U.S. patent application number 17/577139 was filed with the patent office on 2022-05-05 for biaryl derivative as gpr120 agonist.
This patent application is currently assigned to LG CHEM, LTD.. The applicant listed for this patent is LG CHEM, LTD.. Invention is credited to Eun Sil Choi, Hyun Woo Joo, Seung Wan Kang, Byung Gyu Kim, Sung Wook Kim, Young Kwan Kim, Chang Seok Lee, Sang Dae Lee, Seung Yup Paek, Sang Yun Park.
Application Number | 20220135574 17/577139 |
Document ID | / |
Family ID | 1000006090314 |
Filed Date | 2022-05-05 |
United States Patent
Application |
20220135574 |
Kind Code |
A1 |
Kim; Young Kwan ; et
al. |
May 5, 2022 |
BIARYL DERIVATIVE AS GPR120 AGONIST
Abstract
The present invention relates to a biaryl derivative expressed
by the chemical formula 1, a method for producing the biaryl
derivative, a pharmaceutical composition comprising same, and use
of same, the biaryl derivative expressed by the chemical formula 1,
as a GPR120 agonist, promoting GLP-1 generation in the
gastro-intestinal tract, reducing insulin resistance in the liver,
muscles and the like from anti-inflammatory activity in the
macrophage, pancreatic cells and the like, and allowing effective
use in prevention or treatment of inflammation or metabolic
diseases such as diabetes, complications from diabetes, obesity,
non-alcoholic fatty liver disease, fatty liver disease, and
osteoporosis.
Inventors: |
Kim; Young Kwan; (Daejeon,
KR) ; Park; Sang Yun; (Daejeon, KR) ; Joo;
Hyun Woo; (Daejeon, KR) ; Choi; Eun Sil;
(Daejeon, KR) ; Paek; Seung Yup; (Daejeon, KR)
; Kang; Seung Wan; (Daejeon, KR) ; Kim; Byung
Gyu; (Daejeon, KR) ; Lee; Chang Seok;
(Daejeon, KR) ; Kim; Sung Wook; (Daejeon, KR)
; Lee; Sang Dae; (Daejeon, KR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LG CHEM, LTD. |
Seoul |
|
KR |
|
|
Assignee: |
LG CHEM, LTD.
Seoul
KR
|
Family ID: |
1000006090314 |
Appl. No.: |
17/577139 |
Filed: |
January 17, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15539310 |
Jun 23, 2017 |
11261186 |
|
|
PCT/KR2015/014178 |
Dec 23, 2015 |
|
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17577139 |
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Current U.S.
Class: |
514/210.2 |
Current CPC
Class: |
C07C 59/31 20130101;
C07D 401/12 20130101; C07D 487/04 20130101; C07C 317/22 20130101;
C07D 211/34 20130101; C07D 235/16 20130101; C07D 409/04 20130101;
C07D 405/14 20130101; C07D 207/06 20130101; C07D 307/80 20130101;
C07D 213/70 20130101; C07C 2601/04 20170501; C07D 307/42 20130101;
C07D 401/14 20130101; C07D 239/34 20130101; C07D 417/10 20130101;
C07D 413/12 20130101; C07D 241/18 20130101; C07D 231/56 20130101;
C07D 277/34 20130101; C07D 409/10 20130101; C07D 401/10 20130101;
C07D 209/08 20130101; C07D 261/08 20130101; C07D 311/58 20130101;
C07D 213/30 20130101; C07D 405/04 20130101; C07D 409/14 20130101;
C07D 401/04 20130101; A61K 31/4725 20130101; C07D 317/46 20130101;
C07D 213/64 20130101; C07C 229/42 20130101; C07C 229/44 20130101;
C07C 2601/08 20170501; C07D 405/12 20130101; C07D 317/72 20130101;
C07D 413/10 20130101; C07D 407/04 20130101; C07D 333/16
20130101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; C07D 401/04 20060101 C07D401/04; A61K 31/4725 20060101
A61K031/4725; C07C 59/31 20060101 C07C059/31; C07C 229/42 20060101
C07C229/42; C07C 229/44 20060101 C07C229/44; C07C 317/22 20060101
C07C317/22; C07D 207/06 20060101 C07D207/06; C07D 209/08 20060101
C07D209/08; C07D 211/34 20060101 C07D211/34; C07D 213/30 20060101
C07D213/30; C07D 213/64 20060101 C07D213/64; C07D 213/70 20060101
C07D213/70; C07D 231/56 20060101 C07D231/56; C07D 235/16 20060101
C07D235/16; C07D 239/34 20060101 C07D239/34; C07D 241/18 20060101
C07D241/18; C07D 261/08 20060101 C07D261/08; C07D 277/34 20060101
C07D277/34; C07D 307/42 20060101 C07D307/42; C07D 307/80 20060101
C07D307/80; C07D 311/58 20060101 C07D311/58; C07D 317/46 20060101
C07D317/46; C07D 317/72 20060101 C07D317/72; C07D 333/16 20060101
C07D333/16; C07D 401/10 20060101 C07D401/10; C07D 401/12 20060101
C07D401/12; C07D 401/14 20060101 C07D401/14; C07D 405/04 20060101
C07D405/04; C07D 405/12 20060101 C07D405/12; C07D 405/14 20060101
C07D405/14; C07D 407/04 20060101 C07D407/04; C07D 409/04 20060101
C07D409/04; C07D 409/10 20060101 C07D409/10; C07D 409/14 20060101
C07D409/14; C07D 413/10 20060101 C07D413/10; C07D 413/12 20060101
C07D413/12; C07D 417/10 20060101 C07D417/10 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 24, 2014 |
KR |
10-2014-0188399 |
Claims
1. A compound selected from the group consisting of:
3-[6-(2-isopropylsulfanyl-pyridin-3-yl)-quinolin-2-yl]-propionic
acid,
3-[6-(6-isopropylsulfanyl-pyridin-2-yl)-quinolin-2-yl]-propionic
acid, [6-(6-cyclopentyloxy-pyridin-2-yl)-naphthalen-2-yloxy]-acetic
acid, [6-(2-cyclopentyloxy-pyridin-3-yl)-naphthalen-2-yloxy]-acetic
acid,
4-[6-(2-isopropylsulfanyl-pyridin-3-yl)-naphthalen-2-yloxy]-butyric
acid,
4-[6-(6-isopropylsulfanyl-pyridin-2-yl)-naphthalen-2-yloxy]-butyric
acid,
3-[6-(2-isopropylsulfanyl-pyridin-3-yl)-chroman-2-yl]-propionic
acid,
3-[6-(6-isopropylsulfanyl-pyridin-2-yl)-chroman-2-yl]-propionic
acid, 3-[6-(6-cyclopentyloxy-pyridin-2-yl)-chroman-2-yl]-propionic
acid, 3-[6-(2-cyclopentyloxy-pyridin-3-yl)-chroman-2-yl]-propionic
acid,
3-[6-(6-cyclopentyloxy-pyridin-2-yl)-1,2,3,4-tetrahydro-quinolin-2-yl]-pr-
opionic acid,
3-[6-(6-cyclopentyloxy-pyridin-2-yl)-1-methyl-1,2,3,4-tetrahydro-quinolin-
-2-yl]-propionic acid,
[6-(2-isopropylsulfanyl-pyridin-3-yl)-1-oxo-3,4-dihydro-1H-isoquinolin-2--
yl]-acetic acid,
[6-(6-isopropylsulfanyl-pyridin-2-yl)-1-oxo-3,4-dihydro-1H-isoquinolin-2--
yl]-acetic acid,
3-[6-(2-cyclopentyloxy-pyridin-3-yl)-1-oxo-3,4-dihydro-1H-isoquinolin-2-y-
l]-propionic acid,
3-[6-(2-isopropylsulfanyl-pyridin-3-yl)-1-oxo-3,4-dihydro-1H-isoquinolin--
2-yl]-propionic acid,
4-(3'-benzyloxy-3,5-difluoro-biphenyl-4-yloxy)-butyric acid,
4-(3,5-difluoro-3'-isopropoxy-biphenyl-4-yloxy)-butyric acid,
4-(3,5-difluoro-3'-propoxy-biphenyl-4-yloxy)-butyric acid,
4-(3'-cyclopropylmethoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric
acid, 4-(3'-cyclobutoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric
acid,
4-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-2,6-difluoro-phenoxy]-but-
yric acid,
4-[4-(2,2-dimethyl-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenoxy]-
-butyric acid,
4-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]butanenitrile,
2-cyclobutylsulfanyl-3-{3,5-difluoro-4-[3-(1H-tetrazol-5-yl)propoxy]pheny-
l}pyridine,
2-cyclobutylsulfanyl-3-{4-[3-(1H-tetrazol-5-yl)propyl]phenyl}pyridine,
5-[4-(2-cyclobutylsulfanyl-3-pyridyl)phenyl]pentanoic acid,
5-[4-(6-cyclopentylsulfanyl-2-pyridyl)phenyl]pentanoic acid,
5-[4-(2-cyclopentylsulfanyl-3-pyridyl)phenyl]pentanoic acid,
2-cyclobutylsulfanyl-3-[3,5-difluoro-4-(1H-tetrazol-5-ylmethoxy)phenyl]py-
ridine,
5-[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)phenyl]pentanoic
acid, 5-[4-(6-cyclobutoxy-2-pyridyl)-2,6-difluoro-phenyl]pentanoic
acid, 5-[4-(6-cyclopentoxy-2-pyridyl)-2,6-difluoro-phenyl]pentanoic
acid,
5-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenyl]pentanoic
acid,
5-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]pentanoic
acid,
5-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]pentanoi-
c acid,
5-[4-(2-cyclopentoxy-3-pyridyl)-2,6-difluoro-phenyl]pentanoic acid,
{2-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]ethoxy}a-
cetic acid, 5-[4-(2-cyclobutylsulfanyl-3-pyridyl)phenyl]hexanoic
acid, 5-[4-(6-cyclobutoxy-2-pyridyl)-phenyl]hexanoic acid,
5-[4-(6-cyclobutoxy-2-pyridyl)-2,6-difluoro-phenyl]hexanoic acid,
5-[4-(2-ethylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]hexanoic acid,
5-[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)-phenyl]hexanoic
acid, 4-[1-methyl-5-(2-phenoxyphenyl)benzimidazol-2-yl]butanoic
acid, 3-[1-methyl-5-(2-phenoxyphenyl)benzimidazol-2-yl]propanoic
acid, 5-[2,6-difluoro-4-(2-isopropoxy-3-pyridyl)phenyl]hexanoic
acid, 5-(2'-cyclopentylamino-3,5-difluoro-bisphenyl-4-yl)hexanoic
acid,
5-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]hexanoic
acid,
5-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]hexanoic
acid,
5-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)-phenyl]hexanoic
acid, 5-[4-(2-cyclopentoxy-3-pyridyl)-2,6-difluoro-phenyl]hexanoic
acid, 5-(3'-cyclopentylamino-3,5-difluoro-biphenyl-4-yl)-hexanoic
acid,
5-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)-phenyl]hexanoic
acid,
5-[4-(6-cyclopentylsulfanyl-2-pyridyl)-2,6-difluoro-phenyl]hexanoic
acid, 5-[2,6-difluoro-4-(6-propylsulfanyl-2-pyridyl)phenyl]hexanoic
acid, 5-[4-(6-cyclopentoxy-2-pyridyl)-2,6-difluoro-phenyl]hexanoic
acid, 4-[4-(2-isopropoxy-3-pyridyl)phenyl]butanoic acid,
5-[2,6-difluoro-4-(2-hydroxy-3-pyridyl)phenyl]hexanoic acid,
5-[4-(2-cyclobutoxy-3-pyridyl)-2,6-difluoro-phenyl]hexanoic acid,
5-[4-(2-cyclopropylmethoxy-3-pyridyl)-2,6-difluoro-phenyl]hexanoic
acid,
5-[[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]methyl]isoxaz-
ol-3-ol,
N'-hydroxy-4-[4-(2-propylsulfanyl-3-pyridyl)phenyl]butaneamidine,
3-[3-[4-(2-propylsulfanyl-3-pyridyl)phenyl]propyl]-4H-1,2,4-oxadiazol-5-o-
ne,
3-[3-[4-(2-propylsulfanyl-3-pyridyl)phenyl]propyl]-4H-1,2,4-oxadiazol--
5-thione,
5-[[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]met-
hyl]isoxazol-3-ol,
5-[[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)phenoxy]methyl]isoxazol-3--
ol,
5-[[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenoxy]methyl]isoxazo-
l-3-ol,
5-[[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenoxy]methyl]i-
soxazol-3-ol,
5-[[2,6-difluoro-4-(2-isopropoxy-3-pyridyl)phenoxy]methyl]isoxazol-3-ol,
5-[[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]methyl]isoxazol-
-3-ol,
5-[[2,6-difluoro-4-(6-isopropoxy-2-pyridyl)phenoxy]methyl]isoxazol--
3-ol,
5-[[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-phenoxy]methyl-
]isoxazol-3-ol,
5-[[2,6-difluoro-4-(6-propoxy-2-pyridyl)phenoxy]methyl]isoxazol-3-ol,
5-[[2,6-difluoro-4-(2-propoxy-3-pyridyl)phenoxy]methyl]isoxazol-3-ol,
5-[(E)-3-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]allyl]th-
iazolidin-2,4-dione,
5-[[4-[2-(cyclobutoxy)-3-pyridyl]-2,6-difluoro-phenoxy]methyl]isoxazol-3--
ol,
5-[[4-[2-(cyclobutylmethoxy)-3-pyridyl]-2,6-difluoro-phenoxy]methyl]is-
oxazol-3-ol,
5-[[4-[2-(cyclopentoxy)-3-pyridyl]anilino]methyl]isoxazol-3-ol,
5-[[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenoxy]methyl]pyridin-2--
ol,
4-[[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenoxy]methyl]pyridin-
-2-ol,
5-[[4-[2-(cyclopentoxy)-3-pyridyl]phenyl]sulfanylmethyl]isoxazol-3--
ol,
5-[(E)-3-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]allyl]-1,-
1-dioxo-1,2,5-thiadiazolidin-3-one,
5-[[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]sulfanylmethyl]iso-
xazol-3-ol,
5-[[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-anilino]methyl]isoxazol-3-
-ol,
5-[3-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]propyl]-1,1--
dioxo-1,2,5-thiadiazolidin-3-one,
5-[[4-[2-(cyclopentoxy)-3-pyridyl]-N-methyl-anilino]methyl]isoxazol-3-ol,
5-[2-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]ethyl]isoxazol-3-
-ol,
5-[2-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]propyl]isoxa-
zol-3-ol,
5-[2-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenoxy]ethyl]-
isoxazol-3-ol,
5-[2-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-anilino]ethyl]isoxazol--
3-ol,
2-[1-[5-(6-isopropylsulfanyl-2-pyridyl)-2-pyridyl]-3-piperidyl]aceti-
c acid,
4-[[5-(6-isopropylsulfanyl-2-pyridyl)-2-pyridyl]amino]butanoic
acid,
2-[1-[4-(2-cyclobutylsulfanyl-3-pyridyl)phenyl]pyrazol-4-yl]acetic
acid,
5-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-anilino]pentanoic
acid,
5-[4-[2-(cyclopentoxy)-3-pyridyl]-N-ethyl-2,6-difluoro-anilino]pent-
anoic acid,
5-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)anilino]pentanoic
acid,
5-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)anilino]pentanoic
acid,
5-[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-anilino]pentanoic
acid,
5-[4-[2-(cyclopropylmethoxy)-3-pyridyl]-2,6-difluoro-anilino]pentan-
oic acid,
2-[1-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]-4-
-piperidyl]acetic acid,
5-[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-N-methyl-anilino]pen-
tanoic acid,
2-[1-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]-4-piperidyl]ace-
tic acid,
2-[1-[2,6-difluoro-4-(2-tetrahydrofuran-3-yloxy-3-pyridyl)phenyl-
]-4-piperidyl]acetic acid,
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-4-piperidyl]a-
cetic acid,
2-[1-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]-4-piperidyl]a-
cetic acid,
2-[1-[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperid-
yl]acetic acid,
2-[1-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]-3-piperidyl]a-
cetic acid,
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-3-piperidyl]a-
cetic acid,
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]azetidin-3-yl]-
acetic acid,
6-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-6-azaspiro[2.5]o-
ctan-2-carboxylic acid,
6-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]-6-azaspiro[2.5]o-
ctan-2-carboxylic acid,
2-[1-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]azetidin-3--
yl]acetic acid,
2-[1-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]azetidin-3-yl]ac-
etic acid,
2-[1-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]azet-
idin-3-yl]acetic acid,
2-[1-[2,6-difluoro-4-(6-isopropoxy-2-pyridyl)phenyl]azetidin-3-yl]acetic
acid,
2-[1-[4-[6-(cyclopentoxy)-2-pyridyl]-2,6-difluoro-phenyl]azetidin-3-
-yl]acetic acid,
2-[1-[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)phenyl]-4-piperidyl]acet-
ic acid,
2-[1-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]-4-p-
iperidyl]acetic acid,
2-[1-[2,6-difluoro-4-(2-isopropoxy-3-pyridyl)phenyl]-4-piperidyl]acetic
acid,
2-[1-[2,6-difluoro-4-(2-propoxy-3-pyridyl)phenyl]-4-piperidyl]aceti-
c acid,
2-[1-[4-[2-(cyclopropylmethoxy)-3-pyridyl]-2,6-difluoro-phenyl]-4--
piperidyl]acetic acid,
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]pyrazol-4-yl]a-
cetic acid,
2-[1-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]pyrazol-4-yl]a-
cetic acid,
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]pyrrolidin-3-y-
l]acetic acid,
2-[1-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]pyrrolidin-3-y-
l]acetic acid,
3-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-4-piperidyl]p-
ropanoic acid,
3-[1-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]-4-piperidyl]p-
ropanoic acid,
2-[2-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-anilino]ethyl]cycl-
opropane carboxylic acid,
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-3-piperidyl]a-
cetamide,
2-[4-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]piper-
azin-1-yl]acetic acid,
3-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]pyrazol-4-yl]p-
ropanoic acid,
4-[5-(2-cyclopentylsulfanyl-3-pyridyl)indolin-1-yl]butanoic acid,
3-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]azetidin-
-3-yl]propanoic acid,
2-[(3R)-1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]pyrrolidi-
n-3-yl]acetic acid,
2-[(3R)-1-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]pyrrolidin--
3-yl]acetic acid,
2-[(3S)-1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]pyrrolidi-
n-3-yl]acetic acid,
2-[(3S)-1-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]pyrrolidin--
3-yl]acetic acid,
2-[1-[2-fluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-4-piperidyl]aceti-
c acid,
2-[1-[4-[2-(cyclopentoxy)-3-pyridyl]-2-fluoro-phenyl]-4-piperidyl]-
acetic acid,
3-[6-(6-isopropylsulfanyl-pyridin-2-yl)-naphthalen-2-yl]-propanoic
acid, 3-[6-(6-phenoxy-pyridin-2-yl)-naphthalen-2-yl]-propanoic
acid, 3-[6-(2-phenoxy-phenyl)-naphthalen-2-yl]-propanoic acid,
3-[6-(6-cyclopentylsulfanyl-pyridin-2-yl)-naphthalen-2-yl]-propanoic
acid, 3-[6-(2-phenoxy-pyridin-3-yl)-naphthalen-2-yl]-propanoic
acid, 3-[6-(3-phenoxy-phenyl)-naphthalen-2-yl]-propanoic acid,
3-[6-(3-isopropoxy-phenyl)-naphthalen-2-yl]-propanoic acid,
3-[6-(3-cyclobutoxy-phenyl)-naphthalen-2-yl]-propanoic acid,
3-[6-(6-cyclobutoxy-pyridin-2-yl)-naphthalen-2-yl]-propanoic acid,
3-[6-(2-isopropoxy-pyridin-3-yl)-naphthalen-2-yl]-propanoic acid,
3-[6-(2-cyclopentyloxy-pyridin-3-yl)-naphthalen-2-yl]-propanoic
acid, 3-{6-[2-(2-fluoro-phenoxy)-phenyl]-naphthalen-2-yl}-propanoic
acid,
3-{6-[6-(2-fluoro-phenoxy)-pyridin-2-yl]-naphthalen-2-yl}-propanoic
acid,
4-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenylsulfanyl]-bu-
tyric acid,
4-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-fluoro-phenylsulfanyl]-butyri-
c acid,
4-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-phenylsulfanyl]-butyric
acid,
4-(4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-ylphenyl)sulfanylbut-
anoic acid,
4-(2-fluoro-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-phenyl)sulfany-
lbutanoic acid,
5-[4-(2-isopropoxy-pyridin-3-yl)-phenyl]-5-methyl-hexanoic acid,
5-[4-(2-isopropylsulfanyl-pyridin-3-yl)-phenyl]-5-methyl-hexanoic
acid,
5-[4-(2-cyclopentyloxy-pyridin-3-yl)-phenyl]-5-methyl-hexanoic
acid,
5-[4-(2-cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenyl]-5-methyl-hexa-
noic acid,
5-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenyl]-5-met-
hyl-hexanoic acid,
5-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenyl]-5-methyl-hexanoic
acid,
5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-5-methyl-he-
xanoic acid,
5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-phenyl]-5-methyl-hexanoic
acid,
4-{1-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenyl]-cyclopropyl}-
-butyric acid,
4-{1-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-cyclopro-
pyl}-butyric acid,
4-{1-[4-(6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-cyclopropyl}-bu-
tyric acid,
4-{1-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-cycloprop-
yl}-butyric acid,
4-{1-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-cyclopro-
pyl}-butyric acid,
5-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenyl]-hexanoic
acid,
{2-[4-(2-cyclopentyloxy-pyridin-3-yl)-phenyl]-2,2-difluoro-ethoxy}--
acetic acid,
{2-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-phenyl]-2,2-difluoro-ethoxy}-ac-
etic acid,
{2-[4-(6-cyclobutoxy-pyridin-2-yl)-phenyl]-2,2-difluoro-ethoxy}-
-acetic acid,
3-{2-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenyl]-cyclopropyl}-
-propanoic acid,
3-{2-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-cyclopro-
pyl}-propanoic acid,
5-[4-(2-cyclopentyloxy-pyridin-3-yl)-phenyl]-5,5-difluoro-pentanoic
acid,
5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-phenyl]-5,5-difluoro-pentanoic
acid,
3-{2-[2,6-difluoro-4-(2-propylsulfanyl-pyridin-3-yl)-phenyl]-cyclop-
ropyl}-propanoic acid,
3-{2-[4-(6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-cyclopropyl}-pr-
opanoic acid,
5-[4-(2-cyclopropylmethoxy-pyridin-3-yl)-phenyl]-5,5-difluoro-pentanoic
acid,
3-{2-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-c-
yclopropyl}-propanoic acid,
3-{2-[4-(2-cyclopentylamino-pyridin-3-yl)-2,6-difluoro-phenyl]-cyclopropy-
l}-propanoic acid,
5-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenyl]-5,5-difluoro-pentanoic
acid,
5-[4-(2-cyclobutoxy-pyridin-3-yl)-phenyl]-5,5-difluoro-pentanoic
acid,
5-[4-(6-cyclobutoxy-pyridin-2-yl)-phenyl]-5,5-difluoro-pentanoic
acid,
{4-[4-(2-cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenyl]-cyclohexyl}--
acetic acid,
3-{2-[4-(2-cyclobutoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-cyclopropyl}-pr-
opanoic acid,
3-{2-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-cycloprop-
yl}-propanoic acid,
3-(2-{2,6-difluoro-4-[2-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-phenyl}--
cyclopropyl)-propanoic acid,
3-{2-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-cyclopro-
pyl}-propanoic acid,
5,5-difluoro-5-[4-(6-isopropylsulfanyl-pyridin-2-yl)-phenyl]-pentanoic
acid,
4-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-phenoxy]-butyric
acid,
4-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-2-fluoro-phenoxy]-b-
utyric acid,
4-{[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-methyl-ami-
no}-butyric acid,
4-{[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenyl]-methyl-amino}--
butyric acid,
4-{[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-methyl-am-
ino}-butyric acid,
4-{[2,6-difluoro-4-(2-isopropylsulfanyl-pyridin-3-yl)-phenyl]-methyl-amin-
o}-butyric acid,
4-[(3'-cyclobutoxy-3,5-difluoro-biphenyl-4-yl)-methyl-amino]-butyric
acid, 4-[5-(2-cyclopentylsulfanyl-pyridin-3-yl)-indol-1-yl]-butyric
acid,
4-[(3,5-difluoro-3'-pyrrolidin-1-yl-biphenyl-4-yl)-methyl-amino]-butyric
acid,
4-{[4-(6-cyclobutylsulfanyl-pyridin-2-yl)-2,6-difluoro-phenyl]-meth-
yl-amino}-butyric acid,
4-{[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenyl]-methyl-am-
ino}-butyric acid,
4-{[4-(6-cyclopentyloxy-pyridin-2-yl)-2,6-difluoro-phenyl]-methyl-amino}--
butyric acid,
4-{[4-(6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-methyl-amino}-but-
yric acid,
4-{[4-(2-cyclobutoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-methyl--
amino}-butyric acid,
4-{[2,6-difluoro-4-(2-propylsulfanyl-pyridin-3-yl)-phenyl]-methyl-amino}--
butyric acid,
4-{[4-(2-ethylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-methyl-amino}-b-
utyric acid,
4-{[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2-fluoro-phenyl]-methyl-amino}--
butyric acid,
2-{[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylamino]-meth-
yl}-cyclopropane carboxylic acid,
2-{[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenylamino]-methyl}-cycloprop-
ane carboxylic acid,
4-{[2-fluoro-4-(2-isopropylsulfanyl-pyridin-3-yl)-phenyl]-methyl-amino}-b-
utyric acid,
4-{[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2-fluoro-phenyl]-methyl-amino}-
-butyric acid,
4-{[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenyl]-methyl-amino}-buty-
ric acid,
4-[(2'-cyclopentylamino-3,5-difluoro-biphenyl-4-yl)-methyl-amino-
]-butyric acid,
4-[methyl-(3,5,5'-trifluoro-2'-isopropoxy-biphenyl-4-yl)-amino]-butyric
acid,
4-{[4-(2-cyclopentyloxy-5-methyl-pyridin-3-yl)-2,6-difluoro-phenyl]-
-methyl-amino}-butyric acid,
4-{[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-methyl-amin-
o}-butyric acid,
4-{[2,6-difluoro-4-(2-methoxy-pyridin-3-yl)-phenyl]-methyl-amino}-butyric
acid,
4-({2,6-difluoro-4-[2-(tetrahydro-furan-3-yloxy)-pyridin-3-yl]-phen-
yl}-methyl-amino)-butyric acid,
4-[(3,5-difluoro-2'-pyrrolidin-1-yl-biphenyl-4-yl)-methyl-amino]-butyric
acid,
4-[(3,5-difluoro-2'-methylamino-biphenyl-4-yl)-methyl-amino]-butyri-
c acid,
4-{[3,5-difluoro-2'-(isopropyl-methyl-amino)-biphenyl-4-yl]-methyl-
-amino}-butyric acid,
4-{[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-ethyl-amin-
o}-butyric acid,
4-{[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-ethyl-amino-
}-butyric acid,
4-{[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenyl]-ethyl-amino}-butyr-
ic acid,
(R)-5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-
-hexanoic acid,
(E)-(R)-5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-hex-
-2-enoic acid,
(S)-5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-hexanoi-
c acid,
5-{2,6-difluoro-4-[2-(tetrahydro-furan-3-yloxy)-pyridin-3-yl]-phen-
yl}-hexanoic acid,
5-{2,6-difluoro-4-[2-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-phenyl}-hex-
anoic acid,
5-{2,6-difluoro-4-[2-(oxetan-3-yloxy)-pyridin-3-yl]-phenyl}-hexanoic
acid, 4-[4-(2-cyclobutoxy-pyridin-3-yl)-2-fluoro-phenoxy]-butyric
acid,
4-[4-(2-cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenoxy]-butyric
acid,
4-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2-fluoro-phenoxy]-butyric
acid,
4-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2-fluoro-phenoxy]-butyric
acid,
6-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenyl]-heptanoic
acid,
6-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-heptanoic
acid,
4-[4-(2-cyclopropylmethoxy-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-b-
utyric acid,
4-[4-(2-cyclopropylmethoxy-pyridin-3-yl)-2-fluoro-phenoxy]-butyric
acid,
4-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2-fluoro-phenoxy]-butyric
acid, 4-[3-(6-cyclopentyloxy-pyridin-2-yl)-phenoxy]-butyric acid,
4-[3-(2-cyclopentyloxy-pyridin-3-yl)-phenoxy]-butyric acid,
5-[4-(2-cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenyl]-pentanoic
acid, 5-[4-(2-cyclobutoxy-pyridin-3-yl)-2-fluoro-phenyl]-pentanoic
acid,
5-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2-fluoro-phenyl]-pentanoic
acid,
5-[4-(2-cyclopropylmethoxy-pyridin-3-yl)-2-fluoro-phenyl]-pentanoic
acid,
5-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2-fluoro-phenyl]-pentanoic
acid,
5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2-fluoro-phenyl]-pentanoic
acid,
5-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-pentan-
oic acid,
5-[4-(2-cyclobutoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-pentanoic
acid,
5-[4-(2-cyclopropylmethoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-penta-
noic acid,
4-[4-(5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-2,6-di-
fluoro-phenoxy]-butyric acid,
4-[4-(5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-2,6-difluoro-phe-
nylsulfanyl]-butyric acid,
4-{[4-(5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-2,6-difluoro-ph-
enyl]-methyl-amino}-butyric acid,
5-[4-(5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-2,6-difluoro-phe-
nyl]-hexanoic acid,
4-[2,6-difluoro-4-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-ph-
enoxy]-butyric acid,
4-[2,6-difluoro-4-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-ph-
enylsulfanyl]-butyric acid,
4-{[2,6-difluoro-4-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-p-
henyl]-methyl-amino}-butyric acid,
5-[2,6-difluoro-4-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl-phe-
nyl]-hexanoic acid,
4-(2,6-difluoro-4-spiro[3H-benzofuran-2,1'-cyclopentan]-7-yl-phenoxy)-but-
yric acid,
4-(2,6-difluoro-4-spiro[3H-benzofuran-2,1'-cyclopentan]-7-yl-ph-
enylsulfanyl)-butyric acid,
4-(2,6-difluoro-N-methyl-4-spiro[3H-benzofuran-2,1'-cyclopentan]-7-yl-ani-
lino)-butyric acid,
5-(2,6-difluoro-4-spiro[3H-benzofuran-2,1'-cyclopentan]-7-yl-phenyl)-hexa-
noic acid,
7-[4-(3-carboxy-propoxy)-3,5-difluoro-phenyl]-5-fluoro-2,2-dime-
thyl-2,3-dihydro-indol-1-carboxylic acid methyl ester,
4-[2,6-difluoro-4-(5-fluoro-2,2-dimethyl-2,3-dihydro-1H-indol-7-yl)-pheno-
xy]-butyric acid,
4-[4-(3-carboxy-propoxy)-3,5-difluoro-phenyl]-5-fluoro-2,2-dimethyl-2,3-d-
ihydro-indol-1-carboxylic acid methyl ester,
4-[2,6-difluoro-4-(5-fluoro-2,2-dimethyl-2,3-dihydro-1H-indol-4-yl)-pheno-
xy]-butyric acid,
4-[2,6-difluoro-4-(5-fluoro-2,2-dimethyl-2,3-dihydro-1H-indol-7-yl)-pheny-
lsulfanyl]-butyric acid,
3-[6-(2-isopropylsulfanyl-pyridin-3-yl)-thiochroman-2-yl]-propionic
acid,
3-[6-(2-cyclopentoxy-pyridin-3-yl)-thiochroman-2-yl]-propionic
acid,
3-[6-(2-cyclobutylsulfanyl-pyridin-3-yl)-chroman-2-yl]-propionic
acid,
3-[6-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-chroman-2-yl]-p-
ropionic acid,
3-[6-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-thiochroman-2-y-
l]-propionic acid,
3-[6-(2-cyclobutylsulfanyl-pyridin-3-yl)-thiochroman-2-yl]-propionic
acid,
3-[6-(2-cyclopropylmethoxy-pyridin-3-yl)-chroman-2-yl]-propionic
acid, 3-[6-(2-cyclobutoxy-pyridin-3-yl)-chroman-2-yl]-propionic
acid, 3-[6-(2-cyclobutoxy-pyridin-3-yl)-thiochroman-2-yl]-propionic
acid,
3-[6-(2-cyclopropylmethoxy-pyridin-3-yl)-thiochroman-2-yl]-propionic
acid,
3-[6-(2-cyclopentylsulfanyl-pyridin-3-yl)-chroman-2-yl]-propionic
acid,
3-[6-(2-cyclopentylsulfanyl-pyridin-3-yl)-thiochroman-2-yl]-propion-
ic acid,
3-[6-(5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-thiochro-
man-2-yl]-propionic acid,
3-(6-spiro[3H-benzofuran-2,1'-cyclopentan]-7-yl-thiochroman-2-yl)-propion-
ic acid,
3-{6-[2-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-thiochroman-2-yl-
}-propionic acid,
{1-[2,6-difluoro-4-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-p-
henyl]-azetidin-3-yl}-acetic acid,
3-[6-(6-isopropylsulfanyl-pyridin-2-yl)-thiochroman-2-yl]-propionic
acid,
4-(2,6-difluoro-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-phenoxy)bu-
tanoic acid,
4-(4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-ylphenoxy)butanoic
acid,
4-(2-fluoro-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-phenoxy)butano-
ic acid,
4-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenoxy]-b-
utyric acid,
4-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-2,6-difluoro-phenoxy]-but-
yric acid,
4-[4-(2-cyclohexylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]--
butyric acid,
3-[4-(2-cyclopentyloxy-pyridin-3-yl)-benzylsulfanyl]-propionic
acid,
2-[1-[4-[6-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperidyl]acet-
ic acid,
2-[1-[2,6-difluoro-4-(6-propoxy-2-pyridyl)phenyl]-4-piperidyl]ace-
tic acid,
2-[1-[2,6-difluoro-4-(6-isopropoxy-2-pyridyl)phenyl]-4-piperidyl-
]acetic acid,
2-[1-[4-(6-cyclobutylsulfanyl-2-pyridyl)-2,6-difluoro-phenyl]-4-piperidyl-
]acetic acid,
2-[1-[2,6-difluoro-4-(6-propylsulfanyl-2-pyridyl)phenyl]-4-piperidyl]acet-
ic acid,
2-[1-[4-[6-(cyclopentoxy)-2-pyridyl]-2,6-difluoro-phenyl]-4-piper-
idyl]acetic acid,
2-[1-[4-[3-(cyclobutoxy)phenyl]-2,6-difluoro-phenyl]-4-piperidyl]acetic
acid,
2-[1-[4-[3-(cyclopropylmethoxy)phenyl]-2,6-difluoro-phenyl]-4-piper-
idyl]acetic acid,
2-[1-[2,6-difluoro-4-[3-(isopropoxymethyl)phenyl]phenyl]-4-piperidyl]acet-
ic acid,
2-[1-[4-[3-(ethoxymethyl)phenyl]-2,6-difluoro-phenyl]-4-piperidyl-
]acetic acid,
2-[1-[4-[3-(cyclobutoxy)-4-fluoro-phenyl]-2,6-difluoro-phenyl]-4-piperidy-
l]acetic acid,
2-[1-[4-[3-(cyclobutoxy)-4-methoxy-phenyl]-2,6-difluoro-phenyl]-4-piperid-
yl]acetic acid,
2-[1-[4-[3-(cyclobutoxy)-5-fluoro-phenyl]-2,6-difluoro-phenyl]-4-piperidy-
l]acetic acid,
2-[1-[2-chloro-4-[6-(cyclopropylmethoxy)-2-pyridyl]-6-fluoro-phenyl]-4-pi-
peridyl]acetic acid,
2-[1-[4-[6-(cyclobutylmethoxy)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperidy-
l]acetic acid,
2-[1-[4-(6-tert-butoxy-2-pyridyl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
acid,
2-[1-[4-[3-(cyclobutoxy)-2-methyl-phenyl]-2,6-difluoro-phenyl]-4-pi-
peridyl]acetic acid,
2-[1-[4-[5-chloro-6-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenyl]-4-piper-
idyl]acetic acid,
2-[1-[4-[6-(cyclopropanecarbonyl)-2-pyridyl]-2,6-difluoro-phenyl]-4-piper-
idyl]acetic acid,
2-[1-[4-[6-(cyclobutoxymethyl)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperidy-
l]acetic acid,
2-[1-[4-(6-ethoxy-2-pyridyl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
acid,
2-[1-[2,6-difluoro-4-[6-(2,2,2-trifluoroethoxy)-2-pyridyl]phenyl]-4-
-piperidyl]acetic acid,
2-[1-[2,6-difluoro-4-[6-(2,2,2-trifluoro-1-methyl-ethoxy)-2-pyridyl]pheny-
l]-4-piperidyl]acetic acid,
2-[1-[4-(6-cyclopentyl-2-pyridyl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
acid,
2-[1-[4-[6-[cyclopropyl(methoxy)methyl]-2-pyridyl]-2,6-difluoro-phe-
nyl]-4-piperidyl]acetic acid,
2-[1-[2-chloro-4-[6-(cyclobutoxy)-2-pyridyl]-6-fluoro-phenyl]-4-piperidyl-
]acetic acid,
2-[1-[4-[6-(cyclobutoxy)-2-pyridyl]-2-fluoro-phenyl]-4-piperidyl]acetic
acid,
2-[1-[4-[6-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenyl]azetidin-3--
yl]acetic acid,
2-[1-[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-phenyl]azetidin-3-
-yl]acetic acid,
2-[1-[4-(6-butoxy-2-pyridyl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
acid,
2-[1-[4-[2-(cyclobutoxy)thiazol-4-yl]-2,6-difluoro-phenyl]-4-piperi-
dyl]acetic acid,
2-[1-[4-[6-(cyclobutoxy)-4-methyl-2-pyridyl]-2,6-difluoro-phenyl]-4-piper-
idyl]acetic acid,
2-[1-[4-[6-(cyclopentylamino)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperidyl-
]acetic acid,
2-[1-[4-[5-(cyclobutoxy)-3-methyl-isothiazol-4-yl]-2,6-difluoro-phenyl]-4-
-piperidyl]acetic acid,
{1-[4-(4-ethoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin-4-yl}acetic
acid,
{1-[4-(4-ethoxy-5-methyl-thiazol-2-yl)-2,6-difluoro-phenyl]-piperid-
in-4-yl}acetic acid,
2-[1-[4-(6-cyclobutyl-2-pyridyl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
acid,
2-[1-[4-[6-(cyclobutylmethyl)-2-pyridyl]-2,6-difluoro-phenyl]-4-pip-
eridyl]acetic acid,
2-[1-[4-[6-(cyclopentylmethyl)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperidy-
l]acetic acid,
{1-[4-(4-cyclopropylmethoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin--
4-yl}acetic acid,
(1-{2,6-difluoro-4-[4-(4-fluoro-phenyl)-thiazol-2-yl]-phenyl}-piperidin-4-
-yl)-acetic acid,
{1-[4-(4-cyclobutoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin-4-yl}ac-
etic acid,
{1-[4-(4-butoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin-4--
yl}acetic acid,
2-(1-{2,6-difluoro-4-[7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]phe-
nyl}piperidin-4-yl)acetic acid,
2-[1-[4-(6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,6-difluoro-phenyl]-
-4-piperidyl]acetic acid,
4-[2-chloro-4-[6-(cyclobutoxy)-2-pyridyl]-6-fluoro-phenoxy]butanoic
acid, 4-[2,6-dichloro-4-[6-(cyclobutoxy)-2-pyridyl]phenoxy]butanoic
acid,
4-[4-[3-(cyclopropylmethoxymethyl)-2-furyl]-2,6-difluoro-phenoxy]butanoic
acid,
4-[4-[6-(cyclopropylmethoxymethyl)-2-pyridyl]-2,6-difluoro-phenoxy]-
butanoic acid,
4-[2-chloro-4-[3-(cyclobutoxy)-5-fluoro-phenyl]-6-fluoro-phenoxy]butanoic
acid,
4-[4-[3-(cyclopropylmethoxymethyl)-5-methyl-isoxazol-4-yl]-2,6-difl-
uoro-phenoxy]butanoic acid,
4-[4-[6-chloro-4-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenoxy]butanoic
acid,
4-[4-[2-(cyclobutoxy)thiazol-4-yl]-2,6-difluoro-phenoxy]butanoic
acid,
4-[4-[6-(cyclobutoxy)-4-methyl-2-pyridyl]-2,6-difluoro-phenoxy]buta-
noic acid,
4-[4-[2-(cyclopropylmethoxy)thiazol-4-yl]-2,6-difluoro-phenoxy]-
butanoic acid,
4-[2-chloro-4-(6-cyclopentyloxy-pyridin-2-yl)-6-fluoro-phenoxy]-butyric
acid,
4-[2-chloro-4-(6-cyclopropylmethoxy-pyridin-2-yl)-6-fluoro-phenoxy]-
-butyric acid,
4-[2-chloro-6-fluoro-4-(6-isopropoxy-pyridin-2-yl)-phenoxy]-butyric
acid,
4-[2-chloro-4-(6-cyclobutylsulfanyl-pyridin-2-yl)-6-fluoro-phenoxy]-butyr-
ic acid,
4-[2-chloro-6-fluoro-4-(6-isopropylsulfanyl-pyridin-2-yl)-phenoxy-
]-butyric acid,
4-(5-chloro-3'-cyclobutoxy-3-fluoro-biphenyl-4-yloxy)-butyric acid,
4-(5-chloro-3'-cyclopropylmethoxy-3-fluoro-biphenyl-4-yloxy)-butyric
acid,
4-(5-chloro-3'-cyclopropylmethoxy-3-fluoro-4'-methoxy-biphenyl-4-yl-
oxy)-butyric acid,
4-(5-chloro-3'-cyclopropylmethoxy-3,4'-difluoro-biphenyl-4-yloxy)-butyric
acid,
4-(3'-cyclobutylsulfanyl-3,5-difluoro-biphenyl-4-yloxy)-butyric
acid, 5-(3'-cyclobutoxy-3,5-difluoro-biphenyl-4-yl)-hexanoic acid,
5-(5'-cyclobutoxy-3,5,3'-trifluoro-biphenyl-4-yl)-hexanoic acid,
5-(3'-cyclopropylmethoxy-3,5-difluoro-4'-methoxy-biphenyl-4-yl)-hexanoic
acid, 5-(3'-cyclopropylmethoxy-3,5-difluoro-biphenyl-4-yl)-hexanoic
acid,
5-(5'-cyclobutoxy-3'-fluoro-biphenyl-4-yl)-5,5-difluoro-pentanoic
acid,
5-[4-(5-chloro-6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-hexanoic
acid,
4-(3'-cyclobutanesulfonyl-3,5-difluoro-biphenyl-4-yloxy)-butyric
acid,
5-({[4-(6-cyclobutoxy-pyridin-2-yl)-phenyl]-methyl-amino}-methyl)-i-
soxazol-3-ol,
4-[2-chloro-4-(6-chloro-4-cyclobutoxy-pyridin-2-yl)-6-fluoro-phenoxy]-but-
yric acid,
4-[2-chloro-4-(2-cyclobutoxy-thiazol-4-yl)-6-fluoro-phenoxy]-bu-
tyric acid,
4-[2-chloro-4-(2-cyclopropylmethoxy-thiazol-4-yl)-6-fluoro-phenoxy]-butyr-
ic acid,
4-[2-chloro-4-(6-cyclobutoxy-4-methyl-pyridin-2-yl)-6-fluoro-phen-
oxy]-butyric acid,
4-[2-chloro-4-(6-cyclopropylmethoxy-4-methyl-pyridin-2-yl)-6-fluoro-pheno-
xy]-butyric acid,
{(R)-1-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrol-
idin-3-yl}-acetic acid,
{1-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenyl]-piperidin-
-4-yl}-acetic acid,
3-[8-fluoro-6-(2-isopropylsulfanyl-3-pyridyl)thiochroman-2-yl]propanoic
acid, 3-[6-[6-(cyclobutoxy)-2-pyridyl]thiochroman-2-yl]propanoic
acid,
3-[2-[2,6-difluoro-4-(7-methoxy-2,2-dimethyl-3H-benzofuran-4-yl)phenyl]cy-
clopropyl]propanoic acid,
3-[2-(2,6-difluoro-4-spiro[3H-benzofuran-2,1'-cyclopentan]-7-yl-phenyl)cy-
clopropyl]propanoic acid,
3-[6-[6-(cyclobutoxy)-2-pyridyl]chroman-2-yl]propanoic acid,
3-[6-[6-(cyclopropylmethoxy)-2-pyridyl]chroman-2-yl]propanoic acid,
4-[4-(2,3-dimethoxyphenyl)-2,6-difluoro-phenoxy]butanoic acid,
3-[6-[3-(cyclopropylmethoxy)phenyl]chroman-2-yl]propanoic acid,
3-[6-[3-(cyclopentoxy)phenyl]chroman-2-yl]propanoic acid,
4-(2,6-difluoro-N-methyl-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-a-
nilino)butanoic acid,
5-(2,6-difluoro-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-phenyl)hex-
anoic acid,
3-[6-(6-tert-butylsulfanyl-2-pyridyl)chroman-2-yl]propanoic acid,
3-[6-(6-isopropoxy-2-pyridyl)chroman-2-yl]propanoic acid,
2-[1-(2,6-difluoro-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-phenyl)-
-4-piperidyl]acetic acid,
4-[4-(2,3-dipropoxyphenyl)-2,6-difluoro-phenoxy]butanoic acid,
4-[4-[6-(cyclobutoxy)-5-methoxy-2-pyridyl]-2,6-difluoro-phenoxy]butanoic
acid,
4-[4-[6-(cyclobutoxy)-5-methoxy-2-pyridyl]-2,6-difluoro-N-methyl-an-
ilino]butanoic acid,
2-[1-[4-[6-(cyclobutoxy)-5-methoxy-2-pyridyl]-2,6-difluoro-phenyl]-4-pipe-
ridyl]acetic acid,
2-[1-[4-(2,3-dipropoxyphenyl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
acid,
4-[4-[6-(cyclopropylmethoxy)-5-methoxy-2-pyridyl]-2,6-difluoro-phen-
oxy]butanoic acid,
4-[4-(2,3-dipropoxyphenyl)-2,6-difluoro-N-methyl-anilino]butanoic
acid,
4-[4-[6-(cyclopropylmethoxy)-5-methoxy-2-pyridyl]-2,6-difluoro-N-methyl-a-
nilino]butanoic acid,
2-[1-[4-[6-(cyclopropylmethoxy)-5-methoxy-2-pyridyl]-2,6-difluoro-phenyl]-
-4-piperidyl]acetic acid,
4-[4-(6-chloroindol-1-yl)-2,6-difluoro-phenoxy]butanoic acid,
5-[4-[6-(cyclobutoxy)-5-methoxy-2-pyridyl]phenyl]-5,5-difluoro-pentanoic
acid, 4-[2,6-difluoro-4-(5-fluoroindol-1-yl)phenoxy]butanoic acid,
4-[4-[3-(cyclopropylmethylamino)phenyl]-2,6-difluoro-N-methyl-anilino]but-
anoic acid,
4-[2,6-difluoro-N-methyl-4-(6-pyrrolidin-1-yl-2-pyridyl)anilino]butanoic
acid, 4-[2,6-difluoro-4-(5-methoxyindol-1-yl)phenoxy]butanoic acid,
4-[4-(5-cyanoindol-1-yl)-2,6-difluoro-phenoxy]butanoic acid,
4-[4-[3-(cyclopropylmethoxymethyl)-2-furyl]-2,6-difluoro-N-methyl-anilino-
]butanoic acid,
4-[2,6-difluoro-4-(4-fluoroindol-1-yl)phenoxy]butanoic acid,
4-[4-(7-chloroindol-1-yl)-2,6-difluoro-phenoxy]butanoic acid,
4-[4-[5-(cyclopropylmethoxymethyl)-2-furyl]-2,6-difluoro-N-methyl-anilino-
]butanoic acid,
4-[4-[6-(cyclopropylmethoxy)indol-1-yl]-2,6-difluoro-phenoxy]butanoic
acid,
4-[4-(7-chloroindol-1-yl)-2,6-difluoro-N-methyl-anilino]butanoic
acid,
4-[4-[6-(cyclobutoxy)indol-1-yl]-2,6-difluoro-phenoxy]butanoic
acid,
4-[4-[5-(cyclobutoxy)indol-1-yl]-2,6-difluoro-phenoxy]butanoic
acid, 4-[2,6-difluoro-4-(4-methoxyindol-1-yl)phenoxy]butanoic acid,
4-[2,6-difluoro-4-(7-methoxyindol-1-yl)phenoxy]butanoic acid,
4-[2,6-difluoro-4-[5-(methoxymethyl)indazol-1-yl]phenoxy]butanoic
acid,
2-[1-[4-(7-chloroindol-1-yl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
acid,
4-[4-[6-(cyclobutoxy)indazol-1-yl]-2,6-difluoro-phenoxy]butanoic
acid,
4-[2-chloro-4-[6-(cyclobutoxy)indazol-1-yl]-6-fluoro-phenoxy]butano-
ic acid,
4-[4-[2-(cyclobutoxy)thiazol-4-yl]-2,6-difluoro-N-methyl-anilino]-
butanoic acid,
2-[1-[4-[6-(cyclobutoxy)indazol-1-yl]-2,6-difluoro-phenyl]-4-piperidyl]ac-
etic acid,
4-[4-[6-(cyclobutoxy)indazol-1-yl]-2,6-difluoro-N-methyl-anilin-
o]butanoic acid,
4-[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-N-methyl-anilino]but-
anoic acid,
2-[1-[4-[6-(cyclobutoxy)indazol-1-yl]-2,6-difluoro-phenyl]pyrrolidin-3-yl-
]acetic acid,
4-[4-(5-chloro-2-methyl-benzofuran-7-yl)-2,6-difluoro-phenoxy]-butyric
acid,
5-[4-(5-chloro-2-methyl-benzofuran-7-yl)-2,6-difluoro-phenyl]-hexan-
oic acid,
4-[(3'-cyclobutylmethoxy-3,5-difluoro-biphenyl-4-yl)-methyl-amin-
o]-butyric acid,
4-(3'-cyclobutylmethoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric
acid,
4-{[4-(6-cyclobutylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-methyl-amin-
o}-butyric acid,
4-[4-(6-cyclobutylmethoxy-pyridin-2-yl)-2,6-difluoro-phenoxy]-butyric
acid,
4-[(3'-cyclopropylmethoxy-3,5-difluoro-biphenyl-4-yl)-methyl-amino]-
-butyric acid,
4-[(3'-cyclopentyloxy-3,5-difluoro-biphenyl-4-yl)-methyl-amino]-butyric
acid,
4-(3'-cyclopropylmethoxy-3,5-difluoro-4'-methoxy-biphenyl-4-yloxy)--
butyric acid,
4-(3'-cyclopropylmethoxy-3,5,4'-trifluoro-biphenyl-4-yloxy)-butyric
acid, 4-(5'-cyclobutoxy-3,5,3'-trifluoro-biphenyl-4-yloxy)-butyric
acid,
4-[(5'-cyclobutylmethoxy-3,5-difluoro-2'-methyl-biphenyl-4-yl)-methyl-ami-
no]-butyric acid,
4-(5'-cyclobutylmethoxy-3,5-difluoro-2'-methyl-biphenyl-4-yloxy)-butyric
acid,
4-{[4-(5-chloro-6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-me-
thyl-amino}-butyric acid,
4-(3'-cyclopropylmethoxy-3,5-difluoro-4'-methyl-biphenyl-4-yloxy)-butyric
acid,
4-[4-(5-chloro-6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenoxy]-bu-
tyric acid,
4-(4'-chloro-3'-cyclopropylmethoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric
acid, 5-(5'-cyclobutoxy-3,3'-difluoro-biphenyl-4-yl)-pentanoic
acid, 4-(5'-cyclobutoxy-3,3'-difluoro-biphenyl-4-yloxy)-butyric
acid, 5-[4-(6-cyclobutoxy-pyridin-2-yl)-2-fluoro-phenyl]-pentanoic
acid, 4-[4-(6-cyclobutoxy-pyridin-2-yl)-2-fluoro-phenoxy]-butyric
acid,
4-[4-(6-cyclobutylmethoxy-pyridin-2-yl)-2-fluoro-phenoxy]-butyric
acid,
4-[4-(6-cyclobutylsulfanyl-pyridin-2-yl)-2-fluoro-phenoxy]-butyric
acid,
2-(3'-cyclobutoxy-3,5,5'-trifluoro-biphenyl-4-yloxymethyl)-cyclopropane
carboxylic acid,
2-[4-(6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenoxymethyl]-cyclopropan-
e carboxylic acid,
2-[4-(6-cyclobutoxy-4-methyl-pyridin-2-yl)-2,6-difluoro-phenoxymethyl]-cy-
clopropane carboxylic acid,
2-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenoxymethyl]-cycl-
opropane carboxylic acid,
2-[4-(2-cyclobutoxy-thiazol-4-yl)-2,6-difluoro-phenoxymethyl]-cyclopropan-
e carboxylic acid,
2-[2-chloro-4-(6-cyclopropylmethoxy-pyridin-2-yl)-6-fluoro-phenoxymethyl]-
-cyclopropane carboxylic acid,
2-[2-chloro-4-(6-cyclobutoxy-pyridin-2-yl)-6-fluoro-phenoxymethyl]-cyclop-
ropane carboxylic acid,
3-[6-(3-cyclobutoxy-phenyl)-chroman-2-yl]-propionic acid,
3-[6-(6-propoxy-pyridin-2-yl)-chroman-2-yl]-propionic acid,
4-[2,6-difluoro-4-(1H-indol-6-yl)-phenoxy]-butanoic acid,
4-[2,6-difluoro-4-(1-isopropyl-1H-indol-6-yl)-phenoxy]-butanoic
acid,
4-[4-(1-cyclopropylmethyl-1H-indol-6-yl)-2,6-difluoro-phenoxy]-butanoic
acid
{1-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrro-
lidin-3-yl}-acetic acid,
{1-[4-(6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-3-yl}--
acetic acid,
4-[4-(3-chloro-1-isopropyl-1H-indol-6-yl)-2,6-difluoro-phenoxy]-butanoic
acid,
{1-[2,6-difluoro-4-(6-isopropoxy-pyridin-2-yl)-phenyl]-pyrrolidin-3-
-yl}-acetic acid,
{1-[4-(6-cyclobutylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin--
3-yl}-acetic acid,
4-[4-(5-cyclopropylmethoxymethyl-thiophen-2-yl)-2,6-difluoro-phenoxy]-but-
anoic acid,
4-[4-(5-cyclopropylmethoxymethyl-thiophen-3-yl)-2,6-difluoro-phenoxy]-but-
anoic acid,
{1-[4-(5-cyclopropylmethoxymethyl-thiophen-3-yl)-2,6-difluoro-phenyl]-pip-
eridin-4-yl}-acetic acid,
4-[4-(4-cyclopropylmethoxymethyl-2-methyl-thiazol-5-yl)-2,6-difluoro-phen-
oxy]-butanoic acid,
{1-[4-(5-cyclomethoxymethyl-thiophen-2-yl)-2,6-difluoro-phenyl]-piperidin-
-4-yl}-acetic acid,
{1-[4-(4-cyclopropylmethoxymethyl-2-methyl-thiazol-5-yl)-2,6-difluoro-phe-
nyl]-piperidin-4-yl}-acetic acid,
4-[4-(5-cyclobutylmethoxymethyl-thiophen-3-yl)-2,6-difluoro-phenoxy]-buta-
noic acid,
4-[2,6-difluoro-4-(5-isobutoxymethyl-thiophen-3-yl)-phenoxy]-bu-
tanoic acid,
4-[4-(5-cyclobutoxymethyl-thiophen-3-yl)-2,6-difluoro-phenoxy]-butanoic
acid,
4-[4-(3-cyclopropylmethoxymethyl-thiophen-2-yl)-2,6-difluoro-phenox-
y]-butanoic acid,
{1-[4-(6-cyclobutoxy-4-methyl-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrolid-
in-3-yl}-acetic acid,
{1-[4-(2-cyclobutoxy-thiazol-4-yl)-2,6-difluoro-phenyl]-pyrrolidin-3-yl}--
acetic acid,
{1-[4-(2-cyclopropylmethoxy-thiazol-4-yl)-2,6-difluoro-phenyl]-pyrrolidin-
-3-yl}-acetic acid,
{1-[4-(5-cyclobutoxy-3-methyl-isothiazol-4-yl)-2,6-difluoro-phenyl]-pyrro-
lidin-3-yl}-acetic acid,
{1-[2,6-difluoro-4-(5-fluoro-4-isobutoxy-pyrimidin-2-yl)-phenyl]-pyrrolid-
in-3-yl}-acetic acid,
(1-{2,6-difluoro-4-[6-(3-methoxy-propoxy)-pyridin-2-yl]-phenyl}-pyrrolidi-
n-3-yl)-acetic acid,
(1-{2,6-difluoro-4-[6-(tetrahydro-thiopyran-4-yloxy-pyridin-2-yl]-phenyl}-
-pyrrolidin-3-yl)-acetic acid,
(1-{2,6-difluoro-4-[6-(3-methoxy-propoxy)-pyridin-2-yl]-phenyl}-piperidin-
-4-yl)-acetic acid,
{(S)-1-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrol-
idin-3-yl}-acetic acid,
{1-[4-(6-cyclobutoxy-4-trifluoromethyl-pyridin-2-yl)-2,6-difluoro-phenyl]-
-piperidin-4-yl}-acetic acid,
(1-{2,6-difluoro-4-[2-(4-fluoro-phenyl)-benzo[b]thiophen-4-yl]-phenyl}-pi-
peridin-4-yl)-acetic acid,
{1-[2,6-difluoro-4-(2-m-tolyl-benzo[b]thiophen-4-yl)-phenyl]-piperidin-4--
yl}-acetic acid,
3-{1-[2,6-difluoro-4-(6-propoxy-pyridin-2-yl)-phenyl]-piperidin-4-yl}-pro-
pionic acid,
3-{1-[4-(6-cyclobutyl-pyridin-2-yl)-2,6-difluoro-phenyl]-piperidin-4-yl}--
propionic acid, and
3-{1-[4-(6-ethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-piperidin-4-yl}-prop-
ionic acid, or a pharmaceutically acceptable salt or stereoisomer
thereof.
2. A pharmaceutical composition as a GPR120 agonist, comprising the
compound of claim 1, or pharmaceutically acceptable salt or
stereoisomer thereof as an active ingredient and a pharmaceutically
acceptable carrier.
3. A method for the prevention or treatment of a metabolic disease
selected from diabetes, complications of diabetes, obesity,
non-alcoholic fatty liver, steatohepatitis and osteoporosis, or
inflammatory disease, comprising administering the pharmaceutical
composition of claim 2 to a subject in need thereof.
4. The method of claim 3, wherein the complication of diabetes is
selected from neurogenic disease, hyperlipidemia, hypertension,
retinosis and renal failure.
5. A method for lowering blood glucose level, comprising
administering the pharmaceutical composition of claim 2 to a
subject in need thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S. patent
application Ser. No. 15/539,310 filed on Jun. 23, 2017, which is a
35 U.S.C. .sctn. 371 National Phase Entry Application from
PCT/KR2015/014178, filed on Dec. 23, 2015 and designating the
United States, which claims priority under 35 U.S.C. .sctn. 119 to
Korean Patent Application No. 10-2014-0188399 filed on Dec. 24,
2014 with the Korean Intellectual Property Office, all the
disclosures of which are herein incorporated by reference in their
entirety.
TECHNICAL FIELD
[0002] The present invention relates to novel compound derivatives
as GPR120 agonists, a method for preparing the same, a
pharmaceutical composition comprising the same as active
ingredients and use thereof. Herein a GPR120 agonist means a
compound which can be effectively used for preventing or treating
metabolic diseases such as diabetes, complications of diabetes,
obesity, non-alcoholic fatty liver, steatohepatitis and
osteoporosis, or inflammation, by promoting GLP-1 in the
gastrointestinal tract and anti-inflammatory action.
BACKGROUND ART
[0003] Diabetes is largely divided into two types--i.e.,
insulin-dependent type 1 diabetes and insulin-independent
(insulin-resistant) type 2 diabetes which is found in 90% or more
of diabetic patients.
[0004] GPR120 agonists, which are noted for possible treatment of
type 2 diabetes, are known to have (1) an antidiabetic effect
caused by the actions of increasing incretin hormone in intestinal
cells, (2) anti-inflammatory action in macrophages, and (3) an
action of improvement on insulin resistance in lipocytes. They are
also known as a possible treatment of type 1 diabetes due to the
improvement on proliferation of pancreas cells by anti-inflammatory
action.
[0005] G protein-coupled receptor 120 (GPR120) is expressed
copiously in the intestines, lungs, adipose tissue, and macrophages
which induce inflammation, and is activated by long-chain free
fatty acid (FFA). GPR120 stimulates the secretion of glucagon-like
peptide-1 (GLP-1) by FFA. GLP-1, an incretin hormone, is known to
stimulate the secretion of insulin in the pancreas dependently on
blood glucose level, and also to have the effect of improvement of
insulin resistance, proliferation of 0-cells, appetite loss and
increase of satiety. Recently, GPR120 is known to relate with
improvement of insulin resistance and anti-inflammatory effect, and
therefore, it is regarded as a target for developing a drug to
effectively improve insulin resistance, type 2 diabetes and obesity
involving low-level chronic inflammation. Furthermore, in animal
experiments of type 1 diabetes, GPR120 agonists are reported to
improve the secretion of insulin by the action of proliferation of
0-cells.
[0006] Since GPR 120 agonists also have anti-inflammatory action,
they are reported to be a possible treatment of
inflammation-related diseases--for example, steatohepatitis,
rheumatoid arthritis, etc.
[0007] Considering the above, researches on GPR120 agonists are
actively in progress. In the representative compounds presented as
GPR120 agonists, two aryl groups are connected with a center bridge
structure, and the characteristic feature is that one of two aryl
groups is substituted by carboxylic acid. GPR120 agonist compounds
are disclosed in WO 2013/185766, WO 2013/139341, WO 2011/159297, WO
2010/080537, WO 2010/104195, WO 2010/048207, WO 2009/147990, WO
2008/066131, WO 2008/103500 and WO 2008/139879.
DISCLOSURE OF INVENTION
Technical Problem
[0008] The object of the present invention is to provide a novel
biaryl derivative as a GPR120 agonist.
[0009] Another object of the present invention is to provide a
method for preparing the biaryl derivative.
[0010] Still another object of the present invention is to provide
a pharmaceutical composition for the prevention or treatment of
metabolic disease such as diabetes, complications of diabetes,
obesity, non-alcoholic fatty liver, steatohepatitis and
osteoporosis, or inflammation which comprises the biaryl derivative
as an active ingredient, and a method for preparing the
composition.
[0011] A still further object of the present invention is to
provide a method for preventing and treating metabolic disease such
as diabetes, complications of diabetes, obesity, non-alcoholic
fatty liver, steatohepatitis and osteoporosis, or inflammation
which uses the biaryl derivative as an active ingredient.
Solution to Problem
[0012] To accomplish the object, the present invention provides a
biaryl derivative of Formula 1, or a pharmaceutically acceptable
salt or isomer thereof:
##STR00001##
[0013] wherein,
[0014] A and B represent independently aryl or heteroaryl;
[0015] D and E may independently not exist, or represent
independently C, CH, CH.sub.2, N, NH, O or S;
[0016] R.sub.1 and R.sub.2 may independently not exist, or
represent independently hydrogen, halogen, alkyl, cycloalkyl,
heterocycloalkyl, oxo, alkylcycloalkyl, cycloalkylalkyl, haloalkyl,
alkoxy, alkoxyalkyl, alkoxyaryl, cycloalkoxy, cycloalkylalkoxy,
alkylheterocycloalkyl, aryl, alkylaryl, aralkyl, haloaryl,
heteroaryl, alkylheteroaryl or haloalkylaryl;
[0017] R.sub.1 and R.sub.2 may be connected each other, or with D
and/or E to form a ring, or may form a fused ring with A; the ring
is optionally substituted with alkyl, halogen, alkoxycarbonyl,
cycloalkylalkyl, haloaryl or alkylaryl; and when D and E represent
C, CH or N, R.sub.1 and R.sub.2 can represent two or three alkyl,
oxo, cycloalkyl, alkoxy, alkylcycloalkyl, aryl or alkylaryl which
may be the same or different;
[0018] R.sub.3 and R.sub.4 represent independently hydrogen,
halogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, nitrile, oxo,
cycloalkoxy, aryloxy, heteroaryloxy, aminoalkyl, aminocycloalkyl,
aminoaryl, alkylamine, cycloalkylamine, aminoheteroaryl, thioalkyl,
thioaryl or thioheteroaryl;
[0019] m and n represent independently an integer of 0 to 5;
[0020] G represents
--(CR.sub.5R.sub.6).sub.p-J-(CR.sub.5R.sub.6).sub.q, wherein J
represents CH.sub.2, O, N, NH, S or a double bond; R.sub.5 and
R.sub.6 represent independently hydrogen, halogen, alkyl or
cycloalkyl, hydroxy or amine, or may be connected each other to
form cycloalkyl, and when J is N, each of R.sub.5 and R.sub.6 at
two (CR.sub.5R.sub.6)s may be connected to form a ring, or may be
substituted with alkyl; and p and q represent independently an
integer of 0 to 6; and
[0021] R.sub.7 represents carboxylic acid or carboxylic acid
isostere.
[0022] The compound of Formula 1 according to the present invention
may form a pharmaceutically acceptable salt, which includes an
acid-addition salt which is formed from an inorganic acid such as
hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid,
hydrobromic acid and hydroiodic acid; an organic acid such as
tartaric acid, formic acid, citric acid, acetic acid,
trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic
acid, lactic acid, fumaric acid, maleic acid and salicylic acid; or
sulfonic acid such as methanesulfonic acid, ethanesulfonic acid,
benzenesulfonic acid and p-toluenesulfonic acid, which form
non-toxic acid-addition salt including pharmaceutically acceptable
anion. In addition, a pharmaceutically acceptable carboxylic acid
salt includes the salt with alkali metal or alkali earth metal such
as lithium, sodium, potassium, calcium and magnesium; salts with
amino acid such as lysine, arginine and guanidine; an organic salt
such as dicyclohexylamine, N-methyl-D-glucamine,
tris(hydroxymethyl)methylamine, diethanolamine, choline and
triethylamine. The compound of Formula 1 according to the present
invention may be converted into their salts by conventional
methods.
[0023] Meanwhile, since the compound of Formula 1 according to the
present invention can have an asymmetric carbon center and
asymmetric axis or plane, they can exist as E- or Z-isomer, R- or
S-isomer, racemic mixtures or diastereoisomer mixtures and each
diastereoisomer, all of which are within the scope of the present
invention.
[0024] Herein, unless indicated otherwise, the term "the compound
of Formula 1" is used to mean all the compounds of Formula 1,
including the pharmaceutically acceptable salts and isomers
thereof.
[0025] Herein, the following concepts defined to the substituents
are used to define the compound of Formula 1.
[0026] The term "halogen" or "halo" means fluoride (F), chlorine
(Cl), bromine (Br) or iodine (I).
[0027] The term "carboxylic acid isostere" includes, but is not
limited to, isoxazolol, pyrazolol, isothiazolol, thiazolidinedione,
pyrrolidinedione, oxazolidinedione, imidazolidinedione,
thiazolidinedione, imidazoledione, pyrroledione, phenol, pyridinol,
dioxothiadiazolidineone, tetrazole, triazole, imidazole, sulfonic
acid, sulfonamide, acetamide, nitrile, hydroxyacetamidine,
oxadiazoleone, oxadiazolethione and the like.
[0028] The term "alkyl" means straight or branched hydrocarbons,
may include a single bond, a double bond and a triple bond, and is
preferably C.sub.1-C.sub.10-alkyl. Examples of alkyl include, but
are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl,
i-butyl, tert-butyl, acetylene, vinyl, trifluoromethyl and the
like.
[0029] The term "cycloalkyl" means partially or fully saturated
single or fused ring hydrocarbons, and is preferably
C.sub.3-C.sub.10-cycloalkyl. Examples of cycloalkyl include, but
are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cyclohexenyl and the like.
[0030] Unless otherwise defined, the term "alkoxy" means alkyloxy
having 1 to 10 carbon atoms.
[0031] Unless otherwise defined, the term "cycloalkoxy" means
cycloalkyloxy having 3 to 10 carbon atoms.
[0032] Aryl means aromatic hydrocarbons, preferably
C.sub.5-C.sub.12-aryl, more preferably C.sub.6-C.sub.10-aryl, and
includes, but is not limited to, phenyl, naphthyl and the like.
[0033] Heteroaryl means 3- to 12-membered, more preferably 5- to
10-membered aromatic hydrocarbons which form a single or fused
ring--which may be fused with benzo or C.sub.3-C.sub.8
cycloalkyl--including at least one heteroatom selected from N, O
and S as a ring member. Examples of heteroaryl include, but are not
limited to, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,
oxadiazolyl, isoxadiazolyl, tetrazolyl, triazolyl, indolyl,
indazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, furanyl,
benzofuranyl, imidazolyl, thiophenyl, benzthiazole, benzimidazole,
quinolinyl, indolinyl, 1,2,3,4-tetrahydroisoquinolyl,
3,4-dihydroisoquinolinyl, thiazolopyridyl, 2,3-dihydrobenzofuran,
2,3-dihydrothiophene, 2,3-dihydroindole, benzo[1,3]dioxin, chroman,
thiochroman, 1,2,3,4-tetrahydroquinoline, 4H-benzo[1,3]dioxin,
2,3-dihydrobenzo[1,4]-dioxin,
6,7-dihydro-5H-cyclopenta[d]pyrimidine and the like.
[0034] Heterocyclyl means partially or fully saturated hydrocarbons
which form a single or fused ring including at least one heteroatom
selected from N, O and S, and is preferably 3- to 12-membered
heterocyclyl. Examples of heterocyclyl include, but are not limited
to, pyrrolidinyl, piperidinyl, morpholinyl, imidazolinyl,
piperazinyl, tetrahydrofuran, tetrahydrothiofuran and the like.
[0035] Aralkyl, alkylaryl and heteroarylalkyl mean groups which are
formed by the combination of the above-mentioned aryl with alkyl or
heteroaryl with alkyl. Examples include, but are not limited to,
benzyl, thiophene methyl, pyrimidine methyl and the like.
[0036] The above-mentioned amine, alkyl, cycloalkyl, aryl,
heteroaryl, heterocyclyl, aralkyl and heteroarylalkyl may be
substituted by at least one group selected from the following
groups: alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl,
heteroarylalkyl, heterocyclylalkyl, oxo, cyano, halo, nitro, --OR,
--OC(O)R, --OC(O)OR, --SR, --S(O)R, --S(O).sub.2R, --C(O)R,
--C(O)OR, --C(S)R, --C(O)NRR, --NR.sub.2, --NRCHO, --NRC(O)R,
--NRC(O)NRR, --C(S)NRR, --NRC(S)R and --NRC(S)NRR, wherein R is
independently selected from hydrogen, alkyl, cycloalkyl,
heterocyclyl, aryl, heteroaryl, aralkyl and heteroarylalkyl, and
when two Rs are substituted, they may be connected to form
cycloalkyl or heterocyclyl.
[0037] According to one embodiment of the present invention, in the
above Formula 1
[0038] A and B represent independently C.sub.5-C.sub.12 aryl or 3-
to 12-membered heteroaryl having at least one heteroatom selected
from N, O and S;
[0039] D and E may independently not exist, or represent
independently C, CH, CH.sub.2, N, NH, O or S;
[0040] R.sub.1 and R.sub.2 may independently not exist, or
represent independently hydrogen, halogen, C.sub.1-C.sub.10 alkyl,
C.sub.3-C.sub.10 cycloalkyl, 3- to 12-membered heterocycloalkyl,
oxo, C.sub.1-C.sub.10 alkyl-C.sub.3-C.sub.10 cycloalkyl,
C.sub.3-C.sub.10 cycloalkyl-C.sub.1-C.sub.10 alkyl,
halo-C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkoxy,
C.sub.1-C.sub.10 alkoxy-C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10
alkoxy-C.sub.5-C.sub.12 aryl, C.sub.3-C.sub.10 cycloalkoxy,
C.sub.3-C.sub.10 cycloalkyl-C.sub.1-C.sub.10 alkoxy,
C.sub.1-C.sub.10 alkyl-3- to 12-membered heterocycloalkyl,
C.sub.5-C.sub.12 aryl, C.sub.1-C.sub.10 alkyl-C.sub.5-C.sub.12
aryl, C.sub.5-C.sub.12 aryl-C.sub.1-C.sub.10 alkyl,
halo-C.sub.5-C.sub.12 aryl, 3- to 12-membered heteroaryl,
C.sub.1-C.sub.10 alkyl-3- to 12-membered heteroaryl or
halo-C.sub.1-C.sub.10 alkyl-C.sub.5-C.sub.12 aryl, wherein the
heterocycloalkyl and heteroaryl have at least one heteroatom
selected from N, O and S;
[0041] R.sub.1 and R.sub.2 may be connected each other, or with D
and/or E to form C.sub.3-C.sub.10 cycloalkyl, C.sub.5-C.sub.12 aryl
or 3- to 12-membered heterocycloalkyl having at least one
heteroatom selected from N, O and S, or may form 3- to 15-membered
heterocycle or heteroaryl having at least one heteroatom selected
from N, O and S, fused with A; the cycloalkyl, aryl,
heterocycloalkyl, heterocycle or heteroaryl is optionally
substituted with C.sub.1-C.sub.10 alkyl, halogen, C.sub.1-C.sub.10
alkoxycarbonyl, C.sub.3-C.sub.10 cycloalkyl-C.sub.1-C.sub.10 alkyl,
halo-C.sub.5-C.sub.12 aryl or C.sub.1-C.sub.10
alkyl-C.sub.5-C.sub.12 aryl; and when D and E represent C, CH or N,
R.sub.1 and R.sub.2 can represent two or three C.sub.1-C.sub.10
alkyl, oxo, C.sub.3-C.sub.10 cycloalkyl, C.sub.1-C.sub.10 alkoxy,
C.sub.1-C.sub.10 alkyl-C.sub.3-C.sub.10 cycloalkyl,
C.sub.5-C.sub.12 aryl or C.sub.1-C.sub.10 alkyl-C.sub.5-C.sub.12
aryl which may be the same or different;
[0042] R.sub.3 and R.sub.4 represent independently hydrogen,
halogen, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to
12-membered heterocycloalkyl, C.sub.1-C.sub.10 alkoxy, nitrile,
oxo, C.sub.3-C.sub.10 cycloalkoxy, C.sub.5-C.sub.12 aryloxy, 3- to
12 membered heteroaryloxy, amino-C.sub.1-C.sub.10 alkyl,
amino-C.sub.3-C.sub.10 cycloalkyl, amino-C.sub.5-C.sub.12 aryl,
C.sub.1-C.sub.10 alkylamine, C.sub.3-C.sub.10 cycloalkylamine,
amino-3- to 12-membered heteroaryl, thio-C.sub.1-C.sub.10 alkyl,
thio-C.sub.5-C.sub.12 aryl or thio-3 to 12-membered heteroaryl;
[0043] m and n represent independently an integer of 0 to 3;
[0044] G represents
--(CR.sub.5R.sub.6).sub.p-J-(CR.sub.5R.sub.6).sub.q, wherein J
represents CH.sub.2, O, N, NH, S or double bond; R.sub.5 and
R.sub.6 represent independently hydrogen, halogen, C.sub.1-C.sub.10
alkyl or C.sub.3-C.sub.10 cycloalkyl, hydroxy or amine, or may be
connected each other to form C.sub.3-C.sub.10 cycloalkyl, and when
J is N, each of R.sub.5 and R.sub.6 at two (CR.sub.5R.sub.6)s may
be connected to form 3- to 12-membered heteroaryl or 3- to
12-membered heterocycloalkyl having 1 or 2 N atoms, or may be
substituted with C.sub.1-C.sub.10 alkyl; and p and q represent
independently an integer of 0 to 6; and
[0045] R.sub.7 represents carboxylic acid or carboxylic acid
isostere.
[0046] According to another embodiment of the present invention, A
and B represent independently C.sub.6-C.sub.10 aryl or 5- to
10-membered heteroaryl having 1 to 3 heteroatoms selected from N, O
and S.
[0047] According to still another embodiment of the present
invention, R.sub.1 and R.sub.2 may independently not exist, or
represent independently hydrogen, halogen, C.sub.1-C.sub.8 alkyl,
C.sub.3-C.sub.8 cycloalkyl, 3- to 10 membered heterocycloalkyl,
oxo, C.sub.1-C.sub.8 alkyl-C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 cycloalkyl-C.sub.1-C.sub.8 alkyl,
halo-C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
alkoxy-C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkoxy-C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.8 cycloalkoxy,
C.sub.3-C.sub.8 cycloalkyl-C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
alkyl-3- to 10-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl,
C.sub.1-C.sub.8 alkyl-C.sub.6-C.sub.10 aryl, C.sub.6-C.sub.10
aryl-C.sub.1-C.sub.8 alkyl, halo-C.sub.6-C.sub.10 aryl, 5- to
10-membered heteroaryl, C.sub.1-C.sub.8 alkyl-5- to 10-membered
heteroaryl or halo-C.sub.1-C.sub.8 alkyl-C.sub.6-C.sub.10 aryl,
wherein the heterocycloalkyl and heteroaryl have 1 to 3 heteroatoms
selected from N, O and S;
[0048] R.sub.1 and R.sub.2 may be connected each other, or with D
and/or E to form C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl
or 3- to 12-membered heterocycloalkyl having 1 to 3 heteroatoms
selected from N, O and S, or may form 3- to 14-membered heterocycle
or heteroaryl having 1 to 4 heteroatoms selected from N, O and S,
fused with A; the cycloalkyl, aryl, heterocycloalkyl, heterocycle
or heteroaryl is optionally substituted with C.sub.1-C.sub.8 alkyl,
halogen, C.sub.1-C.sub.8 alkoxycarbonyl, C.sub.3-C.sub.8
cycloalkyl-C.sub.1-C.sub.8 alkyl, halo-C.sub.6-C.sub.10 aryl or
C.sub.1-C.sub.8 alkyl-C.sub.6-C.sub.10 aryl; and
[0049] when D and E represent C, CH or N, R.sub.1 and R.sub.2 can
represent two or three C.sub.1-C.sub.8 alkyl, oxo, C.sub.3-C.sub.8
cycloalkyl, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
alkyl-C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl or
C.sub.1-C.sub.8 alkyl-C.sub.6-C.sub.10 aryl which may be the same
or different.
[0050] According to still another embodiment of the present
invention, R.sub.3 and R.sub.4 represent independently hydrogen,
halogen, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to
12-membered heterocycloalkyl, C.sub.1-C.sub.10 alkoxy, nitrile, oxo
or C.sub.3-C.sub.10 cycloalkoxy.
[0051] According to still another embodiment of the present
invention, G represents
--(CR.sub.5R.sub.6).sub.p-J-(CR.sub.5R.sub.6).sub.q, wherein J
represents CH.sub.2, O, N, NH, S or a double bond; R.sub.5 and
R.sub.6 represent independently hydrogen, halogen, C.sub.1-C.sub.8
alkyl or C.sub.3-C.sub.8 cycloalkyl, hydroxy or amine, or may be
connected each other to form C.sub.3-C.sub.8 cycloalkyl, and when J
is N, each of R.sub.5 and R.sub.6 at two (CR.sub.5R.sub.6)s may be
connected to form 3- to 10-membered heteroaryl or 3- to 12-membered
heterocycloalkyl having 1 or 2 N atoms, or may be substituted with
C.sub.1-C.sub.8 alkyl; and p and q represent independently an
integer of 0 to 5.
[0052] Representative compounds of Formula 1 according to the
present invention include, but are not limited to, the following
compounds: [0053]
3-[6-(2-isopropylsulfanyl-pyridin-3-yl)-quinolin-2-yl]-propionic
acid, [0054]
3-[6-(6-isopropylsulfanyl-pyridin-2-yl)-quinolin-2-yl]-propionic
acid, [0055]
[6-(6-cyclopentyloxy-pyridin-2-yl)-naphthalen-2-yloxy]-acetic acid,
[0056]
[6-(2-cyclopentyloxy-pyridin-3-yl)-naphthalen-2-yloxy]-acetic acid,
[0057]
4-[6-(2-isopropylsulfanyl-pyridin-3-yl)-naphthalen-2-yloxy]-butyri-
c acid, [0058]
4-[6-(6-isopropylsulfanyl-pyridin-2-yl)-naphthalen-2-yloxy]-butyric
acid, [0059]
3-[6-(2-isopropylsulfanyl-pyridin-3-yl)-chroman-2-yl]-propionic
acid, [0060]
3-[6-(6-isopropylsulfanyl-pyridin-2-yl)-chroman-2-yl]-propionic
acid, [0061]
3-[P6-(6-cyclopentyloxy-pyridin-2-yl)-chroman-2-yl]-propionic acid,
[0062] 3-[6-(2-cyclopentyloxy-pyridin-3-yl)-chroman-2-yl]-propionic
acid, [0063]
3-[6-(6-cyclopentyloxy-pyridin-2-yl)-1,2,3,4-tetrahydro-quinolin-2-yl]-pr-
opionic acid, [0064]
3-[6-(6-cyclopentyloxy-pyridin-2-yl)-1-methyl-1,2,3,4-tetrahydro-quinolin-
-2-yl]-propionic acid, [0065]
[6-(2-isopropylsulfanyl-pyridin-3-yl)-1-oxo-3,4-dihydro-1H-isoquinolin-2--
yl]-acetic acid, [0066]
[6-(6-isopropylsulfanyl-pyridin-2-yl)-1-oxo-3,4-dihydro-1H-isoquinolin-2--
yl]-acetic acid, [0067]
3-[6-(2-cyclopentyloxy-pyridin-3-yl)-1-oxo-3,4-dihydro-1H-isoquinolin-2-y-
l]-propionic acid, [0068]
3-[6-(2-isopropylsulfanyl-pyridin-3-yl)-1-oxo-3,4-dihydro-1H-isoquinolin--
2-yl]-propionic acid, [0069]
4-(3'-benzyloxy-3,5-difluoro-biphenyl-4-yloxy)-butyric acid, [0070]
4-(3,5-difluoro-3'-isopropoxy-biphenyl-4-yloxy)-butyric acid,
[0071] 4-(3,5-difluoro-3'-propoxy-biphenyl-4-yloxy)-butyric acid,
[0072]
4-(3'-cyclopropylmethoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric
acid, [0073]
4-(3'-cyclobutoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric acid,
[0074]
4-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-2,6-difluoro-pheno-
xy]-butyric acid, [0075]
4-[4-(2,2-dimethyl-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenoxy]-butyric
acid, [0076]
4-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]butanenitrile,
[0077]
2-cyclobutylsulfanyl-3-{3,5-difluoro-4-[3-(1H-tetrazol-5-yl)propox-
y]phenyl}pyridine, [0078]
2-cyclobutylsulfanyl-3-{4-[3-(1H-tetrazol-5-yl)propyl]phenyl}pyridine,
[0079] 5-[4-(2-cyclobutylsulfanyl-3-pyridyl)phenyl]pentanoic acid,
[0080] 5-[4-(6-cyclopentylsulfanyl-2-pyridyl)phenyl]pentanoic acid,
[0081] 5-[4-(2-cyclopentylsulfanyl-3-pyridyl)phenyl]pentanoic acid,
[0082]
2-cyclobutylsulfanyl-3-[3,5-difluoro-4-(1H-tetrazol-5-ylmethoxy)phenyl]py-
ridine, [0083]
5-[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)phenyl]pentanoic
acid, [0084]
5-[4-(6-cyclobutoxy-2-pyridyl)-2,6-difluoro-phenyl]pentanoic acid,
[0085]
5-[4-(6-cyclopentoxy-2-pyridyl)-2,6-difluoro-phenyl]pentanoic acid,
[0086]
5-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenyl]pentanoic
acid, [0087]
5-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]pentanoic
acid, [0088]
5-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]pentano-
ic acid, [0089]
5-[4-(2-cyclopentoxy-3-pyridyl)-2,6-difluoro-phenyl]pentanoic acid,
[0090]
{2-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]ethoxy}-
acetic acid, [0091]
5-[4-(2-cyclobutylsulfanyl-3-pyridyl)phenyl]hexanoic acid, [0092]
5-[4-(6-cyclobutoxy-2-pyridyl)-phenyl]hexanoic acid, [0093]
5-[4-(6-cyclobutoxy-2-pyridyl)-2,6-difluoro-phenyl]hexanoic acid,
[0094]
5-[4-(2-ethylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]hexanoic acid,
[0095]
5-[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)-phenyl]hexanoic
acid, [0096]
4-[1-methyl-5-(2-phenoxyphenyl)benzimidazol-2-yl]butanoic acid,
[0097] 3-[1-methyl-5-(2-phenoxyphenyl)benzimidazol-2-yl]propanoic
acid, [0098]
5-[2,6-difluoro-4-(2-isopropoxy-3-pyridyl)phenyl]hexanoic acid,
[0099] 5-(2'-cyclopentylamino-3,5-difluoro-bisphenyl-4-yl)hexanoic
acid, [0100]
5-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]hexanoic
acid, [0101]
5-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]hexanoi-
c acid, [0102]
5-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)-phenyl]hexanoic
acid, [0103]
5-[4-(2-cyclopentoxy-3-pyridyl)-2,6-difluoro-phenyl]hexanoic acid,
[0104] 5-(3'-cyclopentylamino-3,5-difluoro-biphenyl-4-yl)-hexanoic
acid, [0105]
5-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)-phenyl]hexanoic
acid, [0106]
5-[4-(6-cyclopentylsulfanyl-2-pyridyl)-2,6-difluoro-phenyl]hexanoic
acid, [0107]
5-[2,6-difluoro-4-(6-propylsulfanyl-2-pyridyl)phenyl]hexanoic acid,
[0108] 5-[4-(6-cyclopentoxy-2-pyridyl)-2,6-difluoro-phenyl]hexanoic
acid, [0109] 4-[4-(2-isopropoxy-3-pyridyl)phenyl]butanoic acid,
[0110] 5-[2,6-difluoro-4-(2-hydroxy-3-pyridyl)phenyl]hexanoic acid,
[0111] 5-[4-(2-cyclobutoxy-3-pyridyl)-2,6-difluoro-phenyl]hexanoic
acid, [0112]
5-[4-(2-cyclopropylmethoxy-3-pyridyl)-2,6-difluoro-phenyl]hexanoic
acid, [0113]
5-[[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]methyl-
]isoxazol-3-ol, [0114]
N'-hydroxy-4-[4-(2-propylsulfanyl-3-pyridyl)phenyl]butaneamidine,
[0115]
3-[3-[4-(2-propylsulfanyl-3-pyridyl)phenyl]propyl]-4H-1,2,4-oxadiazol-5-o-
ne, [0116]
3-[3-[4-(2-propylsulfanyl-3-pyridyl)phenyl]propyl]-4H-1,2,4-oxa-
diazol-5-thione, [0117]
5-[[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]methyl]isoxa-
zol-3-ol, [0118]
5-[[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)phenoxy]methyl]isoxazol-3--
ol, [0119]
5-[[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenoxy]methyl]-
isoxazol-3-ol, [0120]
5-[[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenoxy]methyl]isoxazol-
-3-ol, [0121]
5-[[2,6-difluoro-4-(2-isopropoxy-3-pyridyl)phenoxy]methyl]isoxazol-3-ol,
[0122]
5-[[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]methyl]i-
soxazol-3-ol, [0123]
5-[[2,6-difluoro-4-(6-isopropoxy-2-pyridyl)phenoxy]methyl]isoxazol-3-ol,
[0124]
5-[[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-phenoxy]meth-
yl]isoxazol-3-ol, [0125]
5-[[2,6-difluoro-4-(6-propoxy-2-pyridyl)phenoxy]methyl]isoxazol-3-ol,
[0126]
5-[[2,6-difluoro-4-(2-propoxy-3-pyridyl)phenoxy]methyl]isoxazol-3--
ol, [0127]
5-[(E)-3-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-pheny-
l]allyl]thiazolidin-2,4-dione, [0128]
5-[[4-[2-(cyclobutoxy)-3-pyridyl]-2,6-difluoro-phenoxy]methyl]isoxazol-3--
ol, [0129]
5-[[4-[2-(cyclobutylmethoxy)-3-pyridyl]-2,6-difluoro-phenoxy]me-
thyl]isoxazol-3-ol, [0130]
5-[[4-[2-(cyclopentoxy)-3-pyridyl]anilino]methyl]isoxazol-3-ol,
[0131]
5-[[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenoxy]methyl]pyridin-2--
ol, [0132]
4-[[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenoxy]methyl]-
pyridin-2-ol, [0133]
5-[[4-[2-(cyclopentoxy)-3-pyridyl]phenyl]sulfanylmethyl]isoxazol-3-ol,
[0134]
5-[(E)-3-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]allyl-
]-1,1-dioxo-1,2,5-thiadiazolidin-3-one, [0135]
5-[[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]sulfanylmethyl]iso-
xazol-3-ol, [0136]
5-[[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-anilino]methyl]isoxazol-3-
-ol, [0137]
5-[3-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]propyl]-1,1-diox-
o-1,2,5-thiadiazolidin-3-one, [0138]
5-[[4-[2-(cyclopentoxy)-3-pyridyl]-N-methyl-anilino]methyl]isoxazol-3-ol,
[0139]
5-[2-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]ethyl]iso-
xazol-3-ol, [0140]
5-[2-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]propyl]isoxazol--
3-ol, [0141]
5-[2-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenoxy]ethyl]isoxazol--
3-ol, [0142]
5-[2-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-anilino]ethyl]isoxazol--
3-ol, [0143]
2-[1-[5-(6-isopropylsulfanyl-2-pyridyl)-2-pyridyl]-3-piperidyl]acetic
acid, [0144]
4-[[5-(6-isopropylsulfanyl-2-pyridyl)-2-pyridyl]amino]butanoic
acid, [0145]
2-[1-[4-(2-cyclobutylsulfanyl-3-pyridyl)phenyl]pyrazol-4-yl]acetic
acid, [0146]
5-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-anilino]pentanoic
acid, [0147]
5-[4-[2-(cyclopentoxy)-3-pyridyl]-N-ethyl-2,6-difluoro-anilino]pen-
tanoic acid, [0148]
5-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)anilino]pentanoic
acid, [0149]
5-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)anilino]pentanoic
acid, [0150]
5-[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-anilino]pentanoic
acid, [0151]
5-[4-[2-(cyclopropylmethoxy)-3-pyridyl]-2,6-difluoro-anilino]pentanoic
acid, [0152]
2-[1-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]-4-piperidy-
l]acetic acid, [0153]
5-[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-N-methyl-anilino]pen-
tanoic acid, [0154]
2-[1-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]-4-piperidyl]ace-
tic acid, [0155]
2-[1-[2,6-difluoro-4-(2-tetrahydrofuran-3-yloxy-3-pyridyl)phenyl]-4-piper-
idyl]acetic acid, [0156]
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-4-piperidyl]a-
cetic acid, [0157]
2-[1-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]-4-piperidyl]a-
cetic acid, [0158]
2-[1-[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperid-
yl]acetic acid, [0159]
2-[1-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]-3-piperidyl]a-
cetic acid, [0160]
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-3-piperidyl]a-
cetic acid, [0161]
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]azetidin-3-yl]-
acetic acid, [0162]
6-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-6-azaspiro[2.5]o-
ctan-2-carboxylic acid, [0163]
6-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]-6-azaspiro[2.5]o-
ctan-2-carboxylic acid, [0164]
2-[1-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]azetidin-3--
yl]acetic acid, [0165]
2-[1-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]azetidin-3-yl]ac-
etic acid, [0166]
2-[1-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]azetidin-3-yl]-
acetic acid, [0167]
2-[1-[2,6-difluoro-4-(6-isopropoxy-2-pyridyl)phenyl]azetidin-3-yl]acetic
acid, [0168]
2-[1-[4-[6-(cyclopentoxy)-2-pyridyl]-2,6-difluoro-phenyl]azetidin-3-yl]ac-
etic acid, [0169]
2-[1-[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)phenyl]-4-piperidyl]acet-
ic acid, [0170]
2-[1-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]-4-piperidyl-
]acetic acid, [0171]
2-[1-[2,6-difluoro-4-(2-isopropoxy-3-pyridyl)phenyl]-4-piperidyl]acetic
acid, [0172]
2-[1-[2,6-difluoro-4-(2-propoxy-3-pyridyl)phenyl]-4-piperidyl]acetic
acid, [0173]
2-[1-[4-[2-(cyclopropylmethoxy)-3-pyridyl]-2,6-difluoro-phenyl]-4-piperid-
yl]acetic acid, [0174]
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]pyrazol-4-yl]a-
cetic acid, [0175]
2-[1-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]pyrazol-4-yl]a-
cetic acid, [0176]
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]pyrrolidin-3-y-
l]acetic acid, [0177]
2-[1-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]pyrrolidin-3-y-
l]acetic acid, [0178]
3-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-4-piperidyl]p-
ropanoic acid, [0179]
3-[1-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]-4-piperidyl]p-
ropanoic acid, [0180]
2-[2-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-anilino]ethyl]cycl-
opropane carboxylic acid, [0181]
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-3-piperidyl]a-
cetamide, [0182]
2-[4-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]piperazin-1-yl-
]acetic acid, [0183]
3-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]pyrazol-4-yl]p-
ropanoic acid, [0184]
4-[5-(2-cyclopentylsulfanyl-3-pyridyl)indolin-1-yl]butanoic acid,
[0185]
3-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]azetidin-3-yl]-
propanoic acid, [0186]
2-[(3R)-1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]pyrrolidi-
n-3-yl]acetic acid, [0187]
2-[(3R)-1-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]pyrrolidin--
3-yl]acetic acid, [0188]
2-[(3S)-1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]pyrrolidi-
n-3-yl]acetic acid, [0189]
2-[(3S)-1-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]pyrrolidin--
3-yl]acetic acid, [0190]
2-[1-[2-fluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-4-piperidyl]aceti-
c acid, [0191]
2-[1-[4-[2-(cyclopentoxy)-3-pyridyl]-2-fluoro-phenyl]-4-piperidyl]acetic
acid, [0192]
3-[6-(6-isopropylsulfanyl-pyridin-2-yl)-naphthalen-2-yl]-propanoic
acid, [0193]
3-[6-(6-phenoxy-pyridin-2-yl)-naphthalen-2-yl]-propanoic acid,
[0194] 3-[6-(2-phenoxy-phenyl)-naphthalen-2-yl]-propanoic acid,
[0195]
3-[6-(6-cyclopentylsulfanyl-pyridin-2-yl)-naphthalen-2-yl]-propanoic
acid, [0196]
3-[6-(2-phenoxy-pyridin-3-yl)-naphthalen-2-yl]-propanoic acid,
[0197] 3-[6-(3-phenoxy-phenyl)-naphthalen-2-yl]-propanoic acid,
[0198] 3-[6-(3-isopropoxy-phenyl)-naphthalen-2-yl]-propanoic acid,
[0199] 3-[6-(3-cyclobutoxy-phenyl)-naphthalen-2-yl]-propanoic acid,
[0200] 3-[6-(6-cyclobutoxy-pyridin-2-yl)-naphthalen-2-yl]-propanoic
acid, [0201]
3-[6-(2-isopropoxy-pyridin-3-yl)-naphthalen-2-yl]-propanoic acid,
[0202]
3-[6-(2-cyclopentyloxy-pyridin-3-yl)-naphthalen-2-yl]-propanoic
acid, [0203]
3-{6-[2-(2-fluoro-phenoxy)-phenyl]-naphthalen-2-yl}-propanoic acid,
[0204]
3-{6-[6-(2-fluoro-phenoxy)-pyridin-2-yl]-naphthalen-2-yl}-propanoic
acid, [0205]
4-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenylsulfa-
nyl]-butyric acid, [0206]
4-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-fluoro-phenylsulfanyl]-butyri-
c acid, [0207]
4-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-phenylsulfanyl]-butyric
acid, [0208]
4-(4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-ylphenyl)sulfanylbu-
tanoic acid, [0209]
4-(2-fluoro-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-phenyl)sulfany-
lbutanoic acid, [0210]
5-[4-(2-isopropoxy-pyridin-3-yl)-phenyl]-5-methyl-hexanoic acid,
[0211]
5-[4-(2-isopropylsulfanyl-pyridin-3-yl)-phenyl]-5-methyl-hexanoic
acid, [0212]
5-[4-(2-cyclopentyloxy-pyridin-3-yl)-phenyl]-5-methyl-hexanoic
acid, [0213]
5-[4-(2-cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenyl]-5-methyl-hexanoic
acid, [0214]
5-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenyl]-5-methyl-hexano-
ic acid, [0215]
5-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenyl]-5-methyl-hexanoic
acid, [0216]
5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-5-me-
thyl-hexanoic acid, [0217]
5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-phenyl]-5-methyl-hexanoic
acid, [0218]
4-{1-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenyl]-cyclo-
propyl}-butyric acid, [0219]
4-{1-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-cyclopro-
pyl}-butyric acid, [0220]
4-{1-[4-(6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-cyclopropyl}-bu-
tyric acid, [0221]
4-{1-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-cycloprop-
yl}-butyric acid, [0222]
4-{1-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-cyclopro-
pyl}-butyric acid, [0223]
5-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenyl]-hexanoic
acid, [0224]
{2-[4-(2-cyclopentyloxy-pyridin-3-yl)-phenyl]-2,2-difluoro-ethoxy}-acetic
acid, [0225]
{2-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-phenyl]-2,2-difluoro-ethoxy}-ac-
etic acid, [0226]
{2-[4-(6-cyclobutoxy-pyridin-2-yl)-phenyl]-2,2-difluoro-ethoxy}-acetic
acid, [0227]
3-{2-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenyl]-cyclopropyl}-
-propanoic acid, [0228]
3-{2-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-cyclopro-
pyl}-propanoic acid, [0229]
5-[4-(2-cyclopentyloxy-pyridin-3-yl)-phenyl]-5,5-difluoro-pentanoic
acid,
[0230]
5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-phenyl]-5,5-difluoro-pent-
anoic acid, [0231]
3-{2-[2,6-difluoro-4-(2-propylsulfanyl-pyridin-3-yl)-phenyl]-cyclopropyl}-
-propanoic acid, [0232]
3-{2-[4-(6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-cyclopropyl}-pr-
opanoic acid, [0233]
5-[4-(2-cyclopropylmethoxy-pyridin-3-yl)-phenyl]-5,5-difluoro-pentanoic
acid, [0234]
3-{2-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-cyclopr-
opyl}-propanoic acid, [0235]
3-{2-[4-(2-cyclopentylamino-pyridin-3-yl)-2,6-difluoro-phenyl]-cyclopropy-
l}-propanoic acid, [0236]
5-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenyl]-5,5-difluoro-pentanoic
acid, [0237]
5-[4-(2-cyclobutoxy-pyridin-3-yl)-phenyl]-5,5-difluoro-pentanoic
acid, [0238]
5-[4-(6-cyclobutoxy-pyridin-2-yl)-phenyl]-5,5-difluoro-pentanoic
acid, [0239]
{4-[4-(2-cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenyl]-cyclohexyl}-acetic
acid, [0240]
3-{2-[4-(2-cyclobutoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-cyclopropyl}-pr-
opanoic acid, [0241]
3-{2-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-cycloprop-
yl}-propanoic acid, [0242]
3-(2-{2,6-difluoro-4-[2-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-phenyl}--
cyclopropyl)-propanoic acid, [0243]
3-{2-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-cyclopro-
pyl}-propanoic acid, [0244]
5,5-difluoro-5-[4-(6-isopropylsulfanyl-pyridin-2-yl)-phenyl]-pentanoic
acid, [0245]
4-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-phenoxy]-butyric
acid, [0246]
4-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-2-fluoro-phenoxy]--
butyric acid, [0247]
4-{[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-methyl-ami-
no}-butyric acid, [0248]
4-{[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenyl]-methyl-amino}--
butyric acid, [0249]
4-{[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-methyl-am-
ino}-butyric acid, [0250]
4-{[2,6-difluoro-4-(2-isopropylsulfanyl-pyridin-3-yl)-phenyl]-methyl-amin-
o}-butyric acid, [0251]
4-[(3'-cyclobutoxy-3,5-difluoro-biphenyl-4-yl)-methyl-amino]-butyric
acid, [0252]
4-[5-(2-cyclopentylsulfanyl-pyridin-3-yl)-indol-1-yl]-butyric acid,
[0253]
4-[(3,5-difluoro-3'-pyrrolidin-1-yl-biphenyl-4-yl)-methyl-amino]-b-
utyric acid, [0254]
4-{[4-(6-cyclobutylsulfanyl-pyridin-2-yl)-2,6-difluoro-phenyl]-methyl-ami-
no}-butyric acid, [0255]
4-{[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenyl]-methyl-am-
ino}-butyric acid, [0256]
4-{[4-(6-cyclopentyloxy-pyridin-2-yl)-2,6-difluoro-phenyl]-methyl-amino}--
butyric acid, [0257]
4-{[4-(6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-methyl-amino}-but-
yric acid, [0258]
4-{[4-(2-cyclobutoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-methyl-amino}-but-
yric acid, [0259]
4-{[2,6-difluoro-4-(2-propylsulfanyl-pyridin-3-yl)-phenyl]-methyl-amino}--
butyric acid, [0260]
4-{[4-(2-ethylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-methyl-amino}-b-
utyric acid, [0261]
4-{[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2-fluoro-phenyl]-methyl-amino}--
butyric acid, [0262]
2-{[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylamino]-meth-
yl}-cyclopropane carboxylic acid, [0263]
2-{[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenylamino]-methyl}-cycloprop-
ane carboxylic acid, [0264]
4-{[2-fluoro-4-(2-isopropylsulfanyl-pyridin-3-yl)-phenyl]-methyl-amino}-b-
utyric acid, [0265]
4-{[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2-fluoro-phenyl]-methyl-amino}-
-butyric acid, [0266]
4-{[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenyl]-methyl-amino}-buty-
ric acid, [0267]
4-[(2'-cyclopentylamino-3,5-difluoro-biphenyl-4-yl)-methyl-amino]-butyric
acid, [0268]
4-[methyl-(3,5,5'-trifluoro-2'-isopropoxy-biphenyl-4-yl)-amino]-butyric
acid, [0269]
4-{[4-(2-cyclopentyloxy-5-methyl-pyridin-3-yl)-2,6-difluoro-phenyl]-methy-
l-amino}-butyric acid, [0270]
4-{[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-methyl-amin-
o}-butyric acid, [0271]
4-{[2,6-difluoro-4-(2-methoxy-pyridin-3-yl)-phenyl]-methyl-amino}-butyric
acid, [0272]
4-({2,6-difluoro-4-[2-(tetrahydro-furan-3-yloxy)-pyridin-3-yl]-phenyl}-me-
thyl-amino)-butyric acid, [0273]
4-[(3,5-difluoro-2'-pyrrolidin-1-yl-biphenyl-4-yl)-methyl-amino]-butyric
acid, [0274]
4-[(3,5-difluoro-2'-methylamino-biphenyl-4-yl)-methyl-amino]-butyric
acid, [0275]
4-{[3,5-difluoro-2'-(isopropyl-methyl-amino)-biphenyl-4-yl]-methyl-amino}-
-butyric acid, [0276]
4-{[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-ethyl-amin-
o}-butyric acid, [0277]
4-{[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-ethyl-amino-
}-butyric acid, [0278]
4-{[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenyl]-ethyl-amino}-butyr-
ic acid, [0279]
(R)-5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-hexanoi-
c acid, [0280]
(E)-(R)-5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-hex-
-2-enoic acid, [0281]
(S)-5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-hexanoi-
c acid, [0282]
5-{2,6-difluoro-4-[2-(tetrahydro-furan-3-yloxy)-pyridin-3-yl]-phenyl}-hex-
anoic acid, [0283]
5-{2,6-difluoro-4-[2-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-phenyl}-hex-
anoic acid, [0284]
5-{2,6-difluoro-4-[2-(oxetan-3-yloxy)-pyridin-3-yl]-phenyl}-hexanoic
acid, [0285]
4-[4-(2-cyclobutoxy-pyridin-3-yl)-2-fluoro-phenoxy]-butyric acid,
[0286]
4-[4-(2-cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenoxy]-butyric
acid, [0287]
4-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2-fluoro-phenoxy]-butyric
acid, [0288]
4-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2-fluoro-phenoxy]-butyric
acid, [0289]
6-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenyl]-heptanoi-
c acid, [0290]
6-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-heptanoic
acid, [0291]
4-[4-(2-cyclopropylmethoxy-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric
acid, [0292]
4-[4-(2-cyclopropylmethoxy-pyridin-3-yl)-2-fluoro-phenoxy]-butyric
acid, [0293]
4-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2-fluoro-phenoxy]-butyric
acid, [0294] 4-[3-(6-cyclopentyloxy-pyridin-2-yl)-phenoxy]-butyric
acid, [0295] 4-[3-(2-cyclopentyloxy-pyridin-3-yl)-phenoxy]-butyric
acid, [0296]
5-[4-(2-cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenyl]-pentanoic
acid, [0297]
5-[4-(2-cyclobutoxy-pyridin-3-yl)-2-fluoro-phenyl]-pentanoic acid,
[0298]
5-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2-fluoro-phenyl]-pentanoic
acid, [0299]
5-[4-(2-cyclopropylmethoxy-pyridin-3-yl)-2-fluoro-phenyl]-pentanoic
acid, [0300]
5-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2-fluoro-phenyl]-pentano-
ic acid, [0301]
5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2-fluoro-phenyl]-pentanoic
acid, [0302]
5-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-penta-
noic acid, [0303]
5-[4-(2-cyclobutoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-pentanoic
acid, [0304]
5-[4-(2-cyclopropylmethoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-pent-
anoic acid, [0305]
4-[4-(5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-2,6-difluoro-phe-
noxy]-butyric acid, [0306]
4-[4-(5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-2,6-difluoro-phe-
nylsulfanyl]-butyric acid, [0307]
4-{[4-(5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-2,6-difluoro-ph-
enyl]-methyl-amino}-butyric acid, [0308]
5-[4-(5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-2,6-difluoro-phe-
nyl]-hexanoic acid, [0309]
4-[2,6-difluoro-4-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-ph-
enoxy]-butyric acid, [0310]
4-[2,6-difluoro-4-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-ph-
enylsulfanyl]-butyric acid, [0311]
4-{[2,6-difluoro-4-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-p-
henyl]-methyl-amino}-butyric acid, [0312]
5-[2,6-difluoro-4-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl-phe-
nyl]-hexanoic acid, [0313]
4-(2,6-difluoro-4-spiro[3H-benzofuran-2,1'-cyclopentan]-7-yl-phenoxy)-but-
yric acid, [0314]
4-(2,6-difluoro-4-spiro[3H-benzofuran-2,1'-cyclopentan]-7-yl-phenylsulfan-
yl)-butyric acid, [0315]
4-(2,6-difluoro-N-methyl-4-spiro[3H-benzofuran-2,1'-cyclopentan]-7-yl-ani-
lino)-butyric acid, [0316]
5-(2,6-difluoro-4-spiro[3H-benzofuran-2,1'-cyclopentan]-7-yl-phenyl)-hexa-
noic acid, [0317]
7-[4-(3-carboxy-propoxy)-3,5-difluoro-phenyl]-5-fluoro-2,2-dimethyl-2,3-d-
ihydro-indol-1-carboxylic acid methyl ester, [0318]
4-[2,6-difluoro-4-(5-fluoro-2,2-dimethyl-2,3-dihydro-1H-indol-7-yl)-pheno-
xy]-butyric acid, [0319]
4-[4-(3-carboxy-propoxy)-3,5-difluoro-phenyl]-5-fluoro-2,2-dimethyl-2,3-d-
ihydro-indol-1-carboxylic acid methyl ester, [0320]
4-[2,6-difluoro-4-(5-fluoro-2,2-dimethyl-2,3-dihydro-1H-indol-4-yl)-pheno-
xy]-butyric acid, [0321]
4-[2,6-difluoro-4-(5-fluoro-2,2-dimethyl-2,3-dihydro-1H-indol-7-yl)-pheny-
lsulfanyl]-butyric acid, [0322]
3-[6-(2-isopropylsulfanyl-pyridin-3-yl)-thiochroman-2-yl]-propionic
acid, [0323]
3-[6-(2-cyclopentoxy-pyridin-3-yl)-thiochroman-2-yl]-propionic
acid, [0324]
3-[6-(2-cyclobutylsulfanyl-pyridin-3-yl)-chroman-2-yl]-propionic
acid, [0325]
3-[6-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-chroman--
2-yl]-propionic acid, [0326]
3-[6-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-thiochroman-2-y-
l]-propionic acid, [0327]
3-[6-(2-cyclobutylsulfanyl-pyridin-3-yl)-thiochroman-2-yl]-propionic
acid, [0328]
3-[6-(2-cyclopropylmethoxy-pyridin-3-yl)-chroman-2-yl]-propionic
acid, [0329]
3-[6-(2-cyclobutoxy-pyridin-3-yl)-chroman-2-yl]-propionic acid,
[0330]
3-[6-(2-cyclobutoxy-pyridin-3-yl)-thiochroman-2-yl]-propionic acid,
[0331]
3-[6-(2-cyclopropylmethoxy-pyridin-3-yl)-thiochroman-2-yl]-propionic
acid, [0332]
3-[6-(2-cyclopentylsulfanyl-pyridin-3-yl)-chroman-2-yl]-propionic
acid, [0333]
3-[6-(2-cyclopentylsulfanyl-pyridin-3-yl)-thiochroman-2-yl]-propio-
nic acid, [0334]
3-[6-(5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-thiochroman-2-yl-
]-propionic acid, [0335]
3-(6-spiro[3H-benzofuran-2,1'-cyclopentan]-7-yl-thiochroman-2-yl)-propion-
ic acid, [0336]
3-{6-[2-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-thiochroman-2-yl}-propio-
nic acid, [0337]
{1-[2,6-difluoro-4-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-p-
henyl]-azetidin-3-yl}-acetic acid, [0338]
3-[6-(6-isopropylsulfanyl-pyridin-2-yl)-thiochroman-2-yl]-propionic
acid, [0339]
4-(2,6-difluoro-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-phe-
noxy)butanoic acid, [0340]
4-(4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-ylphenoxy)butanoic
acid, [0341]
4-(2-fluoro-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-phenoxy-
)butanoic acid, [0342]
4-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenoxy]-butyric
acid, [0343]
4-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-2,6-difluoro-phenoxy]-but-
yric acid, [0344]
4-[4-(2-cyclohexylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric
acid, [0345]
3-[4-(2-cyclopentyloxy-pyridin-3-yl)-benzylsulfanyl]-propionic
acid, [0346]
2-[1-[4-[6-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperid-
yl]acetic acid, [0347]
2-[1-[2,6-difluoro-4-(6-propoxy-2-pyridyl)phenyl]-4-piperidyl]acetic
acid, [0348]
2-[1-[2,6-difluoro-4-(6-isopropoxy-2-pyridyl)phenyl]-4-piperidyl]acetic
acid, [0349]
2-[1-[4-(6-cyclobutylsulfanyl-2-pyridyl)-2,6-difluoro-phenyl]-4-piperidyl-
]acetic acid, [0350]
2-[1-[2,6-difluoro-4-(6-propylsulfanyl-2-pyridyl)phenyl]-4-piperidyl]acet-
ic acid, [0351]
2-[1-[4-[6-(cyclopentoxy)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperidyl]ace-
tic acid, [0352]
2-[1-[4-[3-(cyclobutoxy)phenyl]-2,6-difluoro-phenyl]-4-piperidyl]acetic
acid, [0353]
2-[1-[4-[3-(cyclopropylmethoxy)phenyl]-2,6-difluoro-phenyl]-4-piperidyl]a-
cetic acid, [0354]
2-[1-[2,6-difluoro-4-[3-(isopropoxymethyl)phenyl]phenyl]-4-piperidyl]acet-
ic acid, [0355]
2-[1-[4-[3-(ethoxymethyl)phenyl]-2,6-difluoro-phenyl]-4-piperidyl]acetic
acid, [0356]
2-[1-[4-[3-(cyclobutoxy)-4-fluoro-phenyl]-2,6-difluoro-phenyl]-4-piperidy-
l]acetic acid, [0357]
2-[1-[4-[3-(cyclobutoxy)-4-methoxy-phenyl]-2,6-difluoro-phenyl]-4-piperid-
yl]acetic acid, [0358]
2-[1-[4-[3-(cyclobutoxy)-5-fluoro-phenyl]-2,6-difluoro-phenyl]-4-piperidy-
l]acetic acid, [0359]
2-[1-[2-chloro-4-[6-(cyclopropylmethoxy)-2-pyridyl]-6-fluoro-phenyl]-4-pi-
peridyl]acetic acid, [0360]
2-[1-[4-[6-(cyclobutylmethoxy)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperidy-
l]acetic acid, [0361]
2-[1-[4-(6-tert-butoxy-2-pyridyl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
acid, [0362]
2-[1-[4-[3-(cyclobutoxy)-2-methyl-phenyl]-2,6-difluoro-phenyl]-4-piperidy-
l]acetic acid, [0363]
2-[1-[4-[5-chloro-6-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenyl]-4-piper-
idyl]acetic acid, [0364]
2-[1-[4-[6-(cyclopropanecarbonyl)-2-pyridyl]-2,6-difluoro-phenyl]-4-piper-
idyl]acetic acid, [0365]
2-[1-[4-[6-(cyclobutoxymethyl)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperidy-
l]acetic acid, [0366]
2-[1-[4-(6-ethoxy-2-pyridyl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
acid, [0367]
2-[1-[2,6-difluoro-4-[6-(2,2,2-trifluoroethoxy)-2-pyridyl]phenyl]-4-piper-
idyl]acetic acid, [0368]
2-[1-[2,6-difluoro-4-[6-(2,2,2-trifluoro-1-methyl-ethoxy)-2-pyridyl]pheny-
l]-4-piperidyl]acetic acid, [0369]
2-[1-[4-(6-cyclopentyl-2-pyridyl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
acid, [0370]
2-[1-[4-[6-[cyclopropyl(methoxy)methyl]-2-pyridyl]-2,6-difluoro-phenyl]-4-
-piperidyl]acetic acid, [0371]
2-[1-[2-chloro-4-[6-(cyclobutoxy)-2-pyridyl]-6-fluoro-phenyl]-4-piperidyl-
]acetic acid, [0372]
2-[1-[4-[6-(cyclobutoxy)-2-pyridyl]-2-fluoro-phenyl]-4-piperidyl]acetic
acid, [0373]
2-[1-[4-[6-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenyl]azetidin-3-yl]ace-
tic acid, [0374]
2-[1-[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-phenyl]azetidin-3-
-yl]acetic acid, [0375]
2-[1-[4-[4-(cyclobutoxy)-6-methyl-pyrimidin-2-yl]-2,6-difluoro-phenyl]-4--
piperidyl]acetic acid, [0376]
2-[1-[4-(6-butoxy-2-pyridyl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
acid, [0377]
2-[1-[4-[2-(cyclobutoxy)-6-methyl-pyrimidin-4-yl]-2,6-difluoro-phenyl]-4--
piperidyl]acetic acid, [0378]
2-[1-[4-[2-(cyclobutoxy)thiazol-4-yl]-2,6-difluoro-phenyl]-4-piperidyl]ac-
etic acid, [0379]
2-[1-[4-[6-(cyclobutoxy)-4-methyl-2-pyridyl]-2,6-difluoro-phenyl]-4-piper-
idyl]acetic acid, [0380]
2-[1-[4-[4-(cyclobutoxy)-6-methyl-pyrimidin-2-yl]-2,6-difluoro-phenyl]aze-
tidin-3-yl]acetic acid, [0381]
2-[1-[4-[6-(cyclobutoxy)pyrazin-2-yl]-2,6-difluoro-phenyl]-4-piperidyl]ac-
etic acid, [0382]
2-[1-[4-[4-(cyclobutoxy)pyrimidin-2-yl]-2,6-difluoro-phenyl]-4-piperidyl]-
acetic acid, [0383]
2-[1-[4-[4-(cyclopropylmethoxy)-6-methyl-pyrimidin-2-yl]-2,6-difluoro-phe-
nyl]-4-piperidyl]acetic acid, [0384]
2-[1-[4-[4-(cyclopropylmethoxy)pyrimidin-2-yl]-2,6-difluoro-phenyl]-4-pip-
eridyl]acetic acid, [0385]
2-[1-[4-[6-(cyclopropylmethoxy)pyrazin-2-yl]-2,6-difluoro-phenyl]-4-piper-
idyl]acetic acid, [0386]
2-[1-[4-[6-(cyclobutoxy)pyrazin-2-yl]-2,6-difluoro-phenyl]azetidin-3-yl]a-
cetic acid, [0387]
2-[1-[4-[6-(cyclopropylmethoxy)pyrazin-2-yl]-2,6-difluoro-phenyl]azetidin-
-3-yl]acetic acid, [0388]
2-[1-[4-[4-(cyclobutoxy)pyrimidin-2-yl]-2,6-difluoro-phenyl]azetidin-3-yl-
]acetic acid, [0389]
2-[1-[4-[4-(cyclopropylmethoxy)pyrimidin-2-yl]-2,6-difluoro-phenyl]azetid-
in-3-yl]acetic acid, [0390]
2-[1-[4-(6-ethoxypyrazin-2-yl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
acid, [0391]
2-[1-[2,6-difluoro-4-(6-isopropoxypyrazin-2-yl)phenyl]-4-piperidyl]acetic
acid, [0392]
2-[1-[2,6-difluoro-4-(6-methoxypyrazin-2-yl)phenyl]-4-piperidyl]acetic
acid, [0393]
2-[1-[2,6-difluoro-4-(6-propoxypyrazin-2-yl)phenyl]-4-piperidyl]acetic
acid, [0394]
2-[1-[2,6-difluoro-4-(6-isobutoxypyrazin-2-yl)phenyl]-4-piperidyl]acetic
acid,
[0395]
2-[1-[4-(6-butoxypyrazin-2-yl)-2,6-difluoro-phenyl]-4-piperidyl]ac-
etic acid, [0396]
2-[1-[4-[6-(cyclopentoxy)pyrazin-2-yl]-2,6-difluoro-phenyl]-4-piperidyl]a-
cetic acid, [0397]
2-[1-[4-(4-ethoxypyrimidin-2-yl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
acid, [0398]
2-[1-[2,6-difluoro-4-(4-isopropoxypyrimidin-2-yl)phenyl]-4-piperidyl]acet-
ic acid, [0399]
2-[1-[2,6-difluoro-4-(4-propoxypyrimidin-2-yl)phenyl]-4-piperidyl]acetic
acid, [0400]
2-[1-[2,6-difluoro-4-(4-isobutoxypyrimidin-2-yl)phenyl]-4-piperidyl]aceti-
c acid, [0401]
2-[1-[4-(4-ethoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenyl]-4-piperid-
yl]acetic acid, [0402]
2-[1-[2,6-difluoro-4-(4-isopropoxy-6-methyl-pyrimidin-2-yl)phenyl]-4-pipe-
ridyl]acetic acid, [0403]
2-[1-[2,6-difluoro-4-(4-methyl-6-propoxy-pyrimidin-2-yl)phenyl]-4-piperid-
yl]acetic acid, [0404]
2-[1-[2,6-difluoro-4-(4-isobutoxy-6-methyl-pyrimidin-2-yl)phenyl]-4-piper-
idyl]acetic acid, [0405]
2-[1-[2,6-difluoro-4-(6-pyrrolidin-1-ylpyrazin-2-yl)phenyl]-4-piperidyl]a-
cetic acid, [0406]
2-[1-[2,6-difluoro-4-[6-(isopropylamino)pyrazin-2-yl]phenyl]-4-piperidyl]-
acetic acid, [0407]
2-[1-[4-[6-(diethylamino)pyrazin-2-yl]-2,6-difluoro-phenyl]-4-piperidyl]a-
cetic acid, [0408]
2-[1-[2,6-difluoro-4-[6-(isobutylamino)pyrazin-2-yl]phenyl]-4-piperidyl]a-
cetic acid, [0409]
2-[1-[4-[6-(cyclopentylamino)pyrazin-2-yl]-2,6-difluoro-phenyl]-4-piperid-
yl]acetic acid, [0410]
2-[1-[4-[6-(cyclopentylamino)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperidyl-
]acetic acid, [0411]
2-[1-[4-[6-(dimethylamino)pyrazin-2-yl]-2,6-difluoro-phenyl]-4-piperidyl]-
acetic acid, [0412]
2-[1-[2,6-difluoro-4-[4-(isobutylamino)pyrimidin-2-yl]phenyl]-4-piperidyl-
]acetic acid, [0413]
2-[1-[4-[6-(cyclobutoxy)-5-methyl-pyrazin-2-yl]-2,6-difluoro-phenyl]-4-pi-
peridyl]acetic acid, [0414]
2-[1-[2,6-difluoro-4-(6-phenylpyrazin-2-yl)phenyl]-4-piperidyl]acetic
acid, [0415]
2-[1-[4-(6-cyclopentylpyrazin-2-yl)-2,6-difluoro-phenyl]-4-piperidyl]acet-
ic acid, [0416]
2-[1-[2,6-difluoro-4-(6-isobutylpyrazin-2-yl)phenyl]-4-piperidyl]acetic
acid, [0417]
2-[1-[2,6-difluoro-4-(4-isobutylpyrimidin-2-yl)phenyl]-4-piperidyl]acetic
acid, [0418]
2-[1-[4-[5-(cyclobutoxy)-3-methyl-isothiazol-4-yl]-2,6-difluoro-phenyl]-4-
-piperidyl]acetic acid, [0419]
{1-[4-(4-ethoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin-4-yl}acetic
acid, [0420]
{1-[4-(4-ethoxy-5-methyl-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin-4-y-
l}acetic acid, [0421]
2-[1-[4-(6-butylpyrazin-2-yl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
acid, [0422]
2-[1-[2,6-difluoro-4-(6-isopentylpyrazin-2-yl)phenyl]-4-piperidyl]acetic
acid, [0423]
2-[1-[4-[4-(cyclobutoxy)-5-fluoro-pyrimidin-2-yl]-2,6-difluoro-phenyl]-4--
piperidyl]acetic acid, [0424]
2-[1-[4-[4-(cyclopropylmethoxy)-5-fluoro-pyrimidin-2-yl]-2,6-difluoro-phe-
nyl]-4-piperidyl]acetic acid, [0425]
2-[1-[4-(6-cyclobutyl-2-pyridyl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
acid, [0426]
2-[1-[4-(6-cyclobutylpyrazin-2-yl)-2,6-difluoro-phenyl]-4-piperidyl]aceti-
c acid, [0427]
2-[1-[4-[6-(cyclobutylmethyl)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperidyl-
]acetic acid, [0428]
2-[1-[4-[6-(cyclopentylmethyl)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperidy-
l]acetic acid, [0429]
{1-[4-(4-cyclopropylmethoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin--
4-yl}acetic acid, [0430]
(1-{2,6-difluoro-4-[4-(4-fluoro-phenyl)-thiazol-2-yl]-phenyl}-piperidin-4-
-yl)-acetic acid, [0431]
{1-[4-(4-cyclobutoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin-4-yl}ac-
etic acid, [0432]
{1-[4-(4-butoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin-4-yl}acetic
acid, [0433]
2-(1-{2,6-difluoro-4-[7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]phe-
nyl}piperidin-4-yl)acetic acid, [0434]
2-[1-[4-(6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,6-difluoro-phenyl]-
-4-piperidyl]acetic acid, [0435]
2-[1-[4-[4-(cyclobutoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]-2,6--
difluoro-phenyl]-4-piperidyl]acetic acid, [0436]
2-[1-[4-[4-(cyclobutoxy)-5,6-dimethyl-pyrimidin-2-yl]-2,6-difluoro-phenyl-
]-4-piperidyl]acetic acid, [0437]
4-[2-chloro-4-[6-(cyclobutoxy)-2-pyridyl]-6-fluoro-phenoxy]butanoic
acid, [0438]
4-[2,6-dichloro-4-[6-(cyclobutoxy)-2-pyridyl]phenoxy]butanoic acid,
[0439]
4-[4-[3-(cyclopropylmethoxymethyl)-2-furyl]-2,6-difluoro-phenoxy]butanoic
acid, [0440]
4-[4-[6-(cyclopropylmethoxymethyl)-2-pyridyl]-2,6-difluoro-phenoxy]butano-
ic acid, [0441]
4-[2-chloro-4-[3-(cyclobutoxy)-5-fluoro-phenyl]-6-fluoro-phenoxy]butanoic
acid, [0442]
4-[4-[3-(cyclopropylmethoxymethyl)-5-methyl-isoxazol-4-yl]-2,6-difluoro-p-
henoxy]butanoic acid, [0443]
4-[2-chloro-4-[4-(cyclobutoxy)-6-methyl-pyrimidin-2-yl]-6-fluoro-phenoxy]-
butanoic acid, [0444]
4-[2-chloro-4-[2-(cyclobutoxy)-6-methyl-pyrimidin-4-yl]-6-fluoro-phenoxy]-
butanoic acid, [0445]
4-[4-[6-chloro-4-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenoxy]butanoic
acid, [0446]
4-[4-[2-(cyclobutoxy)thiazol-4-yl]-2,6-difluoro-phenoxy]butanoic
acid, [0447]
4-[4-[6-(cyclobutoxy)-4-methyl-2-pyridyl]-2,6-difluoro-phenoxy]but-
anoic acid, [0448]
4-[2-chloro-4-[4-(cyclopropylmethoxy)-6-methyl-pyrimidin-2-yl]-6-fluoro-p-
henoxy]butanoic acid, [0449]
4-[4-[2-(cyclopropylmethoxy)thiazol-4-yl]-2,6-difluoro-phenoxy]butanoic
acid, [0450]
4-[4-[6-(cyclobutoxy)pyrazin-2-yl]-2,6-difluoro-phenoxy]butanoic
acid, [0451]
5-[4-[6-(cyclobutoxy)pyrazin-2-yl]-2,6-difluoro-phenyl]hexanoic
acid, [0452]
4-[2-chloro-4-(6-cyclopentyloxy-pyridin-2-yl)-6-fluoro-phenoxy]-butyric
acid, [0453]
4-[2-chloro-4-(6-cyclopropylmethoxy-pyridin-2-yl)-6-fluoro-phenoxy]-butyr-
ic acid, [0454]
4-[2-chloro-6-fluoro-4-(6-isopropoxy-pyridin-2-yl)-phenoxy]-butyric
acid, [0455]
4-[2-chloro-4-(6-cyclobutylsulfanyl-pyridin-2-yl)-6-fluoro-phenoxy-
]-butyric acid, [0456]
4-[2-chloro-6-fluoro-4-(6-isopropylsulfanyl-pyridin-2-yl)-phenoxy]-butyri-
c acid, [0457]
4-(5-chloro-3'-cyclobutoxy-3-fluoro-biphenyl-4-yloxy)-butyric acid,
[0458]
4-(5-chloro-3'-cyclopropylmethoxy-3-fluoro-biphenyl-4-yloxy)-butyr-
ic acid, [0459]
4-(5-chloro-3'-cyclopropylmethoxy-3-fluoro-4'-methoxy-biphenyl-4-yloxy)-b-
utyric acid, [0460]
4-(5-chloro-3'-cyclopropylmethoxy-3,4'-difluoro-biphenyl-4-yloxy)-butyric
acid, [0461]
4-(3'-cyclobutylsulfanyl-3,5-difluoro-biphenyl-4-yloxy)-butyric
acid, [0462] 5-(3'-cyclobutoxy-3,5-difluoro-biphenyl-4-yl)-hexanoic
acid, [0463]
5-(5'-cyclobutoxy-3,5,3'-trifluoro-biphenyl-4-yl)-hexanoic acid,
[0464]
5-(3'-cyclopropylmethoxy-3,5-difluoro-4'-methoxy-biphenyl-4-yl)-he-
xanoic acid, [0465]
5-(3'-cyclopropylmethoxy-3,5-difluoro-biphenyl-4-yl)-hexanoic acid,
[0466]
5-(5'-cyclobutoxy-3'-fluoro-biphenyl-4-yl)-5,5-difluoro-pentanoic
acid, [0467]
5-[4-(5-chloro-6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-hexanoic
acid, [0468]
4-(3'-cyclobutanesulfonyl-3,5-difluoro-biphenyl-4-yloxy)-butyric
acid, [0469]
5-({[4-(6-cyclobutoxy-pyridin-2-yl)-phenyl]-methyl-amino}-methyl)--
isoxazol-3-ol, [0470]
5-[4-(2-cyclobutoxy-6-methyl-pyrimidin-4-yl)-2,6-difluoro-phenyl]-hexanoi-
c acid, [0471]
5-[4-(4-cyclobutoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenyl]-hexanoi-
c acid, [0472]
4-[4-(4-cyclobutoxy-pyrimidin-2-yl)-2,6-difluoro-phenoxy]-butyric
acid, [0473]
4-[4-(2-cyclobutoxy-pyrimidin-4-yl)-2,6-difluoro-phenoxy]-butyric
acid, [0474]
4-[2-chloro-4-(4-cyclobutoxy-pyrimidin-2-yl)-6-fluoro-phenoxy]-butyric
acid, [0475]
4-[2-chloro-4-(2-cyclobutoxy-pyrimidin-4-yl)-6-fluoro-phenoxy]-butyric
acid, [0476]
4-[2-chloro-4-(6-chloro-4-cyclobutoxy-pyridin-2-yl)-6-fluoro-phenoxy]-but-
yric acid, [0477]
4-[4-(4-cyclobutoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenoxy]-butyri-
c acid, [0478]
4-[2-chloro-4-(2-cyclobutoxy-thiazol-4-yl)-6-fluoro-phenoxy]-butyric
acid, [0479]
4-[2-chloro-4-(2-cyclopropylmethoxy-thiazol-4-yl)-6-fluoro-phenoxy]-butyr-
ic acid, [0480]
4-[2-chloro-4-(4-cyclopropylmethoxy-pyrimidin-2-yl)-6-fluoro-phenoxy]-but-
yric acid, [0481]
4-[2-chloro-4-(6-cyclobutoxy-4-methyl-pyridin-2-yl)-6-fluoro-phenoxy]-but-
yric acid, [0482]
4-[2-chloro-4-(6-cyclobutoxy-pyrazin-2-yl)-6-fluoro-phenoxy]-butyric
acid, [0483]
4-[2-chloro-4-(6-cyclopropylmethoxy-pyrazin-2-yl)-6-fluoro-phenoxy]-butyr-
ic acid, [0484]
4-[4-(4-cyclopropylmethoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenoxy]-
-butyric acid, [0485]
4-[4-(4-cyclopropylmethoxy-pyrimidin-2-yl)-2,6-difluoro-phenoxy]-butyric
acid, [0486]
4-[4-(6-cyclopropylmethoxy-pyrazin-2-yl)-2,6-difluoro-phenoxy]-butyric
acid, [0487]
4-[2-chloro-4-(6-cyclopropylmethoxy-4-methyl-pyridin-2-yl)-6-fluoro-pheno-
xy]-butyric acid, [0488]
4-[2-chloro-6-fluoro-4-(6-isopropoxy-pyrazin-2-yl)-phenoxy]-butyric
acid, [0489]
4-[2-chloro-4-(6-ethoxy-pyrazin-2-yl)-6-fluoro-phenoxy]-butyric
acid, [0490]
{(R)-1-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrol-
idin-3-yl}-acetic acid, [0491]
{1-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenyl]-piperidin-
-4-yl}-acetic acid, [0492]
3-[8-fluoro-6-(2-isopropylsulfanyl-3-pyridyl)thiochroman-2-yl]propanoic
acid, [0493]
3-[6-[6-(cyclobutoxy)-2-pyridyl]thiochroman-2-yl]propanoic acid,
[0494]
3-[2-[2,6-difluoro-4-(7-methoxy-2,2-dimethyl-3H-benzofuran-4-yl)phenyl]cy-
clopropyl]propanoic acid, [0495]
3-[2-(2,6-difluoro-4-spiro[3H-benzofuran-2,1'-cyclopentan]-7-yl-phenyl)cy-
clopropyl]propanoic acid, [0496]
3-[6-[6-(cyclobutoxy)-2-pyridyl]chroman-2-yl]propanoic acid, [0497]
3-[6-[6-(cyclopropylmethoxy)-2-pyridyl]chroman-2-yl]propanoic acid,
[0498] 4-[4-(2,3-dimethoxyphenyl)-2,6-difluoro-phenoxy]butanoic
acid, [0499]
3-[6-[3-(cyclopropylmethoxy)phenyl]chroman-2-yl]propanoic acid,
[0500] 3-[6-[3-(cyclopentoxy)phenyl]chroman-2-yl]propanoic acid,
[0501]
4-(2,6-difluoro-N-methyl-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-a-
nilino)butanoic acid, [0502]
5-(2,6-difluoro-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-phenyl)hex-
anoic acid, [0503]
3-[6-(6-tert-butylsulfanyl-2-pyridyl)chroman-2-yl]propanoic acid,
[0504] 3-[6-(6-isopropoxy-2-pyridyl)chroman-2-yl]propanoic acid,
[0505]
2-[1-(2,6-difluoro-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-phenyl)-
-4-piperidyl]acetic acid, [0506]
4-[4-(2,3-dipropoxyphenyl)-2,6-difluoro-phenoxy]butanoic acid,
[0507]
4-[4-[6-(cyclobutoxy)-5-methoxy-2-pyridyl]-2,6-difluoro-phenoxy]butanoic
acid, [0508]
4-[4-[6-(cyclobutoxy)-5-methoxy-2-pyridyl]-2,6-difluoro-N-methyl-anilino]-
butanoic acid, [0509]
2-[1-[4-[6-(cyclobutoxy)-5-methoxy-2-pyridyl]-2,6-difluoro-phenyl]-4-pipe-
ridyl]acetic acid, [0510]
2-[1-[4-(2,3-dipropoxyphenyl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
acid, [0511]
4-[4-[6-(cyclopropylmethoxy)-5-methoxy-2-pyridyl]-2,6-difluoro-phenoxy]bu-
tanoic acid, [0512]
4-[4-(2,3-dipropoxyphenyl)-2,6-difluoro-N-methyl-anilino]butanoic
acid, [0513]
4-[4-[6-(cyclopropylmethoxy)-5-methoxy-2-pyridyl]-2,6-difluoro-N-m-
ethyl-anilino]butanoic acid, [0514]
2-[1-[4-[6-(cyclopropylmethoxy)-5-methoxy-2-pyridyl]-2,6-difluoro-phenyl]-
-4-piperidyl]acetic acid, [0515]
4-[4-(6-chloroindol-1-yl)-2,6-difluoro-phenoxy]butanoic acid,
[0516]
5-[4-[6-(cyclobutoxy)-5-methoxy-2-pyridyl]phenyl]-5,5-difluoro-pentanoic
acid, [0517] 4-[2,6-difluoro-4-(5-fluoroindol-1-yl)phenoxy]butanoic
acid, [0518]
4-[4-[3-(cyclopropylmethylamino)phenyl]-2,6-difluoro-N-methyl-anil-
ino]butanoic acid, [0519]
4-[2,6-difluoro-N-methyl-4-(6-pyrrolidin-1-yl-2-pyridyl)anilino]butanoic
acid, [0520]
4-[2,6-difluoro-4-(5-methoxyindol-1-yl)phenoxy]butanoic acid,
[0521] 4-[4-(5-cyanoindol-1-yl)-2,6-difluoro-phenoxy]butanoic acid,
[0522]
4-[4-[3-(cyclopropylmethoxymethyl)-2-furyl]-2,6-difluoro-N-methyl--
anilino]butanoic acid, [0523]
4-[2,6-difluoro-4-(4-fluoroindol-1-yl)phenoxy]butanoic acid, [0524]
4-[4-(7-chloroindol-1-yl)-2,6-difluoro-phenoxy]butanoic acid,
[0525]
4-[4-[5-(cyclopropylmethoxymethyl)-2-furyl]-2,6-difluoro-N-methyl-anilino-
]butanoic acid, [0526]
4-[4-[6-(cyclopropylmethoxy)indol-1-yl]-2,6-difluoro-phenoxy]butanoic
acid, [0527]
4-[4-(7-chloroindol-1-yl)-2,6-difluoro-N-methyl-anilino]butanoic
acid, [0528]
4-[4-[6-(cyclobutoxy)indol-1-yl]-2,6-difluoro-phenoxy]butanoic
acid, [0529]
4-[4-[5-(cyclobutoxy)indol-1-yl]-2,6-difluoro-phenoxy]butanoic
acid, [0530]
4-[2,6-difluoro-4-(4-methoxyindol-1-yl)phenoxy]butanoic acid,
[0531] 4-[2,6-difluoro-4-(7-methoxyindol-1-yl)phenoxy]butanoic
acid, [0532]
4-[2,6-difluoro-4-[5-(methoxymethyl)indazol-1-yl]phenoxy]butanoic
acid, [0533]
2-[1-[4-(7-chloroindol-1-yl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
acid, [0534]
4-[4-[6-(cyclobutoxy)indazol-1-yl]-2,6-difluoro-phenoxy]butanoic
acid, [0535]
4-[2-chloro-4-[6-(cyclobutoxy)indazol-1-yl]-6-fluoro-phenoxy]butan-
oic acid, [0536]
4-[4-[4-(cyclobutoxy)-6-methyl-pyrimidin-2-yl]-2,6-difluoro-N-methyl-anil-
ino]butanoic acid, [0537]
4-[4-[4-(cyclobutoxy)pyrimidin-2-yl]-2,6-difluoro-N-methyl-anilino]butano-
ic acid, [0538]
4-[4-[2-(cyclobutoxy)thiazol-4-yl]-2,6-difluoro-N-methyl-anilino]butanoic
acid, [0539]
2-[1-[4-[6-(cyclobutoxy)indazol-1-yl]-2,6-difluoro-phenyl]-4-piperidyl]ac-
etic acid, [0540]
4-[4-[6-(cyclobutoxy)pyrazin-2-yl]-2,6-difluoro-N-methyl-anilino]butanoic
acid, [0541]
4-[4-[4-(cyclopropylmethoxy)-6-methyl-pyrimidin-2-yl]-2,6-difluoro-N-meth-
yl-anilino]butanoic acid, [0542]
4-[4-[4-(cyclopropylmethoxy)pyrimidin-2-yl]-2,6-difluoro-N-methyl-anilino-
]butanoic acid, [0543]
4-[4-[6-(cyclopropylmethoxy)pyrazin-2-yl]-2,6-difluoro-N-methyl-anilino]b-
utanoic acid, [0544]
4-[4-[6-(cyclobutoxy)indazol-1-yl]-2,6-difluoro-N-methyl-anilino]butanoic
acid, [0545]
4-[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-N-methyl-anilino]but-
anoic acid, [0546]
2-[1-[4-[6-(cyclobutoxy)indazol-1-yl]-2,6-difluoro-phenyl]pyrrolidin-3-yl-
]acetic acid, [0547]
2-{1-[2,6-difluoro-4-(6-propoxy-pyrazin-2-yl)phenyl]pyrrolidin-3-yl}aceti-
c acid, [0548]
2-{1-[2,6-difluoro-4-(6-isobutoxy-pyrazin-2-yl)phenyl]pyrrolidin-3-yl}ace-
tic acid, [0549]
2-{1-[2,6-difluoro-4-(6-cyclopentoxy-pyrazin-2-yl)phenyl]pyrrolidin-3-yl}-
acetic acid, [0550]
2-{1-[2,6-difluoro-4-(6-butoxy-pyrazin-2-yl)phenyl]pyrrolidin-3-yl}acetic
acid, [0551]
2-{1-[2,6-difluoro-4-(4-propoxy-pyrimidin-2-yl)phenyl]pyrrolidin-3-yl}ace-
tic acid, [0552]
2-{1-[2,6-difluoro-4-(4-isopropoxy-pyrimidin-2-yl)phenyl]pyrrolidin-3-yl}-
acetic acid, [0553]
2-{1-[2,6-difluoro-4-(4-ethoxy-pyrimidin-2-yl)phenyl]pyrrolidin-3-yl}acet-
ic acid, [0554]
2-{1-[2,6-difluoro-4-(4-isobutoxy-pyrimidin-2-yl)phenyl]pyrrolidin-3-yl}a-
cetic acid, [0555]
2-{1-[2,6-difluoro-4-(6-isobutylamino-pyrazin-2-yl)phenyl]pyrrolidin-3-yl-
}acetic acid, [0556]
2-{1-[2,6-difluoro-4-(6-cyclopentylamino-pyrazin-2-yl)phenyl]pyrrolidin-3-
-yl}acetic acid, [0557]
2-{1-[2,6-difluoro-4-(6-isopropylamino-pyrazin-2-yl)phenyl]pyrrolidin-3-y-
l}acetic acid, [0558]
2-{1-[2,6-difluoro-4-(6-diethylamino-pyrazin-2-yl)phenyl]pyrrolidin-3-yl}-
acetic acid, [0559]
3-[6-(6-cyclobutoxy-pyrazin-2-yl)-thiochroman-2-yl]-propionic acid,
[0560]
2-[1-[4-[4-(4-chlorophenoxy)pyrimidin-2-yl]-2,6-difluoro-phenyl]-4-
-piperidyl]acetic acid, [0561]
2-[1-[4-[4-(4-chlorophenoxy)pyrimidin-2-yl]-2,6-difluoro-phenyl]-pyrrolid-
in-3-yl]acetic acid, [0562]
2-[1-[4-[4-phenoxy-pyrimidin-2-yl]-2,6-difluoro-phenyl]-4-piperidyl]aceti-
c acid, [0563]
2-[1-[4-[4-(4-fluorophenoxy)pyrimidin-2-yl]-2,6-difluoro-phenyl]-4-piperi-
dyl]acetic acid, [0564]
2-[1-[4-[4-(4-pyridin-3-yloxy-pyrimidin-2-yl]-2,6-difluoro-phenyl]-4-pipe-
ridyl]acetic acid, [0565]
2-[1-[2,6-difluoro-4-[6-(4-fluorophenoxy)pyrazin-2-yl]phenyl]-4-piperidyl-
]acetic acid,
[0566]
2-[1-[4-[4-(4-methoxyphenoxy)pyrimidin-2-yl]-2,6-difluoro-phenyl]--
4-piperidyl]acetic acid, [0567]
2-[1-[2,6-difluoro-4-[4-(4-fluorophenoxy)-6-methyl-pyrimidin-2-yl]phenyl]-
-4-piperidyl]acetic acid, [0568]
2-[1-[4-[4-(p-tolyloxy)pyrimidin-2-yl]-2,6-difluoro-phenyl]-4-piperidyl]a-
cetic acid, [0569]
2-[1-[4-[4-(3,4-difluorophenoxy)pyrimidin-2-yl]-2,6-difluoro-phenyl]-4-pi-
peridyl]acetic acid, [0570]
4-[4-(5-chloro-2-methyl-benzofuran-7-yl)-2,6-difluoro-phenoxy]-butyric
acid, [0571]
5-[4-(5-chloro-2-methyl-benzofuran-7-yl)-2,6-difluoro-phenyl]-hexanoic
acid, [0572]
4-[(3'-cyclobutylmethoxy-3,5-difluoro-biphenyl-4-yl)-methyl-amino]-butyri-
c acid, [0573]
4-(3'-cyclobutylmethoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric
acid, [0574]
4-{[4-(6-cyclobutylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-meth-
yl-amino}-butyric acid, [0575]
4-[4-(6-cyclobutylmethoxy-pyridin-2-yl)-2,6-difluoro-phenoxy]-butyric
acid, [0576]
4-[(3'-cyclopropylmethoxy-3,5-difluoro-biphenyl-4-yl)-methyl-amino]-butyr-
ic acid, [0577]
4-[(3'-cyclopentyloxy-3,5-difluoro-biphenyl-4-yl)-methyl-amino]-butyric
acid, [0578]
4-(3'-cyclopropylmethoxy-3,5-difluoro-4'-methoxy-biphenyl-4-yloxy)-butyri-
c acid, [0579]
4-(3'-cyclopropylmethoxy-3,5,4'-trifluoro-biphenyl-4-yloxy)-butyric
acid, [0580]
4-(5'-cyclobutoxy-3,5,3'-trifluoro-biphenyl-4-yloxy)-butyric acid,
[0581]
4-[(5'-cyclobutylmethoxy-3,5-difluoro-2'-methyl-biphenyl-4-yl)-met-
hyl-amino]-butyric acid, [0582]
4-(5'-cyclobutylmethoxy-3,5-difluoro-2'-methyl-biphenyl-4-yloxy)-butyric
acid, [0583]
4-{[4-(5-chloro-6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-methyl-a-
mino}-butyric acid, [0584]
4-(3'-cyclopropylmethoxy-3,5-difluoro-4'-methyl-biphenyl-4-yloxy)-butyric
acid, [0585]
4-[4-(5-chloro-6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenoxy]-butyric
acid, [0586]
4-(4'-chloro-3'-cyclopropylmethoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric
acid, [0587]
5-(5'-cyclobutoxy-3,3'-difluoro-biphenyl-4-yl)-pentanoic acid,
[0588] 4-(5'-cyclobutoxy-3,3'-difluoro-biphenyl-4-yloxy)-butyric
acid, [0589]
5-[4-(6-cyclobutoxy-pyridin-2-yl)-2-fluoro-phenyl]-pentanoic acid,
[0590] 4-[4-(6-cyclobutoxy-pyridin-2-yl)-2-fluoro-phenoxy]-butyric
acid, [0591]
4-[4-(6-cyclobutylmethoxy-pyridin-2-yl)-2-fluoro-phenoxy]-butyric
acid, [0592]
4-[4-(6-cyclobutylsulfanyl-pyridin-2-yl)-2-fluoro-phenoxy]-butyric
acid, [0593]
2-(3'-cyclobutoxy-3,5,5'-trifluoro-biphenyl-4-yloxymethyl)-cyclopropane
carboxylic acid, [0594]
2-[4-(4-cyclobutoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenoxymethyl]--
cyclopropane carboxylic acid, [0595]
2-[4-(4-cyclobutoxy-pyrimidin-2-yl)-2,6-difluoro-phenoxymethyl]-cycloprop-
ane carboxylic acid, [0596]
2-[4-(6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenoxymethyl]-cyclopropan-
e carboxylic acid, [0597]
2-[4-(4-cyclopropylmethoxy-pyrimidin-2-yl)-2,6-difluoro-phenoxymethyl]-cy-
clopropane carboxylic acid, [0598]
2-[4-(4-cyclopropylmethoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenoxym-
ethyl]-cyclopropane carboxylic acid, [0599]
2-[4-(6-cyclopropylmethoxy-pyrazin-2-yl)-2,6-difluoro-phenoxymethyl]-cycl-
opropane carboxylic acid, [0600]
2-[4-(6-cyclobutoxy-4-methyl-pyridin-2-yl)-2,6-difluoro-phenoxymethyl]-cy-
clopropane carboxylic acid, [0601]
2-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenoxymethyl]-cycl-
opropane carboxylic acid, [0602]
2-[4-(6-cyclobutoxy-pyrazin-2-yl)-2,6-difluoro-phenoxymethyl]-cyclopropan-
e carboxylic acid, [0603]
2-[4-(2-cyclobutoxy-thiazol-4-yl)-2,6-difluoro-phenoxymethyl]-cyclopropan-
e carboxylic acid, [0604]
2-[2-chloro-4-(6-cyclopropylmethoxy-pyridin-2-yl)-6-fluoro-phenoxymethyl]-
-cyclopropane carboxylic acid, [0605]
2-[2-chloro-4-(4-cyclobutoxy-6-methyl-pyrimidin-2-yl)-6-fluoro-phenoxymet-
hyl]-cyclopropane carboxylic acid, [0606]
2-[2-chloro-4-(6-cyclobutoxy-pyridin-2-yl)-6-fluoro-phenoxymethyl]-cyclop-
ropane carboxylic acid, [0607]
3-[6-(3-cyclobutoxy-phenyl)-chroman-2-yl]-propionic acid, [0608]
3-[6-(6-propoxy-pyridin-2-yl)-chroman-2-yl]-propionic acid, [0609]
4-[2,6-difluoro-4-(1H-indol-6-yl)-phenoxy]-butanoic acid, [0610]
4-[2,6-difluoro-4-(1-isopropyl-1H-indol-6-yl)-phenoxy]-butanoic
acid, [0611]
4-[4-(1-cyclopropylmethyl-1H-indol-6-yl)-2,6-difluoro-phenoxy]-but-
anoic acid [0612]
{1-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-
-3-yl}-acetic acid, [0613]
{1-[4-(6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-3-yl}--
acetic acid, [0614]
4-[4-(3-chloro-1-isopropyl-1H-indol-6-yl)-2,6-difluoro-phenoxy]-butanoic
acid, [0615]
{1-[2,6-difluoro-4-(6-isopropoxy-pyridin-2-yl)-phenyl]-pyrrolidin-3-yl}-a-
cetic acid, [0616]
{1-[4-(6-cyclobutylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin--
3-yl}-acetic acid, [0617]
4-[4-(5-cyclopropylmethoxymethyl-thiophen-2-yl)-2,6-difluoro-phenoxy]-but-
anoic acid, [0618]
4-[4-(5-cyclopropylmethoxymethyl-thiophen-3-yl)-2,6-difluoro-phenoxy]-but-
anoic acid, [0619]
{1-[4-(5-cyclopropylmethoxymethyl-thiophen-3-yl)-2,6-difluoro-phenyl]-pip-
eridin-4-yl}-acetic acid, [0620]
4-[4-(4-cyclopropylmethoxymethyl-2-methyl-thiazol-5-yl)-2,6-difluoro-phen-
oxy]-butanoic acid, [0621]
{1-[4-(5-cyclomethoxymethyl-thiophen-2-yl)-2,6-difluoro-phenyl]-piperidin-
-4-yl}-acetic acid, [0622]
{1-[4-(4-cyclopropylmethoxymethyl-2-methyl-thiazol-5-yl)-2,6-difluoro-phe-
nyl]-piperidin-4-yl}-acetic acid, [0623]
4-[4-(5-cyclobutylmethoxymethyl-thiophen-3-yl)-2,6-difluoro-phenoxy]-buta-
noic acid, [0624]
4-[2,6-difluoro-4-(5-isobutoxymethyl-thiophen-3-yl)-phenoxy]-butanoic
acid, [0625]
4-[4-(5-cyclobutoxymethyl-thiophen-3-yl)-2,6-difluoro-phenoxy]-butanoic
acid, [0626]
4-[4-(3-cyclopropylmethoxymethyl-thiophen-2-yl)-2,6-difluoro-phenoxy]-but-
anoic acid, [0627]
{1-[4-(4-cyclobutoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenyl]-pyrrol-
idin-3-yl}-acetic acid, [0628]
{1-[4-(4-cyclopropylmethoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenyl]-
-pyrrolidin-3-yl}-acetic acid, [0629]
{1-[4-(6-cyclobutoxy-4-methyl-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrolid-
in-3-yl}-acetic acid, [0630]
{1-[4-(6-cyclobutoxy-pyrazin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-3-yl}--
acetic acid, [0631]
{1-[4-(4-cyclobutoxy-pyrimidin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-3-yl-
}-acetic acid, [0632]
{1-[4-(6-cyclopropylmethoxy-pyrazin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-
-3-yl}-acetic acid, [0633]
{1-[4-(4-cyclopropylmethoxy-pyrimidin-2-yl)-2,6-difluoro-phenyl]-pyrrolid-
in-3-yl}-acetic acid, [0634]
{1-[4-(2-cyclobutoxy-thiazol-4-yl)-2,6-difluoro-phenyl]-pyrrolidin-3-yl}--
acetic acid, [0635]
{1-[4-(2-cyclopropylmethoxy-thiazol-4-yl)-2,6-difluoro-phenyl]-pyrrolidin-
-3-yl}-acetic acid, [0636]
{1-[2,6-difluoro-4-(6-methoxy-pyrazin-2-yl)-phenyl]-pyrrolidin-3-yl}-acet-
ic acid, [0637]
{1-[4-(6-ethoxy-pyrazin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-3-yl}-aceti-
c acid, [0638]
{1-[2,6-difluoro-4-(6-isopropoxy-pyrazin-2-yl)-phenyl]-pyrrolidin-3-yl}-a-
cetic acid, [0639]
{1-[2,6-difluoro-4-(4-isopropoxy-6-methyl-pyrimidin-2-yl)-phenyl]-pyrroli-
din-3-yl}-acetic acid, [0640]
{1-[2,6-difluoro-4-(4-isobutoxy-6-methyl-pyrimidin-2-yl)-phenyl]-pyrrolid-
in-3-yl}-acetic acid, [0641]
{1-[2,6-difluoro-4-(4-methyl-6-propoxy-pyrimidin-2-yl)-phenyl]-pyrrolidin-
-3-yl}-acetic acid, [0642]
{1-[4-(4-ethoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin--
3-yl}-acetic acid, [0643]
{1-[4-(5-cyclobutoxy-3-methyl-isothiazol-4-yl)-2,6-difluoro-phenyl]-pyrro-
lidin-3-yl}-acetic acid, [0644]
{1-[4-(4-cyclobutoxy-5-fluoro-pyrimidin-2-yl)-2,6-difluoro-phenyl]-pyrrol-
idin-3-yl}-acetic acid, [0645]
{1-[4-(4-cyclopropylmethoxy-5-fluoro-pyrimidin-2-yl)-2,6-difluoro-phenyl]-
-pyrrolidin-3-yl}-acetic acid, [0646]
{1-[2,6-difluoro-4-(5-fluoro-4-isobutoxy-pyrimidin-2-yl)-phenyl]-pyrrolid-
in-3-yl}-acetic acid, [0647]
(1-{2,6-difluoro-4-[6-(3-methoxy-propoxy)-pyridin-2-yl]-phenyl}-pyrrolidi-
n-3-yl)-acetic acid, [0648]
(1-{2,6-difluoro-4-[6-(tetrahydro-thiopyran-4-yloxy-pyridin-2-yl]-phenyl}-
-pyrrolidin-3-yl)-acetic acid, [0649]
{1-[2,6-difluoro-4-(5-fluoro-4-isobutoxy-pyrimidin-2-yl)-phenyl]-piperidi-
n-4-yl}-acetic acid, [0650]
{1-[2,6-difluoro-4-(5-fluoro-4-propoxy-pyrimidin-2-yl)-phenyl]-piperidin--
4-yl}-acetic acid, [0651]
(1-{2,6-difluoro-4-[4-(3-methyl-butoxy)-pyrimidin-2-yl]-phenyl}-piperidin-
-4-yl)-acetic acid, [0652]
(1-{2,6-difluoro-4-[4-(3-methoxy-propoxy)-pyrimidin-2-yl]-phenyl}-piperid-
in-4-yl)-acetic acid, [0653]
(1-{2,6-difluoro-4-[4-(3-methoxy-propoxy)-6-methyl-pyrimidin-2-yl]-phenyl-
}-piperidin-4-yl)-acetic acid, [0654]
(1-{2,6-difluoro-4-[4-(2-methoxy-ethoxy)-6-methyl-pyrimidin-2-yl]-phenyl}-
-piperidin-4-yl)-acetic acid, [0655]
(1-{2,6-difluoro-4-[6-(3-methoxy-propoxy)-pyridin-2-yl]-phenyl}-piperidin-
-4-yl)-acetic acid, [0656]
{(S)-1-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrol-
idin-3-yl}-acetic acid, [0657]
2-[1-[2,6-difluoro-4-[4-[(6-methyl-3-pyridyl)oxy]pyrimidin-2-yl]phenyl]-4-
-piperidyl]acetic acid, [0658]
2-[1-[2,6-difluoro-4-[6-(4-ethylphenoxy)pyrimidin-2-yl]phenyl]-4-piperidy-
l]acetic acid, [0659]
2-[1-[4-[4-(3-fluorophenoxy)pyrimidin-2-yl]-2,6-difluoro-phenyl]-4-piperi-
dyl]acetic acid, [0660]
2-[1-[2,6-difluoro-4-[4-(3,4-fluorophenoxy)-6-methyl-pyrimidin-2-yl]pheny-
l]-4-piperidyl]acetic acid, [0661]
2-[1-[2,6-difluoro-4-[4-(2-pyridyloxy)pyrimidin-2-yl]phenyl]-4-piperidyl]-
acetic acid, [0662]
2-[1-[2,6-difluoro-4-[4-[4-(trifluoromethyl)phenoxy]pyrimidin-2-yl]phenyl-
]-4-piperidyl]acetic acid, [0663]
2-[1-[2,6-difluoro-4-[4-[3-(trifluoromethyl)phenoxy]pyrimidin-2-yl]phenyl-
]-4-piperidyl]acetic acid, [0664]
2-[1-[2,6-difluoro-4-[4-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-2--
yl]phenyl]-4-piperidyl]acetic acid, [0665]
2-[1-[2,6-difluoro-4-[4-methyl-6-[3-(trifluoromethyl)phenoxy]pyrimidin-2--
yl]phenyl]-4-piperidyl]acetic acid, [0666]
{1-[4-(6-cyclobutoxy-4-trifluoromethyl-pyridin-2-yl)-2,6-difluoro-phenyl]-
-piperidin-4-yl}-acetic acid, [0667]
(1-{2,6-difluoro-4-[2-(4-fluoro-phenyl)-benzo[b]thiophen-4-yl]-phenyl}-pi-
peridin-4-yl)-acetic acid, [0668]
{1-[2,6-difluoro-4-(2-m-tolyl-benzo[b]thiophen-4-yl)-phenyl]-piperidin-4--
yl}-acetic acid, [0669]
{1-[4-(4-cyclobutoxy-6-trifluoromethyl-pyrimidin-2-yl)-2,6-difluoro-pheny-
l]-piperidin-4-yl}-acetic acid, [0670]
{1-[2,6-difluoro-4-(4-propoxy-6-trifluoromethyl-pyrimidin-2-yl)-phenyl]-p-
iperidin-4-yl}-acetic acid, [0671]
(1-{2,6-difluoro-4-[4-(4-fluoro-phenoxy)-6-trifluoromethyl-pyrimidin-2-yl-
]-phenyl}-piperidin-4-yl)-acetic acid, [0672]
3-{1-[2,6-difluoro-4-(6-propoxy-pyridin-2-yl)-phenyl]-piperidin-4-yl}-pro-
pionic acid, [0673]
3-{1-[4-(6-cyclobutyl-pyridin-2-yl)-2,6-difluoro-phenyl]-piperidin-4-yl}--
propionic acid, and [0674]
3-{1-[4-(6-ethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-piperidin-4-yl}-prop-
ionic acid.
[0675] The terms and abbreviations used herein retain their
original meanings unless indicated otherwise.
[0676] The present invention also provides a method for preparing
the compound of Formula 1. Hereinafter, the method for preparing
the compound of Formula 1 is explained based on exemplary reactions
in order to illustrate the present invention. However, a person
skilled in the art could prepare the compound of Formula 1 by
various methods based on the structure of Formula 1, and such
methods should be interpreted as being within the scope of the
present invention. That is, the compound of Formula 1 may be
prepared by the methods described herein or by combining various
methods disclosed in the prior art, which should be interpreted as
being within the scope of the present invention. Accordingly, a
method for preparing the compound of Formula 1 is not limited to
the following methods.
[0677] As represented in the following Reaction Scheme 1, the
compound of Formula 1 according to the present invention can be
prepared by C--C coupling reaction of Compound 2 and Compound 3 in
the presence of a conventional metal catalyst, and, if necessary,
additional hydrolysis.
##STR00002##
[0678] In addition, the compound of Formula 1 according to the
present invention can be prepared by coupling reaction of Compound
4 and Compound 5, Compound 6 or Compound 7 in the presence of
conventional base or coupling reagents and, if necessary,
additional hydrolysis, as represented in the following Reaction
Scheme 2. In the Reaction Scheme 2, Z--R.sub.7 and J of Compounds 4
and 7 represent independently halogen, OH, SH or O-alkyl. When
Z--R.sub.7 is O-alkyl, it is converted to OH by dealkylation
reaction before being subjected to coupling reaction.
##STR00003##
[0679] Furthermore, the compound of Formula 1 according to the
present invention can be prepared by reacting Compound 8
substituted with J radical with Compound 9 or Compound 10 in the
presence of conventional base, metal catalysts or coupling
reagents, as represented in the following Reaction Scheme 3. In
Reaction Scheme 3, J and Y represent independently halogen, OH, SH
or NH.sub.2. When J is amine, "reductive-amination reaction" can be
carried out with Compound 11.
##STR00004##
[0680] In Reaction Scheme 1, Compound 2 can be obtained by the
coupling reaction of Compound 12 and Compound 13 in the presence of
conventional acid, base or coupling reagent, as represented in the
following Reaction Scheme 4.
##STR00005##
[0681] In addition, Compound 2 can be prepared by the coupling
reaction of Compound 14 and Compound 10 in the presence of
conventional base and metal catalyst, as represented in the
following Reaction Scheme 5.
##STR00006##
[0682] Furthermore, Compound 2 in which R.sub.1 and R.sub.2 form a
ring with D and E can be prepared in the presence of conventional
acid, as represented in the following Reaction Scheme 6.
##STR00007##
[0683] Meanwhile, Compound 3 can be prepared by the coupling
reaction of Compound 16 and Compound 17 in the presence of
conventional base or coupling reagent, as represented in the
following Reaction Scheme 7.
##STR00008##
[0684] In the above Reaction Schemes 1 to 7,
[0685] X represents halogen or --OSO.sub.2CF.sub.3,
[0686] Y represents boronic acid or boronic acid ester, and
[0687] A, B, D, E, G, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7,
m, n and p are the same as in the above Formula 1.
[0688] In the above reaction, transition metal such as palladium
(Pd) can be used as a conventional metal catalyst. The above
reactions can be carried out in conventional solvents which do not
have an adverse effect on the reactions. Preferable solvents
include, but are not limited to, one or more selected from
dimethylformamide, dimethylacetamide, tetrahydrofuran,
acetonitrile, methanol, ethanol, water, 1,2-dichloroethane,
dimethylsulfoxide, ethylether, methyl tert-butylether, methylene
chloride and chloroform.
[0689] In the above reactions, unexplained compounds are known
compounds or compounds easily obtainable from known compounds by
known methods or similar methods.
[0690] The compound of Formula 1 obtained by the above methods can
be separated or purified from the reaction products by conventional
methods such as recrystallization, ionospheresis, silica gel column
chromatography or ion-exchange chromatography.
[0691] As explained above, the compounds according to the present
invention, starting materials or intermediates for the preparation
thereof can be prepared by a variety of methods, which should be
interpreted as being within the scope of the present invention.
[0692] The compound of Formula 1 according to the present invention
has the effect of GPR120 agonist. Accordingly, the present
invention provides a pharmaceutical composition as a GPR120 agonist
comprising the compound of Formula 1, a pharmaceutically acceptable
salt or isomer thereof as an active ingredient. Various kinds of
prodrugs, which are converted into the compound of Formula I in
vivo, are also within the scope of the present invention.
[0693] Exemplary diseases which can be prevented or treated by the
pharmaceutical composition according to the present invention as a
GPR120 agonist include, but are not limited to, metabolic diseases
such as diabetes, complications of diabetes, obesity, non-alcoholic
fatty liver, steatohepatitis, osteoporosis and the like, and
inflammation. The complications of diabetes include, but are not
limited to, neurogenic disease, hyperlipidemia, hypertension,
retinosis and renal failure.
[0694] In addition, the present invention provides a method for
preparing the composition for preventing or treating metabolic
diseases such as diabetes, complications of diabetes, obesity,
non-alcoholic fatty liver, steatohepatitis, osteoporosis and the
like, and inflammation which comprises the step of mixing the
compound of Formula 1, a pharmaceutically acceptable salt or isomer
thereof as an active ingredient and a pharmaceutically acceptable
carrier.
[0695] In the present invention, a "pharmaceutical composition" or
a "composition for lowering blood glucose level" may include other
components such as carriers, diluents, excipients, etc., in
addition to the active ingredient of the present invention.
Accordingly, the pharmaceutical composition may include
pharmaceutically acceptable carriers, diluents, excipients or
combinations thereof, if necessary. The pharmaceutical composition
facilitates the administration of compounds into the body. Various
methods for administering the compounds include, but are not
limited to, oral, injection, aerosol, parenteral and local
administration.
[0696] Herein, a "carrier" means a compound that facilitates the
addition of compounds into the cell or tissue. For example,
dimethylsulfoxide (DMSO) is a conventional carrier facilitating the
administration of many organic compounds into living cells or
tissues.
[0697] Herein, a "diluent" means a compound that not only
stabilizes a biologically active form but is diluted in solvent
dissolving the compounds. A dissolved salt in buffer is used as a
diluent in this field. A conventionally used buffer is a phosphate
buffer saline mimicking salt form in body fluid. Since a buffer
solution can control the pH of the solution at low concentration, a
buffer diluent hardly modifies the biological activity of
compounds.
[0698] Herein, "pharmaceutically acceptable" means such property
that does not impair the biological activity and physical property
of compounds.
[0699] The compounds according to the present invention can be
formulated as various pharmaceutically administered dosage forms.
In the preparation of the pharmaceutical composition of the present
invention, an active component-specifically, the compound of
Formula 1 or a pharmaceutically acceptable salt or isomer
thereof--is mixed with selected pharmaceutically acceptable
carriers considering the dosage form to be prepared. For example,
the pharmaceutical composition of the present invention can be
formulated as injections, oral preparations and the like, as
needed.
[0700] The compound of the present invention can be formulated by
conventional methods using known pharmaceutical carriers and
excipients, and inserted into a unit or multi-unit containers. The
formulations may be solution, suspension or emulsion in oil or
aqueous solvent and include conventional dispersing agents,
suspending agents or stabilizing agents. In addition, the compound
may be, for example, dry powder form which is dissolved in
sterilized pyrogen-free water before use. The compound of the
present invention can be formulated into suppositories by using a
conventional suppository base such as cocoa butter or other
glycerides. Solid forms for oral administration include capsules,
tablets, pills, powders and granules. Capsules and tablets are
preferred. Tablets and pills are preferably enteric-coated. Solid
forms are manufactured by mixing the compounds of the present
invention with at least one carrier selected from inert diluents
such as sucrose, lactose or starch, lubricants such as magnesium
stearate, disintegrating agents, binders and the like.
[0701] The compound or a pharmaceutical composition comprising the
same according to the present invention can be administered in
combination with other drugs--for example, other antidiabetics--as
required.
[0702] The dose of the compound of Formula 1 according to the
present invention is determined by a physician's prescription
considering the patient's body weight, age and disease condition. A
typical dose for adults is in the range of about 0.3 to 500 mg per
day according to the frequency and intensity of administration. A
typical daily dose of intramuscular or intravenous administration
for adults is in the range of about 1 to 300 mg per day which can
be administered in divided unit dosages. Some patients need a
higher daily dose.
[0703] The present invention also provides a method for preventing
or treating diseases by using an effective amount of the compound
of Formula 1 or a pharmaceutically acceptable salt or isomer
thereof as an active ingredient of GPR120 agonist. Representative
diseases to be treated by GPR120 agonist include, but are not
limited to, metabolic diseases such as the above-mentioned
diabetes, complications of diabetes, obesity, non-alcoholic fatty
liver, steatohepatitis and osteoporosis, and inflammatory diseases.
Herein, the term "treatment" is used to mean deterring, delaying or
ameliorating the progress of diseases in a subject exhibiting
symptoms of diseases. The term "prevention" is used to mean
deterring, delaying or ameliorating the sign of diseases in a
subject at risk of exhibiting symptoms of diseases, even if he or
she does not exhibit the symptoms.
Effects of the Invention
[0704] The biaryl derivative of Formula 1 according to the present
invention as a GPR120 agonist promotes GLP-1 formation in the
gastrointestinal tract and improve insulin resistance in the liver
or in muscle due to anti-inflammatory action in macrophages,
lipocytes, etc., and can accordingly be effectively used for
preventing or treating metabolic diseases such as diabetes,
complications of diabetes, obesity, non-alcoholic fatty liver,
steatohepatitis, osteoporosis and the like, and inflammatory
diseases.
MODES FOR THE INVENTION
[0705] The present invention is explained in more detail by the
following Examples. However, these Examples seek to illustrate the
present invention only, and the scope of the present invention is
not limited by them.
[0706] Hereinafter, M means molar concentration and N means normal
concentration. In addition, abbreviations used in the following
Preparation Examples and Examples are as follows:
[0707] AcCl: acetyl chloride
[0708] AcOH: acetic acid
[0709] BBr.sub.3: boron tribromide
[0710] BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
[0711] Br.sub.2: bromine
[0712] Bu.sub.4NI: tetrabutylammonium iodide
[0713] CSA: camphosulfonic acid
[0714] CH.sub.3CN: acetonitrile
[0715] Cs.sub.2CO.sub.3: cesium carbonate
[0716] DBU: 1,8-diazabicyclo[5.4.0]undec7-ene
[0717] DCE: 1,2-dichloroethane
[0718] DCM: dichloromethane
[0719] DIBAL-H: diisobutylaluminum hydride
[0720] DIPEA: N,N-diisopropylethylamine
[0721] DME: 1,2-dimethoxyethane
[0722] DMF: N,N-dimethylformamide
[0723] DMS: dimethyl sulfide
[0724] DMSO: dimethyl sulfoxide
[0725] DPPF: 1,1'-bis(diphenylphosphino)ferrocene
[0726] EtOAc: ethyl acetate
[0727] EtOH: ethanol
[0728] Et.sub.2O: diethyl ether
[0729] Fe(acac).sub.3: iron(III)acetylacetonate
[0730] HCl: hydrochloric acid
[0731] Hex: n-hexane
[0732] IBX: 2-iodoxybenzoic acid
[0733] K.sub.2CO.sub.3: potassium carbonate
[0734] KOAc: potassium acetate
[0735] LAH: lithium aluminum hydride
[0736] LiHMDS: bis(trimethylsilyl)amide lithium
[0737] MC: methylene chloride
[0738] mCPBA: 3-chloroperbenzoic acid
[0739] MeOH: methanol
[0740] MgSO.sub.4: magnesium sulfate
[0741] MsCl: methanesulfonyl chloride
[0742] MTBE: tert-butyl methyl ether
[0743] NaBH.sub.4: sodium borohydride
[0744] NaCl: sodium chloride
[0745] Na.sub.2CO.sub.3: sodium carbonate
[0746] NaH: sodium hydride
[0747] NaOAc: sodium acetate
[0748] NaOEt: sodium ethoxide
[0749] NaOH: sodium hydroxide
[0750] NBS: N-bromosuccinimide
[0751] n-BuLi: butyl lithium
[0752] NCS: N-chlorosuccinimide
[0753] NMM: 4-methylmorpholine
[0754] NMP: 1-methylpyrrolidin-2-one
[0755] Pd/C: palladium/carbon
[0756] PdCl.sub.2(dppf)-DCM:
1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride
dichloromethane
[0757] PdCl.sub.2(PPh.sub.3).sub.2:
bis(triphenylphosphine)palladium(II) dichloride
[0758] Pd.sub.2(dba).sub.3:
tris(dibenzylideneacetone)dipalladium(O)
[0759] Pd(OAc).sub.2: palladium(II) acetate
[0760] Pd(PPh.sub.3).sub.4:
tetrakis(triphenylphosphine)palladium(0)
[0761] PtO.sub.2: platinum(IV)oxide
[0762] SOCl.sub.2: thionyl chloride
[0763] SPhos: 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl
[0764] TBAB: tetrabutylammonium bromide
[0765] TEA: triethylamine
[0766] TFA: trifluoroacetic acid
[0767] THF: tetrahydrofuran
[0768] TMEDA: N,N,N',N'-tetramethylethylenediamine
[0769] TMSCl: chlorotrimethylsilane
Preparation Example 1:
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinolin-2-yl]-propio-
nic Acid Ethyl Ester
Step A: 6-bromo-2-methyl-quinoline
[0770] 4-Bromo-phenylamine (3.0 g, 17.44 mmol) was dissolved in 30
mL of 6N HCl. Crotonaldehyde (2.44 g, 34.88 mmol) was slowly added
thereto, and the reaction mixture was stirred at 100.degree. C. for
16 hours. The mixture was cooled to 0.degree. C., neutralized with
aqueous ammonia, extracted with EtOAc and purified by column
chromatography to obtain the title compound (2 g, 52%).
[0771] .sup.1H-NMR (CDCl.sub.3) .delta. 8.02-7.92 (2H, m), 7.89
(1H, d), 7.73 (1H, d), 7.32 (1H, d), 1.60 (3H, s)
Step B: 6-bromo-quinolin-2-carbaldehyde
[0772] 6-Bromo-2-methyl-quinoline (1.0 g, 4.50 mmol) obtained in
Step A was dissolved in 1,4-dioxane. Selenium dioxide (0.65 g, 5.85
mmol) was added thereto, and the reaction mixture was stirred at
80.degree. C. for 3 hours. The mixture was filtered through Celite
and solidified with Et.sub.2O to obtain the title compound (0.93 g,
88%).
[0773] .sup.1H-NMR (CDCl.sub.3) .delta. 10.20 (1H, s), 8.22 (1H,
d), 8.15-8.02 (3H, m), 7.90 (1H, d)
Step C: (E)-3-(6-bromo-quinolin-2-yl)-acrylic Acid Ethyl Ester
[0774] 6-Bromo-quinolin-2-carbaldehyde (0.93 g, 3.95 mmol) obtained
in Step B was dissolved in THF. NaH (60%)(0.17 g, 4.35 mmol) was
slowly added thereto at 0.degree. C., and the reaction mixture was
stirred for 30 minutes. Triethyl phosphonoacetate (0.97 g, 4.35
mmol) was added dropwise, and the reaction mixture was stirred at
room temperature for 16 hours. The reaction solution was extracted
with EtOAc and purified by column chromatography to obtain the
title compound (0.86 g, 72%).
[0775] .sup.1H-NMR (CDCl.sub.3) .delta. 8.10 (1H, d), 8.00-7.92
(2H, m), 7.82-7.70 (2H, m), 7.63 (1H, d), 6.97 (1H, d), 4.30 (2H,
q), 1.36 (3H, t)
Step D:
(E)-3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinolin-2-
-yl]-acrylic Acid Ethyl Ester
[0776] (E)-3-(6-bromo-quinolin-2-yl)-acrylic acid ethyl ester (0.86
g, 2.82 mmol) obtained in Step C, bis(pinacolato)diboron (0.86 g,
3.39 mmol), potassium acetate (0.83 g, 8.47 mmol) and DPPF (0.11 g,
0.2 mmol) were dissolved in 10 mL of 1,4-dioxane and charged with
N.sub.2 gas for 5 minutes. PdCl.sub.2(dppf)-DCM (0.16 g, 0.2 mmol)
was added thereto, and the reaction mixture was stirred at
80.degree. C. for 4 hours. The reaction solution was filtered
through Celite and purified by column chromatography to obtain the
title compound (0.84 g, 86%).
[0777] .sup.1H-NMR (CDCl.sub.3) .delta. 8.31 (1H, s), 8.20 (1H, d),
8.10-8.05 (2H, m), 7.89 (1H, d), 7.60 (1H, d), 6.98 (1H, d), 4.30
(2H, q), 1.35 (12H, s), 1.25 (3H, t)
Step E:
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinolin-2-yl]-
-propionic Acid Ethyl Ester
[0778]
(E)-3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinolin-2--
yl]-acrylic acid ethyl ester (0.83 g, 2.35 mmol) obtained in Step D
was dissolved in MeOH. 10% Pd/C (0.08 g) was added thereto, and the
reaction mixture was stirred at room temperature for 2 hours under
hydrogen atmosphere. After termination of the reaction, the mixture
was filtered through Celite and concentrated under reduced pressure
to obtain the title compound (0.83 g, 99%).
[0779] .sup.1H-NMR (CDCl.sub.3) .delta. 8.29 (1H, s), 8.10-7.90
(3H, m), 7.33 (1H, d), 4.17 (2H, q), 3.32 (2H, t), 2.94 (2H, t),
1.39 (12H, s), 1.25 (3H, t)
Preparation Example 2:
[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yloxy]-ace-
tic Acid Ethyl Ester
Step A: (6-bromo-naphthalen-2-yloxy)-acetic Acid Ethyl Ester
[0780] 6-Bromo-naphthalen-2-ol (1.0 g, 4.48 mmol) was dissolved in
20 mL of DMF and cooled to 0.degree. C. Cs.sub.2CO.sub.3 (1.75 g,
5.38 mmol) and bromoacetic acid ethyl ester (0.75 g, 4.48 mmol)
were added thereto, and the mixture was stirred at room temperature
for 16 hours. Water was added to the reaction solution, and the
solution was extracted with EtOAc to separate an organic layer. The
organic layer was dried with MgSO.sub.4 and purified by column
chromatography to obtain the title compound (1.3 g, 94%).
[0781] .sup.1H-NMR (CDCl.sub.3) .delta. 7.93 (1H, s), 7.70 (1H, d),
7.60 (1H, d), 7.50 (1H, d), 7.24 (1H, d), 7.04 (1H, s), 4.72 (2H,
s), 4.29 (2H, q), 1.29 (3H, t)
Step B:
[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-ylo-
xy]-acetic Acid Ethyl Ester
[0782] (6-Bromo-naphthalen-2-yloxy)-acetic acid ethyl ester (0.5 g,
1.62 mmol) obtained in Step A was reacted in the same manner as in
Step D of Preparation Example 1 to obtain the title compound (0.48
g, 83%).
[0783] .sup.1H-NMR (CDCl.sub.3) .delta. 8.29 (1H, s), 7.80 (2H, d),
7.68 (1H, d), 7.21 (1H, d), 7.06 (1H, s), 4.74 (2H, s), 4.31 (2H,
q), 1.38 (12H, s), 1.29 (3H, t)
Preparation Example 3:
4-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yloxy]-b-
utyric Acid Ethyl Ester
Step A: 4-(6-bromo-naphthalen-2-yloxy)-butyric Acid Ethyl Ester
[0784] 6-Bromo-naphthalen-2-ol (1.0 g, 4.48 mmol) and
4-bromo-butyric acid ethyl ester (0.87 g, 4.48 mmol) were reacted
in the same manner as in Step A of Preparation Example 2 to obtain
the title compound (1.5 g, 94%).
[0785] .sup.1H-NMR (CDCl.sub.3) .delta. 7.91 (1H, s), 7.65 (1H, d),
7.57 (1H, d), 7.48 (1H, d), 7.15 (1H, d), 7.08 (1H, s), 4.20-4.10
(4H, m), 2.55 (2H, t), 2.18 (2H, t), 1.25 (3H, t)
Step B:
4-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-y-
loxy]-butyric Acid Ethyl Ester
[0786] 4-(6-Bromo-naphthalen-2-yloxy)-butyric acid ethyl ester (1
g, 2.96 mmol) obtained in Step A were reacted in the same manner as
in Step D of Preparation Example 1 to obtain the title compound
(0.8 g, 70%).
[0787] .sup.1H-NMR (CDCl.sub.3) .delta. 8.27 (1H, s), 7.78-7.75
(2H, m), 7.69 (1H, d), 7.12-7.08 (2H, m), 4.18-4.10 (4H, m), 2.55
(2H, t), 2.18 (2H, t), 1.33 (12H, s), 1.25 (3H, t)
Preparation Example 4:
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-chroman-2-yl]-propion-
ic Acid Ethyl Ester
Step A: chroman-2-carboxylic Acid
[0788] 4-Oxo-4H-chromene-2-carboxylic acid (4.0 g, 21.03 mmol) was
dissolved in 20 mL of acetic acid. 10% Pd/C (0.4 g) was added
thereto and stirred at room temperature for 16 hours under 60 psi
of hydrogen. The reaction solution was filtered through Celite,
diluted with EtOAc, and extracted with sodium bicarbonate aqueous
solution. The water layer was again acidified with 6N HCl and
extracted with EtOAc. The organic layer was dried with MgSO.sub.4
and concentrated under reduced pressure to obtain the title
compound (3.0 g, 80%).
[0789] .sup.1H-NMR (CDCl.sub.3) .delta. 7.13 (1H, t), 7.05 (1H, d),
6.95-6.85 (2H, m), 4.75 (1H, m), 3.00-2.80 (2H, m), 2.40 (1H, m),
2.20 (1H, m)
Step B: Chroman-2-yl-methanol
[0790] Chroman-2-carboxylic acid (1.0 g, 5.61 mmol) obtained in
Step A was dissolved in 20 mL of THF and cooled to -20.degree. C.
Isobutyl chloroformate (0.84 g, 6.17 mmol) and NMM (0.65 g, 6.45
mmol) were added thereto and the mixture was stirred at the same
temperature for 1 hour. NaBH.sub.4 (0.42 g, 11.22 mmol) was
dissolved in THF at another reactor and cooled to -78.degree. C.
The above reaction solution was filtered through Celite, added to
another reactor, and the mixture was stirred at room temperature
for 2 hours. The reaction solution was extracted with EtOAc, dried
with MgSO.sub.4 and purified by column chromatography to obtain the
title compound (0.8 g, 87%).
[0791] .sup.1H-NMR (CDCl.sub.3) .delta. 7.15-7.05 (2H, m),
6.90-6.80 (2H, m), 4.15 (1H, m), 3.85-3.70 (2H, m), 2.95-2.75 (2H,
m), 2.10-1.80 (3H, m)
Step C: (E)-3-chroman-2-yl-acrylic Acid Ethyl Ester
[0792] Oxalyl chloride (1.16 g, 9.13 mmol) was added to 30 mL of
DCM and cooled to -78.degree. C. DMSO (1.19 g, 15.22 mmol) was
slowly added thereto and stirred for 0.5 hour. The solution in
which chroman-2-yl-methanol (1.0 g, 6.09 mmol) obtained in Step B
was dissolved in 5 mL of DCM and TEA (2.46 g, 24.36 mmol) were
sequentially and slowly added. The mixture was stirred at room
temperature for 1 hour, and
(carbethoxymethylene)triphenylphosphorane (2.54 g, 7.30 mmol) was
then added thereto and the reaction of the mixture was carried out
at room temperature for 16 hours. Water was added to the reaction
solution, and this solution was extracted with DCM to separate an
organic layer. The organic layer was dried with MgSO.sub.4 and
purified by column chromatography to obtain the title compound
(1.47 g, 69%).
[0793] .sup.1H-NMR (CDCl.sub.3) .delta. 7.20-7.00 (3H, m),
6.90-6.80 (2H, m), 6.18 (1H, m), 4.75 (1H, m), 4.24 (2H, q),
2.95-2.70 (2H, m), 2.15 (1H, m), 1.85 (1H, m), 1.26 (3H, t)
Step D: 3-chroman-2-yl-propionic Acid Ethyl Ester
[0794] (E)-3-chroman-2-yl-acrylic acid ethyl ester (0.53 g, 2.28
mmol) obtained in Step C was dissolved in MeOH. 10% Pd/C (0.05 g)
was added thereto, and the reaction mixture was stirred at room
temperature for 16 hours under hydrogen atmosphere. After
termination of the reaction, the mixture was filtered through
Celite and concentrated under reduced pressure to obtain the title
compound (0.51 g, 96%).
[0795] .sup.1H-NMR (CDCl.sub.3) .delta. 7.12-7.00 (2H, m),
6.84-6.77 (2H, m), 4.16 (2H, q), 4.01 (1H, m), 2.90-2.70 (2H, m),
2.68-2.51 (2H, m), 2.05-1.95 (3H, m), 1.75 (1H, m), 1.22 (3H,
t)
Step E: 3-(6-bromo-chroman-2-yl)-propionic Acid Ethyl Ester
[0796] 3-Chroman-2-yl-propionic acid ethyl ester (0.2 g, 0.85 mmol)
obtained in Step D was dissolved in 15 mL of DMF. NBS (0.15 g, 0.85
mmol) was added thereto at 0.degree. C., and the reaction mixture
was stirred at room temperature for 24 hours. The reaction solution
was concentrated and 50 mL of water was added thereto. The reaction
solution was extracted with Et.sub.2O, dried with MgSO.sub.4 and
purified by column chromatography to obtain the title compound
(0.21 g, 80%).
[0797] .sup.1H-NMR (CDCl.sub.3) .delta. 7.17-7.10 (2H, m), 6.65
(1H, d), 4.16 (2H, q), 3.97 (1H, m), 2.90-2.70 (2H, m), 2.65-2.50
(2H, m), 2.05-1.95 (3H, m), 1.72 (1H, m), 1.26 (3H, t)
Step F:
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-chroman-2-yl]--
propionic acid Ethyl Ester
[0798] 3-(6-Bromo-chroman-2-yl)-propionic acid ethyl ester (0.21 g,
0.67 mmol) obtained in Step E was reacted in the same manner as in
Step D of Preparation Example 1 to obtain the title compound (0.19
g, 79%).
[0799] .sup.1H-NMR (CDCl.sub.3) .delta. 7.56-7.52 (2H, m), 6.76
(1H, d), 4.14 (2H, q), 4.04 (1H, m), 2.90-2.75 (2H, m), 2.65-2.50
(2H, m), 2.08-1.97 (3H, m), 1.75 (1H, m), 1.32 (12H, s), 1.26 (3H,
t)
Preparation Example 5:
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiochroman-2-yl]-pro-
pionic Acid Ethyl Ester
Step A: 6-bromo-4-oxo-thiochroman-2-carboxylic Acid
[0800] 4-bromo-benzenethiol (5.0 g, 26.45 mmol) and furan-2,5-dione
(2.6 g, 26.45 mmol) were dissolved in 50 mL of toluene and heated
to 50.degree. C. TEA (0.1 mL) was slowly added thereto and the
reaction mixture was stirred at 50.degree. C. for 1 hour. The
reaction solution was concentrated under reduced pressure,
dissolved in 50 mL of DCM, and cooled to 0.degree. C. AlCl.sub.3
(5.3 g, 39.67 mmol) was added thereto, and the reaction solution
was stirred at room temperature for 1 hours, slowly added dropwise
to cold concentrated HCl solution, and extracted with DCM. The
organic solvent was dried with MgSO.sub.4, concentrated under
reduced pressure and solidified with Et.sub.2O to obtain the title
compound (4.3 g, 57%).
[0801] .sup.1H-NMR (CDCl.sub.3) .delta. 7.98 (1H, d), 7.65 (1H,
dd), 7.31 (1H, d), 4.31 (1H, t), 3.09 (2H, m)
Step B: 6-bromo-4-oxo-thiochroman-2-carboxylic Acid Methyl
Ester
[0802] 6-Bromo-4-oxo-thiochroman-2-carboxylic acid (4.3 g, 14.97
mmol) obtained in Step A was dissolved in 50 mL of methanol.
Concentrated sulfuric acid (0.8 mL) was added thereto, and the
mixture was stirred for 18 hours under reflux. The reaction
solution was concentrated under reduced pressure, extracted with
EtOAc, dried with MgSO.sub.4 and purified by column chromatography
to obtain the title compound (4.2 g, 93%).
[0803] .sup.1H-NMR (CDCl.sub.3) .delta. 8.24 (1H, d), 7.51 (1H,
dd), 7.13 (1H, d), 4.13 (1H, t), 3.74 (3H, s), 3.17 (2H, d)
Step C: 6-bromo-thiochroman-2-carboxylic Acid Methyl Ester
[0804] 6-Bromo-4-oxo-thiochroman-2-carboxylic acid methyl ester
(2.0 g, 6.64 mmol) obtained in Step B was dissolved in 20 mL of
TFA. Triethylsilane (2.1 mL, 13.28 mmol) was added thereto, and the
mixture was stirred at room temperature for 3 hours. The reaction
solution was concentrated under reduced pressure, extracted with
EtOAc, dried with MgSO.sub.4 and purified by column chromatography
to obtain the title compound (1.5 g, 78%).
[0805] .sup.1H-NMR (CDCl.sub.3) .delta. 7.22 (2H, m), 7.00 (1H, d),
4.02 (1H, m), 3.76 (3H, s), 2.96-2.72 (2H, m), 2.33-2.18 (2H,
m)
Step D: 6-bromo-thiochroman-2-carboxylic Acid
[0806] 6-Bromo-thiochroman-2-carboxylic acid methyl ester (1.5 g,
5.22 mmol) obtained in Step C was dissolved in each 15 mL of THF,
MeOH and 1N NaOH aqueous solution, and the mixture was stirred at
room temperature for 2 hours. The organic solvent was removed, and
adjusted to pH 3 by the use of 1N HCl aqueous solution, and
extracted with EtOAc to separate the organic layer. The organic
layer was dried with MgSO.sub.4 and concentrated under reduced
pressure to obtain the title compound (1.4 g, 98%).
Step E: (6-bromo-thiochroman-2-yl)-methanol
[0807] 6-Bromo-thiochroman-2-carboxylic acid (1.4 g, 5.13 mmol)
obtained in Step D was dissolved in 50 mL of THF and cooled to
-20.degree. C. Isobutyl chloroformate (0.74 mL, 5.64 mmol) and NMM
(0.71 mL, 6.48 mmol) were added thereto, and the mixture was
stirred at the same temperature for 1.5 hours. NaBH.sub.4 (0.38 g,
10.26 mmol) was dissolved in 20 mL of THF and 5 mL of MeOH at
another reactor and cooled to -78.degree. C. The above reaction
solution was filtered through Celite and added to another reactor,
and the mixture was stirred at room temperature for 2 hours. The
reaction solution was extracted with EtOAc, dried with MgSO.sub.4
and purified by column chromatography to obtain the title compound
(1.3 g, 98%).
[0808] .sup.1H-NMR (CDCl.sub.3) .delta. 7.19 (2H, m), 7.00 (1H, d),
3.78-3.66 (2H, m), 3.49 (1H, m), 2.83-2.71 (2H, m), 2.22 (1H, m),
1.88-1.78 (2H, m)
Step F: (E)-3-(6-bromo-thiochroman-2-yl)-acrylic Acid Ethyl
Ester
[0809] Oxalyl chloride (0.64 mL, 7.53 mmol) was added to 30 mL of
DCM and cooled to -78.degree. C. DMSO (0.9 mL, 12.55 mmol) was
slowly added, and the mixture was stirred for 0.5 hour. The
solution in which (6-bromo-thiochroman-2-yl)-methanol (1.3 g, 5.02
mmol) obtained in Step E was dissolved in 5 mL of DCM and TEA (2.8
mL, 20.08 mmol) were sequentially added thereto. The mixture was
stirred at room temperature for 1 hour.
(Carbethoxymethylene)triphenylphosphorane (2.1 g, 6.02 mmol) was
added thereto, and the reaction was carried out at room temperature
for 18 hours. Water was added to the reaction solution, and the
mixture was extracted with DCM to separate an organic layer. The
organic layer was dried with MgSO.sub.4 and purified by column
chromatography to obtain the title compound (0.90 g, 55%).
[0810] .sup.1H-NMR (CDCl.sub.3) .delta. 7.20 (2H, m), 6.97 (1H, m),
6.90 (1H, m), 6.00 (1H, d), 4.20 (2H, q), 4.02 (1H, m), 2.81 (2H,
m), 2.28 (1H, m), 1.92 (1H, m), 1.28 (3H, t)
Step G: 3-(6-bromo-thiochroman-2-yl)-propionic Acid Ethyl Ester
[0811] (E)-3-(6-bromo-thiochroman-2-yl)-acrylic acid ethyl ester
(0.90 g, 2.75 mmol) obtained in Step F was dissolved in 30 mL of
DME. p-Toluenesulfonyl hydrazide (3.60 g, 19.25 nmol) was added
little by little and heated to 90.degree. C. Sodium acetate (2.26
g, 27.50 mmol, 1.4 M aqueous solution) was added thereto, and the
mixture was stirred for 18 hours under reflux. Water was added to
the reaction solution and the mixture was extracted with DCM. The
organic layer was dried with MgSO.sub.4 and purified by column
chromatography to obtain the title compound (0.80 g, 88%).
[0812] .sup.1H-NMR (CDCl.sub.3) .delta. 7.16 (2H, m), 6.93 (1H, d),
4.14 (2H, q), 3.29 (1H, m), 2.80 (2H, m), 2.49 (2H, m), 2.20 (1H,
m), 2.02 (1H, m), 1.92 (1H, m), 1.77 (1H, m), 1.25 (3H, t)
Step H:
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiochroman-2--
yl]-propionic Acid Ethyl Ester
[0813] 3-(6-Bromo-thiochroman-2-yl)-propionic acid ethyl ester
(0.80 g, 2.43 mmol) obtained in Step G was reacted in the same
manner as in Step D of Preparation Example 1 to obtain the title
compound (0.68 g, 74%).
[0814] .sup.1H-NMR (CDCl.sub.3) .delta. 7.47 (2H, m), 7.08 (1H, d),
4.14 (2H, q), 3.32 (1H, m), 2.84 (2H, m), 2.49 (2H, m), 2.22 (1H,
m), 2.00 (2H, m), 1.81 (1H, m), 1.32 (12H, s), 1.25 (3H, t)
Preparation Example 6:
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,4-tetrahydro-qu-
inolin-2-yl]-propionic Acid Ethyl Ester
Step A: 3-(1,2,3,4-tetrahydro-quinolin-2-yl)-propionic Acid Ethyl
Ester
[0815] Quinolin-2-carbaldehyde (1 g, 6.36 mmol) was dissolved in
THF. NaH (60%)(0.28 g, 7.00 mmol) was slowly added thereto at
0.degree. C., and the mixture was stirred for 30 minutes. Triethyl
phosphonoacetate (1.57 g, 7.00 mmol) was added dropwise, and the
mixture was stirred at room temperature for 16 hours. The reaction
solution was extracted with EtOAc, purified by column
chromatography and dissolved in 30 mL of methanol. 10% PtO.sub.2
(0.1 g) was added thereto, and the mixture was stirred at room
temperature for 16 hours under hydrogen atmosphere. After
termination of the reaction, the reaction product was filtered
through Celite and concentrated under reduced pressure to obtain
the title compound (0.7 g, 47%).
[0816] .sup.1H-NMR (CDCl.sub.3) .delta. 7.00-6.90 (2H, m), 6.62
(1H, t), 6.46 (1H, d), 4.15 (2H, q), 3.85 (1H, brs), 3.32 (1H, m),
2.84-2.70 (2H, m), 2.45 (2H, m), 1.97-1.80 (3H, m), 1.65 (1H, m),
1.24 (3H, t)
Step B: 3-(6-bromo-1,2,3,4-tetrahydro-quinolin-2-yl)-propionic Acid
Ethyl Ester
[0817] 3-(1,2,3,4-Tetrahydro-quinolin-2-yl)-propionic acid ethyl
ester (0.7 g, 3.00 mmol) obtained in Step A was dissolved in 15 mL
of DMF. NBS (0.53 g, 3.00 mmol) was added thereto at 0.degree. C.,
and the mixture was stirred at room temperature for 24 hours. The
reaction solution was concentrated, and 50 mL of water was added
thereto. The mixture was extracted with Et.sub.2O, dried with
MgSO.sub.4 and purified by column chromatography to obtain the
title compound (0.85 g, 91%).
[0818] .sup.1H-NMR (CDCl.sub.3) .delta. 7.08.about.7.00 (2H, m),
6.37 (1H, d), 4.12 (2H, q), 3.30 (1H, m), 2.80.about.2.65 (2H, m),
2.41 (2H, m), 1.95.about.1.80 (3H, m), 1.50 (1H, m), 1.25 (3H,
t)
Step C:
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,4-tetrah-
ydro-quinolin-2-yl]-propionic Acid Ethyl Ester
[0819] 3-(6-Bromo-1,2,3,4-tetrahydro-quinolin-2-yl)-propionic acid
ethyl ester (0.33 g, 1.07 mmol) obtained in Step B was reacted in
the same manner as in Step D of Preparation Example 1 to obtain the
title compound (0.11 g, 29%).
[0820] .sup.1H-NMR (CDCl.sub.3) .delta. 7.42 (2H, m), 6.44 (1H, d),
4.20.about.4.05 (3H, m), 3.34 (1H, m), 2.80.about.2.70 (2H, m),
2.50.about.2.35 (2H, m), 1.95.about.1.80 (3H, m), 1.75 (1H, m),
1.31 (12H, s), 1.24 (3H, t)
Preparation Example 7:
[1-oxo-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-is-
oquinolin-2-yl]-acetic Acid Ethyl Ester
Step A: 6-bromo-3,4-dihydro-2H-isoquinolin-1-one
[0821] 5-bromo-indan-1-one (2.35 g, 11.13 mmol) was dissolved in 10
mL of DCM and 10 mL of methanesulfonic acid and cooled to 0.degree.
C. Sodium azide (1.45 g, 22.27 mmol) was added thereto, and the
mixture was stirred at room temperature for 16 hours. The reaction
solution was cooled to 0.degree. C., neutralized with NaOH and
extracted with EtOAc. The extract was dried with MgSO.sub.4 and
purified by column chromatography to obtain the title compound
(1.14 g, 45%).
[0822] .sup.1H-NMR (CDCl.sub.3) .delta. 7.92 (1H, d), 7.48 (1H, d),
7.39 (1H, s), 6.10 (1H, brs), 3.57 (2H, t), 2.99 (2H, t)
Step B: (6-bromo-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-acetic Acid
Ethyl Ester
[0823] 6-Bromo-3,4-dihydro-2H-isoquinolin-1-one (0.4 g, 1.77 mmol)
obtained in Step A was dissolved in 10 mL of THF and cooled to
0.degree. C. NaH (60%)(0.14 g, 3.54 mmol) was added thereto, and
the mixture was stirred at room temperature 0.5 hour. Ethyl
bromoacetate (0.44 g, 2.65 mmol) was added to the reaction
solution, and the mixture was stirred for 2 hours under reflux. The
reaction solution was extracted with EtOAc, dried with MgSO.sub.4
and purified by column chromatography to obtain the title compound
(0.49 g, 89%).
[0824] .sup.1H-NMR (CDCl.sub.3) .delta. 7.93 (1H, d), 7.47 (1H, d),
7.37 (1H, s), 4.32 (2H, s), 4.23 (2H, q), 3.66 (2H, t), 3.05 (2H,
t), 1.29 (3H, t)
Step C:
[1-oxo-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydr-
o-1H-isoquinolin-2-yl]-acetic Acid Ethyl Ester
[0825] (6-Bromo-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-acetic acid
ethyl ester (0.79 g, 1.57 mmol) obtained in Step B was reacted in
the same manner as in Step D of Preparation Example 1 to obtain the
title compound (0.54 g, 96%).
[0826] .sup.1H-NMR (CDCl.sub.3) .delta. 8.06 (1H, d), 7.76 (1H, d),
7.64 (1H, s), 4.34 (2H, s), 4.21 (2H, q), 3.65 (2H, t), 3.07 (2H,
t), 1.30 (12H, s), 1.26 (3H, t)
Preparation Example 8:
3-[1-oxo-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H--
isoquinolin-2-yl]-propionic Acid Methyl Ester
Step A: 3-(6-bromo-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-propionic
Acid Methyl Ester
[0827] 6-Bromo-3,4-dihydro-2H-isoquinolin-1-one (0.3 g, 1.32 mmol)
obtained in Step A of Preparation Example 7 was dissolved in 10 mL
of THF and cooled to 0.degree. C. NaH (60%)(0.11 g, 2.65 mmol) was
added thereto, and the mixture was stirred at room temperature for
0.5 hour. 3-Bromo-propionic acid methyl ester (0.33 g, 2.00 mmol)
was added to the reaction solution, and the mixture was stirred for
2 hours under reflux. The reaction solution was extracted with
EtOAc, dried with MgSO.sub.4 and purified by column chromatography
to obtain the title compound (0.38 g, 92%).
[0828] .sup.1H-NMR (CDCl.sub.3) .delta. 7.90 (1H, d), 7.47 (1H, d),
7.34 (1H, s), 3.80 (2H, t), 3.69 (3H, s), 3.63 (2H, t), 2.94 (2H,
t), 2.73 (2H, t)
Step B:
3-[1-oxo-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihy-
dro-1H-isoquinolin-2-yl]-propionic Acid Methyl Ester
[0829] 3-(6-Bromo-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-propionic
acid methyl ester (0.38 g, 1.22 mmol) obtained in Step A was
reacted in the same manner as in Step D of Preparation Example 1 to
obtain the title compound (0.36 g, 82%).
[0830] .sup.1H-NMR (CDCl.sub.3) .delta. 8.03 (1H, d), 7.77 (1H, d),
7.61 (1H, s), 3.82 (2H, t), 3.68 (3H, s), 3.63 (2H, t), 2.98 (2H,
t), 2.72 (2H, t), 1.35 (12H, s)
Preparation Example 9: 3-iodo-2-isopropylsulfanyl-pyridine
[0831] 2-Fluoro-3-iodo-pyridine (0.3 g, 1.34 mmol),
Cs.sub.2CO.sub.3 (0.66 g, 1.34 mmol) and propane-2-thiol (0.125 mL,
1.34 mmol) were added to a reactor, and the mixture was stirred at
room temperature for 8 hours. Water was added to the reaction
solution and the mixture was extracted with EtOAc. An organic layer
was separated, and the separated organic layer was dried with
MgSO.sub.4 and purified by column chromatography to obtain the
title compound (0.21 g, 56%).
[0832] .sup.1H-NMR (CDCl.sub.3) .delta. 8.40 (1H, m), 7.92 (1H, m),
6.69 (1H, m), 3.95 (1H, m), 1.39 (6H, d)
Preparation Example 10: 2-chloro-6-isopropylsulfanyl-pyridine
[0833] 2,6-Dichloropyridine (3.0 g, 20.3 mmol) and propane-2-thiol
(1.88 mL, 20.3 mmol) were reacted in the same manner as in
Preparation Example 9 to obtain the title compound (3.63 g,
95%).
[0834] .sup.1H-NMR (CDCl.sub.3) .delta. 7.40 (1H, t), 7.05 (1H, t),
6.98 (1H, t), 4.00 (1H, m), 1.40 (6H, d)
Preparation Example 11: 2-cyclopentyloxy-3-iodo-pyridine
[0835] Cyclopentanol (0.038 g, 0.44 mmol) and
2-fluoro-3-iodo-pyridine (0.10 g, 0.44 mmol) were reacted in the
same manner as in Preparation Example 34 to obtain the title
compound (0.091 g, 70%).
[0836] .sup.1H-NMR (CDCl.sub.3) .delta. 8.09 (1H, m), 7.99 (1H, m),
6.59 (1H, m), 5.43 (1H, m), 2.00 (2H, m), 1.94 (4H, m), 1.66 (2H,
m)
Preparation Example 12: 2-chloro-6-cyclopentyloxy-pyridine
[0837] 6-Chloro-2-pyridinol (1.95 g, 15 mmol) and K.sub.2CO.sub.3
(4.16 g, 30 mmol) were dissolved in 50 mL of DMF Cyclopentyl
bromide (1.94 mL, 18 mmol) was added thereto, and the mixture was
stirred at 80.degree. C. for 24 hours. Solids were removed, and the
filtrate was concentrated to obtain the title compound (2.92 g,
98%).
[0838] .sup.1H NMR (CDCl.sub.3) .delta. 7.47 (1H, t), 6.84 (1H, d),
6.51 (1H, d), 5.38 (1H, m), 1.97 (2H, m), 1.79 (4H, m), 1.62 (2H,
m)
Preparation Example 13: 2-cyclobutylsulfanyl-3-iodo-pyridine
Step A: Cyclobutane Thiol
[0839] Magnesium (0.99 g, 40.74 mmol) was dissolved in THF (20 mL).
Cyclobutyl bromide (5.0 g, 37.03 mmol) was dissolved in THF (5 mL)
at 50.degree. C. and added thereto, and the mixture was stirred for
2 hours under reflux. Sulfur (1.06 g, 33.33 mmol) was slowly added
thereto at 0.degree. C., and the mixture was stirred at 50.degree.
C. for 2 hours. LAH (0.843 g, 22.22 mmol) was slowly added thereto
at 0.degree. C., and the mixture was stirred for 30 minutes under
reflux stirred. After termination of the reaction by the use of
ammonium chloride aqueous solution (20 mL) and 1N HCl (20 mL) at
0.degree. C., an organic layer was separated and extracted with
Et.sub.2O (30 mL.times.3). The organic layer was dried with
MgSO.sub.4 and used for the next step.
Step B: 2-cyclobutylsulfanyl-3-iodo-pyridine
[0840] Cyclobutane thiol (0.069 g, 0.782 mmol) obtained in Step A
and 2-fluoro-3-iodo-pyridine (0.1 g, 0.43 mmol) were dissolved in
DMF (3 mL). Cs.sub.2CO.sub.3 (0.26 g, 0.86 mmol) was added thereto,
and the mixture was heated to 80.degree. C. and stirred. NaCl
aqueous solution was added to the reaction solution, and the
mixture was extracted with EtOAc. The organic layer was dried with
MgSO.sub.4 and purified by column chromatography (eluent,
EtOAc/Hex=1/4) to obtain the title compound (0.115 g, 91%).
[0841] .sup.1H-NMR (CDCl.sub.3) .delta. 8.36 (1H, m), 7.90 (1H, m),
6.69 (1H, m), 4.33 (1H, m), 2.54 (2H, m), 2.14 (2H, m), 2.05 (2H,
m)
Preparation Example 14: 2-chloro-6-cyclopentylsulfanyl-pyridine
[0842] 2,6-Dichloropyridine (3.08 g, 20.7 mmol) and
Cs.sub.2CO.sub.3 (6.8 g, 20.7 mmol) were dissolved in 40 mL of DMF.
Cyclopentylthiol (2.17 mL, 20.7 mmol) was added thereto, and the
mixture was stirred at 80.degree. C. for 16 hours. Solids were
filtered, and the filtrate was concentrated to obtain the title
compound (4.24 g, 95%).
[0843] .sup.1H NMR (CDCl.sub.3) .delta. 7.40 (1H, t), 7.06 (1H, d),
6.97 (1H, d), 4.01 (1H, m), 2.22 (2H, m), 1.76 (2H, m), 1.64 (4H,
m)
Preparation Example 15: 2-cyclopentylsulfanyl-3-iodo-pyridine
[0844] 2-Fluoro-3-iodo-pyridine (0.065 g, 0.29 mmol),
Cs.sub.2CO.sub.3 (0.19 g, 0.58 mmol) and cyclopentylthiol (0.03 g,
0.291 mmol) were dissolved in 2 mL of DMF, and the mixture was
stirred at 80.degree. C. for 2 hours. NaCl aqueous solution was
added to the reaction solution, and the mixture was extracted with
EtOAc to separate an organic layer. The organic layer was dried
with MgSO.sub.4 and purified by column chromatography (eluent,
EtOAc/Hex=1/4) to obtain the title compound (0.053 g, 65%).
[0845] .sup.1H-NMR (CDCl.sub.3) .delta. 8.38 (1H, m), 7.89 (1H, m),
6.68 (1H, m), 4.00 (1H, m), 2.22 (2H, m), 1.80 (2H, m), 1.66 (4H,
m)
Preparation Example 16:
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric Acid Ethyl Ester
Step A: 4-bromo-2,6-difluoro-phenol
[0846] 2,6-Difluorophenol (1.02 g, 7.8 mmol) was dissolve in 15 mL
of DMF. NBS (1.40 g, 7.84 mmol) was added thereto at 0.degree. C.,
and the mixture was stirred at room temperature for 24 hours. The
reaction solution was concentrated, and 50 mL of water was added
thereto. The reaction solution was extracted with Et.sub.2O and
dried with MgSO.sub.4 to obtain the title compound (1.41 g,
86%).
[0847] .sup.1H NMR (CDCl.sub.3) .delta. 7.08 (2H, m), 5.42 (1H,
brs)
Step B:
2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
[0848] 4-Bromo-2,6-difluoro-phenol (1.414 g, 6.76 mmol) obtained in
Step A, bis(pinacolato)diboron (1.8 g, 7.09 mmol), potassium
acetate (2.66 g, 27 mmol) and DPPF (0.19 g, 0.34 mmol) were
dissolved in 23 mL of 1,4-dioxane. The mixture was charged with
N.sub.2 gas for 5 minutes, and PdCl.sub.2(dppf)-DCM (0.27 g, 0.34
mmol) was added thereto. The mixture was stirred at 80.degree. C.
for 3 hours, filtered through Celite and purified by column
chromatography to obtain the title compound (1.366 g, 79%).
[0849] .sup.1H NMR (CDCl.sub.3) .delta. 7.33 (2H, m), 5.25 (1H, s),
1.32 (12H, s)
Step C:
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
noxy]butyric Acid Ethyl Ester
[0850]
2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
(1.87 g, 7.3 mmol) obtained in Step B, Cs.sub.2CO.sub.3 (4.76 g,
14.6 mmol) and 4-bromo-butyric acid ethyl ester (1.42 g, 7.3 mmol)
were dissolved in 24 mL of DMF. The mixture was stirred at room
temperature for 24 hours. Solids were filtered and purified by
column chromatography to obtain the title compound (1.66 g,
61%).
[0851] .sup.1H NMR (CDCl.sub.3) .delta. 7.29 (2H, m), 4.21 (2H, t),
4.14 (2H, q), 2.56 (2H, t), 2.07 (2H, m), 1.32 (12H, s), 1.25 (3H,
t)
Preparation Example 17: 1-benzyloxy-3-iodo-benzene
[0852] 3-Iodo phenol (0.5 g, 2.27 mmol) was dissolved in
acetonitrile (5 mL). Cs.sub.2CO.sub.3 (2.22 g, 6.81 mmol) and
bromomethylbenzene (0.27 mL, 2.27 mmol) were sequentially added
thereto. The mixture was stirred at 80-85.degree. C. for 2 hours.
After termination of the reaction, the reactions solution was
cooled and filtered through Celite. The filtrate was concentrated
under reduced pressure and purified by column chromatography
(eluent, EtOAc/Hex=1/10) to obtain the title compound (0.7 g,
99%).
[0853] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.39-7.23 (m, 7H),
6.97-6.87 (m, 2H), 4.95 (s, 2H)
Preparation Example 18: 1-iodo-3-isopropoxy-benzene
[0854] 3-Iodo phenol (0.5 g, 2.27 mmol) and 2-bromo-propane (0.21
mL, 2.27 mmol) were reacted in the same manner as in Preparation
Example 17 to obtain the title compound (0.59 g, 99%).
[0855] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.27-7.22 (m, 2H),
6.96 (t, 1H), 6.86-6.81 (m, 1H), 4.54-4.44 (m, 1H), 1.31 (d,
6H)
Preparation Example 19: 1-iodo-3-propoxy-benzene
[0856] 3-Iodo phenol (0.5 g, 2.27 mmol) and 1-bromo-propane (0.21
mL, 2.27 mmol) were reacted in the same manner as in Preparation
Example 17 to obtain the title compound (0.58 g, 97%).
[0857] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.28-7.23 (m, 2H),
6.97 (t, 1H), 6.87-6.82 (m, 1H), 3.85 (t, 2H), 1.83-1.71 (m, 2H),
1.02 (t, 3H)
Preparation Example 20: 1-cyclopropylmethoxy-3-iodo-benzene
[0858] 3-Iodo phenol (0.5 g, 2.27 mmol) and
bromomethyl-cyclopropane (0.22 mL, 2.27 mmol) were reacted in the
same manner as in Preparation Example 17 to obtain the title
compound (0.59 g, 95%).
[0859] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.26-7.20 (m, 2H),
6.93 (t, 1H), 6.84-6.80 (m, 1H), 3.71 (d, 2H), 1.28-1.15 (m, 1H),
0.63-0.57 (m, 2H), 0.33-0.28 (m, 2H)
Preparation Example 21: 1-cyclobutoxy-3-iodo-benzene
[0860] 3-Iodo phenol (0.5 g, 2.27 mmol) was dissolved in
acetonitrile (5 mL). Cs.sub.2CO.sub.3 (2.22 g, 6.81 mmol) and
bromocyclobutane (0.21 mL, 2.27 mmol) were sequentially added
thereto. The mixture was stirred at 80-85.degree. C. for 10 hours,
and the reaction solution was cooled and filtered through Celite.
The filtrate was concentrated under reduced pressure and purified
by column chromatography (eluent, EtOAc/Hex=1/10) to obtain the
title compound (0.45 g, 72%).
[0861] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.25-7.20 (m, 1H),
7.17-7.13 (m, 1H), 6.92 (t, 1H), 6.77-6.72 (m, 1H), 4.59-4.50 (m,
1H), 2.44-2.33 (m, 2H), 2.19-2.05 (m, 2H), 1.88-1.77 (m, 1H),
1.70-1.57 (m, 1H)
Preparation Example 22:
7-iodo-2,2-dimethyl-2,3-dihydro-benzofuran
Step A: 1-iodo-2-(2-methyl-allyloxy)-benzene
[0862] 2-Iodo phenol (0.93 g, 4.23 mmol) was dissolved in DMF (5
mL). K.sub.2CO.sub.3 (0.82 g, 5.92 mmol) and
3-chloro-2-methyl-propene (0.5 mL, 5.08 mmol) were sequentially
added thereto. The mixture was stirred at 70-75.degree. C. for 12
hours. After termination of the reaction, the reactions solution
was cooled. Water was added to the reaction solution, and the
reaction solution was extracted with EtOAc to separate an organic
layer. The organic layer was concentrated under reduced pressure
and purified by column chromatography (eluent, EtOAc/Hex=1/10) to
obtain the title compound (1.05 g, 91%).
[0863] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.77 (d, 1H), 7.27
(t, 1H), 6.79 (d, 1H), 6.70 (t, 1H), 5.19 (s, 1H), 5.02 (s, 1H),
4.48 (s, 2H), 1.87 (s, 3H)
Step B: 2-iodo-6-(2-methyl-allyl)-phenol
[0864] 1-Iodo-2-(2-methyl-allyloxy)-benzene (1.05 g, 3.83 mmol)
obtained in Step A was added to a seal tube, and NMP (5 mL) was
then added thereto. The mixture was stirred at 200.degree. C. for
12 hours. After termination of the reaction, the reactions solution
was cooled. Water was added to the reaction solution, and the
reaction solution was extracted with EtOAc to separate an organic
layer. The organic layer was concentrated under reduced pressure
and purified by column chromatography (eluent, EtOAc/Hex=1/10) to
obtain the title compound (0.25 g, 24%).
[0865] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.46-6.54 (m, 3H),
3.11 (s, 1H), 3.01 (s, 1H), 1.50 (s, 2H), 1.47 (s, 3H)
Step C: 7-iodo-2,2-dimethyl-2,3-dihydro-benzofuran
[0866] HCOOH (5 mL) and water (0.5 mL) were added to
2-iodo-6-(2-methyl-allyl)-phenol (0.25 g, 0.91 mmol) obtained in
Step B. The mixture was stirred for 12 hours under reflux. After
termination of the reaction, the reactions solution was cooled.
Water was added to the reaction solution, and the reaction solution
was extracted with EtOAc to separate an organic layer. The organic
layer was concentrated under reduced pressure and purified by
column chromatography (eluent, EtOAc/Hex=1/10) to obtain the title
compound (0.07 g, 24%).
[0867] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.44 (d, 1H), 7.06
(d, 1H), 6.56 (t, 1H), 3.11 (s, 2H), 1.50 (s, 6H)
Preparation Example 23: 4-iodo-2,2-dimethyl-benzo[1,3]dioxol
Step A: 1-iodo-2,3-dimethoxy-benzene
[0868] THF (5 mL) was added to 1,2-dimethoxy-benzene (0.5 g, 3.62
mmol) and cooled to 0-5.degree. C. n-BuLi (1.6 mL, 3.98 mmol) was
slowly added dropwise thereto, and the mixture was stirred at
0-5.degree. C. for 2 hours. The reaction solution was cooled to
-78.degree. C., and I2 (1.01 g, 3.98 mmol)/THF (5 mL) solution was
added thereto. The temperature was increased to room temperature,
and the reaction solution was stirred for 2 hours. After
termination of the reaction, the reaction solution was concentrated
under reduced pressure. Saturated NaHCO.sub.3 solution was added to
the reaction solution, and extracted with DCM to separate an
organic layer. The organic layer was concentrated under reduced
pressure and purified by column chromatography (eluent,
EtOAc/Hex=1/10) to obtain the title compound (0.62 g, 65%).
[0869] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.36-7.32 (m, 1H),
6.90-6.86 (m, 1H), 6.79 (t, 1H), 3.85 (s, 3H), 3.83 (s, 3H)
Step B: 3-iodo-benzene-1,2-diol
[0870] 1-Iodo-2,3-dimethoxy-benzene (0.62 g, 2.35 mmol) obtained in
Step A was dissolved in DCM (23 mL) and cooled to 0-5.degree. C. 1M
BBr.sub.3 (0.276 mL, 7.05 mmol) was slowly added thereto, and the
mixture was stirred at room temperature for 3 hours. After
termination of the reaction, the reaction solution was cooled to
-20.degree. C. and diluted by slowly adding ethanol. The mixture
was stirred at room temperature for 30 minutes, and saturated
NaHCO.sub.3 aqueous solution was added thereto. The mixture was
extracted with DCM. The organic layer was dried with MgSO.sub.4,
concentrated under reduced pressure and purified by column
chromatography (eluent, EtOAc/Hex=1/4) to obtain the title compound
(0.12 g, 22%).
[0871] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.18 (d, 1H), 6.87
(d, 1H), 6.60 (t, 1H), 5.64 (s, br, 2H)
Step C: 4-iodo-2,2-dimethyl-benzo[1,3]dioxol
[0872] Benzene (5 mL) was added to 3-iodo-benzene-1,2-diol (50 mg,
0.21 mmol) obtained in Step B. 2,2-Dimethoxy-propane (0.052 mL,
0.42 mmol) and p-TsOH.H.sub.2O (catalytic amount) were added
thereto, and the mixture was stirred for 2 hours under reflux.
After termination of the reaction, the reaction solution was
cooled, and saturated NaHCO.sub.3 solution was added thereto. The
reaction solution was extracted with EtOAc to separate an organic
layer. The organic layer was concentrated under reduced pressure
and purified by column chromatography (eluent, EtOAc/Hex=1/10) to
obtain the title compound (40 mg, 58%).
[0873] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.08 (d, 1H), 6.68
(d, 1H), 6.55 (t, 1H), 1.71 (s, 6H)
Preparation Example 24:
4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenol
[0874] 2-Cyclobutylsulfanyl-3-iodo-pyridine (0.193 g, 0.66 mmol)
obtained in Preparation Example 13 and
2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
(0.254 g, 0.992 mmol) obtained in Step B of Preparation Example 16
were reacted in the same manner as in Step A of Example 1 to obtain
the title compound (0.078 g, 40%).
[0875] .sup.1H-NMR (CDCl.sub.3) .delta. 8.39 (1H, m), 7.30 (1H, m),
6.98 (3H, m), 5.15 (1H, s), 4.40 (1H, m), 2.49 (2H, m), 2.02 (4H,
m)
Preparation Example 25:
4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]butanenitrile
Step A: 3-(4-bromophenyl)propan-1-ol
[0876] 3-(4-Bromophenyl)propanoic acid (1.41 g, 6.16 mmol) was
dissolved in THF (20 mL). Borane-THF 1.0 M solution (18.5 mL, 18.5
mmol) was slowly added dropwise at 0.degree. C. The mixture was
stirred at room temperature for 16 hours. After termination of the
reaction, the reaction solution was diluted with water at 0.degree.
C. and washed with 1N HCl. The reaction solution was extracted with
EtOAc, and the organic layer was dried with anhydrous magnesium
sulfate and purified by column chromatography (eluent,
EtOAc/Hex=1/5) to obtain the title compound (1.31 g, 99%).
[0877] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.39 (2H, m), 7.09
(2H, m), 3.67 (2H, m), 2.67 (2H, t), 1.87 (2H, m)
Step B: 3-(4-bromophenyl)propyl Methanesulfonate
[0878] 3-(4-Bromophenyl)propan-1-ol (1.07 g, 4.97 mmol) obtained in
Step A was dissolved in DCM (12 mL). TEA (1.04 mL, 7.46 mmol) was
added thereto, and methanesulfonyl chloride (0.46 mL, 5.96 mmol)
was then slowly added thereto at 0.degree. C. The mixture was
stirred for 2 hours. After termination of the reaction, the
reaction solution was diluted with water at 0.degree. C., washed
with 1N HCl and extracted with DCM. The organic layer was dried
with anhydrous magnesiumsulfate to obtain 1.4 g of the title
compound, which was used in the next step without purification.
Step C: 4-(4-bromophenyl)butanenitrile
[0879] 3-(4-Bromophenyl)propyl methanesulfonate (0.557 g, 1.899
mmol) obtained in Step B was dissolved in DMF (9 mL). Sodium
cyanide (0.372 g, 7.599 mmol) was added thereto, and the reaction
was carried out at 70.degree. C. for 16 hours. After termination of
the reaction, the reaction solution was diluted with sodium
bicarbonate solution and extracted with EtOAc. The organic layer
was dried with anhydrous magnesiumsulfate and purified by column
chromatography (eluent, EtOAc/Hex=1/10) to obtain the title
compound (0.273 g, 64%).
[0880] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.43 (2H, m), 7.05
(2H, m), 2.73 (2H, t), 2.31 (2H, t), 1.95 (2H, m)
Step D:
4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]butaneni-
trile
[0881] 4-(4-bromophenyl)butanenitrile (0.273 g, 1.299 mmol)
obtained in Step C, bis(pinacolato)diboron (0.346 g, 1.364 mmol),
potassium acetate (0.51 g, 5.196 mmol) and DPPF (0.036 g, 0.065
mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was
charged with N.sub.2 gas for 5 minutes, and PdCl.sub.2(dppf)-DCM
(0.053 g, 0.065 mmol) was added thereto. The reaction solution was
stirred at 80.degree. C. for 16 hours, filtered through Celite,
diluted with water and extracted with ethyl acetate. The organic
layer was dried with anhydrous magnesiumsulfate and purified by
column chromatography (eluent, EtOAc/Hex=1/10) to obtain the title
compound (0.203 g, 57%).
[0882] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.74 (2H, m), 7.19
(2H, m), 2.78 (2H, t), 2.29 (2H, t), 1.97 (2H, m), 1.33 (12H,
s)
Preparation Example 26:
5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pentanoic
Acid Ethyl Ester
Step A: 3-(4-bromophenyl)propanal
[0883] Oxalyl chloride (0.599 mL, 6.973 mmol) was dissolved in DCM
(15 mL), and DMSO (0.99 mL, 13.94 mmol) dissolved in DCM (10 mL)
was slowly added thereto at -78.degree. C. The mixture was stirred
for 15 minutes, and 3-(4-bromophenyl)propan-1-ol (1.0 g, 4.64 mmol)
dissolved in DCM (10 mL) was slowly added thereto at -78.degree. C.
The mixture was stirred for 30 minutes, and TEA (1.96 mL) was
slowly added thereto at -78.degree. C. The temperature was slowly
increased to room temperature, and the reaction solution was
stirred for 3 hours. After termination of the reaction, the
reaction solution was diluted with water and extracted with DCM.
The organic layer was dried with anhydrous magnesiumsulfate and
purified by column chromatography (eluent, EtOAc/Hex=1/5) to obtain
the title compound (0.859 g, 86%).
[0884] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 9.81 (1H, s), 7.40
(2H, d), 7.07 (2H, d), 2.91 (2H, m), 2.77 (2H, t)
Step B: (E)-5-(4-bromophenyl)pent-2-enoic Acid Ethyl Ester
[0885] 3-(4-Bromophenyl)propanal (0.859 g, 4.031 mmol) obtained in
Step A and (1-ethoxycarbonylethylidene)triphenylphosphorane (1.685
g, 4.837 mmol) were dissolved in benzene (15 mL), and the mixture
was stirred at 60.degree. C. for 16 hours. After termination of the
reaction, the solvent was distilled under reduced pressure and
purified by column chromatography (eluent, EtOAc/Hex=1/10) to
obtain the title compound (0.903 g, 79%).
[0886] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.40 (2H, m), 7.06
(2H, m), 6.94 (1H, m), 5.82 (1H, m), 4.18 (2H, q), 2.72 (2H, m),
2.49 (2H, m), 1.28 (3H, t)
Step C:
(E)-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pent-
-2-enoic Acid Ethyl Ester
[0887] (E)-5-(4-bromophenyl)pent-2-enoic acid ethyl ester (0.903 g,
3.18 mmol) obtained in Step B was reacted in the same manner as in
Step D of Preparation Example 25 to obtain the title compound
(0.429 g, 40%).
[0888] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.73 (2H, m), 7.18
(2H, m), 6.97 (1H, m), 5.82 (1H, m), 4.16 (2H, q), 2.76 (2H, m),
2.51 (2H, m), 1.33 (12H, s), 1.28 (3H, t)
Step D:
5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pentanoi-
c Acid Ethyl Ester
[0889]
(E)-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pent--
2-enoic acid ethyl ester (0.429 g, 1.29 mmol) and Pd/C (0.05 g)
were dissolved in methanol (13 mL). The mixture was charged with
H.sub.2 gas and stirred at room temperature for 8 hours. After
termination of the reaction, the reaction product was filtered
through Celite to obtain the title compound (0.425 g, 99%).
[0890] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.74 (2H, m), 7.19
(2H, m), 4.10 (2H, q), 2.63 (2H, m), 2.30 (2H, m), 1.64 (4H, m),
1.34 (12H, s), 1.25 (3H, t)
Preparation Example 27:
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pe-
ntanoic Acid Ethyl Ester
Step A: 3-(4-bromo-2,6-difluoro-phenyl)prop-2-enal
[0891] 4-bromo-2,6-difluoro-benzaldehyde (1.21 g, 5.47 mmol) and
ethyl(triphenylphosphoranylidene)acetaldehyde (1.83 g, 6.022 mmol)
were dissolved in benzene (11 mL), and the mixture was stirred at
70.degree. C. for 16 hours. After termination of the reaction, the
reaction product was concentrated under reduced pressure and
purified by column chromatography (eluent, EtOAc/Hex=1/20) to
obtain the title compound (1.27 g, 93%).
[0892] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 9.67 (1H, m), 7.51
(1H, m), 7.18 (2H, m), 6.95 (1H, m)
Step B: (E)-5-(4-bromo-2,6-difluoro-phenyl)penta-2,4-dienoic Acid
Ethyl Ester
[0893] 3-(4-Bromo-2,6-difluoro-phenyl)prop-2-enal (1.27 g, 5.14
mmol) obtained in Step A and
(1-ethoxycarbonylethylidene)triphenylphosphorane (2.15 g, 6.168
mmol) were dissolved in benzene (11 mL), and the mixture was
stirred at 70.degree. C. for 16 hours. After termination of the
reaction, the reaction product was concentrated under reduced
pressure and purified by column chromatography (eluent
EtOAc/Hex=1/20) to obtain the title compound (1.61 g, 98%).
[0894] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.40 (1H, m), 7.15
(3H, m), 6.83 (1H, d), 6.03 (1H, d), 4.22 (2H, q), 1.30 (3H, t)
Step C:
(E)-5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y-
l)phenyl]penta-2,4-dienoic Acid Ethyl Ester
[0895] (E)-5-(4-bromo-2,6-difluoro-phenyl)penta-2,4-dienoic acid
ethyl ester (0.09 g, 0.283 mmol) obtained in Step B was dissolved
in DME (4 mL), and bis(pinacolato)diboron (0.086 g, 0.034 mmol),
potassium acetate (0.083 g, 0.85 mmol) and
PdCl.sub.2(PPh.sub.3).sub.2 (0.012 g, 0.014 mmol) were added
thereto. The mixture was stirred at 80.degree. C. for 16 hours,
filtered through Celite, diluted with water, and extracted with
ethyl acetate. The organic layer was dried with anhydrous
magnesiumsulfate and purified by column chromatography (eluent,
EtOAc/Hex=1/7) to obtain the title compound (0.068 g, 66%).
[0896] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.43 (1H, m),
7.30-7.20 (3H, m), 6.95 (1H, d), 6.03 (1H, d), 4.23 (2H, q), 1.32
(15H, m)
Step D:
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)ph-
enyl]pentanoic Acid Ethyl Ester
[0897]
(E)-5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)phenyl]penta-2,4-dienoic acid ethyl ester (0.068 g, 0.18 mmol)
obtained in Step C and Pd/C (0.01 g) were dissolve in methanol (3
mL). The mixture was charged with H.sub.2 gas and stirred at room
temperature for 8 hours. After termination of the reaction, the
reaction product was filtered through Celite to obtain the title
compound (0.063 g, 92%).
[0898] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.25 (2H, m), 4.10
(2H, q), 2.69 (2H, m), 2.30 (2H, t), 1.70-1.60 (4H, m), 1.32 (12H,
s), 1.23 (3H, t)
Preparation Example 28: 3-iodo-2-propylsulfanyl-pyridine
[0899] After addition of 31 mL of CH.sub.3CN to
2-fluoro-3-iodo-pyridine (2.08 g, 9.3 mmol) and propane-1-thiol
(0.89 mL, 9.8 mmol), Cs.sub.2CO.sub.3 (3.33 g, 10.2 mmol) was added
thereto, and the mixture was stirred for 5 hours under reflux. The
reaction solution was cooled to room temperature. Solids were
filtered, and the filtrate was purified by column chromatography to
obtain the title compound (1.58 g, 60%).
[0900] 1H-NMR (CDCl.sub.3) .delta. 8.40 (1H, m), 7.92 (1H, m), 6.71
(1H, m), 3.13 (2H, t), 1.75 (2H, m), 1.06 (3H, t)
Preparation Example 29: 2-chloro-6-cyclobutoxy-pyridine
[0901] 5 mL of DMF was added to 6-chloro-2-pyridone (0.2 g, 1.5
mmol), bromocyclobutane (0.26 g, 1.8 mmol) and K.sub.2CO.sub.3
(0.43 g. 3 mmol), and the mixture was stirred at 80.degree. C. for
16 hours. The reaction solution was concentrated under reduced
pressure and purified by column chromatography to obtain the title
compound (0.28 g, 98%).
[0902] .sup.1H NMR (CDCl.sub.3) .delta. 7.49 (1H, t), 6.86 (1H, d),
6.59 (1H, d), 5.16 (1H, m), 2.46 (2H, m), 2.13 (2H, m), 1.83 (1H,
m), 1.66 (1H, m)
Preparation Example 30:
{2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
ethoxy}acetic Acid Tert-Butyl Ester
Step A: [2-(4-bromo-2,6-difluoro-phenyl)ethoxy]acetic Acid
Tert-Butyl Ester
[0903] 2-(4-bromo-2,6-difluoro-phenyl)ethanol (0.116 g, 0.489
mmol), tert-butyl bromoacetate (0.57 mL, 3.91 mmol), tert-butyl
ammonium hydrogen sulfate (0.133 g, 0.391 mmol) were dissolved in
toluene (2.5 mL). 6N NaOH (8 mL) was added thereto, and the mixture
was stirred for 5 hours. After termination of the reaction, the
reaction solution was diluted with water, extracted with EtOAc. The
organic layer was dried with anhydrous magnesiumsulfate and
purified by column chromatography (eluent, EtOAc/Hex=1/8) to obtain
the title compound (0.15 g, 77%).
[0904] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.06 (2H, m), 3.95
(2H, s), 3.69 (2H, t), 2.96 (2H, t), 1.46 (9H, s)
Step B:
{2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)--
phenyl]ethoxy}acetic Acid Tert-Butyl Ester
[0905] [2-(4-Bromo-2,6-difluoro-phenyl)ethoxy]acetic acid
tert-butyl ester (0.15 g, 0.42 mmol) obtained in Step A was reacted
in the same manner as in Step C of Preparation Example 27 to obtain
the title compound (0.09 g, 53%).
[0906] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.26 (2H, m), 3.96
(2H, s), 3.70 (2H, t), 3.03 (2H, t), 1.49 (9H, s), 1.33 (12H,
s)
Preparation Example 31:
5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]hexanoic
Acid Ethyl Ester
Step A: 3-(4-bromophenyl)but-2-enoic Acid Ethyl Ester
[0907] NaH (60%) was dissolved in THF (20 mL), and
2-diethoxyphosphoryl acetic acid ethyl ester (3.29 mL, 16.57 mmol)
was slowly added thereto at 0.degree. C. After 30 minutes,
1-(4-bromophenyl)ethanone (2.0 g, 10.04 mmol) dissolved in THF (10
mL) was slowly added thereto. The mixture was stirred at room
temperature for 16 hours. After termination of the reaction, the
reaction solution was diluted with water and extracted with
Et.sub.2O. The organic layer was dried with anhydrous
magnesiumsulfate and purified by column chromatography (eluent,
EtOAc/Hex=1/10) to obtain the title compound (1.89 g, 70%).
[0908] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.51 (2H, m), 7.35
(2H, m), 6.11 (1H, s), 4.22 (2H, q), 2.55 (3H, s), 1.32 (3H, t)
Step B: 3-(4-bromophenyl)butan-1-ol
[0909] 3-(4-Bromophenyl)but-2-enoic acid ethyl ester (1.89 g, 7.02
mmol) obtained in Step A was dissolved in THF (22 mL), and LAH
(0.48 g, 12.86 mmol) was added little by little thereto at
0.degree. C. The mixture was stirred at room temperature for 16
hours. After termination of the reaction, the reaction solution was
diluted with 1N HCl at 0.degree. C. and extracted with DCM. The
organic layer was dried with anhydrous magnesiumsulfate and
purified by column chromatography (eluent, Et.sub.2O/Hex=1/2) to
obtain the title compound (0.437 g, 25%).
[0910] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.41 (2H, m), 7.08
(2H, m), 3.58 (2H, m), 2.88 (1H, m), 1.85 (2H, t), 1.28 (3H, d),
0.88 (1H, t)
Step C: 3-(4-bromophenyl)butanal
[0911] 3-(4-Bromophenyl)butan-1-ol (0.437 g, 1.90 mmol) obtained in
Step B was reacted in the same manner as in Step A of Preparation
Example 26 to obtain the title compound (0.386 g, 89%).
[0912] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 9.70 (1H, s), 7.42
(2H, m), 7.10 (2H, m), 3.33 (1H, m), 2.68 (2H, m), 1.30 (3H, d)
Step D: (E)-5-(4-bromophenyl)hex-2-enoic Acid Ethyl Ester
[0913] 3-(4-Bromophenyl)butanal (0.386 g, 1.69 mmol) obtained in
Step C was reacted in the same manner as in Step B of Preparation
Example 26 to obtain the title compound (0.508 g, 99%).
[0914] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.41 (2H, m), 7.06
(2H, m), 6.83 (1H, m), 5.76 (1H, d), 4.15 (2H, q), 2.87 (1H, m),
2.45 (2H, m), 1.27 (6H, m)
Step E:
(E)-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]hex--
2-enoic acid Ethyl Ester
[0915] (E)-5-(4-bromophenyl)hex-2-enoic acid ethyl ester (0.508 g,
1.70 mmol) obtained in Step D were reacted in the same manner as in
Step C of Preparation Example 26 to obtain the title compound
(0.214 g, 42%).
[0916] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.75 (2H, m), 7.20
(2H, m), 6.85 (1H, m), 5.79 (1H, d), 4.15 (2H, q), 2.89 (1H, m),
2.49 (2H, m), 1.34 (12H, s), 1.27 (6H, m)
Step F:
5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]hexanoic
Acid Ethyl Ester
[0917]
(E)-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]hex-2-
-enoic acid ethyl ester (0.314 g, 0.825 mmol) obtained in Step E
and Pd/C (0.035 g) were dissolved in methanol (6 mL). The mixture
was charged with H.sub.2 gas and stirred at room temperature for 8
hours. After termination of the reaction, the reaction product was
filtered through Celite to obtain the title compound (0.314 g,
99%).
[0918] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.74 (2H, m), 7.19
(2H, m), 4.09 (2H, q), 2.71 (1H, m), 2.24 (2H, m), 1.60 (3H, m),
1.40 (1H), 1.34 (12H, s), 1.25 (6H, m)
Preparation Example 32:
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic Acid Ethyl Ester
Step A: (E)-4-diethoxyphosphorylbut-2-enoic Acid Ethyl Ester
(75%)
[0919] (E)-4-bromobut-2-enoic acid ethyl ester (75%)(10 g, 51.80
mmol) and triethyl-phosphate (8.88 mL, 51.80 mmol) were stirred at
130.degree. C. for 16 hours. The reaction product was washed with
toluene and distilled under reduced pressure. The obtained title
compound was used for the next step without purification.
Step B: (4-bromo-2,6-difluoro-phenyl)-trimethyl-silane
[0920] Diisopropylamine (16.11 mL, 113.99 mL) was dissolved in THF
(100 mL), and 2.3 M n-BuLi (50 mL) was slowly added thereto at
-100.degree. C. The mixture was stirred for 20 minutes, and
1-bromo-3,5-difluoro-benzene (20 g, 103.63 mmol) was dissolved in
THF (30 mL) at -100.degree. C. and slowly added thereto. The
mixture was stirred for 2 hours. TMSCl was dissolved in THF (20 mL)
at -100.degree. C. and slowly added thereto. The mixture was
stirred at room temperature for 16 hours. After termination of the
reaction, the reaction solution was diluted with water at 0.degree.
C. and extracted with Et.sub.2O. The organic layer was dried with
anhydrous magnesiumsulfate and distilled under reduced pressure at
30.degree. C. or below. The obtained title compound was used for
the next step without purification.
[0921] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 6.98 (2H, m), 0.35
(9H, s)
Step C: 1-(4-bromo-2,6-difluoro-phenyl)ethanone
[0922] AlCl.sub.3 (16.89 g, 126.7 mmol) was dissolved in DCM (130
mL), and AcCl (9 mL, 126.7 mmol) was added thereto at 0.degree. C.
The mixture was stirred for 1 hour.
(4-Bromo-2,6-difluoro-phenyl)-trimethyl-silane (27.48 g, 105.59
mmol) obtained in Step B was dissolved in DCM (70 mL) and slowly
added thereto at -80.degree. C. The mixture was stirred for 16
hours. After termination of the reaction, the reaction solution was
diluted with ammonium chloride aqueous solution at 0.degree. C. and
extracted with Et.sub.2O. The organic layer was dried with
anhydrous magnesiumsulfate and purified by column chromatography
(eluent, EtOAc/Hex=1/10) to obtain the title compound (19.89 g,
74%).
[0923] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.16 (2H, m), 2.58
(3H, s)
Step D: (2E,4E)-5-(4-bromo-2,6-difluoro-phenyl)hexa-2,4-dienoic
Acid Ethyl Ester
[0924] (E)-4-diethoxyphosphorylbut-2-enoic acid ethyl ester (75%)
(9.21 g, 36.806 mmol) obtained in Step A was dissolved in THF (70
mL), and LiHMDS (37 mL, 36.80 mmol) was slowly added thereto at
-78.degree. C. The mixture was stirred for 30 minutes and cooled to
-78.degree. C. 1-(4-Bromo-2,6-difluoro-phenyl)ethanone (7.16 g,
28.31 mmol) obtained in Step C was dissolved in THF (25 mL) and
slowly added thereto. The mixture was stirred at room temperature
for 16 hours. The reaction solution was diluted with ammonium
chloride aqueous solution at 0.degree. C. and extracted with
Et.sub.2O. The organic layer was dried with anhydrous
magnesiumsulfate and purified by column chromatography (eluent,
EtOAc/Hex=1/20) to obtain the title compound (7.95 g, 84%).
[0925] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.67 (1H, m), 7.12
(2H, m), 6.26 (1H, d), 5.96 (1H, d), 4.23 (2H, q), 2.20 (3H, m),
1.31 (3H, t)
Step E:
(E)-5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y-
l)phenyl]hexa-2,4-dienoic Acid Ethyl Ester
[0926] (2E,4E)-5-(4-bromo-2,6-difluoro-phenyl)hexa-2,4-dienoic acid
ethyl ester (7.95 g, 24.0 mmol) obtained in Step D was dissolved in
1,4-dioxane (80 mL) and was reacted in the same manner as in Step C
of Preparation Example 27 to obtain the title compound (7.25 g,
79%).
[0927] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.69 (1H, m), 7.34
(2H, m), 6.29 (1H, d), 5.92 (1H, d), 4.22 (2H, q), 2.20 (3H, m),
1.35 (15H, m)
Step F:
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)ph-
enyl]hexanoic Acid Ethyl Ester
[0928]
(E)-5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-
)phenyl]hexa-2,4-dienoic acid ethyl ester (7.25 g, 19.16 mmol),
Pd/C (0.70 g) obtained in Step E was dissolved in methanol (100
mL), charged with H.sub.2 gas and stirred at room temperature for 8
hours. After termination of the reaction, the reaction solution was
filtered through Celite to obtain the title compound (7.16 g,
97%).
[0929] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.22 (2H, m), 4.08
(2H, q), 3.21 (1H, m), 2.24 (2H, m), 1.80 (1H, m), 1.65 (1H, m),
1.60 (1H, m), 1.45 (1H, m), 1.30 (15H, m), 1.20 (3H, t)
Preparation Example 33: 2-ethylsulfanyl-3-iodo-pyridine
[0930] 2-Fluoro-3-iodo-pyridine (0.475 g, 2.13 mmol),
Cs.sub.2CO.sub.3 (3.47 g, 10.65 mmol), ethanethiol (0.239 mL, 3.19
mmol) were reacted in the same manner as in Preparation Example 28
to obtain the title compound (0.512 g, 90%).
[0931] .sup.1H-NMR (CDCl.sub.3) .delta. 8.40 (1H, m), 7.92 (1H, m),
6.72 (1H, m), 3.16 (2H, q), 1.39 (3H, t)
Preparation Example 34: 3-iodo-2-isopropoxy-pyridine
[0932] Isopropyl alcohol (0.043 g, 717 mmol) was dissolved in dry
DMF (3 mL). NaH (60%)(0.03 g, 0.71 mmol) was slowly added dropwise
thereto at 0.degree. C., and the mixture was stirred for 30
minutes. The mixture was slowly added to a flask containing
2-fluoro-3-iodo-pyridine (0.10 g, 0.44 mmol) and stirred at room
temperature for 1 hour. NH.sub.4Cl aqueous solution was added to
the reaction solution, and the reaction solution was extracted with
EtOAc to separate an organic layer. The organic layer was dried
with anhydrous MgSO.sub.4 and purified by column chromatography
(eluent, EtOAc/Hex=1/4) to obtain the title compound (0.029 g,
24%).
[0933] .sup.1H-NMR (CDCl.sub.3) .delta. 8.08 (1H, m), 8.00 (1H, m),
6.59 (1H, m), 5.27 (1H, m), 1.38 (6H, d)
Preparation Example 35: N-cyclopentyl-2-iodo-aniline
[0934] 2-Iodoaniline (0.39 g, 1.78 mmol) was dissolved in 6 mL of
dichloroethane. Cyclopentanone (0.15 g, 1.78 mmol) and acetic acid
(0.11 mL, 1.96 mmol) were added thereto, and the mixture was
stirred at room temperature for 16 hours. Sodium
triacetoxyborohydride (0.56 g, 2.67 mmol) added thereto, and the
mixture was stirred for 5 hours. The reaction solution was diluted
with water and extracted with DCM to separate an organic layer. The
organic layer was dried with MgSO.sub.4 and purified by column
chromatography to obtain the title compound (0.12 g, 23%).
[0935] 1H-NMR (CDCl.sub.3) .delta. 7.64 (1H, d), 7.18 (1H, t), 6.60
(1H, d), 6.40 (1H, t), 4.14 (1H, brs), 3.80 (1H, m), 2.02 (2H, m),
1.76 (2H, m), 1.63 (2H, m), 1.53 (2H, m)
Preparation Example 36: 3-bromo-N-cyclopentyl-aniline
[0936] 3-Bromoaniline (0.306 g, 1.78 mmol) and cyclopentanone (0.15
g, 1.78 mmol) were reacted in the same manner as in Preparation
Example 35 to obtain the title compound (0.347 g, 81%).
[0937] 1H-NMR (CDCl.sub.3) .delta. 6.98 (1H, t), 6.77 (1H, d), 6.72
(1H, m), 6.49 (1H, m), 3.77 (2H, m), 2.02 (2H, m) 1.72 (2H, m),
1.62 (2H, m), 1.45 (2H, m)
Preparation Example 37: 2-bromo-6-propylsulfanyl-pyridine
[0938] 2,6-Dibromopyridine (0.2 g, 0.84 mmol), Cs.sub.2CO.sub.3
(0.412 g, 1.27 mmol) and propanethiol (0.076 mL, 0.84 mmol) were
reacted in the same manner as in Preparation Example 28 to obtain
the title compound (0.184 g, 93%).
[0939] 1H-NMR (CDCl.sub.3) .delta. 7.27 (1H, t), 7.11 (2H, m), 3.13
(2H, t), 1.74 (2H, m), 1.04 (3H, t)
Preparation Example 38:
4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]butanoic
Acid Methyl Ester
Step A: 4-(4-bromophenyl)butanoic Acid Methyl Ester
[0940] 4-(4-Aminophenyl)butanoic acid (0.5 g, 2.87 mmol) was
dissolved in HBr (2 mL) at 0.degree. C. and stirred for 10 minutes.
Sodium nitrite (0.192 g, 2.78 mmol) was dissolved in water (1.3 mL)
at 0.degree. C. and added thereto. CuBr (0.22 g, 1.53 mmol) was
dissolved in HBr (2 mL) at 0.degree. C. and added thereto. The
mixture was stirred at 80.degree. C. for 4 hours. After termination
of the reaction, the reaction solvent was diluted with methanol at
0.degree. C. and extracted with ethyl acetate. The organic layer
was dried with anhydrous magnesiumsulfate, and without purification
diazomethane (6 mL) was added thereto. The solvent was distilled
under reduced pressure and purified by column chromatography
(eluent, EtOAc/Hex=1/4) to obtain the title compound (0.139 g,
19%).
[0941] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.42 (2H, m), 7.04
(2H, m), 3.66 (3H, s), 2.59 (2H, t), 2.31 (2H, m), 1.93 (2H, m)
Step B:
4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]butanoic
Acid Methyl Ester
[0942] 4-(4-Bromophenyl)butanoic acid methyl ester (0.165 g, 0.64
mmol) obtained in Step A was reacted in the same manner as in Step
C of Preparation Example 27 to obtain the title compound (0.039 g,
57%).
[0943] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.72 (2H, m), 7.19
(2H, m), 3.66 (3H, s), 2.67 (2H, t), 2.32 (2H, t), 1.96 (2H, m),
1.34 (12H, s)
Preparation Example 39: 2-cyclobutoxy-3-iodo-pyridine
[0944] Cyclobutanol (0.064 g, 1.34 mmol) and
2-fluoro-3-iodo-pyridine (0.2 g, 0.89 mmol) were reacted in the
same manner as in Preparation Example 34 to obtain the title
compound (0.16 g, 66%).
[0945] 1H-NMR (CDCl.sub.3) .delta. 8.07 (1H, m), 8.00 (1H, m), 6.61
(1H, m), 5.18 (1H, m), 2.47 (2H, m), 2.20 (2H, m), 1.84 (1H, m),
1.67 (1H, m)
Preparation Example 40: 2-cyclopropylmethoxy-3-iodo-pyridine
[0946] Cyclopropyl-methanol (0.089 g, 1.23 mmol) was dissolved in
anhydrous DMF (2 mL), and NaH (60%)(0.054 g, 1.35 mmol) was slowly
added dropwise thereto at 0.degree. C. The mixture was stirred for
30 minutes. The mixture was slowly added to a flask containing
2-fluoro-3-iodo-pyridine (0.137 g, 0.617 mmol) and stirred at room
temperature for 1 hour. NH.sub.4Cl aqueous solution was added to
the reaction solution, and the reaction solution was extracted with
EtOAc to separate an organic layer. The organic layer was dried
with MgSO.sub.4 and purified by column chromatography (eluent,
EtOAc/Hex=1/5) to obtain the title compound (0.141 g, 83%).
[0947] .sup.1H-NMR (CDCl.sub.3) .delta. 8.07 (1H, m), 8.00 (1H, m),
6.61 (1H, m), 4.20 (2H, d), 1.32 (1H, m), 0.60 (2H, m), 0.39 (2H,
m)
Preparation Example 41: 2-cyclobutoxy-3-iodo-pyridine
[0948] Cyclobutanol (0.064 g, 1.34 mmol) and
2-fluoro-3-iodo-pyridine (0.2 g, 0.89 mmol) were reacted in the
same manner as in Preparation Example 34 to obtain the title
compound (0.16 g, 66%).
[0949] 1H-NMR (CDCl.sub.3) .delta. 8.07 (1H, m), 8.00 (1H, m), 6.61
(1H, m), 5.18 (1H, m), 2.47 (2H, m), 2.20 (2H, m), 1.84 (1H, m),
1.67 (1H, m)
Preparation Example 42: 2-bromo-6-isopropoxy-pyridine
[0950] Propan-2-ol (0.065 mL, 0.84 mmol) and 2,6-dibromopyridine
(0.2 g, 0.84 mmol) were reacted in the same manner as in
Preparation Example 34 to obtain the title compound (0.027 g,
14%).
[0951] 1H-NMR (CDCl.sub.3) .delta. 7.37 (1H, t), 7.00 (1H, d), 6.60
(1H, d), 5.27 (1H, m), 1.33 (6H, d)
Preparation Example 43: 2-chloro-6-cyclopropylmethoxy-pyridine
[0952] 6-Chloro-2-pyridone (1.0 g, 7.7 mmol), K.sub.2CO.sub.3 (2.13
g, 15.4 mmol) and (bromomethyl)cyclopropane (1.1 g, 8.1 mmol) were
added to 15 mL of DMF, and the mixture was stirred at 80.degree. C.
for 16 hours. The reaction solution was concentrated under reduced
pressure and purified by column chromatography to obtain the title
compound (0.65 g, 45%).
[0953] .sup.1H NMR (CDCl.sub.3) .delta. 7.50 (1H, t), 6.87 (1H, d),
6.67 (1H, d), 4.12 (2H, d), 1.26 (1H, m), 0.62 (2H, m), 0.36 (2H,
m)
Preparation Example 44: 2-bromo-6-cyclopropylmethoxy-pyridine
[0954] Cyclopropylmethanol (0.068 mL, 0.84 mmol) and
2,6-dibromopyridine (0.2 g, 0.84 mmol) were reacted in the same
manner as in Preparation Example 34 to obtain the title compound
(0.1 g, 53%).
[0955] 1H-NMR (CDCl.sub.3) .delta. 7.39 (1H, t), 7.03 (1H, d), 6.70
(1H, d), 4.12 (2H, d), 1.24 (1H, m), 0.59 (2H, m), 0.35 (2H, m)
Preparation Example 45: 2-bromo-6-propoxy-pyridine
[0956] Propanol (0.07 mL, 0.92 mmol) and 2,6-dibromopyridine (0.2
g, 0.84 mmol) were reacted in the same manner as in Preparation
Example 34 to obtain the title compound (0.067 g, 36%).
[0957] 1H-NMR (CDCl.sub.3) .delta. 7.39 (1H, t), 7.03 (1H, d), 6.65
(1H, d), 4.23 (2H, t), 1.76 (2H, m), 1.00 (3H, t)
Preparation Example 46: 2-chloro-6-isopropoxy-pyridine
[0958] Isopropanol (0.97 g, 16.1 mmol) was dissolved in 45 mL of
THF and cooled to 0.degree. C. NaH (55% in mineral oil, 0.7 g, 16
mmol) was added thereto, and the mixture was stirred at room
temperature for 1 hour. 2,6-Dichloropyridine (2.0 g, 13.5 mmol) was
added thereto, and the mixture was stirred for 16 hours under
reflux. The reaction solution was cooled to room temperature,
diluted with 20 mL of water and extracted with EtOAc. The separated
organic layer was dried with MgSO.sub.4 and purified by column
chromatography to obtain the title compound (1.917 g, 82%).
[0959] .sup.1H NMR (CDCl.sub.3) .delta. 7.48 (1H, t), 6.83 (1H, d),
6.58 (1H, d), 5.29 (1H, m), 1.34 (6H, d)
Preparation Example 47: 3-iodo-2-propoxy-pyridine
[0960] Propanol (0.1 mL, 1.34 mmol) and 2-fluoro-3-iodo-pyridine
(0.2 g, 0.89 mmol) were reacted in the same manner as in
Preparation Example 34 to obtain the title compound (0.11 g,
46%).
[0961] 1H-NMR (CDCl.sub.3) .delta. 8.08 (1H, m), 8.00 (1H, m), 6.61
(1H, m), 4.28 (2H, t), 1.82 (2H, m), 1.04 (3H, t)
Preparation Example 48: 2-cyclobutylmethoxy-3-iodo-pyridine
[0962] Cyclobutyl-methanol (0.37 g, 4.31 mmol) and
2-fluoro-3-iodo-pyridine (0.60 g, 2.69 mmol) were reacted in the
same manner as in Preparation Example 34 to obtain the title
compound (0.75 g, 96%).
[0963] .sup.1H-NMR (CDCl.sub.3) .delta. 8.08 (1H, m), 8.02 (1H, m),
6.63 (1H, m), 4.29 (2H, d), 2.79 (1H, m), 2.12 (2H, m), 1.96 (4H,
m)
Preparation Example 49:
3-iodo-2-(tetrahydro-furan-3-yloxy)-pyridine
[0964] Tetrahydro-furan-3-ol (0.39 g, 4.44 mmol) and
2-fluoro-3-iodo-pyridine (0.66 g, 2.96 mmol) were reacted in the
same manner as in Preparation Example 34 to obtain the title
compound (0.68 g, 80%).
[0965] .sup.1H-NMR (CDCl.sub.3) .delta. 8.08 (1H, m), 8.03 (1H, m),
6.65 (1H, m), 5.53 (1H, m), 4.12 (1H, m), 4.06 (1H, m), 3.94 (2H,
m), 2.23 (2H, m)
Preparation Example 50:
3-iodo-2-(tetrahydro-pyran-4-yloxy)-pyridine
[0966] Tetrahydro-pyran-4-ol (0.45 g, 4.44 mmol) and
2-fluoro-3-iodo-pyridine (0.66 g, 2.96 mmol) were reacted in the
same manner as in Preparation Example 34 to obtain the title
compound (0.80 g, 89%).
[0967] .sup.1H-NMR (CDCl.sub.3) .delta. 8.07 (1H, d), 8.01 (1H, d),
6.63 (1H, m), 5.30 (1H, m), 4.01 (2H, m), 3.68 (2H, m), 2.04 (2H,
m), 1.85 (2H, m)
Preparation Example 51: N-cyclopentyl-3-iodo-pyridin-2-amine
[0968] 2-Fluoro-3-iodo-pyridine (0.3 g, 1.34 mmol),
cyclopentylamine (0.34 g, 4 mmol) and diisopropylethylamine (0.46
mL, 2.68 mmol) were dissolved in 3.3 mL of CH.sub.3CN and the
mixture was stirred at 110.degree. C. for 2 hours by the use of
microwave. The reaction solution was concentrated under reduced
pressure and purified by column chromatography to obtain the title
compound (0.155 g, 40%).
[0969] .sup.1H-NMR (CDCl.sub.3) .delta. 8.07 (1H, d), 7.80 (1H, d),
6.28 (1H, m), 4.88 (1H, brs), 4.30 (1H, m), 2.10 (2H, m), 1.75 (2H,
m), 1.65 (2H, m), 1.48 (2H, m)
Preparation Example 52: 2-bromo-6-cyclobutylsulfanyl-pyridine
[0970] Cyclobutylthiol (0.074 g, 0.84 mmol) and 2,6-dibromopyridine
(0.2 g, 0.84 mmol) were reacted in the same manner as in
Preparation Example 34 to obtain the title compound (0.047 g,
22%).
[0971] .sup.1H-NMR (CDCl.sub.3) .delta. 7.27 (1H, t), 7.11 (1H, d),
7.00 (1H, d), 4.28 (1H, m), 2.53 (2H, m), 2.08 (4H, m)
Preparation Example 53: 1-(3-bromophenyl)pyrrolidine
[0972] 1,3-Dibromobenzene (1.0 g, 4.24 mmol), pyrrolidine (0.43 mL,
5.0 mmol), sodium tert-butoxide (1.14 g, 11.87 mmol) and BINAP (0.2
g, 0.32 mmol) were dissolved in 17 mL of toluene.
Pd.sub.2(dba).sub.3 (0.097 g, 0.1 mmol) was added thereto, and the
mixture was stirred 4 hours under reflux. Solids were filtered
through Celite and purified by column chromatography to obtain the
title compound (0.52 g, 54%).
[0973] 1H-NMR (CDCl.sub.3) .delta. 7.05 (1H, t), 6.75 (1H, d), 6.67
(1H, m), 6.45 (1H, m), 3.26 (4H, m), 2.00 (4H, m)
Preparation Example 54: 2-chloro-6-phenoxy-pyridine
[0974] 2,6-Dichloropyridine (2.0 g, 13.5 mmol) and phenol (1.4 mL,
14.9 mmol) were reacted in the same manner as in Preparation
Example 34 to obtain the title compound (3.5 g, 84%).
[0975] .sup.1H-NMR (CDCl.sub.3) .delta. 7.62 (1H, t), 7.41 (2H, m),
7.21 (1H, t), 7.14 (2H, d), 6.74 (2H, d)
Preparation Example 55: 2-bromo-4-fluoro-1-isopropoxy-benzene
[0976] 2-Bromo-4-fluoro-phenol (0.3 g, 1.57 mmol), 2-bromo-propane
(0.22 mL) and Cs.sub.2CO.sub.3 (1.53 g) were reacted in the same
manner as in Preparation Example 28 to obtain the title compound
(0.33 g, 89%).
[0977] 1H-NMR (CDCl.sub.3) .delta. 7.28 (1H, m), 6.94 (1H, m), 6.88
(1H, m), 4.44 (1H, m), 1.32 (6H, d).
Preparation Example 56: 3-bromo-5-methyl-pyridin-2-ol
[0978] 5-Methyl-pyridin-2-ol (1 g, 9.16 mmol) was dissolved in 4 mL
of CS.sub.2. Br.sub.2 (0.47 mL) was added thereto, and the mixture
was stirred at room temperature for 2 hours. Sodium thiosulfate
(Na.sub.2S.sub.2O.sub.3) aqueous solution was added thereto, and
the reaction solution was extracted with EtOAc. The separated
organic layer was dried with MgSO.sub.4 and concentrated under
reduced pressure to obtain the title compound (1.7 g, 98%) in a
solid form.
[0979] 1H-NMR (CDCl.sub.3) .delta. 7.73 (1H, s), 7.22 (1H, s), 2.10
(3H, s).
Preparation Example 57:
3-bromo-2-cyclopentyloxy-5-methyl-pyridine
[0980] 3-Bromo-5-methyl-pyridin-2-ol (0.5 g, 2.66 mmol) obtained in
Preparation Example 56, bromo-cyclopentan (0.43 mL) and
Cs.sub.2CO.sub.3 (2.6 g) were reacted in the same manner as in
Preparation Example 28 to obtain the title compound (0.25 g,
37%).
[0981] H-NMR (CDCl.sub.3) .delta. 7.86 (1H, s), 7.60 (1H, s), 5.38
(1H, m), 2.21 (3H, s), 1.93 (2H, m), 1.82 (4H, m), 1.61 (2H,
m).
Preparation Example 58:
3-[(4-methoxyphenyl)methoxy]isoxazol-5-carboxylic Acid Methyl
Ester
[0982] 3-Hydroxyisoxazol-5-carboxylic acid methyl ester (4.73 g, 33
mmol) was dissolved in 66 mL of DMF. K.sub.2CO.sub.3 (5.0 g, 36.3
mmol) and 4-methoxybenzyl chloride (4.5 mL, 33 mmol) were added
thereto at 0.degree. C., and the mixture was stirred at 60.degree.
C. for 10 hours. The reaction solution was concentrated under
reduced pressure, diluted with water and extracted with EtOAc. The
organic layer was dried with MgSO.sub.4 and purified by column
chromatography to obtain the title compound (4.06 g, 47%).
[0983] .sup.1H-NMR (CDCl.sub.3) .delta. 7.39 (2H, d), 6.92 (2H, d),
6.54 (1H, s), 5.24 (2H, s), 3.95 (3H, s), 3.81 (3H, s)
Preparation Example 59:
[3-[(4-methoxyphenyl)methoxy]isoxazol-5-yl]methanol
[0984] 3-[(4-Methoxyphenyl)methoxy]isoxazol-5-carboxylic acid
methyl ester (4.06 g, 15.4 mmol) obtained in Preparation Example 58
was dissolved in 51 mL of MeOH. NaBH.sub.4 (0.87 g, 23 mmol) was
added thereto, and the mixture was stirred for 4 hours under
reflux. The reaction solution was diluted with water and extracted
with EtOAc. The organic layer was dried with MgSO.sub.4 and
purified by column chromatography to obtain the title compound
(2.58 g, 71%).
[0985] .sup.1H-NMR (CDCl.sub.3) .delta. 7.38 (2H, d), 6.92 (2H, d),
5.89 (1H, s), 5.19 (2H, s), 4.66 (2H, d), 3.82 (3H, s), 1.95 (1H,
t)
Preparation Example 60:
[3-[(4-methoxyphenyl)methoxy]isoxazol-5-yl]methyl
Methanesulfonate
[0986] [3-[(4-Methoxyphenyl)methoxy]isoxazol-5-yl]methanol (0.19 g,
0.82 mmol) obtained in Preparation Example 59 was dissolved in 4 mL
of DCM. DIPEA (0.29 mL, 1.64 mmol) and methanesulfonyl chloride
(0.07 mL, 0.9 mmol) were sequentially added thereto at 0.degree.
C., and the mixture was stirred at room temperature for 80 minutes.
The reaction solution was diluted with water and extracted with
EtOAc. The organic layer was dried with MgSO.sub.4 and used for the
next reaction without purification.
[0987] .sup.1H-NMR (CDCl.sub.3) .delta. 7.38 (2H, d), 6.93 (2H, d),
6.08 (1H, s), 5.21 (2H, s), 5.18 (2H, s), 3.82 (3H, s), 3.06 (3H,
s)
Preparation Example 61:
3-[(4-methoxyphenyl)methoxy]isoxazol-5-carbaldehyde
[0988] [3-[(4-Methoxyphenyl)methoxy]isoxazol-5-yl]methanol (0.4 g,
1.7 mmol) obtained in Preparation Example 59 was dissolved in 8 mL
of DCM. Pyridinium chlorochromate (0.74 g, 3.4 mmol) was added
thereto, and the mixture was stirred at room temperature for 16
hours. The reaction product was filtered through silica gel to
obtain the title compound (0.22 g, 55%).
[0989] .sup.1H-NMR (CDCl.sub.3) .delta. 9.84 (1H, s), 7.39 (2H, d),
6.93 (2H, d), 6.57 (1H, s), 5.27 (2H, s), 3.83 (3H, s)
Preparation Example 62:
5-[[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]m-
ethyl]-3-[(4-methoxyphenyl)methoxy]isoxazol
[0990] To
2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
ol (2.42 g, 9.43 mmol) obtained in Step B of Preparation Example
16, [3-[(4-methoxyphenyl)methoxy]isoxazol-5-yl]methanol (2.19 g,
9.31 mmol) obtained in Preparation Example 59 and
triphenylphosphine (2.44 g, 9.31 mmol) 93 mL of THF was added and
cooled to 0.degree. C. Diisopropyl azodicarboxylate (1.83 mL, 9.31
mmol) was added thereto, and the mixture was stirred at room
temperature for 16 hours. The reaction solution was concentrated
under reduced pressure and purified by column chromatography to
obtain the title compound (3.07 g, 70%).
[0991] .sup.1H-NMR (CDCl.sub.3) .delta. 7.37 (2H, d), 7.32 (2H, m),
6.91 (2H, d), 6.00 (1H, s), 5.18 (2H, s), 5.17 (2H, s), 3.82 (3H,
s), 1.33 (12H, s)
Preparation Example 63:
3-[(4-methoxyphenyl)methoxy]-5-methyl-isoxazole
[0992] 5-Methylisoxazol-3-ol (0.64 g, 6.46 mmol) was dissolved in
13 mL of DMF.
[0993] K.sub.2CO.sub.3 (0.98 g, 7.1 mmol) and 4-methoxybenzyl
chloride (0.88 mL, 6.46 mmol) were added thereto, and the mixture
was stirred at 60.degree. C. for 4 hours. The filtrate obtained by
filtering solids was purified by column chromatography to obtain
the title compound (0.53 g, 40%).
[0994] .sup.1H-NMR (CDCl.sub.3) .delta. 7.37 (2H, d), 6.91 (2H, d),
5.62 (1H, s), 5.17 (2H, s), 3.82 (3H, s), 2.33 (3H, s)
Preparation Example 64: 4-[2-(cyclopentoxy)-3-pyridyl]aniline
[0995] 2-Cyclopentoxy-3-iodo-pyridine (0.3 g, 1 mmol) obtained in
Preparation Example 11 and
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.22 g, 1
mmol) were reacted in the same manner as in Step A of Example 1 to
obtain the title compound (0.18 g, 72%).
[0996] .sup.1H-NMR (CDCl.sub.3) .delta. 8.06 (1H, m), 7.56 (1H, m),
7.39 (2H, d), 6.89 (1H, m), 6.72 (2H, d), 5.50 (1H, m), 3.73 (2H,
brs), 1.95 (2H, m), 1.83 (2H, m), 1.75 (2H, m), 1.62 (2H, m)
Preparation Example 65:
4-[2-(cyclopentoxy)-3-pyridyl]benzenethiol
[0997] Catalytic amount of copper chloride (I) was added to 12 mL
of water. SOCl.sub.2 (0.2 mL, 2.58 mmol) was added thereto at
0.degree. C., and the mixture was stirred at room temperature for
16 hours. 4-[2-(Cyclopentoxy)-3-pyridyl]aniline (0.18 g, 0.71 mmol)
obtained in Preparation Example 64 was prepared in another reaction
vessel, and 7.1 mL of 3 M HCl aqueous solution was added thereto.
Sodium nitrite (0.054 g, 0.78 mmol, 5 M aqueous solution) was
slowly added thereto at -5.degree. C., and the mixture was stirred
at 0.degree. C. for 1 hour, and slowly added to the mixture
solution of copper chloride (I) and SOCl.sub.2. The reaction
solution was stirred at 0.degree. C. for 3 hours and extracted with
EtOAc. The organic layer was MgSO.sub.4, and 20 mL of THF was added
thereto and cooled to 0.degree. C. Triphenylphosphine (0.27 g, 1
mmol) was added thereto, and the mixture was stirred. After 15
minutes, 20 mL of water was added thereto, and the reaction
solution was stirred at room temperature for 16 hours and extracted
with EtOAc. The organic layer was dried with MgSO.sub.4 and
purified by column chromatography to obtain the title compound
(0.022 g, 11%).
[0998] .sup.1H-NMR (CDCl.sub.3) .delta. 8.12 (1H, m), 7.56 (1H, m),
7.44 (2H, d), 7.30 (2H, d), 6.91 (1H, m), 5.50 (1H, m), 1.94 (2H,
m), 1.80 (2H, m), 1.72 (2H, m), 1.62 (2H, m)
Preparation Example 66:
2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
[0999] 2,6-Difluoro-4-iodo-aniline (9.35 g, 36.7 mmol) was reacted
in the same manner as in Step D of Preparation Example 1 to obtain
the title compound (6.46 g, 69%).
[1000] .sup.1H-NMR (CDCl.sub.3) .delta. 7.24 (2H, m), 3.93 (2H,
brs), 1.31 (12H, s)
Preparation Example 67:
4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-aniline
[1001] 2-Cyclopentoxy-3-iodo-pyridine (1.09 g, 3.8 mmol) obtained
in Preparation Example 11 and
2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(0.925 g, 3.62 mmol) obtained in Preparation Example 66 were
reacted in the same manner as in Step A of Example 1 to obtain the
title compound (0.6 g, 57%).
[1002] .sup.1H-NMR (CDCl.sub.3) .delta. 8.10 (1H, m), 7.54 (1H, m),
7.11 (2H, m), 6.90 (1H, m), 5.51 (1H, m), 3.78 (2H, brs), 1.95 (2H,
m), 1.83 (2H, m), 1.76 (2H, m), 1.65 (2H, m)
Preparation Example 68:
4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-benzenethiol
[1003] 4-[2-(Cyclopentoxy)-3-pyridyl]-2,6-difluoro-aniline (0.42 g,
1.47 mmol) obtained in Preparation Example 67 was reacted in the
same manner as in Preparation Example 65 to obtain the title
compound (0.046 g, 10%).
[1004] .sup.1H-NMR (CDCl.sub.3) .delta. 8.20 (1H, m), 7.61 (1H, m),
7.22 (2H, m), 7.00 (1H, m), 5.56 (1H, m), 1.99 (2H, m), 1.86 (2H,
m), 1.80 (2H, m), 1.70 (2H, m)
Preparation Example 69:
2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic
Acid Methyl Ester
Step A: 4-bromo-2,6-difluoro-benzoic Acid
[1005] 70 mL of THF was cooled to -78.degree. C., and
diisopropylamine (4 mL, 28.5 mmol) and butyllithium (13 mL, 27.2
mmol, 2.1 M hexane solution) were sequentially added thereto. The
mixture was stirred at -78.degree. C. for 1 hour, and
1-bromo-3,5-difluorobenzene (5.0 g, 25.9 mmol) dissolved in 15 mL
was slowly added thereto. The mixture was stirred at -78.degree. C.
for 45 minutes, and the reaction solution was transferred to a
beaker containing solid carbon dioxide and stirred at room
temperature for 16 hours. The reaction solution was adjusted to pH
3 by the addition of 1N HCl aqueous solution and extracted with
EtOAc. The organic layer was collected and dried with MgSO.sub.4 to
obtain the title compound (5.15 g, 84%).
[1006] .sup.1H-NMR (CDCl.sub.3) .delta. 7.20 (2H, m)
Step B: 4-bromo-2,6-difluoro-benzoic Acid Methyl Ester
[1007] 4-Bromo-2,6-difluoro-benzoic acid (5.15 g, 21.7 mmol)
obtained in Step A was dissolve in 54 mL of MeOH. SOCl.sub.2 (2.4
mL, 32.6 mmol) was added thereto, and the mixture was stirred for 3
hours under reflux. The reaction solution was concentrated under
reduced pressure, diluted with sodium bicarbonate aqueous solution,
and extracted with EtOAc. The organic layer was collected and dried
with MgSO.sub.4 to obtain the title compound (2.9 g, 53%).
[1008] .sup.1H-NMR (CDCl.sub.3) .delta. 7.16 (2H, m), 3.95 (3H,
s)
Step C:
2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoi-
c Acid Methyl Ester
[1009] 4-Bromo-2,6-difluoro-benzoic acid methyl ester (1.27 g, 5.0
mmol) obtained in Step B was reacted in the same manner as in Step
D of Preparation Example 1 to obtain the title compound (1.20 g,
80%).
[1010] .sup.1H-NMR (CDCl.sub.3) .delta. 7.34 (2H, m), 3.95 (3H, s),
1.34 (12H, s)
Preparation Example 70:
3-[4-(chloromethyl)-3,5-difluoro-phenyl]-2-(cyclopentoxy)pyridine
Step A: 4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-benzoic Acid
Methyl Ester
[1011] 2-Cyclopentoxy-3-iodo-pyridine (0.96 g, 3.3 mmol) obtained
in Preparation Example 11 and
2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic
acid methyl ester (1.04 g, 3.5 mmol) obtained in Preparation
Example 69 were reacted in the same manner as in Step A of Example
1 to obtain the title compound (0.47 g, 42%).
[1012] .sup.1H-NMR (CDCl.sub.3) .delta. 8.20 (1H, m), 7.61 (1H, m),
7.21 (2H, m), 6.95 (1H, m), 5.53 (1H, m), 3.97 (3H, s), 1.95 (2H,
m), 1.81 (2H, m), 1.74 (2H, m), 1.65 (2H, m)
Step B:
[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]methanol
[1013] 4-[2-(Cyclopentoxy)-3-pyridyl]-2,6-difluoro-benzoic acid
methyl ester (0.47 g, 1.41 mmol) obtained in Step A was dissolved
in 7 mL of THF. Diisobutylaluminum hydride (1.32 mL, 2.1 mmol, 1.6
M toluene solution) was slowly added thereto at -78.degree. C. The
reaction solution was stirred at -78.degree. C. for 2 hours and
additionally stirred at room temperature for 1 hour. After
termination of the reaction, the reaction solution was cooled to
-78.degree. C., and MeOH was added thereto. After addition of HCl
aqueous solution at 0.degree. C., the reaction solution was stirred
for 1 hour. Solids were filtered through Celite, and water was
added to the filtrate. The filtrate was extracted with EtOAc. The
organic layer was dried with MgSO.sub.4 to obtain the title
compound (0.38 g, 90%).
[1014] .sup.1H-NMR (CDCl.sub.3) .delta. 8.17 (1H, m), 7.58 (1H, m),
7.16 (2H, m), 6.95 (1H, m), 5.53 (1H, m), 4.82 (2H, d), 1.95 (2H,
m), 1.89 (1H, t, OH), 1.82 (2H, m), 1.75 (2H, m), 1.64 (2H, m)
Step C:
3-[4-(chloromethyl)-3,5-difluoro-phenyl]-2-(cyclopentoxy)pyridine
[1015] [4-[2-(Cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]methanol
(0.38 g, 1.27 mmol) obtained in Step B was dissolved in 6.4 mL of
CH.sub.3CN, and SOCl.sub.2 (0.19 mL, 2.54 mmol) was slowly added
thereto. The mixture was stirred at room temperature for 90
minutes. The reaction solution was concentrated under reduced
pressure and water was added thereto. The reaction solution was
extracted with EtOAc, and the organic layer was dried with
MgSO.sub.4 to obtain the title compound (0.40 g, 99%).
[1016] .sup.1H-NMR (CDCl.sub.3) .delta. 8.19 (1H, m), 7.59 (1H, m),
7.18 (2H, m), 6.99 (1H, m), 5.53 (1H, m), 4.71 (2H, s), 1.96 (2H,
m), 1.82-1.63 (6H, m)
Preparation Example 71:
4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanenitrile
Step A: 3-(4-bromophenyl)propan-1-ol
[1017] 3-(4-Bromophenyl)propanoic acid (1.67 g, 7.3 mmol) was
dissolved in 24 mL of THF and cooled to 0.degree. C. Borane-THF (22
mL, 22 mmol, 1.0 M THF solution) was added thereto, and the mixture
was stirred at room temperature for 16 hours. The reaction solution
was cooled to 0.degree. C., and water and 1N HCl aqueous solution
were sequentially added thereto. The reaction solution was
extracted with EtOAc, and the organic layer was dried with
MgSO.sub.4 and purified by column chromatography to obtain the
title compound (1.46 g, 93%).
[1018] .sup.1H-NMR (CDCl.sub.3) .delta. 7.40 (2H, d), 7.08 (2H, d),
3.66 (2H, m), 2.67 (2H, m), 1.86 (2H, m), 1.26 (1H, t, OH)
Step B: 3-(4-bromophenyl)propyl Methanesulfonate
[1019] 3-(4-Bromophenyl)propan-1-ol (1.46 g, 6.79 mmol) obtained in
Step A was reacted in the same manner as in Preparation Example 60
to obtain the title compound (1.87 g, 93%).
[1020] .sup.1H-NMR (CDCl.sub.3) .delta. 7.42 (2H, d), 7.07 (2H, d),
4.22 (2H, t), 3.00 (3H, s), 2.72 (2H, t), 2.05 (2H, m)
Step C: 4-(4-bromophenyl)butanenitrile
[1021] 3-(4-Bromophenyl)propyl methanesulfonate (1.04 g, 3.55 mmol)
obtained in Step B was reacted in the same manner as in Step E of
Preparation Example 81 to obtain the title compound (0.73 g,
99%).
[1022] .sup.1H-NMR (CDCl.sub.3) .delta. 7.44 (2H, d), 7.07 (2H, d),
2.74 (2H, t), 2.32 (2H, t), 1.96 (2H, m)
Step D:
4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanenit-
rile
[1023] 4-(4-Bromophenyl)butanenitrile (0.73 g, 3.5 mmol) obtained
in Step C was reacted in the same manner as in Step D of
Preparation Example 1 to obtain the title compound (0.7 g,
73%).
[1024] .sup.1H-NMR (CDCl.sub.3) .delta. 7.70 (2H, d), 7.20 (2H, d),
2.79 (2H, t), 2.30 (2H, t), 1.99 (2H, m), 1.34 (12H, s)
Preparation Example 72:
5-[[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]m-
ethyl]-2-[(4-methoxyphenyl)methoxy]pyridine
Step A: 6-[(4-methoxyphenyl)methoxy]pyridin-3-carboxylic Acid
[1025] (4-Methoxyphenyl)methanol (2.6 mL, 21 mmol) was dissolved in
47 mL of DMF. NaH (1.23 g, 28.1 mmol, 55 wt % in mineral oil) was
added thereto at 0.degree. C., and the mixture was stirred for 30
minutes. 6-Chloropyridin-3-carboxylic acid (2.22 g, 14 mmol) was
added thereto, and the mixture was stirred at 80.degree. C. for 7
hours. The reaction solution was concentrated under reduced
pressure and water was added thereto. The reaction solution was
adjusted to pH 3 by the use of 1 N HCl aqueous solution. The
precipitate was filtered and dried to obtain the title compound
(1.67 g, 45%).
[1026] .sup.1H-NMR (CDCl.sub.3) .delta. 8.92 (1H, s), 8.20 (1H, m),
7.41 (2H, d), 6.92 (2H, d), 6.82 (1H, m), 5.40 (2H, s), 3.82 (3H,
s)
Step B: 6-[(4-methoxyphenyl)methoxy]pyridin-3-carboxylic Acid Ethyl
Ester
[1027] 6-[(4-Methoxyphenyl)methoxy]pyridin-3-carboxylic acid (1.67
g, 6.4 mmol) obtained in Step A was dissolved in 13 mL of THF.
1,1-Carbonyldiimidazole (1.03 g, 6.4 mmol) was added thereto, and
the mixture was stirred at room temperature for 1 hour. 13 mL of
anhydrous ethanol was added thereto, and the mixture was stirred at
room temperature for 16 hours. The reaction solution was
concentrated under reduced pressure and purified by column
chromatography to obtain the title compound (1.49 g, 80%).
[1028] .sup.1H-NMR (CDCl.sub.3) .delta. 8.85 (1H, m), 8.15 (1H, m),
7.40 (2H, d), 6.93 (2H, d), 6.79 (1H, m), 5.37 (2H, s), 4.38 (2H,
q), 3.83 (3H, s), 1.39 (3H, t)
Step C: [6-[(4-methoxyphenyl)methoxy]-3-pyridyl]methanol
[1029] 6-[(4-Methoxyphenyl)methoxy]pyridin-3-carboxylic acid ethyl
ester (1.48 g, 5.18 mmol) obtained in Step B was reacted in the
same manner as in Step B of Preparation Example 70 to obtain the
title compound (0.96 g, 76%).
[1030] .sup.1H-NMR (CDCl.sub.3) .delta. 8.15 (1H, m), 7.62 (1H, m),
7.39 (2H, d), 6.92 (2H, d), 6.79 (1H, m), 5.31 (2H, s), 4.63 (2H,
s), 3.81 (3H, s)
Step D:
5-[[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ph-
enoxy]methyl]-2-[(4-methoxyphenyl)methoxy]pyridine
[1031] [6-[(4-Methoxyphenyl)methoxy]-3-pyridyl]methanol (0.144 g,
0.58 mmol) obtained in Step C and
2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
(0.15 g, 0.58 mmol) obtained in Step B of Preparation Example 16
were reacted in the same manner as in Preparation Example 62 to
obtain the title compound (0.155 g, 55%).
[1032] .sup.1H-NMR (CDCl.sub.3) .delta. 8.15 (1H, m), 7.70 (1H, m),
7.38 (2H, d), 7.28 (2H, m), 6.90 (2H, d), 6.76 (1H, m), 5.29 (2H,
s), 5.13 (2H, s), 3.80 (3H, s), 1.32 (12H, s)
Preparation Example 73:
4-[[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]m-
ethyl]-2-[(4-methoxyphenyl)methoxy]pyridine
Step A: 2-[(4-methoxyphenyl)methoxy]pyridin-4-carboxylic Acid
[1033] 2-Chloropyridin-4-carboxylic acid (2.22 g, 14 mmol) and
(4-methoxyphenyl)methanol (2.6 mL, 21 mmol) were reacted in the
same manner as in Step A of Preparation Example 72 to obtain the
title compound (1.86 g, 51%).
[1034] .sup.1H-NMR (CDCl.sub.3) .delta. 8.33 (1H, m), 7.45 (1H, m),
7.39 (3H, m), 6.92 (2H, d), 5.35 (2H, s), 3.82 (3H, s)
Step B: 2-[(4-methoxyphenyl)methoxy]pyridin-4-carboxylic Acid Ethyl
Ester
[1035] 2-[(4-Methoxyphenyl)methoxy]pyridin-4-carboxylic acid (0.51
g, 1.97 mmol) obtained in Step A was reacted in the same manner as
in Step B of Preparation Example 72 to obtain the title compound
(0.39 g, 68%).
[1036] .sup.1H-NMR (CDCl.sub.3) .delta. 8.28 (1H, m), 7.38 (4H, m),
6.92 (2H, d), 5.36 (2H, s), 4.42 (2H, q), 3.88 (3H, s), 1.38 (3H,
t)
Step C: [2-[(4-methoxyphenyl)methoxy]-4-pyridyl]methanol
[1037] 2-[(4-Methoxyphenyl)methoxy]pyridin-4-carboxylic acid ethyl
ester (0.39 g, 1.34 mmol) obtained in Step B was reacted in the
same manner as in Step C of Preparation Example 72 to obtain the
title compound (0.25 g, 75%).
[1038] .sup.1H-NMR (CDCl.sub.3) .delta. 8.14 (1H, m), 7.39 (2H, d),
6.90 (4H, m), 5.32 (2H, s), 4.69 (2H, s), 3.81 (3H, s)
Step D:
4-[[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ph-
enoxy]methyl]-2-[(4-methoxyphenyl)methoxy]pyridine
[1039] [2-[(4-Methoxyphenyl)methoxy]-4-pyridyl]methanol (0.25 g, 1
mmol) obtained in Step C and
2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
(0.26 g, 1 mmol) obtained in Step B of Preparation Example 16 were
reacted in the same manner as in Preparation Example 62 to obtain
the title compound (0.09 g, 18%).
[1040] .sup.1H-NMR (CDCl.sub.3) .delta. 8.15 (1H, m), 7.40 (2H, d),
7.28 (2H, m), 6.96 (1H, m), 6.90 (3H, m), 5.30 (2H, s), 5.17 (2H,
s), 3.81 (3H, s), 1.32 (12H, s)
Preparation Example 74:
3-[4-(1-chloroethyl)-2,6-difluoro-phenyl]-2-(cyclopentoxy)pyridine
Step A:
1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
nyl]ethaneone
[1041] 1-(4-Bromo-2,6-difluoro-phenyl)ethaneone (0.97 g, 4.13 mmol)
obtained in Step C of Preparation Example 32 was reacted in the
same manner as in Step D of Preparation Example 1 to obtain the
title compound (0.9 g, 77%).
[1042] .sup.1H-NMR (CDCl.sub.3) .delta. 7.35 (2H, m), 2.59 (3H, s),
1.34 (12H, s)
Step B:
1-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]ethaneone
[1043]
1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
yl]ethaneone (0.24 g, 0.89 mmol) obtained in Step A and
2-cyclopentoxy-3-iodo-pyridine (0.024 g, 0.84 mmol) obtained in
Preparation Example 11 were reacted in the same manner as in Step A
of Example 1 to obtain the title compound (0.13 g, 48%).
[1044] .sup.1H-NMR (CDCl.sub.3) .delta. 8.20 (1H, m), 7.60 (1H, m),
7.21 (2H, m), 6.95 (1H, m), 5.54 (1H, m), 2.64 (3H, s), 1.96 (2H,
m), 1.82 (2H, m), 1.75 (2H, m), 1.65 (2H, m)
Step C:
1-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]ethanol
[1045]
1-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]ethaneone
(0.13 g, 0.41 mmol) obtained in Step B was dissolved in 2 mL of
MeOH. NaBH.sub.4 (0.031 g, 0.82 mmol) was added thereto, and the
mixture was stirred at room temperature for 16 hours. After
addition of water, the reaction solution was extracted with EtOAc.
The organic layer was dried with MgSO.sub.4 to obtain the title
compound (0.12 g, 92%).
[1046] .sup.1H-NMR (CDCl.sub.3) .delta. 8.16 (1H, m), 7.58 (1H, m),
7.12 (2H, m), 6.93 (1H, m), 5.53 (1H, m), 5.28 (1H, m), 2.22 (1H,
d, OH), 1.96 (2H, m), 1.80 (4H, m), 1.68 (5H, m)
Step D:
3-[4-(1-chloroethyl)-2,6-difluoro-phenyl]-2-(cyclopentoxy)pyridine
[1047]
1-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]ethanol (0.12
g, 0.37 mmol) obtained in Step C was dissolved in 3.5 mL of
chloroform. SOCl.sub.2 (0.055 mL, 0.75 mmol) was added thereto, and
the mixture was stirred at 60.degree. C. for 3 hours. The reaction
solution was concentrated under reduced pressure to obtain the
title compound (0.12 g, 98%).
[1048] .sup.1H-NMR (CDCl.sub.3) .delta. 8.34 (1H, m), 7.86 (1H, m),
7.18 (1H, m), 7.11 (2H, m), 5.87 (1H, m), 5.48 (1H, m), 2.16 (2H,
m), 1.99 (3H, d), 1.89 (2H, m), 1.74 (4H, m)
Preparation Example 75:
2-[[(E)-3-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]allyl]-sulf-
amoyl-amino]acetic Acid Ethyl Ester
Step A:
(E)-3-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenyl]prop-2-enoic Acid Ethyl Ester
[1049] (E)-3-(4-bromo-2,6-difluoro-phenyl)prop-2-enoic acid ethyl
ester (3.8 g, 13 mmol) obtained in Step A of Preparation Example
195 was reacted in the same manner as in Step D of Preparation
Example 1 to obtain the title compound (2.16 g, 49%).
[1050] .sup.1H-NMR (CDCl.sub.3) .delta. 7.79 (1H, d), 7.33 (2H, m),
6.78 (1H, d), 4.27 (2H, q), 1.34 (15H, m)
Step B:
(E)-3-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]prop-2-e-
noic Acid Ethyl Ester
[1051]
(E)-3-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]prop-2-enoic acid ethyl ester (0.67 g, 1.98 mmol) obtained
in Step A and 2-cyclopentoxy-3-iodo-pyridine (0.55 g, 1.89 mmol)
obtained in Preparation Example 11 were reacted in the same manner
as in Step A of Example 1 to obtain the title compound (0.56 g,
80%).
[1052] .sup.1H-NMR (CDCl.sub.3) .delta. 8.19 (1H, m), 7.82 (1H, d),
7.61 (1H, m), 7.21 (2H, m), 6.96 (1H, m), 6.76 (1H, d), 5.54 (1H,
m), 4.28 (2H, q), 1.96 (2H, m), 1.75 (4H, m), 1.66 (2H, m), 1.35
(3H, t)
Step C:
(E)-3-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]prop-2-e-
n-1-ol
[1053]
(E)-3-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]prop-2-en-
oic acid ethyl ester (0.4 g, 1.07 mmol) obtained in Step B was
reacted in the same manner as in Step B of Preparation Example 70
to obtain the title compound (0.28 g, 78%).
[1054] .sup.1H-NMR (CDCl.sub.3) .delta. 8.17 (1H, m), 7.60 (1H, m),
7.15 (2H, m), 6.93 (1H, m), 6.72 (2H, m), 5.53 (1H, m), 4.40 (2H,
m), 1.95 (2H, m), 1.83 (2H, m), 1.76 (2H, m), 1.65 (2H, m), 1.50
(1H, t, OH)
Step D:
[(E)-3-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]allyl]m-
ethanesulfonate
[1055]
(E)-3-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]prop-2-en-
-1-ol (0.28 g, 0.84 mmol) obtained in Step C was reacted in the
same manner as in Preparation Example 60 to obtain the title
compound (0.28 g, 83%).
[1056] .sup.1H-NMR (CDCl.sub.3) .delta. 8.18 (1H, m), 7.61 (1H, m),
7.17 (2H, m), 6.94 (1H, m), 6.81 (1H, d), 6.67 (1H, m), 5.53 (1H,
m), 4.93 (2H, d), 3.07-2.80 (3H, s), 1.95 (2H, m), 1.85 (2H, m),
1.76 (2H, m), 1.66 (2H, m)
Step E:
2-[[(E)-3-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]ally-
l]amino]acetic Acid Ethyl Ester
[1057]
[(E)-3-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]allyl]
methanesulfonate (0.28 g, 0.7 mmol) obtained in Step D was
dissolved in 3.5 mL of THF. Hydrochloric acid salt of glycine ethyl
ester (0.098 g, 0.7 mmol) and TEA (0.58 mL, 4.2 mmol) was added
thereto, and the mixture was stirred for 16 hours under reflux. The
reaction solution was concentrated under reduced pressure and
purified by column chromatography to obtain the title compound
(0.076 g, 26%).
[1058] .sup.1H-NMR (CDCl.sub.3) .delta. 8.15 (1H, m), 7.60 (1H, m),
7.13 (2H, m), 6.92 (1H, m), 6.60 (2H, m), 5.52 (1H, m), 4.20 (2H,
q), 3.50 (2H, d), 3.47 (2H, s), 1.95 (2H, m), 1.82 (2H, m), 1.76
(2H, m), 1.65 (2H, m), 1.30 (3H, t)
Step F:
2-[[(E)-3-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]ally-
l]-sulfamoyl-amino]acetic Acid Ethyl Ester
[1059] Chlorosulfonyl isocyanate (0.024 mL, 0.27 mmol) was
dissolved in 1 mL of DCM and cooled to 0.degree. C. Tert-butyl
alcohol (0.02 g, 0.27 mmol) was added thereto, and the mixture was
stirred at room temperature for 1 hour.
2-[[(E)-3-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]allyl]amino-
]acetic acid ethyl ester (0.076 g, 0.18 mmol, 0.2M DCM solution)
obtained in Step E and TEA (0.05 mL, 0.36 mmol) were added thereto,
and the mixture was stirred at room temperature for 90 minutes.
After addition of water, the reaction solution was extracted with
EtOAc and purified by column chromatography to obtain the title
compound (0.038 g, 28%).
[1060] .sup.1H-NMR (CDCl.sub.3) .delta. 8.17 (1H, m), 7.59 (1H, m),
7.15 (2H, m), 6.93 (1H, m), 6.61 (2H, m), 5.53 (1H, m), 4.68 (2H,
brs), 4.22 (2H, q), 4.14 (2H, d), 4.11 (2H, s), 1.95 (2H, m), 1.82
(2H, m), 1.75 (2H, m), 1.65 (2H, m), 1.28 (3H, t)
Preparation Example 76:
[(E)-3-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]allyl]
methanesulfonate
Step A:
(E)-3-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]prop-
-2-enoic Acid Ethyl Ester
[1061]
(E)-3-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]prop-2-enoic acid ethyl ester (0.19 g, 0.57 mmol) obtained
in Step A of Preparation Example 75 and
3-iodo-2-cyclobutylsulfanyl-pyridine (0.15 g, 0.51 mmol) obtained
in Preparation Example 13 were reacted in the same manner as in
Step A of Example 1 to obtain the title compound (0.15 g, 80%).
[1062] .sup.1H-NMR (CDCl.sub.3) .delta. 8.44 (1H, m), 7.80 (1H, d),
7.36 (1H, m), 7.05 (3H, m), 6.79 (1H, d), 4.44 (1H, m), 4.29 (2H,
q), 2.51 (2H, m), 2.05 (4H, m), 1.36 (3H, t)
Step B:
(E)-3-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]prop-
-2-en-1-ol
[1063]
(E)-3-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]prop--
2-enoic acid ethyl ester (0.15 g, 0.41 mmol) obtained in Step A was
reacted in the same manner as in Step B of Preparation Example 70
to obtain the title compound (0.13 g, 99%).
[1064] .sup.1H-NMR (CDCl.sub.3) .delta. 8.43 (1H, m), 7.35 (1H, m),
7.04 (1H, m), 6.99 (2H, m), 6.73 (2H, m), 4.41 (3H, m), 2.51 (2H,
m), 2.04 (4H, m)
Step C:
[(E)-3-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]all-
yl]methanesulfonate
[1065]
(E)-3-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]prop--
2-en-1-ol (0.13 g, 0.4 mmol) obtained in Step B was reacted in the
same manner as in Preparation Example 60 to obtain the title
compound (0.14 g, 87%).
[1066] .sup.1H-NMR (CDCl.sub.3) .delta. 8.43 (1H, m), 7.36 (1H, m),
7.02 (3H, m), 6.81 (1H, d), 6.68 (1H, m), 4.94 (2H, d), 4.44 (1H,
m), 3.08 (3H, s), 2.52 (2H, m), 2.04 (4H, m)
Preparation Example 77:
5-[2-[tert-butyl(diphenyl)silyl]oxyethyl]isoxazol-3-ol
[1067] Hydroxylamine hydrochloride (0.63 g, 9 mmol) was dissolved
in 13 mL of MeOH, and NaOH (0.96 g, 24 mmol, 10% aqueous solution)
was added thereto. 5-[Tert-butyl(diphenyl)silyl]oxypent-2-ynoic
acid methyl ester (2.77 g, 7.5 mmol, 1.0 M MeOH solution) was added
thereto, and the mixture was stirred at room temperature for 48
hours. The reaction solution was adjusted to pH 2 by the use of 6 M
HCl aqueous solution, extracted with Et.sub.2O and purified by
column chromatography to obtain the title compound (1.0 g,
36%).
[1068] .sup.1H-NMR (CDCl.sub.3) .delta. 7.62 (4H, m), 7.43 (6H, m),
5.76 (1H, s), 3.91 (2H, t), 2.87 (2H, t), 1.03 (9H, s)
Preparation Example 78:
tert-butyl-[2-[3-[(4-methoxyphenyl)methoxy]isoxazol-5-yl]ethoxy]-diphenyl-
-silane
[1069] 5-[2-[Tert-butyl(diphenyl)silyl]oxyethyl]isoxazol-3-ol (0.28
g, 0.76 mmol) obtained in Preparation Example 77 was dissolved in
2.5 mL of DMF. K.sub.2CO.sub.3 (0.21 g, 1.52 mmol) and
4-methoxybenzyl chloride (0.1 mL, 0.76 mmol) were added thereto,
and the mixture was stirred at 60.degree. C. for 10 hours. The
reaction solution was concentrated under reduced pressure. After
addition of water, the reaction solution was extracted with EtOAc.
The organic layer was dried with MgSO.sub.4 and purified by column
chromatography to obtain the title compound (0.26 g, 70%).
[1070] .sup.1H-NMR (CDCl.sub.3) .delta. 7.72-7.37 (12H, m), 6.91
(2H, d), 5.71 (1H, s), 5.17 (2H, s), 3.89 (2H, t), 3.81 (3H, s),
2.87 (2H, t), 1.02 (9H, s)
Preparation Example 79:
2-[3-[(4-methoxyphenyl)methoxy]isoxazol-5-yl]ethanol
[1071]
Tert-butyl-[2-[3-[(4-methoxyphenyl)methoxy]isoxazol-5-yl]ethoxy]-di-
phenyl-silane (0.26 g, 0.53 mmol) obtained in Preparation Example
78 was dissolved in 10 mL of THF. Tetrabutylammonium fluoride (0.53
mL, 0.53 mmol, 1.0 M THF solution) was slowly added thereto at
0.degree. C., and the mixture was stirred for 30 minutes. After
addition of ammonium chloride aqueous solution, the reaction
solution was extracted with EtOAc. The organic layer was dried with
MgSO.sub.4 and purified by column chromatography to obtain the
title compound (0.075 g, 56%).
[1072] .sup.1H-NMR (CDCl.sub.3) .delta. 7.38 (2H, d), 6.90 (2H, d),
5.75 (1H, s), 5.17 (2H, s), 3.93 (2H, m), 3.82 (3H, s), 2.92 (2H,
t), 1.70 (1H, brs)
Preparation Example 80:
2-fluoro-5-(6-isopropylsulfanyl-2-pyridyl)pyridine
Step A:
2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
[1073] 5-Bromo-2-fluoropyridine (2.0 g, 11.3 mmol), K.sub.2CO.sub.3
(4.46 g, 45 mmol) and bis(pinacolato)diboron (3.17 g, 12.4 mmol)
were dissolved in 38 mL of DMF and charged with nitrogen gas for 5
minutes. After addition of catalytic amount of
PdCl.sub.2(dppf)-DCM, the mixture was stirred at 80.degree. C. for
3 hours. Solids were filtered and purified by column chromatography
to obtain the title compound (1.59 g, 60%).
[1074] .sup.1H-NMR (DMSO-d.sub.6) .delta. 8.45 (1H, d), 8.16 (1H,
m), 7.20 (1H, dd), 1.30 (12H, s)
Step B: 2-fluoro-5-(6-isopropylsulfanyl2-pyridyl)pyridine
[1075] 2-Chloro-6-isopropylsulfanyl-pyridine (0.14 g, 0.7 mmol)
obtained in Preparation Example 10 and
2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(0.2 g, 0.9 mmol) obtained in Step A were dissolved in 1.1 mL of 2
M Na.sub.2CO.sub.3 aqueous solution and 5 mL 1,4-dioxane, and
charged with nitrogen gas for 5 minutes. After addition of
Pd(PPh.sub.3).sub.4 (43 mg, 0.04 mmol), the mixture was stirred for
4 hours under reflux. The reaction solution was diluted with water
and extracted with EtOAc to separate an organic layer. The organic
layer was dried with MgSO.sub.4 and purified by column
chromatography to obtain the title compound (0.114 g, 62%).
[1076] .sup.1H-NMR (CDCl.sub.3) .delta. 8.84 (1H, d), 8.43 (1H, m),
7.56 (1H, t), 7.39 (1H, d), 7.13 (1H, d), 7.04 (1H, dd), 4.13 (1H,
m), 1.46 (6H, d)
Preparation Example 81:
2-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazol-4-yl]-
acetic Acid Methyl Ester
Step A: 1-(4-bromophenyl)pyrazole
[1077] 1H-pyrazole (1.0 g, 14.7 mmol) and 4-bromofluorobenzene
(5.14 g, 29.4 mmol) were dissolved in 80 mL of DMF. Potassium
phosphate (15.6 g, 73.5 mmol) was added thereto, and the mixture
was stirred at 150.degree. C. for 27 hours. After addition of 150
mL of water, the reaction solution was extracted with Et.sub.2O to
obtain the title compound (3.45 g, 99%).
[1078] .sup.1H-NMR (CDCl.sub.3) .delta. 7.90 (1H, m), 7.72 (1H, m),
7.58 (4H, m), 6.48 (1H, m)
Step B: 1-(4-bromophenyl)pyrazol-4-carbaldehyde
[1079] 50 mL of DMF was cooled to 0.degree. C., and POCl.sub.3 was
added thereto. The mixture was stirred for 15 minutes.
1-(4-Bromophenyl)pyrazole (3.45 g, 14.7 mmol) obtained in Step A
was slowly added thereto, and the mixture was stirred at
110.degree. C. for 3 hours. After cooling to room temperature,
sodium bicarbonate aqueous solution was added thereto, and the
mixture was stirred for 30 minutes. The reaction solution was
extracted with Et.sub.2O and purified by column chromatography to
obtain the title compound (0.45 g, 12%).
[1080] .sup.1H-NMR (CDCl.sub.3) .delta. 9.97 (1H, s), 8.42 (1H, s),
8.17 (1H, s), 7.62 (4H, m)
Step C: [1-(4-bromophenyl)pyrazol-4-yl]methanol
[1081] 1-(4-Bromophenyl)pyrazol-4-carbaldehyde (0.45 g, 1.79 mmol)
obtained in Step B was dissolved in 3 mL of THF and 3.6 mL of MeOH.
NaBH.sub.4 (0.14 g, 3.76 mmol) was slowly added thereto, and the
mixture was stirred for 90 minutes. The adjusted to pH 1 at
0.degree. C. After addition of 1 M NaOH aqueous solution (4 mL, 4
mmol), the reaction solution was extracted with EtOAc to obtain the
title compound (0.39 g, 87%).
[1082] .sup.1H-NMR (CDCl.sub.3) .delta. 7.91 (1H, s), 7.72 (1H, s),
7.57 (4H, m), 4.68 (2H, m), 1.60 (1H, brs)
Step D: 1-(4-bromophenyl)-4-(chloromethyl)pyrazole
[1083] [1-(4-Bromophenyl)pyrazol-4-yl]methanol (0.39 g, 1.55 mmol)
obtained in Step C was dissolved in 8 mL of DCM. DIPEA (0.4 mL, 2.3
mmol) and methanesulfonyl chloride (0.13 mL, 1.7 mmol) were
sequentially added thereto at 0.degree. C., and the mixture was
stirred at room temperature for 90 minutes. After addition of
water, the organic layer extracted with DCM was purified by column
chromatography to obtain the title compound (0.25 g, 58%).
[1084] .sup.1H-NMR (CDCl.sub.3) .delta. 7.92 (1H, s), 7.73 (1H, s),
7.57 (4H, m), 4.60 (2H, s)
Step E: 2-[1-(4-bromophenyl)pyrazol-4-yl]acetonitrile
[1085] 1-(4-Bromophenyl)-4-(chloromethyl)pyrazole (0.25 g, 0.9
mmol) obtained in Step D was dissolved in 4.5 mL of DMSO. Sodium
cyanide (0.18 g, 3.6 mmol) was added thereto, and the mixture was
stirred at room temperature. After addition of water, the reaction
solution was extracted with EtOAc to obtain the title compound
(0.19 g, 80%).
[1086] .sup.1H-NMR (CDCl.sub.3) .delta. 7.93 (1H, s), 7.67 (1H, s),
7.58 (4H, m), 3.68 (2H, s)
Step F: 2-[1-(4-bromophenyl)pyrazol-4-yl]acetic Acid
[1087] 2-[1-(4-Bromophenyl)pyrazol-4-yl]acetonitrile (0.19 g, 0.76
mmol) obtained in Step E was dissolved in 0.45 mL of water and 0.4
mL of concentrated sulfuric acid, and the mixture was stirred for 3
hours under reflux. The precipitate formed by the addition of water
was dried to obtain the title compound (0.2 g, 98%).
[1088] .sup.1H-NMR (DMSO-d.sub.6) .delta. 8.39 (1H, s), 7.76 (2H,
d), 7.67 (3H, m), 3.50 (2H, s)
Step G: 2-[1-(4-bromophenyl)pyrazol-4-yl]acetic Acid Methyl
Ester
[1089] 2-[1-(4-Bromophenyl)pyrazol-4-yl]acetic acid (0.2 g, 0.71
mmol) obtained in Step F was dissolved in 2.4 mL of THF.
Diazomethane (3 mL, 0.78 mmol, 0.25 M Et.sub.2O solution) was added
thereto, and the mixture was stirred for 20 minutes. The reaction
solution was concentrated under reduced pressure to obtain the
title compound (0.21 g, 99%).
[1090] .sup.1H-NMR (CDCl.sub.3) .delta. 7.89 (1H, s), 7.64 (1H, s),
7.55 (4H, m), 3.73 (3H, s), 3.73 (2H, s)
Step H:
2-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazo-
l-4-yl]acetic Acid Methyl Ester
[1091] 2-[1-(4-Bromophenyl)pyrazol-4-yl]acetic acid methyl ester
(0.21 g, 0.71 mmol) obtained in Step G, bis(pinacolato)diboron
(0.19 g, 0.74 mmol) and DPPF (0.02 g, 0.035 mmol) were dissolved in
3.6 mL of 1,4-dioxane and charged with nitrogen gas.
PdCl.sub.2(dppf)-DCM (0.03 g, 0.035 mmol) was added thereto, and
the mixture was stirred for 1 hour under reflux. Solids were
filtered through Celite, and the filtrate was concentrated under
reduced pressure and purified by column chromatography to obtain
the title compound (0.096 g, 40%).
[1092] .sup.1H-NMR (CDCl.sub.3) .delta. 7.97 (1H, s), 7.88 (2H, d),
7.67 (3H, m), 3.73 (3H, s), 3.59 (2H, s), 1.36 (12H, s)
Preparation Example 82: benzyl
N-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]car-
bamate
[1093] Benzyl N-(4-bromo-2,6-difluoro-phenyl)carbamate (1.61 g, 4.7
mmol) was reacted in the same manner as in Step D of Preparation
Example 1 to obtain the title compound (1.5 g, 82%).
[1094] .sup.1H-NMR (CDCl.sub.3) .delta. 7.36 (7H, m), 6.20 (1H,
brs), 5.21 (2H, s), 1.33 (12H, s)
Preparation Example 83:
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]pe-
ntanoic Acid Ethyl Ester
Step A:
5-[N-benzyloxycarbonyl-2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-d-
ioxaborolan-2-yl)anilino]pentanoic Acid Ethyl Ester
[1095] Benzyl
N-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]car-
bamate (0.79 g, 2 mmol) obtained in Preparation Example 82 was
dissolved in 6.7 mL of DMF. NaH (0.18 g, 55 wt % in mineral oil, 4
mmol) and 5-bromopentanoic acid ethyl ester (0.44 g, 2.1 mmol) were
sequentially added thereto at 0.degree. C., and the mixture was
stirred at room temperature for 16 hours. The reaction solution was
concentrated under reduced pressure. After addition of ammonium
chloride aqueous solution, the reaction solution was extracted with
EtOAc. The organic layer was collected, dried with MgSO.sub.4 and
purified by column chromatography to obtain the title compound
(0.447 g, 45%).
[1096] .sup.1H-NMR (CDCl.sub.3) .delta. 7.40-7.18 (7H, m), 5.10
(2H, s), 4.08 (2H, q), 3.64 (2H, t), 2.28 (2H, t), 1.62 (2H, m),
1.54 (2H, m), 1.33 (12H, s), 1.21 (3H, t)
Step B:
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ani-
lino]pentanoic Acid Ethyl Ester
[1097]
5-[N-benzyloxycarbonyl-2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-di-
oxaborolan-2-yl)anilino]pentanoic acid ethyl ester (0.46 g, 0.89
mmol) obtained in Step A was dissolved in 5 mL of MeOH. 10 wt %
Pd/C (0.05 g) was added thereto, and the mixture was stirred for 16
hours under hydrogen atmosphere. Solids were filtered through
Celite, and the filtrate was concentrated under reduced pressure to
obtain the title compound (0.35 g, 99%).
[1098] .sup.1H-NMR (CDCl.sub.3) .delta. 7.21 (2H, m), 4.12 (2H, q),
3.39 (2H, t), 2.33 (2H, t), 1.71 (2H, m), 1.62 (2H, m), 1.32 (12H,
s), 1.25 (3H, t)
Preparation Example 84:
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic Acid Methyl Ester
Step A: 2-[1-(2,6-difluoro-4-nitro-phenyl)-4-piperidyl]acetic Acid
Methyl Ester
[1099] 3,4,5-Trifluoronitrobenzene (1.68 g, 9.43 mmol) was
dissolved in 24 mL of DMF. Hydrochloric acid salt of
(4-piperidyl)acetic acid methyl ester (2.02 g, 10.4 mmol) and DIPEA
(4.1 mL, 23.5 mmol) were sequentially added, and the mixture was
stirred at room temperature for 16 hours. The reaction solution was
concentrated under reduced pressure. After addition of water, the
reaction solution was extracted with EtOAc. The organic layer was
collected and dried with MgSO.sub.4 to obtain the title compound
(3.0 g, 99%), which was used for the next step without
purification.
[1100] .sup.1H-NMR (CDCl.sub.3) .delta. 7.74 (2H, m), 3.69 (3H, s),
3.50 (2H, m), 3.20 (2H, m), 2.31 (2H, d), 2.01 (1H, m), 1.80 (2H,
m), 1.42 (2H, m)
Step B: 2-[1-(4-amino-2,6-difluoro-phenyl)-4-piperidyl]acetic Acid
Methyl Ester
[1101] To 2-[1-(2,6-difluoro-4-nitro-phenyl)-4-piperidyl]acetic
acid methyl ester (1.1 g, 3.5 mmol) obtained in Step A, each 12 mL
of THF, MeOH and water were added. Ammonium chloride (1.31 g, 24.5
mmol) and iron (1.37 g, 24.5 mmol) were added thereto, and the
mixture was stirred for 2 hours under reflux. After termination of
the reaction, solids were filtered through Celite. After addition
of water, the filtrate was extracted with EtOAc. The organic layer
was collected and dried with MgSO.sub.4 to obtain the title
compound (0.82 g, 80%), which was used for the next step without
purification.
[1102] .sup.1H-NMR (CDCl.sub.3) .delta. 6.15 (2H, m), 3.68 (3H, s),
3.04 (4H, m), 2.28 (2H, d), 1.90 (1H, m), 1.82 (2H, m), 1.43 (2H,
m)
Step C: 2-[1-(4-bromo-2,6-difluoro-phenyl)-4-piperidyl]acetic Acid
Methyl Ester
[1103] CuBr.sub.2 (0.75 g, 3.36 mmol) was dissolved in 7 mL of
CH.sub.3CN. Tert-butyl nitrite (0.5 mL, 4.2 mmol) was added
thereto, and the mixture was stirred at room temperature for 5
minutes. 2-[1-(4-Amino-2,6-difluoro-phenyl)-4-piperidyl]acetic acid
methyl ester (0.8 g, 2.8 mmol) obtained in Step B was dissolved in
1.5 mL of CH.sub.3CN and added thereto. The reaction solution was
stirred at room temperature for 1 hour and concentrated under
reduced pressure. After addition of water, and reaction solution
was extracted with EtOAc. The organic layer was purified by column
chromatography to obtain the title compound (0.61 g, 60%).
[1104] .sup.1H-NMR (CDCl.sub.3) .delta. 7.00 (2H, m), 3.68 (3H, s),
3.19 (2H, m), 3.09 (2H, m), 2.29 (2H, d), 1.93 (1H, m), 1.75 (2H,
m), 1.42 (2H, m)
Step D:
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]-4-piperidyl]acetic Acid Methyl Ester
[1105] 2-[1-(4-Bromo-2,6-difluoro-phenyl)-4-piperidyl]acetic acid
methyl ester (0.61 g, 1.7 mmol) obtained in Step C was reacted in
the same manner as in Step D of Preparation Example 1 to obtain the
title compound (0.52 g, 77%).
[1106] .sup.1H-NMR (CDCl.sub.3) .delta. 7.22 (2H, m), 3.68 (3H, s),
3.31 (2H, m), 3.10 (2H, m), 2.29 (2H, d), 1.95 (1H, m), 1.74 (2H,
m), 1.43 (2H, m), 1.32 (12H, s)
Preparation Example 85:
2-[2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino-
]ethyl]cyclopropanecarboxylic Acid Ethyl Ester
Step A: (E)-5-(1,3-dioxoisoindolin-2-yl)pent-2-enoic Acid Ethyl
Ester
[1107] 3-(1,3-Dioxoisoindolin-2-yl)propanal (2.5 g, 12.3 mmol) was
dissolved in 80 mL of DCM.
(1-Ethoxycarbonylethylidene)triphenylphosphorane (4.50 g, 12.9
mmol) was added thereto, and the mixture was stirred at room
temperature for 2 hours. The reaction solution was concentrated
under reduced pressure and purified by column chromatography to
obtain the title compound (2.99 g, 89%).
[1108] .sup.1H-NMR (CDCl.sub.3) 67.83 (2H, m), 7.72 (2H, m), 6.91
(1H, m), 5.90 (1H, d), 4.16 (2H, q), 3.83 (2H, t), 2.60 (2H, m),
1.26 (3H, t)
Step B: 2-[2-(1,3-dioxoisoindolin-2-yl)ethyl]cyclopropanecarboxylic
Acid Ethyl Ester
[1109] (E)-5-(1,3-dioxoisoindolin-2-yl)pent-2-enoic acid ethyl
ester (2.0 g, 7.32 mmol) obtained in Step A was dissolved in 10 mL
of THE Diazomethane (88 mL, 22 mmol, 0.25M Et.sub.2O solution) was
added thereto, and palladium (II) acetate (0.18 g, 0.8 mmol) was
then slowly added thereto. The mixture was stirred at room
temperature for 16 hours, and water was added thereto. The reaction
solution was extracted with EtOAc and purified by column
chromatography to obtain the title compound (1.72 g, 82%).
[1110] .sup.1H-NMR (CDCl.sub.3) .delta. 7.84 (2H, m), 7.72 (2H, m),
4.10 (2H, q), 3.79 (2H, m), 1.69 (2H, m), 1.38 (2H, m), 1.23 (3H,
t), 1.17 (1H, m), 0.72 (1H, m)
Step C:
2-[2-(2,6-difluoro-4-nitro-anilino)ethyl]cyclopropanecarboxylic
Acid Ethyl Ester
[1111] 2-[2-(1,3-Dioxoisoindolin-2-yl)ethyl]cyclopropanecarboxylic
acid ethyl ester (1.72 g, 6 mmol) obtained in Step B was dissolved
in 40 mL of EtOH. Hydrazine hydrate (1.4 mL, 30 mmol) was added
thereto, and the mixture was stirred at room temperature for 3
hours. To the precipitate formed by the addition of Et.sub.2O 20 mL
of DMF, 3,4,5-trifluoronitrobenzene (1.06 g, 6 mmol) and DIPEA
(1.57 mL, 9 mmol) were sequentially added, and the mixture was
stirred at room temperature for 72 hours. The reaction solution was
concentrated under reduced pressure, and water was added thereto.
The organic layer extracted with EtOAc was purified by column
chromatography to obtain the title compound (1.1 g, 58%).
[1112] .sup.1H-NMR (CDCl.sub.3) .delta. 7.78 (2H, m), 4.42 (1H,
brs), 4.12 (2H, q), 3.62 (2H, m), 1.65 (2H, m), 1.42 (2H, m), 1.27
(3H, t), 1.22 (1H, m), 0.73 (1H, m)
Step D:
2-[2-(4-amino-2,6-difluoro-anilino)ethyl]cyclopropanecarboxylic
Acid Ethyl Ester
[1113]
2-[2-(2,6-Difluoro-4-nitro-anilino)ethyl]cyclopropanecarboxylic
acid ethyl ester (1.1 g, 3.5 mmol) obtained in Step C was reacted
in the same manner as in Step B of Preparation Example 84 to obtain
the title compound (0.88 g, 88%).
[1114] .sup.1H-NMR (CDCl.sub.3) .delta. 6.20 (2H, m), 4.12 (2H, q),
3.22 (2H, t), 1.58 (1H, m), 1.49 (1H, m), 1.40 (2H, m), 1.26 (3H,
t), 1.18 (1H, m), 0.72 (1H, m)
Step E:
2-[2-(4-bromo-2,6-difluoro-anilino)ethyl]cyclopropanecarboxylic
Acid Ethyl Ester
[1115]
2-[2-(4-Amino-2,6-difluoro-anilino)ethyl]cyclopropanecarboxylic
acid ethyl ester (0.88 g, 3.09 mmol) obtained in Step D was reacted
in the same manner as in Step C of Preparation Example 84 to obtain
the title compound (0.085 g, 8%).
[1116] .sup.1H-NMR (CDCl.sub.3) .delta. 6.97 (2H, m), 4.10 (2H, q),
3.66 (1H, brs), 3.41 (2H, m), 1.56 (2H, m), 1.39 (2H, m), 1.27 (3H,
t), 1.19 (1H, m), 0.72 (1H, m)
Step F:
2-[2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
anilino]ethyl]cyclopropanecarboxylic Acid Ethyl Ester
[1117]
2-[2-(4-Bromo-2,6-difluoro-anilino)ethyl]cyclopropanecarboxylic
acid ethyl ester (0.085 g, 0.24 mmol) obtained in Step E was
reacted in the same manner as in Step D of Preparation Example 1 to
obtain the title compound (0.05 g, 50%).
[1118] .sup.1H-NMR (CDCl.sub.3) .delta. 7.22 (2H, m), 4.10 (2H, q),
3.92 (1H, brs), 3.48 (2H, t), 1.58 (2H, m), 1.40 (2H, m), 1.31
(12H, s), 1.26 (3H, t), 1.20 (1H, m), 0.71 (1H, m)
Preparation Example 86:
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-3-piperidyl]acetonitrile
Step A: tert-butyl 3-(hydroxymethyl)piperidin-1-carboxylate
[1119] 3-Piperidinemethanol (0.91 g, 7.9 mmol) was dissolved in 13
mL of 1,4-dioxane and 8 mL of water. Di-tert-butyl dicarbonate
(1.81 g, 8.3 mmol) and 8 mL of 1N NaOH aqueous solution were added
thereto. The mixture was stirred at room temperature for 5 hours.
After addition of water, the reaction solution was extracted with
EtOAc. The organic layer was separated and dried with MgSO.sub.4 to
obtain the title compound (1.5 g, 90%).
[1120] .sup.1H-NMR (DMSO-d.sub.6) .delta. 4.51 (1H, t), 3.94 (1H,
brs), 3.78 (1H, m), 3.36 (1H, m), 3.29 (1H, m), 3.19 (1H, m), 2.69
(1H, m), 1.67 (1H, m), 1.59 (1H, m), 1.46 (1H, m), 1.38 (9H, s),
1.29 (1H, m), 1.09 (1H, m)
Step B: tert-butyl
3-(methylsulfonyloxymethyl)piperidin-1-carboxylate
[1121] Tert-butyl 3-(hydroxymethyl)piperidin-1-carboxylate (0.31 g,
1.4 mmol) obtained in Step A was dissolved in 7 mL of DCM and
cooled to 0.degree. C. DIPEA (0.57 mL, 3.3 mmol) and
methanesulfonyl chloride (0.12 mL, 1.54 mmol) were added thereto,
and the mixture was stirred for 3 hours. After addition of water,
the reaction solution was extracted with EtOAc to separate an
organic layer. The organic layer was dried with MgSO.sub.4 to
obtain the title compound (0.41 g, 98%).
[1122] .sup.1H-NMR (CDCl.sub.3) .delta. 4.10 (2H, m), 3.95 (1H, m),
3.80 (1H, m), 3.02 (3H, s), 2.93 (1H, m), 2.79 (1H, m), 1.96 (1H,
m), 1.82 (1H, m), 1.66 (1H, m), 1.49 (1H, m), 1.45 (9H, s), 1.33
(1H, m)
Step C: tert-butyl 3-(cyanomethyl)piperidin-1-carboxylate
[1123] Tert-butyl
3-(methylsulfonyloxymethyl)piperidin-1-carboxylate (0.41 g, 1.4
mmol) obtained in Step B was dissolved in 7 mL of DMF. Sodium
cyanide (0.075 g, 1.54 mmol) was added thereto, and the mixture was
stirred at 60.degree. C. for 16 hours. The reaction solution was
concentrated under reduced pressure, diluted with water, and
extracted with EtOAc. The organic layer was separated and dried
with MgSO.sub.4 to obtain the title compound (0.29 g, 93%).
[1124] .sup.1H-NMR (CDCl.sub.3) .delta. 3.90 (1H, m), 3.82 (1H, m),
2.92 (2H, m), 2.30 (2H, m), 1.92 (2H, m), 1.68 (1H, m), 1.49 (1H,
m), 1.46 (9H, s), 1.35 (1H, m)
Step D: 2-(3-piperidyl)acetonitrile Hydrochloride
[1125] Tert-butyl 3-(cyanomethyl)piperidin-1-carboxylate (0.292 g,
1.3 mmol) obtained in Step C was dissolved in 13 mL of DCM and
cooled to 0.degree. C. HCl (1.3 mL, 5.6 mmol, 4 M 1,4-dioxane
solution) was slowly added thereto. After stirring at 0.degree. C.
for 1 hour, the reaction solution was concentrated under reduced
pressure to obtain the title compound (0.18 g, 86%).
[1126] .sup.1H-NMR (DMSO-d.sub.6) .delta. 9.16 (2H, brs), 3.21 (2H,
t), 2.73 (1H, m), 2.61 (3H, m), 2.11 (1H, m), 1.81 (2H, m), 1.69
(1H, m), 1.27 (1H, m)
Step E:
2-[1-(2,6-difluoro-4-nitro-phenyl)-3-piperidyl]acetonitrile
[1127] 2-(3-Piperidyl)acetonitrile hydrochloride (1.67 g, 10.4
mmol) obtained in Step D and 3,4,5-trifluoronitrobenzene (1.67 g,
9.45 mmol) were reacted in the same manner as in Step A of
Preparation Example 84 to obtain the title compound (2.53 g,
95%).
[1128] .sup.1H-NMR (CDCl.sub.3) .delta. 7.76 (2H, m), 3.50 (1H, m),
3.40 (1H, m), 3.17 (1H, m), 3.04 (1H, m), 2.42 (2H, d), 2.16 (1H,
m), 2.00 (1H, m), 1.82 (1H, m), 1.74 (1H, m), 1.44 (1H, m)
Step F:
2-[1-(4-bromo-2,6-difluoro-phenyl)-3-piperidyl]acetonitrile
[1129] 2-[1-(2,6-Difluoro-4-nitro-phenyl)-3-piperidyl]acetonitrile
(2.53 g, 9 mmol) obtained in Step E was reacted in the same manner
as in Steps B and C of Preparation Example 84 to obtain the title
compound (1.16 g, 41%).
[1130] .sup.1H-NMR (CDCl.sub.3) .delta. 7.00 (2H, m), 3.25 (1H, m),
3.13 (1H, m), 3.02 (1H, m), 2.90 (1H, m), 2.44 (2H, m), 2.13 (1H,
m), 1.90 (1H, m), 1.76 (1H, m), 1.70 (1H, m), 1.42 (1H, m)
Step G:
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]-3-piperidyl]acetonitrile
[1131] 2-[1-(4-Bromo-2,6-difluoro-phenyl)-3-piperidyl]acetonitrile
(1.16 g, 3.7 mmol) obtained in Step F was reacted in the same
manner as in Step D of Preparation Example 1 to obtain the title
compound (0.91 g, 68%).
[1132] .sup.1H-NMR (CDCl.sub.3) .delta. 7.23 (2H, m), 3.34 (1H, m),
3.22 (1H, m), 3.07 (1H, m), 2.94 (1H, m), 2.44 (2H, m), 2.13 (1H,
m), 1.92 (1H, m), 1.76 (1H, m), 1.70 (1H, m), 1.43 (1H, m), 1.32
(12H, s)
Preparation Example 87:
5-[N-benzyloxycarbonyl-4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-anilin-
o]pentanoic Acid Ethyl Ester
Step A: benzyl
N-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]carbamate
[1133] 2-Cyclopentoxy-3-iodo-pyridine (0.42 g, 1.47 mmol) obtained
in Preparation Example 11 and benzyl
N-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]car-
bamate (0.063 g, 1.61 mmol) obtained in Preparation Example 82 were
reacted in the same manner as in Step A of Example 1 to obtain the
title compound (0.5 g, 80%).
[1134] .sup.1H-NMR (CDCl.sub.3) .delta. 8.16 (1H, m), 7.58 (1H, m),
7.37 (5H, m), 7.19 (2H, m), 6.93 (1H, m), 6.18 (1H, brs), 5.52 (1H,
m), 5.24 (2H, s), 1.96 (2H, m), 1.81 (2H, m), 1.76 (2H, m), 1.63
(2H, m)
Step B:
5-[N-benzyloxycarbonyl-4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-
-anilino]pentanoic Acid Ethyl Ester
[1135] Benzyl
N-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]carbamate
(0.23 g, 0.54 mmol) obtained in Step A and 5-bromopentanoic acid
ethyl ester (0.12 g, 0.57 mmol) were dissolved in 3.6 mL of DMF.
NaH (0.032 g, 0.81 mmol, 55% in mineral oil) was added thereto, and
the mixture was stirred at room temperature for 4 hours. The
reaction solution was concentrated under reduced pressure. After
addition of water and 1N HCl aqueous solution, the reaction
solution was extracted with EtOAc. The organic layer was dried with
MgSO.sub.4 and purified by column chromatography to obtain the
title compound (0.14 g, 47%).
[1136] .sup.1H-NMR (CDCl.sub.3) .delta. 8.17 (1H, m), 7.59 (1H, m),
7.40-7.20 (7H, m), 6.95 (1H, m), 5.53 (1H, m), 5.13 (2H, s), 4.09
(2H, q), 3.67 (2H, t), 2.33 (2H, t), 1.97 (2H, m), 1.80-1.60 (10H,
m), 1.23 (3H, t)
Preparation Example 88:
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
azetidin-3-yl]acetic Acid Ethyl Ester
Step A: 1-(2,6-difluoro-4-nitro-phenyl)azetidin-3-ol
[1137] 3,4,5-Trifluoronitrobenzene (5.58 g, 31.5 mmol) and
hydrochloric acid salt of 3-hydroxyazetidine (3.8 g, 34.7 mmol)
were reacted in the same manner as in Step A of Preparation Example
84 to obtain the title compound (7.25 g, 99%).
[1138] .sup.1H-NMR (CDCl.sub.3) .delta. 7.71 (2H, m), 4.80 (1H, m),
4.65 (2H, m), 4.27 (2H, m), 1.85 (1H, brs)
Step B: 2-[1-(2,6-difluoro-4-nitro-phenyl)azetidin-3-ylidene]acetic
Acid Ethyl Ester
[1139] Oxalyl chloride (1.68 mL, 19.6 mmol) was added to 130 mL of
DCM and cooled to -78.degree. C. DMSO (2.77 mL, 39 mmol) was added
thereto, and the mixture was stirred for 10 minutes.
1-(2,6-Difluoro-4-nitro-phenyl)azetidin-3-ol (3 g, 13 mmol)
obtained in Step A was slowly added thereto, and the mixture was
stirred at -78.degree. C. for 15 minutes. TEA (8.88 mL, 63.7 mmol)
was added thereto, and the mixture was stirred at -78.degree. C.
for 40 minutes and additionally stirred at room temperature for 30
minutes. (1-ethoxycarbonylethylidene)triphenylphosphorane (4.53 g,
13 mmol) was added thereto, and the mixture was stirred at room
temperature for 16 hours. After addition of water, the reaction
solution was extracted with DCM and purified by column
chromatography to obtain the title compound (2.84 g, 73%).
[1140] .sup.1H-NMR (CDCl.sub.3) .delta. 7.74 (2H, m), 5.81 (1H, m),
5.33 (2H, m), 5.10 (2H, m), 4.21 (2H, q), 1.30 (3H, t)
Step C: 2-[1-(4-amino-2,6-difluoro-phenyl)azetidin-3-yl]acetic Acid
Ethyl Ester
[1141] 2-[1-(2,6-Difluoro-4-nitro-phenyl)azetidin-3-ylidene]acetic
acid ethyl ester (2.84 g, 9.52 mmol) obtained in Step B was
dissolved in 80 mL of MeOH and 40 mL of THF. After addition of 0.5
g of 10 wt % Pd/C, the mixture was stirred for 16 hours under
hydrogen atmosphere. Solids were filtered through Celite to obtain
the title compound (2.36 g, 92%).
[1142] .sup.1H-NMR (CDCl.sub.3) .delta. 6.14 (2H, m), 4.21 (2H, m),
4.13 (2H, q), 3.72 (2H, m), 3.44 (2H, brs), 2.95 (1H, m), 2.66 (2H,
d), 1.26 (3H, t)
Step D: 2-[1-(4-bromo-2,6-difluoro-phenyl)azetidin-3-yl]acetic Acid
Ethyl Ester
[1143] 2-[1-(4-Amino-2,6-difluoro-phenyl)azetidin-3-yl]acetic acid
ethyl ester (2.36 g, 8.7 mmol) obtained in Step C were reacted in
the same manner as in Step C of Preparation Example 84 to obtain
the title compound (1.04 g, 36%).
[1144] .sup.1H-NMR (CDCl.sub.3) .delta. 6.89 (2H, m), 4.34 (2H, m),
4.15 (2H, q), 3.84 (2H, m), 3.01 (1H, m), 2.67 (2H, d), 1.26 (3H,
t)
Step E:
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]azetidin-3-yl]acetic Acid Ethyl Ester
[1145] 2-[1-(4-Bromo-2,6-difluoro-phenyl)azetidin-3-yl]acetic acid
ethyl ester (1.04 g, 3.11 mmol) obtained in Step D was reacted in
the same manner as in Step D of Preparation Example 1 to obtain the
title compound (0.62 g, 51%).
[1146] .sup.1H-NMR (CDCl.sub.3) .delta. 7.15 (2H, m), 4.41 (2H, m),
4.14 (2H, q), 3.91 (2H, m), 3.05 (1H, m), 2.68 (2H, d), 1.31 (12H,
s), 1.27 (3H, t)
Preparation Example 89:
6-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-6--
azaspiro[2.5]octan-2-carboxylic Acid Ethyl Ester
Step A: 1-(2,6-difluoro-4-nitro-phenyl)piperidin-4-one
[1147] 3,4,5-Trifluoronitrobenzene (4.0 g, 22.6 mmol) and
piperidin-4-one hydrochloride (3.37 g, 24.8 mmol) were reacted in
the same manner as in Step A of Preparation Example 84 to obtain
the title compound (5.38 g, 93%).
[1148] .sup.1H-NMR (CDCl.sub.3) .delta. 7.82 (2H, m), 3.66 (4H, m),
2.62 (4H, m)
Step B: 2-[1-(2,6-difluoro-4-nitro-phenyl)-4-piperidylidene]acetic
Acid Ethyl Ester
[1149] 190 mL of THF was cooled to 0.degree. C., and NaH (1.83 g,
42 mmol, 55 wt % in mineral oil) was added thereto. Triethyl
phosphonoacetate (9.7 g, 43.3 mmol) was added thereto, and the
mixture was stirred at room temperature for 30 minutes.
1-(2,6-Difluoro-4-nitro-phenyl)piperidin-4-one (5.38 g, 21 mmol)
obtained in Step A was added thereto, and the mixture was stirred
at room temperature for 2 hours. EtOAc was added thereto, and the
reaction solution was adjusted to pH 4 by the addition of 1N HCl
aqueous solution. The organic layer extracted with EtOAc was
purified by column chromatography to obtain the title compound
(6.85 g, 99%).
[1150] .sup.1H-NMR (CDCl.sub.3) .delta. 7.78 (2H, m), 5.75 (1H, s),
4.17 (2H, q), 3.45 (2H, t), 3.42 (2H, t), 3.12 (2H, t), 2.45 (2H,
t), 1.31 (3H, t)
Step C:
6-(2,6-difluoro-4-nitro-phenyl)-6-azaspiro[2.5]octan-2-carboxylic
Acid Ethyl Ester
[1151] 2-[1-(2,6-Difluoro-4-nitro-phenyl)-4-piperidylidene]acetic
acid ethyl ester (0.55 g, 1.68 mmol) obtained in Step B was
dissolved in 5.6 mL of THF. After addition of iazomethane (40 mL,
10 mmol, 0.25 M Et.sub.2O solution), catalytic amount of
palladium(II) acetate was added thereto, and the mixture was
stirred at room temperature. After termination of the reaction, the
reaction solution was concentrated and purified by column
chromatography to obtain the title compound (0.4 g, 65%).
[1152] .sup.1H-NMR (CDCl3) .delta. 7.77 (2H, m), 4.15 (2H, q),
3.45-3.24 (4H, m), 1.88 (2H, m), 1.59 (3H, m), 1.30 (3H, t), 1.23
(1H, m), 0.97 (1H, m)
Step D:
6-(4-bromo-2,6-difluoro-phenyl)-6-azaspiro[2.5]octan-2-carboxylic
Acid Ethyl Ester
[1153]
6-(2,6-Difluoro-4-nitro-phenyl)-6-azaspiro[2.5]octan-2-carboxylic
acid ethyl ester (0.4 g, 1.1 mmol) obtained in Step C was reacted
in the same manner as in Steps B and C of Preparation Example 84 to
obtain the title compound (0.22 g, 52%).
[1154] .sup.1H-NMR (CDCl.sub.3) .delta. 7.00 (2H, m), 4.16 (2H, q),
3.21-3.04 (4H, m), 1.84 (2H, m), 1.56 (3H, m), 1.28 (3H, t), 1.18
(1H, m), 0.94 (1H, m)
Step E:
6-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
nyl]-6-azaspiro[2.5]octan-2-carboxylic Acid Ethyl Ester
[1155]
6-(4-Bromo-2,6-difluoro-phenyl)-6-azaspiro[2.5]octan-2-carboxylic
acid ethyl ester (0.22 g, 0.58 mmol) obtained in Step D was reacted
in the same manner as in Step D of Preparation Example 1 to obtain
the title compound (0.15 g, 60%).
[1156] .sup.1H-NMR (CDCl.sub.3) .delta. 7.22 (2H, m), 4.14 (2H, q),
3.32-3.10 (4H, m), 1.84 (2H, m), 1.55 (3H, m), 1.30 (12H, s), 1.27
(3H, t), 1.18 (1H, m), 0.94 (1H, m)
Preparation Example 90:
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
pyrazol-4-yl]acetic Acid Methyl Ester
Step A: 1-(2,6-difluoro-4-nitro-phenyl)pyrazol-4-carboxylic Acid
Ethyl Ester
[1157] 3,4,5-Trifluoronitrobenzene (3.17 g, 17.9 mmol) and
4-pyrazolcarboxylic acid ethyl ester (2.50 g, 17.9 mmol) were
reacted in the same manner as in Step A of Preparation Example 84
to obtain the title compound (3.70 g, 70%).
[1158] .sup.1H-NMR (CDCl.sub.3) .delta. 8.25 (1H, s), 8.23 (1H, s),
8.05 (2H, m), 4.36 (2H, q), 1.38 (3H, t)
Step B: 1-(4-bromo-2,6-difluoro-phenyl)pyrazol-4-carboxylic Acid
Ethyl Ester
[1159] 1-(2,6-Difluoro-4-nitro-phenyl)pyrazol-4-carboxylic acid
ethyl ester (3.7 g, 12.4 mmol) obtained in Step A was reacted in
the same manner as in Steps B and C of Preparation Example 84 to
obtain the title compound (3.0 g, 74%).
[1160] .sup.1H-NMR (CDCl.sub.3) .delta. 8.17 (1H, s), 8.14 (1H, s),
7.31 (2H, m), 4.34 (2H, q), 1.37 (3H, t)
Step C: [1-(4-bromo-2,6-difluoro-phenyl)pyrazol-4-yl]methanol
[1161] 1-(4-Bromo-2,6-difluoro-phenyl)pyrazol-4-carboxylic acid
ethyl ester (3.0 g, 9.16 mmol) obtained in Step B was dissolved in
46 mL of Et.sub.2O and cooled to -78.degree. C. Diisobutylaluminum
hydride (15.2 mL, 23 mmol, 1.5 M toluene solution) was slowly added
thereto, and the mixture was stirred at room temperature for 16
hours. Solids, which were formed by the sequential addition of MeOH
and potassium sodium tartrate aqueous solution, were filtered
through Celite. The filtrate was dried with MgSO.sub.4 to obtain
the title compound (2.6 g, 99%).
[1162] .sup.1H-NMR (CDCl.sub.3) .delta. 7.81 (1H, s), 7.64 (1H, s),
7.28 (2H, m), 4.70 (2H, d), 1.60 (1H, t)
Step D: 1-(4-bromo-2,6-difluoro-phenyl)-4-(chloromethyl)pyrazol
[1163] [1-(4-Bromo-2,6-difluoro-phenyl)pyrazol-4-yl]methanol (2.6
g, 9.16 mmol) obtained in Step C was reacted in the same manner as
in Step D of Preparation Example 81 to obtain the title compound
(1.5 g, 53%).
[1164] .sup.1H-NMR (CDCl.sub.3) .delta. 7.82 (1H, s), 7.67 (1H, s),
7.28 (2H, m), 4.61 (2H, s)
Step E:
2-[1-(4-bromo-2,6-difluoro-phenyl)pyrazol-4-yl]acetonitrile
[1165] 1-(4-Bromo-2,6-difluoro-phenyl)-4-(chloromethyl)pyrazol (1.5
g, 4.9 mmol) obtained in Step D was reacted in the same manner as
in Step E of Preparation Example 81 to obtain the title compound
(0.66 g, 45%).
[1166] .sup.1H-NMR (CDCl.sub.3) .delta. 7.76 (1H, s), 7.67 (1H, s),
7.30 (2H, m), 3.69 (2H, s)
Step F: 2-[1-(4-bromo-2,6-difluoro-phenyl)pyrazol-4-yl]acetic
Acid
[1167] 2-[1-(4-Bromo-2,6-difluoro-phenyl)pyrazol-4-yl]acetonitrile
(0.66 g, 2.21 mmol) obtained in Step E was reacted in the same
manner as in Step F of Preparation Example 81 to obtain the title
compound (0.58 g, 82%).
[1168] .sup.1H-NMR (CDCl.sub.3) .delta. 7.76 (1H, s), 7.66 (1H, s),
7.27 (2H, m), 3.65 (2H, s)
Step G: 2-[1-(4-bromo-2,6-difluoro-phenyl)pyrazol-4-yl]acetic Acid
Methyl Ester
[1169] 2-[1-(4-Bromo-2,6-difluoro-phenyl)pyrazol-4-yl]acetic acid
(0.58 g, 1.83 mmol) obtained in Step F was dissolved in 6 mL of THE
Diazomethane (13 mL, 3.25 mmol, 0.25 M Et.sub.2O solution) was
added thereto, and the mixture was stirred at room temperature for
40 minutes. The reaction solution was concentrated under reduced
pressure to obtain the title compound (0.6 g, 99%).
[1170] .sup.1H-NMR (CDCl.sub.3) .delta. 7.74 (1H, s), 7.65 (1H, s),
7.27 (2H, m), 3.74 (3H, s), 3.60 (2H, s)
Step H:
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]pyrazol-4-yl]acetic Acid Methyl Ester
[1171] 2-[1-(4-Bromo-2,6-difluoro-phenyl)pyrazol-4-yl]acetic acid
methyl ester (0.6 g, 1.82 mmol) obtained in Step G was reacted in
the same manner as in Step D of Preparation Example 1 to obtain the
title compound (0.52 g, 76%).
[1172] .sup.1H-NMR (CDCl.sub.3) .delta. 7.75 (1H, s), 7.69 (1H, s),
7.46 (2H, m), 3.74 (3H, s), 3.60 (2H, s), 1.35 (12H, s)
Preparation Example 91:
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
pyrrolidin-3-yl]acetic Acid Ethyl Ester
Step A: tert-butyl 3-hydroxypyrrolidin-1-carboxylate
[1173] 3-Pyrrolidinol (4.66 g, 53 mmol) was dissolved in 90 mL of
DCM. Dimethylaminopyridine (0.65 g, 5.3 mmol) and TEA (8.1 mL, 58.3
mmol) were added thereto. The reaction solution was cooled to
0.degree. C., and di-tert-butyl dicarbonate (12.84 g, 58.8 mmol)
was added thereto. The mixture was stirred at room temperature for
48 hours. 1 M NaOH aqueous solution (53 mL, 53 mmol) was added
thereto, and the mixture was stirred for 10 minutes. After addition
of water, the reaction solution was extracted with DCM and dried
with MgSO.sub.4. The organic layer was purified by column
chromatography to obtain the title compound (8.98 g, 90%).
[1174] .sup.1H-NMR (CDCl.sub.3) .delta. 4.45 (1H, m), 3.46 (3H, m),
3.33 (1H, m), 1.97 (2H, m), 1.42 (9H, s)
Step B: tert-butyl 3-oxopyrrolidin-1-carboxylate
[1175] Oxalyl chloride (6.0 mL, 70.5 mmol) was added to 300 mL of
DCM and cooled to -78.degree. C. DMSO (9.9 mL, 139 mmol) was added
thereto, and the mixture was stirred for 15 minutes. Tert-butyl
3-hydroxypyrrolidin-1-carboxylate (8.98 g, 48 mmol) obtained in
Step A was added thereto, and the mixture was stirred for 20
minutes. TEA (32 mL, 0.23 mol) was added thereto, and the mixture
was stirred at -78.degree. C. for 1 hour and additionally stirred
at room temperature for 1 hour. After addition of water, the
reaction solution was extracted with DCM. The organic layer was
dried with MgSO.sub.4 and purified by column chromatography to
obtain the title compound (7.92 g, 89%).
[1176] .sup.1H-NMR (CDCl.sub.3) .delta. 3.77 (4H, m), 2.59 (2H, t),
1.48 (9H, s)
Step C: tert-butyl
3-(2-ethoxy-2-oxo-ethylidene)pyrrolidin-1-carboxylate
[1177] Tert-butyl 3-oxopyrrolidin-1-carboxylate (1.82 g, 9.82 mmol)
obtained in Step B was dissolved in 49 mL of DCM.
(1-Ethoxycarbonylethylidene)triphenylphosphorane (3.59 g, 10.3
mmol) was added thereto, and the mixture was stirred for 72 hours
under reflux. The reaction solution was concentrated under reduced
pressure and purified by column chromatography to obtain the title
compound (2.0 g, 80%).
[1178] .sup.1H-NMR (CDCl.sub.3) .delta. 5.81 (1H, s), 4.42-4.13
(2H, m), 4.18 (2H, q), 3.56 (2H, m), 3.12-2.74 (2H, t), 1.46 (9H,
s), 1.28 (3H, t)
Step D: tert-butyl
3-(2-ethoxy-2-oxo-ethyl)pyrrolidin-1-carboxylate
[1179] Tert-butyl
3-(2-ethoxy-2-oxo-ethylidene)pyrrolidin-1-carboxylate (2.0 g, 7.83
mmol) obtained in Step C was dissolved in 40 mL of EtOH. 0.2 g of
10 wt % Pd/C was added thereto, and the mixture was stirred for 24
hours under hydrogen atmosphere. Solids were filtered and
concentrated under reduced pressure to obtain the title compound
(1.95 g, 97%).
[1180] .sup.1H-NMR (CDCl.sub.3) .delta. 4.14 (2H, q), 3.58 (1H, m),
3.45 (1H, m), 3.29 (1H, m), 2.92 (1H, m), 2.56 (1H, m), 2.38 (2H,
d), 2.07 (1H, m), 1.51 (1H, m), 1.46 (9H, s), 1.26 (3H, t)
Step E: 2-[1-(2,6-difluoro-4-nitro-phenyl)pyrrolidin-3-yl]acetic
Acid Ethyl Ester
[1181] Tert-butyl 3-(2-ethoxy-2-oxo-ethyl)pyrrolidin-1-carboxylate
(1.95 g, 7.57 mmol) obtained in Step D was dissolved in 7 mL of
DCM. HCl (7.8 mL, 30 mmol, 4 M 1,4-dioxane solution) was added
thereto, and the mixture was stirred at room temperature for 90
minutes. The reaction solution was concentrated under reduced
pressure to obtain hydrochloric acid salt of
2-pyrrolidin-3-ylacetic acid ethyl ester. The obtained hydrochloric
acid salt of 2-pyrrolidin-3-ylacetic acid ethyl ester and
3,4,5-trifluoronitrobenzene (1.34 g, 7.57 mmol) were reacted in the
same manner as in Step A of Preparation Example 84 to obtain the
title compound (2.24 g, 94%).
[1182] .sup.1H-NMR (CDCl.sub.3) .delta. 7.72 (2H, m), 4.17 (2H, q),
3.89 (1H, m), 3.81 (1H, m), 3.76 (1H, m), 3.47 (1H, m), 2.62 (1H,
m), 2.46 (2H, d), 2.16 (1H, m), 1.65 (1H, m), 1.27 (3H, t)
Step F: 2-[1-(4-bromo-2,6-difluoro-phenyl)pyrrolidin-3-yl]acetic
Acid Ethyl Ester
[1183] 2-[1-(2,6-Difluoro-4-nitro-phenyl)pyrrolidin-3-yl]acetic
acid ethyl ester (2.24 g, 7.12 mmol) obtained in Step E was reacted
in the same manner as in Steps B and C of Preparation Example 84 to
obtain the title compound (0.92 g, 37%).
[1184] .sup.1H-NMR (CDCl.sub.3) .delta. 6.93 (2H, m), 4.15 (2H, q),
3.60 (2H, m), 3.49 (1H, m), 3.24 (1H, m), 2.62 (1H, m), 2.44 (2H,
d), 2.13 (1H, m), 1.63 (1H, m), 1.26 (3H, t)
Step G:
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]pyrrolidin-3-yl]acetic Acid Ethyl Ester
[1185] 2-[1-(4-Bromo-2,6-difluoro-phenyl)pyrrolidin-3-yl]acetic
acid ethyl ester (0.92 g, 2.64 mmol) obtained in Step F was reacted
in the same manner as in Step D of Preparation Example 1 to obtain
the title compound (0.82 g, 79%).
[1186] .sup.1H-NMR (CDCl.sub.3) .delta. 7.18 (2H, m), 4.15 (2H, q),
3.70 (2H, m), 3.59 (1H, m), 3.35 (1H, m), 2.60 (1H, m), 2.44 (2H,
m), 2.14 (1H, m), 1.61 (1H, m), 1.36 (12H, s), 1.27 (3H, t)
Preparation Example 92:
3-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]propanoic Acid Ethyl Ester
Step A: tert-butyl
4-[(E)-3-ethoxy-3-oxo-prop-1-enyl]piperidin-1-carboxylate
[1187] Tert-butyl 4-(hydroxymethyl)piperidin-1-carboxylate (4.0 g,
18.6 mmol) was reacted in the same manner as in Step B of
Preparation Example 88 to obtain the title compound (4.36 g,
83%).
[1188] .sup.1H-NMR (CDCl.sub.3) .delta. 6.89 (1H, dd), 5.78 (1H,
d), 4.21 (2H, q), 4.12 (2H, m), 2.76 (2H, m), 2.28 (1H, m), 1.72
(2H, m), 1.45 (9H, s), 1.33 (2H, m), 1.28 (3H, t)
Step B:
(E)-3-[1-(2,6-difluoro-4-nitro-phenyl)-4-piperidyl]prop-2-enoic
Acid Ethyl Ester
[1189] Tert-butyl
4-[(E)-3-ethoxy-3-oxo-prop-1-enyl]piperidin-1-carboxylate (4.33 g,
15.1 mmol) obtained in Step A was dissolved in HCl (15 mL, 60 mmol,
4 M 1,4-dioxane solution) and stirred at 60.degree. C. for 90
minutes. After addition of Et.sub.2O, the reaction solution was
concentrated under reduced pressure to obtain hydrochloric acid
salt of (E)-3-(4-piperidyl)prop-2-enoic acid ethyl ester. The
obtained hydrochloric acid salt of (E)-3-(4-piperidyl)prop-2-enoic
acid ethyl ester and 3,4,5-trifluoronitrobenzene (2.67 g, 15.1
mmol) were reacted in the same manner as in Step A of Preparation
Example 84 to obtain the title compound (5.1 g, 99%).
[1190] .sup.1H-NMR (CDCl.sub.3) .delta. 7.75 (2H, m), 6.94 (1H,
dd), 5.86 (1H, d), 4.20 (2H, q), 3.54 (2H, m), 3.22 (2H, m), 2.36
(1H, m), 1.84 (2H, m), 1.64 (2H, m), 1.30 (3H, t)
Step C:
(E)-3-[1-(4-bromo-2,6-difluoro-phenyl)-4-piperidyl]prop-2-enoic
Acid Ethyl Ester
[1191]
(E)-3-[1-(2,6-difluoro-4-nitro-phenyl)-4-piperidyl]prop-2-enoic
acid ethyl ester (5.1 g, 15 mmol) obtained in Step B were reacted
in the same manner as in Steps B and C of Preparation Example 84 to
obtain the title compound (2.45 g, 43%).
[1192] .sup.1H-NMR (CDCl.sub.3) .delta. 7.00 (2H, m), 6.95 (1H,
dd), 5.84 (1H, d), 4.20 (2H, q), 3.23 (2H, m), 3.10 (2H, m), 2.29
(1H, m), 1.78 (2H, m), 1.61 (2H, m), 1.30 (3H, t)
Step D: 3-[1-(4-bromo-2,6-difluoro-phenyl)-4-piperidyl]propanoic
Acid Ethyl Ester
[1193]
(E)-3-[1-(4-bromo-2,6-difluoro-phenyl)-4-piperidyl]prop-2-enoic
acid ethyl ester (2.45 g, 6.54 mmol) obtained in Step C was
dissolved in 70 mL of DME. p-Toluenesulfonyl hydrazide (8.52 g,
45.6 nmol) was added thereto little by little, and the mixture was
heated to 90.degree. C. Sodium acetate (5.36 g, 65.4 mmol, 1.4 M
aqueous solution) was added thereto, and the mixture was stirred
for 9 hours under reflux. After addition of water, the reaction
solution was extracted with DCM. The organic layer was dried with
MgSO.sub.4 to obtain the title compound (2.46 g, 99%).
[1194] .sup.1H-NMR (CDCl.sub.3) .delta. 6.99 (2H, m), 4.13 (2H, q),
3.18 (2H, m), 3.01 (2H, m), 2.34 (2H, m), 1.71 (2H, m), 1.63 (2H,
m), 1.37 (3H, m), 1.26 (3H, t)
Step E:
3-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]-4-piperidyl]propanoic Acid Ethyl Ester
[1195] 3-[1-(4-Bromo-2,6-difluoro-phenyl)-4-piperidyl]propanoic
acid ethyl ester (2.46 g, 6.54 mmol) obtained in Step D was reacted
in the same manner as in Step D of Preparation Example 1 to obtain
the title compound (2.02 g, 73%).
[1196] .sup.1H-NMR (CDCl.sub.3) .delta. 7.23 (2H, m), 4.14 (2H, q),
3.31 (2H, m), 3.05 (2H, m), 2.34 (2H, m), 1.71 (2H, m), 1.62 (2H,
m), 1.36 (3H, m), 1.32 (12H, s), 1.25 (3H, t)
Preparation Example 93:
2-[4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
piperazin-1-yl]acetic Acid Ethyl Ester
Step A: 4-(2-ethoxy-2-oxo-ethyl)piperazin-1-carboxylic Acid Benzyl
Ester
[1197] 1-Piperazincarboxylic acid benzyl ester (3.12 g, 14.2 mmol)
was dissolved in 47 mL of THF. Bromoacetic acid ethyl ester (1.73
mL, 15.6 mmol) and TEA (5.92 mL, 42.5 mmol) were sequentially added
thereto, and the mixture was stirred for 90 minutes under reflux.
The reaction solution was cooled to at room temperature. Solids
were filtered, and water was added thereto. The organic layer
extracted with EtOAc was dried with MgSO.sub.4 to obtain the title
compound (4.3 g, 99%).
[1198] .sup.1H-NMR (CDCl.sub.3) .delta. 7.35 (5H, m), 5.13 (2H, s),
4.19 (2H, q), 3.56 (4H, m), 3.22 (2H, s), 2.55 (4H, m), 1.27 (3H,
t)
Step B: 2-piperazin-1-ylacetic Acid Ethyl Ester
[1199] 4-(2-Ethoxy-2-oxo-ethyl)piperazin-1-carboxylic acid benzyl
ester (4.30 g, 14.0 mmol) obtained in Step A was dissolved in 70 mL
of MeOH. 0.43 g of 10 wt % Pd/C was added thereto, and the mixture
was stirred for 24 hours under hydrogen atmosphere. Solids were
filtered through Celite to obtain the title compound (2.40 g,
99%).
[1200] .sup.1H-NMR (CDCl.sub.3) .delta. 4.19 (2H, q), 3.20 (2H, s),
2.94 (4H, m), 2.57 (4H, m), 1.28 (3H, t)
Step C: 2-[4-(2,6-difluoro-4-nitro-phenyl)piperazin-1-yl]acetic
Acid Ethyl Ester
[1201] 2-Piperazin-1-ylacetic acid ethyl ester (2.40 g, 13.9 mmol)
obtained in Step B, 3,4,5-trifluoronitrobenzene (2.35 g, 13.3 mmol)
and DIPEA (3.50 mL, 13.9 mmol) were dissolved in 33 mL of DMF and
stirred at room temperature for 16 hours. The reaction solution was
concentrated under reduced pressure. After addition of water, the
reaction solution was extracted with EtOAc to obtain the title
compound (4.37 g, 99%).
[1202] .sup.1H-NMR (CDCl.sub.3) .delta. 7.78 (2H, m), 4.22 (2H, q),
3.50 (4H, m), 3.38 (2H, s), 2.85 (4H, m), 1.30 (3H, t)
Step D: 2-[4-(4-bromo-2,6-difluoro-phenyl)piperazin-1-yl]acetic
Acid Ethyl Ester
[1203] 2-[4-(2,6-Difluoro-4-nitro-phenyl)piperazin-1-yl]acetic acid
ethyl ester (4.34 g, 13.2 mmol) obtained in Step C was reacted in
the same manner as in Steps B and C of Preparation Example 84 to
obtain the title compound (0.27 g, 6%).
[1204] .sup.1H-NMR (CDCl.sub.3) .delta. 7.00 (2H, m), 4.20 (2H, q),
3.26 (2H, s), 3.24 (4H, m), 2.70 (4H, m), 1.27 (3H, t)
Step E:
2-[4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]piperazin-1-yl]acetic Acid Ethyl Ester
[1205] 2-[4-(4-Bromo-2,6-difluoro-phenyl)piperazin-1-yl]acetic acid
ethyl ester (0.27 g, 0.74 mmol) obtained in Step D was reacted in
the same manner as in Step D of Preparation Example 1 to obtain the
title compound (0.12 g, 39%).
[1206] .sup.1H-NMR (CDCl.sub.3) .delta. 7.23 (2H, m), 4.20 (2H, q),
3.30 (4H, m), 3.25 (2H, s), 2.70 (4H, m), 1.33 (12H, s), 1.28 (3H,
t)
Preparation Example 94:
3-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
pyrazol-4-yl]propanoic Acid Ethyl Ester
Step A: tert-butyl 4-(hydroxymethyl)pyrazol-1-carboxylate
[1207] 4-Pyrazolcarboxylic acid ethyl ester (4.45 g, 31.7 mmol) was
dissolved in 30 mL of THF. Dimethylaminopyridine (0.19 g, 1.59
mmol), TEA (5.3 mL, 38.1 mmol) and di-tert-butyl dicarbonate (8.31
g, 38.1 mmol) were sequentially added thereto, and the mixture was
stirred at room temperature for 1 hour. After addition of water,
the reaction solution was extracted with EtOAc. The organic layer
was dried with MgSO.sub.4, and 140 mL of Et.sub.2O was added
thereto. After cooling to -78.degree. C., the mixture was reacted
in the same manner as in Step C of Preparation Example 90 to obtain
the title compound (1.42 g, 22%).
[1208] .sup.1H-NMR (CDCl.sub.3) .delta. 8.02 (1H, s), 7.68 (1H, s),
4.60 (2H, s), 1.63 (9H, s)
Step B: tert-butyl 4-formylpyrazol-1-carboxylate
[1209] Tert-butyl 4-(hydroxymethyl)pyrazol-1-carboxylate (1.42 g,
7.1 mmol) obtained in Step A was dissolved in 40 mL of DCM.
MgSO.sub.4 (1.2 g, 9.9 mmol) and manganese dioxide (4.32 g, 50
mmol) were added thereto, and the mixture was stirred at room
temperature for 16 hours. Solids were filtered and purified by
column chromatography to obtain the title compound (1.03 g,
74%).
[1210] .sup.1H-NMR (CDCl.sub.3) .delta. 9.96 (1H, s), 8.61 (1H, s),
8.13 (1H, s), 1.67 (9H, s)
Step C: tert-butyl
4-[(E)-3-ethoxy-3-oxo-prop-1-enyl]pyrazol-1-carboxylate
[1211] Tert-butyl 4-formylpyrazol-1-carboxylate (1.0 g, 5.28 mmol)
obtained in Step B was reacted in the same manner as in Step A of
Preparation Example 85 to obtain the title compound (1.05 g,
74%).
[1212] .sup.1H-NMR (CDCl.sub.3) .delta. 8.21 (1H, s), 7.89 (1H, s),
7.54 (1H, d), 6.29 (1H, d), 4.25 (2H, q), 1.66 (9H, s), 1.31 (3H,
t)
Step D:
(E)-3-[1-(2,6-difluoro-4-nitro-phenyl)pyrazol-4-yl]prop-2-enoic
Acid Ethyl Ester
[1213] Tert-butyl
4-[(E)-3-ethoxy-3-oxo-prop-1-enyl]pyrazol-1-carboxylate (0.88 g,
3.3 mmol) obtained in Step C was dissolved in 22 mL of DCM. 11 mL
of TFA was added thereto, and the mixture was stirred at room
temperature for 6 hours. After addition of Et.sub.2O, the reaction
solution was concentrated under reduced pressure to obtain solids.
11 mL of DMSO, 3,4,5-trifluoronitrobenzene (0.58 g, 3.3 mmol) and
K.sub.2CO.sub.3 (1.37 g, 9.9 mmol) were sequentially added to the
solids, and the mixture was stirred at 90.degree. C. for 16 hours.
After addition of water, the reaction solution was extracted with
EtOAc. The organic layer was dried with MgSO.sub.4 and purified by
column chromatography to obtain the title compound (0.73 g,
41%).
[1214] .sup.1H-NMR (CDCl.sub.3) .delta. 8.04 (3H, m), 7.92 (1H, s),
7.62 (1H, d), 6.32 (1H, d), 4.27 (2H, q), 1.33 (3H, t)
Step E: 3-[1-(4-bromo-2,6-difluoro-phenyl)pyrazol-4-yl]propanoic
Acid Ethyl Ester
[1215]
(E)-3-[1-(2,6-difluoro-4-nitro-phenyl)pyrazol-4-yl]prop-2-enoic
acid ethyl ester (0.71 g, 2.2 mmol) obtained in Step D was reacted
in the same manner as in Steps C and D of Preparation Example 88 to
obtain the title compound (0.68 g, 86%).
[1216] .sup.1H-NMR (CDCl.sub.3) .delta. 7.66 (1H, s), 7.47 (1H, s),
7.26 (2H, m), 4.14 (2H, q), 2.88 (2H, t), 2.62 (2H, t), 1.25 (3H,
t)
Step F:
3-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]pyrazol-4-yl]propanoic Acid Ethyl
[1217] 3-[1-(4-Bromo-2,6-difluoro-phenyl)pyrazol-4-yl]propanoic
acid ethyl ester (0.075 g, 0.21 mmol) obtained in Step E was
reacted in the same manner as in Step D of Preparation Example 1 to
obtain the title compound (0.03 g, 36%).
[1218] .sup.1H-NMR (CDCl.sub.3) .delta. 7.66 (1H, s). 7.52 (1H, m),
7.47 (2H, m), 4.15 (2H, q), 2.89 (2H, t), 2.63 (2H, t), 1.35 (12H,
s), 1.24 (3H, t)
Preparation Example 95:
4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl]butanoic
Acid Ethyl Ester
Step A: 5-bromoindoline
[1219] 10 mL of acetic acid was added to 5-bromoindole (2.5 g, 12.8
mmol) and cooled to 0.degree. C. Sodium triacetoxyborohydride (2.38
g, 37.9 mmol) was added thereto, and the mixture was stirred at
room temperature for 16 hours. After addition of water, the
reaction solution was extracted with Et.sub.2O, and the organic
layer washed with sodium bicarbonate aqueous solution. The organic
layer was dried with MgSO.sub.4 and purified by column
chromatography to obtain the title compound (0.95 g, 38%).
[1220] .sup.1H-NMR (CDCl.sub.3) .delta. 7.19 (1H, d), 7.09 (1H,
dd), 6.50 (1H, d), 3.74 (1H, brs), 3.56 (2H, t), 3.02 (2H, t)
Step B: 4-(5-bromoindolin-1-yl)butanoic Acid Ethyl Ester
[1221] 5-Bromoindoline (0.95 g, 4.8 mmol) obtained in Step A was
dissolved in 16 mL of DMF K.sub.2CO.sub.3 (1.32 g, 9.6 mmol) and
4-bromobutanoic acid ethyl ester (0.94 g, 4.8 mmol) were added
thereto, and the mixture was stirred at 70.degree. C. for 24 hours.
The reaction solution was concentrated under reduced pressure and
purified by column chromatography to obtain the title compound
(0.59 g, 39%).
[1222] .sup.1H-NMR (CDCl.sub.3) .delta. 7.12 (2H, m), 6.30 (1H, d),
4.11 (2H, q), 3.35 (2H, t), 3.06 (2H, t), 2.94 (2H, t), 2.39 (2H,
t), 1.91 (2H, m), 1.24 (3H, t)
Step C:
4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl]but-
anoic Acid Ethyl Ester
[1223] 4-(5-Bromoindolin-1-yl)butanoic acid ethyl ester (0.59 g,
1.88 mmol) obtained in Step B was reacted in the same manner as in
Step D of Preparation Example 1 to obtain the title compound (0.48
g, 70%).
[1224] .sup.1H-NMR (CDCl.sub.3) .delta. 7.55 (1H, dd), 7.49 (1H,
m), 6.41 (1H, d), 4.11 (2H, q), 3.40 (2H, t), 3.15 (2H, t), 2.96
(2H, t), 2.39 (2H, t), 1.92 (2H, m), 1.31 (12H, s), 1.25 (3H,
t)
Preparation Example 96:
3-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
azetidin-3-yl]propanoic Acid Ethyl Ester
Step A: 1-tert-butoxycarbonylazetidin-3-carboxylic Acid
[1225] 60 mL of THF and 60 mL of 0.5 M NaOH aqueous solution were
added to azetidin-3-carboxylic acid (3 g, 30 mmol). Di-tert-butyl
dicarbonate (6.8 g, 31.1 mmol) was slowly added thereto, and the
mixture was stirred at room temperature for 24 hours. The reaction
solution was concentrated under reduced pressure. The reaction
solution was adjusted to pH 4 by the addition of water and HCl
aqueous solution, and extracted with EtOAc. The organic layer was
dried with MgSO.sub.4 to obtain the title compound (4.5 g,
73%).
[1226] .sup.1H-NMR (CDCl.sub.3) .delta. 4.12 (4H, m), 3.38 (1H, m),
1.44 (9H, s)
Step B:
(E)-3-[1-(2,6-difluoro-4-nitro-phenyl)azetidin-3-yl]prop-2-enoic
Acid Ethyl Ester
[1227] 1-Tert-butoxycarbonylazetidin-3-carboxylic acid (3.5 g, 17.4
mmol) obtained in Step A was sequentially reacted in the same
manner as in Step A of Preparation Example 71, Step E of
Preparation Example 86 and Step B of Preparation Example 88 to
obtain the title compound (0.5 g, 9%).
[1228] .sup.1H-NMR (CDCl.sub.3) .delta. 7.70 (2H, m), 7.14 (1H, m),
5.93 (1H, d), 4.62 (2H, m), 4.28 (2H, m), 4.22 (2H, q), 3.60 (1H,
m), 1.30 (3H, t)
Step C: 3-[1-(4-bromo-2,6-difluoro-phenyl)azetidin-3-yl]propanoic
Acid Ethyl Ester
[1229]
(E)-3-[1-(2,6-difluoro-4-nitro-phenyl)azetidin-3-yl]prop-2-enoic
acid ethyl ester (0.66 g, 2.1 mmol) obtained in Step B was
sequentially reacted in the same manner as in Step C of Preparation
Example 88 and Step C of Preparation Example 84 to obtain the title
compound (0.14 g, 19%).
[1230] .sup.1H-NMR (CDCl.sub.3) .delta. 6.88 (2H, m), 4.25 (2H, m),
4.14 (2H, q), 3.78 (2H, m), 2.67 (1H, m), 2.29 (2H, t), 1.96 (2H,
m), 1.26 (3H, t)
Step D:
3-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]azetidin-3-yl]propanoic Acid Ethyl Ester
[1231] 3-[1-(4-Bromo-2,6-difluoro-phenyl)azetidin-3-yl]propanoic
acid ethyl ester (0.13 g, 0.38 mmol) obtained in Step C was reacted
in the same manner as in Step D of Preparation Example 1 to obtain
the title compound (0.032 g, 21%).
[1232] .sup.1H-NMR (CDCl.sub.3) .delta. 7.15 (2H, m), 4.32 (2H, m),
4.12 (2H, q), 3.85 (2H, m), 2.67 (1H, m), 2.29 (2H, t), 1.97 (2H,
m), 1.32 (12H, s), 1.27 (3H, t)
Preparation Example 97:
2-[(3S)-1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ph-
enyl]pyrrolidin-3-yl]acetic Acid Methyl Ester
Step A: 2-[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanedioic
Acid Ethyl Ester
[1233] (3S)-3-hydroxypyrrolidin-1-carboxylic acid tert-butyl ester
(1.5 g, 8 mmol) was dissolved in 16 mL of toluene and cooled to
-10.degree. C. TEA (1.7 mL, 12 mmol) and methanesulfonyl chloride
(0.8 mL, 10.1 mmol) were slowly added thereto. The mixture was
stirred at room temperature for 80 minutes, and solids were
filtered. The filtrate was washed with sodium bicarbonate aqueous
solution, dried with MgSO.sub.4 and concentrated under reduced
pressure to obtain (3S)-3-methylsulfonyloxypyrrolidin-1-carboxylic
acid tert-butyl ester. 27 mL of EtOH and malonic acid ethyl ester
(2.62 g, 16.4 mmol) were prepared in another flask, and sodium
(0.37 g, 16 mmol) was added thereto little by little. The mixture
was stirred at room temperature for 30 minutes.
(3S)-3-methylsulfonyloxypyrrolidin-1-carboxylic acid tert-butyl
ester was added thereto, and the mixture was stirred for 16 hours
under reflux. The reaction solution was cooled to room temperature
and adjusted to pH 4 by the addition of water and 1N HCl aqueous
solution. The reaction solution was extracted with MTBE to obtain
the title compound (2.08 g, 79%).
[1234] .sup.1H-NMR (CDCl.sub.3) .delta. 4.22 (2H, q), 3.64 (1H, m),
3.50 (1H, m), 3.28 (2H, m), 3.03 (1H, m), 2.81 (1H, m), 2.08 (1H,
m), 1.63 (1H, m), 1.45 (9H, s), 1.27 (6H, t)
Step B: 2-[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanedioic
Acid
[1235] 2-[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanedioic
acid ethyl ester (2.08 g, 6.3 mmol) obtained in Step A was
dissolved in 9 mL of THE 44 wt % KOH aqueous solution (5 g, 39
mmol) was added thereto, and the mixture was stirred at 45.degree.
C. for 24 hours. The reaction solution was cooled to room
temperature and washed with MTBE. The water layer was adjusted to
pH 4 and extracted with EtOAc. The organic layer was dried with
MgSO.sub.4 to obtain the title compound (1.42 g, 83%).
[1236] .sup.1H-NMR (CD.sub.3OD) .delta. 3.63 (1H, m), 3.45 (1H, m),
3.30 (2H, m), 3.05 (1H, m), 2.74 (1H, m), 2.10 (1H, m), 1.71 (1H,
m), 1.45 (9H, s)
Step C: 2-[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]acetic
Acid
[1237] 2-[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanedioic
acid (1.42 g, 5.22 mmol) obtained in Step B was dissolved in 15 mL
of toluene and 0.2 mL of DMSO, and stirred for 16 hours under
reflux. The reaction solution was cooled to room temperature. After
addition of water, the reaction solution was extracted with MTBE.
The organic layer was dried with MgSO.sub.4 to obtain the title
compound (1.05 g, 87%).
[1238] .sup.1H-NMR (CD.sub.3OD) .delta. 3.58 (1H, m), 3.43 (1H, m),
3.27 (1H, m), 2.93 (1H, m), 2.52 (1H, m), 2.40 (2H, d), 2.08 (1H,
m), 1.58 (1H, m), 1.45 (9H, s)
Step D:
2-[(3S)-1-(2,6-difluoro-4-nitro-phenyl)pyrrolidin-3-yl]acetic Acid
Methyl Ester
[1239] 2-[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]acetic acid
(1.05 g, 4.58 mmol) obtained in Step C was dissolved in 15 mL of
THF. Diazomethane (0.25 M Et.sub.2O solution, 27 mL, 6.87 mmol) was
added thereto, and the mixture was stirred at room temperature for
40 minutes. The reaction solution was concentrated under reduced
pressure. After addition of 15 mL of DCM and HCl (4 M 1,4-dioxane
solution, 4.6 mL), the reaction solution was stirred at room
temperature for 90 minutes. The reaction solution was concentrated
under reduced pressure and dissolved in 15 mL of DMF. TEA (1.6 mL,
11.5 mmol) and 3,4,5-trifluoronitrobenzene (0.81 g, 4.58 mmol) were
sequentially added thereto, and the mixture was stirred at room
temperature for 48 hours. The reaction solution was concentrated
under reduced pressure. After addition of water, the reaction
solution was extracted with EtOAc to obtain the title compound
(1.33 g, 97%).
[1240] .sup.1H-NMR (CDCl.sub.3) .delta. 7.72 (2H, m), 3.89 (1H, m),
3.82 (1H, m), 3.76 (1H, m), 3.71 (3H, s), 3.47 (1H, m), 2.63 (1H,
m), 2.49 (2H, d), 2.18 (1H, m), 1.64 (1H, m)
Step E:
2-[(3S)-1-(4-bromo-2,6-difluoro-phenyl)pyrrolidin-3-yl]acetic Acid
Methyl Ester
[1241]
2-[(3S)-1-(2,6-difluoro-4-nitro-phenyl)pyrrolidin-3-yl]acetic acid
methyl ester (1.33 g, 4.43 mmol) obtained in Step D was
sequentially reacted in the same manner as in Steps B and C of
Preparation Example 84 to obtain the title compound (0.38 g,
25%).
[1242] .sup.1H-NMR (CDCl.sub.3) .delta. 6.93 (2H, m), 3.69 (3H, s),
3.60 (2H, m), 3.48 (1H, m), 3.24 (1H, m), 2.63 (1H, m), 2.45 (2H,
d), 2.13 (1H, m), 1.62 (1H, m)
Step F:
2-[(3S)-1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan--
2-yl)phenyl]pyrrolidin-3-yl]acetic Acid Methyl Ester
[1243]
2-[(3S)-1-(4-bromo-2,6-difluoro-phenyl)pyrrolidin-3-yl]acetic acid
methyl ester (0.37 g, 1.1 mmol) obtained in Step E was reacted in
the same manner as in Step D of Preparation Example 1 to obtain the
title compound (0.18 g, 43%).
[1244] .sup.1H-NMR (CDCl.sub.3) .delta. 7.17 (2H, m), 3.70 (5H, m),
3.59 (1H, m), 3.35 (1H, m), 2.61 (1H, m), 2.46 (2H, m), 2.12 (1H,
m), 1.62 (1H, m), 1.31 (12H, s)
Preparation Example 98:
2-[(3R)-1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ph-
enyl]pyrrolidin-3-yl]acetic Acid Methyl Ester
[1245] (3R)-3-hydroxypyrrolidin-1-carboxylic acid tert-butyl ester
(1.0 g, 5.34 mmol) was reacted in the same manner as in Steps A, B,
C, D, E and F of Preparation Example 97 to obtain the title
compound (0.14 g, 7%).
[1246] .sup.1H-NMR (CDCl.sub.3) .delta. 7.17 (2H, m), 3.70 (5H, m),
3.59 (1H, m), 3.35 (1H, m), 2.61 (1H, m), 2.46 (2H, m), 2.12 (1H,
m), 1.62 (1H, m), 1.31 (12H, s)
Preparation Example 99:
2-[1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-p-
iperidyl]acetic Acid Ethyl Ester
Step A: 1-(2-fluoro-4-nitro-phenyl)piperidin-4-one
[1247] 1,2-Difluoro-4-nitro-benzene (1.50 g, 9.42 mmol) was
dissolved in 31 mL of DMF. TEA (3.3 mL, 23.5 mmol) and hydrate of
4-piperidone hydrochloride (1.52 g, 9.9 mmol) were sequentially
added thereto, and the mixture was stirred at room temperature for
48 hours. The reaction solution was concentrated under reduced
pressure. After addition of water, the reaction solution was
extracted with EtOAc. The organic layer was dried with MgSO.sub.4
to obtain the title compound (2.03 g, 91%).
[1248] .sup.1H-NMR (CDCl.sub.3) .delta. 8.02 (1H, m), 7.96 (1H, m),
6.98 (1H, t), 3.65 (4H, t), 2.65 (4H, t)
Step B: 2-[1-(2-fluoro-4-nitro-phenyl)-4-piperidylidene]acetic Acid
Ethyl Ester
[1249] 1-(2-Fluoro-4-nitro-phenyl)piperidin-4-one (2.03 g, 8.55
mmol) obtained in Step A was reacted in the same manner as in Step
B of Preparation Example 89 to obtain the title compound (2.65 g,
99%).
[1250] .sup.1H-NMR (CDCl.sub.3) .delta. 7.95 (1H, m), 7.92 (1H, m),
6.91 (1H, m), 5.76 (1H, s), 4.17 (2H, q), 3.43 (2H, m), 3.38 (2H,
m), 3.16 (2H, m), 2.50 (2H, m), 1.30 (3H, t)
Step C: 2-[1-(4-bromo-2-fluoro-phenyl)-4-piperidyl]acetic Acid
Ethyl Ester
[1251] 2-[1-(2-Fluoro-4-nitro-phenyl)-4-piperidylidene]acetic acid
ethyl ester (2.65 g, 8.6 mmol) obtained in Step B was sequentially
reacted in the same manner as in Step C of Preparation Example 88
and Step C of Preparation Example 84 to obtain the title compound
(0.72 g, 24%).
[1252] .sup.1H-NMR (CDCl.sub.3) .delta. 7.15 (2H, m), 6.81 (1H, t),
4.14 (2H, q), 3.38 (2H, m), 2.67 (2H, m), 2.29 (2H, d), 1.92 (1H,
m), 1.82 (2H, m), 1.48 (2H, m), 1.26 (3H, t)
Step D:
2-[1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
yl]-4-piperidyl]acetic Acid Ethyl Ester
[1253] 2-[1-(4-Bromo-2-fluoro-phenyl)-4-piperidyl]acetic acid ethyl
ester (0.22 g, 0.64 mmol) obtained in Step C was reacted in the
same manner as in Step D of Preparation Example 1 to obtain the
title compound (0.20 g, 80%).
[1254] .sup.1H-NMR (CDCl.sub.3) .delta. 7.48 (1H, m), 7.41 (1H, m),
6.92 (1H, t), 4.14 (2H, q), 3.52 (2H, m), 2.72 (2H, m), 2.29 (2H,
d), 1.94 (1H, m), 1.83 (2H, m), 1.50 (2H, m), 1.32 (12H, s), 1.27
(3H, t)
Preparation Example 100: 1-(6-bromo-naphthalen-2-yl)-ethaneone
[1255] 2-Bromo-naphthalene (0.5 g, 2.41 mmol), AlCl.sub.3 (0.338 g,
2.53 mmol) and AcCl (0.172 mL, 2.41 mmol) were dissolved in 3.4 mL
of nitrobenzene, and stirred at 100.degree. C. for 4 hours under
reflux. After addition of water, the reaction solution extracted
with EtOAc. The organic layer was separated, dried with MgSO.sub.4
and purified by column chromatography to obtain the title compound
(0.3 g, 49%).
[1256] .sup.1H-NMR (CDCl.sub.3) .delta. 8.43 (1H, s), 8.06 (2H, m),
7.82 (2H, t), 7.63 (1H, m), 2.72 (3H, s).
Preparation Example 101: 6-bromo-naphthalen-2-carboxylic Acid
[1257] 1-(6-Bromo-naphthalen-2-yl)-ethaneone (0.22 g, 0.88 mmol)
obtained in Preparation Example 100 was dissolved in 3 mL of
1,4-dioxane. NaOH (0.353 g, 8.8 mmol) dissolved in 3 mL of water
and 9-11% NaOCl solution (1.67 mL, 2.64 mmol) were added thereto,
and the mixture was heated to 70.degree. C. and stirred for 4
hours. After addition of NaHSO.sub.3 aqueous solution and water,
the reaction solution was extracted with ether. 1N HCl was added
thereto, and the organic layer was separated, dried with MgSO.sub.4
and purified by column chromatography to obtain the title compound
(0.156 g, 70%).
[1258] .sup.1H-NMR (CDCl.sub.3) .delta. 8.56 (1H, s), 8.05 (2H, m),
7.79 (2H, m), 7.58 (1H, m).
Preparation Example 102: (6-bromo-naphthalen-2-yl)-methanol
[1259] 6-Bromo-naphthalen-2-carboxylic acid (0.42 g, 1.67 mmol)
obtained in Preparation Example 101 was reacted in the same manner
as in Step B of Preparation Example 31 to obtain the title compound
(0.307 g, 77%).
[1260] .sup.1H-NMR (CDCl.sub.3) .delta. 8.00 (1H, s), 7.83-7.69
(3H, m), 7.57-7.52 (2H, m), 4.85 (2H, m), 1.75 (1H, t).
Preparation Example 103: 2-bromo-6-chloromethyl-naphthalene
[1261] (6-Bromo-naphthalen-2-yl)-methanol (0.307 g, 1.29 mmol)
obtained in Preparation Example 102 was dissolved in 5 mL of
acetonitrile. Thionyl-chloride (0.188 mL, 2.59 mmol) was added
thereto at 0.degree. C., and the mixture was stirred at room
temperature for 1 hour. The reaction solution was distilled under
reduced pressure and purified by column chromatography to obtain
the title compound (0.248 g, 75%).
[1262] .sup.1H-NMR (CDCl.sub.3) .delta. 8.00 (1H, s), 7.83-7.68
(3H, m), 7.58-7.53 (2H, m), 4.73 (2H, s).
Preparation Example 104: 2-(6-bromo-naphthalen-2-ylmethyl)-malonic
Acid Dimethyl Ester
[1263] NaH (60% in mineral oil, 0.058 g, 1.45 mmol) was dissolved
in 3 mL of DMF. Dimethyl malonate (0.166 mL, 1.45 mmol) was added
thereto, and the mixture was stirred for 15 minutes.
2-Bromo-6-chloromethyl-naphthalene (0.248 g, 0.97 mmol) obtained in
Preparation Example 103 was added thereto, and the mixture was
heated to 60.degree. C. and stirred for 4 hours. After addition of
water, the reaction solution was extracted with EtOAc. The organic
layer was separated, dried with MgSO.sub.4 and purified by column
chromatography to obtain the title compound (0.26 g, 76%).
[1264] .sup.1H-NMR (CDCl.sub.3) .delta. 7.96 (1H, s), 7.71-7.62
(3H, m), 7.52 (1H, m), 7.36 (1H, m), 3.75 (1H, m), 3.69 (6H, s),
3.87 (2H, d).
Preparation Example 105: 3-(6-bromo-naphthalen-2-yl)-propionic
Acid
[1265] 2-(6-Bromo-naphthalen-2-ylmethyl)-malonic acid dimethyl
ester (0.26 g, 0.74 mmol) obtained in Preparation Example 104 was
dissolved in 12 mL of ethanol and 12 mL of THF. 6 mL of 4N KOH was
added thereto, and the mixture was heated to 60.degree. C. and
stirred for 1 hour. The reaction solution was distilled under
reduced pressure. Solids obtained by the addition of 2N HCl were
dissolved in 6 mL of pyridine, heated to 60.degree. C. and stirred
for 1 hour. The reaction solution was distilled under reduced
pressure. After addition of 2N HCl and water, the reaction solution
was extracted with EtOAc. The organic layer was separated, dried
with MgSO.sub.4 and purified by column chromatography to obtain the
title compound (0.055 g, 26%).
[1266] .sup.1H-NMR (CDCl.sub.3) .delta. 7.96 (1H, s), 7.70-7.62
(3H, m), 7.53 (1H, m), 7.36 (1H, m), 3.11 (2H, t), 2.77 (2H,
t).
Preparation Example 106: 3-(6-bromo-naphthalen-2-yl)-propionic Acid
Methyl Ester
[1267] 3-(6-Bromo-naphthalen-2-yl)-propionic acid (0.055 g, 0.2
mmol) obtained in Preparation Example 105 was reacted in the same
manner as in Step G of Preparation Example 81 to obtain the title
compound (0.052 g, 91%).
[1268] .sup.1H-NMR (CDCl.sub.3) .delta. 7.96 (1H, s), 7.70-7.61
(3H, m), 7.53 (1H, m), 7.36 (1H, m), 3.67 (3H, s), 3.10 (2H, t),
2.72 (2H, t).
Preparation Example 107:
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-prop-
ionic Acid Methyl Ester
[1269] 3-(6-Bromo-naphthalen-2-yl)-propionic acid methyl ester
(0.085 g, 0.29 mmol) obtained in Preparation Example 106 was
reacted in the same manner as in Step D of Preparation Example 1 to
obtain the title compound (0.083 g, 84%).
[1270] .sup.1H-NMR (CDCl.sub.3) .delta. 8.32 (1H, s), 7.80 (2H, d),
7.75 (1H, d), 7.62 (1H, s), 7.32 (1H, d), 3.67 (3H, s), 3.12 (2H,
t), 2.73 (2H, t), 1.39 (12H, s).
Preparation Example 108:
6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-carboxylic
Acid Methyl Ester
[1271] 6-Bromo-naphthalen-2-carboxylic acid methyl ester (1 g, 3.77
mmol) was reacted in the same manner as in Step D of Preparation
Example 1 to obtain the title compound (0.824 g, 70%).
[1272] .sup.1H-NMR (CDCl.sub.3) .delta. 8.59 (1H, s), 8.39 (1H, s),
8.05 (1H, d), 7.92 (3H, m), 3.98 (3H, s), 1.40 (12H, s).
Preparation Example 109:
6-(6-phenoxy-pyridin-2-yl)-naphthalen-2-carboxylic Acid Methyl
Ester
[1273]
6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-carbo-
xylic acid methyl ester (0.2 g, 0.64 mmol) obtained in Preparation
Example 108 and 2-chloro-6-phenoxy-pyridine (0.132 g, 0.64 mmol)
obtained in Preparation Example 54 were reacted in the same manner
as in Step A of Example 1 to obtain the title compound (0.17 g,
74%).
[1274] .sup.1H-NMR (CDCl.sub.3) .delta. 8.58 (1H, s), 8.45 (1H, s),
8.06 (2H, m), 7.93 (2H, m), 7.78 (1H, t), 7.63 (1H, d), 7.44 (2H,
m), 7.24 (3H, m), 6.82 (1H, d), 3.98 (3H, s).
Preparation Example 110:
2-[6-(6-phenoxy-pyridin-2-yl)-naphthalen-2-ylmethyl]-malonic Acid
Dimethyl Ester
[1275] 6-(6-Phenoxy-pyridin-2-yl)-naphthalen-2-carboxylic acid
methyl ester (0.17 g, 0.48 mmol) obtained in Preparation Example
109 was sequentially reacted in the same manner as in Preparation
Examples 102, 103 and 104 to obtain the title compound (0.125 g,
59%).
[1276] .sup.1H-NMR (CDCl.sub.3) .delta. 8.39 (1H, s), 8.02 (1H, m),
7.82-7.74 (3H, m), 7.61 (2H, m), 7.43 (2H, m), 7.32 (1H, m), 7.23
(3H, m), 6.78 (1H, d), 3.78 (1H, t), 3.69 (6H, s), 3.38 (2H,
d).
Preparation Example 111:
6-(2-phenoxy-phenyl)-naphthalen-2-carboxylic Acid Methyl Ester
[1277]
6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-carbo-
xylic acid methyl ester (0.62 g, 2.34 mmol) obtained in Preparation
Example 108 and 2-phenoxyphenylboronic acid (0.5 g, 2.34 mmol) were
reacted in the same manner as in Step A of Example 1 to obtain the
title compound (0.8 g, 96%).
[1278] .sup.1H-NMR (CDCl.sub.3) .delta. 8.57 (1H, s), 8.03 (2H, m),
7.92 (1H, d), 7.86 (1H, d), 7.77 (1H, m), 7.56 (1H, m), 7.35 (1H,
m), 7.24 (3H, m), 7.05 (2H, m), 6.94 (2H, m), 3.98 (3H, s).
Preparation Example 112:
2-[6-(2-phenoxy-phenyl)-naphthalen-2-ylmethyl]-malonic Acid
Dimethyl Ester
[1279] 6-(2-Phenoxy-phenyl)-naphthalen-2-carboxylic acid methyl
ester (0.8 g, 2.26 mmol) obtained in Preparation Example 111 was
sequentially reacted in the same manner as in Preparation Examples
102, 103 and 104 to obtain the title compound (0.64 g, 64%).
[1280] .sup.1H-NMR (CDCl.sub.3) .delta. 7.95 (1H, s), 7.74 (2H, m),
7.68 (1H, m), 7.61 (1H, m), 7.55 (1H, m), 7.32 (2H, m), 7.25 (3H,
m), 7.04 (2H, m), 6.94 (2H, m), 3.79 (1H, m), 3.68 (6H, s), 3.38
(2H, d).
Preparation Example 113:
6-(6-cyclopentylsulfanyl-pyridin-2-yl)-naphthalen-2-carboxylic Acid
Methyl Ester
[1281]
6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-carbo-
xylic acid methyl ester (0.2 g, 0.64 mmol) obtained in Preparation
Example 108 and 2-chloro-6-cyclopentylsulfanyl-pyridine (0.136 g,
0.64 mmol) obtained in Preparation Example 14 were reacted in the
same manner as in Step A of Example 1 to obtain the title compound
(0.03 g, 13%).
[1282] .sup.1H-NMR (CDCl.sub.3) .delta. 8.62 (1H, s), 8.52 (1H, s),
8.25 (1H, m), 8.08 (1H, m), 8.03 (1H, d), 7.97 (1H, d), 7.58 (2H,
m), 7.15 (1H, m), 4.25 (1H, m), 4.00 (3H, s), 2.30 (2H, m),
1.84-1.73 (6H, m).
Preparation Example 114:
2-[6-(6-cyclopentylsulfanyl-pyridin-2-yl)-naphthalen-2-ylmethyl]-malonic
Acid Dimethyl Ester
[1283]
6-(6-Cyclopentylsulfanyl-pyridin-2-yl)-naphthalen-2-carboxylic acid
methyl ester (0.03 g, 0.08 mmol) obtained in Preparation Example
113 was sequentially reacted in the same manner as in Preparation
Examples 102, 103 and 104 to obtain the title compound (0.019 g,
51%).
[1284] .sup.1H-NMR (CDCl.sub.3) .delta. 8.45 (1H, s), 8.16 (1H, m),
7.86 (2H, m), 7.68 (1H, s), 7.55 (2H, m), 7.35 (1H, m), 7.13 (1H,
m), 4.25 (1H, m), 3.80 (1H, t), 3.70 (6H, s), 3.41 (2H, d), 2.31
(2H, m), 1.73-1.60 (6H, m).
Preparation Example 115:
6-(2-phenoxy-pyridin-3-yl)-naphthalen-2-carboxylic Acid Methyl
Ester
Step A: 3-chloro-2-phenoxy-pyridine
[1285] 2,3-Dichloro-pyridine (0.3 g, 2.03 mmol), phenol (0.286 g,
3.04 mmol), Cu (0.257 g, 4.05 mmol) and Cs.sub.2CO.sub.3 (1.98 g,
6.08 mmol) were reacted in the same manner as in Preparation
Example 17 to obtain the title compound (0.193 g, 77%).
Step B: 6-(2-phenoxy-pyridin-3-yl)-naphthalen-2-carboxylic Acid
Methyl Ester
[1286]
6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-carbo-
xylic acid methyl ester (0.242 g, 0.78 mmol) obtained in
Preparation Example 108 and 3-chloro-2-phenoxy-pyridine (0.16 g,
0.78 mmol) obtained in Step A were reacted in the same manner as in
Step A of Example 1 to obtain the title compound (0.06 g, 22%).
[1287] .sup.1H-NMR (CDCl.sub.3) .delta. 8.63 (1H, s), 8.20 (1H, m),
8.12 (1H, s), 8.08 (1H, m), 7.92 (1H, m), 7.86 (2H, m), 7.39 (2H,
m), 7.20-7.13 (4H, m), 6.80 (1H, m), 4.00 (3H, s).
Preparation Example 116:
[6-(2-phenoxy-pyridin-3-yl)-naphthalen-2-yl]-methanol
[1288] 6-(2-Phenoxy-pyridin-3-yl)-naphthalen-2-carboxylic acid
methyl ester (0.06 g, 0.17 mmol) obtained in Preparation Example
115 was reacted in the same manner as in Step B of Preparation
Example 31 to obtain the title compound (0.024 g, 43%).
[1289] .sup.1H-NMR (CDCl.sub.3) .delta. 8.18 (1H, m), 8.08 (1H, s),
7.88 (3H, m), 7.82 (2H, m), 7.51 (1H, d), 7.38 (2H, t), 7.19-7.12
(4H, m), 4.87 (2H, d), 1.78 (1H, t).
Preparation Example 117:
6-(3-phenoxy-phenyl)-naphthalen-2-carboxylic Acid Methyl Ester
[1290]
6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-carbo-
xylic acid methyl ester (0.125 g, 0.40 mmol) obtained in
Preparation Example 108 and 1-bromo-3-phenoxy-benzene (0.1 g, 0.40
mmol) were reacted in the same manner as in Step A of Example 1 to
obtain the title compound (0.032 g, 22%).
[1291] .sup.1H-NMR (CDCl.sub.3) .delta. 8.62 (1H, s), 8.09-8.00
(3H, m), 7.92 (1H, d), 7.76 (1H, m), 7.46 (2H, m), 7.37 (3H, m),
7.10 (4H, m), 3.99 (3H, s).
Preparation Example 118:
[6-(3-phenoxy-phenyl)-naphthalen-2-yl]-methanol
[1292] 6-(3-Phenoxy-phenyl)-naphthalen-2-carboxylic acid methyl
ester (0.032 g, 0.09 mmol) obtained in Preparation Example 117 was
reacted in the same manner as in Step B of Preparation Example 31
to obtain the title compound (0.029 g, 98%).
[1293] .sup.1H-NMR (CDCl.sub.3) .delta. 8.01 (1H, s), 7.88 (3H, m),
7.71 (1H, m), 7.52-7.34 (6H, m), 7.14-7.03 (4H, m), 4.88 (2H, d),
1.75 (1H, t).
Preparation Example 119:
6-(3-isopropoxy-phenyl)-naphthalen-2-carboxylic Acid Methyl
Ester
Step A: 1-bromo-3-isopropoxy-benzene
[1294] 3-Bromo phenol (0.2 g, 1.16 mmol) and 2-bromo-propane (0.163
mL, 1.73 mmol) were reacted in the same manner as in Preparation
Example 17 to obtain the title compound (0.193 g, 77%).
Step B: 6-(3-isopropoxy-phenyl)-naphthalen-2-carboxylic Acid Methyl
Ester
[1295]
6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-carbo-
xylic acid methyl ester (0.280 g, 0.89 mmol) obtained in
Preparation Example 108 and 1-bromo-3-isopropoxy-benzene (0.193 g,
1.39 mmol) obtained in Step A were reacted in the same manner as in
Step A of Example 1 to obtain the title compound (0.078 g,
27%).
[1296] .sup.1H-NMR (CDCl.sub.3) .delta. 8.63 (1H, s), 8.10-8.00
(3H, m), 7.92 (1H, m), 7.80 (1H, m), 7.39 (1H, m), 7.26 (2H, m),
6.93 (1H, m), 4.66 (1H, m), 3.99 (3H, s), 1.39 (6H, d).
Preparation Example 120:
[6-(3-isopropoxy-phenyl)-naphthalen-2-yl]-methanol
[1297] 6-(3-Isopropoxy-phenyl)-naphthalen-2-carboxylic acid methyl
ester (0.305 g, 0.9 mmol) obtained in Preparation Example 119 was
reacted in the same manner as in Step B of Preparation Example 31
to obtain the title compound (0.196 g, 70%).
[1298] .sup.1H-NMR (CDCl.sub.3) .delta. 8.03 (1H, s), 7.88 (3H, m),
7.73 (1H, m), 7.50 (1H, m), 7.36 (1H, m), 7.26 (2H, m), 6.91 (1H,
m), 4.88 (2H, d), 4.66 (1H, m), 1.77 (1H, t), 1.39 (6H, d).
Preparation Example 121:
6-(3-cyclobutoxy-phenyl)-naphthalen-2-carboxylic Acid Methyl
Ester
Step A: 1-bromo-3-cyclobutoxy-benzene
[1299] 3-Bromo phenol (0.2 g, 1.16 mmol) and bromocyclobutane
(0.163 mL, 1.73 mmol) were reacted in the same manner as in
Preparation Example 17 to obtain the title compound (0.262 g,
100%).
Step B: 6-(3-cyclobutoxy-phenyl)-naphthalen-2-carboxylic Acid
Methyl Ester
[1300]
6-(4,4,5,5-Tetramethyl-[1,3,2]dioxoborolan-2-yl)-naphthalen-2-carbo-
xylic acid methyl ester (0.435 g, 1.39 mmol) obtained in
Preparation Example 108 and 1-bromo-3-cyclobutoxy-benzene (0.317 g,
1.39 mmol) obtained in Step A were reacted in the same manner as in
Step A of Example 1 to obtain the title compound (0.305 g,
65%).
[1301] .sup.1H-NMR (CDCl.sub.3) .delta. 8.63 (1H, s), 8.10-8.00
(3H, m), 7.92 (1H, m), 7.79 (1H, m), 7.38 (1H, m), 7.26 (1H, m),
7.17 (1H, s), 6.86 (1H, m), 4.74 (1H, m), 3.99 (3H, s), 2.50 (2H,
m), 2.24 (2H, m), 1.90 (1H, m), 1.72 (1H, m).
Preparation Example 122:
[6-(3-cyclobutoxy-phenyl)-naphthalen-2-yl]-methanol
[1302] 6-(3-Cyclobutoxy-phenyl)-naphthalen-2-carboxylic acid methyl
ester (0.305 g, 0.9 mmol) obtained in Preparation Example 121 was
reacted in the same manner as in Step B of Preparation Example 31
to obtain the title compound (0.196 g, 70%).
[1303] .sup.1H-NMR (CDCl.sub.3) .delta. 8.02 (1H, s), 7.88 (3H, m),
7.74 (1H, m), 7.50 (1H, m), 7.36 (1H, m), 7.26 (1H, m), 7.17 (1H,
s), 6.83 (1H, m), 4.88 (2H, d), 4.74 (1H, m), 2.50 (2H, m), 2.23
(2H, m), 1.90 (1H, m), 1.73 (2H, m).
Preparation Example 123:
6-(6-cyclobutoxy-pyridin-2-yl)-naphthalen-2-carboxylic Acid Methyl
Ester
[1304]
6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-carbo-
xylic acid methyl ester (0.39 g, 1.25 mmol) obtained in Preparation
Example 108 and 2-chloro-6-cyclobutoxy-pyridine (0.23 g, 1.25 mmol)
obtained in Preparation Example 29 were reacted in the same manner
as in Step A of Example 1 to obtain the title compound (0.21 g,
50%).
[1305] .sup.1H-NMR (CDCl.sub.3) .delta. 8.62 (1H, s), 8.51 (1H, s),
8.22 (1H, m), 8.10-7.91 (3H, m), 7.68 (1H, t), 7.48 (1H, m), 6.70
(1H, d), 5.35 (1H, m), 3.98 (3H, s), 2.60 (2H, m), 2.24 (2H, m),
1.89 (1H, m), 1.76 (1H, m).
Preparation Example 124:
[6-(6-cyclobutoxy-pyridin-2-yl)-naphthalen-2-yl]-methanol
[1306] 6-(6-Cyclobutoxy-pyridin-2-yl)-naphthalen-2-carboxylic acid
methyl ester (0.21 g, 0.6 mmol) obtained in Preparation Example 123
was reacted in the same manner as in Step B of Preparation Example
31 to obtain the title compound (0.155 g, 80%).
[1307] .sup.1H-NMR (CDCl.sub.3) .delta. 8.47 (1H, s), 8.17 (1H, m),
7.93 (2H, m), 7.84 (1H, s), 7.66 (1H, t), 7.48 (2H, m), 6.67 (1H,
d), 5.35 (1H, m), 4.89 (2H, d), 2.57 (2H, m), 2.24 (2H, m), 1.89
(1H, m), 1.78 (2H, m).
Preparation Example 125:
6-(2-isopropoxy-pyridin-3-yl)-naphthalen-2-carboxylic Acid Methyl
Ester
[1308]
6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-carbo-
xylic acid methyl ester (0.144 g, 0.46 mmol) obtained in
Preparation Example 108 and 3-iodo-2-isopropoxy-pyridine (0.124 g,
0.46 mmol) obtained in Preparation Example 34 were reacted in the
same manner as in Step A of Example 1 to obtain the title compound
(0.092 g, 62%).
[1309] .sup.1H-NMR (CDCl.sub.3) .delta. 8.62 (1H, s), 8.18 (1H, m),
8.06 (2H, m), 7.97 (1H, d), 7.89 (1H, d), 7.80 (1H, m), 7.72 (1H,
m), 6.97 (1H, m), 5.45 (1H, m), 3.99 (3H, s), 1.36 (6H, d).
Preparation Example 126:
6-(2-cyclopentyloxy-pyridin-3-yl)-naphthalen-2-carboxylic Acid
Methyl Ester
[1310]
6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-carbo-
xylic acid methyl ester (0.223 g, 0.7 mmol) obtained in Preparation
Example 108 and 2-cyclopentyloxy-3-iodo-pyridine (0.207 g, 0.7
mmol) obtained in Preparation Example 11 were reacted in the same
manner as in Step A of Example 1 to obtain the title compound
(0.123 g, 49%).
[1311] .sup.1H-NMR (CDCl.sub.3) .delta. 8.62 (1H, s), 8.19 (1H, m),
8.08 (1H, m), 8.03 (1H, s), 7.96 (1H, d), 7.89 (1H, d), 7.77 (1H,
m), 7.73 (1H, m), 6.97 (1H, m), 5.57 (1H, m), 4.00 (3H, s), 1.95
(2H, m), 1.85 (2H, m), 1.73 (2H, m), 1.63 (2H, m).
Preparation Example 127: 2-chloro-6-(2-fluoro-phenoxy)-pyridine
[1312] 2,6-Dichloropyridine (0.2 g, 1.35 mmol) and 2-fluoro-phenol
(0.151 g, 1.35 mmol) were reacted in the same manner as in
Preparation Example 12 to obtain the title compound (0.045 g,
15%).
[1313] .sup.1H-NMR (CDCl.sub.3) .delta. 7.64 (1H, m), 7.27 (2H, m),
7.20 (2H, m), 7.05 (1H, d), 6.85 (1H, d).
Preparation Example 128:
3-[6-(2-bromo-phenyl)-naphthalen-2-yl]-propionic Acid Methyl
Ester
[1314] 3-(6-Bromo-naphthalen-2-yl)-propionic acid methyl ester (0.1
g, 0.34 mmol) obtained in Preparation Example 106 and
2-bromophenylboronic acid (0.068 g, 0.34 mmol) were reacted in the
same manner as in Step A of Example 1 to obtain the title compound
(0.012 g, 9%).
[1315] .sup.1H-NMR (CDCl.sub.3) .delta. 7.81-7.23 (9H, m), 7.10
(1H, m), 3.70 (3H, s), 3.07 (2H, t), 2.72 (2H, t).
Preparation Example 129:
3-{6-[2-(2-fluoro-phenoxy)-phenyl]-naphthalen-2-yl}-propionic Acid
Methyl Ester
[1316] 3-[6-(2-Bromo-phenyl)-naphthalen-2-yl]-propionic acid methyl
ester (0.012 g, 0.03 mmol) obtained in Preparation Example 128 was
dissolved in 1 mL of 1,4-dioxane. CuI (0.001 g, 0.006 mmol),
Cs.sub.2CO.sub.3 (0.021 g, 0.06 mmol) and 2-fluoro-phenol (0.006
mL, 0.06 mmol) were added thereto, and the mixture was stirred for
18 hours under reflux. The reaction solution was filtered through
Celite and purified by column chromatography to obtain the title
compound (0.012 g, 92%).
[1317] .sup.1H-NMR (CDCl.sub.3) .delta. 7.82-7.35 (4H, m),
7.20-7.04 (8H, m), 6.80 (2H, m) 3.67 (3H, s), 3.06 (2H, t), 2.70
(2H, t).
Preparation Example 130: 2-(4-bromo-phenyl)-2-methyl-propionic Acid
Ethyl Ester
[1318] (4-Bromo-phenyl)-acetic acid ethyl ester (0.1 g, 0.41 mmol)
was dissolved in 1 mL of THF. t-BuOK (0.092 g, 0.82 mmol) was added
thereto, and iodomethane (0.051 mL, 0.82 mmol) was added thereto at
0.degree. C. The mixture was stirred at room temperature for 18
hours. After addition of 1N HCl and water, the reaction solution
was extracted with EtOAc. The organic layer was separated, dried
with MgSO.sub.4 and purified by column chromatography to obtain the
title compound (0.047 g, 42%).
[1319] .sup.1H-NMR (CDCl.sub.3) .delta. 7.42 (2H, d), 7.21 (2H, d),
4.11 (2H, q), 1.54 (6H, s), 1.18 (3H, t).
Preparation Example 131:
2-(4-bromo-phenyl)-2-methyl-propan-1-ol
[1320] 2-(4-Bromo-phenyl)-2-methyl-propionic acid ethyl ester
(0.236 g, 0.87 mmol) obtained in Preparation Example 130 was
reacted in the same manner as in Step B of Preparation Example 31
to obtain the title compound (0.17 g, 85%).
[1321] .sup.1H-NMR (CDCl.sub.3) .delta. 7.45 (2H, d), 7.26 (2H, d),
3.61 (2H, d), 1.55 (1H, m), 1.31 (6H, s).
Preparation Example 132:
2-(4-bromo-phenyl)-2-methyl-propionaldehyde
[1322] 2-(4-Bromo-phenyl)-2-methyl-propan-1-ol (0.17 g, 0.74 mmol)
obtained in Preparation Example 131 was dissolved in 2.5 mL of MC
and 0.5 mL of DMSO. IBX (0.249 g, 0.89 mmol) was added thereto at
0.degree. C., and the mixture was stirred at room temperature for 4
hours. After addition of water, the reaction solution was extracted
with MC. The organic layer was separated, dried with MgSO.sub.4 and
purified by column chromatography to obtain the title compound
(0.052 g, 30%).
[1323] .sup.1H-NMR (CDCl.sub.3) .delta. 9.46 (1H, s), 7.50 (2H, d),
7.13 (2H, d), 1.44 (6H, s)
Preparation Example 133:
3-(4-bromo-phenyl)-3-methyl-butyraldehyde
[1324] 2-(4-Bromo-phenyl)-2-methyl-propionaldehyde (0.33 g, 1.45
mmol) obtained in Preparation Example 132 was reacted in the same
manner as in Preparation Example 152 to obtain the title compound
(0.275 g, 78%).
[1325] .sup.1H-NMR (CDCl.sub.3) .delta. 9.52 (1H, m), 7.45 (2H, d),
7.24 (2H, d), 2.66 (2H, m), 1.44 (6H, s).
Preparation Example 134:
(E)-5-(4-bromo-phenyl)-5-methyl-hex-2-enoic Acid Ethyl Ester
[1326] 3-(4-Bromo-phenyl)-3-methyl-butyraldehyde (0.275 g, 1.14
mmol) obtained in Preparation Example 133 was reacted in the same
manner as in Step A of Preparation Example 85 to obtain the title
compound (0.348 g, 98%).
[1327] .sup.1H-NMR (CDCl.sub.3) .delta. 7.42 (2H, d), 7.19 (2H, d),
6.69 (1H, m), 5.74 (1H, d), 4.15 (2H, q), 2.48 (2H, d), 1.32 (6H,
s), 1.25 (3H, t).
Preparation Example 135:
(E)-5-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]--
hex-2-enoic Acid Ethyl Ester
[1328] (E)-5-(4-bromo-phenyl)-5-methyl-hex-2-enoic acid ethyl ester
(0.348 g, 1.12 mmol) obtained in Preparation Example 134 was
reacted in the same manner as in Step D of Preparation Example 1 to
obtain the title compound (0.291 g, 72%).
[1329] .sup.1H-NMR (CDCl.sub.3) .delta. 7.75 (2H, d), 7.34 (2H, d),
6.70 (1H, m), 5.76 (1H, d), 4.12 (2H, q), 2.50 (2H, d), 1.33 (18H,
s), 1.24 (3H, t).
Preparation Example 136:
5-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-hexa-
noic Acid Ethyl Ester
[1330]
(E)-5-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-ph-
enyl]-hex-2-enoic acid ethyl ester (0.291 g, 0.81 mmol) obtained in
Preparation Example 135 was reacted in the same manner as in Step E
of Preparation Example 1 to obtain the title compound (0.248 g,
84%).
[1331] .sup.1H-NMR (CDCl.sub.3) .delta. 7.75 (2H, d), 7.33 (2H, d),
4.08 (2H, q), 2.17 (2H, t), 1.65 (2H, m), 1.35 (20H, m), 1.22 (3H,
t).
Preparation Example 137:
2-(4-bromo-2-fluoro-phenyl)-2-methyl-propionitrile
Step A: (4-bromo-2-fluoro-phenyl)-acetonitrile
[1332] 4-Bromo-1-bromomethyl-2-fluoro-benzene (0.5 g, 1.87 mmol)
was reacted in the same manner as in Preparation Example 149 to
obtain the title compound (0.386 g, 96%).
Step B: 2-(4-bromo-2-fluoro-phenyl)-2-methyl-propionitrile
[1333] (4-Bromo-2-fluoro-phenyl)-acetonitrile (0.24 g, 1.12 mmol)
obtained in Step A was reacted in the same manner as in Preparation
Example 143 to obtain the title compound (0.235 g, 86%).
[1334] .sup.1H-NMR (CDCl.sub.3) .delta. 7.40-7.26 (3H, m), 1.78
(6H, s).
Preparation Example 138:
2-(4-bromo-2-fluoro-phenyl)-2-methyl-propionaldehyde
[1335] 2-(4-Bromo-2-fluoro-phenyl)-2-methyl-propionitrile (0.235 g,
0.97 mmol) obtained in Preparation Example 137 was reacted in the
same manner as in Preparation Example 151 to obtain the title
compound (0.2 g, 84%).
[1336] .sup.1H-NMR (CDCl.sub.3) .delta. 9.61 (1H, m), 7.34 (1H, m),
7.26 (1H, m), 7.16 (1H, t), 1.44 (6H, s).
Preparation Example 139:
3-(4-bromo-2-fluoro-phenyl)-3-methyl-butyraldehyde
[1337] 2-(4-Bromo-2-fluoro-phenyl)-2-methyl-propionaldehyde (0.2 g,
0.82 mmol) obtained in Preparation Example 138 was reacted in the
same manner as in Preparation Example 152 to obtain the title
compound (0.067 g, 31%).
[1338] .sup.1H-NMR (CDCl.sub.3) .delta. 9.51 (1H, t), 7.25-7.16
(3H, m), 2.81 (2H, s), 1.43 (6H, s).
Preparation Example 140:
(E)-5-(4-bromo-2-fluoro-phenyl)-5-methyl-hex-2-enoic Acid Ethyl
Ester
[1339] 3-(4-Bromo-2-fluoro-phenyl)-3-methyl-butyraldehyde (0.067 g,
0.26 mmol) obtained in Preparation Example 139 was reacted in the
same manner as in Step A of Preparation Example 85 to obtain the
title compound (0.072 g, 84%).
[1340] .sup.1H-NMR (CDCl.sub.3) .delta. 7.20 (2H, m), 7.08 (1H, t),
6.66 (1H, m), 5.79 (1H, d), 4.14 (2H, q), 2.62 (2H, d), 1.37 (6H,
s), 1.25 (3H, t).
Preparation Example 141:
(E)-5-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]--
5-methyl-hex-2-enoic Acid Ethyl Ester
[1341] (E)-5-(4-bromo-2-fluoro-phenyl)-5-methyl-hex-2-enoic acid
ethyl ester (0.072 g, 0.22 mmol) obtained in Preparation Example
140 was reacted in the same manner as in Step D of Preparation
Example 1 to obtain the title compound (0.045 g, 54%).
[1342] .sup.1H-NMR (CDCl.sub.3) .delta. 7.47 (1H, d), 7.42 (1H, d),
7.23 (1H, t), 6.66 (1H, m), 5.75 (1H, d), 4.11 (2H, q), 2.65 (2H,
d), 1.32 (18H, s), 1.23 (3H, t).
Preparation Example 142:
5-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-5-me-
thyl-hexanoic Acid Ethyl Ester
[1343]
(E)-5-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-ph-
enyl]-5-methyl-hex-2-enoic acid ethyl ester (0.045 g, 0.12 mmol)
obtained in Preparation Example 141 was reacted in the same manner
as in Step E of Preparation Example 1 to obtain the title compound
(0.02 g, 44%).
[1344] .sup.1H-NMR (CDCl.sub.3) .delta. 7.47 (1H, d), 7.38 (1H, d),
7.23 (1H, t), 4.06 (2H, q), 2.19 (2H, t), 1.75 (2H, m), 1.35 (20H,
m), 1.21 (3H, t).
Preparation Example 143:
2-(4-bromo-2,6-difluoro-phenyl)-2-methyl-propionitrile
[1345] (4-Bromo-2,6-difluoro-phenyl)-acetonitrile (0.4 g, 1.72
mmol) obtained in Preparation Example 149 was dissolved in 2 mL of
DMF and 2 mL of THF. NaH (60% in mineral oil, 0.152 g, 3.79 mmol)
and iodomethane (0.236 mL, 3.79 mmol) were added thereto at
0.degree. C., and the mixture was stirred at room temperature for 3
hours. After addition of water, the reaction solution was extracted
with EtOAc. The organic layer was separated, dried with MgSO.sub.4
and purified by column chromatography to obtain the title compound
(0.372 g, 83%).
[1346] .sup.1H-NMR (CDCl.sub.3) .delta. 7.12 (2H, m), 1.86 (6H,
s).
Preparation Example 144:
2-(4-bromo-2,6-difluoro-phenyl)-2-methyl-propionaldehyde
[1347] 2-(4-Bromo-2,6-difluoro-phenyl)-2-methyl-propionitrile
(0.372 g, 1.43 mmol) obtained in Preparation Example 143 was
reacted in the same manner as in Preparation Example 151 to obtain
the title compound (0.328 g, 87%).
[1348] .sup.1H-NMR (CDCl.sub.3) .delta. 9.60 (1H, m), 7.08 (2H, m),
1.50 (6H, s).
Preparation Example 145:
3-(4-bromo-2,6-difluoro-phenyl)-3-methyl-butyraldehyde
[1349] 2-(4-Bromo-2,6-difluoro-phenyl)-2-methyl-propionaldehyde
(0.328 g, 1.25 mmol) obtained in Preparation Example 144 was
reacted in the same manner as in Preparation Example 152 to obtain
the title compound (0.16 g, 46%).
[1350] .sup.1H-NMR (CDCl.sub.3) .delta. 9.61 (1H, s), 7.01 (2H, m),
2.86 (2H, s), 1.54 (6H, s).
Preparation Example 146:
(E)-5-(4-bromo-2,6-difluoro-phenyl)-5-methyl-hex-2-enoic Acid Ethyl
Ester
[1351] 3-(4-Bromo-2,6-difluoro-phenyl)-3-methyl-butyraldehyde (0.16
g, 0.58 mmol) obtained in Preparation Example 145 was reacted in
the same manner as in Step A of Preparation Example 85 to obtain
the title compound (0.17 g, 85%).
[1352] .sup.1H-NMR (CDCl.sub.3) .delta. 6.98 (2H, m), 6.74 (1H, m),
5.78 (1H, d), 4.14 (2H, q), 2.64 (2H, d), 1.46 (6H, s), 1.25 (3H,
t).
Preparation Example 147:
5-(4-bromo-2,6-difluoro-phenyl)-5-methyl-hexanoic Acid Ethyl
Ester
[1353] (E)-5-(4-bromo-2,6-difluoro-phenyl)-5-methyl-hex-2-enoic
acid ethyl ester (0.17 g, 0.49 mmol) obtained in Preparation
Example 146 was reacted in the same manner as in Preparation
Example 174 to obtain the title compound (0.15 g, 87%).
[1354] .sup.1H-NMR (CDCl.sub.3) .delta. 6.96 (2H, m), 4.08 (2H, q),
2.23 (2H, t), 1.72 (2H, m), 1.43 (8H, m), 1.22 (3H, t).
Preparation Example 148:
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]--
5-methyl-hexanoic Acid Ethyl Ester
[1355] 5-(4-Bromo-2,6-difluoro-phenyl)-5-methyl-hexanoic acid ethyl
ester (0.15 g, 0.43 mmol) obtained in Preparation Example 147 was
reacted in the same manner as in Step D of Preparation Example 1 to
obtain the title compound (0.07 g, 41%).
[1356] .sup.1H-NMR (CDCl.sub.3) .delta. 7.20 (2H, m), 4.08 (2H, q),
2.21 (2H, t), 1.75 (2H, m), 1.46 (8H, m), 1.32 (12H, s), 1.21 (3H,
t).
Preparation Example 149:
(4-bromo-2,6-difluoro-phenyl)-acetonitrile
[1357] 5-Bromo-2-bromomethyl-1,3-difluoro-benzene (1.1 g, 3.85
mmol) was dissolved in 6 mL of ethanol and 2 mL of water. KCN
(0.268 g, 4.12 mmol) was added thereto and heated to 60.degree. C.,
and the mixture was stirred for 2 hours. After addition of water,
the reaction solution was extracted with EtOAc. The organic layer
was separated, dried with MgSO.sub.4 and purified by column
chromatography to obtain the title compound (0.8 g, 89%).
[1358] .sup.1H-NMR (CDCl.sub.3) .delta. 7.17 (2H, m), 3.69 (2H,
s).
Preparation Example 150:
1-(4-bromo-2,6-difluoro-phenyl)-cyclopropanecarbonitrile
[1359] (4-Bromo-2,6-difluoro-phenyl)-acetonitrile (0.4 g, 1.72
mmol) obtained in Preparation Example 149 was dissolved in 1 mL of
toluene and 1.7 mL of 50% NaOH aqueous solution.
1-Bromo-2-chloroethane (0.287 mL, 3.44 mmol) and
benzyltriethylammonium chloride (0.098 g, 0.43 mmol) were added
thereto at 0.degree. C., the mixture was heated to 40.degree. C.
and stirred for 18 hours. After addition of water, the reaction
solution was extracted with EtOAc. The organic layer was separated,
dried with MgSO.sub.4 and purified by column chromatography to
obtain the title compound (0.27 g, 60%).
[1360] .sup.1H-NMR (CDCl.sub.3) .delta. 7.12 (2H, m), 1.76 (2H, m),
1.36 (2H, m).
Preparation Example 151:
1-(4-bromo-2,6-difluoro-phenyl)-cyclopropanecarbaldehyde
[1361] 1-(4-Bromo-2,6-difluoro-phenyl)-cyclopropanecarbonitrile
(0.270 g, 1.05 mmol) obtained in Preparation Example 150 was
dissolved in 5 mL of MC. DIBAL-H (0.77 mL, 1.15 mmol) was added
thereto at -78.degree. C., and the mixture was stirred for 2 hours
and additionally stirred at room temperature for 1 hour. After
addition of 1N HCl and KNa tartrate aqueous solution, the reaction
solution was extracted with MC. The organic layer was separated,
dried with MgSO.sub.4 and purified by column chromatography to
obtain the title compound (0.216 g, 79%).
[1362] .sup.1H-NMR (CDCl.sub.3) .delta. 8.83 (1H, s), 7.10 (2H, m),
1.70 (2H, m), 1.46 (2H, m).
Preparation Example 152:
[1-(4-bromo-2,6-difluoro-phenyl)-cyclopropyl]-acetaldehyde
[1363] (Methoxymethyl)triphenylphosphonium chloride (0.425 g, 1.24
mmol) was dissolved in 3 mL of THF. LiHMDS (1.24 mL, 1.24 mmol)
were added thereto at 0.degree. C., and the mixture was stirred for
15 minutes.
1-(4-Bromo-2,6-difluoro-phenyl)-cyclopropanecarbaldehyde (0.216 g,
0.83 mmol) obtained in Preparation Example 151 was added thereto
0.degree. C., and the mixture was stirred at room temperature for
18 hours. After addition of water, the reaction solution was
extracted with EtOAc. The organic layer was separated, dried with
MgSO.sub.4 and purified by column chromatography. The purified
organic layer was dissolved in 2N HCl (0.2 M) and THF (0.1 M), and
heated to 70.degree. C., the mixture was stirred for 18 hours.
After addition of water, the reaction solution was extracted with
EtOAc. The organic layer was separated, dried with MgSO.sub.4 and
purified by column chromatography to obtain the title compound
(0.375 g, 84%).
[1364] .sup.1H-NMR (CDCl.sub.3) .delta. 9.77 (1H, s), 7.02 (2H, m),
2.49 (2H, d), 0.99 (4H, m).
Preparation Example 153:
(E)-4-[1-(4-bromo-2,6-difluoro-phenyl)-cyclopropyl]-but-2-enoic
Acid Ethyl Ester
[1365] [1-(4-Bromo-2,6-difluoro-phenyl)-cyclopropyl]-acetaldehyde
(0.375 g, 1.36 mmol) obtained in Preparation Example 152 was
reacted in the same manner as in Step A of Preparation Example 85
to obtain the title compound (0.443 g, 94%).
[1366] .sup.1H-NMR (CDCl.sub.3) .delta. 7.00 (2H, m), 6.90 (1H, m),
5.72 (1H, d), 4.15 (2H, q), 2.37 (2H, d), 1.27 (3H, t), 0.87 (4H,
m).
Preparation Example 154:
4-[1-(4-bromo-2,6-difluoro-phenyl)-cyclopropyl]-butyric Acid Ethyl
Ester
[1367]
(E)-4-[1-(4-bromo-2,6-difluoro-phenyl)-cyclopropyl]-but-2-enoic
acid ethyl ester (0.443 g, 1.28 mmol) obtained in Preparation
Example 153 was reacted in the same manner as in Preparation
Example 174 to obtain the title compound (0.414 g, 93%).
[1368] .sup.1H-NMR (CDCl.sub.3) .delta. 7.02 (2H, m), 4.10 (2H, q),
2.26 (2H, t), 1.63 (2H, m), 1.50 (2H, m), 1.24 (3H, t), 0.79 (4H,
s).
Preparation Example 155:
4-{1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pheny-
l]-cyclopropyl}-butyric Acid Ethyl Ester
[1369] 4-[1-(4-Bromo-2,6-difluoro-phenyl)-cyclopropyl]-butyric acid
ethyl ester (0.414 g, 1.19 mmol) obtained in Preparation Example
154 was reacted in the same manner as in Step D of Preparation
Example 1 to obtain the title compound (0.322 g, 70%).
[1370] .sup.1H-NMR (CDCl.sub.3) .delta. 7.20 (2H, m), 4.08 (2H, q),
2.24 (2H, t), 1.62 (2H, m), 1.54 (2H, m), 1.32 (12H, s), 1.20 (3H,
t), 0.80 (4H, m).
Preparation Example 156:
1-bromo-4-(2-bromo-1,1-difluoro-ethyl)-benzene
[1371] 2-Bromo-1-(4-bromo-phenyl)-ethaneone (0.5 g, 1.8 mmol) was
dissolved in 4 mL of MC. DAST (diethylaminosulfur trifluoride, 0.58
g, 3.6 mmol) was added thereto at 0.degree. C., and the mixture was
stirred at 0.degree. C. for 1 hour, at room temperature for 2
hours, and at 40.degree. C. for 4 hours. After addition of water,
the reaction solution was extracted with MC. The organic layer was
separated, dried with MgSO.sub.4 and purified by column
chromatography to obtain the title compound (0.345 g, 64%).
[1372] .sup.1H-NMR (CDCl.sub.3) .delta. 7.60 (2H, d), 7.38 (2H, d),
3.72 (2H, t).
Preparation Example 157: acetic acid
2-(4-bromo-phenyl)-2,2-difluoro-ethyl Ester
[1373] 1-Bromo-4-(2-bromo-1,1-difluoro-ethyl)-benzene (0.324 g,
1.08 mmol) obtained in Preparation Example 156 was dissolved in 4
mL of DMF. KOAc (0.424 g, 4.32 mmol) and 18-crown-6 (0.028 g, 0.11
mmol) were added thereto and heated to 80.degree. C., and the
mixture was stirred for 18 hours. After addition of water, the
reaction solution was extracted with ether. The organic layer was
separated, dried with MgSO.sub.4 and purified by column
chromatography to obtain the title compound (0.216 g, 71%).
[1374] .sup.1H-NMR (CDCl.sub.3) .delta. 7.59 (2H, d), 7.38 (2H, d),
4.44 (2H, t), 2.06 (3H, s).
Preparation Example 158:
2-(4-bromo-phenyl)-2,2-difluoro-ethanol
[1375] Acetic acid 2-(4-bromo-phenyl)-2,2-difluoro-ethyl ester
(0.21 g, 0.77 mmol) obtained in Preparation Example 157 was
dissolved in 4 mL of ethanol and 1 mL of water. NaOH (0.062 g, 1.55
mmol) was added thereto, and the mixture was stirred at room
temperature for 2 hours. The reaction solution was concentrated
under reduced pressure. After addition of water, the reaction
solution was extracted with EtOAc. The organic layer was separated,
dried with MgSO.sub.4 and purified by column chromatography to
obtain the title compound (0.176 g, 96%).
[1376] .sup.1H-NMR (CDCl.sub.3) .delta. 7.59 (2H, d), 7.40 (2H, d),
3.96 (2H, m), 1.87 (1H, m).
Preparation Example 159:
[2-(4-bromo-phenyl)-2,2-difluoro-ethoxy]-acetic Acid Ethyl
Ester
[1377] 2-(4-Bromo-phenyl)-2,2-difluoro-ethanol (0.24 g, 1.01 mmol)
obtained in Preparation Example 158 was reacted in the same manner
as in Preparation Example 164 to obtain the title compound (0.24 g,
70%).
[1378] .sup.1H-NMR (CDCl.sub.3) .delta. 7.57 (2H, d), 7.42 (2H, d),
4.20 (2H, q), 4.18 (2H, s), 3.99 (2H, t), 1.26 (3H, t).
Preparation Example 160:
{2,2-difluoro-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-ethoxy}-acetic Acid Ethyl Ester
[1379] [2-(4-Bromo-phenyl)-2,2-difluoro-ethoxy]-acetic acid ethyl
ester (0.24 g, 0.74 mmol) obtained in Preparation Example 159 was
reacted in the same manner as in Step D of Preparation Example 1 to
obtain the title compound (0.22 g, 80%).
[1380] .sup.1H-NMR (CDCl.sub.3) .delta. 7.86 (2H, d), 7.51 (2H, d),
4.20 (2H, q), 4.14 (2H, s), 4.00 (2H, t), 1.34 (12H, s), 1.25 (3H,
t).
Preparation Example 161:
(E)-4-(4-bromo-phenyl)-4,4-difluoro-but-2-enoic Acid Ethyl
Ester
[1381] 2-(4-Bromo-phenyl)-2,2-difluoro-ethanol (0.5 g, 2.11 mmol)
obtained in Preparation Example 158 was reacted in the same manner
as in Step C of Preparation Example 4 to obtain the title compound
(0.42 g, 65%).
[1382] .sup.1H-NMR (CDCl.sub.3) .delta. 7.59 (2H, d), 7.35 (2H, d),
6.95 (1H, m), 6.26 (1H, d), 4.23 (2H, q), 1.28 (3H, t).
Preparation Example 162: 4-(4-bromo-phenyl)-4,4-difluoro-butyric
Acid Ethyl Ester
[1383] (E)-4-(4-bromo-phenyl)-4,4-difluoro-but-2-enoic acid ethyl
ester (0.42 g, 1.38 mmol) obtained in Preparation Example 161 was
reacted in the same manner as in Preparation Example 174 to obtain
the title compound (0.24 g, 57%).
[1384] .sup.1H-NMR (CDCl.sub.3) .delta. 7.56 (2H, d), 7.34 (2H, d),
4.11 (2H, q), 2.47 (4H, m), 1.22 (3H, t).
Preparation Example 163:
4-(4-bromo-phenyl)-4,4-difluoro-butan-1-ol
[1385] 4-(4-Bromo-phenyl)-4,4-difluoro-butyric acid ethyl ester
(0.244 g, 0.79 mmol) obtained in Preparation Example 162 was
reacted in the same manner as in Step C of Preparation Example 90
to obtain the title compound (0.2 g, 95%).
[1386] .sup.1H-NMR (CDCl.sub.3) .delta. 7.56 (2H, d), 7.34 (2H, d),
3.66 (2H, m), 2.20 (2H, m), 1.70 (2H, m), 1.26 (1H, m).
Preparation Example 164: 4-(4-bromo-phenylsulfanyl)-butyric Acid
Ethyl Ester
[1387] 4-Bromo-benzenethiol (0.5 g, 2.64 mmol) was dissolved in 5
mL of THF and cooled to 0.degree. C. NaH (60% in mineral oil, 0.11
g, 2.64 mmol) was added thereto, and the mixture was stirred for 30
minutes. 4-Bromo-butyric acid ethyl ester (0.42 mL, 2.91 mmol) was
added thereto, and the mixture was stirred at room temperature for
4 hours. After addition of ammonium chloride aqueous solution, the
reaction solution was extracted with EtOAc. The organic layer was
separated, dried with MgSO.sub.4 and purified by column
chromatography to obtain the title compound (0.80 g, 99%).
[1388] .sup.1H-NMR (CDCl.sub.3) .delta. 7.38 (2H, d), 7.19 (2H, d),
4.13 (2H, q), 2.93 (2H, t), 2.43 (2H, t), 1.93 (2H, m), 1.24 (3H,
t).
Preparation Example 165: Methanesulfonic Acid
4-(4-bromo-phenyl)-4,4-difluoro-butyl Ester
[1389] 4-(4-Bromo-phenyl)-4,4-difluoro-butan-1-ol (0.263 g, 0.99
mmol) obtained in Preparation Example 163 was reacted in the same
manner as in Step B of Preparation Example 25 to obtain the title
compound (0.28 g, 82%).
[1390] .sup.1H-NMR (CDCl.sub.3) .delta. 7.56 (2H, d), 7.32 (2H, d),
4.26 (2H, t), 3.00 (3H, s), 2.23 (2H, m), 1.94 (2H, m).
Preparation Example 166:
5-(4-bromo-phenyl)-5,5-difluoro-pentanenitrile
[1391] Methanesulfonic acid 4-(4-bromo-phenyl)-4,4-difluoro-butyl
ester (0.28 g, 0.82 mmol) obtained in Preparation Example 165 was
reacted in the same manner as in Step C of Preparation Example 25
to obtain the title compound (0.21 g, 94%).
[1392] .sup.1H-NMR (CDCl.sub.3) .delta. 7.58 (2H, d), 7.34 (2H, d),
2.42 (2H, t), 2.24 (2H, m), 1.87 (2H, m).
Preparation Example 167: 5-(4-bromo-phenyl)-5,5-difluoro-pentanoic
Acid
[1393] 5-(4-Bromo-phenyl)-5,5-difluoro-pentanenitrile (0.21 g, 0.77
mmol) obtained in Preparation Example 166 was dissolved in 2 mL of
ethanol and 2 mL of water. NaOH (0.107 g, 2.68 mmol) was added
thereto, and the mixture was stirred for 3 hours under reflux.
After addition of 1N HCl, the reaction solution was extracted with
EtOAc. The organic layer was separated, dried with MgSO.sub.4 and
purified by column chromatography to obtain the title compound
(0.26 g, 48%).
[1394] .sup.1H-NMR (CDCl.sub.3) .delta. 7.56 (2H, d), 7.34 (2H, d),
2.41 (2H, t), 2.15 (2H, m), 1.78 (2H, m).
Preparation Example 168: 5-(4-bromo-phenyl)-5,5-difluoro-pentanoic
Acid Methyl Ester
[1395] 5-(4-Bromo-phenyl)-5,5-difluoro-pentanoic acid (0.212 g,
0.72 mmol) obtained in Preparation Example 167 was reacted in the
same manner as in Step G of Preparation Example 81 to obtain the
title compound (0.19 g, 85%).
[1396] .sup.1H-NMR (CDCl.sub.3) .delta. 7.57 (2H, d), 7.34 (2H, d),
3.66 (3H, s), 2.35 (2H, t), 2.15 (2H, m), 1.76 (2H, m).
Preparation Example 169:
5,5-difluoro-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]--
pentanoic Acid Methyl Ester
[1397] 5-(4-Bromo-phenyl)-5,5-difluoro-pentanoic acid methyl ester
(0.190 g, 0.62 mmol) obtained in Preparation Example 168 was
reacted in the same manner as in Step D of Preparation Example 1 to
obtain the title compound (0.13 g, 59%).
[1398] .sup.1H-NMR (CDCl.sub.3) .delta. 7.85 (2H, d), 7.46 (2H, d),
3.65 (3H, s), 2.34 (2H, t), 2.16 (2H, m), 1.76 (2H, m), 1.35 (12H,
s).
Preparation Example 170:
(E)-3-(4-bromo-2,6-difluoro-phenyl)-acrylic Acid Ethyl Ester
[1399] 4-Bromo-2,6-difluoro-benzaldehyde (1.52 g, 6.88 mmol) was
reacted in the same manner as in Step A of Preparation Example 85
to obtain the title compound (1.3 g, 65%).
[1400] .sup.1H-NMR (CDCl.sub.3) .delta. 7.66 (1H, d), 7.13 (2H, m),
6.70 (1H, d), 4.27 (2H, q), 1.32 (3H, t).
Preparation Example 171:
2-(4-bromo-2,6-difluoro-phenyl)-cyclopropanecarboxylic Acid Ethyl
Ester
[1401] Trimethylsulfoxonium iodide (0.462 g, 2.10 mmol) was
dissolved in 5 mL of DMSO. NaH (60% in mineral oil, 0.084 g, 2.10
mmol) was added thereto, and the mixture was stirred for 30
minutes. After cooling to 0.degree. C.,
(E)-3-(4-bromo-2,6-difluoro-phenyl)-acrylic acid ethyl ester (0.51
g, 1.75 mmol) obtained in Preparation Example 170 was added
thereto, and the mixture was stirred at room temperature for 4
hours. After addition of water, the reaction solution was extracted
with EtOAc. The organic layer was separated, dried with MgSO.sub.4
and purified by column chromatography to obtain the title compound
(0.26 g, 48%).
[1402] .sup.1H-NMR (CDCl.sub.3) .delta. 7.02 (2H, m), 4.19 (2H, q),
2.42 (1H, m), 2.14 (1H, m), 1.54 (2H, m), 1.28 (3H, t).
Preparation Example 172:
[2-(4-bromo-2,6-difluoro-phenyl)-cyclopropyl]-methanol
[1403] 2-(4-Bromo-2,6-difluoro-phenyl)-cyclopropanecarboxylic acid
ethyl ester (0.26 g, 0.85 mmol) obtained in Preparation Example 171
was reacted in the same manner as in Step C of Preparation Example
90 to obtain the title compound (0.17 g, 76%).
[1404] .sup.1H-NMR (CDCl.sub.3) .delta. 7.00 (2H, m), 3.70 (1H, m),
3.57 (1H, m), 1.66 (2H, m), 1.45 (1H, t), 1.19 (1H, m), 0.93 (1H,
m).
Preparation Example 173:
(E)-3-[2-(4-bromo-2,6-difluoro-phenyl)-cyclopropyl]-acrylic Acid
Ethyl Ester
[1405] [2-(4-Bromo-2,6-difluoro-phenyl)-cyclopropyl]-methanol
(0.314 g, 1.19 mmol) obtained in Preparation Example 172 was
reacted in the same manner as in Step C of Preparation Example 4 to
obtain the title compound (0.36 g, 91%).
[1406] .sup.1H-NMR (CDCl.sub.3) .delta. 7.00 (2H, m), 6.56 (1H, m),
5.93 (1H, d), 4.19 (2H, q), 2.04 (2H, m), 1.63 (1H, m), 1.28 (4H,
m).
Preparation Example 174:
3-[2-(4-bromo-2,6-difluoro-phenyl)-cyclopropyl]-propionic Acid
Ethyl Ester
[1407] (E)-3-[2-(4-bromo-2,6-difluoro-phenyl)-cyclopropyl]-acrylic
acid ethyl ester (0.228 g, 0.69 mmol) obtained in Preparation
Example 173 was dissolved in 5 mL of DME. p-Toluenesulfonhydrazide
(0.897 g, 4.82 mmol) were added thereto, and the mixture was
stirred for 5 minutes under reflux. 4.9 mL of 1.4 M NaOAc solution
was added thereto, and the mixture was stirred for 18 hours under
reflux. The reaction solution was diluted with water and extracted
with DCM to separate an organic layer. The organic layer was dried
with MgSO.sub.4 and purified by column chromatography to obtain the
title compound (0.19 g, 82%).
[1408] .sup.1H-NMR (CDCl.sub.3) .delta. 6.99 (2H, m), 4.12 (2H, q),
2.48 (2H, t), 1.77 (1H, m), 1.67 (1H, m), 1.53 (1H, m), 1.32 (1H,
m), 1.26 (3H, t), 1.12 (1H, m), 0.80 (1H, m).
Preparation Example 175:
3-{2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pheny-
l]-cyclopropyl}-propionic Acid Ethyl Ester
[1409] 3-[2-(4-Bromo-2,6-difluoro-phenyl)-cyclopropyl]-propionic
acid ethyl ester (0.190 g, 0.57 mmol) obtained in Preparation
Example 174 was reacted in the same manner as in Step D of
Preparation Example 1 to obtain the title compound (0.183 g,
84%).
[1410] .sup.1H-NMR (CDCl.sub.3) .delta. 7.18 (2H, m), 4.14 (2H, q),
2.49 (2H, t), 1.77 (1H, m), 1.68 (2H, m), 1.38 (1H, m), 1.32 (12H,
s), 1.24 (4H, m), 0.81 (1H, m).
Preparation Example 176:
8-(4-bromo-2-fluoro-phenyl)-1,4-dioxa-spiro[4.5]dec-7-ene
[1411] 4-Bromo-2-fluoro-1-iodo-benzene (0.68 g, 2.25 mmol) and
8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dioxa-spiro[4.5]dec--
7-ene (0.5 g, 1.88 mmol) were reacted in the same manner as in Step
A of Example 1 to obtain the title compound (0.4 g, 68%).
[1412] .sup.1H-NMR (CDCl.sub.3) .delta. 7.20 (2H, m), 7.12 (1H, t),
5.84 (1H, m), 4.01 (4H, s), 2.58 (2H, m), 2.44 (2H, m), 1.88 (2H,
t).
Preparation Example 177:
8-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,4--
dioxa-spiro[4.5]dec-7-ene
[1413] 8-(4-Bromo-2-fluoro-phenyl)-1,4-dioxa-spiro[4.5]dec-7-ene
(0.27 g, 0.86 mmol) obtained in Preparation Example 176 was reacted
in the same manner as in Step D of Preparation Example 1 to obtain
the title compound (0.2 g, 64%).
[1414] .sup.1H-NMR (CDCl.sub.3) .delta. 7.50 (1H, m), 7.43 (1H, m),
7.27 (1H, m), 5.89 (1H, m), 4.02 (4H, s), 2.64 (2H, m), 2.48 (2H,
m), 1.90 (2H, t), 1.34 (12H, s).
Preparation Example 178:
8-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,4--
dioxa-spiro[4.5]decane
[1415]
8-[2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl-
]-1,4-dioxa-spiro[4.5]dec-7-ene (0.2 g, 0.55 mmol) obtained in
Preparation Example 177 was reacted in the same manner as in Step E
of Preparation Example 1 to obtain the title compound (0.17 g,
84%).
[1416] .sup.1H-NMR (CDCl.sub.3) .delta. 7.52 (1H, m), 7.43 (1H, m),
7.28 (1H, m), 3.98 (4H, s), 2.94 (1H, m), 1.87-1.68 (8H, m), 1.33
(12H, s).
Preparation Example 179:
2-cyclopentyloxy-3-[4-(1,4-dioxa-spiro[4.5]dec-8-yl)-3-fluoro-phenyl]-pyr-
idine
[1417]
8-[2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl-
]-1,4-dioxa-spiro[4.5]decane (0.17 g, 0.47 mmol) obtained in
Preparation Example 178 and 2-cyclopentyloxy-3-iodo-pyridine (0.2
g, 0.7 mmol) obtained in Preparation Example 11 were reacted in the
same manner as in Step A of Example 1 to obtain the title compound
(0.113 g, 60%).
[1418] .sup.1H-NMR (CDCl.sub.3) .delta. 8.12 (1H, m), 7.58 (1H, m),
7.28 (3H, m), 6.90 (1H, m), 3.99 (4H, s), 2.94 (1H, m), 1.89-1.72
(14H, m), 1.54 (2H, m).
Preparation Example 180:
4-[4-(2-cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenyl]-cyclohexanone
[1419]
2-Cyclopentyloxy-3-[4-(1,4-dioxa-spiro[4.5]dec-8-yl)-3-fluoro-pheny-
l]-pyridine (0.113 g, 0.28 mmol) obtained in Preparation Example
179 was added to 1N HCl (0.15 mL) dissolved in 3 mL of THF and
stirred at room temperature for 16 hours. The reaction solution was
diluted with sodium bicarbonate solution and extracted with EtOAc.
The organic layer was separated, dried with MgSO.sub.4 and purified
by column chromatography to obtain the title compound (0.048 g,
48%).
[1420] .sup.1H-NMR (CDCl.sub.3) .delta. 8.14 (1H, m), 7.58 (1H, m),
7.30 (2H, m), 7.25 (1H, m), 6.92 (1H, m), 5.51 (1H, m), 3.37 (1H,
m), 2.53 (4H, m), 2.25 (2H, m), 1.97 (4H, m), 1.75 (4H, m), 1.62
(2H, m).
Preparation Example 181:
{4-[4-(2-cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenyl]-cyclohexylidene}-a-
cetic Acid Ethyl Ester
[1421]
4-[4-(2-Cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenyl]-cyclohexanone
(0.045 g, 0.13 mmol) obtained in Preparation Example 180 was
reacted in the same manner as in Step C of Preparation Example 1 to
obtain the title compound (0.045 g, 83%).
[1422] .sup.1H-NMR (CDCl.sub.3) .delta. 8.13 (1H, m), 7.59 (1H, m),
7.29 (2H, m), 7.20 (1H, m), 6.91 (1H, m), 5.70 (1H, s), 5.52 (1H,
m), 4.16 (2H, q), 4.00 (1H, m), 3.17 (1H, m), 2.42 (2H, m), 2.10
(3H, m), 1.95 (2H, m), 1.84-1.62 (8H, m), 1.30 (3H, t).
Preparation Example 182:
{4-[4-(2-cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenyl]-cyclohexyl}-acetic
Acid Ethyl Ester
[1423]
{4-[4-(2-Cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenyl]-cyclohexylid-
ene}-acetic acid ethyl ester (0.045 g, 0.11 mmol) obtained in
Preparation Example 181 was reacted in the same manner as in Step E
of Preparation Example 1 to obtain the title compound (0.045 g,
99%).
[1424] .sup.1H-NMR (CDCl.sub.3) .delta. 8.13 (1H, m), 7.60 (1H, m),
7.27 (3H, m), 6.91 (1H, m), 5.51 (1H, m), 4.15 (2H, q), 2.85 (1H,
m), 2.49-2.25 (2H, m), 1.95-1.59 (16H, m), 1.26 (3H, t), 1.22 (1H,
m).
Preparation Example 183:
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric Acid Methyl Ester
[1425] 3,4,5-Trifluoronitrobenzene (9.4 g, 53 mmol) and
hydrochloric acid salt of 4-methylamino-butyric acid methyl ester
(8.9 g, 53 mmol) were reacted in the same manner as in Preparation
Example 84 to obtain the title compound (10 g, 51%).
[1426] .sup.1H-NMR (CDCl.sub.3) .delta. 7.24 (2H, d), 3.64 (3H, s),
3.16 (2H, t), 2.88 (3H, m), 2.36 (2H, t), 1.85 (2H, m), 1.31 (12H,
s)
Preparation Example 184:
4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indol-1-yl]-butyric
Acid Ethyl Ester
[1427] 5-Bromo-1H-indole (0.10 g, 0.51 mmol) and 4-bromo-butyric
acid ethyl ester (0.10 g, 0.51 mmol) were reacted in the same
manner as in Preparation Example 3 to obtain the title compound
(0.060 g, 33%).
[1428] .sup.1H-NMR (CDCl.sub.3) .delta. 8.15 (1H, s), 7.65 (1H, d),
7.34 (1H, d), 7.07 (1H, d), 6.51 (1H, d), 4.21 (2H, t), 4.11 (2H,
m), 2.25 (2H, t), 2.14 (2H, m), 1.36 (12H, s), 1.24 (3H, t)
Preparation Example 185: 2-bromo-6-cyclopentyloxy-pyridine
[1429] Cyclopentanol (0.077 mL, 0.84 mmol) and 2,6-dibromopyridine
(0.2 g, 0.84 mmol) were reacted in the same manner as in
Preparation Example 34 to obtain the title compound (0.09 g,
44%).
[1430] .sup.1H-NMR (CDCl.sub.3) .delta. 7.36 (1H, t), 7.00 (1H, d),
6.60 (1H, d), 5.36 (1H, m), 1.98 (2H, m), 1.77 (4H, m), 1.61 (2H,
m)
Preparation Example 186: 2-bromo-6-cyclobutoxy-pyridine
[1431] Cyclobutanol (0.06 mL, 0.84 mmol) and 2,6-dibromopyridine
(0.2 g, 0.84 mmol) were reacted in the same manner as in
Preparation Example 34 to obtain the title compound (0.06 g,
31%).
[1432] .sup.1H-NMR (CDCl.sub.3) .delta. 7.39 (1H, t), 7.01 (1H, d),
6.61 (1H, d), 5.14 (1H, m), 2.45 (2H, m), 2.11 (2H, m), 1.82 (1H,
m), 1.65 (1H, m)
Preparation Example 187:
4-{[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-met-
hyl-amino}-butyric Acid Methyl Ester
[1433] 3,4-Difluoronitrobenzene (1.30 g, 8.17 mmol) and
hydrochloric acid salt of 4-methylamino-butyric acid methyl ester
(1.64 g, 9.81 mmol) were reacted in the same manner as in
Preparation Example 84 to obtain the title compound (0.25 g,
8.7%).
[1434] .sup.1H-NMR (CDCl.sub.3) .delta. 7.45 (1H, m), 7.40 (1H, m),
6.83 (1H, m), 3.65 (3H, s), 3.25 (2H, t), 2.86 (3H, s), 2.36 (2H,
t), 1.91 (2H, m), 1.31 (12H, s)
Preparation Example 188:
4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylamine
[1435] 2-Cyclopentylsulfanyl-3-iodo-pyridine (0.70 g, 2.29 mmol)
obtained in Preparation Example 15 and
2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(0.59 g, 2.29 mmol) obtained in Preparation Example 66 were reacted
in the same manner as in Preparation Example 67 to obtain the title
compound (0.40 g, 57%).
[1436] .sup.1H-NMR (CDCl.sub.3) .delta. 8.40 (1H, m), 7.31 (1H, m),
6.99 (1H, m), 6.93 (2H, m), 4.07 (1H, m), 3.82 (2H, s), 2.19 (2H,
m), 1.71 (2H, m), 1.61 (4H, m)
Preparation Example 189:
4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenylamine
[1437] 2-Cyclopentylsulfanyl-3-iodo-pyridine (1.2 g, 3.9 mmol)
obtained in Preparation Example 15 and
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.86 g, 3.9
mmol) were reacted in the same manner as in Preparation Example 67
to obtain the title compound (1.0 g, 94%).
[1438] .sup.1H-NMR (CDCl.sub.3) .delta. 8.37 (1H, m), 7.33 (1H, m),
7.23 (2H, d), 7.00 (1H, m), 6.74 (2H, d), 4.08 (1H, m), 3.76 (2H,
s), 2.19 (2H, m), 1.70 (2H, m), 1.59 (4H, m)
Preparation Example 190:
4-{[2,6-difluoro-4-(2-fluoro-pyridin-3-yl)-phenyl]-methyl-amino}-butyric
Acid Methyl Ester
[1439] 2-Fluoro-3-iodo-pyridine (0.20 g, 0.90 mmol) and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.33 g, 0.90 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Step A of Example 1 to obtain the title compound (0.25 g,
82%).
[1440] .sup.1H-NMR (CDCl.sub.3) .delta. 8.20 (1H, m), 7.82 (1H, m),
7.28 (1H, m), 7.09 (2H, m), 3.66 (3H, s), 3.18 (2H, t), 2.90 (3H,
s), 2.40 (2H, t), 1.88 (2H, m), 1.59 (4H, m)
Preparation Example 191: 1-(2-iodo-phenyl)-pyrrolidine
Step A: 2-pyrrolidin-1-yl-phenylamine
[1441] Fluoro-2-nitro-benzene (0.70 g, 4.96 mmol) and pyrrolidine
(0.42 g, 5.95 mmol) were sequentially reacted in the same manner as
in Steps A and B of Preparation Example 84 to obtain the title
compound (0.70 g, 87%).
Step B: 1-(2-iodo-phenyl)-pyrrolidine
[1442] 2-Pyrrolidin-1-yl-phenylamine (0.70 g, 4.31 mmol) obtained
in Step A was added to 19 mL of water and cooled to 0.degree. C. 5
mL of sulfuric acid 5 mL was added, and sodium nitrite (0.30 g,
4.31 mmol) dissolved in water was then slowly added thereto. While
maintaining the temperature, the mixture was stirred for 30
minutes. Potassium iodide (0.93 g, 5.60 mmol) dissolved in 10 mL of
water was added thereto. The temperature was increased to
60.degree. C., and the mixture was stirred for 3 hours. After
addition of water, the reaction solution was extracted with EtOAc.
The organic layer was purified by column chromatography to obtain
the title compound (0.18 g, 12%).
[1443] .sup.1H-NMR (CDCl.sub.3) .delta. 7.83 (1H, m), 7.25 (1H, m),
6.95 (1H, m), 6.67 (1H, m), 3.29 (4H, m), 1.94 (4H, m)
Preparation Example 192: (2-iodo-phenyl)-methyl-amine
[1444] Fluoro-2-nitro-benzene (1.00 g, 7.09 mmol) and methylamine
hydrochloride (0.57 g, 8.50 mmol) were reacted in the same manner
as in Preparation Example 191 to obtain the title compound (0.35 g,
21%).
[1445] .sup.1H-NMR (CDCl.sub.3) .delta. 7.65 (1H, m), 7.25 (1H, m),
6.57 (1H, m), 6.46 (1H, m), 4.20 (1H, s), 2.89 (3H, d)
Preparation Example 193: (2-iodo-phenyl)-isopropyl-methyl-amine
[1446] Fluoro-2-nitro-benzene (1.30 g, 9.21 mmol) and
isopropyl-methyl-amine (0.81 g, 11.1 mmol) were reacted in the same
manner as in Preparation Example 191 to obtain the title compound
(0.35 g, 14%).
[1447] .sup.1H-NMR (CDCl.sub.3) .delta. 7.85 (1H, m), 7.28 (1H, m),
7.06 (1H, m), 6.77 (1H, m), 3.48 (1H, m), 2.62 (3H, s), 1.12 (6H,
d)
Preparation Example 194:
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-ethyl-amino}-butyric Acid Methyl Ester
[1448] 3,4,5-Trifluoronitrobenzene (0.68 g, 3.84 mmol) and
hydrochloric acid salt of 4-ethylamino-butyric acid methyl ester
(0.58 g, 3.20 mmol) were reacted in the same manner as in
Preparation Example 84 to obtain the title compound (0.38 g,
31%).
[1449] .sup.1H-NMR (CDCl.sub.3) .delta. 7.25 (2H, m), 3.63 (3H, s),
3.18 (4H, m), 2.35 (2H, t), 1.74 (2H, m), 1.32 (12H, s), 1.02 (3H,
t)
Preparation Example 195:
(R)-5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phen-
yl]-hexanoic Acid Ethyl Ester
Step A: (E)-3-(4-bromo-2,6-difluoro-phenyl)prop-2-enoic Acid Ethyl
Ester
[1450] 4-Bromo-2,6-difluoro-benzaldehyde (2.0 g, 13.6 mmol) and
(1-ethoxycarbonylethylidene)triphenylphosphorane (5.7 g, 16.3 mmol)
were reacted in the same manner as in Step B of Preparation Example
27 to obtain the title compound (3.9 g, 99%).
Step B: (E)-3-(4-bromo-2,6-difluoro-phenyl)-acrylic Acid
[1451] (E)-3-(4-bromo-2,6-difluoro-phenyl)prop-2-enoic acid ethyl
ester (1.13 g, 3.88 mmol) obtained in Step A was reacted in the
same manner as in Step B of Example 1 to obtain the title compound
(1.0 g, 98%).
Step C:
(R)-3-[(E)-3-(4-bromo-2,6-difluoro-phenyl)-acryloyl]-4-phenyl-oxaz-
olidin-2-one
[1452] (E)-3-(4-bromo-2,6-difluoro-phenyl)-acrylic acid (0.50 g,
1.9 mmol) obtained in Step B was dissolved in 10 mL of THF and
cooled to -78.degree. C. Trimethylacetyl chloride (0.29 g, 2.4
mmol) was added thereto, and the mixture was stirred for 15
minutes. (R)-4-phenyl-oxazolidin-2-one (0.42 g, 2.6 mmol) was
dissolved in 10 mL of THF and cooled to -78.degree. C., and
n-butyllithium (1.16 mL, 2.7 mmol) was then added thereto. This
solution was added to the first solution by the use of a cannula.
While maintaining the temperature, the mixture was stirred for 1.5
hours. The temperature was increased to room temperature, and the
mixture was stirred for 16 hours. After termination of the reaction
by the use of saturated ammonium chloride solution, the reaction
solution was extracted with EtOAc. The organic layer was separated,
dried with MgSO.sub.4 and purified by column chromatography to
obtain the title compound (0.50 g, 64%).
Step D:
(R)-3-[(R)-3-(4-bromo-2,6-difluoro-phenyl)-butyryl]-4-phenyl-oxazo-
lidin-2-one
[1453] CuBr-DMS (1.18 g, 5.7 mmol) was added to 10 mL of THF and
stirred at -40.degree. C. for 30 minutes. DMS (3.38 g, 54.4 mmol)
and methylmagnesium bromide (1.74 mL, 5.2 mmol) was added thereto,
and the mixture was stirred for 30 minutes. The temperature was
increased to -20.degree. C., and
(R)-3-[(E)-3-(4-bromo-2,6-difluoro-phenyl)-acryloyl]-4-phenyl-oxazolidin--
2-one (0.52 g, 1.3 mmol) obtained in Step C was dissolved in 3 mL
of THF and slowly added thereto. While maintaining the temperature,
the mixture was stirred for 2.5 hours. The temperature was slowly
increased to room temperature, and the mixture was stirred at room
temperature for 72 hours. After termination of the reaction by the
use of saturated ammonium chloride solution, the reaction solution
was extracted with EtOAc. The organic layer was separated, dried
with MgSO.sub.4 and purified by column chromatography to obtain the
title compound (0.33 g, 61%).
Step E: (E)-(R)-5-(4-bromo-2,6-difluoro-phenyl)-hex-2-enoic Acid
Ethyl Ester
[1454]
(R)-3-[(R)-3-(4-bromo-2,6-difluoro-phenyl)-butyryl]-4-phenyl-oxazol-
idin-2-one (0.33 g, 0.78 mmol) obtained in Step D was sequentially
reacted in the same manner as in Preparation Example 151 and Step A
of Preparation Example 85 to obtain the title compound (0.11 g,
42%).
Step F:
(R)-5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y-
l)-phenyl]-hexanoic Acid Ethyl Ester
[1455] (E)-(R)-5-(4-bromo-2,6-difluoro-phenyl)-hex-2-enoic acid
ethyl ester (0.15 g, 0.45 mmol) obtained in Step E was sequentially
reacted in the same manner as in Steps G and H of Preparation
Example 5 to obtain the title compound (0.070 g, 40%).
[1456] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.22 (2H, m), 4.08
(2H, q), 3.21 (1H, m), 2.24 (2H, m), 1.80 (1H, m), 1.65 (1H, m),
1.60 (1H, m), 1.45 (1H, m), 1.30 (15H, m), 1.20 (3H, t)
Preparation Example 196:
(E)-(R)-5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)--
phenyl]-hex-2-enoic Acid Ethyl Ester
[1457] (E)-(R)-5-(4-bromo-2,6-difluoro-phenyl)-hex-2-enoic acid
ethyl ester (0.11 g, 0.33 mmol) obtained in Step E of Preparation
Example 195 was reacted in the same manner as in Step D of
Preparation Example 1 to obtain the title compound (0.10 g,
80%).
[1458] .sup.1H-NMR (CDCl.sub.3) .delta. 7.24 (2H, m), 6.84 (1H, m),
5.80 (1H, m), 4.15 (2H, m), 3.40 (1H, m), 2.66 (2H, m), 1.30 (18H,
m)
Preparation Example 197:
(S)-5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phen-
yl]-hexanoic Acid Ethyl Ester
Step A:
(S)-3-[(E)-3-(4-bromo-2,6-difluoro-phenyl)-acryloyl]-4-phenyl-oxaz-
olidin-2-one
[1459] (E)-3-(4-bromo-2,6-difluoro-phenyl)-acrylic acid (1.03 g,
3.9 mmol) obtained in Step B of Preparation Example 195 and
(S)-4-phenyl-oxazolidin-2-one (0.86 g, 5.3 mmol) were reacted in
the same manner as in Step C of Preparation Example 195 to obtain
the title compound (1.30 g, 81%).
Step B:
(S)-3-[(S)-3-(4-bromo-2,6-difluoro-phenyl)-butyryl]-4-phenyl-oxazo-
lidin-2-one
[1460]
(S)-3-[(E)-3-(4-bromo-2,6-difluoro-phenyl)-acryloyl]-4-phenyl-oxazo-
lidin-2-one (1.30 g, 3.2 mmol) obtained in Step A of Preparation
Example 197 was reacted in the same manner as in Step D of
Preparation Example 195 to obtain the title compound (1.0 g,
74%).
Step C: (E)-(S)-5-(4-bromo-2,6-difluoro-phenyl)-hex-2-enoic Acid
Ethyl Ester
[1461]
(S)-3-[(S)-3-(4-bromo-2,6-difluoro-phenyl)-butyryl]-4-phenyl-oxazol-
idin-2-one (0.70 g, 1.6 mmol) obtained in Step B Preparation
Example 197 was reacted in the same manner as in Step E of
Preparation Example 195 to obtain the title compound (0.50 g,
91%).
Step D:
(S)-5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y-
l)-phenyl]-hexanoic Acid Ethyl Ester
[1462] ((E)-(S)-5-(4-bromo-2,6-difluoro-phenyl)-hex-2-enoic acid
ethyl ester (0.37 g, 1.12 mmol) obtained in Step C of Preparation
Example 197 was reacted in the same manner as in Step F of
Preparation Example 195 to obtain the title compound (0.16 g,
37%).
[1463] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.22 (2H, m), 4.08
(2H, q), 3.21 (1H, m), 2.24 (2H, m), 1.80 (1H, m), 1.65 (1H, m),
1.60 (1H, m), 1.45 (1H, m), 1.30 (15H, m), 1.20 (3H, t)
Preparation Example 198:
4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyri-
c Acid Ethyl Ester
Step A:
2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
[1464] 4-Bromo-2-fluorophenol (1.9 g, 9.9 mmol),
bis(pinacolato)diboron (2.9 g, 11.4 mmol), potassium acetate (3.90
g, 39.7 mmol) and DPPF (0.27 g, 0.49 mmol) were dissolved in 32 mL
of 1,4-dioxane, and charged with N.sub.2 gas for 5 minutes.
PdCl.sub.2(dppf)-DCM (0.4 g, 0.49 mmol) was added thereto, and the
mixture was stirred for 4 hours under reflux stirred. The reaction
solution was filtered through Celite and purified by column
chromatography to obtain the title compound (2.2 g, 93%).
[1465] .sup.1H NMR (CDCl.sub.3) .delta. 7.49 (2H, m), 6.98 (1H, t),
5.31 (1H, brs), 1.33 (12H, s)
Step B:
4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy-
]butyric acid Ethyl Ester
[1466]
2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
(0.56 g, 2.3 mmol) obtained in Step A, 4-bromo-butyric acid ethyl
ester (0.34 mL, 2.3 mmol) and Cs.sub.2CO.sub.3 (0.92 g, 2.8 mmol)
were dissolved in 8 mL of DMF, and stirred at room temperature for
16 hours. The reaction solution was concentrated and purified by
column chromatography to obtain the title compound (0.52 g,
63%).
[1467] .sup.1H NMR (CDCl.sub.3) .delta. 7.49 (2H, m), 6.93 (1H, t),
4.15 (2H, t), 4.10 (2H, q), 2.53 (2H, t), 2.15 (2H, m), 1.33 (12H,
s), 1.25 (3H, t)
Preparation Example 199:
6-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]--
heptanoic Acid Ethyl Ester
[1468] 1-(4-Bromo-2,6-difluoro-phenyl)ethaneone (2.50 g, 10.6 mmol)
obtained in Step C of Preparation Example 32 and
(methoxymethyl)triphenylphosphonium chloride (4.38 g, 12.8 mmol)
were sequentially reacted in the same manner as in Preparation
Example 152, Step A of Preparation Example 85, Step B of
Preparation Example 70, Step C of Preparation Example 4, Step C of
Preparation Example 26 and Step D of Preparation Example 26 to
obtain the title compound (0.50 g, 13%).
[1469] .sup.1H-NMR (CDCl.sub.3) .delta. 7.23 (2H, m), 4.09 (2H, m),
3.22 (1H, m), 2.22 (2H, t), 1.77 (1H, m), 1.61 (5H, m), 1.33 (18H,
s)
Preparation Example 200:
4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-butyric
Acid Ethyl Ester
[1470] 3-Bromo-phenol (0.75 g, 4.34 mmol) and 4-bromo-butyric acid
ethyl ester (1.01 g, 5.20 mmol) were reacted in the same manner as
in Preparation Example 3 to obtain the title compound (1.1 g,
76%).
[1471] .sup.1H-NMR (CDCl.sub.3) .delta. 7.37 (1H, d), 7.31 (2H, m),
6.99 (1H, m), 4.14 (2H, m), 4.03 (2H, t), 2.52 (2H, t), 2.11 (2H,
m), 1.33 (12H, s), 1.27 (3H, t)
Preparation Example 201:
5-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pent-
anoic Acid Ethyl Ester
[1472] 4-Bromo-2-fluoro-benzaldehyde (0.40 g, 1.97 mmol) and
ethyl(triphenylphosphoranylidene)acetaldehyde (0.66 g, 2.17 mmol)
were reacted in the same manner as in Preparation Example 27 to
obtain the title compound (0.35 g, 51%).
[1473] .sup.1H-NMR (CDCl.sub.3) .delta. 7.48 (1H, d), 7.42 (1H, d),
7.17 (1H, t), 4.12 (2H, m), 2.68 (2H, t), 2.33 (2H, t), 1.67 (4H,
m), 1.34 (12H, s), 1.25 (3H, t)
Preparation Example 202:
4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyr-
ic Acid Ethyl Ester
[1474] 4-(4-Bromo-phenylsulfanyl)-butyric acid ethyl ester (0.83 g,
2.7 mmol) obtained in Preparation Example 164 and
bis(pinacolato)diboron (0.76 g, 3.0 mmol) were reacted in the same
manner as in Step D of Preparation Example 1 to obtain the title
compound (0.73 g, 75%).
[1475] .sup.1H-NMR (CDCl.sub.3) .delta. 7.70 (2H, d), 7.27 (2H, d),
4.11 (2H, q), 2.99 (2H, t), 2.44 (2H, t), 1.96 (2H, m), 1.32 (12H,
s), 1.24 (3H, t).
Preparation Example 203: 4-bromo-2-fluoro-benzenethiol
Step A: 4-bromo-2-fluoro-benzenesulfonyl Chloride
[1476] 4-Bromo-2-fluoroaniline (1 g, 5.26 mmol) was reacted in the
same manner as in Step A of Preparation Example 206 to obtain the
title compound (0.49 g, 34%).
[1477] .sup.1H-NMR (CDCl.sub.3) .delta. 7.85 (1H, m), 7.55 (2H,
m).
Step B: 4-bromo-2-fluoro-benzenethiol
[1478] 4-Bromo-2-fluoro-benzenesulfonyl chloride (0.49 g, 1.79
mmol) obtained in Step A was reacted in the same manner as in Step
B of Preparation Example 206 to obtain the title compound (0.37 g,
99%).
[1479] .sup.1H-NMR (CDCl.sub.3) .delta. 7.23 (1H, m), 7.16 (2H, m),
3.57 (1H, s).
Preparation Example 204:
4-(4-bromo-2-fluoro-phenylsulfanyl)-butyric Acid Ethyl Ester
[1480] 4-Bromo-2-fluoro-benzenethiol (0.37 g, 1.81 mmol) obtained
in Preparation Example 203, NaH (60% in mineral oil, 0.07 g, 1.81
mmol) and 4-bromo-butyric acid ethyl ester (0.28 mL, 1.99 mmol)
were reacted in the same manner as in Preparation Example 164 to
obtain the title compound (0.43 g, 75%).
[1481] .sup.1H-NMR (CDCl.sub.3) .delta. 7.23 (3H, m), 4.12 (2H, q),
2.92 (2H, t), 2.44 (2H, t), 1.90 (2H, m), 1.25 (3H, t).
Preparation Example 205:
4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfan-
yl]-butyric Acid Ethyl Ester
[1482] 4-(4-Bromo-2-fluoro-phenylsulfanyl)-butyric acid ethyl ester
(0.43 g, 1.36 mmol) obtained in Preparation Example 204 and
bis(pinacolato)diboron (0.34 g, 1.50 mmol) were reacted in the same
manner as in Step D of Preparation Example 1 to obtain the title
compound (0.27 g, 53%).
[1483] 1H-NMR (CDCl.sub.3) .delta. 7.50 (1H, d), 7.43 (1H, d), 7.32
(1H, t), 4.11 (2H, q), 2.98 (2H, t), 2.45 (2H, t), 1.93 (2H, m),
1.33 (12H, s), 1.24 (3H, t).
Preparation Example 206: 4-bromo-2,6-difluoro-benzenethiol
Step A: 4-bromo-2,6-difluoro-benzenesulfonyl Chloride
[1484] CuCl.sub.2 (0.77 g, 5.77 mmol) was dissolved in 200 mL of
water. SOCl.sub.2 (29 mL, 0.40 mol) was added thereto at 0.degree.
C., and the mixture was stirred at room temperature for 18 hours.
4-Bromo-2,6-difluoroaniline (20 g, 0.096 mol) was dissolved in 240
mL of HCl and 900 mL of water, and the solution in which NaNO.sub.2
(7 g, 0.10 mol) was dissolved in 200 mL of water was added thereto
at 0.degree. C. The above thionyl chloride solution was added
thereto, and the reaction was carried out at room temperature for 1
hour to obtain the title compound (24 g, 85%) in a solid form.
Step B: 4-bromo-2,6-difluoro-benzenethiol
[1485] 4-Bromo-2,6-difluoro-benzenesulfonyl chloride (24 g, 0.08
mol) obtained in Step A was dissolved in 270 mL of THF. PPh.sub.3
(75 g, 0.28 mol) was added thereto, and the mixture was stirred at
room temperature for 15 minutes. After addition of water, the
mixture was stirred at room temperature for 18 hours. After
addition of water, the reaction solution was extracted with EtOAc.
The organic layer was separated, dried with MgSO.sub.4 and purified
by column chromatography to obtain the title compound (15 g,
83%).
[1486] .sup.1H-NMR (CDCl.sub.3) .delta. 7.10 (2H, d), 3.58 (1H,
s).
Preparation Example 207:
4-(4-bromo-2,6-difluoro-phenylsulfanyl)-butyric Acid Ethyl
Ester
[1487] 4-Bromo-2,6-difluoro-benzenethiol (15 g, 0.066 mol) obtained
in Preparation Example 206, NaH (60% in mineral oil, 2.6 g, 0.066
mol) and 4-bromo-butyric acid ethyl ester (10 mL, 0.073 mol) were
reacted in the same manner as in Preparation Example 164 to obtain
the title compound (18.56 g, 82%).
[1488] .sup.1H-NMR (CDCl.sub.3) .delta. 7.11 (2H, d), 4.11 (2H, q),
2.90 (2H, t), 2.43 (2H, t), 1.82 (2H, m), 1.24 (3H, t).
Preparation Example 208:
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsu-
lfanyl]-butyric Acid Ethyl Ester
[1489] 4-(4-Bromo-2,6-difluoro-phenylsulfanyl)-butyric acid ethyl
ester (11.6 g, 0.034 mol) obtained in Preparation Example 207 and
bis(pinacolato)diboron (9.5 g, 0.038 mol) were reacted in the same
manner as in Step D of Preparation Example 1 to obtain the title
compound (10.6 g, 80%).
[1490] .sup.1H-NMR (CDCl.sub.3) .delta. 7.30 (2H, d), 4.09 (2H, q),
2.94 (2H, t), 2.43 (2H, t), 1.83 (2H, m), 1.33 (12H, s), 1.22 (3H,
t).
Preparation Example 209: 3-iodo-2-(oxetan-3-yloxy)-pyridine
[1491] Oxetan-3-ol (0.93 g, 12.6 mmol) and 2-fluoro-3-iodo-pyridine
(1.40 g, 6.30 mmol) were reacted in the same manner as in
Preparation Example 34 to obtain the title compound (1.60 g,
92%).
[1492] .sup.1H-NMR (CDCl.sub.3) .delta. 8.05 (2H, m), 6.67 (1H, m),
5.61 (1H, m), 5.01 (2H, t), 4.79 (2H, m)
Preparation Example 210:
7-bromo-5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran
[1493] The title compound was obtained by the method disclosed in
WO 2009/119088 A1.
[1494] .sup.1H NMR (CDCl.sub.3) .delta. 7.25 (2H, s), 7.02 (1H, m),
3.06 (2H, s), 1.50 (6H, s)
Preparation Example 211:
4-bromo-7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran
[1495] The title compound was obtained by the method disclosed in
WO 2005/075456 A1.
[1496] .sup.1H NMR (CDCl.sub.3) .delta. 6.94 (1H, d), 6.67 (1H, d),
3.88 (3H, s), 3.08 (2H, s), 1.57 (6H, s)
Preparation Example 212:
7-bromospiro[3H-benzofuran-2,1'-cyclopentan]
[1497] The title compound was obtained by the method disclosed in
WO 2011/159297 A1.
[1498] .sup.1H NMR (CDCl.sub.3) .delta. 7.23 (1H, d), 7.04 (1H, d),
6.67 (1H, t), 3.23 (2H, s), 2.14 (2H, m), 1.93 (2H, m), 1.72 (4H,
m)
Preparation Example 213:
5-fluoro-7-iodo-2,2-dimethyl-2,3-dihydro-indol-1-carboxylic Acid
Methyl Ester
Step A: 5-fluoro-2,2-dimethyl-2,3-dihydro-indol-1-carboxylic Acid
Methyl Ester
[1499] The title compound was obtained by the method disclosed in
US 2013/0109734 A1.
[1500] .sup.1H-NMR (CDCl.sub.3) .delta. 7.71 (1H, brs), 6.83 (2H,
m), 3.84 (3H, s), 2.99 (2H, s), 1.55 (6H, s)
Step B: 5-fluoro-7-iodo-2,2-dimethyl-2,3-dihydro-indol-1-carboxylic
Acid Methyl Ester
[1501] 5-fluoro-2,2-dimethyl-2,3-dihydro-indol-1-carboxylic acid
methyl ester (0.1 g, 0.45 mmol) obtained in Step A was dissolved in
3 mL of THF and cooled to -78.degree. C. 1.7M tert-butyllithium
pentane solution (0.7 mL, 1.16 mmol) was added dropwise thereto,
and the mixture was stirred at -78.degree. C. for 1 hour.
1,2-Diiodo-ethane (0.38 g, 1.35 mmol) was dissolved in 1 mL of THF
and slowly added dropwise thereto, and the mixture was stirred at
-78.degree. C. for 30 minutes. The temperature was increased to
room temperature, and the mixture was additionally stirred for 1
hour. After termination of the reaction by the addition of sodium
thiosulfate aqueous solution and sodium bicarbonate aqueous
solution, the reaction solution was extracted with ethyl acetate to
separate an organic layer. The organic layer was dried with
MgSO.sub.4 and purified by column chromatography to obtain the
title compound (0.074 g, 47%).
[1502] .sup.1H-NMR (CDCl.sub.3) .delta. 7.78 (1H, brs), 6.89 (1H,
t), 3.88 (3H, s), 3.00 (2H, s), 1.61 (6H, s)
Preparation Example 214:
5-fluoro-4-iodo-2,2-dimethyl-2,3-dihydro-indol-1-carboxylic Acid
Methyl Ester
[1503] 5-Fluoro-2,2-dimethyl-2,3-dihydro-indol-1-carboxylic acid
methyl ester (0.26 g, 1.16 mmol) obtained in Step A of Preparation
Example 213 was dissolved in 10 mL of THF. TMEDA (0.8 mL, 5.22
mmol) was added dropwise thereto and cooled to -78.degree. C. 1.4M
sec-BuLi hexane solution (2.5 mL, 3.49 mmol) was added dropwise
thereto, and the mixture was stirred at -78.degree. C. for 1 hour.
1,2-Diiodo-ethane (0.38 g, 1.35 mmol) was dissolved in 5 mL of THF
and slowly added dropwise thereto. The mixture was stirred at
-78.degree. C. for 30 minutes. The temperature was increased to
room temperature, and the mixture was additionally stirred for 1.5
hours. After termination of the reaction by the addition of sodium
thiosulfate aqueous solution and sodium bicarbonate aqueous
solution, the reaction solution was extracted with ethyl acetate to
separate an organic layer. The organic layer was dried with
MgSO.sub.4 and purified by column chromatography to obtain the
title compound (0.170 g, 42%).
[1504] .sup.1H-NMR (CDCl.sub.3) .delta. 7.35 (1H, dd), 6.86 (1H,
dd), 3.81 (3H, s), 2.96 (2H, s), 1.48 (6H, s)
Preparation Example 215:
4-iodospiro[1,3-benzodioxol-2,1'-cyclopentan]
Step A: 1-iodo-2,3-dimethoxy-benzene
[1505] 1,2-Dimethoxybenzene (500 mg, 3.62 mmol) was dissolved in
THF (5 mL) and cooled to 0-5.degree. C. n-BuLi (2.5 M in Hexane,
1.6 mL, 3.98 mmol) was slowly added dropwise thereto, and the
mixture was stirred at 0-5.degree. C. for 2 hours and cooled to
-78.degree. C. I.sub.2 (1.01 g, 3.98 mmol)/THF (5 mL) solution was
slowly added thereto, and the mixture was stirred at room
temperature for 2 hours and concentrated under reduced pressure.
The concentrated solution was diluted with saturated NaHCO.sub.3
solution, extracted with DCM and separated. The extract solution
was concentrated under reduced pressure and purified by column
chromatography (eluent, EtOAc/Hex=1/10) to obtain the title
compound (620 mg, 65% yield).
[1506] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.36-7.32 (m, 1H),
6.90-6.86 (m, 1H), 6.79 (dd, 1H), 3.85 (s, 3H), 3.83 (s, 3H)
Step B: 3-iodo-benzene-1,2-diol
[1507] 1-Iodo-2,3-dimethoxy-benzene (0.62 g, 2.35 mmol) obtained in
Step A was dissolved in DCM (3 mL) and cooled to 0-5.degree. C. 1M
BBr.sub.3 (7.04 mL, 7.05 mmol) was added thereto, and the mixture
was stirred at room temperature for 3 hours stirred. After
termination of the reaction, the reaction solution was cooled to
-20.degree. C. and diluted by slowly adding ethanol. The mixture
was stirred at room temperature for 30 minutes. Saturated
NaHCO.sub.3 aqueous solution was added thereto, and the reaction
solution was extracted with DCM. The organic layer was dried with
anhydrous magnesiumsulfate, concentrated under reduced pressure and
purified by column chromatography (eluent, EtOAc/Hex=1/4) to obtain
the title compound (0.12 g, 22% yield).
[1508] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.18 (d, 1H), 6.87
(d, 1H), 6.60 (dd, 1H), 5.64 (s, br, 2H)
Step C: 4-iodospiro[1,3-benzodioxol-2,1'-cyclopentane]
[1509] Toluene (5 mL) was added to 3-iodo-benzene-1,2-diol (60 mg,
0.254 mmol) obtained in Step B. Cyclopentanone (0.025 mL, 0.28
mmol) and p-TsOH.H.sub.2O (catalytic amount) were added thereto,
and the mixture was stirred at 130-140.degree. C. for 12 hours by
the use of a Dean-Stark apparatus. After termination of the
reaction, the reaction solution was cooled. After addition of
saturated NaHCO.sub.3 solution, the reaction solution was extracted
with EtOAc to separate an organic layer. The organic layer was
concentrated under reduced pressure and purified by column
chromatography (eluent, EtOAc/Hex=1/4) to obtain the title compound
(25 mg, 33%).
[1510] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.08 (d, 1H), 6.68
(d, 1H), 6.55 (dd, 1H), 2.20-2.06 (m, 4H), 1.90-1.79 (m, 4H)
Preparation Example 216: 2-bromo-3-iodophenol
Step A: 2-bromo-3-methoxy-phenylamine
[1511] 2-Bromo-1-methoxy-3-nitrobenzene (1 g, 4.31 mmol), Fe (1.68
g, 30.17 mmol) and NH.sub.4Cl (1.61 g, 30.17 mmol) were dissolved
in THF (4 mL)/MeOH (4 mL)/H.sub.2O (2 mL) solution and stirred for
1 hour under reflux. After termination of the reaction, the
reaction solution was cooled to room temperature, diluted with
saturated NaHCO.sub.3 solution and extracted with EtOAc. The
extract solution was concentrated under reduced pressure and
purified by column chromatography (eluent, EtOAc/Hex=1/5) to obtain
the title compound (0.83 g, 95% yield).
[1512] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.05 (dd, 1H),
6.42 (d, 1H), 6.31 (d, 1H), 3.86 (s, 3H)
Step B: 2-bromo-1-iodo-3-methoxybenzene
[1513] 35% HCl (3 mL) and ice (3 g) were added to
2-bromo-3-methoxy-phenylamine (0.83 g, 4.11 mmol) obtained in Step
A, and cooled to 0-5.degree. C. NaNO.sub.2 (0.31 g, 4.52
mmol)/H.sub.2O (2 mL) solution was slowly added thereto, and the
mixture was stirred at 0-5.degree. C. for 20 minutes. Pre-prepared
KI (6.82 g, 41.1 mmol)/H.sub.2O (10 mL) solution was slowly added
dropwise to the reaction solution, and the reaction was carried out
at room temperature for 12 hours. After termination of the
reaction, NaOH solution was added thereto, and the reaction
solution was extracted with DCM. The organic layer was washed with
saturated NaHCO.sub.3 aqueous solution and water. The extracted
organic layer was concentrated under reduced pressure and purified
by column chromatography (eluent, EtOAc/Hex=1/10) to obtain the
title compound (0.88 g, 68%).
[1514] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.48 (d, 1H), 7.00
(dd, 1H), 6.85 (d, 1H), 3.87 (s, 3H)
Step C: 2-bromo-3-iodophenol
[1515] 2-Bromo-1-iodo-3-methoxybenzene (0.88 g, 2.81 mmol) obtained
in Step B was dissolved in DCM (4 mL) and cooled to 0-5.degree. C.
1M BBr.sub.3 (8.4 mL, 8.43 mmol) was slowly added dropwise thereto,
and the mixture was stirred at 0-5.degree. C. for 1 hour and
additionally stirred at room temperature for 1 hour. After
termination of the reaction, the reaction solution was cooled to
-20.degree. C. and diluted by slowly adding methanol. The mixture
was stirred at room temperature for 30 minutes. After addition of
saturated NaHCO.sub.3 aqueous solution, the reaction solution was
extracted with DCM. The organic layer was dried with anhydrous
magnesiumsulfate, concentrated under reduced pressure and purified
by column chromatography (eluent, EtOAc/Hex=1/5) to obtain the
title compound (0.723 g, 86%).
[1516] 1H NMR (500 MHz, CDCl3) .delta. 7.43-7.39 (m, 1H), 7.02-6.92
(m, 2H), 5.61 (s, 1H)
Preparation Example 217: 4-bromo-2,6-difluoro-benzenethiol
Step A: 4-bromo-2,6-difluoro-benzenesulfonyl Chloride
[1517] CuCl.sub.2 (0.77 g, 5.77 mmol) was dissolved in 200 mL of
water. SOCl.sub.2 (29 mL, 0.40 mol) was added thereto at 0.degree.
C., and the mixture was stirred at room temperature for 18 hours.
4-Bromo-2,6-difluoroaniline (20 g, 0.096 mol) was dissolved in 240
mL of HCl and 900 mL of water, and the solution in which NaNO.sub.2
(7 g, 0.10 mol) was dissolved in 200 mL of water was added thereto
at 0.degree. C. The above thionyl chloride solution was added
thereto, and the reaction was carried out at room temperature for 1
hour to obtain the title compound (24 g, 85%) in a solid form.
Step B: 4-bromo-2,6-difluoro-benzenethiol
[1518] 4-Bromo-2,6-difluoro-benzenesulfonyl chloride (24 g, 0.08
mol) obtained in Step A was dissolved in 270 mL of THF. PPh.sub.3
(75 g, 0.28 mol) was added thereto, and the mixture was stirred at
room temperature for 15 minutes. After addition of water, the
mixture was stirred at room temperature for 18 hours. After
addition of water, the reaction solution was extracted with EtOAc.
The organic layer was separated, dried with MgSO.sub.4 and purified
by column chromatography to obtain the title compound (15 g,
83%).
[1519] .sup.1H-NMR (CDCl.sub.3) .delta. 7.10 (2H, d), 3.58 (1H,
s).
Preparation Example 218:
4-(4-bromo-2,6-difluoro-phenylsulfanyl)-butyric Acid Ethyl
Ester
[1520] 4-Bromo-2,6-difluoro-benzenethiol (15 g, 0.066 mol) obtained
in Preparation Example 217, NaH (60% in mineral oil, 2.6 g, 0.066
mol) and 4-bromo-butyric acid ethyl ester (10 mL, 0.073 mol) were
reacted in the same manner as in Preparation Example 34 to obtain
the title compound (18.56 g, 82%).
[1521] .sup.1H-NMR (CDCl.sub.3) .delta. 7.11 (2H, d), 4.11 (2H, q),
2.90 (2H, t), 2.43 (2H, t), 1.82 (2H, m), 1.24 (3H, t).
Preparation Example 219:
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsu-
lfanyl]-butyric Acid Ethyl Ester
[1522] 4-(4-Bromo-2,6-difluoro-phenylsulfanyl)-butyric acid ethyl
ester (11.6 g, 0.034 mol) obtained in Preparation Example 218,
bis(pinacolo)diboron (9.5 g, 0.038 mol), potassium acetate (8.4 g,
0.085 mol) and
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (2.5 g,
0.003 mol) were reacted in the same manner as in Step D of Example
1 to obtain the title compound (10.6 g, 80%).
[1523] .sup.1H-NMR (CDCl.sub.3) .delta. 7.30 (2H, d), 4.09 (2H, q),
2.94 (2H, t), 2.43 (2H, t), 1.83 (2H, m), 1.33 (12H, s), 1.22 (3H,
t).
Preparation Example 220:
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic Acid Ethyl Ester
Step A: 2-[1-(4-bromo-2,6-difluoro-phenyl)-4-piperidyl]acetic Acid
Ethyl Ester
[1524] 2-[1-(2,6-Difluoro-4-nitro-phenyl)-4-piperidylidene]acetic
acid ethyl ester (11.44 g, 35 mmol) obtained in Step B of
Preparation Example 89 was dissolved in 100 mL of MeOH and 50 mL of
DCM. 0.7 g of 10 wt % Pd/C was added thereto, and the mixture was
stirred for 20 minutes under 40 psi of hydrogen atmosphere. Solids
were filtered through Celite and concentrated under reduced
pressure to obtain
2-[1-(4-amino-2,6-difluoro-phenyl)-4-piperidyl]acetic acid ethyl
ester. This compound was reacted in the same manner as in Step C of
Preparation Example 84 to obtain the title compound (6.53 g,
52%).
[1525] .sup.1H-NMR (CDCl.sub.3) .delta. 6.99 (2H, m), 4.14 (2H, q),
3.18 (2H, m), 3.08 (2H, m), 2.28 (2H, d), 1.93 (1H, m), 1.75 (2H,
m), 1.46 (2H, m), 1.27 (3H, m)
Step B:
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]-4-piperidyl]acetic Acid Ethyl Ester
[1526] 2-[1-(4-Bromo-2,6-difluoro-phenyl)-4-piperidyl]acetic acid
ethyl ester (6.53 g, 18 mmol) obtained in Step A was reacted in the
same manner as in Step D of Preparation Example 84 to obtain the
title compound (4.68 g, 63%).
[1527] .sup.1H-NMR (CDCl.sub.3) .delta. 7.22 (2H, m), 4.14 (2H, q),
3.31 (2H, m), 3.10 (2H, m), 2.28 (2H, d), 1.96 (1H, m), 1.74 (2H,
m), 1.42 (2H, m), 1.32 (12H, s), 1.26 (3H, t)
Preparation Example 221:
4-[2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheno-
xy]butanoic Acid Ethyl Ester
Step A: 4-(4-bromo-2-chloro-6-fluoro-phenoxy)butanoic Acid Ethyl
Ester
[1528] After addition of 15 mL of DMF,
4-bromo-2-chloro-6-fluoro-phenol (2.25 g, 10.0 mmol),
K.sub.2CO.sub.3 (2.07 g, 15.0 mmol) and 4-bromobutanoic acid ethyl
ester (1.95 g, 10.0 mmol) were stirred at 80.degree. C. for 5
hours. The reaction solution was cooled to room temperature. After
addition of water, the reaction solution was extracted with EtOAc.
The organic layer was dried with anhydrous magnesium sulfate and
purified by column chromatography to obtain the title compound
(3.29 g, 97%).
[1529] .sup.1H-NMR (CDCl.sub.3) .delta. 7.32 (1H, m), 7.18 (1H, m),
4.12 (4H, m), 2.60 (2H, t), 2.10 (2H, m), 1.27 (3H, t)
Step B:
4-[2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)phenoxy]butanoic Acid Ethyl Ester
[1530] 4-(4-Bromo-2-chloro-6-fluoro-phenoxy)butanoic acid ethyl
ester (1.45 g, 4.27 mmol) Step A obtained in Step A was reacted in
the same manner as in Step D of Preparation Example 1 to obtain the
title compound (1.42 g, 86%).
[1531] .sup.1H-NMR (CDCl.sub.3) .delta. 7.58 (1H, m), 7.41 (1H, m),
4.16 (4H, m), 2.60 (2H, t), 2.10 (2H, m), 1.32 (12H, s), 1.26 (3H,
t)
Preparation Example 222:
4-[2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tanoic Acid Ethyl Ester
Step A: 4-(4-bromo-2,6-dichloro-phenoxy)butanoic Acid Ethyl
Ester
[1532] After addition of 15 mL of DMF 4-bromo-2,6-dichloro-phenol
(2.42 g, 10.0 mmol), K.sub.2CO.sub.3 (2.07 g, 15.0 mmol) and
4-bromobutanoic acid ethyl ester (1.95 g, 10.0 mmol) were stirred
at 80.degree. C. for 5 hours. The reaction solution was cooled to
room temperature. After addition of water, the reaction solution
was extracted with EtOAc and purified by column chromatography to
obtain the title compound (3.10 g, 87%).
[1533] .sup.1H-NMR (CDCl.sub.3) .delta. 7.44 (2H, s), 4.16 (2H, q),
4.04 (2H, t), 2.63 (2H, t), 2.16 (2H, m), 1.27 (3H, t)
Step B:
4-[2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
noxy]butanoic Acid Ethyl Ester
[1534] 4-(4-Bromo-2,6-dichloro-phenoxy)butanoic acid ethyl ester
(1.20 g, 3.37 mmol) obtained in Step A was reacted in the same
manner as in Step D of Preparation Example 1 to obtain the title
compound (0.825 g, 61%).
[1535] .sup.1H-NMR (CDCl.sub.3) .delta. 7.70 (2H, s), 4.16 (2H, q),
4.07 (2H, t), 2.65 (2H, t), 2.16 (2H, m), 1.33 (12H, s), 1.27 (3H,
t)
Preparation Example 223:
2-[1-[2,6-difluoro-4-(3-hydroxyphenyl)phenyl]-4-piperidyl]acetic
Acid Ethyl Ester
[1536] 3-Iodophenol (0.17 g, 0.77 mmol) and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.35 g, 0.85 mmol) obtained
in Preparation Example 220 was reacted in the same manner as in
Step A of Example 1 to obtain the title compound (0.21 g, 75%).
[1537] .sup.1H-NMR (CDCl.sub.3) .delta. 7.30 (1H, m), 7.06 (3H, m),
6.97 (1H, m), 6.81 (1H, m), 4.88 (1H, brs), 4.15 (2H, q), 3.27 (2H,
m), 3.13 (2H, m), 2.29 (2H, d), 1.96 (1H, m), 1.77 (2H, m), 1.47
(2H, m), 1.27 (3H, t)
Preparation Example 224:
[1-(2,6-difluoro-4-thiocarbamoyl-phenyl)-piperidin-4-yl]-acetic
Acid Ethyl Ester
Step A: [1-(4-cyano-2,6-difluoro-phenyl)-piperidin-4-yl]-acetic
Acid Ethyl Ester
[1538] 3,4,5-Trifluorobenzonitrile (3.14 g, 20 mmol) and
hydrochloric acid salt of 2-(4-piperidin)acetic acid ethyl ester
(4.15 g, 20 mmol) were reacted in the same manner as in Step A of
Preparation Example 84 to obtain the title compound (4.80 g,
78%).
[1539] .sup.1H-NMR (CDCl.sub.3) .delta. 7.16 (2H, m), 4.19 (2H, q),
3.45 (2H, m), 3.19 (2H, m), 2.32 (2H, d), 2.03 (1H, m), 1.82 (2H,
m), 1.43 (2H, m), 1.31 (3H, t)
Step B:
[1-(2,6-difluoro-4-thiocarbamoyl-phenyl)-piperidin-4-yl]-acetic
Acid Ethyl Ester
[1540] [1-(4-Cyano-2,6-difluoro-phenyl)-piperidin-4-yl]-acetic acid
ethyl ester (1.54 g, 5.0 mmol) obtained in Step A, magnesium
dichloride hexahydrate (4.07 g, 40.0 mmol) and sodium thiolate
hydrate (3.70 g, 50.0 mmol) were dissolved in DMF (20 mL) and
stirred for 3 hours. After addition of water, the reaction solution
was extracted with EtOAc. The organic layer was washed with sodium
chloride aqueous solution, dried with anhydrous magnesium sulfate
and purified by column chromatography to obtain the title compound
(1.41 g, 82%).
[1541] .sup.1H-NMR (CDCl.sub.3) .delta. 7.64 (1H, s), 7.45 (2H, m),
7.16 (1H, s), 4.19 (2H, q), 3.42 (2H, m), 3.17 (2H, m), 2.32 (2H,
d), 2.00 (1H, m), 1.80 (2H, m), 1.46 (2H, m), 1.31 (3H, t)
Preparation Example 225:
2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
Step A: 4-bromo-2-chloro-6-fluoro-aniline
[1542] 4-Bromo-2-fluoro-aniline (5.0 g, 26 mmol) was dissolved in
52 mL of CH.sub.3CN. N-chlorosuccinimide (4.37 g, 33 mmol) was
added thereto, and the mixture was stirred for 3 hours under
reflux. The reaction solution was cooled to room temperature. After
addition of NaHCO.sub.3 aqueous solution, the reaction solution was
extracted with DCM. The organic layer was dried with anhydrous
magnesium sulfate and purified by column chromatography to obtain
the title compound (4.41 g, 75%).
[1543] .sup.1H-NMR (CDCl.sub.3) .delta. 7.21 (1H, m), 7.09 (1H, m),
4.08 (2H, brs)
Step B:
2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)a-
niline
[1544] 4-Bromo-2-chloro-6-fluoro-aniline (4.4 g, 20 mmol) obtained
in Step A was reacted in the same manner as in Step D of
Preparation Example 1 to obtain the title compound (3.68 g,
67%).
[1545] .sup.1H-NMR (CDCl.sub.3) .delta. 7.50 (1H, m), 7.32 (1H, m),
4.28 (2H, brs), 1.33 (12H, s)
Preparation Example 226:
4-chloro-2-(cyclopropylmethoxy)-6-methyl-pyrimidine
[1546] 20 mL of THF was added to cyclopropylmethanol (0.36 g, 5.0
mmol) and cooled to 0.degree. C. NaH (60 wt % in mineral oil, 0.24
g, 6.0 mmol) was added thereto, and the mixture was stirred for 30
minutes. 2,6-Dichloro-4-methyl-pyrimidine (0.815 g, 5.0 mmol) was
added thereto, and the mixture was stirred at room temperature for
16 hours. After addition of water, the reaction solution was
extracted with EtOAc. The organic layer was purified by column
chromatography to obtain the title compound (0.37 g, 37%).
[1547] .sup.1H-NMR (CDCl.sub.3) .delta. 6.83 (1H, s), 4.19 (2H, d),
2.43 (3H, s), 1.31 (1H, m), 0.61 (2H, m), 0.37 (2H, m)
Preparation Example 227:
2-chloro-4-(cyclopropylmethoxy)-6-methyl-pyrimidine
[1548] 20 mL of THF was added to cyclopropylmethanol (0.36 g, 5.0
mmol) and cooled to 0.degree. C. NaH (60 wt % in mineral oil, 0.24
g, 6.0 mmol) was added thereto, and the mixture was stirred for 30
minutes. After addition of 2,6-dichloro-4-methyl-pyrimidine (0.815
g, 5.0 mmol), the mixture was stirred at room temperature for 16
hours. After addition of water, the reaction solution was extracted
with EtOAc. The organic layer was purified by column chromatography
to obtain the title compound (0.41 g, 41%).
[1549] .sup.1H-NMR (CDCl.sub.3) .delta. 6.54 (1H, s), 4.23 (2H, d),
2.46 (3H, s), 1.30 (1H, m), 0.56 (2H, m), 0.40 (2H, m)
Preparation Example 228:
2-chloro-4-(cyclobutoxy)-6-methyl-pyrimidine
[1550] 2,6-Dichloro-4-methyl-pyrimidine (0.815 g, 5.0 mmol) and
cyclobutanol (0.36 g, 5.0 mmol) were reacted in the same manner as
in Preparation Example 226 to obtain the title compound (0.455 g,
46%).
[1551] .sup.1H-NMR (CDCl.sub.3) .delta. 6.44 (1H, s), 5.21 (1H, m),
2.45 (2H, m), 2.41 (3H, s), 2.14 (2H, m), 1.85 (1H, m), 1.67 (1H,
m)
Preparation Example 229:
4-chloro-2-(cyclobutoxy)-6-methyl-pyrimidine
[1552] 2,6-Dichloro-4-methyl-pyrimidine (0.815 g, 5.0 mmol) and
cyclobutanol (0.36 g, 5.0 mmol) were reacted in the same manner as
in Preparation Example 226 to obtain the title compound (0.455 g,
46%).
[1553] .sup.1H-NMR (CDCl.sub.3) .delta. 6.81 (1H, s), 5.21 (1H, m),
2.45 (2H, m), 2.41 (3H, s), 2.14 (2H, m), 1.85 (1H, m), 1.67 (1H,
m)
Preparation Example 230: 2-chloro-4-(cyclobutoxy)pyrimidine
[1554] Cyclobutanol (0.58 g, 8.05 mmol) and 2,4-dichloropyrimidine
(1 g, 6.71 mmol) were reacted in the same manner as in Preparation
Example 226 to obtain the title compound (0.4 g, 32%) and the
by-product, 4-chloro-2-cyclobutoxy-pyrimidine (0.4 g, 32%).
[1555] .sup.1H-NMR (CDCl.sub.3) .delta. 8.27 (1H, d), 6.61 (1H, d),
5.26 (1H, m), 2.48 (2H, m), 2.16 (2H, m), 1.88 (1H, m), 1.70 (1H,
m).
Preparation Example 231:
2-chloro-4-(cyclopropylmethoxy)pyrimidine
[1556] Cyclopropylmethanol (0.72 g, 10.0 mmol) and
2,4-dichloropyrimidine (1.49 g, 10.0 mmol) were reacted in the same
manner as in Preparation Example 226 to obtain the title compound
(0.78 g, 42%).
[1557] .sup.1H-NMR (CDCl.sub.3) .delta. 8.32 (1H, m), 6.71 (1H, m),
4.26 (2H, d), 1.30 (1H, m), 0.68 (2H, m), 0.42 (2H, m)
Preparation Example 232: 2-chloro-6-(cyclobutoxy)pyrazine
[1558] Cyclobutanol (0.36 g, 5.0 mmol) and 2,6-dichloropyrazine
(0.745 g, 5.0 mmol) were reacted in the same manner as in
Preparation Example 226 to obtain the title compound (0.53 g,
57%).
[1559] .sup.1H-NMR (CDCl.sub.3) .delta. 8.15 (1H, s), 8.11 (1H, s),
5.22 (1H, m), 2.53 (2H, m), 2.20 (2H, m), 1.91 (1H, m), 1.73 (1H,
m)
Preparation Example 233:
2-chloro-6-(cyclopropylmethoxy)pyrazine
[1560] Cyclopropylmethanol (0.72 g, 10.0 mmol) and
2,6-dichloropyrazine (1.49 g, 10.0 mmol) were reacted in the same
manner as in Preparation Example 226 to obtain the title compound
(1.49 g, 81%).
[1561] .sup.1H-NMR (CDCl.sub.3) .delta. 8.18 (1H, s), 8.16 (1H, s),
4.21 (2H, d), 1.33 (1H, m), 0.68 (2H, m), 0.42 (2H, m)
Preparation Example 234: 2-chloro-6-methoxy-pyrazine
[1562] MeOH (0.27 mL, 6.7 mmol) was dissolve in 15 mL of THF. NaH
(60 wt % in mineral oil, 0.32 g, 8.0 mmol) was added thereto, and
the mixture was stirred at room temperature for 30 minutes.
2,6-Dichloropyrazine (1.0 g, 6.7 mmol) dissolved in 20 mL of THF
was slowly added thereto, and the mixture was stirred at room
temperature for 16 hours. After addition of ammonium chloride
aqueous solution, the reaction solution was extracted with
Et.sub.2O. The organic layer was dried with anhydrous magnesium
sulfate and purified by column chromatography to obtain the title
compound (0.71 g, 73%).
[1563] .sup.1H-NMR (CDCl.sub.3) .delta. 8.14 (1H, s), 8.13 (1H, s),
3.99 (3H, s)
Preparation Example 235: 2-chloro-6-propoxy-pyrazine
[1564] Propan-1-ol (0.4 g, 6.7 mmol) was dissolved in 15 mL of THF.
NaH (60 wt % in mineral oil, 0.32 g, 8.0 mmol) was added thereto,
and the mixture was stirred at room temperature for 30 minutes.
2,6-Dichloropyrazine (1.0 g, 6.7 mmol) dissolved in 20 mL of THF
was slowly added thereto, and the mixture was stirred at room
temperature for 16 hours. After addition of ammonium chloride
aqueous solution, the reaction solution was extracted with
Et.sub.2O. The organic layer was dried with anhydrous magnesium
sulfate and purified by column chromatography to obtain the title
compound (0.77 g, 66%).
[1565] .sup.1H-NMR (CDCl.sub.3) .delta. 8.12 (1H, s), 8.11 (1H, s),
4.29 (2H, t), 1.82 (2H, m), 1.03 (3H, t)
Preparation Example 236: 2-butoxy-6-chloro-pyrazine
[1566] Butan-1-ol (0.5 g, 6.7 mmol) was dissolved in 15 mL of THF.
NaH (60 wt % in mineral oil, 0.32 g, 8.0 mmol) was added thereto,
and the mixture was stirred at room temperature for 30 minutes.
2,6-Dichloropyrazine (1.0 g, 6.7 mmol) dissolved in 20 mL of THF
was slowly added thereto, and the mixture was stirred at room
temperature for 16 hours. After addition of ammonium chloride
aqueous solution, the reaction solution was extracted with
Et.sub.2O. The organic layer was dried with anhydrous magnesium
sulfate and purified by column chromatography to obtain the title
compound (1.15 g, 92%).
[1567] .sup.1H-NMR (CDCl.sub.3) .delta. 8.11 (1H, s), 8.10 (1H, s),
4.33 (2H, t), 1.78 (2H, m), 1.48 (2H, m), 0.98 (3H, t)
Preparation Example 237: 2-chloro-6-isobutoxy-pyrazine
[1568] 2-Methylpropan-1-ol (0.5 g, 6.7 mmol) was dissolved in 15 mL
of THF. NaH (60 wt % in mineral oil, 0.32 g, 8.0 mmol) was added
thereto, and the mixture was stirred at room temperature for 30
minutes. 2,6-Dichloropyrazine (1.0 g, 6.7 mmol) dissolved in 20 mL
of THF was slowly added thereto, and the mixture was stirred at
room temperature for 16 hours. After addition of ammonium chloride
aqueous solution, the reaction solution was extracted with
Et.sub.2O. The organic layer was dried with anhydrous magnesium
sulfate and purified by column chromatography to obtain the title
compound (1.04 g, 83%).
[1569] .sup.1H-NMR (CDCl.sub.3) .delta. 8.12 (2H, s), 4.10 (2H, d),
2.11 (1H, m), 1.03 (6H, d)
Preparation Example 238: 2-chloro-6-(cyclopentoxy)pyrazine
[1570] Cyclopentanol (0.58 g, 6.7 mmol) was dissolved in 15 mL of
THF. NaH (60 wt % in mineral oil, 0.32 g, 8.0 mmol) was added
thereto, and the mixture was stirred at room temperature for 30
minutes. 2,6-Dichloropyrazine (1.0 g, 6.7 mmol) dissolved in 20 mL
of THF was slowly added thereto, and the mixture was stirred at
room temperature for 16 hours. After addition of ammonium chloride
aqueous solution, the reaction solution was extracted with
Et.sub.2O. The organic layer was dried with anhydrous magnesium
sulfate and purified by column chromatography to obtain the title
compound (1.07 g, 80%).
[1571] .sup.1H-NMR (CDCl.sub.3) .delta. 8.09 (1H, s), 8.05 (1H, s),
5.40 (1H, m), 1.98 (2H, m), 1.80 (4H, m), 1.65 (2H, m)
Preparation Example 239: 2-chloro-4-ethoxy-pyrimidine
[1572] 2,4-Dichloropyrimidine (3.0 g, 20.1 mmol) was dissolved in
40 mL of EtOH. NaOEt (1.0 M in EtOH, 20 mL, 20 mmol) was added
thereto, and the mixture was stirred at room temperature for 16
hours. The reaction solution was concentrated under reduced
pressure. After addition of water, the reaction solution was
extracted with Et.sub.2O. The organic layer was dried with
anhydrous magnesium sulfate and purified by column chromatography
to obtain the title compound (1.41 g, 44%).
[1573] .sup.1H-NMR (CDCl.sub.3) .delta. 8.27 (1H, d), 6.64 (1H, d),
4.45 (2H, q), 1.40 (3H, t)
Preparation Example 240: 2-chloro-4-isopropoxy-pyrimidine
[1574] Cs.sub.2CO.sub.3 (7.15 g, 21.9 mmol) and 50 mL of
propan-2-ol were added to 2,4-dichloropyrimidine (3.0 g, 20.1
mmol), and the mixture was stirred for 24 hours under reflux. After
filtering solids, the filtrate was purified by column
chromatography to obtain the title compound (2.24 g, 65%).
[1575] .sup.1H-NMR (CDCl.sub.3) .delta. 8.25 (1H, d), 6.58 (1H, d),
5.40 (1H, m), 1.37 (6H, d)
Preparation Example 241: 2-chloro-4-propoxy-pyrimidine
[1576] Propan-1-ol (1.33 g, 22.1 mmol) was dissolved in 60 mL of
THF. NaH (60 wt % in mineral oil, 0.96 g, 24.1 mmol) was added
thereto, and the mixture was stirred at room temperature for 30
minutes. 2,4-Dichloropyrimidine (3.0 g, 22.1 mmol) was added
thereto, and the mixture was stirred at room temperature for 24
hours. After addition of ammonium chloride aqueous solution, the
reaction solution was extracted with Et.sub.2O. The organic layer
was dried with anhydrous magnesium sulfate and purified by column
chromatography to obtain the title compound (2.06 g, 59%).
[1577] .sup.1H-NMR (CDCl.sub.3) .delta. 8.27 (1H, d), 6.65 (1H, d),
4.34 (2H, t), 1.81 (2H, m), 1.03 (3H, t)
Preparation Example 242: 2-chloro-4-isobutoxy-pyrimidine
[1578] 2-Methylpropan-1-ol (1.64 g, 22.1 mmol) was dissolved in 60
mL of THF. NaH (60 wt % in mineral oil, 0.96 g, 24.1 mmol) was
added thereto, and the mixture was stirred at room temperature for
30 minutes. 2,4-Dichloropyrimidine (3.0 g, 22.1 mmol) was added
thereto, and the mixture was stirred at room temperature for 24
hours. After addition of ammonium chloride aqueous solution, the
reaction solution was extracted with Et.sub.2O. The organic layer
was dried with anhydrous magnesium sulfate and purified by column
chromatography to obtain the title compound.
[1579] .sup.1H-NMR (CDCl.sub.3) .delta. 8.27 (1H, d), 6.65 (1H, d),
4.15 (2H, d), 2.09 (1H, m), 1.00 (6H, d)
Preparation Example 243: 2-chloro-4-ethoxy-6-methyl-pyrimidine
[1580] Cs.sub.2CO.sub.3 (6.6 g, 20.2 mmol) and 46 mL of EtOH were
added to 2,4-dichloro-6-methyl-pyrimidine (3.0 g, 18.4 mmol), and
the mixture was stirred for 48 hours under reflux. After filtering
solids, the filtrate was purified by column chromatography to
obtain the title compound (1.88 g, 59%).
[1581] .sup.1H-NMR (CDCl.sub.3) .delta. 6.47 (1H, s), 4.41 (2H, q),
2.42 (3H, s), 1.39 (3H, t)
Preparation Example 244:
2-chloro-4-isopropoxy-6-methyl-pyrimidine
[1582] Cs.sub.2CO.sub.3 (6.6 g, 20.2 mmol) and 46 mL of propan-2-ol
were added to 2,4-dichloro-6-methyl-pyrimidine (3.0 g, 18.4 mmol),
and the mixture was stirred for 16 hours under reflux. After
filtering solids, the filtrate was purified by column
chromatography to obtain the title compound (1.18 g, 34%).
[1583] .sup.1H-NMR (CDCl.sub.3) .delta. 6.41 (1H, s), 5.38 (1H, m),
2.40 (3H, s), 1.34 (6H, d)
Preparation Example 245: 2-chloro-4-methyl-6-propoxy-pyrimidine
[1584] Cs.sub.2CO.sub.3 (6.6 g, 20.2 mmol) and 46 mL of propan-1-ol
were added to 2,4-dichloro-6-methyl-pyrimidine (3.0 g, 18.4 mmol),
and the mixture was stirred for 16 hours under reflux.
[1585] After filtering solids, the filtrate was purified by column
chromatography to obtain the title compound (1.72 g, 50%).
[1586] .sup.1H-NMR (CDCl.sub.3) .delta. 6.48 (1H, s), 4.31 (2H, t),
2.42 (3H, s), 1.79 (2H, m), 1.00 (3H, t)
Preparation Example 246:
2-chloro-4-isobutoxy-6-methyl-pyrimidine
[1587] 2-Methylpropan-1-ol (3.5 g, 21.4 mmol) was dissolved in 50
mL of THF. NaH (60 wt % in mineral oil, 1.03 g, 25.7 mmol) was
added thereto, and the mixture was stirred at room temperature for
30 minutes. 2,4-Dichloro-6-methyl-pyrimidine (3.0 g, 18.4 mmol)
dissolved in 20 mL of THF was added thereto, and the mixture was
stirred at room temperature for 16 hours. After addition of
ammonium chloride aqueous solution, the reaction solution was
extracted with Et.sub.2O. The organic layer was dried with
anhydrous magnesium sulfate and purified by column chromatography
to obtain the title compound (1.75 g, 41%).
[1588] .sup.1H-NMR (CDCl.sub.3) .delta. 6.49 (1H, s), 4.13 (2H, d),
2.42 (3H, s), 2.07 (1H, m), 1.00 (6H, d)
Preparation Example 247:
2-chloro-4-(2-methoxyethoxy)-6-methyl-pyrimidine
[1589] 2,6-Dichloro-4-methyl-pyrimidine (1.63 g, 10.0 mmol) and
2-methoxyethanol (0.76 g, 10.0 mmol) were reacted in the same
manner as in Preparation Example 226 to obtain the title compound
(1.03 g, 51%).
[1590] .sup.1H-NMR (CDCl.sub.3) .delta. 6.59 (1H, s), 4.56 (2H, m),
3.75 (2H, m), 3.45 (3H, s), 2.45 (3H, s)
Preparation Example 248:
2-chloro-4-(3-methoxy-propoxy)-6-methyl-pyrimidine
[1591] 2,6-Dichloro-4-methyl-pyrimidine (1.63 g, 10.0 mmol) and
3-methoxypropanol (0.90 g, 10.0 mmol) were reacted in the same
manner as in Preparation Example 226 to obtain the title compound
(1.05 g, 48%).
[1592] .sup.1H-NMR (CDCl.sub.3) .delta. 6.52 (1H, s), 4.47 (2H, t),
3.54 (2H, t), 3.38 (3H, s), 2.48 (3H, s), 2.06 (2H, m)
Preparation Example 249: 2-chloro-6-pyrrolidin-1-yl-pyrazine
[1593] 2,6-Dichloropyrazine (2.0 g, 13.4 mmol) was dissolved in 13
mL of DMSO. Pyrrolidine (1.05 g, 14.7 mmol) and DIPEA (2.92 mL,
16.7 mmol) were sequentially added thereto, and the mixture was
stirred at room temperature for 24 hours. The reaction solution was
diluted with water, extracted with EtOAc and purified by column
chromatography to obtain the title compound (2.36 g, 96%).
[1594] .sup.1H-NMR (CDCl.sub.3) .delta. 7.74 (1H, s), 7.71 (1H, s),
3.49 (4H, m), 2.03 (4H, m)
Preparation Example 250: 6-chloro-N-isopropyl-pyrazin-2-amine
[1595] Propan-2-amine (1.7 mL, 20.1 mmol), 1 mL of TEA and 2 mL of
THF were added to 2,6-dichloropyrazine (2.0 g, 13.4 mmol), and the
mixture was stirred at 60.degree. C. for 24 hours. After filtering
solids, the filtrate was purified by column chromatography to
obtain the title compound (1.35 g, 59%).
[1596] .sup.1H-NMR (CDCl.sub.3) .delta. 7.75 (1H, s), 7.71 (1H, s),
4.61 (1H, brs), 4.00 (1H, m), 1.26 (6H, d)
Preparation Example 251: 6-chloro-N-isobutyl-pyrazin-2-amine
[1597] 2-Methylpropan-1-amine (2 mL, 20.1 mmol), 1 mL of TEA and 3
mL of THF were added to 2,6-dichloropyrazine (2.0 g, 13.4 mmol),
and the mixture was stirred at 60.degree. C. for 24 hours. After
filtering solids, the filtrate was purified by column
chromatography to obtain the title compound (1.95 g, 78%).
[1598] .sup.1H-NMR (CDCl.sub.3) .delta. 7.77 (1H, s), 7.75 (1H, s),
4.97 (1H, brs), 3.17 (2H, m), 1.90 (1H, m), 0.99 (6H, d)
Preparation Example 252: 6-chloro-N-cyclopentyl-pyrazin-2-amine
[1599] Cyclopentanamine (1.48 g, 17.4 mmol), 1 mL of TEA and 3 mL
of THF were added to 2,6-dichloropyrazine (2.0 g, 13.4 mmol), and
the mixture was stirred at 60.degree. C. for 24 hours. After
filtering solids, the filtrate was purified by column
chromatography to obtain the title compound (1.84 g, 69%).
[1600] .sup.1H-NMR (CDCl.sub.3) .delta. 7.77 (1H, s), 7.74 (1H, s),
4.80 (1H, brs), 4.09 (1H, m), 2.07 (2H, m), 1.74 (2H, m), 1.67 (2H,
m), 1.48 (2H, m)
Preparation Example 253: 6-chloro-N,N-diethyl-pyrazin-2-amine
[1601] 2,6-Dichloropyrazine (2.0 g, 13.4 mmol) was dissolved in 13
mL of DMSO.
[1602] Diethylamine (1.53 mL, 14.7 mmol) and DIPEA (2.92 mL, 16.7
mmol) were sequentially added thereto, and the mixture was stirred
at room temperature for 24 hours. The reaction solution was diluted
with water, extracted with EtOAc and purified by column
chromatography to obtain the title compound (1.44 g, 58%).
[1603] .sup.1H-NMR (CDCl.sub.3) .delta. 7.80 (1H, s), 7.70 (1H, s),
3.51 (4H, q), 1.21 (6H, t)
Preparation Example 254: 6-chloro-N,N-dimethyl-pyrazin-2-amine
[1604] 2,6-Dichloropyrazine (2.0 g, 13.4 mmol) was dissolved in 13
mL of DMSO. Dimethylamine hydrochloride (1.31 g, 16.08 mmol) and
DIPEA (5.2 mL, 30 mmol) were sequentially added thereto, and the
mixture was stirred at room temperature for 24 hours. The reaction
solution was diluted with water, extracted with EtOAc and purified
by column chromatography to obtain the title compound (1.82 g,
86%).
[1605] .sup.1H-NMR (CDCl.sub.3) .delta. 7.87 (1H, s), 7.77 (1H, s),
3.13 (6H, s)
Preparation Example 255: 2-chloro-N-isobutyl-pyrimidin-4-amine
[1606] 15 mL of THF, 2-methylpropan-1-amine (2.6 mL, 26.1 mmol) and
DIPEA (5.3 mL, 30 mmol) were added to 2,4-dichloropyrimidin (3.0 g,
20.1 mmol), the mixture was stirred at 65.degree. C. for 16 hours.
The reaction solution was concentrated under reduced pressure and
purified by column chromatography to obtain the title compound
(2.57 g, 69%).
[1607] .sup.1H-NMR (CDCl.sub.3) .delta. 8.03 (1H, m), 6.23 (1H, d),
5.40 (1H, brs), 3.07 (2H, m), 1.89 (1H, m), 0.98 (6H, d)
Preparation Example 256:
5-chloro-3-(cyclobutoxy)-2-methyl-pyrazine
Step A: 3,5-dichloro-2-methyl-pyrazine
[1608] 110 mL of THF was added to 2,2,6,6-tetramethylpiperidine
(3.3 mL, 20 mmol) and cooled to -78.degree. C. n-BuLi (2.5 M hexane
solution, 8 mL, 20 mmol) was added thereto, and the mixture was
stirred at -78.degree. C. for 30 minutes. 2,6-Dichloropyrazine (2.0
g, 13.4 mmol) dissolved in 20 mL was added thereto, and the mixture
was stirred at -78.degree. C. for 90 minutes. Iodomethane (3.8 mL,
60 mmol) was added thereto, and the mixture was stirred at room
temperature for 3 hours. Solids were removed by filtration, and the
filtrate was purified by column chromatography to obtain the title
compound (0.77 g, 35%).
[1609] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, s), 2.65 (3H,
s)
Step B: 5-chloro-3-(cyclobutoxy)-2-methyl-pyrazine
[1610] 3,5-Dichloro-2-methyl-pyrazine (0.62 g, 3.8 mmol) obtained
in Step A and cyclobutanol (0.3 g, 4.18 mmol) was reacted in the
same manner as in Preparation Example 226 to obtain the title
compound (0.54 g, 71%).
[1611] .sup.1H-NMR (CDCl.sub.3) .delta. 7.98 (1H, s), 5.20 (1H, m),
2.48 (2H, m), 2.43 (3H, s), 2.15 (2H, m), 1.86 (1H, m), 1.70 (1H,
m)
Preparation Example 257: 2-chloro-6-isobutyl-pyrazine
[1612] 50 mL of THF, 5 mL of NMP and Fe(acac).sub.3 (0.24 g, 0.67
mmol) were added to 2,6-dichloropyrazine (2.0 g, 13.4 mmol), and
the mixture was cooled to 0.degree. C. Isobutylmagnesium bromide
(2.0 M Et.sub.2O solution, 12 mL, 24 mmol) was slowly added
thereto. The reaction solution was stirred at room temperature for
24 hours. After addition of water, the reaction solution was
extracted with Et.sub.2O. The organic layer was dried with
anhydrous magnesium sulfate and purified by column chromatography
to obtain the title compound (0.32 g, 14%).
[1613] .sup.1H-NMR (CDCl.sub.3) .delta. 8.43 (1H, s), 8.31 (1H, s),
2.66 (2H, d), 2.13 (1H, m), 0.95 (6H, d)
Preparation Example 258: 2-chloro-6-cyclopentyl-pyrazine
[1614] 13 mL of toluene, SPhos (1.37 g, 3.3 mmol) and Pd(OAc).sub.2
(0.38 g, 1.67 mmol) were added to 2,6-dichloropyrazine (1.0 g, 6.7
mmol). Cyclopentylzinc bromide (0.5 M THF solution, 20 mL, 10 mmol)
was added thereto, and the mixture was stirred at room temperature
for 16 hours. After addition of ammonium chloride aqueous solution,
the reaction solution was extracted with EtOAc. The organic layer
was purified by column chromatography to obtain the title compound
(0.19 g, 15%).
[1615] .sup.1H-NMR (CDCl.sub.3) .delta. 8.39 (1H, s), 8.36 (1H, s),
3.18 (1H, m), 2.10 (2H, m), 1.85 (4H, m), 1.71 (2H, m)
Preparation Example 259: 2-chloro-4-isobutyl-pyrimidine
[1616] 40 mL of THF, Pd(PPh.sub.3).sub.4 (1.0 g, 0.9 mmol) and
triisobutylaluminum (1.0 M hexane solution, 16 mL, 16 mmol) were
added to 2,4-dichloropyrimidine (2.0 g, 13.4 mmol), and the mixture
was stirred for 20 hours under reflux. After cooling and addition
of water, the reaction solution was extracted with Et.sub.2O. The
organic layer was purified by column chromatography to obtain the
title compound (0.32 g, 14%).
[1617] .sup.1H-NMR (CDCl.sub.3) .delta. 8.49 (1H, d), 7.08 (1H, d),
2.63 (2H, d), 2.14 (1H, m), 0.95 (6H, d)
Preparation Example 260: 2-butyl-6-chloro-pyrazine
[1618] 50 mL of THF, 5 mL of NMP and Fe(acac).sub.3 (0.24 g, 0.67
mmol) were added to 2,6-dichloropyrazine (2.0 g, 13.4 mmol), and
the mixture was cooled to 0.degree. C. Butylmagnesium chloride (0.9
M THF solution, 16 mL, 14.4 mmol) was slowly added thereto. The
reaction solution was stirred at room temperature for 24 hours.
After addition of water, the reaction solution was extracted with
Et.sub.2O. The organic layer was dried with anhydrous magnesium
sulfate and purified by column chromatography to obtain the title
compound (0.38 g, 17%).
[1619] .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, s), 8.35 (1H, s),
2.79 (2H, t), 1.73 (2H, m), 1.39 (2H, m), 0.95 (3H, t)
Preparation Example 261: 2-chloro-6-isopentyl-pyrazine
[1620] 50 mL of THF, 5 mL of NMP and Fe(acac).sub.3 (0.24 g, 0.67
mmol) were added to 2,6-dichloropyrazine (2.0 g, 13.4 mmol), and
the mixture was cooled to 0.degree. C. Isopentylmagnesium bromide
(0.9 M THF solution, 16 mL, 14.4 mmol) was slowly added thereto.
The reaction solution was stirred at room temperature for 24 hours.
After addition of water, the reaction solution was extracted with
Et.sub.2O. The organic layer was dried with anhydrous magnesium
sulfate and purified by column chromatography to obtain the title
compound (0.36 g, 15%).
[1621] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, s), 8.35 (1H, s),
2.79 (2H, m), 1.62 (3H, m), 0.95 (6H, d)
Preparation Example 262: 2-chloro-6-cyclobutyl-pyrazine
[1622] Magnesium (0.326 g, 13.4 mL) and 13.4 mL of THF were added
to a dried flask. Bromocyclobutane (1.81 g, 13.4 mmol) was slowly
added thereto, and the mixture was stirred for 1 hour under reflux.
The reaction solution was cooled to 0.degree. C. Fe(acac).sub.3
(0.24 g, 16 mmol) dissolved in 2 mL of THF was added thereto, and
the mixture was stirred for 5 minutes. 2,6-Dichloropyrazine (2.0 g,
13.4 mmol) dissolved in 20 mL of THF and 2 mL of NMP was added
thereto, and the mixture was stirred for 2 hours. After addition of
ammonium chloride aqueous solution, the reaction solution was
extracted with Et.sub.2O and purified by column chromatography to
obtain the title compound (0.05 g, 2%).
[1623] .sup.1H-NMR (CDCl.sub.3) .delta. 8.40 (1H, s), 8.33 (1H, s),
3.68 (1H, m), 2.38 (4H, m), 2.10 (1H, m), 1.96 (1H, m)
Preparation Example 263:
4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine
Step A: 2-aminocyclopentene-1-carboxylic Acid Methyl Ester
[1624] 2-Oxocyclopentancarboxylic acid methyl ester (9.86 g, 69.3
mmol) was dissolved in 140 mL of MeOH. Ammonium formate (21.9 g,
350 mmol) was added thereto, and the mixture was stirred for 24
hours under reflux. The reaction solution was cooled to room
temperature. Small amount of SiO.sub.2 was added, and the reaction
solution was concentrated under reduced pressure and purified by
column chromatography to obtain the title compound (9.49 g,
97%).
[1625] .sup.1H-NMR (DMSO-d.sub.6) .delta. 6.76 (2H, brs), 3.53 (3H,
s), 2.39 (4H, m), 1.70 (2H, m)
Step B: 2-formamidocyclopentene-1-carboxylic Acid Methyl Ester
[1626] 21 mL of formic acid was cold to 0.degree. C. 30 mL of
acetic anhydride was added, and 2-aminocyclopentene-1-carboxylic
acid methyl ester (4.76 g, 33.7 mmol) obtained in Step A was then
added thereto little by little. The reaction solution was stirred
at room temperature for 16 hours. The organic layer extracted with
EtOAc was purified by column chromatography to obtain the title
compound (4.95 g, 87%).
[1627] .sup.1H-NMR (DMSO-d.sub.6) .delta. 10.28 (0.5H, brs), 9.72
(0.5H, brs), 8.57 (0.5H, brs), 8.28 (0.5H, brs), 3.68 (3H, s), 3.05
(1H, m), 2.88 (1H, m), 2.46 (2H, m), 1.86 (2H, m)
Step C: 6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol
[1628] Ammonium formate (9.94 g, 157 mmol) was dissolved in 15 mL
of formamide. 2-Formamidocyclopentene-1-carboxylic acid methyl
ester (4.94 g, 29.2 mmol) obtained in Step B was added thereto, and
the mixture was stirred at 150.degree. C. for 4 hours. After
cooling to room temperature, the reaction solution was stirred for
16 hours. The formed precipitate was dried to obtain the title
compound (1.56 g, 39%).
[1629] .sup.1H-NMR (DMSO-d.sub.6) .delta. 12.28 (1H, brs), 8.02
(1H, s), 2.75 (2H, t), 2.62 (2H, t), 1.95 (2H, m)
Step D: 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine
[1630] 11 mL of phosphorus oxychloride was added to
6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (1.56 g, 11.4 mmol)
obtained in Step C, and the mixture was stirred for 4 hours under
reflux. The reaction solution was cooled to room temperature. DCM
was added thereto, and water was then added thereto. The water
layer was extracted with DCM, and the organic layer was purified by
column chromatography to obtain the title compound (1.67 g,
95%).
[1631] .sup.1H-NMR (DMSO-d.sub.6) .delta. 8.78 (1H, s), 3.03 (2H,
t), 2.99 (2H, t), 2.10 (2H, m)
Preparation Example 264:
2-chloro-4-(cyclobutoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine
Step A: 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine
[1632] 12 mL of EtOH and 0.6 mL of concentrated HCl were added to
2-oxocyclopentancarboxylic acid methyl ester (5.2 g, 36.6 mmol) and
urea (2.42 g, 40.2 mmol), and the mixture was stirred for 3 hours
under reflux. The reaction solution was cooled to room temperature.
The formed solids were dissolved in 12 mL of 5% NaOH aqueous
solution, and the reaction solution was stirred for 2 hours under
reflux. The reaction solution was cooled to 0.degree. C. and
adjusted to pH 3. The formed solids were filtered to obtain
6,7-dihydro-5H-cyclopenta[d]pyrimidin-2,4-diol (3.34 g, 60%). This
compound was dissolved in 7 mL of phosphorus oxychloride, and the
mixture was stirred for 4 hours under reflux. The reaction solution
was cooled to room temperature. After addition of cold water, the
reaction solution was extracted with DCM to obtain the title
compound (0.98 g, 24%).
[1633] .sup.1H-NMR (CDCl.sub.3) .delta. 3.08 (2H, t), 2.99 (2H, t),
2.22 (2H, m)
Step B:
2-chloro-4-(cyclobutoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine
[1634] Cyclobutanol (0.34 g, 4.75 mmol) was dissolved in 30 mL of
THF and cooled to 0.degree. C. NaH (60 wt % in mineral oil, 0.21 g,
5.18 mmol) was added thereto, and the mixture was stirred for 30
minutes. 2,4-Dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.82
g, 4.32 mmol) obtained in Step A was dissolved in 13 mL of THF and
added thereto. The mixture was stirred at room temperature for 16
hours. After addition of water, the reaction solution was extracted
with EtOAc. The organic layer was purified by column chromatography
to obtain the title compound (0.59 g, 61%).
[1635] .sup.1H-NMR (CDCl.sub.3) .delta. 5.28 (1H, m), 2.93 (2H, m),
2.82 (2H, m), 2.48 (2H, m), 2.13 (4H, m), 1.84 (1H, m), 1.67 (1H,
m)
Preparation Example 265:
2-chloro-4-(cyclobutoxy)-5,6-dimethyl-pyrimidine
Step A: 2,4-dichloro-5,6-dimethyl-pyrimidine
[1636] 5,6-Dimethyl-1H-pyrimidin-2,4-dione (2.5 g, 17.8 mmol) was
dissolved in 12 mL of phosphorus oxychloride, and the mixture was
stirred for 4 hours under reflux. The reaction solution was cooled
to at room temperature and added to cold water. The formed
precipitate was dried to obtain the title compound (3.08 g,
98%).
[1637] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.51 (3H, s), 2.30 (3H,
s)
Step B: 2-chloro-4-(cyclobutoxy)-5,6-dimethyl-pyrimidine
[1638] Cyclobutanol (0.45 g, 6.21 mmol) was dissolved in 40 mL of
THF and cooled to 0.degree. C. NaH (60 wt % in mineral oil, 0.27 g,
6.77 mmol) was added thereto, and the mixture was stirred for 30
minutes. 2,4-Dichloro-5,6-dimethyl-pyrimidine (1.0 g, 5.64 mmol)
obtained in Step A was dissolved in 15 mL of THF and added thereto.
The mixture was stirred at room temperature for 16 hours. After
addition of water, the reaction solution was extracted with EtOAc.
The organic layer was purified by column chromatography to obtain
the title compound (0.84 g, 70%).
[1639] .sup.1H-NMR (CDCl.sub.3) .delta. 5.24 (1H, m), 2.48 (2H, m),
2.40 (3H, s), 2.13 (2H, m), 2.08 (3H, s), 1.84 (1H, m), 1.68 (1H,
m)
Preparation Example 266: (6-bromo-2-pyridyl)methanol
[1640] 6-Bromopyridin-2-carbaldehyde (1.86 g, 10.0 mmol) was
dissolved in 30 mL of MeOH and cooled to 0.degree. C. NaBH.sub.4
(0.38 g, 10.0 mmol) was slowly added thereto, and the mixture was
stirred at room temperature for 30 minutes. After addition of
water, the organic layer extracted with EtOAc was purified by
column chromatography to obtain the title compound (1.86 g,
99%).
[1641] .sup.1H-NMR (CDCl.sub.3) .delta. 7.56 (1H, t), 7.40 (1H, m),
7.28 (1H, m), 4.75 (2H, d), 3.02 (1H, t)
Preparation Example 267:
2-bromo-6-(cyclopropylmethoxymethyl)pyridine
[1642] (6-Bromo-2-pyridyl)methanol (0.376 g, 2.0 mmol) obtained in
Preparation Example 266 was dissolved in 8 mL of THF. NaH (60 wt %
in mineral oil, 0.088 g, 2.2 mmol) was added thereto, and the
mixture was stirred at room temperature for 30 minutes.
Bromomethylcyclopropane (0.297 g, 2.2 mmol) and Bu.sub.4NI (0.074
g, 0.2 mmol) were sequentially added thereto, and the mixture was
stirred at room temperature. The reaction solution was adjusted to
pH 4 by the addition of water. The organic layer extracted with DCM
was purified by column chromatography to obtain the title compound
(0.283 g. 58%).
[1643] .sup.1H-NMR (CDCl.sub.3) .delta. 7.56 (1H, t), 7.47 (1H, m),
7.37 (1H, m), 4.63 (2H, s), 3.41 (2H, d), 1.10 (1H, m), 0.56 (2H,
m), 0.24 (2H, m)
Preparation Example 268:
(6-bromo-2-pyridyl)-cyclopropyl-methanol
[1644] 6-Bromopyridin-2-carbaldehyde (0.93 g, 5.0 mmol) was
dissolved in 20 mL of THF. Cyclopropyl magnesium bromide (0.5 M in
THF, 11 mL, 5.5 mmol) was slowly added thereto, and the mixture was
stirred at room temperature for 15 minutes. After addition of
ammonium chloride aqueous solution, the organic layer extracted
with DCM was purified by column chromatography to obtain the title
compound (1.09 g, 96%).
[1645] .sup.1H-NMR (CDCl.sub.3) .delta. 7.55 (1H, t), 7.40 (1H, d),
7.37 (1H, d), 4.09 (1H, m), 3.62 (1H, d), 1.12 (1H, m), 0.55 (4H,
m)
Preparation Example 269: 2-bromo-6-(cyclobutoxymethyl)pyridine
[1646] (6-Bromo-2-pyridyl)methanol (0.38 g, 2.0 mmol) obtained in
Preparation Example 266 was dissolved in 5 mL of DCM.
2-Bromo-6-(chloromethyl)pyridine obtained by the addition of 1.2 mL
of SOCl.sub.2 and cyclobutanol (0.145 g, 2.0 mmol) were reacted in
the same manner as in Preparation Example 267 to obtain the title
compound (0.365 g, 75%).
[1647] .sup.1H-NMR (CDCl.sub.3) .delta. 7.55 (1H, t), 7.43 (1H, d),
7.38 (1H, d), 4.51 (2H, s), 4.06 (1H, m), 2.23 (2H, m), 2.00 (2H,
m), 1.73 (1H, m), 3.53 (1H, m)
Preparation Example 270: 2,6-dichloro-4-(cyclobutoxy)pyridine
[1648] 2-Chloro-6-cyclobutoxy-pyridine (0.88 g, 4.8 mmol) was
dissolved in 50 mL of DCM. mCPBA (4.45 g, 17.8 mmol) was added
thereto, and the mixture was stirred at room temperature for 3
days. The precipitate was removed by filtration, and the filtrate
was washed with 1N NaOH aqueous solution and extracted with
chloroform. The organic layer was dried with anhydrous magnesium
sulfate for concentration. 15 mL of POCl.sub.3 was added thereto,
and the mixture was stirred at 90.degree. C. for 3 hours. The
reaction solution was concentrated under reduced pressure. Cold
water and 1N NaOH aqueous solution were sequentially added thereto,
and the reaction solution was extracted with DCM. The organic layer
was dried with anhydrous magnesium sulfate and purified by column
chromatography to obtain the title compound (0.956 g, 91%).
[1649] .sup.1H-NMR (CDCl.sub.3) .delta. 6.67 (2H, s), 4.66 (1H, m),
2.46 (2H, m), 2.19 (2H, m), 1.90 (1H, m), 1.70 (1H, m)
Preparation Example 271:
2-chloro-6-(cyclobutoxy)-4-methyl-pyridine
Step A: 2-(cyclobutoxy)-4-methyl-pyridine
[1650] 2-Chloro-4-methyl-pyridine (0.89 g, 7.0 mmol) and
cyclobutanol (0.05 g, 7.0 mmol) were reacted in the same manner as
in Preparation Example 226 to obtain the title compound (0.827 g,
72%).
[1651] .sup.1H-NMR (CDCl.sub.3) .delta. 8.03 (1H, m), 6.71 (1H, m),
6.54 (1H, m), 5.19 (1H, m), 2.49 (2H, m), 2.32 (3H, s), 2.16 (2H,
m), 1.86 (1H, m), 1.70 (1H, m)
Step B: 2-chloro-6-(cyclobutoxy)-4-methyl-pyridine
[1652] 2-(Cyclobutoxy)-4-methyl-pyridine (0.0827 g, 5.07 mmol)
obtained in Step A was reacted in the same manner as in Preparation
Example 270 to obtain the title compound (0.405 g, 40%).
[1653] .sup.1H-NMR (CDCl.sub.3) .delta. 6.75 (1H, m), 6.44 (1H, m),
5.18 (1H, m), 2.49 (2H, m), 2.30 (3H, s), 2.12 (2H, m), 1.85 (1H,
m), 1.70 (1H, m)
Preparation Example 272: 2-tert-butoxy-6-chloro-pyridine
[1654] 45 mL of toluene and potassium tert-butoxide (2.77 g, 24.6
mmol) were added to 2,6-dichloropyridine (3.04 g, 20.5 mmol), and
the mixture was stirred for 24 hours under reflux.
[1655] Solids were filtered through Celite, and the filtrate was
purified by column chromatography to obtain the title compound
(1.57 g, 41%).
[1656] .sup.1H-NMR (CDCl.sub.3) .delta. 7.44 (1H, t), 6.82 (1H, d),
6.54 (1H, d), 1.58 (9H, s)
Preparation Example 273: 2-chloro-6-ethoxy-pyridine
[1657] EtOH (2.8 mL, 47 mmol) was added to 80 mL of THF, and the
mixture was cooled to 0.degree. C. Sodium (0.57 g, 25 mmol) was
slowly added thereto, and the mixture was stirred at 40.degree. C.
for 30 minutes. 2,6-Dichloropyridine (3.51 g, 23.7 mmol) was added
thereto, and the mixture was stirred at 50.degree. C. for 16 hours.
After addition of water, the reaction solution was extracted with
Et.sub.2O and purified by column chromatography to obtain the title
compound (2.27 g, 61%).
[1658] .sup.1H-NMR (CDCl.sub.3) .delta. 7.50 (1H, t), 6.87 (1H, d),
6.62 (1H, d), 4.36 (2H, q), 1.38 (3H, t)
Preparation Example 274:
2-chloro-6-(2,2,2-trifluoroethoxy)pyridine
[1659] 2,2,2-Trifluoroethanol (2.42 g, 24 mmol) was dissolved in 67
mL of THF. NaH (55 wt % in mineral oil, 1.06 g, 24 mmol) was added
thereto, and the mixture was stirred at room temperature for 45
minutes. 2,6-Dichloropyridine (3.0 g, 20 mmol) was added thereto,
and the mixture was stirred at 70.degree. C. for 16 hours. After
addition of water, the reaction solution was extracted with
Et.sub.2O and purified by column chromatography to obtain the title
compound (2.17 g, 51%).
[1660] .sup.1H-NMR (CDCl.sub.3) .delta. 7.60 (1H, t), 7.00 (1H, d),
6.79 (1H, d), 4.73 (2H, m)
Preparation Example 275:
2-chloro-6-(2,2,2-trifluoro-1-methyl-ethoxy)pyridine
[1661] 1,1,1-Trifluoro-2-propanol (2.76 g, 24 mmol) was dissolved
in 67 mL of THF. NaH (55 wt % in mineral oil, 1.06 g, 24 mmol) was
added thereto, and the mixture was stirred at room temperature for
45 minutes. 2,6-Dichloropyridine (3.0 g, 20 mmol) was added
thereto, and the mixture was stirred at 70.degree. C. for 16 hours.
After addition of water, the reaction solution was extracted with
Et.sub.2O and purified by column chromatography to obtain the title
compound (3.58 g, 79%).
[1662] .sup.1H-NMR (CDCl.sub.3) .delta. 7.57 (1H, t), 6.97 (1H, d),
6.73 (1H, d), 5.72 (1H, m), 1.50 (3H, d)
Preparation Example 276: 2-butoxy-6-chloro-pyridine
[1663] Butan-1-ol (1.87 g, 25.2 mmol) was dissolved in 50 mL of DMF
and cooled to 0.degree. C. NaH (55 wt % in mineral oil, 1.10 g,
25.2 mmol) was added thereto, and the mixture was stirred at room
temperature for 45 minutes. 2,6-dichloropyridine (3.55 g, 24.0
mmol) was added thereto, and the mixture was stirred for 16 hours.
After addition of ammonium chloride aqueous solution, the reaction
solution was extracted with Et.sub.2O and purified by column
chromatography to obtain the title compound (4.05 g, 91%).
[1664] .sup.1H-NMR (CDCl.sub.3) .delta. 7.50 (1H, t), 6.87 (1H, d),
6.63 (1H, d), 4.28 (2H, t), 1.74 (2H, m), 1.46 (2H, m), 0.97 (3H,
t)
Preparation Example 277: 2-chloro-6-cyclobutyl-pyridine
[1665] 2,6-Dichloropyridine (1.98 g, 13.4 mmol) and Fe(acac).sub.3
(0.24 g, 0.67 mmol) were dissolved in 49 mL of THF and 5 mL of NMP,
and cooled to 0.degree. C. Cyclobutylmagnesium bromide (0.9 M THF
solution, 18 mL, 16 mmol) was slowly added thereto, and the mixture
was stirred at 0.degree. C. for 6 hours. After termination of the
reaction by the addition of ammonium chloride aqueous solution, the
reaction solution was extracted with Et.sub.2O. The organic layer
was dried with anhydrous magnesiumsulfate and purified by column
chromatography to obtain the title compound (0.43 g, 19%).
[1666] .sup.1H-NMR (CDCl.sub.3) .delta. 7.54 (1H, t), 7.12 (1H, d),
7.08 (1H, d), 3.63 (1H, m), 2.33 (4H, m), 2.05 (1H, m), 1.90 (1H,
m)
Preparation Example 278:
2-bromo-6-(cyclobutylidenemethyl)pyridine
[1667] 35 mL of THF was added to
2-bromo-6-(diethoxyphosphorylmethyl)pyridine (2.2 g, 7.14 mmol),
and the mixture was cooled to 0.degree. C. LiHMDS (1.0 M THF
solution, 8.6 mL, 8.6 mmol) was added thereto, and the mixture was
stirred at 0.degree. C. for 30 minutes. Cyclobutanone (0.50 g, 7.14
mmol) was added thereto, and the mixture was stirred at room
temperature for 16 hours. After addition of ammonium chloride
aqueous solution, the reaction solution was extracted with EtOAc
and purified by column chromatography to obtain the title compound
(1.02 g, 64%).
[1668] .sup.1H-NMR (CDCl.sub.3) .delta. 7.42 (1H, t), 7.20 (1H, d),
7.04 (1H, d), 6.19 (1H, m), 3.13 (2H, m), 2.91 (2H, m), 2.14 (2H,
m)
Preparation Example 279:
2-bromo-6-(cyclopentylidenemethyl)pyridine
[1669] 35 mL of THF was added to
2-bromo-6-(diethoxyphosphorylmethyl)pyridine (2.2 g, 7.14 mmol),
and the mixture was cooled to 0.degree. C. LiHMDS (1.0 M THF
solution, 8.6 mL, 8.6 mmol) was added thereto, and the mixture was
stirred at 0.degree. C. for 30 minutes. Cyclopentanone (0.6 g, 7.14
mmol) was added thereto, and the mixture was stirred at room
temperature for 16 hours. After addition of ammonium chloride
aqueous solution, the reaction solution was extracted with EtOAc
and purified by column chromatography to obtain the title compound
(1.17 g, 69%).
[1670] .sup.1H-NMR (CDCl.sub.3) .delta. 7.43 (1H, t), 7.20 (1H, d),
7.13 (1H, d), 6.41 (1H, m), 2.73 (2H, m), 2.52 (2H, m), 1.81 (2H,
m), 1.68 (2H, m)
Preparation Example 280: 1-bromo-3-(cyclopropylmethoxy)benzene
[1671] 3-Bromophenol (0.865 g, 5.0 mmol) and
bromomethylcyclopropane (1.01 g, 7.5 mmol) were reacted in the same
manner as in Preparation Example 12 to obtain the title compound
(1.09 g, 96%).
[1672] .sup.1H-NMR (CDCl.sub.3) .delta. 7.13 (1H, m), 7.06 (2H, m),
6.88 (1H, m), 3.82 (2H, d), 1.28 (1H, m), 0.65 (2H, m), 0.35 (2H,
m)
Preparation Example 281: 1-bromo-3-(cyclobutoxy)benzene
[1673] 3-Bromophenol (0.865 g, 5.0 mmol) and bromocyclobutane (1.01
g, 7.5 mmol) were reacted in the same manner as in Preparation
Example 12 to obtain the title compound (1.04 g, 91%).
[1674] .sup.1H-NMR (CDCl.sub.3) .delta. 7.10 (1H, t), 7.05 (1H, m),
6.95 (1H, m), 6.74 (1H, m), 4.60 (1H, m), 2.44 (2H, m), 2.14 (2H,
m), 1.85 (1H, m), 1.69 (1H, m)
Preparation Example 282:
4-bromo-2-(cyclopropylmethoxy)-1-methoxy-benzene
[1675] 20 mL of DMF was added to 5-bromo-2-methoxy-phenol (1.8 g,
8.87 mmol), bromomethylcyclopropane (1.44 g, 10.7 mmol),
K.sub.2CO.sub.3 (1.84 g, 13.3 mmol) and Bu.sub.4NI (0.33 g, 0.88
mmol), and the mixture was stirred at 80.degree. C. After
termination of the reaction, the reaction solution was cooled to
room temperature. After addition of water, the reaction solution
was extracted with EtOAc. The organic layer was dried with
anhydrous magnesium sulfate and purified by column chromatography
to obtain the title compound (2.21 g, 97%).
[1676] .sup.1H-NMR (CDCl.sub.3) .delta. 7.02 (1H, m), 6.97 (1H, d),
6.74 (1H, d), 3.85 (3H, s), 3.82 (2H, d), 1.33 (1H, m), 0.65 (2H,
m), 0.35 (2H, m)
Preparation Example 283:
4-bromo-2-(cyclopropylmethoxy)-1-fluoro-benzene
[1677] 5-Bromo-2-fluoro-phenol (0.955 g, 5.0 mmol) and
bromomethylcyclopropane (0.81 g, 6.0 mmol) were reacted in the same
manner as in Preparation Example 12 to obtain the title compound
(1.22 g, 99%).
[1678] .sup.1H-NMR (CDCl.sub.3) .delta. 7.06 (1H, m), 6.95 (2H, m),
3.85 (2H, d), 1.30 (1H, m), 0.66 (2H, m), 0.36 (2H, m)
Preparation Example 284:
1-bromo-3-(cyclobutoxy)-5-fluoro-benzene
[1679] 3-Bromo-5-fluoro-phenol (0.955 g, 5.0 mmol) and
bromocyclobutane (0.81 g, 6.0 mmol) were reacted in the same manner
as in Preparation Example 12 to obtain the title compound (1.19 g,
97%).
[1680] .sup.1H-NMR (CDCl.sub.3) .delta. 6.84 (1H, m), 6.76 (1H, m),
6.46 (1H, m), 4.57 (1H, m), 2.44 (2H, m), 2.15 (2H, m), 1.88 (1H,
m), 1.70 (1H, m)
Preparation Example 285: 1-bromo-3-cyclobutylsulfonyl-benzene
[1681] 20 mL of THF and 20 mL of MeOH were added to
1-bromo-3-cyclobutylsulfanyl-benzene (0.73 g, 3.0 mmol) obtained in
Preparation Example 293. Oxone (9.2 g, 30 mmol) dissolved in 40 mL
of water was added thereto, and the mixture was stirred at room
temperature for 5 hours. After termination of the reaction, water
was added thereto, and the reaction solution was extracted with
EtOAc. The organic layer was dried with anhydrous magnesium sulfate
and purified by column chromatography to obtain the title compound
(0.81 g, 98%).
[1682] .sup.1H-NMR (CDCl.sub.3) .delta. 8.01 (1H, d), 7.79 (2H, m),
7.44 (1H, t), 3.85 (1H, m), 2.60 (2H, m), 2.20 (2H, m), 1.98 (2H,
m)
Preparation Example 286: 1-bromo-3-(isopropoxymethyl)benzene
[1683] 10 mL of 2-propanol and iron(II) sulfate heptahydrate (2.78
g, 6 mmol) were added to 1-bromo-3-(bromomethyl)benzene (2.5 g, 10
mmol), and the mixture was stirred for 36 hours under reflux.
Solids were filtered through Celite and purified by column
chromatography to obtain the title compound (1.5 g, 65%).
[1684] .sup.1H-NMR (CDCl.sub.3) .delta. 7.50 (1H, m), 7.39 (1H, m),
7.27 (1H, m), 7.19 (1H, t), 4.47 (2H, s), 3.67 (1H, m), 1.22 (6H,
d)
Preparation Example 287: 1-bromo-3-(ethoxymethyl)benzene
[1685] 10 mL of EtOH and iron(II) sulfate heptahydrate (2.78 g, 6
mmol) were added to 1-bromo-3-(bromomethyl)benzene (2.5 g, 10 mmol)
and the mixture was stirred for 36 hours under reflux. Solids were
filtered through Celite and purified by column chromatography to
obtain the title compound (1.54 g, 71%).
[1686] .sup.1H-NMR (CDCl.sub.3) .delta. 7.50 (1H, m), 7.40 (1H, m),
7.26 (1H, m), 7.21 (1H, t), 4.47 (2H, s), 3.53 (2H, q), 1.26 (3H,
t)
Preparation Example 288:
1-bromo-3-(cyclobutoxy)-2-methyl-benzene
Step A: 3-bromo-2-methyl-phenol
[1687] 31 mL of 1N sulfuric acid aqueous solution was added to
3-bromo-2-methyl-aniline (4.04 g, 21.7 mmol), and the mixture was
cooled to 0.degree. C. Sodium nitrite (6.0 M aqueous solution, 4.3
mL) was slowly added thereto. After 15 minutes, 10 mL of sulfuric
acid was added thereto, and the mixture was stirred for 1 hour
under reflux. The reaction solution was cooled to room temperature.
After addition of water, the reaction solution was extracted with
Et.sub.2O. The organic layer was dried with anhydrous magnesium
sulfate and purified by column chromatography to obtain the title
compound (2.34 g, 58%).
[1688] .sup.1H-NMR (CDCl.sub.3) .delta. 7.14 (1H, d), 6.92 (1H, t),
6.71 (1H, d), 4.83 (1H, brs), 2.34 (3H, s)
Step B: 1-bromo-3-(cyclobutoxy)-2-methyl-benzene
[1689] 3-Bromo-2-methyl-phenol (0.2 g, 1 mmol) obtained in Step A
was dissolved in 3.6 mL of DMF. Bromocyclobutane (0.17 g, 1.28
mmol) and Cs.sub.2CO.sub.3 (0.7 g, 2.14 mmol) were added thereto,
and the mixture was stirred at 50.degree. C. for 24 hours. The
reaction solution was concentrated under reduced pressure and
purified by column chromatography to obtain the title compound (0.2
g, 83%).
[1690] .sup.1H-NMR (CDCl.sub.3) .delta. 7.12 (1H, d), 6.95 (1H, t),
6.61 (1H, d), 4.60 (1H, m), 2.44 (2H, m), 2.30 (3H, s), 2.16 (2H,
m), 1.86 (1H, m), 1.69 (1H, m)
Preparation Example 289: 4-bromo-2-(cyclobutoxy)thiazole
[1691] Cyclobutanol (0.065 g, 0.9 mmol) was dissolved in 8 mL of
THF. NaH (55 wt % in mineral oil, 0.04 g, 0.9 mmol) was added
thereto, and the mixture was stirred at room temperature for 30
minutes. 2,4-Dibromothiazole (0.2 g, 0.82 mmol) was added thereto,
and the mixture was stirred for 16 hours. After addition of
ammonium chloride aqueous solution, the reaction solution was
extracted with EtOAc and purified by column chromatography to
obtain the title compound (0.13 g, 68%).
[1692] .sup.1H-NMR (CDCl.sub.3) .delta. 6.56 (1H, s), 5.17 (1H, m),
2.48 (2H, m), 2.20 (2H, m), 1.84 (1H, m), 1.65 (1H, m)
Preparation Example 290: 4-bromo-2-(cyclopropylmethoxy)thiazole
[1693] Cyclopropylmethanol (0.14 g, 2.0 mmol) was dissolved in 16
mL of THF. NaH (55 wt % in mineral oil, 0.086 g, 2.0 mmol) was
added thereto, and the mixture was stirred at room temperature for
30 minutes. 2,4-Dibromothiazole (0.4 g, 1.64 mmol) was added
thereto, and the mixture was stirred for 24 hours. After addition
of ammonium chloride aqueous solution, the reaction solution was
extracted with Et.sub.2O and purified by column chromatography to
obtain the title compound (0.23 g, 60%).
[1694] .sup.1H-NMR (CDCl.sub.3) .delta. 6.57 (1H, s), 4.25 (2H, d),
1.30 (1H, m), 0.65 (2H, m), 0.37 (2H, m)
Preparation Example 291:
4-bromo-3-(cyclopropylmethoxymethyl)-5-methyl-isoxazole
Step A: 3-(cyclopropylmethoxymethyl)-5-methyl-isoxazole
[1695] 5-Methylisoxazol-3-carboxylic acid methyl ester (1.5 g, 10.5
mmol) was dissolved in 27 mL of EtOH. NaBH.sub.4 (0.8 g, 21 mmol)
was slowly added thereto, and the mixture was stirred at room
temperature for 16 hours. The reaction solution was neutralized by
the addition of HCl aqueous solution, extracted with EtOAc and
dried with anhydrous magnesium sulfate for concentration. The
obtained concentrate was dissolved in 20 mL of DCM. 1.4 mL of
SOCl.sub.2 was added thereto, and the mixture was stirred at room
temperature for 16 hours and concentrated. The mixed solution of
cyclopropylmethanol (0.31 g, 4.2 mmol), NaH (55 wt % in mineral
oil, 0.19 g, 4.2 mmol) and DMF (20 mL) was added thereto, and the
mixture was stirred at room temperature for 72 hours. The reaction
solution was concentrated under reduced pressure. After addition of
ammonium chloride aqueous solution, the reaction solution was
extracted with EtOAc and purified by column chromatography to
obtain the title compound (0.074 g, 4%).
[1696] .sup.1H-NMR (CDCl.sub.3) .delta. 6.05 (1H, s), 4.56 (2H, s),
3.31 (2H, d), 2.42 (3H, s), 1.07 (1H, m), 0.55 (2H, m), 0.21 (2H,
m)
Step B: 4-bromo-3-(cyclopropylmethoxymethyl)-5-methyl-isoxazole
[1697] 3-(Cyclopropylmethoxymethyl)-5-methyl-isoxazole (0.074 g,
0.44 mmol) obtained in Step A was dissolved in 1.5 mL of DMF.
N-bromosuccinimide (0.078 g, 0.44 mmol) was added thereto, and the
mixture was stirred at room temperature for 48 hours. The reaction
solution was concentrated under reduced pressure. After addition of
water, the reaction solution was extracted with Et.sub.2O and
purified by column chromatography to obtain the title compound
(0.069 g, 55%).
[1698] .sup.1H-NMR (CDCl.sub.3) .delta. 4.57 (2H, s), 3.35 (2H, d),
2.42 (3H, s), 1.10 (1H, m), 0.54 (2H, m), 0.23 (2H, m)
Preparation Example 292:
4-bromo-5-(cyclobutoxy)-3-methyl-isothiazole
[1699] Cyclobutanol (0.32 g, 4.4 mmol) and
4,5-dibromo-3-methyl-isothiazole (1.03 g, 4.0 mmol, WO2013
132376A1) were reacted in the same manner as in Preparation Example
226 to obtain the title compound (0.120 g, 12%).
[1700] .sup.1H-NMR (CDCl.sub.3) .delta. 4.68 (1H, m), 2.52 (2H, m),
2.45 (3H, s), 2.35 (2H, m), 1.94 (1H, m), 1.72 (1H, m)
Preparation Example 293: 1-bromo-3-cyclobutylsulfanyl-benzene
[1701] 3-Bromo-benzenethiol (3 g, 15.87 mmol) and bromocyclobutane
(2.25 mL, 23.80 mmol) were reacted in the same manner as in
Preparation Example 17 to obtain the title compound (3.36 g,
87%).
[1702] .sup.1H-NMR (CDCl.sub.3) .delta. 7.33 (1H, s), 7.26 (1H, m),
7.12 (2H, m), 3.89 (1H, m), 2.47 (2H, m), 2.07 (3H, m), 2.04 (1H,
m).
Preparation Example 294:
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine
[1703] 4-Bromo-phenylamine (1 g, 5.81 mmol), bis(pinacolato)diboron
(1.6 g, 6.39 mmol) and potassium acetate (1.43 g, 14.53 mmol) were
dissolved in 20 mL of 1,4-dioxane and charged with N.sub.2 gas for
5 minutes. PdCl.sub.2(dppf)-DCM (0.425 g, 0.58 mmol) was added
thereto, and the mixture was stirred at 80.degree. C. for 16 hours.
The reaction solution was filtered through Celite, diluted with
water and extracted with ethyl acetate. The organic layer was dried
with anhydrous magnesiumsulfate and purified by column
chromatography to obtain the title compound (0.764 g, 60%).
[1704] .sup.1H-NMR (CDCl.sub.3) .delta. 7.60 (2H, d), 6.66 (2H, d),
3.82 (2H, br), 1.31 (12H, s).
Preparation Example 295:
4-(6-cyclobutoxy-pyridin-2-yl)-phenylamine
[1705] 2-Bromo-6-cyclobutoxy-pyridine (0.251 g, 1.37 mmol) obtained
in Preparation Example 186 and
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (0.2
g, 0.91 mmol) obtained in Preparation Example 294 were reacted in
the same manner as in Step A of Example 1 to obtain the title
compound (0.17 g, 77%).
[1706] .sup.1H-NMR (CDCl.sub.3) .delta. 7.85 (2H, d), 7.55 (1H, t),
7.21 (1H, d), 6.72 (2H, d), 6.51 (1H, d), 5.26 (1H, m), 3.79 (2H,
br), 2.51 (2H, m), 2.18 (2H, m), 1.86 (1H, m), 1.72 (1H, m).
Preparation Example 296:
4-(6-cyclobutoxy-pyridin-2-yl)-phenyl]-[3-(4-methoxy-phenoxy)-isoxazol-5--
ylmethyl]-amine
[1707] 4-(6-Cyclobutoxy-pyridin-2-yl)-phenylamine (0.17 g, 0.71
mmol) obtained in Preparation Example 295 and
3-[(4-methoxyphenyl)methoxy]isoxazol-5-carbaldehyde (0.122 g, 0.71
mmol) obtained in Preparation Example 61 were dissolved in 2.3 mL
of DCE. Sodium triacetoxyborohydride (0.225 g, 1.06 mmol) was added
thereto, and the mixture was stirred at room temperature for 16
hours. After addition of sodium bicarbonate aqueous solution, the
reaction solution was extracted with DCM and purified by column
chromatography. The obtained compound was dissolved in 2 ml of
methanol. NaBH.sub.4 (0.053 g, 1.41 mmol) was added thereto, and
the mixture was stirred at room temperature for 16 hours. The
reaction solution was diluted with water and extracted with ethyl
acetate. The organic layer was dried with anhydrous
magnesiumsulfate and purified by column chromatography to obtain
the title compound (0.1 g, 30%).
[1708] .sup.1H-NMR (CDCl.sub.3) .delta. 7.87 (2H, d), 7.54 (1H, t),
7.34 (2H, d), 7.20 (1H, d), 6.90 (2H, d), 6.69 (2H, d), 6.53 (1H,
d), 5.81 (1H, s), 5.25 (1H, m), 4.40 (2H, d), 3.80 (3H, s), 2.52
(2H, m), 2.18 (2H, m), 1.83 (1H, m), 1.72 (1H, m).
Preparation Example 297: 1-bromo-3-(cyclopentoxy)benzene
[1709] The title compound was obtained by the method disclosed in
WO 2014/209034 A1.
[1710] .sup.1H NMR (CDCl.sub.3) .delta. 7.11 (1H, t), 7.02 (2H, m),
6.80 (1H, dd), 4.72 (1H, m), 1.94-1.73 (6H, m), 1.62 (2H, m)
Preparation Example 298: 3,6-dichloro-2-cyclobutoxy-pyridine
Step A: 6-chloro-2-cyclobutoxy-3-nitro-pyrimidine
[1711] 2,6-Dichloro-3-nitro-pyrimidine (1.93 g, 10.0 mmol) and
cyclobutanol (0.645 g, 9.0 mmol) were reacted in the same manner as
in Preparation Example 227 to obtain the title compound (1.92 g,
93%).
[1712] .sup.1H-NMR (CDCl.sub.3) .delta. 8.27 (1H, d), 7.04 (2H, t),
5.39 (1H, m), 2.56 (2H, m), 2.30 (2H, m), 1.93 (1H, m), 1.78 (1H,
m)
Step B: 3,6-dichloro-2-cyclobutoxy-pyrimidine
[1713] Methanol (60 mL) was added to nickel(II) chloride
hexahydrate (NiCl.sub.2 6H.sub.2O)(1.0 g, 4.21 mmol), and sodium
borohydride (0.30 g, 7.93 mmol) was then added thereto little by
little. The mixture was stirred for 30 minutes, and
6-chloro-2-cyclobutoxy-3-nitro-pyrimidine (1.92 g, 8.40 mmol)
obtained in Step A was added thereto. Sodium borohydride (0.65 g,
17.2 mmol) was slowly added thereto for 10 minutes, and the mixture
was stirred for 30 minutes. The reaction product was filtered
through Celite, and the filtrate was concentrated under reduced
pressure and extracted with water and EtOAc. The organic layer was
dried with anhydrous magnesiumsulfate and purified by column
chromatography to obtain 6-chloro-2-cyclobutoxy-pyridin-3-ylamine
(1.37 g, 82%).
[1714] 6-Chloro-2-cyclobutoxy-pyridin-3-ylamine (0.60 g, 3.0 mmol),
copper chloride(II) (0.484 g, 3.6 mmol) and tBuONO (0.464 g, 4.5
mmol) were reacted in the same manner as in Step C of Preparation
Example 84 to obtain the title compound (0.341 g, 52%).
[1715] .sup.1H-NMR (CDCl.sub.3) .delta. 7.58 (1H, d), 6.87 (1H, d),
5.26 (1H, m), 2.53 (2H, m), 2.24 (2H, m), 1.88 (1H, m), 1.74 (1H,
m)
Preparation Example 299: 2-chloro-6-cyclobutylsulfanyl-pyridine
[1716] The title compound was obtained by the method disclosed in
WO 2014/209034 A1.
[1717] .sup.1H NMR (CDCl.sub.3) .delta. 7.40 (1H, t), 6.98 (2H, m),
4.30 (1H, m), 2.56 (2H, m), 2.08 (4H, m)
Preparation Example 300:
2-chloro-6-cyclopropylmethoxy-4-methyl-pyridine
[1718] Cyclopropylmethanol (0.979 g, 13.58 mmol) and
2,6-dichloro-4-methyl-pyridine (2 g, 12.34 mmol) were reacted in
the same manner as in Preparation Example 226 to obtain the title
compound (1.62 g, 66%).
[1719] .sup.1H-NMR (CDCl.sub.3) .delta. 6.75 (1H, s), 6.43 (1H, s),
5.18 (1H, m), 2.48 (2H, m), 2.30 (3H, s), 2.14 (2H, m), 1.84 (1H,
m), 1.68 (1H, m).
Preparation Example 301: 2-chloro-6-isopropoxy-pyrazine
[1720] Isopropanol (1.85 ml, 24.16 mmol) and 2,6-dichloropyrazine
(3 g, 20.13 mmol) were reacted in the same manner as in Preparation
Example 226 to obtain the title compound (2.77 g, 79%).
[1721] .sup.1H-NMR (CDCl.sub.3) .delta. 8.04-8.09 (2H, d), 5.28
(1H, m), 1.36 (6H, d).
Preparation Example 302: 2-chloro-6-ethoxy-pyrazine
[1722] Ethanol (1.17 ml, 24.16 mmol) and 2,6-dichloropyrazine (3 g,
20.13 mmol) were reacted in the same manner as in Preparation
Example 226 to obtain the title compound (2.63 g, 82%).
[1723] .sup.1H-NMR (CDCl.sub.3) .delta. 8.12 (2H, d), 4.39 (2H, q),
1.40 (3H, t).
Preparation Example 303:
{(R)-1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phe-
nyl]-pyrrolidin-3-yl}-acetic Acid Methyl Ester
Step A: 2-((R)-1-tert-butoxycarbonyl-pyrrolidin-3-yl)-malonic Acid
Diethyl Ester
[1724] (R)-3-hydroxy-pyrrolidin-1-carboxylic acid tert-butyl ester
(1 g, 5.34 mmol) was dissolved in 18 mL of MC. Et.sub.3N (2.22 ml,
16.02 mmol) was added thereto at 0.degree. C., and MsCl (0.62 ml,
8.01 mmol) was then added thereto. The mixture was stirred at room
temperature for 16 hours. The reaction solution was diluted with
water and extracted with MC. The organic layer was dried with
anhydrous magnesiumsulfate and purified by column chromatography to
obtain (R)-3-methanesulfonyloxy-pyrrolidin-1-carboxylic acid
tert-butyl ester. At another flask, diethyl malonate (1.7 ml, 11.3
mmol) was dissolved in 10 ml of ethanol. NaOEt (21% wt, 4.2 ml,
11.3 mmol) was added thereto, and the mixture was stirred at
40.degree. C. for 1 hour. The obtained
(R)-3-methanesulfonyloxy-pyrrolidin-1-carboxylic acid tert-butyl
ester (1.5 g, 5.65 mmol) was dissolved in 8 ml of ethanol and added
thereto. The mixture was stirred at 80.degree. C. for 16 hours. The
reaction solution was adjusted to pH 2 by the use of 6N HCl aqueous
solution and extracted with ether. The organic layer was dried with
anhydrous magnesiumsulfate and purified by column chromatography to
obtain the title compound (0.785 g, 44%).
[1725] .sup.1H-NMR (CDCl.sub.3) .delta. 4.21 (4H, m), 3.63 (1H, m),
3.47 (1H, m), 3.25 (2H, m), 3.01 (1H, m), 2.80 (1H, m), 2.06 (1H,
m), 1.62 (1H, m), 1.42 (9H, s), 1.26 (6H, m).
Step B: (R)-3-carboxymethyl-pyrrolidin-1-carboxylic Acid Tert-Butyl
Ester
[1726] 2-((R)-1-tert-butoxycarbonyl-pyrrolidin-3-yl)-malonic acid
diethyl ester (0.785 g, 2.38 mmol) obtained in Step A was dissolved
in 8 mL of THF. 6N NaOH (2 ml, 11.9 mmol) was added thereto, and
the mixture was stirred at 40.degree. C. for 16 hours. The reaction
solution was adjusted to pH 2 by the use of 6N HCl aqueous solution
and extracted with EtOAc. The organic layer was dried with
anhydrous magnesiumsulfate and concentrated under reduced pressure
to obtain 2-((R)-1-tert-butoxycarbonyl-pyrrolidin-3-yl)-malonic
acid. The obtained compound was dissolved in 4.5 ml of toluene.
0.06 ml of DMSO was added thereto, and the mixture was stirred for
4 hours under reflux. After addition of 10% citric acid, the
reaction solution was extracted with EtOAc. The organic layer was
dried with anhydrous magnesiumsulfate and purified by column
chromatography to obtain the title compound (0.29 g, 53%).
[1727] .sup.1H-NMR (CDCl.sub.3) .delta. 3.62 (1H, m), 3.45 (1H, m),
3.29 (1H, m), 2.96 (1H, m), 2.56 (1H, m), 2.44 (2H, d), 2.07 (1H,
m), 1.57 (1H, m), 1.44 (9H, s).
Step C: (R)-1-(2,6-difluoro-4-nitro-phenyl)-pyrrolidin-3-yl]-Acetic
Acid Methyl Ester
[1728] (R)-3-carboxymethyl-pyrrolidin-1-carboxylic acid tert-butyl
ester (0.29 g, 1.26 mmol) obtained in Step B was dissolved in 10 ml
of MC. 0.25 M CH.sub.2N.sub.2 (10 ml, 2.53 mmol) was was added
thereto at 0.degree. C., and the mixture was stirred at room
temperature for 3 hours. The reaction solution was concentrated
under reduced pressure to obtain
(R)-3-methoxycarbonylmethyl-pyrrolidin-1-carboxylic acid tert-butyl
ester. The obtained compound was dissolved in 5 ml of MC. HCl (1.58
mL, 6.32 mmol, 4 M 1,4-dioxane solution) was added thereto at
0.degree. C., and the mixture was stirred at room temperature for 2
hours. The reaction solution was concentrated under reduced
pressure to obtain hydrochloric acid salt of
(R)-pyrrolidin-3-yl-acetic acid methyl ester. The obtained compound
and 3,4,5-trifluoronitrobenzene (0.163 ml, 1.42 mmol) were reacted
in the same manner as in Step A of Preparation Example 84 to obtain
the title compound (0.38 g, 98%).
[1729] .sup.1H-NMR (CDCl.sub.3) .delta. 7.73 (2H, m), 3.91-3.75
(3H, m), 3.71 (3H, s), 3.48 (1H, m), 2.64 (1H, m), 2.48 (2H, m),
2.18 (1H, m), 1.65 (1H, m).
Step D:
[(R)-1-(4-amino-2,6-difluoro-phenyl)-pyrrolidin-3-yl]-acetic Acid
Methyl Ester
[1730] (R)-1-(2,6-difluoro-4-nitro-phenyl)-pyrrolidin-3-yl]-acetic
acid methyl ester (0.38 g, 1.26 mmol) obtained in Step C was
dissolved in 4 mL of EtOAc. 0.04 g of 10 wt % Pd/C was added
thereto, and the mixture was stirred for 24 hours under hydrogen
atmosphere. Solids were filtered and concentrated under reduced
pressure to obtain the title compound (0.315 g, 92%).
[1731] .sup.1H-NMR (CDCl.sub.3) .delta. 6.17 (2H, m), 3.66 (3H, s),
3.41 (1H, m), 3.28 (2H, m), 2.98 (1H, m), 2.66 (1H, m), 2.45 (2H,
m), 2.13 (1H, m), 1.60 (1H, m).
Step E:
[(R)-1-(4-bromo-2,6-difluoro-phenyl)-pyrrolidin-3-yl]-acetic Acid
Methyl Ester
[1732] [(R)-1-(4-amino-2,6-difluoro-phenyl)-pyrrolidin-3-yl]-acetic
acid methyl ester (0.315 g, 1.16 mmol) obtained in Step D was
dissolved in 3 mL of CH.sub.3CN. CSA (0.345 g, 1.40 mmol),
tert-butyl nitrite (0.166 mL, 1.40 mmol), TBAB (0.751 g, 2.33 mmol)
and CuBr.sub.2 (0.003 g, 0.01 mmol) were added thereto, and the
mixture was stirred at room temperature for 16 hours. Solids were
filtered and concentrated under reduced pressure. After addition of
water, the reaction solution was extracted with EtOAc. The organic
layer was dried with anhydrous magnesiumsulfate and purified by
column chromatography to obtain the title compound (0.2 g,
51%).
[1733] .sup.1H-NMR (CDCl.sub.3) .delta. 6.93 (2H, m), 3.68 (3H, s),
3.59 (2H, m), 3.47 (1H, m), 3.23 (1H, m), 2.61 (1H, m), 2.45 (2H,
m), 2.11 (1H, m), 1.59 (1H, m).
Step F:
{(R)-1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2--
yl)-phenyl]-pyrrolidin-3-yl}-acetic Acid Methyl Ester
[1734] [(R)-1-(4-bromo-2,6-difluoro-phenyl)-pyrrolidin-3-yl]-acetic
acid methyl ester (0.225 g, 0.67 mmol) obtained in Step E was
reacted in the same manner as in Preparation Example 294 to obtain
the title compound (0.09 g, 33%).
[1735] .sup.1H-NMR (CDCl.sub.3) .delta. 7.16 (2H, m), 3.71 (5H, m),
3.60 (1H, m), 3.32 (1H, m), 2.61 (1H, m), 2.44 (2H, d), 2.11 (1H,
m), 1.61 (1H, m), 1.30 (12H, s)
Preparation Example 304:
3-[8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiochroman-2--
yl]propanoic Acid Ethyl Ester
Step A: 4-bromo-2-fluoro-benzenethiol
[1736] The title compound was obtained by the method disclosed in
WO 2006/21759 A1.
[1737] .sup.1H NMR (CDCl.sub.3) .delta. 7.24 (2H, m), 7.16 (2H, m),
3.58 (1H, s)
Step B: 6-bromo-8-fluoro-4-oxo-thiochroman-2-carboxylic Acid
[1738] 4-Bromo-2-fluoro-benzenethiol (3.0 g, 14.48 mmol) and
furan-2,5-dione (1.4 g, 14.48 mmol) were dissolved in 50 mL of
toluene and heated to 50.degree. C. TEA (0.1 ml) was slowly added
thereto, and the mixture was stirred at 50.degree. C. for 1 hour.
The reaction solution was concentrated under reduced pressure,
dissolved in 50 mL of DCM and cooled to 0.degree. C. AlCl.sub.3
(2.9 g, 21.73 mmol) was added thereto, and the mixture was stirred
at room temperature for 1 hour. After slowly adding cold
concentrated HCl solution dropwise, the reaction solution was
extracted with DCM. The organic solvent was dried with MgSO.sub.4,
concentrated under reduced pressure and solidified with Et.sub.2O
to obtain the title compound (2.3 g, 52%).
[1739] .sup.1H-NMR (DMSO-d.sub.6) .delta. 7.89 (2H, m), 4.55 (1H,
t), 3.14 (2H, m)
Step C: 6-bromo-8-fluoro-4-oxo-thiochroman-2-carboxylic Acid Methyl
Ester
[1740] 6-Bromo-8-fluoro-4-oxo-thiochroman-2-carboxylic acid (2.3 g,
7.54 mmol) obtained in Step B was dissolved in 50 mL of methanol.
Concentrated sulfuric acid (0.8 mL) was added thereto, and the
mixture was stirred for 18 hours under reflux. The reaction
solution was concentrated under reduced pressure, extracted with
EtOAc, dried with MgSO.sub.4 and purified by column chromatography
to obtain the title compound (1.5 g, 62%).
[1741] .sup.1H-NMR (CDCl.sub.3) .delta. 8.08 (1H, m), 7.37 (1H,
dd), 4.15 (1H, t), 3.76 (3H, s), 3.18 (2H, d)
Step D: 6-bromo-8-fluoro-thiochroman-2-carboxylic Acid Methyl
Ester
[1742] 6-Bromo-8-fluoro-4-oxo-thiochroman-2-carboxylic acid methyl
ester (1.5 g, 4.70 mmol) obtained in Step C was dissolved in 20 mL
of TFA. Triethylsilane (1.5 mL, 9.40 mmol) was added thereto, and
the mixture was stirred at room temperature for 3 hours. The
reaction solution was concentrated under reduced pressure,
extracted with EtOAc, dried with MgSO.sub.4 and purified by column
chromatography to obtain the title compound (0.34 g, 24%).
[1743] .sup.1H-NMR (CDCl.sub.3) .delta. 7.06 (2H, m), 4.01 (1H, m),
3.78 (3H, s), 3.01-2.93 (1H, m), 2.84-2.77 (1H, m), 2.34-2.20 (2H,
m)
Step E: 6-bromo-8-fluoro-thiochroman-2-carboxylic Acid
[1744] 6-Bromo-8-fluoro-thiochroman-2-carboxylic acid methyl ester
(0.340 g, 1.11 mmol) obtained in Step D was dissolved in each 5 mL
of THF, MeOH and 1N NaOH aqueous solution, and the mixture was
stirred at room temperature for 2 hours. After removing of organic
solvent, the reaction solution was adjusted to pH 3 by the use of
1N HCl aqueous solution and extracted with EtOAc to separate an
organic layer. The organic layer was dried with MgSO.sub.4 and
concentrated under reduced pressure to obtain the title compound
(0.280 g, 86%).
Step F: (6-bromo-8-fluoro-thiochroman-2-yl)-methanol
[1745] 6-Bromo-8-fluoro-thiochroman-2-carboxylic acid (0.28 g, 0.96
mmol) obtained in Step E was dissolved in 10 mL of THF and cooled
to -20.degree. C. Isobutyl chloroformate (0.14 mL, 1.06 mmol) and
NMM (0.12 mL, 1.10 mmol) was added thereto, and the mixture was
stirred at the same temperature for 1.5 hours. At another reactor,
NaBH.sub.4 (0.073 g, 1.92 mmol) was dissolved in 4 mL of THF and 1
mL of MeOH and cooled to -78.degree. C. The above reaction solution
was filtered through Celite and added thereto. The mixture was
stirred at room temperature for 2 hours. The reaction solution was
extracted with EtOAc, dried with MgSO.sub.4 and purified by column
chromatography to obtain the title compound (0.175 g, 66%).
[1746] .sup.1H-NMR (CDCl.sub.3) .delta. 7.06 (2H, m), 3.77 (2H, m),
3.49 (1H, m), 2.90-2.73 (2H, m), 2.22 (1H, m), 1.88 (2H, m)
Step G: (E)-3-(6-bromo-8-fluoro-thiochroman-2-yl)prop-2-enoic Acid
Ethyl Ester
[1747] Oxalyl chloride (0.1 mL, 0.95 mmol) was added to 5 mL of DCM
and cooled to -78.degree. C. DMSO (0.11 ml, 1.57 mmol) was slowly
added thereto, and the mixture was stirred for 0.5 hour. The
solution in which (6-bromo-8-fluoro-thiochroman-2-yl)-methanol
(0.175 g, 0.63 mmol) obtained in Step F was dissolved in 2 mL of
DCM, and TEA (0.35 mL, 2.52 mmol) were sequentially added thereto,
and the mixture was stirred at room temperature for 1 hour.
(Carbethoxymethylene)triphenylphosphorane (0.263 g, 0.76 mmol) was
added thereto, and the mixture was stirred at room temperature for
18 hours. After addition of water, the reaction solution was
extracted with DCM to separate an organic layer. The organic layer
was dried with MgSO.sub.4 and purified by column chromatography to
obtain the title compound (0.180 g, 83%).
[1748] .sup.1H-NMR (CDCl.sub.3) .delta. 7.06 (2H, m), 6.91 (1H, m),
6.03 (1H, d), 4.19 (2H, q), 4.01 (1H, m), 2.82 (2H, m), 2.28 (1H,
m), 1.95 (1H, m), 1.28 (3H, t)
Step H: 3-(6-bromo-8-fluoro-thiochroman-2-yl)propanoic Acid Ethyl
Ester
[1749] (E)-3-(6-bromo-8-fluoro-thiochroman-2-yl)-acetic acid ethyl
ester (0.180 g, 0.52 mmol) obtained in Step G was dissolved in 10
mL of DME. p-Toluenesulfonyl hydrazide (0.680 g, 3.65 nmol) was
added thereto little by little and heated to 90.degree. C. Sodium
acetate (0.427 g, 5.20 mmol, 1.4 M aqueous solution) was added
thereto, and the mixture was stirred for 18 hours under reflux.
After addition of water, the reaction solution was extracted with
DCM. The organic layer was dried with MgSO.sub.4 and purified by
column chromatography to obtain the title compound (0.030 g,
17%).
[1750] .sup.1H-NMR (CDCl.sub.3) .delta. 7.02 (2H, m), 4.14 (2H, q),
3.29 (1H, m), 2.83 (2H, m), 2.49 (2H, m), 2.21 (1H, m), 2.03 (1H,
m), 1.94 (1H, m), 1.78 (1H, m), 1.25 (3H, t)
Step I:
3-[8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiochr-
oman-2-yl]propanoic Acid Ethyl Ester
[1751] 3-(6-Bromo-8-fluoro-thiochroman-2-yl)-propionic acid ethyl
ester (0.070 mg, 0.21 mmol) obtained in Step H was reacted in the
same manner as in Step D of Preparation Example 1 to obtain the
title compound (0.046 g, 57%).
[1752] .sup.1H-NMR (CDCl.sub.3) .delta. 7.27 (2H, m), 4.14 (2H, q),
3.30 (1H, m), 2.88 (2H, m), 2.51 (2H, m), 2.22 (1H, m), 2.00 (2H,
m), 1.82 (1H, m), 1.32 (12H, s), 1.26 (3H, t)
Preparation Example 305: 1-iodo-2,3-dipropoxy-benzene
[1753] 7 mL of DMF was added to 3-iodo benzene-1,2-diol (0.28 g,
1.18 mmol), 1-iodopropane (0.3 mL, 2.96 mmol) and K.sub.2CO.sub.3
(0.49 g. 3.54 mmol), and the mixture was stirred at 80.degree. C.
for 16 hours. The reaction solution was concentrated under reduced
pressure and purified by column chromatography to obtain the title
compound (0.24 g, 64%).
[1754] .sup.1H-NMR (CDCl.sub.3) .delta. 7.32 (1H, m), 6.85 (1H, m),
6.74 (1H, t), 3.94 (4H, m), 1.83 (4H, m), 1.07 (6H, m)
Preparation Example 306:
2-(cyclopropylmethoxy)-6-iodo-3-methoxy-pyridine
Step A: 2-bromo-6-iodo-3-methoxy-pyridine
[1755] The title compound was obtained by the method disclosed in
WO 2006/21759 A1.
[1756] .sup.1H-NMR (MeOH-d4) .delta. 7.64 (1H, d), 7.08 (1H, d),
3.83 (3H, s)
Step B: 2-(cyclopropylmethoxy)-6-iodo-3-methoxy-pyridine
[1757] Cyclopropyl methanol (0.54 mL, 6.62 mmol) was dissolved in
dry DMF (5 mL). NaH (60%)(0.248 g, 6.21 mmol) was slowly added
dropwise thereto at 0.degree. C., and the mixture was stirred for
30 minutes. 2-Bromo-6-iodo-3-methoxy-pyridine (1.3 g, 4.14 mmol)
obtained in Step A was added thereto, and the mixture was stirred
at room temperature for 16 hours. After addition of water, the
reaction solution was extracted with EtOAc. The organic layer was
purified by column chromatography to obtain the title compound
(0.89 g, 70%).
[1758] .sup.1H-NMR (CDCl.sub.3) .delta. 7.20 (1H, d), 6.73 (1H, d),
4.19 (2H, d), 3.84 (3H, s), 1.31 (1H, m), 0.60 (2H, m), 0.38 (2H,
m)
Preparation Example 307:
2-(cyclobutoxy)-6-iodo-3-methoxy-pyridine
[1759] 2-Bromo-6-iodo-3-methoxy-pyridine (1.5 g, 4.78 mmol) and
cyclobutanol (0.6 mL, 7.17 mmol) were reacted in the same manner as
in Preparation Example 306 to obtain the title compound (0.92 g,
63%).
[1760] .sup.1H-NMR (CDCl.sub.3) .delta. 7.19 (1H, d), 6.72 (1H, d),
5.22 (1H, m), 3.83 (3H, s), 2.48 (2H, m), 2.21 (2H, m), 1.83 (1H,
m), 1.67 (1H, m)
Preparation Example 308: 6-(cyclobutoxy)-1H-indole
[1761] 1H-indol-6-ol (0.1 g, 0.75 mmol) and bromocyclobutane (0.203
g, 1.50 mmol) were reacted in the same manner as in Preparation
Example 12 to obtain the title compound (0.068 g, 28%).
[1762] .sup.1H-NMR (CDCl.sub.3) .delta. 7.99 (1H, brs), 7.48 (1H,
d), 7.07 (1H, m), 6.77 (1H, m), 6.73 (1H, m), 6.46 (1H, m), 4.66
(1H, m), 2.46 (2H, m), 2.20 (2H, m), 1.85 (1H, m), 1.70 (1H, m)
Preparation Example 309: 6-(cyclobutoxy)-1H-indazole
[1763] 1H-indazol-6-ol (0.5 g, 3.72 mmol) and bromocyclobutane (0.7
mL, 1.50 mmol) were reacted in the same manner as in Preparation
Example 12 to obtain the title compound (0.4 g, 57%).
[1764] .sup.1H-NMR (CDCl.sub.3) .delta. 10.07 (1H, brs), 7.96 (1H,
m), 7.60 (1H, m), 6.78 (1H, m), 6.73 (1H, m), 4.68 (1H, m), 2.50
(2H, m), 2.22 (2H, m), 1.89 (1H, m), 1.74 (1H, m)
Preparation Example 310: 5-(cyclobutoxy)-1H-indole
[1765] 1H-indol-5-ol (0.1 g, 0.75 mmol) and bromocyclobutane (0.203
g, 1.50 mmol) were reacted in the same manner as in Preparation
Example 12 to obtain the title compound (0.021 g, 19%).
[1766] .sup.1H-NMR (CDCl.sub.3) .delta. 8.06 (1H, s), 7.27 (1H, m),
7.16 (1H, t), 7.00 (1H, m), 6.81 (1H, m), 6.45 (1H, m), 4.66 (1H,
m), 2.47 (2H, m), 2.19 (2H, m), 1.85 (1H, m), 1.69 (1H, m)
Preparation Example 311: 6-(cyclopropylmethoxy)-1H-indole
[1767] 1H-indol-6-ol (0.05 g, 0.38 mmol) and
bromomethylcyclopropane (0.061 g, 0.45 mmol) were reacted in the
same manner as in Preparation Example 12 to obtain the title
compound (0.018 g, 24%).
[1768] .sup.1H-NMR (CDCl.sub.3) .delta. 7.99 (1H, s), 7.50 (1H, d),
7.09 (1H, m), 6.89 (1H, m), 6.81 (1H, m), 6.47 (1H, m), 3.83 (2H,
d), 1.31 (1H, m), 0.64 (2H, m), 0.36 (2H, m)
Preparation Example 312:
2-chloro-4-(4-chloro-phenoxy)-pyrimidine
[1769] 2,4-Dichloro-pyrimidine (1.16 g, 7.78 mmol) and
4-chloro-phenol (1.0 g, 7.78 mmol) were reacted in the same manner
as in Preparation Example 226 to obtain the title compound (0.735
g, 39%).
[1770] .sup.1H-NMR (CDCl.sub.3) .delta. 8.45 (1H, d), 7.40 (2H, m),
7.10 (2H, m), 6.83 (1H, d)
Preparation Example 313: 2-chloro-4-phenoxy-pyrimidine
[1771] 2,4-Dichloro-pyrimidine (1.6 g, 10.62 mmol) and phenol (1.0
g, 10.62 mmol) were reacted in the same manner as in Preparation
Example 226 to obtain the title compound (1.9 g, 86%).
[1772] .sup.1H-NMR (CDCl.sub.3) .delta. 8.43 (1H, d), 7.46 (2H, m),
7.31 (1H, m), 7.15 (2H, m), 6.77 (1H, d)
Preparation Example 314:
2-chloro-4-(4-fluoro-phenoxy)-pyrimidine
[1773] 2,4-Dichloro-pyrimidine (1.3 g, 8.92 mmol) and
4-fluoro-phenol (1.0 g, 8.92 mmol) were reacted in the same manner
as in Preparation Example 226 to obtain the title compound (1.1 g,
55%).
[1774] .sup.1H-NMR (CDCl.sub.3) .delta. 8.44 (1H, d), 7.12 (4H, d),
6.81 (1H, d)
Preparation Example 315:
2-chloro-4-(4-pyridin-3-yloxy)-pyrimidine
[1775] 2,4-Dichloro-pyrimidine (1.57 g, 10.51 mmol) and
pyridin-3-ol (1.0 g, 10.51 mmol) were reacted in the same manner as
in Preparation Example 226 to obtain the title compound (0.52 g,
24%).
[1776] .sup.1H-NMR (CDCl.sub.3) .delta. 8.56 (1H, dd), 8.53 (1H,
d), 8.50 (1H, d), 7.57 (1H, m), 7.40 (1H, m), 6.93 (1H, d)
Preparation Example 316: 2-chloro-4-(4-fluoro-phenoxy)-pyrazine
[1777] 2,6-Dichloro-pyrazine (1.3 g, 8.92 mmol) and 4-fluoro-phenol
(1.0 g, 8.92 mmol) were reacted in the same manner as in
Preparation Example 226 to obtain the title compound (1.1 g,
55%).
[1778] .sup.1H-NMR (CDCl.sub.3) .delta. 8.29 (2H, s), 7.12 (4H,
m)
Preparation Example 317:
2-chloro-4-(4-methoxy-phenoxy)-pyrimidine
[1779] 2,4-Dichloro-pyrimidine (1.2 g, 8.05 mmol) and
4-methoxy-phenol (1.0 g, 8.05 mmol) were reacted in the same manner
as in Preparation Example 226 to obtain the title compound (1.5 g,
79%).
[1780] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, d), 7.07 (2H, m),
6.94 (2H, m), 6.74 (1H, d), 3.83 (3H, s)
Preparation Example 318:
2-chloro-4-(4-fluoro-phenoxy)-6-methyl-pyrimidine
[1781] 2,4-Dichloro-6-methyl-pyrimidine (1.45 g, 8.92 mmol) and
4-fluoro-phenol (1.0 g, 8.92 mmol) were reacted in the same manner
as in Preparation Example 226 to obtain the title compound (1.7 g,
80%).
[1782] .sup.1H-NMR (CDCl.sub.3) .delta. 7.11 (4H, m), 6.61 (1H,
d)
Preparation Example 319: 2-chloro-4-p-tolyloxypyrimidine
[1783] 2,4-Dichloro-pyrimidine (1.38 g, 9.24 mmol) and
4-methyl-phenol (1.0 g, 9.24 mmol) were reacted in the same manner
as in Preparation Example 226 to obtain the title compound (1.4 g,
69%).
[1784] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, d), 7.24 (2H, m),
7.05 (2H, m), 6.75 (1H, d), 2.38 (3H, s)
Preparation Example 320:
2-chloro-4-(3,4-difluoro-phenoxy)-pyrimidine
[1785] 2,4-Dichloro-pyrimidine (1.14 g, 7.69 mmol) and
3,4-difluoro-phenol (1.0 g, 7.69 mmol) were reacted in the same
manner as in Preparation Example 226 to obtain the title compound
(0.8 g, 43%).
[1786] .sup.1H-NMR (CDCl.sub.3) .delta. 8.47 (1H, d), 7.24 (1H, m),
7.04 (1H, m), 6.93 (1H, m), 6.85 (1H, d)
Preparation Example 321:
2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxym-
ethyl]-cyclopropanecarboxylic acid ethyl ester
[1787]
2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
(0.2 g, 0.78 mmol) obtained in Step B of Preparation Example 16,
2-hydroxymethyl-cyclopropanecarboxylic acid ethyl ester (0.17 g,
1.17 mmol), triphenylphosphine (0.51 g, 1.95 mmol) and diisopropyl
azodicarboxylate (0.39 g, 1.95 mmol) were reacted in the same
manner as in Preparation Example 62 to obtain the title compound
(0.25 g, 84%).
[1788] .sup.1H-NMR (CDCl.sub.3) .delta. 7.30 (2H, m), 4.13 (3H, m),
4.03 (1H, m), 1.86 (1H, m), 1.64 (1H, m), 1.32 (12H, s), 1.26 (4H,
m), 0.93 (1H, m)
Preparation Example 322:
2-[2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phe-
noxymethyl]-cyclopropanecarboxylic Acid Ethyl Ester
[1789]
2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ph-
enol (0.75 g, 2.8 mmol), 2-hydroxymethyl-cyclopropanecarboxylic
acid ethyl ester (0.48 g, 6.9 mmol), triphenylphosphine (1.80 g,
6.9 mmol) and diisopropyl azodicarboxylate (1.39 g, 6.9 mmol) were
reacted in the same manner as in Preparation Example 62 to obtain
the title compound (0.82 g, 75%).
[1790] .sup.1H-NMR (CDCl.sub.3) .delta. 7.58 (1H, s), 7.41 (1H, d),
4.13 (3H, m), 3.99 (1H, m), 1.89 (1H, m), 1.65 (1H, m), 1.32 (12H,
s), 1.25 (4H, m), 0.95 (1H, m)
Preparation Example 323: 1-bromo-3-cyclobutylmethoxy-benzene
[1791] 3-Bromo-phenol (1.2 g, 6.94 mmol), Cs.sub.2CO.sub.3 (4.52 g,
13.9 mmol) and bromomethyl-cyclobutane (0.86 mL, 7.63 mmol) were
reacted in the same manner as in Preparation Example 28 to obtain
the title compound (1.70 g, 99%).
[1792] .sup.1H-NMR (CDCl.sub.3) .delta. 7.12 (1H, m), 7.06 (2H, m),
6.83 (1H, m), 3.90 (2H, d), 2.76 (1H, m), 2.14 (2H, m), 1.96 (4H,
m)
Preparation Example 324: 2-chloro-6-cyclobutylmethoxy-pyridine
[1793] 6-Chloro-pyridin-2-ol (2.0 g, 15.4 mmol), K.sub.2CO.sub.3
(4.27 g, 30.1 mmol) and bromomethyl-cyclobutane (1.91 mL, 17.0
mmol) were reacted in the same manner as in Preparation Example 12
to obtain the title compound (2.30 g, 75%).
[1794] .sup.1H-NMR (CDCl.sub.3) .delta. 7.50 (1H, t), 6.87 (1H, d),
6.64 (1H, d), 4.26 (2H, d), 2.76 (1H, m), 2.12 (2H, m), 1.94 (4H,
m)
Preparation Example 325:
2-bromo-4-cyclobutylmethoxy-1-methyl-benzene
[1795] 3-Bromo-4-methyl-phenol (0.5 g, 2.67 mmol), Cs.sub.2CO.sub.3
(1.74 g, 5.35 mmol) and bromomethyl-cyclobutane (0.33 mL, 2.94
mmol) were reacted in the same manner as in Preparation Example 28
to obtain the title compound (0.65 g, 95%).
[1796] .sup.1H-NMR (CDCl.sub.3) .delta. 7.09 (2H, m), 6.76 (1H, m),
3.88 (2H, d), 2.76 (1H, m), 2.31 (3H, s), 2.13 (2H, m), 1.95 (4H,
m)
Preparation Example 326:
4-bromo-1-chloro-2-cyclopropylmethoxy-benzene
[1797] 5-Bromo-2-chloro-phenol (0.5 g, 2.41 mmol), Cs.sub.2CO.sub.3
(1.60 g, 4.82 mmol) and bromomethyl-cyclopropane (0.26 mL, 2.65
mmol) were reacted in the same manner as in Preparation Example 28
to obtain the title compound (0.60 g, 95%).
[1798] .sup.1H-NMR (CDCl.sub.3) .delta. 7.22 (1H, d), 7.02 (2H, m),
3.87 (2H, d), 1.32 (1H, m), 0.67 (2H, m), 0.40 (2H, m)
Preparation Example 327:
4-bromo-2-cyclopropylmethoxy-1-methyl-benzene
[1799] 5-Bromo-2-methyl-phenol (0.5 g, 2.67 mmol), Cs.sub.2CO.sub.3
(1.70 g, 5.35 mmol) and bromomethyl-cyclopropane (0.29 mL, 2.94
mmol) were reacted in the same manner as in Preparation Example 28
to obtain the title compound (0.63 g, 98%).
[1800] .sup.1H-NMR (CDCl.sub.3) .delta. 6.97 (2H, m), 6.89 (1H, s),
3.79 (2H, d), 2.18 (3H, s), 1.26 (1H, m), 0.63 (2H, m), 0.35 (2H,
m)
Preparation Example 328: 7-bromo-5-chloro-2-methyl-benzofuran
Step A: 2-bromo-4-chloro-1-prop-2-ynyloxy-benzene
[1801] 2-Bromo-4-chloro-phenol (1.0 g, 4.82 mmol), 3-bromo-propyne
(0.79 g, 5.30 mmol) and K.sub.2CO.sub.3 (1.47 g, 10.6 mmol) were
reacted in the same manner as in Preparation Example 12 to obtain
the title compound (1.1 g, 93%).
[1802] .sup.1H-NMR (CDCl.sub.3) .delta. 7.55 (1H, d), 7.24 (1H, m),
6.99 (1H, d), 4.76 (2H, d), 2.55 (1H, t)
Step B: 7-bromo-5-chloro-2-methyl-benzofuran
[1803] 2-Bromo-4-chloro-1-prop-2-ynyloxy-benzene (1.1 g, 4.48 mmol)
obtained in Step A and cesium fluoride (0.95 g, 6.27 mmol) were
dissolved in 7.5 mL of diethyl-phenyl-amine, and stirred at
210.degree. C. for 4 hours. The reaction solution was cooled to
room temperature and diluted with hexane. After washing with 1N HCl
three times, the organic layer was separated. The organic layer was
dried with MgSO.sub.4 and purified by column chromatography to
obtain the title compound (0.65 g, 59%).
[1804] .sup.1H-NMR (CDCl.sub.3) .delta. 7.37 (2H, d), 6.39 (1H, s),
2.49 (3H, s)
Preparation Example 329:
2-chloro-4-cyclobutoxy-5-fluoro-pyrimidine
[1805] 2,4-Dichloro-5-fluoro-pyrimidine (0.50 g, 2.99 mmol) and
cyclobutanol (0.26 ml, 3.29 mmol) were reacted in the same manner
as in Preparation Example 226 to obtain the title compound (0.57 g,
89%).
[1806] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 8.17 (d, 1H),
5.37-5.29 (m, 1H), 2.55-2.48 (m, 2H), 2.30-2.20 (m, 2H), 1.94-1.86
(m, 1H), 1.77-1.67 (m, 1H)
Preparation Example 330:
2-chloro-4-cyclopropylmethoxy-5-fluoro-pyrimidine
[1807] 2,4-Dichloro-5-fluoro-pyrimidine (0.50 g, 2.99 mmol) and
cyclopropylmethanol (0.27 ml, 3.29 mmol) were reacted in the same
manner as in Preparation Example 226 to obtain the title compound
(0.52 g, 81%).
[1808] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 8.19-8.18 (d,
1H), 4.32-4.31 (d, 2H), 1.37-1.30 (m, 1H), 0.70-0.65 (m, 2H),
0.43-0.39 (m, 2H)
Preparation Example 331:
2-chloro-5-fluoro-4-isobutoxy-pyrimidine
[1809] 2,4-Dichloro-5-fluoro-pyrimidine (0.50 g, 2.99 mmol) and
2-methyl-propan-1-ol (0.30 ml, 3.29 mmol) were reacted in the same
manner as in Preparation Example 226 to obtain the title compound
(0.51 g, 79%).
[1810] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 8.18 (d, 1H),
4.25-4.10 (d, 2H), 2.21-2.11 (m, 1H), 1.05-1.03 (d, 6H)
Preparation Example 332:
2-chloro-6-(3-methoxy-propoxy)-pyridine
[1811] 2,6-Dichloropyridine (0.50 g, 3.38 mmol) and
3-methoxy-propan-lol (0.40 ml, 4.05 mmol) were reacted in the same
manner as in Preparation Example 226 to obtain the title compound
(0.37 g, 51%).
[1812] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 8.18 (d, 1H),
4.25-4.10 (d, 2H), 2.21-2.11 (m, 1H), 1.05-1.03 (d, 6H)
Preparation Example 333:
2-chloro-6-(tetrahydro-thiopyran-4-yloxy)-pyridine
[1813] 2,6-Dichloropyridine (0.50 g, 3.38 mmol) and
tetrahydro-2H-thiopyran-4-ol (0.44 g, 3.72 mmol) were reacted in
the same manner as in Preparation Example 226 to obtain the title
compound (0.36 g, 44%).
[1814] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 8.18 (d, 1H),
4.25-4.10 (d, 2H), 2.21-2.11 (m, 1H), 1.05-1.03 (d, 6H)
Preparation Example 334: 2-chloro-5-fluoro-4-propoxy-pyrimidine
[1815] 2,4-Dichloro-5-fluoro-pyrimidine (0.40 g, 2.40 mmol) and
propan-1-ol (0.20 ml, 2.64 mmol) were reacted in the same manner as
in Preparation Example 226 to obtain the title compound (0.35 g,
77%).
[1816] .sup.1H-NMR (500 HMz, CDCl.sub.3); .delta. 8.17-8.16 (d,
1H), 4.43-4.41 (t, 2H), 1.89-1.82 (m, 1H), 1.05-1.02 (t, 3H)
Preparation Example 335:
2-chloro-4-(3-methyl-butoxy)-pyrimidine
[1817] 2,4-Dichloropyrimidine (0.50 g, 3.36 mmol) and
3-methylbutan-1-ol (0.40 ml, 3.69 mmol) were reacted in the same
manner as in Preparation Example 226 to obtain the title compound
(0.59 g, 87%).
[1818] .sup.1H-NMR (500 HMz, CDCl.sub.3); a 8.27-8.25 (d, 1H),
6.63-6.62 (d, 1H), 4.41-4.39 (t, 2H), 1.80-1.75 (m, 1H), 1.70-1.65
(q, 2H), 0.96-0.94 (d, 6H)
Preparation Example 336:
2-chloro-4-(3-methoxy-propoxy)-pyrimidine
[1819] 2,4-Dichloropyrimidine (0.50 g, 3.36 mmol) and
3-methoxypropan-1-ol (0.35 ml, 3.69 mmol) were reacted in the same
manner as in Preparation Example 226 to obtain the title compound
(0.34 g, 50%).
[1820] .sup.1H-NMR (500 HMz, CDCl.sub.3); .delta. 8.28-8.27 (d,
1H), 6.65-6.64 (d, 1H), 4.48-4.45 (t, 2H), 3.52-3.50 (t, 2H), 3.34
(s, 3H), 2.05-2.02 (m, 2H)
Preparation Example 337:
5-bromo-4-cyclopropylmethoxymethyl-2-methyl-thiazole
Step A: 4-cyclopropylmethoxymethyl-2-methyl-thiazole
[1821] Cyclopropyl-methanol (0.65 ml, 7.93 mmol) and
4-chloromethyl-2-methyl-thiazole (0.78 g, 5.28 mmol) were reacted
in the same manner as in Preparation Example 226 to obtain the
title compound (0.83 g, 80%).
[1822] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.06 (s, 1H), 4.61
(s, 2H), 3.46-3.40 (d, 2H), 2.71 (s, 3H), 1.15-1.09 (m, 1H),
0.58-0.53 (m, 2H), 0.25-0.21 (m, 2H)
Step B: 5-bromo-4-cyclopropylmethoxymethyl-2-methyl-thiazole
[1823] 4-Cyclopropylmethoxymethyl-2-methyl-thiazole (0.52 g, 2.64
mmol) and 1,3-dibromo-5,5-dimethyl-imidazolin-2,4-dione (0.74 g,
2.64 mmol) were reacted in the same manner as in Step B of
Preparation Example 6 to obtain the title compound (0.66 g,
96%).
[1824] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 4.46 (s, 2H),
3.39-3.38 (d, 2H), 2.66 (s, 3H), 1.16-1.09 (m, 1H), 0.57-0.53 (m,
2H), 0.25-0.22 (m, 2H)
Preparation Example 338: 4-bromo-2-cyclobutoxymethyl-thiophene
[1825] 4-Bromo-2-chloromethyl-thiophene (0.30 g, 1.42 mmol) and
cyclobutanol (0.14 ml, 1.84 mmol) were reacted in the same manner
as in Preparation Example 226 to obtain the title compound (0.065
g, 19%).
[1826] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.17-7.16 (d, 1H),
6.90 (d, 1H), 4.52 (s, 2H), 4.06-3.99 (m, 1H), 2.24-2.16 (m, 2H),
2.01-1.92 (m, 2H), 1.75-1.68 (m, 1H), 1.52-1.47 (m, 1H)
Preparation Example 339: 4-(4-bromo-2,6-difluoro-phenoxy)-butanoic
Acid Ethyl Ester
[1827] 4-Bromo-2,6-difluoro-phenol (19.5 g, 93.3 mmol) obtained in
Step A of Preparation Example 16 and 4-bromo-butyric acid ethyl
ester (21.82 g, 112 mmol) were reacted in the same manner as in
Step C of Preparation Example 16 to obtain the title compound (30.0
g, 99%).
[1828] .sup.1H-NMR (CDCl.sub.3) .delta. 7.09 (2H, m), 4.16 (4H, m),
2.57 (2H, t), 2.08 (2H, m), 1.28 (3H, t)
Preparation Example 340:
2-chloro-4-(6-methyl-pyridin-3-yloxy)-pyrimidine
[1829] 2,4-Dichloro-pyrimidine (1.36 g, 9.16 mmol) and
6-methyl-pyridin-3-ol (1.0 g, 9.16 mmol) were reacted in the same
manner as in Preparation Example 226 to obtain the title compound
(0.850 g, 42%).
[1830] .sup.1H-NMR (CDCl.sub.3) .delta. 8.47 (1H, d), 8.38 (1H, d),
7.44 (1H, m), 7.24 (1H, m), 6.89 (1H, d)
Preparation Example 341:
2-chloro-4-(4-ethyl-phenoxy)-pyrimidine
[1831] 2,4-Dichloro-pyrimidine (1.22 g, 8.18 mmol) and
4-ethyl-phenol (1.0 g, 8.18 mmol) were reacted in the same manner
as in Preparation Example 226 to obtain the title compound (1.5 g,
78%).
[1832] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, d), 7.26 (2H, m),
7.06 (2H, m), 6.74 (1H, d), 2.67 (2H, q), 1.27 (3H, t)
Preparation Example 342:
2-chloro-4-(3-fluoro-phenoxy)-pyrimidine
[1833] 2,4-Dichloro-pyrimidine (1.3 g, 8.92 mmol) and
3-fluoro-phenol (1.0 g, 8.92 mmol) were reacted in the same manner
as in Preparation Example 226 to obtain the title compound (1.2 g,
59%).
[1834] .sup.1H-NMR (CDCl.sub.3) .delta. 8.47 (1H, d), 7.40 (1H, m),
7.04-6.91 (3H, m), 6.84 (1H, d)
Preparation Example 343:
2-chloro-4-(3,4-difluoro-phenoxy)-6-methyl-pyrimidine
[1835] 2,4-Dichloro-6-methyl-pyrimidine (1.25 g, 7.69 mmol) and
3,4-difluoro-phenol (1.0 g, 7.69 mmol) were reacted in the same
manner as in Preparation Example 226 to obtain the title compound
(1.1 g, 55%).
[1836] .sup.1H-NMR (CDCl.sub.3) .delta. 7.22 (1H, q), 7.03 (1H, m),
6.90 (1H, m), 6.67 (1H, s), 2.51 (3H, s)
Preparation Example 344:
2-chloro-4-(pyridin-2-yloxy)-pyrimidine
[1837] 2,4-Dichloro-pyrimidine (1.57 g, 10.51 mmol) and
pyridin-2-ol (1.0 g, 10.51 mmol) were reacted in the same manner as
in Preparation Example 226 to obtain the title compound (0.1 g,
4%).
[1838] .sup.1H-NMR (CDCl.sub.3) .delta. 8.52 (1H, d), 8.38 (1H, m),
7.85 (1H, m), 7.25 (1H, m), 7.15 (1H, d), 7.03 (1H, d)
Preparation Example 345:
2-chloro-4-[4-(trifluoromethyl)phenoxy]pyrimidine
[1839] 2,4-Dichloropyrimidine (2.0 g, 13.4 mmol) and
4-(trifluoromethyl)phenol (2.17 g, 13.4 mmol) were reacted in the
same manner as in Preparation Example 226 to obtain the title
compound (2.62 g, 71%).
[1840] .sup.1H-NMR (CDCl.sub.3) .delta. 8.50 (1H, d), 7.72 (2H, d),
7.30 (2H, d), 6.89 (1H, d)
Preparation Example 346:
2-chloro-4-[3-(trifluoromethyl)phenoxy]pyrimidine
[1841] 2,4-Dichloropyrimidine (2.0 g, 13.4 mmol) and
3-(trifluoromethyl)phenol (2.17 g, 13.4 mmol) were reacted in the
same manner as in Preparation Example 226 to obtain the title
compound (2.7 g, 73%).
[1842] .sup.1H-NMR (CDCl.sub.3) .delta. 8.50 (1H, d), 7.57 (2H, m),
7.44 (1H, m), 7.38 (1H, m), 6.88 (1H, d)
Preparation Example 347:
2-chloro-4-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine
[1843] 2,6-Dichloro-4-methyl-pyrimidine (3.0 g, 18.4 mmol) and
4-(trifluoromethyl)phenol (2.98 g, 18.4 mmol) were reacted in the
same manner as in Preparation Example 226 to obtain the title
compound (3.2 g, 62%).
[1844] .sup.1H-NMR (CDCl.sub.3) .delta. 7.70 (2H, d), 7.27 (2H, d),
6.70 (1H, s), 2.52 (3H, s)
Preparation Example 348:
2-chloro-4-methyl-6-[3-(trifluoromethyl)phenoxy]pyrimidine
[1845] 2,6-Dichloro-4-methyl-pyrimidine (3.0 g, 18.4 mmol) and
3-(trifluoromethyl)phenol (2.98 g, 18.4 mmol) were reacted in the
same manner as in Preparation Example 226 to obtain the title
compound (3.0 g, 57%).
[1846] .sup.1H-NMR (CDCl.sub.3) .delta. 7.56 (2H, m), 7.42 (1H, m),
7.36 (1H, m), 6.69 (1H, s), 2.52 (3H, s)
Preparation Example 349:
2-chloro-4-cyclobutoxy-6-trifluoromethyl-pyrimidine
[1847] 2,6-Dichloro-6-trifluoromethyl-pyrimidine (0.40 g, 1.85
mmol) and cyclobutanol (0.17 ml, 2.22 mmol) were reacted in the
same manner as in Preparation Example 226 to obtain the title
compound (0.40 g, 86%).
[1848] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.08 (s, 1H), 6.83
(s, 1H), 5.24-5.15 (m, 1H), 2.52 (m, 2H), 2.17-2.11 (m, 2H),
1.87-1.84 (m, 1H), 1.73-1.65 (m, 1H)
Preparation Example 350: 4-bromo-benzo[b]thiophene
[1849] 3-Bromo-benzenethiol (0.5 g, 2.64 mmol) was dissolved in 8
mL of DMF Bromoacetaldehyde diethyl acetal (0.52 g, 2.64 mmol) and
K.sub.2CO.sub.3 (0.548 g, 3.97 mmol) were added thereto, and the
mixture was stirred at room temperature for 16 hours. After
addition of water, the reaction solution was extracted with EtOAc.
The organic layer was dried with anhydrous magnesiumsulfate and
concentrated under reduced pressure to obtain
1-bromo-3-(2,2-diethoxy-ethylsulfanyl)-benzene. The obtained
compound was dissolved in 8 ml of MC. 0.7 g of PPA (polyphosphoric
acid) was added thereto, and the mixture was stirred for 4 hours
under reflux. After addition of Na.sub.2CO.sub.3 aqueous solution,
the reaction solution was extracted with MC. The organic layer was
dried with anhydrous magnesiumsulfate and purified by column
chromatography to obtain the mixture of 4-bromo-benzo[b]thiophene
and 6-bromo-benzo[b]thiophene (1:1, 0.33 g, 58%).
[1850] .sup.1H-NMR (CDCl.sub.3) .delta. 8.01 (1H, s), 7.80 (1H, d),
7.66 (1H, d), 7.50 (4H, m), 7.41 (1H, d), 7.29 (1H, d), 7.19 (1H,
t)
Preparation Example 351:
[1-(4-benzo[b]thiophen-4-yl-2,6-difluoro-phenyl)-piperidin-4-yl]-acetic
Acid Ethyl Ester
[1851] The mixture of 4-bromo-benzo[b]thiophene and
6-bromo-benzo[b]thiophene (0.19 g, 0.89 mmol) obtained in
Preparation Example 350 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.365 g, 0.89 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 1 to obtain the title compound (0.11 g, 29%).
[1852] .sup.1H-NMR (CDCl.sub.3) .delta. 7.87 (1H, d), 7.46 (2H, s),
7.39 (1H, t), 7.29 (1H, d), 7.04 (2H, m), 4.14 (2H, q), 3.32 (2H,
m), 3.16 (2H, m), 2.29 (2H, d), 1.96 (1H, m), 1.77 (2H, m), 1.46
(2H, m), 1.26 (3H, t)
Preparation Example 352:
2-chloro-4-cyclobutoxy-6-trifluoromethyl-pyrimidine
[1853] Cyclobutanol (0.365 g, 5.07 mmol) and
2,4-dichloro-6-trifluoromethyl-pyrimidine (1 g, 4.61 mmol) were
reacted in the same manner as in Preparation Example 226 to obtain
the title compound (0.603 g, 51%).
[1854] .sup.1H-NMR (CDCl.sub.3) .delta. 6.93 (1H, s), 5.30 (1H, m),
2.50 (2H, m), 2.18 (2H, m), 1.87 (1H, m), 1.71 (1H, m)
Preparation Example 353:
2-chloro-4-propoxy-6-trifluoromethyl-pyrimidine
[1855] Propanol (0.304 g, 5.07 mmol) and
2,4-dichloro-6-trifluoromethyl-pyrimidine (1 g, 4.61 mmol) were
reacted in the same manner as in Preparation Example 226 to obtain
the title compound (0.602 g, 54%).
[1856] .sup.1H-NMR (CDCl.sub.3) .delta. 6.97 (1H, s), 4.41 (2H, t),
1.83 (2H, m), 1.02 (3H, t)
Preparation Example 354:
2-chloro-4-(4-fluoro-phenoxy)-6-trifluoromethyl-pyrimidine
[1857] 4-Fluoro-phenol (0.568 g, 5.07 mmol) and
2,4-dichloro-6-trifluoromethyl-pyrimidine (1 g, 4.61 mmol) were
reacted in the same manner as in Preparation Example 226 to obtain
the title compound (1.07 g, 79%).
[1858] .sup.1H-NMR (CDCl.sub.3) .delta. 7.15 (5H, m)
Example 1:
3-[6-(2-isopropylsulfanyl-pyridin-3-yl)-quinolin-2-yl]-propioni- c
Acid
##STR00009##
[1859] Step A:
3-[6-(2-isopropylsulfanyl-pyridin-3-yl)-quinolin-2-yl]-propionic
Acid Ethyl Ester
##STR00010##
[1861]
3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinolin-2-yl]--
propionic acid ethyl ester (0.06 g, 0.17 mmol) obtained in
Preparation Example 1 and 3-iodo-2-isopropylsulfanyl-pyridine
(0.047 g, 0.17 mmol) obtained in Preparation Example 9 were
dissolved in 0.25 mL of 2M sodium carbonate and 2 mL of DME, and
charged with nitrogen for 5 minutes. PdCl.sub.2(PPh.sub.3).sub.2
(0.006 g, 0.008 mmol) was added thereto, and the mixture was
stirred for 4 hours under reflux. After addition of water, the
reaction solution was extracted with EtOAc to separate an organic
layer. The organic layer was dried with MgSO.sub.4 and purified by
column chromatography to obtain the title compound (0.040 g,
63%).
[1862] .sup.1H-NMR (CDCl.sub.3) .delta. 8.53 (1H, d),
8.15.about.8.08 (2H, m), 7.82 (1H, s), 7.78 (1H, d), 7.50 (1H, d),
7.39 (1H, d), 7.12 (1H, m), 4.15.about.4.10 (3H, m), 3.34 (2H, t),
2.97 (2H, t), 1.40 (6H, d), 1.30 (3H, t)
Step B:
3-[6-(2-isopropylsulfanyl-pyridin-3-yl)-quinolin-2-yl]-propionic
Acid
[1863]
3-[6-(2-Isopropylsulfanyl-pyridin-3-yl)-quinolin-2-yl]-propionic
acid ethyl ester (0.040 g, 0.10 mmol) obtained in Step A was
dissolved in each 0.3 mL of THF, MeOH and 1N NaOH aqueous solution,
and the mixture was stirred at room temperature for 2 hours. After
removing organic solvent, the reaction solution was adjusted to pH
3 by the use of 1N HCl aqueous solution and extracted with EtOAc to
separate an organic layer. The organic layer was dried with
MgSO.sub.4 and concentrated under reduced pressure to obtain the
title compound (0.030 g, 86%).
[1864] .sup.1H-NMR (CDCl.sub.3) .delta. 8.51 (1H, d), 8.26 (1H, d),
8.11 (1H, d), 7.92-7.80 (2H, m), 7.46 (1H, d), 7.40 (1H, d), 7.10
(1H, m), 4.15 (1H, m), 3.38 (2H, t), 2.98 (2H, t), 1.35 (6H, d)
Example 2:
3-[6-(6-isopropylsulfanyl-pyridin-2-yl)-quinolin-2-yl]-propioni- c
Acid
##STR00011##
[1865] Step A:
3-[6-(6-isopropylsulfanyl-pyridin-2-yl)-quinolin-2-yl]-propionic
Acid Ethyl Ester
##STR00012##
[1867]
3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinolin-2-yl]--
propionic acid ethyl ester (0.06 g, 0.17 mmol) obtained in
Preparation Example 1 and 2-chloro-6-isopropylsulfanyl-pyridine
(0.032 g, 0.17 mmol) obtained in Preparation Example 10 were
reacted in the same manner as in Step A of Example 1 to obtain the
title compound (0.021 g, 33%).
[1868] .sup.1H-NMR (CDCl.sub.3) .delta. 8.50 (1H, s), 8.43 (1H, d),
8.20 (1H, d), 8.14 (1H, d), 7.65-7.60 (2H, m), 7.40 (1H, d), 7.16
(1H, m), 4.31-4.17 (3H, m), 3.34 (2H, t), 2.96 (2H, t), 1.54 (6H,
d), 1.29 (3H, t)
Step B:
3-[6-(6-isopropylsulfanyl-pyridin-2-yl)-quinolin-2-yl]-propionic
Acid
[1869]
3-[6-(6-Isopropylsulfanyl-pyridin-2-yl)-quinolin-2-yl]-propionic
acid ethyl ester (0.021 g, 0.06 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.016 g, 83%).
[1870] .sup.1H-NMR (CDCl.sub.3) .delta. 8.51-8.46 (2H, m), 8.32
(1H, d), 8.11 (1H, d), 7.65-7.55 (2H, m), 7.41 (1H, d), 7.15 (1H,
m), 4.20 (1H, m), 3.39 (2H, t), 2.98 (2H, t), 1.50 (6H, d)
Example 3:
[6-(6-cyclopentyloxy-pyridin-2-yl)-naphthalen-2-yloxy]-acetic
Acid
##STR00013##
[1871] Step A:
[6-(6-cyclopentyloxy-pyridin-2-yl)-naphthalen-2-yloxy]-acetic Acid
Ethyl Ester
##STR00014##
[1873]
[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-ylox-
y]-acetic acid ethyl ester (0.06 g, 0.17 mmol) obtained in
Preparation Example 2 and 2-chloro-6-cyclopentyloxy-pyridine (0.033
g, 0.17 mmol) obtained in Preparation Example 12 were reacted in
the same manner as in Step A of Example 1 to obtain the title
compound (0.013 g, 20%).
[1874] .sup.1H-NMR (CDCl.sub.3) .delta. 8.43 (1H, s), 8.17 (1H, d),
7.86 (1H, d), 7.77 (1H, t), 7.62 (1H, d), 7.42 (1H, d), 7.25 (1H,
d), 7.12 (1H, s), 6.63 (1H, d), 5.60 (1H, m), 4.75 (2H, s), 4.30
(2H, q), 2.20-1.60 (8H, m), 1.22 (3H, t)
Step B:
[6-(6-cyclopentyloxy-pyridin-2-yl)-naphthalen-2-yloxy]-acetic
Acid
[1875]
[6-(6-cyclopentyloxy-pyridin-2-yl)-naphthalen-2-yloxy]-acetic acid
ethyl ester (0.013 g, 0.03 mmol) obtained in Step A was reacted in
the same manner as in Step B of Example 1 to obtain the title
compound (0.010 g, 83%).
[1876] .sup.1H-NMR (CDCl.sub.3) .delta. 8.48 (1H, s), 8.22 (1H, d),
7.94 (1H, d), 7.83 (1H, d), 7.70 (1H, t), 7.47 (1H, d), 7.25 (1H,
d), 7.20 (1H, s), 6.70 (1H, d), 5.63 (1H, m), 4.87 (2H, s),
2.20-1.70 (8H, m)
Example 4:
[6-(2-cyclopentyloxy-pyridin-3-yl)-naphthalen-2-yloxy]-acetic
Acid
##STR00015##
[1877] Step A:
[6-(2-cyclopentyloxy-pyridin-3-yl)-naphthalen-2-yloxy]-acetic Acid
Ethyl Ester
##STR00016##
[1879]
[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-ylox-
y]-acetic acid ethyl ester (0.06 g, 0.17 mmol) obtained in
Preparation Example 2 and 2-cyclopentyloxy-3-iodo-pyridine (0.049
g, 0.17 mmol) obtained in Preparation Example 11 were reacted in
the same manner as in Step A of Example 1 to obtain the title
compound (0.030 g, 45%).
[1880] .sup.1H-NMR (CDCl.sub.3) .delta. 8.21 (1H, d), 8.00 (1H, s),
7.85-7.70 (4H, m), 7.24 (1H, d), 7.18 (1H, s), 6.99 (1H, t), 5.60
(1H, m), 4.80 (2H, s), 4.36 (2H, q), 2.10-1.60 (8H, m), 1.35 (3H,
t)
Step B:
[6-(2-cyclopentyloxy-pyridin-3-yl)-naphthalen-2-yloxy]-acetic
Acid
[1881]
[6-(2-Cyclopentyloxy-pyridin-3-yl)-naphthalen-2-yloxy]-acetic acid
ethyl ester (0.030 g, 0.08 mmol) obtained in Step A was reacted in
the same manner as in Step B of Example 1 to obtain the title
compound (0.018 g, 67%).
[1882] .sup.1H-NMR (CDCl.sub.3) .delta. 8.24 (1H, d), 7.97 (1H, s),
7.85-7.70 (4H, m), 7.30 (1H, d), 7.20 (1H, s), 7.00 (1H, t), 5.57
(1H, m), 4.87 (2H, s), 2.10-1.65 (8H, m)
Example 5:
4-[6-(2-isopropylsulfanyl-pyridin-3-yl)-naphthalen-2-yloxy]-but-
yric Acid
##STR00017##
[1883] Step A:
4-[6-(2-isopropylsulfanyl-pyridin-3-yl)-naphthalen-2-yloxy]-butyric
Acid Ethyl Ester
##STR00018##
[1885]
4-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl-
oxy]-butyric acid ethyl ester (0.05 g, 0.13 mmol) obtained in
Preparation Example 3 and 3-iodo-2-isopropylsulfanyl-pyridine
(0.036 g, 0.13 mmol) obtained in Preparation Example 9 were reacted
in the same manner as in Step A of Example 1 to obtain the title
compound (0.035 g, 66%).
[1886] .sup.1H-NMR (CDCl.sub.3) .delta. 8.50 (1H, d), 7.82-7.75
(3H, m), 7.62-7.48 (2H, m), 7.20 (2H, m), 7.10 (1H, m), 4.25-4.05
(5H, m), 2.63 (2H, t), 2.22 (2H, t), 1.39 (6H, d), 1.30 (3H, t)
Step B:
4-[6-(2-isopropylsulfanyl-pyridin-3-yl)-naphthalen-2-yloxy]-butyri-
c Acid
[1887]
4-[6-(2-Isopropylsulfanyl-pyridin-3-yl)-naphthalen-2-yloxy]-butyric
acid ethyl ester (0.035 g, 0.09 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.025 g, 78%).
[1888] .sup.1H-NMR (CDCl.sub.3) .delta. 8.46 (1H, d), 7.80-7.75
(3H, m), 7.52 (1H, d), 7.45 (1H, d), 7.15 (2H, m), 7.05 (1H, m),
4.18 (2H, t), 4.07 (1H, m), 2.65 (2H, t), 2.22 (2H, t), 1.34 (6H,
d)
Example 6:
4-[6-(6-isopropylsulfanyl-pyridin-2-yl)-naphthalen-2-yloxy]-but-
yric Acid
##STR00019##
[1889] Step A:
4-[6-(6-isopropylsulfanyl-pyridin-2-yl)-naphthalen-2-yloxy]-butyric
Acid Ethyl Ester
##STR00020##
[1891]
4-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl-
oxy]-butyric acid ethyl ester (0.05 g, 0.13 mmol) obtained in
Preparation Example 3 and 2-chloro-6-isopropylsulfanyl-pyridine
(0.024 g, 0.13 mmol) obtained in Preparation Example 10 were
reacted in the same manner as in Step A of Example 1 to obtain the
title compound (0.012 g, 23%).
[1892] .sup.1H-NMR (CDCl.sub.3) .delta. 8.46 (1H, s), 8.20 (1H, d),
7.90-7.80 (2H, m), 7.60 (2H, m), 7.22-7.12 (3H, m), 4.35-4.15 (5H,
m), 2.61 (2H, t), 2.22 (2H, t), 1.54 (6H, d), 1.30 (3H, t)
Step B:
4-[6-(6-isopropylsulfanyl-pyridin-2-yl)-naphthalen-2-yloxy]-butyri-
c Acid
[1893]
4-[6-(6-Isopropylsulfanyl-pyridin-2-yl)-naphthalen-2-yloxy]-butyric
acid ethyl ester (0.012 g, 0.03 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.010 g, 88%).
[1894] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, s), 8.15 (1H, d),
7.84-7.77 (2H, m), 7.53 (2H, m), 7.16-7.12 (2H, m), 7.09 (1H, d),
4.24-4.12 (3H, m), 2.65 (2H, t), 2.21 (2H, t), 1.49 (6H, d)
Example 7:
3-[6-(2-isopropylsulfanyl-pyridin-3-yl)-chroman-2-yl]-propionic
Acid
##STR00021##
[1895] Step A:
3-[6-(2-isopropylsulfanyl-pyridin-3-yl)-chroman-2-yl]-propionic
Acid Ethyl Ester
##STR00022##
[1897]
3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-chroman-2-yl]-p-
ropionic acid ethyl ester (0.06 g, 0.16 mmol) obtained in
Preparation Example 4 and 3-iodo-2-isopropylsulfanyl-pyridine
(0.046 g, 0.16 mmol) obtained in Preparation Example 9 were reacted
in the same manner as in Step A of Example 1 to obtain the title
compound (0.040 g, 66%).
[1898] .sup.1H-NMR (CDCl.sub.3) .delta. 8.40 (1H, d), 7.35 (1H, d),
7.18 (1H, d), 7.08 (1H, s), 7.00 (1H, t), 6.82 (1H, d), 4.17 (2H,
q), 4.15-4.00 (2H, m), 2.95-2.80 (2H, m), 2.70-2.50 (2H, m), 2.05
(3H, m), 1.80 (1H, m), 1.35 (6H, d), 1.28 (3H, t)
Step B:
3-[6-(2-isopropylsulfanyl-pyridin-3-yl)-chroman-2-yl]-propionic
Acid
[1899]
3-[6-(2-Isopropylsulfanyl-pyridin-3-yl)-chroman-2-yl]-propionic
acid ethyl ester (0.040 g, 0.10 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.028 g, 76%).
[1900] .sup.1H-NMR (CDCl.sub.3) .delta. 8.38 (1H, d), 7.33 (1H, d),
7.14 (1H, d), 7.07 (1H, s), 7.00 (1H, t), 6.83 (1H, d), 4.15-4.00
(2H, m), 2.95-2.75 (2H, m), 2.70-2.50 (2H, m), 2.05-1.90 (3H, m),
1.80 (1H, m), 1.34 (6H, d)
Example 8:
3-[6-(6-isopropylsulfanyl-pyridin-2-yl)-chroman-2-yl]-propionic
Acid
##STR00023##
[1901] Step A:
3-[6-(6-isopropylsulfanyl-pyridin-2-yl)-chroman-2-yl]-propionic
Acid Ethyl Ester
##STR00024##
[1903]
3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-chroman-2-yl]-p-
ropionic acid ethyl ester (0.06 g, 0.16 mmol) obtained in
Preparation Example 4 and 2-chloro-6-isopropylsulfanyl-pyridine
(0.031 g, 0.16 mmol) obtained in Preparation Example 10 were
reacted in the same manner as in Step A of Example 1 to obtain the
title compound (0.020 g, 33%).
[1904] .sup.1H-NMR (CDCl.sub.3) .delta. 7.79-7.72 (2H, m), 7.49
(1H, t), 7.33 (1H, d), 7.02 (1H, d), 6.84 (1H, d), 4.20-4.05 (4H,
m), 2.97-2.80 (2H, m), 2.70-2.50 (2H, m), 2.10-2.00 (3H, m), 1.82
(1H, m), 1.45 (6H, d), 1.26 (3H, t)
Step B:
3-[6-(6-isopropylsulfanyl-pyridin-2-yl)-chroman-2-yl]-propionic
Acid
[1905]
3-[6-(6-Isopropylsulfanyl-pyridin-2-yl)-chroman-2-yl]-propionic
acid ethyl ester (0.020 g, 0.05 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.014 g, 75%).
[1906] .sup.1H-NMR (CDCl.sub.3) .delta. 7.78-7.73 (2H, m), 7.46
(1H, t), 7.32 (1H, d), 7.01 (1H, d), 6.85 (1H, d), 4.14-4.07 (2H,
m), 2.97-2.82 (2H, m), 2.75-2.60 (2H, m), 2.08-2.00 (3H, m), 1.80
(1H, m), 1.45 (6H, m)
Example 9:
3-[6-(6-cyclopentyloxy-pyridin-2-yl)-chroman-2-yl]-propionic
Acid
##STR00025##
[1907] Step A:
3-[6-(6-cyclopentyloxy-pyridin-2-yl)-chroman-2-yl]-propionic Acid
Ethyl Ester
##STR00026##
[1909]
3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-chroman-2-yl]-p-
ropionic acid ethyl ester (0.06 g, 0.16 mmol) obtained in
Preparation Example 4 and 2-chloro-6-cyclopentyloxy-pyridine (0.033
g, 0.16 mmol) obtained in Preparation Example 12 were reacted in
the same manner as in Step A of Example 1 to obtain the title
compound (0.013 g, 21%).
[1910] .sup.1H-NMR (CDCl.sub.3) .delta. 7.77-7.70 (2H, m), 7.54
(1H, t), 7.20 (1H, d), 6.85 (1H, d), 6.54 (1H, d), 5.50 (1H, m),
4.13 (2H, q), 4.08 (1H, m), 3.00-2.50 (4H, m), 2.10-1.55 (12H, m),
1.24 (3H, t)
Step B:
3-[6-(6-cyclopentyloxy-pyridin-2-yl)-chroman-2-yl]-propionic
Acid
[1911] 3-[6-(6-Cyclopentyloxy-pyridin-2-yl)-chroman-2-yl]-propionic
acid ethyl ester (0.013 g, 0.03 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.010 g, 83%).
[1912] .sup.1H-NMR (CDCl.sub.3) .delta. 7.72-7.65 (2H, m), 7.45
(1H, t), 7.11 (1H, d), 6.79 (1H, d), 6.49 (1H, d), 5.45 (1H, m),
4.04 (1H, m), 2.95-2.50 (4H, m), 2.10-1.65 (12H, m)
Example 10:
3-[6-(2-cyclopentyloxy-pyridin-3-yl)-chroman-2-yl]-propionic
Acid
##STR00027##
[1913] Step A:
3-[6-(2-cyclopentyloxy-pyridin-3-yl)-chroman-2-yl]-propionic Acid
Ethyl Ester
##STR00028##
[1915]
3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-chroman-2-yl]-p-
ropionic acid ethyl ester (0.06 g, 0.16 mmol) obtained in
Preparation Example 4 and 2-cyclopentyloxy-3-iodo-pyridine (0.049
g, 0.16 mmol) obtained in Preparation Example 11 were reacted in
the same manner as in Step A of Example 1 to obtain the title
compound (0.030 g, 48%).
[1916] .sup.1H-NMR (CDCl.sub.3) .delta. 8.07 (1H, d), 7.56 (1H, d),
7.32-7.26 (2H, m), 6.85 (1H, t), 6.80 (1H, d), 5.49 (1H, m), 4.15
(2H, q), 4.10 (1H, m), 2.95-2.55 (4H, m), 2.10-1.55 (12H, m), 1.26
(3H, t)
Step B:
3-[6-(2-cyclopentyloxy-pyridin-3-yl)-chroman-2-yl]-propionic
Acid
[1917] 3-[6-(2-Cyclopentyloxy-pyridin-3-yl)-chroman-2-yl]-propionic
acid ethyl ester (0.030 g, 0.08 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.018 g, 67%).
[1918] .sup.1H-NMR (CDCl.sub.3) .delta. 8.09 (1H, d), 7.56 (1H, d),
7.31-7.26 (2H, m), 6.88 (1H, t), 6.81 (1H, d), 5.49 (1H, m), 4.08
(1H, m), 2.95-2.60 (4H, m), 2.10-1.65 (12H, m)
Example 11:
3-[6-(6-cyclopentyloxy-pyridin-2-yl)-1,2,3,4-tetrahydro-quinolin-2-yl]-pr-
opionic Acid
##STR00029##
[1919] Step A:
3-[6-(6-cyclopentyloxy-pyridin-2-yl)-1,2,3,4-tetrahydro-quinolin-2-yl]-pr-
opionic Acid Ethyl Ester
##STR00030##
[1921]
3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,4-tetrahy-
dro-quinolin-2-yl]-propionic acid ethyl ester (0.1 g, 0.30 mmol)
obtained in Preparation Example 6 and
2-chloro-6-cyclopentyloxy-pyridine (0.06 g, 0.30 mmol) obtained in
Preparation Example 12 were reacted in the same manner as in Step A
of Example 1 to obtain the title compound (0.035 g, 30%).
[1922] .sup.1H-NMR (CDCl.sub.3) .delta. 7.68 (2H, m), 7.51 (1H, t),
7.15 (1H, d), 6.56-6.48 (2H, m), 5.51 (1H, m), 4.16 (2H, q), 4.05
(1H, brs), 3.40 (1H, m), 2.90-2.80 (2H, m), 2.55-2.40 (2H, m),
2.10-1.60 (12H, m), 1.25 (3H, t)
Step B:
3-[6-(6-cyclopentyloxy-pyridin-2-yl)-1,2,3,4-tetrahydro-quinolin-2-
-yl]-propionic Acid
[1923]
3-[6-(6-Cyclopentyloxy-pyridin-2-yl)-1,2,3,4-tetrahydro-quinolin-2--
yl]-propionic acid ethyl ester (0.012 g, 0.03 mmol) obtained in
Step A was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.010 g, 91%).
[1924] .sup.1H-NMR (CDCl.sub.3) .delta. 7.68 (2H, m), 7.52 (1H, t),
7.16 (1H, d), 6.60-6.48 (2H, m), 5.52 (1H, m), 3.42 (1H, m),
2.90-2.80 (2H, m), 2.60-2.50 (2H, m), 2.05-1.60 (12H, m)
Example 12:
3-[6-(6-cyclopentyloxy-pyridin-2-yl)-1-methyl-1,2,3,4-tetrahydro-quinolin-
-2-yl]-propionic Acid
##STR00031##
[1925] Step A:
3-[6-(6-cyclopentyloxy-pyridin-2-yl)-1-methyl-1,2,3,4-tetrahydro-quinolin-
-2-yl]-propionic Acid Ethyl Ester
##STR00032##
[1927]
3-[6-(6-Cyclopentyloxy-pyridin-2-yl)-1,2,3,4-tetrahydro-quinolin-2--
yl]-propionic acid ethyl ester (0.012 g, 0.03 mmol) obtained in
Step A of Example 11 was dissolved in 5 mL of DCE. Formaldehyde
(0.005 g, 0.06 mmol) and acetic acid (0.002 g, 0.036 mmol) were
added thereto, and the mixture was stirred at room temperature for
1 hour. Sodium triacetoxyborohydride (0.013 g, 0.06 mmol) was added
to the reaction solution, and the reaction was carried out at room
temperature for 16 hours. After addition of 50 mL of water, the
reaction solution was extracted with DCM, dried with MgSO.sub.4 and
purified by column chromatography to obtain the title compound
(0.007 g, 58%).
[1928] .sup.1H-NMR (CDCl.sub.3) .delta. 7.79 (1H, d), 7.68 (1H, s),
7.54 (1H, t), 7.16 (1H, d), 6.61 (1H, d), 6.47 (1H, d), 5.52 (1H,
m), 4.13 (2H, q), 3.32 (1H, m), 3.01 (3H, s), 2.95-2.75 (2H, m),
2.50-2.30 (2H, m), 2.10-1.60 (12H, m), 1.24 (3H, t)
Step B:
3-[6-(6-cyclopentyloxy-pyridin-2-yl)-1-methyl-1,2,3,4-tetrahydro-q-
uinolin-2-yl]-propionic Acid
[1929]
3-[6-(6-Cyclopentyloxy-pyridin-2-yl)-1-methyl-1,2,3,4-tetrahydro-qu-
inolin-2-yl]-propionic acid ethyl ester (0.007 g, 0.02 mmol)
obtained in Step A was reacted in the same manner as in Step B of
Example 1 to obtain the title compound (0.006 g, 92%).
[1930] .sup.1H-NMR (CDCl.sub.3) .delta. 7.80 (1H, d), 7.68 (1H, s),
7.54 (1H, t), 7.18 (1H, d), 6.65 (1H, d), 6.47 (1H, d), 5.52 (1H,
m), 3.36 (1H, m), 3.02 (3H, s), 2.95-2.70 (2H, m), 2.55-2.30 (2H,
m), 2.10-1.60 (12H, m)
Example 13:
[6-(2-isopropylsulfanyl-pyridin-3-yl)-1-oxo-3,4-dihydro-1H-isoquinolin-2--
yl]-acetic Acid
##STR00033##
[1931] Step A:
[6-(2-isopropylsulfanyl-pyridin-3-yl)-1-oxo-3,4-dihydro-1H-isoquinolin-2--
yl]-acetic Acid Ethyl Ester
##STR00034##
[1933]
[1-Oxo-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-
-1H-isoquinolin-2-yl]-acetic acid ethyl ester (0.06 g, 0.16 mmol)
obtained in Preparation Example 7 and
3-iodo-2-isopropylsulfanyl-pyridine (0.047 g, 0.16 mmol) obtained
in Preparation Example 9 were reacted in the same manner as in Step
A of Example 1 to obtain the title compound (0.020 g, 33%).
[1934] .sup.1H-NMR (CDCl.sub.3) .delta. 8.46 (1H, d), 8.15 (1H, d),
7.41-7.35 (2H, m), 7.25 (1H, d), 7.04 (1H, t), 4.36 (2H, s), 4.22
(2H, q), 4.07 (1H, m), 3.73 (2H, t), 3.10 (2H, t), 1.37 (6H, d),
1.26 (3H, t)
Step B:
[6-(2-isopropylsulfanyl-pyridin-3-yl)-1-oxo-3,4-dihydro-1H-isoquin-
olin-2-yl]-acetic Acid
[1935]
[6-(2-Isopropylsulfanyl-pyridin-3-yl)-1-oxo-3,4-dihydro-1H-isoquino-
lin-2-yl]-acetic acid ethyl ester (0.020 g, 0.05 mmol) obtained in
Step A was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.012 g, 63%).
[1936] .sup.1H-NMR (CDCl.sub.3) .delta. 8.47 (1H, d), 8.13 (1H, d),
7.43-7.35 (2H, m), 7.25 (1H, d), 7.05 (1H, t), 4.40 (2H, s), 4.13
(1H, m), 3.74 (2H, t), 3.13 (2H, t), 1.36 (6H, d)
Example 14:
[6-(6-isopropylsulfanyl-pyridin-2-yl)-1-oxo-3,4-dihydro-1H-isoquinolin-2--
yl]-acetic Acid
##STR00035##
[1937] Step A:
[6-(6-isopropylsulfanyl-pyridin-2-yl)-1-oxo-3,4-dihydro-1H-isoquinolin-2--
yl]-acetic Acid Ethyl Ester
##STR00036##
[1939]
[1-Oxo-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-
-1H-isoquinolin-2-yl]-acetic acid ethyl ester (0.06 g, 0.16 mmol)
obtained in Preparation Example 7 and
2-chloro-6-isopropylsulfanyl-pyridine (0.031 g, 0.16 mmol) obtained
in Preparation Example 10 were reacted in the same manner as in
Step A of Example 1 to obtain the title compound (0.014 g,
23%).
[1940] .sup.1H-NMR (CDCl.sub.3) .delta. 8.17 (1H, d), 7.98 (1H, d),
7.89 (1H, s), 7.55 (1H, t), 7.47 (1H, d), 7.12 (1H, d), 4.36 (2H,
s), 4.30-4.15 (3H, m), 3.72 (2H, t), 3.17 (2H, t), 1.47 (6H, d),
1.28 (3H, t)
Step B:
[6-(6-isopropylsulfanyl-pyridin-2-yl)-1-oxo-3,4-dihydro-1H-isoquin-
olin-2-yl]-acetic Acid
[1941]
[6-(6-Isopropylsulfanyl-pyridin-2-yl)-1-oxo-3,4-dihydro-1H-isoquino-
lin-2-yl]-acetic acid ethyl ester (0.014 g, 0.04 mmol) obtained in
Step A was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.010 g, 78%).
[1942] .sup.1H-NMR (CDCl.sub.3) .delta. 8.17 (1H, d), 7.98 (1H, d),
7.89 (1H, s), 7.53 (1H, t), 7.45 (1H, d), 7.12 (1H, d), 4.40 (2H,
s), 4.15 (1H, m), 3.75 (2H, t), 3.16 (2H, t), 1.48 (6H, d)
Example 15:
3-[6-(2-cyclopentyloxy-pyridin-3-yl)-1-oxo-3,4-dihydro-1H-isoquinolin-2-y-
l]-propionic Acid
##STR00037##
[1943] Step A:
3-[6-(2-cyclopentyloxy-pyridin-3-yl)-1-oxo-3,4-dihydro-1H-isoquinolin-2-y-
l]-propionic Acid Methyl Ester
##STR00038##
[1945]
3-[I1-Oxo-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihy-
dro-1H-isoquinolin-2-yl]-propionic acid methyl ester (0.06 g, 0.16
mmol) obtained in Preparation Example 8 and
2-cyclopentyloxy-3-iodo-pyridine (0.048 g, 0.16 mmol) obtained in
Preparation Example 11 were reacted in the same manner as in Step A
of Example 1 to obtain the title compound (0.015 g, 23%).
[1946] .sup.1H-NMR (CDCl.sub.3) .delta. 8.17 (1H, d), 8.09 (1H, d),
7.62 (1H, d), 7.53 (1H, d), 7.37 (1H, s), 6.93 (1H, t), 5.53 (1H,
m), 3.85 (2H, t), 3.77-3.70 (5H, m), 3.00 (2H, t), 2.74 (2H, t),
2.00-1.60 (8H, m)
Step B:
3-[6-(2-cyclopentyloxy-pyridin-3-yl)-1-oxo-3,4-dihydro-1H-isoquino-
lin-2-yl]-propionic Acid
[1947]
3-[6-(2-Cyclopentyloxy-pyridin-3-yl)-1-oxo-3,4-dihydro-1H-isoquinol-
in-2-yl]-propionic acid methyl ester (0.015 g, 0.04 mmol) obtained
in Step A was reacted in the same manner as in Step B of Example 1
to obtain the title compound (0.020 g, 56%).
[1948] .sup.1H-NMR (CDCl.sub.3) .delta. 8.17 (1H, d), 8.06 (1H, d),
7.62 (1H, d), 7.52 (1H, d), 7.37 (1H, s), 6.93 (1H, t), 5.52 (1H,
m), 3.85 (2H, t), 3.71 (2H, t), 3.05 (2H, t), 2.82 (2H, t),
2.00-1.60 (8H, m)
Example 16:
3-[6-(2-isopropylsulfanyl-pyridin-3-yl)-1-oxo-3,4-dihydro-1H-isoquinolin--
2-yl]-propionic Acid
##STR00039##
[1949] Step A:
3-[6-(2-isopropylsulfanyl-pyridin-3-yl)-1-oxo-3,4-dihydro-1H-isoquinolin--
2-yl]-propionic Acid Methyl Ester
##STR00040##
[1951]
3-[I1-Oxo-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihy-
dro-1H-isoquinolin-2-yl]-propionic acid methyl ester (0.06 g, 0.16
mmol) obtained in Preparation Example 8 and
3-iodo-2-isopropylsulfanyl-pyridine (0.047 g, 0.16 mmol) obtained
in Preparation Example 9 were reacted in the same manner as in Step
A of Example 1 to obtain the title compound (0.030 g, 46%).
[1952] .sup.1H-NMR (CDCl.sub.3) .delta. 8.46 (1H, d), 8.11 (1H, d),
7.45-7.35 (2H, m), 7.25 (1H, d), 7.03 (1H, t), 4.07 (1H, m), 3.85
(2H, t), 3.75-3.65 (5H, m), 3.05 (2H, t), 2.75 (2H, t), 1.35 (6H,
d)
Step B:
3-[6-(2-isopropylsulfanyl-pyridin-3-yl)-1-oxo-3,4-dihydro-1H-isoqu-
inolin-2-yl]-propionic Acid
[1953]
3-[6-(2-Isopropylsulfanyl-pyridin-3-yl)-1-oxo-3,4-dihydro-1H-isoqui-
nolin-2-yl]-propionic acid methyl ester (0.030 g, 0.08 mmol)
obtained in Step A was reacted in the same manner as in Step B of
Example 1 to obtain the title compound (0.020 g, 69%).
[1954] .sup.1H-NMR (CDCl.sub.3) .delta. 8.46 (1H, d), 8.10 (1H, d),
7.45-7.35 (2H, m), 7.25 (1H, d), 7.05 (1H, t), 4.05 (1H, m), 3.90
(2H, t), 3.75 (2H, t), 3.05 (2H, t), 2.80 (2H, t), 1.34 (6H, d)
Example 17: 4-(3'-benzyloxy-3,5-difluoro-biphenyl-4-yloxy)-butyric
Acid
##STR00041##
[1955] Step A:
4-(3'-benzyloxy-3,5-difluoro-biphenyl-4-yloxy)-butyric Acid Ethyl
Ester
[1956] 2N Na.sub.2CO.sub.3 (0.5 mL) and 1,4-dioxane (5 mL) were
added to 1-benzyloxy-3-iodo-benzene (42 mg, 0.135 mmol) obtained in
Preparation Example 17,
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (50 mg, 0.135 mmol) obtained in Preparation
Example 16 and PdCl.sub.2(dppf)-DCM (5.5 mg, 0.0068 mmol), and the
mixture was stirred 2 hours under reflux. After termination of the
reaction, the reaction solution was cooled and filtered through
Celite. After addition of water, the reaction solution was
extracted with EtOAc to separate an organic layer. The organic
layer was dried with MgSO.sub.4, concentrated under reduced
pressure and purified by column chromatography (eluent,
EtOAc/Hex=1/10) to obtain the title compound (20 mg, 35%).
[1957] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.48-7.43 (m, 2H),
7.43-7.37 (m, 2H), 7.37-7.31 (m, 2H), 7.13-7.06 (m, 4H), 6.99-6.95
(m, 1H), 4.12 (s, 2H), 4.21 (t, 2H), 4.16 (q, 2H), 2.58 (t, 2H),
2.15-2.06 (m, 2H), 1.27 (t, 3H)
Step B: 4-(3'-benzyloxy-3,5-difluoro-biphenyl-4-yloxy)-butyric
Acid
[1958] 4-(3'-Benzyloxy-3,5-difluoro-biphenyl-4-yloxy)-butyric acid
ethyl ester (20 mg, 0.047 mmol) obtained in Step A was reacted in
the same manner as in Step B of Example 1 to obtain the title
compound (18 mg, 96%).
[1959] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.48-7.43 (m, 2H),
7.43-7.36 (m, 2H), 7.37-7.31 (m, 2H), 7.13-7.06 (m, 4H), 6.99-6.95
(m, 1H), 4.12 (s, 2H), 4.21 (t, 2H), 4.16 (q, 2H), 2.66 (t, 2H),
2.15-2.05 (m, 2H), 1.27 (t, 3H)
Example 18: 4-(3,5-difluoro-3'-isopropoxy-biphenyl-4-yloxy)-butyric
Acid
##STR00042##
[1960] Step A:
4-(3,5-difluoro-3'-isopropoxy-biphenyl-4-yloxy)-butyric Acid Ethyl
Ester
[1961] 2 N Na.sub.2CO.sub.3 (0.5 mL) and 1,4-dioxane (5 mL) were
added to 1-iodo-3-isopropoxy-benzene (35 mg, 0.135 mmol) obtained
in Preparation Example 18,
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (50 mg, 0.135 mmol) obtained in Preparation
Example 16 and PdCl.sub.2(dppf)-DCM (5.5 mg, 0.0068 mmol), and the
mixture was stirred for 2 hours under reflux. After termination of
the reaction, the reaction solution was cooled and filtered through
Celite. After addition of water, the reaction solution was
extracted with EtOAc to separate an organic layer. The organic
layer was dried with MgSO.sub.4, concentrated under reduced
pressure and purified by column chromatography (eluent,
EtOAc/Hex=1/10) to obtain the title compound (32 mg, 63%).
[1962] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.40-7.34 (m, 1H),
7.29-6.97 (m, 4H), 6.96-7.182 (m, 1H), 4.70-4.52 (m, 1H), 4.28-4.08
(m, 4H), 2.69-2.52 (m, 2H), 2.20-2.03 (m, 2H), 1.37 (d, 6H), 1.25
(t, 3H)
Step B: 4-(3,5-difluoro-3'-isopropoxy-biphenyl-4-yloxy)-butyric
Acid
[1963] 4-(3,5-Difluoro-3'-isopropoxy-biphenyl-4-yloxy)-butyric acid
ethyl ester (32 mg, 0.085 mmol) obtained in Step A was reacted in
the same manner as in Step B of Example 1 to obtain the title
compound (28 mg, 95%).
[1964] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.32 (t, 1H),
7.15-7.07 (m, 2H), 7.07-7.03 (m, 1H), 7.03-7.00 (m, 1H), 6.91-6.86
(m, 1H), 4.66-4.56 (m, 1H), 4.22 (t, 2H), 2.67 (t, 2H), 2.16-2.07
(m, 2H), 1.36 (d, 6H)
Example 19: 4-(3,5-difluoro-3'-propoxy-biphenyl-4-yloxy)-butyric
Acid
##STR00043##
[1965] Step A: 4-(3,5-difluoro-3'-propoxy-biphenyl-4-yloxy)-butyric
Acid Ethyl Ester
[1966] 1-Iodo-3-propoxy-benzene (35 mg, 0.135 mmol) obtained in
Preparation Example 19,
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (50 mg, 0.135 mmol) obtained in Preparation
Example 16 and PdCl.sub.2(dppf)-DCM (5.5 mg, 0.0068 mmol) were
reacted in the same manner as in Step A of Example 18 to obtain the
title compound (42 mg, 83%).
[1967] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.32 (t, 1H),
7.16-7.09 (m, 2H), 7.09-7.04 (m, 1H), 7.04-7.00 (m, 1H), 6.92-6.87
(m, 1H), 4.20 (t, 2H), 4.16 (q, 2H), 3.97 (t, 2H), 2.57 (t, 2H),
2.15-2.04 (m, 2H), 1.89-1.78 (m, 2H), 1.28 (t, 3H), 1.06 (t,
3H)
Step B: 4-(3,5-difluoro-3'-propoxy-biphenyl-4-yloxy)-butyric
Acid
[1968] 4-(3,5-Difluoro-3'-propoxy-biphenyl-4-yloxy)-butyric acid
ethyl ester (42 mg, 0.11 mmol) obtained in Step A was reacted in
the same manner as in Step B of Example 1 to obtain the title
compound (37 mg, 95%).
[1969] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.32 (t, 1H),
7.16-7.09 (m, 2H), 7.09-7.00 (m, 2H), 6.93-6.87 (m, 1H), 4.22 (t,
2H), 3.97 (t, 2H), 2.67 (t, 2H), 2.19-2.06 (m, 2H), 1.89-1.78 (m,
2H), 1.05 (t, 3H)
Example 20:
4-(3'-cyclopropylmethoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric
Acid
##STR00044##
[1970] Step A:
4-(3'-cyclopropylmethoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric
Acid Ethyl Ester
[1971] 1-Cyclopropylmethoxy-3-iodo-benzene (37 mg, 0.135 mmol)
obtained in Preparation Example 20,
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (50 mg, 0.135 mmol) obtained in Preparation
Example 16 and PdCl.sub.2(dppf)-DCM (5.5 mg, 0.0068 mmol) were
reacted in the same manner as in Step A of Example 18 to obtain the
title compound (20 mg, 38%).
[1972] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.32 (t, 1H),
7.16-7.09 (m, 2H), 7.09-7.05 (m, 1H), 7.05-7.02 (m, 1H), 6.92-6.87
(m, 1H), 4.20 (t, 2H), 4.16 (q, 2H), 3.85 (d, 2H), 2.59 (t, 2H),
2.15-2.05 (m, 2H), 1.35-1.21 (m, 1H), 1.27 (t, 3H), 0.71-0.62 (m,
2H), 0.41-0.34 (m, 2H)
Step B:
4-(3'-cyclopropylmethoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric
Acid
[1973]
4-(3'-Cyclopropylmethoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric
acid ethyl ester (20 mg, 0.05 mmol) obtained in Step A was reacted
in the same manner as in Step B of Example 1 to obtain the title
compound (18.4 mg, 99%).
[1974] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.32 (t, 1H),
7.15-7.09 (m, 2H), 7.09-7.05 (m, 1H), 7.05-7.02 (m, 1H), 6.92-6.87
(m, 1H), 4.22 (t, 2H), 3.85 (d, 2H), 2.67 (t, 2H), 2.15-2.06 (m,
2H), 1.33-1.21 (m, 1H), 0.70-0.62 (m, 2H), 0.41-0.33 (m, 2H)
Example 21:
4-(3'-cyclobutoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric Acid
##STR00045##
[1975] Step A:
4-(3'-cyclobutoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric Acid Ethyl
Ester
[1976] 1-Cyclobutoxy-3-iodo-benzene (37 mg, 0.135 mmol) obtained in
Preparation Example 21,
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (50 mg, 0.135 mmol) obtained in Preparation
Example 16 and PdCl.sub.2(dppf)-DCM (5.5 mg, 0.0068 mmol) were
reacted in the same manner as in Step A of Example 18 to obtain the
title compound (30 mg, 57%).
[1977] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.31 (t, 1H),
7.14-7.07 (m, 2H), 7.07-7.04 (m, 1H), 6.96-6.92 (m, 1H), 6.83-6.79
(m, 1H), 4.73-4.64 (m, 1H), 4.20 (t, 2H), 4.16 (q, 2H), 2.59 (t,
2H), 2.52-2.41 (m, 2H), 2.26-2.13 (m, 2H), 2.13-2.04 (m, 2H),
1.93-1.82 (m, 1H), 1.78-1.67 (m, 1H), 1.28 (t, 3H)
Step B: 4-(3'-cyclobutoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric
Acid
[1978] 4-(3'-Cyclobutoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric
acid ethyl ester (30 mg, 0.077 mmol) obtained in Step A was reacted
in the same manner as in Step B of Example 1 to obtain the title
compound (27 mg, 97%).
[1979] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.31 (t, 1H),
7.14-7.08 (m, 2H), 7.08-7.03 (m, 1H), 6.96-6.92 (m, 1H), 6.83-6.78
(m, 1H), 4.73-4.64 (m, 1H), 4.22 (t, 2H), 2.67 (t, 2H), 2.51-2.42
(m, 2H), 2.28-2.17 (m, 2H), 2.17-2.07 (m, 2H), 1.92-1.82 (m, 1H),
1.78-1.64 (m, 1H)
Example 22:
4-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-2,6-difluoro-phenoxy]-but-
yric Acid
##STR00046##
[1980] Step A:
4-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-2,6-difluoro-phenoxy]-but-
yric Acid Ethyl Ester
[1981] 7-Iodo-2,2-dimethyl-2,3-dihydro-benzofuran (35 mg, 0.13
mmol) obtained in Preparation Example 22,
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (47 mg, 0.13 mmol) obtained in Preparation
Example 16 and PdCl.sub.2(dppf)-DCM (5.2 mg, 0.0065 mmol) were
reacted in the same manner as in Step A of Example 18 to obtain the
title compound (20 mg, 40%).
[1982] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.35-7.27 (m, 2H),
7.20 (d, 1H), 7.11 (d, 1H), 6.88 (t, 1H), 4.23-4.12 (m, 4H), 3.04
(s, 2H), 2.58 (t, 2H), 2.14-2.04 (m, 2H), 1.51 (s, 6H), 1.26 (t,
3H)
Step B:
4-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-2,6-difluoro-pheno-
xy]-butyric Acid
[1983]
4-[4-(2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl)-2,6-difluoro-phenox-
y]-butyric acid ethyl ester (20 mg, 0.051 mmol) obtained in Step A
was reacted in the same manner as in Step B of Example 1 to obtain
the title compound (17 mg, 92%).
[1984] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.34-7.27 (m, 2H),
7.20 (d, 1H), 7.11 (d, 1H), 6.88 (t, 1H), 4.20 (t, 2H), 3.04 (s,
2H), 2.67 (t, 2H), 2.14-2.06 (m, 2H), 1.51 (s, 6H)
Example 23:
4-[4-(2,2-dimethyl-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenoxy]-butyric
Acid
##STR00047##
[1985] Step A:
4-[4-(2,2-dimethyl-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenoxy]-butyric
Acid Ethyl Ester
[1986] 4-Iodo-2,2-dimethyl-benzo[1,3]dioxole (40 mg, 0.145 mmol)
obtained in Preparation Example 23,
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (53.6 mg, 0.145 mmol) obtained in
Preparation Example 16 and PdCl.sub.2(dppf)-DCM (5.9 mg, 0.0073
mmol) were reacted in the same manner as in Step A of Example 18 to
obtain the title compound (19 mg, 33%).
[1987] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.32-7.24 (m, 2H),
6.94-6.81 (m, 2H), 6.74-6.70 (m, 1H), 4.20 (t, 2H), 4.15 (q, 2H),
2.58 (t, 2H), 2.13-2.05 (m, 2H), 1.72 (s, 6H), 1.26 (t, 3H)
Step B:
4-[4-(2,2-dimethyl-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenoxy]-bu-
tyric Acid
[1988]
4-[4-(2,2-Dimethyl-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenoxy]-but-
yric acid ethyl ester (19 mg, 0.048 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (16 mg, 91%).
[1989] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.32-7.22 (m, 2H),
6.94-6.78 (m, 2H), 6.74-6.68 (m, 1H), 4.21 (t, 2H), 2.65 (t, 2H),
2.14-2.03 (m, 2H), 1.72 (s, 6H)
Example 24:
4-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]butanenitrile
##STR00048##
[1991] 4-(2-Cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenol
(0.06 g, 0.204 mmol) obtained in Preparation Example 24 was
dissolved in DMF (3 mL), and 4-bromobutanenitrile (0.02 mL, 0.204
mmol) was added thereto. Cs.sub.2CO.sub.3 (0.133 g, 0.108 mmol) was
added thereto, and the mixture was stirred at room temperature for
16 hours. After addition of brine aqueous solution, the reaction
solution was extracted with EtOAc. The organic layer was dried with
anhydrous magnesium sulfate and purified by column chromatography
(eluent, EtOAc/Hex=1/2.5) to obtain the title compound (0.056 g,
76%).
[1992] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, m), 7.32
(1H, m), 7.01 (3H, m), 4.43 (1H, m), 4.30 (2H, t), 2.69 (2H, t),
2.52 (2H, m), 2.15 (2H, m), 2.04 (4H, m)
Example 25:
2-cyclobutylsulfanyl-3-{3,5-difluoro-4-[3-(1H-tetrazol-5-yl)propoxy]pheny-
l}pyridin
##STR00049##
[1994]
4-[4-(2-Cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]butaneni-
trile (0.056 g, 0.155 mmol) obtained in Example 24, sodium azide
(0.029 g, 0.434 mmol) and ammonium chloride (0.024 g, 0.434 mmol)
were dissolved in DMF (3 mL), and the mixture was stirred at
120.degree. C. for 16 hours. After termination of the reaction, the
reaction solution was diluted with water and extracted with EtOAc.
The organic layer was dried with anhydrous magnesium sulfate and
purified by column chromatography (eluent, MeOH/DCM=1/20) to obtain
the title compound (0.004 g, 7.2%).
[1995] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, m), 7.32
(1H, m), 7.03 (3H, m), 4.43 (1H, m), 4.31 (2H, t), 3.34 (2H, t),
2.53 (2H, m), 2.32 (2H, m), 2.06 (4H, m)
Example 26:
2-cyclobutylsulfanyl-3-{4-[3-(1H-tetrazol-5-yl)propyl]phenyl}pyridine
##STR00050##
[1996] Step A:
4-[4-(2-cyclobutylsulfanyl-3-pyridyl)phenyl]butanenitrile
##STR00051##
[1998] 2-Cyclobutylsulfanyl-3-iodo-pyridine (0.038 g, 0.177 mmol)
obtained in Preparation Example 13 and
4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]butanenitrile
(0.045 g, 0.166 mmol) obtained in Preparation Example 25 were
reacted in the same manner as in Step A of Example 1 to obtain the
title compound (0.03 g, 55%).
[1999] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.39 (1H, m), 7.34
(3H, m), 7.26 (2H, m), 7.00 (1H, m), 4.22 (1H, m), 2.83 (2H, t),
2.48 (2H, m), 2.37 (2H, t), 2.03 (6H, m)
Step B:
2-cyclobutylsulfanyl-3-{4-[3-(1H-tetrazol-5-yl)propyl]phenyl}pyrid-
ine
[2000] 4-[4-(2-Cyclobutylsulfanyl-pyridin-3-yl)phenyl]butanenitrile
(0.03 g, 0.097 mmol) obtained in Step A was reacted in the same
manner as in Example 25 to obtain the title compound (0.001 g,
4.6%).
[2001] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.39 (1H, m), 7.34
(3H, m), 7.26 (2H, m), 7.03 (1H, m), 4.41 (1H, m), 3.00 (2H, t),
2.77 (2H, m), 2.49 (2H, m), 2.20 (2H, m), 2.01 (4H, m)
Example 27: 5-[4-(2-cyclobutylsulfanyl-3-pyridyl)phenyl]pentanoic
Acid
##STR00052##
[2002] Step A:
5-[4-(2-cyclobutylsulfanyl-3-pyridyl)phenyl]pentanoic Acid Ethyl
Ester
##STR00053##
[2004] 2-Cyclobutylsulfanyl-3-iodo-pyridine (0.08 g, 0.27 mmol)
obtained in Preparation Example 13 and
5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pentanoic
acid ethyl ester (0.085 g, 0.25 mmol) obtained in Preparation
Example 26 were reacted in the same manner as in Step A of Example
1 to obtain the title compound (0.063 g, 62%).
[2005] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.37 (1H, m), 7.33
(3H, m), 7.26 (2H, m), 7.00 (1H, m), 4.41 (1H, m), 4.12 (2H, q),
2.68 (2H, m), 2.48 (2H, m), 2.33 (2H, m), 1.99 (4H, m), 1.71 (4H,
m), 1.24 (3H, t)
Step B: 5-[4-(2-cyclobutylsulfanyl-3-pyridyl)phenyl]pentanoic
Acid
[2006] 5-[4-(2-Cyclobutylsulfanyl-3-pyridyl)phenyl]pentanoic acid
ethyl ester (0.063 g, 0.17 mmol) obtained in Step A was dissolved
in EtOH (2 mL). 1N NaOH (1 mL) was added thereto, and the mixture
was stirred at room temperature for 3 hours. After termination of
the reaction, the reaction solution was concentrated under reduced
pressure, and residues were diluted with water. The water layer was
adjusted to pH 2-3 by the use of 1N HCl and extracted with ethyl
acetate. The organic layer was dried with anhydrous magnesium
sulfate and purified by column chromatography (eluent,
EtOAc/Hex=1/2) to obtain the title compound (0.044 g, 75%).
[2007] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.37 (1H, m), 7.31
(3H, m), 7.26 (2H, m), 7.00 (1H, m), 4.41 (1H, m), 2.68 (2H, m),
2.48 (2H, m), 2.40 (2H, m), 1.99 (4H, m), 1.72 (4H, m)
Example 28: 5-[4-(6-cyclopentylsulfanyl-2-pyridyl)phenyl]pentanoic
Acid
##STR00054##
[2009] 2-Chloro-6-cyclopentylsulfanyl-pyridine (0.042 g, 0.196
mmol) obtained in Preparation Example 14 and
5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pentanoic
acid ethyl ester (0.061 g, 0.183 mmol) obtained in Preparation
Example 26 were reacted in the same manner as in Example 1 to
obtain the title compound (0.015 g, 21%).
[2010] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.94 (2H, m), 7.49
(1H, m), 7.38 (1H, m), 7.26 (2H, m), 7.06 (1H, m), 4.18 (1H, m),
2.68 (2H, m), 2.38 (2H, m), 2.24 (2H, m), 1.76 (2H, m), 1.72-1.60
(8H, m)
Example 29: 5-[4-(2-cyclopentylsulfanyl-3-pyridyl)phenyl]pentanoic
Acid
##STR00055##
[2012] 2-Cyclopentylsulfanyl-3-iodo-pyridine (0.03 g, 0.14 mmol)
obtained in Preparation Example 15 and
5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pentanoic
acid ethyl ester (0.044 g, 0.131 mmol) obtained in Preparation
Example 26 were reacted in the same manner as in Example 1 to
obtain the title compound (0.017 g, 34%).
[2013] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.39 (1H, m), 7.33
(3H, m), 7.26 (2H, m), 7.01 (1H, m), 4.07 (1H, m), 2.67 (2H, m),
2.39 (2H, m), 2.17 (2H, m), 1.70 (6H, m), 1.65 (4H, m)
Example 30:
2-cyclobutylsulfanyl-3-[3,5-difluoro-4-(1H-tetrazol-5-ylmethoxy)phenyl]py-
ridine
##STR00056##
[2014] Step A:
2-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]acetonitrile
##STR00057##
[2016] 4-(2-Cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenol
(0.103 g, 0.351 mmol) obtained in Preparation Example 24 was
dissolved in acetone (5 mL). Bromoacetonitrile (0.03 mL, 0.421
mmol) and K.sub.2CO.sub.3 (0.058 g, 0.421 mmol) were added thereto,
and the mixture was stirred at 70.degree. C. for 2 hours, and
stirred at room temperature for 16 hours. After termination of the
reaction, the reaction solution was diluted with water and
extracted with EtOAc. The organic layer was dried with anhydrous
magnesiumsulfate and purified by column chromatography (eluent,
MeOH/DCM=1/21) to obtain the title compound (0.104 g, 89%).
[2017] .sup.1H-NMR (CDCl.sub.3) .delta. 8.43 (1H, m), 7.33 (1H, m),
7.05 (3H, m), 4.91 (2H, s), 4.41 (1H, m), 2.52 (2H, m), 2.05 (4H,
m)
Step B:
2-cyclobutylsulfanyl-3-[3,5-difluoro-4-(1H-tetrazol-5-ylmethoxy)ph-
enyl]pyridine
[2018]
2-[4-(2-Cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]acetonit-
rile (0.104 g, 0.312 mmol) obtained in Step A was reacted in the
same manner as in Example 25 to obtain the title compound (0.024 g,
20%).
[2019] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.43 (1H, m), 7.31
(1H, m), 7.04 (3H, m), 5.63 (2H, s), 4.41 (1H, m), 2.50 (2H, m),
2.03 (4H, m)
Example 31:
5-[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)phenyl]pentanoic
Acid
##STR00058##
[2021] 3-Iodo-2-propylsulfanyl-pyridine (0.082 g, 0.293 mmol)
obtained in Preparation Example 28 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pe-
ntanoic acid ethyl ester (0.10 g, 0.274 mmol) obtained in
Preparation Example 27 were reacted in the same manner as in
Example 1 to obtain the title compound (0.057 g, 48%).
[2022] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.44 (1H, m), 7.35
(1H, m), 7.04 (1H, m), 6.94 (2H, m), 3.14 (2H, t), 2.74 (2H, t),
2.42 (2H, t), 1.70 (6H, m), 1.00 (3H, t)
Example 32:
5-[4-(6-cyclobutoxy-2-pyridyl)-2,6-difluoro-phenyl]pentanoic
Acid
##STR00059##
[2024] 2-Chloro-6-cyclobutoxy-pyridine (0.017 g, 0.091 mmol)
obtained in Preparation Example 29 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pe-
ntanoic acid ethyl ester (0.031 g, 0.085 mmol) obtained in
Preparation Example 27 were reacted in the same manner as in
Example 1 to obtain the title compound (0.015 g, 49%).
[2025] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.60 (1H, t), 7.50
(2H, m), 7.28 (1H, m), 6.66 (1H, d), 5.27 (1H, m), 2.73 (2H, t),
2.52 (2H, m), 2.41 (2H, t), 2.19 (2H, m), 1.85 (1H, m), 1.72 (5H,
m)
Example 33:
5-[4-(6-cyclopentoxy-2-pyridyl)-2,6-difluoro-phenyl]pentanoic
Acid
##STR00060##
[2027] 2-Chloro-6-cyclopentyloxy-pyridine (0.018 g, 0.091 mmol)
obtained in Preparation Example 12 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pe-
ntanoic acid ethyl ester (0.031 g, 0.085 mmol) obtained in
Preparation Example 27 were reacted in the same manner as in
Example 1 to obtain the title compound (0.017 g, 47%).
[2028] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.49 (1H, t), 7.52
(2H, m), 7.22 (1H, m), 6.64 (1H, d), 5.51 (1H, m), 2.73 (2H, t),
2.40 (2H, t), 2.05 (2H, m), 1.82-1.60 (10H, m)
Example 34:
5-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenyl]pentanoic
Acid
##STR00061##
[2030] 4-Bromo-2,2-difluoro-benzo[1,3]dioxole (0.059 g, 0.248 mmol)
and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pe-
ntanoic acid ethyl ester (0.086 g, 0.232 mmol) obtained in
Preparation Example 27 were reacted in the same manner as in
Example 1 to obtain the title compound (0.038 g, 44%).
[2031] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.26-7.17 (3H, m),
7.07 (1H, m), 7.05 (1H, m), 2.75 (2H, m), 2.41 (2H, m), 1.71-1.60
(4H, m)
Example 35:
5-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]pentanoic
Acid
##STR00062##
[2033] 2-Cyclobutylsulfanyl-3-iodo-pyridine (0.025 g, 0.084 mmol)
obtained in Preparation Example 13 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pe-
ntanoic acid ethyl ester (0.029 g, 0.078 mmol) obtained in
Preparation Example 27 were reacted in the same manner as in
Example 1 to obtain the title compound (0.01 g, 34%).
[2034] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, m), 7.33
(1H, m), 7.03 (1H, m), 6.93 (2H, m), 4.42 (1H, m), 2.73 (2H, t),
2.49 (2H, m), 2.42 (2H, t), 2.10-1.95 (4H, m), 1.73 (4H, m)
Example 36:
5-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]pentanoic
Acid
##STR00063##
[2036] 2-Cyclopentylsulfanyl-3-iodo-pyridine (0.034 g, 0.159 mmol)
obtained in Preparation Example 15 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pe-
ntanoic acid ethyl ester (0.044 g, 0.12 mmol) obtained in
Preparation Example 27 were reacted in the same manner as in
Example 1 to obtain the title compound (0.015 g, 33%).
[2037] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.43 (1H, m), 7.33
(1H, m), 7.03 (1H, m), 6.94 (2H, m), 4.09 (1H, m), 2.73 (2H, t),
2.42 (2H, m), 2.21 (2H, m), 1.71-1.57 (10H, m)
Example 37:
5-[4-(2-cyclopentoxy-3-pyridyl)-2,6-difluoro-phenyl]pentanoic
Acid
##STR00064##
[2039] 2-cyclopentyloxy-3-iodo-pyridine (0.026 g, 0.089 mmol)
obtained in Preparation Example 11 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pe-
ntanoic acid ethyl ester (0.03 g, 0.084 mmol) obtained in
Preparation Example 27 were reacted in the same manner as in
Example 1 to obtain the title compound (0.014 g, 44%).
[2040] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.15 (1H, m), 7.58
(1H, m), 7.09 (2H, m), 6.93 (1H, m), 5.52 (1H, m), 2.73 (2H, t),
2.42 (2H, m), 1.95 (2H, m), 1.71-1.57 (10H, m)
Example 38:
{2-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]ethoxy}acetic
Acid
##STR00065##
[2041] Step A:
{2-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]ethoxy}acetic
Acid Tert-Butyl Ester
##STR00066##
[2043] 2-Cyclobutylsulfanyl-3-iodo-pyridine (0.031 g, 0.107 mmol)
obtained in Preparation Example 13 and
{2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]e-
thoxy}acetic acid tert-butyl ester (0.04 g, 0.10 mmol) obtained in
Preparation Example 30 were reacted in the same manner as in Step A
of Example 1 to obtain the title compound (0.025 g, 58%).
Step B:
{2-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]ethoxy}-
acetic Acid
[2044]
{2-[4-(2-Cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]ethoxy}a-
cetic acid tert-butyl ester (0.025 g, 0.057 mmol) obtained in Step
A was dissolved in DCM (3 mL). TFA (1 mL) was added thereto, and
the mixture was stirred for 4 hours. After termination of the
reaction, the reaction solution was concentrated under reduced
pressure and washed with Et.sub.2O and DCM. The reaction product
was dried with anhydrous magnesium sulfate and purified by column
chromatography (eluent, EtOAc/Hex=1/2) to obtain the title compound
(0.016 g, 76%).
[2045] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, m), 7.33
(1H, m), 7.03 (1H, m), 6.97 (2H, m), 4.42 (1H, m), 4.13 (2H, s),
3.83 (2H, t), 3.07 (2H, m), 2.51 (2H, m), 2.10-1.95 (4H, m)
Example 39: 5-[4-(2-cyclobutylsulfanyl-3-pyridyl)phenyl]hexanoic
Acid
##STR00067##
[2047] 2-Cyclobutylsulfanyl-3-iodo-pyridine (0.033 g, 0.111 mmol)
obtained in Preparation Example 13 and
5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]hexanoic
acid ethyl ester (0.04 g, 0.104 mmol) obtained in Preparation
Example 31 were reacted in the same manner as in Example 1 to
obtain the title compound (0.021 g, 51%).
[2048] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.38 (1H, m), 7.36
(3H, m), 7.26 (2H, m), 7.01 (1H, m), 4.42 (1H, m), 2.75 (1H, m),
2.49 (2H, m), 2.36 (2H, m), 2.10-2.00 (4H, m), 1.67-1.50 (4H, m),
1.30 (3H, d)
Example 40: 5-[4-(6-cyclobutoxy-2-pyridyl)-phenyl]hexanoic Acid
##STR00068##
[2050] 2-Chloro-6-cyclobutoxy-pyridine (0.038 g, 0.206 mmol)
obtained in Preparation Example 29 and
5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]hexanoic
acid ethyl ester (0.051 g, 0.147 mmol) obtained in Preparation
Example 31 were reacted in the same manner as in Example 1 to
obtain the title compound (0.032 g, 63%).
[2051] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.94 (2H, d), 7.59
(1H, m), 7.23 (3H, m), 6.61 (1H, d), 5.29 (1H, m), 2.76 (1H, m),
2.53 (2H, m), 2.33 (2H, m), 2.20 (2H, m), 1.90 (1H, m), 1.80-1.50
(5H, m), 1.28 (3H, d)
Example 41:
5-[4-(6-cyclobutoxy-2-pyridyl)-2,6-difluoro-phenyl]hexanoic
Acid
##STR00069##
[2053] 2-Chloro-6-cyclobutoxy-pyridine (0.068 g, 0.371 mmol)
obtained in Preparation Example 29 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]h-
exanoic acid ethyl ester (0.062 g, 0.337 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 1 to obtain the title compound (0.030 g, 23%).
[2054] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.61 (1H, t), 7.49
(2H, d), 7.23 (1H, m), 6.66 (1H, d), 5.27 (1H, m), 3.24 (1H, m),
2.54 (2H, m), 2.35 (2H, t), 2.20 (2H, m), 1.87 (2H, m), 1.74 (2H,
m), 1.70-1.45 (2H, m), 1.25 (3H, d)
Example 42:
5-[4-(2-ethylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]hexanoic
Acid
##STR00070##
[2056] 2-Ethylsulfanyl-3-iodo-pyridine (0.041 g, 0.154 mmol)
obtained in Preparation Example 33 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.047 g, 0.144 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 1 to obtain the title compound (0.011 g, 21%).
[2057] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.44 (1H, m), 7.37
(1H, m), 7.04 (1H, m), 6.93 (2H, d), 3.27 (1H, m), 3.18 (2H, q),
2.37 (2H, t), 1.85 (1H, m), 1.80-1.50 (3H, m), 1.40-1.30 (6H,
m)
Example 43:
5-[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)-phenyl]hexanoic
Acid
##STR00071##
[2059] 3-Iodo-2-propylsulfanyl-pyridine (0.040 g, 0.143 mmol)
obtained in Preparation Example 28 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.044 g, 0.133 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 1 to obtain the title compound (0.01 g, 18%).
[2060] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.44 (1H, m), 7.35
(1H, m), 7.04 (1H, m), 6.94 (2H, d), 3.24 (1H, m), 3.14 (2H, t),
2.38 (2H, t), 1.85 (1H, m), 1.75-1.60 (5H, m), 1.38 (3H, d), 1.02
(3H, t)
Example 44:
4-[1-methyl-5-(2-phenoxyphenyl)benzimidazol-2-yl]butanoic Acid
##STR00072##
[2061] Step A:
5-[(2-amino-4-bromo-N-methyl-anilino)-5-oxo-pentanoic Acid Ethyl
Ester
##STR00073##
[2063] 4-Bromo-N,N-dimethylaniline (0.341 g, 1.69 mmol) was
dissolved in DCM (8 mL). 5-Chloro-5-oxo-pentanoic acid ethyl ester
(0.217 mL, 1.54 mmol) was slowly added thereto at 0.degree. C. TEA
(0.472 mL, 3.39 mmol) was added thereto at 0.degree. C., and the
mixture was stirred at room temperature for 16 hours. After
termination of the reaction, the reaction solution was diluted with
water and extracted with DCM. The organic layer was dried with
anhydrous magnesium sulfate and used for the next step without
purification.
Step B: 4-(5-bromo-1-methyl-benzimidazol-2-yl)butanoic Acid
##STR00074##
[2065] 5-[(2-Amino-4-bromo-N-methyl-anilino)-5-oxo-pentanoic acid
ethyl ester obtained in Step A was dissolved in AcOH (4 mL) and
stirred at 75.degree. C. for 16 hours. The solvent was distilled
under reduced pressure, and the reaction product was washed with
toluene and distilled under reduced pressure. The obtained product
was used for the next step without purification.
Step C: 4-(5-bromo-1-methyl-benzimidazol-2-yl)butanoic Acid Methyl
Ester
##STR00075##
[2067] Diazomethane (2.5 mL) was added to
4-(5-bromo-1-methyl-benzimidazol-2-yl)butanoic acid (0.091 g, 0.30
mmol) obtained in Step B, and the solvent was distilled under
reduced pressure to obtain the title compound (0.58 g, 63%).
[2068] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.84 (1H, s), 7.35
(1H, d), 7.17 (1H, d), 3.74 (3H, s), 3.67 (3H, s), 2.95 (2H, t),
2.52 (2H, t), 2.21 (2H, m)
Step D: 4-[1-methyl-5-(2-phenoxyphenyl)benzimidazol-2-yl]butanoic
Acid Methyl Ester
##STR00076##
[2070] 2-Phenoxyphenylboronic acid (0.058 g, 0.269 mmol) and
4-(5-bromo-1-methyl-benzimidazol-2-yl)butanoic acid methyl ester
(0.04 g, 0.134 mmol) obtained in Step C were dissolved in DME (3
mL) and water (0.3 mL), and charged with N.sub.2 gas for 5 minutes.
Tetrakis(triphenylphosphine)palladium(0) (0.005 g, 0.004 mmol) and
Cs.sub.2CO.sub.3 (0.175 g, 0.538 mmol) were added thereto, and the
mixture was stirred at 80.degree. C. for 8 hours. After termination
of the reaction, the reaction solution was diluted with water and
extracted with EtOAc. The organic layer was dried with anhydrous
magnesium sulfate and purified by column chromatography (eluent,
EtOAc/Hex=1/1) to obtain the title compound (0.023 g, 21%).
[2071] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.88 (1H, m),
7.70-7.60 (5H, m), 7.20 (4H, m), 7.10 (1H, m), 6.90 (1H, m), 3.74
(3H, s), 3.64 (3H, s), 2.95 (2H, t), 2.51 (2H, t), 2.19 (2H, m)
Step E: 4-[1-methyl-5-(2-phenoxyphenyl)benzimidazol-2-yl]butanoic
Acid
[2072] 4-[1-Methyl-5-(2-phenoxyphenyl)benzimidazol-2-yl]butanoic
acid methyl ester (0.023 g, 0.057 mmol) obtained in Step D was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.003 g, 14%).
[2073] NMR: 1H-NMR (MeOD) .delta. 7.74 (1H, m), 7.53 (1H, m), 7.45
(2H, s), 7.35 (1H, m), 7.29 (1H, m), 7.21 (2H, m), 7.06 (1H, m),
6.95 (1H, m), 6.85 (2H, d), 3.82 (3H, s), 3.02 (2H, t), 2.42 (2H,
t), 2.13 (2H, m)
Example 45:
3-[1-methyl-5-(2-phenoxyphenyl)benzimidazol-2-yl]propanoic Acid
##STR00077##
[2074] Step A: 4-(2-amino-4-bromo-N-methyl-anilino)-4-oxo-butanoic
Acid Ethyl Ester
##STR00078##
[2076] 4-Bromo-N,N-dimethylaniline (0.196 g, 0.974 mmol) was
dissolved in DCM (8 mL). 3-Chlorocarbonyl-propionic acid ethyl
ester (0.125 mL, 0.886 mmol) was slowly added thereto at 0.degree.
C. TEA (0.273 mL, 1.955 mmol) was added thereto at 0.degree. C.,
and the mixture was stirred at room temperature for 16 hours. After
termination of the reaction, the reaction solution was diluted with
water and extracted with DCM. The organic layer was dried with
anhydrous magnesium sulfate and used for the next step with simple
filter purification.
Step B: 3-(5-bromo-1-methyl-benzimidazol-2-yl)propanoic Acid Ethyl
Ester
##STR00079##
[2078] 4-(2-Amino-4-bromo-N-methyl-anilino)-4-oxo-butanoic acid
ethyl ester (0.238 g, 0.722 mmol) obtained in Step A was dissolved
in AcOH (5 mL) and stirred at 75.degree. C. for 16 hours. The
solvent was distilled under reduced pressure, and the product was
washed with toluene and distilled under reduced pressure. The
obtained product was used for the next step with simple filter
purification.
[2079] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.83 (1H, s), 7.34
(1H, d), 7.17 (1H, d), 4.14 (2H, q), 3.76 (3H, s), 3.15 (2H, t),
3.01 (2H, t), 1.26 (2H, t)
Step C: 3-[1-methyl-5-(2-phenoxyphenyl)benzimidazol-2-yl]propanoic
Acid
[2080] 2-Phenoxyphenylboronic acid (0.109 g, 0.507 mmol) and
3-(5-bromo-1-methyl-benzimidazol-2-yl)propanoic acid ethyl ester
(0.079 g, 0.253 mmol) obtained in Step B were sequentially reacted
in the same manner as in Step D of Example 44 and Step B of Example
1 to obtain the title compound (0.011 g, 11%).
[2081] NMR: 1H-NMR (MeOD) .delta. 7.74 (1H, m), 7.53 (1H, m), 7.47
(2H, s), 7.36 (1H, m), 7.33 (1H, m), 7.23 (2H, m), 7.05 (1H, m),
7.03 (1H, m), 6.84 (2H, d), 3.83 (3H, s), 3.19 (2H, t), 2.92 (2H,
t)
Example 46:
5-[2,6-difluoro-4-(2-isopropoxy-3-pyridyl)phenyl]hexanoic Acid
##STR00080##
[2083] 3-Iodo-2-isopropoxy-pyridine (0.052 g, 0.197 mmol) obtained
in Preparation Example 34 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.071 g, 0.184 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 1 to obtain the title compound (0.039 g, 57%).
[2084] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.14 (1H, m), 7.59
(1H, m), 7.10 (2H, m), 6.92 (1H, m), 5.42 (1H, m), 3.23 (1H, m),
2.37 (2H, t), 1.85 (1H, m), 1.80-1.50 (3H, m), 1.37 (9H, m)
Example 47:
5-(2'-cyclopentylamino-3,5-difluoro-bisphenyl-4-yl)hexanoic
Acid
##STR00081##
[2086] N-cyclopentyl-2-iodo-aniline (0.056 g, 0.195 mmol) obtained
in Preparation Example 35 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.07 g, 0.182 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 1 to obtain the title compound (0.035 g, 50%).
[2087] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.25 (1H, m), 7.03
(1H, m), 6.90 (2H, d), 6.70 (2H, m), 4.12 (1H, m), 3.23 (1H, m),
2.38 (2H, t), 2.00 (2H, m), 1.85 (1H, m), 1.80-1.50 (8H, m),
1.50-1.40 (5H, m)
Example 48:
5-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]hexanoic
Acid
##STR00082##
[2089] 2-Cyclobutylsulfanyl-3-iodo-pyridine (0.047 g, 0.161 mmol)
obtained in Preparation Example 13 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]h-
exanoic acid ethyl ester (0.049 g, 0.128 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 1 to obtain the title compound (0.018 g, 39%).
[2090] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, m), 7.34
(1H, m), 7.03 (1H, m), 6.93 (2H, d), 4.43 (1H, m), 3.25 (1H, m),
2.52 (2H, m), 2.38 (2H, t), 2.12-2.00 (4H, m), 1.85 (1H, m), 1.75
(2H, m), 1.58 (1H, m), 1.38 (3H, d)
Example 49:
5-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]hexanoic
Acid
##STR00083##
[2092] 2-Cyclopentylsulfanyl-3-iodo-pyridine (0.03 g, 0.14 mmol)
obtained in Preparation Example 15 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]h-
exanoic acid ethyl ester (0.043 g, 0.131 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 1 to obtain the title compound (0.015 g, 28%).
[2093] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.43 (1H, m), 7.33
(1H, m), 7.02 (1H, m), 6.92 (2H, d), 4.08 (1H, m), 3.23 (1H, m),
2.37 (2H, t), 2.20 (2H, m), 1.80 (1H, m), 1.80-1.50 (9H, m), 1.36
(3H, d)
Example 50:
5-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)-phenyl]hexanoic
Acid
##STR00084##
[2095] 3-Iodo-2-isopropylsulfanyl-pyridine (0.039 g, 0.139 mmol)
obtained in Preparation Example 9 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.043 g, 0.131 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 1 to obtain the title compound (0.013 g, 28%).
[2096] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.44 (1H, m), 7.35
(1H, m), 7.04 (1H, m), 6.92 (2H, d), 4.06 (1H, m), 3.25 (1H, m),
2.38 (2H, t), 1.83 (1H, m), 1.74 (2H, m), 1.58 (1H, m), 1.36 (9H,
m)
Example 51:
5-[4-(2-cyclopentoxy-3-pyridyl)-2,6-difluoro-phenyl]hexanoic
Acid
##STR00085##
[2098] 2-Cyclopentyloxy-3-iodo-pyridine (0.049 g, 0.169 mmol)
obtained in Preparation Example 11 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.052 g, 0.158 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 1 to obtain the title compound (0.026 g, 40%).
[2099] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.15 (1H, m), 7.59
(1H, m), 7.09 (2H, d), 6.92 (1H, m), 5.52 (1H, m), 3.23 (1H, m),
2.37 (2H, t), 1.96 (2H, m), 1.80-1.50 (10H, m), 1.37 (3H, d)
Example 52:
5-(3'-cyclopentylamino-3,5-difluoro-biphenyl-4-yl)-hexanoic
Acid
##STR00086##
[2101] 3-Bromo-N-cyclopentyl-aniline (0.043 g, 0.178 mmol) obtained
in Preparation Example 36 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.062 g, 0.162 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 1 to obtain the title compound (0.03 g, 47%).
[2102] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.20 (1H, m), 7.02
(2H, d), 6.80 (1H, m), 6.70 (1H, m), 6.60 (1H, m), 3.80 (1H, m),
3.20 (1H, m), 2.35 (2H, m), 2.10 (2H, m), 1.85 (1H, m), 1.80-1.42
(9H, m), 1.35 (3H, d)
Example 53:
5-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)-phenyl]hexanoic
Acid
##STR00087##
[2104] 2-Chloro-6-isopropylsulfanyl-pyridine (0.025 g, 0.134 mmol)
obtained in Preparation Example 10 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.048 g, 0.125 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 1 to obtain the title compound (0.019 g, 38%).
[2105] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.53 (3H, m), 7.35
(1H, m), 7.10 (1H, m), 4.15 (1H, m), 3.24 (1H, m), 2.36 (2H, t),
1.83 (1H, m), 1.70-1.60 (3H, m), 1.47 (6H, d), 1.37 (3H, d)
Example 54:
5-[4-(6-cyclopentylsulfanyl-2-pyridyl)-2,6-difluoro-phenyl]hexanoic
Acid
##STR00088##
[2107] 2-Chloro-6-cyclopentylsulfanyl-pyridine (0.03 g, 0.142 mmol)
obtained in Preparation Example 14 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.051 g, 0.133 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 1 to obtain the title compound (0.015 g, 29%).
[2108] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.52 (3H, m), 7.33
(1H, m), 7.11 (1H, m), 4.18 (1H, m), 3.26 (1H, m), 2.37 (2H, t),
2.26 (2H, m), 1.90-1.60 (10H, m), 1.36 (3H, d)
Example 55:
5-[2,6-difluoro-4-(6-propylsulfanyl-2-pyridyl)phenyl]hexanoic
Acid
##STR00089##
[2110] 2-Bromo-6-propylsulfanyl-pyridine (0.046 g, 0.195 mmol)
obtained in Preparation Example 37 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.07 g, 0.183 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 1 to obtain the title compound (0.034 g, 49%).
[2111] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.52 (3H, m), 7.33
(1H, m), 7.13 (1H, m), 3.23 (3H, m), 2.34 (2H, t), 1.84 (3H, m),
1.70-1.60 (3H, m), 1.35 (3H, d), 1.09 (3H, t)
Example 56:
5-[4-(6-cyclopentoxy-2-pyridyl)-2,6-difluoro-phenyl]hexanoic
Acid
##STR00090##
[2113] 2-Chloro-6-cyclopentyloxy-pyridine (0.035 g, 0.176 mmol)
obtained in Preparation Example 12 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.063 g, 0.164 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 1 to obtain the title compound (0.024 g, 37%).
[2114] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 7.59 (1H, t), 7.49
(2H, m), 7.21 (1H, d), 6.64 (1H, d), 5.50 (1H, m), 3.22 (1H, m),
2.33 (2H, t), 2.03 (2H, m), 1.84 (4H, m), 1.75-1.40 (6H, m), 1.34
(3H, d)
Example 57: 4-[4-(2-isopropoxy-3-pyridyl)phenyl]butanoic Acid
##STR00091##
[2116] 3-Iodo-2-isopropoxy-pyridine (0.066 g, 0.249 mmol) obtained
in Preparation Example 34 and
4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]butanoic
acid methyl ester (0.069 g, 0.226 mmol) obtained in Preparation
Example 38 were reacted in the same manner as in Example 1 to
obtain the title compound (0.01 g, 15%).
[2117] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.11 (1H, m), 7.60
(1H, m), 7.51 (2H, m), 7.23 (2H, m), 6.90 (1H, m), 5.40 (1H, m),
2.72 (2H, t), 2.43 (2H, m), 2.02 (2H, m), 1.34 (6H, d)
Example 58: 5-[2,6-difluoro-4-(2-hydroxy-3-pyridyl)phenyl]hexanoic
Acid
##STR00092##
[2118] Step A: 3-iodo-2-(4-methoxy-benzyloxy)-pyridine
##STR00093##
[2120] (4-Methoxy-phenyl)-methanol (0.34 g, 2.46 mmol) was
dissolved in DMF (7.5 mL). NaH (60%)(0.107 g, 2.69 mmol) was added
thereto at 0.degree. C., and the mixture was stirred.
2-Fluoro-3-iodo-pyridine (0.5 g, 2.24 mmol) was added thereto, and
the mixture was stirred for 16 hours. After termination of the
reaction, the reaction solution was diluted with water and
extracted with Et.sub.2O. The organic layer was dried with
anhydrous magnesium sulfate and purified by column chromatography
(eluent, EtOAc/Hex=1/10) to obtain the title compound (0.726 g,
95%).
[2121] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.12 (1H, d), 8.03
(1H, d), 7.44 (2H, d), 6.91 (2H, d), 6.65 (1H, m), 5.37 (2H, s),
3.82 (3H, s)
Step B:
5-{2,6-difluoro-4-[2-(4-methoxy-benzyloxy)-pyridin-3-yl]phenyl}hex-
anoic Acid Methyl Ester
##STR00094##
[2123] 3-Iodo-2-(4-methoxy-benzyloxy)-pyridine (0.102 g, 0.299
mmol) obtained in Step A and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.107 g, 0.279 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in Step A
of Example 1 to obtain the title compound (0.099 g, 75%).
[2124] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.18 (1H, d), 7.62
(1H, d), 7.37 (2H, d), 7.09 (2H, d), 6.98 (1H, m), 6.89 (2H, d),
5.43 (2H, s), 4.11 (2H, q), 3.81 (3H, s), 3.21 (1H, m), 2.30 (2H,
t), 1.81 (1H, m), 1.66-1.55 (3H, m), 1.35 (3H, d), 1.24 (3H, t)
Step C: 5-[2,6-difluoro-4-(2-hydroxy-3-pyridyl)phenyl]hexanoic Acid
Methyl Ester
##STR00095##
[2126]
5-{2,6-Difluoro-4-[2-(4-methoxy-benzyloxy)-pyridin-3-yl]phenyl}hexa-
noic acid methyl ester (0.099 g, 0.21 mmol) obtained in Step B was
dissolved in TFA/DCM (1/1) and stirred for 2 hours. The solvent was
distilled under reduced pressure, and the product was washed with
Et.sub.2O and used for the next step without purification.
Step D: 5-[2,6-difluoro-4-(2-hydroxy-3-pyridyl)phenyl]hexanoic
Acid
[2127] 5-[2,6-Difluoro-4-(2-hydroxy-3-pyridyl)phenyl]hexanoic acid
methyl ester (0.039 g, 0.116 mmol) obtained in Step C was reacted
in the same manner as in Step B of Example 1 to obtain the title
compound (0.029 g, 78%).
[2128] NMR: 1H-NMR (MeOD) .delta. 7.81 (1H, m), 7.46 (1H, m), 7.44
(2H, d), 6.50 (1H, t), 3.25 (1H, m), 2.27 (2H, t), 1.80 (1H, m),
1.75 (1H, m), 1.70-1.40 (2H, m), 1.36 (3H, d)
Example 59:
5-[4-(2-cyclobutoxy-3-pyridyl)-2,6-difluoro-phenyl]hexanoic
Acid
##STR00096##
[2130] 2-Cyclobutoxy-3-iodo-pyridine (0.06 g, 0.218 mmol) obtained
in Preparation Example 39 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.078 g, 0.203 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 1 to obtain the title compound (0.043 g, 56%).
[2131] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.12 (1H, m), 7.59
(1H, m), 7.12 (2H, d), 6.93 (1H, d), 5.28 (1H, m), 3.24 (1H, m),
2.47 (2H, m), 2.37 (2H, t), 2.15 (2H, m), 1.90 (2H, m), 1.70-1.50
(4H, m), 1.37 (3H, d)
Example 60:
5-[4-(2-cyclopropylmethoxy-3-pyridyl)-2,6-difluoro-phenyl]hexanoic
Acid
##STR00097##
[2133] 2-Cyclopropylmethoxy-3-iodo-pyridine (0.062 g, 0.225 mmol)
obtained in Preparation Example 40 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.080 g, 0.21 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 1 to obtain the title compound (0.036 g, 47%).
[2134] NMR: .sup.1H-NMR (CDCl.sub.3) .delta. 8.13 (1H, m), 7.61
(1H, m), 7.14 (2H, d), 6.95 (1H, d), 4.23 (2H, d), 3.24 (1H, m),
2.37 (2H, t), 1.85 (1H, m), 1.84-1.50 (3H, m), 1.40-1.30 (4H, m),
0.61 (2H, m), 0.36 (2H, m)
Example 61:
5-[[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]methyl]isoxaz-
ol-3-ol
##STR00098##
[2135] Step A:
5-[[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxylmethyl]-3-[(4-
-methoxyphenyl)methoxy]isoxazole
[2136]
5-[[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
noxy]methyl]-3-[(4-methoxyphenyl)methoxy]isoxazole (0.21 g, 0.45
mmol) obtained in Preparation Example 62 and
3-iodo-2-cyclobutylsulfanyl-pyridine (0.12 g, 0.41 mmol) obtained
in Preparation Example 13 were reacted in the same manner as in
Step A of Example 1 to obtain the title compound (0.14 g, 65%).
[2137] .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, m), 7.39 (2H, d),
7.32 (1H, m), 7.03 (3H, m), 6.92 (2H, d), 6.07 (1H, s), 5.21 (2H,
s), 5.20 (2H, s), 4.41 (1H, m), 3.82 (3H, s), 2.50 (2H, m), 2.05
(4H, m)
Step B:
5-[[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]methyl-
]isoxazol-3-ol
[2138]
5-[[4-(2-Cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]methyl]-
-3-[(4-methoxyphenyl)methoxy]isoxazole (0.1 g, 0.19 mmol) obtained
in Step A was dissolved in 1.3 mL of DCM. 0.6 mL of TFA and 0.15 mL
of anisole were added thereto, and the mixture was stirred at room
temperature for 5 hours. The reaction solution was concentrated
under reduced pressure. After addition of sodium bicarbonate
aqueous solution, the reaction solution was extracted with EtOAc.
The organic layer was dried with MgSO.sub.4 and purified by column
chromatography to obtain the title compound (0.053 g, 73%).
[2139] .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, m), 7.33 (1H, m),
7.03 (3H, m), 6.13 (1H, s), 5.20 (2H, s), 4.41 (1H, m), 2.52 (2H,
m), 2.06 (4H, m)
Example 62:
N'-hydroxy-4-[4-(2-propylsulfanyl-3-pyridyl)phenyl]butaneamidine
##STR00099##
[2140] Step A:
4-[4-(2-propylsulfanyl-3-pyridyl)phenyl]butanenitrile
[2141]
4-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanenitr-
ile (0.52 g, 1.9 mmol) obtained in Preparation Example 71 and
3-iodo-2-propylsulfanyl-pyridine (0.5 g, 1.79 mmol) obtained in
Preparation Example 28 were reacted in the same manner as in Step A
of Example 1 to obtain the title compound (0.31 g, 56%).
[2142] .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, m), 7.36 (3H, m),
7.26 (2H, d), 7.03 (1H, m), 3.13 (2H, t), 2.82 (2H, t), 2.38 (2H,
t), 2.04 (2H, m), 1.70 (2H, m), 1.01 (3H, t)
Step B:
N-hydroxy-4-[4-(2-propylsulfanyl-3-pyridyl)phenyl]butaneamidine
[2143] 4-[4-(2-Propylsulfanyl-3-pyridyl)phenyl]butanenitrile (0.31
g, 1 mmol) obtained in Step A was dissolved in 0.6 mL of EtOH. 0.3
mL of 50 wt % hydroxylamine aqueous solution was added thereto, and
the mixture was stirred for 16 hours under reflux. The reaction
solution was concentrated under reduced pressure and extracted with
EtOAc to obtain the title compound (0.32 g, 99%).
[2144] .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, m), 7.36 (3H, m),
7.26 (2H, d), 7.04 (1H, m), 4.53 (2H, brs), 3.13 (2H, t), 2.71 (2H,
t), 2.22 (2H, t), 1.95 (2H, m), 1.70 (2H, m), 1.00 (3H, t)
Example 63:
3-[3-[4-(2-propylsulfanyl-3-pyridyl)phenyl]propyl]-4H-1,2,4-oxadiazol-5-o-
ne
##STR00100##
[2146]
N'-hydroxy-4-[4-(2-propylsulfanyl-3-pyridyl)phenyl]butaneamidine
(0.08 g, 0.24 mmol) obtained in Example 62 was dissolved in 1 mL of
pyridine. Chloroformic acid ethyl ester (0.023 mL, 0.24 mmol) was
added thereto at 0.degree. C., and the mixture was stirred at
100.degree. C. for 2 hours. The reaction solution was concentrated
under reduced pressure. After addition of water, the reaction
solution was extracted with EtOAc. The organic layer was dried with
MgSO.sub.4 and purified by column chromatography to obtain the
title compound (0.018 g, 21%).
[2147] .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, m), 7.36 (3H, m),
7.25 (2H, d), 7.05 (1H, m), 3.12 (2H, t), 2.77 (2H, t), 2.61 (2H,
t), 2.08 (2H, m), 1.68 (2H, m), 1.01 (3H, t)
Example 64:
3-[3-[4-(2-propylsulfanyl-3-pyridyl)phenyl]propyl]-4H-1,2,4-oxadiazol-5-t-
hione
##STR00101##
[2149]
N-hydroxy-4-[4-(2-propylsulfanyl-3-pyridyl)phenyl]butaneamidine
(0.11 g, 0.33 mmol) obtained in Example 62 was dissolved in 1.1 mL
of CH.sub.3CN. 1,1'-Thiocarbonyldiimidazole (0.079 g, 0.4 mmol) and
DBU (0.064 g, 0.43 mmol) were added thereto, and the mixture was
stirred at room temperature for 48 hours. The reaction solution was
concentrated under reduced pressure and purified by column
chromatography to obtain the title compound (0.005 g, 4%).
[2150] .sup.1H-NMR (CDCl.sub.3) .delta. 8.36 (1H, m), 7.26 (3H, m),
7.15 (2H, m), 6.95 (1H, m), 3.06 (2H, t), 2.64 (2H, m), 2.58 (2H,
m), 1.99 (2H, m), 1.68 (2H, m), 0.94 (3H, t)
Example 65:
5-[[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]methyl]isoxa-
zol-3-ol
##STR00102##
[2152]
5-[[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
noxy]methyl]-3-[(4-methoxyphenyl)methoxy]isoxazole (0.087 g, 0.18
mmol) obtained in Preparation Example 62 and
2-cyclopentylsulfanyl-3-iodo-pyridine (0.056 g, 0.18 mmol) obtained
in Preparation Example 15 were reacted in the same manner as in
Example 61 to obtain the title compound (0.027 g, 34%).
[2153] .sup.1H-NMR (CDCl.sub.3) .delta. 8.45 (1H, m), 7.34 (1H, m),
7.04 (3H, m), 6.15 (1H, s), 5.19 (2H, s), 4.10 (1H, m), 2.21 (2H,
m), 1.73 (2H, m), 1.60 (4H, m)
Example 66:
5-[[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)phenoxy]methyl]isoxazol-3--
ol
##STR00103##
[2155]
5-[[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
noxy]methyl]-3-[(4-methoxyphenyl)methoxy]isoxazole (0.12 g, 0.25
mmol) obtained in Preparation Example 62 and
3-iodo-2-propylsulfanyl-pyridine (0.064 g, 0.23 mmol) obtained in
Preparation Example 28 were reacted in the same manner as in
Example 61 to obtain the title compound (0.017 g, 20%).
[2156] .sup.1H-NMR (CDCl.sub.3) .delta. 8.44 (1H, m), 7.34 (1H, m),
7.04 (3H, m), 6.12 (1H, s), 5.19 (2H, s), 1.44 (2H, t), 1.69 (2H,
m), 1.02 (3H, t)
Example 67:
5-[[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenoxy]methyl]isoxazol-3-
-ol
##STR00104##
[2158]
5-[[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
noxy]methyl]-3-[(4-methoxyphenyl)methoxy]isoxazole (0.2 g, 0.42
mmol) obtained in Preparation Example 62 and
2-cyclopentoxy-3-iodo-pyridine (0.1 g, 0.35 mmol) obtained in
Preparation Example 11 were reacted in the same manner as in
Example 61 to obtain the title compound (0.06 g, 50%).
[2159] .sup.1H-NMR (CDCl.sub.3) .delta. 8.15 (1H, m), 7.56 (1H, m),
7.18 (2H, m), 6.92 (1H, m), 6.10 (1H, s), 5.52 (1H, m), 5.18 (2H,
s), 1.97 (2H, m), 1.93 (2H, m), 1.74 (2H, m), 1.65 (2H, m)
Example 68:
5-[[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenoxy]methyl]isoxazol-
-3-ol
##STR00105##
[2161]
5-[[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
noxy]methyl]-3-[(4-methoxyphenyl)methoxy]isoxazole (0.2 g, 0.43
mmol) obtained in Preparation Example 62 and
3-iodo-2-isopropylsulfanyl-pyridine (0.11 g, 0.39 mmol) obtained in
Preparation Example 9 were reacted in the same manner as in Example
61 to obtain the title compound (0.033 g, 22%).
[2162] .sup.1H-NMR (CDCl.sub.3) .delta. 8.45 (1H, m), 7.34 (1H, m),
7.03 (3H, m), 6.12 (1H, s), 5.19 (2H, s), 4.06 (1H, m), 1.37 (6H,
d)
Example 69:
5-[[2,6-difluoro-4-(2-isopropoxy-3-pyridyl)phenoxy]methyl]isoxazol-3-ol
##STR00106##
[2164]
5-[[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
noxy]methyl]-3-[(4-methoxyphenyl)methoxy]isoxazole (0.06 g, 0.13
mmol) obtained in Preparation Example 62 and
3-iodo-2-isopropoxy-pyridine (0.03 g, 0.11 mmol) obtained in
Preparation Example 34 were reacted in the same manner as in
Example 61 to obtain the title compound (0.005 g, 12%).
[2165] .sup.1H-NMR (CDCl.sub.3) .delta. 8.14 (1H, m), 7.55 (1H, m),
7.20 (2H, m), 6.92 (1H, m), 6.12 (1H, s), 5.41 (1H, m), 5.18 (2H,
s), 1.35 (6H, d)
Example 70:
5-[[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]methyl]isoxazol-
-3-ol
##STR00107##
[2167]
5-[[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
noxy]methyl]-3-[(4-methoxyphenyl)methoxy]isoxazole (0.093 g, 0.2
mmol) obtained in Preparation Example 62 and
2-chloro-6-isopropylsulfanyl-pyridine (0.034 g, 0.18 mmol) obtained
in Preparation Example 10 were reacted in the same manner as in
Example 61 to obtain the title compound (0.013 g, 19%).
[2168] .sup.1H-NMR (CDCl.sub.3) .delta. 7.59 (2H, m), 7.53 (1H, t),
7.32 (1H, d), 7.10 (1H, d), 6.10 (1H, s), 5.18 (2H, s), 4.13 (1H,
m), 1.46 (6H, d)
Example 71:
5-[[2,6-difluoro-4-(6-isopropoxy-2-pyridyl)phenoxy]methyl]isoxazol-3-ol
##STR00108##
[2170]
5-[[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
noxy]methyl]-3-[(4-methoxyphenyl)methoxy]isoxazole (0.12 g, 0.24
mmol) obtained in Preparation Example 62 and
2-bromo-6-isopropoxy-pyridine (0.053 g, 0.24 mmol) obtained in
Preparation Example 42 were reacted in the same manner as in
Example 61 to obtain the title compound (0.035 g, 40%).
[2171] .sup.1H-NMR (CDCl.sub.3) .delta. 7.58 (3H, m), 7.20 (1H, d),
6.65 (1H, d), 6.10 (1H, s), 5.44 (1H, m), 5.18 (2H, s), 1.40 (6H,
d)
Example 72:
5-[[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-phenoxy]methyl]isox-
azol-3-ol
##STR00109##
[2173]
5-[[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
noxy]methyl]-3-[(4-methoxyphenyl)methoxy]isoxazole (0.094 g, 0.2
mmol) obtained in Preparation Example 62 and
2-bromo-6-(cyclopropylmethoxy)pyridine (0.038 g, 0.16 mmol)
obtained in Preparation Example 44 were reacted in the same manner
as in Example 61 to obtain the title compound (0.006 g, 10%).
[2174] .sup.1H-NMR (CDCl.sub.3) .delta. 7.61 (3H, m), 7.22 (1H, d),
6.74 (1H, d), 6.10 (1H, s), 5.18 (2H, s), 4.23 (2H, d), 1.35 (1H,
m), 0.64 (2H, m), 0.39 (2H, m)
Example 73:
5-[[2,6-difluoro-4-(6-propoxy-2-pyridyl)phenoxy]methyl]isoxazol-3-ol
##STR00110##
[2176]
5-[[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
noxy]methyl]-3-[(4-methoxyphenyl)methoxy]isoxazole (0.094 g, 0.2
mmol) obtained in Preparation Example 62 and
2-bromo-6-propoxy-pyridine (0.036 g, 0.16 mmol) obtained in
Preparation Example 45 were reacted in the same manner as in
Example 61 to obtain the title compound (0.006 g, 10%).
[2177] .sup.1H-NMR (CDCl.sub.3) .delta. 7.60 (3H, m), 7.22 (1H, d),
6.70 (1H, d), 6.10 (1H, s), 5.18 (2H, s), 4.36 (2H, t), 1.85 (2H,
m), 1.06 (3H, t)
Example 74:
5-[[2,6-difluoro-4-(2-propoxy-3-pyridyl)phenoxy]methyl]isoxazol-3-ol
##STR00111##
[2179]
5-[[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
noxy]methyl]-3-[(4-methoxyphenyl)methoxy]isoxazole (0.094 g, 0.2
mmol) obtained in Preparation Example 62 and
3-iodo-2-propoxy-pyridine (0.044 g, 0.16 mmol) obtained in
Preparation Example 47 were reacted in the same manner as in
Example 61 to obtain the title compound (0.023 g, 38%).
[2180] .sup.1H-NMR (CDCl.sub.3) .delta. 8.15 (1H, m), 7.57 (1H, m),
7.19 (2H, m), 6.95 (1H, m), 6.11 (1H, s), 5.18 (2H, s), 4.33 (2H,
t), 1.80 (2H, m), 1.01 (3H, t)
Example 75:
5-[(E)-3-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]allyl]th-
iazolidin-2,4-dione
##STR00112##
[2182] Thiazolidinedione (0.041 g, 0.35 mmol) was dissolved in 1.4
mL of THF and cooled to -78.degree. C. Butyllithium (0.36 mL, 0.73
mmol, 2.0 M hexane solution) was added thereto, and the mixture was
stirred at 0.degree. C. for 30 minutes. The reaction solution was
cooled to -78.degree. C., and
[(E)-3-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]allyl]meth-
anesulfonate (0.14 g, 0.35 mmol) obtained in Preparation Example 76
was added thereto, and the mixture was stirred at room temperature
for 4 hours. After addition of ammonium chloride aqueous solution,
the reaction solution was extracted with EtOAc and purified by
column chromatography to obtain the title compound (0.025 g,
16%).
[2183] .sup.1H-NMR (CDCl.sub.3) .delta. 8.43 (1H, m), 7.95 (1H,
brs), 7.34 (1H, m), 7.05 (1H, m), 6.99 (2H, m), 6.63 (1H, d), 6.53
(1H, m), 4.48 (1H, m), 4.43 (1H, m), 3.14 (1H, m), 2.90 (1H, m),
2.51 (2H, m), 2.04 (4H, m)
Example 76:
5-[[4-[2-(cyclobutoxy)-3-pyridyl]-2,6-difluoro-phenoxy]methyl]isoxazol-3--
ol
##STR00113##
[2185]
5-[[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
noxy]methyl]-3-[(4-methoxyphenyl)methoxy]isoxazole (0.06 g, 0.12
mmol) obtained in Preparation Example 62 and
2-cyclobutoxy-3-iodo-pyridine (0.032 g, 0.11 mmol) obtained in
Preparation Example 41 were reacted in the same manner as in
Example 61 to obtain the title compound (0.01 g, 23%).
[2186] .sup.1H-NMR (CDCl.sub.3) .delta. 8.14 (1H, m), 7.58 (1H, m),
7.22 (2H, m), 6.95 (1H, m), 6.12 (1H, s), 5.27 (1H, m), 5.18 (2H,
s), 2.47 (2H, m), 2.13 (2H, m), 1.84 (1H, m), 1.69 (1H, m)
Example 77:
5-[[4-[2-(cyclobutylmethoxy)-3-pyridyl]-2,6-difluoro-phenoxy]methyl]isoxa-
zol-3-ol
##STR00114##
[2188]
5-[[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
noxy]methyl]-3-[(4-methoxyphenyl)methoxy]isoxazole (0.06 g, 0.12
mmol) obtained in Preparation Example 62 and
2-cyclobutylmethoxy-3-iodo-pyridine (0.033 g, 0.11 mmol) obtained
in Preparation Example 48 were reacted in the same manner as in
Example 61 to obtain the title compound (0.011 g, 26%).
[2189] .sup.1H-NMR (CDCl.sub.3) .delta. 8.15 (1H, m), 7.58 (1H, m),
7.21 (2H, m), 6.96 (1H, m), 6.11 (1H, s), 5.19 (2H, s), 4.32 (2H,
d), 2.78 (1H, m), 2.11 (2H, m), 1.95-1.85 (4H, m)
Example 78:
5-[[4-[2-(cyclopentoxy)-3-pyridyl]anilino]methyl]isoxazol-3-ol
##STR00115##
[2190] Step A:
4-[2-(cyclopentoxy)-3-pyridyl]-N-[[3-[(4-methoxyphenyl)methoxy]isoxazol-5-
-yl]methyl]aniline
[2191] 4-[2-(Cyclopentoxy)-3-pyridyl]-aniline (0.11 g, 0.45 mmol)
obtained in Preparation Example 64 and
3-[(4-methoxyphenyl)methoxy]isoxazol-5-carbaldehyde (0.10 g, 0.45
mmol) obtained in Preparation Example 61 were dissolved in 4.5 mL
of DCE. Sodium triacetoxyborohydride (0.14 g, 0.68 mmol) was added
thereto, and the mixture was stirred at room temperature for 16
hours. After addition of sodium bicarbonate aqueous solution, the
reaction solution was extracted with DCM and purified by column
chromatography to obtain the title compound (0.09 g, 43%).
[2192] .sup.1H-NMR (CDCl.sub.3) .delta. 8.07 (1H, m), 7.54 (1H, m),
7.43 (2H, d), 7.35 (2H, d), 6.92 (2H, d), 6.88 (1H, m), 6.87 (2H,
d), 5.84 (1H, s), 5.50 (1H, m), 5.17 (2H, s), 4.40 (2H, d), 4.20
(1H, t, NH), 3.82 (3H, s), 1.93 (2H, m), 1.82 (2H, m), 1.73 (2H,
m), 1.61 (2H, m)
Step B:
5-[[4-[2-(cyclopentoxy)-3-pyridyl]anilino]methyl]isoxazol-3-ol
[2193]
4-[2-(Cyclopentoxy)-3-pyridyl]-N-[[3-[(4-methoxyphenyl)methoxy]isox-
azol-5-yl]methyl]aniline (0.033 g, 0.07 mmol) obtained in Step A
was reacted in the same manner as in Step B of Example 61 to obtain
the title compound (0.02 g, 84%).
[2194] .sup.1H-NMR (CDCl.sub.3) .delta. 8.07 (1H, m), 7.56 (1H, m),
7.45 (2H, d), 6.88 (1H, m), 6.67 (2H, d), 5.90 (1H, s), 5.49 (1H,
m), 4.41 (2H, s), 1.95 (2H, m), 1.83 (2H, m), 1.75 (2H, m), 1.62
(2H, m)
Example 79:
5-[[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenoxy]methyl]pyridin-2--
ol
##STR00116##
[2196] 2-Cyclopentoxy-3-iodo-pyridine (0.08 g, 0.28 mmol) obtained
in Preparation Example 11 and
5-[[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]m-
ethyl]-2-[(4-methoxyphenyl)methoxy]pyridine (0.14 g, 0.3 mmol)
obtained in Preparation Example 72 were reacted in the same manner
as in Example 61 to obtain the title compound (0.018 g, 16%).
[2197] .sup.1H-NMR (CDCl.sub.3) .delta. 12.8 (1H, brs), 8.14 (1H,
m), 7.66 (1H, m), 7.55 (1H, m), 7.41 (1H, m), 7.15 (2H, m), 6.92
(1H, m), 6.62 (1H, m), 5.50 (1H, m), 4.96 (2H, s), 1.94 (2H, m),
1.78 (2H, m), 1.73 (2H, m), 1.65 (2H, m)
Example 80:
4-[[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenoxy]methyl]pyridin-2--
ol
##STR00117##
[2199] 2-Cyclopentoxy-3-iodo-pyridine (0.05 g, 0.18 mmol) obtained
in Preparation Example 11 and
4-[[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]m-
ethyl]-2-[(4-methoxyphenyl)methoxy]pyridine (0.08 g, 0.18 mmol)
obtained in Preparation Example 73 were reacted in the same manner
as in Example 61 to obtain the title compound (0.018 g, 16%).
[2200] .sup.1H-NMR (CDCl.sub.3) .delta. 12.2 (1H, brs), 8.15 (1H,
m), 7.54 (1H, m), 7.38 (1H, m), 7.14 (2H, m), 6.90 (1H, m), 6.73
(1H, m), 6.48 (1H, m), 5.50 (1H, m), 5.07 (2H, s), 1.94 (2H, m),
1.81 (2H, m), 1.74 (2H, m), 1.65 (2H, m)
Example 81:
5-[[4-[2-(cyclopentoxy)-3-pyridyl]phenyl]sulfanylmethyl]isoxazol-3-ol
##STR00118##
[2202] 4-[2-(Cyclopentoxy)-3-pyridyl]benzenethiol (0.022 g, 0.08
mmol) obtained in Preparation Example 65 and
[3-[(4-methoxyphenyl)methoxy]isoxazol-5-yl]methyl methanesulfonate
(0.03 g, 0.1 mmol) obtained in Preparation Example 60 were
dissolved in 0.8 mL of DMF. K.sub.2CO.sub.3 (0.022 g, 0.16 mmol)
was added thereto, and the mixture was stirred at room temperature
for 5 hours. The reaction solution was concentrated under reduced
pressure, and solids were filtered by the addition of EtOAc. The
filtrate was purified by column chromatography to obtain
5-[[4-[2-(cyclopentoxy)-3-pyridyl]phenyl]sulfanylmethyl]-3-[(4-methoxyphe-
nyl)methoxy]isoxazol. The obtained compound was reacted in the same
manner as in Step B of Example 61 to obtain the title compound
(0.01 g, 36%).
[2203] .sup.1H-NMR (CDCl.sub.3) .delta. 8.14 (1H, m), 7.58 (1H, m),
7.52 (2H, d), 7.38 (2H, d), 6.93 (1H, m), 5.78 (1H, s), 5.50 (1H,
m), 4.05 (2H, s), 1.93 (2H, m), 1.81 (2H, m), 1.72 (2H, m), 1.63
(2H, m)
Example 82:
5-[(E)-3-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]allyl]-1,1-d-
ioxo-1,2,5-thiadiazolidin-3-one
##STR00119##
[2205]
2-[[(E)-3-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]allyl-
]-sulfamoyl-amino]acetic acid ethyl ester (0.038 g, 0.08 mmol)
obtained in Preparation Example 75 was dissolved in 0.8 mL of THF.
NaH (0.005 g, 0.11 mmol, 55 wt % in mineral oil) was added thereto,
and the mixture was stirred at room temperature for 16 hours. After
addition of ammonium chloride aqueous solution, the reaction
solution was extracted with EtOAc. The organic layer was purified
by column chromatography to obtain the title compound (0.022 g,
65%).
[2206] .sup.1H-NMR (CDCl.sub.3) .delta. 8.17 (1H, m), 7.90 (1H,
brs), 7.60 (1H, m), 7.15 (2H, m), 6.94 (1H, m), 6.64 (1H, d), 6.47
(1H, m), 5.53 (1H, m), 4.20 (2H, d), 3.97 (2H, s), 1.95 (2H, m),
1.80 (2H, m), 1.75 (2H, m), 1.66 (2H, m)
Example 83:
5-[[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]sulfanylmethyl]iso-
xazol-3-ol
##STR00120##
[2207] Step A:
5-[[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]sulfanylmethyl]-3--
[(4-methoxyphenyl)methoxy]isoxazole
[2208] 4-[2-(Cyclopentoxy)-3-pyridyl]-2,6-difluoro-benzenethiol
(0.077 g, 0.25 mmol) obtained in Preparation Example 68 and
[3-[(4-methoxyphenyl)methoxy]isoxazol-5-yl]methyl methanesulfonate
(0.08 g, 0.25 mmol) obtained in Preparation Example 60 were
dissolved in 1.5 mL of DMF. K.sub.2CO.sub.3 (0.042 g, 0.3 mmol) was
added thereto, and the mixture was stirred at room temperature for
16 hours. After addition of water, the reaction solution was
extracted with EtOAc and purified by column chromatography to
obtain the title compound (0.1 g, 80%).
[2209] .sup.1H-NMR (CDCl.sub.3) .delta. 8.18 (1H, m), 7.60 (1H, m),
7.35 (2H, d), 7.18 (2H, m), 6.96 (1H, m), 6.89 (2H, d), 5.76 (1H,
s), 5.53 (1H, m), 5.14 (2H, s), 4.04 (2H, s), 3.80 (3H, s), 1.97
(2H, m), 1.81 (2H, m), 1.75 (2H, m), 1.63 (2H, m)
Step B:
5-[[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]sulfanylmet-
hyl]isoxazol-3-ol
[2210]
5-[[4-[2-(Cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]sulfanylmeth-
yl]-3-[(4-methoxyphenyl)methoxy]isoxazole (0.1 g, 0.2 mmol)
obtained in Step A was reacted in the same manner as in Step B of
Example 61 to obtain the title compound (0.067 g, 85%).
[2211] .sup.1H-NMR (CDCl.sub.3) .delta. 8.18 (1H, m), 7.60 (1H, m),
7.19 (2H, m), 6.93 (1H, m), 5.76 (1H, s), 5.52 (1H, m), 4.01 (2H,
s), 1.96 (2H, m), 1.81 (2H, m), 1.75 (2H, m), 1.63 (2H, m)
Example 84:
5-[[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-anilino]methyl]isoxazol-3-
-ol
##STR00121##
[2212] Step A:
4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-N-[[3-[(4-methoxyphenyl)metho-
xy]isoxazol-5-yl]methyl]aniline
[2213] 4-[2-(Cyclopentoxy)-3-pyridyl]-2,6-difluoro-aniline (0.17 g,
0.6 mmol) obtained in Preparation Example 67 and
3-[(4-methoxyphenyl)methoxy]isoxazol-5-carbaldehyde (0.14 g, 0.6
mmol) obtained in Preparation Example 61 were dissolved in 6 mL of
DCE. Sodium triacetoxyborohydride (0.25 g, 1.2 mmol) was added
thereto, and the mixture was stirred at room temperature for 16
hours. After addition of sodium bicarbonate aqueous solution, the
reaction solution was extracted with DCM and purified by column
chromatography to obtain the title compound (0.013 g, 4%).
[2214] .sup.1H-NMR (CDCl.sub.3) .delta. 8.11 (1H, m), 7.54 (1H, m),
7.34 (2H, d), 7.10 (2H, m), 6.90 (3H, m), 5.81 (1H, s), 5.51 (1H,
m), 5.16 (2H, s), 4.55 (2H, d), 4.12 (1H, m, NH), 3.81 (3H, s),
1.95 (2H, m), 1.78 (4H, m), 1.64 (2H, m)
Step B:
5-[[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-anilino]methyl]iso-
xazol-3-ol
[2215]
4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-N-[[3-[(4-methoxyphenyl-
)methoxy]isoxazol-5-yl]methyl]aniline (0.013 g, 0.026 mmol)
obtained in Step A was reacted in the same manner as in Step B of
Example 61 to obtain the title compound (0.007 g, 65%).
[2216] .sup.1H-NMR (CDCl.sub.3) .delta. 8.11 (1H, m), 7.55 (1H, m),
7.12 (2H, m), 6.90 (1H, m), 5.86 (1H, s), 5.51 (1H, m), 4.54 (2H,
s), 4.10 (1H, brs), 1.95 (2H, m), 1.78 (4H, m), 1.63 (2H, m)
Example 85:
5-[3-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]propyl]-1,1-diox-
o-1,2,5-thiadiazolidin-3-one
##STR00122##
[2218]
5-[(E)-3-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]allyl]-
-1,1-dioxo-1,2,5-thiadiazolidin-3-one (0.016 g, 0.035 mmol)
obtained in Example 82 was dissolved in 0.4 mL of MeOH. Catalytic
amount of 10 wt % Pd/C was added thereto, and the mixture was
stirred for 16 hours under hydrogen atmosphere. Solids were
filtered through Celite, and the filtrate was concentrated to
obtain the title compound (0.015 g, 94%).
[2219] .sup.1H-NMR (CDCl.sub.3) .delta. 8.16 (1H, m), 7.65 (1H,
brs), 7.58 (1H, m), 7.12 (2H, m), 6.93 (1H, m), 5.52 (1H, m), 3.94
(2H, s), 3.47 (2H, t), 2.74 (2H, t), 1.96 (2H, m), 1.92 (2H, m),
1.78 (2H, m), 1.75 (2H, m), 1.65 (2H, m)
Example 86:
5-[[4-[2-(cyclopentoxy)-3-pyridyl]-N-methyl-anilino]methyl]isoxazol-3-ol
##STR00123##
[2221]
4-[2-(Cyclopentoxy)-3-pyridyl]-N-[[3-[(4-methoxyphenyl)methoxy]isox-
azol-5-yl]methyl]aniline (0.057 g, 0.12 mmol) obtained in Step A of
Example 78 was dissolved in 1.2 mL of DMF. NaH (0.008 g, 0.18 mmol,
55 wt % in mineral oil) was added thereto at 0.degree. C., and the
mixture was stirred for 30 minutes. Iodomethane (0.01 g, 0.13 mmol)
was added thereto, and the mixture was stirred at room temperature
for 72 hours. The reaction solution was concentrated under reduced
pressure. After addition of water, the reaction solution was
extracted with EtOAc and purified by column chromatography to
obtain
4-[2-(cyclopentoxy)-3-pyridyl]-N-[[3-[(4-methoxyphenyl)methoxy]isoxazol-5-
-yl]methyl]-N-methyl-aniline (0.023 g, 39%). The obtained compound
was reacted in the same manner as in Step B of Example 61 to obtain
the title compound (0.001 g, 6%).
[2222] .sup.1H-NMR (CDCl.sub.3) .delta. 8.08 (1H, m), 7.57 (1H, m),
7.51 (2H, d), 6.90 (1H, m), 6.79 (2H, d), 5.78 (1H, s), 5.50 (1H,
m), 4.52 (2H, s), 3.08 (3H, s), 1.95 (2H, m), 1.83 (2H, m), 1.75
(2H, m), 1.63 (2H, m)
Example 87:
5-[2-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]ethyl]isoxazol-3-
-ol
##STR00124##
[2224] Diisopropylamine (0.13 mL, 0.92 mmol) was dissolved in 3.3
mL of THF. Butyllithium (0.35 mL, 0.87 mmol, 2.5 M hexane solution)
was added thereto at -78.degree. C., and the mixture was stirred
for 15 minutes. 5-Methylisoxazol-3-ol (0.033 g, 0.33 mmol) was
added thereto, and the mixture was stirred at -78.degree. C. for 2
hours.
3-[4-(Chloromethyl)-3,5-difluoro-phenyl]-2-(cyclopentoxy)pyridine
(0.16 g, 0.5 mmol) obtained in Preparation Example 70 was added
thereto, and the mixture was stirred at room temperature for 2
hours. The reaction solution was diluted with Et.sub.2O and cooled
to 0.degree. C. The reaction solution was adjusted to pH 3 and
extracted with EtOAc. The product was dried with MgSO.sub.4 and
purified by column chromatography to obtain the title compound
(0.032 g, 26%).
[2225] .sup.1H-NMR (CDCl.sub.3) .delta. 8.16 (1H, m), 7.58 (1H, m),
7.11 (2H, m), 6.92 (1H, m), 5.71 (1H, s), 5.52 (1H, m), 3.06 (2H,
m), 2.98 (2H, m), 1.95 (2H, m), 1.82 (2H, m), 1.75 (2H, m), 1.65
(2H, m)
Example 88:
5-[2-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]propyl]isoxazol--
3-ol
##STR00125##
[2227] 5-Methylisoxazol-3-ol (0.028 g, 0.28 mmol) and
3-[4-(1-chloroethyl)-3,5-difluoro-phenyl]-2-(cyclopentoxy)pyridine
(0.12 g, 0.37 mmol) obtained in Preparation Example 74 were reacted
in the same manner as in Example 87 to obtain the title compound
(0.007 g, 6%).
[2228] .sup.1H-NMR (CDCl.sub.3) .delta. 8.16 (1H, m), 7.59 (1H, m),
7.08 (2H, m), 6.92 (1H, m), 5.61 (1H, s), 5.52 (1H, m), 3.64 (1H,
m), 3.14 (1H, m), 3.07 (1H, m), 1.95 (2H, m), 1.83-1.63 (6H, m),
1.43 (3H, d)
Example 89:
5-[2-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenoxy]ethyl]isoxazol--
3-ol
##STR00126##
[2229] Step A:
5-[2-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenoxy]ethyl]-3-[(4-me-
thoxyphenyl)methoxy]isoxazole
[2230] 4-[2-(Cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenol (0.087 g,
0.3 mmol) and 2-[3-[(4-methoxyphenyl)methoxy]isoxazol-5-yl]ethanol
(0.075 g, 0.3 mmol) were reacted in the same manner as in
Preparation Example 62 to obtain the title compound (0.065 g,
40%).
[2231] .sup.1H-NMR (CDCl.sub.3) .delta. 8.14 (1H, m), 7.56 (1H, m),
7.39 (2H, d), 7.16 (2H, m), 6.92 (3H, m), 5.90 (1H, s), 5.52 (1H,
m), 5.19 (2H, s), 4.43 (2H, t), 3.82 (3H, s), 3.16 (2H, t), 1.95
(2H, m), 1.82 (2H, m), 1.76 (2H, m), 1.64 (2H, m)
Step B:
5-[2-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenoxy]ethyl]is-
oxazol-3-ol
[2232]
5-[2-[4-[2-(Cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenoxy]ethyl]-3--
[(4-methoxyphenyl)methoxy]isoxazole (0.065 g, 0.12 mmol) obtained
in Step A was reacted in the same manner as in Step B of Example 61
to obtain the title compound (0.038 g, 79%).
[2233] .sup.1H-NMR (CDCl.sub.3) .delta. 8.14 (1H, m), 7.55 (1H, m),
7.17 (2H, m), 6.92 (1H, m), 5.95 (1H, s), 5.52 (1H, m), 4.44 (2H,
t), 3.16 (2H, t), 1.95 (2H, m), 1.82 (2H, m), 1.74 (2H, m), 1.65
(2H, m)
Example 90:
5-[2-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-anilino]ethyl]isoxazol--
3-ol
##STR00127##
[2234] Step A:
N-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]-2-(3-hydroxyisoxaz-
ol-5-yl)acetamide
[2235] 4-[2-(Cyclopentoxy)-3-pyridyl]-2,6-difluoro-aniline (0.17 g,
0.58 mmol) obtained in Preparation Example 67 and
N,N-dicyclohexylcarbodiimide (0.13 g, 0.61 mmol) were dissolved in
2 mL of THF. 2-(3-Hydroxyisoxazol-5-yl)acetic acid (0.083 g, 0.58
mmol) was added thereto, and the mixture was stirred at room
temperature for 72 hours. 2-(3-Hydroxyisoxazol-5-yl)acetic acid
(0.040 g, 0.28 mmol) was additionally added thereto, and the
mixture was stirred at 70.degree. C. for 90 minutes. The reaction
solution was cooled to room temperature, and solids were filtered.
The filtrate was purified by column chromatography to obtain the
title compound (0.067 g, 28%).
[2236] .sup.1H-NMR (CDCl.sub.3) .delta. 8.17 (1H, m), 7.57 (1H, m),
7.22 (2H, m), 7.00 (1H, brs), 6.93 (1H, m), 6.07 (1H, s), 5.52 (1H,
m), 3.89 (1H, brs), 2.33 (2H, s), 1.94 (2H, m), 1.81 (2H, m), 1.74
(2H, m), 1.65 (2H, m)
Step B:
5-[2-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-anilino]ethyl]is-
oxazol-3-ol
[2237]
N-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]-2-(3-hydroxy-
isoxazol-5-yl)acetamide (0.066 g, 0.16 mmol) Obtained in Step A was
dissolved in 1.6 mL of THF. Borane-dimethyl sulfide (0.14 mL, 0.67
mmol, 5.0 M Et.sub.2O solution) was added thereto, and the mixture
was stirred at room temperature for 4 hours. The reaction solution
was concentrated under reduced pressure. After sequential addition
of MeOH and 1 N HCl aqueous solution, the reaction solution was
concentrated under reduced pressure. After addition of water, the
reaction solution was extracted with EtOAc. The organic layer was
purified by column chromatography to obtain the title compound
(0.02 g, 31%).
[2238] .sup.1H-NMR (CDCl.sub.3) .delta. 8.11 (1H, m), 7.56 (1H, m),
7.12 (2H, m), 6.89 (1H, m), 5.77 (1H, s), 5.52 (1H, m), 3.71 (2H,
m), 2.96 (2H, m), 1.97 (2H, m), 1.83 (2H, m), 1.77 (2H, m), 1.65
(2H, m)
Example 91:
2-[1-[5-(6-isopropylsulfanyl-2-pyridyl)-2-pyridyl]-3-piperidyl]acetic
Acid
##STR00128##
[2239] Step A:
2-[1-[5-(6-isopropylsulfanyl-2-pyridyl]-2-pyridyl]-3-piperidyl]acetonitri-
le
[2240] 2-Fluoro-5-(6-isopropylsulfanyl-2-pyridyl)pyridine (0.025 g,
0.1 mmol) obtained in Step B of Preparation Example 80 and
hydrochloric acid salt of 2-(3-piperidyl)acetonitrile (0.06 g, 0.37
mmol) obtained in Step D of Preparation Example 86 were dissolved
in 0.5 mL of DMF. Cs.sub.2CO.sub.3 (0.165 g, 0.5 mmol) was added
thereto, and the mixture was stirred at 50.degree. C. for 4 hours.
After removing solids, the product was purified by column
chromatography to obtain the title compound (0.015 g, 42%).
[2241] .sup.1H-NMR (CDCl.sub.3) .delta. 8.86 (1H, d), 8.14 (1H,
dd), 7.47 (1H, t), 7.30 (1H, d), 7.01 (1H, d), 6.75 (1H, d), 4.38
(1H, m), 4.17 (1H, m), 4.10 (1H, m), 3.09 (1H, m), 2.91 (1H, m),
2.39 (2H, m), 2.05 (2H, m), 1.82 (1H, m), 1.67 (1H, m), 1.50 (1H,
m), 1.44 (6H, d)
Step B:
2-[1-[5-(6-isopropylsulfanyl-2-pyridyl)-2-pyridyl]-3-piperidyl]ace-
tic Acid
[2242] 0.4 mL of EtOH and 6 N NaOH aqueous solution (0.04 mL, 0.25
mmol) were added to
2-[1-[5-(6-isopropylsulfanyl-2-pyridyl)-2-pyridyl]-3-piperidyl]acetonitri-
le (0.015 g, 0.042 mmol) obtained in Step A, and the mixture was
stirred for 16 hours under reflux. The reaction solution was
concentrated under reduced pressure and adjusted to pH 5 by the use
of 1 N HCl aqueous solution. The reaction solution was extracted
with EtOAc and purified by column chromatography to obtain the
title compound (0.005 g, 32%).
[2243] .sup.1H-NMR (CDCl.sub.3) .delta. 8.76 (1H, d), 8.18 (1H, m),
7.47 (1H, t), 7.29 (1H, m), 7.01 (1H, d), 6.78 (1H, d), 4.14 (1H,
m), 3.84 (1H, m), 3.76 (1H, m), 3.60 (1H, m), 3.48 (1H, m), 2.49
(1H, m), 2.30 (1H, m), 2.23 (1H, m), 1.98 (1H, m), 1.68 (2H, m),
1.50 (1H, m), 1.44 (6H, d)
Example 92:
4-[[5-(6-isopropylsulfanyl-2-pyridyl)-2-pyridyl]amino]butanoic
Acid
##STR00129##
[2244] Step A:
4-[[5-(6-isopropylsulfanyl-2-pyridyl)-2-pyridyl]amino]butanoic Acid
Ethyl Ester
[2245] 3 mL of acetone was added to
2-fluoro-5-(6-isopropylsulfanyl-2-pyridyl)pyridine (0.088 g, 0.35
mmol) obtained in Step B of Preparation Example 80, hydrochloric
acid salt of 4-aminobutanoic acid ethyl ester (0.065 g, 0.39 mmol)
and K.sub.2CO.sub.3 (0.147 g, 1.06 mmol), and the mixture was
stirred at 70.degree. C. for 16 hours. The reaction solution was
concentrated under reduced pressure and purified by column
chromatography to obtain the title compound (0.02 g, 16%).
[2246] .sup.1H-NMR (CDCl.sub.3) .delta. 8.78 (1H, m), 8.09 (1H, m),
7.46 (1H, t), 7.27 (1H, d), 7.00 (1H, d), 6.47 (1H, d), 4.88 (1H,
brs), 4.14 (3H, m), 3.42 (2H, m), 2.44 (2H, t), 2.00 (2H, m), 1.45
(6H, d), 1.25 (3H, t)
Step B:
4-[[5-(6-isopropylsulfanyl-2-pyridyl)-2-pyridyl]amino]butanoic
Acid
[2247]
4-[[5-(6-Isopropylsulfanyl-2-pyridyl)-2-pyridyl]amino]butanoic acid
ethyl ester (0.02 g, 0.055 mmol) obtained in Step A was reacted in
the same manner as in Step B of Example 1 to obtain the title
compound (0.01 g, 55%).
[2248] .sup.1H-NMR (MeOH-d.sub.4) .delta. 8.63 (1H, m), 8.16 (1H,
m), 7.55 (1H, t), 7.40 (1H, d), 7.03 (1H, d), 6.70 (1H, d), 4.07
(1H, m), 3.39 (2H, t), 2.40 (2H, t), 1.92 (2H, m), 1.41 (6H, d)
Example 93:
2-[1-[4-(2-cyclobutylsulfanyl-3-pyridyl)phenyl]pyrazol-4-yl]acetic
Acid
##STR00130##
[2249] Step A:
2-[1-[4-(2-cyclobutylsulfanyl-3-pyridyl)phenyl]pyrazol-4-yl]acetic
Acid Methyl Ester
[2250]
2-[1-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazol-
-4-yl]acetic acid methyl ester (0.04 g, 0.11 mmol) obtained in
Preparation Example 81 and 3-iodo-2-cyclobutylsulfanyl-pyridine
(0.034 g, 0.11 mmol) obtained in Preparation Example 13 were
reacted in the same manner as in Step A of Example 1 to obtain the
title compound (0.021 g, 47%).
[2251] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, m), 7.97 (1H, s),
7.75 (2H, d), 7.67 (1H, s), 7.50 (2H, d), 7.40 (1H, m), 7.05 (1H,
m), 4.43 (1H, m), 3.74 (3H, s), 3.60 (2H, s), 2.51 (2H, m), 2.03
(4H, m)
Step B:
2-[1-[4-(2-cyclobutylsulfanyl-3-pyridyl)phenyl]pyrazol-4-yl]acetic
Acid
[2252]
2-[1-[4-(2-Cyclobutylsulfanyl-3-pyridyl)phenyl]pyrazol-4-yl]acetic
acid methyl ester (0.021 g, 0.05 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.006 g, 30%).
[2253] .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, m), 7.99 (1H, s),
7.76 (2H, d), 7.70 (1H, s), 7.51 (2H, d), 7.40 (1H, m), 7.06 (1H,
m), 4.43 (1H, m), 3.67 (2H, s), 2.51 (2H, m), 2.03 (4H, m)
Example 94:
5-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-anilino]pentanoic
Acid
##STR00131##
[2254] Step A:
5-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-anilino]-5-oxo-pentanoic
Acid Ethyl Ester
[2255] 4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-aniline (0.09 g,
0.31 mmol) obtained in Preparation Example 67 was dissolved in 1.6
mL of DCM. DIPEA (0.054 mL, 0.31 mmol) and ethyl glutaryl chloride
(0.05 mL, 0.31 mmol) were added thereto, and the mixture was
stirred at room temperature for 2 hours. After addition of water,
the reaction solution was extracted with EtOAc. The organic layer
was dried with MgSO.sub.4 and purified by column chromatography to
obtain the title compound (0.09 g, 67%).
[2256] .sup.1H-NMR (CDCl.sub.3) .delta. 8.17 (1H, m), 7.57 (1H, m),
7.20 (2H, m), 7.00 (1H, brs), 6.93 (1H, m), 5.52 (1H, m), 4.15 (2H,
q), 2.54 (2H, m), 2.46 (2H, m), 2.08 (2H, m), 1.93 (2H, m), 1.79
(2H, m), 1.74 (2H, m), 1.63 (2H, m), 1.27 (3H, t)
Step B:
5-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-anilino]pentanoic
Acid Ethyl Ester
[2257]
5-[4-[2-(Cyclopentoxy)-3-pyridyl]-2,6-difluoro-anilino]-5-oxo-penta-
noic acid ethyl ester (0.06 g, 0.14 mmol) obtained in Step A was
dissolved in 1.4 mL of THF. Borane-dimethyl sulfide (0.06 mL, 0.28
mmol, 5.0 M Et.sub.2O solution) was added thereto, and the mixture
was stirred at room temperature for 16 hours. The reaction solution
was concentrated under reduced pressure. After addition of water,
the reaction solution was extracted with EtOAc. The organic layer
was dried with MgSO.sub.4 and purified by column chromatography to
obtain the title compound (0.009 g, 15%).
[2258] .sup.1H-NMR (CDCl.sub.3) .delta. 8.09 (1H, m), 7.54 (1H, m),
7.10 (2H, m), 6.88 (1H, m), 5.52 (1H, m), 4.13 (2H, q), 3.65 (1H,
brs), 3.38 (2H, t), 2.35 (2H, t), 1.96 (2H, m), 1.83 (2H, m), 1.75
(4H, m), 1.65 (4H, m), 1.25 (3H, t)
Step C:
5-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-anilino]pentanoic
Acid
[2259]
5-[4-[2-(Cyclopentoxy)-3-pyridyl]-2,6-difluoro-anilino]pentanoic
acid ethyl ester (0.009 g, 0.021 mmol) obtained in Step B was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.004 g, 48%).
[2260] .sup.1H-NMR (CDCl.sub.3) .delta. 8.10 (1H, m), 7.55 (1H, m),
7.12 (2H, m), 6.99 (1H, m), 5.51 (1H, m), 3.39 (2H, t), 2.41 (2H,
t), 1.95 (2H, m), 1.83 (2H, m), 1.75 (4H, m), 1.65 (4H, m)
Example 95:
5-[4-[2-(cyclopentoxy)-3-pyridyl]-N-ethyl-2,6-difluoro-anilino]pentanoic
Acid
##STR00132##
[2261] Step A:
5-[N-acetyl-4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-anilino]pentanoic
Acid Ethyl Ester
[2262]
5-[N-benzyloxycarbonyl-4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro--
anilino]pentanoic acid ethyl ester (0.14 g, 0.25 mmol) obtained in
Preparation Example 87 was dissolved in 1.3 mL of MeOH. Catalytic
amount of 10 wt % Pd/C was added thereto, and the mixture was
stirred for 16 hours under hydrogen atmosphere. Solids were
filtered to obtain
5-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-anilino]pentanoic
acid ethyl ester (0.11 g, 99%). The obtained compound (0.09 g, 0.21
mmol) was dissolved in 2.1 mL of DCM. DIPEA (0.04 mL, 0.23 mmol)
and acetyl chloride (0.015 mL, 0.21 mmol) were added thereto, and
the mixture was stirred at room temperature for 72 hours. After
addition of water, the reaction solution was extracted with EtOAc
and purified by column chromatography to obtain the title compound
(0.064 g, 66%).
[2263] .sup.1H-NMR (CDCl.sub.3) .delta. 8.20 (1H, m), 7.62 (1H, m),
7.28 (2H, m), 6.96 (1H, m), 5.55 (1H, m), 4.10 (2H, q), 3.69 (2H,
t), 2.31 (2H, t), 1.99 (2H, m), 1.92 (3H, s), 1.83 (2H, m), 1.76
(2H, m), 1.66 (4H, m), 1.57 (2H, m), 1.24 (3H, t)
Step B:
5-[4-[2-(cyclopentoxy)-3-pyridyl]-N-ethyl-2,6-difluoro-anilino]pen-
tanoic Acid Ethyl Ester
[2264]
5-[N-acetyl-4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-anilino]pen-
tanoic acid ethyl ester (0.06 g, 0.13 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 94 to obtain the
title compound (0.019 g, 33%).
[2265] .sup.1H-NMR (CDCl.sub.3) .delta. 8.14 (1H, m), 7.58 (1H, m),
7.12 (2H, m), 6.92 (1H, m), 5.52 (1H, m), 4.11 (2H, q), 3.16 (4H,
m), 2.29 (2H, t), 1.97 (2H, m), 1.83 (2H, m), 1.76 (2H, m), 1.65
(4H, m), 1.50 (2H, m), 1.23 (3H, t), 1.05 (3H, t)
Step C:
5-[4-[2-(cyclopentoxy)-3-pyridyl]-N-ethyl-2,6-difluoro-anilino]pen-
tanoic Acid
[2266]
5-[4-[2-(Cyclopentoxy)-3-pyridyl]-N-ethyl-2,6-difluoro-anilino]pent-
anoic acid ethyl ester (0.019 g, 0.04 mmol) obtained in Step B was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.018 g, 99%).
[2267] .sup.1H-NMR (CDCl.sub.3) .delta. 8.14 (1H, m), 7.59 (1H, m),
7.12 (2H, m), 6.92 (1H, m), 5.52 (1H, m), 3.17 (4H, m), 2.35 (2H,
t), 1.97 (2H, m), 1.83 (2H, m), 1.76 (2H, m), 1.68 (4H, m), 1.53
(2H, m), 1.05 (3H, t)
Example 96:
5-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)anilino]pentanoic
Acid
##STR00133##
[2268] Step A:
5-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)anilino]pentanoic
Acid Ethyl Ester
[2269] 0.7 mL of dimethoxyethane and 2M Na.sub.2CO.sub.3 (0.3 mL,
0.6 mmol) were added to
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]pe-
ntanoic acid ethyl ester (0.087 g, 0.23 mmol) obtained in
Preparation Example 83 and 2-chloro-6-isopropylsulfanyl-pyridine
(0.038 g, 0.2 mmol) obtained in Preparation Example 10, and charged
with nitrogen for 5 minutes. Pd(PPh.sub.3).sub.4 (12 mg, 0.01 mmol)
was added thereto, and the mixture was stirred for 16 hours under
reflux. The reaction solution was cooled to room temperature, and
solids were filtered through Celite. The filtrate was purified by
column chromatography to obtain the title compound (0.057 g,
70%).
[2270] .sup.1H-NMR (CDCl.sub.3) .delta. 7.53 (2H, m), 7.47 (1H, t),
7.26 (1H, d), 7.02 (1H, d), 4.14 (3H, m), 3.77 (1H, brs), 3.41 (2H,
m), 2.35 (2H, t), 1.74 (2H, m), 1.65 (2H, m), 1.45 (6H, d), 1.26
(3H, t)
Step B:
5-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)anilino]pentanoic
Acid
[2271]
5-[2,6-Difluoro-4-(6-isopropylsulfanyl-2-pyridyl)anilino]pentanoic
acid ethyl ester (0.057 g, 0.14 mmol) Obtained in Step A was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.037 g, 69%).
[2272] .sup.1H-NMR (CDCl.sub.3) .delta. 7.53 (2H, m), 7.47 (1H, t),
7.26 (1H, d), 7.02 (1H, d), 4.13 (1H, m), 3.42 (2H, m), 2.41 (2H,
t), 1.75 (2H, m), 1.68 (2H, m), 1.46 (6H, d)
Example 97:
5-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)anilino]pentanoic
Acid
##STR00134##
[2274]
5-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anil-
ino]pentanoic acid ethyl ester (0.087 g, 0.23 mmol) obtained in
Preparation Example 83 and 3-iodo-2-isopropylsulfanyl-pyridine
(0.038 g, 0.2 mmol) obtained in Preparation Example 9 were reacted
in the same manner as in Example 1 to obtain the title compound
(0.043 g, 56%).
[2275] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, m), 7.32 (1H, m),
7.02 (1H, m), 6.90 (2H, m), 4.05 (1H, m), 3.41 (2H, m), 2.43 (2H,
t), 1.77 (2H, m), 1.69 (2H, m), 1.37 (6H, d)
Example 98:
5-[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-anilino]pentanoic
Acid
##STR00135##
[2277]
5-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anil-
ino]pentanoic acid ethyl ester (0.087 g, 0.23 mmol) obtained in
Preparation Example 83 and 2-chloro-6-cyclopropylmethoxy-pyridine
(0.037 g, 0.2 mmol) obtained in Preparation Example 43 were reacted
in the same manner as in Example 1 to obtain the title compound
(0.046 g, 61%).
[2278] .sup.1H-NMR (CDCl.sub.3) .delta. 7.58 (1H, m), 7.52 (2H, m),
7.16 (1H, d), 6.65 (1H, d), 4.23 (2H, d), 3.41 (2H, m), 2.42 (2H,
t), 1.76 (2H, m), 1.67 (2H, m), 1.33 (1H, m), 0.63 (2H, m), 0.38
(2H, m)
Example 99:
5-[4-[2-(cyclopropylmethoxy)-3-pyridyl]-2,6-difluoro-anilino]pentanoic
Acid
##STR00136##
[2280]
5-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anil-
ino]pentanoic acid ethyl ester (0.087 g, 0.23 mmol) obtained in
Preparation Example 83 and 2-cyclopropylmethoxy-3-iodo-pyridine
(0.055 g, 0.2 mmol) obtained in Preparation Example 40 were reacted
in the same manner as in Example 1 to obtain the title compound
(0.042 g, 57%).
[2281] .sup.1H-NMR (CDCl.sub.3) .delta. 8.08 (1H, m), 7.57 (1H, m),
7.17 (2H, m), 6.92 (1H, m), 4.22 (2H, d), 3.40 (2H, m), 2.42 (2H,
t), 1.77 (2H, m), 1.68 (2H, m), 1.30 (1H, m), 0.60 (2H, m), 0.35
(2H, m)
Example 100:
2-[1-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]-4-piperidy-
l]acetic Acid
##STR00137##
[2282] Step A:
2-[1-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]-4-piperidy-
l]acetic Acid Methyl Ester
[2283]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid methyl ester (0.082 g, 0.21 mmol)
obtained in Preparation Example 84 and
2-cyclopentylsulfanyl-3-iodo-pyridine (0.053 g, 0.19 mmol) obtained
in Preparation Example 15 were reacted in the same manner as in
Step A of Example 1 to obtain the title compound (0.052 g,
66%).
[2284] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, m), 7.32 (1H, m),
7.01 (1H, m), 6.93 (2H, m), 4.08 (1H, m), 3.69 (3H, s), 3.31 (2H,
m), 3.14 (2H, m), 2.31 (2H, d), 2.03 (2H, m), 1.95 (1H, m), 1.77
(4H, m), 1.72 (4H, m), 1.45 (2H, m)
Step B:
2-[1-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]-4-p-
iperidyl]acetic Acid
[2285]
2-[1-[4-(2-Cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]-4-pi-
peridyl]acetic acid methyl ester (0.052 g, 0.12 mmol) obtained in
Step A was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.024 g, 48%).
[2286] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, m), 7.30 (1H, m),
7.01 (1H, m), 6.92 (2H, m), 4.08 (1H, m), 3.33 (2H, m), 3.15 (2H,
m), 2.36 (2H, d), 2.20 (2H, m), 1.95 (1H, m), 1.82 (2H, m), 1.72
(2H, m), 1.62-1.48 (6H, m)
Example 101:
5-[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-N-methyl-anilino]pen-
tanoic Acid
##STR00138##
[2288]
5-[4-[6-(Cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-anilino]pentan-
oic acid (0.023 g, 0.06 mmol) obtained in Example 98 was dissolved
in 3 mL of DMF. NaH (0.008 g, 55 wt % in mineral oil, 0.18 mmol)
and iodomethane (0.011 mL, 0.18 mmol) were sequentially added
thereto, and the mixture was stirred at room temperature for 1
hour. After addition of ammonium chloride aqueous solution, the
reaction solution was extracted with EtOAc. The organic layer was
dried with anhydrous magnesium sulfate and reacted in the same
manner as in Step B of Example 1 to obtain the title compound
(0.013 g, 54%).
[2289] .sup.1H-NMR (CDCl.sub.3) .delta. 7.60 (1H, t), 7.50 (2H, m),
7.21 (1H, d), 6.70 (1H, d), 4.24 (2H, d), 3.14 (2H, t), 2.90 (3H,
s), 2.35 (2H, t), 1.67 (2H, m), 1.59 (2H, m), 1.33 (1H, m), 0.63
(2H, m), 0.39 (2H, m)
Example 102:
2-[1-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]-4-piperidyl]ace-
tic Acid
##STR00139##
[2291]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid methyl ester (0.082 g, 0.21 mmol)
obtained in Preparation Example 84 and
2-cyclopentoxy-3-iodo-pyridine (0.055 g, 0.19 mmol) obtained in
Preparation Example 11 were reacted in the same manner as in
Example 1 to obtain the title compound (0.04 g, 42%).
[2292] .sup.1H-NMR (CDCl.sub.3) .delta. 8.12 (1H, m), 7.55 (1H, m),
7.08 (2H, m), 6.90 (1H, m), 5.51 (1H, m), 3.32 (2H, m), 3.15 (2H,
m), 2.36 (2H, d), 1.95 (3H, m), 1.84 (6H, m), 1.50 (2H, m), 1.47
(2H, m)
Example 103:
2-[1-[2,6-difluoro-4-(2-tetrahydrofuran-3-yloxy-3-pyridyl)phenyl]-4-piper-
idyl]acetic Acid
##STR00140##
[2294]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid methyl ester (0.082 g, 0.21 mmol)
obtained in Preparation Example 84 and
3-iodo-2-(tetrahydro-furan-3-yloxy)-pyridine (0.055 g, 0.19 mmol)
obtained in Preparation Example 49 were reacted in the same manner
as in Example 1 to obtain the title compound (0.036 g, 46%).
[2295] .sup.1H-NMR (CDCl.sub.3) .delta. 8.10 (1H, m), 7.58 (1H, m),
7.10 (2H, m), 6.96 (1H, m), 5.64 (1H, m), 4.13 (1H, m), 3.93 (3H,
m), 3.32 (2H, m), 3.15 (2H, m), 2.36 (2H, d), 2.25 (1H, m), 2.13
(1H, m), 1.98 (1H, m), 1.82 (2H, m), 1.50 (2H, m)
Example 104:
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-4-piperidyl]a-
cetic Acid
##STR00141##
[2297]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid methyl ester (0.082 g, 0.21 mmol)
obtained in Preparation Example 84 and
3-iodo-2-isopropylsulfanyl-pyridine (0.05 g, 0.19 mmol) obtained in
Preparation Example 9 were reacted in the same manner as in Example
1 to obtain the title compound (0.024 g, 32%).
[2298] .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, m), 7.33 (1H, m),
7.02 (1H, m), 6.91 (2H, m), 4.06 (1H, m), 3.32 (2H, m), 3.16 (2H,
m), 2.36 (2H, d), 1.98 (1H, m), 1.83 (2H, m), 1.51 (2H, m), 1.37
(6H, d)
Example 105:
2-[1-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]-4-piperidyl]a-
cetic Acid
##STR00142##
[2300]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid methyl ester (0.082 g, 0.21 mmol)
obtained in Preparation Example 84 and
2-chloro-6-isopropylsulfanyl-pyridine (0.035 g, 0.19 mmol) obtained
in Preparation Example 10 were reacted in the same manner as in
Example 1 to obtain the title compound (0.024 g, 31%).
[2301] .sup.1H-NMR (CDCl.sub.3) .delta. 7.53 (3H, m), 7.27 (1H, d),
7.05 (1H, d), 4.13 (1H, m), 3.32 (2H, m), 3.17 (2H, m), 2.37 (2H,
d), 1.98 (1H, m), 1.97 (2H, m), 1.49 (8H, m)
Example 106:
2-[1-[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperid-
yl]acetic Acid
##STR00143##
[2303]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid methyl ester (0.082 g, 0.21 mmol)
obtained in Preparation Example 84 and
2-chloro-6-cyclopropylmethoxy-pyridine (0.035 g, 0.19 mmol)
obtained in Preparation Example 43 were reacted in the same manner
as in Example 1 to obtain the title compound (0.027 g, 35%).
[2304] .sup.1H-NMR (CDCl.sub.3) .delta. 7.60 (1H, t), 7.51 (2H, m),
7.20 (1H, d), 6.70 (1H, d), 4.23 (2H, d), 3.32 (2H, m), 3.16 (2H,
m), 2.35 (2H, d), 1.98 (1H, m), 1.82 (2H, m), 1.50 (2H, m), 1.34
(1H, m), 0.64 (2H, m), 0.40 (2H, m)
Example 107:
2-[1-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]-3-piperidyl]a-
cetic Acid
##STR00144##
[2305] Step A:
2-[1-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]-3-piperidyl]a-
cetonitrile
[2306]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-3-piperidyl]acetonitrile (0.12 g, 0.33 mmol) obtained in
Preparation Example 86 and 2-chloro-6-isopropylsulfanyl-pyridine
(0.056 g, 0.3 mmol) obtained in Preparation Example 10 were reacted
in the same manner as in Step A of Example 1 to obtain the title
compound (0.081 g, 70%).
[2307] .sup.1H-NMR (CDCl.sub.3) .delta. 7.52 (3H, m), 7.30 (1H, d),
7.07 (1H, d), 4.13 (1H, m), 3.36 (1H, m), 3.25 (1H, m), 3.11 (1H,
m), 2.98 (1H, m), 2.47 (2H, m), 2.17 (1H, m), 1.93 (1H, m), 1.80
(1H, m), 1.73 (1H, m), 1.47 (7H, m)
Step B:
2-[1-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]-3-pipe-
ridyl]acetic Acid
[2308]
2-[1-[2,6-Difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]-3-piper-
idyl]acetonitrile (0.081 g, 0.21 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 91 to obtain the
title compound (0.046 g, 54%).
[2309] .sup.1H-NMR (CDCl.sub.3) .delta. 7.50 (3H, m), 7.28 (1H, d),
7.05 (1H, d), 4.13 (1H, m), 3.35 (1H, m), 3.25 (1H, m), 3.07 (1H,
m), 2.90 (1H, m), 2.46 (1H, m), 2.35 (1H, m), 2.45 (1H, m), 1.90
(1H, m), 1.75 (2H, m), 1.46 (6H, d), 1.25 (1H, m)
Example 108:
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-3-piperidyl]a-
cetic Acid
##STR00145##
[2310] Step A:
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-3-piperidyl]a-
cetonitrile
[2311]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-3-piperidyl]acetonitrile (0.12 g, 0.33 mmol) obtained in
Preparation Example 86 and 3-iodo-2-isopropylsulfanyl-pyridine
(0.084 g, 0.3 mmol) obtained in Preparation Example 9 were reacted
in the same manner as in Step A of Example 1 to obtain the title
compound (0.072 g, 63%).
[2312] .sup.1H-NMR (CDCl.sub.3) .delta. 8.43 (1H, m), 7.32 (1H, m),
7.02 (1H, m), 6.95 (2H, m), 4.07 (1H, m), 3.36 (1H, m), 3.24 (1H,
m), 3.10 (1H, m), 2.98 (1H, m), 2.47 (2H, m), 2.16 (1H, m), 1.92
(1H, m), 1.80 (1H, m), 1.73 (1H, m), 1.43 (1H, m), 1.36 (6H, d)
Step B:
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-3-pipe-
ridyl]acetic Acid
[2313]
2-[1-[2,6-Difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-3-piper-
idyl]acetonitrile (0.072 g, 0.19 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 91 to obtain the
title compound (0.023 g, 30%).
[2314] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, m), 7.33 (1H, m),
7.02 (1H, m), 6.92 (2H, m), 4.06 (1H, m), 3.35 (1H, m), 3.24 (1H,
m), 3.07 (1H, m), 2.90 (1H, m), 2.45 (1H, m), 2.35 (1H, m), 2.24
(1H, m), 1.89 (1H, m), 1.73 (2H, m), 1.36 (6H, d), 1.26 (1H, m)
Example 109:
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]azetidin-3-yl]-
acetic Acid
##STR00146##
[2315] Step A:
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]azetidin-3-yl]-
acetic Acid Ethyl Ester
[2316]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]azetidin-3-yl]acetic acid ethyl ester (0.076 g, 0.2 mmol)
obtained in Preparation Example 88 and
3-iodo-2-isopropylsulfanyl-pyridine (0.05 g, 0.18 mmol) obtained in
Preparation Example 9 were reacted in the same manner as in Step A
of Example 1 to obtain the title compound (0.046 g, 63%).
[2317] .sup.1H-NMR (CDCl.sub.3) .delta. 8.39 (1H, m), 7.31 (1H, m),
7.00 (1H, m), 6.84 (2H, m), 4.40 (2H, m), 4.15 (2H, q), 4.05 (1H,
m), 3.92 (2H, m), 3.05 (1H, m), 2.71 (2H, d), 1.37 (6H, d), 1.27
(3H, t)
Step B:
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]azetidi-
n-3-yl]acetic Acid
[2318]
2-[1-[2,6-Difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]azetidin-
-3-yl]acetic acid ethyl ester (0.046 g, 0.11 mmol) obtained in Step
A was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.016 g, 40%).
[2319] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, m), 7.31 (1H, m),
7.00 (1H, m), 6.86 (2H, m), 4.42 (2H, m), 4.03 (1H, m), 3.93 (2H,
m), 3.07 (1H, m), 2.78 (2H, d), 1.36 (6H, d)
Example 110:
6-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-6-azaspiro[2.5]o-
ctan-2-carboxylic Acid
##STR00147##
[2320] Step A:
6-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-6-azaspiro[2.5]o-
ctan-2-carboxylic Acid Ethyl Ester
[2321]
6-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
yl]-6-azaspiro[2.5]octan-2-carboxylic acid ethyl ester (0.092 g,
0.21 mmol) obtained in Preparation Example 89 and
3-iodo-2-isopropylsulfanyl-pyridine (0.053 g, 0.19 mmol) obtained
in Preparation Example 9 were reacted in the same manner as in Step
A of Example 1 to obtain the title compound (0.061 g, 72%).
[2322] .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, m), 7.33 (1H, m),
7.02 (1H, m), 6.92 (2H, m), 4.17 (2H, q), 4.06 (1H, m), 3.32-3.11
(4H, m), 1.86 (2H, m), 1.59 (3H, m), 1.34 (6H, d), 1.30 (3H, t),
1.20 (1H, m), 0.96 (1H, m)
Step B:
6-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-6-azaspir-
o[2.5]octan-2-carboxylic Acid
[2323]
6-[2,6-Difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-6-azaspiro-
[2.5]octan-2-carboxylic acid ethyl ester (0.061 g, 0.13 mmol)
obtained in Step A was reacted in the same manner as in Step B of
Example 1 to obtain the title compound (0.04 g, 70%).
[2324] .sup.1H-NMR (CDCl.sub.3+MeOH-d.sub.4) .delta. 8.42 (1H, m),
7.34 (1H, m), 7.04 (1H, m), 6.94 (2H, m), 4.05 (1H, m), 3.40-3.10
(4H, m), 1.90 (2H, m), 1.60 (3H, m), 1.36 (6H, d), 1.19 (1H, m),
0.99 (1H, m)
Example 111:
6-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]-6-azaspiro[2.5]o-
ctan-2-carboxylic Acid
##STR00148##
[2326]
6-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
yl]-6-azaspiro[2.5]octan-2-carboxylic acid ethyl ester (0.092 g,
0.21 mmol) obtained in Preparation Example 89 and
2-chloro-6-isopropylsulfanyl-pyridine (0.036 g, 0.19 mmol) obtained
in Preparation Example 10 were reacted in the same manner as in
Example 1 to obtain the title compound (0.045 g, 57%).
[2327] .sup.1H-NMR (CDCl.sub.3) .delta. 7.51 (3H, m), 7.30 (1H, m),
7.07 (1H, m), 4.12 (1H, m), 3.30-3.19 (4H, m), 1.93 (2H, m), 1.62
(3H, m), 1.46 (6H, d), 1.26 (1H, m), 1.05 (1H, m)
Example 112:
2-[1-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]azetidin-3--
yl]acetic Acid
##STR00149##
[2329]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]azetidin-3-yl]acetic acid ethyl ester (0.10 g, 0.26 mmol)
obtained in Preparation Example 88 and
2-cyclopentylsulfanyl-3-iodo-pyridine (0.072 g, 0.24 mmol) obtained
in Preparation Example 15 were reacted in the same manner as in
Example 1 to obtain the title compound (0.045 g, 46%).
[2330] .sup.1H-NMR (CDCl.sub.3) .delta. 8.39 (1H, m), 7.29 (1H, m),
6.99 (1H, m), 6.85 (2H, m), 4.42 (2H, m), 4.07 (1H, m), 3.94 (2H,
m), 3.05 (1H, m), 2.78 (2H, d), 2.20 (2H, m), 1.74 (2H, m), 1.56
(4H, m)
Example 113:
2-[1-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]azetidin-3-yl]ac-
etic Acid
##STR00150##
[2332]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]azetidin-3-yl]acetic acid ethyl ester (0.10 g, 0.26 mmol)
obtained in Preparation Example 88 and
2-cyclopentoxy-3-iodo-pyridine (0.070 g, 0.24 mmol) obtained in
Preparation Example 11 were reacted in the same manner as in
Example 1 to obtain the title compound (0.035 g, 37%).
[2333] .sup.1H-NMR (CDCl.sub.3) .delta. 8.10 (1H, m), 7.54 (1H, m),
7.05 (2H, m), 6.89 (1H, m), 5.50 (1H, m), 4.41 (2H, m), 3.93 (2H,
m), 3.05 (1H, m), 2.80 (2H, d), 1.95 (2H, m), 1.83 (2H, m), 1.77
(2H, m), 1.64 (2H, m)
Example 114:
2-[1-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]azetidin-3-yl]-
acetic Acid
##STR00151##
[2335]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]azetidin-3-yl]acetic acid ethyl ester (0.10 g, 0.26 mmol)
obtained in Preparation Example 88 and
2-chloro-6-isopropylsulfanyl-pyridine (0.045 g, 0.24 mmol) obtained
in Preparation Example 10 were reacted in the same manner as in
Example 1 to obtain the title compound (0.048 g, 52%).
[2336] .sup.1H-NMR (CDCl.sub.3) .delta. 7.46 (3H, m), 7.25 (1H, d),
7.00 (1H, d), 4.43 (2H, m), 4.12 (1H, m), 3.95 (2H, m), 3.05 (1H,
m), 2.79 (2H, d), 1.46 (6H, d)
Example 115:
2-[1-[2,6-difluoro-4-(6-isopropoxy-2-pyridyl)phenyl]azetidin-3-yl]acetic
Acid
##STR00152##
[2338]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]azetidin-3-yl]acetic acid ethyl ester (0.10 g, 0.26 mmol)
obtained in Preparation Example 88 and
2-chloro-6-isopropoxy-pyridine (0.041 g, 0.24 mmol) obtained in
Preparation Example 46 were reacted in the same manner as in
Example 1 to obtain the title compound (0.012 g, 13%).
[2339] .sup.1H-NMR (CDCl.sub.3) .delta. 7.54 (1H, t), 7.45 (2H, m),
7.12 (1H, d), 6.56 (1H, d), 5.44 (1H, m), 4.42 (2H, m), 3.94 (2H,
m), 3.05 (1H, m), 2.79 (2H, d), 1.39 (6H, d)
Example 116:
2-[1-[4-[6-(cyclopentoxy)-2-pyridyl]-2,6-difluoro-phenyl]azetidin-3-yl]ac-
etic Acid
##STR00153##
[2341]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]azetidin-3-yl]acetic acid ethyl ester (0.10 g, 0.26 mmol)
obtained in Preparation Example 88 and
2-chloro-6-cyclopentoxy-pyridine (0.047 g, 0.24 mmol) obtained in
Preparation Example 12 were reacted in the same manner as in
Example 1 to obtain the title compound (0.012 g, 12%).
[2342] .sup.1H-NMR (CDCl.sub.3) .delta. 7.54 (1H, t), 7.47 (2H, m),
7.12 (1H, d), 6.56 (1H, d), 5.50 (1H, m), 4.42 (2H, m), 3.95 (2H,
m), 3.05 (1H, m), 2.79 (2H, d), 2.05 (2H, m), 1.83 (4H, m), 1.65
(2H, m)
Example 117:
2-[1-[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)phenyl]-4-piperidyl]acet-
ic Acid
##STR00154##
[2344]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid methyl ester (0.11 g, 0.28 mmol)
obtained in Preparation Example 84 and
3-iodo-2-propylsulfanyl-pyridine (0.071 g, 0.25 mmol) obtained in
Preparation Example 28 were reacted in the same manner as in
Example 1 to obtain the title compound (0.038 g, 37%).
[2345] .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, m), 7.33 (1H, m),
7.02 (1H, m), 6.95 (2H, m), 3.32 (2H, m), 3.14 (4H, m), 2.37 (2H,
d), 1.98 (1H, m), 1.83 (2H, m), 1.70 (2H, m), 1.50 (2H, m), 1.01
(3H, t)
Example 118:
2-[1-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenyl]-4-piperidyl-
]acetic Acid
##STR00155##
[2347]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid methyl ester (0.11 g, 0.28 mmol)
obtained in Preparation Example 84 and
3-iodo-2-cyclobutylsulfanyl-pyridine (0.075 g, 0.25 mmol) obtained
in Preparation Example 13 were reacted in the same manner as in
Example 1 to obtain the title compound (0.031 g, 29%).
[2348] .sup.1H-NMR (CDCl.sub.3) .delta. 8.39 (1H, m), 7.31 (1H, m),
7.01 (1H, m), 6.93 (2H, m), 4.42 (1H, m), 3.32 (2H, m), 3.15 (2H,
m), 2.50 (2H, m), 2.37 (2H, d), 2.05 (5H, m), 1.83 (2H, m), 1.50
(2H, m)
Example 119:
2-[1-[2,6-difluoro-4-(2-isopropoxy-3-pyridyl)phenyl]-4-piperidyl]acetic
Acid
##STR00156##
[2350]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid methyl ester (0.11 g, 0.28 mmol)
obtained in Preparation Example 84 and 3-iodo-2-isopropoxy-pyridine
(0.067 g, 0.25 mmol) obtained in Preparation Example 34 were
reacted in the same manner as in Example 1 to obtain the title
compound (0.046 g, 47%).
[2351] .sup.1H-NMR (CDCl.sub.3) .delta. 8.11 (1H, m), 7.55 (1H, m),
7.11 (2H, m), 6.90 (1H, m), 5.40 (1H, m), 3.31 (2H, m), 3.15 (2H,
m), 2.37 (2H, d), 1.97 (1H, m), 1.82 (2H, m), 1.50 (2H, m), 1.36
(6H, d)
Example 120:
2-[1-[2,6-difluoro-4-(2-propoxy-3-pyridyl)phenyl]-4-piperidyl]acetic
Acid
##STR00157##
[2353]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid methyl ester (0.11 g, 0.28 mmol)
obtained in Preparation Example 84 and 3-iodo-2-propoxy-pyridine
(0.067 g, 0.25 mmol) obtained in Preparation Example 47 were
reacted in the same manner as in Example 1 to obtain the title
compound (0.032 g, 33%).
[2354] .sup.1H-NMR (CDCl.sub.3) .delta. 8.12 (1H, m), 7.57 (1H, m),
7.10 (2H, m), 6.93 (1H, m), 4.32 (2H, t), 3.31 (2H, m), 3.15 (2H,
m), 2.37 (2H, d), 1.97 (1H, m), 1.82 (4H, m), 1.50 (2H, m), 1.02
(3H, t)
Example 121:
2-[1-[4-[2-(cyclopropylmethoxy)-3-pyridyl]-2,6-difluoro-phenyl]-4-piperid-
yl]acetic Acid
##STR00158##
[2356]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid methyl ester (0.11 g, 0.28 mmol)
obtained in Preparation Example 84 and
2-cyclopropylmethoxy-3-iodo-pyridine (0.07 g, 0.25 mmol) obtained
in Preparation Example 40 were reacted in the same manner as in
Example 1 to obtain the title compound (0.046 g, 45%).
[2357] .sup.1H-NMR (CDCl.sub.3) .delta. 8.10 (1H, m), 7.58 (1H, m),
7.16 (2H, m), 6.93 (1H, m), 4.22 (2H, d), 3.31 (2H, m), 3.15 (2H,
m), 2.37 (2H, d), 1.98 (1H, m), 1.82 (2H, m), 1.50 (2H, m), 1.30
(1H, m), 0.59 (2H, m), 0.35 (2H, m)
Example 122:
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]pyrazol-4-yl]a-
cetic Acid
##STR00159##
[2358] Step A:
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]pyrazol-4-yl]a-
cetic Acid Methyl Ester
[2359]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrazol-4-yl]acetic acid methyl ester (0.1 g, 0.26 mmol)
obtained in Preparation Example 90 and
3-iodo-2-isopropylsulfanyl-pyridine (0.066 g, 0.23 mmol) obtained
in Preparation Example 9 were reacted in the same manner as in Step
A of Example 1 to obtain the title compound (0.065 g, 70%).
[2360] .sup.1H-NMR (CDCl.sub.3) .delta. 8.48 (1H, m), 7.77 (1H, s),
7.72 (1H, s), 7.39 (1H, m), 7.16 (2H, m), 7.07 (1H, m), 4.10 (1H,
m), 3.75 (3H, s), 3.63 (2H, s), 1.38 (6H, d)
Step B:
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]pyrazol-
-4-yl]acetic Acid
[2361]
2-[1-[2,6-Difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]pyrazol--
4-yl]acetic acid methyl ester (0.065 g, 0.16 mmol) obtained in Step
A was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.021 g, 33%).
[2362] .sup.1H-NMR (CDCl.sub.3) .delta. 8.48 (1H, m), 7.80 (1H, s),
7.74 (1H, s), 7.40 (1H, m), 7.16 (2H, m), 7.08 (1H, m), 4.09 (1H,
m), 3.67 (2H, s), 1.38 (6H, d)
Example 123:
2-[1-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]pyrazol-4-yl]a-
cetic Acid
##STR00160##
[2364]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrazol-4-yl]acetic acid methyl ester (0.1 g, 0.26 mmol)
obtained in Preparation Example 90 and
2-chloro-6-isopropylsulfanyl-pyridine (0.044 g, 0.23 mmol) obtained
in Preparation Example 10 were reacted in the same manner as in
Example 1 to obtain the title compound (0.032 g, 37%).
[2365] .sup.1H-NMR (CDCl.sub.3) .delta. 7.80 (1H, s), 7.75 (2H, m),
7.74 (1H, s), 7.57 (1H, t), 7.41 (1H, d), 7.16 (1H, d), 4.14 (1H,
m), 3.68 (2H, s), 1.48 (6H, d)
Example 124:
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]pyrrolidin-3-y-
l]acetic Acid
##STR00161##
[2366] Step A:
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]pyrrolidin-3-y-
l]acetic Acid Ethyl Ester
[2367]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.105 g, 0.26 mmol)
obtained in Preparation Example 91 and
3-iodo-2-isopropylsulfanyl-pyridine (0.062 g, 0.22 mmol) obtained
in Preparation Example 9 were reacted in the same manner as in Step
A of Example 1 to obtain the title compound (0.055 g, 59%).
[2368] .sup.1H-NMR (CDCl.sub.3) .delta. 8.40 (1H, m), 7.32 (1H, m),
7.01 (1H, m), 6.88 (2H, m), 4.16 (2H, q), 4.05 (1H, m), 3.72 (1H,
m), 3.67 (1H, m), 3.60 (1H, m), 3.33 (1H, m), 2.64 (1H, m), 2.46
(2H, m), 2.13 (1H, m), 1.63 (1H, m), 1.36 (6H, d), 1.27 (3H, t)
Step B:
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]pyrroli-
din-3-yl]acetic Acid
[2369]
2-[1-[2,6-Difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]pyrrolid-
in-3-yl]acetic acid ethyl ester (0.055 g, 0.13 mmol) obtained in
Step A was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.038 g, 74%).
[2370] .sup.1H-NMR (CDCl.sub.3) .delta. 8.39 (1H, m), 7.32 (1H, m),
7.01 (1H, m), 6.89 (2H, m), 4.04 (1H, m), 3.74 (1H, m), 3.66 (1H,
m), 3.60 (1H, m), 3.35 (1H, m), 2.65 (1H, m), 2.53 (2H, m), 2.18
(1H, m), 1.65 (1H, m), 1.36 (6H, d)
Example 125:
2-[1-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]pyrrolidin-3-y-
l]acetic Acid
##STR00162##
[2372]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.105 g, 0.26 mmol)
obtained in Preparation Example 91 and
2-chloro-6-isopropylsulfanyl-pyridine (0.042 g, 0.22 mmol) obtained
in Preparation Example 10 were reacted in the same manner as in
Example 1 to obtain the title compound (0.04 g, 46%).
[2373] .sup.1H-NMR (CDCl.sub.3) .delta. 7.48 (3H, m), 7.26 (1H, d),
7.02 (1H, d), 4.13 (1H, m), 3.76 (1H, m), 3.70 (1H, m), 3.62 (1H,
m), 3.38 (1H, m), 2.66 (1H, m), 2.54 (2H, m), 2.20 (1H, m), 1.66
(1H, m), 1.46 (6H, d)
Example 126:
3-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-4-piperidyl]p-
ropanoic Acid
##STR00163##
[2374] Step A:
3-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-4-piperidyl]p-
ropanoic Acid Ethyl Ester
[2375]
3-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]propanoic acid ethyl ester (0.11 g, 0.26 mmol)
obtained in Preparation Example 92 and
3-iodo-2-isopropylsulfanyl-pyridine (0.062 g, 0.22 mmol) obtained
in Preparation Example 9 were reacted in the same manner as in Step
A of Example 1 to obtain the title compound (0.069 g, 69%).
[2376] .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, m), 73.2 (1H, m),
7.02 (1H, m), 6.92 (2H, m), 4.15 (2H, q), 4.06 (1H, m), 3.31 (2H,
m), 3.10 (2H, m), 2.36 (2H, m), 1.74 (2H, m), 1.65 (2H, m), 1.41
(3H, m), 1.36 (6H, d), 1.27 (3H, t)
Step B:
3-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-4-pipe-
ridyl]propanoic Acid
[2377]
3-[1-[2,6-Difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-4-piper-
idyl]propanoic acid ethyl ester (0.069 g, 0.15 mmol) obtained in
Step A was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.04 g, 62%).
[2378] .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, m), 7.33 (1H, m),
7.02 (1H, m), 6.91 (2H, m), 4.06 (1H, m), 3.32 (2H, m), 3.10 (2H,
m), 2.43 (2H, m), 1.75 (2H, m), 1.67 (2H, m), 1.45 (3H, m), 1.35
(6H, d)
Example 127:
3-[1-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenyl]-4-piperidyl]p-
ropanoic Acid
##STR00164##
[2380]
3-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]propanoic acid ethyl ester (0.11 g, 0.26 mmol)
obtained in Preparation Example 92 and
2-chloro-6-isopropylsulfanyl-pyridine (0.042 g, 0.22 mmol) obtained
in Preparation Example 10 were reacted in the same manner as in
Example 1 to obtain the title compound (0.052 g, 56%).
[2381] .sup.1H-NMR (CDCl.sub.3) .delta. 7.51 (3H, m), 7.29 (1H, d),
7.06 (1H, d), 4.13 (1H, m), 3.33 (2H, m), 3.10 (2H, m), 2.43 (2H,
m), 1.75 (2H, m), 1.68 (2H, m), 1.45 (9H, m)
Example 128:
2-[2-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-anilino]ethyl]cycl-
opropanecarboxylic Acid
##STR00165##
[2383]
2-[2-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)a-
nilino]ethyl]cyclopropanecarboxylic acid ethyl ester (0.04 g, 0.1
mmol) obtained in Preparation Example 85 and
2-cyclopentylsulfanyl-3-iodo-pyridine (0.031 g, 0.1 mmol) obtained
in Preparation Example 15 were reacted in the same manner as in
Example 1 to obtain the title compound (0.021 g, 50%).
[2384] .sup.1H-NMR (CDCl.sub.3) .delta. 8.40 (1H, m), 7.31 (1H, m),
7.00 (1H, m), 6.91 (2H, m), 4.08 (1H, m), 3.49 (2H, t), 2.20 (2H,
m), 1.72-1.45 (9H, m), 1.36 (2H, m), 0.85 (1H, m)
Example 129:
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-3-piperidyl]a-
cetamide
##STR00166##
[2386] 1.9 mL of EtOH and 0.19 mL of 6 M NaOH aqueous solution were
added to
2-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-3-piperidy-
l]acetonitrile (0.072 g, 0.18 mmol) obtained in Step A of Example
108, and the mixture was stirred for 24 hours under reflux. The
reaction solution was concentrated under reduced pressure. After
addition of water, the reaction solution was adjusted to pH 5 by
the use of 1 N HCl aqueous solution and extracted with EtOAc. The
organic layer was dried with MgSO.sub.4 and purified by column
chromatography to obtain the title compound (0.025 g, 33%).
[2387] .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, m), 7.32 (1H, m),
7.02 (1H, m), 6.92 (2H, m), 5.56 (1H, brs), 5.51 (1H, brs), 4.06
(1H, m), 3.33 (1H, m), 3.24 (1H, m), 3.08 (1H, m), 2.89 (1H, m),
2.37 (1H, m), 2.26-2.18 (2H, m), 1.89 (1H, m), 1.74 (2H, m), 1.37
(6H, d), 1.30 (1H, m)
Example 130:
2-[4-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]piperazin-1-yl-
]acetic Acid
##STR00167##
[2389]
2-[4-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]piperazin-1-yl]acetic acid ethyl ester (0.12 g, 0.29 mmol)
obtained in Preparation Example 93 and
3-iodo-2-isopropylsulfanyl-pyridine (0.074 g, 0.26 mmol) obtained
in Preparation Example 9 were reacted in the same manner as in
Example 1 to obtain the title compound (0.002 g, 2%).
[2390] .sup.1H-NMR (MeOH-d4) .delta. 8.47 (1H, m), 7.56 (1H, m),
7.19 (1H, m), 7.07 (2H, m), 3.99 (1H, m), 3.17 (4H, m), 2.74 (2H,
s), 2.57 (4H, m), 1.30 (6H, d)
Example 131:
3-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]pyrazol-4-yl]p-
ropanoic Acid
##STR00168##
[2392]
3-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrazol-4-yl]propanoic acid ethyl ester (0.03 g, 0.07 mmol)
obtained in Preparation Example 94 and
3-iodo-2-isopropylsulfanyl-pyridine (0.019 g, 0.066 mmol) obtained
in Preparation Example 9 were reacted in the same manner as in
Example 1 to obtain the title compound (0.013 g, 49%).
[2393] .sup.1H-NMR (CDCl.sub.3) .delta. 8.48 (1H, m), 7.70 (1H, s),
7.57 (1H, m), 7.38 (1H, m), 7.15 (2H, m), 7.06 (1H, m), 4.10 (1H,
m), 2.92 (2H, t), 2.71 (2H, t), 1.38 (6H, d)
Example 132:
4-[5-(2-cyclopentylsulfanyl-3-pyridyl)indolin-1-yl]butanoic
Acid
##STR00169##
[2394] Step A:
4-[5-(2-cyclopentylsulfanyl-3-pyridyl)indolin-1-yl]butanoic Acid
Ethyl Ester
##STR00170##
[2396]
4-[5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl]buta-
noic acid ethyl ester (0.11 g, 0.26 mmol) obtained in Preparation
Example 95 and 2-cyclopentylsulfanyl-3-iodo-pyridine (0.074 g, 0.24
mmol) obtained in Preparation Example 15 were reacted in the same
manner as in Step A of Example 1 to obtain the title compound (0.05
g, 50%).
[2397] .sup.1H-NMR (CDCl.sub.3) .delta. 8.35 (1H, m), 7.32 (1H, m),
7.11 (2H, m), 6.98 (1H, m), 6.47 (1H, m), 4.14 (2H, q), 4.06 (1H,
m), 3.42 (2H, t), 3.14 (2H, t), 3.01 (2H, t), 2.43 (2H, t), 2.20
(2H, m), 1.97 (2H, m), 1.72-1.65 (6H, m), 1.24 (3H, t)
Step B: 4-[5-(2-cyclopentylsulfanyl-3-pyridyl)indolin-1-yl]butanoic
Acid
[2398] 4-[5-(2-Cyclopentylsulfanyl-3-pyridyl)indolin-1-yl]butanoic
acid ethyl ester (0.05 g, 0.12 mmol) obtained in Step A was reacted
in the same manner as in Step B of Example 1 to obtain the title
compound (0.034 g, 74%).
[2399] .sup.1H-NMR (CDCl.sub.3) .delta. 8.35 (1H, m), 7.32 (1H, m),
7.13 (2H, m), 6.99 (1H, m), 6.50 (1H, m), 4.06 (1H, m), 3.42 (2H,
t), 3.17 (2H, t), 3.02 (2H, t), 2.51 (2H, t), 2.20 (2H, m), 1.98
(2H, m), 1.71-1.52 (6H, m)
Example 133:
3-[1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]azetidin-3-yl]-
propanoic Acid
##STR00171##
[2401]
3-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]azetidin-3-yl]propanoic acid ethyl ester (0.032 g, 0.08 mmol)
obtained in Preparation Example 96 and
3-iodo-2-isopropylsulfanyl-pyridine (0.023 g, 0.08 mmol) obtained
in Preparation Example 9 were reacted in the same manner as in
Example 1 to obtain the title compound (0.002 g, 6%).
[2402] .sup.1H-NMR (CDCl.sub.3) .delta. 8.34 (1H, m), 7.32 (1H, m),
7.01 (1H, m), 6.85 (2H, m), 4.35 (2H, m), 4.05 (1H, m), 3.87 (2H,
m), 2.74 (1H, m), 2.37 (2H, m), 2.01 (2H, m), 1.35 (6H, d)
Example 134:
2-[(3R)-1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]pyrrolidi-
n-3-yl]acetic Acid
##STR00172##
[2404]
2-[(3R)-1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)phenyl]pyrrolidin-3-yl]acetic acid methyl ester (0.07 g, 0.18
mmol) obtained in Preparation Example 98 and
3-iodo-2-isopropylsulfanyl-pyridine (0.046 g, 0.16 mmol) obtained
in Preparation Example 9 were reacted in the same manner as in
Example 1 to obtain the title compound (0.031 g, 49%).
[2405] .sup.1H-NMR (CDCl.sub.3) .delta. 8.39 (1H, m), 7.32 (1H, m),
7.01 (1H, m), 6.89 (2H, m), 4.04 (1H, m), 3.74 (1H, m), 3.66 (1H,
m), 3.60 (1H, m), 3.35 (1H, m), 2.65 (1H, m), 2.53 (2H, m), 2.18
(1H, m), 1.65 (1H, m), 1.36 (6H, d)
Example 135:
2-[(3R)-1-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]pyrrolidin--
3-yl]acetic Acid
##STR00173##
[2407]
2-[(3R)-1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)phenyl]pyrrolidin-3-yl]acetic acid methyl ester (0.07 g, 0.18
mmol) obtained in Preparation Example 98 and
2-cyclopentoxy-3-iodo-pyridine (0.048 g, 0.16 mmol) obtained in
Preparation Example 11 were reacted in the same manner as in
Example 1 to obtain the title compound (0.032 g, 50%).
[2408] .sup.1H-NMR (CDCl.sub.3) .delta. 8.10 (1H, m), 7.55 (1H, m),
7.10 (2H, m), 6.89 (1H, m), 5.51 (1H, m), 3.73 (1H, m), 3.66 (1H,
m), 3.59 (1H, m), 3.35 (1H, m), 2.66 (1H, m), 2.54 (2H, m), 2.18
(1H, m), 1.95 (2H, m), 1.84-1.75 (4H, m), 1.65 (3H, m)
Example 136:
2-[(3S)-1-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]pyrrolidi-
n-3-yl]acetic Acid
##STR00174##
[2410]
2-[(3S)-1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)phenyl]pyrrolidin-3-yl]acetic acid methyl ester (0.085 g, 0.22
mmol) obtained in Preparation Example 97 and
3-iodo-2-isopropylsulfanyl-pyridine (0.056 g, 0.2 mmol) obtained in
Preparation Example 9 were reacted in the same manner as in Example
1 to obtain the title compound (0.042 g, 54%).
[2411] .sup.1H-NMR (CDCl.sub.3) .delta. 8.39 (1H, m), 7.32 (1H, m),
7.01 (1H, m), 6.89 (2H, m), 4.04 (1H, m), 3.74 (1H, m), 3.66 (1H,
m), 3.60 (1H, m), 3.35 (1H, m), 2.65 (1H, m), 2.53 (2H, m), 2.18
(1H, m), 1.65 (1H, m), 1.36 (6H, d)
Example 137:
2-[(3S)-1-[4-[2-(cyclopentoxy)-3-pyridyl]-2,6-difluoro-phenyl]pyrrolidin--
3-yl]acetic Acid
##STR00175##
[2413]
2-[(3S)-1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)phenyl]pyrrolidin-3-yl]acetic acid methyl ester (0.085 g, 0.22
mmol) obtained in Preparation Example 97 and
2-cyclopentoxy-3-iodo-pyridine (0.059 g, 0.2 mmol) obtained in
Preparation Example 11 were reacted in the same manner as in
Example 1 to obtain the title compound (0.032 g, 40%).
[2414] .sup.1H-NMR (CDCl.sub.3) .delta. 8.10 (1H, m), 7.55 (1H, m),
7.10 (2H, m), 6.89 (1H, m), 5.51 (1H, m), 3.73 (1H, m), 3.66 (1H,
m), 3.59 (1H, m), 3.35 (1H, m), 2.66 (1H, m), 2.54 (2H, m), 2.18
(1H, m), 1.95 (2H, m), 1.84-1.75 (4H, m), 1.65 (3H, m)
Example 138:
2-[1-[2-fluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-4-piperidyl]aceti-
c Acid
##STR00176##
[2415] Step A:
2-[1-[2-fluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-4-piperidyl]aceti-
c Acid Ethyl Ester
##STR00177##
[2417]
2-[1-[2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l]-4-piperidyl]acetic acid ethyl ester (0.10 g, 0.25 mmol) obtained
in Preparation Example 99 and 3-iodo-2-isopropylsulfanyl-pyridine
(0.063 g, 0.227 mmol) obtained in Preparation Example 9 were
reacted in the same manner as in Step A of Example 1 to obtain the
title compound (0.07 g, 74%).
[2418] .sup.1H-NMR (CDCl.sub.3) .delta. 8.40 (1H, m), 7.35 (1H, m),
7.12 (2H, m), 7.01 (2H, m), 4.14 (2H, q), 4.04 (1H, m), 3.51 (2H,
m), 2.75 (2H, m), 2.31 (2H, d), 1.96 (1H, m), 1.85 (2H, m), 1.50
(2H, m), 1.36 (6H, d), 1.27 (3H, t)
Step B:
2-[1-[2-fluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-4-piperidy-
l]acetic Acid
[2419]
2-[1-[2-Fluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenyl]-4-piperidyl-
]acetic acid ethyl ester (0.07 g, 0.17 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.044 g, 68%).
[2420] .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, m), 7.34 (1H, m),
7.11 (2H, m), 7.00 (2H, m), 4.05 (1H, m), 3.52 (2H, m), 2.76 (2H,
m), 2.37 (2H, d), 1.97 (1H, m), 1.91 (2H, m), 1.55 (2H, m), 1.35
(6H, d)
Example 139:
2-[1-[4-[2-(cyclopentoxy)-3-pyridyl]-2-fluoro-phenyl]-4-piperidyl]acetic
Acid
##STR00178##
[2421] Step A:
2-[1-[4-[2-(cyclopentoxy)-3-pyridyl]-2-fluoro-phenyl]-4-piperidyl]acetic
Acid Ethyl Ester
##STR00179##
[2423]
2-[1-[2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l]-4-piperidyl]acetic acid ethyl ester (0.10 g, 0.25 mmol) obtained
in Preparation Example 99 and 2-cyclopentoxy-3-iodo-pyridine (0.066
g, 0.227 mmol) obtained in Preparation Example 11 were reacted in
the same manner as in Step A of Example 1 to obtain the title
compound (0.072 g, 74%).
[2424] .sup.1H-NMR (CDCl.sub.3) .delta. 8.10 (1H, m), 7.57 (1H, m),
7.32 (1H, m), 7.25 (1H, m), 6.97 (1H, t), 6.90 (1H, m), 5.51 (1H,
m), 4.16 (2H, q), 3.51 (2H, m), 2.74 (2H, m), 2.30 (2H, d), 1.95
(3H, m), 1.87-1.72 (6H, m), 1.64-1.47 (4H, m), 1.28 (3H, t)
Step B:
2-[1-[4-[2-(cyclopentoxy)-3-pyridyl]-2-fluoro-phenyl]-4-piperidyl]-
acetic Acid
[2425]
2-[1-[4-[2-(Cyclopentoxy)-3-pyridyl]-2-fluoro-phenyl]-4-piperidyl]a-
cetic acid ethyl ester (0.072 g, 0.17 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.043 g, 64%).
[2426] .sup.1H-NMR (CDCl.sub.3) .delta. 8.11 (1H, m), 7.57 (1H, m),
7.31 (1H, m), 7.25 (1H, m), 6.97 (1H, t), 6.90 (1H, m), 5.50 (1H,
m), 3.51 (2H, m), 2.75 (2H, m), 2.38 (2H, d), 2.00-1.88 (5H, m),
1.86-1.72 (4H, m), 1.68-1.52 (4H, m)
Example 140:
3-[6-(6-isopropylsulfanyl-pyridin-2-yl)-naphthalen-2-yl]-propanoic
Acid
##STR00180##
[2428]
3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxoborolan-2-yl)-naphthalen-2-yl-
]-propanoic acid methyl ester (0.082 g, 0.24 mmol) obtained in
Preparation Example 107 and 2-chloro-6-isopropylsulfanyl-pyridine
(0.045 g, 0.24 mmol) obtained in Preparation Example 10 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.003 g, 3%).
[2429] .sup.1H-NMR (CDCl.sub.3) .delta. 8.46 (1H, s), 8.18 (1H,
dd), 7.87 (2H, m), 7.68 (1H, s), 7.56 (2H, m), 7.38 (1H, m), 7.11
(1H, m), 4.22 (1H, m), 3.15 (2H, t), 2.80 (2H, t), 1.50 (6H,
d).
Example 141:
3-[6-(6-phenoxy-pyridin-2-yl)-naphthalen-2-yl]-propanoic Acid
##STR00181##
[2431] 2-[6-(6-Phenoxy-pyridin-2-yl)-naphthalen-2-ylmethyl]-malonic
acid dimethyl ester (0.125 g, 0.28 mmol) obtained in Preparation
Example 110 was reacted in the same manner as in Preparation
Example 105 to obtain the title compound (0.039 g, 37%).
[2432] .sup.1H-NMR (CDCl.sub.3) .delta. 8.40 (1H, s), 8.03 (1H,
dd), 7.85-7.73 (3H, m), 7.64-7.59 (2H, m), 7.43 (2H, m), 7.34 (1H,
dd), 7.25 (3H, m), 6.78 (1H, d), 3.13 (2H, t), 2.78 (2H, t).
Example 142: 3-[6-(2-phenoxy-phenyl)-naphthalen-2-yl]-propanoic
Acid
##STR00182##
[2434] 2-[6-(2-Phenoxy-phenyl)-naphthalen-2-ylmethyl]-malonic acid
dimethyl ester (0.640 g, 1.45 mmol) obtained in Preparation Example
112 was reacted in the same manner as in Preparation Example 105 to
obtain the title compound (0.126 g, 23%).
[2435] .sup.1H-NMR (CDCl.sub.3) .delta. 7.94 (1H, s), 7.76-7.73
(2H, m), 7.68 (1H, dd), 7.61 (1H, s), 7.54 (1H, dd), 7.33-7.29 (2H,
m), 7.26-7.21 (3H, m), 7.04-6.98 (2H, m), 6.93 (2H, m), 3.10 (2H,
t), 2.75 (2H, t).
Example 143:
3-[6-(6-cyclopentylsulfanyl-pyridin-2-yl)-naphthalen-2-yl]-propanoic
Acid
##STR00183##
[2437]
2-[6-(6-Cyclopentylsulfanyl-pyridin-2-yl)-naphthalen-2-ylmethyl]-ma-
lonic acid dimethyl ester (0.019 g, 0.04 mmol) obtained in
Preparation Example 114 was reacted in the same manner as in
Preparation Example 105 to obtain the title compound (0.005 g,
33%).
[2438] .sup.1H-NMR (CDCl.sub.3) .delta. 8.46 (1H, s), 8.16 (1H,
dd), 7.86 (2H, q), 7.67 (1H, s), 7.56 (2H, m), 7.37 (1H, dd), 7.12
(1H, m), 4.23 (1H, m), 3.15 (2H, t), 2.80 (2H, t), 2.31 (2H, m),
1.83-1.72 (6H, m).
Example 144:
3-[6-(2-phenoxy-pyridin-3-yl)-naphthalen-2-yl]-propanoic Acid
##STR00184##
[2440] [6-(2-Phenoxy-pyridin-3-yl)-naphthalen-2-yl]-methanol (0.024
g, 0.07 mmol) obtained in Preparation Example 116 was sequentially
reacted in the same manner as in Preparation Examples 103, 104 and
105 to obtain the title compound (0.009 g, 33%).
[2441] .sup.1H-NMR (CDCl.sub.3) .delta. 8.17 (1H, m), 8.04 (1H, s),
7.87-7.77 (4H, m), 7.67 (1H, s), 7.39-7.37 (3H, m), 7.18-7.11 (4H,
m), 3.13 (2H, t), 2.77 (2H, t).
Example 145: 3-[6-(3-phenoxy-phenyl)-naphthalen-2-yl]-propanoic
Acid
##STR00185##
[2443] [6-(3-Phenoxy-phenyl)-naphthalen-2-yl]-methanol (0.029 g,
0.09 mmol) obtained in Preparation Example 118 was sequentially
reacted in the same manner as in Preparation Examples 103, 104 and
105 to obtain the title compound (0.013 g, 40%).
[2444] .sup.1H-NMR (CDCl.sub.3) .delta. 7.97 (1H, s), 7.82 (2H,
in), 7.69-7.66 (2H, in), 7.42 (2H, in), 7.35 (4H, m), 7.13-7.07
(3H, m), 6.99 (1H, m), 3.13 (2H, t), 2.78 (2H, t).
Example 146: 3-[6-(3-isopropoxy-phenyl)-naphthalen-2-yl]-propanoic
Acid
##STR00186##
[2446] [6-(3-Isopropoxy-phenyl)-naphthalen-2-yl]-methanol (0.054 g,
0.18 mmol) obtained in Preparation Example 120 was sequentially
reacted in the same manner as in Preparation Examples 103, 104 and
105 to obtain the title compound (0.013 g, 20%).
[2447] .sup.1H-NMR (CDCl.sub.3) .delta. 7.99 (1H, s), 7.82 (2H, m),
7.70 (2H, m), 7.37 (2H, m), 7.26 (2H, m), 6.89 (1H, dd), 4.65 (1H,
m), 3.14 (2H, t), 2.78 (2H, t), 1.38 (6H, d).
Example 147: 3-[6-(3-cyclobutoxy-phenyl)-naphthalen-2-yl]-propanoic
Acid
##STR00187##
[2449] [6-(3-Cyclobutoxy-phenyl)-naphthalen-2-yl]-methanol (0.196
g, 0.64 mmol) obtained in Preparation Example 122 was sequentially
reacted in the same manner as in Preparation Examples 103, 104 and
105 to obtain the title compound (0.03 g, 13%).
[2450] .sup.1H-NMR (CDCl.sub.3) .delta. 8.00 (1H, s), 7.86-7.82
(2H, m), 7.74-7.67 (2H, m), 7.35 (2H, m), 7.26 (1H, m), 7.15 (1H,
s), 6.82 (1H, m), 4.73 (1H, m), 3.15 (2H, t), 2.78 (2H, t), 2.50
(2H, m), 2.20 (2H, m), 1.89 (1H, m), 1.70 (1H, m).
Example 148:
3-[6-(6-cyclobutoxy-pyridin-2-yl)-naphthalen-2-yl]-propanoic
Acid
##STR00188##
[2452] [6-(6-Cyclobutoxy-pyridin-2-yl)-naphthalen-2-yl]-methanol
(0.155 g, 0.5 mmol) obtained in Preparation Example 124 was
sequentially reacted in the same manner as in Preparation Examples
103, 104 and 105 to obtain the title compound (0.012 g, 7%).
[2453] .sup.1H-NMR (CDCl.sub.3) .delta. 8.43 (1H, s), 8.14 (1H, m),
7.86 (2H, m), 7.64 (2H, m), 7.44 (1H, m), 7.36 (1H, m), 6.65 (1H,
d), 5.34 (1H, m), 3.14 (2H, t), 2.80 (2H, t), 2.57 (2H, m), 2.24
(2H, m), 1.87 (1H, m), 1.77 (1H, m).
Example 149:
3-[6-(2-isopropoxy-pyridin-3-yl)-naphthalen-2-yl]-propanoic
Acid
##STR00189##
[2455] 6-(2-Isopropoxy-pyridin-3-yl)-naphthalen-2-carboxylic acid
methyl ester (0.092 g, 0.29 mmol) obtained in Preparation Example
125 was sequentially reacted in the same manner as in Preparation
Examples 102, 103, 104 and 105 to obtain the title compound (0.033
g, 34%).
[2456] .sup.1H-NMR (CDCl.sub.3) .delta. 8.15 (1H, m), 7.96 (1H, s),
7.80 (2H, d), 7.72-7.68 (3H, m), 7.36 (1H, d), 6.95 (1H, m), 5.42
(1H, m), 3.15 (2H, t), 2.79 (2H, t), 1.34 (6H, d).
Example 150:
3-[6-(2-cyclopentyloxy-pyridin-3-yl)-naphthalen-2-yl]-propanoic
Acid
##STR00190##
[2458] 6-(2-Cyclopentyloxy-pyridin-3-yl)-naphthalen-2-carboxylic
acid methyl ester (0.123 g, 0.35 mmol) obtained in Preparation
Example 126 was sequentially reacted in the same manner as in
Preparation Example 102, 103, 104 and 105 to obtain the title
compound (0.043 g, 33%).
[2459] .sup.1H-NMR (CDCl.sub.3) .delta. 8.16 (1H, m), 7.96 (1H, s),
7.80 (2H, d), 7.71-7.67 (3H, m), 7.36 (1H, m), 6.96 (1H, m), 5.55
(1H, m), 3.15 (2H, t), 2.80 (2H, t), 1.93 (2H, m), 1.73 (2H, m),
1.62 (2H, m), 1.36 (2H, m).
Example 151:
3-{6-[2-(2-fluoro-phenoxy)-phenyl]-naphthalen-2-yl}-propanoic
Acid
##STR00191##
[2461]
3-{6-[2-(2-Fluoro-phenoxy)-phenyl]-naphthalen-2-yl}-propanoic acid
methyl ester (0.012 g, 0.03 mmol) obtained in Preparation Example
129 was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.005 g, 45%).
[2462] .sup.1H-NMR (CDCl.sub.3) .delta. 7.64-7.29 (10H, m), 7.23
(1H, m), 7.10 (2H, m), 7.03 (1H, m), 3.09 (2H, t), 2.75 (2H,
t).
Example 152:
3-{6-[6-(2-fluoro-phenoxy)-pyridin-2-yl]-naphthalen-2-yl}-propanoic
Acid
##STR00192##
[2464]
3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl-
]-propanoic acid methyl ester (0.067 g, 0.2 mmol) obtained in
Preparation Example 107 and 2-chloro-6-(2-fluoro-phenoxy)-pyridine
(0.045 g, 0.2 mmol) obtained in Preparation Example 127 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.001 g, 1%).
[2465] .sup.1H-NMR (CDCl.sub.3) .delta. 8.48 (1H, s), 8.10 (1H, m),
7.93 (2H, m), 7.79-7.60 (6H, m), 7.40-7.24 (3H, m), 3.15 (2H, t),
2.80 (2H, t).
Example 153:
4-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenylsulfanyl]-bu-
tyric Acid
##STR00193##
[2467]
4-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-ph-
enylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.13 mmol) obtained
in Preparation Example 208 and
4-bromo-2,2-difluoro-benzo[1,3]dioxole (0.034 g, 0.14 mmol) were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.027 g, 54%).
[2468] .sup.1H-NMR (CDCl.sub.3) .delta. 7.30 (2H, m), 7.25 (1H, m),
7.17 (1H, t), 7.09 (1H, d), 2.98 (2H, t), 2.55 (2H, t), 1.90 (2H,
m).
Example 154:
4-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-fluoro-phenylsulfanyl]-butyri-
c Acid
##STR00194##
[2470]
4-[2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl-
sulfanyl]-butyric acid ethyl ester (0.1 g, 0.27 mmol) obtained in
Preparation Example 205 and 4-bromo-2,2-difluoro-benzo[1,3]dioxole
(0.07 g, 0.3 mmol) were sequentially reacted in the same manner as
in Steps A and B of Example 1 to obtain the title compound (0.035
g, 35%).
[2471] .sup.1H-NMR (CDCl.sub.3) .delta. 7.46-7.40 (3H, m), 7.25
(1H, m), 7.14 (1H, t), 7.05 (1H, d), 3.02 (2H, t), 2.56 (2H, t),
1.99 (2H, m).
Example 155:
4-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-phenylsulfanyl]-butyric
Acid
##STR00195##
[2473]
4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-
-butyric acid ethyl ester (0.1 g, 0.28 mmol) obtained in
Preparation Example 202 and 4-bromo-2,2-difluoro-benzo[1,3]dioxole
(0.074 g, 0.31 mmol) were sequentially reacted in the same manner
as in Steps A and B of Example 1 to obtain the title compound
(0.022 g, 22%).
[2474] .sup.1H-NMR (CDCl.sub.3) .delta. 7.62 (2H, d), 7.40 (2H, d),
7.25 (1H, m), 7.12 (1H, t), 7.02 (1H, d), 3.03 (2H, t), 2.55 (2H,
t), 2.00 (2H, m).
Example 156:
4-(4-spiro[1,3-benzodioxol-2,1'-cyclopentane]-4-ylphenyl)sulfanylbutanoic
Acid
##STR00196##
[2476]
4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-
-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in
Preparation Example 202 and
4-iodospiro[1,3-benzodioxol-2,1'-cyclopentane] (0.047 g, 0.16 mmol)
obtained in Preparation Example 215 were sequentially reacted in
the same manner as in Steps A and B of Example 1 to obtain the
title compound (0.027 g, 51%).
[2477] .sup.1H-NMR (CDCl.sub.3) .delta. 7.65 (2H, d), 7.38 (2H, d),
6.97 (1H, d), 6.84 (1H, t), 6.71 (1H, d), 3.01 (2H, t), 2.54 (2H,
t), 2.11 (4H, m), 1.99 (2H, m), 1.84 (4H, m).
Example 157:
4-(2-fluoro-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-phenyl)sulfany-
lbutanoic Acid
##STR00197##
[2479]
4-[2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl-
sulfanyl]-butyric acid ethyl ester (0.05 g, 0.13 mmol) obtained in
Preparation Example 205 and
4-iodospiro[1,3-benzodioxol-2,1'-cyclopentane] (0.045 g, 0.15 mmol)
obtained in Preparation Example 215 were sequentially reacted in
the same manner as in Steps A and B of Example 1 to obtain the
title compound (0.024 g, 45%).
[2480] .sup.1H-NMR (CDCl.sub.3) .delta. 7.48-7.41 (3H, m), 6.96
(1H, d), 6.85 (1H, t), 6.73 (1H, d), 2.99 (2H, t), 2.55 (2H, t),
2.13 (4H, m), 1.96 (2H, m), 1.85 (4H, m).
Example 158:
5-[4-(2-isopropoxy-pyridin-3-yl)-phenyl]-5-methyl-hexanoic Acid
##STR00198##
[2482]
5-Methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl-
]-hexanoic acid ethyl ester (0.05 g, 0.14 mmol) obtained in
Preparation Example 136 and 3-iodo-2-isopropoxy-pyridine (0.055 g,
0.21 mmol) obtained in Preparation Example 34 were sequentially
reacted in the same manner as in Steps A and B of Example 1 to
obtain the title compound (0.017 g, 36%).
[2483] .sup.1H-NMR (CDCl.sub.3) .delta. 8.10 (1H, m), 7.61 (1H, m),
7.53 (2H, d), 7.35 (2H, d), 6.90 (1H, m), 5.39 (1H, m), 2.30 (2H,
t), 1.67 (2H, m), 1.47 (2H, m), 1.34 (12H, m).
Example 159:
5-[4-(2-isopropylsulfanyl-pyridin-3-yl)-phenyl]-5-methyl-hexanoic
Acid
##STR00199##
[2485]
5-Methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl-
]-hexanoic acid ethyl ester (0.05 g, 0.14 mmol) obtained in
Preparation Example 136 and 3-iodo-2-isopropylsulfanyl-pyridine
(0.058 g, 0.21 mmol) obtained in Preparation Example 9 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.022 g, 44%).
[2486] .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, m), 7.36 (5H, m),
7.02 (1H, m), 4.06 (1H, m), 2.26 (2H, t), 1.68 (2H, m), 1.48 (2H,
m), 1.31 (12H, m).
Example 160:
5-[4-(2-cyclopentyloxy-pyridin-3-yl)-phenyl]-5-methyl-hexanoic
Acid
##STR00200##
[2488]
5-Methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl-
]-hexanoic acid ethyl ester (0.05 g, 0.14 mmol) obtained in
Preparation Example 136 and 2-cyclopentyloxy-3-iodo-pyridine (0.06
g, 0.21 mmol) obtained in Preparation Example 11 were sequentially
reacted in the same manner as in Steps A and B of Example 1 to
obtain the title compound (0.026 g, 47%).
[2489] .sup.1H-NMR (CDCl.sub.3) .delta. 8.12 (1H, m), 7.62 (1H, m),
7.52 (2H, d), 7.36 (2H, d), 6.91 (1H, m), 5.50 (1H, m), 2.27 (2H,
t), 1.94 (2H, m), 1.83-1.60 (8H, m), 1.46 (2H, m), 1.35 (6H,
s).
Example 161:
5-[4-(2-cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenyl]-5-methyl-hexanoic
Acid
##STR00201##
[2491]
5-[2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl-
]-5-methyl-hexanoic acid ethyl ester (0.02 g, 0.05 mmol) obtained
in Preparation Example 142 and 2-cyclopentyloxy-3-iodo-pyridine
(0.023 g, 0.08 mmol) obtained in Preparation Example 11 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.011 g, 50%).
[2492] .sup.1H-NMR (CDCl.sub.3) .delta. 8.14 (1H, m), 7.61 (1H, m),
7.27 (3H, m), 6.91 (1H, m), 5.52 (1H, m), 2.30 (2H, t), 1.97 (2H,
m), 1.82-1.73 (6H, m), 1.63 (2H, m), 1.44 (2H, m), 1.40 (6H,
s).
Example 162:
5-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenyl]-5-methyl-hexano-
ic Acid
##STR00202##
[2494]
5-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-ph-
enyl]-5-methyl-hexanoic acid ethyl ester (0.035 g, 0.09 mmol)
obtained in Preparation Example 148 and
2-cyclopentyloxy-3-iodo-pyridine (0.038 g, 0.13 mmol) obtained in
Preparation Example 11 were sequentially reacted in the same manner
as in Steps A and B of Example 1 to obtain the title compound
(0.022 g, 62%).
[2495] .sup.1H-NMR (CDCl.sub.3) .delta. 8.14 (1H, m), 7.60 (1H, m),
7.07 (2H, m), 6.92 (1H, m), 5.51 (1H, m), 2.31 (2H, t), 1.95 (2H,
m), 1.87-1.72 (6H, m), 1.63 (2H, m), 1.52 (2H, m), 1.49 (6H,
s).
Example 163:
5-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenyl]-5-methyl-hexanoic
Acid
##STR00203##
[2497]
5-Methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl-
]-hexanoic acid ethyl ester (0.05 g, 0.14 mmol) obtained in
Preparation Example 136 and 2-cyclopentylsulfanyl-3-iodo-pyridine
(0.063 g, 0.21 mmol) obtained in Preparation Example 15 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.032 g, 60%).
[2498] .sup.1H-NMR (CDCl.sub.3) .delta. 8.40 (1H, m), 7.37 (5H, m),
7.01 (1H, m), 4.07 (1H, m), 2.28 (2H, t), 2.18 (2H, m), 1.69-1.46
(10H, m), 1.34 (6H, s).
Example 164:
5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-5-methyl-he-
xanoic Acid
##STR00204##
[2500]
5-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-ph-
enyl]-5-methyl-hexanoic acid ethyl ester (0.035 g, 0.09 mmol)
obtained in Preparation Example 148 and
2-cyclobutylsulfanyl-3-iodo-pyridine (0.038 g, 0.13 mmol) obtained
in Preparation Example 13 were sequentially reacted in the same
manner as in Steps A and B of Example 1 to obtain the title
compound (0.025 g, 71%).
[2501] .sup.1H-NMR (CDCl.sub.3) .delta. 8.40 (1H, m), 7.33 (1H, m),
7.02 (1H, m), 6.90 (2H, m), 4.42 (1H, m), 2.50 (2H, m), 2.32 (2H,
t), 2.07-2.00 (4H, m), 1.80 (2H, m), 1.54 (2H, m), 1.49 (6H,
s).
Example 165:
5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-phenyl]-5-methyl-hexanoic
Acid
##STR00205##
[2503]
5-Methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl-
]-hexanoic acid ethyl ester (0.05 g, 0.14 mmol) obtained in
Preparation Example 136 and 2-cyclobutylsulfanyl-3-iodo-pyridine
(0.06 g, 0.21 mmol) obtained in Preparation Example 13 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.035 g, 68%).
[2504] .sup.1H-NMR (CDCl.sub.3) .delta. 8.38 (1H, m), 7.36 (5H, m),
7.01 (1H, m), 4.41 (1H, m), 2.49 (2H, m), 2.27 (2H, t), 2.06-1.98
(4H, m), 1.67 (2H, m), 1.48 (2H, m), 1.34 (6H, s).
Example 166:
4-{1-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenyl]-cyclopropyl}-
-butyric Acid
##STR00206##
[2506]
4-{1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenyl]-cyclopropyl}-butyric acid ethyl ester (0.05 g, 0.13 mmol)
obtained in Preparation Example 155 and
2-cyclopentyloxy-3-iodo-pyridine (0.055 g, 0.19 mmol) obtained in
Preparation Example 11 were sequentially reacted in the same manner
as in Steps A and B of Example 1 to obtain the title compound
(0.014 g, 27%).
[2507] .sup.1H-NMR (CDCl.sub.3) .delta. 8.15 (1H, m), 7.58 (1H, m),
7.08 (2H, m), 6.91 (1H, m), 5.51 (1H, m), 2.31 (2H, t), 1.95 (2H,
m), 1.82-1.57 (10H, m), 0.87-0.81 (4H, m).
Example 167:
4-{1-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-cyclopro-
pyl}-butyric Acid
##STR00207##
[2509]
4-{1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenyl]-cyclopropyl}-butyric acid ethyl ester (0.05 g, 0.13 mmol)
obtained in Preparation Example 155 and
2-cyclobutylsulfanyl-3-iodo-pyridine (0.055 g, 0.19 mmol) obtained
in Preparation Example 13 were sequentially reacted in the same
manner as in Steps A and B of Example 1 to obtain the title
compound (0.016 g, 31%).
[2510] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, m), 7.33 (1H, m),
7.01 (1H, m), 6.92 (2H, m), 4.42 (1H, m), 2.49 (2H, m), 2.36 (2H,
t), 2.07-2.00 (4H, m), 1.71 (2H, m), 1.58 (2H, m), 0.88-0.82 (4H,
m).
Example 168:
4-{1-[4-(6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-cyclopropyl}-bu-
tyric Acid
##STR00208##
[2512]
4-{1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenyl]-cyclopropyl}-butyric acid ethyl ester (0.05 g, 0.13 mmol)
obtained in Preparation Example 155 and
2-chloro-6-cyclobutoxy-pyridine (0.035 g, 0.19 mmol) obtained in
Preparation Example 29 were sequentially reacted in the same manner
as in Steps A and B of Example 1 to obtain the title compound
(0.007 g, 14%).
[2513] .sup.1H-NMR (CDCl.sub.3) .delta. 7.60 (1H, t), 7.46 (2H, m),
7.23 (1H, d), 6.66 (1H, d), 5.26 (1H, m), 2.52 (2H, m), 2.33 (2H,
t), 2.18 (2H, m), 1.85 (1H, m), 1.80-1.69 (3H, m), 1.58 (2H, m),
0.86-0.82 (4H, m).
Example 169:
4-{1-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-cycloprop-
yl}-butyric Acid
##STR00209##
[2515]
4-{1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenyl]-cyclopropyl}-butyric acid ethyl ester (0.05 g, 0.13 mmol)
obtained in Preparation Example 155 and
2-cyclobutylmethoxy-3-iodo-pyridine (0.055 g, 0.19 mmol) obtained
in Preparation Example 48 were sequentially reacted in the same
manner as in Steps A and B of Example 1 to obtain the title
compound (0.012 g, 23%).
[2516] .sup.1H-NMR (CDCl.sub.3) .delta. 8.14 (1H, m), 7.59 (1H, m),
7.09 (2H, m), 6.94 (1H, m), 4.32 (2H, d), 2.79 (1H, m), 2.35 (2H,
t), 2.11 (2H, m), 2.0-1.85 (4H, m), 1.70 (2H, m), 1.58 (2H, m),
0.86-0.81 (4H, m).
Example 170:
4-{1-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-cyclopro-
pyl}-butyric Acid
##STR00210##
[2518]
4-{1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenyl]-cyclopropyl}-butyric acid ethyl ester (0.09 g, 0.23 mmol)
obtained in Preparation Example 155 and
2-chloro-6-cyclopropylmethoxy-pyridine (0.063 g, 0.34 mmol)
obtained in Preparation Example 43 were sequentially reacted in the
same manner as in Steps A and B of Example 1 to obtain the title
compound (0.018 g, 20%).
[2519] .sup.1H-NMR (CDCl.sub.3) .delta. 7.61 (1H, t), 7.48 (2H, m),
7.24 (1H, d), 6.73 (1H, d), 4.22 (2H, d), 2.33 (2H, t), 1.69 (2H,
m), 1.58 (2H, m), 1.32 (1H, m), 0.89-0.81 (4H, m), 0.62 (2H, m),
0.38 (2H, m).
Example 171:
5-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenyl]-hexanoic
Acid
##STR00211##
[2521]
5-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phe-
nyl]hexanoic acid ethyl ester (0.05 g, 0.13 mmol) obtained in
Preparation Example 32 and 4-bromo-2,2-difluoro-benzo[1,3]dioxole
(0.027 g, 0.2 mmol) were sequentially reacted in the same manner as
in Steps A and B of Example 1 to obtain the title compound (0.022
g, 44%).
[2522] .sup.1H-NMR (CDCl.sub.3) .delta. 7.25-7.12 (4H, m), 7.06
(1H, d), 3.24 (1H, m), 2.35 (2H, t), 1.84 (1H, m), 1.74 (1H, m),
1.64 (1H, m), 1.53 (1H, m), 1.35 (3H, d).
Example 172:
{2-[4-(2-cyclopentyloxy-pyridin-3-yl)-phenyl]-2,2-difluoro-ethoxy}-acetic
Acid
##STR00212##
[2524]
{2,2-Difluoro-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-p-
henyl]-ethoxy}-acetic acid ethyl ester (0.05 g, 0.13 mmol) obtained
in Preparation Example 160 and 2-cyclopentyloxy-3-iodo-pyridine
(0.058 g, 0.2 mmol) obtained in Preparation Example 11 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.008 g, 15%).
[2525] .sup.1H-NMR (CDCl.sub.3) .delta. 8.17 (1H, m), 7.63 (3H, m),
7.55 (2H, d), 6.93 (1H, m), 5.51 (1H, m), 4.28 (2H, s), 4.05 (2H,
t), 1.93 (2H, m), 1.81 (2H, m), 1.71 (2H, m), 1.62 (2H, m).
Example 173:
{2-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-phenyl]-2,2-difluoro-ethoxy}-ac-
etic Acid
##STR00213##
[2527]
{2,2-Difluoro-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-p-
henyl]-ethoxy}-acetic acid ethyl ester (0.05 g, 0.13 mmol) obtained
in Preparation Example 160 and 2-cyclobutylsulfanyl-3-iodo-pyridine
(0.059 g, 0.2 mmol) obtained in Preparation Example 13 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.005 g, 10%).
[2528] .sup.1H-NMR (CDCl.sub.3) .delta. 8.40 (1H, m), 7.55 (2H, d),
7.46 (2H, d), 7.30 (1H, m), 7.00 (1H, m), 4.39 (1H, m), 4.21 (2H,
s), 4.02 (2H, t), 2.47 (2H, m), 1.99 (4H, m).
Example 174:
{2-[4-(6-cyclobutoxy-pyridin-2-yl)-phenyl]-2,2-difluoro-ethoxy}-acetic
Acid
##STR00214##
[2530]
{2,2-Difluoro-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-p-
henyl]-ethoxy}-acetic acid ethyl ester (0.05 g, 0.13 mmol) obtained
in Preparation Example 160 and 2-chloro-6-cyclobutoxy-pyridine
(0.037 g, 0.2 mmol) obtained in Preparation Example 29 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.008 g, 16%).
[2531] .sup.1H-NMR (CDCl.sub.3) .delta. 8.01 (2H, d), 7.57-7.51
(3H, m), 7.26 (1H, m), 6.64 (1H, d), 5.24 (1H, m), 4.18 (2H, s),
4.00 (2H, t), 2.49 (2H, m), 2.16 (2H, m), 1.84 (1H, m), 1.70 (1H,
m).
Example 175:
3-{2-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenyl]-cyclopropyl}-
-propanoic Acid
##STR00215##
[2533]
3-{2-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenyl]-cyclopropyl}-propanoic acid ethyl ester (0.05 g, 0.13
mmol) obtained in Preparation Example 175 and
2-cyclopentyloxy-3-iodo-pyridine (0.057 g, 0.2 mmol) obtained in
Preparation Example 11 were sequentially reacted in the same manner
as in Steps A and B of Example 1 to obtain the title compound
(0.024 g, 47%).
[2534] .sup.1H-NMR (CDCl.sub.3) .delta. 8.14 (1H, m), 7.55 (1H, m),
7.06 (2H, m), 6.91 (1H, m), 5.51 (1H, m), 2.58 (2H, t), 1.96 (2H,
m), 1.83-1.63 (9H, m), 1.42 (1H, m), 1.24 (1H, m), 0.82 (1H,
m).
Example 176:
3-{2-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-cyclopro-
pyl}-propanoic Acid
##STR00216##
[2536]
3-{2-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenyl]-cyclopropyl}-propanoic acid ethyl ester (0.05 g, 0.13
mmol) obtained in Preparation Example 175 and
2-cyclobutylsulfanyl-3-iodo-pyridine (0.057 g, 0.2 mmol) obtained
in Preparation Example 13 were sequentially reacted in the same
manner as in Steps A and B of Example 1 to obtain the title
compound (0.024 g, 47%).
[2537] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, m), 7.32 (1H, m),
7.02 (1H, m), 6.90 (2H, m), 4.42 (1H, m), 2.59 (2H, t), 2.50 (2H,
m), 2.09-2.00 (4H, m), 1.82 (1H, m), 1.73-1.63 (2H, m), 1.43 (1H,
m), 1.26 (1H, m), 0.83 (1H, m).
Example 177:
5-[4-(2-cyclopentyloxy-pyridin-3-yl)-phenyl]-5,5-difluoro-pentanoic
Acid
##STR00217##
[2539]
5,5-Difluoro-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-ph-
enyl]-pentanoic acid methyl ester (0.05 g, 0.14 mmol) obtained in
Preparation Example 169 and 2-cyclopentyloxy-3-iodo-pyridine (0.061
g, 0.21 mmol) obtained in Preparation Example 11 were sequentially
reacted in the same manner as in Steps A and B of Example 1 to
obtain the title compound (0.03 g, 56%).
[2540] .sup.1H-NMR (CDCl.sub.3) .delta. 8.16 (1H, m), 7.62-7.59
(3H, m), 7.49 (2H, m), 6.93 (1H, m), 5.51 (1H, m), 2.44 (2H, t),
2.22 (2H, m), 1.97-1.61 (10H, m).
Example 178:
5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-phenyl]-5,5-difluoro-pentanoic
Acid
##STR00218##
[2542]
5,5-Difluoro-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-ph-
enyl]-pentanoic acid methyl ester (0.05 g, 0.14 mmol) obtained in
Preparation Example 169 and 2-cyclobutylsulfanyl-3-iodo-pyridine
(0.061 g, 0.21 mmol) obtained in Preparation Example 13 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.025 g, 47%).
[2543] .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, m), 7.55-7.47
(4H, m), 7.35 (1H, m), 7.04 (1H, m), 4.43 (1H, m), 2.51-2.43 (4H,
m), 2.25 (2H, m), 2.09-1.98 (4H, m), 1.87 (2H, m).
Example 179:
3-{2-[2,6-difluoro-4-(2-propylsulfanyl-pyridin-3-yl)-phenyl]-cyclopropyl}-
-propanoic Acid
##STR00219##
[2545]
3-{2-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenyl]-cyclopropyl}-propanoic acid ethyl ester (0.04 g, 0.1 mmol)
obtained in Preparation Example 175 and
3-iodo-2-propylsulfanyl-pyridine (0.044 g, 0.16 mmol) obtained in
Preparation Example 28 were sequentially reacted in the same manner
as in Steps A and B of Example 1 to obtain the title compound
(0.016 g, 40%).
[2546] .sup.1H-NMR (CDCl.sub.3) .delta. 8.43 (1H, m), 7.33 (1H, m),
7.03 (1H, m), 6.91 (2H, m), 3.14 (2H, t), 2.59 (2H, t), 1.84 (1H,
m), 1.73-1.63 (4H, m), 1.43 (1H, m), 1.26 (1H, m), 1.01 (3H, t),
0.85 (1H, m).
Example 180:
3-{2-[4-(6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-cyclopropyl}-pr-
opanoic Acid
##STR00220##
[2548]
3-{2-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenyl]-cyclopropyl}-propanoic acid ethyl ester (0.05 g, 0.13
mmol) obtained in Preparation Example 175 and
2-chloro-6-cyclobutoxy-pyridine (0.036 g, 0.2 mmol) obtained in
Preparation Example 29 were sequentially reacted in the same manner
as in Steps A and B of Example 1 to obtain the title compound
(0.005 g, 10%).
[2549] .sup.1H-NMR (CDCl.sub.3) .delta. 7.61 (1H, t), 7.43 (2H, m),
7.25 (1H, d), 6.65 (1H, d), 5.25 (1H, m), 2.59 (2H, t), 2.52 (2H,
m), 2.18 (2H, m), 1.85 (2H, m), 1.69-1.62 (3H, m), 1.39 (1H, m),
1.24 (1H, m), 0.84 (1H, m).
Example 181:
5-[4-(2-cyclopropylmethoxy-pyridin-3-yl)-phenyl]-5,5-difluoro-pentanoic
Acid
##STR00221##
[2551]
5,5-Difluoro-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-ph-
enyl]-pentanoic acid methyl ester (0.027 g, 0.08 mmol) obtained in
Preparation Example 169 and 2-cyclopropylmethoxy-3-iodo-pyridine
(0.031 g, 0.11 mmol) obtained in Preparation Example 40 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.015 g, 55%).
[2552] .sup.1H-NMR (CDCl.sub.3) .delta. 8.14 (1H, m), 7.67 (2H, d),
7.62 (1H, m), 7.52 (2H, d), 6.95 (1H, m), 4.22 (2H, d), 2.43 (2H,
t), 2.24 (2H, m), 1.86 (2H, m), 1.26 (1H, m), 0.56 (2H, m), 0.32
(2H, m).
Example 182:
3-{2-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-cyclopr-
opyl}-propanoic Acid
##STR00222##
[2554]
3-{2-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenyl]-cyclopropyl}-propanoic acid ethyl ester (0.027 g, 0.07
mmol) obtained in Preparation Example 175 and
2-cyclopentylsulfanyl-3-iodo-pyridine (0.032 g, 0.11 mmol) obtained
in Preparation Example 15 were sequentially reacted in the same
manner as in Steps A and B of Example 1 to obtain the title
compound (0.007 g, 25%).
[2555] .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, m), 7.29 (1H, m),
7.02 (1H, m), 6.87 (2H, m), 4.07 (1H, m), 2.57 (2H, t), 2.19 (2H,
m), 1.81 (1H, m), 1.72-1.53 (8H, m), 1.42 (1H, m), 1.25 (1H, m),
0.82 (1H, m).
Example 183:
3-{2-[4-(2-cyclopentylamino-pyridin-3-yl)-2,6-difluoro-phenyl]-cyclopropy-
l}-propanoic Acid
##STR00223##
[2557]
3-{2-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenyl]-cyclopropyl}-propanoic acid ethyl ester (0.027 g, 0.07
mmol) obtained in Preparation Example 175 and
N-cyclopentyl-3-iodo-pyridin-2-amine (0.031 g, 0.11 mmol) obtained
in Preparation Example 51 were sequentially reacted in the same
manner as in Steps A and B of Example 1 to obtain the title
compound (0.005 g, 18%).
[2558] .sup.1H-NMR (CDCl.sub.3) .delta. 8.13 (1H, m), 7.17 (1H, m),
6.84 (2H, m), 6.59 (1H, m), 4.49 (1H, br), 4.33 (1H, m), 2.58 (2H,
t), 2.04 (2H, m), 1.83 (1H, m), 1.74-1.58 (6H, m), 1.43 (1H, m),
1.33 (2H, m), 1.24 (1H, m), 0.84 (1H, m).
Example 184:
5-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenyl]-5,5-difluoro-pentanoic
Acid
##STR00224##
[2560]
5,5-Difluoro-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-ph-
enyl]-pentanoic acid methyl ester (0.04 g, 0.11 mmol) obtained in
Preparation Example 169 and 2-cyclopentylsulfanyl-3-iodo-pyridine
(0.052 g, 0.17 mmol) obtained in Preparation Example 15 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.016 g, 36%).
[2561] .sup.1H-NMR (CDCl.sub.3) .delta. 8.44 (1H, m), 7.54-7.47
(4H, m), 7.35 (1H, m), 7.05 (1H, m), 4.11 (1H, m), 2.45 (2H, t),
2.31-2.20 (4H, m), 1.87 (2H, m), 1.70-1.52 (6H, m).
Example 185:
5-[4-(2-cyclobutoxy-pyridin-3-yl)-phenyl]-5,5-difluoro-pentanoic
Acid
##STR00225##
[2563]
5,5-Difluoro-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-ph-
enyl]-pentanoic acid methyl ester (0.04 g, 0.11 mmol) obtained in
Preparation Example 169 and 2-cyclobutoxy-3-iodo-pyridine (0.046 g,
0.17 mmol) obtained in Preparation Example 41 were sequentially
reacted in the same manner as in Steps A and B of Example 1 to
obtain the title compound (0.017 g, 42%).
[2564] .sup.1H-NMR (CDCl.sub.3) .delta. 8.13 (1H, m), 7.65 (2H, d),
7.59 (1H, m), 7.51 (2H, d), 6.94 (1H, m), 5.27 (1H, m), 2.45 (4H,
m), 2.24 (2H, m), 2.11 (2H, m), 1.87-1.79 (3H, m), 1.67 (1H,
m).
Example 186:
5-[4-(6-cyclobutoxy-pyridin-2-yl)-phenyl]-5,5-difluoro-pentanoic
Acid
##STR00226##
[2566]
5,5-Difluoro-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-ph-
enyl]-pentanoic acid methyl ester (0.04 g, 0.11 mmol) obtained in
Preparation Example 169 and 2-chloro-6-cyclobutoxy-pyridine (0.03
g, 0.17 mmol) obtained in Preparation Example 29 were sequentially
reacted in the same manner as in Steps A and B of Example 1 to
obtain the title compound (0.004 g, 10%).
[2567] .sup.1H-NMR (CDCl.sub.3) .delta. 8.06 (2H, d), 7.63 (1H, t),
7.54 (2H, d), 7.33 (1H, d), 6.66 (1H, d), 5.28 (1H, m), 2.54 (2H,
m), 2.42 (2H, t), 2.22 (4H, m), 1.88-1.71 (4H, m).
Example 187:
{4-[4-(2-cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenyl]-cyclohexyl}-acetic
Acid
##STR00227##
[2569]
{4-[4-(2-Cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenyl]-cyclohexyl}--
acetic acid ethyl ester (0.045 g, 0.11 mmol) obtained in
Preparation Example 182 was reacted in the same manner as in Step B
of Example 1 to obtain the title compound (0.039 g, 92%).
[2570] .sup.1H-NMR (CDCl.sub.3) .delta. 8.13 (1H, m), 7.60 (1H, m),
7.27 (3H, m), 6.91 (1H, m), 5.51 (1H, m), 2.87 (1H, m), 2.56-2.33
(2H, m), 1.95-1.54 (16H, m), 1.26 (1H, m).
Example 188:
3-{2-[4-(2-cyclobutoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-cyclopropyl}-pr-
opanoic Acid
##STR00228##
[2572]
3-{2-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenyl]-cyclopropyl}-propanoic acid ethyl ester (0.04 g, 0.1 mmol)
obtained in Preparation Example 175 and
2-cyclobutoxy-3-iodo-pyridine (0.043 g, 0.16 mmol) obtained in
Preparation Example 41 were sequentially reacted in the same manner
as in Steps A and B of Example 1 to obtain the title compound
(0.018 g, 46%).
[2573] .sup.1H-NMR (CDCl.sub.3) .delta. 8.11 (1H, m), 7.54 (1H, m),
7.06 (2H, m), 6.92 (1H, m), 5.25 (1H, m), 2.60 (2H, t), 2.45 (2H,
m), 2.12 (2H, m), 1.82 (2H, m), 1.68 (3H, m), 1.41 (1H, m), 1.24
(1H, m), 0.83 (1H, m).
Example 189:
3-{2-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-cycloprop-
yl}-propanoic Acid
##STR00229##
[2575]
3-{2-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenyl]-cyclopropyl}-propanoic acid ethyl ester (0.04 g, 0.1 mmol)
obtained in Preparation Example 175 and
2-cyclobutylmethoxy-3-iodo-pyridine (0.046 g, 0.16 mmol) obtained
in Preparation Example 48 were sequentially reacted in the same
manner as in Steps A and B of Example 1 to obtain the title
compound (0.025 g, 62%).
[2576] .sup.1H-NMR (CDCl.sub.3) .delta. 8.12 (1H, m), 7.57 (1H, m),
7.07 (2H, m), 6.93 (1H, m), 4.30 (2H, d), 2.78 (1H, m), 2.58 (2H,
t), 2.11 (2H, m), 1.99-1.78 (5H, m), 1.71-1.62 (2H, m), 1.40 (1H,
m), 1.23 (1H, m), 0.83 (1H, m).
Example 190:
3-(2-{2,6-difluoro-4-[2-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-phenyl}--
cyclopropyl)-propanoic Acid
##STR00230##
[2578]
3-{2-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenyl]-cyclopropyl}-propanoic acid ethyl ester (0.04 g, 0.1 mmol)
obtained in Preparation Example 175 and
3-iodo-2-(tetrahydro-pyran-4-yloxy)-pyridine (0.048 g, 0.16 mmol)
obtained in Preparation Example 50 were sequentially reacted in the
same manner as in Steps A and B of Example 1 to obtain the title
compound (0.024 g, 57%).
[2579] .sup.1H-NMR (CDCl.sub.3) .delta. 8.11 (1H, m), 7.57 (1H, m),
7.06 (2H, m), 6.92 (1H, m), 5.36 (1H, m), 3.89 (2H, m), 3.63 (2H,
m), 2.58 (2H, t), 2.05 (2H, m), 1.82 (3H, m), 1.73-1.62 (2H, m),
1.41 (1H, m), 1.24 (1H, m), 0.83 (1H, m).
Example 191:
3-{2-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-cyclopro-
pyl}-propanoic Acid
##STR00231##
[2581]
3-{2-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenyl]-cyclopropyl}-propanoic acid ethyl ester (0.04 g, 0.1 mmol)
obtained in Preparation Example 175 and
2-chloro-6-cyclopropylmethoxy-pyridine (0.03 g, 0.16 mmol) obtained
in Preparation Example 43 were sequentially reacted in the same
manner as in Steps A and B of Example 1 to obtain the title
compound (0.0045 g, 11%).
[2582] .sup.1H-NMR (CDCl.sub.3) .delta. 7.60 (1H, t), 7.45 (2H, m),
7.23 (1H, d), 6.71 (1H, d), 4.22 (2H, d), 2.57 (2H, t), 1.82 (1H,
m), 1.65 (2H, m), 1.38 (1H, m), 1.31 (1H, m), 1.22 (1H, m), 0.83
(1H, m), 0.63 (2H, m), 0.38 (2H, m).
Example 192:
5,5-difluoro-5-[4-(6-isopropylsulfanyl-pyridin-2-yl)-phenyl]-pentanoic
Acid
##STR00232##
[2584]
5,5-Difluoro-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-ph-
enyl]-pentanoic acid methyl ester (0.04 g, 0.11 mmol) obtained in
Preparation Example 169 and 2-chloro-6-isopropylsulfanyl-pyridine
(0.03 g, 0.17 mmol) obtained in Preparation Example 10 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.005 g, 13%).
[2585] .sup.1H-NMR (CDCl.sub.3) .delta. 8.10 (2H, d), 7.54 (3H, m),
7.43 (1H, d), 7.10 (1H, d), 4.15 (1H, m), 2.43 (2H, t), 2.23 (2H,
m), 1.82 (2H, m), 1.47 (6H, d).
Example 193:
4-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-phenoxy]-butyric
Acid
##STR00233##
[2586] Step A:
4-[3'-hydroxy-2'-(2-methyl-propenyl)-biphenyl-4-yloxy]-butyric Acid
Ethyl Ester
[2587] 4-(2'-Bromo-3'-hydroxy-biphenyl-4-yloxy)-butyric acid ethyl
ester (36 mg, 0.095 mmol) and
4,4,5,5-tetramethyl-2-(2-methyl-propenyl)-[1,3,2]dioxaborolane (35
mg, 0.19 mmol) were dissolved in 0.5 mL of 1 M sodium carbonate and
4 mL of dimethoxyethane, and charged with nitrogen for 5 minutes.
PdCl.sub.2(PPh.sub.3).sub.2 (3.3 mg, 0.00475 mmol) was added
thereto, and the mixture was stirred for 4 hours under refluxes.
The reaction solution was cooled to room temperature. After
addition of water, the reaction solution extracted with EtOAc to
separate an organic layer. The organic layer was dried with
anhydrous magnesium sulfate and purified by column chromatography
(eluent, EtOAc/Hex=1/4) to obtain the title compound (17 mg, 51%
yield).
[2588] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.23-7.17 (m, 3H),
6.93-6.89 (m, 1H), 6.89-6.84 (m, 3H), 5.85 (s, 1H), 5.36 (s, 1H),
4.16 (q, 2H), 4.03 (t, 2H), 2.53 (t, 2H), 2.17-2.08 (m, 2H), 1.84
(s, 3H), 1.58 (s, 3H), 1.27 (t, 3H)
Step B:
4-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-phenoxy]-butyric
Acid Ethyl Ester
[2589]
4-[3'-Hydroxy-2'-(2-methyl-propenyl)-biphenyl-4-yloxy]-butyric acid
ethyl ester (17 mg, 0.048 mmol) obtained in Step A and Amberlyst 15
resin (17 mg) were reacted in the same manner as in Step C of
Example 291 to obtain the title compound (10 mg, 59% yield).
Step C:
4-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-phenoxy]-butyric
Acid
[2590]
4-[4-(2,2-Dimethyl-2,3-dihydro-benzofuran-4-yl)-phenoxy]-butyric
acid ethyl ester (10 mg, 0.028 mmol) obtained in Step B was reacted
in the same manner as in Step B of Example 287 to obtain the title
compound (7 mg, 76% yield).
[2591] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.37 (d, 2H), 7.16
(dd, 1H), 6.93 (d, 2H), 6.87 (d, 1H), 6.70 (d, 1H), 4.06 (t, 2H),
3.09 (s, 2H), 2.61 (t, 2H), 2.20-2.10 (m, 2H), 1.46 (s, 6H)
Example 194:
4-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-2-fluoro-phenoxy]-butyric
Acid
##STR00234##
[2592] Step A:
4-[3-fluoro-3'-hydroxy-2'-(2-methyl-propenyl)-biphenyl-4-yloxy]-butyric
Acid Ethyl Ester
[2593] 4-(2'-Bromo-3-fluoro-3'-hydroxy-biphenyl-4-yloxy)-butyric
acid ethyl ester (140 mg, 0.35 mmol) and
4,4,5,5-tetramethyl-2-(2-methyl-propenyl)-[1,3,2]dioxaborolane (141
mg, 0.77 mmol) were dissolved in 1 mL of 1 M sodium carbonate and 6
mL of dimethoxyethane, and charged with nitrogen for 5 minutes.
PdCl.sub.2(PPh.sub.3).sub.2 (12 mg, 0.0175 mmol) was added thereto,
and the mixture was reacted in the same manner as in Step A of
Example 193 to obtain the title compound (70 mg, 53% yield).
[2594] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.20 (dd, 1H),
7.04-6.99 (m, 1H), 6.99-6.95 (m, 1H), 6.95-6.89 (m, 2H), 6.84 (d,
1H), 5.83 (s, 1H), 5.42 (s, 1H), 4.15 (q, 2H), 4.10 (t, 2H), 2.55
(t, 2H), 2.19-2.12 (m, 2H), 1.85 (s, 3H), 1.57 (s, 3H), 1.26 (t,
3H)
Step B:
4-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-2-fluoro-phenoxy]--
butyric acid Ethyl Ester
[2595]
4-[3-Fluoro-3'-hydroxy-2'-(2-methyl-propenyl)-biphenyl-4-yloxy]-but-
yric acid ethyl ester (70 mg, 0.188 mmol) obtained in Step A and
Amberlyst 15 resin (70 mg) were reacted in the same manner as in
Step C of Example 291 to obtain the title compound (40 mg, 57%
yield).
[2596] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.20-7.11 (m, 3H),
7.00 (dd, 1H), 6.85 (d, 1H), 6.72 (d, 1H), 4.15 (q, 2H), 4.11 (t,
2H), 3.08 (s, 2H), 2.56 (t, 2H), 2.20-2.12 (m, 2H), 1.47 (s, 6H),
1.26 (t, 3H)
Step C:
4-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-2-fluoro-phenoxy]--
butyric Acid
[2597]
4-[4-(2,2-Dimethyl-2,3-dihydro-benzofuran-4-yl)-2-fluoro-phenoxy]-b-
utyric acid ethyl ester (40 mg, 0.107 mmol) obtained in Step B was
reacted in the same manner as in Step B of Example 287 to obtain
the title compound (36 mg, 97% yield).
[2598] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.20-7.11 (m, 3H),
6.99 (dd, 1H), 6.85 (d, 1H), 6.72 (d, 1H), 4.13 (t, 2H), 3.08 (s,
2H), 2.64 (t, 2H), 2.21-2.14 (m, 2H), 1.47 (s, 6H)
Example 195:
4-{[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-methyl-ami-
no}-butyric Acid
##STR00235##
[2600] 2-Cyclobutylsulfanyl-3-iodo-pyridine (0.045 g, 0.15 mmol)
obtained in Preparation Example 13 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.057 g, 0.15 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.040 g, 66%).
[2601] .sup.1H-NMR (CDCl.sub.3) .delta. 8.40 (1H, m), 7.32 (1H, m),
7.02 (1H, m), 6.94 (2H, m), 4.44 (1H, m), 3.18 (2H, t), 2.89 (3H,
s), 2.50 (4H, m), 2.05 (4H, m), 1.90 (2H, m)
Example 196:
4-{[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenyl]-methyl-amino}--
butyric Acid
##STR00236##
[2603] 2-Cyclopentyloxy-3-iodo-pyridine (0.030 g, 0.10 mmol)
obtained in Preparation Example 11 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.038 g, 0.10 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.015 g, 37%).
[2604] .sup.1H-NMR (CDCl.sub.3) .delta. 8.14 (1H, m), 7.57 (1H, m),
7.11 (2H, m), 6.92 (1H, m), 5.52 (1H, m), 3.19 (2H, t), 2.88 (3H,
s), 2.48 (2H, t), 1.95 (2H, m), 1.89 (6H, m), 1.64 (2H, m)
Example 197:
4-{[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-methyl-am-
ino}-butyric Acid
##STR00237##
[2606] 2-Cyclopentylsulfanyl-3-iodo-pyridine (0.037 g, 0.12 mmol)
obtained in Preparation Example 15 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.045 g, 0.12 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.015 g, 30%).
[2607] .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, m), 7.31 (1H, m),
7.03 (1H, m), 6.95 (2H, m), 4.10 (1H, m), 3.20 (2H, t), 2.89 (3H,
s), 2.50 (2H, t), 2.20 (2H, m), 1.90 (2H, m), 1.62 (6H, m)
Example 198:
4-{[2,6-difluoro-4-(2-isopropylsulfanyl-pyridin-3-yl)-phenyl]-methyl-amin-
o}-butyric Acid
##STR00238##
[2609] 3-Iodo-2-isopropylsulfanyl-pyridine (0.030 g, 0.11 mmol)
obtained in Preparation Example 9 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.040 g, 0.11 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.025 g, 61%).
[2610] .sup.1H-NMR (CDCl.sub.3) .delta. 8.43 (1H, m), 7.34 (1H, m),
7.02 (1H, m), 6.94 (2H, m), 4.09 (1H, m), 3.19 (2H, t), 2.89 (3H,
s), 2.49 (2H, t), 1.90 (2H, m), 1.37 (6H, d)
Example 199:
4-[(3'-cyclobutoxy-3,5-difluoro-biphenyl-4-yl)-methyl-amino]-butyric
Acid
##STR00239##
[2612] 1-Cyclobutoxy-3-iodo-benzene (0.035 g, 0.13 mmol) obtained
in Preparation Example 21 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.047 g, 0.13 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.030 g, 62%).
[2613] .sup.1H-NMR (CDCl.sub.3) .delta. 7.31 (1H, t), 7.07 (3H, m),
6.94 (1H, m), 6.81 (1H, m), 4.70 (1H, m), 3.16 (2H, t), 2.91 (3H,
s), 2.47 (4H, m), 2.21 (2H, m), 1.88 (3H, m), 1.71 (1H, m)
Example 200:
4-[5-(2-cyclopentylsulfanyl-pyridin-3-yl)-indol-1-yl]-butyric
Acid
##STR00240##
[2615] 2-Cyclopentylsulfanyl-3-iodo-pyridine (0.010 g, 0.03 mmol)
obtained in Preparation Example 15 and
4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indol-1-yl]-butyric
acid ethyl ester (0.012 g, 0.03 mmol) obtained in Preparation
Example 184 were reacted in the same manner as in Example 1 to
obtain the title compound (0.006 g, 48%).
[2616] .sup.1H-NMR (CDCl.sub.3) .delta. 7.31 (1H, t), 7.07 (3H, m),
6.94 (1H, m), 6.81 (1H, m), 4.70 (1H, m), 3.16 (2H, t), 2.91 (3H,
s), 2.47 (4H, m), 2.21 (2H, m), 1.88 (3H, m), 1.71 (1H, m)
[2617] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, m), 7.65 (1H, s),
7.41 (2H, m), 7.28 (1H, m), 7.13 (1H, m), 7.03 (1H, m), 6.54 (1H,
d), 4.25 (2H, t), 4.10 (1H, m), 2.40 (2H, t), 2.22 (4H, m), 1.68
(2H, m), 1.60 (4H, m)
Example 201:
4-[(3,5-difluoro-3'-pyrrolidin-1-yl-biphenyl-4-yl)-methyl-amino]-butyric
Acid
##STR00241##
[2619] 1-(3-Bromophenyl)pyrrolidine (0.030 g, 0.13 mmol) obtained
in Preparation Example 53 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.049 g, 0.13 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.025 g, 50%).
[2620] .sup.1H-NMR (CDCl.sub.3) .delta. 7.25 (1H, m), 7.06 (2H, m),
6.78 (1H, d), 6.62 (1H, s), 6.56 (1H, m), 3.33 (4H, m), 3.17 (2H,
t), 2.86 (3H, s), 2.46 (2H, m), 2.03 (4H, m), 1.86 (2H, m)
Example 202:
4-{[4-(6-cyclobutylsulfanyl-pyridin-2-yl)-2,6-difluoro-phenyl]-methyl-ami-
no}-butyric Acid
##STR00242##
[2622] 2-Bromo-6-cyclobutylsulfanyl-pyridine (0.025 g, 0.10 mmol)
obtained in Preparation Example 52 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.038 g, 0.10 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.026 g, 65%).
[2623] .sup.1H-NMR (CDCl.sub.3) .delta. 7.54 (3H, m), 7.30 (1H, d),
7.09 (1H, d), 4.17 (1H, m), 3.21 (2H, t), 2.90 (3H, s), 2.46 (2H,
t), 2.26 (2H, m), 1.89 (2H, m), 1.70 (4H, m)
Example 203:
4-{[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenyl]-methyl-am-
ino}-butyric Acid
##STR00243##
[2625] 4-Bromo-2,2-difluoro-1,3-benzodioxole (0.025 g, 0.11 mmol)
and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.039 g, 0.11 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.025 g, 61%).
[2626] .sup.1H-NMR (CDCl.sub.3) .delta. 7.22 (3H, m), 7.15 (1H, t),
7.04 (1H, d), 3.21 (2H, t), 2.90 (3H, s), 2.47 (2H, t), 1.89 (2H,
m)
Example 204:
4-{[4-(6-cyclopentyloxy-pyridin-2-yl)-2,6-difluoro-phenyl]-methyl-amino}--
butyric Acid
##STR00244##
[2628] 2-Bromo-6-cyclopentyloxy-pyridine (0.030 g, 0.12 mmol)
obtained in Preparation Example 185 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.046 g, 0.12 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.025 g, 52%).
[2629] .sup.1H-NMR (CDCl.sub.3) .delta. 7.58 (1H, t), 7.53 (2H, m),
7.19 (1H, d), 6.63 (1H, d), 5.51 (1H, m), 3.20 (2H, t), 2.89 (3H,
s), 2.47 (2H, t), 2.03 (2H, m), 1.88 (6H, m), 1.65 (2H, m)
Example 205:
4-{[4-(6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-methyl-amino}-but-
yric Acid
##STR00245##
[2631] 2-Bromo-6-cyclobutoxy-pyridine (0.030 g, 0.13 mmol) obtained
in Preparation Example 186 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.049 g, 0.13 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.020 g, 41%).
[2632] .sup.1H-NMR (CDCl.sub.3) .delta. 7.61 (1H, t), 7.51 (2H, m),
7.21 (1H, d), 6.64 (1H, d), 5.27 (1H, m), 3.20 (2H, t), 2.89 (3H,
s), 2.51 (2H, m), 2.47 (2H, t), 2.20 (2H, m), 1.88 (3H, m), 1.75
(1H, m)
Example 206:
4-{[4-(2-cyclobutoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-methyl-amino}-but-
yric Acid
##STR00246##
[2634] 2-Cyclobutoxy-3-iodo-pyridine (0.030 g, 0.11 mmol) obtained
in Preparation Example 41 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.040 g, 0.11 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.022 g, 54%).
[2635] .sup.1H-NMR (CDCl.sub.3) .delta. 8.11 (1H, m), 7.58 (1H, m),
7.15 (2H, m), 6.94 (1H, m), 5.29 (1H, m), 3.20 (2H, t), 2.89 (3H,
s), 2.50 (4H, m), 2.16 (2H, m), 1.90 (3H, m), 1.69 (1H, m)
Example 207:
4-{[2,6-difluoro-4-(2-propylsulfanyl-pyridin-3-yl)-phenyl]-methyl-amino}--
butyric Acid
##STR00247##
[2637] 3-Iodo-2-propylsulfanyl-pyridine (0.030 g, 0.11 mmol)
obtained in Preparation Example 28 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.040 g, 0.11 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.021 g, 51%).
[2638] .sup.1H-NMR (CDCl.sub.3) .delta. 8.43 (1H, m), 7.34 (1H, m),
7.02 (1H, m), 6.96 (2H, m), 3.19 (2H, t), 3.14 (2H, t), 2.89 (3H,
s), 2.50 (2H, m), 1.91 (2H, m), 1.72 (2H, m), 1.03 (3H, t)
Example 208:
4-{[4-(2-ethylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-methyl-amino}-b-
utyric Acid
##STR00248##
[2640] 2-Ethylsulfanyl-3-iodo-pyridine (0.030 g, 0.11 mmol)
obtained in Preparation Example 33 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.042 g, 0.11 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.018 g, 43%).
[2641] .sup.1H-NMR (CDCl.sub.3) .delta. 8.43 (1H, m), 7.35 (1H, m),
7.05 (1H, m), 6.96 (2H, m), 3.19 (4H, m), 2.93 (3H, s), 2.49 (2H,
t), 1.92 (2H, m), 1.35 (3H, t)
Example 209:
4-{[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2-fluoro-phenyl]-methyl-amino}--
butyric Acid
##STR00249##
[2643] 2-Cyclobutylsulfanyl-3-iodo-pyridine (0.040 g, 0.14 mmol)
obtained in Preparation Example 13 and
4-{[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-met-
hyl-amino}-butyric acid methyl ester (0.048 g, 0.14 mmol) obtained
in Preparation Example 187 were reacted in the same manner as in
Example 1 to obtain the title compound (0.025 g, 48%).
[2644] .sup.1H-NMR (CDCl.sub.3) .delta. 8.38 (1H, m), 7.34 (1H, m),
7.12 (2H, m), 7.01 (2H, m), 4.43 (1H, m), 3.25 (2H, t), 2.87 (3H,
s), 2.51 (4H, m), 2.01 (6H, m)
Example 210:
2-{[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylamino]-meth-
yl}-cyclopropanecarboxylic Acid
##STR00250##
[2646]
4-(2-Cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylamine
(0.050 g, 0.16 mmol) obtained in Preparation Example 188 and
2-formyl-cyclopropanecarboxylic acid ethyl ester (0.026 g, 0.18
mmol) were sequentially reacted in the same manner as in
Preparation Example 35 and Step B of Example 1 to obtain the title
compound (0.009 g, 14%).
[2647] .sup.1H-NMR (CDCl.sub.3) .delta. 8.40 (1H, m), 7.30 (1H, m),
7.00 (1H, m), 6.92 (2H, m), 4.09 (1H, m), 3.37 (2H, d), 2.20 (2H,
m), 1.82 (1H, m), 1.72 (2H, m), 1.62 (5H, m), 1.32 (2H, m), 0.98
(1H, m)
Example 211:
2-{[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenylamino]-methyl}-cycloprop-
anecarboxylic Acid
##STR00251##
[2648] Step A:
2-{[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenylamino]-methyl}-cycloprop-
anecarboxylic Acid Ethyl Ester
[2649] 4-(2-Cyclopentylsulfanyl-pyridin-3-yl)-phenylamine (0.140 g,
0.52 mmol) obtained in Preparation Example 189 and
2-formyl-cyclopropanecarboxylic acid ethyl ester (0.081 g, 0.57
mmol) were reacted in the same manner as in Preparation Example 35
to obtain the title compound (0.150 g, 73%).
Step B:
2-{[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenylamino]-methyl}-cy-
clopropanecarboxylic Acid
[2650]
2-{[4-(2-Cyclopentylsulfanyl-pyridin-3-yl)-phenylamino]-methyl}-cyc-
lopropanecarboxylic acid ethyl ester (0.030 g, 0.08 mmol) obtained
in Step A was reacted in the same manner as in Step B of Example 1
to obtain the title compound (0.025 g, 90%).
[2651] .sup.1H-NMR (CDCl.sub.3) .delta. 8.37 (1H, m), 7.34 (1H, m),
7.26 (2H, d), 7.00 (1H, m), 6.66 (2H, d), 4.09 (1H, m), 3.20 (1H,
m), 3.09 (1H, m), 2.19 (2H, m), 1.84 (1H, m), 1.72 (2H, m), 1.60
(5H, m), 1.35 (1H, m), 0.99 (1H, m)
Example 212:
4-{[2-fluoro-4-(2-isopropylsulfanyl-pyridin-3-yl)-phenyl]-methyl-amino}-b-
utyric Acid
##STR00252##
[2653] 3-Iodo-2-isopropylsulfanyl-pyridine (0.030 g, 0.11 mmol)
obtained in Preparation Example 9 and
4-{[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-met-
hyl-amino}-butyric acid methyl ester (0.038 g, 0.11 mmol) obtained
in Preparation Example 187 were reacted in the same manner as in
Example 1 to obtain the title compound (0.021 g, 54%).
[2654] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, m), 7.35 (1H, m),
7.11 (2H, m), 7.01 (2H, m), 4.06 (1H, m), 3.25 (2H, t), 2.87 (3H,
s), 2.51 (2H, t), 1.97 (2H, m), 1.36 (6H, d)
Example 213:
4-{[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2-fluoro-phenyl]-methyl-amino}-
-butyric Acid
##STR00253##
[2656] 2-Cyclopentylsulfanyl-3-iodo-pyridine (0.030 g, 0.10 mmol)
obtained in Preparation Example 15 and
4-{[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-met-
hyl-amino}-butyric acid methyl ester (0.035 g, 0.10 mmol) obtained
in Preparation Example 187 were reacted in the same manner as in
Example 1 to obtain the title compound (0.017 g, 45%).
[2657] .sup.1H-NMR (CDCl.sub.3) .delta. 8.40 (1H, m), 7.34 (1H, m),
7.12 (2H, m), 7.01 (2H, m), 4.09 (1H, m), 3.25 (2H, t), 2.87 (3H,
s), 2.51 (2H, t), 2.20 (2H, m), 1.97 (2H, m), 1.63 (6H, m)
Example 214:
4-{[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenyl]-methyl-amino}-buty-
ric Acid
##STR00254##
[2659] 3-Iodo-2-isopropoxy-pyridine (0.030 g, 0.11 mmol) obtained
in Preparation Example 34 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.042 g, 0.11 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.022 g, 55%).
[2660] .sup.1H-NMR (CDCl.sub.3) .delta. 8.11 (1H, m), 7.55 (1H, m),
7.10 (2H, m), 6.90 (1H, m), 5.41 (1H, m), 3.14 (2H, t), 2.88 (3H,
s), 2.41 (2H, t), 1.86 (2H, m), 1.37 (6H, d)
Example 215:
4-[(2'-cyclopentylamino-3,5-difluoro-biphenyl-4-yl)-methyl-amino]-butyric
Acid
##STR00255##
[2662] N-cyclopentyl-2-iodo-aniline (0.030 g, 0.10 mmol) obtained
in Preparation Example 35 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.039 g, 0.10 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.015 g, 37%).
[2663] .sup.1H-NMR (CDCl.sub.3) .delta. 7.23 (1H, m), 7.01 (1H, m),
6.93 (2H, m), 6.72 (2H, m), 3.77 (1H, m), 3.19 (2H, t), 2.88 (3H,
s), 2.49 (2H, t), 2.01 (2H, m), 1.90 (2H, m), 1.67 (4H, m), 1.43
(2H, m)
Example 216:
4-[methyl-(3,5,5'-trifluoro-2'-isopropoxy-biphenyl-4-yl)-amino]-butyric
Acid
##STR00256##
[2665] 2-Bromo-4-fluoro-1-isopropoxy-benzene (0.030 g, 0.13 mmol)
obtained in Preparation Example 55 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.048 g, 0.13 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.030 g, 61%).
[2666] .sup.1H-NMR (CDCl.sub.3) .delta. 7.08 (2H, m), 6.98 (2H, m),
6.91 (1H, m), 4.37 (1H, m), 3.16 (2H, t), 2.88 (3H, s), 2.47 (2H,
t), 1.87 (2H, m), 1.25 (6H, d)
Example 217:
4-{[4-(2-cyclopentyloxy-5-methyl-pyridin-3-yl)-2,6-difluoro-phenyl]-methy-
l-amino}-butyric Acid
##STR00257##
[2668] 3-Bromo-2-cyclopentyloxy-5-methyl-pyridine (0.030 g, 0.12
mmol) obtained in Preparation Example 57 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.043 g, 0.12 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.025 g, 53%).
[2669] .sup.1H-NMR (CDCl.sub.3) .delta. 7.94 (1H, m), 7.40 (1H, m),
7.13 (2H, m), 5.47 (1H, m), 3.19 (2H, t), 2.88 (3H, s), 2.50 (2H,
t), 2.27 (3H, s), 1.94 (2H, m), 1.89 (2H, m), 1.78 (4H, m), 1.63
(2H, m)
Example 218:
4-{[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-methyl-amin-
o}-butyric Acid
##STR00258##
[2671]
4-{[2,6-Difluoro-4-(2-fluoro-pyridin-3-yl)-phenyl]-methyl-amino}-bu-
tyric acid methyl ester (0.050 g, 0.15 mmol) obtained in
Preparation Example 190 and cyclobutyl-methanol (0.026 g, 0.30
mmol) were reacted in the same manner as in Preparation Example 34
to obtain the title compound (0.020 g, 35%).
[2672] .sup.1H-NMR (CDCl.sub.3) .delta. 8.13 (1H, m), 7.59 (1H, m),
7.14 (2H, m), 6.95 (1H, m), 4.32 (2H, d), 3.17 (2H, t), 2.88 (3H,
s), 2.80 (1H, m), 2.48 (2H, t), 2.10 (2H, m), 1.89 (6H, m)
Example 219:
4-{[2,6-difluoro-4-(2-methoxy-pyridin-3-yl)-phenyl]-methyl-amino}-butyric
Acid
##STR00259##
[2674] In the synthesis process of Example 218, the title compound
(5 mg, 10%) was obtained as a by-product.
[2675] .sup.1H-NMR (CDCl.sub.3) .delta. 8.16 (1H, m), 7.58 (1H, m),
7.11 (2H, m), 6.98 (1H, m), 3.98 (3H, s), 3.19 (2H, t), 2.87 (3H,
s), 2.48 (2H, t), 1.90 (2H, m)
Example 220:
4-({2,6-difluoro-4-[2-(tetrahydro-furan-3-yloxy)-pyridin-3-yl]-phenyl}-me-
thyl-amino)-butyric Acid
##STR00260##
[2677]
4-{[2,6-Difluoro-4-(2-fluoro-pyridin-3-yl)-phenyl]-methyl-amino}-bu-
tyric acid methyl ester (0.050 g, 0.15 mmol) obtained in
Preparation Example 190 and tetrahydro-furan-3-ol (0.026 g, 0.30
mmol) were reacted in the same manner as in Preparation Example 34
to obtain the title compound (0.023 g, 40%).
[2678] .sup.1H-NMR (CDCl.sub.3) .delta. 8.11 (1H, m), 7.59 (1H, m),
7.09 (2H, m), 6.97 (1H, m), 5.64 (1H, m), 4.06 (1H, m), 3.94 (3H,
m), 3.19 (2H, t), 2.89 (3H, s), 2.46 (2H, t), 2.26 (1H, m), 2.16
(1H, m), 1.88 (2H, m)
Example 221:
4-[(3,5-difluoro-2'-pyrrolidin-1-yl-biphenyl-4-yl)-methyl-amino]-butyric
Acid
##STR00261##
[2680] 1-(2-Iodo-phenyl)-pyrrolidine (0.030 g, 0.11 mmol) obtained
in Preparation Example 191 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.041 g, 0.11 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.020 g, 48%).
[2681] .sup.1H-NMR (CDCl.sub.3) .delta. 7.26 (1H, m), 7.12 (1H, m),
6.97 (2H, m), 6.84 (2H, m), 3.16 (2H, t), 2.94 (4H, m), 2.87 (3H,
s), 2.48 (2H, t), 1.88 (2H, m), 1.80 (4H, m)
Example 222:
4-[(3,5-difluoro-2'-methylamino-biphenyl-4-yl)-methyl-amino]-butyric
Acid
##STR00262##
[2683] (2-Iodo-phenyl)-methyl-amine (0.030 g, 0.13 mmol) obtained
in Preparation Example 192 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.048 g, 0.13 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.023 g, 54%).
[2684] .sup.1H-NMR (CDCl.sub.3) .delta. 7.27 (1H, m), 7.04 (1H, m),
6.93 (2H, m), 6.76 (1H, t), 6.69 (1H, d), 3.18 (2H, t), 2.88 (3H,
s), 2.81 (3H, s), 2.48 (2H, t), 2.00 (2H, m)
Example 223:
4-{[3,5-difluoro-2'-(isopropyl-methyl-amino)-biphenyl-4-yl]-methyl-amino}-
-butyric Acid
##STR00263##
[2686] (2-Iodo-phenyl)-isopropyl-methyl-amine (0.030 g, 0.11 mmol)
obtained in Preparation Example 193 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.040 g, 0.11 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.020 g, 48%).
[2687] .sup.1H-NMR (CDCl.sub.3) .delta. 7.25 (1H, m), 7.16 (1H, m),
7.12 (2H, m), 7.05 (2H, m), 3.18 (3H, m), 2.87 (3H, s), 2.58 (3H,
s), 2.50 (2H, t), 1.87 (2H, m), 0.85 (6H, d)
Example 224:
4-{[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-ethyl-amin-
o}-butyric Acid
##STR00264##
[2689] 2-Cyclobutylsulfanyl-3-iodo-pyridine (0.050 g, 0.17 mmol)
obtained in Preparation Example 13 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-ethyl-amino}-butyric acid methyl ester (0.066 g, 0.17 mmol)
obtained in Preparation Example 194 were reacted in the same manner
as in Example 1 to obtain the title compound (0.026 g, 38%).
[2690] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, m), 7.35 (1H, m),
7.02 (1H, m), 6.96 (2H, m), 4.44 (1H, m), 3.24 (2H, t), 3.18 (2H,
m), 2.49 (4H, m), 2.04 (4H, m), 1.83 (2H, m), 1.08 (3H, t)
Example 225:
4-{[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-ethyl-amino-
}-butyric Acid
##STR00265##
[2692] 2-Cyclobutylmethoxy-3-iodo-pyridine (0.050 g, 0.17 mmol)
obtained in Preparation Example 48 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-ethyl-amino}-butyric acid methyl ester (0.066 g, 0.17 mmol)
obtained in Preparation Example 194 were reacted in the same manner
as in Example 1 to obtain the title compound (0.025 g, 35%).
[2693] .sup.1H-NMR (CDCl.sub.3) .delta. 8.14 (1H, m), 7.61 (1H, m),
7.15 (2H, m), 6.96 (1H, m), 4.33 (2H, d), 3.20 (4H, m), 2.81 (1H,
m), 2.48 (2H, t), 2.12 (2H, m), 1.88 (4H, m), 1.79 (2H, m), 1.06
(3H, t)
Example 226:
4-{[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenyl]-ethyl-amino}-butyr-
ic Acid
##STR00266##
[2695] 3-Iodo-2-isopropoxy-pyridine (0.050 g, 0.19 mmol) obtained
in Preparation Example 34 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-ethyl-amino}-butyric acid methyl ester (0.073 g, 0.19 mmol)
obtained in Preparation Example 194 were reacted in the same manner
as in Example 1 to obtain the title compound (0.027 g, 37%).
[2696] .sup.1H-NMR (CDCl.sub.3) .delta. 8.13 (1H, m), 7.57 (1H, m),
7.14 (2H, m), 6.92 (1H, m), 5.42 (1H, m), 3.20 (4H, m), 2.48 (2H,
t), 1.82 (2H, m), 1.37 (6H, d), 1.06 (3H, t)
Example 227:
(R)-5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-hexanoi-
c Acid
##STR00267##
[2698] 2-Cyclobutylsulfanyl-3-iodo-pyridine (0.050 g, 0.17 mmol)
obtained in Preparation Example 13 and
(R)-5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phen-
yl]-hexanoic acid ethyl ester (0.066 g, 0.17 mmol) obtained in
Preparation Example 195 were reacted in the same manner as in
Example 1 to obtain the title compound (0.038 g, 56%).
[2699] .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, m), 7.36 (1H, m),
7.04 (1H, m), 6.93 (2H, m), 4.44 (1H, m), 3.25 (1H, m), 2.51 (2H,
m), 2.38 (2H, t), 2.09 (4H, m), 1.85 (1H, m), 1.70 (2H, m), 1.55
(1H, m), 1.38 (3H, d)
Example 228:
(E)-(R)-5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-hex-
-2-enoic Acid
##STR00268##
[2701] 2-Cyclobutylsulfanyl-3-iodo-pyridine (0.015 g, 0.05 mmol)
obtained in Preparation Example 13 and
(E)-(R)-5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)--
phenyl]-hex-2-enoic acid ethyl ester (0.020 g, 0.05 mmol) obtained
in Preparation Example 196 were reacted in the same manner as in
Example 1 to obtain the title compound (0.010 g, 50%).
[2702] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, m), 7.35 (1H, m),
7.03 (4H, m), 5.87 (1H, d), 4.43 (1H, m), 3.42 (1H, m), 2.70 (2H,
m), 2.52 (2H, m), 2.05 (4H, m), 1.39 (3H, d)
Example 229:
(S)-5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-hexanoi-
c Acid
##STR00269##
[2704] 2-Cyclobutylsulfanyl-3-iodo-pyridine (0.040 g, 0.14 mmol)
obtained in Preparation Example 13 and
(S)-5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phen-
yl]-hexanoic acid ethyl ester (0.049 g, 0.13 mmol) obtained in
Preparation Example 197 were reacted in the same manner as in
Example 1 to obtain the title compound (0.020 g, 39%).
[2705] .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, m), 7.36 (1H, m),
7.04 (1H, m), 6.93 (2H, m), 4.44 (1H, m), 3.25 (1H, m), 2.51 (2H,
m), 2.38 (2H, t), 2.09 (4H, m), 1.85 (1H, m), 1.70 (2H, m), 1.55
(1H, m), 1.38 (3H, d)
Example 230:
5-{2,6-difluoro-4-[2-(tetrahydro-furan-3-yloxy)-pyridin-3-yl]-phenyl}-hex-
anoic Acid
##STR00270##
[2707] 3-Iodo-2-(tetrahydro-furan-3-yloxy)-pyridine (0.040 g, 0.14
mmol) obtained in Preparation Example 49 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.049 g, 0.13 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 1 to obtain the title compound (0.030 g, 56%).
[2708] .sup.1H-NMR (CDCl.sub.3) .delta. 8.13 (1H, m), 7.62 (1H, m),
7.07 (2H, m), 6.98 (1H, m), 5.65 (1H, m), 4.07 (1H, m), 3.95 (3H,
m), 3.23 (1H, m), 2.36 (3H, m), 2.17 (1H, m), 1.83 (1H, m), 1.72
(2H, m), 1.55 (1H, m), 1.36 (3H, d)
Example 231:
5-{2,6-difluoro-4-[2-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-phenyl}-hex-
anoic Acid
##STR00271##
[2710] 3-Iodo-2-(tetrahydro-pyran-4-yloxy)-pyridine (0.040 g, 0.13
mmol) obtained in Preparation Example 50 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.050 g, 0.13 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 1 to obtain the title compound (0.020 g, 43%).
[2711] .sup.1H-NMR (CDCl.sub.3) .delta. 8.13 (1H, m), 7.62 (1H, m),
7.10 (2H, m), 6.95 (1H, m), 5.38 (1H, m), 3.91 (2H, m), 3.64 (2H,
m), 3.24 (1H, m), 2.37 (2H, m), 2.09 (2H, m), 1.85 (3H, m), 1.70
(2H, m), 1.55 (1H, m), 1.37 (3H, d)
Example 232:
5-{2,6-difluoro-4-[2-(oxetan-3-yloxy)-pyridin-3-yl]-phenyl}-hexanoic
Acid
##STR00272##
[2713] 3-Iodo-2-(oxetan-3-yloxy)-pyridine (0.030 g, 0.11 mmol)
obtained in Preparation Example 209 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.041 g, 0.11 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 1 to obtain the title compound (0.013 g, 32%).
[2714] .sup.1H-NMR (CDCl.sub.3) .delta. 8.07 (1H, m), 7.64 (1H, m),
7.12 (2H, m), 7.01 (1H, m), 5.66 (1H, m), 5.02 (2H, m), 4.76 (2H,
m), 3.25 (1H, m), 2.36 (2H, m), 1.85 (1H, m), 1.73 (2H, m), 1.54
(1H, m), 1.37 (3H, d)
Example 233:
4-[4-(2-cyclobutoxy-pyridin-3-yl)-2-fluoro-phenoxy]-butyric
Acid
##STR00273##
[2716] 2-Cyclobutoxy-3-iodo-pyridine (0.030 g, 0.11 mmol) obtained
in Preparation Example 41 and
4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyri-
c acid ethyl ester (0.038 g, 0.11 mmol) obtained in Preparation
Example 198 were reacted in the same manner as in Example 1 to
obtain the title compound (0.025 g, 66%).
[2717] .sup.1H-NMR (CDCl.sub.3) .delta. 8.09 (1H, m), 7.55 (1H, m),
7.40 (1H, m), 7.26 (1H, m), 7.00 (1H, m), 6.92 (1H, m), 5.29 (1H,
m), 4.15 (2H, t), 2.64 (2H, t), 2.46 (2H, m), 2.20 (4H, m), 1.82
(1H, m), 1.68 (1H, m)
Example 234:
4-[4-(2-cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenoxy]-butyric
Acid
##STR00274##
[2719] 2-Cyclopentyloxy-3-iodo-pyridine (0.030 g, 0.10 mmol)
obtained in Preparation Example 11 and
4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyri-
c acid ethyl ester (0.037 g, 0.10 mmol) obtained in Preparation
Example 198 were reacted in the same manner as in Example 1 to
obtain the title compound (0.024 g, 64%).
[2720] .sup.1H-NMR (CDCl.sub.3) .delta. 8.12 (1H, m), 7.56 (1H, m),
7.36 (1H, m), 7.25 (1H, m), 6.97 (1H, m), 6.90 (1H, m), 5.50 (1H,
m), 4.14 (2H, t), 2.64 (2H, t), 2.21 (2H, m), 1.93 (2H, m), 1.81
(4H, m), 1.62 (2H, m)
Example 235:
4-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2-fluoro-phenoxy]-butyric
Acid
##STR00275##
[2722] 2-Cyclobutylsulfanyl-3-iodo-pyridine (0.030 g, 0.10 mmol)
obtained in Preparation Example 13 and
4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyri-
c acid ethyl ester (0.036 g, 0.10 mmol) obtained in Preparation
Example 198 were reacted in the same manner as in Example 1 to
obtain the title compound (0.022 g, 59%).
[2723] .sup.1H-NMR (CDCl.sub.3) .delta. 8.39 (1H, m), 7.32 (1H, m),
7.18 (2H, m), 7.02 (2H, m), 4.42 (1H, m), 4.16 (2H, t), 2.65 (2H,
t), 2.49 (2H, m), 2.20 (2H, m), 2.01 (4H, m)
Example 236:
4-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2-fluoro-phenoxy]-butyric
Acid
##STR00276##
[2725] 2-Cyclopentylsulfanyl-3-iodo-pyridine (0.030 g, 0.10 mmol)
obtained in Preparation Example 15 and
4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyri-
c acid ethyl ester (0.035 g, 0.10 mmol) obtained in Preparation
Example 198 were reacted in the same manner as in Example 1 to
obtain the title compound (0.020 g, 54%).
[2726] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, m), 7.33 (1H, m),
7.16 (1H, m), 7.12 (1H, m), 7.02 (2H, m), 4.15 (2H, t), 4.07 (1H,
m), 2.63 (2H, t), 2.19 (4H, m), 1.70 (2H, m), 1.61 (4H, m)
Example 237:
6-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenyl]-heptanoic
Acid
##STR00277##
[2728] 2-Cyclopentyloxy-3-iodo-pyridine (0.040 g, 0.14 mmol)
obtained in Preparation Example 11 and
6-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]--
heptanoic acid ethyl ester (0.055 g, 0.14 mmol) obtained in
Preparation Example 199 were reacted in the same manner as in
Example 1 to obtain the title compound (0.028 g, 50%).
[2729] .sup.1H-NMR (CDCl.sub.3) .delta. 8.15 (1H, m), 7.60 (1H, m),
7.09 (2H, m), 6.93 (1H, m), 5.52 (1H, m), 3.23 (1H, m), 2.33 (2H,
t), 1.97 (2H, m), 1.85 (5H, m), 1.64 (5H, m), 1.35 (4H, m), 1.25
(1H, m)
Example 238:
6-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl]-heptanoic
Acid
##STR00278##
[2731] 2-Cyclopentylsulfanyl-3-iodo-pyridine (0.040 g, 0.13 mmol)
obtained in Preparation Example 15 and
6-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]--
heptanoic acid ethyl ester (0.052 g, 0.13 mmol) obtained in
Preparation Example 199 were reacted in the same manner as in
Example 1 to obtain the title compound (0.025 g, 45%).
[2732] .sup.1H-NMR (CDCl.sub.3) .delta. 8.43 (1H, m), 7.33 (1H, m),
7.03 (1H, m), 6.93 (2H, m), 4.15 (1H, m), 3.24 (1H, m), 2.34 (2H,
t), 2.20 (2H, m), 1.82 (1H, m), 1.64 (10H, m), 1.36 (3H, d), 1.25
(1H, m)
Example 239:
4-[4-(2-cyclopropylmethoxy-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric
Acid
##STR00279##
[2734]
4-[2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl-
sulfanyl]-butyric acid ethyl ester (0.04 g, 0.11 mmol) obtained in
Preparation Example 205 and 2-cyclopropylmethoxy-3-iodo-pyridine
(0.03 g, 0.11 mmol) obtained in Preparation Example 40 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.020 g, 51%).
[2735] .sup.1H-NMR (CDCl.sub.3) .delta. 8.14 (1H, m), 7.63 (1H, m),
7.44 (3H, m), 6.97 (1H, m), 4.23 (2H, d), 3.04 (2H, t), 2.58 (2H,
t), 2.02 (2H, m), 1.29 (1H, m), 0.61 (2H, m), 0.36 (2H, m)
Example 240:
4-[4-(2-cyclopropylmethoxy-pyridin-3-yl)-2-fluoro-phenoxy]-butyric
Acid
##STR00280##
[2737] 2-Cyclopropylmethoxy-3-iodo-pyridine (0.030 g, 0.11 mmol)
obtained in Preparation Example 40 and
4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyri-
c acid ethyl ester (0.038 g, 0.11 mmol) obtained in Preparation
Example 198 were reacted in the same manner as in Example 1 to
obtain the title compound (0.018 g, 48%).
[2738] .sup.1H-NMR (CDCl.sub.3) .delta. 8.15 (1H, m), 7.64 (1H, m),
7.49 (1H, d), 7.36 (1H, d), 7.07 (1H, t), 7.00 (1H, m), 4.27 (2H,
d), 4.21 (2H, t), 2.71 (2H, t), 2.27 (2H, m), 1.34 (1H, m), 0.65
(2H, m), 0.40 (2H, m)
Example 241:
4-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2-fluoro-phenoxy]-butyric
Acid
##STR00281##
[2740] 2-Cyclobutylmethoxy-3-iodo-pyridine (0.030 g, 0.10 mmol)
obtained in Preparation Example 48 and
4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyri-
c acid ethyl ester (0.037 g, 0.10 mmol) obtained in Preparation
Example 198 were reacted in the same manner as in Example 1 to
obtain the title compound (0.022 g, 59%).
[2741] .sup.1H-NMR (CDCl.sub.3) .delta. 8.16 (1H, m), 7.64 (1H, m),
7.45 (1H, m), 7.32 (1H, m), 7.05 (2H, m), 4.37 (2H, d), 4.21 (2H,
t), 2.85 (1H, m), 2.71 (2H, t), 2.26 (2H, m), 2.12 (2H, m), 1.98
(4H, m)
Example 242: 4-[3-(6-cyclopentyloxy-pyridin-2-yl)-phenoxy]-butyric
Acid
##STR00282##
[2743] 2-Chloro-6-cyclopentyloxy-pyridine (0.030 g, 0.15 mmol)
obtained in Preparation Example 12 and
4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-butyric
acid ethyl ester (0.051 g, 0.15 mmol) obtained in Preparation
Example 200 were reacted in the same manner as in Example 1 to
obtain the title compound (0.035 g, 68%).
[2744] .sup.1H-NMR (CDCl.sub.3) .delta. 7.60 (3H, m), 7.34 (1H, m),
7.27 (1H, m), 6.92 (1H, m), 6.63 (1H, m), 5.53 (1H, m), 4.12 (2H,
t), 2.63 (2H, t), 2.17 (2H, m), 2.04 (2H, m), 1.84 (2H, m), 1.65
(4H, m)
Example 243: 4-[3-(2-cyclopentyloxy-pyridin-3-yl)-phenoxy]-butyric
Acid
##STR00283##
[2746] 2-Cyclopentyloxy-3-iodo-pyridine (0.030 g, 0.10 mmol)
obtained in Preparation Example 11 and
4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-butyric
acid ethyl ester (0.035 g, 0.10 mmol) obtained in Preparation
Example 200 were reacted in the same manner as in Example 1 to
obtain the title compound (0.015 g, 42%).
[2747] .sup.1H-NMR (CDCl.sub.3) .delta. 8.13 (1H, m), 7.61 (1H, m),
7.29 (1H, m), 7.12 (2H, m), 6.92 (1H, m), 6.87 (1H, m), 5.51 (1H,
m), 4.07 (2H, t), 2.61 (2H, t), 2.15 (2H, m), 1.98 (2H, m), 1.82
(2H, m), 1.70 (4H, m)
Example 244:
5-[4-(2-cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenyl]-pentanoic
Acid
##STR00284##
[2749] 2-Cyclopentyloxy-3-iodo-pyridine (0.030 g, 0.10 mmol)
obtained in Preparation Example 11 and
5-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pent-
anoic acid ethyl ester (0.036 g, 0.10 mmol) obtained in Preparation
Example 201 were reacted in the same manner as in Example 1 to
obtain the title compound (0.021 g, 57%).
[2750] .sup.1H-NMR (CDCl.sub.3) .delta. 8.14 (1H, m), 7.58 (1H, m),
7.25 (2H, m), 7.20 (1H, m), 6.91 (1H, m), 5.51 (1H, m), 2.71 (2H,
t), 2.43 (2H, t), 1.95 (2H, m), 1.82 (2H, m), 1.74 (5H, m), 1.66
(3H, m)
Example 245:
5-[4-(2-cyclobutoxy-pyridin-3-yl)-2-fluoro-phenyl]-pentanoic
Acid
##STR00285##
[2752] 2-Cyclobutoxy-3-iodo-pyridine (0.030 g, 0.10 mmol) obtained
in Preparation Example 41 and
5-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pent-
anoic acid ethyl ester (0.036 g, 0.10 mmol) obtained in Preparation
Example 201 were reacted in the same manner as in Example 1 to
obtain the title compound (0.021 g, 57%).
[2753] .sup.1H-NMR (CDCl.sub.3) .delta. 8.11 (1H, m), 7.59 (1H, m),
7.29 (3H, m), 6.94 (1H, m), 5.28 (1H, m), 2.71 (2H, t), 2.45 (4H,
m), 2.15 (2H, m), 1.74 (6H, m)
Example 246:
5-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2-fluoro-phenyl]-pentanoic
Acid
##STR00286##
[2755] 2-Cyclobutylmethoxy-3-iodo-pyridine (0.030 g, 0.10 mmol)
obtained in Preparation Example 48 and
5-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pent-
anoic acid ethyl ester (0.036 g, 0.10 mmol) obtained in Preparation
Example 201 were reacted in the same manner as in Example 1 to
obtain the title compound (0.022 g, 59%).
[2756] .sup.1H-NMR (CDCl.sub.3) .delta. 8.13 (1H, m), 7.62 (1H, m),
7.26 (2H, m), 7.20 (1H, m), 7.95 (1H, m), 4.32 (2H, m), 2.77 (1H,
t), 2.71 (2H, t), 2.42 (2H, t), 2.10 (2H, m), 1.88 (4H, m), 1.72
(4H, m)
Example 247:
5-[4-(2-cyclopropylmethoxy-pyridin-3-yl)-2-fluoro-phenyl]-pentanoic
Acid
##STR00287##
[2758] 2-Cyclopropylmethoxy-3-iodo-pyridine (0.030 g, 0.11 mmol)
obtained in Preparation Example 40 and
5-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pent-
anoic acid ethyl ester (0.038 g, 0.11 mmol) obtained in Preparation
Example 201 were reacted in the same manner as in Example 1 to
obtain the title compound (0.020 g, 53%).
[2759] .sup.1H-NMR (CDCl.sub.3) .delta. 8.11 (1H, m), 7.60 (1H, m),
7.30 (2H, m), 7.21 (1H, m), 6.95 (1H, m), 4.22 (2H, d), 2.71 (2H,
t), 2.43 (2H, m), 1.73 (4H, m), 1.29 (1H, m), 0.58 (2H, m), 0.34
(2H, m)
Example 248:
5-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2-fluoro-phenyl]-pentanoic
Acid
##STR00288##
[2761] 2-Cyclopentylsulfanyl-3-iodo-pyridine (0.030 g, 0.10 mmol)
obtained in Preparation Example 15 and
5-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pent-
anoic acid ethyl ester (0.034 g, 0.10 mmol) obtained in Preparation
Example 201 were reacted in the same manner as in Example 1 to
obtain the title compound (0.023 g, 63%).
[2762] .sup.1H-NMR (CDCl.sub.3) .delta. 8.42 (1H, m), 7.35 (1H, m),
7.25 (1H, m), 7.13 (2H, m), 7.02 (1H, m), 4.09 (1H, m), 2.72 (2H,
t), 2.43 (2H, t), 2.19 (2H, m), 1.73 (6H, m), 1.69 (4H, m)
Example 249:
5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2-fluoro-phenyl]-pentanoic
Acid
##STR00289##
[2764] 2-Cyclobutylsulfanyl-3-iodo-pyridine (0.030 g, 0.10 mmol)
obtained in Preparation Example 13 and
5-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pent-
anoic acid ethyl ester (0.039 g, 0.10 mmol) obtained in Preparation
Example 201 were reacted in the same manner as in Example 1 to
obtain the title compound (0.024 g, 65%).
[2765] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, m), 7.34 (1H, m),
7.25 (1H, m), 7.13 (2H, m), 7.02 (1H, m), 4.43 (1H, m), 2.72 (2H,
t), 2.50 (2H, m), 2.42 (2H, t), 2.06 (4H, m), 1.74 (4H, m)
Example 250:
5-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-pentanoic
Acid
##STR00290##
[2767] 2-Cyclobutylmethoxy-3-iodo-pyridine (0.030 g, 0.10 mmol)
obtained in Preparation Example 48 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pe-
ntanoic acid ethyl ester (0.038 g, 0.10 mmol) obtained in
Preparation Example 27 were reacted in the same manner as in
Example 1 to obtain the title compound (0.024 g, 62%).
[2768] .sup.1H-NMR (CDCl.sub.3) .delta. 8.15 (1H, m), 7.61 (1H, m),
7.12 (2H, m), 6.96 (1H, m), 4.29 (2H, d), 2.78 (3H, m), 2.42 (2H,
t), 2.11 (2H, m), 1.88 (4H, m), 1.71 (4H, m)
Example 251:
5-[4-(2-cyclobutoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-pentanoic
Acid
##STR00291##
[2770] 2-Cyclobutoxy-3-iodo-pyridine (0.030 g, 0.11 mmol) obtained
in Preparation Example 41 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pe-
ntanoic acid ethyl ester (0.040 g, 0.11 mmol) obtained in
Preparation Example 27 were reacted in the same manner as in
Example 1 to obtain the title compound (0.021 g, 53%).
[2771] .sup.1H-NMR (CDCl.sub.3) .delta. 8.13 (1H, m), 7.59 (1H, m),
7.13 (2H, m), 6.94 (1H, m), 5.28 (1H, m), 2.74 (2H, t), 2.46 (4H,
m), 2.15 (2H, m), 1.88 (1H, m), 1.71 (5H, m)
Example 252:
5-[4-(2-cyclopropylmethoxy-pyridin-3-yl)-2,6-difluoro-phenyl]-pentanoic
Acid
##STR00292##
[2773] 2-Cyclopropylmethoxy-3-iodo-pyridine (0.030 g, 0.11 mmol)
obtained in Preparation Example 40 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pe-
ntanoic acid ethyl ester (0.040 g, 0.11 mmol) obtained in
Preparation Example 27 were reacted in the same manner as in
Example 1 to obtain the title compound (0.026 g, 66%).
[2774] .sup.1H-NMR (CDCl.sub.3) .delta. 8.13 (1H, m), 7.61 (1H, m),
7.16 (2H, m), 6.96 (1H, m), 4.22 (2H, d), 2.74 (2H, t), 2.43 (2H,
t), 1.72 (4H, m), 1.31 (1H, m), 0.60 (2H, m), 0.36 (2H, m)
Example 253:
4-[4-(5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-2,6-difluoro-phe-
noxy]-butyric Acid
##STR00293##
[2776] 7-Bromo-5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran (0.093
g, 0.36 mmol) obtained in Preparation Example 210 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (89 mg, 0.24 mmol) obtained in Preparation
Example 16 were reacted in the same manner as in Example 1 to
obtain the title compound (0.053 g, 56%).
[2777] .sup.1H-NMR (CDCl.sub.3) .delta. 7.27 (2H, m), 7.18 (1H, m),
7.07 (1H, m), 4.21 (2H, t), 3.02 (2H, s), 2.66 (2H, t), 2.10 (2H,
m), 1.50 (6H, s)
Example 254:
4-[4-(5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-2,6-difluoro-phe-
nylsulfanyl]-butyric Acid
##STR00294##
[2779] 7-Bromo-5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran (0.098
g, 0.37 mmol) obtained in Preparation Example 210 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenyls-
ulfanyl]butyric acid ethyl ester (0.096 g, 0.25 mmol) obtained in
Preparation Example 219 were reacted in the same manner as in
Example 1 to obtain the title compound (0.024 g, 23%).
[2780] .sup.1H-NMR (CDCl.sub.3) .delta. 7.31 (2H, m), 7.23 (1H, m),
7.10 (1H, m), 3.03 (2H, s), 2.95 (2H, t), 2.56 (2H, t), 1.89 (2H,
m), 1.51 (6H, s)
Example 255:
4-{[4-(5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-2,6-difluoro-ph-
enyl]-methyl-amino}-butyric Acid
##STR00295##
[2782] 7-bromo-5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran (0.101
g, 0.39 mmol) obtained in Preparation Example 210 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.160 g, 0.42 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.101 g, 63%).
[2783] .sup.1H-NMR (CDCl.sub.3) .delta. 7.24 (1H, m), 7.21 (1H, m),
7.19 (1H, m), 7.05 (1H, m), 3.16 (2H, t), 3.02 (2H, s), 2.87 (3H,
s), 2.45 (2H, t), 1.86 (2H, m), 1.51 (6H, s)
Example 256:
5-[4-(5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-2,6-difluoro-phe-
nyl]-hexanoic Acid
##STR00296##
[2785] 7-Bromo-5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran (0.082
g, 0.31 mmol) obtained in Preparation Example 210 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.130 g, 0.34 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 1 to obtain the title compound (0.094 g, 74%).
[2786] .sup.1H-NMR (CDCl.sub.3) .delta. 7.22 (2H, m), 7.19 (1H, m),
7.07 (1H, m), 3.22 (1H, m), 3.02 (2H, s), 2.35 (2H, t), 1.84 (1H,
m), 1.68 (2H, m), 1.52 (1H, m), 1.51 (6H, s), 1.34 (3H, d)
Example 257:
4-[2,6-difluoro-4-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-ph-
enoxy]-butyric Acid
##STR00297##
[2788] 4-Bromo-7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran (0.083
g, 0.32 mmol) obtained in Preparation Example 211 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (0.133 g, 0.36 mmol) obtained in Preparation
Example 16 were reacted in the same manner as in Example 17 to
obtain the title compound (0.097 g, 79%).
[2789] .sup.1H-NMR (CDCl.sub.3) .delta. 6.94 (2H, m), 6.81 (2H, s),
4.21 (2H, t), 3.90 (3H, s), 3.11 (2H, s), 2.67 (2H, t), 2.11 (2H,
m), 1.52 (6H, s)
Example 258:
4-[2,6-difluoro-4-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-ph-
enylsulfanyl]-butyric Acid
##STR00298##
[2791] 4-Bromo-7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran (0.061
g, 0.24 mmol) obtained in Preparation Example 211 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenyls-
ulfanyl]butyric acid ethyl ester (0.100 g, 0.26 mmol) obtained in
Preparation Example 219 were reacted in the same manner as in
Example 17 to obtain the title compound (0.047 g, 48%).
[2792] .sup.1H-NMR (CDCl.sub.3) .delta. 6.98 (2H, m), 6.84 (2H, m),
3.91 (3H, s), 3.14 (2H, s), 2.96 (2H, t), 2.55 (2H, t), 1.88 (2H,
m), 1.53 (6H, s)
Example 259:
4-{[2,6-difluoro-4-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-p-
henyl]-methyl-amino}-butyric Acid
##STR00299##
[2794] 4-Bromo-7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran (0.061
g, 0.24 mmol) obtained in Preparation Example 211 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.100 g, 0.26 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 17 to obtain the title compound (0.107 g, 100%).
[2795] .sup.1H-NMR (CDCl.sub.3) .delta. 6.89 (2H, m), 6.81 (2H, s),
3.90 (3H, s), 3.15 (2H, t), 3.13 (2H, s), 2.46 (2H, t), 1.86 (2H,
m), 1.52 (6H, s)
Example 260:
5-[2,6-difluoro-4-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl-phe-
nyl]-hexanoic Acid
##STR00300##
[2797] 4-Bromo-7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran (0.061
g, 0.24 mmol) obtained in Preparation Example 211 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.099 g, 0.26 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 17 to obtain the title compound (0.077 g, 79%).
[2798] .sup.1H-NMR (CDCl.sub.3) .delta. 6.88 (2H, m), 6.82 (2H, m),
3.90 (3H, s), 3.21 (1H, m), 3.14 (2H, s), 2.35 (2H, t), 1.83 (1H,
m), 1.68 (2H, m), 1.53 (1H, m), 1.52 (6H, s), 1.35 (3H, d)
Example 261:
4-(2,6-difluoro-4-spiro[3H-benzofuran-2,1'-cyclopentan]-7-yl-phenoxy)-but-
yric Acid
##STR00301##
[2800] 7-Bromospiro[3H-benzofuran-2,1'-cyclopentane] (0.062 g, 0.24
mmol) obtained in Preparation Example 212 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (0.100 g, 0.27 mmol) obtained in Preparation
Example 16 were reacted in the same manner as in Example 1 to
obtain the title compound (0.087 g, 93%).
[2801] .sup.1H-NMR (CDCl.sub.3) .delta. 7.32 (2H, m), 7.21 (1H, d),
7.12 (1H, m), 6.88 (1H, t), 4.21 (2H, t), 3.20 (2H, s), 2.67 (2H,
t), 2.11 (4H, m), 1.92 (2H, m), 1.75 (4H, m)
Example 262:
4-(2,6-difluoro-4-spiro[3H-benzofuran-2,1'-cyclopentan]-7-yl-phenylsulfan-
yl)-butyric Acid
##STR00302##
[2803] 7-Bromospiro[3H-benzofuran-2,1'-cyclopentane] (0.067 g, 0.26
mmol) obtained in Preparation Example 212 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenyls-
ulfanyl]butyric acid ethyl ester (0.112 g, 0.29 mmol) obtained in
Preparation Example 219 were reacted in the same manner as in
Example 1 to obtain the title compound (0.053 g, 50%).
[2804] .sup.1H-NMR (CDCl.sub.3) .delta. 7.36 (2H, m), 7.25 (1H, d),
7.15 (1H, m), 6.89 (1H, t), 3.21 (2H, s), 2.94 (2H, t), 2.56 (2H,
t), 2.11 (2H, m), 1.89 (4H, m), 1.75 (4H, m)
Example 263:
4-(2,6-difluoro-N-methyl-4-spiro[3H-benzofuran-2,1'-cyclopentan]-7-yl-ani-
lino)-butyric Acid
##STR00303##
[2806] 7-Bromospiro[3H-benzofuran-2,1'-cyclopentane] (0.067 g, 0.26
mmol) obtained in Preparation Example 212 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.111 g, 0.29 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.064 g, 61%).
[2807] .sup.1H-NMR (CDCl.sub.3) .delta. 7.28 (2H, m), 7.22 (1H, d),
7.11 (1H, m), 6.87 (1H, t), 3.20 (2H, s), 3.17 (2H, t), 2.87 (3H,
s), 2.47 (2H, t), 2.13 (2H, m), 1.90 (4H, m), 1.75 (4H, m)
Example 264:
5-(2,6-difluoro-4-spiro[3H-benzofuran-2,1'-cyclopentan]-7-yl-phenyl)-hexa-
noic Acid
##STR00304##
[2809] 7-Bromospiro[3H-benzofuran-2,1'-cyclopentane] (0.067 g, 0.26
mmol) obtained in Preparation Example 212 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.100 g, 0.26 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 1 to obtain the title compound (0.039 g, 37%).
[2810] .sup.1H-NMR (CDCl.sub.3) .delta. 7.26 (2H, m), 7.23 (1H, m),
7.12 (1H, m), 6.88 (1H, t), 3.22 (1H, m), 3.20 (2H, s), 2.35 (2H,
t), 2.15 (2H, m), 1.93 (2H, m), 1.90-1.52 (8H, m), 1.32 (3H, d)
Example 265:
7-[4-(3-carboxy-propoxy)-3,5-difluoro-phenyl]-5-fluoro-2,2-dimethyl-2,3-d-
ihydro-indol-1-carboxylic Acid Methyl Ester
##STR00305##
[2811] Step A:
7-[4-(3-ethoxycarbonyl-propoxy)-3,5-difluoro-phenyl]-5-fluoro-2,2-dimethy-
l-2,3-dihydro-indol-1-carboxylic Acid Methyl Ester
##STR00306##
[2813] 5-Fluoro-7-iodo-2,2-dimethyl-2,3-dihydro-indol-1-carboxylic
acid methyl ester (0.074 g, 0.21 mmol) obtained in Preparation
Example 213 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (0.063 g, 0.17 mmol) obtained in Preparation
Example 16 were reacted in the same manner as in Step A of Example
1 to obtain the title compound (0.045 g, 46%).
[2814] .sup.1H-NMR (CDCl.sub.3) .delta. 7.73 (1H, brs), 6.96 (1H,
t), 6.91 (2H, m), 4.23 (2H, t), 4.15 (2H, q), 3.86 (3H, s), 2.91
(2H, s), 2.59 (2H, t), 2.11 (2H, m), 1.53 (6H, s), 1.27 (3H, t)
Step B:
7-[4-(3-carboxy-propoxy)-3,5-difluoro-phenyl]-5-fluoro-2,2-dimethy-
l-2,3-dihydro-indol-1-carboxylic Acid Methyl Ester
[2815]
7-[4-(3-ethoxycarbonyl-propoxy)-3,5-difluoro-phenyl]-5-fluoro-2,2-d-
imethyl-2,3-dihydro-indol-1-carboxylic acid methyl ester (0.010 g,
0.021 mmol) obtained in Step A was reacted in the same manner as in
Step B of Example 1 to obtain the title compound (0.006 g,
64%).
[2816] .sup.1H-NMR (CDCl.sub.3) .delta. 7.73 (1H, brs), 6.97 (1H,
t), 6.90 (2H, m), 4.25 (2H, t), 3.86 (3H, s), 2.91 (2H, s), 2.67
(2H, t), 2.13 (2H, m), 1.53 (6H, s)
Example 266:
4-[2,6-difluoro-4-(5-fluoro-2,2-dimethyl-2,3-dihydro-1H-indol-7-yl)-pheno-
xy]-butyric Acid
##STR00307##
[2818]
7-[4-(3-Carboxy-propoxy)-3,5-difluoro-phenyl]-5-fluoro-2,2-dimethyl-
-2,3-dihydro-indol-1-carboxylic acid methyl ester (0.030 g, 0.07
mmol) obtained in Example 265 was dissolved in 3 mL of MeOH and 1
mL of 6N NaOH aqueous solution, and the mixture was stirred at
80.degree. C. for 24 hours under reflux. After removing organic
solvent, the reaction solution was adjusted to pH 3 by the use of
6N HCl aqueous solution and extracted with EtOAc to separate an
organic layer. The organic layer was dried with MgSO.sub.4 and
concentrated under reduced pressure to obtain the title compound
(0.002 g, 8%).
[2819] .sup.1H-NMR (CDCl.sub.3) .delta. 6.97 (2H, m), 6.85 (1H, m),
6.52 (1H, m), 4.28 (2H, t), 2.83 (2H, s), 2.71 (2H, t), 2.17 (2H,
m), 1.35 (6H, s)
Example 267:
4-[4-(3-carboxy-propoxy)-3,5-difluoro-phenyl]-5-fluoro-2,2-dimethyl-2,3-d-
ihydro-indol-1-carboxylic Acid Methyl Ester
##STR00308##
[2820] Step A:
4-[4-(3-ethoxycarbonyl-propoxy)-3,5-difluoro-phenyl]-5-fluoro-2,2-dimethy-
l-2,3-dihydro-indol-1-carboxylic Acid Methyl Ester
##STR00309##
[2822] 5-Fluoro-4-iodo-2,2-dimethyl-2,3-dihydro-indol-1-carboxylic
acid methyl ester (0.085 g, 0.24 mmol) obtained in Preparation
Example 214 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (0.089 g, 0.24 mmol) obtained in Preparation
Example 16 were reacted in the same manner as in Step A of Example
1 to obtain the title compound (0.050 g, 45%).
[2823] .sup.1H-NMR (CDCl.sub.3) .delta. 6.89-6.77 (4H, m), 4.18
(2H, q), 4.17 (2H, t), 3.11 (3H, s), 2.97 (2H, s), 2.57 (2H, t),
2.08 (2H, m), 1.57 (6H, s), 1.27 (3H, t)
Step B:
4-[4-(3-carboxy-propoxy)-3,5-difluoro-phenyl]-5-fluoro-2,2-dimethy-
l-2,3-dihydro-indol-1-carboxylic Acid Methyl Ester
[2824]
4-[4-(3-Ethoxycarbonyl-propoxy)-3,5-difluoro-phenyl]-5-fluoro-2,2-d-
imethyl-2,3-dihydro-indol-1-carboxylic acid methyl ester (0.010 g,
0.021 mmol) obtained in Step A was reacted in the same manner as in
Step B of Example 1 to obtain the title compound (0.009 g,
100%).
[2825] .sup.1H-NMR (CDCl.sub.3) .delta. 6.87-6.78 (4H, m), 4.20
(2H, t), 3.12 (3H, s), 2.97 (2H, s), 2.65 (2H, t), 2.11 (2H, m),
1.57 (6H, s)
Example 268:
4-[2,6-difluoro-4-(5-fluoro-2,2-dimethyl-2,3-dihydro-1H-indol-4-yl)-pheno-
xy]-butyric Acid
##STR00310##
[2827]
4-[4-(3-Ethoxycarbonyl-propoxy)-3,5-difluoro-phenyl]-5-fluoro-2,2-d-
imethyl-2,3-dihydro-indol-1-carboxylic acid methyl ester (0.04 g,
0.085 mmol) obtained in Step A of Example 267 was each 2 mL of MeOH
and 6N NaOH aqueous solution, and the mixture was stirred at
80.degree. C. for 48 hours under reflux. After removing organic
solvent, the reaction solution was adjusted to pH 3 by the use of
6N HCl aqueous solution and extracted with EtOAc to separate an
organic layer. The organic layer was dried with MgSO.sub.4 and
concentrated under reduced pressure to obtain the title compound
(0.001 g, 3%).
[2828] .sup.1H-NMR (CDCl.sub.3) .delta. 7.08 (2H, m), 6.78 (1H, m),
6.71 (1H, m), 4.21 (2H, t), 2.86 (2H, s), 2.66 (2H, t), 2.11 (2H,
m), 1.31 (6H, s)
Example 269:
4-[2,6-difluoro-4-(5-fluoro-2,2-dimethyl-2,3-dihydro-1H-indol-7-yl)-pheny-
lsulfanyl]-butyric Acid
##STR00311##
[2829] Step A:
7-[4-(3-ethoxycarbonyl-propylsulfanyl)-3,5-difluoro-phenyl]-5-fluoro-2,2--
dimethyl-2,3-dihydro-indol-1-carboxylic Acid Methyl Ester
##STR00312##
[2831] 5-Fluoro-7-iodo-2,2-dimethyl-2,3-dihydro-indol-1-carboxylic
acid methyl ester (0.148 g, 0.42 mmol) obtained in Preparation
Example 213 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenyls-
ulfanyl]butyric acid ethyl ester (0.162 g, 0.42 mmol) obtained in
Preparation Example 219 were reacted in the same manner as in Step
A of Example 17 to obtain the title compound (0.135 g, 67%).
[2832] .sup.1H-NMR (CDCl.sub.3) .delta. 7.79 (1H, brs), 7.02 (1H,
t), 6.98 (2H, m), 4.17 (2H, q), 3.90 (2H, s), 3.02 (2H, t), 2.97
(2H, s), 2.54 (2H, t), 1.96 (2H, m), 1.59 (6H, s), 1.29 (3H, t)
Step B:
4-[2,6-difluoro-4-(5-fluoro-2,2-dimethyl-2,3-dihydro-1H-indol-7-yl-
)-phenylsulfanyl]-butyric Acid
[2833]
7-[4-(3-Ethoxycarbonyl-propylsulfanyl)-3,5-difluoro-phenyl]-5-fluor-
o-2,2-dimethyl-2,3-dihydro-indol-1-carboxylic acid methyl ester
(0.065 g, 0.134 mmol) obtained in Step A was reacted in the same
manner as in Example 266 to obtain the title compound (0.005 g,
9%).
[2834] .sup.1H-NMR (CDCl.sub.3) .delta. 6.96 (2H, m), 6.81 (1H, m),
6.50 (1H, m), 2.95 (2H, t), 2.80 (2H, s), 2.54 (2H, t), 1.90 (2H,
m), 1.30 (6H, s)
Example 270:
3-[6-(2-isopropylsulfanyl-pyridin-3-yl)-thiochroman-2-yl]-propionic
Acid
##STR00313##
[2836] 3-Iodo-2-isopropylsulfanyl-pyridine (0.060 g, 0.21 mmol)
obtained in Preparation Example 9 and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiochroman-2-yl]-pro-
pionic acid ethyl ester (0.079 g, 0.21 mmol) obtained in
Preparation Example 5 were reacted in the same manner as in Example
17 to obtain the title compound (0.050 g, 64%).
[2837] .sup.1H-NMR (CDCl.sub.3) .delta. 8.40 (1H, m), 7.34 (1H, m),
7.13 (2H, s), 7.06 (1H, s), 7.01 (1H, m), 4.04 (1H, m), 3.37 (1H,
m), 2.89 (2H, m), 2.59 (2H, m), 2.25 (1H, m), 2.06 (1H, m), 1.99
(1H, m), 1.86 (1H, m), 1.35 (6H, d)
Example 271:
3-[6-(2-cyclopentoxy-pyridin-3-yl)-thiochroman-2-yl]-propionic
Acid
##STR00314##
[2839] 2-Cyclopentyloxy-3-iodo-pyridine (0.072 g, 0.25 mmol)
obtained in Preparation Example 11 and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiochroman-2-yl]-pro-
pionic acid ethyl ester (0.095 g, 0.25 mmol) obtained in
Preparation Example 5 were reacted in the same manner as in Example
17 to obtain the title compound (0.071 g, 74%).
[2840] .sup.1H-NMR (CDCl.sub.3) .delta. 8.09 (1H, m), 7.56 (1H, m),
7.27 (1H, m), 7.10 (1H, d), 6.89 (1H, m), 5.49 (1H, m), 3.37 (1H,
m), 2.87 (2H, m), 2.59 (2H, m), 2.25 (1H, m), 2.11-1.58 (11H,
m)
Example 272:
3-[6-(2-cyclobutylsulfanyl-pyridin-3-yl)-chroman-2-yl]-propionic
Acid
##STR00315##
[2842] 2-Cyclobutylsulfanyl-3-iodo-pyridine (0.050 g, 0.17 mmol)
obtained in Preparation Example 13 and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-chroman-2-yl]-propion-
ic acid ethyl ester (0.061 g, 0.17 mmol) obtained in Preparation
Example 4 were reacted in the same manner as in Example 17 to
obtain the title compound (0.038 g, 61%).
[2843] .sup.1H-NMR (CDCl.sub.3) .delta. 8.36 (1H, m), 7.33 (1H,
dd), 7.14 (1H, dd), 6.99 (1H, m), 6.85 (1H, d), 4.42 (1H, t), 4.10
(1H, m), 2.91 (1H, m), 2.80 (1H, m), 2.68 (2H, m), 2.51 (2H, m),
2.01 (7H, m), 1.81 (1H, m)
Example 273:
3-[6-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-chroman-2-yl]-p-
ropionic Acid
##STR00316##
[2845] 4-Bromo-7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran (0.068
g, 0.26 mmol) obtained in Preparation Example 211 and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-chroman-2-yl]-propion-
ic acid ethyl ester (0.094 g, 0.26 mmol) obtained in Preparation
Example 4 were reacted in the same manner as in Example 17 to
obtain the title compound (0.054 g, 54%).
[2846] .sup.1H-NMR (CDCl.sub.3) .delta. 7.13 (1H, m), 7.08 (1H, m),
6.80 (3H, m), 4.08 (1H, m), 3.88 (3H, s), 3.11 (2H, d), 2.88 (1H,
m), 2.80 (1H, m), 2.65 (2H, m), 2.02 (3H, m), 1.78 (1H, m), 1.50
(6H, d)
Example 274:
3-[6-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-thiochroman-2-y-
l]-propionic Acid
##STR00317##
[2848] 4-Bromo-7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran (0.068
g, 0.26 mmol) obtained in Preparation Example 211 and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiochroman-2-yl]-pro-
pionic acid ethyl ester (0.098 g, 0.26 mmol) obtained in
Preparation Example 5 were reacted in the same manner as in Example
17 to obtain the title compound (0.038 g, 37%).
[2849] .sup.1H-NMR (CDCl.sub.3) .delta. 7.10 (3H, m), 6.80 (2H, m),
3.88 (3H, s), 3.36 (1H, m), 3.11 (2H, s), 2.89 (2H, m), 2.59 (2H,
m), 2.26 (1H, m), 2.06 (1H, m), 1.98 (1H, m), 1.84 (1H, m), 1.50
(6H, s)
Example 275:
3-[6-(2-cyclobutylsulfanyl-pyridin-3-yl)-thiochroman-2-yl]-propionic
Acid
##STR00318##
[2851] 2-Cyclobutylsulfanyl-3-iodo-pyridine (0.060 g, 0.20 mmol)
obtained in Preparation Example 13 and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiochroman-2-yl]-pro-
pionic acid ethyl ester (0.075 g, 0.20 mmol) obtained in
Preparation Example 5 were reacted in the same manner as in Example
17 to obtain the title compound (0.051 g, 66%).
[2852] .sup.1H-NMR (CDCl.sub.3) .delta. 8.38 (1H, m), 7.34 (1H,
dd), 7.14 (2H, s), 7.09 (1H, s), 7.00 (1H, m), 4.41 (1H, m), 3.38
(1H, m), 2.91 (2H, m), 2.63 (2H, m), 2.49 (2H, m), 2.26 (1H, m),
2.13.about.1.98 (6H, m), 1.87 (1H, m)
Example 276:
3-[6-(2-cyclopropylmethoxy-pyridin-3-yl)-chroman-2-yl]-propionic
Acid
##STR00319##
[2854] 2-Cyclopropylmethoxy-3-iodo-pyridine (0.062 g, 0.23 mmol)
obtained in Preparation Example 40 and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-chroman-2-yl]-propion-
ic acid ethyl ester (0.083 g, 0.23 mmol) obtained in Preparation
Example 4 were reacted in the same manner as in Example 17 to
obtain the title compound (0.057 g, 70%).
[2855] .sup.1H-NMR (CDCl.sub.3) .delta. 8.07 (1H, m), 7.58 (1H,
dd), 7.36 (1H, m), 7.33 (1H, s), 6.91 (1H, m), 6.84 (1H, d), 4.20
(2H, d), 4.09 (1H, m), 2.92 (1H, m), 2.82 (1H, m), 2.65 (2H, m),
2.04 (3H, m), 1.81 (1H, m), 1.29 (1H, m), 0.56 (2H, m), 0.35 (2H,
m)
Example 277:
3-[6-(2-cyclobutoxy-pyridin-3-yl)-chroman-2-yl]-propionic Acid
##STR00320##
[2857] 2-Cyclobutoxy-3-iodo-pyridine (0.062 g, 0.22 mmol) obtained
in Preparation Example 41 and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-chroman-2-yl]-propion-
ic acid ethyl ester (0.083 g, 0.22 mmol) obtained in Preparation
Example 4 were reacted in the same manner as in Example 17 to
obtain the title compound (0.054 g, 69%).
[2858] .sup.1H-NMR (CDCl.sub.3) .delta. 8.06 (1H, m), 7.55 (1H,
dd), 7.35 (1H, dd), 7.28 (1H, m), 6.90 (1H, m), 6.84 (1H, d), 5.25
(1H, m), 4.11 (1H, m), 2.91 (1H, m), 2.81 (1H, m), 2.65 (2H, m),
2.46 (2H, m), 2.12 (2H, m), 2.02 (3H, m), 1.80 (2H, m), 1.67 (1H,
m)
Example 278:
3-[6-(2-cyclobutoxy-pyridin-3-yl)-thiochroman-2-yl]-propionic
Acid
##STR00321##
[2860] 2-Cyclobutoxy-3-iodo-pyridine (0.062 g, 0.22 mmol) obtained
in Preparation Example 41 and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiochroman-2-yl]-pro-
pionic acid ethyl ester (0.083 g, 0.22 mmol) obtained in
Preparation Example 5 were reacted in the same manner as in Example
17 to obtain the title compound (0.051 g, 62%).
[2861] .sup.1H-NMR (CDCl.sub.3) .delta. 8.08 (1H, m), 7.57 (1H,
dd), 7.34 (1H, dd), 7.28 (1H, m), 7.13 (1H, d), 6.91 (1H, m), 5.26
(1H, m), 3.38 (1H, m), 2.91 (2H, m), 2.62 (2H, m), 2.46 (2H, m),
2.26 (1H, m), 2.13-1.98 (4H, m), 1.85 (2H, m), 1.68 (1H, m)
Example 279:
3-[6-(2-cyclopropylmethoxy-pyridin-3-yl)-thiochroman-2-yl]-propionic
Acid
##STR00322##
[2863] 2-Cyclopropylmethoxy-3-iodo-pyridine (0.065 g, 0.24 mmol)
obtained in Preparation Example 40 and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiochroman-2-yl]-pro-
pionic acid ethyl ester (0.090 g, 0.24 mmol) obtained in
Preparation Example 5 were reacted in the same manner as in Example
17 to obtain the title compound (0.053 g, 59%).
[2864] .sup.1H-NMR (CDCl.sub.3) .delta. 8.08 (1H, dd), 7.58 (1H,
dd), 7.34 (2H, m), 7.13 (1H, d), 6.92 (1H, m), 4.20 (2H, d), 3.38
(1H, m), 2.91 (2H, m), 2.61 (2H, m), 2.29 (1H, m), 2.06 (2H, m),
1.88 (2H, m), 1.28 (1H, m), 0.56 (2H, m), 0.34 (2H, m)
Example 280:
3-[6-(2-cyclopentylsulfanyl-pyridin-3-yl)-chroman-2-yl]-propionic
Acid
##STR00323##
[2866] 2-Cyclopentylsulfanyl-3-iodo-pyridine (0.068 g, 0.22 mmol)
obtained in Preparation Example 15 and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-chroman-2-yl]-propion-
ic acid ethyl ester (0.079 g, 0.22 mmol) obtained in Preparation
Example 4 were reacted in the same manner as in Example 17 to
obtain the title compound (0.057 g, 67%).
[2867] .sup.1H-NMR (CDCl.sub.3) .delta. 8.39 (1H, dd), 7.33 (1H,
dd), 7.15 (1H, dd), 7.09 (1H, s), 7.00 (1H, m), 6.84 (1H, d), 4.08
(2H, m), 2.93 (1H, m), 2.75 (1H, m), 2.66 (2H, m), 2.19 (2H, m),
2.03 (3H, m), 1.85-1.52 (7H, m)
Example 281:
3-[6-(2-cyclopentylsulfanyl-pyridin-3-yl)-thiochroman-2-yl]-propionic
Acid
##STR00324##
[2869] 2-Cyclopentylsulfanyl-3-iodo-pyridine (0.072 g, 0.23 mmol)
obtained in Preparation Example 15 and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiochroman-2-yl]-pro-
pionic acid ethyl ester (0.087 g, 0.23 mmol) obtained in
Preparation Example 5 were reacted in the same manner as in Example
17 to obtain the title compound (0.074 g, 80%).
[2870] .sup.1H-NMR (CDCl.sub.3) .delta. 8.40 (1H, dd), 7.32 (1H,
dd), 7.14 (2H, m), 7.09 (1H, m), 7.00 (1H, m), 4.07 (1H, m), 3.38
(1H, m), 2.89 (2H, m), 2.59 (2H, m), 2.20 (3H, m), 2.03 (2H, m),
1.85 (2H, m), 1.75-1.49 (5H, m)
Example 282:
3-[6-(5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-thiochroman-2-yl-
]-propionic Acid
##STR00325##
[2872] 7-Bromo-5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran (0.063
g, 0.24 mmol) obtained in Preparation Example 210 and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiochroman-2-yl]-pro-
pionic acid ethyl ester (0.090 g, 0.24 mmol) obtained in
Preparation Example 5 were reacted in the same manner as in Example
17 to obtain the title compound (0.076 g, 78%).
[2873] .sup.1H-NMR (CDCl.sub.3) .delta. 7.41 (1H, dd), 7.33 (1H,
s), 7.20 (1H, s), 7.11 (1H, d), 7.02 (1H, s), 3.36 (1H, m), 3.01
(2H, s), 2.90 (2H, m), 2.59 (2H, m), 2.26 (1H, m), 2.02 (2H, m),
1.85 (1H, m), 1.48 (6H, s)
Example 283:
3-(6-spiro[3H-benzofuran-2,1'-cyclopentan]-7-yl-thiochroman-2-yl)-propion-
ic Acid
##STR00326##
[2875] 7-Bromospiro[3H-benzofuran-2,1'-cyclopentane] (0.058 g, 0.23
mmol) obtained in Preparation Example 212 and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiochroman-2-yl]-pro-
pionic acid ethyl ester (0.090 g, 0.23 mmol) obtained in
Preparation Example 5 were reacted in the same manner as in Example
17 to obtain the title compound (0.047 g, 52%).
[2876] .sup.1H-NMR (CDCl.sub.3) .delta. 7.46 (1H, dd), 7.23 (1H,
m), 7.11 (1H, d), 7.08 (1H, dd), 6.86 (1H, m), 3.36 (1H, m), 3.19
(2H, s), 2.90 (2H, m), 2.59 (2H, m), 2.26 (1H, m), 2.11 (3H, m),
1.97 (1H, m), 1.87 (3H, m), 1.73 (4H, m)
Example 284:
3-{6-[2-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-thiochroman-2-yl}-propio-
nic Acid
##STR00327##
[2878] 3-Iodo-2-(tetrahydro-pyran-4-yloxy)-pyridine (0.080 g, 0.26
mmol) obtained in Preparation Example 50 and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiochroman-2-yl]-pro-
pionic acid ethyl ester (0.098 g, 0.26 mmol) obtained in
Preparation Example 5 were reacted in the same manner as in Example
17 to obtain the title compound (0.090 g, 86%).
[2879] .sup.1H-NMR (CDCl.sub.3) .delta. 8.08 (1H, dd), 7.59 (1H,
dd), 7.30 (2H, m), 7.13 (1H, d), 6.92 (1H, m), 5.35 (1H, m), 3.91
(2H, m), 3.63 (2H, m), 3.38 (1H, m), 2.90 (2H, m), 2.58 (2H, m),
2.28 (1H, m), 2.04 (4H, m), 1.82 (3H, m)
Example 285:
{1-[2,6-difluoro-4-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-p-
henyl]-azetidin-3-yl}-acetic Acid
##STR00328##
[2881] 4-Bromo-7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran (0.083
g, 0.32 mmol) obtained in Preparation Example 211 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
azetidin-3-yl]acetic acid ethyl ester (0.121 g, 0.32 mmol) obtained
in Preparation Example 88 were reacted in the same manner as in
Example 17 to obtain the title compound (0.047 g, 36%).
[2882] .sup.1H-NMR (CDCl.sub.3) .delta. 6.82 (2H, m), 6.78 (2H, s),
4.39 (2H, m), 3.89 (2H, m), 3.88 (3H, s), 3.11 (2H, s), 3.03 (1H,
m), 2.78 (2H, d), 1.51 (6H, s)
Example 286:
3-[6-(6-isopropylsulfanyl-pyridin-2-yl)-thiochroman-2-yl]-propionic
Acid
##STR00329##
[2884] 2-Chloro-6-isopropylsulfanyl-pyridine (0.028 g, 0.15 mmol)
obtained in Preparation Example 10,
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiochroman-2-yl]-pro-
pionic acid ethyl ester (0.057 g, 0.15 mmol) obtained in
Preparation Example 5 and Pd(PPh.sub.3).sub.4 were reacted in the
same manner as in Example 17 to obtain the title compound (0.010 g,
18%).
[2885] .sup.1H-NMR (CDCl.sub.3) .delta. 7.72 (2H, m), 7.48 (1H, m),
7.34 (1H, d), 7.15 (1H, d), 7.03 (1H, d), 4.13 (1H, m), 3.39 (1H,
m), 2.96 (2H, m), 2.62 (2H, m), 2.28 (1H, m), 2.05 (2H, m), 1.86
(1H, m), 1.45 (6H, d)
Example 287:
4-(2,6-difluoro-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-phenoxy)bu-
tanoic Acid
##STR00330##
[2886] Step A: ethyl
4-(2,6-difluoro-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-phenoxy)bu-
tanoate
[2887] 4-Iodospiro[1,3-benzodioxol-2,1'-cyclopentane] (25 mg, 0.083
mmol) obtained in Step C of Preparation Example 215 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (30.6 mg, 0.083 mmol) were dissolved in 0.2
mL of 2 M sodium carbonate and 2 mL of 1,4-dioxane, and charged
with nitrogen for 5 minutes. PdCl.sub.2(dppf) (3.4 mg, 0.004 mmol)
was added thereto, and the mixture was stirred for 1 hour under
reflux. The reaction solution was cooled to room temperature. After
addition of water, the reaction solution was extracted with EtOAc
to separate an organic layer. The organic layer was dried with
anhydrous magnesium sulfate and purified by column chromatography
(eluent, EtOAc/Hex=1/4) to obtain the title compound (9 mg, 26%
yield).
[2888] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.32-7.24 (m, 2H),
6.93-6.90 (m, 1H), 6.84 (dd, 1H), 6.74-6.70 (m, 1H), 4.20 (t, 2H),
4.15 (q, 2H), 2.58 (t, 2H), 2.17-2.11 (m, 4H), 2.10-2.05 (m, 2H),
1.90-1.81 (m, 4H), 1.26 (t, 3H)
Step B:
4-(2,6-difluoro-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-phe-
noxy)butanoic Acid
[2889] Ethyl
4-(2,6-difluoro-4-spiro[1,3-benzodioxol-2,1'-cyclopentane]-4-yl-phenoxy)b-
utanoate (9 mg, 0.022 mmol) obtained in Step A was dissolved in
THF/MeOH/H.sub.2O (2:2:1, 1 mL). LiOH (5.15 mg, 0.22 mmol) was
added thereto, and the mixture was stirred at room temperature for
4 hours. After termination of the reaction, the reaction solution
was concentrated under reduced pressure, adjusted to pH 3 by the
use of 1N HCl aqueous solution and extracted with EtOAc. The
organic layer was dried with anhydrous magnesium sulfate and
concentrated under reduced pressure to obtain the title compound
(8.3 mg, 95% yield).
[2890] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.32-7.24 (m, 2H),
6.93-6.90 (m, 1H), 6.84 (dd, 1H), 6.74-6.70 (m, 1H), 4.21 (t, 2H),
2.67 (t, 2H), 2.18-2.05 (m, 6H), 1.90-1.81 (m, 4H)
Example 288:
4-(4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-ylphenoxy)butanoic
Acid
##STR00331##
[2891] Step A:
4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-ylphenol
[2892] 4-Iodospiro[1,3-benzodioxol-2,1'-cyclopentane] (50 mg, 0.166
mmol) obtained in Step C of Preparation Example 215,
4-hydroxyphenylboronic acid (23 mg, 0.166 mmol) and K.sub.2CO.sub.3
(46 mg, 0.33 mmol) were dissolved in 1,4-dioxane/H.sub.2O (4:1, 2
mL), and charged with nitrogen gas for 5 minutes.
Pd(PPh.sub.3).sub.4 (9.6 mg, 0.0083 mmol) was added thereto, and
the mixture was stirred for 1 hour under reflux. After termination
of the reaction, the reaction solution was diluted with water and
extracted with EtOAc to separate an organic layer. The organic
layer was concentrated under reduced pressure and purified by
column chromatography (eluent, EtOAc/Hex=1/2) to obtain the title
compound (41 mg, 92% yield).
[2893] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.61 (d, 2H), 6.95
(d, 1H), 6.88 (d, 2H), 6.83 (dd, 1H), 6.68 (d, 1H), 2.17-2.08 (m,
4H), 1.88-1.80 (m, 4H)
Step B: ethyl
4-(4-spiro[1,3-benzodioxol-2,1'-cyclopentan]4-ylphenoxy)butanoate
[2894] 4-Spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-ylphenol (41 mg,
0.153 mmol) obtained in Step A was dissolved in AN (5 mL), and
Cs.sub.2CO.sub.3 (124 mg, 0.38 mmol) was added thereto.
4-Bromo-butyric acid ethyl ester (26 .mu.L, 0.18 mmol) was added
thereto, and the mixture was stirred for 1 hour under reflux. The
reaction solution was cooled to room temperature. The reaction
solution was concentrated under reduced pressure and purified by
column chromatography (eluent, EtOAc/Hex=1/10) to obtain the title
compound (28 mg, 48% yield).
[2895] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.65 (d, 2H),
6.98-6.92 (m, 3H), 6.83 (dd, 1H), 6.68 (d, 1H), 4.15 (q, 2H), 4.04
(t, 2H), 2.53 (t, 2H), 2.16-2.08 (m, 6H), 1.88-1.80 (m, 4H), 1.26
(t, 3H)
Step C:
4-(4-spiro[1,3-benzodioxol-2,1'-cyclopentan]4-ylphenoxy)butanoic
Acid
[2896] Ethyl
4-(4-spiro[1,3-benzodioxol-2,1'-cyclopentan]4-ylphenoxy)butanoate
(28 mg, 0.073 mmol) obtained in Step B was reacted in the same
manner as in Step B of Example 287 to obtain the title compound (25
mg, 96% yield).
[2897] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.65 (d, 2H),
6.98-6.92 (m, 3H), 6.83 (dd, 1H), 6.68 (d, 1H), 4.04 (t, 2H), 2.62
(t, 2H), 2.17-2.09 (m, 6H), 1.88-1.80 (m, 4H)
Example 289:
4-(2-fluoro-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-phenoxy)butano-
ic Acid
##STR00332##
[2898] Step A: ethyl
4-(2-fluoro-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-phenoxy)butano-
ate
[2899]
2-Fluoro-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-phenol (28
mg, 0.098 mmol) was reacted in the same manner as in Step B of
Example 288 to obtain the title compound (37 mg, 94% yield).
[2900] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.50 (dd, 1H),
7.44-7.40 (m, 1H), 7.00 (dd, 1H), 6.95 (d, 1H), 6.83 (dd, 1H), 6.70
(d, 1H), 4.18-4.09 (m, 4H), 2.55 (t, 2H), 2.19-2.09 (m, 6H),
1.89-1.80 (m, 4H), 1.26 (t, 3H)
Step B:
4-(2-fluoro-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-phenoxy-
)butanoic Acid
[2901] Ethyl
4-(2-fluoro-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-phenoxy)butano-
ate (28 mg, 0.073 mmol) obtained in Step A was reacted in the same
manner as in Step B of Example 287 to obtain the title compound (25
mg, 96% yield).
[2902] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.50 (dd, 1H),
7.44-7.40 (m, 1H), 7.00 (dd, 1H), 6.95 (d, 1H), 6.83 (dd, 1H), 6.70
(d, 1H), 4.12 (t, 2H), 2.64 (t, 2H), 2.19-2.09 (m, 6H), 1.89-1.80
(m, 4H)
Example 290:
4-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenoxy]-butyric
Acid
##STR00333##
[2903] Step A:
4-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenoxy]-butyric
Acid Ethyl Ester
[2904] 4-Bromo-2,2-difluoro-benzo[1,3]dioxole (50 mg, 0.21 mmol),
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (78 mg, 0.21 mmol) obtained in Preparation
Example 16 and NaOH (25 mg, 0.63 mmol) were dissolved in
1,4-dioxane/H.sub.2O (4:1, 5 mL), and charged with nitrogen for 5
minutes. Pd(PPh.sub.3).sub.4 (12 mg, 0.0105 mmol) was added
thereto, and the mixture was stirred for 1 hour under reflux. After
termination of the reaction, the reaction solution was diluted with
water and extracted with EtOAc to separate an organic layer. The
organic layer was concentrated under reduced pressure and purified
by column chromatography (eluent, EtOAc/Hex=1/3) to obtain the
title compound (20 mg, 24% yield).
[2905] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.29-7.22 (m, 2H),
7.21-7.17 (m, 1H), 7.14 (dd, 1H), 7.07-7.03 (m, 1H), 4.23 (t, 2H),
4.15 (q, 2H), 2.58 (t, 2H), 2.15-2.06 (m, 2H), 1.26 (t, 3H)
Step B:
4-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenoxy]-bu-
tyric Acid
[2906]
4-[4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenoxy]-but-
yric acid ethyl ester (20 mg, 0.045 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 287 to obtain
the title compound (16 mg, 86% yield).
[2907] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.29-7.23 (m, 2H),
7.21-7.17 (m, 1H), 7.14 (dd, 1H), 7.06-7.03 (dd, 1H), 4.25 (t, 2H),
2.67 (t, 2H), 2.16-2.07 (m, 2H)
Example 291:
4-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-2,6-difluoro-phenoxy]-but-
yric Acid
##STR00334##
[2908] Step A:
4-(2'-bromo-3,5-difluoro-3'-hydroxy-biphenyl-4-yloxy)-butyric Acid
Ethyl Ester
[2909] 2-Bromo-3-iodophenol (100 mg, 0.335 mmol) obtained in Step C
of Preparation Example 216 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (124 mg, 0.335 mmol) obtained in Preparation
Example 16 were dissolved in 0.4 mL of 2 M sodium carbonate and 4
mL of 1,4-dioxane, and charged with nitrogen gas for 5 minutes.
PdCl.sub.2(dppf) (14 mg, 0.0168 mmol) was added thereto, and the
mixture was stirred for 1 hour under reflux. The reaction solution
was cooled to room temperature. After addition of water, the
reaction solution was extracted with EtOAc to separate an organic
layer. The organic layer was dried with anhydrous magnesium sulfate
and purified by column chromatography (eluent, EtOAc/Hex=1/4) to
obtain the title compound (70 mg, 50% yield).
[2910] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.24 (dd, 1H),
7.03 (d, 1H), 6.97-6.88 (m, 2H), 6.83 (d, 1H), 5.85 (s, 1H), 4.23
(t, 2H), 4.15 (q, 2H), 2.59 (t, 2H), 2.15-2.07 (m, 2H), 1.27 (t,
3H)
Step B:
4-[3,5-difluoro-3'-hydroxy-2'-(2-methyl-propenyl)-biphenyl-4-yloxy-
]-butyric Acid Ethyl Ester
[2911]
4-(2'-Bromo-3,5-difluoro-3'-hydroxy-biphenyl-4-yloxy)-butyric acid
ethyl ester (70 mg, 0.169 mmol) obtained in Step A and
4,4,5,5-tetramethyl-2-(2-methyl-propenyl)-[1,3,2]dioxaborolan (93
mg, 0.507 mmol) were dissolved in 0.4 mL of 2 M sodium carbonate
and 4 mL of 1,4-dioxane, and charged with nitrogen for 5 minutes.
PdCl.sub.2(dppf) (7 mg, 0.0085 mmol) was added thereto, and the
mixture was stirred for 12 hours under reflux. The reaction
solution was cooled to room temperature. After addition of water
and EtOAc, the reaction solution was stirred for 30 minutes and
filtered through Celite. Separation of the layers was carried out
to separate an organic layer. The organic layer was dried with
anhydrous magnesium sulfate and purified by column chromatography
(eluent, EtOAc/Hex=1/3) to obtain the title compound (17 mg, 26%
yield).
[2912] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.21 (dd, 1H),
6.94 (d, 1H), 6.86-6.78 (m, 3H), 5.83 (s, 1H), 5.36 (s, 1H), 4.19
(t, 2H), 4.15 (q, 2H), 2.58 (t, 2H), 2.13-2.06 (m, 2H), 1.87 (s,
3H), 1.57 (s, 3H), 1.26 (t, 3H)
Step C:
4-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-2,6-difluoro-pheno-
xy]-butyric Acid Ethyl Ester
[2913]
4-[3,5-Difluoro-3'-hydroxy-2'-(2-methyl-propenyl)-biphenyl-4-yloxy]-
-butyric acid ethyl ester (17 mg, 0.044 mmol) obtained in Step B
was dissolved in toluene (2 mL). Amberlyst 15 resin (17 mg) was
added thereto, and the mixture was stirred for 4 hours under
reflux. The reaction solution was cooled to room temperature,
filtered, concentrated under reduced pressure and purified by
column chromatography (eluent, EtOAc/Hex=1/4) to obtain the title
compound (9 mg, 53% yield).
[2914] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.17 (dd, 1H),
7.01-6.93 (m, 2H), 6.82 (d, 1H), 6.74 (d, 1H), 4.20 (t, 2H), 4.15
(q, 2H), 3.08 (s, 2H), 2.58 (t, 2H), 2.13-2.06 (m, 2H), 1.48 (s,
6H), 1.27 (t, 3H)
Step D:
4-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-2,6-difluoro-pheno-
xy]-butyric Acid
[2915]
4-[4-(2,2-Dimethyl-2,3-dihydro-benzofuran-4-yl)-2,6-difluoro-phenox-
y]-butyric acid ethyl ester (9 mg, 0.023 mmol) obtained in Step C
was reacted in the same manner as in Step B of Example 287 to
obtain the title compound (8.2 mg, 98% yield).
[2916] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.17 (dd, 1H),
7.01-6.94 (m, 2H), 6.82 (d, 1H), 6.74 (d, 1H), 4.22 (t, 2H), 3.08
(s, 2H), 2.67 (t, 2H), 2.15-2.07 (m, 2H), 1.48 (s, 6H)
Example 292:
4-[4-(2-cyclohexylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric
Acid
##STR00335##
[2917] Step A:
4-[4-(2-cyclohexylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric
Acid Ethyl Ester
[2918] 4-[2,6-Difluoro-4-(2-fluoro-pyridin-3-yl)-phenoxy]-butyric
acid ethyl ester (50 mg, 0.147 mmol), Cs.sub.2CO.sub.3 (192 mg,
0.588 mmol) and cyclohexanethiol (36 .mu.L, 0.294 mmol)-were
reacted in the same manner as in Step B of Example 288 to obtain
the title compound (5 mg, 8% yield).
[2919] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.42 (d, 1H), 7.32
(d, 1H), 7.03-6.93 (m, 3H), 4.23 (t, 2H), 4.16 (q, 2H), 3.95-3.86
(m, 1H), 2.59 (t, 2H), 2.14-2.07 (m, 2H), 2.07-2.01 (m, 2H),
1.78-1.69 (m, 2H), 1.66-1.57 (m, 1H), 1.49-1.36 (m, 4H), 1.35-1.23
(m, 1H), 1.27 (t, 3H)
Step B:
4-[4-(2-cyclohexylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-but-
yric Acid
[2920]
4-[4-(2-Cyclohexylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-buty-
ric acid ethyl ester (5 mg, 0.0115 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 287 to obtain
the title compound (4.2 mg, 90% yield).
[2921] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.84 (d, 1H), 7.67
(d, 1H), 7.51-7.45 (m, 1H), 7.02-6.93 (m, 2H), 4.29 (t, 2H),
3.32-3.23 (m, 1H), 2.65 (t, 2H), 2.17-1.98 (m, 4H), 1.90-1.81 (m,
1H), 1.68-1.23 (m, 7H)
Example 293:
3-[4-(2-cyclopentyloxy-pyridin-3-yl)-benzylsulfanyl]-propionic
Acid
##STR00336##
[2922] Step A:
[4-(2-cyclopentyloxy-pyridin-3-yl)-phenyl]-methanol
[2923] 2-Cyclopentyloxy-3-iodo-pyridine (100 mg, 0.346 mmol),
[4-(hydroxymethyl)-phenyl]boronic acid (52.6 mg, 0.346 mmol) and
K.sub.2CO.sub.3 (96 mg, 0.692 mmol) were dissolved in
1,4-dioxane/H.sub.2O (4:1, 4 mL), and charged with nitrogen for 5
minutes. Pd(PPh.sub.3).sub.4 (20 mg, 0.0173 mmol) was added
thereto, and the mixture was stirred for 1 hour under reflux. After
termination of the reaction, the reaction solution was diluted with
water and extracted with EtOAc to separate an organic layer. The
organic layer was concentrated under reduced pressure and purified
by column chromatography (eluent, EtOAc/Hex=1/4) to obtain the
title compound (88 mg, 94% yield).
[2924] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.12 (dd, 1H),
7.58 (dd, 1H), 7.54 (d, 2H), 7.39 (d, 2H), 6.90 (dd, 1H), 5.53-5.47
(m, 1H), 4.72 (s, 2H), 2.09 (s, 1H), 1.98-1.88 (m, 2H), 1.85-1.76
(m, 2H), 1.76-1.67 (m, 2H), 1.65-1.55 (m, 2H)
Step B: 3-(4-bromomethyl-phenyl)-2-cyclopentyloxy-pyridin
[2925] [4-(2-Cyclopentyloxy-pyridin-3-yl)-phenyl]-methanol (70 mg,
0.26 mmol) was dissolved in DCM. NBS (69 mg, 0.39 mmol) and
triphenylphosphine (102 mg, 0.39 mmol) were added thereto, and the
mixture was stirred at room temperature for 2 hours. After
termination of the reaction, the reaction solution was diluted with
water and extracted with DCM to separate an organic layer. The
organic layer was concentrated under reduced pressure and purified
by column chromatography (eluent, EtOAc/Hex=1/10) to obtain the
title compound (80 mg, 93% yield).
[2926] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.14 (dd, 1H),
7.59 (dd, 1H), 7.54 (d, 2H), 7.42 (d, 2H), 6.91 (dd, 1H), 5.55-5.50
(m, 1H), 4.54 (s, 2H), 2.00-1.90 (m, 2H), 1.85-1.77 (m, 2H),
1.76-1.68 (m, 2H), 1.67-1.57 (m, 2H)
Step C:
3-[4-(2-cyclopentyloxy-pyridin-3-yl)-benzylsulfanyl]-propionic
Acid
[2927] EtOH (2 mL) and NaOH (19 mg, 0.48 mmol) were added to
3-mercapto-propionic acid (21 .mu.L, 0.24 mmol), and the mixture
was stirred at room temperature for 15 minutes.
3-(4-Bromomethyl-phenyl)-2-cyclopentyloxy-pyridine (80 mg, 0.24
mmol) obtained in Step B was dissolved in EtOH (2 mL) and THF (0.5
mL), and slowly added dropwise to the above solution. The mixture
was stirred at room temperature for 3 hours. The reaction solution
was adjusted to pH 3 by the use of 1N HCl aqueous solution and
extracted with EtOAc. The organic layer was dried with anhydrous
magnesium sulfate and concentrated under reduced pressure to obtain
the title compound (83 mg, 97% yield).
[2928] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.14 (dd, 1H),
7.60 (dd, 1H), 7.50 (d, 2H), 7.34 (d, 2H), 6.92 (dd, 1H), 5.53-5.46
(m, 1H), 3.78 (s, 2H), 2.72 (t, 2H), 2.62 (t, 2H), 1.98-1.88 (m,
2H), 1.84-1.75 (m, 2H), 1.75-1.65 (m, 2H), 1.65-1.55 (m, 2H)
Example 294:
2-[1-[4-[6-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperidyl]acet-
ic Acid
##STR00337##
[2930] 2-Chloro-6-cyclobutoxy-pyridine (0.062 g, 0.33 mmol)
obtained in Preparation Example 29 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid methyl ester (0.147 g, 0.37 mmol) obtained
in Preparation Example 84 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.058 g, 44%).
[2931] .sup.1H-NMR (CDCl.sub.3) .delta. 7.57 (1H, t), 7.49 (2H, m),
7.20 (1H, d), 6.62 (1H, d), 5.26 (1H, m), 3.32 (2H, m), 3.16 (2H,
m), 2.52 (2H, m), 2.36 (2H, d), 2.19 (2H, m), 1.98 (1H, m), 1.84
(3H, m), 1.75 (1H, m), 1.48 (2H, m)
Example 295:
2-[1-[2,6-difluoro-4-(6-propoxy-2-pyridyl)phenyl]-4-piperidyl]acetic
Acid
##STR00338##
[2933] 2-Chloro-6-propoxy-pyridine (0.057 g, 0.33 mmol) and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.097 g, 75%).
[2934] .sup.1H-NMR (CDCl.sub.3) .delta. 7.60 (1H, t), 7.50 (2H, m),
7.19 (1H, d), 6.66 (1H, d), 4.35 (2H, t), 3.31 (2H, m), 3.15 (2H,
m), 2.36 (2H, d), 1.98 (1H, m), 1.83 (4H, m), 1.49 (2H, m), 1.05
(3H, t)
Example 296:
2-[1-[2,6-difluoro-4-(6-isopropoxy-2-pyridyl)phenyl]-4-piperidyl]acetic
Acid
##STR00339##
[2936] 2-Chloro-6-isopropoxy-pyridine (0.057 g, 0.33 mmol) obtained
in Preparation Example 46 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.097 g, 75%).
[2937] .sup.1H-NMR (CDCl.sub.3) .delta. 7.58 (1H, t), 7.49 (2H, m),
7.16 (1H, d), 6.61 (1H, d), 5.44 (1H, m), 3.31 (2H, m), 3.14 (2H,
m), 2.36 (2H, d), 1.98 (1H, m), 1.82 (2H, m), 1.50 (2H, m), 1.39
(6H, d)
Example 297:
2-[1-[4-(6-cyclobutylsulfanyl-2-pyridyl)-2,6-difluoro-phenyl]-4-piperidyl-
]acetic Acid
##STR00340##
[2939] 2-Chloro-6-cyclobutylsulfanyl-pyridine (0.066 g, 0.33 mmol)
and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.036 g, 26%).
[2940] .sup.1H-NMR (CDCl.sub.3) .delta. 7.52 (3H, m), 7.29 (1H, d),
7.01 (1H, d), 4.42 (1H, m), 3.34 (2H, m), 3.18 (2H, m), 2.60 (2H,
m), 2.37 (2H, d), 2.15 (4H, m), 1.99 (1H, m), 1.82 (2H, m), 1.50
(2H, m)
Example 298:
2-[1-[2,6-difluoro-4-(6-propylsulfanyl-2-pyridyl)phenyl]-4-piperidyl]acet-
ic Acid
##STR00341##
[2942] 2-Chloro-6-propylsulfanyl-pyridine (0.077 g, 0.33 mmol) and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.032 g, 24%).
[2943] .sup.1H-NMR (CDCl.sub.3) .delta. 7.51 (3H, m), 7.29 (1H, d),
7.09 (1H, d), 3.33 (2H, m), 3.23 (2H, t), 3.15 (2H, m), 2.37 (2H,
d), 1.99 (1H, m), 1.82 (4H, m), 1.50 (2H, m), 1.08 (3H, t)
Example 299:
2-[1-[4-[6-(cyclopentoxy)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperidyl]ace-
tic Acid
##STR00342##
[2945] 2-Chloro-6-cyclopentyloxy-pyridine (0.066 g, 0.33 mmol)
obtained in Preparation Example 12 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.099 g, 72%).
[2946] .sup.1H-NMR (CDCl.sub.3) .delta. 7.57 (1H, t), 7.51 (2H, m),
7.17 (1H, d), 6.61 (1H, d), 5.51 (1H, m), 3.32 (2H, m), 3.15 (2H,
m), 2.37 (2H, d), 2.05 (3H, m), 1.84 (6H, m), 1.65 (2H, m), 1.49
(2H, m)
Example 300:
2-[1-[4-[3-(cyclobutoxy)phenyl]-2,6-difluoro-phenyl]-4-piperidyl]acetic
Acid
##STR00343##
[2947] Step A:
2-[1-[4-[3-(cyclobutoxy)phenyl]-2,6-difluoro-phenyl]-4-piperidyl]acetic
Acid Ethyl Ester
[2948]
2-[1-[2,6-Difluoro-4-(3-hydroxyphenyl)phenyl]-4-piperidyl]acetic
acid ethyl ester (0.095 g, 0.25 mmol) obtained in Preparation
Example 223 was dissolved in 0.85 mL of DMF. K.sub.2CO.sub.3 (0.07
g, 0.5 mmol) and bromocyclobutane (0.037 g, 0.27 mmol) were added
thereto, and the mixture was stirred at 60.degree. C. for 16 hours.
The reaction solution was concentrated under reduced pressure.
Solids were filtered, and the filtrate was purified by column
chromatography to obtain the title compound (0.049 g, 44%).
[2949] .sup.1H-NMR (CDCl.sub.3) .delta. 7.30 (1H, t), 7.05 (3H, m),
6.94 (1H, m), 6.79 (1H, m), 4.68 (1H, m), 4.15 (2H, q), 3.27 (2H,
m), 3.13 (2H, m), 2.45 (2H, m), 2.29 (2H, d), 2.19 (2H, m), 1.96
(1H, m), 1.88 (1H, m), 1.77 (2H, m), 1.70 (1H, m), 1.45 (2H, m),
1.27 (3H, t)
Step B:
2-[1-[4-[3-(cyclobutoxy)phenyl]-2,6-difluoro-phenyl]-4-piperidyl]a-
cetic Acid
[2950]
2-[1-[4-[3-(Cyclobutoxy)phenyl]-2,6-difluoro-phenyl]-4-piperidyl]ac-
etic acid ethyl ester (0.049 g, 0.11 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.033 g, 75%).
[2951] .sup.1H-NMR (CDCl.sub.3) .delta. 7.30 (1H, t), 7.05 (3H, m),
6.94 (1H, m), 6.78 (1H, m), 4.68 (1H, m), 3.27 (2H, m), 3.14 (2H,
m), 2.47 (2H, m), 2.35 (2H, d), 2.19 (2H, m), 1.96 (1H, m), 1.86
(1H, m), 1.82 (2H, m), 1.71 (1H, m), 1.49 (2H, m)
Example 301:
2-[1-[4-[3-(cyclopropylmethoxy)phenyl]-2,6-difluoro-phenyl]-4-piperidyl]a-
cetic Acid
##STR00344##
[2952] Step A:
2-[1-[4-[3-(cyclopropylmethoxy)phenyl]-2,6-difluoro-phenyl]-4-piperidyl]a-
cetic Acid Ethyl Ester
[2953]
2-[1-[2,6-Difluoro-4-(3-hydroxyphenyl)phenyl]-4-piperidyl]acetic
acid ethyl ester (0.095 g, 0.25 mmol) obtained in Preparation
Example 223 was dissolved in 0.85 mL of DMF. K.sub.2CO.sub.3 (0.07
g, 0.5 mmol) and bromomethylcyclopropane (0.037 g, 0.27 mmol) were
added thereto, and the mixture was stirred at 60.degree. C. for 16
hours. The reaction solution was concentrated under reduced
pressure. Solids were filtered, and the filtrate was purified by
column chromatography to obtain the title compound (0.059 g,
55%).
[2954] .sup.1H-NMR (CDCl.sub.3) .delta. 7.31 (1H, t), 7.05 (4H, m),
6.88 (1H, m), 4.15 (2H, q), 3.85 (2H, d), 3.27 (2H, m), 3.13 (2H,
m), 2.29 (2H, d), 1.96 (1H, m), 1.77 (2H, m), 1.45 (2H, m), 1.27
(4H, m), 0.67 (2H, m), 0.37 (2H, m)
Step B:
2-[1-[4-[3-(cyclopropylmethoxy)phenyl]-2,6-difluoro-phenyl]-4-pipe-
ridyl]acetic Acid
[2955]
2-[1-[4-[3-(Cyclopropylmethoxy)phenyl]-2,6-difluoro-phenyl]-4-piper-
idyl]acetic acid ethyl ester (0.059 g, 0.14 mmol) obtained in Step
A was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.055 g, 99%).
[2956] .sup.1H-NMR (CDCl.sub.3) .delta. 7.31 (1H, t), 7.05 (4H, m),
6.88 (1H, m), 3.85 (2H, d), 3.28 (2H, m), 3.14 (2H, m), 2.36 (2H,
d), 1.97 (1H, m), 1.82 (2H, m), 1.50 (2H, m), 1.29 (1H, m), 0.67
(2H, m), 0.36 (2H, m)
Example 302:
2-[1-[2,6-difluoro-4-[3-(isopropoxymethyl)phenyl]phenyl]-4-piperidyl]acet-
ic Acid
##STR00345##
[2958] 1-Bromo-3-(isopropoxymethyl)benzene (0.076 g, 0.33 mmol)
obtained in Preparation Example 286 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.09 g, 68%).
[2959] .sup.1H-NMR (CDCl.sub.3) .delta. 7.49 (1H, m), 7.41 (2H, m),
7.33 (1H, m), 7.08 (2H, m), 4.55 (2H, s), 3.72 (1H, m), 3.28 (2H,
m), 3.14 (2H, m), 2.36 (2H, d), 1.97 (1H, m), 1.82 (2H, m), 1.49
(2H, m), 1.23 (6H, d)
Example 303:
2-[1-[4-[3-(ethoxymethyl)phenyl]-2,6-difluoro-phenyl]-4-piperidyl]acetic
Acid
##STR00346##
[2961] 1-Bromo-3-(ethoxymethyl)benzene (0.072 g, 0.33 mmol)
obtained in Preparation Example 287 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.07 g, 54%).
[2962] .sup.1H-NMR (CDCl.sub.3) .delta. 7.49 (1H, m), 7.41 (2H, m),
7.32 (1H, m), 7.08 (2H, m), 4.55 (2H, s), 3.58 (2H, q), 3.28 (2H,
m), 3.15 (2H, m), 2.37 (2H, d), 1.97 (1H, m), 1.83 (2H, m), 1.50
(2H, m), 1.27 (3H, t)
Example 304:
2-[1-[4-[3-(cyclobutoxy)-4-fluoro-phenyl]-2,6-difluoro-phenyl]-4-piperidy-
l]acetic Acid
##STR00347##
[2963] Step A:
2-[1-[2,6-difluoro-4-(4-fluoro-3-hydroxy-phenyl)phenyl]-4-piperidyl]aceti-
c Acid Ethyl Ester
[2964] 5-Bromo-2-fluoro-phenol (0.127 g, 0.66 mmol) and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.30 g, 0.73 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 to obtain the title compound (0.19 g,
73%).
[2965] .sup.1H-NMR (CDCl.sub.3) .delta. 7.12 (2H, m), 6.99 (3H, m),
5.22 (1H, brs), 4.14 (2H, q), 3.26 (2H, m), 3.13 (2H, m), 2.30 (2H,
d), 1.96 (1H, m), 1.77 (2H, m), 1.45 (2H, m), 1.27 (3H, t)
Step B:
2-[1-[4-[3-(cyclobutoxy)-4-fluoro-phenyl]-2,6-difluoro-phenyl]-4-p-
iperidyl]acetic Acid Ethyl Ester
[2966] 1 mL of DMF, bromocyclobutane (0.032 g, 0.23 mmol) and
Cs.sub.2CO.sub.3 (0.136 g, 0.42 mmol) were added to
2-[1-[2,6-difluoro-4-(4-fluoro-3-hydroxy-phenyl)phenyl]-4-piperidyl]aceti-
c acid ethyl ester (0.084 g, 0.21 mmol) obtained in Step A, and the
mixture was stirred at 50.degree. C. for 16 hours. Solids were
filtered, and the filtrate was purified by column chromatography to
obtain the title compound (0.068 g, 72%).
[2967] .sup.1H-NMR (CDCl.sub.3) .delta. 7.10 (1H, m), 6.98 (3H, m),
6.92 (1H, m), 4.73 (1H, m), 4.14 (2H, q), 3.26 (2H, m), 3.13 (2H,
m), 2.48 (2H, m), 2.39 (4H, m), 1.97 (1H, m), 1.88 (1H, m), 1.77
(2H, m), 1.70 (1H, m), 1.45 (2H, m), 1.26 (3H, t)
Step C:
2-[1-[4-[3-(cyclobutoxy)-4-fluoro-phenyl]-2,6-difluoro-phenyl]-4-p-
iperidyl]acetic Acid
[2968]
2-[1-[4-[3-(Cyclobutoxy)-4-fluoro-phenyl]-2,6-difluoro-phenyl]-4-pi-
peridyl]acetic acid ethyl ester (0.068 g, 0.15 mmol) obtained in
Step B was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.03 g, 71%).
[2969] .sup.1H-NMR (CDCl.sub.3) .delta. 7.10 (1H, m), 6.98 (3H, m),
6.92 (1H, m), 4.73 (1H, m), 3.27 (2H, m), 3.14 (2H, m), 2.47 (2H,
m), 2.36 (2H, d), 2.26 (2H, m), 1.97 (1H, m), 1.89 (1H, m), 1.82
(2H, m), 1.70 (1H, m), 1.50 (2H, m)
Example 305:
2-[1-[4-[3-(cyclobutoxy)-4-methoxy-phenyl]-2,6-difluoro-phenyl]-4-piperid-
yl]acetic Acid
##STR00348##
[2970] Step A:
2-[1-[2,6-difluoro-4-(3-hydroxy-4-methoxy-phenyl)phenyl]-4-piperidyl]acet-
ic Acid Ethyl Ester
[2971] 5-Bromo-2-methoxy-phenol (0.135 g, 0.66 mmol) and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.30 g, 0.73 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 to obtain the title compound (0.167 g,
62%).
[2972] .sup.1H-NMR (CDCl.sub.3) .delta. 7.09 (1H, m), 7.01 (3H, m),
6.89 (1H, m), 5.64 (1H, brs), 4.16 (2H, q), 3.92 (3H, s), 3.25 (2H,
m), 3.14 (2H, m), 2.29 (2H, d), 1.97 (1H, m), 1.77 (2H, m), 1.46
(2H, m), 1.27 (3H, t)
Step B:
2-[1-[4-[3-(cyclobutoxy)-4-methoxy-phenyl]-2,6-difluoro-phenyl]-4--
piperidyl]acetic Acid Ethyl Ester
[2973] 1 mL of DMF, bromocyclobutane (0.032 g, 0.23 mmol) and
Cs.sub.2CO.sub.3 (0.136 g, 0.42 mmol) were added to
2-[1-[2,6-difluoro-4-(3-hydroxy-4-methoxy-phenyl)phenyl]-4-piperidyl]acet-
ic acid ethyl ester (0.08 g, 0.2 mmol) obtained in Step A, and the
mixture was stirred at 50.degree. C. for 16 hours. Solids were
filtered, and the filtrate was purified by column chromatography to
obtain the title compound (0.045 g, 49%).
[2974] .sup.1H-NMR (CDCl.sub.3) .delta. 7.04 (1H, m), 6.93 (2H, m),
6.90 (1H, m), 6.85 (1H, m), 4.72 (1H, m), 4.14 (2H, q), 3.90 (3H,
s), 3.2 (2H, m), 3.13 (2H, m), 2.50 (2H, m), 2.30 (4H, m), 1.95
(1H, m), 1.88 (1H, m), 1.76 (2H, m), 1.70 (1H, m), 1.47 (2H, m),
1.27 (3H, t)
Step C:
2-[1-[4-[3-(cyclobutoxy)-4-methoxy-phenyl]-2,6-difluoro-phenyl]-4--
piperidyl]acetic Acid
[2975]
2-[1-[4-[3-(Cyclobutoxy)-4-methoxy-phenyl]-2,6-difluoro-phenyl]-4-p-
iperidyl]acetic acid ethyl ester (0.045 g, 0.10 mmol) obtained in
Step B was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.04 g, 94%).
[2976] .sup.1H-NMR (CDCl.sub.3) .delta. 7.04 (1H, m), 6.99 (2H, m),
6.90 (1H, m), 6.86 (1H, m), 4.72 (1H, m), 3.90 (3H, s), 3.26 (2H,
m), 3.14 (2H, m), 2.50 (2H, m), 2.36 (2H, d), 2.30 (2H, m), 1.96
(1H, m), 1.88 (1H, m), 1.82 (2H, m), 1.71 (1H, m), 1.50 (2H, m)
Example 306:
2-[1-[4-[3-(cyclobutoxy)-5-fluoro-phenyl]-2,6-difluoro-phenyl]-4-piperidy-
l]acetic Acid
##STR00349##
[2977] Step A:
2-[1-[2,6-difluoro-4-(3-fluoro-5-hydroxy-phenyl)phenyl]-4-piperidyl]aceti-
c Acid Ethyl Ester
[2978] 3-Bromo-5-fluoro-phenol (0.127 g, 0.66 mmol) and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.30 g, 0.73 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 to obtain the title compound (0.24 g,
85%).
[2979] .sup.1H-NMR (CDCl.sub.3) .delta. 7.02 (2H, m), 6.79 (1H, m),
6.75 (1H, m), 6.55 (1H, m), 5.02 (1H, brs), 4.14 (2H, q), 3.28 (2H,
m), 3.13 (2H, m), 2.30 (2H, d), 1.95 (1H, m), 1.77 (2H, m), 1.45
(2H, m), 1.27 (3H, t)
Step B:
2-[1-[4-[3-(cyclobutoxy)-5-fluoro-phenyl]-2,6-difluoro-phenyl]-4-p-
iperidyl]acetic Acid Ethyl Ester
[2980] 2 mL of DMF, bromocyclobutane (0.058 g, 0.43 mmol) and
Cs.sub.2CO.sub.3 (0.25 g, 0.76 mmol) were added to
2-[1-[2,6-difluoro-4-(3-fluoro-5-hydroxy-phenyl)phenyl]-4-piperidyl]aceti-
c acid ethyl ester (0.15 g, 0.39 mmol) obtained in Step A, and the
mixture was stirred at 50.degree. C. for 16 hours. Solids were
filtered, and the filtrate was purified by column chromatography to
obtain the title compound (0.072 g, 41%).
[2981] .sup.1H-NMR (CDCl.sub.3) .delta. 7.01 (2H, m), 6.76 (1H, m),
6.73 (1H, m), 6.48 (1H, m), 4.64 (1H, m), 4.14 (2H, q), 3.28 (2H,
m), 3.13 (2H, m), 2.47 (2H, m), 2.28 (2H, d), 2.18 (2H, m), 1.96
(1H, m), 1.88 (1H, m), 1.77 (2H, m), 1.70 (1H, m), 1.47 (2H, m),
1.27 (3H, t)
Step C:
2-[1-[4-[3-(cyclobutoxy)-5-fluoro-phenyl]-2,6-difluoro-phenyl]-4-p-
iperidyl]acetic Acid
[2982]
2-[1-[4-[3-(Cyclobutoxy)-5-fluoro-phenyl]-2,6-difluoro-phenyl]-4-pi-
peridyl]acetic acid ethyl ester (0.072 g, 0.16 mmol) obtained in
Step B was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.037 g, 55%).
[2983] .sup.1H-NMR (CDCl.sub.3) .delta. 7.00 (2H, m), 6.77 (1H, m),
6.73 (1H, m), 6.49 (1H, m), 4.65 (1H, m), 3.29 (2H, m), 3.14 (2H,
m), 2.47 (2H, m), 2.35 (2H, d), 2.18 (2H, m), 1.96 (1H, m), 1.88
(1H, m), 1.82 (2H, m), 1.71 (1H, m), 1.48 (2H, m)
Example 307:
2-[1-[2-chloro-4-[6-(cyclopropylmethoxy)-2-pyridyl]-6-fluoro-phenyl]-4-pi-
peridyl]acetic Acid
##STR00350##
[2984] Step A:
2-chloro-4-[6-(cyclopropylmethoxy)-2-pyridyl]-6-fluoro-aniline
[2985] 2-Chloro-6-cyclopropylmethoxy-pyridine (0.23 g, 1.25 mmol)
obtained in Preparation Example 43 and
2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(0.37 g, 1.37 mmol) obtained in Preparation Example 225 were
reacted in the same manner as in Step A of Example 96 to obtain the
title compound (0.28 g, 77%).
[2986] .sup.1H-NMR (CDCl.sub.3) .delta. 7.74 (1H, m), 7.64 (1H, m),
7.58 (1H, m), 7.18 (1H, m), 6.65 (1H, m), 4.22 (2H, d), 4.21 (2H,
brs), 1.33 (1H, m), 0.64 (2H, m), 0.39 (2H, m)
Step B:
2-(4-bromo-3-chloro-5-fluoro-phenyl)-6-(cyclopropylmethoxy)pyridin-
e
[2987]
2-Chloro-4-[6-(cyclopropylmethoxy)-2-pyridyl]-6-fluoro-aniline
(0.27 g, 0.95 mmol) obtained in Step A was reacted in the same
manner as in Step C of Preparation Example 84 to obtain the title
compound (0.146 g, 43%).
[2988] .sup.1H-NMR (CDCl.sub.3) .delta. 7.90 (1H, m), 7.71 (1H, m),
7.65 (1H, m), 7.28 (1H, m), 6.78 (1H, m), 4.23 (2H, d), 1.32 (1H,
m), 0.64 (2H, m), 0.40 (2H, m)
Step C:
2-[1-[2-chloro-4-[6-(cyclopropylmethoxy)-2-pyridyl]-6-fluoro-pheny-
l]-4-piperidyl]acetic Acid Ethyl Ester
[2989] 2.7 mL of 1,4-dioxane was added to
2-(4-bromo-3-chloro-5-fluoro-phenyl)-6-(cyclopropylmethoxy)pyridine
(0.145 g, 0.4 mmol) obtained in Step B, hydrochloric acid salt of
2-(4-piperidyl)acetic acid ethyl ester (0.084 g, 0.4 mmol),
2-dicyclohexylphosphino-2', 6'-dimethoxybiphenyl (0.041 g, 0.1
mmol) and Cs.sub.2CO.sub.3 (0.52 g, 1.6 mmol), and charged with
nitrogen gas for 5 minutes. Pd.sub.2(dba).sub.3 (0.036 g, 0.04
mmol) was added thereto, and the mixture was stirred at 70.degree.
C. for 16 hours. Solids were filtered through Celite, and the
filtrate was purified by column chromatography to obtain the title
compound (0.015 g, 8%).
[2990] .sup.1H-NMR (CDCl.sub.3) .delta. 7.79 (1H, m), 7.60 (2H, m),
7.21 (1H, m), 6.71 (1H, m), 4.23 (2H, d), 4.14 (2H, q), 3.22 (2H,
m), 3.15 (2H, m), 2.31 (2H, d), 1.96 (1H, m), 1.76 (2H, m), 1.49
(2H, m), 1.32 (1H, m), 1.27 (3H, t), 0.64 (2H, m), 0.40 (2H, m)
Step D:
2-[1-[2-chloro-4-[6-(cyclopropylmethoxy)-2-pyridyl]-6-fluoro-pheny-
l]-4-piperidyl]acetic Acid
[2991]
2-[1-[2-Chloro-4-[6-(cyclopropylmethoxy)-2-pyridyl]-6-fluoro-phenyl-
]-4-piperidyl]acetic acid ethyl ester (0.015 g, 0.033 mmol)
obtained in Step C was reacted in the same manner as in Step B of
Example 1 to obtain the title compound (0.014 g, 99%).
[2992] .sup.1H-NMR (CDCl.sub.3) .delta. 7.79 (1H, m), 7.60 (2H, m),
7.21 (1H, m), 6.71 (1H, m), 4.23 (2H, d), 3.23 (2H, m), 3.16 (2H,
m), 2.38 (2H, d), 2.00 (1H, m), 1.82 (2H, m), 1.51 (2H, m), 1.32
(1H, m), 0.64 (2H, m), 0.40 (2H, m)
Example 308:
2-[1-[4-[6-(cyclobutylmethoxy)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperidy-
l]acetic Acid
##STR00351##
[2994] 2-Chloro-6-(cyclobutylmethoxy)pyridine (0.066 g, 0.33 mmol)
obtained in Preparation Example 324 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.11 g, 80%).
[2995] .sup.1H-NMR (CDCl.sub.3) .delta. 7.59 (1H, t), 7.51 (2H, m),
7.19 (1H, m), 6.66 (1H, m), 4.36 (2H, d), 3.32 (2H, m), 3.16 (2H,
m), 2.80 (1H, m), 2.37 (2H, d), 2.14 (2H, m), 1.93 (5H, m), 1.82
(2H, m), 1.51 (2H, m)
Example 309:
2-[1-[4-(6-tert-butoxy-2-pyridyl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
Acid
##STR00352##
[2997] 2-Tert-butoxy-6-chloro-pyridine (0.062 g, 0.33 mmol)
obtained in Preparation Example 272 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.10 g, 78%).
[2998] .sup.1H-NMR (CDCl.sub.3) .delta. 7.55 (1H, t), 7.45 (2H, m),
7.17 (1H, m), 6.58 (1H, m), 3.32 (2H, m), 3.15 (2H, m), 2.37 (2H,
d), 1.97 (1H, m), 1.83 (2H, m), 1.65 (9H, s), 1.50 (2H, m)
Example 310:
2-[1-[4-[3-(cyclobutoxy)-2-methyl-phenyl]-2,6-difluoro-phenyl]-4-piperidy-
l]acetic Acid
##STR00353##
[3000] 1-Bromo-3-(cyclobutoxy)-2-methyl-benzene (0.08 g, 0.33 mmol)
obtained in Preparation Example 288 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.055 g, 40%).
[3001] .sup.1H-NMR (CDCl.sub.3) .delta. 7.12 (1H, t), 6.77 (3H, m),
6.68 (1H, m), 4.65 (1H, m), 3.29 (2H, m), 3.15 (2H, m), 2.46 (2H,
m), 2.36 (2H, d), 2.19 (2H, m), 2.12 (3H, s), 1.97 (1H, m), 1.85
(3H, m), 1.70 (1H, m), 1.50 (2H, m)
Example 311:
2-[1-[4-[5-chloro-6-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenyl]-4-piper-
idyl]acetic Acid
##STR00354##
[3003] 3,6-Dichloro-2-(cyclobutoxy)pyridine (0.080 g, 0.36 mmol)
obtained in Preparation Example 298 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.16 g, 0.39 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.02 g, 13%).
[3004] .sup.1H-NMR (CDCl.sub.3) .delta. 7.63 (1H, d), 7.46 (2H, m),
7.15 (1H, d), 5.32 (1H, m), 3.32 (2H, m), 3.15 (2H, m), 2.54 (2H,
m), 2.37 (2H, d), 2.26 (2H, m), 1.98 (1H, m), 1.80 (4H, m), 1.48
(2H, m)
Example 312:
2-[1-[4-[6-(cyclopropanecarbonyl)-2-pyridyl]-2,6-difluoro-phenyl]-4-piper-
idyl]acetic Acid
##STR00355##
[3005] Step A:
2-[1-[4-[6-[cyclopropyl(hydroxy)methyl]-2-pyridyl]-2,6-difluoro-phenyl]-4-
-piperidyl]acetic Acid Ethyl Ester
[3006]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid ethyl ester (0.205 g, 0.50 mmol)
obtained in Preparation Example 220 and
(6-bromo-2-pyridyl)-cyclopropyl-methanol (0.125 g, 0.55 mmol)
obtained in Preparation Example 268 were reacted in the same manner
as in Step A of Example 96 to obtain the title compound (0.165 g,
77%).
[3007] .sup.1H-NMR (CDCl.sub.3) .delta. 7.77 (1H, m), 7.58 (2H, m),
7.36 (2H, m), 4.58 (1H, m), 4.14 (2H, m), 3.33 (2H, m), 3.16 (2H,
m), 2.30 (2H, m), 1.97 (1H, m), 1.79 (2H, m), 1.46 (2H, m), 1.32
(3H, t), 1.15 (1H, m), 0.60 (4H, m)
Step B:
2-[1-[4-[6-(cyclopropanecarbonyl)-2-pyridyl]-2,6-difluoro-phenyl]--
4-piperidyl]acetic Acid
[3008] 4 mL of DMSO was added to
2-[1-[4-[6-[cyclopropyl(hydroxy)methyl]-2-pyridyl]-2,6-difluoro-phenyl]-4-
-piperidyl]acetic acid ethyl ester (0.053 g, 0.123 mmol) obtained
in Step A. IBX (0.103 g, 0.368 mmol) was added thereto, and the
mixture was stirred at room temperature to obtain
2-[1-[4-[6-(cyclopropanecarbonyl)-2-pyridyl]-2,6-difluoro-phenyl]-4-piper-
idyl]acetic acid ethyl ester (0.05 g, 95%). The obtained compound
was reacted in the same manner as in Step B of Example 1 to obtain
the title compound (0.038 g, 81%).
[3009] .sup.1H-NMR (CDCl.sub.3) .delta. 7.98 (1H, d), 7.95 (1H, t),
7.81 (1H, d), 7.66 (2H, m), 3.67 (1H, m), 3.36 (2H, m), 3.18 (2H,
m), 2.37 (2H, d), 2.00 (1H, m), 1.85 (2H, m), 1.50 (2H, m), 1.29
(2H, m), 1.17 (2H, m)
Example 313:
2-[1-[4-[6-(cyclobutoxymethyl)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperidy-
l]acetic Acid
##STR00356##
[3011]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid ethyl ester (0.082 g, 0.20 mmol)
obtained in Preparation Example 220 and
2-bromo-6-(cyclobutoxymethyl)pyridine (0.053 g, 0.22 mmol) obtained
in Preparation Example 269 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.039 g, 47%).
[3012] .sup.1H-NMR (CDCl.sub.3) .delta. 7.72 (1H, t), 7.49 (3H, m),
7.39 (1H, d), 4.58 (2H, s), 4.10 (1H, m), 3.31 (2H, m), 3.14 (2H,
m), 2.35 (2H, d), 2.25 (2H, m), 2.02 (3H, m), 1.81 (2H, m), 1.73
(1H, m), 1.48 (3H, m)
Example 314:
2-[1-[4-(6-ethoxy-2-pyridyl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
Acid
##STR00357##
[3014] 2-Chloro-6-ethoxy-pyridine (0.053 g, 0.33 mmol) obtained in
Preparation Example 273 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.10 g, 80%).
[3015] .sup.1H-NMR (CDCl.sub.3) .delta. 7.60 (1H, t), 7.51 (2H, m),
7.20 (1H, d), 6.65 (1H, d), 4.45 (2H, q), 3.31 (2H, m), 3.15 (2H,
m), 2.37 (2H, d), 1.97 (1H, m), 1.82 (2H, m), 1.50 (2H, m), 1.43
(3H, t)
Example 315:
2-[1-[2,6-difluoro-4-[6-(2,2,2-trifluoroethoxy)-2-pyridyl]phenyl]-4-piper-
idyl]acetic Acid
##STR00358##
[3017] 2-Chloro-6-(2,2,2-trifluoroethoxy)pyridine (0.071 g, 0.33
mmol) obtained in Preparation Example 274 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.36 mmol) 220 were
reacted in the same manner as in Step A of Example 96 and Step B of
Example 1 to obtain the title compound (0.082 g, 58%).
[3018] .sup.1H-NMR (CDCl.sub.3) .delta. 7.69 (1H, t), 7.46 (2H, m),
7.31 (1H, d), 6.80 (1H, d), 4.84 (2H, q), 3.33 (2H, m), 3.16 (2H,
m), 2.37 (2H, d), 1.98 (1H, m), 1.83 (2H, m), 1.50 (2H, m)
Example 316:
2-[1-[2,6-difluoro-4-[6-(2,2,2-trifluoro-1-methyl-ethoxy)-2-pyridyl]pheny-
l]-4-piperidyl]acetic Acid
##STR00359##
[3020] 2-Chloro-6-(2,2,2-trifluoro-1-methyl-ethoxy)pyridine (0.075
g, 0.33 mmol) obtained in Preparation Example 275 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.127 g, 86%).
[3021] .sup.1H-NMR (CDCl.sub.3) .delta. 7.67 (1H, t), 7.45 (2H, m),
7.28 (1H, d), 6.74 (1H, d), 5.89 (1H, m), 3.33 (2H, m), 3.16 (2H,
m), 2.37 (2H, d), 1.98 (1H, m), 1.83 (2H, m), 1.55 (3H, d), 1.50
(2H, m)
Example 317:
2-[1-[4-(6-cyclopentyl-2-pyridyl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
Acid
##STR00360##
[3023] 2-Bromo-6-cyclopentyl-pyridine (0.067 g, 0.3 mmol) and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.13 g, 0.32 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.06 g, 50%).
[3024] .sup.1H-NMR (CDCl.sub.3) .delta. 7.61 (1H, t), 7.53 (2H, m),
7.41 (1H, d), 7.09 (1H, d), 3.31 (2H, m), 3.22 (1H, m), 3.15 (2H,
m), 2.37 (2H, d), 2.10 (2H, m), 1.97 (1H, m), 1.85 (6H, m), 1.70
(2H, m), 1.50 (2H, m)
Example 318:
2-[1-[4-[6-[cyclopropyl(methoxy)methyl]-2-pyridyl]-2,6-difluoro-phenyl]-4-
-piperidyl]acetic Acid
##STR00361##
[3026]
2-[1-[4-[6-[Cyclopropyl(hydroxy)methyl]-2-pyridyl]-2,6-difluoro-phe-
nyl]-4-piperidyl]acetic acid ethyl ester (0.054 g, 0.125 mmol)
obtained in Step A of Example 312 was dissolved in 4 mL of
CH.sub.3CN. Ag.sub.2O (0.032 g, 0.138 mmol) and iodomethane (0.08
mL, 1.29 mmol) were added thereto, and the mixture was stirred at
room temperature for 7 days. After termination of the reaction,
solids were filtered through Celite, and the filtrate was purified
by column chromatography to obtain
2-[1-[4-[6-[cyclopropyl(methoxy)methyl]-2-pyridyl]-2,6-difluoro-phenyl]-4-
-piperidyl]acetic acid ethyl ester (0.015 g, 27%). The obtained
compound was reacted in the same manner as in Step B of Example 1
to obtain the title compound (0.012 g, 86%).
[3027] .sup.1H-NMR (CDCl.sub.3) .delta. 7.76 (1H, t), 2.52 (3H, m),
7.36 (1H, d), 3.81 (1H, d), 3.35 (3H, s), 3.32 (2H, m), 3.15 (2H,
m), 2.36 (2H, d), 1.96 (1H, m), 1.85 (2H, m), 1.49 (2H, m), 1.20
(1H, m), 0.64 (1H, m), 0.50 (3H, m)
Example 319:
2-[1-[2-chloro-4-[6-(cyclobutoxy)-2-pyridyl]-6-fluoro-phenyl]-4-piperidyl-
]acetic Acid
##STR00362##
[3029] 2-Chloro-6-cyclobutoxy-pyridine (0.23 g, 1.25 mmol) obtained
in Preparation Example 29 and
2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(0.374 g, 1.37 mmol) obtained in Preparation Example 225 were
reacted in the same manner as in Example 307 to obtain the title
compound (0.01 g, 2%).
[3030] .sup.1H-NMR (CDCl.sub.3) .delta. 7.78 (1H, m), 7.60 (2H, m),
7.21 (1H, m), 6.63 (1H, m), 5.25 (1H, m), 3.23 (2H, m), 3.17 (2H,
m), 2.53 (2H, m), 2.38 (2H, d), 2.19 (2H, m), 1.99 (1H, m) 1.88
(1H, m), 1.81 (2H, m), 1.74 (1H, m), 1.50 (2H, m)
Example 320:
2-[1-[4-[6-(cyclobutoxy)-2-pyridyl]-2-fluoro-phenyl]-4-piperidyl]acetic
Acid
##STR00363##
[3032] 2-Chloro-6-cyclobutoxy-pyridine (0.034 g, 0.185 mmol)
obtained in Preparation Example 29 and
2-[1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-p-
iperidyl]acetic acid ethyl ester (0.08 g, 0.2 mmol) obtained in
Preparation Example 99 were reacted in the same manner as in Step A
of Example 96 and Step B of Example 1 to obtain the title compound
(0.009 g, 13%).
[3033] .sup.1H-NMR (CDCl.sub.3) .delta. 7.72 (2H, m), 7.58 (1H, m),
7.24 (1H, m), 7.00 (1H, m), 6.60 (1H, m), 5.27 (1H, m), 3.53 (2H,
m), 2.76 (2H, m), 2.53 (2H, m), 2.38 (2H, m), 2.19 (2H, m), 1.98
(1H, m), 1.89 (3H, m), 1.74 (1H, m), 1.58 (2H, m)
Example 321:
2-[1-[4-[6-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenyl]azetidin-3-yl]ace-
tic Acid
##STR00364##
[3035] 2-Chloro-6-cyclobutoxy-pyridine (0.057 g, 0.31 mmol)
obtained in Preparation Example 29 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
azetidin-3-yl]acetic acid ethyl ester (0.13 g, 0.34 mmol) obtained
in Preparation Example 88 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.018 g, 16%).
[3036] .sup.1H-NMR (CDCl.sub.3) .delta. 7.56 (1H, t), 7.45 (2H, m),
7.15 (1H, m), 6.56 (1H, m), 5.29 (1H, m), 4.42 (2H, m), 3.95 (2H,
m), 3.05 (1H, m), 2.79 (2H, d), 2.51 (2H, m), 2.18 (2H, m), 1.86
(1H, m), 1.74 (1H, m)
Example 322:
2-[1-[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-phenyl]azetidin-3-
-yl]acetic Acid
##STR00365##
[3038] 2-Chloro-6-cyclopropylmethoxy-pyridine (0.057 g, 0.31 mmol)
obtained in Preparation Example 43 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
azetidin-3-yl]acetic acid ethyl ester (0.13 g, 0.34 mmol) obtained
in Preparation Example 88 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.008 g, 7%).
[3039] .sup.1H-NMR (CDCl.sub.3) .delta. 7.57 (1H, t), 7.45 (2H, m),
7.15 (1H, m), 6.65 (1H, m), 4.43 (2H, m), 4.21 (2H, d), 3.94 (2H,
m), 3.05 (1H, m), 2.79 (2H, d), 1.23 (1H, m), 0.63 (2H, m), 0.40
(2H, m)
Example 323:
2-[1-[4-[4-(cyclobutoxy)-6-methyl-pyrimidin-2-yl]-2,6-difluoro-phenyl]-4--
piperidyl]acetic Acid
##STR00366##
[3041] 2-Chloro-4-(cyclobutoxy)-6-methyl-pyrimidine (0.079 g, 0.4
mmol) obtained in Preparation Example 228 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.165 g, 0.4 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.08 g, 48%).
[3042] .sup.1H-NMR (CDCl.sub.3) .delta. 7.87 (2H, m), 6.39 (1H, s),
5.31 (1H, m), 3.35 (2H, m), 3.17 (2H, m), 2.52 (2H, m), 2.45 (3H,
s), 2.36 (2H, d), 2.18 (2H, m), 1.95 (1H, m), 1.90 (1H, m), 1.82
(2H, m), 1.75 (1H, m), 1.50 (2H, m)
Example 324:
2-[1-[4-(6-butoxy-2-pyridyl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
Acid
##STR00367##
[3044] 2-Butoxy-6-chloro-pyridine (0.075 g, 0.4 mmol) obtained in
Preparation Example 276 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.165 g, 0.4 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.06 g, 37%).
[3045] .sup.1H-NMR (CDCl.sub.3) .delta. 7.59 (1H, t), 7.51 (2H, m),
7.19 (1H, m), 6.65 (1H, m), 4.40 (2H, t), 3.32 (2H, m), 3.15 (2H,
m), 2.37 (2H, d), 1.97 (1H, m), 1.81 (4H, m), 1.52 (4H, m), 0.99
(3H, t)
Example 325:
2-[1-[4-[2-(cyclobutoxy)-6-methyl-pyrimidin-4-yl]-2,6-difluoro-phenyl]-4--
piperidyl]acetic Acid
##STR00368##
[3047] 4-Chloro-2-(cyclobutoxy)-6-methyl-pyrimidine (0.051 g, 0.25
mmol) obtained in Preparation Example 229 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.116 g, 0.28 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.06 g, 57%).
[3048] .sup.1H-NMR (CDCl.sub.3) .delta. 7.57 (2H, m), 7.07 (1H, s),
5.27 (1H, m), 3.38 (2H, m), 3.16 (2H, m), 2.52 (2H, m), 2.48 (3H,
s), 2.36 (2H, d), 2.24 (2H, m), 1.98 (1H, m), 1.86 (3H, m), 1.75
(1H, m), 1.47 (2H, m)
Example 326:
2-[1-[4-[2-(cyclobutoxy)thiazol-4-yl]-2,6-difluoro-phenyl]-4-piperidyl]ac-
etic Acid
##STR00369##
[3050] 4-Bromo-2-(cyclobutoxy)thiazole (0.062 g, 0.26 mmol)
obtained in Preparation Example 289 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.12 g, 0.29 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.04 g, 38%).
[3051] .sup.1H-NMR (MeOH-d4) .delta. 7.33 (2H, m), 7.12 (1H, s),
5.18 (1H, m), 3.21 (2H, m), 3.10 (2H, m), 2.51 (2H, m), 2.24 (4H,
m), 1.87 (2H, m), 1.76 (3H, m), 1.41 (2H, m)
Example 327:
2-[1-[4-[6-(cyclobutoxy)-4-methyl-2-pyridyl]-2,6-difluoro-phenyl]-4-piper-
idyl]acetic Acid
##STR00370##
[3053] 2-Chloro-6-(cyclobutoxy)-4-methyl-pyridine (0.06 g, 0.3
mmol) obtained in Preparation Example 271 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.137 g, 0.33 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.038 g, 30%).
[3054] .sup.1H-NMR (CDCl.sub.3) .delta. 7.47 (2H, m), 7.03 (1H, s),
6.44 (1H, s), 5.23 (1H, m), 3.32 (2H, m), 3.14 (2H, m), 2.50 (2H,
m), 2.36 (2H, d), 2.32 (3H, s), 2.17 (2H, m), 1.97 (1H, m), 1.84
(3H, m), 1.75 (1H, m), 1.49 (2H, m)
Example 328:
2-[1-[4-[4-(cyclobutoxy)-6-methyl-pyrimidin-2-yl]-2,6-difluoro-phenyl]aze-
tidin-3-yl]acetic Acid
##STR00371##
[3056] 2-Chloro-4-(cyclobutoxy)-6-methyl-pyrimidine (0.08 g, 0.4
mmol) obtained in Preparation Example 228 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
azetidin-3-yl]acetic acid ethyl ester (0.17 g, 0.44 mmol) obtained
in Preparation Example 88 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.124 g, 80%).
[3057] .sup.1H-NMR (CDCl.sub.3) .delta. 7.82 (2H, m), 6.34 (1H, s),
5.28 (1H, m), 4.46 (2H, m), 3.98 (2H, m), 3.06 (1H, m), 2.79 (2H,
d), 2.52 (2H, m), 2.43 (3H, s), 2.18 (2H, m), 1.87 (1H, m), 1.75
(1H, m)
Example 329:
2-[1-[4-[6-(cyclobutoxy)pyrazin-2-yl]-2,6-difluoro-phenyl]-4-piperidyl]ac-
etic Acid
##STR00372##
[3059] 2-Chloro-6-(cyclobutoxy)pyrazine (0.07 g, 0.38 mmol)
obtained in Preparation Example 232 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.17 g, 0.42 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.12 g, 78%).
[3060] .sup.1H-NMR (CDCl.sub.3) .delta. 8.46 (1H, s), 8.08 (1H, s),
7.48 (2H, m), 5.26 (1H, m), 3.36 (2H, m), 3.17 (2H, m), 2.53 (2H,
m), 2.37 (2H, d), 2.22 (2H, m), 1.99 (1H, m), 1.91 (1H, m), 1.84
(2H, m), 1.76 (1H, m), 1.50 (2H, m)
Example 330:
2-[1-[4-[4-(cyclobutoxy)pyrimidin-2-yl]-2,6-difluoro-phenyl]-4-piperidyl]-
acetic Acid
##STR00373##
[3062] 2-Chloro-4-(cyclobutoxy)pyrimidine (0.07 g, 0.38 mmol)
obtained in Preparation Example 230 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.17 g, 0.42 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.135 g, 88%).
[3063] .sup.1H-NMR (CDCl.sub.3) .delta. 8.45 (1H, d), 7.87 (2H, m),
6.54 (1H, d), 5.32 (1H, m), 3.37 (2H, m), 3.18 (2H, m), 2.54 (2H,
m), 2.37 (2H, d), 2.20 (2H, m), 1.99 (1H, m), 1.89 (1H, m), 1.83
(2H, m), 1.77 (1H, m), 1.49 (2H, m)
Example 331:
2-[1-[4-[4-(cyclopropylmethoxy)-6-methyl-pyrimidin-2-yl]-2,6-difluoro-phe-
nyl]-4-piperidyl]acetic Acid
##STR00374##
[3065] 2-Chloro-4-(cyclopropylmethoxy)-6-methyl-pyrimidine (0.073
g, 0.367 mmol) obtained in Preparation Example 227 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.165 g, 0.40 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.13 g, 85%).
[3066] .sup.1H-NMR (CDCl.sub.3) .delta. 7.88 (2H, m), 6.46 (1H, s),
4.27 (2H, d), 3.35 (2H, m), 3.16 (2H, m), 2.46 (3H, s), 2.36 (2H,
d), 1.99 (1H, m), 1.82 (2H, m), 1.48 (2H, m), 1.31 (1H, m), 0.64
(2H, m), 0.40 (2H, m)
Example 332:
2-[1-[4-[4-(cyclopropylmethoxy)pyrimidin-2-yl]-2,6-difluoro-phenyl]-4-pip-
eridyl]acetic Acid
##STR00375##
[3068] 2-Chloro-4-(cyclopropylmethoxy)pyrimidine (0.07 g, 0.38
mmol) obtained in Preparation Example 231 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.17 g, 0.42 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.12 g, 78%).
[3069] .sup.1H-NMR (CDCl.sub.3) .delta. 8.45 (1H, d), 7.87 (2H, m),
6.62 (1H, d), 4.30 (2H, d), 3.38 (2H, m), 3.18 (2H, m), 2.37 (2H,
d), 1.99 (1H, m), 1.83 (2H, m), 1.50 (2H, m), 1.33 (1H, m), 0.66
(2H, m), 0.41 (2H, m)
Example 333:
2-[1-[4-[6-(cyclopropylmethoxy)pyrazin-2-yl]-2,6-difluoro-phenyl]-4-piper-
idyl]acetic Acid
##STR00376##
[3071] 2-Chloro-6-(cyclopropylmethoxy)pyrazine (0.07 g, 0.38 mmol)
obtained in Preparation Example 233 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.17 g, 0.42 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.13 g, 85%).
[3072] .sup.1H-NMR (CDCl.sub.3) .delta. 8.46 (1H, s), 8.15 (1H, s),
7.50 (2H, m), 4.25 (2H, d), 3.35 (2H, m), 3.16 (2H, m), 2.37 (2H,
d), 1.99 (1H, m), 1.84 (2H, m), 1.51 (2H, m), 1.33 (1H, m), 0.66
(2H, m), 0.41 (2H, m)
Example 334:
2-[1-[4-[6-(cyclobutoxy)pyrazin-2-yl]-2,6-difluoro-phenyl]azetidin-3-yl]a-
cetic Acid
##STR00377##
[3074] 2-Chloro-6-(cyclobutoxy)pyrazine (0.048 g, 0.26 mmol)
obtained in Preparation Example 232 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
azetidin-3-yl]acetic acid ethyl ester (0.10 g, 0.26 mmol) obtained
in Preparation Example 88 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.06 g, 61%).
[3075] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, s), 8.02 (1H, s),
7.44 (2H, m), 5.25 (1H, m), 4.46 (2H, m), 3.98 (2H, m), 3.07 (1H,
m), 2.80 (2H, d), 2.52 (2H, m), 2.21 (2H, m), 1.90 (1H, m), 1.77
(1H, m)
Example 335:
2-[1-[4-[6-(cyclopropylmethoxy)pyrazin-2-yl]-2,6-difluoro-phenyl]azetidin-
-3-yl]acetic Acid
##STR00378##
[3077] 2-Chloro-6-(cyclopropylmethoxy)pyrazine (0.048 g, 0.26 mmol)
obtained in Preparation Example 233 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
azetidin-3-yl]acetic acid ethyl ester (0.10 g, 0.26 mmol) obtained
in Preparation Example 88 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.058 g, 59%).
[3078] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, s), 8.09 (1H, s),
7.45 (2H, m), 4.45 (2H, m), 4.24 (2H, d), 3.98 (2H, m), 3.06 (1H,
m), 2.80 (2H, d), 1.33 (1H, m), 0.66 (2H, m), 0.40 (2H, m)
Example 336:
2-[1-[4-[4-(cyclobutoxy)pyrimidin-2-yl]-2,6-difluoro-phenyl]azetidin-3-yl-
]acetic Acid
##STR00379##
[3080] 2-Chloro-4-(cyclobutoxy)pyrimidine (0.048 g, 0.26 mmol)
obtained in Preparation Example 230 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
azetidin-3-yl]acetic acid ethyl ester (0.10 g, 0.26 mmol) obtained
in Preparation Example 88 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.024 g, 25%).
[3081] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, d), 7.81 (2H, m),
6.49 (1H, d), 5.31 (1H, m), 4.48 (2H, m), 3.99 (2H, m), 3.08 (1H,
m), 2.79 (2H, d), 2.53 (2H, m), 2.20 (2H, m), 1.90 (1H, m), 1.78
(1H, m)
Example 337:
2-[1-[4-[4-(cyclopropylmethoxy)pyrimidin-2-yl]-2,6-difluoro-phenyl]azetid-
in-3-yl]acetic Acid
##STR00380##
[3083] 2-Chloro-4-(cyclopropylmethoxy)pyrimidine (0.048 g, 0.26
mmol) obtained in Preparation Example 231 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
azetidin-3-yl]acetic acid ethyl ester (0.10 g, 0.26 mmol) obtained
in Preparation Example 88 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.054 g, 55%).
[3084] .sup.1H-NMR (CDCl.sub.3) .delta. 8.41 (1H, d), 7.82 (2H, m),
6.56 (1H, d), 4.47 (2H, m), 4.28 (2H, d), 3.99 (2H, m), 3.07 (1H,
m), 2.79 (2H, d), 1.32 (1H, m), 0.64 (2H, m), 0.40 (2H, m)
Example 338:
2-[1-[4-(6-ethoxypyrazin-2-yl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
Acid
##STR00381##
[3086] 2-Chloro-6-ethoxy-pyrazine (0.051 g, 0.32 mmol) obtained in
Preparation Example 302 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.144 g, 0.35 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.083 g, 69%).
[3087] .sup.1H-NMR (CDCl.sub.3) .delta. 8.46 (1H, s), 8.11 (1H, s),
7.51 (2H, m), 4.48 (2H, q), 3.35 (2H, m), 3.16 (2H, m), 2.37 (2H,
d), 1.98 (1H, m), 1.83 (2H, m), 1.45 (5H, m)
Example 339:
2-[1-[2,6-difluoro-4-(6-isopropoxypyrazin-2-yl)phenyl]-4-piperidyl]acetic
Acid
##STR00382##
[3089] 2-Chloro-6-isopropoxy-pyrazine (0.055 g, 0.32 mmol) obtained
in Preparation Example 301 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.144 g, 0.35 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.108 g, 87%).
[3090] .sup.1H-NMR (CDCl.sub.3) .delta. 8.44 (1H, s), 8.06 (1H, s),
7.49 (2H, m), 5.43 (1H, m), 3.35 (2H, m), 3.16 (2H, m), 2.37 (2H,
d), 1.99 (1H, m), 1.84 (2H, m), 1.51 (2H, m), 1.42 (6H, d)
Example 340:
2-[1-[2,6-difluoro-4-(6-methoxypyrazin-2-yl)phenyl]-4-piperidyl]acetic
Acid
##STR00383##
[3092] 2-Chloro-6-methoxy-pyrazine (0.044 g, 0.3 mmol) obtained in
Preparation Example 234 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.135 g, 0.33 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.053 g, 49%).
[3093] .sup.1H-NMR (CDCl.sub.3) .delta. 8.48 (1H, s), 8.14 (1H, s),
7.52 (2H, m), 4.05 (3H, s), 3.35 (2H, m), 3.17 (2H, m), 2.36 (2H,
d), 1.99 (1H, m), 1.83 (2H, m), 1.50 (2H, m)
Example 341:
2-[1-[2,6-difluoro-4-(6-propoxypyrazin-2-yl)phenyl]-4-piperidyl]acetic
Acid
##STR00384##
[3095] 2-Chloro-6-propoxy-pyrazine (0.052 g, 0.3 mmol) obtained in
Preparation Example 235 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.135 g, 0.33 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.057 g, 51%).
[3096] .sup.1H-NMR (CDCl.sub.3) .delta. 8.46 (1H, s), 8.12 (1H, s),
7.50 (2H, m), 4.38 (2H, t), 3.35 (2H, m), 3.16 (2H, m), 2.37 (2H,
d), 1.99 (1H, m), 1.86 (4H, m), 1.48 (2H, m), 1.06 (3H, t)
Example 342:
2-[1-[2,6-difluoro-4-(6-isobutoxypyrazin-2-yl)phenyl]-4-piperidyl]acetic
Acid
##STR00385##
[3098] 2-Chloro-6-isobutoxy-pyrazine (0.056 g, 0.3 mmol) obtained
in Preparation Example 237 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.135 g, 0.33 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.053 g, 44%).
[3099] .sup.1H-NMR (CDCl.sub.3) .delta. 8.45 (1H, s), 8.12 (1H, s),
7.49 (2H, m), 4.18 (2H, d), 3.35 (2H, m), 3.16 (2H, m), 2.37 (2H,
d), 2.15 (1H, m), 1.99 (1H, m), 1.83 (2H, m), 1.50 (2H, m), 1.06
(6H, d)
Example 343:
2-[1-[4-(6-butoxypyrazin-2-yl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
Acid
##STR00386##
[3101] 2-Butoxy-6-chloro-pyrazine (0.056 g, 0.3 mmol) obtained in
Preparation Example 236 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.135 g, 0.33 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.044 g, 36%).
[3102] .sup.1H-NMR (CDCl.sub.3) .delta. 8.45 (1H, s), 8.10 (1H, s),
7.50 (2H, m), 4.41 (2H, t), 3.33 (2H, m), 3.15 (2H, m), 2.36 (2H,
d), 1.98 (1H, m), 1.80 (4H, m), 1.49 (4H, m), 1.00 (3H, t)
Example 344:
2-[1-[4-[6-(cyclopentoxy)pyrazin-2-yl]-2,6-difluoro-phenyl]-4-piperidyl]a-
cetic Acid
##STR00387##
[3104] 2-Chloro-6-(cyclopentoxy)pyrazine (0.06 g, 0.3 mmol)
obtained in Preparation Example 238 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.135 g, 0.33 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.061 g, 49%).
[3105] .sup.1H-NMR (CDCl.sub.3) .delta. 8.43 (1H, s), 8.06 (1H, s),
7.50 (2H, m), 5.50 (1H, m), 3.34 (2H, m), 3.16 (2H, m), 2.37 (2H,
d), 2.02 (2H, m), 1.99 (1H, m), 1.82 (6H, m), 1.67 (2H, m), 1.50
(2H, m)
Example 345:
2-[1-[4-(4-ethoxypyrimidin-2-yl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
Acid
##STR00388##
[3107] 2-Chloro-4-ethoxy-pyrimidine (0.049 g, 0.31 mmol) obtained
in Preparation Example 239 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.156 g, 0.38 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.074 g, 64%).
[3108] .sup.1H-NMR (CDCl.sub.3) .delta. 8.44 (1H, d), 7.87 (2H, m),
6.57 (1H, d), 4.52 (2H, q), 3.37 (2H, m), 3.16 (2H, m), 2.36 (2H,
d), 1.98 (1H, m), 1.82 (2H, m), 1.48 (2H, m), 1.45 (3H, t)
Example 346:
2-[1-[2,6-difluoro-4-(4-isopropoxypyrimidin-2-yl)phenyl]-4-piperidyl]acet-
ic Acid
##STR00389##
[3110] 2-Chloro-4-isopropoxy-pyrimidine (0.059 g, 0.34 mmol)
obtained in Preparation Example 240 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.156 g, 0.38 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.089 g, 67%).
[3111] .sup.1H-NMR (CDCl.sub.3) .delta. 8.43 (1H, d), 7.86 (2H, m),
6.53 (1H, d), 5.52 (1H, m), 3.37 (2H, m), 3.17 (2H, m), 2.36 (2H,
d), 1.98 (1H, m), 1.83 (2H, m), 1.48 (2H, m), 1.41 (6H, d)
Example 347:
2-[1-[2,6-difluoro-4-(4-propoxypyrimidin-2-yl)phenyl]-4-piperidyl]acetic
Acid
##STR00390##
[3113] 2-Chloro-4-propoxy-pyrimidine (0.055 g, 0.32 mmol) obtained
in Preparation Example 241 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.156 g, 0.38 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.079 g, 63%).
[3114] .sup.1H-NMR (CDCl.sub.3) .delta. 8.45 (1H, d), 7.88 (2H, m),
6.58 (1H, d), 4.42 (2H, t), 3.37 (2H, m), 3.16 (2H, m), 2.36 (2H,
d), 1.98 (1H, m), 1.83 (4H, m), 1.48 (2H, m), 1.06 (3H, t)
Example 348:
2-[1-[2,6-difluoro-4-(4-isobutoxypyrimidin-2-yl)phenyl]-4-piperidyl]aceti-
c Acid
##STR00391##
[3116] 2-Chloro-4-isobutoxy-pyrimidine (0.059 g, 0.31 mmol)
obtained in Preparation Example 242 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.156 g, 0.38 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.066 g, 52%).
[3117] .sup.1H-NMR (CDCl.sub.3) .delta. 8.44 (1H, d), 7.88 (2H, m),
6.59 (1H, d), 4.23 (2H, d), 3.37 (2H, m), 3.18 (2H, m), 2.37 (2H,
d), 2.15 (1H, m), 1.99 (1H, m), 1.83 (2H, m), 1.48 (2H, m), 1.04
(6H, d)
Example 349:
2-[1-[4-(4-ethoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenyl]-4-piperid-
yl]acetic Acid
##STR00392##
[3119] 2-Chloro-4-ethoxy-6-methyl-pyrimidine (0.056 g, 0.32 mmol)
obtained in Preparation Example 243 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.148 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.085 g, 67%).
[3120] .sup.1H-NMR (CDCl.sub.3) .delta. 7.89 (2H, m), 6.42 (1H, s),
4.50 (2H, q), 3.36 (2H, m), 3.16 (2H, m), 2.46 (3H, s), 2.36 (2H,
d), 1.98 (1H, m), 1.82 (2H, m), 1.48 (2H, m), 1.42 (3H, t)
Example 350:
2-[1-[2,6-difluoro-4-(4-isopropoxy-6-methyl-pyrimidin-2-yl)phenyl]-4-pipe-
ridyl]acetic Acid
##STR00393##
[3122] 2-Chloro-4-isopropoxy-6-methyl-pyrimidine (0.06 g, 0.32
mmol) obtained in Preparation Example 244 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.148 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.09 g, 69%).
[3123] .sup.1H-NMR (CDCl.sub.3) .delta. 7.88 (2H, m), 6.38 (1H, s),
5.50 (1H, m), 3.36 (2H, m), 3.16 (2H, m), 2.45 (3H, s), 2.36 (2H,
d), 1.98 (1H, m), 1.82 (2H, m), 1.49 (2H, m), 1.39 (6H, d)
Example 351:
2-[1-[2,6-difluoro-4-(4-methyl-6-propoxy-pyrimidin-2-yl)phenyl]-4-piperid-
yl]acetic Acid
##STR00394##
[3125] 2-Chloro-4-methyl-6-propoxy-pyrimidine (0.061 g, 0.32 mmol)
obtained in Preparation Example 245 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.147 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.085 g, 66%).
[3126] .sup.1H-NMR (CDCl.sub.3) .delta. 7.88 (2H, m), 6.42 (1H, s),
4.39 (2H, t), 3.36 (2H, m), 3.15 (2H, m), 2.45 (3H, s), 2.36 (2H,
d), 1.98 (1H, m), 1.81 (4H, m), 1.48 (2H, m), 1.03 (3H, t)
Example 352:
2-[1-[2,6-difluoro-4-(4-isobutoxy-6-methyl-pyrimidin-2-yl)phenyl]-4-piper-
idyl]acetic Acid
##STR00395##
[3128] 2-Chloro-4-isobutoxy-6-methyl-pyrimidine (0.058 g, 0.29
mmol) obtained in Preparation Example 246 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.149 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.079 g, 65%).
[3129] .sup.1H-NMR (CDCl.sub.3) .delta. 7.88 (2H, m), 6.44 (1H, s),
4.21 (2H, d), 3.36 (2H, m), 3.16 (2H, m), 2.46 (3H, s), 2.36 (2H,
d), 2.11 (1H, m), 1.98 (1H, m), 1.82 (2H, m), 1.48 (2H, m), 1.03
(6H, d)
Example 353:
2-[1-[2,6-difluoro-4-(6-pyrrolidin-1-ylpyrazin-2-yl)phenyl]-4-piperidyl]a-
cetic Acid
##STR00396##
[3131] 2-Chloro-6-pyrrolidin-1-yl-pyrazine (0.061 g, 0.33 mmol)
obtained in Preparation Example 249 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.098 g, 74%).
[3132] .sup.1H-NMR (CDCl.sub.3) .delta. 8.12 (1H, s), 7.77 (1H, s),
7.52 (2H, m), 3.56 (4H, m), 3.32 (2H, m), 3.15 (2H, m), 2.32 (2H,
d), 2.05 (4H, m), 1.96 (1H, m), 1.82 (2H, m), 1.47 (2H, m)
Example 354:
2-[1-[2,6-difluoro-4-[6-(isopropylamino)pyrazin-2-yl]phenyl]-4-piperidyl]-
acetic Acid
##STR00397##
[3134] 6-Chloro-N-isopropyl-pyrazin-2-amine (0.057 g, 0.33 mmol)
obtained in Preparation Example 250 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.051 g, 40%).
[3135] .sup.1H-NMR (CDCl.sub.3) .delta. 8.11 (1H, s), 7.75 (1H, s),
7.46 (2H, m), 4.72 (1H, brs), 4.12 (1H, m), 3.33 (2H, m), 3.15 (2H,
m), 2.32 (2H, d), 1.96 (1H, m), 1.83 (2H, m), 1.48 (2H, m), 1.29
(6H, d)
Example 355:
2-[1-[4-[6-(diethylamino)pyrazin-2-yl]-2,6-difluoro-phenyl]-4-piperidyl]a-
cetic Acid
##STR00398##
[3137] 6-Chloro-N,N-diethyl-pyrazin-2-amine (0.055 g, 0.3 mmol)
obtained in Preparation Example 253 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.17 g, 0.41 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.1 g, 82%).
[3138] .sup.1H-NMR (CDCl.sub.3) .delta. 8.11 (1H, s), 7.89 (1H, s),
7.48 (2H, m), 3.60 (4H, q), 3.33 (2H, m), 3.16 (2H, m), 2.36 (2H,
d), 1.99 (1H, m), 1.83 (2H, m), 1.50 (2H, m), 1.25 (6H, t)
Example 356:
2-[1-[2,6-difluoro-4-[6-(isobutylamino)pyrazin-2-yl]phenyl]-4-piperidyl]a-
cetic Acid
##STR00399##
[3140] 6-Chloro-N-isobutyl-pyrazin-2-amine (0.052 g, 0.28 mmol)
obtained in Preparation Example 251 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.08 g, 72%).
[3141] .sup.1H-NMR (CDCl.sub.3) .delta. 8.15 (1H, s), 7.80 (1H, s),
7.45 (2H, m), 4.75 (1H, m), 3.32 (2H, m), 3.25 (2H, t), 3.15 (2H,
m), 2.36 (2H, d), 1.95 (2H, m), 1.83 (2H, m), 1.48 (2H, m), 1.02
(6H, d)
Example 357:
2-[1-[4-[6-(cyclopentylamino)pyrazin-2-yl]-2,6-difluoro-phenyl]-4-piperid-
yl]acetic Acid
##STR00400##
[3143] 6-Chloro-N-cyclopentyl-pyrazin-2-amine (0.056 g, 0.28 mmol)
obtained in Preparation Example 252 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.085 g, 72%).
[3144] .sup.1H-NMR (CDCl.sub.3) .delta. 8.15 (1H, s), 7.79 (1H, s),
7.47 (2H, m), 4.71 (1H, brs), 4.17 (1H, m), 3.32 (2H, m), 3.15 (2H,
m), 2.36 (2H, d), 2.12 (2H, m), 1.97 (1H, m), 1.82-1.46 (10H,
m)
Example 358:
2-[1-[4-[6-(cyclopentylamino)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperidyl-
]acetic Acid
##STR00401##
[3146] 6-Chloro-N-cyclopentyl-pyridin-2-amine (0.065 g, 0.33 mmol)
and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.149 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.048 g, 34%).
[3147] .sup.1H-NMR (CDCl.sub.3) .delta. 7.49 (1H, t), 7.34 (2H, m),
6.82 (1H, d), 6.37 (1H, d), 3.95 (1H, m), 3.28 (2H, m), 3.13 (2H,
m), 2.31 (2H, d), 2.05 (2H, m), 1.93 (1H, m), 1.79 (4H, m), 1.64
(2H, m), 1.57 (2H, m), 1.45 (2H, m)
Example 359:
2-[1-[4-[6-(dimethylamino)pyrazin-2-yl]-2,6-difluoro-phenyl]-4-piperidyl]-
acetic Acid
##STR00402##
[3149] 6-Chloro-N,N-dimethyl-pyrazin-2-amine (0.053 g, 0.33 mmol)
obtained in Preparation Example 254 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.19 g, 0.47 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.06 g, 47%).
[3150] .sup.1H-NMR (CDCl.sub.3+MeOH-d.sub.4) .delta. 8.13 (1H, m),
7.91 (1H, m), 7.51 (2H, m), 3.32 (2H, m), 3.19 (6H, s), 3.15 (2H,
m), 2.31 (2H, d), 1.96 (1H, m), 1.82 (2H, m), 1.48 (2H, m)
Example 360:
2-[1-[2,6-difluoro-4-[4-(isobutylamino)pyrimidin-2-yl]phenyl]-4-piperidyl-
]acetic Acid
##STR00403##
[3152] 2-Chloro-N-isobutyl-pyrimidin-4-amine (0.054 g, 0.29 mmol)
obtained in Preparation Example 255 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.166 g, 0.4 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.035 g, 35%).
[3153] .sup.1H-NMR (CDCl.sub.3) .delta. 8.24 (1H, m), 7.80 (2H, m),
6.21 (1H, d), 3.35 (2H, m), 3.15 (4H, m), 2.35 (2H, d), 1.94 (2H,
m), 1.82 (2H, m), 1.48 (2H, m), 1.00 (6H, d)
Example 361:
2-[1-[4-[6-(cyclobutoxy)-5-methyl-pyrazin-2-yl]-2,6-difluoro-phenyl]-4-pi-
peridyl]acetic Acid
##STR00404##
[3155] 5-Chloro-3-(cyclobutoxy)-2-methyl-pyrazine (0.061 g, 0.3
mmol) obtained in Preparation Example 256 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.064 g, 48%).
[3156] .sup.1H-NMR (CDCl.sub.3) .delta. 8.33 (1H, s), 7.46 (2H, m),
5.27 (1H, m), 3.31 (2H, m), 3.16 (2H, m), 2.53 (2H, m), 2.49 (3H,
s), 2.37 (2H, d), 2.23 (2H, m), 1.99 (1H, m), 1.81 (4H, m), 1.48
(2H, m)
Example 362:
2-[1-[2,6-difluoro-4-(6-phenylpyrazin-2-yl)phenyl]-4-piperidyl]acetic
Acid
##STR00405##
[3158] 2-Chloro-6-phenyl-pyrazine (0.058 g, 0.3 mmol) and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.12 g, 98%).
[3159] .sup.1H-NMR (CDCl.sub.3) .delta. 8.95 (1H, s), 8.86 (1H, s),
8.13 (2H, m), 7.66 (2H, m), 7.54 (3H, m), 3.37 (2H, m), 3.19 (2H,
m), 2.38 (2H, d), 1.99 (1H, m), 1.82 (2H, m), 1.48 (2H, m)
Example 363:
2-[1-[4-(6-cyclopentylpyrazin-2-yl)-2,6-difluoro-phenyl]-4-piperidyl]acet-
ic Acid
##STR00406##
[3161] 2-Chloro-6-cyclopentyl-pyrazine (0.058 g, 0.32 mmol)
obtained in Preparation Example 258 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.155 g, 0.38 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.087 g, 66%).
[3162] .sup.1H-NMR (CDCl.sub.3) .delta. 8.71 (1H, s), 8.37 (1H, s),
7.55 (2H, m), 3.35 (2H, m), 3.26 (1H, m), 3.17 (2H, m), 2.37 (2H,
d), 2.10 (2H, m), 1.99 (1H, m), 1.88 (6H, m), 1.74 (2H, m), 1.49
(2H, m)
Example 364:
2-[1-[2,6-difluoro-4-(6-isobutylpyrazin-2-yl)phenyl]-4-piperidyl]acetic
Acid
##STR00407##
[3164] 2-Chloro-6-isobutyl-pyrazine (0.055 g, 0.32 mmol) obtained
in Preparation Example 257 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.158 g, 0.38 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.10 g, 80%).
[3165] .sup.1H-NMR (CDCl.sub.3) .delta. 8.73 (1H, s), 8.31 (1H, s),
7.54 (2H, m), 3.35 (2H, m), 3.17 (2H, m), 2.71 (2H, d), 2.37 (2H,
d), 2.20 (1H, m), 1.99 (1H, m), 1.83 (2H, m), 1.48 (2H, m), 0.98
(6H, d)
Example 365:
2-[1-[2,6-difluoro-4-(4-isobutylpyrimidin-2-yl)phenyl]-4-piperidyl]acetic
Acid
##STR00408##
[3167] 2-Chloro-4-isobutyl-pyrimidine (0.055 g, 0.32 mmol) obtained
in Preparation Example 259 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.158 g, 0.38 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.102 g, 82%).
[3168] .sup.1H-NMR (CDCl.sub.3) .delta. 8.60 (1H, d), 7.94 (2H, m),
6.97 (1H, d), 3.37 (2H, m), 3.17 (2H, m), 2.65 (2H, d), 2.37 (2H,
d), 2.22 (1H, m), 1.98 (1H, m), 1.83 (2H, m), 1.49 (2H, m), 0.97
(6H, d)
Example 366:
2-[1-[4-[5-(cyclobutoxy)-3-methyl-isothiazol-4-yl]-2,6-difluoro-phenyl]-4-
-piperidyl]acetic Acid
##STR00409##
[3170] 4-Bromo-5-(cyclobutoxy)-3-methyl-isothiazole (0.046 g, 0.19
mmol) obtained in Preparation Example 292 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.091 g, 0.22 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.05 g, 62%).
[3171] .sup.1H-NMR (CDCl.sub.3) .delta. 6.83 (2H, m), 4.60 (1H, m),
3.30 (2H, m), 3.15 (2H, m), 2.47 (2H, m), 2.37 (5H, m), 2.24 (2H,
m), 1.97 (1H, m), 1.84 (3H, m), 1.67 (1H, m), 1.48 (2H, m)
Example 367:
{1-[4-(4-ethoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin-4-yl}acetic
Acid
##STR00410##
[3172] Step A:
{1-[4-(4-ethoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin-4-yl}acetic
Acid Ethyl Ester
[3173]
[1-(2,6-Difluoro-4-thiocarbamoyl-phenyl)-piperidin-4-yl]acetic acid
ethyl ester (0.160 g, 0.47 mmol) obtained in Preparation Example
224 and chloroacetic acid ethyl ester (0.115 g, 0.93 mmol) were
dissolved in EtOH and stirred for 5 hours under reflux. The
reaction solution was cooled to room temperature, concentrated
under reduced pressure and purified by column chromatography to
obtain the title compound (0.061 g, 32%).
[3174] .sup.1H-NMR (CDCl.sub.3) .delta. 7.42 (2H, m), 6.07 (1H, s),
4.24-4.15 (4H, m), 3.35 (2H, m), 3.16 (2H, m), 2.32 (2H, d), 1.99
(1H, m), 1.80 (2H, m), 1.49 (3H, t), 1.43 (2H, m), 1.30 (3H, t)
Step B:
{1-[4-(4-ethoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin-4-yl}-
acetic Acid
[3175]
{1-[4-(4-Ethoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin-4-yl}a-
cetic acid ethyl ester (0.061 g, 0.15 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.046 g, 81%).
[3176] .sup.1H-NMR (CDCl.sub.3) .delta. 7.43 (2H, m), 6.09 (1H, s),
4.22 (2H, q), 3.37 (2H, m), 3.18 (2H, m), 2.40 (2H, d), 2.01 (1H,
m), 1.86 (2H, m), 1.52-1.47 (5H, m)
Example 368:
{1-[4-(4-ethoxy-5-methyl-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin-4-y-
l}acetic Acid
##STR00411##
[3177] Step A:
{1-[4-(4-ethoxy-5-methyl-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin-4-y-
l}acetic Acid Ethyl Ester
[3178]
[1-(2,6-Difluoro-4-thiocarbamoyl-phenyl)-piperidin-4-yl]acetic acid
ethyl ester (0.089 g, 0.26 mmol) obtained in Preparation Example
224 and 2-bromopropanoic acid ethyl ester (0.095 g, 0.52 mmol) were
reacted in the same manner as in Step A of Example 367 to obtain
the title compound (0.059 g, 53%).
[3179] .sup.1H-NMR (CDCl.sub.3) .delta. 7.33 (2H, m), 4.41 (2H, q),
4.19 (2H, q), 3.33 (2H, m), 3.15 (2H, m), 2.32 (2H, d), 2.31 (3H,
s), 1.99 (1H, m), 1.80 (2H, m), 1.49 (2H, m), 1.39 (3H, t), 1.29
(3H, t)
Step B:
{1-[4-(4-ethoxy-5-methyl-thiazol-2-yl)-2,6-difluoro-phenyl]-piperi-
din-4-yl}acetic Acid
[3180]
{1-[4-(4-Ethoxy-5-methyl-thiazol-2-yl)-2,6-difluoro-phenyl]-piperid-
in-4-yl}acetic acid ethyl ester (0.059 g, 0.14 mmol) obtained in
Step A was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.045 g, 82%).
[3181] .sup.1H-NMR (CDCl.sub.3) .delta. 7.35 (2H, m), 4.41 (2H, q),
3.34 (2H, m), 3.17 (2H, m), 2.40 (2H, d), 2.32 (3H, s), 2.01 (1H,
m), 1.86 (2H, m), 1.52 (2H, m), 1.42 (3H, t)
Example 369:
2-[1-[4-(6-butylpyrazin-2-yl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
Acid
##STR00412##
[3183] 2-Butyl-6-chloro-pyrazine (0.06 g, 0.35 mmol) obtained in
Preparation Example 260 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.158 g, 0.39 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.11 g, 81%).
[3184] .sup.1H-NMR (CDCl.sub.3) .delta. 8.72 (1H, s), 8.35 (1H, s),
7.55 (2H, m), 3.34 (2H, m), 3.16 (2H, m), 2.84 (2H, t), 2.37 (2H,
d), 2.00 (1H, m), 1.80 (4H, m), 1.44 (4H, m), 0.97 (3H, t)
Example 370:
2-[1-[2,6-difluoro-4-(6-isopentylpyrazin-2-yl)phenyl]-4-piperidyl]acetic
Acid
##STR00413##
[3186] 2-Chloro-6-isopentyl-pyrazine (0.06 g, 0.32 mmol) obtained
in Preparation Example 261 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.146 g, 0.36 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.11 g, 88%).
[3187] .sup.1H-NMR (CDCl.sub.3) .delta. 8.72 (1H, s), 8.35 (1H, s),
7.54 (2H, m), 3.35 (2H, m), 3.17 (2H, m), 2.85 (2H, m), 2.37 (2H,
d), 2.00 (1H, m), 1.83 (2H, m), 1.68 (3H, m), 1.52 (2H, m), 0.98
(6H, d)
Example 371:
2-[1-[4-[4-(cyclobutoxy)-5-fluoro-pyrimidin-2-yl]-2,6-difluoro-phenyl]-4--
piperidyl]acetic Acid
##STR00414##
[3189] 2-Chloro-4-(cyclobutoxy)-5-fluoro-pyrimidine (0.05 g, 0.25
mmol) obtained in Preparation Example 329 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.11 g, 0.27 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.072 g, 69%).
[3190] .sup.1H-NMR (CDCl.sub.3) .delta. 8.31 (1H, m), 7.78 (2H, m),
5.40 (1H, m), 3.37 (2H, m), 3.16 (2H, m), 2.55 (2H, m), 2.37 (2H,
d), 2.23 (2H, m), 1.95 (2H, m), 1.83 (3H, m), 1.49 (2H, m)
Example 372:
2-[1-[4-[4-(cyclopropylmethoxy)-5-fluoro-pyrimidin-2-yl]-2,6-difluoro-phe-
nyl]-4-piperidyl]acetic Acid
##STR00415##
[3192] 2-Chloro-4-(cyclopropylmethoxy)-5-fluoro-pyrimidine (0.05 g,
0.25 mmol) obtained in Preparation Example 330 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.11 g, 0.27 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.08 g, 77%).
[3193] .sup.1H-NMR (CDCl.sub.3) .delta. 8.32 (1H, m), 7.79 (2H, m),
4.39 (2H, d), 3.36 (2H, m), 3.16 (2H, m), 2.36 (2H, d), 1.99 (1H,
m), 1.82 (2H, m), 1.48 (2H, m), 1.39 (1H, m), 0.68 (2H, m), 0.44
(2H, m)
Example 373:
2-[1-[4-(6-cyclobutyl-2-pyridyl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
Acid
##STR00416##
[3195] 2-Chloro-6-cyclobutyl-pyridine (0.05 g, 0.3 mmol) obtained
in Preparation Example 277 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.134 g, 0.33 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.093 g, 80%).
[3196] .sup.1H-NMR (CDCl.sub.3) .delta. 7.63 (1H, t), 7.56 (2H, m),
7.42 (1H, d), 7.08 (1H, d), 3.70 (1H, m), 3.31 (2H, m), 3.16 (2H,
m), 2.36 (6H, m), 2.09 (1H, m), 1.97 (2H, m), 1.82 (2H, m), 1.51
(2H, m)
Example 374:
2-[1-[4-(6-cyclobutylpyrazin-2-yl)-2,6-difluoro-phenyl]-4-piperidyl]aceti-
c Acid
##STR00417##
[3198] 2-Chloro-6-cyclobutyl-pyrazine (0.05 g, 0.3 mmol) obtained
in Preparation Example 262 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.134 g, 0.33 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.042 g, 36%).
[3199] .sup.1H-NMR (CDCl.sub.3) .delta. 8.72 (1H, s), 8.33 (1H, s),
7.59 (2H, m), 3.74 (1H, m), 3.35 (2H, m), 3.17 (2H, m), 2.38 (6H,
m), 2.11 (1H, m), 1.99 (2H, m), 1.84 (2H, m), 1.48 (2H, m)
Example 375:
2-[1-[4-[6-(cyclobutylmethyl)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperidyl-
]acetic Acid
##STR00418##
[3201] 2-Bromo-6-(cyclobutylidenemethyl)pyridine (0.074 g, 0.33
mmol) obtained in Preparation Example 278 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.150 g, 0.366 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 to obtain
2-[1-[4-[6-(cyclobutylidenemethyl)-2-pyridyl]-2,6-difluoro-phenyl]-4-pipe-
ridyl]acetic acid ethyl ester (0.128 g, 0.3 mmol). 3 mL of MeOH and
catalytic amount of Pd/C were added thereto, and the mixture was
stirred for 150 minutes under hydrogen atmosphere. Solids were
filtered through Celite to obtain
2-[1-[4-[6-(cyclobutylmethyl)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperidyl-
]acetic acid ethyl ester. The obtained compound was reacted in the
same manner as in Step B of Example 1 to obtain the title compound
(0.108 g, 89%).
[3202] .sup.1H-NMR (CDCl.sub.3) .delta. 7.61 (1H, t), 7.51 (2H, m),
7.41 (1H, d), 7.02 (1H, d), 3.31 (2H, m), 3.16 (2H, m), 2.93 (2H,
d), 2.79 (1H, m), 2.37 (2H, d), 2.10 (2H, m), 1.98 (1H, m), 1.87
(2H, m), 1.81 (4H, m), 1.48 (2H, m)
Example 376:
2-[1-[4-[6-(cyclopentylmethyl)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperidy-
l]acetic Acid
##STR00419##
[3204] 2-Bromo-6-(cyclopentylidenemethyl)pyridine (0.080 g, 0.33
mmol) obtained in Preparation Example 279 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.150 g, 0.366 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 to obtain
2-[1-[4-[6-(cyclopentylidenemethyl)-2-pyridyl]-2,6-difluoro-phenyl]-4-pip-
eridyl]acetic acid ethyl ester (0.128 g, 0.29 mmol). 3 mL of MeOH
and catalytic amount of Pd/C were added thereto, and the mixture
was stirred for 150 minutes under hydrogen atmosphere. Solids were
filtered through Celite to obtain
2-[1-[4-[6-(cyclopentylmethyl)-2-pyridyl]-2,6-difluoro-phenyl]-4-piperidy-
l]acetic acid ethyl ester. The obtained compound was reacted in the
same manner as in Step B of Example 1 to obtain the title compound
(0.106, 88%).
[3205] .sup.1H-NMR (CDCl.sub.3) .delta. 7.61 (1H, t), 7.50 (2H, m),
7.41 (1H, d), 7.05 (1H, d), 3.30 (2H, m), 3.15 (2H, m), 2.83 (2H,
d), 2.36 (2H, d), 2.32 (1H, m), 1.97 (1H, m), 1.82 (2H, m), 1.74
(2H, m), 1.65 (2H, m), 1.54 (2H, m), 1.48 (2H, m), 1.26 (2H, m)
Example 377:
{1-[4-(4-cyclopropylmethoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin--
4-yl}acetic Acid
##STR00420##
[3206] Step A:
{1-[4-(4-cyclopropylmethoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin--
4-yl}acetic Acid Ethyl Ester
[3207]
[1-(2,6-Difluoro-4-thiocarbamoyl-phenyl)-piperidin-4-yl]acetic acid
ethyl ester (0.137 g, 0.40 mmol) obtained in Preparation Example
224 and chloroacetic acid cyclopropylmethyl ester (0.119 g, 0.80
mmol) were reacted in the same manner as in Step A of Example 367
to obtain the title compound (0.090 g, 52%).
[3208] .sup.1H-NMR (CDCl.sub.3) .delta. 7.44 (2H, m), 6.08 (1H, s),
4.18 (2H, q), 3.98 (2H, d), 3.35 (2H, m), 3.16 (2H, m), 2.32 (2H,
d), 1.99 (1H, m), 1.80 (2H, m), 1.47 (2H, m), 1.35 (1H, m), 1.31
(3H, t), 0.69 (2H, m), 0.41 (2H, m)
Step B:
{1-[4-(4-cyclopropylmethoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-pip-
eridin-4-yl}acetic Acid
[3209]
{1-[4-(4-Cyclopropylmethoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-pipe-
ridin-4-yl}acetic acid ethyl ester (0.090 g, 0.21 mmol) obtained in
Step A was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.071 g, 83%).
[3210] .sup.1H-NMR (CDCl.sub.3) .delta. 7.45 (2H, m), 6.09 (1H, s),
4.02 (2H, d), 3.37 (2H, m), 3.18 (2H, m), 2.40 (2H, d), 2.01 (1H,
m), 1.86 (2H, m), 1.52 (2H, m), 1.37 (1H, m), 0.69 (2H, m), 0.42
(2H, m)
Example 378:
(1-{2,6-difluoro-4-[4-(4-fluoro-phenyl)-thiazol-2-yl]-phenyl}-piperidin-4-
-yl)-acetic Acid
##STR00421##
[3211] Step A:
(1-{2,6-difluoro-4-[4-(4-fluoro-phenyl)-thiazol-2-yl]-phenyl}-piperidin-4-
-yl)-acetic Acid Ethyl Ester
[3212]
[1-(2,6-Difluoro-4-thiocarbamoyl-phenyl)-piperidin-4-yl]acetic acid
ethyl ester (0.123 g, 0.36 mmol) obtained in Preparation Example
224 and 2-chloro-1-(4-fluoro-phenyl)-ethanone (0.052 g, 0.30 mmol)
were reacted in the same manner as in Step A of Example 367 to
obtain the title compound (0.107 g, 77%).
[3213] .sup.1H-NMR (CDCl.sub.3) .delta. 7.97 (2H, m), 7.52 (2H, m),
7.42 (1H, s), 7.17 (2H, m), 4.20 (2H, q), 3.39 (2H, m), 3.19 (2H,
m), 2.34 (2H, d), 2.02 (1H, m), 1.83 (2H, m), 1.50 (2H, m), 1.32
(3H, t)
Step B:
(1-{2,6-difluoro-4-[4-(4-fluoro-phenyl)-thiazol-2-yl]-phenyl}-pipe-
ridin-4-yl)-acetic Acid
[3214]
(1-{2,6-Difluoro-4-[4-(4-fluoro-phenyl)-thiazol-2-yl]-phenyl}-piper-
idin-4-yl)-acetic acid ethyl ester (0.107 g, 0.23 mmol) obtained in
Step A was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.063 g, 63%).
[3215] .sup.1H-NMR (DMSO-d.sub.6) .delta. 8.19 (1H, s), 8.11 (2H,
m), 7.67 (2H, m), 7.32 (2H, t), 3.34 (2H, m), 3.10 (2H, m), 2.23
(2H, d), 1.85 (1H, m), 1.76 (2H, m), 1.34 (2H, m)
Example 379:
{1-[4-(4-cyclobutoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin-4-yl}ac-
etic Acid
##STR00422##
[3216] Step A:
{1-[4-(4-cyclobutoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin-4-yl}ac-
etic Acid Ethyl Ester
[3217]
[1-(2,6-Difluoro-4-thiocarbamoyl-phenyl)-piperidin-4-yl]acetic acid
ethyl ester (0.103 g, 0.30 mmol) obtained in Preparation Example
224 and chloroacetic acid cyclobutyl ester (0.09 g, 0.60 mmol) were
reacted in the same manner as in Step A of Example 367 to obtain
the title compound (0.072 g, 55%).
[3218] .sup.1H-NMR (CDCl.sub.3) .delta. 7.42 (2H, m), 5.99 (1H, s),
4.80 (1H, m), 4.18 (2H, q), 3.36 (2H, m), 3.16 (2H, m), 2.50 (2H,
m), 2.32 (2H, d), 2.29 (2H, m), 1.96-1.45 (5H, m), 1.47 (2H, m),
1.31 (3H, t)
Step B:
{1-[4-(4-cyclobutoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin--
4-yl}acetic Acid
[3219]
{1-[4-(4-Cyclobutoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin-4-
-yl}acetic acid ethyl ester (0.090 g, 0.21 mmol) obtained in Step A
was reacted in the same manner as in Step B of Example 1 to obtain
the title compound (0.071 g, 83%).
[3220] .sup.1H-NMR (CDCl.sub.3) .delta. 7.45 (2H, m), 6.00 (1H, s),
4.80 (1H, m), 3.37 (2H, m), 3.18 (2H, m), 2.50 (2H, m), 2.40 (2H,
d), 2.29 (2H, m), 1.94-1.84 (4H, m), 1.73 (1H, m), 1.51 (2H, m)
Example 380:
{1-[4-(4-butoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin-4-yl}acetic
Acid
##STR00423##
[3221] Step A:
{1-[4-(4-butoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin-4-yl}acetic
Acid Ethyl Ester
[3222]
[1-(2,6-Difluoro-4-thiocarbamoyl-phenyl)-piperidin-4-yl]acetic acid
ethyl ester (0.103 g, 0.30 mmol) obtained in Preparation Example
224 and chloroacetic acid butyl ester (0.091 g, 0.60 mmol) were
reacted in the same manner as in Step A of Example 367 to obtain
the title compound (0.061 g, 46%).
[3223] .sup.1H-NMR (CDCl.sub.3) .delta. 7.42 (2H, m), 6.07 (1H, s),
4.32 (2H, t), 4.19 (2H, q), 3.42 (2H, m), 3.16 (2H, m), 2.32 (2H,
d), 2.03 (1H, m), 1.86-1.78 (4H, m), 1.56-1.42 (4H, m), 1.30 (3H,
t), 1.01 (3H, t)
Step B:
{1-[4-(4-butoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin-4-yl}-
acetic Acid
[3224]
{1-[4-(4-Butoxy-thiazol-2-yl)-2,6-difluoro-phenyl]-piperidin-4-yl}a-
cetic acid ethyl ester (0.061 g, 0.14 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.044 g, 77%).
[3225] .sup.1H-NMR (CDCl.sub.3) .delta. 7.45 (2H, m), 6.08 (1H, s),
4.15 (2H, t), 3.37 (2H, m), 3.18 (2H, m), 2.40 (2H, d), 2.01 (1H,
m), 1.87-1.82 (4H, m), 1.61-1.47 (4H, m), 1.02 (3H, t)
Example 381:
2-(1-{2,6-difluoro-4-[7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]phe-
nyl}piperidin-4-yl)acetic Acid
##STR00424##
[3226] Step A:
2-(1-{2,6-difluoro-4-[7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]phe-
nyl}piperidin-4-yl)acetic Acid Ethyl Ester
[3227] 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (0.097 g, 0.63 mmol)
and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.284 g, 0.69 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 to obtain
2-[1-[2,6-difluoro-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl]-4-piperidyl-
]acetic acid ethyl ester. The obtained compound was dissolved in
1.6 mL of CH.sub.3CN. Cs.sub.2CO.sub.3 (0.244 g, 0.75 mmol) and
2-iodopropane (0.075 mL, 0.75 mmol) were added thereto, and the
mixture was stirred for 1 hour under reflux. The reaction solution
was purified by column chromatography to obtain the title compound
(0.16 g, 58%).
[3228] .sup.1H-NMR (CDCl.sub.3) .delta. 8.90 (1H, s), 7.66 (2H, m),
7.38 (1H, m), 6.80 (1H, m), 5.20 (1H, m), 4.15 (2H, m), 3.38 (2H,
m), 3.18 (2H, m), 2.30 (2H, d), 1.98 (1H, m), 1.79 (2H, m), 1.55
(6H, d), 1.47 (2H, m), 1.28 (3H, t)
Step B:
2-(1-{2,6-difluoro-4-[7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-
-yl]phenyl}piperidin-4-yl)acetic Acid
[3229]
2-(1-{2,6-Difluoro-4-[7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4--
yl]phenyl}piperidin-4-yl)acetic acid ethyl ester (0.16 g, 0.36
mmol) obtained in Step A was reacted in the same manner as in Step
B of Example 1 to obtain the title compound (0.135 g, 95%).
[3230] .sup.1H-NMR (CDCl.sub.3) .delta. 8.90 (1H, s), 7.65 (2H, m),
7.40 (1H, m), 6.81 (1H, m), 5.19 (1H, m), 3.39 (2H, m), 3.19 (2H,
m), 2.34 (2H, d), 1.99 (1H, m), 1.83 (2H, m), 1.56 (6H, d), 1.51
(2H, m)
Example 382:
2-[1-[4-(6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,6-difluoro-phenyl]-
-4-piperidyl]acetic Acid
##STR00425##
[3232] 4-Chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.052 g,
0.33 mmol) obtained in Preparation Example 263 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.366 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.016 g, 12%).
[3233] .sup.1H-NMR (CDCl.sub.3) .delta. 9.00 (1H, s), 7.48 (2H, m),
3.39 (2H, m), 3.21 (2H, t), 3.17 (2H, m), 3.07 (2H, t), 2.36 (2H,
d), 2.18 (2H, m), 1.99 (1H, m), 1.84 (2H, m), 1.48 (2H, m)
Example 383:
2-[1-[4-[4-(cyclobutoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]-2,6--
difluoro-phenyl]-4-piperidyl]acetic Acid
##STR00426##
[3235]
2-Chloro-4-(cyclobutoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine
(0.052 g, 0.33 mmol) obtained in Preparation Example 264 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.366 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.12 g, 82%).
[3236] .sup.1H-NMR (CDCl.sub.3) .delta. 7.84 (2H, m), 5.35 (1H, m),
3.34 (2H, m), 3.15 (2H, m), 2.97 (2H, t), 2.85 (2H, t), 2.53 (2H,
m), 2.35 (2H, d), 2.19 (2H, m), 2.12 (2H, m), 1.97 (1H, m), 1.87
(1H, m), 1.81 (2H, m), 1.75 (1H, m), 1.47 (2H, m)
Example 384:
2-[1-[4-[4-(cyclobutoxy)-5,6-dimethyl-pyrimidin-2-yl]-2,6-difluoro-phenyl-
]-4-piperidyl]acetic Acid
##STR00427##
[3238] 2-Chloro-4-(cyclobutoxy)-5,6-dimethyl-pyrimidine (0.052 g,
0.33 mmol) obtained in Preparation Example 265 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.366 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.105 g, 74%).
[3239] .sup.1H-NMR (CDCl.sub.3) .delta. 7.84 (2H, m), 5.31 (1H, m),
3.33 (2H, m), 3.16 (2H, m), 2.54 (2H, m), 2.45 (3H, s), 2.36 (2H,
d), 2.18 (2H, m), 2.13 (3H, s), 1.97 (1H, m), 1.87 (1H, m), 1.82
(2H, m), 1.77 (1H, m), 1.49 (2H, m)
Example 385:
4-[2-chloro-4-[6-(cyclobutoxy)-2-pyridyl]-6-fluoro-phenoxy]butanoic
Acid
##STR00428##
[3241]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.255 g, 0.66 mmol) obtained in
Preparation Example 221 and 2-chloro-6-cyclobutoxy-pyridine (0.11
g, 0.60 mmol) obtained in Preparation Example 29 were reacted in
the same manner as in Step A of Example 96 and Step B of Example 1
to obtain the title compound (0.136 g, 60%).
[3242] .sup.1H-NMR (CDCl.sub.3) .delta. 7.79 (1H, m), 7.70 (1H, m),
7.61 (1H, t), 7.22 (1H, m), 6.65 (1H, d), 5.25 (1H, m), 4.21 (2H,
t), 2.72 (2H, t), 2.53 (2H, m), 2.18 (4H, m), 1.87 (1H, m), 1.76
(1H, m)
Example 386:
4-[2,6-dichloro-4-[6-(cyclobutoxy)-2-pyridyl]phenoxy]butanoic
Acid
##STR00429##
[3244]
4-[2,6-Dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
oxy]butanoic acid ethyl ester (0.222 g, 0.55 mmol) obtained in
Preparation Example 222 and 2-chloro-6-cyclobutoxy-pyridine (0.092
g, 0.50 mmol) obtained in Preparation Example 29 were reacted in
the same manner as in Step A of Example 96 and Step B of Example 1
to obtain the title compound (0.038 g, 19%).
[3245] .sup.1H-NMR (CDCl.sub.3) .delta. 7.92 (2H, s), 7.62 (1H, t),
7.22 (1H, m), 6.66 (1H, m), 5.25 (1H, m), 4.12 (2H, t), 2.77 (2H,
t), 2.53 (2H, m), 2.20 (4H, m), 1.88 (1H, m), 1.77 (1H, m)
Example 387:
4-[4-[3-(cyclopropylmethoxymethyl)-2-furyl]-2,6-difluoro-phenoxy]butanoic
Acid
##STR00430##
[3246] Step A: 4-[2,6-difluoro-4-(3-formyl-2-furyl)phenoxy]butanoic
Acid Ethyl Ester
[3247]
4-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
oxy]butanoic acid ethyl ester (0.26 g, 0.8 mmol) obtained in
Preparation Example 16 and (3-formyl-2-furyl)boronic acid (0.168 g,
1.2 mmol) were reacted in the same manner as in Step A of Example
96 to obtain the title compound (0.191 g, 71%).
[3248] .sup.1H-NMR (CDCl.sub.3) .delta. 10.07 (1H, s), 7.41 (3H,
m), 6.90 (1H, m), 4.26 (2H, t), 4.14 (2H, q), 2.58 (2H, t), 2.12
(2H, m), 1.26 (3H, t)
Step B:
4-[2,6-difluoro-4-[3-(hydroxymethyl)-2-furyl]phenoxy]butanoic Acid
Ethyl Ester
[3249] 4-[2,6-Difluoro-4-(3-formyl-2-furyl)phenoxy]butanoic acid
ethyl ester (0.191 g, 0.56 mmol) obtained in Step A was dissolved
in 10 mL of MeOH and cooled to 0.degree. C. NaBH.sub.4 (0.022 g,
0.58 mmol) was added thereto, and the mixture was stirred at room
temperature for 30 minutes. After addition of water, the reaction
solution was extracted with EtOAc. The organic layer was dried with
anhydrous magnesium sulfate and purified by column chromatography
to obtain the title compound (0.189 g, 99%).
[3250] .sup.1H-NMR (CDCl.sub.3) .delta. 7.40 (1H, d), 7.26 (2H, m),
6.53 (1H, d), 4.70 (2H, d), 4.20 (2H, t), 4.14 (2H, q), 2.58 (2H,
t), 2.10 (2H, m), 1.63 (1H, t), 1.26 (3H, t)
Step C:
4-[4-[3-(cyclopropylmethoxymethyl)-2-furyl]-2,6-difluoro-phenoxy]b-
utanoic Acid
[3251]
4-[2,6-Difluoro-4-[3-(hydroxymethyl)-2-furyl]phenoxy]butanoic acid
ethyl ester (0.189 g, 0.55 mmol) obtained in Step B and
bromomethylcyclopropane (0.082 g, 0.61 mmol) were reacted in the
same manner as in Preparation Example 267 to obtain
4-[4-[3-(cyclopropylmethoxymethyl)-2-furyl]-2,6-difluoro-phenoxy]butanoic
acid ethyl ester (0.105 g, 48%). The obtained compound was reacted
in the same manner as in Step B of Example 1 to obtain the title
compound (0.087 g, 89%).
[3252] .sup.1H-NMR (CDCl.sub.3) .delta. 7.40 (1H, d), 7.28 (2H, m),
6.49 (1H, d), 4.46 (2H, s), 4.21 (2H, t), 3.37 (2H, d), 2.66 (2H,
t), 2.10 (2H, m), 1.13 (1H, m), 0.56 (2H, m), 0.25 (2H, m)
Example 388:
4-[4-[6-(cyclopropylmethoxymethyl)-2-pyridyl]-2,6-difluoro-phenoxy]butano-
ic Acid
##STR00431##
[3254]
4-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
oxy]butanoic acid ethyl ester (0.163 g, 0.44 mmol) obtained in
Preparation Example 16 and
2-bromo-6-(cyclopropylmethoxymethyl)pyridine (0.097 g, 0.40 mmol)
obtained in Preparation Example 267 were reacted in the same manner
as in Step A of Example 96 and Step B of Example 1 to obtain the
title compound (0.133 g, 88%).
[3255] .sup.1H-NMR (CDCl.sub.3) .delta. 7.76 (1H, t), 7.57 (2H, m),
7.51 (1H, m), 7.45 (1H, m), 4.72 (2H, s), 4.24 (2H, t), 3.44 (2H,
d), 2.67 (2H, t), 2.11 (2H, m), 2.08 (1H, m), 0.58 (2H, m), 0.26
(2H, m)
Example 389:
4-[2-chloro-4-[3-(cyclobutoxy)-5-fluoro-phenyl]-6-fluoro-phenoxy]butanoic
Acid
##STR00432##
[3257]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (1.55 g, 4.0 mmol) obtained in
Preparation Example 221 and
1-bromo-3-(cyclobutoxy)-5-fluoro-benzene (1.08 g, 4.4 mmol)
obtained in Preparation Example 284 were reacted in the same manner
as in Step A of Example 96 and Step B of Example 1 to obtain the
title compound (1.25 g, 79%).
[3258] .sup.1H-NMR (CDCl.sub.3) .delta. 7.34 (1H, m), 7.18 (1H, m),
6.78 (1H, m), 6.77 (1H, m), 6.51 (1H, m), 4.64 (1H, m), 4.20 (2H,
t), 2.72 (2H, t), 2.58 (2H, m), 2.19 (4H, m), 1.89 (1H, m), 1.72
(1H, m)
Example 390:
4-[4-[3-(cyclopropylmethoxymethyl)-5-methyl-isoxazol-4-yl]-2,6-difluoro-p-
henoxy]butanoic Acid
##STR00433##
[3260] 4-Bromo-3-(cyclopropylmethoxymethyl)-5-methyl-isoxazole
(0.058 g, 0.24 mmol) obtained in Preparation Example 291 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tanoic acid ethyl ester (0.098 g, 0.26 mmol) obtained in
Preparation Example 16 were reacted in the same manner as in Step A
of Example 96 and Step B of Example 1 to obtain the title compound
(0.015 g, 16%).
[3261] .sup.1H-NMR (CDCl.sub.3) .delta. 7.05 (2H, m), 4.50 (2H, s),
4.24 (2H, t), 3.35 (2H, d), 2.67 (2H, t), 2.47 (3H, s), 2.12 (2H,
m), 1.06 (1H, m), 0.55 (2H, m), 0.20 (2H, m)
Example 391:
4-[2-chloro-4-[4-(cyclobutoxy)-6-methyl-pyrimidin-2-yl]-6-fluoro-phenoxy]-
butanoic Acid
##STR00434##
[3263]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.193 g, 0.5 mmol) obtained in
Preparation Example 221 and
2-chloro-4-(cyclobutoxy)-6-methyl-pyrimidine (0.10 g, 0.5 mmol)
obtained in Preparation Example 228 were reacted in the same manner
as in Step A of Example 96 and Step B of Example 1 to obtain the
title compound (0.081 g, 41%).
[3264] .sup.1H-NMR (CDCl.sub.3) .delta. 8.27 (1H, d), 8.11 (1H, m),
6.46 (1H, s), 5.34 (1H, m), 4.27 (2H, t), 2.76 (2H, t), 2.56 (2H,
m), 2.51 (3H, s), 2.24 (4H, m), 1.93 (1H, m), 1.80 (1H, m)
Example 392:
4-[2-chloro-4-[2-(cyclobutoxy)-6-methyl-pyrimidin-4-yl]-6-fluoro-phenoxy]-
butanoic Acid
##STR00435##
[3266]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.193 g, 0.5 mmol) obtained in
Preparation Example 221 and
4-chloro-2-(cyclobutoxy)-6-methyl-pyrimidine (0.10 g, 0.5 mmol)
obtained in Preparation Example 229 were reacted in the same manner
as in Step A of Example 96 and Step B of Example 1 to obtain the
title compound (0.166 g, 84%).
[3267] .sup.1H-NMR (CDCl.sub.3) .delta. 7.92 (1H, d), 7.80 (1H, m),
7.14 (1H, s), 5.30 (1H, m), 4.29 (2H, t), 2.75 (2H, t), 2.54 (5H,
m), 2.29 (2H, m), 2.19 (2H, m), 1.91 (1H, m), 1.77 (1H, m)
Example 393:
4-[4-[6-chloro-4-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenoxy]butanoic
Acid
##STR00436##
[3269] 2,6-Dichloro-4-(cyclobutoxy)pyridine (0.06 g, 0.27 mmol)
obtained in Preparation Example 270 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tanoic acid ethyl ester (0.122 g, 0.33 mmol) obtained in
Preparation Example 16 were reacted in the same manner as in Step A
of Example 96 and Step B of Example 1 to obtain the title compound
(0.021 g, 20%).
[3270] .sup.1H-NMR (CDCl.sub.3) .delta. 7.51 (2H, m), 6.97 (1H, m),
6.66 (1H, m), 4.73 (1H, m), 4.25 (2H, t), 2.66 (2H, m), 2.52 (2H,
m), 2.22 (2H, m), 2.11 (2H, m), 1.95 (1H, m), 1.77 (1H, m)
Example 394:
4-[4-[2-(cyclobutoxy)thiazol-4-yl]-2,6-difluoro-phenoxy]butanoic
Acid
##STR00437##
[3272] 4-Bromo-2-(cyclobutoxy)thiazole (0.07 g, 0.3 mmol) obtained
in Preparation Example 289 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tanoic acid ethyl ester (0.122 g, 0.33 mmol) obtained in
Preparation Example 16 were reacted in the same manner as in Step A
of Example 96 and Step B of Example 1 to obtain the title compound
(0.91 g, 82%).
[3273] .sup.1H-NMR (CDCl.sub.3) .delta. 7.34 (2H, m), 6.78 (1H, s),
5.18 (1H, m), 4.20 (2H, t), 2.65 (2H, t), 2.54 (2H, m), 2.25 (2H,
m), 2.10 (2H, m), 1.88 (1H, m), 1.70 (1H, m)
Example 395:
4-[4-[6-(cyclobutoxy)-4-methyl-2-pyridyl]-2,6-difluoro-phenoxy]butanoic
Acid
##STR00438##
[3275] 2-Chloro-6-(cyclobutoxy)-4-methyl-pyridine (0.06 g, 0.3
mmol) obtained in Preparation Example 271 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tanoic acid ethyl ester (0.124 g, 0.33 mmol) obtained in
Preparation Example 16 were reacted in the same manner as in Step A
of Example 96 and Step B of Example 1 to obtain the title compound
(0.04 g, 35%).
[3276] .sup.1H-NMR (CDCl.sub.3) .delta. 7.56 (2H, m), 7.04 (1H, s),
6.47 (1H, s), 5.23 (1H, m), 4.23 (2H, t), 2.67 (2H, m), 2.51 (2H,
m), 2.33 (3H, s), 2.14 (4H, m), 1.85 (1H, m), 1.74 (1H, m)
Example 396:
4-[2-chloro-4-[4-(cyclopropylmethoxy)-6-methyl-pyrimidin-2-yl]-6-fluoro-p-
henoxy]butanoic Acid
##STR00439##
[3278] 2-Chloro-4-(cyclopropylmethoxy)-6-methyl-pyrimidine (0.065
g, 0.33 mmol) obtained in Preparation Example 227 and
4-[2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheno-
xy]butanoic acid ethyl ester (0.139 g, 0.36 mmol) obtained in
Preparation Example 221 were reacted in the same manner as in Step
A of Example 96 and Step B of Example 1 to obtain the title
compound (0.10 g, 72%).
[3279] .sup.1H-NMR (CDCl.sub.3) .delta. 8.24 (1H, d), 8.07 (1H, m),
6.49 (1H, s), 4.28 (2H, d), 4.23 (2H, t), 2.72 (2H, t), 2.47 (3H,
s), 2.15 (2H, m), 1.31 (1H, m), 0.66 (2H, m), 0.40 (2H, m)
Example 397:
4-[4-[2-(cyclopropylmethoxy)thiazol-4-yl]-2,6-difluoro-phenoxy]butanoic
Acid
##STR00440##
[3281] 4-Bromo-2-(cyclopropylmethoxy)thiazole (0.07 g, 0.3 mmol)
obtained in Preparation Example 290 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tanoic acid ethyl ester (0.122 g, 0.33 mmol) obtained in
Preparation Example 16 were reacted in the same manner as in Step A
of Example 96 and Step B of Example 1 to obtain the title compound
(0.073 g, 66%).
[3282] .sup.1H-NMR (CDCl.sub.3) .delta. 7.34 (2H, m), 6.78 (1H, s),
4.30 (2H, d), 4.20 (2H, t), 2.66 (2H, m), 2.10 (2H, m), 1.35 (1H,
m), 0.67 (2H, m), 0.42 (2H, m)
Example 398:
4-[4-[6-(cyclobutoxy)pyrazin-2-yl]-2,6-difluoro-phenoxy]butanoic
Acid
##STR00441##
[3284] 2-Chloro-6-(cyclobutoxy)pyrazine (0.07 g, 0.38 mmol)
obtained in Preparation Example 232 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tanoic acid ethyl ester (0.154 g, 0.42 mmol) obtained in
Preparation Example 16 were reacted in the same manner as in Step A
of Example 96 and Step B of Example 1 to obtain the title compound
(0.12 g, 87%).
[3285] .sup.1H-NMR (CDCl.sub.3) .delta. 8.48 (1H, s), 8.12 (1H, s),
7.57 (2H, m), 5.26 (1H, m), 4.27 (2H, t), 2.68 (2H, t), 2.53 (2H,
m), 2.22 (2H, m), 2.14 (2H, m), 1.91 (1H, m), 1.77 (1H, m)
Example 399:
5-[4-[6-(cyclobutoxy)pyrazin-2-yl]-2,6-difluoro-phenyl]hexanoic
Acid
##STR00442##
[3287] 2-Chloro-6-(cyclobutoxy)pyrazine (0.053 g, 0.28 mmol)
obtained in Preparation Example 232 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.12 g, 0.31 mmol) obtained in Preparation
Example 32 were reacted in the same manner as in Step A of Example
96 and Step B of Example 1 to obtain the title compound (0.10 g,
98%).
[3288] .sup.1H-NMR (CDCl.sub.3) .delta. 8.50 (1H, s), 8.14 (1H, s),
7.48 (2H, m), 5.27 (1H, m), 3.26 (1H, m), 2.55 (2H, m), 2.38 (2H,
m), 2.21 (2H, m), 1.90 (2H, m), 1.75 (2H, m), 1.64 (2H, m), 1.37
(3H, d)
Example 400:
4-[2-chloro-4-(6-cyclopentyloxy-pyridin-2-yl)-6-fluoro-phenoxy]-butyric
Acid
##STR00443##
[3290]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 221 and 2-chloro-6-cyclopentyloxy-pyridine
(0.077 g, 0.39 mmol) obtained in Preparation Example 12 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.059 g, 57%).
[3291] 1H-NMR (CDCl3) .delta. 7.80 (1H, s), 7.70 (1H, dd), 7.58
(1H, t), 7.20 (1H, d), 6.63 (1H, d), 5.49 (1H, m), 4.20 (2H, t),
2.72 (2H, t), 2.15 (2H, t), 2.04 (2H, m), 1.81 (4H, m), 1.64 (2H,
m).
Example 401:
4-[2-chloro-4-(6-cyclopropylmethoxy-pyridin-2-yl)-6-fluoro-phenoxy]-butyr-
ic Acid
##STR00444##
[3293]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 221 and 2-chloro-6-cyclopropylmethoxy-pyridine
(0.07 g, 0.39 mmol) obtained in Preparation Example 43 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.053 g, 53%).
[3294] .sup.1H-NMR (CDCl.sub.3) .delta. 7.78 (1H, s), 7.69 (1H,
dd), 7.61 (1H, t), 7.22 (1H, d), 6.71 (1H, d), 4.21 (4H, m), 2.71
(2H, t), 2.13 (2H, m), 1.32 (1H, m), 0.62 (2H, m), 0.38 (2H,
m).
Example 402:
4-[2-chloro-6-fluoro-4-(6-isopropoxy-pyridin-2-yl)-phenoxy]-butyric
Acid
##STR00445##
[3296]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 221 and 2-chloro-6-isopropoxy-pyridine (0.066
g, 0.39 mmol) obtained in Preparation Example 46 were sequentially
reacted in the same manner as in Steps A and B of Example 1 to
obtain the title compound (0.053 g, 55%).
[3297] .sup.1H-NMR (CDCl.sub.3) .delta. 7.79 (1H, s), 7.69 (1H,
dd), 7.59 (1H, t), 7.18 (1H, d), 6.64 (1H, d), 5.43 (1H, m), 4.20
(2H, t), 2.72 (2H, t), 2.15 (2H, m), 1.39 (6H, d).
Example 403:
4-[2-chloro-4-(6-cyclobutylsulfanyl-pyridin-2-yl)-6-fluoro-phenoxy]-butyr-
ic Acid
##STR00446##
[3299]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 221 and 2-chloro-6-cyclobutylsulfanyl-pyridine
(0.077 g, 0.39 mmol) obtained in Preparation Example 299 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.04 g, 39%).
[3300] .sup.1H-NMR (CDCl.sub.3) .delta. 7.81 (1H, s), 7.71 (1H,
dd), 7.51 (1H, t), 7.31 (1H, d), 7.02 (1H, d), 4.40 (1H, m), 4.21
(2H, t), 2.72 (2H, t), 2.59 (2H, m), 2.14 (6H, m).
Example 404:
4-[2-chloro-6-fluoro-4-(6-isopropylsulfanyl-pyridin-2-yl)-phenoxy]-butyri-
c Acid
##STR00447##
[3302]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 221 and 2-chloro-6-isopropylsulfanyl-pyridine
(0.073 g, 0.39 mmol) obtained in Preparation Example 10 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.038 g, 38%).
[3303] .sup.1H-NMR (CDCl.sub.3) .delta. 7.81 (1H, s), 7.70 (1H,
dd), 7.51 (1H, t), 7.31 (1H, d), 7.08 (1H, d), 4.22 (2H, t), 4.11
(1H, m), 2.72 (2H, t), 2.14 (2H, m), 1.48 (6H, d).
Example 405:
4-(5-chloro-3'-cyclobutoxy-3-fluoro-biphenyl-4-yloxy)-butyric
Acid
##STR00448##
[3305]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 221 and 1-bromo-3-cyclobutoxy-benzene (0.088 g,
0.39 mmol) obtained in Step A of Preparation Example 121 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.059 g, 60%).
[3306] .sup.1H-NMR (CDCl.sub.3) .delta. 7.35 (1H, s), 7.30 (1H, t),
7.21 (1H, m), 7.05 (1H, m), 6.93 (1H, s), 6.79 (1H, m), 4.68 (1H,
m), 4.18 (2H, t), 2.71 (2H, t), 2.46 (2H, m), 2.15 (4H, m), 1.86
(1H, m), 1.71 (1H, m).
Example 406:
4-(5-chloro-3'-cyclopropylmethoxy-3-fluoro-biphenyl-4-yloxy)-butyric
Acid
##STR00449##
[3308]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 221 and 1-bromo-3-(cyclopropylmethoxy)benzene
(0.088 g, 0.39 mmol) obtained in Preparation Example 280 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.051 g, 52%).
[3309] .sup.1H-NMR (CDCl.sub.3) .delta. 7.37 (1H, s), 7.32 (1H, t),
7.22 (1H, m), 7.04 (1H, m), 7.01 (1H, s), 6.89 (1H, m), 4.18 (2H,
t), 3.83 (2H, d), 2.71 (2H, t), 2.14 (2H, m), 1.28 (1H, m), 0.65
(2H, m), 0.37 (2H, m).
Example 407:
4-(5-chloro-3'-cyclopropylmethoxy-3-fluoro-4'-methoxy-biphenyl-4-yloxy)-b-
utyric Acid
##STR00450##
[3311]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 221 and
4-bromo-2-(cyclopropylmethoxy)-1-methoxy-benzene (0.1 g, 0.39 mmol)
obtained in Preparation Example 282 were sequentially reacted in
the same manner as in Steps A and B of Example 1 to obtain the
title compound (0.055 g, 52%).
[3312] .sup.1H-NMR (CDCl.sub.3) .delta. 7.31 (1H, s), 7.16 (1H, m),
7.03 (1H, m), 6.98 (1H, m), 6.92 (1H, d), 4.17 (2H, t), 3.90 (5H,
m), 2.71 (2H, t), 2.14 (2H, m), 1.36 (1H, m), 0.65 (2H, m), 0.38
(2H, m).
Example 408:
4-(5-chloro-3'-cyclopropylmethoxy-3,4'-difluoro-biphenyl-4-yloxy)-butyric
Acid
##STR00451##
[3314]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 221 and
4-bromo-2-(cyclopropylmethoxy)-1-fluoro-benzene (0.095 g, 0.39
mmol) obtained in Preparation Example 283 were sequentially reacted
in the same manner as in Steps A and B of Example 1 to obtain the
title compound (0.048 g, 46%).
[3315] .sup.1H-NMR (CDCl.sub.3) .delta. 7.30 (1H, s), 7.13 (2H, m),
7.02 (2H, m), 4.18 (2H, t), 3.93 (2H, d), 2.71 (2H, t), 2.13 (2H,
m), 1.32 (1H, m), 0.66 (2H, m), 0.37 (2H, m).
Example 409:
4-(3'-cyclobutylsulfanyl-3,5-difluoro-biphenyl-4-yloxy)-butyric
Acid
##STR00452##
[3317]
4-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
oxy]butyric acid ethyl ester (0.1 g, 0.27 mmol) obtained in
Preparation Example 16 and 1-bromo-3-cyclobutylsulfanyl-benzene
(0.098 g, 0.40 mmol) obtained in Preparation Example 293 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.036 g, 35%).
[3318] .sup.1H-NMR (CDCl.sub.3) .delta. 7.33 (2H, m), 7.25 (2H, m),
7.07 (2H, m), 4.22 (2H, t), 3.93 (1H, m), 2.66 (2H, t), 2.48 (2H,
m), 2.10 (6H, m).
Example 410: 5-(3'-cyclobutoxy-3,5-difluoro-biphenyl-4-yl)-hexanoic
Acid
##STR00453##
[3320]
5-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phe-
nyl]hexanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 32 and 1-bromo-3-cyclobutoxy-benzene (0.089 g,
0.39 mmol) obtained in Step A of Preparation Example 121 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.058 g, 59%).
[3321] .sup.1H-NMR (CDCl.sub.3) .delta. 7.30 (1H, t), 7.08 (1H, m),
7.03 (2H, m), 6.95 (1H, s), 6.82 (1H, m), 4.68 (1H, m), 3.21 (1H,
m), 2.46 (2H, m), 2.35 (2H, m), 2.19 (2H, m), 1.86 (2H, m), 1.72
(2H, m), 1.65 (1H, m), 1.52 (1H, m), 1.35 (3H, d).
Example 411:
5-(5'-cyclobutoxy-3,5,3'-trifluoro-biphenyl-4-yl)-hexanoic Acid
##STR00454##
[3323]
5-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phe-
nyl]hexanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 32 and 1-bromo-3-(cyclobutoxy)-5-fluoro-benzene
(0.096 g, 0.39 mmol) obtained in Preparation Example 284 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.058 g, 56%).
[3324] .sup.1H-NMR (CDCl.sub.3) .delta. 7.00 (2H, m), 6.77 (1H, m),
6.74 (1H, s), 6.52 (1H, m), 4.65 (1H, m), 3.21 (1H, m), 2.46 (2H,
m), 2.36 (2H, m), 2.18 (2H, m), 1.87 (2H, m), 1.73 (2H, m), 1.65
(1H, m), 1.52 (1H, m), 1.35 (3H, d).
Example 412:
5-(3'-cyclopropylmethoxy-3,5-difluoro-4'-methoxy-biphenyl-4-yl)-hexanoic
Acid
##STR00455##
[3326]
5-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phe-
nyl]hexanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 32 and
4-bromo-2-(cyclopropylmethoxy)-1-methoxy-benzene (0.1 g, 0.39 mmol)
obtained in Preparation Example 282 were sequentially reacted in
the same manner as in Steps A and B of Example 1 to obtain the
title compound (0.046 g, 43%).
[3327] .sup.1H-NMR (CDCl.sub.3) .delta. 7.08 (1H, m), 7.00 (3H, m),
6.92 (1H, d), 3.91 (5H, m), 3.20 (1H, m), 2.34 (2H, m), 1.82 (1H,
m), 1.71 (1H, m), 1.62 (1H, m), 1.52 (1H, m), 1.33 (4H, m), 0.65
(2H, m), 0.37 (2H, m).
Example 413:
5-(3'-cyclopropylmethoxy-3,5-difluoro-biphenyl-4-yl)-hexanoic
Acid
##STR00456##
[3329]
5-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phe-
nyl]hexanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 32 and 1-bromo-3-(cyclopropylmethoxy)benzene
(0.089 g, 0.39 mmol) obtained in Preparation Example 280 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.028 g, 28%).
[3330] .sup.1H-NMR (CDCl.sub.3) .delta. 7.32 (1H, t), 7.09 (1H, m),
7.03 (3H, m), 6.90 (1H, m), 3.85 (2H, d), 3.21 (1H, m), 2.36 (2H,
m), 1.83 (1H, m), 1.71 (1H, m), 1.63 (1H, m), 1.52 (1H, m), 1.34
(3H, d), 1.29 (1H, m), 0.66 (2H, m), 0.37 (2H, m).
Example 414:
5-(5'-cyclobutoxy-3'-fluoro-biphenyl-4-yl)-5,5-difluoro-pentanoic
Acid
##STR00457##
[3332]
5,5-Difluoro-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-ph-
enyl]-pentanoic acid methyl ester (0.1 g, 0.28 mmol) obtained in
Preparation Example 169 and
1-bromo-3-(cyclobutoxy)-5-fluoro-benzene (0.104 g, 0.42 mmol)
obtained in Preparation Example 284 were sequentially reacted in
the same manner as in Steps A and B of Example 1 to obtain the
title compound (0.038 g, 35%).
[3333] .sup.1H-NMR (CDCl.sub.3) .delta. 7.58 (2H, d), 7.53 (2H, d),
6.84 (1H, m), 6.81 (1H, s), 6.51 (1H, m), 4.66 (1H, m), 2.43 (4H,
m), 2.21 (4H, m), 1.83 (3H, m), 1.71 (1H, m).
Example 415:
5-[4-(5-chloro-6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-hexanoic
Acid
##STR00458##
[3335]
5-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phe-
nyl]hexanoic acid ethyl ester (0.08 g, 0.21 mmol) obtained in
Preparation Example 32 and 3,6-dichloro-2-cyclobutoxy-pyridine
(0.068 g, 0.31 mmol) obtained in Preparation Example 298 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.032 g, 37%).
[3336] .sup.1H-NMR (CDCl.sub.3) .delta. 7.66 (1H, d), 7.43 (2H, m),
67.18 (1H, d), 5.31 (1H, m), 3.24 (1H, m), 2.54 (2H, m), 2.35 (2H,
m), 2.25 (2H, m), 1.88-1.52 (6H, m), 1.35 (3H, d).
Example 416:
4-(3'-cyclobutanesulfonyl-3,5-difluoro-biphenyl-4-yloxy)-butyric
Acid
##STR00459##
[3338]
2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
(0.1 g, 0.27 mmol) obtained in Step B of Preparation Example 16 and
1-bromo-3-cyclobutylsulfonyl-benzene (0.111 g, 0.40 mmol) obtained
in Preparation Example 285 were sequentially reacted in the same
manner as in Steps A and B of Example 1 to obtain the title
compound (0.052 g, 47%).
[3339] .sup.1H-NMR (CDCl.sub.3) .delta. 8.00 (1H, s), 7.86 (1H, d),
7.76 (1H, d), 7.64 (1H, t), 7.17 (2H, m), 4.26 (2H, t), 3.83 (1H,
m), 2.63 (4H, m), 2.16 (4H, m), 2.02 (2H, m).
Example 417:
5-({[4-(6-cyclobutoxy-pyridin-2-yl)-phenyl]-methyl-amino}-methyl)-isoxazo-
l-3-ol
##STR00460##
[3341]
4-(6-Cyclobutoxy-pyridin-2-yl)-phenyl]-[3-(4-methoxy-phenoxy)-isoxa-
zol-5-ylmethyl]-amine (0.07 g, 0.15 mmol) obtained in Preparation
Example 296 was dissolved in 2 mL of methanol. 0.3 ml of 37%
formaldehyde solution and 0.3 ml of HCl were added thereto. Sodium
cyanoborohydride (0.014 g, 0.23 mmol) was added thereto at
0.degree. C., and the mixture was stirred at room temperature for
30 minutes. The reaction solution was diluted with water and
extracted with ethyl acetate. The organic layer was dried with
anhydrous magnesium sulfate and purified by column chromatography
to obtain the title compound (0.02 g, 37%).
[3342] .sup.1H-NMR (CDCl.sub.3) .delta. 7.94 (2H, d), 7.54 (1H, t),
7.22 (1H, d), 6.79 (2H, d), 6.53 (1H, d), 5.73 (1H, s), 5.26 (1H,
m), 4.52 (2H, s), 3.07 (3H, s), 2.52 (2H, m), 2.18 (2H, m), 1.83
(1H, m), 1.69 (1H, m).
Example 418:
5-[4-(2-cyclobutoxy-6-methyl-pyrimidin-4-yl)-2,6-difluoro-phenyl]-hexanoi-
c Acid
##STR00461##
[3344]
5-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phe-
nyl]hexanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 32 and
4-chloro-2-(cyclobutoxy)-6-methyl-pyrimidine (0.062 g, 0.39 mmol)
obtained in Preparation Example 229 were sequentially reacted in
the same manner as in Steps A and B of Example 1 to obtain the
title compound (0.056 g, 54%).
[3345] .sup.1H-NMR (CDCl.sub.3) .delta. 7.54 (2H, d), 7.12 (1H, s),
5.28 (1H, m), 3.25 (1H, m), 2.51 (5H, m), 2.26 (4H, m), 1.86 (2H,
m), 1.73 (2H, m), 1.55 (1H, m), 1.45 (1H, m), 1.35 (3H, d).
Example 419:
5-[4-(4-cyclobutoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenyl]-hexanoi-
c Acid
##STR00462##
[3347]
5-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phe-
nyl]hexanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 32 and
2-chloro-4-(cyclobutoxy)-6-methyl-pyrimidine (0.062 g, 0.39 mmol)
obtained in Preparation Example 228 were sequentially reacted in
the same manner as in Steps A and B of Example 1 to obtain the
title compound (0.042 g, 41%).
[3348] .sup.1H-NMR (CDCl.sub.3) .delta. 7.86 (2H, d), 6.44 (1H, s),
5.30 (1H, m), 3.25 (1H, m), 2.53 (2H, m), 2.47 (3H, s), 2.34 (2H,
t), 2.19 (2H, m), 1.87 (2H, m), 1.74 (2H, m), 1.63 (1H, m), 1.51
(1H, m), 1.35 (3H, d).
Example 420:
4-[4-(4-cyclobutoxy-pyrimidin-2-yl)-2,6-difluoro-phenoxy]-butyric
Acid
##STR00463##
[3350]
4-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
oxy]butyric acid ethyl ester (0.2 g, 0.54 mmol) obtained in
Preparation Example 16, and the mixture (0.11 g, 0.59 mmol) of
2-chloro-4-(cyclobutoxy)pyrimidine obtained in Preparation Example
230 and 4-chloro-2-cyclobutoxy-pyrimidine were sequentially reacted
in the same manner as in Steps A and B of Example 1 to obtain
4-[4-(4-cyclobutoxy-pyrimidin-2-yl)-2,6-difluoro-phenoxy]-butyric
acid (0.015 g, 7%) and
4-[4-(2-cyclobutoxy-pyrimidin-4-yl)-2,6-difluoro-phenoxy]-butyric
acid (0.088 g, 44%).
[3351] .sup.1H-NMR (CDCl.sub.3) .delta. 8.48 (1H, d), 7.97 (2H, m),
6.58 (1H, d), 5.33 (1H, m), 4.28 (2H, t), 2.67 (2H, t), 2.53 (2H,
m), 2.22 (2H, m), 2.14 (2H, m), 1.89 (1H, m), 1.76 (1H, m).
Example 421:
4-[4-(2-cyclobutoxy-pyrimidin-4-yl)-2,6-difluoro-phenoxy]-butyric
Acid
##STR00464##
[3353]
4-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
oxy]butyric acid ethyl ester (0.2 g, 0.54 mmol) obtained in
Preparation Example 16, and the mixture (0.11 g, 0.59 mmol) of
2-chloro-4-(cyclobutoxy)pyrimidine obtained in Preparation Example
230 and 4-chloro-2-cyclobutoxy-pyrimidine were sequentially reacted
in the same manner as in Steps A and B of Example 1 to obtain
4-[4-(4-cyclobutoxy-pyrimidin-2-yl)-2,6-difluoro-phenoxy]-butyric
acid (0.015 g, 7%) and
4-[4-(2-cyclobutoxy-pyrimidin-4-yl)-2,6-difluoro-phenoxy]-butyric
acid (0.088 g, 44%).
[3354] .sup.1H-NMR (CDCl.sub.3) .delta. 8.54 (1H, d), 7.65 (2H, m),
7.21 (1H, d), 5.27 (1H, m), 4.29 (2H, t), 2.66 (2H, t), 2.50 (2H,
m), 2.27 (2H, m), 2.12 (2H, m), 1.87 (1H, m), 1.73 (1H, m).
Example 422:
4-[2-chloro-4-(4-cyclobutoxy-pyrimidin-2-yl)-6-fluoro-phenoxy]-butyric
Acid
##STR00465##
[3356]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.2 g, 0.52 mmol) obtained in
Preparation Example 221, and the mixture (0.105 g, 0.57 mmol) of
2-chloro-4-(cyclobutoxy)pyrimidine obtained in Preparation Example
230 and 4-chloro-2-cyclobutoxy-pyrimidine were sequentially reacted
in the same manner as in Steps A and B of Example 1 to obtain
4-[2-chloro-4-(4-cyclobutoxy-pyrimidin-2-yl)-6-fluoro-phenoxy]-butyric
acid (0.012 g, 6%) and
4-[2-chloro-4-(2-cyclobutoxy-pyrimidin-4-yl)-6-fluoro-phenoxy]-butyric
acid (0.083 g, 42%).
[3357] .sup.1H-NMR (CDCl.sub.3) .delta. 8.46 (1H, d), 8.22 (1H, s),
8.04 (1H, m), 6.58 (1H, d), 5.33 (1H, m), 4.24 (2H, t), 2.72 (2H,
t), 2.54 (2H, m), 2.18 (4H, m), 1.89 (1H, m), 1.79 (1H, m).
Example 423:
4-[2-chloro-4-(2-cyclobutoxy-pyrimidin-4-yl)-6-fluoro-phenoxy]-butyric
Acid
##STR00466##
[3359]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.2 g, 0.52 mmol) obtained in
Preparation Example 221, and the mixture (0.105 g, 0.57 mmol) of
2-chloro-4-(cyclobutoxy)pyrimidine obtained in Preparation Example
230 and 4-chloro-2-cyclobutoxy-pyrimidine were sequentially reacted
in the same manner as in Steps A and B of Example 1 to obtain
4-[2-chloro-4-(4-cyclobutoxy-pyrimidin-2-yl)-6-fluoro-phenoxy]-butyric
acid (0.012 g, 6%) and
4-[2-chloro-4-(2-cyclobutoxy-pyrimidin-4-yl)-6-fluoro-phenoxy]-butyric
acid (0.083 g, 42%).
[3360] .sup.1H-NMR (CDCl.sub.3) .delta. 8.54 (1H, d), 7.90 (1H, s),
7.77 (1H, m), 7.24 (1H, d), 5.27 (1H, m), 4.27 (2H, t), 2.70 (2H,
t), 2.51 (2H, m), 2.28 (2H, m), 2.17 (2H, m), 1.88 (1H, m), 1.74
(1H, m).
Example 424:
4-[2-chloro-4-(6-chloro-4-cyclobutoxy-pyridin-2-yl)-6-fluoro-phenoxy]-but-
yric Acid
##STR00467##
[3362]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 221 and 2,6-dichloro-4-(cyclobutoxy)pyridine
(0.068 g, 0.31 mmol) obtained in Preparation Example 270 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.028 g, 26%).
[3363] .sup.1H-NMR (CDCl.sub.3) .delta. 7.49 (1H, s), 7.64 (1H, m),
6.97 (1H, s), 6.66 (1H, s), 4.73 (1H, m), 4.21 (2H, t), 2.71 (2H,
t), 2.50 (2H, m), 2.15 (4H, m), 1.94 (1H, m), 1.76 (1H, m).
Example 425:
4-[4-(4-cyclobutoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenoxy]-butyri-
c Acid
##STR00468##
[3365]
4-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
oxy]butyric acid ethyl ester (0.1 g, 0.27 mmol) obtained in
Preparation Example 16 and
2-chloro-4-(cyclobutoxy)-6-methyl-pyrimidine (0.059 g, 0.3 mmol)
obtained in Preparation Example 228 were sequentially reacted in
the same manner as in Steps A and B of Example 1 to obtain the
title compound (0.042 g, 41%).
[3366] .sup.1H-NMR (CDCl.sub.3) .delta. 7.98 (2H, m), 6.42 (1H, s),
5.30 (1H, m), 4.27 (2H, t), 2.67 (2H, t), 2.52 (2H, m), 2.46 (3H,
s), 2.15 (4H, m), 1.87 (1H, m), 1.74 (1H, m).
Example 426:
4-[2-chloro-4-(2-cyclobutoxy-thiazol-4-yl)-6-fluoro-phenoxy]-butyric
Acid
##STR00469##
[3368]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 221 and 4-bromo-2-(cyclobutoxy)thiazole (0.073
g, 0.31 mmol) obtained in Preparation Example 289 were sequentially
reacted in the same manner as in Steps A and B of Example 1 to
obtain the title compound (0.037 g, 37%).
[3369] .sup.1H-NMR (CDCl.sub.3) .delta. 7.58 (1H, s), 7.43 (1H, m),
6.78 (1H, s), 5.16 (1H, m), 4.16 (2H, t), 2.68 (2H, t), 2.51 (2H,
m), 2.24 (2H, m), 2.12 (2H, m), 1.86 (1H, m), 1.68 (1H, m).
Example 427:
4-[2-chloro-4-(2-cyclopropylmethoxy-thiazol-4-yl)-6-fluoro-phenoxy]-butyr-
ic Acid
##STR00470##
[3371]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 221 and 4-bromo-2-(cyclopropylmethoxy)thiazole
(0.073 g, 0.31 mmol) obtained in Preparation Example 290 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.033 g, 33%).
[3372] .sup.1H-NMR (CDCl.sub.3) .delta. 7.59 (1H, s), 7.43 (1H, m),
6.78 (1H, s), 4.28 (2H, d), 4.16 (2H, t), 2.70 (2H, t), 2.13 (2H,
m), 1.34 (1H, m), 0.65 (2H, m), 0.40 (2H, m).
Example 428:
4-[2-chloro-4-(4-cyclopropylmethoxy-pyrimidin-2-yl)-6-fluoro-phenoxy]-but-
yric Acid
##STR00471##
[3374]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 221 and
2-chloro-4-(cyclopropylmethoxy)pyrimidine (0.057 g, 0.31 mmol)
obtained in Preparation Example 231 were sequentially reacted in
the same manner as in Steps A and B of Example 1 to obtain the
title compound (0.038 g, 38%).
[3375] .sup.1H-NMR (CDCl.sub.3) .delta. 8.46 (1H, d), 8.22 (1H, s),
8.04 (1H, m), 6.64 (1H, d), 4.29 (2H, d), 4.24 (2H, t), 2.71 (2H,
t), 2.14 (2H, m), 1.32 (1H, m), 0.65 (2H, m), 0.40 (2H, m).
Example 429:
4-[2-chloro-4-(6-cyclobutoxy-4-methyl-pyridin-2-yl)-6-fluoro-phenoxy]-but-
yric Acid
##STR00472##
[3377]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (1 g, 2.59 mmol) obtained in
Preparation Example 221 and
2-chloro-6-(cyclobutoxy)-4-methyl-pyridine (0.613 g, 3.10 mmol)
obtained in Preparation Example 271 were sequentially reacted in
the same manner as in Steps A and B of Example 1 to obtain the
title compound (0.8 g, 78%).
[3378] .sup.1H-NMR (CDCl.sub.3) .delta. 7.77 (1H, s), 7.65 (1H, m),
7.04 (1H, s), 6.46 (1H, s), 5.22 (1H, m), 4.19 (2H, t), 2.71 (2H,
t), 2.51 (2H, m), 2.32 (3H, s), 2.16 (4H, m), 1.84 (1H, m), 1.73
(1H, m).
Example 430:
4-[2-chloro-4-(6-cyclobutoxy-pyrazin-2-yl)-6-fluoro-phenoxy]-butyric
Acid
##STR00473##
[3380]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 221 and 2-chloro-6-(cyclobutoxy)pyrazine (0.057
g, 0.31 mmol) obtained in Preparation Example 232 were sequentially
reacted in the same manner as in Steps A and B of Example 1 to
obtain the title compound (0.036 g, 36%).
[3381] .sup.1H-NMR (CDCl.sub.3) .delta. 8.48 (1H, s), 8.11 (1H, s),
7.79 (1H, s), 7.65 (1H, m), 5.26 (1H, m), 4.24 (2H, t), 2.70 (2H,
t), 2.51 (2H, m), 2.20 (4H, m), 1.90 (1H, m), 1.75 (1H, m).
Example 431:
4-[2-chloro-4-(6-cyclopropylmethoxy-pyrazin-2-yl)-6-fluoro-phenoxy]-butyr-
ic Acid
##STR00474##
[3383]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 221 and 2-chloro-6-(cyclopropylmethoxy)pyrazine
(0.057 g, 0.31 mmol) obtained in Preparation Example 233 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.028 g, 28%).
[3384] .sup.1H-NMR (CDCl.sub.3) .delta. 8.46 (1H, s), 8.18 (1H, s),
7.80 (1H, s), 7.65 (1H, m), 4.24 (4H, m), 2.71 (2H, t), 2.14 (2H,
m), 1.32 (1H, m), 0.65 (2H, m), 0.39 (2H, m).
Example 432:
4-[4-(4-cyclopropylmethoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenoxy]-
-butyric Acid
##STR00475##
[3386]
4-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
oxy]butyric acid ethyl ester (0.1 g, 0.27 mmol) obtained in
Preparation Example 16 and
2-chloro-4-(cyclopropylmethoxy)-6-methyl-pyrimidine (0.064 g, 0.32
mmol) obtained in Preparation Example 227 were sequentially reacted
in the same manner as in Steps A and B of Example 1 to obtain the
title compound (0.045 g, 44%).
[3387] .sup.1H-NMR (CDCl.sub.3) .delta. 7.99 (2H, m), 6.49 (1H, s),
4.27 (4H, m), 2.67 (2H, t), 2.47 (3H, s), 2.12 (2H, m), 1.32 (1H,
m), 0.64 (2H, m), 0.39 (2H, m).
Example 433:
4-[4-(4-cyclopropylmethoxy-pyrimidin-2-yl)-2,6-difluoro-phenoxy]-butyric
Acid
##STR00476##
[3389]
4-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
oxy]butyric acid ethyl ester (0.1 g, 0.27 mmol) obtained in
Preparation Example 16 and
2-chloro-4-(cyclopropylmethoxy)pyrimidine (0.06 g, 0.32 mmol)
obtained in Preparation Example 231 were sequentially reacted in
the same manner as in Steps A and B of Example 1 to obtain the
title compound (0.048 g, 48%).
[3390] .sup.1H-NMR (CDCl.sub.3) .delta. 8.46 (1H, d), 7.98 (2H, m),
6.64 (1H, d), 4.28 (4H, m), 2.67 (2H, t), 2.12 (2H, m), 1.33 (1H,
m), 0.67 (2H, m), 0.41 (2H, m).
Example 434:
4-[4-(6-cyclopropylmethoxy-pyrazin-2-yl)-2,6-difluoro-phenoxy]-butyric
Acid
##STR00477##
[3392]
4-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
oxy]butyric acid ethyl ester (0.1 g, 0.27 mmol) obtained in
Preparation Example 16 and 2-chloro-6-(cyclopropylmethoxy)pyrazine
(0.06 g, 0.32 mmol) obtained in Preparation Example 233 were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.047 g, 47%).
[3393] .sup.1H-NMR (CDCl.sub.3) .delta. 8.48 (1H, s), 8.18 (1H, s),
7.56 (2H, m), 4.26 (4H, m), 2.67 (2H, t), 2.14 (2H, m), 1.33 (1H,
m), 0.67 (2H, m), 0.40 (2H, m).
Example 435:
4-[2-chloro-4-(6-cyclopropylmethoxy-4-methyl-pyridin-2-yl)-6-fluoro-pheno-
xy]-butyric Acid
##STR00478##
[3395]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 221 and
2-chloro-6-cyclopropylmethoxy-4-methyl-pyridine (0.061 g, 0.31
mmol) obtained in Preparation Example 300 were sequentially reacted
in the same manner as in Steps A and B of Example 1 to obtain the
title compound (0.053 g, 52%).
[3396] .sup.1H-NMR (CDCl.sub.3) .delta. 7.77 (1H, s), 7.66 (1H, m),
7.05 (1H, s), 6.54 (1H, s), 4.19 (4H, m), 2.71 (2H, t), 2.33 (3H,
s), 2.12 (2H, m), 1.30 (1H, m), 0.61 (2H, m), 0.36 (2H, m).
Example 436:
4-[2-chloro-6-fluoro-4-(6-isopropoxy-pyrazin-2-yl)-phenoxy]-butyric
Acid
##STR00479##
[3398]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 221 and 2-chloro-6-isopropoxy-pyrazine (0.053
g, 0.31 mmol) obtained in Preparation Example 301 were sequentially
reacted in the same manner as in Steps A and B of Example 1 to
obtain the title compound (0.043 g, 45%).
[3399] .sup.1H-NMR (CDCl.sub.3) .delta. 8.48 (1H, s), 8.09 (1H, s),
7.79 (1H, s), 7.67 (1H, m), 5.42 (1H, m), 4.23 (2H, t), 2.71 (2H,
t), 2.15 (2H, m), 1.40 (6H, d).
Example 437:
4-[2-chloro-4-(6-ethoxy-pyrazin-2-yl)-6-fluoro-phenoxy]-butyric
Acid
##STR00480##
[3401]
4-[2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenoxy]butanoic acid ethyl ester (0.1 g, 0.26 mmol) obtained in
Preparation Example 221 and 2-chloro-6-ethoxy-pyrazine (0.049 g,
0.31 mmol) obtained in Preparation Example 302 were sequentially
reacted in the same manner as in Steps A and B of Example 1 to
obtain the title compound (0.032 g, 32%).
[3402] .sup.1H-NMR (CDCl.sub.3) .delta. 8.48 (1H, s), 8.14 (1H, s),
7.81 (1H, s), 7.69 (1H, m), 4.49 (2H, q), 4.23 (2H, t), 2.71 (2H,
t), 2.14 (2H, m), 1.45 (3H, t).
Example 438:
{(R)-1-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrol-
idin-3-yl}-acetic Acid
##STR00481##
[3404]
{(R)-1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y-
l)-phenyl]-pyrrolidin-3-yl}-acetic acid methyl ester (0.090 g, 0.23
mmol) obtained in Preparation Example 303 and
2-chloro-6-cyclopropylmethoxy-pyridine (0.084 g, 0.45 mmol)
obtained in Preparation Example 43 were sequentially reacted in the
same manner as in Steps A and B of Example 1 to obtain the title
compound (0.017 g, 19%).
[3405] .sup.1H-NMR (CDCl.sub.3) .delta. 7.58 (1H, t), 7.48 (2H, m),
7.16 (1H, d), 6.65 (1H, d), 4.23 (2H, d), 3.74 (2H, m), 3.61 (1H,
m), 3.36 (1H, m), 2.65 (1H, m), 2.53 (2H, m), 2.16 (1H, m), 1.65
(1H, m), 1.32 (1H, m), 0.63 (2H, m), 0.37 (2H, m).
Example 439:
{1-[4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2,6-difluoro-phenyl]-piperidin-
-4-yl}-acetic Acid
##STR00482##
[3407]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid ethyl ester (0.2 g, 0.49 mmol)
obtained in Preparation Example 220 and
4-bromo-2,2-difluoro-benzo[1,3]dioxole (0.081 ml, 0.59 mmol) were
sequentially reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.090 g, 44%).
[3408] .sup.1H-NMR (CDCl.sub.3) .delta. 7.20 (3H, m), 7.12 (1H, t),
7.02 (1H, d), 3.31 (2H, m), 3.13 (2H, m), 2.35 (2H, d), 1.98 (1H,
m), 1.81 (2H, m), 1.49 (2H, m).
Example 440:
3-[8-fluoro-6-(2-isopropylsulfanyl-3-pyridyl)thiochroman-2-yl]propanoic
Acid
##STR00483##
[3410] 3-Iodo-2-isopropylsulfanyl-pyridine (0.033 g, 0.12 mmol)
obtained in Preparation Example 9 and
3-[8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiochroman-2--
yl]propanoic acid ethyl ester (0.046 g, 0.12 mmol) obtained in
Preparation Example 304 were reacted in the same manner as in Steps
A and B of Example 1 to obtain the title compound (0.027 g,
57%).
[3411] .sup.1H-NMR (CDCl.sub.3) .delta. 8.43 (1H, m), 7.34 (1H, m),
7.02 (1H, m), 6.97 (1H, m), 6.92 (1H, m), 4.09 (1H, m), 3.36 (1H,
m), 2.94 (2H, m), 2.61 (2H, m), 2.24 (1H, m), 2.07 (2H, m), 1.87
(1H, m), 1.36 (6H, d)
Example 441:
3-[6-[6-(cyclobutoxy)-2-pyridyl]thiochroman-2-yl]propanoic Acid
##STR00484##
[3413] 2-Chloro-6-cyclobutoxy-pyridine (0.062 g, 0.34 mmol)
obtained in Preparation Example 29 and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiochroman-2-yl]-pro-
pionic acid ethyl ester (0.13 g, 0.34 mmol) obtained in Preparation
Example 5 were reacted in the same manner as in Step A of Example
96 and Step B of Example 1 to obtain the title compound (0.067 g,
53%).
[3414] .sup.1H-NMR (CDCl.sub.3) .delta. 7.71 (2H, m), 7.58 (1H, t),
7.25 (1H, d), 7.15 (1H, d), 6.59 (1H, d), 5.25 (1H, m), 3.38 (1H,
m), 2.94 (2H, m), 2.62 (2H, m), 2.52 (2H, m), 2.24 (3H, m), 2.05
(2H, m), 1.85 (2H, m), 1.72 (1H, m)
Example 442:
3-[2-[2,6-difluoro-4-(7-methoxy-2,2-dimethyl-3H-benzofuran-4-yl)phenyl]cy-
clopropyl]propanoic Acid
##STR00485##
[3416] 4-Bromo-7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran (0.067
g, 0.26 mmol) obtained in Preparation Example 211 and
4-{1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pheny-
l]-cyclopropyl}-butyric acid ethyl ester (0.099 g, 0.26 mmol)
obtained in Preparation Example 155 were reacted in the same manner
as in Steps A and B of Example 1 to obtain the title compound (0.07
g, 67%).
[3417] .sup.1H-NMR (CDCl.sub.3) .delta. 6.85 (4H, m), 3.90 (3H, s),
3.12 (2H, s), 2.59 (2H, t), 1.84 (1H, m), 1.65 (2H, m), 1.52 (6H,
s), 1.38 (1H, m), 1.22 (1H, m), 0.82 (1H, m)
Example 443:
3-[2-(2,6-difluoro-4-spiro[3H-benzofuran-2,1'-cyclopentan]-7-yl-phenyl)cy-
clopropyl]propanoic acid
##STR00486##
[3419] 7-Bromospiro[3H-benzofuran-2,1'-cyclopentane] (0.067 g, 0.26
mmol) obtained in Preparation Example 212 and
4-{1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pheny-
l]-cyclopropyl}-butyric acid ethyl ester (0.099 g, 0.26 mmol)
obtained in Preparation Example 155 were reacted in the same manner
as in Steps A and B of Example 1 to obtain the title compound
(0.056 g, 54%).
[3420] .sup.1H-NMR (CDCl.sub.3) .delta. 7.22 (3H, m), 7.12 (1H, m),
6.88 (1H, t), 3.20 (2H, s), 2.59 (2H, t), 2.12 (2H, m), 1.93-1.60
(9H, m), 1.37 (1H, m), 1.22 (1H, m), 0.81 (1H, m)
Example 444: 3-[6-[6-(cyclobutoxy)-2-pyridyl]chroman-2-yl]propanoic
Acid
##STR00487##
[3422] 2-Chloro-6-cyclobutoxy-pyridine (0.069 g, 0.37 mmol)
obtained in Preparation Example 29 and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-chroman-2-yl]-propion-
ic acid ethyl ester (0.133 g, 0.37 mmol) obtained in Preparation
Example 4 were reacted in the same manner as in Step A of Example
96 and Step B of Example 1 to obtain the title compound (0.050 g,
38%).
[3423] .sup.1H-NMR (CDCl.sub.3) .delta. 7.73 (2H, m), 7.55 (1H, t),
7.21 (1H, d), 6.85 (1H, d), 6.65 (1H, d), 5.25 (1H, m), 4.09 (1H,
m), 2.87 (3H, m), 2.66 (2H, m), 2.20 (2H, m), 2.03 (4H, m), 1.78
(3H, m)
Example 445:
3-[6-[6-(cyclopropylmethoxy)-2-pyridyl]chroman-2-yl]propanoic
Acid
##STR00488##
[3425] 2-Chloro-6-cyclopropylmethoxy-pyridine (0.090 g, 0.49 mmol)
obtained in Preparation Example 43 and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-chroman-2-yl]-propion-
ic acid ethyl ester (0.176 g, 0.49 mmol) obtained in Preparation
Example 4 were reacted in the same manner as in Step A of Example
96 and Step B of Example 1 to obtain the title compound (0.080 g,
46%).
[3426] .sup.1H-NMR (CDCl.sub.3) .delta. 7.72 (2H, m), 7.57 (1H, t),
7.21 (1H, d), 6.85 (1H, d), 6.63 (1H, d), 4.24 (2H, d), 4.10 (1H,
m), 2.87 (2H, m), 2.65 (2H, m), 2.04 (3H, m), 1.78 (1H, m), 1.33
(1H, m), 0.62 (2H, m), 0.38 (2H, m)
Example 446:
4-[4-(2,3-dimethoxyphenyl)-2,6-difluoro-phenoxy]butanoic Acid
##STR00489##
[3428] 1-Iodo-2,3-dimethoxy-benzene (0.054 g, 0.20 mmol) obtained
in Step A of Preparation Example 215 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (0.075 g, 0.20 mmol) obtained in Preparation
Example 16 were reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.030 g, 43%).
[3429] .sup.1H-NMR (CDCl.sub.3) .delta. 7.11 (3H, m), 6.93 (1H, m),
6.88 (1H, m), 4.23 (2H, t), 3.90 (3H, s), 3.63 (3H, s), 2.68 (2H,
t), 2.12 (2H, m)
Example 447:
3-[6-[3-(cyclopropylmethoxy)phenyl]chroman-2-yl]propanoic Acid
##STR00490##
[3431] 1-Bromo-3-(cyclopropylmethoxy)benzene (0.098 g, 0.43 mmol)
obtained in Preparation Example 280 and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-chroman-2-yl]-propion-
ic acid ethyl ester (0.154 g, 0.43 mmol) obtained in Preparation
Example 4 were reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.056 g, 37%).
[3432] .sup.1H-NMR (CDCl.sub.3) .delta. 7.30 (3H, m), 7.14 (1H, m),
7.11 (1H, m), 6.88 (2H, m), 4.13 (1H, m), 3.89 (2H, d), 2.96 (1H,
m), 2.86 (1H, m), 2.70 (2H, m), 2.08 (3H, m), 1.87 (1H, m), 1.35
(1H, m), 0.70 (2H, m), 0.41 (2H, m)
Example 448: 3-[6-[3-(cyclopentoxy)phenyl]chroman-2-yl]propanoic
Acid
##STR00491##
[3434] 1-Bromo-3-(cyclopentoxy)benzene (0.097 g, 0.40 mmol)
obtained in Preparation Example 297 and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-chroman-2-yl]-propion-
ic acid ethyl ester (0.144 g, 0.40 mmol) obtained in Preparation
Example 4 were reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.064 g, 44%).
[3435] .sup.1H-NMR (CDCl.sub.3) .delta. 7.28 (3H, m), 7.07 (1H, d),
7.03 (1H, m), 6.84 (1H, d), 6.80 (1H, m), 4.81 (1H, m), 4.08 (1H,
m), 2.91 (1H, m), 2.81 (1H, m), 2.64 (2H, m), 2.03 (3H, m), 1.86
(7H, m), 1.62 (2H, m)
Example 449:
4-(2,6-difluoro-N-methyl-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-a-
nilino)butanoic Acid
##STR00492##
[3437] 4-Iodospiro[1,3-benzodioxol-2,1'-cyclopentane] (0.089 g,
0.29 mmol) obtained in Preparation Example 215 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.111 g, 0.29 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Steps A and B of Example 1 to obtain the title compound
(0.031 g, 26%).
[3438] .sup.1H-NMR (CDCl.sub.3) .delta. 7.27 (2H, m), 6.92 (1H, d),
6.84 (1H, t), 6.72 (1H, d), 3.18 (2H, t), 2.87 (3H, s), 2.48 (2H,
t), 2.13 (4H, m), 1.87 (6H, m)
Example 450:
5-(2,6-difluoro-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-phenyl)
hexanoic Acid
##STR00493##
[3440] 4-Iodospiro[1,3-benzodioxol-2,1'-cyclopentane] (0.107 g,
0.35 mmol) obtained in Preparation Example 215 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.107 g, 0.35 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in Steps
A and B of Example 1 to obtain the title compound (0.065 g,
46%).
[3441] .sup.1H-NMR (CDCl.sub.3) .delta. 7.23 (2H, m), 6.96 (1H, d),
6.85 (1H, t), 6.73 (1H, d), 3.23 (1H, m), 2.36 (2H, t), 2.15 (4H,
m), 1.86 (5H, m), 1.72 (1H, m), 1.64 (1H, m), 1.56 (1H, m), 1.35
(3H, d)
Example 451:
3-[6-(6-tert-butylsulfanyl-2-pyridyl)chroman-2-yl]propanoic
Acid
##STR00494##
[3443] 2-Tert-butylsulfanyl-6-chloro-pyridine (0.092 g, 0.45 mmol)
and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-chroman-2-yl]-propion-
ic acid ethyl ester (0.162 g, 0.45 mmol) obtained in Preparation
Example 4 were reacted in the same manner as in Step A of Example
96 and Step B of Example 1 to obtain the title compound (0.045 g,
27%).
[3444] .sup.1H-NMR (CDCl.sub.3) .delta. 7.75 (2H, m), 7.53 (1H, m),
7.43 (1H, m), 7.17 (1H, m), 6.86 (1H, m), 4.11 (1H, m), 2.90 (2H,
m), 2.66 (2H, m), 2.03 (3H, m), 1.81 (1H, m), 1.60 (9H, s)
Example 452: 3-[6-(6-isopropoxy-2-pyridyl)chroman-2-yl]propanoic
Acid
##STR00495##
[3446] 2-Chloro-6-isopropoxy-pyridine (0.084 g, 0.48 mmol) obtained
in Preparation Example 46 and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-chroman-2-yl]-propion-
ic acid ethyl ester (0.172 g, 0.48 mmol) obtained in Preparation
Example 4 were reacted in the same manner as in Step A of Example
96 and Step B of Example 1 to obtain the title compound (0.065 g,
39%).
[3447] .sup.1H-NMR (CDCl.sub.3) .delta. 7.73 (2H, m), 7.60 (1H, t),
7.20 (1H, d), 6.85 (1H, d), 6.58 (1H, d), 5.42 (1H, m), 4.09 (1H,
m), 2.88 (2H, m), 2.65 (2H, m), 2.04 (3H, m), 1.80 (1H, m), 1.41
(6H, d)
Example 453:
2-[1-(2,6-difluoro-4-spiro[1,3-benzodioxol-2,1'-cyclopentan]-4-yl-phenyl)-
-4-piperidyl]acetic Acid
##STR00496##
[3449] 4-Iodospiro[1,3-benzodioxol-2,1'-cyclopentane] (0.80 g, 0.26
mmol) obtained in Preparation Example 215 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.106 g, 0.26 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Steps A and B of Example 1 to obtain the title compound (0.057 g,
51%).
[3450] .sup.1H-NMR (CDCl.sub.3) .delta. 7.26 (2H, m), 6.93 (1H, d),
6.84 (1H, t), 6.72 (1H, d), 3.35 (2H, m), 3.21 (2H, m), 2.38 (2H,
d), 2.12 (4H, m), 1.99 (1H, m), 1.86 (6H, m), 1.62 (2H, m)
Example 454:
4-[4-(2,3-dipropoxyphenyl)-2,6-difluoro-phenoxy]butanoic Acid
##STR00497##
[3452] 1-Iodo-2,3-dipropoxy-benzene (0.086 g, 0.26 mmol) obtained
in Preparation Example 305 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (0.096 g, 0.26 mmol) obtained in Preparation
Example 16 were reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.041 g, 39%).
[3453] .sup.1H-NMR (CDCl.sub.3) .delta. 7.14 (2H, m), 7.06 (1H, t),
6.91 (1H, m), 6.87 (1H, m), 4.22 (2H, t), 3.98 (2H, t), 3.70 (2H,
t), 2.68 (2H, t), 2.11 (2H, m), 1.88 (2H, m), 1.57 (2H, m), 1.07
(3H, t), 0.84 (3H, t)
Example 455:
4-[4-[6-(cyclobutoxy)-5-methoxy-2-pyridyl]-2,6-difluoro-phenoxy]butanoic
Acid
##STR00498##
[3455] 2-(Cyclobutoxy)-6-iodo-3-methoxy-pyridine (0.095 g, 0.31
mmol) obtained in Preparation Example 307 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (0.115 g, 0.31 mmol) obtained in Preparation
Example 16 were reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.046 g, 38%).
[3456] .sup.1H-NMR (CDCl.sub.3) .delta. 7.48 (2H, m), 7.18 (1H, d),
7.06 (1H, d), 5.32 (1H, m), 4.22 (2H, t), 3.89 (3H, s), 2.67 (2H,
t), 2.55 (2H, m), 2.27 (2H, m), 2.11 (2H, m), 1.88 (1H, m), 1.77
(1H, m)
Example 456:
4-[4-[6-(cyclobutoxy)-5-methoxy-2-pyridyl]-2,6-difluoro-N-methyl-anilino]-
butanoic Acid
##STR00499##
[3458] 2-(Cyclobutoxy)-6-iodo-3-methoxy-pyridine (0.076 g, 0.25
mmol) obtained in Preparation Example 307 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.096 g, 0.25 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Steps A and B of Example 1 to obtain the title compound
(0.059 g, 58%).
[3459] .sup.1H-NMR (CDCl.sub.3) .delta. 7.43 (2H, m), 7.19 (1H, m),
7.07 (1H, m), 5.33 (1H, m), 3.90 (3H, s), 3.17 (2H, t), 2.88 (3H,
s), 2.57 (2H, m), 2.46 (2H, t), 2.27 (2H, m), 1.86 (3H, m), 1.76
(1H, m)
Example 457:
2-[1-[4-[6-(cyclobutoxy)-5-methoxy-2-pyridyl]-2,6-difluoro-phenyl]-4-pipe-
ridyl]acetic Acid
##STR00500##
[3461] 2-(Cyclobutoxy)-6-iodo-3-methoxy-pyridine (0.088 g, 0.29
mmol) obtained in Preparation Example 307 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.118 g, 0.29 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Steps A and B of Example 1 to obtain the title compound (0.076 g,
60%).
[3462] .sup.1H-NMR (CDCl.sub.3) .delta. 7.41 (2H, m), 7.17 (1H, d),
7.06 (1H, d), 5.33 (1H, m), 3.89 (3H, s), 3.29 (2H, m), 3.14 (2H,
m), 2.57 (2H, m), 2.33 (2H, d), 2.27 (2H, m), 1.97 (1H, m), 1.81
(4H, m), 1.50 (2H, m)
Example 458:
2-[1-[4-(2,3-dipropoxyphenyl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
Acid
##STR00501##
[3464] 1-Iodo-2,3-dipropoxy-benzene (0.091 g, 0.28 mmol) obtained
in Preparation Example 305 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.115 g, 0.28 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Steps A and B of Example 1 to obtain the title compound (0.069 g,
55%).
[3465] .sup.1H-NMR (CDCl.sub.3) .delta. 7.08 (2H, m), 7.05 (1H, t),
6.88 (2H, m), 3.98 (2H, t), 3.71 (2H, t), 3.30 (2H, m), 3.15 (2H,
m), 2.37 (2H, d), 1.98 (1H, m), 1.83 (4H, m), 1.58 (2H, m), 1.49
(2H, m), 1.07 (3H, t), 0.86 (3H, t)
Example 459:
4-[4-[6-(cyclopropylmethoxy)-5-methoxy-2-pyridyl]-2,6-difluoro-phenoxy]bu-
tanoic Acid
##STR00502##
[3467] 2-(Cyclopropylmethoxy)-6-iodo-3-methoxy-pyridine (0.085 g,
0.28 mmol) obtained in Preparation Example 306 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (0.104 g, 0.28 mmol) obtained in Preparation
Example 16 were reacted in the same manner as in Steps A and B of
Example 1 to obtain the title compound (0.07 g, 57%).
[3468] .sup.1H-NMR (CDCl.sub.3) .delta. 7.49 (2H, m), 7.19 (1H, d),
7.08 (1H, d), 4.32 (2H, d), 4.22 (2H, t), 3.91 (3H, s), 2.67 (2H,
t), 2.10 (2H, m), 1.43 (1H, m), 0.64 (2H, m), 0.42 (2H, m)
Example 460:
4-[4-(2,3-dipropoxyphenyl)-2,6-difluoro-N-methyl-anilino]butanoic
Acid
##STR00503##
[3470] 1-Iodo-2,3-dipropoxy-benzene (0.10 g, 0.31 mmol) obtained in
Preparation Example 305 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.118 g, 0.31 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Steps A and B of Example 1 to obtain the title compound
(0.045 g, 34%).
[3471] .sup.1H-NMR (CDCl.sub.3) .delta. 7.10 (2H, m), 7.06 (1H, t),
6.88 (2H, m), 3.98 (2H, t), 3.72 (2H, t), 3.18 (2H, m), 2.89 (3H,
s), 2.48 (2H, t), 1.87 (4H, m), 1.58 (2H, m), 1.08 (3H, t), 0.84
(3H, t)
Example 461:
4-[4-[6-(cyclopropylmethoxy)-5-methoxy-2-pyridyl]-2,6-difluoro-N-methyl-a-
nilino]butanoic Acid
##STR00504##
[3473] 2-(Cyclopropylmethoxy)-6-iodo-3-methoxy-pyridine (0.09 g,
0.29 mmol) obtained in Preparation Example 306 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.111 g, 0.29 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Steps A and B of Example 1 to obtain the title compound
(0.076 g, 64%).
[3474] .sup.1H-NMR (CDCl.sub.3) .delta. 7.45 (2H, m), 7.20 (1H, d),
7.08 (1H, d), 4.32 (2H, d), 3.91 (3H, s), 3.19 (2H, t), 2.88 (3H,
s), 2.48 (2H, t), 1.88 (2H, m), 1.45 (1H, m), 0.54 (2H, m), 0.42
(2H, m)
Example 462:
2-[1-[4-[6-(cyclopropylmethoxy)-5-methoxy-2-pyridyl]-2,6-difluoro-phenyl]-
-4-piperidyl]acetic Acid
##STR00505##
[3476] 2-(Cyclopropylmethoxy)-6-iodo-3-methoxy-pyridine (0.097 g,
0.31 mmol) obtained in Preparation Example 306 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.126 g, 0.31 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Steps A and B of Example 1 to obtain the title compound (0.064 g,
47%).
[3477] .sup.1H-NMR (CDCl.sub.3) .delta. 7.41 (2H, m), 7.17 (1H, d),
7.07 (1H, d), 4.32 (2H, d), 3.90 (3H, s), 3.29 (2H, m), 3.14 (2H,
m), 2.36 (2H, d), 1.97 (1H, m), 1.83 (2H, m), 1.47 (3H, m), 0.63
(2H, m), 0.42 (2H, m)
Example 463:
4-[4-(6-chloroindol-1-yl)-2,6-difluoro-phenoxy]butanoic Acid
##STR00506##
[3479] Step A:
4-[4-(6-chloroindol-1-yl)-2,6-difluoro-phenoxy]butanoic acid ethyl
ester 6-Chloro-1H-indole (0.042 g, 0.28 mmol),
4-(4-bromo-2,6-difluoro-phenoxy)butanoic acid ethyl ester (0.18 g,
0.56 mmol) obtained in Preparation Example 339, copper iodide
(0.006 g, 0.028 mmol), potassium phosphate (0.12 g, 0.56 mmol),
cyclohexane-1,2-diamine (0.007 mL, 0.056 mmol) and dodecane (0.007
mL, 0.028 mmol) were added to a seal tube. 1,4-Dioxane (1 mL) were
added thereto, and the mixture was stirred at 110.degree. C. for 18
hours. After termination of the reaction, the reaction solution was
cooled and filtered through Celite. The organic layer was
concentrated under reduced pressure and purified by column
chromatography to obtain the title compound (0.083 g, 75%).
[3480] .sup.1H-NMR (CDCl.sub.3) .delta. 7.57 (1H, d), 7.50 (1H, d),
7.22 (1H, d), 7.15 (1H, m), 7.05 (2H, m), 6.65 (1H, d), 4.26 (2H,
t) 4.18 (2H, q), 2.60 (2H, t), 2.15 (2H, m), 1.28 (3H, t)
Step B: 4-[4-(6-chloroindol-1-yl)-2,6-difluoro-phenoxy]butanoic
Acid
[3481] 4-[4-(6-Chloroindol-1-yl)-2,6-difluoro-phenoxy]butanoic acid
ethyl ester (0.083 g, 0.21 mmol) obtained in Step A was reacted in
the same manner as in Step B of Example 1 to obtain the title
compound (0.067 g, 65%).
[3482] .sup.1H-NMR (CDCl.sub.3) .delta. 7.57 (1H, d), 7.50 (1H, d),
7.22 (1H, d), 7.15 (1H, m), 7.05 (2H, m), 6.65 (1H, d), 4.26 (2H,
t), 2.70 (2H, t), 2.15 (2H, m)
Example 464:
5-[4-[6-(cyclobutoxy)-5-methoxy-2-pyridyl]phenyl]-5,5-difluoro-pentanoic
Acid
##STR00507##
[3484] 2-(Cyclobutoxy)-6-iodo-3-methoxy-pyridine (0.088 g, 0.29
mmol) obtained in Preparation Example 307 and
5,5-difluoro-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]--
pentanoic acid methyl ester (0.101 g, 0.29 mmol) obtained in
Preparation Example 169 were reacted in the same manner as in Steps
A and B of Example 1 to obtain the title compound (0.023 g,
20%).
[3485] .sup.1H-NMR (CDCl.sub.3) .delta. 8.00 (2H, d), 7.52 (2H, d),
7.32 (1H, d), 7.10 (1H, d), 5.35 (1H, m), 3.91 (3H, s), 2.57 (2H,
m), 2.42 (2H, t), 2.26 (4H, m), 1.80 (4H, m)
Example 465: 4-[2,6-difluoro-4-(5-fluoroindol-1-yl)phenoxy]butanoic
Acid
##STR00508##
[3487] 5-Fluoro-1H-indole (0.042 g, 0.31 mmol) and
4-(4-bromo-2,6-difluoro-phenoxy)butanoic acid ethyl ester (0.20 g,
0.62 mmol) obtained in Preparation Example 339 were reacted in the
same manner as in Step A of Example 463 and Step B of Example 1 to
obtain the title compound (0.05 g, 46%).
[3488] .sup.1H-NMR (CDCl.sub.3) .delta. 7.44 (1H, m), 7.30 (1H, m),
7.27 (1H, d), 7.05 (2H, m), 6.99 (1H, m), 6.63 (1H, d), 4.25 (2H,
t), 2.69 (2H, t), 2.14 (2H, m)
Example 466:
4-[4-[3-(cyclopropylmethylamino)phenyl]-2,6-difluoro-N-methyl-anilino]but-
anoic Acid
##STR00509##
[3490] 3-Bromo-N-(cyclopropylmethyl)aniline (0.087 g, 0.38 mmol)
and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.146 g, 0.38 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Steps A and B of Example 1 to obtain the title compound
(0.057 g, 40%).
[3491] .sup.1H-NMR (CDCl.sub.3) .delta. 7.26 (1H, t), 7.03 (2H, m),
6.96 (2H, m), 6.83 (1H, m), 3.16 (2H, t), 3.05 (2H, d), 2.86 (3H,
s), 2.45 (2H, t), 1.85 (2H, m), 1.12 (1H, m), 0.57 (2H, m), 0.28
(2H, m)
Example 467:
4-[2,6-difluoro-N-methyl-4-(6-pyrrolidin-1-yl-2-pyridyl)anilino]butanoic
Acid
##STR00510##
[3493] 2-Chloro-6-pyrrolidin-1-yl-pyridine (0.099 g, 0.54 mmol) and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.206 g, 0.54 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Steps A and B of Example 1 to obtain the title compound
(0.108 g, 53%).
[3494] .sup.1H-NMR (CDCl.sub.3) .delta. 7.53 (2H, m), 7.46 (1H, t),
6.88 (1H, d), 6.31 (1H, d), 3.52 (4H, m), 3.16 (2H, t), 2.88 (3H,
s), 2.45 (2H, t), 2.02 (4H, m), 1.85 (2H, m)
Example 468:
4-[2,6-difluoro-4-(5-methoxyindol-1-yl)phenoxy]butanoic Acid
##STR00511##
[3496] 5-Methoxy-1H-indole (0.046 g, 0.31 mmol) and
4-(4-bromo-2,6-difluoro-phenoxy)butanoic acid ethyl ester (0.20 g,
0.62 mmol) obtained in Preparation Example 339 were reacted in the
same manner as in Step A of Example 463 and Step B of Example 1 to
obtain the title compound (0.019 g, 17%).
[3497] .sup.1H-NMR (CDCl.sub.3) .delta. 7.44 (1H, d), 7.21 (1H, d),
7.11 (1H, d), 7.06 (2H, m), 6.90 (1H, m), 6.60 (1H, d), 4.24 (2H,
t), 3.87 (3H, s), 2.69 (2H, t), 2.13 (2H, m)
Example 469: 4-[4-(5-cyanoindol-1-yl)-2,6-difluoro-phenoxy]butanoic
Acid
##STR00512##
[3499] 1H-Indol-5-carbonitrile (0.044 g, 0.31 mmol) and
4-(4-bromo-2,6-difluoro-phenoxy)butanoic acid ethyl ester (0.20 g,
0.62 mmol) obtained in Preparation Example 339 were reacted in the
same manner as in Step A of Example 463 and Step B of Example 1 to
obtain the title compound (0.034 g, 31%).
[3500] .sup.1H-NMR (CDCl.sub.3) .delta. 8.02 (1H, m), 7.55 (1H, d),
7.48 (1H, m), 7.36 (1H, m), 7.06 (2H, m), 6.76 (1H, m), 4.28 (2H,
t), 2.69 (2H, t), 2.14 (2H, m)
Example 470:
4-[4-[3-(cyclopropylmethoxymethyl)-2-furyl]-2,6-difluoro-N-methyl-anilino-
]butanoic Acid
##STR00513##
[3501] Step A:
4-[2,6-difluoro-4-(3-formyl-2-furyl)-N-methyl-anilino]butanoic Acid
Methyl Ester
[3502] (3-Formyl-2-furyl)boronic acid (0.05 g, 0.36 mmol) and
4-(4-bromo-2,6-difluoro-N-methyl-anilino)butanoic acid methyl ester
(0.11 g, 0.32 mmol) were reacted in the same manner as in Step A of
Example 1 to obtain the title compound (0.027 g, 22%).
[3503] .sup.1H-NMR (CDCl.sub.3) .delta. 10.10 (1H, s), 7.45 (1H,
d), 7.35 (2H, m), 6.89 (1H, d), 3.66 (3H, s), 3.22 (2H, t), 2.94
(3H, t), 2.39 (2H, t), 1.89 (2H, m)
Step B:
4-[2,6-difluoro-4-[3-(hydroxymethyl)-2-furyl]-N-methyl-anilino]but-
anoic acid Methyl Ester
[3504]
4-[2,6-Difluoro-4-(3-formyl-2-furyl)-N-methyl-anilino]butanoic acid
methyl ester (0.027 g, 0.08 mmol) obtained in Step A was dissolved
in 3 mL of MeOH. NaBH.sub.4 (0.003 g, 0.08 mmol) were added thereto
at 0.degree. C., and the mixture was stirred at room temperature
for 2 hours. After addition of water, the reaction solution was
extracted with EtOAc. The organic layer was dried with MgSO.sub.4
and purified by column chromatography to obtain the title compound
(0.027 g, 99%).
[3505] .sup.1H-NMR (CDCl.sub.3) .delta. 7.39 (1H, d), 7.17 (2H, m),
6.52 (1H, d), 4.69 (2H, s), 3.65 (3H, s), 3.13 (2H, t), 2.87 (3H,
s), 2.38 (2H, t), 1.84 (2H, m), 1.70 (1H, brs)
Step C:
4-[4-[3-(cyclopropylmethoxymethyl)-2-furyl]-2,6-difluoro-N-methyl--
anilino]butanoic Acid Cyclopropylmethyl Ester
[3506]
4-[2,6-Difluoro-4-[3-(hydroxymethyl)-2-furyl]-N-methyl-anilino]buta-
noic acid methyl ester (0.027 g, 0.08 mmol) obtained in Step B was
dissolved in 3 mL of DMF and cooled to 0.degree. C. NaH (60%)(0.004
g, 0.09 mmol) and 18-crown-6 (0.024 g, 0.09 mmol) were added
thereto, and the mixture was stirred for 0.5 hour.
Bromomethyl-cyclopropane (0.014 g, 0.10 mmol) was added thereto,
and the mixture was stirred at room temperature for 18 hours. The
reaction solution was extracted with EtOAc, dried with MgSO.sub.4
and purified by column chromatography to obtain the title compound
(0.005 g, 14%).
[3507] .sup.1H-NMR (CDCl.sub.3) .delta. 7.40 (1H, d), 7.20 (2H, m),
6.50 (1H, d), 4.47 (2H, s), 3.89 (2H, d), 3.38 (2H, d), 3.15 (2H,
t), 2.89 (3H, s), 2.40 (2H, t), 1.86 (2H, m), 1.12 (2H, m), 0.56
(4H, m), 0.25 (4H, m)
Step D:
4-[4-[3-(cyclopropylmethoxymethyl)-2-furyl]-2,6-difluoro-N-methyl--
anilino]butanoic Acid
[3508]
4-[4-[3-(Cyclopropylmethoxymethyl)-2-furyl]-2,6-difluoro-N-methyl-a-
nilino]butanoic acid cyclopropylmethyl ester (0.005 g, 0.01 mmol)
obtained in Step C was reacted in the same manner as in Step B of
Example 1 to obtain the title compound (0.003 g, 79%).
[3509] .sup.1H-NMR (CDCl.sub.3) .delta. 7.35 (1H, d), 7.22 (2H, m),
6.50 (1H, d), 4.47 (2H, s), 3.38 (2H, d), 3.17 (2H, t), 2.87 (3H,
s), 2.46 (2H, t), 1.86 (2H, m), 1.14 (1H, m), 0.57 (2H, m), 0.25
(2H, m)
Example 471: 4-[2,6-difluoro-4-(4-fluoroindol-1-yl)phenoxy]butanoic
Acid
##STR00514##
[3511] 4-Fluoro-1H-indole (0.05 g, 0.37 mmol) and
4-(4-bromo-2,6-difluoro-phenoxy)butanoic acid ethyl ester (0.18 g,
0.55 mmol) obtained in Preparation Example 339 were reacted in the
same manner as in Step A of Example 463 and Step B of Example 1 to
obtain the title compound (0.056 g, 43%).
[3512] .sup.1H-NMR (CDCl.sub.3) .delta. 7.30 (1H, m), 7.21 (1H, m),
7.17 (1H, m), 7.01 (2H, m), 6.86 (1H, m), 6.77 (1H, m), 4.26 (2H,
t), 2.69 (2H, t), 2.15 (2H, m)
Example 472:
4-[4-(7-chloroindol-1-yl)-2,6-difluoro-phenoxy]butanoic Acid
##STR00515##
[3514] 7-Chloro-1H-indole (0.05 g, 0.37 mmol) and
4-(4-bromo-2,6-difluoro-phenoxy)butanoic acid ethyl ester (0.18 g,
0.55 mmol) obtained in Preparation Example 339 were reacted in the
same manner as in Step A of Example 463 and Step B of Example 1 to
obtain the title compound (0.049 g, 36%).
[3515] .sup.1H-NMR (CDCl.sub.3) .delta. 7.57 (1H, m), 7.19 (1H, m),
7.10 (2H, m), 6.98 (2H, m), 6.65 (1H, d), 4.28 (2H, t), 2.69 (2H,
t), 2.15 (2H, m)
Example 473:
4-[4-[5-(cyclopropylmethoxymethyl)-2-furyl]-2,6-difluoro-N-methyl-anilino-
]butanoic Acid
##STR00516##
[3516] Step A:
4-[2,6-difluoro-4-(5-formyl-2-furyl)-N-methyl-anilino]butanoic Acid
Methyl Ester
[3517] (5-Formyl-2-furyl)boronic acid (0.05 g, 0.36 mmol) and
4-(4-bromo-2,6-difluoro-N-methyl-anilino)butanoic acid methyl ester
(0.11 g, 0.32 mmol) were reacted in the same manner as in Step A of
Example 96 to obtain the title compound (0.025 g, 22%).
Step B:
4-[2,6-difluoro-4-[5-(hydroxymethyl)-2-furyl]-N-methyl-anilino]but-
anoic Acid Methyl Ester
[3518]
4-[2,6-Difluoro-4-(5-formyl-2-furyl)-N-methyl-anilino]butanoic acid
methyl ester (0.025 g, 0.074 mmol) obtained in Step A was dissolved
in 3 mL of MeOH. NaBH.sub.4 (0.003 g, 0.074 mmol) was added thereto
at 0.degree. C., and the mixture was stirred at room temperature
for 30 minutes. After addition of acetic acid, the reaction
solution was extracted with EtOAc. The organic layer was dried with
MgSO.sub.4 and purified by column chromatography to obtain the
title compound (0.018 g, 72%).
Step C:
4-[4-[5-(cyclopropylmethoxymethyl)-2-furyl]-2,6-difluoro-N-methyl--
anilino]butanoic Acid Methyl Ester
[3519]
4-[2,6-Difluoro-4-[5-(hydroxymethyl)-2-furyl]-N-methyl-anilino]buta-
noic acid methyl ester (0.018 g, 0.053 mmol) obtained in Step B was
dissolved in 5 mL of DCM and cooled to 0.degree. C. PBr.sub.3
(0.016 g, 0.058 mmol) was added thereto, and the mixture was
stirred for 0.5 hour. The reaction solution was extracted with DCM,
dried with MgSO.sub.4 and dissolved in 5 mL of DMF.
Cyclopropylmethanol and K.sub.2CO.sub.3 were added thereto, and the
mixture was stirred at 50.degree. C. for 18 hours. After addition
of water, the reaction solution extracted with EtOAc. The organic
layer was dried with MgSO.sub.4 and purified by column
chromatography to obtain the title compound (0.003 g, 14%).
[3520] .sup.1H-NMR (CDCl.sub.3) .delta. 7.14 (2H, m), 6.52 (1H, d),
6.38 (1H, d), 4.50 (2H, s), 3.65 (3H, s), 3.34 (2H, d), 3.12 (2H,
t), 2.86 (3H, s), 2.38 (2H, t), 1.86 (2H, m), 1.09 (1H, m), 0.55
(2H, m), 0.22 (2H, m)
Step D:
4-[4-[5-(cyclopropylmethoxymethyl)-2-furyl]-2,6-difluoro-N-methyl--
anilino]butanoic Acid
[3521]
4-[4-[5-(Cyclopropylmethoxymethyl)-2-furyl]-2,6-difluoro-N-methyl-a-
nilino]butanoic acid methyl ester obtained in Step C was reacted in
the same manner as in Step B of Example 1 to obtain the title
compound (0.002 g, 69%).
[3522] .sup.1H-NMR (CDCl.sub.3) .delta. 7.14 (2H, m), 6.53 (1H, d),
6.38 (1H, d), 4.51 (2H, s), 3.35 (2H, d), 3.15 (2H, t), 2.86 (3H,
s), 2.46 (2H, t), 1.86 (2H, m), 1.09 (1H, m), 0.55 (2H, m), 0.22
(2H, m)
Example 474:
4-[4-[6-(cyclopropylmethoxy)indol-1-yl]-2,6-difluoro-phenoxy]butanoic
Acid
##STR00517##
[3524] 6-(Cyclopropylmethoxy)-1H-indole (0.017 g, 0.09 mmol)
obtained in Preparation Example 311 and
4-(4-bromo-2,6-difluoro-phenoxy)butanoic acid ethyl ester (0.060 g,
0.18 mmol) obtained in Preparation Example 339 were reacted in the
same manner as in Step A of Example 463 and Step B of Example 1 to
obtain the title compound (0.004 g, 11%).
[3525] .sup.1H-NMR (CDCl.sub.3) .delta. 7.52 (1H, m), 7.11 (1H, m),
7.05 (2H, m), 7.01 (1H, m), 6.87 (1H, m), 6.59 (1H, m), 4.25 (2H,
t), 3.82 (2H, d), 2.70 (2H, t), 2.15 (2H, m), 1.26 (1H, m), 0.65
(2H, m), 0.37 (2H, m)
Example 475:
4-[4-(7-chloroindol-1-yl)-2,6-difluoro-N-methyl-anilino]butanoic
Acid
##STR00518##
[3527] 7-Chloro-1H-indole (0.047 g, 0.31 mmol) and
4-(4-bromo-2,6-difluoro-N-methyl-anilino)butanoic acid methyl ester
(0.1 g, 0.31 mmol) were reacted in the same manner as in Step A of
Example 463 and Step B of Example 1 to obtain the title compound
(0.042 g, 36%).
[3528] .sup.1H-NMR (CDCl.sub.3) .delta. 7.57 (1H, m), 7.19 (1H, m),
7.12 (1H, m), 7.08 (1H, t), 6.93 (2H, m), 6.65 (1H, m), 3.21 (2H,
m), 2.92 (3H, s), 2.50 (2H, m), 1.90 (2H, m)
Example 476:
4-[4-[6-(cyclobutoxy)indol-1-yl]-2,6-difluoro-phenoxy]butanoic
Acid
##STR00519##
[3530] 6-(Cyclobutoxy)-1H-indole (0.026 g, 0.14 mmol) obtained in
Preparation Example 308 and
4-(4-bromo-2,6-difluoro-phenoxy)butanoic acid ethyl ester (0.068 g,
0.21 mmol) obtained in Preparation Example 339 were reacted in the
same manner as in Step A of Example 463 and Step B of Example 1 to
obtain the title compound (0.008 g, 14%).
[3531] .sup.1H-NMR (CDCl.sub.3) .delta. 7.50 (1H, m), 7.11 (1H, m),
7.06 (2H, m), 6.94 (1H, m), 6.77 (1H, m), 6.58 (1H, m), 4.66 (1H,
m), 4.24 (2H, t), 2.69 (2H, t), 2.45 (2H, m), 2.16 (4H, m), 1.86
(1H, m), 1.70 (1H, m)
Example 477:
4-[4-[5-(cyclobutoxy)indol-1-yl]-2,6-difluoro-phenoxy]butanoic
Acid
##STR00520##
[3533] 5-(Cyclobutoxy)-1H-indole (0.021 g, 0.14 mmol) obtained in
Preparation Example 310 and
4-(4-bromo-2,6-difluoro-phenoxy)butanoic acid ethyl ester (0.068 g,
0.21 mmol) obtained in Preparation Example 339 were reacted in the
same manner as in Step A of Example 463 and Step B of Example 1 to
obtain the title compound (0.002 g, 3%).
[3534] .sup.1H-NMR (CDCl.sub.3) .delta. 7.41 (1H, m), 7.21 (1H, m),
7.02 (3H, m), 6.85 (1H, m), 6.58 (1H, m), 4.68 (1H, m), 4.24 (2H,
t), 2.67 (2H, m), 2.48 (2H, m), 2.17 (4H, m), 1.81 (1H, m), 1.69
(1H, m)
Example 478:
4-[2,6-difluoro-4-(4-methoxyindol-1-yl)phenoxy]butanoic Acid
##STR00521##
[3536] 4-Methoxy-1H-indole (0.055 g, 0.37 mmol) and
4-(4-bromo-2,6-difluoro-phenoxy)butanoic acid ethyl ester (0.180 g,
0.55 mmol) obtained in Preparation Example 339 were reacted in the
same manner as in Step A of Example 463 and Step B of Example 1 to
obtain the title compound (0.011 g, 8%).
[3537] .sup.1H-NMR (CDCl.sub.3) .delta. 7.15 (3H, m), 7.08 (2H, m),
6.78 (1H, m), 6.59 (1H, m), 4.24 (2H, t), 3.97 (3H, s), 2.68 (2H,
t), 2.14 (2H, m)
Example 479:
4-[2,6-difluoro-4-(7-methoxyindol-1-yl)phenoxy]butanoic Acid
##STR00522##
[3539] 7-Methoxy-1H-indole (0.055 g, 0.37 mmol) and
4-(4-bromo-2,6-difluoro-phenoxy)butanoic acid ethyl ester (0.180 g,
0.55 mmol) obtained in Preparation Example 339 were reacted in the
same manner as in Step A of Example 463 and Step B of Example 1 to
obtain the title compound (0.045 g, 34%).
[3540] .sup.1H-NMR (CDCl.sub.3) .delta. 7.26 (1H, m), 7.08 (2H, m),
6.96 (2H, m), 6.69 (1H, m), 6.62 (1H, m), 4.24 (2H, t), 3.76 (3H,
s), 2.69 (2H, t), 2.14 (2H, m)
Example 480:
4-[2,6-difluoro-4-[5-(methoxymethyl)indazol-1-yl]phenoxy]butanoic
Acid
##STR00523##
[3541] Step A:
4-[2,6-difluoro-4-(5-formylindazol-1-yl)phenoxy]butanoic Acid Ethyl
Ester
[3542] 1H-indazol-5-carbaldehyde (0.054 g, 0.37 mmol) and
4-(4-bromo-2,6-difluoro-phenoxy)butanoic acid ethyl ester (0.180 g,
0.55 mmol) obtained in Preparation Example 339 were reacted in the
same manner as in Step A of Example 463 to obtain the title
compound (0.022 g, 15%).
[3543] .sup.1H-NMR (CDCl.sub.3) .delta. 10.10 (1H, s), 8.35 (2H,
m), 8.04 (1H, m), 7.81 (1H, m), 7.34 (2H, m), 4.26 (2H, t), 4.17
(2H, q), 2.61 (2H, t), 2.14 (2H, m), 1.28 (3H, t)
Step B:
4-[2,6-difluoro-4-[5-(hydroxymethyl)indazol-1-yl]phenoxy]butanoic
Acid Ethyl Ester
[3544] 4-[2,6-Difluoro-4-(5-formylindazol-1-yl)phenoxy]butanoic
acid ethyl ester (0.022 g, 0.057 mmol) obtained in Step A was
dissolved in 3 mL of MeOH. NaBH.sub.4 (0.003 g, 0.057 mmol) was
added thereto at 0.degree. C., and the mixture was stirred at room
temperature for 30 minutes. After addition of acetic acid, the
reaction solution was extracted with EtOAc. The organic layer was
dried with MgSO.sub.4 and purified by column chromatography to
obtain the title compound (0.020 g, 98%).
[3545] .sup.1H-NMR (CDCl.sub.3) .delta. 8.18 (1H, s), 7.79 (1H, m),
7.73 (1H, m), 7.50 (1H, m), 7.34 (2H, m), 4.83 (2H, s), 4.23 (2H,
t), 4.17 (2H, q), 2.60 (2H, t), 2.12 (2H, m), 1.78 (1H, brs), 1.28
(3H, t)
Step C:
4-[2,6-difluoro-4-[5-(methoxymethyl)indazol-1-yl]phenoxy]butanoic
Acid Ethyl Ester
[3546]
4-[2,6-Difluoro-4-[5-(hydroxymethyl)indazol-1-yl]phenoxy]butanoic
acid ethyl ester (0.020 g, 0.057 mmol) obtained in Step B was
dissolved in 1 mL of DMF and cooled to 0.degree. C. NaH (60%)(0.003
g, 0.007 mmol) and tetrabutylammonium iodide (0.021 g, 0.057 mmol)
were added thereto, and the mixture was stirred for 0.5 hour.
Methyl iodide (0.012 g, 0.086 mmol) was added thereto, and the
mixture was stirred at room temperature for 18 hours.
[3547] The reaction solution was extracted with EtOAc, dried with
MgSO.sub.4 and purified by column chromatography to obtain the
title compound (0.002 g, 9%).
Step D:
4-[2,6-difluoro-4-[5-(methoxymethyl)indazol-1-yl]phenoxy]butanoic
Acid
[3548]
4-[2,6-Difluoro-4-[5-(methoxymethyl)indazol-1-yl]phenoxy]butanoic
acid ethyl ester (0.002 g, 0.005 mmol) obtained in Step C was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.0007 g, 37%).
[3549] .sup.1H-NMR (CDCl.sub.3) .delta. 8.16 (1H, m), 7.50 (2H, m),
7.47 (1H, m), 7.34 (2H, m), 4.58 (2H, s), 4.25 (2H, t), 3.42 (3H,
s), 2.69 (2H, t), 2.14 (2H, m)
Example 481:
2-[1-[4-(7-chloroindol-1-yl)-2,6-difluoro-phenyl]-4-piperidyl]acetic
Acid
##STR00524##
[3551] 7-Chloro-1H-indole (0.042 g, 0.28 mmol) and
2-[1-(4-bromo-2,6-difluoro-phenyl)-4-piperidyl]acetic acid ethyl
ester (0.1 g, 0.28 mmol) obtained in Step A of Preparation Example
220 were reacted in the same manner as in Step A of Example 463 and
Step B of Example 1 to obtain the title compound (0.045 g,
40%).
[3552] .sup.1H-NMR (CDCl.sub.3) .delta. 7.56 (1H, m), 7.18 (1H, m),
7.08 (2H, m), 6.91 (2H, m), 6.63 (1H, m), 3.32 (2H, m), 3.18 (2H,
m), 2.40 (2H, m), 2.00 (1H, m), 1.90 (2H, m), 1.52 (2H, m)
Example 482:
4-[4-[6-(cyclobutoxy)indazol-1-yl]-2,6-difluoro-phenoxy]butanoic
Acid
##STR00525##
[3554] 6-(Cyclobutoxy)-1H-indazole (0.04 g, 0.21 mmol) obtained in
Preparation Example 309 and
4-(4-bromo-2,6-difluoro-phenoxy)butanoic acid ethyl ester (0.103 g,
0.32 mmol) obtained in Preparation Example 339 were reacted in the
same manner as in Step A of Example 463 and Step B of Example 1 to
obtain the title compound (0.05 g, 59%).
[3555] .sup.1H-NMR (CDCl.sub.3) .delta. 8.06 (1H, m), 7.63 (1H, m),
7.29 (2H, m), 6.96 (1H, m), 6.84 (1H, m), 4.72 (1H, m), 4.25 (2H,
m), 2.68 (2H, m), 2.50 (2H, m), 2.23 (2H, m), 2.16 (2H, m), 1.90
(1H, m), 1.75 (1H, m)
Example 483:
4-[2-chloro-4-[6-(cyclobutoxy)indazol-1-yl]-6-fluoro-phenoxy]butanoic
Acid
##STR00526##
[3557] 6-(Cyclobutoxy)-1H-indazole (0.1 g, 0.53 mmol) obtained in
Preparation Example 309 and
4-(4-bromo-2-chloro-6-fluoro-phenoxy)butanoic acid ethyl ester (0.2
g, 0.58 mmol) obtained in Step A of Preparation Example 221 were
reacted in the same manner as in Step A of Example 463 and Step B
of Example 1 to obtain the title compound (0.048 g, 22%).
[3558] .sup.1H-NMR (CDCl.sub.3) .delta. 8.06 (1H, m), 7.63 (1H, m),
7.54 (1H, m), 7.41 (1H, m), 6.96 (1H, m), 6.84 (1H, m), 4.72 (1H,
m), 4.22 (2H, t), 2.74 (2H, t), 2.48 (2H, m), 2.19 (4H, m), 1.91
(1H, m), 1.76 (1H, m)
Example 484:
4-[4-[4-(cyclobutoxy)-6-methyl-pyrimidin-2-yl]-2,6-difluoro-N-methyl-anil-
ino]butanoic Acid
##STR00527##
[3560] 2-Chloro-4-(cyclobutoxy)-6-methyl-pyrimidine (0.082 g, 0.41
mmol) obtained in Preparation Example 228 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.157 g, 0.41 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Step A of Example 96 and Step B of Example 1 to obtain the
title compound (0.118 g, 73%).
[3561] .sup.1H-NMR (CDCl.sub.3) .delta. 7.88 (2H, m), 6.40 (1H, s),
5.29 (1H, m), 3.21 (2H, t), 2.92 (3H, s), 2.53 (2H, m), 2.45 (3H,
s), 2.43 (2H, m), 2.19 (2H, m), 1.87 (3H, m), 1.73 (1H, m)
Example 485:
4-[4-[4-(cyclobutoxy)pyrimidin-2-yl]-2,6-difluoro-N-methyl-anilino]butano-
ic Acid
##STR00528##
[3563] 2-Chloro-4-(cyclobutoxy)pyrimidine (0.081 g, 0.44 mmol)
obtained in Preparation Example 230 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butanoic acid methyl ester (0.168 g, 0.44 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Step A of Example 96 and Step B of Example 1 to obtain the
title compound (0.119 g, 72%).
[3564] .sup.1H-NMR (CDCl.sub.3) .delta. 8.46 (1H, d), 7.87 (2H, m),
6.56 (1H, d), 5.32 (1H, m), 3.22 (2H, t), 2.93 (3H, s), 2.53 (2H,
m), 2.44 (2H, t), 2.20 (2H, m), 1.88 (3H, m), 1.78 (1H, m)
Example 486:
4-[4-[2-(cyclobutoxy)thiazol-4-yl]-2,6-difluoro-N-methyl-anilino]butanoic
Acid
##STR00529##
[3566] 4-Bromo-2-(cyclobutoxy)thiazole (0.083 g, 0.35 mmol)
obtained in Preparation Example 289 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.134 g, 0.35 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Step A of Example 96 and Step B of Example 1 to obtain the
title compound (0.085 g, 63%).
[3567] .sup.1H-NMR (CDCl.sub.3) .delta. 7.28 (2H, m), 6.77 (1H, s),
5.18 (1H, m), 3.15 (2H, t), 2.86 (3H, s), 2.54 (2H, m), 2.45 (2H,
t), 2.25 (2H, m), 1.85 (3H, m), 1.67 (1H, m)
Example 487:
2-[1-[4-[6-(cyclobutoxy)indazol-1-yl]-2,6-difluoro-phenyl]-4-piperidyl]ac-
etic Acid
##STR00530##
[3569] 6-(Cyclobutoxy)-1H-indazole (0.1 g, 0.53 mmol) obtained in
Preparation Example 309 and
2-[1-(4-bromo-2,6-difluoro-phenyl)-4-piperidyl]acetic acid ethyl
ester (0.21 g, 0.58 mmol) obtained in Step A of Preparation Example
220 were reacted in the same manner as in Step A of Example 463 and
Step B of Example 1 to obtain the title compound (0.026 g,
11%).
[3570] .sup.1H-NMR (CDCl.sub.3) .delta. 8.09 (1H, s), 7.67 (1H, d),
7.26 (2H, m), 7.00 (1H, m), 6.87 (1H, m), 4.76 (1H, m), 3.34 (2H,
m), 3.22 (2H, t), 2.53 (2H, m), 2.42 (2H, d), 2.27 (2H, m), 2.03
(1H, m), 1.93 (3H, m), 1.80 (1H, m), 1.56 (2H, m)
Example 488:
4-[4-[6-(cyclobutoxy)pyrazin-2-yl]-2,6-difluoro-N-methyl-anilino]butanoic
Acid
##STR00531##
[3572] 2-Chloro-6-(cyclobutoxy)pyrazine (0.06 g, 0.32 mmol)
obtained in Preparation Example 232 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.123 g, 0.32 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Step A of Example 96 and Step B of Example 1 to obtain the
title compound (0.079 g, 65%).
[3573] .sup.1H-NMR (CDCl.sub.3) .delta. 8.46 (1H, s), 8.09 (1H, s),
7.50 (2H, m), 5.26 (1H, m), 3.21 (2H, t), 2.92 (3H, s), 2.54 (2H,
m), 2.44 (2H, t), 2.21 (2H, m), 1.89 (3H, m), 1.75 (1H, m)
Example 489:
4-[4-[4-(cyclopropylmethoxy)-6-methyl-pyrimidin-2-yl]-2,6-difluoro-N-meth-
yl-anilino]butanoic Acid
##STR00532##
[3575] 2-Chloro-4-(cyclopropylmethoxy)-6-methyl-pyrimidine (0.067
g, 0.34 mmol) obtained in Preparation Example 227 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.13 g, 0.34 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Step A of Example 96 and Step B of Example 1 to obtain the
title compound (0.086 g, 64%).
[3576] .sup.1H-NMR (CDCl.sub.3) .delta. 7.89 (2H, m), 6.46 (1H, s),
4.27 (2H, d), 3.21 (2H, t), 2.92 (3H, s), 2.46 (3H, s), 2.43 (2H,
t), 1.88 (2H, m), 1.32 (1H, m), 0.63 (2H, m), 0.39 (2H, m)
Example 490:
4-[4-[4-(cyclopropylmethoxy)pyrimidin-2-yl]-2,6-difluoro-N-methyl-anilino-
]butanoic Acid
##STR00533##
[3578] 2-Chloro-4-(cyclopropylmethoxy)pyrimidine (0.073 g, 0.39
mmol) obtained in Preparation Example 231 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.15 g, 0.39 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Step A of Example 96 and Step B of Example 1 to obtain the
title compound (0.097 g, 66%).
[3579] .sup.1H-NMR (CDCl.sub.3) .delta. 8.46 (1H, d), 7.88 (2H, m),
6.62 (1H, d), 4.30 (2H, d), 3.22 (2H, t), 2.92 (3H, s), 2.44 (2H,
t), 1.89 (2H, m), 1.33 (1H, m), 0.65 (2H, m), 0.41 (2H, m)
Example 491:
4-[4-[6-(cyclopropylmethoxy)pyrazin-2-yl]-2,6-difluoro-N-methyl-anilino]b-
utanoic Acid
##STR00534##
[3581] 2-Chloro-6-(cyclopropylmethoxy)pyrazine (0.065 g, 0.35 mmol)
obtained in Preparation Example 233 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.134 g, 0.35 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Step A of Example 96 and Step B of Example 1 to obtain the
title compound (0.071 g, 53%).
[3582] .sup.1H-NMR (CDCl.sub.3) .delta.8.47 (1H, s), 8.16 (1H, s),
7.50 (2H, m), 4.25 (2H, d), 3.21 (2H, t), 2.92 (3H, s), 2.44 (2H,
t), 1.89 (2H, m), 1.33 (1H, m), 0.66 (2H, m), 0.40 (2H, m)
Example 492:
4-[4-[6-(cyclobutoxy)indazol-1-yl]-2,6-difluoro-N-methyl-anilino]butanoic
Acid
##STR00535##
[3584] 6-(Cyclobutoxy)-1H-indazole (0.1 g, 0.53 mmol) obtained in
Preparation Example 309 and
4-(4-bromo-2,6-difluoro-N-methyl-anilino)butanoic acid methyl ester
(0.187 g, 0.58 mmol) were reacted in the same manner as in Step A
of Example 463 and Step B of Example 1 to obtain the title compound
(0.079 g, 35%).
[3585] .sup.1H-NMR (CDCl.sub.3) .delta. 8.05 (1H, m), 7.63 (1H, d),
7.25 (2H, m), 6.99 (1H, m), 6.83 (1H, m), 4.73 (1H, m), 3.18 (2H,
t), 2.90 (3H, s), 2.50 (4H, m), 2.22 (2H, m), 1.88 (3H, m), 1.77
(1H, m)
Example 493:
4-[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-N-methyl-anilino]but-
anoic Acid
##STR00536##
[3587] 2-Chloro-6-cyclopropylmethoxy-pyridine (0.083 g, 0.45 mmol)
obtained in Preparation Example 43 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.172 g, 0.45 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Step A of Example 96 and Step B of Example 1 to obtain the
title compound (0.14 g, 82%).
[3588] .sup.1H-NMR (CDCl.sub.3) .delta. 7.60 (1H, t), 7.50 (2H, m),
7.20 (1H, d), 6.70 (1H, d), 4.23 (2H, d), 3.17 (2H, t), 2.89 (3H,
s), 2.45 (2H, t), 1.87 (2H, m), 1.32 (1H, m), 0.61 (2H, m), 0.39
(2H, m)
Example 494:
2-[1-[4-[6-(cyclobutoxy)indazol-1-yl]-2,6-difluoro-phenyl]pyrrolidin-3-yl-
]acetic Acid
##STR00537##
[3590] 6-(Cyclobutoxy)-1H-indazole (0.15 g, 0.79 mmol) obtained in
Preparation Example 309 and
2-[1-(4-bromo-2,6-difluoro-phenyl)pyrrolidin-3-yl]acetic acid ethyl
ester (0.302 g, 0.87 mmol) obtained in Step F of Preparation
Example 91 were reacted in the same manner as in Step A of Example
463 and Step B of Example 1 to obtain the title compound (0.05 g,
15%).
[3591] .sup.1H-NMR (CDCl.sub.3) .delta. 8.04 (1H, m), 7.61 (1H, d),
7.17 (2H, m), 6.92 (1H, m), 6.82 (1H, m), 4.71 (1H, m), 3.77 (1H,
m), 3.62 (2H, m), 3.36 (1H, m), 2.70 (1H, m), 2.57 (2H, m), 2.48
(2H, m), 2.27 (3H, m), 1.89 (1H, m), 1.71 (2H, m)
Example 495:
2-{1-[2,6-difluoro-4-(6-propoxy-pyrazin-2-yl)phenyl]pyrrolidin-3-yl}aceti-
c Acid
##STR00538##
[3593] 2-Chloro-6-propoxy-pyrazine (0.063 g, 0.36 mmol) obtained in
Preparation Example 235 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
pyrrolidin-3-yl]acetic acid ethyl ester (0.119 g, 0.30 mmol)
obtained in Preparation Example 91 were reacted in the same manner
as in Step A of Example 96 and Step B of Example 1 to obtain the
title compound (0.029 g, 21%).
[3594] .sup.1H-NMR (CDCl.sub.3) .delta.8.44 (1H, s), 8.07 (1H, s),
7.49 (2H, m), 4.37 (2H, t), 3.79 (2H, m), 3.64 (1H, m), 3.41 (1H,
m), 2.67 (1H, m), 2.55 (2H, m), 2.19 (1H, m), 1.83 (2H, q), 1.65
(1H, m), 1.06 (3H, t)
Example 496:
2-{1-[2,6-difluoro-4-(6-isobutoxy-pyrazin-2-yl)phenyl]pyrrolidin-3-yl}ace-
tic Acid
##STR00539##
[3596] 2-Chloro-6-isobutoxy-pyrazine (0.061 g, 0.33 mmol) obtained
in Preparation Example 237 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
pyrrolidin-3-yl]acetic acid ethyl ester (0.107 g, 0.27 mmol)
obtained in Preparation Example 91 were reacted in the same manner
as in Step A of Example 96 and Step B of Example 1 to obtain the
title compound (0.049 g, 38%).
[3597] .sup.1H-NMR (DMSO-d.sub.6) .delta.8.77 (1H, s), 8.17 (1H,
s), 7.74 (2H, m), 4.19 (2H, d), 3.69 (2H, m), 3.57 (1H, m), 3.34
(1H, m), 2.49 (1H, m), 2.41 (2H, m), 2.10 (2H, m), 1.60 (1H, m),
1.02 (6H, d)
Example 497:
2-{1-[2,6-difluoro-4-(6-cyclopentoxy-pyrazin-2-yl)phenyl]pyrrolidin-3-yl}-
acetic Acid
##STR00540##
[3599] 2-Chloro-6-cyclopentoxy-pyrazine (0.075 g, 0.38 mmol)
obtained in Preparation Example 238 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
pyrrolidin-3-yl]acetic acid ethyl ester (0.123 g, 0.31 mmol)
obtained in Preparation Example 91 were reacted in the same manner
as in Step A of Example 96 and Step B of Example 1 to obtain the
title compound (0.056 g, 36%).
[3600] .sup.1H-NMR (DMSO-d.sub.6) .delta.8.75 (1H, s), 8.11 (1H,
s), 7.74 (2H, m), 5.49 (1H, m), 3.69 (2H, m), 3.57 (1H, m), 3.34
(1H, m), 2.51 (1H, m), 2.41 (2H, m), 2.04 (3H, m), 1.81-1.52 (7H,
m)
Example 498:
2-{1-[2,6-difluoro-4-(6-butoxy-pyrazin-2-yl)phenyl]pyrrolidin-3-yl}acetic
Acid
##STR00541##
[3602] 2-Butoxy-6-chloro-pyrazine (0.071 g, 0.38 mmol) obtained in
Preparation Example 236 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
pyrrolidin-3-yl]acetic acid ethyl ester (0.123 g, 0.31 mmol)
obtained in Preparation Example 91 was reacted in the same manner
as in Step A of Example 96 and Step B of Example 1 to obtain the
title compound (0.1 g, 67%).
[3603] .sup.1H-NMR (DMSO-d.sub.6) .delta.8.77 (1H, s), 8.16 (1H,
s), 7.74 (2H, m), 4.41 (2H, t), 3.69 (2H, m), 3.57 (1H, m), 3.34
(1H, m), 2.49 (1H, m), 2.41 (2H, m), 2.09 (1H, m), 1.77 (2H, m),
1.59 (1H, m), 1.47 (2H, m), 0.96 (3H, t)
Example 499:
2-{1-[2,6-difluoro-4-(4-propoxy-pyrimidin-2-yl)phenyl]pyrrolidin-3-yl}ace-
tic Acid
##STR00542##
[3605] 2-Chloro-4-propoxy-pyrimidine (0.068 g, 0.39 mmol) obtained
in Preparation Example 241 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
pyrrolidin-3-yl]acetic acid ethyl ester (0.130 g, 0.33 mmol)
obtained in Preparation Example 91 were reacted in the same manner
as in Step A of Example 96 and Step B of Example 1 to obtain the
title compound (0.034 g, 23%).
[3606] .sup.1H-NMR (DMSO-d.sub.6) .delta.8.53 (1H, d), 7.82 (2H,
m), 6.77 (1H, d), 4.41 (2H, t), 3.71 (2H, m), 3.59 (1H, m), 3.34
(1H, m), 2.49 (1H, m), 2.41 (2H, m), 2.07 (1H, m), 1.80 (2H, q),
1.59 (1H, m), 1.00 (3H, t)
Example 500:
2-{1-[2,6-difluoro-4-(4-isopropoxy-pyrimidin-2-yl)phenyl]pyrrolidin-3-yl}-
acetic Acid
##STR00543##
[3608] 2-Chloro-4-isopropoxy-pyrimidine (0.073 g, 0.42 mmol)
obtained in Preparation Example 240 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
pyrrolidin-3-yl]acetic acid ethyl ester (0.138 g, 0.35 mmol)
obtained in Preparation Example 91 were reacted in the same manner
as in Step A of Example 96 and Step B of Example 1 to obtain the
title compound (0.042 g, 26%).
[3609] .sup.1H-NMR (DMSO-d.sub.6) .delta.8.52 (1H, d), 7.83 (2H,
m), 6.72 (1H, d), 5.49 (1H, m), 3.71 (2H, m), 3.59 (1H, m), 3.34
(1H, m), 2.50 (1H, m), 2.41 (2H, m), 2.07 (1H, m), 1.59 (1H, m),
1.37 (6H, d)
Example 501:
2-{1-[2,6-difluoro-4-(4-ethoxy-pyrimidin-2-yl)phenyl]pyrrolidin-3-yl}acet-
ic Acid
##STR00544##
[3611] 2-Chloro-4-ethoxy-pyrimidine (0.098 g, 0.61 mmol) obtained
in Preparation Example 239 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
pyrrolidin-3-yl]acetic acid ethyl ester (0.197 g, 0.50 mmol)
obtained in Preparation Example 91 were reacted in the same manner
as in Step A of Example 96 and Step B of Example 1 to obtain the
title compound (0.071 g, 32%).
[3612] .sup.1H-NMR (DMSO-d.sub.6) .delta.8.52 (1H, d), 7.84 (2H,
m), 6.76 (1H, d), 4.51 (2H, q), 3.70 (2H, m), 3.59 (1H, m), 3.34
(1H, m), 2.51 (1H, m), 2.41 (2H, m), 2.09 (1H, m), 1.58 (1H, m),
1.37 (3H, t)
Example 502:
2-{1-[2,6-difluoro-4-(4-isobutoxy-pyrimidin-2-yl)phenyl]pyrrolidin-3-yl}a-
cetic Acid
##STR00545##
[3614] 2-Chloro-4-isobutoxy-pyrimidine (0.083 g, 0.44 mmol)
obtained in Preparation Example 242 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
pyrrolidin-3-yl]acetic acid ethyl ester (0.146 g, 0.37 mmol)
obtained in Preparation Example 91 were reacted in the same manner
as in Step A of Example 96 and Step B of Example 1 to obtain the
title compound (0.059 g, 34%).
[3615] .sup.1H-NMR (DMSO-d.sub.6) .delta.8.53 (1H, d), 7.82 (2H,
m), 6.78 (1H, d), 4.24 (2H, d), 3.70 (2H, m), 3.60 (1H, m), 3.35
(1H, m), 2.51 (1H, m), 2.42 (2H, m), 2.09 (2H, m), 1.59 (1H, m),
1.01 (6H, d)
Example 503:
2-{1-[2,6-difluoro-4-(6-isobutylamino-pyrazin-2-yl)phenyl]pyrrolidin-3-yl-
}acetic Acid
##STR00546##
[3617] 6-Chloro-N-isobutyl-pyrazin-2-amine (0.278 g, 1.50 mmol)
obtained in Preparation Example 251 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
pyrrolidin-3-yl]acetic acid ethyl ester (0.3 g, 0.75 mmol) obtained
in Preparation Example 91 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.172 g, 58%).
[3618] .sup.1H-NMR (CDCl.sub.3) .delta.8.10 (1H, s), 7.75 (1H, s),
7.43 (2H, m), 4.89 (1H, brs), 3.71 (2H, m), 3.61 (1H, m), 3.39 (1H,
m), 3.22 (2H, d), 2.64 (1H, m), 2.52 (2H, m), 2.16 (1H, m), 1.93
(1H, m), 1.65 (1H, m), 0.99 (6H, d)
Example 504:
2-{1-[2,6-difluoro-4-(6-cyclopentylamino-pyrazin-2-yl)phenyl]pyrrolidin-3-
-yl}acetic Acid
##STR00547##
[3620] 6-Chloro-N-cyclopentyl-pyrazin-2-amine (0.297 g, 1.50 mmol)
obtained in Preparation Example 252 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
pyrrolidin-3-yl]acetic acid ethyl ester (0.3 g, 0.75 mmol) obtained
in Preparation Example 91 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.17 g, 56%).
[3621] .sup.1H-NMR (DMSO-d.sub.6) .delta.8.17 (1H, s), 7.75 (1H,
s), 7.60 (2H, m), 7.07 (1H, d), 4.14 (1H, m), 3.61 (2H, m), 3.49
(1H, m), 3.29 (1H, m), 2.47 (1H, m), 2.36 (2H, m), 2.03 (1H, m),
1.94 (2H, m), 1.66 (2H, m), 1.54 (3H, m), 1.44 (2H, m)
Example 505:
2-{1-[2,6-difluoro-4-(6-isopropylamino-pyrazin-2-yl)phenyl]pyrrolidin-3-y-
l}acetic Acid
##STR00548##
[3623] 6-Chloro-N-isopropyl-pyrazin-2-amine (0.257 g, 1.50 mmol)
obtained in Preparation Example 250 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
pyrrolidin-3-yl]acetic acid ethyl ester (0.3 g, 0.75 mmol) obtained
in Preparation Example 91 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.12 g, 42%).
[3624] .sup.1H-NMR (DMSO-d.sub.6) .delta.8.21 (1H, s), 7.78 (1H,
s), 7.64 (2H, m), 6.99 (1H, d), 4.11 (1H, m), 3.65 (2H, m), 3.53
(1H, m), 3.33 (1H, m), 2.51 (1H, m), 2.40 (2H, m), 2.09 (1H, m),
1.58 (1H, m), 1.21 (6H, d)
Example 506:
2-{1-[2,6-difluoro-4-(6-diethylamino-pyrazin-2-yl)phenyl]pyrrolidin-3-yl}-
acetic Acid
##STR00549##
[3626] 6-Chloro-N,N-diethyl-pyrazin-2-amine (0.278 g, 1.50 mmol)
obtained in Preparation Example 253 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
pyrrolidin-3-yl]acetic acid ethyl ester (0.3 g, 0.75 mmol) obtained
in Preparation Example 91 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.17 g, 58%).
[3627] .sup.1H-NMR (DMSO-d.sub.6) .delta.8.31 (1H, s), 8.00 (1H,
s), 7.66 (2H, m), 3.67 (2H, m), 3.59 (4H, q), 3.56 (1H, m), 3.33
(1H, m), 2.50 (1H, m), 2.41 (2H, m), 2.09 (1H, m), 1.58 (1H, m),
1.17 (6H, t)
Example 507:
3-[6-(6-cyclobutoxy-pyrazin-2-yl)-thiochroman-2-yl]-propionic
Acid
##STR00550##
[3629] 2-Chloro-6-(cyclobutoxy)pyrazin-2-amine (0.13/g, 0.74 mmol)
obtained in Preparation Example 232 and
3-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiochroman-2-yl]-pro-
pionic acid ethyl ester (0.14 g, 0.37 mmol) obtained in Preparation
Example 5 were reacted in the same manner as in Step A of Example
96 and Step B of Example 1 to obtain the title compound (0.085 g,
62%).
[3630] .sup.1H-NMR (CDCl.sub.3) .delta.8.51 (1H, s), 8.05 (1H, s),
7.70 (2H, m), 7.18 (1H, d), 5.26 (1H, m), 3.43 (1H, m), 2.97 (2H,
m), 2.60 (2H, m), 2.51 (2H, m), 2.26-2.18 (3H, m), 2.07 (2H, m),
1.91-1.70 (3H, m)
Example 508:
2-[1-[4-[4-(4-chlorophenoxy)pyrimidin-2-yl]-2,6-difluoro-phenyl]-4-piperi-
dyl]acetic Acid
##STR00551##
[3632] 2-Chloro-4-(4-chloro-phenoxy)-pyrimidine (0.235 g, 0.98
mmol) obtained in Preparation Example 312 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.2 g, 0.49 mmol) obtained in
Preparation Example 220 were reacted in the same manner as in Step
A of Example 96 and Step B of Example 1 to obtain the title
compound (0.014 g, 6%).
[3633] .sup.1H-NMR (CDCl.sub.3) .delta. 8.60 (1H, d), 7.71 (2H, m),
7.41 (2H, m), 7.15 (2H, m), 6.73 (1H, d), 3.35 (2H, m), 3.13 (2H,
m), 2.35 (2H, d), 1.97 (1H, m), 1.80 (2H, m), 1.47 (2H, m)
Example 509:
2-[1-[4-[4-(4-chlorophenoxy)pyrimidin-2-yl]-2,6-difluoro-phenyl]-pyrrolid-
in-3-yl]acetic Acid
##STR00552##
[3635] 2-Chloro-4-(4-chloro-phenoxy)-pyrimidine (0.145 g, 0.60
mmol) obtained in Preparation Example 312 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
pyrrolidin-3-yl]acetic acid ethyl ester (0.2 g, 0.50 mmol) obtained
in Preparation Example 91 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.014 g, 10%).
[3636] .sup.1H-NMR (CDCl.sub.3) .delta. 8.56 (1H, d), 7.68 (2H, m),
7.42 (2H, m), 7.15 (2H, m), 6.67 (1H, d), 3.76 (2H, m), 3.64 (1H,
m), 3.42 (1H, m), 2.63 (1H, m), 2.52 (2H, m), 2.16 (1H, m), 1.64
(1H, m)
Example 510:
2-[1-[4-[4-phenoxy-pyrimidin-2-yl]-2,6-difluoro-phenyl]-4-piperidyl]aceti-
c Acid
##STR00553##
[3638] 2-Chloro-4-phenoxy-pyrimidine (0.122 g, 0.59 mmol) obtained
in Preparation Example 313 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.2 g, 0.49 mmol) obtained in
Preparation Example 220 were reacted in the same manner as in Step
A of Example 96 and Step B of Example 1 to obtain the title
compound (0.075 g, 36%).
[3639] .sup.1H-NMR (CDCl.sub.3) .delta. 8.58 (1H, d), 7.74 (2H, m),
7.46 (2H, m), 7.30 (1H, m), 7.20 (2H, m), 6.69 (1H, d), 3.36 (2H,
m), 3.13 (2H, m), 2.34 (2H, d), 1.96 (1H, m), 1.80 (2H, m), 1.45
(2H, m)
Example 511:
2-[1-[4-[4-(4-fluorophenoxy)pyrimidin-2-yl]-2,6-difluoro-phenyl]-4-piperi-
dyl]acetic Acid
##STR00554##
[3641] 2-Chloro-4-(4-fluoro-phenoxy)-pyrimidine (0.133 g, 0.59
mmol) obtained in Preparation Example 314 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.2 g, 0.49 mmol) obtained in
Preparation Example 220 were reacted in the same manner as in Step
A of Example 96 and Step B of Example 1 to obtain the title
compound (0.061 g, 28%).
[3642] .sup.1H-NMR (DMSO-d.sub.6) .delta. 8.70 (1H, d), 7.60 (2H,
m), 7.31 (4H, m), 6.98 (1H, d), 3.35 (2H, m), 3.01 (2H, m), 2.16
(2H, d), 1.78 (1H, m), 1.68 (2H, m), 1.27 (2H, m)
Example 512:
2-[1-[4-[4-(4-pyridin-3-yloxy-pyrimidin-2-yl]-2,6-difluoro-phenyl]-4-pipe-
ridyl]acetic Acid
##STR00555##
[3644] 2-Chloro-4-(4-pyridin-3-yloxy)-pyrimidine (0.122 g, 0.59
mmol) obtained in Preparation Example 315 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.2 g, 0.49 mmol) obtained in
Preparation Example 220 were reacted in the same manner as in Step
A of Example 96 and Step B of Example 1 to obtain the title
compound (0.081 g, 38%).
[3645] .sup.1H-NMR (CDCl.sub.3) .delta. 8.64 (2H, m), 8.57 (1H, d),
7.65 (2H, m), 7.62 (1H, m), 7.45 (1H, m), 6.83 (1H, d), 3.34 (2H,
m), 3.11 (2H, m), 2.33 (2H, d), 1.96 (1H, m), 1.80 (2H, m), 1.45
(2H, m)
Example 513:
2-[1-[2,6-difluoro-4-[6-(4-fluorophenoxy)pyrazin-2-yl]phenyl]-4-piperidyl-
]acetic Acid
##STR00556##
[3647] 2-Chloro-4-(4-fluoro-phenoxy)-pyrazine (0.133 g, 0.59 mmol)
obtained in Preparation Example 316 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.2 g, 0.49 mmol) obtained in
Preparation Example 220 were reacted in the same manner as in Step
A of Example 96 and Step B of Example 1 to obtain the title
compound (0.143 g, 65%).
[3648] .sup.1H-NMR (CDCl.sub.3) .delta. 8.62 (1H, s), 8.28 (1H, s),
7.34 (2H, m), 7.20-7.11 (4H, m), 3.33 (2H, m), 3.13 (2H, m), 2.35
(2H, d), 1.97 (1H, m), 1.82 (2H, m), 1.45 (2H, m)
Example 514:
2-[1-[4-[4-(4-methoxyphenoxy)pyrimidin-2-yl]-2,6-difluoro-phenyl]-4-piper-
idyl]acetic Acid
##STR00557##
[3650] 2-Chloro-4-(4-methoxy-phenoxy)-pyrimidine (0.140 g, 0.59
mmol) obtained in Preparation Example 317 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.2 g, 0.49 mmol) obtained in
Preparation Example 220 were reacted in the same manner as in Step
A of Example 96 and Step B of Example 1 to obtain the title
compound (0.059 g, 26%).
[3651] .sup.1H-NMR (CDCl.sub.3) .delta. 8.56 (1H, d), 7.75 (2H, m),
7.11 (2H, m), 6.96 (2H, m), 6.65 (1H, d), 3.85 (3H, s), 3.36 (2H,
m), 3.13 (2H, m), 2.35 (2H, d), 1.97 (1H, m), 1.80 (2H, m), 1.47
(2H, m)
Example 515:
2-[1-[2,6-difluoro-4-[4-(4-fluorophenoxy)-6-methyl-pyrimidin-2-yl]phenyl]-
-4-piperidyl]acetic Acid
##STR00558##
[3653] 2-Chloro-4-(4-fluoro-phenoxy)-6-methyl-pyrimidine (0.140 g,
0.59 mmol) obtained in Preparation Example 318 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.2 g, 0.49 mmol) obtained in
Preparation Example 220 were reacted in the same manner as in Step
A of Example 96 and Step B of Example 1 to obtain the title
compound (0.097 g, 43%).
[3654] .sup.1H-NMR (CDCl.sub.3) .delta. 7.74 (2H, m), 7.13 (4H, m),
6.52 (1H, s), 3.34 (2H, m), 3.13 (2H, m), 2.51 (3H, s), 2.34 (2H,
d), 1.96 (1H, m), 1.80 (2H, m), 1.47 (2H, m)
Example 516:
2-[1-[4-[4-(p-tolyloxy)pyrimidin-2-yl]-2,6-difluoro-phenyl]-4-piperidyl]a-
cetic Acid
##STR00559##
[3656] 2-Chloro-4-p-tolyloxypyrimidine (0.130 g, 0.59 mmol)
obtained in Preparation Example 319 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.2 g, 0.49 mmol) obtained in
Preparation Example 220 were reacted in the same manner as in Step
A of Example 96 and Step B of Example 1 to obtain the title
compound (0.07 g, 32%).
[3657] .sup.1H-NMR (CDCl.sub.3) .delta. 8.56 (1H, d), 7.76 (2H, m),
7.24 (2H, d), 7.08 (2H, d), 6.66 (1H, d), 3.36 (2H, m), 3.13 (2H,
m), 2.40 (3H, s), 2.35 (2H, d), 1.97 (1H, m), 1.80 (2H, m), 1.47
(2H, m)
Example 517:
2-[1-[4-[4-(3,4-difluorophenoxy)pyrimidin-2-yl]-2,6-difluoro-phenyl]-4-pi-
peridyl]acetic Acid
##STR00560##
[3659] 2-Chloro-4-(3,4-difluoro-phenoxy)-pyrimidine (0.143 g, 0.59
mmol) obtained in Preparation Example 320 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.2 g, 0.49 mmol) obtained in
Preparation Example 220 were reacted in the same manner as in Step
A of Example 96 and Step B of Example 1 to obtain the title
compound (0.08 g, 35%).
[3660] .sup.1H-NMR (CDCl.sub.3) .delta. 8.61 (1H, d), 7.69 (2H, m),
7.24 (1H, m), 7.09 (1H, m), 6.96 (1H, m), 6.76 (1H, d), 3.36 (2H,
m), 3.14 (2H, m), 2.35 (2H, d), 1.97 (1H, m), 1.80 (2H, m), 1.47
(2H, m)
Example 518:
4-[4-(5-chloro-2-methyl-benzofuran-7-yl)-2,6-difluoro-phenoxy]-butyric
Acid
##STR00561##
[3662] 7-Bromo-5-chloro-2-methyl-benzofuran (0.030 g, 0.12 mmol)
obtained in Preparation Example 328 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (0.045 g, 0.12 mmol) obtained in Preparation
Example 16 were reacted in the same manner as in Example 1 to
obtain the title compound (0.023 g, 49%).
[3663] .sup.1H-NMR (CDCl.sub.3) .delta. 7.41 (3H, m), 7.24 (1H, s),
6.38 (1H, s), 4.27 (2H, t), 2.70 (2H, t), 2.49 (3H, s), 2.14 (2H,
m)
Example 519:
5-[4-(5-chloro-2-methyl-benzofuran-7-yl)-2,6-difluoro-phenyl]-hexanoic
Acid
##STR00562##
[3665] 7-Bromo-5-chloro-2-methyl-benzofuran (0.030 g, 0.12 mmol)
obtained in Preparation Example 328 and
5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]he-
xanoic acid ethyl ester (0.047 g, 0.12 mmol) obtained in
Preparation Example 32 were reacted in the same manner as in
Example 1 to obtain the title compound (0.025 g, 53%).
[3666] .sup.1H-NMR (CDCl.sub.3) .delta. 7.41 (1H, s), 7.32 (2H, d),
7.29 (1H, s), 6.38 (1H, s), 3.27 (1H, m), 2.89 (3H, s), 2.38 (2H,
t), 1.86 (1H, m), 1.75 (1H, m), 1.66 (1H, m), 1.55 (1H, m), 1.38
(3H, d)
Example 520:
4-[(3'-cyclobutylmethoxy-3,5-difluoro-biphenyl-4-yl)-methyl-amino]-butyri-
c Acid
##STR00563##
[3668] 1-Bromo-3-cyclobutylmethoxy-benzene (0.050 g, 0.21 mmol)
obtained in Preparation Example 323 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.077 g, 0.21 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.025 g, 31%).
[3669] .sup.1H-NMR (CDCl.sub.3) .delta. 7.43 (1H, t), 7.08 (4H, m),
6.90 (1H, m), 3.97 (2H, d), 3.18 (2H, t), 2.87 (3H, s), 2.81 (1H,
m), 2.48 (2H, t), 2.16 (2H, m), 1.91 (6H, m)
Example 521:
4-(3'-cyclobutylmethoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric
Acid
##STR00564##
[3671] 1-Bromo-3-cyclobutylmethoxy-benzene (0.030 g, 0.12 mmol)
obtained in Preparation Example 323 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (0.046 g, 0.12 mmol) obtained in Preparation
Example 16 were reacted in the same manner as in Example 1 to
obtain the title compound (0.015 g, 32%).
[3672] .sup.1H-NMR (CDCl.sub.3) .delta. 7.32 (1H, t), 7.12 (2H, m),
7.16 (1H, m), 7.02 (1H, m), 6.90 (1H, m), 4.23 (2H, t), 3.97 (2H,
d), 2.80 (1H, m), 2.69 (2H, t), 2.16 (4H, m), 1.91 (4H, m)
Example 522:
4-{[4-(6-cyclobutylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-methyl-amin-
o}-butyric Acid
##STR00565##
[3674] 2-Chloro-6-cyclobutylmethoxy-pyridine (0.050 g, 0.25 mmol)
obtained in Preparation Example 324 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.093 g, 0.25 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.030 g, 30%).
[3675] .sup.1H-NMR (CDCl.sub.3) .delta. 7.61 (1H, t), 7.53 (2H, m),
7.20 (1H, d), 6.68 (1H, d), 4.37 (2H, d), 3.20 (2H, t), 2.89 (3H,
s), 2.81 (1H, m), 2.47 (2H, t), 2.15 (2H, m), 1.92 (6H, m)
Example 523:
4-[4-(6-cyclobutylmethoxy-pyridin-2-yl)-2,6-difluoro-phenoxy]-butyric
Acid
##STR00566##
[3677] 2-Chloro-6-cyclobutylmethoxy-pyridine (0.030 g, 0.15 mmol)
obtained in Preparation Example 324 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (0.056 g, 0.15 mmol) obtained in Preparation
Example 16 were reacted in the same manner as in Example 1 to
obtain the title compound (0.018 g, 31%).
[3678] .sup.1H-NMR (CDCl.sub.3) .delta. 7.60 (3H, m), 7.21 (1H, d),
6.69 (1H, d), 4.36 (2H, d), 4.24 (2H, t), 2.81 (1H, m), 2.69 (2H,
t), 2.14 (4H, m), 1.92 (4H, m)
Example 524:
4-[(3'-cyclopropylmethoxy-3,5-difluoro-biphenyl-4-yl)-methyl-amino]-butyr-
ic Acid
##STR00567##
[3680] 1-Bromo-3-cyclopropylmethoxy-benzene (0.050 g, 0.22 mmol)
obtained in Preparation Example 280 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.081 g, 0.22 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.025 g, 30%).
[3681] .sup.1H-NMR (CDCl.sub.3) .delta. 7.32 (1H, t), 7.07 (4H, m),
6.89 (1H, m), 3.85 (2H, d), 3.16 (2H, t), 2.87 (3H, s), 2.48 (2H,
t), 1.87 (2H, m), 1.31 (1H, m), 0.66 (2H, m), 0.38 (2H, m)
Example 525:
4-[(3'-cyclopentyloxy-3,5-difluoro-biphenyl-4-yl)-methyl-amino]-butyric
Acid
##STR00568##
[3683] 1-Bromo-3-cyclopentyloxy-benzene (0.050 g, 0.21 mmol)
obtained in Preparation Example 297 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.077 g, 0.21 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.026 g, 32%).
[3684] .sup.1H-NMR (CDCl.sub.3) .delta. 7.32 (1H, t), 7.07 (3H, m),
7.00 (1H, m), 6.85 (1H, m), 4.81 (1H, m), 3.16 (2H, t), 2.87 (3H,
s), 2.48 (2H, t), 1.92 (8H, m), 1.64 (2H, m)
Example 526:
4-(3'-cyclopropylmethoxy-3,5-difluoro-4'-methoxy-biphenyl-4-yloxy)-butyri-
c Acid
##STR00569##
[3686] 4-Bromo-2-cyclopropylmethoxy-1-methoxy-benzene (0.050 g,
0.19 mmol) obtained in Preparation Example 282 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (0.072 g, 0.19 mmol) obtained in Preparation
Example 16 were reacted in the same manner as in Example 1 to
obtain the title compound (0.032 g, 42%).
[3687] .sup.1H-NMR (CDCl.sub.3) .delta. 7.06 (3H, m), 6.99 (1H, m),
6.93 (1H, d), 4.21 (2H, t), 3.94 (5H, m), 2.68 (2H, t), 2.13 (2H,
m), 1.37 (1H, m), 0.67 (2H, m), 0.39 (2H, m)
Example 527:
4-(3'-cyclopropylmethoxy-3,5,4'-trifluoro-biphenyl-4-yloxy)-butyric
Acid
##STR00570##
[3689] 4-Bromo-2-cyclopropylmethoxy-1-fluoro-benzene (0.050 g, 0.20
mmol) obtained in Preparation Example 283 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (0.076 g, 0.20 mmol) obtained in Preparation
Example 16 were reacted in the same manner as in Example 1 to
obtain the title compound (0.025 g, 32%).
[3690] .sup.1H-NMR (CDCl.sub.3) .delta. 7.13 (1H, m), 7.05 (4H, m),
4.21 (2H, t), 3.93 (2H, d), 2.68 (2H, t), 2.12 (2H, m), 1.34 (1H,
m), 0.67 (2H, m), 0.39 (2H, m)
Example 528:
4-(5'-cyclobutoxy-3,5,3'-trifluoro-biphenyl-4-yloxy)-butyric
Acid
##STR00571##
[3692] 1-Bromo-3-cyclobutoxy-5-fluoro-benzene (0.050 g, 0.20 mmol)
obtained in Preparation Example 284 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (0.076 g, 0.20 mmol) obtained in Preparation
Example 16 were reacted in the same manner as in Example 1 to
obtain the title compound (0.030 g, 39%).
[3693] .sup.1H-NMR (CDCl.sub.3) .delta. 7.08 (2H, m), 6.77 (1H, m),
6.72 (1H, m), 6.51 (1H, m), 4.66 (1H, m), 4.24 (2H, t), 2.68 (2H,
t), 2.47 (2H, m), 2.12 (4H, m), 1.89 (1H, m), 1.74 (1H, m)
Example 529:
4-[(5'-cyclobutylmethoxy-3,5-difluoro-2'-methyl-biphenyl-4-yl)-methyl-ami-
no]-butyric Acid
##STR00572##
[3695] 2-Bromo-4-cyclobutylmethoxy-1-methyl-benzene (0.050 g, 0.20
mmol) obtained in Preparation Example 325 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.072 g, 0.20 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.024 g, 30%).
[3696] .sup.1H-NMR (CDCl.sub.3) .delta. 7.14 (1H, d), 6.83 (3H, m),
6.74 (1H, m), 3.92 (2H, d), 3.19 (2H, t), 2.88 (3H, s), 2.76 (1H,
m), 2.51 (2H, t), 2.20 (3H, s), 2.14 (2H, m), 1.95 (6H, m)
Example 530:
4-(5'-cyclobutylmethoxy-3,5-difluoro-2'-methyl-biphenyl-4-yloxy)-butyric
Acid
##STR00573##
[3698] 2-Bromo-4-cyclobutylmethoxy-1-methyl-benzene (0.025 g, 0.10
mmol) obtained in Preparation Example 325 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (0.036 g, 0.10 mmol) obtained in Preparation
Example 16 were reacted in the same manner as in Example 1 to
obtain the title compound (0.020 g, 52%).
[3699] .sup.1H-NMR (CDCl.sub.3) .delta. 7.14 (1H, d), 6.86 (3H, m),
6.73 (1H, m), 4.24 (2H, t), 3.91 (2H, d), 2.75 (1H, m), 2.70 (2H,
t), 2.18 (3H, s), 2.14 (4H, m), 1.95 (4H, m)
Example 531:
4-{[4-(5-chloro-6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-methyl-a-
mino}-butyric Acid
##STR00574##
[3701] 3,6-Dichloro-2-cyclobutoxy-pyridine (0.050 g, 0.23 mmol)
obtained in Preparation Example 298 and
4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-
-methyl-amino}-butyric acid methyl ester (0.085 g, 0.23 mmol)
obtained in Preparation Example 183 were reacted in the same manner
as in Example 1 to obtain the title compound (0.015 g, 16%).
[3702] .sup.1H-NMR (CDCl.sub.3) .delta. 7.64 (1H, d), 7.46 (2H, m),
7.16 (1H, d), 5.33 (1H, m), 3.19 (2H, t), 2.89 (3H, s), 2.54 (2H,
m), 2.46 (2H, t), 2.28 (2H, m), 1.89 (3H, m), 1.77 (1H, m)
Example 532:
4-(3'-cyclopropylmethoxy-3,5-difluoro-4'-methyl-biphenyl-4-yloxy)-butyric
Acid
##STR00575##
[3704] 4-Bromo-2-cyclopropylmethoxy-1-methyl-benzene (0.050 g, 0.21
mmol) obtained in Preparation Example 327 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (0.077 g, 0.21 mmol) obtained in Preparation
Example 16 were reacted in the same manner as in Example 1 to
obtain the title compound (0.025 g, 32%).
[3705] .sup.1H-NMR (CDCl.sub.3) .delta. 7.18 (1H, d), 7.09 (2H, m),
6.99 (1H, d), 6.88 (1H, s), 4.22 (2H, t), 3.88 (2H, d), 2.68 (2H,
t), 2.27 (3H, s), 2.12 (2H, m), 1.29 (1H, m), 0.64 (2H, m), 0.39
(2H, m)
Example 533:
4-[4-(5-chloro-6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenoxy]-butyric
Acid
##STR00576##
[3707] 3,6-Dichloro-2-cyclobutoxy-pyridine (0.050 g, 0.23 mmol)
obtained in Preparation Example 298 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (0.085 g, 0.23 mmol) obtained in Preparation
Example 16 were reacted in the same manner as in Example 1 to
obtain the title compound (0.020 g, 22%).
[3708] .sup.1H-NMR (CDCl.sub.3) .delta. 7.65 (1H, d), 7.53 (2H, m),
7.16 (1H, d), 5.33 (1H, m), 4.25 (2H, t), 2.68 (2H, t), 2.55 (2H,
m), 2.26 (2H, m), 2.12 (2H, m), 1.90 (1H, m), 1.77 (1H, m)
Example 534:
4-(4'-chloro-3'-cyclopropylmethoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric
Acid
##STR00577##
[3710] 4-Bromo-1-chloro-2-cyclopropylmethoxy-benzene (0.050 g, 0.19
mmol) obtained in Preparation Example 326 and
4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]bu-
tyric acid ethyl ester (0.071 g, 0.19 mmol) obtained in Preparation
Example 16 were reacted in the same manner as in Example 1 to
obtain the title compound (0.015 g, 20%).
[3711] .sup.1H-NMR (CDCl.sub.3) .delta. 7.40 (1H, d), 7.08 (2H, m),
6.99 (2H, m), 4.23 (2H, t), 3.95 (2H, d), 2.68 (2H, t), 2.13 (2H,
m), 1.35 (1H, m), 0.68 (2H, m), 0.42 (2H, m)
Example 535:
5-(5'-cyclobutoxy-3,3'-difluoro-biphenyl-4-yl)-pentanoic Acid
##STR00578##
[3713] 1-Bromo-3-cyclobutoxy-5-fluoro-benzene (0.050 g, 0.20 mmol)
obtained in Preparation Example 284 and
5-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pent-
anoic acid ethyl ester (0.072 g, 0.20 mmol) obtained in Preparation
Example 201 were reacted in the same manner as in Example 1 to
obtain the title compound (0.025 g, 34%).
[3714] .sup.1H-NMR (CDCl.sub.3) .delta. 7.22 (3H, m), 6.78 (2H, m),
6.51 (1H, m), 4.67 (1H, m), 2.70 (2H, t), 2.46 (4H, m), 2.21 (2H,
m), 1.89 (1H, m), 1.71 (5H, m)
Example 536:
4-(5'-cyclobutoxy-3,3'-difluoro-biphenyl-4-yloxy)-butyric Acid
##STR00579##
[3716] 1-Bromo-3-cyclobutoxy-5-fluoro-benzene (0.025 g, 0.10 mmol)
obtained in Preparation Example 284 and
4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyri-
c acid ethyl ester (0.036 g, 0.10 mmol) obtained in Preparation
Example 198 were reacted in the same manner as in Example 1 to
obtain the title compound (0.021 g, 57%).
[3717] .sup.1H-NMR (CDCl.sub.3) .delta. 7.52 (2H, m), 7.01 (1H, t),
6.75 (2H, m), 6.48 (1H, m), 4.66 (1H, m), 4.14 (2H, t), 2.65 (2H,
t), 2.47 (2H, m), 2.19 (4H, m), 1.89 (1H, m), 1.71 (1H, m)
Example 537:
5-[4-(6-cyclobutoxy-pyridin-2-yl)-2-fluoro-phenyl]-pentanoic
Acid
##STR00580##
[3719] 2-Chloro-6-cyclobutoxy-pyridine (0.050 g, 0.27 mmol)
obtained in Preparation Example 29 and
5-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pent-
anoic acid ethyl ester (0.095 g, 0.27 mmol) obtained in Preparation
Example 201 were reacted in the same manner as in Example 1 to
obtain the title compound (0.019 g, 20%).
[3720] .sup.1H-NMR (CDCl.sub.3) .delta. 7.70 (2H, m), 7.51 (1H, t),
7.36 (1H, d), 7.25 (1H, m), 7.03 (1H, d), 4.46 (1H, m), 2.72 (2H,
m), 2.61 (2H, m), 2.42 (2H, m), 2.20 (4H, m), 1.72 (4H, m)
Example 538:
4-[4-(6-cyclobutoxy-pyridin-2-yl)-2-fluoro-phenoxy]-butyric
Acid
##STR00581##
[3722] 2-Chloro-6-cyclobutoxy-pyridine (0.035 g, 0.19 mmol)
obtained in Preparation Example 29 and
4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyri-
c acid ethyl ester (0.067 g, 0.19 mmol) obtained in Preparation
Example 198 were reacted in the same manner as in Example 1 to
obtain the title compound (0.030 g, 46%).
[3723] .sup.1H-NMR (CDCl.sub.3) .delta. 7.81 (1H, m), 7.73 (1H, d),
7.49 (1H, t), 7.32 (1H, d), 7.01 (2H, m), 4.44 (1H, m), 4.17 (2H,
t), 2.65 (4H, m), 2.20 (6H, m)
Example 539:
4-[4-(6-cyclobutylmethoxy-pyridin-2-yl)-2-fluoro-phenoxy]-butyric
Acid
##STR00582##
[3725] 2-Chloro-6-cyclobutylmethoxy-pyridine (0.030 g, 0.15 mmol)
obtained in Preparation Example 324 and
4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyri-
c acid ethyl ester (0.054 g, 0.15 mmol) obtained in Preparation
Example 198 were reacted in the same manner as in Example 1 to
obtain the title compound (0.024 g, 44%).
[3726] .sup.1H-NMR (CDCl.sub.3) .delta. 7.81 (1H, m), 7.70 (1H, d),
7.59 (1H, t), 7.22 (1H, d), 7.02 (1H, t), 6.64 (1H, d), 4.37 (2H,
d), 4.15 (2H, t), 2.82 (1H, m), 2.65 (2H, t), 2.20 (4H, m), 1.92
(4H, m)
Example 540:
4-[4-(6-cyclobutylsulfanyl-pyridin-2-yl)-2-fluoro-phenoxy]-butyric
Acid
##STR00583##
[3728] 2-Chloro-6-cyclobutylsulfanyl-pyridine (0.030 g, 0.15 mmol)
obtained in Preparation Example 299 and
4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyri-
c acid ethyl ester (0.053 g, 0.15 mmol) obtained in Preparation
Example 198 were reacted in the same manner as in Example 1 to
obtain the title compound (0.025 g, 46%).
[3729] .sup.1H-NMR (CDCl.sub.3) .delta. 7.81 (1H, m), 7.73 (1H, d),
7.49 (1H, t), 7.31 (1H, d), 7.01 (2H, m), 4.44 (1H, m), 4.17 (2H,
t), 2.65 (4H, m), 2.20 (6H, m)
Example 541:
2-(3'-cyclobutoxy-3,5,5'-trifluoro-biphenyl-4-yloxymethyl)-cyclopropaneca-
rboxylic Acid
##STR00584##
[3730] Step A: 5'-cyclobutoxy-3,5,3'-trifluoro-biphenyl-4-ol
[3731] 1-Bromo-3-cyclobutoxy-5-fluoro-benzene (1.0 g, 4.08 mmol)
obtained in Preparation Example 284 and
2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
(1.04 g, 4.08 mmol) obtained in Step B of Preparation Example 16
were reacted in the same manner as in Step A of Example 1 to obtain
the title compound (0.50 g, 42%).
[3732] .sup.1H-NMR (CDCl.sub.3) .delta. 7.10 (2H, m), 6.72 (2H, m),
6.51 (1H, m), 5.21 (1H, s), 4.67 (1H, m), 2.47 (2H, m), 2.19 (2H,
m), 1.89 (1H, m), 1.72 (1H, m)
Step B:
2-(3'-cyclobutoxy-3,5,5'-trifluoro-biphenyl-4-yloxymethyl)-cyclopr-
opanecarboxylic Acid
[3733] 5'-Cyclobutoxy-3,5,3'-trifluoro-biphenyl-4-ol (0.045 g, 0.15
mmol) obtained in Step A and 2-hydroxymethyl-cyclopropanecarboxylic
acid ethyl ester (0.033 g, 0.23 mmol) were sequentially reacted in
the same manner as in Preparation Example 62 and Step B of Example
1 to obtain the title compound (0.035 g, 58%).
[3734] .sup.1H-NMR (CDCl.sub.3) .delta. 7.08 (2H, m), 6.77 (1H, d),
6.72 (1H, s), 6.51 (1H, m), 4.67 (1H, m), 4.17 (1H, m), 4.03 (1H,
m), 2.48 (2H, m), 2.20 (2H, m), 1.96 (1H, m), 1.90 (1H, m), 1.72
(2H, m), 1.36 (1H, m), 1.06 (1H, m)
Example 542:
2-[4-(4-cyclobutoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenoxymethyl]--
cyclopropanecarboxylic Acid
##STR00585##
[3736] 2-Chloro-4-cyclobutoxy-6-methyl-pyrimidine (0.050 g, 0.25
mmol) obtained in Preparation Example 228 and
2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxym-
ethyl]-cyclopropanecarboxylic acid ethyl ester (0.096 g, 0.25 mmol)
obtained in Preparation Example 321 were reacted in the same manner
as in Example 1 to obtain the title compound (0.030 g, 31%).
[3737] .sup.1H-NMR (CDCl.sub.3) .delta. 7.99 (2H, m), 6.42 (1H, s),
5.31 (1H, m), 4.12 (2H, m), 2.51 (2H, m), 2.46 (3H, s), 2.20 (2H,
m), 1.96 (1H, m), 1.89 (1H, m), 1.72 (2H, m), 1.35 (1H, m), 1.08
(1H, m)
Example 543:
2-[4-(4-cyclobutoxy-pyrimidin-2-yl)-2,6-difluoro-phenoxymethyl]-cycloprop-
anecarboxylic Acid
##STR00586##
[3739] 2-Chloro-4-cyclobutoxy-pyrimidine (0.050 g, 0.27 mmol)
obtained in Preparation Example 230 and
2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxym-
ethyl]-cyclopropanecarboxylic acid ethyl ester (0.104 g, 0.27 mmol)
obtained in Preparation Example 321 were reacted in the same manner
as in Example 1 to obtain the title compound (0.022 g, 22%).
[3740] .sup.1H-NMR (CDCl.sub.3) .delta. 8.46 (1H, d), 7.98 (2H, m),
6.59 (1H, d), 5.34 (1H, m), 4.17 (1H, m), 4.10 (1H, m), 2.55 (2H,
m), 2.23 (2H, m), 1.88 (2H, m), 1.78 (2H, m), 1.35 (1H, m), 1.07
(1H, m)
Example 544:
2-[4-(6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenoxymethyl]-cyclopropan-
ecarboxylic Acid
##STR00587##
[3742] 2-Chloro-6-cyclobutoxy-pyridine (0.030 g, 0.16 mmol)
obtained in Preparation Example 29 and
2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxym-
ethyl]-cyclopropanecarboxylic acid ethyl ester (0.062 g, 0.16 mmol)
obtained in Preparation Example 321 were reacted in the same manner
as in Example 1 to obtain the title compound (0.026 g, 42%).
[3743] .sup.1H-NMR (CDCl.sub.3) .delta. 7.60 (3H, m), 7.21 (1H, d),
6.65 (1H, d), 5.26 (1H, m), 4.14 (1H, m), 4.06 (1H, m), 2.52 (2H,
m), 2.20 (2H, m), 2.01 (1H, m), 1.85 (1H, m), 1.75 (2H, m), 1.35
(1H, m), 1.06 (1H, m)
Example 545:
2-[4-(4-cyclopropylmethoxy-pyrimidin-2-yl)-2,6-difluoro-phenoxymethyl]-cy-
clopropanecarboxylic Acid
##STR00588##
[3745] 2-Chloro-4-cyclopropylmethoxy-pyrimidine (0.035 g, 0.19
mmol) obtained in Preparation Example 231 and
2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxym-
ethyl]-cyclopropanecarboxylic acid ethyl ester (0.073 g, 0.16 mmol)
obtained in Preparation Example 321 were reacted in the same manner
as in Example 96 to obtain the title compound (0.030 g, 42%).
[3746] .sup.1H-NMR (CDCl.sub.3) .delta. 8.47 (1H, d), 7.99 (2H, m),
6.65 (1H, d), 4.30 (2H, d), 4.18 (1H, m), 4.12 (1H, m), 1.97 (1H,
m), 1.71 (1H, m), 1.36 (2H, m), 1.07 (1H, m), 0.66 (2H, m), 0.41
(2H, m)
Example 546:
2-[4-(4-cyclopropylmethoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenoxym-
ethyl]-cyclopropanecarboxylic Acid
##STR00589##
[3748] 2-Chloro-4-cyclopropylmethoxy-6-methyl-pyrimidine (0.030 g,
0.15 mmol) obtained in Preparation Example 227 and
2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxym-
ethyl]-cyclopropanecarboxylic acid ethyl ester (0.058 g, 0.25 mmol)
obtained in Preparation Example 321 were reacted in the same manner
as in Example 96 to obtain the title compound (0.026 g, 44%).
[3749] .sup.1H-NMR (CDCl.sub.3) .delta. 7.99 (2H, m), 6.50 (1H, s),
4.28 (2H, d), 4.12 (2H, m), 2.47 (3H, s), 1.98 (1H, m), 1.71 (1H,
m), 1.34 (2H, m), 1.07 (1H, m), 0.65 (2H, m), 0.40 (2H, m)
Example 547:
2-[4-(6-cyclopropylmethoxy-pyrazin-2-yl)-2,6-difluoro-phenoxymethyl]-cycl-
opropanecarboxylic Acid
##STR00590##
[3751] 2-Chloro-6-cyclopropylmethoxy-pyrazine (0.030 g, 0.16 mmol)
obtained in Preparation Example 233 and
2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxym-
ethyl]-cyclopropanecarboxylic acid ethyl ester (0.062 g, 0.25 mmol)
obtained in Preparation Example 321 were reacted in the same manner
as in Example 96 to obtain the title compound (0.015 g, 25%).
[3752] .sup.1H-NMR (CDCl.sub.3) .delta. 8.48 (1H, s), 8.19 (1H, s),
7.59 (2H, m), 4.26 (2H, d), 4.19 (1H, m), 4.06 (1H, m), 1.98 (1H,
m), 1.72 (1H, m), 1.36 (2H, m), 1.06 (1H, m), 0.67 (2H, m), 0.41
(2H, m)
Example 548:
2-[4-(6-cyclobutoxy-4-methyl-pyridin-2-yl)-2,6-difluoro-phenoxymethyl]-cy-
clopropanecarboxylic Acid
##STR00591##
[3754] 2-Chloro-6-cyclobutoxy-4-methyl-pyridine (0.030 g, 0.15
mmol) obtained in Preparation Example 271 and
2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxym-
ethyl]-cyclopropanecarboxylic acid ethyl ester (0.058 g, 0.15 mmol)
obtained in Preparation Example 321 were reacted in the same manner
as in Example 96 to obtain the title compound (0.025 g, 42%).
[3755] .sup.1H-NMR (CDCl.sub.3) .delta. 7.58 (2H, m), 7.05 (1H, s),
6.47 (1H, s), 5.25 (1H, m), 4.14 (1H, m), 4.04 (1H, m), 2.51 (2H,
m), 2.33 (3H, s), 2.17 (2H, m), 1.98 (1H, m), 1.87 (1H, m), 1.72
(2H, m), 1.35 (1H, m), 1.07 (1H, m)
Example 549:
2-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenoxymethyl]-cycl-
opropanecarboxylic Acid
##STR00592##
[3757] 2-Chloro-6-cyclopropylmethoxy-pyridine (0.030 g, 0.16 mmol)
obtained in Preparation Example 43 and
2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxym-
ethyl]-cyclopropanecarboxylic acid ethyl ester (0.062 g, 0.15 mmol)
obtained in Preparation Example 321 were reacted in the same manner
as in Example 96 to obtain the title compound (0.024 g, 36%).
[3758] .sup.1H-NMR (CDCl.sub.3) .delta. 7.62 (3H, m), 7.22 (1H, d),
6.73 (1H, d), 4.24 (1H, d), 4.15 (1H, m), 4.04 (1H, m), 1.98 (2H,
m), 1.72 (1H, m), 1.35 (2H, m), 1.07 (1H, m), 0.65 (2H, m), 0.39
(2H, m)
Example 550:
2-[4-(6-cyclobutoxy-pyrazin-2-yl)-2,6-difluoro-phenoxymethyl]-cyclopropan-
ecarboxylic Acid
##STR00593##
[3760] 2-Chloro-6-cyclobutoxy-pyrazine (0.030 g, 0.16 mmol)
obtained in Preparation Example 232 and
2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxym-
ethyl]-cyclopropanecarboxylic acid ethyl ester (0.062 g, 0.15 mmol)
obtained in Preparation Example 321 were reacted in the same manner
as in Example 96 to obtain the title compound (0.026 g, 40%).
[3761] .sup.1H-NMR (CDCl.sub.3) .delta. 8.52 (1H, s), 8.17 (1H, s),
7.57 (2H, m), 5.28 (1H, d), 4.18 (1H, m), 4.07 (1H, m), 2.54 (2H,
m), 2.23 (2H, m), 1.98 (2H, m), 1.77 (2H, m), 1.36 (1H, m), 1.07
(1H, m)
Example 551:
2-[4-(2-cyclobutoxy-thiazol-4-yl)-2,6-difluoro-phenoxymethyl]-cyclopropan-
ecarboxylic Acid
##STR00594##
[3763] 4-Bromo-2-cyclobutoxy-thiazole (0.030 g, 0.13 mmol) obtained
in Preparation Example 289 and
2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxym-
ethyl]-cyclopropanecarboxylic acid ethyl ester (0.049 g, 0.13 mmol)
obtained in Preparation Example 321 were reacted in the same manner
as in Example 96 to obtain the title compound (0.023 g, 44%).
[3764] .sup.1H-NMR (CDCl.sub.3) .delta. 7.35 (2H, m), 6.78 (1H, s),
5.19 (1H, d), 4.12 (1H, m), 4.02 (1H, m), 2.53 (2H, m), 2.27 (2H,
m), 1.95 (1H, m), 1.89 (1H, m), 1.70 (2H, m), 1.31 (1H, m), 1.04
(1H, m)
Example 552:
2-[2-chloro-4-(6-cyclopropylmethoxy-pyridin-2-yl)-6-fluoro-phenoxymethyl]-
-cyclopropanecarboxylic Acid
##STR00595##
[3766] 2-Chloro-6-cyclopropylmethoxy-pyridine (0.030 g, 0.16 mmol)
obtained in Preparation Example 43 and
2-[2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phe-
noxymethyl]-cyclopropanecarboxylic acid ethyl ester (0.065 g, 0.16
mmol) obtained in Preparation Example 322 were reacted in the same
manner as in Example 96 to obtain the title compound (0.021 g,
33%).
[3767] .sup.1H-NMR (CDCl.sub.3) .delta. 7.80 (1H, s), 7.70 (1H, m),
7.62 (1H, t), 7.23 (1H, d), 6.73 (1H, d), 4.24 (2H, d), 4.15 (1H,
m), 4.01 (1H, m), 2.00 (1H, m), 1.75 (1H, m), 1.36 (2H, m), 1.09
(1H, m), 0.65 (2H, m), 0.44 (2H, m)
Example 553:
2-[2-chloro-4-(4-cyclobutoxy-6-methyl-pyrimidin-2-yl)-6-fluoro-phenoxymet-
hyl]-cyclopropanecarboxylic Acid
##STR00596##
[3769] 2-Chloro-4-cyclobutoxy-6-methyl-pyrimidine (0.030 g, 0.15
mmol) obtained in Preparation Example 228 and
2-[2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phe-
noxymethyl]-cyclopropanecarboxylic acid ethyl ester (0.060 g, 0.15
mmol) obtained in Preparation Example 322 were reacted in the same
manner as in Example 96 to obtain the title compound (0.020 g,
33%).
[3770] .sup.1H-NMR (CDCl.sub.3) .delta. 8.24 (1H, s), 8.08 (1H, d),
6.42 (1H, s), 5.31 (1H, m), 4.17 (1H, m), 4.06 (1H, m), 2.51 (2H,
m), 2.46 (3H, s), 2.21 (2H, m), 2.02 (1H, m), 1.91 (1H, m), 1.77
(2H, m), 1.36 (1H, m), 1.09 (1H, m)
Example 554:
2-[2-chloro-4-(6-cyclobutoxy-pyridin-2-yl)-6-fluoro-phenoxymethyl]-cyclop-
ropanecarboxylic Acid
##STR00597##
[3772] 2-Chloro-6-cyclobutoxy-pyridine (0.030 g, 0.16 mmol)
obtained in Preparation Example 29 and
2-[2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phe-
noxymethyl]-cyclopropanecarboxylic acid ethyl ester (0.065 g, 0.16
mmol) obtained in Preparation Example 322 were reacted in the same
manner as in Example 96 to obtain the title compound (0.024 g,
37%).
[3773] .sup.1H-NMR (CDCl.sub.3) .delta. 7.79 (1H, s), 7.70 (1H, m),
7.60 (1H, t), 7.22 (1H, d), 6.66 (1H, d), 5.26 (1H, m), 4.18 (1H,
m), 4.02 (1H, m), 2.53 (2H, m), 2.19 (2H, m), 2.04 (1H, m), 1.89
(1H, m), 1.76 (2H, m), 1.36 (1H, m), 1.09 (1H, m)
Example 555: 3-[6-(3-cyclobutoxy-phenyl)-chroman-2-yl]-propionic
Acid
##STR00598##
[3774] Step A: 3-[6-(3-cyclobutoxy-phenyl)-chroman-2-yl]-propionic
acid ethyl ester
[3775]
3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-chroman-2-yl]-p-
ropionic acid ethyl ester (0.069 g, 0.19 mmol) obtained in
Preparation Example 4 and 1-cyclobutoxy-3-iodo-benzene (0.058 g,
0.21 mmol) obtained in Preparation Example 21 were reacted in the
same manner as in Step A of Example 1 to obtain the title compound
(0.048 g, 66%).
[3776] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.33-7.27 (m,
3H), 7.10-7.08 (m, 1H), 6.98-6.97 (m, 1H), 6.85-6.83 (d, 1H),
6.75-6.72 (m, 1H), 4.72-4.65 (m, 1H), 4.18-4.13 (q, 2H), 4.09-4.03
(m, 1H), 2.93-2.79 (m, 2H), 2.64-2.43 (m, 4H), 2.24-2.17 (m, 2H),
2.04-2.00 (m, 3H), 1.88-1.58 (m, 3H), 1.29-1.25 (t, 3H)
Step B: 3-[6-(3-cyclobutoxy-phenyl)-chroman-2-yl]-propionic
Acid
[3777] 3-[6-(3-Cyclobutoxy-phenyl)-chroman-2-yl]-propionic acid
ethyl ester (0.048 g, 0.126 mmol) obtained in Step A was reacted in
the same manner as in Step B of Example 1 to obtain the title
compound (0.042 g, 94%).
[3778] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.31-7.27 (m,
3H), 7.10-7.08 (m, 1H), 6.98-3.97 (m, 1H), 6.85-6.83 (d, 1H),
6.75-6.73 (m, 1H), 4.73-7.65 (m, 1H), 4.09-4.06 (m, 1H), 2.94-2.72
(m, 2H), 2.69-2.61 (m, 2H), 2.50-2.43 (m, 2H), 2.22-2.17 (m, 2H),
2.06-2.01 (m, 3H), 1.88-1.66 (m, 3H)
Example 556: 3-[6-(6-propoxy-pyridin-2-yl)-chroman-2-yl]-propionic
Acid
##STR00599##
[3779] Step A:
3-[6-(6-propoxy-pyridin-2-yl)-chroman-2-yl]-propionic Acid Ethyl
Ester
[3780]
3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-chroman-2-yl]-p-
ropionic acid ethyl ester (0.09 g, 0.24 mmol) obtained in
Preparation Example 4 and 2-chloro-6-propoxy-pyridine (0.044 g,
0.26 mmol) were reacted in the same manner as in Step A of Example
1 to obtain the title compound (0.023 g, 27%).
[3781] .sup.1H-NMR (500 HMz, CDCl.sub.3); .delta. 7.75-7.73 (m,
2H), 7.58-7.55 (t, 1H), 7.22-7.20 (d, 1H), 6.85-6.83 (d, 1H),
6.60-6.58 (d, 1H), 4.37-4.34 (t, 2H), 4.18-4.13 (q, 2H), 4.09-4.02
(m, 1H), 2.92-2.81 (m, 2H), 2.65-2.52 (m, 2H), 2.06-2.00 (m, 3H),
1.88-1.74 (m, 3H), 1.28-1.25 (t, 3H), 1.06-1.03 (t, 3H)
Step B: 3-[6-(6-propoxy-pyridin-2-yl)-chroman-2-yl]-propionic
Acid
[3782] 3-[6-(6-Propoxy-pyridin-2-yl)-chroman-2-yl]-propionic acid
ethyl ester (0.048 g, 0.126 mmol) obtained in Step A was reacted in
the same manner as in Step B of Example 1 to obtain the title
compound (0.042 g, 94%).
[3783] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.75-7.73 (m,
2H), 7.58-7.52 (m, 1H), 7.22-7.20 (d, 1H0, 6.86-6.84 (m, 1H),
6.61-6.59 (m, 1H), 4.38-4.34 (t, 2H), 4.11-4.09 (m, 1H), 2.93-2.83
(m, 2H), 2.72-2.60 (m, 2H), 2.06-2.01 (m, 3H), 1.88-1.80 (m, 3H),
1.07-1.03 (t, 3H)
Example 557: 4-[2,6-difluoro-4-(1H-indol-6-yl)-phenoxy]-butanoic
Acid
##STR00600##
[3784] Step A: 4-[2,6-difluoro-4-(1H-indol-6-yl)-phenoxy]-butanoic
Acid Ethyl Ester
[3785] 4-(4-Bromo-2,6-difluoro-phenoxy)-butanoic acid ethyl ester
(0.20 g, 0.62 mmol) obtained in Preparation Example 339 and
6-indolylboronic acid (0.11 g, 0.68 mmol) were reacted in the same
manner as in Step A of Example 1 to obtain the title compound (0.21
g, 94%).
[3786] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 8.23 (br s, 1H),
7.69-7.67 (d, 1H), 7.52 (s, 1H), 7.28-7.27 (m, 2H), 7.20-7.13 (m,
2H), 6.58-6.57 (m, 1H), 4.21-4.13 (m, 4H), 2.61-2.58 (t, 2H),
2.13-2.09 (m, 2H), 1.28-1.25 (t, 3H)
Step B: 4-[2,6-difluoro-4-(1H-indol-6-yl)-phenoxy]-butanoic
Acid
[3787] 4-[2,6-Difluoro-4-(1H-indol-6-yl)-phenoxy]-butanoic acid
ethyl ester (0.025 g, 0.07 mmol) obtained in Step A was reacted in
the same manner as in Step B of Example 1 to obtain the title
compound (0.019 g, 84%).
[3788] .sup.1H-NMR (400 HMz, MeOD-d.sub.4); .delta. 7.63-7.61 (m,
2H), 7.33-7.26 (m, 4H), 6.48-6.47 (m, 1H), 4.22-4.19 (t, 2H),
2.60-2.56 (t, 2H), 2.10-2.03 (m, 2H)
Example 558:
4-[2,6-difluoro-4-(1-isopropyl-1H-indol-6-yl)-phenoxy]-butanoic
Acid
##STR00601##
[3789] Step A:
4-[2,6-difluoro-4-(1-isopropyl-1H-indol-6-yl)-phenoxy]-butanoic
Acid Ethyl Ester
[3790] 4-[2,6-Difluoro-4-(1H-indol-6-yl)-phenoxy]-butanoic acid
ethyl ester (0.05 g, 0.14 mmol) obtained in Step A of Example 557
was dissolved in N,N-dimethylformamide (5 ml) and cooled to
0.degree. C. NaH (60%)(0.003 g, 0.21 mmol) and 2-iodopropane (0.02
ml, 0.21 mmol) were added thereto, and the mixture was stirred at
room temperature for 16 hours. After addition of water, the
reaction solution was extracted to separate an organic layer. The
organic layer was dried with MgSO.sub.4 and purified by column
chromatography to obtain the title compound (0.03 g, 54%).
[3791] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.67-7.65 (d,
1H), 7.47 (s, 1H), 7.28-7.17 (m, 4H), 6.53-6.52 (d, 1H), 4.75-4.73
(m, 1H), 4.21-4.14 (m, 4H), 2.61-2.59 (t, 2H), 2.14-2.10 (m, 2H),
1.56-1.55 (dd, 6H), 1.29-1.26 (t, 3H)
Step B:
4-[2,6-difluoro-4-(1-isopropyl-1H-indol-6-yl)-phenoxy]-butanoic
Acid
[3792]
4-[2,6-difluoro-4-(1-isopropyl-1H-indol-6-yl)-phenoxy]-butanoic
acid ethyl ester (0.03 g, 0.075 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.02 g, 72%).
[3793] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.67-7.65 (d,
1H), 7.47 (s, 1H), 7.28-7.17 (m, 4H), 6.54-6.53 (d, 1H), 4.78-4.71
(m, 1H), 4.24-4.21 (t, 2H), 2.71-2.67 (t, 2H), 2.16-2.09 (m, 2H),
1.57-1.55 (d, 6H)
Example 559:
4-[4-(1-cyclopropylmethyl-1H-indol-6-yl)-2,6-difluoro-phenoxy]-butanoic
Acid
##STR00602##
[3794] Step A:
4-[4-(1-cyclopropylmethyl-1H-indol-6-yl)-2,6-difluoro-phenoxy]-butanoic
Acid Ethyl Ester
[3795] 4-[2,6-Difluoro-4-(1H-indol-6-yl)-phenoxy]-butanoic acid
ethyl ester (0.05 g, 0.14 mmol) obtained in Step A of Example 557
and iodomethyl-cyclopropane (0.02 ml, 0.21 mmol) were reacted in
the same manner as in Step A of Example 1 to obtain the title
compound (0.03 g, 52%).
[3796] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.68-7.66 (d,
1H), 7.47 (s, 1H), 7.28-7.24 (m, 2H), 7.22-7.16 (m, 2H), 6.52-6.51
(m, 1H), 4.22-4.19 (t, 2H), 4.04-4.02 (d, 2H), 3.71 (s, 3H),
2.64-2.60 (t, 2H), 2.15-2.08 (m, 2H), 1.32-1.25 (m, 1H), 0.68-0.63
(m, 2H), 0.41-0.37 (m, 2H)
Step B:
4-[4-(1-cyclopropylmethyl-1H-indol-6-yl)-2,6-difluoro-phenoxy]-but-
anoic Acid
[3797]
4-[4-(1-Cyclopropylmethyl-1H-indol-6-yl)-2,6-difluoro-phenoxy]-buta-
noic acid ethyl ester (0.03 g, 0.073 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.02 g, 72%).
[3798] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.67-7.65 (d,
1H), 7.47 (s, 1H), 7.27-7.24 (m, 2H), 7.23-7.16 (m, 2H), 6.52-6.51
(m, 1H), 4.24-4.21 (t, 2H), 4.03-4.02 (d, 2H), 2.71-2.67 (t, 2H),
2.16-2.09 (m, 2H), 1.35-1.23 (m, 1H), 0.69-0.64 (m, 2H), 0.45-0.37
(m, 2H)
Example 560:
{1-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-
-3-yl}-acetic Acid
##STR00603##
[3799] Step A:
{1-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-
-3-yl}-acetic Acid Ethyl Ester
[3800]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.09 g, 0.23 mmol)
obtained in Preparation Example 91 and
2-chloro-6-cyclopropylmethoxy-pyridine (0.046 g, 0.25 mmol)
obtained in Preparation Example 43 were reacted in the same manner
as in Step A of Example 1 to obtain the title compound (0.043 g,
45%).
[3801] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.60-7.56 (t,
1H), 7.53-7.45 (m, 2H), 7.18-7.16 (d, 1H), 6.66-6.64 (d, 1H),
4.24-4.22 (d, 2H), 4.19-4.13 (q, 2H), 3.76-3.60 (m, 3H), 3.37 (m,
1H), 2.68-2.63 (m, 1H), 2.53-2.47 (m, 2H), 2.18-2.14 (m, 1H),
1.68-1.63 (m, 1H), 1.35-1.30 (m, 1H), 1.28-1.24 (t, 3H), 0.66-0.61
(m, 2H), 0.41-0.37 (m, 2H)
Step B:
{1-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyr-
rolidin-3-yl}-acetic Acid
[3802]
{1-[4-(6-Cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrr-
olidin-3-yl}-acetic acid ethyl ester (0.043 g, 0.10 mmol) obtained
in Step A was reacted in the same manner as in Step B of Example 1
to obtain the title compound (0.037 g, 93%).
[3803] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.60-7.56 (t,
1H), 7.52-7.44 (m, 2H), 7.18-7.16 (d, 1H), 6.66-6.64 (d, 1H),
4.24-4.22 (d, 2H), 3.77-3.61 (m, 3H), 3.40-3.36 (m, 1H), 2.68-2.63
(m, 1H), 2.56-2.52 (m, 2H), 2.21-2.17 (m, 1H), 1.69-1.64 (m, 1H),
1.35-1.31 (m, 1H), 0.66-0.61 (m, 2H), 0.41-0.37 (m, 2H)
Example 561:
{1-[4-(6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-3-yl}--
acetic Acid
##STR00604##
[3804] Step A:
{1-[4-(6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-3-yl}--
acetic Acid Ethyl Ester
[3805]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.09 g, 0.23 mmol)
obtained in Preparation Example 91 and
2-chloro-6-cyclobutoxy-pyridine (0.046 g, 0.25 mmol) obtained in
Preparation Example 29 were reacted in the same manner as in Step A
of Example 1 to obtain the title compound (0.05 g, 53%).
[3806] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.59-7.55 (t,
1H), 7.52-7.46 (m, 2H), 7.17-7.15 (d, 1H), 6.59-6.57 (d, 1H),
5.28-5.24 (m, 1H), 4.19-4.14 (q, 2H), 3.76-3.60 (m, 3H), 3.39-3.35
(m, 1H), 2.68-2.56 (m, 1H), 2.53-2.47 (m, 4H), 2.21-2.14 (m, 3H),
1.88-1.62 (m, 3H), 1.30-1.26 (t, 3H)
Step B:
{1-[4-(6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-
-3-yl}-acetic Acid
[3807]
{1-[4-(6-Cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin--
3-yl}-acetic acid ethyl ester (0.05 g, 0.12 mmol) obtained in Step
A was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.048 g, 96%).
[3808] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.59-7.55 (t,
1H), 7.52-7.46 (m, 2H), 7.17-7.16 (d, 1H), 6.59-6.57 (d, 1H),
5.30-5.24 (m, 1H), 3.78-3.61 (m, 3H), 3.40-3.36 (m, 1H), 2.69-2.61
(m, 1H), 2.57-2.49 (m, 4H), 2.21-2.16 (m, 3H), 1.88-1.64 (m,
3H)
Example 562:
4-[4-(3-chloro-1-isopropyl-1H-indol-6-yl)-2,6-difluoro-phenoxy]-butanoic
Acid
##STR00605##
[3809] Step A:
4-[4-(3-chloro-1-isopropyl-1H-indol-6-yl)-2,6-difluoro-phenoxy]-butanoic
Acid Ethyl Ester
[3810]
4-[2,6-Difluoro-4-(1-isopropyl-1H-indol-6-yl)-phenoxy]butanoic acid
ethyl ester (0.048 g, 0.12 mmol) obtained in Step A of Example 558
and NCS (0.018 g, 0.13 mmol) were reacted in the same manner as in
Step E of Preparation Example 4 to obtain the title compound (0.031
g, 59%).
[3811] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.66-7.64 (d,
1H), 7.45 (s, 1H), 7.33-7.30 (m, 1H), 7.23 (s, 1H), 7.21-7.14 (m,
2H), 4.75-4.67 (m, 1H), 4.23-4.20 (t, 2H), 4.19-4.14 (q, 2H),
2.62-2.58 (t, 2H), 2.15-2.04 (m, 2H), 1.55-1.53 (d, 6H), 1.29-1.26
(t, 3H)
Step B:
4-[4-(3-chloro-1-isopropyl-1H-indol-6-yl)-2,6-difluoro-phenoxy]-bu-
tanoic Acid
[3812]
4-[4-(3-Chloro-1-isopropyl-1H-indol-6-yl)-2,6-difluoro-phenoxy]-but-
anoic acid ethyl ester (0.031 g, 0.071 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.018 g, 63%).
[3813] .sup.1H-NMR (500 HMz, CDCl.sub.3); .delta. 7.66-7.64 (d,
1H), 7.44 (s, 1H), 7.32-7.30 (m, 1H), 7.22 (s, 1H), 7.21-7.15 (m,
2H), 4.73-4.69 (m, 1H), 4.24-4.21 (t, 2H), 2.70-2.67 (t, 2H),
2.15-2.11 (m, 2H), 1.56-1.53 (d, 6H)
Example 563:
{1-[2,6-difluoro-4-(6-isopropoxy-pyridin-2-yl)-phenyl]-pyrrolidin-3-yl}-a-
cetic Acid
##STR00606##
[3814] Step A:
{1-[2,6-difluoro-4-(6-isopropoxy-pyridin-2-yl)-phenyl]-pyrrolidin-3-yl}-a-
cetic Acid Ethyl Ester
[3815]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.16 g, 0.40 mmol)
obtained in Preparation Example 91 and
2-chloro-6-isopropoxy-pyridine (0.076 g, 0.44 mmol) obtained in
Preparation Example 46 were reacted in the same manner as in Step A
of Example 1 to obtain the title compound (0.071 g, 44%).
[3816] .sup.1H-NMR (400 HMz, MeOD-d4); .delta. 7.64-7.60 (t, 1H),
7.58-7.48 (m, 2H), 7.28-7.26 (d, 1H), 6.58-6.56 (d, 1H), 5.46-5.37
(m, 1H), 4.19-4.13 (q, 2H), 3.70-3.66 (m, 2H), 3.64-3.54 (m, 1H),
3.36-3.30 (m, 1H), 2.64-2.56 (m, 1H), 2.50-2.48 (d, 2H), 2.18-2.10
(m, 1H), 1.67-1.58 (m, 1H), 1.40-1.38 (d, 6H), 1.29-1.26 (t,
3H)
Step B:
{1-[2,6-difluoro-4-(6-isopropoxy-pyridin-2-yl)-phenyl]-pyrrolidin--
3-yl}-acetic Acid
[3817]
{1-[2,6-Difluoro-4-(6-isopropoxy-pyridin-2-yl)-phenyl]-pyrrolidin-3-
-yl}-acetic acid ethyl ester (0.071 g, 0.18 mmol) Obtained in Step
A was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.060 g, 90%).
[3818] .sup.1H-NMR (500 HMz, CDCl.sub.3); .delta. 7.58-7.54 (t,
1H), 7.53-7.44 (m, 2H), 7.15-7.13 (d, 1H), 6.58-6.55 (d, 1H),
5.48-5.42 (m, 1H), 3.77-3.61 (m, 3H), 3.40-3.36 (m, 1H), 2.70-2.63
(m, 1H), 2.60-2.50 (m, 2H), 2.21-2.17 (m, 1H), 1.71-1.62 (m, 1H),
1.40-1.38 (d, 6H)
Example 564:
{1-[4-(6-cyclobutylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin--
3-yl}-acetic Acid
##STR00607##
[3819] Step A:
{1-[4-(6-cyclobutylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin--
3-yl}-acetic Acid Ethyl Ester
[3820]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.16 g, 0.4 mmol)
obtained in Preparation Example 91 and
2-chloro-6-cyclobutylmethoxy-pyridine (0.087 g, 0.44 mmol) obtained
in Preparation Example 324 were reacted in the same manner as in
Step A of Example 1 to obtain the title compound (0.053 g,
31%).
[3821] .sup.1H-NMR (500 HMz, CDCl.sub.3); .delta. 7.57-7.54 (t,
1H), 7.52-7.45 (m, 2H), 7.16-7.14 (d, 1H), 6.61-6.60 (d, 1H),
4.37-4.35 (d, 2H), 4.18-4.13 (q, 2H), 3.72-3.67 (m, 2H), 3.61-3.57
(m, 1H), 3.36-3.33 (m, 1H), 2.83-2.78 (m, 1H), 2.67-2.62 (m, 1H),
2.51-2.43 (m, 2H), 2.18-2.12 (m, 3H), 1.96-1.86 (m, 4H), 1.65-1.59
(m, 1H), 1.29-1.26 (t, 3H)
Step B:
{1-[4-(6-cyclobutylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrr-
olidin-3-yl}-acetic Acid
[3822]
{1-[4-(6-Cyclobutylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrro-
lidin-3-yl}-acetic acid ethyl ester (0.053 g, 0.12 mmol) obtained
in Step A was reacted in the same manner as in Step B of Example 1
to obtain the title compound (0.029 g, 59%).
[3823] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.59-7.55 (t,
1H), 7.53-7.46 (m, 2H), 7.17-7.15 (d, 1H), 6.63-6.61 (d, 1H),
4.38-1.36 (d, 2H), 3.78-3.61 (m, 3H), 3.40-3.36 (m, 1H), 2.84-2.71
(m, 1H), 2.69-2.61 (m, 1H), 2.57-2.50 (m, 2H), 2.21-2.12 (m, 3H),
2.00-1.88 (m, 4H), 1.71-1.62 (m, 1H)
Example 565:
4-[4-(5-cyclopropylmethoxymethyl-thiophen-2-yl)-2,6-difluoro-phenoxy]-but-
anoic Acid
##STR00608##
[3824] Step A:
4-[2,6-difluoro-4-(5-formyl-thiophen-2-yl)-phenoxy]-butanoic Acid
Ethyl Ester
[3825]
4-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
oxy]butanoic acid ethyl ester (0.11 g, 0.40 mmol) obtained in
Preparation Example 16 and 5-bromo-thiophen-2-carbaldehyde (0.084
g, 0.44 mmol) were reacted in the same manner as in Step A of
Example 1 to obtain the title compound (0.052 g, 37%).
[3826] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 9.89 (s, 1H),
7.73-7.72 (d, 1H), 7.32-7.31 (d, 1H), 7.22-7.19 (m, 2H), 4.26-4.23
(t, 2H), 4.19-4.13 (q, 2H), 2.59-2.56 (t, 2H0, 2.14-2.07 (m, 2H),
1.29-1.25 (t, 3H)
Step B:
4-[2,6-difluoro-4-(5-hydroxymethyl-thiophen-2-yl)-phenoxy]-butanoi-
c Acid Ethylester
[3827] 4-[2,6-Difluoro-4-(5-formyl-thiophen-2-yl)-phenoxy]-butanoic
acid ethyl ester (0.052 g, 0.15 mmol) obtained in Step A was
dissolved in MeOH (5 ml). NaBH.sub.4 (0.006 g, 0.15 mmol) was added
thereto, and the mixture was stirred for 30 minutes. After addition
of water, the reaction solution was extracted with EtOAc. The
organic layer was dried with MgSO.sub.4 and purified by column
chromatography to obtain the title compound (0.052 g, 99%).
[3828] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.13-7.04 (m, 3H),
6.96-6.95 (d, 1H), 4.82 (s, 2H), 4.20-4.02 (m, 4H), 2.59-2.55 (t,
2H), 2.12-2.05 (m, 2H), 1.94 (br s, 1H), 1.28-1.26 (t, 3H)
Step C:
4-[4-(5-cyclopropylmethoxymethyl-thiophen-2-yl)-2,6-difluoro-pheno-
xy]-butanoic Acid Ethyl Ester
[3829]
4-[2,6-Difluoro-4-(5-hydroxymethyl-thiophen-2-yl)-phenoxy]-butanoic
acid ethyl ester (0.052 g, 0.15 mmol) obtained in Step B was
dissolved in THF (5 ml). NaH (60%)(0.009 mg, 0.22 mmol) was added
thereto at 0.degree. C., and the mixture was stirred for 10
minutes. Bromomethyl-cyclopropane (0.029 ml, 0.29 mmol) and
tetrabutylammonium iodide (0.054 g, 0.15 mmol) were sequentially
added thereto, and the mixture was stirred at 50.degree. C. for 16
hours. After addition of water, the reaction solution was extracted
with EtOAc. The organic layer was dried with MgSO.sub.4 and
purified by column chromatography to obtain the title compound
(0.015 g, 25%).
[3830] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.13-7.07 (m, 3H),
6.94-6.93 (d, 1H), 4.67 (s, 2H), 4.20-4.13 (m, 4H), 3.36-3.34 (d,
2H), 2.60-2.56 (t, 2H), 2.12-2.05 (m, 2H), 1.29-1.25 (t, 3H),
1.13-1.07 (m, 1H), 0.59-0.54 (m, 2H), 0.28-0.20 (m, 2H)
Step D:
4-[4-(5-cyclopropylmethoxymethyl-thiophen-2-yl)-2,6-difluoro-pheno-
xy]-butanoic Acid
[3831]
4-[4-(5-Cyclopropylmethoxymethyl-thiophen-2-yl)-2,6-difluoro-phenox-
y]-butanoic acid ethyl ester (0.015 g, 0.037 mmol) obtained in Step
C was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.014 g, 97%).
[3832] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.11-7.07 (m, 3H),
6.94-6.93 (d, 1H), 4.67 (s, 2H), 4.22-4.19 (t, 2H), 3.36-3.34 (d,
2H), 2.68-2.66 (t, 2H), 2.10-2.04 (m, 2H), 1.10 (m, 1H), 0.58-0.54
(m, 2H), 0.24-0.22 (m, 2H)
Example 566:
4-[4-(5-cyclopropylmethoxymethyl-thiophen-3-yl)-2,6-difluoro-phenoxy]-but-
anoic Acid
##STR00609##
[3833] Step A:
4-[2,6-difluoro-4-(5-formyl-thiophen-3-yl)-phenoxy]-butanoic Acid
Ethyl Ester
[3834]
4-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
oxy]butanoic acid ethyl ester (0.19 g, 0.50 mmol) obtained in
Preparation Example 16 and 4-bromo-thiophen-carbaldehyde (0.11 g,
0.55 mmol) were reacted in the same manner as in Step A of Example
565 to obtain the title compound (0.11 g, 62%).
[3835] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 9.97 (s, 1H), 7.93
(s, 1H), 7.79 (s, 1H), 7.15-7.09 (m, 2H), 4.24-4.21 (t, 2H),
4.19-4.13 (q, 2H), 2.60-2.56 (t, 2H), 2.14-2.09 (m, 2H), 1.29-1.25
(t, 3H)
Step B:
4-[2,6-difluoro-4-(5-hydroxymethyl-thiophen-3-yl)-phenoxy]-butanoi-
c Acid Ethylester
[3836] 4-[2,6-Difluoro-4-(5-formyl-thiophen-3-yl)-phenoxy]-butanoic
acid ethyl ester (0.11 g, 0.21 mmol) obtained in Step A was reacted
in the same manner as in Step B of Example 565 to obtain the title
compound (0.10 g, 90%).
[3837] .sup.1H-NMR (500 HMz CDCl.sub.3); .delta. 7.31 (s, 1H), 7.17
(s, 1H), 7.09-7.04 (m, 2H), 4.84-4.83 (d, 2H), 4.19-4.09 (m, 4H),
2.58-2.55 (t, 2H), 2.10-2.05 (m, 2H), 1.98 (br s, 1H), 1.27-1.24
(t, 3H)
Step C:
4-[4-(5-cyclopropylmethoxymethyl-thiophen-3-yl)-2,6-difluoro-pheno-
xy]-butanoic Acid Ethyl Ester
[3838]
4-[2,6-Difluoro-4-(5-hydroxymethyl-thiophen-3-yl)-phenoxy]-butanoic
acid ethylester (0.10 g, 0.28 mmol) obtained in Step B and
bromomethyl-cyclopropane (0.055 ml, 0.56 mmol) were reacted in the
same manner as in Step C of Example 565 to obtain the title
compound (0.027 g, 23%).
[3839] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.32 (d, 1H), 7.17
(m, 1H), 7.11-7.04 (m, 2H), 4.69 (s, 2H), 4.20-4.13 (m, 4H),
3.37-3.35 (d, 2H), 2.60-2.56 (t, 2H), 2.14-2.05 (m, 2H), 1.29-1.25
(t, 3H), 1.14-1.07 (m, 1H), 0.58-0.54 (m, 2H), 0.24-0.21 (m,
2H)
Step D:
4-[4-(5-cyclopropylmethoxymethyl-thiophen-3-yl)-2,6-difluoro-pheno-
xy]-butanoic Acid
[3840]
4-[4-(5-Cyclopropylmethoxymethyl-thiophen-3-yl)-2,6-difluoro-phenox-
y]-butanoic acid ethyl ester (0.027 g, 0.066 mmol) obtained in Step
C was reacted in the same manner as in Step D of Example 565 to
obtain the title compound (0.015 g, 61%).
[3841] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.33-7.32 (d, 1H),
7.17-7.16 (m, 1H), 7.11-7.05 (m, 2H), 4.70-4.69 (d, 2H), 4.21-4.18
(t, 2H), 3.37-3.35 (d, 2H), 2.68-2.64 (t, 2H), 2.13-2.04 (m, 2H),
1.15-1.07 (m, 1H), 0.58-0.54 (m, 2H), 0.24-0.21 (m, 2H)
Example 567:
{1-[4-(5-cyclopropylmethoxymethyl-thiophen-3-yl)-2,6-difluoro-phenyl]-pip-
eridin-4-yl}-acetic Acid
##STR00610##
[3842] Step A:
{1-[2,6-difluoro-4-(5-formyl-thiophen-3-yl)-phenyl]-piperidin-4-yl}-aceti-
c Acid Ethyl Ester
[3843]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid ethyl ester (0.21 g, 0.50 mmol)
obtained in Preparation Example 220 and
4-bromo-thiophen-carbaldehyde (0.11 g, 0.55 mmol) were reacted in
the same manner as in Step A of Example 565 to obtain the title
compound (0.053 g, 27%).
[3844] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 9.96-9.95 (d, 1H),
7.93-7.92 (d, 1H), 7.77-7.76 (t, 1H), 7.08-7.03 (m, 2H), 4.18-4.13
(q, 2H), 3.30-3.27 (m, 2H), 3.16-3.11 (m, 2H), 2.31-2.29 (d, 2H),
1.97-1.95 (m, 1H), 1.80-1.77 (m, 2H), 1.50-1.41 (m, 2H), 1.29-1.26
(t, 3H)
Step B:
{1-[2,6-difluoro-4-(5-hydroxymethyl-thiophen-3-yl)-phenyl]-piperid-
in-4-yl}-acetic Acid Ethyl Ester
[3845]
{1-[2,6-Difluoro-4-(5-formyl-thiophen-3-yl)-phenyl]-piperidin-4-yl}-
-acetic acid ethyl ester (0.053 g, 0.14 mmol) obtained in Step A
was reacted in the same manner as in Step B of Example 565 to
obtain the title compound (0.053 g, 99%).
[3846] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.31-7.30 (d, 1H),
7.19 (s, 1H), 7.05-6.98 (m, 2H), 4.84 (s, 2H), 4.18-4.12 (q, 2H),
3.26-3.23 (m, 2H), 3.15-3.09 (m, 2H), 2.30-2.28 (d, 2H), 2.00-1.90
(m, 2H), 1.78-1.75 (m, 2H), 1.50-1.40 (m, 2H), 1.29-1.26 (t,
3H)
Step C:
{1-[4-(5-cyclopropylmethoxymethyl-thiophen-3-yl)-2,6-difluoro-phen-
yl]-piperidin-4-yl}-acetic Acid Ethyl Ester
[3847]
{1-[2,6-Difluoro-4-(5-hydroxymethyl-thiophen-3-yl)-phenyl]-piperidi-
n-4-yl}-acetic acid ethyl ester (0.053 g, 0.13 mmol) obtained in
Step B and bromomethyl-cyclopropane (0.026 ml, 0.27 mmol) were
reacted in the same manner as in Step C of Example 565 to obtain
the title compound (0.046 g, 76%).
[3848] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.31-7.30 (d, 1H),
7.17 (s, 1H), 7.05-6.98 (m, 2H), 4.69 (s, 2H), 4.18-4.12 (q, 2H),
3.41-3.36 (d, 2H), 3.26-3.23 (m, 2H), 3.14-3.08 (m, 2H), 2.30-2.28
(d, 2H), 1.98-1.93 (m, 1H), 1.78-1.75 (m, 2H), 1.58-1.43 (m, 2H),
1.29-1.26 (t, 3H), 1.12-1.08 (m, 1H), 0.58-0.53 (m, 2H), 0.24-0.20
(m, 2H)
Step D:
{1-[4-(5-cyclopropylmethoxymethyl-thiophen-3-yl)-2,6-difluoro-phen-
yl]-piperidin-4-yl}-acetic Acid
[3849]
{1-[4-(5-Cyclopropylmethoxymethyl-thiophen-3-yl)-2,6-difluoro-pheny-
l]-piperidin-4-yl}-acetic acid ethyl ester (0.046 g, 0.10 mmol)
obtained in Step C was reacted in the same manner as in Step B of
Example 1 to obtain the title compound (0.040 g, 92%).
[3850] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.31 (d, 1H), 7.18
(s, 1H), 7.05-7.00 (m, 2H), 4.69 (s, 2H), 3.36-3.34 (d, 2H),
3.28-3.25 (m, 2H), 3.16-3.10 (m, 2H), 2.37-2.35 (d, 2H), 1.96-1.95
(m, 1H), 1.83-1.80 (m, 2H), 1.52-1.44 (m, 2H), 1.12-1.08 (m, 1H),
0.58-0.54 (m, 2H), 0.24-0.20 (m, 2H)
Example 568:
4-[4-(4-cyclopropylmethoxymethyl-2-methyl-thiazol-5-yl)-2,6-difluoro-phen-
oxy]-butanoic Acid
##STR00611##
[3851] Step A:
4-[4-(4-cyclopropylmethoxymethyl-2-methyl-thiazol-5-yl)-2,6-difluoro-phen-
oxy]-butanoic Acid Ethyl Ester
[3852]
4-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
oxy]butanoic acid ethyl ester (0.15 g, 0.40 mmol) obtained in
Preparation Example 16 and
5-bromo-4-cyclopropylmethoxymethyl-2-methyl-thiazole (0.12 g, 0.44
mmol) obtained in Preparation Example 337 were reacted in the same
manner as in Step A of Example 1 to obtain the title compound
(0.077 g, 45%).
[3853] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.22-7.09 (m, 2H),
4.49 (s, 2H), 4.23-4.21 (t, 2H), 4.19-4.10 (q, 2H), 3.45-3.43 (d,
2H), 2.70 (s, 3H), 2.60-2.57 (t, 2H), 2.18-2.07 (m, 2H), 1.29-1.26
(t, 3H), 1.21-1.12 (m, 1H), 0.61-0.52 (m, 2H), 0.31-0.25 (m,
2H)
Step B:
4-[4-(4-cyclopropylmethoxymethyl-2-methyl-thiazol-5-yl)-2,6-difluo-
ro-phenoxy]-butanoic Acid
[3854]
4-[4-(4-Cyclopropylmethoxymethyl-2-methyl-thiazol-5-yl)-2,6-difluor-
o-phenoxy]-butanoic acid ethyl ester (0.077 g, 0.18 mmol) obtained
in Step A was reacted in the same manner as in Step B of Example 1
to obtain the title compound (0.063 g, 88%).
[3855] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.19-7.13 (m, 2H),
4.49 (s, 2H), 4.25-4.22 (t, 2H), 3.44-3.42 (d, 2H), 2.70 (s, 3H),
2.68-2.65 (t, 2H), 2.15-2.08 (m, 2H), 1.18-1.14 (m, 1H), 0.60-0.56
(m, 2H), 0.28-0.24 (m, 2H)
Example 569:
{1-[4-(5-cyclomethoxymethyl-thiophen-2-yl)-2,6-difluoro-phenyl]-piperidin-
-4-yl}-acetic Acid
##STR00612##
[3856] Step A:
{1-[2,6-difluoro-4-(5-formyl-thiophen-2-yl)-phenyl]-piperidin-4-yl}-aceti-
c Acid Ethyl Ester
[3857]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid ethyl ester (0.33 g, 0.80 mmol)
obtained in Preparation Example 220 and
5-bromo-thiophen-2-carbaldehyde (0.17 g, 0.88 mmol) were reacted in
the same manner as in Step A of Example 1 to obtain the title
compound (0.16 g, 51%).
[3858] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 9.98 (s, 1H),
7.72-7.71 (d, 1H), 7.30-7.29 (d, 1H0, 7.16-7.10 (m, 2H), 4.18-4.13
(q, 2H), 3.34-3.31 (m, 2H), 3.17-3.11 (m, 2H), 2.30-2.29 (d, 2H),
1.97-1.80 (m, 1H), 1.97-1.77 (m, 2H), 1.55-1.40 (m, 2H), 1.28-1.26
(t, 3H)
Step B:
{1-[2,6-difluoro-4-(5-hydroxymethyl-thiophen-2-yl)-phenyl]-piperid-
in-4-yl}-acetic Acid Ethyl Ester
[3859]
{1-[2,6-Difluoro-4-(5-formyl-thiophen-2-yl)-phenyl]-piperidin-4-yl}-
-acetic acid ethyl ester (0.16 g, 0.40 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 565 to obtain
the title compound (0.14 g, 89%).
[3860] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.08-7.03 (m, 3H),
6.96-9.95 (d, 1H), 4.82 (s, 2H), 4.18-4.12 (q, 2H), 3.28-3.26 (m,
2H), 3.16-3.10 (m, 2H), 2.30-2.28 (d, 2H), 1.79-1.76 (m, 1H),
1.79-1.76 (m, 2H), 1.49-1.46 (m, 2H), 1.29-1.26 (t, 3H)
Step C:
{1-[4-(5-cyclomethoxymethyl-thiophen-2-yl)-2,6-difluoro-phenyl]-pi-
peridin-4-yl}-acetic Acid Ethyl Ester
[3861]
{1-[2,6-Difluoro-4-(5-hydroxymethyl-thiophen-2-yl)-phenyl]-piperidi-
n-4-yl}-acetic acid ethyl ester (0.14 g, 0.36 mmol) obtained in
Step B and bromomethyl-cyclopropane (0.070 ml, 0.54 mmol) were
reacted in the same manner as in Step C of Example 565 to obtain
the title compound (0.12 g, 75%).
[3862] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.06-7.00 (m, 3H),
6.92-6.91 (d, 1H), 4.67 (s, 2H), 4.18-4.12 (q, 2H), 3.35-3.33 (d,
2H), 3.27-3.24 (m, 2H), 3.14-3.09 (m, 2H), 2.30-2.28 (d, 2H), 1.95
(m, 1H), 1.78-1.75 (m, 2H0, 1.48-1.40 (m, 2H), 1.29-1.26 (t, 3H),
1.11-1.08 (m, 1H), 0.58-0.53 (m, 2H), 0.24-0.20 (m, 2H)
Step D:
{1-[4-(5-cyclomethoxymethyl-thiophen-2-yl)-2,6-difluoro-phenyl]-pi-
peridin-4-yl}-acetic Acid
[3863]
{1-[4-(5-Cyclomethoxymethyl-thiophen-2-yl)-2,6-difluoro-phenyl]-pip-
eridin-4-yl}-acetic acid ethyl ester (0.12 g, 0.27 mmol) obtained
in Step C was reacted in the same manner as in Step B of Example 1
to obtain the title compound (0.10 g, 89%).
[3864] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.07-7.01 (m, 3H),
6.93-6.92 (d, 1H), 4.67 (s, 2H), 3.35-3.34 (d, 2H), 3.28-3.25 (m,
2H), 3.15-3.10 (m, 2H), 3.67-3.35 (d, 2H), 1.96 (m, 1H), 1.83-1.80
(m, 2H), 1.51-1.43 (m, 2H), 1.15-1.08 (m, 1H), 0.58-0.53 (m, 2H),
0.24-0.20 (m, 2H)
Example 570:
{1-[4-(4-cyclopropylmethoxymethyl-2-methyl-thiazol-5-yl)-2,6-difluoro-phe-
nyl]-piperidin-4-yl}-acetic Acid
##STR00613##
[3865] Step A:
{1-[4-(4-cyclopropylmethoxymethyl-2-methyl-thiazol-5-yl)-2,6-difluoro-phe-
nyl]-piperidin-4-yl}-acetic Acid Ethyl Ester
[3866]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid ethyl ester (0.16 g, 0.40 mmol)
obtained in Preparation Example 220 and
5-bromo-4-cyclopropylmethoxymethyl-2-methyl-thiazole (0.12 g, 0.44
mmol) obtained in Preparation Example 337 were reacted in the same
manner as in Step A of Example 1 to obtain the title compound
(0.059 g, 32%).
[3867] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.11-7.01 (m, 2H),
4.49 (s, 2H), 4.20-4.13 (q, 2H), 3.45-3.42 (d, 2H), 3.31-3.28 (m,
2H), 3.16-3.10 (m, 2H), 2.75 (s, 3H), 2.30-2.28 (d, 2H), 1.98-1.94
(m, 1H), 1.79-1.76 (m, 2H), 1.49-1.43 (m, 2H), 1.29-1.26 (t, 3H),
1.18-1.14 (m, 1H), 0.60-0.55 (m, 2H), 0.28-0.24 (m, 2H)
Step B:
{1-[4-(4-cyclopropylmethoxymethyl-2-methyl-thiazol-5-yl)-2,6-diflu-
oro-phenyl]-piperidin-4-yl}-acetic Acid
[3868]
{1-[4-(4-Cyclopropylmethoxymethyl-2-methyl-thiazol-5-yl)-2,6-difluo-
ro-phenyl]-piperidin-4-yl}-acetic acid ethyl ester (0.059 g, 0.13
mmol) obtained in Step A was reacted in the same manner as in Step
B of Example 1 to obtain the title compound (0.050 g, 88%).
[3869] .sup.1H-NMR (500 HMz CDCl.sub.3); .delta. 7.08-7.06 (m, 2H),
4.48 (s, 2H), 3.43-3.42 (d, 2H), 3.31-3.28 (m, 2H), 3.16-3.11 (m,
2H), 2.69 (s, 3H), 2.36-2.35 (d, 2H), 1.98 (m, 1H), 1.83-1.81 (m,
2H), 1.49-1.46 (m, 2H), 1.16 (m, 1H), 0.59-0.54 (m, 2H), 0.27-0.25
(m, 2H)
Example 571:
4-[4-(5-cyclobutylmethoxymethyl-thiophen-3-yl)-2,6-difluoro-phenoxy]-buta-
noic Acid
##STR00614##
[3870] Step A:
4-[4-(5-cyclobutylmethoxymethyl-thiophen-3-yl)-2,6-difluoro-phenoxy]-buta-
noic Acid Ethyl Ester
[3871]
4-[2,6-Difluoro-4-(5-hydroxymethyl-thiophen-3-yl)-phenoxy]-butanoic
acid ethylester (0.10 g, 0.29 mmol) obtained in Step B of Example
566 and bromomethyl-cyclobutane (0.062 ml, 0.58 mmol) were reacted
in the same manner as in Step C of Example 565 to obtain the title
compound (0.016 g, 13%).
[3872] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.32 (d, 1H), 7.16
(m, 1H), 7.11-7.05 (m, 2H), 4.66 (s, 2H), 4.20-4.15 (q, 2H),
3.49-3.48 (d, 2H), 2.65-2.56 (m, 3H), 2.27-2.03 (m, 4H), 1.96-1.73
(m, 4H), 1.29-1.27 (t, 3H)
Step B:
4-[4-(5-cyclobutylmethoxymethyl-thiophen-3-yl)-2,6-difluoro-phenox-
y]-butanoic Acid
[3873]
4-[4-(5-Cyclobutylmethoxymethyl-thiophen-3-yl)-2,6-difluoro-phenoxy-
]-butanoic acid ethyl ester (0.016 g, 0.038 mmol) obtained in Step
A was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.014 g, 92%).
[3874] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.32 (d, 1H), 7.16
(m, 1H), 7.17-7.05 (m, 2H), 4.66 (s, 2H), 4.21-4.10 (t, 2H),
2.68-2.64 (t, 2H), 2.63-2.57 (m, 1H), 2.13-2.03 (m, 4H), 1.96-1.73
(m, 4H)
Example 572:
4-[2,6-difluoro-4-(5-isobutoxymethyl-thiophen-3-yl)-phenoxy]-butanoic
Acid
##STR00615##
[3875] Step A:
4-[2,6-difluoro-4-(5-isobutoxymethyl-thiophen-3-yl)-phenoxy]-butanoic
Acid Ethyl Ester
[3876]
4-[2,6-Difluoro-4-(5-hydroxymethyl-thiophen-3-yl)-phenoxy]-butanoic
acid ethylester (0.12 g, 0.34 mmol) obtained in Step B of Example
566 and 1-iodo-2-methyl-propane (0.090 ml, 0.67 mmol) were reacted
in the same manner as in Step C of Example 565 to obtain the title
compound (0.014 g, 10%).
[3877] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.32 (d, 1H), 7.15
(m, 1H), 7.09-7.05 (m, 2H), 4.66 (s, 2H), 4.20-4.15 (q, 2H),
3.29-3.27 (d, 2H), 2.58-2.56 (t, 2H), 2.12-2.06 (m, 2H), 1.96-1.86
(m, 1H), 1.29-1.25 (t, 3H), 0.94-0.92 (t, 3H)
Step B:
4-[2,6-difluoro-4-(5-isobutoxymethyl-thiophen-3-yl)-phenoxy]-butan-
oic Acid
[3878]
4-[2,6-Difluoro-4-(5-isobutoxymethyl-thiophen-3-yl)-phenoxy]-butano-
ic acid ethyl ester (0.014 g, 0.034 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.006 g, 42%).
[3879] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.32 (d, 1H), 7.15
(m, 1H), 7.10-7.07 (m, 2H), 4.66 (s, 2H), 4.22-4.19 (t, 2H),
3.29-3.27 (d, 2H), 2.68-2.65 (t, 2H), 2.14-2.05 (m, 2H), 1.94-1.87
(m, 1H), 0.94-0.92 (d, 6H)
Example 573:
4-[4-(5-cyclobutoxymethyl-thiophen-3-yl)-2,6-difluoro-phenoxy]-butanoic
Acid
##STR00616##
[3880] Step A:
4-[4-(5-cyclobutoxymethyl-thiophen-3-yl)-2,6-difluoro-phenoxy]-butanoic
Acid Ethyl Ester
[3881]
4-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
oxy]butyric acid ethyl ester (0.10 g, 0.28 mmol) obtained in
Preparation Example 16 and 4-bromo-2-cyclobutoxymethyl-thiophene
(0.069 ml, 0.28 mmol) obtained in Preparation Example 338 were
reacted in the same manner as in Step A of Example 1 to obtain the
title compound (0.035 g, 30%).
[3882] .sup.1H-NMR (500 HMz CDCl.sub.3); .delta. 7.31-7.30 (d, 1H),
7.15 (m, 1H), 7.09-7.05 (m, 2H), 4.56 (s, 2H), 4.19-4.12 (m, 4H),
4.09-4.03 (m, 1H), 2.58-2.55 (t, 2H), 2.25-1.98 (m, 2H), 2.11-2.06
(m, 2H), 2.05-1.95 (m, 2H), 1.78-1.68 (m, 1H), 1.56-1.48 (m, 1H),
1.27-1.25 (t, 3H)
Step B:
4-[4-(5-cyclobutoxymethyl-thiophen-3-yl)-2,6-difluoro-phenoxy]-but-
anoic Acid
[3883]
4-[4-(5-Cyclobutoxymethyl-thiophen-3-yl)-2,6-difluoro-phenoxy]-buta-
noic acid ethyl ester (0.035 g, 0.085 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.030 g, 90%).
[3884] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.31 (d, 1H), 7.16
(m, 1H), 7.10-7.05 (m, 2H), 4.57 (s, 2H), 4.22-4.19 (t, 2H),
4.10-4.03 (m, 1H), 2.68-2.65 (t, 2H), 2.26-2.19 (m, 2H), 2.14-1.97
(m, 4H), 1.76-1.69 (m, 1H), 1.58-1.48 (m, 1H)
Example 574:
4-[4-(3-cyclopropylmethoxymethyl-thiophen-2-yl)-2,6-difluoro-phenoxy]-but-
anoic Acid
##STR00617##
[3885] Step A:
4-[2,6-difluoro-4-(3-formyl-thiophen-2-yl)-phenoxy]-butanoic Acid
Ethyl Ester
[3886] 4-(4-Bromo-2,6-difluoro-phenoxy)-butanoic acid ethyl ester
(0.23 g, 0.70 mmol) obtained in Preparation Example 339 and
3-formyl-2-thiopheneboronic acid (0.11 g, 0.70 mmol) were reacted
in the same manner as in Step A of Example 565 to obtain the title
compound (0.16 g, 66%).
[3887] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 9.90-9.89 (d, 1H),
7.76-7.75 (d, 1H), 7.18-7.16 (d, 1H), 7.04-7.00 (m, 2H), 4.28-4.25
(t, 2H), 4.19-4.14 (q, 2H), 2.61-2.57 (t, 2H), 2.16-2.09 (m, 2H),
1.29-1.26 (t, 3H)
Step B:
4-[2,6-difluoro-4-(3-hydroxymethyl-thiophen-2-yl)-phenoxy]-butanoi-
c Acid Ethyl Ester
[3888] 4-[2,6-Difluoro-4-(3-formyl-thiophen-2-yl)-phenoxy]-butanoic
acid ethyl ester (0.16 g, 0.46 mmol) obtained in Step A was reacted
in the same manner as in Step B of Example 565 to obtain the title
compound (0.15 g, 92%).
[3889] .sup.1H-NMR (500 HMz CDCl.sub.3); .delta. 7.32-7.30 (d, 1H),
7.08-7.01 (m, 3H), 4.81-4.80 (d, 2H), 4.23-4.20 (t, 2H), 4.19-4.13
(q, 2H), 2.61-2.57 (t, 2H), 2.14-2.07 (m, 2H), 1.87-1.84 (t, 1H),
1.29-1.25 (t, 3H)
Step C:
4-[4-(3-cyclopropylmethoxymethyl-thiophen-2-yl)-2,6-difluoro-pheno-
xy]-butanoic Acid Ethyl Ester
[3890]
4-[2,6-Difluoro-4-(3-hydroxymethyl-thiophen-2-yl)-phenoxy]-butanoic
acid ethyl ester (0.15 g, 0.43 mmol) obtained in Step B and
bromomethyl-cyclopropane (0.16 ml, 0.43 mmol) were reacted in the
same manner as in Step C of Example 565 to obtain the title
compound (0.082 g, 47%).
[3891] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.29-7.28 (d, 1H),
7.10-7.04 (m, 3H), 4.57 (s, 2H), 4.21-4.14 (m, 4H), 3.39-3.37 (d,
2H), 2.61-2.57 (t, 2H), 2.11-2.08 (m, 2H), 1.28-1.25 (t, 2H),
1.14-1.11 (m, 1H), 0.58-0.55 (m, 2H), 0.26-0.24 (m, 2H)
Step D:
4-[4-(3-cyclopropylmethoxymethyl-thiophen-2-yl)-2,6-difluoro-pheno-
xy]-butanoic Acid
[3892]
4-[4-(3-Cyclopropylmethoxymethyl-thiophen-2-yl)-2,6-difluoro-phenox-
y]-butanoic acid ethyl ester (0.082 g, 0.20 mmol) obtained in Step
C was reacted in the same manner as in Step D of Example 565 to
obtain the title compound (0.074 g, 97%).
[3893] .sup.1H-NMR (400 HMz CDCl.sub.3); .delta. 7.29-7.28 (d, 1H),
7.10-7.04 (m, 3H), 4.57 (s, 2H), 4.23-4.21 (t, 2H), 3.39-3.37 (d,
2H), 2.68-2.66 (t, 2H), 2.12-2.09 (m, 2H), 1.13-1.11 (m, 1H),
0.58-0.55 (m, 2H), 0.25-0.23 (m, 2H)
Example 575:
{1-[4-(4-cyclobutoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenyl]-pyrrol-
idin-3-yl}-acetic Acid
##STR00618##
[3894] Step A:
{1-[4-(4-cyclobutoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenyl]-pyrrol-
idin-3-yl}-acetic Acid Ethyl Ester
[3895]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.099 g, 0.25 mmol)
obtained in Preparation Example 91 and
2-chloro-4-(cyclobutoxy)-6-methyl-pyrimidine (0.099 g, 0.50 mmol)
obtained in Preparation Example 228 were reacted in the same manner
as in Step A of Example 1 to obtain the title compound (0.057 g,
53%).
[3896] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.86-7.81 (m,
2H), 6.34 (s, 1H), 5.33-5.26 (m, 1H), 4.19-4.14 (q, 2H), 3.79-3.64
(m, 3H), 3.42-3.38 (m, 1H), 2.68-2.55 (m, 1H), 2.53-2.46 (m, 4H),
2.44 (s, 3H), 2.23-2.14 (m, 3H), 1.91-1.55 (m, 3H), 1.30-1.26 (t,
3H)
Step B:
{1-[4-(4-cyclobutoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenyl]-
-pyrrolidin-3-yl}-acetic Acid
[3897]
{1-[4-(4-Cyclobutoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenyl]--
pyrrolidin-3-yl}-acetic acid ethyl ester (0.053 g, 0.13 mmol)
obtained in Step A was reacted in the same manner as in Step B of
Example 1 to obtain the title compound (0.048 g, 90%).
[3898] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.88-7.81 (m,
2H), 6.34 (s, 1H), 5.33-5.26 (m, 1H), 3.79-3.64 (m, 3H), 3.44-3.39
(m, 1H), 2.67-2.59 (m, 1H), 2.56-2.48 (m, 4H), 2.44 (s, 3H),
2.21-2.16 (m, 3H), 1.91-1.63 (m, 3H)
Example 576:
{1-[4-(4-cyclopropylmethoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenyl]-
-pyrrolidin-3-yl}-acetic Acid
##STR00619##
[3899] Step A:
{1-[4-(4-cyclopropylmethoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenyl]-
-pyrrolidin-3-yl}-acetic Acid Ethyl Ester
[3900]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.099 g, 0.25 mmol)
obtained in Preparation Example 91 and
2-chloro-4-(cyclopropylmethoxy)-6-methyl-pyrimidine (0.099 g, 0.50
mmol) obtained in Preparation Example 227 were reacted in the same
manner as in Step A of Example 1 to obtain the title compound
(0.068 g, 63%).
[3901] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.90-7.81 (m,
2H), 6.41 (s, 1H), 4.28-4.26 (d, 2H), 4.19-4.14 (q, 2H), 3.79-3.70
(m, 2H), 3.65-3.63 (m, 1H), 3.43-3.37 (m, 1H), 2.68-2.60 (m, 1H),
2.52-2.46 (m, 2H), 2.45 (s, 3H), 2.18-2.11 (m, 1H), 1.67-1.58 (m,
1H), 1.35-1.31 (m, 1H), 1.30-1.26 (t, 3H), 0.66-0.61 (m, 2H),
0.41-0.37 (m, 2H)
Step B:
{1-[4-(4-cyclopropylmethoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro--
phenyl]-pyrrolidin-3-yl}-acetic Acid
[3902]
{1-[4-(4-Cyclopropylmethoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-p-
henyl]-pyrrolidin-3-yl}-acetic acid ethyl ester (0.068 g, 0.016
mmol) obtained in Step A was reacted in the same manner as in Step
B of Example 1 to obtain the title compound (0.062 g, 97%).
[3903] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.87-7.84 (m,
2H), 6.41 (s, 1H), 4.28-4.26 (d, 2H), 3.79-3.65 (m, 3H), 3.41 (m,
1H), 2.67-2.64 (m, 1H), 2.56-2.53 (m, 2H), 2.45 (s, 3H), 2.17 (m,
1H), 1.68-1.63 (m, 1H), 1.31-1.29 (m, 1H), 0.66-0.61 (m, 2H),
0.41-0.38 (m, 2H)
Example 577:
{1-[4-(6-cyclobutoxy-4-methyl-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrolid-
in-3-yl}-acetic Acid
##STR00620##
[3904] Step A:
{1-[4-(6-cyclobutoxy-4-methyl-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrolid-
in-3-yl}-acetic Acid Ethyl Ester
[3905]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.099 g, 0.25 mmol)
obtained in Preparation Example 91 and
2-chloro-6-(cyclobutoxy)-4-methyl-pyridine (0.099 g, 0.50 mmol)
obtained in Preparation Example 271 were reacted in the same manner
as in Step A of Example 1 to obtain the title compound (0.075 g,
69%).
[3906] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.51-7.42 (m,
2H), 7.00 (s, 1H), 6.40 (s, 1H), 5.27-5.20 (m, 1H), 4.19-7.13 (q,
2H), 3.74-3.67 (m, 2H), 3.62-3.58 (m, 1H), 3.37-3.33 (m, 1H),
2.67-2.63 (m, 1H), 2.55-2.46 (m, 4H), 2.31 (s, 3H), 2.19-2.12 (m,
3H), 1.46-1.42 (m, 3H), 1.29-1.26 (t, 3H)
Step B:
{1-[4-(6-cyclobutoxy-4-methyl-pyridin-2-yl)-2,6-difluoro-phenyl]-p-
yrrolidin-3-yl}-acetic Acid
[3907]
{1-[4-(6-Cyclobutoxy-4-methyl-pyridin-2-yl)-2,6-difluoro-phenyl]-py-
rrolidin-3-yl}-acetic acid ethyl ester (0.075 g, 0.17 mmol)
obtained in Step A was reacted in the same manner as in Step B of
Example 1 to obtain the title compound (0.069 g, 98%).
[3908] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.51-7.43 (m,
2H), 7.00 (s, 1H), 6.40 (s, 1H), 5.27-5.20 (m, 1H), 3.77-3.60 (m,
3H), 3.39-3.35 (m, 1H), 2.68-2.60 (m, 1H), 2.56-2.48 (m, 4H), 2.31
(s, 3H), 2.19-2.12 (m, 3H), 1.86-1.64 (m, 3H)
Example 578:
{1-[4-(6-cyclobutoxy-pyrazin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-3-yl}--
acetic Acid
##STR00621##
[3909] Step A:
{1-[4-(6-cyclobutoxy-pyrazin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-3-yl}--
acetic Acid Ethyl Ester
[3910]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.099 g, 0.25 mmol)
obtained in Preparation Example 91 and
2-chloro-6-(cyclobutoxy)pyrazine (0.099 g, 0.50 mmol) obtained in
Preparation Example 232 were reacted in the same manner as in Step
A of Example 1 to obtain the title compound (0.083 g, 80%).
[3911] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 8.43 (s, 1H),
8.02 (s, 1H), 7.50-7.42 (m, 2H), 5.30-5.23 (m, 1H), 4.19-4.14 (q,
2H), 3.78-3.63 (m, 3H), 3.41-3.37 (m, 1H), 2.69-2.61 (m, 1H),
2.57-2.46 (m, 4H), 2.26-2.14 (m, 3H), 1.96-1.59 (m, 3H), 1.30-1.26
(t, 3H)
Step B:
{1-[4-(6-cyclobutoxy-pyrazin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-
-3-yl}-acetic Acid
[3912]
{1-[4-(6-Cyclobutoxy-pyrazin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin--
3-yl}-acetic acid (0.083 g, 0.20 mmol) obtained in Step A was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.067 g, 86%).
[3913] .sup.1H-NMR (500 HMz, MeOD-d.sub.4); .delta. 8.73 (s, 1H),
8.09 (s, 1H), 7.69-7.67 (m, 2H), 5.23-5.19 (m, 1H), 3.65 (m, 2H),
3.53 (m, 1H), 3.29 (m, 1H), 2.45-2.41 (m, 34H), 2.38 (m, 2H),
2.11-2.21 (m, 3H), 1.82-1.68 (m, 2H), 1.59-1.51 (m, 1H)
Example 579:
{1-[4-(4-cyclobutoxy-pyrimidin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-3-yl-
}-acetic Acid
##STR00622##
[3914] Step A:
{1-[4-(4-cyclobutoxy-pyrimidin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-3-yl-
}-acetic Acid Ethyl Ester
[3915]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.099 g, 0.25 mmol)
obtained in Preparation Example 91 and
2-chloro-4-(cyclobutoxy)pyrimidine (0.099 g, 0.50 mmol) obtained in
Preparation Example 230 were reacted in the same manner as in Step
A of Example 1 to obtain the title compound (0.047 g, 44%).
[3916] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 8.42-8.40 (d,
1H), 7.88-7.78 (m, 2H), 6.50-6.48 (d, 1H), 5.36-5.29 (m, 1H),
4.19-4.14 (q, 2H), 3.80-3.64 (m, 2H), 3.44-3.38 (m, 2H), 2.68-2.46
(m, 5H), 2.23-2.13 (m, 3H), 1.90-1.61 (m, 3H), 1.30-1.26 (t,
3H)
Step B:
{1-[4-(4-cyclobutoxy-pyrimidin-2-yl)-2,6-difluoro-phenyl]-pyrrolid-
in-3-yl}-acetic Acid
[3917]
{1-[4-(4-Cyclobutoxy-pyrimidin-2-yl)-2,6-difluoro-phenyl]-pyrrolidi-
n-3-yl}-acetic acid ethyl ester (0.047 g, 0.11 mmol) obtained in
Step A was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.042 g, 99%).
[3918] .sup.1H-NMR (500 HMz, CDCl.sub.3); .delta. 8.43-8.42 (d,
1H), 7.86-7.79 (m, 2H), 6.50-6.49 (d, 1H), 5.35-5.29 (m, 1H),
3.83-3.71 (m, 2H), 3.65 (m, 1H), 3.45-3.41 (m, 1H), 2.68-2.61 (m,
1H), 2.59-2.49 (m, 4H), 2.24-2.15 (m, 3H), 1.89-1.63 (m, 3H)
Example 580:
{1-[4-(6-cyclopropylmethoxy-pyrazin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-
-3-yl}-acetic Acid
##STR00623##
[3919] Step A:
{1-[4-(6-cyclopropylmethoxy-pyrazin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-
-3-yl}-acetic Acid Ethyl Ester
[3920]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.099 g, 0.25 mmol)
obtained in Preparation Example 91 and
2-chloro-6-(cyclopropylmethoxy)pyrazine (0.099 g, 0.50 mmol)
obtained in Preparation Example 233 were reacted in the same manner
as in Step A of Example 1 to obtain the title compound (0.041 g,
38%).
[3921] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 8.43 (s, 1H),
8.09 (s, 1H), 7.52-7.42 (m, 2H), 4.26-4.24 (d, 2H), 4.19-1.14 (q,
2H), 3.78-3.71 (m, 2H), 3.64-3.63 (m, 1H), 3.42-3.37 (m, 1H),
2.69-2.52 (m, 1H), 2.51-2.42 (m, 2H), 2.19-2.12 (m, 1H), 1.68-1.61
(m, 1H), 1.39-1.32 (m, 1H), 1.30-1.26 (t, 3H), 0.68-0.64 (m, 2H),
0.46-0.39 (m, 2H)
Step B:
{1-[4-(6-cyclopropylmethoxy-pyrazin-2-yl)-2,6-difluoro-phenyl]-pyr-
rolidin-3-yl}-acetic Acid
[3922]
{1-[4-(6-Cyclopropylmethoxy-pyrazin-2-yl)-2,6-difluoro-phenyl]-pyrr-
olidin-3-yl}-acetic acid ethyl ester (0.041 g, 0.095 mmol) obtained
in Step A was reacted in the same manner as in Step B of Example 1
to obtain the title compound (0.036 g, 98%).
[3923] .sup.1H-NMR (400 HMz, MeOD-d4); .delta. 8.75 (s, 1H), 8.17
(s, 1H), 7.75-7.72 (m, 2H), 4.26-4.24 (d, 2H), 3.68 (m, 2H), 3.56
(m, 1H), 3.32 (m, 1H), 2.47 (m, 1H), 2.41-2.39 (m, 2H), 2.07 (m,
1H), 1.60-1.55 (m, 1H), 1.29-1.23 (m, 1H), 0.61-0.57 (m, 2H),
0.41-0.38 (m, 2H)
Example 581:
{1-[4-(4-cyclopropylmethoxy-pyrimidin-2-yl)-2,6-difluoro-phenyl]-pyrrolid-
in-3-yl}-acetic Acid
##STR00624##
[3924] Step A:
{1-[4-(4-cyclopropylmethoxy-pyrimidin-2-yl)-2,6-difluoro-phenyl]-pyrrolid-
in-3-yl}-acetic Acid Ethyl Ester
[3925]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.099 g, 0.25 mmol)
obtained in Preparation Example 91 and
2-chloro-4-(cyclopropylmethoxy)pyrimidine (0.099 g, 0.50 mmol)
obtained in Preparation Example 231 were reacted in the same manner
as in Step A of Example 1 to obtain the title compound (0.039 g,
36%).
[3926] .sup.1H-NMR (500 HMz, CDCl.sub.3); .delta. 8.41-8.40 (d,
1H), 7.86-7.81 (m, 2H), 6.55-6.54 (d, 1H), 4.29-4.27 (d, 2H),
4.16-4.13 (q, 2H), 3.79-3.63 (m, 3H), 3.42-3.38 (m, 1H), 2.69-2.59
(m, 1H), 2.49-2.42 (m, 2H), 2.18-2.12 (m, 1H), 1.67-1.62 (m, 1H),
1.35-1.29 (m, 1H), 1.28-1.25 (t, 3H), 0.66-0.63 (m, 2H), 0.41-0.38
(m, 2H)
Step B:
{1-[4-(4-cyclopropylmethoxy-pyrimidin-2-yl)-2,6-difluoro-phenyl]-p-
yrrolidin-3-yl}-acetic Acid
[3927]
{1-[4-(4-Cyclopropylmethoxy-pyrimidin-2-yl)-2,6-difluoro-phenyl]-py-
rrolidin-3-yl}-acetic acid ethyl ester (0.039 g, 0.090 mmol)
Obtained in Step A was reacted in the same manner as in Step B of
Example 1 to obtain the title compound (0.035 g, 98%).
[3928] .sup.1H-NMR (400 HMz, MeOD-d.sub.4); .delta. 8.53-8.51 (d,
1H), 7.83-7.80 (m, 2H), 6.79-6.77 (d, 1H), 4.30-4.28 (d, 2H), 3.70
(m, 2H), 3.58 (m, 1H), 3.32 (m, 1H), 2.49 (m, 1H), 2.41-2.39 (m,
2H), 2.07 (m, 1H), 1.60-1.55 (m, 1H), 1.29-1.27 (m, 1H), 0.61-0.56
(m, 2H), 0.42-0.39 (m, 2H)
Example 582:
{1-[4-(2-cyclobutoxy-thiazol-4-yl)-2,6-difluoro-phenyl]-pyrrolidin-3-yl}--
acetic Acid
##STR00625##
[3929] Step A:
{1-[4-(2-cyclobutoxy-thiazol-4-yl)-2,6-difluoro-phenyl]-pyrrolidin-3-yl}--
acetic Acid Ethyl Ester
[3930]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.099 g, 0.25 mmol)
obtained in Preparation Example 91 and
4-bromo-2-(cyclobutoxy)thiazole (0.099 g, 0.50 mmol) obtained in
Preparation Example 289 were reacted in the same manner as in Step
A of Example 1 to obtain the title compound (0.041 g, 39%).
[3931] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.28-7.19 (m,
2H), 6.67 (s, 1H), 5.21-5.14 (m, 1H), 4.18-4.11 (q, 2H), 3.70-3.61
(m, 2H), 3.57-3.54 (m, 1H), 3.34-3.28 (m, 1H), 2.66-2.62 (m, 1H),
2.55-2.45 (m, 4H), 2.28-2.22 (m, 2H), 2.16-2.12 (m, 1H), 1.89-1.86
(m, 1H), 1.73-1.57 (m, 2H), 1.29-1.25 (t, 3H)
Step B:
{1-[4-(2-cyclobutoxy-thiazol-4-yl)-2,6-difluoro-phenyl]-pyrrolidin-
-3-yl}-acetic Acid
[3932]
{1-[4-(2-Cyclobutoxy-thiazol-4-yl)-2,6-difluoro-phenyl]-pyrrolidin--
3-yl}-acetic acid ethyl ester (0.041 g, 0.097 mmol) obtained in
Step A was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.033 g, 87%).
[3933] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.25-7.20 (m,
2H), 6.68 (s, 1H), 5.19-5.14 (m, 1H), 3.72-3.56 (m, 3H), 3.35-3.31
(m, 1H), 2.67-2.59 (m, 1H), 2.55-2.49 (m, 4H), 2.30-2.16 (m, 3H),
1.89-1.86 (m, 1H), 1.75-1.63 (m, 2H)
Example 583:
{1-[4-(2-cyclopropylmethoxy-thiazol-4-yl)-2,6-difluoro-phenyl]-pyrrolidin-
-3-yl}-acetic Acid
##STR00626##
[3934] Step A:
{1-[4-(2-cyclopropylmethoxy-thiazol-4-yl)-2,6-difluoro-phenyl]-pyrrolidin-
-3-yl}-acetic Acid Ethyl Ester
[3935]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.099 g, 0.25 mmol)
obtained in Preparation Example 91 and
4-bromo-2-(cyclopropylmethoxy)thiazole (0.099 g, 0.50 mmol)
obtained in Preparation Example 290 were reacted in the same manner
as in Step A of Example 1 to obtain the title compound (0.048 g,
45%).
[3936] .sup.1H-NMR (500 HMz, CDCl.sub.3); .delta. 7.25-7.20 (m,
2H), 6.66 (s, 1H), 4.29-4.28 (d, 2H), 4.18-4.12 (q, 2H), 3.69-3.51
(m, 4H), 3.32-3.28 (m, 1H), 2.62-2.59 (m, 1H), 2.47-2.44 (m, 2H),
2.14-2.11 (m, 1H), 1.63-1.59 (m, 1H), 1.38-1.31 (m, 1H), 1.28-1.25
(t, 3H), 0.68-0.63 (m, 2H), 0.41-0.39 (m, 2H)
Step B:
{1-[4-(2-cyclopropylmethoxy-thiazol-4-yl)-2,6-difluoro-phenyl]-pyr-
rolidin-3-yl}-acetic Acid
[3937]
{1-[4-(2-Cyclopropylmethoxy-thiazol-4-yl)-2,6-difluoro-phenyl]-pyrr-
olidin-3-yl}-acetic acid ethyl ester (0.048 g, 0.11 mmol) obtained
in Step was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.031 g, 70%).
[3938] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.26-7.23 (m,
2H), 6.69 (s, 1H), 4.30-4.29 (d, 2H), 3.73-3.56 (m, 3H), 3.34 (m,
1H), 2.68-2.60 (m, 1H), 2.56-2.53 (m, 2H), 2.19-2.16 (m, 1H),
1.69-1.64 (m, 1H), 1.37-1.32 (m, 1H), 0.69-0.64 (m, 2H), 0.43-0.39
(m, 2H)
Example 584:
{1-[2,6-difluoro-4-(6-methoxy-pyrazin-2-yl)-phenyl]-pyrrolidin-3-yl}-acet-
ic Acid
##STR00627##
[3939] Step A:
{1-[2,6-difluoro-4-(6-methoxy-pyrazin-2-yl)-phenyl]-pyrrolidin-3-yl}-acet-
ic acid Ethyl Ester
[3940]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.099 g, 0.25 mmol)
obtained in Preparation Example 91 2-chloro-6-methoxy-pyrazine
(0.072 g, 0.50 mmol) obtained in Preparation Example 234 were
reacted in the same manner as in Step A of Example 1 to obtain the
title compound (0.069 g, 73%).
[3941] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 8.45 (s, 1H),
8.08 (s, 1H), 7.52 (m, 2H), 4.19-4.14 (q, 2H), 4.05 (s, 3H),
3.76-3.64 (m, 3H), 3.40 (m, 1H), 2.67-2.61 (m, 1H), 2.49-2.47 (m,
2H), 2.17-2.15 9 m, 1H), 1.67-1.61 (m, 1H), 1.30-1.26 (t, 3H)
Step B:
{1-[2,6-difluoro-4-(6-methoxy-pyrazin-2-yl)-phenyl]-pyrrolidin-3-y-
l}-acetic Acid
[3942]
{1-[2,6-Difluoro-4-(6-methoxy-pyrazin-2-yl)-phenyl]-pyrrolidin-3-yl-
}-acetic acid ethyl ester (0.069 g, 0.18 mmol) obtained in Step A
was reacted in the same manner as in Step B of Example 1 to obtain
the title compound (0.048 g, 75%).
[3943] .sup.1H-NMR (400 HMz, CDCl.sub.3+MeOD-d.sub.4); .delta. 8.43
(s, 1H), 8.04 (s, 1H), 7.55-7.50 (m, 2H), 4.06 (s, 3H), 3.79-3.64
(m, 3H), 3.41 (m, 1H), 2.67-2.63 (m, 1H), 2.49-2.48 (m, 2H),
2.20-2.16 (m, 1H), 1.70-1.63 (m, 1H)
Example 585:
{1-[4-(6-ethoxy-pyrazin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-3-yl}-aceti-
c Acid
##STR00628##
[3944] Step A:
{1-[4-(6-ethoxy-pyrazin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-3-yl}-aceti-
c acid Ethyl Ester
[3945]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.099 g, 0.25 mmol)
obtained in Preparation Example 91 and 2-chloro-6-ethoxy-pyrazine
(0.079 g, 0.50 mmol) obtained in Preparation Example 302 were
reacted in the same manner as in Step A of Example 1 to obtain the
title compound (0.031 g, 32%).
[3946] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 8.43 (s, 1H),
8.05 (s, 1H), 7.52-7.44 (m, 2H), 4.51-4.46 (q, 2H), 4.19-4.14 (q,
2H), 3.78-3.71 (m, 3H), 3.41-3.37 (m, 1H), 2.67-2.61 (m, 1H),
2.48-2.46 (m, 2H), 2.18-2.13 (m, 1H), 1.68-1.61 (m, 1H), 1.47-1.44
(t, 3H), 1.30-1.25 (t, 3H)
Step B:
{1-[4-(6-ethoxy-pyrazin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-3-yl-
}-acetic Acid
[3947]
{1-[4-(6-Ethoxy-pyrazin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin-3-yl}-
-acetic acid (0.031 g, 0.079 mmol) obtained in Step A was reacted
in the same manner as in Step B of Example 1 to obtain the title
compound (0.023 g, 80%).
[3948] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 8.77 (s, 1H),
8.15 (s, 1H), 7.77-7.73 (m, 2H), 4.49-4.44 (q, 2H), 3.69-3.57 (m,
3H), 3.33 (m, 1H), 2.47 (m, 1H), 2.43-2.41 (m, 2H), 2.08 (m, 1H),
1.62-1.56 (m, 1H), 1.41-1.38 (t, 3H)
Example 586:
{1-[2,6-difluoro-4-(6-isopropoxy-pyrazin-2-yl)-phenyl]-pyrrolidin-3-yl}-a-
cetic Acid
##STR00629##
[3949] Step A:
{1-[2,6-difluoro-4-(6-isopropoxy-pyrazin-2-yl)-phenyl]-pyrrolidin-3-yl}-a-
cetic Acid Ethyl Ester
[3950]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0099 g, 0.25 mmol)
obtained in Preparation Example 91 and
2-chloro-6-isopropoxy-pyrazine (0.086 g, 0.50 mmol) obtained in
Preparation Example 301 were reacted in the same manner as in Step
A of Example 1 to obtain the title compound (0.076 g, 75%).
[3951] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 8.40 (s, 1H),
8.00 (s, 1H), 7.48-7.45 (m, 1H), 5.45-5.39 (m, 1H), 4.19-4.14 (q,
2H), 3.76-3.63 (m, 3H), 3.39-3.37 (m, 1H), 2.67-2.63 (m, 1H).
2.48-2.46 (m, 2H), 2.15 (m, 1H), 1.66-1.61 (m, 1H), 1.42-1.40 (d,
6H), 1.30-1.26 (t, 3H)
Step B:
{1-[2,6-difluoro-4-(6-isopropoxy-pyrazin-2-yl)-phenyl]-pyrrolidin--
3-yl}-acetic Acid
[3952]
{1-[2,6-Difluoro-4-(6-isopropoxy-pyrazin-2-yl)-phenyl]-pyrrolidin-3-
-yl}-acetic acid ethyl ester (0.076 g, 0.19 mmol) obtained in Step
A was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.067 g, 95%).
[3953] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 8.73 (s, 1H),
8.09 (s, 1H), 7.74-7.70 (m, 2H), 5.40-5.35 (m, 1H), 3.68-3.56 (m,
2H), 3.33 (m, 1H), 2.45 (m, 1H), 2.41-2.40 (m, 2H), 2.07 (m, 1H),
1.60-1.55 (m, 1H), 1.37-1.36 (d, 6H)
Example 587:
{1-[2,6-difluoro-4-(4-isopropoxy-6-methyl-pyrimidin-2-yl)-phenyl]-pyrroli-
din-3-yl}-acetic Acid
##STR00630##
[3954] Step A:
{1-[2,6-difluoro-4-(4-isopropoxy-6-methyl-pyrimidin-2-yl)-phenyl]-pyrroli-
din-3-yl}-acetic Acid Ethyl Ester
[3955]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.30 g, 0.75 mmol)
obtained in Preparation Example 91 and
2-chloro-4-isopropoxy-6-methyl-pyrimidine (0.28 g, 1.50 mmol)
obtained in Preparation Example 244 were reacted in the same manner
as in Step A of Example 1 to obtain the title compound (0.254 g,
81%).
[3956] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.90-7.80 (m,
2H), 6.33 (s, 1H), 5.53-5.46 (m, 1H), 4.19-4.14 (q, 2H), 3.79-3.70
(m, 2H), 3.64 (m, 1H), 3.42-3.37 (m, 1H), 2.68 (m, 1H), 2.48-2.46
(m, 2H), 2.43 (s, 3H), 2.18-2.13 (m, 1H), 1.68-1.60 (m, 1H),
1.40-1.38 (d, 6H), 1.30-1.26 (t, 3H)
Step B:
{1-[2,6-difluoro-4-(4-isopropoxy-6-methyl-pyrimidin-2-yl)-phenyl]--
pyrrolidin-3-yl}-acetic Acid
[3957]
{1-[2,6-Difluoro-4-(4-isopropoxy-6-methyl-pyrimidin-2-yl)-phenyl]-p-
yrrolidin-3-yl}-acetic acid ethyl ester (0.254 g, 0.61 mmol)
obtained in Step A was reacted in the same manner as in Step B of
Example 1 to obtain the title compound (0.235 g, 99%).
[3958] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.90-7.81 (m,
2H), 6.34-6.33 (d, 1H), 5.53-5.46 (m, 1H), 3.81-3.65 (m, 3H),
3.44-3.40 (m, 1H), 2.69-2.61 (m, 1H), 2.55-2.51 (m, 2H), 2.44 (s,
3H), 2.20-2.16 (m, 1H), 1.70-1.61 (m, 1H), 1.40-1.38 (d, 6H)
Example 588:
{1-[2,6-difluoro-4-(4-isobutoxy-6-methyl-pyrimidin-2-yl)-phenyl]-pyrrolid-
in-3-yl}-acetic Acid
##STR00631##
[3959] Step A:
{1-[2,6-difluoro-4-(4-isobutoxy-6-methyl-pyrimidin-2-yl)-phenyl]-pyrrolid-
in-3-yl}-acetic Acid Ethyl Ester
[3960]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.30 g, 0.75 mmol)
obtained in Preparation Example 91 and
2-chloro-4-isobutoxy-6-methyl-pyrimidine (0.30 g, 1.50 mmol)
obtained in Preparation Example 246 were reacted in the same manner
as in Step A of Example 1 to obtain the title compound (0.176 g,
54%).
[3961] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.88-7.84 (m,
2H), 6.39 (s, 1H), 4.21-4.14 (m, 4H), 3.76-3.63 (m, 3H), 3.40 (m,
1H), 2.66-2.63 (m, 1H), 2.48-2.46 (m, 2H), 2.45 (s, 3H), 2.15-2.08
(m, 2H), 1.66-1.61 (m, 1H), 1.30-1.26 (t, 3H), 1.04-1.03 (d,
6H)
Step B:
{1-[2,6-difluoro-4-(4-isobutoxy-6-methyl-pyrimidin-2-yl)-phenyl]-p-
yrrolidin-3-yl}-acetic Acid
[3962]
{1-[2,6-Difluoro-4-(4-isobutoxy-6-methyl-pyrimidin-2-yl)-phenyl]-py-
rrolidin-3-yl}-acetic acid ethyl ester (0.176 g, 0.41 mmol)
obtained in Step A was reacted in the same manner as in Step B of
Example 1 to obtain the title compound (0.164 g, 99%).
[3963] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.89-7.85 (m,
2H), 6.40 (s, 1H), 4.21-4.20 (d, 2H), 3.79-3.65 (m, 3H), 3.44-3.42
(m, 1H), 2.68-2.62 (m, 1H), 2.56-2.51 (m, 2H), 2.46 (s, 3H),
2.17-2.08 (m, 2H), 1.68-1.63 (m, 1H), 1.04-1.03 (d, 6H)
Example 589:
{1-[2,6-difluoro-4-(4-methyl-6-propoxy-pyrimidin-2-yl)-phenyl]-pyrrolidin-
-3-yl}-acetic Acid
##STR00632##
[3964] Step A:
{1-[2,6-difluoro-4-(4-methyl-6-propoxy-pyrimidin-2-yl)-phenyl]-pyrrolidin-
-3-yl}-acetic Acid Ethyl Ester
[3965]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.30 g, 0.75 mmol)
obtained in Preparation Example 91 and
2-chloro-4-methyl-6-propoxy-pyrimidine (0.28 g, 1.50 mmol) obtained
in Preparation Example 245 were reacted in the same manner as in
Step A of Example 1 to obtain the title compound (0.281 g,
89%).
[3966] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.89-7.85 (m,
2H), 6.40 (s, 1H), 4.21-4.20 (d, 2H), 3.79-3.65 (m, 3H), 3.44-3.42
(m, 1H), 2.68-2.62 (m, 1H), 2.56-2.51 (m, 2H), 2.46 (s, 3H),
2.17-2.08 (m, 2H), 1.68-1.63 (m, 1H), 1.04-1.03 (d, 6H)
Step B:
{1-[2,6-difluoro-4-(4-methyl-6-propoxy-pyrimidin-2-yl)-phenyl]-pyr-
rolidin-3-yl}-acetic Acid
[3967]
{1-[2,6-Difluoro-4-(4-methyl-6-propoxy-pyrimidin-2-yl)-phenyl]-pyrr-
olidin-3-yl}-acetic acid ethyl ester (0.281 g, 0.67 mmol) obtained
in Step A was reacted in the same manner as in Step B of Example 1
to obtain the title compound (0.183 g, 70%).
[3968] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.90-7.85 (m,
2H), 6.39 (s, 1H), 4.41-4.37 (t, 2H), 3.82-3.65 (m, 3H), 3.44-3.40
(m, 1H), 2.69-2.59 (m, 1H), 2.55-2.51 (m, 2H), 2.45 (s, 3H),
2.20-2.16 (m, 1H), 1.87-1.78 (m, 2H), 1.68-1.61 (m, 1H), 1.06-1.03
(t, 2H)
Example 590:
{1-[4-(4-ethoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin--
3-yl}-acetic Acid
##STR00633##
[3969] Step A:
{1-[4-(4-ethoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenyl]-pyrrolidin--
3-yl}-acetic Acid Ethyl Ester
[3970]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.30 g, 0.75 mmol)
obtained in Preparation Example 91 and
2-chloro-4-ethoxy-6-methyl-pyrimidine (0.259 g, 1.50 mmol) obtained
in Preparation Example 243 were reacted in the same manner as in
Step A of Example 1 to obtain the title compound (0.266 g,
88%).
[3971] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.88-7.85 (m,
2H), 6.37 (s, 1H), 4.52-4.47 (t, 2H), 4.19-4.14 (q, 2H), 3.77-3.64
(m, 3H), 3.40 (m, 1H), 2.66-2.61 (m, 1H), 2.48-2.46 (m, 2H), 2.45
(s, 3H), 2.05 (m, 1H) 1.65-1.60 (m, 1H), 1.44-1.41 (t, 3H),
1.30-1.26 (t, 3H)
Step B:
{1-[4-(4-ethoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenyl]-pyrr-
olidin-3-yl}-acetic Acid
[3972]
{1-[4-(4-Ethoxy-6-methyl-pyrimidin-2-yl)-2,6-difluoro-phenyl]-pyrro-
lidin-3-yl}-acetic acid ethyl ester (0.266 g, 0.66 mmol) obtained
in Step A was reacted in the same manner as in Step B of Example 1
to obtain the title compound (0.234 g, 94%).
[3973] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.90-7.82 (m,
2H), 6.37 (s, 1H), 4.52-4.47 (q, 2H), 3.79-3.64 (m, 3H), 3.49-3.40
(m, 1H), 2.69-2.62 (m, 1H), 2.55-2.51 (m, 2H), 2.45 (s, 3H),
2.20-2.16 (m, 1H), 1.70-1.63 (m, 1H), 1.44-1.41 (t, 3H)
Example 591:
{1-[4-(5-cyclobutoxy-3-methyl-isothiazol-4-yl)-2,6-difluoro-phenyl]-pyrro-
lidin-3-yl}-acetic Acid
##STR00634##
[3974] Step A:
{1-[4-(5-cyclobutoxy-3-methyl-isothiazol-4-yl)-2,6-difluoro-phenyl]-pyrro-
lidin-3-yl}-acetic Acid Ethyl Ester
[3975]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.094 g, 0.24 mmol)
obtained in Preparation Example 91 and
4-bromo-5-(cyclobutoxy)-3-methyl-isothiazole (0.060 g, 0.24 mmol)
obtained in Preparation Example 292 were reacted in the same manner
as in Step A of Example 1 to obtain the title compound (0.048 g,
46%).
[3976] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 6.82-6.77 (m,
2H), 4.62-4.57 (m, 1H), 4.19-4.13 (q, 2H), 3.72-3.58 (m, 3H),
3.34-3.30 (m, 1H), 2.67-2.62 (m, 1H), 2.48-2.46 (m, 4H), 2.36 (s,
3H), 2.26-2.13 (m, 3H), 1.87-1.82 (m, 1H), 1.69-1.63 (m, 2H),
1.30-1.26 (t, 3H)
Step B:
{1-[4-(5-cyclobutoxy-3-methyl-isothiazol-4-yl)-2,6-difluoro-phenyl-
]-pyrrolidin-3-yl}-acetic Acid
[3977]
{1-[4-(5-Cyclobutoxy-3-methyl-isothiazol-4-yl)-2,6-difluoro-phenyl]-
-pyrrolidin-3-yl}-acetic acid ethyl ester (0.048 g, 0.11 mmol)
obtained in Step A was reacted in the same manner as in Step B of
Example 1 to obtain the title compound (0.038 g, 80%).
[3978] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 6.82-6.79 (m,
2H), 4.61-4.58 (m, 1H), 3.72-3.58 (m, 3H), 3.34 (m, 1H), 2.69-2.65
(m, 1H), 2.55-2.53 (m, 2H), 2.49-2.43 (m, 2H), 2.36 (s, 3H),
2.26-2.18 (m, 3H), 1.87-1.85 (m, 1H), 1.69-1.62 (m, 2H)
Example 592:
{1-[4-(4-cyclobutoxy-5-fluoro-pyrimidin-2-yl)-2,6-difluoro-phenyl]-pyrrol-
idin-3-yl}-acetic Acid
##STR00635##
[3979] Step A:
{1-[4-(4-cyclobutoxy-5-fluoro-pyrimidin-2-yl)-2,6-difluoro-phenyl]-pyrrol-
idin-3-yl}-acetic Acid Ethyl Ester
[3980]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.20 g, 0.5 mmol)
obtained in Preparation Example 91 and
2-chloro-4-cyclobutoxy-5-fluoropyrimidine (0.15 g, 0.75 mmol)
obtained in Preparation Example 329 were reacted in the same manner
as in Step A of Example 1 to obtain the title compound (0.16 g,
72%).
[3981] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 8.29-8.27 (d,
1H), 7.78-7.72 (m, 2H), 5.42-5.38 (m, 1H), 4.19-4.4 (q, 2H),
3.77-3.75 (m, 2H), 6.64 (m, 2H), 3.42-3.38 (m, 1H), 2.66-2.53 (m,
3H0, 2.48-2.46 (m, 2H), 2.31-2.26 (m, 2H), 2.17-2.13 (m, 1H),
1.94-1.91 (m, 1H), 1.82-1.75 (m, 1H), 1.66-1.61 (m, 1H), 1.30-1.26
(t, 3H)
Step B:
{1-[4-(4-cyclobutoxy-5-fluoro-pyrimidin-2-yl)-2,6-difluoro-phenyl]-
-pyrrolidin-3-yl}-acetic Acid
[3982]
{1-[4-(4-Cyclobutoxy-5-fluoro-pyrimidin-2-yl)-2,6-difluoro-phenyl]--
pyrrolidin-3-yl}-acetic acid ethyl ester (0.14 g, 0.31 mmol)
obtained in Step A was reacted in the same manner as in Step B of
Example 1 to obtain the title compound (0.10 g, 78%).
[3983] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 8.28-8.27 (d,
1H), 7.74-7.71 (m, 2H), 5.40-5.37 (m, 1H), 3.79-3.64 (m, 3H),
4.43-3.39 (m, 1H), 2.69-2.62 (m, 1H), 2.61-2.52 (m, 4H), 2.31-2.23
(m, 2H), 2.19-2.15 (m, 1H), 1.93-1.90 (m, 1H), 1.80-1.73 (m, 1H),
1.69-1.62 (m, 1H)
Example 593:
{1-[4-(4-cyclopropylmethoxy-5-fluoro-pyrimidin-2-yl)-2,6-difluoro-phenyl]-
-pyrrolidin-3-yl}-acetic Acid
##STR00636##
[3984] Step A:
{1-[4-(4-cyclopropylmethoxy-5-fluoro-pyrimidin-2-yl)-2,6-difluoro-phenyl]-
-pyrrolidin-3-yl}-acetic Acid Ethyl Ester
[3985]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.2 g, 0.5 mmol)
obtained in Preparation Example 91 and
2-chloro-4-cyclopropylmethoxy-5-fluoro-pyrimidine (0.15 g, 0.75
mmol) obtained in Preparation Example 330 were reacted in the same
manner as in Step A of Example 1 to obtain the title compound (0.16
g, 69%).
[3986] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 8.29-8.28 (d,
1H), 7.79-7.71 (m, 2H), 4.39-7.37 (d, 2H), 4.19-4.14 (q, 2H),
3.77-3.64 (m, 3H), 3.42-3.38 (m, 1H), 2.66-2.62 (m, 1H), 2.48-2.46
(m, 2H), 2.17-2.13 (m, 1H), 1.68-1.61 (m, 1H), 1.40-1.37 (m, 1H),
1.30-1.26 (t, 3H), 0.70-0.66 (m, 2H), 0.46-0.42 (m, 2H)
Step B:
{1-[4-(4-cyclopropylmethoxy-5-fluoro-pyrimidin-2-yl)-2,6-difluoro--
phenyl]-pyrrolidin-3-yl}-acetic Acid
[3987]
{1-[4-(4-Cyclopropylmethoxy-5-fluoro-pyrimidin-2-yl)-2,6-difluoro-p-
henyl]-pyrrolidin-3-yl}-acetic acid ethyl ester (0.12 g, 0.27 mmol)
obtained in Step A was reacted in the same manner as in Step B of
Example 1 to obtain the title compound (0.096 g, 81%).
[3988] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 8.29-8.28 (d,
1H), 7.74-7.72 (m, 2H), 4.38-4.36 (d, 2H), 3.81-3.63 (m, 3H),
3.48-3.39 (m, 1H), 2.68-2.61 (m, 1H), 2.54-2.50 (m, 2H), 2.18-2.15
(m, 1H), 1.66-1.64 (m, 1H), 1.39-1.36 (m, 1H), 0.69-0.66 (m, 2H),
0.44-0.42 (m, 2H)
Example 594:
{1-[2,6-difluoro-4-(5-fluoro-4-isobutoxy-pyrimidin-2-yl)-phenyl]-pyrrolid-
in-3-yl}-acetic Acid
##STR00637##
[3989] Step A:
{1-[2,6-difluoro-4-(5-fluoro-4-isobutoxy-pyrimidin-2-yl)-phenyl]-pyrrolid-
in-3-yl}-acetic Acid Ethyl Ester
[3990]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.16 g, 0.40 mmol)
obtained in Preparation Example 91 and
2-chloro-5-fluoro-4-isobutoxy-pyrimidine (0.12 g, 0.60 mmol)
obtained in Preparation Example 331 were reacted in the same manner
as in Step A of Example 1 to obtain the title compound (0.12 g,
63%).
[3991] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 8.28-8.27 (d,
1H), 7.77-7.74 (m, 2H), 4.32-4.30 (d, 2H), 4.19-4.14 (q, 2H),
3.77-3.64 (m, 3H), 3.41 (m, 1H), 2.64-2.63 (m, 1H), 2.48-2.46 (m,
2H), 2.23-2.18 (m, 2H), 1.66-1.61 (m, 1H), 1.30-1.26 (t, 3H),
1.08-1.06 (d, 6H)
Step B:
{1-[2,6-difluoro-4-(5-fluoro-4-isobutoxy-pyrimidin-2-yl)-phenyl]-p-
yrrolidin-3-yl}-acetic Acid
[3992]
{1-[2,6-Difluoro-4-(5-fluoro-4-isobutoxy-pyrimidin-2-yl)-phenyl]-py-
rrolidin-3-yl}-acetic acid ethyl ester (0.12 g, 0.27 mmol) obtained
in Step A were reacted in the same manner as in Step B of Example 1
to obtain the title compound (0.074 g, 68%).
[3993] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 8.28-8.27 (d,
1H), 7.75-7.73 (m, 2H), 4.30-4.29 (d, 2H), 3.79-3.64 (m, 3H),
3.43-3.41 (m, 1H), 2.64-2.62 (m, 1H), 2.54-2.52 (m, 2H), 2.20-2.17
(m, 2H), 1.67-1.64 (m, 1H), 1.07-1.05 (d, 6H)
Example 595:
(1-{2,6-difluoro-4-[6-(3-methoxy-propoxy)-pyridin-2-yl]-phenyl}-pyrrolidi-
n-3-yl)-acetic Acid
##STR00638##
[3994] Step A:
(1-{2,6-difluoro-4-[6-(3-methoxy-propoxy)-pyridin-2-yl]-phenyl}-pyrrolidi-
n-3-yl)-acetic Acid Ethyl Ester
[3995]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.099 g, 0.25 mmol)
obtained in Preparation Example 91 and
2-chloro-6-(3-methoxy-propoxy)-pyridine (0.076 g, 0.38 mmol)
obtained in Preparation Example 332 were reacted in the same manner
as in Step A of Example 1 to obtain the title compound (0.039 g,
34%).
[3996] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.59-7.55 (t,
1H), 7.54-7.45 (m, 2H), 7.18-7.16 (d, 1H), 6.62-6.60 (d, 1H),
4.50-4.47 (t, 2H), 4.19-4.14 (q, 2H), 3.75-3.66 (m, 2H), 3.62-3.55
(m, 3H), 3.38 (s, 3H), 3.36-3.33 (m, 1H), 2.69-2.61 (m, 1H),
2.52-2.42 (m, 2H), 2.17-2.06 (m, 3H), 1.68-1.61 (m, 1H), 1.30-1.26
(t, 3H)
Step B:
(1-{2,6-difluoro-4-[6-(3-methoxy-propoxy)-pyridin-2-yl]-phenyl}-py-
rrolidin-3-yl)-acetic Acid
[3997]
(1-{2,6-Difluoro-4-[6-(3-methoxy-propoxy)-pyridin-2-yl]-phenyl}-pyr-
rolidin-3-yl)-acetic acid ethyl ester (0.039 g, 0.089 mmol)
obtained in Step A was reacted in the same manner as in Step B of
Example 1 to obtain the title compound (0.031 g, 85%).
[3998] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta.7.58-7.55 (t, 1H),
7.55-7.47 (m, 2H), 7.17-7.15 (d, 1H), 6.61-6.59 (d, 1H), 4.49-4.46
(t, 2H), 3.74-3.67 (m, 2H), 3.60-3.55 (m, 3H), 3.38-3.35 (m, 4H),
2.66-2.61 (m, 1H), 2.58-2.52 (m, 2H), 2.21-2.14 (m, 1H), 2.11-2.05
(m, 2H), 1.67-1.62 (m, 1H)
Example 596:
(1-{2,6-difluoro-4-[6-(tetrahydro-thiopyran-4-yloxy-pyridin-2-yl]-phenyl}-
-pyrrolidin-3-yl)-acetic Acid
##STR00639##
[3999] Step A:
(1-{2,6-difluoro-4-[6-(tetrahydro-thiopyran-4-yloxy-pyridin-2-yl]-phenyl}-
-pyrrolidin-3-yl)-acetic Acid Ethyl Ester
[4000]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]pyrrolidin-3-yl]acetic acid ethyl ester (0.099 g, 0.25 mmol)
obtained in Preparation Example 91 and
2-chloro-6-(tetrahydro-thiopyran-4-yloxy)-pyridine (0.086 g, 0.38
mmol) obtained in Preparation Example 333 were reacted in the same
manner as in Step A of Example 1 to obtain the title compound
(0.063 g, 52%).
[4001] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.60-7.56 (t,
1H), 7.47-7.39 (m, 2H), 7.17-7.15 (d, 1H), 6.61-6.59 (d, 1H),
5.32-5.28 (m, 1H), 4.19-4.14 (q, 2H), 3.75-3.60 (m, 3H), 3.38-3.34
(m, 1H), 2.95-2.90 (m, 2H), 2.70-2.61 (m, 3H), 2.52-2.46 (m, 2H),
2.31-2.25 (m, 2H), 2.17-2.04 (m, 3H), 1.68-1.63 (m, 1H), 1.30-1.26
(t, 3H)
Step B:
(1-{2,6-difluoro-4-[6-(tetrahydro-thiopyran-4-yloxy-pyridin-2-yl]--
phenyl}-pyrrolidin-3-yl)-acetic Acid
[4002]
(1-{2,6-Difluoro-4-[6-(tetrahydro-thiopyran-4-yloxy-pyridin-2-yl]-p-
henyl}-pyrrolidin-3-yl)-acetic acid ethyl ester (0.063 g, 0.14
mmol) obtained in Step A was reacted in the same manner as in Step
B of Example 1 to obtain the title compound (0.052 g, 89%).
[4003] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.60-7.56 (t,
1H), 7.47-7.39 (m, 2H), 7.17-7.15 (d, 1H), 6.62-6.60 (d, 1H),
5.32-5.28 (m, 1H), 3.78-3.61 (m, 3H), 3.40-3.36 (m, 1H), 2.95-2.91
(m, 2H), 2.70-2.65 (m, 3H), 2.56-2.53 (m, 2H), 2.31-2.04 (m, 5H),
1.71-1.64 (m, 1H)
Example 597:
{1-[2,6-difluoro-4-(5-fluoro-4-isobutoxy-pyrimidin-2-yl)-phenyl]-piperidi-
n-4-yl}-acetic Acid
##STR00640##
[4004] Step A:
{1-[2,6-difluoro-4-(5-fluoro-4-isobutoxy-pyrimidin-2-yl)-phenyl]-piperidi-
n-4-yl}-acetic Acid Ethyl Ester
[4005]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid ethyl ester (0.16 g, 0.40 mmol)
obtained in Preparation Example 220 and
2-chloro-5-fluoro-4-isobutoxy-pyrimidine (0.12 g, 0.60 mmol)
obtained in Preparation Example 331 were reacted in the same manner
as in Step A of Example 1 to obtain the title compound (0.11 g,
62%).
[4006] .sup.1H-NMR (500 HMz, CDCl.sub.3); .delta. 8.30-8.29 (d,
1H), 7.82-7.77 (m, 2H), 4.31-4.30 (d, 2H), 4.17-4.12 (q, 2H),
3.36-3.34 (m, 2H), 3.17-3.12 (m, 2H), 2.30-2.28 (d, 2H), 2.22-2.16
(m, 1H), 1.98-1.94 (m, 1H), 1.79-1.76 (m, 2H), 1.49-1.41 (m, 2H),
1.28-1.24 (t, 3H), 1.08-1.05 (d, 6H)
Step B:
{1-[2,6-difluoro-4-(5-fluoro-4-isobutoxy-pyrimidin-2-yl)-phenyl]-p-
iperidin-4-yl}-acetic Acid
[4007]
{1-[2,6-Difluoro-4-(5-fluoro-4-isobutoxy-pyrimidin-2-yl)-phenyl]-pi-
peridin-4-yl}-acetic acid ethyl ester (0.11 g, 0.25 mmol) obtained
in Step A was reacted in the same manner as in Step B of Example 1
to obtain the title compound (0.095 g, 90%).
[4008] .sup.1H-NMR (500 HMz, CDCl.sub.3); .delta. 8.31-8.30 (d,
1H), 7.79-7.76 (m, 2H), 4.31-4.30 (d, 2H), 3.37-3.35 (m, 2H),
3.18-3.13 (m, 2H), 2.37-2.35 (d, 2H), 2.21-2.17 (m, 1H), 1.98-1.97
(m, 1H), 1.83-1.81 (m, 2H), 1.51-1.46 (m, 2H), 1.07-1.05 (d,
6H)
Example 598:
{1-[2,6-difluoro-4-(5-fluoro-4-propoxy-pyrimidin-2-yl)-phenyl]-piperidin--
4-yl}-acetic Acid
##STR00641##
[4009] Step A:
{1-[2,6-difluoro-4-(5-fluoro-4-propoxy-pyrimidin-2-yl)-phenyl]-piperidin--
4-yl}-acetic Acid Ethyl Ester
[4010]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid ethyl ester (0.16 g, 0.40 mmol)
obtained in Preparation Example 220 and
2-chloro-5-fluoro-4-propoxy-pyrimidine (0.11 g, 0.60 mmol) obtained
in Preparation Example 334 were reacted in the same manner as in
Step A of Example 1 to obtain the title compound (0.11 g, 60%).
[4011] .sup.1H-NMR (500 HMz, CDCl.sub.3); .delta. 8.30-8.29 (d,
1H), 7.80-7.78 (m, 2H), 4.52-4.49 (t, 2H), 4.15-4.12 (q, 2H),
3.36-3.34 (m, 2H), 3.17-3.12 (m, 2H), 2.30-2.28 (d, 2H), 1.96 (m,
1H), 1.92-1.87 (q, 2H), 1.79-1.76 (m, 2H), 1.51-1.43 (m, 2H),
1.28-1.25 (t, 3H), 1.09-1.06 (t, 3H)
Step B:
{1-[2,6-difluoro-4-(5-fluoro-4-propoxy-pyrimidin-2-yl)-phenyl]-pip-
eridin-4-yl}-acetic Acid
[4012]
{1-[2,6-Difluoro-4-(5-fluoro-4-propoxy-pyrimidin-2-yl)-phenyl]-pipe-
ridin-4-yl}-acetic acid ethyl ester (0.11 g, 0.24 mmol) obtained in
Step A was reacted in the same manner as in Step B of Example 1 to
obtain the title compound (0.092 g, 93%).
[4013] .sup.1H-NMR (500 HMz, CDCl.sub.3); .delta. 8.31-8.30 (d,
1H), 7.80-7.78 (m, 2H), 4.51-4.49 (t, 2H), 3.37-3.35 (m, 2H),
3.18-3.13 (m, 2H), 2.37-2.35 (d, 2H), 1.98 (m, 1H), 1.92-1.87 (m,
2H), 1.83-1.81 (m, 2H), 1.49-1.46 (m, 2H), 1.09-1.06 (t, 3H)
Example 599:
(1-{2,6-difluoro-4-[4-(3-methyl-butoxy)-pyrimidin-2-yl]-phenyl}-piperidin-
-4-yl)-acetic Acid
##STR00642##
[4014] Step A:
(1-{2,6-difluoro-4-[4-(3-methyl-butoxy)-pyrimidin-2-yl]-phenyl}-piperidin-
-4-yl)-acetic Acid Ethyl Ester
[4015]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid ethyl ester (0.21 g, 0.50 mmol)
obtained in Preparation Example 220 and
2-chloro-4-(3-methyl-butoxy)-pyrimidine (0.15 g, 0.75 mmol)
obtained in Preparation Example 335 were reacted in the same manner
as in Step A of Example 1 to obtain the title compound (0.079 g,
35%).
[4016] .sup.1H-NMR (500 HMz, CDCl.sub.3); .delta. 8.43-8.42 (d,
1H), 7.90-7.85 (m, 2H), 6.56-6.55 (d, 1H), 4.50-4.47 (t, 2H),
4.15-4.12 (q, 2H), 3.37-3.35 (m, 2H), 3.17-3.14 (m, 2H), 2.29-2.28
(d, 2H), 1.98-1.95 (m, 1H), 1.84-1.80 (m, 1H), 1.79-1.76 (m, 2H),
1.72-1.68 (q, 2H), 1.49-1.42 (m, 2H), 1.29-1.24 (t, 3H), 0.99-0.96
(d, 6H)
Step B:
(1-{2,6-difluoro-4-[4-(3-methyl-butoxy)-pyrimidin-2-yl]-phenyl}-pi-
peridin-4-yl)-acetic Acid
[4017]
(1-{2,6-Difluoro-4-[4-(3-methyl-butoxy)-pyrimidin-2-yl]-phenyl}-pip-
eridin-4-yl)-acetic acid ethyl ester (0.079 g, 0.18 mmol) obtained
in Step A was reacted in the same manner as in Step B of Example 1
to obtain the title compound (0.067 g, 90%).
[4018] .sup.1H-NMR (500 HMz, CDCl.sub.3); .delta. 8.44-.43 (d, 1H),
7.90-7.86 (m, 2H), 6.57-6.56 (d, 1H), 4.50-4.48 (t, 2H), 3.39-3.36
(m, 2H), 3.18-3.14 (m, 2H), 2.37-2.35 (d, 2H), 2.0-1.96 (m, 1H),
1.84-1.78 (m, 3H), 1.72-1.68 (m, 2H), 1.52-1.45 (m, 2H), 0.99-0.98
(d, 6H)
Example 600:
(1-{2,6-difluoro-4-[4-(3-methoxy-propoxy)-pyrimidin-2-yl]-phenyl}-piperid-
in-4-yl)-acetic Acid
##STR00643##
[4019] Step A:
(1-{2,6-difluoro-4-[4-(3-methoxy-propoxy)-pyrimidin-2-yl]-phenyl}-piperid-
in-4-yl)-acetic Acid Ethyl Ester
[4020]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid ethyl ester (0.16 g, 0.40 mmol)
obtained in Preparation Example 220 and
2-chloro-4-(3-methoxy-propoxy)-pyrimidine (0.12 g, 0.60 mmol)
obtained in Preparation Example 336 were reacted in the same manner
as in Step A of Example 1 to obtain the title compound (0.10 g,
56%).
[4021] .sup.1H-NMR (500 HMz, CDCl.sub.3); .delta. 8.44-8.43 (d,
1H), 7.90-7.88 (m, 2H), 6.58-6.57 (d, 1H), 4.56-4.54 (t, 2H),
4.17-4.13 (q, 2H), 3.56-3.54 (t, 2H), 3.36 (s, 3H), 3.35 (m, 2H),
3.17-3.13 (m, 2H), 2.30-2.28 (d, 2H), 2.11-2.17 (m, 2H), 1.97 (m,
1H), 1.79-1.76 (m, 2H), 1.48-1.42 (m, 2H), 1.28-1.25 (t, 3H)
Step B:
(1-{2,6-difluoro-4-[4-(3-methoxy-propoxy)-pyrimidin-2-yl]-phenyl}--
piperidin-4-yl)-acetic Acid
[4022]
(1-{2,6-Difluoro-4-[4-(3-methoxy-propoxy)-pyrimidin-2-yl]-phenyl}-p-
iperidin-4-yl)-acetic acid ethyl ester (0.10 g, 0.23 mmol) obtained
in Step A was reacted in the same manner as in Step B of Example 1
to obtain the title compound (0.086 g, 90%).
[4023] .sup.1H-NMR (500 HMz, CDCl.sub.3); .delta. 8.45-8.44 (d,
1H), 7.91-7.86 (m, 2H), 6.59-6.58 (d, 1H), 4.57-4.54 (t, 2H),
3.57-3.54 (t, 2H), 3.38-3.34 (m, 5H), 3.18-3.14 (m, 2H), 2.37-2.35
(d, 2H), 2.12-2.07 (m, 2H), 1.99-1.97 (m, 1H), 1.84-1.81 (m, 2H)
1.52-1.44 (m, 2H)
Example 601:
(1-{2,6-difluoro-4-[4-(3-methoxy-propoxy)-6-methyl-pyrimidin-2-yl]-phenyl-
}-piperidin-4-yl)-acetic Acid
##STR00644##
[4024] Step A:
(1-{2,6-difluoro-4-[4-(3-methoxy-propoxy)-6-methyl-pyrimidin-2-yl]-phenyl-
}-piperidin-4-yl)-acetic acid ethyl ester
[4025]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid ethyl ester (0.16 g, 0.40 mmol)
obtained in Preparation Example 220 and
2-chloro-4-(3-methoxy-propoxy)-6-methyl-pyrimidine (0.17 g, 0.80
mmol) obtained in Preparation Example 248 were reacted in the same
manner as in Step A of Example 1 to obtain the title compound (0.15
g, 82%).
[4026] .sup.1H-NMR (500 HMz, CDCl.sub.3); .delta. 7.92-7.87 (m,
2H), 6.42 (s, 1H), 4.53-4.51 (t, 2H), 4.17-4.13 (q, 2H), 3.55-3.53
(t, 2H), 3.36 (s, 3H), 3.34 (m, 2H), 3.17-3.12 (m, 2H), 2.45 (s,
3H), 2.30-2.28 (d, 2H), 2.10-2.05 (m, 2H), 1.97-1.95 (m, 1H),
1.78-1.76 (m, 2H), 1.49-1.41 (m, 2H), 1.28-1.24 (t, 3H)
Step B:
(1-{2,6-difluoro-4-[4-(3-methoxy-propoxy)-6-methyl-pyrimidin-2-yl]-
-phenyl}-piperidin-4-yl)-acetic Acid
[4027]
(1-{2,6-Difluoro-4-[4-(3-methoxy-propoxy)-6-methyl-pyrimidin-2-yl]--
phenyl}-piperidin-4-yl)-acetic acid ethyl ester (0.15 g, 0.33 mmol)
obtained in Step A was reacted in the same manner as in Step B of
Example 1 to obtain the title compound (0.13 g, 90%).
[4028] .sup.1H-NMR (500 HMz, CDCl.sub.3); .delta. 7.92-7.87 (m,
2H), 6.43 (s, 1H), 4.54-4.51 (t, 2H), 3.56-3.53 (t, 2H), 3.36 (s,
3H), 3.34-3.33 (m, 2H), 3.18-3.13 (m, 2H), 2.46 (s, 3H), 2.36-2.35
(d, 2H), 2.09-2.05 (m, 2H), 1.99-1.96 (m, 1H), 1.83-1.81 (m, 2H),
1.52-1.46 (m, 2H)
Example 602:
(1-{2,6-difluoro-4-[4-(2-methoxy-ethoxy)-6-methyl-pyrimidin-2-yl]-phenyl}-
-piperidin-4-yl)-acetic Acid
##STR00645##
[4029] Step A:
(1-{2,6-difluoro-4-[4-(2-methoxy-ethoxy)-6-methyl-pyrimidin-2-yl]-phenyl}-
-piperidin-4-yl)-acetic Acid Ethyl Ester
[4030]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid ethyl ester (0.16 g, 0.40 mmol)
obtained in Preparation Example 220 and
2-chloro-4-(2-methoxyethoxy)-6-methyl-pyrimidine (0.16 g, 0.80
mmol) obtained in Preparation Example 247 were reacted in the same
manner as in Step A of Example 1 to obtain the title compound (0.15
g, 82%).
[4031] .sup.1H-NMR (500 HMz, CDCl.sub.3); .delta. 7.89-7.86 (m,
2H), 6.50 (s, 1H), 4.62-4.60 (t, 2H), 4.17-4.13 (q, 2H), 3.78-3.76
(t, 2H), 3.44 (s, 3H), 3.36-3.33 (m, 2H), 3.17-3.12 (m, 2H), 2.46
(s, 3H), 2.30-2.28 (d, 2H), 1.97-1.95 (m, 1H), 1.79-1.76 (m, 2H),
1.51-1.42 (m, 2H), 1.28-1.25 (t, 3H)
Step B:
(1-{2,6-difluoro-4-[4-(2-methoxy-ethoxy)-6-methyl-pyrimidin-2-yl]--
phenyl}-piperidin-4-yl)-acetic Acid
[4032]
(1-{2,6-Difluoro-4-[4-(2-methoxy-ethoxy)-6-methyl-pyrimidin-2-yl]-p-
henyl}-piperidin-4-yl)-acetic acid ethyl ester (0.15 g, 0.33 mmol)
obtained in Step A was reacted in the same manner as in Step B of
Example 1 to obtain the title compound (0.13 g, 90%).
[4033] .sup.1H-NMR (500 HMz, CDCl.sub.3); .delta. 7.91-7.86 (m,
2H), 6.50 (s, 1H), 4.62-4.60 (t, 2H), 3.78-3.76 (t, 2H), 3.44 (s,
3H), 3.37-3.34 (m, 2H), 3.18-3.13 (m, 2H), 2.46 (s, 3H), 2.36-2.35
(d, 2H), 1.99-1.95 (m, 1H), 1.83-1.81 (m, 2H), 1.52-1.46 (m,
2H)
Example 603:
(1-{2,6-difluoro-4-[6-(3-methoxy-propoxy)-pyridin-2-yl]-phenyl}-piperidin-
-4-yl)-acetic Acid
##STR00646##
[4034] Step A:
(1-{2,6-difluoro-4-[6-(3-methoxy-propoxy)-pyridin-2-yl]-phenyl}-piperidin-
-4-yl)-acetic Acid Ethyl Ester
[4035]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid ethyl ester (0.16 g, 0.40 mmol)
obtained in Preparation Example 220 and
2-chloro-6-(3-methoxy-propoxy)-pyridine (0.16 g, 0.80 mmol)
obtained in Preparation Example 332 were reacted in the same manner
as in Step A of Example 1 to obtain the title compound (0.14 g,
76%).
[4036] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.61-7.58 (t,
1H), 7.54-7.49 (m, 2H), 7.21-7.19 (d, 1H), 6.66-6.64 (d, 1H),
4.49-4.47 (t, 2H), 4.17-4.13 (q, 2H), 3.58-3.55 (t, 2H), 3.37 (s,
3H), 3.34-3.30 (m, 2H), 3.17-3.12 (m, 2H), 2.30-2.28 (d, 2H),
2.11-2.06 (m, 2H), 1.97-1.94 (m, 1H), 1.79-1.76 (m, 2H), 1.51-1.43
(m, 2H), 1.28-1.26 (t, 3H)
Step B:
(1-{2,6-difluoro-4-[6-(3-methoxy-propoxy)-pyridin-2-yl]-phenyl}-pi-
peridin-4-yl)-acetic Acid
[4037]
(1-{2,6-Difluoro-4-[6-(3-methoxy-propoxy)-pyridin-2-yl]-phenyl}-pip-
eridin-4-yl)-acetic acid ethyl ester (0.14 g, 0.31 mmol) obtained
in Step A was reacted in the same manner as in Step B of Example 1
to obtain the title compound (0.12 g, 90%).
[4038] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.61-7.58 (t,
1H), 7.54-7.50 (m, 2H), 7.21-7.19 (d, 1H), 6.66-6.65 (d, 1H),
4.49-4.47 (t, 2H), 3.58-3.56 (t, 2H), 3.37 (s, 3H), 3.33-3.31 (m,
2H), 3.18-3.13 (m, 2H), 2.37-2.35 (d, 2H), 2.11-2.06 (m, 2H),
1.98-1.95 (m, 1H), 1.83-1.81 (m, 2H), 1.53-1.46 (m, 2H)
Example 604:
{(S)-1-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrol-
idin-3-yl}-acetic Acid
##STR00647##
[4039] Step A:
{(S)-1-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-pyrrol-
idin-3-yl}-acetic Acid Methyl Ester
[4040]
2-[(3S)-1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)phenyl]pyrrolidin-3-yl]acetic acid methyl ester (0.02 g, 0.53
mmol) obtained in Preparation Example 97 and
2-chloro-6-cyclopropylmethoxy-pyridine (0.19 g, 1.05 mmol) obtained
in Preparation Example 43 were reacted in the same manner as in
Step A of Example 1 to obtain the title compound (0.15 g, 70%).
[4041] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.60-7.56 (t,
1H), 7.53-7.45 (m, 2H), 7.18-7.16 (d, 1H), 6.67-6.65 (d, 1H),
4.24-4.22 (d, 2H), 3.76-3.61 (m, 6H), 3.39-3.35 (m, 1H), 2.69-2.64
(m, 1H), 2.51-2.46 (m, 2H), 2.18-2.14 (m, 1H), 1.68-1.63 (m, 1H),
1.36-1.30 (m, 1H), 0.66-0.61 (m, 2H), 0.41-0.37 (m, 2H)
Step B:
{(S)-1-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-
-pyrrolidin-3-yl}-acetic Acid
[4042]
{(S)-1-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]--
pyrrolidin-3-yl}-acetic acid methyl ester (0.15 g, 0.37 mmol)
obtained in Step A was reacted in the same manner as in Step B of
Example 1 to obtain the title compound (0.14 g, 97%).
[4043] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.60-7.56 (t,
1H), 7.52-7.44 (m, 2H), 7.18-7.16 (d, 1H), 6.67-6.64 (d, 1H),
4.24-4.22 (d, 2H), 3.77-3.61 (m, 3H), 3.40-3.36 (m, 1H), 2.70-2.63
(m, 1H), 2.56-2.50 (m, 2H), 2.23-2.17 (m, 1H), 1.71-1.62 (m, 1H),
1.35-1.30 (m, 1H), 0.66-0.61 (m, 2H), 0.41-0.37 (m, 2H)
Example 605:
2-[1-[2,6-difluoro-4-[4-[(6-methyl-3-pyridyl)oxy]pyrimidin-2-yl]phenyl]-4-
-piperidyl]acetic Acid
##STR00648##
[4045] 2-Chloro-4-(6-methyl-pyridin-3-yloxy)-pyrimidine (0.131 g,
0.59 mmol) obtained in Preparation Example 340 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.2 g, 0.49 mmol) obtained in
Preparation Example 220 were reacted in the same manner as in Step
A of Example 96 and Step B of Example 1 to obtain the title
compound (0.037 g, 17%).
[4046] .sup.1H-NMR (CDCl.sub.3) .delta. 8.63 (1H, d), 8.56 (1H, d),
7.70 (2H, m), 7.50 (1H, dd), 7.27 (1H, d), 6.81 (1H, d), 3.34 (2H,
m), 3.12 (2H, m), 2.64 (3H, s), 2.34 (2H, d), 1.97 (1H, m), 1.81
(2H, m), 1.43 (2H, m)
Example 606:
2-[1-[2,6-difluoro-4-[6-(4-ethylphenoxy)pyrimidin-2-yl]phenyl]-4-piperidy-
l]acetic Acid
##STR00649##
[4048] 2-Chloro-4-(4-ethyl-phenoxy)-pyrimidine (0.138 g, 0.59 mmol)
obtained in Preparation Example 341 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.2 g, 0.49 mmol) obtained in
Preparation Example 220 were reacted in the same manner as in Step
A of Example 96 and Step B of Example 1 to obtain the title
compound (0.097 g, 43%).
[4049] .sup.1H-NMR (CDCl.sub.3) .delta. 8.56 (1H, d), 7.75 (2H, m),
7.27 (2H, m), 7.11 (2H, m), 6.66 (1H, d), 3.35 (2H, m), 3.14 (2H,
m), 2.71 (2H, q), 2.35 (2H, d), 1.97 (1H, m), 1.82 (2H, m), 1.45
(2H, m), 1.29 (3H, t)
Example 607:
2-[1-[4-[4-(3-fluorophenoxy)pyrimidin-2-yl]-2,6-difluoro-phenyl]-4-piperi-
dyl]acetic Acid
##STR00650##
[4051] 2-Chloro-4-(3-fluoro-phenoxy)-pyrimidine (0.133 g, 0.59
mmol) obtained in Preparation Example 342 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.2 g, 0.49 mmol) obtained in
Preparation Example 220 were reacted in the same manner as in Step
A of Example 96 and Step B of Example 1 to obtain the title
compound (0.091 g, 41%).
[4052] .sup.1H-NMR (CDCl.sub.3) .delta. 8.62 (1H, d), 7.72 (2H, m),
7.41 (1H, m), 7.05-6.95 (3H, m), 6.74 (1H, d), 3.36 (2H, m), 3.13
(2H, m), 2.35 (2H, d), 1.97 (1H, m), 1.80 (2H, m), 1.45 (2H, m)
Example 608:
2-[1-[2,6-difluoro-4-[4-(3,4-fluorophenoxy)-6-methyl-pyrimidin-2-yl]pheny-
l]-4-piperidyl]acetic Acid
##STR00651##
[4054] 2-Chloro-4-(3,4-difluoro-phenoxy)-6-methyl-pyrimidine (0.151
g, 0.59 mmol) obtained in Preparation Example 343 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.2 g, 0.49 mmol) obtained in
Preparation Example 220 were reacted in the same manner as in Step
A of Example 96 and Step B of Example 1 to obtain the title
compound (0.133 g, 57%).
[4055] .sup.1H-NMR (CDCl.sub.3) .delta. 7.72 (2H, m), 7.23 (1H, m),
7.05 (1H, m), 6.94 (1H, m), 6.57 (1H, s), 3.34 (2H, m), 3.13 (2H,
m), 2.53 (3H, s), 2.34 (2H, d), 1.97 (1H, m), 1.80 (2H, m), 1.47
(2H, m)
Example 609:
2-[1-[2,6-difluoro-4-[4-(2-pyridyloxy)pyrimidin-2-yl]phenyl]-4-piperidyl]-
acetic Acid
##STR00652##
[4057] 2-Chloro-4-(pyridin-2-yloxy)-pyrimidine (0.10 g, 0.48 mmol)
obtained in Preparation Example 344 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.164 g, 0.40 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.037 g, 21%).
[4058] .sup.1H-NMR (CDCl.sub.3) .delta. 8.56 (1H, d), 8.41 (1H, m),
7.87 (1H, m), 7.72 (2H, m), 7.27 (1H, m), 7.19 (1H, d), 6.90 (1H,
d), 3.35 (2H, m), 3.12 (2H, m), 2.34 (2H, d), 1.95 (1H, m), 1.80
(2H, m), 1.43 (2H, m)
Example 610:
2-[1-[2,6-difluoro-4-[4-[4-(trifluoromethyl)phenoxy]pyrimidin-2-yl]phenyl-
]-4-piperidyl]acetic Acid
##STR00653##
[4060] 2-Chloro-4-[4-(trifluoromethyl)phenoxy]pyrimidine (0.088 g,
0.32 mmol) obtained in Preparation Example 345 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.144 g, 0.35 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.12 g, 76%).
[4061] .sup.1H-NMR (CDCl.sub.3) .delta. 8.54 (1H, d), 7.70 (4H, m),
7.35 (2H, d), 6.80 (1H, d), 3.36 (2H, m), 3.13 (2H, m), 2.34 (2H,
d), 1.97 (1H, m), 1.81 (2H, m), 1.47 (2H, m)
Example 611:
2-[1-[2,6-difluoro-4-[4-[3-(trifluoromethyl)phenoxy]pyrimidin-2-yl]phenyl-
]-4-piperidyl]acetic Acid
##STR00654##
[4063] 2-Chloro-4-[3-(trifluoromethyl)phenoxy]pyrimidine (0.092 g,
0.33 mmol) obtained in Preparation Example 346 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.15 g, 0.37 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.07 g, 51%).
[4064] .sup.1H-NMR (CDCl.sub.3) .delta. 8.64 (1H, d), 7.68 (2H, m),
7.58 (3H, m), 7.43 (1H, m), 6.80 (1H, d), 3.36 (2H, m), 3.13 (2H,
m), 2.34 (2H, d), 1.97 (1H, m), 1.80 (2H, m), 1.45 (2H, m)
Example 612:
2-[1-[2,6-difluoro-4-[4-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-2--
yl]phenyl]-4-piperidyl]acetic Acid
##STR00655##
[4066] 2-Chloro-4-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine
(0.088 g, 0.3 mmol) obtained in Preparation Example 347 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.135 g, 0.33 mmol) obtained
in Preparation Example 220 were reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.118 g, 77%).
[4067] .sup.1H-NMR (CDCl.sub.3) .delta. 7.72 (4H, m), 7.32 (2H, d),
6.61 (1H, s), 3.35 (2H, m), 3.13 (2H, m), 2.55 (3H, s), 2.35 (2H,
d), 1.97 (1H, m), 1.80 (2H, m), 1.46 (2H, m)
Example 613:
2-[1-[2,6-difluoro-4-[4-methyl-6-[3-(trifluoromethyl)phenoxy]pyrimidin-2--
yl]phenyl]-4-piperidyl]acetic Acid
##STR00656##
[4069] 2-Chloro-4-methyl-6-[3-(trifluoromethyl)phenoxy]pyrimidine
(0.087 g, 0.3 mmol) obtained in Preparation Example 348 and
2-[1-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
-4-piperidyl]acetic acid ethyl ester (0.135 g, 0.33 mmol) obtained
in Preparation Example 220 was reacted in the same manner as in
Step A of Example 96 and Step B of Example 1 to obtain the title
compound (0.124 g, 81%).
[4070] .sup.1H-NMR (CDCl.sub.3) .delta. 7.71 (2H, m), 7.56 (3H, m),
7.39 (1H, m), 6.62 (1H, s), 3.35 (2H, m), 3.13 (2H, m), 2.55 (3H,
s), 2.35 (2H, d), 1.97 (1H, m), 1.80 (2H, m), 1.46 (2H, m)
Example 614:
{1-[4-(6-cyclobutoxy-4-trifluoromethyl-pyridin-2-yl)-2,6-difluoro-phenyl]-
-piperidin-4-yl}-acetic Acid
##STR00657##
[4071] Step A:
{1-[4-(6-cyclobutoxy-4-trifluoromethyl-pyridin-2-yl)-2,6-difluoro-phenyl]-
-piperidin-4-yl}-acetic Acid Ethyl Ester
[4072]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid ethyl ester (0.16 g, 0.40 mmol)
obtained in Preparation Example 220 and
2-chloro-4-cyclobutoxy-6-trifluoromethyl-pyrimidine (0.15 g, 0.60
mmol) obtained in Preparation Example 349 were reacted in the same
manner as in Step A of Example 1 to obtain the title compound (0.09
g, 45%).
[4073] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.54-7.47 (m,
2H), 7.35 (s, 1H), 6.84 (s, 1H), 5.33-5.26 (m, 1H), 4.18-4.11 (q,
2H), 3.36-3.33 (m, 2H), 3.19-3.13 (m, 2H), 2.57-2.50 (m, 2H),
2.33-2.30 (d, 2H), 2.22-2.19 (m, 2H), 2.05-1.88 (m, 2H), 1.80-1.75
(m, 3H), 1.51-1.42 (m, 2H), 1.30-1.26 (t, 3H)
Step B:
{1-[4-(6-cyclobutoxy-4-trifluoromethyl-pyridin-2-yl)-2,6-difluoro--
phenyl]-piperidin-4-yl}-acetic Acid
[4074]
{1-[4-(6-Cyclobutoxy-4-trifluoromethyl-pyridin-2-yl)-2,6-difluoro-p-
henyl]-piperidin-4-yl}-acetic acid ethyl ester (0.09 g, 0.18 mmol)
obtained in Step A was reacted in the same manner as in Step B of
Example 1 to obtain the title compound (0.076 g, 89%).
[4075] .sup.1H-NMR (400 HMz, CDCl.sub.3); .delta. 7.52-7.43 (m,
2H), 7.35 (s, 1H), 6.84 (s, 1H), 5.33-5.25 (m, 1H), 3.37-3.34 (m,
2H), 3.19-3.14 (m, 2H), 2.56-2.50 (m, 2H), 2.38-2.36 (d, 2H),
2.22-2.17 (m, 2H), 1.99 (m, 1H), 1.94-1.73 (m, 4H), 1.53-1.43 (m,
2H)
Example 615:
(1-{2,6-difluoro-4-[2-(4-fluoro-phenyl)-benzo[b]thiophen-4-yl]-phenyl}-pi-
peridin-4-yl)-acetic Acid
##STR00658##
[4077]
[1-(4-Benzo[b]thiophen-4-yl-2,6-difluoro-phenyl)-piperidin-4-yl]-ac-
etic acid ethyl ester (0.11 g, 0.26 mmol) obtained in Preparation
Example 351 was dissolved in 2 mL of DMF 1-Bromo-4-fluoro-benzene
(0.03 g, 0.17 mmol), Pd(OAc).sub.2 (0.5 mol %) and KOAc (0.034 g,
0.34 mmol) were added thereto, and the mixture was stirred at
140.degree. C. for 24 hours. Solids were filtered, and the reaction
solution was concentrated under reduced pressure and purified by
column chromatography to obtain
(1-{2,6-difluoro-4-[2-(4-fluoro-phenyl)-benzo[b]thiophen-4-yl]-phenyl-pip-
eridin-4-yl)-acetic acid ethyl ester. The obtained compound was
reacted in the same manner as in Step B of Example 1 to obtain the
title compound (0.008 g, 9%).
[4078] .sup.1H-NMR (CDCl.sub.3) .delta. 7.82 (1H, d), 7.65 (2H, m),
7.55 (1H, s), 7.35 (1H, t), 7.27 (1H, m), 7.08 (4H, m), 3.36 (2H,
m), 3.21 (2H, m), 2.37 (2H, d), 1.99 (1H, m), 1.84 (2H, m), 1.52
(2H, m).
Example 616:
{1-[2,6-difluoro-4-(2-m-tolyl-benzo[b]thiophen-4-yl)-phenyl]-piperidin-4--
yl}-acetic Acid
##STR00659##
[4080]
[1-(4-Benzo[b]thiophen-4-yl-2,6-difluoro-phenyl)-piperidin-4-yl]-ac-
etic acid ethyl ester (0.07 g, 0.17 mmol) obtained in Preparation
Example 351, 1-bromo-3-methyl-benzene (0.029 g, 0.17 mmol),
Pd(OAc).sub.2 (0.5 mol %) and KOAc (0.034 g, 0.34 mmol) were
reacted in the same manner as in Example 615 to obtain the title
compound (0.004 g, 5%).
[4081] .sup.1H-NMR (CDCl.sub.3) .delta. 7.81 (1H, d), 7.61 (1H, s),
7.48 (2H, m), 7.29 (3H, m), 7.14 (1H, d), 7.08 (2H, m), 3.36 (2H,
m), 3.20 (2H, m), 2.41 (3H, s), 2.39 (2H, d), 2.00 (1H, m), 1.84
(2H, m), 1.53 (2H, m).
Example 617:
{1-[4-(4-cyclobutoxy-6-trifluoromethyl-pyrimidin-2-yl)-2,6-difluoro-pheny-
l]-piperidin-4-yl}-acetic Acid
##STR00660##
[4083]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid ethyl ester (0.1 g, 0.24 mmol)
obtained in Preparation Example 220 and
2-chloro-4-cyclobutoxy-6-trifluoromethyl-pyrimidine (0.074 g, 0.29
mmol) obtained in Preparation Example 352 were reacted in the same
manner as in Step A of Example 1 to obtain
1-[4-(4-cyclobutoxy-6-trifluoromethyl-pyrimidin-2-yl)-2,6-difluoro-phenyl-
]-piperidin-4-yl}-acetic acid ethyl ester. The obtained compound
was dissolved in 2 ml of 1,4-dioxane. 0.45 ml of 1N NaOH was added
thereto, and the mixture was stirred at 60.degree. C. for 4 hours.
The organic solvent was removed, and the reaction product was
adjusted to pH 3 by the use of 1N HCl aqueous solution and
extracted with EtOAc to separate an organic layer. The organic
layer was dried with anhydrous magnesium sulfate and concentrated
under reduced pressure to obtain the title compound (0.072 g,
62%).
[4084] .sup.1H-NMR (CDCl.sub.3) .delta. 7.90 (2H, m), 6.84 (1H, s),
5.38 (1H, m), 3.40 (2H, m), 3.16 (2H, m), 2.53 (2H, m), 2.37 (2H,
d), 2.21 (2H, m), 2.04 (1H, m), 1.89 (1H, m), 1.81 (3H, m), 1.47
(2H, m).
Example 618:
{1-[2,6-difluoro-4-(4-propoxy-6-trifluoromethyl-pyrimidin-2-yl)-phenyl]-p-
iperidin-4-yl}-acetic Acid
##STR00661##
[4086]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid ethyl ester (0.1 g, 0.24 mmol)
obtained in Preparation Example 220 and
2-chloro-4-propoxy-6-trifluoromethyl-pyrimidine (0.07 g, 0.29 mmol)
obtained in Preparation Example 353 were reacted in the same manner
as in Example 617 to obtain the title compound (0.064 g, 57%).
[4087] .sup.1H-NMR (CDCl.sub.3) .delta. 7.90 (2H, m), 6.88 (1H, s),
4.47 (2H, t), 3.40 (2H, m), 3.16 (2H, m), 2.37 (2H, d), 2.04 (1H,
m), 1.85 (4H, m), 1.47 (2H, m), 1.06 (3H, t).
Example 619:
(1-{2,6-difluoro-4-[4-(4-fluoro-phenoxy)-6-trifluoromethyl-pyrimidin-2-yl-
]-phenyl}-piperidin-4-yl)-acetic Acid
##STR00662##
[4089]
2-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]acetic acid ethyl ester (0.1 g, 0.24 mmol)
obtained in Preparation Example 220 and
2-chloro-4-(4-fluoro-phenoxy)-6-trifluoromethyl-pyrimidine (0.086
g, 0.29 mmol) obtained in Preparation Example 354 were reacted in
the same manner as in Example 617 to obtain the title compound
(0.039 g, 31%).
[4090] .sup.1H-NMR (CDCl.sub.3) .delta. 7.71 (2H, m), 7.17 (4H, d),
7.04 (1H, s), 3.38 (2H, m), 3.13 (2H, m), 2.35 (2H, d), 1.96 (1H,
m), 1.79 (2H, m), 1.45 (2H, m).
Example 620:
3-{1-[2,6-difluoro-4-(6-propoxy-pyridin-2-yl)-phenyl]-piperidin-4-yl}-pro-
pionic Acid
##STR00663##
[4092]
3-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]propanoic acid ethyl ester (0.059 g, 0.14 mmol)
obtained in Preparation Example 92 and 2-bromo-6-propoxy-pyridine
(0.030 g, 0.14 mmol) obtained in Preparation Example 45 were
reacted in the same manner as in Example 96 to obtain the title
compound (0.025 g, 45%).
[4093] .sup.1H-NMR (CDCl.sub.3) .delta. 7.59 (1H, t), 7.51 (2H, m),
7.20 (1H, d), 6.66 (1H, d), 4.36 (2H, t), 3.32 (2H, d), 3.12 (2H,
t), 2.44 (2H, t), 1.84 (2H, m), 1.76 (2H, d), 1.67 (2H, m), 1.43
(3H, m), 1.06 (3H, t)
Example 621:
3-{1-[4-(6-cyclobutyl-pyridin-2-yl)-2,6-difluoro-phenyl]-piperidin-4-yl}--
propionic Acid
##STR00664##
[4095]
3-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]propanoic acid ethyl ester (0.076 g, 0.18 mmol)
obtained in Preparation Example 92 and
2-chloro-6-cyclobutyl-pyridine (0.030 g, 0.18 mmol) obtained in
Preparation Example 277 were reacted in the same manner as in
Example 96 to obtain the title compound (0.025 g, 35%).
[4096] .sup.1H-NMR (CDCl.sub.3) .delta. 7.63 (1H, t), 7.56 (2H, m),
7.42 (1H, d), 7.08 (1H, d), 3.71 (1H, m), 3.32 (2H, d), 3.12 (2H,
t), 2.43 (6H, m), 2.07 (1H, m), 1.94 (1H, m), 1.76-1.40 (7H, m)
Example 622:
3-{1-[4-(6-ethoxy-pyridin-2-yl)-2,6-difluoro-phenyl]-piperidin-4-yl}-prop-
ionic Acid
##STR00665##
[4098]
3-[1-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl]-4-piperidyl]propanoic acid ethyl ester (0.081 g, 0.19 mmol)
obtained in Preparation Example 92 and 2-chloro-6-ethoxy-pyridine
(0.030 g, 0.19 mmol) obtained in Preparation Example 273 were
reacted in the same manner as in Example 96 to obtain the title
compound (0.030 g, 40%).
[4099] .sup.1H-NMR (CDCl.sub.3) .delta. 7.59 (1H, t), 7.51 (2H, m),
7.20 (1H, d), 6.65 (1H, d), 4.46 (2H, m), 3.32 (2H, d), 3.12 (2H,
t), 2.44 (2H, t), 1.76 (2H, d), 1.67 (2H, m), 1.44 (6H, m)
Experimental Example: Measurement of Activity of GPR120 Agonist
(Cell-Based Assay)
[4100] CHO-K1 cells expressing Ga16 and hGPR120 were dispensed into
each well of a 96-well plate (3.times.10.sup.4 cells/100
.mu.l/well) and then incubated in 5% CO.sub.2, 37.degree. C.
incubator for 18 hours. Each well was treated with 100 .mu.l of
Calcium 5 dye (Molecular Devices) solution including 2% DMSO and
then incubated in 5% CO.sub.2, 37.degree. C. incubator for 1 hour.
Serially diluted GPR120 agonists were prepared to a final
concentration of 0.5% DMSO in a 96-well plate. Each well was
treated with 50 .mu.l of the agonist compounds using Plexstation
II, and then fluorescence was measured at Ex 485 nm and Em 525
nm.
[4101] Fluorescence increased by the serially diluted GPR120
agonists is calculated as a relative percent (%) value based on the
fluorescence represented by the treatment of 1% DMSO only.
EC.sub.50 refers to the concentration of agonist which shows 50% of
maximum fluorescence increased by the treatment of agonist. The
calculation of measurement was carried out by using statistical
software (Prizm).
[4102] The agonistic effects of the Example compounds obtained by
the above experiment are shown in the following Table 1 with
EC.sub.50 unit (.mu.M). Activity is denoted based on the following
criteria:
[4103] A=>20 .mu.M, B=20-2 .mu.M, C=2-0.2 .mu.M, D=<0.2
.mu.M
[4104] As shown in the table, most of the novel compounds according
to the present invention have superior GPR120 agonistic effects
(EC.sub.50), less than 0.2 .mu.M.
TABLE-US-00001 TABLE 1 Example EC.sub.50 Example EC.sub.50 Example
EC.sub.50 Example EC.sub.50 1 C 2 C 3 C 4 B 5 C 7 D 8 D 9 D 10 D 11
C 12 C 17 B 18 D 19 D 20 D 21 D 22 D 23 D 25 C 26 C 27 D 28 D 29 D
31 D 32 D 33 D 34 D 35 D 36 D 37 D 38 C 39 D 40 D 41 D 42 D 43 D 46
D 47 D 48 D 49 D 50 D 51 D 52 D 53 D 54 D 55 D 56 D 59 D 60 D 61 D
63 B 64 B 65 D 66 D 67 D 68 D 69 D 70 D 71 D 72 D 73 D 74 D 76 D 77
D 78 D 79 B 81 D 83 D 84 D 86 D 87 D 88 D 89 D 90 C 93 B 94 D 95 C
96 C 97 D 98 D 99 D 100 D 101 D 102 D 103 C 104 D 105 D 106 D 108 B
109 D 110 C 111 B 112 D 113 D 114 D 115 D 116 D 117 D 118 C 119 C
120 C 121 D 122 B 123 C 124 D 125 D 126 D 128 D 131 B 132 D 133 C
134 D 135 D 136 D 137 D 138 C 139 C 140 C 141 D 142 C 143 B 144 D
146 C 147 D 148 C 149 D 150 D 151 B 152 C 153 D 154 D 155 D 156 C
157 D 158 C 159 D 160 D 161 C 162 C 163 C 164 C 165 D 166 D 167 C
168 D 169 C 170 D 171 D 172 B 173 B 174 C 175 D 176 D 177 D 178 D
179 D 180 D 181 D 182 D 183 D 184 D 185 D 186 D 187 C 188 D 189 D
190 C 191 D 192 D 193 D 194 D 195 D 196 D 197 D 198 D 199 D 200 C
201 C 202 D 203 D 204 D 205 D 206 D 207 D 208 D 209 D 210 D 211 C
212 D 213 D 214 C 215 D 216 D 217 D 218 D 219 B 221 D 222 C 223 D
224 C 225 C 226 C 227 D 228 D 229 D 230 D 231 D 232 C 233 C 234 D
235 D 236 D 237 D 238 D 239 D 240 C 241 D 244 D 245 D 246 D 247 D
248 D 249 D 250 D 251 D 252 D 253 C 254 C 255 D 256 C 257 D 258 D
259 D 260 D 261 D 262 D 263 D 264 C 265 C 266 C 268 C 269 C 270 D
271 D 272 D 273 B 274 C 275 D 276 C 277 C 278 D 279 D 280 D 281 D
282 C 283 C 284 C 285 B 286 D 287 D 288 D 289 C 290 D 291 D 292 B
293 C 294 D 295 D 296 D 297 C 298 C 299 C 300 C 301 C 302 C 303 C
304 C 305 C 306 C 307 C 308 C 309 C 310 B 311 C 312 C 313 A 314 C
315 C 316 C 317 C 318 B 319 C 320 C 321 D 322 D 323 C 324 C 325 C
326 C 327 C 328 C 329 D 330 D 331 C 332 D 333 D 334 D 335 D 336 D
337 D 338 D 339 D 340 C 341 D 342 D 343 D 344 D 345 D 346 D 347 D
348 D 349 D 350 C 351 D 352 C 353 B 354 C 355 B 356 C 357 C 358 C
360 C 361 C 363 D 364 C 365 C 366 C 367 C 368 C 369 D 370 C 371 D
372 D 373 C 374 D 375 C 376 C 377 D 379 D 380 C 382 A 384 B 385 D
386 D 387 D 388 C 389 D 390 A 391 D 392 D 393 D 394 D 395 D 396 D
397 D 398 D 399 D 400 D 401 D 402 D 403 D 404 D 405 D 406 D 407 D
408 D 409 D 410 D 411 D 412 D 413 D 414 D 415 D 416 C 417 D 418 D
419 D 420 D 421 D 422 D 423 D 424 D 425 D 426 D 427 D 428 D 429 D
430 D 431 D 432 D 433 D 434 D 435 D 436 D 437 D 438 D 439 C 440 C
441 D 442 C 443 C 444 D 445 D 446 C 447 D 448 D 449 D 450 D 451 D
452 D 453 C 454 D 455 D 456 D 457 C 458 C 459 D 460 C 461 C 462 C
463 D 464 D 465 D 466 D 467 C 468 D 469 B 470 C 471 D 472 D 473 C
474 D 475 D 476 D 477 C 478 C 479 D 480 B 481 B 482 D 483 D 484 D
485 D 486 D 487 C 488 D 489 D 490 D 491 D 492 D 493 D 494 C 495 D
496 C 497 C 498 D 499 D 500 D 501 D 502 C 503 C 504 C 505 C 506 C
507 C 508 D 509 C 510 D 511 D 512 C 513 D 514 C 515 C 516 D 517 D
518 D 519 C 520 C 521 D 522 D 523 D 524 D 525 D 526 D 527 D 528 D
529 C 530 D 531 C 532 D 533 C 534 C 535 D 536 D 537 D 538 D 539 C
540 D 541 D 542 D 543 D 544 D 545 C 546 C 547 C 548 D 549 D 550 D
551 C 552 C 553 C 554 D 555 D 556 D 557 B 558 D 559 D 560 D 561 D
562 B 563 D 564 C 565 D 566 D 567 C 568 B 569 B 570 C 571 D 572 D
573 D 574 D 575 C 576 D 577 C 578 D 579 D 580 D 581 D 582 C 583 C
584 C 585 D 586 D 587 C 588 C 589 D 590 D 591 D 592 C 593 C 594 C
595 C 596 C 597 C 598 D 599 C 600 C 601 C 602 C 603 C 604 D 605 C
606 C 607 D 608 C 609 C 610 C 611 C 612 B 613 B 614 B 615 B 616 C
617 A 618 B 619 B 620 C 621 C 622 C
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