U.S. patent application number 16/740735 was filed with the patent office on 2020-07-16 for substituted pyrrolidine amides iii.
This patent application is currently assigned to GRUENENTHAL GMBH. The applicant listed for this patent is Gruenenthal GMBH. Invention is credited to Jo ALEN, Philipp BARBIE, Daniela FRIEBE, Stephanie HENNEN, Florian JAKOB, Sebastian KRUGER.
Application Number | 20200223840 16/740735 |
Document ID | / |
Family ID | 69165383 |
Filed Date | 2020-07-16 |
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United States Patent
Application |
20200223840 |
Kind Code |
A1 |
JAKOB; Florian ; et
al. |
July 16, 2020 |
SUBSTITUTED PYRROLIDINE AMIDES III
Abstract
The invention relates to compounds according to general formula
(I), ##STR00001## which act as modulators of the glucocorticoid
receptor and can be used in the treatment and/or prophylaxis of
disorders which are at least partially mediated by the
glucocorticoid receptor.
Inventors: |
JAKOB; Florian; (Aachen,
DE) ; ALEN; Jo; (Averbode, BE) ; KRUGER;
Sebastian; (Aachen, DE) ; FRIEBE; Daniela;
(Dusseldorf, DE) ; HENNEN; Stephanie; (Aachen,
DE) ; BARBIE; Philipp; (Bergheim, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gruenenthal GMBH |
AACHEN |
|
DE |
|
|
Assignee: |
GRUENENTHAL GMBH
AACHEN
DE
|
Family ID: |
69165383 |
Appl. No.: |
16/740735 |
Filed: |
January 13, 2020 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 471/04 20130101;
C07D 401/14 20130101; C07D 403/14 20130101; C07D 409/14 20130101;
C07D 413/14 20130101; C07D 417/14 20130101; C07D 403/10
20130101 |
International
Class: |
C07D 417/14 20060101
C07D417/14; C07D 403/10 20060101 C07D403/10; C07D 471/04 20060101
C07D471/04; C07D 409/14 20060101 C07D409/14; C07D 403/14 20060101
C07D403/14; C07D 413/14 20060101 C07D413/14; C07D 401/14 20060101
C07D401/14 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 11, 2019 |
EP |
19151406.6 |
Jan 17, 2019 |
EP |
19152282.0 |
Jun 19, 2019 |
EP |
19181203.1 |
Claims
1. A compound according to general formula (I): ##STR00167##
wherein R.sub.1 represents phenyl; --C.sub.1-6-alkylene-phenyl; 5
or 6-membered heteroaryl; --C.sub.1-6-alkylene-(5 or 6-membered
heteroaryl) or --C.sub.1-10-alkyl; R.sub.1' represents H;
--C.sub.1-10-alkyl; or --C.sub.3-10-cycloalkyl; R.sub.2 represents
--C(.dbd.O)--C.sub.1-10-alkyl; --C(.dbd.O)--C.sub.3-10-cycloalkyl;
--C(.dbd.O)--C.sub.1-6-alkylene-C.sub.3-10-cycloalkyl;
--C(.dbd.O)-(3 to 7 membered heterocycloalkyl);
--C(.dbd.O)--C.sub.1-6-alkylene-(3 to 7 membered heterocycloalkyl);
--C(.dbd.O)-phenyl; --C(.dbd.O)--C.sub.1-6-alkylene-phenyl;
--C(.dbd.O)-(5 or 6-membered heteroaryl);
--C(.dbd.O)--C.sub.1-6-alkylene-(5 or 6-membered heteroaryl);
--S(.dbd.O).sub.1-2--C.sub.1-10-alkyl;
--S(.dbd.O).sub.1-2--C.sub.3-10-cycloalkyl;
--S(.dbd.O).sub.1-2--C.sub.1-6-alkylene-C.sub.3-10-cycloalkyl;
--S(.dbd.O).sub.1-2-(3 to 7 membered heterocycloalkyl);
--S(.dbd.O).sub.1-2--C.sub.1-6-alkylene-(3 to 7 membered
heterocycloalkyl); --S(.dbd.O).sub.1-2-phenyl;
--S(.dbd.O).sub.1-2--C.sub.1-6-alkylene-phenyl;
--S(.dbd.O).sub.1-2-(5 or 6-membered heteroaryl); or
--S(.dbd.O).sub.1-2--C.sub.1-6-alkylene-(5 or 6-membered
heteroaryl); R.sub.3 and R.sub.3' independently from one another
represent H; F; Cl; --C.sub.1-10-alkyl; --C.sub.3-6-cycloalkyl;
--CH.sub.2--C.sub.3-6-cycloalkyl; 3 to 7 membered heterocycloalkyl;
--CH.sub.2-(3 to 7 membered heterocycloalkyl); --CH.sub.2-phenyl;
or --CH.sub.2-(5 or 6-membered heteroaryl); or R.sub.3 and R.sub.3'
together with the carbon atom to which they are bound form a
C.sub.3-10-cycloalkyl; or 3 to 7 membered heterocycloalkyl; R.sub.4
represents -phenyl; --C.sub.1-6-alkylene-phenyl; -5 or 6-membered
heteroaryl; or --C.sub.1-6-alkylene-(5 or 6-membered heteroaryl);
A, X, Y and Z independently from one another represent N or CH;
wherein at least one of R.sub.1', R.sub.3 and R.sub.3' is not H;
wherein --C.sub.1-10-alkyl and --C.sub.1-6-alkylene-in each case
independently from one another is linear or branched, saturated or
unsaturated; wherein --C.sub.1-10-alkyl, --C.sub.1-6-alkylene-,
--C.sub.3-10-cycloalkyl and 3 to 7 membered heterocycloalkyl in
each case independently from one another are unsubstituted or mono-
or polysubstituted with one or more substituents selected from --F;
--Cl; --Br; --I; --CN; --C.sub.1-6-alkyl; --CF.sub.3; --CF.sub.2H;
--CFH.sub.2; --CF.sub.2Cl; --CFCl.sub.2;
--C(.dbd.O)--C.sub.1-6-alkyl; --C(.dbd.O)--OH;
--C(.dbd.O)--OC.sub.1-6-alkyl; --C(.dbd.O)--NH.sub.2;
--C(.dbd.O)--NH(C.sub.1-6-alkyl);
--C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2; --OH; .dbd.O; --OCF.sub.3;
--OCF.sub.2H; --OCFH.sub.2; --OCF.sub.2Cl; --OCFCl.sub.2;
--O--C.sub.1-6-alkyl; --O--C(.dbd.O)--C--.sub.6-alkyl;
--O--C(.dbd.O)--O--C.sub.1-6-alkyl; --O--(CO)--NH(C.sub.1-6-alkyl);
--O--C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2;
--O--S(.dbd.O).sub.2--NH.sub.2;
--O--S(.dbd.O).sub.2--NH(C.sub.1-6-alkyl);
--O--S(.dbd.O).sub.2--N(C.sub.1-6-alkyl).sub.2; --NH.sub.2;
--NH(C.sub.1-6-alkyl); --N(C.sub.1-6-alkyl).sub.2;
--NH--C(.dbd.O)--C.sub.1-6-alkyl;
--NH--C(.dbd.O)--O--C.sub.1-6-alkyl; --NH--C(.dbd.O)--NH.sub.2;
--NH--C(.dbd.O)--NH(C.sub.1-6-alkyl);
--NH--C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2;
--N(C.sub.1-6-alkyl)-C(.dbd.O)--C.sub.1-6-alkyl;
--N(C.sub.1-6-alkyl)-C(.dbd.O)--O--C.sub.1-6-alkyl;
--N(C.sub.1-6-alkyl)-C(.dbd.O)--NH.sub.2;
--N(C.sub.1-6-alkyl)-C(.dbd.O)--NH(C.sub.1-6-alkyl);
--N(C.sub.1-6-alkyl)-C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2;
--NH--S(.dbd.O).sub.2OH; NH--S(.dbd.O).sub.2--C.sub.1-6-alkyl;
--NH--S(.dbd.O).sub.2--O--C.sub.1-6-alkyl;
--NH--S(.dbd.O).sub.2--NH.sub.2;
--NH--S(.dbd.O).sub.2--NH(C.sub.1-6-alkyl);
--NH--S(.dbd.O).sub.2N(C.sub.1-6-alkyl).sub.2;
--N(C.sub.1-6-alkyl)-S(.dbd.O).sub.2--OH;
--N(C.sub.1-6-alkyl)-S(.dbd.O).sub.2--C.sub.1-6-alkyl;
--N(C.sub.1-6-alkyl)-S(.dbd.O).sub.2--O--C.sub.1-6-alkyl;
--N(C.sub.1-6-alkyl)-S(.dbd.O).sub.2--NH.sub.2;
--N(C.sub.1-6-alkyl)-S(.dbd.O).sub.2--NH(C.sub.1-6-alkyl);
--N(C.sub.1-6-alkyl)-S(.dbd.O).sub.2--N(C.sub.1-6-alkyl).sub.2;
--SCF.sub.3; --SCF.sub.2H; --SCFH.sub.2; --S--C.sub.1-6-alkyl;
--S(.dbd.O)--C.sub.1-6-alkyl; --S(.dbd.O).sub.2--C.sub.1-6-alkyl;
--S(.dbd.O).sub.2--OH; --S(.dbd.O).sub.2--O--C.sub.1-6-alkyl;
--S(.dbd.O).sub.2--NH.sub.2;
--S(.dbd.O).sub.2--NH(C.sub.1-6-alkyl);
--S(.dbd.O).sub.2--N(C.sub.1-6-alkyl).sub.2;
--C.sub.3-6-cycloalkyl; 3 to 6-membered heterocycloalkyl; phenyl; 5
or 6-membered heteroaryl; --O--C.sub.3-6-cycloalkyl; --O-(3 to
6-membered heterocycloalkyl); --O-phenyl; --O-(5 or 6-membered
heteroaryl); --C(.dbd.O)--C.sub.3-6-cycloalkyl; --C(.dbd.O)-(3 to
6-membered heterocycloalkyl); --C(.dbd.O)-phenyl; --C(.dbd.O)-(5 or
6-membered heteroaryl); --S(.dbd.O).sub.2--(C.sub.3-6-cycloalkyl);
--S(.dbd.O).sub.2-(3 to 6-membered heterocycloalkyl);
--S(.dbd.O).sub.2-phenyl or --S(.dbd.O).sub.2-(5 or 6-membered
heteroaryl); wherein phenyl and 5 or 6-membered heteroaryl in each
case independently from one another are unsubstituted or mono- or
polysubstituted with one or more substituents selected from --F;
--Cl; --Br; --I; --CN; --C.sub.1-6-alkyl; --CF.sub.3; --CF.sub.2H;
--CFH.sub.2; --CF.sub.2Cl; --CFCl.sub.2;
--C.sub.1-4-alkylene-CF.sub.3; --C.sub.1-4-alkylene-CF.sub.2H;
--C.sub.1-4-alkylene-CFH.sub.2; --C(.dbd.O)--C.sub.1-6-alkyl;
--C(.dbd.O)--OH; --C(.dbd.O)--OC.sub.1-6-alkyl;
--C(.dbd.O)--NH(OH); --C(.dbd.O)--NH.sub.2;
--C(.dbd.O)--NH(C.sub.1-6-alkyl);
--C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2; --OH; .dbd.O; --OCF.sub.3;
--OCF.sub.2H; --OCFH.sub.2; --OCF.sub.2Cl; --OCFCl.sub.2;
--O--C.sub.1-6-alkyl; --O--C.sub.3-6-cycloalkyl; --O-(3 to
6-membered heterocycloalkyl); --NH.sub.2; --NH(C.sub.1-6-alkyl);
--N(C.sub.1-6-alkyl).sub.2; --NH--C(.dbd.O)--C.sub.1-6-alkyl;
--N(C.sub.1-6-alkyl)-C(.dbd.O)--C.sub.1-6-alkyl;
--NH--C(.dbd.O)--NH.sub.2; --NH--C(.dbd.O)--NH(C.sub.1-6-alkyl);
--NH--C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2;
--N(C.sub.1-6-alkyl)-C(.dbd.O)--NH(C.sub.1-6-alkyl);
--N(C.sub.1-6-alkyl)-C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2;
--NH--S(.dbd.O).sub.2--C.sub.1-6-alkyl; --SCF.sub.3;
--S--C.sub.1-6-alkyl; --S(.dbd.O)--C.sub.1-6-alkyl;
--S(.dbd.O).sub.2--C.sub.1-6-alkyl; --S(.dbd.O).sub.2--NH.sub.2;
--S(.dbd.O).sub.2--NH(C.sub.1-6-alkyl);
--S(.dbd.O).sub.2--N(C.sub.1-6-alkyl).sub.2--C.sub.3-6-cycloalkyl;
--C.sub.1-4-alkylene-C.sub.3-6-cycloalkyl; 3 to 6-membered
heterocycloalkyl; --C.sub.1-4-alkylene-(3 to 6-membered
heterocycloalkyl); phenyl or 5 or 6-membered heteroaryl; in the
form of the free compound or a physiologically acceptable salt
thereof; with the proviso that the following compounds are
excluded:
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic acid
amide;
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic acid
amide;
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic
acid amide;
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-[1,2,4]oxadiazole-3-carboxy-
lic acid amide;
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic
acid amide;
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-i-
ndazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-thiazole-4-carboxylic
acid amide; and
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-thiazole-4-carboxylic
acid amide.
2. The compound according to claim 1, which has a stereochemistry
according to general formula (II) or (VI): ##STR00168##
3. The compound according to claim 1, wherein A represents N, X
represents CH, represents CH; and Z represents CH; PGP- or A
represents N, X represents N, Y represents CH; and Z represents CH;
or A represents N, X represents CH, Y represents N; and Z
represents CH; or A represents N, X represents CH, Y represents CH;
and Z represents N; or A represents N, X represents N, Y represents
N; and Z represents CH; or A represents N, X represents N, Y
represents CH; and Z represents N; or A represents N, X represents
CH, Y represents N; and Z represents N; or A represents N, X
represents N, Y represents N; and Z represents N; or A represents
CH, X represents CH, Y represents CH; and Z represents CH; or A
represents CH, X represents N, Y represents CH; and Z represents
CH; or A represents CH, X represents CH, Y represents N; and Z
represents CH; or A represents CH, X represents CH, Y represents
CH; and Z represents N; or A represents CH, X represents N, Y
represents N; and Z represents CH; or A represents CH, X represents
N, Y represents CH; and Z represents N; or A represents CH, X
represents CH, Y represents N; and Z represents N; or A represents
CH, X represents N, Y represents N; and Z represents N.
4. The compound according to claim 1, wherein R.sub.1 represents
phenyl; and/or R.sub.1' represents H, CH.sub.3 or cyclopropyl.
5. The compound according to claim 1, wherein R.sub.2 represents
--C(.dbd.O)--C.sub.1-10-alkyl; --C(.dbd.O)--C.sub.3-10-cycloalkyl;
--C(.dbd.O)--C.sub.1-6-alkylene-C.sub.3-10-cycloalkyl;
--C(.dbd.O)-(3 to 7 membered heterocycloalkyl); --C(.dbd.O)-(5 or
6-membered heteroaryl); --S(.dbd.O).sub.2--C.sub.1-10-alkyl;
--S(.dbd.O).sub.2--C.sub.3-10-cycloalkyl;
--S(.dbd.O).sub.2--C.sub.1-6-alkylene-C.sub.3-10-cycloalkyl;
--S(.dbd.O).sub.2-(3 to 7 membered heterocycloalkyl); or
--S(.dbd.O).sub.2-(5 or 6-membered heteroaryl).
6. The compound according to claim 1, wherein R.sub.3 and R.sub.3'
both represent --C.sub.1-10-alkyl.
7. The compound according to claim 1, wherein R.sub.4 represents
-phenyl; or 5 or 6-membered heteroaryl.
8. The compound according to claim 1, wherein R.sub.1 represents
phenyl, unsubstituted or mono- or disubstituted with substituents
independently of one another selected from the group consisting of
--F, --Cl, --Br, --OCH.sub.3, --CH.sub.3, --CF.sub.3, --CN, and
cyclopropyl.
9. The compound according to claim 1, wherein R.sub.2 represents
--C(.dbd.O)--C.sub.1-10-alkyl, unsusbtituted or mono- or
disubstituted with substituents independently of one another
selected from the group consisting of --F, --Cl, and --Br;
--C(.dbd.O)-cyclopropyl, unsubstituted or mono- or disubstituted
with substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --CH.sub.3, --CF.sub.3, --CN,
and --OCH.sub.3; --C(.dbd.O)-2-tetrahydrofuranyl, unsubstituted;
--C(.dbd.O)-(5- to 6-membered heteroaryl), wherein said 5- to
6-membered heteroaryl is selected from the group consisting of
thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1-oxa-2,4-diazolyl,
1,2,5-oxadiazolyl, and isothiazolyl, wherein in each case said 5-
to 6-membered heteroaryl is unsubstituted or mono- or disubstituted
with substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --CH.sub.3, --CF.sub.3, --CN,
.dbd.O, and --OCH.sub.3; --S(.dbd.O).sub.2--C.sub.1-10-alkyl,
unsubstituted; --S(.dbd.O).sub.2-cyclopropyl, unsubstituted;
--S(.dbd.O).sub.2--CH.sub.2-cyclopropyl, unsubstituted;
--S(.dbd.O).sub.2-2-tetrahydrofuranyl, unsubstituted; or
--S(.dbd.O).sub.2-(5- to 6-membered heteroaryl), wherein said 5- to
6-membered heteroaryl is selected from the group consisting of
thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1-oxa-2,4-diazolyl,
1,2,5-oxadiazolyl, and isothiazolyl, wherein in each case said 5-
to 6-membered heteroaryl is unsubstituted or mono- or disubstituted
with substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --CH.sub.3, --CF.sub.3, --CN,
.dbd.O, and --OCH.sub.3.
10. The compound according to claim 1, wherein R.sub.3 and R.sub.3'
both represent --CH.sub.3.
11. The compound according to claim 1, wherein R.sub.4 represents
phenyl, unsubstituted or mono- or disubstituted with substituents
independently of one another selected from the group consisting of
--F, --Cl, --Br, --CH.sub.3, --CF.sub.3, --CN, and --OCH.sub.3; 5-
to 6-membered heteroaryl selected from the group consisting of
pyridyl, pyrazolyl, and pyrimidinyl, wherein in each case said 5-
to 6-membered heteroaryl is unsubstituted or mono- or disubstituted
with substituents independently of one another selected from the
group consisting of .dbd.O, --F, --Cl, --Br, --CH.sub.3,
--CF.sub.3, --CN, and --OCH.sub.3.
12. The compound according to claim 1, wherein R.sub.1 represents
phenyl, unsubstituted or mono- or disubstituted with substituents
independently of one another selected from the group consisting of
--F, --Cl, --Br, --CH.sub.3, and --OCH.sub.3; and/or R.sub.1'
represents H, CH.sub.3, or cyclopropyl; and/or R.sub.2 represents
--C(.dbd.O)--C.sub.1-6-alkyl; --C(.dbd.O)-cyclopropyl; or
--C(.dbd.O)-(5- to 6-membered heteroaryl), unsubstituted or mono-
or disubstituted with substituents independently of one another
selected from the group consisting of --F, --Cl, --Br, and
--CH.sub.3; and/or R.sub.4 represents fluoro-phenyl or
N-methyl-2-oxo-pyridyl.
13. The compound according to claim 1 selected from the group
consisting of: 1
N-[(2R,3S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4,4-dimethyl-5-ox-
o-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide; 2
N-[(2S,3R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4,4-dimethyl-5-oxo-2-ph-
enyl-pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide; 3
N-[rac-(6R,7S)-5-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-oxo-6-phenyl-5-az-
aspiro[2.4]heptan-7-yl]-cyclopropanecarboxylic acid amide; 4
2,2-Difluoro-N-[(2S,3R)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4,4-dimeth-
yl-5-oxo-2-phenyl-pyrrolidin-3-yl]-propionamide; 5
N-[rac-(6R,7S)-5-[1-(4-Fluorophenyl)-1H-indol-5-yl]-4-oxo-6-phenyl-5-azas-
piro[2.4]heptan-7-yl]-cyclopropanecarboxylic acid amide; 6
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-thiazole-2-carboxylic
acid amide; 7
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-
-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-isoxazole-3-carbox-
ylic acid amide; 8
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-2,2-difluoro-propionamide; 9
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-2,2-difluoro-propionamide; 10
2,2-Difluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4,4-dimeth-
yl-5-oxo-2-phenyl-pyrrolidin-3-yl]-propionamide; 12
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic
acid amide; 13
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-oxazole-5-carboxylic acid
amide; 14
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-[1,2,4]oxadiazole-3-carboxy-
lic acid amide; 15
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-thiazole-5-carboxylic acid
amide; 16
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic
acid amide; 17
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1-
H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-thiazole-4-carboxylic
acid amide; 18
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1-
H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-thiazole-4-carbox-
ylic acid amide; 21
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-oxazole-5-carboxylic acid
amide; 22
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-isoxazole-3-carboxylic
acid amide; 24
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1-
H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-thiazole-5-carboxylic
acid amide; 26
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1-
H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-thiazole-2-carbox-
ylic acid amide; 30
N-[rac-(6R,7S)-5-[1-(1-Methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-4-o-
xo-6-phenyl-5-azaspiro[2.4]heptan-7-yl]-cyclopropanecarboxylic acid
amide; 31
N-[rac-(6R,7S)-5-[1-(4-Fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-4-
-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl]-cyclopropanecarboxylic
acid amide; 32
N-[rac-(6R,7S)-5-[1-(4-Fluorophenyl)-1H-pyrazolo[3,4-c]pyridin--
5-yl]-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl]-cyclopropanecarboxylic
acid amide; 33
N-[rac-(6R,7S)-5-[1-(4-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-4-ox-
o-6-phenyl-5-azaspiro[2.4]heptan-7-yl]-cyclopropanecarboxylic acid
amide; 34a
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo--
2-phenylpyrrolidin-3-yl)methane sulfonamide; 34b
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)methane sulfonamide; 35a
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)cyclopropane sulfonamide; 35b
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)cyclopropane sulfonamide; 36a
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)oxazole-5-carboxamide; 36b
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)oxazole-5-carboxamide; 37
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-1-methyl-1H-pyrazole-3-carboxamide; 38a
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-4-methylthiazole-5-carboxamide; 38b
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-4-methylthiazole-5-carboxamide; 39a
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-5-methylthiazole-4-carboxamide; 39b
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-5-methylthiazole-4-carboxamide; 40a
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-3-methylisoxazole-4-carboxamide; 40b
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-3-methylisoxazole-4-carboxamide; 41a
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide; 41b
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide; 42a
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)nicotinamide; 42b
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)nicotinamide; 43a
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)pyrimidine-2-carboxamide; 43b
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)pyrimidine-2-carboxamide; 44a
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-2-methyloxazole-5-carboxamide; 44b
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-2-methyloxazole-5-carboxamide; 45a
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-4-methyloxazole-5-carboxamide; 45b
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-4-methyloxazole-5-carboxamide; 46
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-
-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide; 47
N-[rac-(2R,3S,4S)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-y-
l]-4-methyl-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propionamide; 48
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(3-methoxyphen-
yl)-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic acid
amide; 49
N-[rac-(2R,3S,4S)-2-(4-Fluorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-y-
l]-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic acid
amide; 60
N-[rac(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2--
phenyl-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic acid amide;
61
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-
-phenyl-pyrrolidin-3-yl]-methanesulfonic acid amide; 62
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tol-
yl-5-oxo-pyrrolidin-3-yl]-methanesulfonic acid amide; 63
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tol-
yl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide; 64
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-
-phenyl-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic acid
amide; 65
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-
-phenyl-pyrrolidin-3-yl]-pyridine-3-carboxylic acid amide; 66
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-
-phenyl-pyrrolidin-3-yl]-pyrimidine-2-carboxylic acid amide; 67
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tol-
yl-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic acid
amide; 68
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tol-
yl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic acid amide; 69
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tol-
yl-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic acid amide; 70
N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tol-
yl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide; 71
N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tol-
yl-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic acid
amide; 72
N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tol-
yl-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic acid
amide; 73
N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tol-
yl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic acid amide; 74
N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tol-
yl-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic acid amide; 75
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tol-
yl-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic acid
amide; 76
N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tol-
yl-5-oxo-pyrrolidin-3-yl]-methanesulfonic acid amide; 77
2,2-Difluoro-N-[rac-(2R,3S,4R)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-m-
ethyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-propionamide; 78
N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-y-
l]-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic acid
amide; 79
N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-y-
l]-4-methyl-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propionamide; 80
2,2-Difluoro-N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-m-
ethyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-propionamide; 81
2,2-Difluoro-N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-m-
ethyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-propionamide; 82
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphen-
yl)-4-methyl-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic
acid amide; 83
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-m-
ethoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carbo-
xylic acid amide; 84
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphen-
yl)-4-methyl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic acid
amide; 85
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphen-
yl)-4-methyl-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic acid
amide; 86
N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-y-
l]-4-methyl-5-oxo-pyrrolidin-3-yl]-methanesulfonic acid amide; 87
N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-y-
l]-4-methyl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic acid
amide; 88
N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-y-
l]-4-methyl-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic acid
amide; 89
N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-
-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic acid amide; 90
N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-
-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic acid amide; 91
N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-
-5-oxo-pyrrolidin-3-yl]-methanesulfonic acid amide; 92
N-[rac-(2R,3S,4S)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-y-
l]-4-methyl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic acid
amide; 93
N-[rac-(2R,3S,4S)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-y-
l]-4-methyl-5-oxo-pyrrolidin-3-yl]-methanesulfonic acid amide; 94
N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-y-
l]-4-methyl-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic
acid amide; 95
N-((2R,3R,4S)-4-fluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-
-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide; 96
N-((2R,3R)-4,4-difluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-ph-
enylpyrrolidin-3-yl)cyclopropanecarboxamide; 97
2,2-Difluoro-N-[rac-(2R,3S,4R)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-(-
4-methoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-propionamide; 98
2,2-Difluoro-N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-(-
4-methoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-propionamide; 99
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphen-
yl)-4-methyl-5-oxo-pyrrolidin-3-yl]-methanesulfonic acid amide; 100
2,2-Difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-meth-
yl-5-oxo-2-phenyl-pyrrolidin-3-yl]-propionamide; 101
N-[rac-(2R,3S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-methyl-5-oxo-2-ph-
enyl-pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide; 102
2,2-Difluoro-N-[rac-(2R,3S)-2-methyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl-
)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-propionamide;
103
N-[rac-(2R,3S)-2-Methyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic acid
amide; 104
N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-
-yl]-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic acid
amide; 105
N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-
-yl]-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic acid
amide; 106
N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-
-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide; 107
N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-
-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propionamide; 108
N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-ind-
azol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic
acid amide; 109
N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-ind-
azol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic
acid amide; 110
N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-ind-
azol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxyl-
ic acid amide; 111
N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-ind-
azol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic
acid amide; 112
N-[rac-(2R,3S,4S)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-y-
l]-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic acid
amide; 113
N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-ind-
azol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic
acid amide; 114
N-[(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-
-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-methanesulfonic acid amide;
115
N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-me-
thyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic
acid amide; 116
N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-me-
thyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxyli-
c acid amide; 117
N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-me-
thyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carbox-
ylic acid amide; 118
N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-me-
thyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic
acid amide; 119
N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-me-
thyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic
acid amide; 120
2,2-Difluoro-N-[rac-(2S,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-m-
ethyl-2-(1-methyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-propionamide;
121
N-[rac-(2R,3S,4S)-4-(Cyclopropyl-methyl)-1-[1-(4-fluorophenyl)-1H-ind-
azol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic
acid amide; 122
N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-me-
thyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-methanesulfonic acid
amide; 123
N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-
-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propionamide;
124
N-[rac-(2S,3S,4R)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-
-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic
acid amide; 125
N-[rac-(2S,3S,4R)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-ind-
azol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propionamide;
126
N-[rac-(2R,3S,4S)-4-Ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-2--
phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide; 127
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-4-phenethyl-2-phe-
nylpyrrolidin-3-yl)cyclopropanecarboxamide, diastereomer 2; 128
N-[rac-(2R,3R,4R)-4-Fluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methy-
l-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic acid
amide; 129
N-[rac-(2R,3R,4S)-4-Fluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methy-
l-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic acid
amide; 130
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-4-phenethyl-2-phe-
nylpyrrolidin-3-yl)cyclopropanecarboxamide, diastereomer 1; 131
N-((2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl-
)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide; 132
N-((2R,3S,4R)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl-
)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide; 133
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphen-
yl)-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic acid
amide; 134
N-(rac-(2R,3S,4R)-4-ethyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-
-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide; 135
N-((7R,8S)-6-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-7-phenyl-6-azaspi-
ro[3.4]octan-8-yl)cyclopropanecarboxamide; 136 N-(rac
(2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-
-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide; 137
N-(rac-(2R,3R,4S)-4-benzyl-2-ethyl-4-fluoro-1-(1-(4-fluorophenyl)-1H-inda-
zol-5-yl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide; 138
N-((2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-((3-methyl-1,2,4-o-
xadiazol-5-yl)methyl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamid-
e; 139
N-((2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-((1-methyl-1-
H-pyrazol-4-yl)methyl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxami-
de; 142
N-(rac-(2R,3S)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl-
)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide; 143
N-(rac-(2R,3R)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-
-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide; 144
N-(rac-(2R,3S)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-
-2-phenylpyrrolidin-3-yl)-2,2-difluoropropanamide; 145
N-(rac-(2R,3R)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-
-2-phenylpyrrolidin-3-yl)-2,2-difluoropropanamide; 146
N-(rac-(2R,3S)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-
-2-phenylpyrrolidin-3-yl)oxetane-3-carboxamide; 147
N-(rac-(2R,3R)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-
-2-phenylpyrrolidin-3-yl)oxetane-3-carboxamide; 148
N-(rac-(2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol--
5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide;
149
N-(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-1-(1-(4-fluorophenyl)-1H-indazol--
5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide;
150
N-((2R,3S,4R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenyl-4-(th-
iazol-2-ylmethyl)pyrrolidin-3-yl)cyclopropanecarboxamide; and 151
N-((2S,3S)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-y-
l)-2-methyl-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide; in each
case in the form of the free compound or a physiologically
acceptable salt thereof.
14. A pharmaceutical dosage form comprising a compound according to
claim 1.
15. A method for the treatment and/or prophylaxis of pain and/or
inflammation in a patient in need thereof, said method comprising
administering to said patient an effective amount therefor of at
least one compound according to claim 1.
Description
[0001] This application claims priority of European Patent
Application No. 19 181 203.1, filed Jun. 19, 2019, European Patent
Application No. 19 152 282.0, filed Jan. 17, 2019, and European
Patent Application No. 19 151 406.6, filed Jan. 11, 2019, the
entire contents of which are hereby incorporated herein by
reference.
[0002] The invention relates to compounds according to general
formula (I)
##STR00002##
which act as modulators of the glucocorticoid receptor and can be
used in the treatment and/or prophylaxis of disorders which are at
least partially mediated by the glucocorticoid receptor.
[0003] Glucocorticoids (GC) exert strong anti-inflammatory,
immunosuppressive and disease-modifying therapeutic effects
mediated by the glucocorticoid receptor (GR). They have been widely
used to treat inflammatory and immune diseases for decades and
still represent the most effective therapy in those conditions.
However, chronic GC treatment of inflammatory diseases such as
asthma, rheumatoid arthritis, inflammatory bowel disease, chronic
obstructive pulmonary disease, acute respiratory distress syndrome,
cystic fibrosis, osteoarthritis, polymyalgia rheumatica and giant
cell arteritis is hampered by GC-associated adverse effects. These
undesired side effects include insulin resistance, diabetes,
hypertension, glaucoma, depression, osteoporosis, adrenal
suppression and muscle wasting with osteoporosis and diabetes being
the most severe ones from the physician's point of view (Hapgood
JP. et al., Pharmacol Ther. 2016 September; 165: 93-113; Buttgereit
F. el al, Clin Exp Rheumatol. 2015 July-August; 33(4 Suppl
92):S29-33; Hartmann K. et al, Physiol Rev. 2016 April;
96(2):409-47).
[0004] One example of an oral glucocorticoid is prednisone which is
frequently prescribed for the treatment of several inflammatory
disorders (De Bosscher K et al., Trends Pharmacol Sci. 2016
January; 37(1):4-16; Buttgereit F. et al., JAMA. 2016;
315(22):2442-2458). As GC cause adrenal suppression, prednisolone
withdrawal symptoms can be severe if the drug is discontinued
abruptly when all the signs of the disease have disappeared. Thus
gradual GC tapering to physiological doses is frequently part of
treatment protocols to reduce the risk of relapse and other
withdrawal symptoms (Liu D. et al., Allergy Asthma Clin Immunol.
2013 Aug. 15; 9(1):30). Therefore, there is high medical need for
novel potent anti-inflammatory drugs with less adverse effects.
[0005] Recent research has focused on the development of partial
agonists or selective glucocorticoid receptor modulators which
activate the pathways for the inhibition of inflammation but avoid
targeting the pathways that lead to the GC-associated adverse
effects. Most of these effects have been demonstrated to be
mediated by different GR-dependent genomic mechanisms termed
transactivation and transrepression. The anti-inflammatory actions
of GC are mainly attributable to the transrepression of
inflammatory genes while certain side effects are predominantly
mediated via transactivation of several genes. According to the
nature of a ligand the GR can be selectively modulated in a
specific conformation which favors transrepression over
transactivation resulting in an improved therapeutic benefit (De
Bosscher K et al., Trends Pharmacol Sci. 2016 January; 37(1):4-16).
The concept of such dissociating ligands was already defined about
two decades ago and several compounds have been identified and were
evaluated in preclinical and clinical testing but none of them has
as yet been approved for clinical use.
[0006] Compounds which are active as modulators of the
glucocorticoid receptor are also known e.g. from WO 2007/122165, WO
2008/076048 and WO 2008/043789, WO 2009/035067, WO 2009/142571, WO
2016/046260, and WO 2017/034006.
[0007] It was an object of the invention to provide novel compounds
which are modulators of the glucocorticoid receptor and which
preferably have advantages over the compounds of the prior art.
[0008] The novel compounds should in particular be suitable for use
in the treatment and/or prophylaxis of disorders or diseases which
are at least partially mediated by the glucocorticoid receptor.
[0009] This object has been achieved by the subject-matter of the
patent claims.
[0010] It was surprisingly found that the compounds according to
the invention are highly potent modulators of the glucocorticoid
receptor.
[0011] The invention relates to a compound according to general
formula (I),
##STR00003##
wherein [0012] R.sub.1 represents phenyl;
--C.sub.1-6-alkylene-phenyl; 5 or 6-membered heteroaryl;
--C.sub.1-6-alkylene-(5 or 6-membered heteroaryl); or
--C.sub.1-10-alkyl; [0013] R.sub.1' represents H;
--C.sub.1-10-alkyl; or --C.sub.3-10-cycloalkyl; [0014] R.sub.2
represents --C(.dbd.O)--C.sub.1-10-alkyl;
--C(.dbd.O)--C.sub.3-10-cycloalkyl;
--C(.dbd.O)--C.sub.1-6-alkylene-C.sub.3-10-cycloalkyl;
--C(.dbd.O)-(3 to 7 membered heterocycloalkyl);
--C(.dbd.O)--C.sub.1-6-alkylene-(3 to 7 membered heterocycloalkyl);
--C(.dbd.O)-phenyl; --C(.dbd.O)--C.sub.1-6-alkylene-phenyl;
--C(.dbd.O)-(5 or 6-membered heteroaryl);
--C(.dbd.O)--C.sub.1-6-alkylene-(5 or 6-membered heteroaryl);
--S(.dbd.O).sub.1-2--C.sub.1-10-alkyl;
--S(.dbd.O).sub.1-2--C.sub.3-10-cycloalkyl;
--S(.dbd.O).sub.1-2--C.sub.1-6-alkylene-C.sub.3-10-cycloalkyl;
--S(.dbd.O).sub.1-2-(3 to 7 membered heterocycloalkyl);
--S(.dbd.O).sub.1-2--C.sub.1-6-alkylene-(3 to 7 membered
heterocycloalkyl); --S(.dbd.O).sub.1-2-phenyl;
--S(.dbd.O).sub.1-2--C.sub.1-6-alkylene-phenyl;
--S(.dbd.O).sub.1-2-(5 or 6-membered heteroaryl); or
--S(.dbd.O).sub.1-2--C.sub.1-6-alkylene-(5 or 6-membered
heteroaryl); [0015] R.sub.3 and R.sub.3' independently from one
another represent H; F; Cl; --C.sub.1-10-alkyl;
--C.sub.3-6-cycloalkyl; --CH.sub.2--C.sub.3-6-cycloalkyl; 3 to 7
membered heterocycloalkyl; --CH.sub.2-(3 to 7 membered
heterocycloalkyl); --CH.sub.2-phenyl; or --CH.sub.2-(5 or
6-membered heteroaryl); [0016] or R.sub.3 and R.sub.3' together
with the carbon atom to which they are bound form a
C.sub.3-10-cycloalkyl; or 3 to 7 membered heterocycloalkyl; [0017]
R.sub.4 represents-phenyl; --C.sub.1-6-alkylene-phenyl; -5 or
6-membered heteroaryl; or --C.sub.1-6-alkylene-(5 or 6-membered
heteroaryl); [0018] A, X, Y and Z independently from one another
represent N or CH; [0019] wherein at least one of R.sub.1, R.sub.3
and R.sub.3' is not H; [0020] wherein --C.sub.1-10-alkyl and
--C.sub.1-6-alkylene-in each case independently from one another is
linear or branched, saturated or unsaturated; [0021] wherein
--C.sub.1-10-alkyl, --C.sub.1-6-alkylene-, --C.sub.3-10-cycloalkyl
and 3 to 7 membered heterocycloalkyl in each case independently
from one another are unsubstituted or mono- or polysubstituted with
one or more substituents selected from --F; --Cl; --Br; --I; --CN;
--C.sub.1-6-alkyl; --CF.sub.3; --CF.sub.2H; --CFH.sub.2;
--CF.sub.2Cl; --CFCl.sub.2; --C(.dbd.O)--C.sub.1-6-alkyl;
--C(.dbd.O)--OH; --C(.dbd.O)--OC.sub.1-6-alkyl;
--C(.dbd.O)--NH.sub.2; --C(.dbd.O)--NH(C.sub.1-6-alkyl);
--C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2; --OH; .dbd.O; --OCF.sub.3;
--OCF.sub.2H; --OCFH.sub.2; --OCF.sub.2Cl; --OCFCl.sub.2;
--O--C.sub.1-6-alkyl; --O--C(.dbd.O)--C.sub.1-6-alkyl;
--O--C(.dbd.O)--O--C.sub.1-6-alkyl; --O--(CO)--NH(C.sub.1-6-alkyl);
--O--C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2;
--O--S(.dbd.O).sub.2--NH.sub.2;
--O--S(.dbd.O).sub.2--NH(C.sub.1-6-alkyl);
--O--S(.dbd.O).sub.2--N(C.sub.1-6-alkyl).sub.2; --NH.sub.2;
--NH(C.sub.1-6-alkyl); --N(C.sub.1-6-alkyl).sub.2;
--NH--C(.dbd.O)--C.sub.1-6-alkyl;
--NH--C(.dbd.O)--O--C.sub.1-6-alkyl; --NH--C(.dbd.O)--NH.sub.2;
--NH--C(.dbd.O)--NH(C.sub.1-6-alkyl);
--NH--C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2;
--N(C.sub.1-6-alkyl)-C(.dbd.O)--C.sub.1-6-alkyl;
--N(C.sub.1-6-alkyl)-C(.dbd.O)--O--C.sub.1-6-alkyl;
--N(C.sub.1-6-alkyl)-C(.dbd.O)--NH.sub.2;
--N(C.sub.1-6-alkyl)-C(.dbd.O)--NH(C.sub.1-6-alkyl);
--N(C.sub.1-6-alkyl)-C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2;
--NH--S(.dbd.O).sub.2OH; NH--S(.dbd.O).sub.2--C.sub.1-6-alkyl;
--NH--S(.dbd.O).sub.2--O--C.sub.1-6-alkyl;
--NH--S(.dbd.O).sub.2--NH.sub.2;
--NH--S(.dbd.O).sub.2--NH(C.sub.1-6-alkyl);
--NH--S(.dbd.O).sub.2N(C.sub.1-6-alkyl).sub.2;
--N(C.sub.1-6-alkyl)-S(.dbd.O).sub.2--OH;
--N(C.sub.1-6-alkyl)-S(.dbd.O).sub.2--C.sub.1-6-alkyl;
--N(C.sub.1-6-alkyl)-S(.dbd.O).sub.2--O--C.sub.1-6-alkyl;
--N(C.sub.1-6-alkyl)-S(.dbd.O).sub.2--NH.sub.2;
--N(C.sub.1-6-alkyl)-S(.dbd.O).sub.2--NH(C.sub.1-6-alkyl);
--N(C.sub.1-6-alkyl)-S(.dbd.O).sub.2--N(C.sub.1-6-alkyl).sub.2;
--SCF.sub.3; --SCF.sub.2H; --SCFH.sub.2; --S--C.sub.1-6-alkyl;
--S(.dbd.O)--C.sub.1-6-alkyl; --S(.dbd.O).sub.2--C.sub.1-6-alkyl;
--S(.dbd.O).sub.2--OH; --S(.dbd.O).sub.2--O--C.sub.1-6-alkyl;
--S(.dbd.O).sub.2--NH.sub.2;
--S(.dbd.O).sub.2--NH(C.sub.1-6-alkyl);
--S(.dbd.O).sub.2--N(C.sub.1-6-alkyl).sub.2;
--C.sub.3-6-cycloalkyl; 3 to 6-membered heterocycloalkyl; phenyl; 5
or 6-membered heteroaryl; --O--C.sub.3-6-cycloalkyl; --O-(3 to
6-membered heterocycloalkyl); --O-phenyl; --O-(5 or 6-membered
heteroaryl); --C(.dbd.O)--C.sub.3-6-cycloalkyl; --C(.dbd.O)-(3 to
6-membered heterocycloalkyl); --C(.dbd.O)-phenyl; --C(.dbd.O)-(5 or
6-membered heteroaryl); --S(.dbd.O).sub.2--(C.sub.3-6-cycloalkyl);
--S(.dbd.O).sub.2-(3 to 6-membered heterocycloalkyl);
--S(.dbd.O).sub.2-phenyl or --S(.dbd.O).sub.2-(5 or 6-membered
heteroaryl); [0022] wherein phenyl and 5 or 6-membered heteroaryl
in each case independently from one another are unsubstituted or
mono- or polysubstituted with one or more substituents selected
from --F; --Cl; --Br; --I; --CN; --C.sub.1-6-alkyl; --CF.sub.3;
--CF.sub.2H; --CFH.sub.2; --CF.sub.2Cl; --CFCl.sub.2;
--C.sub.1-4-alkylene-CF.sub.3; --C.sub.1-4-alkylene-CF.sub.2H;
--C.sub.1-4-alkylene-CFH.sub.2; --C(.dbd.O)--C.sub.1-6-alkyl;
--C(.dbd.O)--OH; --C(.dbd.O)--OC.sub.1-6-alkyl;
--C(.dbd.O)--NH(OH); --C(.dbd.O)--NH.sub.2;
--C(.dbd.O)--NH(C.sub.1-6-alkyl);
--C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2; --OH; .dbd.O; --OCF.sub.3;
--OCF.sub.2H; --OCFH.sub.2; --OCF.sub.2Cl; --OCFCl.sub.2;
--O--C.sub.1-6-alkyl; --O--C.sub.3-6-cycloalkyl; --O-(3 to
6-membered heterocycloalkyl); --NH.sub.2; --NH(C.sub.1-6-alkyl);
--N(C.sub.1-6-alkyl).sub.2; --NH--C(.dbd.O)--C.sub.1-6-alkyl;
--N(C.sub.1-6-alkyl)-C(.dbd.O)--C.sub.1-6-alkyl;
--NH--C(.dbd.O)--NH.sub.2; --NH--C(.dbd.O)--NH(C.sub.1-6-alkyl);
--NH--C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2;
--N(C.sub.1-6-alkyl)-C(.dbd.O)--NH(C.sub.1-6-alkyl);
--N(C.sub.1-6-alkyl)-C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2;
--NH--S(.dbd.O).sub.2--C.sub.1-6-alkyl; --SCF.sub.3;
--S--C.sub.1-6-alkyl; --S(.dbd.O)--C.sub.1-6-alkyl;
--S(.dbd.O).sub.2--C.sub.1-6-alkyl; --S(.dbd.O).sub.2--NH.sub.2;
--S(.dbd.O).sub.2--NH(C.sub.1-6-alkyl);
--S(.dbd.O).sub.2--N(C.sub.1-6-alkyl).sub.2--C.sub.3-6-cycloalkyl;
--C.sub.1-4-alkylene-C.sub.3-6-cycloalkyl; 3 to 6-membered
heterocycloalkyl; --C.sub.1-4-alkylene-(3 to 6-membered
heterocycloalkyl); phenyl or 5 or 6-membered heteroaryl; in the
form of the free compound or a physiologically acceptable salt
thereof, with the proviso that the following compounds are
excluded: [0023]
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic acid
amide; [0024]
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-i-
ndazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic
acid amide; [0025]
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic
acid amide; [0026]
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-[1,2,4]oxadiazole-3-carboxy-
lic acid amide; [0027]
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic
acid amide; [0028]
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-thiazole-4-carboxylic acid
amide; and [0029]
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-thiazole-4-carboxylic
acid amide.
[0030] In a preferred embodiment, the compound according to the
invention is present in form of the free compound. For the purpose
of specification, "free compound" preferably means that the
compound according to the invention is not present in form of a
salt. Methods to determine whether a chemical substance is present
as the free compound or as a salt are known to the skilled artisan
such as .sup.14N or .sup.15N solid state NMR, x-ray diffraction,
x-ray powder diffraction, IR, Raman, XPS. .sup.1H-NMR recorded in
solution may also be used to consider the presence of
protonation.
[0031] In another preferred embodiment, the compound according to
the invention is present in form of a physiologically acceptable
salt. For the purposes of this specification, the term
"physiologically acceptable salt" preferably refers to a salt
obtained from a compound according to the invention and a
physiologically acceptable acid or base.
[0032] According to the invention, the compound according to the
invention may be present in any possible form including solvates,
cocrystals and polymorphs. For the purposes of this specification,
the term "solvate" preferably refers to an adduct of (i) a compound
according to the invention and/or a physiologically acceptable salt
thereof with (ii) distinct molecular equivalents of one or more
solvents.
[0033] Further, the compound according to the invention may be
present in form of the racemate, enantiomers, diastereomers,
tautomers or any mixtures thereof.
[0034] The invention also includes isotopic isomers of a compound
of the invention, wherein at least one atom of the compound is
replaced by an isotope of the respective atom which is different
from the naturally predominantly occurring isotope, as well as any
mixtures of isotopic isomers of such a compound. Preferred isotopes
are .sup.2H (deuterium), .sup.3H (tritium), .sup.13C and .sup.14C.
Isotopic isomers of a compound of the invention can generally be
prepared by conventional procedures known to a person skilled in
the art.
[0035] According to the invention, the terms "--C.sub.1-10-alkyl",
"--C.sub.1-8-alkyl", "--C.sub.1-6-alkyl" and "--C.sub.1-4-alkyl"
preferably mean acyclic saturated or unsaturated aliphatic (i.e.
non-aromatic) hydrocarbon residues, which can be linear (i.e.
unbranched) or branched and which can be unsubstituted or mono- or
polysubstituted (e.g. di- or trisubstituted), and which contain 1
to 10 (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10), 1 to 8 (i.e. 1, 2, 3,
4, 5, 6, 7 or 8), 1 to 6 (i.e. 1, 2, 3, 4, 5 or 6) and 1 to 4 (i.e.
1, 2, 3 or 4) carbon atoms, respectively. In a preferred
embodiment, --C.sub.1-10-alkyl, --C.sub.1-8-alkyl,
--C.sub.1-6-alkyl and --C.sub.1-4-alkyl are saturated.
[0036] Preferred --C.sub.1-10-alkyl groups are selected from
methyl, ethyl, ethenyl (vinyl), n-propyl, 2-propyl, 1-propynyl,
2-propynyl, propenyl (--CH.sub.2CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.sub.3, --C(.dbd.CH.sub.2)--CH.sub.3), n-butyl,
1-butynyl, 2-butynyl, 1-butenyl, 2-butenyl, isobutyl, sec-butyl,
tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 1-pentenyl, 2-pentenyl,
1-pentynyl, 2-pentynyl, 2-methylbutyl, 3-methylbutyl,
3-methylbut-2-yl, 2-methylbut-2-yl, 3-methylbut-1-ynyl,
2,2-dimethylpropyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl,
4-methylpentyl, 4-methylpent-2-yl, 2-methylpent-2-yl,
3,3-dimethylbutyl, 3,3-dimethylbut-2-yl, 3-methylpentyl,
3-methylpent-2-yl and 3-methylpent-3-yl; more preferably methyl,
ethyl, n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl
(--CH.sub.2CH.dbd.CH.sub.2, --CH.dbd.CH--CH.sub.3,
--C(.dbd.CH.sub.2)--CH.sub.3), n-butyl, 1-butynyl, 2-butynyl,
1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,
2-pentyl, 3-pentyl, 1-pentenyl, 2-pentenyl, 1-pentynyl, 2-pentynyl,
2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl,
3-methylbut-1-ynyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl, n-octyl,
n-nonyl and n-decyl. Particularly preferred --C.sub.1-10-alkyl
groups are selected from C.sub.1-4-alkyl groups.
[0037] Preferred --C.sub.1-s-alkyl groups are selected from methyl,
ethyl, ethenyl (vinyl), n-propyl, 2-propyl, 1-propynyl, 2-propynyl,
propenyl (--CH.sub.2CH.dbd.CH.sub.2, --CH.dbd.CH--CH.sub.3,
--C(.dbd.CH.sub.2)--CH.sub.3), n-butyl, 1-butynyl, 2-butynyl,
1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,
2-pentyl, 3-pentyl, 1-pentenyl, 2-pentenyl, 1-pentynyl, 2-pentynyl,
2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl,
3-methylbut-1-ynyl, 2,2-dimethylpropyl, n-hexyl, 2-hexyl, 3-hexyl,
2-methylpentyl, 4-methylpentyl, 4-methylpent-2-yl,
2-methylpent-2-yl, 3,3-dimethylbutyl, 3,3-dimethylbut-2-yl,
3-methylpentyl, 3-methylpent-2-yl and 3-methylpent-3-yl; more
preferably methyl, ethyl, n-propyl, 2-propyl, 1-propynyl,
2-propynyl, propenyl (--CH.sub.2CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.sub.3, --C(.dbd.CH.sub.2)--CH.sub.3), n-butyl,
1-butynyl, 2-butynyl, 1-butenyl, 2-butenyl, isobutyl, sec-butyl,
tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 1-pentenyl, 2-pentenyl,
1-pentynyl, 2-pentynyl, 2-methylbutyl, 3-methylbutyl,
3-methylbut-2-yl, 2-methylbut-2-yl, 3-methylbut-1-ynyl,
2,2-dimethylpropyl, n-hexyl, n-heptyl and n-octyl. Particularly
preferred --C.sub.1-8-alkyl groups are selected from
C.sub.1-4-alkyl groups.
[0038] Preferred --C.sub.1-6-alkyl groups are selected from methyl,
ethyl, ethenyl (vinyl), n-propyl, 2-propyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl,
3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl,
2,2-dimethylpropyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl,
4-methylpentyl, 4-methylpent-2-yl, 2-methylpent-2-yl,
3,3-dimethylbutyl, 3,3-dimethylbut-2-yl, 3-methylpentyl,
3-methylpent-2-yl and 3-methylpent-3-yl; more preferably methyl,
ethyl, n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl
(--CH.sub.2--CH.dbd.CH.sub.2, --CH.dbd.CH--CH.sub.3,
--C(.dbd.CH.sub.2)--CH.sub.3), n-butyl, 1-butynyl, 2-butynyl,
1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,
2-pentyl, 3-pentyl, 1-pentenyl, 2-pentenyl, 1-pentynyl, 2-pentynyl,
2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl,
3-methylbut-1-ynyl, 2,2-dimethylpropyl, n-hexyl. Particularly
preferred --C.sub.1-6-alkyl groups are selected from
C.sub.1-4-alkyl groups.
[0039] Preferred --C.sub.1-4-alkyl groups are selected from methyl,
ethyl, ethenyl (vinyl), n-propyl, 2-propyl, 1-propynyl, 2-propynyl,
propenyl (--CH.sub.2CH.dbd.CH.sub.2, --CH.dbd.CH--CH.sub.3,
--C(.dbd.CH.sub.2)--CH.sub.3), n-butyl, 1-butynyl, 2-butynyl,
1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl and
3-methylbut-1-ynyl. More preferred --C.sub.1-4-alkyl groups are
selected from methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl,
sec-butyl, and tert-butyl.
[0040] Further according to the invention, the terms
"--C.sub.1-6-alkylene-"; "--C.sub.1-4-alkylene-" and
"--C.sub.1-2-alkylene-" relate to a linear or branched, preferably
linear, and preferably saturated aliphatic residues which are
preferably selected from the group consisting of methylene
(--CH.sub.2--), ethylene (--CH.sub.2CH.sub.2--), propylene
(--CH.sub.2CH.sub.2CH.sub.2-- or --C(CH.sub.3).sub.2--), butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), pentylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) and hexylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--); more
preferably methylene (--CH.sub.2--) and ethylene
(--CH.sub.2CH.sub.2--) and most preferably methylene
(--CH.sub.2--). Preferably, --C.sub.1-6-alkylene-is selected from
--C.sub.1-4-alkylene-, more preferably from
--C.sub.1-2-alkylene-.
[0041] Still further according to the invention, the terms
"--C.sub.3-10-cycloalkyl" and "--C.sub.3-6-cycloalkyl" preferably
mean cyclic aliphatic hydrocarbons containing 3, 4, 5, 6, 7, 8, 9
or 10 carbon atoms and 3, 4, 5 or 6 carbon atoms, respectively,
wherein the hydrocarbons in each case can be saturated or
unsaturated (but not aromatic), unsubstituted or mono- or
polysubstituted.
[0042] Preferably, --C.sub.3-10-cycloalkyl and
--C.sub.3-6-cycloalkyl are saturated. The --C.sub.3-10-cycloalkyl
and --C.sub.3-6-cycloalkyl can be bound to the respective
superordinate general structure via any desired and possible ring
member of the cycloalkyl group. The --C.sub.3-10-cycloalkyl and
--C.sub.3-6-cycloalkyl groups can also be condensed with further
saturated, (partially) unsaturated, (hetero)cyclic, aromatic or
heteroaromatic ring systems, i.e. with cycloalkyl, heterocyclyl,
aryl or heteroaryl residues, which in each case can in turn be
unsubstituted or mono- or polysubstituted. Further,
--C.sub.3-10-cycloalkyl and --C.sub.3-6-cycloalkyl can be singly or
multiply bridged such as, for example, in the case of adamantyl,
bicyclo[2.2.1]heptyl or bicyclo[2.2.2]octyl. However, preferably,
--C.sub.3-10-cycloalkyl and --C.sub.3-6-cycloalkyl are neither
condensed with further ring systems nor bridged. More preferably,
--C.sub.3-10-cycloalkyl and --C.sub.3-6-cycloalkyl are neither
condensed with further ring systems nor bridged and are saturated.
Preferred --C.sub.3-10-cycloalkyl groups are selected from the
group consisting of cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cyclopentenyl, cyclohexenyl, cycloheptyl, cyclooctyl,
cyclononyl, cyclodecyl, adamantly, cyclopentenyl, cyclohexenyl,
cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]heptyl and
bicyclo[2.2.2]octyl. Particularly preferred --C.sub.3-10-cycloalkyl
groups are selected from --C.sub.3-6-cycloalkyl groups.
[0043] Preferred --C.sub.3-6-cycloalkyl groups are selected from
the group consisting of cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cyclopentenyl and cyclohexenyl. Particularly preferred
--C.sub.3-6-cycloalkyl groups are selected from the group
consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,
most preferably cyclopropyl.
[0044] According to the invention, the terms "3 to 7-membered
heterocycloalkyl" and "3 to 6-membered heterocycloalkyl" preferably
mean heterocycloaliphatic saturated or unsaturated (but not
aromatic) residues having 3 to 7, i.e. 3, 4, 5, 6 or 7 ring members
and 3 to 6, i.e. 3, 4, 5 or 6 ring members, respectively, wherein
in each case at least one, if appropriate also two or three carbon
atoms are replaced by a heteroatom or a heteroatom group each
selected independently of one another from the group consisting of
O, S, S(.dbd.O), S(.dbd.O).sub.2, N, NH and N(C.sub.1-4-alkyl) such
as N(CH.sub.3), wherein the carbon atoms of the ring can be
unsubstituted or mono- or polysubstituted. Preferably, the 3 to
7-membered heterocycloalkyl and the 3 to 6-membered
heterocycloalkyl contain only one heteroatom or heteroatom group
within the ring.
[0045] Preferably, 3 to 7-membered heterocycloalkyl and 3 to
6-membered heterocycloalkyl are saturated. The 3 to 7-membered
heterocycloalkyl and the 3 to 6-membered heterocycloalkyl groups
can also be condensed with further saturated or (partially)
unsaturated cycloalkyl or heterocyclyl, aromatic or heteroaromatic
ring systems. However, more preferably, 3 to 7-membered
heterocycloalkyl and 3 to 6-membered heterocycloalkyl are not
condensed with further ring systems. Still more preferably, 3 to
7-membered heterocycloalkyl and 3 to 6-membered heterocycloalkyl
are not condensed with further ring systems and are saturated. The
3 to 7-membered heterocycloalkyl and the 3 to 6-membered
heterocycloalkyl group can be bound to the superordinate general
structure via any desired and possible ring member of the
heterocycloaliphatic residue if not indicated otherwise. In a
preferred embodiment, 3 to 7-membered heterocycloalkyl and 3 to
6-membered heterocycloalkyl are bound to the superordinate general
structure via a carbon atom.
[0046] Preferred 3 to 7-membered heterocycloalkyl groups are
selected from the group consisting of tetrahydrofuranyl, azepanyl,
dioxepanyl, oxazepanyl, diazepanyl, thiazolidinyl,
tetrahydrothiophenyl, tetrahydropyridinyl, thiomorpholinyl,
tetrahydropyranyl, oxetanyl, oxiranyl, morpholinyl, pyrrolidinyl,
4-methylpiperazinyl, morpholinonyl, azetidinyl, aziridinyl,
dithiolanyl, dihydropyrrolyl, dioxanyl, dioxolanyl,
dihydropyridinyl, dihydrofuranyl, dihydroisoxazolyl,
dihydrooxazolyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl,
piperazinyl, piperidinyl, pyrazolidinyl, pyranyl;
tetrahydropyrrolyl, dihydroquinolinyl, dihydroisoquinolinyl,
dihydroindolinyl, dihydroisoindolyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl and tetrahydroindolinyl. Particularly
preferred 3 to 7-membered heterocycloalkyl groups are selected from
3 to 6-membered heterocycloalkyl groups.
[0047] Preferred 3 to 6-membered heterocycloalkyl groups are
selected from the group consisting of tetrahydrofuranyl,
tetrahydropyranyl, oxetanyl, oxiranyl, thiazolidinyl,
tetrahydrothiophenyl, tetra-hydropyridinyl, thiomorpholinyl,
morpholinyl, pyrrolidinyl, 4-methylpiperazinyl, morpholinonyl,
azetidinyl, aziridinyl, dithiolanyl, dihydropyrrolyl, dioxanyl,
dioxolanyl, dihydropyridinyl, dihydrofuranyl, dihydroisoxazolyl,
dihydrooxazolyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl,
piperazinyl, piperidinyl, pyrazolidinyl, pyranyl,
tetrahydropyrrolyl, dihydroindolinyl, dihydroisoindolyl and
tetrahydroindolinyl. More preferred 3 to 6-membered
heterocycloalkyl groups are selected from the group consisting of
tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, and oxiranyl; still
more preferably tetrahydrofuranyl.
[0048] According to the invention, the term "5- to 6-membered
heteroaryl" preferably means a 5 or 6-membered cyclic aromatic
residue containing at least 1, if appropriate also 2, 3, 4 or 5
heteroatoms, wherein the heteroatoms are each selected
independently of one another from the group S, N and O and the
heteroaryl residue can be unsubstituted or mono- or
polysubstituted, if not indicated otherwise. In the case of
substitution on the heteroaryl, the substituents can be the same or
different and be in any desired and possible position of the
heteroaryl. The binding to the superordinate general structure can
be carried out via any desired and possible ring member of the
heteroaryl residue if not indicated otherwise. Preferably, the 5-
to 6-membered heteroaryl is bound to the suprordinate general
structure via a carbon atom of the heterocycle. The heteroaryl can
also be part of a bi- or polycyclic system having up to 14 ring
members, wherein the ring system can be formed with further
saturated or (partially) unsaturated cycloalkyl or
heterocycloalkyl, aromatic or heteroaromatic ring systems, which
can in turn be unsubstituted or mono- or polysubstituted, if not
indicated otherwise. In a preferred embodiment, the 5- to
6-membered heteroaryl is part of a bi- or polycyclic, preferably
bicyclic, system. In another preferred embodiment, the 5- to
6-membered heteroaryl is not part of a bi- or polycyclic
system.
[0049] Preferably, the 5- to 6-membered heteroaryl is selected from
the group consisting of pyridyl (i.e. 2-pyridyl, 3-pyridyl,
4-pyridyl), thiazolyl, oxazolyl, isoxazolyl, pyrazolyl,
oxadiazolyl, pyridone (pyridinone), pyrimidinyl, pyridazinyl,
pyrazinyl, pyrrolyl, imidazolyl, isothiazolyl, furanyl, thienyl
(thiophenyl), triazolyl, thiadiazolyl,
4,5,6,7-tetrahydro-2H-indazolyl,
2,4,5,6-tetrahydrocyclo-penta[c]pyrazolyl, benzofuranyl,
benzoimidazolyl, benzothienyl, benzothiadiazolyl, benzothiazolyl,
benzotriazolyl, benzooxazolyl, benzooxadiazolyl, quinazolinyl,
quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl,
dibenzothienyl, imidazothiazolyl, indazolyl, indolizinyl, indolyl,
isoquinolinyl, naphthyridinyl, oxazolyl, phenazinyl,
phenothiazinyl, phthalazinyl, purinyl, phenazinyl, tetrazolyl and
triazinyl. Particularly preferred 5- to 6-membered heteroaryl are
selected from the group consisting of pyridyl (i.e. 2-pyridyl,
3-pyridyl, 4-pyridyl), thiazolyl, oxazolyl, isoxazolyl, pyrazolyl,
and oxadiazolyl. As pyridones can be regarded as pyridines that are
substituted with .dbd.O, for the purpose of the specification the
definition of pyridines that may optionally be substituted with
.dbd.O covers pyridones.
[0050] The compounds according to the invention are defined by
substituents, for example by R.sub.1, R.sub.2 and R.sub.3 (1.sup.st
generation substituents) which may optionally be for their part
themselves be substituted (2.sup.nd generation substituents).
Depending on the definition, these substituents of the substituents
can optionally be for their part resubstituted (3.sup.rd generation
substituents). If, for example, R.sub.1=phenyl (1.sup.st generation
substituent), then the phenyl can for its part be substituted, for
example with --C.sub.1-6-alkyl (2.sup.nd generation substituent).
This produces the functional group R.sub.1=phenyl-C.sub.1-6-alkyl.
The --C.sub.1-6-alkyl can then for its part be resubstituted, for
example with --F (3.sup.rd generation substituent). Overall, this
produces the functional group R.sub.1=phenyl-C.sub.1-6-alkyl,
wherein the --C.sub.1-6-alkyl is substituted with --F.
[0051] However, in a preferred embodiment, the 3.sup.rd generation
substituents may not be resubstituted, i.e. there are then no
4.sup.th generation substituents. More preferably, the 2.sup.nd
generation substituents may not be resubstituted, i.e. there are no
3.sup.rd generation substituents.
[0052] If a residue occurs multiply within a molecule, then this
residue can have respectively different meanings for various
substituents: if, for example, both R.sub.3 and R.sub.3' denote
--C.sub.1-10-alkyl, then --C.sub.1-10-alkyl can e.g. represent
ethyl for R.sub.3 and can represent methyl for R.sub.3'.
[0053] In connection with the terms "--C.sub.1-10-alkyl",
"--C.sub.1-6-alkyl", "--C.sub.1-4-alkyl",
"--C.sub.3-10-cycloalkyl", "--C.sub.3-6-cycloalkyl", "3 to 7
membered heterocycloalkyl", "3 to 6-membered heterocycloalkyl",
"--C.sub.1-6-alkylene-", "--C.sub.1-4-alkylene-" and
"--C.sub.1-2-alkylene-", the term "substituted" refers in the sense
of the invention, with respect to the corresponding residues or
groups, to the single substitution (monosubstitution) or multiple
substitution (polysubstitution), e.g. disubstitution or
trisubstitution; more preferably to monosubstitution or
disubstitution; of one or more hydrogen atoms each independently of
one another by at least one substituent. In case of a multiple
substitution, i.e. in case of polysubstituted residues, such as di-
or trisubstituted residues, these residues may be polysubstituted
either on different or on the same atoms, for example
trisubstituted on the same carbon atom, as in the case of
--CF.sub.3, --CH.sub.2CF.sub.3 or disubstituted as in the case of
1,1-difluorocyclohexyl, or at various points, as in the case of
--CH(OH)--CH.dbd.CH--CHCl.sub.2 or 1-chloro-3-fluorocyclohexyl. The
multiple substitution can be carried out using the same or using
different substituents.
[0054] In relation to the terms "phenyl", "heteroaryl" and "5- to
6-membered heteroaryl", the term "substituted" refers in the sense
of this invention to the single substitution (monosubstitution) or
multiple substitution (polysubstitution), e.g. disubstitution or
trisubstitution, of one or more hydrogen atoms each independently
of one another by at least one substituent. The multiple
substitution can be carried out using the same or using different
substituents.
[0055] According to the invention, preferably --C.sub.1-10-alkyl-,
--C.sub.1-6-alkyl, --C.sub.1-4-alkyl, --C.sub.3-10-cycloalkyl,
--C.sub.3-6-cycloalkyl, 3 to 7 membered heterocycloalkyl, 3 to
6-membered heterocycloalkyl, --C.sub.1-6-alkylene-,
--C.sub.1-4-alkylene- and --C.sub.1-2-alkylene-in each case
independently from one another are unsubstituted or mono- or
polysubstituted with one or more substituents selected from --F;
--Cl; --Br; --I; --CN; --C.sub.1-6-alkyl; --CF.sub.3; --CF.sub.2H;
--CFH.sub.2; --CF.sub.2Cl; --CFCl.sub.2;
--C(.dbd.O)--C.sub.1-6-alkyl; --C(.dbd.O)--OH;
--C(.dbd.O)--OC.sub.1-6-alkyl; --C(.dbd.O)--NH.sub.2;
--C(.dbd.O)--NH(C.sub.1-6-alkyl);
--C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2; --OH; .dbd.O; --OCF.sub.3;
--OCF.sub.2H; --OCFH.sub.2; --OCF.sub.2Cl; --OCFCl.sub.2;
--O--C.sub.1-6-alkyl; --O--C(.dbd.O)--C.sub.1-6-alkyl;
--O--C(.dbd.O)--O--C.sub.1-6-alkyl; --O--(CO)--NH(C.sub.1-6-alkyl);
--O--C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2;
--O--S(.dbd.O).sub.2--NH.sub.2;
--O--S(.dbd.O).sub.2--NH(C.sub.1-6-alkyl);
--O--S(.dbd.O).sub.2--N(C.sub.1-6-alkyl).sub.2; --NH.sub.2;
--NH(C.sub.1-6-alkyl); --N(C.sub.1-6-alkyl).sub.2;
--NH--C(.dbd.O)--C.sub.1-6-alkyl;
--NH--C(.dbd.O)--O--C.sub.1-6-alkyl; --NH--C(.dbd.O)--NH.sub.2;
--NH--C(.dbd.O)--NH(C.sub.1-6-alkyl);
--NH--C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2;
--N(C.sub.1-6-alkyl)-C(.dbd.O)--C.sub.1-6-alkyl;
--N(C.sub.1-6-alkyl)-C(.dbd.O)--O--C.sub.1-6-alkyl;
--N(C.sub.1-6-alkyl)-C(.dbd.O)--NH.sub.2;
--N(C.sub.1-6-alkyl)-C(.dbd.O)--NH(C.sub.1-6-alkyl);
--N(C.sub.1-6-alkyl)-C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2;
--NH--S(.dbd.O).sub.2OH; --NH--S(.dbd.O).sub.2--C.sub.1-6-alkyl;
--NH--S(.dbd.O).sub.2--O--C.sub.1-6-alkyl;
--NH--S(.dbd.O).sub.2--NH.sub.2;
--NH--S(.dbd.O).sub.2--NH(C.sub.1-6-alkyl);
--NH--S(.dbd.O).sub.2N(C.sub.1-6-alkyl).sub.2;
--N(C.sub.1-6-alkyl)-S(.dbd.O).sub.2--OH;
--N(C.sub.1-6-alkyl)-S(.dbd.O).sub.2--C.sub.1-6-alkyl;
--N(C.sub.1-6-alkyl)-S(.dbd.O).sub.2--O--C.sub.1-6-alkyl;
--N(C.sub.1-6-alkyl)-S(.dbd.O).sub.2--NH.sub.2;
--N(C.sub.1-6-alkyl)-S(.dbd.O).sub.2--NH(C.sub.1-6-alkyl);
--N(C.sub.1-6-alkyl)-S(.dbd.O).sub.2--N(C.sub.1-6-alkyl).sub.2;
--SCF.sub.3; --SCF.sub.2H; --SCFH.sub.2; --S-C.sub.1-6-alkyl;
--S(.dbd.O)--C.sub.1-6-alkyl; --S(.dbd.O).sub.2--C.sub.1-6-alkyl;
--S(.dbd.O).sub.2--OH; --S(.dbd.O).sub.2--O--C.sub.1-6-alkyl;
--S(.dbd.O).sub.2--NH.sub.2;
--S(.dbd.O).sub.2--NH(C.sub.1-6-alkyl);
--S(.dbd.O).sub.2--N(C.sub.1-6-alkyl).sub.2;
--C.sub.3-6-cycloalkyl; 3 to 6-membered heterocycloalkyl; phenyl; 5
or 6-membered heteroaryl; --O--C.sub.3-6-cycloalkyl; --O-(3 to
6-membered heterocycloalkyl); --O-phenyl; --O-(5 or 6-membered
heteroaryl); --C(.dbd.O)--C.sub.3-6-cycloalkyl; C(.dbd.O)-(3 to
6-membered heterocycloalkyl); --C(.dbd.O)-phenyl; --C(.dbd.O)-(5 or
6-membered heteroaryl); --S(.dbd.O).sub.2--(C.sub.3-6-cycloalkyl);
--S(.dbd.O).sub.2-(3 to 6-membered heterocycloalkyl);
--S(.dbd.O).sub.2-phenyl and --S(.dbd.O).sub.2-(5 or 6-membered
heteroaryl).
[0056] Preferred substituents of --C.sub.1-10-alkyl,
--C.sub.1-6-alkyl, --C.sub.1-4-alkyl, --C.sub.3-10-cycloalkyl,
--C.sub.3-6-cycloalkyl, 3 to 7 membered heterocycloalkyl, 3 to
6-membered heterocycloalkyl, --C.sub.1-6-alkylene- and
--C.sub.1-4-alkylene-are selected from the group consisting of --F;
--Cl; --Br; --I; --CN; --C.sub.1-6-alkyl; --CF.sub.3; --CF.sub.2H;
--CFH.sub.2; --C(.dbd.O)--NH.sub.2;
--C(.dbd.O)--NH(C.sub.1-6-alkyl);
--C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2; --OH; --OCF.sub.3;
--OCF.sub.2H; --OCFH.sub.2; --O--C.sub.1-6-alkyl; --NH.sub.2;
--NH(C.sub.1-6-alkyl); --N(C.sub.1-6-alkyl).sub.2; --SCF.sub.3;
--SCF.sub.2H; --SCFH.sub.2; --S-C.sub.1-6-alkyl;
--S(.dbd.O)--C.sub.1-6-alkyl; --S(.dbd.O).sub.2--C.sub.1-6-alkyl;
--C.sub.3-6-cycloalkyl; 3 to 6-membered heterocycloalkyl; phenyl
and 5 or 6-membered heteroaryl; and particularly preferably --F,
--CN, --CH.sub.3, --CH.sub.2CH.sub.3, --CF.sub.3; --CF.sub.2H;
--CFH.sub.2; --C(.dbd.O)--NH.sub.2; --C(.dbd.O)--NH(CH.sub.3);
--C(.dbd.O)--N(CH.sub.3).sub.2; --OH, --NH.sub.2, --OCH.sub.3,
--SCH.sub.3, --S(.dbd.O).sub.2(CH.sub.3), --S(.dbd.O)(CH.sub.3),
--N(CH.sub.3).sub.2, cyclopropyl and oxetanyl. According to this
embodiment, --C.sub.1-10-alkyl, --C.sub.1-6-alkyl,
--C.sub.1-4-alkyl, --C.sub.3-10-cycloalkyl, --C.sub.3-6-cycloalkyl,
3 to 7 membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl
are preferably each independently from one another unsubstituted,
mono-di- or trisubstituted, more preferably unsubstituted or
monosubstituted or disubstituted with a substituent selected from
the group consisting of --F; --Cl; --Br; --I; --CN;
--C.sub.1-6-alkyl; --CF.sub.3; --CF.sub.2H; --CFH.sub.2;
--C(.dbd.O)--NH.sub.2; --C(.dbd.O)--NH(C.sub.1-6-alkyl);
--C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2; --OH; --OCF.sub.3;
--OCF.sub.2H; --OCFH.sub.2; --O--C.sub.1-6-alkyl; --NH.sub.2;
--NH(C.sub.1-6-alkyl); --N(C.sub.1-6-alkyl).sub.2; --SCF.sub.3;
--SCF.sub.2H; --SCFH.sub.2; --S--C.sub.1-6-alkyl;
--S(.dbd.O)--C.sub.1-6-alkyl; --S(.dbd.O).sub.2--C.sub.1-6-alkyl;
--C.sub.3-6-cycloalkyl; 3 to 6-membered heterocycloalkyl; phenyl
and 5 or 6-membered heteroaryl; more preferably --F; --Cl; --Br;
--CN; --C.sub.1-6-alkyl; --CF.sub.3; --CF.sub.2H; --CFH.sub.2;
--OH; --OCF.sub.3; --OCF.sub.2H; and --OCFH.sub.2; and particularly
preferably --F; --Cl; --Br. Preferably, --C.sub.1-6-alkylene-groups
and --C.sub.1-4-alkylene-groups are unsubstituted.
[0057] According to the invention, preferably phenyl and 5 or
6-membered heteroaryl in each case independently from one another
are unsubstituted or mono- or polysubstituted; preferably
unsubstituted, mono- di- or trisubstituted, still more preferably
unsubstituted or monosubstituted or disubstituted; with one or more
substituents selected from --F; --Cl; --Br; --I; --CN;
--C.sub.1-6-alkyl; --CF.sub.3; --CF.sub.2H; --CFH.sub.2;
--CF.sub.2Cl; --CFCl.sub.2; --C.sub.1-4-alkylene-CF.sub.3;
C.sub.1-4-alkylene-CF.sub.2H; --C.sub.1-4-alkylene-CFH.sub.2;
--C(.dbd.O)--C.sub.1-6-alkyl; --C(.dbd.O)--OH;
--C(.dbd.O)--OC.sub.1-6-alkyl; --C(.dbd.O)--NH(OH);
--C(.dbd.O)--NH.sub.2; --C(.dbd.O)--NH(C.sub.1-6-alkyl);
--C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2; .dbd.O; --OH; --OCF.sub.3;
--OCF.sub.2H; --OCFH.sub.2; --OCF.sub.2Cl; --OCFCl.sub.2;
--O--C.sub.1-6-alkyl; --O--C.sub.3-6-cycloalkyl; --O-(3 to
6-membered heterocycloalkyl); --NH.sub.2; --NH(C.sub.1-6-alkyl);
--N(C.sub.1-6-alkyl).sub.2; --NH--C(.dbd.O)--C.sub.1-6-alkyl;
--N(C.sub.1-6-alkyl)-C(.dbd.O)--C.sub.1-6-alkyl;
--NH--C(.dbd.O)--NH.sub.2; --NH--C(.dbd.O)--NH(C.sub.1-6-alkyl);
--NH--C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2;
--N(C.sub.1-6-alkyl)-C(.dbd.O)--NH(C.sub.1-6-alkyl);
--N(C.sub.1-6-alkyl)-C(.dbd.O)--N(C.sub.1-6-alkyl).sub.2;
--NH--S(.dbd.O).sub.2--C.sub.1-6-alkyl; --SCF.sub.3;
--S-C.sub.1-6-alkyl; --S(.dbd.O)--C.sub.1-6-alkyl;
--S(.dbd.O).sub.2--C.sub.1-6-alkyl; --S(.dbd.O).sub.2--NH.sub.2;
--S(.dbd.O).sub.2--NH(C.sub.1-6-alkyl);
--S(.dbd.O).sub.2--N(C.sub.1-6-alkyl).sub.2;
--C.sub.3-6-cycloalkyl; --C.sub.1-4-alkylene-C.sub.3-6-cycloalkyl;
3 to 6-membered heterocycloalkyl; --C.sub.1-4-alkylene-(3 to
6-membered heterocycloalkyl); phenyl or 5 or 6-membered
heteroaryl.
[0058] Preferred substituents of phenyl and 5 or 6-membered
heteroaryl are selected from the group consisting of --F; --Cl;
--Br; --I; --CN; --C.sub.1-6-alkyl; --CF.sub.3; --CF.sub.2H;
--CFH.sub.2; --C.sub.1-4-alkylene-CF.sub.3;
--C.sub.1-4-alkylene---CF.sub.2H; --C.sub.1-4-alkylene-CFH.sub.2;
--OH; --OCF.sub.3; --OCF.sub.2H; --OCFH.sub.2;
--O--C.sub.1-6-alkyl; --O--C.sub.3-6-cycloalkyl and
--C.sub.3-6-cycloalkyl; and more preferably of --F; --C.sub.1;
--Br; --CN; --CH.sub.3; --CH.sub.2CH.sub.3; --CF.sub.3;
--CF.sub.2H; --CFH.sub.2; --CH.sub.2--CF.sub.3; .dbd.O; --OH;
--OCF.sub.3; --OCF.sub.2H; --OCFH.sub.2; --O--CH.sub.3;
--O-cyclopropyl and cyclopropyl; still more preferably --F; --Cl;
--Br; --CH.sub.3; --CH.sub.2CH.sub.3; --CF.sub.3; --CF.sub.2H;
--CFH.sub.2; .dbd.O; --OH; --OCF.sub.3; and --O--CH.sub.3; and
particularly preferably preferably --F; --Cl; --Br; --CH.sub.3;
.dbd.O; and --O--CH.sub.3. According to this embodiment, phenyl and
5 or 6-membered heteroaryl are preferably each independently from
one another unsubstituted, mono- di- or trisubstituted, more
preferably unsubstituted or monosubstituted or disubstituted with a
substituent selected from the group consisting of --F; --Cl; --Br;
--I; --CN; --C.sub.1-6-alkyl; --CF.sub.3; --CF.sub.2H; --CFH.sub.2;
--C.sub.1-4-alkylene-CF.sub.3; --C.sub.1-4-alkylene-CF.sub.2H;
--C.sub.1-4-alkylene-CFH.sub.2; .dbd.O; --OH; --OCF.sub.3;
--OCF.sub.2H; --OCFH.sub.2; --O--C.sub.1-6-alkyl;
--O--C.sub.3-6-cycloalkyl and --C.sub.3-6-cycloalkyl. A
particularly preferred substituted 5 or 6-membered heteroaryl is
N-methyl-2-oxo-pyridyl.
[0059] In a preferred embodiment, the compound according to the
invention has a stereochemistry according to general formula (II),
(III), (IV), (V), (VI), (VII), (VIII), or (IX)
##STR00004##
[0060] In a preferred embodiment, the compound according to the
invention has a stereochemistry according to general formula (II),
(III), (VI) or (VII), such that the residues --R.sub.1 and
--NH--R.sub.2 on the pyrrolidone ring are oriented trans.
Preferably, the compound according to the invention has a
stereochemistry according to general formula (II) or (VI).
Preferably, the compound according to the invention has a
stereochemistry according to general formula (III) or (VII). The
stereochemistry according to general formula (II) or (VI) is
particularly preferred.
[0061] In another preferred embodiment, the compound according to
the invention has a stereochemistry according to general formula
(IV), (V), (VIII) or (IX), such that the residues --R.sub.1 and
--NH--R.sub.2 on the pyrrolidone ring are oriented cis. Preferably,
the compound according to the invention has a stereochemistry
according to general formula (IV) or (VIII). Preferably, the
compound according to the invention has a stereochemistry according
to general formula (V) or (IX).
[0062] In a particularly preferred embodiment, the compound
according to the invention has a stereochemistry according to
general formula (II) or (VI), more preferably (II).
[0063] In the compound of the invention according to any of general
formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX)
R.sub.1 represents phenyl; --C.sub.1-6-alkylene-phenyl; 5 or
6-membered heteroaryl;--C.sub.1-6-alkylene-(5 or 6-membered
heteroaryl); or --C.sub.1-10-alkyl.
[0064] In a preferred embodiment, R.sub.1 represents phenyl or
ethyl; more preferably phenyl.
[0065] In a particularly preferred embodiment, R.sub.1 represents
phenyl, unsubstituted or mono- or disubstituted with substituents
independently of one another selected from the group consisting of
--F, --Cl, --Br, --OCH.sub.3; --CH.sub.3, --CF.sub.3, --CN, and
cyclopropyl; more preferably --F, --OCH.sub.3; and --CH.sub.3.
[0066] In the compound of the invention according to any of general
formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX)
R.sub.1' represents H; --C.sub.1-10-alkyl; or
--C.sub.3-10-cycloalkyl.
[0067] In a preferred embodiment, R.sub.1' represents H; methyl,
ethyl, n-propyl, cyclopropyl, cyclobutyl, cyclopentyl or
cyclohexyl; more preferably H, methyl, ethyl, cyclopropyl or
cyclobutyl; still more preferably H, methyl or cyclopropyl.
[0068] In a particularly preferred embodiment, R.sub.1' represents
H.
[0069] In the compound of the invention according to any of general
formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX)
R.sub.2 represents --C(.dbd.O)--C.sub.1-10-alkyl;
--C(.dbd.O)--C.sub.3-10-cycloalkyl;
--C(.dbd.O)--C.sub.1-6-alkylene-C.sub.3-10-cycloalkyl;
--C(.dbd.O)-(3 to 7 membered heterocycloalkyl);
--C(.dbd.O)--C.sub.1-6-alkylene-(3 to 7 membered heterocycloalkyl);
--C(.dbd.O)-phenyl; --C(.dbd.O)--C.sub.1-6-alkylene-phenyl;
--C(.dbd.O)-(5 or 6-membered heteroaryl);
--C(.dbd.O)--C.sub.1-6-alkylene-(5 or 6-membered heteroaryl);
--S(.dbd.O).sub.1-2--C.sub.1-10-alkyl;
--S(.dbd.O).sub.1-2--C.sub.3-10-cycloalkyl;
--S(.dbd.O).sub.1-2--C.sub.1-6-alkylene-C.sub.3-10-cycloalkyl;
--S(.dbd.O).sub.1-2-(3 to 7 membered heterocycloalkyl);
--S(.dbd.O).sub.1-2--C.sub.1-6-alkylene-(3 to 7 membered
heterocycloalkyl); --S(.dbd.O).sub.1-2-phenyl;
--S(.dbd.O).sub.1-2--C.sub.1-6-alkylene-phenyl;
--S(.dbd.O).sub.1-2-(5 or 6-membered heteroaryl); or
--S(.dbd.O).sub.1-2--C.sub.1-6-alkylene-(5 or 6-membered
heteroaryl).
[0070] In a preferred embodiment, R.sub.2 represents
--C(.dbd.O)--C.sub.1-10-alkyl; --C(.dbd.O)--C.sub.3-10-cycloalkyl;
--C(.dbd.O)--C.sub.1-6-alkylene-C.sub.3-10-cycloalkyl;
--C(.dbd.O)-(3 to 7 membered heterocycloalkyl); --C(.dbd.O)-(5 or
6-membered heteroaryl); --S(.dbd.O).sub.2--C.sub.1-10-alkyl;
--S(.dbd.O).sub.2--C.sub.3-10-cycloalkyl;
--S(.dbd.O).sub.2--C.sub.1-6-alkylene-C.sub.3-10-cycloalkyl;
--S(.dbd.O).sub.2-(3 to 7 membered heterocycloalkyl); or
--S(.dbd.O).sub.2-(5 or 6-membered heteroaryl).
[0071] In particularly preferred embodiments, R.sub.2 represents
[0072] (i) --C(.dbd.O)--C.sub.1-10-alkyl, unsubstituted or mono- or
disubstituted with substituents independently of one another
selected from the group consisting of --F, --Cl, and --Br; [0073]
(ii) --C(.dbd.O)-cyclopropyl, unsubstituted or mono- or
disubstituted with substituents independently of one another
selected from the group consisting of --F, --Cl, --Br, --CH.sub.3,
--CF.sub.3, --CN, and --OCH.sub.3; [0074] (iii)
--C(.dbd.O)-2-tetrahydrofuranyl, unsubstituted; [0075] (iv)
--C(.dbd.O)-(5- to 6-membered heteroaryl), wherein said 5- to
6-membered heteroaryl is selected from the group consisting of
thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1-oxa-2,4-diazolyl,
1,2,5-oxadiazolyl, and isothiazolyl, wherein in each case said 5-
to 6-membered heteroaryl is unsubstituted or mono- or disubstituted
with substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --CH.sub.3, --CF.sub.3, --CN,
.dbd.O, and --OCH.sub.3; [0076] (v)
--S(.dbd.O).sub.2--C.sub.1-10-alkyl, unsubstituted; [0077] (vi)
--S(.dbd.O).sub.2-cyclopropyl, unsubstituted; [0078] (vii)
--S(.dbd.O).sub.2--CH.sub.2-cyclopropyl, unsubstituted; [0079]
(viii) --S(.dbd.O).sub.2-2-tetrahydrofuranyl; or [0080] (ix)
--S(.dbd.O).sub.2-(5- to 6-membered heteroaryl), wherein said 5- to
6-membered heteroaryl is selected from the group consisting of
thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1-oxa-2,4-diazolyl,
1,2,5-oxadiazolyl, and isothiazolyl, wherein in each case said 5-
to 6-membered heteroaryl is unsubstituted or mono- or disubstituted
with substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --CH.sub.3, --CF.sub.3, --CN,
.dbd.O, and --OCH.sub.3.
[0081] In the compound of the invention according to any of general
formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX)
R.sub.3 and R.sub.3' independently from one another represent H; F;
Cl; --C.sub.1-10-alkyl; --C.sub.3-6-cycloalkyl;
--CH.sub.2--C.sub.3-6-cycloalkyl; 3 to 7 membered heterocycloalkyl;
--CH.sub.2-(3 to 7 membered heterocycloalkyl); --CH.sub.2-phenyl;
or --CH.sub.2-(5 or 6-membered heteroaryl); or R.sub.3 and R.sub.3'
together with the carbon atom to which they are bound form a
C.sub.3-10-cycloalkyl, or 3 to 7 membered heterocycloalkyl.
[0082] In a preferred embodiment, R.sub.3 and R.sub.3' both
represent --C.sub.1-10-alkyl. In a particularly preferred
embodiment, R.sub.3 and R.sub.3' both represent --CH.sub.3.
[0083] In another preferred embodiment, R.sub.3 and R.sub.3'
independently from one another represent H; F; --CH.sub.3;
cyclopropyl; --CH.sub.2-cyclopropyl; or --CH.sub.2-phenyl. In still
another preferred embodiment, R.sub.3 and R.sub.3' both represent
F.
[0084] In another preferred embodiment, at least one of R.sub.3 and
R.sub.3' represents not H. In yet another preferred embodiment, one
of R.sub.3 and R.sub.3' represents H.
[0085] In still another preferred embodiment, R.sub.3 and R.sub.3'
together with the carbon atom to which they are bound form
cyclopropyl.
[0086] In the compound of the invention according to any of general
formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX)
R.sub.4 represents phenyl; --C.sub.1-6-alkylene-phenyl; 5 or
6-membered heteroaryl; or --C.sub.1-6-alkylene-(5 or 6-membered
heteroaryl).
[0087] In a preferred embodiment, R.sub.4 represents phenyl or 5 or
6-membered heteroaryl.
[0088] In particularly preferred embodiments, R.sub.4 represents
phenyl, unsubstituted or mono- or disubstituted with substituents
independently of one another selected from the group consisting of
--F, --Cl, --Br, --CH.sub.3, --CF.sub.3, --CN, and --OCH.sub.3; or
5 or 6-membered heteroaryl selected from the group consisting of
pyridyl, pyrazolyl, and pyrimidinyl, wherein in each case said 5-
to 6-membered heteroaryl is unsubstituted or mono- or disubstituted
with substituents independently of one another selected from the
group consisting of .dbd.O, --F, --Cl, --Br, --CH.sub.3,
--CF.sub.3, --CN, and --OCH.sub.3.
[0089] In a particularly preferred embodiment, R.sub.4 does not
represent N-methylpyridinone.
[0090] In the compound of the invention according to any of general
formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX)
A, X, Y and Z independently from one another represent N or CH. In
a preferred embodiment, A represents N.
[0091] In a preferred embodiment, X represents CH.
[0092] In a preferred embodiment, Y represents CH.
[0093] In a preferred embodiment, Z represents CH.
[0094] In a preferred embodiment of the invention, [0095] (i) A
represents N, X represents CH, Y represents CH; and Z represents
CH; or [0096] (ii) A represents N, X represents N, Y represents CH;
and Z represents CH; or [0097] (iii) A represents N, X represents
CH, Y represents N; and Z represents CH; or [0098] (iv) A
represents N, X represents CH, Y represents CH; and Z represents N;
or [0099] (v) A represents N, X represents N, Y represents N; and Z
represents CH; or [0100] (vi) A represents N, X represents N, Y
represents CH; and Z represents N; or [0101] (vii) A represents N,
X represents CH, Y represents N; and Z represents N; or [0102]
(viii) A represents N, X represents N, Y represents N; and Z
represents N; or [0103] (ix) A represents CH, X represents CH, Y
represents CH; and Z represents CH; or [0104] (x) A represents CH,
X represents N, Y represents CH; and Z represents CH; or [0105]
(xi) A represents CH, X represents CH, Y represents N; and Z
represents CH; or [0106] (xii) A represents CH, X represents CH, Y
represents CH; and Z represents N; or [0107] (xiii) A represents
CH, X represents N, Y represents N; and Z represents CH; or [0108]
(xiv) A represents CH, X represents N, Y represents CH; and Z
represents N; or [0109] (xv) A represents CH, X represents CH, Y
represents N; and Z represents N; or [0110] (xvi) A represents CH,
X represents N, Y represents N; and Z represents N.
[0111] In a particularly preferred embodiment of the invention
according to any of general formulas (I), (II), (III), (IV), (V),
(VI), (VII), (VIII), or (IX) [0112] R.sub.1 represents phenyl,
unsubstituted or mono- or disubstituted with substituents
independently of one another selected from the group consisting of
--F, --Cl, --Br, --CH.sub.3, and --OCH.sub.3; and/or [0113]
R.sub.1' represents H, CH.sub.3, or cyclopropyl and/or [0114]
R.sub.2 represents --C(.dbd.O)--C.sub.1-6-alkyl;
--C(.dbd.O)-cyclopropyl; or or --C(.dbd.O)-(5- to 6-membered
heteroaryl), unsusbtituted or mono- or disubstituted with
substituents independently of one another selected from the group
consisting of --F, --Cl, --Br; and --CH.sub.3; and/or [0115]
R.sub.4 represents fluoro-phenyl or N-methyl-2-oxo-pyridyl.
[0116] In a preferred embodiment, the compound according to the
invention is selected from the group consisting of [0117] 1
N-[(2R,3S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4,4-dimethyl-5-oxo-2-ph-
enyl-pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide [0118] 2
N-[(2S,3R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4,4-dimethyl-5-oxo-2-ph-
enyl-pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide [0119] 3
N-[rac-(6R,7S)-5-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-oxo-6-phenyl-5-az-
aspiro[2.4]heptan-7-yl]-cyclopropanecarboxylic acid amide [0120] 4
2,2-Difluoro-N-[(2S,3R)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4,4-dimeth-
yl-5-oxo-2-phenyl-pyrrolidin-3-yl]-propionamide [0121] 5
N-[rac-(6R,7S)-5-[1-(4-Fluorophenyl)-1H-indol-5-yl]-4-oxo-6-phenyl-5-azas-
piro[2.4]heptan-7-yl]-cyclopropanecarboxylic acid amide [0122] 6
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-thiazole-2-carboxylic
acid amide [0123] 7
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-isoxazole-3-carboxylic
acid amide [0124] 8
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-2,2-difluoro-propionamide
[0125] 9
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-2,2-difluoro-propionamide
[0126] 10
2,2-Difluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4,4-dimeth-
yl-5-oxo-2-phenyl-pyrrolidin-3-yl]-propionamide [0127] 12
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic
acid amide [0128] 13
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-oxazole-5-carboxylic acid
amide [0129] 14
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1-
H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-[1,2,4]oxadiazole-
-3-carboxylic acid amide [0130] 15
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-thiazole-5-carboxylic acid
amide [0131] 16
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1-
H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-4-methyl-thiazole-5-carbox-
ylic acid amide [0132] 17
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-thiazole-4-carboxylic acid
amide [0133] 18
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1-
H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-thiazole-4-carbox-
ylic acid amide [0134] 21
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-oxazole-5-carboxylic acid
amide [0135] 22
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1-
H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-isoxazole-3-carbo-
xylic acid amide [0136] 24
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-thiazole-5-carboxylic acid
amide [0137] 26
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1-
H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-thiazole-2-carbox-
ylic acid amide [0138] 30
N-[rac-(6R,7S)-5-[1-(1-Methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-4-o-
xo-6-phenyl-5-azaspiro[2.4]heptan-7-yl]-cyclopropanecarboxylic acid
amide [0139] 31
N-[rac-(6R,7S)-5-[1-(4-Fluorophenyl)-1H-pyrazolo[3,4-b]pyridin--
5-yl]-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl]-cyclopropanecarboxylic
acid amide [0140] 32
N-[rac-(6R,7S)-5-[1-(4-Fluorophenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl]-4-ox-
o-6-phenyl-5-azaspiro[2.4]heptan-7-yl]-cyclopropanecarboxylic acid
amide [0141] 33
N-[rac-(6R,7S)-5-[1-(4-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridin--
5-yl]-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl]-cyclopropanecarboxylic
acid amide [0142] 34a
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)methanesulfonamide [0143] 34b
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)methanesulfonamide [0144] 35a
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)cyclopropanesulfonamide [0145] 35b
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)cyclopropanesulfonamide [0146] 36a
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)oxazole-5-carboxamide [0147] 36b
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)oxazole-5-carboxamide [0148] 37
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-1-methyl-1H-pyrazole-3-carboxamide [0149] 38a
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-4-methylthiazole-5-carboxamide [0150] 38b
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-4-methylthiazole-5-carboxamide [0151] 39a
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-5-methylthiazole-4-carboxamide [0152] 39b
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-5-methylthiazole-4-carboxamide [0153] 40a
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-3-methylisoxazole-4-carboxamide [0154] 40b
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-3-methylisoxazole-4-carboxamide [0155] 41a
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide [0156] 41b
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide [0157] 42a
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)nicotinamide [0158] 42b
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)nicotinamide [0159] 43a
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)pyrimidine-2-carboxamide [0160] 43b
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)pyrimidine-2-carboxamide [0161] 44a
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-2-methyloxazole-5-carboxamide [0162] 44b
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-2-methyloxazole-5-carboxamide [0163] 45a
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-4-methyloxazole-5-carboxamide [0164] 45b
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)-4-methyloxazole-5-carboxamide [0165] 46
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-
-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide [0166]
47
N-[rac-(2R,3S,4S)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-y-
l]-4-methyl-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propionamide [0167]
48
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(3-methoxyphen-
yl)-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic acid
amide [0168] 49
N-[rac-(2R,3S,4S)-2-(4-Fluorophenyl)-1-[1-(4-fluorophenyl)-1H-i-
ndazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic
acid amide [0169] 60
N-[rac(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2--
phenyl-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic acid amide
[0170] 61
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-ox-
o-2-phenyl-pyrrolidin-3-yl]-methanesulfonic acid amide [0171] 62
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tol-
yl-5-oxo-pyrrolidin-3-yl]-methanesulfonic acid amide [0172] 63
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tol-
yl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide [0173]
64
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-
-phenyl-pyrrolidin-3-yl]-1-methyl-i H-pyrazole-3-carboxylic acid
amide [0174] 65
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-meth-
yl-5-oxo-2-phenyl-pyrrolidin-3-yl]-pyridine-3-carboxylic acid amide
[0175] 66
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-ox-
o-2-phenyl-pyrrolidin-3-yl]-pyrimidine-2-carboxylic acid amide
[0176] 67
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tol-
yl-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic acid amide
[0177] 68
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m--
tolyl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic acid amide
[0178] 69
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tol-
yl-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic acid amide [0179]
70
N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tol-
yl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide [0180]
71
N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tol-
yl-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic acid amide
[0181] 72
N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m--
tolyl-5-oxo-pyrrolidin-3-yl]-1-methyl-i H-pyrazole-3-carboxylic
acid amide [0182] 73
N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-meth-
yl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic acid
amide [0183] 74
N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-meth-
yl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic acid
amide [0184] 75
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-meth-
yl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-1-methyl-i
H-pyrazole-3-carboxylic acid amide [0185] 76
N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tol-
yl-5-oxo-pyrrolidin-3-yl]-methanesulfonic acid amide [0186] 77
2,2-Difluoro-N-[rac-(2R,3S,4R)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-m-
ethyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-propionamide [0187] 78
N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-y-
l]-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic acid
amide [0188] 79
N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-i-
ndazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propionamide
[0189] 80
2,2-Difluoro-N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-
-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-propionamide [0190]
81
2,2-Difluoro-N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-m-
ethyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-propionamide [0191] 82
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphen-
yl)-4-methyl-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic
acid amide [0192] 83
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphen-
yl)-4-methyl-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic
acid amide [0193] 84
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphen-
yl)-4-methyl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic acid
amide [0194] 85
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-m-
ethoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic
acid amide [0195] 86
N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-y-
l]-4-methyl-5-oxo-pyrrolidin-3-yl]-methanesulfonic acid amide
[0196] 87
N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-y-
l]-4-methyl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic acid amide
[0197] 88
N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol--
5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic acid
amide [0198] 89
N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-ind-
azol-5-yl]-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic acid amide
[0199] 90
N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5--
yl]-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic acid amide
[0200] 91
N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-
-5-oxo-pyrrolidin-3-yl]-methanesulfonic acid amide [0201] 92
N-[rac-(2R,3S,4S)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-y-
l]-4-methyl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic acid amide
[0202] 93
N-[rac-(2R,3S,4S)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol--
5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-methanesulfonic acid amide
[0203] 94
N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-y-
l]-4-methyl-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic
acid amide [0204] 95
N-((2R,3R,4S)-4-fluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phe-
nylpyrrolidin-3-yl)cyclopropanecarboxamide [0205] 96
N-((2R,3R)-4,4-difluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-ph-
enylpyrrolidin-3-yl)cyclopropanecarboxamide [0206] 97
2,2-Difluoro-N-[rac-(2R,3S,4R)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-(-
4-methoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-propionamide
[0207] 98
2,2-Difluoro-N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-(-
4-methoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-propionamide
[0208] 99
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphen-
yl)-4-methyl-5-oxo-pyrrolidin-3-yl]-methanesulfonic acid amide
[0209] 100
2,2-Difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-meth-
yl-5-oxo-2-phenyl-pyrrolidin-3-yl]-propionamide [0210] 101
N-[rac-(2R,3S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-methyl-5-oxo-2-ph-
enyl-pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide [0211] 102
2,2-Difluoro-N-[rac-(2R,3S)-2-methyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl-
)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-propionamide
[0212] 103
N-[rac-(2R,3S)-2-Methyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic acid
amide [0213] 104
N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-
-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic acid
amide [0214] 105
N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-
-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic acid amide
[0215] 106
N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-
-yl]-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide
[0216] 107
N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-
-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propionamide [0217] 108
N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-ind-
azol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic
acid amide [0218] 109
N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-ind-
azol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic
acid amide [0219] 110
N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-ind-
azol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxyl-
ic acid amide
[0220] 111
N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-ind-
azol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic
acid amide [0221] 112
N-[rac-(2R,3S,4S)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-y-
l]-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic acid
amide [0222] 113
N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-ind-
azol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic
acid amide [0223] 114
N-[(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-
-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-methanesulfonic acid amide
[0224] 115
N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(-
1-methyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic
acid amide [0225] 116
N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-me-
thyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxyli-
c acid amide [0226] 117
N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-me-
thyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carbox-
ylic acid amide [0227] 118
N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-me-
thyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic
acid amide [0228] 119
N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-me-
thyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic
acid amide [0229] 120
2,2-Difluoro-N-[rac-(2S,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-m-
ethyl-2-(1-methyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-propionamide
[0230] 121
N-[rac-(2R,3S,4S)-4-(Cyclopropyl-methyl)-1-[1-(4-fluorophenyl)-1H-indazol-
-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic acid
amide [0231] 122
N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-me-
thyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-methanesulfonic acid
amide [0232] 123
N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-ind-
azol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propionamide
[0233] 124
N-[rac-(2S,3S,4R)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-ind-
azol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic
acid amide [0234] 125
N-[rac-(2S,3S,4R)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-ind-
azol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propionamide
[0235] 126
N-[rac-(2R,3S,4S)-4-Ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-2--
phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide [0236]
127
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-4-phenethyl-2-phe-
nylpyrrolidin-3-yl)cyclopropanecarboxamide, diastereomer 2 [0237]
128
N-[rac-(2R,3R,4R)-4-Fluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methy-
l-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide
[0238] 129
N-[rac-(2R,3R,4S)-4-Fluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-m-
ethyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic acid
amide [0239] 130
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-4-phenethyl-2-phe-
nylpyrrolidin-3-yl)cyclopropanecarboxamide, diastereomer 1 [0240]
131
N-((2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl-
)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide [0241] 132
N-((2R,3S,4R)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl-
)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide [0242] 133
N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphen-
yl)-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic acid
amide [0243] 134
N-(rac-(2R,3S,4R)-4-ethyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-
-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide [0244] 135
N-((7R,8S)-6-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-7-phenyl-6-azaspi-
ro[3.4]octan-8-yl)cyclopropanecarboxamid [0245] 136 N-(rac
(2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-
-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide
[0246] 137
N-(rac-(2R,3R,4S)-4-benzyl-2-ethyl-4-fluoro-1-(1-(4-fluorophenyl)-1H-inda-
zol-5-yl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide [0247] 138
N-((2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-((3-methyl-1,2,4-o-
xadiazol-5-yl)methyl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamid-
e [0248] 139
N-((2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-((1-methyl-1H-pyra-
zol-4-yl)methyl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanec
arboxamide [0249] 142
N-(rac-(2R,3S)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-
-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide [0250] 143
N-(rac-(2R,3R)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-
-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide [0251] 144
N-(rac-(2R,3S)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-
-2-phenylpyrrolidin-3-yl)-2,2-difluoropropanamide [0252] 145
N-(rac-(2R,3R)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-
-2-phenylpyrrolidin-3-yl)-2,2-difluoropropanamide [0253] 146
N-(rac-(2R,3S)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-
-2-phenylpyrrolidin-3-yl)oxetane-3-carboxamide [0254] 147
N-(rac-(2R,3R)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-
-2-phenylpyrrolidin-3-yl)oxetane-3-carboxamide [0255] 148
N-(rac-(2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol--
5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide
[0256] 149
N-(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-1-(1-(4-fluorophenyl)-1H-indazol--
5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide
[0257] 150
N-((2R,3S,4R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenyl-4-(th-
iazol-2-ylmethyl)pyrrolidin-3-yl)cyclopropanecarboxamide [0258] 151
N-((2S,3S)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-y-
l)-2-methyl-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide in each
case in the form of the free compound or a physiologically
acceptable salt thereof.
[0259] The compounds according to the invention can be synthesized
by standard reactions in the field of organic chemistry known to
the person skilled in the art or in a manner as described herein
(cf. Reaction Schemes below) or analogously. The reaction
conditions in the synthesis routes described herein are known to
the skilled person and are for some cases also exemplified in the
Examples described herein.
[0260] Reaction Scheme 1:
##STR00005##
[0261] Substituted indazole moieties in compounds of formula (D)
and formula (F) are introduced by subjecting lactam (B) or lactam
(E) in a regioselective metal catalyzed C--N coupling reaction with
corresponding indazole halides (C), preferred with corresponding
indazole iodides. Metal catalyzed C--N coupling reactions are
generally known in the art (Current Organic Synthesis, 2011, 8,
53). Favorable C--N coupling reactions are palladium and copper
catalyzed cross-coupling reactions (Chem. Rev., 2016, 116, 12564;
Chem. Soc. Rev., 2014, 43, 3525; Chem. Sci., 2010, 1, 13).
Regioselective C--N couplings with arylhalides are known in the art
(Chem. Sci., 2011, 2, 27; J. Am. Chem. Soc., 2001, 123, 7727).
[0262] Primary amines (A) and (G) are converted to corresponding
amides and sulfonamides (acylation and sulfonamide formation) (B)
and (D) using commercially available acids (activation of acids
using e.g. HATU) or acid chlorides under standard amide coupling
reaction conditions (March's Advanced Organic Chemistry, 2007, 6th
Edition, page 1427-1474).
[0263] Introduction of different orthogonal protecting groups PG
(e.g. Boc, Cbz) to convert (A) to (E) as well as deprotection of
compounds of formula (E) to (A) is well described in the literature
(T. W. Green, P. G. M. Wuts, Protective Groups in Organic
Synthesis, Wiley-Interscience, New York, 1999).
[0264] Reaction Scheme 1.1:
[0265] Compounds (A) and (E) can be synthesized according to
procedures which are described in the literature.
##STR00006##
[0266] Route 1:
[0267] Synthesis of compounds of formula (I) starting from
compounds of formula (H) is described in the literature (Org.
Lett., 2011, 13, 6406, Org. Lett, 2009, 4512, ACS Sustainable Chem.
Eng. 2015, 1873). For R.sub.3 and R.sub.3'=Me the synthesis of the
corresponding acid of (H) is described (Journal of Chemical and
Engineering Data, 1966, 11, 617) and the synthesis can be carried
out in analogy to the references above. Removal of PG=PMB is well
known in the art (Greene's Protective Groups in Organic Synthesis,
2007, 4th Edition, page 905ff). Reduction of nitro groups is well
known in the art (March's Advanced Organic Chemistry, 2007, 6th
Edition, page 1815f).
[0268] Route 2:
[0269] Synthesis of compounds of formula (J) is described in the
literature (Org. Lett., 2007, 9, 4077). Introduction of
substituents R3 and R3' can be achieved via alkylation.
C-alkylations of pyrrolidinones (Tetrahedron, 1999, 55, 13321) and
elimination of sulfonium salts (Tetrahedron Letters 1983, 24, 4331)
are well known in the art. Compounds of formula (A) and (E) can be
synthesized using Curtius rearrangement as key step to convert
carboxylic acid (L) to corresponding primary amine (A) or (E).
Curtius rearrangement is well known in the art (Tetrahedron
Letters, 2010, 51, 385).
[0270] Route 3:
[0271] Synthesis of compounds of formula (N) starting from
compounds of formula (M) is described in the literature (J. Am.
Chem. Soc., 2008, 130, 16146). Amidophosphate cleavage is described
in the literature (J. Am. Chem. Soc., 2008, 130, 16146). Compounds
of formula (A) and (E) can be synthesized using Curtius
rearrangement as key step to convert carboxylic acid (L) to
corresponding primary amine (A) or (E). Curtius rearrangement is
well known in the art (Tetrahedron Letters, 2010, 51, 385).
[0272] Reaction Scheme 2:
##STR00007##
[0273] Compounds of formula (D) can be synthesized via
regioselective C--N coupling of compound (O). Suitable C--N
coupling reactions for N--H containing heterocycles are known in
the art (Synthesis, 2011, 829; Chem. Sci., 2011, 2, 27; Beilstein
J. Org. Chem., 2011, 7, 59; J. Org. Chem., 2004, 69, 5578).
Compound of formula (O) is synthesized via deprotection of compound
(N) under acidic conditions.
[0274] The compounds according to the invention can be produced in
the manner described here or in an analogous manner.
[0275] In a preferred embodiment, the compounds according to the
invention are modulators of the glucocorticoid receptor. In the
sense of the invention, the term "selective modulator of the
glucocorticoid receptor (glucocorticoid receptor modulator)"
preferably means that the respective compound exhibits in a
cellular target engagement assay for agonistic or antagonistic
potency on the glucocorticoid receptor an EC50 or IC50 value on the
glucocorticoid receptor of at most 15 .mu.M (1010.sup.-6 mol/L) or
at most 10 .mu.M; more preferably at most 1 .mu.M; still more
preferably at most 500 nM (10.sup.-9 mol/L); yet more preferably at
most 300 nM; even more preferably at most 100 nM; most preferably
at most 10 nM; and in particular at most 1 nM. In a preferred
embodiment, the compound according to the invention exhibits in a
cellular target engagement assay for agonistic or antagonistic
potency on the glucocorticoid receptor an EC50 or IC50 value on the
glucocorticoid receptor in the range of from 1 .mu.M to 15 .mu.M,
more preferably from 100 nM to 1 .mu.M, most preferably below 100
nM.
[0276] The person skilled in the art knows how to test compounds
for modulation (agonistic or antagonistic) of the activity of the
glucocorticoid receptor. Preferred target engagement assays for
testing compounds for their agonistic or antagonistic potency
(EC50, IC50) on the glucocorticoid receptor are described herein
below:
[0277] Glucocorticoid Receptor Cell-Based Assays
[0278] Potential selective glucocorticoid receptor modulators of
this intervention can be tested for modulation of the activity of
the glucocorticoid receptor using cell-based assays. These assays
involve a Chinese hamster ovary (CHO) cell line which contains
fragments of the glucocorticoid receptor as well as fusion
proteins. The glucocorticoid receptor fragments used are capable of
binding the ligand (e.g. beclomethasone) to identify molecules that
compete for binding with glucocorticoid receptor ligands. In more
detail, the glucocorticoid receptor ligand binding domain is fused
to the DNA binding domain (DBD) of the transcriptionfactor GAL4
(GAL4 DBD-GR) and is stably integrated into a CHO cell line
containing a GAL4-UAS-Luciferase reporter construct. To identify
selective glucocorticoid receptor modulators, the reporter cell
line is incubated with the molecules using an 8-point half-log
compound dilution curve for several hours. After cell lysis the
luminescence that is produced by luciferase after addition of the
substrate is detected and EC50 or IC50 values can be calcuated.
Engagement of molecules which induce gene expression via
glucocortocoid receptor binding to the DNA leads to expression of
the luciferase gene under the control of the fusion protein GAL4
DBD-GR and therefore to a dose-dependent increase of the
luminescence signal. Binding of molecules which repress
beclomethasone-induced gene expression of the luciferase gene under
the control of the fusion protein GAL4 DBD-GR leads to a
dose-dependent reduction of the luminescence signal.
[0279] In a preferred embodiment, the compound according to the
invention exhibits in a cellular target engagement assay for
agonistic or antagonistic potency on the glucocorticoid receptor an
EC50 or IC50 value on the glucocorticoid receptor of at most 1
.mu.M (10.sup.-6 mol/L); still more preferably at most 500 nM
(10.sup.-9 mol/L); yet more preferably at most 300 nM; even more
preferably at most 100 nM; most preferably at most 50 nM; and in
particular at most 10 nM or at most 1 nM.
[0280] In a preferred embodiment, the compound according to the
invention exhibits in a cellular target engagement assay for
agonistic or antagonistic potency on the glucocorticoid receptor an
EC50 or IC50 value on the glucocorticoid receptor in the range of
from 1 .mu.M to 15 .mu.M, more preferably from 100 nM to 1 .mu.M,
most preferably below 100 nM.
[0281] In a preferred embodiment, the compound according to the
invention exhibits in a cellular target engagement assay for
agonistic or antagonistic potency on the glucocorticoid receptor an
EC50 or IC50 value on the glucocorticoid receptor in the range of
from 0.1 nM (10.sup.-9 mol/L) to 1000 nM; still more preferably 1
nM to 800 nM; yet more preferably 1 nM to 500 nM; even more
preferably 1 nM to 300 nM; most preferably 1 nM to 100 nM; and in
particular 1 nM to 80 nM.
[0282] Human Glucocorticoid Receptor (hGR) Ligand-Binding Assay
[0283] Potential selective glucocorticoid receptor modulators of
this intervention can be tested for their binding affinity at the
glucocorticoid receptor using the binding assay described
below.
[0284] Preferably, the glucocortitcoid receptor extracted from
cytosol of IM9 cells is used for competitive radioligand binding
assays to calculate percentage inhibition of the binding of
radiolabeled ligand 3H-dexamethasone at the human glucocorticoid
receptor. Preferably, a fixed concentration of the radioligand
3H-dexamethasone and 1 .mu.M of compound according to the present
invention (as unlabeled competitors of dexamethasone) are mixed
with the extracted glucocorticoid receptor in order to measure the
percentage of inhibition of 3H-dexamethasone binding.
[0285] In a preferred embodiment, the compound according to the
invention exhibits in a hGR ligand-binding assay an inhibition of
3H-dexamethasone binding at 1 .mu.M of at least 40%, more
preferably at least 60%, most preferably at least 85%. In a
preferred embodiment, the compound according to the invention
exhibits in a hGR ligand-binding assay an inhibition of
3H-dexamethasone binding at 1 .mu.M which is in the range from 40%
to 60%, more preferably from greater than 60% to 85%, most
preferably greater than 85%.
[0286] Preferably, the compounds according to the invention are
useful as selective modulators of the glucocorticoid receptor.
[0287] Therefore, the compounds according to the invention are
preferably useful for the in vivo treatment or prevention of
diseases in which participation of the glucocorticoid receptor is
implicated.
[0288] The invention therefore further relates to a compound
according to the invention for use in the modulation of
glucocorticoid receptor activity.
[0289] Therefore, another aspect of the invention relates to a
compound according to the invention for use in the treatment and/or
prophylaxis of a disorder which is mediated at least in part by the
glucocorticoid receptor. Still another aspect of the invention
relates to a method of treatment of a disorder which is mediated at
least in part by the glucocorticoid receptor comprising the
administration of a therapeutically effective amount of a compound
according to the invention to a subject in need thereof, preferably
a human.
[0290] A further aspect of the invention relates to the use of a
compound according to the invention as medicament.
[0291] Another aspect of the invention relates to a pharmaceutical
dosage form comprising a compound according to the invention.
Preferably, the pharmaceutical dosage form comprises a compound
according to the invention and one or more pharmaceutical
excipients such as physiologically acceptable carriers, additives
and/or auxiliary substances; and optionally one or more further
pharmacologically active ingredient. Examples of suitable
physiologically acceptable carriers, additives and/or auxiliary
substances are fillers, solvents, diluents, colorings and/or
binders. These substances are known to the person skilled in the
art (see H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie,
Kosmetik und angrenzende Gebiete, Editio Cantor Aulendoff).
[0292] The pharmaceutical dosage form according to the invention is
preferably for systemic, topical or local administration,
preferably for oral administration. Therefore, the pharmaceutical
dosage form can be in form of a liquid, semisolid or solid, e.g. in
the form of injection solutions, drops, juices, syrups, sprays,
suspensions, tablets, patches, films, capsules, plasters,
suppositories, ointments, creams, lotions, gels, emulsions,
aerosols or in multiparticulate form, for example in the form of
pellets or granules, if appropriate pressed into tablets, decanted
in capsules or suspended in a liquid, and can also be administered
as such.
[0293] The pharmaceutical dosage form according to the invention is
preferably prepared with the aid of conventional means, devices,
methods and processes known in the art. The amount of the compound
according to the invention to be administered to the patient may
vary and is e.g. dependent on the patient's weight or age and also
on the type of administration, the indication and the severity of
the disorder. Preferably 0.001 to 100 mg/kg, more preferably 0.05
to 75 mg/kg, most preferably 0.05 to 50 mg of a compound according
to the invention are administered per kg of the patient's body
weight.
[0294] The glucocorticoid receptor is believed to have potential to
modify a variety of diseases or disorders in mammals such as
humans. These include in particular inflammatory diseases.
[0295] Another aspect of the invention relates to a compound
according to the invention for use in the treatment and/or
prophylaxis of pain and/or inflammation; more preferably
inflammatory pain.
[0296] A further aspect of the invention relates to a method of
treatment of pain and/or inflammation; more preferably inflammatory
pain.
[0297] The following examples further illustrate the invention but
are not to be construed as limiting its scope.
[0298] The following abbreviations are used in the descriptions of
the experiments: AcOH=acetic acid; Cbz=carboxybenzyl;
DCM=dichloromethane; DEA=diethylamine;
DIPEA=N,N-diisopropylethylamine; DMAP=4-(dimethylamino)-pyridine;
DMF=N,N-dimethylformamide; DMSO=dimethylsulfoxide; DPPA=diphenyl
phosphoryl azide; EtOAc=ethyl acetate; EtOH=ethanol;
HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxide hexafluorophosphate; h=hour; MeOH=methanol; min=minute;
sat.=saturated; RT=room temperature; R.sub.t=retention time;
tert=tertiary; TEA=triethylamine; TFA=trifluoro acetic acid;
THF=tetrahydrofuran.
Synthesis of trans-benzyl
4,4-dimethyl-(5-oxo-2-phenylpyrrolidin-3-yl)carbamate (intermediate
A1)
##STR00008##
[0300] Step 1:
[0301] A solution of benzaldehyde (95.18 g, 0.898 mol),
4-methylbenzenethiol (111.37 g, 0.898 mol), maleic anhydride (88.04
g, 0.898 mol) and 2,4-dimethoxybenzylamine (150.00 g, 0.898 mol) in
toluene (600 ml) was stirred at ambient temperature for 2 h and was
then heated to 120.degree. C. for 16 h. After completion of the
reaction (monitored by TLC, mobile phase 5% MeOH-DCM, Rf 0.4) the
reaction mixture was cooled to ambient temperature and was
concentrated under reduced pressure to obtain the crude product
which was triturated with MTBE to afford
1-(2,4-dimethoxy-benzyl)-5-oxo-2-phenyl-3-p-tolylsulfanyl-pyrrolidine-3-c-
arboxylic acid (150.0 g, 35%) as an off white solid.
[0302] Step 2:
[0303] To a suspension of
1-(2,4-dimethoxy-benzyl)-5-oxo-2-phenyl-3-p-tolylsulfanyl-pyrrolidine-3-c-
arboxylic acid (500.0 g, 1.05 mol) in acetone (5 L) was added
K.sub.2CO.sub.3 (579.0 g, 4.19 mol) followed by methyl iodide
(261.0 ml, 4.19 mol). The resulting suspension was stirred at
ambient temperature for 16 h. The reaction mixture was then
filtered and the filtrate was concentrated. The residue was taken
up in EtOAc (1.5 L) and was washed with water. The organic layer
was washed with brine, dried over sodium sulfate and was
concentrated under reduced pressure to afford
1-(2,4-dimethoxy-benzyl)-5-oxo-2-phenyl-3-p-tolylsulfanyl-pyrrolidine-3-c-
arboxylic acid methyl ester (480.0 g, 94%) as an off white
solid.
[0304] Step 3:
[0305] To a solution of
1-(2,4-dimethoxy-benzyl)-5-oxo-2-phenyl-3-p-tolylsulfanyl-pyrrolidine-3-c-
arboxylic acid methyl ester (50.0 g, 0.101 mol) in DMF (0.5 L) was
added sodium hydride (50% in mineral oil, 24.4 g, 0.509 mol) at
0.degree. C. The resulting reaction mixture was stirred at
0.degree. C. for 30 minutes. After 30 minutes, methyl iodide (31.7
ml, 0.509 mol) was added slowly. The resulting reaction mixture was
then stirred for 30 min at 0.degree. C. After completion of the
reaction (monitored by TLC, mobile phase 30%-ethyl acetate-hexane,
Rf 0.3) the reaction was quenched with saturated ammonium chloride
solution and extracted with EtOAc (2.0 L). The combined organic
layers were dried over sodium sulfate and concentrated under
reduced pressure to obtain the crude compound, which was purified
by column chromatography (silica gel, 100-200 mesh, 10-20%
EtOAc/hexane) to afford
1-(2,4-dimethoxy-benzyl)-4,4-dimethyl-5-oxo-2-phenyl-4,5-dihydro-1H-pyrro-
le-3-carboxylic acid methyl ester (28.0 g, 70%) as a pale yellow
solid.
[0306] Step 4.
[0307] To a solution of
1-(2,4-dimethoxy-benzyl)-4,4-dimethyl-5-oxo-2-phenyl-4,5-dihydro-1H-pyrro-
le-3-carboxylic acid methyl ester (26.0 g, 0.117 mol) in methanol
(300 ml) was added 10% palladium on charcoal (50% moisture, 13.4 g,
0.063 mol) and the resulting mixture was stirred for 16 h at
ambient temperature under hydrogen pressure (balloon pressure).
After completion of the reaction (monitored by TLC, mobile phase
30%-ethyl acetate-hexane, R.sub.f 0.30) the reaction mixture was
filtered through a celite pad. The filtrate was concentrated under
reduced pressure to obtain the crude compound which was triturated
in diethyl ether to afford
1-(2,4-dimethoxy-benzyl)-4,4-dimethyl-5-oxo-2-phenyl-pyrrolidine-3-carbox-
ylic acid methyl ester (25.0 g, 96%).
[0308] Step 5:
[0309] A stirred suspension of
1-(2,4-dimethoxy-benzyl)-4,4-dimethyl-5-oxo-2-phenyl-pyrrolidine-3-carbox-
ylic acid methyl ester (25.0 g, 0.063 mol) in TFA (250 ml) was
heated to 90.degree. C. for 16 h. After completion of the reaction
(monitored by TLC, 50% ethyl ether-hexane, R.sub.f-0.3) the
reaction was cooled to ambient temperature and was concentrated
under reduced pressure. The remains were basified with sat.
NaHCO.sub.3 solution, followed by the addition of EtOAc (1 L) and
stirring of the resulting mixture for 30 minutes. The obtained
solid was filtered off and dried under high vacuum to afford
4,4-dimethyl-5-oxo-2-phenyl-pyrrolidine-3-carboxylic acid methyl
ester (18.0 g, crude) which was used in the next step.
[0310] Step 6.
[0311] To a suspension of
4,4-dimethyl-5-oxo-2-phenyl-pyrrolidine-3-carboxylic acid methyl
ester (43.0 g, 0.174 mmol) in MeOH (400 ml) was added 2 M NaOH (174
ml) at 0.degree. C. The resulting suspension was stirred at
100.degree. C. for 4 h. After consumption of the starting material
(monitored by TLC, mobile phase 5% MeOH/DCM, Rf 0.2) the reaction
mixture was concentrated and the residue was diluted with water and
was washed with ethyl acetate (2.times.75 ml). The aqueous layer
was then acidified to pH 3 with 6N HCl and was extracted with 10%
MeOH/DCM (2.times.75 ml). The combined organic layers were dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to afford
trans-4,4-dimethyl-5-oxo-2-phenyl-pyrrolidine-3-carboxylic acid
(22.0 g, 55.0%) as a brown solid.
[0312] Step 7.
[0313] To a stirred solution of
trans-4,4-dimethyl-5-oxo-2-phenyl-pyrrolidine-3-carboxylic acid
(22.0 g, 0.095 mol) in benzene-THF (4:1, 125 ml) was added DPPA
(25.0 ml, 0.114 mol) followed by TEA (13.35 ml, 0.095 mol) at
ambient temperature and the mixture was stirred for 2 h. Benzyl
alcohol (14.8 ml, 0.142 mol) was then added and the reaction
mixture was heated to 90.degree. C. for 4 h. After completion of
the reaction (monitored by TLC) the reaction mixtire was diluted
with water (10 ml) and extracted with ethyl acetate (3.times.100
ml). The combined organic layers were washed with 10% citric acid
solution (100 ml) followed by saturated NaHCO.sub.3 solution
(2.times.100 ml) and were then dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was triturated with diethyl ether (2.times.80 ml). The
obtained solid was filtered off and was dried under high vacuum to
afford intermediate A1 (25.0 g, 78%) as an off white solid.
Synthesis of
N-((trans)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxa-
mide (intermediate A2)
##STR00009##
[0315] Step 1:
[0316] To a stirred solution of intermediate A1 (5.0 g, 14.775
mmol, 1.0 eq.) in methanol:THF (80 mL, 2:1), Pd/C (10.0 g, 10%,
moist) was added and the reaction was stirred under a hydrogen
balloon for 2 h at ambient temperature. After completion,
(monitored by TLC, TLC system 5% methanol in DCM, Rf-0.2) the
reaction mixture was filtered through a celite pad which was then
washed 2-3 times with THF. The filtrate was concentrated to obtain
(trans)-4-amino-3,3-dimethyl-5-phenylpyrrolidin-2-one as a brown
gum (3.0 g, 99%).
[0317] Step 2:
[0318] To a stirred solution of cyclopropanecarboxylic acid (0.253
g, 2.941 mmol, 1.2 eq) in DMF (10 mL), HATU (1.86 g, 4.90 mmol, 2.0
eq), DIPEA (2.0 ml 12.25 mmol, 5.0 eq) and
(trans)-4-amino-3,3-dimethyl-5-phenylpyrrolidin-2-one (0.50 g, 2.45
mmol, 1.0 eq) were added at 0.degree. C. and the reaction was
stirred at ambient temperature for 16 h. After completion of the
reaction (monitored by TLC, TLC system 5% methanol in DCM, Rf-0.3)
the reaction mixture was diluted with EtOAc (50 mL), washed with
ice cold water (3.times.25 mL), dried over Na.sub.2SO.sub.4 and
concentrated to obtain a residue which was purified via column
chromatography (230-400 mesh silica gel; 0 to 2% MeOH-DCM) to
afford intermediate A2 (0.46 g, 70%).
Synthesis of
N-((trans)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-2,2-difluoropropan-
amide (intermediate A3)
##STR00010##
[0320] Step 1:
[0321] To a stirred solution of 2,2-difluoropropanoic acid (0.647
g, 5.88 mmol, 1.2 eq) in DMF (15 mL), HATU (3.72 g, 9.80 mmol, 2.0
eq), DIPEA (4.0 ml 24.50 mmol, 5.0 eq), and
(trans)-4-amino-3,3-dimethyl-5-phenylpyrrolidin-2-one (1.0 g, 4.90
mmol, 1.0 eq) were added at 0.degree. C. and the reaction was
stirred at ambient temperature for 16 h. After completion of the
reaction (monitored by TLC, TLC system 5% methanol in DCM, Rf-0.3)
the reaction mixture was diluted with ethyl acetate (50 mL), washed
with ice cold water (3.times.25 mL), dried over Na.sub.2SO.sub.4
and concentrated to obtain a residue which was purified by column
chromatography (230-400 mesh silica gel; 0 to 2% MeOH-DCM) to
afford intermediate A3 (0.93 g, 64%).
Synthesis of
5-(5-((4S,5R)-4-amino-3,3-dimethyl-2-oxo-5-phenylpyrrolidin-1-yl)-1H-inda-
zol-1-yl)-1-methylpyridin-2(1H)-one (intermediate A4-ent1) and
5-(5-((4R,5S)-4-amino-3,3-dimethyl-2-oxo-5-phenylpyrrolidin-1-yl)-1H-inda-
zol-1-yl)-1-methylpyridin-2(1H)-one (intermediate A4-ent 2)
##STR00011##
[0323] Step 1:
[0324] To a stirred solution of trans-benzyl
4,4-dimethyl-(5-oxo-2-phenylpyrrolidin-3-yl)carbamate (2.0 g, 5.91
mmol) in 1,4-dioxane (80 ml) in a sealed tube was added
5-(5-iodo-indazol-1-yl)-1-methyl-1H-pyridin-2-one (2.28 g, 6.5
mmol) followed by potassium phosphate (2.51 g, 11.83 mmol). The
mixture was degassed under argon atmosphere for 30 minutes.
Trans-N,N'-dimethyl cyclohexane-1,2-diamine (0.37 ml, 2.36 mmol)
and CuI (225 mg, 1.18 mmol) were added and the mixture was heated
to 90.degree. C. for 16 h. After completion of the reaction
(monitored by LCMS) the reaction mixture was filtered through a
celite bed and the celite bed was washed with 1,4-dioxane (100 ml).
The filtrate was then concentrated under reduced pressure. The
reaction was carried out in parallel in four batches (2.0 g each)
and the remains of all batches were purified together by column
chromatography (silica gel, 100-200 mesh, 1-2% MeOH/DCM) to afford
benzyl
((trans)-4,4-dimethyl-1-(1-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-in-
dazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)-carbamate (12.8 g, 48%)
as a pale yellow solid.
[0325] Step 2:
[0326] A stirred suspension of benzyl
((trans)-4,4-dimethyl-1-(1-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-in-
dazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)-carbamate (3.0 g, 5.35
mmol) in TFA (30 ml) was heated to 90.degree. C. for 3 h. After
completion of the reaction (monitored by LCMS, 5% MeOH in DCM), the
reaction mixture was cooled to ambient temperature and was
concentrated under reduced pressure. The remains were then
azeotroped with toluene (2.times.50 ml). The resulting residue was
basified with saturated NaHCO.sub.3 solution and the mixture was
extracted with 5% MeOH/DCM (2.times.150 ml). The combined organic
layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to obtain the crude compound.
This reaction was conducted in parallel in four batches (3.0 g
each) and the combined crude compound was purified by column
chromatography (100-200 Silica gel, 1.5-2% MeOH/DCM as eluent) to
afford
5-(5-((trans)-4-amino-3,3-dimethyl-2-oxo-5-phenylpyrrolidin-1-yl)-1H-inda-
zol-1-yl)-1-methylpyridin-2(1H)-one (7.0 .mu.g, 76%) as a grey
solid.
[0327] Chiral separation (Chiralpak IC (21.0.times.250 mm), 5
.mu.m, mobile phase DCM:EtOH 50:50, flow rate 18.0 mL/min) of the
racemic compound (7.0 g) in normal phase afforded (intermediate
A4-ent1, retention time 5.56 minutes) and (intermediate A4-ent2,
retention time 6.41 minutes).
Synthesis of
N-[rac-((6R,7S)-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl)]cyclopropaneca-
rboxamide (intermediate A5)
##STR00012## ##STR00013##
[0329] Step 1:
[0330] To a stirred solution of
(2,4-dimethoxy-benzyl)-5-oxo-2-phenyl-3-p-tolylsulfanyl-pyrrolidine-3-car-
boxylicacid methyl ester (56.0 g 152.42 mmol) in DMF (560 ml) was
slowly added NaH (18.3 g, 60% dispersion in mineral oil, 457.24
mmol) followed by 1,2-dibromoethane (17.13 ml, 198.14 mmol) at
0.degree. C. The resulting reaction mixture was stirred at
0.degree. C. for 3 h. After completion of the reaction (monitored
by TLC, mobile phase 20%-ethyl acetate-hexane, R.sub.f 0.4) the
reaction mixture was poured into a cold saturated solution of
NH.sub.4Cl. The mixture was then extracted with EtOAc (2.times.1
L). The combined organic layers were washed with brine, dried over
sodium sulfate and concentrated under reduced pressure to obtain
the crude compound which was purified by column chromatography
(100-200 mesh silica gel, 10% ethyl acetate-hexane as eluent) to
afford methyl
5-(2,4-dimethoxybenzyl)-4-oxo-6-phenyl-5-azaspiro[2.4]hept-6-ene-7-
-carboxylate (34.0 g, 57%) as an off-white solid.
[0331] Step 2:
[0332] To a stirred solution of methyl
5-(2,4-dimethoxybenzyl)-4-oxo-6-phenyl-5-azaspiro[2.4]hept-6-ene-7-carbox-
ylate (7.5 g, 19.08 mmol) in MeOH (125 ml) was added 10% Pd/C (3.0
g, 50% moist) and a catalytic amount of AcOH. The reaction mixture
was stirred under hydrogen pressure (using a balloon) until
consumption of starting material (monitored by LCMS) was achieved.
The reaction was carried out in parallel in two batches, which were
united for workup. The combined reaction mixture was filtered
through a celite bed, which was washed with MeOH (75 ml). The
filtrate was then concentrated to afford crude
5-(2,4-dimethoxybenzyl)-4-oxo-6-phenyl-5-aza-spiro[2.4]heptane-7-carboxyl-
ic acid methyl ester (12.0 g), which was used in next step without
further purification.
[0333] Step 3:
[0334] A stirred suspension of
5-(2,4-dimethoxybenzyl)-4-oxo-6-phenyl-5-aza-spiro[2.4]heptane-7-carboxyl-
ic acid methyl ester (16.0 g, 40.5 mmol) in TFA (80 ml) was heated
to 50.degree. C. for 14 h. After completion of the reaction
(monitored by LCMS) the reaction mixture was cooled to ambient
temperature and was concentrated under reduced pressure. The
remains were azeotroped with toluene, were then basified with
NaHCO.sub.3 solution followed by extraction with ethyl acetate
(2.times.125 ml). The combined organic layers were dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure to afford
4-oxo-6-phenyl-5-aza-spiro[2.4]heptane-7-carboxylic acid methyl
ester (9.0 g crude) as a brown solid.
[0335] Step 4:
[0336] To a suspension of
4-oxo-6-phenyl-5-aza-spiro[2.4]heptane-7-carboxylic acid methyl
ester (9.0 g crude) in MeOH (90 ml) was added 2 M NaOH (60 ml, 3.0
eq.) at 10.degree. C. The resulting suspension was then stirred at
100.degree. C. for 4 h. After completion of the reaction (monitored
by TLC, mobile phase 50% EtOAc-hexane, R.sub.f 0.1) the reaction
mixture was concentrated. The residue was diluted with water and
washed with EtOAc. The basic aqueous layer was acidified to pH 2-3
with 6N HCl and was then extracted with 10% MeOH/DCM (3.times.60
ml). The combined organic layers were dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to afford trans-4-oxo-6-phenyl-5-azaspiro[2.4]heptane-7-carboxylic
acid (40 g, 32% over 3 steps) as a brown solid.
[0337] Step 5:
[0338] To a stirred solution of
trans-4-oxo-6-phenyl-5-azaspiro[2.4]heptane-7-carboxylic acid (5.0
g, 21.6 mmol) in benzene-THF (4:1, 80 ml) and DPPA (5.6 ml, 25.9
mmol) was added TEA (3 ml, 21.6 mmol) at ambient temperature. The
resulting reaction mixture was stirred at ambient temperature for 2
h followed by the addition of benzyl alcohol (3.4 ml, 32.4 mmol)
and heating to 90.degree. C. for 4 h. After completion of the
reaction (monitored by TLC, mobile phase 5% MeOH in DCM,
R.sub.f0.4) the reaction mixture was diluted with water and
extracted with ethyl acetate (3.times.20 ml). The combined organic
layers were washed with a 10% citric acid solution, then sat.
NaHCO.sub.3, dried over anhydrous Na.sub.2SO.sub.4 and concentrated
under reduced pressure. The obtained residue was triturated with
10% DCM-Hexane followed by MTBE (25 ml). The obtained solid was
filtered off and dried to afford 6.5 g of the crude compound, which
was purified by prep HPLC to afford
N-(trans-4-oxo-6-phenyl-5-aza-spiro[2.4]hept-7-yl)carbamic acid
benzyl ester (1.16 g, 16%) as an off white solid
[0339] Step 6:
[0340] To a stirred solution of
N-(trans-4-oxo-6-phenyl-5-aza-spiro[2.4]hept-7-yl)carbamic acid
benzyl ester (3.2 g, 9.52 mmol) in MeOH (300 ml) was added 10% Pd/C
(1.7 g, 50% moist) and the reaction mixture was stirred at ambient
temperature under a hydrogen atmosphere using a balloon. After
completion of the reaction (monitored by TLC, mobile phase 10%
MeOH/DCM, R.sub.f 0.2) the reaction mixture was filtered through a
celite bed, which was then washed with MeOH (50 ml.times.2). The
filtrate was concentrated under reduced pressure. The resulting
residue was triturated with diethyl ether (5 ml) to afford crude
trans-7-amino-6-phenyl-5-azaspiro[2.4]heptan-4-one (1.6 g), which
was used without further purification in the next step.
[0341] Step 7:
[0342] To a stirred suspension of
trans-7-amino-6-phenyl-5-azaspiro[2.4]heptan-4-one (1.1 g, 5.44
mmol) in DCM (25 ml) was added TEA (1.3 ml, 1.7 eq.) followed by
the addition of cyclopropanecarbonyl chloride (0.65 ml, 1.3 eq.) at
0.degree. C. The resulting reaction mixture was then stirred for 1
h at the same temperature. After completion of the reaction
(monitored by TLC, mobile phase 5% MeOH/DCM) the reaction mixture
was concentrated and diluted with water. The resulting mixture was
stirred for 30 min at ambient temperature, causing precipitation of
a white solid. The solid was filtered off and was washed with
diethyl ether (10 ml.times.2) and was dried to afford crude
N-(trans-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl)cyclopropanecarboxamid-
e (1.2 g). The reaction was conducted in parallel in two batches.
The obtained solid from both batches batches were mixed together
and were purified by reverse phase prep HPLC to afford intermediate
A5 (436.9 mg, 13%) as an off white solid.
Synthesis of benzyl
(trans-2-methyl-5-oxo-2-phenylpyrrolidin-3-yl)carbamate
(intermediate A6)
##STR00014##
[0344] Step 1:
[0345] To a stirred solution of acetophenone (5 g, 41.614 mmol, 1.0
eq) in EtOH (50 mL) and Hydroxylamine hydrochloride (8.68 g,
124.844 mmol, 3.0 eq), sodium acetate (17.07 g, 208.07 mmol, 5 eq)
was added and the mixture was heated to reflux for 12 h. After
completion (monitored by TLC) the reaction mixture was evaporated
to remove EtOH and diluted with EtOAc (2.times.300 mL) and water
(300 mL). The extracted organic layer was washed with brine (300
mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under
reduced pressure to get crude product. The crude product was
purified by column chromatography (230-400 mesh silica gel, TLC
system: EtOAc/hexane (2:8); R.sub.f=0.3) to give
(E)-1-phenylethan-1-one oxime (4.73 g, 84%).
[0346] Step 2:
[0347] To a stirred solution of (E)-1-phenylethan-1-one oxime (5 g,
36.993 mmol, 1 eq) in DCM (50 mL), TEA (5.7 mL, 40.692 mmol, 1.2
eq) followed by chlorodiphenylphosphane (7.3 mL, 40.692 mmol, 1.1
eq) was added at -40.degree. C. The reaction mixture was then
stirred at RT for 16 h. After completion of reaction (monitored by
TLC, 50% EtOAc in hexane, R.sub.f=0.3), reaction mixture was
quenched with ice and extracted with EtOAc. The organic layer was
washed with water (200 mL), brine (200 mL), dried over
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
get the crude product which was purified by column chromatography
using 230-400 silica gel and 30 to 50% EtOAc in hexane to afford
(E)-P,P-diphenyl-N-(1-phenylethylidene)phosphinic amide (10.1 g,
86%) as brown gum.
[0348] Step 3:
[0349] To a stirred solution of
(E)-P,P-diphenyl-N-(1-phenylethylidene)phosphinic amide (5 g,
15.657 mmol, 1 eq) in THF (75 mL), 1,4-diethyl (2E)-but-2-enedioate
(6.75 g, 39.143 mmol, 2.5 eq), Cu(OAc) (285 mg, 1.5657 mmol, 0.1
eq), PPh.sub.3 (410 mg, 1.5657 mmol, 0.1 eq) were added at RT and
the mixture was stirred at RT for 20 min. Then pinacolborane (5.62
g, 43.839 mmol, 2.8 eq) was added at RT and the reaction mixture
was stirred at RT for 48 h. After completion of reaction (monitored
by TLC, 50% EtOAc in hexane, R.sub.f=0.4), reaction mixture was
diluted with EtOAc, washed with water (100 mL) and brine (100 mL),
dried over Na.sub.2SO.sub.4 and concentrated to get the crude
product which was purified by column chromatography using 230-400
silica gel and 20-40% EtOAc in hexane to afford pure desired ethyl
1-(diphenylphosphoryl)-2-methyl-5-oxo-2-phenylpyrrolidine-3-carboxylate
(4 g, 57%).
[0350] Step 4:
[0351] To a solution of ethyl
1-(diphenylphosphoryl)-2-methyl-5-oxo-2-phenylpyrrolidine-3-carboxylate
(5 g, 11.174 mmol, 1 eq) in EtOH (50 mL), concentrated HCl (6 ml)
was added at RT. The mixture was stirred at 90.degree. C. for 16 h.
After completion of reaction (monitored by TLC, 50% EtOAc in
Hexane, R.sub.f=0.6), reaction mixture was evaporated under reduced
pressure, neutralized with saturated sodium bicarbonate solution,
extracted with EtOAc, dried over Na.sub.2SO.sub.4 and concentrated
to afford ethyl 2-methyl-5-oxo-2-phenylpyrrolidine-3-carboxylate
(1.1 g, 40%) as off white solid.
[0352] Step 5:
[0353] To a solution of ethyl
2-methyl-5-oxo-2-phenylpyrrolidine-3-carboxylate (4 g, 16.1753
mmol, 1 eq) in THF:H.sub.2O (3:1) (80 mL), LiOH.H.sub.2O (1.36 g,
32.351 mmol, 2 eq) was added at RT. The reaction mixture was
stirred at RT for 16 h. After completion of reaction (monitored by
TLC, 5% MeOH in DCM, R.sub.f=0.1), organic solvent was evaporated
under reduced pressure, dissolved in water and washed with ether
and acidified with HCl. A solid precipitate was formed, filtered,
washed with water and hexane, dried over rotary evaporator to
afford 2-methyl-5-oxo-2-phenylpyrrolidine-3-carboxylic acid (3 g,
85%) as white solid.
[0354] Step 6:
[0355] To a stirred solution of
2-methyl-5-oxo-2-phenylpyrrolidine-3-carboxylic acid (3 g, 13.684
mmol, 1.0 eq) in toluene (60 mL) was added TEA (2 mL, 14.368 mmol,
1.05 eq) and DPPA (4.5 g, 16.4203 mmol, 1.2 eq) and the reaction
mixture was stirred at 90.degree. C. for 30 min. Then benzyl
alcohol (2.8 g, 27.3672 mmol, 2.0 eq) was added to the reaction
mixture and the mixture was heated to reflux for 16 h. After
completion (monitored by TLC, TLC system 5% MeOH in DCM,
R.sub.f-0.3), reaction mixture was concentrated under reduced
pressure and diluted with EtOAc (100 mL), washed with water
(2.times.100 mL), dried over anh. Na.sub.2SO.sub.4 and concentrated
under reduced pressure to get the crude product which was purified
by column chromatography (230-400 mesh silica gel; 0-3% MeOH in
DCM) to afford benzyl
(trans-2-methyl-5-oxo-2-phenylpyrrolidin-3-yl)carbamate (1.8 g,
41%).
Synthesis of
(4S,5R)-4-amino-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3,3-dimethyl-5-phe-
nylpyrrolidin-2-one (intermediate A7-ent1) and
(4R,5S)-4-amino-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3,3-dimethyl-5-phe-
nylpyrrolidin-2-one (intermediate A7-ent 2)
##STR00015##
[0357] Step 1:
[0358] To a stirred solution of benzyl
(trans-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)carbamate (2.0 g,
5.91 mmol) in 1,4-dioxane (100 mL) in a sealed tube was added
1-(4-Fluoro-phenyl)-5-iodo-1H-indazole (2.4 g, 7.10 mmol) followed
by potassium phosphate (2.51 g, 11.83 mmol) and the mixture was
degassed using argon for 30 minutes. Then, trans-N,N'-dimethyl
cyclohexane-1,2-diamine (0.4 ml, 2.37 mmol) and copper(I)iodide
(225 mg, 1.18 mmol) were added and the mixture was heated to
100-110.degree. C. for 16 h. After completion of the reaction
(monitored by LCMS, 5% MeOH in DCM), the reaction mixture was
filtered through a celite bed and the celite bed was washed with
1,4-dioxane (100 mL), the filtrate was then concentrated under
reduced pressure. The reaction was carried out in 10 batches in
parallel (2 g each). The combined crude material was purified by
column chromatography (silica gel, 100-200 mesh, 2-2.5% MeOH/DCM)
to afford benzyl
(trans-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenyl-
pyrrolidin-3-yl)carbamate (14.5 g, 45%) as a pale yellow solid.
[0359] Step 2:
[0360] To a stirred solution of benzyl
(trans-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenyl-
pyrrolidin-3-yl)carbamate (4.0 g, 7.68 mmol) in THF/MeOH (500 mL,
1:1) was added 10% Pd/C (50% moist, 2.0 g) and the resulting
mixture was stirred at ambient temperature under H.sub.2 balloon
pressure until completion of the reaction (monitored by TLC, 5%
MeOH in DCM). The reaction mixture was then filtered through celite
and the celite bed was washed with THF. The filtrate was then
concentrated under reduced pressure. The reaction was carried out
in four batches in parallel (4 g each) and the combined crude
material was purified by column chromatography (silica gel, 100-200
mesh, 1.5-2.% MeOH/DCM as eluent) to afford
trans-4-amino-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3,3-dimethyl-5-pheny-
lpyrrolidin-2-one (7.1 g, 56%) as an off-white solid.
[0361] Chiral separation (Chiralpak IC (21.0.times.250 mm), 5
.mu.m, mobile phase n-hexane/EtOAc/EtOH/isopropylamine
70/15/15/0.1, flow rate 21.0 mL/min) of the racemic compound (7.1
g) in normal phase afforded (intermediate A7-ent1, retention time
6.10 minutes) and (intermediate A7-ent2, retention time 7.30
minutes).
Synthesis of methyl 2-methyl-3-nitropropanoate
##STR00016##
[0363] Step 1: Preparation of 3-Nitro-propionic acid methyl ester:
To a stirred solution of 3-Bromo-propionic acid methyl ester (200
g, 1.19 mol) in DMSO (3 l) was added NaNO.sub.2 (120.6 g, 1.74 mol)
portion wise at 0.degree. C. The resulting solution was stirred at
room temperature for 24 h. After the reaction was judged to be
complete, the mixture was was diluted with cold brine (1.5 L) and
extracted with MTBE (3.times.1500 ml). The combined organics were
washed with cold water (500 ml.times.2), followed by brine (500
ml), dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure (bath temp at 30 C) to afford crude 3-Nitro-propionic acid
methyl ester. The crude material was purified by column
chromatography (using silica gel 100-200 mesh, 10% EA-Hexane as
eluent). An oil was obtained, which was further distilled under
reduced pressure (120.degree. C., 0.1-0.5 mm Hg) to afford
3-Nitro-propionic acid methyl ester (45 g, 28%) as light yellow
oil.
[0364] Step 2:
[0365] methyl 2-methyl-3-nitropropanoate: To a stirred solution of
3-nitro-propionic acid methyl ester (25 g, 187.97 mmol) in THF (400
ml) was added LDA (2M in THF, 188 ml, 376 mmol 2.0 eq) at
-78.degree. C. and stirred for 30 min at the same temperature. Mel
(23.4 ml, 375.93 mmol, 2.0 eq.) was added at -78.degree. C. The
reaction mixture was gradually warmed up to 25.degree. C. and
stirring was continued for 16 h. The reaction mixture was quenched
with aqueous NH.sub.4Cl at 0.degree. C. The layers were separated
and the aqueous part was extracted with ethyl acetate (600
ml.times.3). The combined organic layers were washed with brine
(300 ml), dried over Na.sub.2SO.sub.4 and concentrated. Crude was
purified by column chromatography (using 100-200 silica gel, 5-10%
Ethyl acetate-Hexane as eluent) to afford methyl
2-methyl-3-nitropropanoate (10 g, 36%).
Synthesis of intermediate A8
(benzyl(rac-(2R,3S,4S)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)carbamate)
##STR00017##
[0367] Step 1:
[0368] Synthesis of
rac-(3S,4S,5R)-1-(4-methoxybenzyl)-3-methyl-4-nitro-5-phenylpyrrolidin-2--
one: To a stirred solution of benzaldehyde (10.82 g, 102.04 mmol)
in toluene (100 ml) was added 4-methoxy benzylamine (13.99 g,
102.04 mmol) at rt and stirred for 2 h at rt. To this reaction
mixture was added methyl 2-methyl-3-nitropropanoate (10 g, 68.03
mmol) followed by benzoic acid (12.46 g, 102.04 mmol) and stirring
was continued for 16 h at 70.degree. C. After completion of
reaction (monitored by LCMS), the reaction mixture was diluted with
ethyl acetate (400 ml) and washed with water (100 ml.times.2),
followed by sat.NaHCO.sub.3 (100 ml.times.2). The organic layer was
dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude
product was purified through column chromatography (using silica
gel 100-200 mesh; 25-30% ethyl acetate in hexane as eluent) to
afford
rac-(3S,4S,5R)-1-(4-methoxybenzyl)-3-methyl-4-nitro-5-phenylpyrrol-
idin-2-one (10 g, 43%) as brownish solid.
[0369] Step 2:
[0370] Synthesis of
rac-(3S,4S,5R)-3-methyl-4-nitro-5-phenylpyrrolidin-2-one. To a
stirred solution of
rac-(3S,4S,5R)-1-(4-methoxybenzyl)-3-methyl-4-nitro-5-phenylpyrrolidin-2--
one (10 g, 29.41 mmol) in acetonitrile (100 ml) was added a
solution of CAN (48.37 g, 88.24 mmol) in water (100 ml) dropwise at
0.degree. C. The reaction mixture was slowly warmed to 15.degree.
C. and stirring was continued for 3-4 h. After completion
(monitored by TLC, 50% ethyl acetate/hexane, R.sub.f0.2), the
reaction mixture was diluted with ethyl acetate (500 ml) and washed
with water (100 ml.times.2) followed by brine (250 ml). The organic
layer was dried over Na.sub.2SO.sub.4 and concentrated. The crude
material was purified by column chromatography (using silica gel
100-200 mesh; 40-50% ethyl acetate in hexane as eluent) to afford
of rac-(3S,4S,5R)-3-methyl-4-nitro-5-phenylpyrrolidin-2-one (4.00
g, 62%) as light yellow solid.
[0371] Step 3:
[0372] Synthesis of
rac-(3S,4S,5R)-4-amino-3-methyl-5-phenylpyrrolidin-2-one: To a
stirred solution of of
rac-(3S,4S,5R)-3-methyl-4-nitro-5-phenylpyrrolidin-2-one (4.5 g,
20.45 mmol) in EtOAc-MeOH (2:1, 450 ml) was added 6 M aq. HC (102.2
ml) at 0.degree. C. To this reaction mixture was added Zn dust
(80.25 g, 1.227 mol) portionwise at the same temperature. The
resulting suspension was stirred at room temperature for 16 h.
After completion of reaction (monitorrd by LCMS), the reaction
mixture was quenched with saturated NaHCO.sub.3 solution at
0.degree. C., stirred for 1 h, filtered over celite and washed with
EtOAc-MeOH (500 ml, 2:1). The filtrate was concentrated to afford
rac-(3S,4S,5R)-4-amino-3-methyl-5-phenylpyrrolidin-2-one (3.9 g
crude, considered as 100% yield) which was used without further
purification.
[0373] Step 4:
[0374] To a stirred suspension of
rac-(3S,4S,5R)-4-amino-3-methyl-5-phenylpyrrolidin-2-one (3.9 g
crude, 20.45 mmol) in THF:Water (1:1, 225 ml) was added sodium
bicarbonate (9.95 g, 118.42 mmol) at 0.degree. C. and stirred for
30 minutes. Benzyl chloroformate (11.8 ml, 35.53 mmol, 50% in
toluene) was added to the reaction mixture at 0.degree. C. and
stirring was continued for 16 h at rt. After completion (monitored
by LCMS), the reaction mixture was diluted with water (300 ml) and
extracted with ethyl acetate (3.times.500 ml). The combined
organics were washed with water (200 ml.times.2) followed by brine
(200 ml) and dried over Na.sub.2SO.sub.4. After removal of the
solvent, the crude material was purified by column chromatography
(using silica gel 100-200 mesh; 2-2.5% MeOH in DCM as eluent) to
afford intermediate A8 benzyl
(rac-(2R,3S,4S)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)carbamate
(3.5 g, 53% in two steps).
Synthesis of intermediate A10-trans (benzyl
(rac(2R,3S,4S)-4-methyl-5-oxo-2-(m-tolyl)pyrrolidin-3-yl)carbamate)
and intermediate A10-cis (benzyl
(rac(2S,3S,4S)-4-methyl-5-oxo-2-(m-tolyl)pyrrolidin-3-yl)carbamate)
##STR00018##
[0376] Step 1:
[0377] Synthesis of
rac-(4S,5R)-1-(4-methoxybenzyl)-3-methyl-4-nitro-5-(m-tolyl)pyrrolidin-2--
one: To a stirred solution of 3-methyl-benzaldehyde (11.02 g, 91.75
mmol) in toluene (90 ml) was added 4-methoxy benzylamine (12.58 g,
91.75 mmol) at rt and stirred for 2 h. To this reaction mixture was
added methyl 2-methyl-3-nitropropanoate (9.00 g, 61.27 mmol)
followed by benzoic acid (11.2 g, 91.75 mmol) and stirred for 16 h
at 70.degree. C. After completion of reaction (monitored by LCMS),
the reaction mixture was diluted with ethyl acetate (500 ml) and
washed with water (200 ml.times.2), followed by sat.NaHCO.sub.3
(150 ml.times.2). The organic layer was dried over anhydrous
Na.sub.2SO.sub.4 and concentrated to give
rac-(4S,5R)-1-(4-methoxybenzyl)-3-methyl-4-nitro-5-(m-tolyl)pyrrolidin-2--
one (7.1 g, 32.7%) as brown resin.
[0378] Step 2.
[0379] Synthesis of
rac-(4S,5R)-3-methyl-4-nitro-5-(m-tolyl)pyrrolidin-2-one: To a
stirred solution of
rac-(4S,5R)-1-(4-methoxybenzyl)-3-methyl-4-nitro-5-(m-tolyl)pyrrolidin-2--
one (4 g, 11.28 mmol) in acetonitrile (42 ml) was added a solution
of CAN (18.56 g, 33.86 mmol) in water (42 ml) dropwise at 0.degree.
C. Reaction mixture was slowly warmed to 15.degree. C. and
continued stirring was continued for 3-4 h. After completion
(monitored by LCMS), the reaction mixture was diluted with ethyl
acetate (300 ml) and washed with water (100 ml.times.2) followed by
brine (200 ml). The organic layer was dried over Na.sub.2SO.sub.4
and concentrated. The crude material was purified by column
chromatography (using silica gel 100-200 mesh; 1-1.5% MeOH in DCM))
to afford rac-(4S,5R)-3-methyl-4-nitro-5-(m-tolyl)pyrrolidin-2-one
(1.5 g, 56.8%) as off white solid.
[0380] Step 3.
[0381] Synthesis of
rac-(4S,5R)-4-amino-3-methyl-5-(m-tolyl)pyrrolidin-2-one: To a
stirred solution of
rac-(4S,5R)-3-methyl-4-nitro-5-(m-tolyl)pyrrolidin-2-one (1.5 g,
6.37 mmol) in EtOAc-MeOH (2:1, 136 ml) was added 6N aq. HCl (34 ml)
at 0.degree. C. To this reaction mixture was added Zn dust (25.01
g, 382.55 mmol) in small portions the same temperature. The
resulting suspension was stirred at room temperature for 16 h.
After completion of the reaction (monitored by LCMS), the reaction
mixture was quenched with saturated NaHCO.sub.3 solution (until
basic reaction) at 0.degree. C., stirred for 1 h, filtered over
celite and washed with EtOAc:MeOH (250 ml, 2:1). The filtrate was
concentrated to afford
rac-(4S,5R)-4-amino-3-methyl-5-(m-tolyl)pyrrolidin-2-one (1.3 g
crude, considered as 100% yield).
[0382] Step 4.
[0383] Synthesis of intermediate A10-trans and A10-cis a. To a
stirred suspension of
rac-(4S,5R)-4-amino-3-methyl-5-(m-tolyl)pyrrolidin-2-one (1.3 g
crude, 6.37 mmol) in THF-Water (1:1, 160 ml) was added sodium
bicarbonate (2.67 g, 31.89 mmol) at 0.degree. C. and stirred for 30
minutes. To this reaction mixture was added Benzyl chloroformate
(50% in toluene, 3.7 ml) at 0.degree. C. and stirred at rt for 16
h. After completion (monitored by LCMS), the reaction mixture was
diluted with water (75 ml) and extracted with ethyl acetate
(3.times.75 ml). Combined organics were washed with water (50
ml.times.2) followed by brine (50 ml.times.2), dried over
Na.sub.2SO.sub.4 and concentrated. The crude material was mixed
with another batch of the same size and was purified by column
chromatography (using silica gel 100-200 mesh; 1-2% MeOH in DCM as
eluent) to afford intermediate A10-trans (benzyl
(rac-(2R,3S,4S)-4-methyl-5-oxo-2-(m-tolyl)pyrrolidin-3-yl)carbamate,
1.39 g, 20.8% in two steps) and an impure fraction contain which
was further purified by prep HPLC to afford intermediate A10-cis
(benzyl
(rac-(2R,3S,4S)-4-methyl-5-oxo-2-(m-tolyl)pyrrolidin-3-yl)carbamate_690
mg, 10.3% in two steps).
Synthesis of intermediate A12-trans benzyl
(rac-(2R,3S,4S)-2-(2-chlorophenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamat-
e and intermediate A12-cis benzyl
(rac-(2S,3S,4S)-2-(2-chlorophenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamat-
e
##STR00019##
[0385] Step 1:
[0386] Synthesis of
rac-(4S,5R)-5-(2-chlorophenyl)-1-(4-methoxybenzyl)-3-methyl-4-nitropyrrol-
idin-2-one. To a stirred solution of 2-Chloro-benzaldehyde (11.46
g, 81.56 mmol) in Toluene (80 ml) was added 4-methoxy benzylamine
(11.2 g, 81.56 mmol) at rt and stirred for 2 h. To this reaction
mixture was added methyl 2-methyl-3-nitropropanoate (8 g, 54.37
mmol) followed by benzoic acid (9.96 g, 81.56 mmol) and stirred for
16 h at 70.degree. C. After completion of reaction (monitored by
LCMS), the reaction mixture was diluted with ethyl acetate (500 ml)
and washed with water (150 ml.times.2), followed by sat. aq.
NaHCO.sub.3 (150 ml.times.2). The organic layer was dried over
anhydrous Na.sub.2SO.sub.4 and concentrated to afford
rac-(4S,5R)-5-(2-chlorophenyl)-1-(4-methoxybenzyl)-3-methyl-4-n-
itropyrrolidin-2-one (8.2 g, 40.3%) as brown solid.
[0387] Step 2.
[0388] Synthesis of
rac-(4S,5R)-5-(2-chlorophenyl)-3-methyl-4-nitropyrrolidin-2-one. To
a stirred solution of
rac-(4S,5R)-5-(2-chlorophenyl)-1-(4-methoxybenzyl)-3-methyl-4-nitropyrrol-
idin-2-one (8 g, 21.33 mmol) in acetonitrile (80 ml) was added an
aqueous solution of CAN (35 g, 64 mmol) in water (80 ml) dropwise
at 0.degree. C. The reaction mixture was slowly warmed to
15.degree. C. and stirring was continued for 3-4 h. After
completion (monitored by LCMS), the reaction mixture was diluted
with ethyl acetate (500 ml) and washed with water (100 ml.times.2)
followed by brine (200 ml). The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated. The crude material was purified
by column chromatography (using silica gel 100-200 mesh; 25-30%
ethyl acetate in hexane eluent) to afford
rac-(4S,5R)-5-(2-chlorophenyl)-3-methyl-4-nitropyrrolidin-2-one
(2.5 g, 46%) as off white solid.
[0389] Step 3:
[0390]
rac-(4S,5R)-4-amino-5-(2-chlorophenyl)-3-methylpyrrolidin-2-one. To
a stirred solution of
rac-(4S,5R)-5-(2-chlorophenyl)-3-methyl-4-nitropyrrolidin-2-one
(2.5 g, 10.684 mol) in EtOAc/MeOH (2:1, 250 ml) was added 6 N aq.
HCl (53 ml) at 0.degree. C. To this reaction mixture was added Zn
dust (41.92 g, 641 mmol) portionwise at the same temperature. The
resulting suspension was stirred at room temperature for 16 h.
After completion of the reaction (monitored by LCMS), the mixture
was quenched with saturated NaHCO.sub.3 solution (until basic
reaction) at 0.degree. C., stirred for 1 h, filtered over celite
and washed with EtOAc/MeOH (250 ml, 2:1). The filtrate was
concentrated to afford
rac-(4S,5R)-4-amino-5-(2-chlorophenyl)-3-methylpyrrolidin-2-one
(2.2 g crude, considered as 100% yield). The crude product was used
without further purification in the next step.
[0391] Step 4.
[0392] Synthesis of intermediate A 12-trans and intermediate
A12-cis. To a stirred suspension of
rac-(4S,5R)-4-amino-5-(2-chlorophenyl)-3-methylpyrrolidin-2-one
(1.9 g crude, 8.48 mmol) in THF-Water (1:1, 100 ml) was added
sodium bicarbonate (3.56 g, 86.36 mmol) at OoC and the mixture was
stirred for 30 minutes. To this reaction mixture was added benzyl
chloroformate (50% in toluene, 4.3 ml) at 0.degree. C. and stirred
at rt for 16 h. After the reaction was judged to be complete
(monitored by LCMS), the reaction mixture was diluted with water
(100 ml) and extracted with ethyl acetate (3.times.100 ml). The
combined organic layers were washed with water (100 ml.times.2)
followed by brine (100 ml), dried over Na.sub.2SO.sub.4 and
concentrated. The crude product was mixed with another 1.5 g batch
and the combined material was purified by column chromatography
(using silica gel 100-200 mesh; 1-2% MeOH in DCM as eluent) to
afford an mixture of isomers of intermediate A12-trans and
intermediate A12-cis (3.3 g). Prep HPLC purification afforded
intermediate A12-trans benzyl
(rac-(2R,3S,4S)-2-(2-chlorophenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamat-
e (815 mg, 14.9%, in two steps, after prep-purification) and
another fraction (1.7 g) which was further purified further by prep
HPLC to afford intermediate A12-cis benzyl
(rac-(2R,3S,4S)-2-(2-chlorophenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamat-
e (810 mg, 14.8%).
Synthesis of intermediate A14 benzyl
(rac-(2R,3S,4S)-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbama-
te
##STR00020##
[0394] Step 1:
[0395] Synthesis of
rac-(3S,4S,5R)-1-(4-methoxybenzyl)-5-(4-methoxyphenyl)-3-methyl-4-nitropy-
rrolidin-2-one. To a stirred solution of 4-methoxy-benzaldehyde
(13.88 g, 101.95 mmol) in toluene (100 ml) was added
4-methoxybenzyl amine (13.98 g, 101.95 mmol) at rt and the mixture
was stirred for 2 h. To this reaction mixture was added
2-methyl-3-nitropropanoate (10.0 g, 67.96 mmol) followed by benzoic
acid (12.45 g, 101.95 mmol) and stirred for 16 h at 70.degree. C.
After completion of the reaction (monitored by LCMS), the mixture
was diluted with ethyl acetate (250 ml) and washed with water (100
ml), followed by sat. aq. NaHCO.sub.3 (100 ml.times.2). The organic
layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated.
The crude material was purified by column chromatography (using
silica gel 100-200 mesh; 20-25% ethyl acetate/hexanes eluent)
rac-(3S,4S,5R)-1-(4-methoxybenzyl)-5-(4-methoxyphenyl)-3-methyl-4-nitropy-
rrolidin-2-one (11.5 g, 45.7%) as brown solid.
[0396] Step 2.
[0397] Synthesis of
rac-(3S,4S,5R)-5-(4-methoxyphenyl)-3-methyl-4-nitropyrrolidin-2-one.
To a stirred solution of
rac-(3S,4S,5R)-1-(4-methoxybenzyl)-5-(4-methoxyphenyl)-3-methyl-4-nitropy-
rrolidin-2-one (14.5 g, 39.04 mmol) in acetonitrile (150 ml) was
added a solution of CAN (64.2 g, 117.12 mmol) in water (150 ml)
dropwise at 0.degree. C. The reaction mixture was slowly warmed up
to 15.degree. C. and stirring was continued for 3-4 h. After the
starting material was consumed (monitored by TLC, 50% ethyl
acetate/hexane, R.sub.f 0.2), the reaction mixture was diluted with
ethyl acetate (300 ml) and washed with water (100 ml.times.2)
followed by brine (150 ml). The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated. The crude material was purified
by column chromatography (using silica gel 100-200 mesh; 20-30%
ethyl acetate/hexane eluent) to afford
rac-(3S,4S,5R)-5-(4-methoxyphenyl)-3-methyl-4-nitropyrrolidin-2-one
(3.82 g, 39%) as light yellow solid.
[0398] Step 3.
[0399] Synthesis of
rac-(3S,4S,5R)-4-amino-5-(4-methoxyphenyl)-3-methylpyrrolidin-2-one.
To a stirred solution of
rac-(3S,4S,5R)-5-(4-methoxyphenyl)-3-methyl-4-nitropyrrolidin-2-one
(3.8 g, 15.2 mmol) in EtOAc/MeOH (2:1, 380 ml) was added 6N aq. HCl
(76 ml) at 0.degree. C. To this reaction mixture was added Zn dust
(59.64 g, 912 mmol) portionwise at the same temperature. The
resulting suspension was stirred at room temperature for 16 h.
After completion of the reaction (monitored by LCMS), the reaction
mixture was quenched with saturated NaHCO.sub.3 solution at
0.degree. C., stirred for 1 h, filtered over celite and washed with
EtOAc/MeOH (300 ml, 2:1). The filtrate was concentrated to afford
rac-(3S,4S,5R)-4-amino-5-(4-methoxyphenyl)-3-methylpyrrolidin-2-one
(3.52 .mu.g crude, considered as 100% yield). The crude product was
used in the next step without further purification.
[0400] Step 4:
[0401] To a stirred suspension of
rac-(3S,4S,5R)-4-amino-5-(4-methoxyphenyl)-3-methylpyrrolidin-2-one
(3.52 g crude, 15.2 mmol) in THF-Water (1:1, 200 ml) was added
sodium bicarbonate (7.25 g, 86.36 mmol) at 0.degree. C. and stirred
for 30 minutes. To this reaction mixture was added benzyl
chloroformate (50% in toluene, 8.66 ml) at 0.degree. C. and
stirring was continued at rt for 16 h. After completion (monitored
by LCMS), the reaction mixture was diluted with water (100 ml) and
extracted with ethyl acetate (3.times.150 ml). The combined
organics were washed with water (150 ml.times.2) followed by brine
(200 ml), dried over Na.sub.2SO.sub.4 and concentrated. The crude
material was purified by column chromatography (using silica gel
100-200 mesh; 1-2% MeOH in DCM as eluent) to intermediate A14 as an
off-white solid. (2.5 g, 39% in two steps)
Synthesis of Intermediate A16 benzyl
(rac-(2S,3S,4S)-2-(5-chlorothiophen-2-yl)-4-methyl-5-oxopyrrolidin-3-yl)c-
arbamate
##STR00021##
[0403] Step-1:
[0404] Synthesis of
rac-(3S,4S,5S)-5-(5-chlorothiophen-2-yl)-1-(4-methoxybenzyl)-3-methyl-4-n-
itropyrrolidin-2-one. To a stirred solution of
5-chloro-thiophene-2-carbaldehyde (10 g, 0.068 mol) in toluene (250
ml) was added 4-methoxy benzylamine (10.26 g, 0.0748 mol) at rt and
stirred for 2 h. To this reaction mixture was added
2-methyl-3-nitropropanoate (11 g, 0.0748 mol) followed by benzoic
acid (12.46 g, 0.102 mol) and stirred at 80.degree. C. for 16 h.
After completion of the reaction (monitored by TLC, 30% EA/Hexane),
the reaction mixture was diluted with ethyl acetate (200 ml) and
washed with water (500 ml), followed by sat. aq. NaHCO.sub.3(300
ml.times.3). The organic layer was dried over anhydrous
Na.sub.2SO.sub.4 and concentrated. The obtained crude material was
purified through column chromatography (using silica gel 100-200
mesh; 25-30% ethyl acetate/hexane eluent) to afford
rac-(3S,4S,5S)-5-(5-chlorothiophen-2-yl)-1-(4-methoxybenzyl)-3-methyl-4-n-
itropyrrolidin-2-one (8 g, 28%) as a brown resin.
[0405] Step-2:
[0406] Synthesis of
rac-(3S,4S,5S)-5-(5-chlorothiophen-2-yl)-3-methyl-4-nitropyrrolidin-2-one-
. To a stirred solution of
rac-(3S,4S,5S)-5-(5-chlorothiophen-2-yl)-1-(4-methoxybenzyl)-3-methyl-4-n-
itropyrrolidin-2-one (5 g, 0.013 mol) in CH.sub.3CN (50 ml) was
added a solution of CAN (21.38 g, 0.039 mol) in water (50 ml)
dropwise at 0.degree. C. the reaction mixture was stirred at same
temperature for 2 h. After completion (monitored by TLC in 50%
EA-Hexane, R.sub.f 0.3), the reaction mixture was diluted with
ethyl acetate and washed with water followed by brine. The organic
layer was dried over Na.sub.2SO.sub.4 and concentrated. The
obtained crude material was purified by column chromatography
(using silica gel 100-200 mesh, 70% EA-hexane as eluent) to obtain
rac-(3S,4S,5S)-5-(5-chlorothiophen-2-yl)-3-methyl-4-nitropyrrol-
idin-2-one (2.3 g, 82%) as off white solid.
[0407] Step-3:
[0408] Synthesis of
rac-(3S,4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-3-methylpyrrolidin-2-one-
. To a stirred solution of
rac-(3S,4S,5S)-5-(5-chlorothiophen-2-yl)-3-methyl-4-nitropyrrolidin-2-one
(1.8 g, 6.9 mmol) in EtOAc/MeOH (360 ml, 2:1) was added 6 N aq. HCl
(35 ml) at 0.degree. C. To the mixturewas added Zn dust (27.07 g,
414 mmol) portionwise at the same temperature. The resulting
suspension was stirred at room temperature for 16 h. After
completion (monitored by LCMS), the reaction mixture was quenched
with saturated NaHCO.sub.3 solution at 0.degree. C., stirred for 1
h, filtered over celite and washed with EtOAc/MeOH (500 ml, 2:1).
The filtrate was concentrated to afford
rac-(3S,4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-3-methylpyrrolidin-2-one
(1.6 g, crude) as off white solid. The crude product was used in
the next step without further purification.
[0409] Step-4:
[0410] Synthesis of intermediate A16: To a stirred suspension
rac-(3S,4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-3-methylpyrrolidin-2-one
(3 g, 0.013 mol) in THF/Water (60 ml, 1:1) was added sodium
bicarbonate (5.46 g, 0.065 mol) at 0.degree. C. and stirred for 30
minutes. To this was added benzyl chloroformate (50% solution in
toluene, 6.65 g, 0.0195 mol) at the same temperature and stirring
was continued at rt for 16 h. After completion (monitored by LCMS),
the reaction mixture was diluted with water (100 ml) and extracted
with ethyl acetate (3.times.90 ml). The combined organics were
washed with water (90 ml) followed by brine (90 ml). The organic
layer was dried over Na.sub.2SO.sub.4 and concentrated. Crude
material was purified by column chromatography (using silica gel
100-200 mesh; 2-2.5% MeOH/DCM eluent) to afford intermediate A16
benzyl
(rac-(2S,3S,4S)-2-(5-chlorothiophen-2-yl)-4-methyl-5-oxopyrrolidin-3-yl)c-
arbamate (3 g, 79% in 2 steps) as off-white solid.
Synthesis of intermediate A18 benzyl
(rac-(2S,3S,4S)-4-methyl-2-(1-methyl-1H-pyrazol-3-yl)-5-oxopyrrolidin-3-y-
l)carbamate
##STR00022##
[0412] Step-1:
[0413] Preparation of
rac-(3S,4S,5S)-1-(4-methoxybenzyl)-3-methyl-5-(1-methyl-1H-pyrazol-3-yl)--
4-nitropyrrolidin-2-one. To a stirred solution of
1-methyl-1H-pyrazole-3-carbaldehyde (5 g, 45.46 mmol) in Toluene
(75 ml) was added 4-methoxy benzylamine (6.86 g, 50.01 mmol) at rt
and stirred for 2 h. To this reaction mixture was added
2-methyl-3-nitropropanoate (8.68 g, 59.09 mmol) followed by benzoic
acid (8.33 g, 687.18 mmol) and stirring was continued for 16 h at
70.degree. C. After completion of the reaction (monitored by LCMS),
the reaction mixture was diluted with ethyl acetate (200 ml) and
washed with water (200 ml), followed by sat. aq. NaHCO.sub.3 (75
ml.times.2). The organic layer was dried over anhydrous
Na.sub.2SO.sup.4 and concentrated. Crude was purified by column
chromatography (using silica gel 100-200 mesh; 25-30% ethyl
acetate/hexane eluent) to afford
rac-(3S,4S,5S)-1-(4-methoxybenzyl)-3-methyl-5-(1-methyl-1H-pyrazol-3-yl)--
4-nitropyrrolidin-2-one (4 g, 26%) off white solid.
[0414] Step-2:
[0415] Preparation of rac-(3S,4S,5S)-3-methyl-5-(1-methyl-i
H-pyrazol-3-yl)-4-nitropyrrolidin-2-one. To a stirred solution of
rac-(3S,4S,5S)-1-(4-methoxybenzyl)-3-methyl-5-(1-methyl-1H-pyrazol-3-yl)--
4-nitropyrrolidin-2-one (2 g, 5.814 mmol) in CH.sub.3CN (40 ml) was
added a solution of CAN (6.37 g, 11.63 mmol) in water (40 ml)
dropwise at 0.degree. C. The reaction mixture was stirred at same
temperature for 2 h. After completion (monitored by TLC in 50%
EA-Hexane, R.sub.f 0.3), the reaction mixture was diluted with
ethyl acetate and washed with water followed by brine. The organic
layer was dried over Na.sub.2SO.sub.4 and concentrated. Two more
identical batches were conducted using the procedure described
above. The crude material of the composite batch was purified by
column chromatography (using silica gel 100-200 mesh, 70% EA-hexane
as eluent) to afford
rac-(3S,4S,5S)-3-methyl-5-(1-methyl-H-pyrazol-3-yl)-4-nitropyrrolidin-2-o-
ne (2.4 g, 61.4%) as off white solid.
[0416] Step-3:
[0417] Preparation of
rac-(3S,4S,5S)-4-amino-3-methyl-5-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2--
one. To a stirred solution
ofrac-(3S,4S,5S)-3-methyl-5-(1-methyl-1H-pyrazol-3-yl)-4-nitropyrrolidin--
2-one (2.5 g, 11.16 mmol) in EtOAc/MeOH (2; 1, 200 ml) was added
aq. 6 N HCl (56 ml) at 0.degree. C. To this reaction mixture was
added Zn dust (43.8 g, 669.64 mmol) portionwise at the same
temperature. The resulting suspension was stirred at room
temperature for 16 h. After completion (monitored by TLC in 10%
MeOH-DCM, R.sub.f 0.4), the reaction mixture was quenched with
saturated aq. NaHCO.sub.3 solution at 0.degree. C. and filtered
over celite, washed with EtOAc/MeOH (500 ml, 2:1) and concentrated
to afford
rac-(3S,4S,5S)-4-amino-3-methyl-5-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2--
one (2.5 g, crude). The crude product was used in the next step
without further purification.
[0418] Step-4:
[0419] Preparation of intermediate A18: To a stirred suspension of
rac-(3S,4S,5S)-4-amino-3-methyl-5-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2--
one (2.5 g crude, 12.87 mmol) in THF/Water (1; 1, 250 ml) was added
sodium bicarbonate (5.41 g, 64.43 mmol) at 0.degree. C. and stirred
for 30 minutes. To this reaction mixture was added benzyl
chloroformate (6.4 ml, 19.32 mmol, 50% in toluene) at 0.degree. C.
and stirred at rt for 16 h. After completion of the reaction
(monitored by LCMS), the mixture was diluted with water (500 ml)
and extracted with ethyl acetate (3.times.500 ml). The combined
organic layers were washed with water (250 ml.times.2) followed by
brine (500 ml). Organic part was dried over Na.sub.2SO.sub.4 and
concentrated. Crude material was purified by column chromatography
(using silica gel 100-200 mesh; 2-2.5% MeOH/DCM as eluent) to
afford intermediate A18 benzyl
(rac-(2S,3S,4S)-4-methyl-2-(1-methyl-1H-pyrazol-3-yl)-5-oxopyrrolidin-3-y-
l)carbamate (1.99 g, 54.3% in two steps) as off white solid.
Synthesis of intermediate A20 benzyl
(rac-(2R,3S,4S)-4-benzyl-2-ethyl-5-oxopyrrolidin-3-yl)carbamate
##STR00023##
[0421] Step-1:
[0422] Synthesis of methyl 2-benzyl-3-nitropropanoate. To a stirred
solution of LDA (2 M in THF, 22.5 ml, 45.09 mmol) in THF (30 ml)
was added a solution of methyl 3-nitropropanoate (3 g, 22.54 mmol)
and DMPU (27.3 ml, 222.49 mmol) in THF (20 ml) at -78.degree. C.
and stirring was continued for 30 minutes at the same temperature.
A solution of (bromomethyl)benzene (2.69 ml, 22.54 mmol) in THF (15
ml) was added at -78.degree. C. and stirred for 2 h at the same
temperature. The mixture was gradually allowed to reach 25.degree.
C. and stirred for 16 h. The reaction mixture was quenched with 1 N
HCl (100 ml) at 0.degree. C. and extracted with ethyl acetate (100
ml.times.2). The combined organic layers were washed with water
(100 ml), saturated aqueous NaHCO.sub.3 solution (100 ml) followed
by brine (100 ml), dried over Na.sub.2SO.sub.4 and concentrated.
The crude product was purified by column chromatography (using
100-200 silica gel, 10-12% Ethyl acetate-Hexane as eluent) to
afford methyl 2-benzyl-3-nitropropanoate (3.3 g, 65.65%) as light
yellow oil.
[0423] Step-2:
[0424] Synthesis of
rac-(3S,4S,5R)-3-benzyl-5-ethyl-1-(4-methoxybenzyl)-4-nitropyrrolidin-2-o-
ne. To a stirred solution of propionaldehyde (3.61 ml, 50.39 mmol)
in toluene (75 ml) was added 4-methoxy benzylamine (6.91 g, 50.39
mmol) at 25.degree. C. and stirring was continued for 2 h. To this
reaction mixture was added methyl 2-benzyl-3-nitropropanoate (7.5
g, 33.59 mmol) followed by benzoic acid (6.15 g, 50.39 mmol) and
stirred for 7-8 h at 70.degree. C. After completion of the reaction
(monitored by TLC, 30% EA/Hexane, R.sub.f=0.4), the reaction
mixture was diluted with ethyl acetate (300 ml) and washed with
water (300 ml), followed by sat. aq. NaHCO.sub.3 (200 ml.times.2).
The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The crude product was purified bycolumn
chromatography (using silica gel 100-200 mesh; 25-30% ethyl
acetate/hexane eluent) to afford
rac-(3S,4S,5R)-3-benzyl-5-ethyl-1-(4-methoxybenzyl)-4-nitropyrrolidin-2-o-
ne (3.5 g, 28.3%) as brown oil.
[0425] Step-3:
[0426] Synthesis of
rac-(3S,4S,5R)-3-benzyl-5-ethyl-4-nitropyrrolidin-2-one. To a
stirred solution of
rac-(3S,4S,5R)-3-benzyl-5-ethyl-1-(4-methoxybenzyl)-4-nitropyrrolidin-2-o-
ne (3.6 g, 9.77 mmol) in acetonitrile (36 ml) was added a solution
of CAN (16.1 g, 29.31 mmol) in water (36 ml) dropwise at 0.degree.
C. The reaction mixture was slowly warmed up to 10-15.degree. C.
and stirring was continued for 3-4 h. After completion of the
reaction (monitored by TLC, 40% acetone in hexanes, R.sub.f 0.3),
the mixture was diluted with ethyl acetate (200 ml) and washed with
water (200 ml) followed by brine (200 ml). The organic layer was
dried over Na.sub.2SO.sub.4 and concentrated. The crude material
was purified by column chromatography (using silica gel 100-200
mesh; 35-40% ethyl acetate/hexanes as eluent) to afford
rac-(3S,4S,5R)-3-benzyl-5-ethyl-4-nitropyrrolidin-2-one (1.53 g,
63%) as light yellow solid.
[0427] Step-4:
[0428] Synthesis of
rac-(3S,4S,5R)-4-amino-3-benzyl-5-ethylpyrrolidin-2-one. To a
stirred solution of
rac-(3S,4S,5R)-3-benzyl-5-ethyl-4-nitropyrrolidin-2-one (2.8 g,
11.27 mmol) in EtOAc/MeOH (252 ml, 2:1) was added 6M aq. HCl
solution (80 ml) at 0.degree. C. To this was added Zn dust (44.24
g, 676.68 mmol) portionwise at the same temperature. The resulting
suspension was stirred at room temperature for 16 h. After
completion of the reaction (monitored by LCMS), the reaction
mixture was quenched with saturated NaHCO.sub.3 solution at
0.degree. C., stirred for 1 h, filtered over celite and washed with
EtOAc/MeOH (300 ml, 2:1). Filtrate was concentrated to afford
rac-(3S,4S,5R)-4-amino-3-benzyl-5-ethylpyrrolidin-2-one (2.43 g
crude, considered as 100% yield) as off white solid which was used
in next step as such.
[0429] Step-5:
[0430] Synthesis of intermediate A20: To a stirred suspension of
rac-(3S,4S,5R)-4-amino-3-benzyl-5-ethylpyrrolidin-2-one (2.43 g
crude 11.18 mmol) in THF/Water (300 ml, 1:1) was added sodium
bicarbonate (4.69 g, 55.91 mmol) at 0.degree. C. and stirred for 30
minutes. To this was added benzyl chloroformate (5.58 ml, 16.77
mmol, 50% in toluene) at 0.degree. C. and stirred at rt for 16 h.
After completion of the reaction (monitored by LCMS), the reaction
mixture was diluted with water (300 ml) and extracted with ethyl
acetate (3.times.300 ml). The combined organic layers were washed
with water (300 ml) followed by brine (300 ml), dried over
Na.sub.2SO.sub.4 and concentrated. The crude product was purified
by column chromatography (using silica gel 100-200 mesh; 1.5-2%
MeOH/DCM eluent) to afford intermediate A20 benzyl
(rac-(2R,3S,4S)-4-benzyl-2-ethyl-5-oxopyrrolidin-3-yl)carbamate
(2.95 g, 74.9%) as off white solid.
Synthesis of intermediate A9
rac-(3S,4S,5R)-4-amino-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methyl-5--
phenylpyrrolidin-2-one
##STR00024##
[0432] Step 1:
[0433] Synthesis of benzyl
N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)indazol-5-yl]-4-methyl-5-oxo-2-phe-
nyl-pyrrolidin-3-yl]carbamate. In a microwave vial, benzyl
N-[rac(2R,3S,4S)-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]carbamate
(500 mg, 1.54 mmol) was added to 1-(4-fluorophenyl)-5-iodo-indazole
(537 mg, 1.70 mmol), K.sub.3PO.sub.4 (654 mg, 3.08 mmol) and CuI
(58.7 mg, 0.308 mmol). The vial was sealed and purged with
nitrogen. To the mixture, 1,4-dioxane (15.4 mL), followed by
(1R,2R)--N,N'-Dimethyl-1,2-cyclohexandiamine (87.7 mg, 0.617 mmol)
were added subsequently. The mixture was heated to 100.degree. C.
overnight and to 110.degree. C. for 5 h afterwards. After reaction
control (UPLC) showed full conversion of the starting material, the
slurry was allowed to cool down to room temperature and ethyl
acetate followed by sat. NaHCO.sub.3-solution were added. The
mixture was stirred for 5 minutes, the layers were separated and
the aqueous layer was extracted with ethyl acetate once. The
combined organic layers were washed with brine and dried over
MgSO.sub.4. Flash chromatography (40 g silica-cartridge,
cyclohexane/ethyl acetate gradient as eluent) of the crude material
gave
N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)indazol-5-yl]-4-methyl-5-oxo-2-phe-
nyl-pyrrolidin-3-yl]carbamate (465 mg, 0.870 mmol, 56%) as a white
solid.
[0434] Step 2.
[0435] A solution of
N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)indazol-5-yl]-4-methyl-5-oxo-2-phe-
nyl-pyrrolidin-3-yl]carbamate (465 mg, 0.870 mmol) in acetonitrile
(23 ml) was added to NaI (783 mg, 5.22 mmol) in a sealed tube. To
this mixture, trimethylsilyl chloride (0.442 mL, 3.48 mmol) was
added dropwise. The reaction mixture was stirred at room
temperature overnight and was slowly added to ethanol (28 ml) after
reaction control showed completion (UPLC). The resulting solution
was charged on a 5 g SCX cartridge, washed two times with ethanol
(15 ml each) and eluated with 2M ammonia in methanol. The
methanolic fractions were combined. Evaporation of the solvent gave
(rac-3S,4S,5R)-4-amino-1-[1-(4-fluorophenyl)indazol-5-yl]-3-methyl-5-phen-
yl-pyrrolidin-2-one intermediate A9 (316 mg, 0.789 mmol, 91%) as a
white solid.
[0436] The intermediates in the following table were synthesized in
analogy to intermediate 9 described above, using different building
blocks
TABLE-US-00001 Intermedi- ate # Structure Made of A11-trans
##STR00025## Intermediate A-10-trans A11-cis ##STR00026##
Intermediate A-10-cis A13-trans ##STR00027## Intermediate A12-trans
A13-cis ##STR00028## Intermediate A12-cis A19 ##STR00029##
Intermediate A18 A21 ##STR00030## Intermediate A20
Synthesis of intermediates A15-cis benzyl
(rac-(2R,3S,4R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl-
)-4-methyl-5-oxopyrrolidin-3-yl)carbamate and intermediate
A15-trans benzyl
(rac-(2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methox-
yphenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate
##STR00031##
[0438] Step 1:
[0439] Synthesis of benzyl
(rac-(2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl-
)-4-methyl-5-oxopyrrolidin-3-yl)carbamate and benzyl
(rac-(2R,3S,4R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl-
)-4-methyl-5-oxopyrrolidin-3-yl)carbamate. In a microwave vial,
intermediate A14 (500 mg, 1.54 mmol) was added to
1-(4-fluorophenyl)-5-iodo-indazole (524 mg, 1.55 mmol, 1.1 eq.),
K.sub.3PO.sub.4 (599 mg, 2.82 mmol, 2.0 eq.) and CuI (53.7 mg,
0.282 mmol, 0.2 eq.). The vial was sealed and purged with nitrogen.
To the mixture 1,4-dioxane (14.1 mL), followed by
(1R,2R)--N,N'-Dimethyl-1,2-cyclohexandiamine (80.3 mg, 0.564 mmol,
0.4 eq.) were added subsequently. The mixture was heated to
100.degree. C. overnight and to 110.degree. C. for 5 h. After
reaction control (UPLC) showed full conversion of the starting
material, the slurry was allowed to cool down to room temperature
and ethyl acetate followed by sat. NaHCO.sub.3-solution were added.
The mixture was stirred for 5 minutes, the layers were separated
and the aqueous layer was extracted with ethyl acetate once. The
combined organic layers were washed with brine and dried over
MgSO.sub.4. Flash chromatography (40 g silica-cartridge,
cyclohexane/ethyl acetate gradient as eluent) of the crude material
gave benzyl
(rac-(2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methox-
yphenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate (545 mg, 0.965
mmol, 68%) and the epimer benzyl
(rac-(2R,3S,4R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl-
)-4-methyl-5-oxopyrrolidin-3-yl)carbamate (116 mg, 0.206 mmol,
15%).
[0440] Step 2:
[0441] According to the procedure described for intermediate A9,
step 2,
(rac-(2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl-
)-4-methyl-5-oxopyrrolidin-3-yl)carbamate was used to obtain
intermediate A15-trans benzyl
(rac-(2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl-
)-4-methyl-5-oxopyrrolidin-3-yl)carbamate.
[0442] Step 3:
[0443] According to the procedure described for intermediate A9,
step 2,
(rac-(2R,3S,4R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl-
)-4-methyl-5-oxopyrrolidin-3-yl)carbamate was used to obtain
intermediate A15-cis benzyl
((2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl)-4--
methyl-5-oxopyrrolidin-3-yl)carbamate.
Synthesis of intermediate A17-cis
(3R,4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-ind-
azol-5-yl)-3-methylpyrrolidin-2-one and intermediate A17-trans
(3S,4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-ind-
azol-5-yl)-3-methylpyrrolidin-2-one
##STR00032##
[0445] Step 1:
[0446] Synthesis of benzyl
(rac-(2S,3S,4S)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazo-
l-5-yl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate and benzyl
(rac-(2S,3S,4R)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazo-
l-5-yl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate: In analogy to the
procedure described for intermediates A15-trans and A15-cis step 1,
intermediate A16 (500 mg, 1.37 mmol) was coupled with
1-(4-fluorophenyl)-5-iodo-indazole (510 mg, 1.51 mmol, 1.1 eq) to
obtain benzyl
(rac-(2S,3S,4S)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-
-indazol-5-yl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate (644 mg,
1.12 mmol, 82%) and the epimer benzyl
(rac-(2S,3S,4R)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazo-
l-5-yl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate (118 mg, 0.205
mmol, 15%).
[0447] Step 2:
[0448] According to the procedure described for intermediate A9,
step 2,
((2S,3S,4S)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5--
yl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate was deprotected to
obtain intermediate A17-trans
(3S,4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-ind-
azol-5-yl)-3-methylpyrrolidin-2-one.
[0449] Step 3:
[0450] According to the procedure described for intermediate A9,
step 2,
((2S,3S,4R)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5--
yl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate was deprotected to
obtain intermediate A17-cis
(3R,4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-ind-
azol-5-yl)-3-methylpyrrolidin-2-one.
Synthesis of 1-(4-fluorophenyl)-5-iodo-1H-indole (intermediate
B1)
##STR00033##
[0452] Step 1:
[0453] 5-Bromo-1H-indole (750.0 mg, 3.826 mmol, 1.0 eq.),
1-fluoro-4-iodo-benzene (891.7 mg, 4.017 mmol, 1.05 eq.),
K.sub.3PO.sub.4 (1624.1 mg, 6.513 mmol, 2.0 eq.) and copper iodide
(582.9 mg, 3.061 mmol, 0.8 eq.) were weighed out into a vial, a
stir bar was added, the vial was sealed and was purged with
nitrogen. Then, 1,4-dioxane (19.1 mL) and trans-N,N-dimethyl
cyclohexane-1,2-diamine (54.4 mg, 0.3826 mmol, 0.1 eq.) were added,
and the reaction mixture was heated to 100.degree. C. for 16 h. The
reaction mixture was then cooled to ambient temperature, was
diluted with DCM and sat. NaHCO.sub.3 solution and was filtered
through a hydrophobic frit. The organic solvent was removed, and
the remains were purified via silica gel chromatography to yield
5-bromo-1-(4-fluorophenyl)-1H-indole in 35% yield.
[0454] Step 2:
[0455] 5-Bromo-1-(4-fluorophenyl)indole (2300 mg, 7.927 mmol, 1.0
eq.), NaI (5941 mg, 39.6 mmol, 5.0 eq.) K.sub.3PO.sub.4 (3365 mg,
15.8 mmol, 2.0 eq.) and copper iodide (1207 mg, 6.3419 mmol, 0.8
eq.) were weighed out into a flask, a stir bar was added, the vial
was sealed and was purged with nitrogen. Then, 1,4-dioxane (58.4
mL) and trans-N,N-dimethyl cyclohexane-1,2-diamine (112.8 mg, 0.793
mmol, 0.1 eq.) were added, and the reaction mixture was heated to
100.degree. C. for one week. The reaction mixture was then cooled
to ambient temperature, was diluted with DCM and sat. NaHCO.sub.3
solution and was filtered through a hydrophobic frit. The organic
solvent was removed, and the remains were purified via silica gel
chromatography to yield 1580 mg of intermediate B1 (53%).
Synthesis of 5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine
(intermediate B2)
##STR00034##
[0457] Step 1:
[0458] Intermediate B2 was prepared in analogy to the synthesis of
intermediate B4, using 5-bromo-2-fluoro-pyridine-3-carbaldehyde
instead of 6-bromo-3-fluoro-pyridine-2-carbaldehyde. Yield: 66%
Synthesis of 5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine
(intermediate B3)
##STR00035##
[0460] Step 1:
[0461] Intermediate B3 was prepared in analogy to the synthesis of
intermediate B4, using 2-bromo-5-fluoro-pyridine-4-carbaldehyde
instead of 6-bromo-3-fluoro-pyridine-2-carbaldehyde. Yield: 79%
Synthesis of 5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine
(intermediate B4)
##STR00036##
[0463] Step 1:
[0464] 6-Bromo-3-fluoro-pyridine-2-carbaldehyde (300.0 mg, 1.471
mmol, 1.0 eq.) and (4-fluorophenyl)hydrazine hydrochloride (239.1
mg, 1.471 mmol, 1.0 eq.) were dissolved in NMP (3.0 mL) and the
resaction mixture was stirred for 90 minutes. Then,
Cs.sub.2CO.sub.3 (1437.8 mg, 4.412 mmol, 3.0 eq.) was added and the
reaction mixture was heated to 115.degree. C. for 90 minutes. The
reaction mixture was then allowed to warm to ambient temperature,
and was diluted with EtOAc and water. The layers were separated,
and the aqueous phase was extracted two time with EtOAc. The
combined organic layers were washed with water and brine, dried
over MgSO.sub.4 and the solvent was removed under reduced pressure.
The obtained residue was then purified by LC to yield 297.0 mg
(69%) of 5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine.
Synthesis of intermediate C1
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidi-
n-3-yl)cyclopropanecarboxamide
##STR00037##
[0466] Step 1:
[0467] Maleic anhydride (9.8 g, 100 mmol, 1.0 eq), p-thiocresol
(12.4 g, 100 mmol, 1.0 eq), ammonium acetate (7.8 g, 100 mmol, 1.0
eq) and benzaldehyde (10 mL, 100 mmol, 1.0 eq) were put in a sealed
tube and 100 ml toluene was added. The reaction mixture was stirred
at RT for 1 h and then stirred at 150.degree. C. for 16 h. After
cooling to RT, the solvent was evaporated under reduced pressure,
and the residue was basified with sat.NaHCO.sub.3 solution and was
extracted with DCM. The aqueous layer was acidified with 2N HCl
under ice cooling and the crude product was extracted twice with
EtOAc. The combined organic layers were washed with brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated to get the crude
5-oxo-2-phenyl-3-(p-tolylthio)pyrrolidine-3-carboxylic acid (10.0
g, crude).
[0468] Step 2:
[0469] To a stirred solution of crude
5-oxo-2-phenyl-3-(p-tolylthio)pyrrolidine-3-carboxylic acid (10.0
g, 30.58 mmol, 1.0 eq) in acetone (100 mL), potassium carbonate
(16.8 g, 122.32 mmol, 4.0 eq) and methyl iodide (7.6 ml, 122.32
mmol, 4.0 eq) were added at 0.degree. C., and the reaction was
stirred for 16 h at RT. The solvent was removed under reduced
pressure, and the residue was partitioned between DCM and water.
The aqueous layer was extracted twice with DCM. The combined
organic layers were washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The crude product was purified by
column chromatography (100-200 silica gel, 50% EtOAc:hexanes) to
give methyl 5-oxo-2-phenyl-3-(p-tolylthio)pyrrolidine-3-carboxylate
(4.0 g, 38%) as an off-white solid.
[0470] Step 3:
[0471] To a stirred solution of methyl
5-oxo-2-phenyl-3-(p-tolylthio)pyrrolidine-3-carboxylate (4.0 g,
11.73 mmol, 1.0 eq) in EtOH:THF (100 mL, 2:1), Raney Nickel (1 g)
was added and the reaction mixture was stirred for 2 h at RT After
completion, the reaction mixture was filtered through a celite bed
and the celite bed was washed 2-3 times with EtOAc. The combined
organic layers were concentrated and the crude was purified by
column chromatography (100-200 silica gel, 50% EtOAc:hexanes) to
afford methyl 5-oxo-2-phenylpyrrolidine-3-carboxylate (2.2 g, 88%,
syn: anti, 1:1 mixture) as an off-white solid.
[0472] Step 4:
[0473] To a stirred solution of methyl
5-oxo-2-phenylpyrrolidine-3-carboxylate (1.0 g, 4.56 mmol, 1.0 eq)
in MeOH (25 mL) was added 2 NNaOH solution (5 mL) and the reaction
mixture was stirred at 80.degree. C. for 2 h. After completion of
the reaction (monitored by LCMS), the reaction mixture was
concentrated and acidified with 2N HCl solution and was extracted
with 30% isopropanol-DCM. The combined organic layers were dried
over Na.sub.2SO.sub.4 and were concentrated under reduced pressure
to get the desired trans-5-oxo-2-phenylpyrrolidine-3-carboxylic
acid (0.8 g, 85%).
[0474] Step 5:
[0475] To a stirred solution of
trans-5-oxo-2-phenylpyrrolidine-3-carboxylic acid (0.5 g, 2.43
mmol, 1.0 eq) in benzene:THF (25 mL, 4:1) was added TEA (0.68 ml,
4.87 mmol, 2.0 eq) and DPPA (0.68 ml, 3.17 mmol, 1.3 eq) and the
reaction mixture was stirred at RT for 2 h. Then benzyl alcohol
(0.33 mL, 3.17 mmol, 1.3 eq) was added and the reaction mixture was
heated to reflux for 16 h. After completion, the reaction mixture
was concentrated under reduced pressure to get the crude compound
which was extracted with water and EtOAc. The combined organic
layers were dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure to get the crude product which was purified by
column chromatography (100-200 mesh silica gel; 2% MeOH-DCM;
R.sub.f-value-0.5) to afford trans-benzyl
(5-oxo-2-phenylpyrrolidin-3-yl)carbamate (0.38 g, 50%).
[0476] Step 6:
[0477] To a stirred solution of trans-benzyl
(5-oxo-2-phenylpyrrolidin-3-yl)carbamate (1.7 g, 5.48 mmol, 1.0 eq)
in MeOH (20 mL, 2:1), Pd/C (0.058 g, 0.548 mmol, 0.1 eq) was added,
and the reaction was stirred with a hydrogen balloon for 2 h at RT.
After completion, the reaction mixture was filtered through a
celite bed and the celite bed was washed 2-3 times with EtOAc. The
combined organic layers were concentrated to get the desired
trans-4-amino-5-phenylpyrrolidin-2-one as brown gum (0.9 g,
93%).
[0478] Step 7:
[0479] To a stirred solution of cyclopropanecarboxylic acid (0.59
g, 6.818 mmol, 1.2 eq) in DMF (15 mL) was added HATU (4.32 g,
11.363 mmol, 2.0 eq), DIPEA (5.0 mL, 28.409 mmol, 5.0 eq) and
intermediate A2 (1.00 g, 5.681 mmol, 1.0 eq) at 0.degree. C. and
the reaction mixture was then stirred at ambient temperature for 16
h. After completion of the reaction (monitored by TLC, TLC system
5% MeOH in DCM, R.sub.f-0.3), the reaction mixture was diluted with
EtOAc (35 mL) and was washed with ice cold water (3.times.25 mL),
dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure
to get the crude product which was purified by column
chromatography (230-400 mesh silica gel; 0 to 4% MeOH-DCM) to
afford
N-(trans-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide
(0.45 g, 32%).
[0480] Step 8:
[0481] A stirred solution of
N-(trans-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide
(0.450 g, 1.844 mmol, 1.0 eq),
1-(4-fluorophenyl)-5-iodo-1H-indazole (0.748 g, 2.213 mmol, 1.2 eq)
and K.sub.3PO.sub.4 (0.781 g, 3.688 mmol, 2.0 eq) in 1,4-dioxane
(30 mL) was degassed with argon for 30 min. Then,
trans-N,N'-dimethylcyclohexane-1,2-diamine (0.104 g, 0.737 mmol,
0.4 eq) and CuI (0.070 g, 0.368 mmol, 0.2 eq) were added and the
reaction mixture was stirred for 16 h at 90.degree. C. in a sealed
tube. After completion of the reaction (monitored by TLC, TLC
system 5% MeOH in DCM, R.sub.f-0.4), the reaction mixture was
filtered through a celite bed and the celite bed was washed 2-3
times with 1,4-dioxane. The combined organic layers were
concentrated to get the crude product which was purified by column
chromatography (230-400 mesh silica gel; 0 to 2% MeOH in DCM) to
afford the racemic product. Further enantiomer separation was done
by preparative chiral HPLC to afford pure
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidi-
n-3-yl)cyclopropanecarboxamide (0.267 g, 32%; RT=5.56 min; Column
Name: Chiralpak IA (250.times.4.6 mm) 5 .mu.m, Mobile Phase:
Hexane/Isopropanol/DCM/DEA: 70/15/15/0.1, Flow Rate: 1.0 ml/min)
and intermediate C.sub.1--ent1
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidi-
n-3-yl)cyclopropanecarboxamide (0.254 g, 30%; RT=7.13 min; Column
Name: Chiralpak IA (250.times.4.6 mm) 5 .mu.m, Mobile Phase:
Hexane/Isopropanol/DCM/DEA: 70/15/15/0.1, Flow Rate: 1.0
ml/min).
EXAMPLES 1 AND 2
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phe-
nylpyrrolidin-3-yl)cyclopropanecarboxamide (example 1) and
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)cyclopropanecarboxamide (example
##STR00038##
[0483] Step 1:
[0484] A stirred solution of intermediate A2 (0.35 g, 1.286 mmol,
1.0 eq), 1-(4-fluorophenyl)-5-iodo-1H-indazole (0.520 g, 1.54 mmol,
1.2 eq), K.sub.3PO.sub.4 (0.545 g, 2.572 mmol, 2.0 eq) in 1,4
dioxane (20 mL) was degassed with argon for 30 min. Then,
trans-N,N'-dimethyl cyclohexane-1,2-diamine (0.073 g, 0.514 mmol,
0.4 eq) and CuI (0.049 g, 0.257 mmol, 0.2 eq) were added and the
reaction was stirred for 16 h at 90.degree. C. in a sealed tube.
After completion of the reaction (monitored by TLC, TLC system 5%
MeOH in DCM, Rf-0.4) the reaction mixture was filtered through a
celite pad, which was then washed 2-3 times with 1,4-dioxane. The
combined organic layers were concentrated to obtain the crude
product which was purified by column chromatography (230-400 mesh
silica gel; 0 to 2% MeOH in DCM) to afford the racemic compound and
further enantiomer separation was carried out via prep. chiral HPLC
(column: Chiralpak IC (4.6.times.250 mm), 5 .mu.m, mobile phase:
hexane:ethyl acetate:EtOH:isopropylamine 70:15:15:0.1, flow rate:
1.0 mL/min) to afford example 1 (0.055 g, 9%, retention time: 4.62
minutes) and example 2 (0.057 g, 9%, retention time 6.48
minutes).
[0485] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=8.46 (d, 1H),
8.29 (s, 1H), 7.74-7.71 (m, 3H), 7.67 (d, 1H), 7.46 (m, 1H), 7.39
(d, 2H), 7.34-7.32 (m, 2H), 7.22 (t, 2H), 7.14 (t, 2H), 5.11 (d,
1H), 4.29 (t, 1H), 1.69-1.63 (m, 1H), 1.21 (s, 3H), 1.12 (s, 3H),
0.7-0.52 (m, 4H).
EXAMPLE 5
N-trans-(5-(1-(4-fluorophenyl)-1H-indol-5-yl)-4-oxo-6-phenyl-5-azaspiro[2.-
4]heptan-7-yl)cyclopropanecarboxamide
##STR00039##
[0487] Step 1:
[0488] Intermediate A5 (50.0 mg, 0.185 mmol, 1.0 eq.), intermediate
B1 (65.5 mg, 0.194 mmol, 1.05 eq.), K.sub.3PO.sub.4 (78.5 mg, 0.370
mmol, 2.0 eq.) and copper iodide (28.2 mg, 0.148 mmol, 0.8 eq.)
were weighed out into a vial, a stir bar was added, the vial was
sealed and was purged with nitrogen. Then, 1,4-dioxane (0.9 mL) and
trans-N,N'-dimethyl cyclohexane-1,2-diamine (2.5 mg, 0.019 mmol,
0.1 eq.) were added, and the reaction mixture was heated to
100.degree. C. for six days. The reaction mixture was then cooled
to ambient temperature, was diluted with DCM and sat. NaHCO.sub.3
solution and was filtered through a hydrophobic frit. The organic
solvent was removed, and the remains were purified via silica gel
chromatography to yield 4.0 mg (4%) of example 5.
[0489] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.88 (d, 1H), 7.74-7.70
(m, 1H), 7.62-7.54 (m, 3H), 7.45-7.35 (m, 6H), 7.33 (dd, 2H),
7.27-7.19 (m, 1H), 6.63 (d, 1H), 5.22 (d, 1H), 4.01 (dd, 1H),
1.72-1.64 (m, 1H), 1.28-1.05 (m, 2H), 0.97-0.89 (m, 2H), 0.79-0.73
(m, 1H), 0.73-0.68 (m, 3H).
EXAMPLE 7
N-((2R,3S)-4,4-dimethyl-1-(1-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-i-
ndazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)-5-methylisoxazole-3-carboxamid-
e
##STR00040##
[0491] Step 1:
[0492] 5-Methylisoxazole-3-carboxylic acid (22.3 mg, 0.175 mmol,
1.5 eq.) was dissolved in DCM (1.2 mL), followed by the addition of
triethylamine (0.05 mL, 0.351 mmol, 3.0 eq.). Then propylphosphonic
anhydride solution (>50 wt. % in ethyl acetate, 0.14 mL, 2.0
eq.) was added, and the mixture was stirred at ambient temperature
for 20 minutes. Then, intermediate A4 ent1 (50.0 mg, 0.117 mmol,
1.0 eq.), was added, and the mixture was stirred for 48 hours at
ambient temperature. Then, saturated NaHCO.sub.3 solution and more
DCM were added, and the mixture was stirred for 10 minutes. The
mixture was then filtered through a hydrophobic frit, and the
organic solvent was then removed. The crude remains were purified
via silica gel chromatography to yield 36.0 mg (57%) of example
7.
[0493] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.09 (d, 1H), 8.26 (d,
1H), 8.17 (d, 1H), 7.72-7.67 (m, 2H), 7.59 (d, 1H), 7.39 (dd, 1H),
7.38-7.36 (m, 2H), 7.26-7.20 (m, 2H), 7.18-7.12 (m, 1H), 6.54 (d,
1H), 6.51 (d, 1H), 5.50 (d, 1H), 4.47 (t, 1H), 3.50 (s, 3H), 2.47
(d, 3H), 1.32 (s, 3H), 1.17 (s, 3H).
EXAMPLE 31
N-[rac-((6R,7S)-5-(1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-ox-
o-6-phenyl-5-azaspiro[2.4]heptan-7-yl)]cyclopropanecarboxamide
##STR00041##
[0495] Step 1:
[0496] 5-Bromo-1-(4-fluorophenyl)pyrazolo[3,4-b]pyridine (64.8 mg,
0.222 mmol, 1.2 eq.), intermediate A5 (50.0 mg, 0.185 mmol, 1.0
eq.), K.sub.3PO.sub.4 (78.5 mg, 0.370 mmol, 2.0 eq.), CuI (7.0 mg,
0.037 mmol, 0.2 eq.) and NaI (55.4 mg, 0.370 mmol, 2.0 eq.) were
weighed out into a microwave vial. A stir bar was added, the vial
was sealed and purged with nitrogen. Then, 1,4-dioxane (1.0 mL) and
trans-N,N'-dimethyl cyclohexane-1,2-diamine (0.012 mL, 0.074 mmol,
0.4 eq.) were added and the mixture was stirred at 110.degree. C.
for 16 hours. The mixture was then allowed to cool to ambient
temperature and was diluted with sat. NaHCO.sub.3 solution and DCM.
The mixture was then filtered through a hydrophobic frit. The
organic layer was evaporated under reduced pressure and the residue
was purified via LC to yield 42.0 mg (47%) of
N-[rac-((6R,7S)-5-(1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-o-
xo-6-phenyl-5-azaspiro[2.4]heptan-7-yl)]cyclopropanecarboxamide
[0497] .sup.1H NMR (DMSO-d.sub.6): .delta.=8.92-8.86 (m, 2H), 8.44
(d, 1H), 8.40 (s, 1H), 8.25-8.16 (m, 2H), 7.44-7.37 (m, 4H), 7.35
(t, 2H), 7.29-7.23 (m, 1H), 5.37 (d, 1H), 4.13 (dd, 1H), 1.71-1.63
(m, 1H), 1.25 (dd, 1H), 1.18-1.11 (m, 1H), 1.05-0.96 (m, 2H),
0.78-0.68 (m, 4H)
EXAMPLE 32
N-[rac-((6R,7S)-5-(1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-4-ox-
o-6-phenyl-5-azaspiro[2.4]heptan-7-yl)]cyclopropanecarboxamide
##STR00042##
[0499] Example 32 was prepared in analogy to the synthesis
described for example 31, using intermediate B3 instead of
intermediate B2 and requiring an additional HPLC purification.
Yield: 35%
[0500] .sup.1H NMR (DMSO-d.sub.6): .delta.=8.99 (p, 1H), 8.90 (d,
1H), 8.76 (q, 1H), 8.54 (q, 1H), 7.88-7.81 (m, 2H), 7.43-7.36 (m,
2H), 7.36-7.26 (m, 4H), 7.23-7.17 (m, 1H), 5.79 (s, 1H), 3.95 (dd,
1H), 1.72-1.64 (m, 1H), 1.25-1.12 (m, 2H), 1.04-0.91 (m, 2H),
0.81-0.66 (m, 4H)
EXAMPLE 33
N-[rac-((6R,7S)-5-(1-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-4-ox-
o-6-phenyl-5-azaspiro[2.4]heptan-7-yl)]cyclopropanecarboxamide
##STR00043##
[0502] Example 33 was prepared in analogy to the synthesis
described for example 31, using intermediate B4 instead of
intermediate B2. Yield: 32%
[0503] .sup.1H NMR (DMSO-d.sub.6): .delta.=8.91 (d, 1H), 8.62 (d,
1H), 8.39-8.34 (m, 2H), 7.84-7.77 (m, 2H), 7.47-7.40 (m, 2H),
7.40-7.34 (m, 2H), 7.32 (t, 2H), 7.22 (t, 1H), 5.80 (d, 1H),
3.98-3.94 (m, 1H), 1.72-1.62 (m, 1H), 1.26-1.14 (m, 2H), 1.05-0.96
(m, 2H), 0.83-0.75 (m, 1H), 0.75-0.65 (m, 3H)
EXAMPLE 34A
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phe-
nylpyrrolidin-3-yl)methanesulfonamide
##STR00044##
[0505] Step 1:
[0506]
(4S,5R)-4-Amino-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3,3-dimethyl-
-5-phenylpyrrolidin-2-one (50.0 mg, 0.121 mmol, 1.0 eq.) was
weighed out into a vial under a nitrogen atmosphere, followed by
the addition of DCM (1.2 mL) and triethylamine (0.067 mL, 0.483
mmol, 4.0 eq.). The mixture was then cooled to 0.degree. C., then
methanesulfonyl chloride (0.019 mL, 0.241 mmol, 2.0 eq.) was added
and the mixture was allowed to stir for 10 minutes at that
temperature. The reaction mixture was then diluted with sat.
NaHCO.sub.3 solution and DCM. The mixture was then filtered through
a hydrophobic frit and the organic layer was evaporated to dryness
under reduced pressure. The obtained residue was purified via LC to
yield 59.4 mg (76%) of
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-ph-
enylpyrrolidin-3-yl)methanesulfonamide.
[0507] .sup.1H NMR (DMSO-d.sub.6): .delta.=8.28 (d, 1H), 8.02 (d,
1H), 7.76-7.69 (m, 3H), 7.69-7.63 (m, 1H), 7.52-7.47 (m, 2H),
7.44-7.35 (m, 3H), 7.29 (dd, 2H), 7.23-7.18 (m, 1H), 5.07 (d, 1H),
3.70 (t, 1H), 2.03 (s, 3H), 1.26 (s, 3H), 1.14 (s, 3H)
[0508] The examples in the following table were synthesized in
analogy to Example 34a described above, using different
intermediates. The individual reaction times vary.
TABLE-US-00002 Interme- Ex. diate Yield # (INT) Structure (%)
.sup.1H NMR 34a Int A7 ent 2 ##STR00045## 52 .sup.1H NMR
(DMSO-d.sub.6): .delta. = 8.28 (d, 1H), 8.02 (d, 1H), 7.76-7.69 (m,
3H), 7.69-7.63 (m, 1H), 7.52- 7.47 (m, 2H), 7.44-7.35 (m, 3H), 7.29
(dd, 2H), 7.23-7.18 (m, 1H), 5.07 (d, 1H), 3.70 (t, 1H), 2.03 (s,
3H), 1.26 (s, 3H), 1.14 (s, 3H) 35a Int A7 ent 1 ##STR00046## 13
.sup.1H NMR (DMSO-d.sub.6): .delta. = 8.28 (d, 1H), 7.95 (d, 1H),
7.76-7.68 (m, 3H), 7.65 (dd, 1H), 7.49-7.44 (m, 2H), 7.43-7.35 (m,
3H), 7.26 (t, 2H), 7.20-7.14 (m, 1H), 5.09 (d, 1H), 3.74 (t, 1H),
1.46 (tt, 1H), 1.28 (s, 3H), 1.15 (s, 3H), 0.70- 0.49 (m, 2H),
0.49-0.25 (m, 2H) 35b Int A7 ent 2 ##STR00047## 8 .sup.1H NMR
(DMSO-d.sub.6): .delta. = 8.28 (d, 1H), 7.95 (d, 1H), 7.76-7.68 (m,
3H), 7.65 (dd, 1H), 7.49-7.44 (m, 2H), 7.43-7.35 (m, 3H), 7.26 (t,
2H), 7.20-7.14 (m, 1H), 5.09 (d, 1H), 3.74 (t, 1H), 1.46 (tt, 1H),
1.28 (s, 3H), 1.15 (s, 3H), 0.70- 0.49 (m, 2H), 0.49-0.25 (m, 2H)
61 A9 ##STR00048## 74 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.28 (d,
1H), 7.99 (d, 1H), 7.76-7.69 (m, 3H), 7.65 (dt, 1H), 7.48-7.42 (m,
3H), 7.42-7.35 (m, 2H), 7.30- 7.25 (m, 2H), 7.22-7.17 (m, 1H), 5.10
(d, 1H), 3.61 (dt, 1H), 2.68 (dq, 1H), 2.26 (s, 3H), 1.31 (d, 3H)
62 A11- trans ##STR00049## 50 .sup.1H NMR (DMSO-d.sub.6) .delta.:
8.29 (s, 1H), 7.96 (d, 1H), 7.77-7.71 (m, 3H), 7.69-7.64 (m, 1H),
7.44 (dd, 1H), 7.44-7.36 (m, 2H), 7.27 (d, 1H), 7.25-7.21 (m, 1H),
7.16 (t, 1H), 7.01 (d, 1H), 5.05 (d, 1H), 3.58 (dt, 1H), 2.67 (dq,
1H), 2.26 (s, 3H), 2.22 (s, 3H), 1.31 (d, 3H) 76 A11- cis
##STR00050## 40 .sup.1H NMR (DMSO-d.sub.6) .delta.: 7.89 (dd, 1H),
7.79-7.68 (m, 5H), 7.44- 7.37 (m, 2H), 7.24 (t, 1H), 7.19 (d, 1H),
7.17-7.13 (m, 1H), 7.08 (ddd, 1H), 5.24 (d, 1H), 3.97 (d, 1H), 3.01
(p, 1H), 2.87 (s, 3H), 2.27 (s, 3H), 1.18 (d, 3H) 86 A13- cis
##STR00051## 35 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.35 (d, 1H),
8.19 (d, 0H), 7.87 (dd, 1H), 7.80-7.73 (m, 3H), 7.65 (dd, 1H),
7.54-7.48 (m, 1H), 7.44-7.37 (m, 2H), 7.37-7.28 (m, 3H), 5.58 (d,
1H), 4.09 (s, 1H), 3.04 (p, 1H), 2.95 (s, 3H), 1.20 (d, 3H) 91 A21
##STR00052## 42 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.40 (d, 1H),
7.87-7.76 (m, 4H), 7.72 (d, 1H), 7.45 (ddd, 3H), 7.40-7.33 (m, 4H),
7.26 (tt, 1H), 4.07 (td, 1H), 3.62 (ddd, 1H), 3.15 (dd, 1H), 3.09
(dd, 1H), 2.96 (q, 1H), 2.79 (s, 3H), 1.51 (ddd, 1H), 1.22 (dp,
1H), 0.40 (t, 3H) 93 A13- trans ##STR00053## 19 .sup.1H NMR
(Chloroform-d.sub.3) .delta.: 8.10 (d, 1H), 7.68 (dd, 1H),
7.64-7.58 (m, 2H), 7.55 (dd, 1H), 7.38 (dd, 2H), 7.31 (d, 1H),
7.26-7.18 (m, 4H), 5.68 (s, 1H), 4.79 (d, 1H), 2.72 (dq, 1H), 2.51
(s, 3H), 1.55 (d, 3H), 0.97-0.77 (m, 1H) 99 A15- trans ##STR00054##
13 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.28 (d, 1H), 7.93 (d, 1H),
7.75-7.72 (m, 2H), 7.71 (dd, 1H), 7.65 (dt, 1H), 7.43-7.34 (m, 5H),
6.85-6.79 (m, 2H), 5.03 (d, 1H), 3.65 (s, 3H), 3.59 (dt, 1H), 2.65
(dt, 1H), 2.29 (s, 3H), 1.31 (d, 3H) 114 A17- trans ##STR00055## 25
.sup.1H NMR (DMSO-d.sub.6) .delta.: 8.34 (d, 1H), 7.98 (d, 1H),
7.81-7.74 (m, 3H), 7.72 (dt, 1H), 7.47-7.38 (m, 3H), 7.14 (d, 1H),
6.89 (d, 1H), 5.34 (d, 1H), 3.68 (dt, 1H), 2.70 (dq, 1H), 2.64 (s,
3H), 1.31 (d, 3H) 122 A19 ##STR00056## 47 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 8.31 (t, 1H), 7.92 (d, 1H), 7.79-7.73 (m,
2H), 7.72 (dd, 1H), 7.69 (dd, 1H), 7.52 (d, 1H), 7.45-7.37 (m, 3H),
6.27 (dd, 1H), 5.11 (d, 1H), 3.79 (q, 1H), 3.70 (s, 3H), 2.67 2.59
(m, 1H), 2.46 (s, 3H), 1.30 (d, 3H)
EXAMPLES 95 AND 96
(2-(((2R,3R,4S)-4-fluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-ph-
enylpyrrolidin-3-yl)carbamoyl)cyclopropan-1-ylium (example 95) and
N-((2R,3R)-4,4-difluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-ph-
enylpyrrolidin-3-yl)cyclopropanecarboxamide (example 96)
##STR00057##
[0510] Step-1:
[0511] In a dried vessel, intermediate C1-ent 1 (150 mg, 0.33 mmol)
was dissolved in dry THF (3.3 ml) under inert atmosphere. The
solution was cooled down to -78.degree. C. and a solution of LDA (1
M in THF/heptanes/ethyl benzene, 1.32 ml, 4.0 eq.) was added
dropwise. After stirring for 15 min at -78.degree. C.,
N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (NFSI, 229 mg, 0.726
mmol, 2.2 eq.) dissolved in dry THF (1.7 mL) was added dropwise.
The mixture was stirred for two hours at -78.degree. C. before
additional amounts of LDA (330 1, 1 eq.) and NFSI (100 mg, 1 eq.)
were added subsequently. After stirring for another 30 min at
-78.degree. C., the reaction was quenched with sat.
NH.sub.4Cl-solution and ethyl acetate was added after stirring for
5 minutes. The layers were separated, the organic layer was dried
over sodium sulfate and the solvent was removed in vacuo. The crude
material was purified via flash chromatography (silica,
cyclohexane/ethyl acetate gradient as eluent) and subsequent
prep.-HPLC (water/acetonitrile gradient) to obtain example 95 (25.5
mg, 0.054 mmol, 16%) and example 96 (3.0 mg, 0.006 mmol, 2%) as
white solids.
EXAMPLE 95
[0512] .sup.1H NMR (Chloroform-d.sub.3) .delta.: 8.07 (d, 1H), 7.76
(dd, 0.7 Hz, 1H), 7.67-7.50 (m, 2H), 7.58-7.45 (m, 1H), 7.39 (dd,
1H), 7.41-7.06 (m, 6H), 6.31 (d, 1H), 5.86 (dd, 1H), 5.54 (dd, 1H),
3.98 (dq, 1H), 1.44 (tt, 1H), 0.86 (dtd, 2H).
EXAMPLE 96
[0513] .sup.1H NMR (Chloroform-d.sub.3) .delta.: 8.10 (s, 1H), 7.52
(d, 1H), 7.41 (dd, 1H), 7.43-7.19 (m, 5H), 7.28-7.11 (m, 2H), 6.42
(s, 1H), 5.14 (d, 1H), 4.88 (dddd, 1H), 1.51 (tq, 1H), 1.05 (tq,
1H), 0.96-0.74 (m, 2H).
EXAMPLE 100
2,2-difluoro-N-(trans-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-5-ox-
o-2-phenylpyrrolidin-3-yl)propanamide
##STR00058##
[0515] Step 1:
[0516] To a stirred solution of intermediate A6 (1 g, 3.08 mmol,
1.0 eq) in methanol (30 mL), Pd--C(820 g, 10%, moist) was added and
the reaction was stirred with hydrogen balloon for 2 h at RT. After
completion, (monitored by TLC, TLC system 5% MeOH in DCM,
R.sub.f-0.2), the reaction mixture was filtered through celite bed
and washed 2-3 times with MeOH. The filtrate was concentrated to
get the desired trans-4-amino-5-methyl-5-phenylpyrrolidin-2-one as
off-white solid (0.693 g, 94%).
[0517] Step 2:
[0518] To a stirred solution of 2,2-difluoropropanoic acid (0.304
g, 2.759 mmol, 1.5 eq) in DMF (10 mL), DIPEA (1.6 mL 9.14 mmol, 5.0
eq), HATU (1.4 g, 3.678 mmol, 2.0 eq), and
trans-4-amino-5-methyl-5-phenylpyrrolidin-2-one (350 mg, 1.839
mmol, 1 eq) was added at ice cold condition and the reaction was
stirred at RT for 16 h. After completion of the reaction,
(monitored by TLC, TLC system 5% MeOH in DCM, R.sub.f-0.3), the
reaction mixture was diluted with EtOAc (20 mL) and washed with ice
cold water (3.times.25 mL), dried over Na.sub.2SO.sub.4 and
concentrated to get the crude product which was purified by column
chromatography (230-400 mesh silica gel; 0 to 2% MeOH-DCM) to
afford
2,2-difluoro-N-(trans-2-methyl-5-oxo-2-phenylpyrrolidin-3-yl)propanamide
(0.350 g, 67%).
[0519] Step 3:
[0520] A stirred solution of
2,2-difluoro-N-(trans-2-methyl-5-oxo-2-phenylpyrrolidin-3-yl)propanamide
(0.250 g, 0.885 mmol, 1 eq), 1-(4-fluorophenyl)-5-iodo-1H-indazole
(0.359 g, 1.0627 mmol, 1.2 eq), K.sub.3PO.sub.4 (0.376 g, 1.770
mmol, 2 eq) in 1,4 dioxane (10 mL) was degassed with argon for 30
min. N,N'-dimethylethylenediamine (0.032 g, 0.354 mmol, 0.4 eq) and
CuI (0.033 g, 0.177 mmol, 0.2 eq) was added and the reaction
mixture was stirred for 72 h at 90.degree. C. in a sealed tube.
After completion of the reaction, (monitored by TLC, TLC system 5%
MeOH in DCM, R.sub.f-0.4), the reaction mixture was filtered
through celite bed and washed 2-3 times with dioxane. The combined
organic layer was concentrated to get the crude product which was
purified by column chromatography (230-400 mesh silica gel; 0 to 2%
MeOH in DCM) to afford
2,2-difluoro-N-(trans-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-5-o-
xo-2-phenylpyrrolidin-3-yl)propanamide (0.046 g, 11%) as off-white
solid.
[0521] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.49 (d, J=8.84
Hz, 1H), 8.32 (s, 1H), 7.78-7.73 (m, 3H), 7.49-7.30 (m, 9H),
4.53-4.49 (m, 1H), 3.00-2.93 (m, 1H), 2.47-2.42 (m, 1H), 1.78 (t,
J=19.52 Hz, 3H), 1.44 (s, 3H).
EXAMPLE 101
N-(trans-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-5-oxo-2-phenylpyr-
rolidin-3-yl)cyclopropanecarboxamide
##STR00059##
[0523] Step 1:
[0524] To a stirred solution of
trans-4-amino-5-methyl-5-phenylpyrrolidin-2-one (350 mg, 1.84 mmol,
1 eq) in DMF (10 mL) TEA (1.2 mL, 9.14 mmol, 5.0 eq),
cyclopropanecarbonyl chloride (288 mg, 2.76 mmol, 1.5 eq) was added
at ice cold condition and the reaction mixture was stirred at RT
for 2 h. After completion of the reaction, (monitored by TLC, TLC
system 5% MeOH in DCM, R.sub.f-0.3), the reaction mixture was
diluted with EtOAc (50 mL) and washed with ice cold water
(3.times.25 mL), dried over Na.sub.2SO.sub.4 and concentrated to
get the crude product which was purified by column chromatography
(230-400 mesh silica gel; 0 to 2% MeOH-DCM) to afford
N-(trans-2-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide
(350 mg, 74%).
[0525] Step 2:
[0526] A stirred solution of
N-(trans-2-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide
(0.250 g, 0.967 mmol, 1 eq), 1-(4-fluorophenyl)-5-iodo-1H-indazole
(0.393 g, 1.16 mmol, 1.2 eq), K.sub.3PO.sub.4 (0.410 g, 1.93 mmol,
2 eq) in 1,4 dioxane (10 mL) was degassed with argon for 30 min.
N,N'-dimethylethylenediamine (0.034 g, 0.387 mmol, 0.4 eq) and CuI
(0.037 g, 0.193 mmol, 0.2 eq) was added and the reaction mixture
was stirred for 72 h at 90.degree. C. in a sealed tube. After
completion of the reaction, (monitored by TLC, TLC system 5% MeOH
in DCM, R.sub.f-0.4), the reaction mixture was filtered through
celite bed and washed 2-3 times with dioxane. The combined organic
layer was concentrated to get the crude product which was purified
by column chromatography (230-400 mesh silica gel; 0 to 2% MeOH in
DCM) to afford
N-(trans-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-5-oxo-2-phenylpy-
rrolidin-3-yl)cyclopropanecarboxamide (0.046 g, 10%) as off-white
solid.
[0527] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.81 (d, J=8.88
Hz, 1H), 8.35 (s, 1H), 7.79-7.74 (m, 3H), 7.52 (s, 1H), 7.48-7.32
(m, 8H), 4.50-4.45 (m, 1H), 2.91-2.85 (m, 1H), 2.30-2.26 (m, 1H),
1.66-1.63 (m, 1H), 1.44 (s, 3H), 0.69 (d, J=6.2 Hz, 4H).
EXAMPLE 121
N-(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-
-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide
##STR00060## ##STR00061##
[0529] Step-1:
[0530] Synthesis of methyl 3-cyclopropyl-2-(nitromethyl)propanoate.
To a stirred solution of methyl 3-nitropropanoate (15 g, 112.74
mmol) in THF (105 ml) was added LDA (2M in THF, 112.7 ml, 225.5
mmol) at -78.degree. C. and the resulting solution was stirred for
1 h at the same temperature. (Bromomethyl)cyclopropane (21.28 ml,
225.5 mmol) was added at -78 C. The reaction mixture was gradually
allowed to reach rt and stirring was continued for 16 h. The
reaction mixture was quenched with aqueous NH.sub.4Cl at 0.degree.
C. The layers were separated and the aqueous part was extracted
with ethyl acetate (600 ml.times.3). The combined organic layers
were washed with brine (300 ml), dried over Na.sub.2SO.sub.4 and
concentrated. The crude product was purified by column
chromatography (using 100-200 mesh silica gel, 6-8% ethyl
acetate-hexanes as eluent) to afford
3-cyclopropyl-2-(nitromethyl)propanoate as brown oil.
[0531] Step-2:
[0532] Synthesis of
rac-(3S,4S,5R)-3-(cyclopropylmethyl)-1-(4-methoxybenzyl)-4-nitro-5-phenyl-
pyrrolidin-2-one. To a stirred solution of benzaldehyde (6.07 ml,
60.09 mmol) in toluene (112.5 ml) was added 4-methoxy benzylamine
(8.24 g, 60.09 mmol) at rt and stirred for 2 h. methyl
3-cyclopropyl-2-(nitromethyl)propanoate (7.5 g, 40.06 mmol) was
added to the reaction mixture followed by benzoic acid (7.34 g,
60.09 mmol) and the resulting mixture was stirred for 7-8 h at
70.degree. C. After completion of the reaction (monitored by LCMS),
the mixture was diluted with ethyl acetate (300 ml) and washed with
water (200 ml), followed by sat.NaHCO.sub.3 (100 ml.times.2). The
organic layer was dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The crude product was purified by column
chromatography (using silica gel 100-200 mesh; 12-15% ethyl acetate
in hexanes as eluent) to afford 4
rac-(3S,4S,5R)-3-(cyclopropylmethyl)-1-(4-methoxybenzyl)-4-nitro-5-phenyl-
pyrrolidin-2-one (7.5 g, 49.1%) as brown oil.
[0533] Step-3:
[0534]
rac-(3S,4S,5R)-3-(cyclopropylmethyl)-4-nitro-5-phenylpyrrolidin-2-o-
ne. To a stirred solution of
rac-(3S,4S,5R)-3-(cyclopropylmethyl)-1-(4-methoxybenzyl)-4-nitro-5-phenyl-
pyrrolidin-2-one (6 g, 15.77 mmol) in acetonitrile (120 ml) was
dropwise added a solution of CAN (25.93 g, 47.31 mmol) in water
(120 ml) at 0.degree. C. The reaction mixture was slowly warmed to
10-15.degree. C. and stirring was continued for 3-4 h. After
completion of the reaction (monitored by TLC, 30% ethyl
acetate/hexane, Rf 0.3), the mixture was diluted with ethyl acetate
(400 ml) and washed with water (200 ml) followed by brine (200 ml).
The organic layer was dried over Na.sub.2SO.sub.4 and concentrated.
The crude material was purified by column chromatography (using
silica gel 100-200 mesh; 25-30% ethyl acetate in hexane as eluent)
to afford
rac-(3S,4S,5R)-3-(cyclopropylmethyl)-4-nitro-5-phenylpyrrolidin-2-one
(3.51 g, 85.6%) as a colorless oil.
[0535] Step-4:
[0536]
rac-(3S,4S,5R)-4-amino-3-(cyclopropylmethyl)-5-phenylpyrrolidin-2-o-
ne. To a stirred solution of
rac-(3S,4S,5R)-3-(cyclopropylmethyl)-4-nitro-5-phenylpyrrolidin-2-one
(4 g, 15.36 mmol) in ethyl acetate-methanol (360 ml, 2:1) was added
6 N aq. HCl (118 ml) at 0.degree. C. Zinc dust (60.29 g, 922.04
mmol) was added portionwise at the same temperature. The resulting
suspension was stirred at room temperature for 16 h. After
completion of the reaction (monitored by LCMS), it was quenched
with saturated NaHCO.sub.3 solution at 0.degree. C., stirred for 1
h, filtered over celite and washed with ethyl acetate-methanol (500
ml, 2:1). The filtrate was concentrated to afford
rac-(3S,4S,5R)-4-amino-3-(cyclopropylmethyl)-5-phenylpyrrolidin-2-one
(3.53 g crude, considered as 100% yield) as off white solid which
was used in next step without further purification.
[0537] Step-5:
[0538] Synthesis of tert-butyl
(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-5-oxo-2-phenylpyrrolidin-3-yl)carba-
mate. To a stirred suspension of
rac-(3S,4S,5R)-4-amino-3-(cyclopropylmethyl)-5-phenylpyrrolidin-2-one
(3.53 g crude, 15.34 mmol) in THF-Water (1:1, 400 ml) was added
sodium bicarbonate (3.86 g, 46.04 mmol) at 0.degree. C. and the
resulting mixture was stirred for 30 minutes at the same
temperature. Di-tert-butyl dicarbonate (10.6 ml, 46.04 mmol) was
added to the reaction mixture at 0.degree. C. and stirring was
continued for 16 h at rt. After completion of the reaction
(monitored by LCMS), the mixture was diluted with water (200 ml)
and extracted with ethyl acetate (3.times.300 ml). The combined
organic layers were washed with water (300 ml) followed by brine
(300 ml). After drying over Na.sub.2SO.sub.4 and concentrating, the
crude material was purified by column chromatography (using silica
gel 100-200 mesh; 1.5-2% MeOH in DCM as eluent) to afford
(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-5-oxo-2-phenylpyrrolidin-3-yl)carba-
mate (3.52 g, 69.5%) as off white solid.
[0539] Step-6:
[0540] Synthesis is of
rac-(3S,4S,5R)-4-amino-3-(cyclopropylmethyl)-5-phenylpyrrolidin-2-one
hydrochloride. To a stirred suspension of
(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-5-oxo-2-phenylpyrrolidin-3-yl)carba-
mate (2 g, 6.05 mmol) in 1,4-dioxane (10 ml) was added 4 N HCl in
1,4-dioxane at 0.degree. C. and stirring was continued at rt for 16
h. After completion of the reaction (monitored by LCMS), the
mixture was concentrated and trituated with ether to afford
rac-(3S,4S,5R)-4-amino-3-(cyclopropylmethyl)-5-phenylpyrrolidin-2-one
hydrochloride (1.62 g, crude) as off white solid.
[0541] Step-7:
[0542] Synthesis of
N-(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-5-oxo-2-phenylpyrrolidin-3-yl)cyc-
lopropanecarboxamide. To a stirred solution of
4-amino-3-(cyclopropylmethyl)-5-phenylpyrrolidin-2-one
hydrochloride (7) (1.62 g, 6.06 mmol) in DCM (30 ml) was added
Et.sub.3N (2.54 ml, 18.21 mmol) at 0.degree. C. and the resulting
mixture was stirred at the same temperature for 20 minutes. A
solution of cyclopropanecarbonyl chloride (0.56 ml, 6.06 mmol) in
DCM (5 ml) was added and stirring was continued at 0.degree.
C.-10.degree. C. for 3 h. After complete consumption of the
starting material (monitored by LCMS), the reaction was diluted
with H.sub.2O, the formed precipitate was filtered and washed with
cold water followed by pentane-ether to afford
N-(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-5-oxo-2-phenylpyrrolidin-3-yl)cyc-
lopropanecarboxamide (1.41 g, 78%) as off white solid.
[0543] Step-8:
[0544] C--N-coupling was performed in analogy to the procedure
described for example 7 Step 1 using
N-(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-5-oxo-2-phenylpyrrolidin-3-yl)cyc-
lopropanecarboxamide. Yield 53%.
[0545] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.59 (d, 1H), 8.29 (s,
1H), 7.79 (d, 1H), 7.77-7.70 (m, 2H), 7.68 (d, 1H), 7.51 (dd, 1H),
7.43-7.36 (m, 2H), 7.32 (d, 2H), 7.25 (t, 2H), 7.19-7.13 (m, 1H),
5.21 (d, 1H), 4.33 (q, 1H), 2.83 (dt, 1H), 1.67-1.59 (m, 2H), 1.57
(ddd, 1H), 0.90 (ddt, 1H), 0.73-0.60 (m, 4H), 0.50-0.32 (m, 2H),
0.18-0.01 (m, 2H)
EXAMPLE 127
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-4-phenethyl-2-phen-
ylpyrrolidin-3-yl)cyclopropanecarboxamide, diastereomer 2; and
EXAMPLE 130
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-4-phenethyl-2-phen-
ylpyrrolidin-3-yl)cyclopropanecarboxamide, diastereomer 1
##STR00062##
[0547] In a dried vessel, intermediate C1--ent 1 (150 mg, 0.33
mmol) was dissolved in dry THF (3.3 ml) under inert atmosphere. The
solution was cooled down to -78.degree. C. and a solution of
freshly prepared LDA (1 M in THF, 0.825 ml, 2.5 eq.) was added
dropwise. After stirring for 15 min at -78.degree. C.,
(2-Iodoethyl)benzene (99.6 mg, 0.429 mmol, 1.3 eq.) dissolved in
dry THF (1.7 mL) was added dropwise. The mixture was allowed to
warm up to -20.degree. overnight and cooled down again to
-60.degree. C. before additional (2-Iodoethyl)benzene (99.6 mg,
0.429 mmol, 1.3 eq.) and LDA (1 M in THF, 0.682 ml, 2.0 eq.) were
added. After stirring for 90 minutes at -60.degree. C., a third
amount of (2-Iodoethyl)benzene (99.6 mg, 0.429 mmol, 1.3 eq.)
followed by LDA (1 M in THF, 0.34 ml, 1.0 eq.). The mixture was
stirred again overnight at -20.degree. C. and quenched with
saturated NH.sub.4Cl solution at that temperature before the
mixture was diluted with ethyl acetate. The crude material was
purified via flash chromatography (silica, cyclohexane/ethyl
acetate gradient as eluent) and subsequent prep.-HPLC
(water/acetonitrile gradient) to obtain example 127
(N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-4-phenethyl-2-ph-
enylpyrrolidin-3-yl)cyclopropanecarboxamide second eluting
diastereomer, 6 mg, 0.011 mmol, 3%) and example 130
(N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-4-phenethyl-2-ph-
enylpyrrolidin-3-yl)cyclopropanecarboxamide first eluting
diastereomer, 12.0 mg, 0.021 mmol, 6%) as white solids.
EXAMPLE 127
[0548] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.94 (d, 1H), 8.35-8.28
(m, 1H), 8.01 (d, 1H), 7.83 (dd, 1H), 7.80-7.63 (m, 3H), 7.44-7.23
(m, 9H), 7.26-7.16 (m, 1H), 7.19-7.13 (m, 2H), 7.15-7.03 (m, 1H),
5.26 (d, 1H), 4.52 (ddd, 1H), 2.93 (tdd, 1H), 2.65-2.52 (m, 2H),
1.85-1.68 (m, 2H), 1.24 (s, 1H), 1.18 (s, 1H), 0.90-0.69 (m,
3H).
EXAMPLE 128
[0549] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.66 (d, J=8.4 Hz, 1H),
8.29 (d, J=1.3 Hz, 1H), 7.79 (d, J=1.9 Hz, 1H), 7.74 (ddd, 2H),
7.68 (d, 1H), 7.54-7.48 (m, 1H), 7.43-7.36 (m, 2H), 7.36-7.28 (m,
4H), 7.26 (t, 2H), 7.23-7.14 (m, 4H), 5.21 (d, 1H), 4.22 (td, 1H),
2.76 (t, 2H), 2.70 (td, 1H), 2.18 2.06 (m, 2H), 1.88 (dq, 1H), 1.58
(tt, 1H), 0.77-0.62 (m, 4H).
EXAMPLES 128
N-(rac-(2R,3R,4R)-4-fluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-
-5-oxo-2-phenlpyrrolidin-3-yl)cyclopropanecarboxamide and example
129
N-((2R,3R,4S)-4-fluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5--
oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide
##STR00063## ##STR00064##
[0551] Step-1:
[0552] In a 250 ml round-bottom-flask, a solution of intermediate
A8 (2370 mg, 7.31 mmol) in acetonitrile (120 ml) was added to
sodium iodide (6570 mg, 43.8 mmol, 6 eq.) under nitrogen
atmosphere. To the resulting mixture, trimethylsilyl chloride (3.71
ml, 29.2 mmol 4.0 eq.) was added dropwise. After stirring overnight
at room temperature, the reaction mixture was added dropwise to
ethanol (142 ml) and filtered over celite. The filtrate was loaded
on a strong cation exchange-cartridge (SCX, 5 g), flushed two times
with ethanol (15 ml each) and eluated with 2 M NH.sub.3 in methanol
(2.times.10 mL). This procedure was repeated using the
product-containing fractions two times. The clean fractions were
combined, and the solvent was removed in vacuo to obtain
rac-(3S,4S,5R)-4-amino-3-methyl-5-phenylpyrrolidin-2-one (296 mg,
1.56 mmol, 21%) as a colorless resin.
[0553] Step-2:
[0554] rac-(3S,4S,5R)-4-amino-3-methyl-5-phenylpyrrolidin-2-one
(328 mg, 1.72 mmol) and cyclopropanecarboxylic acid (297 mg, 3.45
mmol, 2.0 eq.) were dissolved in dichloromethane (17.2 ml) at room
temperature. Triethylamine (689 mg, 6.90 mmol, 4.0 eq.) was added
dropwise to the mixture which was stirred until all starting
materials had dissolved. Propylphosphonic anhydride solution
(>50 wt. % in ethyl acetate, 2.57 ml, 4.31 mmol, 2.5 eq.) was
added to the reaction and stirring was continued at rt. After 3 h,
reaction control (UPLC) showed full consumption of the starting
materials and the reaction was quenched with 1 M
Na.sub.2CO.sub.3-solution. After stirring for one hour, the product
precipitated and was filtered off yielding
N-(rac-(2R,3S,4S)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarb-
oxamide (264 mg, 1.02 mmol, 59%) as a white solid. The obtained
material was used in the next step without further
purification.
[0555] Step-3:
[0556] To a suspension of
N-(rac-(2R,3S,4S)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarb-
oxamide (263 mg, 1.02 mmol), triethyl amine (206 mg, 2.04 mmol, 2.0
eq.) and 4-dimethylamino pyridine (12.4 mg, 0.102 mmol, 0.1 eq.) in
acetonitrile (10 ml), a solution of di-tert-butyl-dicarbonate (244
mg, 1.12 mmol, 1.1 eq.) in acetonitrile (2 ml) was added in a
sealed tube. The reaction mixture was heated to 80.degree. C. for
30 minutes and stirred overnight at room temperature. Additional
di-tert-butyl-dicarbonate (133 mg, 0.611 mmol, 0.6 eq.) in
acetonitrile (2 ml) was added and stirring was continued at room
temperature until reaction control (UPLC) proved the reaction to be
complete (2 h). Dichloromethane and saturated NaHCO.sub.3-solution
were added to the reaction, the layers were separated and the
aqueous layer was extracted once with dichloromethane. The combined
organic layers were dried over magnesium sulfate and the solvent
was removed in vacuo. The crude material was purified via flash
chromatography (12 g silica, cyclohexane/ethyl acetate gradient as
eluent) and tert-butyl
rac-(3S,4S,5R)-4-(cyclopropanecarbonylamino)-3-methyl-2-oxo-5-phenyl-pyrr-
olidine-1-carboxylate (234 mg, 0.653 mmol, 64%) was obtained as a
white solid.
[0557] Step-4:
[0558] In a dried vessel, tert-butyl
rac-(3S,4S,5R)-4-(cyclopropanecarbonylamino)-3-methyl-2-oxo-5-phenyl-pyrr-
olidine-1-carboxylate (80 mg, 0.223 mmol) was dissolved in dry THF
(2.2 ml) under inert atmosphere. The solution was cooled down to
-78.degree. C. and a solution of lithium bis(trimethylsilyl)amide
(1 M in THF, 0.446 ml, 0, 446 mmol, 2.0 eq) was added carefully.
After stirring for 15 minutes at -78, a solution of
N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (70.4 mg, 0.223 mmol,
1.0 eq) in THF (1 mL) was added dropwise. After stirring for 45 min
at that temperature, another amount of
N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (35.0 mg, 0.111 mmol,
0.5 eq.) in THF (0.5 mL) were added and stirring was continued for
30 min. The reaction was quenched at -78.degree. using sat.
NH.sub.4Cl solution, diluted with DCM and quickly poured over a
hydrophobic frit, before the mixture could warm up. The organic
layer was washed with water and separated again. The crude product
was purified via flash chromatography (12 g silica,
cyclohexane/ethyl acetate gradient as eluent) to yield tert-butyl
(4R,5R)-4-(cyclopropanecarboxamido)-3-fluoro-3-methyl-2-oxo-5-phenylpyrro-
lidine-1-carboxylate (47 mg, 0.125 mmol, 56%) as a mixture of
epimers (3:1).
[0559] Step-5:
[0560] To a solution of tert-butyl
(4R,5R)-4-(cyclopropanecarboxamido)-3-fluoro-3-methyl-2-oxo-5-phenylpyrro-
lidine-1-carboxylate (46.0 mg, 0.122 mmol) in dichloromethane (1.22
ml) was added trifluoroacetic acid (0.094 ml, 1.22 mmol, 10.0 eq.)
at room temperature. After stirring for 30 minutes, reaction
control (UPLC) proved the reaction to be complete and the mixture
was quenched using sat. NaHCO.sub.3-solution. DCM was added to the
mixture and layers were separated by the means of a hydrophobic
frit. Evaporation of the organic layer gave
N-((2R,3R)-4-fluoro-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropaneca-
rboxamide (27 mg, 0.098 mmol, 80%) as a brown oil which was used
without further purification
[0561] Step-6:
[0562] In a sealed tube,
N-((2R,3R)-4-fluoro-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropaneca-
rboxamide (27.0 mg, 0.098 mmol), 1-(4-fluorophenyl)-5-iodo-indazole
(36.3 mg, 0.107 mmol, 1.1 eq.), K.sub.3PO.sub.4 (41.5 mg, 0.195
mmol, 2.0 eq) and CuI (3.7 mg, 0.020 mmol, 0.2 eq.) were dissolved
in degassed 1,4-dioxane (1 ml). To the mixture,
(1R,2R)--N,N'-dimethyl-1,2-cyclohexandiamine (5.6 mg, 0.039 mmol,
0.4 eq.) was added and the reaction was heated to 100.degree. C.
overnight and to 120.degree. C. for 5 h. The reaction was quenched
using sat. NaHCO.sub.3-solution and diluted with dichloromethane.
The layers were separated by the means of a hydrophobic frit and
the aqueous layer was washed multiple times with DCM. The organic
layers were combined and the solvent was evaporated. The crude
material was purified via flash chromatography (silica,
cyclohexane/ethyl acetate gradient as eluent) and subsequent
prep.-HPLC (water/acetonitrile gradient) to obtain example 128
N-((2R,3R,4R)-4-fluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5--
oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide (1.8 mg, 0.003
mmol, 4%) and example 129
N-((2R,3R,4S)-4-fluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5--
oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide (5.8 mg, 0.012
mmol, 12%).
EXAMPLE 128
[0563] .sup.1H NMR (DMSO-d.sub.6) .delta.:8.11 (d, 1H), 7.78 (dd,
1H), 7.67-7.59 (m, 2H), 7.56 (dt, 1H), 7.48 (dd, 1H), 7.39-7.19 (m,
6H), 7.26-7.16 (m, 1H), 6.29-6.20 (m, 1H), 5.15 (d, 1H), 4.66 (ddd,
1H), 1.69 (d, 3H), 1.47 (tt, 1H), 1.01 (dddd, 1H), 0.95-0.90 (m,
1H), 0.82 (m, 2H).
EXAMPLE 129
[0564] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.69 (dd, 1H), 8.33 (d,
1H), 7.87 (d, 1H), 7.82-7.67 (m, 3H), 7.51 (dd, 1H), 7.45-7.30 (m,
4H), 7.26 (t, 2H), 7.22-7.13 (m, 1H), 5.12 (dd, 1H), 4.68 (ddd,
1H), 1.66 (tt, 1H), 1.54 (d, 3H), 0.77-0.65 (m, 3H), 0.58 (dtd,
1H)
EXAMPLE 131
N-((2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-
-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide and example
132
N-((2R,3S,4R)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl-
)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide
##STR00065##
[0566] In a dried vessel, intermediate C1--ent 1 (150 mg, 0.33
mmol) was dissolved in dry THF (3.3 ml) under inert atmosphere. The
solution was cooled down to -78.degree. C. and a solution of
freshly prepared LDA (1 M in THF, 0.825 ml, 2.5 eq.) was added
dropwise. After stirring for 15 min at -78.degree. C.,
1,1-difluoro-2-iodo-ethane (82.4 mg, 0.429 mmol, 1.3 eq.) dissolved
in dry THF (1.7 mL) was added dropwise. The mixture was warmed up
to -40.degree. C. and stirred overnight at that temperature.
Another amount of, 1,1-difluoro-2-iodo-ethane (82.4 mg, 0.429 mmol,
1.3 eq.) was added and the mixture was warmed up to -20.degree. C.
At this temperature, sat. NH.sub.4Cl-solution was added and
stirring was continued before the mixture was diluted with ethyl
acetate. After the layers were separated, the organics were dried
over sodium sulfate and the solvent was removed in vacuo. The crude
material was purified via flash chromatography (12 g silica,
cyclohexane/ethyl acetate gradient as eluent) to obtain example 131
N-((2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl-
)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide (9.0 mg,
0.017 mmol, 5%) and example 132
N-((2R,3S,4R)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl-
)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide (7.0 mg,
0.014 mmol, 4%) as white solids.
EXAMPLE 131
[0567] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.30 (d, J=1.0 Hz, 1H),
7.85-7.64 (m, 3H), 7.68 (d, 1H), 7.56-7.21 (m, 6H), 7.36-7.07 (m,
3H), 5.24 (d, 1H), 4.25 (q, 1H), 2.97 (q, 1H), 2.54-2.34 (m, 1H),
1.25 (s, 2H), 0.81-0.52 (m, 3H).
EXAMPLE 132
[0568] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.95 (d, 1H), 8.33 (s,
1H), 8.02 (d, 1H), 7.85 (dd, J=9.2, 2.1 Hz, 1H), 7.87-7.67 (m, 3H),
7.51-7.19 (m, 7H), 5.28 (s, 1H), 4.42 (t, 1H), 3.22-3.02 (m, 1H),
2.25-2.02 (m, 1H), 1.24 (s, 2H), 0.96-0.63 (m, 4H).
EXAMPLE 134
N-(rac-(2R,3S,4R)-4-ethyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl--
5-oxo-2-phenlpyrrolidin-3-yl)cyclopropanecarboxamide
##STR00066##
[0570] Step-1:
[0571] In a dried vessel, example 46 (50 mg, 0.107 mmol) was
dissolved in dry THF (1.1 ml) under inert atmosphere. The solution
was cooled down to -78.degree. C. and a solution of freshly
prepared LDA (1 M in THF, 0.267 ml, 2.5 eq.) was added dropwise.
After stirring for 15 min at -78.degree. C., iodoethane (25.0 mg,
0.160 mmol, 1.5 eq.) dissolved in dry THF (0.5 mL) was added
dropwise. The mixture was warmed up to -60.degree. C. and stirred
for 90 minutes at that temperature. Then, the reaction was cooled
down again to -78.degree. C. before another amount of Iodoethane
(12.5 mg, 0.080 mmol, 0.75 eq.) dissolved in dry THF (0.5 ml) was
added. After stirring for 1 h at -78.degree. C. the reaction was
quenched with saturated NH.sub.4Cl-solution and diluted with
dichloromethane after stirring for 5 min. The layers were separated
by the means of a hydrophobic frit. The organic layer was washed
with water, separated again and dried over sodium sulfate. After
removal of the solvent, the crude material was purified via flash
chromatography (silica, cyclohexane/ethyl acetate gradient as
eluent) and subsequent prep.-HPLC (water/acetonitrile gradient) to
obtain example 134
N-(rac-(2R,3S,4R)-4-ethyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-
-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide (6 mg, 0.012
mmol, 11%) as a colorless resign.
[0572] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.47 (d, 1H), 8.30 (d,
1H), 7.77-7.71 (m, 3H), 7.68 (d, 1H), 7.46 (dd, 1H), 7.39 (dd, 2H),
7.36-7.33 (m, 2H), 7.24 (t, 2H), 7.15 (td, 1H), 5.15 (d, 1H), 4.33
(t, 1H), 1.72-1.63 (m, 2H), 1.54 (dq, 1H), 1.24 (s, 3H), 0.95 (d,
2H), 0.73-0.67 (m, 1H), 0.63 (qt, 2H), 0.59-0.50 (m, 1H).
EXAMPLE 135
N-((7R,8S)-6-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-7-phenyl-6-azaspir-
o[3.4]octan-8-yl)cyclopropanecarboxamid
##STR00067##
[0574] In a dried vessel, intermediate C1--ent 1 (150 mg, 0.33
mmol) was dissolved in dry THF (3.3 ml) under inert atmosphere. The
solution was cooled down to -78.degree. C. and a solution of
freshly prepared LDA (1 M in THF, 0.825 ml, 2.5 eq.) was added
dropwise. After stirring for 15 min at -78.degree. C.,
1,3-Dibromopropane (93.3 mg, 0.462 mmol, 1.3 eq.) dissolved in dry
THF (1.7 mL) was added dropwise. The mixture was warmed up to room
temperature overnight. The mixture was cooled down again to
-20.degree. C. before additional amounts of LDA (1 M in THF, 0.330
ml, 1.0 eq.) and 1,3-dibromopropane (71.8 mg, 0.355 mmol, 1.0 eq.)
were added. After stirring for 15 minutes, another amount of LDA (1
M in THF, 0.495 ml, 1.5 eq.) was added. The mixture was allowed to
warm up to room temperature again overnight and quenched with sat.
NH.sub.4Cl-solution. Stirring was continued for 5 minutes before
the mixture was diluted with ethyl acetate. After the layers were
separated, the organics were dried over sodium sulfate and the
solvent was removed in vacuo. The crude material was purified via
flash chromatography (12 g silica, cyclohexane/ethyl acetate
gradient as eluent) to obtain example 135
N-((7R,8S)-6-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-7-phenyl-6-azaspi-
ro[3.4]octan-8-yl)cyclopropanecarboxamid (11 mg, 0.022 mmol, 7%)
colorless resin.
[0575] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.09 (d, 1H), 7.99 (dd,
1H), 7.81 (dd, 1H), 7.63 (ddd, 2H), 7.56 (dt, 1H), 7.43-7.39 (m,
2H), 7.35-7.30 (m, 3H), 7.28-7.24 (m, 1H), 7.24-7.20 (m, 2H), 6.03
(d, 1H).
EXAMPLE 137
N-(rac-(2R,3R,4S)-4-benzyl-2-ethyl-4-fluoro-1-(1-(4-fluorophenyl)-1H-indaz-
ol-5-yl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide
##STR00068##
[0577] Step-1:
[0578] In a dried vessel, example 106 (70 mg, 0.141 mmol) was
dissolved in dry THF (1.4 ml) under inert atmosphere. The solution
was cooled down to -78.degree. C. and a solution of freshly
prepared LDA (1 M in THF, 0.352 ml, 2.5 eq.) was added dropwise.
After stirring for 15 min at -78.degree. C.,
N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (NFSI, 66.7 mg, 0.211
mmol, 1.5 eq.) dissolved in dry THF (0.7 mL) was added dropwise.
The mixture was stirred for 15 min at -78.degree. C. and quenched
with saturated NH.sub.4Cl-solution. After stirring for 5 min, the
mixture was diluted with ethyl acetate and the layers were
separated. After removal of the solvent, the crude material was
purified via via flash chromatography (silica, cyclohexane/ethyl
acetate gradient as eluent) to give example 137
N-(rac-(2R,3R,4S)-4-benzyl-2-ethyl-4-fluoro-1-(1-(4-fluorophenyl)-1H-inda-
zol-5-yl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide (4 mg, 0.008
mmol, 6%) as a colorless oil.
[0579] .sup.1H NMR (Chloroform-d.sub.3) .delta.: 8.19 (d, 1H), 7.67
(dd, 3H), 7.57 (d, 1H), 7.39-7.34 (m, 3H), 7.32 (dd, 2H), 7.28-7.25
(m, 2H), 7.22 (dd, 1H), 6.01 (t, 1H), 4.97-4.86 (m, 1H), 3.51-3.42
(m, 1H), 3.34 (dd, 1H), 3.17-3.08 (m, 1H), 1.54 (qd, 2H), 1.42 (tt,
1H), 1.15-1.09 (m, 1H), 1.10-1.05 (m, 1H), 0.94-0.88 (m, 1H), 0.85
(dddd, 1H), 0.75 (t, 3H).
EXAMPLE 138
N-((2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-((3-methyl-1,2,4-ox-
adiazol-5-yl)methyl)-5-oxo-2-phenlpyrrolidin-3-yl)cyclopropanecarboxamide
##STR00069##
[0581] Example 138 was prepared in analogy to the synthesis
described for example 131 using
5-(bromomethyl)-3-methyl-1,2,4-oxadiazole instead of
1,1-difluoro-2-iodo-ethane. Yield: 9%
[0582] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.55 (d, 1H), 8.29 (d,
1H), 7.77-7.70 (m, 3H), 7.70-7.64 (m, 1H), 7.47-7.36 (m, 5H), 7.24
(t, 2H), 7.17-7.10 (m, 1H), 5.27 (d, 1H), 4.41 (q, 1H), 3.46-3.36
(m, 1H), 2.35 (s, 3H), 1.50 (tt, 1H), 0.71-0.50 (m, 4H).
EXAMPLE 139A
N-((2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-((1-methyl-H-pyrazo-
l-4-yl)methyl)-5-oxo-2-phenlpyrrolidin-3-yl)cyclopropanecarboxamide
and example 139b
N-((2R,3S,4R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-((1-methyl-1H-pyra-
zol-4-yl)methyl)-5-oxo-2-phenlpyrrolidin-3-yl)cyclopropanecarboxamide
##STR00070##
[0584] Examples 139a and 139b were prepared in analogy to the
synthesis described for examples 131 and 132 using and 5.0 eq. of
LDA and 4-(bromomethyl)-1-methyl-1H-pyrazole hydrobromide instead
of 1,1-difluoro-2-iodo-ethane. Yields: 7% (139a) and 6% (139b).
EXAMPLE 139A
[0585] .sup.1H NMR (Chloroform-d.sub.3) .delta.: 8.06 (d, 1H), 7.68
(d, 1H), 7.61-7.54 (m, 2H), 7.51-7.43 (m, 2H), 7.37 (dd, 1H), 7.29
(d, 1H), 7.25-7.13 (m, 5H), 7.07-7.00 (m, 2H), 6.13 (d, 1H), 5.13
(d, 1H), 4.23 (dt, 1H), 3.87 (s, 3H), 3.08-2.98 (m, 3H), 1.38 (tt,
1H), 1.05-0.93 (m, 2H), 0.79 (ddddd, 2H).
EXAMPLE 139B
[0586] .sup.1H NMR (Chloroform-d.sub.3) .delta.: 8.07 (d, 1H), 7.95
(d, 1H), 7.69 (dd, 1H), 7.64-7.58 (m, 2H), 7.51 (d, 1H), 7.42-7.33
(m, 5H), 7.32-7.27 (m, 1H), 7.26 (s, 1H), 7.25-7.19 (m, 2H), 6.58
(d, 1H), 5.17 (s, 1H), 4.58 (t, 1H), 3.84 (s, 3H), 3.21-3.11 (m,
2H), 2.92-2.83 (m, 1H), 1.50 (tt, 1H), 1.16-1.07 (m, 2H), 0.94-0.81
(m, 2H).
EXAMPLE 148
N-(rac-(2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-
-yl)-4-methyl-5-oxo-2-phenlpyrrolidin-3-yl)cyclopropanecarboxamide
##STR00071##
[0588] Step-1:
[0589] In a dried vessel, example 46 (71 mg, 0.152 mmol) was
dissolved in dry THF (1.5 ml) under inert atmosphere. The solution
was cooled down to -78.degree. C. and a solution of freshly
prepared LDA (1 M in THF, 0.379 ml, 2.5 eq.) was added dropwise.
After stirring for 15 min at -78.degree. C.,
1,1-difluoro-2-iodo-ethane (43.6 mg, 0.160 mmol, 1.5 eq.) dissolved
in dry THF (0.75 mL) was added dropwise. The mixture was warmed up
to -50.degree. C. and stirred for 45 minutes at that temperature.
Then, another amount of 1,1-difluoro-2-iodo-ethane (11.4 mg, 0.110
mmol, 0.75 eq.) dissolved in dry THF (0.5 ml) was added. After
stirring for 1 h at -78.degree. C. the reaction was quenched with
saturated NH.sub.4Cl-solution and diluted with dichloromethane
after stirring for 5 min. The layers were separated by the means of
a hydrophobic frit. The organic layer was washed with water,
separated again and dried over sodium sulfate. After removal of the
solvent, the crude material was purified via prep.-HPLC
(water/acetonitrile gradient) to obtain example 148
N-(rac-(2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-inda-
zol-5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)
cyclopropanecarboxamide 3.0 mg 0.0056 mmol, 3.7%) as a colorless
resin.
[0590] .sup.1H NMR (Chloroform-d.sub.3) .delta.: 8.07 (d, 1H), 7.63
(d, 1H), 7.60-7.56 (m, 2H), 7.50 (dt, 1H), 7.32 (dd, 1H), 7.29-7.25
(m, 4H), 7.23-7.18 (m, 3H), 6.43 (tdd, 1H), 5.91 (dd, 1H), 4.92 (d,
1H), 4.78 (t, 1H), 2.50-2.39 (m, 1H), 2.39-2.27 (m, 1H), 1.43-1.37
(m, 1H), 1.36 (s, 3H), 0.97 (dddd, 1H), 0.86 (dddd, 1H), 0.83-0.77
(m, 1H), 0.74 (dddd, 1H).
EXAMPLE 149
N-(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-
-yl)-4-methyl-5-oxo-2-phenlpyrrolidin-3-yl)cyclopropanecarboxamide
##STR00072##
[0592] Step-1:
[0593] In a dried vessel, example 121 (150 mg, 0.295 mmol) was
dissolved in dry THF (3 ml) under inert atmosphere. The solution
was cooled down to -78.degree. C. and a solution of freshly
prepared LDA (1 M in THF, 0.737 ml, 2.5 eq.) was added dropwise.
After stirring for 15 min at -78.degree. C., iodomethane (62.8 mg,
0.442 mmol, 1.5 eq.) was added dropwise. The mixture was stirred
for 45 minutes at that temperature. Then, another amount of
iodomethane (42 mg, 0.110 mmol, 1 eq.) was added. After stirring
for 1 h at -78.degree. C. the reaction was quenched with saturated
NH.sub.4Cl-solution and diluted with dichloromethane after stirring
for 5 min. The layers were separated by the means of a hydrophobic
frit. The organic layer was washed with water, separated again and
dried over sodium sulfate. After removal of the solvent, the crude
material was purified via prep.-HPLC (water/acetonitrile gradient)
to obtain Example 149
N-(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-1-(1-(4-fluorophenyl)-1H-indazol--
5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide
(14.0 mg, 0.0268 mmol, 9%) as a colorless resin.
[0594] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.44 (d, 1H), 8.30 (d,
1H), 7.79-7.70 (m, 3H), 7.68 (d, 1H), 7.47 (dd, 1H), 7.43-7.33 (m,
4H), 7.23 (t, 2H), 7.15 (td, 1H), 5.23 (d, 1H), 4.34 (t, 1H), 1.85
(dd, 1H), 1.69 (ddd, 1H), 1.30 (s, 3H), 1.13 (dd, 1H), 1.05 (tt,
1H), 0.71 (tdd, 1H), 0.68-0.58 (m, 2H), 0.55 (tdt, 1H), 0.45-0.36
(m, 2H), 0.08-0.05 (m, 2H).
EXAMPLE 150
N-((2R,3S,4R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenyl-4-(thi-
azol-2-ylmethyl)pyrrolidin-3-yl)cyclopropanecarboxamide
##STR00073##
[0596] Step-1:
[0597] In a dried vessel, intermediate C1--ent 1 (150 mg, 0.295
mmol) was dissolved in dry THF (4.7 ml) under inert atmosphere. The
solution was cooled down to -78.degree. C. and a solution of
freshly prepared LDA (1 M in THF, 1.32 ml, 4 eq.) was added
dropwise. After stirring for 15 min at -78.degree. C.,
2-(chloromethyl)-1,3-thiazole hydrochloride (67 mg, 0.396 mmol, 1.2
eq.) was added as a solid. The mixture was for one hour at
-40.degree. C. Then, another amount of LDA (1 M in THF, 0.165 ml, 1
eq.) followed by 2-(chloromethyl)-1,3-thiazole hydrochloride (28.1
mg, 0.165 mmol, 0.5 eq.) was added. After stirring overnight at
-40.degree. C., the reaction was quenched with saturated
NH.sub.4Cl-solution and diluted with dichloromethane after stirring
for 5 min. The layers were separated by the means of a hydrophobic
frit. The organic layer was washed with water, separated again and
dried over sodium sulfate. After removal of the solvent, the crude
material was purified via prep.-HPLC (water/acetonitrile gradient)
to obtain example 150.
N-((2R,3S,4R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenyl-4-(th-
iazol-2-ylmethyl)pyrrolidin-3-yl)cyclopropanecarboxamide (26.3 mg
0.0477 mmol 14%) as a off-white solid.
[0598] .sup.1H NMR (600 MHz, Chloroform-d.sub.3) .delta.: 9.22 (d,
1H), 8.06 (d, 1H), 7.77 (d, 1H), 7.72 (d, 1H), 7.65-7.58 (m, 2H),
7.53-7.46 (m, 2H), 7.45-7.40 (m, 2H), 7.37-7.31 (m, 3H), 7.31-7.26
(m, 1H), 7.24-7.18 (m, 2H), 5.09 (d, 1H), 4.72 (td, 1H), 3.71 (dd,
1H), 3.58 (td, 1H), 3.44 (dd, 1H), 1.56 (tt, 1H), 1.09-1.02 (m,
2H), 0.85-0.78 (m, 2H).
EXAMPLE 151
N-((2S,3S)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl-
)-2-methyl-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide
##STR00074## ##STR00075##
[0600] Step-1:
[0601] To a stirred solution of
1-(5-chlorothiophen-2-yl)ethan-1-one (20 g, 125 mmol, 1.0 eq) in
EtOH (250 mL) at RT were added NaOAc (50.6 g, 625 mmol, 5.0 eq) and
NH.sub.2OH.HCl (25.7 g, 375 mmol, 3.0 eq) and stirred for 16 h at
80.degree. C. The reaction progress was monitored by TLC. The
reaction mixture was evaporated, diluted with H.sub.2O and the
formed precipitate was washed with H.sub.2O (100 mL) and dried
under vacuum to get (E)-1-(5-chlorothiophen-2-yl)ethan-1-one oxime
(20 g, 94%) as a brown liquid.
[0602] Step-2:
[0603] To a stirred solution of compound
(E)-1-(5-chlorothiophen-2-yl)ethan-1-one oxime (10 g, 57.14 mmol,
1.0 eq) in DCM (100 mL) at -40.degree. C. were added TEA (9.2 mL,
68.57 mmol, 1.2 eq) and the mixture was stirred for 15 min prior to
the addition of chlorodiphenylphosphine (13.8 g, 62.85 mmol, 1.1
eq). The reaction was slowly allowed to warm up to rt and stirred
for 2 h. The reaction progress was monitored by TLC. The reaction
mixture was diluted with H.sub.2O (100 mL), and extracted with DCM
(2.times.200 mL). The combined organic layer was washed with brine
(100 mL), dried over Na.sub.2SO.sub.4 and evaporated. The crude
product was purified by flash chromatography (silica 40-60% EtOAc
in petroleum ether as an eluent) to get compound
(E)-N-(1-(5-chlorothiophen-2-yl)ethylidene)-P,P-diphenylphosphinic
amide (15 g, 73%) as a brown solid.
[0604] Step-3:
[0605] To a stirred solution of compound
(E)-N-(1-(5-chlorothiophen-2-yl)ethylidene)-P,P-diphenylphosphinic
amide (15 g, 41.71 mmol, 1.0 eq) in THF (200 mL) at RT were under
nitrogen atmosphere added Cu(OAc).sub.2 (0.377 g, 2.85 mmol, 0.05
eq), TPP (1.0 g, 4.16 mmol, 0.1 eq). The mixture was stirred for 15
min prior to the addition of diethyl fumarate (18 mL, 104 mmol, 2.5
eq), and pinacolborane (14.8 mL, 116 mmol, 2.8 eq). Stirring was
continued for 16 h at RT. The reaction progress was monitored by
TLC. The reaction mixture was diluted with water (100 mL) and
extracted with EtOAc (2.times.100 mL). The combined organic layers
were washed with brine (100 mL), dried (Na.sub.2SO.sub.4) and
evaporated. The crude compound was purified by flash chromatography
(silica 40-60% EtOAc in petroleum ether as an eluent) to get
compound ethyl
2-(5-chlorothiophen-2-yl)-1-(diphenylphosphoryl)-2-methyl-5-oxopyrrolidin-
e-3-carboxylate (15 g, -75%) as a white solid.
[0606] Step-4:
[0607] To a stirred solution of compound ethyl
2-(5-chlorothiophen-2-yl)-1-(diphenylphosphoryl)-2-methyl-5-oxopyrrolidin-
e-3-carboxylate (15 g, 30.80 mmol, 1.0 eq) in EtOH (150 mL) at RT
was added conc. HCl (15 mL) and stirred for 16 h at 90.degree. C.
The reaction progress was monitored by TLC. The reaction mixture
was evaporated, diluted with water (50 mL), basified with sat
NaHCO.sub.3 (pH=8), and extracted with EtOAc (2.times.200 mL). The
combined organic layers were washed with brine (100 mL), dried
(Na.sub.2SO.sub.4) and evaporated. The crude compound was purified
by flash chromatography (silica 60-70% EtOAc in petroleum ether as
an eluent) to get compound ethyl
rac-(2S,3S)-2-(5-chlorothiophen-2-yl)-2-methyl-5-oxopyrrolidine-3-c-
arboxylate (7.0 g, -81%) as white solid.
[0608] Step-5:
[0609] To a stirred solution of compound ethyl
(2S,3S)-2-(5-chlorothiophen-2-yl)-2-methyl-5-oxopyrrolidine-3-carboxylate
(7 g, 24.39 mmol, 1.0 eq) in THF/MeOH/H.sub.2O (1:1:1, 75 mL) at RT
was added LiOH*H.sub.2O (1.7 g, 48.78 mmol, 2.0 eq) at Rt and
stirring was continued at the same temperature. The reaction
progress was monitored by TLC. The reaction mixture was evaporated,
diluted with water (30 mL), and extracted with Et.sub.2O
(2.times.50 mL). The aqueous layer was acidified with 1N HCl
(pH=4-5), and precipitate formed was filtered and dried to get
compound
(2S,3S)-2-(5-chlorothiophen-2-yl)-2-methyl-5-oxopyrrolidine-3-carboxylic
acid (3.5 g, -97%) as white solid.
[0610] Step-6:
[0611] To a stirred solution of compound
rac-(2S,3S)-2-(5-chlorothiophen-2-yl)-2-methyl-5-oxopyrrolidine-3-carboxy-
lic acid (3.4 g, 13.12 mmol, 1.0 eq) in toluene (70 mL) at RT were
added TEA (2.0 mL, 13.78 mmol, 1.05 eq), DPPA (3.4 mL, 15.74 mmol,
1.2 eq). Stirring was continued for 2 h at 90.degree. C., the
mixture was then cooled to RT, prior to the addition of BnOH (3 mL,
26.25 mmol, 2.0 eq). The resulting mixture was heated for 16 h to
120.degree. C. The reaction progress was monitored by TLC. The
reaction mixture was evaporated, diluted with water (50 mL) and
extracted with EtOAc (2.times.100 mL). The combined organic layers
were washed with brine (50 mL), dried (Na.sub.2SO.sub.4) and
evaporated. The crude compound was purified by flash chromatography
(silica 70-90% EtOAc in petroleum ether as an eluent) to get
compound benzyl
(rac-(2S,3S)-2-(5-chlorothiophen-2-yl)-2-methyl-5-oxopyrrolidin-3-yl)carb-
amate (2.0 g, -41%) as an off-white solid.
[0612] Step-7:
[0613] A stirred solution of compound benzyl
(rac-(2S,3S)-2-(5-chlorothiophen-2-yl)-2-methyl-5-oxopyrrolidin-3-yl)carb-
amate (2.0 g, 5.49 mmol, 1.0 eq) in HBr in AcOH (20 mL) at RT was
stirred for 2 h at RT. The reaction progress was monitored by TLC.
The reaction mixture was quenched with NaHCO.sub.3 solution and
extracted with EtOAc (4.times.100 mL). The combined organic layers
were washed with brine (50 mL), dried (Na.sub.2SO.sub.4) and
evaporated. The crude compound was purified by by flash
chromatography (silica 70-80% EtOAc in petroleum ether as an
eluent) to get compound
rac-(4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-5-methylpyrrolidin-2-one
(1.0 g, -41%) as an off-white solid.
[0614] Step-8:
[0615] To a stirred solution of compound
rac-(4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-5-methylpyrrolidin-2-one
(400 mg, 1.739 mmol, 1.0 eq) and cyclopropane carboxylic acid (224
mg, 2.608 mmol, 1.5 eq) in DMF (10 mL) at 0.degree. C. under
nitrogen atmosphere were added HATU (0.90 g, 2.608 mmol, 1.5 eq),
DIPEA (0.9 mL, 5.217 mmol, 3.0 eq) and stirred for 16 h at RT. The
reaction progress was monitored by TLC. The reaction mixture was
diluted with water (20 mL) and extracted with EtOAc (2.times.20
mL). The combined organic layers were washed with brine (20 mL),
dried (Na.sub.2SO.sub.4) and evaporated. The crude compound was
purified by by flash chromatography (silica 70-90% EtOAc in
petroleum ether as an eluent) to get compound
N-(rac(2S,3S)-2-(5-chlorothiophen-2-yl)-2-methyl-5-oxopyrrolidin-3-yl)cyc-
lopropanecarboxamide (210 mg, -40%).
[0616] Step-9:
[0617] To a stirred solution of compound
N-(rac(2S,3S)-2-(5-chlorothiophen-2-yl)-2-methyl-5-oxopyrrolidin-3-yl)cyc-
lopropanecarboxamide (200 mg, 0.671 mmol, 1.0 eq) and compound
1-(4-fluorophenyl)-5-iodo-1H-indazole (249 mg, 0.738 mmol, 1.5 eq)
in dioxane (10 mL) under nitrogen atmosphere were added CuI (127
mg, 0.671 mmol, 1.5 eq), DMEDA (59 mg 0.671 mmol, 1 eq), and
K.sub.2CO.sub.3 (277 mg, 2.013 mmol, 3.0 eq) and stirred at
130.degree. C. for 16 h. The reaction progress was monitored by
TLC. The reaction mixture was diluted with water (20 mL) and
extracted with EtOAc (2.times.20 mL). The combined organic layers
were washed with brine (20 mL), dried (Na.sub.2SO.sub.4) and
evaporated. The crude compound was purified by by flash
chromatography (silica 70-90% EtOAc in petroleum ether as an
eluent) followed by prep HPLC to get Example 151
N-((2S,3S)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-y-
l)-2-methyl-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide (50 mg,
-53%).
[0618] .sup.1HNMR (500 MHz, DMSO-d.sub.6): .delta. 8.77 (d, 1H),
8.39 (s, 1H), 7.80-7.76 (m, 3H), 7.58 (d, 1H), 7.63 (s, 1H),
7.44-7.40 (m, 2H), 7.22 (dd, 1H), 7.01 (d, 1H), 6.93 (d, 1H),
4.71-4.67 (m, 1H), 3.10 (dd, 1H), 2.43-2.36 (m, 1H), 1.64-1.61 (m,
1H), 1.48 (s, 3H), 0.72-0.6 (m, 4H).
[0619] The examples in the following table were synthesized in
analogy to Example 1 described above, using different
intermediates.
TABLE-US-00003 Inter- Ex. mediate Yield # (INT) Structure (%)
.sup.1H NMR 4 Int A3 ##STR00076## 12 .sup.1H NMR (DMSO-d.sub.6):
.delta. = 9.08 (d, 1H), 8.31 (s, 1H), 7.72-7.69 (m, 4H), 7.41-7.34
(m, 5H), 7.24(s, 2H), 7.17(m, 1H), 5.41 (d, 1H), 4.26 (t, 1H), 1.71
(t, 3H), 1.27 (s, 3H), 1.13 (s, 3H). 9 Int A3 ##STR00077## 10
.sup.1H NMR (DMSO-d.sub.6): .delta. = 9.07 (s, 1H), 8.25 (s, 1H),
8.18 (s, 1H), 7.68-7.58 (m, 3H), 7.34-7.17 (m, 6H), 6.51 (s, 1H),
5.39 (s, 1H), 4.25 (s, 1H), 3.48 (s, 3H), 1.71 (t, 3H), 1.27 (s,
3H), 1.13 (s, 3H) 10 Int A3 ##STR00078## 13 .sup.1H NMR
(DMSO-d.sub.6): .delta. = 9.08 (d, 1H), 8.31 (s, 1H), 7.72-7.69 (m,
4H), 7.41-7.34 (m, 5H), 7.24(s, 2H), 7.17(m, 1H), 5.41 (d, 1H),
4.26 (t, 1H), 1.71 (t, 3H), 1.27 (s, 3H), 1.13 (s, 3H).
[0620] The examples in the following table were synthesized in
analogy to Example 5 described above, using different
intermediates.
TABLE-US-00004 Inter- Ex. mediate Yield # (INT) Structure (%)
.sup.1H NMR 3 Int A5 ##STR00079## 10 .sup.1H NMR (DMSO-d.sub.6)
.delta.: 8.90 (d, 1H), 8.30 (t, 1H), 7.93 (dd, 1H), 7.79-7.69 (m,
4H), 7.43-7.37 (m, 4H), 7.34 (t, 2H), 7.28-7.21 (m, 1H), 5.29 (d,
1H), 4.03 (dd, 1H), 1.68 (tt, 1H), 1.31-0.91 (m, 4H), 0.80-0.62 (m,
4H) 30 Int A5 ##STR00080## 4 .sup.1H NMR (DMSO-d.sub.6) .delta.:
8.89 (d, 1H), 8.25 (d, 1H), 8.18 (d, 1H), 7.92 (dd, 1H), 7.71 (ddd,
2H), 7.61 (dt, 1H), 7.41-7.36 (m, 2H), 7.33 (t, 2H), 7.27-7.21 (m,
1H), 6.54 (dd, 1H), 5.28 (d, 1H), 4.03 (dd, 1H), 3.50 (s, 3H),
1.72-1.64 (m, 1H), 1.26-1.15 (m, 1H), 1.16-1.08 (m, 1H), 0.95 (q,
2H), 0.74 (ddd, 1H), 0.73-0.68 (m, 3H)
[0621] The examples in the following table were synthesized in
analogy to Example 7 described above, using different
intermediates.
TABLE-US-00005 Inter- Ex. mediate Yield # (INT) Structure (%)
.sup.1H NMR 6 Int A 4 ent 1 ##STR00081## 31 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.11 (d, 1H), 8.26 (d, 1H), 8.17 (d, 1H),
7.78 (t, 1H), 7.72-7.67 (m, 2H), 7.59 (d, 1H), 7.40 (d, 1H), 7.39-
7.35 (m, 2H), 7.22 (t, 2H), 7.17- 7.11 (m, 1H), 6.54 (d, 1H), 5.63
(d, 1H), 4.46 (t, 1H), 3.50 (s, 3H), 2.52 (s, 3H), 1.32 (s, 3H),
1.18 (s, 3H) 12 Int A 4 ent 1 ##STR00082## 80 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 8.39 (d, 1H), 8.25 (d, 1H), 8.17 (d, 1H),
7.78 (d, 1H), 7.72-7.68 (m, 2H), 7.59 (d, 1H), 7.40 (dd, 1H), 7.38-
7.35 (m, 2H), 7.21 (t, 2H), 7.15- 7.10 (m, 1H), 6.57 (d, 1H), 6.54
(d, 1H), 5.59 (d, 1H), 4.50 (t, 1H), 3.96 (s, 3H), 3.50 (s, 3H),
1.30 (s, 3H), 1.17 (s, 3H) 13 Int A 4 ent 1 ##STR00083## 85 .sup.1H
NMR (DMSO-d.sub.6) .delta.: 8.96 (dd, 1H), 8.60 (s, 1H), 8.26 (d,
1H), 8.18 (d, 1H), 7.83 (s, 1H), 7.73 (d, 1H), 7.70 (dd, 1H),
7.62-7.57 (m, 1H), 7.41 (dd, 1H), 7.39- 7.36 (m, 2H), 7.23 (t, 2H),
7.18- 7.12 (m, 1H), 6.54 (d, 1H), 5.41 (d, 1H), 4.48 (t, 1H), 3.50
(s, 3H), 1.31 (s, 3H), 1.18 (s, 3H) 14 Int A 4 ent 1 ##STR00084##
64 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.38 (d, 1H), 8.26 (d, 1H),
8.18 (d, 1H), 7.72-7.67 (m, 2H), 7.62-7.57 (m, 1H), 7.41-7.37 (m,
3H), 7.24 (t, 2H), 7.18-7.13 (m, 1H), 6.54 (d, 1H), 5.55 (d, 1H),
4.50 (t, 1H), 3.50 (s, 3H), 2.69 (s, 3H), 1.33 (s, 3H), 1.18 (s,
3H) 15 Int A 4 ent 1 ##STR00085## 70 .sup.1H NMR (DMSO-d.sub.6)
.delta.: 9.25 (d, 1H), 8.95 (dd, 1H), 8.60 (s, 1H), 8.26 (d, 1H),
8.18 (d, 1H), 7.75 (dd, 1H), 7.74-7.67 (m, 1H), 7.60 (dd, 1H),
7.46-7.41 (m, 1H), 7.39 (dd, 2H), 7.24 (t, 2H), 7.18-7.12 (m, 1H),
6.54 (d, 1H), 5.36 (d, 1H), 4.51-4.45 (m, 1H), 3.50 (d, 3H), 1.32
(s, 3H), 1.20 (s, 3H) 16 Int A 4 ent 1 ##STR00086## 60 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.08 (s, 1H), 8.61 (dd, 1H), 8.25 (d, 1H),
8.18 (d, 1H), 7.73 (d, 1H), 7.70 (dd, 1H), 7.59 (d, 1H), 7.42 (dd,
1H), 7.40-7.37 (m, 2H), 7.25 (t, 2H), 7.20-7.14 (m, 1H), 6.54 (d,
1H), 5.37 (d, 1H), 4.47 (t, 1H), 3.50 (s, 3H), 2.51 (s, 3H), 1.34
(s, 3H), 1.18 (s, 3H) 17 Int A 4 ent 1 ##STR00087## 87 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.25 (d, 1H), 8.79 (d, 1H), 8.30 (d, 1H),
8.26 (d, 1H), 8.17 (d, 1H), 7.72- 7.68 (m, 2H), 7.61-7.57 (m, 1H),
7.41 (dd, 1H), 7.39-7.36 (m, 2H), 7.21 (t, 2H), 7.15-7.10 (m, 1H),
6.54 (d, 1H), 5.64 (d, 1H), 4.53 (t, 1H), 3.50 (s, 3H), 1.33 (s,
3H), 1.19 (s, 3H) 18 Int A 4 ent 1 ##STR00088## 73 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.08 (s, 1H), 8.61 (dd, 1H), 8.25 (d, 1H),
8.18 (d, 1H), 7.73 (d, 1H), 7.70 (dd, 1H), 7.61-7.57 (m, 1H), 7.42
(dd, 1H), 7.40-7.36 (m, 2H), 7.25 (t, 2H), 7.20-7.14 (m, 1H), 6.54
(d, 1H), 5.37 (d, 1H), 4.47 (t, 1H), 3.50 (s, 3H), 2.51 (s, 3H),
1.34 (s, 3H), 1.18 (s, 3H) 21 Int A 4 ent 2 ##STR00089## 77 .sup.1H
NMR (DMSO-d.sub.6) .delta.: 8.95 (dd, 1H), 8.60 (s, 1H), 8.26 (d,
1H), 8.17 (d, 1H), 7.83 (s, 1H), 7.74- 7.72 (m, 1H), 7.70 (dd, 1H),
7.62- 7.57 (m, 1H), 7.41 (dd, 1H), 7.39-7.36 (m, 2H), 7.23 (t, 2H),
7.17-7.12 (m, 1H), 6.54 (d, 1H), 5.41 (d, 1H), 4.48 (t, 1H), 3.50
(s, 3H), 1.31 (s, 3H), 1.18 (s, 3H) 22 Int A 4 ent 2 ##STR00090##
80 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.08 (d, 1H), 8.25 (d, 1H),
8.17 (d, 1H), 7.72-7.67 (m, 2H), 7.59 (d, 1H), 7.42-7.35 (m, 3H),
7.23 (t, 2H), 7.18-7.12 (m, 1H), 6.53 (d, 1H), 6.50 (t, 1H), 5.50
(d, 1H), 4.47 (t, 1H), 3.50 (s, 3H), 2.47 (d, 3H), 1.32 (s, 3H),
1.17 (s, 3H) 24 Int A 4 ent 2 ##STR00091## 78 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.25 (d, 1H), 8.95 (dd, 1H), 8.60 (s, 1H),
8.26 (d, 1H), 8.18 (d, 1H), 7.76- 7.73 (m, 1H), 7.70 (dd, 1H),
7.62- 7.57 (m, 1H), 7.43 (dd, 1H), 7.41-7.37 (m, 2H), 7.24 (t, 2H),
7.18-7.12 (m, 1H), 6.54 (d, 1H), 5.36 (d, 1H), 4.48 (t, 1H), 3.50
(s, 3H), 1.32 (s, 3H), 1.20 (s, 3H) 26 Int A 4 ent 2 ##STR00092##
63 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.10 (d, 1H), 8.26 (d, 1H),
8.17 (d, 1H), 7.80-7.75 (m, 1H), 7.72-7.67 (m, 2H), 7.61-7.56 (m,
1H), 7.41- 7.35 (m, 3H), 7.22 (t, 2H), 7.17- 7.11 (m, 1H), 6.53 (d,
1H), 5.62 (d, 1H), 4.45 (t, 1H), 3.50 (s, 3H), 2.53-2.51 (m, 3H),
1.32 (s, 3H), 1.18 (s, 3H) 36a Int A 7 ent 1 ##STR00093## 86
.sup.1H NMR (DMSO-d.sub.6) .delta.: 8.97 (d, 1H), 8.60 (s, 1H),
8.31 (d, 1H), 7.83 (s, 1H), 7.76-7.72 (m, 3H). 7.70 (dd, 1H), 7.46
(dd, 1H), 7.43- 7.35 (m, 4H), 7.23 (dd, 2H), 7.17-7.12 (m, 1H),
5.42 (d, 1H), 4.49 (t, 1H), 1.31 (s, 3H), 1.18 (d, 3H) 36b Int A 7
ent 2 ##STR00094## 40 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.97 (d,
1H), 8.60 (s, 1H), 8.31 (d, 1H), 7.83 (s, 1H), 7.76-7.72 (m, 3H),
7.70 (dd, 1H), 7.46 (dd, 1H), 7.43- 7.35 (m, 4H), 7.23 (dd, 2H),
7.17-7.12 (m, 1H), 5.42 (d, 1H), 4.49 (t, 1H), 1.31 (s, 3H), 1.18
(d, 3H) 37 Int A7 ent 1 ##STR00095## 71 .sup.1H NMR (DMSO-d.sub.6)
.delta.: 8.40 (d, 1H), 8.31 (d, 1H), 7.78 (d, 1H), 7.76-7.71 (m,
3H), 7.69 (dd, 1H), 7.44 (dd, 1H), 7.41-7.35 (m, 4H), 7.24-7.18 (m,
2H), 7.16- 7.10 (m, 1H), 6.58 (dd, 1H), 5.59 (dd, 1H), 4.51 (t,
1H), 3.96 (d, 3H), 1.31 (d, 3H), 1.17 (s, 3H) 38a Int A7 ent 2
##STR00096## 44 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.08 (s, 1H),
8.67-8.57 (m, 1H), 8.31 (d, 1H), 7.80-7.64 (m, 4H), 7.46 (dd, 1H),
7.42-7.35 (m, 4H), 7.25 (dd, 2H), 7.19-7.13 (m, 1H), 5.38 (d, 1H),
4.47 (t, 1H), 2.51 (s, 3H), 1.34 (s, 3H), 1.18 (s, 3H) 38b Int A7
ent 1 ##STR00097## 92 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.08 (s,
1H), 8.67-8.57 (m, 1H), 8.31 (d, 1H), 7.80-7.64 (m, 4H), 7.46 (dd,
1H), 7.42-7.35 (m, 4H), 7.25 (dd, 2H), 7.19-7.13 (m, 1H), 5.38 (d,
1H), 4.47 (t, 1H), 2.51 (s, 3H), 1.34 (s, 3H), 1.18 (s, 3H) 39a Int
A7 ent 1 ##STR00098## 88 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.08
(s, 1H), 8.63-8.58 (m, 1H), 8.31 (d, 1H), 7.78-7.72 (m, 3H), 7.70
(dd, 1H), 7.46 (dd, 1H), 7.43- 7.36 (m, 4H), 7.25 (t, 2H), 7.17 (t,
1H), 5.38 (d, 1H), 4.47 (t, 1H), 2.52 (s, 3H), 1.34 (s, 3H), 1.18
(s, 3H) 39b Int A7 ent 2 ##STR00099## 51 .sup.1H NMR (DMSO-d.sub.6)
.delta.: 9.08 (s, 1H), 8.63-8.58 (m, 1H), 8.31 (d, 1H), 7.78-7.72
(m, 3H), 7.70 (dd, 1H), 7.46 (dd, 1H), 7.43- 7.36 (m, 4H), 7.25 (t,
2H), 7.17 (t, 1H), 5.38 (d, 1H), 4.47 (t, 1H), 2.52 (s, 3H), 1.34
(s, 3H), 1.18 (s, 3H) 40a Int A7 ent 1 ##STR00100## 98 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.37 (d, 1H), 8.64 (d, 1H), 8.31 (d, 1H),
7.78 (dd, 1H), 7.77-7.71 (m, 2H), 7.70 (dd, 1H), 7.47 (dd, 1H),
7.43-7.35 (m, 4H), 7.24 (dd, 2H), 7.19-7.13 (m, 1H), 5.25 (d, 1H),
4.46 (t, 1H), 2.30 (s, 3H), 1.31 (s, 3H), 1.18 (s, 3H) 40b Int A7
ent 2 ##STR00101## 62 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.37 (d,
1H), 8.64 (d, 1H), 8.31 (d, 1H), 7.78 (dd, 1H), 7.77-7.71 (m, 2H),
7.70 (dd, 1H), 7.47 (dd, 1H), 7.43-7.35 (m, 4H), 7.24 (dd, 2H),
7.19-7.13 (m, 1H), 5.25 (d, 1H), 4.46 (t, 1H), 2.30 (s, 3H), 1.31
(s, 3H), 1.18 (s, 3H) 41a Int A7 ent 1 ##STR00102## 79 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 8.31 (d, 1H), 8.26 (d, 1H), 8.16 (s, 1H),
7.88 (d, 1H), 7.78-7.71 (m, 3H), 7.73-7.68 (m, 1H), 7.46 (dd, 1H),
7.43-7.33 (m, 4H), 7.22 (dd, 2H), 7.17-7.11 (m, 1H), 5.30 (d, 1H),
4.47 (t, 1H), 3.87 (s, 3H), 1.29 (s, 3H), 1.15 (s, 3H) 41b Int A7
ent 2 ##STR00103## 35 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.31 (d,
1H), 8.26 (d, 1H), 8.16 (s, 1H), 7.88 (d, 1H), 7.78-7.71 (m, 3H),
7.73-7.68 (m, 1H), 7.46 (dd, 1H), 7.43-7.33 (m, 4H), 7.22 (dd, 2H),
7.17-7.11 (m, 1H), 5.30 (d, 1H), 4.47 (t, 1H), 3.87 (s, 3H), 1.29
(s, 3H), 1.15 (s, 3H) 42a Int A7 ent 1 ##STR00104## 89 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.02 (d, 1H), 8.96-8.91 (m, 1H), 8.77- 8.72
(m, 1H), 8.32 (d, 1H), 8.21- 8.16 (m, 1H), 7.78 (d, 1H), 7.76- 7.73
(m, 2H), 7.71 (d, 1H), 7.55 (dd, 1H), 7.48 (dd, 1H), 7.43- 7.36 (m,
4H), 7.27-7.21 (m, 2H), 7.18-7.12 (m, 1H), 5.41 (d, 1H), 4.55 (t,
1H), 1.34 (s, 3H), 1.21 (s, 3H) 42b Int A7 ent 2 ##STR00105## 27
.sup.1H NMR (DMSO-d.sub.6) .delta.: 9.02 (d, 1H), 8.96-8.91 (m,
1H), 8.77- 8.72 (m, 1H), 8.32 (d, 1H), 8.21- 8.16 (m, 1H), 7.78 (d,
1H), 7.76- 7.73 (m, 2H), 7.71 (d, 1H), 7.55 (dd, 1H), 7.48 (dd,
1H), 7.43- 7.36 (m, 4H), 7.27-7.21 (m, 2H), 7.18-7.12 (m, 1H), 5.41
(d, 1H), 4.55 (t, 1H), 1.34 (s, 3H), 1.21 (s, 3H) 43a Int A7 ent 1
##STR00106## 96 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.23 (d, 1H),
9.00 (d, 2H), 8.31 (d, 1H), 7.76 (dd, 1H), 7.73 (ddd, 3H), 7.70
(dd, 1H), 7.46 (dd, 1H), 7.43- 7.36 (m, 4H), 7.22 (t, 2H), 7.16-
7.11 (m, 1H), 5.64 (d, 1H), 4.56 (dd, 1H), 1.35 (s, 3H), 1.22 (s,
3H) 43b Int A7 ent 2 ##STR00107## 35 .sup.1H NMR (DMSO-d.sub.6)
.delta.: 9.23 (d, 1H), 9.00 (d, 2H), 8.31 (d, 1H), 7.76 (dd, 1H),
7.73 (ddd, 3H), 7.70 (dd, 1H), 7.46 (dd, 1H), 7.43- 7.36 (m, 4H),
7.22 (t, 2H), 7.16- 7.11 (m, 1H), 5.64 (d, 1H), 4.56 (dd, 1H), 1.35
(s, 3H), 1.22 (s, 3H) 44a Int A7 ent 1 ##STR00108## 90 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 8.81 (dd, 1H), 8.31 (s, 1H), 7.77-7.65 (m,
5H), 7.45 (dd, 1H), 7.43-7.35 (m, 4H), 7.23 (t, 2H), 7.18-7.12 (m,
1H), 5.41 (d, 1H), 4.48 (t, 1H), 2.51 (s, 3H), 1.30 (s, 3H), 1.17
(s, 3H) 44b Int A7 ent 2 ##STR00109## 37 .sup.1H NMR (DMSO-d.sub.6)
.delta.: 8.81 (dd, 1H), 8.31 (s, 1H), 7.77-7.65 (m, 5H), 7.45 (dd,
1H), 7.43-7.35 (m, 4H), 7.23 (t, 2H), 7.18-7.12 (m, 1H), 5.41 (d,
1H), 4.48 (t, 1H), 2.51 (s, 3H), 1.30 (s, 3H), 1.17 (s, 3H) 45a Int
A7 ent 1 ##STR00110## 89 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.77
(d, 1H), 8.50 (s, 1H), 8.31 (t, 1H), 7.77-7.72 (m, 3H), 7.70 (dd,
1H), 7.44 (dd, 1H), 7.42-7.35 (m, 4H), 7.23 (t, 2H), 7.18-7.12 (m,
1H), 5.51 (d, 1H), 4.49 (t, 1H), 2.32 (s, 3H), 1.32 (s, 3H), 1.17
(s, 3H) 45b Int A7 ent 2 ##STR00111## 62 .sup.1H NMR (DMSO-d.sub.6)
.delta.: 8.77 (d, 1H), 8.50 (s, 1H), 8.31 (t, 1H), 7.77-7.72 (m,
3H), 7.70 (dd, 1H), 7.44 (dd, 1H), 7.42-7.35 (m, 4H), 7.23 (t, 2H),
7.18-7.12 (m, 1H), 5.51 (d, 1H), 4.49 (t, 1H), 2.32 (s, 3H), 1.32
(s, 3H), 1.17 (s, 3H) 46 A9 ##STR00112## 26 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 8.57 (d, 1H), 8.29 (t, 1H), 7.78 (d, 1H),
7.77-7.71 (m, 2H), 7.68 (d, 1H), 7.51 (dd, 1H), 7.39 (td, 2H), 7.33
(d, 2H), 7.24 (t, 2H), 7.19-7.11 (m, 1H), 5.19 (d, 1H), 4.04 (td,
1H), 2.78-2.70 (m, 1H), 1.57 (tt, 1H), 1.24 (d, 3H), 0.74-0.58 (m,
4H). 47 A13- trans ##STR00113## 43 .sup.1H NMR (DMSO-d.sub.6)
.delta.: 9.21 (s, 1H), 8.33 (s, 1H), 7.73 (dt, 4H), 7.53-7.46 (m,
1H), 7.45-7.32 (m, 3H), 7.27-7.15 (m, 2H), 5.85 (s, 1H), 4.16 (s,
1H), 2.96 (dd, 1H), 2.55 (d, 0H), 1.73 (t, 3H), 1.28 (d, 3H) 60 A9
##STR00114## 30 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.08 (s, 1H),
8.70 (d, 1H), 8.29 (d, 1H), 7.80 (dd, 1H), 7.76-7.72 (m, 2H), 7.68
(dt, 1H), 7.51 (dd, 1H), 7.43-7.34 (m, 4H), 7.28-7.22 (m, 2H),
7.20-7.14 (m, 1H), 5.33 (d, 1H), 4.27 (td, 1H), 2.89 (dq, 1H), 2.56
(s, 3H), 1.31 (d, 3H) 63 A11- trans ##STR00115## 55 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 8.56 (d, 1H), 8.30 (d, 1H), 7.79 (dd, 1H),
7.77-7.71 (m, 2H), 7.69 (dd, 1H), 7.56-7.48 (m, 1H), 7.43- 7.36 (m,
2H), 7.17-7.07 (m, 3H), 6.97 (ddt, 1H), 5.15 (d, 1H), 4.01 (td,
1H), 2.76-2.68 (m, 1H), 2.20 (s, 3H), 1.57 (tt, 1H), 1.23 (d, 3H),
0.74 0.58 (m, 4H) 64 A9 ##STR00116## 28 .sup.1H NMR (DMSO-d.sub.6)
.delta.: 8.60 (d, 1H), 8.29 (d, 1H), 7.78 (d, 1H), 7.77-7.70 (m,
3H), 7.68 (dt, 1H), 7.46 (dd, 1H), 7.43-7.36 (m, 2H), 7.34-7.29 (m,
2H), 7.21 (dd, 2H), 7.16-7.10 (m, 1H), 6.56 (d, 1H), 5.37 (d, 1H),
4.34 (td, 1H), 3.94 (s, 3H), 2.92 (dq, 1H), 1.26 (d, 3H) 65 A9
##STR00117## 44 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.11 (d, 1H),
9.07 - 8.99 (m, 1H), 8.74 (dd, 1H), 8.30 (d, 1H), 8.23 8.18 (m,
1H), 7.82 (dd, 1H), 7.78- 7.71 (m, 2H), 7.70 (dt, 1H), 7.57- 7.51
(m, 2H), 7.43-7.36 (m, 4H), 7.24 (dd, 2H), 7.19-7.13 (m, 1H), 5.38
(d, 1H), 4.32 (td, 1H), 2.92 (dq, 1H), 1.32 (d, 3H) 66 A9
##STR00118## 35 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.45 (d, 1H),
9.00 (d, 2H), 8.30 (d, 1H), 7.78-7.69 (m, 4H), 7.68 (dd, 1H), 7.48
(dd, 1H), 7.44-7.36 (m, 2H), 7.36-7.32 (m, 2H), 7.24- 7.19 (m, 2H),
7.17-7.11 (m, 1H), 5.44 (d, 1H), 4.40 (td, 1H), 3.02-2.94 (m, 1H),
1.30 (d, 3H) 67 A11- trans ##STR00119## 43 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.08 (s, 1H), 8.70 (d, 1H), 8.30 (d, 1H),
7.80 (d, 1H), 7.77-7.71 (m, 2H), 7.69 (d, 1H), 7.51 (dd, 1H), 7.45-
7.36 (m, 2H), 7.18 (d, 1H), 7.17- 7.10 (m, 2H), 6.98 (dt, 1H), 5.28
(d, 1H), 4.23 (td, 1H), 2.94-2.78 (m, 1H), 2.57 (s, 3H), 2.20 (s,
3H), 1.31 (d, 3H) 68 A11- trans ##STR00120## 54 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.10 (d, 1H), 9.04 (d, 1H), 8.74 (dd, 1H),
8.31 (d, 1H), 8.20 (dt, 1H), 7.82 (d, 1H), 7.78-7.72 (m, 2H), 7.71
(dd, 1H), 7.57-7.51 (m, 2H), 7.43-7.36 (m, 2H), 7.21 (t, 1H),
7.19-7.10 (m, 2H), 6.97 (d, 1H), 5.33 (d, 1H), 4.30 (td, 1H), 2.90
(dq, 1H), 2.19 (s, 3H), 1.32 (d, 3H) 69 A11- trans ##STR00121## 23
.sup.1H NMR (DMSO-d.sub.6) .delta.: 9.47 9.42 (m, 1H), 9.00 (d,
1H), 8.31 (s, 1H), 7.78-7.73 (m, 2H), 7.76- 7.69 (m, 2H), 7.69 (d,
1H), 7.48 (dd, 1H), 7.43-7.36 (m, 2H), 7.18-7.07 (m, 4H), 6.95 (d,
1H), 5.39 (d, 1H), 4.39 (td, 1H), 2.97 (dq, 1H), 2.17 (s, 3H), 1.30
(d, 3H) 70 A11-cis ##STR00122## 52 .sup.1H NMR (DMSO-d.sub.6)
.delta.: 8.76 (d, 1H), 8.32 (s, 1H), 7.96 (d, 1H), 7.80 (ddd, 1H),
7.79-7.71 (m, 3H), 7.44-7.37 (m, 2H), 7.22 (t, 1H), 7.18 (d, 1H),
7.14-7.09 (m, 1H), 7.07 (d, 1H), 5.15 (d, 1H), 4.35 (ddd, 1H), 3.04
(p, 1H), 2.27 (s, 3H), 1.78-1.68 (m, 1H), 1.11 (d, 3H), 0.80-0.73
(m, 1H), 0.76- 0.70 (m, 2H) 71 A11-cis ##STR00123## 49 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.08 (s, 0H), 9.01 (d, 1H), 8.32 (d, 1H),
7.94 (dd, 1H), 7.79-7.71 (m, 4H), 7.44-7.36 (m, 2H), 7.26- 7.21 (m,
2H), 7.20-7.15 (m, 1H), 7.08 (ddt, 1H), 5.32 (d, 1H), 4.52 (td,
1H), 3.16 (p, 1H), 2.60 (s, 3H), 2.28 (d, 3H),
2.08 (s, 1H), 1.16 (d, 3H) 72 A11-cis ##STR00124## 48 1H NMR
(DMSO-d6) .delta.: 8.79 (d, 1H), 8.32 (s, 1H), 7.91 (dd, 1H),
7.81-7.67 (m, 6H), 7.44-7.36 (m, 2H), 7.23-7.13 (m, 3H), 7.07- 7.02
(m, 1H), 6.66 (d, 1H), 5.40 (d, 1H), 4.57 (td, 1H), 3.93 (s, 3H),
3.12 (p, 1H), 2.25 (s, 3H), 1.11 (d, 3H) 73 A11-cis ##STR00125## 45
1H NMR (DMSO-d6) .delta.: 9.28 (d, 1H), 9.09 (d, 1H), 8.74 (dd,
1H), 8.32 (t, 1H), 8.27 (dt, 1H), 7.98 (d, 1H), 7.80 (dd, 1H),
7.78-7.71 (m, 3H), 7.54 (ddd, 1H), 7.44- 7.37 (m, 2H), 7.27-7.21
(m, 2H), 7.21-7.16 (m, 1H), 7.08 (d, 1H), 5.37 (d, 1H), 4.62 (ddd,
1H), 3.19 (p, 1H), 2.28 (s, 3H), 1.17 (d, 3H) 74 A11-cis
##STR00126## 49 1H NMR (DMSO-d6) .delta.: 9.53 (d, 1H), 9.00 (dd,
1H), 9.90-6.59 (m, 0H), 8.32 (d, 1H), 7.93 (dd, 1H), 7.79-7.69 (m,
6H), 7.44- 7.36 (m, 2H), 7.25-7.16 (m, 3H), 7.06 (dd, 1H), 5.45 (d,
1H), 4.62 (td, 1H), 3.24-3.16 (m, 1H), 2.26 (s, 3H), 1.15 (d, 3H)
75 A11- trans ##STR00127## 86 .sup.1H NMR (DMSO-d.sub.6) .delta.:
8.59 (d, 1H), 8.30 (d, 1H), 7.78 (d, 1H), 7.78-7.71 (m, 3H), 7.69
(dt, 1H), 7.46 (dd, 1H), 7.43-7.31 (m, 2H), 7.16-7.07 (m, 3H),
6.97- 6.92 (m, 1H), 6.57 (d, 1H), 5.33 (d, 1H), 4.32 (td, 1H), 3.94
(s, 3H), 2.90 (dq, 1H), 2.17 (s, 3H), 1.26 (d, 3H) 77 A11-cis
##STR00128## 54 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.45 (d, 1H),
8.33 (d, 1H), 7.92 (t, 1H), 7.81-7.69 (m, 4H), 7.47-7.35 (m, 2H),
7.29 7.16 (m, 2H), 7.16- 7.10 (m, 1H), 7.10-7.03 (m, 1H), 5.28 (d,
1H), 4.41 (td, 1H), 3.16 (p, 1H), 2.26 (s, 3H), 1.81 (t, 3H), 1.08
(d, 3H) 78 A13-cis ##STR00129## 41 1H NMR (DMSO-d6) .delta.: 8.82
(d, 1H), 8.36 (d, 1H), 7.97 (d, 1H), 7.82-7.73 (m, 4H), 7.51 (dd,
1H), 7.44-7.38 (m, 2H), 7.38- 7.26 (m, 4H), 5.50 (d, 1H), 4.49
(ddd, 1H), 3.03 (p, 1H), 1.68 (tt, 1H), 1.05 (d, 3H), 0.77-0.67 (m,
4H) 79 A13-cis ##STR00130## 54 .sup.1H NMR (DMSO-d.sub.6) .delta.:
9.58 (d, 1H), 8.36 (d, 1H), 7.95 (dd, 1H), 7.83-7.69 (m, 4H), 7.52
(dt, 1H), 7.46-7.35 (m, 2H), 7.38-7.25 (m, 3H), 5.62 (d, 1H), 4.48
(t, 1H), 3.22 3.11 (m, 1H), 1.82 (t, 3H), 1.11-1.01 (m, 4H) 80 A9
##STR00131## 33 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.17 (d, 1H),
8.29 (s, 1H), 7.79-7.70 (m, 3H), 7.68 (d, 1H), 7.47 (dd, 1H),
7.44-7.35 (m, 2H), 7.35-7.29 (m, 2H), 7.24 (t, 2H), 7.20-7.12 (m,
1H), 5.27 (d, 1H), 4.12 (q, 1H), 2.87 (dq, 1H), 1.73 (t, 3H), 1.26
(d, 3H) 81 A11- trans ##STR00132## 62 .sup.1H NMR (DMSO-d.sub.6)
.delta.: 9.16 (d, 1H), 8.30 (d, 1H), 7.78-7.72 (m, 3H), 7.69 (d,
1H), 7.48 (dd, 1H), 7.44-7.35 (m, 2H), 7.15-7.08 (m, 3H), 6.98 (dt,
1H), 5.22 (d, 1H), 4.14-4.04 (m, 1H), 2.85 (dq, 1H), 2.20 (s, 3H),
1.73 (t, 3H), 1.26 (d, 3H) 82 A15- trans ##STR00133## 23 .sup.1H
NMR (DMSO-d.sub.6) .delta.: 9.07 (s, 1H), 8.65 (d, 1H), 8.30 (s,
1H), 7.79-7.71 (m, 3H), 7.68 (d, 1H), 7.48 (dd, 1H), 7.40 (t, 2H),
7.29 (d, 2H), 6.79 (d, 2H), 5.25 (d, 1H), 4.26 (td, 1H), 3.64 (s,
3H), 2.87 (dq, 1H), 2.57 (s, 3H), 1.31 (d, 3H) 83 A15- trans
##STR00134## 18 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.54 (d, 1H),
8.29 (d, 1H), 7.79-7.73 (m, 2H), 7.75-7.70 (m, 2H), 7.67 (dt, 1H),
7.43 (dd, 1H), 7.43 7.36 (m, 2H), 7.27-7.21 (m, 2H), 6.79- 6.73 (m,
2H), 6.56 (d, 1H), 5.30 (d, 1H), 4.33 (td, 1H), 3.94 (s, 3H), 3.63
(s, 3H), 2.90 (dq, 1H), 1.26 (d, 3H) 84 A15- trans ##STR00135## 30
.sup.1H NMR (DMSO-d.sub.6) .delta.: 9.08- 9.02 (m, 2H), 8.74 (dd,
1H), 8.31 (d, 1H), 8.20 (ddd, 1H), 7.79 (dd, 1H), 7.78-7.72 (m,
2H), 7.69 (dt, 1H), 7.54 (ddd, 1H), 7.50 (dd, 1H), 7.43-7.36 (m,
2H), 7.33- 7.28 (m, 2H), 6.81-6.76 (m, 2H), 5.30 (d, 1H), 4.32
(tdd, 1H), 3.64 (s, 3H), 2.89 (dq, 1H), 1.32 (d, 3H) 85 A15- trans
##STR00136## 30 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.39 (d, 1H),
8.99 (dd, 2H), 8.30 (d, 1H), 7.76-7.73 (m, 3H), 7.71 (td, 1H), 7.68
(dd, 1H), 7.44 (dd, 1H), 7.43- 7.36 (m, 2H), 7.29-7.24 (m, 2H),
6.79-6.73 (m, 2H), 5.36 (d, 1H), 4.40 (td, 1H), 3.63 (d, 3H), 2.97
(dq, 1H), 1.30 (d, 3H) 87 A13-cis ##STR00137## 42 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.35 (d, 1H), 9.09 (dd, 1H), 8.75 (dd, 1H),
8.37 (s, 1H), 8.27 (dt, 1H), 8.00 (t, 1H), 7.83-7.74 (m, 4H), 7.58-
7.50 (m, 2H), 7.44-7.37 (m, 2H), 7.33 (dtd, 3H), 5.71 (d, 1H),
4.77-4.71 (m, 1H), 3.19 (p, 1H), 1.12 (d, 3H) 88 A13-cis
##STR00138## 41 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.73 (d, 1H),
9.00 (d, 2H), 8.36 (d, 1H), 7.98 (d, 1H), 7.77 (tq, 4H), 7.71 (t,
1H), 7.53-7.47 (m, 1H), 7.44- 7.34 (m, 3H), 7.34-7.28 (m, 2H), 5.80
(d, 1H), 4.72 (s, 1H), 3.24- 3.16 (m, 1H), 1.12 (d, 3H) 89 A21
##STR00139## 41 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.89 (dd, 1H),
8.82 (d, 1H), 8.72 (dd, 1H), 8.40 (d, 1H), 8.08 (dt, 1H), 7.86-
7.78 (m, 4H), 7.51 (ddd, 1H), 7.48- 7.41 (m, 3H), 7.39-7.34 (m,
2H), 7.28 (t, 2H), 7.19 7.13 (m, 1H), 4.45 (td, 1H), 4.14 (td, 1H),
3.20-3.09 (m, 2H), 3.05 (dd, 1H), 1.47 (ddd, 1H), 1.24 (dp, 1H),
0.52 (t, 3H) 90 A21 ##STR00140## 55 .sup.1H NMR (DMSO-d.sub.6)
.delta.: 9.26 (d, 1H), 8.98 (d, 2H), 8.40 (d, 1H), 7.85-7.79 (m,
3H), 7.76 (dd, 1H), 7.71 (t, 1H), 7.48-7.39 (m, 3H), 7.38-7.33 (m,
2H), 7.29- 7.23 (m, 2H), 7.17-7.11 (m, 1H), 4.47 (td, 1H), 4.20
(td, 1H), 3.27- 3.20 (m, 1H), 3.09 (dd, 1H), 3.01 (dd, 1H), 1.41
(ddt, 1H), 1.26- 1.15 (m, 1H), 0.46 (t, 3H) 92 A13- trans
##STR00141## 73 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.16 (s, 1H),
9.01 (d, 1H), 8.74 (dd, 1H), 8.34 (s, 1H), 8.17 (dt, 1H), 7.78 (s,
1H), 7.77-7.71 (m, 3H), 7.58- 7.50 (m, 2H), 7.46 (s, 1H), 7.43-
7.36 (m, 2H), 7.32 (d, 1H), 7.23 (td, 1H), 7.18 (t, 1H), 5.93 (s,
1H), 4.36 (s, 1H), 3.01 (dq, 1H), 1.34 (d, 3H) 94 A13-cis
##STR00142## 12 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.99 (d, 1H),
8.36 (d, 1H), 7.98-7.95 (m, 1H), 7.81-7.72 (m, 3H), 7.48 (dt, 1H),
7.43-7.38 (m, 2H), 7.35 (dd, 1H), 7.30 (dd, 2H), 6.66 (d, 1H), 5.77
(d, 1H), 4.67 (s, 1H), 3.93 (s, 2H), 3.13 (dd, 1H), 1.08 (d, 3H) 97
A15-cis ##STR00143## 60 1H NMR (DMSO-d.sub.6) .delta.: 9.39 (d,
1H), 8.32 (d, 1H), 7.89 (d, 1H), 7.81-7.71 (m, 3H), 7.68 (dd, 1H),
7.45-7.35 (m, 2H), 7.32- 7.23 (m, 2H), 6.92-6.83 (m, 2H), 5.28 (d,
1H), 4.41 (td, 1H), 3.69 (s, 3H), 3.13 (p, 1H), 1.80 (t, 3H), 1.09
(d, 3H) 98 A15- trans ##STR00144## 24 .sup.1H NMR (DMSO-d.sub.6)
.delta.: 9.11 (d, 1H), 8.29 (d, 1H), 7.78-7.70 (m, 3H), 7.68 (d,
1H), 7.48-7.35 (m, 3H), 7.29-7.20 (m, 2H), 6.83- 6.74 (m, 2H), 5.19
(d, 1H), 4.11 (q, 1H), 3.65 (s, 3H), 2.84 (dq, 1H), 1.73 (t, 3H),
1.26 (d, 3H) 104 A21 ##STR00145## 33 .sup.1H NMR (DMSO-d.sub.6)
.delta.: 8.48 (d, 1H), 8.39 (d, 1H), 7.84-7.77 (m, 4H), 7.73 (d,
1H), 7.44 (t, 2H), 7.40 (dd, 1H), 7.36 (d, 2H), 7.29 (t, 2H), 7.20
(t, 1H), 6.64 (d, 1H), 4.43 (td, 1H), 4.14 (td, 1H), 3.93 (s, 3H),
3.19-3.11 (m, 1H), 3.10 (d, 1H), 2.93 (dd, 1H), 1.38 (dtd, 1H),
1.14 (dp, 1H), 0.41 (t, 3H) 105 A21 ##STR00146## 25 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.05 (s, 1H), 8.43 (d, 1H), 8.40 (d, 1H),
7.84-7.80 (m, 3H), 7.79 (d, 1H), 7.48-7.41 (m, 3H), 7.38-7.33 (m,
2H), 7.30 (t, 2H), 7.23-7.17 (m, 1H), 4.40 (td, 1H), 4.12 (td, 1H),
3.14-3.10 (m, 1H), 3.09 (d, 1H), 3.04 (dd, 1H), 2.54 (s, 3H), 1.46
(dtd, 1H), 1.23 (dp, 1H), 0.51 (t, 3H) 106 A21 ##STR00147## 46
.sup.1H NMR (DMSO-d.sub.6) .delta.: 8.39 (s, 1H), 8.33 (d, 1H),
7.84-7.78 (m, 3H), 7.76 (d, 1H), 7.48-7.38 (m, 3H), 7.34-7.28 (m,
4H), 7.23 (dq, 1H), 4.20 (td, 1H), 3.98 (td, 1H), 3.02 (qd, 2H),
2.92 (dt, 1H), 1.45 (td, 1H), 1.39 (dtd, 1H), 1.18 (dq, 1H),
0.73-0.63 (m, 4H), 0.42 (t, 3H) 107 A21 ##STR00148## 47 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 8.90 (d, 1H), 8.39 (d, 1H), 7.86-7.77 (m,
3H), 7.77 (d, 1H), 7.49-7.38 (m, 3H), 7.31 (d, 4H), 7.23 (tt, 1H),
4.23 (td, 1H), 4.06 (td, 1H), 3.12 (ddd, 1H), 3.06 (dd, 1H), 2.99
(dd, 1H), 1.63 (t, 3H), 1.38 (dtd, 1H), 1.20 (dp, 1H), 0.48 (t, 3H)
108 A17- trans ##STR00149## 27 .sup.1H NMR (DMSO-d.sub.6) .delta.:
8.56 (d, 1H), 8.34 (s, 1H), 7.81 (d, 1H), 7.78 (ddd, 2H), 7.73 (d,
1H), 7.48 (dd, 1H), 7.44-7.40 (m, 2H), 6.96 (d, 1H), 6.85 (dd, 1H),
5.38 (d, 1H), 4.16 4.09 (m, 1H), 2.76 (dq, 1H), 1.58 (ddd, 1H),
1.24 (d, 3H), 0.75-0.70 (m, 3H), 0.68 (td, 1H) 109 A17- trans
##STR00150## 33 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.47 (d, 1H),
9.01 (dd, 2H), 8.35 (d, 1H), 7.80-7.77 (m, 3H), 7.75 (d, 1H), 7.73
(td, 1H), 7.47 (dd, 1H), 7.45- 7.39 (m, 2H), 6.98 (d, 1H), 6.83 (d,
1H), 5.63 (d, 1H), 4.48 (td, 1H), 3.02 (dq, 1H), 1.29 (d, 3H) 110
A17- trans ##STR00151## 31 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.62
(d, 1H), 8.35 (d, 1H), 7.81-7.76 (m, 4H), 7.74 (dt, 1H), 7.45 (dd,
1H), 7.45-7.39 (m, 2H), 6.96 (d, 1H), 6.82 (d, 1H), 6.61 (d, 1H),
5.56 (d, 1H), 4.42 (td, 1H), 3.94 (s, 3H), 2.94 (dq, 1H), 1.25 (d,
3H) 111 A17- trans ##STR00152## 36 .sup.1H NMR (DMSO-d.sub.6)
.delta.: 9.11 (d, 1H), 9.06 (dd, 1H), 8.76 (dd, 1H), 8.36 (d, 1H),
8.22 (dt, 1H), 7.85 (d, 1H), 7.80 7.75 (m, 3H), 7.56 (dd, 1H), 7.52
(dd, 1H), 7.45- 7.39 (m, 2H), 7.02 (d, 1H), 6.85 (dd, 1H), 5.57 (d,
1H), 4.40 (td, 1H), 2.95 (dq, 1H), 1.32 (d, 3H) 112 A13- trans
##STR00153## 32 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.54 (d, 1H),
8.31 (s, 1H), 7.77-7.68 (m, 3H), 7.43 (s, 2H), 7.42-7.35 (m, 2H),
7.33 (d, 1H), 7.19 (dt, 2H), 5.81 (s, 0H), 4.04 (s, 0H), 2.85 (p,
1H), 1.55 (p, 1H), 1.26 (d, 3H), 0.72-0.64 (m, 3H), 0.61 (s, 1H)
113 A17- trans ##STR00154## 28 .sup.1H NMR (DMSO-d.sub.6) .delta.:
9.09 (s, 1H), 8.70 (d, 1H), 8.35 (d, 1H), 7.84 (d, 1H), 7.80-7.76
(m, 2H), 7.75 (d, 1H), 7.50 (dd, 1H), 7.45- 7.39 (m, 2H), 7.01 (d,
1H), 6.86 (d, 1H), 5.53 (d, 1H),4.35 (q, 1H), 2.91 (dq, 1H), 2.60
(s, 3H), 1.31 (d, 3H) 115 A19 ##STR00155## 51 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 8.55 (d, 1H), 8.32 (t, 1H), 7.80-7.73 (m,
3H), 7.70 (dd, 1H), 7.48-7.44 (m, 2H), 7.44-7.40 (m, 2H), 6.15 (d,
1H), 5.17 (d, 1H), 4.21 (td, 1H), 3.68 (s, 3H), 2.71 2.63 (m, 1H),
1.56 (ddd, 1H), 1.26 (d, 3H), 0.72-0.65 (m, 4H) 116 A19
##STR00156## 35 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.07 (s, 1H),
8.67 (d, 1H), 8.33 (d, 1H), 7.80-7.73 (m, 3H), 7.71 (dt, 1H),
7.50-7.45 (m, 2H), 7.45- 7.38 (m, 2H), 6.19 (d, 1H), 5.30 (d, 1H),
4.43 (td, 1H), 3.68 (s, 3H), 2.82 (dq, 1H), 2.59 (s, 3H), 1.33 (d,
3H) 117 A19 ##STR00157## 41 .sup.1H NMR (DMSO-d.sub.6) .delta.:
8.54 (d, 1H), 8.32 (d, 1H), 7.80-7.74 (m, 3H), 7.73-7.68 (m, 2H),
7.47- 7.42 (m, 1H), 7.44-7.38 (m, 3H), 6.59 (dd, 1H), 6.20 (d, 1H),
5.35 (d, 1H), 4.52 (td, 1H), 3.93 (d, 3H), 3.65 (d, 3H), 2.85 (dq,
1H), 1.27 (d, 3H) 118 A19 ##STR00158## 29 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.10 (d, 1H), 9.04 (dd, 1H), 8.74 (dd, 1H),
8.33 (d, 1H), 8.21 (dt, 1H), 7.81- 7.74 (m, 3H), 7.74-7.69 (m, 1H),
7.57-7.52 (m, 1H), 7.52-7.46 (m, 2H), 7.45-7.38 (m, 2H), 6.21 (d,
1H), 5.35 (d, 1H), 4.49 (q, 1H), 3.67 (s, 3H), 2.85 (p, 1H), 1.34
(d, 3H) 119 A19 ##STR00159## 44 .sup.1H NMR (DMSO-d.sub.6) .delta.:
9.41 (d, 1H), 8.99 (dd, 2H), 8.33 (d, 1H), 7.80-7.68 (m, 5H),
7.48-7.38 (m, 4H), 6.23 (t, 1H), 5.41 (dd, 1H), 4.59 (td, 1H), 3.64
(d, 3H), 2.98-2.83 (m, 1H), 1.31 (dd, 3H) 120 A19 ##STR00160## 48
.sup.1H NMR (DMSO-d.sub.6) .delta.: 9.14 (d, 1H), 8.32 (d, 1H),
7.81-7.71 (m, 3H), 7.71 (d, 1H), 7.50-7.36 (m, 4H), 6.16 (d, 1H),
5.25 (d, 1H), 4.29 (td, 1H), 3.68 (s, 3H), 2.78 (dq, 1H), 1.75 (t,
3H), 1.31 1.14 (m, 3H) 123 A17- trans ##STR00161## 35 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.18 (d, 1H), 8.35 (d, 1H), 7.81-7.76 (m,
3H), 7.74 (d, 1H), 7.46 (dd, 1H), 7.44-7.39 (m, 2H), 7.00 (d, 1H),
6.86 (d, 1H), 5.46 (d, 1H), 4.20 (q, 1H), 2.89 (dq, 1H), 1.77 (t,
3H), 1.26 (d, 3H) 124 A17-cis ##STR00162## 24 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 8.76 (d, 1H), 8.36 (d, 1H), 7.99 (dd, 1H),
7.83-7.76 (m, 3H), 7.72 (dd, 1H), 7.46-7.38 (m, 2H), 6.99- 6.92 (m,
2H), 5.42 (d, 1H), 4.51 (ddd, 1H), 3.14 (p, 1H), 1.70 (tt, 1H),
1.11 (d, 3H), 0.80-0.67 (m, 4H) 125 A17-cis ##STR00163## 19 .sup.1H
NMR (DMSO-d.sub.6) .delta.: 9.45 (d, 1H), 8.37 (d, 1H), 7.95 (d,
1H), 7.84-7.74 (m, 3H), 7.67 (dd, 1H), 7.47-7.37 (m, 2H), 7.01 (d,
1H), 6.95 (d, 1H), 5.58 (d, 1H), 4.56 (td, 1H), 3.22 (p, 1H), 1.82
(t, 3H), 1.09 (d, 3H) 133 A15- trans ##STR00164## 33 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 8.54 8.49 (m, 1H), 8.29 (d, 1H), 7.78-7.71
(m, 3H), 7.67 (dd, 1H), 7.47 (dd, 1H), 7.43-7.36 (m, 2H), 7.27-
7.21 (m, 2H), 6.81 6.75 (m, 2H), 5.11 (d, 1H), 4.03 (td, 1H), 3.65
(s, 3H), 2.71 (dq, 1H), 1.56 (tt, 1H), 1.24 (d, 3H), 0.73-0.57 (m,
4H)
[0622] Human Glucocorticoid Receptor (hGR) Ligand-Binding Assay
[0623] The human lymphoblast cell line IM9 (ATCC, Bethesda, Md.)
was cultivated in RPMI 1640 media containing 10% fetal bovine
serum, penicillin (100 U/ml), streptomycin (100 .mu.g/ml), and 2 mM
L-glutamine at 370 and 7% CO2 in a humidified incubator. Cells were
centrifuged for 10 minutes at 1500 g and were washed in PBS and
repelleted. Cell were then resuspended in homogenization buffer
consisting of: 10 mM TES, 10 mM sodium molybdate, 1 mM EDTA, pH
7.4, 20 mM 2-mercaptoethanol, and 10% glycerol. Disruption of the
cells was performed by nitrogen cavitation using 2.times.15 minutes
at 600 to 750 psi nitrogen in a N2 cavitator at 0.degree. C. The
cell preparation was then centrifuged at 27,000 g for 15 minutes,
and the resultant supernatant (=cytosol of IM9 cells) was
centrifuged at 103,000 g for 60 minutes at 4.degree. C. The amount
of protein in the supernatant fraction was determined using a BCA
assay kit and aliquots were snap frozen in a dry ice-acetone bath
and stored at -70.degree. C. Competitive binding assays were done
in duplicate in homogenization buffer with a total volume of 200
.mu.l. To this end, 1 mg of IM9 cytosol, 0.05 .mu.Ci (1.5 nM) of
3H-dexamethasone and unlabeled Example compounds as competitor
compounds at 1 .mu.M were mixed. The reaction was stopped after
incubation at 0.degree. C. for 16 to 18 hours by the addition of
100 .mu.l of a charcoal-dextran mixture (2% activated charcoal,
0.5% dextran in 10 mM Tris, 1 mM EDTA, pH 7.4). Another incubation
step at 0.degree. C. for 10 minutes followed before the samples
were centrifuged for 5 minutes at 8200 g. 100 .mu.l of the
supernatant) was finally assayed for radioactivity by liquid
scintillationspectrometry, and percentage inhibition of
3H-dexamethasone binding was calculated.
[0624] GRE Agonist
[0625] The reporter cell line CHO-Gal4/GR consisted of a chinese
hamster ovary (CHO) cell line (Leibniz Institute DSMZ--German
Collection of Microorganisms and Cell Cultures GmbH: ACC-110)
containing a firefly luciferase gene under the control of the GR
ligand binding domain fused to the DNA binding domain (DBD) of GAL4
(GAL4 DBD-GR) stably integrated into CHO cells. This cell line was
established by stable transfection of CHO cells with a
GAL4-UAS-Luciferase reporter construct. In a subsequent step the
ligand binding domain of the GR cloned into plRES2-EGFP-GAL4
containing the DNA binding domain of GAL4 from pFA-AT2 was
transfected. This fusion construct activated firefly luciferase
expression under the control of a multimerized GAL4 upstream
activation sequence (UAS). The signal of the emitted luminescence
was recorded by the LIPR.sup.TETRA. This allowed for specific
detection of ligand-induced activation of the GR and therefore for
the identification of compounds with agonistic properties. The
GAL4/UAS reporter was premixed with a vector that constitutively
expressed Renilla luciferase, which served as an internal positive
control for transfection efficiency.
[0626] The complete culture medium for the assay was: [0627] DMEM
F-12 (1:1) MIXTURE (LONZA cat. N.sup.o: BE04-687F/U1) 500 mL [0628]
5 mL of 100 mM Sodium Pyruvate (LONZA cat. N.sup.o: BE12-115E)
[0629] 25 mL of 7.5% Sodium Bicarbonate (LONZA cat. N.sup.o
BE17-613E) [0630] 6.5 mL of 1 M Hepes (LONZA cat. N.sup.o:
BE17-737E) [0631] 5 mL of 100.times. Penicillin/Streptomycin (LONZA
cat. N.sup.o DE17-602E) [0632] 50 mL of Fetal Bovine Serum
(Euroclone cat. N.sup.o ECS 0180 L) [0633] 0.25 mL of 10 mg/mL
Puromycin (InvivoGen cat.: ant-pr-1) [0634] 0.5 mL of 100 mg/mL
Zeocin (InvivoGen cat.: ant-zn-1) Cryo-preserved CHO-Gal4/GR cells
were suspended in complete medium and 5000 cells/25 .mu.l/well were
seeded into the wells of 384-well polystyrene assay plates (Thermo
Scientific, cat. #4332) and cultured at 37.degree. C., 5% CO.sub.2
and 95% humidity. After 24 hours growth medium was carefully
removed and replaced by 30 .mu.l Opti-MEM (GIBCO, cat. #31985062)
as assay buffer. To test the compounds an 8-point half-log compound
dilution curve was generated in 100% DMSO starting from a 2 mM
stock and compounds were then diluted 1:50 in Opti-MEM. 10 .mu.l of
compounds were then added to the wells containing 30 .mu.l Opti-MEM
resulting in a final assay concentration range from 10 .mu.M to
0.003 .mu.M in 0.5% DMSO. Compounds were tested at 8 concentrations
in quadruplicate data points. Cells were incubated for 6 hour with
compounds and beclometasone (Sigma, cat. # Y0000351) as control
compound at 37.degree. C., 5% CO.sub.2 and 95% humidity in a total
volume of 40 .mu.l. Finally, cells were lysed with 20 .mu.l of
Triton/Luciferin solution and the signal of the emitted
luminescence was recorded at the FLIPR.sup.TETRA for 2 minutes.
[0635] The relative efficacy of a compound (% effect) was
calculated based on the full effect of the agonist
beclometasone:
% effect=((compound-min)/(max-min)).times.100
[min=Opti-MEM only,max=beclometasone]
To calculate EC.sub.50, max, min and slope factor for each compound
a concentration response curve was fitted by plotting % effect
versus compound concentration using a 4 parameter logistic
equation:
y=A+(B-A)/(1+((1.degree. C.)/x)D)
[A=min y,B=max y,C=log EC.sub.50,D=slope]
[0636] GRE Antagonist
[0637] The reporter cell line CHO-Gal4/GR consisted of a chinese
hamster ovary (CHO) cell line (Leibniz Institute DSMZ--German
Collection of Microorganisms and Cell Cultures GmbH: ACC-110)
containing a firefly luciferase gene under the control of the GR
ligand binding domain fused to the DNA binding domain (DBD) of GAL4
(GAL4 DBD-GR) stably integrated into CHO cells. This cell line was
established by stable transfection of CHO cells with a
GAL4-UAS-Luciferase reporter construct. In a subsequent step the
ligand binding domain of the GR cloned into pIRES2-EGFP-GAL4
containing the DNA binding domain of GAL4 from pFA-AT2 was
transfected. This fusion construct activated firefly luciferase
expression under the control of a multimerized GAL4 upstream
activation sequence (UAS). The signal of the emitted luminescence
was recorded by the FLIPR.sup.TETRA. This allowed for specific
detection of antagonistic properties of compounds by measuring the
ligand-induced inhibition of beclometasone-activated GR. The
GAL4/UAS reporter was premixed with a vector that constitutively
expressed Renilla luciferase, which served as an internal positive
control for transfection efficiency.
[0638] The complete culture medium for the assay was: [0639] DMEM
F-12 (1:1) MIXTURE (LONZA cat. N.sup.o: BE04-687F/U1) 500 mL [0640]
5 mL of 100 mM Sodium Pyruvate (LONZA cat. N.sup.o: BE12-115E)
[0641] 25 mL of 7.5% Sodium Bicarbonate (LONZA cat. N.sup.o
BE17-613E) [0642] 6.5 mL of 1 M Hepes (LONZA cat. N.sup.o:
BE17-737E) [0643] 5 mL of 100.times. Penicillin/Streptomycin (LONZA
cat. N.sup.o DE17-602E) [0644] 50 mL of Fetal Bovine Serum
(Euroclone cat. N.sup.o ECS 0180 L) [0645] 0.25 mL of 10 mg/mL
Puromycin (InvivoGen cat.: ant-pr-1) [0646] 0.5 mL of 100 mg/mL
Zeocin (InvivoGen cat.: ant-zn-1) Cryo-preserved CHO-Gal4/GR cells
were suspended in complete medium and 5000 cells/25 .mu.l/well were
seeded into the wells of 384-well polystyrene assay plates (Thermo
Scientific, cat. #4332) and cultured at 37.degree. C., 5% CO.sub.2
and 95% humidity. After 24 hours growth medium was carefully
removed and replaced by 20 .mu.l Opti-MEM (GIBCO, cat. #31985062)
as assay buffer. For testing compounds an 8-point half-log compound
dilution curve was generated in 100% DMSO starting from a 2 mM
stock and compounds were then diluted 1:50 in Opti-MEM. To test the
compounds in the antagonist mode 10 .mu.l of compounds were then
added to the wells containing 20 .mu.l Opti-MEM and incubated for
10 min. After this pre-incubation 10 .mu.l of the reference agonist
beclometasone (Sigma, cat. # Y0000351) at an EC50 of 2.5 nM were
added resulting in a final assay concentration range from 10 .mu.M
to 0.003 .mu.M in 0.5% DMSO in a total volume of 40 .mu.l.
Compounds were tested at 8 concentrations in quadruplicate data
points. Cells were incubated for 6 hour with compounds and
mifepristone as control compound (Sigma, cat. # M8046) at
37.degree. C., 5% CO.sub.2 and 95% humidity. Finally, cells were
lysed with 20 .mu.l of Triton/Luciferin solution and the signal of
the emitted luminescence was recorded at the FLIPR.sup.TERA for 2
minutes.
[0647] The relative efficacy of a compound (% effect) was
calculated based on the full effect of the antagonist
mifepristone:
% effect=((compound-min)/(max-min)).times.-100
[min=Opti-MEM only,max=mifepristone]
To calculate IC.sub.50, max, min and slope factor for each compound
a concentration response curve was fitted by plotting % effect
versus compound concentration using a 4 parameter logistic
equation:
y=A+(B-A)/(1+((10C)/x)D)
[A=min y,B=max y,C=log IC.sub.50,D=slope]
[0648] Table summarizing biological data:
TABLE-US-00006 IC50 or EC50 % A < 100 nM, inhibition cmpd B =
100 nM-1 .mu.M, hGR at # C = 1 .mu.M-15 .mu.M 1 .mu.M 1 A 99 2 B 91
3 A 98 4 B 95 5 B 95 6 B 97 7 C 96 8 n.a. 12 9 n.a. 86 10 n.a. 100
12 n.a. 83 13 n.a. 20 14 n.a. 84 15 n.a. 87 16 n.a. 30 17 n.a. 80
18 n.a. 29 21 n.a. 22 22 n.a. 18 24 n.a. 12 26 n.a. 28 30 n.a. 27
31 B n.d. 33 C n.d. 34a A n.d. 34b B n.d. 35a A n.d. 36a B n.d. 36b
B n.d. 37 A n.d. 38a B n.d. 38b A n.d. 39a A n.d. 40a A n.d. 40b B
n.d. 41b C n.d. 42a A n.d. 42b B n.d. 43a A n.d. 43b C n.d. 44a A
n.d. 44b B n.d. 45a A n.d. 45b B n.d. 46 A n.d. 47 A n.d. 60 B n.d.
61 B n.d. 62 B n.d. 63 B n.d. 64 A n.d. 65 A n.d. 66 A n.d. 67 A
n.d. 68 B n.d. 69 A n.d. 70 A n.d. 71 B n.d. 72 A n.d. 73 A n.d. 74
B n.d. 75 A n.d. 76 A n.d. 77 A n.d. 82 B n.d. 83 A n.d. 84 B n.d.
85 B n.d. 86 A n.d. 87 A n.d. 88 A n.d. 90 C n.d. 91 C n.d. 92 A
n.d. 93 A n.d. 94 A n.d. 95 A n.d. 96 A n.d. 98 A n.d. 100 A n.d.
101 B n.d. 104 C n.d. 107 C n.d. 108 A n.d. 109 A n.d. 110 A n.d.
111 A n.d. 112 B n.d. 113 B n.d. 114 B n.d. 120 C n.d. 121 A n.d.
123 A n.d. 124 A n.d. 125 A n.d. 126 A n.d. 127 B n.d. 128 B n.d.
129 A n.d. 130 B n.d. 131 B n.d. 132 A n.d. 133 B n.d. 134 B n.d.
135 A n.d. 136 A n.d. 137 A n.d. 138 B n.d. 139a C n.d. 139b C n.d.
148 A n.d. 149 A n.d. 150 B n.d. 151 B n.d. "n.a.": not active in
the GR cell-based assays, neither in the agonistic nor in the
antagonistic mode. "n.d.": not determined.
Prophetic Examples
[0649] The prophetic examples summarized in the following table
could be synthesized in analogy to Example 7 described above. The
person skilled in the art would know how to select suitable
intermediates in order to obtain any of the prophetic examples
shown in the below table.
TABLE-US-00007 Proph. Ex. # Structure 48 ##STR00165## 49
##STR00166## 142 143 144 145 146 147 indicates data missing or
illegible when filed
[0650] In any of the above tables, the example compounds wherein
the substituents which are connected to the central pyrrolidone
have a different relative orientation, e.g. phenyl moiety and
methyl moiety up ("bold bond", ) and amide moiety down ("hashed
bond", ) or vice versa, are the "trans" diastereomer which is a
racemic mixture of the two corresponding trans enantiomers.
* * * * *