U.S. patent application number 16/223925 was filed with the patent office on 2019-06-20 for substituted pyrrolidine amides ii.
The applicant listed for this patent is Gruenenthal GmbH. Invention is credited to Jo ALEN, Daniela FRIEBE, Stephanie HENNEN, Florian JAKOB, Sebastian KRUGER, Markus SCHADE.
Application Number | 20190185470 16/223925 |
Document ID | / |
Family ID | 60673848 |
Filed Date | 2019-06-20 |
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United States Patent
Application |
20190185470 |
Kind Code |
A1 |
JAKOB; Florian ; et
al. |
June 20, 2019 |
Substituted Pyrrolidine Amides II
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; (Vliermaal, BE) ; KRUGER;
Sebastian; (Aachen, DE) ; SCHADE; Markus;
(Aachen, DE) ; FRIEBE; Daniela; (Aachen, DE)
; HENNEN; Stephanie; (Aachen, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gruenenthal GmbH |
Aachen |
|
DE |
|
|
Family ID: |
60673848 |
Appl. No.: |
16/223925 |
Filed: |
December 18, 2018 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 401/14 20130101;
C07D 403/04 20130101; C07D 417/14 20130101; A61P 11/06 20180101;
A61P 19/02 20180101; C07D 413/14 20130101; A61P 29/00 20180101;
C07D 403/14 20130101; C07D 471/04 20130101; C07D 405/14 20130101;
C07D 409/14 20130101 |
International
Class: |
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 417/14 20060101
C07D417/14; C07D 401/14 20060101 C07D401/14; C07D 405/14 20060101
C07D405/14; C07D 403/04 20060101 C07D403/04; A61P 29/00 20060101
A61P029/00 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 18, 2017 |
EP |
17208180.4 |
Claims
1. A compound according to general formula (I), ##STR00147##
wherein R.sub.1 represents --C.sub.1-10-alkyl;
--C.sub.3-10cycloalkyl; --C.sub.1-6-alkylene-C.sub.3-10cycloalkyl;
3 to 7 membered heterocycloalkyl; --C.sub.1-6-alkylene-(3 to 7
membered heterocycloalkyl); aryl; --C.sub.1-6-alkylene-aryl; 5 or
6-membered heteroaryl; or --C.sub.1-6-alkylene-(5 or 6-membered
heteroaryl); 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)-aryl; --C(.dbd.O)--C.sub.1-6-alkylene-aryl;
--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-aryl;
--S(.dbd.O).sub.1-2--C.sub.1-6-alkylene-aryl;
--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 represents --C.sub.1-10-alkyl;
--C.sub.3-10-cycloalkyl;
--C.sub.1-6-alkylene-C.sub.3-10-cycloalkyl; aryl;
--C.sub.1-6-alkylene-aryl; --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)-aryl; --C(.dbd.O)--C.sub.1-6-alkylene-aryl;
--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-aryl; or
--S(.dbd.O).sub.1-2--C.sub.1-6-alkylene-aryl; R.sub.4 represents
--H; --F; --Cl; --Br; --I; --CN; --CH.sub.3; --CF.sub.3;
--CF.sub.2H; --CFH.sub.2 or cyclopropyl; X represents N or
CR.sub.5; wherein R.sub.5 represents --H; --F; --Cl; --Br; --I;
--CN; --C.sub.1-10-alkyl or --C.sub.3-10-cycloalkyl; Y represents N
or CR.sub.6; wherein R.sub.6 represents --H; --F; --Cl; --Br; --I;
--CN; --C.sub.1-10-alkyl or --C.sub.3-10-cycloalkyl; Z represents N
or CR.sub.7; wherein R.sub.7 represents --H; --F; --Cl; --Br; --I;
--CN; --C.sub.1-10-alkyl or --C.sub.3-10-cycloalkyl; wherein
--C.sub.1-10-alkyl, --C.sub.1-4-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.1-4-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.1-6alkyl)-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.1-4-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.1-4-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 aryl 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.1-4-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.1-4-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.
2. The compound according to claim 1, wherein X represents
CR.sub.5, Y represents CR.sub.6; and Z represents CR.sub.7; or X
represents N, Y represents CR.sub.6; and Z represents CR.sub.7; or
X represents CR.sub.5, Y represents N; and Z represents CR.sub.7;
or X represents CR.sub.5, Y represents CR.sub.6; and Z represents
N; or X represents N, Y represents N; and Z represents CR.sub.7; or
X represents N, Y represents CR.sub.6; and Z represents N; or X
represents CR.sub.5, Y represents N; and Z represents N; or X
represents N, Y represents N; and Z represents N.
3. The compound according to claim 2, wherein optionally present
R.sub.5 represents --H; optionally present R.sub.6 represents --H;
and/or optionally present R.sub.7 represents --H
4. The compound according to claim 1, wherein R.sub.1 represents
--C.sub.3-10-cycloalkyl;
--C.sub.1-6-alkylene-C.sub.3-10-cycloalkyl; aryl; or 5 or
6-membered heteroaryl.
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; or
--S(.dbd.O).sub.2-(5 or 6-membered heteroaryl).
6. The compound according to claim 1, wherein R.sub.3 represents
--C.sub.1-10-alkyl; --C.sub.3-10-cycloalkyl;
--C.sub.1-6-alkylene-C.sub.3-10-cycloalkyl; aryl;
--C.sub.1-6-alkylene-aryl.
7. The compound according to claim 1, wherein R.sub.4 represents
--H.
8. The compound according to claim 1, wherein R.sub.1 represents
cyclopropyl, unsubstituted; --CH.sub.2-cyclopropyl, unsubstituted;
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, cyclopropyl and
--OCH.sub.3, wherein phenyl is optionally annealed to a dioxolane
ring by a substituent --O--CH.sub.2CH.sub.2--O--; or pyridyl,
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.
9. The compound according to claim 1, wherein R.sub.2 represents
--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;
--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)-cyclobutyl, 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 and
1-oxa-2,4-diazolyl, 1,2,5-oxadiazolyl, isoxazolyl, 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; 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 and 1-oxa-2,4-diazolyl,
1,2,5-oxadiazolyl, isoxazolyl, 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 represents
--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; cyclohexyl, unsubstituted or
mono- or disubstituted with substituents independently of one
another selected from the group consisting of --F, --Cl, and --Br;
--CH.sub.2-cyclopropyl, unsubstituted; --CH.sub.2-cyclohexyl,
unsubstituted or mono- or disubstituted with substituents
independently of one another selected from the group consisting of
--F, --Cl, and --Br; 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 --CH.sub.2-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.
11. 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, --CF.sub.3, --CN, cyclopropyl and
--OCH.sub.3; and/or R.sub.2 represents
--C(.dbd.O)--C.sub.1-6-alkyl; --C(.dbd.O)-cyclopropyl; or
--C(.dbd.O)-cyclobutyl, unsubstituted or mono- or disubstituted
with substituents independently of one another selected from the
group consisting of --F, --Cl, and --Br; and/or R.sub.3 represents
fluoro-phenyl.
12. The compound according to claim 1, selected from the group
consisting of 1
2,2-difluoro-N-[rac-(2R,3S)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-[-
1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide 2
2,2-difluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-
-pyrrolidin-3-yl]propanamide 3
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-ph-
enyl-pyrrolidin-3-yl]propanamide 4
2,2-difluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(2-methoxy-4-
-pyridyl)-5-oxo-pyrrolidin-3-yl]propanamide 5
2,2-difluoro-N-[rac-(2R,3S)-2-(2,4-difluorophenyl)-1-[1-(4-fluorophenyl)i-
ndazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide 6
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(3,4-difluorophenyl)indazol-5-yl]-5-oxo--
2-phenyl-pyrrolidin-3-yl]propanamide 7
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-metho-
xyphenyl)-5-oxo-pyrrolidin-3-yl]propanamide 8
N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolid-
in-3-yl]cyclopropane-carboxamide 9
N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolid-
in-3-yl]cyclopropane-sulfonamide 10
N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-o-
xo-pyrrolidin-3-yl]cyclopropanesulfonamide 11
2,2-difluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indaz-
ol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide 12
N-[(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-py-
rrolidin-3-yl]-2,2-difluoro-propanamide 13
1-methyl-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-
-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide 14
1-fluoro-N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-
-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide 15
N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-ox-
o-pyrrolidin-3-yl]-1-(trifluoromethyl)cyclopropanecarboxamide 16
N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-ox-
o-pyrrolidin-3-yl]methanesulfonamide 17
N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-o-
xo-pyrrolidin-3-yl-]1-(trifluoromethyl)cyclopropanecarboxamide 18
1-methyl-N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-
-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide 19
N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-ox-
o-pyrrolidin-3-yl]cyclobutanecarboxamide 20
2,2-difluoro-N-[(2S,3R)-2-(4-fluoro-3-methoxy-phenyl)-1-[1-(4-fluoropheny-
l)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide 21
2,2-difluoro-N-[(2R,3S)-2-(4-fluoro-3-methoxy-phenyl)-1-[1-(4-fluoropheny-
l)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide 22
1-methyl-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyph-
enyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide 23
1-fluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyph-
enyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide 24
2,2-difluoro-N-[(2S,3R)-2-(2-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-
-yl]-5-oxo-pyrrolidin-3-yl]propanamide 25
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(3-fluorophenyl)indazol-5-yl]-5-oxo-2-ph-
enyl-pyrrolidin-3-yl]propanamide 26
2,2-difluoro-N-[rac-(2R,3S)-2-(3,5-difluorophenyl)-1-[1-(4-fluorophenyl)i-
ndazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide 27
2,2-difluoro-N-[rac-(2R,3S)-5-oxo-2-phenyl-1-(1-phenylindazol-5-yl)pyrrol-
idin-3-yl]propanamide 28
N-[(2R,3S)-2-(2-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-py-
rrolidin-3-yl]cyclo-propanecarboxamide 29
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-cyanophenyl)indazol-5-yl]-5-oxo-2-phe-
nyl-pyrrolidin-3-yl]propanamide 30
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(3-cyanophenyl)indazol-5-yl]-5-oxo-2-phe-
nyl-pyrrolidin-3-yl]propanamide 31
2,2-difluoro-N-[rac-(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indaz-
ol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide 32
N-[rac-(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-ox-
o-pyrrolidin-3-yl]cyclobutanecarboxamide 33
2,2-difluoro-N-[(2R,3S)-2-(2-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-
-yl]-5-oxo-pyrrolidin-3-yl]propanamide 34
N-[(2R,3S)-2-(4-fluoro-3-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-y-
l]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide 36
2,2-difluoro-N-[rac-(2S,3S)-2-cyclopropyl-1-[1-(4-fluorophenyl)indazol-5--
yl]-5-oxo-pyrrolidin-3-yl]propanamide 37
1-cyclopropyl-N-[rac-(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)inda-
zol-5-yl]-5-oxo-pyrrolidin-3-yl]methanesulfonamide 38
2,2-difluoro-N-[(2S,3R)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(o-tolyl)-5--
oxo-pyrrolidin-3-yl]propanamide 39
N-[(2S,3R)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-
-yl]cyclopropanecarboxamide 42
2,2-difluoro-N-[(2S,3R)-2-(2-fluoro-5-methoxy-phenyl)-1-[1-(4-fluoropheny-
l)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide 43
N-[(2S,3R)-2-(2-fluoro-5-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-y-
l]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide 45 1:1 mixture of
(1
S,2S)-2-fluoro-N-[(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-
-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide and (1
S,2S)-2-fluoro-N-[(2S,3R)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-
-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide 46 rac-(1
S,2R)-2-fluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-met-
hoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide 48
2,2-difluoro-N-[rac-(2S,3R)-2-cyclopropyl-1-[1-(4-fluorophenyl)indazol-5--
yl]-5-oxo-pyrrolidin-3-yl]propanamide 49
N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(2-methoxy-4-pyridyl)-5-o-
xo-pyrrolidin-3-yl]cyclopropanecarboxamide 51
N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-ox-
o-pyrrolidin-3-yl]cyclopropanesulfonamide 52
2-methyl-N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-
-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide 53
N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(o-tolyl)-5-oxo-pyrrolidi-
n-3-yl]cyclopropanecarboxamide 54
N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-ox-
o-pyrrolidin-3-yl]cyclopropanecarboxamide 55
N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-o-
xo-pyrrolidin-3-yl]cyclopropanecarboxamide 56 1:1 mixture of
(1R,2R)-2-fluoro-N-[(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indaz-
ol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide and
(1R,2R)-2-fluoro-N-[(2S,3R)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indaz-
ol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide 61
N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-ox-
o-pyrrolidin-3-yl]cyclopropanecarboxamide 62
N-[(2R,3S)-2-(2-fluoro-5-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-y-
l]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide 63 1:1 mixture of
(1R,2R)-2-fluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-metho-
xyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide and
(1R,2R)-2-fluoro-N-[(2S,3R)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-metho-
xyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide 65
N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-
-yl]cyclopropanecarboxamide 66
N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-ox-
o-pyrrolidin-3-yl]acetamide 67
N-[rac-(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-ox-
o-pyrrolidin-3-yl]cyclopropanecarboxamide 68
2,2-difluoro-N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indaz-
ol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide 69
2,2-difluoro-N-[(2R,3S)-2-(2-fluoro-5-methoxy-phenyl)-1-[1-(4-fluoropheny-
l)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide 70
1-fluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-
-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide 71
N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-ox-
o-pyrrolidin-3-yl]-1-(trifluoromethyl)cyclopropanecarboxamide 72
2,2-difluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(o-tolyl)-5--
oxo-pyrrolidin-3-yl]propanamide 73
1-fluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyr-
rolidin-3-yl]cyclopropanecarboxamide 74
N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-
-yl]-1-methyl-cyclopropanecarboxamide 75
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4,4-difluorocyclohexyl)indazol-5-yl]-5--
oxo-2-phenyl-pyrrolidin-3-yl]propanamide 76
2,2-difluoro-N-[rac-(2R,3S)-1-(1-cyclohexylindazol-5-yl)-5-oxo-2-phenyl-p-
yrrolidin-3-yl]propanamide 77
2,2-difluoro-N-[rac-(2R,3S)-2-(2-fluoro-5-methoxy-phenyl)-1-(1-methylinda-
zol-5-yl)-5-oxo-pyrrolidin-3-yl]propanamide 78
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(2,2-difluoroethyl)indazol-5-yl]-2-(2-fl-
uoro-5-methoxy-phenyl)-5-oxo-pyrrolidin-3-yl]propanamide 79
2,2-difluoro-N-[rac-(2R,3S)-1-[1-[(2-fluorophenyl)methyl]indazol-5-yl]-5--
oxo-2-phenyl-pyrrolidin-3-yl]propanamide 80
2,2-difluoro-N-[rac-(2R,3S)-1-[1-[(3-fluorophenyl)methyl]indazol-5-yl]-5--
oxo-2-phenyl-pyrrolidin-3-yl]propanamide 81
2,2-difluoro-N-[rac-(2R,3S)-1-[1-[(4-fluorophenyl)methyl]indazol-5-yl]-5--
oxo-2-phenyl-pyrrolidin-3-yl]propanamide 82
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(cyclopropylmethyl)indazol-5-yl]-5-oxo-2-
-phenyl-pyrrolidin-3-yl]propanamide 84
2,2-difluoro-N-[rac-(2R,3S)-1-[1-[(4,4-difluorocyclohexyl)methyl]indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide 85
2,2-difluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-[(2-fluorophenyl)meth-
yl]indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide 86
2,2-difluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-[(4-fluorophenyl)meth-
yl]indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide 87
2,2-difluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-[(3-fluorophenyl)meth-
yl]indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide 88
N-[(2R,3S)-2-benzyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidi-
n-3-yl]-2,2-difluoropropanamide 89
2,2-difluoro-N-[rac-(2R,3S)-2-ethyl-1-[1-(4-fluorophenyl)indazol-5-yl]-5--
oxopyrrolidin-3-yl]propanamide 90
2,2-difluoro-N-[rac-(2R,3R)-2-(cyclopropylmethyl)-1-[1-(4-fluorophenyl)in-
dazol-5-yl]-5-oxopyrrolidin-3-yl]propanamide 91
2-cyclopropyl-N-[(2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-p-
henylpyrrolidin-3-yl]acetamide 92
N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidi-
n-3-yl]-1-methyl-1H-pyrazole-3-carboxamide 93
N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidi-
n-3-yl]-1H-imidazole-2-carboxamide 94
N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidi-
n-3-yl]-2-methyloxazole-5-carboxamide 95
N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidi-
n-3-yl]-5-methylthiazole-4-carboxamide 96
N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidi-
n-3-yl]pyrimidine-2-carboxamide 97
N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidi-
n-3-yl]nicotinamide 98
N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidi-
n-3-yl]oxetane-3-carboxamide 99
N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidi-
n-3-yl]thiazole-5-sulfonamide 100
N-[rac-(2R,3R)-2-(5-chlorothiophen-2-yl)-1-[1-(4-fluorophenyl)indazol-5-y-
l]-5-oxopyrrolidin-3-yl]cyclopropanesulfonamide 101
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)pyrazolo[3,4-b]pyridin-5-
-yl]-5-oxo-2-phenylpyrrolidin-3-yl]propanamide 102
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)pyrazolo[3,4-c]pyridin-5-
-yl]-5-oxo-2-phenylpyrrolidin-3-yl]propanamide 103
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-5-
-yl]-5-oxo-2-phenylpyrrolidin-3-yl]propanamide in each case in the
form of the free compound or a physiologically acceptable salt
thereof.
13. A pharmaceutical dosage form comprising a compound according to
claim 1.
14. A method for treatment and/or prophylaxis of pain and/or
inflammations in a subject, comprising a step of administering the
subject a compound according to claim 1.
15. The method according to claim 14 for the treatment and/or
prophylaxis of asthma, rheumatoid arthritis, inflammatory bowel
disease, chronic obstructive pulmonary disease, acute respiratory
distress syndrome, cystic fibrosis, osteoarthritis, polymyalgia
rheumatica, giant cell arteritis, Sjogren syndrome, Duchenne
muscular dystrophy, vasculitis, Behcet's disease, ulcerative
colitis and/or Crohn's disease.
Description
[0001] This application claims foreign priority benefit of European
Application No. 17 208 180.4, filed Dec. 18, 2017, the disclosure
of which patent application is 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. 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.
[0008] This object has been achieved by the subject-matter as
described herein.
[0009] It was surprisingly found that the compounds according to
the invention are highly potent modulators of the glucocorticoid
receptor.
[0010] The invention relates to a compound according to general
formula (I),
##STR00003## [0011] wherein [0012] R.sub.1 represents
--C.sub.1-10-alkyl; --C.sub.3-10-cycloalkyl;
--C.sub.1-6-alkylene-C.sub.3-10-cycloalkyl; 3 to 7 membered
heterocycloalkyl; --C.sub.1-6-alkylene-(3 to 7 membered
heterocycloalkyl); aryl; --C.sub.1-6-alkylene-aryl; 5 or 6-membered
heteroaryl; or --C.sub.1-6-alkylene-(5 or 6-membered heteroaryl);
[0013] 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-cyclo-alkyl;
--C(.dbd.O)-(3 to 7 membered heterocycloalkyl);
--C(.dbd.O)--C.sub.1-6-alkylene-(3 to 7 membered heterocycloalkyl);
--C(.dbd.O)-aryl; --C(.dbd.O)--C.sub.1-6-alkylene-aryl;
--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-aryl;
--S(.dbd.O).sub.1-2--C.sub.1-6-alkylene-aryl;
--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); [0014] R.sub.3 represents --C.sub.1-10-alkyl;
--C.sub.3-10-cycloalkyl;
--C.sub.1-6-alkylene-C.sub.3-10-cycloalkyl; aryl;
--C.sub.1-6-alkylene-aryl; --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)-aryl; --C(.dbd.O)--C.sub.1-6-alkylene-aryl;
--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-aryl; or
--S(.dbd.O).sub.1-2--C.sub.1-6-alkylene-aryl; [0015] R.sub.4
represents --H; --F; --Cl; --Br; --I; --CN; --CF.sub.3;
--CF.sub.2H; --CFH.sub.2 or cyclopropyl; [0016] X represents N or
CR.sub.5; wherein R.sub.5 represents --H; --F; --Cl; --Br; --I;
--CN; --C.sub.1-10-alkyl or --C.sub.3-10-cycloalkyl; [0017] Y
represents N or CR.sub.6; wherein R.sub.6 represents --H; --F;
--Cl; --Br; --I; --CN; --C.sub.1-10-alkyl or
--C.sub.3-10-cycloalkyl; [0018] Z represents N or CR.sub.7; wherein
R.sub.7 represents --H; --F; --Cl; --Br; --I; --CN;
--C.sub.1-10-alkyl or --C.sub.3-10-cycloalkyl; wherein
--C.sub.1-10-alkyl, --C.sub.1-4-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.1-4-alkyl, --C.sub.1-6-alkylene-, --C.sub.3-10-cycloalkyl
and 3 to 7 membered hetero-cycloalkyl 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(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 aryl 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.
[0019] 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.
[0020] 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.
[0021] 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.
[0022] Further, the compound according to the invention may be
present in form of the racemate, enantiomers, diastereomers,
tautomers or any mixtures thereof.
[0023] 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.
[0024] 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. In another
preferred embodiment, --C.sub.1-10-alkyl, --C.sub.1-8-alkyl,
--C.sub.1-6-alkyl and --C.sub.1-4-alkyl are not saturated.
According to this embodiment, --C.sub.1-10-alkyl,
--C.sub.1-8-alkyl, --C.sub.1-6-alkyl and --C.sub.1-4-alkyl comprise
at least one C--C double bond (a C.dbd.C-bond) or at least one C--C
triple bond (a C.ident.C-bond). In still another preferred
embodiment, --C.sub.1-10-alkyl, --C.sub.1-8-alkyl,
--C.sub.1-6-alkyl and --C.sub.1-4-alkyl are (i) saturated or (ii)
not saturated, wherein --C.sub.1-10-alkyl, --C.sub.1-6-alkyl,
--C.sub.1-6-alkyl and --C.sub.1-4-alkyl comprise at least one,
preferably one, C--C triple bond (a C.ident.C-bond).
[0025] 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.
[0026] Preferred --C.sub.1-8-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.
[0027] 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.
[0028] 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.
[0029] 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-.
[0030] 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.
[0031] 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.
[0032] 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.
[0033] 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.
[0034] 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.
[0035] Preferred 3 to 7-membered heterocycloalkyl groups are
selected from the group consisting of azepanyl, dioxepanyl,
oxazepanyl, diazepanyl, thiazolidinyl, tetrahydrothiophenyl,
tetrahydropyridinyl, thiomorpholinyl, tetrahydropyranyl, oxetanyl,
oxiranyl, tetrahydrofuranyl, 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.
[0036] Preferred 3 to 6-membered heterocycloalkyl groups are
selected from the group consisting of tetrahydropyranyl, oxetanyl,
oxiranyl, tetrahydrofuranyl, thiazolidinyl, tetrahydrothiophenyl,
tetrahydropyridinyl, 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. Particularly preferred 3 to 6-membered
heterocycloalkyl groups are selected from the group consisting of
tetrahydropyranyl, oxetanyl, oxiranyl, and tetrahydrofuranyl.
[0037] According to the invention, the term "aryl" preferably means
aromatic hydrocarbons having 6 to 14, i.e. 6, 7, 8, 9, 10, 11, 12,
13 or 14 ring members, preferably having 6 to 10, i.e. 6, 7, 8, 9
or 10 ring members, including phenyls and naphthyls. Each aryl
residue can be unsubstituted or mono- or polysubstituted. The aryl
can be bound to the superordinate general structure via any desired
and possible ring member of the aryl residue. The aryl residues can
also be condensed with further saturated or (partially) unsaturated
cycloalkyl or heterocycloalkyl, aromatic or heteroaromatic ring
systems, which can in turn be unsubstituted or mono- or
polysubstituted. In a preferred embodiment, aryl is condensed with
a further ring system. Examples of condensed aryl residues are
2H-benzo[b][1,4]oxazin-3(4H)-onyl, 1H-benzo[d]imidazolyl,
2,3-dihydro-1H-indenyl, tetrahydronaphthalenyl, isochroman,
1,3-dihydroisobenzofuranyl, benzodioxolanyl and benzodioxanyl.
[0038] Preferably, aryl is selected from the group consisting of
phenyl, 1H-benzo[d]imidazolyl, 2H-benzo[b][1,4]oxazin-3(4H)-onyl,
2,3-dihydro-1H-indenyl, tetrahydronaphthalenyl, isochroman,
1,3-dihydroisobenzofuranyl, 1-naphthyl, 2-naphthyl, fluorenyl and
anthracenyl, each of which can be respectively unsubstituted or
mono- or polysubstituted. In another preferred embodiment, aryl is
not condensed with any further ring system. A particularly
preferred aryl is phenyl, unsubstituted or mono- or
polysubstituted.
[0039] 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.
[0040] Preferably, the 5- to 6-membered heteroaryl is selected from
the group consisting of pyridyl (i.e. 2-pyridyl, 3-pyridyl,
4-pyridyl), pyridone (pyridinone), pyrimidinyl, pyridazinyl,
pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,
thiazolyl, 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, oxadiazolyl, 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). 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.
[0041] The compounds according to the invention are defined by
substituents, for example by R.sub.1, R.sub.2, R.sub.3 and R.sub.4
(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.dbd.--C.sub.1-10-alkyl (1.sup.st generation substituent),
then the --C.sub.1-10-alkyl can for its part be substituted, for
example with a --NH(C.sub.1-6-alkyl) (2.sup.nd generation
substituent). This produces the functional group
R.sub.1.dbd.(--C.sub.1-10-alkyl-NH--C.sub.1-6-alkyl). The
--NH--C.sub.1-6-alkyl can then for its part be resubstituted, for
example with --Cl (3.sup.rd generation substituent). Overall, this
produces the functional group
R.sub.1.dbd.--C.sub.1-10-alkyl-NH--C.sub.1-6-alkyl, wherein the
--C.sub.1-6-alkyl of the --NH--C.sub.1-6-alkyl is substituted by
--Cl.
[0042] 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.
[0043] 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.2 and R.sub.3 denote
--C.sub.1-6-alkyl, then --C.sub.1-6-alkyl can e.g. represent ethyl
for R.sub.2 and can represent methyl for R.sub.3.
[0044] 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.
[0045] In relation to the terms "aryl", "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.
[0046] 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).
[0047] 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 hetero-cycloalkyl; 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. Preferably,
--C.sub.1-6-alkylene-groups and --C.sub.1-4-alkylene-groups are
unsubstituted.
[0048] According to the invention, preferably aryl, 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; .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.
[0049] Preferred substituents of aryl, 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 particularly preferably of --F; --Cl;
--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. According to this embodiment,
aryl, 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.
[0050] In a preferred embodiment, the compound according to the
invention has a stereochemistry according to general formula (II),
(III), (IV) or (V)
##STR00004##
[0051] In a preferred embodiment, the compound according to the
invention has a stereochemistry according to general formula (II)
or (III), 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). Preferably, the compound according to the
invention has a stereochemistry according to general formula (III).
The stereochemistry according to general formula (II) is
particularly preferred.
[0052] In another preferred embodiment, the compound according to
the invention has a stereochemistry according to general formula
(IV) or (V), 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). Preferably, the compound according to the
invention has a stereochemistry according to general formula
(V).
[0053] In the compound of the invention according to any of general
formulas (I), (II), (III), (IV) or (V), R.sub.1 represents
--C.sub.1-10-alkyl; --C.sub.3-10-cycloalkyl;
--C.sub.1-6-alkylene-C.sub.3-10-cycloalkyl; 3 to 7 membered
heterocycloalkyl; --C.sub.1-6-alkylene-(3 to 7 membered
heterocycloalkyl); aryl; --C.sub.1-6-alkylene-aryl; 5 or 6-membered
heteroaryl; or --C.sub.1-6-alkylene-(5 or 6-membered
heteroaryl).
[0054] In a preferred embodiment, R.sub.1 represents
--C.sub.3-10-cycloalkyl;
--C.sub.1-6-alkylene-C.sub.3-10-cycloalkyl; aryl; or 5 or
6-membered heteroaryl.
[0055] In particularly preferred embodiments, R.sub.1 represents
[0056] (i) cyclopropyl, unsubstituted; [0057] (ii)
--CH.sub.2-cyclopropyl, unsubstituted; [0058] (iii) 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, cyclopropyl, and
--OCH.sub.3, wherein phenyl is optionally annealed to a dioxolane
ring by a substituent --O--CH.sub.2CH.sub.2--O--; or [0059] (iv)
pyridyl, 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.
[0060] In the compound of the invention according to any of general
formulas (I), (II), (III), (IV) or (V), 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)-aryl; --C(.dbd.O)--C.sub.1-6-alkylene-aryl;
--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-aryl;
--S(.dbd.O).sub.1-2--C.sub.1-6-alkylene-aryl;
--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).
[0061] 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 or
--S(.dbd.O).sub.2-(5 or 6-membered heteroaryl).
[0062] In particularly preferred embodiments, R.sub.2 represents
[0063] (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; [0064]
(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; [0065] (iii)
--C(.dbd.O)-cyclobutyl, 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; [0066] (iv) --C(.dbd.O)-2-tetrahydrofuranyl,
unsubstituted; [0067] (v) --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 and
1-oxa-2,4-diazolyl, 1,2,5-oxadiazolyl, isoxazolyl, 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; [0068] (vi) --S(.dbd.O).sub.2--C.sub.1-10-alkyl,
unsubstituted; [0069] (vii) --S(.dbd.O).sub.2-cyclopropyl,
unsubstituted; [0070] (viii)
--S(.dbd.O).sub.2--CH.sub.2-cyclopropyl, unsubstituted; or [0071]
(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 and 1-oxa-2,4-diazolyl,
1,2,5-oxadiazolyl, isoxazolyl, 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.
[0072] In the compound of the invention according to any of general
formulas (I), (II), (III), (IV) or (V), R.sub.3 represents
--C.sub.1-10-alkyl; --C.sub.3-10-cycloalkyl;
--C.sub.1-6-alkylene-C.sub.3-10-cycloalkyl; aryl;
--C.sub.1-6-alkylene-aryl; --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)-aryl; --C(.dbd.O)--C.sub.1-6-alkylene-aryl;
--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-aryl; or
--S(.dbd.O).sub.1-2--C.sub.1-6-alkylene-aryl.
[0073] In a preferred embodiment, R.sub.3 represents
--C.sub.1-10-alkyl; --C.sub.3-10-cycloalkyl;
--C.sub.1-6-alkylene-C.sub.3-10-cycloalkyl; aryl;
--C.sub.1-6-alkylene-aryl.
[0074] In particularly preferred embodiments, R.sub.3 represents
[0075] (i) --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; [0076]
(ii) -cyclohexyl, unsubstituted or mono- or disubstituted with
substituents independently of one another selected from the group
consisting of --F, --Cl, and --Br; [0077] (iii)
--CH.sub.2-cyclopropyl, unsubstituted; [0078] (iv)
--CH.sub.2-cyclohexyl, unsubstituted or mono- or disubstituted with
substituents independently of one another selected from the group
consisting of --F, --Cl, and --Br; [0079] (v) 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 [0080] (vi)
--CH.sub.2-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.
[0081] In the compound of the invention according to any of general
formulas (I), (II), (III), (IV) or (V), R.sub.4 represents --H;
--F; --Cl; --Br; --I; --CN; --CH.sub.3; --CF.sub.3; --CF.sub.2H;
--CFH.sub.2 or cyclopropyl.
[0082] In a preferred embodiment, R.sub.4 represents --H.
[0083] In the compound of the invention according to any of general
formulas (I), (II), (III), (IV) or (V), X represents N or CR.sub.5;
wherein R.sub.5 represents --H; --F; --Cl; --Br; --I; --CN;
--C.sub.1-10-alkyl or --C.sub.3-10-cycloalkyl.
[0084] In a preferred embodiment, X represents N or CH.
[0085] In the compound of the invention according to any of general
formulas (I), (II), (III), (IV) or (V), Y represents N or CR.sub.6;
wherein R.sub.6 represents --H; --F; --Cl; --Br; --I; --CN;
--C.sub.1-10-alkyl or --C.sub.3-10-cycloalkyl.
[0086] In a preferred embodiment, Y represents N or CH.
[0087] In the compound of the invention according to any of general
formulas (I), (II), (III), (IV) or (V), Z represents N or CR.sub.7;
wherein R.sub.7 represents --H; --F; --Cl; --Br; --I; --CN;
--C.sub.1-10-alkyl or --C.sub.3-10-cycloalkyl.
[0088] In a preferred embodiment, Z represents N or CH.
[0089] In particularly preferred embodiments, [0090] (i) X
represents CR.sub.5, preferably CH; Y represents CR.sub.6,
preferably CH; and Z represents CR.sub.7, preferably CH; or [0091]
(ii) X represents N; Y represents CR.sub.6, preferably CH; and Z
represents CR.sub.7, preferably CH; or [0092] (iii) X represents
CR.sub.5, preferably CH; Y represents N; and Z represents CR.sub.7,
preferably CH; or [0093] (iv) X represents CR.sub.5, preferably CH;
Y represents CR.sub.G, preferably CH; and Z represents N; or [0094]
(v) X represents N; Y represents N; and Z represents CR.sub.7,
preferably CH; or [0095] (vi) X represents N; Y represents
CR.sub.6, preferably CH; and Z represents N; or [0096] (vii) X
represents CR.sub.5, preferably CH; Y represents N; and Z
represents N; or [0097] (viii) X represents N; Y represents N; and
Z represents N. In particularly preferred embodiments of the
invention according to any of general formulas (I), 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, --CF.sub.3, --CN, and
--OCH.sub.3; and/or R.sub.2 represents
--C(.dbd.O)--C.sub.1-6-alkyl; --C(.dbd.O)-cyclopropyl; or
--C(.dbd.O)-cyclobutyl, unsubstituted or mono- or disubstituted
with substituents independently of one another selected from the
group consisting of --F, --Cl, and --Br; and/or R.sub.3 represents
fluoro-phenyl.
[0098] In a preferred embodiment, the compound according to the
invention is selected from the group consisting of [0099] 1
2,2-difluoro-N-[rac-(2R,3S)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-[1-(4--
fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide [0100]
2
2,2-difluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-
-pyrrolidin-3-yl]propanamide [0101] 3
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-ph-
enyl-pyrrolidin-3-yl]propanamide [0102] 4
2,2-difluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(2-methoxy-4-
-pyridyl)-5-oxo-pyrrolidin-3-yl]propanamide [0103] 5
2,2-difluoro-N-[rac-(2R,3S)-2-(2,4-difluorophenyl)-1-[1-(4-fluorophenyl)i-
ndazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide [0104] 6
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(3,4-difluorophenyl)indazol-5-yl]-5-oxo--
2-phenyl-pyrrolidin-3-yl]propanamide [0105] 7
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-metho-
xyphenyl)-5-oxo-pyrrolidin-3-yl]propanamide [0106] 8
N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolid-
in-3-yl]cyclopropanecarboxamide [0107] 9
N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolid-
in-3-yl]cyclopropanesulfonamide [0108] 10
N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-o-
xo-pyrrolidin-3-yl]cyclopropanesulfonamide [0109] 11
2,2-difluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indaz-
ol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide [0110] 12
N-[(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-py-
rrolidin-3-yl]-2,2-difluoro-propanamide [0111] 13
1-methyl-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-
-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide [0112] 14
1-fluoro-N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-
-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide [0113] 15
N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-ox-
o-pyrrolidin-3-yl]-1-(trifluoromethyl)cyclopropanecarboxamide
[0114] 16
N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-ox-
o-pyrrolidin-3-yl]methanesulfonamide [0115] 17
N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-o-
xo-pyrrolidin-3-yl]-1-(trifluoromethyl)cyclopropanecarboxamide
[0116] 18
1-methyl-N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-
-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide [0117] 19
N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-ox-
o-pyrrolidin-3-yl]cyclobutanecarboxamide [0118] 20
2,2-difluoro-N-[(2S,3R)-2-(4-fluoro-3-methoxy-phenyl)-1-[1-(4-fluoropheny-
l)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide [0119] 21
2,2-difluoro-N-[(2R,3S)-2-(4-fluoro-3-methoxy-phenyl)-1-[1-(4-fluoropheny-
l)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide [0120] 22
1-methyl-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyph-
enyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide [0121] 23
1-fluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyph-
enyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide [0122] 24
2,2-difluoro-N-[(2S,3R)-2-(2-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-
-yl]-5-oxo-pyrrolidin-3-yl]propanamide [0123] 25
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(3-fluorophenyl)indazol-5-yl]-5-oxo-2-ph-
enyl-pyrrolidin-3-yl]propanamide [0124] 26
2,2-difluoro-N-[rac-(2R,3S)-2-(3,5-difluorophenyl)-1-[1-(4-fluorophenyl)i-
ndazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide [0125] 27
2,2-difluoro-N-[rac-(2R,3S)-5-oxo-2-phenyl-1-(1-phenylindazol-5-yl)pyrrol-
idin-3-yl]propanamide [0126] 28
N-[(2R,3S)-2-(2-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-py-
rrolidin-3-yl]cyclopropanecarboxamide [0127] 29
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-cyanophenyl)indazol-5-yl]-5-oxo-2-phe-
nyl-pyrrolidin-3-yl]propanamide [0128] 30
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(3-cyanophenyl)indazol-5-yl]-5-oxo-2-phe-
nyl-pyrrolidin-3-yl]propanamide [0129] 31
2,2-difluoro-N-[rac-(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indaz-
ol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide [0130] 32
N-[rac-(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-ox-
o-pyrrolidin-3-yl]cyclobutanecarboxamide [0131] 33
2,2-difluoro-N-[(2R,3S)-2-(2-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-
-yl]-5-oxo-pyrrolidin-3-yl]propanamide [0132] 34
N-[(2R,3S)-2-(4-fluoro-3-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-y-
l]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide [0133] 36
2,2-difluoro-N-[rac-(2S,3S)-2-cyclopropyl-1-[1-(4-fluorophenyl)indazol-5--
yl]-5-oxo-pyrrolidin-3-yl]propanamide [0134] 37
1-cyclopropyl-N-[rac-(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)inda-
zol-5-yl]-5-oxo-pyrrolidin-3-yl]methanesulfonamide [0135] 38
2,2-difluoro-N-[(2S,3R)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(o-tolyl)-5--
oxo-pyrrolidin-3-yl]propanamide [0136] 39
N-[(2S,3R)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-
-yl]cyclopropanecarboxamide [0137] 42
2,2-difluoro-N-[(2S,3R)-2-(2-fluoro-5-methoxy-phenyl)-1-[1-(4-fluoropheny-
l)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide [0138] 43
N-[(2S,3R)-2-(2-fluoro-5-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-y-
l]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide [0139] 45 1:1
mixture of (1
S,2S)-2-fluoro-N-[(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)inda-
zol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide and (1
S,2S)-2-fluoro-N-[(2S,3R)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-
-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide [0140] 46
rac-(1S,2R)-2-fluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2--
(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide
[0141] 48
2,2-difluoro-N-[rac-(2S,3R)-2-cyclopropyl-1-[1-(4-fluorophenyl)indazol-5--
yl]-5-oxo-pyrrolidin-3-yl]propanamide [0142] 49
N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(2-methoxy-4-pyridyl)-5-o-
xo-pyrrolidin-3-yl]cyclopropanecarboxamide [0143] 51
N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-ox-
o-pyrrolidin-3-yl]cyclopropanesulfonamide [0144] 52
2-methyl-N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-
-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide [0145] 53
N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(o-tolyl)-5-oxo-pyrrolidi-
n-3-yl]cyclopropanecarboxamide [0146] 54
N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-ox-
o-pyrrolidin-3-yl]cyclopropanecarboxamide [0147] 55
N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-o-
xo-pyrrolidin-3-yl]cyclopropanecarboxamide [0148] 56 1:1 mixture of
(1R,2R)-2-fluoro-N-[(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indaz-
ol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide and
(1R,2R)-2-fluoro-N-[(2S,3R)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indaz-
ol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide [0149] 61
N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-ox-
o-pyrrolidin-3-yl]cyclopropanecarboxamide [0150] 62
N-[(2R,3S)-2-(2-fluoro-5-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-y-
l]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide [0151] 63 1:1
mixture of
(1R,2R)-2-fluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-metho-
xyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide and
(1R,2R)-2-fluoro-N-[(2S,3R)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-metho-
xyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide [0152] 65
N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-
-yl]cyclopropanecarboxamide [0153] 66
N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-ox-
o-pyrrolidin-3-yl]acetamide [0154] 67
N-[rac-(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-ox-
o-pyrrolidin-3-yl]cyclopropanecarboxamide [0155] 68
2,2-difluoro-N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indaz-
ol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide [0156] 69
2,2-difluoro-N-[(2R,3S)-2-(2-fluoro-5-methoxy-phenyl)-1-[1-(4-fluoropheny-
l)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide [0157] 70
1-fluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-
-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide [0158] 71
N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-ox-
o-pyrrolidin-3-yl]-1-(trifluoromethyl)cyclopropanecarboxamide
[0159] 72
2,2-difluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(o-tolyl)-5--
oxo-pyrrolidin-3-yl]propanamide [0160] 73
1-fluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyr-
rolidin-3-yl]cyclopropanecarboxamide [0161] 74
N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-
-yl]-1-methyl-cyclopropanecarboxamide [0162] 75
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4,4-difluorocyclohexyl)indazol-5-yl]-5--
oxo-2-phenyl-pyrrolidin-3-yl]propanamide [0163] 76
2,2-difluoro-N-[rac-(2R,3S)-1-(1-cyclohexylindazol-5-yl)-5-oxo-2-phenyl-p-
yrrolidin-3-yl]propanamide [0164] 77
2,2-difluoro-N-[rac-(2R,3S)-2-(2-fluoro-5-methoxy-phenyl)-1-(1-methylinda-
zol-5-yl)-5-oxo-pyrrolidin-3-yl]propanamide [0165] 78
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(2,2-difluoroethyl)indazol-5-yl]-2-(2-fl-
uoro-5-methoxy-phenyl)-5-oxo-pyrrolidin-3-yl]propanamide [0166] 79
2,2-difluoro-N-[rac-(2R,3S)-1-[1-[(2-fluorophenyl)methyl]indazol-5-yl]-5--
oxo-2-phenyl-pyrrolidin-3-yl]propanamide [0167] 80
2,2-difluoro-N-[rac-(2R,3S)-1-[1-[(3-fluorophenyl)methyl]indazol-5-yl]-5--
oxo-2-phenyl-pyrrolidin-3-yl]propanamide [0168] 81
2,2-difluoro-N-[rac-(2R,3S)-1-[1-[(4-fluorophenyl)methyl]indazol-5-yl]-5--
oxo-2-phenyl-pyrrolidin-3-yl]propanamide [0169] 82
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(cyclopropylmethyl)indazol-5-yl]-5-oxo-2-
-phenyl-pyrrolidin-3-yl]propanamide [0170] 84
2,2-difluoro-N-[rac-(2R,3S)-1-[1-[(4,4-difluorocyclohexyl)methyl]indazol--
5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide [0171] 85
2,2-difluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-[(2-fluorophenyl)meth-
yl]indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide [0172] 86
2,2-difluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-[(4-fluorophenyl)meth-
yl]indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide [0173] 87
2,2-difluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-[(3-fluorophenyl)meth-
yl]indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide [0174] 88
N-[(2R,3S)-2-benzyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidi-
n-3-yl]-2,2-difluoropropanamide [0175] 89
2,2-difluoro-N-[rac-(2R,3S)-2-ethyl-1-[1-(4-fluorophenyl)indazol-5-yl]-5--
oxopyrrolidin-3-yl]propanamide [0176] 90
2,2-difluoro-N-[rac-(2R,3R)-2-(cyclopropylmethyl)-1-[1-(4-fluorophenyl)in-
dazol-5-yl]-5-oxopyrrolidin-3-yl]propanamide [0177] 91
2-cyclopropyl-N-[(2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-p-
henylpyrrolidin-3-yl]acetamide [0178] 92
N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidi-
n-3-yl]-1-methyl-1H-pyrazole-3-carboxamide [0179] 93
N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidi-
n-3-yl]-1H-imidazole-2-carboxamide [0180] 94
N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidi-
n-3-yl]-2-methyloxazole-5-carboxamide [0181] 95
N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidi-
n-3-yl]-5-methylthiazole-4-carboxamide [0182] 96
N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidi-
n-3-yl]pyrimidine-2-carboxamide [0183] 97
N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidi-
n-3-yl]nicotinamide [0184] 98
N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidi-
n-3-yl]oxetane-3-carboxamide [0185] 99
N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidi-
n-3-yl]thiazole-5-sulfonamide [0186] 100
N-[rac-(2R,3R)-2-(5-chlorothiophen-2-yl)-1-[1-(4-fluorophenyl)indazol-5-y-
l]-5-oxopyrrolidin-3-yl]cyclopropanesulfonamide [0187] 101
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)pyrazolo[3,4-b]pyridin-5-
-yl]-5-oxo-2-phenylpyrrolidin-3-yl]propanamide [0188] 102
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)pyrazolo[3,4-c]pyridin-5-
-yl]-5-oxo-2-phenylpyrrolidin-3-yl]propanamide [0189] 103
2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-5-
-yl]-5-oxo-2-phenylpyrrolidin-3-yl]propanamide in each case in the
form of the free compound or a physiologically acceptable salt
thereof.
[0190] 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.
##STR00005##
[0191] 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).
[0192] 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).
[0193] 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).
##STR00006##
[0194] Compounds (A) and (E) can be synthesized according to
procedures which are described in the literature.
[0195] Route 1:
[0196] Compounds of formula (A) and (E) can be synthesized starting
from compounds of formula (H) (J. Org. Chem., 2010, 76, 948).
[0197] Route 2:
[0198] Synthesis of compounds of formula (M) and (L) is described
in the literature (J. Org. Chem., 2007, 72, 5016; Org. Lett., 2007,
9, 4077; J. Org. Chem., 2012, 77, 160). 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, 385).
[0199] Route 3:
[0200] Synthesis of compounds of formula (J) is described in the
literature (Org. Lett., 2009, 11, 4512; ACS Sustainable Chem. Eng.,
2015, 3, 1873). Reduction of highly functionalized lactams (J)
gives an alternate route for synthesis of compounds of formula (A)
and (E). Reduction of nitro groups is well known in the art
(March's Advanced Organic Chemistry, 2007, 6th Edition, page
1815f).
[0201] Route 4:
[0202] Synthesis of compounds of formula (K) is described in the
literature (J. Heterocyclic Chem., 2014, 51, E25). Reduction of
highly functionalized lactams (K) gives an alternate route for
synthesis of compounds of formula (A) and (E). Reduction of
enamides/imines is well known in the art (March's Advanced Organic
Chemistry, 2007, 6th Edition, page 1053f and page 1811f).
##STR00007##
[0203] 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 (0) is synthesized via deprotection of compound
(N) under acidic conditions.
[0204] The compounds according to the invention can be produced in
the manner described here or in an analogous manner.
[0205] 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.
[0206] 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:
[0207] Glucocorticoid Receptor Cell-Based Assays
[0208] 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 calculated.
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.
[0209] 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.
[0210] 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.
[0211] 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.
[0212] Preferably, the compounds according to the invention are
useful as selective modulators of the glucocorticoid receptor.
[0213] 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.
[0214] The invention therefore further relates to a compound
according to the invention for use in the modulation of
glucocorticoid receptor activity.
[0215] 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.
[0216] A further aspect of the invention relates to the use of a
compound according to the invention as medicament.
[0217] 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).
[0218] 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.
[0219] 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.
[0220] 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, asthma,
rheumatoid arthritis, inflammatory bowel disease, chronic
obstructive pulmonary disease, acute respiratory distress syndrome,
cystic fibrosis, osteoarthritis, polymyalgia rheumatica, giant cell
arteritis, Sjogren syndrome, Duchenne muscular dystrophy,
vasculitis, Behcet's disease, ulcerative colitis and Crohn's
disease.
[0221] Further diseases and disorders that are believed to be
modulated by the glucocorticoid receptor include endocrine
disorders, preferably selected from primary or secondary
adrenocortical insufficiency, congenital adrenal hyperplasia,
hypercalcemia associated with cancer, and nonsuppurative
thyroiditis; rheumatic disorders; preferably selected from
psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid
arthritis, ankylosing spondilitis, acute and subacute bursistis,
acute nonspecific tenosynovitis, acute gouty arthritis,
post-traumatic osteoarthritis, synovitis of osteoarthritis and
epicondylitis; collagen diseases, preferably selected from systemic
lupus erythematosus, systemic dermatomyositis (polymyositis) and
acute rheumatic carditis; dermatologic diseases, preferably
selected from pemphigus, bullous dermatitis herpetiformis, severe
erythema multiforme (Stevens-Johnson syndrome), exfoliative
dermatitis, mycosis fungoides, psoriasis and seborrheic dermatitis;
allergic states, preferably selected from seasonal or perennial
allergic rhinitis, bronchial asthma, contact dermatitis, atopic
dermatitis, serum sickness and drug hypersensitivity reactions;
ophthalmis diseases, preferably selected from allergic corneal
marginal ulcers, herpes zoster ophthalmicus, anterior segment
inflammation, diffuse posterior uveitis and choroiditis,
sympathetic ophthalmia, allergic conjunctivitis, keratitis,
chorioretinitis, optic neuritis, iritis and iridocyclitis;
respiratory diseases, preferably selected from symptomatic
sarcoidosis, Loeffler's syndrome, berylliosis, fulminating or
disseminated pulmonary tubercolosis when used concurrently with
antituberculous chemotherapy, aspiration pneumonitis; hematologic
disorders, preferably selected from idiopathic thrombocytopenic
purpura, secondary thrombocytopenia, aquired (autoimmune) hemolytic
anemia, erythroblastopenia (RBC anemia), congenital (erythroid)
hypoplastic anemia; neoplastic diseases, preferably selected from
leukemias and lyphomas, acute leukemia of childhood;
gastrointestinal diseases, preferably selected from ulcerative
colitis and regional enteritis.
[0222] 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.
[0223] Another aspect of the invention relates to a compound
according to the invention for use in the treatment and/or
prophylaxis of asthma, rheumatoid arthritis, inflammatory bowel
disease, chronic obstructive pulmonary disease, acute respiratory
distress syndrome, cystic fibrosis, osteoarthritis, polymyalgia
rheumatica, giant cell arteritis, Sjogren syndrome, Duchenne
muscular dystrophy, vasculitis, Behcet's disease, ulcerative
colitis and/or Crohn's disease.
[0224] Still another aspect of the invention relates to a compound
according to the invention for use in the treatment and/or
prophylaxis of endocrine disorders, preferably selected from
primary or secondary adrenocortical insufficiency, congenital
adrenal hyperplasia, hypercalcemia associated with cancer, and
nonsuppurative thyroiditis; rheumatic disorders; preferably
selected from psoriatic arthritis, rheumatoid arthritis, juvenile
rheumatoid arthritis, ankylosing spondilitis, acute and subacute
bursistis, acute nonspecific tenosynovitis, acute gouty arthritis,
post-traumatic osteoarthritis, synovitis of osteoarthritis and
epicondylitis; collagen diseases, preferably selected from systemic
lupus erythematosus, systemic dermatomyositis (polymyositis) and
acute rheumatic carditis; dermatologic diseases, preferably
selected from pemphigus, bullous dermatitis herpetiformis, severe
erythema multiforme (Stevens-Johnson syndrome), exfoliative
dermatitis, mycosis fungoides, psoriasis and seborrheic dermatitis;
allergic states, preferably selected from seasonal or perennial
allergic rhinitis, bronchial asthma, contact dermatitis, atopic
dermatitis, serum sickness and drug hypersensitivity reactions;
ophthalmis diseases, preferably selected from allergic corneal
marginal ulcers, herpes zoster ophthalmicus, anterior segment
inflammation, diffuse posterior uveitis and choroiditis,
sympathetic ophthalmia, allergic conjunctivitis, keratitis,
chorioretinitis, optic neuritis, iritis and iridocyclitis;
respiratory diseases, preferably selected from symptomatic
sarcoidosis, Loeffler's syndrome, berylliosis, fulminating or
disseminated pulmonary tubercolosis when used concurrently with
antituberculous chemotherapy, aspiration pneumonitis; hematologic
disorders, preferably selected from idiopathic thrombocytopenic
purpura, secondary thrombocytopenia, aquired (autoimmune) hemolytic
anemia, erythroblastopenia (RBC anemia), congenital (erythroid)
hypoplastic anemia; neoplastic diseases, preferably selected from
leukemias and lyphomas, acute leukemia of childhood;
gastrointestinal diseases, preferably selected from ulcerative
colitis and regional enteritis.
[0225] A further aspect of the invention relates to a method of
treatment of pain and/or inflammation; more preferably inflammatory
pain. Still a further aspect of the invention relates to a method
of treatment of asthma, rheumatoid arthritis, inflammatory bowel
disease, chronic obstructive pulmonary disease, acute respiratory
distress syndrome, cystic fibrosis, osteoarthritis, polymyalgia
rheumatica, giant cell arteritis, Sjogren syndrome, Duchenne
muscular dystrophy, vasculitis, Behcet's disease, ulcerative
colitis and/or Crohn's disease.
[0226] The following examples further illustrate the invention but
are not to be construed as limiting its scope.
[0227] The following abbreviations are used in the descriptions of
the experiments: AcOH=acetic acid; Attaphos=bis(di-tert-butyl(4
dimethylaminophenyl)phosphine)dichloropalladium(II);
Cbz=carboxybenzyl; DCM=dichloromethane; DEA=diethylamine;
DIPEA=N,N-diisopropylethylamine; DMAP=4-(dimethylamino)-pyridine;
DMF=N,N-dimethylformamid; DMSO=dimethylsulfoxid; DPPA=diphenyl
phosphoryl azide; dppf=1,1'; bis(diphenylphosphanyl)ferrocene;
EA=ethyl acetate; EtOAc=ethyl acetate; EtOH=ethanol;
HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate; h=hour; LDA=lithiumdiisopropylamide;
LiHMDS=lithium bis(trimethylsilyl)amide; MeOH=methanol; min=minute;
n-BuLi=n-butyllithium; sat.=saturated; RT=room temperature;
Rt=retention time; tert=tertiary, TEA=triethylamine; TFA=trifluoro
acetic acid; THF=tetrahydrofuran; p-TSA=para-toluene sulfonic acid;
TMSCl=trimethylsilyl chloride.
Synthesis of trans-4-amino-5-(3-chlorophenyl)pyrrolidin-2-one
(Intermediate A1)
##STR00008## ##STR00009##
[0229] Step 1:
[0230] 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), 3-chlorobenzaldehyde (11.5 mL, 100 mmol, 1.0 eq) and toluene
(100 mL) were put in a sealed tube. 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
2-(3-chlorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylic
acid (10.0 g).
[0231] Step 2:
[0232] To a stirred solution of crude
2-(3-chlorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylic
acid (10.0 g, 27.7 mmol, 1.0 eq) in acetone (100 mL), potassium
carbonate (15.3 g, 110.8 mmol, 4.0 eq) and methyl iodide (7.0 mL,
110.8 mmol, 4.0 eq) were added at 0.degree. C. and the reaction
mixture 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
2-(3-chlorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate
as an off white solid (4.0 g, 38%).
[0233] Step 3:
[0234] To a stirred solution of methyl
2-(3-chlorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate
(10.0 g, 26.66 mmol, 1.0 eq) in EtOH:THF (100 mL, 2:1), Raney
Nickel (2.5 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 then washed 2-3 times with
EtOAc. The combined organic layers were concentrated and the crude
product was purified by column chromatography (100-200 silica gel,
50% EtOAc:hexanes) to give methyl
2-(3-chlorophenyl)-5-oxopyrrolidine-3-carboxylate as an off white
solid (6.0 g, 89%) (syn:anti, 1:1 mixture).
[0235] Step 4:
[0236] To a stirred solution of methyl
2-(3-chlorophenyl)-5-oxopyrrolidine-3-carboxylate (3.0 g, 11.85
mmol, 1.0 eq) in MeOH (50 mL) was added 2 N NaOH solution (10 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 the
crude product was then extracted with 30% isopropanol-DCM. The
combined organic layers were dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to get
trans-2-(3-chlorophenyl)-5-oxopyrrolidine-3-carboxylic acid (2.5 g,
88%).
[0237] Step 5:
[0238] To a stirred solution of
trans-2-(3-chlorophenyl)-5-oxopyrrolidine-3-carboxylic acid (2.0 g,
8.36 mmol, 1.0 eq) in benzene:THF (100 mL, 4:1) were added TEA
(2.35 mL, 16.73 mmol, 2.0 eq) and DPPA (2.35 ml, 10.8 mmol, 1.3 eq)
and the reaction mixture was stirred at RT for 2 h. Then
2,4-dimethoxy benzyl alcohol (1.8 g, 10.87 mmol, 1.3 eq) was added
to the reaction mixture 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 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-2,4-dimethoxybenzyl
(2-(3-chlorophenyl)-5-oxopyrrolidin-3-yl)carbamate (1.5 g,
44%).
[0239] Step 6:
[0240] To a stirred solution of trans-2,4-dimethoxybenzyl
(2-(3-chlorophenyl)-5-oxopyrrolidin-3-yl)carbamate (0.5 g, 1.23
mmol, 1.0 eq) in DCM (10 mL) was added TFA (2 mL) at 0.degree. C.,
and the reaction was stirred for 3 h at RT After completion, the
reaction mixture was diluted with EtOAc and washed with
sat.NaHCO.sub.3 solution. The combined organic layers were dried
over Na.sub.2SO.sub.4 and concentrated to get the desired
trans-4-amino-5-(3-chlorophenyl)pyrrolidin-2-one as a white solid
(0.25 g, 96%).
Synthesis of trans-4-amino-5-phenylpyrrolidin-2-one (Intermediate
A2)
##STR00010## ##STR00011##
[0242] Step 1:
[0243] 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).
[0244] Step 2:
[0245] 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.
[0246] Step 3:
[0247] 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.
[0248] Step 4:
[0249] 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 N NaOH 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%).
[0250] Step 5:
[0251] 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%).
[0252] Step 6:
[0253] 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%).
Synthesis of (4S,5R)-4-amino-5-phenylpyrrolidin-2-one (Intermediate
A2-ent2)
##STR00012##
[0255] To a stirred solution of
trans-4-amino-5-phenyl-pyrrolidin-2-one (intermediate A2) (10.0 g,
0.056 mol) in EtOH (180 mL) and acetonitrile (200 mL) was added
L-tartaric acid (8.5 g, 0.056 mol) at RT. The resulting suspension
was stirred at 90.degree. C. for 1 h. To this refluxing suspension
was slowly added water (110 mL). The resulting reaction mixture was
maintained at 90.degree. C. and was stirred for 4 h. The resulting
clear solution was slowly cooled to RT and was allowed to stand at
RT for 24 h. The solid thus precipitated was collected by
filtration and washed with EtOH (100 mL) to afford 7.5 g of chiral
(ent-2) as the corresponding L-tartrate salt. This solid material
was treated with 1N aq. NaOH solution at RT. The resulting basic
aqueous solution was then extracted with 10% MeOH in DCM (100 mL x
5-6 times) to afford (4S,5R)-4-amino-5-phenyl-pyrrolidin-2-one (3
g, 60%) as a white solid (intermediate A2-ent2).
[0256] Enantiomeric excess (ee) determined by chiral HPLC (Column
Name: Chiralpak IA (4.6.times.250 mm), 5 .mu.m; Mobile Phase:
Hexane/EtOH/IP amine: 80/20/0.1; Flow Rate: 1.0 ml/min; RT=25.0
min): ee=99.7%
[0257] Specific Rotation: [+29.9.degree. ] at 25.degree. C., C=1%
in EtOH.
Synthesis of (4R,5S)-4-amino-5-phenylpyrrolidin-2-one (Intermediate
A2-ent1)
##STR00013##
[0259] To a stirred solution of
trans-4-amino-5-phenyl-pyrrolidin-2-one (intermediate A2) (7.0 g,
39.77 mmol) in EtOH (126 mL) and acetonitrile (140 mL) was added
D-tartaric acid (5.96 g, 39.77 mmol) at RT. The resulting
suspension was stirred at 90.degree. C. for 1 h. To this refluxing
suspension was slowly added water (77 mL). The resulting reaction
mixture was maintained at 90.degree. C. for 4 h. The resulting
clear solution was slowly cooled to RT and was allowed to stand at
RT for 24 h. The solid thus precipitated was collected by
filtration and washed with EtOH (70 mL) to afford 5.2 g of chiral
(ent-1) as the corresponding D-tartrate salt as an off-white solid.
(4R,5S)-4-amino-5-phenylpyrrolidin-2-one
(2R,3R)-2,3-dihydroxysuccinate (5.2 g) was treated with 1N NaOH
solution at RT. The resulting basic aqueous solution was then
extracted with 10% MeOH in DCM (4.times.50 mL) to afford
(4R,5S)-4-amino-5-phenylpyrrolidin-2-one (2.4 g, 34%) as a white
solid.
[0260] Enantiomeric excess (ee) determined by chiral HPLC (Column
Name: Chiralpak IA (4.6.times.250 mm), 5 .mu.m; Mobile Phase:
Hexane/EtOH/IP amine: 80/20/0.1; Flow Rate: 1.0 ml/min; RT=17.65
min): ee=99.1%
[0261] Specific Rotation: [-34.5.degree. ] at 25.degree. C., C=1.0%
in EtOH.
Synthesis of trans-4-amino-5-(2,4-difluorophenyl)pyrrolidin-2-one
(Intermediate A3)
##STR00014##
[0263] Step 1:
[0264] Maleic anhydride (28.9 g, 295.7 mmol, 1.0 eq), p-thiocresol
(36.6 g, 295.7 mmol, 1.0 eq), ammonium acetate (22.7 g, 295.7 mmol,
1.0 eq), and 2,4-difluorobenzaldehyde (42.0 g, 295.7 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 was 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 was
then 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
3-((2,4-difluorophenyl)thio)-5-oxo-2-phenylpyrrolidine-3-carboxylic
acid (120.0 g).
[0265] Step 2:
[0266] To a stirred solution of crude
3-((2,4-difluorophenyl)thio)-5-oxo-2-phenylpyrrolidine-3-carboxylic
acid (107.0 g, crude) in acetone (600 mL), potassium carbonate
(162.7 g, 1170 mmol, 4.0 eq) and methyl iodide (73.3 mL, 1170 mmol,
4.0 eq) were added at 0.degree. C., and the reaction mixture 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) which gave
methyl
3-((2,4-difluorophenyl)thio)-5-oxo-2-phenylpyrrolidine-3-carboxylate
as an off white solid (6.0 g, 5%).
[0267] Step 3:
[0268] To a stirred solution of methyl
3-((2,4-difluorophenyl)thio)-5-oxo-2-phenylpyrrolidine-3-carboxylate
(6.0 g, 15.9 mmol, 1.0 eq) in EtOH:THF (225 mL, 2:1), Raney Nickel
(60.0 g) was added and the reaction 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 product was
purified by column chromatography (100-200 silica gel, 50%
EtOAc:hexanes) which gave methyl
2-(2,4-difluorophenyl)-5-oxopyrrolidine-3-carboxylate (2.8 g, 69%,
syn:anti 1:1) as an off white solid.
[0269] Step 4:
[0270] To a stirred solution of methyl
2-(2,4-difluorophenyl)-5-oxopyrrolidine-3-carboxylate (2.0 g, 7.84
mmol, 1.0 eq) in MeOH (47 mL) was added 2 N NaOH solution (12 mL)
and the reaction mixture was stirred at 70.degree. C. for 3 h.
After completion of the reaction (monitored by LCMS), the reaction
mixture was concentrated and acidified with 2N HCl solution and was
then 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-2-(2,4-difluorophenyl)-5-oxopyrrolidine-3-carboxylic acid
(1.8 g, 95%).
[0271] Step 5:
[0272] To a stirred solution of
trans-2-(2,4-difluorophenyl)-5-oxopyrrolidine-3-carboxylic acid
(1.8 g, 7.46 mmol, 1.0 eq) in benzene:THF (60 mL, 4:1) was added
TEA (2.07 mL, 14.93 mmol, 2.0 eq) and DPPA (2.1 mL, 9.7 mmol, 1.3
eq) and the reaction mixture was stirred at ambient temperature for
2 h. Then benzyl alcohol (1.0 ml, 9.7 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 which was extracted with water and EtOAc.
The combined organic layers were dried over Na.sub.2SO.sub.4 and
were concentrated under reduced pressure to get the crude product
which was purified by flash column chromatography (100-200 mesh
silica gel; 2% MeOH-DCM; R.sub.f-value-0.5) to afford trans-benzyl
(2-(2,4-difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (1.2 g, 46%)
as an off-white solid.
[0273] Step 6:
[0274] To a stirred solution of trans-benzyl
(2-(2,4-difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (1.2 g, 3.46
mmol, 1.0 eq) in MeOH (15 mL), Pd/C (0.12 g, 10% w/w) 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-(2,4-difluorophenyl)pyrrolidin-2-one (0.85 g) as an
off-white solid.
Synthesis of
trans-4-amino-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrrolidin-2-one
(Intermediate A4)
##STR00015## ##STR00016##
[0276] Step 1:
[0277] Maleic anhydride (5.97 g, 60.9 mmol, 1.0 eq), p-thiocresol
(7.55 g, 60.9 mmol, 1.0 eq), ammonium acetate (4.68 g, 60.9 mmol,
1.0 eq), and 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (10.0 g,
60.9 mmol, 1.0 eq) were put in a sealed tube, followed by the
addition of 80 mL of toluene. The reaction mixture was stirred at
RT for 1 h and was then heated to 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 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
2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxo-3-(p-tolylthio)pyrrolidine--
3-carboxylic acid (2.20 g).
[0278] Step 2:
[0279] To a stirred solution of crude
2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxo-3-(p-tolylthio)pyrrolidine--
3-carboxylic acid (2.2 g, 5.707 mmol, 1.0 eq) in acetone (100 mL),
potassium carbonate (3.2 g, 22.831 mmol, 4.0 eq) and methyl iodide
(1.42 mL, 22.831 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) which gave
methyl
2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxo-3-(p-tolylthio)pyrrolidine--
3-carboxylate as an off white solid (0.9 g, 41%).
[0280] Step 3:
[0281] To a stirred solution of methyl
2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxo-3-(p-tolylthio)pyrrolidine--
3-carboxylate (0.9 g, 2.253 mmol, 1.0 eq) in EtOH:THF (60 mL, 2:1),
Raney Nickel (1.0 g) was added, and the reaction 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
remains were purified by column chromatography (100-200 silica gel,
50% EtOAc:hexanes) which gave methyl
2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidine-3-carboxylate
(0.6 g, 96%, syn:anti, 1:1) as an off white solid.
[0282] Step 4:
[0283] To a stirred solution of methyl
2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidine-3-carboxylate
(0.7 g, 2.524 mmol, 1.0 eq) in MeOH (15 mL) was added a 2 N NaOH
solution (3.7 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 then extracted with 30% isopropanol-DCM.
The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and
concentrated under reduced pressure to get the desired
trans-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidine-3-carboxyl-
ic acid (0.5 g, 75%).
[0284] Step 5:
[0285] To a stirred solution of
trans-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidine-3-carboxyl-
ic acid (0.3 g, 1.139 mmol, 1.0 eq) in benzene:THF (15 mL, 4:1)
were added TEA (0.31 mL, 4.87 mmol, 2.0 eq) and DPPA (0.32 mL, 1.48
mmol, 1.3 eq) and the reaction mixture was stirred at RT for 2 h.
Then benzyl alcohol (3 mL) was added and the reaction mixture was
heated to reflux for 16 h. After completion, the reaction mixture
was concentrated under reduced pressure to give the crude which was
extracted with water and EtOAc. The organic layer was dried over
anhydrous 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
(-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidin-3-yl)carbamate
(0.2 g, 47%).
[0286] Step 6:
[0287] To a stirred solution of trans-benzyl
(-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidin-3-yl)carbamate
(0.32 g, 0.869 mmol, 1.0 eq) in MeOH:THF (20 mL, 2:1), Pd/C (50.0
mg) 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 layer was concentrated to get the
desired
trans-4-amino-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrrolidin-2-one
(0.2 g, 98%) as brown gum.
Synthesis of trans-4-amino-5-(3-fluorophenyl)pyrrolidin-2-one
(Intermediate A5)
##STR00017## ##STR00018##
[0289] Step 1:
[0290] Maleic anhydride (19.7 g, 201.61 mmol, 1.0 eq), p-thiocresol
(25.0 g, 201.61 mmol, 1.0 eq), 2,4-dimethoxy benzylamine (33.6 g,
201.61 mmol, 1.0 eq), and 3-fluorobenzaldehyde (25.0 g, 201.61
mmol, 1.0 eq) were put in a round-bottom flask followed by the
addition of 250 mL toluene. The reaction mixture was refluxed for
16 h with vigorous stirring. After completion of the reaction
(monitored by TLC), the reaction mixture was cooled to RT and the
solvent was evaporated under reduced pressure to afford crude
1-(2,4-dimethoxybenzyl)-2-(3-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidi-
ne-3-carboxylic acid (89.0 g, 89%) as a gummy liquid which was used
in the next step without further purification.
[0291] Step 2:
[0292] To a stirred solution of
1-(2,4-dimethoxybenzyl)-2-(3-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidi-
ne-3-carboxylic acid (99.7 g, 201.4 mmol, 1.0 eq) in acetone (1 L),
potassium carbonate (111.3 g, 805.6 mmol, 4.0 eq) and methyl iodide
(51.0 mL, 805.6 mmol, 4.0 eq) were added at 0.degree. C. and the
reaction was stirred for 16 h at RT. After completion of the
reaction (monitored by TLC), the solvent was removed under reduced
pressure and the residue was partitioned between EtOAc and water.
The aqueous layer was extracted twice with EtOAc. 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, 40% EtOAc in hexane) to
afford methyl
1-(2,4-dimethoxybenzyl)-2-(3-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidi-
ne-3-carboxylate (79.0 g, 77%) as an off white solid.
[0293] Step 3:
[0294] To a stirred solution of methyl
1-(2,4-dimethoxybenzyl)-2-(3-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidi-
ne-3-carboxylate (78.0 g, 153.2 mmol, 1.0 eq) in acetonitrile (500
mL), was added CAN (251.9 g, 459.6 mmol, 3.0 eq) dissolved in water
dropwise at 0.degree. C. through an addition funnel. The reaction
mixture was then stirred at RT for 16 h. After completion of the
reaction (monitored by TLC), the reaction mixture was diluted with
water and extracted twice with EtOAc. 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 (230-400 silica gel, 40-50% EtOAc: hexane) to afford
methyl
2-(3-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate
(47.0 g, 85%) as an off white solid.
[0295] Step 4:
[0296] To a stirred solution of methyl
2-(3-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate
(30.0 g, 83.5 mmol, 1.0 eq) in EtOH:THF (500 mL:500 mL, 1:1), Raney
Nickel (20.0 g) was added and the reaction was stirred under a
hydrogen atmosphere for 16 h at RT. After completion (monitored by
TLC) the reaction mixture was filtered through a celite bed and the
celite bed was and washed 4-5 times with THF. The filtrate was
concentrated to afford methyl
2-(3-fluorophenyl)-5-oxopyrrolidine-3-carboxylate (15.2 g, 77%,
syn:anti mixture) as a white solid.
[0297] Step 5:
[0298] To a stirred solution of methyl
2-(3-fluorophenyl)-5-oxopyrrolidine-3-carboxylate (16.0 g, 67.4
mmol, 1.0 eq) in MeOH (320 mL) was added 2 N NaOH solution (75 mL)
and the reaction mixture was stirred at 80.degree. C. for 16 h.
After completion of the reaction (monitored by TLC) the reaction
mixture was concentrated and acidified with 2N HCl solution to get
a solid which was filtered off and was washed with diethyl ether,
and was then dried under vacuum to afford
trans-2-(3-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid (9.3 g,
62%).
[0299] Step 6:
[0300] To a stirred solution of
trans-2-(3-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid (13.0
g, 58.3 mmol, 1.0 eq) in toluene (130 mL) was added TEA (8.5 mL,
61.2 mmol, 1.05 eq) and DPPA (19.3 g, 70.0 mmol, 1.2 eq) and the
reaction mixture was stirred at 90.degree. C. for 30 min. Then
benzyl alcohol (12.6 g, 116.6 mmol, 2.0 eq) was added and the
reaction mixture was heated to reflux for 16 h. After completion
(monitored by TLC), the reaction mixture was concentrated under
reduced pressure. The residue was then diluted with EtOAc (100 mL),
washed with water (2.times.100 mL), dried over anhydrous
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; 0-2% MeOH in DCM) to afford trans-benzyl
(2-(3-fluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (7.0 g,
37%).
[0301] Step 7:
[0302] To a stirred solution of trans-benzyl
(2-(3-fluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (7.0 g, 21.3
mmol, 1.0 eq) in MeOH (50 mL) and THF (20 mL), Pd--C (1.5 g, 14.9
mmol, 0.7 eq) was added and the reaction mixture was stirred with a
hydrogen balloon for 2 h at RT. After completion (monitored by
TLC), the reaction mixture was filtered through a celite bed and
the celite bed was washed 2-3 times with THF. The filtrate was
concentrated to get the desired
trans-4-amino-5-(3-fluorophenyl)pyrrolidin-2-one (3.8 g, 92%) as a
brown gum.
Synthesis of trans-4-amino-5-(2-fluorophenyl)pyrrolidin-2-one
(Intermediate A6)
##STR00019## ##STR00020##
[0304] Step 1:
[0305] Maleic anhydride (19.7 g, 201.4 mmol, 1.0 eq), p-thiocresol
(25.0 g, 201.4 mmol, 1.0 eq), 2,4 dimethoxy benzylamine (33.6 g,
201.4 mmol, 1.0 eq), and 2-fluorobenzaldehyde (25.0 g, 201.4 mmol,
1.0 eq) were taken up in 300 mL of toluene. The reaction mixture
was refluxed for 16 h with vigorous stirring. After completion of
the reaction (monitored by TLC, TLC system 5% MeOH in DCM,
R.sub.f-0.1), the reaction mixture was cooled to RT and the solvent
was evaporated under reduced pressure to afford the crude
1-(2,4-dimethoxybenzyl)-2-(2-fluorophenyl)-5-oxo-3-(p-tolylthio)pyr-
rolidine-3-carboxylic acid as a gummy liquid (95.0 g, 95%) which
was used in the next step without further purification.
[0306] Step 2:
[0307] To a stirred solution of crude
1-(2,4-dimethoxybenzyl)-2-(2-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidi-
ne-3-carboxylic acid (95.0 g, 191.7 mmol, 1.0 eq) in acetone (1 L),
potassium carbonate (111.3 g, 805.0 mmol, 4.2 eq) and methyl iodide
(50.0 mL, 805.0 mmol, 4.2 eq) were added at 0.degree. C., and the
reaction mixture was stirred at RT for 16 h. After completion of
the reaction (monitored by TLC; TLC system 30% EtOAc in hexane,
R.sub.f-0.3), the solvent was removed under reduced pressure and
the residue was partitioned between EtOAc and water. The aqueous
layer was extracted twice with EtOAc. 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, 40% EtOAc in hexane) to afford
the desired methyl
1-(2,4-dimethoxybenzyl)-2-(2-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidi-
ne-3-carboxylate as an off white solid (55.0 g, 56%).
[0308] Step 3:
[0309] To a stirred solution of methyl
1-(2,4-dimethoxybenzyl)-2-(2-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidi-
ne-3-carboxylate (55.0 g, 108.0 mmol, 1.0 eq) in acetonitrile (300
mL), CAN (178.0 g, 324.0 mmol, 3.0 eq) in water (300 mL) was added
dropwise at 0.degree. C. through an addition funnel. The reaction
mixture was then stirred at RT for 16 h. After completion of the
reaction (monitored by TLC, TLC system 50% EtOAc in hexane,
Rf-0.3), the reaction mixture was diluted with water and extracted
twice with EtOAc. 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 (230-400 silica
gel, 40-50% EtOAc: hexane) which gave methyl
2-(2-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate
as an off white solid (15.0 g, 39%).
[0310] Step 4:
[0311] To a stirred solution of methyl
2-(2-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate
(15.0 g, 41.7 mmol, 1.0 eq) in EtOH:THF (300:300 mL, 1:1), Raney
Nickel (15 g) was added, and the reaction was stirred under a
hydrogen atmosphere for 16 h at RT. After completion, (monitored by
TLC, TLC system 70% EtOAc in hexane, Rf-0.4) the reaction mixture
was filtered through a celite bed and the celite bed was washed 4-5
times with THF. The filtrate was concentrated to afford methyl
2-(2-fluorophenyl)-5-oxopyrrolidine-3-carboxylate as a white solid
(9.0 g, 91%; syn:anti mixture).
[0312] Step 5:
[0313] To a stirred solution of methyl
2-(2-fluorophenyl)-5-oxopyrrolidine-3-carboxylate (9.0 g, 37.9
mmol, 1.0 eq) in MeOH (180 mL) was added 2 N NaOH solution (40 mL)
and the reaction mixture was stirred at 80.degree. C. for 16 h.
After completion of the reaction (monitored by TLC, TLC system 5%
MeOH in DCM, Rf-0.1), the reaction mixture was concentrated and
acidified with 2N HCl solution to get a solid which was filtered
off and was then washed with diethyl ether and dried under vacuum
to afford trans-2-(2-fluorophenyl)-5-oxopyrrolidine-3-carboxylic
acid (7.0 g, 83%).
[0314] Step 6:
[0315] To a stirred solution of
trans-2-(2-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid (7.0 g,
31.4 mmol, 1.00 eq) in Toluene (80 mL) was added TEA (4.6 mL, 33.0
mmol, 1.05 eq) and DPPA (10.4 g, 37.7 mmol, 1.2 eq) and the
reaction mixture was stirred at 90.degree. C. for 30 min. Then
benzyl alcohol (6.8 g, 62.8 mmol, 2.0 eq) was added and the
reaction mixture was heated to reflux for 16 h. After completion
(monitored by TLC, TLC system 5% MeOH in DCM, Rf-0.3), the reaction
mixture was concentrated under reduced pressure and was then
diluted with EtOAc (100 mL), washed with water (2.times.100 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; 0-2% MeOH in DCM) to
afford trans-benzyl
(2-(2-fluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (4.7 g,
46%).
[0316] Step 7:
[0317] To a stirred solution of trans-benzyl
(2-(2-fluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (4.7 g, 14.3
mmol, 1.0 eq) in MeOH:THF (20 mL, 2:1), Pd/C (2.0 g, 10% moist) was
added, and the reaction was stirred with a hydrogen balloon for 2 h
at RT. After completion, (monitored by TLC, TLC system 5% MeOH in
DCM, Rf-0.2), the reaction mixture was filtered through a celite
bed and the celite bed was washed 2-3 times with THF. The filtrate
was concentrated to get the desired
trans-4-amino-5-(2-fluorophenyl)pyrrolidin-2-one as a brown gum
(2.5 g, 90%).
Synthesis of
trans-4-amino-5-(4-fluoro-3-methoxyphenyl)pyrrolidin-2-one
(Intermediate A7)
##STR00021## ##STR00022##
[0319] Step 1:
[0320] Maleic anhydride (14.6 g, 149.7 mmol, 1.0 eq), p-thiocresol
(18.5 g, 149.7 mmol, 1.0 eq), 2,4-di-methoxy benzyl amine (25.0 g,
149.7 mmol, 1.0 eq), and 4-fluoro-3-methoxy benzaldehyde (23.0 g,
149.7 mmol, 1.0 eq) were dissolved in 500 mL toluene in a two neck
round bottom flask fitted with a dean stark trap and a condenser.
The reaction mixture was then heated to 150.degree. C. for 16 h.
After cooling to RT, the solvent was evaporated under reduced
pressure to get the crude
1-(2,4-dimethoxybenzyl)-2-(4-fluoro-3-methoxyphenyl)-5-oxo-3-(p-tolylthio-
)-pyrrolidine-3-carboxylic acid which was taken to the next step
without further purification.
[0321] Step 2:
[0322] To a stirred solution of crude
1-(2,4-dimethoxybenzyl)-2-(4-fluoro-3-methoxyphenyl)-5-oxo-3-(p-tolylthio-
)pyrrolidine-3-carboxylic acid (max. 149.7 mmol, 1.0 eq) in acetone
(500 mL), potassium carbonate (82.0 g, 598.0 mmol, 4.0 eq) and
methyl iodide (37.5 mL, 598.0 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) which gave methyl
1-(2,4-dimethoxybenzyl)-2-(4-fluoro-3-methoxyphenyl)-5-oxo-3-(p-tolylthio-
)pyrrolidine-3-carboxylate (72.0 g, 88%) as an off white solid.
[0323] Step 3:
[0324] To a stirred solution of methyl
1-(2,4-dimethoxybenzyl)-2-(4-fluoro-3-methoxyphenyl)-5-oxo-3-(p-tolylthio-
)pyrrolidine-3-carboxylate (70.0 g, 129.0 mmol, 1.0 eq) in
acetonitrile: water (500 mL 1:1), CAN was 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
EtOAc and water. The aqueous layer was extracted twice with EtOAc.
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) which gave methyl
2-(4-fluoro-3-methoxyphenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxyla-
te (25.0 g, 50%) as an off white solid.
[0325] Step 4:
[0326] To a stirred solution of methyl
2-(4-fluoro-3-methoxyphenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxyla-
te (15.0 g, 64.3 mmol, 1.0 eq) in EtOH:THF (300 mL, 2:1), Raney
Nickel (5.0 g) was added, and the reaction was stirred for 2 h at
RT. After completion, the reaction mixture was filtered through a
celite bed and washed 2-3 times with EtOAc. The combined organic
layers were concentrated and the crude product was purified by
column chromatography (100-200 silica gel, 50% EtOAc:hexanes) which
gave methyl
2-(4-fluoro-3-methoxyphenyl)-5-oxopyrrolidine-3-carboxylate (10.0
g, 98%, syn:anti, 1:1 mixture) as an off white solid.
[0327] Step 5:
[0328] To a stirred solution of methyl
2-(4-fluoro-3-methoxyphenyl)-5-oxopyrrolidine-3-carboxylate (10.0
g, 37.5 mmol, 1.0 eq) in MeOH (250 mL) was added 2 N NaOH solution
(50 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, acidified with 2N HCl solution
and then extracted with 30% isopropanol-DCM. The combined organic
layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated
under reduced pressure to get the desired
trans-2-(4-fluoro-3-methoxyphenyl)-5-oxopyrrolidine-3-carboxylic
acid (8.0 g, 84%).
[0329] Step 6:
[0330] To a stirred solution of
trans-2-(4-fluoro-3-methoxyphenyl)-5-oxopyrrolidine-3-carboxylic
acid (2.0 g, 7.90 mmol, 1.0 eq) in benzene:THF (100 mL, 4:1) was
added TEA (2.2 mL, 15.81 mmol, 2.0 eq) and DPPA (2.2 mL, 10.27
mmol, 1.3 eq) and the reaction mixture was stirred at RT for 2 h.
Then benzyl alcohol (1.0 mL, 10.27 mmol, 1.3 eq) was added to the
reaction mixture and heated to reflux for 16 h. After completion,
reaction mixture was concentrated under reduced pressure to get the
crude which was extracted with water and EtOAc. Organic layer was
dried over anhydrous 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;
Re-value-0.5) to afford trans-benzyl
(2-(4-fluoro-3-methoxyphenyl)-5-oxopyrrolidin-3-yl)carbamate (1.4
g, 50%).
[0331] Step 7:
[0332] To a stirred solution of trans-benzyl
(2-(4-fluoro-3-methoxyphenyl)-5-oxopyrrolidin-3-yl)carbamate (7 g,
19.55 mmol, 1 eq) in MeOH:THF (20 mL, 2:1), Pd--C (0.7 g) was
added, and the reaction was stirred for 2 h at RT. After
completion, the reaction mixture was filtered through celite bed
and washed 2-3 times with EtOAc. The combined organic layer was
concentrated to get
trans-4-amino-5-(4-fluoro-3-methoxyphenyl)pyrrolidin-2-one (4 g,
91%) as brown gum.
Synthesis of trans-4-amino-5-(4-fluorophenyl)pyrrolidin-2-one
(Intermediate A8)
##STR00023## ##STR00024##
[0334] Step 1:
[0335] Maleic anhydride (19.7 g, 201.6 mmol, 1.0 eq), p-thiocresol
(25.0 g, 201.6 mmol, 1.0 eq), 2,4 dimethoxy benzylamine (33.6 g,
201.6 mmol, 1.0 eq), and 4-fluorobenzaldehyde (25.0 g, 201.6 mmol,
1.0 eq) were taken up in 250 mL toluene. The reaction mixture was
refluxed for 16 h with vigorous stirring. After completion of the
reaction (monitored by TLC, TLC system 5% MeOH in DCM,
R.sub.1-0.1), the reaction mixture was cooled to RT and the solvent
was evaporated under reduced pressure to give crude
1-(2,4-dimethoxybenzyl)-2-(4-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidi-
ne-3-carboxylic acid (92.0 g, 92%) as a gummy liquid, which was
used in the next step without further purification.
[0336] Step 2:
[0337] To a stirred solution of crude
1-(2,4-dimethoxybenzyl)-2-(4-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidi-
ne-3-carboxylic acid (92.0 g, 201.4 mmol, 1.0 eq) in acetone (1 L),
potassium carbonate (111.3 g, 805.6 mmol, 4.0 eq) and methyl iodide
(50.0 mL, 805.6 mmol, 4.0 eq) were added at 0.degree. C. and the
reaction was stirred for 16 h at RT. After completion of the
reaction (monitored by TLC), the solvent was removed under reduced
pressure and the residue was partitioned between EtOAc and water.
The aqueous layer was extracted twice with EtOAc. 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, 40% EtOAc in hexane) to afford
methyl
1-(2,4-dimethoxybenzyl)-2-(4-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidi-
ne-3-carboxylate (79.0 g, 84%) as an off white solid.
[0338] Step 3:
[0339] To a stirred solution of methyl
1-(2,4-dimethoxybenzyl)-2-(4-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidi-
ne-3-carboxylate (92.0 g, 180.7 mmol, 1.0 eq) in acetonitrile, CAN
(297.0 g, 542.1 mmol, 3.0 eq) in water was added dropwise to the
reaction mixture at 0.degree. C. through an addition funnel. The
reaction was then stirred at RT for 16 h. After completion of the
reaction (monitored by TLC, TLC system 50% EtOAc in hexane,
Rf-0.3), the reaction mixture was diluted with water and extracted
twice with EtOAc. 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 (230-400 silica
gel, 40-50% EtOAc: hexane) which gave methyl
2-(4-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate
(41.0 g, 63%) as an off white solid.
[0340] Step 4:
[0341] To a stirred solution of methyl
2-(4-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate
(13.0 g, 36.2 mmol, 1.0 eq) in EtOH:THF (260:130 mL, 2:1), Raney
Nickel (13.0 g) was added and the reaction mixture was stirred
under a hydrogen atmosphere for 16 h at RT. After completion of the
reaction (monitored by TLC), the reaction mixture was filtered
through a celite bed and the celite bed was washed 4-5 times with
THF. The filtrate was concentrated to give methyl
2-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylate (6.7 g, 78%,
syn:anti mixture) as a white solid.
[0342] Step 5:
[0343] To a stirred solution of methyl
2-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylate (10.0 g, 42.2
mmol, 1.0 eq) in MeOH (200 mL) was added 2N NaOH solution (48 mL)
and the reaction mixture was stirred at 80.degree. C. for 16 h.
After completion of the reaction (monitored by TLC, TLC system 5%
MeOH in DCM, Rf-0.1), the reaction mixture was concentrated and
acidified with 2N HCl solution to obtain a solid which was filtered
and washed with diethyl ether, followed by drying under vacuum to
afford trans 2-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid
(6.4 g, 68%).
[0344] Step 6:
[0345] To a stirred solution of trans
2-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid (5.0 g, 22.4
mmol, 1.00 eq) in toluene (50 mL) was added TEA (3.3 mL, 23.5 mmol,
1.05 eq) and DPPA (7.4 g, 26.9 mmol, 1.20 eq) and the reaction
mixture was heated to 90.degree. C. for 30 min. Then benzyl alcohol
(4.8 g, 44.8 mmol, 2.00 eq) was added and the reaction mixture was
heated to reflux for 16 h. After completion (monitored by TLC), the
reaction mixture was concentrated under reduced pressure. The
residue was then diluted with EtOAc (100 mL), washed with water
(2.times.100 mL), dried over Na.sub.2SO.sub.4 and finally
concentrated under reduced pressure to get the crude product which
was purified by column chromatography (230-400 mesh silica gel;
0-2% MeOH in DCM) to afford trans-benzyl
(2-(4-fluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (4.1 g,
56%).
[0346] Step 7:
[0347] To a stirred solution of trans-benzyl
(2-(4-fluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (2.0 g, 6.1
mmol, 1.0 eq) in MeOH (50 mL) and THF (20 mL), Pd/C (0.3 g, 3.0
mmol, 0.5 eq) was added and the reaction was stirred with a
hydrogen balloon for 2 h at RT. After completion (monitored by
TLC), the reaction mixture was filtered through a celite bed and
the celite bed was washed 2-3 times with THF. The filtrate was
concentrated to get the desired
trans4-amino-5-(4-fluorophenyl)pyrrolidin-2-one (1.1 g, 93%) as a
brown gum.
Synthesis of
trans-4-amino-5-(2-methoxypyridin-4-yl)pyrrolidin-2-one
(Intermediate A9)
##STR00025## ##STR00026##
[0349] Step 1:
[0350] Maleic anhydride (17.2 g, 175.0 mmol, 1.0 eq), p-thiocresol
(21.7 g, 175.0 mmol, 1.0 eq), 2,4-dimethoxy benzylamine (29.2 g,
175.0 mmol, 1.0 eq), and 2-methoxypyridine-4-carbaldehyde (24.0 g,
175.0 mmol, 1.0 eq) were taken up in 300 mL of toluene. The
reaction mixture was refluxed for 16 h with vigorous stirring.
After completion of the reaction (monitored by TLC, TLC system 5%
MeOH in DCM, R.sub.f-0.1), the reaction mixture was cooled to RT
and the solvent was evaporated under reduced pressure to afford the
crude
1-(2,4-dimethoxybenzyl)-2-(2-methoxypyridin-4-yl)-5-oxo-3-(p-tolylthio)py-
rrolidine-3-carboxylic acid as a gummy liquid (80.0 g) which was
used in the next step without further purification.
[0351] Step 2:
[0352] To a stirred solution of
1-(2,4-dimethoxybenzyl)-2-(2-methoxypyridin-4-yl)-5-oxo-3-(p-tolylthio)py-
rrolidine-3-carboxylic acid (57.0 g, 112.1 mmol, 1.0 eq) in acetone
(300 mL), potassium carbonate (61.9 g, 448.3 mmol, 4.0 eq) and
methyl iodide (28.0 mL, 448.3 mmol, 4.0 eq) were added at 0.degree.
C., and the reaction was stirred at RT for 16 h. After completion
of the reaction (monitored by TLC, TLC system 30% EtOAc in hexane,
R.sub.f-0.3), the solvent was removed under reduced pressure and
the residue was partitioned between EtOAc and water. The aqueous
layer was extracted twice with EtOAc. 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, 40% EtOAc in hexane) to afford
methyl
1-(2,4-dimethoxybenzyl)-2-(2-methoxypyridin-4-yl)-5-oxo-3-(p-tolylthio)py-
rrolidine-3-carboxylate as an off white solid (35.0 g, 60%).
[0353] Step 3:
[0354] To a stirred solution of methyl
1-(2,4-dimethoxybenzyl)-2-(2-methoxypyridin-4-yl)-5-oxo-3-(p-tolylthio)py-
rrolidine-3-carboxylate (60.0 g, 114.8 mmol, 1.0 eq) in
acetonitrile (300 mL), CAN (188.8 g, 344.4 mmol, 3.0 eq) in water
(300 mL) was added dropwise at 0.degree. C. through an addition
funnel and the reaction mixture was then stirred at RT for 16 h.
After completion of the reaction (monitored by TLC, TLC system 70%
EtOAc in hexane, Rf-0.3), the reaction mixture was diluted with
water and extracted twice with EtOAc. 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 (230-400 silica gel, 40-50% EtOAc:hexane) to give
methyl
2-(2-methoxypyridin-4-yl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate
as an off white solid (12.0 g, 28%).
[0355] Step 4:
[0356] To a stirred solution of methyl
2-(2-methoxypyridin-4-yl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate
(11.4 g, 30.6 mmol, 1.0 eq) in EtOH:THF (50:100 mL, 1:2), Raney
Nickel (18 g) was added, and the reaction was stirred under a
hydrogen atmosphere for 16 h at RT. After completion, (monitored by
TLC, TLC system 70% EtOAc in hexane, Rf-0.4) the reaction mixture
was filtered through a celite bed and the celite bed was washed 4-5
times with THF. The filtrate was concentrated to afford methyl
2-(2-methoxypyridin-4-yl)-5-oxopyrrolidine-3-carboxylate as a white
solid (7.1 g, 93%, syn:anti mixture).
[0357] Step 5:
[0358] To a stirred solution of methyl
2-(2-methoxypyridin-4-yl)-5-oxopyrrolidine-3-carboxylate (0.7 g,
2.8 mmol, 1 eq) in MeOH (10 mL) was added 2N NaOH solution (6 mL)
and the reaction mixture was stirred at 80.degree. C. for 16 h.
After completion of the reaction (monitored by TLC, TLC system 5%
MeOH in DCM, Rf-0.1), the reaction mixture was concentrated and
acidified with 2N HCl solution to get a solid which was filtered
off and was washed with diethyl ether. After drying under vacuum
trans-2-(2-methoxypyridin-4-yl)-5-oxopyrrolidine-3-carboxylic acid
was obtained (0.4 g, 61%).
[0359] Step 6:
[0360] To a stirred solution of
trans-2-(2-methoxypyridin-4-yl)-5-oxopyrrolidine-3-carboxylic acid
(0.37 g, 1.58 mmol, 1.00 eq) in toluene (20 mL) was added TEA (0.30
mL, 1.66 mmol, 1.05 eq) and DPPA (0.40 mL, 1.89 mmol, 1.20 eq) and
the reaction mixture was stirred at 90.degree. C. for 30 min. Then
benzyl alcohol (0.40 mL, 3.16 mmol, 2.00 eq) was added to the
reaction mixture and heated to reflux for 16 h. After completion,
(monitored by TLC, TLC system 5% MeOH in DCM, Rf-0.3), the reaction
mixture was concentrated under reduced pressure. The residue was
then diluted with EtOAc (100 mL), washed with water (2.times.100
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; 0-2% MeOH in DCM) to
afford trans-benzyl
(2-(2-methoxypyridin-4-yl)-5-oxopyrrolidin-3-yl)carbamate (0.20 g,
37%).
[0361] Step 7:
[0362] To a stirred solution of trans-benzyl
(2-(2-methoxypyridin-4-yl)-5-oxopyrrolidin-3-yl)carbamate (0.2 g,
24.0 mmol, 1.0 eq) in MeOH:THF (20 mL, 2:1), Pd/C (0.2 g, 10%,
moist) was added and the reaction was stirred with a hydrogen
balloon for 2 h at RT. After completion, (monitored by TLC, TLC
system 5% MeOH in DCM, Rf-0.2), the reaction mixture was filtered
through a celite bed and the celite bed was washed 2-3 times with
THF. The filtrate was concentrated to get
trans-4-amino-5-(2-methoxypyridin-4-yl)pyrrolidin-2-one as a brown
gum (0.1 g, 82%).
Synthesis of trans-4-amino-5-(o-tolyl)pyrrolidin-2-one
(Intermediate A10)
##STR00027## ##STR00028##
[0364] Step 1:
[0365] Maleic anhydride (20.3 g, 208.2 mmol, 1.0 eq), p-thiocresol
(25.8 g, 208.2 mmol, 1.0 eq), 2,4-dimethoxy benzylamine (34.7 g,
208.2 mmol, 1.0 eq), and 2-fluorobenzaldehyde (25.0 g, 208.2 mmol,
1.0 eq) were taken up in 300 mL of toluene. The reaction mixture
was refluxed for 16 h with vigorous stirring. After completion of
the reaction (monitored by TLC, TLC system 5% MeOH in DCM,
R.sub.f-0.1), the reaction mixture was cooled to RT and the solvent
was evaporated under reduced pressure to afford the crude
1-(2,4-dimethoxybenzyl)-5-oxo-2-(o-tolyl)-3-(p-tolylthio)pyrrolidin-
e-3-carboxylic acid as a gummy liquid (101.0 g) which was used in
the next step without further purification.
[0366] Step 2:
[0367] To a stirred solution of crude
1-(2,4-dimethoxybenzyl)-5-oxo-2-(o-tolyl)-3-(p-tolylthio)pyrrolidine-3-ca-
rboxylic acid (101.0 g, 208.2 mmol, 1.0 eq) in acetone (1 L),
potassium carbonate (115.0 g, 832.8 mmol, 4.0 eq) and methyl iodide
(52.0 mL, 832.8 mmol, 4.0 eq) were added at 0.degree. C. and the
reaction was stirred at RT for 16 h. After completion of the
reaction (monitored by TLC, TLC system 30% EtOAc in hexane,
R.sub.f-0.3) the solvent was removed under reduced pressure and the
residue was partitioned between EtOAc and water. The aqueous layer
was extracted twice with EtOAc. 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, 40% EtOAc in hexane) to afford
methyl
1-(2,4-dimethoxybenzyl)-5-oxo-2-(o-tolyl)-3-(p-tolylthio)pyrrolidine-3-ca-
rboxylate as an off white solid (80.0 g, 76%).
[0368] Step 3:
[0369] To a stirred solution of methyl
1-(2,4-dimethoxybenzyl)-5-oxo-2-(o-tolyl)-3-(p-tolylthio)pyrrolidine-3-ca-
rboxylate (80.0 g, 158.0 mmol, 1.0 eq) in acetonitrile (300 mL),
CAN (260.0 g, 475.0 mmol, 3.0 eq) in water (300 mL) was added
dropwise to the reaction mixture at 0.degree. C. through an
addition funnel and the reaction mixture was stirred at RT for 16
h. After completion of the reaction (monitored by TLC, TLC system
50% EtOAc in hexane, Rf-0.3), the reaction mixture was diluted with
water and extracted twice with EtOAc. 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 (230-400 silica gel, 40-50% EtOAc: hexane) which
gave methyl
5-oxo-2-(o-tolyl)-3-(p-tolylthio)pyrrolidine-3-carboxylate as an
off white solid (21.5 g, 38%).
[0370] Step 4:
[0371] To a stirred solution of methyl
5-oxo-2-(o-tolyl)-3-(p-tolylthio)pyrrolidine-3-carboxylate (21.5 g,
60.5 mmol, 1.0 eq) in EtOH:THF (300:300 mL, 1:1), Raney Nickel
(.about.18 g) was added, and the reaction was stirred under a
hydrogen atmosphere for 16 h at RT. After completion, (monitored by
TLC, TLC system 70% EtOAc in hexane, Rf-0.4) the reaction mixture
was filtered through a celite bed and the celite bed was washed 4-5
times with THF. The filtrate was concentrated to afford methyl
5-oxo-2-(o-tolyl)pyrrolidine-3-carboxylate as a white solid (11.5
g, 82%, syn:anti mixture).
[0372] Step 5:
[0373] To a stirred solution of methyl
5-oxo-2-(o-tolyl)pyrrolidine-3-carboxylate (11.5 g, 49.3 mmol, 1.0
eq) in MeOH (400 mL) was added 2N NaOH solution (80 mL) and the
reaction mixture was stirred at 80.degree. C. for 16 h. After
completion of the reaction (monitored by TLC, TLC system 5% MeOH in
DCM, Rf-0.1), the reaction mixture was concentrated and acidified
with 2N HCl solution to get a solid which was filtered off and was
washed with diethyl ether. Drying under vacuum then afforded
trans-5-oxo-2-(o-tolyl)pyrrolidine-3-carboxylic acid (8.5 g,
79%).
[0374] Step 6:
[0375] To a stirred solution of
trans-5-oxo-2-(o-tolyl)pyrrolidine-3-carboxylic acid (8.5 g, 38.0
mmol, 1.00 eq) in toluene (110 mL) were added TEA (5.5 mL, 39.9
mmol, 1.05 eq) and DPPA (10.5 g, 45.0 mmol, 1.20 eq) and the
reaction mixture was stirred at 90.degree. C. for 30 min. After 30
min, benzyl alcohol (8.4 g, 77.0 mmol, 2.00 eq) was added and the
reaction mixture was heated to reflux for 16 h. After completion
(monitored by TLC, TLC system 5% MeOH in DCM, Rf-0.3), the reaction
mixture was concentrated under reduced pressure. The residue was
then diluted with EtOAc (100 mL), washed with water (2.times.100
mL), dried over anhydrous Na.sub.2SO.sub.4 and was then
concentrated under reduced pressure to get the crude product which
was purified by column chromatography (230-400 mesh silica gel;
0-2% MeOH in DCM) to afford trans-benzyl
(5-oxo-2-(o-tolyl)pyrrolidin-3-yl)carbamate (8.0 g, 65%).
[0376] Step 7:
[0377] To a stirred solution of trans-benzyl
(5-oxo-2-(o-tolyl)pyrrolidin-3-yl)carbamate (8.0 g, 24.0 mmol, 1.0
eq) in MeOH:THF (20 mL, 2:1), Pd/C (2.0 g, 10%, moist) was added,
and the reaction mixture was stirred with a hydrogen balloon for 2
h at RT. After completion, (monitored by TLC, TLC system 5% MeOH in
DCM, Rf-0.2), the reaction mixture was filtered through a celite
bed and the celite bed was washed 2-3 times with THF. The filtrate
was concentrated to get the desired
trans-4-amino-5-(o-tolyl)pyrrolidin-2-one as brown gum (4.5 g,
99%).
Synthesis of
trans-4-amino-5-(2-fluoro-5-methoxyphenyl)pyrrolidin-2-one
(Intermediate A11)
##STR00029## ##STR00030##
[0379] Step 1:
[0380] Maleic anhydride (14.6 g, 149.7 mmol, 1.0 eq), p-thiocresol
(18.5 g, 149.7 mmol, 1.0 eq), 2,4-dimethoxy benzylamine (25.0 g,
149.7 mmol, 1.0 eq), and 2-fluoro-5-methoxybenzaldehyde (23.0 g,
149.7 mmol, 1.0 eq) were taken up in 300 mL of toluene. The
reaction mixture was refluxed for 16 h with vigorous stirring.
After completion of the reaction (monitored by TLC, TLC system 5%
MeOH in DCM, R.sub.f-0.1), the reaction mixture was cooled to RT
and the solvent was then evaporated under reduced pressure to
afford the crude product as a gummy liquid (75.0 g, 96%) which was
used in the next step without further purification.
[0381] Step 2:
[0382] To a stirred solution of crude
1-(2,4-dimethoxybenzyl)-2-(2-fluoro-5-methoxyphenyl)-5-oxo-3-(p-tolylthio-
)pyrrolidine-3-carboxylic acid (75.0 g, 142.9 mmol, 1.0 eq) in
acetone (1 L), potassium carbonate (78.9 g, 571.4 mmol, 4.0 eq) and
methyl iodide (35.0 mL, 571.4 mmol, 4.0 eq) were added at 0.degree.
C., and the reaction mixture was stirred at RT for 16 h. After
completion of the reaction (monitored by TLC, TLC system 30% EtOAc
in hexane, R.sub.f-0.3), the solvent was removed under reduced
pressure and the residue was partitioned between EtOAc and water.
The aqueous layer was extracted twice with EtOAc. 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, 40% EtOAc in hexane) to afford
the desired methyl
1-(2,4-dimethoxybenzyl)-2-(2-fluoro-5-methoxyphenyl)-5-oxo-3-(p-tolylthio-
)pyrrolidine-3-carboxylate (45.0 g, 58%) as an off white solid.
[0383] Step 3:
[0384] To a stirred solution of methyl
1-(2,4-dimethoxybenzyl)-2-(2-fluoro-5-methoxyphenyl)-5-oxo-3-(p-tolylthio-
)pyrrolidine-3-carboxylate (45.0 g, 83.5 mmol, 1.0 eq) in
acetonitrile, CAN (137.3 g, 250.4 mmol, 3.0 eq) in water was added
dropwise through an addition funnel to the reaction mixture at
0.degree. C. and the reaction mixture was stirred at RT for 16 h.
After completion of the reaction (monitored by TLC, TLC system 50%
EtOAc in hexane, Rf-0.3), the reaction mixture was diluted with
water and extracted twice with EtOAc. 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 (230-400 silica gel, 40-50% EtOAc: hexane) to give
methyl
2-(2-fluoro-5-methoxyphenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxyla-
te (17.0 g, 52%) as an off white solid.
[0385] Step 4:
[0386] To a stirred solution of methyl
2-(2-fluoro-5-methoxyphenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxyla-
te (17.0 g, 43.7 mmol, 1.0 eq) in EtOH: THF (300:300 mL, 1:1),
Raney Nickel (17 g) was added and the reaction mixture was stirred
under a hydrogen atmosphere for 16 h at RT. After completion,
(monitored by TLC, TLC system 70% EtOAc in hexane, Rf-0.4) the
reaction mixture was filtered through a celite bed and the celite
bed was washed 4-5 times with THF. The filtrate was concentrated to
afford the desired methyl
2-(2-fluoro-5-methoxyphenyl)-5-oxopyrrolidine-3-carboxylate (9.0 g,
77%, syn:anti mixture) as a white solid.
[0387] Step 5:
[0388] To a stirred solution of methyl
2-(2-fluoro-5-methoxyphenyl)-5-oxopyrrolidine-3-carboxylate (9.0 g,
33.7 mmol, 1 eq) in MeOH (180 mL) was added 2 N NaOH solution (36
mL) and the reaction mixture was stirred at 80.degree. C. for 16 h.
After completion of the reaction (monitored by TLC, TLC system 5%
MeOH in DCM, Rf-0.1), the reaction mixture was concentrated and
acidified with 2N HCl solution to obtain a solid which was filtered
off and then washed with diethyl ether. Drying under vacuum
afforded
trans-2-(2-fluoro-5-methoxyphenyl)-5-oxopyrrolidine-3-carboxylic
acid (7.9 g, 93%).
[0389] Step 6:
[0390] To a stirred solution of
trans-2-(2-fluoro-5-methoxyphenyl)-5-oxopyrrolidine-3-carboxylic
acid (7.9 g, 31.2 mmol, 1.00 eq) in toluene (80 mL) were added TEA
(4.6 mL, 32.8 mmol, 1.05 eq) and DPPA (10.3 g, 37.46 mmol, 1.20 eq)
and the reaction mixture was stirred at 90.degree. C. for 30 min.
After 30 min, benzyl alcohol (6.7 g, 62.4 mmol, 2.00 eq) was added
and the reaction mixture was heated to reflux for 16 h. After
completion, (monitored by TLC, TLC system 5% MeOH in DCM, Rf-0.3),
the reaction mixture was concentrated under reduced pressure. The
residue was then diluted with EtOAc (100 mL), washed with water
(2.times.100 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; 0-2% MeOH in
DCM) to afford benzyl
(trans-2-(2-fluoro-5-methoxyphenyl)-5-oxopyrrolidin-3-yl)carbamate
(1.5 g, 13%).
[0391] Step 7:
[0392] To a stirred solution of benzyl
(trans-2-(2-fluoro-5-methoxyphenyl)-5-oxopyrrolidin-3-yl)carbamate
(1.5 g, 4.2 mmol, 1.0 eq) in MeOH: THF (20 mL, 2:1), Pd/C (0.3 g,
0.548 mmol, 0.1 eq) was added, and the reaction mixture was stirred
with a hydrogen balloon for 2 h at RT. After completion, (monitored
by TLC, TLC system 5% MeOH in DCM, Rf-0.2), the reaction mixture
was filtered through a celite bed and the celite bed was washed 2-3
times with THF. The filtrate was concentrated to get the desired
trans-4-amino-5-(2-fluoro-5-methoxyphenyl)pyrrolidin-2-one (0.9 g,
96%) as a brown gum.
Synthesis of tert-butyl
(trans-2-cyclopropyl-5-oxopyrrolidin-3-yl)carbamate (Intermediate
A12-Boc) and tert-butyl
(cis-2-cyclopropyl-5-oxopyrrolidin-3-yl)carbamate (Intermediate
A13-Boc)
##STR00031## ##STR00032##
[0394] Step 1:
[0395] To a stirred solution of 2-amino-2-cyclopropylacetic acid
(40.0 g, 347.4 mmol), 0.5N NaOH aqueous solution (240 mL) and
1,4-dioxane (200 mL) was added di-tert-butyl-di-carbonate (83.3 g,
382.1 mmol) at 0.degree. C. Then the reaction mixture was allowed
to warm up to ambient temperature and was stirred for 16 h. The
reaction mixture was acidified with 5% KHSO.sub.4 solution after
completion of the reaction. The aqueous layer was extracted with
EtOAc, the combined organic layers were then washed with brine,
dried over sodium sulfate and concentrated under reduced pressure
to afford 2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid
(40.0 g) as a yellow sticky liquid.
[0396] Step 2:
[0397] To a stirred solution of 2-((tert-butoxycarbonyl)
amino)-2-cyclopropylacetic acid (78.5 g, 365.1 mmol) and DCM (785
mL) were added Meldrum's acid (59.9 g, 401.6 mmol) and DMAP (62.4
g, 511.1 mmol) at 0.degree. C. The reaction mixture was allowed to
stir at this temperature for 30 min. To this reaction mixture was
added EDC.HCl (98.0 g, 511.1 mmol) and the reaction mixture was
stirred at ambient temperature for 12 h. The reaction mixture was
diluted with EtOAc. The organic layer was washed with 5% citric
acid, water and brine. The organic layer was then heated to
75.degree. C. for 1 h, concentrated under reduced pressure. The
obtained residue was triturated with diethyl ether to afford
tert-butyl 2-cyclopropyl-3,5-dioxopyrrolidine-1-carboxylate (33.1
g, 38%) as an off white solid.
[0398] Step 3:
[0399] To a stirred solution of tert-butyl
2-cyclopropyl-3,5-dioxopyrrolidine-1-carboxylate (40.0 g, 167.3
mmol) in 1,4-dioxane (200 mL) was added 1,4-dioxane-HCl (200 mL) at
0.degree. C. The reaction mixture was then stirred at ambient
temperature for 3 h. The reaction mixture was then concentrated
under reduced pressure to afford 5-cyclopropylpyrrolidine-2,4-dione
(30.0 g) as an off white solid.
[0400] Step 4:
[0401] To a stirred solution of 5-cyclopropylpyrrolidine-2,4-dione
(30.0 g, 215.8 mmol) in a mixture of ethanol (270 mL) and acetic
acid (30 mL) was added (4-methoxyphenyl)methanamine (29.6 g, 215.8
mmol) under nitrogen atmosphere. The reaction was then heated to
80.degree. C. for 12 hours. The reaction mixture was concentrated
under reduced pressure, the obtained residue was basified with 1N
NaOH, causing precipitation. The precipitated solid was filtered
off and was then dried under reduced pressure to afford a light
yellow solid.
[0402] .sup.1H NMR (DMSO-d.sub.6) .delta.: 7.17 (d, 2H), 6.98 (q,
1H), 6.83 (d, 2H), 6.66-6.58 (m, 1H), 4.17 (s, 1h) 4.06 (d, 2H),
3.64 (s, 3H), 0.96 (td, 1H), 0.46 (dq, 1H), 0.37 (p, 1H), 0.21 (dt,
1H), 0.12 (dd, 1H).
[0403] Step 5:
[0404] To a stirred solution of
5-cyclopropyl-4-((4-methoxybenzyl)amino)-1,5-dihydro-2H-pyrrol-2-one
(17.0 g, 65.9 mmol) and acetic acid (170 mL) was added sodium cyano
borohydride (24.8 g, 395.3 mmol) at 0.degree. C. and the reaction
was stirred for 1 h at this temperature. The reaction mixture was
then concentrated under reduced pressure; the obtained residue was
basified with 1N NaOH and extracted with EtOAc. The combined
organic layers were washed with water and brine and were then dried
over sodium sulfate and concentrated under reduced pressure to get
the crude product which was used in the next step without further
purification.
[0405] Step 6:
[0406] To a stirred solution of
5-cyclopropyl-4-((4-methoxybenzyl)amino)pyrrolidin-2-one (3.8 g,
14.6 mmol) and MeOH (38 mL) were added 2N HCl (4.0 mL), ammonium
formate (18.4 g, 292.3 mmol) and 10% palladium on carbon (3.8 g)
The reaction mixture was then heated to 80.degree. C. for 12 h. The
reaction mixture was then filtered through a celite bed and the
filtrate was concentrated under reduced pressure to afford
4-amino-5-cyclopropylpyrrolidin-2-one (5.8 g) as a yellow sticky
solid.
[0407] Step 7:
[0408] To a stirred solution of
trans-4-amino-5-cyclopropylpyrrolidin-2-one (5.8 g, 40.25 mmol) and
DCM (25 mL) were added TEA (17.2 mL, 123.17 mmol) and Boc anhydride
(9.8 g, 45.17 mmol) at 0.degree. C. The reaction mixture was then
stirred at RT overnight. The reaction mixture was then diluted with
DCM. The organic layer was washed with water and brine, dried over
sodium sulfate and concentrated under reduced pressure. The
obtained residue was purified by column chromatography using
neutral aluminium oxide and 1% MeOH and CHCl.sub.3 as an eluent to
afford an off-white solid which was further purified by preparative
HPLC to afford tert-butyl
(trans-2-cyclopropyl-5-oxopyrrolidin-3-yl)carbamate (0.42 g) and
tert-butyl (cis-2-cyclopropyl-5-oxopyrrolidin-3-yl)carbamate (1.4
g) as off-white solids.
tert-butyl (trans-2-cyclopropyl-5-oxopyrrolidin-3-yl)carbamate
(Intermediate C12-Boc)
[0409] .sup.1H NMR (DMSO-d.sub.6) .delta.: 7.78 (s, 1H), 7.20 (d,
1H), 3.87 (p, 1H), 2.79 (dd, 1H), 2.46 (d, 1H), 2.01 (dd, 1H), 0.82
(dt, 1H), 0.38 (dd, 2H), 0.26 (dd, 1H), 0.13-0.07 (m, 1H).
tert-butyl (cis-2-cyclopropyl-5-oxopyrrolidin-3-yl)carbamate
(Intermediate C13-Boc)
[0410] .sup.1H NMR (DMSO-d.sub.6) .delta.: 7.84 (s, 1H), 7.25 (d,
1H), 4.18 (q, 1H), 2.88 (t, 1H), 2.25 (d, 2H), 1.38 (s, 9H), 0.74
(dt, 1H), 0.38 (dt, 2H), 0.09 (d, 2H).
Synthesis of tert-butyl
((2R,3R)-2-(cyclopropylmethyl)-5-oxopyrrolidin-3-yl)carbamate
(Intermediate C.sub.1-4-Boc)
##STR00033##
[0412] Step 1:
[0413] To a stirred solution of (R)-2-amino-3-cyclopropylpropanoic
acid (20.0 g, 154.9 mmol) in 1,4-dioxane (100 mL) was added 0.5N
NaOH aqueous solution (120 mL) and di-tert-butyl-di-carbonate (40.6
g, 185.8 mmol) at 0.degree. C., stirring was then continued at RT
for 16 h. The solvent was then concentrated under reduced pressure,
the resulting residue was acidified with 2N HCl solution. The
remains were extracted with EtOAc, washed with water and brine. The
organic layer was then dried over Na.sub.2SO.sub.4 and concentrated
in vacuo to afford
(R)-2-((tert-butoxy-carbonyl)amino)-3-cyclopropylpropanoic acid as
an off white solid (25.0 g).
[0414] Step 2:
[0415] To a stirred solution of
(R)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropanoic acid
(20.0 g, 87.2 mmol) in DCM (200 mL) were added Meldrum's acid (13.8
g, 96.0 mmol) and DMAP (14.9 g, 122.1 mmol) at 0.degree. C. After
30 min EDC.HCl (23.4 g, 122.1 mmol) was added at 0.degree. C., the
reaction mixture was then allowed to stir at ambient temperature
for 20 h. The reaction mixture was diluted with EtOAc (50 ml),
washed with cold 5% KHSO.sub.4 solution and brine. The organic
layer was dried over Na.sub.2SO.sub.4 and the solvent was distilled
off under reduced pressure The remains were diluted with ethyl
acetate (50 mL), and were refluxed for 1 h at 65.degree. C. Removal
of the solvent under reduced pressure afforded tert-butyl
(R)-2-(cyclopropylmethyl)-3-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-1-carbox-
ylate (27.0 g) as a yellow solid.
[0416] .sup.1H NMR (DMSO-d.sub.6) .delta.:12.3 (s, 1H), 6 8.31 (s,
1H), 6 4.89 (s, 1H), 4.4-4.38 (m, 1H), 4.05-3.99 (m, 1H), 1.77-1.73
(m, 1H), 1.38 (s, 9H), 0.45-0.44 (m, 1H), 0.23-0.22 (m, 2H),
0.2-0.1 (m, 2H).
[0417] Step 3:
[0418] To a stirred solution of tert-butyl
(R)-2-(cyclopropylmethyl)-3,5-dioxopyrrolidine-1-carboxylate (10.0
g, 65.4 mmol) in 1,4-dioxane (270 mL) was added 4M HCl in
1,4-dioxane (135 mL) at 0.degree. C. under a nitrogen atmosphere
and the reaction mixture was allowed to stir for 2 h at ambient
temperature. The reaction mixture was then concentrated under
vacuum and the obtained residue was triturated with diethyl ether
to get (R)-5-(cyclopropylmethyl)pyrrolidine-2,4-dione (18.0 g) as a
white gummy solid.
[0419] Step 4:
[0420] To a stirred solution of
(R)-5-(cyclopropylmethyl)pyrrolidine-2,4-dione (10.0 g, 65.4 mmol)
in EtOH:AcOH (100 mL, 9:1 w/v) was added (4-methoxyphenyl)
methanamine (13.4 g, 98.0 mmol) at 0.degree. C. and the reaction
mixture was stirred to 80.degree. C. under a nitrogen atmosphere
for 1 h. The reaction mixture was concentrated under reduced
pressure and the obtained residue was triturated with 1N NaOH to
get
(R)-5-(cyclopropylmethyl)-4-((4-methoxybenzyl)amino)-1,5-dihydro-2H-pyrro-
l-2-one (5.0 g, 23%) as an off white solid.
[0421] Step 5:
[0422] To a stirred solution of
(R)-5-(cyclopropylmethyl)-4-((4-methoxybenzyl)amino)-1,5-dihydro-2H-pyrro-
l-2-one (5.0 g, 18.4 mmol) in AcOH (50 mL) was added NaCNBH.sub.3
(3.4 g, 55.1 mmol) at 0.degree. C. and the reaction mixture was
then stirred at ambient temperature under a nitrogen atmosphere for
2 h. The reaction mixture was then concentrated under reduced
pressure. The obtained residue was basified with 1N NaOH at
0.degree. C. leading to precipitation. The solid was filtered off
and dried in vacuo to afford the crude product which was purified
by combiflash (using MeOH: DCM (0-5%)) to afford
(4R,5R)-5-(cyclopropylmethyl)-4-((4-methoxybenzyl)-amino)pyrrolidin-2-one
(5.0 g).
[0423] Step 6:
[0424] To a solution of
(4R,5R)-5-(cyclopropylmethyl)-4-((4-methoxybenzyl)amino)pyrrolidin-2-one
(7.0 g, 25.5 mmol) in MeOH (210 mL), were added HCOONH.sub.4 (32.1
g, 510.3 mmol) and 10% Pd/C (7.0 g) at ambient temperature under a
nitrogen atmosphere and the reaction mixture was then heated to
75.degree. C. for 2 h. The reaction mixture was then filtered
through celite and the obtained filtrate was concentrated under
reduced pressure to afford
(4R,5R)-4-amino-5-(cyclopropylmethyl)pyrrolidin-2-one (3.9 g).
[0425] Step 7:
[0426] To a solution of
(4R,5R)-4-amino-5-(cyclopropylmethyl)pyrrolidin-2-one (3.9 g, 25.5
mmol) in DCM (39 mL), TEA (4.5 g, 44.6 mmol) and (Boc).sub.2O (6.1
g, 28.0 mmol) were added at 0.degree. C. The mixture was stirred at
ambient temperature for 16 h, then the reaction mixture was diluted
with DCM and washed consecutively with 5% citric acid solution and
brine. The solvent was removed under reduced pressure to afford the
crude product as an off white solid which was washed with diethyl
ether (2.times.1 mL), filtered and the solid was dried in vacuo to
afford tert-butyl
((2S,3S)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidin-3-yl)car-
bamate as a white solid (2.6 g, 40%).
[0427] .sup.1H NMR (DMSO-d.sub.6) .delta. 7.8 (s, 1H), 7.3-7.2 (m,
1H), 4.26-4.21 (m, 1H) 3.70-3.60 (m, 1H), 3.4 (s, 2H), 2.46-2.40
(m, 1H), 1.38 (s, 9H), 0.45-0.44 (m, 1H), 0.23-0.22 (m, 2H),
0.20-0.10 (m, 2H).
Synthesis of (trans)-4-amino-5-(3,5-difluorophenyl)pyrrolidin-2-one
(Intermediate A15)
##STR00034##
[0429] Step 1:
[0430] A solution of 3,5-difluorobenzaldehyde (100.0 g, 0.7 mol,
1.0 eq), 4-methyl-benzenethiol (87.4 g, 0.7 mol, 1 eq), maleic
anhydride (69.0 g, 0.7 mol, 1.0 eq) and ammonium acetate (54.2 g,
0.7 mol, 1.0 eq) in toluene (2.5 L) was stirred at ambient
temperature for 2 hours, followed by heating to 140.degree. C. in
an autoclave for 16 hours. After complete disappearance of the
starting material (monitored by LCMS), the reaction mixture was
cooled to ambient temperature and was concentrated under reduced
pressure to afford
2-(3,5-difluoro-phenyl)-5-oxo-3-p-tolylsulfanyl-pyrrolidine-3-carboxylic
acid (266 g crude material) as a brown gum.
[0431] Step 2:
[0432] To a suspension of
2-(3,5-difluoro-phenyl)-5-oxo-3-p-tolylsulfanyl-pyrrolidine-3-carboxylic
acid (266.0 g, 0.73 mol, 1.0 eq) in acetone (2.6 l) was added
K.sub.2CO.sub.3 (405.1 g, 2.93 mol, 4.0 eq) followed by methyl
iodide (273.7 mL, 4.39 mol, 6.0 eq) and the resulting suspension
was stirred at ambient temperature for 48 hours. The reaction
mixture was then filtered and the filtrate was concentrated under
reduced pressure. The crude residue was purified by column
chromatography (silica 100-200 mesh and 40% ethyl acetate/hexane as
eluent) to afford
2-(3,5-difluoro-phenyl)-5-oxo-3-p-tolylsulfanyl-pyrrolidine-3-carboxylic
acid methyl ester (24.0 g, 9% over two steps) as a brown solid.
[0433] Step 3:
[0434] To a solution of
2-(3,5-difluoro-phenyl)-5-oxo-3-p-tolylsulfanyl-pyrrolidine-3-carboxylic
acid methyl ester (20.0 g, 0.053 mol, 1.0 eq) in an ethanol:THF
mixture (360 mL, 2:1) was added Raney Nickel (10 g). The resulting
suspension was reacted in a Parr shaker at 40 psi of hydrogen
pressure for 4 h. After completion of the reaction (monitored by
LCMS), the reaction mixture was filtered over a bed of celite and
the celite bed was washed with ethanol (2.times.150 ml). The
combined filtrates were concentrated under reduced pressure to
afford 2-(3,5-difluoro-phenyl)-5-oxo-pyrrolidine-3 carboxylic acid
methyl ester (9 g crude material) as a brown gum.
[0435] Step 4:
[0436] To a suspension of
2-(3,5-difluoro-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl
ester (13.0 g, 0.05 mol, 1.0 eq) in MeOH (130 mL) was added 2N NaOH
(75 mL, 0.15 mol, 3.0 eq) at 0.degree. C. and the resulting
suspension was then stirred at 80.degree. C. for 6 hours. After
completion of the reaction (monitored by LCMS), the reaction
mixture was concentrated and the residue was diluted with water and
washed with ethyl acetate (2.times.150 ml). The aqueous basic
mixture was acidified to pH 4 with 6N HCl. The precipitated solids
were filtered, dried and triturated with ethyl acetate and diethyl
ether to afford
trans-5-oxo-2-(3,5-difluorophenyl)pyrrolidine-3-carboxylic acid
(4.1 g) as an off-white solid.
[0437] Step 5:
[0438] To a stirred solution of
trans-5-oxo-2-(3,5-difluorophenyl)pyrrolidine-3-carboxylic acid
(4.6 g, 0.019 mol, 1.0 eq) in a mixture of benzene (60 mL) and THF
(23 mL) was added DPPA (5.43 ml, 0.025 mol, 1.3 eq) followed by
DIPEA (4.96 ml, 0.029 mol, 1.5 eq) at ambient temperature. The
resulting reaction mixture was stirred at ambient temperature for 2
hours, followed by the addition of benzyl alcohol (5.2 g, 0.048
mol, 2.5 eq) and the reaction mixture was heated at 90.degree. C.
for 16 hours. After completion of the reaction (monitored by TLC),
the reaction mixture was concentrated. The crude residue was
purified by column chromatography (silica 100-200 mesh, 10%
EA-Hexane as eluent), followed by trituration using MTBE to afford
trans-benzyl (5-oxo-2-(3,5-difluorophenyl)pyrrolidin-3-yl)carbamate
(intermediate A15-Cbz) (1.2 g, 18%) as an off-white solid.
[0439] Step 6:
[0440]
Trans-benzyl-N-(5-oxo-2-(3,5-difluorophenyl)pyrrolidin-3-yl)carbama-
te (611.0 mg, 1.764 mmol, 1.0 eq) was dissolved in EtOH/EtOAc/AcOH
(35 mL, 24/2/1, v/v/v) and is hydrogenated using a flow
hydrogenation apparatus (Pd/C as catalyst, H.sub.2 pressure below
10 bar). The inlet flask is rinsed repeatedly with the solvent
mixture described above. The solvent is then removed under reduced
pressure, and the remains are purified using ion exchange
chromatography (DSC-SCX).
N-trans-(5-oxo-2-(3,5-difluorophenyl)pyrrolidin-3-yl)amine
(intermediate A15) is obtained in 99% yield (370.1 mg).
Synthesis of benzyl
(trans-2-(3-methoxyphenyl)-5-oxopyrrolidin-3-yl)carbamate
(Intermediate A16-Cbz)
##STR00035##
[0442] Step 1:
[0443] A solution of 3-methoxy-benzaldehyde (100.0 g, 0.73 mol, 1.0
eq), 4-methyl-benzenethiol (91.2 g, 0.73 mol, 1.0 eq), maleic
anhydride (72.0 g, 0.73 mol, 1.0 eq) and ammonium acetate (56.2 g,
0.73 mol, 1.0 eq) in Toluene (2.5 L) was stirred at ambient
temperature for 2 hours, followed by heating to 140.degree. C. in
an autoclave for 16 hours. After completion of the reaction
(monitored by LCMS), the reaction mixture was cooled to ambient
temperature and was concentrated under reduced pressure to afford
2-(3-methoxy-phenyl)-5-oxo-3-p-tolylsulfanyl-pyrrolidine-3-carb-
oxylic acid (262 g crude material) as a brown gum.
[0444] Step 2:
[0445] To a suspension of
2-(3-methoxy-phenyl)-5-oxo-3-p-tolylsulfanyl-pyrrolidine-3-carboxylic
acid (262.0 g, 0.73, 1.0 eq) in acetone (2.6 L), was added
K.sub.2CO.sub.3 (405.7 g, 2.93 mol, 4.0 eq), followed by methyl
iodide (274.1 mL, 4.40 mol, 6.0 eq) and the resulting suspension
was stirred at ambient temperature for 48 hours. The reaction
mixture was filtered and the filtrate was concentrated under
reduced pressure. The crude residue was purified by column
chromatography (silica 100-200 mesh and 15% ethyl acetate/hexane as
eluent) to afford
2-(3-methoxy-phenyl)-5-oxo-3-p-tolylsulfanyl-pyrrolidine-3-carboxylic
acid methyl ester (42.0 g, 15% over 2 steps) as a brown solid.
[0446] Step 3:
[0447] To a solution of
2-(3-methoxy-phenyl)-5-oxo-3-p-tolylsulfanyl-pyrrolidine-3-carboxylic
acid methyl ester (40.0 g, 0.053 mol, 1.0 eq) in an ethanol:THF
mixture (670 mL, 2:1), was added Raney Nickel (40 g) and the
resulting suspension was stirred under hydrogen pressure (using a
hydrogen balloon) for 16 hours. After completion of the reaction
(monitored by LCMS), the reaction mixture was filtered over a bed
of celite and the celite bed was washed with ethanol (2.times.150
ml). The combined filtrates were concentrated under reduced
pressure to afford
2-(3-methoxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl
ester (20.0 g, 77%) as a brown gum.
[0448] Step 4:
[0449] To a suspension of
2-(3-methoxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl
ester (20.0 g, 0.08 mol, 1.0 eq) in MeOH (480 mL) was added 2N NaOH
(240 mL) at 0.degree. C. and the resulting suspension was stirred
at 80.degree. C. for 66 hours. After completion of the reaction
(monitored by LCMS), the reaction mixture was concentrated and the
residue was diluted with water and washed with ethyl acetate
(2.times.250 mL). The basic aqueous layer was acidified to pH 4
with 6N HCl. The precipitated solids were filtered, dried,
triturated with ethyl acetate and diethyl ether to afford
trans-5-oxo-2-(3-methoxyphenyl)pyrrolidine-3-carboxylic acid (9.5
g, 50%) as an off-white solid.
[0450] Step 5:
[0451] To a stirred solution of
trans-5-oxo-2-(3-methoxyphenyl)pyrrolidine-3-carboxylic acid (8.3
g, 0.035 mol, 1.0 eq) in a mixture of benzene (250 mL) and THF (80
mL) was added DPPA (9.9 ml, 0.046 mol, 1.3 eq) followed by TEA (9.8
ml, 0.705 mol, 20.0 eq) at ambient temperature. The resulting
reaction mixture was stirred at ambient temperature for 2 hours,
then benzyl alcohol (4.8 ml, 0.046 mol, 1.3 eq) was added and the
reaction mixture was heated to 90.degree. C. for 16 hours. After
completion of the reaction (monitored by TLC), the reaction mixture
was concentrated and the crude residue was purified by column
chromatography (silica 100-200 mesh, 10% EA-Hexane as eluent),
followed by trituration using MTBE to afford benzyl
(trans-2-(3-methoxyphenyl)-5-oxopyrrolidin-3-yl)carbamate
(intermediate A16-Cbz) (5.6 g, 46%) as an off-white solid.
Synthesis of tert-butyl
((2R,3S)-2-benzyl-5-oxopyrrolidin-3-yl)carbamate (Intermediate
A17-Boc ent1)
##STR00036##
[0453] Step 1:
[0454] Benzaldehyde (150 g, 1.41 mol) was added to a stirred
solution of nitromethane (300 mL), acetic acid (20 mL) and ammonium
acetate (11 g, 0.14 mol) at ambient temperature under argon
atmosphere. The solution was then heated to 110.degree. C. for 4 h.
The reaction mixture was then cooled and diluted with water (1000
mL) and extracted with EtOAc (3.times.500 mL). The combined organic
layers were washed with water and brine. The separated organic
layer was then concentrated to obtain the crude product. This crude
product was purified by column chromatography (silica gel, eluent
EtOAc/hexane 5:95) to afford 130 g (62%) of
(E)-(2-nitrovinyl)benzene as a pale yellow solid. (TLC system: 10%
ethyl acetate in pet-ether; Rf: 0.6).
[0455] Step 2:
[0456] To a stirred solution of NaBH.sub.4 (43 g, 1.13 mol) in EtOH
(300 mL) and 1,4-dioxane (1000 mL) was added a solution of
(E)-(2-nitrovinyl)benzene in 1,4-dioxane (1000 mL) at 0.degree. C.
The resulting reaction mixture was stirred at ambient temperature
for 30 minutes. The reaction mixture was then quenched with
saturated NH.sub.4Cl solution and the mixture was then extracted
with EtOAc (500 mL.times.3). The combined organic layers were
washed with brine (500 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered and the filtrate was concentrated to obtain the crude
product. This crude product was purified by column chromatography
(silica gel, eluent EtOAc/hexane 2:98) to afford 100 g (77%) of
(2-nitroethyl)benzene as a brown liquid (TLC system: 5% ethyl
acetate in pet-ether; Rf: 0.5).
[0457] Step 3:
[0458] To a stirred mixture of (2-nitroethyl)benzene (140 g, 0.927
mol) and dimethyl maleate (116 mL, 0.97 mol) was added
TBAF.3H.sub.2O (58 g, 0.185 mol) at 0.degree. C. The reaction
mixture was then allowed to stir at 25.degree. C. for 16 h. The
reaction mixture was diluted with EtOAc (1000 mL), washed with
water and brine, dried over anhydrous Na.sub.2SO.sub.4, and
concentrated under reduced pressure to give a brown liquid. Flash
column chromatography of this material (eluent hexane/EtOAc 90:10)
gave dimethyl 2-(1-nitro-2-phenylethyl)succinate (200 g, 73%) as a
brown liquid. (TLC system: 30% ethyl acetate in pet-ether; Rf:
0.4).
[0459] Step 4:
[0460] To a stirred solution of dimethyl
2-(1-nitro-2-phenylethyl)succinate (100 g, 0.33 mol) in EtOAc (2
L), were added acetic acid (150 mL), water (50 mL) and zinc (110 g,
1.69 mol, lot wise). The reaction mixture was heated to 80.degree.
C. for 16 h. After completion of the reaction, the reaction mixture
was cooled and filtered, and the filtrate was diluted with EtOAc
and water. The layers were separated, and the separated organic
layer was washed with water and sat. NaHCO.sub.3 solution and was
then concentrated under reduced pressure to give 50 g (65%) of
methyl 2-benzyl-5-oxopyrrolidine-3-carboxylate as a brown liquid.
(TLC: 50% EtOAc in pet ether, Rf: 0.3).
[0461] Step 5:
[0462] To a stirred solution of methyl
2-benzyl-5-oxopyrrolidine-3-carboxylate (50 g, 0.214 mol) in
methanol (500 mL) at ambient temperature was added 2 N NaOH
solution and the mixture was heated to reflux under N.sub.2
atmosphere for 24 h. The mixture was then concentrated under
reduced pressure to give a residue, which was diluted with water
(100 mL), acidified with sat. KHSO.sub.4 solution and was then
extracted with EtOAc (3.times.300 mL). The combined organic layers
were washed with brine and concentrated to give 38 g (82%) of
trans-2-benzyl-5-oxopyrrolidine-3-carboxylic acid as brown liquid.
(TLC system: 20% MeOH/DCM; Rf: 0.1).
[0463] Step 6:
[0464] To a stirred solution of
trans-2-benzyl-5-oxopyrrolidine-3-carboxylic acid (12 g, 54.79
mmol) in THF (120 mL) were added 50% T.sub.3P (35 mL, 54.79) and
TEA (23 mL, 164.3 mmol) and the resulting mixture was stirred at
ambient temperature for 10 min, prior to the addition of TMSN.sub.3
(14.5 mL, 109.56) and the resulting mixture was heated to reflux
for 3 h. The reaction mixture was cooled to ambient temperature,
diluted with water (50 mL) and extracted with EtOAc (3.times.100
mL). The separated organic layer was washed with brine and
concentrated to give the crude product. This crude product was
purified by column chromatography (silicagel, eluent
MeOH/CH.sub.2C2 2:98) to afford 3.0 g (21%) of
(trans-2-benzyl-5-oxopyrrolidin-3-yl)carbamoyl azide as a brown
solid (TLC system: 100% EA; Rf: 0.5).
[0465] Step 7:
[0466] A solution of (trans-2-benzyl-5-oxopyrrolidin-3-yl)carbamoyl
azide (3.0 g, 11.58 mmol) in THF (30 mL) was added drop wise to 30
mL of 2 N NaOH solution at 0.degree. C. The resulting reaction
mixture was stirred at ambient temperature for 30 min and monitored
by TLC, prior to the addition of Boc anhydride (6 mL) at ambient
temperature and the stirring was continued for 16 h. The reaction
mixture was diluted with water (30 mL) and extracted with EtOAc
(3.times.50 mL). The separated organic layer was washed with brine
and concentrated to give the crude product. The crude product was
triturated with 50% EtOAc in pet-ether to afford 2.1 g (63%) of
tert-butyl (trans-2-benzyl-5-oxopyrrolidin-3-yl)carbamate as an
off-white solid which was separated by SFC to give individual
enantiomers.
[0467] Chiral, preparative SFC was conducted as follows: column:
Chiralpak IG (4.6.times.150 mm) 3 .mu.m, co-solvent: methanol
(40%), total flow: 3 g/minute, ABPR: 1500 psi, temperature
30.degree. C. Retention times: enantiomer 1 (intermediate A17-Boc
ent1): 1.329 minutes, enantiomer 2: 1.965 minutes.
Synthesis of trans
{1-[1-(4-Fluoro-phenyl)-1H-indazol-5-yl]-5-oxo-2-ethyl-pyrrolidin-3-yl}-c-
arbamic acid benzyl ester (Intermediate A1-Cbz)
##STR00037##
[0469] Step 1:
[0470] Benzyl N-[(3S)-2,5-dioxotetrahydrofuran-3-yl]carbamate
(500.0 mg, 2.006 mmol, 1.0 eq) was weighed out into a Schlenk
flask, a stir bar was added, the flask was sealed and sparged with
nitrogen. Then THF (20 mL) was added, followed by cooling of the
reaction mixture to -78.degree. C. Then, ethylmagnesiumbromide (3.2
mL of a 1 M solution in THF, 1.6 eq.) was added dropwise over two
minutes, and the mixture was stirred at that temperature for 2
hours. Then, 7 mL of 10% citric acid was added at -78.degree. C.
The mixture was allowed to warm to ambient temperature. Et.sub.2O
was then added as well as water. The layers were separated, and the
aqueous layer was extracted two more times with Et.sub.2O. The
combined organic layers were washed with brine, dried over
MgSO.sub.4, and the solvent was removed under reduced pressure to
yield a colorless oil (638 mg, containing
3-(Benzyloxycarbonylamino)-4-oxo-hexanoic acid and byproducts)
which was used without further purification in the next step.
[0471] Step 2:
[0472] 3-(Benzyloxycarbonylamino)-4-oxo-hexanoic acid (638 mg from
step 1, used crude with all non-volatile byproducts) was dissolved
in ethanol (20 mL). A stir bar was added, the flask was sealed with
a septum, and was sparged with nitrogen. The reaction mixture was
cooled to 0.degree. C. Then, thionyl chloride (0.14 mL, 1.9 mmol)
was added, and the mixture was stirred at ambient temperature for
16 hours. The solvent was evaporated under reduced pressure, and
the crude material was then purified via silica gel chromatography
to yield 438.1 mg of a clear oil containing ethyl
3-(((benzyloxy)carbonyl)amino)-4-oxohexanoate. The desired compound
is accompanied by the an inseparable byproduct.
[0473] Step 3:
[0474] Sodium cyanoborohydride (53.8 mg, 0.855 mmol, 0.6 eq.) and
ammonium acetate (1099.0 mg, 14.250 mmol, 10.0 eq) were weighed out
into a flask, a stir bar was added, the flask was sealed and
sparged with nitrogen. Then,
ethyl-3-(benzyloxycarbonylamino)-4-oxo-hexanoate (438 mg from step
2, used crude with all non-volatile byproducts) in ethanol (5.0 mL)
was added, and the mixture was heated to 50.degree. C. for one
hour. The solvent was then removed, and the remains were taken up
in EtOAc and water. The layers were separated, and the aqueous
phase was extracted two more times with EtOAc. The combined organic
layers were then dried over MgSO.sub.4, the solvent was removed and
the crude material was purified via silica gel chromatography to
yield 125.0 mg (33%) of benzyl
(2-ethyl-5-oxopyrrolidin-3-yl)carbamate.
[0475] Step 4:
[0476] Benzyl N-(2-ethyl-5-oxo-pyrrolidin-3-yl)carbamate (285.0 mg,
1.087 mmol, 1.0 eq.), 1-(4-fluorophenyl)-5-iodo-indazole (404.1 mg,
1.120 mmol, 1.1 eq.), K.sub.3PO.sub.4 (461.2 mg, 2.173 mmol, 2.0
eq.) and copper iodide (165.5 mg, 0.869 mmol, 0.8 eq.) were weighed
out into a microwave vial. A stir bar was added, the vial was
sealed and sparged with nitrogen. Then, 1,4-dioxane (10.8 mL) and
trans-N,N'-dimethylcyclohexane-1,2-diamine (0.108 mmol, 15.4 mg,
0.1 eq.) were added and the mixture was stirred at 90.degree. C.
for 16 hours. The reaction mixture was then cooled to ambient
temperature, sat. NaHCO.sub.3 solution and DCM were added, and the
mixture was filtered through a hydrophobic frit. The organic
solvent was then removed under reduced pressure, and the crude
material was purified via silica gel chromatography to yield 160.0
mg (31%) of
trans-{1-[1-(4-Fluoro-phenyl)-1H-indazol-5-yl]-5-oxo-2-ethyl-pyrrolidin-3-
-yl}-carbamic acid benzyl ester and 70.0 mg (14%) of
cis-{1-[1-(4-Fluoro-phenyl)-1H-indazol-5-yl]-5-oxo-2-ethyl-pyrrolidin-3-y-
l}-carbamic acid benzyl ester.
Synthesis of benzyl
(trans-2-(5-chlorothiophen-2-yl)-5-oxopyrrolidin-3-yl)carbamate
(Intermediate A19-Cbz)
##STR00038##
[0478] Step 1:
[0479] To a suspension of 5-chlorothiophene-2-carbaldehyde (60 g,
409.30 mmol), p-thiocresol (50.7 g, 409.30 mmol) and maleic
anhydride (40.13 g, 409.30 mmol) in toluene (1 L) was added
(2,4-dimethoxyphenyl)methan-amine (68.81 g, 409.30 mmol) at ambient
temperature. The resulting mixture was refluxed using a Dean-Stark
trap for 16 h and was then concentrated. The crude product was
purified via silica-gel (100-200 mesh) column chromatography using
50% EtOAc in pet-ether as an eluent to afford 110 g (52%) of
2-(5-chlorothiophen-2-yl)-1-(2,4-dimethoxybenzyl)-5-oxo-3-(p-tol-
ylthio)pyrrolidine-3-carboxylic acid as a brown solid (TLC system:
EtOAc/pet ether (3:7), Rf: 0.1).
[0480] Step 2:
[0481] To a suspension of
2-(5-chlorothiophen-2-yl)-1-(2,4-dimethoxybenzyl)-5-oxo-3-(p-tolylthio)py-
rrolidine-3-carboxylic acid (95 g, 183.7 mmol) and K.sub.2CO.sub.3
(101.4 g, 735 mmol) in acetone (1.2 L) was added methyl iodide
(47.4 mL, 735 mmol) at 0.degree. C. The resulting mixture was
allowed to stir at ambient temperature for 16 h, was then filtered
and the filtrate was concentrated. The crude product was purified
via silica-gel (100-200 mesh) column chromatography using 5-10%
EtOAc in pet-ether as an eluent to afford 79 g (81%) of methyl
2-(5-chlorothiophen-2-yl)-1-(2,4-dimethoxybenzyl)-5-oxo-3-(p-tolylthio)py-
rrolidine-3-carboxylate as a colorless gummy liquid (TLC system:
EtOAc/pet ether (3:7), Rf 0.44).
[0482] Step 3:
[0483] To a solution of methyl
2-(5-chlorothiophen-2-yl)-1-(2,4-dimethoxybenzyl)-5-oxo-3-(p-tolylthio)py-
rrolidine-3-carboxylate (33 g, 62.14 mmol) in toluene (700 mL) were
added AIBN (5.09 g, 31.07 mmol) and tristrimethylsilyl silane (30.9
g, 124.29 mmol). The resulting mixture was refluxed for 16 h and
was then concentrated. The crude product was triturated with pet
ether; the resulting solid was filtered off and dried under vacuum
to give 20 g (80%) of methyl
2-(5-Chlorothiophen-2-yl)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carb-
oxylate as an off white solid (TLC system: EtOAc/pet ether (5:5),
R.sub.f: 0.5).
[0484] Step 4:
[0485] A solution of methyl
2-(5-Chlorothiophen-2-yl)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carb-
oxylate (10 g, 24.44 mmol) in TFA (100 mL) was stirred at
80.degree. C. for 16 h. The reaction mass was concentrated. The
residue was basified with sat. NaHCO.sub.3 to pH 8, and extracted
with EtOAc (2.times.500 mL). The combined organic layers were
washed with brine (500 mL), dried over Na.sub.2SO.sub.4, and
concentrated. The residue was triturated with n-pentane to give 5 g
of crude product of methyl
2-(5-chlorothiophen-2-yl)-5-oxopyrrolidine-3-carboxylate as an off
white solid (TLC system: EtOAc/pet ether (5:5), R.sub.f: 0.5).
[0486] Step 5:
[0487] A mixture of methyl
2-(5-chlorothiophen-2-yl)-5-oxopyrrolidine-3-carboxylate (5 g, 19.3
mmol) and 2 N NaOH (15 mL) in methanol (100 mL) was stirred at
80.degree. C. for 4 h. The reaction mixture was then concentrated
and triturated with diethyl ether twice. The residue was taken up
in cold water (100 mL) and acidified with 6 N HCl to pH 2 followed
by extraction with EtOAc (2.times.500 mL). The combined organic
layers were then dried over Na.sub.2SO.sub.4 and concentrated to
afford 3.7 g (78%) of
trans-5-oxo-2-(5-chlorothiophen-2-yl)pyrrolidine-3-carboxylic acid
as a solid (TLC system: EtOAc/pet-ether (6:4), R: 0.1).
[0488] Step 6:
[0489] To a solution of
trans-5-oxo-2-(5-chlorothiophen-2-yl)pyrrolidine-3-carboxylic acid
(12 g, 48.97 mmol) in benzene-THF (240 mL and 120 mL) were added
DPPA (13.6 mL, 63.66 mmol) and triethylamine (8.8 mL, 63.66 mmol).
The resulting mixture was stirred at ambient temperature for 3 h,
prior to the addition of benzyl alcohol (6.6 mL, 63.66 mmol). The
resulting mixture was then heated to 80.degree. C. for 16 h. The
reaction mixture was cooled to ambient temperature, diluted with
water (500 mL) and extracted with EtOAc (2.times.500 mL). The
combined organic layers were dried over Na.sub.2SO.sub.4 and
concentrated. The crude product was purified via silica-gel
(100-200 mesh) column chromatography using 40-50% EtOAc in
pet-ether as an eluent to afford 6.3 g (36%) of benzyl
(trans-2-(5-chlorothiophen-2-yl)-5-oxopyrrolidin-3-yl)carbamate as
an off white solid (TLC system: EtOAc/pet-ether (6:4), Rf 0.4).
Synthesis of
trans-N-(1-(1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)-2,2-difluorop-
ropanamide (Intermediate B1)
##STR00039##
[0491] Step 1:
[0492] A stirred solution of intermediate A2 (1.2 g, 4.477 mmol,
1.0 eq), 5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.8 g,
5.373 mmol, 1.2 eq) and K.sub.3PO.sub.4 (1.9 g, 8.955 mmol, 2.0 eq)
in 1,4-dioxane (20 mL) was degassed with argon for 30 min. Then
trans-N,N'-dimethylcyclohexane-1,2-diamine (0.3 g, 1.791 mmol, 0.4
eq) and CuI (0.2 g, 0.985 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, Rf-0.5), 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
desired
trans-2,2-difluoro-N-(5-oxo-2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-i-
ndazol-5-yl)pyrrolidin-3-yl)propanamide (1.5 g, 72%).
[0493] Step 2:
[0494] To a stirred solution of
trans-2,2-difluoro-N-(5-oxo-2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-i-
ndazol-5-yl)pyrrolidin-3-yl)propanamide (1.5 g, 3.20 mmol, 1.0 eq)
in DCM (20 mL), TFA (15 mL) was added at 0.degree. C. and the
reaction was stirred for 16 h at ambient temperature. After
completion of the reaction, (monitored by TLC, TLC system 5% MeOH
in DCM, Rf-0.3), the reaction mixture was concentrated and basified
with NaHCO.sub.3 solution. The aqueous phase was extracted with DCM
(3.times.100 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford
trans-N-(1-(1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)-2,2-difluorop-
ropanamide (1.1 g, 89%) as a solid.
Synthesis of 1-(4,4-difluorocyclohexyl)-5-iodo-1H-indazole
(Intermediate C1)
##STR00040##
[0496] To a stirred solution of 5-iodo-1H-indazole (1.00 g, 4.09
mmol, 1.0 eq) in THF (20 mL), DIAD (1.2 mL, 6.15 mmol, 1.5 eq) and
Ph.sub.3P (1.60 g, 6.15 mmol, 1.5 eq) were added at 0.degree. C.
Then, 4,4-difluoro-cyclohexanol (0.84 g, 6.15 mmol, 1.5 eq) was
added at 0.degree. C. and the reaction mixture was stirred at
ambient temperature for 16 h in the following. After completion of
the reaction (monitored by TLC, TLC system 20% EtOAc in hexane,
Rf-0.3), the reaction mixture was diluted with EtOAc (35 mL),
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 as a mixture of regioisomers which was purified and
separated by column chromatography (230-400 mesh silica gel; 0 to
20% EtOAc in hexane) to afford
1-(4,4-difluorocyclohexyl)-5-iodo-1H-indazole (0.10 g, 7%).
Synthesis of 1-cyclohexyl-5-iodo-1H-indazole (Intermediate C2)
##STR00041##
[0498] Starting from cyclohexanol, intermediate C2 was synthesized
in analogy to the synthetic procedure described for intermediate
C1.
Synthesis of 1-(2-fluorobenzyl)-5-iodo-1H-indazole (Intermediate
C3)
##STR00042##
[0500] To a stirred solution of 5-iodo-1H-indazole (1.00 g, 4.099
mmol, 1.0 eq) in THF (10 mL) NaH (0.24 g, 4.917 mmol, 1.2 eq) was
added at 0.degree. C. under a N.sub.2 atmosphere. After 10 min,
1-(bromomethyl)-2-fluorobenzene (0.93 g, 4.917 mmol, 1.2 eq) was
added at ambient temperature. The reaction mixture was stirred for
1 h at ambient temperature. After completion of the reaction
(monitored by TLC, 20% EtOAc in hexane, Rf-0.6) the reaction
mixture was quenched with ice cold water (20 mL) and extracted with
EtOAc (3.times.20 ml), dried over Na.sub.2SO.sub.4 and was then
concentrated under reduced pressure. The crude product was purified
by column chromatography (using 230-400 silica gel) to separate the
two isomers. The major isomer was the desired
1-(2-fluorobenzyl)-5-iodo-1H-indazole which was confirmed by
.sup.1H-NMR to afford intermediate C3 (0.57 g, 40%).
Synthesis of 1-(3-fluorobenzyl)-5-iodo-1H-indazole (Intermediate
C4)
##STR00043##
[0502] To a stirred solution of 5-iodo-1H-indazole (1.00 g, 4.099
mmol, 1.0 eq) in THF (20 mL) NaH (0.24 g, 4.917 mmol, 1.2 eq) was
added at 0.degree. C. under a N.sub.2 atmosphere. After 10 min,
1-(bromomethyl)-3-fluorobenzene (0.93 g, 4.917 mmol, 1.2 eq) was
added. The reaction mixture was stirred for 1 h at ambient
temperature. After completion of the reaction (monitored by TLC,
20% EtOAc in hexane, Rf-0.6), the reaction mixture was quenched
with ice cold water (20 mL) and extracted with EtOAc (3.times.20
ml), dried over Na.sub.2SO.sub.4 and was then concentrated. The
crude product was purified by column chromatography (using 230-400
silica gel) to separate the two isomers. The major isomer was the
desired 1-(3-fluorobenzyl)-5-iodo-1H-indazole which was confirmed
by .sup.1H-NMR to afford intermediate C4 (0.61 g, 42%).
Synthesis of 1-(4-fluorobenzyl)-5-iodo-1H-indazole (Intermediate
C5)
##STR00044##
[0504] To a stirred solution of 5-iodo-1H-indazole (1.00 g, 4.099
mmol, 1.0 eq) in THF (10 mL) NaH (0.24 g, 4.9174 mmol, 1.2 eq) was
added at 0.degree. C. under a N.sub.2 atmosphere. After 10 min,
1-(bromomethyl)-4-fluorobenzene (0.93 g, 4.917 mmol, 1.2 eq) was
added. The reaction mixture was stirred for 1 h at ambient
temperature. After completion of the reaction (monitored by TLC,
20% EtOAc in hexane, Rf-0.6), the reaction mixture was quenched
with ice cold water (20 mL) and extracted with EtOAc (3.times.20
mL), dried over Na.sub.2SO.sub.4 and was then concentrated to give
the crude product which was purified by column chromatography
(using 230-400 silica gel) to separate the two isomers. The major
isomer was the desired 1-(4-fluorobenzyl)-5-iodo-1H-indazole which
was confirmed by .sup.1H-NMR to afford intermediate C5 (0.54 g,
37%).
Synthesis of 1-(cyclopropylmethyl)-5-iodo-1H-indazole (Intermediate
C6)
##STR00045##
[0506] To an ice cooled stirred solution of 5-iodo-1H-indazole
(1.00 g, 4.09 mmol, 1.0 eq) in DMF (20 mL), NaH (0.23 g, 4.91 mmol,
1.2 eq, 50% by wt) was added and the reaction mixture was stirred
for 15 min. Bromomethyl-cyclopropane (0.43 ml, 4.50 mmol, 1.1 eq)
was dissolved in DMF (10 mL) and was then added dropwise at
0.degree. C. The reaction mixture was then heated to 100.degree. C.
for 16 h. The reaction mixture was next diluted with EtOAc and
washed with water. The combined organic layers were concentrated
under reduced pressure to get the crude product which was purified
by column chromatography (100-200 mesh silica gel; 50%
EtOAc/Hexane; R.sub.f-value-0.5) to separate the two isomers. The
major isomer was the desired
1-(cyclopropylmethyl)-5-iodo-1H-indazole which was confirmed by
.sup.1H-NMR to afford intermediate C6 (0.60 g, 50%).
Synthesis of 1-((4,4-difluorocyclohexyl)methyl)-5-iodo-1H-indazole
(Intermediate C7)
##STR00046##
[0508] Step 1:
[0509] To a stirred solution of (4,4-difluorocyclohexyl)methanol
(2.00 g, 14.372 mmol, 1.0 eq) in DCM (20 mL), PBr.sub.3 (1.63 mL,
17.247 mmol, 1.2 eq) was added at 0.degree. C. and the reaction
mixture was then stirred at ambient temperature for 2 h. After
completion of the reaction (monitored by TLC, TLC system 5% MeOH in
DCM, Rf-0.3), the reaction was quenched with NaHCO.sub.3 solution
(150 mL), extracted with DCM (3.times.150 mL), dried over
Na.sub.2SO.sub.4 and concentrated to get
4-(bromomethyl)-1,1-difluorocyclohexane (2.80 g, 96%).
[0510] Step 2:
[0511] To a stirred solution of 5-iodo-1H-indazole (0.83 g, 5.396
mmol, 0.8 eq) in DMF (15 mL) NaH (0.25 mg, 3.396 mmol, 1.2 eq, 50%
by wt) was added at 0.degree. C., followed by the addition of
4-(bromomethyl)-1,1-difluorocyclohexane (0.90 g, 4.245 mmol, 1.0
eq) and the reaction mixture was stirred at ambient temperature for
16 h. After completion of the reaction (monitored by TLC, TLC
system 5% MeOH/DCM, Rf-0.4), the reaction mixture was quenched with
ice cold water (50 mL), extracted with EtOAc (3.times.50 mL),
washed with brine (50 mL), dried over Na.sub.2SO.sub.4 and was then
concentrated under reduced pressure to get the crude product which
was purified by column chromatography (230-400 mesh silica gel; 0
to 3% MeOH-DCM) to separate the two isomers. The major isomer was
the desired 1-((4,4-difluorocyclohexyl)methyl)-5-iodo-1H-indazole
which was confirmed by .sup.1H-NMR to afford intermediate C7 (0.54
g, 32%).
Synthesis of 5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine
(Intermediate C8)
##STR00047##
[0513] Step 1:
[0514] A mixture of 5-bromo-2-fluoro-pyridine-3-carbaldehyde (200.0
mg, 0.980 mmol, 1.0 eq.) and (4-fluorophenyl)hydrazine
hydrochloride (159.4 mg 0.980 mmol, 1.0 eq.) in NMP (3.0 mL) was
stirred at ambient temperature for two hours, before caesium
carbonate (958.3 mg, 2.941 mmol, 3.0 eq.) was added and the mixture
was heated to 115.degree. C. for 1 hour. The mixture was cooled to
ambient temperature, and was diluted with water/EtOAc. The layers
were separated, and the aqueous layer was extracted two more times
with EtOAc. The combined organic layers were then washed with brine
and were dried over MgSO.sub.4. The solvent was removed under
reduced pressure and the remains were purified using silica gel
chromatography to obtain 184.4 mg (64%) of
5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine.
Synthesis of 5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine
(Intermediate C9)
##STR00048##
[0516] 5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine was
prepared in analogy to
5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine, using
2-bromo-5-fluoroisonicotinaldehyde instead of
5-bromo-2-fluoro-pyridine-3-carbaldehyde. Yield: 47%
Synthesis of
(trans)-4-amino-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(1-(4-fluorophe-
nyl)-1H-indazol-5-yl)pyrrolidin-2-one (Intermediate D1)
##STR00049## ##STR00050##
[0518] Step 1:
[0519] To a stirred solution of furan-2,5-dione (2.98 g, 30.46
mmol, 1.0 eq), 4-methylbenzenethiol (3.78 g, 30.46 mmol, 1.0 eq)
and 2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (5.00 g, 30.46
mmol, 1.0 eq) in dry toluene (100 mL) was added benzyl amine (3.25
g, 30.46 mmol, 1.0 eq) at ambient temperature under a N.sub.2
atmosphere and the reaction mixture was stirred at 111.degree. C.
for 24 hours. After completion of the reaction (monitored by TLC),
the solvent was removed in vacuo and the residue was dissolved in
acetone (100 mL), followed by the addition of K.sub.2CO.sub.3
(16.81 g, 121.83, mmol, 4.0 eq) and methyl iodide (17.29 g, 121.83
mmol, 4.0 eq) at 0.degree. C. The reaction mixture was slowly
warmed to ambient temperature and was stirred overnight. After the
solvent was removed under reduced pressure, water was added and
extraction with EtOAc was performed. The organic layer was washed
with water and brine, dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure. The crude residue was purified by column
chromatography (silicagel, 10-50% EtOAc in hexane) to afford methyl
1-benzyl-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxo-3-(p-tolylthio)pyr-
rolidine-3-carboxylate as a pale yellow liquid. (3.0 g, 21%).
[0520] Step 2:
[0521] To a stirred solution of methyl
1-benzyl-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxo-3-(p-tolylthio)pyr-
rolidine-3-carboxylate (7.0 g, 14.31 mmol, 1.0 eq) in a 1:2 mixture
of THF:EtOH (656 mL) was added Raney Nickel (49.0 g) at room
temperature under a N.sub.2 atmosphere and the reaction mixture was
stirred at ambient temperature for 48 hours. The reaction mixture
was filtered through celite, and the solvent was removed in vacuo.
The reaction mixture was then diluted with water and extracted with
EtOAc. The organic layer was washed with water and brine, dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure to
afford the product as a racemic mixture of
methyl-1-benzyl-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidine--
3-carboxylate as a white solid. (5.0 g, 53%).
[0522] Step 3:
[0523] To a stirred solution of
methyl-1-benzyl-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidine--
3-carboxylate (12.0 g, 32.66 mmol, 1.0 eq) in a 1:1 mixture of
t-butyl alcohol and THF (1.2 L), was added KOtBu (1.1 g, 10.19
mmol, 0.3 eq) at room temperature under N.sub.2 atmosphere and then
the reaction mixture was stirred at ambient temperature overnight.
The solvent was then removed in vacuo, and the crude product was
used in the next step without purification. (Yield: 12 g crude
material).
[0524] Step 4:
[0525] To a stirred solution of methyl
trans-5-oxo-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrrolidine-3-carboxyl-
ate (5.0 g, 8.98 mmol, 1.0 eq) in MeOH (50 mL), IM LiOH (15.71 ml,
15.72 mmol, 1.75 eq) was added at room temperature under a N.sub.2
atmosphere and then the reaction mixture was stirred at room
temperature for 6 hours. After completion of the reaction
(monitored by TLC), the solvent was removed in vacuo. The reaction
mixture was cooled to 0.degree. C. and diluted with water.
Adjustment of the pH to 4 with 1N HCl, caused a solid to slowly
precipitate out. This precipitate was filtered and dried in vacuo
to afford
trans-5-oxo-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrrolidine-3-carboxyl-
ic acid as a white solid. (3.3 g).
[0526] Step 5:
[0527] To a stirred solution of
trans-5-oxo-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrrolidine-3-carboxyl-
ic acid (8.0 g, 22.64, mmol, 1.0 eq) in t-BuOH (50.3 g, 679.17
mmol, 30.0 eq), TEA (2.7 g, 27.17 mmol, 1.2 eq) and DPPA (7.5 g,
27.17 mmol, 1.2 eq) were added at 0.degree. C. under a N.sub.2
atmosphere and then the reaction mixture was stirred at 82.degree.
C. for 1 hour, followed by heating to 100.degree. C. for 5 hours.
The reaction progress was monitored by TLC and upon completion, the
solvent was removed in vacuo. The reaction mixture was cooled to
ambient temperature, diluted with saturated NaHCO.sub.3 and
extracted with EtOAc. The organic layer was washed with water and
brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The crude residue was purified using column
chromatography (silicagel, 10-40% EtOAc in hexane) to afford
tert-butyl
((trans)-1-benzyl-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidin-
-3-yl)carbamate as a white solid. (6.0 g, 63%).
[0528] Step 6:
[0529] In a round-bottom flask containing tert-butyl
((trans)-1-benzyl-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidin-
-3-yl)carbamate (2.0 g, 4.71 mmol, 1.0 eq) in dry THF (81.4 ml),
anhydrous ammonia was condensed at -70.degree. C., sodium (2 g) was
added to the reaction mixture. Stirring was continued at the same
temperature for 30 minutes. At -70.degree. C., solid NH.sub.4Cl was
added to the reaction mixture, which was then slowly warmed to
0.degree. C. The residue was treated with saturated NH.sub.4Cl
solution, warmed to room temperature and extracted with
dichloromethane (3.times.30 mL). The organic extracts were dried
over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The crude residue was purified by column chromatography
(silicagel, 0-70% EtOAc in hexane) to afford tert-butyl
((trans)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidin-3-yl)car-
bamate as a white solid (0.65 g, 41%).
[0530] Step 7:
[0531] To a sealed vial containing tert-butyl
((trans)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidin-3-yl)car-
bamate (100 mg, 0.30 mmol, 1.00 eq), 2,2'-bipyridyl (33 mg, 0.21
mmol, 0.70 eq) and potassium phosphate (130 mg, 0.60 mmol, 2.00 eq)
were added dimethylsulfoxid (2.1 mL) and
1-(4-fluorophenyl)-5-iodo-indazole (150 mg, 0.45 mmol, 1.50 eq) and
the mixture was degassed under a nitrogen atmosphere. After ca. 2
min, copper(I)iodide (2.3 mg, 0.01 mmol, 0.04 eq) was added and the
sealed vial was degassed once more. The resulting mixture was
stirred overnight at 110.degree. C. Then, DCM and a saturated
sodium bicarbonate solution were added, the phases were separated
via a hydrophobic frit, and the organic solvent was removed under
reduced pressure. The crude residue was purified by column
chromatography, followed by preparative HPLC to afford tert-butyl
((trans)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(2,3-dihydrobenzo[b][1,-
4]dioxin-6-yl)-5-oxopyrrolidin-3-yl)carbamate (22 mg, 13%).
[0532] Step 8:
[0533] A solution of tert-butyl
((trans)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(2,3-dihydrobenzo[b][1,-
4]dioxin-6-yl)-5-oxopyrrolidin-3-yl)carbamate (21.0 mg, 0.039 mmol,
1.0 eq) in ethanol (0.45 ml) was cooled to 0.degree. C., and
acetylchloride (0.014 mL, 0.193 mmol, 5.0 eq) was added dropwise.
Then, the ice bath was removed, and the reaction mixture was
stirred at 40.degree. C. for 3 hours. Then, the mixture was allowed
to cool to ambient temperature, and was stirred overnight. The
solvent was then removed under reduced pressure to yield crude
(trans)-4-amino-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(1-(4-fluorophe-
nyl)-1H-indazol-5-yl)pyrrolidin-2-one (Intermediate D1, 15.0 mg,
81%).
Synthesis of
(trans)-4-Amino-1-[1-(4-fluoro-phenyl)-1H-indazol-5-yl]-5-phenyl-pyrrolid-
ine-2-one (Intermediate D2)
##STR00051##
[0535] Step 1:
[0536] To a stirred solution of benzyl
N-[(trans)-2-phenyl-5-oxo-pyrrolidin-3-yl]carbamate (intermediate
A2-Cbz)(1.0 g, 3.22 mmol, 1.0 eq) and
1-(4-fluoro-phenyl)-5-iodo-1H-indazole (1.1 g, 3.22 mmol, 1.0 eq)
in 1,4-dioxane (80 mL) in a sealed tube was added potassium
phosphate (1.4 g, 6.44 mmol, 2.0 eq) followed by
trans-N,N'-dimethylcyclohexane-1,2-diamine (1.02 ml, 0.644 mmol,
0.2 eq). The reaction mixture was degassed under an argon
atmosphere for 30 minutes. CuI (61.3 mg, 0.322 mmol, 0.1 eq) was
added and the reaction was heated to 90.degree. C. for 16 hours
(monitored by LCMS). The reaction mixture was filtered through a
bed of celite and the celite bed was washed with ethyl acetate (500
mL), the combined filtrate was concentrated under reduced pressure
and was purified by column chromatography (100-200 silica gel,
30-40% ethyl acetate-hexane as eluent) to afford trans
{1-[1-(4-Fluoro-phenyl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl}--
carbamic acid benzyl ester (0.70 g, 42%)
[0537] Step 2:
[0538] To a stirred solution of trans
{1-[1-(4-Fluoro-phenyl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl}--
carbamic acid benzyl ester (18.0 g, 34.58 mmol) in THF (800 mL) was
added 10% Pd/C (50% moist, 40 g) and the reaction mixture was then
stirred under a H.sub.2 balloon until completion (monitored by
TLC). The reaction mixture was filtered through a celite bed and
the celite bed was washed with THF. The filtrate was concentrated
and triturated with DCM-pentane to afford trans
4-amino-1-[1-(4-fluoro-phenyl)-1H-indazol-5-yl]-5-phenyl-pyrrolidine-2-on-
e as an off-grey solid (10.8 g, 81%).
[0539] The racemic intermediate D2 can be separated by chiral HPLC
using the following conditions: column: CHIRALPAK AD-H
(4.6.times.2500) mm, mobile Phase: MeOH (100%), temperature:
40.degree. C.
Using those conditions, intermediate D2-ent1 (retention time: 6.15
minutes) and intermediate D2-ent2 (retention time: 9.31 minutes)
can be obtained.
Synthesis of
(trans)-4-amino-5-(3-chlorophenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-
pyrrolidin-2-one (Intermediate D6)
##STR00052##
[0541] Step 1:
[0542] (2,4-dimethoxyphenyl)methyl
N-[(trans)-2-(3-chlorophenyl)-5-oxo-pyrrolidin-3-yl]carbamate
(intermediate A1', 500 mg, 1.235 mmol, 1.00 eq),
1-(4-fluorophenyl)-5-iodo-indazole (438 mg, 1.297 mmol, 1.05 eq),
potassium phosphate (524 mg, 2.470 mmol, 2.00 eq) and CuI (12 mg,
0.062 mmol, 0.05 eq) were weighed into a vial. The reaction mixture
was then degassed under a nitrogen atmosphere. Then, 1,4-dioxane (5
mL) and trans-N,N'-dimethylcyclohexane-1,2-diamine (14 mg, 0.124
mmol, 0.1 eq) were added, and the reaction mixture was heated to
115.degree. C. overnight. The reaction mixture was filtered through
a bed of celite and the celite bed was washed with DCM and the
combined filtrates were concentrated under reduced pressure. The
crude residue was purified by column chromatography (silicagel,
cHex/EtOAc) to afford trans
{1-[1-(4-Fluoro-phenyl)-1H-indazol-5-yl]-5-oxo-2-(3-chlorophenyl)pyrrolid-
in-3-yl}-carbamic acid 2,4-dimethoxybenzyl ester (590 mg, 78%).
[0543] Step 2:
[0544] A solution of trans
{l-[1-(4-Fluoro-phenyl)-1H-indazol-5-yl]-5-oxo-2-(3-chlorophenyl)pyrrolid-
in-3-yl}-carbamic acid 2,4-dimethoxybenzyl ester (590 mg, 0.959
mmol, 1.0 eq) was stirred at ambient temperature. After completion
of the reaction (monitored by LCMS), the reaction mixture is cooled
to 0.degree. C. and was quenched with saturated sodium bicarbonate
solution. Extraction with DCM is then followed by washing of the
combined organic layers with saturated sodium bicarbonate solution
and drying over magnesium sulfate. After filtration, the solution
is concentrated under reduced pressure to afford
(trans)-4-amino-5-(3-chlorophenyl)-1-(1-(4-fluorophenyl)-1H-indazo-
l-5-yl)pyrrolidin-2-one (intermediate D6, 338 mg, 84%).
Synthesis of
(4S,5R)-4-amino-5-benzyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)pyrrolidin-
-2-one (Intermediate D8)
##STR00053##
[0546] Step 1:
[0547] Tert-butyl ((2R,3S)-2-benzyl-5-oxopyrrolidin-3-yl)carbamate
(300 mg, 1.033 mmol, 1.0 eq.), 1-(4-fluorophenyl)-5-iodo-indazole
(366.8 mg, 1.085 mmol, 1.05 eq.), K.sub.3PO.sub.4 (438.6 mg, 2.066
mmol, 2.0 eq.) copper iodide (157.4 mg, 0.826 mmol, 0.8 eq.) and
trans-N,N'-dimethylcyclohexane-1,2-diamine (14.7 mg, 0.103 mmol,
0.1 eq.) were weighed out into a microwave vial. A stir bar was
added, the vial was sealed and sparged with nitrogen. Then,
1,4-dioxane (5.2 mL) was added, and the mixture was heated to
100.degree. C. for 22 hours under microwave irradiation. Then, the
temperature was raised to 120.degree. C. for 16 hours. The reaction
mixture was cooled to ambient temperature, and sat. NaHCO.sub.3
solution and DCM were added. The mixture was filtered through a
hydrophobic frit, and the organic solvent was then evaporated. The
crude remains were purified using silica gel chromatography to
yield 180.0 mg (35%) of tert-butyl
((2R,3S)-2-benzyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin--
3-yl)carbamate.
[0548] Step 2:
[0549] Tert-butyl
((2R,3S)-2-benzyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin--
3-yl)carbamate (180.0 mg, 0.360 mmol, 1.0 eq.) was dissolved in
ethanol (3.6 mL) and the mixture was cooled to 0.degree. C. Then,
acetyl chloride (0.26 mL, 3.596 mmol, 10 eq.) was added, and the
reaction mixture was stirred at ambient temperature for 16 hours.
Then, acetyl chloride (0.26 mL, 3.596 mmol, 10 eq.) and a drop of
water were added, and the mixture was stirred for another 24 hours.
The reaction mixture was then evaporated to dryness to yield 93.0
mg (53%) of
(4S,5R)-4-amino-5-benzyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)pyrrolidin-
-2-one (intermediate D8).
Synthesis of
cis-4-amino-5-(cyclopropylmethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)p-
yrrolidin-2-one Intermediate D9)
##STR00054##
[0551] Step 1:
[0552]
Cis-5-(Cyclopropylmethyl)-4-((4-methoxybenzyl)amino)pyrrolidin-2-on-
e (200.0 mg, 0.729 mmol, 1.0 eq.),
5-bromo-1-(4-fluorophenyl)indazole (318.3 mg, 1.093 mmol, 1.5 eq.),
caesium carbonate (475.0 mg, 1.458 mmol, 2.0 eq.), Xantphos (63.2
mg, 0.109 mmol, 0.15 eq.), and Pd.sub.2dba.sub.3 (33.3 mg, 0.036
mol, 0.05 eq.) were weighed out into a microwave vial, a stir bar
was added, the vial was sealed and purged with nitrogen.
1,4-dioxane (7.5 mL) was then added, and the mixture was heated to
90.degree. C. for 48 h. The reaction mixture was then cooled to
ambient temperature, was then filtered and the solvent was removed
under reduced pressure. The crude remains were then purified via
silica gel chromatography to yield 150.0 mg of
cis-5-(cyclopropylmethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-((4-me-
thoxybenzyl)amino)pyrrolidin-2-one.
[0553] Step 2:
[0554]
Cis-5-(cyclopropylmethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4--
((4-methoxybenzyl)amino)-pyrrolidin-2-one (118.0 mg, 0.244 mmol,
1.0 eq.) was dissolved in ethanol (23.6 mL) and ethyl acetate (23.6
mL). The mixture was then hydrogenated using flow hydrogenation (up
to 10 bar H.sub.2-pressure). The remains were evaporated to dryness
to obtain 81.8 mg (92%) of
cis-4-amino-5-(cyclopropylmethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)p-
yrrolidin-2-one (intermediate D9).
[0555] The intermediates in Table 1 were synthesized in analogy to
the examples described above, using the starting material specified
below.
TABLE-US-00001 Intermediate Structure In analogy to Starting
material Intermediate D3 ##STR00055## Intermediate D2 intermediate
A16- Cbz Intermediate D4 ##STR00056## Intermediate D2 intermediate
A8- Cbz Intermediate D5 ##STR00057## Intermediate D2 intermediate
A5-Cbz Intermediate D7 ##STR00058## Intermediate D1 Intermediate
A12- Boc
EXAMPLE 1:
N-(TRANS-2-(2,3-DIHYDROBENZO[B][1,4]DIOXIN-6-YL)-1-(1-(4-FLUORO-
PHENYL)-1H-INDAZOL-5-YL)-5-OXOPYRROLIDIN-3-YL)-2,2-DIFLUOROPROPANAMIDE
##STR00059##
[0557] 2,2-difluoropropanoic acid (8.6 mg, 0.078 mmol, 2.0 eq) was
weighed out into a vial, followed by the addition of
(trans)-4-amino-5-(2,3-dihydrobenzo[b][,4]dioxin-6-yl)-1-(1-(4-fluorophen-
yl)-1H-indazol-5-yl)pyrrolidin-2-one (intermediate D1, 19.0 mg,
0.039 mmol, 1.0 eq) in dichloromethane (0.19 mL), followed by the
addition of triethylamine (0.011 mL, 0.078 mmol, 2.0 eq) at ambient
temperature. Propylphosphonic anhydride solution (.gtoreq.50 wt. %
in ethyl acetate, 0.046 mL, 0.078 mmol, 2.0 eq) was then added, and
the reaction mixture was stirred overnight. After 16 hours, the
reaction mixture was diluted with sat. NaHCO.sub.3 solution and
DCM. The resulting mixture was stirred for another 30 minutes,
before being filtered through a hydrophobic frit. The solvent was
removed under reduced pressure and the residue was purified by
column chromatography and later HPLC to give example 1 (14.0 mg,
67%).
[0558] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.43 (d, 1H), 8.32 (d,
1H), 7.89 (d, 1H), 7.78-7.74 (m, 2H), 7.73 (d, 1H), 7.64 (dd, 1H),
7.46-7.35 (m, 2H), 6.87-6.74 (m, 3H), 5.22 (d, 1H), 4.30-4.20 (m,
1H), 4.19-4.15 (m, 4H), 3.09 (dd, 1H), 2.60 (dd, 1H), 2.07 (s, 1H),
1.79 (t, 3H).
EXAMPLE 2:
2,2-DIFLUORO-N-((2R,3S)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)--
5-OXO-2-PHENYLPYRROLIDIN-3-YL)PROPANAMIDE
##STR00060##
[0560] Step 1:
[0561] To a stirred solution of intermediate A2 (1.0 g, 5.68 mmol,
1.0 eq) in DMF (20 mL), HATU (3.2 g, 8.52 mmol, 1.5 eq), DIPEA (4.9
mL, 28.40 mmol, 5.0 eq) and 2,2-difluoro-propionic acid (0.8 g,
7.38 mmol, 1.3 eq) were added. The reaction mixture was then
stirred for 16 h at ambient temperature. After completion, the
reaction mixture was diluted with EtOAc and was washed with ice
cold water, sat. NaHCO.sub.3 and sat. NH.sub.4Cl solution. The
combined organic layers were 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-2,2-difluoro-N-(5-oxo-2-phenylpyrrolidin-3-yl)propanamide
(1.4 g, 93%).
[0562] Step 2:
[0563] A stirred solution of
trans-2,2-difluoro-N-(5-oxo-2-phenylpyrrolidin-3-yl)propanamide
(0.50 g, 1.86 mmol, 1.0 eq), 1-(4-fluorophenyl)-5-iodo-1H-indazole
(0.75 g, 2.23 mmol, 1.2 eq) and K.sub.3PO.sub.4 (0.79 g, 3.73 mmol,
2.0 eq) in 1,4-dioxane (20 mL) was degassed with argon for 15 min.
Then, trans-N,N'-dimethylcyclohexane-1,2-diamine (0.10 g, 0.75
mmol, 0.4 eq) and CuI (0.07 g, 0.37 mmol, 0.2 eq) were added and
the reaction was stirred for 16 h at 90.degree. C. 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 crude product which was
purified by column chromatography (100-200 mesh silica gel; 50%
EtOAc-Hexane; R.sub.f-value-0.5) to afford the racemic product.
Further enantiomer separation was done by chiral preparative HPLC
to afford
2,2-difluoro-N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-ph-
enylpyrrolidin-3-yl)propanamide (0.06 g; RT=4.32 min; Column Name:
Chiralpak IA (250.times.4.6 mm) 5 .mu.m, Mobile Phase:
Hexane/EA/EtOH/DEA: 50/25/25/0.1, Flow Rate: 1.0 ml/min) and
2,2-difluoro-N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-ph-
enylpyrrolidin-3-yl)propanamide (0.05 g; RT=5.20 min; Column Nam:
Chiralpak IA (250.times.4.6 mm) 5 .mu.m, Mobile Phase:
Hexane/EA/EtOH/DEA: 50/25/25/0.1, Flow Rate: 1.0 ml/min).
[0564] .sup.1H NMR (DMSO-d.sub.6) .delta.:9.48 (d, 1H), 8.30 (d,
1H), 7.88 (d, 1H), 7.76-7.72 (m, 2H), 7.71 (d, 1H), 7.64 (dd, 1H),
7.42-7.34 (m, 4H), 7.32 (t, 2H), 7.26-7.22 (m, 1H), 5.32 (d, 1H),
4.34-4.25 (m, 1H), 3.11 (dd, 1H), 2.64 (dd, 1H), 1.79 (t, 3H).
EXAMPLE 4:
2,2-DIFLUORO-N-((2R,3S)-1-(1-(4-FLUOROPHENYL-1H-INDAZOL-5-YL)-2-
-(2-METHOXYPYRIDIN-4-YL)-5-OXOPYRROLIDIN-3-YL)PROPANAMIDE
##STR00061##
[0566] Step 1:
[0567] To a stirred solution of 2,2-difluoropropanoic acid (0.64 g,
5.79 mmol, 1.2 eq) in DMF (10 mL) HATU (3.60 g, 9.65 mmol, 2.0 eq),
DIPEA (4.2 mL, 24.13 mmol, 5.0 eq) and intermediate A9 (1.00 g,
4.83 mmol, 1.0 eq) were added 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, Rf-0.3), the reaction mixture was diluted with EtOAc (25 mL),
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
trans-2,2-difluoro-N-(2-(2-methoxypyridin-4-yl)-5-oxopyrrolidin-3-yl)prop-
anamide (0.76 g, 52%).
[0568] Step 2:
[0569] A stirred solution of
trans-2,2-difluoro-N-(2-(2-methoxypyridin-4-yl)-5-oxopyrrolidin-3-yl)prop-
anamide (0.378 g, 1.263 mmol, 1.0 eq),
1-(4-fluorophenyl)-5-iodo-1H-indazole (0.512 g, 1.515 mmol, 1.2 eq)
and K.sub.3PO.sub.4 (0.535 g, 2.526 mmol, 2.0 eq) in 1,4-dioxane
(25 mL) was degassed with argon for 30 min. Then,
trans-N,N'-dimethylcyclohexane-1,2-diamine (0.071 g, 0.505 mmol,
0.4 eq) and CuI (0.048 g, 0.253 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, Rf-0.1), the reaction mixture was filtered
through a celite bed and the celite bed was washed 2-3 times with
dioxane. The combined organic layers were concentrated under
reduced pressure to get the crude product which was purified by
column chromatography (230-400 mesh silica gel; 0 to 6% MeOH in
DCM) to afford the racemic product. Further enantiomer separation
was done by preparative chiral HPLC to afford pure
2,2-difluoro-N-((2S,3R)-1-(1(4-fluorophenyl)-1H-indazol-5-yl)-2-(2-methox-
ypyridin-4-yl)-5-oxopyrrolidin-3-yl)propanamide (0.057 g, RT=6.16
min; Column Name: Chiralpak IA (250.times.4.6 mm) 5 .mu.m, Mobile
Phase: Hexane/EA/EtOH/DEA: 70/15/15/0.1, Flow Rate: 1.0 ml/min) and
2,2-difluoro-N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(2-metho-
xypyridin-4-yl)-5-oxopyrrolidin-3-yl)propanamide (0.047 g, RT=6.89
min; Column Name: Chiralpak IA (250.times.4.6 mm) 5 .mu.m, Mobile
Phase: Hexane/EA/EtOH/DEA: 70/15/15/0.1, Flow Rate: 1.0
ml/min).
[0570] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.51-9.49 (m, 1H), 8.32
(s, 1H), 8.09 (d, 1H), 7.89 (s, 1H), 7.77-7.72 (m, 3H), 7.67-7.64
(m, 1H), 7.42-7.37 (m, 2H), 7.00 (d, 1H), 6.76 (s, 1H), 5.33-5.32
(m, 1H), 4.31-4.29 (m, 1H), 3.76 (s, 3H), 3.14-3.07 (m, 1H),
2.67-2.62 (m, 1H), 1.84-1.74 (m, 3H).
EXAMPLE 5:
N-(TRANS-2-(2,4-DIFLUOROPHENYL)-1-(1-(4-FLUOROPHENYL)-1H-INDAZO-
L-5-YL)-5-OXOPYRROLIDIN-3-YL)-2,2-DIFLUOROPROPANAMIDE
##STR00062##
[0572] Step 1:
[0573] A solution of intermediate A3 (0.85 g, 4.09 mmol, 1.0 eq) in
DMF (12 mL) was treated with 2,2-difluoropropanoic acid (0.57 g,
5.21 mmol, 1.3 eq) in the presence of HATU (3.04 g, 8.01 mmol, 2.0
eq) and DIPEA (3.5 mL, 20.04 mmol, 2.0 eq) and this mixture was
stirred at ambient temperature for 16 h. After ensuring complete
consumption of starting material as evident from LCMS, the reaction
mixture was partitioned between EtOAc and water. The organic
extracts were washed with brine, dried and concentrated under
reduced pressure to afford the crude product which was purified by
flash column chromatography (230-400 mesh silica gel; 5%
MeOH/EtOAc; R.sub.f-value-0.4) to afford
N-(trans-2-(2,4-difluorophenyl)-5-oxopyrrolidin-3-yl)-2,2-difluoropropana-
mide (0.70 g, 58%) as an off white solid.
[0574] Step 2:
[0575] To a stirring solution of
N-(trans-2-(2,4-difluorophenyl)-5-oxopyrrolidin-3-yl)-2,2-difluoropropana-
mide (0.25 g, 0.82 mmol, 1.0 eq) and
1-(4-fluorophenyl)-5-iodo-1H-indazole (0.28 g, 0.82 mmol, 1.0 eq)
in 1,4-dioxane (4 mL), K.sub.3PO.sub.4 (0.35 g, 1.64 mmol, 2.0 eq),
CuI (0.03 g, 0.16 mmol, 0.2 eq) and
trans-N,N'-dimethylcyclohexane-1,2-diamine (0.05 g, 0.32 mmol, 0.4
eq) were added at ambient temperature under a nitrogen atmosphere
and the mixture was degassed with a stream of nitrogen for 5 min.
The resulting mixture was then heated to 90.degree. C. for 16 h.
The reaction mixture was then allowed to cool to ambient
temperature, was filtered and concentrated to afford the crude
product which was purified by flash column chromatography (230-400
mesh silica gel; 5% MeOH/EtOAc; R.sub.f-value-0.4) to afford
N-(trans-2-(2,4-difluorophenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5--
oxopyrrolidin-3-yl)-2,2-difluoropropanamide (0.15 g, 36%) as an off
white solid.
[0576] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.42 (d, 1H), 8.33 (s,
1H), 7.8 (d, 1H), 7.76-7.71 (m, 3H), 7.51-7.45 (m, 2H), 7.4 (t,
2H), 7.22-7.17 (m, 1H), 7.02-6.98 (m, 1H), 5.50 (d, 1H), 4.49 (m,
1H), 3.15-3.08 (m, 1H), 2.70 (dd, 1H), 1.76 (t, 3H).
EXAMPLE 6:
N-(TRANS-1-(1-(3,4-DIFLUOROPHENYL-1H-INDAZOL-5-YL-5-OXO-2-PHENY-
LPYRROLIDIN-3-YL)-2,2-DIFLUOROPROPANAMIDE
##STR00063##
[0578] To a stirred solution of intermediate B1 (0.200 g, 0.521
mmol, 1.0 eq), (3,4-difluorophenyl)boronic acid (0.165 g, 1.042
mmol, 2.0 eq) and pyridine (0.1 mL, 1.042 mmol, 2.0 eq) in DCM (20
mL), was added Cu(OAc).sub.2 (0.142 g, 0.781 mmol, 1.5 eq) and the
reaction mixture was stirred for 16 h at ambient temperature. After
completion of the reaction (monitored by TLC, TLC system 5% MeOH in
DCM, Rf-0.4), the solvent was removed under reduced pressure, and
the residue was partitioned between DCM and water. The aqueous
layer was extracted twice with DCM (2.times.50 mL). The combined
organic layers were washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated. The crude product was purified by
preparative HPLC to afford
N-(trans-1-(1-(3,4-difluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrroli-
din-3-yl)-2,2-difluoropropanamide (0.051 g, 20%).
[0579] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.50-9.49 (m, 1H), 8.34
(s, 1H), 7.89-7.87 (m, 3H), 7.67-7.60 (m, 3H), 7.36-7.23 (m, 5H),
5.32 (s, 1H), 4.29-4.25 (m, 1H), 3.14-3.07 (m, 1H), 2.65-2.60 (m,
1H), 1.83-1.73 (m, 3H).
EXAMPLE 9:
N-TRANS-(1-(1-(4-FLUOROPHENYL-1H-INDAZOL-5-YL)-5-OXO-2-PHENYLPY-
RROLIDIN-3-YL)CYCLOPROPANESULFONAMIDE
##STR00064##
[0581]
N-trans-(1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrro-
lidin-3-yl)amine (intermediate D2, 144.0 mg, 0.373 mmol, 1.0 eq)
was dissolved in DCM (2.0 mL), and the solution was cooled to
0.degree. C. Triethylamine (0.31 mL, 2.236 mmol, 6.0 eq) was then
added, followed by the dropwise addition of cyclopropanesulfonyl
chloride (0.15 mL, 1.491 mmol, 4.0 eq). The reaction mixture was
then allowed to warm to ambient temperature and was stirred for 72
hours. The reaction mixture was then diluted with water and DCM and
was filtered through a hydrophobic frit. The solvent was removed
under reduced pressure and the remains were purified via column
chromatography to give example 9 (69.4 mg, 38%).
[0582] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.30 (s, 1H), 8.00 (d,
1H), 7.83 (d, 1H), 7.76-7.72 (m, 2H), 7.70 (d, 1H), 7.58 (dd, 1H),
7.42-7.35 (m, 4H), 7.32 (t, 2H), 7.26-7.21 (m, 1H), 5.31 (d, 1H),
4.01-3.92 (m, 1H), 3.15 (dd, 1H), 2.62 (dd, 1H), 2.53-2.45 (m, 1H),
0.96-0.87 (m, 2H), 0.87-0.78 (m, 2H).
EXAMPLE 12:
N-((2R,3S)-2-(3-CHLOROPHENYL)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OX-
OPYRROLIDIN-3-YL)-2,2-DIFLUOROPROPANAMIDE
##STR00065##
[0584] Step 1:
[0585] To a stirred solution of intermediate A1 (0.25 g, 1.19 mmol,
1.0 eq) in DMF (10 mL), were added HATU (0.68 g, 1.78 mmol, 1.5
eq), DIPEA (1.0 mL, 5.95 mmol, 5.0 eq) and 2,2-difluoropropanoic
acid (0.17 g, 1.54 mmol, 1.3 eq) and the reaction mixture was then
stirred for 16 h at ambient temperature. After completion, the
reaction mixture was diluted with EtOAc and was washed with ice
cold water, sat. NaHCO.sub.3 and sat. NH.sub.4Cl solution. The
combined organic layers were concentrated 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
N-(trans-2-(3-chlorophenyl)-5-oxopyrrolidin-3-yl)-2,2-difluoropropanamide
(0.19 g, 53%).
[0586] Step 2:
[0587] A stirred solution of
N-(trans-2-(3-chlorophenyl)-5-oxopyrrolidin-3-yl)-2,2-difluoropropanamide
(0.30 g, 0.99 mmol, 1 eq), 1-(4-fluorophenyl)-5-iodo-1H-indazole
(0.40 g, 1.19 mmol, 1.2 eq) and K.sub.3PO.sub.4 (0.42 g, 1.98 mmol,
2.0 eq) in 1,4-dioxane (20 mL) was degassed with argon for 15 min.
Then, trans-N,N'-dimethylcyclohexane-1,2-diamine (0.06 g, 0.40
mmol, 0.4 eq) and CuI (0.04 g, 0.20 mmol, 0.2 eq) were added and
the reaction mixture was stirred for 16 h at 90.degree. C. 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 crude product which was
purified by column chromatography (100-200 mesh silica gel; 50%
EtOAc-Hexane; R.sub.f-value-0.5) to afford the racemic product.
Further enantiomer separation was done by preparative chiral HPLC
to afford
N-((2S,3R)-2-(3-chlorophenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-ox-
opyrrolidin-3-yl)-2,2-difluoropropanamide (0.07 g; RT=5.32 min;
Column Name: Chiralpak IA (250.times.4.6 mm) 5 .mu.m, Mobile Phase:
Hexane/EA/EtOH/DEA: 70/15/15/0.1, Flow Rate: 1.0 ml/min) and
N-((2R,3S)-2-(3-chlorophenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-ox-
opyrrolidin-3-yl)-2,2-difluoropropanamide (0.06 g, RT=7.21 min;
Column Name: Chiralpak IA (250.times.4.6 mm) 5 .mu.m, Mobile Phase:
Hexane/EA/EtOH/DEA: 70/15/15/0.1, Flow Rate: 1.0 ml/min).
[0588] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.48 (d, 1H), 8.32 (s,
1H), 7.89 (s, 1H), 7.77-7.71 (m, 3H), 7.64 (d, 1H), 7.46 (s, 1H),
7.39 (t, 2H), 7.34-7.28 (m, 3H), 5.35 (s, 1H), 4.30 (bs, 1H),
3.15-3.09 (m, 1H), 2.67-2.63 (m, 1H), 1.78 (t, 3H).
EXAMPLE 13:
N-TRANS-(1-(1-(4-FLUORPHENYL)-1H-INDAZOL-5-YL)-5-OXO-2-(4-FLUOROPHENYL)PY-
RROLIDIN-3-YL)-1-METHYLCYCLOPROPANE-1-CARBOXAMIDE
##STR00066##
[0590]
N-trans-(1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-(4-fluoroph-
enyl)pyrrolidin-3-yl)amine (intermediate D2, 50.0 mg, 0.124 mmol,
1.0 eq) was dissolved in dichloromethan (1.4 mL) under a nitrogen
atmosphere, then triethylamine (0.035 mL, 0.247 mmol, 2.0 eq) was
added. The mixture was stirred for ten minutes, before
1-methylcyclopropanecarbonyl chloride (0.03 mL, 0.247 mmol, 2.0 eq)
was added. The reaction mixture was stirred at ambient temperature
for 20 minutes, before sat. NaHCO.sub.3 solution was added. The
mixture was diluted with DCM, and was then filtered through a
hydrophobic frit. The solvent was removed under reduced pressure
and the remains were then purified by column chromatography and
later HPLC to give example 13 (42.0 mg, 70%).
[0591] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.30 (d, 1H), 8.13 (d,
1H), 7.85 (d, 1H), 7.76-7.72 (m, 2H), 7.70 (d, 1H), 7.61 (dd, 1H),
7.44-7.35 (m, 4H), 7.16-7.08 (m, 2H), 5.26 (d, 1H), 4.27-4.19 (m,
1H), 3.02 (dd, 1H), 2.62 (dd, 1H), 1.31 (s, 3H), 1.06-0.94 (m, 2H),
0.56 (d, 2H)
EXAMPLE 20 AND EXAMPLE 21:
2,2-DIFLUORO-N-((2S,3R)-2-(4-FLUORO-3-METHOXYPHENYL)-1-(1-(4-FLUOROPHENYL-
)-1H-INDAZOL-5-YL)-5-OXOPYRROLIDIN-3-YL)PROPANAMIDE AND
2,2-DIFLUORO-N-((2R,3S)-2-(4-FLUORO-3-METHOXYPHENYL)-1-(1-(4-FLUOROPHENYL-
)-1H-INDAZOL-5-YL)-5-OXOPYRROLIDIN-3-YL)PROPANAMIDE
##STR00067##
[0593] Step 1:
[0594] To a stirred solution of intermediate A7 (3.12 g, 13.92
mmol, 1.0 eq) in DMF (30 mL) were added HATU (7.90 g, 20.89 mmol,
1.5 eq), DIPEA (12.0 mL, 69.64 mmol, 5.0 eq) and
2,2-difluoro-propionic acid (2.00 g, 18.10 mmol, 1.3 eq) and the
reaction mixture was stirred for 16 h at ambient temperature. After
completion, the reaction mixture was diluted with EtOAc and was
washed with ice cold water, sat. NaHCO.sub.3 and sat. NH.sub.4Cl
solution. The organic layer was concentrated to get the crude
product which was purified by column chromatography (100-200 mesh
silica gel; 2% MeOH-DCM; Re-value-0.5) to afford
2,2-difluoro-N-(trans-2-(4-fluoro-3-methoxyphenyl)-5-oxopyrrolidin-3-yl)p-
ropanamide (3.50 g, 80%).
[0595] Step 2:
[0596] A stirred solution of
2,2-difluoro-N-(trans-2-(4-fluoro-3-methoxyphenyl)-5-oxopyrrolidin-3-yl)p-
ropanamide (0.30 g, 0.95 mmol, 1.0 eq),
1-(4-fluorophenyl)-5-iodo-1H-indazole (0.38 g, 1.13 mmol, 1.2 eq)
and K.sub.3PO.sub.4 (0.40 g, 1.89 mmol, 2.0 eq) in 1,4-dioxane (20
mL) was degassed with argon for 15 min. Then,
trans-N,N'-dimethylcyclohexane-1,2-diamine (0.05 g, 0.38 mmol, 0.4
eq) and CuI (0.04 g, 0.19 mmol, 0.2 eq) were added and the reaction
mixture was stirred for 16 h at 90.degree. C. After completion, the
reaction mixture was filtered through a celite bed and was washed
2-3 times with EtOAc. The combined organic layers were concentrated
to get the crude product which was purified by column
chromatography (100-200 mesh silica gel; 50% EtOAc-Hexane;
R.sub.f-value-0.5) to afford the racemic product. Further
enantiomer separation was done by preparative chiral HPLC to afford
2,2-difluoro-N-((2S,3R)-2-(4-fluoro-3-methoxyphenyl)-1-(1-(4-fluor-
ophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin-3-yl)propanamide (0.12 g;
RT=3.08 min; Column Name: Chiralpak IA Mobile Phase: MeOH) and
2,2-difluoro-N-((2R,3S)-2-(4-fluoro-3-methoxyphenyl)-1-(1-(4-fluorophenyl-
)-1H-indazol-5-yl)-5-oxopyrrolidin-3-yl)propanamide (0.12 g,
RT=3.78 min; Column Name: Chiralpak IA Mobile Phase: MeOH) as an
off white solid.
[0597] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.45-9.43 (m, 1H), 8.31
(s, 1H), 7.87-7.86 (m, 1H), 7.77-7.71 (m, 3H), 7.63-7.60 (m, 1H),
7.42-7.37 (m, 2H), 7.20-7.17 (m, 1H), 7.13-7.08 (m, 1H), 6.87-6.84
(m, 1H), 5.29 (s, 1H), 4.35-4.28 (m, 1H), 3.78 (s, 3H), 3.13-3.07
(m, 1H), 2.67-2.61 (m, 1H), 1.83-1.78 (m, 3H).
EXAMPLE 24:
2,2-DIFLUORO-N-((2S,3R)-2-(2-FLUOROPHENYL)-1-(1-(4-FLUOROPHENYL)-1H-INDAZ-
OL-5-YL)-5-OXOPYRROLIDIN-3-YL)PROPANAMIDE AND EXAMPLE 33:
2,2-DIFLUORO-N-((2R,3S)-2-(2-FLUOROPHENYL-1-(1-(1-4-FLUOROPHENYL-1H-INDAZ-
OL-5-YL)-5-OXOPYRROLIDIN-3-YL)PROPANAMIDE
##STR00068##
[0599] Starting from intermediate A6, example 24 and example 33
were synthesized in analogy to the synthetic procedure described
for example 20 and example 21.
[0600] Enantiomer separation was done by preparative chiral HPLC to
afford example 24 (0.07 g, RT=6.13 min; Column Name: Chiralpak IA
(250.times.4.6 mm) 5 .mu.m, Mobile Phase: Hexane/EA/EtOH/DEA:
70/15/15/0.1, Flow Rate: 1.0 ml/min) and example 33 (0.06 g,
RT=10.12 min; Column Name: Chiralpak IA (250.times.4.6 mm) 5 .mu.m,
Mobile Phase: Hexane/EA/EtOH/DEA: 70/15/15/0.1, Flow Rate: 1.0
ml/min).
[0601] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.46-9.44 (m, 1H), 8.32
(s, 1H), 7.81 (s, 1H), 7.76-7.71 (m, 3H), 7.54-7.51 (m, 1H),
7.41-7.37 (m, 3H), 7.27-7.24 (m, 1H), 7.16-7.08 (m, 2H), 5.54-5.53
(m, 1H), 4.48-4.46 (m, 1H), 3.17-3.10 (m, 1H), 2.70-2.64 (m, 1H),
1.81-1.71 (m, 3H).
EXAMPLE 25:
2,2-DIFLUORO-N-(TRANS-1-(1-(3-FLUOROPHENYL-1H-INDAZOL-5-YL-5-OXO-2-PHENYL-
PYRROLIDIN-3-YL)PROPANAMIDE
##STR00069##
[0603] Starting from intermediate B1, example 25 was synthesized in
analogy to the synthetic procedure described for example 6.
[0604] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.51-9.49 (m, 1H), 8.35
(s, 1H), 7.90 (s, 1H), 7.85-7.83 (m, 1H), 7.68-7.66 (m, 1H),
7.60-7.58 (m, 3H), 7.37-7.30 (m, 4H), 7.23-7.20 (m, 2H), 5.33-5.32
(m, 1H), 4.29-4.25 (m, 1H), 3.14-3.07 (m, 1H), 2.65-2.60 (m, 1H),
1.83-1.74 (m, 3H).
EXAMPLE 26:
N-TRANS-(1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXO2-(3,5-DIFLUOROPHENY-
L)PYRROLIDIN-3-YL)-2,2-DIFLUOROPROPANAMIDE
##STR00070##
[0606] Step 1:
[0607] 2,2-difluoropropanoic acid (383.9 mg, 3.488 mmol, 2.0 eq)
was weighed out into a flask, a stir bar was added and the flask
was sealed. The flask was purged with nitrogen, followed by the
addition of DCM (2.0 mL) and triethylamine (0.49 mL, 3.488 mmol,
2.0 eq). Propylphosphonic anhydride solution (.gtoreq.50 wt. % in
ethyl acetate, 2.1 mL, 3.488 mmol, 2.0 eq) was added next, and the
mixture was stirred for 10 minutes. Then,
N-trans-(5-oxo-2-(3,5-difluorophenyl)pyrrolidin-3-yl)amine
(intermediate 15, 370.1 mg, 1.744 mmol, 1.0 eq) was added in DCM (7
mL). The reaction mixture was stirred at ambient temperature for 16
hours. The reaction mixture was then diluted with water and EtOAc.
The layers were separated, and the aqueous layer was extracted two
more times with EtOAc. The combined organic layers were then washed
with brine and dried over MgSO.sub.4. The solvent was removed under
reduced pressure and the remains were then purified via column
chromatography to give
trans-2,2-difluoro-N-(5-oxo-2-(3,5-difluorophenyl)pyrrolidin-3-yl)propana-
mide (466.8 mg, 88%) as a white solid.
[0608] Step 2:
[0609]
Trans-2,2-difluoro-N-(5-oxo-2-(3,5-difluorophenyl)pyrrolidin-3-yl)p-
ropanamide (47.0 mg, 0.154 mmol, 1.0 eq), potassium phosphate
tribasic (65.6 mg, 0.309 mmol, 2.0 eq), copper iodide (5.9 mg,
0.031 mmol, 0.2 eq) and 1-(4-fluorophenyl)-5-iodo-indazole (62.7
mg, 0.185 mmol, 1.2 eq) are weighed out into a vial, the vial was
sealed, a stir bar was added and the vial was purged with nitrogen.
1,4-dioxane (1.0 mL) was then added, followed by the addition of
trans-cyclohexane-1,2-diamine (7.4 .mu.L, 0.62 mmol, 0.4 eq). The
reaction mixture was then heated to 110.degree. C. for 16 hours.
After that, the mixture was cooled to ambient temperature and was
diluted with water and DCM. The mixture was filtered through a
hydrophobic frit and the solvent was removed under reduced
pressure. The remains were purified by column chromatography and
later HPLC to give example 26 (14.4 mg, 18%).
[0610] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.45 (d, 1H), 8.33 (d,
1H), 7.92-7.88 (m, 1H), 7.79-7.72 (m, 3H), 7.64 (dd, 1H), 7.41 (t,
2H), 7.16-7.08 (m, 3H), 5.37 (d, 1H), 4.42-4.28 (m, 1H), 3.14 (dd,
1H), 2.67 (dd, 1H), 1.80 (t, 3H).
EXAMPLE 27:
2,2-DIFLUORO-N-(TRANS-5-OXO-2-PHENYL-1-(1-PHENYL-1H-INDAZOL-5-YL)PYRROLID-
IN-3-YL)PROPANAMIDE
##STR00071##
[0612] Starting from intermediate B1, example 27 was synthesized in
analogy to the synthetic procedure described for example 6.
[0613] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.51-9.49 (m, 1H), 8.31
(s, 1H), 7.88 (s, 1H), 7.78-7.70 (m, 3H), 7.65-7.63 (m, 1H),
7.58-7.54 (m, 2H), 7.40-7.23 (m, 6H), 5.32 (s, 1H), 4.29-4.25 (m,
1H), 3.14-3.07 (m, 1H), 2.66-2.59 (m, 1H), 1.83-1.74 (m, 3H).
EXAMPLE 28:
N-((2R,3S)-2-(2-FLUOROPHENYL-1-(1-(4-FLUOROPHENYL-1H-INDAZOL-5-YL)-5-OXOP-
YRROLIDIN-3-YL)CYCLOPROPANECARBOXAMIDE
##STR00072##
[0615] Step 1: To a stirred solution of cyclopropanecarboxylic acid
(0.53 g, 6.18 mmol, 1.2 eq) in DMF (8.0 mL) was added HATU (4.00 g,
10.30 mmol, 2.0 eq), DIPEA (4.5 mL, 25.75 mmol, 5.0 eq) and
intermediate A6 (1.00 g, 5.15 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, Rf-0.3), the reaction mixture was diluted with EtOAc
(25 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 2% MeOH-DCM) to afford
N-(trans-2-(2-fluorophenyl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide
(0.56 g, 41%).
[0616] Step 2:
[0617] A stirred solution of
N-(trans-2-(2-fluorophenyl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide
(0.250 g, 0.953 mmol, 1 eq), 1-(4-fluorophenyl)-5-iodo-1H-indazole
(0.385 g, 1.140 mmol, 1.2 eq) and K.sub.3PO.sub.4 (0.404 g, 1.906
mmol, 2.0 eq) in 1,4-dioxane (10 mL) was degassed with argon for 30
min. Then, trans-N,N'-dimethylcyclohexane-1,2-diamine (0.054 g,
0.381 mmol, 0.4 eq) and CuI (0.036 g, 0.191 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% methanol in DCM, Rf-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)-2-(2-fluorophenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-ox-
opyrrolidin-3-yl)cyclopropanecarboxamide (0.063 g, 14%; RT=7.76
min; Column Name: Chiralpak IA (250.times.4.6 mm) 5 .mu.m, Mobile
Phase: Hexane/EA/EtOH/DEA: 70/15/15/0.1, Flow Rate: 1.0 ml/min) and
N-((2R,3S)-2-(2-fluorophenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-ox-
opyrrolidin-3-yl)cyclopropanecarboxamide (0.036 g, 8%; RT=10.73
min; Column Name: Chiralpak IA (250.times.4.6 mm) 5 .mu.m, Mobile
Phase: Hexane/EA/EtOH/DEA: 70/15/15/0.1, Flow Rate: 1.0
ml/min).
[0618] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.87-8.85 (m, 1H), 8.32
(s, 1H), 7.84 (s, 1H), 7.76-7.71 (m, 3H), 7.57-7.55 (m, 1H),
7.42-7.37 (m, 3H), 7.27-7.26 (m, 1H), 7.16-7.09 (m, 2H), 5.44 (s,
1H), 4.37-4.32 (m, 1H), 3.13-3.07 (m, 1H), 2.54 (s, 1H), 1.59-1.57
(m, 1H), 0.70-0.68 (m, 4H).
EXAMPLE 29:
N-(TRANS-1-(1-(4-CYANOPHENYL)-1H-INDAZOL-5-YL)-5-OXO-2-PHENYLPYRROLIDIN-3-
-YL)-2,2-DIFLUOROPROPANAMIDE
##STR00073##
[0620] A stirred solution of intermediate B1 (0.600 g, 1.563 mmol,
1.0 eq), 4-bromobenzonitrile (0.339 g, 1.875 mmol, 1.2 eq) and
K.sub.3PO.sub.4 (0.662 g, 3.125 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 (0.088 g, 0.625 mmol,
0.4 eq) and CuI (0.060 g, 0.3125 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% methanol in DCM, Rf-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)
followed by further purification using preparative HPLC to afford
pure
N-(trans-1-(1-(4-cyanophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrroli-
din-3-yl)-2,2-difluoropropanamide (0.22 g, 29%).
[0621] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.51-9.49 (m, 1H), 8.43
(s, 1H), 8.02-7.97 (m, 4H), 7.94-7.92 (m, 2H), 7.72-7.70 (m, 1H),
7.36-7.29 (m, 4H), 7.24-7.23 (m, 1H), 5.34 (s, 1H), 4.27 (bs, 1H),
3.15-3.08 (m, 1H), 2.65-2.60 (m, 1H), 1.83-1.73 (m, 3H).
EXAMPLE 30:
N-(TRANS-1-(1-(3-CYANOPHENYL)-1H-INDAZOL-5-YL)-5-OXO-2-PHENYLPYRROLIDIN-3-
-YL)-2,2-DIFLUOROPROPANAMIDE
##STR00074##
[0623] Starting from intermediate B1, example 30 was synthesized in
analogy to the synthetic procedure described for example 29.
[0624] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.51-9.49 (m, 1H), 8.39
(s, 1H), 8.20 (s, 1H), 8.11-8.09 (m, 1H), 7.92-7.89 (m, 2H),
7.84-7.82 (m, 1H), 7.77-7.75 (m, 1H), 7.68-7.66 (m, 1H), 7.37-7.30
(m, 4H), 7.25-7.23 (m, 1H), 5.33 (s, 1H), 4.27 (bs, 1H), 3.14-3.08
(m, 1H), 2.65-2.60 (m, 1H), 1.83-1.73 (m, 3H).
EXAMPLE 34:
N-((2R,3S)-2-(4-FLUORO-3-METHOXYPHENYL)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL--
5-YL)-5-OXOPYRROLIDIN-3-YL)CYCLOPROPANECARBOXAMIDE
##STR00075##
[0626] Step 1:
[0627] To a stirred solution of intermediate A7 (0.70 g, 3.12 mmol,
1.0 eq) in DMF (30 mL) was added HATU (1.78 g, 4.68 mmol, 1.5 eq),
DIPEA (2.7 mL, 15.62 mmol, 5.0 eq) and cyclopropanecarboxylic acid
(0.34 g, 4.06 mmol, 1.3 eq) and the reaction mixture was stirred
for 16 h at ambient temperature. After completion, the reaction
mixture was diluted with EtOAc and was washed with ice cold water,
sat. NaHCO.sub.3 and sat. NH.sub.4Cl solution. The combined organic
layers were 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
N-(trans-2-(4-fluoro-3-methoxyphenyl)-5-oxopyrrolidin-3-yl)cycl-
opropanecarboxamide (0.70 g, 77%).
[0628] Step 2:
[0629] A stirred solution of
N-(trans-2-(4-fluoro-3-methoxyphenyl)-5-oxopyrrolidin-3-yl)cyclopropaneca-
rboxamide (0.25 g, 0.86 mmol, 1.0 eq),
1-(4-fluorophenyl)-5-iodo-1H-indazole (0.35 g, 1.02 mmol, 1.2 eq)
and K.sub.3PO.sub.4 (0.36 g, 1.71 mmol, 2.0 eq) in 1,4-dioxane (20
mL) was degassed with argon for 15 min. Then,
trans-N,N'-dimethylcyclohexane-1,2-diamine (0.05 g, 0.34 mmol, 0.4
eq) and CuI (0.03 g, 0.17 mmol, 0.2 eq) were added and the reaction
mixture was stirred for 16 h at 90.degree. C. 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 crude product which was purified by
column chromatography (100-200 mesh silica gel; 5% MeOH-DCM;
R.sub.f-value-0.5) to afford the racemic product. Further
enantiomer separation was done by preparative chiral HPLC chiral to
afford
N-((2S,3R)-2-(4-fluoro-3-methoxyphenyl)-1-(1-(4-fluorophenyl)-1H-indazol--
5-yl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide (0.07 g,
RT=10.55 min; Column Name: Chiralpak ID (250.times.4.6 mm) 5 .mu.m,
Mobile Phase: Hexane/EtOH/DEA: 80/20/0.1, Flow Rate: 1.0 ml/min)
and
N-((2R,3S)-2-(4-fluoro-3-methoxyphenyl)-1-(1-(4-fluorophenyl)-1H-indazol--
5-yl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide (0.06 g,
RT=13.05 min; Column Name: Chiralpak ID (250.times.4.6 mm) 5 .mu.m,
Mobile Phase: Hexane/EtOH/DEA: 80/20/0.1, Flow Rate: 1.0
ml/min).
[0630] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.87 (d, 1H), 8.31 (s,
1H), 7.90-7.89 (m, 1H), 7.77-7.72 (m, 3H), 7.69-7.66 (m, 1H),
7.42-7.38 (t, 2H), 7.19-7.16 (m, 1H), 7.14-7.09 (m, 1H), 6.86-6.83
(m, 1H), 5.23 (s, 1H), 4.18-4.17 (m, 1H), 3.79 (s, 3H), 3.11-3.05
(m, 1H), 2.44-2.43 (m, 1H), 1.61-1.58 (m, 1H), 0.74-0.69 (m,
4H).
EXAMPLE 38:
2,2-DIFLUORO-N-((2S,3R)-1-(1-(4-FLUOROPHENYL-1H-INDAZOL-5-YL)-5-OXO-2-(O--
TOLYL)PYRROLIDIN-3-YL)PROPANAMIDE AND EXAMPLE 72:
2,2-DIFLUORO-N-((2R,3S)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXO-2-(O-
-TOLYL)PYRROLIDIN-3-YL)PROPANAMIDE
##STR00076##
[0632] Starting from intermediate A10, example 38 and example 72
were synthesized in analogy to the synthetic procedure described
for example 20 and example 21.
[0633] Enantiomer separation was done by preparative chiral HPLC to
afford example 38 (0.07 g, RT=4.01 min; Column Name: Chiralpak IA
(250.times.4.6 mm) 5 .mu.m, Mobile Phase:
Hexane/EA/EtOH/DEA:50/25/25/0.1, Flow Rate: 1.0 ml/min) and example
72 (0.06 g; RT=4.99 min; Column Name: Chiralpak IA (250.times.4.6
mm) 5 .mu.m, Mobile Phase: Hexane/EA/EtOH/DEA: 50/25/25/0.1, Flow
Rate: 1.0 ml/min).
[0634] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.63-9.61 (m, 1H), 8.32
(s, 1H), 7.87 (s, 1H), 7.76-7.71 (m, 3H), 7.64-7.62 (m, 1H),
7.41-7.37 (m, 2H), 7.16-7.13 (m, 4H), 5.54 (s, 1H), 4.27 (s, 1H),
3.17-3.10 (m, 1H), 2.38 (s, 3H), 1.83-1.73 (m, 3H).
EXAMPLE 39:
N-((2S,3R)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXO-2-PHENYLPYRROLIDI-
N-3-YL)CYCLOPROPANECARBOXAMIDE AND EXAMPLE 65:
N-((2R,3S)-1-(1-(4-FLUOROPHENYL-1H-INDAZOL-5-YL-5-OXO-2-PHENYLPYRROLIDIN--
3-YL)CYCLOPROPANECARBOXAMIDE
##STR00077##
[0636] Step 1:
[0637] 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, Rf-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%).
[0638] Step 2:
[0639] 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, Rf-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
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).
[0640] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.90 (s, 1H), 8.30 (s,
1H), 7.91 (s, 1H), 7.73-7.71 (d, 4H), 7.41-7.23 (m, 7H), 5.26 (s,
1H), 4.16-4.12 (m, 1H), 3.09-3.03 (m, 1H), 2.42-2.32 (d, 1H),
1.62-1.58 (m, 1H), 0.71-0.69 (m, 4H).
EXAMPLE 42:
2,2-DIFLUORO-N-((2S,3R)-2-(2-FLUORO-5-METHOXYPHENYL)-1-(1-(4-FLUOROPHENYL-
)-1H-INDAZOL-5-YL)-5-OXOPYRROLIDIN-3-YL)PROPANAMIDE AND EXAMPLE 69:
2,2-DIFLUORO-N-((2R,3S)-2-(2-FLUORO-5-METHOXYPHENYL-1-(1-(4-FLUOROPHENYL--
1H-INDAZOL-5-YL)-5-OXOPYRROLIDIN-3-YL)PROPANAMIDE
##STR00078##
[0642] Starting from intermediate A11, example 42 and example 69
were synthesized in analogy to the synthetic procedure described
for example 20 and example 21.
[0643] Enantiomer separation was done by preparative chiral HPLC to
afford example 42 (0.07 g, RT=7.96 min; Column Name: Chiralpak ID
(250.times.4.6 mm) 5 .mu.m, Mobile Phase: EtOH, Flow Rate: 0.5
ml/min) and example 69 (0.06 g; RT=10.31 min; Column Name:
Chiralpak ID (250.times.4.6 mm) 5 .mu.m, Mobile Phase: EtOH, Flow
Rate: 0.5 ml/min).
[0644] .sup.1H NMR (DMSO-d.sub.6): .delta. 9.42-9.40 (m, 1H), 8.34
(s, 1H), 7.81 (s, 1H), 7.77-7.72 (m, 3H), 7.54-7.51 (m, 1H), 7.42
(t, 2H), 7.08 (t, 1H), 6.92-6.90 (m, 1H), 6.80-6.77 (m, 1H),
5.51-5.50 (m, 1H), 4.49-4.48 (m, 1H), 3.64 (s, 3H), 3.16-3.09 (m,
1H), 2.69-2.64 (m, 1H), 1.81-1.71 (m, 3H).
EXAMPLE 43:
N-((2S,3R)-2-(2-FLUORO-5-METHOXYPHENYL)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL--
5-YL)-5-OXOPYRROLIDIN-3-YL)CYCLOPROPANECARBOXAMIDE AND EXAMPLE 62:
N-((2R,3S)-2-(2-FLUORO-5-METHOXYPHENYL)-1-(1-(4-FLUORPHENYL)-1H-INDAZOL-5-
-YL)-5-OXOPYRROLIDIN-3-YL)CYCLOPROPANECARBOXAMIDE
##STR00079##
[0646] Starting from intermediate A11, example 43 and example 62
were synthesized in analogy to the synthetic procedure described
for example 39 and example 65.
[0647] Enantiomer separation was done by preparative chiral HPLC to
afford example 43 (0.07 g, RT=5.05 min; Column Name: Chiralpak ID
(250.times.4.6 mm) 5 .mu.m, Mobile Phase: Hexane/EA/EtOH/DEA:
50/25/25/0.1, Flow Rate: 1.0 ml/min) and example 62 (0.06 g;
RT=7.12 min; Column Name: Chiralpak ID (250.times.4.6 mm) 5 .mu.m,
Mobile Phase: Hexane/EA/EtOH/DEA: 50/25/25/0.1, Flow Rate: 1.0
ml/min).
[0648] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.84-8.82 (m, 1H), 8.33
(s, 1H), 7.84 (s, 1H), 7.77-7.72 (m, 3H), 7.58-7.55 (m, 1H), 7.42
(t, 2H), 7.08 (t, 1H), 6.87-6.85 (m, 1H), 6.80-6.77 (m, 1H), 5.42
(s, 1H), 4.37-4.35 (m, 1H), 3.64 (s, 3H), 3.13-3.07 (m, 1H),
2.54-2.52 (m, 1H), 1.58-1.55 (m, 1H), 0.70-0.68 (m, 4H).
EXAMPLE 49:
N-((2R,3S)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-2-(2-METHOXYPYRIDIN-4-Y-
L)-5-OXOPYRROLIDIN-3-YL)CYCLOPROPANECARBOXAMIDE
##STR00080##
[0650] Step 1:
[0651] To a stirred solution of cyclopropanecarboxylic acid (0.50
g, 5.79 mmol, 1.2 eq) in DMF (10 mL) was added HATU (3.60 g, 9.65
mmol, 2.0 eq), DIPEA (4.2 mL, 24.13 mmol, 5.0 eq) and intermediate
A9 (1.00 g, 4.82 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, Rf-0.3), the reaction mixture was diluted with EtOAc (25 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 2% MeOH-DCM) to afford
N-(trans-2-(2-methoxypyridin-4-yl)-5-oxopyrrolidin-3-yl)cyclopropanecarbo-
xamide (0.88 g, 66%).
[0652] Step 2:
[0653] A stirred solution of
N-(trans-2-(2-methoxypyridin-4-yl)-5-oxopyrrolidin-3-yl)-cyclopropanecarb-
oxamide (0.444 g, 1.612 mmol, 1.0 eq),
1-(4-fluorophenyl)-5-iodo-1H-indazole (0.654 g, 1.935 mmol, 1.2 eq)
and K.sub.3PO.sub.4 (0.683 g, 3.224 mmol, 2.0 eq) in 1,4-dioxane
(10 mL) was degassed with argon for 30 min. Then
trans-N,N'-dimethylcyclohexane-1,2-diamine (0.092 g, 0.645 mmol,
0.4 eq) and CuI (0.062 g, 0.322 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, Rf-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 6% 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)-2-(2-methoxypyridin-4-y-
l)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide (0.042 g; RT=8.74
min; Column Name: Chiralpak IA (250.times.4.6 mm) 5 .mu.m, Mobile
Phase: Hexane/EA/EtOH/DEA: 70/15/15/0.1, Flow Rate: 1.0 ml/min) and
N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(2-methoxypyridin-4-y-
l)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide (0.060 g; RT=7.54
min; Column Name: Chiralpak IA (250.times.4.6 mm) 5 .mu.m, Mobile
Phase: Hexane/EA/EtOH/DEA: 70/15/15/0.1, Flow Rate: 1.0
ml/min).
[0654] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.92-8.91 (m, 1H), 8.32
(s, 1H), 8.10 (d, 1H), 7.92 (s, 1H), 7.77-7.71 (m, 4H), 7.42 (t,
2H), 7.00 (d, 1H), 6.73 (s, 1H), 5.25-5.24 (m, 1H), 4.18-4.14 (m,
1H), 3.77 (s, 3H), 3.11-3.04 (m, 1H), 2.45-2.44 (m, 1H), 1.59 (bs,
1H), 0.76-0.70 (m, 4H).
EXAMPLE 53:
N-((2R,3S)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXO-2-(O-TOLYL)PYRROL-
IDIN-3-YL)CYCLOPROPANECARBOXAMIDE
##STR00081##
[0656] Starting from intermediate A10, example 53 was synthesized
in analogy to the synthetic procedure described for example 28.
[0657] Enantiomer separation was done by preparative chiral HPLC to
afford
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-(o-tolyl)pyrrol-
idin-3-yl)cyclopropanecarboxamide (0.134 g, RT=4.48 min; Column
Name: Chiralpak IA (250.times.4.6 mm) 5 .mu.m, Mobile Phase:
Hexane/EA/EtOH/DEA: 50/25/25/0.1, Flow Rate: 1.0 ml/min) and
example 63 (0.077 g, RT=5.32 min; Column Name: Chiralpak IA
(250.times.4.6 mm) 5 .mu.m, Mobile Phase: Hexane/EA/EtOH/DEA:
50/25/25/0.1, Flow Rate: 1.0 ml/min).
[0658] .sup.1H NMR (DMSO-d.sub.6): .delta. 9.01 (d, 1H), 8.32 (s,
1H), 7.92 (s, 1H), 7.76-7.72 (m, 3H), 7.69-7.67 (m, 1H), 7.42-7.37
(m, 2H), 7.20-7.17 (m, 1H), 7.13-7.08 (m, 3H), 5.41 (s, 1H),
4.19-4.15 (m, 1H), 3.10-3.04 (m, 1H), 2.42-2.39 (m, 4H), 1.62-1.59
(m, 1H), 0.71-0.69 (m, 4H).
EXAMPLE 73:
1-FLUORO-N-((2R,3S)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXO-2-PHENYL-
PYRROLIDIN-3-YL)CYCLOPROPANE-1-CARBOXAMIDE
##STR00082##
[0660] Starting from intermediate A2, example 73 was synthesized in
analogy to the synthetic procedure described for example 28.
[0661] Enantiomer separation was done by preparative chiral HPLC to
afford
1-fluoro-N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenyl-
pyrrolidin-3-yl)cyclopropane-1-carboxamide (0.07 g; RT=7.17 min;
Column Name: Chiralpak IA (250.times.4.6 mm) 5 .mu.m, Mobile Phase:
Hexane/EA/EtOH/DEA: 70/15/15/0.1, Flow Rate: 1.0 ml/min) and
example 73 (0.10 g, RT=10.00 min; Column Name: Chiralpak IA
(250.times.4.6 mm) 5 .mu.m, Mobile Phase: Hexane/EA/EtOH/DEA:
70/15/15/0.1, Flow Rate: 1.0 ml/min).
[0662] .sup.1H NMR (DMSO-d.sub.6): .delta. 9.20-9.18 (m, 1H), 8.30
(s, 1H), 7.87 (s, 1H), 7.76-7.63 (m, 4H), 7.41-7.28 (m, 6H),
7.23-7.21 (m, 1H), 5.36-5.35 (m, 1H), 4.35-4.31 (m, 1H), 3.10-3.03
(m, 1H), 2.67-2.62 (m, 1H), 1.34-1.30 (m, 2H), 1.21 (s, 2H).
EXAMPLE 74:
N-((2R,3S)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXO-2-PHENYLPYRROLIDI-
N-3-YL)-1-METHYLCYCLOPROPANE-1-CARBOXAMIDE
##STR00083##
[0664] Starting from intermediate A2, example 74 was synthesized in
analogy to the synthetic procedure described for example 28.
[0665] Enantiomer separation was done by preparative chiral HPLC to
afford
N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidi-
n-3-yl)-1-methylcyclopropane-1-carboxamide (0.050 g; RT=4.75 min;
Column Name: Chiralpak ID (250.times.4.6 mm) 5 .mu.m, Mobile Phase:
Hexane/EA/EtOH/DEA: 50/25/25/0.1, Flow Rate: 1.0 ml/min) and
example 74 (0.063 g, RT=6.78 min; Column Name: Chiralpak ID
(250.times.4.6 mm) 5 .mu.m, Mobile Phase: Hexane/EA/EtOH/DEA:
50/25/25/0.1, Flow Rate: 1.0 ml/min).
[0666] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.30 (s, 1H), 8.18 (s,
1H), 7.87 (s, 1H), 7.73-7.66 (m, 4H), 7.39-7.21 (m, 7H), 5.25 (s,
1H), 4.20 (s, 1H), 3.19-3.01 (m, 1H), 2.61 (s, 1H), 1.30 (s, 3H),
1.00 (s, 2H), 0.55 (s, 2H).
EXAMPLE 75:
N-(TRANS-1-(1-(4,4-DIFLUOROCYCLOHEXYL)-1H-INDAZOL-5-YL)-5-OXO-2-PHENYLPYR-
ROLIDIN-3-YL-2,2-DIFLUOROPROPANAMIDE
##STR00084##
[0668] A stirred solution of
2,2-difluoro-N-(trans-5-oxo-2-phenylpyrrolidin-3-yl)propanamide
(for synthesis see example 2, step 1) (0.20 g, 0.75 mmol, 1.0 eq),
intermediate C1 (0.32 g, 0.90 mmol, 1.2 eq) and K.sub.3PO.sub.4
(0.32 g, 1.49 mmol, 2.0 eq) in 1,4-dioxane (20 mL) was degassed
with argon for 30 min. Then,
trans-N,N'-dimethylcyclohexane-1,2-diamine (0.04 g, 0.30 mmol, 0.4
eq) and CuI (0.03 g, 0.15 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-0.5), 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 desired
N-(trans-1-(1-(4,4-difluorocyclohexyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyr-
rolidin-3-yl)-2,2-difluoropropanamide (0.06 g, 15%).
[0669] .sup.1H NMR (DMSO-d.sub.6): .delta. 9.47-9.46 (m, 1H), 8.01
(s, 1H), 7.72 (s, 1H), 7.62-7.60 (m, 1H), 7.53-7.51 (m, 1H),
7.34-7.21 (m, 5H), 5.27 (s, 1H), 4.79 (s, 1H), 4.26 (s, 1H),
3.11-3.05 (m, 1H), 2.63-2.58 (m, 1H), 2.162.07 (m, 7H), 1.96 (s,
2H), 1.83-1.73 (m, 3H).
EXAMPLE 76:
N-(TRANS-1-(1-(CYCLOHEXYL)-1H-INDAZOL-5-YL)-5-OXO-2-PHENYLPYRROLIDIN-3-YL-
)-2,2-DIFLUOROPROPANAMIDE
##STR00085##
[0671] Starting from intermediate C2, example 76 was synthesized in
analogy to the synthetic procedure described for example 75.
[0672] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.47-9.46 (m, 1H), 7.96
(s, 1H), 7.69 (s, 1H), 7.62-7.60 (m, 1H), 7.48-7.45 (m, 1H),
7.34-7.28 (m, 4H), 7.23-7.21 (m, 1H), 5.25 (s, 1H), 4.51-4.47 (m,
1H), 4.27-4.23 (m, 1H), 3.10-3.04 (m, 1H), 2.63-2.57 (m, 1H),
1.83-1.73 (m, 8H), 1.69-1.66 (m, 1H), 1.46-1.43 (m, 2H), 1.24-1.21
(m, 1H).
EXAMPLE 77:
2,2-DIFLUORO-N-(TRANS-2-(2-FLUORO-5-METHOXYPHENYL)-1-(1-METHYL-1H-INDAZOL-
-5-YL)-5-OXOPYRROLIDIN-3-YL)PROPANAMIDE
##STR00086##
[0674] Step 1:
[0675] To a stirred solution of 2,2-difluoropropanoic acid (0.35 g,
3.214 mmol, 1.2 eq) in DMF (8 mL) was added HATU (2.03 g, 5.357
mmol, 2.0 eq), DIPEA (2.4 mL, 13.392 mmol, 5.0 eq) and intermediate
A11 (0.60 g, 2.678 mmol, 1.0 eq) 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% MeOH in DCM, Rf-0.3),
the reaction mixture was diluted with EtOAc (25 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 2% MeOH-DCM) to afford
2,2-difluoro-N-(trans-2-(2-fluoro-5-methoxyphenyl)-5-oxopyrrolidin-3-yl)p-
ropanamide (0.60 g, 71%).
[0676] Step 2:
[0677] A stirred solution of
2,2-difluoro-N-(trans-2-(2-fluoro-5-methoxyphenyl)-5-oxopyrrolidin-3-yl)p-
ropanamide (0.150 g, 0.474 mmol, 1.0 eq),
5-iodo-1-methyl-1H-indazole (0.146 g, 0.569 mmol, 1.2 eq) and
K.sub.3PO.sub.4 (0.200 g, 0.949 mmol, 2.0 eq) in 1,4-dioxane (10
mL) was degassed with argon for 30 min. Then,
trans-N,N'-dimethylcyclohexane-1,2-diamine (0.027 g, 0.189 mmol,
0.4 eq) and CuI (0.018 g, 0.095 mmol, 0.2 eq) were added and the
reaction mixture was stirred for 16 h at 90.degree. C. 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 crude product which was
purified by column chromatography (230-400 mesh silica gel; 3%
MeOH-DCM; R.sub.f-value-0.4) to afford
2,2-difluoro-N-(trans-2-(2-fluoro-5-methoxyphenyl)-1-(1-methyl-1H-indazol-
-5-yl)-5-oxopyrrolidin-3-yl)propanamide (0.059 g, 28%).
[0678] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.39-9.38 (m, 1H), 7.98
(s, 1H), 7.65 (s, 1H), 7.56-7.54 (m, 1H), 7.40-7.37 (m, 1H),
7.05-7.01 (m, 1H), 6.88-6.87 (m, 1H), 6.76-6.74 (m, 1H), 5.47 (s,
1H), 4.50-4.46 (m, 1H), 3.97 (s, 3H), 3.63 (s, 3H), 3.12-3.06 (m,
1H), 2.68-2.62 (m, 1H), 1.80-1.70 (m, 3H).
EXAMPLE 78:
N-(TRANS-1-(1-(2,2-DIFLUOROETHYL)-1H-INDAZOL-5-YL)-2-(2-FLUORO-5-METHOXYP-
HENYL-5-OXOPYRROLIDIN-3-YL-2,2-DIFLUOROPROPANAMIDE
##STR00087##
[0680] Starting from 1-(2,2-difluoroethyl)-5-iodo-1H-indazole and
2,2-difluoro-N-(trans-2-(2-fluoro-5-methoxyphenyl)-5-oxopyrrolidin-3-yl)p-
ropenamide (see example 77, step 1), example 78 was synthesized in
analogy to the synthetic procedure described for example 75.
[0681] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.41-9.39 (m, 1H), 8.11
(s, 1H), 7.69-7.63 (m, 2H), 7.45-7.43 (m, 1H), 7.07-7.02 (m, 1H),
6.90 (s, 1H), 6.77 (s, 1H), 6.38 (s, 1H), 5.47 (s, 1H), 4.90 (t,
2H), 4.48 (s, 1H), 3.63 (s, 3H), 3.11-3.07 (m, 1H), 2.68-2.62 (m,
1H), 1.80-1.70 (m, 3H).
EXAMPLE 79:
2,2-DIFLUORO-N-(TRANS-1-(1-(2-FLUOROBENZYL)-1H-INDAZOL-5-YL)-5-OXO-2-PHEN-
YLPYRROLIDIN-3-YL)PROPANAMIDE
##STR00088##
[0683] Starting from intermediate C3, example 79 was synthesized in
analogy to the synthetic procedure described for example 75.
[0684] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.47-9.45 (m, 1H), 8.03
(s, 1H), 7.73 (s, 1H), 7.63-7.61 (m, 1H), 7.50-7.47 (m, 1H),
7.32-7.21 (m, 7H), 7.12-7.08 (m, 2H), 5.56 (s, 2H), 5.25 (s, 1H),
4.26-4.22 (s, 1H), 3.10-3.03 (m, 1H), 2.66-2.57 (m, 1H), 1.82-1.72
(m, 3H).
EXAMPLE 80:
2,2-DIFLUORO-N-(TRANS-1-(1-(3-FLUOROBENZYL)-1H-INDAZOL-5-YL)-5-OXO-2-PHEN-
YLPYRROLIDIN-3-YL)PROPANAMIDE
##STR00089##
[0686] Starting from intermediate C4, example 80 was synthesized in
analogy to the synthetic procedure described for example 75.
[0687] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.47-9.45 (m, 1H), 8.05
(s, 1H), 7.75 (s, 1H), 7.63-7.61 (m, 1H), 7.51-7.49 (m, 1H),
7.32-7.21 (m, 6H), 7.08-6.97 (m, 3H), 5.60 (s, 2H), 5.26 (s, 1H),
4.27-4.23 (m, 1H), 3.10-3.03 (m, 1H), 2.61-2.57 (m, 1H), 1.82-1.72
(m, 3H).
EXAMPLE 81:
2,2-DIFLUORO-N-(TRANS-1-(1-(4-FLUOROBENZYL)-1H-INDAZOL-5-YL-5-OXO-2-PHENY-
LPYRROLIDIN-3-YL)PROPANAMIDE
##STR00090##
[0689] Starting from intermediate C5, example 81 was synthesized in
analogy to the synthetic procedure described for example 75.
[0690] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.47-9.45 (m, 1H), 8.05
(s, 1H), 7.75 (s, 1H), 7.64-7.61 (m, 1H), 7.51-7.48 (m, 1H),
7.32-7.27 (m, 4H), 7.23-7.21 (m, 1H), 7.06-6.97 (m, 3H), 5.60 (s,
2H), 5.26 (s, 1H), 4.26-4.22 (s, 1H), 3.05-3.03 (m, 1H), 2.62-2.57
(m, 1H), 1.82-1.72 (m, 3H).
EXAMPLE 82:
N-(TRANS-1-(1-(CYCLOPROPYLMETHYL)-1H-INDAZOL-5-YL)-5-OXO-2-PHENYLPYRROLID-
IN-3-YL)-2,2-DIFLUOROPROPANAMIDE
##STR00091##
[0692] Starting from intermediate C6, example 82 was synthesized in
analogy to the synthetic procedure described for example 75.
[0693] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.47-9.46 (m, 1H), 7.96
(s, 1H), 7.71 (s, 1H), 7.61-7.59 (m, 1H), 7.48-7.46 (m, 1H),
7.34-7.28 (m, 4H), 7.23-7.19 (m, 1H), 5.27-5.26 (m, 1H), 4.25-4.20
(m, 3H), 3.10-3.04 (m, 1H), 2.63-2.57 (m, 1H), 1.83-1.73 (m, 3H),
1.21-1.19 (m, 1H), 0.46-0.42 (m, 2H), 0.34-0.33 (m, 2H).
EXAMPLE 84:
N-(TRANS-1-(1-((4,4-DIFLUOROCYCLOHEXYL)METHYL)-1H-INDAZOL-5-YL)-5-OXO-2-P-
HENYLPYRROLIDIN-3-YL)-2,2-DIFLUOROPROPANAMIDE
##STR00092##
[0695] Starting from intermediate C7, example 84 was synthesized in
analogy to the synthetic procedure described for example 75.
[0696] .sup.1H NMR (DMSO-d.sub.6): .delta. 9.48-9.46 (m, 1H), 7.99
(s, 1H), 7.70 (s, 1H), 7.63-7.61 (m, 1H), 7.50-7.48 (m, 1H),
7.33-7.22 (m, 5H), 5.26 (s, 1H), 4.26-4.24 (m, 3H), 3.10-3.04 (m,
1H), 2.66-2.57 (m, 1H), 1.95-1.93 (m, 3H), 1.83-1.66 (m, 5H), 1.51
(s, 2H), 1.26-1.23 (m, 2H).
EXAMPLE 85:
2,2-DIFLUORO-N-((TRANS)-1-(1-(2-FLUOROBENZYL)-1H-INDAZOL-5-YL)-2-(4-FLUOR-
OPHENYL-5-OXOPYRROLIDIN-3-YL)PROPANAMIDE
##STR00093##
[0698] Step 1:
[0699] 5-Bromo-1H-indazole (500.0 mg, 2.538 mmol, 1.0 eq) was
dissolved in DMF (5 mL) and the mixture was cooled to 0.degree. C.
Then sodium hydride (60% dispersion in mineral oil, 121.8 mg, 3.045
mmol, 1.2 eq) was added, and the mixture was stirred for 10
minutes, followed by the addition of
1-(bromomethyl)-2-fluoro-benzene (0.36 mL, 3.045 mmol, 1.2 eq). The
mixture was warmed to ambient temperature overnight. The reaction
mixture was quenched by the addition of water. The mixture was then
extracted three times with EtOAc. The combined organic layers were
washed with water, then with brine and were then dried over
MgSO.sub.4. The solvent was removed and the remains were purified
via column chromatography. The desired compound was obtained in 60%
yield (467.0 mg).
[0700] Step 2:
[0701] 5-bromo-1-(2-fluorobenzyl)-1H-indazole (64.0 mg, 0.210 mmol,
1.2 eq), copper iodide (6.7 mg, 0.035 mmol, 0.2 eq), sodium iodide
(52.4 mg, 0.349 mmol, 2.0 eq),
2,2-difluoro-N-[(trans)-2-(4-fluorophenyl)-5-oxo-pyrrolidin-3-yl]propanam-
ide (50.0 mg, 0.175 mmol, 1.0 eq) and K.sub.3PO.sub.4 (74.2 mg,
0.349 mmol, 2.0 eq) are weighed out into a vial, a stir bar was
added, the vial was sealed and was purged with nitrogen.
1,4-Dioxane (1.0 mL) was added, followed by
trans-N,N'-dimethylcyclohexane-1,2-diamine (9.9 mg, 0.070 mmol, 0.4
eq). The mixture was heated to 110.degree. C. for 16 hours. The
mixture was cooled to ambient temperature and was then diluted with
DCM and water. The mixture was filtered through a hydrophobic frit
and was then purified via column chromatography to afford
2,2-difluoro-N-((trans)-1-(1-(2-fluorobenzyl)-1H-indazol-5-yl)-2-(4-fluor-
ophenyl)-5-oxopyrrolidin-3-yl)propanamide (86.8 mg, 97%).
[0702] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.43 (d, 1H), 8.04 (d,
1H), 7.74 (d, 1H), 7.62 (d, 1H), 7.49 (dd, 1H), 7.42-7.37 (m, 2H),
7.36-7.29 (m, 1H), 7.21-7.15 (m, 1H), 7.15-7.06 (m, 4H), 5.63 (s,
2H), 5.28 (d, 1H), 4.34-4.22 (m, 1H), 3.07 (dd, 1H), 2.64 (dd, 1H),
1.78 (t, 3H).
EXAMPLE 86:
2,2-DIFLUORO-N-((TRANS)-1-(1-(4-FLUOROBENZYL)-1H-INDAZOL-5-YL)-2-(4-FLUOR-
OPHENYL)-5-OXOPYRROLIDIN-3-YL)PROPANAMIDE
##STR00094##
[0704] Example 86 was synthesized in analogy to the synthetic
procedure described for example 85, substituting
1-(bromomethyl)-2-fluoro-benzene for
1-(bromomethyl)-4-fluorobenzene in step 1 (yield 56.4%) and
5-bromo-1-(2-fluorobenzyl)-1H-indazole for
5-bromo-1-(4-fluorobenzyl)-1H-indazole in step 2. Example 86 was
obtained in 41% yield (36.6 mg).
[0705] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.42 (d, 1H), 8.04 (d,
1H), 7.72 (d, 1H), 7.63 (d, 1H), 7.46 (dd, 1H), 7.42-7.36 (m, 2H),
7.28-7.24 (m, 2H), 7.14-7.09 (m, 4H), 5.57 (s, 2H), 5.27 (d, 1H),
4.34-4.22 (m, 1H), 3.07 (dd, 1H), 2.63 (dd, 1H), 1.78 (t, 3H)
EXAMPLE 87:
2,2-DIFLUORO-N-((TRANS)-1-(1-(3-FLUOROBENZYL)-1H-INDAZOL-5-YL)-2-(4-FLUOR-
OPHENYL)-5-OXOPYRROLIDIN-3-YL)PROPANAMIDE
##STR00095##
[0707] Example 87 was synthesized in analogy to the synthetic
procedure described for example 85, substituting
1-(bromomethyl)-2-fluoro-benzene for
1-(bromomethyl)-3-fluorobenzene in step 1 (yield 67%) and
5-bromo-1-(2-fluorobenzyl)-1H-indazole for
5-bromo-1-(3-fluorobenzyl)-1H-indazole in step 2 and requiring
additional purification of the final compound via HPLC. Example 87
was obtained in 43% yield (38.0 mg).
[0708] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.42 (d, 1H), 8.06 (d,
1H), 7.74 (d, 1H), 7.63 (d, 1H), 7.47 (dd, 1H), 7.40-7.37 (m, 2H),
7.35-7.30 (m, 1H), 7.14-7.10 (m, 2H), 7.09-7.05 (m, 1H), 7.03-6.99
(m, 2H), 5.61 (s, 2H), 5.27 (d, 1H), 4.33-4.23 (m, 1H), 3.07 (dd,
1H), 2.63 (dd, 1H), 1.78 (t, 3H)
EXAMPLE 89:
N-(TRANS-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXO-2-ETHYLPYRROLIDIN-3-
-YL)-2,2-DIFLUOROPROPANAMIDE
##STR00096##
[0710] Step 1:
[0711] Sodium iodide (304.5 mg, 2.032 mmol, 6.0 eq.) was weighed
out into a microwave vial, a stir bar was added, the vial was
sealed and sparged with nitrogen. Then
trans-{1-[1-(4-Fluoro-phenyl)-1H-indazol-5-yl]-5-oxo-2-ethyl-pyrrolidin-3-
-yl}-carbamic acid benzyl ester (160.0 mg, 0.339 mmol, 1.0 eq.) in
acetonitrile (8.0 mL) was added, followed by the addition of TMSCl
(0.17 mL, 1.354 mmol, 4.0 eq.), and the resulting mixture was
stirred at ambient temperature for 16 hours. Then ethanol (9.6 mL)
was added and the resulting mixture was purified using a cationic
exchange resin to obtain 170 mg of crude
N-trans-(1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-ethylpyrrolidin-3-
-yl)amine.
[0712] Step 2:
[0713] 2,2-Difluoropropanoic acid (39.0 mg, 0.355 mmol, 1.5 eq.)
was weighed out into a vial, a stir bar was added, the vial was
sealed and purged with nitrogen. Then DCM (2.3 mL) was added,
followed by the addition of T3P (.gtoreq.50 wt. % in ethyl acetate,
0.28 mL, 2.0 eq.) and triethylamine (0.13 mL, 0.946 mmol, 4.0 eq.).
The resulting reaction mixture was stirred for 10 minutes at
ambient temperature. Then
N-trans-(1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-ethylpyrrolidin-3-
-yl)amine (80 mg of the 170 mg obtained in step 1) in DCM (2.3 mL)
was added, and the reaction mixture was stirred at ambient
temperature for 10 minutes. Then, sat. NaHCO.sub.3 solution and
more DCM was added, and the mixture was filtered through a
hydrophobic frit. The organic layers was then evaporated under
reduced pressure and the obtained crude material was purified via
silica gel chromatography to obtain 45.0 mg of
N-(trans-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-ethylpyrrolidin-3-
-yl)-2,2-difluoropropanamide.
[0714] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.33 (d, 1H), 8.39 (s,
1H), 7.92 (s, 1H), 7.86-7.77 (m, 3H), 7.59 (dd, 1H), 7.44 (t, 2H),
4.37-4.28 (m, 1H), 4.15 (dd, 1H), 3.01 (dd, 1H), 2.52-2.44 (m, 1H),
1.80 (t, 3H), 1.66-1.54 (m, 1H), 1.55-1.42 (m, 1H), 0.83 (t,
3H)
EXAMPLE 100:
N-TRANS-(1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXO-2-(5-CHLOROTHIOPHEN-
-2-YL)PYRROLIDIN-3-YL)CYCLOPROPANESULFONAMIDE
##STR00097##
[0716] Step 1:
[0717] A solution of benzyl
(trans-2-(5-chlorothiophen-2-yl)-5-oxopyrrolidin-3-yl)carbamate
(1.7 g, 4.845 mmol, 1.0 eq) in TFA (15 ml) was refluxed for 16
hours. After completion of the reaction (monitored by TLC, 5% of
Methanol in DCM, Rf=0.1), the TFA was evaporated under reduced
pressure and the obtained residue was dissolved in 10% DCM in MeOH
(150 ml) and was washed with saturated aqueous NaHCO.sub.3
(2.times.75 ml) and brine (50 ml). The organic layer was then dried
over Na.sub.2SO.sub.4 and was concentrated under reduced pressure
to obtain the crude product which was purified by column
chromatography (230-400 mesh silica gel; 3-5% MeOH in DCM) to
afford trans-4-amino-5-(5-chlorothiophen-2-yl)pyrrolidin-2-one
(0.75 g, 71%) as a gummy liquid.
[0718] Step 2:
[0719] To a stirred solution of
trans-4-amino-5-(5-chlorothiophen-2-yl)pyrrolidin-2-one (220 mg,
1.015 mmol, 1.0 eq) in DCM (15 ml), DIPEA (0.3 ml, 1.522 mmol, 1.5
eq) and cyclopropane sulfonyl chloride (214 mg, 1.522 mmol, 1.5 eq)
were added at 0.degree. C. and the reaction was then stirred at
ambient temperature for 16 hours. After completion of the reaction
(monitored by TLC, TLC system 5% methanol in DCM, Rf-0.3), the
solvent was removed under reduced pressure to obtain a residue,
which was diluted with DCM (100 mL), washed with sodium bicarbonate
solution (3.times.50 mL), dried over Na.sub.2SO.sub.4 and
concentrated to obtain a residue. This residue was purified by
column chromatography (230-400 mesh silica gel; 2 to 4% MeOH-DCM)
to afford
N-(trans-2-(5-chlorothiophen-2-yl)-5-oxopyrrolidin-3-yl)cyclopropanesulfo-
namide (300 mg, 92%).
[0720] Step 3:
[0721] A stirred solution of
N-(trans-2-(5-chlorothiophen-2-yl)-5-oxopyrrolidin-3-yl)cyclopropanesulfo-
namide (150 mg, 0.467 mmol, 1.0 eq),
1-(4-fluorophenyl)-5-iodo-1H-indazole (205 mg, 0.607 mmol, 1.3 eq)
and K.sub.3PO.sub.4 (198 mg, 0.935 mmol, 2.0 eq) in 1,4-dioxane (25
ml) was degassed with argon for 30 min. Then,
trans-N,N'-dimethylcyclohexane-1,2-diamine (26.6 mg, 0.187 mmol,
0.4 eq) and CuI (17.8 mg, 0.0935 mmol, 0.2 eq) were added and the
reaction was stirred for 16 hours at 90.degree. C. in a sealed
tube. After completion of the reaction (monitored by TLC, TLC
system 5% methanol in DCM, Rf-0.4), the reaction mixture was
concentrated under reduced pressure, diluted with ethyl acetate
(100 mL), washed with water (2.times.75 mL), dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to get the
crude product which was purified by HPLC to afford
N-trans-(1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-(5-chlorothiophen-
-2-yl)pyrrolidin-3-yl)cyclopropanesulfonamide_(47.5 mg, 17%).
[0722] .sup.1H NMR (400 MHz, DMSO-do): 5 8.36 (s, 1H), 8.02 (d,
1H), 7.86 (bs, 1H), 7.79-7.74 (m, 3H), 7.56-7.53 (m, 1H), 7.43-7.39
(m, 2H), 7.03 (d, 1H), 6.93 (d, 1H), 5.48 (d, 1H), 4.07-4.05 (m,
1H), 3.20-3.14 (m, 1H), 2.67-2.58 (m, 2H), 0.99-0.85 (m, 4H).
EXAMPLE 101:
N-(TRANS-2-PHENYL-1-(1-(4-FLUOROPHENYL)-1H-PYRAZOLO[3,4-B]PYRIDIN-5-YL)-5-
-OXOPYRROLIDIN-3-YL)-2 2-DIFLUOROPROPANAMIDE
##STR00098##
[0724] Step 1:
[0725] Example 101 was prepared in analogy to example 102 using
5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine instead of
5-bromo-1-(4-fluorophenyl)pyrazolo[3,4-c]pyridine. Yield: 46%.
[0726] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.48 (d, 1H), 8.75 (d,
1H), 8.43-8.35 (m, 2H), 8.24-8.15 (m, 2H), 7.42-7.36 (m, 4H), 7.32
(dd, 2H), 7.25 (d, 1H), 5.38 (d, 1H), 4.38 (tt, 1H), 3.15 (dd, 1H),
2.68 (dd, 1H), 1.79 (t, 3H).
EXAMPLE 102:
N-(TRANS-2-PHENYL-1-(1-(4-FLUOROPHENYL)-1H-PYRAZOLO[3,4-C]PYRIDIN-5-YL)-5-
-OXOPYRROLIDIN-3-YL)-2,2-DIFLUOROPROPANAMIDE
##STR00099##
[0728] Step 1:
[0729] 5-bromo-1-(4-fluorophenyl)pyrazolo[3,4-c]pyridine (65.3 mg,
0.224 mmol, 1.2 eq.), sodium iodide (55.9 mg, 0.373 mmol, 2.0 eq.),
copper iodide (7.1 mg, 0.037 mmol, 0.2 eq.),
trans-2,2-difluoro-N-(5-oxo-2-phenylpyrrolidin-3-yl)propanamide
(50.0 mg, 0.186 mmol, 1.0 eq.) and potassium phosphate (79.1 mg,
0.373 mmol, 2.0 eq.) were weighed out into a vial, a stir bar was
added, the vial was sealed and was purged with nitrogen.
1,4-Dioxane (1.0 mL) and trans-N,N'-dimethylcyclohexane-1,2-diamine
(0.012 mL, 0.075 mmol, 0.4 eq.) were then added, and the mixture
was heated to 110.degree. C. for 16 hours. The mixture was cooled
to ambient temperature and was diluted with DCM and water. The
mixture was then filtered through a hydrophobic frit and the
solvent was removed. The crude compound was then purified via MPLC
and HPLC to yield 13.3 mg (15%) of example 102.
[0730] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.57 (d, 1H), 8.97 (d,
1H), 8.72 (d, 1H), 8.56 (d, 1H), 7.89-7.79 (m, 2H), 7.42-7.36 (m,
2H), 7.33-7.29 (m, 4H), 7.22 (td, 1H), 5.78 (d, 1H), 4.24 (t, 1H),
3.16 (dd, 1H), 2.69 (dd, 1H), 1.80 (t, 3H).
EXAMPLE 103:
N-(TRANS-2-PHENYL-1-(1-(4-FLUOROPHENYL-1H-PYRAZOLO[4,3-B]PYRIDIN-5-YL-5-O-
XOPYRROLIDIN-3-YL)-2,2-DIFLUOROPROPANAMIDE
##STR00100##
[0732] Step 1:
[0733] Example 103 was prepared in analogy to example 102, using
5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine instead of
5-bromo-1-(4-fluorophenyl)pyrazolo[3,4-c]pyridine. Yield: 61%.
[0734] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.59 (d, 1H), 8.54 (d,
1H), 8.39-8.31 (m, 2H), 7.84-7.75 (m, 2H), 7.43 (dd, 2H), 7.36-7.29
(m, 4H), 7.27-7.20 (m, 1H), 5.78 (d, 1H), 4.26 (ddd, 1H), 3.19 (dd,
1H), 2.68 (dd, 1H), 1.80 (t, 3H).
[0735] The examples in Table 2 were synthesized in analogy to
Example 1 described above, using the appropriate carboxylic acid,
acid chloride or sulfonyl chloride.
TABLE-US-00002 Inter- Ex. mediate Yield # (INT) Structure (%)
.sup.1H NMR 3 INT D2 ##STR00101## 35 .sup.1H NMR (DMSO-d.sub.6)
.delta.: 9.48 (d, 1H), 8.30 (d, 1H), 7.88 (d, 1H), 7.76-7.72 (m,
2H), 7.71 (d, 1H), 7.64 (dd, 1H), 7.42-7.34 (m, 4H), 7.32 (t, 2H),
7.26-7.22 (m, 1H), 5.32 (d, 1H), 4.34-4.25 (m, 1H), 3.11 (dd, 1H),
2.64 (dd, 1H), 1.79 (t, 3H) 7 INT D3 ##STR00102## 28 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.47 (d, 1H), 8.31 (d, 1H), 7.91-7.86 (m,
1H), 7.77-7.73 (m, 2H), 7.73-7.71 (m, 1H), 7.67-7.64 (m, 1H), 7.40
(tt, 2H), 7.23 (tt, 1H), 6.91 (dt, 2H), 6.82-6.79 (m, 1H), 5.30 (d,
1H), 4.33-4.26 (m, 1H), 3.70 (d, 3H), 3.11 (dd, 1H), 2.64 (dd, 1H),
1.79 (t, 3H) 8 INT D2 ##STR00103## 39 .sup.1H NMR (DMSO-d.sub.6)
.delta.: 8.90 (d, 1H), 8.31 (s, 1H), 7.91 (s, 1H), 7.77-7.68 (m,
4H), 7.43-7.35 (m, 4H), 7.33 (t, 2H), 7.24 (td, 1H), 5.27 (d, 1H),
4.21-4.11 (m, 1H), 3.07 (ddd, 1H), 2.47 (dd, 1H), 1.65-1.57 (m,
1H), 0.80-0.67 (m, 4H) 11 INT D4 ##STR00104## 78 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.46 (d, 1H), 8.31 (s, 1H), 7.87 (d, 1H),
7.77-7.72 (m, 2H), 7.71 (d, 1H), 7.61 (dd, 1H), 7.45-7.36 (m, 4H),
7.14 (t, 2H), 5.33 (d, 1H), 4.35-4.27 (m, 1H), 3.11 (dd, 1H), 2.66
(dd, 1H), 1.79 (t, 3H) 14 INT D5 ##STR00105## 98 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.21-9.13 (m, 1H), 8.31 (d, 1H), 7.88 (dd,
1H), 7.76- 7.73 (m, 2H), 7.73-7.68 (m, 1H), 7.68- 7.56 (m, 1H),
7.42-7.37 (m, 2H), 7.34 (td, 1H), 7.28-7.13 (m, 2H), 7.13-6.99 (m,
1H), 5.38 (d, 1H), 4.43-4.32 (m, 1H), 3.09 (dd, 1H), 2.69 (dd, 1H),
1.37-1.30 (m, 2H), 1.30-1.13 (m, 2H) 15 INT D5 ##STR00106## 50
.sup.1H NMR (DMSO-d.sub.6) .delta.: 8.50 (d, 1H), 8.30 (d, 1H),
7.86 (d, 1H), 7.76-7.69 (m, 3H), 7.61 (dd, 1H), 7.41-7.37 (m, 2H),
7.36- 7.28 (m, 1H), 7.23-7.14 (m, 2H), 7.08- 6.99 (m, 1H), 5.27 (d,
1H), 4.38-4.19 (m, 1H), 3.06 (dd, 1H), 2.63-2.55 (m, 1H), 1.42-1.31
(m, 2H), 1.32-1.22 (m, 2H) 17 INT D3 ##STR00107## 57 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 8.48 (d, 1H), 8.31 (s, 1H), 7.88 (s, 1H),
7.78-7.73 (m, 2H), 7.72 (d, 1H), 7.64 (d, 1H), 7.40 (t, 2H), 7.23
(t, 1H), 6.92-6.87 (m, 2H), 6.79 (d, 1H), 5.23 (d, 1H), 4.30-4.21
(m, 1H), 3.70 (s, 3H), 3.05 (dd, 1H), 2.56 (dd, 1H), 1.49-1.36 (m,
2H), 1.34-1.19 (m, 2H) 19 INT D5 ##STR00108## 100 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 8.45 (d, 1H), 8.31 (d, 1H), 7.91 (d, 1H),
7.79-7.64 (m, 4H), 7.43-7.33 (m, 3H), 7.21 (dd, 2H), 7.10- 7.03 (m,
1H), 5.27 (d, 1H), 4.20-4.13 (m, 1H), 3.12-3.02 (m, 2H), 2.47 (dd,
1H), 2.22-2.11 (m, 2H), 2.07-2.02 (m, 2H), 1.95-1.87 (m, 1H),
1.83-1.75 (m, 1H) 23 INT D3 ##STR00109## 100 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.15 (d, 1H), 8.25 (s, 1H), 7.86 (d, 1H),
7.73-7.69 (m, 2H), 7.68-7.61 (m, 2H), 7.34 (t, 2H), 7.19 (t, 1H),
6.94-6.88 (m, 2H), 6.76 (dd, 1H), 5.33 (d, 1H), 4.41-4.33 (m, 1H),
3.06 (dd, 1H), 2.66 (dd, 1H), 1.33-1.26 (m, 2H), 1.23-1.17 (m, 2H)
31 INT D6 ##STR00110## 42 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.32
(d, 1H), 7.93- 7.86 (m, 1H), 7.80-7.69 (m, 3H), 7.66- 7.63 (m, 1H),
7.47-7.46 (m, 1H), 7.40 (t, 2H), 7.37-7.27 (m, 4H), 5.35 (d, 1H),
4.36-4.28 (m, 1H), 3.13 (dd, 1H), 2.67 (dd, 1H), 1.80 (t, 3H) 32
INT D6 ##STR00111## 69 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.45 (d,
1H), 8.31 (d, 1H), 7.91 (d, 1H), 7.78-7.70 (m, 3H), 7.67 (dd, 1H),
7.46 (d, 1H), 7.45-7.35 (m, 2H), 7.34 (d, 1H), 7.33-7.27 (m, 2H),
5.26 (d, 1H), 4.18-4.14 (m, 1H), 3.11- 3.02 (m, 2H), 2.48 (dd, 1H),
2.23-2.11 (m, 2H), 2.11-2.02 (m, 2H), 1.96-1.87 (m, 1H), 1.83-1.74
(m, 1H) 36 INT D7 ##STR00112## 74 .sup.1H NMR (DMSO-d.sub.6)
.delta.: 9.19 (d, 1H), 8.38 (d, 1H), 7.86 (d, 1H), 7.84-7.75 (m,
3H), 7.49 (dd, 1H), 7.44 (t, 2H), 4.82 (p, 1H), 3.63 (dd, 1H),
2.84-2.70 (m, 2H), 1.80 (t, 3H), 0.92-0.80 (m, 1H), 0.38-0.24 (m,
1H), 0.22-0.15 (m, 1H), 0.02--0.07 (m, 1H), -0.24 (dt, 1H) 45 INT
D4 ##STR00113## 84 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.94 (dd,
1H), 8.30 (dd, 1H), 7.88 (dd, 1H), 7.76-7.72 (m, 2H), 7.72-7.70 (m,
1H), 7.63 (ddd, 1H), 7.43-7.37 (m, 4H), 7.14 (td, 2H), 5.26 (dd,
1H), 4.98-4.70 (m, 1H), 4.22- 4.16 (m, 1H), 3.18-3.00 (m, 1H),
2.61- 2.41 (m, 1H), 1.98-1.70 (m, 1H), 1.62- 1.54 (m, 1H),
1.11-0.99 (m, 1H) ##STR00114## 46 INT D3 ##STR00115## 38 .sup.1H
NMR (DMSO-d.sub.6) .delta.: 9.08 (d, 1H), 8.31 (d, 1H), 7.94-7.89
(m, 1H), 7.79-7.67 (m, 4H), 7.44-7.36 (m, 2H), 7.24 (t, 1H),
6.94-6.88 (m, 2H), 6.83-6.76 (m, 1H), 5.24 (d, 1H), 4.92-4.73 (m,
1H), 4.21- 4.11 (m, 1H), 3.70 (s, 3H), 3.09 (dd, 1H), 2.48 (dd,
1H), 2.17-2.10 (m, 1H), 1.47- 1.37 (m, 1H), 1.22-1.15 (m, 1H) 48
INT D7 ##STR00116## 61 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.26 (d,
1H), 8.40 (d, 1H), 7.88 (dd, 1H), 7.88-7.78 (m, 3H), 7.50 (dd, 1H),
7.45 (t, 2H), 4.43- 4.14 (m, 1H), 3.46 (dd, 1H), 3.03 (dd, 1H),
2.47 (dd, 1H), 1.80 (t, 3H), 1.11-0.94 (m, 1H), 0.40-0.34 (m, 1H),
0.31-0.18 (m, 2H), -0.01--0.09 (m, 1H) 52 INT D5 ##STR00117## 80
.sup.1H NMR (DMSO-d.sub.6) .delta.: 8.82 (t, 1H), 8.31 (d, 1H),
7.93 (d, 1H), 7.80-7.65 (m, 4H), 7.43-7.31 (m, 3H), 7.25-7.17 (m,
2H), 7.11-7.03 (m, 1H), 5.39-5.17 (m, 1H), 4.28-4.01 (m, 1H), 3.10
(dd, 1H), 2.49- 2.43 (m, 1H), 1.38-1.31 (m, 1H), 1.26- 1.11 (m,
1H), 1.09-1.03 (m, 3H), 0.99- 0.90 (m, 1H), 0.60-0.52 (m, 1H) 54
INT D4 ##STR00118## 71 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.88 (d,
1H), 8.31 (s, 1H), 7.90 (d, 1H), 7.79-7.69 (m, 3H), 7.67 (dd, 1H),
7.44-7.36 (m, 4H), 7.14 (t, 2H), 5.27 (d, 1H), 4.20-4.13 (m, 1H),
3.08 (dd, 1H), 2.51-2.44 (m, 1H), 1.65- 1.57 (m, 1H), 0.79-0.68 (m,
4H) 55 INT D3 ##STR00119## 84 .sup.1H NMR (DMSO-d.sub.6) .delta.:
8.88 (d, 1H), 8.31 (s, 1H), 7.95-7.89 (m, 1H), 7.78-7.69 (m, 4H),
7.44-7.36 (m, 2H), 7.29-7.20 (m, 1H), 6.94-6.89 (m, 2H), 6.82-6.80
(m, 1H), 5.24 (d, 1H), 4.19-4.13 (m, 1H), 3.70 (d, 3H), 3.07 (dd,
1H), 2.46 (dd, 1H), 1.67-1.57 (m, 1H), 0.80-0.68 (m, 4H) 56 INT D4
##STR00120## 89 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.94 (dd, 1H),
8.31 (dd, 1H), 7.87 (dd, 1H), 7.76-7.70 (m, 3H), 7.63 (ddd, 1H),
7.46-7.30 (m, 4H), 7.14 (td, 2H), 5.26 (dd, 1H), 4.84 (dtd, 1H),
4.22-4.16 (m, 1H), 3.12-3.06 (m, 1H), 2.48 (t, 1H), 1.87-1.80 (m,
1H), 1.62-1.53 (m, 1H), 1.10-1.04 (m, 1H) ##STR00121## 61 INT D5
##STR00122## 72 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.90 (d, 1H),
8.30 (s, 1H), 7.91 (d, 1H), 7.78-7.65 (m, 4H), 7.43-7.29 (m, 3H),
7.25-7.17 (m, 2H), 7.09-7.02 (m, 1H), 5.29 (d, 1H), 4.22- 4.16 (m,
1H), 3.10 (dd, 1H), 2.53-2.46 (m, 1H), 1.66-1.56 (m, 1H), 0.80-0.66
(m, 4H) 63 INT D3 ##STR00123## 53 .sup.1H NMR (DMSO-d.sub.6)
.delta.: 8.94 (dd, 1H), 8.32 (dd, 1H), 7.91 (dd, 1H), 7.77-7.63 (m,
4H), 7.43-7.38 (m, 2H), 7.24 (t, 1H), 6.93-6.87 (m, 2H), 6.81 (ddd,
1H), 5.24 (dd, 1H), 4.93-4.74 (m, 1H), 4.25-4.10 (m, 1H), 3.70 (s,
3H), 3.11-3.05 (m, 1H), 2.47 (dt, 1H), 1.87-1.80 (m, 1H), 1.63-
1.54 (m, 1H), 1.11-1.03 (m, 1H) ##STR00124## 67 INT D6 ##STR00125##
59 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.90 (d, 1H), 8.32 (d, 1H),
7.92 (d, 1H), 7.79-7.71 (m, 3H), 7.72-7.67 (m, 1H), 7.45 (d, 1H),
7.44- 7.36 (m, 2H), 7.38-7.32 (m, 1H), 7.33- 7.28 (m, 2H), 5.28 (d,
1H), 4.21-4.14 (m, 1H), 3.10 (dd, 1H), 2.51-2.45 (m, 1H), 1.65-1.57
(m, 1H), 0.80-0.69 (m, 4H) 68 INT D5 ##STR00126## 93 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.48 (d, 1H), 8.30 (d, 1H), 7.88 (d, 1H),
7.78-7.66 (m, 3H), 7.62 (dd, 1H), 7.44-7.27 (m, 3H), 7.26- 7.16 (m,
2H), 7.05 (td, 1H), 5.35 (d, 1H), 4.38-4.29 (m, 1H), 3.12 (dd, 1H),
2.66 (ddd, 1H), 1.78 (t, 3H) 70 INT D4 ##STR00127## 82 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.15 (d, 1H), 8.31 (s, 1H), 7.86 (d, 1H),
7.77-7.73 (m, 2H), 7.71 (d, 1H), 7.62 (dd, 1H), 7.45-7.37 (m, 4H),
7.16-7.09 (m, 2H), 5.37 (d, 1H), 4.41-4.30 (m, 1H), 3.07 (dd, 1H),
2.69 (dd, 1H), 1.39-1.24 (m, 2H), 1.26-1.14 (m, 2H) 71 INT D4
##STR00128## 44 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.47 (d, 1H),
8.31 (d, 1H), 7.86 (d, 1H), 7.77-7.73 (m, 2H), 7.71 (d, 1H), 7.61
(dd, 1H), 7.43-7.36 (m, 4H), 7.13 (td, 2H), 5.25 (d, 1H), 4.30-
4.22 (m, 1H), 3.05 (dd, 1H), 2.58 (dd, 1H), 1.40 (d, 2H), 1.30-1.22
(m, 2H) 88 INT D8 ##STR00129## 46 .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta. 9.22 (d, 1H), 8.43 (d, 1H), 8.11-8.04 (m,
1H), 7.91-7.78 (m, 3H), 7.78-7.70 (m, 1H), 7.50-7.40 (m, 2H),
7.31-7.22 (m, 2H), 7.25-7.17 (m, 1H), 7.17-7.11 (m, 2H), 4.67-4.59
(m, 1H), 4.35-4.26 (m, 1H), 2.95-2.81 (m, 2H), 2.63-2.54 (m, 1H),
2.34-2.24 (m, 1H), 1.69 (t, J = 19.5 Hz, 3H). 90 INT D9
##STR00130## 46 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.25 (d, 1H),
8.38 (d, 1H), 7.90 (dd, 1H), 7.84-7.77 (m, 3H), 7.56 (dd, 1H),
7.46-7.40 (m, 2H), 4.90-4.76 (m, 1H), 4.58 (ddd, 1H), 2.82 (dd,
1H), 2.66 (dd, 1H), 1.80 (t, 3H), 1.53 (ddd, 1H), 1.09 (ddd, 1H),
0.48 (dtt, 1H), 0.36-0.18 (m, 2H), -0.09--0.20 (m, 2H). 91 INT D2-
ent1 ##STR00131## 86 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.56 (d,
1H), 8.30 (s, 1H), 7.89 (d, 1H), 7.76-7.69 (m, 3H), 7.64 (dd, 1H),
7.43-7.28 (m, 6H), 7.27- 7.20 (m, 1H), 5.26 (d, 1H), 4.16 (tt, 1H),
3.06 (dd, 1H), 2.46 (dd, 1H), 2.12-2.03 (m, 3H), 1.00 (tt, 1H),
0.45 (ddt, 2H), 0.15 (dt, 2H). 92 INT D2- ent2 ##STR00132## 67
.sup.1H NMR (DMSO-d.sub.6) .delta.: 8.89 (d, 1H), 8.29 (d, 1H),
7.86 (dd, 1H), 7.78 (d, 1H), 7.76- 7.72 (m, 2H), 7.69 (dt, 1H),
7.62 (dd, 1H), 7.43-7.35 (m, 4H), 7.30 (t, 2H), 7.25- 7.18 (m, 1H),
6.64 (d, 1H), 5.42 (d, 1H), 4.47 (ddt, 1H), 3.93 (s, 3H), 3.06 (dd,
1H), 2.73 (dd, 1H). 93 INT D2- ent2 ##STR00133## 24 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.21 (d, 1H), 8.29 (d, 1H), 7.84 (d, 1H),
7.76-7.71 (m, 2H), 7.69 (d, 1H), 7.60 (dd, 1H), 7.43-7.36 (m, 4H),
7.31-7.27 (m, 3H), 7.23-7.18 (m, 1H), 7.09 (s, 1H), 5.45 (d, 1H),
4.50 (tt, 1H), 3.07 (dd, 1H), 2.77 (dd, 1H). 94 INT D2- ent2
##STR00134## 27 .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 9.27
(d, 1H), 8.30 (s, 1H), 7.92 (d, 1H), 7.78-7.66 (m, 5H), 7.44-7.37
(m, 4H), 7.36-7.30 (m, 2H), 7.27-7.21 (m, 1H), 5.40 (d, 1H),
4.43-4.36 (m, 1H), 3.15 (dd, 1H), 2.65 (dd, 1H), 2.50 (s, 3H). 95
INT D2- ent2 ##STR00135## 54 .sup.1H NMR (DMSO-d.sub.6) .delta.:
9.07 (s, 1H), 9.03 (d, 1H), 8.30 (s, 1H), 7.91 (s, 1H), 7.78- 7.64
(m, 4H), 7.44-7.37 (m, 4H), 7.34 (t, 2H), 7.24 (t, 1H), 5.41 (d,
1H), 4.40 (dt, 1H), 3.13 (dd, 1H), 2.66 (dd, 1H), 2.62 (s, 3H). 96
INT D2- ent2 ##STR00136## 53 .sup.1H NMR (600 MHz, DMSO-d.sub.6)
.delta. 9.68 (d, 1H), 8.99 (d, 1H), 8.29 (d, 1H), 7.88 (d, 1H),
7.77-7.67 (m, 4H), 7.66-7.61 (m, 1H), 7.43-7.35 (m, 4H), 7.31 (t,
2H), 7.25- 7.19 (m, 1H), 5.50 (d, 1H), 4.54 (tt, 4.6 Hz, 1H),
3.17-3.10 (m, 1H), 2.82-2.75 (m, 1H). 97 INT D2- ent2 ##STR00137##
44 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.39 (d, 1H), 9.10 (dd, 1H),
8.74 (dd, 1H), 8.32-8.25 (m, 2H), 7.94 (t, 1H), 7.77-7.70 (m, 4H),
7.55 (ddd, 1H), 7.46-7.32 (m, 6H), 7.26 (td, 1H), 5.46 (d, 1H),
4.44 (ddd, 1H), 3.19 (dd, 1H), 2.69 (dd, 1H). 98 INT D2- ent2
##STR00138## 75 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.73 (d, 1H),
8.30 (d, 1H), 7.92 (d, 1H), 7.76-7.73 (m, 2H), 7.71 (d, 1H), 7.68
(dd, 1H), 7.42-7.37 (m, 4H), 7.34 (t, 2H), 7.27-7.22 (m, 1H), 5.29
(d, 1H), 4.75-4.60 (m, 4H), 4.19 (tt, 1H), 3.89-3.74 (m, 1H),
3.12-3.06 (m, 1H), 2.45 (dd, 1H).
[0736] The examples in Table 3 were synthesized in analogy to the
Example 9 described above, using the appropriate carboxylic acid,
acid chloride or sulfonyl chloride.
TABLE-US-00003 Inter- Ex. mediate Yield # (INT) Structure (%)
.sup.1H NMR 10 INT D3 ##STR00139## 42 .sup.1H NMR (DMSO-d.sub.6)
.delta.: 8.32 (s, 1H), 7.99 (d, 1H), 7.85 (s, 1H), 7.77-7.73 (m,
2H), 7.72 (d, 1H), 7.60 (dd, 1H), 7.40 (t, 2H), 7.24 (t, 1H),
6.95-6.90 (m, 2H), 6.84- 6.79 (m, 1H), 5.29 (d, 1H), 4.00-3.93 (m,
1H), 3.70 (s, 3H), 3.15 (dd, 1H), 2.60 (dd, 1H), 2.53-2.47 (m, 1H),
0.98-0.88 (m, 2H), 0.88-0.81 (m, 2H) 37 INT D6 ##STR00140## 55
.sup.1H NMR (DMSO-d.sub.6) .delta.: 8.32 (s, 1H), 8.01 (d, 1H),
7.87 (d, 1H), 7.79-7.70 (m, 3H), 7.61 (dd, 1H), 7.47-7.43 (m, 1H),
7.44- 7.28 (m, 5H), 5.34 (d, 1H), 4.02-3.97 (m, 1H), 3.13 (dd, 1H),
2.91 (d, 2H), 2.59 (dd, 1H), 0.98-0.89 (m, 1H), 0.57-0.48 (m, 2H),
0.31-0.23 (m, 2H) 51 INT D4 ##STR00141## 80 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 8.31 (s, 1H), 7.98 (d, 1H), 7.82 (s, 1H),
7.78-7.67 (m, 3H), 7.55 (dd, 1H), 7.46-7.36 (m, 4H), 7.14 (t, 2H),
5.30 (d, 1H), 4.01-3.93 (m, 1H), 3.15 (dd, 1H), 2.63 (dd, 1H),
2.51-2.45 (m, 1H), 0.98-0.88 (m, 2H), 0.88-0.79 (m, 2H) 99 INT D2-
ent2 ##STR00142## 35 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.35 (t,
1H), 8.30 (t, 1H), 8.26 (d, 1H), 7.79 (dd, 1H), 7.76- 7.66 (m, 3H),
7.53 (dt, 1H), 7.43-7.35 (m, 2H), 7.30-7.18 (m, 6H), 5.27 (d, 1H),
3.90-3.84 (m, 1H), 2.99 (dd, 1H), 2.45- 2.38 (m, 1H)
[0737] The examples in Table 4 were synthesized in analogy to the
Example 13 described above, using the appropriate carboxylic acid,
acid chloride or sulfonyl chloride.
TABLE-US-00004 Inter- Ex. mediate Yield # (INT) Structure (%)
.sup.1H NMR 16 INT D5 ##STR00143## 21 .sup.1H NMR (DMSO-d.sub.6)
.delta.: 8.31 (d, 1H), 7.85 (d, 1H), 7.78-7.66 (m, 3H), 7.58 (dd,
1H), 7.43-7.29 (m, 3H), 7.24-7.18 (m, 2H), 7.10-7.01 (m, 1H), 5.32
(d, 1H), 4.02-3.96 (m, 1H), 3.14 (dd, 1H), 2.87 (s, 3H), 2.58 (dd,
1H) 18 INT D5 ##STR00144## 100 .sup.1H NMR (DMSO-d.sub.6) .delta.:
8.31 (d, 1H), 8.19- 8.13 (m, 1H), 7.89 (t, 1H), 7.79-7.63 (m, 4H),
7.44-7.31 (m, 3H), 7.25-7.16 (m, 2H), 7.09-7.01 (m, 1H), 5.31-5.26
(m, 1H), 4.28-4.20 (m, 1H), 3.05 (ddd, 1H), 2.67-2.59 (m, 1H), 1.32
(d, 3H), 1.07-0.96 (m, 2H), 0.59-0.54 (m, 2H) 22 INT D3
##STR00145## 23 .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.31 (d, 1H),
8.13 (d, 1H), 7.88 (d, 1H), 7.77-7.74 (m, 2H), 7.72 (d, 1H), 7.66
(dd, 1H), 7.44-7.37 (m, 2H), 7.22 (t, 1H), 6.93-6.87 (m, 2H), 6.79
(ddd, 1H), 5.24 (d, 1H), 4.24-4.19 (m, 1H), 3.70 (s, 3H), 3.01 (dd,
1H), 2.59 (dd, 1H), 1.31 (s, 3H), 1.04-0.97 (m, 2H), 0.60-0.54 (m,
2H) 66 INT D5 ##STR00146## 39 .sup.1H NMR (DMSO-d.sub.6) .delta.:
8.69 (d, 1H), 8.30 (d, 1H), 7.91 (d, 1H), 7.79-7.68 (m, 3H), 7.66
(dd, 1H), 7.43-7.29 (m, 3H), 7.25- 7.16 (m, 2H), 7.09-7.02 (m, 1H),
5.29 (d, 1H), 4.20-4.13 (m, 1H), 3.09 (dd, 1H), 2.45 (dd, 1H), 1.90
(s, 3H)
[0738] GRE Agonist
[0739] 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.TERTA. 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.
[0740] The complete culture medium for the assay was: [0741] DMEM
F-12 (1:1) MIXTURE (LONZA cat. No: BE04-687F/U1) 500 mL [0742] 5 mL
of 100 mM Sodium Pyruvate (LONZA cat. No: BE12-115E) [0743] 25 mL
of 7.5% Sodium Bicarbonate (LONZA cat. No BE17-613E) [0744] 6.5 mL
of 1 M Hepes (LONZA cat. No: BE17-737E) [0745] 5 mL of 100.times.
Penicillin/Streptomycin (LONZA cat. No DE17-602E) [0746] 50 mL of
Fetal Bovine Serum (Euroclone cat. No ECS 0180L) [0747] 0.25 mL of
10 mg/mL Puromycin (InvivoGen cat.: ant-pr-1) [0748] 0.5 mL of 100
mg/mL Zeocin (InvivoGen cat.: ant-zn-1)
[0749] 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 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.TERTA for 2 minutes.
[0750] 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]
[0751] To calculate EC50, 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 EC.sub.50, D=slope]
[0752] GRE Antagonist
[0753] 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.TERTA. 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.
[0754] The complete culture medium for the assay was:
[0755] DMEM F-12 (1:1) MIXTURE (LONZA cat. No: BE04-687F/U1) 500
mL
[0756] 5 mL of 100 mM Sodium Pyruvate (LONZA cat. No:
BE12-115E)
[0757] 25 mL of 7.5% Sodium Bicarbonate (LONZA cat. No
BE17-613E)
[0758] 6.5 mL of 1 M Hepes (LONZA cat. No: BE17-737E)
[0759] 5 mL of 100.times. Penicillin/Streptomycin (LONZA cat. No
DE17-602E)
[0760] 50 mL of Fetal Bovine Serum (Euroclone cat. No ECS
0180L)
[0761] 0.25 mL of 10 mg/mL Puromycin (InvivoGen cat.: ant-pr-1)
[0762] 0.5 mL of 100 mg/mL Zeocin (InvivoGen cat.: ant-zn-1)
[0763] 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.TETRA for 2 minutes.
[0764] 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]
[0765] 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]
TABLE-US-00005 TABLE 5 IC50 or EC50 A < 100 nM, B = 100 nM-1
.mu.M, Cpd # C = 1 .mu.M-15 .mu.M 1 A 2 A 4 A 5 A 7 A 8 A 9 B 10 B
12 A 13 A 14 A 15 A 16 A 17 A 18 A 19 A 20 B 21 A 22 A 24 B 25 B 26
A 27 A 28 A 29 B 30 B 31 A 32 A 34 A 36 B 37 B 38 B 39 B 42 C 43 C
44 C 45 A 46 A 47 B 48 B 49 B 51 A 52 A 53 A 54 A 55 A 56 A 61 A 62
A 63 A 65 A 66 A 67 A 75 B 76 B 77 C 78 C 79 A 80 A 81 A 82 B 85 B
86 A 87 B 88 A 89 A 90 C 91 C 92 A 93 A 94 A 95 A 96 B 97 B 98 B 99
A 100 B 101 A 102 B 103 B
* * * * *