopropyl-1H-ben-
zo[d]imidazol-1-yl)methyl)piperidine-1-carboxylate
[1398] To a solution of tert-butyl
4-(((2-amino-5-(1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl)phenyl)amino-
)methyl)piperidine-1-carboxylate (1.53 g; 2.55 mmol) in DMSO (5 mL)
was added cyclopropanecarboxaldehyde (0.953 mL; 12.75 mmol) and the
mixture was stirred for 21/2 days at room temperature while open to
the air. HPLC/MS analysis of an aliquot revealed complete
disappearance of starting material with formation of desired
product. The reaction mixture was diluted with water (50 mL) and
extracted with a 1:1 mixture of diethyl ether and EtOAc (100 mL
each). The organic layer was separated, dried over MgSO.sub.4,
filtered, and evaporated. The residue was purified via flash column
chromatography (eluent gradient: 30:70 EtOAc:heptane to 100%
EtOAc). The desired fractions were combined and evaporated to yield
tert-butyl
4-((6-(1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl)-2-cyclopropyl-1H-ben-
zo[d]imidazol-1-yl)methyl)piperidine-1-carboxylate as an off-white
solid.
[1399] Rf (100% EtOAc)=0.65; Purity: 91% pure @ 214 nm and 254 nm;
MH+=648.3/650.3
Step 5: methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-(piperidin-4-ylmethyl)-1H-benz-
o[d]imidazol-6-yl)acetate
[1400] To a solution of tert-butyl
4-((6-(1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl)-2-cyclopropyl-1H-ben-
zo[d]imidazol-1-yl)methyl)piperidine-1-carboxylate (500 mg; 0.771
mmol) in diethyl ether (9.23 mL) and 1,4-dioxane (4.61 mL) was
added a 4N HCl in 1,4-dioxane solution (10 mL) and the mixture was
stirred overnight at room temperature under Argon. Diethyl ether
(50 mL) was added, and the mixture was stirred vigorously for 10
min. The solid was allowed to settle and the solvent was decanted.
The residue was treated with additional diethyl ether (50 mL) and
again decanted. Residual solvent was removed via evaporation and
drying under vacuum to methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-(piperidin-4-ylmethyl)-1H-benz-
o[d]imidazol-6-yl)acetate as a tan solid.
[1401] Purity: 88% pure @ 214 nm and 92% pure @ 254 nm;
MH+=548.3/550.2
Step 6: evaporated methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((1-((trifluoromethyl)sulfonyl-
)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetate
[1402] To a solution of methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-(piperidin-1-ylmethyl)-1H-benz-
o[d]imidazol-6-yl)acetate (0.5 g; 0.805 mmol) and trimethylamine
(0.336 mL; 2.414 mmol) in methylene chloride (20 mL) at 0*C under
Argon was added dropwise a 1M solution of triflic anhydride (1M in
CH.sub.2Cl.sub.2; 0.966 mL). The reaction mixture was allowed to
stir for 1 hour at 0.degree. C. HPLC/MS analysis of an aliquot
revealed .about.2/3 conversion to desired material. Additional of
triflic anhydride (1.932 mL; 1.932 mmol, 1M in CH.sub.2Cl.sub.2)
was added, and the mixture was stirred for another hour at
0.degree. C. HPLC/MS analysis of an aliquot revealed complete
disappearance starting material and formation of desired product.
Sat. NaHCO.sub.3 (10 mL) was added, and the mixture was stirred for
5 min. The organic layer was separated, dried over MgSO.sub.4,
filtered, and evaporated. The residue was purified via flash column
chromatography (eluent gradient: 20% EtOAc in heptane to 100%
EtOAc). The desired fractions were combined and evaporated methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((1-((trifluoromethyl)sulfonyl-
)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetate as a tan
solid.
Step 7:
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((1-((trifluoromethyl)s-
ulfonyl)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetic
acid
[1403] To a solution of methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((1-((trifluoromethyl)sulfonyl-
)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetate (260 mg;
0.382 mmol) in methanol (5 mL) in a sealable tube was added 3N NaOH
in water (2 mL). The tube was sealed and the mixture was heated at
45.degree. C. overnight. HPLC/MS analysis of an aliquot revealed
complete disappearance of starting material and formation of
desired material. EtOAc (50 mL) was added, followed by 2N HCl (6
mL). The organic phase was separated, and the aqueous layer was
extracted with an additional EtOAc (50 mL). The combined organic
layers were dried over MgSO.sub.4, filtered, and evaporated to
yield
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((1-((trifluoromethyl)sulfonyl-
)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetic acid.
[1404] Purity: >95% pure @ 214 nm; 79% pure @ 254 nm;
MH+=666.2/668.1
Step 8:
6-(Bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-((1-((trifluoromethy-
l)sulfonyl)piperidin-4-yl)methyl)-1H-benzo[d]imidazole
[1405]
2,2-Bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((1-((trifluoromethyl)su-
lfonyl)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetic acid
(260 mg; 0.39 mmol) and DBU (0.35 mL; 2.34 mmol) were combined in
toluene (10 mL) under Argon and heated to 90.degree. C. for 3
hours. HPLC/MS analysis of an aliquot revealed complete
disappearance of starting material. The mixture was evaporated,
dissolved in CH.sub.3CN (4 mL) and purified via reverse phase HPLC.
The desired fractions were combined and lyophilized to
6-(Bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-((1-((trifluoromethyl)su-
lfonyl)piperidin-4-yl)methyl)-1H-benzo[d]imidazole as a white
solid.
[1406] Purity: 94% pure @ 214 nm and 95% pure @ 254 nm;
MH+=622.2/624.2; .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm
1.25-1.45 (m, 7H) 1.69 (br d, J=12.72 Hz, 2H) 2.12 (br s, 1H) 3.09
(br t, J=12.72 Hz, 2H) 3.74-3.84 (m, 2H) 4.41 (br d, J=5.62 Hz, 2H)
5.85 (s, 1H) 7.12-7.22 (m, 5H) 7.40 (d, J=8.07 Hz, 4H) 7.61 (br d,
J=8.31 Hz, 1H) 7.71 (br s, 1H)
Step 9:
bis(4-chlorophenyl)(2-cyclopropyl-1-((1-((trifluoromethyl)sulfonyl-
)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)methanol
[1407]
6-(Bis(4-chlorophenyl)methyl)-2-cyclopropyl-1-((1-((trifluoromethyl-
)sulfonyl)piperidin-4-yl)methyl)-1H-benzo[d]imidazole (80 mg; 0.109
mmol) and K.sub.2CO.sub.3 (150.1 mg; 1.085 mmol) were combined in
DMSO (10 mL) in a 2 mL vial and the mixture was stirred overnight
at room temperature while open to the air. HPLC/MS analysis of an
aliquot revealed only presence of 1 A.
[1408] Two pellets (.about.400 mg) of NaOH were added, and the
mixture was continued to stir for 21/2 days at room temperature
while air was being bubbled through the reaction mixture. HPLC/MS
analysis of an aliquot revealed complete conversion to desired
material. Water (50 mL) and diethyl ether (250 mL) were added to
the reaction mixture, and the organic phase was separated. The
aqueous layer was extracted with diethyl ether (150 mL), and the
combined organic layers were washed with brine (25 mL), dried over
K.sub.2CO.sub.3, filtered, and evaporated. The residue was purified
over a short silica column (eluent: 100% EtOAc). The desired
fractions were combined and evaporated to yield
bis(4-chlorophenyl)(2-cyclopropyl-1-((1-((trifluoromethyl)sulfonyl)piperi-
din-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)methanol as a white
powder.
[1409] Purity: >95% pure @ 214 and 254 nm; MH+=638.1/640.2;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.11-1.39 (m, 6H)
1.60 (br d, J=13.20 Hz, 2H) 2.01 (br d, J=15.16 Hz, 1H) 2.19-2.38
(m, 1H) 3.09 (br t, J=12.10 Hz, 2H) 3.78 (br d, J=11.25 Hz, 2H)
4.18 (br d, J=6.85 Hz, 2H) 6.63 (s, 1H) 6.81-6.96 (m, 1H) 7.15-7.46
(m, O H)
Example BD-2
4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)m-
ethyl)-1-((trifluoromethyl)sulfonyl)piperidin-4-ol
##STR00481##
[1410] Step 1: tert-butyl
4-(((5-(1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl)-2-nitrophenyl)amino-
)methyl)-4-hydroxypiperidine-1-carboxylate
[1411] Methyl
2,2-bis(4-chlorophenyl)-2-(3-fluoro-4-nitrophenyl)acetate (2.171 g;
5 mmol), tert-butyl 4-(aminomethyl)-4-hydroxy-tetrahydro-1
(2H)-pyridinecarboxylate (1.382 g; 6 mmol), and
diisopropylethylamine (2.154 mL; 12.5 mmol) were dissolved in
acetonitrile (10.9 mL) in a sealable tube and the mixture was
heated at 75.degree. C. for 1 hour. HPLC/MS analysis of an aliquot
revealed mostly desired material. The reaction mixture was purified
via flash column chromatography to yield tert-butyl
4-(((5-(1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl)-2-nitrophenyl)amino-
)methyl)-4-hydroxypiperidine-1-carboxylate. The material was used
in the next reaction without further purification.
[1412] Purity: >95% pure @ 214 and 254 nm; M-Boc=544.2/546.2
Step 2: tert-butyl
4-(((2-amino-5-(1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl)phenyl)amino-
)methyl)-4-hydroxypiperidine-1-carboxylate
[1413] A solution of tert-butyl
4-(((5-(1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl)-2-nitrophenyl)amino-
)methyl)-4-hydroxypiperidine-1-carboxylate (2.05 g; 3.181 mmol) in
tetrahydrofuran (100 mL) and methanol (10 mL) in a 200 mL Parr
flask was purged with nitrogen, and H.sub.2 was added. The mixture
was hydrogenated at room temperature for 6 hours in a Parr
apparatus under 12 psi hydrogen pressure. HPLC/MS analysis of an
aliquot revealed complete conversion to desired material. The
catalyst was removed via filtration over CELITE. The filtrate was
evaporated to dryness and stored under vacuum overnight to yield
tert-butyl
4-(((2-amino-5-(1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl)phenyl)amino-
)methyl)-4-hydroxypiperidine-1-carboxylate.
[1414] Purity: 93% pure @ 214 nm; >95% pure @ 254 nm;
M+Na=636.2/638.3
Step 3: tert-butyl
4-((6-(1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl)-2-cyclopropyl-1H-ben-
zo[d]imidazol-1-yl)methyl)-4-hydroxypiperidine-1-carboxylate
[1415] To a solution of tert-butyl
4-(((2-amino-5-(1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl)phenyl)amino-
)methyl)-4-hydroxypiperidine-1-carboxylate (1.954 g; 3.18 mmol) in
dimethyl sulfoxide (5 mL) was added cyclopropylcarboxaldehyde
(1.188 mL; 15.9 mmol) and the mixture was stirred overnight at room
temperature while open to the air. HPLC/MS analysis of an aliquot
revealed complete disappearance of starting material with formation
of desired product. The reaction mixture diluted with water (50 mL)
and extracted with a 1:1 mixture of diethyl ether and EtOAc (100 mL
each). The organic layer was separated, dried over MgSO.sub.4,
filtered, and evaporated. The residue was purified via flash column
chromatography (eluent gradient: 1:1 EtOAc:heptane to 100% EtOAc).
The desired fractions were combined and evaporated to yield
tert-butyl
4-((6-(1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl)-2-cyclopropyl-1H-ben-
zo[d]imidazol-1-yl)methyl)-4-hydroxypiperidine-1-carboxylate as an
off-white solid.
[1416] Rf (100% EtOAc)=0.52; Purity: >95% pure @ 214 and 254 nm;
MH+=664.2/666.3
Step 4:
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((4-hydroxypiperidin-4--
yl)methyl)-1H-benzo[d]imidazol-6-yl)acetate
[1417] To a solution of tert-butyl
4-((6-(1,1-bis(4-chlorophenyl)-2-methoxy-2-oxoethyl)-2-cyclopropyl-1H-ben-
zo[d]imidazol-1-yl)methyl)-4-hydroxypiperidine-1-carboxylate (615
mg; 0.925 mmol) in diethyl ether (2.9 mL) and 1,4-dioxane (1.45 mL)
was added a 4N HCl in 1,4-dioxane solution (8 mL) and the mixture
was stirred overnight at room temperature under Argon. Diethyl
ether (50 mL) was added, and the mixture was stirred vigorously for
10 min. The solid was allowed to settle and the solvent was
decanted. The residue was treated with additional diethyl ether (50
mL) and again decanted. Residual solvent was removed via
evaporation and drying under vacuum to yield methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((4-hydroxypiperidin-4--
yl)methyl)-1H-benzo[d]imidazol-6-yl)acetate as a white solid.
[1418] Purity: >95% pure @ 214 and 254 nm; MH+=564.2/566.2
Step 5: A mixture of methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((4-hydroxy-1-((trifluoromethy-
l)sulfonyl)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetate
and methyl
2,2-bis(4-chlorophenyl)-2-(3-(((4-hydroxy-1-((trifluoromethyl)sulf-
onyl)piperidin-4-yl)methyl)amino)-4-(trifluoromethylsulfonamido)phenyl)ace-
tate
[1419] To a solution of methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((4-hydroxypiperidin-4-yl)meth-
yl)-1H-benzo[d]imidazol-6-yl)acetate (0.637 g, 1 mmol) and
2,6-di-tert-butyl-4-methylpyridine (718.7 mg, 3.5 mmol) in
methylene chloride (20 mL) at 0.degree. C. under Argon was added
dropwise 1M triflic anhydride in methylene chloride (1.2 mL, 1.2
mmol). The reaction mixture was allowed to stir for 1 hour at
0.degree. C. HPLC/MS analysis of an aliquot revealed .about.1/3
conversion to desired material and formation of about equal amounts
of P.sub.2. An additional 2.4 equiv of 1M triflic anhydride in
methylene chloride (2.4 mL, 2.4 mmol) was added, and the mixture
was stirred for another hour at 0.degree. C. HPLC/MS analysis of an
aliquot revealed complete disappearance of 1 A and formation of
roughly equal amounts of product. Sat. NaHCO.sub.3 (4 mL) was
added, and the mixture was stirred for 10 min. The organic layer
was separated, dried over MgSO.sub.4, filtered, and evaporated. The
residue was purified via flash column chromatography (eluent
gradient: 20% EtOAc in heptane to 100% EtOAc). The desired
fractions were combined and evaporated to yield a .about.1:1
mixture of methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((4-hydroxy-1-((trifluoromethy-
l)sulfonyl)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetate
and methyl
2,2-bis(4-chlorophenyl)-2-(3-(((4-hydroxy-1-((trifluoromethyl)sulf-
onyl)piperidin-4-yl)methyl)amino)-4-(trifluoromethylsulfonamido)phenyl)ace-
tate, contaminated with .about.15% of an third unknown compound.
The material was used as in the next reaction without further
purification.
Step 6: A mixture of
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((4-hydroxy-1-((trifluoromethy-
l)sulfonyl)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetic
acid and
2,2-bis(4-chlorophenyl)-2-(3-(((4-hydroxy-1-((trifluoromethyl)sulfonyl)pi-
peridin-4-yl)methyl)amino)-4-(trifluoromethylsulfonamido)phenyl)acetic
acid
[1420] To a solution of methyl
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((4-hydroxy-1-((trifluoromethy-
l)sulfonyl)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetate
(230 mg; 33.0%) and methyl
2,2-bis(4-chlorophenyl)-2-(3-(((4-hydroxy-1-((trifluoromethyl)sulfonyl)pi-
peridin-4-yl)methyl)amino)-4-(trifluoromethylsulfonamido)phenyl)acetate
(220 mg; 28.1%) in methanol (10 mL) in a sealable tube was added 3N
NaOH in water (3 mL). The tube was sealed and the mixture was
heated at 45.degree. C. overnight. HPLC/MS analysis of an aliquot
revealed complete disappearance of starting material and formation
of desired material, contaminated with several impurities. EtOAc
(50 mL) was added, followed by 2N HCl (6 mL). The organic phase was
separated, and the aqueous layer was extracted with additional
EtOAc (50 mL). The combined organic layers were dried over
MgSO.sub.4, filtered, and evaporated. The residue, a mixture of
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((4-hydroxy-1-((trifluoromethy-
l)sulfonyl)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetic
acid and
2,2-bis(4-chlorophenyl)-2-(3-(((4-hydroxy-1-((trifluoromethyl)sulfonyl)pi-
peridin-4-yl)methyl)amino)-4-(trifluoromethylsulfonamido)phenyl)acetic
acid, which was used in the next reaction without further
purification.
[1421] MH+=682.0/684.2 and MH+=764.1/766.0
Step 7: Mixture of
4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)-
methyl)-1-((trifluoromethyl)sulfonyl)piperidin-4-ol and
N-(4-(bis(4-chlorophenyl)methyl)-2-(((4-hydroxy-1-((trifluoromethyl)sulfo-
nyl)piperidin-4-yl)methyl)amino)phenyl)-1,1,1-trifluoromethanesulfonamide
[1422] A mixture of
2,2-bis(4-chlorophenyl)-2-(2-cyclopropyl-1-((4-hydroxy-1-((trifluoromethy-
l)sulfonyl)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetic
acid and
2,2-bis(4-chlorophenyl)-2-(3-(((4-hydroxy-1-((trifluoromethyl)sulfonyl)pi-
peridin-4-yl)methyl)amino)-4-(trifluoromethylsulfonamido)phenyl)acetic
acid (430 mg) and DBU (3.78 mmol; 0.565 mL) were combined in
toluene (10 mL) under Argon and heated to 90.degree. C. for 3
hours. HPLC/MS analysis of an aliquot revealed complete
disappearance of starting material. The mixture was evaporated,
dissolved in CH.sub.3CN (4 mL) and purified via reverse phase HPLC.
The desired fractions were combined and lyophilized to yield a
mixture of
4-((6-(bis(4-chlorophenyl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-1-yl)-
methyl)-1-((trifluoromethyl)sulfonyl)piperidin-4-ol as a white
solid and
N-(4-(bis(4-chlorophenyl)methyl)-2-(((4-hydroxy-1-((trifluoromethyl)sulfo-
nyl)piperidin-4-yl)methyl)amino)phenyl)-1,1,1-trifluoromethanesuffonamide
as a pink solid.
[1423] Purity: >95% pure @ 214 and 254 nm; MH+=638.1/640.2;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.32 (br s, 4H)
1.56 (br d, J=12.96 Hz, 2H) 1.77 (br d, J=12.47 Hz, 2H) 2.33 (br s,
1H) 3.24-3.33 (m, 2H) 3.66 (br d, J=12.23 Hz, 2H) 4.49 (br s, 2H)
5.84 (s, 1H) 7.16 (br d, J=8.31 Hz, 4H) 7.26 (br d, J=7.09 Hz, 1H)
7.40 (d, J=8.31 Hz, 4H) 7.61 (br d, J=8.07 Hz, 1H) 7.73 (br s,
1H)
Example BD-3
2-((4-chlorophenyl)(2-ethyl-1-((1-((trifluoromethyl)sulfonyl)piperidin-4-y-
l)methyl)-1H-benzo[d]imidazol-6-yl)methyl)thiazole
##STR00482##
[1424] Step 1: tert-butyl
((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methyl)carbamate
[1425] To a solution of tert-butyl (piperidin-4-ylmethyl)carbamate
(35.93 mmol; 7.7 g) and triethylamine (107.8 mmol; 15 mL) in
dichloromethane (150 mL) at 0.degree. C. under Argon was added
triflic anhydride (46.71 mmol; 7.86 mL) dissolved in
dichloromethane (50 mL), and the reaction mixture was stirred
overnight at room temperature. A sat NaHCO.sub.3 solution (75 mL)
was added, and the mixture was stirred for 10 min. The organic
phase was separated, dried over MgSO.sub.4, filtered, and
evaporated. A brown oil was obtained that was treated with diethyl
ether (200 mL) and stirred vigorously for 15 min. No solid formed.
The diethyl ether was evaporated to yield tert-butyl
((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methyl)carbamate as
an orange oil. The material was used in the next reaction, without
further purification.
[1426] (M-Boc)+=246.9
Step 2:
(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methanamine
[1427] To a solution of tert-butyl
((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methyl)carbamate in
diethyl ether (50 mL) and methanol (5 mL), a 4N HCl in 1,4-dioxane
(50 mL) was added dropwise. The mixture was allowed to stir
vigorously overnight at room temperature. An oil separated. Diethyl
ether (100 mL) was added slowly, and the mixture was stirred
vigorously for 10 min. The mixture was decanted and the residue was
evaporated. The residue was stored overnight under vacuum, yielding
(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methanamine as a brown
solid. The material was used in the next reaction without further
purification.
[1428] MH+=246.9
Step 3:
5-fluoro-2-nitro-N-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)m-
ethyl)aniline
[1429] To a solution of 2.4-difluoronitrobenzene (6 mmol; 0.955 g)
and triethylamine (18 mmol; 2.502 mL) in acetonitrile (20 mL) was
added (1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methanamine (7.8
mmol; 2.205 mg), and the mixture was stirred overnight at room
temperature under Argon. Methylene chloride (50 mL) was added, and
the solution was washed with brine. The organic phase was dried
over MgSO.sub.4, filtered, and evaporated. The residue was purified
via flash column chromatography (eluent gradient: 10% to 50% EtOAc
in heptane), yielding
5-fluoro-2-nitro-N-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methyl)a-
niline as a yellow solid.
[1430] Rf (heptane:EtOAc; 3:1)=0.36
Step 4:
2-(4-chlorophenyl)-2-(4-nitro-3-(((1-((trifluoromethyl)sulfonyl)pi-
peridin-4-yl)methyl)amino)phenyl)acetonitrile
[1431] To a solution of 4-chlorobenzyl cyanide (3.893 mmol; 0.615
g) in tetrahydrofuran (25 mL) and isopropanol (5 mL) at room
temperature under Argon was added potassium tert-butoxide (8.11
mmol; 0.91 mg) and the mixture was stirred for 10 min. A solution
of
5-fluoro-2-nitro-N-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methyl)a-
niline (3.244 mmol; 1.25 g) in tetrahydrofuran (10 mL) was added in
one portion over a 5 min period and the reaction mixture turned a
deep blue. The mixture was allowed to stir for 2 hours at room
temperature. Sat NH.sub.4Cl (10 mL) and EtOAc (50 mL) were added,
and the mixture was stirred vigorously for 10 min. The organic
layer was separated, washed with brine (10 mL), dried over
MgSO.sub.4, filtered, and evaporated. The residue was purified via
flash column chromatography (eluent gradient: 10 to 50% EtOAc in
heptane). The desired fractions were combined and evaporated to
yield
2-(4-chlorophenyl)-2-(4-nitro-3-(((1-((trifluoromethyl)sulfonyl)piperidin-
-4-yl)methyl)amino)phenyl)acetonitrile as a bright yellow
solid.
[1432] Rf (heptane:EtOAc; 3:1)=0.20; M+Na=538.8; Purity: >95% @
214 and 254 nm
Step 5:
2-(4-amino-3-(((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methyl-
)amino)phenyl)-2-(4-chlorophenyl)acetonitrile
[1433] A solution of
2-(4-chlorophenyl)-2-(4-nitro-3-(((1-((trifluoromethyl)sulfonyl)piperidin-
-4-yl)methyl)amino)phenyl)acetonitrile (2.9 mmol; 1.5 g) in
tetrahydrofuran (50 mL) and water (5 mL) in a 200 mL Parr flask was
purged with nitrogen, and Raney-Nickel (4.26 mmol; 0.25 g) was
added. The mixture was hydrogenated at room temperature overnight
on a Parr apparatus under 25 psi hydrogen pressure. HPLC/MS
analysis of an aliquot revealed complete conversion to desired
material. The catalyst was removed via filtration over CELITE. The
filtrate was evaporated and the residue was used in the next
reaction without further purification.
Step 6:
2-(4-chlorophenyl)-2-(2-ethyl-1-((1-((trifluoromethyl)sulfonyl)-pi-
peridin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetonitrile
[1434] To a solution of
2-(4-amino-3-(((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methyl)amino)-
phenyl)-2-(4-chlorophenyl)acetonitrile (1.45 mmol; 705.66 mg) in
DMSO (4 mL) in a 20 mL vial was added propanal (7.25 mmol; 1.02 mL)
and the mixture was stirred overnight at room temperature while
open to the air. HPLC/MS analysis of an aliquot revealed partial
disappearance of starting material with formation of desired
product. Additional propanal (7.25 mmol, 1.02 mL) was added, and
the mixture was stirred overnight while the vial was capped.
HPLC/MS analysis of an aliquot revealed complete disappearance of
starting material with formation of desired product. The reaction
mixture was purified via reverse phase HPLC (eluent gradient: 25 to
70% CH.sub.3CN in H.sub.2O containing 0.1% TFA). The desired
fractions were combined and lyophilized to yield
2-(4-chlorophenyl)-2-(2-ethyl-1-((1-((trifluoromethyl)sulfonyl)-piperidin-
-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetonitrile as a white
solid.
[1435] MH+=524.8; Purity: .about.95% @ 214 and 254 nm
Step 7:
2-(4-chlorophenyl)-2-(2-ethyl-1-((1-((trifluoromethyl)sulfonyl)pip-
eridin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)ethanethioamide
[1436]
2-(4-chlorophenyl)-2-(2-ethyl-1-((1-((trifluoromethyl)sulfonyl)pipe-
ridin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetonitrile (0.372
mmol; 195.5 mg) and phosphorous pentasulfide (0.447 mmol; 0.2 g)
were combined in ethanol (10 mL) in a sealable flask. The mixture
was heated to 70.degree. C. and the flask was sealed. The mixture
was heated overnight at 70.degree. C. and HPLC/MS analysis of an
aliquot revealed clean conversion to desired material. The mixture
was allowed to cool to room temperature, and brine (20 mL) and
ethyl acetate (100 mL) were added. The organic layer was separated
and washed with brine (50 mL). The organic layer was dried over
MgSO.sub.4, filtered, and evaporated. The residue was purified via
flash column chromatography (eluent gradient: 100% EtOAc) to yield
2-(4-chlorophenyl)-2-(2-ethyl-1-((1-((trifluoromethyl)sulfonyl)piperidin--
4-yl)methyl)-1H-benzo[d]imidazol-6-yl)ethanethioamide as a white
solid.
[1437] Rf (100% EtOAc)=0.33; MH+=558.8; Purity: 90% pure @ 214 nm
and >95% pure @ 254 nm
Step 8:
2-((4-chlorophenyl)(2-ethyl-1-((1-((trifluoromethyl)sulfonyl)piper-
idin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)methyl)thiazole
[1438]
2-(4-chlorophenyl)-2-(2-ethyl-1-((1-((trifluoromethyl)sulfonyl)pipe-
ridin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)ethanethioamide (0.116
mmol; 65 mg) and bromoacetaldehyde diethylacetal (0.465 mmol; 0.07
mL) were combined in acetic acid (5 mL) and water (0.2 mL) was
added. The mixture was heated for 1 hour at 80.degree. C. HPLC/MS
analysis of an aliquot revealed complete conversion to desired
material. The reaction mixture was lyophilized and the residue was
purified via reverse phase HPLC (eluent gradient: 20% to 70%
CH.sub.3CN in H.sub.2O, both containing 0.1% TFA). The desired
fractions were combined and lyophilized to yield
2-((4-chlorophenyl)(2-ethyl-1-((1-((trifluoromethyl)sulfonyl)piperidin-4--
yl)methyl)-1H-benzo[d]imidazol-6-yl)methyl)thiazole as an off-white
solid.
[1439] Rf (EtOAc:heptane; 1:1)=0.27; 1H-NMR (DMSO-d6): .sup.1H NMR
(400 MHz, DMSO-d.sub.6) 5 ppm 1.41 (t, J=7.46 Hz, 3H) 1.68 (br d,
J=12.72 Hz, 2H) 2.11 (br 1H) 2.23-2.44 (m, 1H) 3.03-3.22 (m, 4H)
3.67 (br s, 1H) 3.80 (br d, J=13.20 Hz, 2H) 4.31-4.57 (m, 2H) 6.24
(s, 1H) 7.36-7.53 (m, 5H) 7.72 (d, J=3.15 Hz, 1H) 7.76 (d, J=8.63
Hz, 1H) 7.83 (d, J=3.18 Hz, 1H) 8.02 (s, 1H); MH+=582.7; Purity:
93% pure @ 214 nm and >95% pure @ 254 nm
Example BD-4
2-((4-chlorophenyl)(2-cyclopropyl-1-((1-((trifluoromethyl)sulfonyl)piperid-
in-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)methyl)thiazole
##STR00483##
[1440] Step 1:
2-(4-chlorophenyl)-2-(2-cyclopropyl-1-((1-((trifluoromethyl)sulfonyl)pipe-
ridin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetonitrile
[1441] To a solution of
2-(4-amino-3-(((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methyl)amino)-
phenyl)-2-(4-chlorophenyl)acetonitrile (0.75 mmol; 365.21 mg) in
DMSO (4 mL) in a 20 mL vial was added propanal (2.25 mmol; 157.71
mL) and the mixture was stirred overnight at room temperature while
open to the air. HPLC/MS analysis of an aliquot revealed partial
disappearance of starting material. The reaction mixture was
purified via reverse phase HPLC (eluent gradient: 35 to 55%
CH.sub.3CN in H.sub.2O containing 0.1% TFA). The desired fractions
were combined and lyophilized to yield
2-(4-chlorophenyl)-2-(2-cyclopropyl-1-((1-((trifluoromethyl)sulfonyl)pipe-
ridin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetonitrile as a white
solid.
[1442] MH+=536.8; Purity: 95% @ 214 and 254 nm
Step 2:
2-(4-chlorophenyl)-2-(2-cyclopropyl-1-((1-((trifluoromethyl)sulfon-
yl)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)ethanethioamide
[1443]
2-(4-chlorophenyl)-2-(2-cyclopropyl-1-((1-((trifluoromethyl)sulfony-
l)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)acetonitrile
(0.372 mmol; 200 mg) and phosphorous pentasulfide (0.45 mmol; 0.2
g) were combined in ethanol (10 mL) in a sealable flask. The
mixture was heated to 70.degree. C. and the flask was sealed. The
mixture was heated overnight at 70.degree. C. and HPLC/MS analysis
of an aliquot revealed clean conversion to desired material. The
mixture was allowed to cool to room temperature, and brine (20 mL)
and ethyl acetate (100 mL) were added. The organic layer was
separated and washed with brine (50 mL). The organic layer was
dried over MgSO.sub.4, filtered, and evaporated. The residue was
purified via flash column chromatography (eluent gradient: 100%
EtOAc) to yield
2-(4-chlorophenyl)-2-(2-cyclopropyl-1-((1-((trifluoromethyl)sulfonyl)pipe-
ridin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)ethanethioamide as a
white solid.
[1444] Rf (100% EtOAc)=0.59; MH+=570.8; Purity: 90% pure @ 214 nm
and >95% pure @ 254 nm
Step 3:
2-((4-chlorophenyl)(2-cyclopropyl-1-((1-((trifluoromethyl)sulfonyl-
)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)methyl)thiazole
[1445]
2-(4-chlorophenyl)-2-(2-cyclopropyl-1-((1-((trifluoromethyl)sulfony-
l)piperidin-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)ethanethioamide
(0.263 mmol; 150 mg) and bromoacetaldehyde diethylacetal (1.051
mmol; 0.158 mL) were combined in acetic acid (5 mL) and water (0.2
mL) was added. The mixture was heated for 1 hour at 80.degree. C.
HPLC/MS analysis of an aliquot revealed complete conversion to
desired material. The reaction mixture was lyophilized and the
residue was purified via reverse phase HPLC (eluent gradient: 20%
to 70% CH.sub.3CN in H.sub.2O, both containing 0.1% TFA). The
desired fractions were combined and lyophilized to yield
2-((4-chlorophenyl)(2-cyclopropyl-1-((1-((trifluoromethyl)sulfonyl)piperi-
din-4-yl)methyl)-1H-benzo[d]imidazol-6-yl)methyl)thiazole as an
off-white solid.
[1446] Rf (EtOAc:heptane; 1:1)=0.27; 1H-NMR (DMSO-d6): .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.32-1.48 (m, 6H) 1.73 (br d,
J=12.47 Hz, 2H) 2.17 (br s, 1H) 2.54-2.63 (m, 1H) 3.11 (br t,
J=12.23 Hz, 2H) 3.81 (br d, J=12.47 Hz, 2H) 4.44 (br d, J=4.89 Hz,
2H) 6.20 (s, 1H) 7.35-7.46 (m, 5H) 7.65 (d, J=8.31 Hz, 1H) 7.71 (d,
J=3.42 Hz, 1H) 7.83 (d, J=3.18 Hz, 1H) 7.94 (s, 1H); MH+=594.8;
Purity: 95% pure @ 214 nm and >95% pure @ 254 nm
Biological Examples
[1447] CB.sub.1 and CB.sub.2 receptors are Gi-coupled GPCR.
Activation of CB.sub.1 and CB.sub.2 receptors results in a decrease
in cAMP production. An inverse agonist of the CB.sub.1 or CB.sub.2
receptor results in the opposite effect, an increase of cAMP
production. The principle of this assay is based on HTRF.RTM.
technology (Homogeneous Time-Resolved Fluorescence). The method is
a competitive immunoassay between native cAMP produced by cells and
the cAMP labeled with the fluorophore d2. The tracer binding is
quantified by a Mab anti-cAMP labeled with Eu3+TBP-NHS Cryptate
(supplied as part of the assay kit). The specific signal (i.e.
energy transfer) is inversely proportional to the concentration of
cAMP in the standard or sample.
Biological Example 1: CB-1 and CB-2 In Vitro Assay
Preparation of Cells
[1448] Human CB.sub.1R (Cannabinoid receptor 1) was stably
transfected in HEK-293 cells (DiscoveRx, cat: 93-0200C1). Human
CB.sub.2R (Cannabinoid receptor 2) was stably transfected in
HEK-293 cells (DiscoveRx, cat: 93-0201C1). Cell cultures were
maintained in media: DMEM (Invitrogen Cat#12430-054) supplemented
with 10% HI FBS (Invitrogen Cat#16140-071), 1% L-glutamine
(Invitrogen Cat#25030-081), 0.2 mg/ml Hygromycin B (Invitrogen
Cat#10687-010), 600 .mu.g/mL G418 (Invitrogen Cat#10131-035), and
1.times. Penn/Strep (Invitrogen 15140-122). After cell expansion,
aliquots were cryo-stored in media containing 5% DMSO (Pierce
Cat#20684).
Plating Cells from Cryostore
[1449] One day prior to experiments media was warmed to 37.degree.
C. and the cryo-stored cells were thawed in a 37.degree. C. water
bath. The cells were then added to media (10.times. volume) and the
mixture was centrifuged at 1000 RPM for 5 min. The supernate was
removed and the cells were re-suspended in media. A sample of the
cell suspension was evaluated on a Cedex XS automated cell counter
(Innovatis Systems) to determine viable cells/ml. Additional media
was added to the cells to achieve a final cell density of 4E5
cells/mL. The cells were then plated into 384 well PDL white solid
bottom plates (Greiner, Cat#781945) at 20 .mu.L per well using a
Multidrop (Thermo Scientific). Cells were removed from Row P
(location of cAMP standards). Two columns of cells were plated into
a clear bottom 384 well PDL coated plate (Greiner, Cat#781944) to
view confluence the day of the assay. The cell plates were lidded
and stored for 15 minutes in a hood, then transferred to an
incubator (37.degree. C., 5% CO.sub.2, 95% humidity) overnight.
Preparation of Compound Plates
[1450] DMSO was added to all wells of 384 well V bottom polystyrene
plate (Greiner, Cat#781280) except to columns 1 and 13, rows O and
P and wells M13-M23 and N13-N23. Test compounds (60 .mu.L, 10 mM)
were added to Column 1 and 13 (A1 through N1 and A13 through L13).
Test compounds were serially diluted 1/3 by transferring and mixing
20 .mu.l sample with 40 .mu.L DMSO. This process resulted in a
plate of 26 compounds, 11 doses per compound, 10 mM to 0.5
.mu.M.
Preparation of Control Plate
[1451] DMSO (40 .mu.L) was added to wells of 384 well V bottom
polystyrene plate: O2 through O11, M14 through M23, N14 through
N23, and O14 through O23. AM630 (also known as
[6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxypheny-
l)-methanone, Cayman Chemical, Cat#10006974) (60 .mu.L, 10 mM) was
added to O1; and
1-(2,4-dichlorophenyl)-7-[(4-fluorophenyl)methylene]-4,5,6,7-tetrahydro-N-
-1-piperidinyl-1H-benzimidazole-3-carboxamide (60 .mu.L, 10 mM) was
added to N13. The control was serially diluted 1/3 by transferring
and mixing 20 .mu.l sample with 40 .mu.L DMSO. This process
resulted 11 doses per control, 10 mM to 0.5 .mu.M.
cAMP Assay Protocol
[1452] Cells plated the day prior to the assay in clear bottom
plates were viewed on an inverse microscope to ensure confluency in
the range of 60-75%.
[1453] The following mixtures and buffer solutions were prepared:
(a) Buffer 1: HBSS (Mediatech Cat#21-023-CV) with 5 mM HEPES (1 mM
stock, Gibco BRL Cat#15630-056) and 0.1% BSA (7.5% stock,
Invitrogen Cat#15260-037); (b) Buffer 2: 0.5 mM IBMX (200 mM stock
in DMSO, Sigma 15879) in Buffer 1; (c) 1 .mu.M cAMP Standard (50
.mu.M stock, Perkin Elmer Cat# AD0262) diluted in Buffer 2 and
serially diluted in Buffer 2, 12 doses @ 1/2 dilutions resulting in
a dose range of 1 .mu.M to 0.5 nM; (d) d2 labelled cAMP (CisBio
HTRF Detection Kit Cat #62AM4PEB reconstituted with 6 ml dH.sub.20)
diluted 1/20 with lysis buffer (CisBio HTRF Detection Kit Cat
#62AM4PEB); (e) anti-cAMP (CisBio HTRF Detection Kit Cat #62AM4PEB
reconstituted with 5 ml dH.sub.20) diluted 1/20 with lysis buffer
(CisBio HTRF Detection Kit Cat #62AM4PEB); and (f) Forskolin (Sigma
Cat#F6886, 10 mM in DMSO) diluted first in DMSO to 1 mM and then to
1.5 .mu.M in Buffer 2.
[1454] A FLEXDROP (Perkin Elmer) was cleaned with ethanol then
water, and primed with Buffer 2. A 384 well V bottom polypropylene
plate containing d2 labelled cAMP and a second 384 well V bottom
polypropylene plate containing anti-cAMP was prepared (50 .mu.l per
well). Media as "dumped" from the cell plate and 30 .mu.L Buffer 1
was added to each well using a Multidrop. The content of the cell
plate was again "dumped" and 10 .mu.L Buffer 2 was added to each
well using a Flexdrop. 12.5 nL test compound dilutions or control
compound dilutions (10 mM to 0.5 .mu.M) were added to the cell
plate using an ECHO 555 (Labcyte). The cell plate was mixed (Speed
6, Lab-Line Instruments Titer Plate Shaker) and centrifuged (1000
RPMs, 1 min). Using the Flexdrop, 2 .mu.l additions were made into
the cell plate: Buffer 2 was added to Column 24; and, 1.5 .mu.M
Forskolin was added to columns 1 through 23. Final volume of the
cell plate was 12 .mu.l with 250 nM Forskolin in all wells except
column 12, and serial dilutions of test compound or control ranging
from 10 .mu.M to 0.5 nM. The cell plate was again mixed (speed 6)
and centrifuged (1000 RPMs, 1 min). The cell plate was incubated
for 30 minutes at room temperature (.about.27.degree. C.). The
contents of row P were removed and the cAMP standard dilutions were
added in duplicate to Row P (P.sub.1-12 and P.sub.13-24). After
incubation, 6 .mu.L d2 labelled cAMP and 6 .mu.L of Anti-cAMP were
added to all wells of the cell plate using a BioMek FX (Beckman
Coulter). The cell plate was again mixed (speed 6) and centrifuged
(1000 RPMs, 1 min) and was incubated for 60 minutes in the dark at
room Temp (.about.27.degree. C.).
[1455] After this final incubation, the cell plate was read in HTRF
mode (fluorescence at 665 nm and 620 nm) on an Envision plate
Reader (Perkin Elmer). The Envision reader outputs a ratio of
channel 1/channel 2 fluorescence.times.10,000 (Normalized signal
(NS)). Amount of cAMP in nM was calculated for each well (based on
NS) from a cAMP standard curve located on each plate (at P1-12 and
P13-24). EC.sub.50 values were determined from a 4-point fit (Hill
equation) of a single 11-point compound dosing. Hill slope was
fixed at 1.0. The bottom of the dose response curve was fixed
because it was always the same as that of the control wells
containing vehicle (DMSO) instead of compound. The top of the dose
response curve was floated unless a plateau was not reached.
[1456] Representative compounds of formula (I) of the present
invention were tested for activity against the CB-1 and CB-2
receptors, according to assay protocol as outlined in Biological
Example 1, with EC.sub.50 results (in micromolar) as listed in
Table BIO-1, below. Where a compound was tested more than once, the
result presented below represents a mean of the individual
measurements.
TABLE-US-00006 TABLE BIO-1 Biological Activity Against CB-1 and
CB-2 Receptors CB1 HEK_cAMP CB2 HEK_cAMP ID No. EC.sub.50 .mu.M
EC.sub.50 .mu.M 1 0.0114 2.8458 2 0.4790 5.0304 3 NT NT 4 0.0098
2.1597 5 0.0330 0.6324 6 0.0283 3.8761 7 0.0267 7.5998 8 0.0339
0.0782 9 0.0170 0.7978 10 0.3219 1.7494 11 0.0494 4.9694 12 >10
>10 13 >10 >10 14 0.0170 >10 15 0.0730 0.6997 16 0.1732
0.6981 17 0.0829 9.3994 18 0.0533 >10 19 0.0938 >10 20 0.0156
>10 21 0.2526 4.5436 22 0.0890 1.5237 23 0.1817 1.8763 24 1.9364
7.2996 25 1.6523 >10 26 0.1028 3.3136 27 0.0110 >10 28 0.0215
>10 29 NT NT 30 0.0402 1.6222 31 0.1500 2.9999 32 0.0395 2.1563
33 3.8001 2.8774 34 0.0375 6.7999 35 3.3435 4.3631 36 0.0854 0.8692
37 0.0876 7.2594 38 4.3003 1.6971 40 0.1044 5.1156 41 0.0306
>41.9952 42 0.0908 8.6956 43 0.1135 12.1199 44 0.0146 2.4378 45
0.5933 >41.9952 46 0.4503 >41.9952 47 0.0024 17.1317 48
0.0030 3.8415 49 0.0085 4.3954 50 0.0481 >10 52 0.0092 >10 53
0.0267 3.0033 54 0.5962 3.9600 55 0.0123 2.7353 56 0.0193 >10 57
0.0649 8.8389 59 0.0038 >20.9991 61 0.0190 >20.9991 63 >10
>20.9991 64 0.0026 2.3534 65 0.1543 >10 67 0.3633 6.8945 68
0.1304 10.2991 69 0.0086 1.2067 70 0.0083 5.8237 71 0.0274 4.8764
72 NT NT 73 0.0185 5.2481 74 0.0706 5.3889 75 0.0357 1.1476 76
0.0067 2.0578 77 0.0356 >10 78 0.1506 >20.9991 79 0.0326
5.0910 80 0.0866 11.3606 81 0.0141 3.2033 82 0.9949 >41.9952 83
0.0426 11.3006 84 0.0677 >10 85 0.0174 8.1003 86 0.0150 10.2000
87 0.0090 8.9991 88 0.0330 >10 89 0.0072 7.8995 90 0.0224 >10
91 0.0324 9.3994 92 0.0159 5.1916 93 0.0639 1.7494 94 0.0261 4.7621
95 0.0112 >10 96 0.0273 7.9232 97 0.0187 >10 98 0.0162 >10
99 0.0188 4.7370 100 0.0194 6.2994 101 0.0285 >10 102 0.0333
8.1414 104 0.0121 5.9993 105 0.0051 8.0002 106 0.0601 >10 118
0.0980 >10 119 0.0949 6.7406 120 0.0249 5.4338 121 0.0051 7.9689
122 0.0049 9.0991 123 0.0134 7.5007 124 0.0349 >10 125 0.0177
9.8992 126 0.0042 7.7965 127 0.0050 >10 128 0.0069 4.8933 129
0.0198 >10 130 0.0155 8.1003 131 0.0080 6.4998 132 >10 >10
133 0.8125 3.5003 134 4.3441 >10 135 0.0532 >10 136 0.0320
9.0991 137 8.9970 >10 138 0.0139 3.9048 140 0.0799 >10 141
0.0033 >10 142 0.0215 5.2481 143 3.9228 >10 144 0.0152 4.7000
145 0.4316 >10 146 0.0337 >10 147 0.0102 7.5631 148 0.0096
4.9272 150 0.9721 >10 151 0.0665 >10 152 1.5907 6.4003 153
0.0087 3.6058 154 0.3111 8.0002 155 0.0067 >10 157 0.1897 3.3822
158 0.0679 5.7996 159 0.2897 3.6208 160 0.0364 5.7996 161 0.0080
2.1086 162 0.0062 4.4864 163 0.0916 7.7768 164 0.0275 >10 165
>10 >10 166 0.0037 5.0153 167 0.0854 4.3995 168 0.0912 >10
169 0.0450 7.8995 170 0.0044 0.3143 171 0.1673 >10 172 0.0812
>10 173 0.0559 9.2003 174 6.5524 >10 175 5.4225 4.7479 176
>10 >10 177 0.0967 7.8995 178 0.0675 >10 179 0.0017 >10
180 0.0171 >10 181 0.0250 >10 182 0.2552 2.9322 183 0.0314
6.2994 184 0.0314 >10 185 0.1407 7.5998 186 0.0253 >10 187
0.0518 >10 188 0.1600 >10 189 0.0295 >10 190 0.0113 0.6987
191 0.0210 >10 192 5.0478 >10 193 >10 >10 198 4.7995
>10 199 0.1732 6.4998 200 4.7239 6.3067 201 0.0638 0.9899 202
0.0312 >10 203 0.0324 >10 204 0.0944 >10 205 0.0367 5.7319
206 0.1007 >10 207 0.0064 4.6612 211 0.5888 10.2000 212 3.7420
>10 213 8.3081 >10 214 0.0225 5.0478 215 0.0020 >10 216
0.0062 >10 217 0.0092 >10 218 0.0072 1.4421 220 1.3674 5.8398
221 0.0085 3.2984 222 0.0110 4.9636 223 0.0248 3.3435 224 0.0060
>10 225 0.0415 >10 226 0.0167 7.8235 227 2.0446 >10 228
8.3004 >10 229 0.0137 1.7750 230 0.0919 5.8993 231 0.7089 >10
232 0.0176 8.8573 234 0.0161 9.5280 235 0.9404 >10 238 0.0019
>10 239 0.0100 2.6455 240 0.0149 2.1023 241 0.4589 7.8995 242
0.0180 5.6872 243 0.0359 0.3470 244 0.5337 >10 245 0.2834 >10
246 1.4325 >10 247 0.1285 >10 248 4.2355 >10 249 0.0050
1.7147 250 0.0029 9.3994 251 0.0058 0.7301 252 0.0131 6.2445 253
0.0047 2.4221 254 0.0366 1.2491 255 0.0073 >10 256 0.1287 >10
257 0.0054 >10 258 0.0201 >10 259 0.0037 >10 260 0.0015
>10 261 0.0219 >10 262 0.0155 >10 266 0.0184 >10 267
0.0070 >10 268 0.8764 >10 269 1.0316 >10 270 0.0066 9.8992
271 0.0021 >10 272 0.0108 >10 273 0.0336 9.6006 274 0.1327
>10 275 0.0016 >10 276 0.0093 2.6080 277 0.0047 >10 278
0.0505 >10 279 0.0322 >10
280 0.0105 >10 281 0.0125 >10 282 0.0073 >10 283 0.0036
0.9601 284 0.0057 >10 285 0.0034 >10 286 0.0382 >10 287
0.0024 4.5888 288 0.0023 >10 289 0.0292 >10 291 2.2646 >10
292 2.8913 >10 293 7.4302 >10 294 0.0046 >10 295 0.0050
8.9991 297 0.6148 >10 298 0.9057 8.9991 299 0.5778 1.0280 300
0.1631 >10 301 0.0433 >10 303 0.0174 >10 305 2.8145 >10
306 0.4100 >10 308 0.0636 >10 309 0.0034 5.2000 311 0.0172
8.6000 312 0.0492 1.5000 313 0.4163 >10 314 0.0201 2.7855 315
0.0053 5.4001 316 0.0028 3.8646 317 0.0332 3.6543 318 0.0069 >10
319 0.0225 >10 320 0.0693 >10 321 0.0062 4.0253 322 0.6206
>10 323 0.0165 >10 324 0.0102 3.8833 328 0.0084 >13.9991
329 0.3788 >10 330 0.1624 >10 331 0.2395 >10 332 0.0147
4.7000 333 0.4365 >10 334 0.3158 >10 335 0.0056 >10 336
0.2597 7.2260 337 1.1779 >10 338 0.0597 4.0004 339 2.4082 >10
340 1.4421 >10 341 1.3289 >10 342 0.1842 >10 343 0.1959
>10 344 >10 >10 345 >10 >10 346 0.0324 >10 347
2.7829 >10 348 0.8670 >10 349 7.2410 >10 350 0.0347 >10
351 >10 >10 352 >10 >10 353 >10 >10 354 5.4375
>10 355 0.0129 1.9670 356 >10 357 >10 358 >10 359
>10 360 >10 361 2.0179 >10 362 0.2125 >10 363 2.2930
>10 366 >10 >10 367 1.0770 2.7657 368 >10 >10 369
>10 >10 374 1.1179 >10 375 0.7549 >10 376 0.4410 0.2720
377 >10 >10 378 >10 >10 379 >10 >10 380 0.2430
>10 381 0.7190 >10 382 4.3241 >10 383 2.7240 >10 384
0.0120 >10 385 0.5240 >10 386 0.0220 >10 387 0.5509 >10
388 1.7591 1.6308 389 >10 >10 390 0.2420 >10 391 0.0600
>10 393 0.0280 0.0630 394 4.8362 >10 395 0.1370 >10 396
0.2210 0.0910 397 >10 >10 398 0.0210 >10 399 0.1630 >10
400 0.0060 >10 401 6.0200 >10 402 0.1920 >10 403 0.5690
>10 404 6.1518 >10 405 4.4926 3.3504 406 1.6912 >10 408
3.1463 >10 409 0.0478 >10 410 0.3078 >10 411 0.3762 >10
412 0.6232 >10 413 0.3146 >10 414 1.4894 >10 415 >10
>10 416 0.3923 >10 417 2.5369 >10 418 1.0777 >10 419
1.1836 >10 420 0.2312 >10 421 0.1117 >10 422 0.5977 >10
423 0.0170 >10 424 2.3163 >10 429 0.4374 >10 431 0.1114
>10 432 0.0643 >10 433 >10 >10 434 0.0227 >10 435
>10 >10 436 0.4730 >10 437 0.1920 >10 438 0.3150 >10
439 >10 >10 440 0.9991 >10 441 2.0907 >10 442 3.4041
>10 443 1.4332 4.9454 444 0.5353 >10 445 0.9473 >10 446
0.0899 >10 448 0.1000 >10 449 >10 >10 451 452 0.8128
>6.70039 455 2.4149 >7.39946 456 >10 >9.20026 460
>10 >10 462 >10 >6.59933 463 0.1642 >7.59976 464
0.2116 >7.19946 465 0.2428 >10 466 >8.69961 1.4315 474 NT
NT NT = Not Tested
[1457] Additionally, the compound of formula (II) was tested
according to the procedures as described above and measured to
exhibit the following activity against the CB-1 and CB-2 (IC.sub.50
in micromolar): [1458] CB-1 receptor: IC.sub.50=0.0135 .mu.M [1459]
CB-1 receptor: IC.sub.50=>10 .mu.M
Biological Example 2--Prophetic Example
CB-1 & CB-2 Receptor Binding Assay
Experimental Procedure CB-1 Membrane Binding:
[1460] Into Greiner V bottom polypropylene plates, hCB1-CHO-K1
membranes (2 .mu.g/well final concentration) in assay buffer (50 mM
Tris-HCl pH 7.4, 5 mM MgCl.sub.2 and 0.5 mg/ml (0.05%) Ultra fatty
acid free BSA) are dispensed. Membranes were purchased from Perkin
Elmer. Test compounds are then added to each well and then
[.sup.3H] CP 55, 940 (0.4 nM final well concentration) in assay
buffer (50 mM Tris-HCl pH 7.4, 5 mM MgCl.sub.2 and 0.5 mg/ml
(0.05%) Ultra fatty acid free BSA) is added. Samples are mixed and
incubated for 90 min at 30.degree. C. in the Greiner V Bottom
Polypropylene plate. After incubation, assay reagents are
transferred to a blocked 384 well polypropylene filter plates. The
binding reaction is stopped by filtration and washed seven times
with ice cold rinse buffer. Filter plates are then dried overnight
at room temperature. The next day, plate bottoms are sealed with
plate tape and 15 .mu.l MicroScint 20 is added to each well. Plates
are incubated for 2 h and radioactivity is measured by
Topcount.
Experimental Procedure CB-2 Membrane Binding--Prophetic
Example:
[1461] Into Greiner V bottom polypropylene plates, hCB2-HEK293
membranes (2 .mu.g/well final concentration) in assay buffer (50 mM
Tris-HCl pH 7.4, 5 mM MgCl.sub.2 and 0.5 mg/ml (0.05%) Ultra fatty
acid free BSA) are dispensed. Membranes are prepared as described
in FELDER, C. C., et al., Molecular Pharmacology, 1992, pp 838-845,
Vol. 42. Test compounds are then added to each well and then
[.sup.3H] CP 55, 940 (0.5 nM final well concentration) in assay
buffer (50 mM Tris-HCl pH 7.4, 5 mM MgCl.sub.2 and 0.5 mg/ml
(0.05%) Ultra fatty acid free BSA) is added. Samples are mixed and
incubated for 90 min at 30.degree. C. in the Greiner V Bottom
Polypropylene plate. After incubation, assay reagents are
transferred to a blocked 384 well polypropylene filter plates. The
binding reaction is stopped by filtration and washed nine times
with ice cold rinse buffer. Filter plates are then dried overnight
at room temperature. The next day, plate bottoms are sealed with
plate tape and 15 uL MicroScint 20 is added to each well. Plates
are incubated for 2 h and radioactivity is measured by
Topcount.
Total Binding:
[1462] Total Binding levels are achieved by combining membrane,
DMSO, and [.sup.3H] CP-55,940 (also known as
5-(1,1-dimethylheptyl)-2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohe-
xyl]-phenol).
Non-Specific Binding (NSB):
[1463] Non-Specific Binding (NSB) levels are achieved by combining
membrane, 10 .mu.M final concentration WIN-55,212 (also known as
(R)-(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1-
,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate, Tocris
Biosciences Cat#1038), and [.sup.3H] CP-55,940 (also known as
5-(1,1-dimethylheptyl)-2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohe-
xyl]-phenol).
Data Analysis:
[1464] Top Count raw data files are used for data analysis as
follows:
[1465] Non-specific binding (NSB=10 .mu.M
WIN-55,212+Membrane+[.sup.3H] CP-55,940) is used as the negative
control, while the Total Binding (TB=DMSO+Membrane+[.sup.3H]
CP-55,940) is used as the positive control.
[1466] Excel data file reports are generated by the PE TopCount and
imported into Excel for calculations or are imported into a macro
driven Excel template maintained by Lead Generation--Biology.
[1467] IC.sub.50 data is calculated using raw CPM values. Curves
are fitted individually from singlet 11 point dosing curves+1% DMSO
Control. IC.sub.50 values are fit appropriately and calculated
using the following equation:
v = V min + V 0 - V min 1 + ( [ I ] IC 50 ) h ##EQU00001##
[1468] V.sub.min, CPM at maximum inhibition; V.sub.o, CPM at zero
inhibition; IC.sub.50, inhibitor concentration at 50% inhibition;
h, Hill coefficient.
[1469] Maximal compound % inhibition of control treated wells is
also noted since some compounds may exhibit values suitable for
calculating IC.sub.50's.
% Inhibition of Total Binding=(1-(CPM Compound Treated Well CPM
Control Treated Well))*100
In Vivo Biological Assays
Animals, Diets and Test Compound:
[1470] Male 14-20-week old diet-induced obese mice are ordered from
Taconic. Mice were started on a 60% fat diet (D12492, Research
Diets, New Brunswick, N.J.) at 6 weeks of age. Mice are
single-housed.
[1471] Male Sprague Dawley rats are ordered from Charles River
(225-250 gm upon arrival). They are fed standard chow diet (Purina
5001) and housed 2 per cage. Male C57bl/6j mice are ordered from
Charles River at 22-25 g and housed 3 per cage. They are fed
standard chow (Purina 5001). All animals are housed in a
temperature-controlled room with 12-hour light/dark cycle. Animals
are given food and water ad libitum, except as noted.
[1472] Test compounds are formulated in 10% PEG400 and 10% solutol
or 10% PEG400 and 20% solutol. Test compounds are administered by
oral gavage (5 ml kg.sup.-1 or 10 ml kg.sup.-1).
Biological Example 3: Mouse Fast PK/BBB
[1473] Male C57bl/6j mice were dosed with test compounds at 20 or
30 mg/kg. Plasma was collected via retro-orbital bleeding at 1 hr
and 4 hrs after dosing. Whole brain without cerebellum was
collected at 4 hrs after dosing. Wet brain weight was recorded
before freezing. Brains were homogenized in saline and sent for
analysis for determination of concentration of test compound.
[1474] Representative compounds of formula (I) of the present
invention were tested according to the procedure described above,
with results as listed in Table BIO-2 below.
TABLE-US-00007 TABLE BIO-2 Mouse Fast PK/BBB Results Plasma Brain
Mean Conc. (ng/mL) .+-. Mean Conc. (ng/mL) .+-. ID No. Dose Time
Std. Dev (ng/mL) Std. Dev (ng/mL) 400 20 1 hr 1553 .+-. 65.7 362
.+-. 36.9 4 hr 947 .+-. 191 292 .+-. 61.0 335 20 1 hr 3943 .+-. 480
53.3 .+-. 14.0 4 hr 2265 .+-. 822 104 .+-. 19 328 20 1 hr 2644 .+-.
337 39.1 .+-. 1.95 4 hr 1601 .+-. 109 99.3 .+-. 13.3 320 20 1 hr
2895.0 .+-. 244.9 121.5 .+-. 18.1 4 hr 1609.4 .+-. 207.2 167.4 .+-.
9.4 318 20 1 hr 5876 .+-. 1294 57.8 .+-. 14.8 4 hr 2131 .+-. 245
69.4 .+-. 4.4 316 20 1 hr 3979 .+-. 448 22.9 .+-. 2.7 4 hr 247 .+-.
36 30.2 .+-. 5.2 315 20 1 hr 2870.2 .+-. 441.2 33.8 .+-. 5.0 4 hr
785.4 .+-. 190.6 48.4 .+-. 0.4 276 20 1 hr 227 .+-. 67.2 BLOQ .+-.
NA 4 hr 27.7 .+-. 13.1 BLOQ .+-. NA 259 20 1 hr 1422 .+-. 489 BLOQ
.+-. NA 4 hr 436 .+-. 83 BLOQ .+-. NA 242 20 1 hr 789 .+-. NA BLOQ
.+-. NA 4 hr 62.1 .+-. 20.0 BLOQ .+-. NA 232 30 1 hr 81.9 .+-. 22.7
BLOQ .+-. NA 4 hr 7.11 .+-. 6.55 BLOQ .+-. NA 221 20 1 hr 160 .+-.
69.7 BLOQ .+-. NA 4 hr 33.8 .+-. 11.2 BLOQ .+-. NA 148 30 1 hr
13541.7 .+-. 272.8 334.0 .+-. 108.4 4 hr 7745.9 .+-. 3102.4 417.4
.+-. 50.0 129 30 1 hr 1368 .+-. 749 BLOQ .+-. NA 4 hr 84.6 .+-.
62.9 BLOQ .+-. NA 125 30 1 hr 4493 .+-. 1011 BLOQ .+-. NA 4 hr 390
.+-. 157 BLOQ .+-. NA 124 30 1 hr 2023 .+-. 555 BLOQ .+-. NA 4 hr
297 .+-. 107 BLOQ .+-. NA 92 30 1 hr 11383 .+-. 2021 72.4 .+-. 11.1
4 hr 5193 .+-. 277 89.2 .+-. 27.7 89 30 1 hr 7190 .+-. 488 92.6
.+-. 20.4 4 hr 4427 .+-. 227 129 .+-. 33.2 BLOQ = below level of
quantitation; NA = Not applicable
Biological Example 4: Five-Day Study in DIO Mice
[1475] The test compound was formulated in 10% PEG400 and 10%
solutol. DIO mice (n=9) received vehicle or test compound daily for
four days at 4 PM. Body weight and food weight were monitored daily
at this time. On day 5, fed blood glucose, body weight, and food
weight were measured at 9 AM and the mice were dosed at this time.
Two hours later, mice were bled via the retro-orbital sinus under
70% CO.sub.2/30% O.sub.2 anesthesia. Plasma was used to determine
insulin levels and compound concentration.
[1476] Three mice from each treatment group were anesthetized IP
with 0.1 ml of a 4/1 mixture of Ketaset:AnaSed. (Prepared 10 ml
Ketaset (100 mg/ml Ketamine) +2.5 ml AnaSed (20 mg/ml Xylazine) and
then perfused with 60 ml heparinized saline through the left
ventricle of the heart. The brains were removed and homogenized in
PBS (4 ml/gm tissue). The samples were submitted for determination
of plasma and brain compound levels.
[1477] Compound #335 was tested according to the procedure as
described above, with results as listed in BIO-3A through BIO-3E,
below.
TABLE-US-00008 TABLE BIO-3A Mean Daily Food Intake (in Grams (Std
Err)) Vehicle 30 mg/kg Day 1 2.7 (0.2) 0.4 (0.1) Day 2 2.6 (0.2)
0.5 (0.1) Day 3 2.5 (0.1) 0.5 (0.1) Day 4 2.4 (0.1) 1.1 (0.1)
TABLE-US-00009 TABLE BIO-3B Mean Body Weight (in Grams (Std Err))
Vehicle 30 mg/kg Day 0 45.4 (0.7) 45.4 (0.7) Day 1 45.5 (0.7) 42.8
(0.8) Day 2 45.3 (0.7) 41.4 (0.7) Day 3 45.3 (0.8) 40.3 (0.6) Day 4
45.1 (0.7) 39.4 (0.6)
TABLE-US-00010 TABLE BIO-3C Plasma Insulin (in ng/mL (Std Err))
Plasma Insulin Vehicle 6.10 (0.98) 30 mg/kg 2.72 (0.61)
TABLE-US-00011 TABLE BIO-3D Fed Blood Glucose (in mg/dL (Std Err))
Day 0 Day 4 Vehicle 187 (9) 202 (9) 30 mg/kg 187 (9) 160 (6)
TABLE-US-00012 TABLE BIO-3E Plasma and Brain Concentrations, 2
Hours Post Dose, Day 5 Plasma Brain ng/mL (Std Dev) ng/g (Std Dev)
30 mg/kg 7662 (1587) 208 (46)
[1478] Compound #328 was tested according to the procedure as
described above, with results as listed in BIO-4A through BIO-4E,
below.
TABLE-US-00013 TABLE BIO-4A Mean Daily Food Intake (in Grams (Std
Err)) Vehicle 30 mg/kg Day 1 2.1 (0.2) 0.5 (0.1) Day 2 2.5 (0.2)
0.5 (0.1) Day 3 2.4 (0.2) 0.7 (0.1) Day 4 2.3 (0.1) 1.2 (0.1)
TABLE-US-00014 TABLE BIO-4B Mean Body Weight (in Grams (Std Err))
Vehicle 30 mg/kg Day 0 43.4 (0.7) 43.6 (0.7) Day 1 43.4 (0.7) 41.2
(0.7) Day 2 43.0 (0.7) 39.6 (0.6) Day 3 42.9 (0.7) 38.6 (0.6) Day 4
42.7 (0.7) 38.2 (0.7)
TABLE-US-00015 TABLE BIO-4C Plasma Insulin (in ng/mL (Std Err))
Plasma Insulin Vehicle 3.32 (0.58) 30 mg/kg 1.31 (0.13)
TABLE-US-00016 TABLE BIO-4D Fed Blood Glucose (in mg/dL (Std Err))
Day 0 Day 4 Vehicle 183 (9) 182 (6) 30 mg/kg 183 (9) 154 (7)
TABLE-US-00017 TABLE BIO-4E Plasma and Brain Concentrations, 2
Hours Post Dose, Day 5 Plasma Brain ng/mL (Std Dev) ng/g (Std Dev)
30 mg/kg 8364 (959) 291 (84.3)
Biological Example 5: Chronic DIO Mouse
[1479] The test compound was formulated in 10% PEG400 and 10%
solutol. DIO mice received vehicle, test compound (@ 1, 3, 10, and
30 mg/kg) daily for 26 days. At the end of the experiment, the mice
were euthanized and blood and tissues were collected.
[1480] Body weight and food weight (food intake) were monitored
daily for days 1-5 and twice weekly thereafter.
[1481] An insulin tolerance test (0.7 U/kg Humulin, ip) was
performed on day 21 after a 4 hour food removal. Blood glucose was
measured at 0, 15, 30, 60 and 120 minutes after insulin. After an
overnight fast, an oral glucose tolerance test (2 g/kg glucose) was
performed on day 23. Blood glucose was measured at 0, 30, 60 and
120 minutes after glucose challenge.
[1482] Blood glucose was measured from the tail vein with a
Lifescan glucometer. Plasma insulin was measured with an ELISA or
HTRF kit (Cisbio). Plasma parameters were measured with an Olympus
clinical chemistry analyzer.
[1483] Compound #148 was tested according to the procedure as
described above, with results as listed in Table BIO-5A through
Table BIO-5F, below.
TABLE-US-00018 TABLE BIO-5A Mean Daily Food Intake (in Grams (Std
Err)) Vehicle 1 mg/kg 3 mg/kg 10 mg/kg 30 mg/kg Day 2 2.1 (0.2) 2.3
(0.1) 2.0 (0.2) 0.5 (0.1) 0.1 (0.1) Day 3 1.9 (0.2) 2.3 (0.1) 2.0
(0.1) 0.9 (0.1) 0.5 (0.1) Day 4 1.9 (0.3) 2.2 (0.1) 1.9 (0.2) 1.7
(0.2) 0.7 (0.1) Day 5 2.0 (0.3) 2.4 (0.1) 1.8 (0.2) 1.8 (0.2) 1.0
(0.2) Day 8 1.9 (0.2) 2.1 (0.1) 1.7 (0.1) 1.7 (0.1) 1.3 (0.2) Day
11 2.1 (0.1) 2.3 (0.1) 1.8 (0.1) 2.0 (0.1) 1.7 (0.2) Day 15 2.5
(0.1) 2.4 (0.1) 2.5 (0.1) 2.3 (0.1) 2.3 (0.1) Day 18 2.0 (0.2) 1.6
(0.3) 2.2 (0.1) 2.3 (0.1) 1.8 (0.2) Day 24 2.3 (0.1) 2.1 (0.2) 2.2
(0.1) 2.2 (0.2) 2.4 (0.1)
TABLE-US-00019 TABLE BIO-5B Mean Body Weight (in Grams (Std Err))
Vehicle 1 mg/kg 3 mg/kg 10 mg/kg 30 mg/kg Day 0 41.42 (0.63) 42.03
(0.80) 42.28 (0.49) 42.09 (0.85) 42.46 (0.58) Day 1 41.59 (0.77)
42.63 (0.79) 42.94 (0.45) 42.69 (0.74) 43.13 (0.69) Day 2 41.18
(0.77) 42.56 (0.86) 42.12 (0.43) 40.46 (0.66) 39.64 (0.68) Day 3
40.87 (0.83) 42.46 (0.91) 41.85 (0.47) 39.85 (0.68) 38.53 (0.66)
Day 4 40.63 (0.92) 42.26 (0.87) 41.42 (0.44) 39.44 (0.70) 37.46
(0.75) Day 5 40.29 (0.97) 42.31 (0.81) 41.3 (0.36) 38.78 (0.70)
36.67 (0.75) Day 8 39.48 (1.08) 41.62 (0.79) 39.78 (0.29) 37.4
(0.67) 34.95 (0.78) Day 11 39.74 (0.98) 41.91 (0.77) 39.1 (0.41)
36.99 (0.78) 33.79 (0.87) Day 15 40.72 (0.98) 42.67 (1.02) 40.43
(0.40) 37.33 (0.84) 34.19 (0.64) Day 18 39.4 (1.17) 40.54 (1.23)
39.84 (0.53) 37.02 (0.88) 32.47 (0.92) Day 24 40.94 (1.21) 41.11
(1.30) 40.48 (0.48) 36.42 (1.25) 32.86 (0.91)
TABLE-US-00020 TABLE BIO-5C Insulin Tolerance Test Mean Blood
Glucose (in mg/dL (Std Err)) Vehicle 1 mg/kg 3 mg/kg 10 mg/kg 30
mg/kg 0 min 184.2 194.8 185.9 (6.57) 168.8 (7.13) 143 (12.70)
(14.64) (12.69) 15 min 179.4 193.3 160.9 (7.24) 172.6 (9.66) 147.6
(14.38) (13.87) (14.57) 30 min 145 155 138.9 (9.10) 139.1 (7.03)
119.8 (14.33) (15.40) (12.67) 60 min 154.2 161.3 150.9 (11.66)
146.7 (5.80) 121.3 (14.08) (18.83) (13.19) 120 min 161.8 150 136.3
(9.51) 144.8 (5.86) 104.5 (13.33) (13.98) (10.01) AUC 19128 19606.5
17812.5 (1054.85) 17930.25 (556.44) 14575.5 (mg/dL * min) (1598.23)
(1737.27) (1441.54)
TABLE-US-00021 TABLE BIO-5D Oral Glucose Tolerance Test Mean Blood
Glucose (in mg/dL (Std Err)) Vehicle 1 mg/kg 3 mg/kg 10 mg/kg 30
mg/kg 0 min 151.80 139.90 154.89 141.60 125.30 (9.25) (7.77) (4.54)
(6.97) (9.30) 30 min 172.1 179.2 153.11 190.1 184.5 (9.53) (13.61)
(11.51) (6.14) (9.25) 60 min 164.3 168.5 183.89 176.2 179 (7.75)
(10.65) (7.37) (5.23) (4.31) 120 min 158.6 143.5 150.44 132.8 126.9
(11.17) (9.60) (3.48) (5.33) (10.95) AUC 19591.5 19362 19705 19740
19276.5 (mg/ (698.06) (816.66) (543.73) (577.36) (638.04) dL *
min)
TABLE-US-00022 TABLE BIO-5E Plasma Insulin (in ng/mL (Std Err))
Plasma Insulin Vehicle 5.90 (0.64) 1 mg/kg 5.92 (0.92) 3 mg/kg 4.74
(0.83) 10 mg/kg 2.20 (0.13) 30 mg/kg 2.85 (0.27)
TABLE-US-00023 TABLE BIO 5F Plasma and Brain Concentrations, 2
Hours Post Dose, Day 25 Plasma Brain ng/mL (Std Dev) ng/g (Std Dev)
1 mg/kg 288 (56.2) 18.2 (7.56) 3 mg/kg 1346 (321) 29.9 (13.8) 10
mg/kg 3431 (152) 42 (28.3) 30 mg/kg 15237 (11647) 73.5 (93.3)
Biological Example 6: Open Field Locomotor Activity in Rats (CNS
Activity)-Prophetic Example
[1484] Male SD rats are weighed and transferred to the Activity
Chambers with access to water. After a 2-hr acclimation period, the
rats are dosed with vehicle or test compound (@ 3 and 10 mg/kg).
The Activity Chamber monitoring software program is initiated and
automatically records rat activity in each chamber for a period of
4 hours. At the end of the 4 hour monitoring period, the software
is stopped and the rats are removed from the activity chambers. The
rats are anesthetized and blood samples are obtained via
retro-orbital puncture to determine plasma concentration of
compounds. The rats are immediately euthanized with CO.sub.2 and
the brains are removed, washed with PBS, frozen on dry ice and
stored at -80.degree. C. for receptor occupancy (RO) analysis.
[1485] Satellite groups of 3 rats are dosed with test compound at 3
mg/kg and 10 mg/kg respectively. Four hours later, the rats are
anesthetized. Blood is collected from these rats and then perfused
with 400 ml heparinized saline through the left ventricle of the
heart. The brains are removed and homogenized in PBS (4 ml/gm
tissue). The samples are submitted for determination of plasma and
brain compound levels.
Formulation Example 1
Solid, Oral Dosage Form--Prophetic Example
[1486] As a specific embodiment of an oral composition, 100 mg of
the Compound #335 or Compound #328 is formulated with sufficient
finely divided lactose to provide a total amount of 580 to 590 mg
to fill a size O hard gel capsule.
[1487] While the foregoing specification teaches the principles of
the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the
invention encompasses all of the usual variations, adaptations
and/or modifications as come within the scope of the following
claims and their equivalents.
* * * * *