U.S. patent application number 14/093583 was filed with the patent office on 2014-06-12 for indanyloxydihydrobenzofuranylacetic acids.
This patent application is currently assigned to BOEHRINGER INGELHEIM INTERNATIONAL GMBH. The applicant listed for this patent is Matthias ECKHARDT, Sara FRATTINI, Elke LANGKOPF, Holger WAGNER. Invention is credited to Matthias ECKHARDT, Sara FRATTINI, Elke LANGKOPF, Holger WAGNER.
Application Number | 20140163025 14/093583 |
Document ID | / |
Family ID | 47290800 |
Filed Date | 2014-06-12 |
United States Patent
Application |
20140163025 |
Kind Code |
A1 |
ECKHARDT; Matthias ; et
al. |
June 12, 2014 |
INDANYLOXYDIHYDROBENZOFURANYLACETIC ACIDS
Abstract
The present invention relates to compounds of general formula I,
##STR00001## wherein the groups (Het)Ar and R.sup.1 are defined as
in claim 1, which have valuable pharmacological properties, in
particular bind to the GPR40 receptor and modulate its activity.
The compounds are suitable for treatment and prevention of diseases
which can be influenced by this receptor, such as metabolic
diseases, in particular diabetes type 2.
Inventors: |
ECKHARDT; Matthias;
(Biberach an der Riss, DE) ; FRATTINI; Sara;
(Castelleone, IT) ; LANGKOPF; Elke; (Biberach an
der Riss, DE) ; WAGNER; Holger; (Mettenberg,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ECKHARDT; Matthias
FRATTINI; Sara
LANGKOPF; Elke
WAGNER; Holger |
Biberach an der Riss
Castelleone
Biberach an der Riss
Mettenberg |
|
DE
IT
DE
DE |
|
|
Assignee: |
BOEHRINGER INGELHEIM INTERNATIONAL
GMBH
Ingelheim am Rhein
DE
|
Family ID: |
47290800 |
Appl. No.: |
14/093583 |
Filed: |
December 2, 2013 |
Current U.S.
Class: |
514/233.5 ;
514/337; 514/382; 514/397; 514/406; 514/422; 514/469; 544/153;
546/284.1; 548/253; 548/311.4; 548/364.4; 548/525; 549/469 |
Current CPC
Class: |
A61K 31/09 20130101;
A61K 31/357 20130101; A61P 3/10 20180101; A61K 31/343 20130101;
A61K 31/416 20130101; A61K 31/34 20130101; A61P 43/00 20180101;
C07D 405/12 20130101; A61K 31/085 20130101; C07D 417/12 20130101;
A61K 31/36 20130101; A61K 31/506 20130101; A61P 9/04 20180101; A61K
31/351 20130101; A61K 31/404 20130101; A61K 31/443 20130101; A61K
31/41 20130101; A61P 9/00 20180101; A61K 31/4155 20130101; A61P
3/06 20180101; A61P 9/10 20180101; C07D 413/12 20130101; A61K 45/06
20130101; A61K 31/4196 20130101; A61K 31/497 20130101; A61K 31/192
20130101; A61K 31/422 20130101; C07D 307/80 20130101; C07D 407/12
20130101; A61K 31/4178 20130101; A61P 3/04 20180101; A61P 3/00
20180101; C07D 405/14 20130101; A61K 31/427 20130101; A61K 31/4245
20130101; A61K 31/4709 20130101; A61P 9/12 20180101; C07D 401/12
20130101; A61K 31/4025 20130101; A61K 31/5377 20130101 |
Class at
Publication: |
514/233.5 ;
549/469; 514/469; 544/153; 548/525; 514/422; 548/311.4; 514/397;
548/253; 514/382; 546/284.1; 514/337; 548/364.4; 514/406 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/343 20060101 A61K031/343; A61K 31/4025
20060101 A61K031/4025; C07D 405/12 20060101 C07D405/12; A61K 45/06
20060101 A61K045/06; A61K 31/41 20060101 A61K031/41; C07D 405/14
20060101 C07D405/14; A61K 31/443 20060101 A61K031/443; A61K 31/4155
20060101 A61K031/4155; C07D 307/80 20060101 C07D307/80; A61K
31/4178 20060101 A61K031/4178 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 7, 2012 |
EP |
12196011.6 |
Claims
1. A compound of formula (I) ##STR00214## wherein: (Het)Ar is
linked via a carbon atom and is selected from the group consisting
of: phenyl, naphthyl, and a mono- or bicyclic heteroaromatic group
having 5 to 10 ring member atoms of which 2 to 9 ring members are
carbon atoms and either (i) one ring member is an unsubstituted or
substituted heteroatom selected from N, NH, NR.sup.N, O, S,
S(.dbd.O), and S(.dbd.O).sub.2, (ii) one ring member is N and a
second ring member is selected from N, NH, NR.sup.N, O, S,
S(.dbd.O), and S(.dbd.O).sub.2, or (iii) two ring members are N and
a third ring member is selected from N, NH, NR.sup.N, O, S,
S(.dbd.O), and S(.dbd.O).sub.2, wherein in the naphthyl, the ring
not attached to the indanyl-O atom of formula (I) optionally is
partially saturated, and in the bicyclic heteroaromatic group, the
ring not attached to the indanyl-O atom of formula (I) optionally
is partially saturated, while the aromatic ring includes at least
one heteroatom, and optionally (i) one ring member in the partially
or fully saturated bridge is replaced by N, NH, NR.sup.N, O, S,
S(.dbd.O), or S(.dbd.O).sub.2, (ii) one ring member in the
partially or fully saturated bridge is replaced by N, NH, or
NR.sup.N and a second ring member is replaced by NH, NR.sup.N, O,
S, C(.dbd.O), S(.dbd.O), or S(.dbd.O).sub.2, or (iii) two not
vicinal ring members in a fully saturated bridge are replaced by O
atoms, wherein any of these groups is substituted with 1 group
R.sup.2 or 1 NH group is replaced by an NR.sup.2 group and any of
these groups is optionally and independently substituted with 1 to
4 R.sup.3 groups; or (Het)Ar is selected from the group consisting
of 2,3-dihydroindole, 2,3-dihydroisoindole, 2,3-dihydrobenzofuran,
1,3-dihydroisobenzofuran, benzo[1,3]dioxole,
1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline,
chroman, isochroman, and 2,3-dihydrobenzo[1,4]dioxine, wherein any
of these groups is linked via an aromatic carbon atom to the
indanyloxy group in formula (I), and wherein in each of these
bicyclic groups, 1 CH.sub.2 group is optionally replaced by
C(.dbd.O) and each of these bicyclic groups is optionally
substituted with 1 R.sup.2 group and optionally independently
substituted with 1 to 4 R.sup.3 groups; R.sup.1 is H, F, Cl,
F.sub.3C--, NC--, F.sub.3C--O--, or H.sub.3C--S(.dbd.O).sub.2--;
R.sup.2 is C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkinyl,
C.sub.3-6-cycloalkyl-, C.sub.1-4-alkyl-NH--,
(C.sub.1-4-alkyl).sub.2N--, C.sub.1-6-alkyl-O--,
C.sub.3-6-cycloalkyl-O--, C.sub.1-4-alkyl-S--,
C.sub.1-4-alkyl-S(.dbd.O)--, or C.sub.1-4-alkyl-S(.dbd.O).sub.2,
wherein each alkyl and cycloalkyl group is substituted with 1 to 3
groups independently selected from R.sup.4 and optionally
substituted with 1 or more F atoms; or R.sup.2 is
C.sub.1-4-alkyl-C(.dbd.O)--, heterocyclyl-C(.dbd.O)--,
HNR.sup.N--C(.dbd.O)--, C.sub.1-4-alkyl-NR.sup.N--C(.dbd.O)--,
C.sub.3-6-cycloalkyl-NR.sup.N--C(.dbd.O)--,
heterocyclyl-NR.sup.N--C(.dbd.O)--, phenyl-NR.sup.N--C(.dbd.O)--,
heteroaryl-NR.sup.N--C(.dbd.O)--, HO.sub.2C--,
C.sub.1-4-alkyl-O--C(.dbd.O)--,
C.sub.3-6-cycloalkyl-O--C(.dbd.O)--, heterocyclyl-O--C(.dbd.O)--,
--NHR.sup.N, C.sub.1-4-alkyl-C(.dbd.O)NR.sup.N--,
C.sub.3-6-cycloalkyl-C(.dbd.O)NR.sup.N--,
heterocyclyl-C(.dbd.O)NR.sup.N--, phenyl-C(.dbd.O)NR.sup.N--,
heteroaryl-C(.dbd.O)NR.sup.N--,
C.sub.1-4-alkyl-S(.dbd.O).sub.2NR.sup.N--,
C.sub.3-6-cycloalkyl-S(.dbd.O).sub.2NR.sup.N--,
heterocyclyl-S(.dbd.O).sub.2NR.sup.N--,
phenyl-S(.dbd.O).sub.2NR.sup.N--,
heteroaryl-S(.dbd.O).sub.2NR.sup.N--, heterocyclyl-O--, phenyl-O--,
heteroaryl-O--, C.sub.3-6-cycloalkyl-S--, heterocyclyl-S--,
phenyl-S--, heteroaryl-S--, C.sub.3-6-cycloalkyl-S(.dbd.O)--,
heterocyclyl-S(.dbd.O)--, phenyl-S(.dbd.O)--,
heteroaryl-S(.dbd.O)--, C.sub.3-6-cycloalkyl-S(.dbd.O).sub.2--,
heterocyclyl-S(.dbd.O).sub.2--, phenyl-S(.dbd.O).sub.2--,
heteroaryl-S(.dbd.O).sub.2--, HNR.sup.N--S(.dbd.O).sub.2--,
C.sub.1-4-alkyl-NR.sup.N--S(.dbd.O).sub.2--, heterocyclyl, phenyl,
or heteroaryl, wherein each alkyl, cycloalkyl, and heterocyclyl
group is optionally substituted with 1 to 3 groups independently
selected from R.sup.4 and optionally substituted with 1 or more F
atoms, each phenyl and heteroaryl group is optionally substituted
with 1 to substituents independently selected from R.sup.5,
heterocyclyl is (i) a C.sub.4-6-cycloalkyl group wherein 1 CH.sub.2
group is replaced by NR.sup.N, NR.sup.4, O, S, S(.dbd.O), or
S(.dbd.O).sub.2 and/or 1>CH-- group is replaced by N, or (ii) 1
CH.sub.2 group is replaced by NR.sup.N, NR.sup.4, O-- or S, and/or
1>CH-- group is replaced by N, and 1 additional CH.sub.2 group
is replaced by C(.dbd.O) or S(.dbd.O).sub.2, and heteroaryl is (i)
tetrazolyl, (ii) pyridinonyl, (iii) a 5-membered heteroaromatic
ring containing 1 ring member selected from NR.sup.N, NR.sup.5, N,
O, and S, or containing 1 N and 1 ring member selected from
NR.sup.N, NR.sup.5, N, O, and S, or containing 1 NR.sup.N,
NR.sup.5, N, O, or S and 2 N, or (iv) a 6-membered heteroaromatic
ring which contains 1 to 3 N atoms, with the proviso that R.sup.2
is not C.sub.1-4-alkyl-, C.sub.1-4-alkyl-O--C.sub.1-4-alkyl,
HO--C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkinyl,
NH.sub.2, C.sub.1-4-alkyl-NH--, (C.sub.1-4-alkyl).sub.2N--,
C.sub.1-4-alkyl-O--, C.sub.1-4-alkyl-S--,
C.sub.1-4-alkyl-S(.dbd.O)--, or C.sub.1-4-alkyl-S(.dbd.O).sub.2;
R.sup.3 is F, Cl, Br, I, CN, OH, C.sub.1-4-alkyl,
C.sub.3-6-cycloalkyl, HO--C.sub.1-4-alkyl,
C.sub.1-4-alkyl-O--C.sub.1-4-alkyl, --NR.sup.NH,
C.sub.1-4-alkyl-NR.sup.N--, C.sub.1-4-alkyl-O--,
C.sub.3-6-cycloalkyl-O--, C.sub.1-4-alkyl-O--C.sub.1-4-alkyl-O--,
C.sub.1-4-alkyl-S--, C.sub.1-4-alkyl-S(.dbd.O)--, or
C.sub.1-4-alkyl-S(.dbd.O).sub.2--, wherein any alkyl and cycloalkyl
group is optionally substituted with 1 or more F atoms; R.sup.4 is
Cl, Br, I, C.sub.1-4-alkyl, CN, C.sub.3-6-cycloalkyl,
C.sub.1-4-alkyl-C(.dbd.O)--, heterocyclyl-C(.dbd.O)--,
H.sub.2N--C(.dbd.O)--, C.sub.1-4-alkyl-NR.sup.N--C(.dbd.O)--,
C.sub.3-6-cycloalkyl-NR.sup.N--C(.dbd.O)--,
heterocyclyl-NR.sup.N--C(.dbd.O)--, phenyl-NR.sup.N--C(.dbd.O)--,
heteroaryl-NR.sup.N--C(.dbd.O)--, HO--C(.dbd.O)--,
C.sub.1-4-alkyl-O--C(.dbd.O)--, --NHR.sup.N,
C.sub.1-4-alkyl-NR.sup.N--, C.sub.1-4-alkyl-C(.dbd.O)NR.sup.N--,
C.sub.3-6-cycloalkyl-C(.dbd.O)NR.sup.N--,
heterocyclyl-C(.dbd.O)NR.sup.N--, phenyl-C(.dbd.O)NR.sup.N--,
heteroaryl-C(.dbd.O)NR.sup.N--,
C.sub.1-4-alkyl-S(.dbd.O).sub.2NR.sup.N--,
C.sub.3-6-cycloalkyl-S(.dbd.O).sub.2NR.sup.N--,
heterocyclyl-S(.dbd.O).sub.2NR.sup.N--,
phenyl-S(.dbd.O).sub.2NR.sup.N--,
heteroaryl-S(.dbd.O).sub.2NR.sup.N--, --OH, C.sub.1-4-alkyl-O--,
C.sub.1-4-alkyl-O--C.sub.1-4-alkyl-O--, C.sub.3-6-cycloalkyl-O--,
heterocyclyl-O--, phenyl-O--, heteroaryl-O--, C.sub.1-4-alkyl-S--,
C.sub.3-6-cycloalkyl-S--, heterocyclyl-S--, phenyl-S--,
heteroaryl-S--, C.sub.1-4-alkyl-S(.dbd.O)--,
C.sub.3-6-cycloalkyl-S(.dbd.O)--, heterocyclyl-S(.dbd.O)--,
phenyl-S(.dbd.O)--, heteroaryl-S(.dbd.O)--,
C.sub.1-4-alkyl-S(.dbd.O).sub.2--,
C.sub.3-6-cycloalkyl-S(.dbd.O).sub.2--,
heterocyclyl-S(.dbd.O).sub.2--, phenyl-S(.dbd.O).sub.2--,
heteroaryl-S(.dbd.O).sub.2--, H.sub.2N--S(.dbd.O).sub.2--,
C.sub.1-4-alkyl-NR.sup.N--S(.dbd.O).sub.2--, heterocyclyl, phenyl,
or heteroaryl, wherein any alkyl, cycloalkyl, and heterocyclyl
group is optionally substituted with 1 or more F atoms and
optionally substituted with 1 or 2 groups independently selected
from H.sub.3C--, HO--, H.sub.3C--O--, and --CN, heterocyclyl is a
C.sub.4-6-cycloalkyl group wherein 1 CH.sub.2 group is replaced by
NR.sup.N, O, S, S(.dbd.O), or S(.dbd.O).sub.2 and/or 1>CH--
group is replaced by N, or 1 CH.sub.2 group is replaced by
NR.sup.N, O, or S, and/or 1>CH-- group is replaced by N, and 1
additional CH.sub.2 group is replaced by C(.dbd.O) or
S(.dbd.O).sub.2, and heteroaryl is (i) tetrazolyl, (ii)
pyridinonyl, (iii) a 5-membered heteroaromatic ring containing 1
ring member selected from NR.sup.N, O, and S, or containing 1 N and
1 ring member selected from NR.sup.N, O, and S, or containing 1
NR.sup.N, O or S and 2 N, and (iv) a 6-membered heteroaromatic ring
which contains 1 to 3 N atoms, and each heteroaryl group is
optionally substituted with 1 to 3 substituents independently
selected from F, Cl, --CH.sub.3, --CN, and --O--CH.sub.3; R.sup.5
is F, Cl, Br, CN, C.sub.1-4-alkyl, cyclopropyl, F.sub.3C--,
HO--C.sub.1-4-alkyl-, C.sub.1-4-alkyl-O--C.sub.1-4-alkyl-,
C.sub.1-4-alkyl-O--, F.sub.3C--O--, --S(.dbd.O)--C.sub.1-4-alkyl,
or S(.dbd.O).sub.2--C.sub.1-4-alkyl; and R.sup.N is H,
C.sub.1-4-alkyl, C.sub.1-4-alkyl-C(.dbd.O)--,
C.sub.1-4-alkyl-NH--C(.dbd.O)--,
C.sub.1-4-alkyl-N(C.sub.1-4-alkyl)-C(.dbd.O)--,
C.sub.1-4-alkyl-O--C(.dbd.O)--, or
C.sub.1-4-alkyl-S(.dbd.O).sub.2--, wherein any alkyl group or
sub-group is straight-chained or branched, unless specified
otherwise, or a salt thereof.
2. The compound according to claim 1, wherein R.sup.1 is H, or a
salt thereof.
3. The compound according to claim 1, wherein (Het)Ar is phenyl,
pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl,
isoquinolinyl, quinazolinyl, indolinyl, benzoimidazolyl, indazolyl,
benzoxazolyl, or benzothiazolyl, each substituted with one group
R.sup.2 and optionally substituted with 1 to 3 groups independently
selected from R.sup.3, or (Het)Ar is 2,3-dihydrobenzofuran,
benzo[1,3]dioxole, 2,3-dihydro-benzo[1,4]dioxine, or
3,4-dihydro-1H-quinoline-2-one, each optionally substituted with 1
group R.sup.3, or a salt thereof.
4. The compound according to claim 1, wherein (Het)Ar is phenyl
substituted with one group R.sup.2 and optionally substituted with
1 to 3 groups independently selected from R.sup.3, or a salt
thereof.
5. The compound according to claim 1, wherein R.sup.3 is F,
--CH.sub.3, or CN, or a salt thereof.
6. The compound according to claim 1, wherein: R.sup.2 is
C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl-, C.sub.1-4-alkyl-O--, or
C.sub.3-6-cycloalkyl-O--, wherein each alkyl and cycloalkyl group
is substituted with 1 group selected from R.sup.4 and optionally
substituted with 1 or 2 C.sub.1-3-alkyl and/or 1 to 3 F atoms;
R.sup.2 is heterocyclyl-C(.dbd.O)--, H.sub.2N--C(.dbd.O)--,
C.sub.1-3-alkyl-NR.sup.N--C(.dbd.O)--,
C.sub.1-4-alkyl-C(.dbd.O)NR.sup.N--,
C.sub.3-6-cycloalkyl-C(.dbd.O)NR.sup.N--,
heterocyclyl-C(.dbd.O)NR.sup.N--,
C.sub.1-4-alkyl-S(.dbd.O).sub.2NR.sup.N--, heterocyclyl-O--,
heteroaryl-O--, heterocyclyl-S(.dbd.O).sub.2--,
H.sub.2N--S(.dbd.O).sub.2--, heterocyclyl, phenyl, or heteroaryl,
wherein each alkyl, cycloalkyl, and heterocyclyl group is
optionally substituted with 1 group selected from R.sup.4 and
optionally substituted with 1 or 2-CH.sub.3 groups and/or 1 to 3 F
atoms, each phenyl and heteroaryl group is optionally substituted
with 1 to 3 substituents independently selected from R.sup.5,
heterocyclyl is selected from a C.sub.4-6-cycloalkyl group wherein
1 CH.sub.2 group is replaced by NR.sup.N or O and/or 1>CH--
group is replaced by N, and 1 additional CH.sub.2 group is
optionally replaced by C(.dbd.O), heteroaryl is selected from
tetrazolyl, a 5-membered heteroaromatic ring containing 1 ring
member selected from NR.sup.N, NR.sup.5, O, and S, or containing 1
N and 1 ring member selected from NR.sup.N, NR.sup.5, O, and S, or
containing 1 NR.sup.N, NR.sup.5, O, or S and 2 N, and a 6-membered
heteroaromatic ring which contains 1 to 2 N atoms, with the proviso
that R.sup.2 is not C.sub.1-4-alkyl-,
C.sub.1-4-alkyl-O--C.sub.1-4-alkyl, HO--C.sub.1-4-alkyl, or
C.sub.1-4-alkyl-O--, or a salt thereof.
7. The compound according to claim 1, wherein: R.sup.2 is selected
from the group consisting of NC--C.sub.1-2-alkyl-,
HO--C.sub.5-6-alkyl-, tetrahydropyranyl-CH.sub.2--,
pyrrolidin-1-yl-CH.sub.2--, piperidin-1-yl-CH.sub.2--,
morpholin-4-yl-CH.sub.2--, H.sub.3C--C(.dbd.O)--NH--CH.sub.2--,
C.sub.1-2-alkyl-NH--C(.dbd.O)--,
(C.sub.1-2-alkyl).sub.2N--C(.dbd.O)--, pyrrolidin-1-yl-C(.dbd.O)--,
morpholin-4-yl-C(.dbd.O)--, H.sub.3C--C(.dbd.O)--NH--,
pyrrolidin-2-on-1-yl, HO--C.sub.2-5-alkyl-O--,
H.sub.3C--O--C.sub.2-4-alkyl-O--,
H.sub.3C--S(.dbd.O).sub.2--C.sub.1-3-alkyl-O--,
tetrahydrofuranyl-O--, tetrahydropyranyl-O--, tetrahydropyranyl,
and tetrahydropyranyl-CH.sub.2--O-- optionally substituted with one
HO-- group, and pyridinyl, imidazolyl, pyrazolyl, isoxazolyl,
thiazolyl, triazolyl, oxadiazolyl, and tetrazolyl, wherein each
heteroaryl group is optionally substituted with 1 or 2 H.sub.3C--
groups or 1 HO--C(CH.sub.3).sub.2--CH.sub.2-- group, or a salt
thereof.
8. The compound according to claim 1, wherein: (Het)Ar is phenyl,
pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl,
isoquinolinyl, quinazolinyl, indolinyl, benzoimidazolyl, indazolyl,
benzoxazolyl, or benzothiazolyl, each substituted with one group
R.sup.2 and optionally substituted with 1 to 3 groups independently
selected from R.sup.3; or (Het)Ar is 2,3-dihydrobenzofuran,
benzo[1,3]dioxole, 2,3-dihydro-benzo[1,4]dioxine, or
3,4-dihydro-1H-quinoline-2-one, each optionally substituted with 1
group R.sup.3; R.sup.1 is H; R.sup.2 is C.sub.1-4-alkyl,
C.sub.3-6-cycloalkyl-, C.sub.1-4-alkyl-O--, or
C.sub.3-6-cycloalkyl-O--, wherein each alkyl and cycloalkyl group
is substituted with 1 group selected from R.sup.4 and optionally
substituted with 1 or 2 H.sub.3C-- group; R.sup.2 is
heterocyclyl-C(.dbd.O)--, H.sub.2N--C(.dbd.O)--,
C.sub.1-2-alkyl-NH--C(.dbd.O)--,
(C.sub.1-2-alkyl).sub.2N--C(.dbd.O)--,
C.sub.1-3-alkyl-C(.dbd.O)--NH--, heterocyclyl-O--, heteroaryl-O--,
heterocyclyl, or heteroaryl, wherein each heterocyclyl group is
optionally substituted with 1 group selected from R.sup.4 and
optionally substituted with 1 additional H.sub.3C-- group, each
heteroaryl group is optionally substituted with 1 or 2 substituents
independently selected from R.sup.5, heterocyclyl is selected from
a C.sub.4-6-cycloalkyl group wherein 1 CH.sub.2 group is replaced
by O and/or 1>CH-- group is replaced by N, and 1 additional
CH.sub.2 group is optionally replaced by C(.dbd.O), and heteroaryl
is pyridinyl, imidazolyl, pyrazolyl, isoxazolyl, oxazolyl,
thiazolyl, triazolyl, oxadiazolyl, or tetrazolyl; with the proviso
that R.sup.2 is not C.sub.1-4-alkyl-,
C.sub.1-4-alkyl-O--C.sub.1-4-alkyl, HO--C.sub.1-4-alkyl, or
C.sub.1-4-alkyl-O--; R.sup.3 is F, --CH.sub.3, or CN; R.sup.4 is
C.sub.1-2-alkyl-, --CN, H.sub.2N--C(.dbd.O)--,
--C(.dbd.O)NHCH.sub.3, --C(.dbd.O)N(CH.sub.3).sub.2,
--N(CH.sub.3).sub.2, H.sub.3C--C(.dbd.O)NH--,
H.sub.3C--S(.dbd.O).sub.2NH--, --OH, C.sub.1-3-alkyl-O--,
heterocyclyl-O--, H.sub.3C--S(.dbd.O)--,
H.sub.3C--S(.dbd.O).sub.2--, heterocyclyl, or heteroaryl, wherein
heterocyclyl is oxetanyl, pyrrolidinyl, tetrahydrofuranyl,
piperidinyl, tetrahydropyranyl, or morpholin-4-yl, wherein each of
these rings is optionally substituted with 1 CH.sub.3 or 1 OH
group, and heteroaryl is selected from imidazolyl, pyrazolyl,
oxazolyl, or triazolyl, each optionally substituted with 1 or
2-CH.sub.3 groups; and R.sup.5 is F, --CH.sub.3,
HO--C(CH.sub.3).sub.2--CH.sub.2--, --CF.sub.3, --CN, or
--OCH.sub.3; or a salt thereof.
9. The compound according to claim 8, wherein (Het)Ar is phenyl
substituted with one group R.sup.2 and optionally substituted with
1 to 3 groups independently selected from R.sup.3, or a salt
thereof.
10. A pharmaceutically acceptable salt of the compound according to
claim 1.
11. A pharmaceutical composition comprising a compounds according
to claim 1 or a pharmaceutically acceptable salt thereof, and an
inert carrier or diluent.
12. A method for treating diseases or conditions which can be
influenced by the modulation of the function of GPR40 in a patient
in need thereof, the method comprising administering to the patient
an effective amount of the compound according to claim 1 or a
pharmaceutically acceptable salt thereof.
13. (canceled)
14. A method of treating metabolic diseases and conditions
associated with the disease in a patient in need thereof, the
method comprising administering to the patient an effective amount
of the compound according to claim 1 or a pharmaceutically
acceptable salt thereof.
15. The pharmaceutical composition according to claim 11, further
comprising an additional therapeutic agents.
16. The pharmaceutical composition according to claim 15, wherein
the additional therapeutic agents is selected from the group
consisting of antidiabetic agents, agents for the treatment of
overweight and/or obesity, and agents for the treatment of high
blood pressure, heart failure, and/or atherosclerosis.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to novel
indanyloxydihydrobenzofuranylacetic acids, that are agonists of the
G-protein coupled receptor 40 (GPR40, also known as free fatty acid
receptor FFAR 1), to processes for their preparation, to
pharmaceutical compositions containing these compounds and to their
medical use for the prophylaxis and/or treatment of diseases which
can be influenced by the modulation of the function of GPR40.
Particularly, the pharmaceutical compositions of the invention are
suitable for the prophylaxis and/or therapy of metabolic diseases,
such as diabetes, more specifically type 2 diabetes mellitus, and
conditions associated with the disease, including insulin
resistance, obesity, cardiovascular disease and dyslipidemia.
BACKGROUND OF THE INVENTION
[0002] Metabolic diseases are diseases caused by an abnormal
metabolic process and may either be congenital due to an inherited
enzyme abnormality or acquired due to a disease of an endocrine
organ or failure of a metabolically important organ such as the
liver or the pancreas.
[0003] Diabetes mellitus is a disease state or process derived from
multiple causative factors and is defined as a chronic
hyperglycemia associated with resulting damages to organs and
dysfunctions of metabolic processes. Depending on its etiology, one
differentiates between several forms of diabetes, which are either
due to an absolute (lacking or decreased insulin secretion) or to a
relative lack of insulin. Diabetes mellitus Type I (IDDM,
insulin-dependent diabetes mellitus) generally occurs in
adolescents under 20 years of age. It is assumed to be of
auto-immune etiology, leading to an insulitis with the subsequent
destruction of the beta cells of the islets of Langerhans which are
responsible for the insulin synthesis. In addition, in latent
autoimmune diabetes in adults (LADA; Diabetes Care. 8: 1460-1467,
2001) beta cells are being destroyed due to autoimmune attack. The
amount of insulin produced by the remaining pancreatic islet cells
is too low, resulting in elevated blood glucose levels
(hyperglycemia). Diabetes mellitus Type II generally occurs at an
older age. It is above all associated with a resistance to insulin
in the liver and the skeletal muscles, but also with a defect of
the islets of Langerhans. High blood glucose levels (and also high
blood lipid levels) in turn lead to an impairment of beta cell
function and to an increase in beta cell apoptosis.
[0004] Persistent or inadequately controlled hyperglycemia is
associated with a wide range of pathologies. Diabetes is a very
disabling disease, because today's common anti-diabetic drugs do
not control blood sugar levels well enough to completely prevent
the occurrence of high and low blood sugar levels. Out of range
blood sugar levels are toxic and cause long-term complications for
example retinopathy, renopathy, neuropathy and peripheral vascular
disease. There is also a host of related conditions, such as
obesity, hypertension, stroke, heart disease and hyperlipidemia,
for which persons with diabetes are substantially at risk.
[0005] Obesity is associated with an increased risk of follow-up
diseases such as cardiovascular diseases, hypertension, diabetes,
hyperlipidemia and an increased mortality. Diabetes (insulin
resistance) and obesity are part of the "metabolic syndrome" which
is defined as the linkage between several diseases (also referred
to as syndrome X, insulin-resistance syndrome, or deadly quartet).
These often occur in the same patients and are major risk factors
for development of diabetes type II and cardiovascular disease. It
has been suggested that the control of lipid levels and glucose
levels is required to treat diabetes type II, heart disease, and
other occurrences of metabolic syndrome (see e.g., Diabetes 48:
1836-1841, 1999; JAMA 288: 2209-2716, 2002).
[0006] The free fatty acid receptor GPR40 (also referred to as
either FFAR, FFAR1, or FFA1) is a cell-surface receptor and a
member of the gene superfamily of G-protein coupled receptors,
which was first identified as a so-called orphan receptor, i.e. a
receptor without a known ligand, based on the predicted prescence
of seven putative transmembrane regions in the corresponding
protein (Sawzdargo et al. (1997) Biochem. Biophys. Res. Commun.
239: 543-547). GPR40 is found to be highly expressed in several
particular cell types: the pancreatic .beta. cells and
insulin-secreting cell lines, as well as in enteroendocrine cells,
taste cells, and is reported to be expressed in immune cells,
splenocytes, and in the human and monkey brain. Meanwhile, fatty
acids of varying chain lengths are thought to represent the
endogenous ligands for GPR40, activation of which is linked
primarily to the modulation of the Gq family of intra-cellular
signaling G proteins and concomitant induction of elevated calcium
levels, although activation of Gs- and G1-proteins to modulate
intracellular levels of cAMP have also been reported. GPR40 is
activated especially by long-chain FFA, particularly oleate, as
well as the PPAR-gamma agonist rosiglitazone.
[0007] It has been recognized that the fatty acids that serve as
activators for GPR40 augment the elevated plasma glucose-induced
secretion of insulin through GPR40 receptors that are expressed in
the insulin secreting cells (Itoh et al. (2003) Nature 422:
173-176; Briscoe et al. (2003) J. Biol. Chem. 278: 11303-11311;
Kotarsky et al. (2003) Biochem. Biophys. Res. Commun. 301:
406-410). Despite initial controversy, the use of GPR40 agonist
appears to be the appropriate for increasing insulin release for
the treatment of diabetes (see e.g. Diabetes 2008, 57, 2211; J.
Med. Chem. 2007, 50, 2807). Typically, long term diabetes therapy
leads to the gradual diminution of islet activity, so that after
extended periods of treatment Type 2 diabetic patients need
treatment with daily insulin injections instead. GPR40 agonists may
have the potential to restore or preserve islet function,
therefore, GPR40 agonists may be beneficial also in that that they
may delay or prevent the diminution and loss of islet function in a
Type 2 diabetic patient.
[0008] It is well established that the incretins GLP-1
(glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic
peptide; also known as gastric inhibitory peptide) stimulate
insulin secretion and are rapidly inactivated in vivo by DPP-4.
These peptidyl hormones are secreted by endocrine cells that are
located in the epithelium of the small intestine. When these
endocrine cells sense an increase in the concentration of glucose
in the lumen of the digestive tract, they act as the trigger for
incretin release. Incretins are carried through the circulation to
beta cells in the pancreas and cause the beta cells to secrete more
insulin in anticipation of an increase of blood glucose resulting
from the digesting meal. Further studies indicating that the GPR40
modulatory role on the release of incretins from the
enteroendocrine cells, including CCK, GLP-1, GIP, PYY, and possibly
others, suggest that GPR40 modulators may contribute to enhanced
insulin release from the pancreatic beta cells also indirectly by
e.g. a synergistic effect of GLP-1 and possibly GIP on the insulin
release, and the other release incretins may also contribute to an
overall beneficial contribution of GPR40 modulation on metabolic
diseases. The indirect contributions of GPR40 modulation on insulin
release through the elevation of plasma levels of incretins may be
further augmented by the coadministration of inhibitors of the
enzymes responsible for the incretin degradation, such as
inhibitors of DPP-4.
[0009] Insulin imbalances lead to conditions such as type II
diabetes mellitus, a serious metabolic disease. The modulation of
the function of GPR40 in modulating insulin secretion indicates the
therapeutic agents capable of modulating GPR40 function could be
useful for the treatment of disorders such as diabetes and
conditions associated with the disease, including insulin
resistance, obesity, cardiovascular disease and dyslipidemia.
OBJECT OF THE PRESENT INVENTION
[0010] The object of the present invention is to provide new
compounds, hereinafter described as compounds of formula I, in
particular new indanyloxy-2,3-dihydrobenzofuranylacetic acids,
which are active with regard to the G-protein-coupled receptor
GPR40, notably are agonists of the G-protein-coupled receptor
GPR40.
[0011] A further object of the present invention is to provide new
compounds, in particular new indanyloxydihydrobenzofuranylacetic
acids, which have an activating effect on the G-protein-coupled
receptor GPR40 in vitro and/or in vivo and possess suitable
pharmacological and pharmacokinetic properties to use them as
medicaments.
[0012] A further object of the present invention is to provide
effective GPR40 agonists, in particular for the treatment of
metabolic disorders, for example diabetes, dyslipidemia and/or
obesity.
[0013] A further object of the present invention is to provide
methods for treating a disease or condition mediated by the
activation the G-protein-coupled receptor GPR40 in a patient.
[0014] A further object of the present invention is to provide a
pharmaceutical composition comprising at least one compound
according to the invention.
[0015] A further object of the present invention is to provide a
combination of at least one compound according to the invention
with one or more additional therapeutic agents.
[0016] Further objects of the present invention become apparent to
the one skilled in the art by the description hereinbefore and in
the following and by the examples. GPR40 modulators are known in
the art, for example, the compounds disclosed in WO 2004041266 (EP
1559422), WO 2007033002, WO 2009157418 and WO 2012072691. The
indanyloxydihydrobenzofuranylacetic acids of the present invention
may provide several advantages, such as enhanced potency, high
metabolic and/or chemical stability, high selectivity and
tolerability, enhanced solubility, and the possibility to form
stable salts.
SUMMARY OF THE INVENTION
[0017] In a first aspect the invention relates to compounds of
formula I
##STR00002##
wherein [0018] (Het)Ar is linked via a carbon atom and is selected
from the group (Het)Ar-G1 consisting of [0019] phenyl, naphthyl and
a mono- or bicyclic heteroaromatic group having 5 to 10 ring member
atoms of which 2 to 9 ring members are carbon atoms and either
[0020] one ring member is an unsubstituted or substituted
heteroatom selected from N, NH, NR.sup.N, O, S, S(.dbd.O) and
S(.dbd.O).sub.2, or [0021] one ring member is N and a second ring
member is selected from N, NH, NR.sup.N, O, S, S(.dbd.O) and
S(.dbd.O).sub.2, or [0022] two ring members are N and a third ring
member is selected from N, NH, NR.sup.N, O, S, S(.dbd.O) and
S(.dbd.O).sub.2, [0023] wherein in naphthyl the ring not attached
to the indanyl-O atom of formula I optionally is partially
saturated, [0024] wherein in bicyclic heteroaromatic groups the
ring not attached to the indanyl-O atom of formula I optionally is
partially saturated, while the aromatic ring includes at least one
heteroatom, and optionally [0025] one ring member in the partially
or fully saturated bridge is replaced by N, NH, NR.sup.N, O, S,
S(.dbd.O) or S(.dbd.O).sub.2, or [0026] one ring member in the
partially or fully saturated bridge is replaced by N, NH or
NR.sup.N and a second ring member is replaced by NH, NR.sup.N, O,
S, C(.dbd.O), S(.dbd.O) or S(.dbd.O).sub.2, or [0027] two not
vicinal ring members in a fully saturated bridge are replaced by O
atoms, [0028] wherein any of these groups is substituted with 1
group R.sup.2 or 1 NH group is replaced by an NR.sup.2 group; and
[0029] wherein any of these groups is optionally and independently
substituted with 1 to 4 R.sup.3 groups; [0030] or (Het)Ar-G1 is
selected from the group consisting of 2,3-dihydroindole,
2,3-dihydroisoindole, 2,3-dihydrobenzofuran,
1,3-dihydroisobenzofuran, benzo[1,3]dioxole,
1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline,
chroman, isochroman and 2,3-dihydrobenzo[1,4]dioxine, [0031]
wherein any of these groups is linked via an aromatic carbon atom
to the indanyloxy group in formula (I), and wherein in each of
these bicyclic groups 1 CH.sub.2 group is optionally replaced by
C(.dbd.O) and each of these bicyclic groups is optionally
substituted with 1 R.sup.2 group and optionally and independently
substituted with 1 to 4 R.sup.3 groups; [0032] R.sup.1 is selected
from the group R.sup.1-G1 consisting of H, F, Cl, F.sub.3C--, NC--,
F.sub.3C--O-- and H.sub.3C--S(.dbd.O).sub.2--; [0033] R.sup.2 is
selected from the group R.sup.2-G1 consisting of [0034]
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkinyl,
C.sub.3-6-cycloalkyl-, C.sub.1-4-alkyl-NH--,
(C.sub.1-4-alkyl).sub.2N--, C.sub.1-6-alkyl-O--,
C.sub.3-6-cycloalkyl-O--, C.sub.1-4-alkyl-S--,
C.sub.1-4-alkyl-S(.dbd.O)--, and C.sub.1-4-alkyl-S(.dbd.O).sub.2,
[0035] wherein each alkyl and cycloalkyl group is substituted with
1 to 3 groups independently selected from R.sup.4 and optionally
substituted with 1 or more F atoms; [0036] and of
C.sub.1-4-alkyl-C(.dbd.O)--, heterocyclyl-C(.dbd.O)--,
HNR.sup.N--C(.dbd.O)--, C.sub.1-4-alkyl-NR.sup.N--C(.dbd.O)--,
C.sub.3-6-cycloalkyl-NR.sup.N--C(.dbd.O)--,
heterocyclyl-NR.sup.N--C(.dbd.O)--, phenyl-NR.sup.N--C(.dbd.O)--,
heteroaryl-NR.sup.N--C(.dbd.O)--, HO.sub.2C--,
C.sub.1-4-alkyl-O--C(.dbd.O)--,
C.sub.3-6-cycloalkyl-O--C(.dbd.O)--, heterocyclyl-O--C(.dbd.O)--,
--NHR.sup.N, C.sub.1-4-alkyl-C(.dbd.O)NR.sup.N--,
C.sub.3-6-cycloalkyl-C(.dbd.O)NR.sup.N--,
heterocyclyl-C(.dbd.O)NR.sup.N--, phenyl-C(.dbd.O)NR.sup.N--,
heteroaryl-C(.dbd.O)NR.sup.N--,
C.sub.1-4-alkyl-S(.dbd.O).sub.2NR.sup.N--,
C.sub.3-6-cycloalkyl-S(.dbd.O).sub.2NR.sup.N--,
heterocyclyl-S(.dbd.O).sub.2NR.sup.N--,
phenyl-S(.dbd.O).sub.2NR.sup.N--,
heteroaryl-S(.dbd.O).sub.2NR.sup.N--, heterocyclyl-O--, phenyl-O--,
heteroaryl-O--, C.sub.3-6-cycloalkyl-S--, heterocyclyl-S--,
phenyl-S--, heteroaryl-S--, C.sub.3-6-cycloalkyl-S(.dbd.O)--,
heterocyclyl-S(.dbd.O)--, phenyl-S(.dbd.O)--,
heteroaryl-S(.dbd.O)--, C.sub.3-6-cycloalkyl-S(.dbd.O).sub.2--,
heterocyclyl-S(.dbd.O).sub.2--, phenyl-S(.dbd.O).sub.2--,
heteroaryl-S(.dbd.O).sub.2--, HNR.sup.N--S(.dbd.O).sub.2--,
C.sub.1-4-alkyl-NR.sup.N--S(.dbd.O).sub.2--, heterocyclyl, phenyl,
and heteroaryl, [0037] wherein each alkyl, cycloalkyl and
heterocyclyl group is optionally substituted with 1 to 3 groups
independently selected from R.sup.4 and optionally substituted with
1 or more F atoms; [0038] wherein each phenyl and heteroaryl group
is optionally substituted with 1 to 5 substituents independently
selected from R.sup.5; [0039] wherein heterocyclyl is selected from
[0040] a C.sub.4-6-cycloalkyl group wherein 1 CH.sub.2 group is
replaced by NR.sup.N, NR.sup.4, O, S, S(.dbd.O) or S(.dbd.O).sub.2
and/or 1>CH-- group is replaced by N, or [0041] wherein 1
CH.sub.2 group is replaced by NR.sup.N, NR.sup.4, O or S, and/or
1>CH--group is replaced by N, and 1 additional CH.sub.2 group is
replaced by C(.dbd.O) or S(.dbd.O).sub.2; and [0042] wherein
heteroaryl is selected from [0043] tetrazolyl, pyridinonyl, [0044]
a 5-membered heteroaromatic ring containing 1 ring member selected
from NR.sup.N, NR.sup.5, N, O and S, or [0045] containing 1 N and 1
ring member selected from NR.sup.N, NR.sup.5, N, O and S, or [0046]
containing 1 NR.sup.N, NR.sup.5, N, O or S and 2 N, and [0047] a
6-membered heteroaromatic ring which contains 1 to 3 N atoms,
[0048] with the proviso that R.sup.2 in total must not be
C.sub.1-4-alkyl-, C.sub.1-4-alkyl-O--C.sub.1-4-alkyl,
HO--C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkinyl,
NH.sub.2, C.sub.1-4-alkyl-NH--, (C.sub.1-4-alkyl).sub.2N--,
C.sub.1-4-alkyl-O--, C.sub.1-4-alkyl-S--,
C.sub.1-4-alkyl-S(.dbd.O)--, and C.sub.1-4-alkyl-S(.dbd.O).sub.2;
[0049] R.sup.3 is selected from the group R.sup.3-G1 consisting of
F, Cl, Br, I, CN, OH, C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl,
HO--C.sub.1-4-alkyl, C.sub.1-4-alkyl-O--C.sub.1-4-alkyl,
--NR.sup.NH, C.sub.1-4-alkyl-NR.sup.N--, C.sub.1-4-alkyl-O--,
C.sub.3-6-cycloalkyl-O--, C.sub.1-4-alkyl-O--C.sub.1-4-alkyl-O--,
C.sub.1-4-alkyl-S--, C.sub.1-4-alkyl-S(.dbd.O)--, and
C.sub.1-4-alkyl-S(.dbd.O).sub.2--, [0050] wherein any alkyl and
cycloalkyl group is optionally substituted with 1 or more F atoms;
[0051] R.sup.4 is selected from the group R.sup.4-G1 consisting of
Cl, Br, I, C.sub.1-4-alkyl, CN, C.sub.3-6-cycloalkyl,
C.sub.1-4-alkyl-C(.dbd.O)--, heterocyclyl-C(.dbd.O)--,
H.sub.2N--C(.dbd.O)--, C.sub.1-4-alkyl-NR.sup.N--C(.dbd.O)--,
C.sub.3-6-cycloalkyl-NR.sup.N--C(.dbd.O)--,
heterocyclyl-NR.sup.N--C(.dbd.O)--, phenyl-NR.sup.N--C(.dbd.O)--,
heteroaryl-NR.sup.N--C(.dbd.O)--, HO--C(.dbd.O)--,
C.sub.1-4-alkyl-O--C(.dbd.O)--, --NHR.sup.N,
C.sub.1-4-alkyl-NR.sup.N--, C.sub.1-4-alkyl-C(.dbd.O)NR.sup.N--,
C.sub.3-6-cycloalkyl-C(.dbd.O)NR.sup.N--,
heterocyclyl-C(.dbd.O)NR.sup.N--, phenyl-C(.dbd.O)NR.sup.N--,
heteroaryl-C(.dbd.O)NR.sup.N--,
C.sub.1-4-alkyl-S(.dbd.O).sub.2NR.sup.N--,
C.sub.3-6-cycloalkyl-S(.dbd.O).sub.2NR.sup.N--,
heterocyclyl-S(.dbd.O).sub.2NR.sup.N--,
phenyl-S(.dbd.O).sub.2NR.sup.N--,
heteroaryl-S(.dbd.O).sub.2NR.sup.N--, --OH, C.sub.1-4-alkyl-O--,
C.sub.1-4-alkyl-O--C.sub.1-4-alkyl-O--, C.sub.3-6-cycloalkyl-O--,
heterocyclyl-O--, phenyl-O--, heteroaryl-O--, C.sub.1-4-alkyl-S--,
C.sub.3-6-cycloalkyl-S--, heterocyclyl-S--, phenyl-S--,
heteroaryl-S--, C.sub.1-4-alkyl-S(.dbd.O)--,
C.sub.3-6-cycloalkyl-S(.dbd.O)--, heterocyclyl-S(.dbd.O)--,
phenyl-S(.dbd.O)--, heteroaryl-S(.dbd.O)--,
C.sub.1-4-alkyl-S(.dbd.O).sub.2--,
C.sub.3-6-cycloalkyl-S(.dbd.O).sub.2--,
heterocyclyl-S(.dbd.O).sub.2--, phenyl-S(.dbd.O).sub.2--,
heteroaryl-S(.dbd.O).sub.2--, H.sub.2N--S(.dbd.O).sub.2--,
C.sub.1-4-alkyl-NR.sup.N--S(.dbd.O).sub.2--, heterocyclyl, phenyl
and heteroaryl, [0052] wherein any alkyl, cycloalkyl and
heterocyclyl group is optionally substituted with 1 or more F atoms
and optionally substituted with 1 or 2 groups independently
selected from H.sub.3C--, HO--, H.sub.3C--O-- and --CN; [0053]
wherein heterocyclyl is selected from [0054] a C.sub.4-6-cycloalkyl
group wherein 1 CH.sub.2 group is replaced by NR.sup.N, O, S,
S(.dbd.O) or S(.dbd.O).sub.2 and/or 1>CH-- group is replaced by
N, or wherein 1 CH.sub.2 group is replaced by NR.sup.N, O or S,
and/or 1>CH-- group is replaced by N, and 1 additional CH.sub.2
group is replaced by C(.dbd.O) or S(.dbd.O).sub.2; and [0055]
wherein heteroaryl is selected from [0056] tetrazolyl, pyridinonyl,
[0057] a 5-membered heteroaromatic ring containing 1 ring member
selected from NR.sup.N, O and S, or [0058] containing 1 N and 1
ring member selected from NR.sup.N, O and S, or containing 1
NR.sup.N, O or S and 2 N, and [0059] a 6-membered heteroaromatic
ring which contains 1 to 3 N atoms, and each heteroaryl group is
optionally substituted with 1 to 3 substituents independently
selected from F, Cl, --CH.sub.3, --CN and --O--CH.sub.3; [0060]
R.sup.5 is selected from the group R.sup.5-G1 consisting of F, Cl,
Br, CN, C.sub.1-4-alkyl, cyclopropyl, F.sub.3C--,
HO--C.sub.1-4-alkyl-, C.sub.1-4-alkyl-O--C.sub.1-4-alkyl-,
C.sub.1-4-alkyl-O--, F.sub.3C--O--, --S(.dbd.O)--C.sub.1-4-alkyl
and S(.dbd.O).sub.2--C.sub.1-4-alkyl; and [0061] R.sup.N is
selected from the group R.sup.N-G1 consisting of H,
C.sub.1-4-alkyl, C.sub.1-4-alkyl-C(.dbd.O)--,
C.sub.1-4-alkyl-NH--C(.dbd.O)--,
C.sub.1-4-alkyl-N(C.sub.1-4-alkyl)-C(.dbd.O)--,
C.sub.1-4-alkyl-O--C(.dbd.O)-- and
C.sub.1-4-alkyl-S(.dbd.O).sub.2--; wherein in any definition
mentioned hereinbefore and if not specified otherwise, any alkyl
group or sub-group may be straight-chained or branched, the
isoforms, tautomers, stereoisomers, metabolites, prodrugs,
solvates, hydrates, and the salts thereof, particularly the
physiologically acceptable salts thereof with inorganic or organic
acids or bases, or the combinations thereof.
[0062] The expression "optionally substituted with 1 or more F
atoms" means that none or one up to successively all H atoms bound
to carbon atoms of the respective group or submoiety may be
replaced by F atoms, preferably 1 to 5 H atoms or, more preferred,
1 to 3 H atoms may be replaced by F atoms.
[0063] The extension -Gn used within the definitions is meant to
identify genus n of the respective substituent. For example,
R.sup.1-G1 defines genus 1 of the substituent R.sup.1.
[0064] In a further aspect this invention relates to a
pharmaceutical composition, comprising one or more compounds of
general formula I or one or more pharmaceutically acceptable salts
thereof according to the invention, optionally together with one or
more inert carriers and/or diluents.
[0065] In a further aspect this invention relates to a method for
treating diseases or conditions which are mediated by activating
the G-protein-coupled receptor GPR40 in a patient in need thereof
characterized in that a compound of general formula I or a
pharmaceutically acceptable salt thereof is administered to the
patient.
[0066] According to another aspect of the invention, there is
provided a method for treating a metabolic disease or disorder,
such as diabetes, dyslipidemia and/or obesity, in a patient in need
thereof characterized in that a therapeutically effective amount of
a compound of general formula I or a pharmaceutically acceptable
salt thereof is administered to the patient.
[0067] According to another aspect of the invention, there is
provided the use of a compound of the general formula I or a
pharmaceutically acceptable salt thereof for the manufacture of a
medicament for a therapeutic method as described hereinbefore and
hereinafter.
[0068] According to another aspect of the invention, there is
provided a compound of the general formula I or a pharmaceutically
acceptable salt thereof for use in a therapeutic method as
described hereinbefore and hereinafter.
[0069] In a further aspect this invention relates to a method for
treating a disease or condition mediated by the activation of the
G-protein-coupled receptor GPR40 in a patient that includes the
step of administering to the patient in need of such treatment a
therapeutically effective amount of a compound of the general
formula I or a pharmaceutically acceptable salt thereof in
combination with a therapeutically effective amount of one or more
additional therapeutic agents.
[0070] In a further aspect this invention relates to the use of a
compound of the general formula I or a pharmaceutically acceptable
salt thereof in combination with one or more additional therapeutic
agents for the treatment of diseases or conditions which are
mediated by the activation of the G-protein-coupled receptor
GPR40.
[0071] In a further aspect this invention relates to a
pharmaceutical composition which comprises a compound according to
general formula I or a pharmaceutically acceptable salt thereof and
one or more additional therapeutic agents, optionally together with
one or more inert carriers and/or diluents.
[0072] Other aspects of the invention become apparent to the one
skilled in the art from the specification and the experimental part
as described hereinbefore and hereinafter.
DETAILED DESCRIPTION
[0073] Unless otherwise stated, the groups, residues, and
substituents, particularly (Het)Ar, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5 and R.sup.N are defined as above and hereinafter.
If residues, substituents, or groups occur several times in a
compound, they may have the same or different meanings. Some
preferred meanings of individual groups and substituents of the
compounds according to the invention will be given hereinafter. Any
and each of these definitions may be combined with each other.
(Het)Ar:
(Het)Ar-G1:
[0074] The group (Het)Ar is preferably selected from the group
(Het)Ar-G1 as defined hereinbefore.
(Het)Ar-G2:
[0075] According to one embodiment the group (Het)Ar is selected
from the group (Het)Ar-G2 consisting of phenyl, naphthyl, and a
heteroaromatic group linked via a carbon atom having 5 to 10 ring
member atoms of which 2 to 9 atoms are carbon atoms and either
[0076] one ring member is an unsubstituted or substituted
heteroatom selected from N, NH, NR.sup.N, O, S, S(.dbd.O) and
S(.dbd.O).sub.2, or [0077] one ring member is N and a second ring
member is selected from N, NH, NR.sup.N, O, S, S(.dbd.O) and
S(.dbd.O).sub.2, or [0078] two ring members are N and a third ring
member is selected from N, NH, NR.sup.N, O, S, S(.dbd.O) and
S(.dbd.O).sub.2, [0079] wherein in naphthyl the ring not attached
to the indanyl-O atom of formula I optionally is partially
saturated, [0080] wherein in bicyclic heteroaromatic groups the
ring not attached to the indanyl-O atom of formula I optionally is
partially saturated, while the aromatic ring includes at least one
heteroatom, wherein each of these groups is substituted with 1
group R.sup.2 or 1 NH group is replaced by an NR.sup.2 group; and
wherein any of these groups is optionally substituted with 1 to 3
groups independently selected from R.sup.3; or (Het)Ar-G2 denotes
2,3-dihydrobenzofuran, benzo[1,3]dioxole,
2,3-dihydro-benzo[1,4]dioxine or 3,4-dihydro-1H-quinolin-2-one,
which are optionally substituted with 1 or 2 groups independently
selected from R.sup.3.
(Het)Ar-G3:
[0081] According to one embodiment the group (Het)Ar is selected
from the group (Het)Ar-G3 consisting of
phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,
quinolinyl, isoquinolinyl, quinazolinyl, imidazolyl, pyrazolyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, indolinyl, benzoimidazolyl, indazolyl,
benzoxazolyl and benzothiazolyl, wherein each of these groups is
substituted with one group R.sup.2 and optionally substituted with
1 to 3 groups independently selected from R.sup.3; or (Het)Ar-G3
denotes 2,3-dihydrobenzofuran, benzo[1,3]dioxole,
2,3-dihydro-benzo[1,4]dioxine or 3,4-dihydro-1H-quinolin-2-one,
which are optionally substituted with 1 or 2 groups independently
selected from R.sup.3.
(Het)Ar-G4:
[0082] According to one embodiment the group (Het)Ar is selected
from the group (Het)Ar-G4 consisting of
phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl,
isoquinolinyl, quinazolinyl, indolinyl, benzoimidazolyl, indazolyl,
benzoxazolyl and benzothiazolyl, wherein each of these groups is
substituted with one group R.sup.2 and optionally substituted with
1 to 3 groups independently selected from R.sup.3; or (Het)Ar-G4
denotes 2,3-dihydrobenzofuran, benzo[1,3]dioxole,
2,3-dihydro-benzo[1,4]dioxine or 3,4-dihydro-1H-quinolin-2-one,
which are optionally substituted with 1 group R.sup.3.
(Het)Ar-G5:
[0083] In another embodiment the group (Het)Ar is selected from the
group (Het)Ar-G5 consisting of
##STR00003##
wherein each of these groups is substituted with one group R.sup.2
and optionally substituted with 1 to 3 groups independently
selected from R.sup.3.
(Het)Ar-G5a:
[0084] In another embodiment the group (Het)Ar is selected from the
group (Het)Ar-G5a consisting of
##STR00004##
which is substituted with one group R.sup.2 and optionally
substituted with 1 to 3 groups independently selected from
R.sup.3.
(Het)Ar-G5b:
[0085] In another embodiment the group (Het)Ar is selected from the
group (Het)Ar-G5b consisting of
##STR00005##
wherein each of these groups is substituted with one group R.sup.2
and optionally substituted with 1 or 2 groups independently
selected from R.sup.3.
(Het)Ar-G5c:
[0086] In another embodiment the group (Het)Ar is selected from the
group (Het)Ar-G5c consisting of
##STR00006##
wherein each of these groups is substituted with one group R.sup.2
and optionally substituted with 1 to 3 groups independently
selected from R.sup.3.
(Het)Ar-G6:
[0087] In another embodiment the group (Het)Ar is selected from the
group (Het)Ar-G6 consisting of
##STR00007## ##STR00008## ##STR00009## ##STR00010##
##STR00011##
wherein each of the phenyl subgroups is optionally additionally
substituted with 1 or 2 F atoms or 1 CN group.
(Het)Ar-G6a:
[0088] In another embodiment the group (Het)Ar is selected from the
group (Het)Ar-G6a consisting of
##STR00012## ##STR00013## ##STR00014## ##STR00015## ##STR00016##
##STR00017## ##STR00018##
R.sup.1:
R.sup.1-G1:
[0089] The group R.sup.1 is preferably selected from the group
R.sup.1-G1 as defined hereinbefore.
R.sup.1-G2:
[0090] In another embodiment the group R.sup.1 is selected from the
group R.sup.1-G2 consisting of H, F, Cl, F.sub.3C-- and NC--.
R.sup.1-G3:
[0091] In another embodiment the group R.sup.1 is H.
R.sup.2:
R.sup.2-G1:
[0092] The group R.sup.2 is preferably selected from the group
R.sup.2-G1 as defined hereinbefore.
R.sup.2-G2:
[0093] In another embodiment the group R.sup.2 is selected from the
group R.sup.2-G2 consisting of C.sub.1-4-alkyl,
C.sub.3-6-cycloalkyl-, C.sub.1-4-alkyl-O--,
C.sub.3-6-cycloalkyl-O--, C.sub.1-4-alkyl-S(.dbd.O)--, and
C.sub.1-4-alkyl-S(.dbd.O).sub.2--, [0094] wherein each alkyl and
cycloalkyl group is substituted with 1 or 2 groups independently
selected from R.sup.4 and optionally substituted with 1
C.sub.1-3-alkyl and/or 1 to 3 F atoms; and of
heterocyclyl-C(.dbd.O)--, H.sub.2N--C(.dbd.O)--,
C.sub.1-4-alkyl-NR.sup.N--C(.dbd.O)--,
C.sub.3-6-cycloalkyl-NR.sup.N--C(.dbd.O)--,
heterocyclyl-NR.sup.N--C(.dbd.O)--,
heteroaryl-NR.sup.N--C(.dbd.O)--,
C.sub.1-4-alkyl-C(.dbd.O)NR.sup.N--,
C.sub.3-6-cycloalkyl-C(.dbd.O)NR.sup.N--,
heterocyclyl-C(.dbd.O)NR.sup.N--, phenyl-C(.dbd.O)NR.sup.N--,
heteroaryl-C(.dbd.O)NR.sup.N--,
C.sub.1-4-alkyl-S(.dbd.O).sub.2NR.sup.N--,
C.sub.3-6-cycloalkyl-S(.dbd.O).sub.2NR.sup.N--,
heterocyclyl-S(.dbd.O).sub.2NR.sup.N--,
heteroaryl-S(.dbd.O).sub.2NR.sup.N--, heterocyclyl-O--, phenyl-O--,
heteroaryl-O--, C.sub.3-6-cycloalkyl-S(.dbd.O)--,
heterocyclyl-S(.dbd.O)--, phenyl-S(.dbd.O)--,
heteroaryl-S(.dbd.O)--, C.sub.3-6-cycloalkyl-S(.dbd.O).sub.2--,
heterocyclyl-S(.dbd.O).sub.2--, phenyl-S(.dbd.O).sub.2--,
heteroaryl-S(.dbd.O).sub.2--, HNR.sup.N--S(.dbd.O).sub.2--,
C.sub.1-4-alkyl-NR.sup.N--S(.dbd.O).sub.2--, heterocyclyl, phenyl,
and heteroaryl, [0095] wherein each alkyl, cycloalkyl, and
heterocyclyl group is optionally substituted with 1 group selected
from R.sup.4 and optionally substituted with 1 or 2 C.sub.1-3-alkyl
and/or 1 to 3 F atoms; [0096] wherein each phenyl and heteroaryl
group is optionally substituted with 1 to 3 groups independently
selected from R.sup.5; [0097] wherein heterocyclyl is selected from
[0098] a C.sub.4-6-cycloalkyl group wherein 1 CH.sub.2 group is
replaced by NR.sup.N or O, and/or 1>CH-- group is replaced by N,
and 1 additional CH.sub.2 group is optionally replaced by C(.dbd.O)
or S(.dbd.O).sub.2; [0099] wherein heteroaryl is selected from
[0100] tetrazolyl, pyridin-2-onyl, [0101] a 5-membered
heteroaromatic ring containing 1 ring member selected from
NR.sup.N, NR.sup.5, N, O and S, or [0102] containing 1 N and 1 ring
member selected from NR.sup.N, NR.sup.5, N, O and S, or containing
1 NR.sup.N, NR.sup.5, N, O or S and 2 N, and [0103] a 6-membered
heteroaromatic ring which contains 1 or 2 N atoms, with the proviso
that R.sup.2 in total must not be C.sub.1-4-alkyl-,
C.sub.1-4-alkyl-O--C.sub.1-4-alkyl, HO--C.sub.1-4-alkyl,
C.sub.1-4-alkyl-O--, C.sub.1-4-alkyl-S(.dbd.O)--, and
C.sub.1-4-alkyl-S(.dbd.O).sub.2.
R.sup.2-G3:
[0104] In another embodiment the group R.sup.2 is selected from the
group R.sup.2-G3 consisting of C.sub.1-4-alkyl,
C.sub.3-6-cycloalkyl-, C.sub.1-4-alkyl-O-- and
C.sub.3-6-cycloalkyl-O--, [0105] wherein each alkyl and cycloalkyl
group is substituted with 1 group selected from R.sup.4 and
optionally substituted with 1 or 2 C.sub.1-3-alkyl and/or 1 to 3 F
atoms; and of heterocyclyl-C(.dbd.O)--, H.sub.2N--C(.dbd.O)--,
C.sub.1-3-alkyl-NR.sup.N--C(.dbd.O)--,
C.sub.1-4-alkyl-C(.dbd.O)NR.sup.N--C.sub.3-6-cycloalkyl-C(.dbd.O)NR.sup.N-
--, heterocyclyl-C(.dbd.O)NR.sup.N--,
C.sub.1-4-alkyl-S(.dbd.O).sub.2NR.sup.N--, heterocyclyl-O--,
heteroaryl-O--, heterocyclyl-S(.dbd.O).sub.2--,
H.sub.2N--S(.dbd.O).sub.2--, heterocyclyl, phenyl, and heteroaryl,
[0106] wherein each alkyl, cycloalkyl and heterocyclyl group is
optionally substituted with 1 group selected from R.sup.4 and
optionally substituted with 1 or 2-CH.sub.3 groups and/or 1 to 3 F
atoms; [0107] wherein each phenyl and heteroaryl group is
optionally substituted with 1 to 3 substituents independently
selected from R.sup.5; [0108] wherein heterocyclyl is selected from
[0109] a C.sub.4-6-cycloalkyl group wherein 1 CH.sub.2 group is
replaced by NR.sup.N or O and/or 1>CH-- group is replaced by N,
and 1 additional CH.sub.2 group is optionally replaced by
C(.dbd.O); [0110] wherein heteroaryl is selected from [0111]
tetrazolyl, or [0112] a 5-membered heteroaromatic ring containing 1
ring member selected from NR.sup.N, NR.sup.5, N, O and S, or [0113]
containing 1 N and 1 ring member selected from NR.sup.N, NR.sup.5,
N, O and S, or containing 1 NR.sup.N, NR.sup.5, N, O or S and 2 N,
and [0114] a 6-membered heteroaromatic ring which contains 1 to 2 N
atoms, with the proviso that R.sup.2 in total must not be
C.sub.1-4-alkyl-, C.sub.1-4-alkyl-O--C.sub.1-4-alkyl,
HO--C.sub.1-4-alkyl, and C.sub.1-4-alkyl-O--.
R.sup.2-G4:
[0115] In another embodiment the group R.sup.2 is selected from the
group R.sup.2-G4 consisting of C.sub.1-4-alkyl,
C.sub.3-6-cycloalkyl-, C.sub.1-4-alkyl-O-- and
C.sub.3-6-cycloalkyl-O--, [0116] wherein each alkyl and cycloalkyl
group is substituted with 1 group selected from R.sup.4 and
optionally substituted with 1 or 2 H.sub.3C-- group; and of
heterocyclyl-C(.dbd.O)--, H.sub.2N--C(.dbd.O)--,
C.sub.1-2-alkyl-NH--C(.dbd.O)--,
(C.sub.1-2-alkyl).sub.2N--C(.dbd.O)--,
C.sub.1-3-alkyl-C(.dbd.O)--NH--, heterocyclyl-O--, heteroaryl-O--,
heterocyclyl and heteroaryl, [0117] wherein each heterocyclyl group
is optionally substituted with 1 group selected from R.sup.4 and
optionally substituted with 1 additional H.sub.3C-- group; [0118]
wherein each heteroaryl group is optionally substituted with 1 or 2
substituents independently selected from R.sup.5; [0119] wherein
heterocyclyl is selected from a C.sub.4-6-cycloalkyl group wherein
1 CH.sub.2 group is replaced by O and/or 1>CH-- group is
replaced by N, and 1 additional CH.sub.2 group is optionally
replaced by C(.dbd.O); and [0120] wherein heteroaryl is selected
from pyridinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,
thiazolyl, triazolyl, oxadiazolyl and tetrazolyl; with the proviso
that R.sup.2 in total must not be C.sub.1-4-alkyl-,
C.sub.1-4-alkyl-O--C.sub.1-4-alkyl, HO--C.sub.1-4-alkyl, and
C.sub.1-4-alkyl-O--.
R.sup.2-G5:
[0121] According to another embodiment the group R.sup.2 is
selected from the group R.sup.2-G5 consisting of
NC--C.sub.1-2-alkyl-, HO--C.sub.5-6-alkyl-,
tetrahydropyranyl-CH.sub.2--, pyrrolidin-1-yl-CH.sub.2--,
piperidin-1-yl-CH.sub.2--, morpholin-4-yl-CH.sub.2--,
H.sub.3C--C(.dbd.O)--NH--CH.sub.2--,
C.sub.1-2-alkyl-NH--C(.dbd.O)--,
(C.sub.1-2-alkyl).sub.2N--C(.dbd.O)--, pyrrolidin-1-yl-C(.dbd.O)--,
morpholin-4-yl-C(.dbd.O)--, H.sub.3C--C(.dbd.O)--NH--,
pyrrolidin-2-on-1-yl, HO--C.sub.2-5-alkyl-O--,
H.sub.3C--O--C.sub.2-4-alkyl-O--,
H.sub.3C--S(.dbd.O).sub.2--C.sub.1-3-alkyl-O--,
tetrahydrofuranyl-O--, tetrahydropyranyl-O--, tetrahydropyranyl,
and tetrahydropyranyl-CH.sub.2--O-- optionally substituted with one
HO-- group, and pyridinyl, imidazolyl, pyrazolyl, isoxazolyl,
thiazolyl, triazolyl, oxadiazolyl and tetrazolyl, wherein each of
these heteroaryl groups is optionally substituted with 1 or 2
H.sub.3C-- groups or 1 HO--C(CH.sub.3).sub.2--CH.sub.2-- group.
R.sup.2-G6:
[0122] According to another embodiment the group R.sup.2 is
selected from the group R.sup.2-G6 consisting of
##STR00019## ##STR00020##
R.sup.2-G6a:
[0123] According to another embodiment the group R.sup.2 is
selected from the group R.sup.2-G6a consisting of
##STR00021## ##STR00022##
R.sup.3
R.sup.3-G1:
[0124] The group R.sup.3 is preferably selected from the group
R.sup.3-G1 as defined hereinbefore.
R.sup.3-G2:
[0125] In another embodiment the group R.sup.3 is selected from the
group R.sup.3-G2 consisting of F, Cl, CN, C.sub.1-3-alkyl,
C.sub.3-4-cycloalkyl-, C.sub.1-3-alkyl-O-- and
H.sub.3C--S(.dbd.O).sub.2--, wherein any alkyl and cycloalkyl group
is optionally substituted with 1 or more F atoms.
R.sup.3-G3:
[0126] In another embodiment the group R.sup.3 is selected from the
group R.sup.3-G3 consisting of F, --CH.sub.3 and CN.
R.sup.3-G4:
[0127] In another embodiment the group R.sup.3 is F.
R.sup.4
R.sup.4-G1:
[0128] The group R.sup.4 is preferably selected from the group
R.sup.4-G1 as defined hereinbefore.
R.sup.4-G2:
[0129] In one embodiment the group R.sup.4 is selected from the
group R.sup.4-G2 consisting of C.sub.1-4-alkyl-, --CN,
C.sub.3-6-cycloalkyl-, heterocyclyl-C(.dbd.O)--,
H.sub.2N--C(.dbd.O)--, C.sub.1-4-alkyl-NR.sup.N--C(.dbd.O)--,
C.sub.3-6-cycloalkyl-NR.sup.N--C(.dbd.O)--,
heterocyclyl-NR.sup.N--C(.dbd.O)--,
heteroaryl-NR.sup.N--C(.dbd.O)--, --NH.sub.2,
C.sub.1-4-alkyl-NR.sup.N--, C.sub.1-4-alkyl-C(.dbd.O)NR.sup.N--,
C.sub.3-6-cycloalkyl-C(.dbd.O)NR.sup.N--,
heterocyclyl-C(.dbd.O)NR.sup.N--, heteroaryl-C(.dbd.O)NR.sup.N--,
C.sub.1-4-alkyl-S(.dbd.O).sub.2NR.sup.N--, --OH,
C.sub.1-4-alkyl-O--, C.sub.1-4-alkyl-O--C.sub.1-4-alkyl-O--,
C.sub.3-6-cycloalkyl-O--, heterocyclyl-O--, phenyl-O--,
heteroaryl-O--, C.sub.1-4-alkyl-S(.dbd.O)--,
C.sub.3-6-cycloalkyl-S(.dbd.O)--,
C.sub.1-4-alkyl-S(.dbd.O).sub.2--,
C.sub.3-6-cycloalkyl-S(.dbd.O).sub.2--, heterocyclyl and
heteroaryl, [0130] wherein any alkyl, cycloalkyl, and heterocyclyl
group is optionally substituted with 1 or more F atoms and
optionally substituted with 1 or 2 groups independently selected
from H.sub.3C--, HO--, H.sub.3C--O--, and --CN; [0131] wherein
heterocyclyl is selected from [0132] a C.sub.4-6-cycloalkyl group
wherein 1 CH.sub.2 group is replaced by NR.sup.N or O and/or
1>CH-- group is replaced by N, and 1 additional CH.sub.2 group
is optionally replaced by C(.dbd.O); [0133] and wherein heteroaryl
is selected from [0134] imidazolyl, pyrazolyl, oxazolyl, triazolyl,
tetrazolyl, pyridinyl and pyrimidinyl, each of which is optionally
substituted with 1 or 2 substituents independently selected from
--CH.sub.3 and --O--CH.sub.3.
R.sup.4-G3:
[0135] In another embodiment the group R.sup.4 is selected from the
group R.sup.4-G3 consisting of C.sub.1-4-alkyl-, --CN,
C.sub.3-6-cycloalkyl-, heterocyclyl-C(.dbd.O)--,
H.sub.2N--C(.dbd.O)--, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, --N(CH.sub.3).sub.2,
C.sub.1-3-alkyl-C(.dbd.O)NR.sup.N--,
C.sub.1-3-alkyl-S(.dbd.O).sub.2NR.sup.N--, --OH,
C.sub.1-4-alkyl-O--, C.sub.3-6-cycloalkyl-O--, heterocyclyl-O--,
C.sub.1-3-alkyl-S(.dbd.O)--, C.sub.1-3-alkyl-S(.dbd.O).sub.2--,
heterocyclyl and heteroaryl, [0136] wherein any alkyl, cycloalkyl
and heterocyclyl group is optionally substituted with 1 or more F
atoms and optionally substituted with 1 or 2 groups independently
selected from H.sub.3C--, HO--, H.sub.3C--O-- and --CN, [0137]
wherein heterocyclyl is selected from [0138] a C.sub.4-6-cycloalkyl
group wherein 1 CH.sub.2 group is replaced by NR.sup.N or O and/or
1>CH-- group is replaced by N, and 1 additional CH.sub.2 group
is optionally replaced by C(.dbd.O); and wherein heteroaryl is
selected from [0139] imidazolyl, pyrazolyl, oxazolyl, triazolyl,
pyridinyl and pyrimidinyl, each of which is optionally substituted
with 1 or 2 substituents independently selected from --CH.sub.3 and
--O--CH.sub.3.
R.sup.4-G4:
[0140] In another embodiment the group R.sup.4 is selected from the
group R.sup.4-G4 consisting of C.sub.1-2-alkyl-, --CN,
H.sub.2N--C(.dbd.O)--, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, --N(CH.sub.3).sub.2,
H.sub.3C--C(.dbd.O)NH--, H.sub.3C--S(.dbd.O).sub.2NH--, --OH,
C.sub.1-3-alkyl-O--, heterocyclyl-O--, H.sub.3C--S(.dbd.O)--,
H.sub.3C--S(.dbd.O).sub.2--, heterocyclyl, and heteroaryl, [0141]
wherein heterocyclyl is selected from [0142] oxetanyl,
pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl,
and morpholin-4-yl, wherein each of these rings is optionally
substituted with 1 CH.sub.3 or 1 OH group; [0143] and wherein
heteroaryl is selected from [0144] imidazolyl, pyrazolyl, oxazolyl
and triazolyl, each of which is optionally substituted with 1 or
2-CH.sub.3 groups.
R.sup.4-G5:
[0145] According to another embodiment the group R.sup.4 is
selected from the group R.sup.4-G5 consisting of
--CH.sub.3, H.sub.3C--C(.dbd.O)NH--, --OH, H.sub.3C--O--,
H.sub.3C--S(.dbd.O).sub.2--, tetrahydropyranyl,
4-hydroxy-tetrahydropyran-4-yl and morpholin-4-yl.
R.sup.4-G5a:
[0146] According to another embodiment the group R.sup.4 is
selected from the group R.sup.4-G5a consisting of
--CH.sub.3, --CN, H.sub.3C--C(.dbd.O)NH--, --OH, H.sub.3C--O--,
H.sub.3C--S(.dbd.O).sub.2--, pyrrolidin-1-yl, piperidin-1-yl,
tetrahydropyran-4-yl, 4-hydroxy-tetrahydropyran-4-yl and
morpholin-4-yl.
R.sup.4-G6:
[0147] According to another embodiment the group R.sup.4 is
selected from the group R.sup.4-G6 consisting of
--CH.sub.3, --OH, H.sub.3C--O-- and
H.sub.3C--S(.dbd.O).sub.2--.
R.sup.s
R.sup.5-G1:
[0148] The group R.sup.5 is preferably selected from the group
R.sup.5-G1 as defined hereinbefore.
R.sup.5-G2:
[0149] In one embodiment the group R.sup.5 is selected from the
group R.sup.5-G2 consisting of F, Cl, C.sub.1-3-alkyl,
HO--C.sub.1-4-alkyl-, --CF.sub.3, --CN, C.sub.1-3-alkyl-O--,
F.sub.3C--O--, --S(.dbd.O)CH.sub.3 and
--S(.dbd.O).sub.2--CH.sub.3.
R.sup.5-G3:
[0150] In another embodiment the group R.sup.5 is selected from the
group R.sup.5-G3 consisting of F, --CH.sub.3,
HO--C(CH.sub.3).sub.2--CH.sub.2--, --CF.sub.3, --CN and
--OCH.sub.3.
R.sup.5-G4:
[0151] In another embodiment the group R.sup.5 is selected from the
group R.sup.5-G4 consisting of --CH.sub.3 and
HO--C(CH.sub.3).sub.2--CH.sub.2--.
R.sup.N
R.sup.N-G1:
[0152] The group R.sup.N is preferably selected from the group
R.sup.N-G1 as defined hereinbefore.
R.sup.N-G2:
[0153] In another embodiment the group R.sup.N is selected from the
group R.sup.N-G2 consisting of H, C.sub.1-3-alkyl,
H.sub.3C--C(.dbd.O)--, and C.sub.1-3-alkyl-S(.dbd.O).sub.2--.
R.sup.N-G3:
[0154] In another embodiment the group R.sup.N is selected from the
group R.sup.N-G3 consisting of H, H.sub.3C--,
H.sub.3C--C(.dbd.O)--, and C.sub.1-3-alkyl-S(.dbd.O).sub.2--.
[0155] Examples of preferred subgeneric embodiments (E) according
to the present invention are set forth in the following table,
wherein each substituent group of each embodiment is defined
according to the definitions set forth hereinbefore and wherein all
other substituents of the formula I are defined according to the
definitions set forth hereinbefore:
TABLE-US-00001 E (Het)Ar- R.sup.1- R.sup.2- R.sup.3- R.sup.4-
R.sup.5- R.sup.N- E-1 (Het)Ar-G1 R.sup.1-G1 R.sup.2-G1 R.sup.3-G1
R.sup.4-G1 R.sup.5-G1 R.sup.N-G1 E-2 (Het)Ar-G2 R.sup.1-G2
R.sup.2-G2 R.sup.3-G2 R.sup.4-G2 R.sup.5-G2 R.sup.N-G2 E-3
(Het)Ar-G3 R.sup.1-G2 R.sup.2-G3 R.sup.3-G3 R.sup.4-G3 R.sup.5-G3
R.sup.N-G3 E-4 (Het)Ar-G4 R.sup.1-G2 R.sup.2-G4 R.sup.3-G3
R.sup.4-G4 R.sup.5-G3 -- E-5 (Het)Ar-G4 R.sup.1-G3 R.sup.2-G3
R.sup.3-G2 R.sup.4-G3 R.sup.5-G2 R.sup.N-G3 E-6 (Het)Ar-G4
R.sup.1-G3 R.sup.2-G3 R.sup.3-G3 R.sup.4-G4 R.sup.5-G3 R.sup.N-G3
E-7 (Het)Ar-G5a R.sup.1-G2 R.sup.2-G2 R.sup.3-G2 R.sup.4-G2
R.sup.5-G2 R.sup.N-G3 E-8 (Het)Ar-G5a R.sup.1-G2 R.sup.2-G3
R.sup.3-G3 R.sup.4-G3 R.sup.5-G2 R.sup.N-G3 E-9 (Het)Ar-G5a
R.sup.1-G2 R.sup.2-G4 R.sup.3-G3 R.sup.4-G4 R.sup.5-G3 -- E-10
(Het)Ar-G5b R1-G2 R2-G2 R3-G2 R4-G2 R5-G2 RN-G3 E-11 (Het)Ar-G5b
R1-G2 R2-G3 R3-G3 R4-G3 R5-G2 RN-G3 E-12 (Het)Ar-G5b R1-G2 R2-G4
R3-G3 R4-G4 R5-G3 -- E-13 (Het)Ar-G5c R1-G2 R2-G2 R3-G2 R4-G2 R5-G2
RN-G3 E-14 (Het)Ar-G5c R1-G2 R2-G3 R3-G3 R4-G3 R5-G2 RN-G3 E-15
(Het)Ar-G5c R1-G2 R2-G4 R3-G3 R4-G4 R5-G3 -- E-16 (Het)Ar-G4
R.sup.1-G3 R.sup.2-G4 R.sup.3-G3 R.sup.4-G4 R.sup.5-G3 -- E-17
(Het)Ar-G4 R.sup.1-G3 R.sup.2-G4 R.sup.3-G3 R.sup.4-G5 R.sup.5-G3
-- E-18 (Het)Ar-G4 R.sup.1-G3 R.sup.2-G4 R.sup.3-G3 R.sup.4-G5a
R.sup.5-G3 -- E-19 (Het)Ar-G4 R.sup.1-G3 R.sup.2-G4 R.sup.3-G3
R.sup.4-G6 R.sup.5-G4 -- E-20 (Het)Ar-G4 R.sup.1-G3 R.sup.2-G5
R.sup.3-G4 -- -- -- E-21 (Het)Ar-G5 R.sup.1-G3 R.sup.2-G4
R.sup.3-G3 R.sup.4-G4 R.sup.5-G3 -- E-22 (Het)Ar-G5a R.sup.1-G3
R.sup.2-G4 R.sup.3-G3 R.sup.4-G4 R.sup.5-G3 -- E-23 (Het)Ar-G5a
R.sup.1-G3 R.sup.2-G4 R.sup.3-G3 R.sup.4-G5 R.sup.5-G3 -- E-24
(Het)Ar-G5b R.sup.1-G3 R.sup.2-G4 R.sup.3-G3 R.sup.4-G4 R.sup.5-G3
-- E-25 (Het)Ar-G5b R.sup.1-G3 R.sup.2-G4 R.sup.3-G3 R.sup.4-G5
R.sup.5-G3 -- E-26 (Het)Ar-G5c R.sup.1-G3 R.sup.2-G4 R.sup.3-G3
R.sup.4-G4 R.sup.5-G3 -- E-27 (Het)Ar-G5c R.sup.1-G3 R.sup.2-G4
R.sup.3-G3 R.sup.4-G5 R.sup.5-G3 -- E-28 (Het)Ar-G4 R.sup.1-G3
R.sup.2-G4 R.sup.3-G3 R.sup.4-G5a R.sup.5-G3 -- E-29 (Het)Ar-G5a
R.sup.1-G3 R.sup.2-G4 R.sup.3-G3 R.sup.4-G6 R.sup.5-G4 -- E-30
(Het)Ar-G5b R.sup.1-G3 R.sup.2-G4 R.sup.3-G3 R.sup.4-G6 R.sup.5-G4
-- E-31 (Het)Ar-G5c R.sup.1-G3 R.sup.2-G4 R.sup.3-G3 R.sup.4-G6
R.sup.5-G4 -- E-32 (Het)Ar-G5a R.sup.1-G3 R.sup.2-G5 R.sup.3-G4 --
-- -- E-33 (Het)Ar-G5b R.sup.1-G3 R.sup.2-G5 R.sup.3-G4 -- -- --
E-34 (Het)Ar-G5c R.sup.1-G3 R.sup.2-G5 R.sup.3-G4 -- -- -- E-35
(Het)Ar-G5a R.sup.1-G3 R.sup.2-G6 R.sup.3-G4 -- -- -- E-36
(Het)Ar-G5b R.sup.1-G3 R.sup.2-G6 R.sup.3-G4 -- -- -- E-37
(Het)Ar-G5c R.sup.1-G3 R.sup.2-G6 R.sup.3-G4 -- -- -- E-38
(Het)Ar-G5a R.sup.1-G3 R.sup.2-G6a R.sup.3-G4 -- -- -- E-39
(Het)Ar-G5b R.sup.1-G3 R.sup.2-G6a R.sup.3-G4 -- -- -- E-40
(Het)Ar-G5c R.sup.1-G3 R.sup.2-G6a R.sup.3-G4 -- -- -- E-41
(Het)Ar-G6 R.sup.1-G3 -- -- -- -- -- E-42 (Het)Ar-G6a R.sup.1-G3 --
-- -- -- --
[0156] Preferred are those compounds of formula I, wherein [0157]
(Het)Ar is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,
quinolinyl, isoquinolinyl, quinazolinyl, indolinyl,
benzoimidazolyl, indazolyl, benzoxazolyl or benzothiazolyl, wherein
each of these groups is substituted with 1 group R.sup.2 and
optionally substituted with 1 to 3 groups independently selected
from R.sup.3; or [0158] (Het)Ar is 2,3-dihydrobenzofuran,
benzo[1,3]dioxole, 2,3-dihydro-benzo[1,4]dioxine or
3,4-dihydro-1H-quinolin-2-one, which are optionally substituted
with 1 group R.sup.3; [0159] R.sup.1 is H; [0160] R.sup.2 is
C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl-, C.sub.1-4-alkyl-O-- or
C.sub.3-6-cycloalkyl-O--, [0161] wherein each alkyl and cycloalkyl
group is substituted with 1 group R.sup.4 and optionally
substituted with 1 or 2 H.sub.3C-- group; or [0162] R.sup.2 is
heterocyclyl-C(.dbd.O)--, H.sub.2N--C(.dbd.O)--,
C.sub.1-2-alkyl-NH--C(.dbd.O)--,
(C.sub.1-2-alkyl).sub.2N--C(.dbd.O)--,
C.sub.1-3-alkyl-C(.dbd.O)--NH--, heterocyclyl-O--, heteroaryl-O--,
heterocyclyl or heteroaryl, [0163] wherein each heterocyclyl group
is optionally substituted with 1 group selected from R.sup.4 and
optionally substituted with 1 additional H.sub.3C-- group; [0164]
wherein each heteroaryl group is optionally substituted with 1 or 2
substituents independently selected from R.sup.5; [0165] wherein
heterocyclyl is a C.sub.4-6-cycloalkyl group wherein 1 CH.sub.2
group is replaced by O and/or 1>CH-- group is replaced by N, and
1 additional CH.sub.2 group is optionally replaced by C(.dbd.O);
[0166] wherein heteroaryl is pyridinyl, imidazolyl, pyrazolyl,
oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl or
tetrazolyl; with the proviso that R.sup.2 in total must not be
C.sub.1-4-alkyl-, C.sub.1-4-alkyl-O--C.sub.1-4-alkyl,
HO--C.sub.1-4-alkyl, and C.sub.1-4-alkyl-O--; [0167] R.sup.3 is F,
--CH.sub.3 or CN; [0168] R.sup.4 is C.sub.1-2-alkyl-, --CN,
H.sub.2N--C(.dbd.O)--, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, --N(CH.sub.3).sub.2,
H.sub.3C--C(.dbd.O)NH--, H.sub.3C--S(.dbd.O).sub.2NH--, --OH,
C.sub.1-3-alkyl-O--, heterocyclyl-O--, H.sub.3C--S(.dbd.O)--,
H.sub.3C--S(.dbd.O).sub.2--, heterocyclyl, and heteroaryl, [0169]
wherein heterocyclyl is oxetanyl, pyrrolidinyl, tetrahydrofuranyl,
piperidinyl, tetrahydropyranyl or morpholin-4-yl, each of which is
optionally substituted with 1 CH.sub.3 or 1 OH group; [0170]
wherein heteroaryl is imidazolyl, pyrazolyl, oxazolyl or triazolyl,
each of which is optionally substituted with 1 or 2-CH.sub.3
groups; [0171] R.sup.5 is F, --CH.sub.3,
HO--C(CH.sub.3).sub.2--CH.sub.2--, --CF.sub.3, --CN or --OCH.sub.3;
[0172] and the pharmaceutically acceptable salts thereof.
[0173] More preferred are those compounds of formula I, wherein
[0174] (Het)Ar is phenyl, which is substituted with 1 group R.sup.2
and optionally substituted with 1 to 3 groups independently
selected from R.sup.3; [0175] R.sup.1 is H; [0176] R.sup.2 is
C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl-, C.sub.1-4-alkyl-O-- or
C.sub.3-6-cycloalkyl-O--, [0177] wherein each alkyl and cycloalkyl
group is substituted with 1 group R.sup.4 and optionally
substituted with 1 or 2 H.sub.3C-- group; or [0178] R.sup.2 is
heterocyclyl-C(.dbd.O)--, H.sub.2N--C(.dbd.O)--,
C.sub.1-2-alkyl-NH--C(.dbd.O)--,
(C.sub.1-2-alkyl).sub.2N--C(.dbd.O)--,
C.sub.1-3-alkyl-C(.dbd.O)--NH--, heterocyclyl-O--, heteroaryl-O--,
heterocyclyl or heteroaryl, [0179] wherein each heterocyclyl group
is optionally substituted with 1 group selected from R.sup.4 and
optionally substituted with 1 additional H.sub.3C-- group; [0180]
wherein each heteroaryl group is optionally substituted with 1 or 2
substituents independently selected from R.sup.5; [0181] wherein
heterocyclyl is a C.sub.4-6-cycloalkyl group wherein 1 CH.sub.2
group is replaced by O and/or 1>CH-- group is replaced by N, and
1 additional CH.sub.2 group is optionally replaced by C(.dbd.O);
[0182] wherein heteroaryl is pyridinyl, imidazolyl, pyrazolyl,
oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl or
tetrazolyl; with the proviso that R.sup.2 in total must not be
C.sub.1-4-alkyl-, C.sub.1-4-alkyl-O--C.sub.1-4-alkyl,
HO--C.sub.1-4-alkyl, and C.sub.1-4-alkyl-O--; [0183] R.sup.3 is F,
--CH.sub.3 or CN; [0184] R.sup.4 is C.sub.1-2-alkyl-, --CN,
H.sub.2N--C(.dbd.O)--, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, --N(CH.sub.3).sub.2,
H.sub.3C--C(.dbd.O)NH--, H.sub.3C--S(.dbd.O).sub.2NH--, --OH,
C.sub.1-3-alkyl-O--, heterocyclyl-O--, H.sub.3C--S(.dbd.O)--,
H.sub.3C--S(.dbd.O).sub.2--, heterocyclyl, and heteroaryl, [0185]
wherein heterocyclyl is oxetanyl, pyrrolidinyl, tetrahydrofuranyl,
piperidinyl, tetrahydropyranyl or morpholin-4-yl, each of which is
optionally substituted with 1 CH.sub.3 or 1 OH group; [0186]
wherein heteroaryl is imidazolyl, pyrazolyl, oxazolyl or triazolyl,
each of which is optionally substituted with 1 or 2-CH.sub.3
groups; [0187] R.sup.5 is F, --CH.sub.3,
HO--C(CH.sub.3).sub.2--CH.sub.2--, --CF.sub.3, --CN or --OCH.sub.3;
and the pharmaceutically acceptable salts thereof.
[0188] Particularly preferred compounds, including their tautomers
and stereoisomers, the salts thereof, or any solvates or hydrates
thereof, are described in the experimental section hereinafter.
[0189] The compounds according to the invention and their
intermediates may be obtained using methods of synthesis which are
known to the one skilled in the art and described in the literature
of organic synthesis. Preferably the compounds are obtained
analogously to the methods of preparation explained more fully
hereinafter, in particular as described in the experimental
section. In some cases the sequence adopted in carrying out the
reaction schemes may be varied. Variants of these reactions that
are known to the skilled man but are not described in detail here
may also be used. The general processes for preparing the compounds
according to the invention will become apparent to the skilled man
on studying the schemes that follow. Starting compounds are
commercially available or may be prepared by methods that are
described in the literature or herein, or may be prepared in an
analogous or similar manner. Before the reaction is carried out any
corresponding functional groups in the compounds may be protected
using conventional protecting groups. These protecting groups may
be cleaved again at a suitable stage within the reaction sequence
using methods familiar to the skilled man.
[0190] The compounds of the invention I are preferably accessed
from a precursor 1 that bears the carboxylic acid protected as
ester (Scheme 1); (Het)Ar and R.sup.1 have the meanings as defined
hereinbefore and hereinafter. The ester group may be hydrolysed in
the presence of an acid, such as hydrochloric acid or sulfuric
acid, or an alkali metal hydroxide, such as lithium hydroxide,
sodium hydroxide, or potassium hydroxide, to yield the carboxylic
acid. The hydrolysis is preferably conducted in aqueous solvents,
such as water combined with tetrahydrofuran, 1,4-dioxane, alcohol,
e.g. methanol, ethanol and isopropanol, or dimethyl sulfoxide, at 0
to 120.degree. C. A tert-butyl ester is preferably cleaved under
acidic conditions, e.g. trifluoroacetic acid or hydrochloric acid,
in a solvent, such as dichloromethane, 1,4-dioxane, isopropanol or
ethyl acetate. A benzyl ester is advantageously cleaved using
hydrogen in the presence of a transition metal, preferably
palladium on carbon. Benzyl esters bearing electron donating groups
on the phenyl ring, such as methoxy, may also be removed under
oxidative conditions; ceric ammonium nitrate (CAN) or
2,3-dichloro-5,6-dicyanoquinone (DDQ) are reagents commonly used
for this
##STR00023##
[0191] Compound I may be assembled using building blocks 2, 3 and 4
(Scheme 2); (Het)Ar and R.sup.1 have the meanings as defined
hereinbefore and hereinafter.
##STR00024##
[0192] Building blocks 3 and 4 may be combined in a stereoselective
fashion employing the conditions of the Mitsunobu reaction or
variations thereof (Scheme 3); (Het)Ar and R.sup.1 have the
meanings as defined hereinbefore and hereinafter. The reaction is
usually conducted with a phosphine and an azodicarboxylic ester or
amide in tetrahydrofuran, 1,4-dioxane, diethyl ether, toluene,
benzene, dichloromethane, or mixtures thereof, at -30 to
100.degree. C. Phosphines often used are triphenylphosphine and
tributylphosphine, which are commonly combined with dimethyl
azodicarboxylate, diethyl azodicarboxylate, diisopropyl
azodicarboxylate, di-(4-chlorobenzyl) azodicarboxylate, dibenzyl
azodicarboxylate, di-tert-butyl azodicarboxylate, azodicarboxylic
acid bis-(dimethylamide), azodicarboxylic acid dipiperidide, or
azodicarboxylic acid dimorpholide.
##STR00025##
[0193] The group (Het)Ar may be attached to the indane moiety via
an oxygen starting from various precursors (Scheme 4); (Het)Ar and
R.sup.1 have the meanings as defined hereinbefore and hereinafter.
The two parts may be linked using one of them decorated with a
hydroxy group (X or Z denotes OH) and the other one with a boronic
acid group (X or Z denotes B(OH).sub.2). The two building blocks
accordingly equipped may be coupled employing copper(II) acetate in
the presence of a base, e.g. pyridine or triethylamine, molecular
sieves, optionally a co-oxidant, e.g. oxygen, in a solvent, e.g.
dichloromethane, at 0 to 60.degree. C. Alternatively, the linkage
between (Het)Ar and indane via oxygen is formed upon coupling the
indane moiety, bearing an OH group (Z.dbd.OH), and (Het)Ar, bearing
a leaving group (X=e.g., F, Br, Cl, I). The O of the OH group
replaces the leaving group by nucleophilic substitution or a
transition metal catalyzed reaction. The former proceeding is
particularly suited for electron deficient (Het)Ar groups which are
coupled with the hydroxylated indane in the presence of a base,
e.g. Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, KOH, triethylamine or NaH,
preferably in a solvent, e.g. toluene, tetrahydrofuran,
1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidinone, alcohol, water or
mixtures thereof, at 0 to 220.degree. C. The transition metal
catalyzed coupling is used for (Het)Ar groups bearing Cl, Br or I
as leaving group. Suitable transition metal catalysts are commonly
derived from palladium or copper. The active catalyst may be an
elemental form of the transition metal or formed from a salt of the
transition metal, such as fluoride, chloride, bromide, iodide,
acetate, triflate or trifluoroacetate, which are optionally
combined with ligands, such as phosphines, e.g.
tri-tert-butylphosphine, tricyclohexylphosphine, optionally
substituted biphenyl-dicyclohexyl-phosphines, optionally
substituted biphenyl-di-tert-butyl-phosphines,
1,1'-bis(diphenylphosphino)-ferrocene, triphenylphosphine,
tritolylphosphine, or trifurylphosphine, phosphites,
1,3-disubstituted imidazole carbenes, 1,3-disubstituted
imidazolidine carbenes, pyridines or phenanthrolines. The reaction
is usually carried out in the presence of a base, e.g. NaOH, KOH,
Na.sub.2CO.sub.3, K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, triethylamine
or ethyldiisopropylamine, in toluene, tetrahydrofuran,
1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidinone, alcohol, water, or
mixtures thereof, preferably at 10 to 180.degree. C.
##STR00026##
[0194] Intermediate 3 or derivatives thereof, as 3'', may be
obtained from indanone 7, which, in turn, may be prepared from
phenylpropionic acid derivative 6 (Scheme 5); R.sup.1 has the
meaning as defined hereinbefore and hereinafter. For the
intramolecular acylation (Friedel-Crafts acylation), 6.fwdarw.7, a
considerable number of approaches has been reported. The reaction
may be performed starting with a carboxylic acid, carboxylic ester,
carboxylic anhydride, carboxylic chloride or fluoride, or a nitrile
using a Lewis acid as catalyst. The following Lewis acids are some
of the more often used ones: hydrobromic acid, hydroiodic acid,
hydrochloric acid, sulfuric acid, phosphoric acid, P.sub.4O.sub.10,
trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid,
trifluoromethanesulfonic acid, ClSO.sub.3H,
Sc(OSO.sub.2CF.sub.3).sub.3, Tb(OSO.sub.2CF.sub.3).sub.3,
SnCl.sub.4, FeCl.sub.3, AlBr.sub.3, AlCl.sub.3, SbCl.sub.5,
BCl.sub.3, BF.sub.3, ZnCl.sub.2, montmorillonites, POCl.sub.3, and
PCl.sub.5. The reaction may be conducted, e.g., in dichloromethane,
1,2-dichloroethane, nitrobenzene, chlorobenzene, carbon disulfide,
mixtures thereof, or without an additional solvent in an excess of
the Lewis acid, at 0 to 180.degree. C. Carboxylic acids are
preferably reacted in polyphosphoric acid at 0 to 120.degree. C.,
while carboxylic chlorides are preferably reacted with AlCl.sub.3
in dichloromethane or 1,2-dichloroethane at 0 to 80.degree. C.
[0195] The subsequent reduction of the keto group in compound 7
providing the alcohol 3'' in enantiomerically enriched or pure form
may be accomplished using hydrogen or a hydrogen source, such as
formate or silane, and a transition metal catalyst derived from,
e.g., Ir, Rh, Ru or Fe and a chiral auxiliary. For instance, a
ruthenium complex, such as
chloro{[(1S,2S)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)-amido}--
(mesitylene)ruthenium(II), may deliver the hydroxy compound 3''
with high enantiomeric excess using, e.g., formic acid in the
presence of a base, e.g. triethylamine, in dichloromethane, at -20
to 60.degree. C. Alternatively, boranes combined with an
enantiomerically pure [1,3,2]oxazaborol may be used as reducing
agent (Corey-Bakshi-Shibata reaction or Corey-Itsuno reaction).
Typical reaction conditions for this approach are borane (complexed
with, e.g., dimethyl sulfide) and (R)- or
(S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol
in, e.g., dichloromethane, toluene, methanol, tetrahydrofuran, or
mixtures thereof, at 0 to 60.degree. C.
##STR00027##
[0196] The synthetic routes presented may rely on the use of
protecting groups. For example, potentially reactive groups
present, such as hydroxy, carbonyl, carboxy, amino, alkylamino, or
imino, may be protected during the reaction by conventional
protecting groups which are cleaved again after the reaction.
Suitable protecting groups for the respective functionalities and
their removal are well known to the one skilled in the art and are
described in the literature of organic synthesis.
[0197] The compounds of general formula I may be resolved into
their enantiomers and/or diastereomers as mentioned below. Thus,
for example, cis/trans mixtures may be resolved into their cis and
trans isomers and racemic compounds may be separated into their
enantiomers.
[0198] The cis/trans mixtures may be resolved, for example, by
chromatography into the cis and trans isomers thereof. The
compounds of general formula I which occur as racemates may be
separated by methods known per se into their optical antipodes and
diastereomeric mixtures of compounds of general formula I may be
resolved into their diastereomers by taking advantage of their
different physico-chemical properties using methods known per se,
e.g. chromatography and/or fractional crystallization; if the
compounds obtained thereafter are racemates, they may be resolved
into the enantiomers as mentioned below.
[0199] The racemates are preferably resolved by column
chromatography on chiral phases or by crystallization from an
optically active solvent or by reacting with an optically active
substance which forms salts or derivatives such as esters or amides
with the racemic compound. Salts may be formed with
enantiomerically pure acids for basic compounds and with
enantiomerically pure bases for acidic compounds. Diastereomeric
derivatives are formed with enantiomerically pure auxiliary
compounds, e.g. acids, their activated derivatives, or alcohols.
Separation of the diastereomeric mixture of salts or derivatives
thus obtained may be achieved by taking advantage of their
different physico-chemical properties, e.g. differences in
solubility; the free antipodes may be released from the pure
diastereomeric salts or derivatives by the action of suitable
agents. Optically active acids commonly used for such a purpose as
well as optically active alcohols applicable as auxiliary residues
are known to those skilled in the art.
[0200] As mentioned above, the compounds of formula I may be
converted into salts, particularly for pharmaceutical use into the
pharmaceutically acceptable salts. As used herein,
"pharmaceutically acceptable salts" refer to derivatives of the
disclosed compounds wherein the parent compound is modified by
making acid or base salts thereof.
[0201] The compounds according to the invention are advantageously
also obtainable using the methods described in the examples that
follow, which may also be combined for this purpose with methods
known to the skilled man from the literature.
TERMS AND DEFINITIONS
[0202] Terms not specifically defined herein should be given the
meanings that would be given to them by one of skill in the art in
light of the disclosure and the context. As used in the
specification, however, unless specified to the contrary, the
following terms have the meaning indicated and the following
conventions are adhered to.
[0203] The terms "compound(s) according to this invention",
"compound(s) of formula (I)", "compound(s) of the invention" and
the like denote the compounds of the formula (I) according to the
present invention including their tautomers, stereoisomers and
mixtures thereof and the salts thereof, in particular the
pharmaceutically acceptable salts thereof, and the solvates and
hydrates of such compounds, including the solvates and hydrates of
such tautomers, stereoisomers and salts thereof.
[0204] The terms "treatment" and "treating" embrace both
preventative, i.e. prophylactic, or therapeutic, i.e. curative
and/or palliative, treatment. Thus the terms "treatment" and
"treating" comprise therapeutic treatment of patients having
already developed said condition, in particular in manifest form.
Therapeutic treatment may be symptomatic treatment in order to
relieve the symptoms of the specific indication or causal treatment
in order to reverse or partially reverse the conditions of the
indication or to stop or slow down progression of the disease. Thus
the compositions and methods of the present invention may be used
for instance as therapeutic treatment over a period of time as well
as for chronic therapy. In addition the terms "treatment" and
"treating" comprise prophylactic treatment, i.e. a treatment of
patients at risk to develop a condition mentioned hereinbefore,
thus reducing said risk.
[0205] When this invention refers to patients requiring treatment,
it relates primarily to treatment in mammals, in particular
humans.
[0206] The term "therapeutically effective amount" means an amount
of a compound of the present invention that (i) treats or prevents
the particular disease or condition, (ii) attenuates, ameliorates,
or eliminates one or more symptoms of the particular disease or
condition, or (iii) prevents or delays the onset of one or more
symptoms of the particular disease or condition described
herein.
[0207] The terms "modulated" or "modulating", or "modulate(s)", as
used herein, unless otherwise indicated, refer to the activation of
the G-protein-coupled receptor GPR40 with one or more compounds of
the present invention.
[0208] The terms "mediated" or "mediating" or "mediate", as used
herein, unless otherwise indicated, refer to the (i) treatment,
including prevention of the particular disease or condition, (ii)
attenuation, amelioration, or elimination of one or more symptoms
of the particular disease or condition, or (iii) prevention or
delay of the onset of one or more symptoms of the particular
disease or condition described herein.
[0209] The term "substituted" as used herein, means that any one or
more hydrogens on the designated atom, radical or moiety is
replaced with a selection from the indicated group, provided that
the atom's normal valence is not exceeded, and that the
substitution results in an acceptably stable compound.
[0210] In the groups, radicals, or moieties defined below, the
number of carbon atoms is often specified preceding the group, for
example, C.sub.1-6-alkyl means an alkyl group or radical having 1
to 6 carbon atoms. In general, for groups comprising two or more
subgroups, the last named subgroup is the radical attachment point,
for example, the substituent "aryl-C.sub.1-3-alkyl-" means an aryl
group which is bound to a C.sub.1-3-alkyl-group, the latter of
which is bound to the core or to the group to which the substituent
is attached.
[0211] In case a compound of the present invention is depicted in
form of a chemical name and as a formula in case of any discrepancy
the formula shall prevail.
[0212] An asterisk may be used in sub-formulas to indicate the bond
which is connected to the core molecule as defined.
[0213] The numeration of the atoms of a substituent starts with the
atom which is closest to the core or to the group to which the
substituent is attached.
[0214] For example, the term "3-carboxypropyl-group" represents the
following substituent:
##STR00028##
wherein the carboxy group is attached to the third carbon atom of
the propyl group.
[0215] The terms "1-methylpropyl-", "2,2-dimethylpropyl-" or
"cyclopropylmethyl-" group represent the following groups:
##STR00029##
[0216] The asterisk may be used in sub-formulas to indicate the
bond which is connected to the core molecule as defined.
[0217] In a definition of a group the term "wherein each X, Y and Z
group is optionally substituted with" and the like denotes that
each group X, each group Y and each group Z either each as a
separate group or each as part of a composed group may be
substituted as defined. For example a definition "R.sup.ex denotes
H, C.sub.1-3-alkyl, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl or C.sub.1-3-alkyl-O--,
wherein each alkyl group is optionally substituted with one or more
L.sup.ex." or the like means that in each of the beforementioned
groups which comprise the term alkyl, i.e. in each of the groups
C.sub.1-3-alkyl, C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl and
C.sub.1-3-alkyl-O--, the alkyl moiety may be substituted with
L.sup.ex as defined.
[0218] Unless specifically indicated, throughout the specification
and the appended claims, a given chemical formula or name shall
encompass tautomers and all stereo, optical and geometrical isomers
(e.g. enantiomers, diastereomers, E/Z isomers etc. . . . ) and
racemates thereof as well as mixtures in different proportions of
the separate enantiomers, mixtures of diastereomers, or mixtures of
any of the foregoing forms where such isomers and enantiomers
exist, as well as salts, including pharmaceutically acceptable
salts thereof and solvates thereof such as for instance hydrates
including solvates of the free compounds or solvates of a salt of
the compound.
[0219] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, and commensurate with a
reasonable benefit/risk ratio.
[0220] As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds wherein the parent compound
is modified by making acid or base salts thereof.
[0221] Salts of other acids than those mentioned above which for
example are useful for purifying or isolating the compounds of the
present invention (e.g. trifluoro acetate salts) also comprise a
part of the invention.
[0222] The term halogen generally denotes fluorine, chlorine,
bromine and iodine.
[0223] The term "Cl.sub.1-n-alkyl", wherein n is an integer from 1
to n, either alone or in combination with another radical denotes
an acyclic, saturated, branched or linear hydrocarbon radical with
1 to n C atoms. For example the term C.sub.1-5-alkyl embraces the
radicals H.sub.3C--, H.sub.3C--CH.sub.2--,
H.sub.3C--CH.sub.2--CH.sub.2--, H.sub.3C--CH(CH.sub.3)--,
H.sub.3C--CH.sub.2--CH.sub.2--CH.sub.2--,
H.sub.3C--CH.sub.2--CH(CH.sub.3)--,
H.sub.3C--CH(CH.sub.3)--CH.sub.2--, H.sub.3C--C(CH.sub.3).sub.2--,
H.sub.3C--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
H.sub.3C--CH.sub.2--CH.sub.2--CH(CH.sub.3)--,
H.sub.3C--CH.sub.2--CH(CH.sub.3)--CH.sub.2--,
H.sub.3C--CH(CH.sub.3)--CH.sub.2--CH.sub.2--,
H.sub.3C--CH.sub.2--C(CH.sub.3).sub.2--,
H.sub.3C--C(CH.sub.3).sub.2--CH.sub.2--,
H.sub.3C--CH(CH.sub.3)--CH(CH.sub.3)-- and
H.sub.3C--CH.sub.2--CH(CH.sub.2CH.sub.3)--.
[0224] The term "C.sub.1-n-alkylene" wherein n is an integer 1 to
n, either alone or in combination with another radical, denotes an
acyclic, straight or branched chain divalent alkyl radical
containing from 1 to n carbon atoms. For example the term
C.sub.1-4-alkylene includes --(CH.sub.2)--,
--(CH.sub.2--CH.sub.2)--, --(CH(CH.sub.3))--,
--(CH.sub.2--CH.sub.2--CH.sub.2)--, --(C(CH.sub.3).sub.2)--,
--(CH(CH.sub.2CH.sub.3))--, --(CH(CH.sub.3)--CH.sub.2)--,
--(CH.sub.2--CH(CH.sub.3))--,
--(CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2)--,
--(CH.sub.2--CH.sub.2--CH(CH.sub.3))--,
--(CH(CH.sub.3)--CH.sub.2--CH.sub.2)--,
--(CH.sub.2--CH(CH.sub.3)--CH.sub.2)--,
--(CH.sub.2--C(CH.sub.3).sub.2)--, --(C
(CH.sub.3).sub.2--CH.sub.2)--, --(CH(CH.sub.3)--CH(CH.sub.3))--,
--(CH.sub.2--CH(CH.sub.2CH.sub.3))--,
--(CH(CH.sub.2CH.sub.3)--CH.sub.2)--,
--(CH(CH.sub.2CH.sub.2CH.sub.3))--, --(CHCH(CH.sub.3).sub.2)-- and
--C(CH.sub.3)(CH.sub.2CH.sub.3)--.
[0225] The term "C.sub.2-n-alkenyl", is used for a group as defined
in the definition for "C.sub.1-n-alkyl" with at least two carbon
atoms, if at least two of those carbon atoms of said group are
bonded to each other by a double bond. For example the term
C.sub.2-3-alkenyl includes --CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.sub.3, --CH.sub.2--CH.dbd.CH.sub.2.
[0226] The term "C.sub.2-n-alkynyl", is used for a group as defined
in the definition for "C.sub.1-n-alkyl" with at least two carbon
atoms, if at least two of those carbon atoms of said group are
bonded to each other by a triple bond. For example the term
C.sub.2-3-alkynyl includes --C.ident.CH,
--C.ident.C.ident.CH.sub.3, --CH.sub.2--C.ident.CH.
[0227] The term "C.sub.3-n-carbocyclyl" as used either alone or in
combination with another radical, denotes a monocyclic, bicyclic or
tricyclic, saturated or unsaturated hydrocarbon radical with 3 to n
C atoms. The hydrocarbon radical is preferably nonaromatic.
Preferably the 3 to n C atoms form one or two rings. In case of a
bicyclic or tricyclic ring system the rings may be attached to each
other via a single bond or may be fused or may form a spirocyclic
or bridged ring system. For example the term C.sub.3-10-carbocyclyl
includes C.sub.3-10-cylcoalkyl, C.sub.3-10-cycloalkenyl,
octahydropentalenyl, octahydroindenyl, decahydronaphthyl, indanyl,
tetrahydronaphthyl. Most preferably the term C.sub.3-n-carbocyclyl
denotes C.sub.3-n-cylcoalkyl, in particular
C.sub.3-7-cycloalkyl.
[0228] The term "C.sub.3-n-cycloalkyl", wherein n is an integer 4
to n, either alone or in combination with another radical denotes a
cyclic, saturated, unbranched hydrocarbon radical with 3 to n C
atoms. The cyclic group may be mono-, bi-, tri- or spirocyclic,
most preferably monocyclic. Examples of such cycloalkyl groups
include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl,
bicyclo[3.2.1.]octyl, spiro[4.5]decyl, norpinyl, norbonyl,
norcaryl, adamantyl, etc.
[0229] The term "heteroaryl" or heteroaromatic group, unless
specified otherwise, means a mono- or polycyclic, preferably mono-
or bicyclic-ring system containing one or more heteroatoms selected
from N, NH, NR.sup.N, O or S(O).sub.r with r=0, 1 or 2 wherein at
least one of the heteroatoms is part of an aromatic ring, R.sup.N
preferably is a C.sub.1-3-alkyl group, and wherein said ring system
may have a carbonyl group. More preferably the term "heteroaryl" as
used herein, either alone or in combination with another radical,
means a mono- or bicyclic-ring system containing 1, 2, 3 or 4
heteroatoms selected from N, NH, NR.sup.N, O or S(O).sub.r with
r=0, 1 or 2 wherein at least one of the heteroatoms is part of an
aromatic ring, R.sup.N preferably is a methyl group, and wherein
said ring system may have a carbonyl group. The term "heteroaryl"
is intended to include all the possible isomeric forms.
[0230] Thus, the term "heteroaryl" or heteroaromatic group includes
the following exemplary structures which are not depicted as
radicals as each form may be attached through a covalent bond to
any atom so long as appropriate valences are maintained:
##STR00030## ##STR00031##
[0231] Many of the terms given above may be used repeatedly in the
definition of a formula or group and in each case have one of the
meanings given above, independently of one another.
Chemical Stability
[0232] Degradation kinetics is used to simulate chemical stability
of compounds in the acidic part of the gastro intestinal tract. The
compounds of the invention show significantly superior chemical
stability in acidic aqueous media (pH value ca. 1.2) compared to
related compounds bearing electron neutral or releasing groups on
the benzo part of the indane moiety.
[0233] The chemical stability of the compounds of the invention at
pH value of ca. 1.2 is determined as follows:
[0234] Compound is dissolved in an HPLC vial either in a mixture of
acetonitrile/0.1 M aqueous HCl (2:3; pH ca. 1.2) or in a mixture of
acetonitrile/Mcllvaine buffer pH 7.4 (2:3) to get a concentration
of approximately 0.25 mg/ml. The vial was then transferred into an
HPLC autosampler system and maintained at a temperature of
37.degree. C. A first sample is taken and injected immediately into
a standard HPLC system with a UV DAD detector. Further samples are
injected after 2, 4, 6, 8 and 10 hours. Degradation of the compound
is measured by determining the recovery rate of compound [%] for
each injection using an HPLC standard gradient method. Therefore
the peak area of the main peak for the first injection (AU.sub.t0)
is determined and set as 100%. Peak area of the main peak is
determined also for the further injections (AU.sub.tn, n=2, 4, 6,
8, 10) and expressed as fraction of (AU.sub.t0)/(AU.sub.tn, n=2, 4,
6, 8, 10) [%].
[0235] The recovery rate of the compounds according to the
invention after 2 h at pH value of ca. 1.2 determined as described
above is typically above 90%, preferably above 95%.
[0236] The following table compares the recovery rate after 2 h at
pH value of ca. 1.2 of examples described in the experimental part
with the results obtained with two examples XX and XXI disclosed in
WO2012072691. The number of the compound in the table corresponds
to the number of the Example in the experimental section.
TABLE-US-00002 Example XX ##STR00032## Example XXI ##STR00033##
Recovery rate Example after 2 h 1 97.5% 2 >98% 3 97.5% 6 >98%
9 >99% 11 96.5% 12 >99% XX <5% XXI <5%
Pharmacological Activity
[0237] The activity of the compounds of the invention may be
demonstrated using the following assay:
[0238] IP.sub.1 accumulation measurements using the IPOne assay
system--1321 N1 cells stably expressing human GPR40 receptor
(Euroscreen, Belgium) are seeded 24 h before the assay in white
384-well plates in culture medium containing 10% FCS, 1%
Na-Pyruvate and 400 .mu.g/mL G418. IP.sub.1 is assayed according to
the manufacturer's description (Cisbio Bioassays, France). In
brief, the assay is started by substitution of the culture medium
by stimulation buffer (Hepes 10 mM, CaCl.sub.2 1 mM, MgCl.sub.2 0.5
mM, KCl 4.2 mM, NaCl 146 mM, glucose 5.5 mM and LiCl 50 mM, pH
7.4). Cells are stimulated for 1 h at 37.degree. C., 5% CO.sub.2 by
addition of the compounds that are diluted in stimulation buffer
containing LiCl. Assays are stopped by adding HTRF-conjugates
(IP1-d2 and Anti-IP1 cryptate Tb) and lysis buffer, provided by the
manufacturer. After an incubation time of 1 h at room temperature
plates are measured using an EnVision.TM., Perkin Elmer. The
obtained fluorescence ratios at 665/615 nM are then used to
calculate the pEC.sub.50 values using Assay Explorer 3.3 Software
(Accelrys, Inc.) by interpolation using an IP.sub.1 reference curve
and subsequent sigmoidal curve fitting allowing for a variable hill
slope.
[0239] The compounds according to the invention typically have
EC.sub.50 values in the range from about 1 nM to about 10 .mu.M,
preferably less than 1 .mu.M, more preferably less than 100 nM.
[0240] EC.sub.50 values for compounds according to the invention
are shown in the following Table. The number of the compound
corresponds to the number of the Example in the experimental
section.
TABLE-US-00003 Exam- EC.sub.50 Exam- EC.sub.50 Exam- EC.sub.50
Exam- EC.sub.50 ple [nM] ple [nM] ple [nM] ple [nM] 1 7 2 5 3 13 4
15 5 25 6 8 7 55 8 34 9 18 10 11 11 6 12 18 13 282 14 23 15 3 16 9
17 23 18 31 19 12 20 7 21 6 22 5 23 84 24 10 25 6 26 6 27 9 28 20
29 12 30 13 31 58 32 13 33 45 34 6 35 5 36 8 37 8 38 41 39 23 40
733 41 85 42 120 43 18 44 7 45 29 46 62 47 8 48 9 49 17 50 4 51 29
52 31 53 7 54 9 55 6 56 38 57 4 58 18 59 216 60 20 61 13 62 12 63
22 64 27 70 44
[0241] In view of their ability to modulate the activity of the
G-protein-coupled receptor GPR40, in particular an agonistic
activity, the compounds of general formula I according to the
invention, including the corresponding salts thereof, are
theoretically suitable for the treatment of all those diseases or
conditions which may be affected or which are mediated by the
activation of the G-protein-coupled receptor GPR40.
[0242] Accordingly, the present invention relates to a compound of
general formula I as a medicament.
[0243] Furthermore, the present invention relates to the use of a
compound of general formula I or a pharmaceutical composition
according to this invention for the treatment and/or prevention of
diseases or conditions which are mediated by the activation of the
G-protein-coupled receptor GPR40 in a patient, preferably in a
human.
[0244] In yet another aspect the present invention relates to a
method for treating a disease or condition mediated by the
activation of the G-protein-coupled receptor GPR40 in a mammal that
includes the step of administering to a patient, preferably a
human, in need of such treatment a therapeutically effective amount
of a compound or a pharmaceutical composition of the present
invention.
[0245] Diseases and conditions mediated by agonists of the
G-protein-coupled receptor GPR40 embrace metabolic diseases or
conditions. According to one aspect the compounds and
pharmaceutical compositions of the present invention are
particularly suitable for treating diabetes mellitus, in particular
Type 2 diabetes, Type 1 diabetes, complications of diabetes (such
as e.g. retinopathy, nephropathy or neuropathies, diabetic foot,
ulcers or macroangiopathies), metabolic acidosis or ketosis,
reactive hypoglycaemia, hyperinsulinaemia, glucose metabolic
disorder, insulin resistance, metabolic syndrome, dyslipidaemias of
different origins, atherosclerosis and related diseases, obesity,
high blood pressure, chronic heart failure, oedema and
hyperuricaemia.
[0246] The compounds and pharmaceutical compositions of the present
invention are also suitable for preventing beta-cell degeneration
such as e.g. apoptosis or necrosis of pancreatic beta cells. The
compounds and pharmaceutical compositions of the present invention
are also suitable for improving or restoring the functionality of
pancreatic cells, and also for increasing the number and size of
pancreatic beta cells.
[0247] Therefore according to another aspect the invention relates
to compounds of formula I and pharmaceutical compositions according
to the invention for use in preventing, delaying, slowing the
progression of and/or treating metabolic diseases, particularly in
improving the glycaemic control and/or beta cell function in the
patient.
[0248] In another aspect the invention relates to compounds of
formula I and pharmaceutical compositions according to the
invention for use in preventing, delaying, slowing the progression
of and/or treating type 2 diabetes, overweight, obesity,
complications of diabetes and associated pathological
conditions.
[0249] In addition the compounds and pharmaceutical compositions
according to the invention are suitable for use in one or more of
the following therapeutic processes: [0250] for preventing,
delaying, slowing the progression of or treating metabolic
diseases, such as for example type 1 diabetes, type 2 diabetes,
insufficient glucose tolerance, insulin resistance, hyperglycaemia,
hyperlipidaemia, hypercholesterolaemia, dyslipidaemia, syndrome X,
metabolic syndrome, obesity, high blood pressure, chronic systemic
inflammation, retinopathy, neuropathy, nephropathy,
atherosclerosis, endothelial dysfunction or bone-related diseases
(such as osteoporosis, rheumatoid arthritis or osteoarthritis);
[0251] for improving glycaemic control and/or reducing fasting
plasma glucose, postprandial plasma glucose and/or the glycosylated
haemoglobin HbA1c; [0252] for preventing, delaying, slowing or
reversing the progression of disrupted glucose tolerance, insulin
resistance and/or metabolic syndrome to type 2 diabetes; [0253] for
preventing, delaying, slowing the progression of or treating a
condition or a disease selected from among the complications of
diabetes, such as for example retinopathy, nephropathy or
neuropathies, diabetic foot, ulcers or macroangiopathies; [0254]
for reducing weight or preventing weight gain or assisting weight
loss; [0255] for preventing or treating the degradation of
pancreatic beta cells and/or improving and/or restoring the
functionality of pancreatic beta cells and/or restoring the
functionality of pancreatic insulin secretion; [0256] for
maintaining and/or improving insulin sensitivity and/or preventing
or treating hyperinsulinaemia and/or insulin resistance.
[0257] In particular, the compounds and pharmaceutical compositions
according to the invention are suitable for the treatment of
obesity, diabetes (comprising type 1 and type 2 diabetes,
preferably type 2 diabetes mellitus) and/or complications of
diabetes (such as for example retinopathy, nephropathy or
neuropathies, diabetic foot, ulcers or macroangiopathies).
[0258] The compounds according to the invention are most
particularly suitable for treating type 2 diabetes mellitus.
[0259] The dose range of the compounds of general formula I
applicable per day is usually from 0.001 to 10 mg per kg body
weight, for example from 0.01 to 8 mg per kg body weight of the
patient. Each dosage unit may conveniently contain from 0.1 to 1000
mg, for example 0.5 to 500 mg.
[0260] The actual therapeutically effective amount or therapeutic
dosage will of course depend on factors known by those skilled in
the art such as age and weight of the patient, route of
administration and severity of disease. In any case the compound or
composition will be administered at dosages and in a manner which
allows a therapeutically effective amount to be delivered based
upon patient's unique condition.
[0261] The compounds, compositions, including any combinations with
one or more additional therapeutic agents, according to the
invention may be administered by oral, transdermal, inhalative,
parenteral or sublingual route. Of the possible methods of
administration, oral or intravenous administration is
preferred.
Pharmaceutical Compositions
[0262] Suitable preparations for administering the compounds of
formula I, optionally in combination with one or more further
therapeutic agents, will be apparent to those with ordinary skill
in the art and include for example tablets, pills, capsules,
suppositories, lozenges, troches, solutions, syrups, elixirs,
sachets, injectables, inhalatives and powders etc. Oral
formulations, particularly solid forms such as e.g. tablets or
capsules are preferred. The content of the pharmaceutically active
compound(s) is advantageously in the range from 0.1 to 90 wt.-%,
for example from 1 to 70 wt.-% of the composition as a whole.
[0263] Suitable tablets may be obtained, for example, by mixing one
or more compounds according to formula I with known excipients, for
example inert diluents, carriers, disintegrants, adjuvants,
surfactants, binders and/or lubricants. The tablets may also
consist of several layers. The particular excipients, carriers
and/or diluents that are suitable for the desired preparations will
be familiar to the skilled man on the basis of his specialist
knowledge. The preferred ones are those that are suitable for the
particular formulation and method of administration that are
desired. The preparations or formulations according to the
invention may be prepared using methods known per se that are
familiar to the skilled man, such as for example by mixing or
combining at least one compound of formula I according to the
invention, or a pharmaceutically acceptable salt of such a
compound, and one or more excipients, carriers and/or diluents.
Combination Therapy
[0264] The compounds of the invention may further be combined with
one or more, preferably one additional therapeutic agent. According
to one embodiment the additional therapeutic agent is selected from
the group of therapeutic agents useful in the treatment of diseases
or conditions described hereinbefore, in particular associated with
metabolic diseases or conditions such as for example diabetes
mellitus, obesity, diabetic complications, hypertension,
hyperlipidemia. Additional therapeutic agents which are suitable
for such combinations include in particular those which for example
potentiate the therapeutic effect of one or more active substances
with respect to one of the indications mentioned and/or which allow
the dosage of one or more active substances to be reduced.
[0265] Therefore a compound of the invention may be combined with
one or more additional therapeutic agents selected from the group
consisting of antidiabetic agents, agents for the treatment of
overweight and/or obesity and agents for the treatment of high
blood pressure, heart failure and/or atherosclerosis.
[0266] Antidiabetic agents are for example metformin,
sulphonylureas, nateglinide, repaglinide, thiazolidinediones,
PPAR-(alpha, gamma or alpha/gamma) agonists or modulators,
alpha-glucosidase inhibitors, DPPIV inhibitors, SGLT2-inhibitors,
insulin and insulin analogues, GLP-1 and GLP-1 analogues or amylin
and amylin analogues, cycloset, 11.beta.-HSD inhibitors. Other
suitable combination partners are inhibitors of protein
tyrosinephosphatase 1, substances that affect deregulated glucose
production in the liver, such as e.g. inhibitors of
glucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogen
phosphorylase, glucagon receptor antagonists and inhibitors of
phosphoenol pyruvate carboxykinase, glycogen synthase kinase or
pyruvate dehydrokinase, alpha2-antagonists, CCR-2 antagonists or
glucokinase activators. One or more lipid lowering agents are also
suitable as combination partners, such as for example
HMG-CoA-reductase inhibitors, fibrates, nicotinic acid and the
derivatives thereof, PPAR-(alpha, gamma or alpha/gamma) agonists or
modulators, PPAR-delta agonists, ACAT inhibitors or cholesterol
absorption inhibitors such as, bile acid-binding substances such
as, inhibitors of ileac bile acid transport, MTP inhibitors, or
HDL-raising compounds such as CETP inhibitors or ABC1
regulators.
[0267] Therapeutic agents for the treatment of overweight and/or
obesity are for example antagonists of the cannabinoid1 receptor,
MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2
antagonists, .beta.3-agonists, leptin or leptin mimetics, agonists
of the 5HT2c receptor.
[0268] Therapeutic agents for the treatment of high blood pressure,
chronic heart failure and/or atherosclerosis are for example A-II
antagonists or ACE inhibitors, ECE inhibitors, diuretics,
.beta.-blockers, Ca-antagonists, centrally acting
antihypertensives, antagonists of the alpha-2-adrenergic receptor,
inhibitors of neutral endopeptidase, thrombocyte aggregation
inhibitors and others or combinations thereof are suitable.
Angiotensin II receptor antagonists are preferably used for the
treatment or prevention of high blood pressure and complications of
diabetes, often combined with a diuretic such as
hydrochlorothiazide.
[0269] The dosage for the combination partners mentioned above is
usually 1/5 of the lowest dose normally recommended up to 1/1 of
the normally recommended dose.
[0270] Preferably, compounds of the present invention and/or
pharmaceutical compositions comprising a compound of the present
invention optionally in combination with one or more additional
therapeutic agents are administered in conjunction with exercise
and/or a diet.
[0271] Therefore, in another aspect, this invention relates to the
use of a compound according to the invention in combination with
one or more additional therapeutic agents described hereinbefore
and hereinafter for the treatment of diseases or conditions which
may be affected or which are mediated by the activation of the
G-protein-coupled receptor GPR40, in particular diseases or
conditions as described hereinbefore and hereinafter.
[0272] In yet another aspect the present invention relates a method
for treating a disease or condition mediated by the activation of
the G-protein-coupled receptor GPR40 in a patient that includes the
step of administering to the patient, preferably a human, in need
of such treatment a therapeutically effective amount of a compound
of the present invention in combination with a therapeutically
effective amount of one or more additional therapeutic agents
described in hereinbefore and hereinafter,
[0273] The use of the compound according to the invention in
combination with the additional therapeutic agent may take place
simultaneously or at staggered times.
[0274] The compound according to the invention and the one or more
additional therapeutic agents may both be present together in one
formulation, for example a tablet or capsule, or separately in two
identical or different formulations, for example as a so-called
kit-of-parts.
[0275] Consequently, in another aspect, this invention relates to a
pharmaceutical composition which comprises a compound according to
the invention and one or more additional therapeutic agents
described hereinbefore and hereinafter, optionally together with
one or more inert carriers and/or diluents.
[0276] Other features and advantages of the present invention will
become apparent from the following more detailed Examples which
illustrate, by way of example, the principles of the invention.
EXAMPLES
[0277] The Examples that follow are intended to illustrate the
present invention without restricting it.
Preliminary Remarks:
[0278] As a rule, .sup.1H-NMR and/or mass spectra have been
obtained for the compounds prepared. The R.sub.f values are
determined using Merck silica gel 60 F.sub.254 plates and UV light
at 254 nm.
[0279] The terms "ambient temperature" and "room temperature" are
used interchangeably and designate a temperature of about
20.degree. C.
[0280] Analytical HPLC parameters employed for characterization of
products (TFA denotes trifluoroacetic acid and FA denotes formic
acid):
TABLE-US-00004 Method: 1 Device: Agilent 1200 with DA and MS
detector Column: XBridge C18, 3 .times. 30 mm, 2.5 .mu.m Column
Supplier: Waters Gradient/ Temper- Solvent % Solvent % Solvent Flow
ature Time [min] [H.sub.2O, 0.1% TFA] [Methanol] [mL/min] [.degree.
C.] 0.0 95 5 2.2 60 0.05 95 5 2.2 60 1.40 0 100 2.2 60 1.80 0 100
2.2 60
TABLE-US-00005 Method: 2 Device: Agilent 1200 with DA and MS
detector Column: XBridge C18, 3 .times. 30 mm, 2.5 .mu.m Column
Supplier: Waters Gradient/ % Solvent Temper- Solvent % Solvent
[Aceto- Flow ature Time [min] [H.sub.2O, 0.1% FA] nitrile] [mL/min]
[.degree. C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60
1.25 0 100 3 60 1.40 0 100 3 60
TABLE-US-00006 Method: 3 Device: Agilent 1200 with DA and MS
detector Column: XBridge C18, 3 .times. 30 mm, 2.5 .mu.m Column
Supplier: Waters Gradient/ % Solvent Temper- Solvent % Solvent
[Aceto- Flow ature Time [min] [H.sub.2O, 0.1% TFA] nitrile]
[mL/min] [.degree. C.] 0.00 50 50 2.2 60 0.20 50 50 2.2 60 1.20 0
100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60
TABLE-US-00007 Method: 4 Device: Agilent 1200 with DA and MS
detector Column: XBridge C18, 3 .times. 30 mm, 2.5 .mu.m Column
Supplier: Waters Gradient/ % Solvent Temper- Solvent % Solvent
[Aceto- Flow ature Time [min] [H.sub.2O, 0.1% TFA] nitrile]
[mL/min] [.degree. C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100
2.2 60 1.25 0 100 3 60 1.40 0 100 3 60
TABLE-US-00008 Method: 5 Device: Agilent 1200 with DA and MS
detector Column: XBridge C18, 3 .times. 30 mm, 2.5 .mu.m Column
Supplier: Waters Gradient/ % Solvent Temper- Solvent % Solvent
[Aceto- Flow ature Time [min] [H.sub.2O, 0.1% NH.sub.3] nitrile]
[ml/min] [.degree. C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100
2.2 60 1.25 0 100 3 60 1.40 0 100 3 60
TABLE-US-00009 Method: 6 Device: Waters Acquity with 3100 MS
Column: XBridge BEH C18, 3.0 .times. 30 mm, 1.7 .mu.m Column
supplier: Waters Gradient/ % Solvent % Solvent Temper- Solvent
[H.sub.2O, [Aceto- Flow ature Time [min] 0.1% NH.sub.4OH] nitrile]
[ml/min] [.degree. C.] 0.0 95.0 5.0 1.5 60.0 0.80 0.1 99.9 1.5 60.0
0.90 0.1 99.9 1.5 60.0
TABLE-US-00010 Method: 7 Device: ThermoFinnigan HPLC Surveyor DAD,
MSQ single quadrupole Column: Synergi Hydro RP100A, 3 .times. 50
mm, 2.5 .mu.m Column Supplier: Phenomenex Gradient/ % Solvent %
Solvent Temper- Solvent [H.sub.2O/CH.sub.3CN 9:1, + [CH.sub.3CN/
Flow ature Time [min] (NH.sub.4COOH 5 mM)] H.sub.2O 9:1] [mL/min]
[.degree. C.] 0.0 100 0 1.2 25 4.00 0 100 1.2 25 5.30 0 100 1.2 25
5.50 100 0 1.2 25 6.00 100 0 1.2 25
TABLE-US-00011 Method: 8 Device: ThermoFinnigan HPLC Surveyor DAD,
MSQ single quadrupole Column: Synergi Hydro RP100A, 3 .times. 50
mm, 2.5 .mu.m Column Supplier: Phenomenex Gradient/ % Solvent %
Solvent Temper- Solvent [H.sub.2O/CH.sub.3CN 9:1, + [CH.sub.3CN/
Flow ature Time [min] (NH.sub.4COOH 5 mM)] H.sub.2O 9:1] [mL/min]
[.degree. C.] 0.0 100 0 1.2 25 1.50 100 0 1.2 25 9.00 0 100 1.2 25
10.50 0 100 1.2 25 11.00 100 0 1.2 25 12.00 100 0 1.2 25
TABLE-US-00012 Method: 9 Device: Agilent 1200 with DA- and
MS-Detector Column: Sunfire C18, 3.0 .times. 30 mm, 2.5 .mu.m
Column Supplier: Waters Gradient/ % Solvent Temper- Solvent %
Solvent [Aceto- Flow ature Time [min] [H.sub.2O, 0.1% TFA] nitrile]
[mL/min] [.degree. C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100
2.2 60 1.25 0 100 3 60 1.40 0 100 3 60
TABLE-US-00013 Method: 10 Device: Agilent 1200 with DA- and
MS-Detector Column: Sunfire C18, 3.0 .times. 30 mm, 2.5 .mu.m
Column Supplier: Waters Gradient/ % Solvent Temper- Solvent %
Solvent [Aceto- Flow ature Time [min] [H.sub.2O, 0.1% HCOOH]
nitrile] [mL/min] [.degree. C.] 0.00 50 50 2.2 60 0.20 50 50 2.2 60
1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60
TABLE-US-00014 Method: 11 Device: Agilent 1100 with DA, Waters
Autosampler and MS-Detector Column: SunFire C18, 4.6 .times. 30 mm,
3.5 .mu.m Column Supplier: Waters Gradient/ % Solvent Temper-
Solvent % Solvent [Aceto- Flow ature Time [min] [H.sub.2O, 0.1%
TFA] nitrile] [mL/min] [.degree. C.] 0.00 98 2 2.5 60 1.50 0 100
2.5 60 1.80 0 100 2.5 60
TABLE-US-00015 Method: 12 Device: Agilent 1200 with DA- and
MS-Detector Column: Sunfire C18, 3.0 .times. 30 mm, 2.5 .mu.m
Column Supplier: Waters Gradient/ % Solvent Temper- Solvent %
Solvent [Aceto- Flow ature Time [min] [H.sub.2O, 0.1% TFA] nitrile]
[mL/min] [.degree. C.] 0.00 50 50 2.2 60 0.20 50 50 2.2 60 1.20 0
100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60
TABLE-US-00016 Method: 13 Device: Agilent 1200 with DA- and
MS-Detector Column: Sunfire C18, 3.0 .times. 30 mm, 2.5 .mu.m
Column Supplier: Waters Gradient/ % Solvent Temper- Solvent %
Solvent [Aceto- Flow ature Time [min] [H.sub.2O, 0.1% FA] nitrile]
[mL/min] [.degree. C.] 0.00 50 50 2.2 60 0.20 50 50 2.2 60 1.20 0
100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60
TABLE-US-00017 Method: 14 Device: LC/MS Waters Alliance 2695 HPLC
System DAD, Quattro Micro Triple Column: Xbridge Phenyl, 3.5 .mu.m,
3 .times. 30 mm Column Supplier: Waters Gradient/ % Solvent %
Solvent Temper- Solvent [H.sub.2O, 10% CH.sub.3CN [Acetonitrile,
Flow ature Time [min] NH.sub.4HCO.sub.3 5 mM] 10% H.sub.2O]
[mL/min] [.degree. C.] 0.0 100 0 1.3 35 4.50 0 100 1.3 35 5.80 0
100 1.3 35 6.00 100 0 1.3 35
TABLE-US-00018 Method: 15 Device: LC/MS ThermoFinnigan HPLC
Surveyor DAD, LCQFleet Ion Trap Column: Xselect CSH, 2.5 .mu.m, 4.6
.times. 50 mm Column Supplier: Waters % Solvent % Solvent Gradient/
[H.sub.2O, [H.sub.3CCN, Temper- Solvent 10% H.sub.3CCN, 10%
H.sub.2O, Flow ature Time [min] 0.1% FA] 0.1% FA] [mL/min]
[.degree. C.] 0.0 100 0 1.4 25 4.00 0 100 1.4 25 5.30 0 100 1.4 25
5.50 100 0 1.4 25 6.00 100 0 1.2 25
TABLE-US-00019 Method: 16 Device: Agilent 1200 with DA- and MS-
Detector Column: Sunfire C18, 3.0 .times. 30 mm, 2.5 .mu.m Column
Supplier: Waters Gradient/ % Solvent Temper- Solvent % Solvent
[Aceto- Flow ature Time [min] [H.sub.2O, 0.1% FA] nitrile] [mL/min]
[.degree. C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60
1.25 0 100 3 60 1.40 0 100 3 60
TABLE-US-00020 Method: 17 Device: Agilent 1200 with DA and MS
detector Column: XBridge C18, 3 .times. 30 mm, 2.5 .mu.m Column
Supplier: Waters Gradient/ % Solvent Temper- Solvent % Solvent
[Aceto- Flow ature Time [min] [H.sub.2O, 0.1% NH.sub.3] nitrile]
[ml/min] [.degree. C.] 0.00 50 50 2.2 60 0.20 50 50 2.2 60 1.20 0
100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60
TABLE-US-00021 Method: 18 Device: Agilent 1100 with DA, Gilson
Autosampler and MS-Detector Column: SunFire C18, 3.0 .times. 30 mm,
2.5 .mu.m Column Supplier: Waters Gradient/ % Solvent Temper-
Solvent % Solvent [Aceto- Flow ature Time [min] [H.sub.2O, 0.1%
TFA] nitrile] [mL/min] [.degree. C.] 0.00 99 1 2.0 60 0.90 0 100
2.0 60 1.10 0 100 2.0 60
TABLE-US-00022 Method: 19 Device: Agilent 1100 with DA, Waters
Autosampler and MS-Detector Column: SunFire C18, 3.0 .times. 30 mm,
2.5 .mu.m Column Supplier: Waters Gradient/ % Solvent Temper-
Solvent % Solvent [Aceto- Flow ature Time [min] [H.sub.2O, 0.1%
TFA] nitrile] [mL/min] [.degree. C.] 0.00 98 2 2.0 60 1.20 0 100
2.0 60 1.40 0 100 2.0 60
Intermediate 1
[(S)-6-Hydroxy-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl
ester
##STR00034##
[0281] Step 1: (6-hydroxy-benzofuran-3-yl)-acetic acid methyl
ester
[0282] A mixture of (6-hydroxy-benzofuran-3-yl)-acetic acid (for
preparation see WO 2008001931; 14.0 g), concentrated sulfuric acid
(5 mL), and methanol (250 mL) is stirred at reflux temperature for
4 h. After cooling to room temperature, the mixture is
concentrated. Ethyl acetate is added to the residue, and the
resulting mixture is washed with water, saturated aqueous
NaHCO.sub.3 solution and brine and dried (MgSO.sub.4). The solvent
is evaporated, and the residue is chromatographed on silica gel
(cyclohexane/ethyl acetate 2:1.fwdarw.1:2) to give the title
compound. Mass spectrum (ESI.sup.+): m/z=207 [M+H].sup.+.
Step 2: (6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl
ester
[0283] A mixture of (6-hydroxy-benzofuran-3-yl)-acetic acid methyl
ester (5.00 g), 10% palladium on carbon (0.50 g), and methanol (50
mL) is shaken under hydrogen atmosphere (3 bar) at room temperature
for 3 h. The catalyst is separated by filtration and the filtrate
is concentrated. The residue is chromatographed on silica gel
(cyclohexane/ethyl acetate 4:1.fwdarw.1:1) to give the racemic
title compound. Mass spectrum (ESI.sup.+): m/z=209 [M+H].sup.+.
[0284] The enantiomers may be separated by SFC on chiral phase
(column: Daicel ADH, 5 .mu.m, 250 mm.times.20 mm; eluent:
scCO.sub.2/(isopropanol+0.2% diethylamine) 80:20, 70 mL/min):
[0285] (S)-(6-Hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid
methyl ester: t.sub.R=2.33 min.
[0286] (R)-(6-Hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid
methyl ester: t.sub.R=2.75 min.
[0287] Alternatively, the pure enantiomer may be obtained as
described in WO 2008001931.
Intermediate 2
(S)-4-Bromo-7-fluoro-2,3-dihydro-1H-inden-1-ol
##STR00035##
[0289] Formic acid (8.1 mL) is added to a solution of triethylamine
(25.6 mL) in dichloromethane (50 mL) chilled in an ice bath.
4-Bromo-7-fluoro-2,3-dihydro-1H-inden-1-one (14.0 g) is added, the
solution is warmed to room temperature, and the flask is purged
with argon for 5 min.
Chloro{[(1S,2S)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido}-(-
mesitylene)ruthenium(II) (0.85 g; alternatively, the catalyst is
formed in situ from dichloro(p-cymene)-ruthenium(II) dimer and
N-[(1S,2S)-2-amino-1,2-diphenylethyl]-4-methylbenzenesulfonamide)
is added, and the mixture is stirred at room temperature for 16 h.
Water is added and the resulting mixture is extracted with
dichloromethane. The combined extract is washed with saturated
aqueous NaHCO.sub.3 solution and dried (MgSO.sub.4). The solvent is
evaporated and the residue is chromatographed on silica gel
(cyclohexane/ethyl acetate 90:10-50:50) to give the title
compound.
[0290] LC (method 1): t.sub.R=1.04 min; Mass spectrum (ESI.sup.+):
m/z=213/215 (Br) [M+H-H.sub.2O].sup.+.
Intermediate 3
{(S)-6-[(R)-4-Bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-a-
cetic acid methyl ester
##STR00036##
[0292] A solution of di-tert-butyl azodicarboxylate (18.0 g) in
tetrahydrofuran (80 mL) is added dropwise over 45 min to a solution
of [(S)-6-hydroxy-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl
ester (11.0 g), (S)-4-bromo-7-fluoro-2,3-dihydro-1H-inden-1-ol
(12.0 g) and tributylphosphine (19.3 mL) in tetrahydrofuran (320
mL) at -10.degree. C. The resulting solution is stirred for 30 min
and then poured into saturated aqueous NaHCO.sub.3 solution. The
mixture is extracted with dichloromethane, and the combined organic
phases are dried (MgSO.sub.4) and concentrated. The residue is
chromatographed on silica gel (cyclohexane/ethyl acetate
90:10-70:30) to give the title compound. LC (method 1):
t.sub.R=1.41 min; Mass spectrum (ESI.sup.+): m/z=421
[M+H].sup.+.
Intermediate 4
{(S)-6-[(R)-7-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-inda-
n-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl
ester
##STR00037##
[0294] A microwave vial charged with a stir bar,
{(S)-6-[(R)-4-bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}--
acetic acid methyl ester (7.0 g), bis-(pinacolato)-diboron (5.6 g),
potassium acetate (4.2 g) and 1,4-dioxane (100 mL) is purged with
argon for 10 min.
[1,1'-Bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) (0.60
g) is added, the vial is sealed, and the mixture is stirred at
100.degree. C. for 4 h. After cooling to room temperature,
saturated aqueous NH.sub.4Cl solution is added and the resulting
mixture is extracted with diethyl ether. The combined extracts are
dried (MgSO.sub.4) and concentrated. The residue is chromatographed
on silica gel (cyclohexane/ethyl acetate 99:1-70:30) to give the
title compound. LC (method 1): t.sub.R=1.48 min; Mass spectrum
(ESI.sup.+): m/z=469 [M+H].sup.+.
Intermediate 5
{(S)-6-[(R)-7-Fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-
-acetic acid methyl ester
##STR00038##
[0296] Aqueous hydrogen peroxide solution (35%, 3.7 mL) is added
dropwise to a solution of
{(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-ind-
an-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester
(5.0 g) in acetic acid (30 mL) chilled in an ice bath. The solution
is stirred with cooling for 0.5 h and at room temperature for
another 2 h. Ice-cold water (50 mL) and 2 N aqueous NaOH solution
(20 mL) are added, and the mixture is stirred at room temperature
overnight. The mixture is extracted with ethyl acetate, and the
combined extracts are washed with brine and dried (MgSO.sub.4). The
solvent is evaporated and the residue is chromatographed on silica
gel (cyclohexane/ethyl acetate 80:20-60:40) to give the title
compound. LC (method 2): t.sub.R=1.01 min; Mass spectrum
(ESI.sup.+): m/z=359 [M+H].sup.+.
Intermediate 6
[(S)-6-{(R)-4-[4-(Benzyloxy)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-b-
enzofuran-3-yl]acetic acid methyl ester
##STR00039##
[0298] Triethylamine (726 mg) is added to a mixture of
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester (400 mg), 4-(benzyloxy)phenylboronic
acid (509 mg), freshly activated molecular sieves 4A (6.0 g),
copper(II) acetate (204 mg) and dichloromethane (19.5 mL) at room
temperature. The flask is purged with O.sub.2 and sealed. The
reaction mixture is stirred under an O.sub.2 atmosphere (1 bar) at
room temperature over night. The mixture is diluted with
dichloromethane, filtered and concentrated. The residue is
chromatographed on silica gel (cyclohexane/ethyl acetate
90:10-80:20) to give the title compound. LC (method 3):
t.sub.R=0.96 min; Mass spectrum (ESI.sup.+): m/z=541
[M+H].sup.+.
Intermediate 7
{(S)-6-[(R)-7-Fluoro-4-(4-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dihydro-benz-
ofuran-3-yl}-acetic acid methyl ester
##STR00040##
[0300] A mixture of
[(S)-6-{(R)-4-[4-(benzyloxy)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro--
benzofuran-3-yl]acetic acid methyl ester (410 mg), 10% palladium on
carbon (50 mg), and tetrahydrofuran (20 mL) is shaken under a
hydrogen atmosphere (3.5 bar) at room temperature for 2 h. The
catalyst is filtered off and the filtrate is concentrated in vacuo
to give the title compound. LC (method 3): t.sub.R=0.41 min; Mass
spectrum (ESI.sup.+): m/z=451 [M+H].sup.+.
Intermediate 8
[(S)-6-{(R)-7-Fluoro-4-[4-(2-methoxy-ethoxy)-phenoxy]-indan-1-yloxy}-2,3-d-
ihydro-benzofuran-3-yl]-acetic acid methyl ester
##STR00041##
[0302] A mixture of
{(S)-6-[(R)-7-fluoro-4-(4-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dihydro-ben-
zofuran-3-yl}-acetic acid methyl ester (60 mg), toluene-4-sulfonic
acid 2-methoxy-ethyl ester (34 mg), and cesium carbonate (60 mg) in
N,N-dimethylformamide (2 mL) is stirred for 1.5 h at 60.degree. C.
After cooling to room temperature, the mixture is diluted with
water an extracted with ethyl acetate. The combined extracts are
washed with brine, dried (MgSO.sub.4), and concentrated in vacuo.
The residue is chromatographed on silica gel (cyclohexane/ethyl
acetate 80:20.fwdarw.60:40) to give the title compound. LC (method
3): t.sub.R=0.70 min; Mass spectrum (ESI.sup.+): m/z=509
[M+H].sup.+.
Intermediate 9
[(S)-6-{(R)-7-Fluoro-4-[4-(3-hydroxy-3-methyl-butoxy)-phenoxy]-indan-1-ylo-
xy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester
##STR00042##
[0304] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-(4-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dihydro-ben-
zofuran-3-yl}-acetic acid methyl ester and toluene-4-sulfonic acid
3-hydroxy-3-methyl-butyl ester following a procedure analogous to
that described for Intermediate 8. LC (method 3): t.sub.R=0.70 min;
Mass spectrum (ESI.sup.+): m/z=537 [M+H].sup.+.
Intermediate 10
[(S)-6-{(R)-7-Fluoro-4-[4-(2-hydroxy-2-methyl-propoxy)-phenoxy]-indan-1-yl-
oxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester
##STR00043##
[0306] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-(4-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dihydro-ben-
zofuran-3-yl}-acetic acid methyl ester and 2,2-dimethyl-oxirane
following a procedure analogous to that described for Intermediate
8. LC (method 3): t.sub.R=0.66 min; Mass spectrum (ESI.sup.+):
m/z=545 [M+Na].sup.+.
Intermediate 11
[(S)-6-{(R)-7-Fluoro-4-[4-(3-methanesulfonyl-propoxy)-phenoxy]-indan-1-ylo-
xy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester
##STR00044##
[0308] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-(4-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dihydro-ben-
zofuran-3-yl}-acetic acid methyl ester and toluene-4-sulfonic acid
3-methanesulfonyl-propyl ester following a procedure analogous to
that described for Intermediate 8. LC (method 3): t.sub.R=0.52 min;
Mass spectrum (ESI.sup.+): m/z=571 [M+H].sup.+.
Intermediate 12
{(S)-6-[(R)-7-Fluoro-4-(4-morpholin-4-ylmethyl-phenoxy)-indan-1-yloxy]-2,3-
-dihydro-benzofuran-3-yl}-acetic acid methyl ester
##STR00045##
[0310] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester and 4-(4-morpholinylmethyl)phenylboronic
acid following a procedure analogous to that described for
Intermediate 6. LC (method 2): t.sub.R=0.95 min; Mass spectrum
(ESI.sup.+): m/z=534 [M+H].sup.+.
Intermediate 13
{(S)-6-[(R)-4-(3-Acetylamino-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro--
benzofuran-3-yl}-acetic acid methyl ester
##STR00046##
[0312] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester and 3-acetamidophenylboronic acid
following a procedure analogous to that described for Intermediate
6. LC (method 2): t.sub.R=1.11 min; Mass spectrum (ESI.sup.-):
m/z=490 [M-H].sup.-.
Intermediate 14
[(S)-6-{(R)-4-[3-(Acetylamino-methyl)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-
-dihydro-benzofuran-3-yl]-acetic acid methyl ester
##STR00047##
[0314] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester and 3-(acetamidomethyl)-phenylboronic
acid following a procedure analogous to that described for
Intermediate 6. LC (method 2): t.sub.R=1.07 min; Mass spectrum
(ESI.sup.+): m/z=506 [M+H].sup.+.
Intermediate 15
{(S)-6-[(R)-4-(4-Acetylamino-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro--
benzofuran-3-yl}-acetic acid methyl ester
##STR00048##
[0316] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester and 4-acetamidophenylboronic acid
following a procedure analogous to that described for Intermediate
6. LC (method 2): t.sub.R=1.09 min; Mass spectrum (ESI.sup.+):
m/z=492 [M+H].sup.+
Intermediate 16
[(S)-6-{(R)-7-Fluoro-4-[4-(pyrrolidine-1-carbonyl)-phenoxy]-indan-1-yloxy}-
-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester
##STR00049##
[0318] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester and
4-(pyrrolidine-1-carbonyl)phenylboronic acid following a procedure
analogous to that described for Intermediate 6. LC (method 2):
t.sub.R=1.15 min
Intermediate 17
{(S)-6-[(R)-7-Fluoro-4-(4-imidazol-1-yl-phenoxy)-indan-1-yloxy]-2,3-dihydr-
o-benzofuran-3-yl}-acetic acid methyl ester
##STR00050##
[0320] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester and 4-(1H-imidazol-1-yl)phenylboronic
acid following a procedure analogous to that described for
Intermediate 6. LC (method 2): t.sub.R=0.96 min; Mass spectrum
(ESI.sup.+): m/z=501 [M+H].sup.+
Intermediate 18
{(S)-6-[(R)-4-(2,3-Dihydro-benzofuran-5-yloxy)-7-fluoro-indan-1-yloxy]-2,3-
-dihydro-benzofuran-3-yl}-acetic acid methyl ester
##STR00051##
[0322] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester and 2,3-dihydrobenzofuran-5-ylboronic
acid following a procedure analogous to that described for
Intermediate 6. LC (method 2): t.sub.R=1.22 min; Mass spectrum
(ESI.sup.+): m/z=477 [M+H].sup.+
Intermediate 19
{(S)-6-[(R)-4-(4-Ethylcarbamoyl-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihyd-
ro-benzofuran-3-yl}-acetic acid methyl ester
##STR00052##
[0324] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester and 4-(ethylcarbamoyl)phenylboronic acid
following a procedure analogous to that described for Intermediate
6. LC (method 2): t.sub.R=1.11 min; Mass spectrum (ESI.sup.+):
m/z=506 [M+H].sup.+
Intermediate 20
{(S)-6-[(R)-4-(4-Cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzof-
uran-3-yl}-acetic acid methyl ester
##STR00053##
[0326] A mixture of
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester (100 mg), 4-fluoro-benzonitrile (34 mg),
and cesium carbonate (91 mg) in N,N-dimethylformamide (2 mL) is
heated to 130.degree. C. for 30 min in a microwave oven. The
reaction mixture is concentrated in vacuo and the residue is
chromatographed on silica gel (cyclohexane/ethyl acetate
99:1.fwdarw.70:30) to give the title compound. LC (method 2):
t.sub.R=1.18 min; Mass spectrum (ESI.sup.+): m/z=460
[M+H].sup.+.
Intermediate 21
[(S)-6-{(R)-7-Fluoro-4-[4-(1H-tetrazol-5-yl)-phenoxy]-indan-1-yloxy}-2,3-d-
ihydro-benzofuran-3-yl]-acetic acid methyl ester
##STR00054##
[0328] A mixture of
{(S)-6-[(R)-4-(4-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzo-
furan-3-yl}-acetic acid methyl ester (150 mg), sodium azide (83
mg), and ammonium chloride (79 mg) in N,N-dimethylformamide (5 mL)
is stirred at 110.degree. C. over night. More sodium azide (83 mg)
and ammonium chloride (79 mg) are added and the mixture is stirred
at 110.degree. C. for another 8 h. The reaction mixture is cooled
to room temperature, diluted with water, and sodium nitrite (122
mg) is added. The pH is adjusted to 1-2 with 4M HCl and the mixture
is stirred for 1 h at room temperature. The mixture is extracted
with ethyl acetate and the combined extracts are washed with brine,
dried over MgSO.sub.4, and concentrated in vacuo. The residue is
chromatographed on silica gel (cyclohexane/ethyl acetate
90:10-0:100) to give the title compound. LC (method 4):
t.sub.R=1.09 min; Mass spectrum (ESI.sup.-): m/z=501
[M-H].sup.-.
Intermediate 22 and 23
[(S)-6-{(R)-7-Fluoro-4-[4-(1-methyl-1H-tetrazol-5-yl)-phenoxy]-indan-1-ylo-
xy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester and
[(S)-6-{(R)-7-Fluoro-4-[4-(2-methyl-2H-tetrazol-5-yl)-phenoxy]-indan-1-yl-
oxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester
##STR00055##
[0330] The title compounds are prepared by treatment of
[(S)-6-{(R)-7-fluoro-4-[4-(1H-tetrazol-5-yl)-phenoxy]-indan-1-yloxy}-2,3--
dihydro-benzofuran-3-yl]-acetic acid methyl ester with methyl
iodide in the presence of potassium carbonate in
N,N-dimethylformamide at room temperature. Product ratio
Intermediate 22: 23=2:8.
[0331] Intermediate 22: LC (method 4): t.sub.R=1.12 min; Mass
spectrum (ESI+.sup.-): m/z=517 [M+H].sup.+.
[0332] Intermediate 23: LC (method 4): t.sub.R=1.19 min; Mass
spectrum (ESI+.sup.-): m/z=517 [M+H].sup.+.
Intermediate 24
{(S)-6-[(R)-4-(2-bromopyridin-4-yloxy)-7-fluoro-2,3-dihydro-1H-inden-1-ylo-
xy]-2,3-dihydrobenzofuran-3-yl}acetic acid methyl ester
##STR00056##
[0334] A mixture of
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester (300 mg), 2-bromo-4-fluoro-pyridine (155
mg), and cesium carbonate (273 mg) in N,N-dimethylformamide (2 mL)
is heated to 80.degree. C. for 16 h. The reaction mixture diluted
with water and extracted with ethyl acetate. The combined extracts
are dried over MgSO.sub.4 and concentrated in vacuo. The residue is
chromatographed on silica gel (cyclohexane/ethyl acetate
90:10.fwdarw.70:30) to give the title compound. LC (method 2):
t.sub.R=1.18 min; Mass spectrum (ESI.sup.+): m/z=514, 516
[M+H].sup.+.
Intermediate 25
{(S)-6-[(R)-7-fluoro-4-{2-[(S)-tetrahydro-furan-3-yloxy]-pyridin-4-yloxy}--
indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl
ester
##STR00057##
[0336] A mixture of
{(S)-6-[(R)-4-(2-bromopyridin-4-yloxy)-7-fluoro-2,3-dihydro-1H-inden-1-yl-
oxy]-2,3-dihydrobenzofuran-3-yl}acetic acid methyl ester (70 mg),
(S)-tetrahydro-furan-3-ol (23 .mu.L), cesium carbonate (67 mg),
copper(I) iodide (1.3 mg), and
3,4,7,8-tetramethyl-1,10-phenanthroline (3.2 mg) in toluene (2 mL)
is heated to 120.degree. C. for 24 h. The reaction mixture is
cooled to room temperature, diluted with ethyl acetate and washed
with water. The organic phase is concentrated in vacuo and used for
the next reaction step without further purification.
Intermediate 26
4-(6-Fluoro-pyridin-3-yloxy)-2-methyl-butan-2-ol
##STR00058##
[0338] A mixture of 6-fluoro-pyridin-3-ol (280 mg),
toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester (721 mg),
and cesium carbonate (807 mg) in N,N-dimethylformamide (10 mL) is
heated to 50.degree. C. for 2 h. The reaction mixture diluted with
water and extracted with ethyl acetate. The combined extracts are
dried over MgSO.sub.4 and concentrated in vacuo. The residue is
chromatographed on silica gel (cyclohexane/ethyl acetate 70:30) to
give the title compound. LC (method 5): t.sub.R=0.81 min; Mass
spectrum (ESI.sup.+): m/z=200 [M+H].sup.+.
Intermediate 27
[(S)-6-{(R)-7-Fluoro-4-[5-(3-hydroxy-3-methyl-butoxy)-pyridin-2-yloxy]-ind-
an-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl
ester
##STR00059##
[0340] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester and
4-(6-fluoro-pyridin-3-yloxy)-2-methyl-butan-2-ol in
N-methyl-2-pyrrolidinon following a procedure analogous to that
described for Intermediate 20. The crude product is used for the
next reaction step without further purification.
Intermediate 28
{(S)-6-[(R)-7-Fluoro-4-(5-iodo-pyridin-2-yloxy)-indan-1-yloxy]-2,3-dihydro-
-benzofuran-3-yl}-acetic acid methyl ester
##STR00060##
[0342] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester and 2-fluoro-5-iodo-pyridine following a
procedure analogous to that described for Intermediate 24. LC
(method 4): t.sub.R=1.24 min; Mass spectrum (ESI.sup.+): m/z=562
[M+H].sup.+.
Intermediate 29
{(S)-6-[(R)-7-Fluoro-4-{5-[(S)-tetrahydro-furan-3-yloxy}-pyridin-2-yloxy}--
indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl
ester
##STR00061##
[0344] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-(5-iodo-pyridin-2-yloxy)-indan-1-yloxy]-2,3-dihydr-
o-benzofuran-3-yl}-acetic acid methyl ester and
(S)-tetrahydro-furan-3-ol following a procedure analogous to that
described for Intermediate 25. The crude product is used for the
next reaction step without further purification.
Intermediate 30
5-Bromo-1,3-difluoro-2-(3-methanesulfonyl-propoxy)-benzene
##STR00062##
[0346] A mixture of 4-bromo-2,6-difluoro-phenol (500 mg),
methanesulfonic acid 3-methanesulfonyl-propyl ester (517 mg), and
cesium carbonate (1.56 g) in N,N-dimethylacetamide (10 mL) is
heated to 80.degree. C. for 3 h. The reaction mixture diluted with
water and extracted with ethyl acetate. The combined extracts are
dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue
is chromatographed on silica gel (cyclohexane/ethyl acetate
100:0.fwdarw.80:20) to give the title compound.
Intermediate 31
2-(3,5-Difluoro-4-(3-(methylsulfonyl)propoxy)phenyl)-4,4,5,5-tetramethyl-1-
,3,2-dioxaborolane
##STR00063##
[0348] The title compound is prepared from
5-bromo-1,3-difluoro-2-(3-methanesulfonyl-propoxy)-benzene and
bis-(pinacolato)-diboron following a procedure analogous to that
described for Intermediate 4. Mass spectrum (EI.sup.+): m/z=376
[M].sup.+
Intermediate 32
3,5-Difluoro-4-(3-(methylsulfonyl)propoxy)phenylboronic acid
##STR00064##
[0350] A mixture of
2-(3,5-difluoro-4-(3-(methylsulfonyl)propoxy)phenyl)-4,4,5,5-tetramethyl--
1,3,2-dioxaborolane (800 mg), sodium metaperiodate (1.77 g), and
ammonium acetate (557 mg) in acetone (5 mL) and water (10 mL) is
stirred at room temperature for 2 h. Solids are filtered off and
the filtrate is concentrated in vacuo, diluted with water and
extracted with ethyl acetate. The combined extracts are
concentrated in vacuo and the residue is triturated with
cyclohexane, filtered off and dried to give the title compound,
which is used without further purification for the next reaction
step.
Intermediate 33
[(S)-6-{(R)-4-[3,5-Difluoro-4-(3-methanesulfonyl-propoxy)-phenoxy]-7-fluor-
o-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl
ester
##STR00065##
[0352] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester and
3,5-difluoro-4-[3-(methylsulfonyl)propoxy]phenylboronic acid
following a procedure analogous to that described for Intermediate
6. LC (method 7): t.sub.R=3.50 min; Mass spectrum (ESI.sup.+):
m/z=607 [M+H].sup.+
Intermediate 34
2-Methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-y-
l)propan-2-ol
##STR00066##
[0354] A mixture of
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.00
g), cesium carbonate (336 mg), and 2,2-dimethyl-oxirane (5 mL) is
heated in a microwave oven to 120.degree. C. for 30 min. The
reaction mixture is diluted with ethyl acetate and filtered. The
filtrate is concentrated in vacuo to give the title compound, which
is used for the next reaction step without further
purification.
Intermediate 35
3,5-Difluoro-4-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-phenol
##STR00067##
[0356] A mixture of 4-bromo-2,3-difluorophenol (707 mg),
2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1--
yl)propan-2-ol (900 mg), potassium carbonate (1.40 g),
2,6-di-tert-butyl-4-methylphenol (373 mg), tricyclohexylphosphine
(76 mg), and tris(dibenzylideneacetone)dipalladium(0) (124 mg) in
1,4-dioxane (4 mL) and water (1.5 mg) is heated in a microwave oven
under a nitrogen atmosphere to 100.degree. C. for 1 h. The reaction
mixture is diluted with water and extracted with ethyl acetate. The
combined extracts are concentrated in vacuo and the residue
chromatographed on silica gel (cyclohexane/ethyl acetate
100:0.fwdarw.60:40) to give the title compound. Mass spectrum
(EI.sup.+): m/z=268 [M].sup.+.
Intermediate 36
3,5-Difluoro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)phenyl
trifluoromethanesulfonate
##STR00068##
[0358] The title compound is prepared from
3,5-difluoro-4-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-phenol
and trifluoromethanesulfonic anhydride in the presence of
triethylamine in dichloromethane. Mass spectrum (EI.sup.+): m/z=400
[M].sup.+.
Intermediate 37
1-{4-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl-
]-pyrazol-1-yl}-2-methyl-propan-2-ol
##STR00069##
[0360] The title compound is prepared from
3,5-difluoro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)phenyl
trifluoromethanesulfonate following a procedure analogous to that
described for Intermediate 4. Mass spectrum (EI.sup.+): m/z=378
[M].sup.+.
Intermediate 38
3,5-Difluoro-4-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]phenylboronic
acid
##STR00070##
[0362] The title compound is prepared from
1-{4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pheny-
l]-pyrazol-1-yl}-2-methyl-propan-2-ol following a procedure
analogous to that described for Intermediate 32. LC (method 8):
t.sub.R=4.34 min; Mass spectrum (ESI.sup.+): m/z=297
[M+H].sup.+
Intermediate 39
{(S)-6-[(R)-4-{3,5-Difluoro-4-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4--
yl]-phenoxy}-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic
acid methyl ester
##STR00071##
[0364] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester and
3,5-difluoro-4-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]phenylboroni-
c acid following a procedure analogous to that described for
Intermediate 6. LC (method 7): t.sub.R=4.02 min; Mass spectrum
(ESI.sup.+): m/z=609 [M+H].sup.+
Intermediate 40
{(S)-6-[(R)-4-(4-bromo-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzof-
uran-3-yl}-acetic acid methyl ester
##STR00072##
[0366] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester and 4-bromophenylboronic acid following
a procedure analogous to that described for Intermediate 6. LC
(method 2): t.sub.R=1.28 min; Mass spectrum (ESI.sup.+): m/z=514,
516 [M+H].sup.+
Intermediate 41
{(S)-6-[(R)-7-Fluoro-4-(4-thiazol-2-yl-phenoxy)-indan-1-yloxy]-2,3-dihydro-
-benzofuran-3-yl}-acetic acid methyl ester
##STR00073##
[0368] A mixture of
{(S)-6-[(R)-4-(4-bromo-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzo-
furan-3-yl}-acetic acid methyl ester (75 mg), 2-thiazolylzinc
bromide (584 .mu.L), tetrakis(triphenylphosphine) palladium(0) (17
mg), and tetrahydrofuran (2 mL) under an argon atmosphere is heated
to 100.degree. C. for 2 h in a microwave oven. After cooling to
room temperature, the reaction mixture is diluted with methanol and
filtered. The filtrate is concentrated in vacuo and purified by
HPLC on reversed phase using acetonitrile, water and TFA as
eluents. LC (method 4): t.sub.R=1.24 min; Mass spectrum
(ESI.sup.+): m/z=518 [M+H].sup.+.
Intermediate 42
[(S)-6-{(R)-7-Fluoro-4-[4-(2-methyl-thiazol-5-yl)-phenoxy]-indan-1-yloxy}--
2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester
##STR00074##
[0370] A 2 M aqueous Na.sub.2CO.sub.3 solution (72 .mu.L) is added
to a mixture of
{(S)-6-[(R)-4-(4-bromo-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzo-
furan-3-yl}-acetic acid methyl ester (37 mg),
2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole
(19 mg), and
[1,1'-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) (3.5
mg), in 1,4-dioxane (2 mL). The reaction mixture is heated to
100.degree. C. over night under an argon atmosphere. After cooling
to room temperature, the reaction mixture is diluted with water and
extracted with ethyl acetate. The combined extracts are washed with
brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude
product is used for the next reaction step without further
purification. LC (method 4): t.sub.R=1.22 min; Mass spectrum
(ESI.sup.+): m/z=532 [M+H].sup.+.
Intermediate 43
[(S)-6-{(R)-7-Fluoro-4-[5-(4-hydroxy-4-methyl-pent-1-enyl)-pyridin-2-yloxy-
]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl
ester
##STR00075##
[0372] A mixture of
{(S)-6-[(R)-7-fluoro-4-(5-iodo-pyridin-2-yloxy)-indan-1-yloxy]-2,3-dihydr-
o-benzofuran-3-yl}-acetic acid methyl ester (200 mg),
tetrabutylammonium chloride (101 mg), 2-methyl-pent-4-en-2-ol (107
mg), and N,N-diisopropylethylamine (123 mg) in
N,N-dimethylformamide (5 mL) is purged with argon for several
minutes. Palladium(II) acetate (10 mg) is added and the reaction
mixture is heated to 90.degree. C. over night. After cooling to
room temperature, the reaction mixture is filtered and the filtrate
is concentrated in vacuo. The residue is dissolved in acetonitrile
and purified by preparative HPLC. LC (method 2): t.sub.R=1.15 min;
Mass spectrum (ESI.sup.+): m/z=534 [M+H].sup.+.
Intermediate 44
[(S)-6-{(R)-7-Fluoro-4-[5-(4-hydroxy-4-methyl-pentyl)-pyridin-2-yloxy]-ind-
an-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl
ester
##STR00076##
[0374] The title compound is prepared from
[(S)-6-{(R)-7-fluoro-4-[5-(4-hydroxy-4-methyl-pent-1-enyl)-pyridin-2-ylox-
y]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl
ester by hydrogenation in the presence of 10% palladium on carbon
in methanol at room temperature. The crude product is used for the
next reaction step without further purification.
Intermediate 45
(R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yloxy-
]-2,3-dihydro-1H-inden-4-ylboronic acid
##STR00077##
[0376] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-ind-
an-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester
following a procedure analogous to that described for Intermediate
32. LC (method 10): t.sub.R=0.52 min; Mass spectrum (ESI.sup.+):
m/z=387 [M+H].sup.+
Intermediate 46
{(S)-6-[(R)-7-Fluoro-4-(2-oxo-1,2,3,4-tetrahydroquinoline-7-yloxy)-indan-1-
-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester
##STR00078##
[0378] The title compound is prepared from
(R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-ylox-
y}-2,3-dihydro-1H-inden-4-ylboronic acid and
7-hydroxy-3,4-dihydro-1H-quinoline-2-one following a procedure
analogous to that described for Intermediate 6. LC (method 10):
t.sub.R=1.15 min; Mass spectrum (ESI.sup.+): m/z=504
[M+H].sup.+
Intermediate 47
{(S)-6-[(R)-4-(Benzo[d][1,3]dioxol-5-yloxy)-7-fluoro-indan-1-yloxly]-2,3-d-
ihydrobenzofuran-3-yl}-acetic acid methyl ester
##STR00079##
[0380] The title compound is prepared from
(R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-ylox-
y}-2,3-dihydro-1H-inden-4-ylboronic acid and benzo[1,3]dioxol-5-ol
following a procedure analogous to that described for Intermediate
6. LC (method 9): t.sub.R=1.23 min; Mass spectrum (ESI.sup.+):
m/z=479 [M+H].sup.+
Intermediate 48
{(S)-6-[(R)-4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yloxy)-7-fluoro-indan-1-yl-
oxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester
##STR00080##
[0382] The title compound is prepared from
(R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-ylox-
y}-2,3-dihydro-1H-inden-4-ylboronic acid and
2,3-dihydro-benzo[1,4]dioxin-6-ol following a procedure analogous
to that described for Intermediate 6. LC (method 9): t.sub.R=1.24
min; Mass spectrum (ESI.sup.+): m/z=493 [M+H].sup.+
Intermediate 49
((S)-6-{(R)-4-[4-(3,6-Dihydro-2H-pyran-4-yl)-phenoxy]-7-fluoro-indan-1-ylo-
xy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester
##STR00081##
[0383] Step 1:
((S)-6-{(R)-4-[4-(3,6-Dihydro-2H-pyran-4-yl)-phenoxy]-7-fluoro-indan-1-yl-
oxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester
[0384] A mixture of
{(S)-6-[(R)-4-(4-bromo-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzo-
furan-3-yl}-acetic acid methyl ester (22 mg),
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran
(50 mg), K.sub.3PO.sub.4 (10 mg), and water (10 .mu.L) in
tetrahydrofuran (2 mL) is purged with argon.
[1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)pallad-
ium(II) dichloride (PEPPSI-IPr, 5 mg) is added and the mixture is
heated to 80.degree. C. over night under an argon atmosphere. After
cooling to room temperature, the reaction mixture is diluted with
diethyl ether, washed with aqueous NH.sub.4Cl solution, dried over
MgSO.sub.4 and concentrated in vacuo. The residue is
chromatographed on silica gel using petrol ether and ethyl acetate
as eluents. LC (method 12): t.sub.R=0.93 min; Mass spectrum
(ESI.sup.+): m/z=539 [M+Na].sup.+.
Step 2:
((S)-6-{(R)-7-Fluoro-4-[4-(tetrahydro-2H-pyran-4-yl)phenoxy]-indan-
-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
[0385] The title compound is prepared from
((S)-6-{(R)-4-[4-(3,6-dihydro-2H-pyran-4-yl)-phenoxy]-7-fluoro-indan-1-yl-
oxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester by
hydrogenation in the presence of triethylamine and 10% palladium on
carbon in tetrahydrofuran at room temperature. LC (method 12):
t.sub.R=0.93 min; Mass spectrum (ESI.sup.+): m/z=541
[M+Na].sup.+
Intermediate 50
((S)-6-{(R)-7-Fluoro-4-[4-(4-hydroxy-4-methyl
pentyl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic
acid methyl ester
##STR00082##
[0386] Step 1:
5-(9-Bora-bicyclo[3.3.1]non-9-yl)-2-methyl-pentan-2-ol
[0387] A mixture of 2-methyl-pent-4-en-2-ol (50 mg) and
9-bora-bicyclo[3.3.1]nonane (0.5 M solution in tetrahydrofuran, 1
mL) is stirred for 6 h at room temperature. The solution is used
directly for the next step.
Step 2:
((S)-6-{(R)-7-Fluoro-4-[4-(4-hydroxy-4-methylpentyl)phenoxy]-indan-
-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
[0388] The title compound is prepared from
{(S)-6-[(R)-4-(4-bromo-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzo-
furan-3-yl}-acetic acid methyl ester and
5-(9-bora-bicyclo[3.3.1]non-9-yl)-2-methyl-pentan-2-ol (0.45 M
solution in tetrahydrofuran) following a procedure analogous to
that described for Intermediate 49, Step 1. LC (method 12):
t.sub.R=0.91 min; Mass spectrum (ESI.sup.+): m/z=557
[M+Na].sup.+
Intermediate 51
2,5-Difluoro-4-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-phenol
##STR00083##
[0390] The title compound is prepared from
4-bromo-2,5-difluorophenol and
2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1--
yl)propan-2-ol following a procedure analogous to that described
for Intermediate 35. Mass spectrum (EI.sup.+): m/z=268
[M].sup.+.
Intermediate 52
[(S)-6-((R)-4-{2,5-Difluoro-4-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-y-
l]phenoxy}-7-fluoro-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic
acid methyl ester
##STR00084##
[0392] The title compound is prepared from
(R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-ylox-
y}-2,3-dihydro-1H-inden-4-ylboronic acid and
2,5-difluoro-4-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-phenol
following a procedure analogous to that described for Intermediate
6. Mass spectrum (ESI.sup.+): m/z=609 [M+H].sup.+
Intermediate 53
1-(3-Hydroxy-3-methyl-butyl)-1H-indazol-5-ol
##STR00085##
[0393] Step 1: 4-(5-Benzyloxy-indazol-1-yl)-2-methyl-butan-2-ol
[0394] A mixture of 5-benzyloxy-1H-indazole (400 mg) and
toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester (507 mg),
and potassium carbonate (740 mg) in N,N-dimethylformamide (8 mL) is
stirred for 2 days at 60.degree. C. After cooling to room
temperature, the mixture is diluted with water and extracted with
ethyl acetate. The combined extracts are washed with brine, dried
over MgSO.sub.4, and concentrated in vacuo. The residue is
chromatographed on silica gel (cyclohexane/ethyl acetate
80:20.fwdarw.20:80) to give the title compound. LC (method 4):
t.sub.R=1.04 min; Mass spectrum (ESI.sup.+): m/z=311
[M+H].sup.+.
Step 2: 1-(3-Hydroxy-3-methyl-butyl)-1H-indazol-5-ol
[0395] The title compound is prepared from
4-(5-benzyloxy-indazol-1-yl)-2-methyl-butan-2-ol by hydrogenation
in the presence 10% palladium on carbon in methanol at room
temperature. LC (method 4): t.sub.R=0.71 min; Mass spectrum
(ESI.sup.+): m/z=221 [M+H].sup.+
Intermediate 54
((S)-6-{(R)-7-Fluoro-4-[1-(3-hydroxy-3-methylbutyl)-1H-indazol-5-yloxy]-in-
dan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl
ester
##STR00086##
[0397] The title compound is prepared from
(R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-ylox-
y}-2,3-dihydro-1H-inden-4-ylboronic acid and
1-(3-hydroxy-3-methyl-butyl)-1H-indazol-5-ol following a procedure
analogous to that described for Intermediate 6. LC (method 3):
t.sub.R=0.59 min; Mass spectrum (ESI.sup.+): m/z=561
[M+H].sup.+
Intermediate 55
2,6-Difluoro-4-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-phenol
##STR00087##
[0399] The title compound is prepared from
4-bromo-2,6-difluorophenol and
2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1--
yl)propan-2-ol following a procedure analogous to that described
for Intermediate 35. Mass spectrum (EI.sup.+): m/z=268
[M].sup.+.
Intermediate 56
[(S)-6-((R)-4-{2,6-Difluoro-4-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-y-
l]phenoxy}-7-fluoro-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic
acid methyl ester
##STR00088##
[0401] The title compound is prepared from
(R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-ylox-
y}-2,3-dihydro-1H-inden-4-ylboronic acid and
2,6-difluoro-4-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-phenol
following a procedure analogous to that described for Intermediate
6. LC (method 15): t.sub.R=4.24 min; Mass spectrum (ESI.sup.+):
m/z=609 [M+H].sup.+
Intermediate 57
((S)-6-{(R)-7-Fluoro-4-[4-(2-methylthiazol-4-yl)phenoxy]-indan-1-yloxy}-2,-
3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
##STR00089##
[0403] The title compound is prepared from
(R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-ylox-
y}-2,3-dihydro-1H-inden-4-ylboronic acid and
4-(2-methyl-thiazol-4-yl)-phenol following a procedure analogous to
that described for Intermediate 6. The crude product is used for
the next reaction step without further purification.
Intermediate 58
1-(3-Hydroxy-3-methyl-butyl)-1H-indol-5-ol
##STR00090##
[0404] Step 1: 4-(5-Benzyloxy-indol-1-yl)-2-methyl-butan-2-ol
[0405] The title compound is prepared by treatment of
5-benzyloxy-1H-indole with sodium hydride followed by
toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester in
N,N-dimethylformamide at 50.degree. C. LC (method 10): t.sub.R=0.68
min; Mass spectrum (ESI.sup.+): m/z=310 [M+H].sup.+.
Step 2: 1-(3-Hydroxy-3-methyl-butyl)-1H-indol-5-ol
[0406] The title compound is prepared from
4-(5-benzyloxy-indol-1-yl)-2-methyl-butan-2-ol by hydrogenation in
the presence of triethylamine and 10% palladium on carbon in
methanol at room temperature. LC (method 10): t.sub.R=0.82 min;
Mass spectrum (ESI.sup.+): m/z=220 [M+H].sup.+
Intermediate 59
((S)-6-{(R)-7-Fluoro-4-[1-(3-hydroxy-3-methylbutyl)-1H-indol-5-yloxy]-inda-
n-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
##STR00091##
[0408] The title compound is prepared from
(R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-ylox-
y}-2,3-dihydro-1H-inden-4-ylboronic acid and
1-(3-hydroxy-3-methyl-butyl)-1H-indol-5-ol following a procedure
analogous to that described for Intermediate 6. LC (method 10):
t.sub.R=0.88 min; Mass spectrum (ESI.sup.+): m/z=560
[M+H].sup.+
Intermediate 60
2,5-Difluoro-4-(3-hydroxy-3-methyl-butoxy)-phenol
##STR00092##
[0409] Step 1:
4-(4-Bromo-2,5-difluoro-phenoxy)-2-methyl-butan-2-ol
[0410] The title compound is prepared from
4-bromo-2,5-difluoro-phenol and toluene-4-sulfonic acid
3-hydroxy-3-methyl-butyl ester following a procedure analogous to
that described for Intermediate 26. Mass spectrum (EI.sup.+):
m/z=294 [M].sup.+.
Step 2:
4-[2,5-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-p-
henoxy]-2-methyl-butan-2-ol
[0411] The title compound is prepared from
4-(4-bromo-2,5-difluoro-phenoxy)-2-methyl-butan-2-ol and
bis-(pinacolato)-diboron following a procedure analogous to that
described for Intermediate 4. Mass spectrum (EI.sup.+): m/z=342
[M].sup.+
Step 3: 2,5-Difluoro-4-(3-hydroxy-3-methyl-butoxy)-phenol
[0412] The title compound is prepared from
4-[2,5-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-
-2-methyl-butan-2-ol following a procedure analogous to that
described for Intermediate 5. Mass spectrum (EI.sup.+): m/z=232
[M].sup.+
Intermediate 61
((S)-6-{(R)-4-[2,5-Difluoro-4-(3-hydroxy-3-methylbutoxy)phenoxy]-7-fluoro--
indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl
ester
##STR00093##
[0414] The title compound is prepared from
(R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-ylox-
y}-2,3-dihydro-1H-inden-4-ylboronic acid and
2,5-difluoro-4-(3-hydroxy-3-methyl-butoxy)-phenol following a
procedure analogous to that described for Intermediate 6. LC
(method 7): t.sub.R=4.08 min; Mass spectrum (ESI.sup.+): m/z=573
[M+H].sup.+
Intermediate 62
[(S)-6-((R)-7-Fluoro-4-{4-[(tetrahydro-2H-pyran-4-yl)methyl]phenoxy}-indan-
-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid methyl ester
##STR00094##
[0415] Step 1:
4-(9-Bora-bicyclo[3.3.1]non-9-ylmethyl)-tetrahydropyran
[0416] A mixture of 4-methylene-tetrahydropyran (50 mg) and
9-bora-bicyclo[3.3.1]nonane (0.5 M solution in tetrahydrofuran, 1
mL) is stirred for 6 h at room temperature. The solution is used
directly for the next step.
Step 2:
[(S)-6-((R)-7-Fluoro-4-{4-[(tetrahydro-2H-pyran-4-yl)methyl]phenox-
y}-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid methyl
ester
[0417] The title compound is prepared from
{(S)-6-[(R)-4-(4-bromo-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzo-
furan-3-yl}-acetic acid methyl ester and
4-(9-bora-bicyclo[3.3.1]non-9-ylmethyl)-tetrahydropyran (0.45 M
solution in tetrahydrofuran) following a procedure analogous to
that described for Intermediate 49, Step 1. LC (method 12):
t.sub.R=0.99 min; Mass spectrum (ESI.sup.+): m/z=533
[M+H].sup.+
Intermediate 63
1-(3-Hydroxy-3-methyl-butyl)-1H-indazol-5-ol
##STR00095##
[0418] Step 1: 4-(6-Benzyloxy-indazol-1-yl)-2-methyl-butan-2-ol
[0419] The title compound is prepared from 1H-indazol-6-ol and
toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester following a
procedure analogous to that described for Intermediate 53, Step 1.
LC (method 4): t.sub.R=1.04 min; Mass spectrum (ESI.sup.+): m/z=311
[M+H].sup.+.
Step 2: 1-(3-Hydroxy-3-methyl-butyl)-1H-indazol-6-ol
[0420] The title compound is prepared from
4-(6-benzyloxy-indazol-1-yl)-2-methyl-butan-2-ol by hydrogenation
in the presence 10% palladium on carbon in methanol at room
temperature. LC (method 4): t.sub.R=0.74 min; Mass spectrum
(ESI.sup.+): m/z=221 [M+H].sup.+
Intermediate 64
((S)-6-{(R)-7-Fluoro-4-[1-(3-hydroxy-3-methylbutyl)-1H-indazol-6-yloxy]-in-
dan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl
ester
##STR00096##
[0422] The title compound is prepared from
(R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-ylox-
y}-2,3-dihydro-1H-inden-4-ylboronic acid and
1-(3-hydroxy-3-methyl-butyl)-1H-indazol-6-ol following a procedure
analogous to that described for Intermediate 6. LC (method 3):
t.sub.R=0.65 min; Mass spectrum (ESI.sup.+): m/z=561
[M+H].sup.+
Intermediate 65
{(S)-6-[(R)-7-Fluoro-4-(3-fluoro-4-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dih-
ydro-benzofuran-3-yl}-acetic acid methyl ester
##STR00097##
[0423] Step 1:
{(S)-6-[(R)-4-(4-Benzyloxy-3-fluoro-phenoxy)-7-fluoro-indan-1-yloxy]-2,3--
dihydro-benzofuran-3-yl}-acetic acid methyl ester
[0424] The title compound is prepared from
(R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-ylox-
y}-2,3-dihydro-1H-inden-4-ylboronic acid and
4-benzyloxy-3-fluoro-phenol following a procedure analogous to that
described for Intermediate 6. LC (method 4): t.sub.R=1.30 min; Mass
spectrum (ESI.sup.+): m/z=559 [M+H].sup.+
Step 2:
{(S)-6-[(R)-7-Fluoro-4-(3-fluoro-4-hydroxy-phenoxy)-indan-1-yloxy]-
-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester
[0425] The title compound is prepared from
{(S)-6-[(R)-4-(4-benzyloxy-3-fluoro-phenoxy)-7-fluoro-indan-1-yloxy]-2,3--
dihydro-benzofuran-3-yl}-acetic acid methyl ester by hydrogenation
in the presence 10% palladium on carbon in methanol at room
temperature. LC (method 4): t.sub.R=1.13 min; Mass spectrum
(ESI.sup.+): m/z=469 [M+H].sup.+
Intermediate 66
[(S)-6-((R)-7-Fluoro-4-{3-fluoro-4-[(4-hydroxytetrahydro-2H-pyran-4-yl)met-
hoxy]-phenoxy}-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic
acid methyl ester
##STR00098##
[0427] A mixture of
{(S)-6-[(R)-7-fluoro-4-(3-fluoro-4-hydroxy-phenoxy)-indan-1-yloxy]-2,3-di-
hydro-benzofuran-3-yl}-acetic acid methyl ester (32 mg),
1,6-dioxa-spiro[2.5]octane (8 mg), and cesium carbonate (24 mg) in
N,N-dimethylformamide (2 mL) is heated to 80.degree. C. over night.
The reaction mixture is cooled to room temperature and used
directly for the next step. LC (method 4): t.sub.R=1.15 min; Mass
spectrum (ESI.sup.+): m/z=583 [M+H].sup.+
Intermediate 67
((S)-6-{(R)-7-Fluoro-4-[4-(1-methyl-1H-imidazol-2-yl)phenoxy]-indan-1-ylox-
y}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
##STR00099##
[0429] The title compound is prepared from
(R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-ylox-
y}-2,3-dihydro-1H-inden-4-ylboronic acid and
4-(1-methyl-1H-imidazol-2-yl)-phenol following a procedure
analogous to that described for Intermediate 6. The crude product
is used for the next reaction step without further
purification.
Intermediate 68
2,5-Difluoro-4-(3-methanesulfonyl-propoxy)-phenol
##STR00100##
[0430] Step 1:
1-Bromo-2,5-difluoro-4-(3-methylsulfanyl-propoxy)-benzene
[0431] A solution of 4-bromo-2,5-difluoro-phenol (2.00 g) in
tetrahydrofuran is cooled in an ice bath. Di-tert-butyl
azodicarboxylate (2.42 g), triphenylphosphine (2.76 g), and
3-methylthiopropanol (0.99 mL) are added and the resulting solution
is stirred for 30 min at 0.degree. C. The solvent is removed in
vacuo and the residue is chromatographed on silica gel
(cyclohexane/ethyl acetate 100:0.fwdarw.80:20) to give the title
compound. Mass spectrum (EI.sup.+): m/z=296 [M].sup.+.
Step 2:
1-Bromo-2,5-difluoro-4-(3-methanesulfonyl-propoxy)-benzene
[0432] The title compound is prepared from
1-bromo-2,5-difluoro-4-(3-methylsulfanyl-propoxy)-benzene by
oxidation with potassium peroxomonosulfate in a mixture of water
and tetrahydrofuran at room temperature. Mass spectrum (EI.sup.+):
m/z=328 [M].sup.+.
Step 3:
2-[2,5-Difluoro-4-(3-methanesulfonyl-propoxy)-phenyl]-4,4,5,5-tetr-
amethyl-[1,3,2]dioxaborolane
[0433] The title compound is prepared from
1-bromo-2,5-difluoro-4-(3-methanesulfonyl-propoxy)-benzene and
bis-(pinacolato)-diboron following a procedure analogous to that
described for Intermediate 4. Mass spectrum (EI.sup.+): m/z=376
[M].sup.+.
Step 4: 2,5-Difluoro-4-(3-methanesulfonyl-propoxy)-phenol
[0434] The title compound is prepared from
2-[2,5-difluoro-4-(3-methanesulfonyl-propoxy)-phenyl]-4,4,5,5-tetramethyl-
-[1,3,2]dioxaborolane following a procedure analogous to that
described for Intermediate 5. LC (method 7): t.sub.R=1.94 min; Mass
spectrum (ESI.sup.-): m/z=265 [M-H].sup.-.
Intermediate 69
[(S)-6-((R)-4-{2,5-Difluoro-4-[3-(methlsulfonyl)propoxl]phenoxy}-7-fluoro--
indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid methyl
ester
##STR00101##
[0436] The title compound is prepared from
(R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-ylox-
y}-2,3-dihydro-1H-inden-4-ylboronic acid and
2,5-difluoro-4-(3-methanesulfonyl-propoxy)-phenol following a
procedure analogous to that described for Intermediate 6. LC
(method 7): t.sub.R=3.82 min; Mass spectrum (ESI.sup.+): m/z=607
[M+H].sup.+
Intermediate 70
((S)-6-{(R)-7-Fluoro-4-[4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenoxy]--
indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl
ester
##STR00102##
[0438] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester and
[4-(3-hydroxy-3-methyl-butoxy)-2,6-dimethyl-phenyl]-boronic acid
following a procedure analogous to that described for Intermediate
6. LC (method 3): t.sub.R=0.87 min; Mass spectrum (ESI.sup.+):
m/z=587 [M+Na].sup.+.
Intermediate 71
((S)-6-{(R)-4-[2-Cyano-5-(4-hydroxy-4-methyl
pentyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-aceti-
c acid methyl ester
##STR00103##
[0439] Step 1:
{(S)-6-[(R)-4-(5-Bromo-2-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihyd-
robenzofuran-3-yl}-acetic acid methyl ester
[0440] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester and 4-bromo-2-fluoro-benzonitrile
following a procedure analogous to that described for Intermediate
24. LC (method 12): t.sub.R=0.87 min; Mass spectrum (ESI.sup.+):
m/z=538, 540 [M+H].sup.+.
Step 2:
((S)-6-{(R)-4-[2-Cyano-5-(4-hydroxy-4-methylpentyl)-phenoxy]-7-flu-
oro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl
ester
[0441] The title compound is prepared from
{(S)-6-[(R)-4-(5-bromo-2-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihyd-
robenzofuran-3-yl}-acetic acid methyl ester and
2-methyl-pent-4-en-2-ol following a procedure analogous to that
described for Intermediate 62 (Step 1 and 2). LC (method 12):
t.sub.R=0.77 min.
Intermediate 72
{(S)-6-[(R)-4-(2-Cyano-5-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihy-
drobenzofuran-3-yl}-acetic acid methyl ester
##STR00104##
[0442] Step 1:
((S)-6-{(R)-4-[2-Cyano-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-p-
henoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic
acid methyl ester
[0443] The title compound is prepared from
{(S)-6-[(R)-4-(5-bromo-2-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihyd-
robenzofuran-3-yl}-acetic acid methyl ester and
bis-(pinacolato)-diboron following a procedure analogous to that
described for Intermediate 4. LC (method 12): t.sub.R=0.43 min;
Mass spectrum (ESI.sup.+): m/z=586 [M+H].sup.+.
Step 2:
{(S)-6-[(R)-4-(2-Cyano-5-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]--
2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester
[0444] The title compound is prepared from
((S)-6-{(R)-4-[2-cyano-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-p-
henoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic
acid methyl ester following a procedure analogous to that described
for Intermediate 5. LC (method 12): t.sub.R=0.50 min; Mass spectrum
(ESI.sup.+): m/z=476 [M+H].sup.+.
Intermediate 73
((S)-6-{(R)-4-[2-Cyano-5-(3-hydroxy-3-methylbutoxy)-phenoxy]-7-fluoro-inda-
n-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
##STR00105##
[0446] The title compound is prepared from
{(S)-6-[(R)-4-(2-cyano-5-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dih-
ydrobenzofuran-3-yl}-acetic acid methyl ester and
toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester following a
procedure analogous to that described for Intermediate 8. LC
(method 12): t.sub.R=0.71 min; Mass spectrum (ESI.sup.+): m/z=562
[M+H].sup.+.
Intermediate 74
{(S)-6-[(R)-4-(3-Cyano-4-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihy-
drobenzofuran-3-yl}-acetic acid methyl ester
##STR00106##
[0447] Step 1:
4-(tert-Butyl-dimethyl-silanyloxy)-3-cyano-phenyl-boronic acid
[0448] Triisopropyl borate (1.77 mL) is added to a solution of
5-bromo-2-(tert-butyl-dimethyl-silanyloxy)-benzonitrile (800 mg) in
tetrahydrofuran (12 mL) and the mixture is cooled to -78.degree. C.
n-Butyllithium (15% in hexane; 1.92 mL) is added and the reaction
mixture is stirred at -78.degree. C. for 3 h. More n-butyllithium
(15% in hexane; 0.2 mL) is added and the mixture is allowed to warm
to -50.degree. C., and stirred at this temperature for 1.5 h.
Hydrochloric acid (1M, 4.9 mL) is added and the mixture is allowed
to warm to room temperature. After 1 h the reaction mixture is
diluted with brine and extracted with diethyl ether. The combined
extracts are concentrated in vacuo, diluted with hexane, stirred
for 30 min, and left standing over night at room temperature. The
white precipitate is filtered off, washed with hexane, and dried in
vacuo to give the title compound. LC (method 4): t.sub.R=1.08 min;
Mass spectrum (ESI.sup.+): m/z=278 [M+H].sup.+
Step 2:
((S)-6-{(R)-4-[4-(tert-Butyl-dimethyl-silanyloxy)-3-cyano-phenoxy]-
-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid
methyl ester
[0449] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester and
4-(tert-butyl-dimethyl-silanyloxy)-3-cyano-phenyl-boronic acid
following a procedure analogous to that described for Intermediate
6. LC (method 9): t.sub.R=1.35 min; Mass spectrum (ESI.sup.+):
m/z=590 [M+H].sup.+.
Step 3:
{(S)-6-[(R)-4-(3-Cyano-4-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]--
2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester
[0450] The title compound is prepared from
((S)-6-{(R)-4-[4-(tert-butyl-dimethyl-silanyloxy)-3-cyano-phenoxy]-7-fluo-
ro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl
ester by treatment with tetrabutylammonium fluoride in
tetrahydrofuran at room temperature. LC (method 9): t.sub.R=1.14
min; Mass spectrum (ESI.sup.+): m/z=476 [M+H].sup.+.
Intermediate 75
((S)-6-{(R)-4-[3-Cyano-4-((R)-tetrahydrofuran-3-yloxy)phenoxy]-7-fluoro-in-
dan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl
ester
##STR00107##
[0452] The title compound is prepared from
{(S)-6-[(R)-4-(3-cyano-4-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dih-
ydrobenzofuran-3-yl}-acetic acid methyl ester and
toluene-4-sulfonic acid (S)-tetrahydro-furan-3-yl ester following a
procedure analogous to that described for Intermediate 8. LC
(method 9): t.sub.R=1.20 min; Mass spectrum (ESI.sup.+): m/z=546
[M+H].sup.+.
Intermediate 76
((S)-6-{(R)-4-[3-Cyano-4-(3-hydroxy-3-methylbutoxy)phenoxy]-7-fluoro-indan-
-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
##STR00108##
[0454] The title compound is prepared from
{(S)-6-[(R)-4-(3-cyano-4-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dih-
ydrobenzofuran-3-yl}-acetic acid methyl ester and
toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester following a
procedure analogous to that described for Intermediate 8. LC
(method 9): t.sub.R=1.20 min; Mass spectrum (ESI.sup.+): m/z=562
[M+H].sup.+.
Intermediate 77
{(S)-6-[(R)-7-Fluoro-4-(2-fluoro-5-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dih-
ydro-benzofuran-3-yl}-acetic acid methyl ester
##STR00109##
[0455] Step 1:
{(S)-6-[(R)-7-Fluoro-4-(5-bromo-2-fluoro-phenoxy)-indan-1-yloxy]-2,3-dihy-
dro-benzofuran-3-yl}-acetic acid methyl ester
[0456] The title compound is prepared from
(R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-ylox-
y}-2,3-dihydro-1H-inden-4-ylboronic acid and
5-bromo-202-fluoro-phenol following a procedure analogous to that
described for Intermediate 6. LC (method 12): t.sub.R=0.99 min;
Mass spectrum (ESI.sup.+): m/z=531, 533 [M+H].sup.+
Step 2:
((S)-6-{(R)-7-Fluoro-4-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dio-
xaborolan-2-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-aceti-
c acid methyl ester
[0457] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-(5-bromo-2-fluoro-phenoxy)-indan-1-yloxy]-2,3-dihy-
dro-benzofuran-3-yl}-acetic acid methyl ester and
bis-(pinacolato)-diboron following a procedure analogous to that
described for Intermediate 4. LC (method 10): t.sub.R=1.13 min;
Mass spectrum (ESI.sup.+): m/z=579 [M+H].sup.+.
[0458] Step 3:
{(S)-6-[(R)-7-Fluoro-4-(2-fluoro-5-hydroxy-phenoxy)-indan-1-yloxy]-2,3-di-
hydro-benzofuran-3-yl}-acetic acid methyl ester
[0459] The title compound is prepared from
((S)-6-{(R)-7-fluoro-4-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborol-
an-2-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic
acid methyl ester following a procedure analogous to that described
for Intermediate 5. LC (method 10): t.sub.R=0.67 min; Mass spectrum
(ESI.sup.+): m/z=469 [M+H].sup.+.
Intermediate 78
((S)-6-{(R)-7-Fluoro-4-[2-fluoro-5-(3-hydroxy-3-methylbutoxy)phenoxy]-inda-
n-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
##STR00110##
[0461] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-(2-fluoro-5-hydroxy-phenoxy)-indan-1-yloxy]-2,3-di-
hydro-benzofuran-3-yl}-acetic acid methyl ester and
toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester following a
procedure analogous to that described for Intermediate 8. LC
(method 10): t.sub.R=0.84 min; Mass spectrum (ESI.sup.+): m/z=555
[M+H].sup.+.
Intermediate 79
((S)-6-{(R)-7-Fluoro-4-[2-fluoro-5-(tetrahydro-2H-pyran-4-yloxy)phenoxy]-i-
ndan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl
ester
##STR00111##
[0463] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-(2-fluoro-5-hydroxy-phenoxy)-indan-1-yloxy]-2,3-di-
hydro-benzofuran-3-yl}-acetic acid methyl ester and
tetrahydro-pyran-4-ol following a procedure analogous to that
described for Intermediate 3. LC (method 10): t.sub.R=0.92 min;
Mass spectrum (ESI.sup.+): m/z=575 [M+Na].sup.+.
Intermediate 80
{(S)-6-[(R)-4-(2-Cyano-4-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihy-
dro-benzofuran-3-yl}-acetic acid methyl ester
##STR00112##
[0464] Step 1:
{(S)-6-[(R)-4-(4-Benzyloxy-2-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-d-
ihydro-benzofuran-3-yl}-acetic acid methyl ester
[0465] The title compound is prepared from
(R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-ylox-
y}-2,3-dihydro-1H-inden-4-ylboronic acid and
5-benzyloxy-2-hydroxy-benzonitrile following a procedure analogous
to that described for Intermediate 6. LC (method 10): t.sub.R=0.99
min; Mass spectrum (ESI.sup.+): m/z=566 [M+H].sup.+
Step 2:
{(S)-6-[(R)-4-(2-Cyano-4-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]--
2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester
[0466] The title compound is prepared from
{(S)-6-[(R)-4-(4-benzyloxy-2-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-d-
ihydro-benzofuran-3-yl}-acetic acid methyl ester by hydrogenation
in the presence 10% palladium on carbon in methanol at room
temperature. LC (method 10): t.sub.R=0.61 min; Mass spectrum
(ESI.sup.+): m/z=476 [M+H].sup.+
Intermediate 81
((S)-6-{(R)-4-[2-Cyano-4-(3-hydroxy-3-methylbutoxy)phenoxy]-7-fluoro-indan-
-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
##STR00113##
[0468] The title compound is prepared from
{(S)-6-[(R)-4-(2-cyano-4-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dih-
ydro-benzofuran-3-yl}-acetic acid methyl ester and
toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester following a
procedure analogous to that described for Intermediate 8. LC
(method 10): t.sub.R=0.77 min; Mass spectrum (ESI.sup.+): m/z=562
[M+H].sup.+.
Intermediate 82
{(S)-6-[(R)-4-(4-Bromo-2-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydr-
o-benzofuran-3-yl}-acetic acid methyl ester
##STR00114##
[0470] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester and 5-bromo-2-fluoro-benzonitrile
following a procedure analogous to that described for Intermediate
24. LC (method 12): t.sub.R=0.88 min; Mass spectrum (ESI.sup.+):
m/z=538, 540 [M+H].sup.+.
Intermediate 83
((S)-6-{(R)-4-[2-Cyano-4-(1-methyl-1H-pyrazol-5-yl)phenoxy-7-fluoro-indan--
1-yloxy)-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester
##STR00115##
[0472] A mixture of
{(S)-6-[(R)-4-(4-bromo-2-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihyd-
ro-benzofuran-3-yl}-acetic acid methyl ester (80 mg),
1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole
(62 mg), K.sub.3PO.sub.4 (95 mg), toluene (2 mL), and water (200
.mu.L) is purged with argon for 10 min. Palladium(II) acetate (3
mg) and dicyclohexyl-(2',6'-dimethoxy-biphenyl-2-yl)-phosphane
(SPhos; 10 mg) are added and the reaction mixture is stirred at
90.degree. C. under an argon atmosphere for two days. After cooling
to room temperature, the reaction mixture is diluted with aqueous
NH.sub.4Cl solution and extracted with diethyl ether. The combined
extracts are dried over MgSO.sub.4 and concentrated in vacuo. The
residue is chromatographed on silica gel (cyclohexane/ethyl acetate
85:15.fwdarw.50:50) to give the title compound. LC (method 10):
t.sub.R=0.70 min; Mass spectrum (ESI.sup.+): m/z=540
[M+H].sup.+.
Intermediate 84
((S)-6-{(R)-4-[2-Cyano-4-(3,5-dimethylisoxazol-4-yl)phenoxy]-7-fluoro-inda-
n-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
##STR00116##
[0474] The title compound is prepared from
{(S)-6-[(R)-4-(4-bromo-2-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihyd-
ro-benzofuran-3-yl}-acetic acid methyl ester and
3,5-dimethylisoxazole-4-boronic acid following a procedure
analogous to that described for Intermediate 83. LC (method 10):
t.sub.R=0.81 min; Mass spectrum (ESI.sup.+): m/z=555
[M+H].sup.+.
Intermediate 85
{(S)-6-[(R)-7-Fluoro-4-(2-fluoro-4-hydroxy-phenoxy)-indan-1-yloxy]-2,3-dih-
ydro-benzofuran-3-yl}-acetic acid methyl ester
##STR00117##
[0475] Step 1:
{(S)-6-[(R)-7-Fluoro-4-(4-bromo-2-fluoro-phenoxy)-indan-1-yloxy]-2,3-dihy-
dro-benzofuran-3-yl}-acetic acid methyl ester
[0476] The title compound is prepared from
(R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-ylox-
y}-2,3-dihydro-1H-inden-4-ylboronic acid and
4-bromo-2-fluoro-phenol following a procedure analogous to that
described for Intermediate 6. LC (method 10): t.sub.R=1.05 min;
Mass spectrum (ESI.sup.+): m/z=531, 533 [M+H].sup.+
Step 2:
((S)-6-{(R)-7-Fluoro-4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dio-
xaborolan-2-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-aceti-
c acid methyl ester
[0477] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-(4-bromo-2-fluoro-phenoxy)-indan-1-yloxy]-2,3-dihy-
dro-benzofuran-3-yl}-acetic acid methyl ester and
bis-(pinacolato)-diboron following a procedure analogous to that
described for Intermediate 4. LC (method 10): t.sub.R=1.14 min;
Mass spectrum (ESI.sup.+): m/z=579 [M+H].sup.+.
Step 3:
{(S)-6-[(R)-7-Fluoro-4-(2-fluoro-4-hydroxy-phenoxy)-indan-1-yloxy]-
-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester
[0478] The title compound is prepared from
((S)-6-{(R)-7-fluoro-4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborol-
an-2-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic
acid methyl ester following a procedure analogous to that described
for Intermediate 5. LC (method 10): t.sub.R=0.67 min; Mass spectrum
(ESI.sup.+): m/z=469 [M+H].sup.+.
Intermediate 86
((S)-6-{(R)-7-Fluoro-4-[2-fluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenoxy]-i-
ndan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl
ester
##STR00118##
[0480] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-(2-fluoro-4-hydroxy-phenoxy)-indan-1-yloxy]-2,3-di-
hydro-benzofuran-3-yl}-acetic acid methyl ester and
tetrahydro-pyran-4-ol following a procedure analogous to that
described for Intermediate 3. LC (method 13): t.sub.R=0.81 min;
Mass spectrum (ESI.sup.+): m/z=575 [M+Na].sup.+.
Intermediate 87
((S)-6-{(R)-4-[4-Cyano-3-(tetrahydro-2H-pyran-4-yloxy)phenoxy]-7-fluoro-in-
dan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl
ester
##STR00119##
[0482] The title compound is prepared from
{(S)-6-[(R)-4-(4-cyano-3-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dih-
ydro-benzofuran-3-yl}-acetic acid methyl ester and
4-bromo-tetrahydropyran following a procedure analogous to that
described for Intermediate 8. The crude product is used for the
next reaction step without further purification.
Intermediate 88
((S)-6-{(R)-4-[4-Cyano-3-(2-hydroxy-2-methylpropoxy)phenoxy]-7-fluoro-inda-
n-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
##STR00120##
[0484] The title compound is prepared from
{(S)-6-[(R)-4-(4-cyano-3-hydroxy-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dih-
ydro-benzofuran-3-yl}-acetic acid methyl ester and isobutylene
oxide in N,N-dimethylformamide in the presence of Cs.sub.2CO.sub.3
at 80.degree. C. The crude product is used for the next reaction
step without further purification.
Intermediate 89
((S)-6-{(R)-7-Fluoro-4-[2-fluoro-4-(3-hydroxy-3-methylbutoxy)phenoxy]-inda-
n-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
##STR00121##
[0486] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-(2-fluoro-4-hydroxy-phenoxy)-indan-1-yloxy]-2,3-di-
hydro-benzofuran-3-yl}-acetic acid methyl ester and
toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester following a
procedure analogous to that described for Intermediate 8. LC
(method 13): t.sub.R=0.74 min; Mass spectrum (ESI.sup.+): m/z=577
[M+Na].sup.+.
Intermediate 90
((S)-6-{(R)-4-[4-(3,5-Dimethylisoxazol-4-yl)-2-fluorophenoxy]-7-fluoro-ind-
an-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl
ester
##STR00122##
[0488] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-(4-bromo-2-fluoro-phenoxy)-indan-1-yloxy]-2,3-dihy-
dro-benzofuran-3-yl}-acetic acid methyl ester and
3,5-dimethylisoxazole-4-boronic acid following a procedure
analogous to that described for Intermediate 83. LC (method 13):
t.sub.R=0.82 min; Mass spectrum (ESI.sup.+): m/z=548
[M+H].sup.+.
Intermediate 91
((S)-6-{(R)-7-Fluoro-4-[2-fluoro-4-(1-methyl-1H-pyrazol-5-yl)phenoxy]-inda-
n-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
##STR00123##
[0490] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-(4-bromo-2-fluoro-phenoxy)-indan-1-yloxy]-2,3-dihy-
dro-benzofuran-3-yl}-acetic acid methyl ester and
1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole
following a procedure analogous to that described for Intermediate
83. LC (method 13): t.sub.R=0.70 min; Mass spectrum (ESI.sup.+):
m/z=533 [M+H].sup.+.
Intermediate 92
((S)-6-{(R)-4-[2-Cyano-4-(4-hydroxy-4-methyl
pentyl)phenoxy-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic
acid methyl ester
##STR00124##
[0492] The title compound is prepared from
{(S)-6-[(R)-4-(4-bromo-2-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihyd-
ro-benzofuran-3-yl}-acetic acid methyl ester and
2-methyl-pent-4-en-2-ol following a procedure analogous to that
described for Intermediate 62 (Step 1 and 2). LC (method 12):
t.sub.R=0.78 min. Mass spectrum (ESI.sup.+): m/z=560
[M+H].sup.+.
Intermediate 93
((S)-6-{(R)-7-Fluoro-4-[3-(2-oxopyrrolidin-1-yl)phenoxy]-indan-1-yloxy}-2,-
3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
##STR00125##
[0494] The title compound is prepared from
(R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-ylox-
y}-2,3-dihydro-1H-inden-4-ylboronic acid and
1-(3-hydroxy-phenyl)-pyrrolidin-2-one following a procedure
analogous to that described for Intermediate 6. LC (method 9):
t.sub.R=1.18 min; Mass spectrum (ESI.sup.+): m/z=518
[M+H].sup.+.
Intermediate 94
((S)-6-{(R)-7-Fluoro-4-[4-(2-oxopyrrolidin-1-yl)phenoxy]-indan-1-yloxy}-2,-
3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
##STR00126##
[0496] The title compound is prepared from
(R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-ylox-
y}-2,3-dihydro-1H-inden-4-ylboronic acid and
1-(4-hydroxy-phenyl)-pyrrolidin-2-one following a procedure
analogous to that described for Intermediate 6. LC (method 4):
t.sub.R=1.14 min; Mass spectrum (ESI.sup.+): m/z=518
[M+H].sup.+.
Intermediate 95
((S)-6-{(R)-7-Fluoro-4-[4-(pyrrolidin-1-ylmethyl)phenoxy]-indan-1-yloxy}-2-
,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
##STR00127##
[0498] The title compound is prepared from
(R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-ylox-
y}-2,3-dihydro-1H-inden-4-ylboronic acid and
4-pyrrolidin-1-ylmethyl-phenol following a procedure analogous to
that described for Intermediate 6. LC (method 9): t.sub.R=0.95 min;
Mass spectrum (ESI.sup.+): m/z=518 [M+H].sup.+.
Intermediate 96
((S)-6-{(R)-4-[4-(Cyanomethyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-
benzofuran-3-yl)-acetic acid methyl ester
##STR00128##
[0500] The title compound is prepared from
(R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-ylox-
y}-2,3-dihydro-1H-inden-4-ylboronic acid and 4-hydroxybenzyl
cyanide following a procedure analogous to that described for
Intermediate 6. LC (method 9): t.sub.R=1.19 min; Mass spectrum
(ESI.sup.+): m/z=474 [M+H].sup.+.
Intermediate 97
((S)-6-{(R)-4-[4-(2-Cyanoethyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydr-
obenzofuran-3-yl)-acetic acid methyl ester
##STR00129##
[0502] The title compound is prepared from
(R)-7-fluoro-1-[(S)-3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-ylox-
y}-2,3-dihydro-1H-inden-4-ylboronic acid and
3-(4-hydroxy-phenyl)-propionitrile following a procedure analogous
to that described for Intermediate 6. LC (method 4): t.sub.R=1.18
min; Mass spectrum (ESI.sup.+): m/z=488 [M+H].sup.+.
Intermediate 98
((S)-6-{(R)-4-[2-Cyano-4-(3-hydroxy-3-methylbutyl)phenoxy]-7-fluoro-indan--
1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
##STR00130##
[0503] Step 1:
((S)-6-{(R)-4-[2-Cyano-4-(3-hydroxy-3-methyl-but-1-enyl)-phenoxy]-7-fluor-
o-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl
ester
[0504] A mixture of
{(S)-6-[(R)-4-(4-bromo-2-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihyd-
ro-benzofuran-3-yl}-acetic acid methyl ester (5 mg),
2-methyl-but-3-en-2-ol (30 mg), and triethylamine (50 .mu.L) in
N,N-dimethylformamide (0.5 mL) is purged with argon for 10 min.
Palladium(II) acetylacetonate (5 mg) is added and the reaction
mixture is stirred over night at 90.degree. C. under an argon
atmosphere. After cooling to room temperature, the reaction mixture
is diluted with diethyl ether and washed with aqueous NH.sub.4Cl
solution. The organic phase is dried over MgSO.sub.4 and
concentrated in vacuo. The residue is chromatographed on silica gel
(petrol ether/ethyl acetate) to give the title compound. LC (method
12): t.sub.R=0.68 min; Mass spectrum (ESI.sup.+): m/z=544
[M+H].sup.+
Step 2:
((S)-6-{(R)-4-[2-Cyano-4-(3-hydroxy-3-methylbutyl)phenoxy]-7-fluor-
o-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl
ester
[0505] The title compound is prepared from
((S)-6-{(R)-4-[2-cyano-4-(3-hydroxy-3-methyl-but-1-enyl)-phenoxy]-7-fluor-
o-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl
ester by hydrogenation in the presence of triethylamine and 10%
palladium on carbon in tetrahydrofuran at room temperature. LC
(method 12): t.sub.R=0.71 min; Mass spectrum (ESI.sup.+): m/z=546
[M+H].sup.+
Intermediate 99
4-[(R)-7-Fluoro-1-((S)-3-methoxycarbonylmethyl-2,3-dihydro-benzofuran-6-yl-
oxy)-indan-4-yloxy]1-benzoic acid
##STR00131##
[0506] Step 1:
4-[(R)-7-Fluoro-1-((S)-3-methoxycarbonylmethyl-2,3-dihydro-benzofuran-6-y-
loxy)-indan-4-yloxy]-benzoic acid benzyl ester
[0507] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester and 4-(benzyloxycarbonyl)-phenylboronic
acid following a procedure analogous to that described for
Intermediate 6. LC (method 9): t.sub.R=1.30 min; Mass spectrum
(ESI.sup.+): m/z=569 [M+H].sup.+.
Step 2:
4-[(R)-7-Fluoro-1-((S)-3-methoxycarbonylmethyl-2,3-dihydro-benzofu-
ran-6-yloxy)-indan-4-yloxy]-benzoic acid
[0508] The title compound is prepared from
4-[(R)-7-fluoro-1-((S)-3-methoxycarbonylmethyl-2,3-dihydro-benzofuran-6-y-
loxy)-indan-4-yloxy]-benzoic acid benzyl ester by hydrogenation in
the presence of 10% palladium on carbon in ethyl acetate at room
temperature. LC (method 9): t.sub.R=1.13 min; Mass spectrum
(ESI.sup.+): m/z=479 [M+H].sup.+.
Intermediate 100
((S)-6-{(R)-4-[4-(Dimethylcarbamoyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-d-
ihydrobenzofuran-3-yl)-acetic acid methyl ester
##STR00132##
[0510] 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (58 mg) is added to a mixture of
4-[(R)-7-fluoro-1-((S)-3-methoxycarbonylmethyl-2,3-dihydro-benzofuran-6-y-
loxy)-indan-4-yloxy]-benzoic acid (78 mg) and ethyldiisopropylamine
(85 .mu.L) in N,N-dimethylformamide (2 mL). The resulting mixture
is stirred at room temperature for 30 min. Dimethylamine (2 M in
tetrahydrofuran; 85 .mu.L) is added and the reaction mixture is
stirred at room temperature for 2 h. The crude product is used
without further purification for the next reaction step. LC (method
9): t.sub.R=1.14 min; Mass spectrum (ESI.sup.+): m/z=506
[M+H].sup.+.
Intermediate 101
((S)-6-{(R)-7-Fluoro-4-[4-(morpholine-4-carbonyl)phenoxy]-indan-1-yloxy}-2-
,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
##STR00133##
[0512] The title compound is prepared from
4-[(R)-7-fluoro-1-((S)-3-methoxycarbonylmethyl-2,3-dihydro-benzofuran-6-y-
loxy)-indan-4-yloxy]-benzoic acid and morpholine following a
procedure analogous to that described for Intermediate 100. LC
(method 9): t.sub.R=1.13 min; Mass spectrum (ESI.sup.+): m/z=548
[M+H].sup.+.
Intermediate 102
((S)-6-{(R)-4-[2-Cyano-4-(2,6-dimethylpyridin-4-yl)phenoxy)]-7-fluoro-inda-
n-1-yloxy)}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl
ester
##STR00134##
[0513] Step 1:
((S)-6-{(R)-4-[2-Cyano-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-p-
henoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic
acid methyl ester
[0514] The title compound is prepared from
{(S)-6-[(R)-4-(4-bromo-2-cyano-phenoxy)-fluoro-indan-1-yloxy]-2,3-dihydro-
-benzofuran-3-yl}-acetic acid methyl ester and
bis-(pinacolato)-diboron following a procedure analogous to that
described for Intermediate 4. LC (method 10): t.sub.R=1.06 min.
Step 2:
((S)-6-{(R)-4-[2-Cyano-4-(2,6-dimethylpyridin-4-yl)phenoxy)]-7-flu-
oro-indan-1-yloxy)}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl
ester
[0515] The title compound is prepared from
((S)-6-{(R)-4-[2-cyano-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-p-
henoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic
acid methyl ester and 4-bromo-2,6-dimethyl-pyridine following a
procedure analogous to that described for Intermediate 83, using
[1,1'-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) as
catalyst. LC (method 17): t.sub.R=0.70 min; Mass spectrum
(ESI.sup.+): m/z=565 [M+H].sup.+.
Intermediate 103
((S)-6-{(R)-7-Fluoro-4-[2-fluoro-4-(6-methylpyridin-2-yl)phenoxy]-indan-1--
yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
##STR00135##
[0517] The title compound is prepared from
((S)-6-{(R)-7-fluoro-4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborol-
an-2-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic
acid methyl ester and 2-bromo-6-methyl-pyridine following a
procedure analogous to that described for Intermediate 83, using
[1,1'-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) as
catalyst. LC (method 10): t.sub.R=0.97 min; Mass spectrum
(ESI.sup.+): m/z=544 [M+H].sup.+.
Intermediate 104
((S)-6-{(R)-4-[4-(2,6-Dimethylpyridin-4-yl)-2-fluorophenoxy]-7-fluoro-inda-
n-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
##STR00136##
[0519] The title compound is prepared from
((S)-6-{(R)-7-fluoro-4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborol-
an-2-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic
acid methyl ester and 4-bromo-2,6-dimethyl-pyridine following a
procedure analogous to that described for Intermediate 83, using
[1,1'-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) as
catalyst. LC (method 17): t.sub.R=0.82 min; Mass spectrum
(ESI.sup.+): m/z=558 [M+H].sup.+.
Intermediate 105
((S)-6-{(R)-4-[2-Cyano-4-(6-methylpyridin-2-yl)phenoxy]-7-fluoro-indan-1-y-
loxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
##STR00137##
[0521] The title compound is prepared from
((S)-6-{(R)-4-[2-cyano-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-p-
henoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic
acid methyl ester and 2-bromo-6-methyl-pyridine following a
procedure analogous to that described for Intermediate 83, using
[1,1'-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) as
catalyst. LC (method 10): t.sub.R=0.90 min; Mass spectrum
(ESI.sup.+): m/z=551 [M+H].sup.+.
Intermediate 106
{(S)-6-[(R)-4-(2-Cyano-4-formyl-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihyd-
ro-benzofuran-3-yl}-acetic acid methyl ester
##STR00138##
[0522] Step 1:
{6-[4-(2-Cyano-4-vinyl-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzo-
furan-3-yl}-acetic acid methyl ester
[0523] A mixture of
{(S)-6-[(R)-4-(4-bromo-2-cyano-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihyd-
ro-benzofuran-3-yl}-acetic acid methyl ester (320 mg), potassium
vinyltrifluoroborate (200 mg), Cs.sub.2CO.sub.3 (600 mg), and water
(100 .mu.L) in toluene (5 mL) is purged with argon.
1,1'-Bis(diphenylphosphino)ferrocene-dichloropalladium(II) (30 mg)
is added and the reaction mixture is heated over night to
100.degree. C. under an argon atmosphere in an autoclave. After
cooling to room temperature, the reaction mixture is diluted with
diethyl ether, washed with aqueous NH.sub.4Cl solution, dried over
MgSO.sub.4, and concentrated in vacuo. The residue is purified by
silica gel chromatography (petrol ether/ethyl acetate) to give the
title compound. LC (method 12): t.sub.R=0.86 min; Mass spectrum
(ESI.sup.+): m/z=486 [M+H].sup.+.
Step 2:
{(S)-6-[(R)-4-(2-Cyano-4-formyl-phenoxy)-7-fluoro-indan-1-yloxy]-2-
,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester
[0524] A mixture of
{6-[4-(2-cyano-4-vinyl-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzo-
furan-3-yl}-acetic acid methyl ester (165 mg), osmium tetroxide (4%
in water; 100 .mu.L), and water (0.5 mL) in 1,4-dioxane (5 mL) is
stirred at room temperature for 30 min. Sodium (meta)periodate (400
mg) is added and the mixture is stirred at room temperature for 4
h. The mixture is diluted with diethyl ether, washed with aqueous
sodium thiosulfate solution, dried over MgSO.sub.4, and
concentrated in vacuo. The crude product is used for the next
reaction step without further purification. LC (method 12):
t.sub.R=0.67 min; Mass spectrum (ESI.sup.+): m/z=488
[M+H].sup.+.
Intermediate 107
{(S)-6-[(R)-4-(2-Cyano-4-(piperidin-1-ylmethyl)phenoxy]-7-fluoro-indan-1-y-
loxy)-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester
##STR00139##
[0526] A mixture of
{(S)-6-[(R)-4-(2-cyano-4-formyl-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihy-
dro-benzofuran-3-yl}-acetic acid methyl ester (50 mg) and
piperidine (60 mg) in 1,2-dichloroethane (2 mL) is stirred for 1 h
at room temperature. Sodium triacetoxyborohydride (50 mg) is added
and the reaction mixture is stirred over night at room temperature.
The mixture is diluted with diethyl ether, washed with aqueous
NaHCO.sub.3 solution, dried over MgSO.sub.4, and concentrated in
vacuo. The residue is purified by MPLC to give the title compound.
LC (method 4): t.sub.R=1.00 min; Mass spectrum (ESI.sup.+): m/z=557
[M+H].sup.+.
Intermediate 108
((S)-6-{(R)-4-[2-Cyano-4-(morpholin-4-ylmethyl)phenoxy]-7-fluoro-indan-1-y-
loxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
##STR00140##
[0528] The title compound is prepared from
{(S)-6-[(R)-4-(2-cyano-4-formyl-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihy-
dro-benzofuran-3-yl}-acetic acid methyl ester and morpholine
following a procedure analogous to that described for Intermediate
107. LC (method 4): t.sub.R=0.98 min; Mass spectrum (ESI.sup.+):
m/z=559 [M+H].sup.+.
Example 1
[(S)-6-{(R)-7-Fluoro-4-[4-(2-methoxy-ethoxy)-phenoxy]-indan-1-yloxy}-2,3-d-
ihydro-benzofuran-3-yl]-acetic acid
##STR00141##
[0530] 1 M aqueous NaOH solution (0.7 mL) is added to a solution of
[(S)-6-{(R)-7-fluoro-4-[4-(2-methoxy-ethoxy)-phenoxy]-indan-1-yloxy}-2,3--
dihydro-benzofuran-3-yl]-acetic acid methyl ester (62 mg) in
methanol (2 mL) and tetrahydrofuran (2 mL) at room temperature. The
mixture is stirred at room temperature for 6 h. The organic solvent
is evaporated, water is added, and the resulting mixture is
neutralized with 1 M aqueous HCl solution (0.7 mL). The solution is
stirred at room temperature for 0.5 h.
[0531] The precipitate is separated by filtration, washed with
water and dried to give the title compound. LC (method 3):
t.sub.R=0.39 min; Mass spectrum (ESI.sup.-): m/z=493
[M-H].sup.-.
Example 2
[(S)-6-{(R)-7-Fluoro-4-[4-(3-hydroxy-3-methyl-butoxy)-phenoxy]-indan-1-ylo-
xy}-2,3-dihydro-benzofuran-3-yl]-acetic acid
##STR00142##
[0533] The title compound is prepared from
[(S)-6-{(R)-7-fluoro-4-[4-(3-hydroxy-3-methyl-butoxy)-phenoxy]-indan-1-yl-
oxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester
following a procedure analogous to that described for Example 1. LC
(method 3): t.sub.R=0.41 min; Mass spectrum (ESI.sup.-): m/z=521
[M-H].sup.-.
Example 3
[(S)-6-{(R)-7-Fluoro-4-[4-(2-hydroxy-2-methyl-propoxy)-phenoxy]-indan-1-yl-
oxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid
##STR00143##
[0535] The title compound is prepared from
[(S)-6-{(R)-7-fluoro-4-[4-(2-hydroxy-2-methyl-propoxy)-phenoxy]-indan-1-y-
loxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester
following a procedure analogous to that described for Example 1. LC
(method 3): t.sub.R=0.35 min; Mass spectrum (ESI.sup.+): m/z=531
[M+Na].sup.+.
Example 4
[(S)-6-{(R)-7-Fluoro-4-[4-(3-methanesulfonyl-propoxy)-phenoxy]-indan-1-ylo-
xy}-2,3-dihydro-benzofuran-3-yl)-acetic acid
##STR00144##
[0537] The title compound is prepared from
[(S)-6-{(R)-7-fluoro-4-[4-(3-methanesulfonyl-propoxy)-phenoxy]-indan-1-yl-
oxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1. LC
(method 3): t.sub.R=0.22 min; Mass spectrum (ESI.sup.+): m/z=557
[M+H].sup.+.
Example 5
{(S)-6-[(R)-7-Fluoro-4-(4-morpholin-4-ylmethyl-phenoxy)-indan-1-yloxy]-2,3-
-dihydro-benzofuran-3-yl}-acetic acid
##STR00145##
[0539] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-(4-morpholin-4-ylmethyl-phenoxy)-indan-1-yloxy]-2,-
3-dihydro-benzofuran-3-yl}-acetic acid methyl ester following a
procedure analogous to that described for Example 1. LC (method 2):
t.sub.R=0.87 min; Mass spectrum (ESI.sup.-): m/z=518
[M-H].sup.-.
Example 6
{(S)-6-[(R)-4-(3-Acetylamino-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro--
benzofuran-3-yl}-acetic acid
##STR00146##
[0541] The title compound is prepared
{(S)-6-[(R)-4-(3-acetylamino-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-
-benzofuran-3-yl}-acetic acid methyl ester following a procedure
analogous to that described for Example 1. LC (method 2):
t.sub.R=1.01 min; Mass spectrum (ESI.sup.-): m/z=476
[M-H].sup.-.
Example 7
[(S)-6-{(R)-4-[3-(Acetylamino-methyl)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-
-dihydro-benzofuran-3-yl]-acetic acid
##STR00147##
[0543] The title compound is prepared
[(S)-6-{(R)-4-[3-(acetylamino-methyl)-phenoxy]-7-fluoro-indan-1-yloxy}-2,-
3-dihydro-benzofuran-3-yl]-acetic acid methyl ester following a
procedure analogous to that described for Example 1. LC (method 2):
t.sub.R=0.99 min; Mass spectrum (ESI.sup.-): m/z=490
[M-H].sup.-.
Example 8
{(S)-6-[(R)-4-(4-Acetylamino-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro--
benzofuran-3-yl}-acetic acid
##STR00148##
[0545] The title compound is prepared
{(S)-6-[(R)-4-(4-acetylamino-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-
-benzofuran-3-yl}-acetic acid methyl ester following a procedure
analogous to that described for Example 1. LC (method 2):
t.sub.R=1.00 min; Mass spectrum (ESI.sup.-): m/z=476
[M-H].sup.-.
Example 9
[(S)-6-{(R)-7-Fluoro-4-[4-(pyrrolidine-1-carbonyl)-phenoxy]-indan-1-yloxy}-
-2,3-dihydro-benzofuran-3-yl]-acetic acid
##STR00149##
[0547] The title compound is prepared
[(S)-6-{(R)-7-fluoro-4-[4-(pyrrolidine-1-carbonyl)-phenoxy]-indan-1-yloxy-
}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester following a
procedure analogous to that described for Example 1. LC (method 2):
t.sub.R=1.06 min; Mass spectrum (ESI.sup.+): m/z=518
[M+H].sup.+.
Example 10
{(S)-6-[(R)-7-Fluoro-4-(4-imidazol-1-yl-phenoxy)-indan-1-yloxy]-2,3-dihydr-
o-benzofuran-3-yl}-acetic acid
##STR00150##
[0549] The title compound is prepared
{(S)-6-[(R)-7-fluoro-4-(4-imidazol-1-yl-phenoxy)-indan-1-yloxy]-2,3-dihyd-
ro-benzofuran-3-yl}-acetic acid methyl ester following a procedure
analogous to that described for Example 1. LC (method 2):
t.sub.R=0.89 min; Mass spectrum (ESI.sup.+): m/z=487
[M+H].sup.+.
Example 11
{(S)-6-[(R)-4-(2,3-Dihydro-benzofuran-5-yloxy)-7-fluoro-indan-1-yloxy]-2,3-
-dihydro-benzofuran-3-yl}-acetic acid
##STR00151##
[0551] The title compound is prepared from
{(S)-6-[(R)-4-(2,3-dihydro-benzofuran-5-yloxy)-7-fluoro-indan-1-yloxy]-2,-
3-dihydro-benzofuran-3-yl}-acetic acid methyl ester following a
procedure analogous to that described for Example 1. LC (method 2):
t.sub.R=1.13 min; Mass spectrum (ESI.sup.+): m/z=463
[M+H].sup.+.
Example 12
{(S)-6-[(R)-4-(4-Ethylcarbamoyl-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihyd-
ro-benzofuran-3-yl}-acetic acid
##STR00152##
[0553] The title compound is prepared from
{(S)-6-[(R)-4-(4-ethylcarbamoyl-phenoxy)-7-fluoro-indan-1-yloxy]-2,3-dihy-
dro-benzofuran-3-yl}-acetic acid methyl ester following a procedure
analogous to that described for Example 1. LC (method 2):
t.sub.R=1.01 min; Mass spectrum (ESI.sup.-): m/z=490
[M-H].sup.-.
Example 13
[(S)-6-{(R)-7-Fluoro-4-[4-(1H-tetrazol-5-yl)-phenoxy]-indan-1-yloxy}-2,3-d-
ihydro-benzofuran-3-yl]-acetic acid
##STR00153##
[0555] The title compound is prepared from
[(S)-6-{(R)-7-fluoro-4-[4-(1H-tetrazol-5-yl)-phenoxy]-indan-1-yloxy}-2,3--
dihydro-benzofuran-3-yl]-acetic acid methyl ester following a
procedure analogous to that described for Example 1. LC (method 4):
t.sub.R=0.99 min; Mass spectrum (ESI.sup.-): m/z=487
[M-H].sup.-.
Example 14
[(S)-6-{(R)-7-Fluoro-4-[4-(1-methyl-1H-tetrazol-5-yl)-phenoxy]-indan-1-ylo-
xy}-2,3-dihydro-benzofuran-3-yl]-acetic acid
##STR00154##
[0557] The title compound is prepared from
[(S)-6-{(R)-7-fluoro-4-[4-(1-methyl-1H-tetrazol-5-yl)-phenoxy]-indan-1-yl-
oxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester
following a procedure analogous to that described for Example 1. LC
(method 4): t.sub.R=1.04 min; Mass spectrum (ESI.sup.-): m/z=501
[M-H].sup.-.
Example 15
[(S)-6-{(R)-7-Fluoro-4-[4-(2-methyl-2H-tetrazol-5-yl)-phenoxy]-indan-1-ylo-
xy}-2,3-dihydro-benzofuran-3-yl]-acetic acid
##STR00155##
[0559] The title compound is prepared from
[(S)-6-{(R)-7-fluoro-4-[4-(2-methyl-2H-tetrazol-5-yl)-phenoxy]-indan-1-yl-
oxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester
following a procedure analogous to that described for Example 1. LC
(method 4): t.sub.R=1.10 min; Mass spectrum (ESI.sup.-): m/z=501
[M-H].sup.-.
Example 16
{(S)-6-[(R)-7-fluoro-4-{2-[(S)-tetrahydro-furan-3-yloxy]-pyridin-4-yloxy}--
indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid
##STR00156##
[0561] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-{2-[(S)-tetrahydro-furan-3-yloxy]-pyridin-4-yloxy}-
-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl
ester following a procedure analogous to that described for Example
1. LC (method 2): t.sub.R=1.09 min; Mass spectrum (ESI.sup.-):
m/z=506 [M-H].sup.-.
Example 17
[(S)-6-{(R)-7-Fluoro-4-[5-(3-hydroxy-3-methyl-butoxy)-pyridin-2-yloxy]-ind-
an-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid
##STR00157##
[0563] The title compound is prepared from
[(S)-6-{(R)-7-fluoro-4-[5-(3-hydroxy-3-methyl-butoxy)-pyridin-2-yloxy]-in-
dan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester
following a procedure analogous to that described for Example 1.
Mass spectrum (ESI.sup.-): m/z=522 [M-H].sup.-.
Example 18
{(S)-6-[(R)-7-Fluoro-4-{5-[(S)-tetrahydro-furan-3-yloxy}pyridin-2-yloxy}-i-
ndan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid
##STR00158##
[0565] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-{5-[(S)-tetrahydro-furan-3-yloxy}-pyridin-2-yloxy}-
-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl
ester following a procedure analogous to that described for Example
1. LC (method 4): t.sub.R=1.05 min; Mass spectrum (ESI.sup.-):
m/z=506 [M-H].sup.-.
Example 19
[(S)-6-{(R)-4-[3,5-Difluoro-4-(3-methanesulfonyl-propoxy)-phenoxy]-7-fluor-
o-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid
##STR00159##
[0567] The title compound is prepared from
[(S)-6-{(R)-4-[3,5-difluoro-4-(3-methanesulfonyl-propoxy)-phenoxy]-7-fluo-
ro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl
ester following a procedure analogous to that described for Example
1. LC (method 7): t.sub.R=2.76 min; Mass spectrum (ESI.sup.+):
m/z=593 [M+H].sup.+.
Example 20
{(S)-6-[(R)-4-{3,5-Difluoro-4-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4--
yl]-phenoxy}-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic
acid
##STR00160##
[0569] The title compound is prepared from
{(S)-6-[(R)-4-{3,5-difluoro-4-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-
-yl]-phenoxy}-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic
acid methyl ester following a procedure analogous to that described
for Example 1. LC (method 7): t.sub.R=2.89 min; Mass spectrum
(ESI.sup.+): m/z=595 [M+H].sup.+.
Example 21
{(S)-6-[(R)-7-Fluoro-4-(4-thiazol-2-yl-phenoxy)-indan-1-yloxy]-2,3-dihydro-
-benzofuran-3-yl}-acetic acid
##STR00161##
[0571] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-(4-thiazol-2-yl-phenoxy)-indan-1-yloxy]-2,3-dihydr-
o-benzofuran-3-yl}-acetic acid methyl ester following a procedure
analogous to that described for Example 1. LC (method 4):
t.sub.R=1.15 min; Mass spectrum (ESI.sup.+): m/z=504
[M+H].sup.+.
Example 22
[(S)-6-{(R)-7-Fluoro-4-[4-(2-methyl-thiazol-5-yl)-phenoxy]-indan-1-yloxy}--
2,3-dihydro-benzofuran-3-yl]-acetic acid
##STR00162##
[0573] The title compound is prepared from
[(S)-6-{(R)-7-fluoro-4-[4-(2-methyl-thiazol-5-yl)-phenoxy]-indan-1-yloxy}-
-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester following a
procedure analogous to that described for Example 1. LC (method 4):
t.sub.R=1.13 min; Mass spectrum (ESI.sup.+): m/z=518
[M+H].sup.+.
Example 23
[(S)-6-{(R)-7-Fluoro-4-[5-(4-hydroxy-4-methyl-pentyl)-pyridin-2-yloxy]-ind-
an-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid
##STR00163##
[0575] The title compound is prepared from
[(S)-6-{(R)-7-fluoro-4-[5-(4-hydroxy-4-methyl-pentyl)-pyridin-2-yloxy]-in-
dan-1-yloxy}-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester
following a procedure analogous to that described for Example 1. LC
(method 6): t.sub.R=0.39 min; Mass spectrum (ESI.sup.+): m/z=522
[M+H].sup.+.
Example 24
{(S)-6-[(R)-7-Fluoro-4-(2-oxo-1,2,3,4-tetrahydroquinoline-7-yloxy)-indan-1-
-yloxly]-2,3-dihydrobenzofuran-3-yl}-acetic acid
##STR00164##
[0577] The title compound is prepared from
{(S)-6-[(R)-7-fluoro-4-(2-oxo-1,2,3,4-tetrahydroquinoline-7-yloxy)-indan--
1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester
following a procedure analogous to that described for Example 1. LC
(method 9): t.sub.R=1.05 min; Mass spectrum (ESI.sup.+): m/z=490
[M+H].sup.+.
Example 25
{(S)-6-[(R)-4-(Benzo[d][1,3]dioxol-5-yloxy)-7-fluoro-indan-1-yloxly]-2,3-d-
ihydrobenzofuran-3-yl}-acetic acid
##STR00165##
[0579] The title compound is prepared from
{(S)-6-[(R)-4-(benzo[d][1,3]dioxol-5-yloxy)-7-fluoro-indan-1-yloxy]-2,3-d-
ihydrobenzofuran-3-yl}-acetic acid methyl ester following a
procedure analogous to that described for Example 1. LC (method 9):
t.sub.R=1.15 min; Mass spectrum (ESI.sup.+): m/z=465
[M+H].sup.+.
Example 26
{(S)-6-[(R)-4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yloxy)-7-fluoro-indan-1-yl-
oxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid
##STR00166##
[0581] The title compound is prepared from
{(S)-6-[(R)-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yloxy)-7-fluoro-indan-1-y-
loxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester
following a procedure analogous to that described for Example 1. LC
(method 9): t.sub.R=1.14 min; Mass spectrum (ESI.sup.+): m/z=479
[M+H].sup.+.
Example 27
((S)-6-{(R)-7-Fluoro-4-[4-(tetrahydro-2H-pyran-4-yl)phenoxy]-indan-1-yloxy-
}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00167##
[0583] The title compound is prepared from
((S)-6-{(R)-7-fluoro-4-[4-(tetrahydro-2H-pyran-4-yl)phenoxy]-indan-1-ylox-
y}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a
procedure analogous to that described for Example 1. LC (method
11): t.sub.R=1.37 min; Mass spectrum (ESI.sup.-): m/z=503
[M-H].sup.-.
Example 28
((S)-6-{(R)-7-Fluoro-4-[4-(4-hydroxy-4-methyl
pentyl)phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic
acid
##STR00168##
[0585] The title compound is prepared from
((S)-6-{(R)-7-fluoro-4-[4-(4-hydroxy-4-methylpentyl)phenoxy]-indan-1-ylox-
y}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a
procedure analogous to that described for Example 1. LC (method
12): t.sub.R=0.69 min; Mass spectrum (ESI.sup.+): m/z=521
[M+H].sup.+.
Example 29
[(S)-6-((R)-4-{2,5-Difluoro-4-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-y-
l]phenoxy}-7-fluoro-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic
acid
##STR00169##
[0587] The title compound is prepared from
[(S)-6-((R)-4-{2,5-difluoro-4-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4--
yl]phenoxy}-7-fluoro-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic
acid methyl ester following a procedure analogous to that described
for Example 1. LC (method 7): t.sub.R=3.06 min; Mass spectrum
(ESI.sup.+): m/z=595 [M+H].sup.+.
Example 30
((S)-6-{(R)-7-Fluoro-4-[1-(3-hydroxy-3-methylbutyl)-1H-indazol-5-yloxy]-in-
dan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00170##
[0589] The title compound is prepared from
((S)-6-{(R)-7-fluoro-4-[1-(3-hydroxy-3-methylbutyl)-1H-indazol-5-yloxy]-i-
ndan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1. LC
(method 4): t.sub.R=1.07 min; Mass spectrum (ESI.sup.+): m/z=547
[M+H].sup.+.
Example 31
[(S)-6-((R)-4-{2,6-Difluoro-4-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-y-
l]phenoxy}-157-fluoro-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic
acid
##STR00171##
[0591] The title compound is prepared from
[(S)-6-((R)-4-{2,6-difluoro-4-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4--
yl]phenoxy}-7-fluoro-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic
acid methyl ester following a procedure analogous to that described
for Example 1. LC (method 7): t.sub.R=3.03 min; Mass spectrum
(ESI.sup.+): m/z=595 [M+H].sup.+.
Example 32
((S)-6-{(R)-7-Fluoro-4-[4-(2-methylthiazol-4-yl)phenoxy]-indan-1-yloxy}-2,-
3-dihydrobenzofuran-3-yl)-acetic acid
##STR00172##
[0593] The title compound is prepared from
((S)-6-{(R)-7-fluoro-4-[4-(2-methylthiazol-4-yl)phenoxy]-indan-1-yloxy}-2-
,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a
procedure analogous to that described for Example 1. LC (method 2):
t.sub.R=0.94 min; Mass spectrum (ESI.sup.+): m/z=518
[M+H].sup.+.
Example 33
((S)-6-{(R)-7-Fluoro-4-[1-(3-hydroxy-3-methylbutyl)-1H-indol-5-yloxy]-inda-
n-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00173##
[0595] The title compound is prepared from
((S)-6-{(R)-7-fluoro-4-[1-(3-hydroxy-3-methylbutyl)-1H-indol-5-yloxy]-ind-
an-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1. LC
(method 10): t.sub.R=0.73 min; Mass spectrum (ESI.sup.+): m/z=546
[M+H].sup.+.
Example 34
((S)-6-{(R)-4-[2,5-Difluoro-4-(3-hydroxy-3-methylbutoxy)phenoxy]-7-fluoro--
indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00174##
[0597] The title compound is prepared from
((S)-6-{(R)-4-[2,5-difluoro-4-(3-hydroxy-3-methylbutoxy)phenoxy]-7-fluoro-
-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl
ester following a procedure analogous to that described for Example
1. LC (method 7): t.sub.R=3.11 min; Mass spectrum (ESI.sup.+):
m/z=559 [M+H].sup.+.
Example 35
[(S)-6-((R)-7-Fluoro-4-{4-[(tetrahydro-2H-pyran-4-yl)methyl]phenoxy}-indan-
-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid
##STR00175##
[0599] The title compound is prepared from
[(S)-6-((R)-7-Fluoro-4-{4-[(tetrahydro-2H-pyran-4-yl)methyl]phenoxy}-inda-
n-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid methyl ester
following a procedure analogous to that described for Example 1. LC
(method 12): t.sub.R=0.79 min; Mass spectrum (ESI.sup.+): m/z=519
[M+H].sup.+.
Example 36
((S)-6-{(R)-7-Fluoro-4-[1-(3-hydroxy-3-methylbutyl)-1H-indazol-6-yloxy]-in-
dan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00176##
[0601] The title compound is prepared from
((S)-6-{(R)-7-Fluoro-4-[1-(3-hydroxy-3-methylbutyl)-1H-indazol-6-yloxy]-i-
ndan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1. LC
(method 4): t.sub.R=1.08 min; Mass spectrum (ESI.sup.+): m/z=547
[M+H].sup.+.
Example 37
[(S)-6-((R)-7-Fluoro-4-{3-fluoro-4-[(4-hydroxytetrahydro-2H-pyran-4-yl)-me-
thoxy]phenoxy}-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic
acid
##STR00177##
[0603] The title compound is prepared from
[(S)-6-((R)-7-fluoro-4-{3-fluoro-4-[(4-hydroxytetrahydro-2H-pyran-4-yl)me-
thoxy]phenoxy}-indan-1-yloxy)-2,3-dihydro-benzofuran-3-yl]-acetic
acid methyl ester following a procedure analogous to that described
for Example 1. LC (method 9): t.sub.R=1.08 min; Mass spectrum
(ESI.sup.+): m/z=569 [M+H].sup.+.
Example 38
((S)-6-{(R)-7-Fluoro-4-[4-(1-methyl-1H-imidazol-2-yl)phenoxy]1-indan-1-ylo-
xy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00178##
[0605] The title compound is prepared from
((S)-6-{(R)-7-fluoro-4-[4-(1-methyl-1H-imidazol-2-yl)phenoxy]-indan-1-ylo-
xy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following
a procedure analogous to that described for Example 1. LC (method
13): t.sub.R=0.34 min; Mass spectrum (ESI.sup.+): m/z=501
[M+H].sup.+.
Example 39
[(S)-6-((R)-4-{2,5-Difluoro-4-[3-(methlsulfonyl)propoxl]phenoxy}-7-fluoro--
indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid
##STR00179##
[0607] The title compound is prepared from
[(S)-6-((R)-4-{2,5-difluoro-4-[3-(methylsulfonyl)-propoxy]phenoxy}-7-fluo-
ro-indan-1-yloxy)-2,3-dihydrobenzofuran-3-yl]-acetic acid methyl
ester following a procedure analogous to that described for Example
1. LC (method 14): t.sub.R=2.42 min; Mass spectrum (ESI.sup.-):
m/z=591 [M-H].sup.-.
Example 40
((S)-6-{(R)-7-Fluoro-4-[4-(3-hydroxy-3-methylbutoxy)-2,6-dimethyl
phenoxy]-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00180##
[0609] The title compound is prepared from
((S)-6-{(R)-7-fluoro-4-[4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenoxy]-
-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl
ester following a procedure analogous to that described for Example
1. LC (method 3): t.sub.R=0.61 min; Mass spectrum (ESI.sup.+):
m/z=551 [M+H].sup.+.
Example 41
((S)-6-{(R)-4-[2-Cyano-5-(4-hydroxy-4-methyl
pentyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-aceti-
c acid
##STR00181##
[0611] The title compound is prepared from
((S)-6-{(R)-4-[2-cyano-5-(4-hydroxy-4-methylpentyl)phenoxy]-7-fluoro-inda-
n-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1,
using KOH as base and ethanol as solvent. LC (method 12):
t.sub.R=0.50 min; Mass spectrum (ESI.sup.+): m/z=546
[M+H].sup.+.
Example 42
((S)-6-{(R)-4-[2-Cyano-5-(3-hydroxy-3-methylbutoxy)-phenoxy]-7-fluoro-inda-
n-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00182##
[0613] The title compound is prepared from
((S)-6-{(R)-4-[2-cyano-5-(3-hydroxy-3-methylbutoxy)-phenoxy]-7-fluoro-ind-
an-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1,
using KOH as base and ethanol as solvent. LC (method 12):
t.sub.R=0.41 min; Mass spectrum (ESI.sup.+): m/z=548
[M+H].sup.+.
Example 43
((S)-6-{(R)-4-[3-Cyano-4-((R)-tetrahydrofuran-3-yloxy)phenoxy]-7-fluoro-in-
dan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00183##
[0615] The title compound is prepared from
((S)-6-{(R)-4-[3-cyano-4-((R)-tetrahydrofuran-3-yloxy)phenoxy]-7-fluoro-i-
ndan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1. LC
(method 9): t.sub.R=1.11 min; Mass spectrum (ESI.sup.+): m/z=532
[M+H].sup.+.
Example 44
((S)-6-{(R)-4-[3-Cyano-4-(3-hydroxy-3-methylbutoxy)phenoxy]-7-fluoro-indan-
-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00184##
[0617] The title compound is prepared from
((S)-6-{(R)-4-[3-cyano-4-(3-hydroxy-3-methylbutoxy)phenoxy]-7-fluoro-inda-
n-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1. LC
(method 9): t.sub.R=1.11 min; Mass spectrum (ESI.sup.+): m/z=548
[M+H].sup.+.
Example 45
((S)-6-{(R)-7-Fluoro-4-[2-fluoro-5-(3-hydroxy-3-methylbutoxy)phenoxy]-inda-
n-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00185##
[0619] The title compound is prepared from
((S)-6-{(R)-7-fluoro-4-[2-fluoro-5-(3-hydroxy-3-methylbutoxy)phenoxy]-ind-
an-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1,
using KOH as base and ethanol as solvent. LC (method 10):
t.sub.R=0.60 min; Mass spectrum (ESI.sup.+): m/z=541
[M+H].sup.+.
Example 46
((S)-6-{(R)-7-Fluoro-4-[2-fluoro-5-(tetrahydro-2H-pyran-4-yloxy)phenoxy]-i-
ndan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00186##
[0621] The title compound is prepared from
((S)-6-{(R)-7-fluoro-4-[2-fluoro-5-(tetrahydro-2H-pyran-4-yloxy)phenoxy]--
indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1,
using KOH as base and ethanol as solvent. LC (method 10):
t.sub.R=0.68 min; Mass spectrum (ESI.sup.+): m/z=539
[M+H].sup.+.
Example 47
((S)-6-{(R)-4-[2-Cyano-4-(3-hydroxy-3-methylbutoxy)phenoxy]-7-fluoro-indan-
-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00187##
[0623] The title compound is prepared from
((S)-6-{(R)-4-[2-cyano-4-(3-hydroxy-3-methylbutoxy)phenoxy]-7-fluoro-inda-
n-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1,
using KOH as base and ethanol as solvent. LC (method 10):
t.sub.R=0.52 min; Mass spectrum (ESI.sup.+): m/z=548
[M+H].sup.+.
Example 48
((S)-6-{(R)-4-[2-Cyano-4-(1-methyl-1H-pyrazol-5-yl)phenoxy]-7-fluoro-indan-
-1-yloxy)-2,3-dihydrobenzofuran-3-yl}-acetic acid
##STR00188##
[0625] The title compound is prepared from
((S)-6-{(R)-4-[2-cyano-4-(1-methyl-1H-pyrazol-5-yl)phenoxy]-7-fluoro-inda-
n-1-yloxy)-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester
following a procedure analogous to that described for Example 1,
using KOH as base and ethanol as solvent. LC (method 13):
t.sub.R=0.26 min; Mass spectrum (ESI.sup.+): m/z=526
[M+H].sup.+.
Example 49
((S)-6-{(R)-4-[2-Cyano-4-(3,5-dimethylisoxazol-4-yl)phenoxy]-7-fluoro-inda-
n-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00189##
[0627] The title compound is prepared from
((S)-6-{(R)-4-[2-cyano-4-(3,5-dimethylisoxazol-4-yl)phenoxy]-7-fluoro-ind-
an-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1,
using KOH as base and ethanol as solvent. LC (method 13):
t.sub.R=0.47 min; Mass spectrum (ESI.sup.+): m/z=541
[M+H].sup.+.
Example 50
((S)-6-{(R)-7-Fluoro-4-[2-fluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenoxy]-i-
ndan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00190##
[0629] The title compound is prepared from
((S)-6-{(R)-7-fluoro-4-[2-fluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenoxy]--
indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1,
using KOH as base and ethanol as solvent. LC (method 13):
t.sub.R=0.59 min; Mass spectrum (ESI.sup.+): m/z=539
[M+H].sup.+.
Example 51
((S)-6-{(R)-4-[4-Cyano-3-(tetrahydro-2H-pyran-4-yloxy)phenoxy]-7-fluoro-in-
dan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00191##
[0631] The title compound is prepared from
((S)-6-{(R)-4-[4-cyano-3-(tetrahydro-2H-pyran-4-yloxy)phenoxy]-7-fluoro-i-
ndan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1. LC
(method 9): t.sub.R=1.13 min; Mass spectrum (ESI.sup.+): m/z=546
[M+H].sup.+.
Example 52
((S)-6-{(R)-4-[4-Cyano-3-(2-hydroxy-2-methylpropoxy)phenoxy]-7-fluoro-inda-
n-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00192##
[0633] The title compound is prepared from
((S)-6-{(R)-4-[4-cyano-3-(2-hydroxy-2-methylpropoxy)phenoxy]-7-fluoro-ind-
an-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1. LC
(method 9): t.sub.R=1.09 min; Mass spectrum (ESI.sup.+): m/z=534
[M+H].sup.+.
Example 53
((S)-6-{(R)-7-Fluoro-4-[2-fluoro-4-(3-hydroxy-3-methylbutoxy)phenoxy]-inda-
n-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00193##
[0635] The title compound is prepared from
((S)-6-{(R)-7-fluoro-4-[2-fluoro-4-(3-hydroxy-3-methylbutoxy)phenoxy]-ind-
an-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1,
using KOH as base and ethanol as solvent. LC (method 13):
t.sub.R=0.47 min; Mass spectrum (ESI.sup.+): m/z=541
[M+H].sup.+.
Example 54
((S)-6-{(R)-4-[4-(3,5-Dimethylisoxazol-4-yl)-2-fluorophenoxy]-7-fluoro-ind-
an-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00194##
[0637] The title compound is prepared from
((S)-6-{(R)-4-[4-(3,5-dimethylisoxazol-4-yl)-2-fluorophenoxy]-7-fluoro-in-
dan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1,
using KOH as base and ethanol as solvent. LC (method 10):
t.sub.R=0.71 min; Mass spectrum (ESI.sup.+): m/z=534
[M+H].sup.+.
Example 55
((S)-6-{(R)-7-Fluoro-4-[2-fluoro-4-(1-methyl-1H-pyrazol-5-yl)phenoxy]-inda-
n-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00195##
[0639] The title compound is prepared from
((S)-6-{(R)-7-fluoro-4-[2-fluoro-4-(1-methyl-1H-pyrazol-5-yl)phenoxy]-ind-
an-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1,
using KOH as base and ethanol as solvent. LC (method 10):
t.sub.R=0.54 min; Mass spectrum (ESI.sup.+): m/z=519
[M+H].sup.+.
Example 56
((S)-6-{(R)-4-[2-Cyano-4-(4-hydroxy-4-methyl
pentyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-aceti-
c acid
##STR00196##
[0641] The title compound is prepared from
((S)-6-{(R)-4-[2-cyano-4-(4-hydroxy-4-methylpentyl)phenoxy]-7-fluoro-inda-
n-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1,
using KOH as base and ethanol as solvent. LC (method 12):
t.sub.R=0.52 min; Mass spectrum (ESI.sup.-): m/z=544
[M-H].sup.-.
Example 57
((S)-6-{(R)-7-Fluoro-4-[3-(2-oxopyrrolidin-1-yl)phenoxy]-indan-1-yloxy}-2,-
3-dihydrobenzofuran-3-yl)-acetic acid
##STR00197##
[0643] The title compound is prepared from
((S)-6-{(R)-7-fluoro-4-[3-(2-oxopyrrolidin-1-yl)phenoxy]-indan-1-yloxy}-2-
,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a
procedure analogous to that described for Example 1. LC (method 9):
t.sub.R=1.09 min; Mass spectrum (ESI.sup.+): m/z=504
[M+H].sup.+.
Example 58
((S)-6-{(R)-7-Fluoro-4-[4-(2-oxopyrrolidin-1-yl)phenoxy]-indan-1-yloxy}-2,-
3-dihydrobenzofuran-3-yl)-acetic acid
##STR00198##
[0645] The title compound is prepared from
((S)-6-{(R)-7-fluoro-4-[4-(2-oxopyrrolidin-1-yl)phenoxy]-indan-1-yloxy}-2-
,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a
procedure analogous to that described for Example 1. LC (method 4):
t.sub.R=1.05 min; Mass spectrum (ESI.sup.+): m/z=504
[M+H].sup.+.
Example 59
((S)-6-{(R)-7-Fluoro-4-[4-(pyrrolidin-1-ylmethyl)phenoxy]-indan-1-yloxy}-2-
,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00199##
[0647] The title compound is prepared from
((S)-6-{(R)-7-fluoro-4-[4-(pyrrolidin-1-ylmethyl)phenoxy]-indan-1-yloxy}--
2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a
procedure analogous to that described for Example 1. LC (method 9):
t.sub.R=0.89 min; Mass spectrum (ESI.sup.+): m/z=504
[M+H].sup.+.
Example 60
((S)-6-{(R)-4-[4-(Cyanomethyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-
benzofuran-3-yl)-acetic acid
##STR00200##
[0649] The title compound is prepared from
((S)-6-{(R)-4-[4-(cyanomethyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydr-
obenzofuran-3-yl)-acetic acid methyl ester following a procedure
analogous to that described for Example 1. LC (method 9):
t.sub.R=1.10 min; Mass spectrum (ESI.sup.+): m/z=460
[M+H].sup.+.
Example 61
((S)-6-{(R)-4-[4-(2-Cyanoethyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydr-
obenzofuran-3-yl)-acetic acid
##STR00201##
[0651] The title compound is prepared from
((S)-6-{(R)-4-[4-(2-cyanoethyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihyd-
robenzofuran-3-yl)-acetic acid methyl ester following a procedure
analogous to that described for Example 1. LC (method 4):
t.sub.R=1.09 min; Mass spectrum (ESI.sup.+): m/z=474
[M+H].sup.+.
Example 62
((S)-6-{(R)-4-[2-Cyano-4-(3-hydroxy-3-methylbutyl)phenoxy]-7-fluoro-indan--
1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00202##
[0653] The title compound is prepared from
((S)-6-{(R)-4-[2-cyano-4-(3-hydroxy-3-methylbutyl)phenoxy]-7-fluoro-indan-
-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1,
using KOH as base and ethanol as solvent. LC (method 12):
t.sub.R=0.41 min; Mass spectrum (ESI.sup.+): m/z=532
[M+H].sup.+.
Example 63
((S)-6-{(R)-4-[4-(Dimethylcarbamoyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3-d-
ihydrobenzofuran-3-yl)-acetic acid
##STR00203##
[0655] The title compound is prepared from
((S)-6-{(R)-4-[4-(dimethylcarbamoyl)phenoxy]-7-fluoro-indan-1-yloxy}-2,3--
dihydrobenzofuran-3-yl)-acetic acid methyl ester following a
procedure analogous to that described for Example 1. LC (method 9):
t.sub.R=1.04 min; Mass spectrum (ESI.sup.+): m/z=492
[M+H].sup.+.
Example 64
((S)-6-{(R)-7-Fluoro-4-[4-(morpholine-4-carbonyl)phenoxy]-indan-1-yloxy}-2-
,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00204##
[0657] The title compound is prepared from
((S)-6-{(R)-7-fluoro-4-[4-(morpholine-4-carbonyl)phenoxy]-indan-1-yloxy}--
2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester following a
procedure analogous to that described for Example 1. LC (method 9):
t.sub.R=1.03 min; Mass spectrum (ESI.sup.+): m/z=534
[M+H].sup.+.
Example 65
((S)-6-{(R)-4-[2-Cyano-4-(2,6-dimethylpyridin-4-yl)phenoxy)]-7-fluoro-inda-
n-1-yloxy)}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00205##
[0659] The title compound is prepared from
((S)-6-{(R)-4-[2-cyano-4-(2,6-dimethylpyridin-4-yl)phenoxy)]-7-fluoro-ind-
an-1-yloxy)}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1,
using KOH as base and ethanol as solvent. LC (method 16):
t.sub.R=0.85 min; Mass spectrum (ESI.sup.+): m/z=551
[M+H].sup.+.
Example 66
((S)-6-{(R)-7-Fluoro-4-[2-fluoro-4-(6-methylpyridin-2-yl)phenoxy]-indan-1--
yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00206##
[0661] The title compound is prepared from
((S)-6-{(R)-7-fluoro-4-[2-fluoro-4-(6-methylpyridin-2-yl)phenoxy]-indan-1-
-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1,
using KOH as base and ethanol as solvent. LC (method 10):
t.sub.R=0.74 min; Mass spectrum (ESI.sup.+): m/z=530
[M+H].sup.+.
Example 67
((S)-6-{(R)-4-[4-(2,6-Dimethylpyridin-4-yl)-2-fluorophenoxy]-7-fluoro-inda-
n-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00207##
[0663] The title compound is prepared from
((S)-6-{(R)-4-[4-(2,6-dimethylpyridin-4-yl)-2-fluorophenoxy]-7-fluoro-ind-
an-1-yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1,
using KOH as base and ethanol as solvent. LC (method 16):
t.sub.R=0.87 min; Mass spectrum (ESI.sup.+): m/z=544
[M+H].sup.+.
Example 68
((S)-6-{(R)-4-[2-Cyano-4-(6-methylpyridin-2-yl)phenoxy]-7-fluoro-indan-1-y-
loxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00208##
[0665] The title compound is prepared from
((S)-6-{(R)-4-[2-cyano-4-(6-methylpyridin-2-yl)phenoxy]-7-fluoro-indan-1--
yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1,
using KOH as base and ethanol as solvent. LC (method 10):
t.sub.R=0.67 min; Mass spectrum (ESI.sup.+): m/z=537
[M+H].sup.+.
Example 69
{(S)-6-[(R)-4-(2-Cyano-4-(piperidin-1-ylmethyl)phenoxy]-7-fluoro-indan-1-y-
loxy)-2,3-dihydrobenzofuran-3-yl}-acetic acid
##STR00209##
[0667] The title compound is prepared from
{(S)-6-[(R)-4-(2-cyano-4-(piperidin-1-ylmethyl)phenoxy]-7-fluoro-indan-1--
yloxy)-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester
following a procedure analogous to that described for Example 1,
using KOH as base and ethanol as solvent. LC (method 18):
t.sub.R=0.58 min; Mass spectrum (ESI.sup.+): m/z=543
[M+H].sup.+.
Example 70
((S)-6-{(R)-4-[2-Cyano-4-(morpholin-4-ylmethyl)phenoxy]-7-fluoro-indan-1-y-
loxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid
##STR00210##
[0669] The title compound is prepared from
((S)-6-{(R)-4-[2-cyano-4-(morpholin-4-ylmethyl)phenoxy]-7-fluoro-indan-1--
yloxy}-2,3-dihydrobenzofuran-3-yl)-acetic acid methyl ester
following a procedure analogous to that described for Example 1,
using KOH as base and ethanol as solvent. LC (method 19):
t.sub.R=0.62 min; Mass spectrum (ESI.sup.+): m/z=545
[M+H.sup.+.
[0670] The following compounds are obtained from the respective
methyl ester employing the procedure described for Example 1. The
methyl esters of the following compounds are prepared from either
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester and the corresponding phenyl or
heteroaryl boronic acid following a procedure analogous to that
described for Intermediate 6, or
{(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl-
}-acetic acid methyl ester and the corresponding fluoro-benzene or
heteroaryl fluoride following a procedure analogous to that
described for Intermediate 20. The individual (Het)Ar groups used
in the coupling reaction, bearing either a boronic acid group or
fluorine atom, are prepared using the procedures described above or
other methods known to the skilled man and described in the
literature. Alternatively, the residue attached to the (Het)Ar
group, already linked to the rest of the molecule via the O in
compounds I, is elaborated from an appropriate precursor group,
e.g., iodine, bromine or chlorine atom or hydroxy group, using
routinely employed proceedings described in the literature of
organic chemistry and in the experimental part above.
##STR00211## ##STR00212## ##STR00213##
* * * * *