U.S. patent application number 10/451295 was filed with the patent office on 2004-04-15 for thiazole and oxazole derivatives as activators of human peroxisome proliferator activated receptors.
Invention is credited to Banker, Pierette, Cadilla, Rodolfo, Lambert lll, Millard Hurst, Rafferty, Stephen William, Sternbach, Daniel David, Sznaidman, Marcos Luis.
Application Number | 20040072838 10/451295 |
Document ID | / |
Family ID | 32071235 |
Filed Date | 2004-04-15 |
United States Patent
Application |
20040072838 |
Kind Code |
A1 |
Banker, Pierette ; et
al. |
April 15, 2004 |
Thiazole and oxazole derivatives as activators of human peroxisome
proliferator activated receptors
Abstract
The present invention provides a compound of formula (1) wherein
R.sub.1-R.sub.5, R.sub.25, R.sub.26, Y and X.sub.2 are defined as
in claim 1. The compounds activate human peroxisome proliferator
activated receptors (hPPARs) and arc useful for the treatment of
associated disorders such as cardiovascular disease and
hypercholesteremia. 1
Inventors: |
Banker, Pierette; (Durham,
NC) ; Cadilla, Rodolfo; (Durham, NC) ; Lambert
lll, Millard Hurst; (Durham, NC) ; Rafferty, Stephen
William; (Durham, NC) ; Sternbach, Daniel David;
(Durham, NC) ; Sznaidman, Marcos Luis; (Durham,
NC) |
Correspondence
Address: |
DAVID J LEVY, CORPORATE INTELLECTUAL PROPERTY
GLAXOSMITHKLINE
FIVE MOORE DR., PO BOX 13398
RESEARCH TRIANGLE PARK
NC
27709-3398
US
|
Family ID: |
32071235 |
Appl. No.: |
10/451295 |
Filed: |
October 31, 2003 |
PCT Filed: |
June 20, 2001 |
PCT NO: |
PCT/US01/41056 |
Current U.S.
Class: |
514/252.11 ;
514/252.19; 514/253.09; 514/254.02; 544/295; 544/357; 544/360;
544/368 |
Current CPC
Class: |
C07D 417/06 20130101;
C07D 277/26 20130101; C07D 277/28 20130101; C07D 277/24 20130101;
C07D 417/12 20130101; C07D 263/32 20130101; C07D 417/10
20130101 |
Class at
Publication: |
514/252.11 ;
514/253.09; 514/252.19; 514/254.02; 544/295; 544/357; 544/360;
544/368 |
International
Class: |
A61K 031/496; C07D
417/14; C07D 413/14 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 20, 2000 |
GB |
0031103.5 |
Claims
1. A compound of formula (I) or a pharmaceutically acceptable salt,
solvate, or hydrolyzable ester thereof wherein: 24R.sup.1 and
R.sup.2 are independently hydrogen or C.sub.1-3 alkyl; X.sup.2 is
O, S, or CH.sub.2; R.sup.3, R.sup.4, and R.sup.5 are independently
H, C.sub.1-3alkyl, OCH.sub.3, CF.sub.3, OCF.sub.3, CN, allyl, or
halogen; Y is S or O; each R.sup.25 is independently CH.sub.3,
OCH.sub.3, CF.sub.3, or halogen; y is 0, 1, 2, 3, 4 or 5; and
R.sup.26 is selected from the group consisting of the moieties A
through K depicted below: 25wherein R.sup.12 is selected from the
group consisting of C.sub.1-6alkyl, C.sub.1-6alkylenearyl, and the
moieties depicted below in Group II, 26wherein R.sup.17 and
R.sup.18 are independently hydrogen, halogen, hydroxy, --CN,
C.sub.1-6alkyl, C.sub.1-6 perfluoroalkyl, C.sub.1-6acyl,
--OC.sub.1-6alkyl, perfluoroOC.sub.1-6alkyl, or
C.sub.1-6hydroxyalkyl; R.sup.19 is hydrogen or C.sub.1-6alkyl;
R.sup.21 is C.sub.1-6alkyl, --C.sub.1-6alkylenearyl, aryl, or
-aryl-heteroaryl; R.sup.22 is C.sub.1-6alkyl, aryl, or
--C.sub.1-6alkylenearyl; R.sup.23 is C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, or aryl; R.sup.24 is C.sub.1-6alkyl,
--C.sub.1-6alkylenearyl, C.sub.3-6cycloalkyl, or aryl; 27wherein Z
is O, N or S (note that when Z is N, the depicted bond can be
attached to the nitrogen in the ring as well as any of the carbons
in the ring); 28wherein R.sup.20 is C.sub.1-6alkyl, aryl,
--OC.sub.1-6alkyl, hydroxy, C.sub.1-6hydroxyalkyl, or
1-alkoxyC.sub.1-6alkyl; 29wherein R.sup.13 and R.sup.14 are
independently hydrogen, halogen, CN, perfluroC.sub.1-6alkyl,
perflurOC.sub.1-6alkyl, C.sub.1-6alkyl, --OC.sub.1-6alkyl,
--C.sub.1-6alkyleneOC.sub.1-6alkyl, --SC.sub.1-6alkyl, or aryl;
30wherein R.sup.21 is independently as defined above; 31wherein
R.sup.15 and R.sup.16 are independently hydrogen, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl optionally substituted with 1 or 2
C.sub.1-3alkyl groups, or R.sup.12 as defined above; 32I
--(CH.sub.2).sub.nPh wherein n is 1-3 J --O--R.sup.21 wherein
R.sup.21 is independently as defined above; and K --S--R.sup.21
wherein R.sup.21 is independently as defined above.
2. A compound according to claim 1 wherein R.sup.1 and R.sup.2 are
independently H or CH.sub.3.
3. A compound according to claim 2 wherein R.sup.1 and R.sup.2 are
either both H or both CH.sub.3.
4. A compound according to any of claims 1-3 wherein X.sup.2 is O
or S.
5. A compound according to any of claims 14 wherein R.sup.3 is
CH.sub.3 or H.
6. A compound according to any of claims 1-5 wherein R.sup.4 and
R.sup.5 are H.
7. A compound according to any preceding claim wherein Y is S.
8. A compound according to any of claims 1-8 wherein y is 1 or
2.
9. A compound according to claim 8 wherein each R.sup.5 is
independently halogen or CF.sub.3.
10. A compound according to any preceding claim wherein R.sup.26 is
selected from the group consisting of 33where in R.sup.12, Z,
R.sup.13, and R.sup.14 are as defined in claim 1.
11. A compound according to any preceeding claim wherein R.sup.13
and R.sup.14 are independently fluorine, bronime, phenyl, thienyl,
CF.sub.3, OCF.sub.3, OCH.sub.3, SCH.sub.3, or t-butyl, R.sup.17 and
R.sup.18 are independently hydrogen, OH, CN, OC.sub.1-3alkyl,
halogen, CF.sub.3, COCH.sub.3, CH(OH)CH.sub.3, or OCF.sub.3,
R.sup.21 is phenyl optionally substituted by methyl or CN,
--C.sub.1-3alkylenephenyl, or phenyl-5-methyl-1,2,4-oxadiazol-3-yl,
R.sup.22 is C.sub.1-6 alkyl, phenyl, or benzyl, R.sup.23 is
C.sub.1-6alkyl, furanyl, thienyl, phenyl optionally substituted by
a halogen a methoxy or a dimethylamino group,
methoxymethylcyclopropyl, or C.sub.3-6cyclalkyl, and R.sup.24 is H,
C.sub.1-6alkyl, cyclohexyl, m-methoxyphenyl, p-fluorophenyl, or
--CH.sub.2CH.sub.2-phenyl.
12. A compound according to claim 11 wherein R.sup.26 is 34and
R.sup.12 is selected from the moieties shown in Group IV. 35
13. A compound according to claim 12 wherein R.sup.17 is fluorine,
chlorine, OC.sub.1-3alkyl or COCH.sub.3 and R.sup.18 is OCH.sub.3
or hydrogen, and R.sup.19 is hydrogen.
14. A compound according to claim 10 wherein R.sup.26 is 36
15. A compound according to claim 14 wherein R.sup.14 is thienyl,
OCH.sub.3, OCF.sub.3, CF.sub.3, or fluorine, and R.sup.13 is
hydrogen or fluorine.
16. A compound of formula (I) selected from:
2-[4-({[4-{[4-(4-acetylphenyl-
)-1-piperazinyl]methyl}-2-(4-fluorophenyl)1,3-thiazol-5-yl]methyl}sulfanyl-
)-2-methylphenoxy]-2-methylpropanoic acid,
2-methyl-2-{2-methyl-4-[({4-[4--
(methylsulfanyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}met-
hyl)sulfanyl]phenoxy}propanoic acid,
{2-methyl-4-[({4-(3-thienylmethyl)-2--
[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}aceti-
c acid,
{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}meth-
yl)sulfanyl]-2,5-dimethylphenoxy}acetic acid,
2-{4-[({4-{[4-(4-acetylpheny-
l)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}me-
thyl)sulfanyl]-2-methylphenoxy)propanoic acid,
2-{4-[({4-{[4-(4-acetylphen-
yl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}m-
ethyl)sulfanyl]-2-ethylphenoxy}propanoic acid,
2-{2-methyl-4-[({4-(2-thien-
ylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]p-
henoxy}propanoic acid,
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methy-
l}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methy-
lphenoxy}propanoic acid,
2-{4-[({4-{[4-(4-ethoxyphenyl)-1-piperazinyl]meth-
yl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-meth-
ylphenoxy}propanoic acid,
2-methyl-2-{2-methyl-4-[({4-{[4-(phenoxycarbonyl-
)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}met-
hyl)sulfanyl]phenoxy}propanoic acid,
2-{4-[({4-{[4-(4-acetylphenyl)-1-pipe-
razinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulf-
anyl]-2-propylphenoxy}propanoic acid,
{2-methyl-4-[({4-[4-(3-thienyl)benzy-
l]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-
acetic acid,
2-(4-{[(2-(4-fluorophenyl)-4-{[4-(4-methoxyphenyl)-1-piperazi-
nyl]methyl}-1,3-thiazol-5-yl)methyl]sulfanyl}-2-methylphenoxy)-2-methylpro-
panoic acid,
2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpr-
opanoic acid,
2-{4-[({4-{[4-(2,4-dimethoxyphenyl)-1-piperazinyl]methyl}-2--
[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphen-
oxy}propanoic acid,
{2-isopropyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperaziny-
l]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]p-
henoxy}acetic acid,
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}--
2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylph-
enoxy}propanoic acid,
2-{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-t-
hiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,
2-{2-ethyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifl-
uoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
acid,
2-methyl-2-{2-methyl-4-[({4-[4-(trifluoromethyl)benzyl]-2-[4-(trifl-
uoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
acid,
2-{4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methy-
lpropanoic acid,
{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(-
trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}-
acetic acid,
{4-[({4-([1,1'-biphenyl]-4-ylmethyl)-2-[4-(trifluoromethyl)ph-
enyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic
acid,
2-{4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethy-
l)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic
acid,
{4[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-4-(trifluorome-
thyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic
acid,
2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]--
1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid,
{4-[({4-{[4-(2-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl-
)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic
acid,
2-{2-isopropyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(t-
rifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
acid,
2-{4-[({4-(4-tert-butylbenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-th-
iazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic
acid,
2-{4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluorometh-
yl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic
acid,
2-{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}met-
hyl)sulfanyl]-2,3-dimethylphenoxy}propanoic acid,
2-{4-[({4-{[4-(4-chlorop-
henyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-y-
l}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,
2-{4-[({4-benzyl-2-[4-(-
trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-fluorophenoxy}-
propanoic acid,
2-{4-[({4-{[4-(2,4-difluorophenyl)-1-piperazinyl]methyl}-2-
-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphe-
noxy}propanoic acid,
{4-[({4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyl)ph-
enyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic
acid,
2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethy-
l)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropa-
noic acid,
2-methyl-2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluorome-
thyl)phenyl]-1,3-thiazol-5-yl)methyl)sulfanyl]phenoxy}propanoic
acid,
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluorometh-
yl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic
acid,
{2-ethyl-4-[({4-{4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic
acid,
2-{4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiaz-
ol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid,
2-methyl-2-{4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
acid,
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluorometh-
yl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylprop-
anoic acid,
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpr-
opanoic acid,
2-methyl-2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[-
4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propan-
oic acid,
2-{4-[({4-{[4-(4-isopropoxyphenyl)-1-piperazinyl]methyl}-2-[4-(t-
rifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}p-
ropanoic acid,
2-{2-methyl-4-[({4-{[4-(2-pyrimidinyl)-1-piperazinyl]methyl-
}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}p-
ropanoic acid.
{2-methyl-4-[({4-(3-phenylpropyl)-2-[4-(trifluoromethyl)phe-
nyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,
[4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulf-
anyl]-2-(trifluoromethyl)phenoxy]acetic acid,
{2-methyl-4-[({4-{[(5-methyl-
-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-th-
iazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,
{4-[({4-benzyl-2-[4-(trifl-
uoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-5-chloro-2-methylphen-
oxy}acetic acid,
{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol--
5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid,
{4-[({4-(4-methoxybenzy-
l)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methy-
lphenoxy}acetic acid,
{2,5-dimethyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic
acid,
{2-methyl-4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2-[4-(trifluorom-
ethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,
{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulf-
anyl]-2,3-dimethylphenoxy}acetic acid,
[4-({[2-(4-chlorophenyl)-4-methyl-1-
,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetic acid,
{2-methyl-4-[({4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethyl)pheny-
l]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,
{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulf-
anyl]-2-bromophenoxy}acetic acid,
{2-methyl-4-[({4-[(2-phenylethoxy)methyl-
]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl)methyl)sulfanyl]phenoxy}a-
cetic acid,
{2-methyl-4-[({4-(2-phenylethyl)-2-[4-(trifluoromethyl)phenyl]-
-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid, and
pharmaceutically acceptable salts, solvates, and hydrolyzable
esters thereof.
17. A compound of formula (I) selected from:
2-methyl-2-{2-methyl-4-[({4-(-
3-thienylmethyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sul-
fanyl]phenoxy}propanoic acid,
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperaziny-
l]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]--
2-methylphenoxy}propanoic acid,
{2-ethyl-4-[({4-{[4-(4-methoxyphenyl)-1-pi-
perazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)su-
lfanyl]phenoxy}acetic acid,
2-{4-[({4-(4-methoxybenzyl)2-[4-(trifluorometh-
yl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylprop-
anoic acid,
2-methyl-2-{4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2-[-
4-(trifluoromethyl)phenyl-1,3-thiazol-5-ylmethyl)sulfanyl]phenoxy}propanoi-
c acid,
2-{4-[({[4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifl-
uoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-me-
thylpropanoic acid,
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}--
2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2--
methylpropanoic acid,
2-methyl-2-{2-methyl-4-[({4-[4-(trifluoromethoxy)ben-
zyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenox-
y)propanoic acid,
2-{4-[({4-{[4-(4-isopropoxyphenyl)-1-piperazinyl]methyl}-
-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylp-
henoxy}propanoic acid,
2-{2-methyl-4-[({4-{[4-(2-pyrimidinyl)-1-piperaziny-
l]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]p-
henoxy}propanoic acid, and pharmaceutically acceptable salts,
solvates, or hydrolyzable esters thereof
18. A compound according to any preceding claim which is a
hPPAR.delta. agonist.
19 A compound according to claim 18 which is also a hPPAR.alpha. or
hPPARgamma agonist.
20. A compound according to any preceding claim which is a hPPAR
pan agonist.
21. A compound according to any of claims 1-20 for use in
therapy.
22. A pharmaceutical composition comprising a compound according to
any of claims 120.
23. A pharmaceutical composition according to claim 22 further
comprising a pharmaceutically acceptable diluent or carrier.
24. Use of a compound according to any of claims 1-20 for the
manufacture of a medicament for the treatment of a hPPAR disease or
condition.
25. Use according to claim 24 wherein the hPPAR mediated disease or
condition is dyslipidemia, syndrome X, heart failure,
hypercholesteremia, cardiovascular disease, type II diabetes
mellitus, type I diabetes, insulin resistance, hyperlipidemia,
obesity, anorexia bulimia and anorexia nervosa
26. A method of treating a hPPAR mediated disease or condition in a
patient comprising the administration of a therapeutically
effective amount of a compound according to any of claims 1-20.
27. A method according to claim 26 wherein the hPPAR mediated
disease or condition is dyslipidemia, syndrome X, heart failure,
hypercholesteremia, cardiovascular disease, type II diabetes
mellitus, type I diabetes, insulin resistance, hyperlipidemia,
obesity, anorexia bulimia and anorexia nervosa.
Description
[0001] The present invention relates to certain novel compounds. In
particular, the present invention relates to compounds that
activate human peroxisome proliferator activated receptors
("hPPARs"). The present invention also relates to methods for
preparing the compounds, their use in medicine, pharmaceutical
compositions containing them and methods for the prevention or
treatment of PPAR mediated diseases or conditions.
[0002] Several independent risk factors have been associated with
cardiovascular disease. These include hypertension, increased
fibrinogen levels, high levels of triglycerides, elevated LDL
cholesterol, elevated total cholesterol, and low levels of HDL
cholesterol. HMG CoA reductase inhibitors ("statins") are useful
for treating conditions characterized by high LDL-c levels. It has
been shown that lowering LDL-c is not sufficient for reducing the
risk of cardiovascular disease in some patients, particularly those
with normal LDL-c levels. This population pool is identified by the
independent risk factor of low HDL-c. The increased risk of
cardiovascular disease associated with low HDL-c levels has not yet
been successfully addressed by drug therapy (i.e. currently there
are no drugs on the market that are useful for raising HDL-c).
(Bisgaier, C. L.; Pape, M. E. Curr. Pharm. Des. 1998, 4,
53-70).
[0003] Syndrome X (including metabolic syndrome) is loosely defined
as a collection of abnormalities including hyperinsulinemia,
obesity, elevated levels of trigycerides, uric acid, fibrinogen,
small dense LDL particles, and plasminogen activator inhibitor 1
(PAI-1), and decreased levels of HDL-c.
[0004] NIDDM is described as insulin resistance which in turn
causes anomalous glucose output and a decrease in glucose uptake by
skeletal muscle. These factors eventually leac to impaired glucose
tolerance (IGT) and hyperinsulinemia.
[0005] Peroxisome Proliferator Activated Receptors (PPARs) are
ophan receptors belonging to the steroid/retinoid receptor
superfamily of ligand-activated transcription factors. See, for
example Willson T. M. and Wahli, W., Curr. Opin. Chem. Biol. (1997)
Vol 1 pp 235-241 and Willson T. M. et. al., J. Med. Chem (2000) Vol
43 p527-549. The binding of agonist ligands to the receptor results
in changes in the expression level of mRNA's encoded by PPAR target
genes.
[0006] Three mammalian Peroxisome Proliferator-Activated Receptors
have been isolated and termed PPAR-alpha, PPAR-gamma, and
PPAR-delta (also known as NUC1 or PPAR-beta). These PPARs regulate
expression of target genes by binding to DNA sequence elements,
termed PPAR response elements (PPRE). To date, PPRE's have been
identified in the enhancers of a number of genes encoding proteins
that regulate lipid metabolism suggesting that PPARs play a pivotal
role in the adipogenic signaling cascade and lipid homeostasis (H.
Keller and W. Wahli, Trends Endocrin. Met 291-296, 4 (1993).
[0007] It has now been reported that thiazolidinediones are potent
and selective activators of PPAR-grams and bind directly to the
PPAR-gamma receptor (J. M. Lehmann et. al., J. Biol. Chem.
12953-12956, 270 (1995)), providing evidence that PPAR-gamma is a
possible target for the therapeutic actions of the
thiazolidinediones.
[0008] Activators of the nuclear receptor PPAR.gamma., for example
troglitazone, have been shown in the clinic to enhance
insulin-action, reduce serum glucose and have small but significant
effects on reducing serum triglyceride levels in patients with Type
2 diabetes. See, for example, D. E. Kelly et al., Curr. Opin.
Endocrinol. Diabetes, 90-96, 5 (2), (1998); M. D. Johnson et al.,
Ann. Pharmacother., 337-348, 32 (3), (1997); and M. Leutenegger et
al., Curr. Ther. Res., 403-416, 58 (7), (1997).
[0009] The mechanism for this triglyceride lowering effect appears
to be predominantly increased clearance of very low density
lipoproteins (VLDL) through induction of liporotein lipase (LPL)
gene expression. See, for example, B. Staels et al., Arterloscier.
Thromb., Vasc. Biol., 17561764, 17 (9), (1997).
[0010] Fibrates are a class of drugs which may lower serum
triglycerides 20-50%, lower LDLc 10-15%, shift the LDL particle
size from the more atherogenic small dense to normal dense LDL, and
increase HDLc 10-15%. Experimental evidence indicates that the
effects of fibrates on serum lipids are mediated through activation
of PPAR.alpha.. See, for example, B. Staels et al., Curr. Pharm.
Des., 1-14, 3 (1), (1997). Activation of PPAR.alpha. results in
transcription of enzymes that increase fatty acid catabolism and
decrease de-novo fatty acid synthesis in the liver resulting in
decreased triglyceride synthesis and VLDL production/secretion. In
addition, PPAR.alpha. activation decreases production of apoC-III.
Reduction in apoC-III, an inhibitor of LPL activity, increases
clearance of VLDL. See, for example, J. Auwerx et al.,
Atherosclerosis, (Shannon, Irel.), S29-537, 124 (Suppl),
(1996).
[0011] Certain compounds that activate or otherwise interact with
one or more of the PPARs have been implicated in the regulation of
triglyceride and cholesterol levels in animal models. See, for
example, U.S. Pat. No. 5,847,008 (Doebber et al.) and U.S. Pat. No.
5,859,051 (Adams et al.) and PCT publications WO 97/28149
(Leibowitz et al.) and WO99/04815 (Shimokawa et al.). In a recent
report (Berger et al., J. Biol. Chem. 1999), vol. 274,
pp.6718-6725) it was stated that PPAR.quadrature. activation does
not appear to modulate glucose or triglyceride levels.
[0012] In one aspect, the present invention provides compounds of
formula (I) and pharmaceutically acceptable salts, solvates, and
hydrolysable esters thereof wherein; 2
[0013] R.sup.1 and R.sup.2 are independently hydrogen or C.sub.1-3
alkyl;
[0014] X.sup.2 is O, S, or CH.sub.2;
[0015] R.sup.3, R.sup.4, and R.sup.5 are independently H,
C.sub.1-3alkyl, OCH.sub.3, CF.sub.3, OCF.sub.3, allyl, CN, or
halogen;
[0016] Y is S or O;
[0017] each R.sup.25 is independently CH.sub.3, OCH.sub.3,
OCF.sub.3, CF.sub.3, or halogen;
[0018] y is 0, 1, 2, 3, 4 or 5; and
[0019] R.sup.26 is selected from the group consisting of the
moieties A through K depicted below: 3
[0020] wherein R.sup.12 is selected from the group consisting of
C.sub.1-6alkyl, C.sub.1-6alkylenearyl, and the moieties depicted
below in Group II, 4
[0021] wherein R.sup.17 and R.sup.18 are independently hydrogen,
halogen, hydroxy, --CN, C.sub.1-6 alkyl, C.sub.1-6 perfluoroalkyl,
C.sub.1-6acyl, --OC.sub.1-6alkyl, perfluoroOC.sub.1-6alkyl, or
C.sub.1-6hydroxyalkyl;
[0022] R.sup.19 is hydrogen or C.sub.1-6alkyl;
[0023] R.sup.21 is C.sub.1-6alkyl, --C.sub.1-6alkylenearyl, aryl,
or -aryl-heteroaryl;
[0024] R.sup.22 is C.sub.1-6alkyl, aryl, or
--C.sub.1-6alkylenearyl;
[0025] R.sup.23 is C.sub.1-6alkyl, C.sub.3-6cycloalkyl, or
aryl;
[0026] R.sup.24 is C.sub.1-6alkyl, --C.sub.1-6alkylenearyl,
C.sub.3-6cycloalkyl, or aryl; 5
[0027] wherein Z is O, N or S (note that when Z is N, the depicted
bond can be attached to the nitrogen in the ring as well as any of
the carbons in the ring); 6
[0028] wherein R.sup.20 is C.sub.1-6alkyl, aryl, --OC.sub.1-6alkyl,
hydroxy, C.sub.1-6hydroxyalkyl, or 1-alkoxyC.sub.1-6alkyl; 7 8
[0029] wherein R.sup.13 and R.sup.14 are independently hydrogen,
halogen, CN, perfluroC.sub.1-6alkyl, perfluroOC.sub.1-6alkyl,
C.sub.1-6alkyl, --OC.sub.1-6alkyl,
--C.sub.1-6alkyleneOC.sub.1-6alkyl, --SC.sub.1-6alkyl, or aryl;
9
[0030] wherein R.sup.21 is independently as defined above; 10
[0031] wherein R.sup.15 and R.sup.16 are independently hydrogen,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl optionally substituted with 1
or 2 C.sub.1-3alkyl groups, or R.sup.12 as defined above; 11
[0032] I
--(CH.sub.2)nPh
[0033] wherein n is 1-3
[0034] J
--O--R.sup.21
[0035] wherein R.sup.21 is independently as defined above; and
[0036] K
--S--R.sup.21
[0037] wherein R.sup.21 is independently as defined above. As used
herein "aryl" or in any phrase or tern including "aryl" such as
"--C.sub.1-6alkylenearyl", th "aryl" means a phenyl group or a 5 or
6 membered heteroaryl group. As used hereing "heteroaryl" means a 5
or 6 membered heteroaryl group. As used herein any such "aryl" or
"heteroaryl" group may opbonally be substittued with one or two
substituents selected from the group consisting of halogen, CN,
dimethylamino, perfluroC.sub.1-6alkyl, perfluroOC.sub.1-6 alkyl,
C.sub.1-6alkyl, --OC.sub.1-6alkyl,
--C.sub.1-6alkyleneOC.sub.1-6alkyl, and --SC.sub.1-6alkyl.
[0038] In another aspect, the present invention discloses a method
for prevention or treatment of a disease or condition mediated by
one or more human PPAR alpha, gamma or delta ("hPPARs") comprising
administration of a therapeutically effective amount of a compound
of this invention. hPPAR mediated diseases or conditions Include
dyslipidemia including associated diabetic dyslipidemia and mixed
dyslipidemia, syndrome X (as defined in this application this
embraces metabolic syndrome), heart failure, hypercholesteremia,
cardiovascular disease including atherosclerosis, arteriosclerosis,
and hypertriglyceridemia, type II diabetes mellitus, type I
diabetes, insulin resistance, hyperlipidemia, inflammation,
epithelial hyperproliferative diseases Including eczema and
psoriasis and conditions associated with the lung and gut and
regulation of appetite and food intake in subjects suffering from
disorders such as obesity, anorexia bulimia, and anorexia nervosa.
In particular, the compounds of this invention are useful in the
treatment and prevention of diabetes and cardiovascular diseases
and conditions including atherosclerosis, arteriosclerosis,
hypertriglyceridemia, and mixed dyslipidaemia.
[0039] In another aspect, the present invention provides
pharmaceutical compositions comprising a compound of the invention,
preferably in association with a pharmaceutically acceptable
diluent or carrier.
[0040] In another aspect, the present invention provides a compound
of the invention for use in therapy, and in particular, in human
medicine.
[0041] In another aspect, the present invention provides the use of
a compound of the invention for the manufacture of a medicament for
the treatment of a hPPAR mediated disease or condition.
[0042] As used herein, "a compound of the invention" means a
compound of formula (I) or a pharmaceutically acceptable
hydrolyzable ester or, solvate, thereof.
[0043] While hydrolyzable esters are included in the scope of this
invention, the acids are preferred because the data suggests that
while the esters are useful compounds, it may actually be the acids
to which they hydrolyze that are the active compounds. Esters that
hydrolyze readily can produce the carboxylic acid in the assay
conditions or in vivo. Generally the carboxylic acid is active in
both the binding and transient transfection assays, while the ester
does not usually bind well but is active in the transient
transfection assay presumably due to hydrolysis. Preferred
hydrolysable esters are Cue alkyl esters wherein the alkyl group
may be straight chain or branched chain. Methyl or ethyl esters are
more preferred.
[0044] Preferably R.sup.1 and R.sup.2 are independently H or
CH.sub.3. Most preferably R.sup.1 and R.sup.2 are either both H or
both CH.sub.3.
[0045] Preferably X.sup.2 is O or S. More preferably X.sup.2 is
S;
[0046] Preferably R.sup.3 is CH.sub.3 or H;
[0047] Preferably R.sup.4 and R.sup.5 are H.
[0048] Preferably Y is S.
[0049] Preferably y is 1 or 2. When y is 2, preferably one R.sup.25
is halogen; more preferably one is halogen and the other is
CF.sub.3. When y is 1, preferably the R.sup.25 is in the para
position on the ring and is more preferably CF.sub.3.
[0050] Preferably R.sup.26 is selected from the moieties shown
below in Group III. 12
[0051] Preferably R.sup.12 is selected from the moieties shown
below in Group IV. 13
[0052] Preferably R.sup.13 or R.sup.14 are independently fluorine,
bromine, phenyl, thienyl, CF.sub.3, OCF.sub.3, OCH.sub.3,
SCH.sub.3, or t-butyl. Most preferably R.sup.14 is thienyl,
OCH.sub.3, OCF.sub.3, CF.sub.3, or fluorine. Most preferably
R.sup.14 is substituted para to the depicted open valence. Most
preferably R.sup.13 is hydrogen or fluorine.
[0053] Preferably R.sup.17 and R.sup.18 are independently hydrogen,
OH, OC.sub.1-3alkyl, CN, halogen, CF.sub.3, COCH.sub.3,
CH(OH)CH.sub.3, or OCF.sub.3. Most preferably R.sup.17 is fluorine,
chlorine, OC.sub.1-3alkyl, or COCH.sub.3 and R.sup.18 is OCH.sub.3
or hydrogen. Most preferably R.sup.17 is substituted para to the
depicted open valence.
[0054] Preferably R.sup.20 is phenyl, methyl, OCH.sub.3, OH, or
CH.sub.2OH.
[0055] Preferably R.sup.21 is --C.sub.1-3alkylenephenyl,
phenyl-5-methyl-1,2,4-oxadiazol-3-yl, or phenyl optionally
substituted by methyl or CN.
[0056] Preferably R.sup.22 is C.sub.1-6alkyl, phenyl, or
benzyl.
[0057] Preferably R.sup.23 is C.sub.1-6alkyl, furanyl, thienyl,
methoxymethyl, C.sub.3-6cyclalkyl, or phenyl optionally substituted
by a halogen a methoxy or a dimethylamino group.
[0058] Preferably R.sup.24 is H, C.sub.1-6alkyl, cyclohexyl,
m-methoxyphenyl, p-fluorophenyl, or CH.sub.2CH.sub.2-phenyl.
[0059] Preferably R.sup.19 is hydrogen.
[0060] Particularly preferred compounds will be those is which most
or all of the variables are selected from the preferred or most
preferred groups for each variable.
[0061] While the preferred groups for each variable have generally
been listed above separately for each variable, preferred compounds
of this invention include those in which several or each variable
in Formula (I) is selected from the preferred, more preferred, or
most preferred groups for each variable. Therefore, this invention
is intended to include all combinations of preferred, more
preferred, and most preferred groups.
[0062] Suitable compounds of formula (I) include:
[0063]
2-[4-({[4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-(4-fluorophe-
nyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]-2-methylpropanoic
acid,
[0064]
2-methyl-2-{2-methyl-4-[({4-[4-(methylsulfanyl)benzyl]-2-[4-(triflu-
oromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
acid,
[0065]
{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,-
3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,
[0066]
{4[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl-
)sulfanyl]-2,5-dimethylphenoxy}acetic acid,
[0067]
2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoi-
c acid,
[0068]
2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-ethylphenoxy}propanoic
acid,
[0069]
2-{2-methyl-4-[({4-(2-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]--
1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid,
[0070]
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl)methyl)sulfanyl]-2-methylphenoxy}propano-
ic acid,
[0071]
2-{4-[({4-{[4-(4-ethoxyphenyl)-piperazinyl]methyl}-2-[4-(trifluorom-
ethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic
acid,
[0072]
2-methyl-2-{2-methyl-4-[({4-{[(phenoxycarbonyl)-1-piperazinyl]methy-
l)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-
propanoic acid,
[0073]
2-{4-[({4-[4-(4-acetylphenyl)1-piperazinyl]methyl}-2-[4-(trifluorom-
ethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}propanoic
acid,
[0074]
{2-methyl-4-[({4-[4-(3-thienyl)benzyl]-2-[4-(trifluoromethyl)phenyl-
]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,
[0075]
2-(4-{[(2-(4-fluorophenyl)-4-{[4-(4-methoxyphenyl)-1-piperazinyl]me-
thyl}1,3-thiazol-5-yl)methyl]sulfanyl}-2-methylphenoxy)-2-methylpropanoic
acid,
[0076]
2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy)-2-methylpropanoi-
c acid,
[0077]
2-{4-[({4-{[4-(2,4-dimethoxyphenyl-1-piperazinyl]methyl}-2-[4-(trif-
luoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}prop-
anoic acid,
[0078]
{2-isopropyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[-
4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic
acid,
[0079]
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}propano-
ic acid,
[0080]
2-{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}met-
hyl)sulfanyl]-2-methylphenoxy}propanoic acid,
[0081]
2-{2-ethyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4--
(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoi-
c acid,
[0082]
2-methyl-2-{2-methyl-4-[({4-[4-(trifluoromethyl)benzyl]-2-[4-(trifl-
uoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
acid,
[0083]
2-{4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl)methyl)sulfanyl]-2-methylphenoxy-}2-methy-
lpropanoic acid,
[0084]
{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluorom-
ethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}acetic
acid,
[0085]
{4-[({4-([1,1'-biphenyl]-ylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,-
3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid,
[0086]
2-{4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoi-
c acid,
[0087]
{4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoro-
methyl)phenyl]-1,3-thiazol-5-yl)methyl)sulfanyl]-2-methylphenoxy}acetic
acid,
[0088]
2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]--
1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy)propanoic acid,
[0089]
{4-[({4-{[4-(2-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoro-
methyl)phenyl]-1,3-thiazol-5-yl)methyl)sulfanyl]-2-methylphenoxy}acetic
acid,
[0090]
2-{2-isopropyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl)-2-
-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy)prop-
anoic acid,
[0091]
2-{4-[({4-(4-tert-butylbenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-th-
iazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic
acid,
[0092]
2-{4-[({4-{[4-(3-methoxyphenyl)-piperazinyl]methyl}-2-[4-(trifluoro-
methyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic
acid,
[0093]
2-{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}met-
hyl)sulfanyl]-2,3-dimethylphenoxy}propanoic acid,
[0094]
2-{4-[({4-{[4-(4-chlorophenyl)-1-piperazinyl]methyl)-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoi-
c acid,
[0095]
2-{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}met-
hyl)sulfanyl]-2-fluorophenoxy}propanoic acid,
[0096]
2-{4-[({4-{[4-(2,4-difluorophenyl-piperazinyl]methyl}-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propano-
ic acid,
[0097]
{4-[({4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thia-
zol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid,
[0098]
2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methy-
lpropanoic acid,
[0099]
2-methyl-2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl-
)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
acid,
[0100]
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoi-
c acid,
[0101]
{2-ethyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(t-
rifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic
acid,
[0102]
2-{4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiaz-
ol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic
acid,
[0103]
2-methyl-2-{4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl)-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
acid,
[0104]
2-{4-[({4-([4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-meth-
ylpropanoic acid,
[0105]
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl-}2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpropano-
ic acid,
[0106]
2-methyl-2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trif-
luoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
acid,
[0107]
2-{4-[({4-{[4-(4-isopropoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trif-
luoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}prop-
anoic acid,
[0108]
2-{2-methyl-4-[({4-{[4-(2-pyrimidinyl]piperazinyl]methyl}-2-[4-(tri-
fluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
acid,
[0109]
{2-methyl-4-[({4-(3-phenylpropyl)-2-[4-(trifluoromethyl)phenyl]-1,3-
-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,
[0110]
[4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methy-
l)sulfanyl]-2-(trifluoromethyl)phenoxy]acetic acid,
[0111]
{2-methyl-4-[({4-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-
-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}ac-
etic acid,
[0112]
{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methy-
l)sulfanyl]-5-chloro-2-methylphenoxy}acetic acid,
[0113]
{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methy-
l)sulfanyl]-2-methylphenoxy}acetic acid,
[0114]
{4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-
-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid,
[0115]
{2,5-dimethyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl-
]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,
[0116]
{2-methyl-4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2-[4-(trif-
luoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic
acid,
[0117]
{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methy-
l)sulfanyl]-2,3-dimethylphenoxy}acetic acid,
[0118]
[4-({[2-(4-chlorophenyl)-4-methyl-1,3-thiazol-5-yl]methyl}sulfanyl)-
-2-methylphenoxy]acetic acid,
[0119]
{2-methyl-4-[({4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethyl-
)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,
[0120]
{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methy-
l)sulfanyl]-2-bromophenoxy}acetic acid,
[0121]
{2-methyl-4-[({4-[(2-phenylethoxy)methyl]-2-[4-(trifluoromethyl)phe-
nyl]-1,3-thiazol-5-yl)methyl)sulfanyl]phenoxy}acetic acid,
[0122]
{2-methyl-4-[({4-(2-phenylethyl)-2-[4-(trifluoromethyl)phenyl]-1,3--
thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid, and
[0123] pharmaceutically acceptable salts, solvates, and
hydrolyzable esters thereof.
[0124] More preferred compounds of formula (I) include:
[0125]
2-methyl-2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl-
)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
acid,
[0126]
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propano-
ic acid,
[0127]
{2-ethyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(t-
rifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic
acid,
[0128]
2-{4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiaz-
ol-5-yl}methyl)sulfanyl]-2-methylphenoxy)-2-methylpropanoic
acid,
[0129]
2-methyl-2-{4-[({4-{[4-(2-pyrazinyl)1-piperazinyl]methyl}-2-[4-(tri-
fluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
acid,
[0130]
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-meth-
ylpropanoic acid,
[0131]
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpropano-
ic acid,
[0132]
2-methyl-2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trif-
luoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
acid,
[0133]
2-{4-[({4-{[4-(4-isopropoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trif-
luoromethyl)phenyl)-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}prop-
anoic acid,
[0134]
2-{2-methyl-4-[({4-{[4-(2-pyrimidinyl)-1-piperazinyl]methyl}-2-[4-(-
trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
acid, and
[0135] pharmaceutically acceptable salts, solvates, and
hydrolyzable esters thereof.
[0136] Preferably, the compounds of formula (I) are hPPAR agonists.
The hPPAR agonists of formula (I) may be agonists of only one type
("selective agonists"), agonists for two PPAR subtypes ("dual
agonists"), or agonists for all three subtypes ("pan agonists"). As
used herein, by "agonist", or "activating compound", or
"activator", or the like, is meant those compounds which have a pKi
of at least 5.0 preferably at least 6.0 to the relevant PPAR, for
example hPPAR.quadrature. in the binding assay described below, and
which achieve at least 30% activation of the relevant PPAR relative
to the appropriate indicated positive control in the transfection
assay described below at concentrations of 10.sup.-5 M or less.
More preferably, the compounds of this invention achieve 30%
activation of at least one human PPAR in the relevant transfection
assay at concentrations of 10.sup.-6 M or less. More preferably the
compounds of the invention achieve 30% activation of at least one
human PPAR in the relevant transfection assay at concentrations of
10.sup.-7M or less.
[0137] Preferably the compounds of formula (I) are hPPAR.delta.
agonists. More preferably they are also agonists of at least one of
PPAR.gamma. or PPAR.alpha.. Most preferably they are pan hPPAR
agonists.
[0138] It will also be appreciated by those skilled in the art that
the compounds of the present invention may also be utilized in the
form of a pharmaceutically acceptable salt or solvate thereof. The
physiologically acceptable salts of the compounds of formula (I)
include conventional salts formed from pharmaceutically acceptable
inorganic or organic acids or bases as well as quaternary ammonium
acid addition salts. More specific examples of suitable acid salts
include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric,
perchloric, fumaric, acetic, propionic, succinic, glycolic, formic,
lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic,
phenylacetic, glutamic, benzoic, salicylic, fumaric,
toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic,
benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic,
tannic and the like. Other acids such as oxalic, while not in
themselves pharmaceutically acceptable, may be useful in the
preparation of salts useful as intermediates in obtaining the
compounds of the invention and their pharmaceutically acceptable
salts. More specific examples of suitable basic salts include
sodium, lithium, potassium, magnesium, aluminium, calcium, zinc,
N,N'-dibenzylethylenediam- ine, chloroprocaine, choline,
diethanolamine, ethylenediamine, N-methylglucamine and procaine
salts. Those skilled in the art of organic chemistry will
appreciate that many organic compounds can form complexes with
solvents in which they are reacted or from which they are
precipitated or crystallized. These complexes are known as
"solvates". For example, a complex with water is known as a
"hydrate". Solvates of the compound of formula (I) are within the
scope of the invention. References hereinafter to a compound
according to the invention include both compounds of formula (I)
and their pharmaceutically acceptable salts and solvates.
[0139] The compounds of the invention and their pharmaceutically
acceptable derivatives are conveniently administered in the form of
pharmaceutical compositions. Such compositions may conveniently be
presented for use in conventional manner in admixture with one or
more physiologically acceptable carriers or excipients.
[0140] While it is possible that compounds of the present invention
may be therapeutically administered as the raw chemical, it is
preferable to present the active ingredient as a pharmaceutical
formulation. The carrier(s) must be "acceptable" in the sense of
being compatible with the other ingredients of the formulation and
not deleterious to the recipient thereof.
[0141] Accordingly, the present invention further provides for a
pharmaceutical formulation comprising a compound of formula (I) or
a pharmaceutically acceptable salt or solvate thereof together with
one or more pharmaceutically acceptable carriers therefore and,
optionally, other therapeutic and/or prophylactic ingredients.
[0142] The formulations include those suitable for oral, parenteral
(including subcutaneous e.g. by injection or by depot tablet,
intradermal, Intrathecal, intramuscular e.g. by depot and
intravenous), rectal and topical (including dermal, buccal and
sublingual) administration although the most suitable route may
depend upon for example the condition and disorder of the
recipient. The formulations may conveniently be presented in unit
dosage form and may be prepared by any of the methods well known in
the art of pharmacy. All methods include the step of bringing into
association the compounds ("active ingredient") with the carrier
which constitutes one or more accessory ingredients. In general the
formulations are prepared by uniformly and intimately bringing into
association the active ingredient with liquid carriers or finely
divided solid carriers or both and then, if necessary, shaping the
product into the desired formulation.
[0143] Formulations suitable for oral administration may be
presented as discrete units such as capsules, cachets or tablets
(e.g. chewable tablets in particular for paediatric administration)
each containing a predetermined amount of the active ingredient; as
a powder or granules; as a solution or a suspension in an aqueous
liquid or a non-aqueous liquid; or as an oil-in-water liquid
emulsion or a water-in-oil liquid emulsion. The active ingredient
may also be presented as a bolus, electuary or paste.
[0144] A tablet may be made by compression or moulding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing In a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with other conventional excipients such as binding agents,
(for example, syrup, acacia, gelatin, sorbitol, tragacanth,
mucilage of starch or polyvinylpyrrolidone), fillers (for example,
lactose, sugar, microcrystalline cellulose, maize-starch, calcium
phosphate or sorbitol), lubricants (for example, magnesium
stearate, stearic acid, talc, polyethylene glycol or silica),
disintegrants (for example, potato starch or sodium starch
glycollate) or wetting agents, such as sodium lauryl sulfate.
Moulded tablets may be made by moulding in a suitable machine a
mixture of the powdered compound moistened with an inert liquid
diluent. The tablets may optionally be coated or scored and may be
formulated so as to provide slow or controlled release of the
active ingredient therein. The tablets may be coated according to
methods well-known in the art.
[0145] Alternatively, the compounds of the present invention may be
incorporated into oral liquid preparations such as aqueous or oily
suspensions, solutions, emulsions, syrups or elixirs, for example.
Moreover, formulations containing these compounds may be presented
as a dry product for constitution with water or other suitable
vehicle before use. Such liquid preparations may contain
conventional additives such as suspending agents such as sorbitol
syrup, methyl cellulose, glucose/sugar syrup, gelatin,
hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate
gel or hydrogenated edible fats; emulsifying agents such as
lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles
(which may include edible oils) such as almond oil, fractionated
coconut oil, oily esters, propylene glycol or ethyl alcohol; and
preservatives such as methyl or propyl p-hydroxybenzoates or sorbic
acid. Such preparations may also be formulated as suppositories,
e.g., containing conventional suppository bases such as cocoa
butter or other glycerides.
[0146] Formulations for parenteral administration include aqueous
and non-aqueous sterile injection solutions which may contain
anti-oxidants, buffers, bacteriostats and solutes which render the
formulation isotonic with the blood of the intended recipient; and
aqueous and non-aqueous sterile suspensions which may include
suspending agents and thickening agents.
[0147] The formulations may be presented in unit-dose or multi-dose
containers, for example sealed ampoules and vials, and may be
stored in a freeze-dried (lyophilised) condition requiring only the
addition of a sterile liquid carrier, for example,
water-for-injection, Immediately prior to use. Extemporaneous
injection solutions and suspensions may be prepared from sterile
powders, granules and tablets of the kind previously described.
[0148] Formulations for rectal administration may be presented as a
suppository with the usual carriers such as cocoa butter, hard fat
or polyethylene glycol.
[0149] Formulations for topical administration in the mouth, for
example buccally or sublingually, include lozenges comprising the
active ingredient in a flavoured basis such as sucrose and acacia
or tragacanth, and pastilles comprising the active ingredient in a
basis such as gelatin and glycerin or sucrose and acacia.
[0150] The compounds may also be formulated as depot preparations.
Such long acting formulations may be administered by implantation
(for example subcutaneously or intramuscularly) or by intramuscular
injection. Thus, for example, the compounds may be formulated with
suitable polymeric or hydrophobic materials (for example as an
emulsion in an acceptable oil) or ion exchange resins, or as
sparingly soluble derivatives, for example, as a sparingly soluble
salt.
[0151] In addition to the ingredients particularly mentioned above,
the formulations may include other agents conventional in the art
having regard to the type of formulation in question, for example
those suitable for oral administration may include flavouring
agents.
[0152] It will be appreciated by those skilled in the art that
reference herein to treatment extends to prophylaxis as well as the
treatment of established diseases or symptoms. Moreover, it will be
appreciated that the amount of a compound of the invention required
for use in treatment will vary with the nature of the condition
being treated and the age and the condition of the patient and will
be ultimately at the discretion of the attendant physician or
veterinarian. In general, however, doses employed for adult human
treatment will typically be in the range of 0.02-5000 mg per day,
preferably 1-1500 mg per day. The desired dose may conveniently be
presented in a single dose or as divided doses administered at
appropriate intervals, for example as two, three, four or more
sub-doses per day. The formulations according to the invention may
contain between 0.1-99% of the active ingredient, conveniently from
30-95% for tablets and capsules and 3-50% for liquid
preparations.
[0153] The compound of formula (I) for use in the instant invention
may be used in combination with other therapeutic agents for
example, statins and/or other lipid lowering drugs for example MTP
inhibitors and LDLR upregulators. The compounds of the invention
may also be used in combination with antidiabetic agents, e.g.
metformin, sulfonylureas and/or PPAR gamma, PPAR alpha or PPAR
alpha/gamma agonists (for example thiazolidinediones such as e.g.
Pioglitazone and Rosiglitazone). The compounds may also be used in
combination with antihypertensive agents such as angistensin
antagonists e.g. telmisartan, calcium channel antagonists e.g.
lacidipine and ACE inhibitors e.g. enalapril. The invention thus
provides in a further aspect the use of a combination comprising a
compound of formula (I) with a further therapeutic agent in the
treatment of a hPPAR mediated disease.
[0154] When the compounds of formula (I) are used in combination
with other therapeutic agents, the compounds may be administered
either sequentially or simultaneously by any convenient route.
[0155] The combinations referred to above may conveniently be
presented for use in the form of a pharmaceutical formulation and
thus pharmaceutical formulations comprising a combination as
defined above optimally together with a pharmaceutically acceptable
carrier or excipient comprise a further aspect of the invention.
The individual components of such combinations may be administered
either sequentially or simultaneously in separate or combined
pharmaceutical formulations.
[0156] When combined in the same formulation it will be appreciated
that the two compounds must be stable and compatible with each
other and the other components of the formulation and may be
formulated for administration. When formulated separately they may
be provided in any convenient formulation, conveniently in such a
manner as are known for such compounds in the art.
[0157] When a compound of formula (I) is used in combination with a
second therapeutic agent active against the same hPPAR mediated
disease, the dose of each compound may differ from that when the
compound is used alone. Appropriate doses will be readily
appreciated by those skilled in the art.
[0158] There is further provided processes for the preparation of
compounds of 1. Unless otherwise indicated all definitions are as
above.
[0159] In general when X.sup.2 is O or S the compounds could be
assembled by coupling through an alkylation step such as that shown
below. 14
[0160] The esters are commercially available or made by the
following general route when X.sup.2 is S. 15
[0161] The heterocycle when Y is O or S and Z is N was generally
made as shown below from an appropriate amide or thioamide: 16
[0162] In specific cases the overall coupling step could be carried
out directly after chlorosulfonation of the ester component without
the need for formation of the chloride of the heterocyclic moiety,
as shown below: 17
[0163] In some cases R.sup.9 was further elaborated through
palladium coupling at the ester stage as shown below: 18
[0164] Alternatively R.sup.9 was elaborated after the coupling
reaction by nucleophilic displacement of a mesylate shown below:
19
EXAMPLES
[0165] The invention is further illustrated by the following
Examples which should not be construed as constituting a limitation
thereto.
[0166] Ethyl
4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl-1,3-thiazole-5-c-
arboxylate
[0167] To a 2-L round-bottom flask equipped with an mechanical
overhead stirrer, a reflux condenser and a N.sub.2 inlet was added
ethyl
4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate
(85 g, 0.27 moles, 1.0 eq) and dry carbon tetrachloride (750 ml,
0.38M). Freshly recrystallized N-bromo succinimide (52.72 g, 1.1
eq) was added as a solid, Benzoyl peroxide (6.5 g, 10 mol %) was
added at room temperature all at once as a solid, and the reaction
mixture was refluxed for 5 hrs. The reaction was monitored by
.sup.1H NMR and was determined to be composed of a 9:1 mixture of
mono-bromination product (i.e. desired product) and di-bromination
product with a 90% conversion. After cooling to 0.degree. C. (to
precipitate out the succinimide) the reaction was filtered through
Celite and the solvent was removed under reduced pressure to yield
a brown oil. The oil was crystallized using hexanes to yield 100 g
(94%) of an off-white product of 90% purity.
[0168] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.10 (d, 2H, J=8.20
Hz), 7.72 (d, 2H, J=8.20 Hz), 4.99 (s, 2H), 4.40 (q, 2H, J=7.18
Hz), 1.41 (t, 3H, J=7.18 Hz),
[0169] TLC(15% EtOAc/Hexanes) R.sub.f=0.55
[0170] Ethyl
4-(bromomethyl)-2-phenyl-1,3-thiazole-5-carboxylate
[0171] The title compound was made using the same procedure as
above.
[0172] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.98 (dd, 2H,
J=7.86, 1.54 Hz), 7.47 (m, 3H), 4.99 (s, 2H), 4.39 (q, 2H, J=7.12
Hz), 1.40 (t, 3H, J=7.12 Hz),
[0173] TLC(15% EtOAc/Hexanes) R.sub.f=0.50
[0174] Ethyl
4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole--
5-carboxylate
[0175] To a stirred solution of ethyl
4-(bromomethyl)-2-[4-(trifluoromethy-
l)phenyl]-1,3-thiazole-5-carboxylate (50 g, 0.127 moles, 1 eq) in
dry DMF (300 ml) under a positive N.sub.2 flow was added silver
trifluoroacetate (42.02 g, 0.191 moles, 1.5 eq) all at once as a
solid. This was stirred at room temperature for 3.5 hrs. The
reaction was partitioned between ethyl ether (1.5 L) and water (500
ml). The phases were separated and the organic phase was washed
twice with water (500 ml). After separation of the phases, the
organic fraction was dried with Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The crude trifluoroacetate product was used
without characterization. Ethanol (300 ml) was added and the
reaction was refluxed for 10 hrs. After cooling to room temperature
the ethanol was removed in vacuo to yield 42 g (100%) of the title
compound. The product was used without purification.
[0176] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.09 (d, 2H, J=8.20
Hz), 7.73 (d, 2H, J=8.20 Hz), 5.09 (s, 2H), 4.41 (q, 2H, J=7.12
Hz), 1.40 (t, 3H, J=7.12 Hz),
[0177] Ethyl
4-(hydroxymethyl)-2-phenyl-1,3-thiazole-5-carboxylate
[0178] The title compound was made using the same procedure as
above.
[0179] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.95 (m, 2H), 7.48
(m, 3H), 5.09 (s, 2H), 4.40 (q, 2H, J=7.12 Hz), 1.41 (t, 3H, J=7.12
Hz),
[0180] Ethyl
4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl-
)phenyl]-1,3-thiazole-5-carboxylate
[0181] To a 1-L round-bottom flask equipped with a magnetic
stir-bar and a N.sub.2 inlet was added Ethyl
4-(hydroxymethyl)-2-[4-(trifluoromethyl)phe-
nyl]-1,3-thiazole-5-carboxylate (42 g, 0.127 moles, 1 eq) and dry
CH.sub.2Cl.sub.2 (300 ml) at room temperature. This was followed by
the addition of 3,4-dihydro-2H-pyran (14 ml, 0.152 moles, 1.2 eq)
as a neat liquid and pyridinium p-toluenesulfonate (6.4 g, 25.4
mmoles, 20 mol %). The reaction mixture was stirred at room
temperature overnight (10 hrs). The volatiles were then removed in
vacuo and the residue was purified by flash silica gel
chromatography (10% EtOAc/Hexanes to 30% EtOAc/Hexanes) to yield 34
g (64%) of pure title compound.
[0182] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.09 (d, 2H, J=8.20
Hz), 7.69 (d, 2H, J=8.20 Hz), 5.18 (d, 1H, J.quadrature..30 Hz),
4.99 (d, 1H, J=0.30 Hz), 4.90 (t, 1H, J=3.42 Hz), 4.36 (q, 2H,
J=7.12 Hz), 3.98 (m, 1H), 3.56 (m, 1H), 1.69 (m, 6H), 1.37 (t, 3H,
J=7.12 Hz),
[0183] TLC(30% EtOAc/Hexanes)=0.64
[0184] Ethyl
2-phenyl-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazole-
-5-carboxylate
[0185] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (m, 2H), 7.43
(m, 3H), 5.17 (d, 1H, J=0.13 Hz), 4.98 (d, 1H, J 13 Hz), 4.91 (t,
1H, J=3.33 Hz), 4.35 (q, 2H, J=7.12 Hz), 3.98 (m, 1H), 3.54 (m,
1H), 1.69 (m, 6H), 1.36 (t, 3H, J=7.12 Hz),
[0186] Ethyl
244-fluorophenyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl-1,3--
thiazole-5-carboxylate
[0187] .sup.1H NMR .delta. 7.97 (m, 2H), 7.11 (m, 2H), 5.16 (d, 1H,
J=0.24 Hz), 4.97 (d, 1H, J=0.24 Hz), 4.90 (t, 1H, J=3.36 Hz), 4.34
(q, 2H, J=7.13 Hz), 3.98 (m, 1H), 3.55 (m, 1H), 1.86 (m, 2H), 1.70
(m, 2H), 1.55 (m, 2H), 1.36 (t, 3H, J=7.13 Hz),
[0188] Suzuki Coupling
[0189] Ethyl
4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1-
,3-thiazole-5-carboxylate
[0190] To a solution of ethyl
4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl-
]-1,3-thiazole-5-carboxylate (0.25 g, 0.63 mmol) in 4 ml of
2-methoxyethyl ether was added
tetrakis(triphenylphosphine)palladium(0), (0.02 g, 0.019 mmol) and
then sodium carbonate (0.13 g, 1.2 mmol) in 0.5 ml water. After
brief stirring, 4-(trifluoromethyl)phenyl boronic acid (0.13 g, 0.7
mmol) in 1 ml ethanol was added. After heating at 110.degree. C.
for 15 hours, the reaction was complete by HPLC and was treated
with water (5 ml) and extracted with tert-butyl methyl ether
(2.times.30 ml). The organic layers were dried with magnesium
sulfate and immediately loaded onto silica to give a crude residue
which was purified on a Biotage FlashElute with a 40M silica
cartridge, eluting with 10% ethyl acetate in hexanes to yield ethyl
4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1-
,3-thiazole-5-carboxylate as a white solid (0.09 g, 35%).
[0191] .sup.1H NMR (CDCl.sub.3): .delta. 8.18 (d, 2H), 7.78 (d,
2H), 7.58 (m, 4H), 4.68 (s, 2H), 4.40 (q, 2H), 1.40 (t, 3H); MS m/z
460 (M+1).
[0192] The following compounds were made using the the same
palladium catalyzed coupling procedure using the appropriate
boronic acid.
[0193] Ethyl
4-[4-(trifluoromethoxy)benzyl-2-[4-(trifluoromethyl)phenyl]-1-
,3-thiazole-5-carboxylate
[0194] From ethyl
4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazo-
le-5-carboxylate (0.259, 0.63 mmol), ethyl
4-14-(trifluoromethoxy)benzyl]--
2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate (0.12 g,
43%) was obtained as a light yellow solid.
[0195] .sup.1H NMR (CDCl.sub.3): .delta. 8.18 (d, 2H), 7.77 (d,
2H), 7.46 (d, 2H), 7.18 (d, 2H), 4.60 (s, 2H) 4.40 (q, 2H), 1.40
(t, 3H); MS m/z 476 (M+1).
[0196] Ethyl
4-[4-methoxybenzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-
e-5-carboxylate
[0197] From ethyl
4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazo-
le-5-carboxylate (0.25 g, 0.63 mmol), ethyl
4-[4-methoxybenzyl]-2-[4-(trif-
luoromethyl)phenyl]-1,3-thiazole-5-carboxylate (0.16 g, 63%) was
obtained as a yellow semi-solid.
[0198] .sup.1H NMR (CDCl.sub.3): .delta. 8.18 (d, 2H), 7.70 (d,
2H), 7.40 (d, 2H), 6.80 (d, 2H), 4.57 (s, 2H), 4.40 (q, 2H), 3.80
(s, 3H), 1.40 (t, 3H); MS m/z 422 (M+1).
[0199] Ethyl
4-[4-(methylsulfanyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,-
3-thiazole-5-carboxylate
[0200] From ethyl
4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazo-
le-5-carboxylate (0.4 g, 1.01 mmol), ethyl
4-[4-(methylsulfanyl)benzyl]-2--
[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-carboxylate (0.44 g,
100%) was obtained as a light yellow solid.
[0201] .sup.1H NMR (CDCl.sub.3): .delta. 8.11 (d, 2H), 7.71 (d,
2H), 7.38 (d, 2H), 7.21 (d, 2H), 4.52 (s, 2H), 4.38 (q, 2H), 2.49
(s, 3H), 1.40 (t, 3H); MS m/z 438 (M+1).
[0202] Ethyl
4-[4-tert-butylbenzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thia-
zole-5-carboxylate
[0203] From ethyl
4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazo-
le-5-carboxylate (0.4 g, 1.01 mmol), ethyl
4-[4-tert-butylbenzyl]-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate (0.24 g, 54%) was
obtained as a white solid.
[0204] .sup.1H NMR (CDCl.sub.3): .delta. 8.11 (d, 2H), 7.73 (d,
2H), 7.56 (d, 1H), 7.49 (d, 1H), 7.34 (m, 2H), 4.58 (s, 2H), 4.40
(q, 2H), 1.40 (t, 3H), 1.27 (s, 9H); MS m/z 448 (M+1).
[0205] Ethyl
4-[3-thienylmethyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-
e-5-carboxylate
[0206] From ethyl
4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazo-
le-5-carboxylate (0.4 g, 1.01 mmol), ethyl
4-[3-thienylmethyl]-2-[4-(trifl-
uoromethyl)phenyl]-1,3-thiazole-5-carboxylate (0.4 g 100%) was
obtained as a yellow solid.
[0207] .sup.1H NMR (CDCl.sub.3): .delta. 8.12 (d, 2H), 7.77 (d,
2H), 7.40 (d, 1H), 7.28 (d, 1H), 7.20 (s, 1H), 4.61 (s, 2H), 4.41
(q, 2H), 1.40 (t, 3H); MS m/z 398 (M+1).
[0208] Ethyl
4-[2-furylmethyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole--
5-carboxylate
[0209] From ethyl
4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazo-
le-5-carboxylate (0.4 g, 1.01 mmol), ethyl
4-[2-furylmethyl]-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazole-5-carboxylate (0.204 g, 53%) was
obtained as a white solid.
[0210] MS m/z 382 (M+1); HPLC RT 4.072 (C18 4.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[0211] Ethyl
4-[3-furylmethyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-
-carboxylate
[0212] From ethyl
4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazo-
le-5-carboxylate (0.4 g, 1.01 mmol), ethyl
4-[3-furylmethyl]-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazole-5-carboxylate (0.217 g, 56%) was
obtained as a white solid.
[0213] MS m/z 382 (M+1); HPLC RT 4.091 (C18 4.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[0214] Ethyl
4-[2-thienylmethyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-
e-5-carboxylate
[0215] From ethyl
4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazo-
le-5-carboxylate (0.4 g, 1.01 mmol), ethyl
4-[2-thienylmethyl]-2-[4-(trifl-
uoromethyl)phenyl]-1,3-thiazole-5-carboxylate (0.248 g, 62%) was
obtained as a yellow solid.
[0216] MS m/z 398 (M+1); HPLC RT 4.224 (C18 4.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[0217] Ethyl
4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]--
1,3-thiazole-5-carboxylate
[0218] From ethyl
4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazo-
le-5-carboxylate (0.6 g, 1.52 mmol), ethyl
4-[(4-methyl-2-thienyl)methyl]--
2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate (0.5 g,
81%) was obtained as a yellow solid.
[0219] MS m/z 412 (M+1); HPLC RT 4.682 (C18 4.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[0220] Ethyl
4-[2,4-difluorobenzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thia-
zole-5-carboxylate
[0221] From ethyl
4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazo-
le-5-carboxylate (0.6 g, 1.52 mmol), ethyl
4-[2,4-difluorobenzyl]-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate (0.222 g, 35%) was
obtained as a white solid.
[0222] MS m/z 428 (M+1); HPLC RT 4.618 (C18 4.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[0223]
4-[(Tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)pheny-
l]-1,3-thiazol-5-yl}methanol
[0224] To a stirred solution of lithium aluminum hydride (95%, 3.3
g, 81.84 mmoles, 1 eq) in dry ethyl ether (300 ml) at 0.degree. C.
was added ethyl 4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4
(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate (34 g, 81.84
mmoles, 1 eq) in dry ethyl ether (50 ml) dropwise via an addition
funnel maintaining the internal reaction temperature below
5.degree. C. This was stirred at 0.degree. C. for 1 hr. At
0.degree. C. 3.5 ml water was added dropwise very carefully and was
then allowed to warm to room temperature. This was followed by the
addition 3.5 ml 5N NaOH and 10 ml water. The mixture was stirred at
room temperature for 2 hrs. At this point a fine white precipitate
formed. The reaction was filtered through Celite and the resulting
aluminum salts were washed with 500 ml EtOAc. The ether/EtOAc
solution was concentrated in vacuo to 30.6 g (100%) of titled
alcohol.
[0225] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.07 (d, 2H, J=8.20
Hz), 7.72 (d, 2H, J=8.20 Hz), 4.93 (m, 4H), 4.78 (t, 1H. J=3.32
Hz), 3.90 (m, 1H), 3.61 (m, 1H), 1.73 (m, 6H),
[0226] TLC(30% EtOAc/Hexanes)=0.20
[0227] The following intermediates were reduced as above for
4-[(Tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-
-thiazol-5-yl}methanol.
[0228]
{4-[(Tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phen-
yl]-1,3-thiazol-5-yl}methanol
[0229] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.07 (d, 2H, J=8.20
Hz), 7.72 (d, 2H, J=8.20 Hz), 4.93 (m, 4H), 4.78 (t, 1H, J=3.32
Hz), 3.90 (m, 1H), 3.61 (m, 1H), 1.73 (m, 6H),
[0230] TLC(30% EtOAc/Hexanes)=0.20
[0231]
{2-(4-Fluorophenyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thi-
azol-5-yl}methanol
[0232] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.89 (m, 2H), 7.09
(m, 2H), 4.81 (m, 5H), 3.84 (m, 1H), 3.55 (m, 1H), 1.67 (m,
6H),
[0233]
{2-Phenyl-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazol-5-yl}-
methanol
[0234] .sup.1H NMR (CDCl3) 400 MHz .delta. 7.96 (m, 2H), 7.47 (m,
3H), 4.92 (m, 4H), 4.79 (t, 1H, J=3.45 Hz); 3.91 (m, 1H), 3.60 (m,
1H), 1.73 (m, 6H),
[0235]
{2-(4-{trifuloromethyl}phenyl)-4[(2-phenylethoxy)methyl]-1,3-thiazo-
l-5-yl}methanol
[0236] .sup.1H (CDCl.sub.3) 300 MHz .delta. 7.99 (d, 2H, J=8.79
Hz), 7.67 (d, 2H, J=8.79 Hz), 7.26 (m, 5H), 4.78 (s, 2H), 4.71 (s,
2H), 3.84 (t, 2H, J=6.94 Hz), 2.95 (t, 2H, J=6.94 Hz), 2.63 (s,
1H),
[0237]
[2-(4-{trifuloromethyl}phenyl)-4-(3-phenylpropyl)-1,3-thiazol-5-yl]-
methanol
[0238] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.02 (d, 2H, J=8.79
Hz), 7.67 (d, 2H, J=8.79 Hz), 7.23 (m, 4H), 4.76 (s, 2H), 2.84 (t,
2H, 7.28 Hz), 2.67 (t, 2H, 7.28 Hz), 2.12 (m, 2H),
[0239]
[4-benzyl-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5-yl]methanol
[0240] .sup.1H (CDCl.sub.3) 300 MHz .delta. 8.01 (d, 2H, J=8.79
Hz), 7.65 (d, 2H, J=8.79 Hz), 7.26 (m, 5H), 4.78 (s, 2H), 4.15 (s,
2H),
[0241] TLC(20% EtOAc/Hexanes) R.sub.f=0.18
[0242] MS(ES.sup.+) M+H=350
[0243]
[2-(4-{trifluoromethyl}phenyl)-4-(2-phenylethyl)-1,3-thiazol-5-yl]m-
ethanol
[0244] .sup.1H (CDCl.sub.3) 300 MHz .delta. 8.06 (d, 2H, J=9.61
Hz), 7.70 (d, 1H, J=9.48 Hz), 7.23 (m, 4H), 7.06 (m, 2H), 4.40 (d,
2H, J=5.63 Hz), 3.07 (s, 4H), 1.08 (s, 1H),
[0245] TLC(20% EtOAc/Hexanes) R.sub.f=0.18
[0246] MS(ES.sup.+) M+H=364
[0247]
[4-[(Benzyloxy)methyl]-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5--
yl]methanol
[0248] .sup.1H (CDCl.sub.3) 300 MHz .delta. 8.02 (d, 2H, J=8.79
Hz), 7.68 (d, 2H, J=8.79 Hz), 7.35 (m, 5H), 4.82 (m, 4H), 4.68 (s,
2H),
[0249] TLC(20% EtOAc/Hexanes) R.sub.f=0.14
[0250]
[4-(4-Bromobenzyl)-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5-yl]m-
ethanol
[0251] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.99 (d, 2H, J=8.10
Hz), 7.66 (d, 2H, J=8.10 Hz), 7.40 (d, 2H, J=8.38 Hz), 7.15 (d, 2H,
J=8.38 Hz), 4.81 (s, 2H), 4.10 (s, 2H),
[0252] TLC(20% EtOAc/Hexanes) R.sub.f=0.14
[0253]
{4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-th-
iazol-5-yl}methanol
[0254] From ethyl
4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phen-
yl]-1,3-thiazole-5-carboxylate (0.096 g, 0.21 mmol),
{4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol--
5-yl}methanol (0.09 g, 100%) was obtained as a white solid.
[0255] .sup.1H NMR (CDCl.sub.3): .delta. 8.16 (d, 2H), 7.73 (d,
2H), 7.59 (d, 2H), 7.44 (d, 2H), 4.90 (d, 2H), 4.26 (t, 2H); MS m/z
418 (M+1).
[0256]
{4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-t-
hiazol-5-yl}methanol
[0257] From ethyl
4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phe-
nyl]-1,3-thiazole-5-carboxylate (0.123 g 0.26 mmol),
{4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-
-5-yl)methanol (0.13 g, 99%) was obtained as a white solid.
[0258] .sup.1H NMR (CDCl.sub.3): .delta. 8.07 (d, 2H), 7.71 (d,
2H), 7.38 (d, 2H), 7.18 (d, 2H), 4.80 (d, 2H), 4.20 (s, 2H); MS m/z
434 (M+1).
[0259]
{4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl-
}methanol
[0260] From ethyl
4-[4-methoxybenzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-th-
iazole-5-carboxylate (0.16 g, 0.38 mmol),
{4-(4-methoxybenzyl)-2-[4-(trifl-
uoromethyl)phenyl]-1,3-thiazol-5-yl}methanol (0.06 g, 40%) was
obtained as a white solid.
[0261] MS m/z 380 (M+1); HPLC RT 3.552 (C18 4.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[0262]
{4-[4-(methylsulfanyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thi-
azol-5-yl}methanol
[0263] From ethyl
4-[4-(methylsulfanyl)benzyl]-2-[4-(trifluoromethyl)pheny-
l]-1,3-thiazole-5-carboxylate (0.44 g, 1.0 mmol),
{4-[4-(methylsulfanyl)be-
nzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol (0.3
g, 76%) was obtained as a white solid.
[0264] MS m/z 396 (M+1); HPLC RT 3.699 (C18 4.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[0265]
{4-(4-tert-butylbenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-y-
l}methanol
[0266] From ethyl
4-[4-tert-butylbenzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-
-thiazole-5-carboxylate (0.24 g, 0.54 mmol),
{4-(4-tert-butylbenzyl)-2-[4--
(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol (0.13 g, 64%)
was obtained as a white solid.
[0267] MS m/z 406 (M+1); HPLC RT 4.002 (C18 4.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[0268]
{4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl-
}methanol
[0269] From ethyl
4-[3-thienylmethyl]-2-[4-(trifluoromethyl)phenyl]-1,3-th-
iazole-5-carboxylate (0.44 g, 1.11 mmol),
{4-(3-thienylmethyl-2-[4-(triflu-
oromethyl)phenyl]-1,3-thiazol-5-yl)methanol (0.098 g, 25%) was
obtained as a yellow solid.
[0270] MS m/z 356 (M+1); HPLC RT 3.513 (C18 4.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[0271]
{4-(2-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}m-
ethanol
[0272] From ethyl
4-[2-furylmethyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thia-
zole-5-carboxylate (0.204 g, 0.53 mmol),
{4-(2-furylmethyl)-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methanol (0.1629, 89%) was
obtained as a white solid.
[0273] MS m/z 340 (M+1); HPLC RT 3.382 (C18 4.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[0274]
{4-(3-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]m-
ethanol
[0275] From ethyl
4-[3-furylmethyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thia-
zole-5-carboxylate (0.217 g 0.57 mmol),
{4-(3-furylmethyl)-2-[4-(trifluoro-
methyl)phenyl]-1,3-thiazol-5-yl}methanol (0.180 g, 88%) was
obtained as a white solid.
[0276] MS m/z 340 (M+1); HPLC RT 3.385 (C18 4.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[0277]
{4-(2-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl-
]methanol
[0278] From ethyl
4-[2-thienylmethyl]-2-[4-(trifluoromethyl)phenyl]-1,3-th-
iazole-5-carboxylate (0.248 g, 0.62 mmol),
{4-(2-thienylmethyl)-2-[4-(trif-
luoromethyl)phenyl]-1,3-thiazol-5-yl}methanol (0.186 g, 87%) was
obtained as a yellow solid.
[0279] MS m/z 356 (M+1); HPLC RT 3.528 (C18 4.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[0280]
{4-[(4-Methyll-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3--
thiazol-5-yl}methanol
[0281] From ethyl
4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethyl)phe-
nyl]-1,3-thiazole-5-carboxylate (0.5 g, 1.22 mmol),
{4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-
-5-yl}methanol (0.084 g, 19%) was obtained as a yellow solid.
[0282] MS m/z 370 (M+1); HPLC RT 3.913 (C18 4.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[0283]
{4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-
-yl}methanol
[0284] From ethyl
4-[2,4-difluorobenzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-
-thiazole-5-carboxylate (0.46 g, 1.08 mmol),
{4-(2,4-difluorobenzyl)-2-[4--
(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol (0.222 g, 54%)
was obtained as a white solid.
[0285] MS m/z 386 (M+1); HPLC RT 3.900 (C18 4.2.times.1100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[0286]
5-(Chloromethyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trif-
luoromethyl)phenyl]-1,3-thiazole
[0287] To a 500-ml round-bottom flask equipped with a magnetic
stir-bar, an addition funnel and a N.sub.2 inlet was added
4-[(Tetrahydro-2H-pyran--
2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol
(15 g, 40.17 mmoles, 1 eq) and dry CH.sub.2Cl.sub.2 (150 ml,
0.27M). Methanesulfonyl chloride (3.73 ml, 48.20 mmoles, 1.2 eq)
was added neat all at once followed by the dropwise addition of
triethylamine (8.44 ml, 60.26 mmoles, 1.5 eq) over 10 minutes. This
solution was stirred at room temperature for 1 hr. The reaction was
transferred to a separatory funnel and washed with water and brine.
After the phases were separated the CH.sub.2Cl.sub.2 fraction was
dried over Na.sub.2SO.sub.4 and the solvent was removed in vacuo.
This yielded 15.74 g (100%) of a brown oil. The crude product was
used as is and required no purification.
[0288] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.08 (d, 2H, J=8.20
Hz), 7.73 (d, 2H, J=8.20 Hz), 5.00 (m, 3H), 4.80 (m, 2H), 3.97 (m,
1H), 3.64 (m, 1H), 1.77 (m, 6H),
[0289] TLC(25% EtOAc/Hexanes) R.sub.f=0.64
[0290] The following intermediates were also prepared using the
above mesylation/chloride displacement procedure:
[0291]
5-(Chloromethyl)-2-(4-fluorophenyl)-4-[(tetrahydro-2H-pyran-2-yloxy-
)methyl]-1,3-thiazole
[0292] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.90 (m, 2H), 7.11
(m, 2H), 4.94 (s, 2H), 4.91 (d, 1H. J.quadrature..45 Hz), 4.76 (t,
1H, J=3.39 Hz), 4.72 (d, 1H, J=0.45 Hz), 3.92 (m, 1H), 3.58 (m,
1H), 1.69 (m, 6H),
[0293] [5-(Chloromethyl)-2-phenyl-1,3-thiazol-4-yl]methyl
tetrahydro-2H-pyran-2-yl ether
[0294] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.95 (m, 2H), 7.47
(m, 3H), 4.98 (m, 3H), 4.80 (m, 2H), 3.98 (m, 1H), 3.63 (m, 1H),
1.73 (m, 6H),
[0295] TLC(25% EtOAc/Hexanes) 1=0.57
[0296]
5-(Chloromethyl)-2-(4-{trifluoromethyl}phenyl)-4-[4-(3-thienyl)benz-
yl]-1,3-thiazole
[0297] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.06 (d, 2H, J=8.23
Hz), 7.71 (d, 2H, J=8.23 Hz), 7.58 (d, 2H, J=8.23 Hz), 7.41 (m,
5H), 4.84 (s, 2H), 4.26 (s, 2H),
[0298] TLC(20% EtOAc/Hexanes) R.sub.f 0.66
[0299]
4-[(Benzyloxy)methyl]-5-(chloromethyl)-2-[44-(trifluoromethyl)pheny-
l]-1,3-thiazole
[0300] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.03 (d, 2H, J=8.79
Hz), 7.69 (d, 2H, J=8.79 Hz), 7.37 (m, 5H), 4.90 (s, 2H), 4.77 (s,
2H), 4.66 (s, 2H)
[0301]
4-Benzyl-5-(chloromethyl)-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-
e
[0302] .sup.1H (CDCl.sub.3) 300 MHz .delta. 8.02 (d, 2H, J=8.79
Hz), 7.67 (d, 2H, J=8.79 Hz), 7.26 (m, 5H), 4.77 (s, 2H), 4.21 (s,
2H),
[0303] TLC(20% EtOAc/Hexanes) R.sub.f=0.66
[0304]
5-(chloromethyl)-2-(4{-trifluoromethyl}phenyl)-4-(2-phenylethyl)-1,-
3-thiazole
[0305] .sup.1H (CDCl.sub.3) 300 MHz .delta. 8.05 (d, 2H, J=8.79
Hz), 7.70 (d, 2H, J=8.79 Hz), 7.22 (m, 5H), 4.46 (s, 2H), 3.09 (s,
4H),
[0306] TLC(20% EtOAc/Hexanes) R.sub.f 0.67
[0307]
5-(Chloromethyl)-2-(4-{trifluoromethyl}phenyl)-4[(2-phenylethoxy)me-
thyl]-1,3-thiazole
[0308] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.01 (d, 2H, J=8.79
Hz), 7.68 (d, 2H, J=8.79 Hz), 7.26 (m, 5H), 4.76 (s, 2H), 4.74 (s,
2H), 3.78 (t, 2H, J=6.94 Hz), 2.94 (t, 2H, J=6.94 Hz),
[0309] TLC(20% EtOAc/Hexanes) R.sub.f=0.56
[0310]
5-(Chloromethyl)-2-(4-{trifluoromethyl}phenyl)4-(3-phenylpropyl)-1,-
3-thiazole
[0311] TLC(20% EtOAc/Hexanes) R.sub.f=0.63
[0312]
4-(4-Bromobenzyl)-5-(chloromethyl)-2-(4-trifluoromethylphenyl)-1,3--
thiazole
[0313] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.00 (d, 2H, J=8.10
Hz), 7.67 (d, 2H, J=8.10 Hz), 7.42 (d, 2H, J=8.38 Hz), 7.18 (d, 2H,
J=8.38 Hz), 4.77 (s, 2H), 4.14 (s, 2H),
[0314] TLC(20% EtOAc/Hexanes) R.sub.f=0.66
[0315]
4-([1,1'-Biphenyl]-4-ylmethyl)-5-(chloromethyl)-2-(4-{trifluorometh-
yl}phenyl)-1,3-thiazole
[0316] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.07 (d, 2H, J=8.23
Hz), 7.72 (d, 2H, J=8.23 Hz), 7.57 (m, 4H), 7.39 (m, 5H), 4.85 (s,
2H), 4.28 (s, 2H),
[0317] TLC(20% EtOAc/Hexanes) R.sub.f=0.69
[0318]
5-(chloromethyl)-4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluoromethy-
l)phenyl]-1,3-thiazole
[0319] From
{4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1-
,3-thiazol-5-yl)methanol (0.09 g, 0.216 mmol),
5-(chloromethyl)-4-[4-(trif-
luoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole
(0.087 g, 93%) was obtained as a yellow oil and immediately taken
on without purification.
[0320]
5-(chloromethyl)-4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluorometh-
yl)phenyl]-1,3-thiazole
[0321] From
{4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]--
1,3-thiazol-5-yl}methanol (0.13 g, 0.3 mmol),
5-(chloromethyl)-4-[4-(trifl-
uoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole
(0.135 g, 100%) was obtained as a yellow oil and immediately taken
on without purification.
[0322]
5-(chloromethyl)-4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]--
1,3-thiazole
[0323] From
{4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-
-5-yl]methanol (0.06 g, 0.158 mmol),
5-(chloromethyl)-4-(4-methoxybenzyl)--
2-[4-(trifluoromethyl)phenyl]-1,3-thiazole (0.08 g, 100%) was
obtained as a yellow oil and immediately taken on without
purification.
[0324]
5-chloromethyl)-4-[4-(methylsulfanyl)benzyl]-2-[4-(trifluoromethyl)-
phenyl]-1,3-thiazole
[0325] From
{4-[4-(methylsulfanyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,-
3-thiazol-5-yl}methanol (0.3 g, 0.76 mmol),
5-(chloromethyl)-4-[4-(methyls-
ulfanyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole (0.33 g,
100%) was obtained as a yellow oil and immediately taken on without
purification.
[0326] MS m/z 414 (M+1).
[0327]
4-(4-tert-butylbenzyl)-5-chloromethyl)-2-[4-(trifluoromethyl)phenyl-
-1,3-thiazole
[0328] From
{4-(4-tert-butylbenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thia-
zol-5-yl}methanol (0.13 g, 0.32 mmol),
4-(4-tert-butylbenzyl)-5-(chloromet-
hyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole (0.151 g, 100%) was
obtained as a yellow oil and immediately taken on without
purification.
[0329] MS m/z 424 (M+1).
[0330]
5-(chloromethyl)-4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]--
1,3-thiazole
[0331] From
{4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-
-5-yl}methanol (0.098 g, 0.28 mmol),
5-(chloromethyl)-4-(3-thienylmethyl)--
2-[4-(trifluoromethyl)phenyl]-1,3-thiazole (0.105 g, 100%) was
obtained as a yellow oil and immediately taken on without
purification.
[0332] MS m/z 374 (M+1).
[0333]
5-(chloromethyl)-4-(2-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,-
3-thiazole
[0334] From
{4-(2-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-
-yl)methanol (0.162 g, 0.48 mmol),
5-(chloromethyl)-4-(2-furylmethyl)-2-[4-
-(trifluoromethyl)phenyl]-1,3-thiazole (0.097 g, 57%) was obtained
as a yellow oil and immediately taken on without purification.
[0335] MS m/z 358 (M+1).
[0336]
5-(chloromethyl)4-(3-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-
-thiazole
[0337] From
{4-(3-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-
-yl}methanol (0.18 g, 0.53 mmol),
5-(chloromethyl)-4-(3-furylmethyl)-2-[4--
(trifluoromethyl)phenyl]-1,3-thiazole (0.172 g, 91%) was obtained
as a yellow oil and immediately taken on without purification.
[0338] MS m/z 358 (M+1).
[0339]
5-(chloromethyl)-4-(2-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]--
1,3-thiazole
[0340] From
{4-(2-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-
-5-yl)methanol (0.186 g, 0.52 mmol), 5-(chloromethyl)-4
(2-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole (0.185
g, 95%) was obtained as a yellow oil and immediately taken on
without purification.
[0341] MS m/z 374 (M+1).
[0342]
5-(chloromethyl)-4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluorometh-
yl)phenyl]-1,3-thiazole
[0343] From
{4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]--
1,3-thiazol-5-yl}methanol (0.084 g, 0.23 mmol),
5-(chloromethyl)-4-[(4-met-
hyl-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole
(0.123 g, 100%) was obtained as a yellow oil and immediately taken
on without purification.
[0344]
5-(chloromethyl)-4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyl)pheny-
l]-1,3-thiazole
[0345] From
{4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thia-
zol-5-yl}methanol (0.222 g, 0.58 mmol),
5-(chloromethyl)-4-(2,4-difluorobe-
nzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole (0.279 g, 100%)
was obtained as a yellow oil and immediately taken on without
purification.
[0346] Ethyl 2-methyl-2-phenoxypropanoate
[0347] To a solution of potassium t-butoxide (1M in THF, 531 ml,
0.531 moles, 1 eq) precooled to 0.degree. C. (ice bath) was added
phenol (50 g, 0.531 moles, 1 eq) in dry THF (50 ml) dropwise via an
addition funnel over 20 minutes maintaining the internal
temperature of the reaction below 5 degrees centigrade.
Ethyl-2-bromoisobutyrate (70.14 ml, 0.9 eq, 0.478 moles) in dry THF
(20 ml) was added dropwise over 10 minutes maintaining the internal
reaction temperature below 5.degree. C. After the addition was
complete, the ice bath was removed and the reaction was allowed to
warm to room temperature. The reaction was brought to reflux and
maintained at this reflux temperature for 8 hours. Following the
cooling of the reaction to 0.degree. C. the volatiles were removed
in vacuo. The residue was then partitioned between EtOAc and 1 N
NaOH. The phases were separated and the organic phase was washed
with 1 N NaOH, H.sub.2O, brine and dried over Na.sub.2SO.sub.4.
After filtration the solution was concentrated under reduced
pressure to yield 83 g (75%) of clean title compound.
[0348] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.21 (m, 2H), 6.95
(t, 1H, J=7.41 Hz), 6.82 (m, 2H), 4.21 (q, 2H, J=7.13 Hz), 1.57 (s,
6H), 1.22 (t, 3H, J=7.13 Hz),
[0349] Ethyl (2-ethylphenoxy)acetate
[0350] To a stirred solution of 2-ethylphenol (5 ml, 42.4 mmoles, 1
eq) in dry DMF (120 ml, 0.35M) was added potassium carbonate (6.45
g, 46.6 mmoles, 1.1 eq) and ethylbromoacetate (4.7 ml, 42.2 mmoles,
1 eq) and heated to 60.degree. C. overnight. After cooling to room
temperature the reaction mixture was partitioned between ethyl
ether and 1N NaOH. The phases were separated and the organic
portion was washed twice with 1N NaOH, twice with H.sub.2O, brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to
yield 7.2 g (82%) of product.
[0351] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.14 (m, 2H), 6.92
(t, 1H, J=8.24 Hz), 6.70 (d, 1H, J=8.24 Hz), 4.62 (s, 2H), 4.24 (q,
2H, J=7.14 Hz), 2.70 (q, 2H, J=7.51 Hz), 1.27 (t, 3H, J=7.14 Hz),
1.21 (t, 3H, J=7.51 Hz),
[0352] The following were compounds were made using the same
alkylation procedure:
[0353] Ethyl (2-isopropylphenoxy)acetate
[0354] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.23 (d, 1H, J=7.69
Hz), 7.11 (t, 1H. J=7.69 Hz), 6.96 (t, 1H, J=7.69 Hz), 6.70 (d, 1H,
J=7.69 Hz), 4.62 (s, 2H), 4.25 (q, 2H, J=7.14 Hz), 3.41 (m, 1H),
1.26 (m, 9H),
[0355] Ethyl (2-propylphenoxy)acetate
[0356] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.12 (m, 2H), 6.90
(t, 1H, J=8.24 Hz), 6.69 (d, 1H, J=8.24 Hz), 4.61 (s, 2H), 4.24 (q,
2H, J=7.14 Hz), 2.64 (t, 2H, J=7.33 Hz), 1.64 (m, 2H), 1.27 (t, 3H,
J=7.14 Hz), 0.94 (t, 3H, J=7.33 Hz),
[0357] Ethyl [4-(chlorosulfonyl)-2-ethylphenoxy]acetate
[0358] To a 250 ml round-bottom flask containing chlorosulfonic
acid (30 ml) cooled to 0.degree. C. was added ethyl
(2-ethylphenoxy)acetate (7.2 g, 34.6 mmoles) dropwise. Once the
addition was complete the ice-bath was removed and the reaction was
allowed to warm to room temperature at which the reaction was
stirred for 3 hours. The reaction was then slowly added to ice and,
once the excess chlorosulfonic acid was quenched, the mixture was
diluted with CH.sub.2Cl.sub.2 (200 ml). The phases were separated
and the aqueous fraction was washed with CH.sub.2Cl.sub.2 twice.
The combined organic fractions were dried over Na.sub.2SO.sub.4 and
filtered and concentrated in vacuo to yield 7.2 g (70%) of crude
product. The crude product was used with no purification.
[0359] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.84 (m, 2H), 6.79
(d, 1H, J=8.24 Hz), 4.75 (s, 2H), 4.26 (q, 2H, J=7.14 Hz), 2.77 (q,
2H, J=7.51 Hz), 1.26 (m, 6H),
[0360] The following were compounds were made using the same
chlorosulfonation procedure:
[0361] Ethyl [4-(chlorosulfonyl)-2-methylphenoxy]acetate
[0362] .sup.1H NMR (d6-DMSO) 300 MHz .delta. 7.41 (m, 2H), 6.79 (d,
1H, J=8.23 Hz), 4.82 (s, 2H), 4.16 (q, 2H, J=7.17 Hz), 2.21 (s,
3H), 1.21 (t, 3H, J=7.17 Hz),
[0363] Ethyl 2-[4-(chlorosulfonyl)-2-methylphenoxy]propanoate
[0364] .sup.1H NMR (d6-DMSO) 300 MHz .delta. 7.44 (m, 1H), 7.39
(dd, 1H, J=8.23, 2.39 Hz), 6.74 (d, 1H, J=8.23 Hz), 4.96 (q, 1H,
J=6.81 Hz), 4.13 (q, 2H, J=7.08 Hz), 2.20 (s, 3H), 1.54 (d, 3H,
J=6.81 Hz), 1.18 (t, 3H, J=7.08 Hz),
[0365] Ethyl
2-[4-(chlorosulfonyl)-2-isopropylphenoxy]propanoate
[0366] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.81 (m, 2H), 6.76
(d, 1H, J=8.42 Hz), 4.87 (q, 1H, J=6.78 Hz), 4.21 (q, 2H, J=7.14
Hz), 3.40 (m, 1H), 1.65 (d, 3H, J=6.78 Hz), 1.24 (m, 9H),
[0367] Ethyl [4-(chlorosulfonyl)-2-isopropylphenoxy]acetate
[0368] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.84 (m, 2H), 6.80
(d, 1H, J=8.42 Hz), 4.75 (s, 2H), 4.26 (q, 2H, J=7.14 Hz), 3.42 (m,
1H), 1.27 (m, 9H),
[0369] Ethyl 2-[4-(chlorosulfonyl)-2-propylphenoxy]propanoate
[0370] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.80 (m, 2H), 6.75
(d, 1H, J=8.42 Hz), 4.85 (q, 1H, J=6.78 Hz), 4.21 (q, 2H, J=7.14
Hz), 2.69 (t, 2H, J=7.51 Hz), 1.66 (m, 5H), 1.23 (t, 3H, J=7.14
Hz), 0.95 (t, 3H, J=7.51 Hz),
[0371] Ethyl [4-(chlorosulfonyl)-2-propylphenoxy]acetate
[0372] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.83 (m, 2H), 6.79
(d, 1H, J=8.42 Hz), 4.73 (s, 2H), 4.26 (q, 2H, J=7.14 Hz), 2.70 (t,
2H, J=7.51 Hz), 1.67 (m, 2H), 1.29 (t, 3H, J=7.14 Hz), 0.95 (t, 3H,
J=7.51 Hz),
[0373] Ethyl 2-[4-(chlorosulfonyl)-2-ethylphenoxy]propanoate
[0374] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.81 (m, 2H), 6.75
(d, 1H, J=8.42 Hz), 4.86 (q, 1H. J=6.78 Hz), 4.21 (q. 2H, J=7.08
Hz), 2.75 (m, 2H), 1.68 (d, 3H, J=6.78 Hz), 1.23 (m, 6H),
[0375] Ethyl 2-[4-(chlorosulfonyl)phenoxy]-2-methylpropanoate
[0376] To a 3-L three-neck round-bottom flask equipped with a
magnetic stir-bar, low temperature thermometer with thermometer
adapter, addition funnel and a N.sub.2 inlet was added ethyl
2-methyl-2-phenoxypropanoate (83 g, 0.399 moles, 1 eq) and dry
CH.sub.2Cl.sub.2 (1 L, 0.4M). After cooling the reaction to
0.degree. C. (ice bath) chlorosulfonic acid (26.5 ml, 0.399 moles,
1 eq) in dry CH.sub.2Cl.sub.2 (50 ml) was added dropwise over 30
minutes via addition funnel maintaining the internal temperature
below 5.degree. C. Following this dropwise addition the reaction
was allowed to stir at 0.degree. C. for 3 hours. The reaction was
monitored by HPLC and after 3 hours complete conversion was
observed [(C-18, 3 .mu.m) 0%-95% Acetonitrile/Water over 8 minutes
R.sub.t=2.96 minutes]. At this point dry DMF (124 ml, 4 eq) was
added slowly maintaining the internal temperature below 5.degree.
C. This was followed by the dropwise addition of thionyl chloride
(43.77 ml, 0.599 moles, 1.5 eq) in dry CH.sub.2Cl.sub.2 (50 ml)
over 25 minutes maintaining the internal temperature below
5.degree. C. After stirring at 0.degree. C. for 1.5 hours and
monitoring by HPLC [(C-18, 3 .mu.m) 0%95% Acetonitrile/water over 8
minutes R.sub.t=5.97 minutes] the reaction was allowed to warm to
room temperature. The reaction mixture was then washed with 0.1N
HCl and the phases were separated, with discarding the aqueous
fraction. The organic fraction was washed with 0.1N HCl, H.sub.2O,
brine and dried over Na.sub.2SO.sub.4. The solution was filtered
and concentrated in vacuo to yield 119.95 g (98%) of pure sulfonyl
chloride.
[0377] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.89 (d, 2H, J=9.31
Hz), 6.89 (d, 2H, J=9.31 Hz), 4.21 (q, 2H, J=7.16 Hz), 166 (s, 6H),
1.20 (t, 3H, J=7.16 Hz),
[0378] HPLC (C-18, 3 .mu.m) 0%-95% Acetonitrile/Water over 8
minutes R.sub.t=5.97 minutes
[0379] Ethyl 2-methyl-2-(4-sulfanylphenoxy)propanoate
[0380] To a 3-L three-neck round-bottom flask equipped with an
overhead mechanical stirrer, addition funnel and a N.sub.2 inlet
was added ethyl 2-[4-(chlorosulfonyl)phenoxy]-2-methylpropanoate
(53 g, 0.173 moles, 1 eq) and absolute EtOH (500 ml). Tin powder
(325 mesh, 123.06 g, 1.04 moles, 6 eq) was added as a solid. The
overhead stirrer was adjusted so that the rotor is as close as
possible to the bottom of the round-bottom flask and stirring speed
was accelerated to a very high setting before adding the HCl to
prevent the clumping of the tin metal. Hydrogen chloride (4N in
dioxane, 300 ml) was added dropwise over the course of 1 hour. The
reaction mixture was refluxed for 4 hours at which point the hot
ethanolic solution was poured into a 2-L Erlenmeyer flask
containing CH.sub.2Cl.sub.2 (1L) and ice. After stirring for 10
minutes the biphasic mixture was filtered through Celite. After
transferring to a separatory funnel the phases were separated and
the aqueous fraction was washed with CH.sub.2Cl.sub.2 (2.times.100
ml). The combined organic fractions were dried over
Na.sub.2SO.sub.4, filtered and concentrated n vacuo. A bright
yellow oil with a white precipitate suspended resulted. This yellow
mixture was dissolved in a minimum amount of CH.sub.2Cl.sub.2 and
filtered once again through Celite to yield 30 g (75%) of a bright
yellow oil.
[0381] .sup.1H NMR (CD.sub.3OD) 300 MHz .delta. 7.18 (m, 2H), 6.73
(d, 2H, J=8.00 Hz), 4.23 (q, 2H, J=7.17 Hz), 3.69 (s, 1H), 1.59 (s,
6H), 1.26 (t, 3H, J=7.17 Hz),
[0382] The following were compounds were made using the same
reduction procedure:
[0383] Ethyl (2-methyl-4-sulfanylphenoxy)acetate
[0384] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.15 (m, 2H), 6.63
(d, 1H, J=8.23 Hz), 4.64 (s, 2H), 4.29 (q, 2H, J=7.17 Hz), 3.36 (s,
1H), 2.29 (s, 3H), 1.33 (t, 3H, J=7.17 Hz),
[0385] Ethyl 22-methyl-4-sulfanylphenoxy)propanoate
[0386] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.12 (d, 1H, J=2.39
Hz), 7.04 (dd, 1H, J=8.37, 2.39 Hz), 6.56 (d, 1H, J=8.37 Hz), 4.67
(q, 1H, J=6.72 Hz), 4.19 (q, 2H, J=7.12 Hz), 3.31 (s, 1H), 2.22 (s,
3H), 1.61 (d, 3H, J=6.72 Hz), 1.23 (t, 3H, J=7.12 Hz),
[0387] TLC(20% EtOAc/Hexanes) R.sub.f=0.60
[0388] Ethyl (2-ethyl-4-sulfanylphenoxy)acetate
[0389] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.13 (d, 1H, J=2.20
Hz), 7.08 (dd, 1H, J=8.42, 2.38 Hz), 6.58 (d, 1H, J=8.42 Hz), 4.59
(s, 2H), 4.24 (q, 2H, J=7.14 Hz), 3.33 (s, 1H), 2.64 (q, 2H, J=7.51
Hz), 1.28 (t, 3H, J=7.14 Hz), 1.18 (t, 3H, J=7.51 Hz),
[0390] Ethyl 2-(2-ethyl-4-sulfanylphenoxy)propanoate
[0391] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.15 (d, 1H, J=2.20
Hz), 7.07 (dd, 1H, J=8.42, 2.20 Hz), 6.55 (d, 1H, J=8.42 Hz), 4.74
(q, 1H, J=6.78 Hz), 4.17 (m, 2H), 3.32 (s, 1H), 2.61 (q, 2H, J=7.51
Hz), 1.61 (d, 3H, J=6.59 Hz), 1.19 (m, 6H),
[0392] The following four compounds were made in the same way and
used without further purification.
[0393] Ethyl (2-propyl-4-sulfanylphenoxy)acetate
[0394] Ethyl 2-(2-propyl-4-sulfanylphenoxy)propanoate
[0395] Ethyl (2-isopropyl-4-sulfanylphenoxy)acetate
[0396] Ethyl 2-(2-isopropyl-4-sulfanylphenoxy)propanoate Ethyl
2-methyl-2-4-[(4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromet-
hyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxypropanoate
[0397] To a 250 ml round-bottom flask equipped with a magnetic
stir-bar and N.sub.2 inlet was added
5-(chloromethyl)-4-[(tetrahydro-2H-pyran-2-yl-
oxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole (7.87 g,
20.09 mmoles, 1 eq) and dry CH.sub.3CN (100 ml, 0.27M). Solid
cesium carbonate (16.4 g, 50.22 mmoles, 2.5 eq) was added all at
once followed by the quick addition of ethyl
2-methyl-2-(4-sulfanylphenoxy)propanoate (5.79 g, 24.11 mmoles, 1.2
eq) in dry CH.sub.3CN (10 ml). The reaction was allowed to stir at
room temperature for 2 hours at which point the solvent was removed
under reduced pressure. The resulting residue was partitioned
between EtOAc and 1N NaOH. After the phases were separated the
organic fraction was washed with H.sub.2O, brine and dried over
Na.sub.2SO.sub.4. After filtration the volatiles were removed in
vacuo to yield the titled compound in >100% yield. Sometimes
because of the difficult separation between the thiophenol and the
product, the crude product was carried forward without
purification.
[0398] The following compounds were made using the same alkylation
procedure. Where selectivity was an issue the alkylations were
carried out below room temperature.
[0399] Ethyl
2-{2-methyl-4-[({2-phenyl-4-[(tetrahydro-2H-pyran-2-yloxy)met-
hyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy)propanoate
[0400] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.93 (m, 2H), 7.44
(m, 3H), 7.28 (d, 1H, J=2.39 Hz), 7.15 (dd, 1H, J=8.23, 2.39 Hz),
6.61 (d, 1H, J=8.23 Hz), 4.72 (m, 3H), 4.50 (d, 1H, J=0.21 Hz),
4.32 (s, 2H), 4.23 (q, 2H, J=7.08 Hz), 3.93 (m, 1H), 3.59 (m, 1H),
2.26 (s, 3H), 1.71 (m, 9H), 1.28 (t, 3H, J=7.08 Hz),
[0401] Ethyl
2-{2-methyl-4-[({4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-
-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propano-
ate
[0402] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.04 (d, 2H, J=8.23
Hz), 7.70 (d, 2H, J=8.23 Hz), 7.27 (d, 1H, J=2.39 Hz), 7.15 (dd,
1H, J=8.49, 2.39 Hz), 6.60 (d, 1H, J=8.49 Hz), 4.73 (m, 3H), 4.51
(d, 1H, J.quadrature..21 Hz), 4.32 (s, 2H), 4.20 (q, 2H, J=7.17
Hz), 3.93 (m, 1H), 3.60 (m, 1H), 2.27 (m, 3H), 1.71 (m, 9H), 1.27
(t, 3H, J=7.17 Hz),
[0403] TLC(30% EtOAc/Hexanes)=0.73
[0404] Ethyl
2-{4-[({2-(4-fluorophenyl)-4-[(tetrahydro-2H-pyran-2-yloxy)me-
thyl-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
[0405] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.88 (m, 2H), 7.19
(d, 1H, J=2.24 Hz), 7.08 (m, 3H), 6.54 (d, 1H, J=8.45 Hz), 4.65 (m,
3H), 4.44 (m, 1H), 4.24 (s, 2H), 4.16 (q, 2H, J=7.13 Hz), 3.86 (m,
1H), 3.53 (m, 1H), 2.21 (s, 3H), 1.66 (m, 9H), 1.20 (t, 3H, J=7.13
Hz),
[0406] Ethyl
{2-ethyl-4-[({4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(t-
rifluoromethyl)phenyl-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
[0407] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.98 (d, 2H, J=8.24
Hz), 7.64 (d, 2H, J=8.24 Hz), 7.20 (d, 1H, J=2.20 Hz), 7.15 (dd,
1H, J=8.42, 2.20 Hz), 6.60 (d, 1H, J=8.42 Hz), 4.63 (m, 4H), 4.42
(d, 1H, J=0.27 Hz), 4.24 (m, 4H), 3.87 (m, 1H), 3.54 (m, 1H), 2.64
(q, 2H, J=7.51 Hz), 1.66 (m, 6H), 1.26 (t, 3H, J=7.14 Hz), 1.15 (t,
3H, J=7.51 Hz),
[0408] Ethyl
2-{2-ethyl-4-[({4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4--
(trifluoromethyl)phenyl]1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoat-
e
[0409] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.98 (d, 2H, J=8.24
Hz), 7.64 (d, 2H, J=8.24 Hz), 7.17 (d, 1H, J=2.38 Hz), 7.11 (dd,
1H, J=8.42, 2.38 Hz), 6.56 (d, 1H, J=8.42 Hz), 4.71 (q, 1H, J=6.78
Hz), 4.66 (t, 1H, J=3.39 Hz), 4.60 (d, 1H, J=0.27 Hz), 4.41 (d, 1H,
J=0.27 Hz), 4.26 (s, 2H), 4.16 (q, 2H, J=7.14 Hz), 3.87 (m, 1H),
3.54 (m, 1H), 2.62 (q, 2H, J=7.51 Hz), 1.60 (m, 9H), 1.20 (t, 3H,
J=7.14 Hz), 1.15 (t, 3H, J=7.51 Hz),
[0410] Ethyl
{2-propyl-4-[({4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(-
trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
[0411] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.20
Hz), 7.64 (d, 2H, J=8.20 Hz), 7.16 (m, 2H), 6.59 (d, 1H, J=8.24
Hz), 4.66 (m, 1H), 4.61 (m, 3H), 4.43 (d, 1H, J=0.27 Hz), 4.23 (m,
4H), 3.88 (m, 1H), 3.54 (m, 1H), 2.57 (t, 2H, J=7.33 Hz), 1.68 (m,
8H), 1.26 (t, 3H, J=7.14 Hz), 0.88 (t, 3H, J=7.33 Hz),
[0412] Ethyl
2-{2-propyl-4-[({4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-
-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propano-
ate
[0413] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.24
Hz), 7.64 (d, 2H, J=8.24 Hz), 7.17 (d, 1H, J=2.38 Hz), 7.11 (dd,
1H, J=8.42, 2.38 Hz), 6.55 (d, 1H, J=8.42 Hz), 4.70 (q, 1H, J=6.78
Hz), 4.66 (t, 1H, J=3.39 Hz), 4.62 (d, 1H, J=0.27 Hz), 4.43 (d, 1H,
J=0.27 Hz), 4.25 (s, 2H), 4.15 (q, 2H, J=7.14 Hz), 3.88 (m, 1H),
3.54 (m, 1H), 2.56 (t, 2H, J=7.33 Hz), 1.60 (m, 1H), 1.21 (t, 3H,
J=7.14 Hz), 0.88 (t, 3H, J=7.33 Hz),
[0414] Ethyl
{2-isopropyl-4-[({4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[-
4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetat-
e
[0415] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.98 (d, 2H, J=8.24
Hz), 7.64 (d, 2H, J=8.24 Hz), 7.20 (d, 1H, J=2.38 Hz), 7.15 (dd,
1H, J=8.42, 2.38 Hz), 6.60 (d, 1H, J=8.42 Hz), 4.65 (t, 1H, J=3.48
Hz), 4.60 (s, 2H), 4.56 (d, 1H, J=0.09 Hz), 4.38 (d, 1H, J=0.09
Hz), 4.23 (m, 4H), 3.87 (m, 1H), 3.53 (m, 1H), 3.32 (m, 1H), 1.66
(m, 6H), 1.26 (t, 3H, J=7.14 Hz), 1.15 (d, 6H, J=6.96 Hz),
[0416] Ethyl
2-{4-[({4-(2-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-t-
hiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
[0417] From
5-(chloromethyl)-4-(2-furylmethyl)-2-[4-(trifluoromethyl)pheny-
l]-1,3-thiazole (0.097 g, 0.27 mmol), ethyl
2-{4-[({4-(2-furylmethyl)-2-[4-
-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenox-
y}propanoate (0.091 g, 60%) was obtained as a white solid.
[0418] .sup.1H NMR (CDCl.sub.3): .delta. 8.00 (d, 2H), 7.68 (d,
2H), 7.23 (m, 2H), 6.62 (m 2H), 6.30 (s, 1H), 6.02 (s, 1H), 4.76
(q, 1H), 4.21 (q, 2H), 4.17 (s, 2H), 3.98 (s, 2H), 2.29 (s, 3H),
1.63 (s, 3H), 1.24 (t, 3H); MS m/z 562 (M+1).
[0419] Ethyl
2-{4-[({4-(3-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-t-
hiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
[0420] From
5-(chloromethyl)-4-(3-furylmethyl)-2-[4-(trifluoromethyl)pheny-
l]-1,3-thiazole (0.172 g, 0.48 mmol), ethyl
2-{4-[({4-(3-furylmethyl)-2-[4-
-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenox-
y}propanoate (0.177 g, 65%) was obtained as a white solid.
[0421] .sup.1H NMR (CDCl.sub.3): .delta. 8.00 (d, 2H), 7.70 (d,
2H), 7.28 (m, 2H), 7.16, (d, 1H), 6.61 (m, 2H), 6.31 (s, 1H), 4.78
(q, 1H), 4.27 (q, 2H), 4.18 (s, 2H), 3.68 (s, 2H), 2.22 (s, 3H),
1.68 (s, 3H), 1.30 (t, 3H); MS m/z 578 (M+1).
[0422] Ethyl
2-{4-[({4-(2-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-
-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
[0423] From
5-(chloromethyl)-4-(3-furylmethyl)-2-[4-(trifluoromethyl)pheny-
l]-1,3-thiazole (0.185 g, 0.50 mmol), ethyl
2-{4-[({4-(2-thienylmethyl)-2--
[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphen-
oxy}propanoate (0.21 g, 73%) was obtained as a yellow solid.
[0424] .sup.1H NMR (CDCl.sub.3): .delta. 8.01 (d, 2H), 7.70 (d,
2H), 7.20 (s, 1H), 7.17 (m, 1H), 6.93 (m, 1H), 6.80 (s, 1H), 6.60
(m, 2H), 4.74 (q, 1H), 4.20 (q, 2H), 4.19 (s, 2H), 4.17 (s, 2H),
2.29 (s, 3H), 1.67 (s, 3H), 1.30 (t, 3H); MS m/z 578 (M+1).
[0425] Ethyl
2-methyl-2(4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluor-
omethyl)phenyl-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
[0426] From
5-(chloromethyl)-4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazole (0.166 g, 0.37 mmol) (prepared as in
U16097-118-2), ethyl
2-methyl-2-{4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-
-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulanyl]phenoxy}propanoa-
te (0.210 g, 87%) was obtained as a white solid.
[0427] MS m/z 656 (M+1); HPLC RT 4.862 (C18 4.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[0428] Ethyl
2-methyl-2-{4-[({4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
[0429] From
5-(chloromethyl)-4-(2-thienylmethyl)2-[4-(trifluoromethyl)phen-
yl]-1,3-thiazole (0.062 g, 0.16 mmol), ethyl
2-methyl-2-{4-[({4-[(4-methyl-
-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)s-
ulfanyl]phenoxy}propanoate (0.17 g, 100%) was obtained as a yellow
oil.
[0430] MS m/z 592 (M+1); HPLC RT 4.534 (C18 4.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[0431] Ethyl
{2-methyl-4-[({4-[(4-methyl-2-thienyl)methyl]-2-[4-trifluorom-
ethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
[0432] From
5-(chloromethyl)-4(2-thienylmethyl)-2-[4-(trifluoromethyl)phen-
yl]-1,3-thiazole (0.062 g, 0.16 mmol), ethyl
{2-methyl-4-[({4-[(4-methyl-2-
-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sul-
fanyl]phenoxy}acetate (0.13 g, 100%) was obtained as a yellow
oil.
[0433] MS m/z 578 (M+1); HPLC RT 4.338 (C18 4.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[0434] Ethyl
{4-[({4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyl)phenyl]-1,-
3-thiazol-5-yl}methyl)sulfanyl]2-methylphenoxy}acetate
[0435] From
5-(chloromethyl)-4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyl)-
phenyl]-1,3-thiazole (0.139 g, 0.34 mmol), ethyl
{4-[({4-(2,4-difluorobenz-
yl)2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methy-
lphenoxy}acetate, (0.19, 49%) was obtained as a white solid.
[0436] MS m/z 594 (M+1); HPLC RT 4.337 (C18 4.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[0437] Ethyl
{4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-t-
hiazol-5-yl}methyl)sulfanyl]2-methylphenoxy}acetate
[0438] From
5-(chloromethyl)-4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phe-
nyl]-1,3-thiazole (0.09 g, 0.4 mmol) (prepared as in U17097-118-3),
ethyl
{4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl)-
methyl)sulfanyl]-2-methylphenoxy}acetate (0.160 g, 68%) was
obtained as a white solid.
[0439] MS m/z 588 (M+1); HPLC RT 4.631 (C18 4.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[0440]
2-Methyl-4-[({4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenol
[0441] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.10
Hz), 7.63 (d, 2H, J=8.10 Hz), 7.16 (d, 1H, J=2.24 Hz), 7.06 (dd,
1H, J=8.28, 2.24 Hz), 6.63 (d, 1H, J=8.28 Hz), 4.64 (t, 1H, J=3.53
Hz), 4.59 (d, 1H, J=0.24 Hz), 4.40 (d, 1H, J=0.24 Hz), 4.23 (s,
2H), 3.86 (m, 1H), 3.53 (m, 1H), 2.16 (s, 3H), 1.66 (m, 6H),
[0442]
2-Methyl-4-[({44-trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phen-
yl]-1,3-thiazol-5-yl}m ethyl)sulfanyl]phenol
[0443] From
5-(chloromethyl)-4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluoro-
methyl)phenyl]-1,3-thiazole (0.82 g, 0.19 mmol),
2-methyl-4-[({4-(4-triflu-
oromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)su-
lfanyl]phenol (0.021 g, 21%) was obtained as a white solid.
[0444] .sup.1H NMR (CDCl.sub.3): .delta. 8.00 (d, 2H), 7.69 (d,
2H), 7.52 (d, 2H), 7.29 (d, 2H), 7.18 (s, 1H), 7.16 (d, 1H), 6.70
(d, 1H), 4.15 (s, 2H), 4.00 (s, 2H), 2.20 (s, 3H); MS m/z 540
(M+1).
[0445]
2-Methyl-4-[({4-(4-trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)p-
henyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenol
[0446] From
5-(chloromethyl)-4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazole (0.147 g, 0.33 mmol),
2-methyl-4-[({4-(4-trif-
luoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl-
)sulfanyl]phenol (0.048 g, 27%) was obtained as a white solid.
[0447] .sup.1H NMR (CDCl.sub.3): .delta. 8.01 (d, 2H), 7.71 (d,
2H), 7.13 (m, 6H), 6.69 (d, 1H), 4.18 (s, 2H), 3.96 (s, 2H), 2.22
(s, 3H); MS m/z 556 (M+1).
[0448]
4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol--
5-yl}methyl)sulfanyl]-2-methylphenol
[0449] From
5-(chloromethyl)-4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phe-
nyl]-1,3-thiazole (0.063 g, 0.16 mmol),
4-[({4-(4-methoxybenzyl)-2-[4-(tri-
fluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenol
(0.022 g, 28%) was obtained as a white solid.
[0450] .sup.1H NMR (CDCl.sub.3): .delta. 8.00 (d, 2H), 7.68 (d,
2H), 7.19 (s, 1H), 7.09 (m, 3H), 6.82 (d, 2H), 6.70 (d, 1H), 4.14
(s, 2H), 3.90 (s, 2H), 2.20 (s, 3H); MS m/z 502 (M+1).
[0451]
2-Methyl-4-[({4-(4-methylsulfanyl)benzyl]-2-[4-(trifluoromethyl)phe-
nyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenol
[0452] From
5-(chloromethyl)-4-[4-(methylsulfanyl)benzyl]-2-[4-(trifluorom-
ethyl)phenyl]-1,3-thiazole (0.33 g, 0.78 mmol),
2-methyl-4-[({4-(4-methyls-
ulfanyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulf-
anyl]phenol (0.296 g, 72%) was obtained as a white solid.
[0453] MS m/z 518 (M+1).
[0454]
4-[({4-(4-tert-butylbenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiaz-
ol-5-yl}methyl)sulfanyl]-2-methylphenol
[0455] From
4-(4-tert-butylbenzyl)-5-(chloromethyl)-2-[4-(trifluoromethyl)-
phenyl]-1,3-thiazole (0.151 g, 0.36 mmol),
4-[({4-(4-tert-butylbenzyl)-2-[-
4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylpheno-
l (0.113 g, 60%) was obtained as a white solid. MS m/z 528
(M+1).
[0456]
2-Methyll-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,-
3-thiazol-5-yl}methyl)sulfanyl]phenol
[0457] From
5-(chloromethyl)-4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phe-
nyl]-1,3-thiazole (0.105 g, 0.28 mmol),
2-methyl-4-[({4-(3-thienylmethyl)--
2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenol
(0.072 g, 54%) was obtained as a yellow oil. MS m/z 478 (M+1).
[0458] The following three compounds were also prepared by the same
route but were carried on without purification:
[0459] Ethyl
22-isopropyl-4-[({4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[-
4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propan-
oate
[0460]
4-[({4-[(Tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)-
phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenol
[0461]
4-[({2-(4-Fluorophenyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-
-thiazol-5-yl)methyl)sulfanyl]-2-methylphenol
[0462] Ethyl
2-(2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy)propanoate
[0463] From
2-methyl-4-[({4-(4-trifluoromethoxy)benzyl]-2-[4-(trifluoromet-
hyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenol (0.17 g, 0.31
mmol), ethyl 2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-
[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}prop-
anoate (0.17 g, 83%) was obtained as a white solid.
[0464] MS m/z 656 (M+1); HPLC RT 4.553 (C18 4.2.times.1 00 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @2541220 nm).
[0465] Methyl
{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
[0466] From
2-methyl-4[({4-(4-trifluoromethoxy)benzyl]2-[4-(trifluoromethy-
l)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenol (0.17 g, 0.31
mmol), methyl
{2-methyl-4[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl-
)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate (0.15 g,
80%) was obtained as a white solid: MS m/z 628 (M+1); HPLC RT 4.398
(C18 4.2.times.100 mm, 0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2
ml/min @254/220 nm).
[0467] Ethyl
2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)ph-
enyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
[0468] From
2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl-
]-1,3-thiazol-5-yl}methyl)sulfanyl]phenol, ethyl
242-methyl-4-[({4-(3-thie-
nylmethyl)-2-[4-(trifluoromethyl)phenyl-1,3-thiazol-5-yl}methyl)sulfanyl]p-
henoxy}propanoate (0.225 g, 0.47 mmol), (0.255 g, 91%) was obtained
as a yellow oil.
[0469] MS m/z 578 (M+1); HPLC RT 4.412 (C18 4.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
Methyl
{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thia-
zol-5-yl}methyl)sulfanyl]phenoxy}acetate
[0470] From
2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl-
]-1,3-thiazol-5-yl}methyl)sulfanyl]phenol, methyl
{2-methyl-4-[({4-(3-thie-
nylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-
phenoxy}acetate (0.225 g, 0.47 mmol), (0.259 g, 94%) was obtained
as a yellow oil.
[0471] MS m/z 550 (M+1); HPLC RT 4.243 (C18 4.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[0472] Ethyl
2-{4-[({4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-t-
hiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpropanoate
[0473] To a stirred solution of crude ethyl
{2-methyl-4-[({4-[(tetrahydro--
2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}me-
thyl)sulfanyl]phenoxy}acetate (11.98 g, 20.09 mmoles, 1 eq) in MeOH
(100 ml, 0.20M) was added as a solid p-toluenesulfonic acid (800
mg, 25 mol %) at room temperature. The reaction mixture was stirred
at room temperature for 3 hours. The MeOH was removed in vacuo and
the residue was purified by silica gel chromatography (15%
EtOAc/Hexanes to 30% EtOAc/Hexanes) to yield 8 g (78%) of pure
tilted alcohol.
[0474] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.96 (d, 2H, J=8.06
Hz), 7.65 (d, 2H, J=8.06 Hz), 7.23 (d, 2H, J=8.79 Hz), 6.73 (d, 2H,
J=8.79 Hz), 4.44 (s, 2H), 4.17 (m, 4H), 2.33 (br s, 1H), 1.56 (s,
6H), 1.21 (t, 3H, J=7.14 Hz),
[0475] TLC(30% EtOAc/Hexanes) R.sub.f=0.32
[0476]
4-[({4-(Hydroxymethyl)-2-[4-(trifluoromethyl)phenyl-1,3-thiazol-5-y-
l}methyl)sulfanyl]-2-methylphenol
[0477] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.95 (d, 2H, J=7.93
Hz), 7.64 (d, 2H, J=7.93 Hz), 7.15 (d, 1H, J=2.07 Hz), 6.98 (dd,
1H, J=8.10, 2.07 Hz), 6.62 (d, 1H, J=8.10 Hz), 4.39 (s, 2H), 4.11
(s, 2H), 2.14 (s, 3H),
[0478] Ethyl
2-{4-[({4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-t-
hiazol-5-yl}methyl)sulfanyl]-2-isopropylphenoxy}propanoate
[0479] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.06
Hz), 7.66 (d, 2H, J=8.06 Hz), 7.13 (d, 1H, J=2.38 Hz), 7.10 (dd,
1H, J=8.24, 2.38 Hz), 6.55 (d, 1H, J=8.24 Hz), 4.70 (q, 1H, J=6.78
Hz), 4.43 (s, 2H), 4.14 (m, 4H), 2.55 (t, 2H, J=7.33 Hz), 2.19
(brs, 1H), 1.55 (m, 5H), 1.21 (t, 3H, J=7.14 Hz), 0.85 (t, 3H,
J=7.33 Hz),
[0480] Methyl
{4-[({4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-th-
iazol-5-yl}methyl)sulfanyl]-2-isopropylphenoxy}acetate
[0481] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.42
Hz), 7.66 (d, 2H, J=8.42 Hz), 7.15 (m, 2H), 6.60 (d, 1H, J=8.79
Hz), 4.64 (s, 2H), 4.38 (s, 2H), 4.15 (s, 2H), 3.77 (s, 3H), 3.31
(m, 1H), 2.03 (br s, 1H), 1.12 (d, 6H, J=6.96 Hz),
[0482] Ethyl
2-{4-[({4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-t-
hiazol-5-yl}methyl)sulfanyl]-2-isopropylphenoxy}propanoate
[0483] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.24
Hz), 7.66 (d, 2H, J=8.24 Hz), 7.15 (d, 1H, J=2.38 Hz), 7.11 (dd,
1H, J=8.42, 2.38 Hz), 6.56 (d, 1H, J=8.42 Hz), 4.73 (q, 1H, J=6.78
Hz), 4.38 (s, 2H), 4.14 (m, 4H), 3.30 (m, 1H), 1.60 (d, 3H, J=6.78
Hz), 1.17 (m, 9H),
[0484] Ethyl
2-{4-[({4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl-11,3-t-
hiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
[0485] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.00 (d, 2H, J=8.23
Hz), 7.69 (d, 2H, J=8.23 Hz), 7.22 (d, 1H, J=2.39 Hz), 7.12 (dd,
1H, J=8.23, 2.39 Hz), 6.59 (d, 1H, J=8.23 Hz), 4.74 (q, 1H, J=6.77
Hz), 4.51 (s, 2H), 4.19 (m, 4H), 3.68 (br s, 1H), 2.26 (s, 3H),
1.65 (d, 3H, J=6.77 Hz), 1.26 (t, 3H, J=7.17 Hz),
[0486] TLC(50% EtOAc/Hexanes) R.sub.f=0.40
[0487] The following four compounds were deprotected as above but
used without further purification:
[0488] Ethyl
2-[4-({[2-(4-fluorophenyl)-4-(hydroxymethyl)-1,3-thiazol-5-yl-
]methyl}sulfanyl)-2-methylphenoxy]propanoate
[0489] Ethyl
{2-ethyl-4-[({4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-
-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
[0490] Ethyl
2-{2-ethyl-4-[({4-(hydroxymethyl)-2-[4-(trifluoromethyl)pheny-
l]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
[0491] Ethyl
{4-[({4-hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thia-
zol-5-yl}methyl)sulfanyl]-2-propylphenoxy}acetate
[0492] Ethyl {(tert-butyl(diphenyl)silyl]oxy}acetate
[0493] To a 500 ml round-bottom flask equipped with a magnetic
stir-bar, N.sub.2 inlet was added ethyl glycolate (10 g, 96.0
mmoles, 1 eq) and dry CH.sub.2Cl.sub.2 (200 ml, 0.5M). This was
followed by the addition of triethylamine (40 ml, 0.288 moles, 3
eq) and DMAP (1.17 g, 9.6 mmoles, 10 mol %) followed by the
dropwise addition of TBDPSCI (27.5 ml, 0.106 moles, 1.1 eq) in dry
CH.sub.2Cl.sub.2 (20 ml). The reaction mixture was allowed to stir
at room temperature overnight at which time the reaction mixture
was diluted with CH.sub.2Cl.sub.2 and washed with 1N HCl, saturated
sodium bicarbonate, H.sub.2O and dried over Na.sub.2SO.sub.4. After
filtration the volatiles were removed in vacuo to yield 30 g (91%)
of titled compound.
[0494] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.69 (m, 4H), 7.39
(m, 6H), 4.23 (s, 2H), 4.14 (q, 2H, J=7.14 Hz), 1.22 (t, 3H, J=7.14
Hz), 1.08 (m, 9H),
[0495] TLC(20% EtOAc/Hexanes) R.sub.f=0.67
[0496] {[tert-Butyl(diphenyl)silyl]oxy}acetic Acid
[0497] To a stirred solution of ethyl
{[tert-butyl(diphenyl)silyl]oxy}acet- ate (20 g, 58.4 mmoles, 1 eq)
in THF (100 ml, 0.58M) was added 1N NaOH (6 ml, 0.117 moles, 2 eq)
and was allowed to stir at room temperature overnight. The THF was
removed in vacuo and the residue was partitioned between
CH.sub.2Cl.sub.2 and 1N HCl until a pH of 2 was reached. The phases
were separated and the aqueous phase was washed twice with
CH.sub.2Cl.sub.2. The combined organic fractions were dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to yield 17 g
(90%) of product.
[0498] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.68 (m, 4H), 7.41
(m, 6H), 4.22 (s, 2H), 1.11 (s, 9H),
[0499] TLC(5% MeOH/CH.sub.2Cl.sub.2) R.sub.f=0.37
[0500] {[tert-Butyl(diphenyl)silyl]oxy}acetyl Chloride
[0501] In a 500 ml round-bottom flask was mixed
{[tert-butyl(diphenyl)sily- l]oxy}acetic acid (17 g, 54.0 mmoles, 1
eq), thionyl chloride (11.7 g, 0.162 moles, 3 eq) and dry
CH.sub.2Cl.sub.2 (120 ml, 0.45M). This mixture was refluxed for 5
hours. After cooling to room temperature the volatiles were removed
in vacuo. The resulting residue was washed twice with toluene and
the toluene was subsequently removed in vacuo to remove excess
thionyl chloride. This resulted in 18 g (100%) of titled
compound.
[0502] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.72 (m, 4H), 7.44
(m, 6H), 4.54 (s, 2H), 1.11 (m, 9H),
[0503] Ethyl 4-{[tert-butyl(diphenyl)silyl]oxy}-3-oxobutanoate
[0504] To a 1-L round-bottom flask equipped with a magnetic
stir-bar, addition funnel, low temperature thermometer with
thermometer adapter and a N.sub.2 inlet was added monoethyl
malonate (14.53 g, 0.11 moles, 2 eq) in dry THF (150 ml, 0.73M) and
20 mg of 2,2'-dipyridyl. After cooling the reaction mixture to
-78.degree. C. (dry ice/acetone), n-BuLi (2.5M in Hexanes, 88 ml,
0.22 moles, 4 eq) was added at a rate to maintain the internal
temperature below -10.degree. C. Once the addition was complete the
reaction was allowed to warm to -10.degree. C. by removal of the
cold bath. The reaction remained a light pink color; this
designates that there was ample amount of n-BuLi to deprotonate the
monoethyl malonate. (If the color had turned yellow the reaction
would have had to have been re-cooled to -78.degree. C. and
additional n-BuLi would have had to have been added followed be
re-warming to -10.degree. C.) At this point the reaction mixture
was cooled to -78.degree. C. followed by the dropwise addition of
neat {[tert-Butyl(diphenyl)silyl]oxy}acetyl chloride (18 g, 54
mmoles, 1 eq) over a period of 15 minutes maintaining the internal
reaction temperature below 60.degree. C. This was allowed to stir
at -78.degree. C. for 10 minutes at which point the reaction was
transferred to a separatory funnel containing diethyl ether (900
ml) and 1N HCl (450 ml). This was agitated and vented until further
gas evolution ceased after which the phases were separated and the
organic phase was washed with saturated sodium bicarbonate, brine
and dried over Na.sub.2SO.sub.4. This was then filtered,
concentrated in vacuo and purified by silica gel chromatography (5%
EtOAc/Hexanes to 20% EtOAc/Hexanes) to yield 12.2 g (60%) of
product.
[0505] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.63 (m, 4H), 7.41
(m, 6H), 4.19 (m, 4H), 3.63 (s, 2H), 1.27 (t, 3H, J=7.14 Hz), 1.08
(s, 9H),
[0506] TLC(20% EtOAc/Hexanes) R.sub.f=0.53
[0507] The following compounds were made according to W. Wierenga
(J. Org. Chem. 1979 vol 44 p 310):
[0508] Ethyl 4-(4-bromophenyl)-3-oxobutanoate
[0509] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.45 (d, 2H, J=8.38
Hz), 7.10 (d, 2H, J=8.38 Hz), 4.17 (q, 2H, J=7.14 Hz), 3.79 (s,
2H), 3.45 (s, 2H), 1.26 (t, 3H, J=7.14 Hz),
[0510] Ethyl 3-oxo-42-phenylethoxy)butanoate
[0511] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.26 (m, 5H), 4.15
(q, 4H, J=7.14 Hz), 3.71t, 2H, J=6.94 Hz), 3.46 (s, 2H), 2.92 (t,
2H, J=6.94 Hz), 1.27 (t, 3H, J=7.14 Hz),
[0512] Ethyl 3-oxo-6-phenylhexanoate
[0513] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.22 (m, 5H), 4.18
(q, 2H, J=7, 14 Hz), 3.39 (s, 2H), 2.62 (t, 2H, J=7.28 Hz), 2.53
(t, 2H, J=7.28 Hz), 1.92 (m, 2H), 1.25 (t, 3H, J=7.14 Hz),
[0514] Ethyl 3-oxo-4-phenylbutanoate
[0515] .sup.1H (CDCl.sub.3) 300 MHz 7.29 (m, 5H), 4.18 (q, 2H,
J=7.14 Hz), 3.83 (s, 2H), 3.44 (s, 2H), 1.26 (t, 3H, J=7.14
Hz),
[0516] TLC(20% EtOAc/Hexanes) R.sub.f=0.36
[0517] Ethyl 4(-benzyloxy)-3-oxobutanoate
[0518] .sup.1H (CDCl.sub.3) 300 MHz 7.35 (m, 5H), 4.59 (s, 2H),
4.16 (q, 4H, J=7.14 Hz), 3.53 (s, 2H), 1.26 (t, 3H, J=7.14 Hz),
[0519] Ethyl 3-oxo-5-phenylpentanoate
[0520] .sup.1H NMR (CDCl.sub.3) 300 MHz 7.24 (m, 5H), 4.18 (q, 2H,
J=7.14 Hz), 3.42 (s, 2H), 2.90 (m, 4H), 1.27 (t, 3H, J=7.14 Hz)
[0521] Ethyl
4-{[tert-butyl(diphenyl)silyl]oxy}-2-chloro-3-oxobutanoate
[0522] To a 100 ml round-bottom flask equipped with a magnetic
stir-bar and a N.sub.2 inlet was added ethyl
4-{[tert-butyl(diphenyl)silyl]oxy}-3-- oxobutanoate (4 g, 10.4
mmoles, 1 eq) and dry CH.sub.2Cl.sub.2 (25 ml, 0.42M) at room
temperature. This was followed by the addition of neat sulfuryl
chloride (.sup.0.833 ml. 10.4 mmoles, 1 eq) and the reaction was
allowed to stir overnight at room temperature. After dilution with
CH.sub.2Cl.sub.2 (50 ml) the reaction mixture was treated with
saturated sodium bicarbonate until bubbling ceased. The phases were
separated and the organic fraction was washed with sat.
NaHCO.sub.3, brine and dried over Na.sub.2SO.sub.4. After
filtration and concentration in vacuo was yielded 4.2 g (96%) of
crude chloride. This crude product was used without
purification.
[0523] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.62 (m, 4H), 7.41
(m, 6H), 5.26 (s, 1H), 4.40 (m, 2H), 4.25 (m, 2H), 1.28 (t, 3H,
J=7.14 Hz), 1.09 (s, 9H),
[0524] The following intermediates were made by the same procedure
as that used for Ethyl
4-{[tert-butyl(diphenyl)silyl]oxy}-2-chloro-3-oxobutanoate
[0525] Ethyl 4-(benzyloxy)-2-chloro-3-oxobutanoate
[0526] .sup.1H (CDCl.sub.3) 300 MHz .delta. 7.36 (m, 5H), 5.10 (s,
1H), 4.59 (s, 2H), 4.32 (s, 2H), 4.23 (q, 2H, J=7.23 Hz), 1.28 (t,
3H, J=7.14 Hz),
[0527] Ethyl 2-chloro-3-oxo-6-phenylhexanoate
[0528] .sup.1H (CDCl.sub.3) 300 MHz .delta. 7.23 (m, 5H), 4.75 (s,
1H), 4.27 (q, 2H, J=7.14 Hz), 2.72 (t, 2H, J=7.28 Hz), 2.63 (t, 2H,
J=7.28 Hz), 1.97 (m, 2H, J=7.28 Hz), 1.28 (t, 3H, J=7.14 Hz),
[0529] Ethyl 2-chloro-3-oxo-42-phenylethoxy)butanoate
[0530] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.25 (m, 5H), 5.03
(s, 1H), 4.29 (m, 2H), 4.24 (q, 2H, J=7.14 Hz), 3.73 (t, 2H, J=7.00
Hz), 2.91 (t, 2H, J=7.00 Hz), 1.29 (t, 3H, J=7.14 Hz),
[0531] Ethyl 2-chloro-3-oxo-4-phenylbutanoate
[0532] .sup.1H (CDCl.sub.3) 300 MHz 7.29 (m, 5H), 4.87 (s, 1H),
4.23 (m, 2H, J=7.14, 7.00, 7.14, 1.10, 1.24, 1.24, 0.82 Hz), 4.02
(d, 2H, J=4.53 Hz), 1.31 (t, 3H, J=7.14 Hz),
[0533] TLC(20% EtOAc/Hexanes) R.sub.f=0.51
[0534] Ethyl 2-chloro-3-oxo-5-phenylpentanoate
[0535] .sup.1H (CDCl.sub.3) 300 MHz 7.25 (m, 5H), 4.76 (s, 1H),
4.25 (q, 2H, J=7.14 Hz), 2.99 (m, 4H), 1.31 (t, 3H, J=7.14 Hz),
[0536] TLC(20% EtOAc/Hexanes) R.sub.f=0.46
[0537] Ethyl 44-bromophenyl)-2-chloro-3-oxobutanoate
[0538] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.48 (d, 2H, J=8.51
Hz), 7.10 (d, 2H, J=8.51 Hz), 4.84 (s, 1H), 4.25 (q, 2H, J=7.14
Hz), 3.97 (s, 2H), 1.29 (t, 3H, J=7.14 Hz),
[0539] TLC(20% EtOAc/Hexanes) R.sub.f=0.58
[0540] Ethyl
4-[{tert-butyl(diphenyl)silyl]oxy}methyl)-2-(4-{trifluorometh-
yl}phenyl)-1,3-thiazole-5-carboxylate
[0541] To a 500 ml round-bottom flask equipped with a magnetic
stir-bar was mixed ethyl
4-{[tert-butyl(diphenyl)silyl]oxy}2-chloro-3-oxobutanoate (20.4 g,
52.88 mmoles, 1 eq), 4-trifluoromethylthiobenzamide (12.29, 59.5
mmoles, 1.1 eq), 1,2-dichloroethane (150 ml, 0.44M) and H.sub.2O (3
ml). This mixture was refluxed for 12 hrs. After cooling to room
temperature, the reaction mixture was diluted with CH.sub.2Cl.sub.2
(100 ml) and washed with sat. NaHCO.sub.3. Once the phases were
separated, the organic phase was washed with water, brine and dried
over Na.sub.2SO.sub.4. This was then filtered, concentrated in
vacuo and purified via silica gel chromatography (5% EtOAc/Hexanes
to 20% EtOAc/Hexanes) to yield 20.3 g (76%) of the titled
compound.
[0542] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.07 (d, 2H, J=8.37
Hz), 7.76 (m, 4H), 7.71 (d, 2H, J=8.37 Hz), 7.37 (m, 6H), 5.24 (s,
2H), 4.26 (q, 2H, J=7.18 Hz), 1.29 (t, 3H, J=7.18 Hz), 1.11 (s,
9H),
[0543] TLC(20% EtOAc/Hexanes) R.sub.f=0.72
[0544] Ethyl
4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-phenyl-1,3-thiaz-
ole-5-carboxylate
[0545] Analogous procedure to that used for ethyl
4-({[tert-butyl(diphenyl-
)silyl]oxy}methyl)-2-(4-{trifluoromethyl}phenyl)-1,3-thiazole-5-carboxylat-
e except thiobenzamide is the starting material.
[0546] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.98 (m, 2H), 7.76
(m, 4H), 7.40 (m, 9H), 5.21 (s, 2H), 4.23 (q, 2H, J=7.12 Hz), 1.28
(t, 3H, J=7.12 Hz), 1.08 (s, 9H),
[0547] TLC(20% EtOAc/Hexanes) R.sub.f=0.67
[0548] The following intermediates were made using the same
procedure as Ethyl
4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-(4-{trifluoromethyl}ph-
enyl]-1,3-thiazole-5-carboxylate:
[0549] Ethyl
2-{4-{trifluoromethyl}phenyl)-4-[(2-phenylethoxy)methyl]-1,3--
thiazole-5-carboxylate
[0550] .sup.1H (CDCl.sub.3) 300 MHz .delta. 8.10 (d, 2H, J=8.79
Hz), 7.71 (d, 2H, J=8.79 Hz), 7.23 (m, 5H), 5.02 (s, 2H), 4.37 (q,
2H, J=7.14 Hz), 3.86 (t, 2H, J=7.42 Hz), 2.99 (t, 2H, J=7.42 Hz),
1.41 (t, 3H, J=7.14 Hz),
[0551] Ethyl
2-{4-{trifluoromethyl}phenyl)-4-(3-phenylpropyl)-1,3-thiazole-
-5-carboxylate .sup.1H (CDCl.sub.3) 300 MHz .delta. 8.08 (d, 2H,
J=8.24 Hz), 7.71 (d, 2H, J=8.24 Hz), 7.23 (m, 5H), 4.34 (q, 2H,
J=7.14 Hz), 3.25 (t, 2H, J=7.69 Hz), 2.71 (t, 2H, J=7.69 Hz), 2.13
(m, 2H), 1.35 (t, 3H, J=7.14 Hz),
[0552] Ethyl
4-[(benzyloxy)methyl]-2-(4-{trifluoromethyl}phenyl)-1,3-thiaz-
ole-5-carboxylate
[0553] .sup.1H (CDCl.sub.3) 300 MHz .delta. 8.12 (d, 2H, J=8.79
Hz), 7.72 (d, 2H, J=8.79 Hz), 7.35 (m, 5H), 5.04 (s, 2H), 4.74 (s,
2H), 4.36 (q, 2H, J=7.10 Hz), 1.38 (t, 3H, J=7.14 Hz),
[0554] TLC(20% EtOAc/Hexanes) R.sub.f=0.49
[0555] Ethyl
4-(4-bromobenzyl)-2-(4-{trifluoromethyl}phenyl)-1,3-thiazole--
5-carboxylate
[0556] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.07 (d, 2H, J=8.79
Hz), 7.69 (d, 2H, J=8.79 Hz), 7.43 (d, 2H, J=8.51 Hz), 7.28 (d, 2H,
J=8.51 Hz), 4.51 (s, 2H), 4.38 (q, 2H, J=7.14 Hz), 1.39 (t, 3H,
J=7.14 Hz),
[0557] TLC(20% EtOAc/Hexanes) R.sub.f=0.66
[0558] Ethyl
4-(2-phenylethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole--
5-carboxylate
[0559] .sup.1H (CDCl.sub.3) 300 MHz 8.10 (d, 2H; J=8.79 Hz), 7.72
(d, 2H, J=8.79 Hz), 7.24 (m, 5H), 4.37 (q, 2H, J=7.14 Hz), 3.51 (m,
2H), 3.10 (m, 2H), 1.40 (t, 3H, J=7.14 Hz),
[0560] MS(ES.sup.+) M+H=405.99
[0561] Ethyl
4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxy-
late
[0562] .sup.1H (CDCl.sub.3) 300 MHz 8.08 (d, 2H, J=8.79 Hz), 7.70
(d, 2H, J=8.79 Hz), 7.42 (d, 2H, J=9.61 Hz), 7.23 (m, 3H), 4.58 (s,
2H), 4.38 (q, 2H, J=7.14 Hz), 1.39 (t, 3H, J=7.14 Hz),
[0563] TLC(20% EtOAc/Hexanes) R.sub.f=0.57
[0564] MS(ES.sup.+) M+H=391.9
[0565]
{4-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-2-[4-(trifluoromethyl)p-
henyl]-1,3-thiazol-5-yl}methanol
[0566] Analogous reduction as in the synthesis of
4-[(tetrahydro-2H-pyran--
2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol.
[0567] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.03
Hz), 7.68 (m, 6H), 7.41 (m, 6H), 4.97 (s, 2H), 4.84 (s, 2H), 1.08
(s, 9H),
[0568]
[4-({([tert-Butyl(diphenyl)silyl]oxy}methyl)-2-phenyl-1,3-thiazol-5-
-yl]methanol
[0569] Analogous reduction as in the synthesis of
4-[(tetrahydro-2H-pyran--
2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol.
[0570] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.90 (m, 2H), 7.75
(m, 4H), 7.45 (m, 9H), 5.00 (s, 2H), 4.86 (s, 2H), 1.13 (s,
9H),
[0571] The following compounds were all made by the general
alkylation procedure with the appropriate thiols made above and the
alkyl halides made from either
{4-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-2-[4-(triflu-
oromethyl)phenyl]-1,3-thiazol-5-yl}methanol or
{4-({[tert-Butyl(diphenyl)s-
ilyl]oxy}methyl)2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol
via the chlorides as described above.
[0572] Ethyl
[4-({([4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-phenyl-1,-
3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetate
[0573] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.85 (m, 2H), 7.68
(m, 4H), 7.39 (m, 9H), 7.12 (d, 1H, J=2.39 Hz), 7.03 (dd, 1H,
J=8.37, 2.39 Hz), 6.50 (d, 1H, J=8.37 Hz), 4.61 (s, 2H), 4.55 (s,
2H), 4.24 (q, 2H, J=7.12 Hz), 4.10 (s, 2H), 2.18 (s, 3H), 1.26 (t,
3H, J=7.12 Hz), 1.05 (s, 9H),
[0574] TLC(20% EtOAc/Hexanes) R.sub.f=0.43
[0575] Ethyl
2-{4-[({4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-[4-(trif-
luoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}prop-
anoate
[0576] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.94 (d, 2H, J=8.20
Hz), 7.67 (m, 6H), 7.39 (m, 6H), 7.11 (d, 1H, J=2.39 Hz), 7.00 (dd,
1H, J=8.37, 2.39 Hz), 6.49 (d, 1H, J=8.37 Hz), 4.65 (m, 2H), 4.17
(q, 2H, J=7.18 Hz), 4.09 (s, 2H), 2.17 (s, 3H), 1.60 (d, 3H, J=6.84
Hz), 1.21 (t, 3H, J=7.18 Hz), 1.05 (s, 9H),
[0577] TLC(20% EtOAc/Hexanes) R.sub.f=0.57
[0578] Ethyl
2-[4-({[4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-phenyl-1-
,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]propanoate
[0579] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.85 (m, 2H), 7.68
(m, 4H), 7.38 (m, 9H), 7.11 (d, 1H, J=2.39 Hz), 6.99 (dd, 1H,
J=8.55, 2.39 Hz), 6.49 (d, 1H, J=8.55 Hz), 4.64 (m, 3H), 4.16 (q,
2H, J=7.12 Hz), 4.07 (s, 2H), 2.17 (s, 3H), 1.59 (d, 3H, J=6.84
Hz), 1.20 (t, 3H, J=7.12 Hz), 1.05 (m, 9H),
[0580] TLC (20% EtOAc/Hexanes) R.sub.f=0.48
[0581] Ethyl
{4-[({3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-[4-(triflu-
oromethyl)phenyl]-2-thienyl}methyl)sulfanyl]-2-methylphenoxy}acetate
[0582] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.94 (d, 2H, J=8.20
Hz), 7.66 (m, 6H), 7.38 (m, 6H), 7.11 (d, 1H, J=2.22 Hz), 7.03 (dd,
1H, J=8.37, 2.22 Hz), 6.50 (d, 1H, J=8.37 Hz), 4.63 (s, 2H), 4.56
(s, 2H), 4.23 (q, 2H, J=7.12 Hz), 4.10 (s, 2H), 2.18 (s, 3H), 1.27
(t, 3H, J=7.12 Hz), 1.04 (s, 9H),
[0583] TLC(20% EtOAc/Hexanes) R.sub.f=0.50
[0584] Ethyl
[4-({[4-(hydroxymethyl)-2-(4-{trifluoromethyl}phenyl)-1,3-thi-
azol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetate
[0585] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.97 (d, 2H, J=8.23
Hz), 7.67 (d, 2H, J=8.23 Hz), 7.22 (d, 1H, J=2.39 Hz), 7.14 (dd,
1H, J=8.23, 2.39 Hz), 6.61 (d, 1H, J=8.23 Hz), 4.63 (s, 2H), 4.50
(s, 2H), 4.26 (q, 2H, J=7.17 Hz), 4.18 (s, 2H), 2.83 (s, 1H), 2.25
(s, 3H), 1.29 (t, 3H, J=7.17 Hz),
[0586] TLC(50% EtOAc/Hexanes) R.sub.f=0.51
[0587] (4-Bromophenyl)acetyl Chloride
[0588] To a stirred solution of 4-bromophenylacetic acid (10 g,
46.5 mmoles, 1 eq) in dry CH.sub.2Cl.sub.2 (100 ml, 0.47M) was
added thionyl chloride (20.2 ml, 0.280 moles, 6 eq) and refluxed
for 36 hours. After cooling to room temperature the reaction was
concentrated in vacuo to yield 10.86 g (100%) of acid chloride.
[0589] .sup.1H (CDCl.sub.3) 300 MHz .delta. 7.50 (d, 2H, J=8.38
Hz), 7.14 (d, 2H, J=8.38 Hz), 4.09 (s, 2H),
[0590] 4-Phenylbutanoyl Chloride
[0591] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.25 (m, 5H), 2.90
(t, 2H, J=7.28 Hz), 2.69 (t, 2H, J=7.28 Hz), 2.05 (m, 2H),
[0592] (2-Phenylethoxy)acetyl Chloride
[0593] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.26 (m, 5H), 4.39
(s, 2H), 3.80 (t, 2H, J=6.94 Hz), 2.93 (t, 2H, J=6.94 Hz)
[0594]
[4-([1,1'-Biphenyl]-4-ylmethyl)-2-(4-{trifluoromethyl}phenyl)1,3-th-
iazol-5-yl]methanol
[0595] To a stirred solution of
[4-(4-Bromobenzyl)-2-(4-{trifluoromethyl}p-
henyl)-1,3-thiazol-5-yl]methanol (0.33 g, 0.78 mmoles, 1 eq) in dry
1,2-dimethoxyethane (5 ml, 0.16M) was added
tetrakis(triphenylphosphino) palladium I (0.45 g, 0.39 mmoles, 0.5
eq) and stirred for 5 minutes at room temperature. Phenylboronic
acid (0.143 g, 1.2 mmoles, 1.5 eq) was then added followed by the
addition of sodium carbonate (2M aqueous solution, 2.3 ml, 4.68
mmoles, 6 eq). The reaction mixture was heated at 100 degrees
centigrade for 13 hours at which point, after cooling to room
temperature, the reaction was partitioned between EtOAc and water.
After separation of the phases the organic phase was washed with
brine, dried over anhydrous sodium sulfate, filtered, concentrated
in vacuo to yield after purification by silica gel chromatography
(CH.sub.2Cl.sub.2 to 2% MeOH/CH.sub.2Cl.sub.2) 268 mg (80%) of
product.
[0596] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.03 (d, 2H, J=8.20
Hz), 7.67 (d, 2H, J=8.20 Hz), 7.54 (m, 4H), 7.36 (m, 5H), 4.85 (s,
2H), 4.22 (s, 2H),
[0597] The following Intermediate was prepared in using the same
procedure:
[0598]
{2-(4-{trifluoromethyl}phenyl)-4-[4-(3-thienyl)benzyl]-1,3-thiazol--
5-yl}methanol
[0599] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.03 (d, 2H, J=8.20
Hz), 7.67 (d, 2H, J=8.20 Hz), 7.52 (d, 2H, J=8.37 Hz), 7.35 (m,
5H), 4.84 (s, 2H), 4.20 (s, 2H),
[0600] The following componds were made by the same prcedure for
phenol alkylation.
[0601] Ethyl
{2-methyl-4-[({4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(-
trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
[0602] To a 250 ml round-bottom flask equipped with a magnetic
stir-bar and N.sub.2 inlet was added
5-(chloromethyl)-4-[(tetrahydro-2H-pyran-2-yl-
oxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole (7.87 g,
20.09 mmoles, 1 eq) and dry CH.sub.3CN (100 ml, 0.27M). Solid
cesium carbonate (16.4 g, 50.22 mmoles, 2.5 eq) was added all at
once followed by the quick addition of ethyl
2-methyl-2-(4-sulfanylphenoxy)propanoate (5.79 g, 24.11 mmoles, 1.2
eq) in dry CH.sub.3CN (10 ml). The reaction was allowed to stir at
room temperature for 2 hours at which point the solvent was removed
under reduced pressure. The resulting residue was partitioned
between EtOAc and 1N NaOH. After the phases were separated the
organic fraction was washed with H.sub.2O, brine and dried over
Na.sub.2SO.sub.4. After filtration the volatiles were removed in
vacuo to yield the titled compound in >100% yield. Because of
the difficult separation between the thiophenol and the product,
the crude product was carried forward without purification.
[0603]
4-[({4-(Bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl-
}methyl)sulfanyl]-2-methylphenol
[0604] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.01 (d, 2H, J=8.10
Hz), 7.68 (d, 2H, J=8.10 Hz), 7.17 (d, 1H, J=2.41 Hz), 7.08 (dd,
1H, J=8.10, 2.41 Hz), 6.67 (d, 1H, J=8.10 Hz), 4.63 (s, 2H), 4.14
(s, 2H),
[0605] Ethyl 2-[4-[({4-{[4-(4-methoxyphenyl)-1
piperazinyl]methyl}-2-[4-(t-
rifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylp-
ropanoate.
[0606] To a 500 ml 3-neck round-bottom flask equipped with a
magnetic stir-bar, low temperature thermometer with thermometer
adapter, addition funnel and N.sub.2 inlet was added ethyl
2-{4-[({4-(hydroxymethyl)2-[4-(t-
rifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy)2-methylpr-
opanoate (16 g, 31.28 mmoles, 1 eq) and dry CH.sub.2Cl.sub.2 (120
ml, 0.26M) and cooled to 0.degree. C. Methanesulfonyl chloride
(2.91 ml, 37.54 mmoles, 1.2 eq) was added neat all at once.
Triethylamine (6.6 ml, 46.92 mmoles, 1.5 eq) was added dropwise
over 20 minutes maintaining the internal temperature below
5.degree. C. and was stirred at 0.degree. C. for 30 minutes. The
reaction mixture was transferred to a separatory funnel and washed
with H.sub.2O, brine and the organic fraction was dried over
Na.sub.2SO.sub.4. After filtration the solvent was removed under
reduced pressure to yield the corresponding mesylate in quantitatve
yield. Because of the unstable nature of the mesylate, the product
was not characterized and was progressed onto the next stage
without purification.
[0607] To the crude mesylate dissolved in dry THF (200 ml, 0.16M)
was added 4-methoxyphenyl piperazine (13 g, 62.56 mmoles, 2 eq) and
the reaction mixture was refluxed for 5 hours. After cooling to
room temperature the solvent was removed in vacuo to yield a yellow
solid residue. The residue was washed with a minimal amount of
EtOAc and filtered through Celite to remove the 4-methoxyphenyl
piperazine hydrochloride salt. The EtOAc was removed in vacuo and
the resulting solid was filtered through a "plug" of silica gel
using 30% EtOAC/Hexanes to yield 20.37 g (95%) of a light-yellow
solid.
[0608] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.96 (d, 2H, J=8.24
Hz), 7.63 (d, 2H, J=8.24 Hz), 7.27 (d, 2H, J=8.79 Hz), 6.87 (d, 2H,
J=9.16 Hz), 6.80 (d, 2H, J=9.16 Hz), 6.74 (d, 2H, J=8.79 Hz), 4.32
(s, 2H), 4.17 (q, 2H, J=7.14 Hz), 3.73 (s, 3H), 3.56 (s, 2H), 3.06
(br s, 4H), 2.59 (br s, 4H), 1.55 (s, 6H), 1.21 (t, 3H, J=7.14
Hz),
[0609] HPLC (C-18, 3 .mu.m) 0%-95% Acetonitrile/Water over 8
minutes R.sub.t=6.06 minutes
[0610] The follow intermediates were made using the same alkylation
conditions:
[0611]
4-[({4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluorom-
ethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenol
[0612] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.94 (d, 2H, J=8.10
Hz), 7.64 (d, 2H, J=8.10 Hz), 7.16 (d, 1H, J=2.07 Hz), 7.07 (dd,
1H, J=8.10, 2.07 Hz), 6.86 (m, 2H), 6.80 (d, 2H, J=8.97 Hz), 6.66
(d, 1H, J=8.10 Hz), 4.27 (s, 2H), 3.73 (s, 3H), 3.59 (s, 2H), 3.15
(br s, 4H), 2.67 (br s, 4H), 2.16 (s, 3H),
[0613] Ethyl
[2-methyl-4-({[2-4-{trifluoromethyl}phenyl)-4-(4-morphollnylm-
ethyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]acetate
[0614] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.02 (d, 2H, J=8.23
Hz), 7.69 (d, 2H, J=8.23 Hz), 7.27 (m, 1H), 7.17 (dd, 1H, J=8.23,
2.39 Hz), 6.62 (d, 1H, J=8.23 Hz), 4.64 (s, 2H), 4.36 (s, 2H), 4.25
(q, 2H, J=7.17 Hz), 3.72 (t, 4H, J=4.51 Hz), 3.53 (s, 2H), 2.48 (t,
4H, J=4.51 Hz), 2.27 (s, 3H), 1.32 (t, 3H, J=7.17 Hz),
[0615] TLC(50% EtOAc/Hexanes) R.sub.f=0.26
[0616] Ethyl
[4-({[4-[(4-benzyl-1-piperazinyl)methyl]-2-(4-{trifluoromethy-
l}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetate
[0617] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.02 (d, 2H, J=8.76
Hz), 7.68 (d, 2H, J=8.76 Hz), 7.31 (m, 6H), 7.16 (dd, 1H, J=8.49,
2.39 Hz), 6.62 (d, 1H, J=8.49 Hz), 4.63 (s, 2H), 4.35 (s, 2H), 4.27
(q, 2H, J=7.17 Hz), 3.54 (m, 4H), 2.51 (br s, 8H), 2.27 (s, 3H),
1.32 (t, 3H, J=7.17 Hz),
[0618] TLC(50% EtOAc/Hexanes)=0.19
[0619] Ethyl
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(t-
rifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}p-
ropanoate
[0620] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta.7.99 (d, 2H, J=8.20
Hz), 7.66 (d, 2H, J=8.20 Hz), 7.23 (d, 1H, J=2.39 Hz), 7.13 (dd,
1H, J=8.37, 2.39 Hz), 6.89 (d, 2H, J=9.23 Hz), 6.83 (d, 2H, J=9.23
Hz), 6.57 (d, 1H, J=8.37 Hz), 4.70 (q, 1H, J=6.84 Hz), 4.34 (s,
2H), 4.17 (q, 2H, J=7.18 Hz), 3.76 (s, 3H), 3.58 (s, 2H), 3.09 (m,
4H), 2.63 (m, 4H), 2.24 (s, 3H), 1.62 (d, 3H, J=6.84 Hz), 1.21 (t,
3H, J=7.18 Hz),
[0621] TLC(30% EtOAc/Hexanes)=0.29
[0622] Ethyl
{2-methyl-4-[({2-(4-{trifluoromethyl}phenyl)-4-[(4-phenyl-1-p-
iperazinyl)methyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
[0623] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.04 (d, 2H, J=8.23
Hz), 7.70 (d, 2H, J=8.23 Hz), 7.29 (m, 3H), 7.21 (dd, 1H, J=8.23,
2.39 Hz), 6.92 (m, 3H), 6.63 (d, 1H, J=8.23 Hz), 4.64 (s, 2H), 4.38
(s, 2H), 4.27 (q, 2H, J=7.17 Hz), 3.63 (s, 2H), 3.21 (m, 4H), 2.66
(m, 4H), 2.28 (s, 3H), 1.32 (t, 3H, J=7.17 Hz),
[0624] TLC(50% EtOAc/Hexanes) R.sub.f=0.52
[0625] Ethyl
4([5-({[4-(2-ethoxy-2-oxoethoxy)-3-methylphenyl]sulfanyl}meth-
yl)-2-{trifluoromethyl}phenyl)-1,3-thiazol-4-yl]methyl}-1-piperazinecarbox-
ylate
[0626] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.99 (d, 2H, J=8.23
Hz), 7.68 (d, 2H, J=8.23 Hz), 7.25 (m, 1H), 7.17 (dd, 1H, J=8.49,
2.12 Hz), 6.61 (d, 1H, J=8.49 Hz), 4.64 (s, 2H), 4.28 (m, 4H), 4.14
(t, 2H, J=7.17 Hz), 3.50 (m, 6H), 2.44 (br s, 4H), 2.26 (s, 3H),
1.29 (t, 3H, J=7.17 Hz),
[0627] TLC(50% EtOAc/Hexanes) R.sub.f=0.17
[0628] Ethyl
{2-methyl-4-[({2-(4-{trifluoromethyl}phenyl)-4-[(4-phenyl-1-p-
iperidinyl)methyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
[0629] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.04 (d, 2H, J=8.23
Hz), 7.70 (d, 2H, J=8.23 Hz), 7.27 (m, 7H), 6.64 (d, 1H, J=8.49
Hz), 4.64 (s, 2H), 4.41 (s, 2H), 4.28 (q, 2H, J=7.17 Hz), 3.60 (s,
2H), 3.02 (m, 2H), 2.53 (m, 1H), 2.30 (s, 3H), 2.18 (m, 2H), 1.84
(m, 4H), 1.32 (t, 3H, J=7.17 Hz),
[0630] TLC(50% EtOAc/Hexanes) R.sub.f=0.48
[0631] Ethyl
{2-methyl-4-[({2-(4-{trifluoromethyl}phenyl)-4-[(4-methyl-1-p-
iperidinyl)methyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
[0632] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.02 (d, 2H, J=8.23
Hz), 7.68 (d, 2H, J=8.23 Hz), 7.28 (d, 1H, J=2.39 Hz), 7.19 (dd,
1H, J=8.49, 2.39 Hz), 6.62 (d, 1H, J=8.49 Hz), 4.64 (s, 2H), 4.38
(s, 2H), 4.28 (q, 2H, J=7.17 Hz), 3.51 (s, 2H), 2.84 (m, 4H), 2.28
(s, 3H), 2.02 (m, 4H), 1.61 (m, 4H), 1.30 (m, 8H), 0.94 (d, 3H,
J=6.11 Hz),
[0633] TLC(50% EtOAc/Hexanes) R.sub.f=0.36
[0634] Ethyl
(2-methyl-4-{[(2-(4-{trifluoromethyl}phenyl)-4-([4-(2-methylp-
henyl)-1-piperazinyl]methyl}-1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)acet-
ate
[0635] .sup.1H (CDCl.sub.3) 400 MHz .delta. 7.99 (d, 2H, J=8.20
Hz), 7.66 (d, 2H, J=8.20 Hz), 7.25 (m, 1H), 7.16 (m, 3H), 6.98 (m,
2H), 6.60 (d, 1H, J=8.55 Hz), 4.60 (s, 2H), 4.37 (s, 2H), 4.23 (q,
2H, J=7.12 Hz), 3.59 (s, 2H), 2.93 (s, 4H), 2.63 (s, 4H), 2.29 (s,
3H), 2.24 (s, 3H), 1.27 (t, 5H, J=7.12 Hz),
[0636] TLC(50% EtOAc/Hexanes) R.sub.f=0.73
[0637] Ethyl
[4-({[4-([4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2(4-{trif-
luoromethyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acet-
ate
[0638] .sup.1H (CDCl.sub.3) 400 MHz .delta. 7.99 (d, 2H, J=8.20
Hz), 7.65 (d, 2H, J=8.20 Hz), 7.24 (dd, 1H, J=2.39 Hz), 7.16 (dd,
1H, J=8.37, 2.39 Hz), 6.84 (m, 4H), 6.58 (d, 1H, J=8.37 Hz), 4.59
(s, 2H), 4.33 (s, 2H), 4.23 (q, 2H, J=7.18 Hz), 3.75 (s, 3H), 3.57
(s, 2H), 3.07 (m, 4H), 2.62 (s, 4H), 2.24 (s, 3H), 1.27 (t, 3H,
J=7.18 Hz),
[0639] TLC(50% EtOAc/Hexanes) R.sub.f=0.44
[0640] Ethyl
(2-methyl-4-{[(2-(4-{trifluoromethyl}phenyl)-4-([4-(3-methylp-
henyl)-1-piperazinyl]methyl}1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)aceta-
te
[0641] .sup.1H (CDCl.sub.3) 400 MHz .delta. 7.99 (d, 2H, J=8.20
Hz), 7.66 (d, 2H, J=8.20 Hz), 7.24 (m, 1H), 7.14 (m, 2H), 6.70 (s,
3H), 6.59 (d, 1H, J=8.55 Hz), 4.60 (s, 2H), 4.33 (s, 2H), 4.23 (q,
2H, J=7.12 Hz), 3.57 (s, 2H), 3.16 (br s, 4H), 2.62 (br s, 4H),
2.30 (s, 3H), 2.24 (s, 3H), 1.26 (t, 3H, J=7.12 Hz),
[0642] TLC(50% EtOAc/Hexanes) R.sub.f=0.64
[0643] Ethyl (2-methyl
4-{[(2-(4-{trifluoromethyl}phenyl)-4-{[4-(4-methylp-
henyl)-1-piperazinyl]methyl}1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)aceta-
te
[0644] .sup.1H (CDCl.sub.3) 400 MHz .delta. 7.99 (d, 2H, J=8.20
Hz), 7.65 (d, 2H, J=8.20 Hz), 7.24 (d, 1H, J=2.39 Hz), 7.15 (dd,
1H, J=8.37, 2.39 Hz), 7.04 (d, 2H, J=8.55 Hz), 6.82 (d, 2H, J=8.55
Hz), 6.58 (d, 1H, J=8.37 Hz), 4.60 (s, 2H), 4.32 (s, 2H), 4.23 (q,
2H, J=7.12 Hz), 3.57 (s, 2H), 3.10 (s, 4H), 2.60 (s, 4H), 2.26 (s,
3H), 2.23 (s, 3H), 1.26 (t, 3H, J=7.12 Hz),
[0645] TLC(50% EtOAc/Hexanes) R.sub.f=0.64
[0646] Ethyl
[4-({[4-{[4-(2-furoyl)-1-piperazinyl]methyl}-2-{4-{trifluorom-
ethyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetate
[0647] .sup.1H (CDCl.sub.3) 400 MHz .delta. 7.98 (d, 2H, J=8.20
Hz), 7.65 (d, 2H, J=8.20 Hz), 7.46 (m, 1H), 7.22 (d, 1H, J=2.39
Hz), 7.13 (dd, 1H, J=8.37, 2.39 Hz), 6.96 (d, 1H, J=3.42 Hz), 6.59
(d, 1H, J=8.37 Hz), 6.46 (m, 1H), 4.62 (s, 2H), 4.29 (s, 2H), 4.21
(q, 2H, J=7.12 Hz), 3.80 (s, 4H), 3.50 (s, 2H), 2.53 (s, 4H), 2.23
(s, 3H), 1.26 (t, 3H, J=7.18 Hz),
[0648] TLC(50% EtOAc/Hexanes) R.sub.f=0.06
[0649] Ethyl
(2-methyl-4-{[(2-(4-{trifluoromethyl}phenyl)-4-([4-(2-pyridin-
yl)-1-piperazinyl]methyl}-1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)acetate
[0650] .sup.1H (CDCl.sub.3) 400 MHz .delta. 8.16 (m, 1H), 7.98 (d,
2H, J=8.20 Hz), 7.63 (d, 2H, J=8.20 Hz), 7.45 (s, 1H), 7.25 (d, 1H,
J=2.22 Hz), 7.15 (dd, 1H, J=8.37, 2.22 Hz), 6.56 (m, 3H), 4.60 (s,
2H), 4.33 (s, 2H), 4.21 (q, 2H, J=7.12 Hz), 3.53 (m, 6H), 2.57 (s,
4H), 2.23 (s, 3H), 1.27 (t, 3H, J=7.12 Hz),
[0651] TLC(50% EtOAc/Hexanes) R.sub.f=0.25
[0652] Ethyl
[4-({[4-{[4-(4-chlorobenzyl)-1-piperazinyl]methyl}-2-(4-{trif-
luoromethyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acet-
ate
[0653] .sup.1H (CDCl.sub.3) 400 MHz .delta. 7.96 (d, 2H, J=8.20
Hz), 7.64 (d, 2H, J=8.20 Hz), 7.25 (m, 5H), 7.13 (dd, 1H, J=8.37,
2.39 Hz), 6.58 (d, 1H, J=8.37 Hz), 4.59 (s, 2H), 4.31 (s, 2H), 4.22
(q, 2H, J=7.18 Hz), 3.52 (s, 2H), 3.42 (s, 2H), 2.48 (br s, 8H),
2.20 (s, 3H), 1.26 (t, 3H, J=7.18 Hz),
[0654] TLC(50% EtOAc/Hexanes) R.sub.f=0.23
[0655] Ethyl
[4-({[4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-(4-{trif-
luoromethyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acet-
ate
[0656] .sup.1H (CDCl.sub.3) 400 MHz .delta. 7.98 (d, 2H, J=8.20
Hz), 7.85 (d, 2H, J=9.06 Hz), 7.66 (d, 2H, J=8.20 Hz), 7.24 (d, 1H,
J=2.39 Hz), 7.16 (dd, 1H, J=8.20, 2.39 Hz), 6.84 (d, 2H, J=9.06
Hz), 6.58 (d, 1H, J=8.20 Hz), 4.61 (s, 2H), 4.31 (s, 2H), 4.22 (q,
2H, J=7.18 Hz), 3.58 (s, 2H), 3.33 (br s, 4H), 2.60 (br s, 4H),
2.50 (m, 3H), 2.24 (s, 3H), 1.27 (t, 3H, J=7.18 Hz),
[0657] TLC(50% EtOAc/Hexanes) R.sub.f=0.23
[0658] Ethyl
[4-({[4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-(4-{trif-
luoromethyl}phenyl)-1,3-thiazol-5-yl]methyl{sulfanyl)-2-methylphenoxy]acet-
ate
[0659] .sup.1H (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.20
Hz), 7.64 (d, 2H, J=8.20 Hz), 7.23 (d, 1H, J=2.22 Hz), 7.14 (dd,
1H, J=8.37, 2.22 Hz), 6.58 (d, 1H, J=8.37 Hz), 4.60 (s, 2H), 4.30
(s, 2H), 4.22 (q, 2H, J=7.12 Hz), 3.60 (m, 2H), 3.50 (s, 2H), 2.94
(s, 1H), 2.53 (m, 10H), 2.23 (s, 3H), 1.26 (t, 3H, J=7.12 Hz),
[0660] Ethyl
(2-methyl-4-{[(2-(4-{trifluoromethyl}phenyl)-4{[(3-pyridinylm-
ethyl)amino]methyl}-1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)acetate
[0661] .sup.1H (CDCl.sub.3) 400 MHz .delta. 8.55 (m, 1H), 8.50 (m,
1H), 7.98 (d, 2H, J=8.20 Hz), 7.71 (m, 1H), 7.65 (m, 2H), 7.24 (m,
1H), 7.17 (m, 1H), 7.10 (m, 1H), 6.55 (d, 1H, J=8.37 Hz), 4.58 (s,
2H), 4.22 (q, 2H, J=7.12 Hz), 4.12 (s, 2H), 3.77 (s, 2H), 3.63 (s,
2H), 2.64 (brs, 1H), 2.21 (s, 3H), 1.27 (t, 3H, J=7.12 Hz),
[0662] Ethyl
(4-{[(4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl{2-phenyl-1-
,3-thiazol-5-yl)methyl]sulfanyl}-2-methylphenoxy)acetate
[0663] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta.7.88 (m, 2H), 7.40
(m, 3H), 7.25 (d, 1H, J=2.39 Hz), 7.17 (dd, 1H, J=8.37, 2.39 Hz),
6.89 (d, 2H, J=9.06 Hz), 6.81 (d, 2H, J=9.06 Hz), 6.58 (d, 1H,
J=8.37 Hz), 4.59 (s, 2H), 4.32 (s, 2H), 4.23 (q, 2H, J=7.12 Hz),
3.74 (s, 3H), 3.56 (s, 2H), 3.06 (m, 4H), 2.62(m, 4H), 2.24 (s,
3H), 1.27 (t, 3H, J=7.12 Hz),
[0664] Ethyl
2-(4[(4-{[4-methoxyphenyl)-1-piperazinyl]methyl}-2-phenyl-1,3-
-thiazol-5-yl)methyl]sulfanyl}-2-methylphenoxy)propanoate
[0665] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta.7.88 (m, 2H), 7.40
(m, 3H), 7.25 (d, 1H, J=2.39 Hz), 7.14 (dd, 1H, J=8.37, 2.39 Hz),
6.89 (d, 2H, J=9.40 Hz), 6.82 (d, 2H, J=9.40 Hz), 6.57 (d, 1H,
J=8.37 Hz), 4.70 (q, 1H, J=6.84 Hz), 4.32 (s, 2H), 4.17 (q, 2H,
J=7.18 Hz), 3.76 (s, 3H), 3.56 (s, 2H), 3.08 (m, 4H), 2.63 (m, 4H),
2.23 (m, 3H), 1.61 (d, 3H, J=6.84 Hz), 1.25 (t, 3H, J=7.18 Hz),
[0666] Ethyl
{2-methyl-4-[({2-(4-{trifluoromethyl}phenyl)-4-[(pentylamino)-
methyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
[0667] .sup.1H (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.20
Hz), 7.65 (d, 2H, J=8.20 Hz), 7.20 (d, 1H, J=2.39 Hz), 7.12 (dd,
1H, J=8.37, 2.39 Hz), 6.58 (d, 1H, J=8.37 Hz), 4.60 (s, 2H), 4.23
(q, 2H, J=7.18 Hz), 4.18 (s, 2H), 3.64 (s, 2H), 2.58 (t, 2H, J=6.92
Hz), 2.22 (s, 3H), 1.50 (m, 2H), 1.28 (m, 7H), 0.87 (t, 3H, J=6.92
Hz),
[0668] Ethyl
2-{4-[({4-{[4-(4-hydroxyphenyl)-1-piperazinyl]methyl}-2-[4-(t-
rifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}p-
ropanoate
[0669] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.08 (d, 2H, J=8.28
Hz), 7.75 (d, 2H, J=8.28 Hz), 7.27 (d, 1H, J=2.21 Hz), 7.17 (dd,
1H, J=8.28, 2.21 Hz), 6.87 (d, 2H, J=8.83 Hz), 6.73 (d, 2H, J=8.83
Hz), 6.66 (d, 1H, J=8.28 Hz), 4.83 (q, 1H, J=6.81 Hz), 4.34 (s,
2H), 4.15 (q, 2H, J=7.08 Hz), 3.47 (s, 2H), 3.00 (t, 4H, J=4.83
Hz), 2.57 (t, 4H, J=4.83 Hz), 2.20 (s, 3H), 1.57 (d, 3H, J=6.81
Hz), 1.20 (t, 3H, J=7.08 Hz),
[0670] Ethyl
2-{4-[({4-{[4-(3,4-dimethoxyphenyl)-1-piperazinyl]methyl}-2-[-
44-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphen-
oxy)propanoate
[0671] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.06 (d, 2H, J=8.28
Hz), 7.72 (d, 2H, J=8.28 Hz), 7.26 (d, 1H, J=2.21 Hz), 7.16 (dd,
1H, J=8.55, 2.21 Hz), 6.82 (d, 1H, J=8.55 Hz), 6.64 (m, 2H), 6.47
(dd, 1H, J=8.55, 2.21 Hz), 4.81 (q, 1H, J=6.99 Hz), 4.34 (s, 2H),
4.14 (q, 2H, J=7.17 Hz), 3.82 (s, 3H), 3.77 (s, 3H), 3.52 (s, 2H),
3.07 (t, 4H, J=4.55 Hz), 2.63 (t, 4H, J=4.55 Hz), 2.20 (s, 3H),
1.57 (d, 3H, J=6.99 Hz), 1.18 (t, 3H, J=7.17 Hz),
[0672] Ethyl
2-(4-{[(4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-pheny-
l-1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)-2-methylpropanoate
[0673] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.87 (m, 2H), 7.40
(m, 3H), 7.28 (d, 2H, J=8.89 Hz), 6.89 (d, 2H, J=9.23 Hz), 6.82 (d,
2H, J=9.23 Hz), 6.75 (d, 2H, J=8.89 Hz), 4.33 (s, 2H), 4.19 (q, 2H,
J=7.18 Hz), 3.76 (s, 3H), 3.56 (s, 2H), 3.09 (br s, 4H), 2.65 (br
s, 4H), 1.58 (s, 6H), 1.20 (t, 3H, J=7.18 Hz),
[0674] Ethyl
{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(tri-
fluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
[0675] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta.6.99 (d, 2H, J=8.20
Hz), 7.66 (d, 2H, J=8.20 Hz), 7.35 (d, 2H, J=8.89 Hz), 6.88 (d, 2H,
J=9.40 Hz), 6.83 (m, 4H), 4.58 (s, 2H), 4.34 (s, 2H), 4.24 (q, 2H,
J=7.18 Hz), 3.76 (s, 3H), 3.57 (s, 2H), 3.08 (m, 4H), 2.63 (m, 4H),
1.27 (t, 3H, J=7.18 Hz),
[0676] Ethyl
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(t-
rifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
[0677] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.99 (d, 2H, J=8.20
Hz), 7.66 (d, 2H, J=8.20 Hz), 7.32 (d, 2H, J=8.89 Hz), 6.89 (d, 2H,
J=9.23 Hz), 6.83 (d, 2H, J=9.23 Hz), 6.79 (d, 2H, J=8.89 Hz), 4.70
(q, 1H, J=6.78 Hz), 4.33 (s, 2H), 4.16 (q, 2H, J=7.09 Hz), 3.75 (s,
3H), 3.57 (s, 2H), 3.08 (m, 4H), 2.63 (m, 4H), 1.60 (d, 3H, J=6.78
Hz), 1.24 (t, 3H, J=7.09 Hz),
[0678] Ethyl
2-(4-{[(4-[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-phenyl-
-1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)propanoate
[0679] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta.8.87 (m, 2H), 7.39
(m, 3H), 7.32 (d, 2H, J=8.85 Hz), 6.87 (d, 2H, J=9.06 Hz), 6.82 (d,
2H, J=9.06 Hz), 6.77 (d, 2H, J=8.85 Hz), 4.69 (q, 1H, J=6.78 Hz),
4.31 (s, 2H), 4.18 (q, 2H, J=7.12 Hz), 3.75 (s, 3H), 3.54 (s, 2H),
3.08 (m, 4H), 2.62 (m, 4H), 1.59 (d, 3H, J=6.78 Hz), 1.20 (t, 3H,
J=7.12 Hz),
[0680] Ethyl
2-{4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(t-
rifluoromethyl)phenyl]-1,3-thiazol-yl}methyl)sulfanyl]-2-methylphenoxy}-2--
methylpropanoate
[0681] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.96 (d, 2H, J=8.28
Hz), 7.63 (d, 2H, J=8.28 Hz), 7.21 (d, 1H, J=2.41 Hz), 7.13 (t, 1H,
J=8.10 Hz), 7.07 (dd, 1H, J=8.45, 2.41 Hz), 6.53 (m, 2H), 6.43 (t,
1H, J=2.24 Hz), 6.38 (dd, 1H, J=8.10, 2.24 Hz), 4.31 (s, 2H), 4.18
(q, 2H, J=7.16 Hz), 3.75 (s, 3H), 3.55 (s, 2H), 3.16 (t, 4H, J=4.83
Hz), 2.58 (t, 4H, J=4.83 Hz), 2.17 (s, 3H), 1.57 (s, 6H), 1.22 (t,
3H, J=7.16 Hz),
[0682] Ethyl
2-{4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-
-methylpropanoate
[0683] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.96 (d, 2H, J=8.28
Hz), 7.62 (d, 2H, J=8.28 Hz), 7.21 (d, 1H, J=2.41 Hz), 7.06 (dd,
1H, J=8.45, 2.41 Hz), 6.91 (m, 2H), 6.83 (m, 2H), 6.53 (d, 1H.
J=8.45 Hz), 4.30 (s, 2H), 4.13 (q, 2H, J=7.16 Hz), 3.55 (s, 2H),
3.06 (t, 4H, J=4.66 Hz), 2.57 (t, 4H, J=0.66 Hz), 2.15 (s, 3H),
1.55 (s, 6H), 1.21 (t, 3H, J=7.16 Hz),
[0684] Ethyl
2-{4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(t-
rifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylp-
ropanoate
[0685] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.96 (d, 2H, J=8.10
Hz), 7.63 (d, 2H, J=8.10 Hz), 7.26 (d, 2H, J=8.79 Hz), 7.14 (t, 1H,
J=8.28 Hz), 6.74 (d, 2H, J=8.79 Hz), 6.51 (dd, 1H, J=8.28, 2.24
Hz), 6.43 (t, 1H, J=2.24 Hz), 6.39 (dd, 1H, J=8.28, 2.24 Hz), 4.31
(s, 2H), 4.16 (q, 2H, J=7.07 Hz), 3.74 (s, 3H), 3.54 (s, 2H), 3.17
(t, 4H, J=4.66 Hz), 2.58 (t, 4H, J=4.66 Hz), 1.56 (s, 6H), 1.20 (t,
3H, J=7.07 Hz),
[0686] Ethyl
2-{4-[({4-{[4-(4-chlorophenyl)-1-piperazinyl]methyl}-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpr-
opanoate
[0687] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.96 (d, 2H, J=8.10
Hz), 7.63 (d, 2H, J=8.10 Hz), 7.27 (d, 2H, J=8.79 Hz), 7.15 (d, 2H,
J=9.14 Hz), 6.80 (d, 2H, J=9.14 Hz), 6.73 (d, 2H, J=8.79 Hz), 4.30
(s, 2H), 4.17 (q, 2H, J=7.16 Hz), 3.54 (s, 2H), 3.12 (t, 4H, J=4.74
Hz), 2.57 (m, 4H), 1.55(s. 6H), 1.17 (t, 3H, J=7.16 Hz),
[0688] Ethyl
2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2[4-(tri-
fluoromethyl)phenyl]-1,3-thiazol-yl}methyl)sulfanyl]phenoxy)-2-methylpropa-
noate
[0689] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.95 (d, 2H, J=8.28
Hz), 7.83 (d, 2H, J=9.14 Hz), 7.62 (d, 2H, J=8.28 Hz), 7.26 (d, 2H,
J=8.62 Hz), 6.82 (d, 2H, J=9.14 Hz), 6.73 (d, 2H, J=8.62 Hz), 4.29
(s, 2H), 4.17 (q, 2H, J=7.07 Hz), 3.53 (s, 2H), 3.32 (t, 4H, J=4.66
Hz), 2.57 (br s, 4H), 2.48 (s, 3H), 1.55 (s, 6H), 1.17 (t, 3H,
J=7.07 Hz),
[0690] Ethyl
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl)-2-[4-(t-
rifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylp-
ropanoate
[0691] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.96 (d, 2H, J=8.28
Hz), 7.63 (d, 2H, J=8.28 Hz), 7.26 (d, 2H, J=8.79 Hz), 6.87 (d, 2H,
J=9.14 Hz), 6.81 (d, 2H, J=9.14 Hz), 6.73 (d, 1H, J=8.79 Hz), 4.32
(s, 2H), 4.17 (q, 2H, J=7.16 Hz), 3.73 (s, 3H), 3.54 (s, 2H), 3.06
(t, 4H, J=4.83 Hz), 2.60 (br s, 4H), 1.55 (s, 6H), 1.20 (t, 3H,
J=7.16 Hz),
[0692] Ethyl
2-(4-{[(2-(4-fluorophenyl)-4-{[4-(4-methoxyphenyl)-1-piperazi-
nyl]methyl}-1,3-thiazol-5-yl)methyl]sulfanyl}-2-methylphenoxy)-2-methylpro-
panoate
[0693] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.84 (m, 2H), 7.20
(d, 1H, J=2.20 Hz), 7.07 (m, 3H), 6.87 (d, 2H, J=9.16 Hz), 6.81 (d,
2H, J=9.16 Hz), 6.54 (d, 1H, J=8.42 Hz), 4.29 (s, 2H), 4.19 (q, 2H,
J=7.14 Hz), 3.75 (s, 3H), 3.54 (s, 2H), 3.07 (t, 4H, J=4.76 Hz),
2.61 (br s, 4H), 2.15 (s, 3H), 1.54 (s, 6H), 1.21 (t, 3H, J=7.14
Hz),
[0694] Ethyl
2-[4-({[4-{[4-acetylphenyl)-1-piperazinyl]methyl}-2-(4-fluoro-
phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]-2-methylpropano-
ate
[0695] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.84 (m, 4H), 7.20
(d, 1H, J=2.38 Hz), 7.07 (m, 3H), 6.83 (d, 2H, J=9.16 Hz), 6.53 (d,
1H, J=8.42 Hz), 4.28 (s, 2H), 4.18 (q, 2H, J=7.14 Hz), 3.53 (s,
2H), 3.33 (t, 4H, J=4.58 Hz), 2.58 (br s, 4H), 2.48 (s, 3H), 2.16
(s, 3H), 1.58 (s, 6H), 1.23 (t, 3H, J=7.14 Hz),
[0696] Ethyl
2-(4-{[(2-(4-fluorophenyl)-4-{[4-(3-methoxyphenyl)-1-piperazi-
nyl]methyl}-1,3-thiazol-5-yl)methyl]sulfanyl}-2-methylphenoxy}-2-methylpro-
panoate
[0697] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.85 (m, 2H), 7.20
(d, 1H, J=2.38), 7.14 (t, 1H, J=8.24 Hz), 7.07 (m, 3H), 6.53 (m,
2H), 6.44 (t, 1H, J=2.29 Hz), 6.39 (dd, 1H, J=8.06, 2.38 Hz), 4.29
(s, 2H), 4.19 (q, 2H, J=7.14 Hz), 3.76 (s, 3H), 3.53 (s, 2H), 3.17
(t, 4H, J=4.67 Hz), 2.59 (br s, 4H), 2.16 (s, 3H), 1.55 (s, 6H),
1.21 (t, 3H, J=7.14 Hz),
[0698] Ethyl
4-{[5-({[4-(2-ethoxy-1,1-dimethyl-2-oxoethoxy)-3-methylphenyl-
]sulfanyl}methyl)-2-(4-fluorophenyl)-1,3-thiazol-4-yl]methyl}-1-piperazine-
carboxylate
[0699] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.82 (m, 2H), 7.18
(d, 1H, J=2.38 Hz), 7.06 (m, 3H), 6.53 (d, 1H, J=8.61 Hz), 4.25 (s,
2H), 4.19 (q, 2H, J=7.14 Hz), 4.10 (q, 2H, J=7.08 Hz), 3.45 (m,
6H), 2.40 (br s, 4H), 2.16 (s, 3H), 1.55 (s, 6H), 1.21 (m, 6H),
[0700] Ethyl
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl)-2-[4-(t-
rifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}--
2-methylpropanoate
[0701] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.96 (d, 2H, J=8.28
Hz), 7.63 (d, 2H, J=8.28 Hz), 7.21 (d, 1H, J=2.24 Hz), 7.07 (dd,
1H, J=8.45, 2.24 Hz), 6.86 (d, 2H, J=9.14 Hz), 6.80 (d, 2H, J=9.14
Hz), 6.53 (d, 1H, J=8.45 Hz), 4.31 (s, 2H), 4.17 (q, 2H, J=7.16
Hz), 3.72 (s, 3H), 3.55 (s, 2H), 3.05 (t, 4H, J=4.66 Hz), 2.59 (t,
4H, J=4.66 Hz), 2.16 (s, 3H), 1.55 (s, 6H), 1.20 (t, 3H, J=7.16
Hz),
[0702] Ethyl
2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl)-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-
-methylpropanoate
[0703] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.95 (d, 2H, J=8.10
Hz), 7.82 (d, 2H, J=8.97 Hz), 7.62 (d, 2H, J=8.10 Hz), 7.19 (d, 1H,
J=2.41 Hz), 7.06 (dd, 1H, J=8.45, 2.41 Hz), 6.82 (d, 2H, J=8.97
Hz), 6.52 (d, 1H, J=8.45 Hz), 4.27 (s, 2H), 4.16 (q, 2H, J=7.07
Hz), 3.53 (s, 2H), 3.29 (t, 4H, J=4.66 Hz), 2.54 (t, 4H, J=4.66
Hz), 2.47 (s, 3H), 2.14 (s, 3H), 1.55 (s, 6H), 1.18 (t, 3H, J=7.07
Hz),
[0704] Ethyl
2-{4-[({4-{[(4-acetyl-1-piperazinyl)methyl]-2-[4-(trifluorome-
thyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
[0705] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.00 (d, 2H, J=8.23
Hz), 7.68 (d, 2H, J=8.23 Hz), 7.27 (d, 1H, J=2.39 Hz), 7.14 (dd,
1H, J=8.23, 2.39 Hz), 6.59 (d, 1H, J=8.23 Hz), 4.73 (q, 1H, J=6.72
Hz), 4.30 (s, 2H), 4.20 (q, 2H, J=7.17 Hz), 3.65 (t, 2H, J=4.65
Hz), 3.54 (s, 2H), 3.45 (t, 2H, J=4.65 Hz), 2.48 (t, 4H, J=4.65
Hz), 2.26 (s, 3H), 2.09 (s, 3H), 1.65 (d, 3H, J=6.72 Hz), 1.25 (dd,
3H, J=7.17 Hz),
[0706]
2-Methyl-2-{4-[({4-{[4-(phenoxycarbonyl)-1-piperazinyl]methyl}-2-[4-
-(trifluoromethyl)phenyl]1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoi-
c acid
[0707] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.95 (d, 2H, J=8.28
Hz), 7.65 (d, 2H, J=8.28 Hz), 7.33 (m, 2H), 7.26 (d, 2H, J=8.79
Hz), 7.17 (t, 1H, J=7.59 Hz), 7.06 (d, 2H, J=7.59 Hz), 6.74 (d, 2H,
J=8.79 Hz), 4.32 (s, 2H), 4.18 (q, 2H, J=7.07 Hz), 3.61 (m, 6H),
2.51 (br s, 4H), 1.57 (s, 6H), 120 (t, 3H, J=7.07 Hz),
[0708] tert-Butyl
4-({5-({[4-(2-ethoxy-1,1-dimethyl-2-oxoethoxy)phenyl]sul-
fanyl}methyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)-1-pip-
erazinecarboxylate
[0709] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.94 (d, 2H, J=8.28
Hz), 7.63 (d, 2H, J=8.28 Hz), 7.24 (d, 2H, J=8.79 Hz), 6.72 (d, 2H,
J=8.79 Hz), 4.29 (s, 2H), 4.18 (q, 2H, J=7.07 Hz), 3.44 (m, 6H),
2.43 (br s, 4H), 1.56 (s, 6H), 1.42 (s, 9H), 1.19 (t, 3H, J=7.07
Hz),
[0710] Ethyl
2-methyl-2-{4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2--
[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propa-
noate
[0711] .sup.1H NMR (CDCl.sub.3)400 MHz .delta. 8.12 (s, 1H), 8.04
(s, 1H), 7.94 (d, 2H, J=8.28 Hz), 7.83 (s, 1H), 7.65 (d, 2H, J=8.28
Hz), 7.26 (d, 2H, J=8.79 Hz), 6.73 (d, 2H, J=8.79 Hz), 4.32 (s,
2H), 4.17 (q, 2H, J=7.07 Hz), 3.62 (m, 6H), 2.64 (br s, 4H), 1.56
(s, 6H), 1.18 (t, 3H, J=7.07 Hz),
[0712] Ethyl
2-{4-[({4-{[4-(2-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(t-
rifluoromethyl)phenyl]1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpr-
opanoate.
[0713] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.96 (d, 2H, J=8.28
Hz), 7.64 (d, 2H, J=8.28 Hz), 7.27 (d, 2H, J=8.97 Hz), 6.98 (m,
1H), 6.90 (m, 2H), 6.83 (m, 1H), 6.73 (d, 2H, J=8.97 Hz), 4.35 (s,
2H), 4.17 (q, 2H, J=7.07 Hz), 3.83 (s, 3H), 3.60 (s, 2H), 3.11 (br
s, 4H), 2.72 (br s, 4H), 1.58 (s, 6H), 1.18 (t, 3H, J=7.07 Hz),
[0714] tert-Butyl
4-({5-({[4-(2-methoxy-2-oxoethoxy)-3-methylphenyl]sulfan-
yl}methyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)-1-pipera-
zinecarboxylate
[0715] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.90 (d, 2H, J=8.28
Hz), 7.58 (d, 2H, J=8.28 Hz), 7.16 (d, 1H, J=2.24 Hz), 7.08 (dd,
1H, J=8.45, 2.24 Hz), 6.52 (d, 1H, J=8.45 Hz), 4.56 (s, 2H), 4.20
(s, 2H), 3.70 (s, 3H), 3.44 (s, 2H), 3.36 (t, 4H, J=4.48 Hz), 2.32
(br s, 4H), 2.17 (s, 3H), 1.38 (s, 9H),
[0716] Ethyl
2-{2-methyl-4-[({4-{[4-(4-pyridinyl)-1-piperazinyl]methyl}-2--
[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propa-
noate
[0717] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.28 (d, 2H, J=6.37
Hz), 8.02 (d, 2H, J=8.23 Hz), 7.69 (d, 2H, J=8.23 Hz), 7.28 (d, 1H,
J=2.39 Hz), 7.16 (dd, 1H, J=8.49, 2.39 Hz), 6.68 (d, 2H, J=6.37
Hz), 6.60 (d, 1H, J=8.49 Hz), 4.73 (q, 1H, J=6.72 Hz), 4.32 (s,
2H), 4.20 (q, 2H, J=7.08 Hz), 3.59 (s, 2H), 3.34 (t, 4H, J=5.04
Hz), 2.58 (t, 4H, J=5.04 Hz), 2.26 (s, 3H), 1.65 (d, 3H, J=6.72
Hz), 1.25 (t, 3H, J=7.08 Hz),
[0718] Ethyl
2-(4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(t-
rifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}p-
ropanoate
[0719] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta.7.99 (d, 2H, J=8.20
Hz), 7.66 (d, 2H, J=8.20 Hz), 7.23 (d, 1H, J=2.39 Hz), 7.13 (dd,
1H, J=8.37, 2.39 Hz), 6.89 (d, 2H, J=9.23 Hz), 6.83 (d, 2H, J=9.23
Hz), 6.57 (d, 1H, J=8.37 Hz), 4.70 (q, 1H, J=6.84 Hz), 4.34 (s,
2H), 4.17 (q, 2H, J=7.18 Hz), 3.76 (s, 3H), 3.58 (s, 2H), 3.09 (m,
4H), 2.63 (m, 4H), 2.24 (s, 3H), 1.62 (d, 3H, J=6.84 Hz), 1.21 (t,
3H, J=7.18 Hz),
[0720] TLC(30% EtOAc/Hexanes)=0.29
[0721] Ethyl
2-{4-[({4-([4-(2,4-difluorophenyl)-1-piperazinyl]methyl}-2-[4-
-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenox-
y}propanoate
[0722] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.03 (d, 2H, J=8.28
Hz), 7.69 (d, 2H, J=8.28 Hz), 7.27 (d, 1H, J=2.21 Hz), 7.17 (dd,
1H, J=8.28, 2.21 Hz), 6.86 (m, 3H), 6.61 (d, 1H, J=8.28 Hz), 4.73
(q, 1H, J=6.71 Hz), 4.36 (s, 2H), 4.21 (q, 2H, J=7.17 Hz), 3.62 (s,
2H), 3.06 (t, 4H, J=4.55 Hz), 2.67 (t, 4H, J=4.55 Hz), 2.27 (s,
3H), 1.65 (d, 3H, J=6.71 Hz), 1.26 (t, 3H, J=7.17 Hz),
[0723] Ethyl
2-{2-methyl-4-[({4-({4-[4-(trifluoromethoxy)phenyl]-1-piperaz-
inyl}methyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfany-
l]phenoxy}propanoate
[0724] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 7.97 (d, 2H, J=8.24
Hz), 7.63 (d, 2H, J=8.24 Hz), 7.19 (s, 1H), 7.10 (dd, 1H, J=8.42,
2.20 Hz), 7.03 (d, 2H, J=9.16 Hz), 6.85 (d, 2H, J=9.16 Hz), 6.57
(d, 1H, J=8.42 Hz), 4.73 (q, 1H, J=6.78 Hz), 4.27 (s, 2H), 4.07 (m,
2H), 3.41 (s, 2H), 3.03 (br s, 4H), 2.48 (br s, 4H), 2.13 (s, 3H),
1.51 (d, 3H, J=6.78 Hz), 1.11 (t, 3H, J=7.14 Hz),
[0725] Ethyl
2-{4-[({4-{[4-(4-ethoxyphenyl)-1-piperazinyl]methyl}-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}pr-
opanoate
[0726] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.01 (d, 2H, J=8.28
Hz), 7.70 (d, 2H, J=8.28 Hz), 7.21 (d, 1H, J=2.24 Hz), 7.11 (dd,
1H. J=8.45, 2.24 Hz), 6.86 (d, 2H, J=9.14 Hz), 6.76 (d, 2H, J=9.14
Hz), 6.61 (d, 1H, J=8.45 Hz), 4.77 (q, 1H, J=6.72 Hz), 4.29 (s,
2H), 4.10 (q, 2H, J=7.16 Hz), 3.91 (q, 2H, J=6.98 Hz), 3.40 (s,
2H), 2.96 (t, 4H, J=4.83 Hz), 2.50 (t, 4H, J=4.83 Hz), 2.14 (s,
3H), 1.52 (d, 3H, J=6.72 Hz), 1.30 (t, 3H, J=6.98 Hz), 1.14 (t, 3H,
J=7.16 Hz),
[0727] Ethyl
2-{2-methyl-4-[({4-{[4-(4-propoxyphenyl)-1-piperazinyl]methyl-
}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}p-
ropanoate
[0728] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 7.96 (d, 2H, J=8.10
Hz), 7.63 (d, 2H, J=8.10 Hz), 7.18 (s, 1H), 7.09 (d, 1H, J=8.45
Hz), 6.81 (d, 2H, J=8.97 Hz), 6.73 (d, 2H, J=8.97 Hz), 6.56 (d, 1H,
J=8.45 Hz), 4.71 (q, 1H, J=6.47 Hz), 4.25 (s, 2H), 4.06 (q, 2H,
J=7.07 Hz), 3.76 (t, 2H, J=7.41 Hz), 3.39 (s, 2H), 2.92 (br s, 4H),
2.48 (br s, 4H), 2.12 (s, 3H), 1.67 (m, 2H), 1.49 (d, 3H, J=6.47
Hz). 1.11 (t, 3H, J=7.07 Hz), 0.94 (t, 3H, J=7.41 Hz),
[0729] Ethyl
2-{4-[({4-{[4-(4-isopropoxyphenyl)-1-piperazinyl]methyl}-2-[4-
-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methyl)sulfanyl]-2-methylphenox-
y}propanoate
[0730] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 7.96 (d, 2H, J=8.28
Hz), 7.64 (d, 2H, J=8.28 Hz), 7.18 (d, 1H, J=2.24 Hz), 7.09 (dd,
1H, J=8.45, 2.24 Hz), 6.81 (d, 2H, J=9.14 Hz), 6.73 (d, 2H, J=9.14
Hz), 6.57 (d, 1H, J=8.45 Hz), 4.71 (q, 1H, J=6.78 Hz), 4.36 (m,
1H), 4.24 (s, 2H), 4.06 (q, 2H, J=7.16 Hz), 3.39 (s, 2H), 2.92 (t,
4H, J=4.57 Hz), 2.47 (t, 4H, J=4.57 Hz), 2.11 (s, 3H), 1.48 (d, 3H,
J=6.78 Hz), 1.19 (d, 6H, J=6.21 Hz), 1.11 (t, 3H, J=7.16 Hz),
[0731] Ethyl
4-({5-({[4-(2-ethoxy-1,1-dimethyl-2-oxoethoxy)phenyl]sulfanyl-
}methyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)-1-piperazi-
necarboxylate
[0732] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.94 (d, 2H, J=8.28
Hz), 7.63 (d, 2H, J=8.28 Hz), 7.24 (m, 2H), 6;72(d; 2H, J=8.79 Hz),
4.30 (s, 2H), 4.18 (q, 2H, J=7.07 Hz), 4.10 (q, 2H, J=7.13 Hz),
3.49 (m, 6H), 2.46 (br s, 4H), 1.58 (s, 6H), 1.21 (m, 6H),
[0733] Ethyl
4-({5-({[4-(2-methoxy-2-oxoethoxy)-3-methylphenyl]sulfanyl}me-
thyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)-1-piperazinec-
arboxylate
[0734] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.95 (d, 2H, J=8.10
Hz), 7.64 (d, 2H, J=8.10 Hz), 7.20 (d, 1H, J=2.21 Hz), 7.13 (dd,
1H, J=8.45, 2.21 Hz), 6.57 (d, 1H, J=8.45 Hz), 4.62 (s, 2H), 4.30
(s, 2H), 4.10 (q, 2H, J=7.16 Hz), 3.77 (s, 3H), 3.49 (m, 6H), 2.45
(br s, 4H), 2.21 (s, 3H), 1.23 (t, 3H, J=7.16 Hz),
[0735] Methyl
{4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(tr-
ifluoromethyl)phenyl-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}ace-
tate
[0736] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.28
Hz), 7.64 (d, 2H, J=8.28 Hz), 7.21 (d, 1H, J=2.24 Hz), 7.14 (m,
2H), 6.57 (d, 1H, J=8.45 Hz), 6.49 (dd, 1H, J=8.10, 220 Hz), 6.40
(s, 2H), 4.60 (s, 2H), 4.33 (s, 2H), 3.76 (s, 6H), 3.59 (s, 2H),
3.21 (br s, 4H), 2.68 (br s, 4H), 2.21 (s, 3H),
[0737] Methyl
{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(tri-
fluoromethyl)phenyl]1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acet-
ate
[0738] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.93 (d, 2H, J=8.28
Hz), 7.82 (d, 2H, J=8.97 Hz), 7.61 (d, 2H, J=8.28 Hz), 7.20 (d, 1H,
J=2.24 Hz), 7.13 (dd, 1H, J=8.45, 2.24 Hz), 6.80 (d, 2H, J=8.97
Hz), 6.55 (d, 1H. J=8.45 Hz), 4.57 (s, 2H), 4.27 (s, 2H), 3.73 (s,
3H), 3.52 (s, 2H), 3.27 (t, 4H, J=4.83 Hz), 2.54 (t, 4H, J=4.83
Hz), 2.45 (s, 3H), 2.20 (s, 3H),
[0739] Methyl
{4-[({4-{[4-(2-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}ac-
etate
[0740] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.10
Hz), 7.65 (d, 2H, J=8.10 Hz), 7.21 (m, 1H), 7.15 (dd, 1H, J=8.45,
2.07 Hz), 6.98 (brs, 1H), 6.89 (m, 2H), 6.83 (d, 1H, J=7.41 Hz),
6.57 (d, 1H, J=8.45 Hz), 4.61 (s, 2H), 4.35 (s, 2H), 3.83 (s, 3H),
3.75 (s, 3H), 3.61 (s, 2H), 3.11 (br s, 4H), 2.70 (br s, 4H), 2.22
(s, 3H),
[0741] Methyl
{2-methyl-4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2-[-
4-(trifluoromethyl)phenyl-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
[0742] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.07 (s, 1H), 7.99
(m, 1H), 7.94 (d, 2H, J=8.10 Hz), 7.77 (d, 1H, J=2.59 Hz), 7.60 (d,
2H, J=8.10 Hz), 7.20 (d, 1H, J=2.24 Hz), 7.12 (dd, 1H, J=8.45, 2.24
Hz), 6.54 (d, 1H, J=8.45 Hz), 4.58 (s, 2H), 4.26 (s, 2H), 3.73 (s,
3H), 3.52 (m, 6H), 2.52 (t, 4H, J=4.83 Hz), 2.19 (s, 3H),
[0743] Ethyl
(4-{[(4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-phenyl--
1,3-thiazol-5-yl)methyl]sulfanyl}-2-methylphenoxy)acetate
[0744] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta.7.88 (m, 2H), 7.40
(m, 3H), 7.25 (d, 1H, J=2.39 Hz), 7.17 (dd, 1H, J=8.37, 2.39 Hz),
6.89 (d, 2H, J=9.06 Hz), 6.81 (d, 2H, J=9.06 Hz), 6.58 (d, 1H,
J=8.37 Hz), 4.59 (s, 2H), 4.32 (s, 2H), 4.23 (q, 2H, J=7.12 Hz),
3.74 (s, 3H), 3.56 (s, 2H), 3.06 (m, 4H), 2.62 (m, 4H), 2.24 (s,
3H), 1.27 (t, 3H, J=7.12 Hz),
[0745] Ethyl
2-(4-{[(4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-pheny-
l-1,3-thiazol-5-yl)methyl]sulfanyl}-2-methylphenoxy)propanoate
[0746] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta.3.88 (m, 2H), 7.40
(m, 3H), 7.25 (d, 1H, J=2.39 Hz), 7.14 (dd, 1H, J=8.37, 2.39 Hz),
6.89 (d, 2H, J=9.40 Hz), 6.82 (d, 2H, J=9.40 Hz), 6.57 (d, 1H,
J=8.37 Hz), 4.70 (q, 1H, J=6.84 Hz), 4.32 (s, 2H), 4.17 (q, 2H,
J=7.18 Hz), 3.76 (s, 3H), 3.56 (s, 2H), 3.08 (m, 4H), 2.63 (m, 4H),
2.23 (m, 3H), 1.61 (d, 3H, J=6.84 Hz), 1.25 (t, 3H, J=7.18 Hz),
[0747] Ethyl
2-(4-{[4-{[(4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-pheny-
l-1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)-2-methylpropanoate
[0748] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.87 (m, 2H), 7.40
(m, 3H), 7.28 (d, 2H, J=8.89 Hz), 6.89 (d, 2H, J=9.23 Hz), 6.82 (d,
2H, J=9.23 Hz), 6.75 (d, 2H, J=8.89 Hz), 4.33 (s, 2H), 4.19 (q, 2H,
J=7.18 Hz), 3.76 (s, 3H), 3.56 (s, 2H), 3.09 (br s, 4H), 2.65 (br
s, 4H), 1.58 (s, 6H), 1.20 (t, 3H, J=7.18 Hz),
[0749] Ethyl
2-{4-[({4-{[4-(2-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(t-
rifluoromethyl)phenyl]-1,3-thiazol-5-yl)methyl)sulfanyl]-2-methylphenoxy}p-
ropanoate
[0750] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.03 (d, 2H, J=8.28
Hz), 7.69 (d, 2H, J=8.28 Hz), 7.28 (d, 1H, J=2.21 Hz), 7.17 (dd,
1H, J=8.28, 2.21 Hz), 7.00 (m, 3H), 6.88 (d, 1H, J=7.73 Hz), 6.61
(d, 1H, J=8.28 Hz), 4.74 (q, 1H, J=6.81 Hz), 4.39 (s, 2H), 4.21 (q,
2H, J=7.17 Hz), 3.89 (s, 3H), 3.63 (s, 2H), 3.12 (br s, 4H), 2.72
(br s, 4H), 2.27 (s, 3H), 1.65 (d, 3H, J=6.81 Hz), 1.26 (t, 3H,
J=7.17 Hz),
[0751] Ethyl
2-[2-methyl-4-({[2-[4-(trifluoromethyl)phenyl]-4-({4-[3-(trif-
luoromethyl)phenyl]-1-piperazinyl}methyl)-1,3-thiazol-5-yl]methyl}sulfanyl-
)phenoxy]propanoate
[0752] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.03 (d, 2H, J=8.28
Hz), 7.70 (d, 2H, J=8.28 Hz), 7.36 (t, 1H, J=8.00 Hz), 7.29 (d, 1H,
J=2.21 Hz), 7.13 (m, 4H), 6.61 (d, 1H, J=8.28 Hz), 4.74 (q, 1H,
J=6.90 Hz), 4.36 (s, 2H), 4.18 (q, 2H, J=7.08 Hz), 3.62 (s, 2H),
3.26 (t, 4H, J=4.83 Hz), 2.65 (t, 4H, J=4.83 Hz), 2.26 (s, 3H),
1.65 (d, 3H, J=6.90 Hz), 1.27 (t, 3H, J=7.08 Hz),
[0753] Ethyl
2-{2-methyl-4-[({4-({4-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1-pipe-
razinyl}methyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulf-
anyl]phenoxy}propanoate
[0754] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.96 (d, 2H, J=8.28
Hz), 7.63 (d, 2H, J=8.28 Hz), 7.20 (d, 1H, J=2.21 Hz), 7.10 (dd,
1H, J=8.28, 2.21 Hz), 6.56 (d, 1H, J=8.28 Hz), 4.69 (q, 1H, J=6.71
Hz), 4.30 (s, 2H), 4.16 (q, 2H, J=7.08 Hz), 3.47 (m, 8H), 3.10 (s,
2H), 2.54 (m, 6H), 2.20 (s, 3H), 1.85 (m, 4H), 1.60 (d, 3H, J=6.71
Hz), 1.20 (t, 3H, J=7.08 Hz),
[0755] Ethyl
2-{2-methyl-4-[({4-{[4-(2-pyrimidinyl)-1-piperazinyl]methyl}--
2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}pro-
panoate
[0756] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.31 (d, 2H, J=4.69
Hz), 8.01 (d, 2H, J=8.28 Hz), 7.68 (d, 2H, J=8.28 Hz), 7.27 (d, 1H,
J=2.21 Hz), 7.16 (dd, 1H, J=8.28, 2.21 Hz), 6.60 (d, 1H, J=8.28
Hz), 6.48 (t, 1H, J=4.69 Hz), 4.74 (q, 1H, J=6.71 Hz), 4.35 (s,
2H), 4.20 (q, 2H, J=7.08 Hz), 3.85 (t, 4H, J=4.97 Hz), 3.57 (s,
2H), 2.54 (t, 4H, J=4.97 Hz), 2.24 (s, 3H), 1.64 (d, 3H, J=6.71
Hz), 1.24 (t, 3H, J=7.08 Hz),
[0757] Ethyl
2-{2-methyl-4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2--
[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propa-
noate
[0758] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.14 (m, 1H), 8.06
(m, 1H), 8.01 (d, 2H, J=8.28 Hz), 7.85 (d, 1H, J=2.48 Hz), 7.67 (d,
2H, J=8.28 Hz), 7.27 (d, 1H, J=2.21 Hz), 7.15 (dd, 1H, J=8.28, 2.21
Hz), 6.59 (d, 1H, J=8.28 Hz), 4.73 (q, 1H, J=6.71 Hz), 4.33 (s,
2H), 4.16 (q, 2H, J=7.17 Hz), 3.60 (m, 6H), 2.58 (t, 4H, J=4.83
Hz), 2.25 (s, 3H), 1.64 (d, 3H, J=6.71 Hz), 1.25 (t, 3H, J=7.17
Hz),
[0759] Ethyl
2-[2-methyl-4-({[2-[4-(trifluoromethyl)phenyl]-4-({4-[4-(trif-
luoromethyl)phenyl]-1-piperazinyl}methyl)-1,3-thiazol-5-yl]methyl}sulfanyl-
)phenoxy]propanoate
[0760] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.03 (d, 2H, J=8.28
Hz), 7.70 (d, 2H, J=8.28 Hz), 7.51 (d, 2H, J=8.55 Hz), 7.28 (d, 1H,
J=2.21 Hz), 7.18 (dd, 1H, J=8.28, 2.21 Hz), 6.94 (d, 2H, J=8.55
Hz), 6.61 (d, 1H, J=8.28 Hz), 4.74 (q, 1H, J=6.71 Hz), 4.35 (s,
2H), 4.21 (q, 2H, J=7.17 Hz), 3.62 (s, 2H), 3.33 (t, 4H, J=4.55
Hz), 2.66 (t, 4H, J=4.55 Hz), 2.27 (s, 3H), 1.66 (d, 3H, J=6.71
Hz), 1.26 (t, 3H, J=7.17 Hz),
[0761] Ethyl
2-{4-[({4-[(4-acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromet-
hyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-isopropylphenoxy}propanoat-
e
[0762] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.94 (d, 2H, J=8.10
Hz), 7.64 (d, 2H, J=8.10 Hz), 7.17 (d, 1H, J=2.24 Hz), 7.11 (dd,
1H, J=8.45, 2.24 Hz), 6.54 (d, 1H, J=8.45 Hz), 4.72 (q, 1H, J=6.78
Hz), 4.23 (s, 2H), 4.14 (q, 2H, J=7.13 Hz), 3.59 (s, 2H), 3.42 (br
s, 4H), 3.30 (m, 1H), 2.42 (br s, 4H), 2.04 (s, 3H), 1.59 (d, 3H,
J=6.78 Hz), 1.17 (m, 9H),
[0763] Ethyl
2-{4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-isopropylphenoxy-
}propanoate
[0764] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.28
Hz), 7.64 (d, 2H, J=8.28 Hz), 7.20 (d, 1H, J=2.24 Hz), 7.13 (dd,
1H, J=8.45, 2.24 Hz), 6.92 (m, 2H), 6.83 (m, 2H), 6.55 (d, 1H,
J=8.45 Hz), 4.71 (q, 1H, J=6.78 Hz), 4.28 (s, 2H), 4.14 (q, 2H,
J=7.18 Hz), 3.48 (s, 2H), 3.31 (m, 1H), 3.07 (t, 4H, J=4.83 Hz),
2.59 (br s, 4H), 1.59 (d, 3H, J=6.78 Hz), 1.15 (m, 9H),
[0765] Ethyl
2-{2-isopropyl-4-[({4-(4-morpholinylmethyl)-2-[4-(trifluorome-
thyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
[0766] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.95 (d, 2H, J=8.28
Hz), 7.63 (d, 2H, J=8.28 Hz), 7.19 (d, 1H, J=2.24 Hz), 7.12 (dd,
1H, J=8.45, 2.24 Hz), 6.55 (d, 1H, J=8.45 Hz), 4.71 (q, 1H, J=6.78
Hz), 4.26 (s, 2H), 4.14 (q, 2H, J=7.13 Hz), 3.67 (m, 4H), 3.41 (s,
2H), 3.30 (m, 1H), 2.42 (br s, 4H), 1.59 (d, 3H, J=6.78 Hz), 1.16
(m, 9H),
[0767] Ethyl
2-{2-methyl-4-[({4-(1-piperazinylmethyl)-2-[4-(trifluoromethy-
l)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy)propanoate
[0768] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.01 (d, 2H, J=8.23
Hz), 7.67 (d, 2H, J=8.23 Hz), 7.27 (d, 1H, J=2.39 Hz), 7.15 (dd,
1H, J=8.23, 2.39 Hz), 6.59 (d, 1H, J=8.23 Hz), 4.73 (q, 1H, J=6.64
Hz), 4.34 (s, 2H), 4.20 (q, 2H, J=7.08 Hz), 3.52 (s, 2H), 2.91 (t,
4H, J=4.91 Hz), 2.46 (m, 4H), 2.33 (br s, 1H), 2.26 (s, 3H), 1.64
(d, 3H, J=6.64 Hz), 1.25 (t, 3H, J=7.08 Hz),
[0769] tert-Butyl
4-({5-({[4-(2-ethoxy-1-methyl-2-oxoethoxy)-3-methylpheny-
l]sulfanyl}methyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)--
1-piperazinecarboxylate
[0770] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.01 (d, 2H, J=8.23
Hz), 7.68 (d, 2H, J=8.23 Hz), 7.27 (d, 1H, J=2.39 Hz), 7.15 (dd,
1H, J=8.49, 2.39 Hz), 6.60 (d, 1H, J=8.49 Hz), 4.74 (q, 1H, J=6.72
Hz), 4.33 (s, 2H), 4.22 (q, 2H, J=7.08 Hz), 3.54 (s, 2H), 3.46 (m,
4H), 2.44 (m, 4H), 2.27 (s, 3H), 1.65 (d, 3H, J=6.72 Hz), 1.48 (s,
9H), 1.26 (t, 3H, J=7.08 Hz),
[0771] Ethyl
2-(4-[({4-{[4-(4-chlorophenyl)-1-piperazinyl]methyl}-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}pr-
opanoate
[0772] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.03 (d, 2H, J=8.23
Hz), 7.70 (d, 2H, J=8.23 Hz), 7.22 (m, 4H), 6.86 (d, 2H, J=9.03
Hz), 6.61 (d, 1H, J=8.49 Hz), 4.73 (q, 1H, J=6.81 Hz), 4.36 (s,
2H), 4.18 (q, 2H, J=7.08 Hz), 3.61 (s, 2H), 3.17 (m, 4H), 2.64 (m,
4H), 2.27 (s, 3H), 1.65 (d, 3H, J=684 Hz), 1.27 (t, 3H, J=7.08
Hz),
[0773] Ethyl
24-[({4-[(3,5-dimethyl-1-piperazinyl)methyl]-2-[4-(trifluorom-
ethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
[0774] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.01 (d, 2H, J=8.23
Hz), 7.68 (d, 2H, J=8.23 Hz), 7.27 (d, 1H, J=2.39 Hz), 7.15 (dd,
1H, J=8.49, 2.39 Hz), 6.60 (d, 1H, J=8.49 Hz), 4.74 (q, 1H, J=6.72
Hz), 4.35 (s, 2H), 4.21 (q, 2H, J=7.08 Hz), 3.53 (s, 2H), 2.96 (m,
2H), 2.78 (m, 2H), 2.26 (s, 3H), 1.73 (m, 2H), 1.65 (d, 3H, J=6.72
Hz), 1.26 (t, 3H, J=7.08 Hz), 1.09 (d, 6H, J=6.37 Hz),
[0775] Ethyl
2-{4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(tr-
ifluoromethyl)phenyl-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy]pro-
panoate
[0776] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.03 (d, 2H, J=8.49
Hz), 7.70 (d, 2H, J=8.49 Hz), 7.28 (d, 1H, J=2.39 Hz), 7.18 (dd,
1H, J=8.23, 2.39 Hz), 6.94 (m, 4H), 6.62 (d, 1H, J=8.23 Hz), 4.74
(q, 1H, J=6.72 Hz), 4.37 (s, 2H), 4.21 (q, 2H, J=7.08 Hz), 3.63 (s,
2H), 3.14 (t, 4H, J=4.51 Hz), 2.67 (t, 4H, J=4.51 Hz), 2.28 (s,
3H), 1.65 (d, 3H, J=6.72 Hz), 1.26 (t, 3H, J=7.08 Hz),
[0777] Ethyl
2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}pr-
opanoate
[0778] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.02 (d, 2H, J=8.23
Hz), 7.89 (d, 2H, J=8.76 Hz), 7.69 (d, 2H, J=8.23 Hz), 7.28 (br s,
1H), 7.17 (dd, 1H, J=8.23, 2.39 Hz), 6.88 (d, 2H, J=8.76 Hz), 6.60
(d, 1H, J=8.23 Hz), 4.73 (q, 1H, J=6.81 Hz), 4.34 (s, 2H), 4.18 (q,
2H, J=7.17 Hz), 3.60 (s, 2H), 3.37 (m, 4H), 2.63 (m, 4H), 2.54 (s,
3H), 2.26 (s, 3H), 1.65 (d, 3H, J=6.81 Hz), 1.27 (t, 3H, J=7.17
Hz),
[0779] Ethyl
4-({5-({[4-(2-ethoxy-1-methyl-2-oxoethoxy)-3-methylphenyl]sul-
fanyl}methyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)-1-pip-
erazinecarboxylate
[0780] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.00 (d, 2H, J=8.23
Hz), 7.68 (d, 2H, J=8.23 Hz), 7.27 (d, 1H, J=2.39 Hz), 7.14 (dd,
1H, J=8.23, 2.39 Hz), 6.60 (d, 1H, J=8.23 Hz), 4.73 (q, 1H, J=6.81
Hz), 4.31 (s, 2H), 4.18 (m, 4H), 3.50 (m, 6H), 2.44 (m, 4H), 2.26
(s, 3H), 1.65 (d, 3H, J=6.81 Hz), 1.26 (m, 6H),
[0781] Ethyl
2-{2-methyl-4-[({4-(4-morpholinylmethyl)-2-[4-(trifluoromethy-
l)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
[0782] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.01 (d, 2H, J=8.23
Hz), 7.68 (d, 2H, J=8.23 Hz), 7.27 (d, 1H, J=2.39 Hz), 7.16 (dd,
1H, J=8.49, 2.39 Hz), 6.60 (d, 1H, J=8.49 Hz), 4.73 (q, 1H, J=6.72
Hz), 4.34 (s, 2H), 4.21 (q, 2H, J=7.08 Hz), 3.73 (t, 4H, J=4.51
Hz), 3.54 (s, 2H), 2.49 (t, 4H, J=4.51 Hz), 2.26 (s, 3H), 1.65 (d,
3H, J=6.72 Hz), 1.26 (t, 3H, J=7.08 Hz),
[0783] Ethyl
2-{4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}pr-
opanoate
[0784] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.04 (d, 2H, J=8.23
Hz), 7.70 (d, 2H, J=8.23 Hz), 7.28 (m, 1H), 7.18 (m, 2H), 6.62 (d,
1H, J=8.23 Hz), 6.56 (dd, 1H, J=8.23, 2.39 Hz), 6.50 (t, 1H, J=2.26
Hz), 6.45 (dd, 1H, J=8.23, 2.39 Hz), 4.74 (q, 1H, J=6.81 Hz), 4.37
(s, 2H), 4.21 (q, 2H, J=7.08 Hz), 3.82 (s, 3H), 3.61 (s, 2H), 3.22
(t, 4H, J=4.65 Hz), 2.65 (t, 4H, J=4.65 Hz), 2.28 (s, 3H), 1.66 (d,
3H, J=6.81 Hz), 1.26 (t, 3H, J=7.08 Hz),
[0785] Ethyl
2-{4-[({4-[(4-acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromet-
hyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}propanoate
[0786] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.95 (d, 2H, J=8.06
Hz), 7.63 (d, 2H, J=8.06 Hz), 7.16 (d, 1H, J=2.38 Hz), 7.11 (dd,
1H, J=8.24, 2.38 Hz), 6.55 (d, 1H, J=8.24 Hz), 4.70 (q, 1H, J=6.84
Hz), 4.23 (s, 2H), 4.13 (q, 2H, J=7.14 Hz), 3.59 (br s, 2H), 3.47
(s, 2H), 3.40 (t, 2H, J=4.58 Hz), 2.55 (t, 2H, J=7.33 Hz), 2.40(ml,
1H), 2.05 (s, 3H), 1.56 (m, 5H), 1.20 (t, 3H, J=7.14 Hz), 0.86 (t,
3H, J=7.33 Hz),
[0787] Ethyl
2-{4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}pr-
opanoate
[0788] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.24
Hz), 7.64 (d, 2H, J=8.24 Hz), 7.19 (d, 1H, J=2.38 Hz), 7.14 (dd,
1H, J=8.42, 2.38 Hz), 6.93 (m, 2H), 6.84 (m, 2H), 6.56 (d, 1H,
J=8.42 Hz), 4.69 (q, 1H, J=6.78 Hz), 4.30 (s, 2H), 4.14 (q, 2H,
J=7.14 Hz), 3.54 (s, 2H), 3.07 (t, 4H, J=4.58 Hz), 2.58 (m, 6H),
1.57 (m, 5H), 1.22 (t, 3H, J=7.14 Hz), 0.86 (t, 3H, J=7.33 Hz),
[0789] Ethyl
2-{4-[({4-(4-morpholinylmethyl)-2-[4-(trifluoromethyl)phenyl]-
-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}propanoate
[0790] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.95 (d, 2H, J=8.24
Hz), 7.63 (d, 2H, J=8.24 Hz), 7.17 (d, 1H, J=2.38 Hz), 7.12 (dd,
1H, J=8.42, 2.38 Hz), 6.55 (d, 1H, J=8.42 Hz), 4.69 (q, 1H, J=6.78
Hz), 4.27 (s, 2H), 4.14 (q, 2H, J=7.14 Hz), 3.66 (t, 4H, J=4.67
Hz), 3.45 (s, 2H), 2.56 (t, 2H, J=7.33 Hz), 2.42 (m, 4H), 1.56 (m,
5H), 1.21 (t, 3H, J=7.14 Hz), 0.86 (t, 3H, J=7.33 Hz),
[0791] Methyl
{4-[({4-[(4-acetyl-1-piperazinyl)methyl]-2-[4-(trifluorometh-
yl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-isopropylphenoxy}acetate
[0792] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.95 (d, 2H, J=8.61
Hz), 7.64 (d, 2H, J=8.61 Hz), 7.20 (d, 1H, J=2.20 Hz), 7.15 (dd,
1H, J=8.42, 2.20 Hz), 6.59 (d, 1H, J=8.42 Hz), 4.63 (s, 2H), 4.25
(s, 2H), 3.76 (s, 3H), 3.56 (s, 2H), 3.41 (m, 4H), 3.31 (m, 1H),
2.38 (m, 4H), 2.05 (s, 3H), 1.11 (d, 6H, J=6.78 Hz),
[0793] Methyl
{4-[({4-{(4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(tri-
fluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-isopropylphenoxy}-
acetate
[0794] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.98 (d, 2H, J=8.24
Hz), 7.65 (d, 2H, J=8.24 Hz), 7.23 (d, 1H, J=2.20 Hz), 7.18 (dd,
1H, J=8.42, 2.20 Hz), 6.94 (m, 2H), 6.83 (m, 2H), 6.60 (d, 1H,
J=8.42 Hz), 4.61 (s, 2H), 4.30 (s, 2H), 3.76 (s, 3H), 3.49 (s, 2H),
3.34 (m, 1H), 3.07 (t, 4H, J=4.58 Hz), 2.59 (m, 4H), 1.13 (d, 6H,
J=6.96 Hz),
[0795] Methyl
{2-isopropyl-4-[({4-(4-morpholinylmethyl)-2-[4-(trifluoromet-
hyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
[0796] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.96 (d, 2H, J=8.24
Hz), 7.64 (d, 2H, J=8.24 Hz), 7.21 (d, 1H, J=2.38 Hz), 7.16 (dd,
1H, J=8.42, 2.38 Hz), 6.59 (d, 1H, J=8.42 Hz), 4.62 (s, 2H), 4.28
(s, 2H), 3.76 (s, 3H), 3.66 (t, 4H, J=4.58 Hz), 3.41 (s, 2H), 3.32
(m, 1H), 2.42 (m, 4H), 1.15 (d, 6H, J=6.96 Hz),
[0797] Methyl
{2-isopropyl-4-[({4-{[4(4-methoxyphenyl)-1-piperazinyl]methy-
l)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-
acetate
[0798] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.98 (d, 2H, J=8.24
Hz), 7.65 (d, 2H, J=8.24 Hz), 7.23 (d, 1H, J=2.20 Hz), 7.18 (dd,
1H, J=8.42, 2.20 Hz), 6.87 (d, 2H, J=9.16 Hz), 6.81 (d, 2H, J=9.16
Hz), 6.60 (d, 1H, J=8.42 Hz), 4.61 (m, 2H), 4.31 (s, 2H), 3.77 (s,
3H), 3.74 (s, 3H), 3.50 (s, 2H), 3.33 (m, 1H), 3.05 (m, 4H), 2.60
(br s, 4H), 1.15 (d, 6H, J=6.96 Hz),
[0799] Methyl
{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(tri-
fluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-isopropylphenoxy}-
acetate
[0800] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.95 (d, 2H, J=8.28
Hz), 7.84 (d, 2H, J=9.14 Hz), 7.62 (d, 2H, J=8.28 Hz), 7.21 (d, 1H,
J=2.24 Hz), 7.16 (dd, 1H, J=8.45, 2.24 Hz), 6.80 (d, 2H, J=9.14
Hz), 6.58 (d, 1H, J=8.45 Hz), 4.59 (s, 2H), 4.27 (s, 2H), 3.73 (s,
3H), 3.46 (s, 2H), 3.30 (m, 5H), 2.54 (t, 4H, J=4.57 Hz), 2.47 (s,
3H), 1.12 (d, 6H, J=6.90 Hz),
[0801] Methyl
{2-isopropyl-4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]meth-
yl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy-
}acetate
[0802] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.98 (d, 2H, J=8.28
Hz), 7.65 (d, 2H, J=8.28 Hz), 7.24 (d, 1H, J=2.38 Hz), 7.19 (dd,
1H, J=8.42, 2.38 Hz), 7.14 (t, 1H, J=8.24 Hz), 6.60 (d, 1H, J=8.42
Hz), 6.51 (dd, 1H, J=8.24, 2.38 Hz), 6.44 (t, 1H, J=2.29 Hz), 6.39
(dd, 1H, J=8.24, 2.38 Hz), 4.62 (s, 2H), 4.30 (s, 2H), 3.75 (m,
6H), 3.48 (s, 2H), 3.34 (m, 1H), 3.16 (t, 4H, J=4.67 Hz), 2.57 (t,
4H, J=4.67 Hz), 1.14 (d, 6H, J=6.78 Hz),
[0803] Ethyl
2-{2-isopropyl-4-[({4-{[4(4-methoxyphenyl)-1-piperazinyl]meth-
yl}-2-(4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy-
}propanoate
[0804] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.04 (d, 2H, J=8.24
Hz), 7.71 (d, 2H, J=8.24 Hz), 7.16 (m, 2H), 6.87 (d, 2H, J=9.16
Hz), 6.78 (d, 2H, J=9.16 Hz), 6.64 (d, 1H, J=8.42 Hz), 4.81 (q, 1H,
J=6.71 Hz), 4.27 (s, 2H), 4.11 (q, 2H, J=7.08 Hz), 3.69 (s, 3H),
3.28 (m, 3H), 2.96 (t, 4H, J=4.94 Hz), 2.51 (t, 4H, J=4.94 Hz),
1.54 (d, 3H, J=6.71 Hz), 1.12 (m, 9H),
[0805] Ethyl
2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-isopropylphenoxy-
}propanoate
[0806] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.96 (d, 2H, J=8.28
Hz), 7.83 (d, 2H, J=9.14 Hz), 7.64 (d, 2H, J=8.28 Hz), 7.19 (d, 1H,
J=2.24 Hz), 7.12 (dd, 1H, J=8.45, 2.24 Hz), 6.81 (d, 2H, J=9.14
Hz), 6.55 (d, 1H, J=8.45 Hz), 4.71 (q, 1H, J=6.78 Hz), 4.26 (s,
2H), 4.12 (q, 2H, J=7.16 Hz), 3.47 (s, 2H), 3.29 (m, 5H), 2.56 (br
s, 4H), 2.48 (s, 3H), 1.58 (d, 3H, J=6.78 Hz), 1.15 (m, 9H),
[0807] Ethyl 2-{2-isopropyl-4-[({4-{[4-(3-meth
xyphenyl)-1-piperazinyl]met-
hyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenox-
y}propanoate
[0808] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.98 (d, 2H, J=8.24
Hz), 7.65 (d, 2H, J=8.24 Hz), 7.21 (d, 1H, J=2.38 Hz), 7.14 (m,
2H), 6.58 (d, 1H, J=8.61 Hz), 6.51 (dd, 1H, J=8.24, 2.20 Hz), 6.43
(t, 1H, J=2.29 Hz), 6.39 (dd, 1H, J=8.24, 2.20 Hz), 4.72 (q, 1H,
J=6.78 Hz), 4.29 (s, 2H), 4.15 (q, 2H, J=7.14 Hz), 3.76 (s, 3H),
3.48 (s, 2H), 3.33 (m, 1H), 3.16 (br s, 4H), 2.59 (br s, 4H), 1.60
(d, 3H, J=6.78 Hz), 1.16 (m, 9H),
[0809] Ethyl
{4-[({4-(4-morpholinylmethyl)-2-[4-(trifluoromethyl)phenyl]-1-
,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}acetate
[0810] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.95 (d, 2H, J=8.24
Hz), 7.63 (d, 2H, J=8.24 H), 7.19 (m, 2H), 6.58 (d, 1H, J=8.24 Hz),
4.59 (s, 2H), 4.28 (s, 2H), 4.21 (q, 2H, J=7.14 Hz), 3.66 (t, 4H,
J=4.49 Hz), 3.45 (s, 2H), 2.56 (t, 2H, J=7.33 Hz), 2.42 (m, 4H),
1.56 (m, 2H), 1.24 (t, 3H, J=7.14 Hz), 0.87 (t, 3H, J=7.33 Hz),
[0811] Ethyl
{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trif-
luoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-ethylphenoxy}aceta-
te
[0812] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.24
Hz), 7.83 (d, 2H, J=9.16 Hz), 7.63 (d, 2H, J=8.24 Hz), 7.21 (d, 1H,
J=2.20 Hz), 7.16 (dd, 1H, J=8.42, 2.20 Hz), 6.82 (d, 2H, J=9.16
Hz), 6.59 (d, 1H, J=8.42 Hz), 4.59 (s, 2H), 4.29 (s, 2H), 4.21 (q,
2H, J=7.14 Hz), 3.52 (s, 2H), 3.31 (t, 4H, J=4.80 Hz), 2.64 (q, 2H,
J=7.51 Hz), 2.55 (t, 4H, J=4.80 Hz), 2.47 (s, 3H), 1.24 (t, 3H,
J=7.14 Hz), 1.14 (t, 3H, J=7.51 Hz),
[0813] Ethyl {2-ethyl-4-[({4-{[4-(3-methoxyphenyl)-1
piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl-
)sulfanyl]phenoxy}acetate
[0814] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.98 (d, 2H, J=8.24
Hz), 7.65 (d, 2H, J=8.24 Hz), 7.22 (s, 1H), 7.16 (m, 2H), 6.60 (d,
1H, J=8.42 Hz), 6.51 (d, 1H, J=8.42 Hz), 6.44 (s, 1H), 6.39 (dd,
1H, J=8.24, 1.28 Hz), 4.60 (s, 2H), 4.32 (s, 2H), 4.22 (q, 2H,
J=7.14 Hz), 3.76 (s, 3H), 3.52 (s, 2H), 3.16 (t, 4H, J=4.67 Hz),
2.65 (q, 2H, J=7.51 Hz), 2.57 (t, 4H, J=4.67 Hz), 1.26 (t, 3H,
J=7.14 Hz), 1.16 (t, 3H, J=7.51 Hz),
[0815] Ethyl
{4-[({4-[(4-acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromethy-
l)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-ethylphenoxy}acetate
[0816] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.93 (d, 2H, J=8.28
Hz), 7.61 (d, 2H, J=8.28 Hz), 7.16 (d, 1H, J=2.24 Hz), 7.12 (dd,
1H, J=8.28, 2.24 Hz), 6.56 (d, 1H, J=8.28 Hz), 4.58 (s, 2H), 4.20
(m, 4H), 3.55 (t, 4H, J=4.91 Hz), 3.43 (s, 2H), 3.37 (t, 4H, J=4.91
Hz), 2.60 (q, 2H, J=7.50 Hz), 2.02 (s, 3H), 1.22 (t, 3H, J=7.14
Hz), 1.11 (t, 3H, J=7.50 Hz),
[0817] Ethyl
{2-ethyl-4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2--
[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl)methyl)sulfanyl]phenoxy}aceta-
te
[0818] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.03 (d, 2H, J=8.28
Hz), 7.69 (d, 2H, J=8.28 Hz), 7.25 (m, 2H), 6.93 (m, 4H), 6.64 (d,
1H, J=8.28 Hz), 4.64 (s, 2H), 4.36 (s, 2H), 4.26 (q, 2H, J=7.08
Hz), 3.58 (s, 2H), 3.11 (t, 4H, J=4.97 Hz), 2.66 (m, 6H), 1.29 (t,
3H, J=7.08 Hz), 1.19 (t, 3H, J=7.54 Hz),
[0819] Ethyl
{2-ethyl-4-[({4-(4-morpholinylmethyl)-2-[4-(trifluoromethyl)p-
henyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
[0820] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.01 (d, 2H, J=8.28
Hz), 7.68 (d, 2H, J=8.28 Hz), 7.24 (m, 2H), 6.63 (d, 1H, J=8.28
Hz), 4.64 (s, 2H), 4.34 (s, 2H), 4.26 (q, 2H, J=7.17 Hz), 3.70 (t,
4H, J=4.42 Hz), 3.49 (s, 2H), 2.67 (q, 2H, J=7.54 Hz), 2.46 (t, 4H,
J=4.42 Hz), 1.30 (t, 3H, J=7.17 Hz), 1.19 (t, 3H, J=7.54 Hz),
[0821] Ethyl
2-{2-ethyl-4-[({4-{[4(4-methoxyphenyl)-1-piperazinyl]methyl}--
2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}pro-
panoate
[0822] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.03 (d, 2H, J=8.28
Hz), 7.70 (d, 2H, J=8.28 Hz), 7.26 (d, 1H, J=2.21 Hz), 7.19 (dd,
1H, J=8.28, 2.21 Hz), 6.93 (d, 2H, J=9.11 Hz), 6.86 (d, 2H, J=9.11
Hz), 6.62 (d, 1H, J=8.28 Hz), 4.76 (q, 1H, J=6.90 Hz), 4.36 (s,
2H), 4.19 (q, 2H, J=7.17 Hz), 3.80 (s, 3H), 3.58 (s, 2H), 3.11 (t,
4H, J=4.69 Hz), 2.67 (m, 6H), 1.65 (d, 3H, J=6.90 Hz), 1.24 (m,
6H),
[0823] Ethyl
2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-ethylphenoxy}pro-
panoate
[0824] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.02 (d, 2H, J=8.28
Hz), 7.89 (d, 2H, J=8.83 Hz), 7.69 (d, 2H, J=8.28 Hz), 7.25 (d, 1H,
J=2.21 Hz), 7.18 (dd, 1H, J=8.28, 2.21 Hz), 6.88 (d, 2H, J=8.83
Hz), 6.61 (d, 1H, J=8.28 Hz), 4.76 (q, 1H, J=6.90 Hz), 4.33 (s,
2H), 4.18 (q, 2H, J=7.17 Hz), 3.57 (s, 2H), 3.36 (m, 4H), 2.66 (m,
6H), 2.53 (s, 3H), 1.65 (d, 3H, J=6.90 Hz), 1.23 (m, 6H),
[0825] Ethyl
2-{2-ethyl-4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-
-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}pr-
opanoate
[0826] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.03 (d, 2H, J=8.28
Hz), 7.70 (d, 2H, J=8.28 Hz), 7.26 (d, 1H, J=2.21 Hz), 7.18 (m,
2H), 6.62 (d, 1H, J=8.28 Hz), 6.56 (dd, 1H, J=8.00, 1.66 Hz), 6.49
(m, 1H), 6.44 (dd, 1H, J=8.00, 1.66 Hz), 4.76 (q, 1H, J=6.62 Hz),
4.35 (s, 2H), 4.19 (q, 2H, J=7.17 Hz), 3.81 (s, 3H), 3.57 (s, 2H),
3.21 (t, 4H, J=4.83 Hz), 2.66 (m, 6H), 1.65 (d, 3H, J=6.62 Hz),
1.24 (m, 6H),
[0827] Ethyl
2-(4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(t-
rifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}p-
ropanoate
[0828] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.24
Hz), 7.64 (d, 2H, J=8.24 Hz), 7.19 (d, 1H, J=2.38 Hz), 7.14 (dd,
1H, J=8.42, 2.38 Hz), 6.88 (d, 2H, J=9.16 Hz), 6.81 (d, 2H, J=9.16
Hz), 6.56 (d, 1H, J=8.42 Hz), 4.70 (q, 1H, J=6.78 Hz), 4.31 (s,
2H), 4.15 (q, 2H, J=7.14 Hz), 3.74 (s, 3H), 3.54 (s, 2H), 3.05 (t,
4H, J=4.85 Hz), 2.57 (m, 6H), 1.56 (m, 5H), 1.20 (t, 3H, J=7.14
Hz), 0.86 (t, 3H, J=7.33 Hz),
[0829] Ethyl
2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}pr-
opanoate
[0830] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.95 (d, 2H, J=8.24
Hz), 7.84 (d, 2H, J=9.14 Hz), 7.63 (d, 2H, J=8.24 Hz), 7.17 (d, 1H,
J=2.24 Hz), 7.12 (dd, 1H, J=8.45, 2.24 Hz), 6.82 (d, 2H, J=9.14
Hz), 6.54 (d, 1H, J=8.45 Hz), 4.68 (q, 1H, J=6.78 Hz), 4.27 (s,
2H), 4.13 (q, 2H, J=7.07 Hz), 3.51 (m, 2H), 3.31 (t, 4H, J=4.91
Hz), 2.55 (m, 6H), 2.47 (s, 3H), 1.55 (m, 5H), 1.17 (t, 3H, J=7.07
Hz), 0.85 (t, 3H, J=7.41 Hz),
[0831] Ethyl
2-{4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(t-
rifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}p-
ropanoate
[0832] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.28
Hz), 7.64 (d, 2H, J=8.28 Hz), 7.15 (m, 3H), 6.56 (d, 1H, J=8.45
Hz), 6.50 (dd, 1H, J=8.10, 2.07 Hz), 6.43 (t, 1H, J=2.07 Hz), 6.39
(dd, 1H, J=8.10, 2.07 Hz), 4.70 (q, 1H, J=6.72 Hz), 4.29 (s, 2H),
4.14 (q, 2H, J=7.07 Hz), 3.76 (s, 3H), 3.52 (s, 2H), 3.16 (t, 4H,
J=4.83 Hz), 2.58 (m, 6H), 1.57 (m, 5H), 1.19 (t, 3H, J=7.07 Hz),
0.87 (t, 3H, J=7.33 Hz),
[0833] Ethyl
2-(4-{[(2-(4-fluorophenyl)-4-{[4-(4-methoxyphenyl)-1-piperazi-
nyl]methyl}-1,3-thiazol-5-yl)methyl]sulfanyl}-2-methylphenoxy)propanoate
[0834] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.85 (m, 2H), 7.22
(d, 1H, J=2.38 Hz), 7.09 (m, 3H), 6.87 (d, 2H, J=9.16 Hz), 6.81 (d,
2H, J=9.16 Hz), 6.56 (d, 1H, J=8.42 Hz), 4.68 (q, 1H, J=6.78 Hz),
4.30 (s, 2H), 4.16 (q, 2H, J=7.20 Hz), 3.74 (s, 3H), 3.53 (s, 2H),
3.07 (t, 4H, J=4.58 Hz), 2.62 (br s, 4H), 2.21 (s, 3H), 1.60 (d,
3H, J=6.78 Hz), 1.20 (t, 3H, J=7.20 Hz),
[0835] Ethyl
2-[4-({[4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-(4-flu-
orophenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]propanoate
[0836] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.85 (m, 4H), 7.23
(d, 1H, J=2.38 Hz), 7.09 (m, 3H), 6.83 (d, 2H, J=9.16 Hz), 6.55 (d,
1H, J=8.42 Hz), 4.68 (q, 1H, J=6.78 Hz), 4.27 (s, 2H), 4.16 (q, 2H,
J=7.14 Hz), 3.52 (s, 2H), 3.32 (t, 4H, J=4.94 Hz), 2.59 (br s, 4H),
2.49 (s, 3H), 2.21 (s, 3H), 1.60 (d, 3H, J=6.78 Hz), 1.21 (t, 3H,
J=7.14 Hz),
[0837] Ethyl
2-(4-{[(2-(4-fluorophenyl)-4-{[4-(3-methoxyphenyl)-1-piperazi-
nyl]methyl}-1,3-thiazol-5-yl)methyl]sulfanyl}-2-methylphenoxy)propanoate
[0838] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.85 (m, 2H), 7.23
(d, 1H, J=2.20 Hz), 7.11 (m, 4H), 6.56 (d, 1H, J=8.24 Hz), 6.51
(dd, 1H, J=8.24, 2.20 Hz), 6.44 (t, 1H, J=2.20 Hz), 6.39 (dd, 1H,
J=8.24, 2.20 Hz), 4.69 (q, 1H, J=6.78 Hz), 4.29 (s, 2H), 4.16 (q,
2H, J=7.14 Hz), 3.76 (s, 3H), 3.52 (s, 2H), 3.16 (t, 4H, J=4.76
Hz), 2.60 (br s, 4H), 2.21 (s, 3H), 1.59 (d, 3H, J=6.78 Hz), 1.22
(t, 3H, J=7.14 Hz),
[0839] Ethyl
4-{[5-({[4-(2-ethoxy-1-methyl-2-oxoethoxy)-3-methylphenyl]sul-
fanyl}methyl)-2-(4-fluorophenyl)-1,3-thiazol-4-yl]methyl}1-piperazinecarbo-
xylate
[0840] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.83 (m, 2H), 7.20
(d, 1H, J=2.20 Hz), 7.08 (m, 3H), 6.55 (d, 1H. J=8.42 Hz), 4.68 (q,
1H, J=6.78 Hz), 4.23 (s, 2H), 4.16 (q, 2H, J=7.14 Hz), 4.09 (q, 2H,
J=7.14 Hz), 3.42 (m, 6H), 2.38 (br s, 4H), 2.18 (s, 3H), 1.57 (d,
3H, J=6.78 Hz), 1.13 (m, 6H),
[0841] Ethyl
{2-ethyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-
-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acet-
ate
[0842] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.98 (d, 2H, J=8.24
Hz), 7.65 (d, 2H, J=8.24 Hz), 7.22 (s, 1H), 7.17 (d, 1H, J=8.42
Hz), 6.87 (d, 2H, J=9.16 Hz), 6.81 (d, 2H, J=9.16 Hz), 6.59 (d, 1H,
J=8.42 Hz), 4.60 (s, 2H), 4.32 (s, 2H), 4.22 (q, 2H, J=7.14 Hz),
3.74 (s, 3H), 3.53 (s, 2H), 3.05 (t, 4H, J=4.76 Hz), 2.62 (m, 6H),
1.26 (t, 3H, J=7.14 Hz), 1.16 (t, 3H, J=7.33 Hz),
[0843] Ethyl
2-{4-[({4-[(4-acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromet-
hyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-ethylphenoxy}propanoate
[0844] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.99 (d, 2H, J=8.28
Hz), 7.68 (d, 2H, J=8.28 Hz), 7.22 (d, 1H, J=2.21 Hz), 7.15 (dd,
1H, J=8.28, 2.21 Hz), 6.60 (d, 1H, J=8.28 Hz), 4.75 (q, 1H, J=6.81
Hz), 4.29 (s, 2H), 4.19 (q, 2H, J=7.17 Hz), 3.62 (t, 2H, J=4.69
Hz), 3.50 (s, 2H), 3.43 (t, 2H, J=4.69 Hz), 2.66 (q, 2H, J=7.45
Hz), 2.43 (br s, 4H), 2.09 (s, 3H), 1.64 (d, 3H, J=6.81 Hz), 1.22
(m, 6H),
[0845] Ethyl
2-{2-ethyl-4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}--
2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}pro-
panoate
[0846] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.03 (d, 2H, J=8.28
Hz), 7.69 (d, 2H, J=8.28 Hz), 7.26 (d, 1H, J=2.21 Hz), 7.19 (dd,
1H, J=8.55, 2.21 Hz), 6.94 (m, 4H), 6.62 (d, 1H, J=8.55 Hz), 4.75
(q, 1H, J=6.90 Hz), 4.35 (s, 2H), 4.19 (q, 2H, J=7.17 Hz), 3.58 (s,
2H), 3.12 (t, 4H, J=4.97 Hz), 2.66 (m, 6H), 1.64 (d, 3H, J=6.90
Hz), 1.24 (m, 6H),
[0847] Ethyl
2-{2-ethyl-4-[({4-(4-morpholinylmethyl)-2-[4-(trifluoromethyl-
)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
[0848] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.01 (d, 2H, J=8.28
Hz), 7.68 (d, 2H, J=8.28 Hz), 7.24 (d, 1H, J=2.21 Hz), 7.16 (dd,
1H, J=8.28, 2.21 Hz), 6.60 (d, 1H, J=8.28 Hz), 4.75 (q, 1H, J=6.62
Hz), 4.32 (s, 2H), 4.17 (s, 2H), 3.70 (t, 4H, J=4.42 Hz), 3.49 (s,
2H), 2.66 (q, 2H, J=7.54 Hz), 2.45 (t, 4H, J=4.42 Hz), 1.63 (d, 3H,
J=6.62 Hz), 1.22 (m, 6H),
[0849] Ethyl
{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(tri-
fluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}ace-
tate
[0850] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.03 (d, 2H, J=8.28
Hz), 7.69 (d, 2H, J=8.28 Hz), 7.23 (m, 2H), 6.89 (m, 4H), 6.64 (d,
1H, J=8.28 Hz), 4.62 (s, 2H), 4.36 (s, 2H), 4.26 (q, 2H, J=7.08
Hz), 3.79 (s, 3H), 3.60 (s, 2H), 3.11 (m, 4H), 2.64 (m, 6H), 1.62
(m, 2H), 1.30 (t, 3H, J=7.08 Hz), 0.93 (t, 3H, J=7.45 Hz),
[0851] Ethyl
{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trif-
luoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}acet-
ate
[0852] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.02 (d, 2H, J=8.28
Hz), 7.89 (d, 2H, J=9.11 Hz), 7.69 (d, 2H, J=8.28 Hz), 7.24 (m,
2H), 6.87 (d, 2H, J=9.11 Hz), 6.64 (d, 1H, J=8.28 Hz), 4.62(s 2H),
4.34 (s, 2H), 4.26 (q, 2H, J=7.17 Hz), 3.58 (s, 2H), 3.35 (t, 4H,
J=4.97 Hz), 2.62 (m, 6H), 2.54 (s, 3H), 1.61 (m, 2H), 1.29 (t, 3H,
J=7.17 Hz), 0.91 (t, 3H, J=7.45 Hz),
[0853] Ethyl
{4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(tri-
fluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}ace-
tate
[0854] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.28
Hz), 7.64 (d, 2H, J=8.28 Hz), 7.17 (m, 3H), 6.58 (d, 1H, J=8.10
Hz), 6.51 (dd, 1H, J=8.10, 2.07 Hz), 6.43 (t, 1H, J=2.07 Hz), 6.38
(dd, 1H, J=8.10, 2.07 Hz), 4.58 (s, 2H), 4.30 (s, 2H), 4.21 (q, 2H,
J=7.13 Hz), 3.75 (s, 3H), 3.53 (s, 2H), 3.15 (t, 4H, J=4.66 Hz),
2.57 (m, 6H), 1.57 (m, 2H), 1.24 (t, 3H, J=7.13 Hz), 0.87 (t, 3H,
J=7.41 Hz),
[0855] Ethyl
{4-[({4-[(4-acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromethy-
l)phenyl-11,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}acetate
[0856] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.93 (d, 2H, J=8.28
Hz), 7.62 (d, 2H, J=8.28 Hz), 7.14 (m, 2H), 6.57 (d, 1H, J=8.28
Hz), 4.58 (s, 2H), 4.20 (m, 4H), 3.56 (t, 2H, J=4.91 Hz), 3.45 (s,
2H), 3.38 (t, 2H, J=4.91 Hz), 2.55 (t, 2H, J=7.33 Hz), 2.37 (m,
4H), 2.03 (s, 3H), 1.53 (m, 2H), 1.22 (t, 3H, J=7.16 Hz), 0.85 (t,
3H, J=7.33 Hz),
[0857] Ethyl
{4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trif-
luoromethyl)phenyl]-1,3-thiazol-5-yl]methyl)sulfanyl]-2-propylphenoxy}acet-
ate
[0858] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.28
Hz), 7.64 (d, 2H, J=8.28 Hz), 7.19 (m, 2H), 6.92 (m, 2H), 6.83 (m,
2H), 6.58 (d, 1H, J=8.28 Hz), 4.56 (s, 2H), 4.29 (s, 2H), 4.20 (q,
2H, J=7.13 Hz), 3.53 (s, 2H), 3.06 (t, 4H, J=4.91 Hz), 2.57 (m,
6H), 1.55 (m, 2H), 1.24 (t, 3H, J=7.13 Hz), 0.86 (t, 3H, J=7.41
Hz),
[0859] Ethyl
2-{4-[({4-{[4-(2,4-dimethoxyphenyl)-1-piperazinyl]methyl}-2-[-
4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylpheno-
xy}propanoate
[0860] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.02 (d, 2H, J=8.28
Hz), 7.67 (d, 2H, J=8.28 Hz), 7.26 (d, 1H, J=2.21 Hz), 7.16 (dd,
1H, J=8.55, 2.21 Hz), 6.87 (d, 1H, J=8.55 Hz), 6.60 (d, 1H, J=8.55
Hz), 6.50 (d, 1H, J=2.48 Hz), 6.42 (dd, 1H, J=8.55, 2.48 Hz), 4.72
(q, 1H, J=6.90 Hz), 4.38 (s, 2H), 4.21 (q, 2H, J=7.08 Hz), 3.85 (s,
3H), 3.79 (s, 3H), 3.61 (s, 2H), 3.04 (br s, 4H), 2.70 (br s, 4H),
2.26 (s, 3H), 1.63 (d, 3H, J=6.90 Hz), 1.24 (t, 3H, J=7.04 Hz),
[0861] phenyl
4-({5-({[4-(2-ethoxy-1,1-dimethyl-2-oxoethoxy)phenyl]thio}me-
thyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)piperazine-1-c-
arboxylate
[0862] To a 500 ml 3-neck round-bottom flask equipped with a
magnetic stir-bar, low temperature thermometer with thermometer
adapter, addition funnel and N.sub.2 inlet was added ethyl
2-{4-[({4-(hydroxymethyl)-2-[4-(-
trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy)-2-methyl-
propanoate (300 mg, 0.59 mmoles, 1 eq) and dry CH.sub.2Cl.sub.2 (4
ml, 0.15M) and cooled to 0.degree. C. Methanesulfonyl chloride
(0.055 ml, 0.71 mmoles, 1.2 eq) was added neat all at once.
Triethylamine (0.12 ml, 0.89 mmoles, 1.5 eq) was added dropwise
maintaining the internal temperature below 5.degree. C. and was
stirred at 0.degree. C. for 30 minutes. The reaction mixture was
transferred to a separatory funnel and washed with H.sub.2O, brine
and the organic fraction was dried over Na.sub.2SO.sub.4. After
filtration the solvent was removed under reduced pressure to yield
the corresponding mesylate in quantitative yield. Because of the
unstable nature of the mesylate, the product was not characterized
and was progressed onto the next stage without purification.
[0863] To the crude mesylate dissolved in dry THF (3 ml, 0.20M) was
added piperazine (559 mg, 5.9 mmoles, 10 eq) and the reaction
mixture was refluxed for 5 hours. After cooling to room temperature
the solvent was removed in vacuo. The residue was partitioned
between EtOAc and H.sub.2O and after the phases were separated the
organic fraction was dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to yield a quantitative amount of product.
The product was used without characterization and purification.
[0864] The crude piperazine was dissolved In dry CH.sub.2Cl.sub.2
(5 ml, 0.12M) and to it was added phenylchloroformate (0.08 ml,
0.65 mmoles, 1.1 eq) and triethylamine (0.248 ml, 1.8 mmoles, 3 eq)
and was stirred at room temperature overnight. The reaction mixture
was diluted with EtOAc and washed with 0.1N HCl twice, H.sub.2O,
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo to yield after silica gel chromatography 125 mg (32% over
three steps) of product.
[0865] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.95 (d, 2H, J=8.28
Hz), 7.65 (d, 2H, J=8.28 Hz), 7.33 (m, 2H), 7.26 (d, 2H, J=8.79
Hz), 7.17 (t, 1H, J=7.59 Hz), 7.06 (d, 2H, J=7.59 Hz), 6.74 (d, 2H,
J=8.79 Hz), 4.32 (s, 2H), 4.18 (q, 2H, J=7.07 Hz), 3.61 (m, 6H),
2.51 (br s, 4H), 1.57 (s, 6H), 1.20 (t, 3H, J=7.07 Hz),
[0866] The following compounds were made the same procedure used
for phenyl
4-({5-({[4-(2-ethoxy-1,1-dimethyl-2-oxoethoxy)phenyl]thio}methyl)--
2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)piperazine-1-carboxy-
late except no extra base was used when the other reactant was an
isocyanate.
[0867] Phenyl
4-({5-({[4-(2-ethoxy-1-methyl-2-oxoethoxy)-3-methylphenyl]su-
lfanyl}methyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)-1-pi-
perazinecarboxylate
[0868] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.97 (d, 2H, J=8.28
Hz), 7.77 (d, 2H, J=8.28 Hz), 7.60 (m, 5H), 7.20 (d, 1H, J=2.21
Hz), 7.10 (dd, 1H, J=8.55, 2.21 Hz), 6.57 (d, 1H, J=8.55 Hz), 4.74
(q, 1H, J=6.71 Hz), 4.20 (m, 4H), 3.48 (s, 2H), 3.06 (br s, 4H),
2.56 (br s, 4H), 2.24 (s, 3H), 1.65 (d, 3H, J=6.71 Hz), 1.25 (t,
3H, J=7.04 Hz),
[0869] benzyl
4-({5-({[4-(2-ethoxy-1-methyl-2-oxoethoxy)-3-methylphenyl]th-
io}methyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)piperazin-
e-1-carboxylate
[0870] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.01 (d, 2H, J=8.00
Hz), 7.69 (d, 2H, J=8.00 Hz), 7.36 (m, 5H), 7.26 (d, 1H, J=2.21
Hz), 7.15 (dd, 1H, J=8.55, 2.21 Hz), 6.60 (d, 1H, J=8.55 Hz), 5.16
(s, 2H), 4.74 (q, 1H, J=6.62 Hz), 4.31 (s, 2H), 4.21 (q, 2H, J=7.08
Hz), 3.55 (m, 6H), 2.47 (br s, 4H), 2.26 (s, 3H), 1.65 (d, 3H,
J=6.62 Hz), 1.25 (t, 3H, J=7.08 Hz),
[0871] Isopropyl
4-{[5-({[4-(2-ethoxy-1-methyl-2-oxoethoxy)-3-methylphenyl-
]sulfanyl}methyl)-2-(4-fluorophenyl)-1,3-thiazol-4-yl]methyl})1-piperazine-
carboxylate
[0872] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.84 (m, 2H), 7.22
(d, 1H, J=2.20 Hz), 7.09 (m, 3H), 6.55 (d, 1H, J=8.42 Hz), 4.89 (m,
1H), 4.68 (q, 1H, J=6.78 Hz), 4.26 (s, 2H), 4.16 (q, 2H, J=7.20
Hz), 3.47 (m, 6H), 2.40 (br s, 4H), 2.22 (s, 3H), 1.61 (d, 3H,
J=6.78 Hz), 1.27 (m, 9H),
[0873] Ethyl
2-{4-[({4-{[4-(cyclopentylcarbonyl)-1-piperazinyl]methyl}-2-[-
4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylpheno-
xy}propanoate
[0874] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.00 (d, 2H, J=8.28
Hz), 7.67 (d, 2H, J=8.28 Hz), 7.24 (d, 1H, J=2.21 Hz), 7.14 (dd,
1H, J=8.28, 2.21 Hz), 6.59 (d, 1H, J=8.28 Hz), 4.73 (q, 1H, J=6.71
Hz), 4.31 (s, 2H), 4.19 (q, 2H, J=7.17 Hz), 3.65 (br s, 2H), 3.50
(br s, 4H), 2.87 (m, 1H), 2.45 (t, 4H, J=4.69 Hz), 2.23 (s, 3H),
1.73 (m, 1H), 1.24 (t, 3H, J=7.17 Hz),
[0875] Ethyl
2-{4-[({4-{[4-(cyclopropylcarbonyl)-1-piperazinyl]methyl}-2-[-
4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylpheno-
xy}propanoate
[0876] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.00 (d, 2H, J=8.28
Hz), 7.68 (d, 2H, J=8.28 Hz), 7.27 (d, 1H, J=2.21 Hz), 7.15 (dd,
1H, J=8.28, 2.21 Hz), 6.59 (d, 1H, J=8.28 Hz), 4.73 (q, 1H, J=6.71
Hz), 4.31 (s, 2H), 4.20 (q, 2H, J=7.08 Hz), 3.67 (br s, 4H), 3.55
(s, 2H), 2.49 (br s, 4H), 2.26 (s, 3H), 1.74 (m, 1H), 1.64 (d, 3H,
J=6.71 Hz), 1.25 (t, 3H, J=7.08 Hz), 1.00 (m, 2H), 0.76 (m,
2H),
[0877] Ethyl
2-{4-[({4-{[4-(cyclobutylcarbonyl)-1-piperazinyl]methyl}-2-[4-
-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl)methyl)sulfanyl]-2-methylphenox-
y}propanoate
[0878] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.99 (d, 2H, J=8.28
Hz), 7.67 (d, 2H, J=8.28 Hz), 7.24 (d, 1H, J=2.21 Hz), 7.13 (dd,
1H, J=8.28, 2.21 Hz), 6.58 (d, 1H, J=8.28 Hz), 4.73 (q, 1H, J=6.71
Hz), 4.28 (s, 2H), 4.19 (q, 2H, J=7.17 Hz), 3.64 (t, 2H, J=4.83
Hz), 3.52 (s, 2H), 3.36 (t, 2H, J=4.83 Hz), 3.24 (m, 1H), 2.47 (m,
4H), 2.08 (m, 9H), 1.63 (d, 3H, J=6.71 Hz), 1.24 (t, 3H, J=7.17
Hz),
[0879] Methyl
4-({5-({[4-(2-ethoxy-1-methyl-2-oxoethoxy)-3-methylphenyl]su-
lfanyl}methyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)-1-pi-
perazinecarboxylate
[0880] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.00 (d, 2H, J=8.28
Hz), 7.68 (d, 2H, J=8.28 Hz), 7.26 (d, 1H, J=2.21 Hz), 7.14 (dd,
1H, J=8.28, 2.21 Hz), 6.59 (d, 1H, J=8.28 Hz), 4.73 (q, 1H, J=6.71
Hz), 4.31 (s, 2H), 4.20 (q, 2H, J=7.17 Hz), 3.71 (s, 3H), 3.50 (m,
6H), 2.44 (br s, 4H), 2.26 (s, 3H), 1.65 (d, 3H, J=6.71 Hz), 1.25
(t, 3H, J=7.17 Hz),
[0881] Ethyl
2-{2-methyl-4-[({4-{[4-(3-methylbutanoyl)-1-piperazinyl]methy-
l}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-
propanoate
[0882] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.00 (d, 2H, J=8.28
Hz), 7.67 (d, 2H, J=8.28 Hz), 7.24 (d, 1H, J=2.21 Hz), 7.14 (dd,
1H, J=8.55, 2.48 Hz), 6.59 (d, 1H, J=8.55 Hz), 4.73 (q, 1H, J=6.71
Hz), 4.30 (s, 2H), 4.20 (q, 2H, J=7.08 Hz), 3.65 (br s, 2H), 3.54
(s, 2H), 3.47 (t, 2H, J=4.69 Hz), 2.45 (t, 4H, J=4.83 Hz), 2.26 (s,
3H), 2.12 (m, 3H), 1.64 (d, 3H, J=6.71 Hz), 1.24 (t, 3H, J=7.08
Hz), 0.96 (d, 6H, J=6.35 Hz),
[0883] Ethyl
2-{4-[({(4-{[4-(4-fluorobenzoyl)-1-piperazinyl]methyl}-2-[4-(-
trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-
propanoate
[0884] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.00 (d, 2H, J=8.28
Hz), 7.69 (d, 2H, J=8.28 Hz), 7.43 (m, 2H), 7.24 (d, 1H, J=2.39
Hz), 7.11 (m, 3H), 6.59 (d, 1H, J=8.55 Hz), 4.73 (q, 1H, J=6.71
Hz), 4.30 (s, 2H), 4.19 (q, 2H, J=7.17 Hz), 3.65 (m, 6H), 2.53 (m,
4H), 2.25 (s, 3H), 1.64 (d, 3H, J=6.71 Hz), 1.25 (t, 3H, J=7.17
Hz),
[0885] Ethyl
2-{2-methyl-4-[({4-{[4-(propylsulfonyl)-1-piperazinyl]methyl}-
-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}pr-
opanoate
[0886] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta., 8.00 (d, 2H,
J=8.28 Hz), 7.68 (d, 2H, J=8.28 Hz), 7.26 (d, 1H, J=2.21 Hz), 7.15
(dd, 1H, J=8.28, 2.21 Hz), 6.59 (d, 1H, J=8.28 Hz), 4.74 (q, 1H,
J=6.71 Hz), 4.28 (s, 2H), 4.20 (q, 2H, J=7.08 Hz), 3.55 (s, 2H),
3.30 (t, 4H, J=4.55 Hz), 2.89 (m, 2H), 2.56 (t, 4H, J=4.28 Hz),
2.26 (s, 3H), 1.87 (m, 2H), 1.65 (d, 3H, J=6.62 Hz), 1.25 (t, 3H,
J=7.04 Hz), 1.07 (t, 3H, J=7.17 Hz).
[0887] Ethyl
2-{4-[({4-[(4-butyryl-1-piperazinyl)methyl]-2-[4-(trifluorome-
thyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
[0888] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.00 (d, 2H, J=8.28
Hz), 7.67 (d, 2H, J=8.28 Hz), 7.26 (d, 1H, J=2.21 Hz), 7.14 (dd,
1H, J=8.55, 2.21 Hz), 6.59 (d, 1H, J=8.55 Hz), 4.73 (q, 1H, J=6.71
Hz), 4.30 (s, 2H), 4.20 (q, 2H, J=7.08 Hz), 3.64 (m, 2H), 3.54 (s,
2H), 3.45 (t, 2H, J=4.83 Hz), 2.45 (t, 4H, J=4.83 Hz), 2.31 (t, 2H,
J=7.31 Hz), 2.25 (s, 3H), 1.66 (m, 5H), 1.24 (t, 3H, J=7.08 Hz),
0.98 (t, 3H, J=7.31 Hz),
[0889] Ethyl
2-{2-methyl-4-[({4-[(4-pentanoyl)1-piperazinyl)methyl]-2-[4-(-
trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoat-
e
[0890] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.00 (d, 2H, J=8.28
Hz), 7.67 (d, 2H, J=8.28 Hz), 7.26 (d, 1H, J=2.21 Hz), 7.14 (dd,
1H, J=8.28, 2.21 Hz), 6.58 (d, 1H, J=8.28 Hz), 4.73 (q, 1H, J=6.71
Hz), 4.30 (s, 2H), 4.19 (q, 2H, J=7.27 Hz), 3.64 (m, 2H), 3.54 (s,
2H), 3.46 (t, 2H, J=4.83 Hz), 2.45 (t, 4H, J=4.83 Hz), 2.32 (t, 2H,
J=7.45 Hz), 2.24 (s, 3H), 1.61 (m, 5H), 1.37 (m, 2H), 1.24 (t, 3H,
J=7.27 Hz), 0.93 (t, 3H, J=7.45 Hz),
[0891] Ethyl
2-{4-[({4-([4-(4-methoxybenzoyl)-1-piperazinyl]methyl}-2-[4-(-
trifluoromethyl)phenyl]-1,3-thiazol-5-yl)methyl)sulfanyl]-2-methylphenoxy}-
propanoate
[0892] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.00 (d, 2H, J=8.28
Hz), 7.67 (d, 2H, J=8.28 Hz), 7.40 (d, 2H, J=8.83 Hz), 7.24 (d, 1H,
J=2.21 Hz), 7.14 (dd, 1H, J=8.28, 2.21 Hz), 6.92 (d, 2H, J=8.83
Hz), 6.59 (d, 1H, J=8.28 Hz), 4.73 (q, 1H, J=6.71 Hz), 4.30 (s,
2H), 4.19 (q, 2H, J=7.08 Hz), 3.84 (s, 3H), 3.63 (m, 6H), 2.49 (br
s, 4H), 2.25 (s, 3H), 1.64 (d, 3H, J=6.71 Hz), 1.24 (t, 3H, J=7.08
Hz),
[0893] Ethyl
2-{4-[({4-[(4-benzoyl-1-piperazinyl)methyl]-2-[4-(trifluorome-
thyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
[0894] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.99 (d, 2H, J=8.55
Hz), 7.67 (d, 2H, J=8.55 Hz), 7.41 (m, 5H), 7.24 (d, 1H, J=2.21
Hz), 7.15 (dd, 1H, J=8.55, 2.21 Hz), 6.59 (d, 1H, J=8.55 Hz), 4.73
(q, 1H, J=6.71 Hz), 4.30 (s, 2H), 4.19 (q, 2H, J=7.04 Hz), 3.83 (br
s, 2H), 3.56 (s, 2H), 3.39 (br s, 2H), 2.50 (br s, 4H), 2.25 (s,
3H), 1.64 (d, 3H, J=6.71 Hz), 1.24 (t, 3H, J=7.04 Hz),
[0895] isobutyl
4-({5-({[4-(2-ethoxy-1-methyl-2-oxoethoxy)-3-methylphenyl]-
sulfanyl}methyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)-1--
piperazinecarboxylate
[0896] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta., 8.00 (d, 2H,
J=8.28 Hz), 7.68 (d, 2H, J=8.28 Hz), 726 (d, 1H, J=2.21 Hz), 7.14
(dd, 1H, J=8.28, 2.21 Hz), 6.59 (d, 1H, J=8.55 Hz), 4.73 (q, 1H,
J=6.71 Hz), 4.32 (s, 2H), 4.20 (q, 2H, J=7.08 Hz), 3.88 (d, 2H,
J=6.62 Hz), 3.53 (m, 6H), 2.46 (br s, 4H), 2.25 (s, 3H), 1.94 (m,
1H), 1.65 (d, 3H, J=6.62 Hz), 1.25 (t, 3H, J=7.17 Hz), 0.95 (d, 6H,
J=6.62 Hz).
[0897] Ethyl
2-{2-methyl-4-[({4-{[4-(2-thienylcarbonyl)-1-piperazinyl]meth-
yl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy-
}propanoate
[0898] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.01 (d, 2H, J=8.28
Hz), 7.68 (d, 2H, J=8.28 Hz), 7.45 (d, 1H, J=4.97 Hz), 7.30 (d, 1H,
J=3.59 Hz), 7.25 (d, 1H, J=2.21 Hz), 7.15 (dd, 1H, J=8.28, 2.21
Hz), 7.05 (m, 1H), 6.60 (d, 1H, J=8.28 Hz), 4.74 (q, 1H, J=6.71
Hz), 4.31 (s, 2H), 4.19 (q, 2H, J=7.08 Hz), 3.78 (t, 4H, J=4.69
Hz), 3.56 (s, 2H), 2.55 (t, 4H, J=4.69 Hz), 2.25 (s, 3H), 1.65 (d,
3H, J=6.71 Hz), 1.25 (t, 3H, J=7.08 Hz),
[0899] Phenyl
4-{[5-({[4-(2-ethoxy-1-methyl-2-oxoethoxy)-3-methylphenyl]su-
lfanyl}methyl)-2-(4-fluorophenyl)-1,3-thiazol-4-yl]methyl}-1-piperazinecar-
boxylate
[0900] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.85 (m, 2H), 7.33
(m, 2H), 7.15 (m, 7H), 6.57 (d, 1H, J=8.61 Hz), 4.69 (q, 1H, J=6.78
Hz), 4.27 (s, 2H), 4.14 (q, 2H, J=7.14 Hz), 3.63 (br s, 4H), 3.50
(s, 2H), 2.49 (br s, 4H), 2.23 (s, 3H), 1.60 (d, 3H, J=6.78 Hz),
1.22 (t, 3H, J=7.14 Hz),
[0901] Ethyl
2-{4-[({4-({4-[4-(dimethylamino)benzoyl]-1-piperazinyl}methyl-
)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methyl-
phenoxy}propanoate
[0902] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.01 (d, 2H, J=8.28
Hz), 7.68 (d, 2H, J=8.28 Hz), 7.37 (d, 2H, J=8.83 Hz), 7.25 (d, 1H,
J=2.21 Hz), 7.15 (dd, 1H, J=8.28, 2.21 Hz), 6.68 (d, 2H, J=8.83
Hz), 6.60 (d, 1H, J=8.28 Hz), 4.73 (q, 1H, J=6.71 Hz), 4.32 (s,
2H), 4.20 (q, 2H, J=7.17 Hz), 3.67 (br s, 4H), 3.55 (s, 2H), 3.02
(s, 6H), 2.51 (brs, 4H), 2.26 (s, 3H), 1.65 (d, 3H, J=6.71 Hz),
1.25 (t, 3H, J=7.17 Hz),
[0903] Ethyl
2-(4-[({4-{[4-(cyclohexylcarbonyl)-1-piperazinyl]methyl}-2-[4-
-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenox-
y}propanoate
[0904] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.00 (d, 2H, J=8.28
Hz), 7.68 (d, 2H, J=8.28 Hz), 7.26 (d, 1H, J=2.21 Hz), 7.14 (dd,
1H, J=8.28, 2.21 Hz), 6.59 (d, 1H, J=8.28 Hz), 4.73 (q, 1H, J=6.71
Hz), 4.30 (s, 2H), 4.20 (q, 2H, J=7.08 Hz), 3.58 (m, 6H), 2.47 (m,
5H), 2.26 (s, 3H), 1.63 (m, 11H), 1.27 (m, 5H),
[0905] Ethyl
2-(2-methyl-4-[({4-({4-[(methylamino)carbonyl]-1-piperazinyl}-
methyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phe-
noxy}propanoate
[0906] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.01 (d, 2H, J=8.28
Hz), 7.67 (d, 2H, J=8.28 Hz), 7.27 (d, 1H, J=2.21 Hz), 7.14 (dd,
1H, J=8.55, 2.21 Hz), 6.53 (d, 1H, J=8.55 Hz), 4.84 (m, 1H), 4.70
(q, 1H, J=6.90 Hz), 4.25 (m, 4H), 3.52 (m, 2H), 3.29 (m, 4H), 2.80
(d, 3H, J=4.42 Hz), 2.35 (t, 4H, J=4.83 Hz), 2.22 (s, 3H), 1.64 (d,
3H, J=6.90 Hz), 1.25 (t, 3H, J=7.17 Hz),
[0907] Ethyl
2-{4-[({4-({4-[(tert-butylamino)carbonyl]-1-piperazinyl}methy-
l)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methy-
lphenoxy}propanoate
[0908] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.00 (d, 2H, J=8.28
Hz), 7.67 (d, 2H, J=8.28 Hz), 7.27 (d, 1H, J=2.21 Hz), 7.14 (dd,
1H, J=8.28, 2.21 Hz), 6.56 (d, 1H, J=8.28 Hz), 4.72 (q, 1H, J=6.81
Hz), 4.42 (s, 1H), 4.33 (d, 1H, J=0.63 Hz), 4.26 (d, 1H, J=63 Hz),
4.20 (q, 2H, J=7.08 Hz), 3.53 (s, 2H), 3.29 (m, 4H), 2.40 (t, 4H,
J=4.69 Hz), 2.25 (s, 3H), 1.63 (d, 3H, J=6.81 Hz), 1.35 (s, 9H),
1.25 (t, 3H, J--7.09 Hz),
[0909] Ethyl
2-(4-[({4-({4-[(4-methoxyanilino)carbonyl]-1-piperazinyl}meth-
yl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-meth-
ylphenoxy}propanoate
[0910] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.05 (d, 2H, J=8.28
Hz), 7.73 (d, 2H, J=8.28 Hz), 7.23 (m, 4H), 6.84 (d, 2H, J=6.90
Hz), 6.66 (d, 1H, J=8.55 Hz), 4.83 (q, 1H, J=6.76 Hz), 4.36 (d, 1H,
J=63 Hz), 4.30 (d, 1H, J=0.63 Hz), 4.16 (q, 2H, J=7.08 Hz), 3.75
(s, 3H), 3.46 (m, 6H), 2.43 (t, 4H, J=4.83 Hz), 2.21 (s, 3H), 1.58
(d, 3H, J=6.76 Hz), 1.20 (t, 3H, J=7.08 Hz),
[0911] Ethyl
2-{2-methyl-4-[({4-[(4-{[(2-phenylethyl)amino]carbonyl}-1-pip-
erazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sul-
fanyl]phenoxy}propanoate
[0912] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.01 (d, 2H, J=8.28
Hz), 7.68 (d, 2H, J=8.28 Hz), 7.24 (m, 7H), 6.57 (d, 1H, J=8.55
Hz), 4.74 (m, 2H), 4.33 (d, 1H, J=0.35 Hz), 4.26 (d, 1H, J=0.35
Hz), 4.20 (q, 2H, J=7.04 Hz), 3.50 (m, 4H), 3.28 (m, 4H), 2.84 (t,
2H, J=7.04 Hz), 2.38 (t, 4H, J=4.83 Hz), 2.25 (s, 3H), 1.65 (d, 3H,
J=6.62 Hz), 1.26 (t, 3H, J=7.04 Hz),
[0913] Ethyl
2-{2-methyl-4-[({4-([4-(phenylsulfonyl)-1-piperazinyl]methyl}-
-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-ylmethyl)sulfanyl]phenoxy}pro-
panoate
[0914] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.97 (d, 2H, J=8.28
Hz), 7.77 (d, 2H, J=8.28 Hz), 7.59 (m, 5H), 7.20 (d, 1H, J=2.21
Hz), 7.10 (dd, 1H, J=8.55, 2.21 Hz), 6.58 (d, 1H, J=8.55 Hz), 4.73
(q, 1H, J=6.71 Hz), 4.19 (m, 4H), 3.48 (s, 2H), 3.07 (br s, 4H),
2.56 (br s, 4H), 2.25 (s, 3H), 1.65 (d, 3H, J=6.71 Hz), 1.25 (t,
3H, J=7.04 Hz),
[0915] Ethyl
2-{2-methyl-4-[({2-[4-(trifluoromethyl)phenyl]-4-[(4-{[4-(tri-
fluoromethyl)phenyl]sulfonyl}-1-piperazinyl)methyl]-1,3-thiazol-5-yl}methy-
l)sulfanyl]phenoxy}propanoate
[0916] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.98 (d, 2H, J=8.28
Hz), 7.90 (d, 2H, J=8.55 Hz), 7.81 (d, 2H, J=8.55 Hz), 7.67 (d, 2H,
J=8.28 Hz), 7.21 (d, 1H, J=2.21 Hz), 7.10 (dd, 1H, J=8.28, 2.21
Hz), 6.58 (d, 1H, J=8.28 Hz), 4.74 (q, 1H, J=6.71 Hz), 4.21 (m,
4H), 3.49 (s, 2H), 3.09 (br s, 4H), 2.58 (br s, 4H), 2.24 (s, 3H),
1.66 (d, 3H, J=6.71 Hz), 1.26 (t, 3H, J=7.17 Hz),
[0917] Ethyl
2-{4-[({4-(4-[(4-methoxyphenyl)sulfonyl]-1-piperazinyl}methyl-
)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methyl-
phenoxy}propanoate
[0918] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.97 (d, 2H, J=8.28
Hz), 7.67 (m, 4H), 7.20 (d, 1H, J=2.21 Hz), 7.09 (dd, 1H, J=8.55,
2.21 Hz), 6.99 (d, 2H, J=8.83 Hz), 6.58 (d, 1H, J=8.55 Hz), 4.74
(q, 1H, J=6.71 Hz), 4.20 (m, 4H), 3.87 (s, 3H), 3.49 (s, 2H), 3.05
(br s, 4H), 2.54 (br s, 4H), 2.24 (s, 3H), 1.66 (d, 3H, J=6.71 Hz),
1.25 (t, 3H, J=7.04 Hz),
[0919] Ethyl
2-{4[({4-{[4-(ethylsulfonyl)-1-piperazinyl]methyl{2-[4-(trifl-
uoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propa-
noate
[0920] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.00 (d, 2H, J=8.28
Hz), 7.68 (d, 2H, J=8.28 Hz), 7.26 (d, 1H, J=2.48 Hz), 7.15 (d, 1H,
J=2.48 Hz), 6.59 (d, 1H, J=8.28 Hz), 4.74 (q, 1H. J=6.81 Hz), 4.28
(s, 2H), 4.20 (q, 2H, J=7.17 Hz), 3.55 (s, 2H), 3.32 (t, 4H, J=4.69
Hz), 2.96 (q, 2H, J=7.45 Hz), 2.55 (br s, 4H), 2.25 (s, 3H), 1.65
(d, 3H, J=6.81 Hz), 1.38 (t, 3H, J=7.45 Hz), 1.25 (t, 3H, J=7.17
Hz),
[0921] Ethyl
2-{2-methyl-4-[({4-{[4-(methylsulfonyl)-1-piperazinyl]methyl}-
-2-[4-(trifluoromethyl)phenyl]1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}pro-
panoate
[0922] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.00 (d, 2H, J=8.55
Hz), 7.68 (d, 2H, J=8.55 Hz), 7.26 (d, 1H, J=2.21 Hz), 7.15 (dd,
1H, J=8.55, 2.21 Hz), 6.59 (d, 1H, J=8.55 Hz), 4.73 (q, 1H, J=6.71
Hz), 4.27 (s, 2H), 4.20 (q, 2H, J=7.17 Hz), 3.56 (s, 2H), 3.24 (t,
4H, J=4.55 Hz), 2.78 (s, 3H), 2.58 (t, 4H, J=4.55 Hz), 2.24 (s,
3H), 1.64 (d, 3H, J=6.71 Hz), 1.25 (t, 3H, J=7.17 Hz),
[0923] Ethyl
2-{4-[({4-[(4-{[4-(acetylamino)phenyl]sulfonyl}-1-piperazinyl-
)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-
-methylphenoxy}propanoate
[0924] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.40 (s, 1H), 7.96
(d, 2H, J=8.28 Hz), 7.66 (m, 6H), 7.16 (d, 1H, J=2.21 Hz), 7.07
(dd, 1H, J=8.28, 2.21 Hz), 6.56 (d, 1H, J=8.28 Hz), 4.73 (q, 1H,
J=6.71 Hz), 4.22 (m, 4H), 3.51 (s, 2H), 3.03 (br s, 4H), 2.55 (br
s, 4H), 2.19 (m, 6H), 1.65 (d, 3H, J=6.71 Hz), 1.27 (t, 3H, J=7.04
Hz),
[0925] Ethyl
2-{4-[({4-({4-[(4-fluorophenyl)sulfonyl]-1-piperazinyl}methyl-
)-2-[4-(trifluoromethyl)phenyl]1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylp-
henoxy}propanoate
[0926] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.97 (d, 2H, J=8.28
Hz), 7.77 (m, 2H), 7.66 (d, 2H, J=8.28 Hz), 7.22 (m, 3H), 7.10 (dd,
1H, J=8.55, 2.21 Hz), 6.58 (d, 1H, J=8.55 Hz), 4.74 (q, 1H, J=6.81
Hz), 4.20 (m, 4H), 3.49 (s, 2H), 3.07 (br s, 4H), 2.57 (t, 4H,
J=4.42 Hz), 2.24 (s, 3H), 1.65 (d, 3H, J=6.81 Hz), 1.27 (t, 3H,
J=7.17 Hz),
[0927] Ethyl
2-{4-[({4-{4[4-(2-furoyl)-1-piperazinyl}methyl)-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propano-
ate
[0928] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.00 (d, 2H, J=8.28
Hz), 7.67 (d, 2H, J=8.28 Hz), 7.48 (s, 1H), 7.24 (d, 1H, J=2.21
Hz), 7.15 (dd, 1H, J=8.28, 2.21 Hz), 6.99 (d, 1H, J=3.59 Hz), 6.60
(d, 1H, J=8.28 Hz), 6.48 (m, 1H), 4.73 (q, 1H, J=6.71 Hz), 4.31 (s,
2H), 4.20 (q, 2H, J=7.08 Hz), 3.83 (br s, 4H), 3.55 (s, 2H), 2.54
(t, 4H, J=4.83 Hz), 2.25 (s, 3H), 1.64 (d, 3H, J=6.71 Hz), 1.24 (t,
3H, J=7.08 Hz),
[0929] Ethyl
2-{4-[({4-({4-[(isopropylamino)carbonyl]-1-piperazinyl}methyl-
)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methyl)sulfanyl]-2-methyl-
phenoxy}propanoate
[0930] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta., 8.01 (d, 2H,
J=8.28 Hz), 7.67 (d, 2H, J=8.28 Hz), 7.27 (d, 1H, J=1.93 Hz), 7.14
(ddd, 1H, J=8.55, 2.21, 0.55 Hz), 6.55 (d, 1H, J=8.28 Hz), 4.72 (q,
1H, J=6.81 Hz), 4.47 (d, 1H, J=7.17 Hz), 4.26 (m, 4H), 3.99 (m,
1H), 3.52 (m, 2H), 3.29 (m, 4H), 2.37 (t, 4H, J=4.69 Hz), 2.24 (s,
3H), 1.64 (d, 3H, J=6.62 Hz), 1.25 (t, 3H, J=7.17 Hz), 1.15 (m,
6H),
[0931] Ethyl
2-{4-[({4-{[4-(methoxyacetyl)-1-piperazinyl]methyl}-2-[4-(tri-
fluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}pro-
panoate
[0932] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.00 (d, 2H, J=8.28
Hz), 7.67 (d, 2H, J=8.28 Hz), 7.24 (d, 1H, J=2.21 Hz), 7.14 (dd,
1H, J=8.28, 2.21 Hz), 6.58 (d, 1H, J=8.28 Hz), 4.73 (q, 1H, J=6.71
Hz), 4.29 (s, 2H), 4.20 (q, 2H, J=7.17 Hz), 4.10 (s, 2H), 3.64 (m,
2H), 3.54 (s, 2H), 3.48 (m, 2H), 3.42 (s, 3H), 2.47 (m, 4H), 2.25
(s, 3H), 1.64 (d, 3H, J=6.71 Hz), 1.24 (t, 3H, J=7.17 Hz),
[0933] Ethyl
2-{4-[({4-[(4-isobutyryl-1-piperazinyl)methyl]-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoa-
te
[0934] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.00 (d, 2H, J=8.28
Hz), 7.68 (d, 2H, J=8.28 Hz), 7.24 (d, 1H, J=2.48 Hz), 7.14 (dd,
1H, J=8.55, 2.48 Hz), 6.59 (d, 1H, J=8.55 Hz), 4.74 (q, 1H, J=6.71
Hz), 4.30 (s, 2H), 4.20 (q, 2H, J=7.17 Hz), 3.58 (m, 6H), 2.79 (m,
1H), 2.46 (t, 4H, J=4.55 Hz), 2.24 (s, 3H), 1.64 (d, 3H, J=6.71
Hz), 1.24 (t, 3H, J=7.17 Hz), 1.13 (d, 6H, J=6.71 Hz),
[0935] Ethyl
2-{4-[({4-{[4-(2,2-dimethylpropanoyl)-1-piperazinyl]methyl}-2-
-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphe-
noxy}propanoate
[0936] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.00 (d, 2H, J=8.28
Hz), 7.68 (d, 2H, J=8.28 Hz), 7.24 (d, 1H, J=2.21 Hz), 7.15 (dd,
1H, J=8.28, 2.21 Hz), 6.60 (d, 1H, J=8.28 Hz), 4.73 (q, 1H, J=6.71
Hz), 4.31 (s, 2H), 4.20 (q, 2H, J=7.08 Hz), 3.66 (t, 4H, J=4.69
Hz), 3.52 (s, 2H), 2.48 (t, 4H, J=4.69 Hz), 2.26 (s, 3H), 1.65 (d,
3H, J=6.71 Hz), 1.27 (m, 12H),
[0937] Ethyl
2-{4-[({4-({4-[(4-fluoroanilino)carbonyl]-1-piperazinyl}methy-
l)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methy-
lphenoxy}propanoate
[0938] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.04 (d, 2H, J=8.28
Hz), 7.69 (d, 2H, J=8.28 Hz), 7.33 (m, 2H), 7.17 (dd, 1H, J=8.55,
2.21 Hz), 6.96 (m, 2H), 6.52 (d, 1H, J=8.55 Hz), 4.72 (q, 1H,
J=6.90 Hz), 4.27 (m, 4H), 3.59 (d, 1H, J=0.52 Hz), 3.51 (d, 1H,
J=0.52 Hz), 3.34 (m, 4H), 2.33 (t, 4H, J=4.97 Hz), 2.22 (s, 3H),
1.62 (d, 3H, J=6.90 Hz), 1.26 (t, 3H, J=7.17 Hz),
[0939] Ethyl
2-{4-[({4-({4-[(3-methoxyanilino)carbonyl]-1-piperazinyl}meth-
yl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl)methyl)sulfanyl]-2-meth-
ylphenoxy}propanoate
[0940] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.04 (d, 2H, J=8.28
Hz), 7.69 (d, 2H, J=8.28 Hz), 7.31 (d, 1H, J=2.21 Hz), 7.16 (m,
2H), 6.89 (m, 2H), 6.59 (dd, 1H, J=8.28, 2.21 Hz), 6.53 (m, 1H),
4.73 (q, 1H, J=6.90 Hz), 4.27 (m, 4H), 3.79 (s, 3H), 3.56 (m, 2H),
3.37 (m, 4H), 2.36 (t, 4H, J=4.69 Hz), 2.23 (s, 3H), 1.63 (d, 3H,
J=6.90 Hz), 1.26 (t, 3H, J=7.17 Hz),
[0941] Ethyl
2-{4-[({4-{[4-(aminocarbonyl)-1-piperazinyl]methyl}-2-[4-(tri-
fluoromethyl)phenyl]-1,3-thiazol-5-yl)methyl)sulfanyl]-2-methylphenoxy}pro-
panoate
[0942] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.01 (d, 2H, J=8.28
Hz), 7.68 (d, 2H, J=8.28 Hz), 7.26 (d, 1H, J=2.21 Hz), 7.15 (dd,
1H, J=8.55, 2.21 Hz), 6.56 (d, 1H, J=8.55 Hz), 4.83 (s, 2H), 4.71
(q, 1H, J=6.81 Hz), 4.26 (m, 4H), 3.55 (m, 2H), 3.34 (m, 4H), 2.41
(t, 4H, J=4.55 Hz), 2.24 (s, 3H), 1.63 (d, 3H, J=6.81 Hz), 1.25 (t,
3H, J=7.04 Hz),
[0943] Ethyl
2-{4-[({4-({4-[(cyclohexylamino)carbonyl]-1-piperazinyl}methy-
l)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methy-
lphenoxy}propanoate
[0944] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.00 (d, 2H, J=8.28
Hz), 7.67 (d, 2H, J=8.28 Hz), 7.26 (d, 1H, J=2.21 Hz), 7.14 (dd,
1H, J=8.55, 2.21 Hz), 6.54 (d, 1H, J=8.55 Hz), 4.72 (q, 1H, J=6.81
Hz), 4.49 (d, 1H, J=7.45 Hz), 4.25 (m, 4H), 3.64 (m, 1H), 3.52 (m,
2H), 3.28 (m, 4H), 2.38 (t, 4H, J=4.83 Hz), 2.24 (s, 3H), 1.95 (m,
2H), 1.65 (m, 7H), 1.38 (m, 2H), 1.24 (t, 3H, J=7.04 Hz), 1.10 (m,
2H),
[0945] Ethyl
2-[2-methyl-4-[({4-[(propylamino)carbonyl]-1-piperazinyl}meth-
yl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy-
}propanoate
[0946] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.01 (d, 2H, J=8.00
Hz), 7.68 (d, 2H, J=8.00 Hz), 7.27 (d, 1H, J=2.21 Hz), 7.14 (dd,
1H, J=8.28, 2.21 Hz), 6.54 (d, 1H, J=8.28 Hz), 4.75 (m, 2H), 4.26
(m, 4H), 3.53 (m, 2H), 3.33 (m, 4H), 3.19 (m, 2H), 2.36 (t, 4H,
J=4.69 Hz), 2.23 (s, 3H), 1.64 (d, 3H, J=6.90 Hz), 1.52 (m, 2H),
1.25 (t, 3H, J=7.17 Hz), 0.92 (t, 3H, J=7.45 Hz),
[0947] Ethyl
2-{4-[({4-({4-[(ethylamino)carbonyl]-1-piperazinyl}methyl)-2--
[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphen-
oxy}propanoate
[0948] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.02 (d, 2H, J=8.28
Hz), 7.69 (d, 2H, J=8.28 Hz), 7.27 (d, 1H, J=2.21 Hz), 7.15 (dd,
1H, J=8.55, 2.21 Hz), 6.54 (d, 1H, J=8.55 Hz), 4.72 (m, 2H), 4.26
(m, 4H), 3.54 (m, 2H), 3.29 (m, 6H), 2.38 (t, 4H, J=4.28 Hz), 2.25
(s, 3H), 1.65 (d, 3H, J=6.90 Hz), 1.26 (t, 3H, J=7.04 Hz), 1.15 (t,
3H, J=7.31 Hz),
[0949] Ethyl
[2-methyl-4-({[4-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]m-
ethyl}-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phen-
oxy]acetate
[0950] To a stirred solution of ethyl
[4-({[4-(hydroxymethyl)-2-(4-{triflu-
oromethyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetat-
e (40 mg, 0.08 mmoles, 1 eq) in dry toluene (2 ml) was added
3-(5-methyl-1,2,4-oxadiazol-3-yl)phenol (15 mg, 0.088 mmoles, 1.1
eq) followed by triphenylphosphine (25 mg, 0.096 mmoles, 1.2 eq) as
a solid. Diisopropylazodicarboxylate (0.017 ml, 0.088 mmoles, 1.1
eq) was then added dropwise and the reaction was stirred for 2
hours at room temperature. The reaction was then partitioned
between EtOAc and H.sub.2O. After the separation of the phases the
organic phase was washed with 0.1N NaOH, brine, dried over
Na.sub.2SO.sub.4, filtered, concentrated in vacuo and purified via
flash chromatography (10% EtOAc/Hexanes to 35% EtOAc/Hexanes) to
yield 40 mg (76%) of product.
[0951] .sup.1H (CDCl.sub.3) 400 MHz .delta. 8.02 (d, 2H, J=8.20
Hz), 7.68 (m, 4H), 7.38 (t, 1H, J=7.95 Hz), 7.19 (d, 1H, J=1.54),
7.12 (dd, 1H, J=8.37, 2.39 Hz), 7.06 (dd, 1H, J=8.20, 2.39 Hz),
6.57 (d, 1H, J=8.20 Hz), 4.95 (s, 2H), 4.59 (s, 2H), 4.27 (s, 2H),
4.22 (q, 2H, J=7.12 Hz), 2.65 (s, 3H), 2.18 (s, 3H), 1.25 (t, 3H,
J=7.12 Hz). TLC(50% EtOAc/Hexanes) R.sub.f=0.76
[0952] The following compounds were made using the general
Mitsunobu reaction conditions detailed above:
[0953] Ethyl
2-{2-methyl-4-[({4-({[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenox-
y]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]p-
henoxy}propanoate
[0954] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.03 (d, 2H, J=8.20
Hz), 7.69 (m, 4H), 7.39 (m, 1H), 7.20 (m, 1H), 7.09 (m, 2H), 6.55
(d, 1H, J=8.37 Hz), 4.99 (d, 1H, J=0.62 Hz), 4.95 (d, 1H. J 0.62
Hz), 4.70 (q, 1H, J=6.78 Hz), 4.16 (q, 2H, J=7.18 Hz), 2.65 (m,
3H), 2.18 (s, 3H), 1.61 (d, 3H, J=6.78 Hz), 1.20 (t, 3H, J=7.18
Hz),
[0955] Ethyl
(2-methyl-4-{[(4-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]m-
ethyl}-2-phenyl-1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)acetate
[0956] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.91 (m, 2H), 7.69
(m, 2H), 7.40 (m, 4H), 7.20 (d, 1H, J=2.39 Hz), 7.13 (dd, 1H,
J=8.37, 2.39 Hz), 7.07 (dd, 1H, J=8.37, 2.39 Hz), 6.57 (d, 1H,
J=8.37 Hz), 5.29 (s, 2H), 4.59 (s, 2H), 4.27 (s, 2H), 4.23 (q, 2H,
J=7.18 Hz), 2.65 (s, 3H), 2.19 (s, 3H), 1.27 (t, 3H, J=7.18
Hz).
[0957] Ethyl
[2-methyl-4-({[2-(4-{trifluoromethyl}phenyl)-4-(phenoxymethyl-
)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]acetate
[0958] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.04 (d, 2H, J=8.23
Hz), 7.71 (d, 2H, J=8.23 Hz), 7.34 (m, 2H), 7.23 (d, 1H, J=2.39
Hz), 7.15 (dd, 1H, J=8.49, 2.39 Hz), 7.00 (m, 3H), 6.59 (d, 1H,
J=8.49 Hz), 4.94 (s, 2H), 4.64 (s, 2H), 4.27 (m, 4H), 2.26 (s, 3H),
1.32 (t, 3H, J=7.17 Hz). TLC(30% EtOAc/Hexanes) R.sub.f=0.71
[0959] Ethyl
[2-methyl-4-({[4-[(2-methylphenoxy)methyl]-2-(4-{trifluoromet-
hyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]acetate
[0960] .sup.1H (CDCl.sub.3) 300 MHz .delta. 8.05 (d, 2H, J=8.23
Hz), 7.72 (d, 2H, J=8.23 Hz), 7.21 (m, 4H), 6.93 (m, 2H), 6.59 (d,
1H, J=8.49 Hz), 5.00 (s, 2H), 4.64 (s, 2H), 4.29 (m, 4H), 2.26 (m,
6H), 1.32 (t, 3H, J=7.17 Hz). TLC(20% EtOAc/Hexanes)
R.sub.f=0.70
[0961] Ethyl
[2-methyl-4-({[4-[(3-methylphenoxy)methyl]-2-(4-{trifluoromet-
hyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]acetate
[0962] .sup.1H (CDCl.sub.3) 300 MHz .delta. 8.05 (d, 2H, J=8.49
Hz), 7.71 (d, 2H, J=8.49 Hz), 7.35 (m, 1H), 7.26 (dd, 1H, J=2.39,
0.53 Hz), 7.21 (t, 1H, J=7.43 Hz), 7.15 (ddd, 1H, J=8.49, 2.39,
0.53 Hz), 6.81 (m, 2H), 6.60 (d, 1H, J=8.49 Hz), 4.92 (s, 2H), 4.65
(s, 2H), 4.29 (m, 4H), 2.38 (s, 3H), 2.25 (s, 3H), 1.32 (t, 3H,
J=7.17 Hz). TLC(20% EtOAc/Hexanes) R.sub.f=0.70
[0963] Ethyl
[2-methyl-4-({[4-[(4-methylphenoxy)methyl]-2-(4-{trifluoromet-
hyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]acetate
[0964] .sup.1H (CDCl.sub.3) 300 MHz .delta. 8.04 (d, 2H, J=8.23
Hz), 7.71 (d, 2H, J=8.23 Hz), 7.27 (dd, 1H, J=2.39, 0.80 Hz), 7.14
(m, 3H), 6.88 (d, 2H, J=8.49 Hz), 6.60 (d, 1H, J=8.23 Hz), 4.92 (s,
2H), 4.64 (s, 2H), 4.29 (m, 4H), 2.33 (s, 3H), 2.26 (s, 3H), 1.32
(t, 3H, J=7.17 Hz). TLC(20% EtOAc/Hexanes) R.sub.f=0.70
[0965] Ethyl
[4-({[4-[(3-cyanophenoxy)methyl]-2-(4-{trifluoromethyl}phenyl-
)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetate
[0966] .sup.1H (CDCl.sub.3) 300 MHz .delta. 8.03 (d, 2H, J=8.23
Hz), 7.71 (d, 2H, J=8.23 Hz), 7.24 (m, 6H), 6.61 (d, 1H, J=8.23
Hz), 4.88 (s, 2H), 4.67 (s, 2H), 4.28 (m, 4H), 2.24 (s, 3H), 1.31
(t, 3H, J=7.17 Hz). TLC(20% EtOAc/Hexanes) R.sub.f=0.52
[0967] Ethyl
[4-({[4-[(4-cyanophenoxy)methyl]-2-(4-{trifluoromethyl}phenyl-
)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetate
[0968] .sup.1H (CDCl.sub.3) 300 MHz .delta. 8.03 (d, 2H, J=8.23
Hz), 7.73 (d, 2H, J=8.23 Hz), 7.61 (d, 2H, J=9.03 Hz), 7.23 (dd,
1H, J=2.39, 0.53 Hz), 7.14 (ddd, 1H, J=8.49, 2.39, 0.53 Hz), 7.01
(d, 2H, J=9.03 Hz), 6.59 (d, 1H, J=8.49 Hz), 4.91 (s, 2H), 4.66 (s,
2H), 4.28 (m, 4H), 2.25 (s, 3H), 1.32 (t, 3H, J=7.17 Hz). TLC(20%
EtOAc/Hexanes) R.sub.f=0.52
[0969] Ethyl
[2-methyl-4-({[4-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]m-
ethyl})-2(4-{trifluoro}methylphenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phen-
oxy]acetate
[0970] .sup.1H (CDCl.sub.3) 400 MHz .delta. 7.99 (m, 4H), 7.67 (d,
2H, J=8.20 Hz), 7.21 (dd, 1H, J=2.39, 0.68 Hz), 7.10 (m, 1H), 7.02
(m, 2H), 6.54 (d, 1H, J=8.37 Hz), 4.90 (s, 2H), 4.59 (s, 2H), 4.23
(m, 4H), 2.62 (s, 3H), 2.20 (s, 3H), 1.26 (t, 3H, J=7.18 Hz).
TLC(50% EtOAc/Hexanes) R.sub.f=0.68
[0971] Ethyl
(2-methyl-4-{[(4-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]m-
ethyl}-2-phenyl-1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)acetate
[0972] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.98 (d, 2H, J=8.89
Hz), 7.89 (m, 2H), 7.42 (m, 3H), 7.21 (d, 1H, J=2.39 Hz), 7.10 (dd,
1H, J=8.37, 2.39 Hz), 7.02 (d, 2H, J=8.89 Hz), 6.54 (d, 1H, J=8.37
Hz), 4.89 (s, 2H), 4.59 (s, 2H), 4.23 (q, 2H, J=7.18 Hz), 3.47 (s,
2H), 2.62 (s, 3H), 2.20 (s, 3H), 1.27 (t, 3H, J=7.18 Hz),
[0973] Ethyl
2-{2-methyl-4-[({4-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy-
]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]ph-
enoxy}propanoate
[0974] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.04 (m, 4H), 7.71
(d, 2H, J=8.23 Hz), 7.25 (d, 1H, J=2.39 Hz), 7.11 (dd, 1H, J=8.49,
2.39 Hz), 7.06 (d, 2H, J=9.03 Hz), 6.57 (d, 1H, J=8.49 Hz), 4.97
(d, 1H, J=0.68 Hz), 4.91 (d, 1H, J=0.68 Hz), 4.73 (q, 1H, J=6.81
Hz), 4.29 (s, 2H), 4.20 (q, 2H, J=7.17 Hz), 2.67 (s, 3H), 2.23 (s,
3H), 1.65 (d, 3H, J=6.81 Hz), 1.25 (t, 3H, J=7.17 Hz),
[0975] Ethyl
2-(2-methyl-4-{[(4-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy-
]methyl}-2-phenyl-1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)propanoate
[0976] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.99 (d, 2H, J=9.06
Hz), 7.89 (m, 2H), 7.42 (m, 3H), 7.20 (d, 1H, J=2.22 Hz), 7.06 (dd,
1H, J=8.37, 2.22 Hz), 7.02 (d, 2H, J=9.06 Hz), 6.52 (d, 1H, J=8.37
Hz), 4.89 (d, 1H, J=0.62 Hz), 4.85 (d, 1H, J=0.62 Hz), 4.68 (q, 1H,
J=6.78 Hz), 4.23 (s, 2H), 4.17 (q, 2H, J=7.12 Hz), 2.62 (s, 2H),
2.19 (s, 3H), 1.61 (d, 3H, J=6.78 Hz), 1.21 (t, 3H, J=7.12 Hz),
[0977] 4-(Chloromethyl)-2-methylphenyl Methyl Ether
[0978] To a stirred solution of (4-methoxy-3-methylphenyl)methanol
(2.31 g, 15.18 mmoles, 1 eq) in anhydrous CH.sub.2Cl.sub.2 (50 ml,
0.3M) was added hexachloroethane (3.59 g, 15.18 mmoles, 1 eq) and
triphenylphosphine (3.98 g, 15.18 mmoles, 1 eq). This mixture was
stirred at room temperature overnight at which point the reaction
was transferred to a separatory funnel and washed with H.sub.2O,
brine, dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuo
and filtered through a plug of silica gel (30% EtOAc/Hexanes) to
yield 2.59 g (100%) of product.
[0979] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.16 (m, 2H), 6.76
(d, 1H, J=8.10 Hz), 4.52 (s, 2H), 3.81 (s, 3H), 2.19 (s, 3H),
[0980] (4-Methoxy-3-methylbenzyl)(triphenyl)phosphonium
Chloride
[0981] To a 250 ml round-bottom flask equipped with a magnetic
stir-bar and N.sub.2 inlet was added
4-(Chloromethyl)-2-methylphenyl methyl ether (2.59 g, 15.18 mmoles,
1 eq), dry toluene (50 ml, 0.3M) and triphenylphosphine (3.98 g,
15.18 mmoles, 1 eq). The reaction mixture was refluxed overnight.
After cooling to room temperature the solvent was removed in vacuo,
the residue washed with hexanes and the solid/liquid mixture was
filtered to yield 4.48 g (71%) of solid product.
[0982] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.66 (m, 15H), 6.93
(m, 1H), 6.54 (m, 2H), 5.24 (d, 2H, J=0.79 Hz), 3.68 (s, 3H), 1.90
(s, 3H),
[0983]
4-[(Tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)pheny-
l]-1,3-thiazole-5-carbaldehyde
[0984] To a stirred mixture of pyridinium chlorochromate (6.9 g,
32.12 mmoles, 4 eq) in dry CH.sub.2Cl.sub.2 (40 ml, 0.2M) was added
{4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,-
3-thiazol-5-yl}methanol (3.0 g, 8.03 mmoles, 1 eq) in
CH.sub.2Cl.sub.2 (10 ml). The mixture was stirred at room
temperature for 4 hours at which time the reaction mixture was
quenched by allowing it to stir with sat. NaHCO.sub.3. Once the
quenching had ceased the reaction was filtered through Celite and
the filtrate was transferred to a separatory funnel where the
phases were separated. The organic phase was dried over
Na.sub.2SO.sub.4 and concentrated in vacuo to yield 2.18 g (73%) of
clean aldehyde. The crude product was used without
purification.
[0985] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 10.39 (s, 1H), 8.09
(d, 2H, J=8.28 Hz), 7.70 (d, 2H, J=8.28 Hz), 5.22 (d, 1H, J=0.97
Hz), 4.96 (d, 1H, J=0.97 Hz), 4.83 (m, 1H), 3.87 (m, 1H), 3.58 (m,
1H), 1.81 (m, 2H), 1.61 (m, 4H),
[0986]
5-[(E)-2-(4-Methoxy-3-methylphenyl)ethenyl]-4-[(tetrahydro-2H-pyran-
-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole
[0987] To a suspension of NaH (60% dispersion in mineral oil, 242
mg, 6.32 mmoles, 1.4 eq) in dry CH.sub.2Cl.sub.2 (15 ml) was added
(4-Methoxy-3-methylbenzyl)(triphenyl)phosphonium chloride (2.62 g,
6.32 mmoles, 1.4 eq). This was allowed to stir at room temperature
for 1.5 hours followed by the dropwise addition of
4-[(tetrahydro-2H-pyran-2-ylox-
y)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carbaldehyde
(1.68 g, 4.51 mmoles, 1 eq) in anhydrous carbon tetrachloride (25
ml). The resulting reaction mixture was refluxed overnight at which
point (after cooling to room temperature) the reaction was washed
with 1N NaOH, H.sub.2O, brine, dried over Na.sub.2SO.sub.4 and
concentrated in vacuo to yield a >100% yield of a light green
oil. The crude material was used without purification.
[0988] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.05 (d, 2H, J=8.24
Hz), 7.68 (d, 2H, J=8.24 Hz), 7.29 (m, 3H), 6.85 (m, 2H), 4.98 (d,
1H, J=12.09 Hz), 4.81 (m, 2H), 4.01 (m, 1H), 3.86 (s, 3H), 3.62 (m,
1H), 2.26 (s, 3H), 1.72 (m, 6H),
[0989]
{5-[2-(4-Methoxy-3-methylphenyl)ethyl]-2-[4-(trifluoromethyl)phenyl-
]-1,3-thiazol-4-yl}methanol
[0990] To a stirred solution of
5-[(E)-2-[4-Methoxy-3-methylphenyl)ethenyl-
]-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,-
3-thiazole (2.20 g, 4.51 mmoles, 1 eq) in EtOH (50 ml, 0.1 M) was
added 10% Pd/C (500 mg). The system was degassed using an aspirator
and H.sub.2 was introduced via a balloon. The reaction was heated
to 60.degree. C. overnight which, after cooling to room
temperature, was filtered through Celite, washed with EtOAc and
concentrated in vacuo. This reaction yielded after chromatography
760 mg (41%) of clean alcohol.
[0991] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.98 (d, 2H, J=8.24
Hz), 7.66 (d, 2H, J=8.24-Hz), 6.91 (m, 2H), 6.72 (d, 1H, J=8.10
Hz), 4.54 (s, 2H), 3.80 (s, 3H), 3.11 (t, 2H, J=7.42 Hz), 2.87(t,
2H, J=7.42 Hz), 2.18 (s, 3H), 2.05 (br s, 1H),
[0992]
4-(Bromomethyl)-5-[2-(4-methoxy-3-methylphenyl)ethyl]-2-[4-(trifluo-
romethyl)phenyl]1,3-thiazole
[0993] To a 100 ml round-bottom flask equipped with a magnetic
stir-bar and N.sub.2 inlet was added
{5-[2-(4-Methoxy-3-methylphenyl)ethyl]-2-[4-(-
trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methanol (0.708 g, 1.74
mmoles, 1 eq), CH.sub.2Cl.sub.2 (20 ml), carbon tetrabromide (0.634
g, 1.91 mmoles, 1.1 eq) and triphenylphosphine (0.501 g, 1.91
mmoles, 1.1 eq) in that order. The reaction was stirred overnight
at which time it was diluted with CH.sub.2Cl.sub.2 and washed with
H.sub.2O, brine, dried over Na.sub.2SO.sub.4, concentrated in vacuo
and purified via silica gel chromatography to yield 573 mg (70%) of
product.
[0994] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.10
Hz), 7.64 (d, 2H, J=8.10 Hz), 6.94 (m, 2H), 6.73 (d, 1H, J=8.10
Hz), 4.46 (m, 2H), 3.79 (m, 3H), 3.12 (t, 2H, J=7.24 Hz), 2.91 (t,
2H, J=7.24 Hz), 2.19 (s, 3H),
[0995]
4-(2-[4-(Bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-y-
l}ethyl)-2-methylphenol
[0996] To a 50 ml round-bottom flask equipped with a magnetic
stir-bar, an addition funnel and N.sub.2 inlet was added
4-(Bromomethyl)-5-[2-(4-metho-
xy-3-methylphenyl)ethyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole
(468 mg, 1.0 mmoles, 1 eq) and dry CH.sub.2Cl.sub.2 (15 ml, 0.1M).
The mixture was cooled to -78.degree. C. (dry ice/acetone) after
which boron tribromide (1M in CH.sub.2Cl.sub.2, 3 ml, 3.0 mmoles, 3
eq) was added dropwise over the course of 15 minutes. After the
addition was complete, the cold bath was removed and the reaction
was allowed to warm to room temperature and stirred for 1 hour.
After this time, the reaction was cooled to 0.degree. C. and
quenched very carefully with water. Once the reaction was quenched,
it was transferred to a separatory funnel where the phases were
separated. The aqueous fraction was washed three times with
CH.sub.2Cl.sub.2 and the combined organic fractions were dried over
Na.sub.2SO.sub.4, filtered, concentrated in vacuo to yield a
quantitative yield of the titled phenol. The product was used
without purification.
[0997] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.96 (d, 2H, J=8.28
Hz), 7.65 (d, 2H, J=8.28 Hz), 6.93 (m, 1H), 6.85 (d, 1H, J=8.10
Hz), 6.68 (d, 1H, J=8.10 Hz), 5.42 (br s, 1H), 4.45 (s, 2H), 3.10
(t, 2H, J=7.41 Hz), 2.89 (t, 2H, J=7.41 Hz), 2.20 (s, 3H),
[0998] The following compounds were made by amine displacement as
described above for General Alkylation with an Amine:
[0999]
4-(2-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromet-
hyl)phenyl]-1,3-thiazol-5-yl}ethyl)-2-methylphenol
[1000] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.94 (d, 2H, J=8.28
Hz), 7.59 (d, 2H, J=8.28 Hz), 6.91 (d, 1H, J=2.24 Hz), 6.86 (d, 2H,
J=9.31 Hz), 6.80 (d, 2H, J=9.31 Hz), 6.74 (dd, 1H, J=8.10, 2.24
Hz), 6.58 (s, 1H), 6.51 (d, 1H, J=8.10 Hz), 3.73 (s, 3H), 3.58 (s,
2H), 3.12 (t, 2H, J=7.50 Hz), 3.05 (t, 4H, J=4.48 Hz), 2.84 (t, 2H,
J=7.50 Hz), 2.64 (t, 4H, J--4.48 Hz), 2.20 (s, 3H),
[1001]
1-{4-[4-({5-[2-(4-Hydroxy-3-methylphenyl)ethyl]-2-[4-(trifluorometh-
yl)phenyl]-1,3-thiazol-4-yl}methyl)-1-piperazinyl]phenyl}ethanone
[1002] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.07 (d, 2H, J=8.28
Hz), 7.85 (d, 2H, J=9.14 Hz), 7.73 (d, 2H, J=8.28 Hz), 6.92 (d, 2H,
J=9.14 Hz), 6.88 (d, 1H, J=2.24 Hz), 6.77 (dd, 1H, J=8.28, 2.24
Hz), 6.60 (d, 1H, J=8.28 Hz), 3.49 (s, 2H), 3.32 (t, 4H, J=4.83
Hz), 3.18 (t, 2H, J=7.07 Hz), 2.88 (t, 2H, J=7.07 Hz), 2.51 (t, 4H,
J=4.83 Hz), 2.47 (s, 3H), 2.10 (s, 3H),
[1003]
4-(2-{4-([4-(3-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoro-
methyl)phenyl]-1,3-thiazol-5-yl}ethyl)-2-methylphenol
[1004] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.07 (d, 2H, J=8.10
Hz), 7.72 (d, 2H, J=8.10 Hz), 7.09 (t, 1H, J=8.28 Hz), 6.88 (s,
1H), 6.77 (dd, 1H, J=8.45, 2.24 Hz), 6.59 (d, 1H, J=8.45 Hz), 6.51
(dd, 1H, J=8.28, 2.24 Hz), 6.46 (t, 1H, J=2.24 Hz), 6.38 (dd, 1H,
J=8.28, 2.24 Hz), 3.72 (s, 3H), 3.49 (s, 2H), 3.18 (t, 2H, J=6.47
Hz), 3.09 (br s, 4H), 2.87 (t, 2H, J=6.47 Hz), 2.52 (br s, 4H),
2.10 (s, 3H),
[1005]
4-(2-{4-{[4-(4-Chlorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluorom-
ethyl)phenyl]-1,3-thiazol-5-yl}ethyl)-2-methylphenol
[1006] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.07 (d, 2H, J=8.10
Hz), 7.73 (d, 2H, J=8.10 Hz), 7.15 (d, 2H, J=9.14 Hz), 6.89 (m,
3H), 6.77 (dd, 1H, J=8.45, 2.41 Hz), 6.59 (d, 1H, J=8.45 Hz), 3.49
(s, 2H), 3.18 (t, 2H, J=7.16 Hz), 3.09 (t, 4H, J=5.09 Hz), 2.87 (t,
2H, J=7.16 Hz), 2.53 (t, 4H, J=5.09 Hz), 2.10 (s, 3H),
[1007]
2-[4-(2-{4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(triflu-
oromethyl)phenyl]-1,3-thiazol-5-yl}ethyl)-2-methylphenoxy]-2-methylpropano-
ic Acid
[1008] To a 25 ml round-bottom flask equipped with a magnetic
stir-bar and N.sub.2 inlet was added
4-(2-{4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methy-
l)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}ethyl)-2-methylphenol
(53 mg, 0.094 mmoles, 1 eq) in acetone (2 ml, 0.05M) followed by
the addition of 2-trichloromethyl-2-propanol (33 mg, 0.188 mmoles,
2 eq) and NaOH (pellets, 30 mg, 0.752 mmoles, 8 eq). This was
stirred at room temperature overnight after which the acetone was
removed in vacuo and the resulting residue was partitioned between
EtOAc and 1N HCl. The phases were then separated and the organic
fraction was washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated in vacuo to yield after chromatography 23 mg (40%) of
product.
[1009] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.95 (d, 2H, J=8.28
Hz), 7.62 (d, 2H, J=8.28 Hz), 6.88 (m, 5H), 6.67 (br s, 1H), 6.54
(br s, 1H), 3.72 (s, 3H), 3.61 (s, 2H), 3.23 (m, 8H), 2.80 (m, 4H),
2.15 (s, 3H), 1.54 (s, 6H),
[1010] MS(ES.sup.-) M-H=652.2
[1011] The following compounds were also made by alkylation of a
phenol with trichloromethyl-2-propanol as above:
[1012]
2-[4-(2-{4-{[4-(4-Chlorophenyl)-1-piperazinyl]methyl)-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}ethyl)-2-methylphenoxy]-2-methylpropanoi-
c acid
[1013] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 7.99 (d, 2H, J=8.28
Hz), 7.66 (d, 2H, J=8.28 Hz), 7.55 (s, 1H), 7.14 (d, 2H, J=8.10
Hz), 6.91 (s, 1H), 6.82 (d, 2H, J=8.10 Hz), 6.66 (br s, 1H), 3.55
(s, 2H), 3.28 (m, 2H) buried under MeOH signal, 3.12 (br s, 4H),
2.85 (s, 2H), 2.65 (br s, 4H), 2.13 (s, 3H), 1.52 (s, 6H),
[1014] MS(ES.sup.+) M+H=659.0
[1015]
2-[4-(2-{4-{[4-(3-Methoxyphenyl)-1-piperazinyl]methyl)-2-[4-(triflu-
oromethyl)phenyl-1,3-thiazol-5-yl}ethyl)-2-methylphenoxy]-2-methylpropanoi-
c acid
[1016] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.02 (d, 2H, J=8.10
Hz), 7.68 (d, 2H, J=8.10 Hz), 7.09 (t, 1H, J=8.10 Hz), 6.92 (s,
1H), 6.76 (m, 2H), 6.50 (dd, 1H, J=8.10, 2.07 Hz), 6.42 (t, 1H,
J=2.07 Hz), 6.37 (dd, 1H, J=8.10, 2.07 Hz), 3.72 (s, 3H), 3.51 (s,
2H), 3.28 (m, 2H) buried under MeOH signal, 3.12 (m, 4H), 2.83 (t,
2H, J=7.16 Hz), 2.61 (m, 4H), 2.15 (s, 3H), 1.48 (s, 6H),
[1017] MS(ES.sup.-) M-H=652.1
[1018]
2-[4-(2-{4-{[4-(4-Acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}ethyl)-2-methylphenoxy]-2-methylpropanoi-
c acid
[1019] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.01 (d, 2H, J=8.10
Hz), 7.82 (d, 2H, J=9.14 Hz), 7.67 (d, 2H, J=8.10 Hz), 6.90 (m,
3H), 6.66 (m, 2H), 3.61 (s, 2H), 3.37 (br s, 4H), 3.13 (t, 2H,
J=6.81 Hz), 2.82 (t, 2H, J=6.81 Hz), 2.68 (br s, 4H), 2.44 (s, 3H),
2.11 (s, 3H), 1.50 (s, 6H),
[1020]
2-Methyll-2-{2-methyl-4-[({4-[4-(trifluoromethyl)benzyl]-2-[4-(trif-
luoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
acid
[1021] From
2-methyl-4-[({4-(4-(trifluoromethyl)benzyl]-2-[4-(trifluoromet-
hyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenol (0.021 g, 0.04
mmol),
2-methyl-2-{2-methyl-4-[({4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluorome-
thyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
acid (0.006 g, 25%) was obtained as a white solid.
[1022] .sup.1H NMR (CD.sub.3OD): .delta. 8.02 (d, 2H), 7.78 (d,
2H), 7.60 (d, 2H), 7.30 (d, 2H), 7.23 (s, 1H), 7.16 (d, 1H), 6.73
(d, 1H), 4.29 (s, 2H), 4.00 (s, 2H), 2.17 (s, 3H), 1.61 (s, 6H);
.sup.19F NMR (CD.sub.3OD): .delta.-64.18 (s), -64.73 (s); MS m/z
626 (M+1); HPLC RT 4.273 (C18 4.2.times.100 mm, 0-100% ACN/H.sub.2O
(0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[1023]
2-Methyll-2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(tri-
fluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
acid
[1024] From
2-methyl-4-[({4-(4-trifluoromethoxy)benzyl]-2-[4-(trifluoromet-
hyl)phenyl-1,3-thiazol-5-yl}methyl)sulfanyl]phenol (0.048 g, 0.086
mmol),
2-methyl-2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluorom-
ethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
acid (0.013 g, 23%) was obtained as a white solid.
[1025] .sup.1H NMR (CD.sub.3OD): .delta. 8.04 (d, 2H), 7.74 (d,
2H), 7.20 (m, 6H), 6.72 (d, 1H), 4.26 (s, 2H), 3.95 (s, 2H), 2.15
(s, 3H), 1.61 (s, 6H); .sup.19F NMR (CD.sub.3OD): .delta. -59.86
(s), -64.72 (s); MS m/z 642 (M+1); HPLC RT 4.307 (C18 4.2.times.100
mm, 0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220
nm).
[1026]
2-{4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiaz-
ol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic
Acid
[1027] From
4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thi-
azol-5-yl}methyl)sulfanyl]-2-methylphenol (0.022 g, 0.04 mmol),
2-(4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl-1,3-thiazol-5-yl-
}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid (0.003 g,
12%) was obtained as a white solid.
[1028] .sup.1H NMR (CD.sub.3OD): .delta. 8.04 (d, 2H), 7.76 (d,
2H), 7.19 (s, 1H), 7.14 (d, 1H), 7.02 (d, 2H), 6.81 (d, 2H), 6.69
(d, 1H), 4.21 (s, 2H), 3.83 (s, 2H), 3.78 (s, 3H), 2.17 (s, 3H),
1.60 (s, 6H); MS m/z 588 (M+1); HPLC RT 4.136 (C18 4.2.times.100
mm, 0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220
nm).
[1029]
2-Methyll-2-{2-methyl-4-[({4-[4-methylsulfanyl)benzyl]-2-[4-(triflu-
oromethyl)phenyl-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
Acid
[1030] From
2-methyl-4-[({4-(4-methylsulfanyl)benzyl]-2-[4-(trifluoromethy-
l)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenol (0.296 g, 0.57
mmol),
2-methyl-2-{2-methyl-4-[({4-[4-(methylsulfanyl)benzyl]-2-[4-(trifluoromet-
hyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
(0.087 g, 25%) was obtained as a white solid.
[1031] .sup.1H NMR (CD.sub.3OD): .delta. 8.04 (d, 2H), 7.78 (d,
2H), 7.13 (m, 6H), 6.70 (d, 1H), 4.22 (s, 2H), 3.87 (s, 2H), 2.47
(s, 3H), 2.15 (s, 3H), 1.60 (s, 6H); MS m/z 604 (M+1); HPLC RT
4.220 (C18 4.2.times.110 mm, 0-100% ACN/H.sub.2O (0.1% TFA), 6 min
@ 2 ml/min @254/220 nm).
[1032]
2-{4-[({4-(4-tert-butylbenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-th-
iazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic
Acid
[1033] From
4-[({4-(4-tert-butylbenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3--
thiazol-5-yl}methyl)sulfanyl]-2-methylphenol (0.113 g, 0.21 mmol),
2-{4[-({4-(4-tert-butylbenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol--
5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanolc acid
(0.012 g, 9%) was obtained as a white solid.
[1034] .sup.1H NMR (CD.sub.3OD): .delta. 8.04 (d, 2H), 7.76 (d,
2H), 7.29 (d, 2H), 7.22 (s, 1H), 7.16 (d, 1H), 7.03 (d, 2H), 6.74
(d, 1H); MS m/z 614 (M+1); HPLC RT 4.464 (C184.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[1035]
2-Methyll-2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethy-
l)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
Acid
[1036] From
2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl-
]-1,3-thiazol-5-yl}methyl)sulfanyl]phenol (0.072 g, 0.15 mmol),
2-methyl-2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)pheny-
l]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid (0.039
g, 46%) was obtained as a cream solid.
[1037] .sup.1H NMR (CD.sub.3OD): .delta. 8.05 (d, 2H), 7.76 (d,
2H), 7.37 (t, 1H), 7.20 (s, 1H), 7.15 (d, 1H), 7.02 (s, 1H), 6.96
(d, 1H), 6.70 (d, 1H), 4.23 (s, 2H), 3.96 (s, 2H), 2.20 (s, 3H),
1.60 (s, 6H); MS m/z 564 (M+1); HPLC RT 4.112 (C184.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @2 ml/min @254/220 nm).
[1038] Ethyl
2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
[1039] From
2-methyl-4-[({4-(4-trifluoromethoxy)benzyl]-2-[4-(trifluoromet-
hyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenol (0.17 g, 0.31
mmol), ethyl
2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluorometh-
yl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
(0.17 g, 83%) was obtained as a white solid. MS m/z 656 (M+1); HPLC
RT 4.553 (C18 4.2.times.1100 mm, 0-100% ACN/H.sub.2O (0.1% TFA), 6
min @ 2 ml/min @254/220 nm).
[1040] Methyl
{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
[1041] From
2-methyl-4-[({4-(4-trifluoromethoxy)benzyl]-2-[4-(trifluoromet-
hyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenol (0.17 g, 0.31
mmol), methyl
{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethy-
l)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate (0.15 g,
80%) was obtained as a white solid. MS m/z 628 (M+1); HPLC RT 4.398
(C18 4.2.times.100 mm, 0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2
ml/min @2541220 nm).
[1042] Ethyl
2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)ph-
enyl]-1,3-thiazol-5-yl]methyl)sulfanyl]phenoxy}propanoate
[1043] From
2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl-
]-1,3-thiazol-5-yl)methyl)sulfanyl]phenol, ethyl
2-{2-methyl-4-[({4-(3-thi-
enylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl-
]phenoxy}propanoate (0.225 g, 0.47 mmol), (0.255 g, 91%) was
obtained as a yellow oil.
[1044] MS m/z 578 (M+1); HPLC RT 4.412 (C18 4.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[1045] Methyl
{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phe-
nyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
[1046] From
2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl-
]-1,3-thiazol-5-yl}methyl)sulfanyl]phenol, methyl
{2-methyl-4-[({4-(3-thie-
nylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-
phenoxy}acetate (0.225 g, 0.47 mmol), (0.259 g, 94%) was obtained
as a yellow oil.
[1047] MS m/z 550 (M+1); HPLC RT 4.243 (C18 4.2.times.100 mm,
0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[1048] The following 2 compounds were made by the Mitsunobu
reaction of
4-[({4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)-
phenyl)-1,3-thiazol-5-yl)methyl)sulfanyl]-2-methylphenol with R and
S Methyl lactate:
[1049] Methyl
(2S)-2-{4-[({4-4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-
-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylp-
henoxy}propanoate
[1050] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.24
Hz), 7.64 (d, 2H, J=8.24 Hz), 7.21 (d, 1H, J=2.20 Hz), 7.11 (dd,
1H, J=8.42, 2.20 Hz), 6.86 (d, 2H, J=9.16 Hz), 6.80 (d, 2H, J=9.16
Hz), 6.54 (d, 1H, J=8.42 Hz), 4.70 (q, 1H, J=6.78 Hz), 4.30 (s,
2H), 3.74 (s, 3H), 3.69 (s, 3H), 3.55 (s, 2H), 3.06 (br s, 4H),
2.62 (br s, 4H), 2.21 (s, 3H), 1.60 (d, 3H, J=6.78 Hz),
[1051] Methyl
(2R)-2-{4-[({4-([4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-
-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphe-
noxy}propanoate
[1052] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.24
Hz), 7.64 (d, 2H, J=8.24 Hz), 7.22 (d, 1H, J=2.01 Hz), 7.12 (dd,
1H, J=8.42, 2.01 Hz), 6.88 (d, 2H, J=9.16 Hz), 6.80 (d, 2H, J=9.16
Hz), 6.55 (d, 1H, J=8.42 Hz), 4.70 (q, 1H, J=6.78 Hz), 4.32 (s,
2H), 3.73 (s, 3H), 3.69 (s, 3H), 3.55 (s, 2H), 3.06 (t, 4H, J=4.76
Hz), 2.61 (br s, 4H), 2.22 (s, 3H), 1.60 (d, 3H, J=6.78 Hz),
[1053]
2-{4-[({4-{[4(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpropanoi-
c Acid
[1054] To a stirred solution of ethyl
2-{4-[({4-{[4-(4-methoxyphenyl)-1-pi-
perazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)su-
lfanyl]phenoxy}-2-methylpropanoate (77.0 g, 0.112 moles, 1 eq) in
THF (600 ml, 0.19M) was added MeOH (50 ml) and a 1N LiOH solution
(6.18 g in 250 ml H.sub.2O, 2.3 eq). The mixture was refluxed for 5
hrs after which the THF was removed in vacuo. The residue was
diluted with EtOAc and to it was added 1N HCl until a pH of about 5
was reached. The phases were separated and the organic fraction was
concentrated in vacuo, then titrated with isopropyl acetate twice
which was subsequently removed in vacuo each time. The crude
product was then recrystallized from EtOH to yield 52 g (71%) of a
white solid.
[1055] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.08 (d, 2H, J=8.24
Hz), 7.75 (d, 2H, J=8.24 Hz), 7.25 (d, 2H, J=8.61 Hz), 6.94 (d, 2H,
J=9.16 Hz), 6.82 (m, 4H), 4.28 (s, 2H), 3.72 (s, 3H), 3.59 (s, 2H),
3.16 (t, 4H, J=4.94 Hz), 2.96 (t, 4H, J=4.94 Hz), 1.54 (s, 6H),
[1056] CHN Analysis: Theory (C, 60.26%; H, 5.21%; N, 6.39%) Found
(C, 60.11%; H, 5.31%; N, 6.23%)
[1057] HPLC (C-18, 3 .mu.m) 0%-95% Acetonitrile/Water over 8
minutes R.sub.f=5.48 minutes
[1058]
{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methy-
l)sulfanyl]-2,5-dimethylphenoxy}acetic Acid
[1059] Mass spec: calculated for
C.sub.28H.sub.24F.sub.3NO.sub.3S.sub.2: 543. Found: 544 (MH.sup.+).
HPLC trace: retention time=13.5 min (Alltima C.sub.18, 5 micron,
250 mm column, Gradient elution with 70-100%
CH.sub.3CN/H.sub.2O).
[1060]
2-{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}met-
hyl)sulfanyl]-2-methylphenoxy}propanoic Acid
[1061] Elemental analysis calculated for
C.sub.28H.sub.24F.sub.3NO.sub.3S.- sub.2: C: 61.8%, H: 4.5%, N:
2.6%. Found: C: 61.77%, H: 4.64%, N: 2.51%. HPLC trace: retention
Time 0.7 min (Alltima C.sub.18, 5 micron, 250 mm column, gradient
elution with 70-100% CH.sub.3CN/H.sub.2O).
[1062]
2-{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}met-
hyl)sulfanyl]-2,3-dimethylphenoxy}propanoic Acid
[1063] Elememtal analysis calculated for
C.sub.29H.sub.26F.sub.3NO.sub.3S.- sub.2: C: 62.4%, H: 4.7%, N:
2.5%. Found: C: 62.58%, H: 4.93%, N: 2.44%. HPLC trace: retention
time=14.7 min (Alltima C.sub.18, 5 micron, 250 mm column using
gradient elution with 70-100% CH.sub.3CN/H.sub.2O).
[1064]
2-{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}met-
hyl)sulfanyl]2-fluorophenoxy}propanoic Acid
[1065] Mass spec calculated for
C.sub.27H.sub.21F.sub.4NO.sub.3S.sub.2: 547. Found: 548 (MH.sup.+).
HPLC, Trace: retention time=12.1 min (Alltima C.sub.18, 5 micron,
250 mm column using gradient elution with 70-100%
CH.sub.3CN/H.sub.2O).
[1066]
(2S)-2-{4-[({4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(tr-
ifluoromethyl)phenyl-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}pro-
panoic Acid
[1067] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.07 (d, 2H, J=8.24
Hz), 7.74 (d, 2H, J=8.24 Hz), 7.19 (d, 1H, J=2.20 Hz), 7.09 (dd,
1H, J=8.42, 2.20 Hz), 6.91 (d, 2H, J=9.16 Hz), 6.80 (d, 2H, J=9.16
Hz), 6.62 (d, 1H, J=8.42 Hz), 4.68 (q, 1H, J=6.78 Hz), 4.28 (s,
2H), 3.71 (s, 3H), 3.48 (s, 2H), 3.05 (t, 4H, J=4.76 Hz), 2.69 (t,
4H, J=4.76 Hz), 2.18 (s, 3H), 1.57 (d, 3H, J=6.78 Hz),
[1068] Chiral HPLC (Chiralpak, 2 cm) 75% Carbon Dioxide/25%
Methanol over 65 minutes R.sub.f@0.88 minutes
[1069]
(2R)-2-(4-[({4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}pr-
opanoic Acid
[1070] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.11 (d, 2H, J=8.24
Hz), 7.76 (d, 2H, J=8.24 Hz), 7.15 (d, 1H, J=2.20 Hz), 7.08 (dd,
1H, J=8.42, 2.20 Hz), 6.93 (d, 2H, J=9.16 Hz), 6.82 (d, 2H, J=9.16
Hz), 6.67 (d, 1H, J=8.42 Hz), 4.57 (q, 1H, J=6.78 Hz), 4.24 (s,
2H), 3.71 (s, 3H), 3.54 (s, 2H), 3.17 (t, 4H, J=4.76 Hz), 3.02 (t,
4H, J=4.76 Hz), 2.18 (s, 3H), 1.55 (d, 3H, J=6.78 Hz),
[1071] Chiral HPLC (Chiralpak, 2 cm) 75% Carbon Dioxide/25%
Methanol over 65 minutes R.sub.tT.58 minutes
[1072] 2-(4-{[-(2-(4-Fluor
phenyl)-4-{[4-(4-methoxyphenyl)-1-piperazinyl]m-
ethyl}-1,3-thiazol-5-yl)methyl]sulfanyl}-2-methylphenoxy}-2-methylpropanoi-
c Acid
[1073] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 7.95 (m, 2H), 7.18
(m, 3H), 7.05 (br s, 1H), 6.93 (d, 2H, J=8.61 Hz), 6.81 (d, 2H,
J=8.61 Hz), 6.69 (br s, 1H), 4.22 (s, 2H), 3.72 (s, 3H), 3.55 (s,
2H), 3.17 (br s, 4H), 2.93 (br s, 4H), 2.14 (s, 3H), 1.59 (s,
6H),
[1074]
[4-({[4-[(4-Benzyl-1-piperazinyl)methyl]-2-(4-{trifluoromethyl}phen-
yl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetic
Acid
[1075] .sup.1H (CD.sub.3OD) 300 MHz .delta. 8.15 (d, 2H, J=8.23
Hz), 7.81 (d, 2H, J=8.23 Hz), 7.48 (m, 5H), 7.24 (s, 2H), 6.74 (s,
1H), 4.55 (s, 2H), 4.28 (s, 2H), 4.15 (s, 2H), 3.46 (s, 2H), 3.06
(s, 4H), 2.49 (s, 4H), 2.09 (s, 3H). MS(ES.sup.-) M-H=625.98.
TLC(10% MeOH/CH.sub.2Cl.sub.2) R.sub.f=0.35
[1076]
{2-Methyl-4-[({2-(4-(4-trifluoromethyl}phenyl)-4-[(4-methyl-1-piper-
idinyl)methyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic
Acid
[1077] .sup.1H (CD.sub.3OD) 300 MHz .delta. 8.20 (d, 2H, J=7.97
Hz), 7.85 (d, 2H, J=7.97 Hz), 7.27 (s, 1H), 7.08 (s, 1H), 6.68 (s,
1H), 4.62 (s, 2H), 4.29 (s, 2H), 3.70 (s, 2H), 2.86 (s, 2H), 2.26
(s, 3H), 1.90 (s, 2H), 1.48 (m, 5H), 1.06 (s, 3H). MS(ES.sup.-)
M-H=548.91. TLC(10% MeOH/CH.sub.2Cl.sub.2) R.sub.f=0.24
[1078]
[2-Methyl-4-({[4-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-
-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]ac-
etic Acid
[1079] .sup.1H (CDCl.sub.3) 400 MHz .delta. 8.03 (d, 2H, J=8.03
Hz), 7.93 (d, 2H, J=8.89 Hz), 7.70 (d, 2H, J=8.03 Hz), 7.19 (d, 1H,
J=2.22 Hz), 7.07 (dd, 1H, J=8.37, 2.22 Hz), 6.96 (d, 2H, J=8.89
Hz), 6.53 (d, 1H, J=8.37 Hz), 4.88 (s, 2H), 4.64 (s, 2H), 4.27 (s,
2H), 2.65 (s, 3H), 2.17 (s, 3H). TLC(5% MeOH/CH.sub.2Cl.sub.2)
R.sub.f=0.13. MS(ES.sup.-) M-H=625.92
[1080]
[2-Methyl-4-({[4-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl)-
-2(4-{trifluoromethyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]ace-
tic Acid
[1081] .sup.1H (CDCl.sub.3) 400 MHz .delta. 8.04 (d, 2H, J=8.20
Hz), 7.69 (m, 3H), 7.37 (s, 2H), 7.16 (dd, 1H, J=8.20, 2.22 Hz),
7.05 (dd, 1H, J=8.20, 2.22 Hz), 6.91 (d, 1H, J=2.22 Hz), 6.62 (d,
1H, J=8.20 Hz), 4.72 (s, 2H), 4.43 (s, 2H), 4.19 (s, 2H), 2.73 (s,
3H), 2.09 (s, 3H). TLC(5% MeOH/CH.sub.2Cl.sub.2) R.sub.f=0.1 3.
MS(ES.sup.-) M-H=625.86
[1082]
(2-Methyl-4{[(2-(4-{trifluoromethyl}phenyl)-4-([4-(2-methylphenyl)--
1-piperazinyl]methyl}-1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)acetic
Acid
[1083] .sup.1H (CDCl.sub.3) 400 MHz .delta. 8.10 (d, 2H, J=8.03
Hz), 7.73 (d, 2H, J=8.03 Hz), 7.16 (m, 4H), 7.01 (br s, 2H), 6.73
(d, 1H, J=8.37 Hz), 4.79 (s, 2H), 4.08 (s, 2H), 3.80 (m, 4H), 3.53
(m, 2H), 3.24 (m, 4H), 2.40 (s, 3H), 2.18 (s, 3H). TLC(5%
MeOH/CH.sub.2Cl.sub.2) R.sub.f=0.10. MS(ES.sup.-) M-H=625.94
[1084]
[4-({[4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-(4-trifluorom-
ethyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetic
Acid
[1085] .sup.1H (CDCl.sub.3) 400 MHz .delta. 8.04 (d, 2H, J=8.20
Hz), 7.72 (d, 2H, J=8.20 Hz), 7.12 (s, 1H), 6.96 (m, 3H), 6.81 (d,
2H, J=8.89 Hz), 6.74 (d, 1H, J=8.37 Hz), 4.76 (s, 2H), 4.05 (s,
2H), 3.74 (s, 3H), 3.38 (m, 10H), 2.16 (s, 3H). TLC(5%
MeOH/CH.sub.2Cl.sub.2) R.sub.f=0.13. MS(ES.sup.-) M-H=641.90
[1086]
(2-Methyl-4-{[(2-(4-{trifluoromethyl}phenyl)-4-{[4-(3-methylphenyl)-
-1-piperazinyl]methyl}-1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)acetic
Acid
[1087] .sup.1H (CDCl.sub.3) 400 MHz .delta. 8.05 (d, 2H, J=8.20
Hz), 7.72 (d, 2H, J=8.20 Hz), 7.20 (s, 1H), 7.06 (d, 2H, J=9.06
Hz), 6.91 (m, 3H), 6.72 (d, 1H, J=8.37 Hz), 4.77 (s, 2H), 4.06 (s,
2H), 3.54 (br s, 8H), 3.27 (s, 2H), 2.30 (s, 3H), 2.16 (s, 3H).
TLC(5% MeOH/CH.sub.2Cl.sub.2) R.sub.f=0.10. MS(ES.sup.-)
M-H=625.99
[1088]
(2-Methyl-4-{[(2-(4-{trifluoromethyl}phenyl)-4-{(4-(4-methylphenyl)-
-1-piperazinyl]methyl}-1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)acetic
Acid
[1089] .sup.1H (CDCl.sub.3) 400 MHz .delta. 8.03 (d, 2H, J=8.20
Hz), 7.71 (d, 2H, J=8.20 Hz), 7.02 (m, 6H), 6.71 (d, 1H, J=8.55
Hz), 4.76 (s, 2H), 4.08 (s, 2H), 3.52 (brs, 8H), 3.31 (s, 2H), 2.27
(s, 3H), 2.16 (s, 3H). TLC(5% MeOH/CH.sub.2Cl.sub.2) R.sub.f=0.10.
MS(ES.sup.-) M-H=625.94
[1090]
[4-({[4-{[4-(2-Furoyl)-1-piperazinyl]methyl}-2-(4-{trifluoromethyl}-
phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetic
Acid
[1091] .sup.1H (CDCl.sub.3) 400 MHz .delta. 8.02 (d, 2H, J=8.20
Hz), 7.71 (d, 2H, J=8.20 Hz), 7.48 (d, 1H, J=2.05 Hz), 7.16 (dd,
1H, J=8.20, 2.05 Hz), 7.07 (m, 1H), 6.90 (d, 1H, J=2.39 Hz), 6.74
(d, 1H, J=8.20 Hz), 6.49 (m, 1H), 4.77 (s, 2H), 4.62 (s, 2H), 4.05
(s, 2H), 3.46 (s, 2H), 3.27 (s, 2H), 3.05 (br s, 4H), 2.15 (s, 3H)
TLC(5% MeOH/CH.sub.2Cl.sub.2) R.sub.f=0.10. MS(ES.sup.-)
M-H=629.83
[1092]
(2-Methyl-4-{[(2-(4-(trifluoromethylphenyl)-4-{[4-(2-pyridinyl)-1-p-
iperazinyl]methyl}-1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)acetic
Acid
[1093] .sup.1H (CDCl.sub.3) 400 MHz .delta. 8.22 (m, 1H), 7.99 (d,
2H, J=8.20 Hz), 7.68 (d, 2H, J=8.20 Hz), 7.60 (s, 1H), 7.20 (dd,
1H, J=8.37, 2.39 Hz), 7.14 (s, 1H), 6.76 (m, 1H), 6.68 (m, 1H),
4.68 (s, 2H), 4.14 (s, 2H), 3.72 (br s, 4H), 3.59 (s, 2H), 2.87 (br
s, 4H), 2.17 (s, 3H). TLC(5% MeOH/CH.sub.2Cl.sub.2) R.sub.f=0.10.
MS(ES.sup.-) M-H=612.99
[1094]
[4-({[4-{[4-(4-Chlorobenzyl)-1-piperazinyl]methyl}-2-(4-{trifluorom-
ethyl)phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetic
Acid
[1095] .sup.1H (CDCl.sub.3) 400 MHz .delta. 8.04 (d, 2H, J=8.20
Hz), 7.70 (d, 2H, J=8.20 Hz), 7.41 (m, 4H), 7.14 (m, 1H), 7.03 (m,
1H), 6.69 (d, 1H, J=8.37 Hz), 4.72 (s, 2H), 4.02 (s, 2H), 3.18 (m,
12H), 2.10 (s, 3H). TLC(5% MeOH/CH.sub.2Cl.sub.2) R.sub.f=0.10.
MS(ES.sup.-) M-H=659.78
[1096]
[4-({[4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-(4-(trifluorom-
ethyl)phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetic
Acid
[1097] .sup.1H (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.03
Hz), 7.85 (d, 2H, J=8.89 Hz), 7.70 (d, 2H, J=8.03 Hz), 7.16 (dd,
1H, J=8.37, 2.22 Hz), 6.86 (m, 3H), 6.75(d, 1H, J=8.37 Hz), 4.77
(s, 2H), 4.04 (s, 2H), 3.80 (m, 4H), 3.45 (m, 4H), 3.29 (s, 2H),
2.51 (s, 3H), 2.17 (s, 3H). TLC(5% MeOH/CH.sub.2Cl.sub.2)
R.sub.f=0.10. MS(ES.sup.-) M-H=653.99
[1098]
(4-{[(4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-phenyl-1,3-th-
iazol-5-yl)methyl]sulfanyl}-2-methylphenoxy)acetic Acid
[1099] .sup.1H NMR (CDCl.sub.3) 400 MHz 9.94 (s, 1H), 7.84 (m, 2H),
7.41 (m, 3H), 7.11 (d, 1H. J=2.22 Hz), 7.06 (dd, 1H, J=8.37, 2.22
Hz), 6.79 (m, 4H), 6.60 (d, 1H, J=8.37 Hz), 4.54 (s, 2H), 4.18 (s,
2H), 3.76 (s, 2H), 3.22 (m, 8H), 2.18 (s, 3H). HPLC(C-18, 3 .mu.m)
1% MeOH/0-90% CH.sub.3CN/Water (0.1% TFA)/(50 mM Et.sub.3N/TFA) 4
min run R.sub.f=2.67 min
[1100]
2-{4-[(4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoi-
c Acid
[1101] .sup.1H NMR (CDCl.sub.3) 400 MHz. .delta.9.69 (s, 1H), 7.96
(d, 2H, J=8.20 Hz), 7.65 (d, 2H, J=8.20 Hz), 7.07 (d, 1H, J=2.05
Hz), 7.02 (dd, 1H, J=8.55, 2.05 Hz), 6.87 (d, 2H, J=9.23 Hz), 6.80
(d, 2H, J=9.23 Hz), 6.66 (d, 1H, J=8.55 Hz), 4.66 (q, 1H, J=6.95
Hz), 4.10 (d, 1H, J=0.70 Hz), 4.05 (d, 1H, J=0.70 Hz), 3.74 (s,
3H), 3.57 (d, 1H, J=0.18 Hz), 3.51 (d, 1H, J=0.18 Hz), 3.15 (br s,
4H), 2.96 (br s, 4H), 2.17 (s, 3H), 1.59 (d, 3H, J=6.95 Hz).
HPLC(C-18, 3 .mu.m) 1% MeOH/0-90% CH.sub.3CN/Water (0.1% TFA)/(50
mM Et.sub.3N/TFA) 4 min run R.sub.f=2.91 min
[1102]
2-(4-{[(4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-phenyl-1,3--
thiazol-5-yl)methyl]sulfanyl}-2-methylphenoxy)propanoic Acid
[1103] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.81 (m, 2H), 7.34
(m, 3H), 7.09 (m, 1H), 6.90 (m, 1H), 6.79 (m, 4H), 6.48 (d, 1H,
J=8.37 Hz), 4.35 (m, 1H), 4.16 (s, 2H), 3.70 (s, 3H), 3.32 (s, 2H),
3.00 (m, 4H), 2.60 (m, 4H), 2.09 (s, 3H), 1.34 (m, 3H). HPLC(C-18,
3 .mu.m) 1% MeOH/0-90% CH.sub.3CN/Water (0.1% TFA)/(50 mM
Et.sub.3N/TFA) 4 min run R.sub.t=2.78 min
[1104]
{2-Methyl-4-[({2-(4-{trifluoromethyl}phenyl)-4-[(4-phenyl-1-piperaz-
inyl)methyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic
Acid
[1105] .sup.1H (CD.sub.3OD) 300 MHz .delta. 8.16 (d, 2H, J=8.49
Hz), 7.81 (d, 2H, J=8.49 Hz), 7.26 (br s, 3H), 7.09 (br s, 1H),
6.98 (d, 2H, J=7.96 Hz), 6.88 (m, 1H), 6.66 (br s, 1H), 4.57 (s,
2H), 4.29 (s, 2H), 3.55 (s, 2H), 3.26 (br s, 4H), 2.91 (br s, 4H),
2.23 (s, 3H). MS(ES.sup.-) M-H=611.85. TLC(10%
MeOH/CH.sub.2Cl.sub.2) R.sub.f=0.30
[1106]
[4-({[4-{[4-(Ethoxycarbonyl)-1-piperazinyl]methyl}-2-(4-{trifluorom-
ethyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetic
Acid
[1107] .sup.1H (CD.sub.3OD) 300 MHz .delta. 8.14 (d, 2H, J=8.23
Hz), 7.81 (d, 2H, J=8.23 Hz), 7.26 (s, 1H), 7.12 (s, 1H), 6.71 (s,
1H), 4.63 (s, 2H), 4.32 (s, 2H), 4.16 (q, 2H, J=7.08 Hz), 3.55 (br
s, 4H), 3.44 (s, 2H), 2.60 (br s, 4H), 2.25 (s, 3H), 1.30 (t, 3H,
J=7.08 Hz). MS(ES.sup.-) M-H=607.86. TLC(10% MeOH/CH.sub.2Cl.sub.2)
R.sub.f=0.28
[1108]
{2-Methyl-4-[({2-(4-{trifluoromethyl}phenyl)-4-[(4-phenyl-1-piperid-
inyl)methyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic
Acid
[1109] .sup.1H (CD.sub.3OD) 300 MHz .delta. 8.14 (d, 2H, J=8.23
Hz), 7.77 (d, 2H, J=8.23 Hz), 7.28 (s, 7H), 6.75 (d, 1H, J=8.23
Hz), 4.45 (s, 2H), 4.34 (s, 2H), 3.53 (s, 2H), 3.08 (m, 2H), 2.57
(m, 1H), 2.35 (m, 2H), 2.22 (s, 3H), 1.80 (m, 4H). MS(ES.sup.-)
M-H=610.91. TLC(10% MeOH/CH.sub.2Cl.sub.2) R.sub.f=0.30
[1110]
[4-({[4-{[(Cyclopropylmethyl)amino]methyl}-2-(4-(trifluoromethylphe-
nyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetic
Acid
[1111] .sup.1H NMR 300 MHz .delta. 8.08 (d, 2H, J=8.20 Hz), 7.74
(d, 2H, J=8.20 Hz), 7.14 (dd, 1H, J=8.49, 2.39 Hz), 7.01 (s, 1H),
6.72 (d, 1H, J=8.49 Hz), 4.77 (s, 2H), 4.03 (s, 2H), 3.29 (s, 2H),
2.77 (d, 2H, J=7.43 Hz), 2.17 (s, 3H), 1.17 (m, 1H), 0.62 (m, 2H),
0.28 (m, 2H). MS(ES.sup.-) M-H=520.90. HPLC(C-18, 3 .mu.m) 1%
MeOH/0-90% CH.sub.3CN/Water (0.1% TFA)/(50 mM Et.sub.3N/TFA) 4 min
run R.sub.t=2.67 min
[1112]
{2-Methyl-4-[({2-(4-{trifluoromethyl}phenyl)-4-[(pentylamino)methyl-
]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic Acid
[1113] .sup.1H NMR 300 MHz .delta. 8.06 (d, 2H, J=8.23 Hz), 7.69
(d, 2H, J=8.23 Hz), 7.05 (m, 2H), 6.66 (d, 1H, J=8.23 Hz), 4.67 (s,
2H), 4.06 (s, 2H), 3.35 (s, 2H), 2.78 (t, 2H, J=6.64 Hz), 2.17 (s,
3H), 1.71 (m, 2H), 1.22 (m, 4H), 0.83 (t, 3H, J=6.64 Hz).
MS(ES.sup.-) M-H=536.90. HPLC(C-18, 3 .mu.m) 1% MeOH/0-90%
CH.sub.3CN/Water (0.1% TFA)/(50 mM Et.sub.3N/TFA) 4 min run
R.sub.t=2.80 min
[1114]
4-({[4-{[4-(2-Hydroxyethyl)-1-piperazinyl]methyl}-2-(4-{trifluorome-
thyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetic
Acid
[1115] .sup.1H NMR (CD.sub.3OD) 300 MHz .delta. 8.16 (d, 2H, J=8.23
Hz), 7.80 (d, 2H, J=8.23 Hz), 7.26 (m, 2H), 6.80 (d, 1H, J=8.49
Hz), 4.76 (s, 2H), 4.40 (s, 2H), 3.95 (m, 2H), 3.84 (s, 2H), 3.54
(br s, 4H), 3.33 (m, 2H), 3.20 (br s, 4H), 2.22 (s, 3H). HPLC(C-18,
3 .mu.m) 1% MeOH/0-90% CH.sub.3CN/Water (0.1% TFA)/(50 mM
Et.sub.3N/TFA) 4 min run R.sub.t=2.48 min
[1116]
(2-Methyl-4-{[(2-(4-{trifluoromethyl}phenyl)-4-{[(3-pyridinylmethyl-
)amino]methyl}-1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)acetic
Acid
[1117] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.58 (d, 1H, J=1.59
Hz), 8.48 (dd, 1H, J=4.78, 1.59 Hz), 8.03 (m, 3H), 7.66 (d, 2H,
J=8.23 Hz), 7.24 (m, 1H), 7.06 (d, 1H. J=2.39 Hz), 6.99 (d, 1H,
J=2.39 Hz), 6.59 (d, 1H, J=8.49 Hz), 4.61 (s, 2H), 4.04 (s, 2H),
3.93 (s, 2H), 3.28 (s, 2H), 2.13 (s, 3H). MS(ES.sup.-) M-H=557.80.
HPLC(C-18, 3 .mu.m) 1% MeOH/0-90% CH.sub.3CN/Water (0.1% TFA)/(50
mM Et.sub.3N/TFA) 4 min run R.sub.t=2.44 min
[1118]
[4-({[4-[(3-Hydroxy-1-piperidinyl)methyl]-2-(4-{trifluoromethyl}phe-
nyl)-1,3-thiazol-5-yl]methyl]sulfanyl)-2-methylphenoxy]acetic
Acid
[1119] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.00 (d, 2H, J=8.37
Hz), 7.69 (d, 2H, J=8.37 Hz), 7.23 (dd, 1H, J=8.55, 2.20 Hz), 6.94
(d, 1H, J=2.20 Hz), 6.69 (d, 1H, J=8.55 Hz), 4.68 (s, 2H), 4.21 (s,
2H), 3.16 (m, 7H), 2.12 (s, 3H), 1.63 (m, 4H). MS(ES.sup.-)
M-H=550.8. HPLC(C-18, 3 .mu.m) 1% MeOH/0-90% CH.sub.3CN/Water (0.1%
TFA)/(50 mM Et.sub.3N/TFA) 4 min run R.sub.t=2.58 min
[1120]
[4-({[4-[(4-Hydroxy-1-piperidinyl)methyl]-2-(4-{trifluoromethyl}phe-
nyl)- 1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetic
Acid
[1121] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.97 (d, 2H, J=8.23
Hz), 7.65 (d, 2H, J=8.23 Hz), 7.11 (m, 2H), 6.58 (d, 1H, J=8.23
Hz), 4.53 (s, 2H), 4.18 (s, 2H), 3.86 (br s, 1H), 3.62 (m, 2H),
3.12 (m, 2H), 2.95 (m, 2H), 2.15 (s, 3H), 2.04 (m, 2H), 1.77 (m,
2H). HPLC(C-18, 3 .mu.m) 1% MeOH/0-90% CH.sub.3CN/Water (0.1%
TFA)/(50 mM Et.sub.3N/TFA) 4 min run R.sub.t=2.54 min
[1122]
[4-({[4-{[2-(hydroxymethyl)-1-piperidinyl]methyl}-2-(4-{trifluorome-
thyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetic
Acid
[1123] MS(ES.sup.-) M-H=564.94. HPLC(C-18, 3 .mu.m) 1% MeOH/0-90%
CH.sub.3CN/Water (0.1% TFA)/(50 mM Et.sub.3N/TFA) 4 min run
R.sub.t=2.66 min
[1124]
[4-({[4-{[4-(Hydroxymethyl)-1-piperidinyl]methyl}-2-(4-{trifluorome-
thyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetic
Acid
[1125] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.94 (d, 2H, J=8.20
Hz), 7.64 (d, 2H, J=8.20 Hz), 7.13 (dd, 1H, J=8.55, 2.39 Hz), 7.06
(d, 1H, J=2.39 Hz), 6.58 (d, 1H, J=8.55 Hz), 4.60 (s, 2H), 4.45 (s,
2H), 4.18 (s, 2H), 3.56 (m, 6H), 2.75 (br s, 1H), 2.11 (s, 3H),
1.68 (m, 4H). MS(ES.sup.-) M-H=564.93. HPLC(C-18, 3 .mu.m) 1%
MeOH/0-90% CH.sub.3CN/Water (0.1% TFA)/(50 mM Et.sub.3N/TFA) 4 min
run R.sub.t=2.56 min
[1126]
[2-Methyl-4-({[2-(4-{trifluoromethyl}phenyl)-4-(4-morpholinylmethyl-
)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]acetic Acid
[1127] .sup.1H NMR (CD.sub.3OD) 300 MHz .delta. 8.11 (d, 2H, J=8.23
Hz), 7.79 (d, 2H, J=8.23 Hz), 7.25 (br s, 1H), 7.17 (dd, 1H,
J=8.23, 2.39 Hz), 6.74 (d, 1H, J=8.23 Hz), 4.46 (s, 2H), 4.32 (s,
2H), 3.69 (brs, 4H), 3.47 (s, 2H), 2.50 (br s, 4H), 2.23 (s, 3H).
MS(ES.sup.-) M-H-536.43. TLC(20% MeOH/CH.sub.2Cl.sub.2) R.sub.f
0.39
[1128]
[4-({[4-[(Cyclohexylamino)methyl]-2-(4-{trifluoromethyl}phenyl)-1,3-
-thiazol-5-yl]methyl]sulfanyl)-2-methylphenoxy]acetic Acid
[1129] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.01 (d, 2H, J=8.20
Hz), 7.66 (d, 2H, J=8.20 Hz), 7.04 (m, 2H), 6.61 (d, 1H, J=8.20
Hz), 4.64 (s, 2H), 4.14 (s, 2H), 3.39 (s, 2H), 2.86 (m, 1H), 2.14
(s, 3H), 2.01 (m, 2H), 1.73 (m, 2H), 1.48 (m, 4H), 1.08 (m, 2H).
MS(ES.sup.-) M-H=548.7. HPLC(C-18, 3 .mu.m) 1% MeOH/0-90%
CH.sub.3CN/Water (0.1% TFA)/(50 mM Et.sub.3N/TFA) 4 min run
R.sub.t=2.75 min
[1130]
[2-Methyl-4-({[7-{[(2-methylcyclohexyl)amino]methyl}-23-(4-{trifluo-
romethyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]acetic
Acid
[1131] .sup.1H NMR 400 MHz .delta. 7.98 (d, 2H, J=8.20 Hz), 7.68
(d, 2H, J=8.20 Hz), 7.09 (dd, 1H, J=8.37, 2.39 Hz), 6.98 (d, 1H,
J=2.39 Hz), 6.65 (d, 1H, J=8.37 Hz), 4.66 (s, 2H), 4.15 (d, 1H,
J=0.70 Hz), 4.00 (d, 1H, J=0.70 Hz), 3.53 (d, 1H, J=0.04 Hz), 3.33
(d, 1H, J=0.04 Hz), 2.53 (m, 1H), 2.10 (s, 3H), 1.74 (m, 7H), 1.37
(m, 2H), 1.03 (d, 3H, J=6.32 Hz). MS(ES.sup.-) M-H=562.80.
HPLC(C-18, 3 .mu.m) 1% MeOH/0-90% CH.sub.3CN/Water (0.1% TFA)/(50
mM Et.sub.3N/TFA) 4 min run R.sub.t=2.87 min
[1132]
[2-Methyl-4-({[4-{[(3-methylcyclohexyl)amino]methyl)-2-(4-{trifluor-
omethyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]acetic
Acid
[1133] .sup.1H NMR 400 MHz .delta. 8.01 (d, 2H, J=8.20 Hz), 7.68
(d, 2H, J=8.20 Hz), 7.05 (m, 2H), 6.62 (d, 1H, J=8.37 Hz), 4.68 (s,
2H), 4.29 (s, 2H), 3.32 (s, 2H), 2.90 (m, 1H), 2.15 (s, 3H), 2.00
(m, 5H), 1.56 (m, 4H), 0.89 (d, 3H, J=6.32 Hz). MS(ES.sup.-)
M-H=562.9. HPLC(C-18, 3 .mu.m) 1% MeOH/0-90% CH.sub.3CN/Water (0.1%
TFA)/(50 mM Et.sub.3N/TFA) 4 min run R.sub.t=2.85 min
[1134]
[2-Methyl-4-({[4-{[(4-methylcyclohexyl)amino]methyl}-2-(4-{trifluor-
omethyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]acetic
Acid
[1135] .sup.1H NMR 400 MHz .delta. 7.99 (d, 2H, J=8.20 Hz), 7.64
(d, 2H, J=8.20 Hz), 7.02 (m, 2H), 6.59 (d, 1H, J=8.03 Hz), 4.58 (s,
2H), 4.16 (s, 2H), 3.44 (s, 2H), 2.90 (brs, 1H), 2.12 (s, 3H), 2.01
(m, 3H), 1.62 (m, 6H), 0.90 (d, 3H, J=6.84 Hz). MS(ES.sup.-)
M-H=562.90. HPLC(C-18, 3 .mu.m) 1% MeOH/0-90% CH.sub.3CN/Water
(0.1% TFA)/(50 mM Et.sub.3N/TFA) 4 min run R.sub.t=2.85 min
[1136]
[2-Methyl-4-({[4-[(2-methylphenoxy)methyl]-2-(4-{trifluoromethyl}ph-
enyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]acetic Acid
[1137] .sup.1H (CDCl.sub.3) 300 MHz .delta. 8.03 (d, 2H, J=8.23
Hz), 7.72 (d, 2H, J=8.23 Hz), 7.17 (m, 4H), 6.91 (m, 2H), 6.59 (d,
1H, J=8.49 Hz), 4.96 (s, 2H), 4.67 (s, 2H), 2.25 (s, 3H), 2.21 (s,
3H). MS(ES.sup.-) M-H=557.8
[1138]
[2-Methyl-4-({[4-[(3-methylphenoxy)methyl]-2-4-{trifluoromethyl}phe-
nyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]acetic Acid
[1139] .sup.1H (CDCl.sub.3) 300 MHz .delta. 8.06 (d, 2H, J=8.23
Hz), 7.73 (d, 2H, J=8.23 Hz), 7.26 (dd, 1H, J=2.39, 0.53 Hz), 7.20
(t, 1H, J=7.83 Hz), 7.12 (ddd, 1H, J=8.49, 2.39, 0.53 Hz), 6.80 (m,
3H), 6.61 (d, 1H, J=8.49 Hz), 4.86 (s, 2H), 4.67 (s, 2H), 4.32 (s,
2H), 2.36 (s, 3H), 2.23 (s, 3H). MS(ES.sup.-) M-H=557.83
[1140]
[2-Methyll-4-({[4-[(4-Methyllphenoxy)methyl]-2-(4-{trifluoromethyl}-
phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]acetic Acid
[1141] MS(ES.sup.-) M-H=557.8
[1142] CHN Analysis: Theory 1.5H.sub.2O(C, 57.33%; H, 4.64%; N,
2.39%) Found (C, 57.34%; H, 4.24%; N, 2.37%)
[1143]
[4-({[4-[(3-Cyanophenoxy)methyl]-2-(4-{trifluoromethyl}phenyl)-1,3--
thiazol-5-yl]methyl}sulfanyl)-2-Methyllphenoxy]acetic Acid
[1144] .sup.1H (CDCl.sub.3) 300 MHz .delta. 8.05 (d, 2H, J=8.23
Hz), 7.74 (d, 2H, J=8.23 Hz), 7.38 (m, 2H), 7.17 (m, 4H), 6.67 (d,
1H, J=8.23 Hz), 4.76 (s, 2H), 4.72 (s, 2H), 4.25 (s, 2H), 2.23 (s,
3H). MS(ES.sup.-) M-H=569.2
[1145]
[4-({[4-[(4-Cyanophenoxy)methyl]-2-(4-{trifluoromethyl}phenyl)-1,3--
thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetic Acid
[1146] .sup.1H (CDCl.sub.3) 300 MHz .delta. 9.94 (s, 1H), 8.03 (d,
2H, J=8.23 Hz), 7.73 (d, 2H, J=8.23 Hz), 7.60 (d, 2H, J=9.03 Hz),
7.27 (d, 1H, J=2.12 Hz), 7.10 (dd, 1H, J=8.49, 2.12 Hz), 7.00 (d,
2H, J=9.03 Hz), 6.61 (d, 1H, J=8.49 Hz), 4.85 (s, 2H), 4.69 (s,
2H), 4.25 (s, 2H), 2.21 (s, 3H). MS(ES.sup.-) M-H=569.2
[1147]
(2-Methyl-4{[(4-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}--
2-phenyl-1,3-thiazol-5-yl)methyl]sulfanyl}phenoxyacetic Acid
[1148] .sup.1H (CDCl.sub.3)400 MHz 7.95 (d, 2H, J=9.06 Hz), 7.87
(m, 2H), 7.43 (m, 3H), 7.20 (d, 1H, J=2.39 Hz), 7.05 (dd, 1H,
J=8.55, 2.39 Hz), 6.95 (d, 2H, J=9.06 Hz), 6.52 (d, 1H, J=8.55 Hz),
4.80 (s, 2H), 4.61 (s, 2H), 4.24 (s, 2H), 2.63 (s, 3H), 2.17 (s,
3H). MS(ES.sup.-) M-H=558.40
[1149]
2-(2-Methyl-4-{[(4-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methy-
l}-2-phenyl-1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)propanoic
Acid
[1150] .sup.1H (CDCl.sub.3) 400 MHz .delta. 7.93 (d, 2H, J=9.06
Hz), 7.85 (m, 2H), 7.40 (m, 3H), 7.19 (d, 1H, J=2.22 Hz), 7.02 (dd,
1H, J=8.37, 2.22 Hz), 6.94 (d, 2H, J=9.06 Hz), 6.52 (d, 1H, J=8.37
Hz), 4.81 (d, 1H, J=0.79 Hz), 4.74 (d, 1H, J=0.79 Hz), 4.68 (q, 1H.
J=6.78 Hz), 4.21 (s, 2H), 2.62 (m, 3H), 2.16 (s, 3H), 1.61 (d, 3H,
J=6.78 Hz). MS(ES.sup.-) M-H=571.50
[1151]
2-{2-Methyl-4-[({4-([3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methy-
l}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-
propanoic Acid
[1152] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.99 (d, 2H, J=8.20
Hz), 7.67 (m, 3H), 7.47 (m, 1H), 7.36 (t, 1H, J=8.03 Hz), 7.10 (dd,
1H, J=8.37, 2.39 Hz), 7.04 (dd, 1H, J=8.37, 2.39 Hz), 6.99 (m, 1H),
6.61 (d, 1H, J=8.37 Hz), 4.75 (q, 1H, J=6.84 Hz), 4.62 (d, 1H,
J=0.45 Hz), 4.43 (d, 1H, J=0.45 Hz), 4.23 (d, 1H, J=0.70 Hz), 4.16
(d, 1H, J=0.70 Hz), 2.70 (s, 3H), 2.12 (s, 3H), 1.68 (d, 3H, J=6.84
Hz). MS(ES.sup.+) M+H=642.00
[1153]
2-(2-Methyl-4-{[(4-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methy-
l}-2-phenyl-1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)propanoic
Acid
[1154] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.90 (m, 2H), 7.67
(t, 1H, J=7.52 Hz), 7.46 (m, 1H), 7.42 (m, 3H), 7.35 (t, 1H, J=7.52
Hz), 7.08 (dd, 1H, J=8.37, 2.39 Hz), 7.04 (d, 1H, J=8.37 Hz), 7.00
(d, 1H, J=2.39 Hz), 6.61 (d, 1H, J=8.37 Hz), 4.73 (q, 1H, J=6.84
Hz), 4.58 (d, 1H, J=0.45 Hz), 4.43 (d, 1H, J=0.45 Hz), 4.20 (d, 1H,
J=0.70 Hz), 4.15 (d, 1H, J=0.70 Hz), 2.69 (s, 3H), 2.12 (s, 3H),
1.66 (d, 3H, J=6.84 Hz). MS(ES.sup.+) M+H=573.80
[1155]
[2-Methyl-4-(}[2-(4-{trifluoromethyl}phenyl)-4-(phenoxymethyl)-1,3--
thiazol-5-yl]methyl}sulfanyl)phenoxy]acetic Acid
[1156] .sup.1H (CDCl.sub.3) 300 MHz .delta. 8.02 (d, 2H, J=8.23
Hz), 7.70 (d, 2H, J=8.23 Hz), 7.33 (m, 2H), 7.22 (s, 1H), 7.12 (d,
1H, J=9.03 Hz), 6.98 (m, 3H), 6.58 (d, 1H, J=8.49 Hz), 4.87 (s,
2H), 4.63 (s, 2H), 4.30 (s, 2H), 2.22 (s, 3H). TLC(5%
MeOH/CH.sub.2Cl.sub.2) R.sub.f=0.17
[1157]
(2-Methyl-4-{[(4-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-
-2-phenyl-1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)acetic Acid
[1158] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.91 (m, 2H), 7.95
(d, 1H, J=7.69 Hz), 7.47 (m, 1H), 7.42 (m, 3H), 7.35 (t, 1H, J=7.95
Hz), 7.13 (dd, 1H, J=8.37, 2.39 Hz), 7.04 (s, 2H), 6.60 (d, 1H,
J=8.37 Hz), 4.67 (s, 2H), 4.57 (s, 2H), 4.20 (s, 2H), 2.69 (s, 3H),
2.12 (s, 3H),
[1159] MS(ES.sup.+) M+H=560.30
[1160]
2-{2-Methyl-4-[({4-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methy-
l}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-
propanoic Acid
[1161] .sup.1H (CDCl.sub.3)400 MHz .delta. 7.94 (m, 4H), 7.66 (d,
2H, J=8.20 Hz), 7.18 (d, 1H, J=2.22 Hz), 7.03 (dd, 1H, J=8.20, 2.22
Hz), 6.94 (d, 2H, J=8.89 Hz), 6.53 (d, 1H, J=8.20 Hz), 4.85 (d, 1H,
J=0.79 Hz), 4.80 (d, 1H, J=0.79 Hz), 4.69 (q, 1H, J=6.84 Hz), 4.26
(d, 1H, J=0.70 Hz), 4.21 (d, 1H, J=0.70 Hz), 2.63 (m, 3H), 2.18 (s,
3H), 1.62 (d, 3H, J=6.84 Hz),
[1162] MS(ES.sup.-) M-H=640.00
[1163]
{2-Ethyl-4-[({4-([4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic
Acid
[1164] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.98 (d, 2H, J=8.06
Hz), 7.67 (d, 2H, J=8.06 Hz), 7.11 (dd, 1H, J=8.61, 2.20 Hz), 7.02
(d, 1H, J=2.20 Hz), 6.93 (m, 2H), 6.82 (m, 2H), 6.68 (d, 1H, J=8.61
Hz), 4.62 (s, 2H), 4.12 (s, 2H), 3.44 (s, 2H), 3.25 (m, 4H), 3.02
(br s, 4H), 2.58 (q, 2H, J=7.51 Hz), 1.10 (t, 3H, J=7.51 Hz),
[1165] MS(ES.sup.-) M-H=644.5
[1166]
{4-[({4-[(4-Acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phen-
yl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-ethylphenoxy}acetic
Acid
[1167] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.04 (d, 2H, J=8.28
Hz), 7.75 (d, 2H, J=8.28 Hz), 7.22 (dd, 1H, J=8.55. 221 Hz), 7.03
(s, 1H), 6.74 (d, 1H, J=8.55 Hz), 4.74 (s, 2H), 4.13 (s, 2H), 0.76
(br s, 4H), 3.36 (s, 2H), 2.99 (br s, 2H), 2.72 (br s, 2H), 2.61
(q, 2H, J=7.45 Hz), 2.09 (s, 3H), 1.12 (t, 3H, J=7.45 Hz),
[1168] MS(ES.sup.+) M+H=594.1
[1169]
{4-[({4-{[4-(4-Acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluorom-
ethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-ethylphenoxy}acetic
Acid
[1170] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.95 (d, 2H, J=8.42
Hz), 7.84 (d, 2H, J=8.97 Hz), 7.67 (d, 2H, J=8.42 Hz), 7.14 (dd,
1H, J=8.42, 2.20 Hz), 6.95 (s, 1H), 6.80 (d, 2H, J=8.97 Hz), 6.70
(d, 1H, J=8.42 Hz), 4.66 (s, 2H), 4.08 (s, 2H), 3.54 (br s, 4H),
3.38 (s, 2H), 3.06 (br s, 4H), 2.56 (q, 2H, J=7.60 Hz), 2.49 (s,
3H), 1.08 (t, 3H, J=7.60 Hz),
[1171]
{2-Ethyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(t-
rifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic
Acid
[1172] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.28
Hz), 7.68 (d, 2H, J=8.28 Hz), 7.15 (dd, 1H, J=8.45, 2.24 Hz), 6.94
(d, 1H, J=2.24 Hz), 6.88 (d, 2H, J=9.14 Hz), 6.79 (d, 2H, J=9.14
Hz), 6.72 (d, 1H, J=8.45 Hz), 4.66 (s, 2H), 4.08 (s, 2H), 3.72 (s,
3H), 3.32 (m, 6H), 3.09 (br s, 4H), 2.56 (q, 2H, J=7.50 Hz), 1.08
(t, 3H, J=7.50 Hz),
[1173] MS(ES.sup.-) M-H=656.2
[1174]
2-(4-{[(2-(4-Fluorophenyl)-4-{[4-(phenoxycarbonyl)-1-piperazinyl]me-
thyl}-1,3-thiazol-5-yl)methyl]sulfanyl}-2-methylphenoxy)propanoic
Acid
[1175] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.91 (m, 2H), 7.35
(m, 3H), 7.19 (m, 3H), 7.12 (br s, 1H), 7.07 (d, 2H, J=8.79 Hz),
6.67 (br s, 1H), 4.58 (br s, 1H), 4.27 (s, 2H), 3.59 (m, 4H), 3.41
(s, 2H), 2.51 (br s, 4H), 2.19 (s, 3H), 1.54 (d, 1H, J=6.59
Hz),
[1176] MS(ES.sup.-) M-H=620.4
[1177]
2-(4-{[(2-(4-Fluorophenyl)-4-{[4-(isopropoxycarbonyl)-1-piperazinyl-
]methyl}-1,3-thiazol-5-yl)methyl]sulfanyl}-2-methylphenoxy)propanoic
Acid
[1178] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.94 (m, 2H), 7.19
(m, 3H), 7.05 (br s, 1H), 6.64 (d, 1H, J=8.42 Hz), 4.69 (br s, 1H),
4.47 (br s, 1H), 4.21 (s, 2H), 3.50 (br s, 4H), 3.36 (s, 2H), 2.64
(br s, 4H), 2.18 (s, 3H), 1.57 (d, 3H, J=5.68 Hz), 1.22 (d, 6H,
J=6.23 Hz),
[1179] MS(ES.sup.-) M-H=586.2
[1180]
2-[4-({[4-{[4-(Ethoxycarbonyl)-1-piperazinyl]methyl}-2-(4-fluorophe-
nyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]propanoic
Acid
[1181] .sup.1H NMR (CD.sub.3OD)400 MHz .delta. 7.93 (m, 2H), 7.19
(m, 3H), 7.09 (brs, 1H), 6.67 (brs, 1H), 4.70 (br s, 1H), 4.21 (s,
2H), 4.10 (q, 2H, J=7.14 Hz), 3.49 (m, 4H), 3.37 (s, 2H), 2.60 (br
s, 4H), 2.18 (s, 3H), 1.58 (br s, 3H), 1.23 (t, 3H, J=7.14 Hz),
[1182] MS(ES.sup.-) M-H=572.2
[1183]
2-(4-{[(2-(4-Fluorophenyl)-4-{[4-(3-methoxyphenyl)-1-piperazinyl]me-
thyl}-1,3-thiazol-5-yl)methyl]sulfanyl}-2-methylphenoxy)propanoic
Acid
[1184] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.84 (m, 2H), 7.13
(m, 4H), 6.92 (br s, 1H), 6.72 (br s, 1H), 6.44 (m, 3H), 4.38 (br
s, 1H), 4.00 (s, 2H), 3.74 (s, 3H), 3.40 (m, 6H), 3.03 (m, 4H),
2.17 (s, 3H), 1.61 (m, 3H),
[1185] MS(ES.sup.-) M-H=606.2
[1186]
2-[4-(}[4-{[4-(4-Acetylphenyl)-1-piperazinyl]methyl}-2-(4-fluorophe-
nyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]propanoic
Acid
[1187] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 7.94 (m, 2H), 7.85
(d, 2H, J=8.97 Hz), 7.18 (m, 3H), 7.03 (br s, 1H), 6.92 (d, 2H,
J=8.97 Hz), 6.67 (brs, 1H), 4.61 (brs, 1H), 4.19 (s, 2H), 3.41 (m,
6H), 2.73 (brs, 4H), 2.48 (s, 3H), 2.17 (s, 3H), 1.61 (brs,
3H),
[1188] MS(ES.sup.-) M-H=618.2
[1189]
2-(4-{[(2-(4-Fluorophenyl)-4-{[4-methoxyphenyl)-1-piperazinyl]methy-
l}-1,3-thiazol-5-yl)methyl]sulfanyl}-2-methylphenoxy)propanoic
acid
[1190] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 7.97 (m, 2H), 7.18
(m, 3H), 7.02 (br s, 1H), 6.91 (d, 2H, J=8.79 Hz), 6.81 (d, 2H,
J=8.79 Hz), 6.62 (brs, 1H), 4.66 (brs, 1H), 4.17 (s, 2H), 3.72(s;
3H), 3.41 (s, 2H), 3.15 (br s, 4H), 2.92 (br s, 4H), 2.18 (s, 3H),
1.59 (br s, 3H),
[1191] MS(ES.sup.-) M-H=606.2
[1192]
{4-[({4-[(4-Acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phen-
yl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}acetic
Acid
[1193] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.07 (d, 2H, J=8.28
Hz), 7.75 (d, 2H, J=8.28 Hz), 7.21 (dd, 1H, J=8.45, 2.41 Hz), 7.09
(d, 1H, J=2.41 Hz), 6.74 (d, 1H, J=8.45 Hz), 4.65 (s, 2H), 4.26 (s,
2H), 3.60 (br s, 4H), 3.53 (s, 2H), 2.75 (t, 2H, J=4.74 Hz), 2.69
(t, 2H, J=4.74 Hz), 2.52 (t, 2H, J=7.41 Hz), 2.07 (s, 3H), 1.50 (m,
2H), 0.80 (t, 3H, J=7.41 Hz),
[1194] MS(ES.sup.-) M-H=606.3
[1195]
{4-[({4-{[4-(3-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoro-
methyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}acetic
Acid
[1196] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.1 1 (d, 2H,
J=8.28 Hz), 7.77 (d, 2H, J=8.28 Hz), 7.19 (dd, 1H, J=8.28, 2.41
Hz), 7.13 (t, 1H, J=8.45 Hz), 7.08 (d, 1H, J=2.41 Hz), 6.73 (t, 1H,
J=8.45 Hz), 6.54 (dd, 1H, J=8.28, 2.41 Hz), 6.49 (t, 1H, J=2.33
Hz), 6.45 (dd, 1H, J=8.28, 2.41 Hz), 4.58 (s, 2H), 4.26 (s, 2H),
3.73 (s, 3H), 3.69 (s, 2H), 3.31 (m, 4H), 3.11 (t, 4H, J=4.66 Hz),
2.52 (t, 2H, J=7.33 Hz), 1.49 (s, 2H), 0.80 (t, 3H, J=7.33 Hz),
[1197] MS(ES.sup.-) M-H=670.3
[1198]
{4-[({4-{[4-(4-Acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluorom-
ethyl)phenyl-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}acetic
Acid
[1199] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.93 (d, 2H, J=8.45
Hz), 7.82 (d, 2H, J=8.97 Hz), 7.68 (d, 2H, J=8.45 Hz), 7.19 (dd,
1H, J=8.45, 2.41 Hz), 6.78 (m, 4H), 4.73 (s, 2H), 4.03 (s, 2H),
3.71 (t, 4H, J=5.09 Hz), 3.28 (m, 6H), 2.47 (m, 5H), 1.46 (m, 2H),
0.86 (t, 3H, J=7.24 Hz),
[1200] MS(ES.sup.-) M-H 682.1
[1201]
{4-[({4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoro-
methyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}acetic
Acid
[1202] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.11 (d, 2H, J=8.10
Hz), 7.77 (d, 2H, J=8.10 Hz), 7.19 (dd, 1H, J=8.62, 2.24 Hz), 7.08
(d, 1H, J=2.24 Hz), 6.93 (d, 2H, J=9.14 Hz), 6.82 (d, 2H, J=9.14
Hz), 6.74 (d, 1H, J=8.62 Hz), 4.59 (s, 2H), 4.26 (s, 2H), 3.73 (s,
2H), 3.71 (s, 3H), 3.18 (m, 8H), 2.52 (t, 2H, J=7.33 Hz), 1.48 (m,
2H), 0.80 (t, 3H, J=7.33 Hz),
[1203] MS(ES.sup.+) M+H=672.2
[1204]
2-{2-Ethyl-4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4--
(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy)propanoi-
c Acid
[1205] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.95 (d, 2H, J=8.28
Hz), 7.66 (d, 2H, J=8.28 Hz), 7.12 (m, 2H), 6.90 (s, 1H), 6.76 (d,
1H, J=8.28 Hz), 6.45 (m, 3H), 4.80 (q, 1H, J=6.90 Hz), 4.02 (s,
2H), 3.73 (s, 3H), 3.35 (m, 4H), 3.21 (d, 1H, J=0.66 Hz), 3.15 (d,
1H, J=0.66 Hz), 2.95 (brs, 4H), 2.55 (s, 2H), 1.62 (d, 3H, J=6.90
Hz), 1.07 (t, 3H, J=7.50 Hz),
[1206] MS(ES.sup.-) M-H=670.0
[1207]
2-{4-[({4-{[4-(4-Acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-ethylphenoxy}propanoic
Acid
[1208] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.93 (d, 2H, J=8.28
Hz), 7.82 (d, 2H, J=8.97 Hz), 7.65 (d, 2H, J=8.28 Hz), 7.08 (dd,
1H, J=8.62, 2.41 Hz), 6.87 (d, 1H, J=2.41 Hz), 6.79 (d, 2H, J=8.97
Hz), 6.72 (d, 1H, J=8.62 Hz), 4.80 (q, 1H, J=6.72 Hz), 4.04 (d, 1H,
J=0.66 Hz), 3.98 (d, 1H, J=0.66 Hz), 3.49 (br s, 4H), 3.28 (d, 1H,
J=0.83 Hz), 3.14 (d, 1H, J=0.83 Hz), 3.00 (br s, 4H), 2.54 (m, 5H),
1.63 (d, 3H, J=6.72 Hz), 1.06 (t, 3H, J=7.50 Hz),
[1209] MS(ES.sup.-) M-H=682.2
[1210]
2-{2-Ethyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4--
(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoi-
c Acid
[1211] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.45
Hz), 7.66 (d, 2H, J=8.45 Hz), 7.10 (dd, 1H. J=8.45, 2.24 Hz), 6.94
(d, 1H, J=2.24 Hz), 6.89 (d, 2H, J=9.14 Hz), 6.80 (d, 2H, J=9.14
Hz), 6.75 (d, 1H, J=8.45 Hz), 4.77 (q, 1H, J=6.72 Hz), 4.04 (s,
2H), 3.73 (s, 3H), 3.25 (m, 6H), 2.96 (br s, 4H), 2.57 (s, 2H),
1.61 (d, 3H, J=6.72 Hz), 1.09 (t, 3H, J=7.50 Hz),
[1212] MS(ES.sup.-) M-H=670.3
[1213]
2-{2-Ethyl-4-[({4-(4-morpholinylmethyl)-2-[4-(trifluoromethyl)pheny-
l]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic Acid
[1214] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.01 (d, 2H, J=8.42
Hz), 7.70 (d, 2H, J=8.42 Hz), 7.13 (dd, 1H, J=8.42, 2.20 Hz), 6.86
(s, 1H), 6.76 (d, 1H, J=8.42 Hz), 4.84 (q, 1H, J=6.65 Hz), 4.04 (d,
1H, J=0.47 Hz), 3.98 (d, 1H, J=0.47 Hz), 3.87 (br s, 4H), 3.21 (d,
1H, J=0.83 Hz), 3.08 (d, 1H, J=0.83 Hz), 2.95 (br s, 4H), 2.55 (s,
2H), 1.64 (d, 3H, J=6.65 Hz), 1.07 (t, 3H, J=7.51 Hz),
[1215] MS(ES.sup.-) M-H=565.0
[1216]
2-{2-Ethyl-4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl)-2-[4-(-
trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
Acid
[1217] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.12 (d, 2H, J=8.24
Hz), 7.78 (d, 2H, J=8.24 Hz), 7.17 (dd, 1H, J=8.61, 2.20 Hz), 7.10
(d, 1H, J=2.20 Hz), 6.98 (m, 4H), 6.71 (d, 1H, J=8.61 Hz), 4.71 (q,
1H, J=6.90 Hz), 4.27 (s, 2H), 3.66 (s, 2H), 3.20 (m, 8H), 2.59 (q,
2H, J=7.51 Hz), 1.57 (d, 3H, J=6.90 Hz), 1.09 (t, 3H, J=7.51
Hz),
[1218] MS(ES.sup.-) M-H=658.0
[1219]
2-{4-[({4-[(4-Acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)ph-
enyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-ethylphenoxy}propanoic
Acid
[1220] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.10 (d, 2H, J=8.24
Hz), 7.77 (d, 2H, J=8.24 Hz), 7.19 (t, 1H, J=2.38 Hz), 7.09 (d, 1H,
J=2.38 Hz), 6.71 (d, 1H, J=8.24 Hz), 4.80 (q, 1H, J=6.78 Hz), 4.26
(s, 2H), 3.65 (m, 6H), 3.56 (d, 1H, J 0.92 Hz), 3.51 (d, 1H, J=0.92
Hz), 2.83 (m, 4H), 2.58 (q, 2H, J=7.60 Hz), 2.09 (s, 3H), 1.60 (d,
3H, J=6.78 Hz), 1.09 (t, 3H, J=7.60 Hz),
[1221] MS(ES.sup.-) M-H=606.0
[1222]
{2-Ethyl-4-[({4-(4-morpholinylmethyl)-2-[4-(trifluoromethyl)phenyl]-
-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic Acid
[1223] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.05 (d, 2H, J=8.28
Hz), 7.75 (d, 2H, J=8.28 Hz), 7.19 (dd, 1H, J=8.55, 2.21 Hz), 6.98
(s, 1H), 6.76 (d, 1H, J=8.55 Hz), 4.74 (s, 2H), 4.12 (s, 2H), 3.95
(br s, 4H), 3.32 (s, 2H), 3.06 (br s, 4H), 2.61 (q, 2H, J=7.54 Hz),
1.14 (t, 3H, J=7.54 Hz),
[1224] MS(ES.sup.-) M-H=551.3
[1225]
2-{2-isopropyl-4-[({4-(4-morpholinylmethyl)-2-4-(trifluoromethyl)ph-
enyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic Acid
[1226] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.11 (d, 2H, J=8.24
Hz), 7.78 (d, 2H, J=8.24 Hz), 7.25 (dd, 1H, J=8.42, 2.38 Hz), 7.00
(d, 1H, J=2.38 Hz), 6.74 (d, 1H, J=8.42 Hz), 4.88 (q, 1H, J=6.78
Hz), 4.25 (s, 2H), 3.84 (m, 5H), 3.66 (d, 1H, J=0.28 Hz), 3.22 (m,
5H), 1.60 (d, 3H, J=6.78 Hz), 1.05 (m, 6H),
[1227] MS(ES.sup.-) M-H=579.0
[1228]
2-{4-[({4-{[4-(4-Fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-isopropylphenoxy}propa-
noic Acid
[1229] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.13 (d, 2H, J=8.06
Hz), 7.79 (d, 2H, J=8.06 Hz), 7.26 (d, 1H, J=8.42 Hz), 7.06 (s,
1H), 6.99 (m, 4H), 6.75 (d, 1H, J=8.42 Hz), 4.88 (q, 1H, J=6.78
Hz), 4.29 (s, 2H), 3.91 (d, 1H, J=0.10 Hz), 3.80 (d, 1H, J=0.10
Hz), 3.33 (m, 9H), 1.60 (d, 3H, J=6.78 Hz), 1.08 (m, 6H),
[1230] MS(ES.sup.-) M-H=672.0
[1231]
2-{4-[({4-[(4-Acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)ph-
enyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-isopropylphenoxy}propanoic
Acid
[1232] MS(ES.sup.-) M-H=620.0
[1233]
2-{2-isopropyl-4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-
-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}prop-
anoic Acid
[1234] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.13 (d, 2H, J=8.06
Hz), 7.79 (d, 2H, J=8.06 Hz), 7.26 (d, 1H, J=8.42 Hz), 7.16 (t, 1H,
J=8.42 Hz), 7.06 (s, 1H), 6.74 (d, 1H, J=8.42 Hz), 6.56 (d, 1H,
J=8.42 Hz), 6.50 (br s, 2H), 4.90 (q, 1H, J=6.78 Hz), 4.27 (s, 2H),
3.89 (d, 1H, J=0.10 Hz), 3.79 (d, 1H, J=0.10 Hz), 3.74 (s, 3H),
3.34 (m, 9H), 1.60 (d, 3H, J=6.78 Hz), 1.07 (m, 6H),
[1235] MS(ES.sup.-) M-H=684.1
[1236]
2-{4-[({4-{[4-(4-Acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-isopropylphenoxy}propa-
noic acid
[1237] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.13 (d, 2H, J=8.24
Hz), 7.91 (d, 2H, J=8.97 Hz), 7.78 (d, 2H, J=8.24 Hz), 7.25 (d, 1H,
J=8.97 Hz), 7.04 (m, 3H), 6.74 (d, 1H, J=8.24 Hz), 4.89 (q, 1H,
J=6.78 Hz), 4.28 (s, 2H), 3.90 (d, 1H. J 0.55 Hz), 3.79 (d, 1H,
J=0.55 Hz), 3.60 (br s, 4H), 3.32 (m, 5H), 2.50 (s, 3H), 1.61 (d,
3H, J=6.78 Hz), 1.07 (d, 6H, J=7.51 Hz),
[1238] MS(ES.sup.-) M-H=696.2
[1239]
2-{2-isopropyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-
-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}prop-
anoic Acid
[1240] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.13 (d, 2H, J=8.24
Hz), 7.79 (d, 2H, J=8.24 Hz), 7.27 (d, 1H, J=8.61 Hz), 7.05 (s,
1H), 6.95 (d, 2H, J=8.79 Hz), 6.84 (d, 2H, J=8.79 Hz), 6.75 (d, 1H,
J=8.61 Hz), 4.88 (m, 1H) buried under MeOH signal, 4.28 (s, 2H),
3.90 (d, 1H, J=0.28 Hz), 3.80 (d, 1H, J=0.28 Hz), 3.71 (s, 3H),
3.56 (br s, 4H), 3.28 (m, 1H) buried under MeOH signal, 2.96 (br s,
4H), 1.58 (d, 3H, J=6.59 Hz), 1.07 (m, 6H),
[1241] MS(ES.sup.-) M-H=684.1
[1242]
{2-isopropyl-4-[({4-(4-morpholinylmethyl)-2-[4-(trifluoromethyl)phe-
nyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic Acid
[1243] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.12 (d, 2H, J=8.06
Hz), 7.79 (d, 2H, J=8.06 Hz), 7.27 (d, 1H, J=8.42 Hz), 7.04 (s,
1H), 6.80 (d, 1H, J=8.42 Hz), 4.76 (s, 2H), 4.27 (s, 2H), 3.87 (m,
6H), 3.22 (m, 5H), 1.07 (d, 6H, J=6.78 Hz),
[1244] MS(ES.sup.-) M-H=565.0
[1245]
{4-[({4-{[4-(4-Fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluorom-
ethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-isopropylphenoxy}acetic
Acid
[1246] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.13 (d, 2H, J=8.06
Hz), 7.79 (d, 2H, J=8.06 Hz), 7.28 (d, 1H, J=8.42 Hz), 7.09 (s,
1H), 6.98 (m, 4H), 6.81 (d, 1H, J=8.42 Hz), 4.74 (s, 2H), 4.28 (s,
2H), 3.89 (s, 2H), 3.61 (br s, 4H), 3.29 (m, 1H) buried under MeOH
signal, 3.02 (br s, 4H), 1.07 (d, 6H, J=6.78 Hz),
[1247] MS(ES.sup.-) M-H=658.0
[1248]
{4-[({4-[(4-Acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phen-
yl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-isopropylphenoxy}acetic
Acid
[1249] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.13 (d, 2H, J=8.06
Hz), 7.79 (d, 2H, J=8.06 Hz), 7.28 (d, 1H, J=8.42 Hz), 7.03 (br s,
1H), 6.80 (d, 1H, J=8.42 Hz), 4.76 (s, 2H), 4.27 (s, 2H), 3.80 (m,
6H), 3.21 (m, 5H), 2.11 (s, 3H), 1.06 (d, 6H, J=6.78 Hz),
[1250] MS(ES.sup.-) M-H=606.2
[1251]
2-{4-[({4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl)methyl)sulfanyl]-2-propylphenoxy}propano-
ic Acid
[1252] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.12 (d, 2H, J=8.28
Hz), 7.79 (d, 2H, J=8.28 Hz), 7.23 (dd, 1H, J=8.45, 2.24 Hz), 7.09
(d, 1H, J=2.24 Hz), 6.95 (d, 2H, J=9.14 Hz), 6.84 (d, 2H, J=9.14
Hz), 6.71 (d, 1H, J=8.45 Hz), 4.81 (q, 1H, J=6.72 Hz), 4.29 (s,
2H), 3.98 (d, 1H, J=0.14 Hz), 3.90 (d, 1H, J=0.14 Hz), 3.71 (s,
3H), 3.50 (br s, 4H), 3.21 (m, 4H), 2.50 (t, 2H, J=7.33 Hz), 1.58
(d, 3H, J=6.72 Hz), 1.48 (m, 2H), 0.79 (t, 3H, J=7.33 Hz),
[1253] MS(ES.sup.-) M-H=684.0
[1254]
{4-[({4-(4-Morpholinylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thi-
azol-5-yl}methyl)sulfanyl]-2-propylphenoxy}acetic Acid
[1255] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.10 (d, 2H, J=8.79
Hz), 7.78 (d, 2H, J=8.79 Hz), 7.20 (dd, 1H, J=8.42, 2.20 Hz), 7.08
(d, 1H, J=2.20 Hz), 6.75 (d, 1H, J=8.42 Hz), 4.63 (s, 2H), 4.26 (s,
2H), 3.79 (t, 4H, J=4.21 Hz), 3.64 (s, 2H), 2.97 (t, 4H, J=4.21
Hz), 2.53 (t, 2H, J=7.42 Hz), 1.50 (s, 2H), 0.82 (t, 3H, J=7.42
Hz),
[1256] MS(ES.sup.-) M-H=658.0
[1257]
{4-[({4-{[4-(4-Fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluorom-
ethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}acetic
Acid
[1258] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.24
Hz), 7.67 (d, 2H, J=8.24 Hz), 7.12 (dd, 1H, J=8.42, 2.20 Hz), 7.01
(d, 1H, J=2.20 Hz), 6.93 (m, 2H), 6.83 (m, 2H), 6.69 (d, 1H, J=8.42
Hz), 4.62 (s, 2H), 4.12 (s, 2H), 3.45 (s, 2H), 3.26 (t, 4H, J=4.85
Hz), 3.04 (t, 4H, J=4.85 Hz), 2.52 (t, 2H, J=7.33 Hz), 1.51 (s,
2H), 0.83 (t, 3H, J=7.33 Hz),
[1259]
2-{4-[({4-[(3,5-Dimethyl-1-piperazinyl)methyl]-2-[4-(trifluoromethy-
l)
phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic
Acid
[1260] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.03 (d, 2H, J=8.23
Hz), 7.71 (d, 2H, J=8.23 Hz), 7.20 (m, 2H), 6.66 (d, 1H, J=8.55
Hz), 4.72 (q, 1H, J=6.64 Hz), 4.26 (d, 1H, J=0.87 Hz), 4.18 (d, 1H,
J=0.87 Hz), 3.34 (m, 2H), 3.05 (m, 2H), 2.71 (m, 2H), 2.21 (s, 3H),
1.97 (m, 2H), 1.63 (d, 3H, J=6.64 Hz), 1.35 (m, 6H),
[1261] MS(ES.sup.+) M+H=580.1
[1262] HPLC(C-18 3 .mu.m) 1% MeOH/0-99% Acetonitrile/Water (0.1%
TFA) 5 min run R.sub.t=3.98
[1263]
2-{4-[({4-{[4-(4-Chlorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy)propanoi-
c Acid
[1264] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 10.42 (s, 1H), 7.92
(d, 2H, J=8.20 Hz), 7.64 (d, 2H, J=8.20 Hz), 7.15 (d, 2H, J=9.06
Hz), 7.01 (d, 1H, J=2.20 Hz), 6.96 (d, 1H, J=8.37 Hz), 6.72 (d, 2H,
J=9.06 Hz), 6.59 (d, 1H, J=8.37 Hz), 4.64 (q, 1H, J=6.78 Hz), 4.09
(s, 2H), 3.58 (d, 1H, J=0.18 Hz), 3.49 (d, 1H, J=0.18 Hz), 3.26 (m,
4H), 3.05 (m, 4H), 2.13 (s, 3H), 1.56 (d, 3H, J=6.78 Hz),
[1265] MS(ES.sup.+) M+H=662.0
[1266] HPLC(C-18 3 .mu.m) 1% MeOH/0-99% Acetonitrile/Water (0.1%
TFA) 5 min run R.sub.t=4.13
[1267]
2-{4-[({4-{[4-tert-Butoxycarbonyl)-1-piperazinyl]methyl}-2-[4-(trif-
luoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy)prop-
anoic Acid
[1268] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 10.07 (s, 1H), 7.93
(d, 2H, J=8.23 Hz), 7.63 (d, 2H, J=8.23 Hz), 7.04 (s, 1H), 6.98 (d,
1H, J=8.37 Hz), 6.58 (d, 1H, J=8.37 Hz), 4.65 (q, 1H, J=6.78 Hz),
4.12 (d, 1H, J=0.70 Hz), 4.05 (d, 1H, J=0.70 Hz), 3.47 (m, 6H),
2.73 (m, 4H), 2.14 (s, 3H), 1.57 (d, 3H, J=6.78 Hz), 1.38 (s,
9H),
[1269] MS(ES.sup.+) M+H=652.0
[1270] HPLC(C-18 3 .mu.m) 1% MeOH/0-99% Acetonitrile/Water (0.1%
TFA) 5 min run R.sub.t=4.16
[1271]
2-{2-Methyl-4-[({4-(1-piperazinylmethyl)-2-[4-(trifluoromethyl)phen-
yl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic Acid
[1272] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 9.26 (br s, 1H),
7.97 (br s, 2H), 7.63 (br s, 2H), 7.10 (br s, 2H), 6.67 (br s, 1H),
4.56 (br s, 1H), 4.11 (br s, 2H), 3.39 (br s, 2H), 2.98 (br s, 4H),
2.41 (br s, 4H), 2.07 (br s, 3H), 1.44 (br s, 3H),
[1273] MS(ES.sup.+) M+H=552
[1274] HPLC(C-18 3 .mu.m) 1% MeOH/0-99% Acetonitrile/Water (0.1%
TFA) 5 min run R=3.80
[1275]
{2-isopropyl-4-[({4-([4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[-
4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl)methyl)sulfanyl]phenoxy}acetic
Acid
[1276] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.13 (d, 2H, J=8.06
Hz), 7.79 (d, 2H, J=8.06 Hz), 7.28 (d, 1H. J=8.24 Hz), 7.15 (m,
1H), 7.09 (s, 1H), 6.80 (d, 1H, J=8.24 Hz), 6.52 (m, 3H), 4.74 (s,
2H), 4.28 (s, 2H), 3.88 (s, 2H), 3.73 (m, 3H), 3.48 (br s, 4H),
3.29 (m, 1H) buried under MeOH signal, 3.05 (s, 4H), 1.06 (d, 6H,
J=6.59 Hz),
[1277] MS(ES.sup.-) M-H=670.0
[1278]
{4-[({4-{[4-(4-Acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluorom-
ethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-isopropylphenoxy}acetic
Acid
[1279] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.13 (d, 2H, J=7.87
Hz), 7.91 (d, 2H, J=8.79 Hz), 7.78 (d, 2H, J=7.87 Hz), 7.27 (d, 1H,
J=8.24 Hz), 7.09 (br s, 1H), 7.02 (d, 2H, J=8.24 Hz), 6.80 (d, 1H,
J=8.79 Hz), 4.74 (s, 2H), 4.29 (s, 2H), 3.89 (s, 2H), 3.62 (br s,
4H), 3.30 (m, 5H), 2.51 (s, 3H), 1.07 (d, 6H, J=6.78 Hz),
[1280] MS(ES.sup.-) M-H=682.0
[1281]
{2-isopropyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[-
4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic
Acid
[1282] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.13 (d, 2H, J=8.06
Hz), 7.79 (d, 2H, J=8.06 Hz), 7.29 (d, 1H, J=8.45 Hz), 7.09 (s,
1H), 6.98 (d, 2H, J=8.45 Hz), 6.83 (m, 3H), 4.73 (s, 2H), 4.30 (s,
2H), 3.90 (s, 3H), 3.35 (m, 11H), 1.07 (d, 6H, J=6.59 Hz),
[1283] MS(ES.sup.-) M-H=670.0
[1284]
2-{4-[({4-(4-Morpholinylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-t-
hiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}propanoic Acid
[1285] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.18 (d, 2H, J=8.00
Hz), 7.84 (d, 2H, J=8.00 Hz), 7.30 (dd, 1H, J=8.55, 2.48 Hz), 7.11
(d, 1H, J=2.48 Hz), 6.78 (d, 1H, J=8.55 Hz), 4.91 (s, 1H) buried
under MeOH signal, 4.33 (s, 2H), 3.94 (m, 6H), 3.24 (br s, 4H),
2.56 (t, 2H, J=7.45 Hz), 1.59 (m, 5H), 0.86 (t, 3H, J=7.45 Hz),
[1286] MS(ES.sup.-) M-H=579.0
[1287]
2-{4-[({4-{[4-(4-Fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}propanoi-
c Acid
[1288] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.18 (d, 2H, J=8.28
Hz), 7.85 (d, 2H, J=8.28 Hz), 7.30 (dd, 1H, J=8.55, 2.21 Hz), 7.16
(d, 1H, J=2.21 Hz), 7.06 (m, 4H), 6.78 (d, 1H, J=8.55 Hz), 4.89 (br
s, 1H) hidden under MeOH signal, 4.35 (s, 2H), 4.06 (d, 1H, J=0.35
Hz), 3.98 (d, 1H, J=0.35 Hz), 3.68 (br s, 4H), 3.08 (br s, 4H),
2.56 (t, 2H, J=7.45 Hz), 1.57 (m, 5H), 0.86 (t, 3H, J=7.45 Hz),
[1289] MS(ES.sup.-) M-H=672.0
[1290]
2-{4-[({4-[(4-Acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)ph-
enyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}propanoic
Acid
[1291] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.17 (d, 2H, J=8.28
Hz), 7.84 (d, 2H, J=8.28 Hz), 7.29 (dd, 1H, J=8.55, 2.21 Hz), 7.10
(d, 1H, J=2.21 Hz), 6.77 (d, 1H, J=8.55 Hz), 4.93 (q, 1H, J=6.78
Hz), 4.32 (s, 2H), 3.86 (m, 6H), 3.27 (m, 4H), 2.56 (m, 2H), 2.18
(s, 3H), 1.66 (d, 3H, J=6.78 Hz), 1.54 (m, 2H), 0.85 (t, 3H, J=7.31
Hz),
[1292] MS(ES.sup.-) M-H=620.0
[1293]
2-{4-[({4-{[4-(3-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluo-
romethyl)phenyl-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}propanoi-
c Acid
[1294] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.18 (d, 2H, J=8.55
Hz), 7.85 (d, 2H, J=8.55 Hz), 7.30 (dd, 1H, J=8.55, 2.21 Hz), 7.22
(t, 1H, J=8.55 Hz), 7.16 (d, 1H, J=2.21 Hz), 6.77 (d, 1H, J=8.55
Hz), 6.58 (m, 3H), 4.80 (m, 1H), 4.34 (s, 2H), 4.06 (d, 1H, J=0.07
Hz), 3.97 (d, 1H, J=0.07 Hz), 3.79 (s, 3H), 3.60 (br s, 4H), 3.08
(brs, 4H), 2.56 (t, 2H, J=7.17 Hz), 1.58 (m, 5H), 0.85 (t, 3H,
J=7.17 Hz),
[1295] MS(ES.sup.-) M-H=684.1
[1296]
2-{4-[({4-{[4-(4-Acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}propanoi-
c Acid
[1297] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.12 (d, 2H, J=8.28
Hz), 7.91 (d, 2H, J=9.14 Hz), 7.78 (d, 2H, J=8.28 Hz), 7.22 (dd,
1H, J=8.28, 2.24 Hz), 7.10 (d, 1H, J=2.24 Hz), 7.03 (d, 2H, J=9.14
Hz), 6.71 (d, 1H, J=8.28 Hz), 4.81 (q, 1H, J=6.72 Hz), 4.29 (s,
2H), 3.99 (d, 1H, J=0.14 Hz), 3.91 (d, 1H, J=0.14 Hz), 3.60 (br s,
4H), 3.33 (m, 4H), 2.48 (m, 5H), 1.59 (d, 3H, J=6.72 Hz), 1.48 (m,
2H), 0.78 (t, 3H, J=7.41 Hz),
[1298] MS(ES.sup.-) M-H=696.1
[1299]
2-{2-Methyl-4-[({4-{[4-(2-pyrimidinyl)-1-piperazinyl]methyl}-2-[4-(-
trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
Acid
[1300] .sup.1H NMR (CD.sub.3OD) 300 MHz .delta. 8.35 (d, 2H, J=4.69
Hz), 8.13 (d, 2H, J=8.28 Hz), 7.80 (d, 2H, J=8.28 Hz), 7.21 (s,
1H), 7.13 (d, 1H, J=8.28 Hz), 6.71 (d, 1H, J=8.28 Hz), 6.63 (t, 1H,
J=4.69 Hz), 4.59 (m, 1H), 4.31 (s, 2H), 3.86 (t, 4H, J=4.69 Hz),
3.50 (s, 2H), 2.69 (t, 4H, J=4.69 Hz), 2.22 (s, 3H), 1.59 (d, 3H,
J=6.78 Hz),
[1301] MS(ES.sup.-) M-H=628.5
[1302]
2-{4-[({4-{[4-(2,4-Dimethoxyphenyl)-1-piperazinyl]methyl}-2-[4-(tri-
fluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}pro-
panoic Acid
[1303] .sup.1H NMR (CD.sub.3OD) 300 MHz .delta. 8.17 (d, 2H, J=8.00
Hz), 7.80 (d, 2H, J=8.00 Hz), 7.20 (br s, 1H), 7.04 (br s, 1H),
6.92 (d, 1H. J=8.55 Hz), 6.67 (br s, 1H), 6.56 (m, 1H), 6.48 (m,
1H), 4.59 (br s, 1H), 4.27 (s, 2H), 3.84 (s, 3H), 3.78 (s, 3H),
3.55 (s, 2H), 3.07(m 8H), 2.21 (s, 3H), 1.56 (br s, 3H),
[1304] MS(ES.sup.-) M-H=685.6
[1305]
2-{2-Methyl-4-[({4-({4-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1-piperaziny-
l}methyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]p-
henoxy}propanoic Acid
[1306] MS(ES.sup.-) M-H=660.7
[1307] CHN Analysis 0.3H.sub.2O (Theoretical % C=53.62, % H=6.05, %
N=7.82; Found % C=53.33, % H=6.01, % N=7.95)
[1308]
2-[2-Methyl-4-({[2-[4-(trifluoromethyl)phenyl]-4-({4-[3-(trifluorom-
ethyl)phenyl]-1-piperazinyl}methyl)-1,3-thiazol-5-yl]methyl}sulfanyl)pheno-
xy]propanoic Acid
[1309] .sup.1H NMR (CD.sub.3OD) 300 MHz .delta. 8.09 (d, 2H, J=8.28
Hz), 7.77 (d, 2H, J=8.28 Hz), 7.40 (s, 1H), 7.19 (m, 4H), 7.07 (d,
1H, J=7.73 Hz), 6.71 (d, 1H, J=8.28 Hz), 4.47 (m, 1H), 4.33 (s,
2H), 3.53 (s, 2H), 3.23 (m, 4H), 2.64 (m, 4H), 2.22 (s, 3H), 1.57
(d, 3H, J=6.78 Hz),
[1310] MS(ES.sup.-) M-H=694.5
[1311]
2-{4-[({4-{[4-(2-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propano-
ic Acid
[1312] .sup.1H NMR (CD.sub.3OD) 300 MHz .delta. 8.09 (d, 2H, J=8.28
Hz), 7.77 (d, 2H, J=8.28 Hz), 7.25 (s, 1H), 7.17 (s, 1H), 6.96 (m,
4H), 6.70 (s, 1H), 4.51 (m, 1H), 4.34 (s, 2H), 3.86 (s, 3H), 3.57
(s, 2H), 3.07 (br s, 4H), 2.76 (br s, 4H), 2.23 (br s, 3H), 1.54
(br s, 3H),
[1313] MS(ES.sup.-) M-H=656.5
[1314]
2-{4-[({4-[(4-Acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)ph-
enyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic
Acid
[1315] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.93 (d, 2H, J=8.20
Hz), 7.63 (d, 2H, J=8.20 Hz), 7.02 (m, 2H), 6.57 (d, 1H, J=8.20
Hz), 4.65 (q, 1H, J=6.78 Hz), 4.16 (d, 1H, J=0.87 Hz), 4.09 (d, 1H,
J=0.87 Hz), 3.55 (m, 6H), 2.74 (m, 4H), 2.11 (s, 3H), 1.98 (s, 3H),
1.55 (d, 3H, J=6.78 Hz),
[1316] MS(ES.sup.+) M+H=594.0
[1317] HPLC(C-18 3 .mu.m) 1% MeOH/0-99% Acetonitrile/Water (0.1%
TFA) 5 min run R.sub.t=3.79
[1318]
2-{2-Methyl-4-[({4-{[4-(4-pyridinyl)-1-piperazinyl]methyl}-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
Acid
[1319] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.01 (d, 2H, J=8.20
Hz), 7.95 (d, 2H, J=8.20 Hz), 7.64 (d, 2H, J=8.20 Hz), 7.16 (d, 1H,
J=2.22 Hz), 7.09 (dd, 1H, J=8.37, 2.22 Hz), 6.97 (d, 2H, J=8.20
Hz), 6.63 (d, 1H, J=8.37 Hz), 4.48 (q, 1H, J=6.78 Hz), 4.19 (s,
2H), 3.57 (t, 4H, J=5.10 Hz), 3.48 (s, 2H), 2.46 (t, 4H, J=5.10
Hz), 2.14 (s, 3H), 1.54 (d, 3H, J=6.78 Hz),
[1320] MS(ES.sup.+) M+H=629.0
[1321] HPLC(C-18 3 .mu.m) 1% MeOH/0-99% Acetonitrile/Water (0.1%
TFA) 5 min run R.sub.t=4.22
[1322]
2-{4-[({4-{[4-(3-Methoxyphenyl)-1-piperazinyl]methyl)-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propano-
ic Acid
[1323] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 10.57 (s, 1H), 7.91
(d, 2H, J=8.20 Hz), 7.63 (d, 2H, J=8.20 Hz), 7.11 (t, 1H, J=8.20
Hz), 6.98 (m, 2H), 6.60 (d, 1H, J=8.20 Hz), 6.41 (dd, 2H, J=8.20,
2.22 Hz), 6.35 (t, 1H, J=2.22 Hz), 4.65 (q, 1H, J=6.84 Hz), 4.10
(s, 2H), 3.72 (s, 3H), 3.59 (d, 1H, J=0.18 Hz), 3.49 (d, 1H, J=0.18
Hz), 3.35 (m, 4H), 3.10 (m, 4H), 2.12 (s, 3H), 1.55 (d, 3H, J=6.84
Hz),
[1324] MS(ES.sup.+) M+H=658.0
[1325] HPLC(C-18 3 .mu.m) 1% MeOH/0-99% Acetonitrile/Water (0.1%
TFA) 5 min run R.sub.t=4.09
[1326]
2-{2-Methyl-4-[({4-(4-morpholinylmethyl)-2-[4-(trifluoromethyl)phen-
yl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic Acid
[1327] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 11.61 (s, 1H), 8.00
(d, 2H, J=8.23 Hz), 7.69 (d, 2H, J=8.23 Hz), 7.10 (dd, 1H, J=8.37,
2.20 Hz), 6.83 (d, 1H, J=2.20 Hz), 6.71 (d, 1H, J=8.37 Hz), 4.84
(q, 1H, J=6.72 Hz), 4.12 (m, 4H), 3.84 (m, 2H), 3.43 (m, 3H), 3.19
(m, 2H), 2.88 (m, 1H), 2.10 (s, 3H), 1.61 (d, 3H, J=6.72 Hz),
[1328] MS(ES.sup.+) M+H=553.0
[1329] HPLC(C-18 3 .mu.m) 1% MeOH/0-99% Acetonitrile/Water (0.1%
TFA) 5 min run R.sub.t=3.89
[1330]
2-(4-[({4-{[4-(Ethoxycarbonyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl)methyl)sulfanyl]-2-methylphenoxy}propanoi-
c Acid
[1331] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 10.39 (s, 1H), 7.93
(d, 2H, J=8.23 Hz), 7.64 (d, 2H, J=8.23 Hz), 7.05 (d, 1H, J=2.39
Hz), 6.97 (d, 1H, J=8.37 Hz), 6.57 (d, 1H, J=8.37 Hz), 4.65 (q, 1H,
J=6.78 Hz), 4.09 (q, 4H, J=7.06 Hz), 3.58 (m, 4H), 3.39 (m, 2H),
2.74 (m, 4H), 2.14 (s, 3H), 1.57 (d, 3H, J=6.78 Hz), 1.21 (t, 3H,
J=7.06 Hz),
[1332] MS(ES.sup.+) M+H=624.0
[1333] HPLC(C-18 3 .mu.m) 1% MeOH/0-99% Acetonitrile/Water (0.1%
TFA) 5 min run R.sub.t=3.93
[1334]
2-{4-[({4-{[4-(4-Acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoi-
c Acid
[1335] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 9.84 (s, 1H), 7.91
(d, 2H, J=8.20 Hz), 7.81 (d, 2H, J=8.89 Hz), 7.63 (d, 2H; J=8.20
Hz), 7.00 (d, 1H, J=2.20 Hz), 6.93 (dd, 1H, J=8.37, 2.20 Hz), 6.76
(d, 2H, J=8.89 Hz), 6.58 (d, 1H, J=8.37 Hz), 4.66 (q, 1H, J=6.78
Hz), 4.08 (s, 2H), 3.45 (m, 6H), 2.96 (m, 4H), 2.47 (s, 3H), 2.13
(s, 3H), 1.59 (d, 3H, J=6.78 Hz),
[1336] MS(ES.sup.+) M+H=670.0
[1337] HPLC(C-18 3 .mu.m) 1% MeOH/0-99% Acetonitrile/Water (0.1%
TFA) 5 min run R.sub.t=4.03
[1338]
2-{4-[({4-{[4(4-Fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoro-
methyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic
Acid
[1339] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.92 (d, 2H, J=8.23
Hz), 7.62 (d, 2H, J=8.23 Hz), 7.05 (s, 1H), 6.89 (m, 2H), 6.75 (m,
2H), 6.55 (d, 1H, J=8.23 Hz), 4.59 (m, 1H), 4.17 (m, 2H), 3.53 (m,
2H), 3.21 (m, 4H), 2.97 (m, 4H), 2.12 (s, 3H), 1.51 (d, 3H, J=6.78
Hz),
[1340] MS(ES.sup.+) M+H=646.0
[1341] HPLC(C-18 3 .mu.m) 1% MeOH/0-99% Acetonitrile/Water (0.1%
TFA) 5 min run R.sub.t=4.11
[1342]
2-{4-[({4-({4-[(4-Fluorophenyl)sulfonyl]-1-piperazinyl}methyl)-2-[4-
-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenox-
y}propanoic Acid
[1343] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.03 (d, 2H, J=8.20
Hz), 7.83 (t, 2H, J=7.69 Hz), 7.73 (d, 2H, J=8.20 Hz), 7.33 (t, 2H,
J=7.69 Hz), 7.17 (s, 1H), 7.08 (d, 1H, J=8.20 Hz), 6.64 (d, 1H,
J=8.20 Hz), 4.67 (br s, 1H), 4.22 (s, 2H), 3.37 (s, 2H), 2.99 (br
s, 4H), 2.50 (br s, 4H), 2.16 (s, 3H), 1.57 (d, 3H, J=6.84 Hz),
[1344] MS(ES.sup.-) M-H=708.0
[1345]
2-{2-Methyl-4-[({4-{[4-(3-methylbutanoyl)-1-piperazinyl]methyl}-2-[-
4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propan-
oic Acid
[1346] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.12 (d, 2H, J=8.28
Hz), 7.80 (d, 2H, J=8.28 Hz), 7.23 (d, 1H, J=2.21 Hz), 7.17 (dd,
1H, J=8.28, 2.21 Hz), 6.72 (d, 1H, J=8.28 Hz), 4.72 (q, 1H, J=6.44
Hz), 4.32 (s, 2H), 3.63 (br s, 4H), 3.44 (s, 2H), 2.59 (br s, 4H),
2.31 (d, 2H, J=6.90 Hz), 2.21 (s, 3H), 2.06 (m, 1H), 1.62 (d, 3H,
J=6.44 Hz), 0.98 (d, 6H, J=6.90 Hz),
[1347] MS(ES.sup.-) M-H=634.0
[1348]
2-{4-[({4-{[4-(Cyclohexylcarbonyl)-1-piperazinyl]methyl}-2-[4-(trif-
luoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}prop-
anoic Acid
[1349] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.06 (d, 2H, J=8.10
Hz), 7.74 (d, 2H, J=8.10 Hz), 7.16 (d, 1H, J=2.24 Hz), 7.09 (dd,
1H, J=8.45, 2.24 Hz), 6.64 (d, 1H, J=8.45 Hz), 4.68 (q, 1H, J=6.78
Hz), 4.25 (s, 2H), 3.60 (br s, 4H), 3.42 (s, 2H), 2.62 (br s, 4H),
2.16 (s, 3H), 1.72 (m, 5H), 1.56 (d, 3H, J=6.72 Hz), 1.31 (m,
6H),
[1350] MS(ES.sup.-) M-H=661.0
[1351]
2-{2-Methyl-4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
Acid
[1352] .sup.1H NMR (CD.sub.3OD) 300 MHz 8 8.17 (m, 4H), 7.81 (m,
3H), 7.26 (br s, 1H), 7.13 (br s, 1H), 6.75 (br s, 1H), 4.68 (br s,
1H), 4.32 (s, 2H), 3.65 (br s, 4H), 3.48 (s, 2H), 2.64 (br s, 4H),
2.20 (s, 3H), 1.60 (br s, 3H),
[1353] MS(ES.sup.-) M-H=628.3
[1354]
2-{4-[({4-({4-{[4-(dimethylamine)benzyl]-1-piperazinyl}methyl)-2-[4-
-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenox-
y}propanoic Acid
[1355] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta., 8.12 (d, 2H,
J=8.28 Hz), 7.80 (d, 2H, J=8.28 Hz), 7.35 (d, 2H, J=9.11 Hz), 7.21
(d, 1H, J=2.21 Hz), 7.14 (d, 1H, J=8.55 Hz), 6.78 (d, 2H, J=9.11
Hz), 6.70 (d, 1H, J=8.55 Hz), 4.68 (q, 1H, J=6.62 Hz), 4.31 (s,
2H), 3.70 (br s, 4H), 3.45 (s, 2H), 3.02 (s, 6H), 2.63 (br s, 4H),
2.19 (s, 3H), 1.59 (d, 3H, J=6.62 Hz),
[1356] MS(ES.sup.-) M-H=697.0
[1357]
2-{4-[({4-{[4-(2-Furoyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethy-
l)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic
Acid
[1358] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.06 (d, 2H, J=8.28
Hz), 7.73 (d, 2H, J=8.2? Hz), 7.65 (m, 1H), 7.16 (d, 1H, J=2.20
Hz), 7.07 (d, 1H, J=8.55 Hz), 7.01 (d, 1H, J=3.62 Hz), 6.63 (d, 1H,
J=8.45 Hz), 6.55 (m, 1H), 4.66 (q, 1H, J=6.55 Hz), 4.25 (s, 2H),
3.77 (br s, 4H), 3.39 (s, 2H), 2.59 (br s, 4H), 2.14 (s, 3H), 1.54
(d, 3H, J=6.55 Hz),
[1359] MS(ES.sup.-) M-H=644.1
[1360]
2-{4-[({4-{[4-(Cyclopentylcarbonyl)-1-piperazinyl]methyl}-2-[4-(tri-
fluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}pro-
panoic Acid
[1361] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.13 (d, 2H, J=8.28
Hz), 7.80 (d, 2H, J=8.28 Hz), 7.23 (d, 1H J=2.39 Hz), 7.15 (d, 1H,
J=8.28 Hz), 6.71 (br s, 1H), 4.73 (q, 1H, J=6.78 Hz), 4.31 (s, 2H),
3.67 (br s, 4H), 3.45 (s, 2H), 3.06 (m, 1H), 2.62 (br s, 4H), 2.22
(s, 3H), 1.75 (m, 14H),
[1362] MS(ES.sup.-) M-H=646.2
[1363]
2-{4-[({4-{[4-(Cyclobutylcarbonyl)-1-piperazinyl]methyl}-2-[4-(trif-
luoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}prop-
anoic Acid
[1364] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.09 (d, 2H, J=8.20
Hz), 7.77 (d, 2H, J=8.20 Hz), 7.18 (d, 1H, J=2.22 Hz), 7.13 (dd,
1H, J=8.55, 2.22 Hz), 6.68 (d, 1H, J=8.55 Hz), 4.71 (q, 1H, J=6.75
Hz), 4.28 (s, 2H), 3.60 (br s, 2H), 3.46 (br s, 2H), 3.41 (s, 2H),
2.57 (t, 4H, J=4.44 Hz), 2.22 (m, 6H), 2.00 (m, 2H), 1.83 (m, 2H),
1.60 (d, 3H, J=6.75 Hz),
[1365] MS(ES.sup.-) M-H=633.1
[1366]
2-{4-[({4-{[4-(Cyclopropylcarbonyl)-1-piperazinyl]methyl}-2-[4-(tri-
fluoromethyl)phenyl]-1,3-thiazol-5-yl)methyl)sulfanyl]-2-methylphenoxy}pro-
panoic Acid
[1367] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.10 (d, 2H, J=8.23
Hz), 7.76 (d, 2H, J=8.23 Hz), 7.21 (d, 1H, J=2.20 Hz), 7.11 (d, 1H,
J=8.20 Hz), 6.67 (s, 1H), 4.68 (q, 1H, J=6.84 Hz), 4.28 (s, 2H),
3.68 (br s, 4H), 3.42 (s, 2H), 2.59 (br s, 4H), 2.19 (s, 3H), 1.95
(m, 1H), 1.57 (d, 3H, J=6.84 Hz), 0.84 (m, 4H),
[1368] MS(ES.sup.-) M-H=619.1
[1369]
2-{2-Methyl-4-[({4-{[4-(2-thienylcarbonyl)-1-piperazinyl]methyl}-2--
[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propa-
noic Acid
[1370] .sup.1H NMR (CD.sub.3OD) 300 MHz .delta. 8.10 (d, 2H, J=8.20
Hz), 7.76 (d, 2H, J=8.20 Hz), 7.63 (d, 1H, J=5.13 Hz), 7.37 (d, 1H,
J=5.13 Hz), 7.22 (brs, 1H), 7.10 (brs, 1H), 7.02 (brs, 1H), 6.64
(brs, 1H), 4.67 (br s, 1H), 4.27 (s, 2H), 3.74 (br s, 4H), 3.40 (s,
2H), 2.53 (br s, 4H), 2.16 (br s, 3H), 1.57 (br s, 3H),
[1371] MS(ES.sup.-) M-H=660.1
[1372]
2-{4-[({4-{[4-(2,4-Difluorophenyl)-1-piperazinyl]methyl}-2-[4-(trif-
luoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}prop-
anoic Acid
[1373] .sup.1H NMR (CD.sub.3OD) 300 MHz .delta. 8.10 (d, 2H, J=8.28
Hz), 7.73 (d, 2H, J=8.28 Hz), 7.20 (br s, 1H), 6.92 (m, 4H), 6.60
(d, 1H, J=8.55 Hz), 4.59 (br s, 1H), 4.23 (s, 2H), 3.44 (s, 2H),
3.06 (br s, 4H), 2.80 (br s, 4H), 2.17 (s, 3H), 1.53 (d, 3H, J=6.35
Hz),
[1374] MS(ES.sup.-) M-H=661.2
[1375]
2-[2-Methyl-4-({[2-[4-(trifluoromethyl)phenyl]-4-({4-[(trifluoromet-
hyl)phenyl]-1-piperazinyl}methyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy-
]propanoic Acid
[1376] .sup.1H NMR (CD.sub.3OD) 300 MHz .delta. 8.11 (d, 2H, J=8.28
Hz), 7.78 (d, 2H, J=8.28 Hz), 7.49 (d, 2H, J=8.55 Hz), 7.24 (d, 1H,
J=2.39 Hz), 7.15 (d, 1H, J=8.55 Hz), 7.04 (d, 2H, J=8.55 Hz), 6.71
(d, 1H, J=8.55 Hz), 4.55 (br s, 1H), 4.32 (s, 2H), 3.51 (s, 2H),
3.31 (m, 4H), 2.68 (t, 4H, J=4.97 Hz), 2.22 (s, 3H), 1.59 (d, 3H,
J=6.07 Hz),
[1377] MS(ES.sup.-) M-H=694.5
[1378]
2-{4-[({4-{[4-(isobutoxycarbonyl)-1-piperazinyl]methyl}-2-[4-(trifl-
uoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propa-
noic Acid
[1379] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.13 (d, 2H, J=8.28
Hz), 7.80 (d, 2H, J=8.28 Hz), 7.22 (d, 1H, J=2.21 Hz), 7.15 (dd,
1H, J=8.28, 2.21 Hz), 6.71 (d, 1H, J=8.28 Hz), 4.75 (q, 1H, J=6.90
Hz), 4.31 (s, 2H), 3.89 (d, 2H, J=6.90 Hz), 3.57 (br s, 4H), 2.68
(t, 4H, J=4.69 Hz), 2.22 (s, 3H), 1.96 (m, 1H), 1.62 (d, 3H, J=6.90
Hz), 0.96 (d, 6H, J=6.90 Hz),
[1380] MS(ES.sup.-) M-H=650
[1381]
2-{4-[({4-({4-[(Benzyloxy)carbonyl]-1-piperazinylmethyl)-2-[4-(trif-
luoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}prop-
anoic Acid
[1382] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.06 (d, 2H, J=8.03
Hz), 7.73 (d, 2H, J=8.03 Hz), 7.30 (m, 5H), 7.15 (br s, 1H), 7.08
(dd, 1H, J=8.20, 2.22 Hz), 6.64 (d, 1H, J=8.20 Hz), 5.08 (s, 2H),
4.65 (q, 1H, J=6.72 Hz), 4.23 (s, 2H), 3.51 (br s, 4H), 3.37 (s,
2H), 2.57 (br s, 4H), 2.15 (s, 3H), 1.55 (d, 3H, J=6.72 Hz),
[1383] MS(ES.sup.-) M-H=684.0
[1384]
2-{4-[({4-([4-(Methoxycarbonyl)-1-piperazinyl]methyl)-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propano-
ic Acid
[1385] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.06 (d, 2H, J=8.37
Hz), 7.74 (d, 2H, J=8.37 Hz), 7.16 (d, 1H, J=2.21 Hz), 7.10 (dd,
1H, J=8.55, 2.39 Hz), 6.66 (d, 1H, J=8.55 Hz), 4.59 (brs, 1H), 4.25
(s, 2H), 3.65 (s, 3H), 3.45 (t, 4H, J=4.79 Hz), 3.38 (s, 2H), 2.49
(br s, 4H), 2.17 (s, 3H), 1.55 (d, 3H, J=6.32 Hz),
[1386] MS(ES.sup.-) M-H=608.0
[1387]
2-{2-Methyl-4-[({4-{[4-phenoxycarbonyl)-1-piperazinyl]methyl}-2-[4--
(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoi-
c Acid
[1388] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.08 (d, 2H, J=8.20
Hz), 7.75 (d, 2H, J=8.20 Hz), 7.34 (m, 2H), 7.19 (m, 2H), 7.13 (dd,
1H, J=8.20, 2.22 Hz), 7.06 (m, 2H), 6.66 (d, 1H, J=8.20 Hz), 4.69
(q, 1H, J=6.78 Hz), 4.27 (s, 2H), 3.69 (br s, 2H), 3.54 (br s, 2H),
3.43 (s, 2H), 2.62 (br s, 4H), 2.17 (s, 3H), 1.54 (d, 3H, J=6.78
Hz),
[1389] MS(ES.sup.-) M-H=670.0
[1390]
2-{2-Methyl-4-[({4-{[4-(phenylsulfonyl)-1-piperazinyl]methyl}-2-[4--
(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoi-
c Acid
[1391] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.01 (d, 2H, J=8.20
Hz), 7.72 (m, 4H), 7.63 (d, 1H, J=8.20 Hz), 7.56(M, 2H), 7.13 (d,
1H, J=2.22 Hz), 7.05 (dd, 1H, J=8.20, 2.22 Hz), 6.62 (d, 1H, J=8.20
Hz), 4.70 (q, 1H, J=6.61 Hz), 4.19 (s, 2H), 3.34 (s, 2H), 2.97 (br
s, 4H), 2.51 (br s, 4H), 2.13 (s, 3H), 1.57 (d, 3H, J=6.61 Hz),
[1392] MS(ES.sup.-) M-H=690.0
[1393]
2-{2-Methyl-4-[({2-[4-(trifluoromethyl)phenyl]-4-[(4-{[4-(trifluoro-
methyl)phenyl]sulfonyl}-1-piperazinyl)methyl]-1,3-thiazol-5-yl}methyl)sulf-
anyl]phenoxy}propanoic Acid
[1394] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.01 (d, 2H, J=8.20
Hz), 7.91 (m, 4H), 7.71 (d, 2H, J=8.20 Hz), 7.15 (d, 1H, J=2.22
Hz), 7.08 (dd, 1H, J=8.20, 2.22 Hz), 6.62 (d, 1H, J=8.20 Hz), 4.71
(q, 1H, J=6.58 Hz), 4.20 (s, 2H), 3.33 (s, 2H), 3.01 (br s, 4H),
2.49 (br s, 4H), 2.14 (s, 3H), 1.57 (d, 3H, J=6.58 Hz),
[1395] MS(ES.sup.-) M-H=758.0
[1396]
2-{4-[({4-({4-[(4-Methoxyphenyl)sulfonyl]-1-piperazinyl}methyl)-2-[-
4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylpheno-
xy}propanoic Acid
[1397] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.02 (d, 2H, J=8.37
Hz), 7.72 (d, 2H, J=8.37 Hz), 7.66 (d, 2H, J=8.72 Hz), 7.14 (d, 1H,
J=2.21 Hz), 7.07 (m, 3H), 6.63 (d, 1H, J=8.37 Hz), 4.71 (q, 1H,
J=6.72 Hz), 4.20 (s, 2H), 3.84 (s, 3H), 3.35 (s, 2H), 2.97 (br s,
4H), 2.53 (t, 4H, J=4.61 Hz), 2.14 (s, 3H), 1.58 (d, 3H, J=6.72
Hz),
[1398] MS(ES.sup.-) M-H=720.0
[1399]
2-{2-Methyl-4-[({4-{[4-(propylsulfonyl)-1-piperazinyl]methyl}-2-[4--
(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoi-
c Acid
[1400] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.07 (d, 2H, J=8.20
Hz), 7.75 (d, 2H, J=8.20 Hz), 7.19 (s, 1H), 7.13 (d, 1H, J=8.20
Hz), 6.66 (d, 1H, J=8.20 Hz), 4.70 (q, 1H, J=6.67 Hz), 4.26 (s,
2H), 3.40 (s, 2H), 3.22 (br s, 4H), 2.95 (t, 2H, J=7.43 Hz), 2.54
(br s, 4H), 2.17 (s, 3H), 1.76 (m, 2H), 1.57 (d, 3H, J=6.67 Hz),
1.02 (t, 3H, J=7.43 Hz),
[1401] MS(ES.sup.-) M-H=656.0
[1402]
2-{4-[({4-{[4-(Ethylsulfonyl)-1-piperazinyl]methyl}-2-[4-(trifluoro-
methyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic
Acid
[1403] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.07 (d, 2H, J=8.03
Hz), 7.74 (d, 2H, J=8.03 Hz), 7.19 (s, 1H), 7.11 (d, 1H, J=8.03
Hz), 6.65 (d, 1H, J=8.03 Hz), 4.64 (q, 1H, J=6.49 Hz), 4.26 (s,
2H), 3.39 (s, 2H), 3.23 (br s, 4H), 2.99 (q, 2H, J=7.41 Hz), 2.51
(br s, 4H), 2.16 (s, 3H), 1.55 (d, 3H, J=6.49 Hz), 1.27 (t, 3H,
J=7.41 Hz),
[1404] MS(ES.sup.-) M-H=642.0
[1405]
2-{2-Methyl-4-[({4-{[4-(methylsulfonyl)-1-piperazinyl]methyl}-2-[4--
(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoi-
c Acid
[1406] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.06 (d, 2H, J=8.03
Hz), 7.74 (d, 2H, J=8.03 Hz), 7.19 (s, 1H), 7.13 (dd, 1H, J=8.03,
2.22 Hz), 6.66 (d, 1H, J=8.03 Hz), 4.65 (q, 1H, J=6.84 Hz), 4.27
(s, 2H), 3.40 (s, 2H), 3.17 (t, 4H, J=4.19 Hz), 2.80 (s, 3H), 2.53
(t, 4H, J=4.19 Hz), 2.17 (s, 3H), 1.56 (d, 3H, J=6.84 Hz),
[1407] MS(ES.sup.-) M-H=628.0
[1408]
2-{4-[({4-{[4-(4-Fluorobenzoyl)-1-piperazinyl]methyl}-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propano-
ic Acid
[1409] .sup.1H NMR (CD.sub.3OD) 300 MHz .delta. 8.09 (d, 2H, J=8.28
Hz), 7.76 (d, 2H, J=8.28 Hz), 7.52(M, 2H), 7.22(M, 3H), 7.13 (dd,
1H, J=8.28, 2.20 Hz), 6.68 (d, 1H, J=8.28 Hz), 4.67 (q, 1H, J=6.81
Hz), 4.32 (s, 2H), 3.79 (br s, 4H), 3.66 (s, 2H), 2.90 (br s, 4H),
2.17 (s, 3H), 1.59 (d, 3H, J=6.81 Hz),
[1410] MS(ES.sup.-) M-H=671.9
[1411]
2-{4-[({4-[(4-{[4-(Acetylamino)phenyl]sulfonyl}-1-piperazinyl)methy-
l]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methy-
lphenoxy}propanoic Acid
[1412] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.07 (d, 2H, J=8.28
Hz), 7.83 (d, 2H, J=8.83 Hz), 7.77 (d, 2H, J=8.28 Hz), 7.71 (d, 2H,
J=8.83 Hz), 7.18 (d, 1H, J=2.20 Hz), 7.10 (dd, 1H, J=8.28, 2.20
Hz), 6.68 (d, 1H, J=8.28 Hz), 4.71 (q, 1H, J=6.53 Hz), 4.26 (s,
2H), 3.42 (s, 2H), 3.03 (br s, 4H), 2.56 (t, 4H, J=4.83 Hz), 2.20
(m, 6H), 1.63 (d, 3H, J=6.53 Hz),
[1413] MS(ES.sup.-) M-H=747.0
[1414]
2-{4-[({4-({4-[(4-Fluoroanilino)carbonyl]-1-piperazinyl}methyl)-2-[-
44-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphen-
oxy}propanoic Acid
[1415] MS(ES.sup.-) M-H=687.5
[1416]
2-{4-[({4-{[4-(4-Methoxybenzoyl)-1-piperazinyl]methyl}-2-[4-(triflu-
oromethyl
phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propan-
oic Acid
[1417] .sup.1H NMR (CD.sub.3OD) 300 MHz .delta. 8.02 (d, 2H, J=8.20
Hz), 7.69 (d, 2H, J=8.20 Hz), 7.38 (d, 2H, J=8.79 Hz), 7.12 (d, 1H,
J=2.24 Hz), 7.06 (dd, 1H, J=8.28, 2.24 Hz), 6.95 (d, 2H, J=8.79
Hz), 6.61 (d, 1H, J=8.28 Hz), 4.58 (q, 1H, J=6.78 Hz), 4.25 (s,
2H), 3.78 (s, 3H), 3.71 (br s, 4H), 3.64 (s, 2H), 2.88 (br s, 4H),
2.10 (s, 3H), 1.52 (d, 3H, J=6.78 Hz),
[1418] MS(ES.sup.-) M-H=683.6
[1419]
2-{4-[({4-({4-[(3-Methoxyanilino)carbonyl]-1-piperazinyl}methyl)-2--
[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphen-
oxy}propanoic Acid
[1420] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.04 (d, 2H, J=8.28
Hz), 7.69 (d, 2H, J=8.28 Hz), 7.31 (d, 1H, J=2.21 Hz), 7.16 (m,
2H), 6.89 (m, 2H), 6.59 (dd, 1H, J=8.28, 2.21 Hz), 6.53 (d, 1H,
J=8.28 Hz), 4.73 (q, 1H, J=6.90 Hz), 4.33 (d, 1H, J=0.63 Hz), 4.23
(d, 1H, J=0.63 Hz), 3.79 (s, 3H), 3.45 (m, 6H), 2.36 (t, 4H, J=4.69
Hz), 2.24 (s, 3H), 1.64 (d, 3H, J=6.90 Hz),
[1421] MS(ES.sup.-) M-H=699.6
[1422]
2-{4-[({4-{[4-(Aminocarbonyl)-1-piperazinyl]methyl}-2-[4-(trifluoro-
methyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic
Acid
[1423] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.15 (d, 2H, J=8.28
Hz), 7.83 (d, 2H, J=8.28 Hz), 7.27 (d, 1H, J=2.48 Hz), 7.19 (dd,
1H, J=8.55, 2.48 Hz), 6.74 (d, 1H, J=8.55 Hz), 4.65 (br s, 1H),
4.36 (s, 2H), 3.57 (s, 2H), 3.48 (br s, 4H), 2.64 (br s, 4H), 2.24
(s, 3H), 1.62 (d, 3H, J=6.62 Hz),
[1424] MS(ES.sup.-) M-H=593.1
[1425]
2-{4-[({4-({4-[(Cyclohexylamino)carbonyl]-1-piperazinyl}methyl)-2-[-
4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methyl)sulfanyl]-2-methylpheno-
xy}propanoic Acid
[1426] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.15 (d, 2H, J=8.28
Hz), 7.81 (d, 2H, J=8.28 Hz), 7.24 (br s, 1H), 7.13 (br s, 1H),
6.73 (br s, 1H), 4.75 (br s, 1H), 4.30 (s, 2H), 3.52 (m, 7H), 2.68
(br s, 4H), 2.24 (s, 3H), 1.75 (m, 7H), 1.26 (m, 6H),
[1427] MS(ES.sup.-) M-H=675.0
[1428]
2-{2-Methyl-4-[({4-({4-[(propylamino)carbonyl]-1-piperazinyl}methyl-
)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}p-
ropanoic Acid
[1429] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.15 (d, 2H, J=8.00
Hz), 7.81 (d, 2H, J=8.00 Hz), 7.25 (d, 1H, J=2.21 Hz), 7.15 (dd,
1H, J=8.55, 2.21 Hz), 6.70 (d, 1H, J=8.55 Hz), 4.68 (q, 1H, J=6.53
Hz), 4.30 (s, 2H), 3.60 (s, 2H), 3.48 (br s, 4H), 3.14 (t, 2H,
J=7.45 Hz), 2.73 (t, 4H, J=5.10 Hz), 2.22 (s, 3H), 1.63 (d, 3H,
J=6.53 Hz), 1.52 (s, 2H), 0.93 (t, 3H, J=7.45 Hz),
[1430] MS(ES.sup.-) M-H=635.3
[1431]
2-{4-[({4-({4-[(Ethylamino)carbonyl]-1-piperazinyl}methyl)-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}pr-
opanoic Acid
[1432] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.15 (d, 2H, J=8.28
Hz), 7.81 (d, 2H, J=8.28 Hz), 7.25 (d, 1H, J=2.48 Hz), 7.14 (dd,
1H, J=8.28, 2.48 Hz), 6.70 (d, 1H, J=8.28 Hz), 4.67 (br s, 1H),
4.29 (s, 2H), 3.56 (s, 2H), 3.46 (br s, 4H), 3.22 (q, 2H, J=7.17
Hz), 2.68 (t, 4H, J=4.92 Hz), 2.21 (s, 3H), 1.61 (d, 3H, J=6.35
Hz), 1.14 (t, 3H, J=7.17 Hz),
[1433] MS(ES.sup.-) M-H=621.1
[1434]
2-{2-Methyl-4[({4-({4-[(methylamine)carbonyl]-1-piperazinyl}methyl)-
-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}pr-
opanoic Acid
[1435] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.05 (d, 2H, J=8.20
Hz), 7.72 (d, 2H, J=8.20 Hz), 7.17 (d, 1H, J=2.22 Hz), 7.09 (dd,
1H, J=8.37, 2.22 Hz), 6.61 (d, 1H, J=8.37 Hz), 4.66 (q, 1H, J=6.75
Hz), 4.20 (s, 2H), 3.56 (s, 2H), 3.42 (br s, 4H), 2.69 (m, 7H),
2.15 (s, 3H), 1.58 (d, 3H, J=6.75 Hz),
[1436] MS(ES.sup.-) M-H=607.0
[1437]
2-{4-[({4-({4-[(Isopropylamino)carbonyl]-1-piperazinyl}methyl)-2-[4-
-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenox-
y}propanoic Acid
[1438] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.09 (d, 2H, J=8.20
Hz), 7.75 (d, 2H, J=8.20 Hz), 7.17 (br s, 1H), 7.08 (d, 1H, J=8.20
Hz), 6.64 (d, 1H, J=8.20 Hz), 4.63 (q, 1H, J=6.49 Hz), 4.23 (s,
2H), 3.84 (m, 1H), 3.46 (m, 6H), 2.68 (br s, 4H), 2.16 (s, 3H),
1.57 (d, 3H, J=6.49 Hz), 1.10 (d, 6H, J=6.32 Hz),
[1439] MS(ES.sup.-) M-H=635.0
[1440]
2-{4-[({4-({4-[(tert-Butylamino)carbonyl]-1-piperazinyl}methyl)-2-[-
4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylpheno-
xy}propanoic Acid
[1441] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.08 (d, 2H, J=8.20
Hz), 7.75 (d, 2H, J=8.20 Hz), 7.16 (d, 1H, J=2.22 Hz), 7.07 (dd,
1H, J=8.37, 2.22 Hz), 6.64 (d, 1H, J=8.37 Hz), 4.61 (q, 1H, J=6.75
Hz), 4.21 (s, 2H), 3.44 (m, 6H), 2.71 (br s, 4H), 2.16 (s, 3H),
1.55 (d, 3H, J=6.75 Hz), 1.27 (s, 9H),
[1442] MS(ES.sup.-) M-H=649.0
[1443]
2-{2-Methyl-4-[({4-[(4-{[(2-phenylethyl)amino]carbonyl}-1-piperazin-
yl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-
phenoxy)propanoic Acid
[1444] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.08 (d, 2H, J=8.03
Hz), 7.75 (d, 2H, J=8.03 Hz), 7.17 (s, 7H), 6.64 (d, 1H, J=8.55
Hz), 4.61 (q, 1H, J=6.84 Hz), 4.24 (s, 2H), 3.43 (m, 9H), 2.76 (t,
2H, J=7.52 Hz), 2.62 (br s, 4H), 2.16 (s, 3H), 1.56 (d, 3H, J=6.67
Hz),
[1445] MS(ES.sup.-) M-H=697.0
[1446]
2-{4-[({4-[(4-Benzoyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)p-
henyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic
Acid
[1447] .sup.1H NMR (CD.sub.3OD) 300 MHz .delta. 8.03 (d, 2H, J=8.28
Hz), 7.70 (d, 2H, J=8.28 Hz), 7.42 (m, 5H), 7.13 (d, 1H, J=2.24
Hz), 7.07 (dd, 1H, J=8.45, 2.24 Hz), 6.62 (d, 1H, J=8.45 Hz), 4.61
(q, 1H, J=6.78 Hz), 4.26 (s, 2H), 3.83 (br s, 4H), 3.62 (s, 2H),
2.86 (br s, 4H), 2.11 (s, 3H), 1.53 (d, 3H, J=6.78 Hz),
[1448] MS(ES.sup.-) M-H=653.7
[1449]
2-{2-Methyl-4-[({4-{[4-(4-propoxyphenyl)-1-piperazinyl]methyl}-2-[4-
-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propano-
ic Acid
[1450] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.11 (d, 2H, J=7.69
Hz), 7.77 (d, 2H, J=7.69 Hz), 7.15 (s, 1H), 7.08(dd, 1H, J=8.61,
2.20 Hz), 6.93 (d, 2H, J=8.97 Hz), 6.82 (d, 2H, J=8.97 Hz), 6.67
(d, 1H, J=8.61 Hz), 4.57 (q, 1H, J=6.78 Hz), 4.24 (s, 2H), 3.85 (t,
2H, J=7.01 Hz), 3.55 (s, 2H), 3.18 (br s, 4H), 3.03 (br s, 4H),
2.16 (s, 3H), 1.73 (m, 2H), 1.54 (d, 3H, J=6.78 Hz), 1.00 (t, 3H,
J=7.01 Hz),
[1451] MS(ES.sup.-) M-H=684.0
[1452]
2-{4-[({4-{[4-(4-Ethoxyphenyl)-1-piperazinyl]methyl}-2-[4-trifluoro-
methyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic
Acid
[1453] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.11 (d, 2H, J=8.06
Hz), 7.77 (d, 2H, J=8.06 Hz), 7.15 (s, 1H), 7.08 (dd, 1H, J=8.42,
2.20 Hz), 6.92 (d, 2H, J=8.97 Hz), 6.81 (d, 2H, J=8.97 Hz), 6.67
(d, 1H, J=8.42 Hz), 4.59 (q, 1H, J=6.78 Hz), 4.24 (s, 2H), 3.95 (q,
2H, J=6.78 Hz), 3.54 (s, 2H), 3.17 (br s, 4H), 3.04 (br s, 4H),
2.17 (s, 3H), 1.55 (d, 3H, J=6.78 Hz), 1.32 (t, 3H, J=6.78 Hz),
[1454] MS(ES.sup.-) M-H=671.0
[1455]
2-{2-Methyl-4-[({4-({4-[4-(trifluoromethoxy)phenyl]-1-piperazinyl}m-
ethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phen-
oxy}propanoic Acid
[1456] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.10 (d, 2H, J=8.28
Hz), 7.75 (d, 2H, J=8.28 Hz), 7.15 (d, 1H, J=2.24 Hz), 7.12 (d, 2H,
J=9.14 Hz), 7.08 (dd, 1H, J=8.45, 2.24 Hz), 7.00 (d, 2H, J=9.31
Hz), 6.66 (d, 1H, J=8.45 Hz), 4.59 (q, 1H, J=6.72 Hz), 4.24 (s,
2H), 3.54 (s, 2H), 3.27 (m, 4H), 2.97 (t, 4H, J=4.83 Hz), 2.16 (s,
3H), 1.54 (d, 3H, J=6.72 Hz),
[1457] MS(ES.sup.-) M-H=710.0
[1458]
2-{4-[({4-{[4-(3,4-Dimethoxyphenyl)-1-piperazinyl]methyl}-2-[4-(tri-
fluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}pro-
panoic Acid
[1459] .sup.1H NMR (CD.sub.3OD) 300 MHz .delta. 8.17 (d, 2H, J=8.28
Hz), 7.82 (d, 2H, J=8.28 Hz), 7.20 (br s, 1H), 7.12 (br s, 1H),
6.89 (d, 1H, J=8.83 Hz), 6.72 (m, 2H), 6.55 (dd, 1H, J=8.83, 2.76
Hz), 4.66 (br s, 1H), 4.29 (s, 2H), 3.84 (s, 3H), 3.80 (s, 3H),
3.57 (s, 2H), 3.25 (br s, 4H), 3.07 (br s, 4H), 2.23 (s, 3H), 1.61
(br s, 3H),
[1460] MS(ES.sup.-) M-H=686.0
[1461]
2-{4-[({4-{[4-(4-Hydroxyphenyl)-1-piperazinyl]methyl)-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propano-
ic Acid
[1462] .sup.1H NMR (CD.sub.3OD) 300 MHz .delta. 8.14 (br s, 2H),
7.80 (br s, 2H), 7.24 (br s, 1H), 7.12 (br s, 1H), 6.92 (br s, 2H),
6.76 (br s, 2H), 6.63(sbr, 1H), 4.54 (br s, 1H), 4.31 (br s, 2H),
3.67 (br s, 2H), 3.06 (br s, 8H), 2.23 (br s, 3H), 1.60 (br s,
3H),
[1463] MS(ES.sup.-) M-H=642.3
[1464]
2-{4-[({4-{[4-(3-Hydroxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propano-
ic Acid
[1465] .sup.1H NMR (CD.sub.3OD) 300 MHz .delta. 8.15 (d, 2H, J=8.28
Hz), 7.81 (d, 2H, J=8.28 Hz), 7.22 (d, 1H, J=2.21 Hz), 7.15 (dd,
1H, J=8.28, 2.21 Hz), 7.08 (t, 1H, J=8.14 Hz), 6.71 (d, 1H, J=8.28
Hz), 6.49 (dd, 1H, J.quadrature.14, 2.21 Hz), 6.45 (t, 1H, J=2.21
Hz), 6.39 (dd, 1H, J=8.14, 2.21 Hz), 4.74 (q, 1H, J=6.81 Hz), 4.30
(s, 2H), 3.85 (s, 2H), 3.36 (m, 4H), 3.24 (m, 4H), 2.21 (s, 3H),
1.61 (d, 3H, J=6.81 Hz),
[1466] MS(ES.sup.-) M-H=642.0
[1467]
2-{4-[({4-{[4-(2-Hydroxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propano-
ic Acid
[1468] .sup.1H NMR (CD.sub.3OD) 300 MHz .delta. 8.20 (d, 2H, J=8.00
Hz), 7.80 (d, 2H, J=8.00 Hz), 7.23 (br s, 1H), 7.01 (m, 3H), 6.82
(m, 2H), 6.66 (br s, 1H), 4.74 (br s, 1H), 4.26 (s, 2H), 3.56 (s,
2H), 3.12 (m, 8H), 2.19 (s, 3H), 1.58 (br s, 3H),
[1469] MS(ES.sup.-) M-H=642.1
[1470]
2-{4-[({4-[(4-Butyryl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)p-
henyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic
Acid
[1471] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.05 (d, 2H, J=8.55
Hz), 7.72 (d, 2H, J=8.55 Hz), 7.17 (d, 1H, J=2.22 Hz), 7.08 (d, 1H,
J=8.55 Hz), 6.64 (s, 1H), 4.56 (q, 1H, J=6.55 Hz), 4.26 (s, 2H),
3.54 (br s, 4H), 3.38 (s, 2H), 2.46 (br s, 4H), 2.33 (t, 2H, J=7.43
Hz), 2.16 (s, 3H), 1.58 (m, 5H), 0.93 (t, 3H, J=7.43 Hz),
[1472] MS(ES.sup.-) M-H=620.0
[1473]
2-(2-Methyl-4-[({4-[(4-pentanoyl-1-piperazinyl)methyl]-2-[4-(triflu-
oromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
Acid
[1474] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.06 (d, 2H, J=8.20
Hz), 7.74 (d, 2H, J=8.20 Hz), 7.17 (d, 1H, J=2.22 Hz), 7.10 (dd,
1H, J=8.20, 2.22 Hz), 6.65 (d, 1H, J=8.20 Hz), 4.68 (q, 1H, J=6.75
Hz), 4.25 (s, 2H), 3.56 (br s, 4H), 3.40 (s, 2H), 2.56 (br s, 4H),
2.36 (t, 2H, J=7.35 Hz), 2.16 (s, 3H), 1.54 (m, 5H), 1.34 (m, 2H),
0.90 (t, 3H, J=7.35 Hz),
[1475] MS(ES.sup.-) M-H=634.0
[1476]
2-{4-[({4-{([4-Methoxyacetyl)-1-piperazinyl]methyl}-2-[4-(trifluoro-
methyl)phenyl-11,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic
Acid
[1477] .sup.1H NMR (CD.sub.3OD) 300 MHz .delta. 8.07 (d, 2H, J=8.37
Hz), 7.75 (d, 2H, J=8.37 Hz), 7.18 (d, 1H, J=2.20 Hz), 7.11 (d, 1H,
J=8.37 Hz), 6.65 (d, 1H, J=8.37 Hz), 4.68 (q, 1H, J=6.72 Hz), 4.26
(s, 2H), 4.12 (s, 2H), 3.57 (br s, 2H), 3.46 (br s, 2H), 3.39 (s,
2H), 3.35 (s, 3H), 2.53 (t, 4H, J=4.79 Hz), 2.16 (s, 3H), 1.56 (d,
3H, J=6.72 Hz),
[1478] MS(ES.sup.-) M-H=622.0
[1479]
2-{4-[({4-[(4-Isobutyryl-1-piperazinyl)methyl]-2-[4-(trifluoromethy-
l)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic
Acid
[1480] .sup.1H NMR (CD.sub.3OD) 300 MHz .delta. 8.10 (d, 2H, J=8.28
Hz), 7.76 (d, 2H, J=8.28 Hz), 7.20 (d, 1H, J=2.21 Hz), 7.13 (dd,
1H, J=8.55, 2.21 Hz), 6.69 (d, 1H, J=8.55 Hz), 4.67 (q, 1H, J=6.81
Hz), 4.31 (s, 2H), 3.76 (brs, 4H), 3.69 (s, 2H), 2.92 (m, 5H), 2.20
(s, 3H), 1.59 (d, 3H, J=6.81 Hz), 1.10 (d, 6H, J=6.62 Hz),
[1481] MS(ES.sup.-) M-H=620.4
[1482]
2-{4-[({4-{[4-(2,2-Dimethylpropanoyl)-1-piperazinyl]methyl}-2-[4-(t-
rifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}p-
ropanoic Acid
[1483] .sup.1H NMR (CD.sub.3OD) 300 MHz .delta. 8.10 (d, 2H, J=8.28
Hz), 7.76 (d, 2H, J=8.28 Hz), 7.19 (d, 1H, J=2.21 Hz), 7.13 (dd,
1H, J=8.28, 2.21 Hz), 6.69 (d, 1H, J=8.28 Hz), 4.68 (q, 1H, J=6.71
Hz), 4.32 (s, 2H), 3.83 (br s, 4H), 3.71 (s, 2H), 2.98 (t, 4H,
J=4.83 Hz), 2.20 (s, 3H), 1.60 (d, 3H, J=6.71 Hz), 1.28 (s,
9H),
[1484] MS(ES.sup.-) M-H=634.2
[1485]
2-Methyl-2[4-(}[2-[4-(trifluoromethyl)phenyl]-4-(4-[3-(trifluoromet-
hyl)phenyl]-1-piperazinyl}methyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy-
]propanoic Acid
[1486] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.10 (d, 2H, J=8.06
Hz), 7.76 (d, 2H, J=8.06 Hz), 7.40 (t, 1H, J=7.69 Hz), 7.28 (d, 2H,
J=8.79 Hz), 7.18 (s, 2H), 7.09 (d, 1H, J=7.69 Hz), 6.81 (d, 2H,
J=8.79 Hz), 4.31 (s, 2H), 3.59 (s, 2H), 3.31 (t, 4H, J=4.94 Hz),
2.88 (t, 4H, J=4.94 Hz), 1.54 (s, 6H),
[1487] MS(ES.sup.-) M-H=694.5
[1488] CHN Analysis (Theoretical % C=56.97, % H=4.49, % N-6.04;
Found % C=56.69, % H=4.66, % N=5.77)
[1489]
{4-[({4-{[4-(tert-Butoxycarbonyl)-1-piperazinyl]methyl)-2-[4-(trifl-
uoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}aceti-
c Acid
[1490] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.05 (d, 2H, J=8.28
Hz), 7.73 (d, 2H, J=8.28 Hz), 7.18 (s, 1H), 7.11 (br s, 1H), 6.66
(br s, 1H), 4.54 (s, 2H), 4.26 (s, 2H), 3.42 (m, 6H), 2.50 (br s,
4H), 2.19 (s, 3H), 1.43 (s, 9H),
[1491] MS(ES.sup.-) M-H=636.5
[1492]
{2-Methyl-[4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2-[4-(tri-
fluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic
Acid
[1493] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.21 (s, 1H), 8.09
(d, 3H, J=8.10 Hz), 7.80 (s, 1H), 7.75 (d, 2H, J=8.28 Hz), 7.19 (d,
1H, J=2.07 Hz), 7.13 (dd, 1H, J=8.45, 2.24 Hz), 6.70 (d, 1H, J=8.45
Hz), 4.57 (s, 2H), 4.27 (s, 2H), 3.66 (br s, 4H), 3.53 (s, 2H),
2.77 (br s, 4H), 2.17 (s, 3H),
[1494] MS(ES.sup.-) M-H=612.4
[1495]
{4-[({4-{[4-(2-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoro-
methyl)phenyl-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic
Acid
[1496] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.10 (d, 2H, J=8.28
Hz), 7.75 (d, 2H, J=8.28 Hz), 7.18 (d, 1H, J=2.20 Hz), 7.02 (s,
2H), 6.92 (dd, 2H, J=8.10, 2.20 Hz), 6.86 (s, 1H), 6.62 (d, 1H,
J=8.45 Hz), 4.48 (s, 2H), 4.25 (s, 2H), 3.81 (s, 3H), 3.55 (s, 2H),
3.11 (br s, 4H), 2.96 (br s, 4H), 2.17 (s, 3H),
[1497] MS(ES.sup.-) M-H=640.5
[1498]
{4-[({4-([4-(3-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoro-
methyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic
Acid
[1499] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.10 (d, 2H, J=8.28
Hz), 7.75 (d, 2H, J=8.28 Hz), 7.18 (d, 1H, J=2.24 Hz), 7.10 (s,
2H), 6.67 (d, 1H, J=8.23 Hz), 6.53 (dd, 1H, J=8.28, 2.24 Hz), 6.47
(t, 1H, J=2.24 Hz), 6.43 (dd, 1H, J=8.28, 2.24 Hz), 4.52 (s, 2H),
4.25 (s, 2H), 3.72 (s, 3H), 3.58 (s, 2H), 3.24 (t, 4H, J=5.09 Hz),
2.98 (t, 4H, J=5.09 Hz), 2.17 (s, 3H),
[1500] MS(ES.sup.-) M-H=642.0
[1501]
2-Methyl-2-{4-[({4-{[4-(phenoxycarbonyl)-1-piperazinyl]methyl}-2-[4-
-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propano-
ic Acid
[1502] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.07 (d, 2H, J=8.28
Hz), 7.73 (d, 2H, J=8.28 Hz), 7.34 (t, 2H, J=7.59 Hz), 7.27 (d, 2H,
J=8.45 Hz), 7.18 (t, 1H, J=7.59 Hz), 7.06 (d, 2H, J=7.59 Hz), 6.80
(d, 2H, J=8.45 Hz), 4.33 (s, 2H), 3.68 (br s, 2H), 3.53 (br s, 2H),
3.44 (s, 2H), 2.56 (br s, 4H), 1.52 (s, 6H),
[1503] CHN Analysis 1 MeOH (Theoretical % C=58.02, % H=5.16, %
N=5.97; Found % C=58.33, % H=5.09, % N=5.72)
[1504]
2-{4-[({4-{[4-(tert-Butoxycarbonyl)-1-piperazinyl]methyl}-2-[4-(tri-
fluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpro-
panoic Acid
[1505] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.04 (d, 2H, J=8.28
Hz), 7.71 (d, 2H, J=8.28 Hz), 7.22 (d, 2H, J=8.10 Hz), 6.78 (d, 2H,
J=8.10 Hz), 4.27 (s, 2H), 3.40 (m, 6H), 2.49 (br s, 4H), 1.50 (s,
6H), 1.41 (s, 9H),
[1506] MS(ES.sup.-) M-H=650.5
[1507]
2-Methyl-2-{4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
Acid
[1508] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.21 (s, 1H), 8.07
(m, 3H), 7.79 (s, 1H), 7.73 (d, 2H, J=8.28 Hz), 7.25 (d, 2H, J=8.10
Hz), 6.79 (d, 2H, J=8.10 Hz), 4.30 (s, 2H), 3.65 (br s, 4H), 3.53
(s, 2H), 2.72 (br s, 4H), 1.53 (s, 6H),
[1509] MS(ES.sup.-) M-H=627.6
[1510]
2-{4-[({4-{[4-(2-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluo-
romethyl)phenyl-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpropanoi-
c Acid
[1511] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.10 (d, 2H, J=8.28
Hz), 7.74 (d, 2H, J=8.28 Hz), 7.21 (d, 2H, J=8.42 Hz), 7.00 (m,
1H), 6.92 (m, 2H), 6.86 (m, 1H), 6.78 (d, 2H, J=8.42 Hz), 4.27 (s,
2H), 3.81 (s, 3H), 3.59 (s, 2H), 3.14 (br s, 4H), 3.01 (br s, 4H),
1.51 (s, 6H),
[1512] MS(ES.sup.-) M-H=656.0
[1513]
2-{4-[({4-{[4-(Ethoxycarbonyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpropanoi-
c Acid
[1514] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.05 (d, 2H, J=8.10
Hz), 7.72 (d, 2H, J=8.10 Hz), 7.24 (d, 2H, J=8.42 Hz), 6.79 (d, 2H,
J=8.42 Hz), 4.30 (s, 2H), 4.09 (q, 2H, J=7.16 Hz), 3.44 (m, 6H),
2.50 (s, 4H), 1.52 (s, 6H), 1.21 (t, 3H, J=7.16 Hz),
[1515] MS(ES.sup.-) M-H=621.7
[1516]
2-{4-[({4-{[4-(4-isopropoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trif-
luoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy)prop-
anoic Acid
[1517] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.13 (d, 2H, J=8.06
Hz), 7.79 (d, 2H, J=8.06 Hz), 7.13 (m, 2H), 6.92 (d, 2H, J=8.97
Hz), 6.81 (d, 2H, J=8.97 Hz), 6.67 (d, 1H, J=8.42 Hz), 4.61 (q, 1H,
J=6.78 Hz), 4.46 (m, 1H), 4.25 (s, 2H), 3.56 (s, 2H), 3.19 (br s,
4H), 3.06 (br s, 4H), 2.17 (s, 3H), 1.55 (d, 3H, J=6.78 Hz), 1.24
(d, 6H, J=6.87 Hz),
[1518] MS(ES.sup.-) M-H=685.0
[1519]
[4-(}[4-([1,1'-Biphenyl]-4-ylmethyl)-2-(4-{trifluoromethyl}phenyl)--
1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetic Acid
[1520] TLC(5% MeOH/CH.sub.2Cl.sub.2) R.sub.f=0.16
[1521] MS(ES.sup.-) M-H=603
[1522]
{2-Methyl-4-[({2-(4-{trifluoromethyl}phenyl)-4-[4-(3-thienyl)benzyl-
]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic Acid
[1523] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.93 (d, 2H, J=8.23
Hz), 7.61 (d, 2H, J=8.23 Hz), 7.44 (d, 2H, J=8.23 Hz), 7.36 (s,
1H), 7.29 (m, 2H), 7.08 (m, 3H), 6.54 (d, 1H, J=8.23 Hz), 4.52 (s,
2H), 4.06 (s, 2H), 3.90 (s, 2H), 2.15 (s, 3H),
[1524] TLC(5% MeOH/CH.sub.2Cl.sub.2) R.sub.f=0.18
[1525] MS(ES.sup.-) M-H=609
[1526]
[4-({[4-Benzyl-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5-yl]methy-
l}sulfanyl)phenoxy]acetic Acid
[1527] .sup.1H NMR (CD.sub.3OD) 300 MHz .delta. 8.04 (d, 2H, J=8.23
Hz), 7.75 (d, 2H, J=8.23 Hz), 7.34 (d, 2H, J=8.76 Hz), 7.20 (m,
5H), 6.88 (d, 2H, J=9.76 Hz), 4.66 (s, 2H), 4.25 (s, 2H), 3.93 (s,
2H),
[1528] MS(ES.sup.-) M-H=513.86
[1529] TLC(20% MeOH/CH.sub.2Cl.sub.2) R.sub.f 0.37
[1530]
2-[4-({[4-Benzyl-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5-yl]met-
hyl}sulfanyl)phenoxy]propanoic Acid
[1531] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 8.02 (d, 2H, J=8.23
Hz), 7.69 (d, 2H, J=8.23 Hz), 7.26 (m, 7H), 6.83 (d, 2H, J=8.76
Hz), 4.80 (q, 1H, J=6.72 Hz), 4.14 (s, 2H), 3.90 (m, 2H), 1.68 (d,
3H, J=6.72 Hz),
[1532] MS(ES.sup.-) M-H=528.43
[1533] TLC(20% MeOH/CH.sub.2Cl.sub.2) R.sub.f=0.60
[1534]
[2-Methyl-4-({[2-(4-{trifluoromethyl}phenyl)-42-phenylethyl)-1,3-th-
iazol-5-yl]methyl}sulfanyl)phenoxy]acetic Acid
[1535] .sup.1H (CDCl.sub.3) 300 MHz .delta. 7.99 (d, 2H, J=8.79
Hz), 7.67 (d, 2H, J=8.93 Hz), 7.18 (m, 8H), 6.60 (d, 1H, J=8.51
Hz), 4.64 (s, 2H), 3.85 (s, 2H), 2.90 (m, 2H), 2.80 (m, 2H), 2.23
(s, 3H),
[1536]
[4-({[4-[(Benzyloxy)methyl]-2-(4-{trifluoromethyl}phenyl)-1,3-thiaz-
ol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetic Acid
[1537] .sup.1H (CDCl.sub.3) 300 MHz .delta. 7.99 (d, 2H, J=8.79
Hz), 7.67 (d, 2H, J=8.79 Hz), 7.33 (m, 4H), 7.28 (s, 2H), 7.18 (dd,
1H, J=2.33, 0.55 Hz), 7.08 (ddd, 1H, J=8.38, 2.33, 0.55 Hz), 6.56
(d, 1H, J=8.38 Hz), 4.63 (s, 2H), 4.53 (s, 2H), 4.39 (s, 2H), 4.19
(s, 2H), 221 (s, 3H),
[1538]
[2-Methyl-4-({[2-(4-{trifluoromethyl}phenyl)-4-(3-phenylpropyl)-1,3-
-thiazol-5-yl]methyl}sulfanyl)phenoxy]acetic Acid
[1539] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.82 (m, 2H), 7.50
(m, 2H), 6.94 (m, 8H), 3.95 (s, 2H), 2.55 (m, 4H), 1.99 (m,
7H),
[1540]
{2-Methyl-4-[({2-(4-{trifluoromethyl}phenyl)-4-[(2-phenylethoxy)met-
hyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic Acid
[1541] .sup.1H NMR (CDCl.sub.3) 300 MHz .delta. 7.92 (m, 2H), 7.62
(m, 2H), 7.20 (m, 7H), 7.05 (br s, 1H), 4.55 (s, 2H), 4.38 (s, 2H),
4.09 (s, 2H), 3.66 (br s, 2H), 2.87 (br s, 2H), 2.17 (s, 3H),
[1542] TLC(5% MeOH/Dichloromethane) R.sub.f=0.65
[1543]
[4-({[4-(4-Bromobenzyl)-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5-
-yl]methyl}sulfanyl)-2-methylphenoxy]acetic Acid
[1544] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.82 (d, 2H, J=8.20
Hz), 7.53 (d, 2H, J=8.20 Hz), 7.22 (d, 2H, J=8.55 Hz), 7.05 (m,
1H), 6.97 (dd, 1H, J=8.37, 2.39 Hz), 6.88 (d, 2H, J=8.55 Hz), 6.47
(d, 1H, J=8.37 Hz), 4.47 (s, 2H), 3.72 (s, 2H), 3.36 (s, 2H), 2.08
(s, 3H),
[1545] TLC(5% MeOH/CH.sub.2Cl.sub.2) R.sub.f 0.16
[1546]
[4-({[4-Benzyl-2-(4-{triflurormethyl}phenyl)-1,3-thiazol-5-yl]methy-
l}sulfanyl)-2-methylphenoxy]acetic Acid
[1547] .sup.1H (CDCl.sub.3) 300 MHz .delta. 7.97 (d, 2H, J=8.79
Hz), 7.64 (d, 2H, J=9.48 Hz), 7.21 (m, 8H), 6.58 (d, 1H, J=8.38
Hz), 4.65 (s, 2H), 4.11 (s, 2H), 3.93 (s, 2H), 2.22 (s, 3H),
[1548] MS(ES.sup.+) M+H=529.99
[1549]
2-{4-[({4-{[3-(5-Methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-[4-(-
trifluoromethyl)phenyl]-1,3-thiazol-5-yl)methyl)sulfanyl]phenoxy}propanoic
Acid
[1550] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.01 (d, 2H, J=8.03
Hz), 7.68 (m, 3H), 7.43 (m, 1H), 7.36 (t, 1H, J=8.03 Hz), 7.20 (d,
2H, J=8.89 Hz), 7.05 (dd, 1H, J=8.20, 2.39 Hz), 6.79 (d, 2H, J=8.89
Hz), 4.76 (q, 1H, J=6.78 Hz), 4.66 (d, 1H, J=0.28 Hz), 4.36 (d, 1H,
J=0.28 Hz), 4.24 (d, 1H, J=0.70 Hz), 4.15 (d, 1H. J 0.70 Hz), 2.71
(s, 3H), 1.67 (m, 3H),
[1551] MS(ES.sup.+) M+H=628.0
[1552]
2-{4-[({4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propano-
ic Acid
[1553] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 9.03 (br s, 1H),
7.96 (d, 2H, J=8.20 Hz), 7.67 (d, 2H, J=8.20 Hz), 7.15 (d, 2H,
J=8.72 Hz), 6.81 (m, 6H), 4.12 (s, 2H), 3.73 (s, 3H), 3.50 (s, 2H),
3.27 (br s, 4H), 3.15 (br s, 4H), 1.63 (s, 6H),
[1554] HPLC(C-18, 3 .mu.n) 1% MeOH/0-90% CH.sub.3CN/Water (0.1%
TFA)/(50 mM Et.sub.3N/TFA) 4 min run R.sub.t=2.89 min
[1555]
2-(4-{[(4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-phenyl-1,3--
thiazol-5-yl)methyl]sulfanyl}phenoxy)-2-methylpropanoic Acid
[1556] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.87 (m, 2H), 7.44
(m, 3H), 7.15 (d, 2H, J=8.55 Hz), 6.82 (m, 6H), 4.08 (s, 2H), 3.73
(s, 3H), 3.46 (s, 2H), 3.31 (m, 4H), 3.18 (m, 4H), 1.65 (s,
6H),
[1557] HPLC(C-18, 3 .mu.m) 1% MeOH/0-90% CH.sub.3CN/Water (0.1%
TFA)/(50 mM Et.sub.3N/TFA) 4 min run R.sub.t=2.74 min
[1558]
{4-[({4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoro-
methyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic
Acid
[1559] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 10.00 (s, 1H), 7.96
(d, 2H, J=8.20 Hz), 7.66 (d, 2H, J=8.20 Hz), 7.27 (d, 2H, J=8.72
Hz), 6.82 (m, 6H), 4.51 (s, 2H), 4.22 (s, 2H), 3.80 (s, 2H), 3.72
(s, 3H), 3.21 (m, 8H),
[1560] HPLC(C-18, 3 .mu.m) 1% MeOH/0-90% CH.sub.3CN/Water (0.1%
TFA)/(50 mM Et.sub.3N/TFA) 4 min run R.sub.t=2.74 min
[1561]
(4-{[(4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-phenyl-1,3-th-
iazol-5-yl)methyl]sulfanyl}phenoxy)acetic Acid
[1562] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 9.49 (br s, 1H),
7.86 (m, 2H), 7.42 (m, 3H), 7.24 (d, 2H, J=8.55 Hz), 6.80 (m, 6H),
4.50 (s, 2H), 4.22 (s, 2H), 3.81 (s, 2H), 3.71 (s, 3H), 3.24 (m,
8H),
[1563] HPLC(C-18, 3 .mu.m) 1% MeOH/0-90% CH.sub.3CN/Water (0.1%
TFA)/(50 mM Et.sub.3N/TFA) 4 min run R.sub.t=2.55 min
[1564]
2-{4-[({4-{4[-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
Acid
[1565] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta.9.31 (s, 1H), 7.96
(d, 2H, J=8.20 Hz), 7.68 (d, 2H, J=8.20 Hz), 7.18 (d, 2H, J=8.55
Hz), 6.82 (m, 6H), 4.73 (q, 1H, J=6.67 Hz), 4.16 (d, 1H, J=0.87
Hz), 4.10 (d, 1H, J=0.87 Hz), 3.72 (s, 3H), 3.58 (d, 1H, J=0.53
Hz), 3.51 (d, 1H, J=0.53 Hz), 3.24 (m, 8H), 1.59 (d, 3H, J=6.67
Hz),
[1566] HPLC(C-18, 3 .mu.m) 1% MeOH/0-90% CH.sub.3CN/Water (0.1%
TFA)/(50 mM Et.sub.3N/TFA) 4 min run R.sub.t=2.80 min
[1567]
2-(4-{[4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-phenyl-1,3-t-
hiazol-5-yl)methyl]sulfanyl}phenoxy)propanoic Acid
[1568] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 8.42 (s, 1H), 7.84
(m, 2H), 7.40 (m, 3H), 7.17 (d, 2H, J=8.72 Hz), 6.81 (m, 6H), 4.69
(q, 1H, J=6.67 Hz), 4.11 (d, 1H, J=0.18 Hz), 4.07 (d, 1H, J=0.18
Hz), 3.73 (s, 3H), 3.57 (d, 1H, J=0.87 Hz), 3.49 (d, 1H, J=0.87
Hz), 3.18 (m, 8H), 1.59 (d, 3H, J=6.67 Hz),
[1569] HPLC(C-18, 3 .mu.m) 1% MeOH/0-90% CH.sub.3CN/Water (0.1%
TFA)/(50 mM Et.sub.3N/TFA) 4 min run R.sub.t=2.63 min
[1570]
{4-[({4-{[3-(5-Methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic
Acid
[1571] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 10.17 (s, 1H), 8.02
(d, 2H, J=8.20 Hz), 7.67 (m, 3H), 7.46 (m, 1H), 7.36 (t, 1H, J=7.95
Hz), 7.22 (d, 2H, J=8.72 Hz), 7.06 (dd, 1H, J=8.37, 2.39 Hz), 6.79
(d, 2H, J=8.72 Hz), 4.69 (s, 2H), 4.58 (s, 2H), 4.22 (s, 2H), 2.73
(s, 3H),
[1572] MS(ES.sup.+) M+H=614.00
[1573]
2-Methyl-2-{4-[({4-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methy-
l}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methyl)sulfanyl]phenoxy}-
propanoic Acid
[1574] .sup.1H (CDCl.sub.3) 400 MHz .delta. 7.98 (d, 2H, J=8.03
Hz), 7.92 (d, 2H, J=9.06 Hz), 7.67 (d, 2H, J=8.03 Hz), 7.18 (d, 2H,
J=9.06 Hz), 6.96 (d, 2H, J=8.75 Hz), 6.74 (d, 2H, J=8.75 Hz), 4.98
(s, 2H), 4.29 (s, 2H), 2.66 (s, 3H), 1.57 (s, 6H)
[1575] MS(ES.sup.-) M-H=640.00
[1576]
2-Methyl-2-(4-{[(4-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methy-
l}-2-phenyl-1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)propanoic
Acid
[1577] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta.8.93 (d, 2H, J=9.06
Hz), 7.86 (m, 2H), 7.42 (m, 3H), 7.17 (d, 2H, J=8.72 Hz), 6.96 (d,
2H, J=9.06 Hz), 6.73 (d, 2H, J=8.72 Hz), 4.92 (s, 2H), 4.27 (s,
2H), 2.66 (s, 3H), 1.57 (s, 6H),
[1578] MS(ES.sup.-) M-H=571.50
[1579]
{4-[({4-{[4-(5-Methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic
Acid
[1580] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.98 (d, 2H, J=8.20
Hz), 7.93 (d, 2H, J=9.06 Hz), 7.66 (d, 2H, J=8.20 Hz), 7.28 (d, 2H,
J=8.89 Hz), 6.96 (d, 2H, J=9.06 Hz), 6.76 (d, 2H, J=8.89 Hz), 4.86
(s, 2H), 4.60 (s, 2H), 4.25 (s, 2H), 2.62 (s, 3H),
[1581] MS(ES.sup.-) M-H=611.80
[1582]
(4-}[(4-{[4-(5-Methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-phenyl-
-1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)acetic Acid
[1583] .sup.1H NMR (CDCl.sub.3) 400 MHz 7.92 (d, 2H, J=9.06 Hz),
7.83 (m, 2H), 7.39 (m, 3H), 7.23 (d, 2H, J=8.90 Hz), 6.95 (d, 2H,
J=9.06 Hz), 6.76 (d, 2H, J=8.90 Hz), 4.70 (s, 2H), 4.54 (s, 2H),
4.18 (s, 2H), 2.60 (s, 3H),
[1584] MS(ES.sup.+) M+H=546.20
[1585]
2-{4-[({4-{[4-(5-Methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-[4-(-
trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
Acid
[1586] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.97 (d, 2H, J=8.20
Hz), 7.92 (d, 2H, J=8.89 Hz), 7.65 (d, 2H, J=8.20 Hz), 7.22 (d, 2H,
J=8.89 Hz), 6.94 (d, 2H, J=8.89 Hz), 6.73 (d, 2H, J=8.89 Hz), 4.86
(d, 1H, J=0.79 Hz), 4.80 (d, 1H, J=0.96 Hz), 4.66 (q, 1H, J=6.89
Hz), 4.26 (d, 1H, J=0.87 Hz), 4.20 (d, 1H. J 0.87 Hz), 2.62 (s,
3H), 1.58 (d, 3H, J=6.89 Hz),
[1587] MS(ES.sup.-) M-H=626.00
[1588]
2-(4-{[(4-{[4-(5-Methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-phen-
yl-1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)propanoic Acid
[1589] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta.7.93 (d, 2H, J=9.06
Hz), 7.85 (m, 2H), 7.41 (m, 3H), 7.24 (d, 2H, J=8.89 Hz), 6.95 (d,
2H, J=9.06 Hz), 6.74 (d, 2H, J=8.89 Hz), 4.82 (s, 2H), 4.68 (q, 1H,
J=6.89 Hz), 4.25 (d, 1H, J=0.87 Hz), 4.19 (d, 1H, J=0.87 Hz), 2.64
(s, 3H), 1.61 (d, 3H, J=6.89 Hz),
[1590] MS(ES.sup.-) M-H=558.30
[1591]
2-{4-[({4-{[4-(4-Acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpropanoi-
c Acid
[1592] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.04 (d, 2H, J=8.10
Hz), 7.85 (d, 2H, J=9.14 Hz), 7.72 (d, 2H, J=8.10 Hz), 7.25 (d, 2H,
J=8.79 Hz), 6.93 (d, 2H, J=9.14 Hz), 6.81 (d, 2H, J=8.79 Hz), 4.32
(s, 2H), 3.47 (s, 2H), 3.35 (t, 4H, J=4.91 Hz), 2.59 (t, 4H, J=4.91
Hz), 2.47 (s, 3H), 1.47 (s, 6H),
[1593] MS(ES.sup.-) M-H=668.1
[1594]
2-{4-[({4-{[4-(4-Chlorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpropanoi-
c Acid
[1595] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.05 (d, 2H, J=8.10
Hz), 7.73 (d, 2H, J=8.10 Hz), 7.24 (d, 2H, J=8.79 Hz), 7.15 (d, 2H,
J=8.97 Hz), 6.90 (d, 2H, J=8.97 Hz), 6.80 (d, 2H, J=8.79 Hz), 4.30
(s, 2H), 3.57 (s, 2H), 3.18 (t, 4H, J=5.00 Hz), 2.77 (t, 4H, J=5.00
Hz), 1.49 (s, 6H),
[1596] CHN Analysis: Theory (C, 58.04%; H, 4.72%; N, 6.35%) Found
(C, 57.65%; H. 4.80%; N, 6.13%)
[1597]
2-{4-[({4-{[4-(3-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpropano-
ic Acid
[1598] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 7.98 (d, 2H, J=7.93
Hz), 7.63 (d, 2H, J=7.93 Hz), 7.12 (m, 3H), 6.73 (m, 2H), 6.47 (m,
1H), 6.38 (m, 2H), 4.18 (s, 2H), 3.70 (s, 3H), 3.50 (s, 2H), 3.14
(br s, 4H), 2.76(sbr, 4H), 1.49 (s, 6H),
[1599] CHN Analysis: Theory (C, 60.26%; H, 5.21%; N, 6.39%) Found
(C, 59.83%; H, 5.29%; N, 6.32%)
[1600]
2-(4-{[(2-(4-Fluorophenyl)-4-{[4-(phenoxycarbonyl)-1-piperazinyl]me-
thyl}-1,3-thiazol-5-yl)methyl]sulfanyl}-2-methylphenoxy}-2-methylpropanoic
Acid
[1601] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.93 (m, 2H), 7.35
(m, 3H), 7.19 (m, 4H), 7.08 (m, 2H), 6.69 (br s, 1H), 4.27 (s, 2H),
3.60 (br s, 4H), 3.39 (s, 2H), 2.54 (br s, 4H), 2.14 (s, 3H), 1.55
(s, 6H),
[1602] MS(ES.sup.-) M-H=634.1
[1603]
2-{4-[({4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-meth-
ylpropanoic Acid
[1604] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.05 (br s, 2H),
7.66 (d, 2H, J=8.28 Hz), 7.15 (s, 1H), 6.84 (m, 6H), 4.19 (s, 2H),
3.44 (s, 2H) 3.69 (s, 3H), 3.10 (m, 4H), 2.82 (br s, 4H), 2.10 (s,
3H), 1.52 (s, 6H),
[1605] MS(ES.sup.+) M+H=672.2
[1606]
2-{4-[({4-{[4-(4-Acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methy-
lpropanoic Acid
[1607] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 7.97 (d, 2H, J=8.10
Hz), 7.80 (d, 2H, J=8.42 Hz), 7.65 (d, 2H, J=8.10 Hz), 7.16 (br s,
1H), 7.01 (br s, 1H), 6.84 (d, 2H, J=8.42 Hz), 6.60 (br s, 1H),
4.23 (s, 2H), 3.44 (s, 2H), 3.27 (br s, 4H), 2.55 (br s, 4H), 2.44
(s, 3H), 2.11 (s, 3H), 1.52 (s, 6H),
[1608] MS(ES.sup.+) M+H=684.2
[1609]
2-{4-[({4-{[4-(3-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluo-
romethyl)phenyl]-1,3-thiazol-5-yl)methyl)sulfanyl]-2-methylphenoxy}-2-meth-
ylpropanoic Acid
[1610] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 7.96 (d, 2H, J=8.10
Hz), 7.61 (d, 2H, J=8.10 Hz), 7.03 (m, 3H), 6.38 (m, 4H), 4.18 (s,
2H), 3.69 (s, 3H), 3.33 (s, 2H), 3.11 (m, 4H), 2.66 (brs, 4H), 2.09
(s, 3H), 1.50 (s, 6H),
[1611] MS(ES.sup.-) M-H=670.0
[1612]
2-{4-[({4-{[4-(4-Fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluor-
omethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methy-
lpropanoic Acid
[1613] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.08 (d, 2H, J=8.24
Hz), 7.73 (d, 2H, J=8.24 Hz), 7.18 (br s, 1H), 7.04 (br s, 1H),
6.92 (m, 4H), 6.72 (br s, 1H), 4.26 (s, 2H), 3.58 (s, 2H), 3.14 (br
s, 4H), 2.84 (br s, 4H), 2.10 (s, 3H), 1.60 (s, 6H),
[1614] MS(ES.sup.-) M-H=658.4
[1615]
2-Methyl-2-{2-methyl-4-[({4-([4-(phenoxycarbonyl)-1-piperazinyl]met-
hyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenox-
y}propanoic Acid
[1616] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 8.04 (br s, 2H),
7.71 (br s, 2H), 7.34 (m, 2H), 7.19 (m, 3H), 7.04 (m, 3H), 4.28 (s,
2H), 3.65 (s, 2H), 3.45 (br s, 4H), 2.47 (br s, 4H), 2.12 (s, 3H),
1.61 (s, 6H),
[1617] MS(ES.sup.-) M-H=684.0
[1618]
2-[4-({[4-{[4-(4-Acetylphenyl)-1-piperazinyl]methyl}-2-(4-fluorophe-
nyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]-2-methylpropanoic
Acid
[1619] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 7.93 (m, 2H), 7.86
(d, 2H, J=9.16 Hz), 7.18 (m, 3H), 7.07 (br s, 1H), 6.95 (d, 2H,
J=9.16 Hz), 6.69 (br s, 1H), 4.23 (s, 2H), 3.42 (m, 6H), 2.69 (br
s, 4H), 2.49 (s, 3H), 2.13 (s, 3H), 1.56 (s, 6H),
[1620] MS(ES.sup.-) M-H=632.3
[1621]
2-(4-{[(2-(4-Fluorophenyl)-4-{[4-(3-methoxyphenyl)-1-piperazinyl]me-
thyl}-1,3-thiazol-5-yl)methyl]sulfanyl}-2-methylphenoxy}-2-methylpropanoic
Acid
[1622] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 7.96 (m, 2H), 7.19
(m, 3H), 7.12 (t, 1H, J=8.24 Hz), 7.01 (br s, 1H), 6.66 (br s, 1H),
6.54 (dd, 1H, J=8.24, 2.20 Hz), 6.47 (t, 1H, J=2.20 Hz), 6.43 (dd,
1H. J=8.24, 2.20 Hz), 4.20 (s, 2H), 3.73 (s, 3H), 3.55 (s, 2H),
3.24 (br s, 4H), 2.91 (br s, 4H), 2.13 (s, 3H), 1.56 (s, 6H),
[1623] MS(ES.sup.-) M-H=620.0
[1624]
2-[4-({[4-{[4-(Ethoxycarbonyl)-1-piperazinyl]methyl}-2-(4-fluorophe-
nyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]-2-methylpropanoic
Acid
[1625] .sup.1H NMR (CD.sub.3OD) 400 MHz .delta. 7.94 (m, 2H), 7.19
(m, 3H), 7.00 (br s, 1H), 6.66 (br s, 1H), 4.23 (s, 2H), 4.09 (q,
2H, J=7.05 Hz), 3.48 (m, 6H), 2.49 (br s, 4H), 2.13 (s, 3H), 1.56
(s, 6H), 1.23 (t, 3H, J=7.05 Hz),
[1626] MS(ES.sup.-) M-H=586.2
[1627]
2-(4-{[(2-(4-Fluorophenyl)-4-{[4-(isopropoxycarbonyl)-1-piperazinyl-
]methyl}-1,3-thiazol-5-yl)methyl]sulfanyl}-2-methylphenoxy}-2-methylpropan-
oic Acid
[1628] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.90 (m, 2H), 7.18
(m, 3H), 7.07 (br s, 1H), 6.74 (br s, 1H), 4.64 (m, 1H), 4.26 (s,
2H), 3.44 (t, 4H, J=4.58 Hz), 3.36 (s, 2H), 2.43 (br s, 4H), 2.13
(s, 3H), 1.55 (s, 6H), 1.22 (d, 6H, J=6.23 Hz),
[1629] MS(ES.sup.-) M-H=600.0
[1630]
2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluorometh-
yl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
Acid
[1631] From ethyl
2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
(0.167 g, 0.25 mmol),
2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[-
4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propan-
oic acid (0.066 g, 41%) was obtained as a white solid.
[1632] .sup.1H NMR (CD.sub.3OD): .delta. 8.05 (d, 2H), 7.77 (d,
2H), 7.20 (m, 6H), 6.71 (d, 1H), 4.80 (q, 1H), 4.25 (s, 2H), 3.93
(s, 2H), 2.20 (s, 3H), 1.60 (d, 3H); .sup.19F NMR (CD.sub.3OD):
.delta. -59.87 (s) -64.72 (s); MS m/z 628 (M+1); Anal. Calcd. for
C.sub.29H.sub.23FNOS.sub.2: C, 55.5; H, 3.69; N, 2.23%; found: C,
55.27; H, 3.80; N, 2.21%.
[1633]
{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl-
)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic Acid
[1634] From methyl
{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(tri-
fluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
(0.15 g, 0.24 mmol),
{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(-
trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic
acid (0.053 g, 36%) was obtained as a white solid.
[1635] .sup.1H NMR (CD.sub.3OD): .delta. 8.05 (d, 2H), 7.77 (d,
2H), 7.20 (m, 6H), 6.71 (d, 1H), 4.70 (s, 2H), 4.27 (s, 2H), 3.94
(s, 2H), 2.20 (s, 3H); .sup.19F NMR (CD.sub.3OD): .delta. -59.88
(s) -64.72 (s); MS m/z 614 (M+1); Anal. Calcd. for
C.sub.28H.sub.21F.sub.6NO.sub.4S.sub.2: C, 54.81; H, 3.45; N,
2.28%; found: C, 54.64; H, 3.46; N, 2.23%.
[1636]
2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]--
1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic Acid
[1637] From ethyl
2-{2-methyl-4-[({4-(thienylmethyl)-2-[4-(trifluoromethyl-
)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate (0.255
g, 0.44 mmol),
2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)ph-
enyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
(0.058 g, 24%) was obtained as a white solid.
[1638] .sup.1H NMR (CD.sub.3OD): .delta. 8.05 (d, 2H), 7.77 (d,
2H), 7.33 (t, 1H), 7.18 (m, 2H), 6.95 (m, 2H), 6.69 (d, 1H), 4.80
(q, 1H), 4.22 (s, 2H), 3.95 (s, 2H), 2.20 (s, 3H), 1.61 (d, 3H); MS
m/z 550 (M+1); HPLC RT 4.056 (C18 4.2.times.100 mm, 0-100%
ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm). Anal.
Calcd. for C.sub.26H.sub.22F.sub.3NO.sub.3S.su- b.3: C, 56.82; H,
4.03; N, 2.55%; found: C, 56.84; H, 4.16; N, 2.53%.
[1639]
{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,-
3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic Acid
[1640] From methyl
{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethy-
l)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate (0.259
g, 0.47 mmol),
{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1-
,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid (0.138 g, 55%)
was obtained as a white solid.
[1641] .sup.1H NMR (CD.sub.3OD): .delta. 8.05 (d, 2H), 7.77 (d,
2H), 7.33 (t, 1H), 7.18 (m, 2H), 6.95 (m, 2H), 6.69 (d, 1H), 4.70
(s, 2H), 4.24 (s, 2H), 3.95 (s, 2H), 2.21 (s, 3H); MS m/z 536
(M+1); HPLC RT 3.979 (C18 4.2.times.1 00 mm, 0-100% ACN/H.sub.2O
(0.1% TFA), 6 min @ 2 ml/min @254/220 nm). Anal. Calcd. for
C.sub.25H.sub.20F.sub.3NO.sub.3S.sub.3: C, 56.06; H, 3.76; N,
2.61%; found: C, 55.90; H, 3.88; N, 2.62%.
[1642]
2-{4-[({4-(2-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-
-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic Acid
[1643] From ethyl
2-{4-[({4-(2-furylmethyl)-2-[4-(trifluoromethyl)phenyl]--
1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate (0.091
g, 0.16 mmol),
2-{4-[({4-(2-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-t-
hiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid (0.019
g, 22%) was obtained as a white solid.
[1644] .sup.1H NMR (CD.sub.3OD): .delta. 8.05 (d, 2H), 7.77 (d,
2H), 7.37 (s, 1H), 7.21 (s, 1H), 7.17 (d, 1H), 6.72 (d, 1H), 6.31
(s, 1H), 5.99 (s, 1H), 4.80 (q, 1H), 4.22 (s, 2H), 3.97 (s, 2H),
2.22 (s, 3H), 1.63 (d, 3H); MS m/z 534 (M+1); HPLC RT 3.929 (C18
4.2.times.100 mm, 0-100% ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min
@254/220 nm). Anal. Calcd. for
C.sub.26H.sub.22F.sub.3NO.sub.4S.sub.2: C, 58.53; H, 4.16; N,
2.62%; found: C, 58.04; H, 4.76; N, 2.47%
[1645]
2-{4-[({4-(3-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-
-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic Acid
[1646] From ethyl
2-{4-[({4-(3-furylmethyl)-2-[4-(trifluoromethyl)phenyl]--
1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate (0.177
g, 0.32 mmol),
24-[({4-(3-furylmethyl)-2-[4-(trifluoromethyl)phenyl-1,3-thia-
zol-5-yl)methyl)sulfanyl]-2-methylphenoxy}propanoic acid (0.030 g,
18%) was obtained as a white solid.
[1647] .sup.1H NMR (CD.sub.3OD): .delta. 8.05 (d, 2H), 7.77 (d,
2H), 7.39 (s, 1H), 7.20 (m, 3H), 6.70 (d, 1H), 6.29 (s, 1H), 4.80
(q, 1H), 4.22 (s, 2H), 3.70 (s, 2H), 2.20 (s, 3H), 1.62 (d, 3H); MS
m/z 534 (M+1); HPLC RT 3.966 (C18 4.2.times.1100 mm, 0-100%
ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm). Anal.
Calcd. for C.sub.26H.sub.22F.sub.3NO.sub.4S.su- b.2: C, 58.53; H,
4.16; N, 2.62%; found: C, 58.38; H, 4.30; N, 2.54%
[1648]
2{2-methyl-4-[({4-(2-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1-
,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic Acid
[1649] From ethyl
2-{4-[({4-(2-thienylmethyl)-2-[4-(trifluoromethyl)phenyl-
]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
(0.219, 0.36 mmol),
22-methyl-4-[({4-(2-thienylmethyl)-2-[4-(trifluoromethyl)phen-
yl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid (0.019
g, 10%) was obtained as a white solid.
[1650] .sup.1H NMR (CD.sub.3OD): .delta. 8.05 (d, 2H), 7.77 (d,
2H), 7.20 (m, 3H), 6.91 (t, 1H), 6.79 (s, 1H), 6.69 (d, 1H), 4.80
(q, 1H), 4.24 (s, 2H), 4.09 (s, 2H), 2.20 (s, 3H), 1.62 (d, 3H); MS
m/z 550 (M+1); HPLC RT 4.074 (C18 4.2.times.100 mm, 0-100%
ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[1651]
2-methyl-2-{4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluorometh-
yl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
Acid
[1652] From ethyl
2-methyl-2-{4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
(0.210 g, 0.32 mmol),
2-methyl-2-{4-[({4-[4-(trifluoromethoxy)benzyl]-2-[-
4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propan-
oic acid (0.035 g, 17%) was obtained as a cream solid.
[1653] .sup.1H NMR (CD.sub.3Cl.sub.3): .delta. 8.05 (d, 2H), 7.77
(d, 2H), 7.28 (d, 2H), 7.22 (d, 2H), 7.13 (d, 2H), 6.86 (d, 2H),
4.19 (s, 2H), 3.96 (s, 2H), 1.63 (s, 6H); .sup.19F NMR
(CD.sub.3Cl.sub.3): .delta. -58.26 (s) -63.16 (s); MS m/z 628
(M+1); HPLC RT 4.526 (C18 4.2.times.100 mm, 0-100% ACN/H.sub.2O
(0.1% TFA), 6 min @ 2 ml/min @254/220 nm). Anal. Calcd. for
C.sub.29H.sub.23F.sub.6NO.sub.4S.sub.2: C, 55.5; H, 3.69; N, 2.23%;
found: C, 55.78; H, 3.83; N, 2.10%
[1654]
{2-Methyll-4-[({4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethy-
l)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic Acid
[1655] From ethyl
{2-methyl-4-[({4-[(4-methyl-2-thienyl)methyl]-2-[4-(trif-
luoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
(0.13 g, 0.23 mmol),
{2-methyl-4-[({4-[(4-methyl-2-thienyl)methyl]-2-[4-(triflu-
oromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic
acid (0.011 g, 9%) was obtained as a cream solid.
[1656] .sup.1H NMR (CD.sub.3Cl.sub.3): 67 8.01 (d, 2H), 7.68 (d,
2H), 7.24 (s, 1H), 7.15 (d, 2H), 6.72 (s, 1H), 6.64 (d, 1H), 4.75
(s, 2H), 4.19 (s, 2H), 4.05 (s, 2H), 2.20 (s, 3H), 2.29 (s, 3H); MS
m/z 550 (M+1); HPLC RT 4.366 (C18 4.2.times.100 mm, 0-100%
ACN/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[1657]
{4-[({4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thia-
zol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic Acid
[1658] From ethyl
{4-[({4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyl)pheny-
l]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetate, (0.1
g, 0.17 mmol),
{4-[({4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thi-
azol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid (0.027 g,
28%) was obtained as a cream solid.
[1659] .sup.1H NMR (CD.sub.3Cl.sub.3): .delta. 7.99 (d, 2H), 7.68
(d, 2H), 7.22 (s, 1H), 7.13 (m, 2H), 6.79 (m, 2H), 6.62 (d, 1H),
4.70 (s, 2H), 4.20 (s, 2H), 3.86 (s, 2H), 2.23 (s, 3H); .sup.19F
NMR (CD.sub.3Cl.sub.3): .delta. -63.15 (s)-114.03 (s) -114.06 (s);
MS m/z 566 (M+1); HPLC RT 4.356 (C18 4.2.times.100 mm, 0-100%
ACM/H.sub.2O (0.1% TFA), 6 min @ 2 ml/min @254/220 nm). Anal.
Calcd. for C.sub.27H.sub.20F.sub.5NO.sub.3S.sub.20.5H.sub.2O: C,
56.44; H, 3.68; N, 2.44%; found: C, 56.40; H, 3.79; N, 2.20%
[1660]
{4[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol--
5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic Acid
[1661] From ethyl
{4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]--
1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetate (0.160 g
0.27 mmol),
{4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazo-
l-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid (0.005 g, 3%)
was obtained as a cream solid.
[1662] .sup.1H NMR (CD.sub.3Cl.sub.3): .delta. 8.01 (d, 2H), 7.68
(d, 2H), 7.23 (s, 1H), 7.11 (m, 3H), 6.82 (d, 2H), 6.62 (d, 1H),
4.90 (s, 2H), 4.17 (s, 2H), 3.90 (s, 2H), 3.80 (s, 3H), 2.25 (s,
3H); MS m/z 560.
[1663]
2-Methyll-2-{4-[({4-[(4-methyl-2-thienyl)methyl]-2-4-(trifluorometh-
yl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic
Acid
[1664] From ethyl
2-methyl-2-{4-[({4-[(4-methyl-2-thienyl)methyl]-2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
(0.17 g 0.29 mmol),
2-methyl-2-{4-[({4-[(4-methyl-2-thienyl)methyl]-2-[4--
(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoi-
c acid (0.002 g, 1.2%) was obtained as a cream solid.
[1665] .sup.1H NMR (CD.sub.3Cl.sub.3): .delta. 8.01 (d, 2H), 7.78
(d, 2H), 7.28 (d, 2H), 6.86 (d 2H), 6.73 (s, 1H), 6.63 (s, 1H),
4.18 (s, 2H), 3.99 (s, 2H), 2.21 (s, 3H), 1.63 (s, 6H); MS m/z 564
(M+1); HPLC RT 4.413 (C18 4.2.times.100 mm, 0-100% ACN/H.sub.2O
(0.1% TFA), 6 min @ 2 ml/min @254/220 nm).
[1666] The following is an alternative procedure for the synthesis
of Ethyl
2-{4-[({4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-
-5-yl}methyl)sulfanyl]phenoxy}-2-methylpropanoate
[1667] Ethyl 2-[4-(chlorosulfonyl)phenoxy]-2-methylpropanoate
[1668] Cool a solution of the ethyl 2-methyl-2-phenoxypropanoate,
(1.0 wt, 1.0 eq), in dichloromethane (7.5 vols) to 0.degree. C.
with stirring under a nitrogen atmosphere. Slowly add neat
chlorosulfonic acid (0.78 wt, 1.4 eq) to the reaction mixture at a
rate such that the reaction temperature never rises above
5.0.degree. C. The addition typically takes 30 minutes to complete.
Following the completion of the addition, stir the reaction mixture
at 0-1.degree. C. Follow the course of the reaction by HPLC. The
reaction is typically complete after 30 minutes. At this point,
slowly treat the reaction mixture with DMF (1.75 L) (1.40 wt, 4.0
eq). The addition of DMF to the reaction mixture is very
exothermic. Adjust the rate of addition so that the reaction
temperature never rises above 10.0.degree. C. The addition of DMF
to the reaction mixture takes approximately 30 minutes. Following
the completion of the DMF addition, re-cool the reaction mixture to
0.5 to 1.degree. C. Treat the cooled reaction mixture with neat
thionyl chloride (619 mL, 1.01 kg) (0.86 wt, 1.5 eq). Adjust the
rate of addition so that the process temperature never reaches
5.degree. C. The addition of thionyl chloride to the r action
mixture is not very exothermic at all. Hence, the addition of
thionyl chloride is typically complete in 5 minutes. Following the
completion of the DMF addition, warm the reaction mixture to
20.degree. C. with stirring. Follow the course of the reaction via
HPLC. After 2.0 h, the reaction is typically complete. At this
point cool the reaction mixture to 0-1.degree. C. and carefully
treat the reaction mixture with water (8.8 L) (7.5 vols). [Note:
The addition of water may be somewhat exothermic depending upon how
much unreacted thionyl chloride is left in the reaction mixture.]
Separate the organic layer and wash the organic layer with aqueous
0.1 N HCl solution (2.times.7.5 vols). Separate the organic layer,
concentrate the organic layer to a minimum stir volume, treat the
organic layer with isopropyl acetate (1.times.5.0 vols) and then
concentrate the resulting solution via vacuum distillation to
afford the titled compound as a translucent bronze colored oil.
[1669] Yield (% theory): 85-98%.
[1670] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.90 (2H, bd),
6.90 (2H, bd), 4.22 (2H, q, J=7.0 Hz), 1.67 (6H, s), 1.20 (3H, t,
J=7.0 Hz)
[1671] Diethyl
2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-4,5-dicarboxylat- e
[1672] Heat a solution of the 4-fluorobenzenecarbothioamide, (1.0
wt, 1.0 eq), in absolute ethanol (3 vols) to 50.degree. C. with
stirring under a nitrogen atmosphere. Add diethyl
2-chloro-3-oxosuccinate (1.2 wt, 1.1 eq), in one portion. Some
warming is seen during the addition which is typically complete in
less then 30 minutes. After the addition is complete, heat the
reaction mixture to about 68.degree. C. Hold the reaction mixture
at 67-69.degree. C. for 6 h and then cool the reaction mixture to
ambient temperature overnight. Dilute the resulting yellow hazy
solution slowly with aqueous 50% ethanol solution (3 vols), stir at
ambient temperature for 4h, and then cool the reaction mixture to
<5.degree. C. Filter the solids. Wash the wet cake with aqueous
50% ethanol solution (3 vols) and dry at 45.degree. C. to constant
weight to afford the title compound as an off-white to white
colored solid.
[1673] Yield (% theory): 78-83%.
[1674] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.14 (2H, d, J=8.2
Hz), 7.76 (2H, d, J=8.2 Hz), 4.52 (2H, q, J=7.1 Hz), 4.43 (2H, q,
J=7.1 Hz), 1.47 (3H, t, J=7.1 Hz), 1.42 (3H, t, J=7.1 Hz).
[1675]
{5-Hydroxymethyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}met-
hanol
[1676] To a suspension of lithium aluminum hydride (0.14 wt) in THF
(3.4 vols), add a solution of the diethyl
2-[4-(trifluoromethyl)phenyl]-1,3-th- iazole-4,5-dicarboxylate (1.0
wt, 1.0 eq), dissolved in THF (2 vols) at a rate such that the
temperature of the reaction mixture is maintained at below
-10.degree. C. The addition time is 1.5-3.0 hr. After the addition
is complete, stir the reaction mixture at ambient temperature for
18 h. Quench the reaction by adding aqueous 16% sulfuric acid (2.4
vols). Charge ethyl acetate (5 vols) with stirring to the reaction
mixture followed with water (5 vols). Filter the resulting two
phase mixture through celite (0.4 wt). Separate the layers and wash
the organic layer with water (4.times.4 vols) and with brine
(2.times.4 vol). Reduce the total volume of the reaction mixture
via vacuum distillation to leave the solid suspended in ethyl
acetate (1-1.5 vols). Dilute the slurry with dichloromethane (5
vols) and stir the suspension for at least 6 h. Filter the
tan-colored solid. Wash the wet cake with dichloromethane (2 vols)
and dry the wet cake at 45.degree. C. under mild vacuum to afford
the fide compound as an off-white solid.
[1677] Yield (% theory): 6585%.
[1678] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.15(2H, d, J=8.3
Hz), 7.79(2H, d, J=8.3 Hz), 4.92 (2H, s), 4.90 (2H, s), 4.77(2H,
s).
[1679] Ethyl
2-{4-[({4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-t-
hiazol-5-yl}methyl)-sulfanyl]phenoxy}-2-methylpropanoate.
[1680] To a stirred suspension of zinc dust (0.75 wt, 3.5 eq) in
isopropyl acetate (5 vols), add a solution of DME (0.5 vol) and
water (0.5 eq). Heat the resulting solution from room temperature
to 40.degree. C. Treat the reaction mixture with a solution of
ethyl 2-[4-(chlorosulfonyl)phenox- y]-2-methylpropanoate (1.0 wt,
1.0 eq) and dichlorodimethylsilane (0.32 wt, 0.75 eq) in isopropyl
acetate (3 vols) over a period of 2 h as this addition is mildly
exothermic. After the addition is complete, increase the process
temperature to 60.degree. C. Treat the suspension at 60.degree. C.
slowly with neat dichlorodimethylsilane (0.95 wt, 2.3 eq) over a
period of 1 h. When the reduction of the sulfonylchloride is deemed
complete (by HPLC), treat the reaction mixture with
{5-Hydroxymethyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methanol
(1.04 wt, 1.1 eq) in one portion at 60.degree. C. After the
addition is complete, increase the process temperature to
89.degree. C. and stir the reaction mixture at this temperature for
3 to 5 h then cool to ambient temperature. Filter the reaction
mixture to remove unreacted zinc residue, wash the filtrate with
water (2.times.8 vols) and concentrate the organic layer to about
3.5 volumes via vacuum distillation at 40-45.degree. C. Dissolve
the resultant, somewhat syrupy, residue in ethanol (2 vols) and
treat the resulting solution with iso-octane (2 vols). Cool the
clear yellow-tinted solution to ambient temperature to induce
crystallization of the product. Collect the solid via filtration.
Wash the wet cake with iso-octane/EtOH (9:1, 1 vol) and dry under
vacuum (.about.21 Torr) at 60.degree. C. for 12 h to afford the
title compound as an off-white solid.
[1681] Yield (% theory): 45-55%.
[1682] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.96 (2H, d, J=8.5
Hz), 7.66 (2H, d, J=8.5 Hz), 7.24 (2H, d, J=8.8 Hz), 6.74 (2H, d,
J=8.8 Hz), 4.45 (2H, d, J=3.5 Hz), 4.19 (2H, q, J=7.2 Hz), 4.16
(2H, s), 2.30 (1H, br s), 1.57 (6H, s), 1.20 (3H, t, J=7.2 Hz).
[1683] The following intermediates and ligands were prepared for
the binding and transfection assays described below:
[1684] i)
2-{2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thia-
zol-5-yl}methyl)sulfanyl]phenoxy}acetic Acid
[1685] This compound was used as a PPAR delta reference in the
transfection assays described below and was prepared according to
the following method: 20
[1686] Chlorosulfonic acid (15 mL) was cooled to 0.degree. C. then
10.0 g (0.05M) of ethyl (2-methylphenoxyacetate was added over 10
m. The reaction mixture was stirred at 0-5.degree. C. for 30 m, the
bath was removed and stirring continued for 2 h. The reaction
mixture was poured into ice, forming a white solid which was washed
with ice water and dried under high vacuum affording the title
compound (12.846 g, 86%). 21
[1687] To a well stirred solution of LiAlH.sub.4 (1.52 g, 40 mmol)
in dry THF (50 mL) at 0.degree. C., was slowly added a solution of
ethyl 4-methyl-2-[4-(trifluoromethyl)phenyl]-thiazole-5-carboxylate
(12.6 g, 40 mmol) in dry THF (50 mL). The mixture was stirred at
room temperature for 2 hs. The reaction was quenched by slow
addition at 0.degree. C. of water (2 mL), 5N NaOH (2 mL) and water
(6 mL). The precipitate was filtered, washed with EtOAc, MeOH,
CH.sub.2Cl.sub.2 and THF. After evaporation, a yellow solid was
obtained, that was crystallyzed from MeOH-water to afford
intermediate 1 depicted above (9.90 g, 36 mmol, 90%) as a yellow
solid mp 120-122.degree. C. 22
[1688] To a cold (0.degree. C.) stirred solution of intermediate 1
(8.2 g, 30 mmol) and Et.sub.3N (6.07 g, 8.36 mL, 60 mmol), in dry
CH.sub.2Cl.sub.2 (120 mL) was slowly added MeSO.sub.2Cl (5.49 g,
3.71 mL, 48 mmol). After 2 hs at 0.degree. C. more Et.sub.3N (6
mmol) and MeSO.sub.2Cl (4.8 mmol) were added. After 2 more h a tic
(hexane:EtOAc, 1:1) showed complete reaction. The reaction mixture
was diluted with CH.sub.2Cl.sub.2 (120 mL) and washed with
NaHCO.sub.3 (sat.) (2.times.240 mL) and water (2.times.240 mL),
dried, filtered and evaporated to afford intermediate 2 (8.0 g, 27
mmol, 90%) as a yellow solid.
[1689]
2-{2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-
-5-yl}methyl)sulfanyl]phenoxy}acetic Acid: 23
[1690] Intermediate A (4.68 g, 16 mM) was refluxed with 9.6 g of
tin powder in ethanol (20 mL) and dioxane/HCl (20 mL). After 3 h
the reaction mixture was poured into ice and CH.sub.2Cl.sub.2 (200
mL) and filtered. The phases were separated and the aqueous layer
was extracted 2.times.50 mL CH.sub.2Cl.sub.2. The combined organic
layers were dried (MgSO.sub.4), filtered and evaporated to yield
3.5 g (97%). This material readily forms disulfides and therefore
was used immediately. It was dissolved in acetonitrile (50 mL) with
intermediate C (4.0 g, 14.0 mM) and Cs.sub.2CO.sub.3 (10.1 g, 31.0
mM) and stirred for 1 h then diluted with ether (200 mL) and water
(200 mL). The phases were separated and the organic phase was
washed 2.times.NaOH 0.1N (50 mL), dried (MgSO.sub.4), filtered and
evaporated to afford crude product (6.57 g,) which was slurried in
hexane:ether (1:1) and filtered to yield pure intermediate D (5.0
g, 74%). This material was hydrolyzed as described below to prepare
the title compound. A solution of the corresponding ester
(Intermediate D) (1 mmol) in THF (10 mL) (in some cases few drops
of MeOH were added to help solubility), was treated with 1N LiOH in
water (2 mL, 2 mmol), and stirred 16 h at room temperature (when
reactions were slow, the temperature was elevated to 50.degree.
C.). The solution was neutralized with 1N HCl (2 mL, 2 mmol) and
the organic solvent evaporated to afford an aqueous solution with
an insoluble product. If the insoluble was a solid, it was filtered
and dried to afford the final product. If the insoluble was an oil,
it was extracted with EtOAc (30 mL). The organic solution was
separated, washed with water (2.times.30 mL), dried, filtered, and
evaporated to afford the final product.
[1691] Binding Assay:
[1692] Compounds were tested for their ability to bind to hPPAR
gamma hPPAR alpha or PPAR delta using a Scintillation Proximity
Assay (SPA). The PPAR ligand binding domain (LBD) was expressed in
E. coli as polyHis tagged fusion proteins and purified. The LBD was
then labeled with biotin and immobilized on streptavidin-modified
scintillation proximity beads. The beads were then incubated with a
constant amount of the appropriate radioligand (3H-BRL 49653 for
PPAR gamma, radiolabelled
2-(4-(2(2,3-Ditritio-1-heptyl-3-(2,4-difluorophenyl)ureido)ethyl)phenoxy)-
-2-methylbutanoic acid for hPPAR alpha (see WO 00/08002) and
labelled GW 2433 (see Brown, P. J et al. Chem. Biol., 4, 909-918
(1997). For the structure and synthesis of this ligand) for PPAR
delta) and variable concentrations of test compound, and after
equilibration the radioactivity bound to the beads was measured by
a scintillation counter. The amount of nonspecific binding, as
assessed by control wells containing 50 .mu.M of the corresponding
unlabeled ligand, was subtracted from each data point. For each
compound tested, plots of ligand concentration vs. CPM of
radioligand bound were constructed and apparent Ki values were
estimated from nonlinear least squares fit of the data assuming
simple competitive binding. The details of this assay have been
reported elsewhere (see, Blanchard, S. G. et. al. Development of a
Scintillation Proximity Assay for Peroxisome Proliferator-Activated
Receptor gamma Ligand Binding Domain. Anal. Biochem., 257, 112-119
(1998)).
[1693] Transfection Assay:
[1694] Compounds were screened for functional potency in transient
transfection assays in CV-1 cells for their ability to activate the
PPAR subtypes (transactivation assay). A previously established
chimeric receptor system was utilized to allow comparison of the
relative transcriptional activity of the receptor subtypes on the
same target gene and to prevent endogenous receptor activation from
complicating the interpretation of results. See, for example,
Lehmann, J. M.; Moore, L. B.; Smith-Oliver, T. A.; Wilkison, W. O.;
Willson, T. M.; Kliewer, S. A., An antidiabetic thiazolidinedione
is a high affinity ligand for peroxisome proliferator-activated
receptor gamma (PPARgamma), J. Biol. Chem., 270, 12953-6 (1995).
The ligand binding domains for murine and human PPAR alpha, PPAR
gamma, and PPAR delta were each fused to the yeast transcription
factor GAL4 DNA binding domain. CV-1 cells were transiently
transfected with expression vectors for the respective PPAR chimera
along with a reporter construct containing five copies of the GAL4
DNA binding site driving expression of secreted placental alkaline
phosphatase (SPAP) and beta-galactosidase. After 16 h, the medium
was exchanged to DME medium supplemented with 10% delipidated fetal
calf serum and the test compound at the appropriate concentration.
After an additional 24h, cell extracts were prepared and assayed
for alkaline phosphatase and .quadrature.-galactosidase activity.
Alkaline phosphatase activity was corrected for transfection
efficiency using the beta-galactosidase activity as an internal
standard (see, for example, Kliewer, S. A., et. al. Cell 83,
813-819 (1995)). Rosiglitazone (BRL 49653) was used as a positive
control in the hPPAR gamma assay. The positive control for PPAR
delta assays was
2-{2-methyl-4-[({4-methyl-2{trifluoromethyl)phenyl]-1,3--
thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid.
[1695] The positive control in the hPPARalpha transfection assay
was
2-[4-(2-(3-(4-fluorophenyl)-1-heptylureido)ethyl)-phenoxy]-2-methylpropio-
nic acid, which can be prepared as described in Brown, Peter J.,
et. al. Synthesis Issue 7, 778-782 (1997), or patent publication WO
9736579.
[1696] All of the above examples of this invention were agonists of
at least one hPPAR subtype.
* * * * *